The association between exposure to famine in early life and risks of diabetic complications in adult patients with type two diabetes.

Background: In this study, we aimed to assess the associations between early exposure to famine and the risks of diabetic complications in adult patients with type two diabetes. Methods: The participants in this study were selected from China National HbA1c Surveillance System (2009-13) and further stratified according to the birth year. The participants born between 1956-59, 1959-61, and 1962-64 were classified as foetal exposed group with 70 852, infant/toddler exposed group with 93 616, and unexposed group with 72 723 participants. The association between exposure to famine in early life and risks of diabetic complications were analysed by logistic regression. We assessed the attributing effects of the interaction between exposure to famine in early life and modifiable risk factors by the multiplicative and additive interactive models. Results: After adjustments for sex, famine severity, economic status in adulthood, body mass index, blood pressure, low-density lipoprotein cholesterol, glycated haemoglobin, diabetes duration, and the use of antidiabetic agents, the increased risks of coronary heart disease (odds ratio (OR) = 1.31; 95% CI (confidence interval) = 1.26, 1.36), cerebrovascular disease (OR = 1.32; 95% CI = 1.24, 1.41), and diabetic retinopathy (OR = 1.06; 95% CI = 1.02, 1.10) were observed in patients with early-life exposure to famine. The reduced risk of diabetic kidney disease (OR = 0.94; 95% CI = 0.90, 0.99) was observed in patients with early-life exposure to famine compared with those without famine exposure. The interaction analyses indicated that obesity might exacerbate the increased risk of coronary heart disease (OR = 1.26; 95% CI = 1.22, 1.30), cerebrovascular disease (OR = 1.26; 95% CI = 1.21, 1.32), and diabetic retinopathy associated with early-life exposure to famine (OR = 1.09; 95% CI = 1.06, 1.12) in patients with type two diabetes. Moreover, high economic status in adulthood might also exacerbate the increased risk of coronary heart disease (OR = 1.35; 95% CI = 1.30, 1.40) and cerebrovascular disease (OR = 1.33; 95% CI = 1.23, 1.43) associated with early-life exposure to famine in patients with type two diabetes. Conclusions: Early-life exposure to famine in patients with type two diabetes might be associated with increased risks of coronary heart disease, cerebrovascular disease, and diabetic retinopathy but a reduced risk of diabetic kidney disease in adulthood. Obesity and high economic status might further exacerbate the risk of diabetic complications associated with early-life exposure to famine. Improving early-life nutritional status may promote better risk prevention and management of diabetic complications in patients with type two diabetes.

Efficacy and safety of Bacteroides fragilis BF839 for pediatric autism spectrum disorder: a randomized clinical trial.

Background: The clinical utility of Bacteroides fragilis in treating autism spectrum disorder (ASD) remains unclear. Therefore, this randomized, double-blind, placebo-controlled study aimed to explore the therapeutic effects and safety of B. fragilis BF839 in the treatment of pediatric ASD. Methods: We examined 60 children aged 2-10 years diagnosed with ASD, and participants received either BF839 powder (10 g/bar with ≥106 CFU/bar of viable bacteria, two bars/day) or placebo for 16 weeks. The primary outcomes was Autism Behavior Checklist (ABC) score. The secondary outcomes were Childhood Autism Rating Scale (CARS), Social Responsiveness Scale (SRS), Normal Development of Social Skills from Infants to Junior High School Children (S-M), Gastrointestinal Symptom Rating Scale (GSRS) scores, and fecal microbiome composition. Assessments were performed on day 0 and at weeks 8 and 16. Results: Compared with the placebo group, the BF839 group showed significant improvement in the ABC body and object use scores at week 16, which was more pronounced in children with ASD aged <4 years. Among children with a baseline CARS score ≥30, the BF839 group showed significant improvements at week 16 in the ABC total score, ABC body and object use score, CARS score, and GSRS score compared to the placebo group. Only two patients (6.67%) in the BF839 group experienced mild diarrhea. Compared with baseline and placebo group levels, the BF839 group showed a significant post-intervention increase in abundance of bifidobacteria and change in the metabolic function of neuroactive compounds encoded by intestinal microorganisms. Conclusion: BF839 significantly and safely improved abnormal behavior and gastrointestinal symptoms in children with ASD.

Protein identification and potential bioactive peptides from pumpkin (Cucurbita maxima) seeds.

