Shailendra Dwivedi

Vitamin C in Disease Prevention and Cure: An Overview

The recognition of vitamin C is associated with a history of an unrelenting search for the cause of the ancient haemorrhagic disease scurvy. Isolated in 1928, vitamin C is essential for the development and maintenance of connective tissues. It plays an important role in bone formation, wound healing and the maintenance of healthy gums. Vitamin C plays an important role in a number of metabolic functions including the activation of the B vitamin, folic acid, the conversion of cholesterol to bile acids and the conversion of the amino acid, tryptophan, to the neurotransmitter, serotonin. It is an antioxidant that protects body from free radical damage. It is used as therapeutic agent in many diseases and disorders. Vitamin C protects the immune system, reduces the severity of allergic reactions and helps to fight off infections. However the significance and beneficial effect of vitamin C in respect to human disease such as cancer, atherosclerosis, diabetes, neurodegenerative disease and metal toxicity however remains equivocal. Thus further continuous uninterrupted efforts may open new vistas to understand its significance in disease management.

Recent scenario of obesity and male fertility

The aim of this review was to provide current scenario linking obesity and male fertility. Obesity has been linked to male fertility because of lifestyle changes, internal hormonal environment alterations, and sperm genetic factors. A few studies assessing the impact of obesity on sperm genetic factor have been published, but they did not lead to a strong consensus. Our objective was to explore further the relationship between sperm genetic factor and obesity. There are emerging facts that obesity negatively affects male reproductive potential not only by reducing sperm quality, but in particular it alters the physical and molecular structure of germ cells in the testes and ultimately affects the maturity and function of sperm cells. Inhibition of microRNA in the male pronucleus of fertilized zygotes produces offspring of phenotypes of variable severity depending on miRNAs ratios. Hence, these RNAs have a role in the oocyte development during fertilization and in embryo development, fetal survival, and offspring phenotype. It has been reported that the miRNA profile is altered in spermatozoa of obese males, however, the impact of these changes in fertilization and embryo health remains as yet not known.

Tobacco Exposure by Various Modes May Alter Proinflammatory (IL-12) and Anti-Inflammatory (IL-10) Levels and Affects the Survival of Prostate Carcinoma Patients: An Explorative Study in North Indian Population

Objective. Inflammation is an important hallmark of all cancers and net inflammatory response is determined by a delicate balance between pro- and anti-inflammatory cytokines, which may be affected by tobacco exposure, so the present study was designed to explore the effect of various modes of tobacco exposure on interleukin-12 (IL-12) and interleukin-10 (IL-10) inflammatory cytokine levels and survival in prostate carcinoma (PCa) patients. Methods. 285 cancer patients and equal controls with 94 BPH (benign prostatic hyperplasia) were recruited; baseline levels of serum IL-12 and IL-10 were measured and analyzed in various tobacco exposed groups by appropriate statistical tool. Five-year survivals of patients were analyzed by Log-rank (Mantel-Cox) test (graph pad version 5). Results. The expression of serum proinflammatory (IL-12) and anti-inflammatory (IL-10) cytokines was correlated with tobacco exposed group as smokers, chewers, and alcohol users have shown significantly higher levels (P < 0.001) with significantly lower median survivals (27.1 months, standard error = 2.86, and 95% CI: 21.4–32.62); than nonusers. Stages III and IV of tobacco addicted patients have also shown significantly increased levels of IL-12 and IL-10. Conclusions. IL-12 and IL-10 seem to be affected by various modes of tobacco exposure and inflammation also affects median survival of cancer patients.

Genetic variability at promoters of IL-18 (pro-) and IL-10 (anti-) inflammatory gene affects susceptibility and their circulating serum levels: An explorative study of prostate cancer patients in North Indian populations.

