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.

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.

The biological activities of postbiotics in gastrointestinal disorders.

According to outcomes from clinical studies, an intricate relationship occurs between the beneficial microbiota, gut homeostasis, and the host's health status. Numerous studies have confirmed the health-promoting effects of probiotics, particularly in gastrointestinal diseases. On the other hand, the safety issues regarding the consumption of some probiotics are still a matter of debate, thus to overcome the problems related to the application of live probiotic cells in terms of clinical, technological, and economic aspects, microbial-derived biomolecules (postbiotics) were introducing as a potential alternative agent. Presently scientific literature confirms that the postbiotic components can be used as promising tools for both prevention and treatment strategies in gastrointestinal disorders with less undesirable side-effects, particularly in infants and children. Future head-to-head trials are required to distinguish appropriate strains of parent cells, optimal dosages of postbiotics, and assessment of the cost-effectiveness of postbiotics compared to alternative drugs. This review provides an overview of the concept and safety issues regarding postbiotics, with emphasis on their biological role in the treatment of some important gastrointestinal disorders.

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.

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.

Curcumin nanoformulations: Beneficial nanomedicine against cancer.

Curcumin is a phytochemical achieved from the plant turmeric. It is extensively utilized for the treatment of several types of diseases such as cancers. Nevertheless, its efficiency has been limited because of rapid metabolism, low bioavailability, poor water solubility, and systemic elimination. Scientists have tried to solve these problems by exploring novel drug delivery systems such as lipid-based nanoparticles (NPs) (e.g., solid lipid NPs, nanostructured lipid carriers, and liposomes), polymeric NPs, micelles, nanogels, cyclodextrin, gold, and mesoporous silica NPs. Among these, liposomes have been the most expansively studied. This review mainly focuses on the different curcumin nanoformulations and their use in cancer therapy in vitro, in vivo, and clinical studies. Despite the development of curcumin-containing NPs for the treatment of cancer, potentially serious side effects, including interactions with other drugs, some toxicity aspects of NPs may occur that require more high-quality investigations to firmly establish the clinical efficacy.

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.

Therapeutic benefits of rutin and its nanoformulations.

BACKGROUND: Rutin as a natural flavonoid compound has revealed an extensive range of therapeutic potentials. PURPOSE: The current paper is focused on the numerous studies on rutin nanoformulations regarding its broad spectrum of therapeutic potentials. STUDY AND METHODS: A review was conducted in electronic databases (PubMed) to identify relevant published literature in English. No restrictions on publication date were imposed. RESULTS: The literature search provided 7,078 results for rutin. Among them, 25 papers were related to the potential biological activities of rutin nanoformulations. Polymeric nanoparticles were the most studied nanoformulations for rutin (14 titles) and lipid nanoparticles (5 titles) were in second place. The reviewed literature showed that rutin has been used as an antimicrobial, antifungal, and anti-allergic agent. Improving the bioavailability of rutin using novel drug-delivery methods will help the investigators to use its useful effects in the treatment of various chronic human diseases. CONCLUSION: It can be concluded that the preparation of rutin nanomaterials for the various therapeutic objects confirmed the enhanced aqueous solubility as well as enhanced efficacy compared to conventional delivery of rutin. However, more investigations should be conducted to confirm the improved bioavailability of the rutin nanoformulations.

Medicinal signaling cells: A potential antimicrobial drug store.

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.

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.

Bitter apricot ethanolic extract induces apoptosis through increasing expression of Bax/Bcl-2 ratio and caspase-3 in PANC-1 pancreatic cancer cells.

