Th17/Treg balance and macrophage polarization ratio in lower extremity arteriosclerosis obliterans

Objective:To explore the balance of peripheral blood T helper 17 cells/regulatory T cell(Th17/Treg)ratio and the polarization ratio of M1 and M2 macrophages in lower extremity arteriosclerosis obliterans(ASO).Methods:A rat model of lower extremity ASO was established,and blood samples from patients with lower extremity ASO before and after surgery were obtained.ELISA was used to detect interleukin 6(IL-6),IL-10,and IL-17.Real-time RCR and Western blot analyses were used to detect Foxp3,IL-6,IL-10,and IL-17 expression.Moreover,flow cytometry was applied to detect the Th17/Treg ratio and M1/M2 ratio.Results:Compared with the control group,the iliac artery wall of ASO rats showed significant hyperplasia,and the concentrations of cholesterol and triglyceride were significantly increased(P<0.01),indicating the successful establishment of ASO.Moreover,the levels of IL-6 and IL-17 in ASO rats were pronouncedly increased(P<0.05),while the IL-10 level was significantly decreased(P<0.05).In addition to increased IL-6 and IL-17 levels,the mRNA and protein levels of Foxp3 and IL-10 in ASO rats were significantly decreased compared with the control group.The Th17/Treg and M1/M2 ratios in the ASO group were markedly increased(P<0.05).These alternations were also observed in ASO patients.After endovascular surgery(such as percutaneous transluminal angioplasty and arterial stenting),all these changes were significantly improved(P<0.05).Conclusions:The Th17/Treg and M1/M2 ratios were significantly increased in ASO,and surgery can effectively improve the balance of Th17/Treg,and reduce the ratio of M1/M2,and the expression of inflammatory factors.

Outcome of bariatric surgery in patients with unexpected liver cirrhosis: A multicenter study from China

Background and aims Liver cirrhosis is a complex disease that may result in increased morbidity and mortality following bariatric surgery(BS).This study aimed to explore the outcome of BS in patients with unexpected cirrhosis,focusing on postoperative complications and the progression of liver disease.Methods A retrospective study of bariatric patients with cirrhosis from four centers in China between 2016 and 2023 was conducted,with follow-up for one year after BS.The primary outcome was the safety of BS in patients with unexpected cirrhosis,while the secondary outcome was the metabolic efficacy of BS in this group postoperatively.Results A total of 47 patients met the study criteria,including 46 cases of Child-Pugh class A cirrhosis and 1 case of Child-Pugh B.Pathological examination confirmed nodular cirrhosis in 21 patients(44.68%),pseudolobule formation in 1 patient(2.13%),lipedema degeneration with inflammatory cell infiltration in 3 patients(6.38%),and chronic hepatitis in 1 patient(2.13%).The average percentage of total weight loss was 29.73±6.53%at one year postoperatively.During the 30-day postoperative period,the complication rate was 6.38%,which included portal vein thrombosis,gastrointestinal bleeding,and intra-abdominal infection.Moreover,no cases of liver decompensation or mortality were reported during the follow-up period.The remission rates of comorbidities among 41 patients one year after surgery were as follows:dyslipidemia 100%,type 2 diabetes 82.61%,hypertension 84.62%,and obstructive sleep apnea syndrome 85.71%.Conclusions BS can be safely performed in patients with unexpected cirrhosis in the compensated stage of liver disease,with low postoperative morbidity and no mortality observed during one-year follow-up.

