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Shu-Tong Huang,1,2,* Jin-Chong Luo,1,3,* Guo-Hui Zhong,1,2 Li-Ping Teng,4 Cai-Yan Yang,4 Chun-Li Tang,1 Lin Jing,1 Zhong-Bo Zhou,4 Jing Liu,1,3 Neng Jiang1,2 1Department of Pharmacy, Guangxi Medical University Cancer Hospital, Nanning, Guangxi, People’s Republic of China; 2Pharmaceutical College, Guangxi Medical University, Nanning, Guangxi, People’s Republic of China; 3School of Pharmacy, Jiangxi University of Chinese Medicine, Nanchang, People’s Republic of China; 4School of Pharmacy, Youjiang Medical University for Nationalities, Baise, Guangxi, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jing Liu, School of Pharmacy, Jiangxi University of Chinese Medicine, No. 56, Yangming Road, Donghu District, Nanchang, Jiangxi, 330006, People’s Republic of China, Email liujing860828@163.com Neng Jiang, Department of Pharmacy, Guangxi Medical University Cancer Hospital, 71 Hedi Road, Qingxiu District, Nanning, Guangxi, 530021, People’s Republic of China, Tel/Fax +86-17307711726, Email cpujnh@163.comPurpose: Alzheimer’s disease (AD) is the most common neurodegenerative disease, and its multifactorial nature increases the difficulty of medical research. To explore an effective treatment for AD, a series of novel tacrine-selegiline hybrids with ChEs and MAOs inhibitory activities were designed and synthesized as multifunctional drugs.Methods: All designed compounds were evaluated in vitro for their inhibition of cholinesterases (AChE/BuChE) and monoamine oxidases (MAO-A/B) along with their blood-brain barrier permeability. Then, further biological activities of the optimizing compound 7d were determined, including molecular model analysis, in vitro cytotoxicity, acute toxicity studies in vivo, and pharmacokinetic and pharmacodynamic property studies in vivo.Results: Most synthesized compounds demonstrated potent inhibitory activity against ChEs/MAOs. Particularly, compound 7d exhibited good and well-balanced activity against ChEs (hAChE: IC50 = 1.57 μM, hBuChE: IC50 = 0.43 μM) and MAOs (hMAO-A: IC50 = 2.30 μM, hMAO-B: IC50 = 4.75 μM). Molecular modeling analysis demonstrated that 7d could interact simultaneously with both the catalytic active site (CAS) and peripheral anionic site (PAS) of AChE in a mixed-type manner and also exhibits binding affinity towards BuChE and MAO-B. Additionally, 7d displayed excellent permeability of the blood-brain barrier, and under the experimental conditions, it elicited low or no toxicity toward PC12 and BV-2 cells. Furthermore, 7d was not acutely toxic in mice at doses up to 2500 mg/kg and could improve the cognitive function of mice with scopolamine-induced memory impairment. Lastly, 7d possessed well pharmacokinetic characteristics.Conclusion: In light of these results, it is clear that 7d could potentially serve as a promising multi-functional drug for the treatment of AD. Keywords: Alzheimer’s disease, cholinesterase, monoamine oxidase, multi-target, designed

Zhu-Quan Su,1,* Wei-Jie Guan,1,* Shi-Yue Li,1,* Ming Ding,2 Yu Chen,1 Mei Jiang,1 Xiao-Bo Chen,1 Chang-Hao Zhong,1 Chun-Li Tang,1 Nan-Shan Zhong1 1State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, People’s Republic of China; 2Department of Respiratory Medicine, The Affiliated Zhongda Hospital of Southeast University, Medical School of Southeast University, Nanjing, People’s Republic of China *These authors contributed equally to this work Background: Spirometry confers limited value for identifying small-airway disorders (SADs) in early-stage COPD, which can be detected with impulse oscillometry (IOS) and endobronchial optical coherence tomography (EB-OCT). Whether IOS is useful for reflecting small-airway morphological abnormalities in COPD remains unclear. Objectives: To compare the diagnostic value of spirometry and IOS for identifying SADs in heavy-smokers and COPD based on the objective assessment with EB-OCT. Methods: We recruited 59 COPD patients (stage I, n=17; stage II, n=18; stage III–IV, n=24), 26 heavy-smokers and 21 never-smokers. Assessments of clinical characteristics, spirometry, IOS and EB-OCT were performed. Receiver operation characteristic curve was employed to demonstrate the diagnostic value of IOS and spirometric parameters. Results: More advanced staging of COPD was associated with greater abnormality of IOS and spirometric parameters. Resonant frequency (Fres) and peripheral airway resistance (R5–R20) conferred greater diagnostic values than forced expiratory volume in one second (FEV1%) and maximal (mid-)expiratory flow (MMEF%) predicted in discriminating SADs in never-smokers from heavy-smokers (area under curve [AUC]: 0.771 and 0.753 vs 0.570 and 0.558, respectively), and heavy-smokers from patients with stage I COPD (AUC: 0.726 and 0.633 vs 0.548 and 0.567, respectively). The combination of IOS (Fres and R5–R20) and spirometric parameters (FEV1% and MMEF% predicted) contributed to a further increase in the diagnostic value for identifying SADs in early-stage COPD. Small airway wall area percentage (Aw% 7–9), an EB-OCT parameter, correlated significantly with Fres and R5–R20 in COPD and heavy-smokers, whereas EB-OCT parameters correlated with FEV1% and MMEF% in advanced, rather than early-stage, COPD. Conclusions: IOS parameters correlated with the degree of morphologic abnormalities of small airways assessed with EB-OCT in COPD and heavy-smokers. Fres and R5–R20 might be sensitive parameters that reliably reflect SADs in heavy-smokers and early-stage COPD. Keywords: chronic obstructive pulmonary disease, optical coherence tomography, diagnostic value, impulse oscillometry, small airway disorder

Bile acids (BAs) play a crucial role in lipid metabolism of children. However, the association between per- and polyfluoroalkyl substance (PFAS) exposure and BAs in children is scarce. To address this need, we selected 252 children from the Maoming Birth Cohort and measured 32 PFAS, encompassing short- and long-chain perfluorocarboxylic acids (PFCAs) and perfluorosulfonic acids (PFSAs) in the cord blood. Additionally, we analyzed nine primary and eight secondary BAs in the serum of three-year-old children. Generalized linear models with FDR-adjusted and Bayesian kernel machine regression (BKMR) were used to explore the associations of individual and mixture effects of PFAS and BAs. We found negative associations between cord blood long-chain PFCAs exposure and serum primary BAs in three-year-old children. For example, one ln-unit (ng/mL) increase of perfluoro-n-tridecanoic acid (PFTrDA), perfluoro-n-undecanoic acid (PFUnDA) and perfluoro-n-decanoic acid (PFDA) were associated with decreased taurochenodeoxycholic acid, with estimated percentage change of -24.28% [95% confidence interval (CI): -36.75%, -9.35%], -25.84% (95% CI: -39.67%, -8.83%), and -22.97% (95% CI: -34.45%, -9.47%) respectively. Notably, the observed associations were more pronounced in children with lower vegetable intake. Additionally, the BKMR model also demonstrated a monotonical decline in primary BAs as the PFAS mixture increased. We provided the first evidence of the association between intrauterine exposure to PFAS and its mixture with BAs in children. Further large-sample-size studies are needed to verify this finding., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Sinonasal carcinoma, a rare and challenging malignancy, originating in the nasal cavity and paranasal sinuses, poses diagnostic and management complexities. This 8-year retrospective analysis at Sarawak General Hospital aims to elucidate demographic trends, histopathological entities, and management outcomes, shedding light on this multifaceted malignancy. Emphasizing the significance of accurate histopathological classification, the study explores the impact on prognostication and treatment strategies. Spanning 2013 to 2021, the study involved 54 patients with sinonasal malignancies. Demographic, clinical, and histopathological details were examined, adhered to the AJCC staging criteria. Analysis involved demographic distributions, tumour characteristics, treatment modalities, and instances of treatment failure. Statistical analysis was done using SPSS version 29.02. The cohort, predominantly male (57.4%) and of Iban ethnicity (44.4%), with a mean age of 52.8 years, exhibited diverse histopathologies, with squamous cell carcinoma as the most common (38.9%). Epistaxis and nasal blockage were common clinical presentations. Advanced stages (III and IV) were prevalent, with the nasal cavity as the primary site. Surgical interventions, mainly endoscopic endonasal excision, were complemented by adjuvant therapies. Complications occurred in 24% of cases. The study highlights a male predilection, occupational risk factors, and a significant association between tobacco smoking and sinonasal cancers. Surgical interventions predominantly utilized the endoscopic approach. Despite a mean survival of 46.6 months, treatment failure occurred in 29.6% of cases, with recurrence and metastasis. Histopathological analysis revealed comparable 5-year disease survival rates between squamous and non-squamous histologies. Treatment failure was significantly associated with the mode of surgery, with open surgery showing a lower incidence. However, nodal status, histopathology types, T staging, and overall staging did display positive associations with treatment failure. This 8-year review provides comprehensive insights into sinonasal carcinoma, addressing demographic, clinical, and histopathological dimensions. The study underlines the complexity of managing this challenging malignancy, emphasizing the need for a holistic approach to patient care. The findings contribute to the understanding of sinonasal carcinoma, guiding clinical decision-making and fostering further research., Competing Interests: Competing InterestsThe are no competing interest or funding from any side regarding the above article., (© Association of Otolaryngologists of India 2024. Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.)

