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Weiming Yan,1,* Qiurui He,2,* Pan Long,3,* Lei Zhang,4 Haiyan Wang,4 Tao Chen5 1Department of Ophthalmology, Fuzong Clinical Medical College of Fujian Medical University, Dongfang Hospital Affiliated to Xiamen University, Fuzhou, People’s Republic of China; 2Department of Cardiovascular Intervention, The Third Hospital of Zhangzhou, Zhangzhou, People’s Republic of China; 3Department of Ophthalmology, The General Hospital of Western Theatre Command, PLA, Chengdu, People’s Republic of China; 4Department of Ophthalmology, The Shaanxi Eye Hospital, Xi’an People’s Hospital (Xi’an Fourth Hospital), Xi’an, People’s Republic of China; 5Center of Clinical Aerospace Medicine, Air Force Military Medical University, Xi’an, People’s Republic of China*These authors contributed equally to this workCorrespondence: Weiming Yan; Tao Chen, Email ywming@fjmu.edu.cn; baiidtf0506@126.comObjective: With the aids of ophthalmic imaging techniques for animals, the spatiotemporal characterization of MNU-induced retinitis pigmentosa (RP) rats were performed.Methods: Sprague-Dawley (SD) rats were randomly divided into normal group (N), MNU-low-dose group (L) and MNU-high-dose group (H). Rats in the L and H group were given intraperitoneally injection with 40 and 60 mg/kg of MNU, a kind of alkylating agent, respectively. The body weight, electroretinogram (ERG) and retinal structure were observed on day one (D1), D3, and D7 after MNU administration. FFA, OCT, TUNEL staining, and immunostaining of Iba1 were also performed.Results: After MNU injection, the weight and ERG amplitudes of rats in both L and H groups decreased gradually, compared to those of the normal group (P

Fengjiao Bu,1,2,* Yong-Soon Cho,3,4,* Qingfeng He,1 Xiaowen Wang,1 Saurav Howlader,3,4 Dong-Hyun Kim,3,4 Mingshe Zhu,5 Jae Gook Shin,3,4 Xiaoqiang Xiang1,6 1Department of Clinical Pharmacy and Pharmacy Administration, School of Pharmacy, Fudan University, Shanghai, People’s Republic of China; 2Department of Pharmacy, Eye and ENT Hospital, Fudan University, Shanghai, People’s Republic of China; 3Department of Pharmacology and Pharmacogenomics Research Center, Inje University College of Medicine, Busan, Republic of Korea; 4Center for Personalized Precision Medicine of Tuberculosis, Inje University College of Medicine, Busan, Republic of Korea; 5Department of DMPK, MassDefect Technologies, Princeton, NJ, USA; 6Department of Preclinical Evaluation, Quzhou Fudan Institute, Quzhou, Zhejiang Province, 324002, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jae Gook Shin; Xiaoqiang Xiang, Email phshinjg@gmail.com; xiangxq@fudan.edu.cnBackground: Anlotinib was approved as a third line therapy for advanced non-small cell lung cancer in China. However, the impact of concurrent administration of various clinical drugs on the drug–drug interaction (DDI) potential of anlotinib remains undetermined. As such, this study aims to evaluate the DDI of anlotinib as a victim by establishing a physiologically based pharmacokinetic (PBPK) model.Methods: The PBPK model of anlotinib as a victim drug was constructed and validated in the Simcyp® incorporating parameters derived from in vitro studies, pre-clinical investigations, and clinical research encompassing patients with cancer. Subsequently, plasma exposure of anlotinib in cancer patients was predicted for single- and multi-dose co-administration with typical perpetrators mentioned in Food and Drug Administration (FDA) industrial guidance.Results: Based on predictions, the CYP3A potent inhibitor ketoconazole demonstrated the most significant DDI with anlotinib, regardless of whether anlotinib is administered as a single dose or multiple doses. Ketoconazole increased the area under the concentration-time curve (AUC) and maximum concentration (Cmax) of single-dose anlotinib to 1.41-fold and 1.08-fold, respectively. In contrast, rifampicin, a potent inducer of CYP3A enzymes, exhibited a relatively higher level of DDI, with AUCR and CmaxR values of 0.44 and 0.79, respectively.Conclusion: Based on the PBPK modeling, there is a low risk of DDI between anlotinib and potent CYP3A/1A2 inhibitors, but caution and enhanced monitoring for adverse reactions are advised. To mitigate the risk of anti-tumor treatment failure, it is recommended to avoid concurrent use of strong CYP3A inducers. In conclusion, our study enhances understanding of anlotinib’s interaction with medications, aiding scientists, prescribers, and drug labels in gauging the expected impact of CYP3A/1A2 modulators on anlotinib’s pharmacokinetics. Keywords: anlotinib, DDIs, CYP3A, CYP1A2, PBPK

Wenyu Zhang,1,* Linquan Li,1,* Yaguang Wu,1 Chengzhilin Li,1 Zi’ang Xu,1 Nianlei Zhang,1 Xinyu Wang,1 Yingchun Zhao,1 Tingjian Zu,1 Qingbin He,1 Jianwei Jiao,2 Runxiao Zheng1 1School of Clinical and Basic Medical Sciences, Medical Science and Technology Innovation Center, Shandong Provincial Hospital, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, 250000, People’s Republic of China; 2State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, People’s Republic of China*These authors contributed equally to this workCorrespondence: Runxiao Zheng, Medical Science and Technology Innovation Center, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, 250000, People’s Republic of China, Email zhengrunxiao@sdfmu.edu.cn Jianwei Jiao, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, 100101, People’s Republic of China, Email jwjiao@ioz.ac.cnIntroduction: Immunotherapy has led to a paradigm shift in reinvigorating treatment of cancer. Nevertheless, tumor associated macrophages (TAMs) experience functional polarization on account of the generation of suppressive metabolites, contributing to impaired antitumor immune responses.Methods: Hence, metabolic reprogramming of tumor microenvironment (TME) can synergistically improve the efficacy of anti-tumor immunotherapy. Herein, we engineered an iron-based nanoplatform termed ERFe3O4 NPs. This platform features hollow Fe3O4 nanoparticles loaded with the natural product emodin, the outer layer is coated with red blood cell membrane (mRBCs) inserted with DSPE-PEG2000-galactose. This effectively modulates lactate production, thereby reversing the tumor immune suppressive microenvironment (TIME).Results: The ERFe3O4 NPs actively targeted TAMs on account of their ability to bind to M2-like TAMs with high expression of galectin (Mgl). ERFe3O4 NPs achieved efficient ability to reverse TIME via the production of reducing lactate and prompting enrichment iron of high concentrations. Furthermore, ERFe3O4 NPs resulted in heightened expression of CD16/32 and enhanced TNF-α release, indicating promotion of M1 TAMs polarization. In vitro and in vivo experiments revealed that ERFe3O4 NPs induced significant apoptosis of tumor cells and antitumor immune response.Discussion: This study combines Traditional Chinese Medicine (TCM) with nanomaterials to synergistically reprogram TAMs and reverse TIME, opening up new ideas for improving anti-tumor immunotherapy. Keywords: metabolic immunotherapy, nanoparticles, reprograming, iron oxide, macrophages

