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  • Hypoxia-induced miR-210-3p expression in lung adenocarcinoma potentiates tumor development by regulating CCL2 mediated monocyte infiltration. Molecular oncology Arora, L., Patra, D., Roy, S., Nanda, S., Singh, N., Verma, A. K., Chakraborti, A., Dasgupta, S., Pal, D. 2024; 18 (5): 1278-1300

    Abstract

    In most cancers, tumor hypoxia downregulates the expression of C-C motif chemokine 2 (CCL2), and this downregulation has been implicated in monocyte infiltration and tumor progression; however, the molecular mechanism is not yet clear. We compared noncancerous and lung-adenocarcinoma human samples for hypoxia-inducible factor 1-alpha (HIF-1A), microRNA-210-3p (mir-210-3p), and CCL2 levels. Mechanistic studies were performed on lung adenocarcinoma cell lines and 3D tumor spheroids to understand the role of hypoxia-induced miR-210-3p in the regulation of CCL2 expression and macrophage polarization. HIF-1Α stabilization increases miR-210-3p levels in lung adenocarcinoma and impairs monocyte infiltration by inhibiting CCL2 expression. Mechanistically, miR-210-3p directly binds to the 3'untranslated region (UTR) of CCL2 mRNA and silences it. Suppressing miR-210-3p substantially downregulates the effect of hypoxia on CCL2 expression. Monocyte migration is significantly hampered in miR-210-3p mimic-transfected HIF-1A silenced cancer cells. In contrast, inhibition of miR-210-3p in HIF-1A-overexpressed cells markedly restored monocyte migration, highlighting a direct link between the miR-210-3p level and tumor monocyte burden. Moreover, miR-210-3p inhibition in 3D tumor spheroids promotes monocyte recruitment and skewing towards an antitumor M1 phenotype. Anti-hsa-miR-210-3p-locked nucleic acid (LNA) delivery in a lung tumor xenograft zebrafish model caused tumor regression, suggesting that miR-210-3p could be a promising target for immunomodulatory therapeutic strategies against lung adenocarcinoma.

    View details for DOI 10.1002/1878-0261.13260

    View details for PubMedID 35658112

    View details for PubMedCentralID PMC11077004

  • Adipose tissue macrophage-derived microRNA-210-3p disrupts systemic insulin sensitivity by silencing GLUT4 in obesity. The Journal of biological chemistry Patra, D., Ramprasad, P., Sharma, S., Dey, U., Kumar, V., Singh, S., Dasgupta, S., Kumar, A., Tikoo, K., Pal, D. 2024: 107328

    Abstract

    Management of chronic obesity-associated metabolic disorders is a key challenge for biomedical researchers. During chronic obesity, visceral adipose tissue (VAT) undergoes substantial transformation characterized by a unique lipid-rich hypoxic AT microenvironment (ATenv) which plays a crucial role in VAT dysfunction, leading to insulin resistance (IR) and type 2 diabetes(T2D). Here, we demonstrate that obese ATenv triggers the release of miR-210-3p microRNA-loaded extracellular vesicles (EVs) from adipose tissue macrophages (ATMs), which disseminate miR-210-3p to neighboring adipocytes, skeletal muscle cells, and hepatocytes through paracrine and endocrine actions, thereby influencing insulin sensitivity. Moreover, EVs collected from Dicer-silenced miR-210-3p-overexpressed bone marrow-derived macrophages (BMDMs), induce glucose intolerance and IR in lean mice. Mechanistically, miR-210-3p interacts with the 3'-UTR of GLUT4 mRNA and silences its expression, compromising cellular glucose uptake and insulin sensitivity. Therapeutic inhibition of miR-210-3p in VAT notably rescues high-fat diet (HFD)-fed mice from obesity-induced systemic glucose intolerance. Thus, targeting ATM-specific miR-210-3p during obesity could be a promising strategy for managing IR and T2D.