Inflammation is an important hallmark of all types of cancers with a well-established role in carcinogenesis. The net inflammatory response is determined by the balance between pro- and anti-inflammatory cytokines, the levels of which may be affected by the genetic make-up. Interleukin (IL)-18, a pro-inflammatory cytokine expressed by various cells including those of the prostate, is a key mediator of anti-cancer immune response. IL-10, an anti-inflammatory cytokine associated with tumour malignancy, causes escape from immune surveillance. This study hypothesizes that genetic variants of IL-18 (-607 C/A and -137 G/T) and IL-10 (-819 C/T and -592 C/A) may influence the circulating levels of these interleukins, thereby generating susceptibility risk to prostate cancer. The study was conducted on 676 subjects (controls and patients of prostate cancer (PCa): 291 each; and 94 patients with benign prostate hypertrophy (BPH)). Genotyping was performed by PCR-RFLP and Real-Time PCR probe-based method. Circulating interleukin levels were obtained by ELISA. Circulating IL-18 levels were significantly elevated in cancer and BPH patients carrying GG genotypes for -137 of IL-18. The trend of circulating IL-18 levels was GG>GC>CC, observed in all groups. The -137 genetic variants of IL-18 significantly associated with PCa risk were GC, CC, and GC+CC, compared to GG (OR: 1.71, 95% CI: 1.20-2.46; OR: 3.35, 95% CI: 2.03-5.53; and OR: 2.05, 95% CI: 1.46-2.87, respectively). A significant association of AA and CA+AA against CC genotype was observed at -607 locus of IL-18 (OR: 0.46, 95%CI: 0.29-0.72; OR: 0.61, 95% CI: 0.41-0.90, respectively). Significantly elevated levels of IL-10 were observed with TT (wild) genotype at -819 of IL-10, compared to the CC (homozygous mutant) genotype in all three groups of subjects. However, no significant association was found between IL-10 promoter genotypes and PCa risk. We conclude that genetic variants of IL-18 and IL-10 promoters influence the circulating levels of these interleukins. Variations at -137 and -607 loci of IL-18 are associated with susceptibility to PCa.

Functional genetic variability at promoters of pro-(IL-18) and anti-(IL-10) inflammatory affects their mRNA expression and survival in prostate carcinoma patients: Five year follow-up study.

Inflammation is an important hallmark of all cancers. The net inflammatory response is determined by a delicate balance between pro‐ and anti‐inflammatory cytokines, which, in turn, is determined by the genetic make‐up. The present study investigates the role of variations in the promoter regions of IL‐18 and IL‐10 (anti‐inflammatory) cytokines on mRNA expressions and survival in prostate cancer (PCa) patients.

Pro-(IL-18) and Anti-(IL-10) Inflammatory Promoter Genetic Variants (Intrinsic Factors) with Tobacco Exposure (Extrinsic Factors) May Influence Susceptibility and Severity of Prostate Carcinoma: A Prospective Study

BACKGROUND It has been hypothesized that IL-18 (pro-) and IL-10 (anti-) inflammatory genetic variants at -607 C/A-137G/C and -819C/T,-592C/A, respectively, may generate susceptibility and severity risk with various modes of tobacco exposure in prostate carcinoma (PCa) patients. IL-18 is a pro-inflammatory cytokine expressed on various cells including prostate gland elements, and is a key mediator of immune responses with anti-cancerous properties. IL-10 is an anti-inflammatory cytokine that is associated with tumour malignancy which causes immune escape. MATERIALS AND METHODS The present study was conducted with 540 subjects, comprising 269 prostate carcinoma patients and 271 controls. Genotyping was performed by PCR-RFLP and confirmed by real time PCR probe-based methods. RESULTS The findings indicated that the mutant heterozygous and homozygous genotype CC and GC+CC showed significant negative associations (p=0.01, OR=0.21; 95% CI: 0.08-0.51 and p=0.011, OR=0.43; 95% CI: 0.22-0.81, respectively) thus, less chance to be diagnosed as cancer against GG genotype of tobacco smoking patients. In addition, a heterozygous GC genotype at the same locus of IL-18 pro-inflammatory cytokine may aggravate the severity (OR=2.82; 95%CI 1.09-7.29 :p=001) so that patients are more likely to be diagnosed in advanced stage than with the GG wild homozygous genotype. Our results also illustrated that anti-inflammatory cytokine (IL-10) genetic variants, although showing no significant association with susceptibility to cancer of the prostate, may gave profound effects on severity of the disease, as -819 TC (OR=4.60; 95%CI 1.35-15.73), and -592 AC (OR=5.04; 95%CI 1.08-25.43) of IL-10 in tobacco chewers and combined users (both chewers and smokers) respectively, are associated with diagnosis in more advanced stage than with other variants. CONCLUSIONS We conclude that promoter genetic variants of IL-18 and IL-10 with various modes of tobacco exposure may affect not only susceptibility risk but also severity in prostate cancer.

