Gossypol suppresses mouse T lymphocytes via inhibition of NFκB,NFAT and AP-1 pathways

Abstract

Gossypol is a kind of yellow polyphenolic compounds extracted from root stem and seed of the cotton plant. In the present study, we investigated its immunosuppressive mechanism by using BALB/c mouse T lymphocytes in vitro. When mouse splenocytes was incubated with gossypol, the extract effectively suppress the overproduction of the cell stimulated by concanavalin A (ConA) in a dose manner. This inhibitive activity was mainly due to interfering Th1 and Th2 cytokines production and decreasing CD4⁺ T cell populations and ratio of CD4⁺/CD8⁺. Furthermore, we also showed that signal transduction via NF-κB, NFAT and AP-1 are critical to the ConA-induced T cell activation in mice. The data revealed that gossypol could down-regulate activation of ConA-induced NF-κB, NFAT and AP-1 signal transduction pathways in mouse T lymphocyte. These observations indicated that gossypol exhibited immunosuppressive effects by inhibition T lymphocyte activation in vitro.     

NF-κB和AP-1在胶原性关节炎小鼠滑膜组织中的表达及活性升高

类风湿关节炎(rheumatoid arthritis,RA)是一种以累及周围关节为主要表现的系统性自身免疫病.炎性细胞因子过度表达是导致RA滑膜炎症和骨质破坏的重要因素.而在炎性介质的表达调节中,核转录因子Kappa B(nuclear factor κB,NF-κB)和激活蛋白1(activator protein-1,AP-1)被认为是最重要的转录调控分子,它们的表达和活性增加可促进炎性细胞因子的生成[1-2].本研究观察了胶原性关节炎(collagen-induced arthritis,CIA)小鼠滑膜中NF-κB和AP-1表达及活性变化,以探讨RA病变的机制.     

Inhibition of Lipopolysaccharide-Induced Inflammatory and Oxidative Responses by Trans-cinnamaldehyde in C2C12 Myoblasts

Background: Trans-cinnamaldehyde (tCA), a bioactive component found in Cinnamomum cassia, has been reported to exhibit anti-inflammatory and antioxidant effects, but its efficacy in muscle cells has yet to be found. In this study, we investigated the inhibitory effect of tCA on inflammatory and oxidative stress induced by lipopolysaccharide (LPS) in C2C12 mouse skeletal myoblasts.Methods: To investigate the anti-inflammatory and antioxidant effects of tCA in LPS-treated C2C12 cells, we measured the levels of pro-inflammatory mediator, cytokines, and reactive oxygen species (ROS). To elucidate the mechanism underlying the effect of tCA, the expression of genes involved in the expression of inflammatory and oxidative regulators was also investigated. We further evaluated the anti-inflammatory and antioxidant efficacy of tCA against LPS in the zebrafish model.Results: tCA significantly inhibited the LPS-induced release of pro-inflammatory mediators and cytokines, which was associated with decreased expression of their regulatory genes. tCA also suppressed the expression of Toll-like receptor 4 (TLR4) and myeloid differentiation factor, and attenuated the nuclear translocation of nuclear factor-kappa B (NF-κB) and the binding of LPS to TLR4 on the cell surface in LPS-treated C2C12 cells. Furthermore, tCA abolished LPS-induced generation of ROS and expression levels of ROS producing enzymes, NADPH oxidase 1 (NOX1) and NOX2. However, tCA enhanced the activation of nuclear translocation of nuclear factor-E2-related factor 2 (Nrf2) and the expression of heme oxygenase-1 (HO-1) in LPS-stimulated C2C12 myoblasts. In addition, tCA showed strong protective effects against NO and ROS production in LPS-injected zebrafish larvae.Conclusions: Our findings suggest that tCA exerts its inhibitory ability against LPS-induced inflammatory and antioxidant stress in C2C12 myoblasts by targeting the TLR4/NF-κB, which might be mediated by the NOXs and Nrf2/HO-1 pathways.     

