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

Aim To investigate the effects of m6A demethylase ALKBH5 on cardiomyocytes pyroptosis in mice with myocardial infarction(MI).Methods The MI model of left anterior descending coronary artery ligation surgery was established by knocking down ALKBH5 using adeno-associated virus,and the hypox-ia model of mouse cardiomyocytes(HL-1)was estab-lished by knocking down small interfering RNA.The effects of ALKBH5 on the pyroptosis of MI mice and hypoxic HL-1 cells were observed.Subsequently,mechanism studies were conducted at the cellular lev-el,and the binding of ALKBH5 and IGF2BP2 to NL-RP3 mRNA was detected through RNA pull down and RNA immunoprecipitation(RIP)experiments.The MeRIP-qPCR method was used to determine the effects of ALKBH5 on the mRNA m6A level of NLRP3.Acti-nomycin D for RNA stability experiments were conduc-ted to detect the effects of ALKBH5 and IGF2BP2 on the stability of NLRP3 mRNA.Results Knocking down ALKBH5 in vivo and in vitro both inhibited NL-RP3 inflammasome activation and alleviated pyroptosis in MI mice and hypoxic HL-1 cells.Mechanistically,the results showed that NLRP3 mRNA could bind to ALKBH5 protein in HL-1 cells;knocking down ALK-BH5 could increase the m6A level of NLRP3 and re-duce the stability of NLRP3 mRNA;subsequently,it was confirmed that NLRP3 mRNA and IGF2BP2 pro-tein bound to each other;knocking down IGF2BP2 in-creased the mRNA stability of NLRP3.The Rescue ex-periment showed that knocking down IGF2BP2 re-versed the decrease in NLRP3 mRNA expression caused by knocking down ALKBH5.Conclusions ALKBH5 mediated m6A modification of NLRP3 pro-motes cardiomyocytes pyroptosis in mice with myocardi-al infarction.

Aim To investigate the effects of m6A demethylase ALKBH5 on cardiomyocytes pyroptosis in mice with myocardial infarction(MI).Methods The MI model of left anterior descending coronary artery ligation surgery was established by knocking down ALKBH5 using adeno-associated virus,and the hypox-ia model of mouse cardiomyocytes(HL-1)was estab-lished by knocking down small interfering RNA.The effects of ALKBH5 on the pyroptosis of MI mice and hypoxic HL-1 cells were observed.Subsequently,mechanism studies were conducted at the cellular lev-el,and the binding of ALKBH5 and IGF2BP2 to NL-RP3 mRNA was detected through RNA pull down and RNA immunoprecipitation(RIP)experiments.The MeRIP-qPCR method was used to determine the effects of ALKBH5 on the mRNA m6A level of NLRP3.Acti-nomycin D for RNA stability experiments were conduc-ted to detect the effects of ALKBH5 and IGF2BP2 on the stability of NLRP3 mRNA.Results Knocking down ALKBH5 in vivo and in vitro both inhibited NL-RP3 inflammasome activation and alleviated pyroptosis in MI mice and hypoxic HL-1 cells.Mechanistically,the results showed that NLRP3 mRNA could bind to ALKBH5 protein in HL-1 cells;knocking down ALK-BH5 could increase the m6A level of NLRP3 and re-duce the stability of NLRP3 mRNA;subsequently,it was confirmed that NLRP3 mRNA and IGF2BP2 pro-tein bound to each other;knocking down IGF2BP2 in-creased the mRNA stability of NLRP3.The Rescue ex-periment showed that knocking down IGF2BP2 re-versed the decrease in NLRP3 mRNA expression caused by knocking down ALKBH5.Conclusions ALKBH5 mediated m6A modification of NLRP3 pro-motes cardiomyocytes pyroptosis in mice with myocardi-al infarction.

Octapeptin has strong antibacterial activity against Gram-negative bacteria such as Escherichia coli, Klebsiella pneumoniae and Acinetobacter baumannii, while it also has activity against some Gram-positive bacteria. This study used natural octapeptin A3 and B3 as lead compounds for structural modification. Twenty-one peptide derivatives (including A3 and B3) containing eight amino acid residues were prepared by solid-phase synthesis, and evaluated for antibacterial activity and renal cytotoxicity. Among them, three compounds 6, 7 and 17 exhibited broad-spectrum antibacterial activity and significantly enhanced the activity for Gram-positive bacteria while maintaining the activity of Gram-negative bacteria. Several compounds improved the activity for Pseudomonas aeruginosa. Compound 7 was active against all test strains and had relatively low renal cytotoxicity. The results provide a basis for the further development of novel polypeptide antibiotics.

177Lu-prostate specific membrane antigen(PSMA)radio-ligand therapy has been approved abroad for advanced prostate cancer and has been in several clinical trials in China.Based on domestic clinical practice and experimental data and referred to international experience and viewpoints,the expert group forms a consensus on the clinical application of 177Lu-PSMA radio-ligand therapy in prostate cancer to guide clinical practice.

