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Celastrol, a pentacyclic triterpenoid found in Chinese herb Tripterygium wilfordii, is considered as one of the top-five natural medicinal compounds with high antioxidant property. However, celastrol has poor aqueous solubility and thereby low bioavailability, restricting its clinical application as drug. To overcome this problem, we nanonized celastrol by entrapping it within hydrophilic nanocarrier - calcium phosphate nanoparticle. The synthesized calcium phosphate celastrol nanoparticle (CPCN) had average size of 35 nm, spherical shape, significant stability with (-) 37 mV zeta potential, celastrol entrapment efficiency around 75 % and low celastrol release kinetics spanning over 7 days, as measured by different techniques like FESEM, AFM, DLS, and spectrophotometry. Studies on the antioxidant potency of CPCN by flow cytometry and fluorescence microscopy depicted that the toxicity developed in human neuroblastoma cells SH-SY5Y by treatment with the selective neurotoxin MPP + iodide (N-Methyl-4-phenylpyridinium iodide) got reduced by pretreatment of the cells with CPCN. Determination of cellular ROS content, depolarization level of mitochondrial membrane potential, cell cycle analysis and nuclear damage in MPP + -exposed cells demonstrated that CPCN had about 65 % more antioxidant efficacy over that of bulk celastrol. Thus, the nanonization process transformed hydrophobic celastrol into hydrophilic CPCN, having high potentiality to be developed as an effective antioxidant drug., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Prof. Tarakdas Basu has patent A PROCESS FOR SYNTHESIS OF CELASTROL-LOADED CALCIUM PHOSPHATE NANOPARTICLE AS A POTENT ANTIOXIDANT pending to UNIVERSITY OF KALYANI. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The Genus Dysoxylum (Meliaceae) consists of approximately 80 species that are abundant in structurally diverse triterpenoids. The present study focused on isolating new triterpenoids from the bark of Dysoxylum malabaricum, one of the predominant species of Dysoxylum present in India. The methanol-dichloromethane bark extract was subjected to LCMS profiling followed by silica gel column chromatography and HPLC analysis to target new compounds. Two new ring A-modified cycloartane-type triterpenoids (1 and 2) were isolated from the bark extract. Spectroscopic methods like NMR, HRESIMS data, and electronic circular dichroism calculations elucidated the structuresandabsolute configurations of the isolated compounds. These compounds were evaluated for their cytotoxic potential against breast cancer cells and displayed notable cytotoxicity. Compound 1 exhibited the highest cytotoxicity against the MDA-MB-231 cells and induced apoptotic cell death. Also, it was able to inhibit glucose uptake and increase nitric oxide production in breast cancer cells., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Bisphenol A (BPA) is a chemical partially soluble in water and exists in a solid state. Its structural similarity with estrogen makes it an endocrine-disrupting chemical. BPA can disrupt signaling pathways at very low doses and may cause organellar stress. According to in vitro and in vivo studies, BPA interacts with various cell surface receptors to cause organellar stress, producing free radicals, cellular toxicity, structural changes, DNA damage, mitochondrial dysfunction, cytoskeleton remodeling, centriole duplication, and aberrant changes in several cell signaling pathways. The current review summarizes the impact of BPA exposure on the structural and functional aspects of subcellular components of cells such as the nucleus, mitochondria, endoplasmic reticulum, lysosome, ribosome, Golgi apparatus, and microtubules and its consequent impact on human health., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Hexabromocyclododecane (HBCD) is a brominated flame retardant (BFR) labeled by the Stockholm Convention as a persistent organic pollutant (POP) and exists primarily as three stereoisomers, i.e. α-, β-, and γ. One of the major routes of human exposure to HBCD is dust found in homes, offices, and cars and dust may be the most important route of HBCD exposure in young children. A study was conducted to determine the oral bioavailability of HBCD from household dust in rats over a 21-d feeding period relative to HBCD bioavailability from a corn oil matrix. Twenty-four hours after the last exposure, rats were sacrificed, and various tissues were collected. HBCD diastereomers were detected in adipose, blood, and liver of both dose groups, suggesting HBCD is bioavailable from both oil and dust. β-HBCD concentrations were below the limit of detection in all tissues, but α-HBCD was detected in the brain of oil-dose rats and in adipose and liver of both dose groups. γ-HBCD was the dominant diastereomer in adipose, blood, and liver samples regardless of dosing matrix. Except for γ-HBCD in muscle of the oil-dosed group, muscle did not contain measurable HBCDs. Adipose tissue accumulated HBCD to a greater extent than muscle or liver, having bioaccumulation factors greater than 1., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Published by Elsevier Inc.)

Mitochondria is a unique cellular organelle involved in multiple cellular processes and is critical for maintaining cellular homeostasis. This semi-autonomous organelle contains its circular genome - mtDNA (mitochondrial DNA), that undergoes continuous cycles of replication and repair to maintain the mitochondrial genome integrity. The majority of the mitochondrial genes, including mitochondrial replisome and repair genes, are nuclear-encoded. Although the repair machinery of mitochondria is quite efficient, the mitochondrial genome is highly susceptible to oxidative damage and other types of exogenous and endogenous agent-induced DNA damage, due to the absence of protective histones and their proximity to the main ROS production sites. Mutations in replication and repair genes of mitochondria can result in mtDNA depletion and deletions subsequently leading to mitochondrial genome instability. The combined action of mutations and deletions can result in compromised mitochondrial genome maintenance and lead to various mitochondrial disorders. Here, we review the mechanism of mitochondrial DNA replication and repair process, key proteins involved, and their altered function in mitochondrial disorders. The focus of this review will be on the key genes of mitochondrial DNA replication and repair machinery and the clinical phenotypes associated with mutations in these genes., (Copyright © 2022 Elsevier B.V. All rights reserved.)

