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.

Mechanisms involved in the antinociceptive and anti-inflammatory effects of xanthotoxin.

Xanthotoxin (XAT) is a natural furanocoumarin clinically used in the treatment of skin diseases such as vitiligo and psoriasis. Recent studies have also investigated its effects on anti-inflammatory, anti-cognitive dysfunction, and anti-amnesia as a guideline for clinic application. However, little is known about its effects on pain relief. Here, we tested the analgesic effects of XAT in serious acute pain and chronic pain models. For acute pain, we used hot-, capsaicin- and formalin-induced paw licking. Nociceptive threshold was measured by mechanical stimuli with von Frey filaments. For chronic pain, we injected complete Freund's adjuvant (CFA) into the mice's plantar surface of the hind paw to induce inflammatory pain. Heat and mechanical hyperalgesia were evaluated by radiant heat and von Frey filament tests, respectively. To investigate the mechanisms underlying the analgesic effect of XAT, we used calcium imaging and western blot to assess transient receptor potential vanilloid 1 (TRPV1) activity and expression in isolated L4-L6 dorsal root ganglion (DRG) neurons. Haematoxylin and eosin (HE) staining, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and enzyme-linked immunosorbent assay (ELISA) were used to examine immune cell recruitment and proinflammatory factor release from skin tissue from paw injection sites. Our results demonstrated that XAT not only reduced acute pain behaviors generated by hot, capsaicin, and formalin but also attenuated CFA-induced heat and mechanical hyperalgesia. The analgesic activity of XAT may be achieved by controlling peripheral inflammation, lowering immune cell infiltration at the site of inflammatory tissue, reducing inflammatory factor production, and therefore inhibiting TRPV1 channel sensitization and expression.

Degradation potential and pathways of methylcyclohexane by bacteria derived from Antarctic surface water.

Cycloalkanes pose a tremendous environmental risk due to their high concentration in petroleum hydrocarbons and hazardous effects to organisms. Numerous studies have documented the biodegradation of acyclic alkanes and aromatic hydrocarbons. However, insufficient attention has been paid to studies on the microbial degradation of cycloalkanes, which might be closely linked to psychrophilic microbes derived from low-temperature habitats. Here we show that endemic methylcyclohexane (MCH, an abundant cycloalkane species in oil) consumers proliferated in seawater samples derived from the Antarctic surface water (AASW). The MCH-consuming bacterial communities derived from AASW exhibited a distinct species composition compared with their counterparts derived from other cold-water habitats. We also probed Colwellia and Roseovarius as the key active players in cycloalkane degradation by dilution-to-extinction-based incubation with MCH as sole source of carbon and energy. Furthermore, we propose two nearly complete MCH degradation pathways, lactone formation and aromatization, concurrently in the high-quality metagenome-assembled genomes of key MCH consumer Roseovarius. Overall, we revealed that these Antarctic microbes might have strong interactions that enhance the decomposition of more refractory hydrocarbons through complementary degradation pathways.

Selenium enhanced phytoremediation of diesel contaminated soil by Alternanthera philoxeroides.

Using a 60-day pot culture experiment, we investigated the effect of selenium on phytoremediation of soil containing high-level diesel by Alternanthera philoxeroides (alligator weed). Diesel (20 g kg-1) decreased the growth of A. philoxeroides and induced oxidative stress, as indicated by tissue levels of hydrogen peroxide (H2O2) and malondialdehyde (MDA). Adding Se (0.5 or 1.5 mg kg-1) to diesel-treated soil alleviated oxidative stress and improved biomass production, and the low dose was as effective as the high dose. After 60 days, the reduction in rhizospheric soil diesel was 20.1 ±â€¯0.55% without Se and 35.2 ±â€¯3.6% with Se, showing a significant increase in efficiency. Again, the low Se dose was as effective as the high dose. These findings advance the field phytoremediation by demonstrating that Se, at 0.5 mg kg-1, enhances removal and increases plant tolerance to petroleum hydrocarbons.

Se enhanced phytoremediation of diesel in soil by Trifolium repens.

