Publications by authors named "Hridayesh Prakash"

37 Publications

Rapid Arc-SBRT: Non-invasive immune adjuvant for advanced stage Non-Small Cell Lung Carcinoma.

Anticancer Agents Med Chem 2021 Mar 21. Epub 2021 Mar 21.

Amity Institute of Virology and Immunology, Amity University, Uttar Pradesh, Sector -125, NOIDA, India.

In conjunction with Radio-chemotherapy, pulmonary resection is recommended for early-stage Non-small-cell lung carcinoma but not for advanced-stage NSCLC patients with having high-grade metastatic lesions. In these cases, Rapid Arc-Stereotactic body radiotherapy (Ra-SBRT) technique offers a therapeutic advantage by delivering focal irradiation to metastatic lung lesions and reduces the bystander toxicity to normal tissues. We have previously demonstrated that Ra-SBRT ablates metastatic lesions and induces tumor immune rejection of metastatic tumors by promoting in situ programming of M2 TAM towards M1-TAM and infiltration of Siglec-8+ Eosinophils. Most interestingly, Ra SBRT has very low abscopal impact and spares normal tissues, which are the significant limitations with conventional radiotherapy. In view of this and Immune adjuvant potential of Ra SBRT, it promotes normalization of aberrant vasculature and inhibits the metastatic potential of NSCLC lesions. In view of this we here propose that Ra-SBRT indeed represents an immunogenic approach for the effective management of advanced-stage NSCLC.
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http://dx.doi.org/10.2174/1871520621666210322105641DOI Listing
March 2021

Editorial: Modulation of Macrophage Signaling Pathways During Bacterial Infections.

Front Cell Infect Microbiol 2021 15;11:689759. Epub 2021 Jun 15.

Amity Institute of Virology and Immunology, Amity University, Noida, India.

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http://dx.doi.org/10.3389/fcimb.2021.689759DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8240064PMC
July 2021

MicroRNAs and Long Noncoding RNAs as Novel Therapeutic Targets in Estrogen Receptor-Positive Breast and Ovarian Cancers.

Int J Mol Sci 2021 Apr 15;22(8). Epub 2021 Apr 15.

Department of Zoology, Central University of Punjab, Ghudda 151 401, Punjab, India.

Aromatase inhibitors (AIs) such as anastrozole, letrozole, and exemestane have shown to prevent metastasis and angiogenesis in estrogen receptor (ER)-positive breast and ovarian tumors. They function primarily by reducing estrogen production in ER-positive post-menopausal breast and ovarian cancer patients. Unfortunately, current AI-based therapies often have detrimental side-effects, along with acquired resistance, with increased cancer recurrence. Thus, there is an urgent need to identify novel AIs with fewer side effects and improved therapeutic efficacies. In this regard, we and others have recently suggested noncoding RNAs (ncRNAs), specifically microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), as potential molecular targets for utilization in modulating cancer hallmarks and overcoming drug resistance in several cancers, including ER-positive breast and ovarian cancer. Herein, we describe the disruptive functions of several miRNAs and lncRNAs seen in dysregulated cancer metabolism, with a focus on the gene encoding for aromatase (CYP19A1 gene) and estrogen synthesis as a novel therapeutic approach for treating ER-positive breast and ovarian cancers. Furthermore, we discuss the oncogenic and tumor-suppressive roles of several miRNAs (oncogenic miRNAs: MIR125b, MIR155, MIR221/222, MIR128, MIR2052HG, and MIR224; tumor-suppressive miRNAs: Lethal-7f, MIR27B, MIR378, and MIR98) and an oncogenic lncRNA (MIR2052HG) in aromatase-dependent cancers via transcriptional regulation of the CYP19A1 gene. Additionally, we discuss the potential effects of dysregulated miRNAs and lncRNAs on the regulation of critical oncogenic molecules, such as signal transducer, and activator of transcription 3, β-catenin, and integrins. The overall goal of this review is to stimulate further research in this area and to facilitate the development of ncRNA-based approaches for more efficacious treatments of ER-positive breast and ovarian cancer patients, with a slight emphasis on associated treatment-delivery mechanisms.
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http://dx.doi.org/10.3390/ijms22084072DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8071157PMC
April 2021

Yin and yang of immunological memory in controlling infections: Overriding self defence mechanisms.

Int Rev Immunol 2021 Apr 19:1-12. Epub 2021 Apr 19.

Amity Institute of Virology and Immunology, Amity University, Noida, India.

Immunological memory is critical for host immunity and decisive for individual to respond exponentially to previously encountered infection. Both T and B cell memory are known to orchestrate immunological memory with their central and effector memory arms contributing in prolonged immunity/defence mechanisms of host. While central memory helps in maintaining prolonged immunity for a particular infection, effector memory helps in keeping local/seasonal infection in control. In addition to this, generation of long-lived plasma cells is pivotal for generating neutralizing antibodies which can enhance recall and B cell memory to control re-infection. In view of this, scaling up memory response is one of the major objectives for the expected outcome of vaccination. In this line, this review deals with the significance of memory cells, molecular pathways of their development, maintenance, epigenetic regulation and negative regulation in various infections. We have also highlighted the significance of both T and B cell memory responses in the vaccination approaches against range of infections which is not fully explored so far.[Box: see text].
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http://dx.doi.org/10.1080/08830185.2021.1912037DOI Listing
April 2021

Prophylactic administration of podophyllotoxin and rutin combination assists the revival of radiation-induced hematopoietic suppression in lethally irradiated mice.

