Piribedil and thymol mitigate vancomycin-evoked nephrotoxicity in rats through modulation of Keap-1/Nrf2/HO-1 and NF-κB/Bax/caspase 3 signalingsYahia, Hassan, Abo-Youssef
et alDrug Chem Toxicol (2025)
Abstract: Nephrotoxicity is a sign in which endogenous or exogenous toxicants have damaged the kidney-specific detoxification and excretion processes. Vancomycin (VAN) exposure mostly causes kidney damage and a loss of body homeostasis regulation. This study aimed to investigate the protective effects of piribedil and thymol and its basic mechanisms against nephrotoxicity caused by VAN. Randomly, the animals were categorized into six groups (n = 8). For 7 d, Group I only received vehicles, Group II received piribedil (5 mg/kg/once daily, i.p.), Group III received thymol (25 mg/kg/once daily, i.p), Group IV was administered a single daily dose of VAN (200 mg/kg, i.p.), VAN+ piribedil was administered to Group V, and VAN + thymol was administered to Group VI. The findings showed that piribedil or thymol improved renal function parameters by an increase in serum albumin level in parallel to a decrease in serum creatinine and blood urea nitrogen (BUN) levels in addition to decreased levels of KIM-1 and serum cystatin C. Furthermore, enhanced oxidative stress biomarkers as GSH, myeloperoxidase (MPO), and malondialdehyde (MDA) as well as tumor necrosis factor-alpha (TNF-α) and interleukin-1beta (IL-1β), indicators of inflammatory mediators, were markedly reduced compared to VAN group. Moreover, piribedil or thymol markedly improved the histopathological aberrations provoked by VAN, increased the Nrf-2 and HO-1 renal protein expressions and reduced VAN-induced elevation of Keap-1 protein expression. In addition, NF-kB, Bax, and caspase 3 expression levels were considerably declined after piribedil or thymol co-treatment. These findings revealed that co-administration of piribedil or thymol with VAN may be a sensible therapeutic approach for reducing renal intoxication caused by VAN.
Combination of 10-hydroxy-decanoic acid and ZnO nanoparticles abrogates lead acetate-induced nephrotoxicity in rats: targeting oxidative stress and inflammatory signallingSaleh, Agwah, Elblehi
et alBMC Pharmacol Toxicol (2025) 26 (1), 69
Abstract: Lead is a heavy metal contaminant that can cause significant alterations in renal structure and function, resulting in nephrotoxicity. The fatty acids of royal jelly exhibit immunoregulatory, anticancer, anti-inflammatory, and antioxidant properties, which have garnered significant interest. The most prevalent among them is 10-hydroxydecanoic acid (10-HDA). Zinc oxide nanoparticles (ZnONPs) demonstrate a renoprotective effect, likely due to their antioxidant, anti-inflammatory, and antiapoptotic properties. This study evaluated the therapeutic efficacy of 10-HDA and ZnONPs, administered either as monotherapy or in combination, against lead-induced nephrotoxicity. Male rats were orally administered lead acetate (PbAc) for three months, followed by the administration of 10-HDA and/or ZnONPs for one month. Exposure to PbAc resulted in elevated renal lead concentration, as well as increased serum levels of urea, creatinine, and cystatin C. The condition resulted in damage to the renal parenchyma, characterised by degenerative glomeruli and tubules, and exhibited the highest lesion score. Nrf2 and HO-1 exhibited reduced expression and diminished antioxidant enzyme levels subsequent to PbAc poisoning. Additionally, there was an increase in the inflammatory and apoptotic signalling through the p-IKK/NF-κB axis. The administration of 10-HDA and ZnONPs significantly decreased renal lead levels and improved antioxidant capacity. Moreover, renal inflammatory markers (TNF-α, p-IKK, IL-1β, IL-6, and IL-8) and proapoptotic indicators (Bax and Caspase-3) were significantly suppressed. The combined therapy demonstrated a synergistic effect (combination index < 1). In conclusion, the results indicated that 10-HDA and ZnONPs have the potential to be a supplement or even an effective treatment to alleviate the adverse effects of lead poisoning. This is potentially attributed to their potent ameliorative actions against oxidation, inflammation, and apoptosis.© 2025. The Author(s).