Caloric restriction-mimetics for the reduction of heart failure risk in aging heart: with consideration of gender-related differences

The literature is full of claims regarding the consumption of polyphenol or polyamine-rich foods that offer some protection from developing cardiovascular disease(CVD). This is achieved by preventing cardiac hypertrophy and protecting blood vessels through improving the function of endothelium. However, do these interventions work in the aged human hearts? Cardiac aging is accompanied by an increase in left ventricular hypertrophy, along with diastolic and systolic dysfunction. It also confers significant cardiovascular risks for both sexes. The incidence and prevalence of CVD increase sharply at an earlier age in men than women. Furthermore, the patterns of heart failure differ between sexes, as do the lifetime risk factors. Do caloric restriction(CR)-mimetics, rich in polyphenol or polyamine, delay or reverse cardiac aging equally in both men and women? This review will discuss three areas:(1) mechanisms underlying age-related cardiac remodeling;(2) gender-related differences and potential mechanisms underlying diminished cardiac response in older men and women;(3) we select a few polyphenol or polyamine rich compounds as the CRmimetics, such as resveratrol, quercetin, curcumin, epigallocatechin gallate and spermidine, due to their capability to extend health-span and induce autophagy. We outline their abilities and issues on retarding aging in animal hearts and preventing CVD in humans. We discuss the confounding factors that should be considered for developing therapeutic strategies against cardiac aging in humans.

Global trends in diabetic eye disease research from 2012 to 2021

Diabetic eye disease refers to a group of eye complications that occur in diabetic patients and include diabetic retinopathy, diabetic macular edema, diabetic cataracts, and diabetic glaucoma. However, the global epidemiology of these conditions has not been well characterized. In this study, we collected information on diabetic eye disease-related research grants from seven representative countries––the United States, China, Japan, the United Kingdom, Spain, Germany, and France––by searching for all global diabetic eye disease journal articles in the Web of Science and Pub Med databases, all global registered clinical trials in the Clinical Trials database, and new drugs approved by the United States, China, Japan, and EU agencies from 2012 to 2021. During this time period, diabetic retinopathy accounted for the vast majority(89.53%) of the 2288 government research grants that were funded to investigate diabetic eye disease, followed by diabetic macular edema(9.27%). The United States granted the most research funding for diabetic eye disease out of the seven countries assessed. The research objectives of grants focusing on diabetic retinopathy and diabetic macular edema differed by country. Additionally, the United States was dominant in terms of research output, publishing 17.53% of global papers about diabetic eye disease and receiving 22.58% of total citations. The United States and the United Kingdom led international collaborations in research into diabetic eye disease. Of the 415 clinical trials that we identified, diabetic macular edema was the major disease that was targeted for drug development(58.19%). Approximately half of the trials(49.13%) pertained to angiogenesis. However, few drugs were approved for ophthalmic(40 out of 1830;2.19%) and diabetic eye disease(3 out of 1830;0.02%) applications. Our findings show that basic and translational research related to diabetic eye disease in the past decade has not been highly active, and has yielded few new treatment methods and newly approved drugs.

Mechanical regulation of lipid and sugar absorption by Piezo1 in enterocytes

Obesity is primarily caused by excessive intake as well as absorption of sugar and lipid.Postprandial surge in distention pressure and intestinal motility accelerates the absorption of nutrients.The response of intestinal epithelial cells to mechanical stimulation is not fully understood.Piezo1,a mechanosensitive ion channel,is widely expressed throughout the digestive tract.However,its function in intestinal nutrient absorption is not yet clear.In our study,excessive lipid deposition was observed in the duodenum of obese patients,while duodenal Piezo1-CaMKK2-AMPKa was decreased when compared to normal-weight individuals.Under high-fat diet condition,the Piezo1iKO mice exhibited abnormally elevated sugar and lipid absorption as well as severe lipid deposition in the duodenum and liver.These phenotypes were mainly caused by the inhibition of duodenal CaMKK2-AMPKa and the upregulation of SGLT1 and DGAT2.In contrast,Yoda1,a Piezo1 agonist,was found to reduce intestinal lipid absorption in diet induced obese mice.Overexpression of Piezo1,stretch and Yoda1 inhibited lipid accumulation and the expression of DGAT2 and SGLT1,whereas knockdown of Piezo1 stimulated lipid accumulation and DGAT2 in Caco-2 cells.Our study reveals a previously unexplored mechanical regulation of nutrient absorption in intestinal epithelial cells,which may shed new light on the therapy of obesity.

