Publications by authors named "Marek Los"

113 Publications

Statins in patients with COVID-19: a retrospective cohort study in Iranian COVID-19 patients.

Transl Med Commun 2021 25;6(1). Epub 2021 Jan 25.

Health Policy Research Center, Institute of Health, Shiraz University of Medical Sciences, Shiraz, Iran.

Background: The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has profoundly affected the lives of millions of people. To date, there is no approved vaccine or specific drug to prevent or treat COVID-19, while the infection is globally spreading at an alarming rate. Because the development of effective vaccines or novel drugs could take several months (if not years), repurposing existing drugs is considered a more efficient strategy that could save lives now. Statins constitute a class of lipid-lowering drugs with proven safety profiles and various known beneficial pleiotropic effects. Our previous investigations showed that statins have antiviral effects and are involved in the process of wound healing in the lung. This triggered us to evaluate if statin use reduces mortality in COVID-19 patients.

Results: After initial recruitment of 459 patients with COVID-19 (Shiraz province, Iran) and careful consideration of the exclusion criteria, a total of 150 patients, of which 75 received statins, were included in our retrospective study. Cox proportional-hazards regression models were used to estimate the association between statin use and rate of death. After propensity score matching, we found that statin use appeared to be associated with a lower risk of morbidity [HR = 0.85, 95% CI = (0.02, 3.93),  = 0.762] and lower risk of death [(HR = 0.76; 95% CI = (0.16, 3.72),  = 0.735)]; however, these associations did not reach statistical significance. Furthermore, statin use reduced the chance of being subjected to mechanical ventilation [OR = 0.96, 95% CI = (0.61-2.99),  = 0.942] and patients on statins showed a more normal computed tomography (CT) scan result [OR = 0.41, 95% CI = (0.07-2.33),  = 0.312].

Conclusions: Although we could not demonstrate a significant association between statin use and a reduction in mortality in patients with COVID19, we do feel that our results are promising and of clinical relevance and warrant the need for prospective randomized controlled trials and extensive retrospective studies to further evaluate and validate the potential beneficial effects of statin treatment on clinical symptoms and mortality rates associated with COVID-19.
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http://dx.doi.org/10.1186/s41231-021-00082-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7829327PMC
January 2021

Quercetin as a Natural Therapeutic Candidate for the Treatment of Influenza Virus.

Biomolecules 2020 12 24;11(1). Epub 2020 Dec 24.

Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R3E 0J9, Canada.

The medical burden caused by respiratory manifestations of influenza virus (IV) outbreak as an infectious respiratory disease is so great that governments in both developed and developing countries have allocated significant national budget toward the development of strategies for prevention, control, and treatment of this infection, which is seemingly common and treatable, but can be deadly. Frequent mutations in its genome structure often result in resistance to standard medications. Thus, new generations of treatments are critical to combat this ever-evolving infection. Plant materials and active compounds have been tested for many years, including, more recently, active compounds like flavonoids. Quercetin is a compound belonging to the flavonols class and has shown therapeutic effects against influenza virus. The focus of this review includes viral pathogenesis as well as the application of quercetin and its derivatives as a complementary therapy in controlling influenza and its related symptoms based on the targets. We also touch on the potential of this class of compounds for treatment of SARS-COV-2, the cause of new pandemic.
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http://dx.doi.org/10.3390/biom11010010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7824064PMC
December 2020

Orbital reconstruction - applied materials, therapeutic agents and clinical problems of restoration of defects.

Eur J Pharmacol 2021 Feb 27;892:173766. Epub 2020 Nov 27.

Biotechnology Centre, Silesian University of Technology, Poland; and Linkocare Life Sciences AB, Linkoping, Gliwice, Sweden. Electronic address:

Reconstruction of large cavities in the skull and facial regions is important not only to restore health but also for the correction of facial distortions. Every visible deformity in the facial region of the patient affects their mental wellness and perception by society, entailing both, deterioration of health, but also a decrease in the performance in society, which translates into its productivity. With the progressive degradation of the natural environment, cancer, in the coming years, will be on the leading causes of morbidity and mortality. The review focuses on two main aspects: (i) the causes of injuries leading to the necessity of removal of orbital cavities occupied by the tumor and then their reconstruction, with the focus on the anatomical structure of the orbital cavity, (ii) the materials used to reconstruct the orbital cavities and analyze their advantages and disadvantages. The manuscript also underlines the not yet fully met challenges in the area of facial- and craniofacial reconstruction in people affected by cancer.
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http://dx.doi.org/10.1016/j.ejphar.2020.173766DOI Listing
February 2021

Pleiotropic effects of statins: A focus on cancer.

Biochim Biophys Acta Mol Basis Dis 2020 12 12;1866(12):165968. Epub 2020 Sep 12.

Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, Canada; Health Policy Research Center, Institute of Health, Shiraz University of Medical Sciences, Shiraz, Iran; Research Institute of Oncology and Hematology, Cancer Care Manitoba, University of Manitoba, Winnipeg, Canada. Electronic address:

The statin drugs ('statins') potently inhibit hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase by competitively blocking the active site of the enzyme. Statins decrease de novo cholesterol biosynthesis and thereby reduce plasma cholesterol levels. Statins exhibit "pleiotropic" properties that are independent of their lipid-lowering effects. For example, preclinical evidence suggests that statins inhibit tumor growth and induce apoptosis in specific cancer cell types. Furthermore, statins show chemo-sensitizing effects by impairing Ras family GTPase signaling. However, whether statins have clinically meaningful anti-cancer effects remains an area of active investigation. Both preclinical and clinical studies on the potential mechanisms of action of statins in several cancers have been reviewed in the literature. Considering the contradictory data on their efficacy, we present an up-to-date summary of the pleiotropic effects of statins in cancer therapy and review their impact on different malignancies. We also discuss the synergistic anti-cancer effects of statins when combined with other more conventional anti-cancer drugs to highlight areas of potential therapeutic development.
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http://dx.doi.org/10.1016/j.bbadis.2020.165968DOI Listing
December 2020

FDA approved drugs with pharmacotherapeutic potential for SARS-CoV-2 (COVID-19) therapy.