Deciphering genetic causality between plasma BDNF and 91 circulating inflammatory proteins through bidirectional mendelian randomizationSun, Shi, Ohm
et alSci Rep (2025) 15 (1), 10312
Abstract: Prior studies reported an association between the levels of brain-derived neurotrophic factor (BDNF) circulating in the bloodstream and those of different inflammatory factors. However, their causal relationship remains unclear. Here, we performed a Mendelian randomization (MR) study to investigate the causal relationships between plasma BDNF levels and 91 circulating inflammatory proteins to shed light on the possible role of BDNF in the pathogenesis and progression of inflammation-related neurological diseases in order to distinguish correlation from possible causal effects. Data for plasma BDNF levels were derived from a genome-wide association study (GWAS) encompassing 3,301 European participants. Genetic association estimates for 91 inflammation proteins were extracted from a GWAS meta-analysis that enrolled 14,824 European participants. The primary MR analysis employed the inverse variance weighted (IVW) method and was corroborated by additional methods including MR-Egger, weighted median, weighted mode, and simple mode. Analyses of sensitivity were performed by evaluating the heterogeneity, horizontal pleiotropy, and robustness of the results. Genetic evidence indicated that elevated plasma BDNF levels possibly contribute to decreased concentrations of 13 inflammation proteins (OR: 0.951-0.977), including beta-nerve growth factor (Beta-NGF), caspase 8 (CASP-8), interleukin-15 receptor subunit alpha (IL-15RA), interleukin-17 A (IL-17 A), interleukin-17 C (IL-17 C), interleukin-2 (IL-2), interleukin-20 (IL-20), interleukin-20 receptor subunit alpha (IL-20RA), interleukin-24 (IL-24), interleukin-33 (IL-33), leukemia inhibitory factor (LIF), neurturin (NRTN), as well as neurotrophin-3 (NT-3). The associations between BDNF and IL-33 remained statistically significant after FDR correction (FDR > 0.05). Furthermore, reverse MR analysis showed that C-C motif chemokine 23 (CCL23), CUB domain-containing protein 1 (CDCP1), and NRTN is suggestive for a positive causal effect on BDNF plasma levels (OR: 1.240-1.422). Moreover, 5 proteins are likely to be associated with lower plasma levels of BDNF (OR: 0.742-0.971), including adenosine deaminase (ADA), cystatin D (CST5), interleukin-13 (IL-13), interleukin-17 A (IL-17 A), and vascular endothelial growth factor A (VEGF-A). Genetically determined plasma BDNF levels influence IL-33 and are possibly associated with 12 circulating inflammatory proteins. The data suggest that 8 inflammatory proteins exhibit either negative or protective roles to BDNF levels, respectively. Of these, 5 are negatively associated with BDNF levels, while 3 play protective roles. These findings may offer new theoretical and empirical insights into the pathogenesis and progression of inflammation-related neurological diseases.© 2025. The Author(s).
Proximal tubular deletion of superoxide dismutase-2 reveals disparate effects on kidney function in diabetesTrambas, Bowen, Thallas-Bonke
et alRedox Biol (2025) 82, 103601
Abstract: There is a large body of evidence implicating mitochondrial reactive oxygen species (ROS) overproduction and oxidative stress in the development of diabetic kidney disease and the deficiency of mitochondrial antioxidant systems in the kidney, such as manganese superoxide dismutase (MnSOD/SOD2) have been identified. The proximal tubules of the kidney are densely packed with mitochondria thereby providing energy via oxidative phosphorylation in order to drive active transport for proximal tubular reabsorption of solutes from the glomerular filtrate. We hypothesized that maintenance of MnSOD function in the proximal tubules would be critical to maintain kidney health in diabetes. Here, we induced targeted deletion of SOD2 in the proximal tubules of the kidney in Ins2Akita diabetic mice (SODptKO mice) and show that 20 weeks of SOD2 deletion leads to no major impairment of kidney function and structure, despite these mice displaying enhanced albuminuria and kidney lipid peroxidation (8-isoprostanes). Plasma cystatin C, which is a surrogate marker of glomerular filtration was not altered in SODptKO diabetic mice and histological assessment of the kidney cortex revealed no change in kidney fibrosis. Thus, our findings suggest that deletion of SOD2 in the proximal tubular compartment of the kidney induces a more subtle phenotype than expected, shedding light on the involvement of SOD2 and the proximal tubular compartment in the pathogenesis of diabetic kidney disease.Copyright © 2025 The Authors. Published by Elsevier B.V. All rights reserved.
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