Modulating Nrf-2/HO-1, apoptosis and oxidative stress signaling pathways by gabapentin ameliorates sepsis-induced acute kidney injury.

PURPOSE: Globally, sepsis, which is a major health issue resulting from severe infection-induced inflammation, is the fifth biggest cause of death. This research aimed to evaluate, for the first time, the molecular effects of gabapentin's possible nephroprotective potential on septic rats by cecal ligation and puncture (CLP). METHODS: Sepsis was produced by CLP in male Wistar rats. Evaluations of histopathology and renal function were conducted. MDA, SOD, GSH, TNF-α, IL-1ß, and IL-6 levels were measured. qRT-PCR was utilized to determine the expression of Bax, Bcl-2, and NF-kB genes. The expression of Nrf-2 and HO-1 proteins was examined by western blotting. RESULTS: CLP caused acute renal damage, elevated the blood levels of creatinine, BUN, TNF-α, IL-1ß, and IL-6, reduced the expression of Nrf-2 and HO-1 proteins and the Bcl-2 gene expression, and upregulated NF-kB and Bax genes. Nevertheless, gabapentin dramatically diminished the degree of the biochemical, molecular, and histopathological alterations generated by CLP. Gabapentin reduced the levels of proinflammatory mediators and MDA, improved renal content of GSH and SOD, raised the expression of Nrf-2 and HO-1 proteins and Bcl-2 gene, and reduced the renal expression of NF-kB and Bax genes. CONCLUSION: Gabapentin mitigated the CLP-induced sepsis-related acute kidney injury through up-regulating Nrf-2/HO-1 pathway, repressing apoptosis, and attenuating the oxidative stress status by reducing the levels of the proinflammatory mediators and enhancing the antioxidant status.

Hepatoprotective potential of gabapentin in cecal ligation and puncture-induced sepsis; targeting oxidative stress, apoptosis, and NF-kB/MAPK signaling pathways.

AIMS: Sepsis is a severe inflammatory response to infection with an incidence rate exceeding 48 million cases and 11 million sepsis-related deaths yearly. Furthermore, sepsis remains the fifth most common cause of death worldwide. The present study aimed to examine, for the first time, the potential hepatoprotective activity of gabapentin on cecal ligation and puncture (CLP)-induced sepsis in rats at the molecular level. MAIN METHODS: CLP was used as a model of sepsis in male Wistar rats. Histological examination and liver functions were evaluated. Levels of MDA, GSH, SOD, IL-6, IL-1ß, and TNF-α were investigated using ELISA. mRNA levels of Bax, Bcl-2, and NF-kB were assessed by qRT-PCR. Western blotting investigated the expression of ERK1/2, JNK1/2, and cleaved caspase 3 proteins. KEY FINDINGS: CLP resulted in liver damage, elevated serum levels of ALT, AST, ALP, MDA, TNF-α, IL-6, and IL-1ß, increased expression of ERK1/2, JNK1/2, and cleaved caspase 3 proteins, and upregulated Bax and NF-κB genes expression while it down-regulated Bcl-2 gene expression. However, gabapentin treatment significantly reduced the severity of CLP-induced biochemical, molecular, and histopathological changes. Gabapentin attenuated the levels of the proinflammatory mediators, decreased the expression of JNK1/2, ERK1/2, and cleaved caspase 3 proteins, suppressed Bax and NF-κB genes expression and increased the expression of the Bcl-2 gene. SIGNIFICANCE: Consequently, Gabapentin reduced hepatic injury resulting from CLP-induced sepsis by reducing proinflammatory mediators, attenuating apoptosis, and inhibiting the intracellular MAPK (ERK1/2, JNK1/2)-NF-kB signaling pathway.

Vitis vinifera leaf extract liposomal Carbopol gel preparation's potential wound healing and antibacterial benefits: in vivo, phytochemical, and computational investigation.

Vitis vinifera Egyptian edible leaf extract loaded on a soybean lecithin, cholesterol, and Carbopol gel preparation (VVL-liposomal gel) was prepared to maximize the in vivo wound healing and anti-MRSA activities for the crude extract, using an excision wound model and focusing on TLR-2, MCP-1, CXCL-1, CXCL-2, IL-6 and IL-1ß, and MRSA (wound infection model, and peritonitis infection model). VVL-liposomal gel was stable with significant drug entrapment efficiency reaching 88% ± 3, zeta potential value ranging from -50 to -63, and a size range of 50-200 µm nm in diameter. The in vivo evaluation proved the ability of VVL-liposomal gel to gradually release the drugs in a sustained manner with greater complete wound healing effect and tissue repair after 7 days of administration, with a significant decrease in bacterial count compared with the crude extract. Phytochemical investigation of the crude extract of the leaves yielded fourteen compounds: two new stilbenes (1, 2), along with twelve known ones (3-14). Furthermore, a computational study was conducted to identify the genes and possible pathways responsible for the anti-MRSA activity of the isolated compounds, and inverse docking was used to identify the most likely molecular targets that could mediate the extract's antibacterial activity. Gyr-B was discovered to be the best target for compounds 1 and 2. Hence, VVL-liposomal gel can be used as a novel anti-dermatophytic agent with potent wound healing and anti-MRSA capacity, paving the way for future clinical research.