Publications by authors named "Prabhakar B"

355 Publications

Vemurafenib may overcome TNF-related apoptosis-inducing ligand (TRAIL) resistance in anaplastic thyroid cancer cells.

Endocrine 2020 01 3;67(1):117-123. Epub 2019 Aug 3.

Department of Medical and Surgical Sciences and Neurosciences, University of Siena, Siena, Italy.

Purpose: Anaplastic thyroid cancer (ATC) is rare but with poor prognosis. TRAIL can selectively induce apoptosis in cancer cells; however, resistance is quite common. Aim of our study was to evaluate TRAIL-induced apoptosis in ATC-derived cell lines, in vitro and in vivo, and the effect of combination with tyrosine kinase inhibitors (TKIs) selective for BRAF (vemurafenib) or Akt (MK-2206).

Methods: Four ATC-derived cell lines were used: C643, CAL62, HTh7, with activating mutation of RAS and copy gain of PI3K (HTh7) and, 8505C with activating mutation of BRAF. Cells were treated with TRAIL alone or in combination with vemurafenib or MK-2206. The pro-apoptotic effect of TRAIL alone or combined with TKIs was, also, evaluated in two mouse xenograft models (HTh7 and 8505C).

Results: C643, CAL62, and HTh7 cells were sensitive to TRAIL-induced apoptosis, whereas 8505C cells were resistant. Both in vitro and in vivo vemurafenib was able to increase the TRAIL-induced apoptosis in 8505C cells causing a slower tumor growth in 8505C xenograft compared to placebo, while MK-2206 did not have any additive effect on TRAIL treatment in HTh7 model.

Conclusions: TRAIL is a promising therapeutic agent in ATC and in case of resistance vemurafenib may be a valid complementary therapy.
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http://dx.doi.org/10.1007/s12020-019-02028-2DOI Listing
January 2020

Heat Shock Proteins and their Protective Roles in Stem Cell Biology.

Stem Cell Rev Rep 2019 10;15(5):637-651

Shobhaben Pratapbhai Patel School of Pharmacy and Technology Management, SVKM's NMIMS, V.L. Mehta Road, Vile Parle (W), Mumbai, India.

Stem cells (SCs) are discovered long back but the idea that SCs possess therapeutic potential came up just a few decades back. In a past decade stem cell therapy is highly emerged and displayed tremendous potential for the treatment of a wide range of diseases and disorders such as blindness and vision impairment, type I diabetes, infertility, HIV, etc. SCs are very susceptible to destruction after transplantation into the host because of the inability to sustain elevated stress conditions inside the damaged tissue/organ. Heat shock proteins (HSPs) are molecular chaperones/stress proteins expressed in response to stress (elevated temperature, harmful chemicals, ischemia, viruses, etc) inside a living cell. HSPs protect the cell from damage by assisting in the proper folding of cellular proteins. This review briefly summarises different types of HSPs, their classification, cellular functions as well as the role of HSPs in regulating SC self-renewal and survival in the transplanted host. Applications of HSP modulated SCs in regenerative medicine and for the treatment of ischemic heart disease, myocardial infarction (MI), osteoarthritis, ischemic stroke, spinocerebellar ataxia type 3 (SCA3), leukemia, hepatic ischemia-reperfusion injury, Graft-versus-host disease (GVHD) and Parkinson's disease (PD) are discussed. In order to provide potential insights in understanding molecular mechanisms related to SCs in vertebrates, correlations between HSPs and SCs in cnidarians and planarians are also reviewed. There is a need to advance research in order to validate the use of HSPs for SC therapy and establish effective treatment strategies.
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http://dx.doi.org/10.1007/s12015-019-09903-5DOI Listing
October 2019

An Oncolytic Adenovirus Targeting Transforming Growth Factor β Inhibits Protumorigenic Signals and Produces Immune Activation: A Novel Approach to Enhance Anti-PD-1 and Anti-CTLA-4 Therapy.

Hum Gene Ther 2019 09 1;30(9):1117-1132. Epub 2019 Jul 1.

Gene Therapy Program, Department of Medicine, NorthShore Research Institute, an Affiliate of the University of Chicago, Evanston, Illinois.

In an effort to develop a new therapy for cancer and to improve antiprogrammed death inhibitor-1 (anti-PD-1) and anticytotoxic T lymphocyte-associated protein (anti-CTLA-4) responses, we have created a telomerase reverse transcriptase promoter-regulated oncolytic adenovirus rAd.sT containing a soluble transforming growth factor receptor II fused with human IgG Fc fragment (sTGFβRIIFc) gene. Infection of breast and renal tumor cells with rAd.sT produced sTGFβRIIFc protein with dose-dependent cytotoxicity. In immunocompetent mouse 4T1 breast tumor model, intratumoral delivery of rAd.sT inhibited both tumor growth and lung metastases. rAd.sT downregulated the expression of several transforming growth factor β (TGFβ) target genes involved in tumor growth and metastases, inhibited Th2 cytokine expression, and induced Th1 cytokines and chemokines, and granzyme B and perforin expression. rAd.sT treatment also increased the percentage of CD8 T lymphocytes, promoted the generation of CD4 T memory cells, reduced regulatory T lymphocytes (Tregs), and reduced bone marrow-derived suppressor cells. Importantly, rAd.sT treatment increased the percentage of CD4 T lymphocytes, and promoted differentiation and maturation of antigen-presenting dendritic cells in the spleen. In the immunocompetent mouse Renca renal tumor model, similar therapeutic effects and immune activation results were observed. In the 4T1 mammary tumor model, rAd.sT improved the inhibition of tumor growth and lung and liver metastases by anti-PD-1 and anti-CTLA-4 antibodies. Analysis of the human breast and kidney tumors showed that a significant number of tumor tissues expressed high levels of TGFβ and TGFβ-inducible genes. Therefore, rAd.sT could be a potential enhancer of anti-PD-1 and anti-CTLA-4 therapy for treating breast and kidney cancers.
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http://dx.doi.org/10.1089/hum.2019.059DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6761593PMC
September 2019

MADD silencing enhances anti-tumor activity of TRAIL in anaplastic thyroid cancer.

Endocr Relat Cancer 2019 06;26(6):551-563

Department of Microbiology and Immunology, University of Illinois College of Medicine, Chicago, Illinois, USA.

