Publications by authors named "Sreya Chattopadhyay"

36 Publications

Self Nano-Emulsifying Curcumin (SNEC30) attenuates arsenic-induced cell death in mice.

Toxicol Rep 2021 17;8:1428-1436. Epub 2021 Jul 17.

Cancer Research Laboratory, Department of Zoology, University of Calcutta, 35 Ballygunge Circular Road, Kolkata, 700 019, India.

Several precedents have confirmed numerous infirmities caused by arsenic poisoning, including immune suppression and cancer. Exposure to arsenic leads to alterations of the cellular machinery and eventually cell death, depending on the dose and duration of exposure. Oxidative stress induced by arsenic is the major mechanism by which it inflicts cellular toxicity, challenging the survival-support - autophagy and culminating in apoptosis in the thymus and spleen of mice. Curcumin, a potent dietary anti-oxidant with known anti-apoptotic and anti-inflammatory properties, was assessed for therapeutic benefits. However, the major caveat of this polyphenol is its low water solubility and limited bioavailability. Therefore, Self Nano-Emulsifying Curcumin (SNEC30) was used to treat mice exposed to arsenic. When administered, SNEC30 effectively ameliorated the adverse effects of arsenic in mice, by restoring structural alterations and reducing ROS-mediated cell death, thereby endorsing the importance of nutraceuticals in counteracting heavy metal-induced cellular toxicity.
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http://dx.doi.org/10.1016/j.toxrep.2021.07.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8322040PMC
July 2021

Delivery of novel coumarin-dihydropyrimidinone conjugates through mixed polymeric nanoparticles to potentiate therapeutic efficacy against triple-negative breast cancer.

Biomater Sci 2021 Aug 14;9(16):5665-5690. Epub 2021 Jul 14.

Center for Research in Nanoscience and Nanotechnology, Technology Campus, University of Calcutta, JD-2, Sector-III, Salt Lake, Kolkata-700106, West Bengal, India.

To date, most of the accessible therapeutic options are virtually non-responsive towards triple-negative breast cancer (TNBC) due to its highly aggressive and metastatic nature. Interestingly, chemotherapy reacts soundly in many TNBC cases compared to other types of breast cancer. However, the side effects of many chemotherapeutic agents are still under cross-examination, and thus prohibit their extensive uses. In this present study, we have developed a series of coumarin-dihydropyrimidinone conjugates (CDHPs) and subsequently their poly(lactic-co-glycolic acid) (PLGA)-PEG mixed copolymer nanoparticles as excellent chemotherapeutic nanomedicine to control TNBC. Among all the synthesized CDHPs, CDHP-4 (prepared by the combination of EDCO with 3,4-difluorobenzaldehyde) showed excellent therapeutic effect on a wide variety of cancer cell lines, including TNBC. Besides, it can control the metastasis and stemness property of TNBC. Furthermore, the nano-encapsulation of CDHP-4 in a mixed polymer nanoparticle system ([email protected]) and simultaneous delivery showed much improved therapeutic efficacy at a much lower dose, and almost negligible side effects in normal healthy cells or organs. The effectiveness of the present therapeutic agent was observed both in intravenous and oral mode of administration in in vivo experiments. Moreover, on elucidating the molecular mechanism, we found that [email protected] could exhibit apoptotic, anti-migratory, as well as anti-stemness activity against TNBC cell lines through the downregulation of miR-138. We validated our findings in MDA-MB-231 xenograft chick embryos, as well as in 4T1-induced mammary tumor-bearing BALB/c mice models, and studied the bio-distribution of [email protected] on the basis of the photoluminescence property of nanoparticles. Our recent study, hence for the first time, unravels the synthesis of [email protected] and the molecular mechanism behind the anti-migration, anti-stemness and anti-tumor efficacy of the nanoparticles against the TNBC cells through the miR-138/p65/TUSC2 axis.
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http://dx.doi.org/10.1039/d1bm00424gDOI Listing
August 2021

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

Oleic acid as a restorative agent in alleviating adrenaline induced altered morphofunctional milieu of gastric tissue and mitochondria.

Heliyon 2021 Mar 17;7(3):e06476. Epub 2021 Mar 17.

Oxidative Stress and Free Radical Biology Laboratory, Department of Physiology, University of Calcutta, 92, A.P.C. Road, Kolkata, 700009, India.

The role of oleic acid as a protective antioxidant has recently been recognized. The present study is aimed to explore whether oleic acid can afford protection to rat gastric tissue when challenged with adrenaline. Sixty adult healthy male albino rats were divided into 10 groups comprising of 6 animals each. First group constituted the control. Rats of the second group were injected sub-cutaneously with adrenaline bitartrate at the dose of 0.3mg/kg body weight, every day for a period of 17 days. Rats of the third, to the sixth groups were orally fed with different doses of oleic acid (2.5, 5, 10, 20 mg/kg body weight/day) respectively. The rats of seventh to tenth groups were orally fed with doses of oleic acid as mentioned above and subsequently injected with adrenaline bitartrate at 0.3mg/kg body weight sub-cutaneously. After the treatment period, the animals were euthanized through cervical dislocation following light ether anaesthesia and gastric tissues were collected for morphological and biochemical studies. Subcutaneously administered pharmacological dose of adrenaline bitartrate caused oxidative stress inducing gastric lesion in male albino rats as evident from the altered levels of biomarkers of oxidative stress, activities of antioxidant and mitochondrial enzymes related to energy metabolism with changes in tissue morphology. Pre-treatment of rats with oleic acid dose-dependently protected against these gastric injuries induced by adrenaline indicating the potentiality of oleic acid in protecting against adrenaline induced gastric injury in male albino rats where antioxidant mechanisms appear to play a pivotal role in mediating such protection.
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http://dx.doi.org/10.1016/j.heliyon.2021.e06476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7980076PMC
March 2021

Hyaluronic acid engrafted metformin loaded graphene oxide nanoparticle as CD44 targeted anti-cancer therapy for triple negative breast cancer.

