Plant-derived antimalarial agents: from crude extracts to isolated bioactive compounds

Despite decades of intense research, malaria remains a deadly disease of the developing worlds. Drugresistance to limited available antimalarials, in part, has contributed to the persistence of this infectious disease. Likewise, the use of antimalarials such as artemisinin, though effective in global malaria control programs, is hampered by high cost and limited supply. Therefore, identification of an antimalarial drug that is easy to isolate and produce, inexpensive, and demonstrates little toxicity across a diverse population represents the ideal agent needed for global malaria control programs and eradication of this deadly disease. This review discusses several antimalarial compounds containing unique structural composition that have been isolated and characterized from plant sources. These compounds have exhibited promising antimalarial activities in vitro and in vivo. However, limitations such as toxicity, low bioavailability and/or poor solubility have probably restricted the scope of use for several plant products in humans. Nevertheless, plants provide novel leads, which can be developed into safe drugs by synthetic strategies as exemplified by artemether and quinoline class of antimalarials. Therefore, plant bioactive compounds described herein provide useful alternatives, which could be modulated to obtain antimalarials active against not only drug-sensitive, but also drug-resistant and multi-drug resistant strains of Plasmodium. In this direction, semi synthetic approaches to newer and modified antimalarials have provided useful insights into their applicability in antimalarial drug discovery

Does genetic polymorphisms affect health?

Genetic polymorphisms are variations found in DNA sequences and they are integral to the development of genetic markers to identify individuals at risk and it requires certain techniques and strategies to detect the mutations. Most of the variations found in DNA sequences are stable and occur in the form of single nucleotide polymorphism (SNPs),insertion/deletion (I/D) and variable tandem repeats. Among the genetic polymorphisms, SNPs are the most abundant form in the human genome, accounting for more than 90% of all differences among individuals. Variation occurs when a single nucleotide (A, T, C, or G) alters in the genome sequence. SNPs are stable, di-allelic and the two alleles represent the “wild-type” and the “mutant type” forms. SNPs are frequently studied in relation to various cancers for their known biochemical or physiological function. Several studies have been done in understanding the possible role of genetic variation in the human genome. Identifying the association between the ancestral variants in genes are common in polygenic diseases which become increasingly reasonable with improved methods for detecting genetic variants on a genome-wide scale. Over the years, several researches have been conducted to detect the cause of various genetic disorders. Genetic polymorphisms play an important role in human health especially in the development of essential hypertension and type 2 diabetes mellitus. Our genetic research group works toward understanding the interaction between genes and environmental exposures in various human diseases such as congenital heart disease, hypertension, metabolic syndrome, end stage renal disease, prostate cancer, polycystic kidney disease etc. Our group research has two main elements: investigating the role of environmental exposure in critical target gene mutation and the role of genetic susceptibility and environmental exposure in those disorders. In addition, more fundamental researches are going on in order to know the genetic and allelic frequency of certain susceptibility genes for the development of various disorder

Association of variable number of tandem repeats polymorphism in the IL-4 gene with end-stage renal disease in Malaysian patients.

Variable number of tandem repeats (VNTR) polymorphism in the interleukin 4 (IL-4) gene has been associated with end-stage renal disease (ESRD) subjects in many different populations, although with conflicting results. We determined the 70 bp of VNTR polymorphism at intron 3 of the IL-4 gene in Malaysian ESRD subjects. Buccal cells were collected from 160 case and 160 control subjects; genomic DNA was amplified using PCR, followed by agarose gel electrophoresis. There were significant differences in genotypes and alleles of the IL-4 gene. We conclude that VNTR polymorphism of the IL-4 gene is a risk factor for the development of ESRD among Malaysians

No association of BgII dimorphism of human renin gene in hypertensive subjects in Malaysia.

The presence of a dimorphic BglI site in the first intron of the Renin (REN) gene is an increased risk in essential hypertension. Several studies have found the association between BglI dimorphism and essential hypertension with conflicting results in various populations, which might be due to ethnic and geographical variations. The objective of this study is to determine the relationship between the BglI dimorphism of REN gene and Essential Hypertension (EHT) with or without Type 2 Diabetes Mellitus (T2DM) in Malaysian subjects. The study includes 70 EHT, 60 EHT with T2DM and 70 unrelated healthy subjects from the three ethnic groups of Malaysian Subjects. The genotype of BglI dimorphism was done by PCR-RFLP method using BglI restriction enzyme. The frequency of the BglI (+) allele was 37.86% in EHT, 40.83% in EHT with T2DM subjects and 35.71% in control subjects. The results of this study indicate that the BglI (+) allele of REN gene is not associated with essential hypertension with or without T2DM in Malaysian Subjects

Analysis of 14 genetic polymorphisms for risk factors in Malaysian essential hypertension with or without type 2 diabetes mellitus subjects