Saliva biopsy of nasopharyngeal carcinoma (NPC) has been developed in our latest study, indicating the application of oral sampling in NPC detection. Further exploration of the potential for self-sampling from the oral cavity is necessary. A total of 907 various samples from oral cavity, including saliva ( n  = 262), oropharyngeal swabs ( n  = 250), oral swabs ( n  = 210), and mouthwash ( n  = 185), were collected. Epstein‒Barr virus (EBV) DNA methylation at the 12,420 bp CpG site in EBV genome from the repeat-copy W promoter (Wp) region and at the 11,029 bp CpG site in the single-copy C promoter (Cp) region were simultaneously detected in these samples. A significant increase in EBV methylation, no matter at Wp or Cp region, was found in all types of samples from NPC patients. However, EBV DNA methylation in saliva and oropharyngeal swab showed a better diagnostic performance in detecting NPC. The combination of these two sample types and two markers could help to improve the detection of NPC. Our study further explored the optimal self-sampling methods and detection target in the detection of NPC and may facilitate the application of EBV DNA methylation detection in a home-based large-scale screening of NPC., Competing Interests: The authors declare they have no conflicts of interest., (© 2024 The Author(s). MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.)

Background: Primary hepatic lymphoma (PHL) is a lymphoproliferative disorder confined to the liver without peripheral lymph node involvement and bone marrow invasion. PHL is extremely rare in clinical practice. The etiology and pathogenesis of PHL are largely unknown. There are no common standard protocols or guidelines for the treatment of PHL., Case Summary: We report the case of a 66-year-old man who presented with fever and abdominal pain for three weeks. Computed tomography and magnetic resonance imaging scans showed a pyogenic liver abscess. The patient underwent a right posterior hepatectomy. The surgical pathology revealed aggressive B-cell lymphoma, with a primary consideration of diffuse large B-cell lymphoma of non-germinal center origin., Conclusion: This article reviews the characteristics, mechanism and treatment of PHL and provides insight into the diagnosis of PHL., Competing Interests: Conflict-of-interest statement: The authors have no conflicts of interest to declare., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: Colorectal cancer (CRC) has a high incidence and mortality. Recent studies have shown that indole derivatives involved in gut microbiota metabolism can impact the tumorigenesis, progression, and metastasis of CRC., Aim: To investigate the effect of indole-3-acetaldehyde (IAAD) on CRC., Methods: The effect of IAAD was evaluated in a syngeneic mouse model of CRC and CRC cell lines (HCT116 and DLD-1). Cell proliferation was assessed by Ki-67 fluorescence staining and cytotoxicity tests. Cell apoptosis was analysed by flow cytometry after staining with Annexin V-fluorescein isothiocyanate and propidium iodide. Invasiveness was investigated using the transwell assay. Western blotting and real-time fluorescence quantitative polymerase chain reaction were performed to evaluate the expression of epithelial-mesenchymal transition related genes and aryl hydrocarbon receptor (AhR) downstream genes. The PharmMapper, SEA, and SWISS databases were used to screen for potential target proteins of IAAD, and the core proteins were identified through the String database., Results: IAAD reduced tumorigenesis in a syngeneic mouse model. In CRC cell lines HCT116 and DLD1, IAAD exhibited cytotoxicity starting at 24 h of treatment, while it reduced Ki67 expression in the nucleus. The results of flow cytometry showed that IAAD induced apoptosis in HCT116 cells but had no effect on DLD1 cells, which may be related to the activation of AhR. IAAD can also increase the invasiveness and epithelial-mesenchymal transition of HCT116 and DLD1 cells. At low concentrations (< 12.5 μmol/L), IAAD only exhibited cytotoxic effects without promoting cell invasion. In addition, predictions based on online databases, protein-protein interaction analysis, and molecular docking showed that IAAD can bind to matrix metalloproteinase-9 (MMP9), angiotensin converting enzyme (ACE), poly(ADP-ribose) polymerase-1 (PARP1), matrix metalloproteinase-2 (MMP2), and myeloperoxidase (MPO)., Conclusion: Indole-3-aldehyde can induce cell apoptosis and inhibit cell proliferation to prevent the occurrence of CRC; however, at high concentrations (≥ 25 μmol/L), it can also promote epithelial-mesenchymal transition and invasion in CRC cells. IAAD activates AhR and directly binds MMP9, ACE, PARP1, MMP2, and MPO, which partly reveals why it has a bidirectional effect., Competing Interests: Conflict-of-interest statement: The authors declare that they have no conflict of interest to disclose., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Thallium chemistry is experiencing unprecedented importance. Therefore, it is valuable to characterize some of the simplest thallium compounds. Stationary points along the singlet and triplet Tl   2 H   2 potential energy surface have been characterized. Stationary point geometries were optimized with the CCSD(T)/aug-cc-pwCVQZ-PP method. Harmonic vibrational frequencies were computed at the same level of theory while anharmonic vibrational frequencies were computed at the CCSD(T)/aug-cc-pwCVTZ-PP level of theory. Final energetics were obtained with the CCSDT(Q) method. Basis sets up to augmented quintuple-zeta cardinality (aug-cc-pwCV5Z-PP) were employed to obtain energetics in order to extrapolate to the complete basis set limits using the focal point approach. Zero-point vibrational energy corrections were appended to the extrapolated energies in order to determine relative energies at 0 K. It was found that the planar dibridged isomer lies lowest in energy while the linear structure lies highest in energy. The results were compared to other group 13 M   2 H   2 (M = B, Al, Ga, In, and Tl) theoretical studies and some interesting variations are found. With respect to experiment, incompatibilities exist., (© 2024 Wiley Periodicals LLC.)

Objectives: To analyze the effects of electroacupuncture (EA) at "Fenglong" (ST40) and "Zusanli" (ST36) of different intensities and durations on rats with non-alcoholic fatty liver disease (NAFLD) based on the protein kinase R-like endoplasmic reticulum kinase (PERK)-activating transcription factor 4 (ATF4)-C/EBP homologous protein (CHOP) signaling pathway, so as to explore its mechanism underlying improvement of NAFLD., Methods: SD rats were randomly divided into normal diet group, high-fat model group, sham EA group, strong stimulation EA (SEA) group, and weak stimulation EA (WEA) group, with 15 rats in each group. Each group was further divided into 2, 3, and 4-week subgroups. NAFLD rat model was established by feeding a high-fat diet. After successful modeling, rats in the SEA and WEA groups received EA at bilateral ST40 and ST36 with dense and sparse waves (4 Hz/20 Hz) at current intensities of 4 mA (SEA group) and 2 mA (WEA group), lasting for 20 minutes, once a day, 5 days a week with 2 days of rest. The sham EA group only had the EA apparatus connected without electricity. Different duration subgroups were intervened for 2, 3, and 4 weeks. After the intervention, the contents of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in rats were detected by an automatic biochemical analyzer；liver morphological changes were observed by Oil Red O staining；real-time fluorescence quantitative PCR and Western blot were used to detect the expression of PERK, ATF4, and CHOP mRNAs and proteins in the rat liver tissue., Results: In the high-fat model group, there was a significant accumulation of red lipid droplets in the liver cells, which was reduced significantly in the SEA group at the 4 th week. Compared with the normal diet group with the same treatment duration, the contents of serum ALT, AST, and the expression of PERK, ATF4, and CHOP mRNAs and proteins in the liver tissue were elevated ( P <0.01) in the high-fat model group . Compared with the high-fat model group with the same treatment duration, the contents of serum ALT, AST, and the expression of PERK, ATF4, CHOP mRNAs and proteins in the liver tissue were decreased ( P <0.01, P <0.05) in the SEA and WEA groups. Compared with the sham EA group with the same treatment duration, the contents of serum ALT, AST, and the expression of PERK, ATF4, and CHOP mRNAs were decreased ( P <0.01, P <0.05) in the SEA and WEA groups, the expression of PERK, ATF4, and CHOP proteins in the liver tissue was decreased ( P <0.01) in the SEA group at the 2 nd , 3 rd , and 4 th week, the expression of PERK and CHOP proteins at the 2 nd , 3 rd , 4 th week and ATF4 protein at 2 nd week in the liver tissue were decreased ( P <0.01, P <0.05) in the WEA group. Compared with the SEA group with the same treatment duration, the contents of serum ALT, AST, and the expression of PERK, ATF4, and CHOP mRNAs and proteins in the liver tissue were elevated ( P <0.05, P <0.01) in the WEA group. Compared with the 2-week time point within the groups, the contents of serum ALT, AST, and the expression of PERK, ATF4, and CHOP mRNAs and PERK proteins in the liver tissue were decreased ( P <0.01, P <0.05) in the SEA and WEA groups at 3 rd and 4 th week, the expression of ATF4 proteins in the liver tissue was decreased ( P <0.01) in the SEA group at 3 rd and 4 th week, and the expression of CHOP proteins in the liver tissue was decreased ( P <0.01) in the SEA group at 4 th week and in the WEA group at 3 rd and 4 th week. Compared with the 3-week time point within the groups, the contents of serum ALT, AST, and the expression of PERK, ATF4, and CHOP mRNAs were significantly decreased ( P <0.05, P <0.01) in the SEA and WEA groups at 4 th week, the expression of PERK and CHOP proteins in the liver tissue was decreased ( P <0.01) in the SEA and WEA groups at 4 th week, and the expression of ATF4 protein in the liver tissue was decreased ( P <0.05) in the SEA group at 4 th week., Conclusions: EA at ST40 and ST36 can significantly improve liver function in NAFLD rats, and its mechanism of action may involve inhibiting PERK expression thereby targeting the downstream ATF4/CHOP signaling pathway to suppress endoplasmic reticulum stress, exerting a liver protective effect；the optimal effect was observed with EA intensity of 4 mA for 4 weeks.