Biochim Biophys Acta Gen Subj 2021 03 5;1865(3):129841. Epub 2021 Jan 5.

Centre for Research in Nanoscience and Nanotechnology, University of Calcutta, JD-2, Sector III, Salt lake, Kolkata 700098, India. Electronic address:

Background: Triple negative breast cancer (TNBC) is the most aggressive form of breast cancer with limited treatment modalities. It is associated with high propensity of cancer recurrence.

Methods: UV Spectroscopy, FTIR, DLS, Zeta potential, TEM and SEM were employed to characterize nanoparticles. MTT assay, Wound healing assay, SEM, Immunocytochemistry analysis, Western blot, RT-PCR, mammosphere formation assay were employed to study apoptosis, cell migration and stemness. Tumor regression was studied in chick embryo xenograft and BALB/c mice model.

Results: Hylaluronic acid engrafted metformin loaded graphene oxide (HA-GO-Met) nanoparticles exhibited an anti-cancer efficacy at much lower dosage as compared to metformin alone. HA-GO-Met nanoparticles induced apoptosis and inhibited cell migration of TNBC cells by targeting miR-10b/PTEN axis via NFkB-p65. Upregulation of PTEN affected pAKT(473) expression that induced apoptosis. Cell migration was inhibited by reduction of pFAK/integrinβ1 expressions. Treatment inhibited epithelial mesenchymal transition (EMT) and reduced stemness as evident from the increase in E-cadherin expression, inhibition of mammosphere formation and low expression levels of stemness markers including nanog, oct4 and sox2 as compared to control. Moreover, tumor regression was studied in chick embryo xenograft and BALB/c mice model. HA-GO-Met nanoparticle treatment reduced tumor load and nullified toxicity in peripheral organs imparted by tumor.

Conclusions: HA-GO-Met nanoparticles exhibited an enormous anti-cancer efficacy in TNBC in vitro and in vivo.

General Significance: HA-GO-Met nanoparticles induced apoptosis and attenuated cell migration in TNBC. It nullified overall toxicity imparted by tumor load. It inhibited EMT and reduced stemness and thereby addressed the issue of cancer recurrence.
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http://dx.doi.org/10.1016/j.bbagen.2020.129841DOI Listing
March 2021

Delivery of dual miRNA through CD44-targeted mesoporous silica nanoparticles for enhanced and effective triple-negative breast cancer therapy.

Biomater Sci 2020 May 22;8(10):2939-2954. Epub 2020 Apr 22.

Center for Research in Nanoscience and Nanotechnology, Technology Campus, University of Calcutta, JD-2, Sector-III, Salt Lake City, Kolkata 700106, India.

The development of new therapeutic strategies to target triple-negative breast cancer (TNBC) is in much demand to overcome the roadblocks associated with the existing treatment procedures. In this regard, therapies targeting the CD44 receptor have drawn attention for more than a decade. MicroRNAs (miRNAs) modulate post-transcriptional gene regulation and thus, the correction of specific miRNA alterations using miRNA mimics or antagomiRs is an emerging strategy to normalize the genetic regulation in the tumor microenvironment. It has been acknowledged that miR-34a is downregulated and miR-10b is upregulated in TNBC, which promotes tumorigenesis and metastatic dissemination. However, there are a few barriers related to miRNA delivery. Herein, we have introduced tailored mesoporous silica nanoparticles (MSNs) for the co-delivery of miR-34a-mimic and antisense-miR-10b. MSN was functionalized with a cationic basic side chain and then loaded with the dual combination to overexpress miR-34a and downregulate miR-10b simultaneously. Finally, the loaded MSNs were coated with an hyaluronic acid-appended PEG-PLGA polymer for specific targeting. The cellular uptake, release profile, and subsequent effect in TNBC cells were evaluated. In vitro and in vivo studies demonstrated high specificity in TNBC tumor targeting, leading to efficient tumor growth inhibition as well as the retardation of metastasis, which affirmed the clinical application potential of the system.
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http://dx.doi.org/10.1039/d0bm00015aDOI Listing
May 2020

Delivery of thymoquinone through hyaluronic acid-decorated mixed Pluronic® nanoparticles to attenuate angiogenesis and metastasis of triple-negative breast cancer.

J Control Release 2020 06 31;322:357-374. Epub 2020 Mar 31.

