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Guanxiang Huang,1– 3,&ast; Wenyu Lin,1– 3,&ast; Hangjing Gao,1– 3 Yuan Ren,1– 3 Jun Shen,4 Shuxia Xu,5 Dabin Liu,6 Yuanjun Cai,6 Chengbin Lin,6 Xite Lin,1– 3 Tingting Jiang,1– 3 Binhua Dong,1– 3 Pengming Sun1– 3 1College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, Fujian, 350001, People’s Republic of China; 2Fujian Key Laboratory of Women and Children’s Critical Diseases Research, Fujian Maternity and Child Health Hospital (Fujian Women and Children’s Hospital), Fuzhou, Fujian, 350001, People’s Republic of China; 3Fujian Clinical Research Center for Gynecological Oncology, Fujian Maternity and Child Health Hospital (Fujian Obstetrics and Gynecology Hospital), Fuzhou, Fujian, 350001, People’s Republic of China; 4Fujian Provincial Cervical Disease Diagnosis and Treatment Health Center, Fujian Maternity and Child Health Hospital, Fuzhou, Fujian, 350001, People’s Republic of China; 5Department of Pathology, Fujian Maternity and Child Health Hospital, Fuzhou, Fujian, 350001, People’s Republic of China; 6Department of Gynecology, Fujian Maternity and Child Health Hospital, Fuzhou, Fujian, 350001, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Pengming Sun; Binhua Dong, Laboratory of Gynecologic Oncology, Department of Gynecology, Fujian Maternity and Child Health Hospital, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Medical University, Fuzhou, Fujian, 350001, People’s Republic of China, Tel +86-591-87558732 ; +86-13599071900, Fax +86-591-87551247, Email fmsun1975@fjmu.edu.cn, sunfemy@hotmail.com; dongbinhua86@fjmu.edu.cn, dbh18-jy@126.comBackground: There are currently few prognostic models for conization in patients with high-grade squamous intraepithelial lesion (HSIL) because it is a rapid procedure that typically collects less case information. The present study aimed to establish a rapid/accurate postoperative prognostic assessment model for these patients.Methods: This study included 631 nonpregnant participants with HSIL confirmed by histopathology from January 2015 to January 2018. The recurrent/residual cervical intraepithelial neoplasia (CIN) were divided into residual CIN, simple recurrent CIN and recurrent CIN accompanied with CIN progression. The recurrence/residual-free survival (RFS) time was defined as the time span from the time of surgery (baseline) until the first lesion of CIN was detected or the 1-/3-/5-year follow-up endpoint was reached.Results: After LASSO regression selection, the higher platelet-to-lymphocyte ratio (PLR) (OR = 1.006, p = 0.002), positive margin status (OR = 2.451, p = 0.021), HPV-16 (OR = 4.414, p < 0.001), − 18 (OR = 3.040, p = 0.009), − 56 (OR = 10.715, p=0.021), and non-HR-HPV (OR = 2.487, p = 0.028) infection showed significant difference in the Logistic model. And HPV-16 infection (OR = 6.159, p = 0.001) could promote recurrent CIN accompanied with CIN progression. In multivariate Cox regression models, the higher PLR (HR = 1.005/1.005/1.005, p = 0.020/0.002/0.003) and HPV-16 infection (HR = 2.758/2.836/2.674, p < 0.001) showed statistical difference during 1-/3-/5-year follow-up. While gland invasion (p = 0.081), margin status (p = 0.075) and HPV infection genotype (p = 0.150) did not showed statistical difference in multivariate Cox regression models based on LASSO regression. And gland invasion (p = 0.251/0.686) and HPV-58 infection (p = 0.148/0.813) also showed no statistical difference in optimized Logistic regression models.Conclusion: HPV-16, − 18, − 56 and non-HR-HPV infection status can be considered as indicators for recurrent CIN during the 5-year follow-up, especially for HPV-16 infection, which also lead to a CIN recurrence accompanied with disease progression. And the preoperative PLR level, gland invasion, positive margin may be predictors for recurrent/residual CIN during 1-, 3- and 5-year follow-up.Keywords: cervical intraepithelial neoplasia, higher platelet-to-lymphocyte ratio, human papillomavirus, conization, prognosis

Xinyu Yang,1,2 Qiaochu Li,1,2 Linbang Wang,3 Jiaxing Chen,1,2 Zhengxue Quan1,2 1Department of Orthopedics, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, People’s Republic of China; 2Orthopedic Laboratory of Chongqing Medical University, Chongqing, 400016, People’s Republic of China; 3Department of Orthopedics, Peking University Third Hospital, Beijing, 100191, People’s Republic of ChinaCorrespondence: Zhengxue Quan; Jiaxing Chen, Email quanzx18@126.com; cqykdxcjx@163.comPurpose: Ferroptosis is an underlying mechanism for various degenerative diseases, but its role in intervertebral disc degeneration remains elusive. This study aims to explore the key ferroptosis-related genes and its role in nucleus pulposus (NP) and annulus fibrosus (AF) degeneration.Methods: We analyzed the gene expression profiles of NP and AF from the Gene Expression Omnibus database. The ferroptosis-related differentially expressed genes (FRDEGs) in degenerated NP and AF were filtered, followed by GO and KEGG analysis. Feature FRDEGs were identified by the LASSO and SVM-RFE algorithms, and then Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA) were conducted. Immune infiltration analysis was conducted by CIBERSORT algorithm. We established drug networks via the Drug–Gene Interaction Database and competitive endogenous RNA (ceRNA) networks via miRanda, miRDB, and TargetScan database. The expression levels of the feature FRDEGs were assessed by the validation sets, single-cell RNA-seq, and experimental verification.Results: A total of 15 and 18 FRDEGs were obtained for NP and AF, respectively. GO and KEGG analysis revealed their implication in oxidative stress. Four (AKR1C1, AKR1C3, MUC1, ENPP2) and five (SCP2, ABCC1, KLF2, IDO1, CREB3) feature genes were identified for NP and AF, respectively. The GSEA and GSVA analysis showed that these feature genes were enriched in lots of biological functions, including immune response. CREB3 in degenerated AF was negatively correlated with Eosinophils via CIBERSORT algorithm. The drugs and ceRNAs targeting CREB3 and MUC1 were identified. Experimental verification and single-cell RNA-seq analysis revealed that MUC1 and CREB3 were downregulated in degenerated NP and AF, respectively.Conclusion: MUC1 and CREB3 were considered novel biomarkers for NP and AF ferroptosis, respectively. Drug and ceRNA networks were constructed for future drug development and investigation of new mechanisms of ferroptosis.Keywords: bioinformatics analysis, experimental verification, ferroptosis, nucleus pulposus, annulus fibrosus, single-cell RNA-seq

Zijun Hu,1,&ast; Lujian Zhu,2,&ast; Yanglin Zhu,3 Yejin Xu2 1School of Medicine, Shaoxing University, Shaoxing, Zhejiang, People’s Republic of China; 2Department of Infectious Disease, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, People’s Republic of China; 3Department of Hepatobiliary Pancreatic Gastrointestinal Surgery 2, Affiliated Jinhua Hospital of Wenzhou Medical University, Jinhua, Zhejiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yejin Xu, Department of Infectious Disease, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, People’s Republic of China, Email xuyejin-fox@163.comAbstract: Lung diseases are associated with high morbidity and mortality rates, thereby jeopardizing human health and imposing a great burden on society. Currently, lung diseases are mainly treated with medications, oxygen therapy and mechanical ventilation, but these approaches are unable to effectively reduce the mortality rate. Therefore, lung transplantation remains the ultimate treatment for various chronic lung diseases, but this treatment is also hindered by the limited availability of lung sources, immature technology and a low survival rate after transplantation. With constant changes in the environment, pathogens, type and amount of harmful substances and the prevalence of respiratory diseases, there is an urgent need to identify alternative treatment methods. Research on stem cell therapy has been very successful in recent years, and mesenchymal stem cells (MSCs), together with their secretory bodies, play a significant therapeutic role. Extracellular vesicles of MSCs (MSC-EVs) are also major components of the paracrine secretion of MSCs, including exosomes, microvesicles, and apoptotic bodies, among which exosomes are the most typical. MSC-EVs are believed to be present in various tissues of the human body where they can carry proteins, DNA, RNA and biologically active factors, just to name a few. They can also transmit various biological signals to participate in different biological activities, including the maintenance of homeostasis within the tissue. Several studies have further demonstrated that MSCs and their generated extracellular vesicles play an important role in the treatment of diseases. In this paper, the origin, properties and roles of MSCs and MSC-EVs are reviewed, the mechanisms of different lung diseases, the limitations of current therapeutic options and the roles of MSC-EVs in Chronic Obstructive Pulmonary Disease, asthma, infectious lung disease, lung cancer, pulmonary fibrosis, pulmonary arterial hypertension, and acute lung injury/ acute respiratory distress syndrome are also discussed (Figure 1). In addition, the current limitations and possible future research directions are also discussed in view of providing new ideas for the role of MSC-EVs in the treatment of lung diseases.Keywords: mesenchymal stem cells, exosomes, lung disease, immunomodulation, epithelial mesenchymal transition (EMT), MSC-EVs

Qing Gao,1,&ast; Shang Gao,2,3,&ast; Haiyang Li,1,&ast; Zuoguan Chen,2 Ran Zhang,2 Yongjun Li,2 Hongjia Zhang1 1Department of Cardiovascular Surgery, Beijing Anzhen Hospital, Capital Medical University, Beijing, People’s Republic of China; 2Department of Vascular Surgery, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China; 3Graduate School of Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yongjun Li; Hongjia Zhang, Email liyongjun4679@bjhmoh.cn; zhanghongjia722@ccmu.edu.cnIntroduction: Takayasu arteritis (TAK) is an autoimmune disease affecting the aorta and its branches. Despite anti-inflammatory treatments, some patients require surgical vascular reconstruction due to rapid disease progression. The mechanisms behind persistent inflammation are unclear due to a lack of arterial samples. This study explores ferroptosis in TAK using high-throughput and single-cell transcriptomics.Methods: Transcriptomic data were collected from 8 TAK patients (2 for single cell RNA-seq and 6 for bulk RNA-seq) and 8 renal transplant donors, with single-cell data from 3 public carotid artery samples for control. Bioinformatic analysis was performed to identify ferroptosis-related genes in inflamed arteries.Results: We identified 1526 differentially expressed genes and 46 ferroptosis-related genes, with 6 genes including PTGS2 and HIF1A as hub genes. Single-cell analysis of 27,828 cells revealed increased M1-like macrophages, with PTGS2 highly expressed in these cells. Enrichment analysis indicated NF-κB signal pathway involvement.Conclusion: PTGS2 is a core ferroptosis-related gene in TAK vascular inflammation, highly expressed in M1-like macrophages, potentially upregulated via the IL1B-NF-κB pathway.Keywords: Takayasu arteritis, single-cell RNA sequencing, bulk RNA sequencing, ferroptosis, PTGS2

Young Sang Lyu,1 Hongyup Ahn,2 Sangmo Hong,3 Cheol-Young Park4 1Division of Endocrinology and Metabolism, Department of Internal Medicine, Chosun University Hospital, Gwangju, Republic of Korea; 2Department of Statistics, Dongguk University, Seoul, Republic of Korea; 3Department of Internal Medicine, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri, Republic of Korea; 4Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Republic of KoreaCorrespondence: Cheol-Young Park, Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, 29 Saemunan-ro,Jongno-gu, Seoul, 03181, Republic of Korea, Email cydoctor@skku.eduPurpose: To investigate the safety and effectiveness of naltrexone-bupropion in Korean adults with obesity.Patients and methods: This was a prospective, observational multicenter study from April 29, 2016, to April 28, 2022. Individuals with obesity with a body mass index of ≥ 30 kg/m2 or ≥ 27 kg/m2 who had obesity-related comorbidities were included. The naltrexone-bupropion dose was gradually titrated weekly from 8/90 to 32/360 mg and maintained at the maximum tolerated dose. In total, 612 and 300 individuals were evaluated for safety and effectiveness, respectively.Results: In total, 41.34% individuals reported drug-related adverse reactions, such as nausea (19.12%), headache (7.68%), and dizziness (5.23%). Older age and comorbidities were significantly associated with adverse events. At 12 weeks after reaching the maintenance dose, naltrexone-bupropion 32/360 mg resulted in the greatest weight reduction (− 7.21%) compared with other doses, which persisted at week 24 (− 7.69%). The naltrexone-bupropion 16/180 mg resulted in significant weight reduction, achieving − 5.99% and − 9.18% reductions at weeks 12 and 24, similar to that with naltrexone-bupropion 32/360 mg. Young age and no comorbidities were significantly associated > 5% weight reduction.Conclusion: Naltrexone-bupropion demonstrated marked stability and weight loss effectiveness, particularly in young individuals with obesity without comorbidities. Therefore, individualized treatment is necessary when prescribing naltrexone-bupropion.Keywords: naltrexone-bupropion, obesity management, post-marketing survey, weight loss efficacy, adverse events

Jin Cheng,1,&ast; Honglei Ju,1,&ast; Guixiang Wang,2,&ast; Chiyi He,1 Wei Wang1 1Department of Gastroenterology, Yijishan Hospital of Wannan Medical College, Wuhu, People’s Republic of China; 2Department of Gastroenterology, The Second Affiliated Hospital of Wannan Medical College, Wuhu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wei Wang, Department of Gastroenterology, Yijishan Hospital of Wannan Medical College, No. 2, Zheshan West Road, Wuhu, Anhui Prov, 241000, People’s Republic of China, Email wwwy@wnmc.edu.cnBackground: The Systemic Inflammation Response Index (SIRI) has demonstrated predictive capabilities for clinical outcomes in various diseases. However, its prognostic utility in decompensated liver cirrhosis (DLC) remains underexplored. This study aimed to investigate the association between SIRI and the risk of short-term (3 and 6 months) all-cause mortality in DLC patients.Methods: A total of 926 eligible patients with DLC from diverse etiologies was included in this study. In the initial cohort, the predictive accuracy of SIRI was evaluated using receiver operating characteristic (ROC) curve analysis. Patients were categorized into high- and low-SIRI groups based on the Youden index. Multivariable logistic regression analysis was employed to evaluate the independent association between SIRI and all-cause mortality. Restricted cubic spline (RCS) analysis was utilized to visualize the relationship between the continuous variable SIRI and mortality risk. These findings were validated in a validation cohort.Results: The initial cohort had mortality rates of 8.8% and 11.6% at 3 and 6 months, respectively. The SIRI level was significantly higher in the deceased group compared to the survival group. At both time points, SIRI was an independent indicator of all-cause mortality. RCS analysis demonstrated the risk of the risk of increased with an increase in SIRI value. The Validation cohort validated the independent association between higher SIRI levels and lower short-term all-cause mortality.Conclusion: This study’s findings underscore the prognostic value of SIRI in DLC patients, indicating that higher SIRI levels are significantly associated with short-term adverse outcomes.Keywords: decompensated liver cirrhosis, systemic inflammation response index, prognosis, all-cause mortality

Ding Yang,1 Rulan Bai,1 Chengzhong Li,2 Yan Sun,2 Hongyu Jing,1 Zixu Wang,1 Yaoxing Chen,1 Yulan Dong1 1College of Veterinary Medicine, China Agricultural University, Beijing, People’s Republic of China; 2Department of Horticulture and Landscape Architecture, Jiangsu Agri-Animal Husbandry Vocational College, Taizhou, People’s Republic of ChinaCorrespondence: Yulan Dong, Email ylbcdong@cau.edu.cnBackground: The early childhood period is a critical development stage, and experiencing stress during this time may increase the risk of gastrointestinal disorders, including irritable bowel syndrome (IBS). Neonatal maternal separation (NMS) in rodent models has been shown to cause bowel dysfunctions similar to IBS, and 5-HT is considered to be a key regulator regulating intestinal function, but the precise underlying mechanisms remain unclear.Results: We established a maternal separation stress mouse model to simulate early-life stress, exploring the expression patterns of 5-HT under chronic stress and its mechanisms affecting gut function. We observed a significant increase in 5-HT expression due to NMS, leading to disruptions in intestinal structure and function. However, inhibiting 5-HT reversed these effects, suggesting its potential as a therapeutic target. Furthermore, our research revealed that excess 5-HT in mice with early life stress increased intestinal neural network density and promoted excitatory motor neuron expression. Mechanistically, 5-HT activated the Wnt signaling pathway through the 5-HT4 receptor, promoting neurogenesis within the intestinal nervous system.Conclusion: These findings shed light on the intricate changes induced by early life stress in the intestines, confirming the regulatory role of 5-HT in the enteric nervous system and providing potential insights for the development of novel therapies for gastrointestinal disorders.Keywords: 5-HT, IBS, early-life stress, neurogenesis

