BACKGROUND: Knee osteoarthritis (OA) is still challenging to prevent or treat. Enhanced endoplasmic reticulum (ER) stress and increased pyroptosis in chondrocytes may be responsible for cartilage degeneration. This study aims to investigate the effect of ER stress on chondrocyte pyroptosis and the upstream regulatory mechanisms, which have rarely been reported. METHODS: The expression of the histone methyltransferase enhancer of zeste homolog 2 (EZH2), microRNA-142-3p (miR-142-3p), and high mobility group box 1 (HMGB1) and the levels of ER stress, pyroptosis, and metabolic markers in normal and OA chondrocytes were investigated by western blotting, quantitative polymerase chain reaction, immunohistochemistry, fluorescence in situ hybridization, fluorescein amidite-tyrosine-valine-alanine-aspartic acid-fluoromethyl ketone (FAM-YVAD-FMK)/Hoechst 33342/propidium iodide (PI) staining, lactate dehydrogenase (LDH) release assays, and cell viability assessments. The effects of EZH2, miR-142-3p, and HMGB1 on ER stress and pyroptosis and the hierarchical regulatory relationship between them were analyzed by chromatin immunoprecipitation, luciferase reporters, gain/loss-of-function assays, and rescue assays in interleukin (IL)-1β-induced OA chondrocytes. The mechanistic contribution of EZH2, miR-142-3p, and HMGB1 to chondrocyte ER stress and pyroptosis and therapeutic prospects were validated radiologically, histologically, and immunohistochemically in surgically induced OA rats. RESULTS: Increased EZH2 and HMGB1, decreased miR-142-3p, enhanced ER stress, and activated pyroptosis in chondrocytes were associated with OA occurrence and progression. EZH2 and HMGB1 exacerbated and miR-142-3p alleviated ER stress and pyroptosis in OA chondrocytes. EZH2 transcriptionally silenced miR-142-3p via H3K27 trimethylation, and miR-142-3p posttranscriptionally silenced HMGB1 by targeting the 3'-UTR of the HMGB1 gene. Moreover, ER stress mediated the effects of EZH2, miR-142-3p, and HMGB1 on chondrocyte pyroptosis. In vivo experiments mechanistically validated the hierarchical regulatory relationship between EZH2, miR-142-3p, and HMGB1 and their effects on chondrocyte ER stress and pyroptosis. CONCLUSIONS A novel EZH2/miR-142-3p/HMGB1 axis mediates chondrocyte pyroptosis and cartilage degeneration by regulating ER stress in OA, contributing novel mechanistic insights into OA pathogenesis and providing potential targets for future therapeutic research.
Enhancer of Zeste Homolog 2 Protein/genetics* ; Osteoarthritis, Knee/pathology* ; Chondrocytes/metabolism* ; Pyroptosis/physiology* ; HMGB1 Protein/genetics* ; MicroRNAs/metabolism* ; Endoplasmic Reticulum Stress/genetics* ; Humans ; Animals ; Rats ; Male ; Rats, Sprague-Dawley ; Middle Aged

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder of the gastrointestinal tract, which increases the incidence of colorectal cancer (CRC). In the pathophysiology of IBD, ubiquitination/deubiquitination plays a critical regulatory function. Josephin domain containing 2 (JOSD2), a deubiquitinating enzyme, controls cell proliferation and carcinogenesis. However, its role in IBD remains unknown. Colitis mice model developed by dextran sodium sulfate (DSS) or colon tissues from individuals with ulcerative colitis and Crohn's disease showed a significant upregulation of JOSD2 expression in the macrophages. JOSD2 deficiency exacerbated the phenotypes of DSS-induced colitis by enhancing colon inflammation. DSS-challenged mice with myeloid-specific JOSD2 deletion developed severe colitis after bone marrow transplantation. Mechanistically, JOSD2 binds to the C-terminal of inosine-5'-monophosphate dehydrogenase 2 (IMPDH2) and preferentially cleaves K63-linked polyubiquitin chains at the K134 site, suppressing IMPDH2 activity and preventing activation of nuclear factor kappa B (NF-κB) and inflammation in macrophages. It was also shown that JOSD2 knockout significantly exacerbated increased azoxymethane (AOM)/DSS-induced CRC, and AAV6-mediated JOSD2 overexpression in macrophages prevented the development of colitis in mice. These outcomes reveal a novel role for JOSD2 in colitis through deubiquitinating IMPDH2, suggesting that targeting JOSD2 is a potential strategy for treating IBD.