Spinal nerve ligation-induced activation of nuclear factor kappaB is facilitated by prostaglandins in the affected spinal cord and is a critical step in the development of mechanical allodynia

This study investigated the effect of 5th and 6th lumbar nerve (L5/L6) spinal nerve ligation (SNL) on activated nuclear factor kappaB (NFkBa) in nuclear extracts from the lumbar dorsal horn of the rat, and its relationship to prostaglandin (PG)-dependent spinal hyperexcitability and allodynia 3 days later. Male Sprague-Dawley rats, fitted with intrathecal (i.t.) catheters, underwent SNL- or sham-surgery. Paw withdrawal threshold (PWT), electromyographic analysis of the biceps femoris flexor reflex, and immunoblotting of the spinal cord were used. Both allodynia (PWT 相似文献   

细菌性脑膜炎的氧化应激与抗氧化治疗

细菌性脑膜炎(BM)确切的发病机制尚不完全清楚，氧化应激所致神经损伤是BM的病理机制之一。大量研究证实氧化应激可以引起大脑皮层神经元的坏死和海马神经元的凋亡，而这些神经损伤均与脑膜炎后神经系统后遗症密切相关。研究发现，外源性给予维生素类、化学合成类、酶类等抗氧化剂对细菌性脑膜炎的神经损伤有一定的保护作用。     

Oxidative stress in obstructive nephropathy

Unilateral ureteric obstruction (UUO) is one of the most commonly applied rodent models to study the pathophysiology of renal fibrosis. This model reflects important aspects of inflammation and fibrosis that are prominent in human kidney diseases. In this review, we present an overview of the factors contributing to the pathophysiology of UUO, highlighting the role of oxidative stress.     

Activation of NF-kappaB in lymphocytes and increase in serum immunoglobulin in hyperthyroidism: possible role of oxidative stress

This study evaluated oxidative stress, serum IgM and IgG, and nuclear factor (NF)-κB signaling in lymphocytes of hyperthyroidism patients. GSH content in lymphocytes was significantly lower and serum malondialdehyde, IgM and IgG levels were significantly higher in hyperthyroidism as compared to controls. In lymphocytes, the NF-κB signaling pathway was studied by western blot analysis of p65 and p-IκB. Density of p-IκB and p65 (in nuclear fraction) was significantly higher in hyperthyroidism as compared to controls. The density of p-IκB and p65 had significant positive correlation with serum malondialdehyde level and negative correlation with lymphocyte GSH level in hyperthyroid cases. The serum IgG and IgM levels were correlated significantly with density of p-IκB and p65. As immunoglobulin production is regulated by the NF-κB pathway, we conclude that the oxidative stress-induced activation of the NF-κB pathway might play a role in the rise of serum immunoglobulin level in hyperthyroidism.     

Spaceflight and simulated microgravity suppresses macrophage development via altered RAS/ERK/NFκB and metabolic pathways

Spaceflight-associated immune system weakening ultimately limits the ability of humans to expand their presence beyond the earth''s orbit. A mechanistic study of microgravity-regulated immune cell function is necessary to overcome this challenge. Here, we demonstrate that both spaceflight (real) and simulated microgravity significantly reduce macrophage differentiation, decrease macrophage quantity and functional polarization, and lead to metabolic reprogramming, as demonstrated by changes in gene expression profiles. Moreover, we identified RAS/ERK/NFκB as a major microgravity-regulated pathway. Exogenous ERK and NFκB activators significantly counteracted the effect of microgravity on macrophage differentiation. In addition, microgravity also affects the p53 pathway, which we verified by RT-qPCR and Western blot. Collectively, our data reveal a new mechanism for the effects of microgravity on macrophage development and provide potential molecular targets for the prevention or treatment of macrophage differentiation deficiency in spaceflight.     

The molecular chaperone heat shock protein-90 positively regulates rotavirus infectionx

Rotaviruses are the major cause of severe dehydrating gastroenteritis in children worldwide. In this study, we report a positive role of cellular chaperone Hsp90 during rotavirus infection. A highly specific Hsp90 inhibitor, 17-allylamono-demethoxygeldanamycin (17-AAG) was used to delineate the functional role of Hsp90. In MA104 cells treated with 17-AAG after viral adsorption, replication of simian (SA11) or human (KU) strains was attenuated as assessed by quantitating both plaque forming units and expression of viral genes. Phosphorylation of Akt and NFκB observed 2–4 hpi with SA11, was strongly inhibited in the presence of 17-AAG. Direct Hsp90–Akt interaction in virus infected cells was also reduced in the presence of 17-AAG. Anti-rotaviral effects of 17-AAG were due to inhibition of activation of Akt that was confirmed since, PI3K/Akt inhibitors attenuated rotavirus growth significantly. Thus, Hsp90 regulates rotavirus by modulating cellular signaling proteins. The results highlight the importance of cellular proteins during rotavirus infection and the possibility of targeting cellular chaperones for developing new anti-rotaviral strategies.