Background: Colorectal cancer (CRC) is the third highest incidence cancer and is the leading cause of cancer mortality worldwide. Metastasis to distal organ is the major cause of cancer mortality. However, the underlying genetic factors are unclear. This study aimed to identify metastasis-relevant genes and pathways for better management of metastasis-prone patients., Methods: A case-case genome-wide association study comprising 2677 sporadic Chinese CRC cases (1282 metastasis-positive vs 1395 metastasis-negative) was performed using the Human SNP6 microarray platform and analysed with the correlation/trend test based on the additive model. SNP variants with association testing -log10 p value ≥5 were imported into Functional Mapping and Annotation (FUMA) for functional annotation., Results: Glycolysis was uncovered as the top hallmark gene set. Transcripts from two of the five genes profiled, hematopoietic substrate 1 associated protein X 1 ( HAX1 ) and hyaluronan-mediatedmotility receptor ( HMMR ), were significantly upregulated in the metastasis-positive tumours. In contrast to disease-risk variants, HAX1 appeared to act synergistically with HMMR in significantly impacting metastasis-free survival. Examining the subtype datasets with FUMA and Ingenuity Pathway Analysis (IPA) identified distinct pathways demonstrating sexual dimorphism in CRC metastasis., Conclusions: Combining genome-wide association testing with in silico functional annotation and wet-bench validation identified metastasis-relevant genes that could serve as features to develop subtype-specific metastasis-risk signatures for tailored management of patients with stage I-III CRC., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

The study of immune regulation mechanisms induced by parasites may help develop new treatment methods for inflammatory diseases including type 1 diabetes, which is related to type 1 immune responses. The negative correlation between schistosomiasis infection and type 1 diabetes has been confirmed, and the mechanism of Schistosoma-mediated prevention of type 1 diabetes may be related to the adaptive and innate immune systems. Schistosoma-related molecules affect immune cell composition and macrophage polarization and stimulate an increase in natural killer T cells. Furthermore, Schistosoma-related molecules can regulate the adaptive immune responses related to the prevention of type 1 diabetes and change the Th1/Th2 and Th17/Treg axis. Our previous review showed the role of regulatory T cells in the protective of type 1 diabetes mediated by Schistosoma. Here, we aim to review the other mechanisms of schistosomiasis infection and Schistosoma-related products in regulating the immune response associated with the treatment of type 1 diabetes., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023. Published by Elsevier B.V.)

Background: Due to the prolonged life expectancy and increased risk of colorectal cancer (CRC) among patients with human immunodeficiency virus (HIV) infection, the prognosis and pathological features of CRC in HIV-positive patients require examination., Aim: To compare the differences in oncological features, surgical safety, and prognosis between patients with and without HIV infection who have CRC at the same tumor stage and site., Methods: In this retrospective study, we collected data from HIV-positive and -negative patients who underwent radical resection for CRC. Using random stratified sampling, 24 HIV-positive and 363 HIV-negative patients with colorectal adenocarcinoma after radical resection were selected. Using propensity score matching, we selected 72 patients, matched 1:2 (HIV-positive:negative = 24:48). Differences in basic characteristics, HIV acquisition, perioperative serological indicators, surgical safety, oncological features, and long-term prognosis were compared between the two groups., Results: Fewer patients with HIV infection underwent chemotherapy compared to patients without. HIV-positive patients had fewer preoperative and postoperative leukocytes, fewer preoperative lymphocytes, lower carcinoembryonic antigen levels, more intraoperative blood loss, more metastatic lymph nodes, higher node stage, higher tumor node metastasis stage, shorter overall survival, and shorter progression-free survival compared to patients who were HIV-negative., Conclusion: Compared with CRC patients who are HIV-negative, patients with HIV infection have more metastatic lymph nodes and worse long-term survival after surgery. Standard treatment options for HIV-positive patients with CRC should be explored., Competing Interests: Conflict-of-interest statement: All the authors have no conflict of interest related to the manuscript., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Background: As an oncovirus, EBV is associated with multiple cancers, including solid tumors and hematological malignancies. EBV methylation plays an important role in regulating tumor occurrence. However, the EBV methylation profiles in EBV-associated tumor tissues are poorly understood., Results: In this study, EBV methylation capture sequencing was conducted in several different tumor tissue samples, including NPC, EBVaGC, lung LELC and parotid LELC. Besides, EBV capture sequencing and following qMSP were performed on nasopharyngeal brushing samples from NPC and nasal NKTCL patients. Our results showed that the EBV genome among different types of tumors displayed specific methylation patterns. Among the four types of tumors from epithelial origin (NPC, EBVaGC, lung LELC and parotid LELC), the most significant differences were found between EBVaGC and the others. For example, in EBVaGC, all CpG sites within 1,44,189-1,45,136 bp of the EBV genome sequence on gene RPMS1 were hyper-methylated compared to the others. Differently, significant differences of EBV CpG sites, particularly those located on gene BILF2, were observed between NPC and nasal NKTCL patients in nasopharyngeal brushing samples. Further, the methylated level of BILF2 was further detected using qMSP, and a diagnostic model distinguishing NPC and nasal NKTCL was established. The AUC of the model was 0.9801 (95% CI 0.9524-1.0000), with the sensitivity and specificity of 98.81% (95% CI 93.63-99.94%) and 76.92% (95% CI 49.74-91.82%), respectively., Conclusions: Our study reveals more clues for further understanding the pathogenesis of EBV, and provides a possibility for distinguishing EBV-related tumor by detecting specific EBV CpG sites., (© 2024. The Author(s).)

Type 1 diabetes mellitus is a chronic disease caused by the destruction of pancreatic beta cells. Based on the hygiene hypothesis, a growing body of evidence suggests a negative association between parasitic infections and diabetes in humans and animal models. The mechanism of parasite-mediated prevention of type 1 diabetes mellitus may be related to the adaptive and innate immune systems. Macrophage polarization is a new paradigm for the treatment of type 1 diabetes mellitus, and different host macrophage subsets play various roles during parasite infection. Proinflammatory cytokines are released by M1 macrophages, which are important in the development of type 1 diabetes mellitus. Parasite-activated M2 macrophages prevent the development of type 1 diabetes mellitus and can influence the development of adaptive immune responses through several mechanisms, including Th2 cells and regulatory T cells. Here, we review the role and mechanism of macrophage polarization in parasitic protection against type 1 diabetes mellitus., Competing Interests: Declaration of competing interest No., (Copyright © 2023. Published by Elsevier Inc.)

Sevoflurane has been widely used in clinical anesthesia as an inhalation anesthetic. With the development of medicine, there have been several new applications in recent years, such as daytime surgery, labor analgesia, and combined nerve block for some surgeries. Moreover, as research progresses, it has been found that it not only has potential organ protection effects but can also be used to treat severe asthma and relieve the tracheal spasm state. In addition, local administration can effectively treat vascular ulcers. We briefly review the organ protective effect of sevoflurane, its application in dental treatment, asthma treatment, vascular ulcer treatment and some new progress in clinical application., (Copyright © 2024 Copyright: © 2024 Medical Gas Research.)

Background: Endobronchial ultrasonography-guided transbronchial needle aspiration biopsy (EBUS-TBNA) has been used for more than 10 years in China. Its clinical application and diagnostic value in different diseases with large sample was lack of report., Methods: A retrospective analysis was performed about the application and diagnostic value of EBUS-TBNA in different disease of patients in Respiratory Intervention Center of Guangzhou Institute of Respiratory Health from January 2012 to July 2020., Results: A total 5758 patients were included with 182 patients excluded for lack of information. Finally, data of 5576 patients (3798 males and 1778 females) were analyzed. For anesthetize, most patients were undergoing general anesthesia of intravenous with spontaneous breathing (69.4%), followed by general anesthesia of intravenous and inhalation with tracheal intubation and mechanical ventilation (17.9%) and conscious sedation and analgesia (12.8%). Lymph nodes were the main sites of biopsy obtained (76.4%). Tumors accounted for the highest proportion of disease (66.4%), followed by infection diseases (9.9%), sarcoidosis (3.9%), lymphoma (1.1%), and others (18.7%). The sensitivity of EBUS-TBNA for diagnosis of tumor was 89.7%, and 40.8% for infection diseases. There were significant differences in the puncture site and proportions of diseases between male and females (both p < 0.05). Higher diagnostic value was found in male patients (p < 0.05)., Conclusion: EBUS-TBNA has good diagnostic value for different mediastinal and central pulmonary space-occupying lesions diseases, with highest sensitivity for tumors. Higher diagnostic value was found in male patients., (© 2023. BioMed Central Ltd., part of Springer Nature.)

