Buspirone attenuates cyclophosphamide-induced renal dysfunction in association with alterations in miR-205/EGLN2, Nrf2, and PERK/ATF4/CHOP signaling

Cardioprotective role of vincamine in cyclophosphamide-induced cardiotoxicity through modulation of AMPK/SIRT1, PI3K/Akt, and MAPK pathways.

Protective effect of Dapagliflozin on hepatic encephalopathy induced by thioacetamide in rats: involvement of ERK, JNK, and Nrf2/HO-1 pathways.

Hepatic encephalopathy (HE) is a neuropsychiatric disorder associated with oxidative stress, neuroinflammation, and hyperammonaemia secondary to hepatic dysfunction. This study aimed to investigate dapagliflozin's effects (DAPA) against HE induced by thioacetamide (TAA) in rats and to elucidate the roles of the extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and nuclear factor erythroid 2-related factor 2/Heme oxygenase-1 (Nrf2/HO-1) signaling pathways. HE was induced by injection of TAA (200 mg/kg) intraperitoneally 2 times every other day. Two groups were pretreated with DAPA at 5 and 10 mg/kg for 15 days; on the 13th day, rats were given TAA (200 mg/kg, i.p.) twice, 2 days apart. Behavioral assessments, including object recognition and rotarod tests, were conducted, and serum and tissue samples were collected for biochemical and molecular analyses. DAPA pretreatment ameliorated TAA effects, improved recognition memory, enhanced muscular tone and motor coordination. DAPA also reduced ALT (alanine aminotransferase), AST (aspartate aminotransferase), and ammonia serum levels. Additionally, it restored antioxidant balance, decreased malonaldehyde (MDA) and increased reduced glutathione (GSH). Moreover, it reduced tissue inflammation and inhibited apoptosis; where tumor necrosis factor-alpha (TNF-α) and caspase-3 expression were suppressed. DAPA was associated with increased Nrf2/HO-1 pathway-related protein expression while decreasing pERK/total ERK and pJNK/total JNK ratios, along with nuclear factor kappa-light-chain-enhancer of activated B cells, p65 subunit (NF-κB-p65) protein expression. Histopathologically, DAPA improved hepatic and brain architecture. Collectively, DAPA exhibits hepatoprotective and neuroprotective effects against TAA-induced HE accompanied by modulation in oxidative-, inflammatory-, and apoptotic-related protein expression, highlighting its therapeutic potential in hepatic encephalopathy.

Targeting TRAF6/MYD88/TLR4, Nrf2, and VEGF signaling pathways by Tranexamic acid as a Novel Therapeutic Approach Protects Against Isotretinoin-Induced Liver Toxicity in Rats.

BACKGROUND Isotretinoin is a widely prescribed retinoid for severe acne but is limited by dose-dependent hepatotoxicity. Tranexamic acid (TXA), an antifibrinolytic agent with emerging anti-inflammatory and antioxidant effects, may offer hepatoprotective potential. Aim: This study evaluated whether TXA mitigates isotretinoin-induced liver injury in rats and explored the underlying molecular mechanisms. METHODS Thirty-two male Wistar rats were assigned to four groups (n = 8 each): control, TXA-only, isotretinoin (ISO, 7.5 mg/kg/day, 30 days), and TXA (100 mg/kg/day for 30 days) + ISO. Serum alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase were measured for hepatic function. Oxidative stress was assessed by hepatic malondialdehyde, myeloperoxidase (MPO), and reduced glutathione (GSH). Inflammatory cytokines tumor necrosis factor-alpha (TNF-α), interleukin1β (IL-1β), interleukin-10 (IL-10), and signaling proteins TNF receptor-associated factor 6 (TRAF6) and nuclear factor erythroid 2-related factor 2 (Nrf2) were quantified by ELISA. Vascular endothelial growth factor (VEGF) and nuclear factor kappa B (NF-κB) expressions by immunohistochemistry. Myeloid differentiation primary response 88 (MYD88) and toll-like receptor-4 (TLR4) protein expression were analyzed via Western blot. Histopathological scoring was performed to evaluate tissue injury. RESULTS ISO administration significantly elevated serum ALT and AST by approximately 3-fold (p < 0.001), along with a marked increase in hepatic MDA and MPO, reduced GSH, heightened TNF-α and IL-1β, and suppressed IL-10 (p < 0.05). Hepatic TRAF6, NF-κB, MYD88/TLR4, and VEGF were upregulated significantly (p < 0.05), while Nrf2 was downregulated (p < 0.05), and histology revealed severe degeneration and congestion. TXA co-treatment significantly attenuated these changes (p < 0.05), reducing liver enzyme activities and inflammatory markers while restoring antioxidant defense mechanisms. CONCLUSION TXA pretreatment markedly attenuated these effects, normalizing liver enzymes, restoring oxidative balance, reducing inflammation, and suppressing aberrant signaling. TXA effectively protects against isotretinoin-induced hepatotoxicity, primarily through antioxidant and anti-inflammatory mechanisms.

Alogliptin mitigates doxorubicin-induced cardiotoxicity in rats: Implications of SIRT3/NRF2 pathway and miRNA-133a.