Maoliang Tian,1,* Wenqiang Li,1,* Xiaoyu He,2 Qian He,3 Qian Huang,4 Zhiping Deng1 1Zigong First People’s Hospital, Zigong City, Sichuan Province, 643000, People’s Republic of China; 2North Sichuan Medical College, Nanchong, Sichuan Province, 637000, People’s Republic of China; 3West China Second Hospital of Sichuan University, Chengdu, Sichuan Province, 610044, People’s Republic of China; 4Dazhou Dachuan District People’s Hospital (Dazhou Third People’s Hospital), Dazhou, Sichuan Province, 635000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qian Huang, Dazhou Dachuan District People’s Hospital (Dazhou Third People’s Hospital), Dazhou, Sichuan Province, 635000, People’s Republic of China, Email hq15196767955@163.com Zhiping Deng, Zigong First People’s Hospital, Zigong City, Sichuan Province, 643000, People’s Republic of China, Email dengzp1016@163.comBackground: In human health, vitamins play a vital role in various metabolic and regulatory processes and in the proper functioning of cells. Currently, the effect of Vitamin E (VE) intake on multiple causes of death in Chronic obstructive pulmonary disease (COPD) patients is unclear. Therefore, this paper aims to investigate the relationship between VE and multiple causes of death in COPD patients, to guide the rationalization of dietary structure and reduce the risk of COPD death.Methods: This study screened patients with COPD aged ≥ 40 years from the National Health and Nutrition Examination Survey (NHANES) database 2008– 2018. Weighted COX regression was used to analyze the association between VE intake and multiple causes of death in COPD. The restricted cubic spline(RCS) is drawn to show their relationship. Finally, we conducted a subgroup analysis for further verification.Results: A total of 1261 participants were included in this study. After adjustment for multiple covariates, VE intake was associated with all-cause death in COPD patients, and chronic lower respiratory disease (CLRD) deaths were linearly associated with cardiovascular disease (CVD) deaths there was no such correlation. Subgroup analyses showed no interaction between subgroups, further validating the robustness of the relationship.Conclusion: In COPD patients, VE intake was negatively associated with all-cause mortality and CLRD death. Higher VE intake reduces the risk of all-cause mortality and CLRD death in COPD patients.Keywords: vitamin E, COPD, CVD, CLRD, COX regression analyses

Junqi Liao,1,&ast; Yuan Zhu,1,2,&ast; Aimei Zhang,1 Dan Wu,1 Xiaohui Yan,1 Qiuhua He,1 Fantao Song,1 Jingyi Chen,1 Yunze Li,1 Li Li,1 Zhaoyao Chen,1 Wenlei Li,1 Qin Yang,2 Zhuyuan Fang,3 Minghua Wu1 1Department of Neurology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, 210029, People’s Republic of China; 2Department of Medicine, Physiology and Biophysics, UC Irvine Diabetes Center, University of California Irvine (UCI), Irvine, CA, USA; 3Department of Cardiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, Nanjing, 210029, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Minghua Wu, Department of Neurology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, 155 Hanzhong Road, Nanjing, 210029, People’s Republic of China, Email yfy0069@njucm.edu.cn Zhuyuan Fang, Department of Cardiology, Affiliated Hospital of Nanjing University of Chinese Medicine, Jiangsu Province Hospital of Chinese Medicine, 155 Hanzhong Road, Nanjing, 210029, People’s Republic of China, Email fangzhuyuan@njucm.edu.cnBackground: The relationship between insulin resistance-related indices and the outcomes of acute ischemic stroke (AIS) is still unclear. This study aimed to explore the association between the Apo B/Apo A-1 ratio and the Prognostic Nutritional Index (PNI) with the 90-day outcomes of AIS.Methods: A total of 2011 AIS patients with a 3-month follow-up were enrolled in the present study from January 2017 to July 2021. Multivariate logistic regression modeling was performed to analyze the relationship between Apo B/Apo A-1 ratio, PNI, and AIS poor outcomes. The mediating effect between the three was analyzed using the Bootstrap method with PNI as the mediating variable.Results: Among the 2011 included AIS patients, 20.3% had a poor outcome. Patients were categorized according to quartiles of Apo B/Apo A-1 ratio and PNI. Multivariate logistic regression revealed that the fourth Apo B/Apo A-1 ratio quartile had poorer outcomes than the first quartile (OR 1.75,95%CL 1.21– 2.53, P=0.003), and the fourth PNI quartile exhibited a lower risk of poor outcomes than the first quartile (OR 0.40, 95%CL 0.27– 0.61, P< 0.001). PNI displayed a significant partially mediating effect (21.4%) between the Apo B/Apo A-1 ratio and poor AIS outcomes.Conclusion: The Apo B/Apo A-1 ratio is a risk factor for poor AIS outcomes, whereas PNI acts as a protective factor. The association between the ApoB/ApoA-1 ratio and poor AIS outcomes was partially mediated by PNI.Keywords: insulin resistance, Apo B/Apo A-1 ratio, prognostic nutritional index, acute ischemic stroke, outcomes

Li Ye,1 Xiwei Sun,2 Yiping Li,1 Yali Zeng,1 Lacuo Zhuoma,1 Dinglun Zhou,2 Qinying He,3 Ju Wang,4 Wei Yang,1 Hang Yu,1 Yihui Yang,1 Shu Liang,1 Dan Yuan1 1Center for AIDS/STD Control and Prevention, Sichuan Center for Disease Control and Prevention, Chengdu, Sichuan, People’s Republic of China; 2West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 3Center for AIDS/STD Control and Prevention, Chengdu Center for Disease Control and Prevention, Chengdu, Sichuan, People’s Republic of China; 4Center for AIDS/STD Control and Prevention, Liangshan Center for Disease Control and Prevention, Xichang, Sichuan, People’s Republic of ChinaCorrespondence: Dan Yuan; Shu Liang, Email ydtv1130@163.com; liangshu523@163.comBackground: Sichuan Province was severely affected by the HIV, and there was a scarcity of data regarding the survival time and influencing factors for People Living with HIV/AIDS (PLWH) in Sichuan Province who have received Antiretroviral Therapy (ART). Therefore, it is necessary to conduct a survival analysis for PLWH receiving ART.Methods: A retrospective cohort study was conducted on PLWH who had received ART≥ 6 months in Sichuan Province from January 1, 2003, to December 31, 2022. The Kaplan-Meier method was used to calculate median survival time and plot survival curves, while a Cox proportional hazards regression model was applied to analyze factors affecting survival time. Bilateral tests were performed, with P≤ 0.05 considered statistically significant.Results: The cumulative survival rates at 1, 3, 5, and 10 years for the 223,386 subjects were 94.54%, 89.07%, 84.82%, and 76.44%, respectively. Multivariate analysis using the Cox regression model indicated lower mortality risks for females (HR=0.59, 95% CI: 0.54– 0.65), homosexual transmission (HR=0.43, 95% CI: 0.33– 0.55), and baseline BMI≥ 24 (HR=0.81, 95% CI: 0.72– 0.90). Higher mortality risks were associated with age≥ 50 years at diagnosis (HR=3.21, 95% CI: 2.94– 3.50), being unmarried or divorced (HR=1.23, 95% CI: 1.11– 1.37), living separately (HR=1.32, 95% CI: 1.22– 1.43), baseline BMI < 18.5 (HR=1.27, 95% CI: 1.13– 1.41), presence of single-drug resistance (HR=1.25, 95% CI: 1.15– 1.36), baseline WHO stage IV (HR=1.27, 95% CI: 1.09– 1.47), and a diagnosis-to-treatment interval > 12 months (HR=1.27, 95% CI: 1.15– 1.41). Compared to those with CD4(+) T cell count of 200– 350cells/μL, 350– 500cells/μL, and > 500cells/μL at baseline, individuals with < 200cells/μL had higher mortality risks (HR=0.73, 95% CI: 0.67– 0.79; HR=0.57, 95% CI: 0.51– 0.64; and HR=0.58, 95% CI: 0.51– 0.66, respectively).Conclusion: The survival rate for PLWH receiving ART in Sichuan Province was relatively high. Male gender, age over 50 at diagnosis, being unmarried, divorced, or living separately, presence of single-drug resistance, low baseline BMI, baseline CD4+ T cell < 200cells/μL, baseline WHO stage IV, and a diagnosis-to-treatment interval > 12 months were risk factors for the survival of PLWH.Keywords: PLWH, antiretroviral therapy, survival analysis

