The circadian clock plays a critical role in regulating various physiological processes, including gene expression, metabolic regulation, immune response, and the sleep-wake cycle in living organisms. Post-translational modifications (PTMs) are crucial regulatory mechanisms to maintain the precise oscillation of the circadian clock. By modulating the stability, activity, cell localization and protein-protein interactions of core clock proteins, PTMs enable these proteins to respond dynamically to environmental and intracellular changes, thereby sustaining the periodic oscillations of the circadian clock. Different types of PTMs exert their effects through distincting molecular mechanisms, collectively ensuring the proper function of the circadian system. This review systematically summarized several major types of PTMs, including phosphorylation, acetylation, ubiquitination, SUMOylation and oxidative modification, and overviewed their roles in regulating the core clock proteins and the associated pathways, with the goals of providing a theoretical foundation for the deeper understanding of clock mechanisms and the treatment of diseases associated with circadian disruption.
Protein Processing, Post-Translational/physiology* ; Circadian Rhythm/physiology* ; Humans ; Animals ; CLOCK Proteins/physiology* ; Circadian Clocks/physiology* ; Phosphorylation ; Acetylation ; Ubiquitination ; Sumoylation

OBJECTIVE: To determine the role of Tripterygium wilfordii multiglycoside (TGW) in the treatment of psoriatic dermatitis from a cellular immunological perspective. METHODS: Mouse models of psoriatic dermatitis were established by imiquimod (IMQ). Twelve male BALB/c mice were assigned to IMQ or IMQ₊TGW groups according to a random number table. Histopathological changes in vivo were assessed by hematoxylin and eosin staining. Ratios of immune cells and cytokines in mice, as well as PAM212 cell proliferation in vitro were assessed by flow cytometry. Pro-inflammatory cytokine expression was determined using reverse transcription quantitative polymerase chain reaction. RESULTS: TGW significantly ameliorated the severity of IMQ-induced psoriasis-like mouse skin lesions and restrained the activation of CD45⁺ cells, neutrophils and T lymphocytes (all P<0.01). Moreover, TGW significantly attenuated keratinocytes (KCs) proliferation and downregulated the mRNA levels of inflammatory cytokines including interleukin (IL)-17A, IL-23, tumor necrosis factor α, and chemokine (C-X-C motif) ligand 1 (P<0.01 or P<0.05). Furthermore, it reduced the number of γ δ T17 cells in skin lesion of mice and draining lymph nodes (P<0.01). CONCLUSIONS TGW improved psoriasis-like inflammation by inhibiting KCs proliferation, as well as the associated immune cells and cytokine expression. It inhibited IL-17 secretion from γ δ T cells, which improved the immune-inflammatory microenvironment of psoriasis.
Male ; Animals ; Mice ; Tripterygium ; Psoriasis/drug therapy* ; Keratinocytes ; Skin Diseases/metabolism* ; Cytokines/metabolism* ; Imiquimod/metabolism* ; Dermatitis/pathology* ; Disease Models, Animal ; Mice, Inbred BALB C ; Skin/metabolism*

Objective:To investigate the current status of endoscopic treatment for gastroesophageal varices in portal hypertension in China, and to provide supporting data and reference for the development of endoscopic treatment.Methods:In this study, initiated by the Liver Health Consortium in China (CHESS), a questionnaire was designed and distributed online to investigate the basic condition of endoscopic treatment for gastroesophageal varices in portal hypertension in 2022 in China. Questions included annual number and indication of endoscopic procedures, adherence to guideline for preventing esophagogastric variceal bleeding (EGVB), management and timing of emergent EGVB, management of gastric and isolated varices, and improvement of endoscopic treatment. Proportions of hospitals concerning therapeutic choices to all participant hospitals were calculated. Guideline adherence between secondary and tertiary hospitals were compared by using Chi-square test.Results:A total of 836 hospitals from 31 provinces (anotomous regions and municipalities) participated in the survey. According to the survey, the control of acute EGVB (49.3%, 412/836) and the prevention of recurrent bleeding (38.3%, 320/836) were major indications of endoscopic treatment. For primary [non-selective β-blocker (NSBB) or endoscopic therapies] and secondary prophylaxis (NSBB and endoscopic therapies) of EGVB, adherence to domestic guideline was 72.5% (606/836) and 39.2% (328/836), respectively. There were significant differences in the adherence between secondary and tertiary hospitals in primary prophylaxis of EGVB [71.0% (495/697) VS 79.9% (111/139), χ2=4.11, P=0.033] and secondary prophylaxis of EGVB [41.6% (290/697) VS 27.3% (38/139), χ2=9.31, P=0.002]. A total of 78.2% (654/836) hospitals preferred endoscopic therapies treating acute EGVB, and endoscopic therapy was more likely to be the first choice for treating acute EGVB in tertiary hospitals (82.6%, 576/697) than secondary hospitals [56.1% (78/139), χ2=46.33, P<0.001]. The optimal timing was usually within 12 hours (48.5%, 317/654) and 12-24 hours (36.9%, 241/654) after the bleeding. Regarding the management of gastroesophageal varices type 2 and isolated gastric varices type 1, most hospitals used cyanoacrylate injection in combination with sclerotherapy [48.2% (403/836) and 29.9% (250/836), respectively], but substantial proportions of hospitals preferred clip-assisted therapies [12.4% (104/836) and 26.4% (221/836), respectively]. Improving the skills of endoscopic doctors (84.2%, 704/836), and enhancing the precision of pre-procedure evaluation and quality of multidisciplinary team (78.9%, 660/836) were considered urgent needs in the development of endoscopic treatment. Conclusion:A variety of endoscopic treatments for gastroesophageal varices in portal hypertension are implemented nationwide. Participant hospitals are active to perform emergent endoscopy for acute EGVB, but are inadequate in following recommendations regarding primary and secondary prophylaxis of EGVB. Moreover, the selection of endoscopic procedures for gastric varices differs greatly among hospitals.