Linmei Xiao,1,&ast; Jingjing Ma,2,&ast; Ruidong Chen,2,3,&ast; Jie Chen,4 Qiang Wang,5 Nana Tang,2 Xiaojing Zhao,2 Hongjie Zhang,2 Chunhua Jiao2 1Department of Liver Disease, Wuxi No.5 People’s Hospital Affiliated to Jiangnan University, Wuxi, People’s Republic of China; 2Department of Gastroenterology, The First Affiliated Hospital with Nanjing Medical University, Nanjing, Jiangsu Province, People’s Republic of China; 3Department of Gastroenterology, The Second Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China; 4Northern Jiangsu People’s Hospital/Northern Jiangsu People’s Hospital of Jiangsu Province, Yangzhou, Jiangsu Province, People’s Republic of China; 5Jiangsu Shengze Hospital, Suzhou, Jiangsu Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Chunhua Jiao; Hongjie Zhang, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu Province, 210029, People’s Republic of China, Tel +86 13913928581, Email jch0409@163.com; hjzhang06@163.comPurpose: Cytomegalovirus (CMV) infection exacerbates intestinal inflammation in ulcerative colitis (UC) patients, yet the effect of CMV infection on UC relapse has not been fully elucidated. This study aimed to investigate the impact of CMV infection on UC relapse and identify associated risk factors.Patients and Methods: This multicenter retrospective cohort study included UC patients who visited research centers from January 2016 to December 2020. Univariate and multivariate Cox regression analyses were conducted to explore risk factors for UC relapse. Propensity score matching was used to balance the differences in the clinical characteristics between the groups.Results: A total of 298 UC patients participated in this study, including 19 with CMV colitis, 37 with CMV viremia, and 242 CMV-negative patients. The 2-year cumulative recurrence rate was higher in patients with CMV colitis than that in CMV-negative patients (84.21% vs 51.65%, p = 0.01). Univariate and multivariate Cox regression analyses confirmed that fecal calprotectin ≥ 250 μg/g, Montreal classification E3, CMV colitis, duration > 48 months, and serum albumin < 30 g/L were independent risk factors for UC relapse at 2 years, whereas the use of biologics for induction of remission was identified as an independent protective factor.Conclusion: Our study suggests that the risk of relapse increases among UC patients with CMV colitis over two years. Risk factors for UC relapse at 2 years include fecal calprotectin ≥ 250 μg/g, Montreal classification E3, CMV colitis, UC duration > 48 months, and albumin < 30 g/L, whereas the use of biologics during induction is a protective factor.Plain Language Summary: Patients with ulcerative colitis and cytomegalovirus colitis are at a higher risk of relapse over a 2-year period than those who are CMV negative. Additionally, we identified several risk factors for UC relapse at 2 years, including fecal calprotectin ≥ 250 μg/g, Montreal classification E3, CMV colitis, duration of UC ≥ 48 months, and albumin < 30 g/L, whereas the administration of biologics during remission induction contributed to reducing UC relapse.Keywords: Ulcerative colitis, cytomegalovirus colitis, relapse, risk factors

Changhong Xu,1,&ast; Yun Deng,1,&ast; Xinyi Gong,2,&ast; Huabin Wang,1 Jiangwei Man,1 Hailong Wang,1 Kun Cheng,1 Huiming Gui,1 Shengjun Fu,1 Shenghu Wei,3 Xiaoling Zheng,4 Tuanjie Che,4 Liyun Ding,3 Li Yang1 1Department of Urology, Institute of Urology, Gansu Province Clinical Research Center for Urinary System Disease, Lanzhou University Second Hospital, Lanzhou, Gansu, 730030, People’s Republic of China; 2The Second Clinical Medical College of Lanzhou University, Lanzhou, Gansu, 730030, People’s Republic of China; 3School of Physical Science and Technology, Lanzhou University, Lanzhou, 730000, People’s Republic of China; 4Innovation Center of Functional Genomics and Molecular Diagnostics Technology of Gansu Province, Lanzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Li Yang; Liyun Ding, Email ery_yangli@lzu.edu.cn; dingly@lzu.edu.cnBackground: Renal ischemia-reperfusion injury (RIRI) is a significant cause of acute kidney injury, complicating clinical interventions such as kidney transplants and partial nephrectomy. Recent research has indicated the role of cuproptosis, a copper-dependent cell death pathway, in various pathologies, but its specific involvement in RIRI remains insufficiently understood. This study aims to investigate the role of cuproptosis-related genes in RIRI and establish robust diagnostic models.Methods: We analyzed transcriptomic data from 203 RIRI and 188 control samples using bioinformatics tools to identify cuproptosis-related differentially expressed genes (CRDEGs). The relationship between CRDEGs and immune cells was explored using immune infiltration analysis and correlation analysis. Gene Set Enrichment Analysis (GSEA) was conducted to identify pathways associated with CRDEGs. Machine learning models, including Least Absolute Shrinkage and Selection Operator(LASSO) logistic regression, Support Vector Machine Recursive Feature Elimination (SVM-RFE), Clustering analysis, and weighted gene co-expression network analysis (WGCNA), were used to construct diagnostic gene models. The models were validated using independent datasets. Experimental validation was conducted in vivo using a mouse bilateral RIRI model and in vitro using an HK-2 cell hypoxia-reoxygenation (HR) model with copper chelation intervention. HE, PAS, and TUNEL staining, along with plasma creatinine and blood urea nitrogen (BUN) measurements, were used to evaluate the protective effect of the copper chelator D-Penicillamine (D-PCA) on RIRI in mice. JC-1 and TUNEL staining were employed to assess apoptosis in HK-2 cells under hypoxia-reoxygenation conditions. Immunofluorescence and Western blot (WB) techniques were used to verify the expression levels of the SDHB and NDUFB6 genes.Results: A total of 18 CRDEGs were identified, many of which were significantly correlated with immune cell infiltration. GSEA revealed that these genes were involved in pathways related to oxidative phosphorylation and immune response regulation. Four key cuproptosis marker genes (LIPA, LIPT1, SDHB, and NDUFB6) were incorporated into a Cuproptosis Marker Gene Model(CMGM), achieving an area under the curve (AUC) of 0.741– 0.834 in validation datasets. In addition, a five-hub-gene SVM model (MOAP1, PPP2CA, SYL2, ZZZ3, and SFRS2) was developed, demonstrating promising diagnostic performance. Clustering analysis revealed two RIRI subtypes (C1 and C2) with distinct molecular profiles and pathway activities, particularly in oxidative phosphorylation and immune responses. Experimental results showed that copper chelation alleviated renal damage and cuproptosis in both in vivo and in vitro models.Conclusion: Our study reveals that cuproptosis-related genes are significantly involved in RIRI, particularly influencing mitochondrial dysfunction and immune responses. The diagnostic models developed showed promising predictive performance across independent datasets. Copper chelation demonstrated potential therapeutic effects, suggesting that cuproptosis regulation may be a viable therapeutic strategy for RIRI. This work provides a foundation for further exploration of copper metabolism in renal injury contexts.Keywords: cuproptosis, renal ischemia-reperfusion injury, RIRI, gene diagnostic models, copper chelators, bioinformatics analysis

Anon Paichitrojjana, Thep Chalermchai School of Anti-Aging and Regenerative Medicine, Mae Fah Luang University, Bangkok, ThailandCorrespondence: Thep Chalermchai, School of Anti-Aging and Regenerative Medicine, Mae Fah Luang University, Khlong Toei Nuea, Watthana, Bangkok, 10110, Thailand, Email thep_chalermchai@hotmail.comBackground: Dermatologists consistently face challenges in treating demodicosis due to its high recurrence rate and difficulty normalizing the Demodex density (Dd) even after clinical improvement. Oral ivermectin has proven to be an effective treatment for demodicosis. However, there is a lack of comprehensive information on the clinical and acaricidal effects of oral ivermectin in treating demodicosis.Purpose: This study aims to evaluate the effectiveness of oral ivermectin on clinical symptoms and Dds of patients with demodicosis.Methods: This prospective, quasi-experimental study included 40 demodicosis patients (20 with Demodex densities (Dds) < 20 D/cm2, 20 with Dds ≥ 20 D/cm2). Both groups of patients were treated with oral ivermectin (200 μg/kg/week) until excellent clinical improvement (Grade 4 according to the Quartile Grading Scale), and Dds ≤ 5 D/cm2 or treated with oral ivermectin for a total of eight weeks period.Results: In our study, 75% of patients achieved clinical remission, showing excellent clinical improvement with Dds ≤ 5 D/cm2. All patients with a Dds < 20 D/cm² experienced remission, while 50% with a Dds ≥ 20 D/cm² achieved remission. The median time to remission after oral ivermectin treatment was 28 days for Dds < 20 D/cm² and 56 days for Dds ≥ 20 D/cm² (p < 0.001).Conclusion: Oral ivermectin effectively improves clinical symptoms and normalizes Dds in patients with demodicosis. Patients with higher Dds require a longer treatment than those with lower Dds.Keywords: ivermectin, demodicosis, Rosacea, Demodex mite, Demodex folliculorum, Demodex brevis

Yong Chen,1 Yan-Juan Chen,1 Jian-Feng Luo,2 Mang He,1 Si-Jin Zhao,3 Shi-Dan Tian,1 Yong-Qiao Zhang,3 Xiao-Long Chen,3 Chuan-Jie Yang,3 Yu-Zhuo Luo,3 Kutty Selva Nandakumar,4 Mei Tian1 1Department of Rheumatology and Immunology, Affiliated Hospital of Zunyi Medical University, Zunyi, People’s Republic of China; 2Department of Biostatistics, School of Public Health, Fudan University, Shanghai, People’s Republic of China; 3The First School of Clinical Medicine, Zunyi Medical University, Zunyi, People’s Republic of China; 4Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, SwedenCorrespondence: Mei Tian, Department of Rheumatology and Immunology, Affiliated Hospital of Zunyi Medical University, 149 Dalian Road, Huichuan District, Zunyi City, Guizhou Province, 563000, People’s Republic of China, Email 348820517@qq.com Kutty Selva Nandakumar, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, 17177, Sweden, Email ksnandakumar@outlook.comPurpose: The quality of life (QoL) of elderly patients with rheumatoid arthritis (RA) in Zunyi China based on health parameters has not been previously analyzed. This study compares the 36-Item Short Form Health Survey (SF-36) scores and prevailing health complications between < 60y and ≥ 60y patients with RA. Data from 1166 patients with RA who visited the rheumatology department of Zunyi Medical University Hospital were followed up and retrospectively analyzed.Patients and Methods: Data from 1166 patients with RA who visited the rheumatology department of Zunyi Medical University Hospital (2021.1– 2022.8) were followed up and retrospectively analyzed.Results: Twenty cases passed away at 61.55 ± 8.11y, which was 6.75 years less than the local average age of death. Elderly patients with RA reported lower recovery levels, and their levels of inflammatory markers such as Immunoglobulin M-rheumatoid factor (IgM-RF), erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) levels were significantly higher than those of younger patients during their past one-year observation period. The SF-36 results indicated that eight items of QoL in the elderly patients were all significantly inferior to < 60y patients, while the complications of interstitial lung disease (ILD), latent tuberculosis infection (LTBI) and, lung and herpes zoster infections were significantly higher.Conclusion: Elderly patients had a higher disease activity along with poor QoL, more health-related complications, and susceptibility to infections. Our study emphasizes the imperative need for optimization of RA treatment modalities in the elderly to alleviate their sufferings.Keywords: elderly rheumatoid arthritis, SF-36 scores, clinical characteristics, treatment outcomes

Yashi Ruan,1,&ast; Lixia Guan,2,&ast; Yuting Wang,2 Yifei Geng,2 Xiaoran Wang,2 Miao-Miao Niu,2 Li Yang,1 Cen Xu,1 Zhen Xu1 1Department of Urology, Reproductive Medicine and Oncology, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou, 225300, People’s Republic of China; 2Department of Pharmaceutical Analysis, China Pharmaceutical University, Nanjing, 211198, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Li Yang; Cen Xu, Department of Urology, Reproductive Medicine and Oncology, The Affiliated Taizhou People’s Hospital of Nanjing Medical University, Taizhou, 225300, People’s Republic of China, Email proyangli@163.com; cenxu263128@163.comPurpose: Dual inhibition of ataxia telangiectasia mutated (ATM) and histone deacetylase 2 (HDAC2) may be a potential strategy to improve antitumor efficacy in testicular cancer.Methods: A combined virtual screening protocol including pharmacophore modeling and molecular docking was used for screening potent dual-target ATM/HDAC2 inhibitors. In order to obtain the optimal lead compound, the dual ATM/HDAC2 inhibitory activity of the screened compounds was further evaluated using enzyme inhibition methods. The binding stability of the optimal compound to the dual targets was verified by molecular dynamics (MD) simulation. MTT assay and in vivo antitumor experiment were performed to validate antitumor efficacy of the optimal compound in testicular cancer.Results: Here, we successfully discovered six potent dual-target ATM/HDAC2 inhibitors (AMHs 1– 6), which exhibited good inhibitory activity against both ATM and HDAC2. Among them, AMH-4 showed strong inhibitory activity against both ATM (IC50 = 1.12 ± 0.03 nM) and HDAC2 (IC50 = 3.04 ± 0.08 nM). MD simulation indicated that AMH-4 binds to ATM and HDAC2 with satisfactory stability. Importantly, AMH-4 had significant antiproliferative activity on human testicular tumor cells, especially NTERA-2 cL.D1 cells, and no inhibitory effect on normal human testicular cells. In vivo experiments exhibited that AMH-4 was more effective than lartesertib and vorinostat in inhibiting the growth of NTERA-2 cL.D1 xenograft tumors with low toxicity.Conclusion: Overall, these results suggest that AMH-4 is an effective and low toxicity candidate for the treatment of testicular germ cell tumors.Keywords: ataxia telangiectasia mutated, histone deacetylase 2, dual-targeting inhibitors, testicular germ cell tumors, structure-based virtual screening

Xiuwen Ling,1,&ast; Jun Shen,2,&ast; Junqing Liang,2 Kai Yang,1 Jianzhong Yang1 1Emergency & Trauma Center, The First Affiliated Hospital of Xinjiang Medical University, Xinjiang, People’s Republic of China; 2Cardiac Pacing and Electrophysiology Department, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jianzhong Yang, Emergency & Trauma Center, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, 830011, People’s Republic of China, Tel/Fax +86 18040399020, Email 18040399020@163.comBackground: New-onset atrial fibrillation (AF) in sepsis significantly impacted patient morbidity and mortality, yet the optimal animal model for studying this condition remains undetermined. This study aimed to establish a stable animal model for new-onset AF in sepsis and to explore the molecular mechanisms involved.Methods: Forty-seven Sprague-Dawley rats were utilized, with the cecal ligation and puncture (CLP) group divided into 0.6 mm and 1.0 mm needle outer diameter subgroups, and the lipopolysaccharide (LPS) group into 5 mg/kg, 10 mg/kg, 15 mg/kg, and 20 mg/kg dosage subgroups. The incidence of new-onset AF and five-day mortality rates were compared to identify the most stable modeling conditions. Selected subgroups underwent further analysis, including cardiac ultrasound, electrophysiology, and pathological examinations. Inflammation-related molecular levels in the atrium were assessed using ELISA and Western blotting (WB).Results: The intraperitoneal injection of 10 mg/kg LPS was identified as the most stable model for new-onset AF in sepsis, with significant findings including increased left atrial area and fibrosis, left ventricular pump dysfunction, uncoordinated ventricular wall motion, and impaired electrical impulse conduction. The effective atrial refractory period was markedly shorter, and susceptibility to AF was higher in the LPS group compared to the CLP group. Molecular analysis revealed elevated levels of NOD-like receptor protein 3(NLRP3) inflammasomes, apoptosis-associated speck-like protein containing a CARD(ASC), Caspase-1 p20 Elevated levels of three inflammation-related proteins and increased activity of the Sphingosine 1-phosphate/Sphingosine 1-phosphate Receptor 2(S1P/S1P2) signaling axis.Conclusion: Intraperitoneal injection of 10 mg/kg of LPS can successfully construct a new-onset AF model in sepsis, and NLRP3 inflammatory vesicles mediated by the S1P/S1P2 signaling axis may promote new-onset AF in sepsis.Keywords: sepsis, atrial fibrillation, rat model, lipopolysaccharide, NLRP3 inflammasome, S1P/S1P2 signaling axis

