Anti-Inflammatory Effects of Red Rice Bran Extract Ameliorate Type I Interferon Production via STING Pathway.

Type I interferons (IFNs-I) are inflammatory cytokines that play an essential role in the pathogenesis of inflammation and autoimmune diseases. Signaling through nucleic acid sensors causes the production of IFNs-I. A stimulator of interferon genes (STING) is a DNA sensor that signals transduction, leading to the production of IFNs-I after their activation. This study aims to determine the anti-inflammatory effects of red rice bran extract (RRBE) on macrophages through the activation of STING signaling. RAW264.7 macrophage cells were stimulated with STING agonist (DMXAA) with and without RRBE. Cells and supernatant were collected. The level of mRNA expression was determined by qPCR, and inflammatory cytokine production was investigated by ELISA. The results indicate that RRBE significantly lowers the transcription of STING and interferon-stimulated genes (ISGs). Moreover, RRBE suppresses the phosphorylation of STING, leading to a decrease in the expression of Irf3, a transcription factor that initiates IFN-I signaling. Our results provide evidence that red rice bran extract may be a protective compound for inflammatory diseases by targeting STING signaling.

Hexahydrocurcumin ameliorates hypertensive and vascular remodeling in L-NAME-induced rats.

Hexahydrocurcumin (HHC), a major metabolite of curcumin, possesses several biological activities such as antioxidant, anti-inflammation, and cardioprotective properties. This study aimed to investigate the effect of HHC on high blood pressure, vascular dysfunction, and remodeling induced by N-nitro L-arginine methyl ester (L-NAME) in rats. Male Wistar rats (200-250 g) received L-NAME (40 mg/kg) via drinking water for seven weeks. HHC at doses of 20, 40 or 80 mg/kg or enalapril 10 mg/kg was orally administered for the last three weeks. Blood pressure was measured weekly. Rats induced with L-NAME showed the development of hypertension, vascular dysfunction, and remodeling as demonstrated by an increase in wall thickness, cross-sectional area, and collagen deposition in the aorta. The overexpression of nuclear factor kappa B (NF-кB), vascular cell adhesion molecule 1 (VCAM1), intercellular adhesion molecule 1 (ICAM1), tumor necrosis factor-alpha (TNF-α), phosphorylated-extracellular-regulated kinase 1/2 (p-ERK1/2), phosphorylated-c-Jun N-terminal kinases (p-JNK), phosphorylated-mitogen activated protein kinase p38 (p-p38), transforming growth factor-beta 1 (TGF-ß1), matrix metalloproteinase-9 (MMP-9) and collagen type 1 was observed in L-NAME-induced hypertensive rats. Increased oxidative stress markers, decreased plasma nitric oxide (NO) levels and the down-regulation of endothelial nitric oxide synthase (eNOS) expression in aortic tissues were also found in L-NAME-induced rats. Moreover, L-NAME-induced rats showed enhanced synthetic protein expression in aortic tissues. These alterations were suppressed in hypertensive rats treated with HHC or enalapril. The present study shows that HHC exhibited antihypertensive effects by improving vascular function and ameliorated the development of vascular remodeling. The responsible mechanism may involve antioxidant and anti-inflammation potential.

Vasorelaxant and Antihypertensive Effects of Neferine in Rats: An In Vitro and In Vivo Study.

The present study was performed to examine the antihypertensive effect of neferine in hypertensive rats and its relaxant mechanisms in isolated rat thoracic aorta. The antihypertensive effect was evaluated by tail-cuff methods on NG-nitro-L-arginine methyl ester (L-NAME) (40 mg/kg BW) 4-week hypertensive-induced hypertensive rats. The vasorelaxant effect and its mechanisms were studied by the organ bath technique in the thoracic aorta isolated from normotensive rats. The results indicated that the treatment of neferine (1 mg/kg and 10 mg/kg) markedly decreased the systolic blood pressure (SBP) when compared with the hypertension group (137.75 ± 10.14 mmHg and 132.23 ± 9.5 mmHg, respectively, p < 0.001), without affecting the heart rate. Moreover, neferine (10-12 - 10-4 M) exhibited concentration-dependent vasorelaxation in endothelium-intact rings (Emax values = 98.95 ± 0.66% and pD2 = 7.93 ± 0.28) and endothelium-denuded rings (Emax values = 90.61 ± 1.91% and pD2 = 6.85 ± 0.36). The effects of neferine were reduced by pre-incubation with L-NAME and 1H-[1,2,4]oxadiazolo[4,3-a] quinoxalin-1-one (ODQ) but not with pre-incubation with indomethacin and K+channel blockers. Neferine attenuated the contractions induced by phenylephrine and caffeine in a Ca2+-free solution and also inhibited in CaCl2- and phenylephrine-induced contracted rings. Our study suggests that neferine exhibited hypertensive potential, induced vasorelaxation through the endothelium nitric oxide synthase (eNOS)/nitric oxide (NO)/soluble guanylyl cyclase (sGC) pathway and involved the modulation of Ca2+ influx through Ca2+ channels and intracellular Ca2+ release from the sarcoplasmic reticulum.

