De Novo Sphingolipid Biosynthesis in Atherosclerosis.

Atherosclerosis is the formation of fibrofatty lesions in the arterial wall, and this inflammatory state of the artery is the main cause of advanced pathological processes, including myocardial infarction and stroke. Dyslipidemic conditions with excess cholesterol accumulate within the arterial vessel wall and initiate atherogenic processes. Following vascular reaction and lipid accumulation, the vascular wall gradually thickens. Together with the occurrence of local inflammation, early atherosclerotic lesions lead to advanced pathophysiological events, plaque rupture, and thrombosis. Ceramide and sphingomyelin have emerged as major risk factors for atherosclerosis and coronary artery disease. Currently, the clinical association between de novo sphingolipid biosynthesis and coronary artery disease has been established. Furthermore, therapeutic strategies to modulate this pathway, especially those involving serine palmitoyltransferase and sphingomyelin synthase, against atherosclerosis, cancer, type 2 diabetes, and non-alcoholic fatty liver disease are actively under development. In this chapter, we focus on the relationship between de novo sphingolipid biosynthesis and coronary artery disease.

Upregulation of the serine palmitoyltransferase subunit SPTLC2 by endoplasmic reticulum stress inhibits the hepatic insulin response.

Endoplasmic reticulum (ER) stress is induced by various conditions, such as inflammation and the presence of excess nutrients. Abnormal accumulation of unfolded proteins leads to the activation of a collective signaling cascade, termed the unfolded protein response (UPR). ER stress is reported to perturb hepatic insulin response metabolism while promoting insulin resistance. Here, we report that ER stress regulates the de novo biosynthesis of sphingolipids via the activation of serine palmitoyltransferase (SPT), a rate-limiting enzyme involved in the de novo biosynthesis of ceramides. We found that the expression levels of Sptlc1 and Sptlc2, the major SPT subunits, were upregulated and that the cellular concentrations of ceramide and dihydroceramide were elevated by acute ER stress inducers in primary hepatocytes and HepG2 cells. Sptlc2 was upregulated and ceramide levels were elevated by tunicamycin in the livers of C57BL/6J wild-type mice. Analysis of the Sptlc2 promoter demonstrated that the transcriptional activation of Sptlc2 was mediated by the spliced form of X-box binding protein 1 (sXBP1). Liver-specific Sptlc2 transgenic mice exhibited increased ceramide levels in the liver and elevated fasting glucose levels. The insulin response was reduced by the inhibition of the phosphorylation of insulin receptor ß (IRß). Collectively, these results demonstrate that ER stress induces activation of the de novo biosynthesis of ceramide and contributes to the progression of hepatic insulin resistance via the reduced phosphorylation of IRß in hepatocytes.

Annona muricata leaf extract attenuates hepatic lipogenesis and adipogenesis.

Annona muricata (graviola) is a medicinal plant that can be used to alleviate chronic human diseases by providing antioxidants and inducing immunomodulation. In this study, we found that treatment of AML12 hepatocytes with steam (SGE) and ethanol (EGE) extracts of graviola leaf downregulated the expression of fatty acid (FA) oxidation genes, including ACOX1, CPT1, and PPARα, with no change in the expression of FA synthesis genes. However, whereas EGE inhibited the differentiation and lipid accumulation of 3T3-L1 adipocytes and downregulated FA synthesis genes, no similar changes were observed in response to treatment with SGE. In an in vivo experiment using mice fed a high-fat diet (HFD), body weight was reduced in response to treatment with EGE, which also dose-dependently alleviated liver hepatocyte ballooning induced by the consumption of a HFD. However, genes involved in FA oxidation and the secretion of very low density lipoprotein (VLDL) were downregulated. We also found that the size of adipocytes was reduced in response to EGE treatment, and that there was a downregulated expression of genes involved in adipogenesis and FA synthesis. Furthermore, we detected increases in the levels of cholesterol in the plasma, whereas ALT activity was reduced. Collectively, these results indicates that EGE inhibits lipid influx into the liver and adipogenesis in adipose tissues. These bioactive properties of EGE indicate its potential as a natural ingredient that can be used to prevent obesity.