Center for Research in Nanoscience and Nanotechnology, University of Calcutta, Technology Campus, JD-2, Sector-III, Salt Lake, Kolkata 700106, West Bengal, India. Electronic address:

Triple-negative breast cancer (TNBC) is a highly aggressive and metastatic subtype of breast cancer showing non-responsiveness to most available therapeutic options. Therefore, smart therapeutic approaches to selectively transport and target TNBCs are required. Herein, we developed thymoquinone (TQ)-loaded, hyaluronic acid (HA)-conjugated Pluronic® P123 and F127 copolymer nanoparticles (HA-TQ-Nps) as a selective drug-carrying vehicle to deliver anticancer phytochemical TQ to TNBC cells. The mean size of nanoparticles was around 19.3 ± 3.2 nm. and they were stable at room temperature up to 4 months. HA-TQ-Nps were immensely cytotoxic towards TNBC cells but did not show the toxic effect on normal cells. Detailed investigations also demonstrated its pro-apoptotic, anti-metastatic and anti-angiogenic activity. In-depth mechanistic studies highlighted that HA-TQ-Nps retarded cell migration of TNBC cells through up-regulation of microRNA-361 which in turn down-regulated Rac1 and RhoA mediated cell migration and also perturbed the cancer cell migration under the influence of the autocrine effect of VEGF-A. Moreover, HA-TQ-Np-treatment also perturbed tumor-induced vascularization by reducing the secretion of VEGF-A. The anti-metastatic and anti-angiogenic activity of HA-TQ-Nps was found to be evident in both MDA-MB-231 xenograft chick embryos and 4T1-mammary solid tumor model in syngeneic mice. Thus, an innovative targeted nano-therapeutic approach is being established to reduce the tumor burden and inhibit metastasis and angiogenesis simultaneously for better management of TNBC.
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http://dx.doi.org/10.1016/j.jconrel.2020.03.033DOI Listing
June 2020

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

Effects of bamboo shoots (Bambusa balcooa) on thyroid hormone synthesizing regulatory elements at cellular and molecular levels in thyrocytes.

J Ethnopharmacol 2020 Mar 12;250:112463. Epub 2019 Dec 12.

Department of Human Physiology, Ramkrishna Mahavidyalaya (Govt. of Tripura), Kailashahar, Unakoti District, Tripura, 799 277, India.

Ethnopharmacological Relevance: Bamboo shoots (BS) are consumed in various forms and used largely in naturopathy for curing ailments since ancient times to present days. It is eaten in South East Asian countries in several indigenous preparations. In north east India, it is consumed predominantly and used as natural cure to treat various diseases. Although known for its beneficial effects, adverse effects including goitrogenic/antithyroidal potential are emerging.

Aim Of The Study: Endemic goiter exists in Manipur, India even after adequate iodine intake for consumption of BS. It is thus important to study the impact of this goitrogenic food on certain thyroid hormone synthesizing regulatory factors at cellular and molecular level in thyrocytes.

Materials And Methods: Phytochemical analysis of BS - Bambusa balcooa Roxb (BSBR) extract conducted. IC of the extract on thyrocytes in culture was determined. To study the antithyroid effects of this goitrogenic food, activity status of Na-K-ATPase, TPO and Deiodinase, mRNA and protein expressions of NIS, TPO and PAX8 were investigated with and without extra iodine in culture media. Simultaneously ROS generation in terms of HO and antioxidant status, NO, LPO were assayed.

Results: Activities of the studied enzymes decreased depending on dose and time with increased HO, decreased antioxidants followed by increased NO with LPO. DNA damage and LDH also increased while mRNA and protein expression of NIS, TPO and PAX8 were downregulated. Extra iodine ameliorated all such effects partially.

Conclusions: Bioactive constituents of the extract imbalances oxidative status of thyrocytes impairing action of hormone synthesizing elements at cellular and molecular level.
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http://dx.doi.org/10.1016/j.jep.2019.112463DOI Listing
March 2020

High-intensity exercise-induced oxidative stress in sedentary pre-pubertal & post-pubertal boys: A comparative study.

Indian J Med Res 2019 08;150(2):167-174

Sports & Exercise Physiology Laboratory, Department of Physiology, University of Calcutta, University Colleges of Sciences & Technology, Kolkata, India.

Background & Objectives: High-intensity exercise results in oxidative stress in adult population. Impact of pubertal attainment on high-intensity exercise-induced oxidative stress in sedentary paediatric population has not been investigated in detail. The present study was conducted to investigate the extent of high-intensity exercise-induced oxidative stress in sedentary pre- and post-pubertal boys through estimation of serum thiobarbituric acid reactive substances (TBARS), total thiol content and activities of superoxide dismutase (SOD) and catalase (CAT).

Methods: Sixty four sedentary pre-pubertal (n=32, age = 10.21±0.67 yr) and post-pubertal (n=32, age = 15.58±0.47 yr) boys performed incremental treadmill running exercise at 80 per cent of the age predicted maximum heart rate till volitional exhaustion. Blood sample (5 ml) was drawn from each individual before and after the exercise for estimation of oxidative stress markers.

Results: Pre-exercise SOD activity and total thiol level showed significant positive relationship with age and were significantly higher in post-pubertal boys. Serum TBARS level, SOD and CAT activities increased while total thiol content decreased in both the groups following exercise. Post-exercise percentage change in TBARS, SOD activity and total thiol level was significantly higher in post-pubertal boys, and these variables had significant positive relationship with age. No significant intergroup variations were noted in CAT activity before or after exercise.