Drug Resist Updat 2020 12 15;53:100719. Epub 2020 Jul 15.

Biotechnology Centre, Silesian University of Technology, Krzywoustego 8 Str., 44-100, Gliwice, Poland. Electronic address:

In December 2019, a novel SARS-CoV-2 coronavirus emerged, causing an outbreak of life-threatening pneumonia in the Hubei province, China, and has now spread worldwide, causing a pandemic. The urgent need to control the disease, combined with the lack of specific and effective treatment modalities, call for the use of FDA-approved agents that have shown efficacy against similar pathogens. Chloroquine, remdesivir, lopinavir/ritonavir or ribavirin have all been successful in inhibiting SARS-CoV-2 in vitro. The initial results of a number of clinical trials involving various protocols of administration of chloroquine or hydroxychloroquine mostly point towards their beneficial effect. However, they may not be effective in cases with persistently high viremia, while results on ivermectin (another antiparasitic agent) are not yet available. Interestingly, azithromycin, a macrolide antibiotic in combination with hydroxychloroquine, might yield clinical benefit as an adjunctive. The results of clinical trials point to the potential clinical efficacy of antivirals, especially remdesivir (GS-5734), lopinavir/ritonavir, and favipiravir. Other therapeutic options that are being explored involve meplazumab, tocilizumab, and interferon type 1. We discuss a number of other drugs that are currently in clinical trials, whose results are not yet available, and in various instances we enrich such efficacy analysis by invoking historic data on the treatment of SARS, MERS, influenza, or in vitro studies. Meanwhile, scientists worldwide are seeking to discover novel drugs that take advantage of the molecular structure of the virus, its intracellular life cycle that probably elucidates unfolded-protein response, as well as its mechanism of surface binding and cell invasion, like angiotensin converting enzymes-, HR1, and metalloproteinase inhibitors.
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http://dx.doi.org/10.1016/j.drup.2020.100719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7362818PMC
December 2020

Reprogramming and transdifferentiation - two key processes for regenerative medicine.

Eur J Pharmacol 2020 Sep 18;882:173202. Epub 2020 Jun 18.

Department of Pathology, Pomeranian Medical University, Szczecin, Poland.

Regenerative medicine based on transplants obtained from donors or foetal and new-born mesenchymal stem cells, encounter important obstacles such as limited availability of organs, ethical issues and immune rejection. The growing demand for therapeutic methods for patients being treated after serious accidents, severe organ dysfunction and an increasing number of cancer surgeries, exceeds the possibilities of the therapies that are currently available. Reprogramming and transdifferentiation provide powerful bioengineering tools. Both procedures are based on the somatic differentiated cells, which are easily and unlimitedly available, like for example: fibroblasts. During the reprogramming procedure mature cells are converted into pluripotent cells - which are capable to differentiate into almost any kind of desired cells. Transdifferentiation directly converts differentiated cells of one type into another differentiated cells type. Both procedures allow to obtained patient's dedicated cells for therapeutic purpose in regenerative medicine. In combination with biomaterials, it is possible to obtain even whole anatomical structures. Those patient's dedicated structures may serve for them upon serious accidents with massive tissue damage but also upon cancer surgeries as a replacement of damaged organ. Detailed information about reprogramming and transdifferentiation procedures as well as the current state of the art are presented in our review.
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http://dx.doi.org/10.1016/j.ejphar.2020.173202DOI Listing
September 2020

Endoplasmic reticulum as a potential therapeutic target for covid-19 infection management?

Eur J Pharmacol 2020 Sep 17;882:173288. Epub 2020 Jun 17.

Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, Canada; Research Institute in Oncology and Hematology, CancerCare Manitoba, University of Manitoba, Winnipeg, MB, Canada; Faculty of Medicine, Katowice School of Technology, Katowice, Poland. Electronic address:

In December 2019, many pneumonia cases with unidentified sources appeared in Wuhan, Hubei, China, with clinical symptoms like viral pneumonia. Deep sequencing analysis of samples from lower respiratory tract revealed a novel coronavirus, called 2019 novel coronavirus (2019-nCoV). Currently there is a rapid global spread. World Health Organization declare the disease a pandemic condition. The pathologic source of this disease was a new RNA virus from Coronaviridae family, which was named COVID-19. SARS-CoV-2 entry starts with the binding of the spike glycoprotein expressed on the viral envelope to ACE2 on the alveolar surface followed by clathrin-dependent endocytosis of the SARS-CoV-2 and ACE2 complex. SARS-CoV-2 enters the cells through endocytosis process, which is possibly facilitated, via a pH dependent endosomal cysteine protease cathepsins. Once inside the cells, SARS-CoV-2 exploits the endogenous transcriptional machinery of alveolar cells to replicate and spread through the entire lung. Endosomal acidic pH for SARS-CoV-2 processing and internalization is critical. After entering the cells, it possibly activates or hijack many intracellular pathways in favor of its replication. In the current opinion article, we will explain the possible involvement of unfolded protein response as a cellular stress response to the SARS-CoV-2 infection.
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http://dx.doi.org/10.1016/j.ejphar.2020.173288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297682PMC
September 2020

Therapeutic potential of bone marrow-derived mesenchymal stem cells and imatinib in a rat model of liver fibrosis.

Eur J Pharmacol 2020 Sep 11;882:173263. Epub 2020 Jun 11.