Abstract Wood is considered to be one of the most important materials in the global economy. Wood loses shelf life in countries with severe winters. Pentachlorophenol (PCP) was predominantly used as a wood preservative because of its efficacy in controlling wood decay. This study discussed the overall impact of PCP across various environmental matrices, including soil, plants, water, air, and humans. Pentachlorophenol is a phenol substituted with five chloro-groups. High chlorination levels and stability of PCP make it hazardous to the environment, and persistent, and it also interferes with human, aquatic, and soil microbial health. PCP is volatile; thus, it is constantly discharged into the atmosphere and ingested by the human population. Owing to its hazardous nature, it was added to the Stockholm Convention’s list of persistent organic pollutants (POPs) and phased out of the industry in 2023. This review has summarized PCP properties, usage, production volume, different transformation pathways, and its harmful effects on different environmental matrices such as air, water, soil, crops, and human health which have helped to outline the expected features of the new chemical compared with PCP. The improved chemical is intended to have quick degradability, fewer chlorine atoms, no aromatic structure, be non-toxic, environmentally benign, and efficient against wood deterioration while also penetrating the wood better.

Guanxiong Liu,&ast; Duo Zhu,&ast; Quansheng He,&ast; Churen Zhou, Li He, Zhengran Li, Zaibo Jiang, Mingsheng Huang, Boyang Chang, Chun Wu Department of Interventional Radiology, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510630, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Boyang Chang; Chun Wu, Email changby3@mail.sysu.edu.cn; wuch26@mail.sysu.edu.cnPurpose: This study aimed to assess the effectiveness and safety of combining hepatic arterial infusion chemotherapy (HAIC) with lenvatinib (LEN) and PD-1 inhibitors in treating arterioportal shunt (APS) in hepatocellular carcinoma (HCC) patients with portal vein tumor thrombus (PVTT).Patients and Methods: Conducted retrospectively, the study enrolled 54 HCC patients with APS and PVTT treated with HAIC, LEN, and PD-1 inhibitors at our center between January 2021 and October 2023. APS improvement, APS recanalization, tumor response, PVTT response rate, overall survival (OS), intrahepatic progression-free survival (InPFS), and adverse events were evaluated.Results: APS improvement was observed in 42 patients (77.8%), with all improvement occurring within two treatment sessions. Complete APS occlusion was achieved in 40 patients (74.1%), and no recanalization occurred. The best objective response rate (ORR) and ORR after two HAIC sessions were 74.1% and 66.7%, respectively. The best PVTT response and PVTT response after two HAIC sessions were 98.1% and 94.4%, respectively. The median OS and InPFS were 10.0 months and 5.0 months, respectively. OS and InPFS were longer in patients with APS occlusion compared to those without (OS 12.1 vs 4.4 months, P< 0.001, InPFS 6.2 vs 2.3 months, P=0.049). ALBI grade, extrahepatic spread, APS disappearance were potential prognostic factors for OS, while APS grade and extrahepatic spread being independently associated with InPFS. No treatment-related mortality occurred.Conclusion: Combining HAIC with LEN and PD-1 inhibitors proves to be both effective and safe in managing APS in HCC with PVTT, potentially improving patient survival.Keywords: hepatocellular carcinoma, shunt, portal vein tumor thrombus, hepatic arterial infusion chemotherapy, combination therapy

Ying Lan,1 Die Hu,1 Shijing Huang,1 Qing Ma,1 Li Chen,2,3 Min Xu,1 Qin He1 1Department of Pharmacy, Affiliated Hospital of Southwest Jiaotong University, The Third People’s Hospital of Chengdu, Chengdu, Sichuan, 610031, People’s Republic of China; 2Department of Pharmacology, Faculty of Medicine, University of the Basque Country, UPV/EHU, Leioa, Spain; 3Department of Pharmacy and Evidence-Based Pharmacy Center, West China Second University Hospital, Sichuan University, Chengdu, People’s Republic of ChinaCorrespondence: Ying Lan; Li Chen, Email lanying0212@126.com; chenl_hxey@scu.edu.cnPurpose: This study conducted a pharmacovigilance analysis based on the FDA Adverse Event Reporting System (FAERS) database to compare the infection risk of inhaled or nasal Beclomethasone, Fluticasone, Budesonide, Ciclesonide, Mometasone, and Triamcinolone Acetonide.Methods: We used proportional imbalance analysis to evaluate the correlation between ICS /INCs and infection events. The data was extracted from the FAERS database from April 2015 to September 2023. Further analysis was conducted on the clinical characteristics, site of infection, and pathogenic bacteria of ICS and INCs infection adverse events (AEs). We used bubble charts to display their top 5 infection adverse events.Results: We analyzed 21,837 reports of infection AEs related to ICS and INCs, with an average age of 62.12 years. Among them, 61.14% of infection reports were related to females. One-third of infections reported to occur in the lower respiratory tract with Fluticasone, Budesonide, Ciclesonidec, and Mometasone; over 40% of infections reported by Triamcinolone Acetonide were eye infections; the rate of oral infections caused by Beclomethasone were 7.39%. The reported rates of fungal and viral infections caused by beclomethasone were 21.15% and 19.2%, respectively. The mycobacterial infections caused by Budesonide and Ciclesonidec account for 3.29% and 2.03%, respectively. Bubble plots showed that the ICS group had more fungal infections, oral infections, pneumonia, tracheitis, etc. The INCs group had more eye symptoms, rhinitis, sinusitis, nasopharyngitis, etc.Conclusion: Women who use ICS and INCs are more prone to infection events. Compared to Budesonide, Fluticasone seemed to have a higher risk of pneumonia and oral candidiasis. Mometasone might lead to more upper respiratory tract infections. The risk of oral infection was higher with Beclomethasone. Beclomethasone causes more fungal and viral infections, while Ciclesonide and Budesonide are more susceptible to mycobacterial infections.Keywords: data mining, FAERS, ICS, INCs, pharmacovigilance, infections

