Publications by authors named "Sreetama Choudhury"

9 Publications

  • Page 1 of 1

Pomegranate Polyphenols Attenuate Inflammation and Hepatic Damage in Tumor-Bearing Mice: Crucial Role of NF-κB and the Nrf2/GSH Axis.

J Nutr Biochem 2021 Jul 2;97:108812. Epub 2021 Jul 2.

Department of Physiology, University of Calcutta; Kolkata, India; Centre for Research in Nanoscience and Nanotechnology, University of Calcutta, Kolkata, India. Electronic address:

It has been widely reported that cancer, along with its treatment regimens, cause severe toxicity in the host. A suitable agent having chemopreventive properties as well as capabilities of ameliorating tumor- and drug-induced toxicities is of imminent need. Pomegranate has been projected as an excellent anti-tumor, anti-inflammatory and anti-oxidant agent. In this study, for the first time, we delineated the exact signaling cascade by which dietary supplementation of pomegranate fruit extract (PFE) protects tumor-bearing mice from tumor-induced hepatotoxicity. Increased activities of serum Alanine transaminase, Aspartate transaminase, Lactate dehydrogenase and Alkaline phosphatase, as well as histological studies confirmed the establishment of a state of hepatic dysfunction in tumor-bearers. Further investigations revealed that increased hepatic reactive oxygen species content and glutathione depletion-initiated apoptosis in these hepatocytes as we observed an alteration in the apoptotic proteins. PFE supplementation in tumor-bearing mice, on the other hand, differentially modulated redox-sensitive transcription factors Nrf2 and NF-κB, ultimately decreasing tumor-induced hepatic oxidative damage and cell death. siRNA-mediated inhibition of Nrf2 and NF-κB completely abolished the hepato-protective activities of PFE while pre-treatment of tumor-conditioned hepatocytes with N-acetyl cysteine augmented the cyto-protective properties of PFE. The present study clearly identified Nrf2/NF-κB/glutathione axis as the key factor behind the hepatoprotective potential of PFE. These findings would add to the existing knowledge about cancer chemoprevention by dietary polyphenols and might lead to the application of pomegranate polyphenols as supplement to escalate the effectiveness of cancer therapy by protecting normal cells from cancer related toxicities.
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http://dx.doi.org/10.1016/j.jnutbio.2021.108812DOI Listing
July 2021

Inflammation-induced behavioral changes is driven by alterations in Nrf2-dependent apoptosis and autophagy in mouse hippocampus: Role of fluoxetine.

Cell Signal 2020 04 24;68:109521. Epub 2019 Dec 24.

Department of Physiology, University of Calcutta; UCSTA, 92, Acharya Prafulla Chandra Road, Kolkata 700009, India; Centre for Research in Nanoscience and Nanotechnology, University of Calcutta, JD-2, Salt Lake, Sector III, Kolkata 700098, India. Electronic address:

Inflammation has been associated with the progression of many neurological diseases. Peripheral inflammation has also been vaguely linked to depression-like symptoms in animal models, but the underlying pathways that orchestrate inflammation-induced behavioral or molecular changes in the brain are still elusive. We have recently shown that intraperitoneal injections of lipopolysaccharide (LPS) to Swiss albino mice triggers systemic inflammation, leading to an activated immune response along with changes in monoamine levels in the brain. Herein we pinpoint the fundamental pathways linking peripheral inflammation and depression-like behavior in a mouse model, thereby identifying suitable targets of intervention to combat the situation. We show that LPS-induced peripheral inflammation provoked a depression-like behavior in mice and a distinct pro-inflammatory bias in the hippocampus, as evident from increased microglial activation and elevated levels of pro-inflammatory cytokines IL-6 and TNF-α, and activation of NFκB-p65 pathway. Significant alterations in Nrf2-dependent cellular redox status, coupled with altered autophagy and increased apoptosis were noticed in the hippocampus of LPS-exposed mice. We and others have previously shown that, fluoxetine (an anti-depressant) has effective anti-inflammatory and antioxidant properties by virtue of its abilities to regulate NFκB and Nrf2 signaling. We observed that treatment with fluoxetine or the Nrf2 activator tBHQ (tert-butyl hydroquinone), could reverse depression-like-symptoms and mitigate alterations in autophagy and cell death pathways in the hippocampus by activating Nrf2-dependent gene expressions. Taken together, the data suggests that systemic inflammation potentiates Nrf2-dependent changes in cell death and autophagy pathway in the hippocampus, eventually leading to major pathologic sequelae associated with depression. Therefore, targeting Nrf2 could be a novel approach in combatting depression and ameliorating its associated pathogenesis.
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http://dx.doi.org/10.1016/j.cellsig.2019.109521DOI Listing
April 2020