ATC is an aggressive disease with limited therapeutic options due to drug resistance. TRAIL is an attractive anti-cancer therapy that can trigger apoptosis in a cancer cell-selective manner. However, TRAIL resistance is a major clinical obstacle for its use as a therapeutic drug. Previously, we demonstrated that MADD is a cancer cell pro-survival factor that can modulate TRAIL resistance. However, its role, if any, in overcoming TRAIL resistance in ATC is unknown. First, we characterized ATC cell lines as either TRAIL resistant, TRAIL sensitive or moderately TRAIL sensitive and evaluated MADD expression/cellular localization. We determined the effect of MADD siRNA on cellular growth and investigated its effect on TRAIL treatment. We assessed the effect of combination treatment (MADD siRNA and TRAIL) on mitochondrial membrane potential (MMP) and reactive oxygen species (ROS) levels. The effect of combination treatment on tumor growth was assessed in vivo. We found increased levels of MADD in ATC cells relative to Nthy-ori 3-1. MADD protein localizes in the cytosol (endoplasmic reticulum and Golgi body) and membrane. MADD knockdown resulted in spontaneous cell death that was synergistically enhanced when combined with TRAIL treatment in otherwise resistant ATC cells. Combination treatment resulted in a significant reduction in MMP and enhanced generation of ROS indicating the putative mechanism of action. In an orthotopic mouse model of TRAIL-resistant ATC, treatment with MADD siRNA alone reduced tumor growth that, when combined with TRAIL, resulted in significant tumor regressions. We demonstrated the potential clinical utility of MADD knockdown in sensitizing cells to TRAIL-induced apoptosis in ATC.
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http://dx.doi.org/10.1530/ERC-18-0517DOI Listing
June 2019

Advanced multimodal diagnostic approaches for detection of lung cancer.

Expert Rev Mol Diagn 2019 05 22;19(5):409-417. Epub 2019 Apr 22.

a Shobhaben Pratapbhai Patel School of Pharmacy and Technology Management , Shri Vile Parle Kelavani Mandal'S Narsee Monjee Institute of Management Studies University , Mumbai , India.

Introduction: Lung cancer (LC) emerges as a principle cause of death among smokers and is also one of the most lethal forms of cancer in nonsmokers. LC is mainly classified as non-small cell lung cancer (NSCLC), small cell LC, and lung carcinoid tumor. NSCLC is the most prevalent form of LC and its early stage diagnosis is essential to reduce mortality rate of patients and provide specific therapy. The field of LC diagnostics witnessed a gradual escalation with advancement in technology. Areas covered: This comprehensive review focuses on classification of LC and advanced diagnostics for LC detection like biosensors, biomarkers, nanotechnology-based diagnostics, wearable devices, mobile health, artificial intelligence (AI), aptamers, and molecularly imprinted polymers (MIPs). Expert opinion: Liquid biopsy and breath analysis developments are the most promising and advanced technologies for the detection of biomarkers associated with LC. Wearable devices and AI are two niche areas that require development and standardization for commercialization. The upcoming technology based on nanosystems includes robots, fibers, and particles for sensitive detection of LC. In the near future, nanotechnology-based theranostics, aptamers, and MIPs will emerge in early-stage diagnosis of LC.
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http://dx.doi.org/10.1080/14737159.2019.1607299DOI Listing
May 2019

Synthesis of coumarin analogs appended with quinoline and thiazole moiety and their apoptogenic role against murine ascitic carcinoma.

Biomed Pharmacother 2019 Apr 27;112:108707. Epub 2019 Feb 27.

Department of Chemistry, Yuvaraja's College (Autonomous), University of Mysore, Mysuru, 570005, Karnataka, India. Electronic address:

The synthesis and antiproliferative effect of a series of quinoline and thiazole containing coumarin analogs 12a-d and 13a-f respectively, on mice leukemic cells was performed. The chemical structures of newly synthesized compounds were confirmed by IR, H NMR, C NMR and mass spectral analysis. The result indicates that, 7-methoxy-2-oxo-2H-chromene-3-carboxylic acid [4-(4-methoxy-phenyl)-thiazol-2-yl]-amide (13f) showed potent activity against EAC and DLA cells in MTT (15.3 μM), tryphan blue (15.6 μM) and LDH (14.2 μM) leak assay with 5-fluorouracil as a standard. Further, the anti-neoplastic effect of the compound 13f was verified against Ehrlich ascites tumour by BrdU incorporation, TUNEL, FACS and DNA fragmentation assays. Experimental data showed that compound 13f induces the apoptotic cell death by activating apoptotic factors such as caspase-8 &-3, CAD, Cleaved PARP, γ-H2AX and by degrading genomic DNA of cancer cells and thereby decreasing the ascitic tumour development in mice. Besides, compound 13f was also subjected for docking studies to approve the in vitro and in vivo studies. The data revealed that the compound 13f has very good interaction with caspase 3 protein by binding with amino acid Arg 207 through hydrogen bond.
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http://dx.doi.org/10.1016/j.biopha.2019.108707DOI Listing
April 2019

Protein Aggregation Capture on Microparticles Enables Multipurpose Proteomics Sample Preparation.

Mol Cell Proteomics 2019 05 4;18(5):1027-1035. Epub 2019 Mar 4.

The Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Denmark;. Electronic address:

Universal proteomics sample preparation is challenging because of the high heterogeneity of biological samples. Here we describe a novel mechanism that exploits the inherent instability of denatured proteins for nonspecific immobilization on microparticles by protein aggregation capture. To demonstrate the general applicability of this mechanism, we analyzed phosphoproteomes, tissue proteomes, and interaction proteomes as well as dilute secretomes. The findings present a practical, sensitive and cost-effective proteomics sample preparation method.
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http://dx.doi.org/10.1074/mcp.TIR118.001270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6495262PMC
May 2019

Loss of MADD expression inhibits cellular growth and metastasis in anaplastic thyroid cancer.

Cell Death Dis 2019 02 13;10(2):145. Epub 2019 Feb 13.

Department of Microbiology and Immunology, University of Illinois at Chicago, Chicago, IL, 60612, USA.

Anaplastic Thyroid Cancer (ATC) is an aggressive malignancy with limited therapeutic options and dismal patient survival. We have previously shown MADD to be differentially overexpressed in multiple cancer histologies and to contribute to tumor cell growth and survival. Therefore, we targeted MADD by gene silencing, explored its effect on cellular proliferation and metastases and examined its therapeutic potential in an orthotopic ATC model in athymic nude mice. When compared to untreated control and scramble siRNA, MADD siRNA treatment inhibited the proliferative capacity of 8505C, C643 and HTH7 cells in vitro and 8505C-derived-orthotopic tumor growth in vivo. MADD ablation caused a significant reduction in cellular migration and invasion potential; clonogenic capacity; as well as, mitochondrial length and potential in vitro. This MADD siRNA-induced anti-migratory/invasive effect corresponded with inhibition of epithelial-mesenchymal transition (EMT) and Wnt signaling. Mechanistically, MADD siRNA inhibited TNFα induced activation of pERK, pGSK3β and β-catenin, suggesting that MADD knockdown might exert its anti-migratory/invasive effects, by blocking TNFα/ERK/GSK3β axis. MADD siRNA can inhibit β-catenin nuclear translocation and consequently, the expression of its target genes in ATC cells. In in vivo experiments, along with tumor regression, MADD siRNA treatment also decreased evidence of lung metastases. Immunohistochemically, MADD siRNA-treated tumor tissues exhibited a reduction in Ki67 and N-Cadherin expression, and an increase in E-Cadherin expression. In conclusion, we show the crucial role of MADD in ATC tumorigenesis and metastasis and its potential implications as a molecular target for ATC therapy.
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http://dx.doi.org/10.1038/s41419-019-1351-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6374448PMC
February 2019

Cancer immunotherapy with check point inhibitor can cause autoimmune adverse events due to loss of Treg homeostasis.