Bo-Ran Deng,1,&ast; Yang Zhang,2,&ast; Zi-Feng Xie,3,&ast; Ding-Ding Wang,4,&ast; Tao Zeng,1 Dong-Bo Zhang,3 Li Huang,1 Qi-Yan Wang,1 Tu Shen,3 Qiao-Ling Wu3 1Surgical Anesthesia Center, Zigong Hospital of TCM, Zigong, 643000, People’s Republic of China; 2Department of Anesthesia, Da’an District Maternal and Child Health Hospital, Zigong, 643000, People’s Republic of China; 3Department of Anesthesia, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, 121000, People’s Republic of China; 4Department of Anesthesia, EYE & ENT Hospital of Fudan University, Shanghai, 200031, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Tu Shen; Qiao-Ling Wu, Department of Anesthesia, the First Affiliated Hospital of Jinzhou Medical University, No. 40, Section 3, Songpo Road, Linghe District, Jinzhou, 121000, People’s Republic of China, Email shentu2011@sina.com; wqiaoling2013@sina.comPurpose: The debate continues over the differential impact of remimazolam vs propofol on hemodynamic stability. This study aims to elucidate the effects of a combination of remimazolam and esketamine vs propofol and esketamine on hemodynamic parameters in elderly patients undergoing painless colonoscopies.Patients and Methods: We conducted a randomized controlled trial involving 754 patients, divided equally between two treatment groups. The remimazolam-esketamine group (RE group) received 0.15 mg/kg of remimazolam and 0.3 mg/kg of esketamine. Conversely, the propofol-esketamine group (PE group) was administered 1.5 mg/kg of propofol with 0.3 mg/kg of esketamine. Primary outcomes focused on the incidence of hypotension. Secondary outcomes assessed were other hemodynamic adverse events, intraoperative blood pressure and heart rate fluctuations, usage of vasoactive agents, sedation efficacy, and additional adverse reactions.Results: Hypotension occurred significantly less frequently in the RE group (9.78%, 95% confidence interval[CI]: 6.67– 12.87%) compared to the PE group (23.57%, 95% CI: 21.22– 30.52%), P< 0.001. The RE group also showed lower incidences of sinus tachycardia, sinus bradycardia, and required less support from vasoactive agents (P< 0.001). Additionally, the RE group experienced smaller fluctuations in blood pressure and heart rate (P< 0.05). Both groups achieved a 100% sedation success rate. Notably, the RE group had a longer induction period but a quicker recovery time (P< 0.001), and lower rates of respiratory depression (P=0.006) and injection pain (P< 0.001).Conclusion: Remimazolam combined with esketamine offers superior hemodynamic stability and significantly reduces adverse event rates compared to propofol plus esketamine in elderly patients undergoing painless colonoscopies, while maintaining effective sedation.Keywords: remimazolam, esketamine, colonoscopy, elderly patients, hemodynamic effects

Xiao-ling Wu, Ya-nan Guo Intensive Care Unit, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People’s Republic of ChinaCorrespondence: Ya-nan Guo, Intensive Care Unit, The Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, 26 Shengli Street, Wuhan, 430014, People’s Republic of China, Tel +86-18186120762, Fax +86-27-82811446, Email guoyanan1104@sina.comIntroduction: Sepsis is the leading cause of death in critically ill patients; it results in multiorgan dysfunction, including acute respiratory distress syndrome (ARDS). Our study was conducted to determine the role of cellular senescence genes and immune infiltration in sepsis and sepsis-induced ARDS via bioinformatic analyses.Experimental Procedures: Datasets GSE66890 and GSE145227 were obtained from the Gene Expression Omnibus (GEO) database and utilized for bioinformatics analyses. Gene Ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses of the differentially expressed genes (DEGs) were performed to identify the key functional modules. Two machine learning algorithms, least absolute shrinkage and selection operator (LASSO) and support vector machine recursive feature elimination (SVM-RFE), were used to screen for characteristic genes in sepsis and sepsis-induced ARDS. ROC curves were generated to evaluate the predictive ability of gene hubs. Differences in immune infiltration levels between the disease and control groups were compared via ssGSEA. The diagnostic value of the hub genes was verified via quantitative PCR (qPCR) in hospitalized patients.Results: Four characteristic genes (ATM, CCNB1, CCNA1, and E2F2) were identified as biomarkers for the progression of sepsis-induced ARDS. E2F2 showed the highest predictive ability for the occurrence of ARDS in patients with sepsis. CD56bright and plasmacytoid dendritic cells exhibited high infiltration in the sepsis-induced ARDS group, whereas eosinophils, MDSCs, macrophages, and neutrophils exhibited low infiltration. In addition, ATM expression was lower in patients with sepsis than in those without sepsis (n = 6).Conclusion: Sepsis-induced ARDS is correlated with circulating immune responses, and the expression of ATM, CCNB1, CCNA1, and E2F2 may serve as potential diagnostic biomarkers and therapeutic targets in sepsis-induced ARDS.Keywords: sepsis, cellular senescence genes, immune infiltration, acute respiratory distress syndrome, bioinformatics analysis

Jiahua Cheng,1,&ast; Wujuan Li,1,&ast; Lanlin Wang,1,&ast; Yu Gao,1 Yueran Ma,1 Min Zhou,1 Tian Yang,1 Changwu Yue,1,2 Long Yan,3 Yuhong Lyu1,2 1Yan’an Key Laboratory of Microbial Drug Innovation and Transformation, School of Basic Medicine, Yan’an University, Yan’an, Shaanxi, People’s Republic of China; 2Shaanxi Engineering and Technological Research Center for Conversation and Utilization of Regional Biological Resources, Yan’an University, Yan’an, Shaanxi, People’s Republic of China; 3Medical Imaging Center, Yan’an Traditional Chinese Medicine Hospital, Yan’an, Shaanxi, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Long Yan; Yuhong Lyu, Email yanlong840212@163.com; yuhonglyu@126.comPurpose: To explore the protective effects and mechanisms of Jiawei Qifuyin on APP/PS1 mice, a model for Alzheimer’s disease (AD).Methods: Network pharmacology tools were used to predict anti-AD targets and signaling pathways affected by Jiawei Qifuyin. In vitro studies assessed antioxidant and oxygen radical scavenging abilities, immune cell proliferation, and inflammatory cytokine levels in lipopolysaccharide-induced BV2 microglial cells. Cognitive ability in APP/PS1 mice was evaluated using the Morris Water Maze test. mRNA expression of neuroinflammatory factors, changes in intestinal microbiota, and short-chain fatty acid content were analyzed post-treatment.Results: Network pharmacology predicted that Jiawei Qifuyin affects AKT1, TNF-α, and AGE/RAGE pathways. It showed concentration-dependent antioxidant effects and modulated immune cell proliferation. IL-2, IL-6, and TNF-α levels in LPS-induced BV2 cells were significantly reduced. Treated animals exhibited improved cognitive performance, decreased brain amyloid-beta levels, and downregulated expression of IL-1β, IL-6, RAGE, and NF-κB. Significant changes in intestinal microbiota composition and SCFA content were observed.Conclusion: Jiawei Qifuyin may enhance immunity and improve cognitive impairment in APP/PS1 mice through regulation of inflammatory factors, gut microbiota, and the gut-brain axis.Keywords: Alzheimer’s disease, Jiawei Qifuyin, neuroinflammation, intestinal microbiota, short chain fatty acid

Yunfeng Jia,1 Yayi Liu,1 Yiming Zuo,1 Junping Zhang,1 Yanyang Li,2,3 Xuezheng Liu,1 Shichao Lv1 1Department of Geriatrics, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine (National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion), Tianjin, 300381, People’s Republic of China; 2Department of Integrated Traditional and Western Medicine, Tianjin Medical University Cancer Institute and Hospital, Tianjin, 300060, People’s Republic of China; 3Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, People’s Republic of ChinaCorrespondence: Shichao Lv; Xuezheng Liu, Department of Geriatrics, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, No. 88 Changling Street, Xiqing District, Tianjin, 300193, People’s Republic of China, Email dr_lv@foxmail.com; drhare1975@163.comAbstract: Heart failure (HF) represents a serious manifestation or advanced stage of various cardiac diseases. HF continues to impose a significant global disease burden, characterized by high rates of hospitalization and fatality. Furthermore, the pathogenesis and pathophysiological processes underlying HF remain incompletely understood, complicating its prevention and treatment strategies. One significant pathophysiological mechanism associated with HF is the systemic inflammatory response. PANoptosis, a novel mode of inflammatory cell death, has been extensively studied in the context of infectious diseases, neurodegenerative disorders, cancers, and other inflammatory conditions. Recent investigations have revealed that PANoptosis-related genes are markedly dysregulated in HF specimens. Consequently, the PANoptosis-mediated inflammatory response may represent a potential mechanism and therapeutic target for HF. This paper conducts a comprehensive analysis of the molecular pathways that drive PANoptosis. We discuss its role and potential therapeutic targets in HF, thereby providing valuable insights for clinical treatment and the development of novel therapies.Keywords: PANoptosis, pyroptosis, apoptosis, necroptosis, cell death, heart failure

Chantal Emade Nkwelle,1,2 Smith B Babiaka,3,4 Clovis S Metuge,2,3 Kimberly Liang,5 Unique Stephens,5 Seraphine Nkie Esemu,1 David S Zuzga,5 Kristy Shuda McGuire,5 Luis J Montaner,5 Roland N Ndip,1 Ian Tietjen,5 Fidele Ntie-Kang2,3,6 1Department of Microbiology and Parasitology, Faculty of Science, University of Buea, Buea, Cameroon; 2Center for Drug Discovery, Faculty of Science, University of Buea, Buea, Cameroon; 3Department of Chemistry, Faculty of Science, University of Buea, Buea, Cameroon; 4Department of Microbial Bioactive Compound, University of Tübingen, Tübingen, Germany; 5Drug Discovery, The Wistar Institute of Anatomy and Biology, Philadelphia, PA, USA; 6Institute of Pharmacy, Martin-Luther University Halle-Wittenberg, Halle, GermanyCorrespondence: Ian Tietjen, The Wistar Institute, 3601 Spruce Street, Philadelphia, PA, 19104, USA, Tel +1-215-898-3938, Email itietjen@wistar.org Fidele Ntie-Kang, Center for Drug Discovery, Faculty of Science, University of Buea, P. O. Box 63, Buea, Cameroon, Tel +237-673872475, Email fidele.ntie-kang@ubuea.cmBackground: Croton oligandrus Pierre & Hutch is a tropical tree that grows in West and Central Africa, used in ethnomedicine to treat cancer, diabetes, headaches, convulsions, urinary diseases, and inflammatory diseases. As other Croton species have been observed to possess chemical compounds that target HIV latency-reversal, we hypothesized that this species may have similar properties.Aim of the Study: The identification of extracts and compounds of this species, which have HIV-1 latency-reversing activity in J-Lat T cell lines.Methods: The stem bark was obtained, air-dried, powdered, and extracted using dichloromethane. In vitro flow cytometry was used to monitor GFP expression, a marker of HIV latency reversal, following treatment of J-Lat T cells with extracts and compounds.Results: Four extracts were found to reverse HIV latency, the most active extract showing better activity (ie, latency reversal in 69.7 ± 7.1% [mean ± s.e.m.] of J-Lat 10.6 cells at 1 μg/mL) than control agents prostratin (46.2 ± 9.5% at 1.2 μg.mL) and the “Mukungulu” (Croton megalobotrys) extract (34.9 ± 24.2% at 1 μg/mL). Extracts reversed HIV latency through mechanisms over and above protein kinase C (PKC) activation and distinct from histone deacetylase (HDAC) inhibition. The most active extract also synergized with the control HDAC inhibitor romidepsin but did not synergize with other extracts. Isolated compounds (β-Stigmasterol and lupeol) had limited but consistent latency reversal on their own.Conclusion: The plant extracts and compounds reverse HIV latency through mechanisms additional to PKC activation and/or synergize with romidepsin in vitro. Extracts and compounds from this plant may enhance the activity of current HIV latency-reversing agents being assessed in HIV cure studies.Keywords: antiviral, compounds, extracts, HIV-1, latency reversal, screening

Jinbao Shi, Aliang Xu, Liuying Huang, Shaojie Liu, Binxuan Wu, Zuhong Zhang Department of Nephrology, Ningde Hospital of Traditional Chinese Medicine, Ningde, Fujian, People’s Republic of ChinaCorrespondence: Jinbao Shi, Department of Nephrology, Ningde Hospital of Traditional Chinese Medicine, No. 16 Donghu Road, Ningde, Fujian, People’s Republic of China, Email shijinbao00721@aliyun.comBackground: Chronic kidney disease (CKD) involves complex immune dysregulation and altered gene expression profiles. This study investigates immune cell infiltration, differential gene expression, and pathway enrichment in CKD patients to identify key diagnostic biomarkers through machine learning methods.Methods: We assessed immune cell infiltration and immune microenvironment scores using the xCell algorithm. Differentially expressed genes (DEGs) were identified using the limma package. Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA) were performed to evaluate pathway enrichment. Machine learning techniques (LASSO and Random Forest) pinpointed diagnostic genes. A nomogram model was constructed and validated for diagnostic prediction. Spearman correlation explored associations between key genes and immune cell recruitment.Results: The CKD group exhibited significantly altered immune cell infiltration and increased immune microenvironment scores compared to the normal group. We identified 2335 DEGs, including 124 differentially expressed immune-related genes. GSEA highlighted significant enrichment of inflammatory and immune pathways in the high immune score (HIS) subgroup, while GSVA indicated upregulation of immune responses and metabolic processes in HIS. Machine learning identified four key diagnostic genes: RGS1, IL4I1, NR4A3, and SOCS3. Validation in an independent dataset (GSE96804) and clinical samples confirmed their diagnostic potential. The nomogram model integrating these genes demonstrated high predictive accuracy. Spearman correlation revealed positive associations between the key genes and various immune cells, indicating their roles in immune modulation and CKD pathogenesis.Conclusion: This study provides a comprehensive analysis of immune alterations and gene expression profiles in CKD. The identified diagnostic genes and the constructed nomogram model offer potent tools for CKD diagnosis. The immunomodulatory roles of RGS1, IL4I1, NR4A3, and SOCS3 warrant further investigation as potential therapeutic targets in CKD.Keywords: chronic kidney disease, diagnostic biomarkers, immune microenvironment, GSEA, GSVA, machine learning

