To the Editor：I read with great interest the article by Cao et al[1] re- porting a potential therapeutic utility of p38 inhibitors for acute pancreatitis. Using a preclinical mouse model where acute pancreatitis was ...To the Editor：I read with great interest the article by Cao et al[1] re- porting a potential therapeutic utility of p38 inhibitors for acute pancreatitis. Using a preclinical mouse model where acute pancreatitis was induced by administra- tion of cerulein （a cholecystokinin analog derived from the tree frog Litoria caerulea）, the authors reported that the p38 MAPK inhibitor SB203580, administered intra- peritoneally before and after the first administration of cerulein, relieved signs associated with acute pancreatitis, including decreased HSP60 and HSP70 expression, and serum IL-6, amylase and lipase activities. Although the study remains descriptive and pharmacodynamic aspects were not examined in depth, it still has a merit as it undoubtedly provides a basis for further investigation into the potential utility of targeting p38 signaling for acute pancreatitis, a common serious condition that can be life-threatening.展开更多
AIM: To assess whether juvenile chronic ferric iron ingestion limit colitis and dysbiosis at adulthood in rats and mice. METHODS: Two sets of experiments were designed. In the first set, recently weaned mice were eith...AIM: To assess whether juvenile chronic ferric iron ingestion limit colitis and dysbiosis at adulthood in rats and mice. METHODS: Two sets of experiments were designed. In the first set, recently weaned mice were either orally administered ferrous (Fe2+) iron salt or ferric (Fe3+) microencapsulated iron for 6 wk. The last week of experiments trinitrobenzene sulfonic acid (TNBS) colitis was induced. In the second set, juvenile rats received the microencapsulated ferric iron for 6 wk and were also submitted to TNBS colitis during the last week of experiments. In both sets of experiments, animals were sacrificed 7 d after TNBS instillation. Severity of the inflammation was assessed by scoring macroscopic lesions and quantifying colonic myeloperoxidase (MPO) activity. Alteration of the microflora profile was estimated usingquantitative polymerase chain reaction (qPCR) by measuring the evolution of total caecal microflora, Bacteroidetes, Firmicutes and enterobacteria. RESULTS: Neither ferrous nor ferric iron daily exposures at the juvenile period result in any effect in control animals at adulthood although ferrous iron repeated administration in infancy limited weight gain. Ferrous iron was unable to limit the experimental colitis (1.71 ± 0.27 MPO U/mg proteinvs 2.47 ± 0.22 MPO U/mg protein in colitic mice). In contrast, ferric iron significantly prevented the increase of MPO activity (1.64 ± 0.14 MPO U/mg protein) in TNBS-induced colitis. Moreover, this positive effect was observed at both the doses of ferric iron used (75 and 150 mg/kg per day po - 6 wk). In the study we also compared, in both rats and mice, the consequences of chronic repeated low level exposure to ferric iron (75 mg/kg per day po - 6 wk) on TNBS-induced colitis and its related dysbiosis. We confirmed that ferric iron limited the TNBS-induced increase of MPO activity in both the rodent species. Furthermore, we assessed the ferric iron incidence on TNBS-induced intestinal microbiota dysbiosis. At first, we needed to optimize the isolation and quantify DNA copy numbers using standard curves to perform by qPCR this interspecies comparison. Using this approach, we determined that total microflora was similar in control rats and mice and was mainly composed of Firmicutes and Bacteroidetes at a ratio of 10/1. Ferric juvenile administration did not modify the microflora profile in control animals. Total microflora numbers remained unchanged whichever experimental conditions studied. Following TNBS-induced colitis, the Firmicutes/Bacteroidetes ratio was altered resulting in a decrease of the Firmicutes numbers and an increase of the Bacteroidetes numbers typical of a gut inflammatory reaction. In parallel, the subdominant population, the enterobacteria was also increased. However, ferric iron supplementation for the juvenile period prevented the increase of Bacteroidetes and of enterobacteria numbers consecutive to the colitis in both the studied species at adulthood.CONCLUSION: Rats and mice juvenile chronic ferric iron ingestion prevents colitis and dysbiosis at adulthood as assessed by the first interspecies comparison.展开更多
GPR54 is highly expressed in the central nervous system and plays a crucial role in pubertal development. However, GRP54 is also expressed in the immune system, implying possible immunoregulatory functions. Here we in...GPR54 is highly expressed in the central nervous system and plays a crucial role in pubertal development. However, GRP54 is also expressed in the immune system, implying possible immunoregulatory functions. Here we investigated the role of GPR54 in T cell and immune tolerance. GPR54 deficiency led to an enlarged thymus, an increased number of thymocytes, and altered thymic micro-architecture starting around puberty, indicating GPR54 function in T-cell development through its regulatory effect on the gonadal system. However, flow cytometry revealed a significant reduction in the peripheral regulatory T cell population and a moderate decrease in CD4 single-positive thymocytes in prepubertal Gpr54^(-/-) mice. These phenotypes were confirmed in chimeric mice with GPR54 deficient bone marrow-derived cells. In addition, we found elevated T cell activation in peripheral and thymic T cells in Gpr54^(-/-) mice. When intact mice were immunized with myelin oligodendrocyte glycoprotein, a more severe experimental autoimmune encephalomyelitis(EAE) developed in the Gpr54^(-/-) mice. Interestingly, aggravated EAE disease was also manifested in castrated and bone marrow chimeric Gpr54^(-/-) mice compared to the respective wild-type control,suggesting a defect in self-tolerance resulting from GPR54 deletion through a mechanism that bypassed sex hormones. These findings demonstrate a novel role for GPR54 in regulating self-tolerant immunity in a sex hormone independent manner.展开更多
文摘To the Editor：I read with great interest the article by Cao et al[1] re- porting a potential therapeutic utility of p38 inhibitors for acute pancreatitis. Using a preclinical mouse model where acute pancreatitis was induced by administra- tion of cerulein （a cholecystokinin analog derived from the tree frog Litoria caerulea）, the authors reported that the p38 MAPK inhibitor SB203580, administered intra- peritoneally before and after the first administration of cerulein, relieved signs associated with acute pancreatitis, including decreased HSP60 and HSP70 expression, and serum IL-6, amylase and lipase activities. Although the study remains descriptive and pharmacodynamic aspects were not examined in depth, it still has a merit as it undoubtedly provides a basis for further investigation into the potential utility of targeting p38 signaling for acute pancreatitis, a common serious condition that can be life-threatening.