Despite therapy with potent antiviral agents, chronic hepatitis B (CHB) patients remain at high risk of hepatocellular carcinoma (HCC). While metabolites have been rediscovered as active drivers of biological processes including carcinogenesis, the specific metabolites modulating HCC risk in CHB patients are largely unknown. Here, we demonstrate that baseline plasma from CHB patients who later developed HCC during follow-up exhibits growth-promoting properties in a case-control design nested within a large-scale, prospective cohort. Metabolomics analysis reveals a reduction in long-chain acylcarnitines (LCACs) in the baseline plasma of patients with HCC development. LCACs preferentially inhibit the proliferation of HCC cells in vitro at a physiological concentration and prevent the occurrence of HCC in vivo without hepatorenal toxicity. Uptake and metabolism of circulating LCACs increase the intracellular level of acetyl coenzyme A, which upregulates histone H3 Lys14 acetylation at the promoter region of KLF6 gene and thereby activates KLF6/p21 pathway. Indeed, blocking LCAC metabolism attenuates the difference in KLF6/p21 expression induced by baseline plasma of HCC/non-HCC patients. The deficiency of circulating LCACs represents a driver of HCC in CHB patients with viral control. These insights provide a promising direction for developing therapeutic strategies to reduce HCC risk further in the antiviral era.

Alzheimer's disease (AD) is a progressive neurodegenerative disease associated with dysfunctions related to thinking, learning, and memory of the brain. AD has multiple pathological characteristics with complicated causes, constructing a suitable pathological model is crucial for the research of AD. Microfluidic chip technology integrates multiple functional units on a chip, which can realize microenvironmental control similar to the physiological environment. It is well applied in the construction of pathological model, early diagnosis as well as drug screening of AD. This paper focuses on the construction of AD microfluidic chips model from the perspective of cell type, culture formats and the chips structure as well as the research progress of microfluidic chips in AD application based on the pathological characteristics of AD, which will provide a reference for further elucidation of AD mechanism and drug development.

Objective:To explore the association between serum 25-hydroxyvitamin D[25(OH)D]and handgrip strength in middle-aged and elderly people in 5 cities of Western China.Methods:Based on the data of a cross-sectional survey conducted in the 5 cities of Western China from February to July 2023,the relevant demographic characteristics of people were collected by questionnaire,handgrip strength was collected by physical examination,and serum 25(OH)D was detected by HPLC-MS/MS.The association between the serum 25(OH)D and handgrip strength was analyzed using Logistic regres-sion and Chi-square test for between-group comparisons models.Results:The prevalence of 25(OH)D deficiency and insufficiency among the middle-aged and elderly people in the 5 cities of Western China was 52.9％and 34.5％,respectively.The people who were older,female,and sampled in winter had lower serum 25(OH)D levels(P＜0.05).The prevalence of loss of handgrip strength among the mid-dle-aged and elderly people was 25.3％.The prevalence of handgrip strength loss was higher in the aged 65-80 participants with 25(OH)D deficiency(45.0％)than in those with 25(OH)D insufficiency(32.6％)and 25(OH)D sufficiency(20.6％).The highest prevalence of loss of handgrip strength was found in the aged 75-80 participants with 25(OH)D deficiency(62.1％),followed by the 25(OH)D insufficient group(11.1％,P＜0.05).The study found that middle-aged and elderly people with 25(OH)D deficiency had a 1.4-fold increased risk of handgrip strength loss compared with those with 25(OH)D sufficiency(OR=2.403,95％CI:1.202-4.804,P=0.013).No significant association was found between 25(OH)D insufficiency and handgrip strength status in the middle-aged and elderly people.For every 5 μg/L increase in total serum 25(OH)D,the risk of handgrip strength loss reduced by 13.1％(OR=0.869,95％CI:0.768-0.982,P=0.025).For every 5 μg/L increase in serum 25(OH)D2,the risk of handgrip strength loss reduced by 24.1％(OR=0.759,95％CI:0.582-0.990,P=0.042).No significant association was found between serum 25(OH)D3 levels and the risk of hand-grip strength loss.The risk of handgrip strength loss in middle-aged and elderly people was reduced by 25.2％for each incremental increase in the total serum 25(OH)D levels(deficient,insufficient and suf-ficient)(OR=0.748,95％CI:0.598-0.936,P=0.011).The risk of handgrip loss was reduced by 40.0％for each incremental increase in serum 25(OH)D levels in the aged 65-80 and aged 65-69 participants,and by 80.0％for each incremental increase in 25(OH)D levels in the aged 75-80 parti-cipants.Conclusion:Serum total 25(OH)D and 25(OH)D2 levels are associated with handgrip strength status in middle-aged and elderly people in the 5 cities of Western China.

