The gut constantly interacts with both pathogens and dietary signals, but how it balances immune and metabolic responses remains unclear. Here we show that intestinal cGAS, a key DNA sensor, acts as a regulator linking gut immunity to whole-body metabolism. We show that cGAS signalling is activated in the intestines of humans and male mice with obesity, leading to increased type I interferon production and heightened immune activity in intestinal cells. Strikingly, deleting cGAS specifically in intestinal epithelial cells enhances energy expenditure, protects against diet-induced obesity and improves metabolic health. These effects depend on the gut microbiota, particularly Lactobacillus murinus and its metabolite indole-3-acetic acid (IAA), which promotes adipose thermogenesis. Our findings position intestinal cGAS as a key driver of obesity through gut-to-fat signalling and suggest that targeting the intestinal cGAS-microbiota IAA axis could offer promising strategies to combat obesity and related metabolic diseases.

With the rapid development and maturation of high-risk human papillomavirus (hrHPV) genotyping kits, it is crucial to understand the specific patterns of methylation in different hrHPV statuses, rather than simply categorizing them as hrHPV positive or negative. To achieve this goal, we first assessed the prevalence and CIN3+ risk of specific hrHPV genotypes in 184 cervical scrapings and then evaluated the performance of five host genes methylation to distinguish CIN3+ from <CIN3 not only among hrHPV-positive and hrHPV-negative women, but also among women positive for HPV16, HPV18, HPV52, and HPV58. The results showed that women with HPV16 infections had a higher risk of developing CIN3+ than women with other hrHPV infections. More importantly, we found that hrHPV testing caused a high false-positive rate (43.54%) and leading to over-referral of <CIN3 cases. Triage of patients with HPV 52/58 positive using ZIC1m could accurately identify all CIN3+ cases to avoid over-referral of false-positive cases. In addition, implementing primary hrHPV testing resulted in 5.7% of CIN3+ patients being missed in our study. Our exploratory analysis found that DNA methylation of specific genes, including ZIC1m, ZNF582m, PAX1m, and MIR129-2m, could lower the high false-positive rate and find 80% (4/5) missed CIN3+ cases caused by hrHPV testing. This study substantiates the dual role of DNA methylation detection in cervical cancer screening. By incorporating methylation detection, the existing HPV-based screening strategy can be further optimized to achieve precise risk stratification and facilitate the shift from cervical cancer screening to personalized and precise management.

Abstract Excessive hepatic glucose production is a hallmark of fasting hyperglycemia in type 2 diabetes mellitus, yet the epitranscriptomic mechanisms that sustain this dysregulation remain incompletely understood. Here, we show that dexamethasone/forskolin-induced gluconeogenic activation triggers widespread remodeling of RNA m 6 A methylation in mouse primary hepatocytes. Among the m 6 A regulators examined, the demethylase ALKBH5 is robustly induced both in vitro and in fasted livers. This induction is mediated by the glucocorticoid receptor, which binds to the Alkbh5 promoter and activates its transcription. Functionally, ALKBH5 overexpression enhances gluconeogenic gene expression and glucose production, whereas both global and hepatocyte-specific Alkbh5 knockout mice exhibit suppressed hepatic gluconeogenesis. Mechanistically, we identify Ogt as a primary downstream target, defining an ALKBH5–OGT epitranscriptomic axis in hepatocytes. ALKBH5 demethylates and stabilizes Ogt mRNA, thereby elevating OGT expression and promoting gluconeogenic gene expression. Consistently, the pro-gluconeogenic effects of ALKBH5 are largely abrogated by OGT knockdown. Finally, pharmacological inhibition of ALKBH5 with 18l effectively improves glucose tolerance and suppresses hepatic gluconeogenesis in both wild-type and db/db mice. Together, these findings reveal a glucocorticoid-responsive epitranscriptomic mechanism whereby ALKBH5 stabilizes Ogt mRNA to drive gluconeogenesis and highlight ALKBH5 as a promising therapeutic target for type 2 diabetes mellitus.

