The impacts of dietary antioxidants on cardiovascular events in hemodialysis patients: An update on the cellular and molecular mechanisms.

Cardiovascular-related complications (CVCs) are the primary cause of death in patients undergoing hemodialysis (HD), accounting for greater than half of all deaths. Beyond traditional risk factors, chronic inflammation, extreme oxidative stress (OS), and endothelial dysfunction emerge as major contributors to accelerated CVCs in HD patients. Ample evidence shows that HD patients are constantly exposed to excessive OS, due to uremic toxins and pro-oxidant molecules that overwhelm the defense antioxidant mechanisms. The present study highlights the efficiency of natural antioxidant supplementation in managing HD-induced inflammation, OS, and consequently CVCs. Moreover, it discusses the underlying molecular mechanisms by which these antioxidants can decrease mitochondrial and endothelial dysfunction and ameliorate CVCs in HD patients. Given the complex nature of OS and its molecular pathways, the utilization of specific antioxidants as a polypharmacotherapy may be necessary for targeting each dysregulated signaling pathway and reducing the burden of CVCs.

An update on Glycerophosphodiester Phosphodiesterases; From Bacteria to Human.

The hydrolysis of deacylated glycerophospholipids into sn-glycerol 3-phosphate and alcohol is facilitated by evolutionarily conserved proteins known as glycerophosphodiester phosphodiesterases (GDPDs). These proteins are crucial for the pathogenicity of bacteria and for bioremediation processes aimed at degrading organophosphorus esters that pose a hazard to both humans and the environment. Additionally, GDPDs are enzymes that respond to multiple nutrients and could potentially serve as candidate genes for addressing deficiencies in zinc, iron, potassium, and especially phosphate in important plants like rice. In mammals, glycerophosphodiesterases (GDEs) play a role in regulating osmolytes, facilitating the biosynthesis of anandamine, contributing to the development of skeletal muscle, promoting the differentiation of neurons and osteoblasts, and influencing pathological states. Due to their capacity to enhance a plant's ability to tolerate various nutrient deficiencies and their potential as pharmaceutical targets in humans, GDPDs have received increased attention in recent times. This review provides an overview of the functions of GDPD families as vital and resilient enzymes that regulate various pathways in bacteria, plants, and humans.

The Possible Association of IL-6R Gene Polymorphisms in the Development of Diabetic Nephropathy.

BACKGROUND: Diabetic nephropathy (DN) is a common complication of type 2 diabetes (T2D). Chronic inflammation and a combination of environmental and genetic factors are involved in the pathogenesis and development of DN. OBJECTIVE: This case-control study aimed to determine the relationship between rs7529229 and rs2228145 polymorphisms of the IL-6R gene with the incidence of nephropathy among T2D patients. METHODS: Fifty-six diabetic patients with nephropathy and 57 T2D patients without nephropathy were included based on inclusion criteria, along with 150 healthy individuals. METHODS: Fifty-six diabetic patients with nephropathy and 57 T2D patients without nephropathy were included based on inclusion criteria, along with 150 healthy individuals. RESULTS: The frequencies of AC and CC genotype distributions of the rs2228145 polymorphism in DN patients were significantly higher than in healthy individuals (24.1 and 9.3% versus 10.7 and 6.7%, respectively, P= 0.02). Moreover, the frequency of allele C was higher in DN patients compared to healthy controls (21.30% versus 12%, P=0.025). However, genotype distribution and allele frequencies of the rs7529229 IL-6R polymorphism in DN patients were not statistically significant in comparison with diabetic patients and healthy individuals (P> 0.05). CONCLUSION: The results showed that the allele and genotype distribution frequencies of rs2228145 IL-6R gene polymorphism in patients with DN were significantly higher than in healthy individuals. Therefore, the presence of this polymorphism may be involved in the development of diabetic nephropathy in this population.

Biofactors regulating mitochondrial function and dynamics in podocytes and podocytopathies.