Dietary pomegranate supplement alleviates murine pancreatitis by modulating Nrf2-p21 interaction and controlling apoptosis to survival switch.

J Nutr Biochem 2019 04 21;66:17-28. Epub 2018 Dec 21.

Department of Physiology, University of Calcutta, UCSTA, 92, A.P.C. Road, Kolkata, 700009, West Bengal, India. Electronic address:

Dietary supplementation of polyphenol-rich pomegranate extract (POMx) has been shown to have anti-oxidant and anti-inflammatory activities. Here, we evaluate the efficacy of POMx in mitigating pancreatitis in mice and provide a mechanistic outline of the process. Age-matched male Swiss albino mice were injected with Lipopolysaccharide (LPS) and given POMx supplement alone or in combination with LPS. After 4 weeks of treatment histological scoring for pancreatic edema and vacuolization was performed. Serum insulin levels were estimated and the glucose tolerance test (IPGTT) data revealed that POMx reduced inflammation induced hyperglycemia in mice. Analysis of TLR4, IκB expression, and NF-κB nuclear translocation, and concentrations of IL-6 and TNFα showed that POMx is able to modulate the molecular instigators of inflammatory responses. Annexin V assay indicated that POMx protects against inflammation-mediated apoptosis in the pancreas. Expression profile of SAPK/JNK pathway, p53, Bax, Bcl-2 and Caspase-3 validate an apoptotic to survival shift in POMx treatment group. Co-immunoprecipitation studies show that POMx stabilizes p21 and Nrf2 interaction and increases its nuclear translocation. The study also proves that the nuclear fraction of Nrf2 is able to bind to the Bcl-2 promoter and activate an anti-apoptotic program. The findings of our study underline an anti-inflammatory, anti-oxidative and anti-apoptotic role of POMx and provide a mechanistic idea of how POMx confers protection during pancreatitis.
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http://dx.doi.org/10.1016/j.jnutbio.2018.12.009DOI Listing
April 2019

Fluoxetine triggers selective apoptosis in inflammation-induced proliferating (Ki-67 ) thymocytes.

Immunol Cell Biol 2019 05 14;97(5):470-484. Epub 2019 Feb 14.

Department of Physiology, University of Calcutta, UCSTA, 92, Acharya Prafulla Chandra Road, 700009, Kolkata, India.

Inappropriate functioning of the immune system is observed during sustained systemic inflammation, which might lead to immune deficiencies, autoimmune disorders and cancer. Primary lymphoid organs may progress to a deregulated proliferative state in response to inflammatory signals in order to intensify host defense mechanisms and exacerbate an inflammatory niche. Fluoxetine, a selective serotonin reuptake inhibitor, has recently been projected as an anti-inflammatory agent. This study had been designed to evaluate the potential novel role of fluoxetine in reversing inflammation-induced immune dysfunction. Lipopolysaccharide (LPS) administration in Swiss albino mice potentiated a systemic inflammatory response, along with increased proliferation of thymocytes and peripheral blood mononuclear cells, as evident from increased Ki-67 expression. The proliferative changes in the immune system were mainly associated with increased phosphorylation of PI3k, AKT and IκB along with elevated NFκB-p65 nuclear translocation. The Ki-67 thymocytes obtained from LPS administered mice demonstrated significantly low p53 nuclear activity, which was established to be mediated by NFκB through reduced nuclear translocation of p53 during LPS-induced proliferative conditions, thereby blocking p53-dependent apoptosis. Fluoxetine supplementation not only reversed the proinflammatory condition, but also induced selective apoptosis in the proliferation-dictated Ki-67 thymocytes possibly by modulating the hypothalamus-pituitary-adrenal axis and inducing glucocorticoid receptor activation and apoptosis in these proliferation-biased immune cells, authenticating a novel antiproliferative role of an established drug.
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http://dx.doi.org/10.1111/imcb.12227DOI Listing
May 2019

