Associations of the EAT-Lancet reference diet with metabolic dysfunction-associated steatotic liver disease and its severity: A multicohort study.

BACKGROUND AND AIMS: The EAT-Lancet Commission devised a globally sustainable dietary pattern to jointly promote human health and sustainability. However, the extent to which this diet supports metabolic dysfunction-associated steatotic liver disease (MASLD) has not yet been assessed. This study aimed to investigate the association between the EAT-Lancet diet and the risk of MASLD and its severity. APPROACH AND RESULTS: This prospective multicohort study included 15,263 adults from the Tianjin Chronic Low-grade Systemic Inflammation and Health (TCLSIH) cohort, 1137 adults from the Guangzhou Nutrition and Health Study (GNHS) cohort, and 175,078 adults from the UK Biobank. In addition, 228 Chinese adults from the Prospective Epidemic Research Specifically of Non-alcoholic Steatohepatitis (PERSONS) with biopsy-proven MASLD were included. An EAT-Lancet diet index was created to reflect adherence to the EAT-Lancet reference diet. The TCLSIH cohort recorded 3010 MASLD cases during 53,575 person-years of follow-up, the GNHS cohort documented 624 MASLD cases during 6454 person-years of follow-up, and the UK Biobank developed 1350 MASLD cases during 1,745,432 person-years of follow-up. In multivariable models, participants in the highest tertiles of the EAT-Lancet diet index had a lower risk of MASLD compared with those in the lowest tertiles (TCLSIH: HR = 0.87, 95% CI: 0.78, 0.96; GNHS: HR = 0.79, 95% CI: 0.64, 0.98; UK Biobank: HR = 0.73, 95% CI: 0.63, 0.85). Moreover, liver-controlled attenuation parameter decreased with increasing the diet index in individuals with biopsy-proven MASLD (ß = -5.895; 95% CI: -10.014, -1.775). CONCLUSIONS: Adherence to the EAT-Lancet reference diet was inversely associated with the risk of MASLD as well as its severity.

Safety evaluation of Indocalamus Iatifolius McClure leaves based on acute toxicity, harmful metals, and 9 organochlorine residue determination.

To investigate the safety of Indocalamu Iatifolius McClur leaves sold in the market, a study was conducted using Indocalamu Iatifolius McClur leaves randomly collected from an online store and a large supermarket. Acute toxicity experiments were performed on mice, and their body weight was monitored for 14 days after administration. After the observation period, blood samples were collected for biochemical analysis, and organ pathology was examined. Then, the content of copper (Cu), lead (Pb), cadmium (Cd), mercury (Hg), arsenic (As), and the residues of nine organochlorine pesticides in Indocalamu Iatifolius McClur leaves were measured according to the National Food Safety Standard (GB/T5009-2003) and the pesticide residue determination methods in the 2020 edition of the Chinese Pharmacopoeia. The results showed that the mice in the Indocalamu Iatifolius McClur leaves (online store) group experienced mortality and severe liver and lung damage. The levels of lead, cadmium, mercury, arsenic, and the nine organochlorine pesticides met the relevant standards and regulations. However, the copper content in the Indocalamu Iatifolius McClur leaves (online store) group was nearly 80 times higher than that in the supermarket group. Mice in the Indocalamu Iatifolius McClur leaves (supermarket) group remained healthy without any abnormalities, and the levels of harmful metals and organochlorine pesticides complied with the standards and regulations. The study suggests the need for regulatory policies and safety standards for the sale of Indocalamu Iatifolius McClur leaves.

Analysis of the microbial community diversity in various regions of the healthy oral cavity.

