Publications by authors named "Sepideh Zununi Vahed"

86 Publications

Host Serine Proteases: A Potential Targeted Therapy for COVID-19 and Influenza.

Front Mol Biosci 2021 30;8:725528. Epub 2021 Aug 30.

Kidney Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.

The ongoing pandemic illustrates limited therapeutic options for controlling SARS-CoV-2 infections, calling a need for additional therapeutic targets. The viral spike S glycoprotein binds to the human receptor angiotensin-converting enzyme 2 (ACE2) and then is activated by the host proteases. Based on the accessibility of the cellular proteases needed for SARS-S activation, SARS-CoV-2 entrance and activation can be mediated by endosomal (such as cathepsin L) and non-endosomal pathways. Evidence indicates that in the non-endosomal pathway, the viral S protein is cleaved by the furin enzyme in infected host cells. To help the virus enter efficiently, the S protein is further activated by the serine protease 2 (TMPRSS2), provided that the S has been cleaved by furin previously. In this review, important roles for host proteases within host cells will be outlined in SARS-CoV-2 infection and antiviral therapeutic strategies will be highlighted. Although there are at least five highly effective vaccines at this time, the appearance of the new viral mutations demands the development of therapeutic agents. Targeted inhibition of host proteases can be used as a therapeutic approach for viral infection.
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http://dx.doi.org/10.3389/fmolb.2021.725528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8435734PMC
August 2021

An association between incontinence and antipsychotic drugs: A systematic review.

Biomed Pharmacother 2021 Oct 12;142:112027. Epub 2021 Aug 12.

Student Research Committee, Alborz University of Medical Sciences, Karaj, Iran. Electronic address:

To date, due to the increasing prevalence of psychiatric diseases, the use of antipsychotic drugs has expanded. One of the proven side effects of these drugs is incontinence. Treatment of this complication improves the quality of life in these patients, increases self-confidence, and betters cope with their psychiatric illness. The exact mechanism of this side effect is not fully understood, but various methods have been used experimentally to deal with it. Strategies such as behavior therapy, discontinuation or change of drugs, reducing the dose of drugs, and adding drugs with less incontinence have been used. Each of these methods and studies has different results that need to be summarized to make optimal use of them. Since most of these reports are case reports with a low statistical population, our study has systematically reviewed these studies to find a comprehensive model to deal with this complication.
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http://dx.doi.org/10.1016/j.biopha.2021.112027DOI Listing
October 2021

Targeting Mitochondrial Biogenesis with Polyphenol Compounds.

Oxid Med Cell Longev 2021 12;2021:4946711. Epub 2021 Jul 12.

Pharmacology and Toxicology Department, Maragheh University of Medical Sciences, Maragheh, Iran.

Appropriate mitochondrial physiology is an essential for health and survival. Cells have developed unique mechanisms to adapt to stress circumstances and changes in metabolic demands, by meditating mitochondrial function and number. In this context, sufficient mitochondrial biogenesis is necessary for efficient cell function and haemostasis, which is dependent on the regulation of ATP generation and maintenance of mitochondrial DNA (mtDNA). These procedures play a primary role in the processes of inflammation, aging, cancer, metabolic diseases, and neurodegeneration. Polyphenols have been considered as the main components of plants, fruits, and natural extracts with proven therapeutic effects during the time. These components regulate the intracellular pathways of mitochondrial biogenesis. Therefore, the current review is aimed at representing an updated review which determines the effects of different natural polyphenol compounds from various plant kingdoms on modulating signaling pathways of mitochondrial biogenesis that could be a promising alternative for the treatment of several disorders.
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http://dx.doi.org/10.1155/2021/4946711DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8289611PMC
July 2021

Perturbation of miR-146b and relevant inflammatory elements in esophageal carcinoma patients supports an immune downregulatory mechanism.

Pathol Res Pract 2021 Sep 20;225:153560. Epub 2021 Jul 20.

Women's Reproductive Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. Electronic address:

Background: Esophageal Cancer is known as one of the deadliest cancers worldwide with the squamous cell carcinoma (ESCC) being the predominant subtype. There is a growing body of evidence linking the dysregulated microRNA (miRNA) pathway of immune cells to the progression of several tumors. In a previous study, we investigated molecular alterations pertaining to miR-146a and some components of NF-kB signaling pathway and proposed a possible immune downregulatory mechanism in peripheral blood mononuclear cells (PBMCs) of ESCC patients. Here, we further scrutinized other components of this pathway by evaluating PBMC levels of miR-146b, TLR4, IL10, and TNFA.

Methods: Gene expressions were quantified using RT-qPCR assays. To prevent the vulnerability of results to the expression instability of reference genes, nine additional transcripts were quantified, and stable reference genes for normalizing qPCR data were identified using the NormFinder and the geNorm algorithms. The efficiency-corrected normalized relative quantity values were used to compare gene expressions among study groups.

Results: The PBMC expression of miR-146b and TNFA was downregulated in ESCC patients as compared to healthy subjects. While the level of TLR4 was not different among the study groups, the PBMC level of IL10 was upregulated in ESCC patients. Logistic regression analyses coupled with the ROC curve and cross-validation analysis suggested that PBMC expression may serve as potential candidate biomarker for discriminating ESCC patients from healthy subjects.