Semin Cancer Biol 2020 08 1;64:29-35. Epub 2019 Feb 1.

Department of Microbiology and Immunology, University of Illinois-College of Medicine, Chicago, IL, USA. Electronic address:

Regulatory T-cells (Tregs) can facilitate immune evasion by tumor cells by dampening anti-tumor immunity. Reduced Teff/Treg ratio and enhanced Treg functional activity have been observed in patients suffering from different types of cancers, and attenuated Treg numbers/functions can serve as prognostic indicators. Normally, Tregs play an essential role in the maintenance of immune tolerance and prevention of autoimmunity. The most common immune checkpoint blockers (ICB) targeting co-inhibitory receptors such as anti-CTLA4 (ipilimumab and tremelimumab) and anti-PD1 (pembrolizumab and nivolumab)/anti-PD-L1 (atezolizumab) have achieved unprecedented success in cancer treatment by facilitating an effective anti-tumor immune response, at least in part, by blocking Treg mediated immunosuppression. While ICBs have shown remarkable success in cancer immunotherapy, immune-related adverse events (IRAEs) arising from ICB have forced consideration of ways to maintain immune homeostasis post ICB treatment. Preclinical models of IRAEs have shown a negative correlation between Treg numbers and IRAEs. Therefore, understanding the "ying-yang" role of Tregs in the regulation of autoimmunity and anti-tumor immunity is critical to provoking an effective anti-tumor response while maintaining immune homeostasis. Studies aimed at developing effective approaches to minimize IRAEs without compromising anti-tumor immunity are underway. Herein, we discuss 1) the critical role of key co-inhibitory receptors on Treg homeostasis and tumor tolerance; 2) how co-receptor blockade by cancer immunotherapy can lead to autoimmune adverse events; and 3) recently emerging management strategies to minimize autoimmune adverse events arising from ICB.
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http://dx.doi.org/10.1016/j.semcancer.2019.01.006DOI Listing
August 2020

Recent therapeutic strategies targeting beta amyloid and tauopathies in Alzheimer's disease.

Brain Res Bull 2019 03 8;146:171-184. Epub 2019 Jan 8.

Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKMs NMIMS, V.L.Mehta Road, Vile Parle (W), Mumbai, Maharashtra, 400056, India. Electronic address:

Alzheimer's disease (AD) has been a global concern for years due to its severe implications that affects the quality of life of the patients. The available line of therapy for treating Alzheimer's includes acetylcholinesterase inhibitors, NMDA(N-methyl-D-aspartate) antagonists and their combination which gives only symptomatic relief rather than treating the root cause of AD. Senile plaques and neurofibrillary tangles are the characteristic features underlying Alzheimer's pathology. Several attempts have been made towards exploring the niceties of these hallmarks and targeting various aspects of amyloid and tau pathology at different stages to eliminate the ultimate cause. Approaches targeting cleavage and formation of toxic amyloid fragments by secretases, aggregation of amyloid monofilaments, and immunotherapy against amyloid deposits has been extensively studied to treat amyloid pathology. Similarly, for tau pathology, tau hyperphosphorylation, microtubule stabilization, anti-tau immunotherapy has been explored. This article focuses on AD pathology and current pharmacotherapy, precisely for amyloid and tau. Furthermore, preclinical and clinical studies along with potential leads discovered under these approaches have also been included in this article. However, despite extensive research in drug development, overcoming clinical barrier still remain a major challenge for Alzheimer's pharmacotherapy.
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http://dx.doi.org/10.1016/j.brainresbull.2019.01.004DOI Listing
March 2019

Molecular aberrations and signaling cascades implicated in the pathogenesis of anaplastic thyroid cancer.

Biochim Biophys Acta Rev Cancer 2019 12 31;1872(2):188262. Epub 2018 Dec 31.

Department of Microbiology and Immunology, University of Illinois-College of Medicine, Chicago, IL, United States; Jesse Brown VA Medical Center, Chicago, IL, United States. Electronic address:

Anaplastic Thyroid Cancer (ATC) accounts for >40% thyroid cancer-related deaths and has a dismal prognosis. In the past decade, significant efforts have been made towards understanding the pathogenesis of this disease and developing novel therapeutics. Unfortunately, effective treatment is still lacking and a more thorough understanding of ATC pathogenesis may provide new opportunities to improve ATC therapeutics. This review provides insights into ATC clinical presentation and pathology, and the putative role of genetic aberrations and alterations in molecular signaling pathways in ATC pathogenesis. We reviewed prevalent mutations, chromosomal abnormalities and fusions, epigenetic alterations and dysregulations in ATC, and highlighted several signaling cascades which appeared to be integral to ATC pathogenesis. Moreover, these features offer insights into de-differentiated, aggressive and drug-resistant phenotype of ATC, and thus may help in exploring potential new molecular targets for developing novel therapeutics.
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http://dx.doi.org/10.1016/j.bbcan.2018.12.003DOI Listing
December 2019

Emerging vistas in theranostic medicine.

Int J Pharm 2019 Mar 29;558:29-42. Epub 2018 Dec 29.

Shobhaben Pratapbhai Patel School of Pharmacy & Technology Management, SVKM's NMIMS Deemed to be University, V.L. Mehta Road, Vile Parle (W), Mumbai 400 056, India.

Recent years have witnessed a paradigm shift in the focus of healthcare towards development of customized therapies which cater to the unmet needs in a myriad of disease areas such as cancer, infections, cardiovascular diseases, neurodegenerative disorders and inflammatory disorders. The term 'theranostic' refers to such multifunctional systems which combine the features of diagnosis and treatment in a single platform for superior control of the disease. Theranostic systems enable detection of disease, treatment and real time monitoring of the diseased tissue. Theranostic nanocarriers endowed with multiple features of imaging, targeting, and providing on-demand delivery of therapeutic agents have been designed for enhancement of therapeutic outcomes. Fabrication of theranostics involves utilization of materials having distinct properties for imaging, targeting, and programming drug release spatially and temporally. Although the field of theranostics has been widely researched and explored so far for treatment of different types of cancer, there have been considerable efforts in the past few years to extend its scope to other areas such as infections, neurodegenerative disorders and cardiovascular diseases. This review showcases the potential applications of theranostics in disease areas other than cancer. It also highlights the cardinal issues which need to be addressed for successful clinical translation of these theranostic tools.
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http://dx.doi.org/10.1016/j.ijpharm.2018.12.068DOI Listing
March 2019

Vaccination With Mitoxantrone-Treated Primary Colon Cancer Cells Enhances Tumor-Infiltrating Lymphocytes and Clinical Responses in Colorectal Liver Metastases.

