Protective effects of naringenin against hypoxic-ischemic brain damage in neonatal rats through suppression of NOD2/RIP2/NF-κB pathway / 中国药理学通报

Aim To explore the protective effects of naringin on hypoxic ischemic brain injury in neonatal rats and its mechanism. Methods Ninety-six healthy 7-day neonatal SD rats were randomly divided into sham operation group, hypoxic-ischemic brain damage group (HIBD group),HIBD with low-dose naringenin group(50 mg·kg-1, NG-L) and HIBD with high-dose naringenin group(100 mg·kg-1,NG-H). Neu-rological deficit, HE staining and brain water content were measured 48h after operation. Immunoblotting was used to detect the expressions of NOD2,RIP2 and NF-κB. Enzyme linked immunosorbent assay(ELISA) method was adopted to detect TNF-α and IL-1β ex-pression. Results Compared with HIBD group, the neurological deficit score decreased, the pathological damage was reduced, and the water content of brain tissues markedly decreased by naringenin(50,100 mg ·kg-1) treatment(P<0.05). Western blot revealed the down-regulation of NOD2,RIP2 and NF-κB by na-ringenin (50,100mg·kg-1) treatment (P<0.05). The content of TNF-α and IL-1β in brain tissues was lower than that of HIBD group (P <0.05). Conclu-sion Naringenin is likely to exert a protective role in neonatal rats of hypoxic ischemic brain injury perhaps through decreasing the expression of NOD2, RIP2 and NF-κB,and reducing the secretion of TNF-α and IL-1β.

LRRK2 enhances Nod1/2-mediated inflammatory cytokine production by promoting Rip2 phosphorylation

The innate immune system is critical for clearing infection, and is tightly regulated to avert excessive tissue damage. Nod1/2-Rip2 signaling, which is essential for initiating the innate immune response to bacterial infection and ER stress, is subject to many regulatory mechanisms. In this study, we found that LRRK2, encoded by a gene implicated in Crohn's disease, leprosy and familial Parkinson's disease, modulates the strength of Nod1/2-Rip2 signaling by enhancing Rip2 phosphorylation. LRRK2 deficiency markedly reduces cytokine production in macrophages upon Nod2 activation by muramyl dipeptide (MDP), Nod1 activation by D-gamma-Glu-meso-diaminopimelic acid (iE-DAP) or ER stress. Our biochemical study shows that the presence of LRRK2 is necessary for optimal phosphorylation of Rip2 upon Nod2 activation. Therefore, this study reveals that LRRK2 is a new positive regulator of Rip2 and promotes inflammatory cytokine induction through the Nod1/2-Rip2 pathway.

Association of genetic polymorphism of CCNE1 and RIP2 with bladder cancer risk / 天津医药

Objective To evaluate the relationship between the CCNE1 or RIP2, identified at a single nucleotide poly?morphism, and the risk, clinic stage and pathological grade of bladder cancer. Methods Peripheral venous blood samples were obtained from 176 patients with bladder cancer and 210 controls without cancer. DNA was extracted. Polymerase chain reaction (PCR) method was used to detect CCNE1 (rs8102137) and RIP2 (rs42490) polymorphism. According to the postoper?ative pathological results, patients with bladder cancer were determined the grading and staging. The genotype differences of medium gene and the distribution gene were analyzed and compared in bladder cancer group and control group. The relation?ship of CCNE1 (rs8102137) and RIP2 (rs42490) genotypes and clinical data of patients with bladder cancer was analyzed, and the relationship of them with the genetic susceptibility to bladder cancer was also analyzed. Results The genotype dis?tribution was with good group representative in control group. The frequency of CCNE1(rs8102137) variant allele was signifi?cantly higher in bladder cancer group (40.91%) than that of control group (30.95%,OR=1.54,95%CI:1.02-2.45, P<0.05). The frequency of RIP2 (rs42490) variant allele was significantly higher in bladder cancer group (72.73%) than that of control group (62.38%, OR=1.61, 95%CI:1.04-2.48, P<0.05). There were no significant differences in gene polymorphisms of CC?NE1(rs8102137) and RIP2 (rs42490) between different pathological grades and different clinical stages of bladder cancer. Conclusion The CCNE1 (rs8102137) and RIP2 (rs42490) polymorphism have interaction in occurrence of bladder cancer process. There is higher risk of bladder cancer in individuals carrying mutant alleles than that of individuals carrying wild type.

Receptor Interacting Protein 2 (RIP2) Is Dispensable for OVA-Induced Airway Inflammation in Mice

PURPOSE: Asthma is a pulmonary chronic inflammatory disease characterized by airway obstruction and hyperresponsiveness. Pattern recognition receptors are known to play a key role in the development of allergic diseases as well as host defenses against microbial infection. Receptor interacting protein 2 (RIP2), a serine/threonine kinase, is an adaptor molecule of NOD1 and NOD2, and genetic variation in this receptor is known to be associated with the severity of allergic asthma in children. In this study, we examined the role of RIP2 in the development of allergic airway inflammation in a mouse model. METHODS: Airway inflammation was induced in mice through intranasal administration of ovalbumin (OVA) after 2 intraperitoneal immunizations with OVA. Lung inflammation and mucus hypersecretion were examined histologically and total cell infiltration in bronchoalveolar (BAL) fluids was determined. Levels of the Th2-related cytokines, IL-5 and IL-13, in lung extracts were measured by ELISA. Serum antigen-specific IgE and IgG1 levels were also assessed. RESULTS: OVA-induced lung inflammation and mucus hypersecretion were not different between WT and RIP2-deficient mice. The IL-5 and IL-13 levels in the bronchoalveolar (BAL) fluids were also not impaired in RIP2-deficient mice compared to WT mice. Moreover, RIP2 deficiency did not affect serum OVA-specific IgG1 and IgE levels. CONCLUSIONS: Our results suggest that RIP2 is not associated with the development of allergic airway inflammation.