Pumpkin is an economically important crop all over the world. Approximately, 18%-21% of pumpkins, consisting of peels and seeds by-products, are wasted during processing. In addition, the seeds are rich in protein and have the potency of bioactive peptide production. This study aims to recognize the proteins and investigate the potential bioactive peptides from pumpkin (Cucurbita maxima) seeds. Pumpkin seeds were subjected to hot air drying (HAD) at 55°C for 12 h and freeze-drying (FD) at -80°C for 54 h before they were powdered, analyzed, and precipitated by isoelectric point to obtain pumpkin seed protein isolates (PSPI). PSPI comprised 11S globulin subunit beta, 2S seed storage albumin, and chaperonin CPN60-1. To generate hydrolysate peptides, PSPI was hydrolyzed using papain, pepsin, and bromelain. FD group pepsin hydrolysates had the highest peptide content of 420.83 mg/g. ACE inhibition and DPP-IV inhibition activity were analyzed for each enzymatic hydrolysate. The pepsin hydrolyzed sample exhibited the highest ACE inhibition of 70.26%, and the papain hydrolyzed sample exhibited the highest DPP-IV inhibition of 30.51%. The simulated gastrointestinal digestion (SGID) conducted by pepsin and pancreatin increased ACE inhibitory activity from 76.93% to 78.34%, and DPP-IV inhibited activity increased from 58.62% to 77.13%. Pepsin and papain hydrolysates were fractionated using ultrafiltration to measure ACE and DPP-IV inhibition activity. The highest free radical scavenging abilities were exhibited by the <1 kDa hydrolysate fractions with 78.34% ACE inhibitory activities and 79.55% DPP-IV inhibitory activities. This research revealed that pumpkin seeds had the potency to produce bioactive peptides.

Association between high-density lipoprotein and functional outcome of ischemic stroke patients in a Taiwanese population.

Despite recent findings indicating a paradoxical association between high-density lipoprotein cholesterol (HDL-C) levels and cardiovascular disease (CVD) mortality, the impact of HDL-C on subsequent outcomes after ischemic stroke remains unclear. The study aims to investigate the relationships between HDL-C levels and post-stroke functional outcomes while examining the potential modifying influence of HDL-C-related single nucleotide polymorphisms identified through genome-wide association studies. This cohort study included 1,310 patients diagnosed with acute ischemic stroke (AIS), all of whom had their admission serum lipid profile and genotyping information. Participants were categorized into four groups based on gender and HDL-C level. Prognostic outcomes were assessed using a modified Rankin Scale (mRS) at 1, 3, and 12 months post-admission. Multivariate logistic regression and restricted cubic spline regression analysis were used to assess the associations between HDL-C levels and outcomes. The mean age of patients was 61.17 ± 12.08 years, and 69.31% were men. After adjusting confounders, patients with the highest HDL-C level group had a significantly higher risk of poor functional outcomes at 1, 3, and 12 months following stroke compared to the reference group. Restricted cubic splines depicted a nonlinear association between HDL-C levels and poor prognosis in both men and women. The ABCA1 gene rs2575876 AA genotype combined with abnormal HDL-C levels exhibited a significantly heightened risk of post-stroke adverse outcomes at 1 and 3 months compared to patients with normal HDL-C levels and GG + GA genotype. These findings suggest that the combined effects of ABCA1 genetic variants with either low or high HDL-C levels could further heighten this risk.

The Association between GLP-1 Receptor-Based Agonists and the Incidence of Asthma in Patients with Type 2 Diabetes and/or Obesity: A Meta-Analysis.