Objective:To investigate the distribution and antimicrobial resistance profile of clinical bacteria isolated from blood culture in China.Methods:The clinical bacterial strains isolated from blood culture from member hospitals of Blood Bacterial Resistant Investigation Collaborative System (BRICS) were collected during January 2018 to December 2019. Antibiotic susceptibility tests were conducted with agar dilution or broth dilution methods recommended by US Clinical and Laboratory Standards Institute (CLSI). WHONET 5.6 was used to analyze data.Results:During the study period, 14 778 bacterial strains were collected from 50 hospitals, of which 4 117 (27.9%) were Gram-positive bacteria and 10 661(72.1%) were Gram-negative bacteria. The top 10 bacterial species were Escherichia coli (37.2%), Klebsiella pneumoniae (17.0%), Staphylococcus aureus (9.7%), coagulase-negative Staphylococci (8.7%), Pseudomonas aeruginosa (3.7%), Enterococcus faecium (3.4%), Acinetobacter baumannii(3.4%), Enterobacter cloacae (2.9%), Streptococci(2.8%) and Enterococcus faecalis (2.3%). The the prevalence of methicillin-resistant S. aureus (MRSA) and methicillin-resistant coagulase-negative Staphylococcus were 27.4% (394/1 438) and 70.4% (905/1 285), respectively. No glycopeptide-resistant Staphylococcus was detected. More than 95% of S. aureus were sensitive to amikacin, rifampicin and SMZco. The resistance rate of E. faecium to vancomycin was 0.4% (2/504), and no vancomycin-resistant E. faecalis was detected. The ESBLs-producing rates in no carbapenem-resistance E. coli, carbapenem sensitive K. pneumoniae and Proteus were 50.4% (2 731/5 415), 24.6% (493/2001) and 35.2% (31/88), respectively. The prevalence of carbapenem-resistance in E. coli and K. pneumoniae were 1.5% (85/5 500), 20.6% (518/2 519), respectively. 8.3% (27/325) of carbapenem-resistance K. pneumoniae was resistant to ceftazidime/avibactam combination. The resistance rates of A. baumannii to polymyxin and tigecycline were 2.8% (14/501) and 3.4% (17/501) respectively, and that of P. aeruginosa to carbapenem were 18.9% (103/546). Conclusions:The surveillance results from 2018 to 2019 showed that the main pathogens of bloodstream infection in China were gram-negative bacteria, while E. coli was the most common pathogen, and ESBLs-producing strains were in majority; the MRSA incidence is getting lower in China; carbapenem-resistant E. coli keeps at a low level, while carbapenem-resistant K. pneumoniae is on the rise obviously.