BACKGROUND: Microbiomics offers new methods for conducting epidemiological surveys of oral microbiota in large populations. Compared to curette sampling, swab sampling is more convenient and less technically sensitive, making it more suitable for such surveys. To verify the feasibility of using swabs for buccal mucosa sampling in large-scale studies, we collected samples from the buccal mucosa and tooth surfaces of healthy individuals using both swabs and curettes. Microbiomics was employed to analyze and compare microbial abundance and diversity between these two methods. METHODS: Four sites were assessed: the buccal mucosa on both sides and the buccal surfaces of the left and right mandibular first molars. Two sampling methods, swab and curette, were used to collect bacterial communities from healthy individuals. Specifically, buccal mucosa samples (n = 10) and tooth surface samples (n = 20) were analyzed using 16 S rDNA gene sequencing. Bacterial signals were detected through fluorescence in situ hybridization (FISH), targeting the bacterial 16 S rDNA gene. Metastats analysis and Wilcoxon test were used. RESULTS: A total of 383 OTUs were detected in the 30 samples, which belonged to 1 kingdom (bacteria), 11 phyla, 23 classes, 40 orders, 75 families, 143 genus, and 312 species. Among them, 223 OTUs were found on both the buccal mucosa and tooth surfaces. The statistics suggest that although there were no significant differences in colony composition, there were differences in the abundance and distribution of colonies on the dental and buccal mucosal surfaces. When detecting oral disease-causing pathogens such as Enterococcus faecalis and Porphyromonas gingivalis, the efficiency of detection is higher when using curette sampling. Compared to right tooth sampling with a curette, the swab sampling group had higher levels of Firmicutes, while Fusobacteria and Bacteroidetes were more prevalent in the curette tissues. CONCLUSIONS: In oral health individuals, there is no difference in the bacterial composition of the oral buccal mucosa and the dental surface, differing only in abundance. Thus, the buccal mucosa can act as a substitute for the teeth in epidemiological investigations exploring the bacterial composition of the oral cavity.

Glutamine deprivation in glioblastoma stem cells triggers autophagic SIRT3 degradation to epigenetically restrict CD133 expression and stemness.

Glioblastoma multiforme (GBM) is a highly malignant brain tumor, and glioblastoma stem cells (GSCs) are the primary cause of GBM heterogeneity, invasiveness, and resistance to therapy. Sirtuin 3 (SIRT3) is mainly localized in the mitochondrial matrix and plays an important role in maintaining GSC stemness through cooperative interaction with the chaperone protein tumor necrosis factor receptor-associated protein 1 (TRAP1) to modulate mitochondrial respiration and oxidative stress. The present study aimed to further elucidate the specific mechanisms by which SIRT3 influences GSC stemness, including whether SIRT3 serves as an autophagy substrate and the mechanism of SIRT3 degradation. We first found that SIRT3 is enriched in CD133+ GSCs. Further experiments revealed that in addition to promoting mitochondrial respiration and reducing oxidative stress, SIRT3 maintains GSC stemness by epigenetically regulating CD133 expression via succinate. More importantly, we found that SIRT3 is degraded through the autophagy-lysosome pathway during GSC differentiation into GBM bulk tumor cells. GSCs are highly dependent on glutamine for survival, and in these cells, we found that glutamine deprivation triggers autophagic SIRT3 degradation to restrict CD133 expression, thereby disrupting the stemness of GSCs. Together our results reveal a novel mechanism by which SIRT3 regulates GSC stemness. We propose that glutamine restriction to trigger autophagic SIRT3 degradation offers a strategy to eliminate GSCs, which combined with other treatment methods may overcome GBM resistance to therapy as well as relapse.

Serum immunoglobulin concentrations and risk of type 2 diabetes mellitus in adults: a prospective cohort study from the TCLSIH study.

Type 2 diabetes mellitus (T2DM) is a metabolic disorder characterized by hyperglycemia resulting from defects in insulin secretion and/or insulin action. Increasing evidence suggests that inflammation played an important role in the pathogenesis of T2DM. Prospective studies on the link between immunoglobulins concentrations and the risk of T2DM in adults are limited. We developed a cohort study including 7,093 adults without T2DM history. The incidence of T2DM was 16.45 per 1,000 person-years. Compared with the lowest quartiles, the hazard ratios (95% confidence intervals) of T2DM for the highest quartiles of IgG, IgE, IgM and IgA were 0.64 (0.48-0.85), 0.94 (0.72-1.23), 0.68 (0.50-0.92) and 1.62 (1.24-2.11) (P for trend was < 0.01, 0.84, 0.02 and < 0.0001), respectively, suggesting that serum IgG and IgM concentrations were inversely associated with the incidence of T2DM, and IgA levels were positively associated with the risk of T2DM in a general adult population.

