Modifiers of γ-Globin Gene Expression and Treatment of β-Thalassemia

Beta thalassemia (β-thalassemia) is an autosomal recessive genetic disease with many genes involved. It is a heterogeneous disorder caused by variations in the inactivation mechanism of the Beta-globin (β-globin) genes. Despite seemingly similar genotypes, the patients with Beta-thalassemia have a remarkable variability in anaemia, growth development, and hepatospleenomegaly and transfusion requirements. The genetic factors may differ in each race or ethnic group for therapy and prevention. Despite remarkable successes in the treatment of Beta-thalassemia in the past decades, it is still the leading cause of death and premature disability in developed and developing countries. Possible factors that influence the severity of anaemia in thalassemia may be inherited or non-inherited. The inherited factors include the type of β-thalassemia, coinheritance of alpha thalassemia (α-thalassemia) and factors that stimulate fetal hemoglobin (HbF) production. In this chapter, respective contributions of known modifiers and also the pharmaceutical agents currently in use and under clinical trials for regulating the globin gene expression will be discussed

Induction of apoptosis in HeLa cells by chloroform fraction of seed extracts of Nigella sativa

<p>Abstract</p> <p>Background</p> <p>Cancer remains one of the most dreaded diseases causing an astonishingly high death rate, second only to cardiac arrest. The fact that conventional and newly emerging treatment procedures like chemotherapy, catalytic therapy, photodynamic therapy and radiotherapy have not succeeded in reverting the outcome of the disease to any drastic extent, has made researchers investigate alternative treatment options. The extensive repertoire of traditional medicinal knowledge systems from various parts of the world are being re-investigated for their healing properties. This study progresses in the direction of identifying component(s) from <it>Nigella sativa </it>with anti cancer acitivity. In the present study we investigated the efficacy of Organic extracts of <it>Nigella sativa </it>seed powder for its clonogenic inhibition and induction of apoptosis in HeLa cancer cell.</p> <p>Results</p> <p>Methanolic, n-Hexane and chloroform extracts of <it>Nigella sativa </it>seedz effectively killed HeLa cells. The IC₅₀values of methanolic, n-hexane, and chloroform extracts of <it>Nigella sativa </it>were 2.28 μg/ml, 2.20 μg/ml and 0.41 ng/ml, respectively. All three extracts induced apoptosis in HeLa cells. Apoptosis was confirmed by DNA fragmentation, western blot and terminal transferase-mediated dUTP-digoxigenin-end labeling (TUNEL) assay.</p> <p>Conclusion</p> <p>Western Blot and TUNEL results suggested that <it>Nigella sativa </it>seed extracts regulated the expression of pro- and anti- apoptotic genes, indicating its possible development as a potential therapeutic agent for cervical cancer upon further investigation.</p

Genetic basis of stroke: An overview

Stroke or "brain attack" is a complex disease caused by a combination of multiple risk factors. It has major social and economic consequences. Various epidemiological studies in families and twins have revealed that there is a genetic component to stroke risk. Stroke may be the outcome of single gene disorders or more commonly, a polygenic multifactorial disease. Mutations in several candidate genes have been found to be associated with stroke. However, association studies in population-based samples have failed to identify reliable disease markers. The publication of the "Human Genome Project" has indeed improved our knowledge about the potential role of genetics in complex disorders including stroke. Rapidly expanding field of genetics is in a state of transforming medicine into a new kind in future, the individualized medicine, using tailor made drugs according to the genetic makeup of the individuals. However, this involves integrating genome wide genetic information with medical information. The first genome wide association study on ischemic stroke has been published recently. Further studies will hopefully tell us how far the genetic information will assist us to tailor clinical and therapeutic decisions to an individual′s genotype

Nutrigenomics: Looking to DNA for nutrition advice

32-40With the success of ‘Human Genome Project’ and the powerful tools of molecular biology, we have entered the era of genetic nutrition. The publication of the human ‘blue print’ has triggered an explosion in pharmaceutical research to utilize this knowledge in prescription of drugs to be tailored according to the genetic make up of susceptible individuals or in other words personalized medicine. Propelled by the recent unraveling of human genome; nutritional sciences are discovering the application of the so-called “omics” sciences. This has the potential of identifying and validating targets to improve personalized nutritional health and thus serves to define the added value for the next generation of foods and the crops. The first new term to emerge in this area was “Nutrigenomics.” Today, the term nutrigenomics generally refers to the study of how dietary components interact with the genome and modify subsequent gene expression1. It is envisaged that nutrigenomics will lead to evidence-based dietary interventions for prevention of diet related common diseases

