作者: Roche Lima, Abiel ; Ferchmin, Pedro A ; Alicia, Sorangely Vázquez ; Rivera-Moctezuma, Félix G. ; Vázquez Alicia, Sorangely ; Pérez, Dinely ; Rivera-Moctezuma, Félix G ; Sabeva, Nadezhda ; Tosado-Rodríguez, Eduardo L. ; Ferchmin, Pedro A. ; Marrero Valentín, José L ; Tosado-Rodríguez, Eduardo L ; Marrero Valentín, José L.

Gulf War Illness (GWI) has been consistently linked to exposure to pyridostigmine (PB), N,N-Diethyl-meta-toluamide (DEET), permethrin (PER), and traces of sarin. In this study, diisopropylfluorophosphate (DFP, sarin surrogate) and the GWI-related chemicals were found to reduce the number of functionally active neurons in rat hippocampal slices. These findings confirm a link between GWI neurotoxicants and N-Methyl-D-Aspartate (NMDA)-mediated excitotoxicity, which was successfully reversed by Edelfosine (a phospholipase Cβ (PLCβ3) inhibitor) and Flupirtine (a Kv7 channel agonist). To test whether 4R-cembranoid (4R), a nicotinic α7 acetylcholinesterase receptor (α7AChR) modulator known for its neuroprotective properties, can restore hippocampal neurons from glutamate-induced neurotoxicity, we exposed rat hippocampal slices with DFP for 10 min followed by 60 min treatment with 4R. We investigated the 4R mechanisms of neuroprotection after preincubation with LY294002, PD98059, and KN-62. The inhibition of the phosphatidylinositol 3-kinase (PI3K), mitogen-activated protein kinase (MEK1/2), and calcium/calmodulin-dependent protein kinase (CaMKII) abrogated the protective effect of 4R against DFP-induced neurotoxicity. In separate experiments, after incubation with DFP, followed by 4R for 1 h, cellular extracts were prepared for Western blotting of phospho-Akt, phospho-GSK3β, phosphorylated extracellular signal-regulated kinase (ERK)1/2, CaMKII and cAMP response element-binding protein (CREB). Our results show that DFP induces neuronal dysfunction by dephosphorylation, while 4R restores the phosphorylation of Akt, GSK3, ERK1/2, CREB, and CaMKII. Moreover, our proteomics analysis supported the notion that 4R activates additional signaling pathways related to enhancing neuronal signaling, synaptic plasticity, and apoptotic inhibition to promote cell survival against DFP, offering biomarkers for developing treatment against GWI.

2024-12-01·TISSUE & CELL

Quercetin and its potential therapeutic effects on aluminum phosphide-induced cardiotoxicity in rats: Role of NOX4, FOXO1, ERK1/2, and NF-κB

Article

作者: Mostafa, Enas M A ; Ameen, Angie M ; El-Kherbetawy, Mohamed K ; Maher, Shymaa Ahmed ; Atta, Rasha

Acute Aluminum phosphide (AlP) poisoning poses a serious global issue, yet the exact mechanisms behind AlP-induced cardiotoxicity are still not well understood. Moreover, there is no specific antidote available for AlP toxicity. Nevertheless, Quercetin (QE) has emerged as a promising therapeutic candidate in various contexts. Accordingly, our study aimed to evaluate the QE potential therapeutic effects against AlP-induced cardiotoxicity and the mechanisms underlying such effects. Rats were assigned into four groups: Group I (control group), Group II (vehicle (corn oil) group), Group III (AlP group) received a single dose of AlP (10 mg/kg body weight) dissolved in corn oil by oral gavage, and Group IV (AlP + QE group) received a single dose of QE (400 mg/kg body weight) dissolved in saline, one hour after AlP administration. AlP-induced cardiotoxicity was evidenced by the increase in cardiac troponin I (cTnI) as well as the hemodynamic, ECG, and histopathological abnormalities. The AlP group denoted a decrease of the antioxidant enzymes; catalase and SOD and an increase of the lipid peroxidation marker; MDA. This was associated with a notable increase in inflammatory cytokines (TNFα, IL-6, and IL1β), in addition to a significant upregulation of the expression of NOX4, FOXO1, ERK1/2, and NF-κB. Moreover, Caspase3, and BAX showed strong immunopositive expression, while Bcl-2 showed mild immunoexpression. On the other hand, treatment with QE showed an improvement in the cardiotoxic effects of AlP, as indicated by significant enhancements in biomarkers, functional assessments, and histopathological findings. These results suggest that QE may be a promising candidate for treating AlP-induced cardiotoxicity, attributed to its antioxidant, anti-inflammatory, and anti-apoptotic properties, particularly emphasizing the roles of NOX4, FOXO1, ERK1/2, and NF-κB.

2024-11-16·Natural product research

Article

作者: Lu, Naiyan ; Xiang, Wen ; Zhang, Li ; Wei, Jiayi ; Jiang, Wentao ; Yu, Xinghui ; Xie, Yan ; Lv, Lifei

In this study, water-soluble polysaccharides purified from burdock root were used to intervene in carbon tetrachloride (CCl₄)-induced acute liver injury (ALI) of BRL3A hepatocytes and rats. Our results indicated that CCl₄ significantly inhibited hepatocyte viability and upregulated the expression of reactive oxygen species (ROS), malondialdehyde (MDA), pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6), and the pro-apoptotic protein Bax. However, Arctium lappa L. root polysaccharides (ALP) could effectively ameliorate liver function and histopathology, oxidative stress, and inflammatory markers. In addition, ALP reduced the expression of apoptotic markers and promoted the proliferation of damaged hepatocytes. In conclusion, ALP possesses a hepatoprotective effect mediated by attenuating oxidative damage, inflammation and apoptosis in ALI.

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