Hanrui Wang,1– 4,&ast; Xiaoyu Song,1– 4,&ast; Yao Wang,1– 4 Ting Yang,1– 4 Wanchen Liu,1– 4 Yakui Mou,1– 4,&ast; Chao Ren,1– 5 Xicheng Song1– 4 1Department of Otorhinolaryngology, Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, People’s Republic of China; 2Shandong Provincial Key Laboratory of Neuroimmune Interaction and Regulation, Yantai Yuhuangding Hospital, Yantai, People’s Republic of China; 3Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai Yuhuangding Hospital, Yantai, People’s Republic of China; 4Yantai Key Laboratory of Otorhinolaryngologic Diseases, Yantai Yuhuangding Hospital, Qingdao University, Yantai, People’s Republic of China; 5Department of Neurology, Yantai Yuhuangding Hospital, Qingdao University, Yantai, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xicheng Song; Chao Ren, Yantai Yuhuangding Hospital, Qingdao University, No. 20, East Road, Zhifu District, Yantai, 264000, People’s Republic of China, Tel +86535 6691999, Fax +86535 6240341, Email drxchsong@163.com; renchaotg@126.comBackground: The nasal mucosal epithelial barrier is the primary site of allergic rhinitis (AR). Interleukin-1β (IL-1β), as a crucial factor in immune inflammation, not only plays a crucial role in hypersensitivity reactions but also affects the digestive mucosa and skin epithelial barrier. However, the role of IL-1β in the nasal mucosal epithelial barrier in AR has not been reported, and this study aimed to investigate the effect and possible mechanisms involved.Methods: Dermatophagoides pteronyssinus 1 was used as an allergen to construct an AR mouse model and stimulate human nasal mucosal epithelial cells (HNEpCs) and observe the expression changes of IL-1β and epithelial barrier indicators CLDN1 and OCLN in mouse nasal mucosa and HNEpCs. Then, the possible mechanisms of action were explored via exogenous IL-1β stimulation and pharmacological inhibition of IL-1β or its receptor interleukin-1 receptor type 1 (IL-1R1).Results: The results showed that Dermatophagoides pteronyssinus 1-primed mouse nasal mucosa or human HENpCs had increased expression of IL-1β and decreased CLDN1 and OCLN, and IL-1β could directly lead to reduced expression of epithelial barrier indexes in HNEpCs. In addition, inhibition of IL-1β or IL-1R1 can effectively alleviate the damage to the epithelial barrier.Conclusion: IL-1β has a destructive effect on the nasal mucosal epithelial barrier in AR, and inhibition of IL-1β or its receptor IL-1R1 can effectively protect the nasal mucosal barrier. IL-1β is a potential target for the treatment of AR.Keywords: interleukin-1β, allergic rhinitis, nasal mucous membrane, epithelial barrier, DerP1

Ya-zhi Xi,1,2 Xue-lian Wei,1,2 Lei Xie,1,2 Xiao-yu Jia,2 Zhen-ping Li,2 Qing-he Zhou2 1Anesthesia Medicine, Zhejiang Chinese Medical University, Hangzhou City, Zhejiang Province, People’s Republic of China; 2Department of Anesthesiology and Pain Medicine, the Affiliated Hospital of Jiaxing University, Jiaxing City, Zhejiang Province, People’s Republic of ChinaCorrespondence: Qing-he Zhou, Department of Anesthesiology and Pain Medicine, the Affiliated Hospital of Jiaxing University, No. 1882, South of the Second Ring Road, Jiaxing City, Zhejiang Province, 314000, People’s Republic of China, Tel +8613732573379, Fax +86057389997760, Email zqh10980@zjxu.edu.cnBackground: The effects of intraoperative permissive hypercapnia (PaCO2 of 45– 55 mmHg) on the central nervous system remain unclear. Neurofilament light chain (NfL, a protein found in the axons and nerve fibers of neurons) has been associated with central nervous system disorders. This study investigated the effect of intraoperative permissive hypercapnia on plasma NfL concentration 1 day postoperatively, and in turn on the central nervous system, during laparoscopic surgery.Methods: This investigation was a prospective, single-blind randomized controlled trial. Eighty-four individuals aged above 60 years were randomly allocated to either the normocapnia group with an PaCO2 of 35– 45 mmHg (n=42) or the hypercapnia group with a PaCO2 of 45– 55 mmHg (n=42). The primary outcome was the 1-day postoperative plasma NfL concentration. Secondary outcomes included the area under the curve (AUC) values for PaCO2 and regional cerebral oxygen saturation (rSO2). The Mann–Whitney U-test was mainly used to analyze the outcomes.Results: The final analysis included 38 and 40 patients in the normocapnia and hypercapnia groups, respectively. There was no statistically significant difference observed between the groups regarding the preoperative and 1-day postoperative plasma NfL concentration (14.0 [11.1, 19.9] vs 16.3 [9.06, 19.9] pg/mL, P> 0.05; 23.4 [16.8, 32.3] vs 21.5 [15.6, 29.9] pg/mL, P> 0.05, respectively). However, in both groups, the postoperative plasma concentration of NfL showed a significant increase when compared with the preoperative levels (both P < 0.001). The AUCs of PaCO2 and rSO2 from the beginning to the end of the pneumoperitoneum were significantly higher in the hypercapnia group compared with the normocapnia group (both P

Xing Zhou,1,&ast; Quan Lu,2,&ast; Qiu Wang,2,&ast; Wenxin Chu,2 Jianhao Huang,2 Jinming Yu,2 Yuechou Nong,2 Wensheng Lu2,&ast; 1Pharmacy Department, Guangxi Academy of Medical Sciences and the People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, People’s Republic of China; 2Department of Endocrinology and Metabolism, National Key Endocrine Clinical Construction Specialty, Guangxi Academy of Medical Sciences and the People’s Hospital of Guangxi Zhuang Autonomous Region, Nanning, Guangxi, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wensheng Lu; Yuechou Nong, Department of Endocrinology and Metabolism, National Key Endocrine Clinical Construction Specialty, Guangxi Academy of Medical Sciences and the People’s Hospital of Guangxi Zhuang Autonomous Region, No. 6, Taoyuan Road, Nanning, Guangxi, 530021, People’s Republic of China, Email Lwswxqz@163.com; wslu@gxams.org.cn; yuechou_gx@163.comBackground: Mitochondrial calcium uptake-induced mitophagy may play an essential role in myocardial ischemia/reperfusion (MI/R) injury. Diltiazem hydrochloride (DIL), a traditional calcium channel blocker, can alleviate MI/R injury by blocking calcium overload. However, whether the protective mechanism of DIL involves mitophagy remains elusive. This study aimed to clarify the underlying molecular mechanism by which DIL ameliorates MI/R injury by downregulating mitophagy in vivo and in vitro.Methods: Thirty rats were randomized into three groups: the sham, MI/R, and MI/R+DIL (1 mg/kg) groups (n = 10/per group). MI/R injury was induced by ligating the left anterior descending (LAD) artery for 30 min followed by 60 min of reperfusion in vivo. H9C2 cells were selected to establish an oxygen-glucose deprivation/recovery (OGD/R) model to simulate MI/R injury in vitro. The potential mechanism by which DIL alleviates MI/R injury was analyzed based on tissue morphology, mitophagy-related gene transcription, and protein expression.Results: According to histological and immunohistochemical evaluations, DIL significantly alleviated myocardial damage in vivo. Moreover, DIL significantly increased cell viability, attenuated OGD/R-induced apoptosis, and inhibited mitochondrial autophagy in vitro. Mechanistically, DIL attenuated mitochondrial autophagy through the upregulation of dual-specificity protein phosphatase 1 (DUSP1) and the downregulation of c-Jun N-terminal kinase (JNK) and Bcl2 interacting protein 3-like (BNIP3L, also known as NIX) expression.Conclusion: Diltiazem hydrochloride protects against myocardial ischemia/reperfusion injury in a BNIP3L/NIX-mediated mitophagy manner in vivo and in vitro.Keywords: diltiazem hydrochloride, calcium channel blockers, myocardial infarction, myocardial ischemia/reperfusion injury, mitophagy

Yan Wang,1– 4,&ast; He Zhao,2– 4,&ast; Kun Zhao,1– 4,&ast; Huhuifen He,1– 4,&ast; Xinyu Li,5 Jingjing Qiu,2– 4 Limei Cui,2– 4 Liang Chen,2– 4 Wenjing Shang,6,7 Yan Sun2– 4 1The Second Medical College, Binzhou Medical University, Yantai, Shandong, People’s Republic of China; 2Department of Otolaryngology and Head and Neck Surgery, Yantai Yuhuangding Hospital, Qingdao University, Yantai, Shandong, People’s Republic of China; 3Shandong Provincial Clinical Research Center for Otorhinolaryngologic Diseases, Yantai, Shandong, People’s Republic of China; 4Yantai Key Laboratory of Otorhinolaryngologic Diseases, Yantai, Shandong, People’s Republic of China; 5The First Medical College, Binzhou Medical University, Yantai, Shandong, People’s Republic of China; 6Key Laboratory for Genetic Hearing Disorders in Shandong, Binzhou Medical University, Yantai, Shandong, 264003, People’s Republic of China; 7Department of Biochemistry and Molecular Biology, Binzhou Medical University, Yantai, Shandong, 264003, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yan Sun; Wenjing Shang, Email entsunyan@126.com; wenjshang@bzmc.edu.cnIntroduction: Age-related hearing loss (ARHL) is a degenerative condition that involves both peripheral and central auditory system pathologies. There is a close relationship between chronic inflammation and ARHL, but there is currently a lack of in-depth exploration of this relationship, particularly regarding causality.Methods: Using age-appropriate mice for basic experiments to examine changes in central auditory nervous system inflammation, a cohort study was conducted to select relevant clinical data and observe inflammation changes in the elderly population with ARHL. Mendelian randomization was employed to investigate the causal relationship between chronic inflammation and ARHL.Results: Clinical results indicate that CRP levels in the ARHL group are significantly higher than those in the normal group. Chronic inflammation also occurs in the auditory centers. Mendelian randomization studies provide causal evidence that genetic chronic inflammation factors do not increase the risk of ARHL.Discussion: This article provides reliable causal evidence of the relationship between chronic inflammation and ARHL, confirming the accumulation of inflammatory factors in the auditory center, which provides a basis for the prevention and treatment of ARHL and has a good prevention prospect. However, due to the differences of research objects, this study has limitations and needs further research.Keywords: CRP, TNF-α, chronic inflammation, age-related hearing loss, Mendelian randomization

Sumaiah J Alarfaj,1 Mostafa M Bahaa,2 Thanaa A Elmasry,3 Eman I Elberri,4 Eman El-Khateeb,4 Amir O Hamouda,5 Muhammed M Salahuddin,5 Marwa Kamal,6 Abdel-Naser Abdel-Atty Gadallah,7 Nashwa Eltantawy,8 Mohamed Yasser,9– 11 Walaa A Negm,12 Manal A Hamouda,13 Amsha S Alsegiani,14 Sarah Alrubia,14 Mamdouh Eldesoqui,15 Mahmoud S Abdallah16,17 1Department of Pharmacy Practice, College of Pharmacy, Princess Nourah Bint Abdulrahman University, Riyadh, Saudi Arabia; 2Pharmacy Practice Department, Faculty of Pharmacy, Horus University, New Damietta, Egypt; 3Pharmacology and Toxicology Department, Faculty of Pharmacy, Tanta University, Tanta, Egypt; 4Clinical Pharmacy Department, Faculty of Pharmacy, Tanta University, Tanta, Egypt; 5Department of Biochemistry and Pharmacology, Faculty of Pharmacy, Horus University, New Damietta, Egypt; 6Department of Clinical Pharmacy, Faculty of Pharmacy, Fayoum University, Fayoum, Egypt; 7Internal Medicine Department, Faculty of Medicine, Menofia University, Menofia, Egypt; 8Department of Pharmacy Practice, Faculty of Pharmacy and Drug Technology, Egyptian Chinese University, Cairo, Egypt; 9Department of Pharmaceutics, Faculty of Pharmacy, Port Said University, Port Said, Egypt; 10Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Horus University, New Damietta, Egypt; 11Department of Pharmaceutics, Faculty of Pharmacy, East Port Said National University, Port Said, Egypt; 12Pharmacognosy Department, Faculty of Pharmacy, Tanta University, Tanta, Egypt; 13Department of Clinical Pharmacy, Faculty of Pharmacy, Menofia University, Menofia, Egypt; 14Pharmaceutical Chemistry Department, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia; 15Department of Basic Medical Sciences, College of Medicine, AlMaarefa University, Riyadh, Saudi Arabia; 16Department of Clinical Pharmacy, Faculty of Pharmacy, University of Sadat City (USC), Sadat City, Menoufia, Egypt; 17Department of PharmD, Faculty of Pharmacy, Jadara University, Irbid, JordanCorrespondence: Mostafa M Bahaa, Pharmacy Practice Department, Faculty of Pharmacy, Horus University, New Damietta, 34517, Egypt, Tel +0201025538337, Email mbahaa@horus.edu.egBackground: Ulcerative colitis (UC) is an idiopathic chronic inflammation of colonic and rectal mucosa. The peroxisome proliferator-activated receptor α (PPARα) has been identified as having protective effects in UC.Aim: The study aimed to investigate the efficacy of fenofibrate, a PPARα agonist, in UC.Methods: A total of 70 patients with mild to moderate UC were allocated randomly and assigned to two groups (n = 35 each) from Gastroenterology Department, Faculty of Medicine, Menoufia University. The mesalamine group received a placebo along with 1 g of mesalamine three times daily, while the fenofibrate group received 1 g of mesalamine three times and fenofibrate 160 mg once daily. The study duration was for six months. A gastroenterologist assessed patients by non-invasive Partial Mayo Score (PMS) and the Inflammatory Bowel Disease Questionnaire (IBDQ) to evaluate clinical response and remission. The serum levels of silent information regulator 1 (SIRT1), NOD-like receptor protein 3 (NLRP3), and adenosine monophosphate activated protein kinase (AMPK), as well as fecal calprotectin levels were examined to determine the biological effect of fenofibrate.Results: After treatment, the fenofibrate group showed statistically significant reductions in PMS (p = 0.044) and improved digestive domain of IBDQ (p = 0.023). Additionally, there were significant decreases in serum NLRP3 (p = 0.041) and fecal calprotectin (p = 0.035), along with significant increases in SIRT1 (p = 0.002) and AMPK (p = 0.0003). The fenofibrate group also had higher response and remission rates compared to the mesalamine group.Conclusion: Fenofibrate may be a promising adjunct for improving clinical outcomes, quality of life, and modulating inflammation in mild to moderate patients with UC.Trial Registration Identifier: NCT05781698.Keywords: Ulcerative colitis, Fenofibrate, Mesalamine, NLRP3/AMPK, PPAR&#x03B1

DongJu Long,1 Kai Chen,1 YaXi Li,1 PeiYao He,1 XinNing Li,1,2 XiuNan Qin,1 YaPing Wang,1,2 YanYing Xiao1,2 1Department of Anesthesiology and Pain Management, The Second Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China; 2Department of Pain Management, Clinical Research Center for Pain Medicine in Hunan Province, Changsha, Hunan, People’s Republic of ChinaCorrespondence: YanYing Xiao, Department of Anesthesiology and Pain Management, The Second Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of China, Tel +86-13467609491, Fax +86-731-85292115, Email xiaoyanying192@csu.edu.cnBackground: Trigeminal neuralgia usually presents as incapacitating facial pain. Percutaneous balloon compression (PBC) is frequently utilized to manage this ailment. Trigeminocardiac reflex (TCR) commonly presents with sudden severe bradycardia or even asystole, alongside a sudden increase in blood pressure during this surgical procedure. Notably, remimazolam has been reported to maintain higher heart rate (HR) levels during anesthesia than propofol. Thus, this study aims to assess the impact of remimazolam anesthesia versus propofol on TCR occurrence during this procedure.Methods: This randomized controlled trial involved patients with trigeminal neuralgia scheduled for elective PBC. Patients were randomly assigned to receive either remimazolam or propofol for anesthesia. The primary outcome was the incidence of TCR, a potential complication during the procedure. Secondary outcomes included the occurrence of severe TCR, usage of atropine, HR at the time of foramen ovale puncture (T4), HR at the time of trigeminal ganglion compression (T5), and any adverse events.Results: A total of 80 patients were included in the study, with 40 patients in each group. The incidence of TCR was significantly lower in the remimazolam group compared to the propofol group (30.0% vs 82.5%; risk difference − 52.5%, 95% CI − 67.3% to − 18.6%; P < 0.001). The remimazolam group also showed a lower incidence of severe TCR (7.5% vs 45.0%) and significantly lower usage of atropine compared to the propofol group (P < 0.001). Furthermore, HR at T4 and T5 were higher in the remimazolam than in the propofol group (P < 0.001). There was no significant difference in the incidence of adverse events between the two groups.Conclusion: In PBC surgery for trigeminal neuralgia, remimazolam-based intravenous anesthesia showed a higher HR and a lower incidence of TCR than propofol without any increased adverse events.Keywords: remimazolam, propofol, trigeminal neuralgia, balloon occlusion, methods, reflex, trigeminocardiac, hemodynamics

