Gastrodin alleviates NTG-induced migraine-like pain via inhibiting succinate/HIF-1α/TRPM2 signaling pathway in trigeminal ganglion.

BACKGROUND: Increasing evidence highlights the involvement of metabolic disorder and calcium influx mediated by transient receptor potential channels in migraine; however, the relationship between these factors in the pathophysiology of migraine remains unknown. Gastrodin is the major component of the traditional Chinese medicine Tianma, which is extensively used in migraine therapy. PURPOSE: Our work aimed to explore the analgesic action of gastrodin and its regulatory mechanisms from a metabolic perspective. METHODS/RESULTS: After being treated with gastrodin, the mice were given nitroglycerin (NTG) to induce migraine. Gastrodin treatment significantly raised the threshold of sensitivity in response to both mechanical and thermal stimulus evidenced by von Frey and hot plate tests, respectively, and decreased total contact numbers in orofacial operant behavioral assessment. We found that the expression of transient receptor potential melastatin 2 (TRPM2) channel was increased in the trigeminal ganglion (TG) of NTG-induced mice, resulting in a sustained Ca2+ influx to trigger migraine pain. The content of succinate, a metabolic biomarker, was elevated in blood samples of migraineurs, as well as in the serum and TG tissue from NTG-induced migraine mice. Calcium imaging assay indicated that succinate insult elevated TRPM2-mediated calcium flux signal in TG neurons. Mechanistically, accumulated succinate upregulated hypoxia inducible factor-1α (HIF-1α) expression and promoted its translocation into nucleus, where HIF-1α enhanced TRPM2 expression through transcriptional induction in TG neurons, evidenced by luciferase reporter measurement. Gastrodin treatment inhibited TRPM2 expression and TRPM2-dependent Ca2+ influx by attenuating succinate accumulation and downstream HIF-1α signaling, and thereby exhibited analgesic effect. CONCLUSION: This work revealed that succinate was a critical metabolic signaling molecule and the key mediator of migraine pain through triggering TRPM2-mediated calcium overload. Gastrodin alleviated NTG-induced migraine-like pain via inhibiting succinate/HIF-1α/TRPM2 signaling pathway in TG neurons. These findings uncovered the anti-migraine effect of gastrodin and its regulatory mechanisms from a metabolic perspective and provided a novel theoretical basis for the analgesic action of gastrodin.

Chicoric acid ameliorates sepsis-induced cardiomyopathy via regulating macrophage metabolism reprogramming.

BACKGROUND: Sepsis-related cardiac dysfunction is believed to be a primary cause of high morbidity and mortality. Metabolic reprogramming is closely linked to NLRP3 inflammasome activation and dysregulated glycolysis in activated macrophages, leading to inflammatory responses in septic cardiomyopathy. Succinate dehydrogenase (SDH) and succinate play critical roles in the progression of metabolic reprogramming in macrophages. Inhibition of SDH may be postulated as an effective strategy to attenuate macrophage activation and sepsis-induced cardiac injury. PURPOSE: This investigation was designed to examine the role of potential compounds that target SDH in septic cardiomyopathy and the underlying mechanisms involved. METHODS/RESULTS: From a small molecule pool containing about 179 phenolic compounds, we found that chicoric acid (CA) had the strongest ability to inhibit SDH activity in macrophages. Lipopolysaccharide (LPS) exposure stimulated SDH activity, succinate accumulation and superoxide anion production, promoted mitochondrial dysfunction, and induced the expression of hypoxia-inducible factor-1α (HIF-1α) in macrophages, while CA ameliorated these changes. CA pretreatment reduced glycolysis by elevating the NAD+/NADH ratio in activated macrophages. In addition, CA promoted the dissociation of K(lysine) acetyltransferase 2A (KAT2A) from α-tubulin, and thus reducing α-tubulin acetylation, a critical event in the assembly and activation of NLRP3 inflammasome. Overexpression of KAT2A neutralized the effects of CA, indicating that CA inactivated NLRP3 inflammasome in a specific manner that depended on KAT2A inhibition. Importantly, CA protected the heart against endotoxin insult and improved sepsis-induced cardiac mitochondrial structure and function disruption. Collectively, CA downregulated HIF-1α expression via SDH inactivation and glycolysis downregulation in macrophages, leading to NLRP3 inflammasome inactivation and the improvement of sepsis-induced myocardial injury. CONCLUSION: These results highlight the therapeutic role of CA in the resolution of sepsis-induced cardiac inflammation.