J Surg Res 2019 01 17;233:57-64. Epub 2018 Aug 17.

Division of Surgical Oncology, Department of Surgery, University of Illinois at Chicago, Chicago, Illinois. Electronic address:

Background: Colorectal cancer remains a leading cause of cancer-related mortality worldwide. Metastases to the liver are often present at initial presentation and will form in most patients during their course of disease. We have previously demonstrated that enhanced trafficking and activation of tumor-infiltrating lymphocytes in colorectal liver metastases (CRLM) may improve antitumor immune responses. Thus, development of novel mechanisms to increase lymphocyte infiltration and activation are needed to improve patient outcomes.

Methods: CT26 murine colorectal cancer cells were treated with physiologic levels of the potent inducer of immunogenic cell death mitoxantrone (MTX). An in situ vaccine was created with treated cells in an established model of CRLM. Cells were evaluated by flow cytometry for cell cycle evaluation and calreticulin expression. Splenic and tumor-infiltrating lymphocytes were isolated for phenotypic studies.

Results: MTX-treatment of colon cancer cells resulted in a sub-G1 peak, inhibition of G1 cell cycle progression, and increased G2/M cell fractions while simultaneously increasing dynamic exposure of calreticulin on the cell surface (P < 0.05). Vaccination with MTX-treated cells resulted in significant decreases in CRLM formation associated with increased tumor-infiltrating leukocytes that displayed increased expression of the T cell surface activation marker CD69.

Conclusions: Vaccination with MTX-treated primary colon cancer cells enhances tumor-infiltrating lymphocytes and clinical responses in CRLM.
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http://dx.doi.org/10.1016/j.jss.2018.07.068DOI Listing
January 2019

Restoring self-tolerance in autoimmune diseases by enhancing regulatory T-cells.

Cell Immunol 2019 05 29;339:41-49. Epub 2018 Sep 29.

Department of Microbiology and Immunology, University of Illinois - College of Medicine, Chicago, IL, USA. Electronic address:

Self-tolerance, the state of unresponsiveness to self-tissues/antigens, is maintained through central and peripheral tolerance mechanisms, and a breach of these mechanisms leads to autoimmune diseases. Foxp3 + T-regulatory cells (Tregs) play an essential role in suppressing autoimmune response directed against self-antigens and thereby regulate self-tolerance. Natural Tregs are differentiated in the thymus on the basis of their higher TCR-affinity to self-antigens and migrate to the periphery where they maintain peripheral tolerance. In addition, extra-thymic differentiation of induced Tregs can occur in the periphery which can control abrupt immune responses under inflammatory conditions. A defect in Treg cell numbers and/or function is found to be associated with the development of autoimmune disease in several experimental models and human autoimmune diseases. Moreover, augmentation of Tregs has been shown to be beneficial in treating autoimmunity in preclinical models, and Treg based cellular therapy has shown initial promise in clinical trials. However, emerging studies have identified an unstable subpopulation of Tregs which expresses pro-inflammatory cytokines under both homeostatic and autoimmune conditions, as well as in ex vivo cultures. In addition, clinical translation of Treg cellular therapy is impeded by limitations such as lack of easier methods for selective expansion of Tregs and higher cost associated with GMP-facilities required for cell sorting, ex vivo expansion and infusion of ex vivo expanded Tregs. Here, we discuss the recent advances in molecular mechanisms regulating Treg differentiation, Foxp3 expression and lineage stability, the role of Tregs in the prevention of various autoimmune diseases, and critically review their clinical utility for treating human autoimmune diseases.
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http://dx.doi.org/10.1016/j.cellimm.2018.09.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6440877PMC
May 2019

Anti-Arthritic Effect of Garcinol Enriched Fraction Against Adjuvant Induced Arthritis.

Recent Pat Inflamm Allergy Drug Discov 2019 ;13(1):49-56

SPP- School of Pharmacy & Technology Management, SVKM's NMIMS, V.L. Mehta Road, Vile Parle (W), Mumbai 400056, Maharashtra, India.

Background: Garcinia indica also known as kokum is used in traditional system of medicine for relieving inflammation and rheumatic pain. Garcinol, a benzophenone obtained from its fruit rind is reported to have anti-inflammatory effect via modulating arachidonic acid metabolism, suppressing iNOS expression, NF-κB activation and COX-2 expression. It has also been studied for antioxidant and anticancer activity. Apart from these, few patents claim that garcinol also has anti-obesity and hepatoprotective effect and has a potential to be used for the treatment of renal disorders, endometriosis and cardiac dysfunction.

Objective: Garcinol Enriched Fraction (GEF) from the fruit rind of Garcinia indica should be effective in the treatment of arthritis, one of the chronic inflammatory disorder owing to its anti-inflammatory property as indicated by earlier experiments.

Methods: GEF was prepared from the fruit rind of Garcinia indica and quantified using LC-MS/MS. It was found to contain 89.4% w/w of garcinol. GEF was evaluated at the dose of 10mg/kg for its efficacy against Complete Freund's Adjuvant (CFA) induced arthritis in Wistar albino rats. Paw volumes of both sides were measured by Plethysmometer and body weight was recorded on 0, 1, 5, 12 and 21st day. The hyperalgesic response was also measured by motility test and stair climbing test.

Results: GEF showed a significant reduction in paw swelling (p < 0.0001) and arthritis index (p < 0.0001) exhibiting anti-inflammatory potential. It also improves the motility and stair climbing ability of experimental animals (p < 0.05), thus reducing hyperalgesia.

Conclusion: Garcinol enriched fraction shows anti-arthritic activity in experimental animals.
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http://dx.doi.org/10.2174/1872213X12666181120091528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6778983PMC
January 2020

Therapeutic advances in anaplastic thyroid cancer: a current perspective.

Mol Cancer 2018 10 23;17(1):154. Epub 2018 Oct 23.

Department of Microbiology and Immunology, University of Illinois-College of Medicine, Chicago, IL, USA.

