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

OBJECTIVES: Chronic obstructive pulmonary disease (COPD) is a major chronic respiratory condition with high morbidity and mortality, imposing a serious economic and public health burden. The World Health Organization ranks COPD among the top 4 chronic diseases worldwide. Zangsiwei Qingfei Mixture (ZSWQF), a novel Tibetan herbal formulation independently developed by our research team, has shown therapeutic potential for chronic respiratory diseases. This study aims to evaluate the effects of aerosolized ZSWQF on cigarette smoke-induced COPD in mice and explore its underlying mechanisms. METHODS: Thirty C57 mice were randomly divided into a Control group, a COPD group, and a ZSWQF group. The Control group received saline aerosol inhalation without cigarette smoke exposure; both the COPD group and the ZSWQF group were exposed to cigarette smoke, with the former receiving saline inhalation and the latter treated with ZSWQF aerosol. White blood cell (WBC) count was performed using a fully automatic blood cell analyzer. Serum, alanine transaminase (ALT), and serum creatinine (SCr), as well as interleukin (IL)-6, IL-8, and tumor necrosis factor (TNF)-α levels in serum and bronchoalveolar lavage fluid (BALF) were measured by enzyme-linked immunosorbent assay (ELISA). BALF cell classification was determined using a hematology analyzer. Lung function was assessed with a small animal pulmonary function system, including airway resistance (RI) and cyclic dynamic compliance (CyDN). Lung tissues were stained with hematoxylin and eosin (HE), and mean linear intercept (MLI) and destruction index (DI) were calculated to evaluate morphological changes. Network pharmacology was applied to identify disease-related and ZSWQF-related targets, followed by intersection and protein-protein interaction (PPI) network analysis, and enrichment analysis of biological functions and pathways. Primary type II alveolar epithelial cell (AEC II) from SD rats were isolated and divided into a Control group, a lipopolysaccharide (LPS) group, a normal serum group, a water extract of ZSWQF (W-ZSWQF) group, a ZSWQF containing serum group, and a MLN-4760 [angiotensin-converting enzyme (ACE) 2 inhibitor]. Western blotting was performed to assess protein expression of ACE, p38 [a mitogen-activated protein kinase (MAPK)], phospho (p)-p38, extracellular signal-regulated kinases 1 and 2 (ERK1/2), p-ERK1/2, c-Jun N-terminal kinase (JNK), p-JNK, inhibitor of nuclear factor-kappa B alpha (IκBα), p-IκBα, and p-p65 subunit of nuclear factor-kappa B (NF-κBp65). RESULTS: WBC counts were significantly higher in the COPD group than in controls (P<0.01) and decreased following ZSWQF treatment (P<0.05). No significant intergroup differences were found in organ weights, ALT, or SCr (all P>0.05). Serum and BALF levels of IL-6, IL-8, and TNF-α, as well as total BALF cells, neutrophils, and macrophages, were elevated in the COPD group compared with controls and reduced by ZSWQF treatment (P<0.05). COPD mice exhibited increased RI, decreased CyDN, marked alveolar congestion, inflammatory infiltration, thickened septa, and higher MLI and DI values versus controls (P<0.05); ZSWQF treatment significantly reduced MLI and DI (P<0.05). Network pharmacology identified 151 potential therapeutic targets for ZSWQF against COPD, with key nodes including TNF, IL-6, protein kinase B (Akt) 1, albumin (ALB), tumor protein p53 (TP53), non-receptor tyrosine kinase (SRC), epidermal growth factor receptor (EGFR), signal transducer and activator of transcription 3 (STAT) 3, matrix metalloproteinase (MMP)-9, and beta-catenin (CTNNB1). Enrichment analysis indicates involvement of cancer-related, phosphatidylinositol 3-kinase (PI3K)/Akt, hypoxia-inducible factor (HIF)-1, calcium, and MAPK signaling pathways. Western blotting results showed that compared with the LPS group, AEC II treated with ZSWQF-containing serum exhibited decreased expression of ACE, p-p38/p38, p-ERK1/2/ERK1/2, p-JNK/JNK, p-IκBα/IκBα, and p-NF-κBp65, while ACE2 expression was upregulated, consistent with the MAPK/nuclear factor-kappa B (NF-κB) pathway regulation predicted by network pharmacology. CONCLUSIONS Aerosolized ZSWQF provides protective effects in COPD mice by reducing airway inflammation and remodeling.
Animals ; Pulmonary Disease, Chronic Obstructive/etiology* ; Drugs, Chinese Herbal/therapeutic use* ; Mice ; Mice, Inbred C57BL ; Male ; Network Pharmacology ; Smoke/adverse effects* ; Bronchoalveolar Lavage Fluid ; Administration, Inhalation ; Inflammation/drug therapy* ; Tumor Necrosis Factor-alpha ; Lung/drug effects* ; Interleukin-6/blood*