Qiwen Yu,1 Chaopeng Mei,1 Mengwei Cui,1 Qianqian He,1 Xudong Liu,2 Xiaoxiao Du2 1Department of Emergency Medicine, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People’s Republic of China; 2Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People’s Republic of ChinaCorrespondence: Xiaoxiao Du, Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital of Zhengzhou University, 1 Jianshe East Road, Erqi, Zhengzhou, Henan, People’s Republic of China, Email xiaoxiao5811@126.comBackground: Nepetoidin B (NB) has been reported to possess anti-inflammatory, antibacterial, and antioxidant properties. However, its effects on liver ischemia/reperfusion (I/R) injury remain unclear.Methods: In this study, a mouse liver I/R injury model and a mouse AML12 cell hypoxia reoxygenation (H/R) injury model were used to investigate the potential role of NB. Serum transaminase levels, liver necrotic area, cell viability, oxidative stress, inflammatory response, and apoptosis were evaluated to assess the effects of NB on liver I/R and cell H/R injury. Quantitative polymerase chain reaction (qPCR) and Western blotting were used to measure mRNA and protein expression levels, respectively. Molecular docking was used to predict the binding capacity of NB and mitogen-activated protein kinase phosphatase 5 (MKP5).Results: The results showed that NB significantly reduced serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels, liver necrosis, oxidative stress, reactive oxygen species (ROS) content, inflammatory cytokine content and expression, inflammatory cell infiltration, and apoptosis after liver I/R and AML12 cells H/R injury. Additionally, NB inhibited the JUN protein amino-terminal kinase (JNK)/P38 pathway. Molecular docking results showed good binding between NB and MKP5 proteins, and Western blotting results showed that NB increased the protein expression of MKP5. MKP5 knockout (KO) significantly diminished the protective effects of NB against liver injury and its inhibitory effects on the JNK/P38 pathway.Conclusion: NB exerts hepatoprotective effects against liver I/R injury by regulating the MKP5-mediated P38/JNK signaling pathway.Keywords: liver ischemia/reperfusion injury, nepetoidin B, MKP5, JNK/P38 pathway

Wei Ao,1 Ping Duan,2 Ping Luo,1 Dikai Xiang,1 Qin Wang,1 Yanjiao Ren,1 Qiwei He1 1Department of Cardiology, Yueyang People’s Hospital, Hunan Normal University, Yueyang City, Hunan Province, 414000, People’s Republic of China; 2Department of Cardiology, Shanghai Seventh People’s Hospital, Shanghai City, 200000, People’s Republic of ChinaCorrespondence: Qiwei He, Department of Cardiology, Yueyang People’s Hospital, Hunan Normal University, No. 263 Baling East Road, Yueyanglou District, Yueyang City, Hunan Province, 414000, People’s Republic of China, Tel +8615173044525, Email Yueshao1990@163.comObjective: To explore the clinical application of PTEN-induced kinase 1 (PINK1) and acyl-CoA synthetase long chain family 4 (ACSL4) protein levels in patients with acute myocardial infarction (AMI) and the prognosis evaluation after percutaneous coronary intervention (PCI).Methods: 152 AMI patients who underwent PCI at our hospital from October 2021 to February 2023 were selected as the study group. They were divided into a MACE group (31 cases) and a non MACE group (121 cases) based on the major adverse cardiovascular events (MACE) within 28 days after PCI. Additionally, 152 angina pectoris patients admitted during the same period were selected as the control group. Measure and analyze the levels and clinical significance of PINK1 and ACSL4 proteins in all study subjects.Results: The PINK1 protein level in the study group was lower than that in the control group, while the PINK1 protein level in the MACE group was lower than that in the non MACE group (P< 0.05), while the ACSL4 protein level was the opposite (P< 0.05); PINK1 expression was negatively correlated with SYNTAX score (r=− 0.602, P< 0.05), while ACSL4 expression was positively correlated with SYNTAX score (r=0.683, P< 0.05); Age, LVEF, and ACSL4 were risk factors for poor prognosis in AMI patients after PCI, while PINK1 was a protective factor (P< 0.05); The combined prediction of PINK1 and ACSL4 for the postoperative prognosis of AMI patients after PCI was superior to the individual detection of PINK1 and ACSL4 (P< 0.05).Conclusion: The expression levels of PINK1 and ACSL4 are related to the occurrence of AMI, and their combined detection has high predictive power for the prognosis of AMI patients after PCI.Keywords: acute myocardial infarction, PTEN-induced kinase 1, Acyl-CoA synthetase long chain family 4, percutaneous coronary intervention, prognosis

Lina Zhang,1– 3,&ast; Ruibin Wu,2,3,&ast; Tenghui Ma,2,3 Wenwen Fu,2,3 Jiamin Chen,2,3 Lingling Li,2,3 Qing He2,3 1The First Clinical Medical College, Guangzhou University of Chinese Medicine, Guangzhou, 510080, People’s Republic of China; 2Department of Clinical Nutrition and Microbiome; Biomedical Innovation Center, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, 510655, People’s Republic of China; 3Key Laboratory of Human Microbiome and Chronic Diseases (Sun Yat-sen University), Ministry of Education, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qing He, Email heqing5@mail.sysu.edu.cnObjective: To explore the active substances and targets of Danbie Capsules in Endometriosis therapy.Methods: This study was conducted through TCMSP and published literature screened and obtained 183 active substances of Danbie Capsules, combined and intersected with Endometriosis target genes collected and screened in the GEO database, obtained 24 target genes for Endometriosis treatment, and mapped the target network map of Danbie Capsules active substances against Endometriosis. The network was analyzed with the aid of Cytoscape version 3.9.1. With the aid of the platform of the STRING data analysis, PPI network analysis was conducted on 24 anti-Endometriosis targets of the Danbie Capsules.Results: The research results obtained three critical active substances, namely, Quercetin, β-sitosterol, and Luteolin. Seven critical targets were identified, and two representative genes (TP53 and AKT1) have been verified in Macromolecular docking and immunohistochemical verification.Conclusion: The active substances of Danbie Capsules in the treatment of Endometriosis are Quercetin, β-sitosterol and Luteolin, and the main targets are TP53 and AKT1.Keywords: danbie capsules, endometriosis, network pharmacology

Use of plant extracts as antimicrobials has recently gained wide attention over the continued use of synthetic antibiotics. In this work, Chinese mango leaves were subjected to different extraction regimes namely decoction (50 °C for 48 h and boiling for 3 h) and solvent extraction (50% ethanolic solution at 62 °C for 1 h). The extract solutions were lyophilized yielding 24–26% powdered extracts that were used for the antimicrobial tests against four pathogenic (Salmonella typhi, Escherichia coli, Staphylococcus aureus, Bacillus cereus) and two generally regarded as safe (Streptococcus thermophilus, and Lactobacillus acidophilus) microbial strains. Antimicrobial activity was assessed by inhibition diameters which were found to range from 9–15.5 mm for the three extracts against all the bacterial strains tested and inhibition growth curves which showed the extracts as first acting within the first 20 min after which a steady state (bacteriostatic) was attained and maintained throughout the testing time (360 min) with a significant difference (p