A pot-culture experiment was conducted to assess the effects of selenium (Se) (0.5 mg kg-1) on Trifolium repens exposed to various levels of diesel (0, 15, 20, 25 g kg-1) for 30 days and 60 days. Exposure to diesel for 60 day led to concentration-dependent decreases in root morphogenesis, chlorophyll content and CAT activity, and to dose-dependent increases in MDA content and SOD activity. The residual diesel concentration in soil increased and the removal efficiency decreased with soil diesel concentration. The chlorophyll content and residual diesel concentration after were slightly higher at 30 days than at 60days. Application of Se to soil increased Trifolium repens tolerance to diesel and significantly increased the phytoremediation effect at 60 days, with a removal rate of 36 ±â€¯8%, compared to 28 ±â€¯7% in the control. These results contribute to the ongoing effort to develop an effective phytoremediation system for soils highly contaminated by diesel.

Selenium alleviates phytotoxicity of phenanthrene and pyrene in Alternanthera Philoxeroides.

To investigate if selenium can alleviate phytotoxicity of phenanthrene and pyrene, two high molecular weight (HMW) PAHs (polycyclic aromatic hydrocarbons) in Alternanthera philoxeroides are considered. A 60-day pot-culture experiment was carried out to assess the effects of selenium (0.5 mg Se·kg-1 soil) on A. philoxeroides exposed to two PAH pollutants, pyrene (PYR) and phenanthrene (PHE), at levels of 10, 100, and 1000 mg·kg-1. The test index included growth, chlorophyl, gas exchange and chlorophyl fluorescence parameters, and indicators of oxidative stress (H2O2 and malondialdehyde MDA). The response of plants to PAH exposure was concentration dependent; indicators of plant health declined, while indicators of plant stress rose. The maximum values of H2O2 and MDA were recorded at 1000 mg·kg-1 PYR, followed by 1000 mg·kg-1 PHE. However, application of Se (0.5 mg·kg-1) to the soil significantly decreased the phytotoxic response to PAH exposure. This study demonstrated that Se increases the tolerance of A. philoxeroides to PYR and PHE, improving the feasibility of phytoremediating high level PAH contamination and expediting ecological restoration.

Use of selenium to alleviate naphthalene induced oxidative stress in Trifolium repens L.

Polycyclic aromatic hydrocarbons (PAHs) are among the most dangerous of environmental contaminants, due to their toxicity, carcinogenicity and mutagenicity. This study investigated the use of selenium (Se) to protect plants from the toxic effects of naphthalene (NPH). Exposing Trifolium repens L. (white clover) to a high concentration of NPH (soil spiked to 500mgkg-1) for 60 d significantly decreased biomass, CO2 assimilation rate (Pn), stomatal conductance (Gs) and intercellular CO2 concentration (Ci), while inducing production of H2O2 and malondialdehyde (MDA). Application of Se (soil spiked to 0.5mgkg-1) to plants exposed to NPH clearly protected the plants; biomass, Pn, Gs and Ci were significantly higher and contents of MDA and H2O2 decreased. The protection provided to Trifolium repens L. by Se is attributed primarily to an increase in photosynthesis and a decrease in oxidative stress. This study demonstrates that a low concentration of Se protects plants against oxidative stress induced by NPH and can provide a means for improving phytoremediation in PAHs contaminated soils.

[Effects of prenatal taurine on mRNA expression of PKA CREB signal pathway and glial cell line derived neurotrophic factor in fetal rat brains of intrauterine growth restriction].

OBJECTIVE: This study examined the effects of prenatal application of taurine on mRNA expression of protein kinase A cAMP response element binding protein (PKA-CREB) signal pathway and glial cell line derived neurotrophic factor (GDNF) in fetal rat brains of intrauterine growth restriction (IUGR). METHODS: Pregnant rats were randomly divided into 4 groups: normal control, IUGR model, low dose (100 mg/kg x d) and high dose (300 mg/kg x d) taurine treatment IUGR (n = 5 each). IUGR was induced by food restriction throughout pregnancy. PKA, CREB and GDNF mRNA expression in brains of newborn rats was detected by reverse transcription polymerase chain reaction (RT-PCR). RESULTS: PKA, CREB and GDNF mRNA expression in the IUGR model group was significantly higher than that in the normal control group (p<0.05). Compared with the IUGR model group, mRNA expression of PKA and CREB in both the low dose and high dose taurine treatment groups increased significantly (p<0.05); GDNF mRNA expression in the high dose taurine treatment group also increased significantly (p<0.01). CONCLUSIONS: Taurine can increase mRNA expression of PKA, CREB and GDNF in fetal rat brains of IUGR. This suggests that prenatal application of taurine may increase neurogenesis of the central nervous system and endogenous secretion of neurotrophic factors, thus providing neuroprotective effects.