Superior Rectal Artery Preservation in Laparoscopically Assisted Subtotal Colectomy and Ileorectal Anastomosis for Slow-Transit Constipation.

Our previous retrospective observational study demonstrated the safety of laparoscopically assisted subtotal colectomy with ileorectal anastomosis and preservation of the superior rectal artery (SRA), without instances of leakage, in patients with slow-transit constipation (STC). Thus, we extended the enrollment period and enlarged the sample size to detect the differences in the postoperative complications and surgical and functional outcomes between patients who underwent laparoscopically assisted subtotal colectomy with and without SRA preservation. We conducted a retrospective single-center analysis of patients with STC who underwent laparoscopically assisted subtotal colectomy between 2016 and 2020. The diagnosis of STC was based on the colonic transit and anal functional tests and barium enema to exclude secondary causes. Patients were divided into group A, which underwent surgery with SRA preservation, and group B, which underwent ligation of the SRA during surgery. Outcome assessments for both groups included the incidence of anastomotic breakdown, intraoperative complications, length of hospital stay, estimated blood loss, time to first flatus, and complications. Propensity score matching allocated 34 patients to groups A and B each. Postoperative bowel function, including time to first flatus, stool, and oral intake, recovered better in group A than in group B. Anastomotic leakage, a significant postoperative complication, was less frequent in patients with SRA preservation. In conclusion, preservation of the SRA in patients undergoing laparoscopically assisted subtotal colectomy with ileorectal anastomosis for STC is associated with favorable postoperative bowel function recovery and lower anastomotic leakage rates.

Effect of cytokines on advanced hepatocellular carcinoma prognosis receiving radiotherapy and tislelizumab plus anlotinib: a single-center phase II clinical trial.

The purpose of this study was to investigate the relationship between circulating cytokines and liver function and prognosis of patients with advanced hepatocellular carcinoma (HCC) treated with radiotherapy combined with tislelizumab and anlotinib. The liver function indexes and pre-treatment levels of cytokines in 47 patients were measured by chemical method and flow cytometry. The median follow-up was 23.1 months. The objective response and the disease control rates were 46.8% and 68.1%, while overall survival (OS) and progression-free survival (PFS) were 12.6 and 11.4 months, respectively. Adverse events (2.1%) were grade 3-4. In addition to stage, intrahepatic metastasis and Child-Pugh score, pre-treatment interleukin-6 (IL-6) was the main cytokine affecting OS and PFS (p < 0.05). The OS (14.63 pg/mL as cutoff value) and PFS (9.85 pg/mL as cutoff value) of patients with low IL-6 levels exceeded those with high levels (21.0 and 6.9, 15.8 and 10.0 months, respectively). The risks of death and disease progression were reduced by 63.0% (HR = 0.37, 95% CI: 0.19-0.72) and 43.0% (HR = 0.57, 95% CI: 0.22-1.47), respectively. Pre-treatment IL-6 levels may be a simple and effective prognostic indicator for patients with advanced HCC treated with radiotherapy combined with immunotargeted therapy.

Association of Overweight and Inflammatory Indicators with Breast Cancer: A Cross-Sectional Study in Chinese Women.

Objective: This cross-sectional study aimed to explore the association of overweight and inflammatory indicators with breast cancer risk in Chinese patients. Methods: Weight, height, and peripheral blood inflammatory indicators, including white blood cell count (WBC), neutrophil count (NE), lymphocyte count (LY), platelet count (PLT) and the concentration of hypersensitivity C-reactive protein (hsCRP), were collected in 383 patients with benign breast lumps (non-cancer) and 358 patients with malignant breast tumors (cancer) at the First Affiliated Hospital of Soochow University, China, from March 2018 to July 2020. Body mass index (BMI), neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR) and systemic immune-inflammation index (SII) were determined according to the ratio equation. The correlations among overweight, inflammatory indicators, and the proportion of non-cancer or cancer cases were analyzed. Results: BMI is associated with an increased breast cancer risk. Compared with non-cancer patients, the average WBC count, NE count, NLR, and level of hsCRP were significantly higher in cancer patients. The level of hsCRP was closely associated with the size of malignant breast tumors. Conclusion: We conclude that overweight and high levels of hsCRP may serve as putative risk factors for malignant breast tumors in Chinese women.