Biochem Biophys Res Commun 2021 04 8;549:214-220. Epub 2021 Mar 8.

Division of Radioprotective Drug Development and Research, Institute of Nuclear Medicine and Allied Sciences, Brig. S.K. Mazumdar Marg, Delhi, 110054, India. Electronic address:

Hematopoietic syndrome contributes to mortality after exposure to high doses of low LET radiation. In this context, we have earlier demonstrated the potential of G-003 M (a combination of podophyllotoxin and rutin) in alleviating radiation-induced bone marrow suppression. Similarly, we here demonstrate that G-003 M protected mice from death (>83% protection) and increased the populations of CD 34 (Cluster of differentiation 34) as well as CD 117 (Cluster of differentiation 117) positive cell population and their colony forming capacity. This was accompanied with increase in the serum titre of granulocyte colony stimulating factor (G-CSF), granulocyte-macrophage colony stimulating factor (GM-CSF). Interestingly, G-003 M lowered down the titre of fms-like tyrosine kinase (Flt-3) ligands. Our results furthermore demonstrates that G-003 M facilitated the nuclear translocation of β-catenin and upregulated the expression of Wnt 10b. Conditioning of animal with G-003 M activated the expression of survivin, inhibited the activation of Caspase-3 in CD 34/117 progenitor stem cells and protected the bone marrow vascularity and splenic colonies in lethally irradiated animals, which collectively promoted hemopoietic recovery in lethally irradiated mice.
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http://dx.doi.org/10.1016/j.bbrc.2021.02.085DOI Listing
April 2021

Omics technologies for improved diagnosis and treatment of colorectal cancer: Technical advancement and major perspectives.

Biomed Pharmacother 2020 Nov 19;131:110648. Epub 2020 Oct 19.

Gene Regulation Laboratory, National Institute of Immunology, New Delhi 110067, India. Electronic address:

Colorectal cancer (CRC) ranks third among the most commonly occurring cancers worldwide, and it causes half a million deaths annually. Alongside mechanistic study for CRC detection and treatment by conventional techniques, new technologies have been developed to study CRC. These technologies include genomics, transcriptomics, proteomics, and metabolomics which elucidate DNA markers, RNA transcripts, protein and, metabolites produced inside the colon and rectum part of the gut. All these approaches form the omics arena, which presents a remarkable opportunity for the discovery of novel prognostic, diagnostic and therapeutic biomarkers and also delineate the underlying mechanism of CRC causation, which may further help in devising treatment strategies. This review also mentions the latest developments in metagenomics and culturomics as emerging evidence suggests that metagenomics of gut microbiota has profound implications in the causation, prognosis, and treatment of CRC. A majority of bacteria cannot be studied as they remain unculturable, so culturomics has also been strengthened to develop culture conditions suitable for the growth of unculturable bacteria and identify unknown bacteria. The overall purpose of this review is to succinctly evaluate the application of omics technologies in colorectal cancer research for improving the diagnosis and treatment strategies.
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http://dx.doi.org/10.1016/j.biopha.2020.110648DOI Listing
November 2020

Host sphingolipids: Perspective immune adjuvant for controlling SARS-CoV-2 infection for managing COVID-19 disease.

Prostaglandins Other Lipid Mediat 2021 02 2;152:106504. Epub 2020 Nov 2.

Institute of Nutritional Science, Department of Nutritional Toxicology, University of Potsdam Nuthetal, Germany.

Sphingolipids are potent bioactive agents involved in the pathogenesis of various respiratory bacterial infections. To date, several sphingolipid derivatives are known, but S1P (Sphingosine-1-phosphate) and Ceramide are the best-studied sphingolipid derivatives in the context of human diseases. These are membrane-bound lipids that influence host-pathogen interactions. Based on these features, we believe that sphingolipids might control SARS-CoV-2 infection in the host. SARS-CoV-2 utilizes the ACE-II receptor (Angiotensin-converting enzyme II receptor) on epithelial cells for its entry and replication. Activation of the ACE-II receptor is indirectly associated with the activation of S1P Receptor 1 signaling which is associated with IL-6 driven fibrosis. This is expected to promote pathological responses during SARS-CoV-2 infection in COVID-19 cases. Given this, mitigating S1P signaling by application of either S1P Lyase (SPL) or S1P analog (Fingolimod / FTY720) seems to be potential approach for controlling these pathological outcomes. However, due to the immunosuppressive nature of FTY720, it can modulate hyper-inflammatory responses and only provide symptomatic relief, which may not be sufficient for controlling the novel COVID-19 infection. Since Th1 effector immune responses are essential for the clearance of infection, we believe that other sphingolipid derivatives like Cermaide-1 Phosphate with antiviral potential and adjuvant immune potential can potentially control SARS-CoV-2 infection in the host by its ability in enhancing autophagy and antigen presentation by DC to promote T cell response which can be helpful in controlling SARS-CoV-2 infection in novel COVID-19 patients.
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http://dx.doi.org/10.1016/j.prostaglandins.2020.106504DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605809PMC
February 2021

Emerging neo adjuvants for harnessing therapeutic potential of M1 tumor associated macrophages (TAM) against solid tumors: Enusage of plasticity.

Ann Transl Med 2020 Aug;8(16):1029

Amity Institute of Virology and Immunology, Amity University Uttar Pradesh, Sector 125, Noida, India.