Role of SGLT2 Inhibitors in Diabetes Management: Focus on HbA1c Levels, Weight Loss and Genetic Variation

Sodium Glucose Co-transporters-2 (SGLT2) inhibitors are the recent addition to treatment strategies for Type 2 Diabetes Mellitus (T2DM). It is a non-insulin dependent anti-diabetic therapeutic approach that eliminates plasma glucose by urination. The study was carried out with the aim of evaluating the effect of SGLT2 inhibitors on HbA1c levels and weight loss in responders and non-responders. In addition, the role of two significant variants, SLC5A2 (rs9934336) and UGT1A9 (rs72551330), affecting the inter-individual variation in response to SGLT2 inhibitors was evaluated in the study population. 200 confirmed T2DM patients on SGLT2 inhibitors were enrolled for the study. Patients with decreased HbA1c levels and body weight were categorized as responders, whereas the ones who did not show a significant decrease in these two parameters after treatment were categorised as non-responders. Association of HbA1c levels and weight loss before as well as after treatment with responders and non-responders was evaluated. Patients were screened for two significant variants, SLC5A2 (rs9934336) and UGT1A9 (rs72551330), affecting the inter-individual variation in response to SGLT2 inhibitors by Sanger Sequencing. A significant difference in HbA1c levels and weight was found in responders and non-responders before and after the treatment. However, both of the variants, SLC5A2 (rs9934336) and UGT1A9 (rs72551330), were not found to be significantly associated with the drug response. In conclusion, SGLT2 inhibitors reduced HbA1c levels and weight effectively in responders. However, the targeted gene variants need not to be involved in genetic testing before prescribing this class of drugs to T2DM patients from Malwa region of Punjab. Highlights: Treatment of Type 2 diabetes mellitus (T2DM) with Sodium Glucose co-transporter-2 (SGLT2) inhibitors is an insulin-independent method of reducing blood glucose levels by lowering renal tubular glucose reabsorption. Significant decrease in HbA1c levels and weight loss in responders was observed after the treatment with SGLT2 inhibitors. Pharmacogenetic analysis was carried out for two gene variants, SLC5A2 (rs9934336) and UGT1A9 (rs72551330), reported to be involved in inter-individual response to SGLT2 inhibitors. None of the tested variants were found to be significantly associated with inter-individual response to SGLT2 inhibitors. Pharmacogenetic testing for the two most commonly reported variants is not required for the T2DM patients on SGLT2 inhibitors from the Malwa region of Punjab

Association of BCL11A genetic variant (rs11886868) with severity in β-thalassaemia major & sickle cell anaemia

Background & objectives: The amount of foetal haemoglobin that persists in adulthood affects the clinical severity of haemoglobinopathies including β-thalassaemia major and sickle cell anaemia (SCA). The present study was undertaken to analyse β-thalassaemia as well as SCA patients for the single nucleotide polymorphism (SNP), rs11886868 (T/C) in BCL11A gene and to evaluate the association between this polymorphism and severity of β-thalassaemia major and SCA. Methods: a total of 620 samples (420 β-thalassaemia major and 200 SCA cases) were analysed before blood transfusion using basic screening tests like complete blood analysis and osmotic fragility and further confirmed by high performance liquid chromatography (HPLC), amplification refractory mutation system-polymerase chain reaction (ARMS-PCR) and reverse dot blot techniques. All patients were transfusion dependent. Patients with β-thalassaemia and SCA were classified into mild, moderate, severe according to the severity score based on Hb levels, age of onset, age at which patients received their first blood transfusion, the degree of growth retardation and splenectomy. β-thalassaemia as well as SCA patients were analysed for the SNP, rs11886868 (T/C) in BCL11A gene and association between this polymorphism and severity of β-thalassaemia major as well as SCA was evaluated. Results: There was a significant difference in genotypic and allelic frequencies of BCL11A gene polymorphism between mild and moderate and mild and severe cases in both the groups. A significant (P<0.001) difference was observed in the mean HbF levels between the three genotypes in different severity groups. HbF levels were found to be high in CC genotype bearing individuals followed by TC and TT in β-thalassaemia major as well as SCA. Interpretation & conclusions: This study confirms that the T/C variant (rs11886868) of the BCL11A gene causing downregulation of BCL11A gene expression in adult erythroid precursors results in the induction of HbF and ameliorates the severity of β-thalassaemia as well as SCA