Podocytes are terminally differentiated kidney cells acting as the main gatekeepers of the glomerular filtration barrier; hence, inhibiting proteinuria. Podocytopathies are classified as kidney diseases caused by podocyte damage. Different genetic and environmental risk factors can cause podocyte damage and death. Recent evidence shows that mitochondrial dysfunction also contributes to podocyte damage. Understanding alterations in mitochondrial metabolism and function in podocytopathies and whether altered mitochondrial homeostasis/dynamics is a cause or effect of podocyte damage are issues that need in-depth studies. This review highlights the roles of mitochondria and their bioenergetics in podocytes. Then, factors/signalings that regulate mitochondria in podocytes are discussed. After that, the role of mitochondrial dysfunction is reviewed in podocyte injury and the development of different podocytopathies. Finally, the mitochondrial therapeutic targets are considered.

Decoding the Possible Molecular Mechanisms in Pediatric Wilms Tumor and Rhabdoid Tumor of the Kidney through Machine Learning Approaches.

Objective: Wilms tumor (WT) and Rhabdoid tumor (RT) are pediatric renal tumors and their differentiation is based on histopathological and molecular analysis. The present study aimed to introduce the panels of mRNAs and microRNAs involved in the pathogenesis of these cancers using deep learning algorithms. Methods: Filter, graph, and association rule mining algorithms were applied to the mRNAs/microRNAs data. Results: Candidate miRNAs and mRNAs with high accuracy (AUC: 97%/93% and 94%/97%, respectively) could differentiate the WT and RT classes in training and test data. Let-7a-2 and C19orf24 were identified in the WT, while miR-199b and RP1-3E10.2 were detected in the RT by analysis of Association Rule Mining. Conclusion: The application of the machine learning methods could identify mRNA/miRNA patterns to discriminate WT from RT. The identified miRNAs/mRNAs panels could offer novel insights into the underlying molecular mechanisms that are responsible for the initiation and development of these cancers. They may provide further insight into the pathogenesis, prognosis, diagnosis, and molecular-targeted therapy in pediatric renal tumors.

The Impact of Single Nucleotide Polymorphisms on the Pharmacokinetics of Tacrolimus in Kidney Allograft Recipients of Northern-West, Iran.

Purpose: Calcineurin inhibitors (CNIs) such as tacrolimus are a major immunosuppressive therapy after renal transplantation, which inhibit cytokine expression. The pharmacokinetics of such drugs is influenced by cytochrome P450 (CYP) enzymes, multi-drug resistance-1 (MDR-1), and C25385T pregnane X receptor (PXR). This study aimed to investigate the impact of single nucleotide polymorphisms (SNP) in these genes on the ratio of tacrolimus level per drug dosage (C/D ratio), acute graft rejection, and viral infections. Methods: Kidney transplantation recipients (n=65) under similar immunosuppressive treatment were included. Amplification refractory mutation systempolymerase chain reaction (ARMS-PCR) method was applied to amplify the loci containing the SNPs of interest. Results: Overall, 65 patients with a male/female ratio of 37/28 were included. The mean age was 38±1.75 years. The variant allele frequencies of CYP3A5*3, MDR-1 C3435T, and PXR C25385T were 95.38, 20.77, and 26.92%, respectively. No significant correlations were found between the studied SNPs and the tacrolimus C/D ratios. However, there was a significant difference in the C/D ratios at 2 and 8 weeks in homozygote CYP3A5 *3/*3 carriers (P=0.015). No significant association was found between the studied polymorphisms and viral infections and acute graft rejection (P>0.05). Conclusion: Homozygote CYP3A5 *3/*3 genotype could influence the tacrolimus metabolism rate (C/D ratio).

Circular RNAs as novel biomarkers in glomerular diseases.

Circular RNAs (circRNAs) regulate gene expression and biological procedures by controlling target genes or downstream pathways by sponging their related miRNA (s). Three types of circRNAs have been identified; exonic circRNAs (ecircRNAs), intronic RNAs (ciRNAs), and exon-intron circRNAs (ElciRNAs). It is clarified that altered levels of circRNAs have dynamic pathological and physiological functions in kidney diseases. Evidence suggests that circRNAs can be considered novel diagnostic biomarkers and therapeutic targets for renal diseases. Glomerulonephritis (GN) is a general term used to refer to a wide range of glomerular diseases. GN is an important cause of chronic kidney diseases. Here, we review the biogenesis of circRNAs, and their molecular and physiological functions in the kidney. Moreover, the dysregulated expression of circRNAs and their biological functions are discussed in primary and secondary glomerulonephritis. Moreover, diagnostic and therapeutic values of circRNAs in distinguishing or treating different types of GN are highlighted.