Conclusion: The present findings, in line with our previous report, propose a particular gene expression pattern in PBMCs of ESCC patients, providing evidence in support of an immune downregulatory mechanism.
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http://dx.doi.org/10.1016/j.prp.2021.153560DOI Listing
September 2021

The clinical significance of the glucocorticoid receptors: Genetics and epigenetics.

J Steroid Biochem Mol Biol 2021 Jul 16;213:105952. Epub 2021 Jul 16.

Kidney Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. Electronic address:

The impacts of glucocorticoids (GCs) are mainly mediated by a nuclear receptor (GR) existing in almost every tissue. The GR regulates a wide range of physiological functions, including inflammation, cell metabolism, and differentiation playing a major role in cellular responses to GCs and stress. Therefore, the dysregulation or disruption of GR can cause deficiencies in the adaptation to stress and the preservation of homeostasis. The number of GR polymorphisms associated with different diseases has been mounting per year. Tackling these clinical complications obliges a comprehensive understanding of the molecular network action of GCs at the level of the GR structure and its signaling pathways. Beyond genetic variation in the GR gene, epigenetic changes can enhance our understanding of causal factors involved in the development of diseases and identifying biomarkers. In this review, we highlight the relationships of GC receptor gene polymorphisms and epigenetics with different diseases.
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http://dx.doi.org/10.1016/j.jsbmb.2021.105952DOI Listing
July 2021

The Impact of Intravenous Iron Supplementation on Hematinic Parameters and Erythropoietin Requirements in Hemodialysis Patients.

Adv Ther 2021 08 12;38(8):4413-4424. Epub 2021 Jul 12.

Kidney Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.

Introduction: Anemia is one of the most common complications of chronic kidney disease (CKD). As a result of the side effects of high doses of recombinant human erythropoietin (rhEPO) and the differences in the standard dose of the injectable iron, this study aimed to evaluate the effect of high and low intravenous iron supplementation on hematinic parameters and EPO requirements in patients under hemodialysis.

Methods: This multicenter, randomized, double-blind clinical trial was conducted on 60 patients with CKD admitted to Sina and 29 Bahman hospitals in Tabriz, Iran in 2019-2020 to undergo hemodialysis. In the two studied groups, low (100 mg/week) and high (400 mg/week) doses of iron were administered and subjects were followed up for 6 months. The incidence of acute myocardial ischemia, stroke, and mortality during 6 months was recorded.

Results: The required rhEPO dosage (mg/week) to maintain hemoglobin levels between 10 and 12 g/dL in the high-dose iron group was significantly decreased during the follow-up period (52,129.03 ± 23,810 vs. 45,760 ± 20,978.71, P ≤ 0.028). Transferrin saturation (TSAT) index had a significant upward trend after iron injection and significant correlations with the serum levels of Fe (r ≥ 0.353, P ≤ 0.007), ferritin (r ≥ 0.315, P ≤ 0.016), and total iron binding capacity (r ≥ 0.219, P < 0.050) during the follow-up period in the studied groups.

Conclusion: High-dose intravenous iron (400 mg/week) can reduce the mean dose of rhEPO requirements and increase the TSAT index over a period of 6 months in hemodialysis patients. High-dose IV iron administration can decrease cardiovascular events in hemodialysis patients with iron deficiency anemia.
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http://dx.doi.org/10.1007/s12325-021-01826-3DOI Listing
August 2021

Thrombotic microangiopathy during pregnancy.

Microvasc Res 2021 Nov 9;138:104226. Epub 2021 Jul 9.

Kidney Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. Electronic address:

Pregnancy is a high-risk time for the development of different kinds of thrombotic microangiopathy (TMA). Three major syndromes including TTP (thrombotic thrombocytopenic purpura), PE/HELLP (preeclampsia/hemolysis, elevated liver function tests, low platelets), and aHUS (atypical hemolytic- uremic syndrome) should be sought in pregnancy-TMA. These severe disorders share multiple clinical features and overlaps and even the coexistence of more than one pathologic mechanism. Each of these disorders finally ends in endothelial damage and fibrin thrombi formation within the microcirculation that fragments RBCs (schystocytes), aggregates platelets, and creates ischemic injury in the targeted organs i.e.; kidney and brain. Although the mechanisms of these severe disorders have been revealed, pregnancy-related TMA still interfaces with diagnostic and therapeutic challenges. Here, we highlight the current knowledge of diagnosis and management of these complications during pregnancy.
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http://dx.doi.org/10.1016/j.mvr.2021.104226DOI Listing
November 2021

Podocyte-derived microparticles in IgA nephropathy.

Biomed Pharmacother 2021 Sep 5;141:111891. Epub 2021 Jul 5.

Kidney Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. Electronic address:

Microparticles are a general term for different types of cell plasma membrane-originated vesicles that are released into the extracellular environment. The paracrine action of these nano-sized vesicles is crucial for intercellular communications through the transfer of diverse lipids, cytosolic proteins, RNA as well as microRNAs. The progression of different diseases influences the composition, occurrence, and functions of these cell-derived particles. Podocyte injury has been shown to have an important role in the pathophysiology of many glomerular diseases including IgA nephropathy (IgAN). This review would focus on the possible potential of podocyte-derived microparticles detected in urine to be used as a diagnostic tool in IgAN.
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http://dx.doi.org/10.1016/j.biopha.2021.111891DOI Listing
September 2021

Critical roles of microRNA-196 in normal physiology and non-malignant diseases: Diagnostic and therapeutic implications.