Macrophages are a major component of the tumor microenvironment (TME) of most tumors. They are characterized by a high degree of functional plasticity which enable these cells to both promote and eliminate established tumors. Under the influence of immunosuppressive TME, tumor infiltrating iNOS+ and CD11b+ M-1 effector macrophages get polarized towards tumor associated macrophages (TAM) which are tropic to variety of tumors. Increased infiltration and density of TAM is associated with tumor progression and poor prognosis in the plethora of tumors due to their angiogenetic and tissue re-modelling nature. Importantly, TAMs are also responsible for developing endothelium anergy, a major physical barrier for majority of cancer directed immune/chemotherapies. Therefore, functional retuning/re-educating TAM to M-1 phenotypic macrophages is paramount for effective immunotherapy against established tumors. In this review, we discuss and provide comprehensive update on TAM-targeted approaches for enhancing immunity against various solid tumors.
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http://dx.doi.org/10.21037/atm-20-695DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7475467PMC
August 2020

Long Non-Coding RNAs as Strategic Molecules to Augment the Radiation Therapy in Esophageal Squamous Cell Carcinoma.

Int J Mol Sci 2020 Sep 16;21(18). Epub 2020 Sep 16.

Department of Zoology, Central University of Punjab, Bathinda 151 001, Punjab, India.

Intrinsic resistance to ionizing radiation is the major impediment in the treatment and clinical management of esophageal squamous cell carcinoma (ESCC), leading to tumor relapse and poor prognosis. Although several biological and molecular mechanisms are responsible for resistance to radiotherapy in ESCC, the molecule(s) involved in predicting radiotherapy response and prognosis are still lacking, thus requiring a detailed understanding. Recent studies have demonstrated an imperative correlation amongst several long non-coding RNAs and their involvement in complex cellular networks like DNA damage and repair, cell cycle, apoptosis, proliferation, and epithelial-mesenchymal transition. Additionally, accumulating evidence has suggested abnormal expression of lncRNAs in malignant tumor cells before and after radiotherapy effects in tumor cells' sensitivity. Thus, lncRNAs indeed represent unique molecules that can influence tumor cell susceptibility for various clinical interventions. On this note, herein, we have summarized the current status of lncRNAs in augmenting resistance/sensitivity in ESCC against radiotherapy. In addition, we have also discussed various strategies to increase the radiosensitivity in ESCC cells under clinical settings.
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http://dx.doi.org/10.3390/ijms21186787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576487PMC
September 2020

A panel of circulating long non-coding RNAs as liquid biopsy biomarkers for breast and cervical cancers.

Biochimie 2020 Sep 4;176:62-70. Epub 2020 Jul 4.

Department of Zoology, Central University of Punjab, Bathinda, Punjab, India. Electronic address:

The early detection and diagnosis of cancer is critical to optimize the treatment and management of cancer patients. Typical methods such as imaging and tissue biopsy are invasive, time-consuming, and often imprecise. Thus, recent technological advances of dependable, facile, and minimally invasive collectible oncogenic biomarkers using human biofluids and secretions have been an active area of research. Recently, circulating long non-coding RNAs (lncRNAs) have been identified as promising biomarkers that fulfill many recommended properties of successful biomarkers for cancer diagnosis and prognosis. LncRNAs play essential roles in many cellular processes including DNA repair, cell proliferation, and epithelial-to-mesenchymal transition (EMT) by regulating the expression of various genes associated with cancer development and progression. Herein, we discuss the regulatory functions/pathways associated with multiple cancer-associated lncRNAs and their potential as prognostic/diagnostic markers for breast and cervical cancers. Additionally, we provide a correlation between lncRNA levels in the blood and clinicopathological data, including sensitivity, specificity, and Area Under Curve (AUC) merits of model performance value.
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http://dx.doi.org/10.1016/j.biochi.2020.06.012DOI Listing
September 2020

Sphingosine-1-Phosphate (S-1P) Promotes Differentiation of Naive Macrophages and Enhances Protective Immunity Against .

Front Immunol 2019 24;10:3085. Epub 2020 Jan 24.

Laboratory of Translational Medicine, School of Life Science, University of Hyderabad, Hyderabad, India.

Sphingosine-1-phosphate (S-1P) is a key sphingolipid involved in the pathobiology of various respiratory diseases. We have previously demonstrated the significance of S-1P in controlling non-pathogenic mycobacterial infection in macrophages, and here we demonstrate the therapeutic potential of S-1P against pathogenic (H37Rv) in the mouse model of infection. Our study revealed that S-1P is involved in the expression of iNOS proteins in macrophages, their polarization toward M1 phenotype, and secretion of interferon (IFN)-γ during the course of infection. S-1P is also capable of enhancing infiltration of pulmonary CD11b+ macrophages and expression of S-1P receptor-3 (S-1PR3) in the lungs during the course of infection. We further revealed the influence of S-1P on major signaling components of inflammatory signaling pathways during infection, thus highlighting antimycobacterial potential of S-1P in animals. Our data suggest that enhancing S-1P levels by sphingolipid mimetic compounds/drugs can be used as an immunoadjuvant for boosting immunity against pathogenic mycobacteria.
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http://dx.doi.org/10.3389/fimmu.2019.03085DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6993045PMC
November 2020

SNHG12: An LncRNA as a Potential Therapeutic Target and Biomarker for Human Cancer.

Front Oncol 2019 18;9:901. Epub 2019 Sep 18.

Department of Animal Sciences, Central University of Punjab, Bathinda, India.