Diseases and Molecular Diagnostics: A Step Closer to Precision Medicine

The current advent of molecular technologies together with a multidisciplinary interplay of several fields led to the development of genomics, which concentrates on the detection of pathogenic events at the genome level. The structural and functional genomics approaches have now pinpointed the technical challenge in the exploration of disease-related genes and the recognition of their structural alterations or elucidation of gene function. Various promising technologies and diagnostic applications of structural genomics are currently preparing a large database of disease-genes, genetic alterations etc., by mutation scanning and DNA chip technology. Further the functional genomics also exploring the expression genetics (hybridization-, PCR- and sequence-based technologies), two-hybrid technology, next generation sequencing with Bioinformatics and computational biology. Advances in microarray “chip” technology as microarrays have allowed the parallel analysis of gene expression patterns of thousands of genes simultaneously. Sequence information collected from the genomes of many individuals is leading to the rapid discovery of single nucleotide polymorphisms or SNPs. Further advances of genetic engineering have also revolutionized immunoassay biotechnology via engineering of antibody-encoding genes and the phage display technology. The Biotechnology plays an important role in the development of diagnostic assays in response to an outbreak or critical disease response need. However, there is also need to pinpoint various obstacles and issues related to the commercialization and widespread dispersal of genetic knowledge derived from the exploitation of the biotechnology industry and the development and marketing of diagnostic services. Implementation of genetic criteria for patient selection and individual assessment of the risks and benefits of treatment emerges as a major challenge to the pharmaceutical industry. Thus this field is revolutionizing current era and further it may open new vistas in the field of disease management.

Prospects of Molecular Biotechnology in Diagnostics: Step Towards Precision Medicine

Molecular diagnostic tools as nucleotide sequences have been extensively utilized through persistent advancement in the molecular biology and biotechnology in diagnosis of cancerous, neurological, genetic and microbial diseases. Automated and more cutting-edge technology have revolutionized the amplification and screening of nucleic acid sequence for microbial agents, using various nucleic acid amplification technologies such as PCR, real time PCR etc. These robotic systems have provided perfection of not only in assay efficiency but also in quality control of the tests and have contributed to the standardization of traditional biomarkers. It is recognised since Gregor Mendel that factors are accountable for development of characters and after the draft of human genome the depiction of genotype to phenotype relationship appears more bright and diverse. These functions of genes and proteins have been deliberated by post-genomics cutting-edge technologies such as expression profiling using DNA microarray, proteomics, and single nucleotide polymorphisms analysis, coupled with bioinformatics. Now, genetics has become the driving force inmedical research and is now prepared for integration into medical practice. Human genome draft (bio-informatics) with innovation in current techniques now opens new vistas in the fields of novel therapeutics such as Pharmacogenomics, Chemo-informatics and Nutrigenomics that may revolutionize the management of untreated disease and disorders. The recent innovation of molecular technologies together with a multidisciplinary interaction of several fields led to the expansion of genomics, which focusses on the detection of pathogenic events at the genome level. The structural and functional genomics tactics have now pinpointed the technical challenge in the screening of disease-related genes and the recognition of their structural variations or elucidation of gene function. Several promising technologies and diagnostic applications of structural genomics are now preparing a large database of disease-genes, genetic alterations etc. by mutation scanning and DNA chip technology. Further the functional genomics also exploring the expression genetics (hybridization-, PCRand sequence-based technologies), two-hybrid technology, next generation sequencing with Bioinformatics and computational biology. Progresses in microarray ‘‘chip’’ technology as microarrays have permitted the parallel analysis of gene expression patterns of thousands of genes concurrently. Sequence information poised from the genomes of several individuals is leading to the prompt discovery of single nucleotide polymorphisms or SNPs. Further, evolutions of genetic engineering have also revolutionized immunoassay biotechnology via engineering of antibody-encoding genes and the phage display technology. The Biotechnology shows an important role in the development of diagnostic assays in response to an outburst or critical disease response need. An example is the field validation of the SNP assay for Equine Herpesvirus-1 during an outburst on 3 California race tracks in 2006/2007, and lately the development and validation of a real-time PCR assay for the detection of very virulent variant of Infectious Bursal Disease virus in 2009 [1].