Pomegranate protects against arsenic-induced p53-dependent ROS-mediated inflammation and apoptosis in liver cells.

J Nutr Biochem 2016 12 6;38:25-40. Epub 2016 Sep 6.

Department of Physiology, University of Calcutta, UCSTA, 92, Acharya Prafulla Chandra Road, Kolkata 700009, India; Centre for Research in Nanoscience and Nanotechnology, University of Calcutta, JD-2, Salt Lake, Sector III, Kolkata 700098, India. Electronic address:

Molecular mechanisms involved in arsenic-induced toxicity are complex and elusive. Liver is one of the most favored organs for arsenic toxicity as methylation of arsenic occurs mostly in the liver. In this study, we have selected a range of environmentally relevant doses of arsenic to examine the basis of arsenic toxicity and the role of pomegranate fruit extract (PFE) in combating it. Male Swiss albino mice exposed to different doses of arsenic presented marked hepatic injury as evident from histological and electron microscopic studies. Increased activities of enzymes alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase and alkaline phosphatase corroborated extensive liver damage. It was further noted that arsenic exposure initiated reactive oxygen species (ROS)-dependent apoptosis in the hepatocytes involving loss of mitochondrial membrane potential. Arsenic significantly increased nuclear translocation of nuclear factor erythroid 2-related factor 2 (Nrf2) and nuclear factor-κB (NF-κB), coupled with increase in phosphorylated Iκ-B, possibly as adaptive cellular survival strategies. Arsenic-induced oxidative DNA damage to liver cells culminated in p53 activation and increased expression of p53 targets like miR-34a and Bax. Pomegranate polyphenols are known to possess remarkable antioxidant properties and are capable of protecting normal cells from various stimuli-induced oxidative stress and toxicities. We explored the protective role of PFE in ameliorating arsenic-induced hepatic damage. PFE was shown to reduce ROS generation in hepatocytes, thereby reducing arsenic-induced Nrf2 activation. PFE also inhibited arsenic-induced NF-κB-inflammatory pathway. Data revealed that PFE reversed arsenic-induced hepatotoxicity and apoptosis by modulating the ROS/Nrf2/p53-miR-34a axis. For the first time, we have mapped the possible signaling pathways associated with arsenic-induced hepatotoxicity and its rescue by pomegranate polyphenols.
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http://dx.doi.org/10.1016/j.jnutbio.2016.09.001DOI Listing
December 2016

Arsenic-induced dose-dependent modulation of the NF-κB/IL-6 axis in thymocytes triggers differential immune responses.

Toxicology 2016 05 8;357-358:85-96. Epub 2016 Jun 8.

