In silico tools to assess the potential allergenicity of shiitake mushrooms (Lentinula edodes).

BACKGROUND: Computational tools may have an edge over conventional methods for the preliminary evaluation of food allergenicity. In this study, the allergenic potential of Lentinula edodes was evaluated and validated using in silico tools. RESULTS: The potential cross-reactivity of mushroom proteins with fungal allergens was determined using sequence alignment - the Fast Alignment (FASTA) and Basic Local Alignment Search Tool (BLAST) algorithm. Eight L. edodes proteins were cross-reactive with allergens from fungal origin, showing 52%-89% sequence identity using FASTA algorithm-based alignment. The BLAST data were corroborated by percentage identity and query coverage. Physico-chemical property-based allergenicity was deciphered by AlgPred, Allermatch, and AllergenFP software, which predicted six out of eight proteins as potential allergens. Sequence alignment showed 66%-86% conservancy between mushroom protein and known fungal allergens. Secondary structure and amino acid composition supported structural affinity between query and fungal proteins. Three-dimensional structures of five mushroom proteins were generated, quality assessed, and superimposed with fungal allergens, suggesting possible allergenicity of mushroom proteins. An enzyme-linked immunosorbent assay (ELISA) demonstrated immunoglobulin E (IgE) binding in 13 out of 21 food-hypersensitive patients' sera. CONCLUSION: In silico tools provide preliminary indications about the potential allergenicity and cross-reactivity of mushroom proteins. This approach may be used for the prelusive allergenicity assessment of allergen sources. © 2022 Society of Chemical Industry.

Mitochondrial microRNA (MitomiRs) in cancer and complex mitochondrial diseases: current status and future perspectives.

Mitochondria are not only important for cellular bioenergetics but also lie at the heart of critical metabolic pathways. They can rapidly adjust themselves in response to changing conditions and the metabolic needs of the cell. Mitochondrial involvement as well as its dysfunction has been found to be associated with variety of pathological processes and diseases. mitomiRs are class of miRNA(s) that regulate mitochondrial gene expression and function. This review sheds light on the role of mitomiRs in regulating different biological processes-mitochondrial dynamics, oxidative stress, cell metabolism, chemoresistance, apoptosis,and their relevance in metabolic diseases, neurodegenerative disorders, and cancer. Insilico analysis of predicted targets of mitomiRs targeting energy metabolism identified several significantly altered pathways (needs in vivo validations) that may provide a new therapeutic approach for the treatment of human diseases. Last part of the review discusses about the clinical aspects of miRNA(s) and mitomiRs in Medicine.

Susceptibility to high-altitude pulmonary edema is associated with circulating miRNA levels under hypobaric hypoxia conditions.

Hypobaric hypoxia poses stress to sojourners traveling to high-altitude. A cascade of physiological changes occurs to cope with or adapt to hypobaric hypoxia. However, an insufficient physiological response to the hypoxic condition resulting from imbalanced vascular homeostasis pathways results in high-altitude pulmonary edema (HAPE). The present study aims to identify the implication of miRNAs associating with HAPE and adaptation. We analyzed the expression of 1,113 miRNAs in HAPE-patients (HAPE-p), HAPE-free controls (HAPE-f), and highland natives (HLs). Based on miRNA profiling and in silico analyses, miR-124-3p emerged relevantly. We observed a significant overexpression of miR-124-3p in HAPE-p. In silico analyses revealed a direct interaction of miR-124-3p with vascular homeostasis and hypoxia-associated genes NOS3 (endothelial nitric oxide synthase), Apelin, and ETS1 (V-Ets avian erythroblastosis virus E2 oncogene homolog 1). Moreover, the transcript and biolevel expression of these genes were significantly decreased in HAPE-p when compared with HAPE-f or HLs. Our in vitro analysis in human umbilical vein endothelial cells demonstrated a significant knockdown of these genes both at transcript and protein levels following miR-124-3p overexpression. Conclusively, our results showed that miR-124-3p might play a plausible role in HAPE pathophysiology by inhibiting the expression of NOS3, Apelin, and ETS1.

Effect of Social Networking Sites on the Quality of Life of College Students: A Cross-Sectional Study from a City in North India.

