Geniposide reduced oxidative stress-induced apoptosis in HK-2 cell through PI3K/AKT3/FOXO1 by m6A modification.

Exogenous hydrogen peroxide (H2O2) may generate excessive oxidative stress, inducing renal cell apoptosis related with kidney dysfunction. Geniposide (GP) belongs to the iridoid compound with anti-inflammatory, antioxidant and anti-apoptotic effects. This study aimed to observe the intervention effect of GP on H2O2-induced apoptosis in human kidney-2 (HK-2) cells and to explore its potential mechanism in relation to N6-methyladenosine (m6A) RNA methylation. Cell viability, apotosis rate and cell cycle were tested separately after different treatments. The mRNA and protein levels of m6A related enzymes and phosphoinositide 3-kinase (PI3K)/a serine/threonine-specific protein kinase 3 (AKT3)/forkhead boxo 1 (FOXO1) and superoxide dismutase 2 (SOD2) were detected by reverse transcription-quantitative real-time PCR (RT-qPCR) and Western blot. The whole m6A methyltransferase activity and the m6A content were measured by ELISA-like colorimetric methods. The changes of m6A methylation levels of PI3K/AKT3/FOXO1 and SOD2 were determined by methylated RNA immunoprecipitation (MeRIP)-qPCR. Multiple comparisons were performed by ANOVA with Turkey's post hoc test. Exposed to 400 µmol/L H2O2, cells were arrested in G1 phase and the apoptosis rate increased, which were significantly alleviated by GP. Compared with the H2O2 apoptosis group, both the whole m6A RNA methyltransferase activity and the m6A contents were increased due to GP intervention. Besides, the SOD2 protein was increased, while PI3K and FOXO1 decreased. The m6A methylation level of AKT3 was negatively correlated with its protein level. Taken together, GP affects the global m6A methylation microenvironment and regulates the expression of PI3K/AKT3/FOXO1 signaling pathway via m6A modification, alleviating cell cycle arrest and apoptosis caused by oxidative stress in HK-2 cells with a good application prospect.

New aspects characterizing non-obese NAFLD by the analysis of the intestinal flora and metabolites using a mouse model.

Non-alcoholic fatty liver disease (NAFLD) is a major public health problem due to the high incidence affecting approximately one-third of the world's population. NAFLD is usually linked to obesity and excessive weight. A subset of patients with NAFLD expresses normal or low body mass index; thus, the condition is called non-obese NAFLD or lean NAFLD. However, patients and healthcare professionals have little awareness and understanding of NAFLD in non-obese individuals. Furthermore, preclinical results from non-obese animal models with NAFLD are unclear. Gut microbiota and their metabolites in non-obese/lean-NAFLD patients differ from those in obese NAFLD patients. Therefore, we analyzed the biochemical indices, intestinal flora, and intestinal metabolites in a non-obese NAFLD mouse model established using a methionine-choline-deficient (MCD) diet. The significantly lean MCD mice had a remarkable fatty liver with lower serum triglyceride and free fatty acid levels, as well as higher alanine transaminase and aspartate transaminase levels than normal mice. 16S RNA sequencing of fecal DNA showed that the overall richness and diversity of the intestinal flora decreased in MCD mice, whereas the Firmicutes:Bacteroidota ratio was increased. g_Tuzzerella, s_Bifidobacterium pseudolongum, and s_Faecalibaculum rodentium were the predominant species in non-obese NAFLD mice. Fecal metabolomics using liquid chromatography-tandem mass spectrometry revealed the potential biomarkers for the prognosis and diagnosis of non-obese NAFLD, including high levels of tyramine glucuronide, 9,12,13-TriHOME, and pantetheine 4'-phosphate, and low levels of 3-carbamoyl-2-phenylpropionaldehyde, N-succinyl-L,L-2,6-diaminopimelate, 4-methyl-5-thiazoleethanol, homogentisic acid, and estriol. Our findings could be useful to identify and develop drugs to treat non-obese NAFLD and lean NAFLD. IMPORTANCE: Patients and healthcare professionals have little awareness and understanding of NAFLD in non-obese individuals. In fact, about 40% of people with NAFLD worldwide are non-obese, and nearly one-fifth are lean. Lean NAFLD unfortunately may be unnoticed for years and remains undetected until hepatic damage is advanced and the prognosis is compromised. This study focused on the lean NAFLD, screened therapeutic agents, and biomarkers for the prognosis and diagnosis using MCD-induced male C57BL/6J mice. The metabolites tyramine glucuronide, 9,12,13-TriHOME, and pantetheine 4'-phosphate, together with the predominant flora including g_Tuzzerella, s_Bifidobacterium pseudolongum, and s_Faecalibaculum rodentium, were specific in non-obese NAFLD mice and might be used as targets for non-obese NAFLD drug exploration. This study is particularly significant for non-obese NAFLDs that need to be more actively noticed and vigilant.

