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Aims In acute stroke, neurological damage is due to oxidative stress and neuronal apoptotic death. This study investigated whether Nogo-A 290-562 residues region (M9), fused to the transduction domain of the HIV trans-activator ( TAT) protein, is neuroprotective against cerebral ischemia and the mechanisms. Methods Transient focal cerebral ischemia was induced by middle cerebral artery occlusion in male C57 BL/6J mice. TAT-M9, its mutation or vehicle was applied via intraperitoneal injection at the onset of reperfusion. The neurobehavioral scores, infarction volumes, neuronal apoptosis, and the ratio of Bax/Bcl-2 were evaluated. Malondialdehyde ( MDA), reactive oxygen species ( ROS) levels, and NADPH oxidase activation were measured in the presence or absence of the NADPH oxidase inhibitor apocynin or activator tetrabromocinnamic acid ( TBCA). Results Immunofluorescence results confirmed that TAT-M9 was transduced into brain parenchyma, and it significantly improved neurological behavior, reduced infarct volumes, protected neuronal cells from apoptosis, inhibited activation of NADPH oxidase, and decreased MDA and ROS contents. Furthermore, apocynin imitated the beneficial effects of TAT-M9, while TBCA abolished them. Conclusions Our results demonstrate that TAT-M9 administration attenuates cerebral ischemia by inhibiting NADPH oxidase-mediated oxidative damage and neuronal apoptosis in mice. TAT-M9 may be a potential treatment for cerebrovascular disease. [ABSTRACT FROM AUTHOR]

Diagram of TUG891 in Cisplatin-induced AKI. TUG891 modulated the activities of PERK pathway of unfolded protein response, and consequently remitting apoptosis, ER stress and inflammation in cisplatin-induced AKI. • The GPR120 expression is downregulated in the kidneys of cisplatin-induced AKI. • TUG891, a synthetic GPR120 agonist, protected against cisplatin-induced AKI. • Activation of GPR120 by TUG891 inhibited ER stress and apoptosis in cisplatin injured kidneys. Activation of G protein-coupled receptor 120 (GPR120) could inhibit apoptosis and inflammation in cerebral ischemic injury and liver ischemia-reperfusion injury. However, whether GPR120 agonism exerted potential for cisplatin-induced acute kidney injury and the involved mechanisms remained unknown. In our study, pharmacological activation of GPR120 by TUG891 treatment remarkably reduced the elevated serum creatinine level and attenuated tubular injury. Cisplatin triggered ATF6, PERK and IRE1 pathways of unfolded protein response (UPR) of ER stress in the injured kidney tissue, as well as the downstream molecules eIF2α, ATF4 and XBP1. Protein of ER stress-mediated apoptosis, CHOP, was overexpressed in the cisplatin group. Oral application of TUG891 displayed effective inhibition of ER stress and apoptosis. TUG891 treatment significantly decreased the TUNEL positive cells and the flow cytometry of HK-2 cells delineated the similar results that the apoptosis rates were considerably reduced in the TUG891 group compared to cisplatin group. Collectively, activation of GPR120 by TUG891 exhibited renal protection against cisplatin-induced AKI via suppressing ER-associated apoptosis in tubular epithelial cells. [ABSTRACT FROM AUTHOR]

Schematic diagram of fisetin in LPS-induced septic AKI. Fisetin modulated the activities of TLR4/Src-mediated NF-κB p65 and MAPK pathways, thus alleviating kidney inflammation and apoptosis in LPS-induced septic AKI. • Fisetin is a polyphenolic flavonoid in many fruits and vegetables. • Fisetin alleviated kidney injury against LPS-induced septic AKI. • Fisetin inhibited LPS-induced kidney inflammation and apoptosis. • Fisetin inhibited renal Src-mediated NF-κB and MAPK signalling pathways in LPS-induced septic AKI. Sepsis is defined as end-organ dysfunction resulting from the host's inflammatory response to infection. One of the most common sepsis-injured organs is the kidneys, resulting in acute kidney injury (AKI) that contributes to the high morbidity and mortality, especially patients in the intensive care unit. Fisetin, a naturally occurring flavonoid, has been reported to protect against the rat of lipopolysaccharide (LPS)-induced acute lung injury. However, the effect of fisetin on septic AKI remains unknown. The current study proposed to systematically investigate the renoprotective effects and the underlying mechanisms of fisetin in septic AKI mice. The model of septic AKI was established on male C57BL/6 J mice by a single intraperitoneal injection of LPS (10 mg/kg). Fisetin was administrated by gavage at 100 mg/kg for 3 consecutive days before LPS injection and the mice were sacrificed at 16 h after LPS injection. The serum and kidney samples were evaluated for biochemical analysis, histopathological examinations as well as inflammation and apoptosis related gene/protein expression. Pretreatment with fisetin significantly alleviated the elevated levels of serum creatinine and blood urea nitrogen in LPS-treated mice. Consistently, LPS induced renal damage as implied by histopathological score and the increased injury markers NGAL and KIM-1, which was attenuated by fisetin. Meanwhile, LPS injection triggered proinflammatory cytokine production and inflammation related proteins in the kidneys. However, fisetin inhibited renal expression of IL-6, IL-1β, TNF-α, HMGB1, iNOS and COX-2 to improve inflammatory response. Furthermore, fisetin effectively reduced the number of TUNEL positive apoptotic cells and suppressed apoptotic protein of Bcl-2, BAX and cleaved caspase-3 in the kidneys of LPS-induced septic AKI. Mechanistically, LPS stimulated the expression of TLR4 and the phosphorylation of NF-κB p65, MAPK (p38, ERK1/2 and JNK), Src and AKT in the injured kidneys, while fisetin notably suppressed the corresponding protein expression. Fisetin alleviated kidney inflammation and apoptosis to protect against LPS-induced septic AKI mice via inhibiting Src-mediated NF-κB p65 and MAPK signaling pathways [ABSTRACT FROM AUTHOR]

Ultraviolet (UV) radiation and reactive oxygen species (ROS) impair the physiological functions of retinal pigment epithelium (RPE) cells by inducing cell apoptosis, which is the main cause of age-related macular degeneration (AMD). The mechanism by which UV/ROS induces RPE cell death is not fully addressed. Here, we observed the activation of a ceramide-endoplasmic reticulum (ER) stress-AMP activated protein kinase (AMPK) signaling axis in UV and hydrogen peroxide (H2O2)-treated RPE cells. UV and H2O2 induced an early ceramide production, profound ER stress and AMPK activation. Pharmacological inhibitors against ER stress (salubrinal), ceramide production (fumonisin B1) and AMPK activation (compound C) suppressed UV- and H2O2-induced RPE cell apoptosis. Conversely, cell permeable short-chain C6 ceramide and AMPK activator AICAR (5-amino-1-β-D-ribofuranosyl-imidazole-4-carboxamide) mimicked UV and H2O2's effects and promoted RPE cell apoptosis. Together, these results suggest that UV/H2O2 activates the ceramide-ER stress-AMPK signaling axis to promote RPE cell apoptosis. [ABSTRACT FROM AUTHOR]