Silent information regulator sirtuin 1 ameliorates acute liver failure via the p53/glutathione peroxidase 4/gasdermin D axis.

BACKGROUND: Acute liver failure (ALF) has a high mortality with widespread hepatocyte death involving ferroptosis and pyroptosis. The silent information regulator sirtuin 1 (SIRT1)-mediated deacetylation affects multiple biological processes, including cellular senescence, apoptosis, sugar and lipid metabolism, oxidative stress, and inflammation. AIM: To investigate the association between ferroptosis and pyroptosis and the upstream regulatory mechanisms. METHODS: This study included 30 patients with ALF and 30 healthy individuals who underwent serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) testing. C57BL/6 mice were also intraperitoneally pretreated with SIRT1, p53, or glutathione peroxidase 4 (GPX4) inducers and inhibitors and injected with lipopolysaccharide (LPS)/D-galactosamine (D-GalN) to induce ALF. Gasdermin D (GSDMD)-/- mice were used as an experimental group. Histological changes in liver tissue were monitored by hematoxylin and eosin staining. ALT, AST, glutathione, reactive oxygen species, and iron levels were measured using commercial kits. Ferroptosis- and pyroptosis-related protein and mRNA expression was detected by western blot and quantitative real-time polymerase chain reaction. SIRT1, p53, and GSDMD were assessed by immunofluorescence analysis. RESULTS: Serum AST and ALT levels were elevated in patients with ALF. SIRT1, solute carrier family 7a member 11 (SLC7A11), and GPX4 protein expression was decreased and acetylated p5, p53, GSDMD, and acyl-CoA synthetase long-chain family member 4 (ACSL4) protein levels were elevated in human ALF liver tissue. In the p53 and ferroptosis inhibitor-treated and GSDMD-/- groups, serum interleukin (IL)-1ß, tumour necrosis factor alpha, IL-6, IL-2 and C-C motif ligand 2 levels were decreased and hepatic impairment was mitigated. In mice with GSDMD knockout, p53 was reduced, GPX4 was increased, and ferroptotic events (depletion of SLC7A11, elevation of ACSL4, and iron accumulation) were detected. In vitro, knockdown of p53 and overexpression of GPX4 reduced AST and ALT levels, the cytostatic rate, and GSDMD expression, restoring SLC7A11 depletion. Moreover, SIRT1 agonist and overexpression of SIRT1 alleviated acute liver injury and decreased iron deposition compared with results in the model group, accompanied by reduced p53, GSDMD, and ACSL4, and increased SLC7A11 and GPX4. Inactivation of SIRT1 exacerbated ferroptotic and pyroptotic cell death and aggravated liver injury in LPS/D-GalN-induced in vitro and in vivo models. CONCLUSION: SIRT1 activation attenuates LPS/D-GalN-induced ferroptosis and pyroptosis by inhibiting the p53/GPX4/GSDMD signaling pathway in ALF.

Identification of circular RNA hsa_circ_0034621 as a novel biomarker for carotid atherosclerosis and the potential function as a regulator of NLRP3 inflammasome.

BACKGROUND AND AIMS: NLRP3 inflammasome plays a key role in vascular inflammation and atherosclerosis. Circular RNAs (circRNAs) are involved in disease development by regulating gene expression, and have emerged as promising novel disease biomarkers. This study aimed to identify the NLRP3 inflammasome-associated circRNA biomarkers of carotid atherosclerosis. METHODS: Based on the differential expression profiles of circRNAs in patients with carotid artery plaque (CAP) and healthy controls, hsa_circ_0043621, hsa_circ_0051995, and hsa_circ_0123388 were screened and validated using real-time quantitative polymerase chain reaction (RT-qPCR). Potential circRNA-miRNA-mRNA interactions were explored using a luciferase assay. The biological roles of the validated circRNAs were investigated in human umbilical vein endothelial cells (HUVECs) using Western blotting, transwell, and CCK-8 assays. Clinical significance was assessed using receiver operating characteristic (ROC) curves and logistic regression analysis. RESULTS: The expression levels of all candidate circRNAs were significantly higher in patients with CAP than in controls (p<0.05), which was consistent with the results of the microarray analysis. Overexpression of hsa_circ_0043621 significantly increased the expression of NLRP3, induced migration of HUVECs, and inhibited cell proliferation. hsa_circ_0043621 demonstrated reasonable diagnostic accuracy for CAP detection and increased intima-media thickness (IMT). hsa_circ_0043621 upregulation was an independent predictor of an increased risk of CAP and increased IMT. CONCLUSIONS: hsa_circ_0043621 is a valuable circulating biomarker of carotid atherosclerosis and may contribute to its pathogenesis by regulating the NLRP3 inflammasome.