Methamphetamine (METH)-provoked psychiatric symptoms are a major health concern, with depression being a prevalent symptom among METH abusers. Recently, gut microbiota-derived metabolites have been involved in various psychosis pathogenesis, but their roles in METH-induced depression remain unclear. This study investigates the implication of gut microbiota-derived metabolite trimethylamine N-oxide (TMAO) in METH-induced depressive-like behaviors (DLBs). We examined the circulating TMAO levels post-METH exposure besides exploring the impacts of TMAO on METH-triggered DLBs. Then, potential causes of TMAO alterations were explored, along with its effects on hippocampal neuronal damage and neuroinflammation. The findings showcased that METH-treated mice displayed DLBs accompanied by increased serum TMAO levels. Similarly, introducing TMAO to the drinking water elevated serum TMAO levels and induced DLBs. Although METH exposure did not notably alter the abundance of the gut microbiota, antibiotic (ABX) therapy suppressed the increased serum TMAO levels and the onset of DLBs. Additionally, choline and L-carnitine levels were elevated following METH exposure, which may be a potential mechanism for TMAO metabolic dysregulation. Elevated TMAO levels resulted in an elevation in Nissl-positive dead cells, the number of microglia, TNF-α, and IL-1β levels, along with TLR-4, NF-κB, and MyD88 expression in the hippocampal CA3 region. Inhibition of TMAO synthesis mitigated METH-provoked neuronal damage and neuroinflammation.

Myelin, a lipid-rich sheath that insulates axons, is essential for efficient neural signal transmission and the modulation of neural circuits. Its formation, maintenance, and regeneration are tightly regulated processes that shape neurodevelopment, cognition, and emotional stability. Recent evidence positions the gut microbiota as a critical modulator of myelination, orchestrating metabolic signaling, immune homeostasis, and neuroinflammatory responses. Notably, the synchronized development and remodeling of gut microbiota and myelin across key life stages suggest a dynamic and bidirectional interplay essential for sustaining neurological health. Disruptions in this axis are increasingly recognized as contributing factors in dysmyelination-related disorders, including autism spectrum disorder, Alzheimer's disease, and multiple sclerosis. Harnessing microbiota-targeted interventions-such as fecal microbiota transplantation, dietary modulation, and probiotic therapies-holds promise for restoring myelin integrity and mitigating disease pathology. This review provides a comprehensive synthesis of the gut microbiota-myelin interface, delineating mechanistic insights and translational opportunities for microbiome-based therapeutic strategies in neuroprotection.

Quinazolinones are key scaffolds in anticancer drug development. We previously identified the lead compound 16h from a series of 6-(1H-benzo[d]imidazol-6-yl) quinazolin-4(3H)-one derivatives. In this study, we optimized 16h to develop new 6-(2-aminobenzo[d]thiazol-5-yl) quinazolin-4(3H)-one derivatives, with compound 45 showing the best antiproliferative activity against A549 lung cancer cells (IC50: 0.44 μM) and good selectivity. Mechanistic studies revealed that compound 45 induced G1-phase arrest, inhibited ALK/PI3K/AKT signaling, disrupted mitochondrial membrane potential, and promoted apoptosis. It also significantly inhibited spheroid formation in a 3D cell culture model. In summary, the results suggest that compound 45 might have potential for the development of anticancer drugs.