Thyroid cancer incidence is increasing at an alarming rate, almost tripling every decade. In 2017, it was the fifth most common cancer in women. Although the majority of thyroid tumors are curable, about 2-3% of thyroid cancers are refractory to standard treatments. These undifferentiated, highly aggressive and mostly chemo-resistant tumors are phenotypically-termed anaplastic thyroid cancer (ATC). ATCs are resistant to standard therapies and are extremely difficult to manage. In this review, we provide the information related to current and recently emerged first-line systemic therapy (Dabrafenib and Trametinib) along with promising therapeutics which are in clinical trials and may be incorporated into clinical practice in the future. Different categories of promising therapeutics such as Aurora kinase inhibitors, multi-kinase inhibitors, epigenetic modulators, gene therapy using oncolytic viruses, apoptosis-inducing agents, and immunotherapy are reviewed. Combination treatment options that showed synergistic and antagonistic effects are also discussed. We highlight ongoing clinical trials in ATC and discuss how personalized medicine is crucial to design the second line of treatment. Besides using conventional combination therapy, embracing a personalized approach based on advanced genomics and proteomics assessment will be crucial to developing a tailored treatment plan to improve the chances of clinical success.
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http://dx.doi.org/10.1186/s12943-018-0903-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6198524PMC
October 2018

Identification of a Novel OX40L Dendritic Cell Subset That Selectively Expands Regulatory T cells.

Sci Rep 2018 10 8;8(1):14940. Epub 2018 Oct 8.

Department of Microbiology and Immunology, University of Illinois College of Medicine, Chicago, Illinois, USA.

We have previously shown GM-CSF derived bone-marrow dendritic cells (G-BMDCs) can induce the selective expansion of Tregs through the surface-bound molecule OX40L; however, the physiological role of this ex vivo derived DC subset remained to be elucidated. We determined GM-CSF administration to mice induced the generation of in vivo derived OX40L DCs, phenotypically similar to ex vivo OX40LG-BMDCs, in the spleen, brachial lymph nodes and liver. The generation of OX40L DCs correlated with increased percentages of functionally suppressive Tregs in the spleen, brachial lymph nodes, and liver of GM-CSF treated mice. DCs from GM-CSF treated mice expanded Tregs in CD4 T-cell co-cultures in an OX40L dependent manner, suggesting OX40L DCs may play a role in peripheral Treg homeostasis. Furthermore, comparing the transcriptome data of OX40L DCs to that of all immune cell types revealed OX40L DCs to be distinct from steady-state immune cells and, microarray analysis of OX40LG-BMDCs and OX40LG-BMDCs revealed higher expression of molecules that are associated with tolerogenic phenotype and could play important roles in the function of OX40L DCs. These findings suggest that OX40L DCs may represent a unique DC subset induced under inflammatory conditions that may play an essential role in maintaining Treg homeostasis.
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http://dx.doi.org/10.1038/s41598-018-33307-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6175872PMC
October 2018

A comprehensive review on the role of co-signaling receptors and Treg homeostasis in autoimmunity and tumor immunity.

J Autoimmun 2018 12 31;95:77-99. Epub 2018 Aug 31.

Department of Microbiology and Immunology, University of Illinois-College of Medicine, Chicago, IL, USA; Department of Ophthalmology, Associate Dean for Technological Innovation and Training, University of Illinois College of Medicine, Room E-705, (M/C 790), 835 S. Wolcott Ave, Chicago, IL, 60612, USA. Electronic address:

The immune system ensures optimum T-effector (Teff) immune responses against invading microbes and tumor antigens while preventing inappropriate autoimmune responses against self-antigens with the help of T-regulatory (Treg) cells. Thus, Treg and Teff cells help maintain immune homeostasis through mutual regulation. While Tregs can contribute to tumor immune evasion by suppressing anti-tumor Teff response, loss of Treg function can result in Teff responses against self-antigens leading to autoimmune disease. Thus, loss of homeostatic balance between Teff/Treg cells is often associated with both cancer and autoimmunity. Co-stimulatory and co-inhibitory receptors, collectively known as co-signaling receptors, play an indispensable role in the regulation of Teff and Treg cell expansion and function and thus play critical roles in modulating autoimmune and anti-tumor immune responses. Over the past three decades, considerable efforts have been made to understand the biology of co-signaling receptors and their role in immune homeostasis. Mutations in co-inhibitory receptors such as CTLA4 and PD1 are associated with Treg dysfunction, and autoimmune diseases in mice and humans. On the other hand, growing tumors evade immune surveillance by exploiting co-inhibitory signaling through expression of CTLA4, PD1 and PDL-1. Immune checkpoint blockade (ICB) using anti-CTLA4 and anti-PD1 has drawn considerable attention towards co-signaling receptors in tumor immunology and created renewed interest in studying other co-signaling receptors, which until recently have not been as well studied. In addition to co-inhibitory receptors, co-stimulatory receptors like OX40, GITR and 4-1BB have also been widely implicated in immune homeostasis and T-cell stimulation, and use of agonistic antibodies against OX40, GITR and 4-1BB has been effective in causing tumor regression. Although ICB has seen unprecedented success in cancer treatment, autoimmune adverse events arising from ICB due to loss of Treg homeostasis poses a major obstacle. Herein, we comprehensively review the role of various co-stimulatory and co-inhibitory receptors in Treg biology and immune homeostasis, autoimmunity, and anti-tumor immunity. Furthermore, we discuss the autoimmune adverse events arising upon targeting these co-signaling receptors to augment anti-tumor immune responses.
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http://dx.doi.org/10.1016/j.jaut.2018.08.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6289740PMC
December 2018

Current trends and emerging diagnostic techniques for lung cancer.

Biomed Pharmacother 2018 Oct 28;106:1586-1599. Epub 2018 Jul 28.

Shobhaben Pratapbhai Patel School of Pharmacy and Technology Management, SVKM'S NMIMS, V.L. Mehta Road, Vile Parle (W), Mumbai, India.

Cancer is one of most fatal forms of disease with rapid, abnormal and uncontrolled division of cells which spreads into different organs in the body. The primary aim of this review is to showcase the current and emerging diagnostic techniques that are used in lung cancer detection. Lung cancer is a leading cause of death among smokers and it has been emerging in non-smokers due to passive smoke inhalation by non-smokers. The mortality rate of patients with lung cancer is very high due to the change in lifestyle and environmental factors. It is often misdiagnosed as tuberculosis in India as tuberculosis is prevalent in India. On the contrary tuberculosis is not prevalent in the western countries Like U.S.A., U.K., Canada, etc. The major setback in lung cancer is that the symptoms of lung cancer occur at very later stages when the tumor has spread profusely. Hence, highly advanced techniques are employed for detection, accurate staging and treatment of lung cancer. The review focuses on the various novel and emerging diagnostic tools like biomarkers and biosensors, radiogenomics and artificial intelligence. This review also gives an insight of the various conventional techniques like CT-imaging, sputum cytology, biopsy and bronchoscopy which have been modified over the years for better sensitivity and accuracy. It also encompasses the regulatory provisions like IDE, CLIA-certification, etc. for manufacturing and sale of diagnostics in India, U.S.A., Japan and Australia.
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http://dx.doi.org/10.1016/j.biopha.2018.07.145DOI Listing
October 2018

A single high-fat meal alters human soluble RAGE profiles and PBMC RAGE expression with no effect of prior aerobic exercise.

