Publications by authors named "Debarati Mukherjee"

42 Publications

The association of a novel digital tool for assessment of early childhood cognitive development, 'DEvelopmental assessment on an E-Platform (DEEP)', with growth in rural India: A proof of concept study.

EClinicalMedicine 2021 Jul 18;37:100964. Epub 2021 Jun 18.

Child Development Group, Sangath, Goa, India.

Background: There is an urgent need to fill the gap of scalable cognitive assessment tools for preschool children to enable identification of children at-risk of sub-optimal development and to support their timely referral into interventions. We present the associations between growth in early childhood, a well-established marker of cognitive development, and scores on a novel digital cognitive assessment tool called DEvelopmental Assessment on an E-Platform (DEEP) on a sample of 3-year old pre-schoolers from a rural region in north India.

Methods: Between February 2018 and March 2019, 1359 children from the Sustainable Programme Incorporating Nutrition and Games (SPRING) programme were followed up at 3-years age and data on DEEP, anthropometry and a clinical developmental assessment, the Bayley's Scale of Infant and Toddler Development, 3rd edition (BSID-III) was collected. DEEP data from 200 children was used to train a machine learning algorithm to predict their score on the cognitive domain of BSID-III. The DEEP score of the remaining 1159 children was then predicted using this algorithm to examine the cross-sectional and prospective association of growth with the DEEP score.

Findings: The magnitude of the concurrent positive association between height-for-age and cognitive -scores in 3-year olds was similar when cognition was measured by BSID-III (0.20 standard deviations increase for every unit change in specifically age-adjusted height (HAZ), 95% CI = 0.06-0.35) and DEEP (0.26 CI, 0.11-0.41). A similar positive prospective relationship was found between growth at 18 (0.21 CI, 0.17-0.26) and 12-months (0.18 CI, 0.13-0.23) and DEEP score measured at 3-years. Additionally, the relationship between growth and cognitive development was found to be dependant on socioeconomic status (SES).

Interpretation: In this study, we suggest the utility of DEEP, a scalable, digital cognitive assessment tool, to measure cognition in preschool children. Further validation in different and larger datasets is necessary to confirm our findings.

Funding: The SPRING Programme was funded through a Wellcome Trust programme grant and the follow-up study by the Corporate Social Responsibility initiative grant from Madura Microfinance Ltd.
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http://dx.doi.org/10.1016/j.eclinm.2021.100964DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8225699PMC
July 2021

Engineering of Interfacial Energy Bands for Synthesis of Photoluminescent 0D/2D Coupled MOF Heterostructure with Enhanced Selectivity toward the Proton-Exchange Membrane.

ACS Appl Mater Interfaces 2021 Jun 10;13(25):29619-29630. Epub 2021 Jun 10.

Department of Chemical Engineering, Indian Institute of Technology Tirupati, Tirupati 517506, India.

Engineering of the interface for tuning the structural, functional, and electronic properties of materials via the formation of heterostructure composites exhibits immense potential in the current research scenario. This study reports a novel ternary composite synthesized by decoration of zero-dimensional Pd nanoparticles (NPs) and two-dimensional (2D) graphite oxide (GO) sheets in the UiO-66 metal-organic framework (MOF). A mixed matrix membrane was fabricated by incorporating this composite in the SPEEK polymer matrix, which exhibited higher selectivity compared to commercial Nafion 117. The synthesized composite and fabricated membranes were thoroughly characterized in terms of their chemical structures, microstructural morphologies, physicochemical, thermal, photo-electrochemical, and optical properties, ion-exchange capacity, proton conductivity, and methanol permeability. As per our knowledge, this is the first study which explores the effect of noble metal NPs and carbon 2D material simultaneously on the electronic structure of the MOF, resulting in improved selectivity. The electron-accepting nature of GO and surface plasmon resonance effect of Pd alter the energy band positions and scavenge the electrons, improving the proton conduction of the composite. The introduction of oxygen vacancies in lattice leads to efficient charge separation. The formation of a Schottky junction results in the localized electric field effect due to electron density fluctuation which aids in ion transport. The current study opens up a new route to overcome the major challenge associated with direct methanol fuel cells (DMFCs), that is, high/low methanol crossover by improving the proton conduction.
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http://dx.doi.org/10.1021/acsami.1c06152DOI Listing
June 2021

Role of krüppel-like factor 8 for therapeutic drug-resistant multi-organ metastasis of breast cancer.

Am J Cancer Res 2021 15;11(5):2188-2201. Epub 2021 May 15.

Burnett School of Biomedical Sciences University of Central Florida College of Medicine 6900 Lake Nona Boulevard, Orlando, FL 32827, USA.

Metastasis and drug resistance are intertwined processes that are responsible for the vast majority of patient deaths from breast cancer. The underlying mechanisms remain incompletely understood. We previously demonstrated that KLF8 activates CXCR4 transcription in metastatic breast cancer. Here, we report a novel role of KLF8-CXCR4 signaling for converting single organ metastasis into multiple organ metastasis associated with chemotherapeutic resistance. We show that KLF8 expression in metastatic breast cancer cells can be over-induced by chemotherapeutic drugs. Analysis of data from large-cohorts of patients indicates that post-chemotherapy there is a close correlation between the aberrant high levels of KLF8 and CXCR4 and that this correlation is well associated with drug resistance, metastasis, and poor prognosis. To mimic their aberrant high levels, we overexpressed KLF8 or CXCR4 in a human breast cancer cell line known to metastasize only to the lungs after intravenous injection in nude mice. As expected, these cells become more resistant to chemotherapeutic drugs. Surprisingly, these KLF8 or CXCR4 overexpressing cells, even implanted orthotopically, metastasized extensively to multiple organs particularly the CXCL12-rich organs. Tube formation assay, Ki67 staining and Western blotting revealed that KLF8 or CXCR4 overexpression enhanced angiogenesis involving increased expression and secretion of VEGF protein. We also found that KLF8 or CXCR4 overexpression strongly enhanced formation of filopodium-like protrusions and proliferation via CXCR4 stimulation in a 3D culture model mimicking the colonization step of metastasis. Taken together, these results suggest that the chemo-induction of KLF8 upregulation be critical for drug resistance and systemic metastasis through enhanced tumor angiogenesis and colonization via CXCR4 over-activation and that KLF8-CXCR4 signaling axis may be a new therapeutic target for drug-resistant breast cancer metastasis.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8167685PMC
May 2021

Potential Anti-leishmanial Activity of a Semi-purified Fraction Isolated from the Leaves of Parthenium hysterophorus.

Acta Parasitol 2021 Jun 2. Epub 2021 Jun 2.