Objective: Recent studies have indicated potential anti-inflammatory effects of glucagon-like peptide-1 receptor agonists (GLP-1RAs) on asthma, which is often comorbid with type 2 diabetes mellitus (T2DM) and obesity. Therefore, we conducted a meta-analysis to assess the association between the administration of glucagon-like peptide-1 (GLP-1) receptor-based agonists and the incidence of asthma in patients with T2DM and/or obesity. Methods: PubMed, Web of Science, Embase, the Cochrane Central Register of Controlled Trials, and Clinicaltrial.gov were systematically searched from inception to July 2023. Randomized controlled trials (RCTs) of GLP-1 receptor-based agonists (GLP-1RA, GLP-1 based dual and triple receptor agonist) with reports of asthma events were included. Outcomes were computed as risk ratios ( RR) using a fixed-effects model. Results: Overall, 39 RCTs with a total of 85,755 participants were included. Compared to non-GLP-1 receptor-based agonist users, a trend of reduced risk of asthma was observed in patients with T2DM or obesity using GLP-1 receptor-based agonist treatments, although the difference was not statistically significant [ RR = 0.91, 95% confidence interval ( CI): 0.68 to 1.24]. Further Subgroup analyses indicated that the use of light-molecular-weight GLP-1RAs might be associated with a reduced the risk of asthma when compared with non-users ( RR = 0.65, 95% CI: 0.43 to 0.99, P = 0.043). We also performed sensitivity analyses for participant characteristics, study design, drug structure, duration of action, and drug subtypes. However, no significant associations were observed. Conclusion: Compared with non-users, a modest reduction in the incidence of asthma was observed in patients with T2DM or obesity using GLP-1 receptor-based agonist treatments. Further investigations are warranted to assess the association between GLP-1 receptor-based agonists and the risk of asthma.

Renoprotective effect of rosmarinic acid by inhibition of indoxyl sulfate-induced renal interstitial fibrosis via the NLRP3 inflammasome signaling.

We previously reported that rosmarinic acid (RA) ameliorated renal fibrosis in a unilateral ureteral obstruction (UUO) murine model of chronic kidney disease. This study aimed to determine whether RA attenuates indoxyl sulfate (IS)-induced renal fibrosis by regulating the activation of the NLRP3 inflammasome/IL-1ß/Smad circuit. We discovered the NLRP3 inflammasome was activated in the IS treatment group and downregulated in the RA-treated group in a dose-dependent manner. Additionally, the downstream effectors of the NLRP3 inflammasome, cleaved-caspase-1 and cleaved-IL-1ß showed similar trends in different groups. Moreover, RA administration significantly decreased the ROS levels of reactive oxygen species in IS-treated cells. Our data showed that RA treatment significantly inhibited Smad-2/3 phosphorylation. Notably, the effects of RA on NLRP3 inflammasome/IL-1ß/Smad and fibrosis signaling were reversed by the siRNA-mediated knockdown of NLRP3 or caspase-1 in NRK-52E cells. In vivo, we demonstrated that expression levels of NLRP3, c-caspase-1, c-IL-1ß, collagen I, fibronectin and α-SMA, and TGF- ß 1 were downregulated after treatment of UUO mice with RA or RA + MCC950. Our findings suggested RA and MCC950 synergistically inhibited UUO-induced NLRP3 signaling activation, revealing their renoprotective properties and the potential for combinatory treatment of renal fibrosis and chronic kidney inflammation.

Asiatic acid inhibits osteosarcoma cell migration and invasion via the AKT/Sp1/MMP1 axis.

Osteosarcoma is a malignant bone tumor affecting adolescents and children. No effective treatment is currently available. Asiatic acid (AA), a triterpenoid compound found in Centella asiatica, possesses anti-tumor, anti-inflammatory, and anti-oxidant properties in various types of tumor cells. This study aims to determine whether AA exerts antitumor effects in human osteosarcoma cells. Our results indicate that AA does not influence the viability, proliferative rate, or cell cycle phase of human osteosarcoma cells under non-toxic conditions. AA suppressed osteosarcoma cell migration and invasion by down-regulating matrix metalloproteinase 1 (MMP1) expression. Data in the TNMplot database suggested MMP1 expression was higher in osteosarcoma than in normal tissues, with associated clinical significance observed in osteosarcoma patients. Overexpression of MMP1 in osteosarcoma cells reversed the AA-induced suppression of cell migration and invasion. AA treatment decreased the expression of specificity protein 1 (Sp1), while Sp1 overexpression abolished the effect of AA on MMP1 expression and cell migration and invasion. AA inhibited AKT phosphorylation, and treatment with a PI3K inhibitor (wortmannin) increased the anti-invasive effect of AA on osteosarcoma cells via the p-AKT/Sp1/MMP1 axis. Thus, AA exhibits the potential for use as an anticancer drug against human osteosarcoma.

A randomized trial of Bacteroides fragilis 839 on preventing chemotherapy-induced myelosuppression and gastrointestinal adverse effects in breast cancer patients.