Pancreatic cancer is the fourth common cause of cancer death. Surgery and chemotherapy are the common treatment strategies for pancreatic cancer patients; however, the response rate is less than 20% at advanced stages. In recent years, growing interest has been dedicated to natural products. Bitter apricot seeds possess a number of pharmacological properties including antitumor activity and amygdalin from bitter apricot seeds can induce apoptosis. In this study, we investigated the cyto/genotoxic effects of bitter apricot ethanolic extract (BAEE) and amygdalin on human pancreatic cancer PANC-1 and normal epithelial 293/KDR cells. BAEE was assessed using high-performance liquid chromatography for the confirmation of the structure. The biological impacts of BAEE and amygdalin on PANC-1 and 293/KDR cells were evaluated by MTT assay, DAPI staining, AnnexinV/PI and Real-time qPCR analysis. BAEE and amygdalin inhibited cancer cell growth in a dose- and time-dependent manner. DAPI staining and flow cytometric analysis revealed fragmented nuclei and elevated numbers of early and late apoptotic cells, respectively. Also, increased Bax/Bcl-2 ratio and upregulation of caspase-3 further confirmed the occurrence of apoptosis in PANC-1 cells, but not in non-cancerous 293/KDR cells. These results indicate that BAEE could mediate apoptosis induction in cancer cells through a mitochondria dependent pathway. These findings suggest that BAEE functions as a potent pro-apoptotic factor for human pancreatic cancer cells without a significant effect on 293/KDR cells. Though, the potent anti-cancer components of BAEE should be further identified. Moreover, in vivo investigations are required to confirm bitter apricot ethanolic extract's clinical value as an anti-tumor drug.

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.

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.

Identification of common genes and pathways underlying imatinib and nilotinib treatment in CML: a Bioinformatics Study.

Imatinib (IMA) and nilotinib are the first and second generations of BCR-ABL tyrosine kinase inhibitors, which widely applied in chronic myeloid leukemia (CML) treatment. Here we aimed to provide new targets for CML treatment by transcriptome analysis. Microarray data GSE19567 was downloaded and analyzed from Gene Expression Omnibus (GEO) to identify common genes, which are downregulated or upregulated in K562-imatinib and K562-nilotinib treated cells. The differentially expressed genes (DEGs) were assessed, and STRING and Cytoscape were used to create the protein-protein interaction (PPI) network. In imatinib and nilotinib treated groups' comparison, there were common 626 upregulated and 268 downregulated genes, which were differentially expressed. The GO analysis represented the enrichment of DEGs in iron ion binding, protein tyrosine kinase activity, transcription factor activity, ATP binding, sequence-specific DNA binding, cytokine activity, the mitochondrion, sequence-specific DNA binding, plasma membrane and cell-cell adherens junction. KEGG pathway analysis revealed that downregulated DEGs were associated with pathways including microRNAs in cancer and PI3K-Akt signaling pathway. Furthermore, upregulated DEGs were involved in hematopoietic cell lineage, lysosome and chemical carcinogenesis. Among the upregulated genes, MYH9, MYH14, MYL10, MYL7, MYL5, RXRA, CYP1A1, FECH, AKR1C3, ALAD, CAT, CITED2, CPT1A, CYP3A5, CYP3A7, FABP1, HBD, HMBS and PPOX genes were found as hub genes. Moreover, 20 downregulated genes, YARS, AARS, SARS, GARS, CARS, IARS, RRP79, CEBPB, RRP12, UTP14A, PNO1, CCND1, DDX10, MYC, WDR43, CEBPG, DDIT3, VEGFA, PIM1 and TRIB3 were identified as hub genes. These genes have the potential to become target genes for diagnosis and therapy of CML patients.

Phenotypic and functional characterization of subpopulation of Imatinib resistant chronic myeloid leukemia cell line.