Department of Human Anatomy and Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada; Research Institute in Oncology and Hematology, Cancer Care Manitoba, University of Manitoba, ON, Canada; Faculty of Medicine, University of Technology in Katowice, Katowice, Poland. Electronic address:

Considering the global increase in the prevalence of hepatic fibrosis and ineffective disease treatment, novel therapies are urgently needed. The current study is focused on comparing the therapeutic effects of mesenchymal stem cells (MSC)/imatinib combination therapy to single (MSCs or imatinib) therapy, in a rat model of carbon tetrachloride (CCL4)-induced liver fibrosis. Using rats, hepatic fibrosis was induced by injection of CCL4. Rats were divided into 5 groups: CCL4-induced hepatic fibrosis, phosphate buffered saline (PBS) treatment (vehicle control), Bone marrow-MSCs (BM_MSCs), imatinib, and bone marrow-MSCs/imatinib co-treatment. The therapeutic impact of these approaches was determined using histopathology, sirius-red staining, serum markers, and qRT-PCR for over expression of matrix components. IHC and Western blot were conducted for further confirmation of the results. Single treatment with MSCs or imatinib and the combination therapy, all significantly reduced serum levels of ALT, AST, and ALP concomitant with down-regulation of α-SMA, pro-collagen I, pro-collagen III, collagen IV, and laminin. A significant reduction of ECM components deposits and a decrease in α-SMA expression were detected in all treatment groups. Pathological observations demonstrated that 20% and 40% of the rats in the MSC and MSC/imatinib group were in grade F0 respectively, while 80% of the rats of the imatinib group were in grade 2. Even though all treatment strategies studied resulted in an equally potent reduction in the mRNA and protein expression levels of pro-fibrotic markers, in aspect of pathological observations, our results demonstrate the highest therapeutic potential of utilizing combination of BM-MSCs and imatinib.
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http://dx.doi.org/10.1016/j.ejphar.2020.173263DOI Listing
September 2020

Pelargonidin exhibits restoring effects against amyloid β-induced deficits in the hippocampus of male rats.

Med J Islam Repub Iran 2019 12;33:135. Epub 2019 Dec 12.

Cellular and Molecular Research Center, Department of Anatomy, Iran University of Medical Sciences, Tehran, Iran.

Alzheimer's disease (AD) is characterized by amyloid-beta plaques, neuronal loss, and cognitive dysfunction. Oxidative stress plays a key role in the pathophysiology of AD, and it has been suggested that antioxidants may slow the progress of the disease. In this study, the possible protective effects of pelargonidin (a natural flavonoid) against amyloid β (Aβ)-induced behavioral deficits was investigated in rats. Adult Wistar male rats were treated with intrahippocampal injections of the Aβ (aa 25-35) and intraperitoneal injection of pelargonidin. Learning and spatial memory were tested using the Morris water maze (MWM) task. The antioxidant activity was evaluated using the ferric reducing/antioxidant power assay (FRAP assay). Data were analyzed using SPSS 20, and value of p≤0.05 was considered significant. The results of this study showed that Aβ significantly increased escape latency and the distance traveled in the MWM, and pelargonidin attenuated these behavioral changes. Aβ induced a significant decrease in the total thiol content of hippocampus, and pelargonidin restored the hippocampal antioxidant capacity. The results of this study suggest that pelargonidin can improve Aβ-induced behavioral changes in rats.
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http://dx.doi.org/10.34171/mjiri.33.135DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7137812PMC
December 2019

HSP70/IL-2 Treated NK Cells Effectively Cross the Blood Brain Barrier and Target Tumor Cells in a Rat Model of Induced Glioblastoma Multiforme (GBM).

Int J Mol Sci 2020 Mar 25;21(7). Epub 2020 Mar 25.

Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran 16635-148, Iran.

Natural killer (NK) cell therapy is one of the most promising treatments for Glioblastoma Multiforme (GBM). However, this emerging technology is limited by the availability of sufficient numbers of fully functional cells. Here, we investigated the efficacy of NK cells that were expanded and treated by interleukin-2 (IL-2) and heat shock protein 70 (HSP70), both in vitro and in vivo. Proliferation and cytotoxicity assays were used to assess the functionality of NK cells in vitro, after which treated and naïve NK cells were administrated intracranially and systemically to compare the potential antitumor activities in our in vivo rat GBM models. In vitro assays provided strong evidence of NK cell efficacy against C6 tumor cells. In vivo tracking of NK cells showed efficient homing around and within the tumor site. Furthermore, significant amelioration of the tumor in rats treated with HSP70/Il-2-treated NK cells as compared to those subjected to nontreated NK cells, as confirmed by MRI, proved the efficacy of adoptive NK cell therapy. Moreover, results obtained with systemic injection confirmed migration of activated NK cells over the blood brain barrier and subsequent targeting of GBM tumor cells. Our data suggest that administration of HSP70/Il-2-treated NK cells may be a promising therapeutic approach to be considered in the treatment of GBM.
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http://dx.doi.org/10.3390/ijms21072263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7178276PMC
March 2020

Correction: Association of PDCD6 polymorphisms with the risk of cancer: Evidence from a meta-analysis.

Oncotarget 2020 Mar 3;11(9):893. Epub 2020 Mar 3.

Department of Human Anatomy and Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.

[This corrects the article DOI: 10.18632/oncotarget.25324.].
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http://dx.doi.org/10.18632/oncotarget.27483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7061740PMC
March 2020

Correction to: Human Gyrovirus-Apoptin Interferes with the Cell Cycle and Induces G2/M Arrest Prior to Apoptosis.

Arch Immunol Ther Exp (Warsz) 2020 Feb 20;68(1). Epub 2020 Feb 20.