BACKGROUND AND OBJECTIVES: To evaluate the potential benefits of Bacteroides fragilis 839 (BF839), a next-generation probiotics, in reducing myelosuppression and gastrointestinal toxicity associated with chemotherapy in breast cancer patient. METHODS AND STUDY DESIGN: 40 women with early breast cancer were randomly assigned to the BF839 (n=20) or placebo (n=20) during the administration of adjuvant chemotherapy (4 cycles of epirubicin 100mg/m2 and cyclophosphamide 600mg/m2). Myelosuppression and gastrointestinal adverse effects were monitored in both groups. RESULTS: Throughout the four treatment cycles, the percentage of patients experiencing myelosuppression was 42.5% in the BF839 group, significantly lower than the 66.3% observed in the control group (p=0.003). Two patients in the BF839 group and three patients in the placebo group received recombinant human granulocyte colony-stimulating factor (rhG-CSF) due to leuko-penia/neutropenia. When considering an ITT analysis, which included all patients regardless of rhG-CSF treatment, the BF839 group exhibited less reduction from baseline in white blood cells (-0.31±1.19 vs -1.15±0.77, p=0.012) and neutrophils (0.06±1.00 vs -0.84±0.85, p=0.004) compared to the placebo group. The difference became even more significant when excluding the patients who received rhG-CSF injections. Throughout the four treatment cycles, compared to the placebo group, the BF839 group had significantly lower rates of 3-4 grade nausea (35.0% vs 71.3%, p=0.001), vomiting (20.0% vs 45.0%, p=0.001), and diarrhea (15.0% vs 30.0%, p=0.023). CONCLUSIONS: These findings suggest that BF839 has the potential to effectively mitigate myelosuppression and gastrointestinal toxicity associated with chemotherapy in breast cancer patients.

Delayed neurological dysfunction following posterior laminectomy with lateral mass screw fixation: A case report and review of literature.

BACKGROUND: While most complications of cervical surgery are reversible, some, such as symptomatic postoperative spinal epidural hematoma (SEH), which generally occurs within 24 h, are associated with increased morbidity and mortality. Delayed neurological dysfunction is diagnosed in cases when symptoms present > 3 d postoperatively. Owing to its rarity, the risk factors for delayed neurological dysfunction are unclear. Consequently, this condition can result in irreversible neurological deficits and serious consequences. In this paper, we present a case of postoperative SEH that developed three days after hematoma evacuation. CASE SUMMARY: A 68-year-old man with an American Spinal Injury Association (ASIA) grade C injury was admitted to our hospital with neck pain and tetraplegia following a fall. The C3-C7 posterior laminectomy and the lateral mass screw fixation surgery were performed on the tenth day. Postoperatively, the patient showed no changes in muscle strength or ASIA grade. The patient experienced neck pain and subcutaneous swelling on the third day postoperatively, his muscle strength decreased, and his ASIA score was grade A. Magnetic resonance imaging showed hypointense signals on T1 weighted image (T1WI) and T2WI located behind the epidural space, with spinal cord compression. Emergency surgical intervention for the hematoma was performed 12 h after onset. Although hypoproteinemia and pleural effusion did not improve in the perioperative period, the patient recovered to ASIA grade C on day 30 after surgery, and was transferred to a functional rehabilitation exercise unit. CONCLUSION: This case shows that amelioration of low blood albumin and pleural effusion is an important aspect of the perioperative management of cervical surgery. Surgery to relieve the pressure on the spinal cord should be performed as soon as possible to decrease neurological disabilities.

The opportunities and challenges of the disease-modifying immunotherapy for type 1 diabetes: A systematic review and meta-analysis.