Gemigliptin Alleviates Succinate-Induced Hepatic Stellate Cell Activation by Ameliorating Mitochondrial Dysfunction.

BACKGRUOUND: Dipeptidyl peptidase-4 inhibitors (DPP-4Is) are used clinically as oral antidiabetic agents. Although DPP-4Is are known to ameliorate liver fibrosis, the protective mechanism of DPP-4Is in liver fibrosis remains obscure. In this study, gemigliptin was used to investigate the potential of DPP-4Is to alleviate the progression of liver fibrosis. METHODS: To clarify the effects and mechanisms of gemigliptin, we conducted various experiments in LX-2 cells (immortalized human hepatic stellate cells [HSCs], the principal effectors of hepatic fibrogenesis), which were activated by succinate and exhibited elevated expression of α-smooth muscle actin, collagen type 1, and pro-inflammatory cytokines and increased cell proliferation. In vivo, we examined the effects and mechanisms of gemigliptin on a high-fat, high-cholesterol-induced mouse model of nonalcoholic steatohepatitis (NASH). RESULTS: Gemigliptin decreased the expression of fibrogenesis markers and reduced the abnormal proliferation of HSCs. In addition, gemigliptin reduced the succinate-induced production of mitochondrial reactive oxygen species (ROS), intracellular ROS, and mitochondrial fission in HSCs. Furthermore, in the mouse model of NASH-induced liver fibrosis, gemigliptin alleviated both liver fibrosis and mitochondrial dysfunction. CONCLUSION: Gemigliptin protected against HSC activation and liver fibrosis by alleviating mitochondrial dysfunction and ROS production, indicating its potential as a strategy for preventing the development of liver disease.

Succinate Modulates Intestinal Barrier Function and Inflammation Response in Pigs.

Succinate is a metabolic intermediate of the tricarboxylic acid (TCA) cycle in all aerobic organisms, and is also a vital microbial metabolite in the gut. Although succinate is known to regulate intestinal metabolism and immune function, its role in the protection of the intestinal epithelial barrier function and inflammation is poorly characterized. In this study, we evaluated the effects of succinate on intestinal epithelial barrier function and inflammation in pigs. Twenty-four growing pigs were distributed into three groups (n = 8) and received either a basal diet (control group) or the same diet supplemented with 0.1% succinate or 1% succinate. The diet supplemented with 1% succinate led to alterations in the intestinal morphology. We confirmed in vitro that 5 mM succinate treatment modulated intestinal epithelial permeability by increased transepithelial electrical resistance (TEER) in intestinal porcine epithelial cell (IPEC)-J2 cells. Furthermore, succinate treatment increased the abundance of tight junction proteins claudin-1, zona occluden (ZO)-1, and ZO-2 in the jejunum in vivo and in vitro. In addition, dietary succinate supplementation promoted the expression of inflammatory cytokines interleukin (IL)-25, IL-10, IL-8, and IL-18 in the jejunum. Taken together, these data identify a novel role of succinate in the modulation of intestinal epithelial barrier function, which may be a nutritional target to improve gut health in animals.

A succinate-based composition reverses menopausal symptoms without sex hormone replacement therapy.

