12 results on '"Yetirajam, Rajesh"'
Search Results
2. Dissecting the Balance Between Metabolic and Oncogenic Functions of Astrocyte‐Elevated Gene‐1/Metadherin
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Yetirajam Rajesh, Saranya Chidambaranathan Reghupaty, Rachel G. Mendoza, Debashri Manna, Indranil Banerjee, Mark A. Subler, Korri Weldon, Zhao Lai, Shah Giashuddin, Paul B. Fisher, Arun J. Sanyal, Rebecca K. Martin, Mikhail G. Dozmorov, Jolene J. Windle, and Devanand Sarkar
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Diseases of the digestive system. Gastroenterology ,RC799-869 - Abstract
Obesity is an enormous global health problem, and obesity‐induced nonalcoholic steatohepatitis (NASH) is contributing to a rising incidence and mortality for hepatocellular carcinoma (HCC). Increase in de novo lipogenesis and decrease in fatty acid β‐oxidation (FAO) underlie hepatic lipid accumulation in NASH. Astrocyte‐elevated gene‐1/metadherin (AEG‐1) overexpression contributes to both NASH and HCC. AEG‐1 harbors an LXXLL motif through which it blocks activation of peroxisome proliferator activated receptor α (PPARα), a key regulator of FAO. To better understand the role of LXXLL motif in mediating AEG‐1 function, using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 technology, we generated a mouse model (AEG‐1‐L24K/L25H) in which the LXXLL motif in AEG‐1 was mutated to LXXKH. We observed increased activation of PPARα in AEG‐1‐L24K/L25H livers providing partial protection from high‐fat diet–induced steatosis. Interestingly, even with equal gene dosage levels, compared with AEG‐1–wild‐type livers, AEG‐1‐L24K/L25H livers exhibited increase in levels of lipogenic enzymes, mitogenic activity and inflammation, which are attributes observed when AEG‐1 is overexpressed. These findings indicate that while LXXLL motif favors steatotic activity of AEG‐1, it keeps in check inflammatory and oncogenic functions, thus maintaining a homeostasis in AEG‐1 function. AEG‐1 is being increasingly appreciated as a viable target for ameliorating NASH and NASH‐HCC, and as such, in‐depth understanding of the functions and molecular attributes of this molecule is essential. Conclusion: The present study unravels the unique role of the LXXLL motif in mediating the balance between the metabolic and oncogenic functions of AEG‐1.
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- 2022
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3. Mouse Bone Marrow Cell Isolation and Macrophage Differentiation
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Mendoza, Rachel, primary, Banerjee, Indranil, additional, Manna, Debashri, additional, Reghupaty, Saranya Chidambaranathan, additional, Yetirajam, Rajesh, additional, and Sarkar, Devanand, additional
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- 2022
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4. Isolation and Culture of Mouse Hepatocytes and Kupffer Cells (KCs)
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Mendoza, Rachel, primary, Banerjee, Indranil, additional, Reghupaty, Saranya Chidambaranathan, additional, Yetirajam, Rajesh, additional, Manna, Debashri, additional, and Sarkar, Devanand, additional
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- 2022
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5. Innate Immune Cell Death in Neuroinflammation and Alzheimer’s Disease
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Yetirajam Rajesh and Thirumala-Devi Kanneganti
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neuroinflammation ,innate immunity ,cell death ,pyroptosis ,apoptosis ,necroptosis ,Cytology ,QH573-671 - Abstract
Alzheimer’s disease (AD) is a neurodegenerative disorder molecularly characterized by the formation of amyloid β (Aβ) plaques and type 2 microtubule-associated protein (Tau) abnormalities. Multiple studies have shown that many of the brain’s immunological cells, specifically microglia and astrocytes, are involved in AD pathogenesis. Cells of the innate immune system play an essential role in eliminating pathogens but also regulate brain homeostasis and AD. When activated, innate immune cells can cause programmed cell death through multiple pathways, including pyroptosis, apoptosis, necroptosis, and PANoptosis. The cell death often results in the release of proinflammatory cytokines that propagate the innate immune response and can eliminate Aβ plaques and aggregated Tau proteins. However, chronic neuroinflammation, which can result from cell death, has been linked to neurodegenerative diseases and can worsen AD. Therefore, the innate immune response must be tightly balanced to appropriately clear these AD-related structural abnormalities without inducing chronic neuroinflammation. In this review, we discuss neuroinflammation, innate immune responses, inflammatory cell death pathways, and cytokine secretion as they relate to AD. Therapeutic strategies targeting these innate immune cell death mechanisms will be critical to consider for future preventive or palliative treatments for AD.