Biomimetic Total Synthesis of Bimagnolignan: A Natural Anti-Breast Cancer Agent.

A short scalable biomimetic route to bioactive natural product bimagnolignan (1) was accomplished. Compound 1 was successfully prepared through a three-step metal-free synthesis from honokiol (2). Alternatively, 1 was also synthesized by biomimetic transformations that mimic tyrosinase in four steps. The key reactions feature a regioselective acetylation, a highly efficient C(sp2)-H oxidation, a cascade aerobic oxidative cyclization/coupling, and a Cu-catalyzed direct oxidative coupling. In addition, cell-based assays validate that 1 is a promising natural lead for HER2-positive breast cancer treatment.

Association of gestational metabolic syndrome with the Chinese Healthy Eating Index in mid-pregnancy: a cross-sectional study.

BACKGROUND: This study aims to investigate the relationship between gestational metabolic syndrome (GMS) and the Chinese Healthy Eating Index (CHEI) in mid-pregnancy, and to identify potentially beneficial or high-risk dietary habits. We have developed a mid-pregnancy version of CHEI-2022, adapting the Chinese Healthy Eating Index to align with the food quantity recommendations outlined in the 2022 Dietary Guidelines for Chinese Residents for mid-pregnancy. METHODS: Using the inclusion and exclusion criteria, data from 2411 mid-pregnant individuals were collected through interviews. The Total CHEI score and its component scores were determined through analysis of responses from the food frequency questionnaire. GMS diagnosis involved conducting physical examinations and performing blood biochemical tests. A logistic regression model was employed to analyze the relationship between GMS or related indices and both the total CHEI score and its component scores. RESULTS: The study identified an overall GMS prevalence of 21.65% (522 out of 2411 participants). During mid-pregnancy, participants diagnosed with GMS exhibited higher BMI, FBG, 1hPBG, 2hPBG, TC, TG, HDL, SBP, as well as higher educational levels and daily activity, compared to those without GMS (P < 0.001). After adjusting for potential confounders, participants with higher total CHEI scores (≥ 80) were found to have lower odds of GMS or related indices (P < 0.05). Increasing dietary intake of potatoes, whole grains, beans, dark green vegetables, and fruits, as per the CHEI recommendations, was associated with reduced odds of GMS or related indices (P < 0.05). CONCLUSION: A high-quality diet, as indicated by a total CHEI score of 80 or higher, and increased consumption of specific dietary components, namely potatoes, beans, dark green vegetables, and fruits, were found to effectively reduce the odds of GMS or related indices during mid-pregnancy.

Factors influencing willingness to participate in ophthalmic clinical trials and strategies for effective recruitment.