OBJECTIVE: To evaluate the safety and clinical therapeutic effect of in-line mechanical in-exsufflation to assist sputum clearance in patients with invasive mechanical ventilation. METHODS: A prospective observational study was conducted at the department of critical care medicine, the First Affiliated Hospital of Sun Yat-sen University from April 2022 to May 2023. Patients who were invasively ventilated and treated with in-line mechanical in-exsufflation to assist sputum clearance were enrolled. Baseline data were collected. Sputum viscosity, oxygenation index, parameters of ventilatory function and respiratory mechanics, clinical pulmonary infection score (CPIS) and vital signs before and after day 1, 2, 3, 5, 7 of use of the in-line mechanical in-exsufflation were assessed and recorded. Statistical analyses were performed by using generalized estimating equation (GEE). RESULTS: A total of 13 invasively ventilated patients using in-line mechanical in-exsufflation were included, all of whom were male and had respiratory failure, with the main cause being cervical spinal cord injury/high-level paraplegia (38.46%). Before the use of the in-line mechanical in-exsufflation, the proportion of patients with sputum viscosity of grade III was 38.46% (5/13) and decreased to 22.22% (2/9) 7 days after treatment with in-line mechanical in-exsufflation. With the prolonged use of the in-line mechanical in-exsufflation, the patients' CPIS scores tended to decrease significantly, with a mean decrease of 0.5 points per day (P < 0.01). Oxygenation improved significantly, with the oxygenation index (PaO₂/FiO₂) increasing by a mean of 23.3 mmHg (1 mmHg ≈ 0.133 kPa) per day and the arterial partial pressure of oxygen increasing by a mean of 12.6 mmHg per day (both P < 0.01). Compared to baseline, the respiratory mechanics of the patients improved significantly 7 days after in-line mechanical in-exsufflation use, with a significant increase in the compliance of respiratory system (Cst) [mL/cmH₂O (1 cmH₂O ≈ 0.098 kPa): 55.6 (50.0, 58.0) vs. 40.9 (37.5, 50.0), P < 0.01], and both the airway resistance and driving pressure (DP) were significantly decreased [airway resistance (cmH₂O×L^-1×s^-1): 9.6 (6.9, 10.5) vs. 12.0 (10.0, 13.0), DP (cmH₂O): 9.0 (9.0, 12.0) vs. 11.0 (10.0, 15.0), both P < 0.01]. At the same time, no new lung collapse was observed during the treatment period. No significant discomfort was reported by patients, and there were no substantial changes in heart rate, systolic blood pressure, diastolic blood pressure, and mean arterial pressure before and after the in-line mechanical in-exsufflation treatment. CONCLUSIONS The combined use of the in-line mechanical in-exsufflation to assist sputum clearance in patients on invasive mechanical ventilation can effectively improve sputum characteristics, oxygenation and respiratory mechanics. The in-line mechanical in-exsufflation was well tolerated by the patients, with no treatment-related adverse events, which demonstrated its effectiveness and safety.
Humans ; Prospective Studies ; Respiration, Artificial/methods* ; Respiratory Insufficiency/therapy* ; Sputum