ENT Department, School of Medicine, Medical University of Silesia in Katowice, Katowice, Poland.

The authors would like to correct the following error.
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http://dx.doi.org/10.1007/s00005-020-00570-wDOI Listing
February 2020

LMO1 polymorphisms and the risk of neuroblastoma: Assessment of meta-analysis of case-control studies.

J Cell Mol Med 2020 01 12;24(2):1160-1168. Epub 2019 Dec 12.

Biotechnology Centre, Silesian University of Technology, Gliwice, Poland.

Neuroblastoma (NB), a neuroendocrine tumour, is one of the most prevalent cancers in children. The link between LMO1 polymorphisms and NB has been investigated by several groups, rendering inconclusive results. Here, with this comprehensive systematic review and up-to-date meta-analysis, we aim to distinctively elucidate the possible correlation between LMO1 polymorphisms and NB susceptibility. Eligible studies were systematically researched and identified using PubMed, Web of Science and Scopus databases up to 10 February 2019. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the strength of the associations. Our findings revealed that rs110419 and rs2168101 polymorphisms were significantly associated with a decreased risk of NB in all genetic models. In addition, the rs4758051 variant appeared protective against NB in homozygous, dominant and allele genetic models, whereas the rs10840002 variant markedly decreased the risk of NB in the allele model. In contrast, the rs204938 polymorphism showed a positive association with NB susceptibility in allele genetic models. In summary, our meta-analysis is the first to provide clear evidence of an association between specific polymorphisms of LMO1 and susceptibility to NB. Of note, additional larger well-designed studies would be helpful to further evaluate and confirm this association.
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http://dx.doi.org/10.1111/jcmm.14836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6991665PMC
January 2020

Betulin and its derivatives as novel compounds with different pharmacological effects.

Biotechnol Adv 2020 Jan - Feb;38:107409. Epub 2019 Jun 18.

Department of Human Anatomy and Cell Science, Rady College of Medicine, Max Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada; Biology of Breathing Theme, Children Hospital Research Institute of Manitoba, University of Manitoba, Winnipeg, Canada; Health Policy Research Center, Institute of Health, Shiraz University of Medical Sciences, Shiraz, Iran; Research Institute of Oncology and Hematology, CancerCare Manitoba, University of Manitoba, Winnipeg, Canada. Electronic address:

Betulin (B) and Betulinic acid (BA) are natural pentacyclic lupane-structure triterpenoids which possess a wide range of pharmacological activities. Recent evidence indicates that B and BA have several properties useful for the treatment of metabolic disorders, infectious diseases, cardiovascular disorders, and neurological disorders. In the current review, we discuss B and BA structures and derivatives and then comprehensively explain their pharmacological effects in relation to various diseases. We also explain antiviral, antibacterial and anti-cancer effects of B and BA. Finally, we discuss the delivery methods, in which these compounds most effectively target different systems.
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http://dx.doi.org/10.1016/j.biotechadv.2019.06.008DOI Listing
February 2020

Neuropathological and genomic characterization of glioblastoma-induced rat model: How similar is it to humans for targeted therapy?

J Cell Physiol 2019 12 23;234(12):22493-22504. Epub 2019 May 23.

Pediatric Stem Cell Transplant Department, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran.

Glioblastoma multiforme (GBM) is a unique aggressive tumor and mostly develops in the brain, while rarely spreading out of the central nervous system. It is associated with a high mortality rate; despite tremendous efforts having been made for effective therapy, tumor recurrence occurs with high prevalence. To elucidate the mechanisms that lead to new drug discovery, animal models of tumor progression is one of the oldest and most beneficial approaches to not only investigating the aggressive nature of the tumor, but also improving preclinical research. It is also a useful tool for predicting novel therapies' effectiveness as well as side effects. However, there are concerns that must be considered, such as the heterogeneity of tumor, biological properties, pharma dynamic, and anatomic shapes of the models, which have to be similar to humans as much as possible. Although several methods and various species have been used for this approach, the real recapitulation of the human tumor has been left under discussion. The GBM model, which has been verified in this study, has been established by using the Rat C6 cell line. By exploiting bioinformatic tools, the similarities between aberrant gene expression and pathways have been predicted. In this regard, 610 common genes and a number of pathways have been detected. Moreover, while magnetic resonance imaging analysis enables us to compare tumor features between these two specious, pathological findings provides most of the human GBM characteristics. Therefore, the present study provides genomics, pathologic, and imaging evidence for showing the similarities between human and rat GBM models.
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http://dx.doi.org/10.1002/jcp.28813DOI Listing
December 2019

Heterogeneous Mixture of Amniotic Cells is Likely a Better Source of Stem Cells than Adipose Tissue.

Arch Immunol Ther Exp (Warsz) 2019 Jun 16;67(3):189-196. Epub 2019 Apr 16.

Chair and Department of Descriptive and Topographic Anatomy, School of Medicine, Division of Dentistry in Zabrze, Medical University of Silesia, Zabrze Rokitnica, Poland.

Stem cells are increasingly being used in the course of burn treatment. As several different types of stem cells are available for the purposes, it is important to chose the most efficient and the most practicable stem cell type. The aim of this study was to compare the potential of heterogeneous amnion cell mixture with the presently used standard therapy, the adipose tissue-derived stem cells. The placenta was collected during a Cesarean section procedure. Adipose tissue tissue-derived cells were isolated using the Cytori's Celution® System. Cells were tested for fulfillment of the minimum criteria for stem cells. The efficiency of cell cultures was tested by an analysis of population doubling, cell proliferation, cell cycle and cell migration. Amniotic cells presented a higher ability for differentiation to chondrocytes and osteocytes than adipose-derived regenerative cells but a lower ability for differentiation toward adipocytes. Additionally, in vitro experiments have demonstrated a higher applicability of amniotic cells than adipose tissue-derived stem cells. Amniotic cells show several advantages: easy access to placenta, low costs and a lack of ethical dilemmas related to stem cell harvesting. The main disadvantage is, however, their availability, as isogenic treatment would only be possible for women around children-bearing age, unless personalized banks for amniotic cells would be established.
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http://dx.doi.org/10.1007/s00005-019-00538-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6509077PMC
June 2019

Glioblastoma cancer stem cell biology: Potential theranostic targets.

