Targeted inhibition of CX3CL1 limits podocytes ferroptosis to ameliorate cisplatin-induced acute kidney injury.

BACKGROUND: It is widely acknowledged that cisplatin-induced nephrotoxicity hinders its efficacy during clinical therapy. Effective pharmaceutical interventions for cisplatin-induced acute kidney injury (Cis-AKI) are currently lacking. Prior studies have implicated the chemokine CX3CL1 in the development of lipopolysaccharide-induced AKI; however, its specific role in Cis-AKI remains uncertain. This research aimed to comprehensively characterize the therapeutic impact and mechanism of CX3CL1 inhibition on Cis-AKI. METHODS: This study employed an in vivo Cis-AKI mouse model and in vitro cisplatin-treated podocytes. Kidney pathological changes were assessed using hematoxylin-eosin (HE) and Periodic-Schiff (PAS) staining. Transcriptome changes in mouse kidney tissue post-cisplatin treatment were analyzed through RNA sequencing (RNA-seq) datasets. Evaluation parameters included the expression of inflammatory markers, intracellular free iron levels, ferroptosis-related proteins-solute carrier family 7 member 11 (SLC7A11/XCT) and glutathione peroxidase 4 (GPX4)-as well as lipid peroxidation markers and mitochondrial function proteins. Mitochondrial morphological changes were visualized through transmission electron microscopy. The impact of CX3CL1 on the glucose-regulated protein 78/eukaryotic translation initiation factor 2A/CCAAT enhancer binding protein-homologous protein (GRP78/eIF2α/CHOP) and hypoxia-inducible factor 1-alpha/heme oxygenase-1 (HIF1A/HO-1) pathways in Cis-AKI was assessed via Western Blot and Immunofluorescence experiments, both in vivo and in vitro. RESULTS: Kidney CX3CL1 levels were elevated following cisplatin injection in wild-type (WT) mice. Cisplatin-treated CX3CL1-Knockout mice exhibited reduced renal histological changes, lowered blood creatinine (Cre) and blood urea nitrogen (BUN) levels, and decreased expression of inflammatory mediators compared to cisplatin-treated WT mice. RNA-seq analysis revealed the modulation of markers associated with oxidative stress and lipid metabolism related to ferroptosis in the kidneys of mice with Cis-AKI. Both the in vivo Cis-AKI mouse model and in vitro cisplatin-treated podocytes demonstrated that CX3CL1 inhibition could mitigate ferroptosis. This effect was characterized by alleviated intracellular iron overload, malondialdehyde (MDA) content, and reactive oxygen species (ROS) production, alongside increased glutathione/glutathione disulfide ratio, superoxide dismutase (SOD), XCT, and GPX4 activity. CX3CL1 inhibition also ameliorated mitochondrial dysfunction and upregulated expression of mitochondrial biogenesis proteins-uncoupling protein (UCP), mitofusin 2 (Mfn2), and peroxisome proliferators-activated receptor γ coactivator l-alpha (PGC1α)-both in vivo and in vitro. Furthermore, CX3CL1 inhibition attenuated cisplatin-induced endoplasmic reticulum (ER) stress in podocytes. Notably, CX3CL1 inhibition reduced cisplatin-induced expression of HIF-1α and HO-1 in vivo and in vitro. CONCLUSION: Our findings suggest that CX3CL1 inhibition exerts therapeutic effects against Cis-AKI by suppressing podocyte ferroptosis.

HGF ameliorates cardiomyocyte apoptosis and inflammatory response in sepsis via the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway.

OBJECTIVE: This study aimed to analyze the impact of HGF on cardiomyocyte injury, apoptosis, and inflammatory response induced by lipopolysaccharide (LPS). METHODS: Enzyme-linked immunosorbent assay (ELISA) was utilized to quantify the levels of HGF, interleukin (IL)-6, IL-10, creatine phosphokinase-isoenzyme-MB (CK-MB), and cardiac troponin I (cTnI) in the samples. qPCR and Western blotting (WB) were employed to assess the mRNA and protein expressions of HGF, IL-10, IL-6, PI3K, AKT, p-PI3K, and p-AKT. RESULTS: The outcomes of the in vivo experiment revealed that serum levels of IL-6, IL-10, HGF and SOFA scores in the SC group were elevated in contrast to the non-SC group. The correlation analysis indicated a substantial and positive association among serum HGF, IL-6, and IL-10 levels and SOFA scores. Relative to IL-6, IL-10 levels, and SOFA scores, serum HGF demonstrated the highest diagnostic value for SC. Following LPS administration to stimulate H9c2 cells across various periods (0, 12, 24, 48, and 72 h), the levels of myocardial injury markers (CK-MB and cTnI) in the cell supernatants, intracellular inflammatory factors (mRNA and protein levels of IL-10 and IL-6), apoptosis and ROS levels, exhibited a gradual increase followed by a subsequent decline. Following the overexpression of HGF, there was an increase in cell viability, and a decrease in apoptosis, inflammation, oxidative stress injuries, and the protein phosphorylation expressions of PI3K and AKT. After knockdown of HGF expression, the activity of LPS-induced H9c2 cells was further reduced, leading to increased cell injury, apoptosis, inflammation, oxidative stress,and the expression levels of PI3K and Akt protein phosphorylation were further elevated. CONCLUSION: HGF was associated with decreased LPS-induced H9c2 apoptosis and inflammation in H9c2 cells, alongside an improvement in cell viability, indicating potential cytoprotective effects. The mechanism underlying these impacts may be ascribed to the suppression of the PI3K/AKT signaling pathway.