Zichen Wang,1– 3,&ast; Wen Wang,1– 3,&ast; Mingqi Wang,1– 3 Qiao He,1– 3 Jiayue Xu,1– 3 Kang Zou,1– 3 Yan Kang,4 Xin Sun1– 3 1Institute of Integrated Traditional Chinese and Western Medicine, Chinese Evidence-Based Medicine Center and Cochrane China Center, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 2NMPA Key Laboratory for Real World Data Research and Evaluation in Hainan, Chengdu, 610041, People’s Republic of China; 3Sichuan Center of Technology Innovation for Real World Data, Chengdu, People’s Republic of China; 4Intensive Care Unit, West China Hospital of Sichuan University, Chengdu, 610041, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yan Kang; Xin Sun, Email kangyan@scu.edu.cn; sunxin@wchscu.cnObjective: To identify subclasses of acute pancreatitis (AP) patients in the intensive care unit (ICU) by analyzing blood urea nitrogen (BUN) trajectories.Methods: AP patients in West China Hospital System (development cohort) and three public databases in the United States (validation cohort) were included. Latent class trajectory modelling was used to identify subclasses based on BUN trajectories within the first 21 days after ICU admission. Clinical characteristics and outcomes were compared, and results were externally validated.Results: The study comprised 2971 and 930 patients in the development and validation cohorts, respectively, with five subclasses: Class 1 (“Moderate-azotemia, slow decreasing”), Class 2 (“Non-azotemia”), Class 3 (“Severe-azotemia, slow decreasing”), Class 4 (“Moderate-azotemia, rapid increasing”), and Class 5 (‘Moderate-azotemia, slow increasing) identified. Azotemia patients showed significantly higher 30-day mortality risk in development and validation cohorts. Specifically, Class 4 patients exhibited notably highest mortality risk in both the development cohort (HR 5.32, 95% CI 2.62– 10.82) and validation cohort (HR 6.23, 95% CI 2.93– 13.22). Regarding clinical characteristics, AP patients in Class 4 showed lower mean arterial pressure and a higher proportion of renal disease. We also created an online early classification model to further identify Class 4 patients among all patients with moderate azotemia at baseline.Conclusion: This multinational study uncovers heterogeneity in BUN trajectories among AP patients. Patients with “Moderate-azotemia, rapid increasing” trajectory, had a higher mortality risk than patients with severe azotemia at baseline. This finding complements studies that solely rely on baseline BUN for risk stratification and enhanced our understanding of longitudinal progression of AP.Keywords: acute pancreatitis, BUN, trajectories analysis, ICU

Lina Chang,&ast; Xiaohui Ma,&ast; Menghua Yuan,&ast; Li Ding, Yian Gu, Lili Liu, Yan Li, Hua Shu, Ming Liu, Qing He Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qing He; Ming Liu, Department of Endocrinology and Metabolism, Tianjin Medical University General Hospital, Tianjin, 300052, People’s Republic of China, Email heqing202301@tmu.edu.cn; mingliu@tmu.edu.cnPurpose: Understanding factors that influence blood glucose levels in patients with type 2 diabetes mellitus (T2DM) is crucial for managing hyperglycemia. Currently, there is no standardized interpretation method for glucagon levels in oral glucose tolerance test (OGTT). This study aims to assess the relationship between the lowest glucagon/highest C-peptide ratio (Lglc/Hcp) in OGTT and glucose control levels in T2DM.Patients and Methods: Clinical data from 120 patients with T2DM were examined to compare the correlations of Lglc/Hcp and other pancreatic islet function-associated indices with fasting blood glucose (G0), glucose at 120 minutes in OGTT (G120), hemoglobin A1c (HbA1c), and the area under the glucose curve in OGTT (AUCglu). Additionally, the study investigated difference in Lglc/Hcp between patient groups based on the highest blood glucose levels (Hglu) in OGTT (Hglu ≥ 16.7 mmol/L vs Hglu < 16.7 mmol/L).Results: The generalized linear model suggested that Lglc/Hcp significantly correlated with G0 (B = 0.85, P < 0.001), G120(B = 1.46, P < 0.001), HbA1c (B = 0.67, P < 0.001), and AUCglu (B = 3.46, P < 0.001). This correlation surpassed C-peptide and glucagon-related parameters, even after adjusting for confounding factors. Furthermore, Lglc/Hcp was notably higher in patients with Hglu ≥ 16.7 mmol/L compared to those with Hglu < 16.7 mmol/L (Z = − 3.71, p < 0.001).Conclusion: Lglc/Hcp in OGTT closely relates to blood glucose control in patients with T2DM, potentially reflecting the overall pancreatic islet function in regulating glucose levels. Moreover, inhibiting glucagon secretion may be a crucial consideration for patients requiring insulin treatment. Keywords: C-peptide, glucose control, glucagon, type 2 diabetes mellitus

Gehang Ju,1– 3 Xin Liu,1– 3 Wenyu Yang,4 Nuo Xu,4 Lulu Chen,3,5 Chenchen Zhang,6 Qingfeng He,4 Xiao Zhu,4,&ast; Dongsheng Ouyang1– 3,5,&ast; 1Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 2Institute of Clinical Pharmacology, Central South University, Changsha, People’s Republic of China; 3Hunan Key Laboratory for Bioanalysis of Complex Matrix Samples, Changsha Duxact Biotech Co., Ltd, Changsha, People’s Republic of China; 4Department of Clinical Pharmacy, School of Pharmacy, Fudan University, Shanghai, People’s Republic of China; 5Changsha Duxact Biotech Co., Ltd, Changsha, People’s Republic of China; 6School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Dongsheng Ouyang; Xiao Zhu, Email 801940@csu.edu.cn; xiaozhu@fudan.edu.cnIntroduction: Isoniazid (INH) is a crucial first-line anti tuberculosis (TB) drug used in adults and children. However, various factors can alter its pharmacokinetics (PK). This article aims to establish a population pharmacokinetic (popPK) models repository of INH to facilitate clinical use.Methods: A literature search was conducted until August 23, 2022, using PubMed, Embase, and Web of Science databases. We excluded published popPK studies that did not provide full model parameters or used a non-parametric method. Monte Carlo simulation works was based on RxODE. The popPK models repository was established using R. Non-compartment analysis was based on IQnca.Results: Fourteen studies included in the repository, with eleven studies conducted in adults, three studies in children, one in pregnant women. Two-compartment with allometric scaling models were commonly used as structural models. NAT2 acetylator phenotype significantly affecting the apparent clearance (CL). Moreover, postmenstrual age (PMA) influenced the CL in pediatric patients. Monte Carlo simulation results showed that the geometric mean ratio (95% Confidence Interval, CI) of PK parameters in most studies were within the acceptable range (50.00– 200.00%), pregnant patients showed a lower exposure. After a standard treatment strategy, there was a notable exposure reduction in the patients with the NAT2 RA or nonSA (IA/RA) phenotype, resulting in a 59.5% decrease in AUC0-24 and 83.2% decrease in Cmax (Infants), and a 49.3% reduction in AUC0-24 and 73.5% reduction in Cmax (Adults).Discussion: Body weight and NAT2 acetylator phenotype are the most significant factors affecting the exposure of INH. PMA is a crucial factor in the pediatric population. Clinicians should consider these factors when implementing model-informed precision dosing of INH. The popPK model repository for INH will aid in optimizing treatment and enhancing patient outcomes.Keywords: Isoniazid, model-informed precision dosing, population pharmacokinetics, nonlinear mixed-effects model

