Brucine inhibits TNF-α-induced HFLS-RA cell proliferation by activating the JNK signaling pathway.

Rheumatoid arthritis (RA) is a diffuse connective tissue disease. Brucine selectively inhibits cell immunity, immune hypersensitivity and induces apoptosis. The current study aimed to investigate effects of brucine on human fibroblast-like synoviocytes (HFLS) of RA and to clarify associated molecular mechanisms. HFLS-RA were treated with tumor necrosis factor (TNF)-α prior to treatment with brucine at carrying concentrations. Cell Counting Kit-8 assays were performed to evaluate HFLS-RA proliferation. Western blot assays were employed to examine c-Jun N-terminal kinase (JNK) expression and phosphorylation in TNF-α-induced HFLS-RA. An association between brucine treatment and JNK phosphorylation was assessed by employing a linear regression analysis. The results suggested that low doses of brucine (0.125 and 0.25 mg/ml) significantly reversed proliferation effects induced by TNF-α, however, final cell viabilities were increased compared with the untreated control (P>0.05 and P<0.05, respectively). High brucine doses (≥0.5 mg/ml) significantly reversed TNF-α-induced proliferation and further inhibited viability compared with the untreated control (P<0.05). Regarding JNK expression, there were no significant differences among the brucine treatment, and between the Control and the TNF-α groups (P>0.05). Brucine treatment significantly decreased JNK phosphorylation compared with the TNF-α group (P<0.05). JNK specific inhibitor, SP600125, significantly inhibited brucine-induced cell viability enhancement compared with the brucine-treated groups without inhibitor (P<0.05). A linear regression analysis suggested that brucine was associated with JNK phosphorylation in TNF-α-treated HFLS-RA. In conclusion, brucine significantly inhibited TNF-α-induced HFLS-RA proliferation by activating the JNK signaling pathway. Therefore, brucine may have potential clinical applications in the treatment of RA.

Attenuating Pulmonary Hypertension by Protecting the Integrity of Glycocalyx in Rats Model of Pulmonary Artery Hypertension.

The endothelial glycocalyx has been proved to be a polysaccharide protein complex covering the surface of vascular endothelial cells, playing an important role in vascular permeability, blood flow shear stress induction, and prevention of endothelial cell adhesion. The pathogenesis of PAH includes pulmonary arterial endothelial cell dysfunction and pulmonary arterial smooth muscle cell (PASMCs) proliferation. Based on the physicochemical properties of endothelial glycocalyx involving pathogenesis of pulmonary hypertension. We hypothesized that the endothelial glycocalyx is involved in the development of pulmonary hypertension; pulmonary hypertension can be regulated by protecting the integrity of glycocalyx. Expression of glycocalyx markers including heparin sulfate proteoglycan (HSPG), hyaluronan (HA), and syndecan-1 (SDC-1) was detected in monocrotaline (MCT)-induced PAH in rats and these components were detected when the PAH rats were treated with heparin that protected the role of glycocalyx. Results showed that plasma levels of HSPG, HA, and SDC-1 were increased in MCT group when compared with control group. However, rats in treatment group showed reduced levels of HSPG, HA, and SDC-1. Expression of HSPG, HA, and SDC-1 in pulmonary arteries was also reduced in MCT group when compared with those in the control group. By contrast, expression of HSPG, HA, and SDC-1 in pulmonary arteries increased in treatment group. In conclusion, destruction of glycocalyx was involved in the development of pulmonary hypertension. Pulmonary hypertension can be regulated by protecting the integrity of glycocalyx.

Association of angiotensin-converting enzyme insertion/deletion polymorphism with susceptibility to systemic lupus erythematosus: a meta-analysis.

BACKGROUND: The aim of this study was to determine whether the angiotensin-converting enzyme (ACE) insertion/deletion (I/D) gene polymorphism confers susceptibility to systemic lupus erythematosus (SLE)/lupus nephritis (LN). METHODS: A meta-analysis was conducted on the association between the ACE I/D polymorphism and SLE/LN (when available) using: (i) the allelic contrast; (ii) the recessive; (iii) the dominant; and (iv) the additive models. RESULTS: A total of 27 relevant comparisons meeting the inclusion criteria were identified, involving 2718 SLE patients and 3655 controls. Meta-analysis showed a significant association between SLE and the allele D in overall populations (odds ratio [OR] = 1.25, 95% CI: 1.07-1.48, P = 0.004). Stratification by ethnicity indicated a strong association between the allele D and SLE in Asians (OR = 1.36, 95% CI: 1.05-1.75, P = 0.019). Meta-analysis also showed a significant association between SLE and the DD genotype in overall populations (additive model) (OR = 1.38, 95% CI: 1.05-1.83, P = 0.022). In addition, we found significant associations between the recessive model and SLE in overall populations, Asians and Europeans (OR = 1.44, 95% CI: 1.11-1.88, P = 0.007; OR = 1.69, 95% CI: 1.07-2.68, P = 0.024; and OR = 1.31, 95% CI: 1.06-1.62, P = 0.013, respectively). With respect to the association between ACE I/D gene polymorphism and LN risk, there was no significant association in either the overall populations or subpopulations. CONCLUSION: The present study might suggest that ACE I/D polymorphism may be a genetic molecular marker to predict SLE, while this polymorphism may not correlate with LN susceptibility.

Hypoxia-Inducible Factor-1α and Autoimmune Lupus, Arthritis.

Hypoxia elicits an orchestrated response in cells, tissues, and entire organisms to survive a hypoxic challenge. On a molecular level, this response can be controlled by oxygen-dependent stabilization of the transcription factor hypoxia-inducible factor (HIF)-1α. Recently, studies have shown that HIF-1α plays an important role in the development and function of T helper (Th) cells, regulatory T (Treg) cells, and dendritic cells (DCs). Because these cells are critical in the pathogenesis of autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis, the roles of HIF-1α in these autoimmune disorders cannot be neglected. In this review, we discuss recent findings on the important roles of HIF-1α in immune cells and the possible pathologic roles of HIF-1α in autoimmune diseases. The obtained information may lead to deeper insights into the roles of HIF-1α in these disorders.