DOC2B is a ubiquitously expressed isoform of the double C-2 protein family that requires Ca 2+ for most of its physiological functions. Initial findings have indicated that DOC2B participates in exocytosis, vesicular transport, insulin secretion and regulation, glucose homeostasis, and neurotransmitter release. Aberrant expression of DOC2B has been reported in diabetes, leukemia, and cervical cancer (CC). Our earlier studies have demonstrated the inhibitory effects of DOC2B on CC cell proliferation, migration, invasion, and EMT and suggested the possible role of DOC2B in Wnt signaling inhibition. However, the association between DOC2B downregulation and Wnt/β-catenin signaling activation and the underlying molecular mechanism remain elusive. Herein, we found that DOC2B inhibited Wnt/β-catenin pathway by enhancing the expression of the components of the CTNNB1 destruction complex and by fostering proteasomal degradation of CTNNB1. The translocation of CTNNB1 to the nucleus and its interaction with TCF/LEF family transcription factors was perturbed in the presence of DOC2B in a GSK3β independent manner. Further, we have identified DKK1 as one of the upregulated genes in the presence of DOC2B. DKK1 inhibition in DOC2B expressing cells by WAY262611 reactivated Wnt/β-catenin signaling, relieved DOC2B induced senescence, and alleviated the inhibitory effects of DOC2B on the aforementioned malignant behaviors. We have provided evidence for DOC2B-DKK1-senescence-Wnt/β-catenin-EMT signaling crosstalk to have tumor growth regulatory functions in CC. Thus, targeting DOC2B-DKK1-senescence-Wnt/β-catenin-EMT signaling crosstalk via activation of DOC2B may offer a novel approach to restraint malignant behaviors in CC., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Despite tremendous advancements in oncology research and therapeutics, cancer remains a primary cause of death worldwide. One of the significant factors in this critical challenge is a precise diagnosis and limited knowledge on how the tumor microenvironment (TME) behaves to the treatment and its role in chemo-resistance. Therefore, it is critical to understand the contribution of a heterogeneous TME in cancer drug response in individual patients for effective therapy management. Micro-physiological systems along with tissue engineering have facilitated the development of more physiologically relevant platforms, known as Organ-on-Chips (OoC). OoC platforms recapitulate the critical hallmarks of the TME in vitro and subsequently abet in sensitivity and efficacy testing of anti-cancer drugs before clinical trials. The OoC platforms incorporating conventional in vitro models enable researchers to control the cellular, molecular, chemical, and biophysical parameters of the TME in precise combinations while analyzing how they contribute to tumor progression and therapy response. This review discusses the application of OoC platforms integrated with conventional 2D cell lines, 3D organoids and spheroid models, and the organotypic tissue slices, including patient-derived and xenograft tumor slice cultures in cancer treatment responses. We summarize the relevance and drawbacks of conventional in vitro models in assessing cancer treatment response, challenges and limitations associated with OoC models, and future opportunities enabled by the OoC technologies towards developing personalized cancer diagnostics and therapeutics., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: Plg-R KT , a unique transmembrane plasminogen receptor, enhances the activation of plasminogen to plasmin, and localizes the proteolytic activity of plasmin on the cell surface., Objectives: We investigated the role of Plg-R KT in adipose function, metabolic homeostasis, and obesity., Methods: We used adipose tissue (AT) sections from bariatric surgery patients and from high fat diet (HFD)-induced obese mice together with immunofluorescence and real-time polymerase chain reaction to study adipose expression of Plg-R KT . Mice genetically deficient in Plg-R KT and littermate controls fed a HFD or control low fat diet (LFD) were used to determine the role of Plg-R KT in insulin resistance, glucose tolerance, type 2 diabetes, and associated mechanisms including adipose inflammation, fibrosis, and ectopic lipid storage. The role of Plg-R KT in adipogenesis was determined using 3T3-L1 preadipocytes and primary cultures established from Plg-R KT -deficient and littermate control mice., Results: Plg-R KT was highly expressed in both human and mouse AT, and its levels dramatically increased during adipogenesis. Plg-R KT -deficient mice, when fed a HFD, gained more weight, developed more hepatic steatosis, and were more insulin resistant/glucose intolerant than HFD-fed wild-type littermates. Mechanistically, these metabolic defects were linked with increased AT inflammation, AT macrophage and T-cell accumulation, adipose and hepatic fibrosis, and decreased insulin signaling in the AT and liver. Moreover, Plg-R KT regulated the expression of PPARγ and other adipogenic molecules, suggesting a novel role for Plg-R KT in the adipogenic program., Conclusions: Plg-R KT coordinately regulates multiple aspects of adipose function that are important to maintain efficient metabolic homeostasis., (© 2021 International Society on Thrombosis and Haemostasis.)

