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New strategies focused on endoplasmic reticulum for treatment of human diseases

Horakova Lubica

Institute of Experimental Pharmacology and Toxicology, Slovak Academy of Sciences, Slovakia

E-mail : bhuvaneswari.bibleraaj@uhsm.nhs.uk

DOI: 10.15761/MRI.1000112

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Accumulating evidence suggests that many serious human diseases related to oxidative stress (diabetes, cancer, heart and neurodegenerative diseases) are associated with stress of endoplasmic reticulum (ER) and are called also ER diseases. Proper function of ER requires a steep calcium gradient. In the extracellular space,  the Ca2+ level reaches 1 mM, whereas in the intracellular space it is maintained around the value of 100 nM [1]. Without this gradient cells undergo ER stress and cell death. ER is a network of membranes with mutual functions, focused on production, processing, and transport of proteins and lipids  as well as on maintaining the calcium storage. Moreover, ER possesses regulatory abilities like redox controlling, cell signaling and cell death. To summarize these properties, ER is deciding about survival or death of cells.

A novel therapeutic approach is to develop drugs targeted to ER dysfunction.  ER homeostasis, i.e. normal  function of ER,  is maintained by calcium and redox homeostasis as well as by correct protein folding. Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) is an enzyme playing a crucial role in maintaining a physiological level of Ca2+ inside the cells.

In addition to the SERCA, the calcium channels such as ryanodine receptors and inositol trisphospate receptors are another possibilities as targets to influence ER calcium homeostasis [2].

Both physiological and pathophysiological levels of ROS/RNS regulate cell functions by modifications of SERCA. This regulation of cell function may suggest new strategies to prevent vascular diseases and development of cancer. Flavonoids and other small molecules are able to elevate cytosolic (Ca2+) at least partially via SERCA and thus may be a useful tool for preventing cancer development. On the other hand, some flavonoids significantly increased cell viability and protected against cardiomyocyte apoptosis via preservation of SERCA function, which can be a novel strategy against cardiovascular diseases associated with oxidative stress [3,4]. ER plays also a more important role in type 2 diabetes and its complications than believed previously. Pancreatic beta cells and neurons are particularly sensitive to ER dysfunction associated with impairment of calcium homeostasis.

Recently we found a correlation between decrease of SERCA activity induced by the quercetin derivative chloronaphtochinonequercetin and its anticancer effect in colorectal cell lines HCT-116 and HT-29 [5]. Relationship between SERCA activity decrease and apoptosis was indicated also with respect to curcumin [6]. On the other hand, tetra(trimethylgalloyl)oxyferuloylquercetin, a derivative which increased SERCA activity, showed protective effect on pancreatic beta cells  [7].

Acknowledgements

This work was supported by APVV-15-0455.

References

  1. Rizzuto R, Marchi S, Bonora M, Aguiari P, Bononi A, et al. (2009) Ca(2+) transfer from the ER to mitochondria: when, how and why. Biochim Biophys Acta 1787: 1342-1351. [Crossref]
  2. Urano F (2016) Wolfram Syndrome: Diagnosis, Management, and Treatment. Curr Diab Rep 16: 6. [Crossref] 
  3. Horakova L (2011) Flavonoids in prevention of diseases with respect to modulation of Ca-pump function. Interdiscip Toxicol 4: 114-124. [Crossref]
  4. Horakova L, Strosova M, Spickett CM, Blaskovic D (2013) Impairment of calcium ATPases by high glucose and potential pharmacological protection. Free Radic Res 47: 81-92. [Crossref]
  5. Zizkova P, Stefek M, Rackova L, Soltesova-Prnova M, Horakova L (2017) Novel quercetin derivatives: From redox properties to promising treatment of oxidative stress related diseases. Chem-biol interactions 265: 36-46.
  6. Bilmen JG, Khan SZ, Javed MH, Michelangeli F (2001) Inhibition of the SERCA Ca2+ pumps by curcumin. Curcumin putatively stabilizes the interaction between the nucleotide-binding and phosphorylation domains in the absence of ATP. Eur J Biochem 268: 6318-6327. [Crossref]
  7. Heger V. Zizkova P. Viskupicova J. (2017) Tetra(trimethylgalloyl)oxyferuloyl quercetin: protective effect on beta cell viability decrease induced by methylglyoxal in the pancreatic INS-1E cell line. Eur Pharm J. [In press]. 

Editorial Information

Editor-in-Chief

Kazuhisa Bessho
2021 Copyright OAT. All rights reserv Kyoto University

Article Type

Letter to Editor

Publication history

Received date: June 03, 2017
Accepted date: June 23, 2017
Published date: June 26, 2017

Copyright

© 2017 Lubica H. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Citation

Lubica H (2016) New strategies focused on endoplasmic reticulum for treatment of human diseases. Med Res Innov. 1: DOI: 10.15761/MRI.1000112

Corresponding author

Horakova Lubica

Institute of Experimental Pharmacology and Toxicology, Slovak academy of Sciences, Bratislava, Slovakia.

E-mail : bhuvaneswari.bibleraaj@uhsm.nhs.uk

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