As one of the famous karst springs in Shanxi Province, the Gudui spring is the only medium-low temperature hot spring, with a long history of development and a rich cultural accumulation. The karst groundwater in the Gudui spring catchment was taken as the research object. Through systematic sample collection and isotope analysis, hydrochemistry (Durov map, ion ratio, Gibbs map, and hydrogen and oxygen isotope) methods were comprehensively used to analyze groundwater hydrochemistry and groundwater system runoff characteristics. The 87 Sr/ 86 Sr value of karst groundwater in the Gudui spring catchment was 0.709 to 0.717, and the Mg/(Mg+Ca) value was 0.27 to 0.74. By analyzing the Sr isotope composition and Mg/(Mg+Ca) and 1/Sr variation characteristics, it was concluded that the karst groundwater in the Gudui spring catchment was a mixture of deep hot water and shallow cold water. The karst water subsystem of Nanliang spring presented the characteristics of carbonate stratum runoff. The karst water subsystem of Fuling Mountain Gaoxian Haitou spring and the deep circulation subsystem of Houma Basin exhibited the runoff characteristics of carbonate rock and igneous rock strata. The karst water subsystem of Taiershan Jiuyuanshan Gudui spring presented the runoff characteristics of carbonate rock and ancient silicoaluminate strata. The δ 18 O value in karst groundwater of Guodui spring area ranged from -11.46‰ to -7.81‰, and the average value was -10.08‰. The range of the δ D value was -83.7‰ to -60.8‰, and the average value was -73.6‰. This showed that karst groundwater in the spring area was the result of mixing of various types of water. Through comparative analysis of hydrogen and oxygen isotopes of 2014 and 2021 sampling points at the same location, it was concluded that the change in water samples at the Guduiquan resulted from the gradual accumulation of water supplied by Sanquan Reservoir. The change in Sanquan Reservoir was due to the influence of Yellow River diversion. The karst groundwater in the spring area were characterized by large calcium ion, magnesium ion, and sodium ion values; a small potassium ion value; a large sulfate value; and a small chloride value. The hydrochemical types of karst groundwater in Gudui spring catchment could be divided into SO 4 -Na, SO 4 -Ca, HCO 3 -Na, HCO 3 -Ca, and Cl-Na. The hydrochemical types of karst groundwater showed evident hydrochemical composition zoning from HCO 3 -Ca, and Cl-Na. The hydrochemical types of karst groundwater showed evident hydrochemical composition zoning from HCO 3 -Ca·Mg→HCO 3 ·SO 4 -Ca·Mg→SO 4 ·HCO 3 ·Cl-Na·Ca. According to the comprehensive analysis of hydrochemical isotope and hydrogeological conditions, the karst water subsystem of Nanliang spring was primarily recharged by rainfall infiltration in the exposed limestone area and river infiltration, and its karst groundwater was recharged by runoff from south to north to the karst water subsystem of Fuling Mountain Gaoxian Haitou spring and the deep circulation subsystem of Houma Basin. The karst water subsystem of Taier Jiuyuan Mountain Gudui spring received rainfall infiltration supplement and upstream runoff supplement from the exposed limestone area. Its karst groundwater flowed from north to south and received the supply of Sanquan Reservoir from Yellow River water in the natural discharge area of Gudui spring.4 ·Cl-Na·Ca. According to the comprehensive analysis of hydrochemical isotope and hydrogeological conditions, the karst water subsystem of Nanliang spring was primarily recharged by rainfall infiltration in the exposed limestone area and river infiltration, and its karst groundwater was recharged by runoff from south to north to the karst water subsystem of Fuling Mountain Gaoxian Haitou spring and the deep circulation subsystem of Houma Basin. The karst water subsystem of Taier Jiuyuan Mountain Gudui spring received rainfall infiltration supplement and upstream runoff supplement from the exposed limestone area. Its karst groundwater flowed from north to south and received the supply of Sanquan Reservoir from Yellow River water in the natural discharge area of Gudui spring.

Saliva sampling is a non-invasive method, and could be performed by donors themselves. However, there are few studies reporting biomarkers in saliva in the diagnosis of NPC. A total of 987 salivary samples were used in this study. First, EBV DNA methylation was profiled by capture sequencing in the discovery cohort (n = 36). Second, a q-PCR based method was developed and five representative EBV DNA CpG sites (11 029 bp, 45 849 bp, 57 945 bp, 66 226 bp and 128 102 bp) were selected and quantified to obtain the methylated density in the validation cohort1 (n = 801). Third, a validation cohort2 (n = 108) was used to further verify the differences of EBV methylation in saliva. A significant increase of EBV methylation was found in NPC patients compared with controls. The methylated score of EBV genome obtained by capture sequencing could distinguish NPC from controls (sensitivity 90%, specificity 100%). Further, the methylated density of EBV DNA CpG sites revealed by q-PCR showed a good diagnostic performance. The sensitivity and specificity of detecting a single CpG site (11 029 bp) could reach 75.4% and 99.7% in the validation cohort1, and 78.2% and 100% in the validation cohort2. Besides, the methylated density of the CpG site was found to decrease below the COV in NPC patients after therapy, and increase above the COV after recurrence. Our study provides an appealing alternative for the non-invasive detection of NPC without clinical setting. It paves the way for conducting a home-based large-scale screening in the future., (© 2023 UICC.)

Objective: To observe the effect of electroacupuncture(EA) on neural function and spinal cord pathological morphology in spinal cord injury(SCI) mice and investigate the anti-inflammatory molecular mechanism of EA on SCI mice from the aspects of gene by using bioinformatics., Methods: Seventy-two female C57BL/6 mice were randomized into sham operation, model and EA groups, with 24 mice in each group. The SCI model was established by clamping the spinal cord with a serrefine after laminectomy at the 1 st lumbar vertebra(L1). EA(1.5 Hz/7.5 Hz, 1.0 mA) was applied to bilateral "Jiaji"(EX-B2) and "Zusanli"(ST36) for 10 min, once a day for 14 consecutive days. Basso Mouse Scale(BMS) score was used to assess the hindlimb locomotor function of mice. Histopathological changes of the injured area of the spinal cord were determined by HE staining. The spinal cord RNA was sequenced by using RNA-Seq technology. The bioinformatic analysis was then performed to detect the diffe-rential genes between groups, and the function classification and the involved pathways were enriched. The mRNA and protein expressions of differential genes were detected and verified by using qRT-PCR and Western blot., Results: Compared with the sham operation group, BMS score of the model group was significantly decreased( P <0.05), while that of EA group was increased relevant to the model group ( P <0.05). HE staining showed loose and disordered structure and arrangement, cavitation, more inflammatory infiltration, nucleus pycnosis, and neuronal necrosis in the model group, which was alleviated in the EA group. Compared with the sham operation group, 565 differential genes were detected in the model group, including 545 up-regulated and 20 down-regulated, while 41 were detected between the EA and the model group, including 2 up-regulated and 39 down-regulated in the EA group. Fifteen genes that were all up-regulated after modeling and down-regulated after EA intervention were detected by using Venn plot, which are Retn, Adipoq, Myh1, Actn2, Pck1, Klhl41, Fabp4, Hspb7, Myot, Ankrd2, Hrc, Cox6a2, Obscn, Col2a1, Mybpc1, and 3 inflammation-related genes(Fabp4, Adipoq and Pck1) were finally acquired. The 15 differential genes were annotated into main biological processes, cell composition and molecular function in the GO function classification analysis. The 15 differential genes were then enriched into different KEGG pathways, including the peroxisome proliferatorsactivated receptor (PPAR) signaling pathway, Adipocytokine signaling pathway. The mRNA and protein expressions of Fabp4, Adipoq and Pck1 in spinal cord detected by qRT-PCR and Western blot were significantly increased in the model group ( P <0.001, P <0.01), while these were significantly decreased in the EA group relevant to the model group( P <0.001, P <0.01, P <0.05)., Conclusion: EA can promote the repair of nerve function and improve inflammatory infiltration in SCI mice. The mechanism may be closely related to the down-regulation of inflammatory factors Fabp4, Adipoq and Pck1 expression, and the regulation of PPAR and Adipocytokine signaling pathways.

Au decorated with type I collagen (Col) was used as a core material to cross-link with stromal cell-derived factor 1α (SDF1α) in order to investigate biological performance. The Au-based nanoparticles were subjected to physicochemical determination using scanning electron microscopy (SEM), dynamic light scattering (DLS) and ultraviolet-visible (UV-Vis) and Fourier-transform infrared spectroscopy (FTIR). Mesenchymal stem cells (MSCs) were used to evaluate the biocompatibility of this nanoparticle using the MTT assay and measuring reactive oxygen species (ROS) production. Also, the biological effects of the SDF-1α-conjugated nanoparticles (Au-Col-SDF1α) were assessed and the mechanisms were explored. Furthermore, we investigated the cell differentiation-inducing potential of these conjugated nanoparticles on MSCs toward endothelial cells, neurons, osteoblasts and adipocytes. We then ultimately explored the process of cell entry and transportation of the nanoparticles. Using a mouse animal model and retro-orbital sinus injection, we traced in vivo biodistribution to determine the biosafety of the Au-Col-SDF1α nanoparticles. In summary, our results indicate that Au-Col is a promising drug delivery system; it can be used to carry SDF1α to improve MSC therapeutic efficiency.

Background: Dendritic Cell Cytokine-induced killer cell (DC-CIK) coculture treatment in cancer immunotherapy has been shown to be effective. However, the cost of DC- CIK therapy is prohibitive for many patients, and the lack of standard manufacturing processes and treatment strategies are major limitations. Our study used tumor lysate as a tumor-associated antigen source and DCs and CIK cells in coculture. We developed an efficient method to obtain autologous DCs- and CIK cells from peripheral blood. We used flow cytometry to assess DC activation and the cytometric bead array assay to quantify cytokines secreted by CIK cells., Results: We evaluated the antitumor activity of DC- CIK coculture in vitro with the K562 cell line. We demonstrated that a manufacturing process employing frozen immature DCs can yield the lowest loss with the highest economic benefits. DC-CIK coculture can effectively upgrade CIK cells' immunological specificity to tumors in the presence of tumor-associated antigens., Conclusion: In vitro experiments revealed that when the DC- CIK cell ratio was 1: 20 in the coculture, CIK cells secreted the highest number of cytokines on the 14th day and the antitumor immune effect showed the highest potency. CIK cells' cytotoxicity to K562 cells was highest when the CIK: K562 cell ratio was 25: 1. We developed an efficient manufacturing process for DC- CIK coculture, while also establishing the optimal DC- CIK cell ratio for immunological activity and the best cytotoxic CIK: K562 cell ratio., (© 2023. The Author(s).)