CagA-positive Helicobacter pylori may promote and aggravate scrub typhus.

Helicobacter pylori (H. pylori) infection may alter the host's resistance to tsutsugamushi disease pathogens through the Th1 immune response, leading to potential synergistic pathogenic effects. A total of 117 scrub typhus cases at Beihai People's Hospital and affiliated hospitals of Youjiang University for Nationalities and Medical Sciences were studied from January to December 2022, alongside 130 healthy individuals forming the control group. All participants underwent serum H. pylori antibody testing. The prevalence of H. pylori infection was significantly higher among scrub typhus patients (89.7%) compared to healthy individuals (54.6%) (p < 0.05). Moreover, type I H. pylori infection was notably more prevalent in scrub typhus cases (67.5%) compared to healthy individuals (30%) (p < 0.05). Multifactorial analysis demonstrated type I H. pylori infection as an independent risk factor for scrub typhus (adjusted odds ratio: 2.407, 95% confidence interval: 1.249-4.64, p = 0.009). Among scrub typhus patients with multiple organ damage, the prevalence of type I H. pylori infection was significantly higher (50.6%) than type II H. pylori infection (15.4%) (χ2 = 4.735, p = 0.030). These results highlight a higher incidence of H. pylori infection in scrub typhus patients compared to the healthy population. Additionally, type I H. pylori strain emerged as an independent risk factor for scrub typhus development. Moreover, individuals infected with type I H. pylori are more susceptible to multiple organ damage. These findings suggest a potential role of H. pylori carrying the CagA gene in promoting and exacerbating scrub typhus.

Causal relationship between gut microbiota and puerperal sepsis: a 2-sample Mendelian randomization study.

Background: Some recent observational studies have shown that gut microbiota composition is associated with puerperal sepsis (PS) and no causal effect have been attributed to this. The aim of this study was to determine a causal association between gut microbiota and PS by using a two-sample Mendelian randomization (MR) analysis. Methods: This study performed MR analysis on the publicly accessible genome-wide association study (GWAS) summary level data in order to explore the causal effects between gut microbiota and PS. Gut microbiota GWAS (n = 18,340) were obtained from the MiBioGen study and GWAS-summary-level data for PS were obtained from the UK Biobank (PS, 3,940 cases; controls, 202,267 cases). Identification of single nucleotide polymorphisms associated with each feature were identified based on a significance threshold of p < 1.0 × 10-5. The inverse variance weighted (IVW) parameter was used as the primary method for MR and it was supplemented by other methods. Additionally, a set of sensitivity analytical methods, including the MR-Egger intercept, Mendelian randomized polymorphism residual and outlier, Cochran's Q and the leave-one-out tests were carried out to assess the robustness of our findings. Results: Our study found 3 species of gut microbiota, Lachnospiraceae FCS020, Lachnospiraceae NK4A136, and Ruminococcaceae NK4A214, to be associated with PS. The IVW method indicated an approximately 19% decreased risk of PS per standard deviation increase with Lachnospiraceae FCS020 (OR = 0.81; 95% CI 0.66-1.00, p = 0.047). A similar trend was also found with Lachnospiraceae NK4A136 (OR = 0.80; 95% CI 0.66-0.97, p = 0.024). However, Ruminococcaceae NK4A214 was positively associated with the risk of PS (OR = 1.33, 95% CI: 1.07-1.67, p = 0.011). Conclusion: This two-sample MR study firstly found suggestive evidence of beneficial and detrimental causal associations of gut microbiota on the risk of PS. This may provide valuable insights into the pathogenesis of microbiota-mediated PS and potential strategies for its prevention and treatment.

Genotypic Resistance Remains A Concern In Chronic Hepatitis B Patients With High Viral Load After Lamivudine And Adefovir Combination Therapy.

AIMS: Previous studies have shown that baseline high viral load is closely related to treatment response in chronic hepatitis B (CHB). This study was designed to evaluate the differences of treatment responses between de novo lamivudine (LAM) plus adefovir (ADV) combination therapy compared with entecavir monotherapy (ETV). METHODS: A total of 185 HBeAg-positive CHB patients with high viral load were enrolled and assigned to the LAM+ADV group (n=90) or ETV group (n=95). Clinical variables are extracted from medical records. RESULTS: No significant differences in baseline variables were found between the two groups before antiviral treatment. After 104 weeks of antiviral therapy, the mean HBV DNA viral load in the LAM+ADV group decreased from 8.01±0.65 log10 copies/mL to 0.41±1.04 log10 copies/mL, compared with 8.04±0.57 log10 copies/mL to 0.57±1.28 log10 copies/mL in the ETV group (P=0.35). The virological response rate of LAM+ADV group was 82.2% (74/90) at 104 weeks of treatment, and 80.0% (76/95) in the ETV group (P=0.70). For HBeAg serological responses, HBeAg loss occurred in 23.3% (21/90) and 17.9% (17/95) in the LAM+ADV group and the ETV group, respectively (P=0.36). HBeAg seroconversion was observed in 15.6% (14/90) and 15.8% (15/95) in the LAM+ADV group and ETV group, respectively (P=0.96). However, after 104 weeks of treatment, genotypic resistance was confirmed in 8 cases in the LAM+ADV group, a proportion of 8.8% (8/90), compared with an absence of genotypic resistance in the ETV group (P=0.003). CONCLUSION: Both de novo combination therapy of LAM+ADV and ETV monotherapy could effectively inhibit HBV replication in patients with high viral load. However, the rate of genotypic resistance in LAM+ADV treatment remains a concern. For CHB patients with high viral load, ETV treatment may be superior.