Escitalopram moderately outperforms citalopram towards anti-neuroinflammation and neuroprotection in 6-hydroxydopamine-induced mouse model of Parkinson's disease.

Citalopram and escitalopram are structurally close-related antidepressants and both forms are widely used in the world. We aimed to comparatively evaluate the anti-neuroinflammatory and neuroprotective effects of escitalopram and citalopram in Parkinson's disease (PD) mouse model. Mice were randomly divided into six groups and received 6-hydroxydopamine (6-OHDA) or vehicle administration. The mice were then treated with escitalopram, citalopram or saline for consecutive 7 days. Behaviors, neuroinflammation, neurotransmitters, and neurotoxicity were assessed. Results showed that citalopram but not escitalopram worsened body weight loss and increased freezing time in the PD mice. Both drugs had no impact on the anxiety-like behaviors but ameliorated the depressive-like behaviors as in elevated plus maze and sucrose splash tests. Escitalopram but not citalopram ameliorated motor discoordination in the PD mice as in rotarod test. In accordance, escitalopram but not citalopram attenuated the 6-OHDA-induced nigrostriatal dopaminergic loss. Further mechanistic investigations showed that both drugs mitigated activations of microglia and astrocytes and/or levels of pro-inflammatory cytokines in the PD mice, but escitalopram showed appreciably better effects in the substantia nigra. Neurotransmitter examination in the prefrontal cortex suggested that the two drugs had comparable effects on the disturbed neurotransmitters in the PD mice, but citalopram was prone to disrupt certain normal homeostasis. In conclusion, escitalopram is moderately superior than citalopram to suppress neuroinflammation and to protect against dopaminergic neuronal death and motor discoordination in the 6-OHDA-induced PD mice. Our findings imply that escitalopram shall be prescribed with priority over citalopram to treat PD patients with depression as escitalopram may meanwhile provide greater additional benefits to the patients.

Microbial-derived Urolithin A Targets GLS1 to Inhibit Glutaminolysis and Attenuate Cirrhotic Portal Hypertension.

BACKGROUND & AIMS: Cirrhotic portal hypertension (CPH) is the leading cause of mortality in patients with cirrhosis. Over 50% of patients with CPH treated with current clinical pharmacotherapy still present variceal bleeding or sometimes death owing to insufficient reduction in portal pressure. Elevated intrahepatic vascular resistance (IHVR) plays a fundamental role in increasing portal pressure. Because of its potent effect in reducing portal pressure and maintaining normal portal inflow to preserve liver function, lowering the IHVR is acknowledged as an optimal anti-CPH strategy but without clinical drugs. We aimed to investigate the protective effect of microbial-derived Urolithin A (UroA) in IHVR and CPH. METHODS: Carbon tetrachloride or bile duct ligation surgery was administered to mice to induce liver fibrosis and CPH. 16S rRNA gene sequencing was used for microbial analysis. Transcriptomics and metabolomics analyses were employed to study the host and cell responses. RESULTS: UroA was remarkably deficient in patients with CPH and was negatively correlated with disease severity. UroA deficiency was also confirmed in CPH mice and was associated with a reduced abundance of UroA-producing bacterial strain (Lactobacillus murinus, L. murinus). Glutaminolysis of hepatic stellate cells (HSCs) was identified as a previously unrecognized target of UroA. UroA inhibited the activity of glutaminase1 to suppress glutaminolysis, which counteracted fibrogenesis and contraction of HSCs and ameliorated CPH by relieving IHVR. Supplementation with UroA or L. murinus effectively ameliorated CPH in mice. CONCLUSIONS: We for the first time identify the deficiency of gut microbial metabolite UroA as an important cause of CPH. We demonstrate that UroA exerts an excellent anti-CPH effect by suppressing HSC glutaminolysis to lower the IHVR, which highlighted its great potential as a novel therapeutic agent for CPH.

Efficacy and safety of insulin glargine 300 U/mL in people with type 2 diabetes in China: The INITIATION study.