Detecting EBV DNA load in nasopharyngeal (NP) brushing samples for the diagnosis of nasopharyngeal carcinoma (NPC) has attracted widespread attentions. Currently, NP brush sampling mostly relies on endoscopic guidance, and there are few reports on diagnostic markers suitable for nonguided conditions (blind brush sampling), which is of great significance for extending its application. One hundred seventy nasopharyngeal brushing samples were taken from 98 NPC patients and 72 non-NPC controls under the guidance of endoscope, and 305 blind brushing samples were taken without endoscopic guidance from 164 NPC patients and 141 non-NPC controls (divided into discovery and validation sets). Among these, 38 cases of NPC underwent both endoscopy-guided NP brushing and blind brushing. EBV DNA load targeting BamHI-W region and EBV DNA methylation targeting 11029 bp CpG site located at Cp-promoter region were detected by quantitative polymerase chain reaction (q-PCR). EBV DNA load showed good classification accuracy for NPC in endoscopy-guided brushing samples (AUC = 0.984). However, in blind bushing samples, the diagnostic performance was greatly reduced (AUC = 0.865). Unlike EBV DNA load, the accuracy of EBV DNA methylation was less affected by brush sampling methods, whether in endoscopy-guided brushing (AUC = 0.923) or blind brushing (AUC = 0.928 in discovery set and AUC = 0.902 in validation set). Importantly, EBV DNA methylation achieved a better diagnostic accuracy than EBV DNA load in blind brushing samples. Overall, detection of EBV DNA methylation with blind brush sampling shows great potential in the diagnosis of NPC and may facilitate its use in nonclinical screening of NPC., (© 2023 UICC.)

Airway stents are commonly used to treat patients with central airway obstruction, but several complications have been identified, including mucus plugging, granulation tissue, stent migration, and infection. Stent associated respiratory tract infection (SARTI) has often been neglected by the practicing clinicians. Therefore, we reviewed the available current literatures on the diagnosis and management of stent associated respiratory tract infection.

Background: Motile ciliary disorder (MCD) has been implicated in chronic inflammatory airway diseases such as asthma and COPD., Research Question: What are the characteristics of MCD of the nasal epithelium and its association with disease severity and inflammatory endotypes in adults with bronchiectasis?, Study Design and Methods: In this observational study, we recruited 167 patients with bronchiectasis and 39 healthy control participants who underwent brushing of the nasal epithelium. A subgroup of patients underwent bronchoscopy for bronchial epithelium sampling (n = 13), elective surgery for bronchial epithelium biopsy (n = 18), and blood sampling for next-generation sequencing (n = 37). We characterized systemic and airway inflammatory endotypes in bronchiectasis. We conducted immunofluorescence assays to profile ultrastructural (dynein axonemal heavy chain 5 [DNAH5], dynein intermediate chain 1 [DNAI1], radial spoke head protein 9 [RSPH9]) and ciliogenesis marker expression (Ezrin)., Results: MCD was present in 89.8% of patients with bronchiectasis, 67.6% showed secondary MCD, and 16.2% showed primary plus secondary MCD. Compared with healthy control participants, patients with bronchiectasis yielded abnormal staining patterns of DNAH5, DNAI1, and RSPH9 (but not Ezrin) that were more prominent in moderate to severe bronchiectasis. MCD pattern scores largely were consistent between upper and lower airways and between large-to-medium and small airways in bronchiectasis. Coexisting nasal diseases and asthma did not confound nasal ciliary ultrastructural marker expression significantly. The propensity of MCD was unaffected by the airway or systemic inflammatory endotypes. MCD, particularly an ultrastructural abnormality, was notable in patients with mild bronchiectasis who showed blood or sputum eosinophilia., Interpretation: Nasal ciliary markers profiling provides complimentary information to clinical endotyping of bronchiectasis., (Copyright © 2022 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

In the present study, the various concentrations of AuNP (1.25, 2.5, 5, 10 ppm) were prepared to investigate the biocompatibility, biological performances and cell uptake efficiency via Wharton's jelly mesenchymal stem cells and rat model. The pure AuNP, AuNP combined with Col (AuNP-Col) and FITC conjugated AuNP-Col (AuNP-Col-FITC) were characterized by Ultraviolet-visible spectroscopy (UV-Vis), Fourier-transform infrared spectroscopy (FTIR) and Dynamic Light Scattering (DLS) assays. For in vitro examinations, we explored whether the Wharton's jelly MSCs had better viability, higher CXCR4 expression, greater migration distance and lower apoptotic-related proteins expression with AuNP 1.25 and 2.5 ppm treatments. Furthermore, we considered whether the treatments of 1.25 and 2.5 ppm AuNP could induce the CXCR4 knocked down Wharton's jelly MSCs to express CXCR4 and reduce the expression level of apoptotic proteins. We also treated the Wharton's jelly MSCs with AuNP-Col to investigate the intracellular uptake mechanisms. The evidence demonstrated the cells uptake AuNP-Col through clathrin-mediated endocytosis and the vacuolar-type H + -ATPase pathway with good stability inside the cells to avoid lysosomal degradation as well as better uptake efficiency. Additionally, the results from in vivo examinations elucidated the 2.5 ppm of AuNP attenuated foreign body responses and had better retention efficacy with tissue integrity in animal model. In conclusion, the evidence demonstrates that AuNP shows promise as a biosafe nanodrug delivery system for development of regenerative medicine coupled with Wharton's jelly MSCs.

The effect of spinal anatomical anomalies on the efficacy of percutaneous endoscopic lumbar discectomy (PELD) for disc herniation repair is unclear. This retrospective review aims to assess the safety and effectiveness of PELD for treating L5-S1 disc herniation with a range of characteristics and to determine the prevalence of lumbosacral transitional vertebrae (LSTV) anatomical anomalies to facilitate pre-surgical planning. From July 2005 to June 2019, 345 patients with L5-S1 disc herniations were treated with PELD. The primary outcome was 1-year postoperative visual analogue scale scores for low back and lower limb pain. The secondary outcomes included the surgical approach used, lumbosacral bony anomalies, presence of a ruptured disc or severely calcified disc, pediatric lumbar disc herniation, recurrent disc herniation management, and the long-term outcome. visual analogue scale scores for most patients were significantly improved after surgery. The prevalence of LSTVs was 4.05% (14/345 patients) in lumbar sacralization and 7.53% (26/345 patients) in sacral lumbarization. The prevalence of ruptured and severely calcified discs was 18.55% (64/345) and 5.79% (20/345), respectively. The prevalence of pediatric lumbar disc herniation was 2.02% (7/345). The recurrence rate was 4.34% (15/345). Two durotomy cases without sequelae and 8 cases of lower limb dysesthesia lasting longer than 3 months postoperatively were reported. PELD is safe and effective for treating L5-S1 disc herniation, including cases complicated by calcified lumbar disc herniation, disc rupture with migration, and the presence of LSTV. Appropriate imaging is essential to identify case-specific factors, including the prevalent LSTV anatomical anomalies, before surgery., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objective: To investigate the bronchoscopy resource allocation and technology application in county-level hospitals in China. Methods: A cross-sectional survey was conducted. In 2021, 12 provinces were sampled from all provinces in China according to the regional Gross Domestic Product (GDP) and the number of counties, in which a total of 291 county-level hospitals were randomly enrolled. Two county-level hospitals which carried out bronchoscopy technology in each province were randomly sampled to investigate the status of bronchoscopy resources, technical application, decontamination and anesthesia by using questionnaires. Independent sample t test or two related sample nonparametric test were used for comparison between groups. Spearman correlation analysis was used to explore the correlation. Bilateral P <0.05 was considered statistically significant. Results: According to the sampling results, it was estimated that in the county-level hospitals, the proportion of those performing bronchoscopy was 11.4% (9.9%, 13.8%), which was significantly correlated with the population in the province ( r =0.64, P =0.025) and the regional GDP ( r =0.65, P =0.025).The 24 county-level hospitals interviewed were equipped with (1.6±1.0) bronchoscopes on average, and the number of hospitals with electronic bronchoscopes and fiberoptic bronchoscopes was 22 (91.7%) and 6 (25.0%), respectively. Six (25.0%) hospitals performed bronchoscopy every working day. Twelve (50.0%) hospitals had relatively permanent physicians and nurses. All operating doctors had received special training. There was a significant increase in the number of bronchoscopy cases per hospital in 2020 compared to 2019 [140(70, 335) vs. 100(29, 254), P =0.001]. All hospitals used standard cleaning and sterilization workbenches, cleaning agents and disinfectants. Surface anesthesia was available in 24 hospitals, and bronchoscopy techniques under sedation and analgesia were performed in 10 (41.7%) hospitals. Atropine was still used to prevent airway secretions in 2 (8.3%) hospitals,although not recommended by guidelines. Conclusions: There was a large gap between the current status of bronchoscopy technology in county-level hospitals and the standards of the National Health Commission, together with regional disparities. Bronchoscopist training in the standardization and the decontamination work met the requirements. In some hospitals, the use of complementary medicines was not standardized or the sedatives were not given routinely according to the guidelines. We should promote the popularization and standardization of bronchoscopy technology, and strengthen the allocation of related resources in China's county hospitals.

Background: A few studies have reported the medium-sized and small airway morphological abnormalities of bronchiolitis. Whether spirometry or impulse oscillometry (IOS) is correlated with airway remodeling of bronchiolitis remains unclear., Objectives: Aiming to demonstrate the airway morphological abnormalities of bronchiolitis obliterans (BO) and diffuse panbronchiolitis (DPB) assessed by endobronchial optical coherence tomography (EB-OCT), and elucidate whether spirometric and IOS parameters have correlation with the airway remodeling of bronchiolitis., Methods: We recruited 18 patients with bronchiolitis (BO, n  = 9; DPB, n  = 9) and 17 control subjects. Assessments of clinical features, St. George's respiratory questionnaire (SGRQ), chest computed tomography (CT), spirometry, IOS, and EB-OCT were performed in all enrolled subjects. The correlation between EB-OCT and lung function parameters was studied and analyzed., Results: The magnitude of abnormalities of spirometric and IOS parameters was significantly greater in patients with bronchiolitis than that in control subjects ( p  < 0.05). Patients with BO had notably lower forced expiratory volume in 1 s (FEV 1 ), forced vital capacity (FVC), FEV 1 /FVC, maximal mid-expiratory flow (MMEF)% pred and higher resonant frequency (Fres), and area of reactance (AX) than those with DPB ( p  < 0.05). The EB-OCT measurement among patients with bronchiolitis and between the bronchus in the left and the right lung demonstrated a heterogeneous distribution of airway calibers, presenting a high intra- and inter-individual variability. Patients with bronchiolitis had notably greater airway wall area ( p  < 0.05) compared with control, while BO presented greater magnitude of airway abnormalities than DPB. Fres and the difference in airway resistance at 5 and 20 Hz (R 5 -R 20 ) correlated negatively with medium-sized and small airway inner area, and correlated positively with airway wall area ( p  < 0.05), whose correlation coefficients were higher than those of spirometric parameters., Conclusion: Bronchiolitis, BO and DPB, manifested a heterogeneous distribution of airway calibers with significant intra- and inter-individual variability. IOS parameters, rather than spirometry, correlated better with medium-sized and small airway remodeling in bronchiolitis assessed by EB-OCT measurement.