Limitations in current diagnostic procedures warrant identification of new methodologies to improve diagnoses of cancer patients. In this context, long non-coding RNAs (lncRNAs) have emerged as stable biomarkers which are expressed abundantly in tumors. Importantly, these can be detected at all stages of tumor development, and thus may provide potential biomarkers and/or therapeutic targets. Recently, we suggested that aberrant levels of lncRNAs can be used to determine the invasive and metastatic potential of tumor cells. Further, direct correlations of lncRNAs with cancer-derived inflammation, metastasis, epithelial-to-mesenchymal transition, and other hallmarks of cancer indicate their potential as biomarkers and targets for cancer. Thus, in this review we have discussed the importance of small nucleolar RNA host gene 12 (SNHG12), a lncRNA, as a potential biomarker for a variety of cancers. A meta-analysis of a large cohort of cancer patients revealed that SNHG12 may also serve as a potential target for cancer-directed interventions due to its involvement in unfolded protein responses, which many tumor cells exploit to both evade immune-mediated attack and enhance the polarization of effector immune cells (e.g., macrophages and T cells). Thus, we propose that SNHG12 may serve as both a biomarker and a druggable therapeutic target with promising clinical potential.
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http://dx.doi.org/10.3389/fonc.2019.00901DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6759952PMC
September 2019

Circulating microRNA-590-5p functions as a liquid biopsy marker in non-small cell lung cancer.

Cancer Sci 2020 Mar 31;111(3):826-839. Epub 2020 Jan 31.

Department of Animal Sciences, Central University of Punjab, Bathinda, Punjab, India.

Despite the availability of various diagnostic procedures, a tissue biopsy is still indispensable for the routine diagnosis of lung cancer. However, inaccurate diagnoses can occur, leading to inefficient cancer management. In this context, use of circulating microRNAs (miRNAs) may serve as diagnostic tools as liquid biopsies, and as biomarkers to better understand the molecular mechanisms involved in the progression of cancer. We identified miR-590-5p as a potential prognostic marker in the progression of non-small cell lung cancer (NSCLC). We were able to detect this miRNA in blood plasma samples of NSCLC patients through quantitative real-time PCR. Our data showed an ~7.5-fold downregulation of miR-590-5p in NSCLC patients compared to healthy controls, which correlated with several clinicopathological features. Further, overexpression of miR-590-5p led to decreased cell viability, proliferation, colony formation, migration, and invasion potential of lung cancer cells, whereas its knockdown showed the opposite effect. In addition, the levels of several proteins involved in the epithelial-to-mesenchymal transition negatively correlated with miR-590-5p levels in lung adenocarcinoma cells and tumors of NSCLC patients. Further, dual-luciferase reporter assays identified STAT3 as a direct target of miR-590-5p, which negatively regulated STAT3 activation and its downstream signaling molecules (eg, Cyclin D1, c-Myc, Vimentin, and β-catenin) involved in tumorigenesis. Taken together, our study suggests that miR-590-5p functions as a tumor suppressor in NSCLC through regulating the STAT3 pathway, and may serve as a useful biomarker for the diagnosis/prognosis of NSCLC, and as a potential therapeutic target for the treatment of NSCLC.
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http://dx.doi.org/10.1111/cas.14199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7060464PMC
March 2020

Dysbiosis Disrupts Gut Immune Homeostasis and Promotes Gastric Diseases.

Int J Mol Sci 2019 May 16;20(10). Epub 2019 May 16.

Amity Institute of Virology and Immunology, Amity University, Sector 125, Noida 201313, Uttar Pradesh, India.

Perturbation in the microbial population/colony index has harmful consequences on human health. Both biological and social factors influence the composition of the gut microbiota and also promote gastric diseases. Changes in the gut microbiota manifest in disease progression owing to epigenetic modification in the host, which in turn influences differentiation and function of immune cells adversely. Uncontrolled use of antibiotics, chemotherapeutic drugs, and any change in the diet pattern usually contribute to the changes in the colony index of sensitive strains known to release microbial content in the tissue micromilieu. Ligands released from dying microbes induce Toll-like receptor (TLR) mimicry, skew hypoxia, and cause sterile inflammation, which further contributes to the severity of inflammatory, autoimmune, and tumorous diseases. The major aim and scope of this review is both to discuss various modalities/interventions across the globe and to utilize microbiota-based therapeutic approaches for mitigating the disease burden.
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http://dx.doi.org/10.3390/ijms20102432DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6567003PMC
May 2019

Podophyllotoxin and Rutin Modulate M1 (iNOS+) Macrophages and Mitigate Lethal Radiation (LR) Induced Inflammatory Responses in Mice.

Front Immunol 2019 12;10:106. Epub 2019 Feb 12.

Laboratory of Translational Medicine, School of Life Science, University of Hyderabad, Hyderabad, India.

Accidental exposure to lethal doses of Gamma radiation leads to the systemic inflammatory syndrome which causes mortality. In view of this, management of hemopoietic syndrome by modulating pro-inflammatory response in clinically manageable time period seems to be the most appropriate strategy for encountering radiation induced damage and recovery. As both tissue and peripheral macrophages are critical for the management of radiation induced injuries, we have unraveled the immunomodulatory potential of radioprotective formulation (G-003M) on peripheral macrophages populations in this study. G-003M inhibited lethal radiation induced NO and Th1 effector cytokines in the exposed macrophages indicating its M1 dim polarizing capacity. In similar lines, conditioning of mice with G-003M before lethal irradiation (LR) inhibited LR induced titre of Th1 effector cytokines in both serums as well as in lung, small intestine, and spleen tissue confirming its immunomodulatory potential. G-003M potentially down modulated inflammatory response in LPS induced inflammatory model and enhanced M2 polarization of iNOS+ M1 effector macrophages providing a molecular hint on G-003M mechanism of action on macrophages. These observations revealed that G-003M potentially modulate pro-inflammatory programming of macrophages and mitigate radiation-induced inflammatory stress which is believed to contribute significantly to radioprotective attribute of G-003M. In this study, we demonstrate that Rutin and Podophyllotoxin drive M1/M2 polarization of LR primed macrophages apart from protecting DNA from radiation. These drugs have the capacity to programme innate immune cells like macrophages which may be involved in homeostasis during recovery.
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http://dx.doi.org/10.3389/fimmu.2019.00106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6379314PMC
December 2019

Stabilization of miRNAs in esophageal cancer contributes to radioresistance and limits efficacy of therapy.