Objectives: To evaluate the positive rate of left posterior lymph nodes of the superior mesenteric artery (14cd-LN) in patients undergoing pancreaticoduodenectomy for pancreatic head carcinoma,to analyze the impact of 14cd-LN dissection on lymph node staging and tumor TNM staging. Methods: The clinical and pathological data of 103 consecutive patients with pancreatic cancer who underwent pancreaticoduodenectomy at Pancreatic Center,the First Affiliated Hospital of Nanjing Medical University from January to December 2022 were analyzed,retrospectively. There were 69 males and 34 females,with an age(M (IQR))of 63.0 (14.0) years (range:48.0 to 86.0 years). The χ² test and Fisher's exact probability method was used for comparison of the count data between the groups,respectively. The rank sum test was used for comparison of the measurement data between groups. Univariate and multivariate Logistic regression analyzes were used for the analysis of risk factors. Results: All 103 patients underwent pancreaticoduodenectomy successfully using the left-sided uncinate process and the artery first approach. Pathological examination showed pancreatic ductal adenocarcinoma in all cases. The location of the tumors was the pancreatic head in 40 cases,pancreatic head-uncinate in 45 cases,and pancreatic head-neck in 18 cases. Of the 103 patients,38 cases had moderately differentiated tumor and 65 cases had poorly differentiated tumor. The diameter of the lesions was 3.2 (0.8) cm (range:1.7 to 6.5 cm),the number of lymph nodes harvested was 25 (10) (range:11 to 53),and the number of positive lymph nodes was 1 (3) (range:0 to 40). The lymph node stage was stage N0 in 35 cases (34.0%),stage N1 in 43 cases (41.7%),and stage N2 in 25 cases (24.3%). TNM staging was stage ⅠA in 5 cases (4.9%),stage ⅠB in 19 cases (18.4%),stage ⅡA in 2 cases (1.9%),stage ⅡB in 38 cases (36.9%),stage Ⅲ in 38 cases (36.9%),and stage Ⅳ in 1 case (1.0%). In 103 patients with pancreatic head cancer,the overall positivity rate for 14cd-LN was 31.1% (32/103),and the positive rates for 14c-LN and 14d-LN were 21.4% (22/103) and 18.4% (19/103),respectively. 14cd-LN dissection increased the number of lymph nodes (P<0.01) and positive lymph nodes (P<0.01). As a result of the 14cd-LN dissection,the lymph node stage was changed in 6 patients,including 5 patients changed from N0 to N1 and 1 patient changed from N1 to N2. Similarly,the TNM stage was changed in 5 patients,including 2 patients changed from stage ⅠB to ⅡB,2 patients changed from stage ⅡA to ⅡB,and 1 patient changed from stage ⅡB to Ⅲ. Tumors located in the pancreatic head-uncinate (OR=3.43,95%CI:1.08 to 10.93,P=0.037) and the positivity of 7,8,9,12 LN (OR=5.45,95%CI:1.45 to 20.44,P=0.012) were independent risk factors for 14c-LN metastasis; while tumors with diameter >3 cm (OR=3.93,95%CI:1.08 to 14.33,P=0.038) and the positivity of 7,8,9,12 LN (OR=11.09,95%CI:2.69 to 45.80,P=0.001) were independent risk factors for 14d-LN metastasis. Conclusion: Due to its high positive rate in pancreatic head cancer,dissection of 14cd-LN during pancreaticoduodenectomy should be recommended,which can increase the number of lymph nodes harvested,provide a more accurate lymph node staging and TNM staging.
Male ; Female ; Humans ; Pancreaticoduodenectomy/methods* ; Retrospective Studies ; Prognosis ; Lymph Node Excision/methods* ; Lymph Nodes/pathology* ; Pancreatic Neoplasms/pathology* ; Neoplasm Staging

【Objective】 To explore the relationship between the storage time of leukodepleted red blood cells and transfusion adverse reactions by analyzing the occurrence of transfusion adverse reactions of patients after leukodepleted red blood cells transfusion from four hospitals. 【Methods】 By using the electronic medical record management system, the collection and transfusion dates of leukodepleted red blood cells from four hospitals in Enshi Prefecture from 2018 to 2022, as well as the information on transfusion adverse reactions, were retrieved. 【Results】 From 2018 to 2022, a total of 697 61 bags of leukodepleted red blood cells were transfused in four hospitals, resulting in 166 cases of transfusion adverse reactions, among which 93 were allergic reactions, 63 were non hemolytic febrile reactions, and 10 were others, with a total incidence rate of transfusion adverse reactions at 0.24%. The average storage time of leukodepleted red blood cells with and without transfusion adverse reactions was (20.25±6.31) and (19.88±5.50) days, respectively. With a storage time of 7 days as the threshold, the incidence of transfusion adverse reactions was the lowest for a storage time of 15~21 days. The incidence of transfusion adverse reactions of leukodepleted red blood cells in two groups (with storage days ≤21 days and >21 days) was not statistically significant(P>0.05). 【Conclusion】 Allergic reactions were the main type of transfusion adverse reaction caused by leukodepleted red blood cells, and the incidence of transfusion adverse reactions decreased and then increased with the prolongation of the storage time of leukodepleted red blood cells. There was no significant difference in the incidence of transfusion adverse reactions with leukodepleted red blood cells stored for ≤ 21 days and >21 days.