Role of Mitochondrial DNA (mtDNA) Variations in Cancer Development: A Systematic Review.

mtDNA is the closed circular, ds-DNA present in mitochondria of eukaryotic cells and are inherited maternally. Besides being the power house of the cell, mitochondria are also responsible for the regulation of redox homeostasis, signaling, metabolism, immunity, survival and apoptosis. Lack of a 'Systematic Review' on mtDNA variations and cancers encouraged us to perform the present study. Pubmed', 'Embase' and 'Cochrane Library' databases were searched using keywords 'Mitochondrial DNA' OR 'mtDNA' OR 'mDNA' AND 'polymorphism' AND 'cancer' AND 'risk' to retrieve literature. Polymorphisms occupy first rank among mtDNA variations followed by CNV, MSI, mutations and hold a great potential to emerge as key predictors for human cancers.

ANDB: Development of a Database Based on a Global Survey of Literature on Areca Nut and Associated Health Effects.

Areca nut (AN), commonly known as "Supari" in India is an addictive substance and widely consumed with or without tobacco as a part of customs in many South East Asian countries. Owing to the adverse health effects of AN, public awareness and stringent government policies to prohibit AN production and regulation of products containing AN should be addressed without further delay. Lack of a research database, motivated us to develop a comprehensive online portal on global survey of published articles with reference to AN. The Areca nut database (ANDB) is a manually curated database which provides the information on global literature according to the publication year, author, population, harmful effects, and associated disease. The present study is an attempt to deliver the relevant information which would be helpful to researchers in prioritizing the research areas with respect to AN and associated health effects. The portal has been developed in MySQL and the interface has been designed using core PhP and CSS, HTML. ANDB is an online resource available to provide global literature of AN in a user-friendly manner. It can be accessed freely on http://arecanut.icmr.org.in/. To the best of our knowledge, ANDB is the first portal delivering inclusive scientific literature related to AN and its health effects. This evidence-based scientific information would be useful for policy makers to make guidelines for increasing awareness and implementing the laws for regulated use of this potentially carcinogenic substance, thereby controlling the burden of many dreaded diseases primarily oral submucous fibrosis, cardiovascular disease, and cancers.

Developing a hybrid antimicrobial resistance surveillance system in India: Needs & challenges.

Growing resistance to antimicrobials has become one of the most important problems of the 21st century. The development of new antibiotics is a time-consuming process involving huge financial resources. An alternate approach is proper utilization of the existing antibiotics through the surveillance of resistance. An important component of surveillance is the informatics tool for collection, management and analysis of antimicrobial resistance susceptibility testing data. Based on the scope, antimicrobial resistance surveillance resistance tools can be broadly classified as collectors and integrators. Individually, both the integrators and collectors have limitations which restrict their use in India. There is a strong requirement to develop a hybrid AMR surveillance tool that captures standardized data from small laboratories and integrates data from multiple sources to present a complete picture of the country. Here we describe a tooli-AMRSS developed by the Indian Council of Medical Research for collection, storage and management of AMR data from collaborating institutes/laboratories and to generate real-time analytics and reports.

Setting research priorities in smokeless tobacco control: A retrospective review.

BACKGROUND & OBJECTIVES: Smokeless tobacco (SLT) has become a global menace; India being one of the high-burden countries contributes about 67 per cent of its users. Although research is ongoing on various aspects of SLT use and its effects, there is a need to identify the still under-researched areas in this field. This study was aimed at delineating the quantum of research on various topics of SLT, with intent to delineate research gaps for guiding future research priorities. METHODS: Data about research in SLT were collected from PubMed database using 'smokeless tobacco' as a keyword and applying Medical Subject Headings (MeSH) terms filter. Data were extracted in XML (Extensible Markup Language) format and parsed into database to extract necessary fields such as PubMed IDs, authors' names, affiliations and MeSH terms. Quantum of research in various aspects of SLT was identified for individual MeSH terms and compared for global and Indian data. RESULTS: Data analysis of 2857 records revealed that maximum number of articles was devoted to adverse effects (35.6%) followed by epidemiology (32.4%). In comparison, India contributed only 11.7 per cent of records with maximum number of articles on the topics of epidemiology (26%) and adverse effects (45.8%). Higher proportion of research was published on epidemiology, aetiology and prevention and control at global level, while adverse effects of SLT were researched more in Indian studies as compared to global data. INTERPRETATION & CONCLUSIONS: The present analysis highlighted the paucity of research studies on important topics such as economics and alternative strategies of SLT control, both on the global and regional levels.