Cellular Immunology and Experimental Therapeutics Laboratory, Department of Zoology, West Bengal State University, Dt: 24 PGS (N), Barasat, West Bengal, 700126, India.

Purpose: In the present perspective, emergence of resistant strains of Leishmania donovani and severe side effects resulting from the use of conventional anti-leishmanial therapies present an urgent need for developing novel agents against this parasite. We have explored the effectiveness of secondary plant metabolites as alternative choices in the treatment for visceral leishmaniasis (vl).

Methods: The plant Parthenium hysterophorus L. (Asteraceae) was collected from the West Bengal State University Campus, Barasat, West Bengal, India. The leaves of this plant were extracted by different solvents, such as ethyl acetate, water, petroleum ether and hexane. Gas chromatography-mass spectrometry (GC-MS) analysis was also carried out for the identification of compounds in the hexane soluble fraction (PHFd) with substantial anti-leishmanial activities. The antipromastigote activity and cytotoxicity of this fraction were evaluated by the tetrazolium MTT assay. Other biochemical and physiological parameters were studied by microscopic observation and flow cytometric analyses.

Results: PHFd showed considerable activity against L. donovani promastigotes (IC: 20 µg/ml). The PHFd also inhibited in vitro growth of L. major LV39 promastigotes dose dependently with an IC of 40 µg/ml. The GC-MS studies of this particular fraction revealed the presence of four major compounds with different retention times (RT) of 26.08, 33.11, 36.41, and 41.20 min. In this study, we also established that PHFd could induce DNA damage and subsequent apoptosis of L. donovani promastigotes with a concomitant increase in generations of reactive oxygen species (ROS) in a time-dependent manner. This fraction was also found to be effective in nitric oxide-mediated inhibition of intracellular amastigotes (IC:12.5 µg/ml) without any noticeable cytotoxicity towards murine splenocytes in vitro.

Conclusion: This study provides the basis for additional phytochemical and pharmacological studies on the antiprotozoal applications of P. hysterophorus.
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http://dx.doi.org/10.1007/s11686-021-00416-1DOI Listing
June 2021

Targeting the Trypanothione Reductase of Tissue-Residing in Hosts' Reticuloendothelial System: A Flexible Water-Soluble Ferrocenylquinoline-Based Preclinical Drug Candidate.

J Med Chem 2020 12 9;63(24):15621-15638. Epub 2020 Dec 9.

Cellular Immunology and Experimental Therapeutics Laboratory, Department of Zoology, West Bengal State University, Barasat, North 24 Parganas, Pin-700126, West Bengal, India.

Since inception, the magic bullets developed against leishmaniasis traveled a certain path and then dropped down due to either toxicity or the emergence of resistance. The route of administration is also an important concern. We developed a series of water-soluble ferrocenylquinoline derivatives, targeting , among which CQFC1 showed the highest efficacy even in comparison to other drugs, in use or used, both in oral and intramuscular routes. It did not induce any toxicity to splenocytes and on hematopoiesis, induced protective cytokines, and did not hamper the drug-metabolizing enzymes in hosts. It acts through the reduction and the inhibition of parasites' survival enzyme trypanothione reductase of replicating amastigotes in hosts' reticuloendothelial tissues. Unlike conventional drugs, this molecule did not induce the resistance-conferring genes in laboratory-maintained resistant lines. Experimentally, this easily bioavailable preclinical drug candidate overcame all of the limitations causing the discontinuation of the other conventional antileishmanial drugs.
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http://dx.doi.org/10.1021/acs.jmedchem.0c00690DOI Listing
December 2020

Proof of Concept of a Gamified DEvelopmental Assessment on an E-Platform (DEEP) Tool to Measure Cognitive Development in Rural Indian Preschool Children.

Front Psychol 2020 10;11:1202. Epub 2020 Jun 10.

Centre for Chronic Conditions and Injuries, Public Health Foundation of India, Gurugram, India.

Over 250 million children in developing countries are at risk of not achieving their developmental potential, and unlikely to receive timely interventions because existing developmental assessments that help identify children who are faltering are prohibitive for use in low resource contexts. To bridge this "detection gap," we developed a tablet-based, gamified cognitive assessment tool named DEvelopmental assessment on an E-Platform (DEEP), which is feasible for delivery by non-specialists in rural Indian households and acceptable to all end-users. Here we provide proof-of-concept of using a supervised machine learning (ML) approach benchmarked to the Bayley's Scale of Infant and Toddler Development, 3rd Edition (BSID-III) cognitive scale, to predict a child's cognitive development using metrics derived from gameplay on DEEP. Two-hundred children aged 34-40 months recruited from rural Haryana, India were concurrently assessed using DEEP and BSID-III. Seventy percent of the sample was used for training the ML algorithms using a 10-fold cross validation approach and ensemble modeling, while 30% was assigned to the "test" dataset to evaluate the algorithm's accuracy on novel data. Of the 522 features that computationally described children's performance on DEEP, 31 features which together represented all nine games of DEEP were selected in the final model. The predicted DEEP scores were in good agreement (ICC [2,1] > 0.6) and positively correlated (Pearson's = 0.67) with BSID-cognitive scores, and model performance metrics were highly comparable between the training and test datasets. Importantly, the mean absolute prediction error was less than three points (<10% error) on a possible range of 31 points on the BSID-cognitive scale in both the training and test datasets. Leveraging the power of ML which allows iterative improvements as more diverse data become available for training, DEEP, pending further validation, holds promise to serve as an acceptable and feasible cognitive assessment tool to bridge the detection gap and support optimum child development.
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http://dx.doi.org/10.3389/fpsyg.2020.01202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7299081PMC
June 2020

Combination of and Heat-Induced Promastigotes Cures Drug-Resistant Infection: Critical Role of Interleukin-6-Producing Classical Dendritic Cells.

Infect Immun 2020 05 20;88(6). Epub 2020 May 20.