Interpretation & Conclusions: Extent of post-exercise oxidative stress increased significantly with attainment of puberty. However, baseline and post-exercise antioxidation status also increased significantly as a function of age with pubertal maturation allowing the post-pubertal boys to counter relatively higher oxidative stress more efficiently than their pre-pubertal counterparts. Post-exercise upregulation in CAT activity might not be influenced by age or pubertal maturation in this age group.
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http://dx.doi.org/10.4103/ijmr.IJMR_2094_17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6829783PMC
August 2019

Arsenic-induced immunomodulatory effects disorient the survival-death interface by stabilizing the Hsp90/Beclin1 interaction.

Chemosphere 2020 Jan 22;238:124647. Epub 2019 Aug 22.

Cancer Research Laboratory, Department of Zoology, University of Calcutta, 35 Ballygunge Circular Road, Kolkata, 700 019, India. Electronic address:

Ground water arsenic contamination is a global menace. Since arsenic may affect the immune system, leading to immunesuppression, we investigated the effects of acute arsenic exposure on the thymus and spleen using Swiss albino mice, exposed to 5 ppm, 15 ppm and 300 ppm of sodium arsenite for 7 d. Effects on cytokine balance and cell survivability were subsequently analyzed. Our data showed that arsenic treatment induced debilitating alterations in the tissue architecture of thymus and spleen. A dose-dependent decrease in the ratio of CD4-CD8 T-cells was observed along with a pro-inflammatory response and redox imbalance. In addition, pioneering evidences established the ability of arsenic to induce an up regulation of Hsp90, eventually resulting in stabilization of its client protein Beclin-1, an important autophagy-initiating factor. This association initiated the autophagic process, confirmed by co-immunoprecipitation assay, acridine orange staining and Western blot, indicating the effort of cells trying to survive at lower doses. However, increased arsenic assault led to apoptotic cell death in the lymphoid organs, possibly by increased ROS generation. There are several instances of autophagy and apoptosis taking place either simultaneously or sequentially due to oxidative stress. Since arsenic is a potent environmental stress factor, exposure to arsenic led to a dose-dependent increase in both autophagy and apoptosis in the thymus and spleen, and cell death could therefore possibly be induced by autophagy. Therefore, exposure to arsenic leads to serious effects on the immune physiology in mice, which may further have dire consequences on the health of exposed animals.
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http://dx.doi.org/10.1016/j.chemosphere.2019.124647DOI Listing
January 2020

Transferrin-decorated thymoquinone-loaded PEG-PLGA nanoparticles exhibit anticarcinogenic effect in non-small cell lung carcinoma via the modulation of miR-34a and miR-16.

Biomater Sci 2019 Oct 14;7(10):4325-4344. Epub 2019 Aug 14.

Center for Research in Nanoscience and Nanotechnology, Technology Campus, University of Calcutta, JD-2, Sector III, Salt Lake City, Kolkata-700106, West Bengal, India.

Non-small cell lung carcinoma (NSCLC) is a highly lethal type of cancer with limited therapeutic avenues available to date. In the present study, we formulated PEGylated PLGA thymoquinone nanoparticles (TQ-Np) for improved TQ delivery to NSCLC cells. Transferrin (TF), a biodegradable, non-immunogenic and non-toxic protein, is well known to bind to TFR (transferrin receptor) over-expressed in non-small cell lung carcinoma A549 cells. Thus, the further decoration of the PEGylated PLGA thymoquinone nanoparticles with transferrin (TF-TQ-Np) enhanced the internalization of the nanoparticles within the A549 cells and the activity of TQ. We established TF-TQ-Np as a potent anti-tumorigenic agent through the involvement of p53 and the ROS feedback loop in regulating the microRNA (miRNA) circuitry to control apoptosis and migration of NSCLC cells. TF-TQ-Np-mediated p53 up-regulation favored the potential simultaneous activation of miR-34a and miR-16 targeting Bcl2 to induce apoptosis in the A549 cells. Additionally, TF-TQ-Np also restricted the migration through actin de-polymerization via activation of the p53/miR-34a axis. Further studies in chick CAM xenograft models confirmed the anti-cancer activity of TF-TQ-Np by controlling the p53/miR-34a/miR-16 axis. Furthermore, in vivo experiments conducted in a xenograft model in immunosuppressed Balb/c mice also proved the efficacy of the nanoparticles as an antitumor agent against NSCLC. Thus, our findings cumulatively suggest that the transferrin-adorned TQ-Np successfully coupled two distinct miRNA pathways to potentiate the apoptotic death cascade in the very lethal NSCLC cells and also restricts the migration of these cells without imparting any significant toxicity, which occurs in the widely used chemotherapeutic combinations. Thereby, our findings rekindle new hopes for the development of improved targeted therapeutic options with specified molecular objectives for combating the deadly NSCLC.
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http://dx.doi.org/10.1039/c9bm00912dDOI Listing
October 2019

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

Radiosensitizing effect of ellagic acid on growth of Hepatocellular carcinoma cells: an in vitro study.

Sci Rep 2017 10 25;7(1):14043. Epub 2017 Oct 25.

Department of Physiology, Centre for Nanoscience and Nanotechnology, University of Calcutta, 92 APC Road, Kolkata, 700 009, West Bengal, India.