Association between HDL-C and intensive blood pressure control in patients with hypertension: A post-hoc analysis of SPRINT.

Previous studies in patients with hypertension have demonstrated that there is a U-shaped association between HDL-C (high-density lipoprotein cholesterol) and the risk of cardiovascular events in male patients with hypertension. However, to the best of our knowledge, the relationship between HDL-C and intensive blood pressure control in specific cardiovascular events has never been investigated. To fill this knowledge gap, the authors analyzed the relationship between HDL-C levels and cardiovascular events in hypertensive patients within the Systolic Blood Pressure Intervention Trial (SPRINT). The SPRINT evaluated the impact of intensive blood pressure control (systolic blood pressure < 120 mm Hg) versus standard blood pressure control (systolic blood pressure < 140 mm Hg). The Cox proportional risk regression was used to investigate the association between different HDL-C status and clinical outcomes. Additional stratified analyzes were performed to evaluate the robustness of sex difference. A total of 9323 participants (6016 [64.53%] males and 3307 [35.47%] females) with hypertension from the SPRINT research were included in the analysis. The median follow-up period was 3.26 years. Our population was divided into five groups based on the HDL-C plasma levels: HDL-C < 30 mg/dL, HDL-C between 30 and 40 mg/dL, HDL-C between 40 and 60 mg/dL, HDL-C between 60 and 80 mg/dL and HDL-C > 80 mg/dL. Sensitivity analyzes showed that in the SPRINT, women in the HDL-C high population had a higher risk of mortality from all causes than men. In this cohort study, results suggest that patients with HDL-C levels higher than 80 mg/dL had lower risk of SPRINT primary outcome, cardiovascular death, and stroke, but this study tested association, not causation. HDL-C levels were associated with composite cardiovascular outcomes in male but not female patients. Our results demonstrated that in patients with hypertension, the association between HDL-C and risk of cardiovascular events is L-shaped.

Association between the ZJU index and risk of new-onset non-alcoholic fatty liver disease in non-obese participants: a Chinese longitudinal prospective cohort study.

Background: Non-alcoholic fatty liver disease (NAFLD) is increasingly observed in non-obese individuals. The ZJU (Zhejiang University) index has been established as a new and efficient tool for detecting NAFLD, but the relationship between the ZJU index and NAFLD within non-obese individuals still remains unclear. Methods: A post-hoc evaluation was undertaken using data from a health assessment database by the Wenzhou Medical Center. The participants were divided into four groups based on the quartile of the ZJU Index. Cox proportional hazards regression, Kaplan-Meier analysis and tests for linear trends were used to evaluate the relationship between the ZJU index and NAFLD incidence. Subgroup analysis was conducted to test the consistency of the correlation between ZJU and NAFLD in subsgroups. Receiver operative characteristic (ROC) curve analysis was performed to evaluate the predictive performance of the ZJU index, compared with the Atherogenic index of plasma (AIP) and Remnant lipoprotein cholesterol (RLP-C) index. Results: A total of 12,127 were included in this study, and 2,147 participants (17.7%) developed NAFLD in 5 years follow-up. Participants in higher ZJU quartiles tended to be female and have higher liver enzymes (including ALP, GGT, ALT, AST), GLU, TC, TG, LDL and higher NAFLD risk. Hazard Ratios (HR) and 95% confidence intervals (CI) for new-onset NAFLD in Q2, Q3, and Q4 were 3.67(2.43 to 5.55), 9.82(6.67 to 14.45), and 21.67(14.82 to 31.69) respectively in the fully adjusted model 3. With increased ZJU index, the cumulative new-onset NAFLD gradually increased. Significant linear associations were observed between the ZJU index and new-onset NAFLD (p for trend all<0.001). In the subgroup analysis, we noted a significant interaction in sex, with HRs of 3.27 (2.81, 3.80) in female and 2.41 (2.21, 2.63) in male (P for interaction<0.01). The ZJU index outperformed other indices with an area under the curve (AUC) of 0.823, followed by AIP (AUC=0.747) and RLP-C (AUC=0.668). Conclusion: The ZJU index emerges as a promising tool for predicting NAFLD risk in non-obese individuals, outperforming other existing parameters including AIP and RLP-C. This could potentially aid in early detection and intervention in this specific demographic.