Exp Mol Pathol 2021 Jun 21;122:104664. Epub 2021 Jun 21.

Women's Reproductive Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. Electronic address:

MicroRNAs (miRNAs) have emerged as a critical component of regulatory networks that modulate and fine-tune gene expression in a post-transcriptional manner. The microRNA-196 family is encoded by three loci in the human genome, namely hsa-mir-196a-1, hsa-mir-196a-2, and hsa-mir-196b. Increasing evidence supports the roles of different components of this miRNA family in regulating key cellular processes during differentiation and development, ranging from inflammation and differentiation of stem cells to limb development and remodeling and structure of adipose tissue. This review first discusses about the genomic context and regulation of this miRNA family and then take a bird's eye view on the updated list of its target genes and their biological processes to obtain insights about various functions played by members of the microRNA-196 family. We then describe evidence supporting the involvement of the human microRNA-196 family in regulating critical cellular processes both in physiological and non-malignant inflammatory conditions, highlighting recent seminal findings that carry implications for developing novel therapeutic or diagnostic strategies.
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http://dx.doi.org/10.1016/j.yexmp.2021.104664DOI Listing
June 2021

Application of Advanced Nanomaterials for Kidney Failure Treatment and Regeneration.

Materials (Basel) 2021 May 29;14(11). Epub 2021 May 29.

Pharmaceutical Analysis Research Center, Tabriz University of Medical Sciences, Tabriz 5166614756, Iran.

The implementation of nanomedicine not only provides enhanced drug solubility and reduced off-target adverse effects, but also offers novel theranostic approaches in clinical practice. The increasing number of studies on the application of nanomaterials in kidney therapies has provided hope in a more efficient strategy for the treatment of renal diseases. The combination of biotechnology, material science and nanotechnology has rapidly gained momentum in the realm of therapeutic medicine. The establishment of the bedrock of this emerging field has been initiated and an exponential progress is observed which might significantly improve the quality of human life. In this context, several approaches based on nanomaterials have been applied in the treatment and regeneration of renal tissue. The presented review article in detail describes novel strategies for renal failure treatment with the use of various nanomaterials (including carbon nanotubes, nanofibrous membranes), mesenchymal stem cells-derived nanovesicles, and nanomaterial-based adsorbents and membranes that are used in wearable blood purification systems and synthetic kidneys.
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http://dx.doi.org/10.3390/ma14112939DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8198057PMC
May 2021

Vitamin D Receptor and Vitamin D Binding Protein Gene Polymorphisms Are Associated with Renal Allograft Outcome.

Nutrients 2021 Mar 27;13(4). Epub 2021 Mar 27.

Center of Experimental Orthopaedics, Saarland University Medical Center, D-66421 Homburg, Germany.

Vitamin D deficiency has adverse effects on renal allograft outcomes, and polymorphisms of genes encoding vitamin D-binding protein (VDBP) and vitamin D receptor (VDR) are defined to play a role in these conditions. The goal of the current investigation was to evaluate the connection between those polymorphisms with acute rejection, viral infection history, and recipients' vitamin D status. In this study, 115 kidney transplant recipients and 100 healthy individuals were included. VDR polymorphisms including I (rs2228570), (rs7975232), (rs1544410), as well as VDBP (rs7040) polymorphisms were studied using high resolution melting (PCR-HRM) analysis among the studied groups. The frequency of G allele in rs7975232 polymorphism in the kidney transplant recipients was 0.63 times lower than healthy individuals ( = 0.026). Further, the G allele frequency in VDBP rs7040 polymorphism was significantly lower in patients with allograft rejection ( = 0.002). Considering the incidence of viral infection, significant differences were identified between the frequencies of VDR I (OR = 2.035; 95% CI 1.06-2.89, = 0.030) and VDBP rs7040 (OR = 0.40; 95% CI 0.24-0.67, < 0.001) T alleles in the studied groups. Moreover, the VDBP rs7040 GG genotype distribution was low in the recipients with a history of viral infection ( = 0.004). VDR (I) and VDBP (rs7040) alleles and their genotype distribution are significantly associated with allograft outcomes including allograft rejection and viral infection in the studied population.
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http://dx.doi.org/10.3390/nu13041101DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8067077PMC
March 2021

Antimicrobial and antibiofilm activities of meropenem loaded-mesoporous silica nanoparticles against carbapenem-resistant .

J Biomater Appl 2021 Mar 15:8853282211003848. Epub 2021 Mar 15.

Dental and Periodontal Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.