There are multiple disease-modifying immunotherapies showing the potential of preventing or delaying the progression of type 1 diabetes (T1D). We designed and performed this systematic review and meta-analysis to gain an overview of what a role immunotherapy plays in the treatment of T1D. We searched PubMed, Embase and Cochrane Central Register of Controlled Trials (CENTRAL) from inception to December 2023. We included clinical trials of immunotherapy conducted in patients with T1D that reported the incidence of hypoglycemia or changes from baseline in at least one of following outcomes: 2 h and 4 h mixed-meal-stimulated C-peptide area under the curve (AUC), fasting C-peptide, daily insulin dosage, glycated hemoglobin (HbA1c) and fasting plasma glucose (FPG). The results were computed as the weighted mean differences (WMDs) or odds ratios (ORs) and 95% confidence intervals (CIs) in random-effect model. In all, 34 clinical trials were included. When compared with control groups, 2 h C-peptide AUC was marginally higher in patient treated with nonantigen-based immunotherapies (WMD, 0.04nmol/L, 95% CI, 0.00-0.09 nmol/L, P=0.05), which was mainly driven by the effects of T cell-targeted therapy. A greater preservation in 4 h C-peptide AUC was observed in patients with nonantigen-based immunotherapies (WMD, 0.10nmol/L, 95% CI, 0.04-0.16 nmol/L, P=0.0007), which was mainly driven by the effects of tumor necrosis factor α (TNF-α) inhibitor and T cell-targeted therapy. After excluding small-sample trials, less daily insulin dosage was observed in patient treated with nonantigen-based immunotherapies when compared with control groups (WMD, -0.07units/kg/day, 95% CI, -0.11 to -0.03units/kg/day, P=0.0004). The use of antigen-based immunotherapies was also associated with a lower daily insulin dosage versus control groups (WMD, -0.11units/kg/day, 95% CI, -0.23 to -0.00units/kg/day, P=0.05). However, changes of HbA1c or FPG were comparable between nonantigen-based immunotherapies or antigen-based immunotherapies and control groups. The risk of hypoglycemia was not increased in patients treated with nonantigen-based immunotherapies or patients treated with antigen-based immunotherapies when compared with control groups. In conclusion, nonantigen-based immunotherapies were associated with a preservation of 2 h and 4 h C-peptide AUC in patients with T1D when compared with the controls, which was mainly driven by the effects of TNF-a inhibitor and T cell-targeted therapy. Both nonantigen-based immunotherapies and antigen-based immunotherapies tended to reduce the daily insulin dosage in patients with T1D when compared with the controls. However, they did not contribute to a substantial improvement in HbA1c or FPG. Both nonantigen-based immunotherapies and antigen-based immunotherapies were well tolerated with not increased risk of hypoglycemia in patients with T1D.

Solution-Induced Degradation of the Silicon Nanobelt Field-Effect Transistor Biosensors.

Field-effect transistor (FET)-based biosensors are powerful analytical tools for detecting trace-specific biomolecules in diverse sample matrices, especially in the realms of pandemics and infectious diseases. The primary concern in applying these biosensors is their stability, a factor directly impacting the accuracy and reliability of sensing over extended durations. The risk of biosensor degradation is substantial, potentially jeopardizing the sensitivity and selectivity and leading to inaccurate readings, including the possibility of false positives or negatives. This paper delves into the documented degradation of silicon nanobelt FET (NBFET) biosensors induced by buffer solutions. The results highlight a positive correlation between immersion time and the threshold voltage of NBFET devices. Secondary ion mass spectrometry analysis demonstrates a gradual increase in sodium and potassium ion concentrations within the silicon as immersion days progress. This outcome is ascribed to the nanobelt's exposure to the buffer solution during the biosensing period, enabling ion penetration from the buffer into the silicon. This study emphasizes the critical need to address buffer-solution-induced degradation to ensure the long-term stability and performance of FET-based biosensors in practical applications.

Licochalcone A induces endoplasmic reticulum stress-mediated apoptosis of endometrial cancer cells via upregulation of GRP78 expression.

Licochalcone A (LicA), a natural compound extracted from licorice root, has been shown to exert a variety of anticancer activities. Whether LicA has such effects on endometrial cancer (EMC) is unclear. This study aims to investigate the antitumor effects of LicA on EMC. Our results show that LicA significantly reduced the viability and induced apoptosis of EMC cells and EMC-7 cells from EMC patients. LicA was also found to induce endoplasmic reticulum (ER) stress, leading to increased expression of ER-related proteins (GRP78/PERK/IRE1α/CHOP) in EMC cell lines. Suppression of GRP78 expression in human EMC cells treated with LicA significantly attenuated the effects of LicA, resulting in reduced ER-stress mediated cell apoptosis and decreased expression of ER- and apoptosis-related proteins. Our findings demonstrate that LicA induces apoptosis in EMC cells through the GRP78-mediated ER-stress pathway, emphasizing the potential of LicA as an anticancer therapy for EMC.

Weight reduction and the risk of gallbladder and biliary disease: A systematic review and meta-analysis of randomized clinical trials.

