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Arecoline, the predominant bioactive substance extracted from areca nut (AN), is the world's fourth most frequently used psychoactive material. Research has revealed that chewing AN can affect the central nervous system (CNS) and may lead to neurocognitive deficits that are possibly linked to the action of arecoline. However, the mechanism behind the neurotoxicity caused by arecoline remains unclear. This study aimed to investigate the neurotoxic effects of arecoline and its underlying mechanism. The results showed that arecoline caused cytotoxicity against HT22 cells in a dose‐dependent manner and induced apoptosis by upregulating the expression of pro‐apoptotic caspase and Bcl‐2 family proteins. Furthermore, arecoline escalated intracellular reactive oxygen species (ROS) levels and Ca2+ concentration with increasing doses, thereby motivating endoplasmic reticulum stress (ERS) and ERS‐associated apoptotic protein expression. Additionally, the study found that arecoline attenuates intracellular antioxidant defense by inhibiting the translocation of NF‐E2‐related factor‐2 (Nrf2) into the nucleus and decreasing downstream Heme oxygenase‐1 (HO‐1) levels. The specific inhibitor Sodium 4‐phenylbutyrate (4‐PBA) can dramatically attenuate arecoline‐mediated cell apoptosis and ERS‐associated apoptotic pathway expression by blocking ERS. The antioxidant N‐Acetylcysteine (NAC) also effectively reverses the arecoline‐mediated increase of ERS‐related apoptotic pathway protein levels by scavenging intracellular ROS accumulation. In conclusion, this study suggests that arecoline induces neurotoxicity in HT22 cells via ERS mediated by oxidative stress‐ and Ca2+ disturbance, as well as by downregulation of the Nrf2/HO‐1 pathway. [ABSTRACT FROM AUTHOR]

AIM: To investigate the effect of melatonin (MEL) on the depression behavior in mice induced by chronic restraint stress (CRS). METHODS: Forty-eight SPF-grade male C57BL/6J mice were randomly divided into control group (;i=12) and CRS group (n-36). The mice in CRS group were further divided into 3 groups (n-12) : CRS+vehicle group, CRS+fluoxetine (FLX) group, and CRS+MEL group. Mouse depression model was established by the CRS method for 14 d, and then the depression-like behaviors were observed for modeling validation. After 14 d of drug intervention combined with CRS, the behaviors were detected again. Nissl staining, RT-qPCR, Western blot and immunofluorescence staining were performed in mouse brain tissues. RESULTS: Compared with control group, the weight changes of the mice in CRS group were significantly lowered, the immobility time of forced swimming and tail suspension tests was significantly increased, the consumption rate of sugar water decreased significantly, and the central time and movement distance in open-field test decreased significantly (P<0.01). Compared with CRS+vehicle group, the depression-like behaviors induced by CRS were successfully reversed by the drugs in both CRS+FLX and CRS+MEL groups. Furthermore, compared with CRS+vehicle group, the mRNA levels of brain-derived neurotrophic factor (BDNF), extracellular signal-regulated kinase (ERK) and cAMP response element-binding protein (CREB), and the protein levels of BDNF, phosphorylated ERK1/2 and CREB were increased significantly in both CRS+FLX and CRS+MEL groups (P«X 01). The results of Nissl staining showed that the neurons in CRS+vehicle group were irregularly arranged, and the number of Nissl bodies was decreased (P<0. 01). The neuron status and number of Nissl bodies in both CRS+FLX and CRS+MEL groups were significantly improved (P<0. 01). Immunofluorescence staining showed that the number of c-Fos-positive cells in the frontal cortex and hippocampal CA1 region of the mice in CRS+vehicle group was significantly larger than that in control group (P< 0.01). Conversely, the number of c-Fos-positive cells in CRS+FLX and CRS+MEL groups was significantly smaller than that in CRS+vehicle group (P<0. 01). CONCLUSION: Melatonin can significantly alleviate depression-like behavior induced by CRS in mice, which may be related to the activation of BDNF-ERK-CREB signaling pathway. [ABSTRACT FROM AUTHOR]

Hepatic ischemia/reperfusion injury (HIRI) is a common complication of liver surgery requiring hepatic disconnection, such as hepatectomy and liver transplantation. The aim of this study was to investigate the effects of cordycepin on HIRI and to elucidate the underlying mechanisms. Balb/c mice were randomly divided into six groups: a normal control group, sham group, H-cordycepin group, HIRI group, L-cordycepin (25 mg/kg) + HIRI group, and H-cordycepin (50 mg/kg) + HIRI group. Mice were subjected to I/R, and cordycepin was intragastrically administered for seven consecutive days before surgery. Orbital blood and liver specimens were collected at 6 and 24 h after HIRI. Serum levels of ALT and AST were decreased in the cordycepin pretreatment groups. Notably, cordycepin attenuated the inflammatory response and the production of proapoptosis proteins, while increasing expression of antiapoptosis proteins and decreasing expression of autophagy-linked proteins. Furthermore, cordycepin inhibited activation of the MAPK/NF-κB signaling pathway. Collectively, these results indicate that cordycepin pretreatment ameliorated hepatocyte injury caused by HIRI. As compared with the HIRI group, cordycepin pretreatment mitigated the inflammatory response and inhibited apoptosis and autophagy via regulation of the MAPK/NF-κB signaling pathway. [ABSTRACT FROM AUTHOR]

Hepatic ischemia-reperfusion (IR) injury is a clinically significant process that frequently occurs in liver transplantation, partial hepatectomy, and hemorrhagic shock. The aim of this study was to explore the effectiveness of luteolin in hepatic IR injury and the underlying mechanism. BALB/c mice were randomly divided into six groups, including normal controls (NC), luteolin (50 mg/kg), sham procedure, IR+25 mg/kg luteolin, and IR+50 mg/kg luteolin group. Serum and tissue samples were collected at 6 and 24 h after reperfusion to assay liver enzymes, inflammatory factors, expression of proteins associated with apoptosis and autophagy, and factors associated with the extracellular signal-regulated kinase/peroxisome proliferator-activated receptor alpha (ERK/PPAR α ) pathway. Luteolin preconditioning decreased hepatocyte injury caused by ischemia-reperfusion, downregulated inflammatory factors, and inhibited apoptosis and autophagy. Luteolin also inhibited ERK phosphorylation and activated PPAR α ., Competing Interests: The authors declare that there is no conflict of interest regarding the publication of this paper., (Copyright © 2022 Yuhui Jiang et al.)