Sodium-glucose co-transporter protein 2 inhibitor(SGLT2i)has steadily demonstrated benefits in the treatment of type 2 diabetes complicated with cardiovascular diseases based on evidence-based medicine,but its precise mechanism is yet unknown.We identified type 2 diabetes patients with HFpEF by searching PubMed,Web of Science,China knowledge network(CNKI),and other databases.We then summarized the pathological mechanism of HFpEF caused by type 2 diabetes.At the same time,to link to evidence-based medical,we explored the future of SGLT2i in clinical application.

Objective:To analyze and compare the differences of expression profiles between RPL and normal adipose tissue by transcriptome sequencing(RNA-Seq),then identify the key genes related to prognosis and explore their potential mechanisms.Methods:Tumor tissues and normal adipose tissues of patients with RPL were collected for RNA-Seq,and then the differentially ex-pressed genes were analyzed by GO and KEGG enrichment analysis.Based on TCGA,the high-risk genes related to prognosis were screened and verified by Kaplan-Meier curve and receiver operat-ing characteristic(ROC)curve.Results:Compared with normal adipose tissue,279 differentially expressed genes were simultaneously up-regulated in RPL tissues,which were mainly enriched in immune response and PPAR signaling pathway.Combined with TCGA,7 stable prognostic high risk genes were identified and the overall survival rate of the high risk group was significantly lower than that of the low risk group(P＜0.05).Conclusion:KCNQ5,RBPJ and some other genes may be re-lated to the poor prognosis of RPL patients.The analysis of the mechanism of these genes in RPL is expected to provide new evidence for the formulation of diagnosis and treatment strategies for RPL patients.

Coronary atherosclerotic heart disease(CHD)is an ischemic cardiovascular condition caused by the narrowing or blockage of the vascular lumen due to coronary atherosclerosis.Clinically,it presents as angina pectoris,heart failure,or sud-den cardiac death,and stands as one of the primary causes of mortality among both urban and rural populations in China.Cir-cRNA,classified as non-coding RNAs,can function as upstream regulatory molecules for miRNA or RNA-binding proteins.They actively participate in various pathological processes associated with CHD,including endothelial cell dysfunction,smooth mus-cle cell migration,macrophage-derived foam cell formation,an-giogenesis,myocardial injury,and repair,as well as post-in-farction heart failure.The expression pattern of these molecules is highly specific to the illness and tissue,indicating their poten-tial as therapeutic targets for disease management and as biomar-kers.Furthermore,they also open up new avenues for drug tar-get development in the field of traditional Chinese medicine.This article aims to provide an overview of the recent research progress on circRNA in the regulation of coronary heart disease,as well as the mechanisms involved in traditional Chinese medi-cine.It serves as a valuable reference for future research on cor-onary heart disease.

METRNL is a recently identified secreted protein with emerging functions. This study is to find major cellular source of circulating METRNL and to determine METRNL novel function. Here, we show METRNL is abundant in human and mouse vascular endothelium and released by endothelial cells using endoplasmic reticulum-Golgi apparatus pathway. By creating endothelial cell-specific Metrnl knockout mice, combined with bone marrow transplantation to produce bone marrow-specific deletion of Metrnl, we demonstrate that most of circulating METRNL (approximately 75%) originates from the endothelial cells. Both endothelial and circulating METRNL decrease in atherosclerosis mice and patients. By generating endothelial cell-specific Metrnl knockout in apolipoprotein E-deficient mice, combined with bone marrow-specific deletion of Metrnl in apolipoprotein E-deficient mice, we further demonstrate that endothelial METRNL deficiency accelerates atherosclerosis. Mechanically, endothelial METRNL deficiency causes vascular endothelial dysfunction including vasodilation impairment via reducing eNOS phosphorylation at Ser1177 and inflammation activation via enhancing NFκB pathway, which promotes the susceptibility of atherosclerosis. Exogenous METRNL rescues METRNL deficiency induced endothelial dysfunction. These findings reveal that METRNL is a new endothelial substance not only determining the circulating METRNL level but also regulating endothelial function for vascular health and disease. METRNL is a therapeutic target against endothelial dysfunction and atherosclerosis.