AIM: To explore the factors influencing individuals' willingness to participate in ophthalmic clinical trials. METHODS: A questionnaire survey was conducted from January to April 2021 among patients and their family members at Zhongshan Ophthalmic Center, Sun Yat-sen University, in Guangzhou, China. The survey gathered data on respondents' willingness, demographic and socioeconomic profiles, as well as their reasons and concerns regarding engagement in clinical trials. RESULTS: Of the 1078 residents surveyed (mean age 31.2±13.1y; 65.8% females) in Guangzhou, 749 (69.5%) expressed a willingness to participate in future ophthalmic clinical trials. Specific characteristics associated with greater willingness included a younger age, lower annual income, higher education, prior participation experience, previous ophthalmic treatment, and a better understanding of clinical trials. With the exception of age, these characteristics were significantly linked to a higher willingness. The primary barrier to participation, expressed by 64.8% of those willing and 54.4% of those unwilling, was "Uncertain efficacy". In terms of motivations, the willing group ranked "Better therapeutic benefits" (35.0%), "Professional monitoring" (34.3%), and "Trust in healthcare professionals" (33.1%) as their top three reasons, whereas the unwilling participants indicated "Full comprehension of the protocol" (46.2%) as the key facilitator. CONCLUSION: This study reveals a substantial willingness to participate in ophthalmic clinical trials and demonstrates the predictive role of demographic and socioeconomic factors. Variations in motivators and concerns between willing and unwilling participants highlight the significance of tailored recruitment strategies. Importantly, the need for and trust in healthcare professionals stand out as powerful motivations, underscoring the importance of enhancing physician-patient relationships, adopting patient-centered communication approaches, and addressing individualized needs to improve accrual rates.

Association between systemic immune inflammatory/inflammatory response index and hypertension: A cohort study of functional community.

BACKGROUND AND AIMS: In prospective studies, there is limited evidence of the association between inflammation and hypertension. We aimed to explore the relationship between systemic immune inflammatory index (SII)/systemic inflammatory response index (SIRI) and hypertension in a prospective cohort study to identify the best inflammatory cell markers that predict hypertension. METHODS AND RESULTS: This study was conducted in a functional community cohort in Beijing. In 2015, a total of 6003 individuals without hypertension were recruited and followed up until 2021. Using a restriction cubic spline with baseline SII/SIRI as a continuous variable, the dose-response relationship between hypertension and SII/SIRI was explored. Logistic regression was used to analyze the correlation between hypertension and SII/SIRI trajectory groups. At a mean follow-up of 6 years, 970 participants developed hypertension. SII showed a significant nonlinear dose-response relationship with hypertension (P < 0.05). Higher SII/SIRI was associated with an increased risk of hypertension (SII: RR = 1.003, 95%CI: 1.001-1.004; SIRI: RR = 1.228, 95%CI: 1.015-1.486). Both SII and SIRI were more predictive in males than females (SII: 0.698 vs. 0.695; SIRI: 0.686 vs. 0.678). CONCLUSION: Both systemic immune inflammatory index (SII) and systemic inflammatory response Index (SIRI) independently increased the risk of hypertension, and both were effective inflammatory cell indicators that predict the risk of hypertension.

EMNPD: a comprehensive endophytic microorganism natural products database for prompt the discovery of new bioactive substances.

The discovery and utilization of natural products derived from endophytic microorganisms have garnered significant attention in pharmaceutical research. While remarkable progress has been made in this field each year, the absence of dedicated open-access databases for endophytic microorganism natural products research is evident. To address the increasing demand for mining and sharing of data resources related to endophytic microorganism natural products, this study introduces EMNPD, a comprehensive endophytic microorganism natural products database comprising manually curated data. Currently, EMNPD offers 6632 natural products from 1017 endophytic microorganisms, targeting 1286 entities (including 94 proteins, 282 cell lines, and 910 species) with 91 diverse bioactivities. It encompasses the physico-chemical properties of natural products, ADMET information, quantitative activity data with their potency, natural products contents with diverse fermentation conditions, systematic taxonomy, and links to various well-established databases. EMNPD aims to function as an open-access knowledge repository for the study of endophytic microorganisms and their natural products, thereby facilitating drug discovery research and exploration of bioactive substances. The database can be accessed at http://emnpd.idrblab.cn/ without the need for registration, enabling researchers to freely download the data. EMNPD is expected to become a valuable resource in the field of endophytic microorganism natural products and contribute to future drug development endeavors.

Metatranscriptome of human lung microbial communities in a cohort of mechanically ventilated COVID-19 Omicron patients.