Nutrigenomics and Nutrigenetics: New Insight in Disease Prevention and Cure

The perception that diet influences health is an ancient one and association between nutrient and diseases had been established in past, which is now being explored through modern epidemiological studies. Environmental factors (including food nutrients), and genetic makeup play an important role in phenotypic appearance of a trait via central dogma of biology. Environmental factors include various exposure factors that come in contact by oral intake, air and via skin commonly. Several bioactive food components, including both essential and non-essential nutrients, can regulate gene expression patterns. It is conceivable that with the alteration in the food habits and life styles, people are becoming more disposed to diet related diseases and disorders. Relentless progress in molecular biology and techniques over the past decades now resolve the association of nutrients and diseases at the personalized levels [1–3]. Thus, Nutrigenomics is providing the effects of ingested nutrients and other food components on gene expression and gene regulation, i.e., diet-gene interaction in order to identify the dietetic components having beneficial or detrimental health effects. Like Phenylketonuria (PKU) an inborn error of metabolism which is caused by a change (mutation) in a single gene. Diagnosed individuals have to avoid food containing the amino acid phenylalanine. Recent advances in the fields of functional foods, nutraceuticals and its impact on human health have been concluded into modern molecular nutrition with a more precise term of ‘‘Nutrigenomics or Nutrigenetics’’. Nutrigenomics as a new and emerging field of genomics which comprises the analysis of effect of nutrient intake on the whole genome (complete genetic make-up; including epigenetic changes), the proteome (the sum total of all proteins), and the metabolome (the sum of all metabolites). For example, Galactosemia is a disease that results from an inherited genetic deficiency of one of the three enzymes that are implicated in the metabolism of galactose. In contrary, Nutrigenetics includes the study of individual differences at the genetic level that sways individual responses to diet. These individual differences may be at the level of single nucleotide polymorphisms rather than at the gene level. Thus it emphasizes to clarify the different response of the gene variability (of different individuals) to the same nutrient. Methylene-tetra-hydro folate reductase gene (MTHFR) is a well-known example of nutrigenetics presenting a gene-nutrient interaction. Specifically, this enzyme is required for conversion of 5, 10-methylenetetrahydrofolate to a molecule called 5-methyltetrahydrofolate. This reaction is required for the multistep process that converts the amino acid homocysteine to another amino acid, methionine. MTHFR is involved in the metabolism of folic acid and maintenance of the normal blood level of homocysteine. A particular MTHFR gene SNP (C677T and A1298C) is associated with elevated homocysteine levels of in the blood of carriers, especially if there is a dietary deficiency of folic acid. Individuals with low activity of the MTHFR enzyme may present with elevated homocysteine levels, which have been associated with inflammation and heart disease, birth defects, difficult pregnancies, and potentially an impaired ability to detoxify. Nutrient deficiencies in Folate, B6 and B12 have been associated with elevated homocysteine. The basic elements of nutritional genomics includes: (1) diet is supposed to be a main predisposing factor for & Praveen Sharma praveensharma55@gmail.com

Tissue-Resident Memory Cells: New Marked Shield to Fight Cancers

According to WHO, Cancer is one of the leading causes of morbidity and mortality worldwide, with approximately 14 million new cases in 2012. The number of new cases is expected to rise by about 70% over the next 2 decades. Globally, nearly 1 in 6 deaths is due to cancer. Approximately 70% of deaths from cancer occur in lowand middle-income countries. The economic impact of cancer is significant and is increasing. The total annual economic cost of cancer in 2010 was estimated at approximately US