Efficacy and safety of olmesartan medoxomil­amlodipine besylate tablets (Sevikar®) in older patients with essential hypertension: Subgroup analysis from the Sevikar study.

Essential hypertension is a notable threat for the older (age, ≥65 years) population. However, to the best of our knowledge, a real-world study assessing olmesartan medoxomil-amlodipine besylate (OM-AML) tablets in older Chinese patients with essential hypertension has not been performed. Therefore, the present study aimed to evaluate the efficacy and safety of OM-AML tablets in these patients. A total of 463 older Chinese patients with essential hypertension treated with OM-AML (20/5 mg) tablets (Sevikar®) were analyzed in a prospective, single-arm, multi-center, real-world study. Seated systolic blood pressure (SeSBP) and seated diastolic blood pressure (SeDBP) at baseline, and at week (W)4 and W8 after OM-AML tablet administration were measured. The mean ± standard error change of SeSBP/SeDBP was -10.3±0.8/-4.6±0.5 and -12.5±0.8/-5.6±0.5 mmHg at W4 and W8, respectively. At W4, 74.1 and 26.8% of patients achieved BP target according to the China and American Heart Association (AHA) criteria, while at W8, 78.0 and 38.7% of patients reached these BP targets accordingly. Finally, 76.5 and 80.5% of patients achieved BP response at W4 and W8, respectively. Furthermore, home-measured SeSBP and SeDBP were significantly decreased from W1 to W8 (both P<0.001). Additionally, the satisfaction of both patients and physicians was elevated at W8 compared with at W0 (both P<0.001). The medication possession rate from baseline to W4 and W8 was 95.5 and 92.5%. The most common drug-associated adverse events by system organ classes were nervous system disorder (4.5%), vascular disorder (2.8%), and general disorder and administration site conditions (2.6%), which were generally mild. In conclusion, OM-AML tablets may be considered effective and safe in lowering BP, enabling the achievement of guideline-recommended BP targets in older Chinese patients with essential hypertension.

Healthy plant-based diet might be inversely associated with gastric precancerous lesions: new evidence from a case-control study based on dietary pattern and fecal metabolic profiling.

Preventing the progression of gastric precancerous lesions (GPLs) can reduce the morbidity and mortality of gastric cancer (GC). The preventive effect of a plant-based diet on cancers has been widely recognised. In this case-control study, 1,130 subjects were included using 1:1 propensity score matching for age and sex. Dietary habits, anthropometry and sample collection were conducted using standard and effective methods. Plant-based diet indices (PDIs) were calculated using a previously reported method. Faecal samples were analysed by untargeted metabolomics. Our study found that adherence to a healthy plant-based diet was inversely associated with the occurrence of GPLs. Metabolomic analysis identified six different metabolites correlated with GPLs, among which luteolin-related metabolites may be used as biomarkers of the association between PDIs and GPLs. In addition, the difference in N-acyl amides found in PDIs needs further verification. Our findings suggest that a healthy plant-based diet may have a protective effect against GPLs.

Efficacy and safety of olmesartan medoxomil-amlodipine besylate tablet in Chinese patients with essential hypertension: A prospective, single-arm, multi-center, real-world study.

There lacks real-world study with a large sample size assessing olmesartan medoxomil-amlodipine besylate (OM-AML) tablet. Therefore, this study aimed to evaluate the efficacy and safety of OM-AML tablet in patients with essential hypertension. Totally, 1341 patients from 36 medical centers with essential hypertension who took OM-AML (20/5 mg) tablet were analyzed in the current prospective, single-arm, multi-center, real-world study (SVK study). Seated systolic blood pressure (SeSBP) and seated diastolic blood pressure (SeDBP) at baseline, week (W)4 and W8 were measured. The mean (±SE) change of SeSBP/SeDBP was -10.8 ± 0.4/-6.6 ± 0.3 mmHg at W4 and -12.7 ± 0.5/-7.6 ± 0.3 mmHg at W8, respectively. At W4, 78.8% and 29.0% patients achieved BP target by China and American Heart Association (AHA) criteria; at W8, 84.7% and 36.5% patients reached blood pressure (BP) target by China and AHA criteria, accordingly. Meanwhile, 80.2% and 86.4% patients achieved BP response at W4 and W8, respectively. Home-measured SeSBP and SeDBP decreased from W1 to W8 (both p < .001). Besides, patients' and physicians' satisfaction were elevated at W8 compared with W0 (both p < .001). The medication possession rate was 94.8% from baseline to W4 and 91.3% from baseline to W8. The most common drug-related adverse events were nervous system disorders (4.6%), vascular disorders (2.6%), and general disorders and administration site conditions (2.3%) by system organ class, which were generally mild and manageable. In conclusion, OM-AML tablet is one of the best antihypertensive agents in patients with essential hypertension.