AIM: To evaluate the efficacy and safety of insulin glargine 300 U/mL (Gla-300) in people with suboptimally controlled type 2 diabetes (T2D) in China. METHODS: INITIATION (NCT05002933) was a prospective, interventional, multicentre, single-arm, phase IV study conducted in China. Individuals with suboptimally controlled T2D who were insulin naïve or switching from another basal insulin (insulin experienced) were included. The primary endpoint was the change in HbA1c from baseline to week 24. Safety assessments included hypoglycaemia and adverse events (AEs). RESULTS: In total, 568 participants were enrolled and 562 initiated Gla-300 treatment (189 in the insulin-naïve subgroup; 373 in the insulin-experienced subgroup). At week 24, the mean ± standard error (SE) change in HbA1c from baseline was -0.91% ± 0.05% (-9.9 ± 0.5 mmol/mol; P < .0001). Significant HbA1c reductions were also observed in the insulin-naïve (mean ± SE change: -1.38% ± 0.09% [-15.1 ± 1.0 mmol/mol]) and insulin-experienced (-0.68% ± 0.05% [-7.4 ± 0.5 mmol/mol]) subgroups (both P < .0001). During the 24-week treatment period, the incidence of confirmed hypoglycaemia (plasma glucose ≤ 3.9 mmol/L) was 39.7% for all hypoglycaemia and 13.3% for nocturnal hypoglycaemia; the incidence of severe hypoglycaemia was low (0.5%). Overall, treatment-emergent AEs (TEAEs) were reported in 126 participants (22.4%), with no serious treatment-related TEAEs. CONCLUSIONS: Gla-300 was effective in improving glycaemic control and had a relatively low risk of hypoglycaemia in people with suboptimally controlled T2D who were insulin naïve or switching from another basal insulin in China.

SENP3-regulated Nodal signaling plays a potential role in cardiac left-right asymmetry development.

Congenital heart disease (CHD) is a type of major defect that occurs during embryonic development. Although significant advances have been made in the treatment of CHD, its etiology and molecular mechanism remain unclear. To identify the critical role of SUMOylation in cardiac development, we generated SENP3 knockout mice and showed that SENP3 knockout mice die on embryonic day 8.5 with an open neural tube and reversed left-right cardiac asymmetry. Moreover, SENP3 knockout promoted apoptosis and senescence of H9C2 cells. Further studies showed that Nodal, a critical gene that forms left-right asymmetry, is regulated by SENP3 and that SENP3 regulates cell apoptosis and senescence in a Nodal-dependent manner. Furthermore, Nodal was hyper-SUMOylated after SENP3 knockout, and SUMOylation of Nodal inhibited its ubiquitination and ubiquitin-proteasome degradation pathway. Nodal overexpression enhanced cell apoptosis and senescence; however, the mutation at the SUMOylation site of Nodal reversed its effect on the apoptosis and senescence of H9C2 cells. More importantly, the SENP3-Nodal axis regulates cell senescence by inducing cell autophagy. These results suggest that the SENP3-Nodal signaling axis regulates cardiac senescence-autophagy homeostasis, which in turn affects cardiac development and results in the occurrence of CHD.

Chronic active Epstein-Barr virus infection with reinfection of SARS-CoV-2: a case report.

We describe the case of a 57-year-old male with jaundice, abdominal distension and fatigue. He was diagnosed as chronic active Epstein-Barr virus infection (CAEBV) due to intermittent elevated liver enzymes, hepatosplenomegaly and pancytopenia, with persistent positive of EBV biomarkers in blood and also positive in liver tissue. The patient was reinfected by SARS-CoV-2 within 2 months companied with CAEBV. The patient's second infection with SARS-CoV-2 led to the aggravated liver dysfunction with pneumonia and re-admission. After receiving symptomatic treatment, the patient showed significantly improvement of symptoms with partially restoration of liver function. After discharge, the patient's health status continued to deteriorate and eventually died. The instances of SARS-CoV-2 co-infection with the original chronic virus are not uncommon, but the exact mechanism of EBV and SARS-CoV-2 coinfection and the relationship between them are still unclear. Since co-infection of SARS-CoV-2 with original chronic virus might affect each other and lead disease aggravated and complicated, it is necessary to differentiate in the diagnosis of disease and it is important to be aware of the re-infection signs of SARS-CoV-2 in people with chronic virus infection diseases, as well as the risk of co-infection of SARS-CoV-2 with other viruses.