Objective:To investigate Helicobactor pylori (H. pylori) infection status and interfamilial transmission pattern in Zhengzhou area. Methods:A cross-sectional study was conducted from September 2020 to march 2021, among 731 individual from 266 families randomly selected from 9 communities of Zhengzhou area. H. pylori infection status was determined by serum antibody tests, and 13C-urea breath test was performed in the previously eradicated population to clarify the current infection status. The individual and familial infection rate, infection status for couples and children and adolescent were analyzed. Results:Among 731 individuals from 266 families, 397 of them were H. pylori positive. The individual infection rate was 54.31% (397/731); among infected individuals 77.83% (307/397) were infected with type Ⅰ strain, 22.67% (90/397) were infected by type Ⅱ strain. Annual household income ( χ2=0.419, 0.410, 0.213, all P>0.05), smoking history (χ 2=0.071, P>0.05), drinking history ( χ2=0.071, P>0.05), dining place ( χ2=0.009, P>0.05), gastrointestinal symptoms ( χ2=0.047, P>0.05), family history of gastric disease ( χ2=0.069, P>0.05), and history of gastric cancer ( χ2=0.004, P>0.05) had no significant differences between H. pylori-positive and -negative groups, but the infection rate in individuals with higher education level was lower ( χ2=4.449, P<0.05). The infection rate was significantly higher in≥18 age groups compared with<18 age groups ( χ2=6.531, 23.362, 20.671, 24.244, 37.948, 14.597 and 5.170, all P<0.05). The familial H. pylori infection rate was 87.59% (233/266), and in 61 families all member were infected (26.18%, 61/233). The positive rate was 23.08% (6/26) in 50 families with children under 18 years when both parents were infected. Among 231 coupled families, both couples were infected in 78 families (33.76%), one couple was infected in 113 families (48.92%), and both couples were not infected in 40 (17.32%). With the increase of marriage time, the infection rate of both spouses increased significantly ( χ2=7.775, 12.662, 15.487, all P<0.05). Conclusions:The distribution of H. pylori infection presents a family cluster pattern, and intrafamilial infection is an important transmission rout of H. pylori. The type I strain of H. pylori is the dominate strain in this area.

Enterotoxigenic Escherichia coli（ETEC）infection can induce watery diarrhea，leading to dehydration，electrolyte disturbance，and even death in severe cases. Recombinant B subunit/inactivated whole-cell cholera（rBS/WC）vaccine is effective in preventing ETEC infectious diarrhea. On the basis of the latest evidence on etiology and epidemiology of ETEC，as well as the effectiveness，safety，and health economics of rBS/WC vaccine，National Clinical Research Center for Child Health（The Children’s Hospital，Zhejiang University School of Medicine）and Zhejiang Provincial Center for Disease Control and Prevention invited experts to develop expert consensus on rBS/WC vaccine in prevention of ETEC infectious diarrhea. It aims to provide the clinicians and vaccination professionals with guidelines on using rBS/WC vaccine to reduce the incidence of ETEC infectious diarrhea.

Background: We found microRNA (miR)-1246 to be significantly differentially expressed between severe active alopecia areata (AA) patients and healthy individuals. Objective: To explore the role and mechanism of miR-1246 in severe AA. Methods: Expression of miR-1246, dual-specific tyrosine phosphorylation-regulated kinase 1A (DYRK1A), and nuclear factor of activated T cells 1c (NFATc1) in peripheral CD4+ T cells and in scalp tissues of patients were detected using RT-qPCR, Western blot, and immunohistochemistry assays. Peripheral CD4+ T cells from the AA patients were transfected with lentiviral vectors overexpressing miR-1246. RT-qPCR and Western blot analysis were used to measure mRNA or protein expression of retinoic-acid-receptor-related orphan nuclear receptor gamma (ROR-γt), interleukin (IL)-17, DYRK1A, NFATc1, and phosphorylated NFATc1. Flow cytometry was used to assay the CD4+ IL-17+ cells proportion. ELISA was used to measure cytokine levels. Results: miR-1246 levels decreased and DYRK1A and NFATc1 mRNA levels significantly increased in the peripheral CD4+ T cells and scalp tissues of severe active AA samples.NFATc1 protein expression was also significantly increased in the peripheral CD4+ T cells but not in the scalp tissues. NFATc1 positive cells were mainly distributed among infiltrating inflammatory cells around hair follicles. In peripheral CD4+ T cells of severe active AA, overexpression of miR-1246 resulted in significant downregulation of DYRK1A, NFATc1, ROR-γt, and IL-17 mRNA and phosphorylated NFATc1 protein, as well as a decrease in the CD4+ IL-17+ cells proportion and the IL-17F level. Conclusion miR-1246 can inhibit NFAT signaling and Th17 cell activation, which may be beneficial in the severe AA treatment.