The aims of the present study were the determination of antimicrobial and antibiofilm effects of meropenem-loaded mesoporous silica nanoparticles (MSNs) on carbapenem resistant () and cytotoxicity properties . The meropenem-loaded MSNs had shown antibacterial and biofilm inhibitory activities on all isolates at different levels lower than MICs and BICs of meropenem. The viability of HC-04 cells treated with serial concentrations as MICs and BICs of meropenem-loaded MSNs was 92-100%. According to the obtained results, meropenem-loaded MSNs display the significant antibacterial and antibiofilm effects against carbapenem resistant and biofilm forming and low cell toxicity . Then, the prepared system can be an appropriate option for the delivery of carbapenem for further evaluation assays.
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http://dx.doi.org/10.1177/08853282211003848DOI Listing
March 2021

A Comprehensive Review of Detection Methods for SARS-CoV-2.

Microorganisms 2021 Jan 22;9(2). Epub 2021 Jan 22.

Center of Experimental Orthopaedics, Saarland University Medical Center, D-66421 Homburg/Saar, Germany.

Recently, the outbreak of the coronavirus disease 2019 (COVID-19), caused by the SARS-CoV-2 virus, in China and its subsequent spread across the world has caused numerous infections and deaths and disrupted normal social activity. Presently, various techniques are used for the diagnosis of SARS-CoV-2 infection, with various advantages and weaknesses to each. In this paper, we summarize promising methods, such as reverse transcription-polymerase chain reaction (RT-PCR), serological testing, point-of-care testing, smartphone surveillance of infectious diseases, nanotechnology-based approaches, biosensors, amplicon-based metagenomic sequencing, smartphone, and wastewater-based epidemiology (WBE) that can also be utilized for the detection of SARS-CoV-2. In addition, we discuss principles, advantages, and disadvantages of these detection methods, and highlight the potential methods for the development of additional techniques and products for early and fast detection of SARS-CoV-2.
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http://dx.doi.org/10.3390/microorganisms9020232DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7911200PMC
January 2021

Tightly controlled response to oxidative stress; an important factor in the tolerance of Bacteroides fragilis.

Res Microbiol 2021 Mar 21;172(2):103798. Epub 2021 Jan 21.

Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Microbiology Department, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran. Electronic address:

The exposure of Bacteroides fragilis to highly oxygenated tissues induces an oxidative stress due to a shift from the reduced condition of the gastrointestinal tract to an aerobic environment of host tissues. The potent and effective responses to reactive oxygen species (ROS) make the B. fragilis tolerant to atmospheric oxygen for several days. The response to oxidative stress in B. fragilis is a complicated event that is induced and regulated by different agents. In this review, we will focus on the B. fragilis response to oxidative stress and present an overview of the regulators of responses to oxidative stress in this bacterium.
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http://dx.doi.org/10.1016/j.resmic.2021.103798DOI Listing
March 2021

Dysregulated levels of glycogen synthase kinase-3β (GSK-3β) and miR-135 in peripheral blood samples of cases with nephrotic syndrome.

PeerJ 2020 16;8:e10377. Epub 2020 Dec 16.

Center of Experimental Orthopaedics, Universität des Saarlandes, Homburg/Saar, Germany.

Background: Glycogen synthase kinase-3 (GSK-3β) is a serine/threonine kinase with multifunctions in various physiological procedures. Aberrant level of GSK-3β in kidney cells has a harmful role in podocyte injury.

Methods: In this article, the expression levels of GSK-3β and one of its upstream regulators, miR-135a-5p, were measured in peripheral blood mononuclear cells (PBMCs) of cases with the most common types of nephrotic syndrome (NS); focal segmental glomerulosclerosis (FSGS) and membranous glomerulonephritis (MGN). In so doing, fifty-two cases along with twenty-four healthy controls were included based on the strict criteria.

Results: Levels of GSK-3β mRNA and miR-135 were measured with quantitative real-time PCR. There were statistically significant increases in GSK-3β expression level in NS ( = 0.001), MGN ( = 0.002), and FSGS ( = 0.015) groups compared to the control group. Dysregulated levels of miR-135a-5p in PBMCs was not significant between the studied groups. Moreover, a significant decrease was observed in the expression level of miR-135a-5p in the plasma of patients with NS ( = 0.020), MGN ( = 0.040), and FSGS ( = 0.046) compared to the control group. ROC curve analysis approved a diagnostic power of GSK-3β in discriminating patients from healthy controls (AUC: 0.72,  = 0.002) with high sensitivity and specificity.

Conclusions: Dysregulated levels of GSK-3β and its regulator miR-135a may participate in the pathogenesis of NS with different etiology. Therefore, more research is needed for understanding the relationship between them.
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http://dx.doi.org/10.7717/peerj.10377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7749650PMC
December 2020

Protective effects of Gamma Oryzanol on distant organs after kidney ischemia-reperfusion in rats: A focus on liver protection.

Hum Exp Toxicol 2021 Jun 16;40(6):1022-1030. Epub 2020 Dec 16.

Kidney Research Center, 48432Tabriz University of Medical Sciences, Tabriz, Iran.

Background: Acute kidney injury (AKI) is the main clinical concern resulted from ischemia-reperfusion injury (IRI). Ample clinical data indicates that AKI is associated with distant organ dysfunctions and poor patients' outcomes. Oxidative stress and inflammation have a critical role in the pathogenesis of organ injuries following IRI. The objectives of this study were to determine the impact of Gamma Oryzanol (GO), extracted from rice bran oil, on distant organs in rats after IRI.