Objective: The objective of this study was identification of the transcription factor binding sites (TFBS) in the promoter of HOX genes and elucidation of the comprehensive interaction of transcription factors (TFs)/genes with HOX., Methodology: Promoter sequences of HOXA3, HOXA5, HOXA9, HOXA10, HOXA13, HOXB5, HOXC10, HOXC12, and HOXD10 were analyzed to predict the TFBS and their targets using TRANSFAC, TRRUST, and Harmonizome. Functional analysis of the processed data sets was carried out using DAVID and GATHER gene annotation tools. A network of regulatory interactions was constructed using NetworkAnalyst and a comprehensive illustration of the TF-gene network was constructed with HOX as a central hub using the Encyclopedia of DNA Elements chromatin immunoprecipitation sequencing data. Further, the enriched network was constructed to elucidate the roles of these genes in the various pathways., Results: Binding sites for E2F1, HNF3α, SP3, and KLF6 were common to promoter regions of all of the HOX genes. The functional annotation and pathway analysis elucidated the regulatory activity of a distinct set of TF-genes in interaction with HOX. A P value ≤.05 and false discovery rate ≤0.01 were considered statistically significant., Conclusion: We have confirmed that the predicted TFBSs in the HOX gene promoters function in transcriptional regulation by modulating target gene activity. TF-gene interactions are crucial to understanding oral carcinogenesis., (Crown Copyright © 2021. Published by Elsevier Inc. All rights reserved.)

Objectives: Oxidative stress has been hypothesized as a central component of both placental and endothelial dysfunction, leading to PE. This oxidative stress leading to mitochondrial dysfunction may be due to variations in mtDNA copy numbers as an adaptive response. In the present study we aimed to analyse mtDNA copy numbers in the placenta obtained after delivery from the women with PE as compared to the controls., Study Design: It was a prospective case control study. A total of 32 placental samples were analyzed (Cases: 17; Controls: 15). Samples were collected ex vivo, after childbirth. MtDNA content was determined useing real-time quantitative PCR qRT-PCR) using TaqMan probes designed for two genes: MT-ND1 and a mitochondrial gene encoding for the NADH dehydrogenase 1 protein., Results: We found that the median (IQR) mtDNA copy number was higher in PE cases 24.32 (9.260-33.51) as compared with controls 20.32 (13.33-26.22). On subgroup analysis, the median (IQR) mtDNA copy number was higher in early onset PE 28.06 (20.80-36.87) as compared to late onset PE 9.215 (4.150-56.45) as well as the controls 20.32 (13.33-26.22)., Conclusion: Our findings support a higher mtDNA copy number in early onset PE as compared to late onset PE and control population. Although, mtDNA may only be increased in very severe cases of early onset preeclampsia. Future research may be directed to ascertain if mtDNA copy numbers can be a novel biomarker to predict or prognosticate early onset preeclampsia., (Copyright © 2020 International Society for the Study of Hypertension in Pregnancy. Published by Elsevier B.V. All rights reserved.)

Micro RNAs (miRNAs) are small non-coding RNAs that are essential for regulation of gene expression of the target genes. Large number of miRNAs are organized into defined units known as miRNA clusters (MCs). The MCs consist of two or more than two miRNA encoding genes driven by a single promoter, transcribed together in the same orientation, that are not separated from each other by a transcription unit. Aberrant miRNA clusters expression is reported in breast cancer (BC), exhibiting both pro-tumorogenic and anti-tumorigenic role. Altered MCs expression facilitates to breast carcinogenesis by promoting the breast cells to acquire the various hallmarks of the cancer. Since miRNA clusters contain multiple miRNA encoding genes, targeting cluster may be more attractive than targeting individual miRNAs. Besides targeting dysregulated miRNA clusters in BC, studies have focused on the mechanism of action, and its contribution to the progression of the BC. The present review provides a comprehensive overview of dysregulated miRNA clusters and its role in the acquisition of cancer hallmarks in BC. More specifically, we have presented the regulation, differential expression, classification, targets, mechanism of action, and signaling pathways of miRNA clusters in BC. Additionally, we have also discussed the potential utility of the miRNA cluster as a diagnostic and prognostic indicator in BC., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Background: Neurodegenerative disorders such as hereditary ataxia often manifest overlapping symptoms and are likely to be misdiagnosed based on clinical phenotypes. To identify the genes associated with such disorders for diagnostic purposes, geneticists often use high throughput technologies which generate an enormous amount of data on variants whose relevance can be unclear. Besides, analysis and interpretation of high throughput data require gleaning of several web-based resources which can be laborious and time-consuming. To overcome these, we have created a Database for Inherited Ataxia (DINAX), a repository of gene variants from publicly available information., Methods: DINAX is implemented as a MySQL relational database using the PHP scripting language. Web interfaces were developed using HTML, CSS, and JavaScript. Variant and phenotype information was collected and manually curated from published literature and primary databases such as OMIM and ClinVar. These were further analyzed to decipher expression and pathway analysis., Results: DINAX is an inventory of 7166 genomic variants (single nucleotide polymorphisms, deletions, insertions, and translocations) reported till date among the 185 genes associated with different subtypes of inherited ataxia. DINAX implements a dual search methodology for genes and phenotypes linking to ataxia associated genes, variants, and their source. Pathway analysis confirmed their association with ataxia., Conclusion: The database is created to provide a single web source for obtaining information about ataxia related genes. Besides, the database facilitates easy identification of known and reported variants as well as the novel or unreported variants. DINAX is freely available at http://slsdb.manipal.edu/dinax., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Cu-Ag-ZnO nanocomposite (NC) has been successfully synthesized by mechanical alloying the Cu, Zn and Ag powder mixture under Ar atmosphere within 4 h of milling. The nanocomposite is then conjugated with the antifungal drug fluconazole by adding 5 wt% powdered drug to the NC and mechanical alloying the total powder mixture for one more hour. The Rietveld refinement of XRD data and FTIR spectrum analyses reveal the detailed structural and microstructural characterizations of the nanocomposite-drug conjugate (NC-DC). Presence of Cu, Ag, ZnO and drug in the 5 h milled powder are confirmed by analyzing TEM images and FESEM-EDS spectrum. Results obtained from FESEM and TEM images reveal the measure of particle size of the nanocomposite-drug conjugate and it agrees well with the crystallite size obtained from the Rietveld refinement. A significant antifungal activity of NC-DC against Candida sp. fungi has been revealed using disk agar diffusion method. Minimum inhibitory concentration (MIC) test confirms that NC-DC with only 5 wt% fluconazole produces similar antifungal activity of the pure (100 wt%) and conventional fluconazole. Thus, the conjugation of conventional drug to a nanocomposite results in enhancement of drug efficiency by a factor 20 folds. This is very important, particularly, for those antibiotics which are very effective in controlling several epidemic diseases but show intense side effects when used at higher dose and/or for a longer duration., (Copyright © 2019 Elsevier B.V. All rights reserved.)