Cellular Immunology and Experimental Therapeutics Laboratory, Department of Zoology, West Bengal State University, Barasat, West Bengal, India

The major issues in available therapeutic modalities against leishmaniasis are cost, toxicity, and the emergence of drug resistance. The aim of this work was to develop a successful therapeutic adjuvant against drug-resistant infection by means of combining with heat-induced promastigotes (HIP). One-month postinfected BALB/c mice were administered subcutaneously with (10 cells) and HIP (100 μg) for 5 days. Spleens were harvested for flow cytometric and reverse transcriptase PCR analysis. The antileishmanial effect of the combination strategy was associated with induction of a disease-resolving Th1 and Th17 response with simultaneous downregulation of CD4 CD25 Foxp3 (nTreg) cells and CD4 CD25 Foxp3 (Tr1) cells in the spleen. The significant expansion of CD4 T (CD4 CD44 CD11a CD62L) cells was a further interesting outcome of this therapeutic strategy in the context of long-term protection of hosts against secondary infection. Toll-like receptor 2 (TLR2) was also found instrumental in this antiparasitic therapy. Induced interleukin-6 (IL-6) production from expanded CD11c CD8α (cDC1) and CD11c CD11b (cDC2) dendritic cells (DCs) but not from the CD11b Ly6c inflammatory monocytes (iMOs), was found critical in the protective expansion of Th17 as evidenced by an IL-6 neutralization assay. It also promoted the hematopoietic conversion toward DC progenitors (pre-DCs) from common dendritic cell progenitors (CDPs), the immediate precursors, in bone marrow. This novel combinational strategy demonstrated that expansion of Th17 by IL-6 released from CD11c classical DCs is crucial, together with the conventional Th1 response, to control drug-resistant infection.
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http://dx.doi.org/10.1128/IAI.00222-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7240079PMC
May 2020

Thermal management of photonic integrated circuits: impact of holder material and epoxies.

Appl Opt 2019 Aug;58(22):6126-6135

The thermal management of photonic integrated circuits (PICs) poses a few challenges at the packaging level. The integration of a PIC with a proper holder provides mechanical support and electrical interconnection, as well as spreading of the heat generated during PIC operation. This study proposes and evaluates the thermal behavior of silicon and diamond holders and estimates the impact of integrating them with PICs as a packaged system; to this end, the thermal profile of a PIC with distributed feedback lasers mounted on silicon or diamond holders was simulated for different power levels using ANSYS Mechanical software. The impact of the epoxy resin used to mount the PIC on the holder and the thermal crosstalk between the active components were also evaluated. Based on steady-state thermal analysis, when the PIC is assembled via wire bonding, the replacement of the silicon holder with a diamond holder brings only a marginal advantage. The choice of epoxy has a larger impact on the maximum PIC temperature and the thermal crosstalk between active components. Choosing a large-thermal-conductivity-value epoxy is thus a mandatory requirement in order to guarantee the proper thermal management of PICs and their corresponding holders.
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http://dx.doi.org/10.1364/AO.58.006126DOI Listing
August 2019

CaMKK2 in myeloid cells is a key regulator of the immune-suppressive microenvironment in breast cancer.

Nat Commun 2019 06 4;10(1):2450. Epub 2019 Jun 4.

Department of Pharmacology and Cancer Biology, Duke University School of Medicine, Durham, NC, 27710, USA.

Tumor-associated myeloid cells regulate tumor growth and metastasis, and their accumulation is a negative prognostic factor for breast cancer. Here we find calcium/calmodulin-dependent kinase kinase (CaMKK2) to be highly expressed within intratumoral myeloid cells in mouse models of breast cancer, and demonstrate that its inhibition within myeloid cells suppresses tumor growth by increasing intratumoral accumulation of effector CD8 T cells and immune-stimulatory myeloid subsets. Tumor-associated macrophages (TAMs) isolated from Camkk2 mice expressed higher levels of chemokines involved in the recruitment of effector T cells compared to WT. Similarly, in vitro generated Camkk2 macrophages recruit more T cells, and have a reduced capability to suppress T cell proliferation, compared to WT. Treatment with CaMKK2 inhibitors blocks tumor growth in a CD8 T cell-dependent manner, and facilitates a favorable reprogramming of the immune cell microenvironment. These data, credential CaMKK2 as a myeloid-selective checkpoint, the inhibition of which may have utility in the immunotherapy of breast cancer.
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http://dx.doi.org/10.1038/s41467-019-10424-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6547743PMC
June 2019

Development, feasibility and acceptability of a gamified cognitive DEvelopmental assessment on an E-Platform (DEEP) in rural Indian pre-schoolers - a pilot study.

Glob Health Action 2019 ;12(1):1548005

d Department of Global Health and Social Medicine , Harvard Medical School and the Harvard Chan School of Public Health , Boston , MA , USA.

: Assessment of cognitive development is essential to identify children with faltering developmental attainment and monitor the impact of interventions. A key barrier to achieving these goals is the lack of standardized, scalable tools to assess cognitive abilities. : This study aimed to develop a tablet-based gamified assessment of cognitive abilities of 3-year-old children which can be administered by non-specialist field workers. : Workshops among domain experts, literature search for established and gamified paradigms of cognitive assessments and rapid review of mobile games for 3-year-old children was done to conceptualize games for this study. Formative household visits (N = 20) informed the design and content of the games. A cross-sectional pilot study (N = 100) was done to assess feasibility of the tool and check if increasing levels of difficulty and the expected variability between children were evident in game metrics. In-depth interviews (N = 9) were conducted with mothers of participating children to assess its acceptability. : Six cognitive domains were identified as being integral to learning - divided attention, response inhibition, reasoning, visual form perception and integration and memory. A narrative, musical soundtrack and positive reinforcement were incorporated into the tool to enhance participant engagement. Child performance determined level timers and difficulty levels in each game. Pilot data indicate that children differ in their performance profile on the tool as measured by the number of game levels played and their accuracy and completion time indicating that it might be possible to differentiate children based on these metrics. Qualitative data suggest high levels of acceptability of the tool amongst participants. : A DEvelopmental assessment on an E-Platform (DEEP) has been created comprising distinct games woven into a narrative, which assess six cognitive domains, and shows high levels of acceptability and generates metrics which may be used for validation against gold standard cognitive assessments.
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http://dx.doi.org/10.1080/16549716.2018.1548005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6338262PMC
October 2019

Development of graphene oxide/chitosan composite membrane on ceramic support for atrazine remediation by MBR process.

Environ Sci Pollut Res Int 2018 Nov 26;25(33):33334-33352. Epub 2018 Sep 26.

Ceramic Membrane Division, CSIR-Central Glass and Ceramic Research Institute, 196, Raja S.C.Mullick Road, Jadavpur, Kolkata, 700032, India.