Physiol Rep 2018 07;6(14):e13811

Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, Illinois.

A high-fat diet can induce inflammation and metabolic diseases such as diabetes and atherosclerosis. The receptor for advanced glycation endproducts (RAGE) plays a critical role in metabolic disease pathophysiology and the soluble form of the receptor (sRAGE) can mitigate these effects. However, little is known about RAGE in the postprandial condition and the effect of exercise in this context. Thus, we aimed to determine the effects of a single high-fat meal (HFM) with and without prior exercise on peripheral blood mononuclear cell (PBMC) RAGE biology. Healthy males (n = 12) consumed a HFM on two occasions, one without prior exercise and one 16-18 hours following acute aerobic exercise. Total soluble RAGE (sRAGE) and endogenous secretory RAGE (esRAGE) were determined via ELISA and cleaved RAGE (cRAGE) was calculated as the difference between the two. Isolated PBMCs were analyzed for RAGE, ADAM10, TLR4, and MyD88 protein expression and ADAM10 activity. The HFM significantly (P < 0.01) attenuated sRAGE, esRAGE, and cRAGE by 9.7%, 6.9%, and 10.5%, respectively. Whereas, the HFM increased PBMC RAGE protein expression by 10.3% (P < 0.01), there was no meal effect on PBMC TLR4, MYD88, or ADAM10 protein expression, nor ADAM10 activity. There was also no exercise effect on any experimental outcomes. These findings suggest that PBMC RAGE and soluble RAGE may be important in the postprandial response to a HFM, and that prior aerobic exercise does not alter these processes in young healthy adult males. The mechanisms by which a HFM induces RAGE expression and reduces circulating soluble RAGE isoforms requires further study.
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http://dx.doi.org/10.14814/phy2.13811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6060105PMC
July 2018

Implementing a STEMI system of care in urban Bangalore: Rationale and Study Design for heart rescue India.

Contemp Clin Trials Commun 2018 Jun 5;10:105-110. Epub 2018 Apr 5.

University of Illinois at Chicago Department of Emergency Medicine and Center for Global Health, 1940 Taylor M/C 584, Chicago, IL, USA.

Background: A system of care designed to measure and improve process measures such as symptom recognition, emergency response, and hospital care has the potential to reduce mortality and improve quality of life for patients with ST-elevation myocardial infarction (STEMI).

Objective: To document the methodology and rationale for the implementation and impact measurement of the Heart Rescue India project on STEMI morbidity and mortality in Bangalore, India.

Study Design: A hub and spoke STEMI system of care comprised of two interventional, hub hospitals and five spoke hospitals will build and deploy a dedicated emergency response and transport system covering a 10 Km. radius area of Bangalore, India. High risk patients will receive a dedicated emergency response number to call for symptoms of heart attack. A dedicated operations center will use geo-tracking strategies to optimize response times including first responder motor scooter transport, equipped with ECG machines to transmit ECG's for immediate interpretation and optimal triage. At the same time, a dedicated ambulance will be deployed for transport of appropriate STEMI patients to a hub hospital while non-STEMI patients will be transported to spoke hospitals. To enhance patient recognition and initiation of therapy, school children will be trained in basic CPR and signs and symptom of chest pain. Hub hospitals will refine their emergency department and cardiac catheterization laboratory protocols using continuous quality improvement techniques to minimize treatment delays. Prior to hospital discharge, secondary prevention measures will be initiated to enhance long-term patient outcomes.
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http://dx.doi.org/10.1016/j.conctc.2018.04.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6047311PMC
June 2018

Synthesis and amelioration of inflammatory paw edema by novel benzophenone appended oxadiazole derivatives by exhibiting cyclooxygenase-2 antagonist activity.

Biomed Pharmacother 2018 Jul 7;103:1446-1455. Epub 2018 May 7.

Department of Chemistry, Yuvaraja's College, University of Mysore, Mysore, 570005 Karnataka, India. Electronic address:

Ten new 2(4-hydroxy-3-benzoyl) benzamide-5-phenyl-1,3,4-oxadiazole derivatives (10a-j) were synthesized by coupling 3-benzoyl-4-hydroxybenzoic acid (5) with 2-amino-5-phenyl-1,3,4-oxadiazoles (9a-j). The structures of these compounds were confirmed by IR, H, C NMR, and mass spectra, and also by elemental analyses. The anti-inflammatory activity of the compounds 10a-j were investigated by screening them against human red blood cells (HRBC) in-vitro. The results reveal that among this series, compound 10j with hydroxy substituent, particularly at the ortho position of the phenyl ring attached to the 5th carbon atom of the oxadiazole ring possess significant membrane stabilizing activity in comparison with the control. Further, in-vivo chick chorioallantoic membrane (CAM) and rat corneal anti-angiogenesis assays were performed to assess the effect of compound 10j on endothelial cell migration. This confirmed that compound 10j inhibits the proliferation of endothelial cells. Anti-inflammatory studies detected the amelioration of carrageen induced rat hind paw edema. Further in-vivo and in-silico approaches revealed the inhibition of inflammatory marker enzyme cyclooxygenase-2 (Cox-2) and myleoperoxidase (MPO). The study reports that the compound 10j effectively act against the inflammatory mediated anti-angiogenic disorders which could be translated into a new drug in future.
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http://dx.doi.org/10.1016/j.biopha.2018.04.167DOI Listing
July 2018

Critical role of OX40 signaling in the TCR-independent phase of human and murine thymic Treg generation.

Cell Mol Immunol 2019 02 26;16(2):138-153. Epub 2018 Mar 26.

Department of Microbiology and Immunology, University of Illinois-College of Medicine, Chicago, IL, USA.