Department of Physiology, UCSTA, University of Calcutta, 92, A.P.C. Road, Kolkata 700009, India. Electronic address:

Arsenic contamination of drinking water is a matter of global concern. Arsenic intake impairs immune responses and leads to a variety of pathological conditions including cancer. In order to understand the intricate tuning of immune responses elicited by chronic exposure to arsenic, a mouse model was established by subjecting mice to different environmentally relevant concentrations of arsenic in drinking water for 30days. Detailed study of the thymus, a primary immune organ, revealed arsenic-mediated tissue damage in both histological specimens and scanning electron micrographs. Analysis of molecular markers of apoptosis by Western blot revealed a dose-dependent activation of the apoptotic cascade. Enzymatic assays supported oxidative stress as an instigator of cell death. Interestingly, assessment of inflammatory responses revealed disparity in the NF-κB/IL-6/STAT3 axis, where it was found that in animals consuming higher amounts of arsenic NF-κB activation did not lead to the classical IL-6 upregulation response. This deviation from the canonical pathway was accompanied with a significant rise in numbers of CD4+ CD25+ FoxP3 expressing cells in the thymus. The cytokine profile of the animals exposed to higher doses of arsenic also indicated an immune-suppressed milieu, thus validating that arsenic shapes the immune environment in context to its dose of exposure and that at higher doses it leads to immune-suppression. Our study establishes a novel role of arsenic in regulating immune homeostasis in context to its dose, where, at higher doses, arsenic related upregulation of NF-κB cascade takes on an alternative role that is correlated with increased immune-suppression.
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http://dx.doi.org/10.1016/j.tox.2016.06.005DOI Listing
May 2016

Gold-conjugated green tea nanoparticles for enhanced anti-tumor activities and hepatoprotection--synthesis, characterization and in vitro evaluation.

J Nutr Biochem 2015 Nov 26;26(11):1283-97. Epub 2015 Jul 26.

Department of Physiology, University of Calcutta; UCSTA, 92, Acharya Prafulla Chandra Road, Kolkata-700009, India; Centre for Research in Nanoscience and Nanotechnology, University of Calcutta, JD-2, Salt Lake, Sector III, Kolkata-700098, India. Electronic address:

Green tea (GT)-based chemoprevention has shown promising results in various cancer models. However, the effective dose may not be far from the toxic dose because of inefficient systemic delivery and limited bio-availability of GT polyphenols. We have used GT polyphenols to successfully reduce gold to corresponding gold nanoparticles (NPs) in a single step; a process that fulfils all criteria of green nanotechnology as no "man-made" chemical other than gold acids are used. GT and (-) - epigallocatechin-3-gallate (EGCG) conjugated gold NPs (diameters <50 nm), showed remarkable stability, significantly rapid cellular uptake and excellent in vitro anti-oxidant activities. These NPs were observed to be selectively toxic towards cancer cells (Ehrlich's Ascites Carcinoma and MCF-7) while showing absolutely no lethality towards normal primary mouse hepatocytes. In cancer cells, NPs altered the redox status and limited Nrf2 activation by almost 50%. These NPs significantly decreased nuclear translocation of NF-κB, coupled with decreased phosphorylation of IĸB and down-regulation of NF-κB-dependent anti-apoptotic proteins Bcl2 and Akt in a dose-dependent manner, triggering onset of apoptosis. Culturing normal hepatocytes with tumor-conditioned media prompted apoptosis by increasing reactive oxygen species (ROS) and depleting the anti-oxidant defense mechanism of hepatocytes. Pre-treatment with NPs protected hepatocytes from tumor-induced cellular damage by scavenging excess ROS, increasing the levels of reduced glutathione and anti-oxidant enzymes. There was evidence of decreased Bax/Bcl2 ratio and active Caspase 3 levels in these hepatocytes, indicating apoptosis escape. Nanoformulations of GT-based polyphenols might serve as an operative platform for effective delivery, increased bio-availability, enhanced effects and minimal chemotherapy-associated toxicities.
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http://dx.doi.org/10.1016/j.jnutbio.2015.06.003DOI Listing
November 2015

Reactive oxygen species in the tumor niche triggers altered activation of macrophages and immunosuppression: Role of fluoxetine.

Cell Signal 2015 Jul 27;27(7):1398-412. Epub 2015 Mar 27.