Background: The long-term efficacy of the Dumon stent in the treatment of benign airway stenosis is unclear., Objective: The objective of this study was to evaluate the long-term efficacy and safety of the Dumon stent in patients with benign airway stenosis., Methods: We retrospectively reviewed patients with benign airway stenosis who were treated with a Dumon stent at the First Affiliated Hospital of Guangzhou Medical University between March 2014 and October 2021. We included patients with successful removal of silicone stents after implantation. The clinical data and information on bronchoscopic interventional procedures and related complications were collected and analyzed., Results: Ninety-nine patients with benign airway stenosis were included. The stent was placed mainly in the trachea (44.4%) and left main bronchus (43.4%). The main type of stenosis was post-tuberculosis bronchial stenosis (57.6%). The overall cure rate was 60.6%. Stent-related complications included retention of secretions (70.7%), granuloma formation (67.7%), stent angulation (21.2%), and stent migration (12.1%). The stent was less effective for left main bronchus stenosis ( p  = 0.012). Multivariate logistic regression analysis identified that stent placement for more than 13 months, a stent-intervention number of ⩽ 1 predicted a favorable outcome., Conclusion: The efficacy and safety of the Dumon stent for benign airway stenosis need improvement. The stent is less effective for left main bronchus stenosis; regular follow-up is required in such cases. Stent placement for > 13 months and no more than once stent intervention within a 6-month period were associated with a favorable outcome.

Background: Small cell lung cancer (SCLC) is an aggressive tumor with high brain metastasis (BM) potential. There has been no significant progress in the treatment of SCLC for more than 30 years. Cordycepin has shown the therapeutic potential for cancer by modulating multiple cellular signaling pathways. However, the effect and mechanism of cordycepin on anti-SCLC BM remain unknown., Purpose: In this study, we focused on the anti-SCLC BM effect of cordycepin in the zebrafish model and its potential mechanism., Study Design and Methods: A SCLC xenograft model based on zebrafish embryos and in vitro cell migration assay were established. Cordycepin was administrated by soaking and microinjection in the zebrafish model. RNA-seq assay was performed to analyze transcriptomes of different groups. Geno Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment were performed to reveal the underlying mechanism. Real-time qPCR was used to verify the effects of cordycepin on the key genes., Results: Cordycepin showed lower cytotoxicity in vitro compared with cisplatin, anlotinib and etoposide, but showed comparable anti-proliferation and anti-BM effects in zebrafish SCLC xenograft model. Cordycepin showed significant anti-SCLC BM effects when administrated by both soaking and microinjection. RNA-seq demonstrated that cordycepin was involved in vitamin D metabolism, lipid transport, and proteolysis in cellular protein catabolic process pathways in SCLC BM microenvironment in zebrafish, and was involved in regulating the expressions of key genes such as cyp24a1, apoa1a, ctsl. The anti-BM effect of cordycepin in SCLC was mediated by reversing the expression of these genes., Conclusion: Our work is the first to describe the mechanism of cordycepin against SCLC BM from the perspective of regulating the brain microenvironment, providing new evidence for the anti-tumor effect of cordycepin., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022. Published by Elsevier GmbH.)

Background: Manual measurement of endobronchial optical coherence tomography (EB-OCT) images means a heavy workload in the clinical practice, which can also introduce bias if the subjective opinions of doctors are involved., Objective: We aim to develop a convolutional neural network (CNN)-based EB-OCT image analysis algorithm to automatically identify and measure EB-OCT parameters of airway morphology., Methods: The ResUNet, MultiResUNet, and Siamese network were used for analyzing airway inner area (Ai), airway wall area (Aw), airway wall area percentage (Aw%), and airway bifurcate segmentation obtained from EB-OCT imaging, respectively. The accuracy of the automatic segmentations was verified by comparing with manual measurements., Results: Thirty-three patients who were diagnosed with asthma (n = 13), chronic obstructive pulmonary disease (COPD, n = 13), and normal airway (n = 7) were enrolled. EB-OCT was performed in RB9 segment (lateral basal segment of the right lower lobe), and a total of 17,820 OCT images were collected for CNN training, validation, and testing. After training, the Ai, Aw, and airway bifurcate were readily identified in both normal airway and airways of asthma and COPD. The ResUNet and the MultiResUNet resulted in a mean dice similarity coefficient of 0.97 and 0.95 for Ai and Aw segmentation. The accuracy Siamese network in identifying airway bifurcate was 96.6%. Bland-Altman analysis indicated there was a negligible bias between manual and CNN measurements for Ai (bias = -0.02 to 0.01, 95% CI = -0.12 to 0.14) and Aw% (bias = -0.06 to 0.12, 95% CI = -1.98 to 2.14)., Conclusion: EB-OCT imaging in conjunction with ResUNet, MultiResUNet, and Siamese network could automatically measure normal and diseased airway structure with an accurate performance., (© 2023 S. Karger AG, Basel.)

Background: Chemoradiotherapy (CRT), which might affect the autonomic system, is the mainstay therapy for advanced esophageal squamous cell carcinoma (ESCC). Autonomic dysfunction has been found to possibly lead to cancer mortality in those with elevated resting heart rates (RHR). Skin sympathetic nerve activity (SKNA) is a new method of stimulating electrical signals in skin to evaluate autonomic function from sympathetic tone. In this study, we investigated the association between changes in RHR and autonomic function and ESCC mortality., Methods: Thirty-nine stage II-IV ESCC patients receiving CRT between March 2019 and November 2020 were prospectively enrolled and carefully selected, followed up and received the same meticulous supportive care. Serial RHR was recorded every two weeks from before CRT to eight weeks after CRT and average SKNA were recorded before and four weeks after CRT. All-cause mortality was defined as primary outcome., Results: We found the RHR of ESCC patients to be significantly elevated and peaking at four weeks after CRT (p < 0.001) and then to gradually decrease. Those with an elevated RHR above the cutoff level (18 beat-per-minute) at eight weeks after CRT had worse overall survival. In addition, those with higher baseline sympathetic tone (average SKNA ≥ 0.86 μV) also had poor outcome., Conclusions: Increased pre-treatment sympathetic tone and elevated RHR after CRT are alarm signs of poor ESCC outcome. Further exploration of the mechanisms underlying these associations could potentially lead to intervention strategies for reducing mortality., Trial Registration: This study is registered with ClinicalTrials.gov, identifier: NCT03243448., (© 2022. The Author(s).)

Traditional medicines have greatly contributed to people's health worldwide. However, in recent years, the frequent occurrence of herb-induced liver injury (HILI) has raised public concerns regarding the safety of herbs. HILI not only severely impacts public health, thus increasing its medical burden, but also consumes medical resources. However, the pharmacoepidemiology and risk factors of HILI are still unclear due to the complexity of herbs (medication theory, drug composition, dual properties of drugs and food, etc.). China is the country with the most extensive use of herbs and cases of HILI worldwide. The safety profile of herbs (especially with respect to HILI) has also affected the use of herbs internationally. Therefore, this review focuses on the epidemic situation of HILI in mainland China to compile its characteristics, while focusing on the three main aspects of patients, drugs, and unreasonable prescriptions to explore the potential risk factors. Our objective was to provide a reference for HILI pharmacovigilance and risk prevention and control and contribute to Chinese knowledge of the realisation of the "Medication without Harm" global safe medication strategic goal of the World Health Organization., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Yang, Ge, Tang, Qin, Zeng, Yao, Xiao, Bai and Tang.)

The Fenhe River Basin is the mother river of Shanxi Province. Due to the over-exploitation of water resources and the impact of social and economic development, the ecological environment has deteriorated. After a series of treatment and protection measures, the water quality has since been improved. Mathematical statistics, Piper diagrams, Gibbs model, hydrogen and oxygen isotopes, and other methods were used to analyze the characteristics and sources of hydrochemistry in the surface water of the Fenhe River basin, which revealed the evolution process of surface water quality of the Fenhe River basin. The results showed that the content of the main hydrochemical components in the main stream surface water of Fenhe River basin increased gradually along the runoff path. The hydrochemical types of surface water of Fenhe River basin were mainly HCO 3 ·SO 4 ·Cl-Ca·Na·Mg and SO 4 ·HCO 3 ·Cl-Ca·Na·Mg. There were great differences in hydrochemical components of tributaries and karst water in the basin. There were also great differences in hydrochemical components of tributaries in the basin. The hydrochemical types of surface water of karst water were mainly SO 4 ·HCO 3 -Ca·Mg. The hydrochemical composition of surface water in Fenhe River basin was mainly affected by rock weathering and evaporation crystallization, whereas rainfall had little effect. Na + and K + mainly came from the dissolution of evaporated salt rocks with Na in the surrounding loess. Ca 2+ , Mg 2+ , and HCO 3 - mainly came from the dissolution of carbonate rocks. SO 4 2- may have also come from the dissolution of sulfide minerals in the loess layer around Fenhe River in addition to the dissolution of gypsum. The values of δ D and δ 18 O of Fenhe River surface water were gradually enriched from upstream to downstream. The characteristics of hydrogen and oxygen isotopes further showed that the surface water was mainly affected by evaporation. The results of this study can provide evidence for ecological restoration and protection and ecological civilization construction in the Fenhe River basin.