INTRODUCTION: With the advent and extensive use of the Internet and smartphones, social networking has become a pervasive part of human interaction. The use of these social networking sites or the Internet affects the physical, mental, and spiritual health of the people. Hence, there is need to understand how the time spent on social networking is affecting the quality of life (QOL) as a whole, especially among college-going students who are most likely users of social networking sites (18-21 years). MATERIALS AND METHODS: A cross-sectional survey was conducted among 220 college-going students (18-21 years) in Chandigarh in 2012. The data were collected using a pretested self-administered questionnaire, adapted from Young's Internet usage questionnaire. Appropriate statistical analysis was done. RESULTS: Almost all (98%) of the respondents use the Internet. As compared to nondaily users of social networking sites, daily users were better able to handle stress related to (1) relationships (moderate to severe stress among daily users vs. nondaily users, 15.2% vs. 30.5%) and (2) work (moderate to severe stress among daily users vs. nondaily users, 18.2% vs. 35.4%). The daily users of social networking sites feel significantly more satisfied with their classmates, the way they handle the problems, their physical appearance, and their accomplishments in their life. CONCLUSION: Social networking sites are steadily penetrating in the lives of adolescents in India. The advantages on quality of life for daily users of social networking sites versus nondaily users are enormous. Also currently, Internet use might not have reached the levels where it embarks on the existing state of health; therefore, continuous and critical observation of the changing trends is warranted.

MiR-195 regulates mitochondrial function by targeting mitofusin-2 in breast cancer cells.

Mitochondrial dynamics is a highly dysregulated process in cancer. Apoptosis and mitochondrial fission are two concurrent events wherein increased mitochondrial fragmentation serves as a hallmark of apoptosis. We have shown earlier that miR-195 exerts pro-apoptotic effects in breast cancer cells. Herein, we have demonstrated miR-195 as a modulator of mitochondrial dynamics and function. Imaging experiments upon miR-195 treatment have shown that mitochondria undergo extensive fission. We validated mitofusin2 as a potential target of miR-195. This may provide a molecular explanation for the respiratory defects induced by miR-195 over-expression in breast cancer cells. Active, but not total, mitochondrial mass, was reduced with increasing levels of miR-195. We have further shown that miR-195 enhances mitochondrial SOD-2 expression but does not affect PINK1 levels in breast cancer cells. Collectively, we have revealed that miR-195 is a modulator of mitochondrial dynamics by targeting MFN2 thereby impairing mitochondrial function. Concomitantly, it enhances the scavenger of reactive oxygen species (SOD-2) to maintain moderate levels of oxidative stress. Our findings suggest a therapeutic potential of miR-195 in both ER-positive as well as ER-negative breast cancer cells.

PI3K/AKT/mTOR activation and autophagy inhibition plays a key role in increased cholesterol during IL-17A mediated inflammatory response in psoriasis.

Psoriasis is an immune-mediated inflammatory disease of the skin. Previous studies including ours have shown that IL-17A plays a major role in its pathogenesis; however, its precise molecular mechanism of action is not well understood. Cytokines like TNF α and IL-23 are also important in mediating the disease and some studies have also reported autophagy as a novel mechanism by which cytokines controls the immune response. Herein, we investigated the effect of IL-17A on autophagy and reveal crosstalk between autophagy and cholesterol signaling in keratinocytes. Our results suggest that IL-17A stimulated keratinocytes activated PI3K/AKT/mTOR signaling and inhibited autophagy by simultaneously inhibiting autophagosome formation and enhancing autophagic flux. Western blotting was utilized to detect the expression of autophagic markers (LC3 and p62), PI3K, mTOR and AKT. Induction of autophagy by mTOR inhibitor rapamycin and/or starvation also inhibited the levels of IL-17A secreted IL-8, CCL20 and S100A7 in keratinocytes. Herein, we also observed that inhibition of autophagy by IL-17A was accompanied by enhanced cellular cholesterol levels which in turn regulated the autophagic flux. To investigate crosstalk between autophagy and cellular cholesterol, we used methyl-ß-cyclodextrin (MßCD), which disrupts detergent-insoluble microdomains (DIMs) by depleting cells of cholesterol and checked autophagy. Decreased expression of LC3-II in psoriatic lesional skin compared to non-lesional skin and induction of autophagy by anti-psoriatic drug methotrexate in keratinocytes further confirms the role of autophagy in psoriasis. Our findings suggest that modulators of autophagy and/or cholesterol levels may be developed, and also may lead to new therapeutic agents for psoriasis treatment.

miR-4516, a microRNA downregulated in psoriasis inhibits keratinocyte motility by targeting fibronectin/integrin α9 signaling.

