Oxidative stress and inflammatory signaling in cerulein pancreatitis

Oxidative stress is considered to be an important regulator of the pathogenesis of acute pancreatitis. Reactive oxygen species (ROS) regulate the activation of inflammatory cascades, the recruitment of inflammatory cells and tissue damage in acute pancreatitis. A hallmark of the inflammatory response in pancreatitis is the induction of cytokine expression, which is regulated by a number of signaling molecules including oxidant-sensitive transcription factors such as nuclear factor-κB (NF-κB) and activator protein-1 (AP-1), signal transducer and activator of transcription 3 (STAT3), and mitogen-activated protein kinases (MAPKs). Cross-talk between ROS and pro-inflammatory cytokines is mediated by NF-κB, AP-1, STAT3, and MAPKs; this crosstalk amplifies the inflammatory cascade in acute pancreatitis. Therapeutic studies have shown that antioxidants and natural compounds can have beneficial effects for patients with pancreatitis and can also influence the expression of proinflammatory cytokines in cerulein-induced pancreatitis. Since oxidative stress may activate inflammatory signaling pathways and contribute to the development of pancreatitis, antioxidant therapy may alleviate the symptoms or prevent the development of pancreatitis. Since chronic administration of high doses of antioxidants may have deleterious effects, dosage levels and duration of antioxidant treatment should be carefully determined.

Resveratrol and its derivates improve inflammatory bowel disease by targeting gut microbiota and inflammatory signaling pathways

Inflammatory bowel disease(IBD)is a chronic inflammatory lesion of the intestine,mainly manifested by infiltration of intestinal inflammatory cells and imbalance of gut microbiota.Conventional treatments for IBD include antibiotics,immunosuppressive agents,5-aminosalicylic acid,steroids and surgery,which have high toxic side effects.Resveratrol is a natural polyphenol,and its various derivatives have anti-oxidation and anti-inflammatory properties.In this paper,we comprehensively review the mechanism of resveratrol and its derivates to alleviate IBD by improving intestinal barrier,regulating the unbalanced gut microbiota,and targeting various inflammatory signaling pathways.

Red Yeast Rice Prevents Atherosclerosis through Regulating Inflammatory Signaling Pathways

Objective： To observe the effects of red yeast rice（RYR） on blood lipid levels, aortic atherosclerosis（AS）, and plaque stability in apolipoprotein E gene knockout（Apo E-/-） mice. Methods： Twentyfour Apo E-/-mice were fed with a high-fat diet starting from 6 weeks of age. Mice were randomized into three groups（n = 8 in each group）： model group（Apo E-/-group）, RYR group（Apo E-/-＋ RYR group）, and simvastatin group（Apo E-/-＋ simvastatin group）. Eight 6-week-old C57BL/6 mice were assigned as the control group and fed with a basic diet. After 36 weeks, plasma lipids and inflammatory factors were measured. Aortic atherosclerotic lesions by microscope, scanning electron microscope and transmission electron microscope were observed. Plasma levels of interleukin-6（IL-6） and tumor necrosis factor-α（TNF-α） were measured with enzymelinked immunosorbent assay. The level of high sensitivity C-reaction protein（Hs-CRP） was detected by the scattering immunoturbidimetric assay. Protein expression of matrix metalloproteinase-9（MMP-9） and nuclear factor κB（NF-κB） in aorta were tested by immunohistochemistry. Results： Compared with the model group, treatment with RYR significantly decreased the levels of total cholesterol, triglyceride, low-density lipoprotein cholesterol, lipoprotein（a）, and apolipoprotein B100 in Apo E-/-mice（P〈0.01）. Compared with the model group, treatment with RYR decreased the levels of Hs-CRP, IL-6, and TNF-α（P〈0.01）. RYR also reduced the protein levels of NF-κB and MMP-9 of the aorta. Conclusions： RYR has the anti-atherosclerotic and stabilizing unstable plaque effects. The mechanism might be related to the inflammatory signaling pathways.

TLR signaling that induces weak inflammatory response and SHIP1 enhances osteogenic functions

Toll-like receptor （TLR）-mediated inflammatory response could negatively affect bone metabolism. In this study, we determined how osteogenesis is regulated during inflammatory responses that are downstream of TLR signaling. Human primary osteoblasts were cultured in collagen gels. Pam3CSK4 （P3C） and Escherichia coli lipopolysaccharide （EcLPS） were used as TLR2 and TLR4 ligand respectively. Porphyromonas gingivalis LPS having TLR2 activity with either TLR4 agonism （Pg1690） or TLR4 antagonism （Pg1449） and mutant E. coli LPS （LPxE/LPxF/WSK） were used. IL-lp, SH2-containing inositol phosphatase-1 （SHIP1） that has regulatory roles in osteogenesis, alkaline phosphatase and mineralization were analyzed. 3α-Aminocholestane （3AC） was used to inhibit SHIP1. Our results suggest that osteoblasts stimulated by P3C, poorly induced IL-1β but strongly upregulated SHIP1 and enhanced osteogenic mediators. On the contrary, EcLPS significantly induced IL-1β and osteogenic mediators were not induced. While Pg1690 downmodulated osteogenic mediators, Pg1449 enhanced osteogenic responses, suggesting that TLR4 signaling annuls osteogenesis even with TLR2 activity. Interestingly, mutant E. coli LPS that induces weak inflammation upregulated osteogenesis, but SHIP1 was not induced. Moreover, inhibiting SHIP1 significantly upregulated TLR2-mediated inflammatory response and downmodulated osteogenesis. In conclusion, these results suggest that induction of weak inflammatory response through TLR2 （with SHIP1 activity） and mutant TLR4 ligands could enhance osteogenesis.