RESEARCH QUESTION:What are the lipidomic alterations in the myometrial tissue from adenomyotic lesions? DESIGN:This was a two-centre, prospective, observational study conducted between July 2023 and June 2024. Forty-four premenopausal patients were enrolled: 22 patients with adenomyosis confirmed by post-operative pathology and 22 control participants undergoing hysterectomy for benign conditions without adenomyosis. Myometrial tissue samples were collected during surgery, and lipid extraction performed by liquid-liquid extraction and lipidomic profiling carried out using a liquid chromatography-tandem mass spectrometry platform. Data analysis included multivariate statistical methods, such as principal component analysis and orthogonal partial least squares discriminant analysis, to identify lipid metabolites differentially expressed between the adenomyosis and control groups. RESULTS:A total of 1100 lipid species were identified, with 84 showing significant differences between adenomyosis patients and control participants. Of these, 76 lipids were upregulated and eight were down-regulated. The highest differentially expressed lipid content was mainly concentrated in glyceropholipids, with notable alterations in acylcarnitines and lysophosphatidylcholines. CONCLUSION:This study reveals significant lipidomic changes in adenomyosis, with upregulated acylcarnitines and elevated lysophosphatidylcholines.

Differentially abundant proteins (DAPs) in the eye muscle (EM) and dorsal muscle (DM) of bighead carp were compared at the initial state (-0) and after six months of frozen storage (-6) using proteomics. The WHC of EM and DM decreased by 21.08% and 12.79% after 6 months of frozen storage. Further comparative proteomic analysis revealed that a total of 20, 21, 78 and 58 DAPs were identified and focused in DM-6 vs. DM-0, EM-6 vs. EM-0, EM-0 vs. DM-0 and EM-6 vs. DM-6, respectively. Additionally, in DM-6 vs. DM-0, up-regulated DAPs involved myosin isoforms, actinin, and iron metabolism, while down-regulated DAPs involved myosin isoforms, actin, lactate synthesis, and protein degradation. In EM-6 vs. EM-0, up-regulated DAPs involved myosin isoforms, and down-regulated DAPs involved myosin isoforms, actin, glycolysis, and protein degradation. DAPs function analysis indicated that EM showed better MP repair, antioxidation, aerobic metabolism, and protein degradation but inferior glycolytic metabolism compared to DM. Tubulin beta chain could serve as a biomarker to reflect the extent of freezing in bighead carp muscle. Malate dehydrogenase had the potential to evaluate WHC difference between EM and DM. These results offer insights into the causes of WHC differences between EM and DM in bighead carp, providing a theoretical foundation for optimizing fish processing and tailoring storage in the industry.

Cerebral ischemia-reperfusion injury (CIRI) is a devastating condition that triggers neuronal death and cerebral infarction. O-sialoglycoprotein endopeptidase (OSGEP), identified as a crucial element of the highly conserved KEOPS complex, regulated cellular proliferation and mitochondrial metabolism. Despite its known role in cellular homeostasis, the potential contribution of OSGEP to the development of CIRI remains elusive. This study was designed to investigate the potential role of ferroptosis in the pathogenesis of CIRI and indicate whether OSGEP could suppress ferroptosis to alleviate CIRI by modulating GPX4 m6A methylation. To this end, MCAO and OGD/R models were employed to closely simulate the CIRI. The potent ferroptosis inhibitors conferred prominent neuroprotection in both in vivo and in vitro models. Moreover, OSGEP expression level was not only downregulated in MCAO-treated mice and in cultured cerebrocortical neurons subjected to OGD/R, but also it was related to the prognosis of acute ischemic stroke (AIS) cases. Additionally, OSGEP overexpression exerted potent anti-ferroptotic effects in both MCAO and OGD/R models, while OSGEP depletion exhibited the opposite effect. Moreover, OSGEP regulated GPX4 expression by modulating m6A methylation of its mRNA. Furthermore, the inhibitory effect of OSGEP on ferroptosis was dependent on the presence of GPX4. Specifically, OSGEP knockout exacerbated ferroptosis-like cell death under MCAO condition. Besides, OSGEP regulated GPX4 mRNA stability through competition with YTHDC1 for binding to GPX4 mRNA and forming a complex with HNRNPUL1 in the neuronal primary cultures subjected to OGD/R. These findings highlighted the critical role of OSGEP, as a new contributing anti-ferroptotic factor, in the pathogenesis of CIRI.