Methods: Twelve out of 24 Wistar rats were treated by one dosage of GO (100mg/kg) 1 h before I/R induction through both oral gavage and intraperitoneal injection. Then, the AKI model rats were induced by IRI. Oxidative stress and antioxidant protein levels were assessed in the brain, heart, and liver tissues in the experimental groups. Furthermore, the effects of GO on IRI-induced liver dysfunction, apoptosis, and inflammation were measured by Western blot.

Results: GO pretreatment could significantly restore the levels and activity of antioxidant proteins in the brain, heart, and liver tissues (P < 0.05). Moreover, GO pretreatment could decrease the inflammatory cytokine (IL-1, IL-6, and TNF-α) in the liver (P < 0.01). By reducing Bax/Bcl-2 ratio and down-regulating caspase-3, GO could significantly diminish apoptosis in the liver tissue after the kidney I/R (P < 0.01). Additionally, GO could significantly diminish the deterioration of liver function in the kidney I/R model.

Conclusion: GO protects distant organs against renal IRI-induced oxidative stress. Furthermore, it ameliorates liver function and remarkably exerts anti-oxidative, anti-inflammatory, and anti-apoptotic roles in the liver as an important detoxifying organ.
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http://dx.doi.org/10.1177/0960327120979014DOI Listing
June 2021

Nrf-2 as a therapeutic target in acute kidney injury.

Life Sci 2021 Jan 13;264:118581. Epub 2020 Oct 13.

Kidney Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. Electronic address:

Multifaceted cellular pathways exhibit a crucial role in the preservation of homeostasis at the molecular, cellular, and organism levels. One of the most important of these protective cascades is Nuclear factor E2-related factor (Nrf-2) that regulates the expression of several genes responsible for cellular detoxification, antioxidant function, anti-inflammation, drug/xenobiotic transportation, and stress-related factors. A growing body of evidence provides information regarding the protective role of Nrf-2 against a number of kidney diseases. Acute kidney injury (AKI) is a substantial clinical problem that causes a huge social burden. In the kidneys, Nrf-2 exerts a dynamic role in improving the injury triggered by inflammation and oxidative stress. Understanding of the exact molecular mechanisms underlying AKI is vital in order to determine the equilibrium between renal adaptation and malfunction and thus reduce disease progression. This review highlights the role of Nrf-2 targeting against AKI and provides evidence that targeting Nrf-2 to prevail oxidative damage and its consequences might exhibit protective effects in kidney diseases.
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http://dx.doi.org/10.1016/j.lfs.2020.118581DOI Listing
January 2021

Glucocorticoid receptors and their upstream epigenetic regulators in adults with steroid-resistant nephrotic syndrome.

Biofactors 2020 Nov 8;46(6):995-1005. Epub 2020 Oct 8.

Kidney Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.

Steroid-resistant nephrotic syndrome (SRNS) is a clinical challenge with variable clinical outcomes. In patients with SRNS, unsuccessful anti-inflammatory and anti-proteinuric effects of steroids lead to end-stage renal disease (ESRD). Our objective was to define the expression pattern of the glucocorticoid receptors (GR) α and β and their epigenetic regulators (miR-24, miR-30a, and miR-370) in a group of adults with SRNS. In this regard, sixty primary NS patients with focal segmental glomerulosclerosis (FSGS, N = 30) and membranous glomerulonephritis (MGN, N = 30) and also healthy volunteers (N = 24) were enrolled. Real-time PCR was performed to evaluate the expression levels of the aforementioned genes in peripheral blood mononuclear cell (PBMC) samples. Furthermore, an in-silico analysis was performed to understand the signaling pathways and biological procedures that may be targeted by these microRNAs in NS. The decreased and increased levels of GRα and GRβ were not significant, respectively. Statistically significant reduced miR-24 levels were observed between control/MGN (p = .022) and MGN/FSGS (p = .032) groups. Additionally, a decrease was detected in miR-30a between MGN and FSGS (p = .049) groups. There was a significant increase in miR-370 expression level between control and NS groups (p = .029), as well as control/MGN (p = .008), and MGN/FSGS (p = .046). Bioinformatics analysis predicted the possible targets of the studied genes including genes involved in TGF-β, Notch1, and p53 signaling pathways, regulation of gene expression, intracellular signal transduction, negative regulation of response to the stimulus, cell-cell signaling, and cell activation in the pathogenesis of SRNS. Taken all together, dysregulated levels of GRα, GRβ were not attributed to SRNS in our patients. It seems that pharmacokinetics and the genetic variations in podocyte-related genes may be associated with the steroid-resistance in our adult patients with NS rather than GR expression.
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http://dx.doi.org/10.1002/biof.1680DOI Listing
November 2020

Covid-19 and kidney injury: Pathophysiology and molecular mechanisms.

Rev Med Virol 2021 05 6;31(3):e2176. Epub 2020 Oct 6.

Kidney Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.

