Kazinol B protects H9c2 cardiomyocytes from hypoxia/reoxygenation-induced cardiac injury by modulating the AKT/AMPK/Nrf2 signalling pathway.

CONTEXT: Kazinol B (KB), an isoprenylated flavan derived from Broussonetia kazinoki Sieb. (Moraceae) root, has long been used in folk medicine. OBJECTIVE: This study examines the protective effects of KB and its underlying mechanisms in hypoxia and reoxygenation (H/R)-induced cardiac injury in H9c2 rat cardiac myoblasts. MATERIALS AND METHODS: H9c2 cells were incubated with various concentrations of KB (0, 0.3, 1, 3, 10 and 30 µM) for 2 h and then subjected to H/R insults. The protective effects of KB and its underlying mechanisms were explored. RESULTS: KB significantly elevated cell viability (1 µM, 1.21-fold; 3 µM, 1.36-fold, and 10 µM, 1.47-fold) and suppressed LDH release (1 µM, 0.77-fold; 3 µM, 0.68-fold, and 10 µM, 0.59-fold) in H/R-induced H9c2 cells. Further, 10 µM KB blocked apoptotic cascades, as shown by the Annexin-V/PI (0.41-fold), DNA fragmentation (0.51-fold), caspase-3 (0.52-fold), PARP activation (0.27-fold) and Bax/Bcl-2 expression (0.28-fold) assays. KB (10 µM) downregulated reactive oxygen species production (0.51-fold) and lipid peroxidation (0.48-fold); it upregulated the activities of GSH-Px (2.08-fold) and SOD (1.72-fold). KB (10 µM) induced Nrf2 nuclear accumulation (1.94-fold) and increased ARE promoter activity (2.15-fold), HO-1 expression (3.07-fold), AKT (3.07-fold) and AMPK (3.07-fold) phosphorylation. Nrf2 knockdown via using Nrf2 siRNA abrogated KB-mediated protective effects against H/R insults. Moreover, pharmacological inhibitors of AKT and AMPK also abrogated KB-induced Nrf2 activation and its protective function. DISCUSSION AND CONCLUSIONS: KB prevented H/R-induced cardiomyocyte injury via modulating the AKT and AMPK-mediated Nrf2 induction. KB might be a promising drug candidate for managing ischemic cardiac disorders.

Suppressive Effects of Isofraxidin on Depressive-like Behaviors Induced by Chronic Unpredictable Mild Stress in Mice.

Isofraxidin is an active component of several traditional and functional plants that have beneficial properties for neurodegenerative diseases. In this study, we examined whether isofraxidin exhibited antidepressant-like effects in chronic unpredictable mild stress (CUMS)-induced mice. Firstly, isofraxidin could reverse CUMS-induced decrease in body weight gain in mice. Additionally, in the sucrose preference test (SPT), isofraxidin reversed the decrease in sucrose consumption due to CUMS-induced depressive-like behavior. Isofraxidin also increased locomotor activity in the open field test (OFT) and alleviated immobility duration in the forced swimming test (FST) and tail-suspension test (TST). Furthermore, isofraxidin decreased levels of corticosterone (CORT), adrenocorticotropic hormone (ACTH), and hypothalamus corticotrophin-releasing hormone (CRH) in the serum after CUMS-induced hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis. Also, isofraxidin suppresses tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and IL-6 expression in the hippocampus of CUMS mice. Further investigations demonstrated that isofraxidin inhibited CUMS-induced activation of nuclear factor kappa B (NF-κB) and NOD-like receptor protein 3 (NLRP3) inflammasomes in the hippocampus. Summarily, in CUMS-induced mice, isofraxidin reduced depressive-like behaviors, accompanied by its inhibitory effects on hyperactivity of the HPA axis and NF-κB /NLRP3 inflammasomes pathways.

Protective effects of isofraxidin against scopolamine-induced cognitive and memory impairments in mice involve modulation of the BDNF-CREB-ERK signaling pathway.