Sen Li,1 Shuling Liang,2 Shunyu Xie,1 Haixia Chen,1 Haoying Huang,1 Qixin He,3 Huayan Zhang,4,5 Xiaohui Wang1 1Guangzhou Women and Children’s Medical Center, State Key Laboratory of Respiratory Disease and Guangzhou Medical University, Guangzhou, Guangdong Province, People’s Republic of China; 2Guangdong Provincial Research Center for Child Health, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, Guangdong Province, People’s Republic of China; 3Sun Yat-sen University Cancer Center, Guangzhou, Guangdong Province, People’s Republic of China; 4Division of Neonatology and Center for Newborn Care, Guangzhou Women and Children’s Medical Center, Guangzhou, Guangdong Province, People’s Republic of China; 5Division of Neonatology, Department of Pediatrics, Children’s Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USACorrespondence: Xiaohui Wang; Huayan Zhang, Email xiaohuiwang2021621818@gzhmu.edu.cn; zhangh@chop.eduBackground: Bronchopulmonary dysplasia (BPD) has become a major cause of morbidity and mortality in preterm infants worldwide, yet its pathogenesis and underlying mechanisms remain poorly understood. The present study sought to explore microRNA-mRNA regulatory networks and immune cells involvement in BPD through a combination of bioinformatic analysis and experimental validation.Methods: MicroRNA and mRNA microarray datasets were obtained from the Gene Expression Omnibus (GEO) database. Differentially expressed microRNAs (DEMs) were identified in BPD patients compared to control subjects, and their target genes were predicted using miRWalk, miRNet, miRDB, and TargetScan databases. Subsequently, protein-protein interaction (PPI) and functional enrichment analyses were conducted on the target genes. 30 hub genes were screened using the Cytohubba plugin of the Cytoscape software. Additionally, mRNA microarray data was utilized to validate the expression of hub genes and to perform immune infiltration analysis. Finally, real-time PCR (RT-PCR), immunohistochemistry (IHC), and flow cytometry were conducted using a mouse model of BPD to confirm the bioinformatics findings.Results: Two DEMs (miR-15b-5p and miR-20a-5p) targeting genes primarily involved in the regulation of cell cycle phase transition, ubiquitin ligase complex, protein serine/threonine kinase activity, and MAPK signaling pathway were identified. APP and four autophagy-related genes (DLC1, PARP1, NLRC4, and NRG1) were differentially expressed in the mRNA microarray dataset. Analysis of immune infiltration revealed significant differences in levels of neutrophils and naive B cells between BPD patients and control subjects. RT-PCR and IHC confirmed reduced expression of APP in a mouse model of BPD. Although the proportion of total neutrophils did not change appreciably, the activation of neutrophils, marked by loss of CD62L, was significantly increased in BPD mice.Conclusion: Downregulation of APP mediated by miR-15b-5p and miR-20a-5p may be associated with the development of BPD. Additionally, increased CD62L− neutrophil subset might be important for the immune-mediated injury in BPD.Keywords: bronchopulmonary dysplasia, CD62L− neutrophil, immune infiltration analysis, miRNA-mRNA regulatory circuits

Yahui Wang,1,2,&ast; Chengfei Xu,3,&ast; Peng Liu,2 Qiuli He,1 Shihua Zhang,1 Zhihao Liu,1 Chaobo Ni,1 Liping Chen,1 Tong Zhi,1 Longsheng Xu,1 Liang Cheng,3 Xuewu Lin,2 Ming Yao,1 Huadong Ni1,4 1Department of Anesthesiology and Pain Research Center, the Affiliated Hospital of Jiaxing University, Jiaxing, 314001, People’s Republic of China; 2Department of Pain Management, the First Affiliated Hospital of Bengbu Medical College, Bengbu City, 233000, People’s Republic of China; 3Department of Anesthesiology, Bengbu Third People’s Hospital, Bengbu City, 233000, People’s Republic of China; 4Institute of Neuroscience, Soochow University, Suzhou, 215123, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Huadong Ni; Ming Yao, Department of Anesthesiology and Pain Research center, the Affiliated Hospital of Jiaxing University, 1882 Zhonghuan South Road, Jiaxing, 314001, People’s Republic of China, Email huadongni@zjxu.edu.cn; jxyaoming@zjxu.edu.cnBackground: Bone cancer pain (BCP) represents one of the most challenging comorbidities associated with cancer metastasis. Long non-coding RNAs (lncRNAs) have garnered attention as potential therapeutic agents in managing neuropathic pain. However, their role in the regulation of nociceptive information processing remains poorly understood. In this study, we observed a significant down-regulation of the spinal lncRNA ENSRNOG00000051325 (lncRNA51325) in a rat model of bone cancer pain. Our study sought to elucidate the potential involvement of lncRNA51325 in the development of BCP by modulating the expression of molecules associated with pain modulation.Methods: We established the BCP model by injecting Walker 256 cells into the tibial plateau of rats. We conducted tests on the pain behaviors and anxiety-like responses of rats through von-Frey test, Gait analysis, and Open Field Test. Spinal lumbar expansion was harvested for molecular biology experiments to explore the relationship between lncRNA51325 and Pumilio RNA binding family member 2 (Pum2).Results: Notably, the overexpression of lncRNA51325 effectively attenuated mechanical allodynia in rats afflicted with BCP, whereas the knockdown of lncRNA51325 induced pain behaviors and anxiety-like responses in naïve rats. Additionally, we observed a time-dependent increase in the expression of Pum2 in BCP-afflicted rats, and intrathecal injection of Pum2-siRNA alleviated hyperalgesia. Furthermore, our investigations revealed that lncRNA51325 exerts a negative modulatory effect on Pum2 expression. The overexpression of lncRNA51325 significantly suppressed Pum2 expression in BCP rats, while the knockdown of lncRNA51325 led to elevated Pum2 protein levels in the spinal cord of naïve rats. Subsequent treatment with Pum2-siRNA mitigated the downregulation of lncRNA51325-induced mechanical allodynia in naïve rats.Conclusion: Our findings indicate that lncRNA51325 plays a role in regulating bone cancer pain by inhibiting Pum2 expression, offering a promising avenue for novel treatments targeting nociceptive hypersensitivity induced by bone metastatic cancer.Keywords: long non-coding RNA, bone cancer pain, Pum2, spinal cord

Nan Peng,1 Qinghong He,2 Jie Bai,1 Chen Chen,3 Gordon G Liu1,4 1School of International Pharmaceutical Business, China Pharmaceutical University, Nanjing, Jiangsu, 211198, People’s Republic of China; 2Institute of Economics, Chinese Academy of Social Sciences, Beijing, 100836, People’s Republic of China; 3Department of Global Health, School of Public Health, Wuhan University, Wuhan, 430071, People’s Republic of China; 4Institute for Global Health and Development, Peking University, Beijing, 100080, People’s Republic of ChinaCorrespondence: Gordon G Liu, Institute for Global Health and Development, Peking University, Beijing, 100080, People’s Republic of China, Email gordonliu@nsd.pku.edu.cnPurpose: The aim of this study is to investigate the factors influencing hospitalization costs for patients diagnosed with acute appendicitis in China.Methods: We conducted a cross-sectional study using data from Provincial Health Statistics Support System Database from S Province in China. This dataset contained all hospital’s electronic medical records from January 1, 2015 to December 31, 2018 including both public and private hospitals. The target population was identified based on the principal diagnosis of appendicitis (ICD-10: K35). To examine the impact of various factors on hospitalization costs, we conducted a multivariate linear regression analysis. Furthermore, we employed the Shapley value decomposition method to gain a more comprehensive understanding of the factors that influenced hospitalization costs and their respective levels of importance.Results: Our study comprised 317,200 cases. During the period from 2015 to 2018, the average hospitalization expenses for patients with acute appendicitis were estimated at approximately 7014 RMB (1061 USD), which accounts for a considerable 12% of China’s per capita GDP. The results of this study demonstrate a significant correlation between various factors, such as the patient’s age, gender, marital status, occupation, payment method, number of complications, treatment method, hospital tier, and ownership, and the total hospitalization costs and subcomponents of hospitalization costs. Notably, the treatment method employed had the most substantial impact on hospitalization costs.Conclusion: To the best of knowledge, this is one of the first studies to investigate the hospitalization costs of acute appendicitis incorporating both patient-level and hospital-level covariates, using a large sample size. To reduce the costs associated with acute appendicitis in China, it is recommended to consider suitable treatment options and explore the option of receiving medical care at lower-tier and privately-owned healthcare facilities.Keywords: appendicitis, hospitalization costs, influencing factors, multivariate regression