Drug Resist Updat 2019 01 8;42:35-45. Epub 2019 Mar 8.

Pediatric Stem Cell Transplant Department, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran. Electronic address:

Glioblastoma multiforme (GBM) is among the most incurable cancers. GBMs survival rate has not markedly improved, despite new radical surgery protocols, the introduction of new anticancer drugs, new treatment protocols, and advances in radiation techniques. The low efficacy of therapy, and short interval between remission and recurrence, could be attributed to the resistance of a small fraction of tumorigenic cells to treatment. The existence and importance of cancer stem cells (CSCs) is perceived by some as controversial. Experimental evidences suggest that the presence of therapy-resistant glioblastoma stem cells (GSCs) could explain tumor recurrence and metastasis. Some scientists, including most of the authors of this review, believe that GSCs are the driving force behind GBM relapses, whereas others however, question the existence of GSCs. Evidence has accumulated indicating that non-tumorigenic cancer cells with high heterogeneity, could undergo reprogramming and become GSCs. Hence, targeting GSCs as the "root cells" initiating malignancy has been proposed to eradicate this devastating disease. Most standard treatments fail to completely eradicate GSCs, which can then cause the recurrence of the disease. To effectively target GSCs, a comprehensive understanding of the biology of GSCs as well as the mechanisms by which these cells survive during treatment and develop into new tumor, is urgently needed. Herein, we provide an overview of the molecular features of GSCs, and elaborate how to facilitate their detection and efficient targeting for therapeutic interventions. We also discuss GBM classifications based on the molecular stem cell subtypes with a focus on potential therapeutic approaches.
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http://dx.doi.org/10.1016/j.drup.2018.03.003DOI Listing
January 2019

Amniotic cells share clusters of differentiation of fibroblasts and keratinocytes, influencing their ability to proliferate and aid in wound healing while impairing their angiogenesis capability.

Eur J Pharmacol 2019 Jul 28;854:167-178. Epub 2019 Feb 28.

Dr Stanislaw Sakiel's Center for Burn Treatment, Jana Pawła II 2, 41-100 Siemianowice Śląskie, Poland; Chair and Department of Descriptive and Topographic Anatomy, School of Medicine with the Division of Dentistry in Zabrze, Medical University of Silesia, Jordana 19, 41-808 Zabrze Rokitnica, Poland.

An alternative to cultured skin cell grafts usage in burn treatment is the graft of allogenic stem cells. We verified whether amniotic stem cells are better than the present therapeutic standard: grafts of autologous keratinocytes and fibroblasts along with autologous adipose-derived stem cells, and whether amniotic stem cells can support the growth of autologous keratinocytes and fibroblasts in the culture. The study was performed on the material from 18 amnia. Skin cells were obtained from 3 patients. In order to assess the influence of stem cells on keratinocytes and fibroblasts, the following experiments were performed: impact on viability and cell cycle, wound healing capability, angiogenesis capability, influence on the proliferation speed and capability to differentiate into skin cells. We demonstrated that human amniotic membrane-derived mesenchymal stem cells (hAMMSCs) share amniotic proteins with skin cells. Amniotic stem cells may replace skin fibroblasts in grafts due to the close similarity in their surface antigens, with significantly larger proliferative potential and ability to stimulate wound healing. It was shown that adding amniotic cells to both keratinocytes and fibroblast cultures accelerates directional migration by ≥ 40%. We confirmed in this study the influence of amniotic cells on the proliferation and cell cycle of fibroblasts and keratinocytes. Amniotic stem cells can be successfully used not only as a first choice graft but also to replace 3T3 line cells, supporting the proliferation of the cells during the culturing, as well as a supplementary graft supporting an autologous graft of keratinocytes and fibroblasts.
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http://dx.doi.org/10.1016/j.ejphar.2019.02.043DOI Listing
July 2019

Composite Nanofibers Containing Multiwall Carbon Nanotubes as Biodegradable Membranes in Reconstructive Medicine.

Nanomaterials (Basel) 2019 Jan 4;9(1). Epub 2019 Jan 4.

Centre of Biotechnology, Silesian University of Technology, 44-100 Gliwice, Poland.

We have tested titanium (Ti) plates that are used for bone reconstruction in maxillofacial surgery, in combination with five types of novel long-resorbable biomaterials: (i) PCL₀-polycaprolactone without additives, (ii) PCL-polycaprolactone with the addition of multiwall carbon nanotubes (MWCNT), (iii) PCL-polycaprolactone doped with multiwall carbon nanotubes (MWCNT) containing ⁻OH hydroxyl groups, (iv) PCL-polycaprolactone with the addition of multiwall carbon nanotubes (MWCNT) containing carboxyl groups, and (v) PCL-polycaprolactone with the addition of Ti nanoparticles. The structure and properties of the obtained materials have been examined with the use of Scanning Electron Microscopy (SEM), Transmission Electron Microscopy (TEM), Raman spectroscopy, Fourier transform infrared spectroscopy (FTIR), and/or X-ray powder diffraction (XRD). Titanium BR plates have been covered with: (i) PCL₀ fibers (PCL-connection plates), (ii) PCL fibers (PCL-plates), (iii) PCL fibers (PCL-plates), (iv) PCL (PCL-plates), (v) PCL fiber (PCL-connection plates). Such modified titanium plates were exposed to X-ray doses corresponding to those applied in head and neck tumor treatment. The potential leaching of toxic materials upon the irradiation of such modified titanium plates, and their effect on normal human dermal fibroblasts (NHDF) have been assessed by MTT assay. The presented results show variable biological responses depending on the modifications to titanium plates.
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http://dx.doi.org/10.3390/nano9010063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6359440PMC
January 2019

Novel trends in application of stem cells in skin wound healing.