BCR-ABL^T315I mutation is the main mechanism of resistance to the first and second generation tyrosine kinase inhibitor (TKI) for patients with chronic myeloid leukemia (CML). Ponatinib as the third generation TKI has been found that can significantly improve the prognosis of CML patients with T315I mutation. However, the latest report has discovered that the T315I compound mutant is even resistant to ponatinib, which aroused the enthusiasm of research on the mechanism of CML resistance and targeted therapy once again. Previous studies have shown that TKI combined with other targeted drugs is effective to CML patients with drug resistance or relapse due to T315I mutation. The latest research has found that the allosteric inhibitor asciminib combined with TKI therapy is equally effective to CML patients with T315I compound mutant, but the specific mechanism is not yet clarified. This review will focus on the latest research progress of therapy for CML with BCR-ABL^T315I mutation, hoping to provide reference for researching new drugs and improve therapy for treating CML with T315I mutation.
Humans ; Drug Resistance, Neoplasm/genetics* ; Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics* ; Fusion Proteins, bcr-abl/genetics* ; Protein Kinase Inhibitors/therapeutic use* ; Mutation ; Antineoplastic Agents/pharmacology*

OBJECTIVE: To evaluate the associations of lipid indicators and mortality in Beijing Elderly Comprehensive Health Cohort Study. METHODS: A prospective cohort was conducted based on Beijing Elderly Comprehensive Health Cohort Study with 4499 community older adults. After the baseline survey, the last follow-up was March 31, 2021 with an average 8.13 years of follow-up. Cox proportional hazard model was used to estimate the hazard ratios (HR) with 95% CI for cardiovascular disease (CVD) death and all-cause death in associations with baseline lipid indicators. RESULTS: A total of 4499 participants were recruited, and the mean levels of uric acid, body mass index, systolic blood pressure, diastolic blood pressure, fasting plasma glucose, total cholesterol (TC), triglyceride, and low-density lipoprotein cholesterol (LDL-C) showed an upward trend with the increasing remnant cholesterol (RC) quarters (P_trend < 0.05), while the downward trend was found in high-density lipoprotein cholesterol (HDL-C). During the total 36,596 person-years follow-up, the CVD mortality and all-cause mortality during an average 8.13 years of follow-up was 3.87% (95% CI: 3.30%-4.43%) and 14.83% (95% CI: 13.79%-15.86%) with 174 CVD death participants and 667 all-cause death participants. After adjusting for confounders, the higher level of TC (HR = 0.854, 95% CI: 0.730-0.997), LDL-C (HR = 0.817, 95% CI: 0.680-0.982) and HDL-C (HR = 0.443, 95% CI: 0.271-0.724) were associated with lower risk of CVD death, and the higher level of HDL-C (HR = 0.637, 95% CI: 0.501-0.810) were associated with lower risk of all-cause death. The higher level of RC (HR = 1.276, 95% CI: 1.010-1.613) increase the risk of CVD death. Compared with the normal lipid group, TC ≥ 6.20 mmol/L group and LDL-C ≥ 4.10 mmol/L group were no longer associated with lower risk of CVD death, while RC ≥ 0.80 mmol/L group was still associated with higher risk of CVD death. In normal lipid group, the higher levels of TC, LDL-C and HDL-C were related with lower CVD death. CONCLUSIONS In community older adults, higher levels of TC and HDL-C were associated with lower CVD mortality in normal lipid reference range. Higher RC was associated with higher CVD mortality, which may be a better lipid indicator for estimating the CVD death risk in older adults.

Coptis chinensis is a commonly used traditional Chinese medicine with the effects of clearing heat and drying dampness,purging fire for removing toxin.The main active ingredients are alkaloids,like berberine,jateorhizine,coptisine,epiberberine and some other alkaloids.Modern pharmacological studies have shown that Coptis chinensis possess antibacterial,antioxidant,immunomod-ulatory and other pharmacological effects,and is widely used in the treatment of bacterial dysentery,gastritis,ulcerative colitis and other gastrointestinal diseases.In recent years,compound formulas containing Coptis chinensis,Coptis chinensis extracts and the alka-loid components from Coptis chinensis have shown therapeutic potential in the treatment of ulcerative colitis.Based on this,this paper systematically analyses and summarizes the anti-ulcerative colitis mechanisms of Coptis chinensis and its alkaloid components from the perspectives of regulating inflammatory response,normalizing immune imbalance,regulating gut microbiota-host interactions,and maintaining the intestinal mucosal barrier integrity,so as to provide references for the development of Coptis chinensis and therapeutic drugs for ulcerative colitis.