Association of added sugar intake and its forms and sources with handgrip strength decline among middle-aged and older adults: A prospective cohort study.

PURPOSE: The consumption of added sugar has increased rapidly in recent years. Limited knowledge exists regarding the association between added sugar intake and muscle strength, although the latter is a predictor of physical disability in older adults. This study aimed to investigate the association between added sugar intake and longitudinal changes in handgrip strength among middle-aged and elderly Chinese adults. METHODS: This prospective cohort study included 5298 adults aged 40 years and older (62.6% men) from the TCLSIH (Tianjin Chronic Low-grade Systemic Inflammation and Health) cohort study. Added sugar intake was obtained through a frequency questionnaire containing 100 items of food. Handgrip strength is measured annually using a handheld digital dynamometer. Multivariate linear regression models were used to examine the association between added sugars intake and the annual changes in handgrip strength and weight-adjusted handgrip strength. RESULTS: In the fully adjusted model, the annual change in handgrip strength for one unit increase in total added sugar, solid added sugar, and liquid added sugar intake was -0.0353 kg, (95% confidence intervals (CI) -0.000148, -0.0000164; P = 0.01), -0.0348 kg (95% CI: -0.000227, -0.0000269; P = 0.01) and -0.0189 kg (95% CI -0.000187, 0.0000338; P = 0.17), respectively. Added sugar from bread and biscuits sources were remarkably associated with a decline in handgrip strength (ß = -0.0498; 95%CI -0.00281, -0.000787) and (ß = -0.0459; 95%CI 0.00158, 0.00733) (P < 0.01). CONCLUSIONS: Our data suggest that the higher the intake of solid added sugars, but not liquid sugars, were associated with the declined handgrip strength in the Chinese middle-aged and elderly population. In addition, the consumption of added sugars from bread and biscuits sources was also associated with a decline in grip strength.

Research progress of prodrugs for the treatment of cerebral ischemia.

It is well-known that pharmacotherapy plays a pivotal role in the treatment and prevention of cerebral ischemia. Nevertheless, existing drugs, including numerous natural products, encounter various challenges when applied in cerebral ischemia treatment. These challenges comprise poor brain absorption due to low blood-brain barrier (BBB) permeability, limited water solubility, inadequate bioavailability, poor stability, and rapid metabolism. To address these issues, researchers have turned to prodrug strategies, aiming to mitigate or eliminate the adverse properties of parent drug molecules. In vivo metabolism or enzymatic reactions convert prodrugs into active parent drugs, thereby augmenting BBB permeability, improving bioavailability and stability, and reducing toxicity to normal tissues, ultimately aiming to enhance treatment efficacy and safety. This comprehensive review delves into multiple effective prodrug strategies, providing a detailed description of representative prodrugs developed over the past two decades. It underscores the potential of prodrug approaches to improve the therapeutic outcomes of currently available drugs for cerebral ischemia. The publication of this review serves to enrich current research progress on prodrug strategies for the treatment and prevention of cerebral ischemia. Furthermore, it seeks to offer valuable insights for pharmaceutical chemists in this field, offer guidance for the development of drugs for cerebral ischemia, and provide patients with safer and more effective drug treatment options.

Longitudinal association between soft drink consumption and handgrip strength in adults: a prospective analysis from the Tianjin Chronic Low-Grade Systemic Inflammation and Health (TCLSIH) cohort study.

Soft drink consumption has become a highly controversial public health issue. Given the pattern of consumption in China, sugar-sweetened beverage is the main type of soft drink consumed. Due to containing high levels of fructose, a soft drink may have a deleterious effect on handgrip strength (HGS) due to oxidative stress, inflammation and insulin resistance. However, few studies show an association between soft drink consumption and HGS in adults. We aimed to investigate the association between soft drink consumption and longitudinal changes in HGS among a Chinese adult population. A longitudinal population-based cohort study (5-year follow-up, median: 3·66 years) was conducted in Tianjin, China. A total of 11 125 participants (56·7 % men) were enrolled. HGS was measured using a handheld digital dynamometer. Soft drink consumption (mainly sugar-containing carbonated beverages) was measured at baseline using a validated FFQ. ANCOVA was used to evaluate the association between soft drink consumption and annual change in HGS or weight-adjusted HGS. After adjusting for multiple confounding factors, the least square means (95 % CI) of annual change in HGS across soft drink consumption frequencies were -0·70 (-2·49, 1·09) for rarely drinks, -0·82 (-2·62, 0·97) for < 1 cup/week and -0·86 (-2·66, 0·93) for ≥ 1 cup/week (Pfor trend < 0·05). Likewise, a similar association was observed between soft drink consumption and annual change in weight-adjusted HGS. The results indicate that higher soft drink consumption was associated with faster HGS decline in Chinese adults.