Psoriasis is recognized as a T cell mediated inflammatory hyperproliferative skin disorder. Several microRNAs (miRNAs) have been implicated in the pathogenesis of psoriasis however, understanding of their mechanistic involvement remains unclear. Previously, we have shown that PUVA induced miR-4516 downregulates signal transducer and activator of transcription 3 (STAT3) by direct binding to its 3' untranslated region (3'UTR) and suppresses STAT3 downstream genes (Bcl xl, Cyclin D1). Here, we demonstrate for the first time that expression of miR-4516 is significantly downregulated in psoriatic skin. We additionally validated extracellular matrix protein fibronectin 1 (FN1) and integrin subunit α9 (ITGA9) as direct targets of miR-4516. Interestingly, ITGA9 expression was found to be increased in the suprabasal psoriatic epidermis. We further showed that ectopic expression of miR-4516 in human keratinocytes not only suppresses cell motility and proliferation via significant downregulation of genes orchestrating cytoskeletal reorganization (Rac1, RhoA, Cdc42), but also inhibits F-actin assembly and induces terminal differentiation. Collectively, our results provide evidence that loss of expression of miR-4516 in psoriatic skin might be contributing to accelerated migration, resistance to apoptosis and differentiation as seen in psoriasis lesional keratinocytes and also highlight its potential as a novel small molecule for therapeutic intervention in psoriasis.

Systematic Analysis of Mycobacterial Acylation Reveals First Example of Acylation-mediated Regulation of Enzyme Activity of a Bacterial Phosphatase.

Protein lysine acetylation is known to regulate multiple aspects of bacterial metabolism. However, its presence in mycobacterial signal transduction and virulence-associated proteins has not been studied. In this study, analysis of mycobacterial proteins from different cellular fractions indicated dynamic and widespread occurrence of lysine acetylation. Mycobacterium tuberculosis proteins regulating diverse physiological processes were then selected and expressed in the surrogate host Mycobacterium smegmatis. The purified proteins were analyzed for the presence of lysine acetylation, leading to the identification of 24 acetylated proteins. In addition, novel lysine succinylation and propionylation events were found to co-occur with acetylation on several proteins. Protein-tyrosine phosphatase B (PtpB), a secretory phosphatase that regulates phosphorylation of host proteins and plays a critical role in Mycobacterium infection, is modified by acetylation and succinylation at Lys-224. This residue is situated in a lid region that covers the enzyme's active site. Consequently, acetylation and succinylation negatively regulate the activity of PtpB.

STAT6 silencing up-regulates cholesterol synthesis via miR-197/FOXJ2 axis and induces ER stress-mediated apoptosis in lung cancer cells.

MiRNAs and transcription factors have emerged as important regulators for gene expression and are known to regulate various biological processes, including cell proliferation, differentiation and apoptosis. Previously, using genome-wide expression profiling studies, we have shown an inverse relationship of STAT6 and cholesterol biosynthesis and also identified FOXJ2 binding sites in the upstream region of 3 key genes (HMGCR, HMGCS1 and IDI1) of the cholesterol synthesis pathway. Our previous study also provided clues toward the anti-apoptotic role played by STAT6. For better understanding of the cellular response and underlying signaling pathways activated by STAT6 silencing, we examined the changes in miRNome profile after the siRNA-mediated silencing of STAT6 gene in NCI-H460 cells using LNA-based miRNA microarray. Our analysis showed significant downregulation of miRNAs, let-7b and miR-197, out of which miR-197 was predicted to target FOXJ2. We here show that miR-197 not only negatively regulates FOXJ2 expression through direct binding to its respective binding site in its 3'UTR but also alters total cholesterol levels by regulating genes associated with cholesterol biosynthesis pathway. We further demonstrated that STAT6 silencing elicited ER stress-mediated apoptosis in NCI-H460 cells through C/EBP homologous protein (CHOP) induction, alteration of BH3 only proteins expression and ROS production. The apoptosis induced by STAT6 downregulation was partially reversed by NAC, the ROS scavenger. Based on the above findings, we suggest that ER stress plays a major role in STAT6-induced apoptosis.