Department of Physiology, University of Calcutta, UCSTA, 92, Acharya Prafulla Chandra Road, Kolkata-700009, India; Centre for Research in Nanoscience and Nanotechnology, University of Calcutta, JD-2, Salt Lake, Sector III, Kolkata-700098, India. Electronic address:

Macrophages are projected as one of the key players responsible for the progression of cancer. Classically activated (M1) macrophages are pro-inflammatory and have a central role in host defense, while alternatively activated (M2) macrophages are associated with immunosuppression. Macrophages residing at the site of neoplastic growth are alternately activated and are referred to as tumor-associated macrophages (TAMs). These "cooperate" with tumor tissue, promoting increased proliferation and immune escape. Selective serotonin reuptake inhibitors like fluoxetine have recently been reported to possess anti-inflammatory activity. We used fluoxetine to target tumor-associated inflammation and consequent alternate polarization of macrophages. We established that murine peritoneal macrophages progressed towards an altered activation state when exposed to cell-free tumor fluid, as evidenced by increased IL-6, IL-4 and IL-10 levels. These polarized macrophages showed significant pro-oxidant bias and increased p65 nuclear localization. It was further observed that these altered macrophages could induce oxidative insult and apoptosis in cultured mouse CD3(+) T cells. To validate these findings, we replicated key experiments in vivo, and observed that there was increased serum IL-6, IL-4 and IL-10 in tumor-bearing animals, with increased % CD206(+) cells within the tumor niche. TAMs showed increased nuclear localization of p65 with decreased Nrf2 expression in the nucleus. These results were associated with increase in apoptosis of CD3(+) T cells co-cultured with TAM-spent media. We could establish that fluoxetine treatment could specifically re-educate the macrophages both in vitro and in vivo by skewing their phenotype such that immune suppression mediated by tumor-dictated macrophages was successfully mitigated.
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http://dx.doi.org/10.1016/j.cellsig.2015.03.013DOI Listing
July 2015

Pomegranate reverses methotrexate-induced oxidative stress and apoptosis in hepatocytes by modulating Nrf2-NF-κB pathways.

J Nutr Biochem 2013 Dec;24(12):2040-50

Department of Physiology, University of Calcutta, Kolkata, West Bengal 700009, India.

The clinical efficacy of the widely used chemotherapeutic drug methotrexate (MTX) is limited due to its associated hepatotoxicity. Pomegranate polyphenols are of huge health benefits and known to possess remarkable antioxidant properties capable of protecting normal cells from various stimuli-induced oxidative stress and cell death. In this study, we explored the protective role of pomegranate fruit extract (PFE) in ameliorating MTX-induced hepatic damage. Male Swiss albino mice exposed to MTX (20 mg/kg body weight) exhibited distinct markers of toxicity such as increased activities of enzymes alanine transaminase, aspartate transaminase, lactate dehydrogenase and alkaline phosphatase and also increased oxidative stress in liver evidenced by increased ROS generation and lipid peroxidation. Decrease in reduced glutathione levels, superoxide dismutase, catalase, hepatic heme oxygenase 1 and NQO-1 activities were also observed. Tracing the signal transduction pathways, it was seen that MTX exposure significantly increased nuclear translocation of NF-κB coupled with increase in phosphorylated Iκ-B and down-regulation of NF-kappaB-dependent antiapoptotic protein Bcl-2. Treatment with MTX increased the expression of the apoptotic enhancer Rho/Cdc42 as well as the phosphorylation of SAPK/JNK. A shift in the Bax/Bcl-2 ratio towards apoptosis and increase in the caspase 3 level was also evident. Administration of PFE for 7 consecutive days before and after MTX challenge suppressed MTX-induced cell death, mitigated the injurious effects of MTX and offered protection against apoptosis. PFE was shown to reduce ROS generation in hepatocytes by activating the Nrf2-ARE pathway and inhibiting NF-κB as a consequence of which the antioxidant defense mechanism in the liver was up-regulated, thereby conferring protection against MTX-induced hepatotoxicity and apoptosis.
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http://dx.doi.org/10.1016/j.jnutbio.2013.07.005DOI Listing
December 2013
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