The novel coronavirus (SARS-CoV-2) has turned into a life-threatening pandemic disease (Covid-19). About 5% of patients with Covid-19 have severe symptoms including septic shock, acute respiratory distress syndrome, and the failure of several organs, while most of them have mild symptoms. Frequently, the kidneys are involved through direct or indirect mechanisms. Kidney involvement mainly manifests itself as proteinuria and acute kidney injury (AKI). The SARS-CoV-2-induced kidney damage is expected to be multifactorial; directly it can infect the kidney podocytes and proximal tubular cells and based on an angiotensin-converting enzyme 2 (ACE2) pathway it can lead to acute tubular necrosis, protein leakage in Bowman's capsule, collapsing glomerulopathy and mitochondrial impairment. The SARS-CoV-2-driven dysregulation of the immune responses including cytokine storm, macrophage activation syndrome, and lymphopenia can be other causes of the AKI. Organ interactions, endothelial dysfunction, hypercoagulability, rhabdomyolysis, and sepsis are other potential mechanisms of AKI. Moreover, lower oxygen delivery to kidney may cause an ischaemic injury. Understanding the fundamental molecular pathways and pathophysiology of kidney injury and AKI in Covid-19 is necessary to develop management strategies and design effective therapies.
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http://dx.doi.org/10.1002/rmv.2176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7646060PMC
May 2021

Dysregulated Expression of miR-146a and Its Associated Immune Effectors in Peripheral Blood Mononuclear Cells of Esophageal Carcinoma Patients.

Immunol Invest 2020 Oct 2:1-11. Epub 2020 Oct 2.

Women's Reproductive Health Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.

Esophageal cancer is one of the least studied aggressive tumors, with the squamous cell carcinoma (ESCC) being the most frequent histological type around the world. Growing evidence has shown that the abnormal expression of microRNAs (miRNAs) in peripheral blood mononuclear cells (PBMCs) is closely related to the pathogenesis of cancers. MiR-146a is a crucial regulator of inflammatory cascades. There is currently no data available regarding the possible role of miR-146a in PBMCs of ESCC patients. We evaluated the expression of miR-146a, as well as its target genes (IRAK1 and TRAF6) and its associated immune effectors (NF-κB1, IL1B, and IL6) in PBMCs of 40 ESCC patients and 50 control subjects. The geometric mean expression of five transcripts was used for normalizing expressions. The PBMC level of miR-146a, as measured by RT-qPCR, was upregulated, whereas levels of its target genes, IRAK1 and TRAF6, were downregulated in ESCC patients. NF-κB1 and IL6 was downregulated in PBMCs of ESCC patients. There was no difference in terms of the IL1B level between patients and the control group. Logistic regression and receiver operating characteristic curve analysis suggested that a model with PBMC levels of either NF-κB1+ IL6 or NF-κB1+ miR-146a as predictors may discriminate ESCC patients from subjects of the control group. Our findings, in the context of the current literature, may suggest a possible downregulatory mechanism of immune responses in PBMCs of ESCC patients.
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http://dx.doi.org/10.1080/08820139.2020.1828454DOI Listing
October 2020

Molecular pathophysiology of acute kidney injury: The role of sirtuins and their interactions with other macromolecular players.

J Cell Physiol 2021 05 28;236(5):3257-3274. Epub 2020 Sep 28.

Kidney Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.

Acute kidney injury (AKI), a rapid drop in kidney function, displays high mortality and morbidity, and its repeated or severe status can shift into chronic kidney disease or even end-stage renal disease. How and which events cause AKI still is controversial. In addition, no specific therapies have emerged that can attenuate AKI or expedite recovery. Some central mechanisms including tubular epithelial cells injury, endothelial injury, renal cell apoptosis, and necrosis signaling cascades, and inflammation have been reported in the pathophysiology of AKI. However, the timing of the activation of each pathway, their interactions, and the hierarchy of these pathways remain unknown. The main molecular mechanisms that might be complicated in this process are the mitochondrial impairment and alteration/shifting of cellular metabolites (e.g., acetyl-CoA and NAD /NADH) acting as cofactors to alter the activities of many enzymes, for instance, sirtuins. Moreover, alteration of mitochondrial structure over the fusion and fission mechanisms can regulate cellular signaling pathways by modifying the rate of reactive oxygen species generation and metabolic activities. The aim of this review is to better understand the underlying pathophysiological and molecular mechanisms of AKI. In addition, we predicted the main other molecular players in interaction with sirtuins as energy/stresses monitoring proteins for the development of future approaches in the treatment or prevention of ischemic AKI.
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http://dx.doi.org/10.1002/jcp.30084DOI Listing
May 2021

To resist and persist: Important factors in the pathogenesis of Bacteroides fragilis.

Microb Pathog 2020 Dec 17;149:104506. Epub 2020 Sep 17.

Infectious and Tropical Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Microbiology Department, School of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran; Students' Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran. Electronic address:

Bacteroides fragilis is a most frequent anaerobic pathogen isolated from human infections, particularly found in the abdominal cavity. Different factors contribute to the pathogenesis and persistence of B. fragilis at infection sites. The knowledge of the virulence factors can provide applicable information for finding alternative options for the antibiotic therapy and treatment of B. fragilis caused infections. Herein, a comprehensive review of the important B. fragilis virulence factors was prepared. In addition to B. fragilis toxin (BFT) and its potential role in the diarrhea and cancer development, some other important virulence factors and characteristics of B. fragilis are described including capsular polysaccharides, iron acquisition, resistance to antimicrobial agents, and survival during the prolonged oxidative stress, quorum sensing, and secretion systems.
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http://dx.doi.org/10.1016/j.micpath.2020.104506DOI Listing
December 2020

Expression Levels of miR-30c and miR-186 in Adult Patients with Membranous Glomerulonephritis and Focal Segmental Glomerulosclerosis.