    View details for DOI 10.1016/j.jbc.2024.107328

    View details for PubMedID 38679332

  • Pharmacological inhibition of DNMT1 restores macrophage autophagy and M2 polarization in Western diet-induced nonalcoholic fatty liver disease. The Journal of biological chemistry Pant, R., Kabeer, S. W., Sharma, S., Kumar, V., Patra, D., Pal, D., Tikoo, K. 2023; 299 (6): 104779

    Abstract

    Nonalcoholic fatty liver disease (NAFLD) is associated with an increased ratio of classically activated M1 macrophages/Kupffer cells to alternatively activated M2 macrophages, which plays an imperative role in the development and progression of NAFLD. However, little is known about the precise mechanism behind macrophage polarization shift. Here, we provide evidence regarding the relationship between the polarization shift in Kupffer cells and autophagy resulting from lipid exposure. High-fat and high-fructose diet supplementation for 10 weeks significantly increased the abundance of Kupffer cells with an M1-predominant phenotype in mice. Interestingly, at the molecular level, we also observed a concomitant increase in expression of DNA methyltransferases DNMT1 and reduced autophagy in the NAFLD mice. We also observed hypermethylation at the promotor regions of autophagy genes (LC3B, ATG-5, and ATG-7). Furthermore, the pharmacological inhibition of DNMT1 by using DNA hypomethylating agents (azacitidine and zebularine) restored Kupffer cell autophagy, M1/M2 polarization, and therefore prevented the progression of NAFLD. We report the presence of a link between epigenetic regulation of autophagy gene and macrophage polarization switch. We provide the evidence that epigenetic modulators restore the lipid-induced imbalance in macrophage polarization, therefore preventing the development and progression of NAFLD.

    View details for DOI 10.1016/j.jbc.2023.104779

    View details for PubMedID 37142224

    View details for PubMedCentralID PMC10248527

  • A small molecule potent IRAK4 inhibitor abrogates lipopolysaccharide-induced macrophage inflammation in-vitro and in-vivo. European journal of pharmacology Choudhary, S. A., Patra, D., Sinha, A., Mazumder, S., Pant, R., Chouhan, R., Jha, A. N., Prusty, B. M., Manna, D., Das, S. K., Tikoo, K., Pal, D., Dasgupta, S. 2023; 944: 175593

    Abstract

    Increasing evidence supports vanillin and its analogs as potent toll-like receptor signaling inhibitors that strongly attenuate inflammation, though, the underlying molecular mechanism remains elusive. Here, we report that vanillin inhibits lipopolysaccharide (LPS)-induced toll-like receptor 4 activation in macrophages by targeting the myeloid differentiation primary-response gene 88 (MyD88)-dependent pathway through direct interaction and suppression of interleukin-1 receptor-associated kinase 4 (IRAK4) activity. Moreover, incubation of vanillin in cells expressing constitutively active forms of different toll-like receptor 4 signaling molecules revealed that vanillin could only able to block the ligand-independent constitutively activated IRAK4/1 or its upstream molecules-associated NF-κB activation and NF-κB transactivation along with the expression of various proinflammatory cytokines. A significant inhibition of LPS-induced IRAK4/MyD88, IRAK4/IRAK1, and IRAK1/TRAF6 association was evinced in response to vanillin treatment. Furthermore, mutations at Tyr262 and Asp329 residues in IRAK4 or modifications of 3-OMe and 4-OH side groups in vanillin, significantly reduced IRAK4 activity and vanillin function, respectively. Mice pretreated with vanillin followed by LPS challenge markedly impaired LPS-induced IRAK4 activation and inflammation in peritoneal macrophages. Thus, the present study posits vanillin as a novel and potent IRAK4 inhibitor and thus providing an opportunity for its therapeutic application in managing various inflammatory diseases.