The Omicron variant of the severe acute respiratory syndrome coronavirus 2 (SARS­CoV­2) infected a substantial proportion of Chinese population, and understanding the factors underlying the severity of the disease and fatality is valuable for future prevention and clinical treatment. We recruited 64 patients with invasive ventilation for COVID-19 and performed metatranscriptomic sequencing to profile host transcriptomic profiles, plus viral, bacterial, and fungal content, as well as virulence factors and examined their relationships to 28-day mortality were examined. In addition, the bronchoalveolar lavage fluid (BALF) samples from invasive ventilated hospital/community-acquired pneumonia patients (HAP/CAP) sampled in 2019 were included for comparison. Genomic analysis revealed that all Omicron strains belong to BA.5 and BF.7 sub-lineages, with no difference in 28-day mortality between them. Compared to HAP/CAP cohort, invasive ventilated COVID-19 patients have distinct host transcriptomic and microbial signatures in the lower respiratory tract; and in the COVID-19 non-survivors, we found significantly lower gene expressions in pathways related viral processes and positive regulation of protein localization to plasma membrane, higher abundance of opportunistic pathogens including bacterial Alloprevotella, Caulobacter, Escherichia-Shigella, Ralstonia and fungal Aspergillus sydowii and Penicillium rubens. Correlational analysis further revealed significant associations between host immune responses and microbial compositions, besides synergy within viral, bacterial, and fungal pathogens. Our study presents the relationships of lower respiratory tract microbiome and transcriptome in invasive ventilated COVID-19 patients, providing the basis for future clinical treatment and reduction of fatality.

Prenatal diagnosis, management, and outcomes of fetuses with tetralogy of Fallot in China after prenatal counseling: a prospective cohort study.

Objective: The study aimed to monitor fetuses with tetralogy of Fallot (TOF) after prenatal counseling and how it influenced the decision of parents to terminate the pregnancy. Methods: Fetuses with isolated TOF diagnosed between January 2019 and December 2021 were prospectively enrolled. The follow-up period extended until termination or 6 months after the operation. Results: Of the 1,026 fetuses diagnosed with cardiac defects, 129 were identified to have isolated TOF and completed the follow-up. A total of 55 (42.6%) fetuses were terminated, with larger maternal age (odds ratio: 0.893, 95% confidence interval: 0.806-0.989, P = 0.031) as the protective factor. The maternal anxiety score, gestational weeks, and pulmonary-to-aortic-diameter ratio lost significance in multivariate analysis. Subjectively, the two most common reasons for terminating the pregnancy were worries about the prognosis (41.8%) and concerns about the possible suffering of the unborn child (18.2%). The prenatal diagnosis was accurate in 73 of the 74 (98.6%) live births. Out of the 64 live births that underwent surgical repair in our center, 57 (89.1%) received primary repair, with a median age of 104 days, and 49 (76.6%) underwent valve-sparing repair. No perioperative death occurred. Conclusions: Termination for fetuses with TOF remains common in China. Live births with TOF can be safely and effectively managed.

Association between hypertriglyceridemic-waist phenotype and circadian syndrome risk: a longitudinal cohort study.

Recently, circadian syndrome (CircS) has been proposed as a new predictor of cardiometabolic risk. We aimed to investigate the relationship between the hypertriglyceridemic-waist phenotype and its dynamic status with CircS in China. We conducted a two-stage study based on the China Health and Retirement Longitudinal Study (CHARLS) from 2011 to 2015. Multivariate logistic regression models in cross-sectional analysis and Cox proportional hazards regression models in longitudinal analysis were used to estimate the associations of hypertriglyceridemic-waist phenotypes with CircS and its components. We then applied multiple logistic regression analysis to evaluate the odds ratios (ORs) and 95% confidence intervals (CIs) for CircS risk by transformation into the hypertriglyceridemic-waist phenotype. A total of 9863 participants were included in the cross-sectional analysis and 3884 participants in the longitudinal analysis. Compared with normal waist circumference (WC) and normal triglyceride (TG) level (NWNT), CircS risk was increased with enlarged WC and high TG level (EWHT) (hazard ratio (HR) 3.87 [95% CI: 2.38, 5.39]). Similar results were observed in subgroup analyses by sex, age, smoking status, and drinking status. During follow-up, CircS risk was increased in group K (stable EWNT during follow-up) (OR 9.97 [95% CI: 6.41, 15.49]) compared with group A (stable NWNT during follow-up), while group L (baseline enlarged WC and normal TG level transformed to follow-up EWHT) had the highest risk of CircS (OR 116.07 [95% CI: 72.77, 185.14]). In conclusion, the hypertriglyceridemic-waist phenotype and its dynamic status were associated with the risk of developing CircS in Chinese adults.

