Search

Abstract Digestive and psychiatric disorders tend to co-occur, yet mechanisms remain unclear. Leveraging genetic and transcriptomic data integration, we conduct multi-trait analysis of GWAS (MTAG) and weighted gene co-expression network analysis (WGCNA) to explore shared mechanism between psychiatric and gastrointestinal disorders. Significant genetic correlations were found between these disorders, especially in irritable bowel syndrome (IBS), gastroesophageal reflux disease (GERD), depression (DEP), and neuroticism (NE). MTAG identify 60 novel pleiotropic loci for IBS and 14 for GERD, predominantly located near genes associated with neurological pathways. Further WGCNA identifies multiple co-expression modules enriched with genes involved in neurological pathways in digestive tissues, with some modules strongly preserved across brain and digestive tissues. Moreover, our network analysis suggests BSN, CELF4, and NRXN1 as central players in the regulation of the gut-brain axis (GBA). This study enhances our understanding of the GBA and underscores BSN, CELF4, and NRXN1 as crucial targets for future research.

Although 5-fluorouracil (5-FU) is the primary chemotherapy treatment for colorectal cancer (CRC), its efficacy is limited by drug resistance. Ferroptosis activation is a promising treatment for 5-FU-resistant cancer cells; however, potential therapeutic targets remain elusive. This study investigated ferroptosis vulnerability and dihydroorotate dehydrogenase (DHODH) activity using stable, 5-FU-resistant CRC cell lines and xenograft models. Ferroptosis was characterized by measuring malondialdehyde levels, assessing lipid metabolism and peroxidation, and using mitochondrial imaging and assays. DHODH function is investigated through gene knockdown experiments, tumor behavior assays, mitochondrial import reactions, intramitochondrial localization, enzymatic activity analyses, and metabolomics assessments. Intracellular lipid accumulation and mitochondrial DHODH deficiency led to lipid peroxidation overload, weakening the defense system of 5-FU-resistant CRC cells against ferroptosis. DHODH, primarily located within the inner mitochondrial membrane, played a crucial role in driving intracellular pyrimidine biosynthesis and was redistributed to the cytosol in 5-FU-resistant CRC cells. Cytosolic DHODH, like its mitochondrial counterpart, exhibited dihydroorotate catalytic activity and participated in pyrimidine biosynthesis. This amplified intracellular pyrimidine pools, thereby impeding the efficacy of 5-FU treatment through molecular competition. These findings contribute to the understanding of 5-FU resistance mechanisms and suggest that ferroptosis and DHODH are promising therapeutic targets for patients with CRC exhibiting resistance to 5-FU.

Abstract Background Diabetic cardiomyopathy is a serious complication of obesity with type 2 diabetes and is a major cause of mortality. Metabolic surgery, such as duodenal‐jejunal bypass (DJB), can effectively improve diabetic cardiomyopathy; however, the underlying mechanisms remain elusive. Oxidative stress is one of the pivotal mechanisms of diabetic cardiomyopathy. Our objective was to investigate the effect and potential mechanisms of DJB on oxidative stress in the heart of diabetic cardiomyopathy rats. Methods High‐fat diet combined with intraperitoneal injection of streptozotocin was used to establish diabetic cardiomyopathy rats. DJB was performed on diabetic cardiomyopathy rats, and high glucose and palmitate were used to simulate diabetic cardiomyopathy in H9C2 cells in vitro. Sera from different groups of rats were used for experiments in vivo and in vitro. Results DJB effectively improved oxidative stress and activated the adenosine monophosphate (AMP)‐activated protein kinase (AMPK) pathway to increase endothelial nitric oxide synthase (eNOS) phosphorylation level and the expression of antioxidative system‐related proteins and genes in the heart of diabetic cardiomyopathy rats. AMPK agonists and serum from DJB rats activated the AMPK pathway to increase eNOS phosphorylation level and the expression of antioxidative system‐related proteins and genes and decreased the content of reactive oxygen species in H9C2 cells, but this improvement was almost eliminated by the addition of AMPK inhibitors. Conclusions DJB activates eNOS and enhances the antioxidant system by activating the AMPK pathway—and not solely by improving blood glucose—to improve oxidative stress in the heart of diabetic cardiomyopathy rats.

