Author: Green, Douglas R ; Sun, Huan ; Actis, Marisa ; Pruett-Miller, Shondra M ; Min, Jaeki ; Rankovic, Zoran ; Guy, Cliff S ; Narina, Shilpa ; Peng, Junmin ; Quarato, Giovanni ; Llambi, Fabien

The ability of mitochondria to buffer a rapid rise in cytosolic Ca²⁺ is a hallmark of proper cell homeostasis. Here, we employed m-3M3FBS, a putative phospholipase C (PLC) agonist, to explore the relationships between intracellular Ca²⁺ imbalance, mitochondrial physiology, and cell death. m-3M3FBS induced a potent dose-dependent Ca²⁺ release from the endoplasmic reticulum (ER), followed by a rise in intra-mitochondrial Ca²⁺. When the latter exceeded the organelle buffering capacity, an abrupt mitochondrial inner membrane permeabilization (MIMP) occurred, releasing matrix contents into the cytosol. MIMP was followed by cell death that was independent of Bcl-2 family members and inhibitable by the intracellular Ca²⁺ chelator BAPTA-AM. Cyclosporin A (CsA), capable of blocking the mitochondrial permeability transition (MPT), completely prevented cell death induced by m-3M3FBS. However, CsA acted upstream of mitochondria by preventing Ca²⁺ release from ER stores. Therefore, loss of Ca²⁺ intracellular balance and mitochondrial Ca²⁺ overload followed by MIMP induced a cell death process that is distinct from Bcl-2 family-regulated mitochondrial outer membrane permeabilization (MOMP). Further, the inhibition of cell death by CsA or its analogues can be independent of effects on the MPT.

01 Jan 2018·Cellular Physiology and Biochemistry

Micro Integral Membrane Protein (MIMP), a Newly Discovered Anti-Inflammatory Protein of Lactobacillus Plantarum, Enhances the Gut Barrier and Modulates Microbiota and Inflammatory Cytokines

Article

Author: Wei, Qing ; Ma, Yanlei ; Weng, Wenhao ; Gao, Renyuan ; Shen, Tongyi ; Li, Hao ; Zhu, Qi ; Qin, Huanlong ; Yin, Mingming ; Pan, Cheng ; Yang, Yongzhi ; Liu, Minfeng ; Yan, Xuebing

Background/Aims: Recent studies have demonstrated that the manipulation of the gut microbiome represents a promising treatment for inflammatory bowel disease (IBD). We previously identified micro integral membrane protein (MIMP) as the smallest domain of surface layer protein from Lactobacillus Plantarum. However, the therapeutic relevance of MIMP in IBD remains unknown. Methods: We initially employed a dextran sodium sulphate (DSS)-induced colitis model and evaluated the effect of MIMP on the inflammation response, intestinal barrier and gut microbiota using histological examination, Fluorescein isothiocyanate-Dextran detection and pyrosequencing analysis respectively. We then established peripheral blood mononuclear cells (PBMCs) and an epithelial CaCO-2 co-culture model to investigate the regulatory role of MIMP in inflammatory cytokines. The level changes of inflammatory cytokines were detected using Enzyme-linked immunosorbent and real-time polymerase chain reaction assay. The involved regulatory mechanisms were investigated mainly using dual luciferase reporter and chromatin immunoprecipitation assay. Results: In the DSS-induced colitis model, we observed that MIMP intervention effectively improved the body weight loss, increased the colon length and decreased disease activity index. Consistently, the inflammation scores in the MIMP treatment group were significantly lower than those in the DSS treatment group. Furthermore, MIMP intervention was found to successfully neutralize DSS treatment by decreasing the expression of pro-inflammatory cytokines (IFN-γ, IL-17 and IL-23) and increasing the expression of anti-inflammatory cytokines (IL-4 and IL-10). Notably, the permeability assay demonstrated that the MIMP treatment group was remarkably lower than that in the DSS treatment group. We also showed that MIMP improved gut microbiota dysbiosis caused by DSS-induced inflammation. Additionally, in PBMCs and the CaCO-2 co-culture model, MIMP showed an obvious suppressive effect on lipopolysaccharide-induced inflammation in a time- and dose-dependent manner. Furthermore, we revealed that MIMP could modulate inflammatory cytokine expression through the toll-like receptor 4 pathway and histone acetylation. Conclusions: Our results suggested that MIMP showed a significant anti-inflammatory effect through regulating the gut barrier, microbiota and inflammatory cytokines. MIMP may have translational relevance as clinically relevant therapy for IBD patients.

01 Apr 2012·Infection and ImmunityQ2 · MEDICINE

Involvement of the Mannose Receptor and p38 Mitogen-Activated Protein Kinase Signaling Pathway of the Microdomain of the Integral Membrane Protein after Enteropathogenic Escherichia coli Infection

Q2 · MEDICINE

Article

Author: Moyer, Mary Pat ; Zhang, Peng ; Liu, Zhihua ; Shi, Chenzhang ; Qin, Huanlong ; Ma, Yanlei

ABSTRACTThe microdomain of the integral membrane protein (MIMP) has been shown to adhere to mucin and to antagonize the adhesion of enteropathogenicEscherichia coli(EPEC) to epithelial cells; however, the mechanism has not been fully elucidated. In this study, we further identified the receptor of MIMP on NCM460 cells and investigated the mechanism (the p38 mitogen-activated protein kinase [MAPK] pathway) following the interaction of MIMP and its corresponding receptor, mannose receptor. We first identified the target receptor of MIMP on the surfaces of NCM460 cells using immunoprecipitation-mass spectrometry technology. We also verified the mannose receptor and examined the degradation and activation of the p38 MAPK signaling pathway. The results indicated that MIMP adhered to NCM460 cells by binding to the mannose receptor and inhibited the phosphorylation of p38 MAPK stimulated after EPEC infection via inhibition of the Toll-like receptor 5 pathway. These findings indicated that MIMPs relieve the injury of NCM460 cells after enteropathogenicE. coliinfection through the mannose receptor and inhibition of the p38 MAPK signaling pathway, both of which may therefore be potential therapeutic targets for intestinal diseases, such as inflammatory bowel disease.

100 Deals associated with Viral disease therapeutic research program(IRX Therapeutics, Inc.)

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Indication	Highest Phase	Country/Location	Organization	Date
Virus Diseases	Preclinical	US	IRX Therapeutics, Inc.	31 May 2007

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