Graphene oxide (GO)-based composite ultrafiltration (UF) membranes were prepared on macroporous ceramic support tubes following a new way. Chitosan was used as an intermediate matrix between the substrate and GO coating. It has hydroxyl and amine groups, which enhances its film forming capacity with hydrophilic GO. This led us to use them as precursors for membrane development. Process efficiency of the prepared UF membrane was assessed in terms of the removal of toxic pesticide atrazine in side-stream membrane bioreactor (MBR) processes. Response surface methodology (RSM) was used to optimize the atrazine biodegradation efficiency. Enhanced atrazine removal of > 95% was obtained in the MBR treatment at the optimized conditions. Hermia's model equations were applied to analyze the mechanism of membrane fouling in the UF-MBR system. The influencing parameters were studied in details and pneumatic backpulsing was applied to minimize fouling in the UF-MBR system by statistical analysis. Mixed liquor suspended solids (MLSS) was found to affect both atrazine biodegradation and membrane fouling; hence, its effect was thoroughly analyzed. The developed process hence proved to be highly proficient in terms of such organic pesticides removal for long-term operations.
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http://dx.doi.org/10.1007/s11356-018-3255-9DOI Listing
November 2018

Cerium Oxide Nanoparticles Sensitize Pancreatic Cancer to Radiation Therapy through Oxidative Activation of the JNK Apoptotic Pathway.

Cancers (Basel) 2018 Sep 1;10(9). Epub 2018 Sep 1.

Burnett School of Biomedical Sciences University of Central Florida College of Medicine, Orlando, FL 32827, USA.

Side effects of radiation therapy (RT) remain the most challenging issue for pancreatic cancer treatment. Cerium oxide nanoparticles (CONPs) are currently being tested in pre-clinical trials as an adjuvant to sensitize pancreatic cancer cells to RT and protect normal tissues from the harmful side effects. CONPs were not able to significantly affect RT-induced DNA damage in cancer cells, thereby ruling out sensitization through increased mitotic catastrophe. However, activation of c-Jun terminal kinase (JNK), a key driver of RT-induced apoptosis, was significantly enhanced by co-treatment with CONPs and RT in pancreatic cancer cells in vitro and human pancreatic tumors in nude mice in vivo compared to CONPs or RT treatment alone. Further, CONP-driven increase in RT-induced JNK activity was associated with a marked increase in Caspase 3/7 activation, indicative of apoptosis. We have previously shown that CONPs increase reactive oxygen species (ROS) production in cancer cells. ROS has been shown to drive the oxidation of thioredoxin 1 (TRX1) which results in the activation of apoptosis signaling kinase 1 (ASK1). The increase in ASK1 activation following the co-treatment with CONPs followed by RT suggests that the increased JNK activation is the result of increased TRX1 oxidation. The ability of CONPs to sensitize pancreatic cancer cells to RT was mitigated when the TRX1 oxidation was prevented by mutagenesis of a cysteine residue or when the JNK activation was blocked by an inhibitor. Taken together, these data demonstrate an important mechanism for CONPs in specifically killing cancer cells and provide novel insights into the utilization of CONPs as a radiosensitizer and therapeutic agent for pancreatic cancer.
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http://dx.doi.org/10.3390/cancers10090303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6162528PMC
September 2018

Selective in vitro inhibition of Leishmania donovani by a semi-purified fraction of wild mushroom Grifola frondosa.

Exp Parasitol 2018 Sep 21;192:73-84. Epub 2018 Jul 21.

Cellular Immunology and Experimental Therapeutics Laboratory, Department of Zoology, West Bengal State University, Barasat, West Bengal, India. Electronic address:

The current study was designed to assess the anti-leishmanial effect of a semi-purified fraction of wild mushroom Grifola frondosa against Leishmania donovani, in vitro. A total of five extracts from three wild mushrooms [Grifola frondosa (family, Meripilaceae) Laetiporus sulphurous (family, Polyporaceae) and Meripilus giganteus (family, Meripilaceae) were explored for novel anti-leishmanial leads against promastigotes. The ethanol extract of G. frondosa was selected as the most efficient against L. donovani promastigotes (IC: 93.9 μg/mL). A semi-purified fraction was obtained from an active ethanol extract of G. frondosa and found to inhibit the survival of promastigotes of L. donovani (MHOM/IN/83/AG83) significantly (IC: 20.37 μg/mL) and it also had some effect against L. major LV39 (MRHO/Sv/59/P strain) and L. tropica WR683 (MHOM/SU/58/OD) strains at higher concentrations (IC: 46.08 μg/mL and 53.79 μg/mL respectively). The semi-purified fraction also interfered in lipid biosynthesis, altered parasite morphology and induced apoptosis in L. donovani promastigotes. The semi-purified fraction was also effective against intracellular amastigotes in infected macrophages and enhanced the release of nitric oxide and pro-inflammatory cytokines, in vitro. Interestingly, the 50% inhibitory concentration of the semi-purified fraction against the intracellular amastigotes (IC: 2.48 μg/mL) was much lower in comparison to promastigotes (IC: 20.37 μg/mL). The semi-purified fraction was found to inhibit the intracellular amastigotes slightly more efficiently in comparison to conventional anti-leishmanial drugs; sodium antimony gluconate, amphotericin B, miltefosine and paromomycin and noticeably non-toxic towards host splenocytes. The findings of the present study established that G. frondosa might be a natural resource for development of a new anti-leishmanial lead.
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http://dx.doi.org/10.1016/j.exppara.2018.07.006DOI Listing
September 2018

Synthesis and biological evaluation of polyhydroxylated oxindole derivatives as potential antileishmanial agent.

Bioorg Med Chem Lett 2018 04 12;28(6):1056-1062. Epub 2018 Feb 12.

Department of Chemistry, University of Calcutta, 92, A.P.C. Road, Kolkata 700 009, India. Electronic address:

The devastating appearance of numerous drug-unresponsive strains of Leishmania donovani and severe toxic side effects of conventional antileishmanial therapy necessitates the search for novel leads, to treat visceral leishmaniasis efficiently. The current study deals with the synthesis and biological evaluation of a unique C-5 functionalized oxindole based polyphenol to ascertain its activities against L. donovani infection, in vitro. The polyhydroxylated oxindole derivative (1) was generated by coupling styrene derivatives with 5-bromo bis-arylidene oxindole using Heck coupling reaction. The synthesized molecule 1 was tested for its antileishmanial activity using both promastigote and amastigote stages of L. donovani. Molecule 1 showed promising anti-promastigote and anti-amastigote activities with IC values 15 µM and 1 µM, respectively, with no cytotoxicity towards host splenocytes. The results revealed that this compound induced parasite death by promoting oxidative stress, thereby triggering apoptosis.
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http://dx.doi.org/10.1016/j.bmcl.2018.02.023DOI Listing
April 2018

Park availability and major depression in individuals with chronic conditions: Is there an association in urban India?

Health Place 2017 Sep 25;47:54-62. Epub 2017 Jul 25.