The tissue factor (TF) pathway serves both hemostasis and cell signaling, but how cells control these divergent functions of TF remains incompletely understood. TF is the receptor and scaffold of coagulation proteases cleaving protease-activated receptor 2 (PAR2) that plays pivotal roles in angiogenesis and tumor development. Here we demonstrate that coagulation factor VIIa (FVIIa) elicits TF cytoplasmic domain-dependent proangiogenic cell signaling independent of the alternative PAR2 activator matriptase. We identify a Lys-Gly-Glu (KGE) integrin-binding motif in the FVIIa protease domain that is required for association of the TF-FVIIa complex with the active conformer of integrin β1. A point mutation in this motif markedly reduces TF-FVIIa association with integrins, attenuates integrin translocation into early endosomes, and reduces delayed mitogen-activated protein kinase phosphorylation required for the induction of proangiogenic cytokines. Pharmacologic or genetic blockade of the small GTPase ADP-ribosylation factor 6 (arf6) that regulates integrin trafficking increases availability of TF-FVIIa with procoagulant activity on the cell surface, while inhibiting TF-FVIIa signaling that leads to proangiogenic cytokine expression and tumor cell migration. These experiments delineate the structural basis for the crosstalk of the TF-FVIIa complex with integrin trafficking and suggest a crucial role for endosomal PAR2 signaling in pathways of tissue repair and tumor biology., (© 2018 by The American Society of Hematology.)

A new charge detection mass spectrometer that combines array detection and electrostatic ion trapping to repeatedly measure the masses of single ions is described. This instrument has four detector tubes inside an electrostatic ion trap with conical electrodes (cone trap) to provide multiple measurements of an ion on each pass through the trap resulting in a signal gain over a conventional trap with a single detection tube. Simulations of a cone trap and a dual ion mirror trap design indicate that more passes through the trap per unit time are possible with the latter. However, the cone trap has the advantages that ions entering up to 2 mm off the central axis of the trap are still trapped, the trapping time is less sensitive to the background pressure, and only a narrow range of energies are trapped so it can be used for energy selection. The capability of this instrument to obtain information about the molecular weight distributions of heterogeneous high molecular weight samples is demonstrated with 8 MDa polyethylene glycol (PEG) and 50 and 100 nm amine modified polystyrene nanoparticle samples. The measured mass distribution of the PEG sample is centered at 8 MDa. The size distribution obtained from mass measurements of the 100 nm nanoparticle sample is similar to the size distribution obtained from transmission electron microscopy (TEM) images, but most of the smaller nanoparticles observed in TEM images of the 50 nm nanoparticles do not reach a sufficiently high charge to trigger the trap on a single pass and be detected by the mass spectrometer. With the maximum trapping time set to 100 ms, the charge uncertainty is as low as ±2 charges and the mass uncertainty is approximately 2% for PEG and polystyrene ions.

This paper presents a theoretical analysis along with simulations to show that increased robustness can be achieved for discrete time sliding mode control systems by choosing the sliding variable, or the output, to be of relative degree two instead of relative degree one. In other words it successfully reduces the ultimate bound of the sliding variable compared to the ultimate bound for standard discrete time sliding mode control systems. It is also found out that for such a selection of relative degree two output of the discrete time system, the reduced order system during sliding becomes finite time stable in absence of disturbance. With disturbance, it becomes finite time ultimately bounded., (Copyright © 2016 ISA. Published by Elsevier Ltd. All rights reserved.)