In-silico study of toxicokinetics and disease association of chemicals present in smokeless tobacco products.

Smokeless tobacco (SLT) products are consumed by millions of people in over 130 countries around the world. Consumption of SLT has been estimated to cause a number of diseases accounting to more than 0.65 million deaths per year. There is sufficient epidemiological evidence on the association of SLT products with nicotine addiction, cancers of oral cavity and digestive systems but there is a lack of understanding of the role of toxic chemicals in these diseases. We provide the first comprehensive in-silico analysis of chemical compounds present in different SLT products used worldwide. Many of these compounds are found to have good absorption, solubility and permeability along with mutagenic and toxic properties. They are also found to target more than 350 human proteins involved in a plethora of human biological processes and pathways. Along with all the previously known diseases, the present study has identified the association of compounds of SLT products with a number of unknown diseases like neurodegenerative, immune and cardiac diseases (Left ventricular non compaction, dilated cardiomyopathy etc). These findings indicate far-reaching impact of SLT products on human health than already known which needs further validations using epidemiological, in-vitro and in-vivo methodologies. Thus, this study will provide one stop information for the policy makers in development of regulatory policies on toxic contents of SLT products.

Signature of genetic associations in oral cancer.

Oral cancer etiology is complex and controlled by multi-factorial events including genetic events. Candidate gene studies, genome-wide association studies, and next-generation sequencing identified various chromosomal loci to be associated with oral cancer. There is no available review that could give us the comprehensive picture of genetic loci identified to be associated with oral cancer by candidate gene studies-based, genome-wide association studies-based, and next-generation sequencing-based approaches. A systematic literature search was performed in the PubMed database to identify the loci associated with oral cancer by exclusive candidate gene studies-based, genome-wide association studies-based, and next-generation sequencing-based study approaches. The information of loci associated with oral cancer is made online through the resource "ORNATE." Next, screening of the loci validated by candidate gene studies and next-generation sequencing approach or by two independent studies within candidate gene studies or next-generation sequencing approaches were performed. A total of 264 loci were identified to be associated with oral cancer by candidate gene studies, genome-wide association studies, and next-generation sequencing approaches. In total, 28 loci, that is, 14q32.33 (AKT1), 5q22.2 (APC), 11q22.3 (ATM), 2q33.1 (CASP8), 11q13.3 (CCND1), 16q22.1 (CDH1), 9p21.3 (CDKN2A), 1q31.1 (COX-2), 7p11.2 (EGFR), 22q13.2 (EP300), 4q35.2 (FAT1), 4q31.3 (FBXW7), 4p16.3 (FGFR3), 1p13.3 (GSTM1-GSTT1), 11q13.2 (GSTP1), 11p15.5 (H-RAS), 3p25.3 (hOGG1), 1q32.1 (IL-10), 4q13.3 (IL-8), 12p12.1 (KRAS), 12q15 (MDM2), 12q13.12 (MLL2), 9q34.3 (NOTCH1), 17p13.1 (p53), 3q26.32 (PIK3CA), 10q23.31 (PTEN), 13q14.2 (RB1), and 5q14.2 (XRCC4), were validated to be associated with oral cancer. "ORNATE" gives a snapshot of genetic loci associated with oral cancer. All 28 loci were validated to be linked to oral cancer for which further fine-mapping followed by gene-by-gene and gene-environment interaction studies is needed to confirm their involvement in modifying oral cancer.

OrCanome: a Comprehensive Resource for Oral Cancer.

Oral cancer is one of the most prevalent cancers in India but the underlying mechanisms are minimally unraveled. Cancer research has immensely benefited from genome scale high throughput studies which have contributed to expanding the volume of data. Such datasets also exist for oral cancer genes but there has been no consolidated approach to integrate the data to reveal meaningful biological information. OrCanome is one of the largest and comprehensive, user-friendly databases of oral cancer. It features a compilation of over 900 genes dysregulated in oral cancer and provides detailed annotations of the genes, transcripts and proteins along with additional information encompassing expression, inhibitors, epitopes and pathways. The resource has been envisioned as a one-stop solution for genomic, transcriptomic and proteomic annotation of these genes and the integrated approach will facilitate the identification of potential biomarkers and therapeutic targets.