Lipid rafts in immune signalling: current progress and future perspective.

Lipid rafts are dynamic assemblies of proteins and lipids that harbour many receptors and regulatory molecules and so act as a platform for signal transduction. They float freely within the liquid-disordered bilayer of cellular membranes and can cluster to form larger ordered domains. Alterations in lipid rafts are commonly found to be associated with the pathogenesis of several human diseases and recent reports have shown that the raft domains can also be perturbed by targeting raft proteins through microRNAs. Over the last few years, the importance of lipid rafts in modulating both innate and acquired immune responses has been elucidated. Various receptors present on immune cells like B cells, T cells, basophils and mast cells associate with lipid rafts on ligand binding and initiate signalling cascades leading to inflammation. Furthermore, disrupting lipid raft integrity alters lipopolysaccharide-induced cytokine secretion, IgE signalling, and B-cell and T-cell activation. The objective of this review is to summarize the recent progress in understanding the role of lipid rafts in the modulation of immune signalling and its related therapeutic potential for autoimmune diseases and inflammatory disorders.

MicroRNA: a connecting road between apoptosis and cholesterol metabolism.

Resistance to apoptosis leads to tumorigenesis and failure of anti-cancer therapy. Recent studies also highlight abrogated lipid/cholesterol metabolism as one of the root causes of cancer that can lead to metastatic transformations. Cancer cells are dependent on tremendous supply of cellular cholesterol for the formation of new membranes and continuation of cell signaling. Cholesterol homeostasis network tightly regulates this metabolic need of cancer cells on cholesterol and other lipids. Genetic landscape is also shared between apoptosis and cholesterol metabolism. MicroRNAs (miRNAs) are the new fine tuners of signaling pathways and cellular processes and are known for their ability to post-transcriptionally repress gene expression in a targeted manner. This review summarizes the current knowledge about the cross talk between apoptosis and cholesterol metabolism via miRNAs. In addition, we also emphasize herein recent therapeutic modulations of specific miRNAs and their promising potential for the treatment of deadly diseases including cancer and cholesterol related pathologies. Understanding of the impact of miRNA-based regulation of apoptosis and metabolic processes is still at its dawn and needs further research for the development of future miRNA-based therapies. As both these physiological processes affect cellular homeostasis, we believe that this comprehensive summary of miRNAs modulating both apoptosis and cholesterol metabolism will open uncharted territory for scientific exploration and will provide the foundation for discovering novel drug targets for cancer and metabolic diseases.

Prognostic significance of NADPH oxidase-4 as an indicator of reactive oxygen species stress in human retinoblastoma.

BACKGROUND: Reactive oxygen species (ROS) have been shown to enhance the proliferation of cancer cells. NADPH oxidases (NOX4) are a major intracellular source of ROS and are found to be associated with cancer and tumor cell invasion. Therefore, the purpose of this study is to evaluate the expression of NOX4 protein in human retinoblastoma. METHODS: Immunohistochemical expression of NOX4 protein was analyzed in 109 specimens from prospective cases of retinoblastoma and then correlated with clinicopathological parameters and patient survival. Western blotting confirmed and validated the immunoreactivity of NOX4 protein. RESULTS: In our study we found a male preponderance (55.9 %), and 25/109 (22.9 %) were bilateral. Massive choroidal invasion was the histopathological high-risk factor (HRF) most frequently observed, in 42.2 % of the cases. NOX4 protein was expressed in 67.88 % (74/109) of primary retinoblastoma cases and was confirmed by Western blotting. NOX4 was statistically significant with massive choroidal invasion and pathological TNM staging. There was a statistically significant difference in overall survival in patients with NOX4 expression (p = 0.0461). CONCLUSION: This is the first study to show the expression of NOX4 protein in retinoblastoma tumors. Hence, a retinoblastoma tumor may exhibit greater ROS stress. This protein may prove to be useful as a future therapeutic target for improving the management of retinoblastoma.

