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.

The synergistic effects of betanin and radiotherapy in a prostate cancer cell line: an in vitro study.

BACKGROUND: Prostate cancer is among the most common cancers in men with an increasing incidence rate. Radiation therapy (RT) is a therapeutic strategy for the management of prostate cancer after surgery; nonetheless, it has different side effects on neighboring healthy cells/tissues. Moreover, radioresistance has been an increasing phenomenon in the recent years. Therefore, there is an urgent need for the introduction of a safe and effective radiosensitizing agent. Accordingly, the recent trend in the development of novel drugs is accompanied by a push toward natural compounds. Our study evaluated the effects of betanin combined with RT as a potential radiosensitizing agent in the PC-3 cell line. METHODS AND RESULTS: MTT assay was utilized to determine the growth inhibitory impact of betanin. The possible synergistic effect was evaluated with CompuSyn software upon Trypan blue exclusion test. Apoptosis-related gene expression was evaluated via Real-time PCR and the protein expression of P21 was determined using western blotting. A synergistic anticancer effect with an optimal combination index of 0.61 was achieved by treating PC-3 cells with betanin and RT. The results pointed out that betanin synergistically triggered RT-mediated apoptosis and cell cycle arrest through modulating gene and protein expression in comparison with each of the monotherapies. CONCLUSION: These findings shed light on the synergistic antitumor effect of betanin and RT in prostate cancer, indicating the potential use of betanin as a radiosensitizer agent.

Ischemic tubular injury: Oxygen-sensitive signals and metabolic reprogramming.

The kidneys are the most vulnerable organs to severe ischemic insult that results in cellular hypoxia under pathophysiological conditions. Large amounts of oxygen are consumed by the kidneys, mainly to produce energy for tubular reabsorption. Beyond high oxygen demand and the low oxygen supply, different other factors make kidneys vulnerable to ischemia which is deemed to be a major cause of acute kidney injury (AKI). On the other hand, kidneys are capable of sensing and responding to oxygen alternations to evade harms resulting from inadequate oxygen. The hypoxia-inducible factor (HIF) is the main conserved oxygen-sensing mechanism that maintains homeostasis under hypoxia through direct/indirect regulation of several genes that contribute to metabolic adaptation, angiogenesis, energy conservation, erythropoiesis, and so on. In response to oxygen availability, prolyl-hydroxylases (PHDs) control the HIF stability. This review focuses on the oxygen-sensing mechanisms in kidneys, particularly in proximal tubular cells (PTCs) and discusses the molecules involved in ischemic response and metabolic reprogramming. Moreover, the possible roles of non-coding RNAs (microRNAs and long non-coding RNAs) in the development of ischemic AKI are put forward.

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.

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.

Migrasomes and exosomes; different types of messaging vesicles in podocytes.

Podocytes, highly specified kidney epithelial cells, live under several pathological stimuli and stresses during which they adapt themselves to keep homeostasis. Nevertheless, under extreme stress, a complex scenario of podocyte damage and its consequences occur. Podocyte damage causes foot process effacement and their detachment from the glomerular basement membrane, leading to proteinuria. Podocyte-derived extracellular vesicles (pEVs), mainly microparticles and exosomes are considered as signaling mediators of intercellular communication. Recently, it has been shown that throughout the injury-related migration procedure, podocytes are capable of releasing the injury-related migrasomes. Evidence indicates that at the early stages of glomerular disorders, increased levels of pEVs are observed in urine. At the early stage of nephropathy, pEVs especially migrasomes seem to be more sensitive and reliable indicators of podocyte stress and/or damage than proteinuria. This review highlights the current knowledge of pEVs and their values for the diagnosis of different kidney diseases.

Herpes simplex encephalitis following ChAdOx1 nCoV-19 vaccination: a case report and review of the literature.

BACKGROUND: Ever since the administration of early doses of COVID-19 vaccines, instances of adverse effects have been reported. Viral infections, specifically herpes simplex reinfection and coinfections, have been reported following administration of different types of vaccines. To our knowledge, there have not been any reports of herpes simplex encephalitis following administration of any type of COVID-19 vaccine to date. CASE PRESENTATION: In this article intends to report a case of herpes simplex encephalitis in a 27-year-old male patient who was vaccinated with the ChAdOx1 nCoV-19 vaccine. CONCLUSIONS: Our study suggests a possible but very rare side effect of ChAdOx1 nCoV-19 vaccine, which requires immediate medical attention and can lead to devastating consequences if left undiagnosed and untreated.

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

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.

The Role of Cytokines in Nephrotic Syndrome.