Failure of treatment for cancer in clinic by radio/chemotherapy is generally attributed to tumour resistance. Therefore, it is important to develop strategies to increase the cytotoxicity of tumour cells by radiation in combination with unique tumour selective cytotoxic agents. We evaluated the potential of ellagic acid (EA) as an enhancer of oxidative stress in cancer cells. HepG2 cells were treated with EA (10 µM) for 12 h prior to exposure of single 7.5 Gy dose of irradiation. Treatment of HepG2 cells with EA and gamma radiation showed increased reactive oxygen species generation, up regulation of p53 protein expression, decreased survival markers level like p-Akt, p-NF-kB and p-STAT3 which were significantly higher after radiation treatment alone. We also found that combination treatment increased G2/M phase cell population, decreased IL-6, COX-2 and TNF-α expression and caused a loss in mitochondrial membrane potential with decreased level of angiogenesis marker MMP-9. Over expression of Bax and activation of caspase 3 indicated the apoptosis of the cells. The results provided a strong unique strategy to kill cancer cells HepG2, using less radiation dose along with effective pro-oxidant dose of EA.
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http://dx.doi.org/10.1038/s41598-017-14211-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5656621PMC
October 2017

High-Intensity Exercise Induced Oxidative Stress and Skeletal Muscle Damage in Postpubertal Boys and Girls: A Comparative Study.

J Strength Cond Res 2018 Apr;32(4):1045-1052

Sports and Exercise Physiology Laboratory, Department of Physiology, University of Calcutta, University Colleges of Science and Technology, Kolkata, India.

Pal, S, Chaki, B, Chattopadhyay, S, and Bandyopadhyay, A. High-intensity exercise induced oxidative stress and skeletal muscle damage in post-pubertal boys and girls: a comparative study. J Strength Cond Res 32(4): 1045-1052, 2018-The purpose of this study was to examine the sex variation in high-intensity exercise induced oxidative stress and muscle damage among 44 sedentary postpubertal boys and girls through estimation of postexercise release pattern of muscle damage markers like creatine kinase, lactate dehydrogenase (LDH), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and oxidative stress markers like extent of lipid peroxidation (thiobarbituric acid-reactive substances) and catalase activity. Muscle damage markers like creatine kinase, LDH, ALT, and AST were measured before, immediately after, and 24 and 48 hours after high-intensity incremental treadmill running. Oxidative stress markers like thiobarbituric acid-reactive substances and catalase activity were estimated before and immediately after the exercise. Lipid peroxidation and serum catalase activity increased significantly in both groups after exercise (p < 0.001) with postexercise values and percentage increase significantly higher in postpubertal boys as compared to girls (p < 0.001). Creatine kinase and LDH activity also increased significantly above pre-exercise level at 24 and 48 hours after exercise in both the sexes, (p < 0.001) with values significantly higher for boys than the girls (p < 0.001). Although ALT and AST increased significantly in both the groups after exercise, the pattern of postexercise release of these markers were found to be similar in both the groups. Accordingly, it has been concluded from the present investigation that high-intensity exercise induces significant oxidative stress and increases indices of skeletal muscle damage in both postpubertal girls and boys. However, postpubertal girls are relatively better protected from oxidative stress and muscle damage as compared to the boys of similar age and physical activity level. It is further evident that sex difference may not be apparent for all the biomarkers of muscle damage in this age group.
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http://dx.doi.org/10.1519/JSC.0000000000002167DOI Listing
April 2018

Activating the AKT2-nuclear factor-κB-lipocalin-2 axis elicits an inflammatory response in age-related macular degeneration.

J Pathol 2017 04 20;241(5):583-588. Epub 2017 Feb 20.

Department of Ophthalmology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.

Age-related macular degeneration (AMD) is a complex and progressive degenerative eye disease resulting in severe loss of central vision. Recent evidence indicates that immune system dysregulation could contribute to the development of AMD. We hypothesize that defective lysosome-mediated clearance causes accumulation of waste products in the retinal pigmented epithelium (RPE), activating the immune system and leading to retinal tissue injury and AMD. We have generated unique genetically engineered mice in which lysosome-mediated clearance (both by phagocytosis and autophagy) in RPE cells is compromised, causing the development of features of early AMD. Our recent data indicate a link between lipocalin-2 (LCN-2) and the inflammatory responses induced in this mouse model. We show that nuclear factor-κB (NF-κB) and STAT-1 may function as a complex in our animal model system, together controlling the upregulation of LCN-2 expression in the retina and stimulating an inflammatory response. This study revealed increased infiltration of LCN-2-positive neutrophils in the choroid and retina of early AMD patients as compared with age-matched controls. Our results demonstrate that, both in our animal model and in human AMD, the AKT2-NF-κB-LCN-2 signalling axis is involved in activating the inflammatory response, making this pathway a potential target for AMD treatment. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.4870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5357190PMC
April 2017

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

Tailored-CuO-nanowire decorated with folic acid mediated coupling of the mitochondrial-ROS generation and miR425-PTEN axis in furnishing potent anti-cancer activity in human triple negative breast carcinoma cells.

Biomaterials 2016 Jan 21;76:115-32. Epub 2015 Oct 21.

