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      Cirrhosis of liver: Interference of serpins in quantification of SERPINA4 – A preliminary study

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          Abstract

          Background

          Cirrhosis of liver is a pathological condition, wherein functions of liver are impaired by chronic liver exploitations. Due to decrease in synthetic capacity, expressions of plasma proteins tend to decrease in blood stream. Serpins (Serine protease inhibitors) are class of plasma proteins expressed from liver with structural similarities and diverse functions. SERPINA4 (Kallistatin) is a multifunctional serpin clade A protein expressed from liver and concentration in serum is the reflection of extent of liver dysfunction.

          Objective

          To identify interference of other serpins by immunological cross reactivity with SERPINA4 in cirrhotic liver and healthy subjects.

          Materials and methods

          Blood samples were collected from 20 subjects (10 cirrhotic liver, 10 healthy) from R.L. Jalappa Hospital and Research Centre, Kolar, Karnataka, India. Separation of proteins was carried out by SDS-PAGE. Cross reactivity study was analyzed using western blot.

          Results

          Proteins present in cirrhotic liver and healthy subject's serum were separated by SDS PAGE. There was no band detection on both (cirrhotic liver and healthy) PVDF (polyvinylidene diflouride) membranes. However, a significant band was observed with recombinant kallistatin.

          Conclusion

          Structurally similar serpins with minor amino acid sequence similarities did not show any immunological cross reactivity with SERPINA4 due to non identical epitope in cirrhotic liver and healthy subjects. Present study revealed that there is no interference of serpins for immunological reactions in quantitative estimation of kallistatin which needs further validation.

          Highlights

          • To rule out structurally similar Serpins interference in SERPINA4 quantitative estimations by immunological interactions.

          • A preliminary study for the evaluation of method in evolution of biomarker Kallistatin for Cirrhosis of Liver.

          • Case control study using analytical methods SDS-PAGE and western blot.

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          Most cited references24

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          Pathogenesis of liver cirrhosis.

          Liver cirrhosis is the final pathological result of various chronic liver diseases, and fibrosis is the precursor of cirrhosis. Many types of cells, cytokines and miRNAs are involved in the initiation and progression of liver fibrosis and cirrhosis. Activation of hepatic stellate cells (HSCs) is a pivotal event in fibrosis. Defenestration and capillarization of liver sinusoidal endothelial cells are major contributing factors to hepatic dysfunction in liver cirrhosis. Activated Kupffer cells destroy hepatocytes and stimulate the activation of HSCs. Repeated cycles of apoptosis and regeneration of hepatocytes contribute to pathogenesis of cirrhosis. At the molecular level, many cytokines are involved in mediation of signaling pathways that regulate activation of HSCs and fibrogenesis. Recently, miRNAs as a post-transcriptional regulator have been found to play a key role in fibrosis and cirrhosis. Robust animal models of liver fibrosis and cirrhosis, as well as the recently identified critical cellular and molecular factors involved in the development of liver fibrosis and cirrhosis will facilitate the development of more effective therapeutic approaches for these conditions.
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            Structure of a serpin-protease complex shows inhibition by deformation.

            The serpins have evolved to be the predominant family of serine-protease inhibitors in man. Their unique mechanism of inhibition involves a profound change in conformation, although the nature and significance of this change has been controversial. Here we report the crystallographic structure of a typical serpin-protease complex and show the mechanism of inhibition. The conformational change is initiated by reaction of the active serine of the protease with the reactive centre of the serpin. This cleaves the reactive centre, which then moves 71 A to the opposite pole of the serpin, taking the tethered protease with it. The tight linkage of the two molecules and resulting overlap of their structures does not affect the hyperstable serpin, but causes a surprising 37% loss of structure in the protease. This is induced by the plucking of the serine from its active site, together with breakage of interactions formed during zymogen activation. The disruption of the catalytic site prevents the release of the protease from the complex, and the structural disorder allows its proteolytic destruction. It is this ability of the conformational mechanism to crush as well as inhibit proteases that provides the serpins with their selective advantage.
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              Conformational disease.

              Several diverse disorders, including the prevalent dementias and encephalopathies, are now believed to arise from the same general disease mechanism. In each, there is abnormal unfolding and then aggregation of an underlying protein. The gradual accumulation of these aggregates and the acceleration of their formation by stress explain the characteristic late or episodic onset of the clinical disease. The understanding of these processes at the molecular level is opening prospects of more rational approaches to investigation and therapy.
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                Author and article information

                Contributors
                Journal
                Pract Lab Med
                Pract Lab Med
                Practical Laboratory Medicine
                Elsevier
                2352-5517
                07 October 2017
                December 2017
                07 October 2017
                : 9
                : 53-57
                Affiliations
                [0005]Department of Biochemistry, Sri Devaraj Urs Medical College, SDUAHER, Tamaka, Kolar, Karnataka, India
                Author notes
                [* ]Corresponding author. drshashikn1971@ 123456yahoo.co.in
                Article
                S2352-5517(17)30043-4
                10.1016/j.plabm.2017.10.002
                5683666
                def39a2d-83be-483e-a90c-6d75872bc7f4
                © 2017 The Authors

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                History
                : 10 July 2017
                : 28 August 2017
                : 6 October 2017
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