Fabricio Beltrame,1,2 Bianca Nascimento-Carlos,3 Jaqueline S da Silva,1,3 Rodolfo Couto Maia,4 Tadeu Lima Montagnoli,3,4 Eliezer J Barreiro3,4 ,† Gisele Zapata-Sudo1– 4 1Programa de Pós-Graduação em Medicina (Cardiologia), Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; 2Instituto do Coração Edson Saad, Faculdade de Medicina, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; 3Programa de Pós-Graduação em Farmacologia e Química Medicinal, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil; 4Programa de Pesquisa em Desenvolvimento de Fármacos, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil†Professor Eliezer Barreiro passed away on April 8, 2024Correspondence: Gisele Zapata-Sudo, Universidade Federal do Rio de Janeiro, Instituto do Coração Edson Saad, Faculdade de Medicina, Centro de Ciências da Saúde, Bloco J, Sala 11, Rio de Janeiro, RJ, 21941-902, Brasil, Tel/Fax +55-21-39386505, Email gsudo@icb.ufrj.br; gzsudo@gmail.comBackground and Purpose: Current treatments for acute myocardial infarction (AMI) include pain relief and attempts to improve survival. This study investigated the effects of two new ligands of the adenosine receptor, LASSBio-1027 and LASSBio-1860, on cardiac function in an experimental model of AMI.Methods: AMI was induced in Wistar rats by ligating the anterior descending coronary arteries. Infarcted animals were treated orally with vehicle (DMSO), LASSBio-1027 (30 and 70 μmol/kg), or LASSBio-1860 (70 μmol/kg) for seven days. Hemodynamic parameters were observed using echocardiography, whereas inflammation and fibrosis were detected using histological analysis.Results: MI increased the filling pressure from 23.0 ± 1.6 and 14.0 ± 2.0 to 37.0 ± 3.7 and 33.2 ± 8.0, respectively indicating diastolic dysfunction. However, treatment with LASSBio-1027 (70 μmol/kg) and LASSBio-1860 (70 μmol/kg) reduced this parameter to 23.9 ± 5.4 and 17.1 ± 6.7. An impairment in ejection fraction from 57.1 ± 3.2 to 36.6 ± 2.0% was observed after MI, partially recovered to 47.0 ± 7.4% by LASSBio-1027 and fully restored to 61.8 ± 4.3% after 7 days of treatment with LASSBio-1860. After MI, collagen deposition in LV free wall was increased to 31.4 ± 11.0% and treatment with LASSBio-1027 reduced to 23.4 ± 6.0 and 19.7 ± 8.0% at 30 and 70 μmol/kg, respectively. Similarly, LASSBio-1860 reduced collagen levels to 63.1 ± 2.0%.Conclusion: Fibrosis and inflammatory components of MI reduced following treatment with agonist of adenosine receptor subtype A2A. Cardiac remodeling induced by LASSBio-1027 and LASSBio-1860 may be responsible for the improvement in cardiac function in AMI through the activation of A2A adenosine receptors.Keywords: cardiac remodeling, inflammation, myocardial infarction, adenosine receptors

Sebawe Syaj, Anwaar Saeed Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USACorrespondence: Anwaar Saeed, Division of Hematology-Oncology, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA, Email saeeda3@upmc.eduAbstract: Colorectal cancer (CRC) is a prevalent and deadly cancer, with metastatic CRC (mCRC) often leading to poor outcomes despite advancements in screening and chemotherapy. Anti-angiogenic agents targeting vascular endothelial growth factor (VEGF) pathways have become essential in mCRC treatment. Bevacizumab, a VEGF inhibitor, was the first agent used in this context. However, drug resistance prompted the development of more selective inhibitors, such as fruquintinib, a tyrosine kinase inhibitor (TKI) that targets VEGFR-1, − 2, and − 3. Fruquintinib has shown promise in clinical trials, particularly for third-line mCRC treatment. The Phase III FRESCO trial in China demonstrated its efficacy, significantly improving overall survival (OS) and progression-free survival (PFS) compared to placebo, with manageable safety concerns like hypertension and hand-foot skin reactions. The FRESCO-2 trial extended these findings to European and North American populations, leading to a recent FDA approval for previously treated mCRC patients. The pharmacodynamic profile of fruquintinib includes potent inhibition of VEGFR, angiogenesis, and lymphangiogenesis. It has shown synergistic effects when combined with other treatments like chemotherapy and immune checkpoint inhibitors (ICIs). Current research focuses on exploring fruquintinib’s combination with ICIs, such as PD-1 inhibitors, to enhance treatment efficacy, especially in microsatellite stable (MSS) CRC. Ongoing trials are investigating Fruquintinib’s potential in combination with other therapies and its use in earlier lines of treatment. While promising, further studies are required to optimize its place in therapy and identify predictive biomarkers for better patient selection.Keywords: fruquintinib, angiogenesis, VEGF inhibitor, refractory mCRC, third-line

Lijuan Xia,1,2,&ast; Fanxing Yang,3,&ast; Naoko Hayashi,2,&ast; Yuan Ma,4 Bin Yan,4 Yingxin Du,5 Sujuan Chen,1 Yuke Xia,4 Fang Feng,6 Zhifang Ma1 1Department of Radiotherapy, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, People’s Republic of China; 2Department of Oncology Nursing and Palliative Care/ Chronic Illness and Conditions Nursing, St. Luke’s International University, Tokyo, Japan; 3Department of Labor Delivery Recovery Postpartum, People’s Hospital of Zhengzhou, Zhengzhou, Henan, People’s Republic of China; 4Ningxia Medical University, Yinchuan, Ningxia, People’s Republic of China; 5Department of Clinical Nutrition, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, People’s Republic of China; 6Department of Rheumatology and Immunology, General Hospital of Ningxia Medical University, Yinchuan, Ningxia, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lijuan Xia, Department of Radiotherapy, General Hospital of Ningxia Medical University, 804 Shengli South Street, Xingqing District, Yinchuan City, Ningxia, 750004, People’s Republic of China, Email 24DN009@slcn.ac.jp; 974286683@qq.com, Fang Feng, Email 13995409352@163.comIntroduction: Nutritional status is a critical indicator of overall health and immune function, significantly influencing treatment outcomes. Despite its importance, the nutritional status of patients with systemic lupus erythematosus (SLE) often receives insufficient attention. This study aims to evaluate the nutritional status of patients with SLE, identify factors associated with malnutrition, and develop a risk prediction model for malnutrition in this population.Methods: We collected clinical data from a convenience sample of SLE patients at a general hospital in Ningxia Province, China, between January and December 2022. Univariate and multivariate logistic regression analyses were performed to determine the independent risk factors for malnutrition. A risk prediction model was constructed and evaluated using the receiver operating characteristic (ROC) curve.Results: This study included 420 patients with SLE (mean age: 41.43 years, 91.7% women), of whom 46.2% were malnourished based on their serum albumin levels. Multivariate logistic regression analysis identified monthly income (OR=0.192, P< 0.05), sleep quality (OR=2.559, P< 0.05), kidney involvement (OR=4.269, P< 0.05), disease activity (OR=2.743, P< 0.05), leukocyte count (OR=1.576, P< 0.05), lymphocyte count (OR=0.393, P< 0.05), hemoglobin (OR=0.972, P< 0.05), complement C3 (OR=0.802, P< 0.05), and complement C4 (OR=0.493, P< 0.05) as independent risk factors for malnutrition. The prediction model showed good predictive value with an area under the ROC curve of 0.895 (95% CI: 0.823– 0.840), sensitivity of 0.907, and specificity of 0.827. The Hosmer-Lemeshow test indicated a good model fit (χ²=10.779, P=0.215).Discussion: Malnutrition is a significant concern among SLE patients, influenced by a range of socioeconomic and clinical factors. Our risk prediction model, with its high sensitivity and specificity, provides a robust tool for early identification of malnutrition in this population. Implementing this model in clinical practice can guide healthcare providers in prioritizing at-risk patients, enabling proactive nutritional interventions that could potentially improve clinical outcomes, enhance quality of life, and reduce healthcare costs associated with SLE.Keywords: systemic lupus erythematosus, nutritional status, associated factors, malnutrition, risk prediction model, nomogram

Weichao Li,1,2 YuYan Liu,2 Xunhu Gu1 1Department of Neurology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, People’s Republic of China; 2Department of Anesthesiology, Affiliated Qingyuan Hospital (Qingyuan People’s Hospital), Guangzhou Medical University, QingYuan, Guangdong, People’s Republic of ChinaCorrespondence: Xunhu Gu, Doctor of Medicine (MD), Department of Neurology, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi, 330006, People’s Republic of China, Email 540523118@qq.comBackground: Catecholamine vasopressors are commonly used for intra- or post-operative hypotension for cardiac surgery, which have a side effect of new-onset atrial fibrillation (AF) and myocardial ischemia. However, it is not entirely clear whether catecholamine vasopressors increase the risk of new-onset AF after noncardiac surgery.Aim: The aim of this study was to analyze the association between the use of catecholamine vasopressors and the risk of developing new-onset AF after noncardiac surgery.Methods: In this prospective trial, available data from eligible elderly individuals receiving noncardiac surgery at a single center from November 2022 to January 2024 were gathered. Propensity score matching (PSM) was used to balance patient baseline characteristics and to control for confounders. To determine the association between catecholamine vasopressors and the risk of new-onset AF, univariate and multivariate logistic regression analyses were performed.Results: A total of 6000 subjects were included in this study (mean [SD] age, 70.73 [6.37] years; 910 [50.9%] males). After PSM, the patients were stratified into catecholamine vasopressor (n = 357) and comparator groups (n = 1432). A total of 18/357 patients in the catecholamine vasopressor group developed AF, and 25/1432 patients in the comparator group developed AF (incidence rate, 5.0% vs 1.7%). Compared with the comparator group, the catecholamine vasopressor group had an increased risk of new-onset AF (aOR, 2.77; 95% CI, 1.28– 5.89). Some sensitivity analyses also revealed consistent findings of increased new-onset AF risk associated with catecholamine vasopressor treatment.Conclusion: The findings from this study suggest that catecholamine vasopressor treatment is associated with an increased risk of new-onset AF and may help physicians select a modest medication for patients while also assessing the risk of new-onset AF. Keywords: catecholamine vasopressors, new-onset atrial fibrillation, risk, prospective trial, noncardiac procedures

Chao Wang,1,&ast; Mei Zhao,2,&ast; Yuanyuan Yue,3 Chao Hu,2 Chunqiu Zhou,2 Zhongyi Zhang,2 Yunliang He,4 Yaqi Luo,4 Tao Shen,2 Sijie Dang,4 Yang Yang,4 Yong Zhang2,4 1Traditional Chinese Medicine Department, Qitai Hospital of the Sixth Division, Xinjiang, 831899, People’s Republic of China; 2College of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, People’s Republic of China; 3Department of Ultrasound, Chengdu First People’s Hospital, Chengdu, 610095, People’s Republic of China; 4Institute of Traditional Chinese Medicine, Sichuan Academy of Chinese Medicine Sciences, Chengdu, 610014, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yong Zhang; Yang Yang, Institute of Traditional Chinese Medicine, Sichuan Academy of Chinese Medicine Sciences, Chengdu, People’s Republic of China, Email 18692213920@163.com; 18721326@qq.comBackground: Modified Suanmei-Tang (MST) comprises four plants common to both traditional Chinese medicine and culinary applications, and it can potentially alleviate metabolic-associated fatty liver disease (MAFLD) triggered by a high-fat diet (HFD).Purpose: This research aims to investigate the impact and underlying mechanisms of MST in ameliorating MAFLD caused by an HFD.Methods: UHPLC-Q-Orbitrap-MS/MS was used to determine the constituents of MST and to evaluate its effects on MAFLD mouse models. Transcriptomics, network pharmacology, and bioinformatics analysis (including Kyoto Encyclopedia of Genes and Genomes and Gene Set Enrichment Analysis) were utilized to further clarify the mechanisms by which MST acts on MAFLD. The experimental methods included ELISA, real time quantitative PCR (RT-qPCR), Western blot, immunohistochemistry, molecular docking, and metabolomics. Transcriptomics was integrated with metabolomics to find correlations between differentially expressed genes and metabolites, and crucial genes were validated through RT-qPCR.Results: A total of 23 components of MST were identified. The formulation was found to alleviate metabolic disorders, obesity, insulin resistance, inflammation, and oxidative stress in mice with MAFLD. The findings indicate that MST promoted autophagy by suppressing phosphorylation in the PI3K/AKT/mTOR pathway and enhancing lipid management in the livers of MAFLD mice.Conclusion: MST could effectively improve lipid metabolism disorders and liver lipid deposition in MAFLD mice, and its mechanism might be related to regulating the PI3K/AKT/mTOR pathway to improve autophagy. Keywords: modified Suanmei-Tang, MAFLD, transcriptomics, network pharmacology, metabolomics

Qingqing Xu, Xue Cheng, Hong Sun, Guangyuan Su, Yuanhui Fei, Chunhui Wang, Chao Han Department of Anesthesiology, The Affiliated Yixing Hospital of Jiangsu University, Yixing, Jiangsu, People’s Republic of ChinaCorrespondence: Chao Han, Department of Anesthesiology, The Affiliated Yixing Hospital of Jiangsu University, Yixing, Jiangsu, 214200, People’s Republic of China, Tel +8613961568178, Email staff940@yxph.comPurpose: This study aimed to compare the impact of remimazolam-based versus propofol-based intravenous anesthesia on surgical stress and post-operative immune function in patients undergoing gastric radical surgery.Patients and Methods: Sixty-eight patients aged 50 to 80 undergoing gastric radical surgery were randomly assigned to the remimazolam group (group R) or the propofol group (group P), receiving remimazolam or propofol-based intravenous anesthesia, respectively. The primary outcome measured was peri-operative serum stress indicators and lymphocyte subtypes. Secondary outcomes included hemodynamic vitals, recovery quality, postoperative pain profiles and potential adverse effects.Results: The demographic and surgical characteristics of the 60 analyzed patients were comparable. The absolute counts of CD3+CD4+ and CD3+CD8+ cell decreased significantly on POD1 compared with baseline. On POD3, the numbers of CD3+CD4+ cells in group R were lower than baseline and Group P, whereas the CD3+CD8+ cell counts in both groups were lower than baseline, with group R higher than group P. The CD3-CD16+CD56+ cell numbers in both groups on POD1 and POD3 decreased significantly compared to baseline with group P lower than group R on POD3. The serum levels of IL-1β, IL-6, TNF-α, ACTH and COR rose sharply 2 hours after the beginning of surgery compared to baseline. Notably, all these parameters in group R were higher than those in group P. Additionally, blood pressure and intra-operative vasoactive drug frequency in group R were higher than that in group P. No significant differences in recovery quality, postoperative pain profiles, and potential adverse effects were observed.Conclusion: Remimazolam-based intravenous anesthesia might favour the recovery of cellular immune function in early postoperative period compared to propofol. On the contrary, remimazolam was inferior to propofol in suppressing surgical stress. Further studies with larger sample sizes are needed to confirm our findings.Keywords: remimazolam, propofol, surgical stress, post-operative immune function, gastric radical surgery