Int J Nephrol Renovasc Dis 2020 10;13:193-201. Epub 2020 Aug 10.

Kidney Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.

Background: Nephrotic syndrome is a common renal problem with different histopathogenesis. MicroRNAs are reported to be involved in the pathophysiology of the syndrome. The aim of this study was to study the levels of miR-30c and miR-186 in NS patients.

Methods: Sixty patients with primary NS (membranous glomerulonephritis (MGN, N=30) and focal segmental glomerulosclerosis (FSGS, N=30)) and 24 healthy volunteers were included. Expression levels of the miR-30c and miR-186 were evaluated in plasma and peripheral blood mononuclear cell (PBMC) samples of adult patients with NS using real-time PCR. Moreover, an in-silico analysis was performed to understand the signaling pathways and biological procedures that may be regulated by these miRNAs.

Results: In the MGN group, significantly elevated levels of miR-30c and miR-186 were observed in PBMC (P= 0.037) and plasma (P= 0.035) samples, respectively. Moreover, there was a significant increase in miR-30c levels in PBMC samples of the FSGS group when compared to healthy controls (P= 0.004). In ROC curve analysis, combined levels of the studied miRNAs could discriminate cases from controls in plasma and blood cells (AUC≥0.72, P<0.05).

Conclusion: A panel of miRNAs may be potential biomarkers in plasma and PBMCs samples of NS patients with different subclasses. More investigations are needed with a large sample size to validate the diagnostic values of the reported miRNAs.
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http://dx.doi.org/10.2147/IJNRD.S258624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7428378PMC
August 2020

Horizontal Gene Transfer: From Evolutionary Flexibility to Disease Progression.

Front Cell Dev Biol 2020 19;8:229. Epub 2020 May 19.

Faculty of Medicine, Cardinal Stefan Wyszyński University in Warsaw, Warsaw, Poland.

Flexibility in the exchange of genetic material takes place between different organisms of the same or different species. This phenomenon is known to play a key role in the genetic, physiological, and ecological performance of the host. Exchange of genetic materials can cause both beneficial and/or adverse biological consequences. Horizontal gene transfer (HGT) or lateral gene transfer (LGT) as a general mechanism leads to biodiversity and biological innovations in nature. HGT mediators are one of the genetic engineering tools used for selective introduction of desired changes in the genome for gene/cell therapy purposes. HGT, however, is crucial in development, emergence, and recurrence of various human-related diseases, such as cancer, genetic-, metabolic-, and neurodegenerative disorders and can negatively affect the therapeutic outcome by promoting resistant forms or disrupting the performance of genome editing toolkits. Because of the importance of HGT and its vital physio- and pathological roles, here the variety of HGT mechanisms are reviewed, ranging from extracellular vesicles (EVs) and nanotubes in prokaryotes to cell-free DNA and apoptotic bodies in eukaryotes. Next, we argue that HGT plays a role both in the development of useful features and in pathological states associated with emerging and recurrent forms of the disease. A better understanding of the different HGT mediators and their genome-altering effects/potentials may pave the way for the development of more effective therapeutic and diagnostic regimes.
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http://dx.doi.org/10.3389/fcell.2020.00229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7248198PMC
May 2020

Vascular Calcification: An Important Understanding in Nephrology.

Vasc Health Risk Manag 2020 12;16:167-180. Epub 2020 May 12.

Kidney Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.

Vascular calcification (VC) is a life-threatening state in chronic kidney disease (CKD). High cardiovascular mortality and morbidity of CKD cases may root from medial VC promoted by hyperphosphatemia. Vascular calcification is an active, highly regulated, and complex biological process that is mediated by genetics, epigenetics, dysregulated form of matrix mineral metabolism, hormones, and the activation of cellular signaling pathways. Moreover, gut microbiome as a source of uremic toxins (eg, phosphate, advanced glycation end products and indoxyl-sulfate) can be regarded as a potential contributor to VC in CKD. Here, an update on different cellular and molecular processes involved in VC in CKD is discussed to elucidate the probable therapeutic pathways in the future.
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http://dx.doi.org/10.2147/VHRM.S242685DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7229867PMC
June 2020

Dicer and Drosha expression in patients with nephrotic syndrome.

Biofactors 2020 Jul 15;46(4):645-652. Epub 2020 May 15.

Kidney Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.

Podocytes play an essential role in the regulation of glomerular filtration and the appropriate function of the kidney. Podocytes injury is involved in the pathogenesis of nephrotic syndrome (NS), a common renal glomerulus dysfunction characterized by proteinuria. Some in vivo studies in Dicer/Drosha knockout mice indicate the importance of Dicer, Drosha, and microRNAs (miRNAs) in the pathogenesis of NS. In the present study, the expression levels of Dicer and Drosha along with miR-30 family, miR-186, miR-193, and miR-217 were evaluated in peripheral blood mononuclear cell samples of patients with NS (N = 60) using real-time PCR. Dicer expression level in NS patients was significantly upregulated when compared to healthy controls (p = .008). No significant change was observed in the Drosha expression level in the NS group. Upregulated levels of the studied microRNAs were observed in NS group in comparison to controls, the miR-30c-5p (p = .005) and miR-193-3p (p = .041) were statistically significant. In conclusion, dysregulation in expression level of Dicer and Drosha and consequently, alteration in miRNA levels are involved in the pathophysiology of NS.
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http://dx.doi.org/10.1002/biof.1638DOI Listing
July 2020

Medicinal signaling cells: A potential antimicrobial drug store.