BackgroundThe obesity epidemic has been on the rise due to changes in living standards and lifestyles. To combat this issue, sleeve gastrectomy (SG) has emerged as a prominent bariatric surgery technique, offering substantial weight reduction. Nevertheless, the mechanisms that underlie SG-related bodyweight loss are not fully understood.MethodsIn this study, we conducted a collection of preoperative and 3-month postoperative serum and fecal samples from patients who underwent laparoscopic SG at the First Affiliated Hospital of Shandong First Medical University (Jinan, China). Here, we took an unbiased approach of multi-omics to investigate the role of SG-altered gut microbiota in anti-obesity of these patients. Non-target metabolome sequencing was performed using the fecal and serum samples.ResultsOur data show that SG markedly increased microbiota diversity and Rikenellaceae, Alistipes, Parabacteroides, Bactreoidales, and Enterobacteraies robustly increased. These compositional changes were positively correlated with lipid metabolites, including sphingolipids, glycerophospholipids, and unsaturated fatty acids. Increases of Rikenellaceae, Alistipes, and Parabacteroide were reversely correlated with body mass index (BMI).ConclusionIn conclusion, our findings provide evidence that SG induces significant alterations in the abundances of Rikenellaceae, Alistipes, Parabacteroides, and Bacteroidales, as well as changes in lipid metabolism-related metabolites. Importantly, these changes were found to be closely linked to the alleviation of obesity. On the basis of these findings, we have identified a number of microbiotas that could be potential targets for treatment of obesity.

BackgroundPlacement of an indwelling transanal drainage tube (TDT) to prevent anastomotic leakage (AL) after anterior rectal cancer surgery has become a routine choice for surgeons in the recent years. However, the specific indwelling time of the TDT has not been explored. We performed this meta-analysis and considered the indwelling time a critical factor in re-analyzing the effectiveness of TDT placement in prevention of AL after anterior rectal cancer surgery.MethodsRandomized controlled trials (RCTs) and cohort studies which evaluated the effectiveness of TDT in prevention of AL after rectal cancer surgery and considered the indwelling time of TDT were identified using a predesigned search strategy in databases up to November 2022. This meta-analysis was performed to estimate the pooled AL rates (Overall and different AL grades) and reoperation rates at different TDT indwelling times and stoma statuses.ResultsThree RCTs and 15 cohort studies including 2381 cases with TDT and 2494 cases without TDT were considered eligible for inclusion. Our meta-analysis showed that the indwelling time of TDT for ≥5-days was associated with a significant reduction (TDT vs. Non-TDT) in overall AL (OR=0.46,95% CI 0.34-0.60, p0.05) when the indwelling time of TDT was less than 5 days.ConclusionExtending the postoperative indwelling time of TDT to 5 days may reduce the overall AL and the need for reoperation in patients without a prophylactic DS.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023407451, identifier CRD42023407451.