Idiopathic nephrotic syndrome (INS) is an important primary glomerular disease characterized by severe proteinuria. Evidence supports a role for T cell dysfunction in the pathogenesis of INS. Glucocorticoids are the primary therapy for INS; however, steroid-resistant NS (SRNS) patients are at a higher risk of drug-induced side effects and harbor poor prognosis. Although the exact mechanism of the resistance is unknown, the imbalances of T helper subtype 1 (Th1), Th2, and regulatory T cells (Tregs) and their cytokines may be involved in the pathogenesis of glucocorticoid responsiveness. Up to now, no confirmed biomarkers have been able to predict SRNS; however, a panel of cytokines may predict responsiveness and identify SRNS patients. Thus, the introduction of distinctive cytokines as novel biomarkers of SRNS enables both preventions of drug-related toxicity and earlier switch to more effective therapies. This review highlights the impacts of T cell population imbalances and their downstream cytokines on response to glucocorticoid responsiveness state in INS.

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.

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

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.

Thrombotic microangiopathy during pregnancy.

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.

How SARS-CoV-2 might affect potassium balance via impairing epithelial sodium channels?

Severe acute respiratory syndrome coronaviruses 2 (SARS-CoV-2) is the causative agent of current coronavirus disease 2019 (COVID-19) pandemic. Electrolyte disorders particularly potassium abnormalities have been repeatedly reported as common clinical manifestations of COVID-19. Here, we discuss how SARS-CoV-2 may affect potassium balance by impairing the activity of epithelial sodium channels (ENaC). The first hypothesis could justify the incidence of hypokalemia. SARS-CoV-2 cell entry through angiotensin-converting enzyme 2 (ACE2) may enhance the activity of renin-angiotensin-aldosterone system (RAAS) classical axis and further leading to over production of aldosterone. Aldosterone is capable of enhancing the activity of ENaC and resulting in potassium loss from epithelial cells. However, type II transmembrane serine protease (TMPRSS2) is able to inhibit the ENaC, but it is utilized in the case of SARS-CoV-2 cell entry, therefore the ENaC remains activated. The second hypothesis describe the incidence of hyperkalemia based on the key role of furin. Furin is necessary for cleaving both SARS-CoV-2 spike protein and ENaC subunits. While the furin is hijacked by the virus, the decreased activity of ENaC would be expected, which causes retention of potassium ions and hyperkalemia. Given that the occurrence of hypokalemia is higher than hyperkalemia in COVID-19 patients, the first hypothesis may have greater impact on potassium levels. Further investigations are warranted to determine the exact role of ENaC in SARS-CoV-2 pathogenesis.

Pre-Eclampsia: Microbiota possibly playing a role.

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.

The Use of Nanomaterials in Tissue Engineering for Cartilage Regeneration; Current Approaches and Future Perspectives.

The repair and regeneration of articular cartilage represent important challenges for orthopedic investigators and surgeons worldwide due to its avascular, aneural structure, cellular arrangement, and dense extracellular structure. Although abundant efforts have been paid to provide tissue-engineered grafts, the use of therapeutically cell-based options for repairing cartilage remains unsolved in the clinic. Merging a clinical perspective with recent progress in nanotechnology can be helpful for developing efficient cartilage replacements. Nanomaterials, < 100 nm structural elements, can control different properties of materials by collecting them at nanometric sizes. The integration of nanomaterials holds promise in developing scaffolds that better simulate the extracellular matrix (ECM) environment of cartilage to enhance the interaction of scaffold with the cells and improve the functionality of the engineered-tissue construct. This technology not only can be used for the healing of focal defects but can also be used for extensive osteoarthritic degenerative alterations in the joint. In this review paper, we will emphasize the recent investigations of articular cartilage repair/regeneration via biomaterials. Also, the application of novel technologies and materials is discussed.

Cell-free microRNA-148a is associated with renal allograft dysfunction: Implication for biomarker discovery.

BACKGROUND: Chronic allograft dysfunction (CAD), the foremost cause of renal graft loss worldwide, is a serious challenge for most of the recipients. As the epigenetic era is emerging, epigenetic biomarkers especially microRNAs (miRNAs) may reflect the current stage of the disease and patient's therapy response. The current study investigated the potential significance of circulating miRNA-148a in predicting the renal graft function. DESIGN AND METHODS: Circulating miRNAs were isolated from 53 plasma samples of recipients with histologically validated interstitial fibrosis and tubular atrophy (IFTA, n = 26), and recipients with stable graft function (SGF, n = 27), and also healthy individuals ( n = 15). The level of miRNA-148a was evaluated by the quantitative polymerase chain reaction (qPCR) and correlated with clinical and histological parameters. RESULTS: Significantly, miRNA-148a decreased in IFTA compared with SGF subjects (P < 0.001). MiRNA-148a levels indicated a significant association with serum creatinine levels ( r = 0.451, P = 0.021) and glomerular filtration rate ( r = -0.520, P = 0.006). MiRNA-148a expression levels could discriminate IFTA cases from SGF individuals with an area under the curve of 0.89 ( P < 0.001), 97% sensitivity, and 72% specificity. A number of predicted targets that might be involved in CAD by miRNA-148a were predicted. CONCLUSION: Plasma cell-free miRNA-148a correlated with renal function and histological grades; therefore, it may be further investigated as a novel noninvasive molecular marker of the progression to IFTA in renal transplant recipients; moreover, the emerging biomarker may become a therapeutic target in the future clinic.