Biochimie 2019 Jan 13;156:148-157. Epub 2018 Oct 13.

Department of Animal Sciences, Central University of Punjab, Bathinda, Punjab, India. Electronic address:

The five-year survival rate of esophageal cancer patients is less than 20%. This may be due to increased resistance (acquired or intrinsic) of tumor cells to chemo/radiotherapies, often caused by aberrant cell cycle, deregulated apoptosis, increases in growth factor signaling pathways, and/or changes in the proteome network. In addition, deregulation in non-coding RNA-mediated signaling pathways may contribute to resistance to therapies. At the molecular level, these resistance factors have now been linked to various microRNA (miRNAs), which have recently been shown to control cell development, differentiation and neoplasia. The increased stability and dysregulated expression of miRNAs have been associated with increased resistance to various therapies in several cancers, including esophageal cancer. Therefore, miRNAs represent the next generation of molecules with tremendous potential as biomarkers and therapeutic targets. However, detailed studies on miRNA-based therapeutic interventions are still in their infancy. Hence, in this review, we have summarized the current status of microRNAs in dictating the resistance/sensitivity of tumor cells to chemotherapy and radiotherapy. In addition, we have discussed various strategies to increase radiosensitivity, including targeted therapy, and the use of miRNAs as radiosensitive/radioresistance biomarkers for esophageal cancer in the clinical setting.
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http://dx.doi.org/10.1016/j.biochi.2018.10.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7052947PMC
January 2019

Low dose radiation primed iNOS + M1macrophages modulate angiogenic programming of tumor derived endothelium.

Mol Carcinog 2018 11 10;57(11):1664-1671. Epub 2018 Aug 10.

Laboratory of Translational Medicine, School of Life Sciences, University of Hyderabad, Hyderabad, Telangana, India.

Solid tumors are covered by stroma, which is hypoxic in nature and composed of various non-malignant components such as endothelial cells, fibroblasts, and pericytes that support tumor growth. Tumor stroma represents a mechanical barrier for tumor infiltration of CD8+ effector T cells in particular. In this context, our previous studies have demonstrated the therapeutic impact of Low-Dose Radiation (LDR)-primed and M1-retuned (iNOS+) peritumoral macrophages that produce inducible nitric oxide, have immunological roles on tumor infiltration of effector T cells, cancer-related inflammation, and subsequent tumor immune rejection in a mouse model of pancreatic cancer. These findings suggested a possible modification of tumor endothelium by LDR-primed macrophages. In line with these observations, here we demonstrate the influence of LDR in down-modulating HIF-1 in irradiated tumors in the course of polarization of irradiated tumor-associated macrophages toward an M1 phenotype. Furthermore, we demonstrate that M1 macrophages which are primed by LDR can directly influence angiogenic responses in eNOS+ endothelial cells which produce nitric oxide having both vascular and physiological roles. Furthermore, we demonstrate that naïve macrophages, upon differentiating to an M1 phenotype either by Th1 stimuli or LDR, potentially modify sphingosine-1-phosphate/VEGF-induced angiogenic signaling in tumor-derived endothelial cells with tumorigenic potential, thus indicating the significance of iNOS+ macrophages in modulating signaling in eNOS+ tumor-derived endothelium. Our study suggests that iNOS+ macrophages can activate tumor endothelium which may contribute to cancer-directed immunotherapy in particular.
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http://dx.doi.org/10.1002/mc.22879DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7051861PMC
November 2018

Inhibitors of Apoptosis Protein Antagonists (Smac Mimetic Compounds) Control Polarization of Macrophages during Microbial Challenge and Sterile Inflammatory Responses.

Front Immunol 2017 9;8:1792. Epub 2018 Jan 9.

Laboratory of Translational Medicine, School of Life Sciences, University of Hyderabad, Telangana, India.

Apoptosis is a physiological cell death process essential for development, tissue homeostasis, and for immune defense of multicellular animals. Inhibitors of apoptosis proteins (IAPs) regulate apoptosis in response to various cellular assaults. Using both genetic and pharmacological approaches we demonstrate here that the IAPs not only support opportunistic survival of intracellular human pathogens like but also control plasticity of iNOS+ M1 macrophage during the course of infection and render them refractory for immune stimulation. Treatment of Th1 primed macrophages with birinapant (IAP-specific antagonist) inhibited NO generation and relevant proteins involved in innate immune signaling. Accordingly, birinapant promoted hypoxia, angiogenesis, and tumor-induced M2 polarization of iNOS+ M1 macrophages. Interestingly, birinapant-driven changes in immune signaling were accompanied with changes in the expression of various proteins involved in the metabolism, and thus revealing the new role of IAPs in immune metabolic reprogramming in committed macrophages. Taken together, our study reveals the significance of IAP targeting approaches (Smac mimetic compounds) for the management of infectious and inflammatory diseases relying on macrophage plasticity.
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http://dx.doi.org/10.3389/fimmu.2017.01792DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5767188PMC
January 2018

The regulatory roles of long non-coding RNAs in the development of chemoresistance in breast cancer.