Objective In this study,we analyzed the transcriptome sequences of Kupffer cells exposed to simulated microgravity for 3 d and conducted biological experiments to determine how microgravity initiates apoptosis in Kupffer cells. Methods Rotary cell culture system was used to construct a simulated microgravity model.GO and KEGG analyses were conducted using the DAVID database.GSEA was performed using the R language.The STRING database was used to conduct PPI analysis.qPCR was used to measure the IL1B,TNFA,CASP3,CASP9,and BCL2L11 mRNA expressions.Western Blotting was performed to detect the level of proteins CASP3 and CASP 9.Flow cytometry was used to detect apoptosis and mitochondrial membrane cells.Transmission electron microscopy was used to detect changes in the ultrastructure of Kupffer cells. Results Transcriptome Sequencing indicated that simulated microgravity affected apoptosis and the inflammatory state of Kupffer cells.Simulated microgravity improved the CASP3,CASP9,and BCL2L11 expressions in Kupffer cells.Annexin-V/PI and JC-1 assays showed that simulated microgravity promoted apoptosis in Kupffer cells.Simulated microgravity causes M1 polarization in Kupffer cells. Conclusion Our study found that simulated microgravity facilitated the apoptosis of Kupffer cells through the mitochondrial pathway and activated Kupffer cells into M1 polarization,which can secrete TNFA to promote apoptosis.

Objective:Chronic obstructive pulmonary disease(COPD)is a significant global public health issue.Modern medical treatments have both benefits and limitations,prompting increasing attention from scholars worldwide on traditional ethnic medicine,and the Zangsiwei Qingfei Mixture is a newly developed formula derived from the effective components of classical Tibetan medicine to treat chronic respiratory diseases.This study aims to investigate the clinical efficacy and safety of the Zangsiwei Qingfei Mixture combined with conventional treatment in patients with acute exacerbation of chronic obstructive pulmonary disease(AECOPD). Methods:Sixty AECOPD patients admitted to the Second Xiangya Hospital of Central South University from May 2021 to May 2023 were enrolled and randomly divided into 2 groups,with 30 patients in each group.The control group received conventional treatment,including bronchodilators,anti-infection agents,expectorants,and oxygen therapy.The experimental group received the Zangsiwei Qingfei Mixture in addition to conventional treatment.The treatment duration was 7 d for both groups.Baseline data such as gender,age,body mass index(BMI),smoking status,Global Initiative for Chronic Obstructive Lung Disease(GOLD)classification,COPD course,and the number of COPD exacerbations in the past year were collected.The primary efficacy indicators were assessed using the modified Medical Research Council(mMRC)dyspnea scale and the modified Borg scale.Secondary indicators included arterial lactic acid(LAC)and serum tumor necrosis factor alpha(TNF-α)levels.Safety indicators included liver and kidney function[alanine transaminase(ALT),aspartate transaminase(AST),serum creatinine(SCr),serum uric acid(SUA)],coagulation function[activated partial thromboplastin time(APTT),prothrombin time(PT),fibrinogen(FIB),and D-dimer].The generalized linear mixed model(GLMM)was used to evaluate the clinical efficacy and safety of the Zangsiwei Qingfei Mixture. Results:Before treatment,there were no statistically significant differences in general baseline data,grading of mMRC dyspnea scale,score of modified Borg scale,arterial LAC,ALT,AST,SCr,SUA,APTT,FIB,and D-dimer between the 2 groups(all P＞0.05).However,serum TNF-α and PT levels in the experimental group were significantly lower than those in the control group(both P＜0.05).GLMM analysis showed that after adjusting for pre-and post-treatment,gender,age,BMI,smoking status,GOLD classification,COPD course,and the number of COPD exacerbations in the past year,the experimental group demonstrated significantly lower grading of mMRC dyspnea scale(coefficient=-0.329,P=0.036),score of modified Borg scale(coefficient=-1.077,P=0.001),serum TNF-α level(coefficient=-14.378,P＜0.001),and arterial LAC level(coefficient=-0.409,P=0.012)compared to the control group.The Zangsiwei Qingfei Mixture had no significant effect on liver,kidney,or coagulation function indicators(all P＞0.05). Conclusion:The Zangsiwei Qingfei Mixture combined with conventional treatment can improve clinical symptoms and promote homeostasis in AECOPD patients,demonstrating safety and reliability.Combining modem medicine with traditional ethnic medicine offers a feasible approach to treating chronic respiratory diseases in the future.