Menopausal transition is often accompanied by a variety of adverse pathological symptoms, currently treated with hormone replacement therapy, which is associated with a number of health risks. This report investigated the role of a food supplement--a composition of energy-exchange metabolites, with succinate as the main component--for treating menopausal syndrome. We studied the impact of a 4-week succinate-based food composition (SBC) treatment on the estral cycle, and bone mass and calcium content of aging mice. The impact of SBC on hormone levels and on the progression of several neurovegetative and psycho-emotional symptoms was further investigated in a randomized, double-blind, placebo-controlled clinical study of early menopausal women. Data were collected from questionnaires, Kupperman index scores, Spielberger-Hanin tests, and blood analysis of hormone levels taken at baseline and throughout the 5-week study. A "rejuvenating" effect of SBC on menopausal animals was observed, expressed as restoration of the estral cycle and an increase in the weight and calcium content of bone tissue. Furthermore, in the randomized, placebo-controlled clinical study in menopausal women, SBC-based monotherapy significantly lowered most subjectively evaluated characteristics of menopausal syndrome and increased blood serum levels of estradiol fourfold. This monotherapy also alleviated symptoms of some neurovegetative and psycho-emotional disorders, such as hot flushes, headache, and anxiety. Succinate-based therapy alleviated many biochemical symptoms of menopause in aging mice and early menopausal women, as well as neurovegetative and psycho-emotional disorders in women. Succinate-based therapy appeared to be free of adverse side effects.

Topographic and radiographic profile assessment of dental erosion. Part II: effect of citrus fruit juices on human dentition.

This study sought to monitor changes in the topography, morphology, and radiographic profiles of human permanent teeth that had been exposed to citrus fruit juices. The effect of long-term exposure was monitored for a prolonged duration of 20 weeks according to set criteria. Topographic and morphologic changes were observed at weekly intervals following challenge by test fluids (orange, lemon, and grapefruit juices) and compared with control fluids (acetic acid and water). The qualitative changes in the specimens' topography and the morphology of citrus fruit juices and control fluids are described as a function of time, in specific details. The digitized radiographic images obtained at four-week intervals were analyzed and the changes were assessed. The results indicated that orange juice specimens demonstrated the mildest changes, while lemon juice specimens displayed the most severe damage to the coronal segments of the teeth. This damage manifested as loss of cusp height, cervical enamel, and coronal radius, as well as reduction of enamel cap height. Of the tested and control fluids, lemon juice displayed the most eros ion, followed by acetic acid, grapefruit juice, orange juice, and water, which had no effect. Continued immersion in the four acidic fluids led to varying degrees of enamel loss progression.

Succinate causes oxidative damage through N-methyl-D-aspartate-mediated mechanisms.

In this study we investigated whether succinate, the accumulating substrate in succinate dehydrogenase (SDH) deficiencies and SDH inhibitor intoxication, causes lipoperoxidation and protein carbonylation, and if NMDA receptors are involved in the succinate-induced oxidative damage. Adult male mice (30-40 g) received an intracerebroventricular injection of succinic acid (0.7, 1.0 and 1.7 micromol/5 microl) or 0.9% NaCl (5 microl) and had their exploratory behavior assessed in an open field for 10 min. Succinate (0.7 and 1.0 micromol/5 microl) decreased locomotor activity behavior and increased thiobarbituric acid reactive substances (TBARS) and protein carbonylation in the forebrain. Conversely, 1.7 micromol of succinate did not alter locomotor activity or oxidative damage parameters. The involvement of NMDA receptors in the succinate-induced increase of total protein carbonylation content and exploratory behavior inhibition was assessed by co-administrating MK-801 (7 nmol/2.5 microl icv), a noncompetitive NMDA receptor antagonist, with succinate (1 micromol/2.5 microl icv). The co-administration of MK-801 protected against succinate-induced increase of total protein carbonylation and decrease of locomotor activity. These results suggest the involvement of NMDA receptors in these effects of succinate, which may of particular relevance for succinate-accumulating conditions, such as SDH inhibitors intoxication and inherited SDH deficiencies.

The phytotoxicity to tobacco plants of short-chain carboxylic acids at atmospheric concentration levels in urban areas.

In this paper, we describe the influence of monocarboxylic acids (formic acid and acetic acid) and dicarboxylic acids (succinic acid and adipic acid), which are usually contained in aerosol particles and fog water, on the growth of tobacco plant. Their influence was examined by spraying the acid solutions on intact plants and by administering them in a culture medium for suspension-cultured cells. Their growth rates suggest that the influence of short-chain monocarboxylic acids was not significant in both the intact plant experiment and the cell culture experiment. In contrast, dicarboxylic acids exhibited significant influence on the growth of intact plants and no influence on culture cells, indicating that their toxicity is exerted mainly on the tissue of leaf surface. Phytotoxicity of dicarboxylic acids is higher than that of monocarboxylic acids.