Background: Type 2 diabetes mellitus (T2DM) is characterized by elevated fasting glucagon and impaired suppression of postprandial glucagon secretion, which may participate in diabetic complications. Therefore, we investigated the associations of plasma glucagon with estimated glomerular filtration rate (eGFR), albuminuria and diabetic kidney disease (DKD) in T2DM patients. Methods: Fasting glucagon and postchallenge glucagon (assessed by area under the glucagon curve [AUCgla]) levels were determined during oral glucose tolerance tests. Patients with an eGFR <60 mL/min/1.73 m2 and/or a urinary albumin-to-creatinine ratio (UACR) ≥30 mg/g who presented with diabetic retinopathy were identified as having DKD. Results: Of the 2,436 recruited patients, fasting glucagon was correlated with eGFR and UACR (r=–0.112 and r=0.157, respectively; P<0.001), and AUCgla was also correlated with eGFR and UACR (r=–0.267 and r=0.234, respectively; P<0.001). Moreover, 31.7% (n=771) presented with DKD; the prevalence of DKD was 27.3%, 27.6%, 32.5%, and 39.2% in the first (Q1), second (Q2), third (Q3), and fourth quartile (Q4) of fasting glucagon, respectively; and the corresponding prevalence for AUCgla was 25.9%, 22.7%, 33.7%, and 44.4%, respectively. Furthermore, after adjusting for other clinical covariates, the adjusted odds ratios (ORs; 95% confidence intervals) for DKD in Q2, Q3, and Q4 versus Q1 of fasting glucagon were 0.946 (0.697 to 1.284), 1.209 (0.895 to 1.634), and 1.521 (1.129 to 2.049), respectively; the corresponding ORs of AUCgla were 0.825 (0.611 to 1.114), 1.323 (0.989 to 1.769), and 2.066 (1.546 to 2.760), respectively. Additionally, when we restricted our analysis in patients with glycosylated hemoglobin <7.0% (n=471), we found fasting glucagon and AUCgla were still independently associated with DKD. Conclusion Both increased fasting and postchallenge glucagon levels were independently associated with DKD in T2DM patients.

Objective: Although single port laparoscopic surgery has achieved good clinical results, many surgeons are discouraged by the difficulties of operation, conflict of instruments, lack of antagonistic traction, and straight-line perspective. Therefore, some surgeons have proposed a single incision plus one hole laparoscopic surgery (SILS+1) surgical method. This study explored the safety and feasibility of SILS+1 for radical resection of colorectal cancer. Methods: A descriptive cohort study was carried out. The clinical data, including the operation, pathology and recovery situation, of 178 patients with colorectal cancer undergoing SILS+1 at Department of General Surgery, Nanfang Hospital, Southern Medical University from March 2018 to January 2019 were prospectively collected and retrospectively analyzed. Clavien-Dindo criteria was used for postoperative complication evaluation and visual analog scale was used for pain standard. Follow-up studies were conducted through outpatient service or telephone and the follow-up period was up to May 2019. Results: A total of 178 patients with colorectal cancer underwent SILS+1, including 111 male patients (62.4%) with an average age of 59 years. Eleven (6.2%) patients received added 1-3 operation ports during operation, and 1 patient was converted to open surgery due to ileocolic artery hemorrhage. The operative time was (135.2±42.3) minutes. The intraoperative blood loss was (34.6±35.5) ml. The number of harvested lymph nodes was 33.1±17.6. The distal margin was (4.7±17.8) cm. The proximal margin was (10.2±5.3) cm. Operation-related complications were observed in 16 patients (9.0%) within 30 days after the operation, of whom 6 had Clavien-Dindo III complications (3.4%). The postoperative pain scores were lower than 3. The average postoperative hospital stay was (5.6±2.6) days. Three patients (1.7%) returned to hospital within 30 days after operation due to intestinal obstruction and infection around stoma. The cosmetic evaluation of all the patients was basically satisfied. Conclusion: SILS+1 is safe and feasible in the treatment of colorectal cancer, and can reduce the postoperative pain.
Colorectal Neoplasms/surgery* ; Feasibility Studies ; Female ; Humans ; Laparoscopy/methods* ; Length of Stay ; Male ; Middle Aged ; Pain, Postoperative/prevention & control* ; Retrospective Studies ; Treatment Outcome