Geniposide alleviated hydrogen peroxide-induced apoptosis of human hepatocytes via altering DNA methylation.

Geniposide (GP) is the homology of medicine and food with bioactive effects of antioxidation and resistance to apoptosis in the liver. It's of great significance to explore the biosafety exposure limits and action mechanisms of GP. This study detected the global DNA methylation microenvironment and the regulation of specific genes in GP against cellular apoptosis induced by hydrogen peroxide (H2O2) of human hepatocyte L-02 cells. The half inhibitory concentration (IC50) of GP on normal L-02 cells was 57.7 mg/mL. GP exerted new epigenetic activity, increased DNMT1, decreased TET1 and TET2 expression, and reversed the demethylation effect to some extent, thereby increasing the overall genomic DNA methylation level at the concentration of 900 µg/mL. GP pretreatment could also adjust the level of P53, Bcl-2 and AKT altered by H2O2, reducing their specific DNA methylation levels in the promoter regions of AKT and Bcl-2 to inhibit apoptosis. Taken together, GP regulates the global DNA methylation level and controls the expression changes of P53, Bcl-2 and AKT, jointly inhibiting the occurrence of apoptosis in human hepatocytes and providing the newly theoretical references for its safety evaluation.

An adversarially consensus model of augmented unlabeled data for cardiac image segmentation (CAU+).

High quality medical images play an important role in intelligent medical analyses. However, the difficulty of acquiring medical images with professional annotation makes the required medical image datasets, very expensive and time-consuming. In this paper, we propose a semi-supervised method, $ {\mathrm{C}\mathrm{A}\mathrm{U}}^{+} $, which is a consensus model of augmented unlabeled data for cardiac image segmentation. First, the whole is divided into two parts: the segmentation network and the discriminator network. The segmentation network is based on the teacher student model. A labeled image is sent to the student model, while an unlabeled image is processed by CTAugment. The strongly augmented samples are sent to the student model and the weakly augmented samples are sent to the teacher model. Second, $ {\mathrm{C}\mathrm{A}\mathrm{U}}^{+} $ adopts a hybrid loss function, which mixes the supervised loss for labeled data with the unsupervised loss for unlabeled data. Third, an adversarial learning is introduced to facilitate the semi-supervised learning of unlabeled images by using the confidence map generated by the discriminator as a supervised signal. After evaluating on an automated cardiac diagnosis challenge (ACDC), our proposed method $ {\mathrm{C}\mathrm{A}\mathrm{U}}^{+} $ has good effectiveness and generality and $ {\mathrm{C}\mathrm{A}\mathrm{U}}^{+} $ is confirmed to have a improves dice coefficient (DSC) by up to 18.01, Jaccard coefficient (JC) by up to 16.72, relative absolute volume difference (RAVD) by up to 0.8, average surface distance (ASD) and 95% Hausdorff distance ($ {HD}_{95} $) reduced by over 50% than the latest semi-supervised learning methods.

Synergistic effects of low-dose arsenic and N-methyl-N'-nitro-N-nitrosoguanidine co-exposure by altering gut microbiota and intestinal metabolic profile in rats.

Biological organisms are exposed to low-dose arsenic or N-nitro compounds (NOCs) alone or in combination worldwide, especially in areas with high cancer prevalence through drinking water or food exposure; however, information on their combined exposure effects is limited. Here, we conducted an in-depth study of the effects on the gut microbiota, metabolomics, and signaling pathways using rat models exposed to arsenic or N-methyl-N'-nitro-N-nitrosoguanidine (MNNG), one of the most active carcinogenic NOCs, separately or in combination with metabolomics and high-throughput sequencing. Compared to exposure alone, combined exposure to arsenic and MNNG exacerbated damage to gastric tissue morphology, interfered with intestinal microflora and substance metabolism, and exerted a stronger carcinogenic effect. This may be related to intestinal microbiota disorders, including Dyella, Oscillibacter, Myroides, and metabolic pathways such as glycine, serine, and threonine metabolism, arginine biosynthesis, central carbon metabolism in cancer, and purine and pyrimidine metabolism, thereby enhancing the cancer-causing effects of gonadotrophin-releasing hormone (GnRH), P53, and Wnt signaling pathways.

