Oxidative stress has been implicated in the pathogenesis of Alzheimer's disease (AD). Mitochondrial dysfunction is linked to oxidative stress and reactive oxygen species (ROS) in neurotoxicity during AD. Impaired mitochondrial metabolism has been associated with mitochondrial dysfunction in brain damage of AD. While the role of NADPH oxidase 4 (NOX4), a major source of ROS, has been identified in brain damage, the mechanism by which NOX4 regulates ferroptosis of astrocytes in AD remains unclear. Here, we show that the protein levels of NOX4 were significantly elevated in impaired astrocytes of cerebral cortex from patients with AD and APP/PS1 double-transgenic mouse model of AD. The levels of 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA), a marker of oxidative stress-induced lipid peroxidation, were significantly also elevated in impaired astrocytes of patients with AD and mouse AD. We demonstrate that the over-expression of NOX4 significantly increases the impairment of mitochondrial metabolism by inhibition of mitochondrial respiration and ATP production via the reduction of five protein complexes in the mitochondrial ETC in human astrocytes. Moreover, the elevation of NOX4 induces oxidative stress by mitochondrial ROS (mtROS) production, mitochondrial fragmentation, and inhibition of cellular antioxidant process in human astrocytes. Furthermore, the elevation of NOX4 increased ferroptosis-dependent cytotoxicity by the activation of oxidative stress-induced lipid peroxidation in human astrocytes. These results suggest that NOX4 promotes ferroptosis of astrocytes by oxidative stress-induced lipid peroxidation via the impairment of mitochondrial metabolism in AD.
Diabetes mellitus is a serious metabolic disease affecting major populations worldwide. The number of people with diabetes is anticipated to rise from current estimate of 150 to 220 million in 2010, and 300 million in 2025.1) Lifestyle in industrialized societies such as high caloric-diet and sedentary lifestyle gives the fundamental causes of this fast-spread 'epidemic'. Diabetes mellitus is divided into two main forms. Type 1 diabetes mellitus (T1DM) is mainly due to an autoimmune-mediated destruction of pancreatic b-cell islets. On the other hand, type 2 diabetes mellitus (T2DM) is characterized by insufficient insulin secretion and insulin resistance.2) Epidemiological studies and clinical trials strongly support the notion that hyperglycemia is the principal cause of microvascular and macrovascular complications. Therefore, effective blood glucose control is the key to preventing or reversing diabetic complications and improving quality of life in diabetic patients. 3,4) Although no cure is yet available for T2DM, oral hypoglycemic agents have been developed and are widely used. These therapies, however, are not perfect and characterized by insufficient efficacy, limited tolerability, or significant mechanism-based adverse effects. Therefore, novel treatment options are urgently needed that take advantage of physiological regulatory mechanisms and that result in weight loss or lack of weight gain.Ginseng has been used as tonic and restorative remedies in traditional Chinese medicine for several thousand years. The pharmacological properties of ginseng are mainly attributed to ginsenosides, which are the active components found in the extracts of different species of ginseng. 5) There have been plenty of studies demonstrating the anti-diabetic activity of ginsenosides, [6][7][8] however, the active component with antidiabetic activity is yet to be identified. In our preliminary study, protopanaxadiol ginsenosides potentiated an insulin secretion stimulated by a low concentration of glucose. Ginsenoside Rg3, 3b,12b, (Fig. 1), showed the most potent insulin secretion-stimulating activity. Ginsenoside Rg3 has been shown to inhibit tumor metastasis in mice as well as the invasion and metastasis of several tumors of rats and human in vitro.9-11) However, anti-diabetic effect of Rg3 has not been studied elsewhere as of this writing. Therefore, it would be interesting to examine whether and how Rg3 has anti-diabetic activity. To investigate anti-diabetic activity of Rg3, firstly we examined the insulin secretion-stimulating activity of Rg3 using HIT-T15 cells, followed by the oral glucose tolerance test using ICR mice. Next, we explored whether Rg3 activates an AMP-activated protein kinase (AMPK), a master switch regulating glucose and lipid metabolism, in C2C12 myotubes. Although Panax ginseng has been widely used in oriental countries for pharmacological effects such as antidiabetic, anti-inflammatory, adaptogenic and anti-fatigue activities, the active ingredient is not yet fully identified. In our preliminary ...
Solid electrolyte interphases generated using electrolyte additives are key for anode-electrolyte interactions and for enhancing the lithium-ion battery lifespan. Classical solid electrolyte interphase additives, such as vinylene carbonate and fluoroethylene carbonate, have limited potential for simultaneously achieving a long lifespan and fast chargeability in high-energy-density lithium-ion batteries (LIBs). Here we report a next-generation synthetic additive approach that allows to form a highly stable electrode-electrolyte interface architecture from fluorinated and silylated electrolyte additives; it endures the lithiation-induced volume expansion of Si-embedded anodes and provides ion channels for facile Li-ion transport while protecting the Ni-rich LiNi0.8Co0.1Mn0.1O2 cathodes. The retrosynthetically designed solid electrolyte interphase-forming additives, 5-methyl-4-((trifluoromethoxy)methyl)-1,3-dioxol-2-one and 5-methyl-4-((trimethylsilyloxy)methyl)-1,3-dioxol-2-one, provide spatial flexibility to the vinylene carbonate-derived solid electrolyte interphase via polymeric propagation with the vinyl group of vinylene carbonate. The interface architecture from the synthesized vinylene carbonate-type additive enables high-energy-density LIBs with 81.5% capacity retention after 400 cycles at 1 C and fast charging capability (1.9% capacity fading after 100 cycles at 3 C).
Although compound K (CK), an intestinal metabolite of ginseng protopanaxadiol saponins, has been known to induce apoptosis in various cancer cells, association of AMP-activated protein kinase (AMPK) with apoptosis in HT-29 colon cancer cells remains unclear. We hypothesized that CK may exert an anticancer activity through modulating the AMPK pathway in HT-29 cells. CK-induced apoptosis was associated with the disruption of the mitochondrial membrane potential, release of apoptogenic factors (cytochrome c and apoptosis-inducing factor) from mitochondria, and cleavage of caspase-9, caspase-3, caspase-8, Bid, and PARP proteins. This apoptotic effect of CK on colon cancer cells was found to be initiated by AMPK activation, and AMPK was activated through phosphorylation by Ca2+/calmodulin-activated protein kinase-IV (CAMK-IV). Treatment of HT-29 cells with compound C (AMPK inhibitor) or siRNA for AMPK completely abolished the CK-induced apoptosis. STO-609, CAMKs inhibitor, also attenuated CK-induced AMPK activation and apoptosis. In conclusion, the present study demonstrates that CK-mediated cell death of HT-29 colon cancer cells is regulated by CAMK-IV/AMPK pathways, and these findings provide a molecular basis for the anticancer effect of CK.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.