Deciphering the molecular nexus of BTG2 in periodontitis and diabetic kidney disease.

OBJECTIVE: To investigate the role of BTG2 in periodontitis and diabetic kidney disease (DKD) and its potential underlying mechanism. METHODS: Gene expression data for periodontitis and DKD were acquired from the Gene Expression Omnibus (GEO) database. Differential expression analysis identified co-expressed genes between these conditions. The Nephroseq V5 online nephropathy database validated the role of these genes in DKD. Pearson correlation analysis identified genes associated with our target gene. We employed Gene Set Enrichment Analysis (GSEA) and Protein-Protein Interaction (PPI) networks to elucidate potential mechanisms. Expression levels of BTG2 mRNA were examined using quantitative polymerase Chain Reaction (qPCR) and immunofluorescence assays. Western blotting quantified proteins involved in epithelial-to-mesenchymal transition (EMT), apoptosis, mTORC1 signaling, and autophagy. Additionally, wound healing and flow cytometric apoptosis assays evaluated podocyte migration and apoptosis, respectively. RESULTS: Analysis of GEO database data revealed BTG2 as a commonly differentially expressed gene in both DKD and periodontitis. BTG2 expression was reduced in DKD compared to normal conditions and correlated with proteinuria. GSEA indicated enrichment of BTG2 in the EMT and mTORC1 signaling pathways. The PPI network highlighted BTG2's relevance to S100A9, S100A12, and FPR1. Immunofluorescence assays demonstrated significantly lower BTG2 expression in podocytes under high glucose (HG) conditions. Reduced BTG2 expression in HG-treated podocytes led to increased levels of EMT markers (α-SMA, vimentin) and the apoptotic protein Bim, alongside a decrease in nephrin. Lower BTG2 levels were associated with increased podocyte mobility and apoptosis, as well as elevated RPS6KB1 and mTOR levels, but reduced autophagy marker LC3. CONCLUSION: Our findings suggest that BTG2 is a crucial intermediary gene linking DKD and periodontitis. Modulating autophagy via inhibition of the mTORC1 signaling pathway, and consequently suppressing EMT, may be pivotal in the interplay between periodontitis and DKD.

Ischemia/reperfusion-activated ferroptosis in the early stage triggers excessive inflammation to aggregate lung injury in rats.

Objective: Lung ischemia/reperfusion injury (LIRI) is a clinical syndrome of acute lung injury that occurs after lung transplantation or remote organ ischemia. Ferroptosis and inflammation are involved in the pathogenesis of LIRI according to the results of several studies on animal models. However, the interactive mechanisms between ferroptosis and inflammation contributing to LIRI remain unclear. Methods: HE staining and indicators of oxidative stress were used to evaluated the lung injury. The reactive oxygen species (ROS) level was examined by DHE staining. The quantitative Real-time PCR (qRT-PCR) and western blot analysis were employed to detect the level of inflammation and ferroptosis, and deferoxamine (DFO) was used to assess the importance of ferroptosis in LIRI and its effect on inflammation. Results: In the present study, the link of ferroptosis with inflammation was evaluated at reperfusion 30-, 60- and 180-minute time points, respectively. As the results at reperfusion 30-minute point shown, the pro-ferroptotic indicators, especially cyclooxygenase (COX)-2 and acyl-CoA synthetase long-chain family member 4 (ACSL4), were upregulated while the anti-ferroptotic factors glutathione peroxidase 4 (GPX4), cystine-glumate antiporter (XCT) and ferritin heavy chain (FTH1) were downregulated. Meanwhile, the increased level of interleukin (IL)-6, tumor necrosis factor alpha (TNF-α) and IL-1ß were observed beginning at reperfusion 60-minute point but mostly activated at reperfusion 180-minute point. Furthermore, deferoxamine (DFO) was employed to block ferroptosis, which can alleviate lung injury. Expectedly, the survival rate of rats was increased and the lung injury was mitigated containing the improvement of type II alveolar cells ultrastructure and ROS production. In addition, at the reperfusion 180-minute point, the inflammation was observed to be dramatically inhibited after DFO administration as verified by IL-6, TNF-α and IL-1ß detection. Conclusion: These findings suggest that ischemia/reperfusion-activated ferroptosis plays an important role as the trigger for inflammation to further deteriorate lung damages. Inhibiting ferroptosis may have therapeutic potential for LIRI in clinical practice.

Effectiveness of Probiotics and Prebiotics Against Acute Liver Injury: A Meta-Analysis.