Objectives The objective of this study was to determine the association of insertion/deletion (I/D), G2350A and T3892C polymorphisms of angiotensin converting enzyme (ACE) gene, A20C and A6G polymorphism of angiotensinogen (AGT) gene, BglI and MboI polymorphisms of renin gene, I/D of alpha 2B adrenoceptor gene, Gly460Trp of aldosterone synthase gene, Lys173Arg of adducin gene, A6244G polymorphism of the insulin receptor gene, S477X polymorphism of the lipoprotein lipase gene, C511T polymorphism of the interleukin gene and C825T polymorphism of the G protein beta 3 subunit (GNβ3) gene in essential hypertension (EHT) with or without type 2 diabetes mellitus (T2DM) of Malaysian subjects. Methods This cross-sectional study includes 70 EHT without T2DM, 65 EHT with T2DM and 75 unrelated healthy control subjects. Genomic DNA was extracted from the peripheral blood. The polymerase chain reaction (PCR)-restriction fragment length polymorphism, mutagenically PCR and the hot-start PCR methods were carried out to detect the genotypes of the various genetic polymorphisms. All the PCR products and the restricted fragments were resolved electrophoretically on agarose and polyacrylamide gels. Statistical analyses was done using SPPS version 14.0. Results Among the 14 genetic polymorphisms, only I/D and G2350A polymorphism of ACE gene, I/D polymorphism of alpha adrenoceptor gene and A6G variant of AGT gene differed significantly (p0.05) when compared to control subjects. Conclusions The alleles of I/D and G2350A polymorphisms of ACE, A6G of AGT and I/D of alpha 2B adrenoceptor genes can be considered as possible genetic markers or predisposing risk factors for EHT with or without T2DM in Malaysian subjects

Linkage analysis between prostate cancer occurrence and Y-chromosomal DYS loci in Malaysian male subjects

Prostate cancer has become the second leading cancer among men across ethnic groups in the world. Since it is influenced by a complex genetics that may affect the level of susceptibility for the development of the disease, four Y-linked short tandem repeats (STRs), DYS388, DYS435, DYS437, and DYS439 were genotyped to compare Malaysian prostate cancer patients and normal controls males. A total of 175 subjects comprising 84 patients and 91 healthy individuals from three major ethnics were recruited. Multiplex PCR was optimized to co-amplify all four DYS loci. All samples were genotyped for alleles of four DYS loci using a Genetic Analysis System. Result showed that allele 10 (A) of DYS388 had a significantly lower incidence towards disease than other alleles of this locus, while allele 12 (C) of DYS388 and allele 14 (E) of DYS439 showed a significantly higher risk to develop prostate cancer compared to other alleles of these loci. Moreover, among 47 different haplotypes comprising different alleles of four DYS loci found in the overall study samples, it is noticed that AABC and CAAA showed a lower and higher frequency among cases than controls, respectively. As a conclusion, Malaysian males who belong to Y-lineages with either allele 12 of DYS388, allele 14 of DYS439, or haplotype CAAA tend to develop prostate cancer. Meanwhile, those belonging to Y-lineages with allele 10 of DYS388 or haplotype AABC are more resistant to the disease. Thus, it is suggested that genetic elements give an influence on the development of prostate cancer

Analysis of renin-angiotensin aldosterone system gene polymorphisms in malaysian essential hypertensive and type 2 diabetic subjects

<p>Abstract</p> <p>Background</p> <p>The renin-angiotensin aldosterone system (RAAS) plays an important role in regulating the blood pressure and the genetic polymorphisms of RAAS genes has been extensively studied in relation to the cardiovascular diseases in various populations with conflicting results. The aim of this study was to determine the association of five genetic polymorphisms (A6G and A20C of angiotensinogen (AGT), <it>MboI </it>of renin, Gly460Trp of aldosterone synthase and Lys173Arg of adducin) of RAAS genes in Malaysian essential hypertensive and type 2 diabetic subjects.</p> <p>Methods</p> <p>RAAS gene polymorphisms were determined using mutagenically separated PCR and PCR-RFLP method in a total of 270 subjects consisting of 70 hypertensive subjects without type 2 diabetes mellitus (T2DM), 60 T2DM, 65 hypertensive subjects with T2DM and 75 control subjects.</p> <p>Results</p> <p>There was significant difference found in age, body mass index, systolic/diastolic blood pressure, fasting plasma glucose and high density lipoprotein cholesterol levels between the hypertensive subjects with or without T2DM and control subjects. No statistically significant differences between groups were found in the allele frequency and genotype distribution for A20C variant of AGT gene, <it>MboI </it>of renin, Gly460Trp of aldosterone and Lys173Arg of adducin (p > 0.05). However, the results for A6G of AGT gene revealed significant differences in allele and genotype frequencies in essential hypertension with or without T2DM (p < 0.001).</p> <p>Conclusion</p> <p>Among the five polymorphisms of RAAS genes only A6G variant of AGT gene was significantly associated in Malaysian essential hypertensive and type 2 diabetic subjects. Therefore, A6G polymorphism of the AGT gene could be a potential genetic marker for increased susceptibility to essential hypertension with or without T2DMin Malaysian subjects.</p

Gene expression of CDK6 and CCND1 genes in basal cell carcinoma

Basal cell carcinoma (BCC) is the most common cancer among skin cancers. Cell cycle deregulation in G1-phase is a critical event during the course of carcinogenesis, which is probably much more important than other phases of cell cycle, during the course of skin carcinogenesis. CCND1 and CDK6 are important components of Retinoblastoma regulatory pathway in arrest and uncontrolled proliferation of cell cycle. To determine the expression pattern of CDK6, CCND1 in BCC, this study involved ten samples of paraffin embedded of BCC tissues. Two selected normal skin tissue were investigated using RT in situ PCR and Immunohistochemistry (IHC) techniques. Nuclear and cytoplasmic staining intensity of samples within tumor cells and normal tissue illustrated a different mRNA and protein expression. This study represents significant expression of CCND1 and CDK6 genes in BCC (alpha level is 0.05). CDK6 and CCND1 mRNA, and protein of these genes are expressed to induce the cell cycle proliferation and the influence proliferation of cell cycle and BCC