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- 2022
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6. Association of Adipose Tissue and Adipokines with Development of Obesity-Induced Liver Cancer
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Yetirajam Rajesh and Devanand Sarkar
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adipose tissue ,adiponectin ,adipokines ,leptin ,NAFLD/NASH ,HCC ,Biology (General) ,QH301-705.5 ,Chemistry ,QD1-999 - Abstract
Obesity is rapidly dispersing all around the world and is closely associated with a high risk of metabolic diseases such as insulin resistance, dyslipidemia, and nonalcoholic fatty liver disease (NAFLD), leading to carcinogenesis, especially hepatocellular carcinoma (HCC). It results from an imbalance between food intake and energy expenditure, leading to an excessive accumulation of adipose tissue (AT). Adipocytes play a substantial role in the tumor microenvironment through the secretion of several adipokines, affecting cancer progression, metastasis, and chemoresistance via diverse signaling pathways. AT is considered an endocrine organ owing to its ability to secrete adipokines, such as leptin, adiponectin, resistin, and a plethora of inflammatory cytokines, which modulate insulin sensitivity and trigger chronic low-grade inflammation in different organs. Even though the precise mechanisms are still unfolding, it is now established that the dysregulated secretion of adipokines by AT contributes to the development of obesity-related metabolic disorders. This review focuses on several obesity-associated adipokines and their impact on obesity-related metabolic diseases, subsequent metabolic complications, and progression to HCC, as well as their role as potential therapeutic targets. The field is rapidly developing, and further research is still required to fully understand the underlying mechanisms for the metabolic actions of adipokines and their role in obesity-associated HCC.
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- 2021
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7. Molecular Mechanisms Regulating Obesity-Associated Hepatocellular Carcinoma
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Yetirajam Rajesh and Devanand Sarkar
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HCC ,obesity ,NASH ,genetic factors ,epigenetic changes ,therapeutics ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 - Abstract
Obesity is a global, intractable issue, altering inflammatory and stress response pathways, and promoting tissue adiposity and tumorigenesis. Visceral fat accumulation is correlated with primary tumor recurrence, poor prognosis and chemotherapeutic resistance. Accumulating evidence highlights a close association between obesity and an increased incidence of hepatocellular carcinoma (HCC). Obesity drives HCC, and obesity-associated tumorigenesis develops via nonalcoholic fatty liver (NAFL), progressing to nonalcoholic steatohepatitis (NASH) and ultimately to HCC. The better molecular elucidation and proteogenomic characterization of obesity-associated HCC might eventually open up potential therapeutic avenues. The mechanisms relating obesity and HCC are correlated with adipose tissue remodeling, alteration in the gut microbiome, genetic factors, ER stress, oxidative stress and epigenetic changes. During obesity-related hepatocarcinogenesis, adipokine secretion is dysregulated and the nuclear factor erythroid 2 related factor 1 (Nrf-1), nuclear factor kappa B (NF-κB), mammalian target of rapamycin (mTOR), phosphatidylinositol-3-kinase (PI3K)/phosphatase and tensin homolog (PTEN)/Akt, and Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathways are activated. This review captures the present trends allied with the molecular mechanisms involved in obesity-associated hepatic tumorigenesis, showcasing next generation molecular therapeutic strategies and their mechanisms for the successful treatment of HCC.