Adherence to a healthy lifestyle including sleep and sedentary behaviors and risk of metabolic dysfunction-associated steatotic liver disease in Chinese adults.

OBJECTIVE: Various lifestyle factors including smoking, alcohol, physical activity, sedentary behavior, diet quality, sleep behavior, and overweight have been related to metabolic dysfunction-associated steatotic liver disease (MASLD); however, their joint impact on risk of MASLD is not well known. We prospectively investigated the association between a combination of lifestyle factors and risk of MASLD. METHODS: This prospective cohort study included 13,303 participants (mean age: 39.1 ± 11.3 years, female: 60.1%) in China. A novel healthy lifestyle score was created combining seven healthy factors: not smoking, no alcohol intake, regular physical activity, short sedentary time, healthy diet, healthy sleep, and healthy weight. Incident MASLD cases were ascertained annually by liver ultrasound and cardiometabolic risk factors. Multivariable Cox proportional hazards regression models were used to estimate the association of healthy lifestyle score with risk of MASLD. RESULTS: Within 48,036 person-years of follow-up, 2823 participants developed MASLD. After adjusting for age, sex, education, occupation, household income, personal and family history of disease, and total energy intake, compared with participants with 0-2 healthy lifestyle factors, the multivariable hazard ratios (95% confidence interval) of MASLD were 0.81 (0.73, 0.89), 0.67 (0.61, 0.75), and 0.55 (0.49, 0.62) for healthy lifestyle score of 3, 4, and 5-7, respectively (P for trend <0.0001). Such associations were consistent across subgroup and sensitivity analyses. CONCLUSION: Our results indicate that a higher healthy lifestyle score is associated with a lower risk of MASLD.

The association between raw garlic consumption and the risk of depressive symptoms: the TCLSIH cohort study.

Background: Garlic has antioxidant, anti-inflammatory, cardiovascular improvement and other beneficial effects on human health. However, few studies have evaluated the association of garlic intake with the risk of depressive symptoms. The aim of this prospective cohort was to examine the association between the frequency of raw garlic consumption and depressive symptoms in the general adult population. Methods: A total of 7427 participants (mean ± standard deviation: 39.7 ± 10.5 years) without baseline depressive symptoms were included in the cohort study. Garlic consumption was assessed using a validated food frequency questionnaire, and depressive symptoms were assessed by a Chinese version of the Self-rating Depression Scale score (SDS score ≥ 45). Multivariable Cox proportional hazards models were used to determine the association between garlic consumption and the risk of depressive symptoms. Results: This study identified 1070 cases of depressive symptoms during a median follow-up of 2.0 years, with a depression prevalence of 73.4 cases per 1000 person-years. After multivariate adjustment, the hazard ratios (95% confidence intervals) for depressive symptoms in males were 1.00 (reference) for almost never, 1.05 (0.84, 1.32) for ≤1 time per week, 1.16 (0.90, 1.49) for 2-3 times per week, and 1.31 (0.97, 1.78) for ≥4 times per week, and in females, they were 1.00 (reference) for almost never, 0.85 (0.69, 1.06) for ≤1 time per week, 0.72 (0.54, 0.97) for 2-3 times per week, and 0.78 (0.53, 1.13) for ≥4 times per week. Conclusion: In a large general population, we demonstrate for the first time that moderate raw garlic consumption is associated with a reduced risk of depressive symptoms in females, but not in males. Additional prospective studies with long-term follow-up and randomized controlled trials are necessary to confirm the preliminary results of the current study.

Comprehensive geriatric assessment of older patients with renal disease: a cross-sectional survey.