Abstract Background Acquired resistance of 5-fluorouracil (5-FU) remains a clinical challenge in colorectal cancer (CRC), and efforts to develop targeted agents to reduce resistance have not yielded success. Metabolic reprogramming is a key cancer hallmark and confers several tumor phenotypes including chemoresistance. Glucose metabolic reprogramming events of 5-FU resistance in CRC has not been evaluated, and whether abnormal glucose metabolism could impart 5-FU resistance in CRC is also poorly defined. Methods Three separate acquired 5-FU resistance CRC cell line models were generated, and glucose metabolism was assessed by measuring glucose and lactate utilization, RNA and protein expressions of glucose metabolism-related enzymes and changes of intermediate metabolites of glucose metabolite pool. The protein levels of hypoxia inducible factor 1α (HIF-1α) in primary tumors and circulating tumor cells of CRC patients were detected by immunohistochemistry and immunofluorescence. Stable HIF1A knockdown in cell models was established with a lentiviral system. The influence of both HIF1A gene knockdown and pharmacological inhibition on 5-FU resistance in CRC was evaluated in cell models in vivo and in vitro. Results The abnormality of glucose metabolism in 5-FU-resistant CRC were described in detail. The enhanced glycolysis and pentose phosphate pathway in CRC were associated with increased HIF-1α expression. HIF-1α-induced glucose metabolic reprogramming imparted 5-FU resistance in CRC. HIF-1α showed enhanced expression in 5-FU-resistant CRC cell lines and clinical specimens, and increased HIF-1α levels were associated with failure of fluorouracil analog-based chemotherapy in CRC patients and poor survival. Upregulation of HIF-1α in 5-FU-resistant CRC occurred through non-oxygen-dependent mechanisms of reactive oxygen species-mediated activation of PI3K/Akt signaling and aberrant activation of β-catenin in the nucleus. Both HIF-1α gene knock-down and pharmacological inhibition restored the sensitivity of CRC to 5-FU. Conclusions HIF-1α is a potential biomarker for 5-FU-resistant CRC, and targeting HIF-1a in combination with 5-FU may represent an effective therapeutic strategy in 5-FU-resistant CRC.

IntroductionObesity is a metabolic disease accompanied by abnormalities in lipid metabolism that can cause hyperlipidemia, non-alcoholic fatty liver disease, and artery atherosclerosis. Sleeve gastrectomy (SG) is a type of bariatric surgery that can effectively treat obesity and improve lipid metabolism. However, its specific underlying mechanism remains elusive.MethodsWe performed SG, and sham surgery on two groups of diet-induced obese mice. Histology and lipid analysis were used to evaluate operation effect. Immunohistochemistry, immunoblotting, real-time quantitative PCR, immunoprecipitation, immunofluorescence and mass spectrometry were used to reveal the potential mechanisms of SG.ResultsCompared to the sham group, the SG group displayed a downregulation of deubiquitinase ubiquitin-specific peptidase 20 (USP20). Moreover, USP20 could promote lipid accumulation in vitro. Co-immunoprecipitation and mass spectrometry analyses showed that heat-shock protein family A member 2 (HSPA2) potentially acts as a substrate of USP20. HSPA2 was also downregulated in the SG group and could promote lipid accumulation in vitro. Further research showed that USP20 targeted and stabilized HSPA2 via the ubiquitin-proteasome pathway.ConclusionThe downregulation of the USP20-HSPA2 axis in diet-induced obese mice following SG improved lipid dysmetabolism, indicating that USP20-HSPA2 axis was a noninvasive therapeutic target to be investigated in the future.

ObjectiveTo investigate the effects of sleeve gastrectomy (SG) on diabetes-related cognitive decline (DCD) in rats with diabetic mellitus (DM).Methods and methodsForty Wistar rats were randomly divided into control (CON) group (n=10), diabetes mellitus (DM) group (n=10), sham operation (SHAM) group (n=10) and SG group (n=10). DM model was established by high-fat diet (HFD) combined with intraperitoneal injection of streptozocin (STZ). Behavioral evaluation was given using Morris water maze test and Y-maze. In addition, PET-CT, TUNEL assay, histological analysis, transmission electron microscopy (TEM), immunohistochemistry (IHC) and Western blot analysis were used to evaluate the alleviating effects and potential mechanisms of SG on DCD in DM rats.ResultsCompared with the sham group, SG induced significant improvement in the metabolic indices such as blood glucose and body weight. Besides, it could attenuate the insulin resistance compared with SHAM group. In addition, SG could improve the cognitive function of DM rats, which were featured by significant decrease in the escape latency (P