Objective:To investigate the prognostic value of enteroscopic grading for the prognostic assessment of patients with malignant hematological diseases who developed intestinal acute graft-versus-host disease (IT-aGVHD) after unrelated cord blood transplantation (UCBT) .Methods:Fifty patients with IT-aGVHD who developed hormone resistance after UCBT from June 2016 to June 2023 at Anhui Provincial Hospital were collected to compare the effective and survival rates of IT-aGVHD treatment in the group with milder enteroscopic mucosal injury (27 cases, enteroscopic grading of Ⅰ and Ⅱ) and the group with more severe injury (23 cases, enteroscopic grading of Ⅲ and Ⅳ) and to retrospectively analyze the factors affecting patients’ prognosis.Results:Patients in the mild and severe groups had an effective rate of 92.6% and 47.8% at 28 days after colonoscopy ( P<0.001), 81.5% and 39.1% at 56 days after colonoscopy ( P=0.002), with optimal effective rate of 92.6% and 65.2% ( P=0.040), respectively, and the differences were statistically significant. The multifactorial analysis found that enteroscopic grading was an independent risk factor affecting the effective rate of IT-aGVHD treatment. The overall survival rate at 2 years after colonoscopy was 70.4% (95% CI 52.0% -88.8% ) and 34.8% (95% CI 14.8% -54.8% ) for patients in the mild and severe groups, respectively, and the difference was statistically significant ( P=0.003). Multifactorial analysis revealed that enteroscopic grading, cytomegalovirus infection status, second-line treatment regimen, and patients’ age were independent risk factors for survival. Conclusion:The treatment efficacy and prognosis of patients in the group with less severe enteroscopic injury (grades Ⅰ and Ⅱ) were better than those in the group with more severe injury (grades Ⅲ and Ⅳ) .

Objective To observe the effect of neuromuscular electrical stimulation(NMES)on interleukin-6(IL-6)/STAT3 signaling pathway in mice after spinal cord injury,and to explore the mechanism of its effect on motor function recovery.Methods Seventy-two SPF grade mice were randomly divided into sham operation group,spinal cord injury(SCI)group and NMES group.BMS score,inclined plane test and neuromuscular electrophysiology(EMG)were used to evaluate the recovery of spinal cord injury in mice.Western blotting and Real-time PCR were used to detect the expression of inflammatory factors,IL-6/STAT3,glial fibrillary acidic protein(GFAP)and brain-derived neurotrophic factor(BDNF)in spinal cord tissues of three groups of mice.HE staining was used to observe the pathological changes of spinal cord injury.Results BMS scores and the inclined plane test of mice in the NMES group were higher than those in SCI group(P＜0.05).The maximum amplitude of motor evoked potential in NMES group was higher than that in SCI group(P＜0.05).The expressions of TNF-α,IL-12A and GFAP in the spinal cord of NMES group were lower than that of SCI group(P＜0.05),while the expressions of TGF-β,IL-10 and BDNF were higher than that of SCI group(P＜0.05).The protein expressions of IL-6/STAT3 signaling pathway of NMES group were lower than that of SCI group(P＜0.05).Conclusion Neuromuscular electrical stimulation plays an anti-inflammatory role by inhibiting the IL-6/STAT3 signaling pathway,thereby promoting the recovery of hind limb motor function in mice after spinal cord injury.

