Dihydromyricetin Modulates Nrf2 and NF-κB Crosstalk to Alleviate Methotrexate-Induced Lung Toxicity.

BACKGROUND: Methotrexate (MTX) is an effective anticancer, anti-inflammatory, and immunomodulatory agent. However, it induces a serious pneumonitis that leads to irreversible fibrotic lung damage. This study addresses the protective role of the natural flavonoid dihydromyricetin (DHM) against MTX-induced pneumonitis via modulation of Nrf2/NF-κB signaling crosstalk. METHODS: Male Wistar rats were divided into 4 groups: control, which received the vehicle; MTX, which received a single MTX (40 mg/kg, i.p) at day 9 of the experiment; (MTX + DHM), which received oral DHM (300 mg/kg) for 14 days and methotrexate (40 mg/kg, i.p) on the 9th day; and DHM, which received DHM (300 mg/kg, p.o) for 14 days. RESULTS: Lung histopathological examination and scoring showed a decline in MTX-induced alveolar epithelial damage and decreased inflammatory cell infiltration by DHM treatment. Further, DHM significantly alleviated the oxidative stress by decreasing MDA while increasing GSH and SOD antioxidant levels. Additionally, DHM suppressed the pulmonary inflammation and fibrosis through decreasing levels of NF-κB, IL-1ß, and TGF-ß1 while promoting the expression of Nrf2, a positive regulator of antioxidant genes, and its downstream modulator, HO-1. CONCLUSION: This study identified DHM as a promising therapeutic target against MTX-induced pneumonitis via activation of Nrf2 antioxidant signaling while suppressing the NF-κB mediated inflammatory pathways.

Dihydromyricetin alleviates methotrexate-induced hepatotoxicity via suppressing the TLR4/NF-κB pathway and NLRP3 inflammasome/caspase 1 axis.

The anticancer drug methotrexate (MTX) is known to cause hepatotoxicity as a possibly fatal adverse effect that hinders its clinical application. Although the natural flavonoid, dihydromyricetin (DHM), has antioxidant and anti-inflammatory effects; its role against MTX-induced hepatotoxicity has not been explored yet. For this, rats were administrated DHM orally for two weeks at a dose of 300 mg/kg per day, with or without a single i.p. injection of 40 mg/kg MTX on the 9th day of the experiment. MTX caused deterioration in liver structure and function, depicted by an increase in liver enzymes; ALT and AST. Moreover, MTX induced oxidative stress, shown by increasing malondialdehyde and decreasing reduced glutathione and total antioxidant capacity, initiated the inflammatory response via upregulated expression of Toll-like receptor 4 (TLR4) and its downstream transcription factor, nuclear factor-kappa B (NF-κB p65). Consequent to TLR4 signaling cascade, Nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammosome was activated and caused caspase 1 mediated transformation of proinflammatory cytokines interleukin 1ß (IL-1ß) and interleukin 18 (IL-18) into their active forms. Interestingly, administering DHM with MTX improved liver structure and function, as well as significantly decreased all oxidative stress and inflammatory signaling. Collectively, DHM possesses antioxidant and anti-inflammatory properties that can ameliorate MTX-induced hepatotoxicity, through down-regulation of liver TLR4/NF-κB and therefore prohibit activation of NLRP3/caspase 1 pathway.

Dihydromyricetin protects against high glucose-induced endothelial dysfunction: Role of HIF-1α/ROR2/NF-κB.

OBJECTIVES: Dihydromyricetin (DHM), a natural flavonoid isolated from vine tea with anti-inflammatory activity was evaluated for its ability to prevent vascular endothelial dysfunction caused by hyperglycaemia. METHODS: Vasoconstrictor (phenylephrine-PE) and vasodilator (acetylcholine-ACh) responses were monitored for female rat aorta rings maintained in a bioassay organ bath for 3 h at 37 °C in either low (LG: 10 mM) or high (HG: 40 mM, to mimic hyperglycaemia) glucose-Krebs buffer in the absence or presence of 50 µM DHM. Tissues recovered from the organ bath at 3 h were fixed and analyzed for morphological changes and their expression of eNOS, iNOS, HIF-1α, GLUT1, ROR2 tyrosine kinase, NF-κB, TNF-α, Bax, Bcl2, caspase-3, and forindices of increased oxidative stress. KEY FINDINGS: HG-incubated tissues showed increased PE-stimulated contractile response and decreased ACh-mediated endothelial vasodilation. DHM prevented both of these changes. Besides, HG incubation increased the immunoreactivity to iNOS, HIF-1α, GLUT1, ROR2, NF-κB, TNF-α, Bax, and active caspase-3, and decreased the expression of eNOS and Bcl2. Hyperglycaemia-like conditions also increased the indices of oxidative/nitrosative stress. These HG-induced changes, which were accompanied by an increase in tissue adventitial thickness and inflammatory cell infiltration, were all prevented by DHM. CONCLUSION: Our data demonstrate an anti-inflammatory protective action of DHM to preserve vascular function in the setting of hyperglycaemia.

Angiotensin aldosterone inhibitors improve survival and ameliorate kidney injury induced by sepsis through suppression of inflammation and apoptosis.

Sepsis is an extensive life-threatening illness that occurs due to an abnormal host response that extends through the initial storm of inflammation and oxidative stress and terminates at the late stage of immunosuppression. Among global intensive care units, sepsis-induced acute kidney injury is reported with high mortality rate. The purpose of this study was to evaluate the protective effect of the renin angiotensin aldosterone system (RAAS) inhibition on sepsis outcomes. Cecal ligation and puncture (CLP) procedure was applied for sepsis induction. The experimental design constituted of five groups of rats: sham, CLP-nontreated and CLP-treated with ramipril (10 mg/kg, p.o.), losartan (20 mg/kg, i.p.) and spironolactone (25 mg/kg, p.o.). Twenty-four hours after surgery, rats were euthanized for blood and tissue samples, which were used for assessment of serum inflammatory markers, and oxidative stress parameters, as well as to kidney function parameters. The tissue samples were used for histological and caspase-3 assessment. A survival study was conducted using another set of animals. Our results showed that the different RAAS inhibitors showed protective effects evidenced by enhanced overall survival following sepsis (80% in ramipril and spironolactone-treated and 60% in losartan-treated vs. 10% in the septic group), in addition to improved renal function parameters and reduction of oxidative stress and inflammation. The timely use of RAAS inhibitors during sepsis might represent a new therapeutic approach in septic patient.