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.

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.

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.

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.

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.

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.

Evidence for Health-Promoting Properties of Lepidium sativum L.: An Updated Comprehensive Review.

Lepidium sativum L. is a common herb distributed worldwide, used as a food ingredient and therapeutic agent in traditional medicine for treating health-related disorders. L. sativum and its extracts have been described to possess numerous biological activities including antimicrobial, antidiabetic, antioxidant, antidiarrheal, anticancer, and numerous health-promoting effects in in vivo and in vitro studies. The purpose of this review is to summarize the findings describing important biological functions and therapeutic effects of L. sativum in various cell lines and animal models. In this review, the English-language articles were gathered from electronic databases including Web of Science, PubMed and Google Scholar with no time limit applied to any database. The search terms used in this review include, "Lepidium sativum L." and/or "chemical composition", "health benefits", "antimicrobial", "antioxidant", "anticancer", "diuretic", "nephro-protection", "antidiarrheal", "antidiabetic", "anti-asthmatic", "neuroprotection", "metabolic", "bone fracture", and "reproductive performance". Additional and eligible studies were collected from reference lists of appropriate articles. The information presented will be helpful to attract more interest toward medicinal plants by defining and developing novel clinical applications and new drug formulations in the future. Pre-clinical studies showed that L. sativum possesses potent health-promoting effects involving various molecular mechanisms. Taken all together, data suggested that identified herbal plants such as L. sativum, can be exploited as nutritional and therapeutic agents to combat various ailments. Despite much research in this field, further comprehensive in vitro/in vivo studies and clinical trials are needed to identify the mechanisms underlying the biological and therapeutic activities of L. sativum.

Microbial exopolysaccharides-ß-glucans-as promising postbiotic candidates in vaccine adjuvants.

The urgent task of creating new, enhanced adjuvants is closely related to our comprehension of their mechanisms of action. A few adjuvants have shown sufficient efficacy and low toxicity to be allowed for use in human vaccines, despite the fact that they have a long history and an important function. Adjuvants have long been used without a clear understanding of how precisely they augment the immune response. The rational production of stronger and safer adjuvants has been impeded by this lack of information, which necessitates more mechanistic research to support the development of vaccines. Carbohydrate structures-polygalactans, fructans, ß-D-glucans, α-D-glucans, D-galactose, and D-glucose-are desirable candidates for the creation of vaccine adjuvants and immunomodulators because they serve important functions in nature and are often biocompatible, safe, and well tolerated. In this review, we have discussed recent advances in microbial-derived carbohydrate-based adjuvants, their immunostimulatory activity, and the implications of this for vaccine development, along with the critical view on the microbial sources, chemical composition, and biosynthetic pathways.

Microbiota and glomerulonephritis: An immunological point of view.

Glomerular injury is the major cause of chronic kidney diseases (CKD) worldwide and is characterized by proteinuria. Glomerulonephritis (GN) has a wide spectrum of etiologies, the intensity of glomerular damage, histopathology, and clinical outcomes that can be associated with the landscape of the nephritogenic immune response. Beyond impaired immune responses and genetic factors, recent evidence indicates that microbiota can be contributed to the pathogenesis of GN and patients' outcomes by impacting many aspects of the innate and adaptive immune systems. It is still unknown whether dysbiosis induces GN or it is a secondary effect of the disease. Several factors such as drugs and nutritional problems can lead to dysbiosis in GN patients. It has been postulated that gut dysbiosis activates immune responses, promotes a state of systemic inflammation, and produces uremic toxins contributing to kidney tissue inflammation, apoptosis, and subsequent proteinuric nephropathy. In this review, the impact of gastrointestinal tract (GI) microbiota on the pathogenesis of the primary GN will be highlighted. The application of therapeutic interventions based on the manipulation of gut microbiota with special diets and probiotic supplementation can be effective in GN.

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.

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.

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.

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

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.

Osteogenic Differentiation of Mesenchymal Stem Cells via Curcumin-Containing Nanoscaffolds.

The diverse pleiotropic pharmacological effects of curcumin nanoformulations have turned it into an attractive natural compound in different health-related problems. A great body of evidence has shown the impact of curcumin and its nanoformulations on the differentiation of stem cells. The current review highlights cellular and molecular mechanisms connected with the osteogenic differentiation of mesenchymal stem cells (MSCs) in the scaffolds benefiting from the presence of nanocurcumin pointing toward the role of inhibitory or stimulant signal transduction pathways in detail. Moreover, the effects of different concentrations as well as the structural modifications of curcumin on the differentiation of MSCs have been addressed.

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.

Yeast exopolysaccharides and their physiological functions.

Mounting evidence indicated the capability of various microorganisms in biosynthesis of exopolysaccharides (EPSs). A wide range of evidence extensively investigated the ability of bacterial species for EPS synthesis and their favorable effects, so little is known regarding yeast species. Many factors like composition of growth media and fermentation conditions are related to the structural and physical properties of EPSs. The EPS protects the producer yeast strain against extreme environment. Researchers proposed that yeast EPSs have priority over bacterial EPSs because of high yields of EPS biosynthesis and easy separation methods from growth media. Besides, they have drawn increasing attention due to their interesting biological activities, food, pharmaceutical, and cosmetics applications. Although a limited number of studies exist, this review aims to highlight the EPS structure and various applications of known yeast species in detail.

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.