The role of microbiota in the pathogenesis of lupus: Dose it impact lupus nephritis?

Systemic lupus erythematosus (SLE) is a complex, inflammatory, and autoimmune disease triggered by complicated interactions of different factors. A major contributor to morbidity and mortality in SLE is lupus nephritis (LN). To date, the cause of SLE and LN is incompletely understood but a combination of genetic and environmental factors is thought to be involved. In recent years, there have been attempts to consider the intestinal microbial profiles, microbiota, and its role in the pathogenesis of the disease. The composition and elements of gut microbiota have major roles in antibody production, shaping the human B cell repertoire, homeostasis of different populations of helper T cell and Th17:Treg balance, and regulation of the levels of different Th17 cell subpopulations. Disturbance of gut microbiota, called dysbiosis, leads to the development of autoimmunity. To date, few studies have characterized the microbiota composition in SLE. In this review, we will highlight novel findings describing the effect of genetic, epigenetic, and environmental factors on gut microbiota and immune system. Moreover, we will discuss the possible association between SLE and microbiota composition and concerning how its changes may contribute to the onset of SLE and LN. Interest in this area has been grown to consider the microbiome as a potential therapeutic target in future.

TRPC6 and NPHS2 gene variants in adult patients with steroid-resistant nephrotic syndrome in North-West of Iran.

Podocyte gene mutations and their role in the development of nephrotic syndrome (NS) have been reported in some ethnic groups. The aim of this study was to evaluate the presence of possible variants in TRCP6 and NPHS2 (podocin) genes and their association with clinical manifestations in a group of adult patients with steroid resistant nephrotic syndrome (SRNS). All participants including 36 patients with SRNS and 71 healthy volunteers were genotyped using polymerase chain reaction (PCR) and direct sequencing. Whole exons of NPHS2 gene and -254 C > G, -218 C > T, and -361 A > T polymorphisms in the promoter of TRPC6 gene were studied. There were no significant differences in the allele and genotype frequencies of aforementioned TRCP6 polymorphisms between cases and controls (P > 0.05). However, four novel polymorphisms including - 257 T > C, - 266 G > A, - 293 G > C, and - 21 G > A found in the promoter region of TRPC6 gene that may be involved in SRNS in our cohort. In NPHS2 gene, three different polymorphisms in the NPHS2 gene were found in 7 patients with FSGS and none of the previously reported risk polymorphisms was detected in our patients. Podocin related mutations are not too much associated with SRNS in adults, but we should consider the possibility of TRPC6 gene mutation in this population.

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.

Podocyte-specific proteins in urinary extracellular vesicles of patients with IgA nephropathy: Vasorin and ceruloplasmin.

Introduction: Urinary extracellular vesicles (uEVs) can be considered biomarkers of kidney diseases. EVs derived from podocytes may reflect podocyte damage in different glomerular diseases. IgA nephropathy (IgAN) is one of the most common forms of glomerulonephritis (GN) characterized by proteinuria and hematuria. This study aimed to analyze the uEVs of IgAN patients to understand the pathophysiological processes of the disease at the protein level. Methods: Patients with GN [biopsy-proven IgAN (n = 16) and membranous glomerulonephritis (MGN, n = 16)], and healthy controls (n = 16) were included in this study. The uEVs were extracted, characterized, and analyzed to evaluate the protein levels of candidate markers of IgAN, including vasorin precursor, aminopeptidase N, and ceruloplasmin by western-blot analysis. Results: Higher levels of both podocytes and EVs-related proteins were observed in the pooled urine samples of GN patients compared to the healthy controls. In IgAN patients, uEV-protein levels of vasorin were statistically lower while levels of ceruloplasmin were significantly higher compared to MGN (P = 0.002, P = 0.06) and healthy controls, respectively (P = 0.020, P= 0.001). Conclusion: Different levels of the studied proteins in uEVs may indicate podocyte injury and represent a direct association with the pathology of IgAN and MGN.