Adilet Nazarbayev,1 Ardak Nurbakyt,1 Bibigul Omirbayeva,2 Anuar Akhmetzhan,1 Lyazzat Kosherbayeva1,3 1Asfendiyarov Kazakh National Medical University, Almaty, Kazakhstan; 2Salidat Kairbekova National Research Center for Health Development, Astana, Kazakhstan; 3Al-Farabi Kazakh National University, Almaty, KazakhstanCorrespondence: Anuar Akhmetzhan, Asfendiyarov Kazakh National Medical University, 88 Tole bi Street, Almaty, Kazakhstan, Email anuar.akh@bk.ruBackground and Objectives: Limited information is available regarding the distribution of increasing pharmaceutical expenditures within large representative samples of national populations globally. The aim was to investigate the distribution of pharmaceutical costs in outpatient treatment and analyze the primary characteristics of users of expensive drugs within the healthcare system of Kazakhstan.Methods: This study utilized data from the Information System for Outpatient Drug Supply, which includes nationally representative data from all regions of Kazakhstan, covering both rural and urban populations. The key explanatory variables in this study included age, gender, number of prescribed medications, disease categories based on ICD-10 codes, and insurance coverage status. These variables were selected to capture demographic, clinical, and healthcare access factors influencing prescription drug costs. In total, 2.2 million people, who were prescribed outpatient medications were included. High-cost users (HCUs) were characterized as individuals whose prescription drug expenses ranked within the highest 5%.Results: The distribution of pharmaceutical costs exhibits significant discrepancy, with 5% of the population receiving prescription drugs covered by the state budget and social medical insurance fund contributing to nearly three-quarters of all costs. Notably, these HCUs tended to be younger than low-cost drug users. HCUs, on average, consumed a greater quantity of medications compared to non-HCUs. Among children, the top diseases contributing to high costs were rare hereditary diseases and malignancies, while in adults, cancer and diabetes were the primary cost drivers.Conclusion: There is a concentration of public drug program spending within a small percentage of beneficiaries with high drug costs in Kazakhstan. This discovery offers valuable insights for shaping policies tailored to this specific population, aiming to mitigate escalating costs and enhance the optimal use of medications.Plain Language Summary: The pronounced skewness in the consumption of reimbursed outpatient drugs within the healthcare system of the Republic of Kazakhstan highlights the need for targeted cost containment strategies, in addition to broader measures such as price regulation and adjustments to reimbursement lists that impact the general population.The highest average costs in the high-cost group are observed in children under 5 years of age. Costs associated with chronic diseases (diabetes and others) rank in the top three, while when assessing costs in the high-cost user group, rare inherited diseases and cancer have a significant impact.Keywords: Pharmaceutical Expenditure, Prescription Drugs, Cost Distribution, Medicine user, High-cost patients

Joana Hygino,1,&ast; Marisa C Sales,2,&ast; Priscila M Sacramento,1 Taissa M Kasahara,3 Júlio César Costa da Silva,3 Rafaela Bilhão,3 Regis M Andrade,4 Cláudia Cristina Ferreira Vasconcelos,1 Cleonice AM Bento1,3– 5 1Post-Graduate Program in Neurology, Federal University of the State of Rio de Janeiro, Rio de Janeiro City, Brazil; 2Post-Graduate Program in Microbiology, University of the State of Rio de Janeiro, Rio de Janeiro City, Brazil; 3Post-graduate Program in Molecular and Cellular Biology, Federal University of the State of Rio de Janeiro, Rio de Janeiro City, Brazil; 4Department of General Medicine, Federal University of the State of Rio de Janeiro, Rio de Janeiro City, Brazil; 5Department of Microbiology and Parasitology, Federal University of the State of Rio de Janeiro, Rio de Janeiro City, Brazil&ast;These authors contributed equally to this workCorrespondence: Cleonice AM Bento, Department of Microbiology and Parasitology, Federal University of the State of Rio de Janeiro, Frei Caneca 94, 20.261-040, Rio de Janeiro, RJ, Brazil, Tel/Fax + 55-21-2531-7906, Email cbento@unirio.brPurpose: The presence of T cells expressing TLR-2 and TLR-4 has been associated with relapsing-remitting multiple sclerosis (RRMS) pathogenesis. Here, we evaluated whether the effectiveness of DMT in controlling clinical activity of the disease would be associated with modulation of proportion of TLRs+ T cells.Patients and Methods: Whole peripheral blood mononuclear cells, purified CD4+ and CD8+ T cells from RRMS patients were cultured with different stimuli. The frequency of IL-17-secreting CD4+ and CD8+ T cells positive for TLR-2 and TLR-4 was determined by flow cytometry. The cytokine profile of these T cells following TLR-2 and TLR-4 stimulation was determined by Multiplex. Some of these T cell cultures were treated with hydrocortisone. The levels of LPS-binding protein (LBP) were dosed by ELISA. Clinical (occurrence of relapses) and radiological (number of active brain lesions) activity were evaluated during the 1-year follow-up.Results: Despite DMT, high intensity of TLR-2 and TLR-4 expression on (CD4+ and CD8+) T-cells, as well as the frequency of IL-17-secreting (CD4+ and CD8+) T-cells, are predictive of future RRMS relapses. Moreover, higher cytokine production related to Th17/Tc-17 phenotypes in response to TLR-2 and TLR-4 agonists was observed in DMT-treated patients and displayed an elevated number of brain lesions. The hyperresponsiveness of MS-derived T-cells to TLR-2 and TLR-4 ligands, with high levels of IL-1β, IL-6, IL-17, IFN-γ and GM-CSF in response to both TLR agonists, positively correlated with plasma LBP levels. Interestingly, corticoid was less efficient in reducing Th17 and Tc-17 cytokine production induced by TLR-2 and TLR-4 ligands in DMT-treated patients who relapsed during follow-up.Conclusion: Collectively, the data suggested that persistence of circulating Th17 and Tc17 cells expressing elevated levels of functional TLR-2 and TLR-4 could indicate high disease activity and lower therapeutic efficacy in RRMS patients.Keywords: multiple sclerosis, toll-like receptors, T cells, Th17, LPS-binding protein

Bowen Xu,1,2,&ast; Hongye Li,1,2,&ast; Hongping Chen,3 Da Teng,1,2 Lei Gong,2 Lin Zhong,2 Jun Yang2 1Qingdao Medical College of Qingdao University, Qingdao, Shandong, 266000, People’s Republic of China; 2Department of Cardiology, Yantai Yuhuangding Hospital, Yantai, Shandong, 264000, People’s Republic of China; 3Department of Cardiology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lin Zhong; Jun Yang, Email linzhongyhd1971@sina.com; yangjyhd@hotmail.comObjective: Atherosclerosis(AS) is a vascular disease characterized by the development of plaque in the arteries, and atrial fibrillation (AF) is a common heart arrhythmia. These two conditions share several risk factors in common, such as aging, diabetes, obesity, and hypertension. Ferroptosis is a new mode of non-apoptotic cell death that plays a key role in cardiomyocyte death and has been associated with a variety of cardiac diseases. This study aimed to investigate the ferroptosis biomarkers and underlying biological mechanisms associated with AF and AS.Materials and Methods: The gene expression dataset was obtained from GEO database, differentially expressed genes (DEGs) and ferroptosis expressed genes (FDGs) were obtained by data processing and screening, and then functional enrichment, network construction, transcription factor prediction, identification of biomarkers by LASSO and SVM - RFE algorithms, and also immune infiltration analyses and cellular experiments were performed.Results: In AF and AS, 1627 and 571 DEGs were identified respectively, and 128 were intersected, and 47 common FDGs were also identified. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of DEGs revealed that they were associated with biological processes and pathways such as leukocyte immunity, and FDGs were also involved in specific functions and pathways. Fifteen key genes were identified, CSF1R and ITGAM expression differences were verified, and seven transcription factors were predicted to be differentially expressed. Characterized genes were screened to construct models with good diagnostic efficacy, and immune infiltration showed that NUPR1 was associated with altered immune environments, and WB indicated that NUPR1 was highly expressed in the disease model.Conclusion: Our study demonstrates that the ferroptosis gene NUPR1 plays a role in the pathogenesis of atrial fibrillation and atherosclerosis, and also provides valuable insights into their molecular mechanisms, which may contribute to the development of new targets and strategies for the treatment of these diseases.Keywords: atrial fibrillation, AF, atherosclerosis, AS, ferroptosis, CSF1R, ITGAM, NUPR1

Ying Wang,1 Xiangzhuo Zhao,2 Jingxu Wang,2 Xiaoli Zhu3 1Department of Endocrine Nephrology, The First Affiliated Hospital of Xingtai Medical College (Xingtai First Hospital), Xingtai, Hebei Province, 054001, People’s Republic of China; 2Department of Rheumatic Immunology, Xingtai People’s Hospital, Xingtai, Hebei Province, 054000, People’s Republic of China; 3Department of Critical Care Medicine, Xingtai People’s Hospital, Xingtai, Hebei Province, 054000, People’s Republic of ChinaCorrespondence: Ying Wang, Department of Endocrine Nephrology, The First Affiliated Hospital of Xingtai Medical College (Xingtai First Hospital), Xingtai, Hebei Province, 054001, People’s Republic of China, Email wangying1990z@sina.comIntroduction: Rheumatoid arthritis (RA) is a chronic autoimmune disorder marked by persistent joint inflammation, pain, and tissue degradation. This study evaluates the therapeutic potential of Norisoboldine (NOR), an isoquinoline alkaloid from Lindera aggregata, in a rat model of RA.Methods: Rats were divided into five groups: normal control (G1), RA model (G2), NOR-treated groups at 15 mg/kg (G3) and 30 mg/kg (G4), and methotrexate-treated group (G5). NOR’s anti-arthritic effects were assessed by measuring clinical arthritis scores and inflammatory markers (RF, CRP, TNF-α, IL-6, IL-10). Oxidative stress markers (MDA, SOD, catalase, GPx) and pathways (NF-κB/IKKβ and Nrf2/Keap1) were also evaluated. Histopathology assessed synovial inflammation and tissue degradation.Results: NOR treatment significantly reduced arthritis severity, as evidenced by decreased clinical arthritis scores and inflammatory markers in RA rats. NOR also exhibited strong antioxidant effects, demonstrated by decreased MDA levels and enhanced SOD, catalase, and GPx activities. NOR further downregulated matrix metalloproteinases (Mmp-2, Mmp-3), aggrecanases (Adamts-4, Adamts-5), and PCNA expression. Histopathology confirmed marked reductions in synovial inflammation and tissue damage in NOR-treated groups.Discussion: These findings suggest that NOR’s anti-inflammatory and antioxidant properties contribute to reducing both inflammation and the overall severity of RA. NOR’s multifaceted actions support its potential as a novel therapeutic agent for RA.Conclusion: NOR demonstrates protective effects in RA rats by reducing inflammation, oxidative stress, and extracellular matrix degradation, offering promise as a therapeutic option to manage RA pathology comprehensively.Keywords: Norisoboldine, methotrexate, rheumatoid arthritis, inflammation, oxidative stress

Yan-Hua Liu,1,&ast; Jin-Wen Su,2,&ast; Jing Jiang,3 Bing-Fen Yang,1 Zhi-Hong Cao,1 Fei Zhai,1 Wen-Na Sun,1 Ling-Xia Zhang,1 Xiao-Xing Cheng1 1Beijing Key Laboratory of New Techniques of Tuberculosis Diagnosis and Treatment, Institute of Tuberculosis Research, Senior Department of Tuberculosis, the Eighth Medical Center of PLA General Hospital, Beijing, 100091, People’s Republic of China; 2Division of Critical Care Medicine, Senior Department of Tuberculosis, the Eighth Medical Center of PLA General Hospital, Beijing, 100091, People’s Republic of China; 3Institute of Research, Beijing Key Laboratory of Organ Transplantation and Immune Regulation, Senior Department of Respiratory and Critical Care Medicine, the Eighth Medical Center of PLA General Hospital, Beijing, 100091, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Xiao-Xing Cheng; Ling-Xia Zhang, Beijing Key Laboratory of New Techniques of Tuberculosis Diagnosis and Treatment, Institute of Tuberculosis Research, Senior Department of Tuberculosis, Eighth Medical Center of PLA General Hospital, 17 hei Shan Hu Road, Haidian, Beijing, 100091, People’s Republic of China, Fax +86 10 51520496 ; +86 10 66775969, Email xcheng79@outlook.com; zhanglingxia7@163.comPurpose: Tuberculosis (TB) is a major global health threat and its diagnosis remains challenging. This study aimed to develop a nomogram that incorporated peripheral blood transcriptional signatures and other blood tests for the diagnosis of tuberculosis.Patients and Methods: Patients with TB, patients with other definite pulmonary diseases (OPD), individuals with latent tuberculosis infection (LTBI), and healthy controls (HC) were retrospectively enrolled between May 2017 and April 2018. The results of the interferon-γ release assay (IGRA) and blood counts were obtained from medical records, and the transcripts of 10 genes were detected using reverse transcription polymerase chain reaction (RT-PCR). Variable selection was performed using least absolute shrinkage and selection operator regression (LASSO) and multivariate logistic regression was performed for the optimal prediction model with backward direction. The model was displayed as a nomogram, and its performance was evaluated for discrimination ability, calibration ability, and clinical usefulness. Internal validation of the prediction model was conducted using bootstrap resampling.Results: A total of 185 participants were enrolled, including 84 patients with TB and 101 controls. A prediction nomogram composed of IGRA, percentage of neutrophils, and expression levels of CD64, granzyme A (GZMA), and PR/SET domain 1 (PRDM1) was established. The nomogram demonstrated good discrimination, with an unadjusted area under the curve (AUC) of 0.914 (95% CI: 0.875– 0.954) and a bootstrap-corrected AUC of 0.914 (95% CI: 0.874– 0.947). With a cutoff value of 0.519, the sensitivity and specificity for discriminating PTB from controls were 0.81 and 0.871, respectively. The nomogram also showed good calibration with the Hosmer–Lemeshow test (P=0.58) and good clinical practicality displayed by the decision curve analysis.Conclusion: A nomogram composed of IGRA, percentage of neutrophils, and expression of CD64, GZMA, and PRDM1 was established. The nomogram demonstrated a sensitivity and specificity of 81% and 87%, respectively, for differentiating TB from controls.Keywords: tuberculosis, prediction model, peripheral blood, interferon gamma release assay, transcripts of gene

Tao Yang,1,2,&ast; Pengcui Wu,2,&ast; Luping Jiang,2 Ran Chen,2 Qiao Jin,2 Guohong Ye2 1Department of Cardiovascular Medicine, The Second Affiliated Hospital, School of Medicine, The Chinese University of Hong Kong, Shenzhen & Longgang District People’s Hospital of Shenzhen, Guangdong, 518172, People’s Republic of China; 2Department of Cardiovascular Medicine, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, 410004, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Guohong Ye; Qiao Jin, Department of Cardiovascular Medicine, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, No. 161 Shaoshan South Road, Changsha, 410004, People’s Republic of China, Email ygh120811@163.com; jinqiaonhdx@163.comObjective: Ferroptosis is intricately associated with the pathophysiology processes of myocardial ischemia. Cardamonin (CAR) has been shown to provide significant protection against tissue damage due to multiple ischemia/reperfusion. This study aimed to examine the cardioprotective properties of CAR in myocardial ischemia/reperfusion injury (MIRI) and provide insights into the possible mechanisms involved.Methods: An MIRI mice model was conducted by coronary artery ligation, and the effects of CAR on myocardial tissue damage were evaluated by infarct size assessment, echocardiography, and H&E staining. The extent of ferroptosis was detected by examining the levels of ferroptosis-related proteins and lipid reactive oxygen species (ROS). The function pathway of CAR was analyzed by network pharmacology and verified using Western blotting. In addition, we induced hypoxia/reoxygenation (H/R) in cardiomyocytes to detect SLC7A11 expression, ROS level, mitochondrial iron content, and oxidative stress marker levels. The target protein of CAR was identified by Western blotting and molecular docking. We then evaluated the regulatory role of STAT3 on MIRI-induced ferroptosis by silencing STAT3.Results: In our study, CAR demonstrated a reduction in myocardial histopathological damage and mitigation of ferroptosis in MIRI mice. Through network pharmacology analysis and Western blotting, our findings indicated that CAR modulates the AGE-RAGE signaling pathway, particularly impacting STAT3. Meanwhile, in vitro experiments revealed that advanced-glycation end products (AGEs) exacerbated H/R-induced ferroptosis, whereas CAR alleviated this ferroptosis in the presence of both AGEs and H/R. CAR was observed to enhance STAT3 expression in H/R+AGRs-treated cardiomyocytes. Molecular docking results demonstrated favorable binding interactions between CAR and STAT3. Our study confirmed that CAR mitigated MIRI-induced myocardial injury and ferroptosis through targeting STAT3 in mice.Conclusion: In conclusion, CAR inhibited ferroptosis by activating the STAT3 signaling, thereby mitigating MIRI.Keywords: cardamonin, myocardial ischemia/reperfusion injury, ferroptosis, STAT3, AGE-RAGE signaling pathway