Association of variability in metabolic parameters with the incidence of type 2 diabetes: evidence from a functional community cohort.

BACKGROUND: To investigate the association of variability in metabolic parameters such as total cholesterol concentrations (TC), uric acid (UA), body mass index (BMI), visceral adiposity index (VAI) and systolic blood pressure (SBP) with incident type 2 diabetes (T2D) and whether variability in these metabolic parameters has additive effects on the risk of T2D. METHODS: Based on the Beijing Functional Community Cohort, 4392 participants who underwent three health examinations (2015, 2016, and 2017) were followed up for incident T2D until the end of 2021. Variability in metabolic parameters from three health examinations were assessed using the coefficient of variation, standard deviation, variability independent of the mean, and average real variability. High variability was defined as the highest quartile of variability index. Participants were grouped according to the number of high-variability metabolic parameters. Cox proportional hazards models were performed to assess the hazard ratio (HR) and 95% confidence interval (CI) for incident T2D. RESULTS: During a median follow-up of 3.91 years, 249 cases of incident T2D were identified. High variability in TC, BMI, VAI and SBP was significantly associated with higher risks of incident T2D. As for UA, significant multiplicative interaction was found between variability in UA and variability in other four metabolic parameters for incident T2D. The risk of T2D significantly increased with the increasing numbers of high-variability metabolic parameters. Compared with the group with low variability for 5 parameters, the HR (95% CI) for participants with 1-2, 3, 4-5 high-variability metabolic parameters were 1.488 (1.051, 2.107), 2.036 (1.286, 3.222) and 3.017 (1.549, 5.877), respectively. Similar results were obtained in various sensitivity analyses. CONCLUSIONS: High variability of TC, BMI, VAI and SBP were independent predictors of incident T2D, respectively. There was a graded association between the number of high-variability metabolic parameters and incident T2D.

Di- and Triterpenoids from the Rhizomes of Isodon amethystoides and Their Anti-inflammatory Activities.

Amethystoidesic acid (1), a triterpenoid with an unprecedented 5/6/6/6 tetracyclic skeleton, and six undescribed diterpenoids, amethystoidins A-F (2-7), were isolated from the rhizomes of Isodon amethystoides along with 31 known di- and triterpenoids (8-38). Their structures were fully elucidated via extensive spectroscopic analysis including 1D and 2D NMR, high-resolution electrospray ionization mass spectrometry (HRESIMS), and electronic circular dichroism (ECD) calculations. Compound 1 is the first example of a triterpenoid possessing a rare ring system (5/6/6/6) derived from a contracted A-ring and the 18,19-seco-E-ring of ursolic acid. Compounds 6, 16, 21, 22, 24, and 27 significantly inhibited nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated RAW264.7 cells, which could be partly mediated by the downregulation of LPS-induced inducible nitric oxide synthase (iNOS) protein expression.

Identification of Metabolism-Related Proteins as Biomarkers of Insulin Resistance and Potential Mechanisms of m6A Modification.

