Malvidin alleviates mitochondrial dysfunction and ROS accumulation through activating AMPK-α/UCP2 axis, thereby resisting inflammation and apoptosis in SAE mice

Abstract

This study aimed to explore the protective roles of malvidin in life-threatened sepsis-associated encephalopathy (SAE) and illustrate the underlying mechanism. SAE mice models were developed and treated with malvidin for subsequently protective effects evaluation. Malvidin restored neurobehavioral retardation, declined serum S100β and NSE levels, sustained cerebrum morphological structure, improved blood-brain barrier integrity with elevated tight junction proteins, and decreased evans blue leakage, and finally protect SAE mice from brain injury. Mechanistically, malvidin prevented cerebrum from mitochondrial dysfunction with enhanced JC-1 aggregates and ATP levels, and ROS accumulation with decreased lipid peroxidation and increased antioxidant enzymes. UCP2 protein levels were found to be decreased after LPS stimulation in the cerebrum and BV-2 cells, and malvidin recovered its levels in a ROS dependent manner. In vivo inhibition of UCP2 with genipin or in vitro interference with siRNA UCP2 both disrupted the mitochondrial membrane potential, decreased ATP levels and intensified DCF signals, being a key target for malvidin. Moreover, dorsomorphin block assays verified that malvidin upregulated UCP2 expression through phosphorylating AMPK in SAE models. Also, malvidin alleviated SAE progression through inhibition of ROS-dependent NLRP3 inflammasome activation mediated serum pro-inflammatory cytokines secretion and mitochondrial pathway mediated apoptosis with weakened apoptosis body formation and tunel positive signals, and decreased Bax, cytochrome C, caspase-3 and increased Bcl-2 protein levels. Overall, this study illustrated that malvidin targeted AMPK-α/UCP2 axis to restore LPS-induced mitochondrial dysfunction and alleviate ROS accumulation, which further inhibits NLRP3 inflammasome activation and mitochondrial apoptosis in a ROS dependent way, and ultimately protected SAE mice, providing a reference for the targeted development of SAE prophylactic approach.

Grape/Blueberry Anthocyanins and Their Gut-Derived Metabolites Attenuate LPS/Nigericin-Induced Inflammasome Activation by Inhibiting ASC Speck Formation in THP-1 Monocytes

“…Moreover, NLRP3 protein expression was also significantly inhibited to varying extents depending on the respective blueberry variety [38]. In other studies, malvidin, which is the predominating anthocyanin in blueberries [39], inhibited LPS-induced NLRP3 protein expression in various mouse tissues [26,27,40,41]. In contrast, the observed effects of malvidin on ASC protein expression are more inconsistent.…”

“…In contrast, the observed effects of malvidin on ASC protein expression are more inconsistent. While LPS-induced ASC protein expression has been found to be significantly decreased by malvidin treatment in liver and kidney tissues of mice, ASC expression in mice cerebrum was not affected [26,27,40]. Similarly, in a randomized placebo-controlled clinical trial, mRNA levels of ASC and NLRP3 were not significantly lower in peripheral blood mononuclear cells (PBMCs) from patients with nonalcoholic fatty liver disease (NAFLD), compared to the control group, after 12 weeks of anthocyanin supplementation [42].…”

AP39, a novel mitochondria-targeted hydrogen sulfide donor ameliorates doxorubicin-induced cardiotoxicity by regulating the AMPK/UCP2 pathway

“…For example, in a model of nonalcoholic fatty liver disease, LB100 regulated UCP2 expression by inhibiting AMPK [ 34 ]. Malvidin alleviates mitochondrial dysfunction and ROS accumulation by activating the AMPK-α/UCP2 axis, thereby preventing inflammation and apoptosis in mice with sepsis-associated encephalopathy [ 26 ]. Indole sulfate induces oxidative stress and hypertrophy in cardiomyocytes by inhibiting the AMPK/UCP2 signaling pathway [ 70 ].…”

“…Uncoupling protein 2 (UCP2) is located within the inner mitochondrial membrane and affects mitochondrial function and metabolism through oxidative phosphorylation uncoupling. AMPK attenuates oxidative stress damage, reduces apoptosis [ 24 ], attenuates mitochondrial damage [ 25 ], and attenuates inflammatory responses [ 26 ] by upregulating UCP2.…”

Regulation of UCP2 in nonalcoholic fatty liver disease: From mechanisms to natural product

“…UCP2 is also associated with AMP‐activated protein kinase (AMPK), an evolutionarily conserved stress‐sensitive protein kinase that is activated by detecting ATP reduction to maintain cellular metabolic homeostasis (Zhao et al., 2023), UCP2 activation may be related to pathways that depend on its upstream AMPK‐mediated antioxidant response (Yu et al., 2019). In the liver, AMPK promotes FAs oxidation and ketogenesis and inhibits cholesterol and triglyceride formation (Carling, 2004).…”