In this study our main objective was to find out a novel target of the major bioactive green tea polyphenol, Epigallocatechin-3-gallate (EGCG), in cervical carcinoma HeLa cells. We found that EGCG showed antiproliferative activity against HeLa cells through depolymerization of cellular microtubule. EGCG also prevented the reformation of the cellular microtubule network distorted by cold treatment and inhibited polymerization of tubulin in cell-free system with IC50 of 39.6 ± 0.63 μM. Fluorescence spectroscopic analysis showed that EGCG prevented colchicine binding to tubulin and in silico study revealed that EGCG bound to the α-subunit of tubulin at the interphase of the α-and β-heterodimers and very close to colchicine binding site. The binding is entropy driven (ΔS(0) was 18.75 ± 1.48 cal K(-1) mol(-1)) with Kd value of 3.50 ± 0.40 μM. This is a novel mechanism of antipriliferative activity of EGCG., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Failure to inhibit hepatic gluconeogenesis is a major mechanism contributing to fasting hyperglycemia in type 2 diabetes and, along with steatosis, is the hallmark of hepatic insulin resistance. Obesity is associated with chronic inflammation in multiple tissues, and hepatic inflammation is mechanistically linked to both steatosis and hepatic insulin resistance. Here, we delineate a role for coagulation signaling via tissue factor (TF) and proteinase-activated receptor 2 (PAR2) in obesity-mediated hepatic inflammation, steatosis, and gluconeogenesis. In diet-induced obese mice, TF tail signaling independent of PAR2 drives CD11b(+)CD11c(+) hepatic macrophage recruitment, and TF-PAR2 signaling contributes to the accumulation of hepatic CD8(+) T cells. Transcripts of key pathways of gluconeogenesis, lipogenesis, and inflammatory cytokines were reduced in high-fat diet-fed mice that lack the cytoplasmic domain of TF (F3) (TF(ΔCT)) or that are deficient in PAR2 (F2rl1), as well as by pharmacological inhibition of TF-PAR2 signaling in diet-induced obese mice. These gluconeogenic, lipogenic, and inflammatory pathway transcripts were similarly reduced in response to genetic ablation or pharmacological inhibition of TF-PAR2 signaling in hematopoietic cells and were mechanistically associated with activation of AMP-activated protein kinase (AMPK). These findings indicate that hematopoietic TF-PAR2 signaling plays a pivotal role in the hepatic inflammatory responses, steatosis, and hepatic insulin resistance that lead to systemic insulin resistance and type 2 diabetes in obesity., (Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

In our continued quest for identifying novel molecules from ethnomedicinal source we have isolated an alkaloid 7-methoxy-1-methyl-4,9-dihydro-3H-pyrido[3,4-b]indole, also known as Harmaline (HM), from an ethnomedicinal herb Ophiorrhiza nicobarica. The compound exhibited a potent anti-HSV-1 activity against both wild type and clinical isolates of HSV-1. Further we demonstrated that HM did not interfere in viral entry but the recruitment of lysine-specific demethylase-1 (LSD1) and the binding of immediate-early (IE) complex on ICP0 promoter. This leads to the suppression of viral IE gene synthesis and thereby the reduced expression of ICP4 and ICP27. Moreover, HM at its virucidal concentration is nontoxic and reduced virus yields in cutaneously infected Balb/C mice. Thus, the interference in the binding of IE complex, a decisive factor for HSV lytic cycle or latency by HM reveals an interesting target for developing non-nucleotide antiherpetic agent with different mode of action than Acyclovir., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The objective of this cross-sectional study was to assess growth and nutritional status of Car Nicobarese children and compare it with Moplah children, who live in a similar environment. A total of 436 Car Nicobarese children and 438 Moplah children, aged 6-10 years, were selected for the study. The anthropometric measurements included stature, body weight, sitting height, bi-acromial breadth, bi-iliac breadth, mid-upper arm circumference, skinfold thickness of biceps, triceps and subscapular region. 50th percentile (median) growth curves were calculated among the studied children and compared with Centers for Disease Control and Prevention (CDC) 2000 reference. Z scores of weight for age (WAZ), height for age (HAZ) and BMI for age (BMIZ) were computed using growth references of the CDC 2000. It was observed that the Car Nicobarese children were shorter but heavier than Moplah children of both sexes all through the age range, which was also reflected in median value of anthropometric variables. Car Nicobarese children were nutritionally better compared to Moplah children based on the nutritional indices. The major differences between Car Nicobarese and Moplah children were found in their arm muscularity rather than arm adiposity. Overall, Car Nicobarese children were nutritionally in normal and better condition than Moplah children. However, present dietary change (intake of high calories and fat diet) of Car Nicobarese population may be reflected in the form of childhood obesity in the recent future, which has already been observed in their adult population., (Copyright © 2014 Elsevier GmbH. All rights reserved.)

Background: Tumor cell tissue factor (TF)-initiated coagulation supports hematogenous metastasis by fibrin formation, platelet activation and monocyte/macrophage recruitment. Recent studies identified host anticoagulant mechanisms as a major impediment to successful hematogenous tumor cell metastasis., Objective: Here we address mechanisms that contribute to enhanced metastasis in hyperthrombotic mice with functional thrombomodulin deficiency (TM(Pro) mice)., Methods: Pharmacological and genetic approaches were combined to characterize relevant thrombin targets in a mouse model of experimental hematogenous metastasis., Results: TF-dependent, but contact pathway-independent, syngeneic breast cancer metastasis was associated with marked platelet hyperreactivity and formation of leukocyte-platelet aggregates in immune-competent TM(Pro) mice. Blockade of CD11b or genetic deletion of platelet glycoprotein Ibα excluded contributions of these receptors to enhanced platelet-dependent metastasis in hyperthrombotic mice. Mice with very low levels of the endothelial protein C receptor (EPCR) did not phenocopy the enhanced metastasis seen in TM(Pro) mice. Genetic deletion of the thrombin receptor PAR1 or endothelial thrombin signaling targets alone did not diminish enhanced metastasis in TM(Pro) mice. Combined deficiency of PAR1 on tumor cells and the host reduced metastasis in TM(Pro) mice., Conclusions: Metastasis in the hyperthrombotic TM(Pro) mouse model is mediated by platelet hyperreactivity and contributions of PAR1 signaling on tumor and host cells., (© 2013 International Society on Thrombosis and Haemostasis.)