Eur J Pharmacol 2019 Jan 8;843:307-315. Epub 2018 Dec 8.

Centre of Biotechnology, Silesian University of Technology, Gliwice, Poland; LinkoCare Life Sciences AB, Sweden; Centre de Biophysique Moléculaire, UPR4301 CNRS CS80054, Rue Charles Sadron, 45071 Orleans cedex 2, France.

The latest findings indicate the huge therapeutic potential of stem cells in regenerative medicine, including the healing of chronic wounds. Main stem cell types involved in wound healing process are: epidermal and dermal stem cells, mesenchymal stem cells (MSCs), endothelial progenitor cells (EPCs) and hematopoietic stem cells (HSCs). In the therapy of chronic wounds, they can be administrated either topically or using different matrix like hydrogels, scaffolds, dermal substitutes and extracellular matrix (ECM) derivatives. Stem cells are proven to positively influence wound healing by different direct and indirect mechanisms including residing cells stimulation, biomolecules release, inflammation control and ECM remodelling. MSCs are especially worth mentioning as they can be easily derived from bone-marrow or adipose tissue. Apart from traditional approach of administering living stem cells to wounds, new trends have emerged in recent years. Good healing results are obtained using stem cell secretome alone, for example exosomes or conditioned media. There are also attempts to improve healing potential of stem cells by their co-culture with other cell types as well as by their genetic modifications or pretreatment using different chemicals or cell media. Moreover, stem cells have been tested for novel therapeutic purposes like for example acute burns and have been used in experiments on large animal models including pigs and sheep. In this review we discuss the role of stem cells in skin wound healing acceleration. In addition, we analyse possible new strategies of stem cells application in treatment of chronic wounds.
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http://dx.doi.org/10.1016/j.ejphar.2018.12.012DOI Listing
January 2019

Detection of Small GTPase Prenylation and GTP Binding Using Membrane Fractionation and GTPase-linked Immunosorbent Assay.

J Vis Exp 2018 11 11(141). Epub 2018 Nov 11.

Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba; Biology of Breathing Theme, Children Hospital Research Institute of Manitoba, University of Manitoba; Health Policy Research Center, Institute of Health, Shiraz University of Medical Sciences;

The Rho GTPase family belongs to the Ras superfamily and includes approximately 20 members in humans. Rho GTPases are important in the regulation of diverse cellular functions, including cytoskeletal dynamics, cell motility, cell polarity, axonal guidance, vesicular trafficking, and cell cycle control. Changes in Rho GTPase signaling play an essential regulatory role in many pathological conditions, such as cancer, central nervous system diseases, and immune system-dependent diseases. The posttranslational modification of Rho GTPases (i.e., prenylation by mevalonate pathway intermediates) and GTP binding are key factors which affect the activation of this protein. In this paper, two essential and simple methods are provided to detect a broad range of Rho GTPase prenylation and GTP binding activities. Details of the technical procedures that have been used are explained step by step in this manuscript.
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http://dx.doi.org/10.3791/57646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426020PMC
November 2018

Psoriasis Treatment Changes the Expression Profile of Selected Caspases and their Regulatory MicroRNAs.

Cell Physiol Biochem 2018 11;50(2):525-537. Epub 2018 Oct 11.

Centre de Biophysique Moléculaire, Orleans, France.

Background/aims: Psoriasis, an autoimmune diseases of the skin, characterized by patches of abnormal/inflammed skin, although not usually life-threatening, it causes severe discomfort, esthetic impairments, and may lead to impaired social functions and social withdrawal. Besides UV-phototherapy, various anti-inflammatory treatments are applied, depending on the severity of symptoms. In 2008, adalimumab (fully humanized human anti-TNF antibody) was launched for the treatment of psoriasis. In the quest to better understand the pathomechanism of adalimumab's therapeutic effects, and the acquired resistance to the drug, we have investigated how its administration affect the regulation of the expression of selected caspases, including those activated by inflammosome.

Methods: The research was initially carried out on normal human dermal fibroblasts (NHDF) treated with adalimumab for 2, 8 and 24 hours in vitro. Then, expression profile of genes encoding caspases and their regulatory micro-RNAs was determined with the use of oligonucleotide microarray. The validation of the microarray results was carried out by qRT-PCR. The in vitro study was followed by ex-vivo investigation of adalimumab's effects on the expression of caspase-6 in blood of the psoriatic patients. The samples were collected before, and 2 hours after adalimumab's administration and the analysis was determined by qRT-PCR.

Results: The result of the analysis indicated that introduction of adalimumab to the NHDF culture resulted in the change of the transcription activity of genes encoding caspases and genes encoding miRNAs. The analysis revealed 5 different miRNA molecules regulating the expression of: CASP2, CASP3 and CASP6. There were no statistically significant differences in the expression of gene encoding caspase-6 in the patients' blood before and 2 hours after the anti-TNF drug administration.