Centre for Control of Chronic Conditions, Gurgaon, India; Centre for Chronic Disease Control, Gurgaon, India; Public Health Foundation of India, Gurgaon, India; London School of Hygiene&Tropical Medicine, UK. Electronic address:

Green space exposure has been positively correlated with better mental-health indicators in several high income countries, but has not been examined in low- and middle-income countries undergoing rapid urbanization. Building on a study of mental health in adults with a pre-existing chronic condition, we examined the association between park availability and major depression among 1208 adults surveyed in Delhi, India. Major depression was measured using the Mini International Neuropsychiatric Interview. The ArcGIS platform was used to quantify park availability indexed as (i) park distance from households, (ii) area of the nearest park; and within one km buffer area around households - the (iii) number and (iv) total area of all parks. Mixed-effects logistic regression models adjusted for socio-demographic characteristics indicated that relative to residents exposed to the largest nearest park areas (tertile 3), the odds [95% confidence interval] of major depression was 3.1 [1.4-7.0] times higher among residents exposed to the smallest nearest park areas (tertile 1) and 2.1 [0.9-4.8] times higher in residents with mid-level exposure (tertile 2). There was no statistically significant association between other park variables tested and major depression. We hypothesized that physical activity in the form of walking, perceived stress levels and satisfaction with the neighborhood environment may have mediating effects on the association between nearest park area and major depression. We found no significant mediation effects for any of our hypothesized variables. In conclusion, our results provide preliminary and novel evidence from India that availability of large parks in the immediate neighborhood positively impacts mental well-being of individuals with pre-existing chronic conditions, at the opportune time when India is embarking on the development of sustainable cities that aim to promote health through smart urban design - one of the key elements of which is the inclusion of urban green spaces.
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http://dx.doi.org/10.1016/j.healthplace.2017.07.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5601029PMC
September 2017

Translating neuroscience to the front lines: point-of-care detection of neuropsychiatric disorders.

Lancet Psychiatry 2016 Oct;3(10):915-917

Centre for Chronic Conditions and Injuries, Public Health Foundation of India, Gurgaon, India; Centre for Global Mental Health, London School of Hygiene and Tropical Medicine, London, UK. Electronic address:

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http://dx.doi.org/10.1016/S2215-0366(16)30186-9DOI Listing
October 2016

Antileishmanial ferrocenylquinoline derivatives: Synthesis and biological evaluation against Leishmania donovani.

Eur J Med Chem 2016 Nov 24;124:468-479. Epub 2016 Aug 24.

Department of Chemistry, University of Calcutta, 92, A.P.C. Road, Kolkata, 700 009, India. Electronic address:

The emergence of resistance against existing antileishmanial drugs necessitates the search for new classes of antileishmanial compounds. Herein a series of structurally diverse ferrocenylquinolines have been synthesized and evaluated for in vitro antileishmanial activity against Leishmania donovani using the MTT assay. Thirteen (M2-M14) substituted ferrocenylquinoline congeners possessing triazole rings were generated by palladium mediated Suzuki-Miyaura coupling reaction of 5-iodoferrocenylquinolinetriazole and substituted arylboronic acids. All the synthesized compounds were tested for its antileishmanial activity using both promastigote and amastigote stages of L. donovani. Among them, three compounds (M4, M7 and M9) exhibited promising anti-promastigote activity, with an IC value of 28.7 μM, 22.1 μM and 28 μM, respectively, and no cytotoxicity toward host splenocytes. These three compounds are equally effective against the intracellular amastigote stage of L. donovani showing the IC values of 16 μM (M4), 8 μM (M7) and 16 μM (M9), respectively, with consistent nitric oxide generation as required for parasite clearance. From the battery of tests conducted in this study, it appears that these compounds induce parasite death by promoting cell cycle arrest and triggering apoptosis.
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http://dx.doi.org/10.1016/j.ejmech.2016.08.049DOI Listing
November 2016

ERK2 phosphorylates Krüppel-like factor 8 protein at serine 48 to maintain its stability.

Am J Cancer Res 2016 1;6(5):910-23. Epub 2016 May 1.

Burnett School of Biomedical Sciences University of Central Florida College of Medicine Orlando, Florida 32827.

Krüppel-like factor 8 (KLF8) plays important roles in cancer and is strictly regulated by various post-translational modifications such as sumoylation, acetylation, ubiquitylation and PARylation. Here we report a novel phosphorylation of KLF8 by ERK2 responsible and critical for the stability of KLF8 protein. The full-length KLF8 protein displays a doublet in SDS-PAGE gel. The upper band of the doublet, however, disappeared when the N-terminal 50 amino acids were deleted. In its full-length the upper band disappeared upon phosphatase treatment or mutation of the serine 48 (S48) to alanine whereas the lower band was lost when the S48 was mutated to aspartic acid that mimics phosphorylated S48. These results suggest that S48 phosphorylation is responsible for the motility up-shift of KLF8 protein. Pharmacological and genetic manipulations of various potential kinases identified ERK2 as the likely one that phosphorylates KLF8 at S48. Functional studies indicated that this phosphorylation is crucial for protecting KLF8 protein from degradation in the nucleus and promoting cell migration. Taken together, this study identifies a novel mechanism of phosphorylation critical for KLF8 protein stabilization and function.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4889709PMC
June 2016

Krüppel-like factor 8 activates the transcription of C-X-C cytokine receptor type 4 to promote breast cancer cell invasion, transendothelial migration and metastasis.

Oncotarget 2016 Apr;7(17):23552-68

Burnett School of Biomedical Sciences University of Central Florida College of Medicine, Orlando, FL, USA.

Krüppel-like factor 8 (KLF8) has been strongly implicated in breast cancer metastasis. However, the underlying mechanisms remain largely unknown. Here we report a novel signaling from KLF8 to C-X-C cytokine receptor type 4 (CXCR4) in breast cancer. Overexpression of KLF8 in MCF-10A cells induced CXCR4 expression at both mRNA and protein levels, as determined by quantitative real-time PCR and immunoblotting. This induction was well correlated with increased Boyden chamber migration, matrigel invasion and transendothelial migration (TEM) of the cells towards the ligand CXCL12. On the other hand, knockdown of KLF8 in MDA-MB-231 cells reduced CXCR4 expression associated with decreased cell migration, invasion and TEM towards CXCL12. Histological and database mining analyses of independent cohorts of patient tissue microarrays revealed a correlation of aberrant co-elevation of KLF8 and CXCR4 with metastatic potential. Promoter analysis indicated that KLF8 directly binds and activates the human CXCR4 gene promoter. Interestingly, a CXCR4-dependent activation of focal adhesion kinase (FAK), a known upregulator of KLF8, was highly induced by CXCL12 treatment in KLF8-overexpressing, but not KLF8 deficient cells. This activation of FAK in turn induced a further increase in KLF8 expression. Xenograft studies showed that overexpression of CXCR4, but not a dominant-negative mutant of it, in the MDA-MB-231 cells prevented the invasive growth of primary tumor and lung metastasis from inhibition by knockdown of KLF8. These results collectively suggest a critical role for a previously unidentified feed-forward signaling wheel made of KLF8, CXCR4 and FAK in promoting breast cancer metastasis and shed new light on potentially more effective anti-cancer strategies.
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http://dx.doi.org/10.18632/oncotarget.8083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5029647PMC
April 2016

Successful Therapy of Murine Visceral Leishmaniasis with Astrakurkurone, a Triterpene Isolated from the Mushroom Astraeus hygrometricus, Involves the Induction of Protective Cell-Mediated Immunity and TLR9.