PURPOSE: Chronic myeloid leukemia (CML) is a hematological malignancy characterized by the presence of BCR-ABL protein. Imatinib (IMA) is considered as the first line therapy in management of CML which particularly targets the BCR-ABL tyrosine kinase protein. However, emergence of resistance to IMA hinders its clinical efficiency. Hence, identifying novel targets for therapeutic approaches in CML treatment is of great importance. Here, we characterize a new subpopulation of highly adherent IMA-resistant CML cells that express stemness and adhesion markers compared to naive counterparts. MATERIALS AND METHODS: We performed several experimental assays including FISH, flow cytometry, and gene expression assays. Additionally, bioinformatics analysis was performed by normalized web-available microarray data (GSE120932) to revalidate and introduce probable biomarkers. Protein-protein interactions (PPI) network was analyzed by the STRING database employing Cytoscape v3.8.2. RESULTS: Our findings demonstrated that constant exposure to 5 â€‹µM IMA led to development of the adherent phenotype (K562R-adh). FISH and BCR-ABL expression analysis indicated that K562R-adh cells were derived from the original cells (K562R). In order to determine the role of various genes involved in epithelial-mesenchymal transition (EMT) and stem cell characterization, up/down-regulation of various genes including cancer stem cell (CSC), adhesion and cell surface markers and integrins were observed which was similar to the findings of the GSE120932 dataset. CONCLUSION: Treating CML patients with tyrosine kinase inhibitors (TKIs) as well as targeting adhesion molecules deemed to be effective approaches in prevention of IMA resistance emergence which in turn may provide promising effects in the clinical management of CML patients.

Eplerenone reduces renal ischaemia/reperfusion injury by modulating Klotho, NF-κB and SIRT1/SIRT3/PGC-1α signalling pathways.

OBJECTIVES: Acute kidney injury (AKI) is a sudden impairment in kidney function that is associated with high morbidity and mortality. Inflammation, oxidative stress, mitochondrial impairment and energy depletion, along with organ dysfunction are hallmarks of AKI. This study aimed to evaluate the effects of Eplerenone, an aldosterone receptor antagonist, on the kidney injury caused by ischaemia/reperfusion (I/R). METHODS: Male Wistar rats (n = 24) were randomly allocated into four groups: sham, IR, Eplerenone and Eplerenone+IR. Rats in the two last groups 1 h before I/R induction, were treated with Eplerenone (100 mg/kg) via intraperitoneal injection. Protein levels of Klotho, heat shock protein 70 (HSP70), sirtuin1 (SIRT1), SIRT3 and peroxisome proliferator-activated receptor-gamma coactivator 1-α (PGC-1α) along with antioxidant, apoptotic (caspase 3, Bax and Bcl2) and inflammatory [nuclear factor kappa-B (NF-κB) p65, Interleukin-6 (IL-6), tumour necrosis factor-α (TNF-α) and cyclooxygenase-2 (COX-2)] factors were evaluated in the kidney tissues of the experimental groups. KEY FINDINGS: Eplerenone pre-treatment significantly could improve IR-induced pathological changes and kidney function and increase the renal antioxidant factors compared to the IR group (P < 0.05). Furthermore, in the Eplerenone + IR group, significant elevation of the Klotho, SIRT1, SIRT3 and PGC-1α at the protein level was identified compared to the IR group. Eplerenone pretreatment could not only downregulate NF-κB signalling and its downstream inflammatory factors (IL-6, COX-2 and TNF-α) but also could decrease apoptotic factors (P ≤ 0.01). CONCLUSIONS: The results recommended that Eplerenone exerts a protective effect against kidney IR injury by up-regulating Klotho, HSP70, sirtuins and PGC-1α to preserve mitochondrial function and cell survival. Moreover, it hinders renal inflammation by suppressing NF-κB signalling. These results offer insight into the prevention or treatment of AKI in the future.

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.

Exosomes as versatile nanoscaled biocompartments in cancer therapy and/or resistance.

Cancer remains to be a major hurdle to global health. Exosomes as a versatile bio-derived platform, hold a bright prospect in nano-scaled delivery/targeting strategies. Shreds of evidence indicate that exosomes have a critical role in drug resistance in cancer cells through various mechanisms including shuttling of miRNAs, drug efflux transporters, and anti-apoptotic signaling. Exosomes' cargo, particularly miRNAs, may exert both resistance and in a few cases sensitivity to the anticancer agents in targeted cells. Therefore, the source and components of the exosomes should be carefully considered before any application. Our aim in this editorial is to further highlight the role of exosomes in the development of resistance to therapy in cancer cells. As a new chapter for drug delivery, the challenges should be elucidated before exosomes emerge as novel nanoplatforms for cancer therapy.