    View details for DOI 10.1016/j.ejphar.2023.175593

    View details for PubMedID 36804543

  • miR-210-3p Promotes Obesity-Induced Adipose Tissue Inflammation and Insulin Resistance by Targeting SOCS1-Mediated NF-κB Pathway. Diabetes Patra, D., Roy, S., Arora, L., Kabeer, S. W., Singh, S., Dey, U., Banerjee, D., Sinha, A., Dasgupta, S., Tikoo, K., Kumar, A., Pal, D. 2023; 72 (3): 375-388

    Abstract

    Under the condition of chronic obesity, an increased level of free fatty acids along with low oxygen tension in the adipose tissue creates a pathophysiological adipose tissue microenvironment (ATenv), leading to the impairment of adipocyte function and insulin resistance. Here, we found the synergistic effect of hypoxia and lipid (H + L) surge in fostering adipose tissue macrophage (ATM) inflammation and polarization. ATenv significantly increased miR-210-3p expression in ATMs which promotes NF-κB activation-dependent proinflammatory cytokine expression along with the downregulation of anti-inflammatory cytokine expression. Interestingly, delivery of miR-210-3p mimic significantly increased macrophage inflammation in the absence of H + L co-stimulation, while miR-210-3p inhibitor notably compromised H + L-induced macrophage inflammation through increased production of suppressor of cytokine signaling 1 (SOCS1), a negative regulator of the NF-κB inflammatory signaling pathway. Mechanistically, miR-210 directly binds to the 3'-UTR of SOCS1 mRNA and silences its expression, thus preventing proteasomal degradation of NF-κB p65. Direct delivery of anti-miR-210-3p LNA in the ATenv markedly rescued mice from obesity-induced adipose tissue inflammation and insulin resistance. Thus, miR-210-3p inhibition in ATMs could serve as a novel therapeutic strategy for managing obesity-induced type 2 diabetes.

    View details for DOI 10.2337/db22-0284

    View details for PubMedID 36469307

  • Lipid-induced monokine cyclophilin-A promotes adipose tissue dysfunction implementing insulin resistance and type 2 diabetes in zebrafish and mice models of obesity. Cellular and molecular life sciences : CMLS Banerjee, D., Patra, D., Sinha, A., Roy, S., Pant, R., Sarmah, R., Dutta, R., Kanta Bhagabati, S., Tikoo, K., Pal, D., Dasgupta, S. 2022; 79 (5): 282

    Abstract

    Several studies have implicated obesity-induced macrophage-adipocyte cross-talk in adipose tissue dysfunction and insulin resistance. However, the molecular cues involved in the cross-talk of macrophage and adipocyte causing insulin resistance are currently unknown. Here, we found that a lipid-induced monokine cyclophilin-A (CyPA) significantly attenuates adipocyte functions and insulin sensitivity. Targeted inhibition of CyPA in diet-induced obese zebrafish notably reduced adipose tissue inflammation and restored adipocyte function resulting in improvement of insulin sensitivity. Silencing of macrophage CyPA or pharmacological inhibition of CyPA by TMN355 effectively restored adipocytes' functions and insulin sensitivity. Interestingly, CyPA incubation markedly increased adipocyte inflammation along with an impairment of adipogenesis, however, mutation of its cognate receptor CD147 at P309A and G310A significantly waived CyPA's effect on adipocyte inflammation and its differentiation. Mechanistically, CyPA-CD147 interaction activates NF-κB signaling which promotes adipocyte inflammation by upregulating various pro-inflammatory cytokines gene expression and attenuates adipocyte differentiation by inhibiting PPARγ and C/EBPβ expression via LZTS2-mediated downregulation of β-catenin. Moreover, inhibition of CyPA or its receptor CD147 notably restored palmitate or CyPA-induced adipose tissue dysfunctions and insulin sensitivity. All these results indicate that obesity-induced macrophage-adipocyte cross-talk involving CyPA-CD147 could be a novel target for the management of insulin resistance and type 2 diabetes.

    View details for DOI 10.1007/s00018-022-04306-1

    View details for PubMedID 35511344

    View details for PubMedCentralID PMC11072608