Antimicrob Agents Chemother 2016 05 22;60(5):2696-708. Epub 2016 Apr 22.

Cellular Immunology and Experimental Therapeutics Laboratory, Department of Zoology, West Bengal State University, Barasat, West Bengal, India

In our previous report, we showed that astrakurkurone, a triterpene isolated from the Indian mushroom Astraeus hygrometricus (Pers.) Morgan, induced reactive oxygen species, leading to apoptosis in Leishmania donovani promastigotes, and also was effective in inhibiting intracellular amastigotes at the 50% inhibitory concentration of 2.5 μg/ml. The aim of the present study is to characterize the associated immunomodulatory potentials and cellular activation provided by astrakurkurone, leading to effective antileishmanial activity in vitro and in vivo Astrakurkurone-mediated antileishmanial activity was evaluated by real-time PCR and flow cytometry. The involvement of Toll-like receptor 9 (TLR9) was studied by in vitro assay in the presence of a TLR9 agonist and antagonist and by in silico modeling of a three-dimensional structure of the ectodomain of TLR9 and its interaction with astrakurkurone. Astrakurkurone caused a significant increase in TLR9 expression of L. donovani-infected macrophages along with the activation of proinflammatory responses. The involvement of TLR9 in astrakurkurone-mediated amastigote killing has been evidenced from the fact that a TLR9 agonist (CpG, ODN 1826) in combination with astrakurkurone enhanced the amastigote killing, while a TLR9 antagonist (bafilomycin A1) alone or in combination with astrakurkurone curbed the amastigote killing, which could be further justified by in silico evidence of docking between mouse TLR9 and astrakurkurone. Astrakurkurone was found to reduce the parasite burden in vivo by inducing protective cytokines, gamma interferon and interleukin 17. Moreover, astrakurkurone was nontoxic toward peripheral blood mononuclear cells of immunocompromised patients with visceral leishmaniasis. Astrakurkurone, a nontoxic antileishmanial, enhances the immune efficiency of host cells, leading to parasite clearance in vitro and in vivo.
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http://dx.doi.org/10.1128/AAC.01943-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4862535PMC
May 2016

Induction of apoptosis by zerumbone isolated from Zingiber zerumbet (L.) Smith in protozoan parasite Leishmania donovani due to oxidative stress.

Braz J Infect Dis 2016 Jan-Feb;20(1):48-55. Epub 2015 Nov 28.

Cellular Immunology and Experimental Therapeutics Laboratory, Department of Zoology, West Bengal State University, Barasat, West Bengal, India. Electronic address:

In the present context of emergence of resistance aligned with the conventional anti-leishmanial drugs and occasional treatment failure compelled us to continue the search for replaceable therapeutic leads against Leishmania infection. Various ginger spices of the Zingiberaceae family are widely used as spices, flavouring agents, and medicines in Southeast Asia because of their unique flavour as well as due to their medicinal properties. Zerumbone, a natural component of Zingiber zerumbet (L.) Smith, has been studied for its pharmacological potential as antiulcer, antioxidant, anticancer, and antimicrobial. In this study, we have shown that zerumbone could induce ROS mediated apoptosis in Leishmania donovani promastigotes and also found effective in reducing intracellular amastigotes in infected-macrophages. We emphasized the potential of zerumbone to be employed in the development of new therapeutic drugs against L. donovani infection and provided the basis for future research on the application of transitional medicinal plants.
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http://dx.doi.org/10.1016/j.bjid.2015.10.002DOI Listing
August 2016

Identification of epidermal growth factor receptor and its inhibitory microRNA141 as novel targets of Krüppel-like factor 8 in breast cancer.

Oncotarget 2015 Aug;6(25):21428-42

Burnett School of Biomedical Sciences, University of Central Florida College of Medicine, Orlando, FL, USA.

Krüppel-like factor 8 (KLF8) is a dual transcriptional factor critical for breast cancer progression. Epidermal growth factor receptor (EGFR) is frequently overexpressed in aggressive such as triple-negative breast cancer and associated with poor clinical outcomes. Here we report a novel KLF8-EGFR signaling axis in breast cancer. We identified a highly correlated co-overexpression between KLF8 and EGFR in invasive breast cancer cells and patient tumor samples. Overexpression of KLF8 in the non-tumorigenic MCF-10A cells induced the expression of EGFR, whereas knockdown of KLF8 from the MDA-MB-231 cells decreased it. Promoter activation and binding assays indicated that KLF8 promotes the EGFR expression by directly binding its gene promoter. We also revealed that KLF8 directly represses the promoter of miR141 and miR141 targets the 3'-untranslational region of EGFR transcript to inhibit EGFR translation. Treatment with the EGFR inhibitor AG1478 or overexpression of miR141 blocked the activity of ERK downstream of EGFR and inhibited KLF8-depndent cell invasiveness, proliferation and viability in cell culture and invasive growth and lung metastasis in nude mice. Conversely, overexpression of an inhibitory sponge of miR141 led to the opposite phenotypes. Taken together, these findings demonstrate a novel KLF8 to miR141/EGFR signaling pathway potentially crucial for breast cancer malignancy.
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http://dx.doi.org/10.18632/oncotarget.4077DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4673276PMC
August 2015

A novel triterpene from Astraeus hygrometricus induces reactive oxygen species leading to death in Leishmania donovani.

Future Microbiol 2015 ;10(5):763-89

4Department of Chemistry, Vidyasagar Evening College, Kolkata, West Bengal, India.

Aim: The effect of astrakurkurone, a novel triterpene, isolated from Indian mushroom Astraeus hygrometricus has been investigated to elucidate the mechanisms involved in selective cell death of Leishmania donovani.