Conclusion: We have found that adalimumab administration affects caspases expression, thus they may be used as molecular markers for monitoring the therapy with the use of an anti-TNF drugs, including adalimumab. It is likely that the mechanisms responsible for changed expression profiles of genes encoding caspase-2,-3, and -6, may be caused by the upregulation of the respective microRNA molecules. Increased expression of genes encoding specific caspases may induce inflammatory processes, as well as trigger apoptosis. Furthermore, the proapoptotic activity of caspases may be enhanced by miRNA molecules, which exhibit proapoptotic function. The overexpression of such miRNAs was observed in our study.
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http://dx.doi.org/10.1159/000494166DOI Listing
November 2018

HMGA2 as a functional antagonist of PARP1 inhibitors in tumor cells.

Mol Oncol 2019 02 28;13(2):153-170. Epub 2018 Nov 28.

Department of Human Anatomy and Cell Science, Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba, Winnipeg, Canada.

Poly(ADP-ribose) polymerase 1 inhibitors alone or in combination with DNA damaging agents are promising clinical drugs in the treatment of cancer. However, there is a need to understand the molecular mechanisms of resistance to PARP1 inhibitors. Expression of HMGA2 in cancer is associated with poor prognosis for patients. Here, we investigated the novel relationship between HMGA2 and PARP1 in DNA damage-induced PARP1 activity. We used human triple-negative breast cancer and fibrosarcoma cell lines to demonstrate that HMGA2 colocalizes and interacts with PARP1. High cellular HMGA2 levels correlated with increased DNA damage-induced PARP1 activity, which was dependent on functional DNA-binding AT-hook domains of HMGA2. HMGA2 inhibited PARP1 trapping to DNA and counteracted the cytotoxic effect of PARP inhibitors. Consequently, HMGA2 decreased caspase 3/7 induction and increased cell survival upon treatment with the alkylating methyl methanesulfonate alone or in combination with the PARP inhibitor AZD2281 (olaparib). HMGA2 increased mitochondrial oxygen consumption rate and spare respiratory capacity and increased NAMPT levels, suggesting metabolic support for enhanced PARP1 activity upon DNA damage. Our data showed that expression of HMGA2 in cancer cells reduces sensitivity to PARP inhibitors and suggests that targeting HMGA2 in combination with PARP inhibition may be a promising new therapeutic approach.
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http://dx.doi.org/10.1002/1878-0261.12390DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6360374PMC
February 2019

LAPTM4B gene polymorphism augments the risk of cancer: Evidence from an updated meta-analysis.

J Cell Mol Med 2018 12 25;22(12):6396-6400. Epub 2018 Sep 25.

Department of Molecular Biology, School of Pharmacy with the Division of Laboratory Medicine in Sosnowiec, Medical University of Silesia in Katowice, Katowice, Poland.

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http://dx.doi.org/10.1111/jcmm.13896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6237586PMC
December 2018

Association of PDCD6 polymorphisms with the risk of cancer: Evidence from a meta-analysis.

Oncotarget 2018 May 15;9(37):24857-24868. Epub 2018 May 15.

Department of Human Anatomy and Cell Science, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.

This study was designed to evaluate the relationship between Programmed cell death protein 6 (PDCD6) polymorphisms and cancer susceptibility. The online databases were searched for relevant case-control studies published up to November 2017. Review Manage (RevMan) 5.3 was used to conduct the statistical analysis. The pooled odds ratio (OR) with its 95% confidence interval (CI) was employed to calculate the strength of association. Overall, our results indicate that PDCD6 rs3756712 T>G polymorphism was significantly associated with decreased risk of cancer under codominant (OR = 0.82, 95%CI = 0.70-0.96, = 0.01, TG vs TT; OR = 0.53, 95%CI = 0.39-0.72, < 0.0001, GG vs TT), dominant (OR = 0.76, 95%CI = 0.66-0.89, = 0.0004, TG+GG vs TT), recessive (OR = 0.57, 95%CI = 0.43-0.78, = 0.0003, GG vs TT+TG), and allele (OR = 0.76, 95%CI = 0.67-0.86, < 0.00001, G vs T) genetic model. The finding did not support an association between rs4957014 T>G polymorphism of PDCD6, and different cancers risk.
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http://dx.doi.org/10.18632/oncotarget.25324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5973848PMC
May 2018

Structure and properties of slow-resorbing nanofibers obtained by (co-axial) electrospinning as tissue scaffolds in regenerative medicine.

PeerJ 2017 18;5:e4125. Epub 2017 Dec 18.

Małopolska Center of Biotechnology, Kraków, Poland.

With the rapid advancement of regenerative medicine technologies, there is an urgent need for the development of new, cell-friendly techniques for obtaining nanofibers-the raw material for an artificial extracellular matrix production. We investigated the structure and properties of PCL nanofibers, PCL/PCL core-shell type nanofibers, as well as PCL/PCL nanofibres prepared by electrospinning. For the production of the fiber variants, a 5-10% solution of polycaprolactone (PCL) (M = 70,000-90,000), dissolved in a mixture of formic acid and acetic acid at a ratio of 70:30 m/m was used. In order to obtain fibers containing PCL 1% of silver nanoparticles was added. The electrospin was conducted using the above-described solutions at the electrostatic field. The subsequent bio-analysis shows that synthesis of core-shell nanofibers PCL/PCL, and the silver-doped variant nanofiber core shell PCL/PCL, by using organic acids as solvents, is a robust technique. Furthermore, the incorporation of silver nanoparticles into PCL/PCL makes such nanofibers toxic to model microbes without compromising its biocompatibility. Nanofibers obtained such way may then be used in regenerative medicine, for the preparation of extracellular scaffolds: (i) for controlled bone regeneration due to the long decay time of the PCL, (ii) as bioscaffolds for generation of other types of artificial tissues, (iii) and as carriers of nanocapsules for local drug delivery. Furthermore, the used solvents are significantly less toxic than the solvents for polycaprolactone currently commonly used in electrospin, like for example chloroform (CHCl), methanol (CHOH), dimethylformamide (CHNO) or tetrahydrofuran (CHO), hence the presented here electrospin technique may allow for the production of multilayer nanofibres more suitable for the use in medical field.
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http://dx.doi.org/10.7717/peerj.4125DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5738967PMC
December 2017

Impact of Antibiotics on the Proliferation and Differentiation of Human Adipose-Derived Mesenchymal Stem Cells.