J Cell Physiol 2020 11 30;235(11):7731-7746. Epub 2020 Apr 30.

Kidney Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.

Medicinal signaling cells (MSCs) are multipotent cells derived from mammalian bone marrow and periosteum that can be extended in culture. They can keep their ability in vitro to form a variety of mesodermal phenotypes and tissues. Over recent years, there has been great attention over MSCs since they can impact the organ transplantation as well as autoimmune and bacterial diseases. MSCs can secrete different bioactive factors such as growth factors, antimicrobial peptides/proteins and cytokines that can suppress the immune system and prevent infection via direct and indirect mechanisms. Moreover, MSCs are able to increase bacterial clearance in sepsis models by producing antimicrobial peptides such as defensins, cathelicidins, lipocalin and hepcidin. It is the aim of the present review to focus on the antibacterial effector functions of MSCs and their mechanisms of action against the pathogenic microbes.
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http://dx.doi.org/10.1002/jcp.29728DOI Listing
November 2020

Anti-microbial activity of curcumin nanoformulations: New trends and future perspectives.

Phytother Res 2020 Aug 13;34(8):1926-1946. Epub 2020 Mar 13.

Dental and Periodontal Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.

Curcumin has been used in numerous anti-microbial research because of its low side effects and extensive traditional applications. Despite having a wide range of effects, the intrinsic physicochemical characteristics such as low bioavailability, poor water solubility, photodegradation, chemical instability, short half-life and fast metabolism of curcumin derivatives limit their pharmaceutical importance. To overcome these drawbacks and improve the therapeutic ability of curcuminoids, novel approaches have been attempted recently. Nanoparticulate drug delivery systems can increase the efficiency of curcumin in several diseases, especially infectious diseases. These innovative strategies include polymeric nanoparticles, hydrogels, nanoemulsion, nanocomposite, nanofibers, liposome, nanostructured lipid carriers (NLCs), polymeric micelles, quantum dots, polymeric blend films and nanomaterial-based combination of curcumin with other anti-bacterial agents. Integration of curcumin in these delivery systems has displayed to improve their solubility, bioavailability, transmembrane permeability, prolong plasma half-life, long-term stability, target-specific delivery and upgraded the therapeutic effects. In this review paper, a range of in vitro and in vivo studies have been critically discussed to explore the therapeutic viability and pharmaceutical significance of the nano-formulated delivery systems to elevate the anti-bacterial activities of curcumin and its derivatives.
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http://dx.doi.org/10.1002/ptr.6658DOI Listing
August 2020

The Battle of Probiotics and Their Derivatives Against Biofilms.

Infect Drug Resist 2020 26;13:659-672. Epub 2020 Feb 26.

Kidney Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.

Biofilm-related infections have been a major clinical problem and include chronic infections, device-related infections and malfunction of medical devices. Since biofilms are not fully available for the human immune system and antibiotics, they are difficult to eradicate and control; therefore, imposing a global threat to human health. There have been avenues to tackle biofilms largely based on the disruption of their adhesion and maturation. Nowadays, the use of probiotics and their derivatives has gained a growing interest in battling against pathogenic biofilms. In the present review, we have a close look at probiotics with the ultimate objective of inhibiting biofilm formation and maturation. Overall, insights into the mechanisms by which probiotics and their derivatives can be used in the management of biofilm infections would be warranted.
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http://dx.doi.org/10.2147/IDR.S232982DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7049744PMC
February 2020

Pre-Eclampsia: Microbiota possibly playing a role.

Pharmacol Res 2020 05 15;155:104692. Epub 2020 Feb 15.

Kidney Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. Electronic address:

Pre-eclampsia (PE) is a complication of pregnancy that is associated with mortality and morbidity in mothers and fetuses worldwide. Oxygen dysregulation in the placenta, abnormal remodeling of the spiral artery, defective placentation, oxidative stress at the fetal-maternal border, inflammation and angiogenic impairment in the maternal circulation are the main causes of this syndrome. These events result in a systemic and diffuse endothelial cell dysfunction, an essential pathophysiological feature of PE. The impact of bacteria on the multifactorial pathway of PE is the recent focus of scientific inquiry since microbes may cause each of the aforementioned features. Microbes and their derivatives by producing antigens and other inflammatory factors may trigger infection and inflammatory responses. A mother's bacterial communities in the oral cavity, gut, vagina, cervix and uterine along with the placenta and amniotic fluid microbiota may be involved in the development of PE. Here, we review the mechanistic and pathogenic role of bacteria in the development of PE. Then, we highlight the impact of alterations in a set of maternal microbiota (dysbiosis) on the pathogenesis of PE.
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http://dx.doi.org/10.1016/j.phrs.2020.104692DOI Listing
May 2020
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