Background and Aims: Acute liver injury (ALI) is a clinical syndrome characterized by rapid loss of liver function, which may progress to life-threatening liver failure. We conducted this meta-analysis to examine the evidence on the effects of probiotics or prebiotics on ALI. Methods and Results: Several databases, including PubMed, EMBASE, and Cochrane Library, were scrutinized from the inception through February 2021 by combining key search terms, yielding 26 eligible studies, which concluded that modulation of gut microbiota significantly decreased aspartate transaminase [standardized mean difference (SMD): -1.51, 95% confidence interval (CI): -2.03 to -1.00], alanine aminotransferase (SMD: -1.42, 95% CI: -1.85 to -0.98), and bilirubin (SMD: -0.91, 95% CI: -1.33 to -0.49). In addition, administration of probiotics or prebiotics also promoted proliferation of Bifidobacterium (SMD: 1.21, 95% CI: -0.18 to 2.60) and inhibited Enterococcus (SMD: -1.00, 95% CI: -1.39 to -0.61), contributing to lower levels of endotoxin (SMD: -2.14, 95% CI: -2.91 to -1.37). Tight junction protein ZO-1 (SMD: 1.95, 95% CI: 0.14 to 3.76) was upregulated after intervention, thereby reducing bacterial translocation to the liver [odds ratio (OR) = 0.23, 95% CI: 0.13-0.44] and mesenteric lymph node (OR = 0.14, 95% CI: 0.08 to 0.26), with decreased tumor necrosis factor-α (SMD: -2.84, 95% CI: -3.76 to -1.93) and interleukin-6 (SMD: -2.62, 95% CI: -4.14 to -1.10). Oxidative stress was also relieved by reducing malondialdehyde (SMD: -1.83, 95% CI: -2.55 to -1.10) while elevating superoxide dismutase (SMD: 1.78, 95% CI: 1.00-2.55) and glutathione (SMD: 1.83, 95% CI: 0.76-2.91). Conclusion: Our findings suggest that probiotics and prebiotics could be a promising therapeutic strategy in ALI and possess a potential for clinical applications. Systematic Review Registration:https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=255888, CRD42021255888.

Hybrid Nanoparticles Modified by Hyaluronic Acid Loading an HSP90 Inhibitor as a Novel Delivery System for Subcutaneous and Orthotopic Colon Cancer Therapy.

BACKGROUND: As a therapeutic target for cancer treatment, HSP90 has been explored extensively. However, the significant side effects of the HSP90 inhibitor 17AAG have limited its clinical use. METHODS: In this study, we used hyaluronic acid (HA)-decorated DOTAP-PLGA hybrid nanoparticles (HA-DOTAP-PLGA NPs) as 17AAG-delivery carriers for targeted colon cancer therapy. RESULTS: Different methods were used to characterize the successful fabrication of these hybrid PLGA NPs. Our results demonstrated that internalization of HA-NPs in colon cancer cells was governed by CD44receptor-mediated endocytosis. Annexin V-propidium iodide staining experiments revealed that cell apoptosis induced by HA-NPs-17AAG in colon cancer cells was more efficient than free 17AAG. In two animal models used to screen anticancer efficacy (Luc-HT29 subcutaneous xenograft and AOM/DSS-induced orthotopic tumor model), HA-NPs-17AAG significantly inhibited xenograft and orthotopic tumor growth, demonstrating HA-NPs-17AAG had much better therapeutic efficiency than free 17AAG. It is worth noting that great biocompatibility of HA-DOTAP-PLGA NPs was observed both in vitro and in vivo. CONCLUSION: Our research offers a preclinical proof of concept for colon cancer therapy with DOTAP-PLGA NPs as a creative drug-delivery system.

A Meta-Analysis of Microbial Therapy Against Metabolic Syndrome: Evidence From Randomized Controlled Trials.

Background and aims: Metabolic syndrome (MetS), accompanied with significant intestinal dysbiosis, causes a great public health burden to human society. Here, we carried out a meta-analysis to qualify randomized controlled trials (RCTs) and to systematically evaluate the effect of microbial therapy on MetS. Methods and results: Forty-two RCTs were eligible for this meta-analysis after searching the PubMed, Cochrane, and Embase databases. Pooled estimates demonstrated that treatment with microbial therapy significantly reduced the waist circumference (WC) (SMD = -0.26, 95% CI -0.49, -0.03), fasting blood glucose (FBG) (SMD = -0.35, 95% CI -0.52, -0.18), total cholesterol (TC) (SMD = -0.36, 95% CI -0.55, -0.17), low-density lipoprotein cholesterol (LDL-C) (SMD = -0.42, 95% CI -0.61, -0.22), and triacylglycerol (TG)(SMD = -0.38, 95% CI -0.55, -0.20), but increased the high-density lipoprotein cholesterol (HDL-C) (SMD = 0.28, 95% CI.03, 0.52). Sensitivity analysis indicated that after eliminating one study utilizing Bifidobacteriumlactis, results became statistically significant in diastolic blood pressure (DBP) (SMD = -0.24, 95% CI -0.41, -0.07) and in Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) (SMD = -0.28, 95% CI -0.54, -0.03), while the body mass index (BMI) showed significant difference after eliminating one study utilizing oat bran (SMD = -0.16, 95% CI -0.31, -0.01). There was still no significant effect in systolic blood pressure (SBP) and in hemoglobin A1c (HbA1c%). Conclusion: In patients with MetS, the conditioning with microbial therapy notably improves FBG, TC, TG, HDL-C, LDL-C, WC, BMI (except for the study using oat bran), HOMA-IR, and DBP (except for the Study using Bifidobacteriumlactis), however, with no effect in SBP and in HbA1c%.