OBJECTIVE:Despite the high risk of cervical intraepithelial neoplasia grade 3 (CIN3) progressing to cervical cancer, approximately 50 percent of CIN3 lesions were overtreated. Furthermore, CIN3 patients who underwent surgery experienced complications and adverse obstetric outcomes. Therefore, exploring reliable biomarkers to differentiate regressing CIN3 lesions from persistent ones is imperative to preserve female fertility. METHODS:This study evaluated the association between the methylation level of zinc finger protein 671 (ZNF671m) and the regression of CIN3 lesions by examining the postoperative pathology of the cones removed by cold knife conization (CKC) or loop electrosurgical excision procedure (LEEP). RESULTS:In the analysis of 127 cervical scraping cells from CIN3 patients, negative ZNF671m results were significantly associated with downgraded postoperative pathology (OR = 0.225, 95 % CI: 0.084-0.599). Compared to the overall (CKC and LEEP) group, the predictive performance of ZNF671m in the CKC subgroup was improved by 58.7 % (OR = 0.093, 95 % CI: 0.018-0.480). Our results showed that the ZNF671m/cytology/HPV16/18 combination (OR = 0.033, 95 % CI: 0.003-0.376) improved the accuracy of detecting cervical intraepithelial neoplasia grade 1 or less (CIN1-) in the CKC subgroup. However, none of the tests could distinguish the postoperative pathology CIN1- from CIN2+ in the LEEP group. CONCLUSION:These results support that ZNF671m has the potential to predict the regression of CIN3 lesions, and the improved predictive performance of the ZNF671m/cytology/HPV16/18 combination may inform individualized treatment of CIN3 patients planning to undergo CKC.

Despite nifedipine's satisfactory efficacy, patients with higher blood pressure often require combination therapy or increased dosages. The reasons for the reduced efficacy of nifedipine in this population remain unclear. Here, this study aimed to explore whether there are differences in nifedipine pharmacokinetics among rats with different blood pressure level and to assess the role of gut microbiota in this process. Spontaneously hypertensive rats (SHR) at 8, 12, and 16 weeks and age-matched Wistar-Kyoto (WKY) rats were used to study the pharmacokinetics of nifedipine. The WKY rats were used as the control group. We examined the pharmacokinetics of nifedipine in both SHR and WKY rats of different ages, analyzing the composition of gut microbiota and the bile acids profile in these age groups. The area under the concentration-time curve and Cmax of nifedipine in SHR decreased progressively with age. Compared with 8-week-old SHR, the expression of CYP3A1 in the liver was significantly upregulated in both 12-week-old and 16-week-old SHR. Five bacterial genera potentially related to the pharmacokinetics of nifedipine were identified: Romboutsia, the Lachnospiraceae_NK4A136_group, Alistipes, Anaerostipes, and Ruminococcaceae_UCG-013. We found that 8 bile acids, including cholic acid, ursodeoxycholic acid, glycocholic acid, taurolithocholic acid, glycolithocholic acid, glycoursodeoxycholic acid, glycochenodeoxycholic acid, and tauro-β-muricholic acid, were reduced with increasing age in SHR. In conclusion, our results suggest that there are significant differences in nifedipine pharmacokinetics among SHR of different blood pressure. The increasing expression of CYP3A1 in the liver and direct metabolism of gut microbiota were likely the main reasons. SIGNIFICANCE STATEMENT: This study explores blood pressure-dependent differences in nifedipine pharmacokinetics in spontaneously hypertensive rats and reveals the roles of liver enzyme expression and gut microbiota metabolism in the process. Understanding these factors is crucial for addressing disease-related variability in drug efficacy and resistance, offering insights that could enhance personalized treatment strategies for hypertension and other associated diseases.

