Acute renal failure (ARF) is a sudden, significant, and often reversible decline in kidney function, with 25% of all hospital-administered pharmaceuticals potentially causing nephrotoxicity. The study investigates the effectiveness of a novel nanoparticle (NP) formulation of glutathione (GSH) and Lepidium sativum (LS) in improving therapeutic outcomes in a rat model of ARF. Sixty adult male albino rats were allocated into ten groups, comprising six rats each, for the study. ARF was created by daily gentamicin (GN) administration for seven consecutive days and various treatment protocols, including chitosan (CS) NPs, spanlastics NPs, as well as conventional, NP formulations of GSH, LS, and their respective combinations. The effect was evaluated through various tests, and properties of nanoparticles were confirmed through characterization processes. The NP compositions markedly enhanced renal function, as seen by reduced urine concentrations of albumin and glucose. Furthermore, the serum concentrations of creatinine (SCr), blood urea nitrogen (BUN), and cystatin C were decreased. Tissue concentrations of nitrite, superoxide dismutase (SOD), and malondialdehyde (MDA), as markers of oxidative stress, were enhanced by both conventional and NP formulations. Additionally, they decreased inflammatory markers such as kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL), tumor necrosis factor alpha (TNF-α), and interleukin-6 (IL-6). Histological analysis and immunohistochemical testing revealed that the combination therapy, particularly with the nanoforms, significantly decreased caspase 3 cellular immunoexpression, a sign of kidney cellular damage. The findings show that the ARF renal damage is considerably reduced when NPs containing GSH and LS are administered together. The study suggests a promising pharmacological approach for enhancing kidney regeneration and preserving renal function, potentially aiding in new therapeutic interventions for ARF treatment.

Purpose

A multitude of inflammatory cells and chemical mediators initiate a complex cascade that ultimately leads to hepatocyte death and a systemic inflammatory response. This research aimed to investigate the potential effects of sildenafil and neem (Azadirachta indica) extract, in both conventional and nanoparticle (NP) forms, in the treatment of moderate acute liver damage induced by orogastric carbon tetrachloride (CCL₄).

Methods

To induce moderate acute hepatic damage a single oral dosage of CCL₄ (2.5 mL/kg body weight) was provided 24 h before euthanasia. In liver damage-induced CCL₄, sildenafil and neem extract were given in conventional and nanoparticle (PLGA or niosome) forms. To find histological anomalies and hepatic changes, behavioral, biochemical, histopathological, and immunohistochemical methods were used.

Results

The findings indicated that sildenafil and/or neem extract, especially in NP combination, significantly mitigated CCL₄-induced acute moderate liver damage. Indicators of liver function, including aspartate aminotransferase (AST), alkaline phosphatase (ALP), alanine aminotransferase (ALT), albumin, bilirubin and gamma-glutamyl transferase (GGT), shown improvement, particularly with the nanoparticulation of both therapies. Treatment, particularly in NP forms, improved the levels of malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase activity (GPx) in liver tissues. A significant reduction in NF-κB expression in hepatic tissue was shown in treatment groups. Also, medication resulted in lower levels of interleukin-1 beta (IL-1β), tumor necrosis factor alpha (TNF-α), caspase-3, and transforming growth factor-beta (TGF-β) in the liver tissue homogenates. Liver function was more significantly improved by the drug-NP combination.

Conclusions

This study verified the beneficial therapeutic effects of the combination of sildenafil and neem extract, particularly in NP forms, using biochemical, histological, and immunohistochemical analyses in a rat model of liver damage.

In this study, ten derivatives of 2-iminothiazolidin-4-one were designed and synthesized as potential antagonists of the LasR protein, guided by extensive molecular docking studies and molecular dynamics simulations (MDS). The synthesized compounds were assessed for their antimicrobial activity and the potential as quorum sensing (QS) inhibitors against Pseudomonas aeruginosa by targeting biofilm formation and associated virulence factors such as pyocyanin, rhamnolipids, protease, and hemolysin. Among these, compounds 8f, 8 g, and 8h showed significant inhibition of P. aeruginosa biofilm formation with percent inhibition of 88.87 %, 87.74 %, and 88.77 %, respectively, compared to azithromycin 66.6 %. Further studies demonstrated that 8f, 8 g, and 8h exerted QS inhibitory activity of P. aeruginosa (in sub-MIC) pyocyanin, rhamnolipid, protease, and hemolysin and rhamnolipid inhibition assays with inhibition percentages ranged from 73.86 % to 85.40 % surpassing the inhibition observed with azithromycin (54–69.91 %). Further evaluation for the most active analogs, compounds 8f, 8 g, and 8h, using an in vitro LasR inhibition assay, revealed IC₅₀ values of 1.45, 1.38 and 1.22 μM, respectively. Additionally, extensive in-silico and molecular dynamic experiments showed that compound 8f exhibited strong interactions with the LasR ligand-binding pocket, leading to the complete dissociation of the protein's dimeric form over approximately 400 ns of MDS. This confirms its action as a LasR inhibitor. These findings establish a robust functional model for LasR inhibition and highlight the potential of 2-iminothiazolidin-4-one derivatives as promising QS modulators for combating P. aeruginosa infections.

Benzimidazole derivatives have garnered significant attention in medicinal chemistry owing to their versatile pharmacological properties, particularly their potent antimicrobial activity. This review comprehensively explores the advancements in the synthesis of benzimidazoles and their antimicrobial property evaluation from 2018 to 2024. Recent synthetic methodologies emphasize green chemistry approaches including solvent-free and catalyst-driven reactions, offering improved yields, selectivity, and environmental sustainability. Structural modifications, such as functionalization at positions 2 and 5/6 of the benzimidazole ring, were extensively investigated to enhance the antimicrobial efficacy against a broad spectrum of pathogens including multidrug-resistant bacterial and fungal strains. Furthermore, we elucidate the structure–activity relationships (SARs) of benzimidazole derivatives, enabling the rational design of highly potent antimicrobial agents. The mentioned period also witnessed the integration of hybrid molecules, wherein benzimidazoles were conjugated with other bioactive scaffolds to achieve synergistic antimicrobial effects.

In this study, two series of benzimidazole hybrids were developed and designed using different strategies. The target compounds were designed through straight chemistry pathways and were screened as possible antimicrobial agents. Twenty new compounds were synthesized, among which compounds 11 and 12 displayed excellent activity against Candida albicans and Cryptococcus neoformans with growth inhibition percentage ranging from 86.42% to 100%. For gaining better insights into the mechanistic ability of the active candidates 11 and 12, their inhibitory activity against lanosterol 14α-demethylase was studied. Results showed IC₅₀ values of 5.6 and 7.1 μM for 11 and 12, respectively, which were comparable to the reference value of fluconazole (2.3 μM), indicating low drug interaction possibilities. Notably, compound 11 displayed excellent inhibition of biofilm metabolic activity. In addition, their synergistic activity against C. neoformans displayed a 2-fold increase compared with fluconazole. Furthermore, it exhibited sustained antifungal activity with time clearance of over 24 h, which was better than the time clearance of fluconazole (6 h). Moreover, compounds 11 and 12 displayed considerable safety profiles, with no cytotoxicity reported against human embryonic kidney cells or hemolysis of red blood cells. Molecular dynamics simulation (MDS) experiments over 100 ns of compound 11 showed its ability to interact with the HEM binding site as the co-crystallized ligand (fluconazole). Finally, in silico ADMET studies predicted its significant oral bioavailability as antifungal candidates