Aiping Bai

The Effect of the Cholinergic Anti-Inflammatory Pathway on Experimental Colitis

Inflammatory bowel diseases (IBD) are characterized by proinflammatory cytokines, tissue damage and loss of neuron in inflamed mucosa, which implies the cholinergic anti‐inflammatory pathway may be destroyed during the process of inflammatory response. In the study, we identified the effect of cholinergic agonist as anabaseine (AN) and nicotinic receptor antagonist as chlorisondamine diiodide (CHD) on trinitrobenzene sulfonic acid (TNBS)‐induced colitis, to investigate the potential therapeutic effect of the cholinergic anti‐inflammatory pathway on IBD. Experimental colitis was induced by TNBS at day 1, 10u2003μg AN or 1.5u2003μg CHD was injected i.p. to mouse right after the induction of colitis, and repeated on interval day till the mice were sacrificed at day 8. Colonic inflammation was examined by histological analysis, myeloperoxidase (MPO) activity, and the production of tumour necrosis factor (TNF)‐α in tissue. Lamina propria mononuclear cells (LPMC) were isolated, and NF‐κB activation was detected by western blot. The mice with colitis treated by AN showed less tissue damage, less MPO activity, less TNF‐α production in colon, and inhibited NF‐κB activation in LPMC, compared with those mice with colitis untreated, whereas the mice with colitis treated by CHD showed the worst tissue damage, the highest MPO activity, the highest TNF‐α level, and enlarged NF‐κB activation in LPMC. Agonist of the cholinergic anti‐inflammatory pathway inhibits colonic inflammatory response by downregulating the production of TNF‐α, and inhibiting NF‐κB activation, which suggests that modulating the cholinergic anti‐inflammatory pathway may be a new potential management for IBD.

Tanshinone IIA Ameliorates Trinitrobenzene Sulfonic Acid (TNBS)-Induced Murine Colitis

Inflammatory bowel diseases are characterized by proinflammatory cytokines, oxidative stress, and tissue damage. Recently, tanshinone had been shown to act as an antioxidant, and to have anti-inflammatory bioactivity. The study was carried out to investigate the effect of tanshinone IIA on the inflammatory response of experimental colitis. Murine colitis was induced by trinitrobenzene sulfonic acid (TNBS). Ten or 20xa0mg tanshinone IIA was administrated to mice 4xa0h before the induction of colitis, and repeated daily until the mice were sacrificed. Colonic inflammation was examined by histological analysis, myeloperoxidase (MPO) activity, and the production of proinflammatory cytokines in colonic tissue. Activation of nuclear factor-kappa B was identified by western blot and immunohistochemistry, and oxidative stress was shown by glutathione (GSH) level in tissue. The mice with colitis treated by tanshinone IIA showed less tissue damage, lower MPO activity, less production of TNF-α and IL-1β, a higher level of GSH in colonic tissue, and downregulated activation of nuclear factor-kappa B in lamina propria mononuclear cells, compared with those of the untreated colitis group. Our data indicates that tanshinone IIA inhibits inflammatory response of colitis by downregulating the production of proinflammatory cytokines, and attenuating oxidative stress, which suggests that tanshinone IIA may be a new potential management for inflammatory bowel diseases.

AMPK Inhibition Blocks ROS-NFκB Signaling and Attenuates Endotoxemia-Induced Liver Injury

Background AMP-activated protein kinase (AMPK) is an important enzyme in regulation of cellular energy homeostasis. We have previously shown that AMPK activation by 5-aminoimidazole-4-carboxamide (AICAR) results in suppression of immune responses, indicating the pivotal role of AMPK in immune regulation. However, the cellular mechanism underpinning AMPK inhibition on immune response remains largely to be elucidated. The study aimed to investigate the effects of AMPK inhibition on reactive oxygen species (ROS)-nuclear factor κB (NFκB) signaling and endotoxemia-induced liver injury. Methodology/Principal Findings RAW 264.7 cells were pretreated with AMPK activator or inhibitor, followed by LPS challenge. In addition, LPS was injected intraperitoneally into mice to induce systemic inflammation. The parameters of liver injury and immune responses were determined, and survival of mice was monitored respectively. LPS challenge in RAW 264.7 cells resulted in AMPK activation which was then inhibited by compound C treatment. Both AMPK activation by AICAR or inhibition by compound C diminished LPS-induced ROS generation, inhibited phosphorylation of IKK, IκB, and NFκB p65, and consequently, decreased TNF production of RAW 264.7 cells. AICAR or compound C treatment decreased ALT, AST, and TNF levels in serum, reduced CD68 expression and MPO activity in liver tissue of mice with endotoxemia. Moreover, AICAR or compound C treatment improved survival of endotoxemic mice. Conclusions AICAR or compound C treatment attenuates LPS-induced ROS-NFκB signaling, immune responses and liver injury. Strategies to activate or inhibit AMPK signaling may provide alternatives to the current clinical approaches to inhibit immune responses of endotoxemia.

All-trans retinoic acid attenuates experimental colitis through inhibition of NF-κB signaling

Inflammatory bowel disease (IBD) is characterized by excessive innate immune cell activation, which is responsible for tissue damage and induction of adaptive immune responses. All-trans retinoic acid (ATRA), the ligand of retinoic acid receptors (RAR), has been previously shown to regulate adaptive immune responses and restore Th17/Treg balance, while its role in regulation of innate immune cell function such as macrophages remains to be elucidated. The study was performed to explore the effect of ATRA on regulation of innate immune responses during dextran sulfate sodium (DSS) induced murine colitis. The mice with DSS colitis were administered with vehicle, ATRA, or LE135. Colitis was evaluated by clinical symptoms, tissue myeloperoxidase (MPO) activity, and the expressions of CD68 and nuclear factor (NF) κB p65, and tumor necrosis factor (TNF) level in inflamed colon. RAW 264.7 cells were pretreated with vehicle, ATRA, or LE135, followed by LPS challenge in vitro. ATRA administration ameliorates DSS-induced colitis evidenced with decreased TNF level and CD68 expression, while LE135 leads to exacerbation of colitis. ATRA treatment in vitro dampens LPS induced NF-κB activation and TNF production of RAW 264.7 cells. Together, our data show a crucial role of ATRA in the progress of acute colitis through inhibiting NF-κB activation, and suggest that ATRA represents a novel therapeutic approach for the management of IBD.