基金Supported by Institut Polytechnique LaSalle Beauvais
文摘AIM: To assess whether juvenile chronic ferric iron ingestion limit colitis and dysbiosis at adulthood in rats and mice. METHODS: Two sets of experiments were designed. In the first set, recently weaned mice were either orally administered ferrous (Fe2+) iron salt or ferric (Fe3+) microencapsulated iron for 6 wk. The last week of experiments trinitrobenzene sulfonic acid (TNBS) colitis was induced. In the second set, juvenile rats received the microencapsulated ferric iron for 6 wk and were also submitted to TNBS colitis during the last week of experiments. In both sets of experiments, animals were sacrificed 7 d after TNBS instillation. Severity of the inflammation was assessed by scoring macroscopic lesions and quantifying colonic myeloperoxidase (MPO) activity. Alteration of the microflora profile was estimated usingquantitative polymerase chain reaction (qPCR) by measuring the evolution of total caecal microflora, Bacteroidetes, Firmicutes and enterobacteria. RESULTS: Neither ferrous nor ferric iron daily exposures at the juvenile period result in any effect in control animals at adulthood although ferrous iron repeated administration in infancy limited weight gain. Ferrous iron was unable to limit the experimental colitis (1.71 ± 0.27 MPO U/mg proteinvs 2.47 ± 0.22 MPO U/mg protein in colitic mice). In contrast, ferric iron significantly prevented the increase of MPO activity (1.64 ± 0.14 MPO U/mg protein) in TNBS-induced colitis. Moreover, this positive effect was observed at both the doses of ferric iron used (75 and 150 mg/kg per day po - 6 wk). In the study we also compared, in both rats and mice, the consequences of chronic repeated low level exposure to ferric iron (75 mg/kg per day po - 6 wk) on TNBS-induced colitis and its related dysbiosis. We confirmed that ferric iron limited the TNBS-induced increase of MPO activity in both the rodent species. Furthermore, we assessed the ferric iron incidence on TNBS-induced intestinal microbiota dysbiosis. At first, we needed to optimize the isolation and quantify DNA copy numbers using standard curves to perform by qPCR this interspecies comparison. Using this approach, we determined that total microflora was similar in control rats and mice and was mainly composed of Firmicutes and Bacteroidetes at a ratio of 10/1. Ferric juvenile administration did not modify the microflora profile in control animals. Total microflora numbers remained unchanged whichever experimental conditions studied. Following TNBS-induced colitis, the Firmicutes/Bacteroidetes ratio was altered resulting in a decrease of the Firmicutes numbers and an increase of the Bacteroidetes numbers typical of a gut inflammatory reaction. In parallel, the subdominant population, the enterobacteria was also increased. However, ferric iron supplementation for the juvenile period prevented the increase of Bacteroidetes and of enterobacteria numbers consecutive to the colitis in both the studied species at adulthood.CONCLUSION: Rats and mice juvenile chronic ferric iron ingestion prevents colitis and dysbiosis at adulthood as assessed by the first interspecies comparison.
基金supported by the National Natural Science Foundation of China(31271468)the Science and Technology Commission of Shanghai Municipality(12ZR1408700)
文摘GPR54 is highly expressed in the central nervous system and plays a crucial role in pubertal development. However, GRP54 is also expressed in the immune system, implying possible immunoregulatory functions. Here we investigated the role of GPR54 in T cell and immune tolerance. GPR54 deficiency led to an enlarged thymus, an increased number of thymocytes, and altered thymic micro-architecture starting around puberty, indicating GPR54 function in T-cell development through its regulatory effect on the gonadal system. However, flow cytometry revealed a significant reduction in the peripheral regulatory T cell population and a moderate decrease in CD4 single-positive thymocytes in prepubertal Gpr54^(-/-) mice. These phenotypes were confirmed in chimeric mice with GPR54 deficient bone marrow-derived cells. In addition, we found elevated T cell activation in peripheral and thymic T cells in Gpr54^(-/-) mice. When intact mice were immunized with myelin oligodendrocyte glycoprotein, a more severe experimental autoimmune encephalomyelitis(EAE) developed in the Gpr54^(-/-) mice. Interestingly, aggravated EAE disease was also manifested in castrated and bone marrow chimeric Gpr54^(-/-) mice compared to the respective wild-type control,suggesting a defect in self-tolerance resulting from GPR54 deletion through a mechanism that bypassed sex hormones. These findings demonstrate a novel role for GPR54 in regulating self-tolerant immunity in a sex hormone independent manner.