Continuously rising trends in diabetes render this disease spectrum an epidemic proportion worldwide. As the disease progresses, the pathological effects of diabetes may impair the normal function of several vital organs, eventually leading to increase the risk of other diabetic comorbidities with advanced fibrosis such as non-alcoholic fatty liver disease, diabetic cardiomyopathy, and diabetic kidney disease. Currently, lifestyle changes and drug therapies of hypoglycemic and lipid-lowering are effective in improving multi-organ function, but therapeutic efficacy is difficult to maintain due to poor compliance and drug reactions. Bariatric surgery, including sleeve gastrectomy and Roux-en-Y gastric bypass surgery, has shown better results in terms of prognosis for diabetes through long-term follow-up. Moreover, bariatric surgery has significant long-term benefits on the function of the heart, liver, kidneys, and other organs through mechanisms associated with reversal of tissue fibrosis. The aim of this review is to describe the impact of type 2 diabetes mellitus on hepatic, cardiac and renal fibrosis and to summarize the potential mechanisms by which bariatric surgery improves multiple organ function, particularly reversal of fibrosis.

Chemoresistance against 5-fluorouracil (5-FU) is a major issue for colorectal cancer (CRC) patients. Increasing evidence for the roles of CD147 in glycolipid metabolic reprogramming and chemoresistance of tumor cells has emerged in recent years. However, whether CD147 contributes to 5-FU resistance in CRC and the role of abnormal glycolipid metabolism in this process remain poorly understood. We analyzed CD147 expression in primary tumor samples of CRC patients and found that upregulated CD147 correlated with decreased 5-FU chemosensitivity and an unfavorable prognosis of CRC patients. Moreover, in vivo and in vitro experiments confirmed that CD147 regulates glycolipid metabolism through two separate pathways. Mechanistically, CD147 upregulates HIF-1α-mediated glycolysis by activating the PI3K/AKT/mTOR pathway and CD147 also attenuates PPARα-mediated fatty acid oxidation by activation of the MAPK pathway. Most importantly, we found that CD147 confers 5-FU resistance in CRC via these glycolipid metabolic signatures. Our results demonstrated that CD147 is a potential 5-FU resistance biomarker for CRC patients and a candidate therapeutic target to restore 5-FU sensitivity of 5-FU-resistant CRC by remodeling glycolipid metabolism.

Background The early mortality after surgery for infective endocarditis is high. Although risk models help identify patients at high risk, most current scoring systems are inaccurate or inconvenient. The objective of this study was to construct an accurate and easy‐to‐use prediction model to identify patients at high risk of early mortality after surgery for infective endocarditis. Methods and Results A total of 476 consecutive patients with infective endocarditis who underwent surgery at 2 centers were included. The development cohort consisted of 276 patients. Eight variables were selected from 89 potential predictors as input of the XGBoost model to train the prediction model, including platelet count, serum albumin, current heart failure, urine occult blood ≥(++), diastolic dysfunction, multiple valve involvement, tricuspid valve involvement, and vegetation >10 mm. The completed prediction model was tested in 2 separate cohorts for internal and external validation. The internal test cohort consisted of 125 patients independent of the development cohort, and the external test cohort consisted of 75 patients from another center. In the internal test cohort, the area under the curve was 0.813 (95% CI, 0.670–0.933) and in the external test cohort the area under the curve was 0.812 (95% CI, 0.606–0.956). The area under the curve was significantly higher than that of other ensemble learning models, logistic regression model, and European System for Cardiac Operative Risk Evaluation II (all, P