Management and outcomes of gastric leak after sleeve gastrectomy:results from the 2010-2020 national registry

Background:Management of gastric leak after sleeve gastrectomy(SG)is challenging due to its unpredictable outcomes.We aimed to summarize the characteristics of SG leaks and analyze interventions and corresponding outcomes in a real-world setting.Methods:To retrospectively review of 15,721 SG procedures from 2010 to 2020 based on a national registry.A cumulative sum analysis was used to identify a fitting curve of gastric leak rate.The Kaplan-Meier method and log-rank tests were performed to calculate and compare the probabilities of relevant outcomes.The logistic regression analysis was conducted to determine the predictors of acute leaks.Results:A total of 78 cases of SG leaks were collected with an incidence of 0.5%(78/15,721)from this registry(6 patients who had the primary SG in non-participating centers).After accumulating 260 cases in a bariatric surgery center,the leak rate decreased to a stably low value of under 1.17%.The significant differences presented in sex,waist circumference,and the proportion of hypoproteinemia and type 2 diabetes at baseline between patients with SG leak and the whole registry population(P=0.005,=0.026,<0.001,and=0.001,respectively).Moreover,83.1%(59/71)of the leakage was near the esophagogastric junction region.Leakage healed in 64(88.9%,64/72)patients.The median healing time of acute and non-acute leaks was 5.93 months and 8.12 months,respectively.Acute leak(38/72,52.8%)was the predominant type with a cumulative reoperation rate>50%,whereas the cumulative healing probability in the patients who required surgical treatment was significantly lower than those requring non-surgical treatment(P=0.013).Precise dissection in the His angle area was independently associated with a lower acute leak rate,whereas preservation≥2 cm distance from the His angle area was an independent risk factor.Conclusions:Male sex,elevated waist circumference,hypoproteinaemia,and type 2 diabetes are risk factors of gastric leaks after SG.Optimizing surgical techniques,including precise dissection of His angle area and preservation of smaller gastric fundus,should be suggested to prevent acute leaks.

The alarming link between neonicotinoid insecticides and kidney injury

Neonicotinoid insecticides(NEOs)have been extensively approved for application in agricultural production both in China and globally.Previous studies indicated that human exposure to NEOs would have adverse health effects.However,studies on occurrences of NEOs in kidney injury patients and their association with nephrotoxicity are limited.This study investigates the potential correlation between exposure to NEOs and kidney injury within a subset(n=224)of the population residing in South China.Levels of 8 NEOs and 5 metabolites were quantified in blood samples obtained from both the 110 healthy and 114 kidney injury cohorts in South China.We found that target analytes were frequently detected in samples from the healthy and kidney injury cohorts(61%-100%).Dinotefuran is the predominant NEO in the healthy(42.3%)and kidney injury cohort(49.6%).Significantly positive(p<0.05)associations between blood NEO concentrations and kidney injury were found,indicating that these pollutants may increase the odds of human kidney injury prevalence.Through multilinear regression analysis,it was observed that the concentrations of various NEOs exhibited a significant association(p<0.05)with hematological parameters linked to nephrotoxicity.Our study represents the pioneering investigation examining the relationships between NEOs and kidney injury,thereby offering novel insights into the nephrotoxicity associated with these pollutants.This discovery carries significant implications for public health policies and environmental conservation practices.

Hepatic COX1 loss leads to impaired autophagic flux and exacerbates nonalcoholic steatohepatitis