Moxifloxacin and ciprofloxacin induces S-phase arrest and augments apoptotic effects of cisplatin in human pancreatic cancer cells via ERK activation.

BACKGROUND: Pancreatic cancer, one of the most dreadful gastrointestinal tract malignancies, with the current chemotherapeutic drugs has posed a major impediment owing to poor prognosis and chemo-resistance thereby suggesting critical need for additional drugs as therapeutics in combating the situation. Fluoroquinolones have shown promising and significant anti-tumor effects on several carcinoma cell lines. METHODS: Previously, we reported growth inhibitory effects of fourth generation fluoroquinolone Gatifloxacin, while in the current study we have investigated the anti-proliferative and apoptosis-inducing mechanism of older generation fluoroquinolones Moxifloxacin and Ciprofloxacin on the pancreatic cancer cell-lines MIA PaCa-2 and Panc-1. Cytotoxicity was measured by MTT assay. Apoptosis induction was evaluated using annexin assay, cell cycle assay and activation of caspase-3, 8, 9 were measured by western blotting and enzyme activity assay. RESULTS: Herein, we found that both the fluoroquinolones suppressed the proliferation of pancreatic cancer cells by causing S-phase arrest and apoptosis. Blockade in S-phase of cell cycle was associated with decrease in the levels of p27, p21, CDK2, cyclin-A and cyclin-E. Herein we also observed triggering of extrinsic as well as intrinsic mitochondrial apoptotic pathway as suggested by the activation of caspase-8, 9, 3, and Bid respectively. All this was accompanied by downregulation of antiapoptotic protein Bcl-xL and upregulation of proapoptotic protein Bak. Our results strongly suggest the role of extracellular-signal-regulated kinases (ERK1/2), but not p53, p38 and c-JUN N-terminal kinase (JNK) in fluoroquinolone induced growth inhibitory effects in both the cell lines. Additionally, we also found both the fluoroquinolones to augment the apoptotic effects of broad spectrum anticancer drug Cisplatin via ERK. CONCLUSION: The fact that these fluoroquinolones synergize the effect of cisplatin opens new insight into therapeutic index in treatment of pancreatic cancer.

Expression of pro-apoptotic Bax and anti-apoptotic Bcl-2 proteins in human retinoblastoma.

BACKGROUND: Regulation of apoptosis is a complex process that involves a number of genes, including Bcl-2, Bcl-x, Bax and other Bcl-2 family members. The aim of the present study is to assess the expression of Bcl- 2 and Bax in retinoblastoma, and correlate them with clinical and histopathological parameters. METHODS: The expression of Bcl-2 and Bax proteins were examined using immunohistochemistry, Western blotting and reverse transcriptase-polymerase chain reaction in a series of 60 prospective cases of primary retinoblastoma tissues. RESULTS: Immunohistochemistry showed expression of Bcl-2 in 40/60 (66.6%), whereas Bax expression was found only in 18/60 (30%) cases, and these correlated with mRNA expression. The Western blotting results also correlated well with the immunohistochemical expression of Bcl-2 (25 kDa) and Bax (21 kDa) proteins. Bcl-2 was expressed in 96% (24/25) of invasive tumours and in 45.7% (16/35) of non-invasive tumours. Expression of Bcl-2 significantly correlated with tumour invasiveness (P = 0.0274) and poor differentiation (P = 0.0163), whereas loss of Bax correlated with massive choroidal invasion and Pathological Tumor-Node-Metastasis (pTNM) (P = 0.0341). However, no correlation was found between Bax and Bcl-2 expression. CONCLUSIONS: Our findings suggest that these apoptotic regulatory proteins may serve as poor prognostic markers and can be used as a therapeutic target for the treatment of invasive retinoblastoma. Further functional studies are required to explore the role of Bax and Bcl-2 in retinoblastoma.

hsa-miR-4516 mediated downregulation of STAT3/CDK6/UBE2N plays a role in PUVA induced apoptosis in keratinocytes.

