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.

Sepsis is a potentially fatal condition characterized by the failure of one or more organs due to a disordered host response to infection. The development of sepsis is closely linked to immune dysfunction. As a result, immunotherapy has gained traction as a promising approach to sepsis treatment, as it holds the potential to reverse immunosuppression and restore immune balance, thereby improving the prognosis of septic patients. However, due to the highly heterogeneous nature of sepsis, it is crucial to carefully select the appropriate patient population for immunotherapy. This review summarizes the current and evolved treatments for sepsis-induced immunosuppression to enhance clinicians' understanding and practical application of immunotherapy in the management of sepsis.

Objective: To assess the efficacy and safety of polymyxin B in neutropenic patients with hematologic disorders who had refractory gram-negative bacterial bloodstream infection. Methods: From August 2021 to July 2022, we retrospectively analyzed neutropenic patients with refractory gram-negative bacterial bloodstream infection who were treated with polymyxin B in the Department of Hematology of the First Affiliated Hospital of the Soochow University between August 2021 to July 2022. The cumulative response rate was then computed. Results: The study included 27 neutropenic patients with refractory gram-negative bacterial bloodstream infections. Polymyxin B therapy was effective in 22 of 27 patients. The median time between the onset of fever and the delivery of polymyxin B was 3 days [interquartile range (IQR) : 2-5]. The median duration of polymyxin B treatment was 7 days (IQR: 5-11). Polymyxin B therapy had a median antipyretic time of 37 h (IQR: 32-70). The incidence of acute renal dysfunction was 14.8% (four out of 27 cases), all classified as "injury" according to RIFLE criteria. The incidence of hyperpigmentation was 59.3%. Conclusion: Polymyxin B is a viable treatment option for granulocytopenia patients with refractory gram-negative bacterial bloodstream infections.
Humans ; Polymyxin B/adverse effects* ; Retrospective Studies ; Gram-Negative Bacterial Infections/complications* ; Fever/drug therapy* ; Sepsis/drug therapy* ; Anti-Bacterial Agents/therapeutic use* ; Bacteremia/complications*

BACKGROUND: Bendamustine was approved in China on May 26th, 2019 by the National Medical Product Administration for the treatment of indolent B-cell non-Hodgkin lymphoma (NHL). The current study was the registration trial and the first reported evaluation of the efficacy, safety, and pharmacokinetics of bendamustine in Chinese adult patients with indolent B-cell NHL following relapse after chemotherapy and rituximab treatment. METHODS: This was a prospective, multicenter, open-label, single-arm, phase 3 study (NCT01596621; C18083/3076) with a 2-year follow-up period. Eligible patients received bendamustine hydrochloride 120 mg/m2 infused intravenously on days 1 and 2 of each 21-day treatment cycle for at least six planned cycles (and up to eight cycles). The primary endpoint was the overall response rate (ORR); and secondary endpoints were duration of response (DoR), progression-free survival (PFS), safety, and pharmacokinetics. Patients were classified according to their best overall response after initiation of therapy. Proportions of patients in each response category (complete response [CR], partial response [PR], stable disease, or progressive disease) were summarized along with a two-sided binomial exact 95% confidence intervals (CIs) for the ORR. RESULTS: A total of 102 patients were enrolled from 20 centers between August 6th, 2012, and June 18th, 2015. At the time of the primary analysis, the ORR was 73% (95% CI: 63%-81%) per Independent Review Committee (IRC) including 19% CR and 54% PR. With the follow-up period, the median DoR was 16.2 months by IRC and 13.4 months by investigator assessment; the median PFS was 18.6 months and 15.3 months, respectively. The most common non-hematologic adverse events (AEs) were gastrointestinal toxicity, pyrexia, and rash. Grade 3/4 neutropenia was reported in 76% of patients. Serious AEs were reported in 29 patients and five patients died during the study. Pharmacokinetic analysis indicated that the characteristics of bendamustine and its metabolites M3 and M4 were generally consistent with those reported for other ethnicities. CONCLUSION: Bendamustine is an active and effective therapy in Chinese patients with relapsed, indolent B-cell NHL, with a comparable risk/benefit relationship to that reported in North American patients. CLINICAL TRIAL REGISTRATION ClinicalTrials.gov, No. NCT01596621; https://clinicaltrials.gov/ct2/show/NCT01596621.
Adult ; Antineoplastic Combined Chemotherapy Protocols ; Bendamustine Hydrochloride/therapeutic use* ; China ; Humans ; Lymphoma, Non-Hodgkin/drug therapy* ; Neoplasm Recurrence, Local/drug therapy* ; Prospective Studies ; Rituximab/therapeutic use*