In this meta-analysis, we aim to evaluate the risk of gallbladder and biliary disease of weight management strategies and investigate the association between weight reduction and risk of gallbladder or biliary disease. Randomized controlled trials (RCTs) with a duration of at least 12 weeks that compare antiobesity medications (AOMs) with placebo or bariatric surgery with less intensive weight management strategy were concluded. Weight management strategy was associated with a significant increased risk of gallbladder or biliary disease (OR 1.361, 95% CI 1.147 to 1.614, P < 0.001, I2 = 3.5%), cholelithiasis, cholecystitis, and cholecystectomy compared with placebo or controls. The increased risk of gallbladder or biliary disease was observed both in pharmacotherapies subgroup and bariatric surgery subgroup. With regards of specific pharmacotherapies, an increased risk of gallbladder or biliary disease was observed in trials with glucagon-like peptide 1 receptor agonist (GLP-1 RA) treatments. In addition, trials with indication of obesity and overweight treatment and trials with higher doses showed significant higher risk of gallbladder or biliary disease compared with placebo or controls. In conclusion, weight management strategy was associated with an increased risk of gallbladder or biliary disease when compared with placebo or control groups.

The Biosynthesis of Astaxanthin Esters in Schizochytrium sp. is Mediated by a Bifunctional Diacylglycerol Acyltransferase.

Astaxanthin esters are a major form of astaxanthin found in nature. However, the exact mechanisms of the biosynthesis and storage of astaxanthin esters were previously unknown. We found that Schizochytrium sp. synthesized both astaxanthin and docosahexaenoic acid (DHA)-enriched lipids. The major type of astaxanthin produced was free astaxanthin along with astaxanthin-DHA monoester and other esterified forms. DHA accounted for 41.0% of the total fatty acids from astaxanthin monoesters. These compounds were deposited mainly in lipid droplets. The biosynthesis of the astaxanthin esters was mainly carried out by a novel diacylglycerol acyltransferase ScDGAT2-1, while ScDGAT2-2 was involved only in the production of triacylglycerol. We also identified astaxanthin ester synthases from the astaxanthin-producing algae Haematococcus pluvialis and Chromochloris zofingiensis, as well as a thraustochytrid Hondaea fermentalgiana with an unknown carotenoid profile. This investigation enlightens the application of thraustochytrids for the production of both DHA and astaxanthin and provides enzyme resources for the biosynthesis of astaxanthin esters in the engineered microbes.

Tetracosanuclear nickel complexes as effective catalysts for cycloaddition of carbon dioxide with epoxides.

A series of well-defined tetracosanuclear nickel complexes 3-7 facilely produced by one-pot synthesis were active catalysts for cycloaddition of CO2 and cyclohexene oxide (CHO). These nickel complexes were doughnut-like supramolecular coordination complexes involving eight repeating units, and each of them contains one Schiff base ligand and three nickel(II) ions. Notably, the 24-nuclear nickel cluster complex 3 in combination with nucleophilic additives was the most efficient catalyst to mediate CO2 coupling with CHO to generate CO2-based cis-cyclohexene carbonates. In addition to CO2/CHO cycloaddition, complex 3 was also found to effectively couple CO2 with other alicyclic epoxides, generating the corresponding cyclic carbonates. Additionally, kinetic investigations for CO2 cycloaddition of CHO using 3 were reported.

Dapagliflozin treatment and cardiovascular outcome in RBP4/TTRVal30Met (transthyretin cardiac amyloidosis) mice.