Objective:The storage of medical data has been digitized in China, but a unified and structured model has not yet been established. The standardized collection, analysis and sorting of tumor clinical data is the foundation of improving the standard of tumor diagnosis and treatment. Therefore, establishing a database platform of gastric cancer (GC) is an urgent need to integrate data resources and improve the level of diagnosis and treatment. The population economics indexes of GC patients in the last 20 years are analyzed in a single-center GC database. The medical records were structured by natural language processing technology. Authors aim to investigate the clinical pathological characteristics, staging and survival of the GC patients with gastrectomy.Method:A retrospective cohort study was carried out. Clinicopatological data of patients receiving surgical treatment from 2000 to 2019 were retrospectively collected. According to the gastric cancer TNM staging guidelines from the Union for International Cancer Control and the American Joint Committee on Cancer (UICC/AJCC) 8th edition, the structured gastric cancer clinicopathological data were re-evaluated and interpreted. The Kaplan-Meier method and the log-rank test were used to compare survival rate among different groups of patients with complete follow-up data of 2010-2016.Results:Clinicopathological data of 13 492 GC patients were enrolled. The ratio of men to women in the whole group was 3.25:1.00, including 10 320 men with average onset age of 59.68 years, which was basically stable in recent 20 years, and 3172 women with average onset age of 55.93 years, which presented a trend of average increasement of 0.17 year per year. The average hospitalization duration for GC patients showed a decreasing trend year by year, which was 13.87 days in 2019. Average hospitalization cost for GC patients was increasing year by year, with a peak of 83 600 CNY in 2017 and 75 400 CNY in 2019. By natural language identification and exclusion criteria screening, a total of 7218 GC patients obtained structured clinicopathological information. Analysis on clinicopathological characteristics of 3626 GC patients in the last 5 years showed that the average diameter of tumor was (4.44±2.61) cm; the average number of harvested lymph node was 24.30±13.29; the proportion of surgical methods were as following: open surgery in 1398 cases (38.55%), laparoscopic surgery in 1856 cases (51.19%) and robotic surgery in 372 cases (10.26%). The postoperative pathological stage was as following: IA in 658 cases (18.15%), IB in 318 cases (8.77%), IIA in 559 cases (15.42%), IIB in 543 (14.98%), III A in 632 (17.43%), III B in 612 cases (16.88%), III C in 276 cases (7.61%), and IV in 28 cases (0.77%). Complete follow-up data of 3431 patients from 2010 to 2016 were presented. The 1-, 3- and 5-year survival rates were 82%, 69% and 60%, respectively for the whole group. The 1-, 3- and 5-year survival rates for patients undergoing laparoscopic surgery were 83%, 70% and 64%, respectively, and for those undergoing open surgery were 81%, 67% and 56%, respectively, and the difference between the two groups was not statistically significant ( P=0.109). The 5-year survival rate of GC patients with different AJCC stages was as following: 88% in IA, 77% in IB, 70% in II A, 62% in II B, 44% in III A, 32% in III B, 22% in III C, and 17% in IV. Conclusion:This study provides basic data for the establishment of comprehensive diagnosis and treatment model of multicenter, shedding light on the improvement of comprehensive treatment of GC in China.

Objective:To analyze the effects of HIV non-occupational post-exposure prophylaxis (nPEP) in men who have sex with men (MSM) in Nanning and Liuzhou, Guangxi Zhuang Autonomous Region.Methods:Participants were recruited through community publicity and advocacy under a "Trinity" approach among non-governmental organizations (NGO), CDCs/hospitals and pharmacies. Basic information, drug taking and follow-up tests of participants who had enrolled for 28 days of the research were collected. Descriptive statistics were used for data analysis.Results:From September 2017 to March 2019, a total of 213 MSM cases consulted for nPEP service, 159 of them were eligible for nPEP, and 154 were enrolled in the study for drug taking. For 132 cases enrolled in the study for 28 days and above, 118 completed the 28-day course of antiretroviral therapy (ART), while 10 failed to complete the 28-day course of ART, and 4 could not be confirmed whether completed the full course of ART due to loss of contact. For those who completed 28-day course of ART, 94.1% (111/118) and 75.4% (89/118) respectively received HIV tests at 4-6 weeks and 3 months after exposure, the results were all HIV negative.Conclusion:Under the "Trinity" approach, taking antiviral drugs earlier after HIV non-occupational exposure can effectively reduce the risk of HIV infection and to some extent, reduce the new infection cases.