Psoriasis is a chronic inflammatory skin disorder mediated by cross-talk occurring between epidermal keratinocytes, dermal vascular cells and immunocytes. Literature reveals that Signal transducer and activator of transcription 3 (STAT3), a protein involved in transmitting extracellular signals to the nucleus, is a possible important link between keratinocytes and immunocytes and is crucial to the development of psoriasis. Although photochemotherapy using UV in combination with 8 methoxypsoralen is one of the most effective therapy for moderate to severe plaque psoriasis, its mechanism of action is largely unknown. Herein, we studied the change in miRNA profiles of cultured human keratinocytes (HaCaT cells) before and after in vitro PUVA treatment by 8 methoxypsoralen and found significant up regulation of hsa-miR-4516. We for the first time demonstrate that ectopic expression of hsa-miR-4516 directly targets STAT3 protein by binding to its 3'UTR in HaCaT cells as confirmed by Luciferase reporter assays and Western blot analysis. We further show that overexpression of hsa-miR-4516 downregulates STAT3, p-STAT3, CDK6, and UBE2N proteins that are consistently upregulated in psoriasis and induces apoptosis in HaCaT cells. We also observed that anti-miR-4516 treatment was able to partially inhibit PUVA-induced apoptosis, suggesting that miR-4516 is involved in PUVA-induced apoptosis. Taken together, these results not only indicate the mechanistic involvement of hsa-miR-4516 in PUVA mediated effects by down-regulating STAT3 in HaCaT keratinocytes, but also highlight the potential of hsa-miR-4516 in development of novel therapeutic strategies. J. Cell. Physiol. 229: 1630-1638, 2014. © 2014 Wiley Periodicals, Inc.

Brain microRNAs and insights into biological functions and therapeutic potential of brain enriched miRNA-128.

MicroRNAs, the non-coding single-stranded RNA of 19-25 nucleotides are emerging as robust players of gene regulation. Plethora of evidences support that the ability of microRNAs to regulate several genes of a pathway or even multiple cross talking pathways have significant impact on a complex regulatory network and ultimately the physiological processes and diseases. Brain being a complex organ with several cell types, expresses more distinct miRNAs than any other tissues. This review aims to discuss about the microRNAs in brain development, function and their dysfunction in brain tumors. We also provide a comprehensive summary of targets of brain specific and brain enriched miRNAs that contribute to the diversity and plasticity of the brain. In particular, we uncover recent findings on miRNA-128, a brain-enriched microRNA that is induced during neuronal differentiation and whose aberrant expression has been reported in several cancers. This review describes the wide spectrum of targets of miRNA-128 that have been identified till date with potential roles in apoptosis, angiogenesis, proliferation, cholesterol metabolism, self renewal, invasion and cancer progression and how this knowledge might be exploited for the development of future miRNA-128 based therapies for the treatment of cancer as well as metabolic diseases.

Downregulation of BCL2 by miRNAs augments drug-induced apoptosis--a combined computational and experimental approach.

A number of anti-cancer strategies aim to target the mitochondrial apoptotic machinery to induce tumour cell death. Mitochondria play a key role as death amplifiers by releasing apoptogenic factors from the mitochondrial inter-membrane space into the cytosol. BCL2 proteins are known for their ability to regulate both mitochondrial physiology and cell death, and their deregulated expression often renders cancer cells insensitive to apoptosis-inducing anticancer drugs. Recently, a few microRNAs, a novel class of gene regulators, have been demonstrated to regulate expression of some members of the BCL2 family. Here, we have combined computational and experimental approaches to identify miRNAs that can regulate the anti-apoptotic protein BCL2. We report that miR-195, miR-24-2 and miR-365-2 act as negative regulators of BCL2 through direct binding to their respective binding sites in the 3'-UTR of the human BCL2 gene. Ectopic expression of miR-195, miR-24-2 and miR-365-2 individually led to a significant reduction of the levels of BCL2 protein. Additionally, we found that overexpression of these miRNAs induced dissipation of the mitochondrial membrane potential and release of cytochrome c from mitochondria into the cytosol. Furthermore, we demonstrated that overexpression of these miRNAs not only caused an increase in apoptosis but also augmented the apoptotic effect of etoposide in breast cancer MCF7 cells. These data not only show the apoptotic nature of miR-195, miR-24-2 and miR-365-2 but also highlight the therapeutic potential of these miRNAs.

MicroRNAs in cancer stem cells: current status and future directions.