BACKGROUND: Insulin resistance (IR) is a major contributing factor to the pathogenesis of metabolic syndrome and type 2 diabetes mellitus (T2D). Adipocyte metabolism is known to play a crucial role in IR. Therefore, the aims of this study were to identify metabolism-related proteins that could be used as potential biomarkers of IR and to investigate the role of N6-methyladenosine (m6A) modification in the pathogenesis of this condition. METHODS: RNA-seq data on human adipose tissue were retrieved from the Gene Expression Omnibus database. The differentially expressed genes of metabolism-related proteins (MP-DEGs) were screened using protein annotation databases. Biological function and pathway annotations of the MP-DEGs were performed through Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses. Key MP-DEGs were screened, and a protein-protein interaction (PPI) network was constructed using STRING, Cytoscape, MCODE, and CytoHubba. LASSO regression analysis was used to select primary hub genes, and their clinical performance was assessed using receiver operating characteristic (ROC) curves. The expression of key MP-DEGs and their relationship with m6A modification were further verified in adipose tissue samples collected from healthy individuals and patients with IR. RESULTS: In total, 69 MP-DEGs were screened and annotated to be enriched in pathways related to hormone metabolism, low-density lipoprotein particle and carboxylic acid transmembrane transporter activity, insulin signaling, and AMPK signaling. The MP-DEG PPI network comprised 69 nodes and 72 edges, from which 10 hub genes (FASN, GCK, FGR, FBP1, GYS2, PNPLA3, MOGAT1, SLC27A2, PNPLA3, and ELOVL6) were identified. FASN was chosen as the key gene because it had the highest maximal clique centrality (MCC) score. GCK, FBP1, and FGR were selected as primary genes by LASSO analysis. According to the ROC curves, GCK, FBP1, FGR, and FASN could be used as potential biomarkers to detect IR with good sensitivity and accuracy (AUC = 0.80, 95% CI: 0.67-0.94; AUC = 0.86, 95% CI: 0.74-0.94; AUC = 0.83, 95% CI: 0.64-0.92; AUC = 0.78, 95% CI: 0.64-0.92). The expression of FASN, GCK, FBP1, and FGR was significantly correlated with that of IGF2BP3, FTO, EIF3A, WTAP, METTL16, and LRPPRC (p < 0.05). In validation clinical samples, the FASN was moderately effective for detecting IR (AUC = 0.78, 95% CI: 0.69-0.80), and its expression was positively correlated with the methylation levels of FASN (r = 0.359, p = 0.001). CONCLUSION: Metabolism-related proteins play critical roles in IR. Moreover, FASN and GCK are potential biomarkers of IR and may be involved in the development of T2D via their m6A modification. These findings offer reliable biomarkers for the early detection of T2D and promising therapeutic targets.

Occupational stress is associated with insulin resistance and incident type 2 diabetes: A prospective cohort study of functional community.

BACKGROUND: To exploit the association of occupational stress with the development of insulin resistance (IR) and type 2 diabetes (T2D) in a Chinese population-based cohort. METHODS: A total of 6109 participants from a functional community cohort in Beijing were enrolled in 2015 and followed up until 2021. Copenhagen Psychosocial Questionnaire (COPSOQ) were used to evaluate occupational stress. RESULTS: At baseline, increase values of all five scales of COPSOQ and total COPSOQ were significantly associated with IR. During an average 5.63 y follow-up, 732 individuals developed T2D. Increasing in values of "Demands at work", "Insecurity at work", "Job satisfaction" and total COPSOQ were significantly associated with incident T2D (P < 0.01). Mediation analysis showed that subjectively perceived occupational stress promoted T2D mainly by affecting plasma cortisol and the mediation effects of HOMA-IR, SBP, DBP, TG, Urea and UA were significant on the association between cortisol and incident T2D, with proportion mediated of 37.1%, 8.12%, 2.02%, 2.94%, 2.35% and 2.70%. CONCLUSION: Occupational stress was independently associated with the development of IR and T2D. IR, BP, TG, Urea and UA all partly mediated the association between occupational stress and incident T2D.