Oncotarget 2017 Dec 8;8(66):110671-110684. Epub 2017 Nov 8.

Center for Animal Sciences, Central University of Punjab, Bathinda, Punjab, India.

Chemoresistance is one of the major hurdles in the treatment of breast cancer, which limits the effect of both targeted and conventional therapies in clinical settings. Therefore, understanding the mechanisms underpinning resistance is paramount for developing strategies to circumvent resistance in breast cancer patients. Several published reports have indicated that lncRNAs play a dynamic role in the regulation of both intrinsic and acquired chemoresistance through a variety of mechanisms that endow cells with a drug-resistant phenotype. Although a number of lncRNAs have been implicated in chemoresistance of breast cancer, their mechanistic roles have not been systematically reviewed. Thus, here we present a detailed review on the latest research findings and discoveries on the mechanisms of acquisition of chemoresistance in breast cancer related to lncRNAs, and how lncRNAs take part in various cancer signalling pathways involved in breast cancer cells. Knowledge obtained from this review could assist in the development of new strategies to avoid or reverse drug resistance in breast cancer chemotherapy.
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http://dx.doi.org/10.18632/oncotarget.22577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5746413PMC
December 2017

Poly-N-acryloyl-(l-phenylalanine methyl ester) hollow core nanocapsules facilitate sustained delivery of immunomodulatory drugs and exhibit adjuvant properties.

Nanoscale 2017 Sep;9(37):14006-14014

School of Engineering Science and Technology, University of Hyderabad, Prof. C. R. Rao Road, 500046, Hyderabad, Telangana, India.

Polymeric hollow nanocapsules have attracted significant research attention as novel drug carriers and their preparation is of particular concern owing to the feasibility to encapsulate a broad range of drug molecules. This work presents for the first time the synthesis and development of novel poly-N-acryloyl l-phenylalanine methyl ester hollow core nanocapsules (NAPA-HPNs) of avg. size ca. 100-150 nm by the mini-emulsion technique. NAPA-HPNs are biocompatible and capable of encapsulating sodium nitroprusside (SNP) at a rate of ∼1.3 μM per mg of capsules. These NAPA-HPNs + SNP nano-formulations maintained homeostasis of macrophages which carry and facilitate the action of various drug molecules used against various diseases. These NAPA-HPNs also facilitate the prolonged release of a low level of nitric oxide (NO) and enhance the metabolic activities of pro-inflammatory macrophages, which are important for the action of various drugs in body fluids. NAPA-HPN mediated skewing of naïve macrophages toward the M1 phenotype potentially demonstrates its adjuvant action on the innate immune system. These results potentially suggested that NAPA-HPNs can serve both as a carrier of drugs as well as an adjuvant for the immune system. Thus, these nanocapsules could be used for the effective management of various infectious or tumor diseases where immune-stimulation is paramount for treatment.
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http://dx.doi.org/10.1039/c7nr03724dDOI Listing
September 2017

A Combination of Podophyllotoxin and Rutin Alleviates Radiation-Induced Pneumonitis and Fibrosis through Modulation of Lung Inflammation in Mice.

Front Immunol 2017 9;8:658. Epub 2017 Jun 9.

Institute of Nuclear Medicine and Allied Sciences (INMAS), DRDO, New Delhi, India.

Pneumonitis and pulmonary fibrosis are predominant consequences of radiation exposure, whether planned or accidental. The present study, demonstrates radioprotective potential of a formulation, prepared by combining podophyllotoxin and rutin (G-003M), in mice exposed to 11 Gy thoracic gamma radiation (TGR). Treated mice were observed for survival and other symptomatic features. Formation of reactive oxygen species (ROS)/nitric oxide (NO) was measured in bronchoalveolar lavage cells. DNA damage and cell death were assessed in alveolar cells by terminal deoxynucleotidyl transferase dUTP nick-end labeling assay. Total protein (TP), lactate dehydrogenase (LDH), and alkaline phosphatase (ALP) were measured in bronchoalveolar lavage fluid (BALF)/serum of mice to assess lung vascular permeability. Interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), transforming growth factor-β1 (TGF-β1), cluster of differentiation 45, inducible nitric oxide synthase (iNOS), and nitrotyrosine were also estimated in lungs/BALF of differentially treated mice. Our observations revealed 100% survival in G-003M-pretreated mice against 66.50% in 11 Gy TGR exposed. Other symptoms like reduction in graying of hair, weight loss, and breathing rate were also observed in pretreated groups. Significant decline in ROS/NO and cell death in formulation pretreated mice were also observed. Decreased level of TP, LDH, and ALP in BALF/serum samples revealed G-003M-induced inhibition in lung permeability. Level of IL-6, TNF-α, and TGF-β1 in the lungs of these mice was found corresponding to control group at 8 weeks posttreatment. On the contrary, these cytokines raised significantly in 11 Gy TGR-exposed mice. Lung pneumonitis and fibrosis were found significantly countered in these mice. The observations revealed that G-003M could regulate immune system by curtailing radiation-induced oxidative and inflammatory stress, which has helped in minimizing radiation-inflicted pneumonitis and fibrosis.
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http://dx.doi.org/10.3389/fimmu.2017.00658DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5465247PMC
June 2017

The phosphodiesterase 4 inhibitor apremilast inhibits Th1 but promotes Th17 responses induced by 6-sulfo LacNAc (slan) dendritic cells.