Multidimensional health function impairments are common in older patients with chronic kidney disease (CKD). The purpose of this study was to explore whether the risk or severity of geriatric syndrome increased with a decline in renal function. This survey was conducted for CKD patients aged ≥ 60 years and hospitalized at West China Hospital of Sichuan University (Center of Gerontology and Geriatrics, Nephrology, and Endocrinology) and Chengdu Kangfu Kidney Disease Hospital from September 01, 2013 to June 30, 2014. Patients underwent multidimensional individualized assessments by trained doctors. Logistic regression analysis found that the risk of assisted walking (P = 0.001) and urinary incontinence (P = 0.039) increased with a decline in renal function. Regression analysis revealed that the scores of activities of daily living (P = 0.024), nutritional status (P = 0.000), total social support (P = 0.014), and objective support (P = 0.000) decreased with a decline in renal function.

Identification of N7-methylguanosine-related miRNAs as potential biomarkers for prognosis and drug response in breast cancer.

Objectives: The impact of N7-methylguanosine (m7G) on tumor progression and the regulatory role of microRNAs (miRNAs) in immune function significantly influence breast cancer (BC) prognosis. Investigating the interplay between m7G modification and miRNAs provides novel insights for assessing prognostics and drug responses in BC. Materials and methods: RNA sequences (miRNA and mRNA profiles) and clinical data for BC were acquired from the Cancer Genome Atlas (TCGA) database. A miRNA signature associated with 15 m7G in this cohort was identified using Cox regression and LASSO. The risk score model was evaluated using Kaplan-Meier and time-dependent ROC analysis, categorizing patients into high-risk and low-risk groups. Functional enrichment analyses were conducted to explore potential pathways. The immune system, including scores, cell infiltration, function, and drug sensitivity, was examined and compared between high-risk and low-risk groups. A nomogram that combines risk scores and clinical factors was developed and validated. Single-sample gene set enrichment analysis (ssGSEA) was employed to explore m7G-related miRNA signatures and immune cell relationships in the tumor microenvironment. Additionally, drug susceptibility was compared between risk groups. Results: Fifteen m7G-related miRNAs were independently correlated with overall survival (OS) in BC patients. Time-dependent ROC analysis yielded area under the curve (AUC) values of 0.742, 0.726, and 0.712 for predicting 3-, 5-, and 10-year survival rates, respectively. The Kaplan-Meier analysis revealed a significant disparity in OS between the high-risk and low-risk groups (p = 1.3e-6). Multiple regression identified the risk score as a significant independent prognostic factor. An excellent calibration nomogram with a C-index of 0.785 (95 % CI: 0.728-0.843) was constructed. In immune analysis, low-risk patients exhibited heightened immune function and increased responsiveness to immunotherapy and chemotherapy compared to high-risk patients. Conclusion: This study systematically analyzed m7G-related miRNAs and revealed their regulatory mechanisms concerning the tumor microenvironment (TME), pathology, and the prognosis of BC patient. Based on these miRNAs, a prognostic model and nomogram were developed for BC patients, facilitating prognostic assessments. These findings can also assist in predicting treatment responses and guiding medication selection.

CircTBC1D22A inhibits the progression of colorectal cancer through autophagy regulated via miR-1825/ATG14 axis.

Distant metastasis is the main cause of death in patients with colorectal cancer (CRC). A better understanding of the mechanisms of metastasis can greatly improve the outcome of patients with CRC. Accumulating evidence suggests that circRNA plays pivotal roles in cancer progression and metastasis, especially acting as a miRNA sponge to regulate the expression of the target gene. A public database bioinformatics analysis found that miR-1825 was highly expressed in CRC tissues. In this study, miR-1825 was highly expressed in CRC tissues, which was positively correlated with lymph node metastasis and distant metastasis. In vitro and in vivo experiments confirmed that miR-1825 was positively correlated with the proliferation and migration of CRC cells. This event can be inhibited by circTBC1D22A. CircTBC1D22A can directly interact with miR-1825 and subsequently act as a miRNA sponge to regulate the expression of the target gene ATG14, which collectively advances the autophagy-mediated progression and metastasis of CRC.

