The recent discovery of HIV-1 genome-encoded novel microRNA (miRNA; designated as hiv1-mir-H1) having ability to target selectively and specifically human cellular AATF gene, prompted us to explore the role of this miRNA in the regulation of genes involved in cellular apoptosis, proliferation and nucleic acid-based immune mechanism governed by miRNAs. Such a study revealed that this miRNA-induced knockdown of AATF gene, within normal human blood mononuclear cells, was responsible for the suppression of genes coding for Bcl-2, c-myc, Par-4 and Dicer. Further, hiv1-mir-H1 had the capacity to downregulate expression of cellular miR149 gene recognized to target Vpr gene encoded by HIV-1. Based upon these findings, we propose an “Epigenomic Pathway” through which hiv1-mir-H1 induced AATF gene knockdown within human mononuclear cells initiates their apoptosis.

BackgroundChemicals like Monobenzyl Ether of Hydroquinone (MBEH) and 4-Tertiary Butyl Phenol (4-TBP) have been widely recognized to induce clinical lesions that resemble vitiligo, but exact molecular pathway through which these chemicals initiate vitiligo is still far from clear.ObjectivesSince vitiligo is widely considered as an autoimmune disease, this study was an attempt to understand miR-2909 RNomics in vitiligo pathogenesis using MBEH treated primary melanocytes as an archetype cellular model because MBEH causes pathological features indistinguishable from clinical vitiligo.MethodsPrimary melanocytes were treated with MBEH and 4-TBP and the role of miR-2909 RNomics at transcriptional and translational level was explored through qRT-PCR, western blot analysis, flow cytometry, immunocytochemistry, immunohistochemistry and in silico binding affinities. 4 mm punch biopsies were also obtained from lesional sites of vitiligo patients to validate the results observed in cell culture experiments.ResultsMBEH induced miR-2909 RNomics led to downregulation of MITF, TYR, TYRP1, and TYRP2 leading to decreased melanin synthesis which in turn is a characteristic trait of vitiligo. On the other hand, 4-TBP increased TGF-β which also has the intrinsic capacity to downregulate MITF leading to decreased melanin synthesis and thereby initiation of vitiligo.ConclusionBased upon our results we propose a molecular pathway which has the inherent capacity to resolve the mechanism through which these chemicals may induce vitiligo. This mechanism was also found to be involved in the lesional biopsies of vitiligo patients. These results could be exploited in better understanding the pathogenesis as well as in treatment of vitiligo.

Investigation of immune modulatory anti-leishmanial molecules is now being strongly encouraged to overcome the immunosuppression manifested during visceral leishmaniasis (VL), resistance, toxicity and high cost associated with conventional therapeutics. In the present study, we explored the protective efficacy of vitamin D 3 , retinoic acid and isoprenoid chenodeoxycholic acid (CDCA) combinations against L . donovani infected BALB/c mice. We also probed the immune modulatory response (Th1 & Th2 cytokines) and infection dynamics following experimental infections with drug treated animals. Our results indicate that Vit.D 3 /RA and CDCA/RA combination treatment led to significant inhibition of parasite load on days 21 and 28 post treatment. Furthermore, there was a marked inhibition of Th2 type immune responses in IL-4, IL-5 and polarization of Th1 biased immunity along with upregulation of IL-1, IFN-γ, and TNF-α levels on day 28 post treatment. In addition, mice treated with Vit.D 3 /RA and CDCA/RA demonstrates here that splenic histological recovery against the virulent challenge of L . donovani by day 28 was comparable to control group. The conclusions derived from this study suggests that a combination of vitamin A, D 3 and isoprenoids may have a potential immunomodulatory therapeutic role against leishmaniasis.

Genomic regulation and functional significance of PVT‐1 gene locus, in the MYC‐driven cancers, has remained enigmatic ever since its discovery. With the present study, an attempt is made to establish that cellular AATF genome encoded miR‐2909 RNomics pathway involving crucial genes coding for KLF4, Deptor, mTORC1, STAT3, and p53 has the inherent capacity to ensure sustained co‐amplification of PVT‐1 gene locus together with c‐Myc gene. Based upon these results, we propose that miR‐2909 RNomics pathway may play a crucial role in the regulation of tumorigenic PVT‐1 gene locus.