Doxorubicin (DOX) is an anticancer antibiotic that is widely utilized. Nevertheless, this therapeutic potential is hampered by its cardiotoxicity. Alogliptin (ALO), an antidiabetic, recently is being repurposed for the management of various organs ailments owing to its discovered biological activities as an antioxidant, anti-inflammatory, anti-apoptotic and antifibrotic through multiple pathways. This study is directed to evaluate the possible protective effect of ALO against DOX-induced cardiac molecular and histopathological alterations. Twenty-four adult Wistar rats were grouped into control in addition to ALO (20 mg/kg, p.o, 21 days), DOX (18 mg/kg, i.p; six equal divided doses on alternative days starting at day 8), and Dox + ALO treated groups. On the 21st day, blood samples are collected to assess cardiac biomarkers. Additionally, the hearts of all rats were separated and processed for histological evaluation, ultrastructural examination, and collagen content determination by Masson Triciumus staining, and biochemical studies. The DOX group had pronounced deleterious histological and ultrastructural disorganization accompanied with abundant collagen disposition. Biochemically, DOX group demonstrated significant elevation of cardiomyocytes content of MDA, NF-κB, TNF-α, IL-6, BAX, and TGF-β1 which mirrored as significantly elevated serum LDH, CKMB, and cTnI levels. However, SOD and CAT activities as well as GSH, BCL-2, SIRT3 and NRF2 content along with miRNA-133a gene expression are significantly decreased. Present results proved the prophylactic ALO antioxidant, anti-inflammatory, anti-apoptotic, and anti-fibrotic influence on the DOX-induced cardiotoxicity with proposed mechanisms entailing the activation of SIRT3 pathway that may be governed by miRNA-133a. However, these results are limited by the inspection lack of echocardiography or hemodynamic alterations, gain and loss of function, caspase activation, and mitochondrial health tests. Thus, ALO has the potential to be an appropriate therapy for DOX-induced cardiotoxicity.

A closer insight into the molecular effect of canagliflozin on gentamicin–induced nephrotoxicity in rats: attention to SIRT1/Nrf2/HO-1, p38 MAPK/NF-κB signaling pathways, and expression of miR-21 and miR-155

Abstract Objective: Nephrotoxicity is considered the most detrimental effect of gentamicin (GM). In this study, we investigated the potential effects for canagliflozin (CANA) to protect against GM-induced nephrotoxicity, besides the multiple molecular pathways underlying these effects. Methods: Four groups with six rats in each were used: control; GM (100 mg/kg, intraperitoneal injection) for 7 days; CANA + GM group: Rats were given CANA (10 mg/kg, by oral gavage) for 14 days, and GM (100 mg/kg, by IP) was co-administered with CANA in the last 7 days; and CANA group: Rats were given CANA (10 mg/Kg, by oral gavage) for 14 days. Results: Relative to GM-challenged rats, CANA ameliorated GM-induced changes in the state of oxidative stress. Also, CANA alleviated the GM-evoked reduction in the renal expression of SIRT1 and Nrf2. Furthermore, CANA decreased the renal expression of NF-ҡB and reduced p38-MAPK levels in kidneys of GM-treated animals. Simultaneously, GM-induced changes in the renal expression of miR-21 and miR-155 have been successfully amended by CANA. Conclusion: Altogether, current outcomes imply that modification of the SIRT1/Nrf2/HO-1, the p38-MAPK/NF-ҡB pathways, and microRNAs (miRNAs) play an important role adressing CANA’s ‘protective properties against GM nephrotoxicity. Graphical AbstractFlowchart illustrating Canagliflozin's effects on three pathways: Sirt1/Nrf2/NF-?B, p38-MAPK/NF-?B, and microRNAs related to Gentamicin-induced nephrotoxicity.The flowchart presents three panels illustrating Canagliflozin's impact on pathways involved in Gentamicin-induced nephrotoxicity. The top section covers the Sirt1/Nrf2/NF-?B pathway, showing interactions among Sirt-1, Nrf2, and NF-?B, highlighting antioxidant effects. The middle section details the p38-MAPK/NF-?B pathway, emphasizing its role in inflammation and apoptosis. The bottom section focuses on microRNAs, depicting their mediation of Bcl-2 and apoptotic factors. Each panel summarizes Canagliflozin's antioxidant, anti-inflammatory, and anti-apoptotic actions on these pathways.

Pterostilbene Combating Cyclophosphamide-Induced Central Neuro-Inflammation in Rats: Effect on GFAP, PPAR- γ, NLRP3, COX-2 and Nrf2/HO-1 Pathway

Background/Objectives: The clinical efficacy of cyclophosphamide, a commonly used chemotherapeutic drug, is often restricted by off-target neurotoxicity, which is primarily caused by oxidative stress, neuroinflammation, and apoptosis. With the aim of finding natural neuroprotective agents, pterostilbene was investigated in this study, either in conventional form or when solubilized as a nanoemulsion, for its neuroprotective potential against cyclophosphamide-induced neurotoxicity. Methods: Female Wistar rats were orally administered pterostilbene, either in its conventional form (50 mg/kg p.o) or nanoemulsion form (25 and 50 mg/kg p.o), for 15 days. Cyclophosphamide was injected once on day 14 (200 mg/kg ip). Results: Our findings revealed that administering pterostilbene as a nanoemulsion or in its conventional powder form managed to counteract the cyclophosphamide-induced intoxication features via disrupting the oxidative stress–inflammasome–cytokine axis; by upregulating cortical and hippocampal PPAR-γ, Nrf2, HO-1, BCL2 levels and the BCL2/Bax ratio; and downregulating NLRP3, IL-1β, COX-2, Bax and GFAP levels. Further histopathological and immunohistochemical evaluation confirmed the improved neuronal morphology, reduced degeneration and apoptosis, restoration of cortical and hippocampal architecture, and normalization of GFAP expression levels, approaching those of the control group upon treatment with either conventional or nanoformulated pterostilbene. Conclusions: The promising nature of the nanoemulsion formulation, particularly when administered at the high dose level, was evidenced, hence emphasizing the important role of proper formulation of natural bioactives such as pterostilbene in maximizing their therapeutic potential.