Centre for Research in Nanoscience and Nanotechnology, University of Calcutta, JD-2, Sector III, Salt Lake, Kolkata, 700098, WB, India. Electronic address:

Metal oxide nanoparticles are the forthcoming anti-tumor therapeutics and provide a versatile platform in the development of therapeutic approaches for drug-resistant cancers such as triple negative breast cancer (TNBC). Copper oxide nanoparticles have been characterized as anti-cancer agents but its toxicity has been a matter of concern. Herein, we have developed a targeted CuO Nanowire fabricated with Folic acid (CuO-Nw-FA) that enables enhanced cellular uptake in TNBC cells without imparting significant toxicity in normal cellular system. In the present study, we enumerated that CuO-Nw-FA caused mitochondrial-dependent apoptosis in MDAMB-231 cells. Furthermore, CuO-Nw-FA mediated cytosolic retardation of NF-κB favoured inactivation of miR-425 and henceforth activated PTEN to induce apoptosis in TNBC cells. Simultaneously, CuO-Nw-FA also restricted the in-vitro cell migration through the miR-425/PTEN axis via pFAK. Studies extended to ex-ovo and in-vivo mice models further validated the efficacy of CuO-Nw-FA. Additionally, the accumulations of nanoparticles in tumor as well as different organs in mice were examined by in-vivo biodistribution and ex-vivo optical imaging studies. Thus our results cumulatively propose that CuO-Nw-FA cross-talks two distinct signalling pathways to induce apoptosis and retard migration in TNBC cells and raises the possibility for the use of CuO-Nw-FA as a potent anti-tumor agent.
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http://dx.doi.org/10.1016/j.biomaterials.2015.10.044DOI Listing
January 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

Simple synthesis of biocompatible biotinylated porous hexagonal ZnO nanodisc for targeted doxorubicin delivery against breast cancer cell: In vitro and in vivo cytotoxic potential.

Colloids Surf B Biointerfaces 2015 Sep 6;133:88-98. Epub 2015 Jun 6.

Centre for Research in NanoScience and NanoTechnology, Technology Campus, University of Calcutta, JD 2, Sec III, Salt lake, Kolkata 700098, India.

Targeted drug delivery with porous materials features great promise as improved therapeutic potential for treatment of various diseases. In the present study we have attempted a microwave synthesis of porous hexagonal nanodisc of zinc oxide (PZHD) for the first time and its subsequent targeted delivery to breast cancer cells, MCF7. PZHD has been fabricated suitably with 3-aminopropyltriethoxysilane to impart additional stability and surface amines to anchor site directing ligand NHS-biotin. Biotinylated scaffold showed targeted delivery of anticancer drug doxorubicin and pH triggered release to MCF 7 cells with preferential distribution on specified domain. A detailed in vitro cytotoxicity study was associated with it to evaluate the mode of action of Dox loaded PZHD on MCF-7 cells by means of cell cycle analysis, apoptosis assays, Western blot and immuno-fluorescence image analysis. The efficacy of the Dox loaded PZHD was further validated from our in vivo tumor regression studies. Finally, the whole study has been supported by in vitro and in vivo bio-safety studies which also signified its biocompatibility with real time applications. To the best of our knowledge this is the first effort to use biotinylated PZHD for targeted delivery of doxorubicin within MCF 7 cells with a detailed study of its mechanistic application. This study might thus hold future prospects for therapeutic intervention for treatment of cancer.
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http://dx.doi.org/10.1016/j.colsurfb.2015.05.052DOI Listing
September 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

PEGylated-thymoquinone-nanoparticle mediated retardation of breast cancer cell migration by deregulation of cytoskeletal actin polymerization through miR-34a.

Biomaterials 2015 May 17;51:91-107. Epub 2015 Feb 17.

Centre for Research in Nanoscience and Nanotechnology, University of Calcutta, JD-2, Sector III, Salt Lake, Kolkata 700098, West Bengal, India. Electronic address:

Thymoquinone (TQ), a major active constituent of black seeds of Nigella sativa, has potential medical applications including spectrum of therapeutic properties against different cancers. However, little is known about their effect on breast cancer cell migration, which is the cause of over 90% of deaths worldwide. Herein, we have synthesized TQ-encapsulated nanoparticles using biodegradable, hydrophilic polymers like polyvinylpyrrolidone (PVP) and polyethyleneglycol (PEG) to overcome TQ's poor aqueous solubility, thermal and light sensitivity as well as consequently, minimal systemic bioavailability which can greatly improve the cancer treatment efficiency. Sizes of synthesized TQ-Nps were found to be below 50 nm and they were mostly spherical in shape with smooth surface texture. Estimation of the zeta potential also revealed that all the three TQ-Nps were negatively charged which also facilitated their cellular uptake. In the present investigation, we provide direct evidence that TQ-Nps showed more efficiency in killing cancer cells as well as proved to be less toxic to normal cells at a significantly lower dose than TQ. Interestingly, evaluation of the anti-migratory effect of the TQ-Nps, revealed that PEG4000-TQ-Nps showed much potent anti-migratory properties than the other types. Further studies indicated that PEG4000-TQ-Nps could significantly increase the expression of miR-34a through p53. Moreover, NPs mediated miR-34a up-regulation directly down-regulated Rac1 expression followed by actin depolymerisation thereby disrupting the actin cytoskeleton which leads to significant reduction in the lamellipodia and filopodia formation on cell surfaces thus retarding cell migration. Considering the biodegradability, non-toxicity and effectivity of PEG4000-TQ-Nps against cancer cell migration, TQ-Nps may provide new insights into specific therapeutic approach for cancer treatment.
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http://dx.doi.org/10.1016/j.biomaterials.2015.01.007DOI Listing
May 2015

Protective effect of coconut water concentrate and its active component shikimic acid against hydroperoxide mediated oxidative stress through suppression of NF-κB and activation of Nrf2 pathway.