The presence of stem-like cells in cancer, popularly known as cancer stem cells, have been known for a long time but it was the research of Bonnet and Dick in leukemia which got cancer researchers interested in them. Over the past few years, a lot of research has gone into the characterization of cancer stem cells (CSCs) from different tumors. CSCs have been elucidated in almost all solid tumors. The growth of this field has not been without controversies as many researchers considered CSCs to be a transient population of little consequence. The field has nevertheless progressed providing us not only a better understanding of cancer and its related facets like proliferation, EMT, and metastasis but also generating a hope for new generation therapeutics with CSCs as their targets. This search for drugs which target CSCs has also focused on miRNAs. miRNAs are small non-coding regulatory RNA molecules capable of fine-tuning the gene expression. The miRNA profile of CSCs is remarkably different from non-stem cancer cells and many miRNAs have also been shown to regulate self-renewal and differentiation properties of CSCs. The differential miRNA profile in CSCs make them probable biomarkers for the prognosis of cancer and their specificity in targeting the properties of CSCs make them potential targets for therapeutic intervention. This review critically analyzes the advancement of the miRNA research in CSC context and also explores the prospect of miRNA therapies against CSCs.

Identifying the mitochondrial metabolism network by integration of machine learning and explainable artificial intelligence in skeletal muscle in type 2 diabetes.

Imbalance in glucose metabolism and insulin resistance are two primary features of type 2 diabetes/diabetes mellitus. Its etiology is linked to mitochondrial dysfunction in skeletal muscle tissue. The mitochondria are vital organelles involved in ATP synthesis and metabolism. The underlying biological pathways leading to mitochondrial dysfunction in type 2 diabetes can help us understand the pathophysiology of the disease. In this study, the mitochondrial gene expression dataset were retrieved from the GSE22309, GSE25462, and GSE18732 using Mitocarta 3.0, focusing specifically on genes that are associated with mitochondrial function in type 2 disease. Feature selection on the expression dataset of skeletal muscle tissue from 107 control patients and 70 type 2 diabetes patients using the XGBoost algorithm having the highest accuracy. For interpretation and analysis of results linked to the disease by examining the feature importance deduced from the model was done using SHAP (SHapley Additive exPlanations). Next, to comprehend the biological connections, study of protein-protien and mRNA-miRNA networks was conducted using String and Mienturnet respectively. The analysis revealed BDH1, YARS2, AKAP10, RARS2, MRPS31, were potential mitochondrial target genes among the other twenty genes. These genes are mainly involved in the transport and organization of mitochondria, regulation of its membrane potential, and intrinsic apoptotic signaling etc. mRNA-miRNA interaction network revealed a significant role of miR-375; miR-30a-5p; miR-16-5p; miR-129-5p; miR-1229-3p; and miR-1224-3p; in the regulation of mitochondrial function exhibited strong associations with type 2 diabetes. These results might aid in the creation of novel targets for therapy and type 2 diabetes biomarkers.

Role of miR-128-3p and miR-195-5p as biomarkers of coronary artery disease in Indians: a pilot study.

Coronary artery disease (CAD) imposes a significant economic burden in developing countries like India. Timely diagnosis and treatment should be prioritized to mitigate the disease. Current diagnostic tools being invasive and less specific raise the need to develop less invasive and more reliable molecular biomarkers. MicroRNAs (miRNAs) are an emerging class of molecules that can serve as a potential source of non-invasive biomarkers for CAD. The objective of this study was to determine the potential of circulatory miRNAs as diagnostic biomarkers in CAD. In this study, we have reported two microRNAs, miR-128-3p and miR-195-5p in the serum of CAD patients in Indian Population. A total of 124 subjects were recruited which included 89 angiographically proven CAD patients and 35 control subjects. Our results show a significant decrease in the levels of miR-128-3p in CAD patients while there were no significant changes in the levels of miR-195-5p. Further bioinformatics analysis revealed the potential role of miR-128-3p in cholesterol homeostasis. Altered homeostasis due to cholesterol accumulation in macrophages is the driving force behind formation of foam cells which in turn accelerates the progression of CAD. Here, we have shown that miR-128-3p increases cholesterol levels in macrophages by decreasing cholesterol efflux in-vitro.