China prospective multicenter birth cohort (Prospective Omics Health Atlas birth cohort, POHA birth cohort) study was officially launched in 2022. This study, in collaboration with 12 participating units, aims to establish a high-quality, multidimensional cohort comprising 20 000 naturally conceived families and assisted reproductive families. The study involves long-term follow-up of parents and offspring, with corresponding biological samples collected at key time points. Through multi-omics testing and analysis, the study aims to conduct multi-omics big data research across the entire maternal and infant life cycle. The goal is to identify new biomarkers for maternal and infant diseases and provide scientific evidence for risk prediction related to maternal diseases and neonatal health.

The prevalence of diabetes in China is increasing year by year， and has become a health issue of close concern to the whole society. Glucagon-like peptide-1 （GLP-1） receptor agonist （GLP-1RA）， as a new class of glucose-lowering drugs， is now widely used in the treatment of type 2 diabetes mellitus （T2DM） because of its significant glucose-lowering efficacy and low risk of hypoglycemia. As the level of evidence for its effects on improving cardiovascular system and renal protection and reducing body mass continues to improve， its status in the treatment guidelines for T2DM is gradually increasing. Currently， nine GLP-1RA drugs have been approved for the clinical treatment of T2DM in China. Although all of these drugs exert hypoglycemic effects based on the activation of GLP-1 receptors in the body， the differences in their own structures and natural GLP-1 amino acid homology lead to large differences in pharmacokinetic parameters and clinical efficacy among different analogs. In order to enable clinicians and pharmacists to have a full understanding of the characteristics and clinical evidence of these analogs and to better perform their therapeutic effects， Liaoning Provincial Pharmaceutical Society organized clinical medicine and pharmacy experts to develop a medication guide for nine GLP-1RA drugs to provide a reference for clinical medication needs and promote rational and standardized use by compiling and summarizing the pharmacological characteristics， clinical applications， adverse reactions， interactions， the medications in special populations and medication management.

OBJECTIVE: To study the clinical manifestations and treatment of intervertebral space infection after percutaneous lumbar radiofrequency ablation of nucleus pulposus. METHODS: A retrospective analysis was performed of 496 patients who underwent percutaneous lumbar disc decompression using low-temperature plasma radiofrequency ablation nucleus pulposus from June 2009 to June 2019. Six patients had lumbar infection, and the infection rate was 1.21%. All patients were male, ranging in age from 20 to 61 years old. Three patients underwent single segment radiofrequency ablation, two patients underwent dual segments ablation;and one patient underwent three segment ablation, totaling 10 intervertebral discs. One patient was complicated with type 2 diabetes before operation. The interval between infection occurrence ranged from 21 to 65 days. RESULTS: All 6 patients were followed up, and the duration ranged from 18 to 40 months, with an average of 24 months. Among them, 2 patients presented with symptoms of low back pain accompanied by fever, and imaging examination showed intervertebral space infection accompanied by abscess. In addition, 4 patients experienced low back pain but no fever, and MRI showed abnormal signals of the infected intervertebral endplate or vertebral body. One patient showed staphylococcus aureus in blood culture, while the remaining 5 patients showed negative bacterial culture. All the patients were treated with antibiotics after diagnosis. Four patients were treated with conservative management to control infection;1 patient was treated with debridement of posterior lumbar infection focus, and 1 patient was treated with debridement of posterior lumbar infection focus combined with interbody fusion and internal fixation. CONCLUSION The occurrence of intervertebral space infection during lumbar radiofrequency ablation nucleoplasty should be given sufficient attention. Strict aseptic technique, avoiding repeated multi segment puncture, realizing early detection and treatment, and selecting appropriate treatment methods according to the severity of infection is the guarantee of achieving curative effect.
Humans ; Male ; Young Adult ; Adult ; Middle Aged ; Female ; Low Back Pain ; Nucleus Pulposus ; Diabetes Mellitus, Type 2 ; Retrospective Studies ; Spinal Puncture