The mechanisms underlying autophagic defects in nonalcoholic steatohepatitis(NASH)remain largely unknown.We aimed to elucidate the roles of hepatic cyclooxygenase 1(COX1)in autophagy and the pathogenesis of diet-induced steatohepatitis in mice.Human nonalcoholic fatty liver disease(NAFLD)liver samples were used to examine the protein expression of COX1 and the level of autophagy.Cox1^(Δhepa)mice and their wildtype littermates were generated and fed with 3 different NASH models.We found that hepatic COX1 expression was increased in patients with NASH and diet induced NASH mice models accompanied by impaired autophagy.COX1 was required for basal autophagy in hepatocytes and liver specific COX1 deletion exacerbated steatohepatitis by inhibiting autophagy.Mechanistically,COX1 directly interacted with WD repeat domain,phosphoinositide interacting 2(WIPI2),which was crucial for autophagosome maturation.Adeno-associated virus(AAV)-mediated rescue of WIPI2 reversed the impaired autophagic flux and improved NASH phenotypes in Cox1^(Δhepa)mice,indicating that COX1 deletion-mediated steatohepatitis was partially dependent on WIPI2-mediated autophagy.In conclusion,we demonstrated a novel role of COX1 in hepatic autophagy that protected against NASH by interacting with WIPI2.Targeting the COX1 WIPI2 axis may be a novel therapeutic strategy for NASH.

Melatonin alleviates alcoholic liver disease via EGFR-BRG1-TERT axis regulation

Chronic alcohol consumption causes liver steatosis,cell death,and inflammation.Melatonin(MLT)is reported to alleviate alcoholic liver disease(ALD)-induced injury.However,its direct regulating targets in hepatocytes are not fully understood.In the current study,a cell-based screening model and a chronic ethanol-fed mice ALD model were used to test the protective mechanisms of MLT.MLT ameliorated ethanol-induced hepatocyte injury in both cell and animal models(optimal doses of 10μmol/L and 5 mg/kg,respectively),including lowered liver steatosis,cell death,and inflammation.RNA-seq analysis and loss-of-function studies in AML-12 cells revealed that telomerase reverse transcriptase(TERT)was a key downstream effector of MLT.Biophysical assay found that epidermal growth factor receptor(EGFR)on the hepatocyte surface was a direct binding and regulating target of MLT.Liver specific knock-down of Tert or Egfr in the ALD mice model impaired MLT-mediated liver protection,partly through the regulation of nuclear brahma-related gene-1(BRG1).Long-term administration(90 days)of MLT in healthy mice did not cause evident adverse effect.In conclusion,MLT is an efficacious and safe agent for ALD alleviation.Its direct regulating target in hepatocytes is EGFR and downstream BRG1-TERT axis.MLT might be used as a complimentary agent for alcoholics.

Hepatitis B virus X protein induces ALDH2 ubiquitin-dependent degradation to enhance alcoholic steatohepatitis

Background:Excessive alcohol intake with hepatitis B virus(HBV)infection accelerates chronic liver disease progression and patients with HBV infection are more susceptible to alcohol-induced liver disease.Hepatitis B virus X protein(HBx)plays a crucial role in disease pathogenesis,while its specific role in alcoholic liver disease(ALD)progression has not yet been elucidated.Here,we studied the role of HBx on the development of ALD.Methods:HBx-transgenic(HBx-Tg)mice and their wild-type littermates were exposed to chronic plus binge alcohol feeding.Primary hepatocytes,cell lines,and human samples were used to investigate the interaction between HBx and acetaldehyde dehydrogenase 2(ALDH2).Lipid profiles in mouse livers and cells were assessed by using liquid chromatography–mass spectrometry.Results:We identified that HBx significantly aggravated alcohol-induced steatohepatitis,oxidative stress,and lipid peroxidation in mice.In addition,HBx induced worse lipid profiles with high lysophospholipids generation in alcoholic steatohepatitis,as shown by using lipidomic analysis.Importantly,serum and liver acetaldehyde were markedly higher in alcoholfed HBx-Tg mice.Acetaldehyde induced lysophospholipids generation through oxidative stress in hepatocytes.Mechanistically,HBx directly bound to mitochondrial ALDH2 to induce its ubiquitin–proteasome degradation,resulting in acetaldehyde accumulation.More importantly,we also identified that patients with HBV infection reduced ALDH2 protein levels in the liver.Conclusions:Our study demonstrated that HBx-induced ubiquitin-dependent degradation of mitochondrial ALDH2 aggravates alcoholic steatohepatitis.