BACKGROUND:Gastrointestinal (GI) cancers are among the most prevalent and lethal malignancies worldwide. Early, non-invasive detection is essential for timely intervention and improved survival. To address this clinical need, we developed GutSeer, a blood-based assay combining DNA methylation and fragmentomics for multi-GI cancer detection. METHODS:Genome-wide methylome profiling identified 1,656 markers specific to five major GI cancers and their tissue origins. Based on these findings, we designed GutSeer, a targeted bisulfite sequencing panel, which was trained and validated using plasma samples from 1,057 cancer patients and 1,415 non-cancer controls. The locked model was blindly tested in an independent cohort of 846 participants, encompassing both inpatient and outpatient settings across five hospitals. RESULTS:In the validation cohort, GutSeer achieved an area under the curve (AUC) of 0.950 [95% Confidence Interval (CI): 0.937-0.962] for cancer detection, with 82.8% sensitivity (95% CI: 79.5-86.0) and 95.8% specificity (95% CI: 94.3-97.2). It detected 92.2% of colorectal, 75.5% of esophageal, 65.3% of gastric, 92.9% of liver, and 88.6% of pancreatic cancers. The independent test cohort included 198 early-stage cancers (stage I/II, 66.4%) and 63 advanced precancerous lesions. GutSeer maintained robust performance, with 81.5% sensitivity (95% CI: 77.1-85.9) for GI cancers and 94.4% specificity (95% CI: 92.4-96.5). It also demonstrated the ability to detect advanced precancerous lesions in the colorectum, esophagus, and stomach as a single, non-invasive blood test. CONCLUSIONS:By integrating DNA methylation and fragmentomics into a compact panel, GutSeer outperformed genome-wide sequencing in both accuracy and clinical applicability. Its high sensitivity for early-stage GI cancers and practicality as a non-invasive assay highlights its potential to revolutionize early cancer detection and improve patient outcomes. TRIAL REGISTRATION:ClinicalTrials.gov identifier: NCT05431621.

Ophiopogon japonicus,a precious medicinal plant endemic to Zhejiang Province.Its tuberous roots are rich in bioactive components such as flavonoids,possessing anti-inflammatory,antioxidant,and immunomodulatory properties.To elucidate the impact of cadmium(Cd)stress on the accumulation and biosynthetic pathway of flavonoids in O.japonicus,this study exposed O.japonicus to different concentrations of Cd stress and explored the changes through integrated transcriptomics and metabolomics analysis.The results demonstrated that Cd stress(1 mg/L and 10 mg/L)significantly increased the content of flavonoids in O.japonicus in a concentration-dependent manner.The metabolomics analysis revealed a total of 110 flavonoids including flavones,flavanols,flavonols,flavone and flavonol derivatives,flavanones,isoflavonoids,chalcones and dihydrochalcones,and anthocyanins in O.japonicus,among which flavones,flavonols,flavone and flavonol derivatives,and anthocyanins increased under Cd stress.The transcriptomics analysis identified several key flavonoid biosynthesis-associated genes with up-regulated expression under Cd stress,including 14 genes encoding 4-coumarate Co A ligase(4CL),2 genes encoding chalcone isomerase(CHI),and 14 genes encoding phenylalanine ammonia lyase(PAL).The gene-metabolite regulatory network indicated significant positive correlations of 4CL(Cluster-21637.5012,Cluster-21637.90648,and Cluster-21637.62637)and CHI(Cluster-21637.111909 and Cluster-21637.123300)with flavonoid metabolites,suggesting that these genes promoted the synthesis of specific flavonoid metabolites,which led to the accumulation of total flavonoids under Cd stress.These findings provide theoretical support for the cultivation and utilization of medicinal plants in Cd-contaminated environments and offered new perspectives for studying plant responses to heavy metal stress.