The effect of Fingolimod on patients with moderate to severe COVID-19.

Hyper-inflammation, cytokine storm, and recruitment of immune cells lead to uncontrollable endothelial cell damage in patients with coronavirus disease 2019 (COVID-19). Sphingosine 1-phosphate (S1P) signaling is needed for endothelial integrity and its decreased serum level is a predictor of clinical severity in COVID-19. In this clinical trial, the effect of Fingolimod, an agonist of S1P, was evaluated on patients with COVID-19. Forty patients with moderate to severe COVID-19 were enrolled and divided into two groups including (1) the control group (n = 21) receiving the national standard regimen for COVID-19 patients and (2) the intervention group (n = 19) that prescribed daily Fingolimod (0.5 mg) for 3 days besides receiving the standard national regimen for COVID-19. The hospitalization period, re-admission rate, intensive care unit (ICU) administration, need for mechanical ventilation, and mortality rate were assessed as primary outcomes in both groups. The results showed that re-admission was significantly decreased in COVID-19 patients who received Fingolimod compared to the controls (p = .04). In addition, the hemoglobin levels of the COVID-19 patients in the intervention group were increased compared to the controls (p = .018). However, no significant differences were found regarding the intubation or mortality rate between the groups (p > .05). Fingolimod could significantly reduce the re-admission rate after hospitalization with COVID-19. Fingolimod may not enhance patients' outcomes with moderate COVID-19. It is necessary to examine these findings in a larger cohort of patients with severe to critical COVID-19.

Dysregulation of immunity in COVID-19 and SLE.

The immune response plays a crucial role in preventing diseases, such as infections. There are two types of immune responses, specific and innate immunity, each of which consists of two components: cellular immunity and humoral immunity. Dysfunction in any immune system component increases the risk of developing certain diseases. Systemic lupus erythematosus (SLE), an autoimmune disease in the human body, develops an immune response against its own components. In these patients, due to underlying immune system disorders and receipt of immunosuppressive drugs, the susceptibility to infections is higher than in the general population and is the single largest cause of mortality in this group. COVID-19 infection, which first appeared in late 2019, has caused several concerns in patients with SLE. However, there is no strong proof of additional risk of developing COVID-19 in patients with SLE, and in some cases, studies have shown less severity of the disease in these individuals. This review paper discusses the immune disorders in SLE and COVID-19.

Evaluating the effect of Edaravone on clinical outcome of patients with severe COVID-19 admitted to ICU: a randomized clinical trial.

Cytokine storm is the most prominent hallmark in patients with coronavirus disease 2019 (COVID-19) that stimulates the free radical storm, both of which induce an overactive immune response during viral infection. We hypothesized that owning to its radical-scavenging and anti-inflammatory properties, Edaravone could reduce multi-organ injury, clinical complications, and mortality in severe COVID-19 cases. This single-center randomized clinical trial was accompanied in the intensive care units (ICUs) of the teaching hospital of Tabriz University of Medical Sciences to evaluate the effect of Edaravone on the outcome of patients with severe COVID-19. Thirty-eight patients admitted to ICU were included and randomized into two control and intervention arms. Patients in the intervention group received 30 mg Edaravone by slow intravenous infusion for three days in addition to receiving national therapy. The primary outcome was the need for intubation, the intubation length, and mortality rate. Secondary endpoints were clinical improvement. Edaravone administration improved the primary outcomes; it decreased the need for endotracheal intubation and mechanical ventilation [10.52% (n = 2) versus 42.1% (n = 8); p = 0.03] and intubation length [3 (1-7) versus 28 (4-28), p = 0.04] compared to control group. Baseline characteristics and laboratory tests were similar between the studied groups. No marked differences were observed in secondary endpoints (p > 0.05). Administration of Edaravone could decrease the need for mechanical ventilation and length of intubation in severe COVID-19 patients admitted to ICU.

