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Nonalcoholic steatohepatitis (NASH) and hepatic fibrosis are leading causes of cirrhosis with rising morbidity and mortality worldwide. Currently, there is no appropriate treatment for NASH and hepatic fibrosis. Many studies have shown that oxidative stress is a main factor inducing NASH. Nomilin (NML) and obacunone (OBA) are limonoid compounds naturally occurring in citrus fruits with various biological properties. However, whether OBA and NML have beneficial effects on NASH remains unclear. Here, we demonstrated that OBA and NML inhibited hepatic tissue necrosis, inflammatory infiltration and liver fibrosis progression in methionine and choline‐deficient (MCD) diet, carbon tetrachloride (CCl4)‐treated and bile duct ligation (BDL) NASH and hepatic fibrosis mouse models. Mechanistic studies showed that NML and OBA enhanced anti‐oxidative effects, including reduction of malondialdehyde (MDA) level, increase of catalase (CAT) activity and the gene expression of glutathione S‐transferases (GSTs) and Nrf2‐keap1 signaling. Additional, NML and OBA inhibited the expression of inflammatory gene interleukin 6 (Il‐6), and regulated the bile acid metabolism genes Cyp3a11, Cyp7a1, multidrug resistance‐associated protein 3 (Mrp3). Overall, these findings indicate that NML and OBA may alleviate NASH and liver fibrosis in mice via enhancing antioxidant and anti‐inflammation capacity. Our study proposed that NML and OBA may be potential strategies for NASH treatment. [ABSTRACT FROM AUTHOR]

Fibroblast growth factor 21 (FGF21) is a metabolism‐regulating hepatokine, and its expression is finely controlled by the nutrients and cellular stressors. α‐Lipoic acid (ALA) regulates fuel metabolism as a nutrient, but it also arouses mitochondrial and endoplasmic reticulum (ER) stress as well as oxidative stress in hepatocytes. However, the role of cellular stress in ALA‐regulated FGF21 expression has not been demonstrated as yet. The present study found that ALA up‐regulated FGF21 gene expression while it reduced FGF21 protein levels in HepG2 cells, which was accompanied by mitochondrial damage that was shown by ATP reduction and ROS elevation. ALA led to mitochondrial stress and ER stress as shown by the increased expression of HSP60, ATF6 and ATF4. Inhibition of ER stress by 4‐PBA significantly attenuated ALA‐stimulated FGF21 gene expression while it did not influence the reduction of FGF21 protein levels. H2O2‐induced oxidative stress reduced FGF21 protein levels in HepG2 cells, and anti‐oxidation by Tempol blocked ALA‐induced reduction of FGF21 proteins. In conclusion, ALA up‐regulates FGF21 gene expression through the stimulation of mitochondrial and ER stress while it reduces FGF21 protein levels through the induction of oxidative stress in HepG2 cells. Further studies are needed to demonstrate the in vivo effect of ALA on hepatic FGF21 expression. [ABSTRACT FROM AUTHOR]

Background and Purpose: Inhibition of PDE5 improves synaptic plasticity and memory via enhancing cGMP expression, thus activating the cGMP/cAMP response element binding protein (CREB) signalling pathway. This study investigated the effects of a PDE5 inhibitor on scopolamine-induced cognitive dysfunction, using memory-related behavioural tests and biochemical assays.Experimental Approach: In mice were pretreated with PDE5 inhibitor, amnesia was induced by scopolamine. The learning and memory abilities of mice were tested using the Morris water maze test, the Y-maze test, the passive avoidance test and the novel object recognition test in sequence. Expression of memory-related bio-molecules and oxidative stress parameters in brain tissue were measured using Western blot and spectrophotometry respectively.Key Results: KJH-1002, a novel and potent inhibitor of PDE5 (IC50 0.059 ± 0.04 nmol·L-1 ), was synthesized. In the behavioural tests, it markedly improved the memory performance impaired by scopolamine, indicating a restoration of cognitive function in the mice. Moreover, KJH-1002 increased cGMP levels in the cortex and the scopolamine-reduced expression of phosphorylated CREB, Levels of ERK 1/2, Akt and brain-derived neurotrophic factor in the cortex and hippocampus were restored by KJH-1002 treatment. In addition, KJH-1002 administration increased the activities of SOD, glutathione peroxidase and glutathione reductase, and decreased the level of malondialdehyde.Conclusion and Implications: KJH-1002 restored cognitive function in scopolamine-induced amnesia mice by activating the cGMP/CREB signalling pathway and attenuating oxidative stress. The beneficial effects of KJH-1002 on cognition indicate its potential as a therapeutic candidate for Alzheimer's disease. [ABSTRACT FROM AUTHOR]

Caveolae are intracellular vesicles with diameters ranging from 50 to 100 nm. The role of caveolins in mediating oxidative stress, autophagy, apoptosis, fibrosis, and vascular remodeling has attracted increasing attention in cardiovascular therapy. Several studies have suggested that caveolin could be a therapeutic target for the treatment of cardiac and/or vascular injury via several pathophysiological mechanisms. Despite substantial advances in our understanding of the basic biology of vesicles over the past decade, the relevance and specific role of these mechanisms in cardiovascular homeostasis remains ambiguous. Here, we review the macroscopic role of caveolins in protecting cardiac function and, at the microscopic level, examine possible cardioprotective caveolar mechanisms, including their antioxidative stress, antiapoptosis, autophagy‐regulatory, antifibrosis, and angiogenesis‐promoting properties. We believe that the role of caveolins in cardiac functioning has not been fully elucidated and is an important line of future research with several cardioprotective implications. [ABSTRACT FROM AUTHOR]