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- 2020
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8. Therapeutic targeting of RBPJ, an upstream regulator of ETV6 gene, abrogates ETV6-NTRK3 fusion gene transformations in glioblastoma
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Angana Biswas, Yetirajam Rajesh, Subhayan Das, Indranil Banerjee, Neelkamal Kapoor, Pralay Mitra, and Mahitosh Mandal
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DNA-Binding Proteins ,Repressor Proteins ,Cancer Research ,Phosphatidylinositol 3-Kinases ,Oncology ,Oncogene Proteins, Fusion ,Proto-Oncogene Proteins c-ets ,Immunoglobulin J Recombination Signal Sequence-Binding Protein ,Humans ,Receptor, trkC ,Glioblastoma ,Transcription Factors - Abstract
Fusion genes are abnormal genes resulting from chromosomal translocation, insertion, deletion, inversion, etc. ETV6, a rather promiscuous partner forms fusions with several other genes, most commonly, the NTRK3 gene. This fusion leads to the formation of a constitutively activated tyrosine kinase which activates the Ras-Raf-MEK and PI3K/AKT/MAPK pathways, leading the cells through cycles of uncontrolled division and ultimately resulting in cancer. Targeted therapies against this ETV6-NTRK3 fusion protein are much needed. Therefore, to find a targeted approach, a transcription factor RBPJ regulating the ETV6 gene was established and since the ETV6-NTRK3 fusion gene is downstream of the ETV6 promoter/enhancer, this fusion protein is also regulated. The regulation of the ETV6 gene via RBPJ was validated by ChIP analysis in human glioblastoma (GBM) cell lines and patient tissue samples. This study was further followed by the identification of an inhibitor, Furamidine, against transcription factor RBPJ. It was found to be binding with the DNA binding domain of RBPJ with antitumorigenic properties and minimal organ toxicity. Hence, a new target RBPJ, regulating the production of ETV6 and ETV6-NTRK3 fusion protein was found along with a potent RBPJ inhibitor Furamidine.
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- 2022
9. Lumefantrine, an antimalarial drug, reverses radiation and temozolomide resistance in glioblastoma
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Angana Biswas, Mahitosh Mandal, Webster K. Cavenee, Swadesh K. Das, Luni Emdad, Paul B. Fisher, Santanu Maji, Yetirajam Rajesh, Utkarsh Kumar, Subhayan Das, and Indranil Banerjee
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Epithelial-Mesenchymal Transition ,medicine.disease_cause ,Lumefantrine ,Antimalarials ,chemistry.chemical_compound ,In vivo ,Cell Line, Tumor ,Heat shock protein ,Radioresistance ,Temozolomide ,Humans ,Medicine ,Epithelial–mesenchymal transition ,Antineoplastic Agents, Alkylating ,Heat-Shock Proteins ,Multidisciplinary ,Brain Neoplasms ,business.industry ,Microfilament Proteins ,fungi ,Biological Sciences ,Gene Expression Regulation, Neoplastic ,chemistry ,Drug Resistance, Neoplasm ,Apoptosis ,Trans-Activators ,Cancer research ,Glioblastoma ,business ,Carcinogenesis ,Molecular Chaperones ,medicine.drug - Abstract
Glioblastoma multiforme (GBM) is an aggressive cancer without currently effective therapies. Radiation and temozolomide (radio/TMZ) resistance are major contributors to cancer recurrence and failed GBM therapy. Heat shock proteins (HSPs), through regulation of extracellular matrix (ECM) remodeling and epithelial mesenchymal transition (EMT), provide mechanistic pathways contributing to the development of GBM and radio/TMZ-resistant GBM. The Friend leukemia integration 1 (Fli-1) signaling network has been implicated in oncogenesis in GBM, making it an appealing target for advancing novel therapeutics. Fli-1 is linked to oncogenic transformation with up-regulation in radio/TMZ-resistant GBM, transcriptionally regulating HSPB1. This link led us to search for targeted molecules that inhibit Fli-1. Expression screening for Fli-1 inhibitors identified lumefantrine, an antimalarial drug, as a probable Fli-1 inhibitor. Docking and isothermal calorimetry titration confirmed interaction between lumefantrine and Fli-1. Lumefantrine promoted growth suppression and apoptosis in vitro in parental and radio/TMZ-resistant GBM and inhibited tumor growth without toxicity in vivo in U87MG GBM and radio/TMZ-resistant GBM orthotopic tumor models. These data reveal that lumefantrine, an FDA-approved drug, represents a potential GBM therapeutic that functions through inhibition of the Fli-1/HSPB1/EMT/ECM remodeling protein networks.