Wenfang He,1,&ast; Siqiang Zheng,1,&ast; Hua Zhang,2 Bowen Gao,3 Juan Jin,1 Mingzhen Zhang,3,4 Qiang He1 1Department of Nephrology, the First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Traditional Chinese Medicine), Hangzhou, Zhejiang, 310000, People’s Republic of China; 2Hangzhou Medical College, Hangzhou, Zhejiang, People’s Republic of China; 3School of Basic Medical Sciences, Xi’an Key Laboratory of Immune Related Diseases, Xi’an Jiaotong University, Xi’an, Shaanxi, 710061, People’s Republic of China; 4Key Laboratory of Environment and Genes Related to Diseases, Xi’an Jiaotong University, Ministry of Education, Xi’an, Shaanxi, 710061, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qiang He; Mingzhen Zhang, Email qianghe1973@126.com; mzhang21@xjtu.edu.cnAbstract: The utilization of plant-derived vesicle-like nanoparticles (PDVLNs) has shown effectiveness in the prevention/treatment of inflammatory-mediated diseases, malignancies, and immune-related diseases, such as acute liver injury, allergic asthma, gastric cancer and so on. This highlights the promising potential of PDVLNs as biotherapeutics. Furthermore, it should be noted that PDVLNs possess the ability to function as both natural and engineered drug carriers, making them an appealing option. This review aims to present the appropriate extraction methods of PDVLNs, summarize the applications of PDVLNs in different diseases, and provide an outlook on the prospects of PDVLNs. At the same time, the authors also express their discussion on the current limitations of PDVLNs.Keywords: plant-derived vesicle-like nanoparticles, extraction methods, anti-inflammatory, immune regulation, antitumor

Xin Liu,1– 3 Gehang Ju,1– 3 Wenyu Yang,4 Lulu Chen,3,5,6 Nuo Xu,4 Qingfeng He,4 Xiao Zhu,4,&ast; Dongsheng Ouyang1– 3,5,&ast; 1Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, People’s Republic of China; 2Institute of Clinical Pharmacology, Central South University, Changsha, People’s Republic of China; 3Hunan Key Laboratory for Bioanalysis of Complex Matrix Samples, Changsha Duxact Biotech Co., Ltd, Changsha, People’s Republic of China; 4Department of Clinical Pharmacy and Pharmacy Administration, School of Pharmacy, Fudan University, Shanghai, People’s Republic of China; 5Changsha Duxact Biotech Co., Ltd, Changsha, People’s Republic of China; 6Department of Pharmacy, Affiliated Hospital of Xiangnan University, Chenzhou, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Dongsheng Ouyang, Changsha Duxact Biotech Co., Ltd, Lutian Road 28, Changsha, 410221, People’s Republic of China, Tel +86 0731-84805380, Email ouyangyj@163.com Xiao Zhu, Department of Clinical Pharmacy and Pharmacy Administration, School of Pharmacy, Fudan University, Zhangheng Road 826, Shanghai, 201203, People’s Republic of China, Tel +862151980024, Email xiaozhu@fudan.edu.cnAbstract: Escitalopram (SCIT) represents a first-line antidepressant and antianxiety medication. Pharmacokinetic studies of SCIT have demonstrated considerable interindividual variability, emphasizing the need for personalized dosing. Accordingly, we aimed to create a repository of parametric population pharmacokinetic (PPK) models of SCIT to facilitate model-informed precision dosing. In November 2022, we searched PubMed, Embase, and Web of Science for published PPK models and identified eight models. All the structural models reported in the literature were either one- or two-compartment models. In order to investigate the variances in model performance, the parameters of all PPK models were derived from the literature published. A representative virtual population, characterized by an age of 30, a body weight of 70 kg, and a BMI of 23 kg/m2, was generated for the purpose of replicating these models. To accomplish this, the rxode2 package in the R programming language was employed. Subsequently, we compared simulated concentration–time profiles and evaluated the impact of covariates on clearance. The most significant covariates were CYP2C19 phenotype, weight, and age, indicating that dosing regimens should be tailored accordingly. Additionally, among Chinese psychiatric patients, SCIT showed nearly double the exposure compared to other populations, specifically when considering the same CYP2C19 population restriction, which is a knowledge gap that needs further investigation. Furthermore, this repository of parametric PPK models for SCIT has a wide range of potential applications, like design miss or delay dose remedy strategies and external PPK model validation.Keywords: escitalopram, population pharmacokinetics, precision medicine, CYP2C19

Ying Lan,1 Nan Yang,2 Yirong Wang,1 Yan Yang,1 Min Xu,1 Qin He1 1Department of Pharmacy, Affiliated Hospital of Southwest Jiaotong University, the Third People’s Hospital of Chengdu, Chengdu, Sichuan, 610031, People’s Republic of China; 2West China School of Pharmacy, Sichuan University, Chengdu, People’s Republic of ChinaCorrespondence: Ying Lan, Email lanying0212@126.comPurpose: Tiotropium/olodaterol (TIO/OLO) fixed-dose combination (FDC) can improve lung function and quality of life for patients with chronic obstructive pulmonary disease (COPD), and is not inferior to other LAMA/LABAs. The aim of this study was to assess the cost-effectiveness of TIO/OLO FDC in patients with moderate to very severe COPD in China.Methods: A Markov model was developed to estimate the cost-effectiveness of TIO/OLO FDC versus TIO in the treatment of COPD from Chinese health system perspective. Four health states were based on 2021 Global Initiative for Chronic Obstructive Lung Disease (GOLD 2021), which included moderate (GOLD II, 50% ≤ FEV1 ≤ 80% of predicted), severe (GOLD III, 30% ≤ FEV1 ≤ 50% of predicted) and very severe (GOLD IV, FEV1 > 30% of predicted) COPD and death. The model simulated in cycles yearly. The indicators of total costs, number of COPD exacerbations, life years (LYs) and quality-adjusted life-years (QALYs) were used as the model output. Costs and outcomes were discounted at a 5% annual rate. A cost-effectiveness analysis was conducted over a 10-year time horizon. The threshold of incremental total cost per unit effectiveness gained (ICER) was 1.5 times of GDP per capita. Uncertainty was assessed by one-way and probabilistic sensitivity analysis.Results: TIO/OLO was 0.007 QALYs more than TIO but 0.012 LYs lower, which increased the total cost by &dollar;2268.17 per patient, but the total exacerbations number was less. Incremental cost effectiveness analysis had shown that the ICER exceeded the willingness to pay threshold. Results were robust under most parameter variation, except the parameters of total drug cost of TIO/OLO FDC in univariate sensitivity analyses.Conclusion: Although TIO/OLO FDC could reduce the exacerbation risk, it was not cost-effective, and needed to be repriced.Keywords: tiotropium, olodaterol, cost-effectiveness, chronic obstructive pulmonary disease, COPD, Markov