Safety and effectiveness of metformin plus lifestyle intervention compared with lifestyle intervention alone in preventing progression to diabetes in a Chinese population with impaired glucose regulation: a multicentre, open-label, randomised controlled trial.

BACKGROUND: Impaired glucose regulation (defined as either impaired glucose tolerance or impaired fasting glucose) is an important risk factor for the development of diabetes. We aimed to evaluate the safety and effectiveness of metformin plus lifestyle intervention compared with lifestyle intervention alone in preventing diabetes in Chinese participants with impaired glucose regulation. METHODS: We did a multicentre, open-label, randomised controlled trial at 43 endocrinology departments in general hospitals across China. Eligible participants were individuals with impaired glucose regulation (ie, impaired glucose tolerance or impaired fasting glucose, or both), men or women aged 18-70 years with a BMI of 21-32 kg/m2. Eligible participants were randomly assigned (1:1) via a computer-generated randomisation to receive either standard lifestyle intervention alone or metformin (850 mg orally once per day for the first 2 weeks and titrated to 1700 mg orally per day [850 mg twice per day]) plus lifestyle intervention. Block randomisation was used with a block size of four, stratified by glucose status (impaired fasting glucose or impaired glucose tolerance), hypertension, and use of any anti-hypertensive medication. Lifestyle intervention advice was given by investigators at all participating sites. The primary endpoint was the incidence of newly diagnosed diabetes at the end of the 2-year follow-up. Analysis was done using the full analysis set and per-protocol set. This study is registered with ClinicalTrials.gov, number NCT03441750, and is completed. FINDINGS: Between April, 2017, and June, 2019, 3881 individuals were assessed for eligibility, of which 1678 (43·2%) participants were randomly assigned to either the metformin plus lifestyle intervention group (n=831) or the lifestyle intervention alone group (n=847) and received the allocated intervention at least once. During a median follow-up of 2·03 years, the incidence rate of diabetes was 17·27 (95% CI 15·19-19·56) per 100 person-years in the metformin plus lifestyle intervention group and 19·83 (17·67-22·18) per 100 person-years in the lifestyle intervention alone group. The metformin plus lifestyle intervention group showed a 17% lower risk of developing diabetes than the lifestyle intervention alone group (HR 0·83 [95% CI 0·70-0·99]; log-rank p=0·043). A higher proportion of participants in the metformin plus lifestyle intervention group reported adverse events than in the lifestyle intervention alone group, primarily due to more gastrointestinal adverse events. The percentage of participants reporting a serious adverse event was similar in both groups. INTERPRETATION: Metformin plus lifestyle intervention further reduced the risk of developing diabetes than lifestyle intervention alone in Chinese people with impaired glucose regulation, showing additional benefits of combined intervention in preventing progression to diabetes without new safety concerns. FUNDING: Merck Serono China, an affiliate of Merck KGaA, Darmstadt, Germany. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

A nomogram for predicting cancer-specific survival in patients with uterine clear cell carcinoma: a population-based study.

Uterine clear cell carcinoma (UCCC) is a relatively rare endometrial cancer. There is limited information on its prognosis. This study aimed to develop a predictive model predicting the cancer-specific survival (CSS) of UCCC patients based on data from the Surveillance, Epidemiology, and End Results (SEER) database between 2000 and 2018. A total of 2329 patients initially diagnosed with UCCC were included in this study. Patients were randomized into training and validation cohorts (7:3). Multivariate Cox regression analysis identified that age, tumor size, SEER stage, surgery, number of lymph nodes detected, lymph node metastasis, radiotherapy and chemotherapy were independent prognostic factors for CSS. Based on these factors, a nomogram for predicting the prognosis of UCCC patients was constructed. The nomogram was validated using concordance index (C-index), calibration curves, and decision curve analyses (DCA). The C-index of the nomograms in the training and validation sets are 0.778 and 0.765, respectively. Calibration curves showed good consistency of CSS between actual observations and nomogram predictions, and DCA showed that the nomogram has great clinical utility. In conclusion, a prognostic nomogram was firstly established for predicting the CSS of UCCC patients, which can help clinicians make personalized prognostic predictions and provide accurate treatment recommendations.

Close association of PFASs exposure with hepatic fibrosis than steatosis: evidences from NHANES 2017-2018.