It is widely believed that selective packaging of nucleic acids, especially microRNAs, into exosomes secreted by the cancer cells not only ensures their growth and survival but also helps in the escape from immune surveillance. Keeping in view the fact that human cellular miR‐2909 has emerged to regulate genes involved in oncogenesis and immunity, the present study was addressed to reveal the nature of miR‐2909 expression within cancer cells of different tissue origin and its incorporation into exosomes secreted by these cells. Post‐transcriptional modification, especially 3′‐end adenylation and uridylation of miR‐2909, exerts opposing effects that may contribute to direct its sorting into exosomes secreted by cancer cells. Our study also revealed that selective partitioning of adenosine kinase, between cancer cells and their secreted exosomes, may be responsible for the nature of post‐transcriptional modification of miR‐2909 observed within these cells.

Background There exists a general recognition of the fact that mitochondrial remodelling as a result of aerobic glycolysis ensures human somatic cells to revert to a more primitive-form exhibiting stem-like phenotype. The present study is an attempt to demonstrate that miR-2909 RNomics within human peripheral blood mononuclear cells (PBMCs) has the inherent capacity to re-program these cells to exhibit mitochondrial remodelling paralleled by aerobic glycolysis together with intracellular lipid inclusions. Such re-programmed PBMCs also expressed genes having ability to sustain their de-differentiation state and survival. Material and methods Human PBMCs were programed to ectopically express miR-2909. Expression levels of genes including glucose transporter-1 (Glut-1), hexokinase (HK), hypoxia inducia factor-1 (HIF-1α), c-Myc, p53,mechanistic target of rapamycin complex (mTORC1), polycombcomplex protein (Bmi-1), Notch,Nanog,Tie-2, Oct-4,CD59, p53, CD34, B-cell lymphoma-2 (Bcl2),sterol regulatory element-binding protein2 (SREBP2), peroxisome proliferator-activated receptor gamma (PPARγ) nuclear respiratory factor 1 (NRF1), mitochondrial transcription factor A (Tfam), peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α) within miR-2909 expression vector transfected human PBMCs as well as PBMCs transfected with control vector containing scrambled sequence after 48h post-transfection using RT-qPCR and cellular ultrastructural features induced by miR-2909 ectopic expression were observed using transmission electron microscopy and morphometric analysis of an electron micrograph. Results Ectopic expression of miR-2909 within human PBMCs resulted in their reprogramming into stem-like phenotype indicated by mitochondrial globular shaped coupled with cristae-poor morphology. Nuclear to cytoplasmic ratio (N/C), quantification of ATP levels, GSSG/GSH ratio, mitochondrial cytochrome c oxidase activity, secreted lactate concentrations, activity of antioxidant enzymes, levels of esterified cholesterol and triglycerides and flow-cytometric detection of apoptosis confirmed the compromised nature of mitochondrial function induced by ectopic miR-2909 expression in human PBMCs. Conclusion Based upon these results we propose that AATF gene-encoded miR-2909 may act as an epigenetic switch for cellular aerobic-glycolysis to ensure de-differentiation.

Most of the cancer types in general and melanoma in particular exhibit mitochondrial dysfunction leading to the Warburg effect. Our present study stemmed from the observation that human A-375 and melanoma B16 cells displayed overexpression of a novel micro-RNA, miR-2909, shown in our earlier studies to be involved in aerobic glycolysis. Consequently, our study attempts to demonstrate the role of miR-2909 in the regulation of mitochondrial function within human melanocytes. Based upon such a study, we hypothesize that mitochondrial dysfunction observed in melanomas may result from deregulated miR-2909 expression within such cells.