Regulatory T cells (Tregs) play a pivotal role in immune-tolerance, and loss of Treg function can lead to the development of autoimmunity. Natural Tregs generated in the thymus substantially contribute to the Treg pool in the periphery, where they suppress self-reactive effector T cells (Teff) responses. Recently, we showed that OX40L (TNFSF4) is able to drive selective proliferation of peripheral Tregs independent of canonical antigen presentation (CAP-independent) in the presence of low-dose IL-2. Therefore, we hypothesized that OX40 signaling might be integral to the TCR-independent phase of murine and human thymic Treg (tTreg) development. Development of tTregs is a two-step process: Strong T-cell receptor (TCR) signals in combination with co-signals from the TNFRSF members facilitate tTreg precursor selection, followed by a TCR-independent phase of tTreg development in which their maturation is driven by IL-2. Therefore, we investigated whether OX40 signaling could also play a critical role in the TCR-independent phase of tTreg development. OX40 mice had significantly reduced numbers of CD25Foxp3 tTreg precursors and CD25Foxp3 mature tTregs, while OX40L treatment of WT mice induced significant proliferation of these cell subsets. Relative to tTeff cells, OX40 was expressed at higher levels in both murine and human tTreg precursors and mature tTregs. In ex vivo cultures, OX40L increased tTreg maturation and induced CAP-independent proliferation of both murine and human tTregs, which was mediated through the activation of AKT-mTOR signaling. These novel findings show an evolutionarily conserved role for OX40 signaling in tTreg development and proliferation, and might enable the development of novel strategies to increase Tregs and suppress autoimmunity.
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http://dx.doi.org/10.1038/cmi.2018.8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6355936PMC
February 2019

Evolving Trends in Racial Disparities for Peri-Operative Outcomes with the New Kidney Allocation System (KAS) Implementation.

J Racial Ethn Health Disparities 2018 12 19;5(6):1171-1179. Epub 2018 Mar 19.

Department of Transplant Surgery, MUSC, Charleston, SC, USA.

Introduction: To improve kidney transplant allocation equitability, a new Kidney Allocation System (KAS) was implemented December 4, 2014. The purpose of this study was to determine if the impact of KAS on peri-operative outcomes differed by recipient race/ethnicity.

Methods: This was a time series analysis using data aggregated in monthly intervals from October 2012 through September 2015 using the University HealthSystem Consortium (UHC). This includes national data aggregated at the center level of all US kidney transplant centers that participate in the UHC (416 centers). Segmented regression with interaction terms was used to determine the impact of KAS on outcomes and differences by race/ethnicity.

Results: A total of 28,809 deceased donor kidney transplants were included with 25 months of pre-KAS data and 10 months of post-KAS data. After KAS implementation, the estimated transplant rate per month decreased significantly for Caucasians by 17.6 cases per month (p = 0.0001), and increased significantly for AAs by 37.8 (p = 0.0001), Hispanics by 16.3 (p = 0.0001), and other races by 8.2 cases per month (p = 0.0001). Delayed graft function, 7- and 14-day readmissions significantly increased after KAS, which did not differ by race. Hispanics saw a 7.7% decrease in ICU admissions after KAS, which differed as compared to other racial/ethnic cohorts (p = 0.0026). Costs of kidney transplantation increased significantly after KAS in all groups except Hispanics. Mortality, length of stay, in-hospital complications, and 30-day readmissions were not significantly impacted by KAS, also not differing by race/ethnicity.

Conclusion: KAS had substantial impact on transplant rates by race/ethnicity. KAS also led to increased costs, readmissions, and delayed graft function (DGF) across all racial/ethnic groups. The impact of KAS on ICU cases solely within Hispanics requires further investigation into potential etiologies.
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http://dx.doi.org/10.1007/s40615-018-0464-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6190482PMC
December 2018

Evolving Trends in Racial Disparities for Peri-Operative Outcomes with the New Kidney Allocation System (KAS) Implementation.

J Racial Ethn Health Disparities 2018 12 19;5(6):1171-1179. Epub 2018 Mar 19.

Department of Transplant Surgery, MUSC, Charleston, SC, USA.

Introduction: To improve kidney transplant allocation equitability, a new Kidney Allocation System (KAS) was implemented December 4, 2014. The purpose of this study was to determine if the impact of KAS on peri-operative outcomes differed by recipient race/ethnicity.

Methods: This was a time series analysis using data aggregated in monthly intervals from October 2012 through September 2015 using the University HealthSystem Consortium (UHC). This includes national data aggregated at the center level of all US kidney transplant centers that participate in the UHC (416 centers). Segmented regression with interaction terms was used to determine the impact of KAS on outcomes and differences by race/ethnicity.

Results: A total of 28,809 deceased donor kidney transplants were included with 25 months of pre-KAS data and 10 months of post-KAS data. After KAS implementation, the estimated transplant rate per month decreased significantly for Caucasians by 17.6 cases per month (p = 0.0001), and increased significantly for AAs by 37.8 (p = 0.0001), Hispanics by 16.3 (p = 0.0001), and other races by 8.2 cases per month (p = 0.0001). Delayed graft function, 7- and 14-day readmissions significantly increased after KAS, which did not differ by race. Hispanics saw a 7.7% decrease in ICU admissions after KAS, which differed as compared to other racial/ethnic cohorts (p = 0.0026). Costs of kidney transplantation increased significantly after KAS in all groups except Hispanics. Mortality, length of stay, in-hospital complications, and 30-day readmissions were not significantly impacted by KAS, also not differing by race/ethnicity.

Conclusion: KAS had substantial impact on transplant rates by race/ethnicity. KAS also led to increased costs, readmissions, and delayed graft function (DGF) across all racial/ethnic groups. The impact of KAS on ICU cases solely within Hispanics requires further investigation into potential etiologies.
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http://dx.doi.org/10.1007/s40615-018-0464-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6190482PMC
December 2018

Amelioration of progressive autoimmune encephalomyelitis by epigenetic regulation involves selective repression of mature neutrophils during the preclinical phase.

Exp Neurol 2018 06 14;304:14-20. Epub 2018 Feb 14.

Dept. of Microbiology & Immunology, 909 South Wolcott Avenue, University of Illinois at Chicago, Chicago, IL 60612, USA; Dept. of Surgery, University of Illinois College of Medicine at Peoria, 624 NE Glen Oak Ave, Suite 2675, Peoria, IL 61603, USA. Electronic address:

We have recently demonstrated that treatment of NOD mice with the epigenetic drug Trichostatin A (TSA) ameliorated myelin peptide induced progressive experimental autoimmune encephalomyelitis (P-EAE). Protection was accompanied by induction of antigen-specific T-cell tolerance in the periphery and reduced influx of T cells into the spinal cord. In this investigation, we examined whether the epigenetic drug could impact the innate immune system as well. Whereas the mature (MHC class II) CD11bLy-6G neutrophils expanded substantially in the peripheral lymphoid compartment during the preclinical phase, the MHC class II, CD11bLy-6C mature monocytes increased modestly throughout the disease course. Amelioration of the clinical disease by TSA treatment was accompanied by diminished abundance of CD11bLy-6G activated neutrophils in secondary lymphoid organs and their influx into the spinal cord without affecting monocytes. Interestingly, the co-inhibitory ligand CD274 (PD-L1) but not CD275 (ICOS-L), CD39 or CD11c dendritic cells were decreased in the peripheral lymphoid compartment of drug treated mice. Thus, in addition to myelin-specific T cell tolerance induction observed previously, selective repression of mature neutrophils and PD-L1 cells is critically involved in the epigenetic regulation of P-EAE.
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http://dx.doi.org/10.1016/j.expneurol.2018.02.008DOI Listing
June 2018

The Novel 4-Phenyl-2-Phenoxyacetamide Thiazoles modulates the tumor hypoxia leading to the crackdown of neoangiogenesis and evoking the cell death.