Multiple animals and in vitro studies have demonstrated that perfluoroalkyl and polyfluoroalkyl substances (PFASs) exposure causes liver damage associated with fat metabolism. However, it is lack of population evidence for the correlation between PFAS exposure and nonalcoholic fatty liver disease (NAFLD). A cross-sectional analysis was performed of 1150 participants aged over 20 from the US. Liver ultrasound transient elastography was to identify the participants with NAFLD and multiple biomarkers were the indicators for hepatic steatosis and hepatic fibrosis. Logistics regression and restricted cubic splines models were used to estimate the association between PFASs and NAFLD. PFASs had not a significant association with NAFLD after adjustment. The hepatic steatosis indicators including fatty liver index, NAFLD liver fat score, and Framingham steatosis index were almost not significantly correlated with PFASs exposure respectively. But fibrosis indicators including fibrosis-4 index (FIB-4), NAFLD fibrosis score, and Hepamet fibrosis score were positively correlated with each type of PFASs exposure. After adjustment by gender, age, race, education, and poverty income rate, there was also a significant correlation between PFOS and FIB-4 with 0.07 (0.01, 0.13). The mixed PFASs were associated with FIB-4, with PFOS contributing the most (PIP = 1.000) by the Bayesian kernel machine regression model. The results suggested PFASs exposure appeared to be more closely associated with hepatic fibrosis than steatosis, and PFOS might be the main cause of PFASs associated with hepatic fibrosis.Key messagesCurrent exposure doses of PFAS did not significantly change the risk of developing NAFLD.PFASs exposure appeared to be more closely associated with hepatic fibrosis than steatosis.PFOS might be the main cause of PFASs associated with hepatic fibrosis.

Co-exposure to iron, copper, zinc, selenium and titanium is associated with the prevention of gastric precancerous lesions.

Gastric cancer is the third leading cause of cancer death, and gastric precancerous lesions (GPLs) are an important stage in the transformation of normal gastric mucosa to gastric cancer. Matched for age and sex, a total of 316 subjects were eventually included from our prospective observation population (including 1007 patients with GPLs and 762 normal controls), and a questionnaire survey was conducted. In total, 10 plasma elements (iron, copper, zinc, selenium, rubidium, strontium, titanium, aluminum, vanadium and arsenic) were measured by applying inductively coupled plasma‒mass spectrometry (ICP‒MS). A multivariate conditional logistic regression model and Bayesian kernel logistic regression model (BKMR) were used to analyze the association between plasma element concentrations and GPLs. In the multimetal model, plasma titanium concentrations were significantly and positively associated with the prevalence of GPLs, with a fourth-quartile OR of 11.56 ([95% CI]: [2.78-48.13]). Plasma selenium and copper were negatively correlated with GPLs, with the highest quartiles of selenium and copper having an OR of 0.03 ([95% CI]: [0.01-0.15]; P < 0.001) and 0.24 ([95% CI]: [0.07-0.82]), respectively. In the BKMR model, there was a significant negative combined correlation of five metals on GPLs: iron, copper, zinc, selenium, and titanium. The results of this study showed that plasma concentrations of selenium and copper were negatively correlated with GPLs, while plasma concentrations of titanium were positively correlated with GPLs, and the combined action of the five elements was negatively correlated with GPLs.

Association between perfluoroalkyl and polyfluoroalkyl internal exposure and serum α-Klotho levels in middle-old aged participants.

Purpose: Exposure to perfluoroalkyl and polyfluoroalkyl substances causes oxidative stress, which is strongly associated with adverse health effects. Klotho protein plays an anti-aging role via antioxidation activity. Methods: We investigated the levels of serum α-Klotho and PFAS exposure in adults who participated in the National Health and Nutrition Examination Survey from 2013 to 2016. A nationally representative subsample of 1,499 adults aged 40-79 years was analyzed for the associations of serum α-Klotho levels with serum PFAS exposures by correlation analysis and multiple general linear models. Of note, the potential confounding factors including age and gender were adjusted. Quantile-based g-computation models were used to assess the effects of mixed PFAS exposure on serum α-Klotho levels. Results: The weighted geometric mean of serum α-Klotho was 791.38 pg/mL for the subjects during 2013-2016. After adjusting for potential confounders, serum Klotho levels showed a statistically significant downward trend with increasing quartiles of PFOA and PFNA. Multivariate adjusted general linear regression analysis showed that increased exposure to PFNA was substantially associated with lower serum levels of α-Klotho, and each 1-unit increase in PFNA concentration was accompanied by a 20.23 pg/mL decrease in α-Klotho level; while no significant association was observed between other PFAS exposures and serum α-Klotho levels. It was negatively correlated between α-Klotho and Q4 for PFNA relative to the lowest quartile (Q1) of exposure (P = 0.025). It was found that the strongest negative correlation between PFNA exposure and serum α-Klotho levels was in the middle-aged (40-59 years) female participants. Furthermore, the mixture of the four PFAS substances showed an overall inverse association with serum α-Klotho concentrations, with PFNA being the major contributor. Conclusions: Taken together, in a representative sample of the U.S. middle-aged and elderly populations, serum concentrations of PFAS, especially PFNA, have been negatively associated with serum levels of α-Klotho, which is strongly associated with cognition and aging. It was important to note that the majority of associations were limited to middle-aged women. It will be meaningful to clarify the causal relationship and the pathogenic mechanisms of PFAS exposure and α-Klotho levels, which is helpful to aging and aging-related diseases.