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- 2020
10. Transcriptional regulation of HSPB1 by Friend leukemia integration-1 factor modulates radiation and temozolomide resistance in glioblastoma
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Yetirajam Rajesh, Biswas, A., Banik, P., Pal, I., Das, S., Borkar, S. A., Sardana, H., Saha, A., Das, S. K., Emdad, L., Fisher, P. B., and Mandal, M.
11. Isolation and Culture of Mouse Hepatocytes and Kupffer Cells (KCs).
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Mendoza R, Banerjee I, Reghupaty SC, Yetirajam R, Manna D, and Sarkar D
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- Animals, Hepatocytes, Liver, Mice, Mice, Inbred C57BL, Reproducibility of Results, Kupffer Cells, Non-alcoholic Fatty Liver Disease pathology
- Abstract
Nonalcoholic steatohepatitis (NASH) is characterized by accumulation of lipids in the hepatocytes (steatosis) and chronic inflammation. Liver resident macrophages (Kupffer cells) play a pivotal role in inducing inflammation. Cross-talk between hepatocytes and Kupffer cells (KCs) regulate both steatosis and inflammation during the pathogenesis of NASH. Isolated hepatocytes and KC serve as important tools to study mechanistic events during NASH in an in vitro setting. Because mice and humans share identical genes, primary mouse hepatocytes and KC are valuable ex vivo models for NASH studies. However, isolation of mouse liver cells is challenging and requires specific technical procedure and skills. Here, we elaborate a method for effective isolation of both primary hepatocytes and KC from adult liver of the same mouse. This protocol can be used for isolation of liver cells from both wild-type (WT) and genetically-engineered mice. The principle of the method is based on a two-step collagenase perfusion technique in which the liver is washed by perfusion, liver cells are segregated by collagenase treatment, and hepatocytes and KC are then purified and cultured. We optimized this protocol in terms of reproducibility, yield of different population of liver cells, and viability., (© 2022. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)
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- 2022
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12. Mouse Bone Marrow Cell Isolation and Macrophage Differentiation.
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Mendoza R, Banerjee I, Manna D, Reghupaty SC, Yetirajam R, and Sarkar D
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- Animals, Bone Marrow Cells, Cell Differentiation physiology, Cells, Cultured, Macrophages metabolism, Mice, Monocytes, Hematopoiesis, Macrophage Colony-Stimulating Factor metabolism, Macrophage Colony-Stimulating Factor pharmacology
- Abstract
The rapid increase in the incidence of obesity contributes to a parallel increase in nonalcoholic steatohepatitis (NASH). Monocyte-derived macrophages, recruited from the bone marrow to the liver, promote NASH-related inflammation and fibrosis. In addition, adipose tissue macrophages (ATMs) release pro-inflammatory cytokines (PICs) which stimulate adipose tissue lipolysis liberating free fatty acids (FFAs) that can accumulate in the liver as triglycerides (TGs), thereby inducing steatosis. As such, bone marrow-derived macrophages (BMDMs) function as an essential tool to study the pathogenesis of NASH. BMDMs are primary bone marrow-derived cells which are differentiated into macrophages in vitro in the presence of growth factors. Macrophage colony-stimulating factor (M-CSF) is required for the proliferation and differentiation of committed myeloid progenitors into cells of the macrophage/monocyte lineage. Here, we describe a protocol for the isolation of mouse bone marrow cells and subsequent macrophage differentiation in which bone marrow cells are cultured in the presence of M-CSF, supplemented either by conditioned medium from L929 cells or in purified form. The efficiency of the differentiation is confirmed by immunofluorescent staining of macrophage surface antigen F4/80. The BMDMs serve as an excellent ex vivo model for a variety of studies, including hepatocyte-macrophage and adipocyte-macrophage cross-talk regulating NASH., (© 2022. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)
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- 2022
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