Human glioblastoma (GBM) is one of the common cancer death in adults worldwide, and its metastasis will lead to difficult treatment. Finding compounds for future to develop treatment is urgent. Bisdemethoxycurcumin (BDMC), a natural product, was isolated from the rhizome of turmeric (Curcuma longa), which has been shown to against many human cancer cells. In the present study, we evaluated the antimetastasis activity of BDMC in human GBM cells. Cell proliferation, cell viability, cellular uptake, wound healing, migration and invasion, and western blotting were analyzed. Results indicated that BDMC at 1.5-3 μM significantly decreased the cell proliferation by MTT assay. BDMC showed the highest uptake by cells at 3 h. After treatment of BDMC at 12-48 h significantly inhibited cell motility in GBM 8401 cells by wound healing assay. BDMC suppressed cell migration and invasion at 24 and 48 h treatment by transwell chamber assay. BDMC significantly decreased the levels of proteins associated with PI3K/Akt, Ras/MEK/ERK pathways and resulted in the decrease in the expressions of NF-κB, MMP-2, MMP-9, and N-cadherin, leading to the inhibition of cell migration and invasion. These findings suggest that BDMC may be a potential candidate for the antimetastasis of human GBM cells in the future., (© 2022 Wiley Periodicals LLC.)

Background: A feasible and economical bronchoscopic navigation method in guiding peripheral pulmonary nodule biopsy is lacking., Objective: To investigate the utility of hierarchical clock-scale hand-drawn mapping for bronchoscopic navigation in peripheral pulmonary nodules., Methods: We developed a hierarchical clock-scale hand-drawn mapping for bronchoscopic navigation in peripheral pulmonary nodules. Patients with peripheral pulmonary nodules were recruited and assigned to two groups in this retrospective study, subjects in VBN group received conventional bronchoscopy in conjunction with virtual bronchoscopic navigation (VBN) and radial probe endobronchial ultrasound (RP-EBUS) for biopsy (VBN group), while HBN group underwent ultrathin bronchoscopy and RP-EBUS under the guidance of hand-drawn bronchoscopic navigation (HBN). The demographic characteristics, procedural time, operating cost and diagnostic yield were compared between these two groups., Results: Forty-eight patients with peripheral pulmonary nodule were enrolled in HBN group, while 42 in VBN group. There were no significant differences between VBN and HBN groups in terms of age, gender, lesion size, location and radiographic type. The time of planning pathway (1.32 vs. 9.79 min, P < 0.001) and total operation (23.63 vs. 28.02 min, P = 0.002), as well as operating cost (758.31 ± 125.21 vs.1327.70 ± 116.25 USD, P < 0.001) were markedly less in HBN group, compared with those in VBN group. The pathological diagnostic efficiency of benign and malignant disease in HBN group appeared similar with those in VBN group, irrespective of the size of pulmonary lesion (larger or smaller than 20 mm). The total diagnostic yield of HBN had no marked difference from that of VBN (75.00% vs. 61.90%, P = 0.25)., Conclusions: Hierarchical clock-scale hand-drawn mapping for bronchoscopic navigation could serve as a feasible and economical method for guiding peripheral pulmonary nodule biopsy, providing a comparable diagnostic yield in comparison with virtual bronchoscopic navigation., (© 2022. The Author(s).)

Background: Acetaminophen-related hepatic injury (ARHI) is a kind of acute hepatic injury caused by overdosing acetaminophen, which is mainly related to toxic metabolite production, oxidative stress, and mitochondrial dysfunction. The extract of Paederia scandens (Lour.) Merr. (PSM) has the abilities of anti-inflammatory, antivirus, and antioxidation. Research studies showed that PSM could improve acute or chronic hepatic injury, while the mechanism of which is still indistinct., Methods: Here, the authors applied the approach based on serum metabonomics combined with network pharmacology to study the protection of PSM on ARHI rats., Results: 10 serum potential biomarkers were found to be closely related to ARHI by metabonomics, while 3 compounds (L-ascorbyl 2,6-dipalmitate, squalene, and tributyl O-acetylcitrate) and 3 targets (NOS2, MAOB, and PDE3A) were found that might be the potential active components and active site of PSM on treating ARHI by network pharmacology analysis. Furthermore, molecular biology strategy was performed to validate whether iNOS/NF- κ B signaling pathway is the potential mechanism of PSM treating ARHI., Conclusions: This study indicated that PSM could ameliorate ARHI by iNOS/NF- κ B signaling pathway. During ARHI treatment by PSM, L-ascorbyl 2, 6-dipalmitate, squalene, and tributyl O-acetylcitrate might be the potential active components, while the possible active site might be NOS2, MAOB, and PDE3A., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Chao-Ling Tang et al.)

Background: Patients with recurrent implantation failure (RIF) may have more uterine contractions. Several observational studies suggested that atosiban administration around embryo transfer resulted in higher pregnancy rates in RIF patients. This study aimed to evaluate the effect of atosiban given before fresh embryo transfer on pregnancy outcomes of women with RIF., Methods: A prospective, randomized, double-blind controlled clinical trial was performed in IVF center of Shanghai First Maternity and Infant Hospital. According to a computer-generated randomization list, 194 infertile women with RIF received fresh embryo transfer between July 2017 and December 2019 were randomly allocated into the atosiban (n = 97) and the placebo (n = 97) groups. Women in the treatment group received atosiban intravenously about 30 min before embryo transfer with a bolus dose of 6.75 mg over one minute. Those in the placebo group received only normal saline infusion for the same duration., Results: There was no significant difference in the live birth rate between the atosiban and placebo groups (42.3% vs 35.1%, P = 0.302, RR = 1.206 (0.844-1.723)). No significant differences were found between the two groups in the positive pregnancy test, clinical pregnancy, ongoing pregnancy, miscarriage, multiple pregnancy, ectopic pregnancy and implantation rates. Similar results were found when stratified by the number of embryos previously transferred, number of previous failed embryo transfers, frequency of endometrial peristalsis on embryo transfer day (≥ 3 waves/min) or serum estradiol (E 2 ) on the day of hCG above the median level. And, there was no correlation between the serum E 2 level on the day of hCG and the frequency of endometrial peristalsis on embryo transfer day. The frequency of endometrial peristalsis on embryo transfer day, total FSH/HMG dosage and duration were the significant factors which independently predicted the likelihood of a live birth., Conclusions: These results suggested that atosiban treatment before fresh embryo transfer might not improve the live birth rate in RIF patients., Trial Registration: The study had been approved by the Institutional Review Board of the hospital (2017 ethics No.43) and was registered under Clinicaltrials.gov with an identifier NCT02893722., (© 2022. The Author(s).)

Objective: To observe the effect of electroacupuncture (EA) on the expressions of tight junction related proteins Claudin-5, ZO-1 in the colon and hippocampus, Toll-like receptor 4/nuclear factor-kappa B/NOD-like receptor protein 3 (TLR4/NF-κB/NLRP3) pathway in the hippocampus of APP/PS1 mice, so as to explore its mechanisms underlying improvement of cognitive impairment., Methods: Eighteen 5-month-old male APP/PS1 mice were equally randomized into model and EA groups,and nine 5-month-old male C57BL/6 mice were used as the normal control. EA(2 Hz, 1 mA) was applied to "Baihui" (GV20), "Dachangshu" (BL25) and "Zusanli" (ST36) for 15 min, once daily, 5 days a week for 5 weeks. The Morris water maze swimming test was used to evaluate the mice's cognitive impairment. Nissl staining was used to observe the pathological morphology of hippocampus. The expression of amyloid β-peptide (Aβ) in brain tissue was detect by immunohistochemistry; the contents of lipopolysaccharide (LPS) in colon, serum and hippocampus were detected by ELISA; the expression levels of Claudin-5, ZO-1 in colon and hippocampus, and TLR4/NF-κB/NLRP3 pathway related proteins in hippocampus were detected by Western blot., Results: Compared with the normal group, the escape latency of the mice in the model group was prolonged from the 3 rd day ( P <0.05, P <0.01), the number of crossing the platform and the percentage of target quadrant residence time were significantly decreased ( P <0.01), and the contents of LPS in colon, serum and hippocampus were significantly increased ( P <0.01), the expression levels of TLR4, NF-κB p65, NLRP3, Caspase-1, interleukin (IL)-1β and tumor necrosis factor (TNF)-α in hippocampus and Aβ in brain tissue were significantly increased ( P <0.01), while the expression levels of Claudin-5, ZO-1 in colon and hippocampus were significantly decreased ( P <0.01). Compared with the model group, the escape latency of mice in the EA group was shortened from the 4th day ( P <0.05, P <0.01), the number of crossing the platform and the percentage of target quadrant residence time were increased ( P <0.01, P <0.05), and the contents of LPS in serum and hippocampus were decreased ( P <0.05), and the expression levels of TLR4, NF-κB p65, Caspase-1, NLRP3, IL-1β, TNF-α in hippocampus and Aβ in brain tissue were significantly decreased ( P <0.05, P <0.01), while the expression levels of Claudin-5, ZO-1 in colon and hippocampus were significantly increased ( P <0.05, P <0.01). Outcomes of Nissl staining showed dispersed arrangement of neurons with nuclear pyknosis or hyperchromasia in the hippocampus, and a decreased number of cell layers in the model group, which was relatively milder in the EA group., Conclusion: EA may improve the cognitive impairment of APP/PS1 mice by up-regulating the expression of Claudin-5 and ZO-1, reducing the transposition of gut-derived LPS to the central nervous system, inhibiting the over-activation of TLR4/NF-κB/NLRP3 pathway, and alleviating the inflammatory reaction of the central nervous system.