Endothelium-independent vasorelaxation effects of 16-O-acetyldihydroisosteviol on isolated rat thoracic aorta.

AIMS: The aim of this study is to investigate the vasorelaxant effect of 16-O-acetyldihydroisosteviol (ADIS) and its underlying mechanisms in isolated rat aorta. MAIN METHODS: Rat aortic rings were isolated, suspended in organ baths containing Kreb's solution, maintained at 37°C, and mounted on tungsten wire and continuously bubbled with a mixture of 95% O2 and 5% CO2 under a resting tension of 1g. The vasorelaxant effects of ADIS were investigated by means of isometric tension recording experiment. KEY FINDINGS: ADIS (0.1µM-3mM) induced relaxation of aortic rings pre-contracted by phenylephrine (PE, 10µM) and KCl (80mM) with intact-endothelium (Emax=79.26±3.74 and 79.88±3.79, respectively) or denuded-endothelium (Emax=88.05±3.69 and 78.22±6.86, respectively). In depolarization Ca(2+)-free solution, ADIS inhibits calcium chloride (CaCl2)-induced contraction in endothelium-denuded rings in a concentration-dependent manner. In addition, ADIS attenuates transient contractions in Ca(2+)-free medium containing EGTA (1mM) induced by PE (10µM) and caffeine (20mM). By contrast, relaxation was not affected by tetraethylammonium (TEA, 5mM), 4-aminopyridine (4-AP, 1mM), glibenclamide (10µM), barium chloride (BaCl2, 1mM), and 1H-[1,2,3]oxadiazolo[4,3-α]quinoxalin-1-one (ODQ, 1µM). SIGNIFICANCE: These findings reveal the vasorelaxant effect of ADIS, through endothelium-independent pathway. It acts as a Ca(2+) channel blocker through both intracellular and extracellular Ca(2+) release.

Hypotensive and vasorelaxant effects of sericin-derived oligopeptides in rats.

Sericin-derived oligopeptides obtained from silk cocoons were investigated for the in vivo hypotensive effect and investigated for the underlying mechanism involved in vasodilation in isolated rat thoracic aorta. In normotensive anesthetized rats, oligopeptides induced an immediate and transient hypotensive activity. In rat aortic rings, oligopeptides induced a concentration-dependent vasorelaxation in vessels precontracted with both KCl and phenylephrine (PE) with endothelium-intact or endothelium-denuded rings. In endothelium-intact rings, pretreatment with N ω -Nitro-L-arginine methyl ester hydrochloride (L-NAME, 100 µM), an inhibitor of the NO synthase (NOS) or 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ, 1 µM), a selective inhibitor of the guanylyl cyclase enzyme, significantly reduced the relaxant effect of oligopeptides. However, indomethacin, an inhibitor of the cyclooxygenase, had no effect on oligopeptides-induced relaxation. In addition, pretreatment with tetraethylammonium (TEA, 5 mM) reduced the maximal relaxant effect induced by oligopeptides. By contrast, relaxation was not affected by 4-aminopyridine (4-AP, 1 mM), glibenclamide (10 µM), or barium chloride (BaCl2, 1 mM). In depolarization Ca(2+)-free solution, oligopeptides inhibited calcium chloride- (CaCl2-) induced contraction in endothelium-denuded rings in a concentration-dependent manner. Nevertheless, oligopeptides attenuated transient contractions in Ca(2+)-free medium containing EGTA (1 mM) induced by 1 µM PE, but they were not affected by 20 mM caffeine. It is obvious that potent vasodilation effect of oligopeptides is mediated through both the endothelium and the vascular smooth muscle.