Diabetic cardiomyopathy (DCM) is characterized by impaired diastolic and systolic myocardial performance and is a major cause of morbidity and mortality in patients with diabetes. Surgical bariatric procedures, such as sleeve gastrectomy (SG), result in remission of type 2 diabetes (T2DM) and have benefits with myocardial function. Maintaining cardiac mitochondrial homeostasis is a promising therapeutic strategy for DCM. However, whether SG surgery affects mitochondrial function and its underlying mechanism remains unclear. This study aimed to investigate the effect of SG surgery on mitochondrial homeostasis and intracellular oxidative stress in rats with DCM. We also examined cellular phenotypes and molecular mechanisms in high glucose and high fat-stimulated myocytes. The rat model of DCM was established by high-fat diet feeding and low-dose streptozotocin injection. We observed a remarkably metabolic benefit of SG, including a reduced body weight, food intake, blood glucose levels, and restored glucose tolerance and insulin sensitivity post-operatively. Also, SG ameliorated the pathological cardiac hypertrophy, myocardial fibrosis and the dysfunction of myocardial contraction and diastole, consequently delayed the progression of DCM. Also, SG restored the mitochondrial dysfunction and fragmentation through the AMPK signaling activation mediated nuclear receptor subfamily 4 group A member 1 (NR4A1)/DRP1 suppression in vivo. H9c2 cardiomyocytes showed that activation of AMPK could reverse the mitochondrial dysfunction somehow. Collectively, our study provided evidence that SG surgery could alleviate mitochondrial dysfunction in DCM. Moreover, AMPK-activated NR4A1/DRP1 repression might act as a significant reason for maintaining mitochondrial homeostasis in the myocardium, thus contributing to morphological and functional alleviation of DCM.

Noise exposure causes noise-induced hearing loss (NIHL). NIHL exhibits loss of inner ear sensory hair cells and is often irreparable. Although oxidative stress is involved in hearing loss, the complex mechanisms involved in NIHL are unclear. Hypoxia-inducible factor 1α (HIF-1α) has been suggested to be essential for protecting sensory hair cells. Additionally, it has been shown that ROS is involved in modulating the stability of HIF-1α. To investigate the NIHL pathogenesis, we established a tert-butyl hydroperoxide (t-BHP)-induced oxidative stress damage model in hair-like HEI-OC1 cells and an NIHL model in C57BL/6 mice. Protein and mRNA expression were determined, and biochemical parameters including reactive oxygen species (ROS) accumulation, glucose uptake, adenosine triphosphat (ATP) production, and mitochondrial content were evaluated. In HEI-OC1 cells, t-BHP induced ROS accumulation and reduced mitochondrial content and oxygen consumption, but the ATP level was unaffected. Additionally, there was increased glucose uptake and lactate release along with elevated expression of HIF-1α, glucose transporter 1, and several glycolytic enzymes. Consistently, noise trauma induced oxidative stress and the expression of HIF-1α and glycolytic enzymes in mice. Thus, we concluded that ROS induced HIF-1α expression, which promoted glycolysis, suggesting a metabolic shift maintained the ATP level to attenuate hair cell damage in NIHL.

Background: Cardiac hypertrophy as a main pathological manifestation of diabetic cardiomyopathy (DCM), is a significant complication of diabetes. Bariatric surgery has been proven to relieve DCM; however, whether it can alleviate diabetes-induced cardiac hypertrophy is undefined.Methods: Diabetic and obese rats were performed sleeve gastrectomy (SG) after having diabetes for 16weeks. The rats were euthanized 8weeks after SG. Metabolic parameters, heart function parameters, myocardial glucose uptake, morphometric and histological changes, and the expression level of mitogen-activated protein kinases (MAPKs) were determined and compared among the control group (CON group), diabetes mellitus group (DM group), sham operation group (SHAM group), and SG group.Results: Compared with the SHAM group, the blood glucose, body weight, insulin resistance, and other metabolic parameters were significantly improved in the SG group. There was also a marked improvement in myocardial morphometric and histological parameters after SG. Furthermore, the myocardial glucose uptake and heart function were reversed after SG. Additionally, the phosphorylation of MAPKs was inhibited after SG, including p38 MAPKs, c-Jun N-terminal kinases (JNKs), and extracellular signal-regulated kinases 1/2 (ERK1/2). The expression of DUSP6, which dephosphorylates ERK1/2, was upregulated after SG. These findings suggest that SG ameliorated diabetes-induced cardiac hypertrophy correlates with the MAPK signaling pathway.Conclusion: These results showed that diabetes-induced cardiac hypertrophy was ameliorated after SG was closely related to the inhibition of the MAPK signaling pathway and upregulation of DUSP6. Therefore, this study provides a novel strategy for treating diabetes-induced cardiac hypertrophy.