Chronic exposure of humans to inorganic arsenic as a potential risk for the incidence of diabetes has received wide attention. However, the biological mechanism through which arsenic plays a role in the development of diabetes is still being evaluated. One of the hallmark of diabetes is the β-cell dysfunction followed by the changes in the insulin secretion. Pancreatic duodenal homeobox 1 (PDX1) has been widely recognized to play crucial role in the β-cell development, survival and its regulation of insulin gene expression. Many of the arsenic mediated cellular affects have been shown to be regulated by miR-2909 in vitro. Our present study provides evidence to reveal that arsenic affects miR-2909 expression in the pancreatic β-cell and this novel miRNA regulates PDX1 transcriptional expression indirectly through genes coding for c-Jun, MafA, PI3K and directly at the translational level by targeting the PDX1 mRNA. We provide further evidence for this miR-2909 RNomics in pancreatic tissue obtained from NOD mice where the expression of miR-2909 was high compared to the control mice. Keeping in view the fact that arsenic is known to cause β-cell dysfunction and most of the cellular effects of arsenic have been shown to be mediated through miR-2909 RNomics, our study revealed that arsenic employs miR-2909 (at low doses) and c-Jun (at high doses) to down regulate PDX1 in order to cause β-cell dysfunction leading to diabetic state.

Cross-talk between coding RNAs and regulatory non-coding microRNAs, within human genome, has provided compelling evidence for the existence of flexible checkpoint control of T-Cell activation. The present study attempts to demonstrate that the interplay between miR-2909 and its effector KLF4 gene has the inherent capacity to regulate genes coding for CTLA4, CD28, CD40, CD134, PDL1, CD80, CD86, IL-6 and IL-10 within normal human peripheral blood mononuclear cells (PBMCs). Based upon these findings, we propose a pathway that links miR-2909 RNomics with the genes coding for immune checkpoint regulators required for the maintenance of immune homeostasis.

Human immune cells have evolved with a membrane trafficking pathway called Autophagy, responsible for engulfing the invading pathogens and thereby equipping these cells with the innate and adaptive immune responses against numerous pathogens. On the other hand, the various pathogens have developed strategies to either block or use the autophagy mechanism to their own advantage [1]. Human immunodeficiency virus type 1 (HIV-1) infects mainly CD4+ Tlymphocytes and macrophages through the interaction of the viral (Env) glycoproteins (Gp120 and Gp41) with CD4 as well as coreceptor, mainly CCR5, expressed at the surface of the target cells. Such type of interaction induces a structural rearrangement in glycoprotein 41 and the insertion of its N-terminus fusion peptide into the target cell membrane, leading to the cellular endocytosis of the HIV-1 viral particles [2]. The HIV-1 replication cycle is governed in two phases: the early phase, from viral entry to provirus integration with cellular genome, and the late phase, from transcription of viral genes to the release of new particles [2].

The global occurrence of prostate cancer with a range of patient outcome has prompted various investigators to explore novel molecular biomarkers that can precisely detect and track this type of cancer severity. Several studies suggest that micro-RNAs have emerged to act as a new largely unexplored class of biomarkers because of their inherent stability, resilience and recruitment into exosomes present in various human body fluids. With this study, we aim to reveal the nature of urinary-exosomal miR-2909 & miR-615-3p recruitment in patients suffering from either prostate cancer (n=90) or bladder cancer (n=60) as compared to that in either prostate disease-control subjects having benign prostate hyperplasia (n=10) or healthy subjects (n=50). Unlike miR-615-3p, the urinary- exosomal miR-2909 recruitment was not only observed conspicuously in subjects having prostate cancer in comparison to bladder cancer but also the extent of urinary exosomal miR-2909 recruitment showed characteristic variation as a function of prostate cancer aggressiveness as compared to that of either urinary- exosomal miR-615-3p level or existing widely recognised serum prostate specifics antigen (PSA) biomarker of this cancer. In summary, we propose that the extent of urinary exosomal miR-2909 recruitment may provide a potential non-invasive candidate diagnostic marker for the detection of prostate cancer and its aggressiveness.