The extracellular Ca(2+)-sensing receptor (CaSR) is a robust promoter of differentiation in colonic epithelial cells and functions as a tumor suppressor in colon cancer. CaSR mediates its biologic effects through diverse mechanisms. Loss of CaSR expression activates a myriad of stem cell-like molecular features that drive and sustain the malignant and drug-resistant phenotypes of colon cancer. This CaSR-null phenotype, however, is not irreversible and induction of CaSR expression in CaSR-null cells promotes cell death mechanisms and restores drug sensitivity. The CaSR also functions as a tumor suppressor in breast cancer and promotes cellular sensitivity to cytotoxic drugs. BRCA1 and CaSR functions intersect in breast cancer cells, and CaSR activation can rescue breast cancer cells from the deleterious effect of BRCA1 mutations., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

CaSR and TGFβ are robust promoters of differentiation in the colonic epithelium. Loss of cellular responses to TGFβ or loss of CaSR expression is tightly linked to malignant progression. Human colonic epithelial CBS cells, originally developed from a differentiated human colon tumor, retain CaSR expression and function, TGFβ responsiveness and TGFβ receptor expression. Thus, these cells offer a unique opportunity in determining the functional linkage (if any) between CaSR and TGFβ. Knocking down CaSR expression abrogated TGFβ-mediated cellular responses and attenuated the expression of TGFβ receptors. Ca²⁺ or vitamin D treatment induced CaSR expression with a concurrent up-regulation of TGFβ receptor expression. Ca²⁺ or vitamin D, however, did not induce CaSR in CaSR knocked down cells and without CaSR; there was no up-regulation of TGFβ receptor. It is concluded that TGFβ receptor expression and TGFβ mediated responses requires CaSR expression and function., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Clinically, retroperitoneal abscesses present insidiously and the diagnosis may be delayed. This, with inadequate drainage, may result in increased morbidity and mortality. Most cases result from a renal or gastrointestinal process, but in a small number of patients there is no identifiable source and the abscess is designated as "primary." Most retroperitoneal abscesses are polymicrobial, and cultures often reveal organisms such as Proteus mirabilis, Staphylococcus species, Peptostreptococcus, Enterococcus, Enterobacter, Escherichia coli and Bacteroides species. Fungal causes appear to be very rare, and in this study, a case of a patient with primary Candida glabrata retroperitoneal abscess is reported.

CD40L on CD4(+) T cells plays a vital role in the activation of antigen-presenting cells, thus catalyzing a positive feedback loop for T-cell activation. Despite the pivotal juxtaposition of CD40L between antigen-presenting cells and T-cell activation, only a T-cell receptor stimulus is thought to be required for early CD40L surface expression. We show, for the first time, that CD40L expression on peripheral blood CD4(+) T cells is highly dependent on a cell-cell interaction with CD14(hi)CD16(-) monocytes. Interactions with ICAM-1, LFA-3, and to a lesser extent CD80/CD86 contribute to this enhancement of CD40L expression but are not themselves sufficient. The contact-mediated increase in CD40L expression is dependent on new mRNA and protein synthesis. Circulating myeloid dendritic cells also possess this costimulatory activity. By contrast, CD14(lo)CD16(+) monocytes, plasmacytoid dendritic cells, B-cell lymphoma lines, and resting, activated, and Epstein-Barr virus-immortalized primary B cells all lack the capacity to up-regulate early CD40L. The latter indicates that a human B cell cannot activate its cognate T cell to deliver CD40L-mediated help. This finding has functional implications for the role of biphasic CD40L expression, suggesting that the early phase is associated with antigen-presenting cell activation, whereas the late phase is related to B-cell activation.