Eur J Med Chem 2018 Jan 4;143:1826-1839. Epub 2017 Nov 4.

Department of Chemistry, Yuvaraja's College, University of Mysore, Mysore 570005, Karnataka, India. Electronic address:

Tumor microenvironment is a complex multistep event which involves several hallmarks that transform the normal cell into cancerous cell. Designing the novel antagonistic molecule to reverse the tumor microenvironment with specific target is essential in modern biological studies. The novel 4-phenyl-2-phenoxyacetamide thiazole analogues 8 were synthesized in multistep process, then screened and assessed for cytotoxic and anti-proliferative effects in vitro against multiple cancer cells of different origin such as MCF-7, A549, EAC and DLA cells which revealed that compound 8f with fluoro and methyl substitute has potential cytotoxic efficacy with an average IC value of ˜ 13 μM. The mechanism of cytotoxicity assessed for anti-tumor studies both in ascites and solid tumor models in-vivo inferred the regressed tumor activity. This is due to changes in the cause of tumor microenvironment with crackdown of neovascularization and evoking apoptosis process as assessed by CAM, corneal vascularization and apoptotic hallmarks in 8f treated cells. The molecular gene studies inferred involvement of HIF-1upregulation and stabilization of p53 which are interlinked in signaling as conferred by immunoblot analysis.
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http://dx.doi.org/10.1016/j.ejmech.2017.10.082DOI Listing
January 2018

Mitochondrial protein 18 (MTP18) plays a pro-apoptotic role in chemotherapy-induced gastric cancer cell apoptosis.

Oncotarget 2017 Aug 28;8(34):56582-56597. Epub 2017 Apr 28.

Department of Microbiology and Immunology, College of Medicine, University of Illinois at Chicago, Chicago, IL, USA.

One of the severe limitations of chemotherapy is the development of drug resistance. However, the mechanisms underlying chemotherapy resistance remain to be elucidated. Mitochondrial mediated apoptosis is a form of cell death induced by chemotherapy. Several chemotherapeutic agents have been shown to induce mitochondrial fission, and finally activate the apoptosis cascade in various cancer cells. Here, we report that the mitochondrial membrane protein 18 (MTP18) induced mitochondrial fragmentation in gastric cancer cells under doxorubicin (DOX) exposure. Upon over-expression of MTP18, a sub-cytotoxic dose of DOX could sensitize a significant number of cells to undergo mitochondrial fission and subsequent apoptosis. These findings suggest that MTP18 can enhance the sensitivity of gastric cancer cells to DOX. Mechanistically, we found that MTP18 enriched dynamic-related protein 1 (DRP1) accumulation in mitochondria and it was responsible for mediating DOX-induced signaling required for mitochondrial fission. Intriguingly, MTP18 expression was downregulated during DOX treatment. Thus, down-regulation of MTP18 expression could be one of the resistance factors interfering with DOX-induced apoptosis in gastric cancer cells.
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http://dx.doi.org/10.18632/oncotarget.17508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5593585PMC
August 2017

Design and synthesis of conjugated azo-hydrazone analogues using nano BF·SiO targeting ROS homeostasis in oncogenic and vascular progression.

Biomed Pharmacother 2017 Nov 12;95:419-428. Epub 2017 Sep 12.

Department of Chemistry, Yuvaraja's College (Autonomous), University of Mysore, Mysore, Karnataka, India. Electronic address:

Disrupted redox balance is implicated in multiple pathologies including malignant progression and tumor angiogenesis. In this investigation, we report the design and development of novel and effective ROS detoxifying azo-hydrazone molecules targeting malignant pathologies and neoangiogenesis. A series of azo-derivatives conjugated to hydrazones moieties (9a-j) were synthesized using Nano BF·SiO. The compounds (9a-j) were screened for in-vitro antioxidant and lipid peroxidation inhibitory activity. Among the series 9a-j, compound 9f potently quenched biologically relevant radicals such as superoxide and hydrogen peroxide which emerged as the lead ROS detoxifying molecules. Compound 9f potently inhibited the proliferative capability of Daltons Lymphoma Ascites (DLA) tumor cells in-vivo in dose dependent manner. Regressed tumor progression was correlated with pronounced endogenous antioxidant enzyme superoxide dismutase and catalase in-vivo. Also, ROS levels were severely suppressed in 9f treated mice as assessed by lapsed lipid peroxidation. Altered enzymic and ROS levels in-vivo by 9f were implicated in suppressed VEGF secretion leading to regressed tumor neovasculature and tumor growth. Considering together, it is evident that the synthetic azo-hydrazone analogue 9f with potent ROS scavenging efficacy inhibits tumor progression and neo-angiogenesis.
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http://dx.doi.org/10.1016/j.biopha.2017.08.076DOI Listing
November 2017

PKC-ѳ is dispensable for OX40L-induced TCR-independent Treg proliferation but contributes by enabling IL-2 production from effector T-cells.

Sci Rep 2017 07 26;7(1):6594. Epub 2017 Jul 26.

Department of Microbiology and Immunology, University of Illinois College of Medicine, Chicago, Illinois, USA.

We have previously shown that OX40L/OX40 interaction is critical for TCR-independent selective proliferation of Foxp3 Tregs, but not Foxp3 effector T-cells (Teff), when CD4 T-cells are co-cultured with GM-CSF derived bone marrow dendritic cells (G-BMDCs). Events downstream of OX40L/OX40 interaction in Tregs responsible for this novel mechanism are not understood. Earlier, OX40L/OX40 interaction has been shown to stimulate CD4 T-cells through the formation of a signalosome involving TRAF2/PKC-Ѳ leading to NF-kB activation. In this study, using CD4 T-cells from WT and OX40 mice we first established that OX40 mediated activation of NF-kB was critical for this Treg proliferation. Although CD4 T-cells from PKC-Ѳ mice were also defective in G-BMDC induced Treg proliferation ex vivo, this defect could be readily corrected by adding exogenous IL-2 to the co-cultures. Furthermore, by treating WT, OX40, and PKC-Ѳ mice with soluble OX40L we established that OX40L/OX40 interaction was required and sufficient to induce Treg proliferation in vivo independent of PKC-Ѳ status. Although PKC-Ѳ is dispensable for TCR-independent Treg proliferation per se, it is essential for optimum IL-2 production by Teff cells. Finally, our findings suggest that OX40L binding to OX40 likely results in recruitment of TRAF1 for downstream signalling.
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http://dx.doi.org/10.1038/s41598-017-05254-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5529425PMC
July 2017
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