J Cell Physiol. 2013 Aug;228(8):1665-75. doi: 10.1002/jcp.24266.
α-2-Macroglobulin: a physiological guardian.
Rehman AA1, Ahsan H, Khan FH.
Author information
Abstract

Alpha macroglobulins are large glycoproteins which are present in the body fluids of both invertebrates and vertebrates. Alpha-2-macroglobulin (α2 M), a key member of alpha macroglobulin superfamily, is a high-molecular weight homotetrameric glycoprotein. α2 M has many diversified and complex functions, but it is primarily known by its ability to inhibit a broad spectrum of proteases without the direct blockage of the protease active site. α2 M is also known to be involved in the regulation, transport, and a host of other functions. For example, apart from inhibiting proteinases, it regulates binding of transferrin to its surface receptor, binds defensin and myelin basic protein, etc., binds several important cytokines, including basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), nerve growth factor (NGF), interleukin-1β (IL-1β), and interleukin-6 (IL-6), and modify their biological activity. α2 M also binds a number of hormones and regulates their activity. α2 M is said to protect the body against various infections, and hence, can be used as a biomarker for the diagnosis and prognosis of a number of diseases. However, this multipurpose antiproteinse is not “fail safe” and could be damaged by reactive species generated endogenously or exogenously, leading to various pathophysiological conditions.

Copyright © 2012 Wiley Periodicals, Inc.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5871670/

https://www.ncbi.nlm.nih.gov/pubmed/32203452

One new paradigm

March 31, 2020

https://www.frontiersin.org/articles/10.3389/fimmu.2018.00312/full

Mini Review ARTICLE

Front. Immunol., 26 February 2018 | https://doi.org/10.3389/fimmu.2018.00312

Interaction of the Human Contact System with Pathogens—An Update

imageSonja Oehmcke-Hecht* and imageJuliane Köhler

Classically, it is stated that FXII has to interact with negatively charged surfaces for activation, but the current paradigm is that any artificial surface has the potential for FXII autoactivation (2).HK, which is in a noncovalent complex with PPK (3), also binds to the surface, thereby exposing PPK for activation by FXII cleavage. In turn, activated plasma kallikrein (PK) cleaves and activates more FXII, forming a powerful activation feedback loop. When sufficient amounts of FXII are activated on the surface, FXII activates coagulation factor XI (FXI), leading to subsequent thrombin formation. This result—in vitro—in the formation of a fibrin clot and is used as a diagnostic coagulation test—the activated partial thromboplastin time (aPTT). However, individuals with congenital deficiencies in FXII, PPK, or HK, who show a prolonged aPTT, do not have bleeding diathesis or abnormal hemostasis, indicating that the intrinsic coagulation pathway does not contribute to physiological hemostasis (4). Moreover, contact activation in vivo always occurs under pathological conditions, such as thrombosis (5), sepsis, or ARDS (6, 7), which makes FXII a promising therapeutic target to limit thrombosis without increasing bleeding risk (8). Thus, it has been questioned whether activation of the intrinsic coagulation by FXII is really its main physiological function. Instead, it was suggested that the pro-inflammatory arm of the contact system—the kallikrein–kinin system—is more related to physiological in vivo functions (9).

 

J Gastroenterol Hepatol. 2020 Mar 25. doi: 10.1111/jgh.15047. [Epub ahead of print]
Covid-19 and the Digestive System.
Wong SH1,2, Lui RN1,2, Sung JJ1,2.
Author information
Abstract

The novel coronavirus disease (Covid-19) is currently causing a major pandemic. It is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a member of the Betacoronavirus genus that also includes the SARS-CoV and Middle East Respiratory Syndrome Coronavirus (MERS-CoV). While patients typically present with fever and a respiratory illness, some patients also report gastrointestinal symptoms such as diarrhoea, vomiting and abdominal pain. Studies have identified the SARS-CoV-2 RNA in stool specimens of infected patients, and its viral receptor angiotensin converting enzyme 2 (ACE2) was found to be highly expressed in gastrointestinal epithelial cells. These suggest that SARS-CoV-2 can actively infect and replicate in the gastrointestinal tract. This has important implications to the disease management, transmission, and infection control. In this article, we review the important gastrointestinal aspects of the disease.

This article is protected by copyright. All rights reserved.

https://www.sciencedirect.com/science/article/pii/S2211383520302999

ORIGINAL ARTICLE

Analysis of therapeutic targets for SARS-CoV-2 and discovery of potential drugs by computational methods

MengzhuZhengaLixiaChenbHuaLiab

Under a Creative Commons license

 

Coronavirus: Hungary Confirmed Cases Reach 343, Another Elderly Patient Dead

https://www.ncbi.nlm.nih.gov/pubmed/30143555

2018 Aug 24;3(26). pii: eaar6689. doi: 10.1126/sciimmunol.aar6689.

Gasdermin D plays a vital role in the generation of neutrophil extracellular traps.

Abstract

The death of a cell is an inevitable part of its biology. During homeostasis, most cells die through apoptosis. If homeostasis is disturbed, cell death can switch to proinflammatory forms of death, such as necroptosis, pyroptosis, or NETosis. We demonstrate that the formation of neutrophil extracellular traps (NETs), a special form of neutrophil cell death that releases chromatin structures to the extracellular space, is dependent on gasdermin D (GSDMD). GSDMD is a pore-forming protein and an executor of pyroptosis. We screened a chemical library and found a small molecule based on the pyrazolo-oxazepine scaffold that efficiently blocks NET formation and GSDMD-mediated pyroptotic cell death in human cells. During NETosis, GSDMD is proteolytically activated by neutrophil proteases and, in turn, affects protease activation and nuclear expansion in a feed-forward loop. In addition to the central role of GSDMD in pyroptosis, we propose that GSDMD also plays an essential function in NETosis.

https://doi.org/10.1016/j.str.2018.03.002. SUMMARY. Pyroptosis is an inflammatory form of programmed cell death 

   Structures of the Gasdermin D C-Terminal Domains Reveal Mechanisms of Autoinhibition

Graphical Abstract

AuthorsZhonghua Liu, Chuanping Wang,Joseph K. Rathkey, Jie Yang,George R. Dubyak, Derek W. Abbott,Tsan Sam Xiao

The gasdermin family members are dangerous molecules capable of forming membrane pores that induce cytolysis, and thus may have evolved autoinhibition mechanisms that regulate cell death through their C-terminal domains.It remains to be determined how most of the gasdermin family members are maintained in their autoinhibited states and how they are activated through protease cleavage or other post-translational modifications, and ultimately how they function under physiological and pathological conditions. Understanding the molecular mechanisms of gasdermin transformation from soluble proteins to transmembrane pores will provide valuable insights into the roles of pyroptosis in immune protection against infections and in inflammatory disorders. These will pave the way for therapeutic targeting of various inflammatory disorders such as sepsis (Jo-gensen and Miao,2015), multiple sclerosis (Guoetal.,2015;Martinet al., 2016), and inflammatory bowel disease (Zaki et al., 2011).

…our data are consistent with the idea that the GSDMD-C domain serves important functioning suppressing cell death by the GSDMD-N domain, and that reduced autoinhibition may promote the assembly of membrane pores by GSDMD-N and spontaneous cell death.

 

 

 

 

 

 

Scientific report:

March 26, 2020

https://www.nature.com/articles/s41598-020-60182-4#Fig1

A universal reporter cell line for bioactivity evaluation of engineered cytokine products

 

 

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