AIMS: Whether sodium-glucose co-transporter 2 inhibitors are effective for heart failure caused by ATTR-CA (transthyretin cardiac amyloidosis) remains uncertain. The aim of this study is to investigate the cardiovascular prognosis in ATTR-CA mice model with dapagliflozin treatment. METHODS AND RESULTS: Humanized RBP4/TTRVal50Met and RBP4/TTR mice models were constructed with clustered regularly interspaced short palindromic repeats and associated Cas9 endonuclease (CRISPR-Cas9) techniques and multiple generations breeding. A total of 6 RBP4/TTR mice received placebo treatment, when 12 RBP4/TTRVal50Met received dapagliflozin (1 mg/kg/day, 6 mice) and placebo (6 mice) treatment. Fasting glucose, intraperitoneal glucose tolerance test, and plasma brain natriuretic peptide (BNP) concentration were measured at Day 0, Week 2, and Week 4. BNP, transforming growth factor-beta (TGF-ß), collagen type I alpha 1 (COL1A1) protein levels, and Cola1, TGFß1, TNFα, IL-1ß, BNP relative quantities in cardiac, along with cardiac pathology examination including right ventricular collagen percentage, ventricular septum thickness, left ventricular wall thickness, and left ventricular internal diameter were measured at Week 4 after treatment procedure. All 18 mice completed the experiment. The baseline characteristics were balanced among three treatment groups. In placebo-treated mice, the cardiac BNP relative quantity was significantly higher in RBP4/TTRVal50Met mice than RBP4/TTR mice (RBP4[KI/KI], TTR [KI/KI]: 0.72 ± 0.46, RBP4[KI/KI], TTRVal50Met [KI/KI]: 1.44 ± 0.60, P = 0.043), indicating more significant heart failure progression in ATTR-CA mice than normal mice. In ATTR-CA mice, the cardiovascular prognosis measurements including heart failure (plasma BNP concentration and relative quantities of BNP), cardiac inflammation (relative quantities of Cola1, TGFß1, TNFα, and IL-1ß), and pathological changes (right ventricular collagen percentage, ventricular septum thickness, left ventricular wall thickness, and left ventricular internal diameter) were statistically comparable between those under dapagliflozin and placebo treatment. CONCLUSIONS: Dapagliflozin did not improve cardiovascular prognosis including the progression of heart failure, cardiac inflammation, and pathological changes in ATTR-CA mice compared with placebo. The results of this study were not in support of dapagliflozin's therapeutic effects for ATTR-CA. More pre-clinical and clinical researches to validate these findings and demonstrate the underlying mechanisms are still required.

Study on effect of Wumei Pill on apoptosis of colon cells in rats with ulcerative colitis and its mechanism by regulating miR-146a / 中国免疫学杂志

Objective:To investigate effect of Wumei Pill on colon cell apoptosis in ulcerative colitis(UC)rats by regulating miR-146a and its mechanism.Methods:A total of 50 SD rats were selected,with 10 rats in each group,and divided into control group,model group,Wumei Pill low,medium and high doses groups.Transfected with anti-miR-NC,anti-miR-146a,miR-NC,miR-146a as anti-miR-NC group,anti-miR-146a group,Wumei Pill+miR-NC group,Wumei Pill+miR-146a group.CCK-8 was used to de-tect cell proliferation;flow cytometry was used to detect cell apoptosis;RT-qPCR was used to detect cell miR-146a expression;ELI-SA was used to detect cell IL-1β and IL-13 contents;Western blot was used to detect expressions of B-cell lymphoma 2(Bcl-2)and Bax proteins.Results:Compared with control group,cell survival rate,Bcl-2 protein expression in model group were decreased,while apoptosis rate,Bax protein expression,IL-1β,IL-13 contents and miR-146a expression were increased(P<0.05).Compared with model group,Wumei Pill significantly increased cell survival rate and Bcl-2 protein expression,decreased cell apoptosis rate,Bax protein expression,IL-1β,IL-13 contents and miR-146a expression(P<0.05).Inhibition of miR-146a increased cell survival rate,Bcl-2 protein expression,decreased cell apoptosis rate,IL-1β,IL-13 contents and Bax protein expression(P<0.05).Overexpression of miR-146a reversed effects of Wumei Pills on proliferation and apoptosis of colon cells in UC rats.Conclusion:Wumei Pill can reduce apoptosis of colon cells in UC rats by up-regulating expression of miR-146a.

Primary aldosteronism and obstructive sleep apnea: A meta-analysis of prevalence and metabolic characteristics.