Materials & Methods: The hypotheses were investigated using flow-cytometry, scanning electron microscopy and confocal microscopy.

Results: The time dependent elevation of astrakurkurone-induced reactive oxygen species (ROS) was found intimately associated with apoptosis. The involvement of ROS in promastigote death was found confirmed as NAC and GSH could decrease the ROS level and restored the mitochondrial membrane potential (ΔΨ(m)). It also inhibited the intracellular amastigotes.

Conclusion: We claim the present invention as substantial in depth evidences that mushroom derived active molecules can be exploited as target specific, comparatively nontoxic leads for antileishmanial therapy.
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http://dx.doi.org/10.2217/fmb.14.149DOI Listing
February 2016

Protective effect of Croton caudatus Geisel leaf extract against experimental visceral leishmaniasis induces proinflammatory cytokines in vitro and in vivo.

Exp Parasitol 2015 Apr-May;151-152:84-95. Epub 2015 Feb 2.

Cellular Immunology and Experimental Therapeutics Laboratory, Department of Zoology, West Bengal State University, Barasat, West Bengal, India. Electronic address:

In the present state of overwhelming emergence of drug-unresponsive phenotypes of Leishmania donovani and persistent severe toxicity in conventional anti-leishmanial therapy, in search for novel leads, the aim of this study has been fixed to identify the active extract(s) of Croton caudatus Geisel. var. tomentosus Hook effective against the parasitic protozoans in vitro and in vivo. C. caudatus Geisel. is often used by Chakma and Hmar community, the local tribes of north-east India for medicinal and veterinary purposes. Among the five semi-purified extracts tested, C. caudatus leaves, extracted in hexane and subsequently semi-purified in a column packed with silica gel (70-130 µM; mesh size 60 A°) using ethyl acetate-hexane solvent (9:1), was found to be the most effective growth inhibitor (JDHex) against the Leishmania promastigotes and amastigotes. JDHex significantly altered the biochemical parameters (protein, lipid and carbohydrates) in promastigotes followed by the morphological changes, DNA condensation and subsequent apoptosis in L. donovani. In consequent steps, it has been also proved that JDHex reduced the replication of intracellular amastigotes with concomitant release of nitric oxide and pro-inflammatory cytokines, IL-12 and TNF-α in vitro. Significantly, the 50% inhibitory concentration of JDHex was estimated much lower against the intracellular amastigotes (2.5 µg/mL) in comparison to promastigotes (10 µg/mL). JDHex was also found efficient in reducing parasite burden in spleen and liver when treated in vivo and increased the intracellular IFN-γ and decreased the IL-10 in CD4+ T cells in splenocytes of orally treated animals. The results of this study support the importance in exploration of novel anti-leishmanial leads from C. caudatus Geisel. var. tomentosus Hook. against the L. donovani (MHOM/IN/83/AG83) infection. Partial chemical characterization of JDHex revealed the presence of terpenoids. However, the further chemical investigation of JDHex is warranted.
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http://dx.doi.org/10.1016/j.exppara.2015.01.012DOI Listing
May 2015

Synthesis and biological evaluation of ferrocenylquinoline as a potential antileishmanial agent.

ChemMedChem 2015 Mar 23;10(3):546-54. Epub 2015 Jan 23.

Department of Chemistry, University of Calcutta, 92 A.P.C. Road, Kolkata 700 009 (India).

The emergence of resistance against antileishmanial drugs in current use necessitates the search for new classes of antileishmanial compounds. Herein we report the design, synthesis, and evaluation of a novel ferrocenylquinoline for activity against Leishmania donovani. 7-Chloro-N-[2-(1H-5-ferrocenyl-1,2,3-triazol-1-yl)ethyl]quinolin-4-amine (1) was generated by coupling an iron(II) ethynylferrocene species with 4-(2-ethylazido)amino-7-chloroquinoline using click chemistry. The synthesized compound 1 was tested for its antileishmanial activity using both promastigote and amastigote stages of L. donovani. Compound 1 showed promising anti-promastigote activity, with an IC50 value of 15.26 μM and no cytotoxicity toward host splenocytes. From the battery of tests conducted in this study, it appears that this compound induces parasite death by promoting oxidative stress and depolarizing the mitochondrial membrane potential, thereby triggering apoptosis. These results suggest that ferrocenylquinoline 1 is a suitable lead for the development of new antileishmanial drugs.
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http://dx.doi.org/10.1002/cmdc.201402537DOI Listing
March 2015

Indian freshwater edible snail Bellamya bengalensis lipid extract prevents T cell mediated hypersensitivity and inhibits LPS induced macrophage activation.

J Ethnopharmacol 2014 Nov 5;157:320-9. Epub 2014 Oct 5.

Department of Physiology, University of Calcutta, West Bengal, India. Electronic address:

Ethnopharmacological Relevance: Soup prepared from the foot of fresh water edible snail, Bellamya bengalensis, is traditionally consumed by the tribes of Jharkhand against rheumatism like bone and joint inflammation. As rheumatism has underlying involvement of cell mediated hypersensitivity, in vivo delayed-type hypersensitivity (DTH) model and in vitro LPS-induced macrophage signaling were studied to delineate the mechanism by which Bellamya bengalensis exerts its ethnomedicinal function. Since the whole meat is consumed, the lipid of Bellamya bengalensis (BBL) was hypothesized to be the active part.

Methods And Materials: BBL isolated from the foot part of this species, was characterized and given by gavage daily (10mg BBL/kg; 20mg BBL/kg) to mice for 3 weeks prior to initiating development of DTH. Effects of DTH induced changes in paw diameter, serum nitric oxide (NO), serum tumor necrosis factor (TNF)-α level, CINC1 level, splenic CD4(+)/CD8(+) cell ratios, and level of splenic Treg cells were then compared with values in untreated control mice. In vitro effect of BBL on LPS-stimulated macrophage, the immune cell that is active in DTH, was assessed by NF-kB p65 nuclear translocation, reactive oxygen species (ROS), TNFα, and NO production.

Results: BBL was characterized, and its supplementation in situ led to significant decrease in paw edema, tissue myeloperoxidase activity, NO level, serum TNFα level and CINC 1 level as well as decrease in splenic CD4(+)/CD8(+) ratios and increase in level of Treg cells. BBL was shown to inhibit ROS, NO, and TNFα production along with NF-kB p65 nuclear translocation in LPS stimulated macrophage.