J Dermatol Sci 2017 Aug 20;87(2):110-115. Epub 2017 Apr 20.

Department of Dermatology, University Hospital Heidelberg, Germany. Electronic address:

Background: The phosphodiesterase 4 (PDE4) inhibitor apremilast increases cellular cAMP levels and has proven effective in the treatment of psoriasis and psoriasis arthritis. We recently described 6-sulfo LacNAc dendritic cells (slanDCs) as immature DCs in blood and as a subset of inflammatory dermal DCs in psoriasis with a pronounced capacity to produce proinflammatory cytokines and to program Th17/Th1 T cell responses.

Objective: The aim of this study was to investigate possible immune regulatory effects of the PDE4 inhibitor apremilast on slanDCs.

Methods: In vitro studies were performed analyzing the effects of apremilast on the proinflammatory function of slanDCs and their capacity to induce Th1/Th17-biased T cell responses.

Results: Increasing cAMP levels in slanDCs by PDE4 inhibition strongly reduced production of IL-12 and TNF-α. In line with these findings, co-culture experiments with apremilast-pulsed slanDCs and allogeneic T cells either from psoriasis patients or healthy controls, revealed a significant reduction of IFN-γ production and expression of the transcription factor T-bet. In parallel, production of IL-23 and IL-1ß by slanDCs was increased and co-cultured T cells revealed a largely augmented IL-17 production and an upregulated RORyt expression.

Conclusions: We here demonstrate anti-inflammatory as well as Th17-promoting effects of apremilast when studying blood precursors of human inflammatory dermal dendritic cells. In the concert of the broad anti-inflammatory effects of apremilast on keratinocytes, fibroblasts and endothelial cells, the dual effect on slan inflammatory dermal DCs should be taken into account and may constrain therapeutic responses.
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http://dx.doi.org/10.1016/j.jdermsci.2017.04.005DOI Listing
August 2017

Sphingolipids Are Dual Specific Drug Targets for the Management of Pulmonary Infections: Perspective.

Front Immunol 2017 29;8:378. Epub 2017 Mar 29.

Laboratory of Translational Medicine, School of Life Sciences, University of Hyderabad , Hyderabad, Telengana , India.

Sphingolipids are the major constituent of the mucus secreted by the cells of epithelial linings of lungs where they maintain the barrier functions and prevent microbial invasion. Sphingolipids are interconvertible, and their primary and secondary metabolites have both structural and functional roles. Out of several sphingolipid metabolites, sphingosine-1 phosphate (S1P) and ceramide are central molecules and decisive for sphingolipid signaling. These are produced by enzymatic activity of sphingosine kinase-1 (SK-1) upon the challenge with either biological or physiological stresses. S1P and ceramide rheostat are important for the progression of various pathologies, which are manifested by inflammatory cascade. S1P is a well-established secondary messenger and associated with various neuronal, metabolic, and inflammatory diseases other than respiratory infections such as , and . These pathogens are known to exploit sphingolipid metabolism for their opportunistic survival. Decreased sphingosine kinase activity/S1P content in the lung and peripheral blood of tuberculosis patients clearly indicated a dysregulation of sphingolipid metabolism during infection and suggest that sphingolipid metabolism is important for management of infection by the host. Our previous study has demonstrated that gain of SK-1 activity is important for the maturation of phagolysosomal compartment, innate activation of macrophages, and subsequent control of mycobacterial replication/growth in macrophages. Furthermore, S1P-mediated amelioration of lung pathology and disease severity in TB patients is believed to be mediated by the selective activation or rearrangement of various S1P receptors (S1PR) particularly S1PR2, which has been effective in controlling respiratory fungal pathogens. Therefore, such specificity of S1P-S1PR would be paramount for triggering inflammatory events, subsequent activation, and fostering bactericidal potential in macrophages for the control of TB. In this review, we have discussed and emphasized that sphingolipids may represent effective novel, yet dual specific drug targets for controlling pulmonary infections.
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http://dx.doi.org/10.3389/fimmu.2017.00378DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5372786PMC
March 2017

Podophyllotoxin and Rutin Modulates Ionizing Radiation-Induced Oxidative Stress and Apoptotic Cell Death in Mice Bone Marrow and Spleen.

Front Immunol 2017 27;8:183. Epub 2017 Feb 27.

Division of Radioprotective Drug Development and Research, Institute of Nuclear Medicine and Allied Sciences, Defense Research and Development Organization , Delhi , India.

The present study is aimed to investigate the radioprotective efficacy of G-003M (combination of podophyllotoxin and rutin) against gamma radiation-induced oxidative stress and subsequent cell death in mice bone marrow and spleen. Prophylactic administration of G-003M (-1 h) rendered more than 85% survival in mice exposed to 9 Gy (lethal dose) with dose reduction factor of 1.26. G-003M pretreated mice demonstrated significantly reduced level of reactive oxygen species, membrane lipid peroxidation, and retained glutathione level. In the same group, we obtained increased expression of master redox regulator, nuclear factor erythroid-derived like-2 factor (Nrf-2), and its downstream targets (heme oxygenase-1, Nqo-1, glutathione -transferase, and thioredoxin reductase-1). In addition, G-003M preadministration has also shown a significant reduction in Keap-1 level (Nrf-2 inhibitor). Radiation-induced lethality was significantly amended in combination-treated (G-003M) mice as demonstrated by reduced 8-OHdG, annexin V FITC cells, and restored mitochondrial membrane potential. Expression of antiapoptotic protein Bcl-2 and Bcl-xL was restored in G-003M pretreated group. However, proapoptotic proteins (Puma, Bax, Bak, Caspase-3, and Caspase-7) were significantly declined in this group. Further analysis of immune cells revealed G-003M-mediated restoration of CD3 and CD19 receptor, which was found decreased to significant level following irradiation. Similarly, Gr-1, a marker of granulocytes, was also retained by G-003M administration prior to radiation. Modulatory potential of this formulation (G-003M) can be exploited as a safe and effective countermeasure against radiation-induced lymphohemopoietic injury.
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http://dx.doi.org/10.3389/fimmu.2017.00183DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5326804PMC
February 2017