Effects of Intestinal Microorganisms on Influenza-Infected Mice with Antibiotic-Induced Intestinal Dysbiosis, through the TLR7 Signaling Pathway.

BACKGROUND: Stability of intestinal flora is not only important for maintaining stable immune functions; it is also a key immune channel communicating the interaction between lung and intestine. In this study, probiotics and fecal microbiota transplantation (FMT) were used to regulate influenza-infected mice with antibiotic-induced intestinal dysbiosis and the effects of intestinal microorganisms on these mice were subsequently observed and evaluated. METHODS: Mice are housed in a normal environment with intranasal infection with influenza virus (FM1). Real-time quantitative polymerase chain reaction (RT-qPCR) was used to determine messenger RNA expression and lung viral replication of toll-like receptor 7 (TLR7), myeloid differentiation primary reaction 88 (MyD88) and nuclear factor κB (ss) p65 in the TLR7 signaling pathway. Western blotting is used to measure the expression levels of TLR7, MyD88, and NF-κB p65 proteins. Flow cytometry was used to detect the proportion of Th17/T regulated cells. RESULTS: Results showed that compared with the simple virus group, both diversity and species of intestinal flora in influenza-infected mice with antibiotic-induced intestinal dysbiosis were lower, in vivo viral replication was significantly increased, lung and intestinal tissues were seriously damaged, degree of inflammation increased, expression of the TLR7 signaling pathway increased, and the Th1/Th2:Th17/Treg ratio decreased. Probiotics and FMT effectively regulated intestinal flora, improved pathological lung changes and inflammation caused by influenza infection, and adjusted the TLR7 signaling pathway and the Th1/Th2:Th17/Treg ratio. This effect was not obvious in TLR7-⁣/- mice.In summary, by affecting the TLR7 signaling pathway, intestinal microorganisms reduced the inflammatory response in the lungs of influenza-infected mice with imbalances in antibiotic flora. CONCLUSIONS: By affecting the TLR7 signaling pathway, intestinal microorganisms reduced the inflammatory response in the lungs of influenza-infected mice with imbalances in antibiotic flora. In summary, damage to lung tissue and intestinal mucosa in influenza-infected mice with antibiotic-induced intestinal dysbiosis is more serious compared to simple virus-infected mice. Improving intestinal flora using probiotics or FMT can alleviate intestinal inflammation and improve pulmonary inflammation through the TLR7 signaling pathway.

Epidemiological characteristics of community-acquired pneumonia and effects from the COVID-19 pandemic in Shenzhen of China.

OBJECTIVE: This study aimed to observe the impact of the coronavirus disease 2019 (COVID-19) pandemic on the incidence of non-COVID-19 community-acquired pneumonia (CAP) in Shenzhen of China, offering new ideas for evaluating the effects of non-pharmaceutical interventions. METHODS: A retrospective analysis was conducted of inpatients with pneumonia from 2017 to 2021. Epidemiological characteristics of CAP and effects from the COVID-19 pandemic were analyzed by the basic characteristics, time distribution, etiology and disease burden. RESULTS: There were a total of 5746 CAP inpatient cases included from 2017 to 2021. The number of CAP hospitalizations decreased during the pandemic from 2020 to 2021, with seasonal variations of being higher in spring and winter and lower in summer and autumn, whereas it was prevalent throughout the year prior to the pandemic. The children group decreased significantly during the pandemic, with a 15% decrease in the share of CAP inpatients. The detection rates of bacteria and mycoplasma decreased in CAP patients, while the detection rate of the virus increased, and the number of moderate and severe cases reduced more than that of the mild. CONCLUSION: Non-pharmaceutical interventions from COVID-19 have led to a decrease in the number of CAP inpatients, especially for children, with a specific seasonal prevalence in spring and winter, when the prevention interventions should be strengthened further for adults during the pandemic.

New roles of N6-methyladenosine methylation system regulating the occurrence of non-alcoholic fatty liver disease with N6-methyladenosine-modified MYC.