Evaluation of telomeric KIR genes and their association with CMV infection in kidney transplant recipients.

Cytomegalovirus (CMV) infection is a common complication after organ transplantation. Despite the immunosuppressed state, natural killer (NK) cells remain the major immune defense cells against viral infections in transplanted patients. The present study aimed at elucidating the correlation between the number of inhibitory and activating genes and the incidence of CMV infection in kidney transplanted recipients. Kidney transplanted recipients including 51 CMV+ and 50 CMV- were genotyped for the presence or absence of 4 activating (KIR2DS1, KIR2DS4, KIR2DS5, KIR3DS1) and 2 inhibitory (KIR3DL1, KIR2DL5a) genes using polymerase chain reaction sequence-specific primers (PCR-SSP) assay. Our results showed that CMV infection occurred in 50.49% of kidney allograft recipients. In addition, there was a significant correlation between the presence of the KIR2DS1 activating gene in the CMV- group compared to the CMV+ group (p = 0.033). The other three activating KIR receptors did not show a correlation with CMV infection. Our results suggest that the prevalence of the KIR activating KIR2DS1 gene may reduce the rate of CMV infection after kidney transplantation in our population.

The Association of Sleep Quality and Vitamin D Levels in Hemodialysis Patients.

BACKGROUND: To date, hemodialysis (HD) is the most common therapy for chronic kidney disease (CKD) patients. However, it causes different complications such as sleep disorders. Sleep regulation is connected to vitamin D; hence, its deficiency might influence the quality and duration of sleep. This study is aimed at evaluating the correlation of sleep quality and vitamin D levels in 80 HD patients. METHODS: This cross-sectional study was performed on 80 hemodialysis patients admitted to 29 Bahman hospitals in Tabriz, Iran. Before beginning of dialysis, serum 25 (OH) D levels were assessed among patients and the sleep patterns and sleep quality of patients were accurately calculated by the Pittsburgh sleep quality index (PSQI) standard questionnaire. RESULTS: Our results showed that 22 HD patients (27.5%) had severe sleep disorders. In addition, it was found that serum levels of vitamin D had significant correlation with sleep quality (r = -0.341, p = 0.002) in general, even after adjusting confounding factors such as calcium (Ca), phosphate (P), and parathyroid hormone (PTH) level. In poor sleepers (PSQI ≤ 5), a negative correlation was observed between the levels of vitamin D and PSQI score (r = -0.397, p = 0.004). PSQI scores in the normal range of PTH (r = -0.377, p = 0.006) and in >600 pg/ml of PTH (r = -0.675, p = 0.011) had a correlation with vitamin D levels. The level of vitamin D was the single independent predictor of sleep efficiency (ß coefficient = -0.386, p = 0.001). CONCLUSION: The present project reported that the positive effect of vitamin D is associated with sleep disorder in HD patients. In future studies, normal levels of Ca and P should be considered along with normal vitamin D levels among the included patients.

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

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.

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

BACKGROUND: Glycogen synthase kinase-3 (GSK-3ß) is a serine/threonine kinase with multifunctions in various physiological procedures. Aberrant level of GSK-3ß in kidney cells has a harmful role in podocyte injury. METHODS: In this article, the expression levels of GSK-3ß 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-3ß mRNA and miR-135 were measured with quantitative real-time PCR. There were statistically significant increases in GSK-3ß expression level in NS (P = 0.001), MGN (P = 0.002), and FSGS (P = 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 (P = 0.020), MGN (P = 0.040), and FSGS (P = 0.046) compared to the control group. ROC curve analysis approved a diagnostic power of GSK-3ß in discriminating patients from healthy controls (AUC: 0.72, P = 0.002) with high sensitivity and specificity. CONCLUSIONS: Dysregulated levels of GSK-3ß 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.

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

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 ß 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 GRß 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-ß, 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, GRß 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.

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

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.

Dicer and Drosha expression in patients with nephrotic syndrome.

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.