CD14/TLR4 priming potentially recalibrates and exerts anti-tumor efficacy in tumor associated macrophages in a mouse model of pancreatic carcinoma.

Sci Rep 2016 08 11;6:31490. Epub 2016 Aug 11.

Department of Visceral Surgery, University Medical Center, Heidelberg, Germany.

Pancreatic cancer is the fourth major cause of cancer related deaths in the world and 5 year survival is below 5%. Among various tumor directed therapies, stimulation of Toll-like receptors (TLR) has shown promising effects in various tumor models. However, pancreatic cancer cells frequently express these receptors themselves and their stimulation (TLR 2 and/or 4 particularly) within tumor microenvironment is known to potentially enhance tumor cell proliferation and cancer progression. Consistent stimulation of tumor associated macrophages (TAMs), in particular with tumor derived TLR ligand within the tumor microenvironment promotes cancer related inflammation, which is sterile, non-immunogenic and carcinogenic in nature. In view of this, recalibrating of TAM has the potential to induce immunogenic inflammation. Consistent with this, we provide experimental evidence for the first time in this study that priming of TAMs with TLR4 ligend (LPS) alone or in combination with IFN-γ not only recalibrates pancreatic tumor cells induced M2 polarization, but also confers anti-tumor potential in TAMs. Most interestingly, reduced tumor growth in macrophage depleted animals suggests that macrophage directed approaches are important for the management of pancreatic tumors.
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http://dx.doi.org/10.1038/srep31490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4980608PMC
August 2016

Recent Advances in Biosensor Technology for Potential Applications - An Overview.

Front Bioeng Biotechnol 2016 16;4:11. Epub 2016 Feb 16.

School of Life Sciences, University of Hyderabad , Hyderabad , India.

Imperative utilization of biosensors has acquired paramount importance in the field of drug discovery, biomedicine, food safety standards, defense, security, and environmental monitoring. This has led to the invention of precise and powerful analytical tools using biological sensing element as biosensor. Glucometers utilizing the strategy of electrochemical detection of oxygen or hydrogen peroxide using immobilized glucose oxidase electrode seeded the discovery of biosensors. Recent advances in biological techniques and instrumentation involving fluorescence tag to nanomaterials have increased the sensitive limit of biosensors. Use of aptamers or nucleotides, affibodies, peptide arrays, and molecule imprinted polymers provide tools to develop innovative biosensors over classical methods. Integrated approaches provided a better perspective for developing specific and sensitive biosensors with high regenerative potentials. Various biosensors ranging from nanomaterials, polymers to microbes have wider potential applications. It is quite important to integrate multifaceted approaches to design biosensors that have the potential for diverse usage. In light of this, this review provides an overview of different types of biosensors being used ranging from electrochemical, fluorescence tagged, nanomaterials, silica or quartz, and microbes for various biomedical and environmental applications with future outlook of biosensor technology.
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http://dx.doi.org/10.3389/fbioe.2016.00011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4754454PMC
February 2016

Low doses of gamma irradiation potentially modifies immunosuppressive tumor microenvironment by retuning tumor-associated macrophages: lesson from insulinoma.

Carcinogenesis 2016 Mar 19;37(3):301-313. Epub 2016 Jan 19.

Translational Immunology Division , German Cancer Research Center (DKFZ) and National Center of Tumor Diseases (NCT) , Im-Neuenheimer Feld 460 , 69120 Heidelberg , Germany.

Tumor infiltrating iNOS+ macrophages under the influence of immunosuppressive tumor microenvironment gets polarized to tumor-promoting and immunosuppressive macrophages, known as tumor-associated macrophages (TAM). Their recruitment and increased density in the plethora of tumors has been associated with poor prognosis in cancer patients. Therefore, retuning of TAM to M1 phenotype would be a key for effective immunotherapy. Radiotherapy has been a potential non-invasive strategy to improve cancer immunotherapy and tumor immune rejection. Irradiation of late-stage tumor-bearing Rip1-Tag5 mice twice with 2 Gy dose resulted in profound changes in the inflammatory tumor micromilieu, characterized by induction of M1-associated effecter cytokines as well as reduction in protumorigenic and M2-associated effecter cytokines. Similarly, in vitro irradiation of macrophages with 2 Gy dose-induced expression of iNOS, NO, NFκBpp65, pSTAT3 and proinflammatory cytokines secretion while downregulating p38MAPK which are involved in iNOS translation and acquisition of an M1-like phenotype. Enhancement of various M2 effecter cytokines and angiogenic reprogramming in iNOs+ macrophage depleted tumors and their subsequent reduction by 2 Gy dose in Rip1-Tag5 transgenic mice furthermore demonstrated a critical role of peritumoral macrophages in the course of gamma irradiation mediated M1 retuning of insulinoma.
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http://dx.doi.org/10.1093/carcin/bgw007DOI Listing
March 2016
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