Yue Fang,1,2,&ast; Yi Yue,3,&ast; Sensen Hao,1 Ying Zhang,4 Nan Liu,1 Shengling Wang,1 Yan Li,1 Hongzhi Wang1 1Galactophore Oncology Center, Hefei Cancer Hospital, Chinese Academy of Sciences, Hefei City, Anhui Province, People’s Republic of China; 2Science Island Branch, Graduate School of University of Science and Technology of China, Hefei City, Anhui Province, People’s Republic of China; 3The Second Clinical College, Anhui Medical University, Hefei City, Anhui Province, People’s Republic of China; 4Department of Pathology, First Affiliated Hospital of Anhui Medical University, Hefei City, Anhui Province, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hongzhi Wang, Email wanghz@hfcas.ac.cnBackground: Serpin B9 is highly expressed in breast cancer, melanoma, and various malignant cells and inhibits NK cell killing through the Serpin B9-GrB axle. However, the current studies have only validated the role of Serpin B9 in vivo and vitro, and lack of systematic studies on the expression of Serpin B9 in patients’ tumor tissues and its prognostic implications. In this study, we propose to further validate the role of Serpin B9 by comparing its expression level in tissues of lung adenocarcinoma patients and its correlation with the efficacy of immunotherapy.Methods: This study included 200 patients with LUAD between Feb 2022 and Feb 2023. IHC scoring assessed Serpin B9 expression in the tumor and adjacent tissues, with an H-score of 2 as the cutoff value. Patients were divided into high- and low-expression groups. T-tests were used to compare Serpin B9 expression and treatment efficacy between the tumor and adjacent tissues in both groups. Baseline characteristics were compared using X2 tests. Prognostic risk factors were identified using Cox regression and Kaplan-Meier survival curves.Results: The expression level of Serpin B9 in LUAD tumor tissues are higher than adjacent tissues and positively correlated with the TNM stage and negative correlated with PFS in patients with LUAD. Additionally, immunotherapy efficacy was inversely correlated with Serpin B9 expression.Conclusion: The increased expression of Serpin B9 in LUAD tumor tissues is negatively linked to prognosis and immunotherapy efficacy. This underscores their potential as prognostic and therapeutic targets.Keywords: serine proteinase inhibitor B9, lung adenocarcinoma, progression free survival, PD-1/PD-L1

Xudong Cui,1,&ast; Tiewei Li,2,&ast; Jingping Yang,3 Xiaojuan Li,2 Pengfei Xuan,3 Hongyan Wang3 1Respiratory and Critical Care Medicine Department, Inner Mongolia Baogang Hospital, Inner Mongolia Medical University, Hohhot, People’s Republic of China; 2Department of Clinical Laboratory, Children’s Hospital Affiliated to Zhengzhou University, Zhengzhou Key Laboratory of Children’s Infection and Immunity, Zhengzhou, People’s Republic of China; 3Respiratory and Critical Care Medicine Department, Inner Mongolia Baogang Hospital, The Third Affiliated Hospital of Inner Mongolia Medical University, Baotou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Tiewei Li; Jingping Yang, Email litieweind@163.com; yangron@sina.comBackground: Previous studies have demonstrated that neutrophil extracellular traps (NETs) are crucial in infectious diseases. This study aims to evaluate the clinical value of NET-related biomarkers in identifying the risk of COVID-19 and diagnosing the disease.Methods: This study involved 32 patients who tested positive for COVID-19 via polymerase chain reaction (PCR) between April and August 2023. During the same period, 30 healthy volunteers were enrolled as a control group. The principal biomarkers related to NETs are citrullinated histone H3 (CitH3), double-stranded DNA (dsDNA), myeloperoxidase-DNA complex (MPO-DNA), and Nucleosome. Elevated levels in two or more of these biomarkers indicate raised NET concentrations. Multivariable logistic regression analysis was employed to assess whether NET-related biomarkers were the independent risk factor of COVID-19. The diagnostic value of NET-related biomarkers in COVID-19 was further evaluated using receiver operating characteristic (ROC) curve analysis. Statistical procedures were executed in SPSS software (version 24.0, USA).Results: Compared with the control group, patients infected with COVID-19 had higher levels of dsDNA and nucleosomes (P < 0.001). Correlation analysis revealed a positive correlation between dsDNA levels and neutrophil count (r = 0.309, P = 0.015) as well as between nucleosome levels and neutrophil count (r = 0.446, P < 0.001). Further analysis showed that dsDNA and nucleosomes were independent risk factors for COVID-19 infection. ROC curve analysis showed that dsDNA area under the curve (AUC) = 0.777, 95% confidence interval (CI), 0.661– 0.893, P < 0.001, and nucleosomes (AUC = 0.884, 95% CI, 0.778– 0.991, P < 0.001) had well diagnostic value in the diagnosing COVID-19 infection.Conclusion: NET-related biomarkers, dsDNA and nucleosomes, were independent risk factors of COVID-19 infection and potentially useful biomarkers in diagnosing COVID-19 infection in older patients.Keywords: neutrophil extracellular traps, COVID-19, pneumonia, dsDNA, nucleosomes, older patient

Wen Hu,1,&ast; Xiaoyuan Zhang,1,&ast; Zhen Wu,1,&ast; Yushan Luo,1,&ast; Bailong Hu,2 Xiaohua Zou2 1Guizhou Medical University, Guiyang, Guizhou, 550004, People’s Republic of China; 2Department of Anesthesiology, The Affiliated Hospital of Guizhou Medical University, Guiyang, Guizhou, 550004, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Bailong Hu; Xiaohua Zou, Department of Anesthesiology, The Affiliated Hospital of Guizhou Medical University, No. 28 Guiyi Street, Yunyan District, Guiyang, Guizhou, 550004, People’s Republic of China, Tel +86-13809416036, Fax +86-851-86771013, Email 375896605@qq.com; zouxiaohuazxh@163.comPurpose: Sepsis can induce sepsis-associated encephalopathy (SAE), with Ulinastatin (UTI) serving a critical anti-inflammatory role. This study aimed to identify the hub genes in an SAE mouse model following UTI intervention and investigate the underlying molecular mechanisms.Materials and Methods: Through differential expression analysis to obtain differentially expressed genes (DEGs), ie, UTI vs CLP (DEGs1) and Con vs CLP (DEGs2). After taking the intersection of the genes with opposite differential trends in these two parts and immune-related genes (IRGs), DE-IRGs were obtained. Hub genes in the protein-protein interaction (PPI) network were then determined using six algorithms from the Cytohubba plugin in Cytoscape. Gene set enrichment analysis (GSEA) was employed to explore the functional relevance of these hub genes. Additionally, the immune microenvironment across the three groups was compared, and hub gene-related drugs were predicted using an online database. Finally, qRT-PCR was used to validate the expression of the hub genes in hippocampal tissue from CLP mice.Results: RNA sequencing obtained 864 differentially expressed genes (DEGs) (CLP vs Con) and 279 DEGs (UTI vs CLP). Taking the intersection of DEGs with opposite expression trends yielded 165 DEGs. Six key genes (ICAM - 1, IRF7, IL - 1β, CCL2, IL - 6 and SOCS3) were screened by six algorithms. Immune infiltration analysis found that Treg cells were reversed after treatment with UTI in the diseased state. A total of 106 hub - gene - related drugs were predicted, among which BINDARIT - CCL2 and LIFITEGRAST - ICAM1 showed particularly high affinities. The qRT - PCR verification results were consistent with the sequencing results.Conclusion: In conclusion, ICAM-1, IRF7, IL-1β, CCL2, IL-6, and SOCS3 were identified as potential therapeutic targets in SAE mice treated with UTI. This study offers theoretical support for UTI as a treatment option for SAE.Keywords: sepsis-associated encephalopathy, ulinastatin, immune, Treg cells, RNA sequencing

Yueming Li, Fanyou Zhu, Rui Wen, Tingting Hou, Rou Xie, Jiao Qin Department of Rheumatology and Immunology, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China, Changsha, Hunan, People’s Republic of ChinaCorrespondence: Jiao Qin, Email 2018050712@usc.edu.cnAbstract: Felty’s syndrome (FS) is an uncommon disorder with a poor prognosis, and most patients die from infections caused by neutropenia. Currently, there is no standardized treatment strategy, and treatment options are based on case reports and clinical experience. To date, no cases of FS complicated by coronavirus disease-2019 (COVID-19) have been reported. This article reports a successful case of FS complicated by COVID-19. We emphasized treating rheumatic diseases with immunosuppressive therapy at appropriate doses based on strong and effective anti-infection when co-infected.Keywords: Felty’s syndrome, rheumatoid arthritis, neutropenia, COVID-19, molnupiravir

Mohammad M Al-Sanea,1,&ast; Hani M Hafez,2 Ahmed AB Mohamed,3,&ast; Hamed W El-Shafey,4 Abdullah A Elgazar,5 Samar S Tawfik,4 Wafaa A Ewes,4 Shaimaa Hussein,6 Tariq G Alsahli,6 Abdelrahman Hamdi4 1Department of Pharmaceutical Chemistry, College of Pharmacy, Jouf University, Sakaka, Aljouf, 72388, Saudi Arabia; 2Pharmaceutical Chemistry Department, College of Pharmacy, Al-Esraa University, Baghdad, Iraq; 3Department of Medicinal Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt; 4Department of Pharmaceutical Organic Chemistry, Faculty of Pharmacy, Mansoura University, Mansoura, 35516, Egypt; 5Department of Pharmacognosy, Faculty of Pharmacy, Kafrelsheikh University, Kafr El Sheikh, Egypt; 6Department of Pharmacology, College of Pharmacy, Jouf University, Sakaka, Aljouf, 72388, Saudi Arabia&ast;These authors contributed equally to this workCorrespondence: Mohammad M Al-Sanea, Email mmalsanea@ju.edu.saBackground: In response to the urgent need for continuous discovery of new anti-proliferative agents, a new series of quinazoline compounds 5a-r was prepared.Methods: As a reference, four cancer cell lines—HCT116, HePG2, Hela, and MCF-7—and sorafenib (SOR) were used to assess the novel motifs’ in vitro anticancer efficacy. The most cytotoxic compounds were tested in a VEGFR-2 suppressive test and flow cytometric test. Docking analysis was done to the three novel motifs.Results: Compound 5d showed the best anti-tumor activity of the tested compounds with IC50 6.09, 2.39, 8.94 and 4.81 μM in succession. In addition, compound 5h revealed a potent anticancer effect against HCT116 and HePG2 with IC50 5.89 and 6.74 μM, respectively. Also, compound 5p exhibited very strong activity against HCT116, HePG2 & MCF7 with IC50 8.32, 9.72 and 7.99, respectively. Compound 5p had the highest inhibition against VEGFR-2 with an IC50 of 0.117 μM, in contrast to 0.069 μM for SOR. According to flow cytometric testing, the most effective VEGFR-2 inhibitory agent, 5p, was shown to suppress the G1/S cell population in MCF-7 cells. Docking analysis confirmed that the three novel motifs could bind to the VEGFR-2 enzyme’s binding region like the co-crystallized ligand SOR did.Conclusion: The enzyme inhibitory test of compound 5p showed that it is the most potent hybrid that caused MCF-7 cells to undergo apoptosis and generated a G1/S cell cycle arrest. Confirmation of the obtained results was done with the aid of the docking study, which showed that the three motifs might adhere to the enzyme’s major active sites, and the results were in good accordance with the experimental VEGFR-2 inhibitory results. We can conclude that the new quinazoline compounds 5a-r could be used as candidates for development of more efficient anticancer inhibitors. Keywords: quinazolines, VEGFR-2 inhibitors, molecular docking, cell cycle analysis, apoptosis

Lijuan Zhang,1,2,&ast; Liyan Liu,3,&ast; Guosheng Yan,2 Xu Ma,2 Guizhen Zhu,2 Xinxin Dong,2 Yang Lu,2 Hongtao Zhang1,2,4 1Department of Nephrology, People’s Hospital of Zhengzhou University, Zhengzhou, Henan, People’s Republic of China; 2Blood Purification Center, Henan Provincial People’s Hospital, Zhengzhou, Henan, People’s Republic of China; 3Department of Nephrology, The Fifth People’s Hospital of Jinan, Jinan, Shandong, People’s Republic of China; 4Department of Nephrology, Fuwai Central China Cardiovascular Hospital, Zhengzhou, Henan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hongtao Zhang, Blood Purification Center, Henan Provincial People’s Hospital, Zhengzhou, Henan, People’s Republic of China, Tel +86-13526614646, Email zhtzzu@zzu.edu.cnPurpose: The predictive value of the Systemic Immune-Inflammation Index (SII) on mortality in patients with sepsis-associated acute kidney injury (S-AKI) remains unclear. This study aims to investigate the predictive value of SII levels at the Intensive Care Unit (ICU) on the 28-day mortality of S-AKI patients.Patients and Methods: S-AKI patients admitted to the ICU of Henan Provincial People’s Hospital from January 1, 2023, to December 31, 2023. Patients who were diagnosed with S-AKI were divided into survival and death groups based on their 28-day outcome after ICU admission. Using receiver operating characteristic (ROC) curves to determine the best cut-off values and prognostic abilities of various parameters. Kaplan-Meier survival curves describe the 28-day survival of patients after ICU admission. Cox regression analysis identified the main risk factors associated with mortality in S-AKI patients, constructing a predictive nomogram. The concordance index (C-index) and decision curve analysis were used to validate the predictive ability of this model.Results: A total of 216 patients with S-AKI were included. ROC analysis showed that SII had the highest predictive value for mortality risk in S-AKI patients after ICU admission. Compared with the low-SII group, the high-SII group had higher 28-day (86.7% vs 32.4%, respectively, P < 0.001) mortality rate. Based on Cox regression analysis, a nomogram predictive model was constructed, including age, respiratory failure, SII levels, number of organ dysfunctions at ICU admission, sequential organ failure assessment (SOFA), and acute physiology and chronic health evaluation II (APACHEII). The C-index for predicting the 28-day survival rate was 0.682. Decision curve analysis indicated a high level of clinical predictive efficacy.Conclusion: SII serves as a potential biomarker for predicting the prognosis of S-AKI patients. The constructed nomogram prognostic model can aid in assessing the prognosis of S-AKI patients.Keywords: systemic immune-inflammation index, sepsis-associated acute kidney injury, prognosis, mortality, prediction model

Olivier Sibomana Department of General Medicine and Surgery, College of Medicine and Health Sciences, University of Rwanda, Kigali, RwandaCorrespondence: Olivier Sibomana, Email oliviersibomana917@gmail.comIntroduction: Africa, a continent considered to be the cradle of human beings has the largest genetic diversity among its population than other continents. This review discusses the implications of this high African genetic diversity to the development of personalized and precision medicine.Methodology: A comprehensive search across PubMed, Google Scholar, Science Direct, DOAJ, AJOL, and the Cochrane Library electronic databases and manual Google searches was conducted using key terms “genetics”, “genetic diversity”, “Africa”, “precision medicine”, and “personalized medicine”. Updated original and review studies focusing on the implications of African high genetic diversity on personalized and precision medicine were included. Included studies were thematically synthesized to elucidate their positive or negative implications for personalized healthcare, aiming to foster informed clinical practice and scientific inquiry.Results: African populations’ high genetic diversity presents opportunities for personalized and precision medicine including improving pharmacogenomics, understanding gene interactions, discovering new variants, mapping disease genes, creating updated genomic reference panels, and validating biomarkers. However, challenges include underrepresentation in studies, scarcity of reference genomes, inaccuracy of genetic testing and interpretation, and ancestry misclassification. Addressing these requires the establishment of genomic research centers, increasing funding, creating biobanks and repositories, education, infrastructure, and international cooperation to enhance healthcare equity and outcomes through personalized and precision medicine.Conclusion: High African genetic diversity presents both positive and negative implications for personalized and precision medicine. Deep further research is recommended to harness the challenges and use the opportunities to develop customized treatments.Keywords: genetic diversity, pharmacogenomics, precision medicine, Africa