Non-alcoholic fatty liver disease (NAFLD) has become a major chronic disease in contemporary society, affected by N6-methyladenosine (m6A) RNA methylation, one of the most common RNA modifications. Compared with healthy control, m6A RNA methyltransferase 3 (METTL3) and METTL14 increased, while Wilms tumor 1-associated protein (WTAP) and RNA-binding motif protein 15 (RBM15) decreased significantly in NAFLD, and the m6A demethylases fat mass and obesity-associated protein (FTO) elevated. Meanwhile, the m6A binding proteins, YT521-B homology (YTH) domain-containing 1 (YTHDC1), YTHDC2, insulin-like growth factor 2 mRNA binding protein 1 (IGF2BP1), heterogeneous nuclear ribonucleoprotein C (HNRNPC), and HNRNPA2B1 were decreased, while eukaryotic translation initiation factor 3 subunit H (EIF3H) was increased significantly. All these changes of m6A regulators had significant differences between healthy control and NAFLD, but no differences between the NAFL and NASH group. The expression level of RBM15, HNRNPC, and HNRNPA2B1 were related to body fat index. RBM15, YTHDC2, HNRNPC, HNRNPA2B1, and EIF3H were related to steatosis. Also, KIAA1429 and YTH domain family 1 (YTHDF1) were related to lobular inflammation. Taken together, m6A regulators were involved in the occurrence of NAFLD. More importantly, abnormal MYC was determined as a key link to m6A regulation of NAFLD. The higher MYC mRNA level was accompanied by higher HDL cholesterol and unsaturated fatty acid proportions, as well as lower fat mass, glucose, and transaminase. Taken together, dysregulation of m6A methylation caused steatosis and fibrosis, affecting the occurrence of NAFLD, and MYC might be its potential target.

Novel Roles of RNA m6A Methylation Regulators in the Occurrence of Alzheimer's Disease and the Subtype Classification.

Alzheimer's disease (AD) is one of the most common forms of dementia, closely related to epigenetic factors. N6-methyladenosine (m6A) is the most abundant RNA modification, affecting the pathogenesis and development of neurodegenerative diseases. This study was the first exploration of the combined role of 25 common m6A RNA methylation regulators in AD through the integrated bioinformatics approaches. The 14 m6A regulators related to AD were selected by analyzing differences between AD patients and normal controls. Based on the selected m6A regulators, AD patients could be well classified into two m6A models using consensus clustering. The two clusters of patients had different immune profiles, and m6A regulators were associated with the components of immune cells. Additionally, there were 19 key AD genes obtained by screening differential genes through weighted gene co-expression network and least absolute shrinkage and selection operator regression analysis, which were highly associated with important m6A regulators during the occurrence of AD. More interestingly, NOTCH2 and NME1 could be potential targets for m6A regulation of AD. Taken together, these findings indicate that dysregulation of m6A methylation affects the occurrence of AD and is vital for the subtype classification and immune infiltration of AD.

Effect of theaflavin-3,3'-digallate on leptin-deficient induced nonalcoholic fatty liver disease might be related to lipid metabolism regulated by the Fads1/PPARδ/Fabp4 axis and gut microbiota.

Nonalcoholic fatty liver disease (NAFLD), one of the risk factors for hepatitis, cirrhosis, and even hepatic carcinoma, has been a global public health problem. The polyphenol compound theaflavin-3,3'-digallate (TF3), mainly extracted from black tea, has been reported to produce an effect on hypoglycemic and antilipid deposition in vitro. In our study, we further investigated the function and novel mechanisms of TF3 in protecting NAFLD in vivo. By using leptin-deficient obese (ob/ob) mice with NAFLD symptoms, TF3 treatment prevented body weight and waistline gain, reduced lipid accumulation, and alleviated liver function injury, as well as decreased serum lipid levels and TG levels in livers in ob/ob mice, observing no side effects. Furthermore, the transcriptome sequencing of liver tissue showed that TF3 treatment corrected the expression profiles of livers in ob/ob mice compared with that of the model group. It is interesting to note that TF3 might regulate lipid metabolism via the Fads1/PPARδ/Fabp4 axis. In addition, 16S rRNA sequencing demonstrated that TF3 increased the abundance of Prevotellaceae_UCG-001, norank_f_Ruminococcaceae, and GCA-900066575 and significantly decreased that of Parvibacter. Taken together, the effect of TF3 on NAFLD might be related to lipid metabolism regulated by the Fads1/PPARδ/Fabp4 axis and gut microbiota. TF3 might be a promising candidate for NAFLD therapy.