Objective: To develop a set of data elements and standardized definitions of Coronary Artery Disease and Creative Antithrombotic Clinical Research Collaboration (CardiaCare), aiming to facilitate the exchange of disparate data sources, enhance the abilities to support multicenter researches, and subsequently ensure the databases use under standardized process and criteria. Methods: The Cardiacare writing committee members reviewed data elements and definitions from published guidelines, clinical trials, databases, and standardized documents, then determined the data elements and standardized definitions, which should be included in CardiaCare. The writing committee also considered the specific domestic clinical management strategies during the establishment of Cardiacare. The resulting documents provide a series of key data elements and standardized definitions used in the management of coronary artery disease patients. Key data elements from CardiaCare could be sorted by clinical management flowsheet and outcome from hospitalization to long-term follow-up. Results: The Cardiacare standardized set comprised 864 data elements from admission to post-hospital follow-up visit. There were 8 tables in the documents, including demographic and admission information (23 elements), medical history and risk factors (102 elements), clinical presentations and diagnosis (22 elements), diagnostic and laboratory tests (111 elements), interventional diagnosis and treatment (118 elements), pharmacological therapy (213 elements), clinical outcomes (161 elements), and special subpopulations (114 elements: 87 elements for transcatheter valve replacement and 27 elements with cardiac rehabilitation). Conclusions: The Cardiacare standardized data elements set could provide support for real-world clinical research in consecutive data collection and databases mining. A wider applicability in various settings of CardiaCare needs to be explored further.
Cardiac Rehabilitation ; Coronary Artery Disease/drug therapy* ; Fibrinolytic Agents ; Humans

Urinary tract infection (UTI) in traditional Chinese medicine (TCM) belongs to the category of stranguria. This article describes the unsatisfactory situations in clinical practice such as antibiotics abuse, increasing of drug-resistant bacteria, high recurrence rate, etc. According to evidence-based medicine, literatures as evidence are collected for summarizing and analyzing and the result shows the advantages of TCM of relieving symptoms, reducing the dosage of antibiotics, less side effects, lower recurrence rate, etc. In the field of fundamental research, literatures associated with UTI are also summarized and analysed from several perspectives, such as causes, pathogenesis, syndrome differentiation, pharmacological effects of Chinese herbal medicine, working mechanism of non-drug therapy, etc and the result presents that integrated treatment of TCM in UTI has significant advangtages and its own characteristic.

In this study,a new type of impedimetric immunosensor was constructed based on graphene paper for detection of Schistosoma japonicum circulating antigen.The prepared graphene paper was modified with nanobody and gold nanoparticls and the surface morphology and crystal structure of the graphene paper was characterized by scanning electron microscope,atomic force microscope,raman spectroscopy.At the same time,specificity and sensibility of this immuosensor were analyzed.It is demonstrated that the developed impedimetric immunosensor possesses excellent specificity and sensibility,the detection level of S.japonicum soluble egg antigen(SEA) reaches 0.01 ng/mL;The detection rate of suspected schistosomiasis patients was 66.7%,which was better than that (56.7%) of ELISA,and the coincidence rate with ELISA was 90%.The immunosensor has high sensitivity and specificity for detecting S.japonicum circulating antigen.The method is simple,fast and has good potential for application.

Abstract?AlM:To compare the effects of different adjustable suture in glaucoma trabeculectomy on early tear film function.?METHODS:Sixty-eight cases of primary glaucoma ( 76 eyes) during January 2012 to June 2014 in our hospital were selected and divided into exposure conjunctival suture group ( 34 cases, 36 eyes ) and embedded conjunctival suture group ( 34 cases, 40 eyes ) according to treatment. Adjustable suture exposed conjunctival suture and embedding conjunctival suture was given to two groups, respectively. lntraocular pressure ( lOP ) before and after treatment 7, 14, 30d were observed and Schirmer test, tear break-up time, No Hikaru sensitivity and the occurrence of adverse reactions after treatment 1, 30d were recorded.?RESULTS: After the treatment, the mean lOP of two groups were decreased significantly ( P < 0. 05 ). The average lOP after treatment of 1d in the two groups were not statistically different (P>0. 05), after treatment 7, 14, 30d embedded conjunctival suture group was significantly higher than that of exposure conjunctival suture group ( P<0. 05). After 1d of treatment, Schirmer test, tear break-up time, No Hikaru sensitivity of two groups compared no significant difference (P<0. 05). After treatment 7, 14, 30d embedded conjunctival suture group Schirmer test, tear break- up time, was significantly superior to expose conjunctiva suture group (P<0. 05). The 30d package after treatment of conjunctival suture group buried adverse reaction rate was significantly lower than that of exposed conjunctival suture group (P<0. 05).? CONCLUSlON: Trabeculectomy operation with adjustable thread embedding conjunctival suture has few effects on the tear film function in patients with early postoperative complications, lower, and operation effect is better than that of exposed conjunctival suture.