J Ethnopharmacol 2014 Aug 14;155(1):132-46. Epub 2014 May 14.

ICMR Virus Unit, ID & BG Hospital, GB-4, First Floor, 57 Dr. Suresh C Banerjee Road, Beliaghata, Kolkata 700010, West Bengal, India.

Ethnopharmacological Relevance: Conventionally coconut water has been used as an 'excellent hydrating' drink that maintain the electrolyte balance and help in treating diverse ailments related to oxidative stress including liver function. The present study was aimed to elucidate whether and how the coconut water concentrate (CWC) and its major active phytoconstituent shikimic acid (SA) can effectively protect murine hepatocytes from the deleterious effect of hydroperoxide-mediated oxidative stress.

Materials And Methods: Bioactivity guided fractionation of CWC resulted in the isolation of a couple of known compounds. Freshly isolated murine hepatocytes were exposed to hydrogen peroxide (H2O2) (1 and 3mM) in the presence or absence of CWC (200 and 400 μg/ml) and SA (40 μM) for the determination of antioxidative, DNA protective, cellular ROS level by modern methods, including immunoblot and flowcytometry to find out the possible mechanism of action.

Results: Pre-treatment of hepatocyte with CWC and SA showed significant prevention of H2O2-induced intracellular ROS generation, nuclear DNA damage along with the formation of hepatic TBARS and cellular nitrite. Further, the H2O2 induced cell death was arrested in the presence of CWC through the inhibition of CDC42 mediated SAPK/JNK pathways and activation of other molecules of apoptotic pathways, including Bax and caspase3. Moreover, CWC and SA help in maintaining the GSH level and endogenous antioxidants like Mn-SOD, to support intracellular defense mechanisms, probably through the transcriptional activation of Nrf2; and inhibition of nuclear translocation of NF-κB.

Conclusion: CWC and its active components SA reversed the H2O2 induced oxidative damage in hepatocytes, probably through the inhibition of NF-κB, with the activation of PI3K/Akt/Nrf2 pathway and reduction of apoptosis by interfering the SAPK/JNK/Bax pathway.
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http://dx.doi.org/10.1016/j.jep.2014.04.046DOI Listing
August 2014

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

Targeting RET to induce medullary thyroid cancer cell apoptosis: an antagonistic interplay between PI3K/Akt and p38MAPK/caspase-8 pathways.

Apoptosis 2013 May;18(5):589-604

Division of Molecular Medicine, Bose Institute, P-1/12, Calcutta Improvement Trust Road, Scheme VII M, Kolkata, West Bengal, 700 054, India.

Mutations in REarranged during Transfection (RET) receptor tyrosine, followed by the oncogenic activation of RET kinase is responsible for the development of medullary thyroid carcinoma (MTC) that responds poorly to conventional chemotherapy. Targeting RET, therefore, might be useful in tailoring surveillance of MTC patients. Here we showed that theaflavins, the bioactive components of black tea, successfully induced apoptosis in human MTC cell line, TT, by inversely modulating two molecular pathways: (i) stalling PI3K/Akt/Bad pathway that resulted in mitochondrial transmembrane potential (MTP) loss, cytochrome-c release and activation of the executioner caspases-9 and -3, and (ii) upholding p38MAPK/caspase-8/caspase-3 pathway via inhibition of Ras/Raf/ERK. Over-expression of either constitutively active myristoylated-Akt-cDNA (Myr-Akt-cDNA) or dominant-negative-caspase-8-cDNA (Dn-caspase-8-cDNA) partially blocked theaflavin-induced apoptosis, while co-transfection of Myr-Akt-cDNA and Dn-caspase-8-cDNA completely eradicated the effect of theaflavins thereby negating the possibility of existence of other pathways. A search for the upstream signaling revealed that theaflavin-induced disruption of lipid raft caused interference in anchorage of RET in lipid raft that in turn stalled phosphorylation of Ras and PI3Kinase. In such anti-survival cellular micro-environment, pro-apoptotic signals were triggered to culminate into programmed death of MTC cell. These findings not only unveil a hitherto unexplained mechanism underlying theaflavin-induced MTC death, but also validate RET as a promising and potential target for MTC therapy.
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http://dx.doi.org/10.1007/s10495-013-0803-0DOI Listing
May 2013

Gain of cellular adaptation due to prolonged p53 impairment leads to functional switchover from p53 to p73 during DNA damage in acute myeloid leukemia cells.

J Biol Chem 2010 Oct 30;285(43):33104-33112. Epub 2010 Jul 30.

From the Division of Molecular Medicine, Bose Institute, P-1/12 CIT Scheme VII M, Kolkata 700 054, India. Electronic address:

Tumor suppressor p53 plays the central role in regulating apoptosis in response to genotoxic stress. From an evolutionary perspective, the activity of p53 has to be backed up by other protein(s) in case of any functional impairment of this protein, to trigger DNA damage-induced apoptosis in cancer cells. We adopted multiple experimental approaches to demonstrate that in p53-impaired cancer cells, DNA damage caused accumulation of p53 paralogue p73 via Chk-1 that strongly impacted Bax expression and p53-independent apoptosis. On the contrary, when p53 function was restored by ectopic expression, Chk-2 induced p53 accumulation that in turn overshadowed p73 activity, suggesting an antagonistic interaction between p53 family members. To understand such interaction better, p53-expressing cells were impaired differentially for p53 activity. In wild-type p53-expressing cancer cells that were silenced for p53 for several generations, p73 was activated, whereas no such trend was observed when p53 was transiently silenced. Prolonged p53 interference, even in functional p53 settings, therefore, leads to the "gain of cellular adaptation" in a way that alters the cellular microenvironment in favor of p73 activation by altering p73-regulatory proteins, e.g. Chk1 activation and dominant negative p73 down-regulation. These findings not only unveil a hitherto unexplained mechanism underlying the functional switchover from p53 to p73, but also validate p73 as a promising and potential target for cancer therapy in the absence of functional p53.
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http://dx.doi.org/10.1074/jbc.M110.122705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2963387PMC
October 2010

Curcumin reverses T cell-mediated adaptive immune dysfunctions in tumor-bearing hosts.

Cell Mol Immunol 2010 Jul 22;7(4):306-15. Epub 2010 Mar 22.

Division of Molecular Medicine, Bose Institute, Kolkata, India.

Immune dysfunction is well documented during tumor progression and likely contributes to tumor immune evasion. CD8(+) cytotoxic T lymphocytes (CTLs) are involved in antigen-specific tumor destruction and CD4(+) T cells are essential for helping this CD8(+) T cell-dependent tumor eradication. Tumors often target and inhibit T-cell function to escape from immune surveillance. This dysfunction includes loss of effector and memory T cells, bias towards type 2 cytokines and expansion of T regulatory (Treg) cells. Curcumin has previously been shown to have antitumor activity and some research has addressed the immunoprotective potential of this plant-derived polyphenol in tumor-bearing hosts. Here we examined the role of curcumin in the prevention of tumor-induced dysfunction of T cell-based immune responses. We observed severe loss of both effector and memory T-cell populations, downregulation of type 1 and upregulation of type 2 immune responses and decreased proliferation of effector T cells in the presence of tumors. Curcumin, in turn, prevented this loss of T cells, expanded central memory T cell (T(CM))/effector memory T cell (T(EM)) populations, reversed the type 2 immune bias and attenuated the tumor-induced inhibition of T-cell proliferation in tumor-bearing hosts. Further investigation revealed that tumor burden upregulated Treg cell populations and stimulated the production of the immunosuppressive cytokines transforming growth factor (TGF)-beta and IL-10 in these cells. Curcumin, however, inhibited the suppressive activity of Treg cells by downregulating the production of TGF-beta and IL-10 in these cells. More importantly, curcumin treatment enhanced the ability of effector T cells to kill cancer cells. Overall, our observations suggest that the unique properties of curcumin may be exploited for successful attenuation of tumor-induced suppression of cell-mediated immune responses.
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http://dx.doi.org/10.1038/cmi.2010.11DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4003225PMC
July 2010

Tumor-shed PGE(2) impairs IL2Rgammac-signaling to inhibit CD4 T cell survival: regulation by theaflavins.

PLoS One 2009 Oct 8;4(10):e7382. Epub 2009 Oct 8.

Division of Molecular Medicine, Bose Institute, P-1/12 CIT Scheme VIIM, Kolkata, India.

Background: Many tumors are associated with decreased cellular immunity and elevated levels of prostaglandin E2 (PGE2), a known inhibitor of CD4+ T cell activation and inducer of type-2 cytokine bias. However, the role of this immunomodulator in the survival of T helper cells remained unclear. Since CD4+ T cells play critical roles in cell-mediated immunity, detail knowledge of the effect tumor-derived PGE2 might have on CD4+ T cell survival and the underlying mechanism may, therefore, help to overcome the overall immune deviation in cancer.

Methodology/principal Findings: By culturing purified human peripheral CD4+ T cells or Jurkat cells with spent media of theaflavin- or celecoxib-pre-treated MCF-7 cells, we show that tumor-shed PGE2 severely impairs interleukin 2 receptor gammac (IL2Rgammac)-mediated survival signaling in CD4+ T cells. Indeed, tumor-shed PGE2 down-regulates IL2Rgammac expression, reduces phosphorylation as well as activation of Janus kinase 3 (Jak-3)/signal transducer and activator of transcription 5 (Stat-5) and decreases Bcl-2/Bax ratio thereby leading to activation of intrinsic apoptotic pathway. Constitutively active Stat-5A (Stat-5A1 6) over-expression efficiently elevates Bcl-2 levels in CD4+ T cells and protects them from tumor-induced death while dominant-negative Stat-5A over-expression fails to do so, indicating the importance of Stat-5A-signaling in CD4+ T cell survival. Further support towards the involvement of PGE2 comes from the results that (a) purified synthetic PGE2 induces CD4+ T cell apoptosis, and (b) when knocked out by small interfering RNA, cyclooxygenase-2 (Cox-2)-defective tumor cells fail to initiate death. Interestingly, the entire phenomena could be reverted back by theaflavins that restore cytokine-dependent IL2Rgammac/Jak-3/Stat-5A signaling in CD4+ T cells thereby protecting them from tumor-shed PGE2-induced apoptosis.

Conclusions/significance: These data strongly suggest that tumor-shed PGE2 is an important factor leading to CD4+ T cell apoptosis during cancer and raise the possibility that theaflavins may have the potential as an effective immunorestorer in cancer-bearer.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0007382PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2753647PMC
October 2009
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