BACKGROUND: Isofraxidin is a coumarin compound mainly isolated from several traditional and functional edible plants beneficial for neurodegenerative diseases, including Sarcandra glabra and Apium graveolens, and Siberian Ginseng. OBJECTIVE: This study aimed to assess effects of isofraxidin against memory impairments and cognition deficits in a scopolamine-induced mouse model. MATERIALS & METHODS: Animals were randomly divided into 6 groups, control, vehicle, donepezil (10 mg/kg, p.o.), and isofraxidin (3, 10, and 30 mg/kg, p.o.). Isofraxidin or donepezil was administered for 44 days, once per day. The scopolamine insults (1 mg/kg, i.p.) was given from the 21st day, once per day. Morris water maze test and Y-maze test were used for the behavioral test. After that, brain samples were collected for analysis. RESULTS: Firstly, isofraxidin significantly improved scopolamine-induced behavioral impairments and cognition deficits in Morris water maze and Y-maze test. Then, isofraxidin facilitated cholinergic activity via inhibiting acetylcholinesterase (AChE) activity. Besides, isofraxidin decreased lipid peroxidation level but enhanced levels of glutathione, glutathione peroxidase, and superoxide dismutase. Moreover, isofraxidin suppressed the expression of inflammatory mediators and cytokines. Further investigations showed that isofraxidin up-regulated expression of brain-derived neurotrophic factor (BDNF), and promoted phosphorylation of tropomyosin-related kinase B (TrkB), cyclic AMP-response element-binding protein (CREB), and extracellular signal-regulated kinase (ERK). DISCUSSION & CONCLUSIONS: These results suggested that isofraxidin ameliorated scopolamine-induced cognitive and memory impairments, possibly through regulating AChE activity, suppressing oxidative stress and inflammatory response, and modulating BDNF-CREB-ERK pathways.

Pinocembrin-7-Methylether Protects SH-SY5Y Cells Against 6-Hydroxydopamine-Induced Neurotoxicity via Modulating Nrf2 Induction Through AKT and ERK Pathways.

The present study aimed to evaluate the neuroprotective effects and underlying mechanisms of pinocembrin-7-methylether (PME), a natural bioflavonoid, in 6-hydroxydopamine (6-OHDA)-induced models of Parkinson's disease in vivo and in vitro. First, we found that PME decreased apoptosis in 6-OHDA-intoxicated SH-SY5Y cells. PME also blocked several 6-OHDA-induced mitochondrial apoptotic cascades, including loss of mitochondrial membrane potential, caspase 3 and PARP activation, and a decrease in the Bcl-2/Bax ratio. Also, PME suppressed 6-OHDA-induced oxidative stress while increasing antioxidant enzymatic activity. Further investigations indicated that PME significantly enhanced nuclear accumulation of Nrf2, improved ARE promoter activity, and upregulated HO-1 and NQO1 expression levels. In addition, siRNA-mediated Nrf2 knockdown abolished PME-induced anti-oxidative and anti-apoptotic effects. Interestingly, we found that PME promoted phosphorylation of AKT and ERK, whereas pharmacological inhibition of AKT or ERK pathways diminished PME-induced Nrf2 activation and protective actions. Moreover, PME attenuated 6-OHDA-induced loss of dopaminergic neurons and ameliorated locomotor deficiency in zebrafish, supporting the neuroprotective actions of PME in vivo. In summary, we found that PME conferred neuroprotection against 6-OHDA-induced neurotoxicity in PD models in vivo and in vitro. Taken together, our findings suggest that activation of Nrf2/ARE/HO-1 signaling cascades contributes to PME-induced anti-oxidative and neuroprotective actions, which are at least partially mediated by AKT and ERK pathways.

A halogen ion-selective phosphorescence turn-on probe based on induction of Pt-Pt interactions.

Square-planar cyclometalated platinum(ii) complexes have been found to serve as turn-on phosphorescent probes selectively for biological halogen ions. This is based on the halogen ion induced self-assembly of Pt(ii) compounds in aqueous media, resulting in intermolecular Pt-Pt interaction associated emission.