Both BRCA1 and CaSR have been shown to suppress the expression of survivin and promote sensitivity to paclitaxel in human breast cancer cells. In this study we determined the functional linkage, if any, between BRCA1 and CaSR. We found that mutant cells (harboring mutant BRCA1 with loss of BRCA1 expression) had a significant reduction in the expression of CaSR with a concurrent up-regulated expression of survivin and were resistant to paclitaxel by comparison to wild type cells (harboring wild type BRCA1 and expressing BRCA1). Knocking down the expression of BRCA1 in wild type cells resulted in a reduction in CaSR expression with a concurrent up-regulated expression of survivin and reduction in sensitivity to paclitaxel. Re-expression of BRCA1 in BRCA1 knocked-down wild type cells restored CaSR expression with a concurrent down-regulated expression of survivin and restoration of sensitivity to paclitaxel. Corollary, ectopic expression of BRCA1 in mutant cells induced CaSR expression, suppressed the expression of survivin and restored sensitivity to paclitaxel. These results suggest that BRCA1 action is linked to that of CaSR. In a final series of experiments, we show that ectopic expression of CaSR in either the BRCA1 knocked-down wild type or mutant cells suppressed the expression of survivin and promoted sensitivity to paclitaxel. Thus, CaSR can rescue BRCA1 defective cells from the deleterious effects of loss of BRCA1 function. CaSR expression, however, had no effect on the expression of BRCA1. BRCA1 could stimulate the transcriptional activities of the CaSR gene and shRNA targeting CaSR circumvented the action of BRCA1. We conclude, and report for the first time, that BRCA1 regulates the expression of CaSR and that it functions through CaSR in suppressing the expression of survivin and promoting sensitivity to paclitaxel., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Objective: The aim of the present study is to assess the change in the prevalence of overweight and obesity among Nicobarese adults from 1960s to 1999 using WHO recommendations for the classification of overweight and obesity., Methods: The sample includes 774 individuals (424 men and 350 women) during 1960s and 484 individuals (259 men and 225 women) during 1999, aged 20-64 years from Nicobar Islands, India. Height (cm), weight (kg) and sitting height (cm) were measured and BMI (kg/m(2)) was calculated. Overweight and obesity were defined as BMI ≥ 25 kg/m(2) and BMI ≥ 30 kg/m(2), respectively., Results: There was significant increase of height, weight and BMI among both the men and women of 20-39, and 40 and above years age groups. However, the higher magnitude of increment was observed in 20-39 years. The prevalence of overweight increased from 5.42% to 22.01% among men and from 4% to 21.78% among women, while obese individual was absent during 1960s and the prevalence of obesity increased to 2.70% in men and 8.89% in women. The magnitude of increment was higher among women compared to men., Conclusion: The results indicate remarkable increase in the prevalence of both overweight and obesity among Nicobarese adult in Nicobar Islands., (© 2010 Asian Oceanian Association for the Study of Obesity . Published by Elsevier Ltd. All rights reserved.)

The function of Ca(2+) and the calcium sensing receptor (CaSR) in breast epithelium and its relationship to mammary carcinogenesis is poorly understood. In this study, we determined the function of this ligand receptor system in regulating the biologic properties of the estrogen receptor-positive MCF-7 and the estrogen receptor-negative MDA-MB-435 human breast cancer cells. Physiologic concentration of extracellular Ca(2+) (by comparison to cells cultured in control low Ca(2+) medium) down-modulated cellular proliferation, cellular invasion and growth in soft agarose in both of these cell lines. Physiologic concentration of extracellular Ca(2+) also down-modulated the expression of the anti-apoptotic protein survivin, survivin gene transcriptional activity, survivin mRNA expression and promoted a cytotoxic response to paclitaxel. These responses to extracellular Ca(2+) were found to require CaSR expression because knocking down CaSR expression in these cells abrogated the cellular responses to extracellular Ca(2+). Each cell line was found to contain small subpopulations that did not express CaSR but expressed a higher level of survivin. These subpopulations were relatively resistant to paclitaxel by comparison to cells that expressed CaSR with a lower level of survivin expression. It is concluded that extracellular Ca(2+) and CaSR may constitute a robust ligand-receptor system in regulating the biologic phenotype of breast epithelial cells and loss of CaSR expression may promote malignancy and resistance to cytotoxic drugs.

This paper aims to carry out a biological investigation of the body form and nutritional status of the major social groups of Orissa and Bihar States in India. For this, Cormic Index (CI) and Body Mass Index (BMI) have been computed using data on height, sitting height and weight, taken from adult males of age 18-62 years of various ethnic groups in these two states. The subjects have been classified on the basis of chronic energy deficiency (CED). It is found that a substantial proportion of the people with CED are in the grade II and grade III categories. ANOVA, t-tests, correlation and regression were carried out separately. The results reveal that in Orissa, Scheduled Tribes are shorter, lighter and have lowest mean values of BMI and Cormic Index compared to other groups, but in Bihar, though the Scheduled Tribes are shorter, Scheduled Castes are lower in weight and have the lowest mean values of BMI. There are significant differences in BMI as well as in CI between Scheduled Tribes of Orissa and Bihar. Scheduled Castes and Tribes of Bihar have the highest percentage of CED with 64.71% and 57.45%, respectively. Muslims of Bihar are also affected (52.95%), but overall prevalence of CED is lower in Orissa (49.11%) than in Bihar (54.62%). BMI and CI are highly correlated for each of the social groups in Bihar and Orissa.

Objective: Increasing evidence suggests that hyperinsulinemia plays an important role in the pathogenesis of polycystic ovary syndrome (PCOS). However, the timing for the onset of hyperinsulinemia is not clear. The objective of this study was to examine the effect of peripubertal hyperinsulinemia on the maturing female reproductive axis., Methods: Hyperinsulinemia was induced in 28-day-old peripubertal female rats by infusing insulin (0.04 IU/d) via subcutaneously implanted Alzet minipumps (Model #2004; Durect Corp, Cupertino, CA; constant flow rate 0.25 muL/h) for 4 weeks. Control animals were administered normal saline. Estrus cyclicity was monitored regularly. Upon termination of the experimental period, the animals were killed, trunk blood and pituitaries were collected for hormone assays, and ovaries were collected for histological and immunocytochemical studies., Results: In contrast to the control animals, hyperinsulinemic animals had (1) erratic estrus cycles, with prolonged (2 to 3 days) metestrus-diestrus or diestrus-proestrus stages; (2) significantly (P <.05) decreased levels of serum progesterone, and significantly (P <.05) increased levels of serum testosterone and dehydroepiandrostene sulfate; (3) prematurely luteinized ovarian follicles with prominent thecal and interfollicular stromal proliferation; and (4) markedly reduced expression of growth differentiation factor-9 (GDF-9) and activin receptors (ActR) I and IB in the ovaries., Conclusion: Peripubertal hyperinsulinemia in rats causes hormonal and ovarian changes similar to those in women with PCOS. Based on these novel findings, we speculate that peripubertal hyperinsulinemia may be a risk factor for the development of PCOS later in life.