This study aims to investigate the effect of probiotic Lactobacillus paracasei N1115 on Type 2 diabetes mellitus (T2DM) rats. SD rats were randomly divided into 5 groups, including control group (ND), diabetes mellitus (DM) group, and high (10 9 CFU/mL), medium (10 8 CFU/mL), or low (10 7 CFU/mL) doses of probiotics intervention groups. The ND rats were fed a normal diet, and the others were fed a high‐fat diet and injected with streptozotocin (STZ) to build a T2DM model. In the three probiotic intervention groups, rats were given high, medium, or low doses of L. paracasei N1115 by gavage for 12 weeks. Results indicated that probiotics could prevent weight loss and decrease the blood glucose levels of T2DM rats, in a dose‐dependent manner. A high dose of L. paracasei N1115 also led to a significant decline in the inflammatory response by regulating the TLR4/NF‐κB inflammatory pathway and reducing proinflammatory cytokines, such as tumor necrosis factor‐ α (TNF‐α), interleukin‐1β (IL‐1β), and lipopolysaccharide (LPS) ( p < 0.05). Besides, the memory factor cAMP and the cognitive regulatory pathway BDNF/TrkB were increased by high dose of L. paracasei N1115 treatment ( p < 0.05), revealing an enhanced cognitive memory competence. In addition, analysis of the gut microbiome showed that a high dose of L.paracasei N1115 decreased Firmicutes/Bacteroidota ratio and increased the relative abundance of beneficial bacteria, such as unclassified_Lachnospiraceae, Ligilactobacillus, and Lachnospiraceae_NK4A136_group. The microbial gene contents associated with metabolic pathways, nicotinate and nicotinamide metabolism, glycine, serine, and threonine metabolism and the citrate cycle were upregulated under L. paracasei N1115 treatment. In summary, this study elucidated the regulatory effects of L. paracasei N1115 on T2DM in rats and revealed a promising dietary supplement for the treatment of T2DM.

Precise and convenient detection of azodicarbonamide (ADC) is indispensable for safeguarding food safety and public health. Herein, a new ratio fluorescence strategy was strategically designed for monitoring ADC with excellent sensitivity and strong resistance to interference based on gold nanoclusters anchored cobalt oxyhydroxide nanocomposite (AuNCs@CoOOH). The AuNCs@CoOOH integrated two functions of CoOOH (quencher and mimetic oxidase) and fluorescence property of AuNCs, which can catalyze oxidation of non-fluorescent thiamine to fluorescent thiochrome. Meanwhile, the fluorescence emitted by AuNCs was attenuated by CoOOH via a fluorescence resonance energy transfer, forming a ratio response. Owing to analyte-initiated reduction of CoOOH, the AuNCs@CoOOH recognized glutathione. Coupling with specific reactions of ADC and glutathione, a ratio-based fluorescent platform is devised for sensitive detection of ADC, achieving a detection limit of 0.034 μM. The method proved an effective way for accurately monitoring ADC in flour samples, thereby enhancing its practical utility in ensuring food safety.

Compound probiotics have been widely used and commonly coadministered with other drugs for treating various chronic illnesses, yet their effects on drug pharmacokinetics remain underexplored. This study elucidated the impact of VSL#3 on the metabolism of probe drugs for cytochrome P450 enzymes (P450s), specifically omeprazole, tolbutamide, midazolam, metoprolol, phenacetin, and chlorzoxazone. Male Wistar rats were administered drinking water containing VSL#3 or not for 14 days and then intragastrically administered a P450 probe cocktail; this was done to investigate the host P450's metabolic phenotype. Stool, liver/jejunum, and serum samples were collected for 16S ribosomal RNA sequencing, RNA sequencing, and bile acid profiling. The results indicated significant differences in both α and β diversity of intestinal microbial composition between the probiotic and vehicle groups in rats. In the probiotic group, the bioavailability of omeprazole increased by 269.9%, whereas those of tolbutamide and chlorpropamide decreased by 28.1% and 27.4%, respectively. The liver and jejunum exhibited 1417 and 4004 differentially expressed genes, respectively, between the two groups. In the probiotic group, most of P450 genes were upregulated in the liver but downregulated in the jejunum. The expression of genes encoding metabolic enzymes and drug transporters also changed. The serum-conjugated bile acids in the probiotic group were significantly reduced. Shorter duodenal villi and longer ileal villi were found in the probiotic group. In summary, VSL#3 administration altered the gut microbiota, host drug-processing gene expression, and intestinal structure in rats, which could be reasons for pharmacokinetic changes. SIGNIFICANCE STATEMENT: This study focused on the effects of the probiotic VSL#3 on the pharmacokinetic profile of cytochrome P450 probe drugs and the expression of host drug metabolism genes. Compared with previous studies, the present study provides a comprehensive explanation for the host drug metabolism profile modified by probiotics, combined here with the bile acid profile and histopathological analysis.