Objective: To observe the effect of electroacupuncture (EA) on pyroptosis-related proteins in synovium of knee joint in rats with knee osteoarthritis(KOA), in order to explore its mechanism underlying improvement of KOA., Methods: Forty male SD rats were randomly divided into control， model, EA and medication groups, with 10 rats in each group. The KOA model was established by injecting 0.2 mL 4% papain solution into the right intra-articular cavity, followed by repeating the injection again on day 4 and 7 after the first injection. After successful modeling, rats of the EA group received EA stimulation of "Neixiyan" (EX-LE4) and "Dubi"(ST35) on the right limb for 15 min, once every day, 6 days per week, for a total of 4 weeks, and those of the medication group received gavage of celecoxib 24 mg/kg, once every day, 6 days per week, for a total of 4 weeks. The severity of dysfunction of the right knee was assessed by using Lequesne's score. Serum interleukin(IL)-1β and IL-18 contents were detected by ELISA. Histopathological changes of the synovium tissue of the right knee joint were observed to give score (synovial pathological score) after H.E. staining. The expression position and intensity of Nod-like receptor pyrin domain 3 (NLRP3) in syno-vial tissue were observed by immunohistochemistry. The expression levels of NLRP3, apoptosis-associated speck-like protein containing card (ASC), Caspase-1, Gasdermin D(GSDMD), IL-1β and IL-18 mRNAs and proteins (including GSDMD-N) in the synovial tissue of the right knee joint were detected by real-time fluorescence quantitative PCR and Western blot, separately., Results: Compared with the control group, the model group had a significant increase in the Lequesne's score, synovial pathological score, serum IL-1β and IL-18 contents, and the expression levels of NLRP3, ASC, Caspase-1, GSDMD, IL-1β, IL-18 mRNAs and proteins and GSDMD-N protein ( P <0.01). Whereas relevant to the model group, both the EA and medication groups had marked lower levels of Lequesne's score and synovial pathological score, serum IL-1β and IL-18 contents, and expression levels of NLRP3, ASC, Caspase-1, IL-1β, IL-18 mRNAs and proteins, GSDMD mRNA and GSDMD-N protein ( P <0.01, P <0.05). Comparison between two intervention groups showed that the contents of serum IL-1β and IL-18, and the expression levels of IL-1β mRNA and protein were significantly higher in the EA group than in the medication group ( P <0.05, P <0.01). No significant differences were found between the EA and medication groups in the Lequesne's score, synovial pathological score, NLRP3, ASC, Caspase-1 and IL-18 mRNAs and proteins, as well as GSDMD mRNA ( P >0.05)., Conclusion: EA can alleviate the inflammatory response of synovial tissues of knee joints in KOA rats, which may be related to its function in down-regulating the expression levels of synovial NLRP3, ASC, Caspase-1, IL-1β and IL-18 mRNAs and proteins, and GSDMD mRNA and GSDMD-N proteins, reducing the occurrence of pyroptosis.

Chitosan (Chi) is a natural polymer that has been demonstrated to have potential as a promoter of neural regeneration. In this study, Chi was prepared with various amounts (25, 50, and 100 ppm) of gold (Au) nanoparticles for use in in vitro and in vivo assessments. Each as-prepared material was first characterized by UV-visible spectroscopy (UV-Vis), Fourier-transform infrared spectroscopy (FTIR), atomic force microscopy (AFM), scanning electron microscopy (SEM), and Dynamic Light Scattering (DLS). Through the in vitro experiments, Chi combined with 50 ppm of Au nanoparticles demonstrated better biocompatibility. The platelet activation, monocyte conversion, and intracellular ROS generation was remarkably decreased by Chi-Au 50 pm treatment. Furthermore, Chi-Au 50 ppm could facilitate colony formation and strengthen matrix metalloproteinase (MMP) activation in mesenchymal stem cells (MSCs). The lower expression of CD44 in Chi-Au 50 ppm treatment demonstrated that the nanocomposites could enhance the MSCs undergoing differentiation. Chi-Au 50 ppm was discovered to significantly induce the expression of GFAP, β-Tubulin, and nestin protein in MSCs for neural differentiation, which was verified by real-time PCR analysis and immunostaining assays. Additionally, a rat model involving subcutaneous implantation was used to evaluate the superior anti-inflammatory and endothelialization abilities of a Chi-Au 50 ppm treatment. Capsule formation and collagen deposition were decreased. The CD86 expression (M1 macrophage polarization) and leukocyte filtration (CD45) were remarkably reduced as well. In summary, a Chi polymer combined with 50 ppm of Au nanoparticles was proven to enhance the neural differentiation of MSCs and showed potential as a biosafe nanomaterial for neural tissue engineering.

Transient receptor potential channel TRPV4 and nicotinamide adenine dinucleotide phosphate oxidase (Nox2) are involved in oxidative stress that increases endothelial permeability. It has been shown that obesity enhances the physical association of TRPV4 and Nox2, but the role of TRPV4-Nox2 association in obesity has not been clarified. In this study we investigated the function of TRPV4-Nox2 complex in reducing oxidative stress and regulating abnormal vascular permeability in obesity. Obesity was induced in mice by feeding a high-fat diet (HFD) for 14 weeks. The physical interaction between TRPV4 and Nox2 was measured using FRET, co-immunoprecipitation and GST pull-down assays. The functional interaction was measured by rhodamine phalloidin, CM-H 2 DCFDA in vitro, the fluorescent dye dihydroethidium (DHE) staining assay, and the Evans blue permeability assay in vivo. We demonstrated that TRPV4 physically and functionally associated with Nox2, and this physical association was enhanced in aorta of obese mice. Furthermore, we showed that interrupting TRPV4-Nox2 coupling by TRPV4 knockout, or by treatment with a specific Nox2 inhibitor Nox2 dstat or a specific TRPV4 inhibitor HC067046 significantly attenuated obesity-induced ROS overproduction in aortic endothelial cells, and reversed the abnormal endothelial cytoskeletal structure. In order to discover small molecules disrupting the over-coupling of TPRV4 and Nox2 in obesity, we performed molecular docking analysis and found that compound M12 modulated TRPV4-Nox2 association, reduced ROS production, and finally reversed disruption of the vascular barrier in obesity. Together, this study, for the first time, provides evidence for the TRPV4 physically interacting with Nox2. TRPV4-Nox2 complex is a potential drug target in improving oxidative stress and disruption of the vascular barrier in obesity. Compound M12 targeting TRPV4-Nox2 complex can improve vascular barrier function in obesity., (© 2021. The Author(s), under exclusive licence to CPS and SIMM.)

Background: Breast cancer is the most common malignancy affecting women, yet effective targets and related candidate compounds for breast cancer treatment are still lacking. The lipogenic enzyme, stearoyl-CoA desaturase-1 (SCD1), has been considered a potential target for breast cancer treatment. Icaritin (ICT), a prenylflavonoid derivative from the Traditional Chinese Medicine Epimedii Herba, has been reported to exert anticancer effects in various types of cancer. The purpose of the present study was to explore the effect of the new ICT derivative, IC2, targeting SCD1 on breast cancer cells and to explore the specific mechanism., Methods: Immunohistochemistry and semiquantitative evaluation were performed to detect the expression level of SCD1 in normal and tumor samples. Computer-aided drug design (CADD) technology was used to target SCD1 by molecular docking simulation, and several new ICT derivatives were prepared by conventional chemical synthesis. Cell viability was evaluated by an MTT assay and dead cell staining. SCD1 expression in cancer cells was determined by Western blot and qRT-PCR analyses. The enzymatic activity of SCD1 was evaluated by detecting the conversion rate of [d31] palmitic acid (PA) using Gas chromatography-mass spectrometry (GC-MS). DAPI staining, flow cytometry and Western blot were used to detect cell apoptosis. Mitochondrial membrane potential and reactive oxygen species (ROS) assays were used to determine cell mitochondrial function. Lentiviral transduction was utilized to generate SCD1-overexpressing cell lines., Results: We found that SCD1 was overexpressed and correlated with poor prognosis in breast cancer patients. Among a series of ICT derivatives, in vitro data showed that IC2 potentially inhibited the viability of breast cancer cells, and the mechanistic study revealed that IC2 treatment resulted in ROS activation and cellular apoptosis. We demonstrated that IC2 inhibited SCD1 activity and expression in breast cancer cells in a dose-dependent manner. Moreover, SCD1 overexpression alleviated IC2-induced cytotoxicity and apoptosis in breast cancer cells., Conclusions: The new ICT derivative, IC2, was developed to induce breast cancer cell apoptosis by inhibiting SCD1, which provides a basis for the development of IC2 as a potential clinical compound for breast cancer treatment., (© 2022. The Author(s).)

The diversity of fused filament fabrication (FFF) filaments continues to grow rapidly as the popularity of FFF-3D desktop printers for the use as home fabrication devices has been greatly increased in the past decade. Potential harmful emissions and associated health risks when operating indoors have induced many emission studies. However, the lack of standardization of measurements impeded an objectifiable comparison of research findings. Therefore, we designed a chamber-based standard method, i.e., the strand printing method (SPM), which provides a standardized printing procedure and quantifies systematically the particle emission released from individual FFF-3D filaments under controlled conditions. Forty-four marketable filament products were tested. The total number of emitted particles (TP) varied by approximately four orders of magnitude (10 9  ≤ TP ≤ 10 13 ), indicating that origin of polymers, manufacturer-specific additives, and undeclared impurities have a strong influence. Our results suggest that TP characterizes an individual filament product and particle emissions cannot be categorized by the polymer type (e.g., PLA or ABS) alone. The user's choice of a filament product is therefore decisive for the exposure to released particles during operation. Thus, choosing a filament product awarded for low emissions seems to be an easily achievable preemptive measure to prevent health hazards., (© 2022 The Authors. Indoor Air published by John Wiley & Sons Ltd.)