Ye Yang,1,&ast; Lin Wang,1,&ast; Zhiyang Zeng,2 Chunmeng He,1 Yanqiu Wang,1 Ying Huang1 1Department of Gastroenterology, Children’s Hospital of Fudan University/National Children’s Medical Center, Shanghai, 201102, People’s Republic of China; 2Department of Central Laboratory, Fengxian Central Hospital Affiliated to Southern Medical University, Shanghai, 201499, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ying Huang, Department of Gastroenterology, Children’s Hospital of Fudan University/National Children’s Medical Center, No. 399 Wanyuan Road, Minhang District, Shanghai, 201102, People’s Republic of China, Tel +86-21-64931727, Email yhuang815@163.comPurpose: Spleen tyrosine kinase (Syk) is a widely-expressed cytoplasmic non-receptor tyrosine kinase involved in regulating various signaling pathways and plays an important role in chronic inflammation and autoimmune diseases. Gain-of-function SYK variants have been implicated in pediatric inflammatory bowel diseases. This study aimed to investigate the effects of gain-of-function SYK variants on the susceptibility to experimental colitis and macrophage function.Methods: Colitis was induced using dextran sodium sulfate and dinitrobenzene sulfonic acid in mice harboring a gain-of-function variant in SYK (SykS544Y). Intestinal inflammation was assessed via disease activity index, histological analysis, and Western blotting. The frequencies of macrophages, phagocytosis, and reactive oxygen species (ROS) production in bone marrow-derived macrophages (BMDM) were measured via flow cytometry. Chemokines and BMDM chemotaxis were analyzed using real-time quantitative reverse transcription polymerase chain reaction and Transwell assays. The expression of nucleotide-binding domain leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome-related proteins were detected using immunohistochemistry, enzyme-linked immunoassay and Western blotting.Results: SykS544Y mice exhibited increased susceptibility to experimental colitis, and macrophage infiltration in colon tissues significantly increased. We observed increased expression of macrophage chemokines in colon tissues and enhanced chemotaxis in SykS544Y BMDM. Additionally, we detected increased levels of fluorescent microspheres and 2.7-dichloride-hydro fluorescein diacetate-labeled ROS in SykS544Y BMDM. Moreover, enhanced levels of NLRP3 inflammasome-related proteins were observed in the colon tissues and BMDM from SykS544Y mice.Conclusion: Gain-of-function variant in SYK may contribute to the pathogenesis of pediatric inflammatory bowel diseases by promoting macrophage migration, phagocytosis, ROS production and activation of NLRP3 inflammasomes.Keywords: inflammatory bowel disease, SYK, gain-of-function variant, macrophage

Jaesik Park,1 Kwon Hui Seo,2 Jueun Kwak,2 Hyebin Baek2 1Department of Anesthesiology and Pain Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea; 2Department of Anesthesiology and Pain Medicine, Yeouido St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of KoreaCorrespondence: Kwon Hui Seo, Department of Anesthesiology and Pain Medicine, Yeouido St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, 10 63-ro, Yeoungdeungpo-gu, Seoul, 07345, Republic of Korea, Tel +82-2-3779-1268, Fax +82-2-783-0368, Email julianakh@hanmail.netPurpose: Pharmacokinetic and pharmacodynamic (PKPD) models exist for remimazolam, but data for target-controlled infusion (TCI) are limited. The Schüttler PKPD model, a three-compartment model including body weight as a covariate, does not account for age as a variable. This study aimed to investigate remimazolam’s effect-site concentration (Ce) in different age groups during sedation and general anesthesia with TCI using Schüttler PKPD model.Patients and methods: Records of patients who underwent remimazolam TCI with the Schüttler model were reviewed. During anesthesia induction, the target Ce of remimazolam was gradually increased until loss of responsiveness, and it was titrated to maintain bispectral index of 40– 70 during operation. Patients were categorized into young (20– 40 years, n=24), middle-aged (41– 60 years, n=27), and elderly (61– 80 years, n=35) groups. Bispectral index and hemodynamic variables were also assessed.Results: The elderly group had significantly lower remimazolam Ce compared to the young and middle-aged groups at all sedation levels, intubation, and surgery. Mean highest intraoperative Ce was 0.78± 0.10, 0.71± 0.07, and 0.61± 0.10 μg/mL in young, middle-aged, and elderly groups, respectively (P< 0.001). The recovery of responsiveness during emergence occurred at significantly lower Ce in the elderly group (0.28± 0.06 μg/mL) than in the young (0.41± 0.07 μg/mL) and middle-aged groups (0.35± 0.07 μg/mL, P< 0.001). Ce during sedation and general anesthesia was comparable between the young and middle-aged groups. The bispectral index was similar across groups but fluctuated more in the elderly group during general anesthesia. Elderly patients also showed the greatest systolic blood pressure suppression (18.4 ± 13.29% before intubation and 34.31 ± 14.91% during surgery).Conclusion: Older patients may require lower target Ce during remimazolam TCI for sedation and anesthesia, with emergence occurring at lower Ce. Blood pressure suppression may be greater in elderly patients under deep sedation or general anesthesia.Keywords: remimazolam, pharmacology, anesthesia, general, sedation, elderly

Furui Zhai, Shanshan Mu, Yinghui Song, Min Zhang, Cui Zhang, Ze Lv Gynecological Clinic, Cangzhou Central Hospital, Cangzhou, Hebei, People’s Republic of ChinaCorrespondence: Furui Zhai, Gynecological Clinic, Cangzhou Central Hospital, 16 Xinhua West Road, Cangzhou, Hebei, 061001, People’s Republic of China, Email zfr860708@126.comBackground: High-grade cervical intraepithelial neoplasia (CIN2/3) is a precursor to invasive cervical cancer, necessitating effective management. While the Loop Electrosurgical Excision Procedure (LEEP) is a successful treatment, recurrence remains a significant concern. This study evaluates the predictive value of preoperative immune-inflammatory markers, including the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and systemic immune-inflammation index (SII), in assessing the risk of residual or recurrent CIN post-LEEP.Methods: A retrospective analysis was performed on 423 women who underwent LEEP for CIN2/3 at Cangzhou Central Hospital between 2016 and 2020. Cox proportional hazards regression models with restricted cubic splines were used to evaluate linear and non-linear associations between immune-inflammatory indices and recurrence risk. Multivariate models were adjusted for confounding factors, and subgroup analyses were conducted to test the robustness of the associations. Threshold non-linear fitting and saturation effect analyses were also performed to identify inflection points influencing residual or recurrent disease risk.Results: Significant differences in age, menopausal status, TCT results, HPV status, degrees of CIN and margin status were observed between recurrence and non-recurrence groups. NLR demonstrated a U-shaped relationship with recurrence risk, with a threshold effect. NLR values below 3.15 were associated with a reduced recurrence risk, while higher values increased the risk. PLR and SII showed a modest protective effect below their respective thresholds.Conclusion: Systemic inflammation plays a key role in CIN recurrence following LEEP. NLR serves as a valuable prognostic marker, highlighting the potential for personalised follow-up strategies. Further research is needed to confirm these findings and elucidate the underlying mechanisms.Keywords: cervical intraepithelial neoplasia, loop electrosurgical excision procedure, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, systemic immune-inflammation index, residual disease/recurrence

Haoran Chen,1 Meng Wang,2,3 Lin Yang,1,4 Jiao Li,1,4,&ast; Zixiao Li2,3,5,&ast; 1Institute of Medical Information/Library, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, People’s Republic of China; 2Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, People’s Republic of China; 3China National Clinical Research Center for Neurological Diseases, Beijing, People’s Republic of China; 4Key Laboratory of Medical Information Intelligent Technology, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China; 5Research Unit of Artificial Intelligence in Cerebrovascular Disease, Chinese Academy of Medical Sciences, Beijing, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jiao Li, Institute of Medical Information/Library, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 3 Yabao Road, Chaoyang District, Beijing, 100020, People’s Republic of China, Email li.jiao@imicams.ac.cn Zixiao Li, Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, No. 119 West Road, Southern Fourth Ringroad, Fengtai District, Beijing, 100070, People’s Republic of China, Email lizixiao2008@hotmail.comAim: The interaction between inflammatory biomarkers (high-sensitivity C-reactive protein, hsCRP) and antioxidants (uric acid, UA) regarding prognosis after ischemic stroke or transient ischemic attack (TIA) remains inadequately explored. This study aimed to assess (1) the individual and joint effects of hsCRP and UA, and (2) the neuroprotective role of UA in patients with elevated hsCRP levels concerning poor functional outcomes at 90 days.Methods: A prospective cohort study was conducted involving 2140 consecutive ischemic stroke or TIA patients with hsCRP and UA levels. The primary outcome was defined as a poor functional outcome, indicated by a modified Rankin Scale (mRS) score of 3– 6 at 90 days, with a shift in the mRS score as a secondary outcome. Logistic regression and propensity score (PS) analyses were employed to ensure robustness.Results: Poor functional outcome occurred in 345 (16.1%) patients. Individual effects found that the highest quartiles of hsCRP (adjusted OR = 3.090; 95% CI 2.150– 4.442) and UA (adjusted OR = 0.671; 95% CI 0.551– 0.883) were associated with increased or decreased risk of poor functional outcome, respectively. Joint effects (adjusted OR = 3.994; 95% CI 2.758– 5.640) between hsCRP and UA on the primary outcome were more apparent in patients with high hsCRP levels (hsCRP > 1.60 mg/L) and low UA levels (UA ≤ 291.85 μmol/L). For the patients with high hsCRP levels, patients with low UA levels had a higher risk of primary and secondary outcomes, compared with those with high UA levels, after unadjusted or adjusted for hsCRP. Similar and reliable results were observed in PS-based models.Conclusion: In patients with ischemic stroke or TIA, joint high levels of hsCRP and low UA levels significantly correlate with increased risk of poor functional outcome at 90 days. In addition, high UA levels could reduce the risk of poor functional outcome for patients with high hsCRP levels. Keywords: biomarkers, ischemic stroke, poor functional outcome, joint effects, neuroprotective effects

Darpan Radheshyam Thakare,1,2,&ast; Kritika Singh,1,&ast; Tooba Qamar,1 Deeksha Singh,1 Sandeep Balakrishnan,1 Upendra Rathore,1 Neeraj Jain,3 Manish Ora,4 Durga Prasanna Misra1 1Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences (SGPGIMS), Lucknow, Uttar Pradesh, India; 2Department of Clinical Immunology and Rheumatology, King George Medical University (KGMU), Lucknow, Uttar Pradesh, India; 3Department of Radiodiagnosis, Sanjay Gandhi Postgraduate Institute of Medical Sciences (SGPGIMS), Lucknow, Uttar Pradesh, India; 4Department of Nuclear Medicine, Sanjay Gandhi Postgraduate Institute of Medical Sciences (SGPGIMS), Lucknow, Uttar Pradesh, India&ast;These authors contributed equally to this workCorrespondence: Durga Prasanna Misra, Department of Clinical Immunology and Rheumatology, Sanjay Gandhi Postgraduate Institute of Medical Sciences (SGPGIMS), Lucknow, 226014, Uttar Pradesh, India, Email durgapmisra@gmail.com; dpmisra@sgpgi.ac.inPurpose: Existing biomarkers including C-reactive protein (CRP) do not adequately distinguish active and inactive TAK. We compared serum p-glycoprotein (p-gp)/Multidrug Resistance Protein 1 (MDR1), monomeric CRP (mCRP), CRP, and mCRP:CRP ratio in Takayasu arteritis (TAK) and healthy controls and their relationship with disease activity.Patients and Methods: Serum p-gp mCRP (ELISA) and CRP (nephelometry) were compared between consecutive adults with TAK (> 18 years) enrolled from a prospective cohort (n = 92) and healthy controls (n = 29), and between active vs inactive TAK (n = 46 each). In a subset of active immunosuppressive-naïve TAK (n = 29), correlation was assessed between serum p-gp and p-gp expression on circulating T helper lymphocyte populations: overall (CD4+), Th17 (CD4+IL-17+), Th17.1 (CD4+IL-17+IFN-γ+) lymphocytes [normalized to Tregs (CD4+CD25+FoxP3+)]. Changes in serum p-gp, mCRP, CRP, and mCRP:CRP were compared before and after immunosuppression (n = 29). Data was represented using median (Q1-Q3). Receiver operating characteristics (ROC) curves were generated for TAK vs controls, and active vs inactive TAK with serum p-gp, mCRP, CRP, and mCRP:CRP. Multivariable-adjusted linear regression was used to predict active disease with serum p-gp, mCRP, CRP, or mCRP:CRP.Results: Serum p-gp (11.19 vs 8.05 ng/mL), mCRP (1.61 vs 1.25 μg/L), and CRP (5.40 vs 2.1 mg/L) were elevated in TAK vs controls (p < 0.05 for all). CRP was higher and mCRP:CRP ratio was lower in active vs inactive TAK (p < 0.001). ROC curves identified moderate prediction for active disease with CRP and inactive disease with serum p-gp (area under ROC curve 0.705 and 0.392, respectively). Multivariable-adjusted linear regression confirmed association of CRP with active disease (p = 0.009) and serum p-gp with inactive disease (p = 0.041). In treatment-naïve TAK, serum p-gp negatively correlated with p-gp+Th17.1 lymphocytes (Spearman’s rho=− 0.39, p = 0.046). CRP and serum p-gp were significantly lowered following immunosuppressive therapy in treatment-naïve TAK (p < 0.05).Conclusion: Serum p-gp and mCRP are elevated in TAK. Serum p-gp is associated with inactive disease.Keywords: Takayasu arteritis, MDR1 protein, C-reactive protein, large vessel vasculitis, aortoarteritis, disease activity

Xiaoying Cheng,1,2,&ast; Jianhua Wan,1,2,&ast; Denglong Sun,1,2 Yang Zhan,1,2 Jingting Yu,1,2 Yingmeng Li,1,2 Yanxia Xiong,1,2 Wenjun Liu1,2 1State Key Laboratory for the Modernization of Classical and Famous Prescriptions of Chinese Medicine, Nanchang, 330096, People’s Republic of China; 2Research and Development Department, Jiangzhong Pharmaceutical Co., Ltd., Nanchang, 330103, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Wenjun Liu, Email crjzliuwenjun@163.comBackground: Jianweixiaoshi tablets (JWXS) is widely used in traditional Chinese medicine for treating functional dyspepsia with spleen deficiency (SD-FD) in China. However, the molecular mechanisms underlying the therapeutic effects of JWXS remain incompletely understood.Methods: Functional dyspepsia was induced in rats with spleen deficiency by iodoacetamide in combination with the modified multiple platform method. The SD-FD rats were administered JWXS at both low and high doses, as well as domperidone. We conducted a comprehensive evaluation of the treatment effects of JWXS, including body weight, gastrointestinal motility, immune organ index, biochemical analysis, gastrointestinal hormones, and hematological studies. Quantitative proteomic analysis based on data-independent acquisition (DIA) was used to determine the changes in protein profiles of gastric and duodenal tissues in SD-FD rats and JWXS intervention rats.Results: The results showed that JWXS effectively alleviated gastrointestinal motility disorders in SD-FD rats, as indicated by accelerated gastric emptying and intestinal propulsion, increased levels of gastrin, motilin, and ghrelin, and reduced levels of cholecystokinin-octapeptide, vasoactive intestinal peptide, and somatostatin. Additionally, JWXS increased the spleen and thymus index, increased %lymphocyte in blood, reduced white blood cell count and %neutrophil, and improved immune function. Through quantitative proteomic analysis of gastric tissues, we identified 333 differentially expressed proteins in the JWXS treatment group and the model group. Notably, the mechanism by which JWXS accelerated gastric emptying may be related to PLC-γ and SERCA2 in the calcium signaling pathway. Furthermore, JWXS treatment altered the expression of 732 proteins in rat duodenal samples. The differentially expressed proteins were enriched in immune-related functions and pathways, including antigen processing and presentation, as well as the intestinal immune network for IgA production.Conclusion: In conclusion, JWXS exhibits a multi-faceted impact on various pathways, demonstrating its efficacy in treating SD-FD. These findings provide a foundation for the clinical application of JWXS in managing SD-FD.Keywords: Jianweixiaoshi tablets, functional dyspepsia, spleen deficiency, traditional Chinese medicine, proteomic