Huangqin Decoction ameliorates ulcerative colitis by regulating fatty acid metabolism to mediate macrophage polarization via activating FFAR4-AMPK-PPARα pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Huangqin Decoction (HQD), a traditional Chinese medicine (TCM) formula chronicled in Shang Han Lun, is safe and effective for treatment of ulcerative colitis (UC). AIM OF THE STUDY: To investigate the effect of HQD against dextran sulfate sodium (DSS)-induced UC mice by regulating gut microbiota and metabolites, and further explore the mechanism of fatty acid metabolism on macrophage polarization. MATERIALS AND METHODS: Based on 3% dextran sulfate sodium (DSS)-induced UC mice model, clinical symptoms observation (body weight, DAI, and colon length) and histological inspection were used to evaluate the efficacy of HQD and fecal microbiota transplantation (FMT) from HQD-treated mice. The gut microbiota and metabolites were detected by 16S rRNA sequencing and metabolomics analysis. The parameters of fatty acid metabolism, macrophage polarization, and FFAR1/FFAR4-AMPK-PPARα pathway were analyzed by immunofluorescence analysis, western blotting, and real-time PCR. Then, the effects of FFAR1 and FFAR4 on macrophage polarization were examined by agonists based on LPS-induced RAW264.7 cell model. RESULTS: The results showed that FMT, like HQD, ameliorated UC by improving weight loss, restoring colon length, and reducing DAI scores and histopathological scores. Besides, HQD and FMT both enhanced the richness of gut microbiota, and modulated intestinal bacteria and metabolites to achieve a new balance. Untargeted metabolomics analysis revealed that fatty acids, especially long-chain fatty acids (LCFAs), dominated in HQD against DSS-induced UC by regulating the gut microenvironment. Further, FMT and HQD recovered the expression of fatty acid metabolism-related enzymes, and simultaneously activated FFAR1/FFAR4-AMPK-PPARα pathway but suppressed NF-κB pathway. Combined with cell experiment, HQD and FMT promoted macrophage polarization from M1 toward M2, which were well associated with anti-inflammatory cytokines and combined with the activated FFAR4. CONCLUSIONS: The mechanism of HQD against UC was related to regulating fatty acid metabolism to mediate M2 macrophage polarization by activating the FFAR4-AMPK-PPARα pathway.

Associations between long-term exposure to ambient fine particulate pollution with the decline of kidney function and hyperuricemia: a longitudinal cohort study.

Evidence of associations between ambient fine particulate matter (PM2.5) and risks of decline of kidney function and hyperuricemia is limited. We aimed to investigate the associations between long-term exposure to PM2.5 with decline of kidney function and hyperuricemia in China. We conducted a two-stage study based on China Health and Retirement Longitudinal Study (CHARLS) from 2011 to 2015. Cox proportional hazard regression models and restricted cubic splines were used to evaluate the associations of PM2.5 with risks of decline of kidney function and hyperuricemia. Latent class trajectory models (LCTM) were used to identify trajectories of PM2.5 from 2011 to 2015 in the sensitivity analysis. A total of 9760 participants were included in baseline analysis, and 5902 participants were in follow-up analysis. PM2.5 was associated with the risks of decline of kidney function [hazard ratio (HR): 2.14; 95% confidence interval (CI): (1.03, 4.44)] and hyperuricemia [HR 1.40 (95% CI: 1.10, 1.79)] in the second quartile group versus the lowest quartile group of PM2.5. We also observed nonlinear relationships between PM2.5 and the risks of the decline of kidney function and hyperuricemia (Pnon-linear < 0.001). In sensitivity analysis, four trajectory groups were identified. "Maintaining a high PM2.5" [odds ratio (OR): 2.20; 95%CI: (1.78, 2.73)] and "moderately high starting PM2.5 then steadily decreased" [OR (95%CI): 5.15 (1.55, 16.13)] were associated with hyperuricemia risk, using "low starting PM2.5 then steadily decreased" trajectory as reference. In conclusion, improved air quality is essential for prevention of decline of kidney function and hyperuricemia.

A systematic review of state-of-the-art strategies for machine learning-based protein function prediction.

New drug discovery is inseparable from the discovery of drug targets, and the vast majority of the known targets are proteins. At the same time, proteins are essential structural and functional elements of living cells necessary for the maintenance of all forms of life. Therefore, protein functions have become the focus of many pharmacological and biological studies. Traditional experimental techniques are no longer adequate for rapidly growing annotation of protein sequences, and approaches to protein function prediction using computational methods have emerged and flourished. A significant trend has been to use machine learning to achieve this goal. In this review, approaches to protein function prediction based on the sequence, structure, protein-protein interaction (PPI) networks, and fusion of multi-information sources are discussed. The current status of research on protein function prediction using machine learning is considered, and existing challenges and prominent breakthroughs are discussed to provide ideas and methods for future studies.