Jie Li,1,&ast; Chun-Hong Wang,2,&ast; De-Hou Yu,2 Qin He,2 Wei He1 1Department of Dermatology, GuiQian International General Hospital, Guiyang, Guizhou, 550018, People’s Republic of China; 2Department of Dermatology, The Affiliated Hospital of Guizhou University, Guiyang, Guizhou, 550001, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Qin He, Department of Dermatology, The Affiliated Hospital of Guizhou University, No. 28, Guiyi Street, Guiyang, Guizhou, 550001, People’s Republic of China, Tel +86 18585037228, Email Heqin_230215@163.com Wei He, Department of Dermatology, GuiQian International General Hospital, No. 1, Dongfeng Street, Wudang District, Guiyang, Guizhou, 550018, People’s Republic of China, Email Wei_he66@21cn.comAbstract: Leprosy is a chronic infectious disease primarily affecting the skin and peripheral nerves and is caused by Mycobacterium leprae. Although effective control measures have significantly reduced its global incidence in recent years, its insidious onset and diverse skin manifestations pose considerable challenges to early diagnosis, particularly among young medical practitioners. This study reports a case of tuberculoid leprosy accompanied by a type I reaction (T1R) to leprosy, aiming to contribute to the broader understanding and management of the disease. The patient came from a leprosy-endemic region and had a family history of leprosy. They first presented with neuritis, characterised by numbness in the left upper limb, which is an early-stage symptom often overlooked. This case accentuates the importance of comprehensive examination techniques, including bacteriological and histological investigations, ultrasound and magnetic resonance imaging, to identify early nerve damage, which is critical for prompt diagnosis and intervention. According to World Health Organization data, approximately 200,000 new cases of leprosy are reported worldwide each year, with a prevalence rate of 0.2 cases per 10,000 individuals. The disease exhibits two clinical forms based on the host’s immune response: tuberculoid leprosy in a well-immunised population and lepromatous leprosy in a poorly immunised host. The patient in this study demonstrated signs of tuberculoid leprosy, marked by isolated skin papules and plaques, and a T1R, a tissue-destructive, immune-driven inflammatory process. This case underscores the need for ongoing education and updated diagnostic tools to facilitate the early detection of leprosy, particularly in endemic areas. Moreover, attention must be given to the comprehensive care of patients, encompassing both physical and psychological aspects, to improve their quality of life and mitigate social discrimination and prejudice.Keywords: leprosy, tuberculoid leprosy, leprosy reaction

Qin Yang,1,2,&ast; Tiantian Tan,2,&ast; Qin He,2 Chenqi Guo,2 Dan Chen,2 Yulu Tan,2 Jiaxing Feng,2 Xu Song,2 Tao Gong,2 Jia Li3 1School of Pharmacy, North Sichuan Medical College, Nanchong 637100, People’s Republic of China; 2Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, People’s Republic of China; 3West China Hospital of Stomatology, Sichuan University, Chengdu 610041, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jia Li, West China Hospital of Stomatology, Sichuan University, No. 14, Block 3, Southern Renmin Road, Chengdu, 610041, People’s Republic of China, Tel +862885503503, Email lijia816@163.comIntroduction: Silybin (SLB) as an effective hepatoprotective phytomedicine has been limited by its hydrophobicity, poor bioavailability and accumulation at lesion sites. Additionally, present drug loading methods are impeded by their low drug loading capacity, potential hazard of materials and poor therapeutic effects. Consequently, there is a pressing need to devise an innovative approach for preparing nanosuspensions loaded with both SLB and Silybin Meglumine salt (SLB-M), as well as to investigate the therapeutic effects of SLB nanosuspensions against hepatic fibrosis.Methods: The SLB nanosuspension (NS-SLB) was prepared and further modified with a hyaluronic acid–cholesterol conjugate (NS-SLB-HC) to improve the CD44 targeting proficiency of NS-SLB. To validate the accumulation of CD44 and ensure minimal cytotoxicity, cellular uptake and cytotoxicity assessments were carried out for the nanosuspensions. Western blotting was employed to evaluate the anti-hepatic fibrosis efficacy in LX-2 cells by inhibiting the secretion of collagen I. Hepatic fibrosis mouse models were used to further confirm the effectiveness of NS-SLB and NS-SLB-HC against hepatic fibrosis in vivo.Results: Uniform nanosuspensions were prepared through self-assembly, achieving high drug loading rates of 89.44% and 60.67%, respectively. Both SLB nanosuspensions showed minimal cytotoxicity in cellular environments and mitigated hepatic fibrosis in vitro. NS-SLB-HC was demonstrated to target activated hepatic stellate cells by receptor-ligand interaction between HA and CD44. They can reverse hepatic fibrosis in vivo by downregulating TGF-β and inhibiting the secretion of α-SMA and collagen I.Conclusion: Designed as a medical excipient analogue, SLB-M was aimed to establish an innovative nanosuspension preparation method, characterized by high drug loading capacity and a notable impact against hepatic fibrosis.Keywords: nanosuspension, LX-2 cells, phytomedicines, surfactant, drug delivery system

Jianv Wang,1,&ast; Hongye Liao,1,&ast; Jieming Ban,2 Sen Li,2 Xia Xiong,1 Qingqing He,1 Xinyu Shi,2 Hongping Shen,2 Sijin Yang,2 Changzhen Sun,2 Li Liu1 1Department of Dermatology, the Affiliated Hospital of Southwest Medical University, Luzhou, 646000, People’s Republic of China; 2Drug Research Center of Integrated Traditional Chinese and Western Medicine, National Traditional Chinese Medicine Clinical Research Base, the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, 646000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Changzhen Sun, Drug Research Center of Integrated Traditional Chinese and Western Medicine, National Traditional Chinese Medicine Clinical Research Base, the Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, 646000, People’s Republic of China, Tel/Fax +86-136-9949-2406, Email sunchangzhen@swmu.edu.cn Li Liu, Department of Dermatology, the Affiliated Hospital of Southwest Medical University, Luzhou, 646000, People’s Republic of China, Tel/Fax +86-193-3860-9127, Email liuli@swmu.edu.cnBackground: Near-infrared cyanine dyes have high sensitivity and spatial resolution imaging capabilities, but they also have unavoidable drawbacks such as photobleaching, low water solubility, fluorescence quenching, and toxic side effects. As an effective biologic drug carrier, albumin combines with cyanine dyes to form albumin@dye nanoparticles. These nanoparticles can alleviate the aforementioned issues and are widely used in tumor imaging and photothermal therapy.Methods: Herein, a newly synthesized near-infrared dye IR-817 was combined with bovine serum albumin (BSA) to create BSA@IR-817 nanoparticles. Through the detection of fluorescence emission and absorption, the optimal concentration and ratio of BSA and IR-817 were determined. Subsequently, dynamic light scattering (DLS) measurements and scanning electron microscopy (SEM) were used for the physical characterization of the BSA@IR-817 nanoparticles. Finally, in vitro and in vivo experiments were conducted to assess the fluorescence imaging and photothermal therapeutic potential of BSA@IR-817 nanoparticles.Results: IR-817 was adsorbed onto the BSA carrier by covalent conjugation and supramolecular encapsulation, resulting in the formation of dispersed, homogeneous, and stable nanoparticles with a particle size range of 120– 220 nm. BSA@IR-817 not only improved the poor water solubility, fluorescence quenching, and toxic side effects of IR-817 but also enhanced the absorption and fluorescence emission peaks in the near-infrared region, as well as the fluorescence in the visible spectrum. In addition, BSA@IR-817 combined with laser 808 irradiation was able to convert light energy into heat energy with temperatures exceeding 50 °C. By creating a mouse model of subcutaneous melanoma, it was discovered that the tumor inhibition rate of BSA@IR-817 was greater than 99% after laser irradiation and that it achieved nearly complete tumor ablation without causing significant toxicity.Conclusion: Our research, therefore, proposes the use of safe and effective photothermal nanoparticles for the imaging, diagnosis, and treatment of melanoma, and offers a promising strategy for future biomedical applications.Keywords: albumin, cyanine dyes, near-infrared imaging, photothermal therapy, melanoma