Seasonality in Flares and Months of Births of Patients with Ulcerative Colitis in a Chinese Population

Background and Aims Reports on seasonality in flares or months of births of inflammatory bowel disease patients have been inconsistent, but little data are available in a Chinese population. The aim of this study was to determine whether symptom flares and births of ulcerative colitis (UC) patients follow a seasonal pattern. Methods Patients with a diagnosis of UC established between January 1990 and December 2007 were investigated according to the occurrence of flares of symptoms and months of births. The expected flares or births were calculated on a monthly basis over the study period, taking into consideration the difference in the number of days in the month in each year. Results A total of 409 UC patients were included in the study, and 1030 flares of symptoms were determined. The peak number of flares occurred during the spring and summer, especially in June, while the nadir occurred in the winter, especially in January (χ2(11 df)xa0=xa032.74304, Pxa0<xa00.005). The symptom flares also occurred more frequently in the spring–summer period than in the autumn–winter period (χ2(3 df)xa0=xa022.1269, Pxa0<xa00.001). There was no statistical difference in birth distribution on a monthly or seasonal (spring, summer, autumn, winter) basis. However, the births of UC patients occurred more frequently in the autumn–winter period than in the spring–summer period when the data were merged into these two seasonal components (χ2(1 df)xa0=xa05.255607, Pxa0<xa00.025). Conclusions The data indicate that the symptom flares of UC occurred more frequently in the spring and summer, while the births of UC patients occurred more often in the autumn and winter. Environmental recurring factors may be associated with the symptom flares of UC, and these factors during pregnancy or postpartum may be associated with susceptibility to UC later in life.

β2-glycoprotein I and its antibodies involve in the pathogenesis of the antiphospholipid syndrome

The antiphospholipid syndrome (APS) is characterized by venous or arterial thrombosis, and associated with dysfunctions of endothelial cells and monocytes. β2-glycoprotein I is a phospholipid-binding glycoprotein, and its antibodies have been reported to correlate strongly with thrombotic risk and play putative role in the pathogenesis of APS, whereas the biofunctions of anti-β2-glycoprotein I antibodies remain largely uncertain. It is noted that β2-glycoprotein I exhibits direct interaction with membrane Toll-like receptors, and through this interaction, the complex of β2-glycoprotein I and its antibodies induces intracellular signals via Toll-like receptors, resulting in activation of endothelial cells and monocytes, and expression of proinflammatory cytokines. In this review, we further discussed the recent findings of β2-glycoprotein I/antibody complex. Once activated by β2-glycoprotein I/antibody and their signals, endothelial cells release microparticle/extracellular vesicles which can further stimulate the surrounding rest cells with procoagulant and pro-inflammatory properties in a paracrine or/and autocrine manner. Novel evidence of β2-glycoprotein I/antibody complex bioactivities may provide insight into the molecular mechanisms that the complex regulates cell function and involves in APS pathogenesis.

Thalidomide is a therapeutic agent that is effective in inducing and maintaining endoscopic remission in adult CD patients.

BACKGROUND AND AIMSnPrevious studies have indicated that thalidomide may be effective in achieving clinical remission and response; however, there is a lack of studies on its effect in endoscopic remission. The aim of this study was to assess the efficacy and safety of thalidomide in inducing and maintaining endoscopic remission.nnnMETHODSnA retrospective study was conducted in adult Crohns disease (CD) patients treated with thalidomide. Patients were assessed based on their medical records. Endoscopy was performed after 4-6 months of thalidomide administration, and the simple endoscopic score for CD (SES-CD) was obtained.nnnRESULTSnTwenty of the 21 (95.2%) eligible patients were recruited. Endoscopic remission was achieved in 7 of the 14 (50%) endoscopy active patients who received thalidomide treatment, whereas 10 (71.4%) patients showed an endoscopy response. The other 6 patients in endoscopic remission still maintained remission after thalidomide treatment. The SES-CD in endoscopy active patients was significantly reduced after thalidomide treatment (P<0.05). A total of 32 adverse events occurred in 17 of the 21 (81.0%) patients. Adverse events resolved spontaneously in 11 (64.7%) patients and resulted in treatment discontinuation and dose reduction in 4 (19.1%) and 2 (9.5%) patients, respectively.nnnCONCLUSIONSnThalidomide therapy is effective in inducing and maintaining endoscopic remission in adult CD patients. However, side effects may limit its clinical use in CD treatment.

Treatment of inflammatory bowel disease with neural stem cells expressing choline acetyltransferase.

Inflammatory bowel disease (IBD) is a chronic inflammatory disorder, with increasing incidence and prevalence in the last one-half century. IBD patients suffer from autonomic vagal neuropathy and nerve dysfunction, with deficiency of acetylcholine in inflamed mucosa. Recent studies showed that death of enteric neuron in local tissue was induced during the process of IBD, which also played a crucial role in the pathogenesis of disease. Stem cells have been demonstrated a new biological treatment for IBD, therefore, we proposal that neural stem cells expressing choline acetyltransferase may enhance enteric neural cell regeneration, restore acetylcholine production in intestinal mucosa, and thus inhibit immune responses of IBD.