The myocardium is capable of utilizing different energy substrates, which is referred to as “metabolic flexibility.” This process assures ATP production from fatty acids, glucose, lactate, amino acids, and ketones, in the face of varying metabolic contexts. In the normal physiological state, the oxidation of fatty acids contributes to approximately 60% of energy required, and the oxidation of other substrates provides the rest. The accumulation of lactate in ischemic and hypoxic tissues has traditionally be considered as a by-product, and of little utility. However, recent evidence suggests that lactate may represent an important fuel for the myocardium during exercise or myocadiac stress. This new paradigm drives increasing interest in understanding its role in cardiac metabolism under both physiological and pathological conditions. In recent years, blood lactate has been regarded as a signal of stress in cardiac disease, linking to prognosis in patients with myocardial ischemia or heart failure. In this review, we discuss the importance of lactate as an energy source and its relevance to the progression and management of heart diseases.

Introduction: While intracorporeal anastomosis (IA) has been widely used in totally laparoscopic right colectomy, its application in laparoscopic segmental left colectomy for splenic flexure cancer remains underexplored, particularly in large-scale studies with longterm outcomes. This research aims to assess the technical feasibility and oncological efficacy of IA in treating colonic splenic flexure carcinoma, drawing insights from both short-term and long-term outcomes of a retrospective cohort. Materials and methods: A retrospective analysis was conducted on 342 patients diagnosed with colonic splenic flexure carcinoma in three Chinese medical centers. These patients underwent laparoscopic segmental left colectomy between December 2014 and December 2019 across three medical institutions. Comprehensive data encompassing demographics, disease features, pathological characteristics, operative details, and both short-term and long-term outcomes were gathered and scrutinized. Using propensity scores, each patient from the IA cohort was paired with a counterpart from the extracorporeal anastomosis (EA) cohort. Results: IA was performed on 129 patients, while 213 underwent EA. Post-propensity score matching resulted in 129 matched pairs. After matching, many baseline characteristics were balanced. The IA cohort exhibited several advantages, including shorter incision lengths (P<0.001) and more extensive proximal and distal resection margins (P=0.003, P<0.001). Additionally, the IA method facilitated a more rapid postoperative recovery as indicated by quicker return of bowel movements (resumption of passing flatus [2.7 (1.0-7.0) days vs. 3.3 (2.0-8.0) days, P<0.001] and defecation [3.7 (1.0-9.0)] days vs. 4.5 (2.0-9.0) days, P<0.001]), faster discharges [6.6 (3.0-15.0) days vs. 8.3 (5.0-20.0) days, P<0.001], and decreased need for rescue analgesics (P<0.001). The rate of postoperative complications, as rated by the Clavien-Dindo classification, remained consistent across both techniques (P =0.087). Furthermore, the cosmetic outcome rated by Patient Scar Assessment Questionnaire and Scoring System (PSAQ) was markedly superior in the IA group (P< 0.001). Both approaches demonstrated equivalent 5-year overall (82.7% vs. 82.1%, P =0.419) and disease-free survival (80.9% vs. 78.1%, P=0.476). Subsequent stratification analysis revealed that IA achieved comparable 5-year overall (80.7% vs. 82.0%, P=0.647) and disease-free survival (78.1% vs. 76.4%, P=0.734) in patients with locally advanced colon cancer. Conclusion: Employing IA for laparoscopic segmental left colectomy in cases of splenic flexure carcinoma is not only safe but also offers enhanced cosmetic results and expedited postoperative recovery. Oncologically speaking, IA in left segmental colectomy for splenic flexure carcinoma can yield therapeutic outcomes comparable to those of EA, even in patients with locally advanced colon cancer. [ABSTRACT FROM AUTHOR]