Conclusion: Bellamya bengalensis, traditionally used against diseases with underlying etiology of cell mediated immunity as in rheumatism, which acts through inhibition of overexpressed cell mediated immunity. The factor exerting this activity probably is the oleic acid and cyclopropane fatty acid rich lipid, isolated after the ethnomedicinal clue, from the foot of this species.
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http://dx.doi.org/10.1016/j.jep.2014.09.009DOI Listing
November 2014

Bem3: Filling the GAP between cell polarity and secretion.

Commun Integr Biol 2013 Nov 9;6(6):e26702. Epub 2013 Oct 9.

Department of Biological Sciences; Purdue University; West Lafayette, IN USA.

A highly conserved member of the Rho family of small GTPases, Cdc42 functions as the "master regulator of cell polarity." It has been reported that for proper establishment and maintenance of cell polarity, Cdc42 regulates and requires vesicle trafficking. Importantly, we recently discovered that in budding yeast, vesicle trafficking also controls the localization and function of Bem3, a GTPase activating protein for Cdc42. Specifically, we observed that Bem3 partitioned between the plasma membrane and an internal membrane-bound compartment. This Bem3-containing compartment was present during extended periods of apical growth, required actin tracks for trafficking to polarized sites and functioned as a recycling station that was positioned at the junction of endocytic and secretory pathways. Strikingly, many of these features are reminiscent of the Spitzenkörper, a dynamic structure involved in polarized growth during hyphal development in several filamentous fungi. Furthermore, Bem3 was not merely a passive cargo but actively recruited the secretory Rab GTPase Sec4 to this Spitzenkörper-like compartment. Importantly, this function of Bem3 was independent of its GAP activity. Our work demonstrates the existence of a complementary regulation between Bem3, a regulator of Cdc42 signaling and Sec4, a key component of the secretory machinery.
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http://dx.doi.org/10.4161/cib.26702DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3984288PMC
November 2013

RhoGTPase-binding proteins, the exocyst complex and polarized vesicle trafficking.

Small GTPases 2014 10;5:e28453. Epub 2014 Jun 10.

Department of Biological Sciences; Purdue University; West Lafayette, IN USA.

Cell polarity, the asymmetric distribution of proteins and lipids, is essential for a variety of cellular functions. One mechanism orchestrating cell polarity is polarized vesicle trafficking; whereby cargo loaded secretory vesicles are specifically transported to predetermined areas of the cell. The evolutionarily conserved exocyst complex and its small GTPase regulators play crucial roles in spatiotemporal control of polarized vesicle trafficking. In studies on neuronal membrane remodeling and synaptic plasticity, conserved mechanisms of exocyst regulation and cargo recycling during polarized vesicle trafficking are beginning to emerge as well. Recently, our lab demonstrated that RhoGTPase-binding proteins in both yeast (Bem3) and mammals (Ocrl1) are also required for the efficient traffic of secretory vesicles to sites of polarized growth and signaling. Together with our studies, we highlight the evolutionary conservation of the basic elements essential for polarized vesicle traffic across different cellular functions and model systems. In conclusion, we emphasize that studies on RhoGTPase-binding proteins in these processes should be included in the next level of investigation, for a more complete understanding of their hitherto unknown roles in polarized membrane traffic and exocyst regulation.
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http://dx.doi.org/10.4161/sgtp.28453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4114650PMC
February 2015

Selective inhibition of Leishmania donovani by active extracts of wild mushrooms used by the tribal population of India: An in vitro exploration for new leads against parasitic protozoans.

Exp Parasitol 2014 Mar 17;138:9-17. Epub 2014 Jan 17.

Cellular Immunology and Experimental Therapeutics Laboratory, Department of Zoology, West Bengal State University, Barasat, West Bengal, India. Electronic address:

The study was intended at evaluating the anti-proliferating effect of mushrooms used in traditional folklore of Santal tribal population in India against Leishmania donovani (MHOM/IN/83/AG83). A total of eighteen extracts, three estracts from each mushroom [(80% ethanol extracted; Fa), (water-soluble polysaccharide fraction; Fb), (polyphenolic fraction; Fc)], from six wild mushrooms were obtained. These extracts were tested against the promastigotes and amastigotes for their antileishmanial capacity. Fa fractions (250 μg/mL) of Astraeus hygrometricus and Tricholoma giganteum significantly inhibited the growth of L. donovani promastigotes and interfered in lipid biosynthesis. Moreover, both fractions induced apoptosis in promastigotes. Water soluble Fb fractions of A. hygrometricus, Russula laurocerasi, Russula albonigra, Termitomyces eurhizus, Russula delica and polyphenolic Fc fraction of R. laurocerasi were found to inhibit the replication of intracellular amastigotes in macrophages dose dependently. Significantly, 50% inhibitory concentration of the active extracts against intracellular amastigotes induced release of nitric oxide and IL-12 in murine macrophages and dendritic cells assay and also found considerably non-toxic on murine splenocytes. Results of this study can be used as a basis for further phytochemical and pharmacological investigations in the effort for search of novel anti-leishmanial leads.
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http://dx.doi.org/10.1016/j.exppara.2014.01.002DOI Listing
March 2014

Prevention of arthritis markers in experimental animal and inflammation signalling in macrophage by Karanjin isolated from Pongamia pinnata seed extract.

Phytother Res 2014 Aug 7;28(8):1188-95. Epub 2014 Jan 7.

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

Karanjin, the furanoflavonoid reported to possess gastroprotective and anti-diabetic properties, was investigated against experimental arthritis and its molecular signalling in inflammation was explored in macrophages. Karanjin was isolated from hexane extract of Pongamia pinnata seeds and was evaluated on arthritis markers in adjuvant induced arthritis model (AIA) in two doses (per oral; 10 mg/kg/day and 20 mg/kg/day). Karanjin dose dependently reduced collagen and cartilage breakdown markers viz. urinary hydroxyproline and glucosamine, respectively, serum lysosomal enzymes responsible for articular cartilage damage, and major proinflammatory cytokine TNFα, secreted by macrophages involved in articular inflammation and destruction. Karanjin also prevented joint damage as evidenced from arthritis score, radiographic and histopathological analysis. To delineate the molecular target of Karanjin, in vitro study on LPS induced macrophages were performed at calibrated non toxic doses (4 µg/mL and 6 µg/mL). Karanjin reduced TNFα production and also showed potent inhibitory effect on nitric oxide and reactive oxygen species production which is generally induced by TNFα from activated macrophages. NF-κB, the key regulator of TNFα signalling during inflammation was significantly suppressed by Karanjin. Our study for the first time highlights the anti-inflammatory role of Karanjin in experimental arthritis model as well as on macrophage signalling, thereby depicting its probable mechanism of action.
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http://dx.doi.org/10.1002/ptr.5113DOI Listing
August 2014
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