Int J Mol Sci 2017 11 24;18(12). Epub 2017 Nov 24.

Małopolska Centre of Biotechnology, Jagiellonian University, Gronostajowa 7A str., 30-387 Krakow, Poland

Adipose tissue is a promising source of mesenchymal stem cells. Their potential to differentiate and regenerate other types of tissues may be affected by several factors. This may be due to in vitro cell-culture conditions, especially the supplementation with antibiotics. The aim of our study was to evaluate the effects of a penicillin-streptomycin mixture (PS), amphotericin B (AmB), a complex of AmB with copper (II) ions (AmB-Cu) and various combinations of these antibiotics on the proliferation and differentiation of adipose-derived stem cells in vitro. Normal human adipose-derived stem cells (ADSC, Lonza) were routinely maintained in a Dulbecco's Modified Eagle Medium (DMEM) that was either supplemented with selected antibiotics or without antibiotics. The ADSC that were used for the experiment were at the second passage. The effect of antibiotics on proliferation was analyzed using the 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) and sulforhodamine-B (SRB) tests. Differentiation was evaluated based on Alizarin Red staining, Oil Red O staining and determination of the expression of ADSC, osteoblast and adipocyte markers by real-time RT-qPCR. The obtained results indicate that the influence of antibiotics on adipose-derived stem cells depends on the duration of exposure and on the combination of applied compounds. We show that antibiotics alter the proliferation of cells and also promote natural osteogenesis, and adipogenesis, and that this effect is also noticeable in stimulated osteogenesis.
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http://dx.doi.org/10.3390/ijms18122522DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5751125PMC
November 2017

Transdifferentiation and reprogramming: Overview of the processes, their similarities and differences.

Biochim Biophys Acta Mol Cell Res 2017 Jul 28;1864(7):1359-1369. Epub 2017 Apr 28.

Małopolska Centre of Biotechnology, Jagiellonian University, Gronostajowa 7A str., 30-387 Krakow, Poland. Electronic address:

Reprogramming, or generation of induced pluripotent stem (iPS) cells (functionally similar to embryonic stem cells or ES cells) by the use of transcription factors (typically: Oct3/4, Sox2, c-Myc, Klf4) called "Yamanaka factors" (OSKM), has revolutionized regenerative medicine. However, factors used to induce stemness are also overexpressed in cancer. Both, ES cells and iPS cells cause teratoma formation when injected to tissues. This raises a safety concern for therapies based on iPS derivates. Transdifferentiation (lineage reprogramming, or -conversion), is a process in which one mature, specialized cell type changes into another without entering a pluripotent state. This process involves an ectopic expression of transcription factors and/or other stimuli. Unlike in the case of reprogramming, tissues obtained by this method do not carry the risk of subsequent teratomagenesis.
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http://dx.doi.org/10.1016/j.bbamcr.2017.04.017DOI Listing
July 2017

Human Gyrovirus-Apoptin Interferes with the Cell Cycle and Induces G2/M Arrest Prior to Apoptosis.

Arch Immunol Ther Exp (Warsz) 2017 Dec 6;65(6):545-552. Epub 2017 Apr 6.

ENT Department, School of Medicine, Medical University of Silesia in Katowice, Katowice, Poland.

The human gyrovirus-Apoptin (HGyv-Apoptin) is a protein that gained attention because it is selectively cytotoxic toward cancer cells. In this study, we have investigated the effect of HGyv-Apoptin on cell cycle progression of cancer cells. We also compared HGyv-Apoptin's action to its homologue chicken anemia virus Apoptin (CAV-Apoptin). We show that HGyv-Apoptin induces G2/M arrest in cancer cells. This is at least in part due to the fact that HGyv-Apoptin induces an abnormal spindle formation in mitotic cells that do not progress properly throughout the cell cycle. HGyv-Apoptin most likely inhibits APC function leading to a sustained cyclin-B1-expression. These results indicate that HGyv-Apoptin has a similar mechanism of action as its homolog CAV-Apoptin and further supports its cancer therapeutic potential.
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http://dx.doi.org/10.1007/s00005-017-0464-8DOI Listing
December 2017

New frontiers in the treatment of colorectal cancer: Autophagy and the unfolded protein response as promising targets.

Autophagy 2017 May 23;13(5):781-819. Epub 2017 Feb 23.

b Department of Human Anatomy and Cell Science , Rady Faculty of Health Sciences, Max Rady College of Medicine, University of Manitoba , Winnipeg , MB , Canada.

Colorectal cancer (CRC), despite numerous therapeutic and screening attempts, still remains a major life-threatening malignancy. CRC etiology entails both genetic and environmental factors. Macroautophagy/autophagy and the unfolded protein response (UPR) are fundamental mechanisms involved in the regulation of cellular responses to environmental and genetic stresses. Both pathways are interconnected and regulate cellular responses to apoptotic stimuli. In this review, we address the epidemiology and risk factors of CRC, including genetic mutations leading to the occurrence of the disease. Next, we discuss mutations of genes related to autophagy and the UPR in CRC. Then, we discuss how autophagy and the UPR are involved in the regulation of CRC and how they associate with obesity and inflammatory responses in CRC. Finally, we provide perspectives for the modulation of autophagy and the UPR as new therapeutic options for CRC treatment.
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http://dx.doi.org/10.1080/15548627.2017.1290751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5446063PMC
May 2017