Objective: Hypertension is linked to gut dysbiosis. Here, the impact of the angiotensin receptor antagonist irbesartan on the gut microbiota of spontaneously hypertensive rats (SHR) were investigated. In addition, we assessed their contribution to its antihypertensive effect. Methods: Eight-week-old Wistar–Kyoto (WKY) rats and SHR were administered irbesartan for 8 weeks. Fecal microbiota transplantation (FMT) was performed from SHR treated with irbesartan or untreated SHR to recipient untreated SHR. The preventive effect of Lactobacillus on hypertension in SHR was evaluated. Blood pressure (BP) was calculated using a tail-sleeve sphygmomanometer. To better assess the composition of the gut microbiota, the V3–V4 region of the 16S rRNA gene was amplified while short-chain fatty acids (SCFAs) in feces were tested by liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS). Results: Irbesartan restored gut dysbiosis, increased the abundance of Lactobacillus , and improved anti-inflammatory ability, antioxidative ability, intestinal integrity, and intestinal inflammation in SHR. The microbiota in SHR-treated irbesartan could reduce BP and improve antioxidative ability and gut integrity in SHR. Lactobacillus johnsonii ( L. johnsonii ) and Lactobacillus reuteri ( L. reuteri ) reduced BP, restored gut dysbiosis and improved anti-inflammatory ability, antioxidative ability, intestinal integrity in SHR. Most notably, irbesartan, L. johnsonii , and L. reuteri can significantly increase SCFA content in SHR feces. Conclusion: The current study demonstrated that irbesartan treatment ameliorated gut dysbiosis in SHR. Irbesartan induced alterations in gut microbiota, with increased prevalence of Lactobacillus .

BACKGROUND:Clear cell renal cell carcinoma (ccRCC) is the most common kidney cancer. The crosstalk between tumor tissue and adjacent adipose tissue has been appreciated recently. This study examines the predictive usefulness of brown adipocyte-related genes (BARGs) in ccRCC. METHODS:The transcriptome and clinical data of ccRCC patients were obtained from TCGA-KIRC and USA-ccRCC cohorts (848 tumor samples; 72 normal samples). Lasso-Cox methods were used to construct the risk prognostic signature model. We used Kaplan-Meier survival analysis to evaluate the prognostic significance of the risk model with ROC curves ascertaining prediction accuracy. The differences in immune cell infiltrates and signature risk scores between different risk categories were analyzed. Finally, biological experiments were performed to explore the functions of candidate genes. RESULTS:TCGA-KIRC patients were classified into two clusters that differed significantly regarding overall survival (OS) and tumor microenvironment. After screening BARGs candidates, a signature consisting of PPP1R1A, DPYSL3, and PTPRM was created to calculate risk score. Patients were assigned to the high or low-risk group, and the high-risk group had a significantly worse prognosis. Consistent trend was validated in external USA-ccRCC cohort. Meanwhile, the signature risk score affected immune cell infiltrates within the ccRCC microenvironment, positively correlated with the infiltration of CD4+ T cells, CD8+ T cells, CD56dim, CD56bright NK cells, MDSCs, and macrophage cells, while negatively correlated with neutrophil, iDCs, mast cells, and eosinophil. Finally, knockdown of PPP1R1A and DPYSL3 in renal cancer cells showed impairment in tumor proliferation ability of ccRCC in vitro and in vivo. Conversely, knockdown of PTPRM exhibited a promotive effect. CONCLUSION:We developed a predictive BARGs-related risk signature for early diagnosis and classifying ccRCC patients, which offers potential targets for individualized treatment of ccRCC.