BACKGROUND: Primary aldosteronism (PA) and obstructive sleep apnea (OSA) are both causes for resistant hypertension and contribute to adverse cardiovascular outcome. However, the association of these two disorders remains to be investigated. We conducted this meta-analysis to estimate the prevalence and metabolic characteristics of the coexistence of PA and OSA. METHODS: The databases of MEDLINE, EMBASE and Cochrane Reviews were searched for studies investigating the prevalence or clinical characteristics of PA and OSA until Jan 2023. Single proportions of PA and OSA were meta-analyzed for pooled prevalence and 95% confidence intervals (CIs). Odds ratios (ORs) and 95% CIs were calculated for the comparison of the prevalence. Mean differences (MDs) and 95% CIs were calculated for comparisons of the characteristics between patients with both OSA and PA and control groups. RESULTS: A total of 16 studies were included. The pooled prevalence of PA was 27% (95% CI = 24-29%) in all patients with OSA (n = 3498). The prevalence of PA in patients with OSA was significantly higher than that in the patients without OSA (OR = 2.03, 95% CI = 1.30, 3.16, p = 0.002). The pooled prevalence (95% CI) of OSA was 46% (39-54%) in patients with PA (n = 2335). Compared with the hypertensive patients without PA, the prevalence of OSA in the patients with PA was significantly higher (OR = 2.01, 95% CI = 1.37, 2.95, p < 0.001). Compared with the patients of control groups, the patients with both PA and OSA had higher blood pressure and body mass index (BMI). CONCLUSION: Screening for the coexistence of PA and OSA was warranted.

Magnolin targeting of the JNK/Sp1/MMP15 signaling axis suppresses cervical cancer microenvironment and metastasis via microbiota modulation.

Magnolin (MGL), a compound derived from the magnolia plant, has inhibitory effects on tumor cell invasion and growth. His study aims to explore the antitumor effect and underlying molecular mechanism of MGL against human cervical cancer. We found that MGL inhibited the proliferation, migration, and invasiveness of cervical cancer cells in vitro and in vivo. The underlying mechanism was shown to involve MGL-induced inhibition of JNK/Sp1-mediated MMP15 transcription and translation. Overexpression of JNK/Sp1 resulted in significant restoration of MMP15 expression and the migration and invasion capabilities of MGL-treated cervical cancer cells. MGL modulated the cervical cancer microenvironment by inhibiting cell metastasis via targeting IL-10/IL-10 receptor B (IL-10RB) expression, thereby attenuating JNK/Sp1-mediated MMP15 expression. Analysis of the gut microbiota of mice fed MGL revealed a significant augmentation in Lachnospiraceae bacteria, known for their production of sodium butyrate. In vivo experiments also demonstrated synergistic inhibition of cervical cancer cell metastasis by MGL and sodium butyrate co-administration. Our study provides pioneering evidence of a novel mechanism by which MGL inhibits tumor growth and metastasis through the IL-10/IL-10RB targeting of the JNK/Sp1/MMP15 axis in human cervical cancer cells.

A Transient π-π or Cation-π Interaction between Degron and Degrader Dual Residues: A Key Step for the Substrate Recognition and Discrimination in the Processive Degradation of SulA by ClpYQ (HslUV) Protease in Escherichia coli.

The Escherichia coli ATP-dependent ClpYQ protease constitutes ClpY ATPase/unfoldase and ClpQ peptidase. The Tyr91st residue within the central pore-I site of ClpY-hexamer is important for unfolding and translocating substrates into the catalytic site of ClpQ. We have identified the degron site (GFIMRP147th) of SulA, a cell-division inhibitor recognized by ClpYQ and that the Phe143rd residue in degron site is necessary for SulA native folded structure. However, the functional association of this degron site with the ClpYQ degrader is unknown. Here, we investigated the molecular insights into substrate recognition and discrimination by the ClpYQ protease. We found that the point mutants ClpYY91FQ, ClpYY91HQ, and ClpYY91WQ, carrying a ring structure at the 91st residue of ClpY, efficiently degraded their natural substrates, evidenced by the suppressed bacterial methyl-methane-sulfonate (MMS) sensitivity, the reduced ß-galactosidase activity of cpsB::lacZ, and the lowest amounts of MBP-SulA in both in vivo and in vitro degradation analyses. Alternatively, mimicking the wild-type SulA, SulAF143H, SulAF143K and SulAF143W, harboring a ring structure or a cation side-group in 143rd residue of SulA, were efficiently degraded by ClpYQ in the bacterial cells, also revealing shorter half-lives at 41 °C and higher binding affinities towards ClpY in pull-down assays. Finally, ClpYY91FQ and ClpYY91HQ, were capable of effectively degrading SulAF143H and SulAF143K, highlighting a correspondingly functional interaction between the SulA 143rd and ClpY 91st residues. According to the interchangeable substituted amino acids, our results uniquely indicate that a transient π-π or cation-π interaction between the SulA 143rd and ClpY 91st residues could be aptly gripped between the degron site of substrates and the pore site of proteases (degraders) for substrate recognition and discrimination of the processive degradation.