Comprehensive analysis of the protein phosphatase 2A regulatory subunit B56ε in pan-cancer and its role and mechanism in hepatocellular carcinoma.

BACKGROUND: B56ε is a regulatory subunit of the serine/threonine protein phosphatase 2A, which is abnormally expressed in tumors and regulates various tumor cell functions. At present, the application of B56ε in pan-cancer lacks a comprehensive analysis, and its role and mechanism in hepatocellular carcinoma (HCC) are still unclear. AIM: To analyze B56ε in pan-cancer, and explore its role and mechanism in HCC. METHODS: The Cancer Genome Atlas, Genotype-Tissue Expression, Gene Expression Profiling Interactive Analysis, and Tumor Immune Estimation Resource databases were used to analyze B56ε expression, prognostic mutations, somatic copy number alterations, and tumor immune characteristics in 33 tumors. The relationships between B56ε expression levels and drug sensitivity, immunotherapy, immune checkpoints, and human leukocyte antigen (HLA)-related genes were further analyzed. Gene Set Enrichment Analysis (GSEA) was performed to reveal the role of B56ε in HCC. The Cell Counting Kit-8, plate cloning, wound healing, and transwell assays were conducted to assess the effects of B56ε interference on the malignant behavior of HCC cells. RESULTS: In most tumors, B56ε expression was upregulated, and high B56ε expression was a risk factor for adrenocortical cancer, HCC, pancreatic adenocarcinoma, and pheochromocytoma and paraganglioma (all P < 0.05). B56ε expression levels were correlated with a variety of immune cells, such as T helper 17 cells, B cells, and macrophages. There was a positive correlation between B56ε expression levels with immune checkpoint genes and HLA-related genes (all P < 0.05). The expression of B56ε was negatively correlated with the sensitivity of most chemotherapy drugs, but a small number showed a positive correlation (all P < 0.05). GSEA analysis showed that B56ε expression was related to the cancer pathway, p53 downstream pathway, and interleukin-mediated signaling in HCC. Knockdown of B56ε expression in HCC cells inhibited the proliferation, migration, and invasion capacity of tumor cells. CONCLUSION: B56ε is associated with the microenvironment, immune evasion, and immune cell infiltration of multiple tumors. B56ε plays an important role in HCC progression, supporting it as a prognostic marker and potential therapeutic target for HCC.

Aqueous extract of Sargentodoxa cuneata alleviates ulcerative colitis and its associated liver injuries in mice through the modulation of intestinal flora and related metabolites.

Background: Ulcerative colitis (UC) is a refractory disease worldwide. Liver injury can be found clinically with UC, and now, it is found that gut dysbiosis is an important mechanism in the pathogenesis of UC. Sargentodoxa cuneata has been used as a traditional Chinese medicine and is commonly used clinically for the treatment of UC. The main objective of this study was to investigate the intrinsic mechanisms of Sargentodoxa cuneata in the treatment of UC and its associated liver injuries from the perspective of intestinal flora and related metabolites. Methods: Ultra-performance liquid chromatography-mass spectrometry was used to identify the components in the aqueous extract of Sargentodoxa cuneata (AESc). Mice with UC induced by dextran sulfate sodium were used to study the effects of AESc on UC and its associated liver injuries. Furthermore, 16S rRNA gene sequencing and analysis were performed on intestinal contents, and correlation analysis of intestinal flora with short-chain fatty acids (SCFAs) and organic acids was performed. Results: A total of 114 compounds were identified in AESc. AESc improved disease activity index scores, liver index, and colon length in mice with UC and had a good protective effect on intestine and liver injuries. Moreover, the administration of AESc regulated gut microbiota dysbiosis and the levels of a few SCFAs and organic acids in mice with UC. In addition, the correlation analysis results showed that the Megamonas and Bifidobacterium were the key intestinal flora related to the levels of differential SCFAs and organic acids in mice with UC after AESc intervention. Conclusion: AESc has a good protective effect on UC and UC related liver injuries. Modulation of the intestinal flora and its metabolites (SCFAs and a few organic acids) is an important pathway for AESc in the treatment of UC and also provides a rationale for the clinical use of Sargentodoxa cuneata in the treatment of UC.