Modulation of events characteristic of carcinogenesis or of cancer cells is being emphasized as a rational strategy to control cancer. Green tea polyphenol epigallocatechin gallate (EGCG) has been shown to be highly active as a cancer chemopreventive agent. Certain cellular and molecular events relevant to carcinogenesis are also modified by EGCG. The present investigation was carried out to examine the effects of EGCG on the cytogenetic change and DNA damage induced by toxicant H(2)O(2) and carcinogen N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) in Chinese hamster V-79 cells in culture. Cytogenetic change as evident by the formation of micronuclei and DNA damage in the form of comet tail length during single cell gel electrophoresis was found to be significantly suppressed by EGCG in a dose dependent manner. Cells preincubated with EGCG were protected from subsequent damage by the genotoxic agents. Apoptosis, a highly organized physiological mechanism to eliminate injured or abnormal cells, is also implicated in multistage carcinogenesis. Initiated cells, cells at promotional stage or fully transformed cells can be eliminated through apoptosis. It was observed that EGCG suppressed growth and proliferation of K-562 cells derived from human chronic myelogenic leukemia. Morphological features of treated cells and characteristic DNA fragmentation revealed that the cytotoxicity was due to induction of apoptosis. This was mediated by activation of caspase 3 and caspase 8. Results show that EGCG not only protects normal cells against genotoxic hazard but also eliminate cancer cells through induction of apoptosis., (Copyright 2002 Elsevier Science B.V.)

We investigated the incidence of ventricular arrhythmias, extent of myocardial infarction and alteration in haemodynamic parameters during 30 minutes of coronary arterial occlusion in rabbits anaesthetized with halothane, alpha chloralose and pentobarbitone. Ventricular tachycardia and fibrillation occurred in 10 of 15 given halothane and in 11 of 15 animals given alpha chloralose while of 15 animals given pentobarbitone, 5 developed tachycardia and 8 had fibrillation. Following ligation, blood pressure promptly fell in each group to 71-76% of control values at 1 minute and remained low throughout the occlusion period. This was most marked in the group receiving halothane which had significantly lower pressures at 30 minutes than those anaesthetized with alpha chloralose or pentobarbitone (P less than 0.01 in each case). Those receiving halothane also recovered less on reperfusion. Heart rate remained stable with pentobarbitone anaesthesia during coronary occlusion and reperfusion, but promptly declined in the first minute of occlusion in the groups given halothane and alpha-chloralose and then remained low throughout occlusion, especially in the group given alpha-chloralose (P less than 0.001 vs pentobarbitone and P less than 0.01 vs halothane). The extent of myocardial damage was measured from nitroblue tetrazolium-stained sections and expressed as a percentage of the zone at risk, which was obtained in five hearts following 90 minutes coronary ligation. Values were 44.0% with pentobarbitone, 54.0% with alpha chloralose (P less than 0.01 vs pentobarbitone) and 62.1% with halothane (P less than 0.001 vs pentobarbitone). Thus, the choice of anaesthetic employed during experimental myocardial ischaemia may have significant effects on the incidence of ventricular tachycardia, haemodynamic changes and extent of necrosis observed.(ABSTRACT TRUNCATED AT 250 WORDS)

The steroid 5 alpha-stigmastane-3 beta, 5, 6 beta-triol 3-monobenzoate at a dose of 40 mg/kg of body weight has 100% interceptive activity when administered orally in a single dose during 6-7 days of gestation but it has no action on pregnancy if treated on 10th, 13th or 16th day of pregnancy. The interceptive activity of the steroid is lost by simultaneous injection of prolactin, progesterone or LH.

The steroid 5 alpha-stigmastane-3 beta, 5, 6 beta-triol-3-monobenzoate at a dose of 40 mg/kg/day showed significant antifertility activity when administered orally in a single or in consecutive doses during pre-implantation stage of pregnancy in mice. In the rabbit interceptive activity was obtained when the test steroid was administered on Day 8 of pregnancy in a single dose level. The compound failed to show any distinct estrogenic or androgenic property following bioassay method. But in McPhial test, the compound showed some progestagenic activity.

Crossed immunoelectrophoresis was employed in the analysis of cytosol antigens of a human colon adenocarcinoma cell line. Other immunoelectrophoretic techniques - crossed immunoelectrophoresis in the presence of Ampholine (incorporation of Ampholine in the first dimension electrophoresis gel), crossed immunotachophoresis and crossed immunoelectrofocusing - were also investigated ad compared with crossed immunoelectrphoresis in an attempt to select the optimal immunoelectrophoretic system for the analysis of cytosol antigens. The results of these comparisons showed that each technique offered its own advantages. The maximum number of immunoprecipitin peaks were detected by crossed immunoelectrophoresis. Both crossed immunoelectrophoresis in the presence of Ampholine and crossed immunotachophoresis provided the greatest resolution of electrophoretically similar antigens. Crossed immunoelectrofocusing provided IP values for these antigens. It was concluded that these techniques, when employed in combination, provided a more complete analysis of the complex cytosol antigenic mixture and may be useful when employed in combination to other antigen-antibody systems.