BACKGROUND:Effective screening for colorectal cancer (CRC) enables earlier diagnosis and intervention to improve patient survival. METHODS:In this study, we prospectively conducted a blood-based CRC screening program for community residents in Hanjiang District, Yangzhou City, and evaluated the screening efficacy of a blood-based multi-locus DNA methylation assay (ColonAiQ). The ColonAiQ-positive rate and colonoscopy participation rate of the population, detection rate of intestinal lesions, and positive predictive value (PPV) of CRC and advanced adenoma (AA) were calculated, and the associated factors were explored. RESULTS:A total of 105,285 participants were enrolled from January 2021 to December 2022, all of whom completed the ColonAiQ assay, yielding a positive rate of 6.42% (6759/105,285). The colonoscopy compliance rate was 48.56% (3282/6759). Intestinal lesions were detected in 1773 individuals (54.02%), including 63 cases of CRCs (predominately early-stage), 1195 adenomas (441 cases of AAs), 327 polyps, and 188 other benign lesions. CRC patients exhibited higher ColonAiQ scores and more positive loci compared to healthy individuals. The PPVs were 1.92% for CRC and 13.44% for AA. Among participants, 66,121 (62.8%) completed questionnaires graded by the Asia-Pacific Colorectal Screening score, with 12,139 (18.36%) classified in the high-risk tier. High-risk participants had a higher ColonAiQ-positive rate (11.07%) and PPVs for CRC (3.46%) and AA (22.18%). Factors associated with increased detection rates for CRC and AA included male gender, older age, a history of alcohol consumption, and prior polyps. CONCLUSIONS:Our study demonstrated that ColonAiQ assay effectively identifies high-risk population. These findings strongly suggest that the ColonAiQ assay represents a promising strategy for the early detection of CRC and AA in individuals at average risk. TRIAL REGISTRATION:Registered at ClinicalTrials.gov (NCT05336539).

Iron overload-dependent ferroptosis is believed to contribute to the brain injury of ischemia/reperfusion (I/R), whereas toll-like receptor 4 (TLR4) can exert pro-ferroptosis effect via inhibiting the glutathione peroxidase 4 (GPX4) level, but the mechanisms behind these phenomenon are not fully elucidated. Tumor necrosis factor receptor correlated factor 3-interaction Jun amino-terminal kinase [JNK]-activating modulator (T3JAM) can activate specific molecule and its downstream signaling pathways, including TLR4. This study aims to explore whether targeting T3JAM can reduce I/R-induced ferroptosis in brain via downregulating TLR4. A Sprague Dawley (SD) rat model of cerebral I/R injury was established by 2h-ischemia plus 24 h-reperfusion, which displayed brain injury (increases in neurological deficit score and infarct volume) and upregulation of T3JAM and TLR4, concomitant with the increased ferroptosis, reflected by increases in the levels of transferrin receptor protein 1 (TfR1), total iron, Fe2+ and lipid peroxidation (LPO) while decreases in the levels of ferroportin (FPN) and GPX4. Consistently, similar results were achieved in the cultured HT22 cells subjected to 8h-oxygen-glucose deprivation plus 12h-reoxygenation (OGD/R), and knockdown of T3JAM reversed these phenomena. Moreover, Telaprevir, an anti-hepatitis C virus (HCV) drug, could also provide beneficial effect on alleviating ischemic brain injury via inhibition of T3JAM. Based on these observations, we conclud that inhibition of T3JAM can reduce I/R-induced brain cell ferroptosis through downregulating TLR4 and that T3JAM could be a potential target for identifying novel or existing drugs (such as Telaprevir) to treat cerebral I/R injury.