Current Pharmacogenomics, Vol. 3, No. 2, 2005
Contents
Genetic Diversity
of Human SP-A, a Molecule with Innate host Defense and Surfactant-Related
Functions; Characteristics, Primary Function, and Significance Pp.87-95
Joanna Floros, Guirong Wang and Zhenwu Lin
Innate Immunity
and Intracellular Trafficking: Insights for Novel Anti-HIV-1 Therapeutics Pp.97-117
Kate L. Jones and Johnson Mak
Gene-Nutrient
Interaction in Type 2 Diabetes: An Appraisal of the Role of the Peroxisome
Proliferator-Activated Receptor Pathway Pp.119-128
Tianhua Niu and Simin Liu
Telomeres,
Senescence and Longevity: The Role of Oxidative Stress and Antioxidants Pp.129-156
Gabriele C. Saretzki
Pharmacogenetic
Studies of Psychotropic Drug-Induced Adverse Effects Pp.157-164
Shih-Jen Tsai and Chen-Jee Hong
Abstracts
[Back
to top] Genetic Diversity of Human SP-A, a
Molecule with Innate host Defense and Surfactant-Related Functions;
Characteristics, Primary Function, and Significance
Joanna Floros, Guirong Wang and Zhenwu Lin
Pulmonary surfactant, a lipoprotein complex, is essential for life. It lowers the surface tension at the air-liquid interphase of the distal lung airspaces (alveoli) to prevent alveolar collapse at low lung volumes. Alveolar stability is critical in maintaining a normal O2/CO2 exchange. Surfactant deficiency in the prematurely born infant can lead to respiratory problems or respiratory distress syndrome (RDS); a major complication of infants with RDS is infection. Surfactant dysfunction has been associated with several pulmonary diseases characterized with impaired O2/CO2 exchange, deranged inflammatory processes and host defense. Pulmonary surfactant consists of approximately 90% lipids, with phospholipids constituting the major lipid component, and about 10% of proteins with surfactant protein A (SP-A) found in great abundance. SP-A has been identified with several diverse functions. Broadly, these include surfactantrelated and host defense-related functions. Human SP-A is encoded by two genes, SP-A1 and SP-A2, and exhibits extensive complexity at the DNA, RNA, and protein level, compared to rodent SP-A and even to that of the primates. Although, the significance of such complexity is not currently understood, a number of studies have revealed associations between certain SP-A variants or levels of SP-A and pulmonary disease. Moreover, functional, structural, and biochemical differences have been observed between in vitro expressed SP-A1 and SP-A2 variants. We speculate that the human SP-complexity provides diversity in the overall SP-A functional activities. We suggest that because of its complexity, which appears to translate in quantitative and qualitative differences among individuals, SP-A can provide a good model for study of the basis of individual variability to disease susceptibility and/or to drug response. In this paper, we review types of SP-A complexity and comment on the significance of such variability, summarize associations between SP-A genetic variants and pulmonary diseases, and speculate on the SP-A primary function (surfactant or the host defense) by discussing a number of attributes. The focus of this mini review is on the human SP-A genes and alleles.
[Back
to top] Innate Immunity and Intracellular
Trafficking: Insights for Novel Anti-HIV-1 Therapeutics
Kate L. Jones and Johnson Mak
It is now evident that host cells have evolved a remarkable variety of antiretroviral activities to defend themselves against viral invaders and in return viruses have developed ingenious ways to circumvent these defences and, in some cases, actually hijack cellular proteins in order to facilitate their replication. Study of this cat and mouse interplay between viruses and their host cells throughout evolution has lead to the identification of some of the most sophisticated antiviral strategies that mammals have developed to prevent viral infection. Recently, a wave of publications has significantly enhanced our understanding of the relationship between human immunodeficiency virus type 1 (HIV-1) and its host, including: 1) the HIV-1 protein Vif and its interaction with host cell nucleic acid editing enzymes; 2) the host cell restrictive factors that provide protection against retroviral infection, such as TRIM5a; and 3) the late domains of retroviruses and their relationship with the host cell vacuolar protein sorting pathway. The focus of this review is to provide an up-to-date account of these important areas of HIV-1 research and highlight how some of these new discoveries can potentially be exploited for the development of novel anti-retroviral therapeutics.
[Back to top] Gene-Nutrient Interaction
in Type 2 Diabetes: An Appraisal of the Role of the Peroxisome
Proliferator-Activated Receptor Pathway
Tianhua Niu and Simin Liu
Type 2 diabetes mellitus (T2DM), characterized by insulin resistance and b-cell dysfunction, is a complex, multifactorial disease, which has become a worldwide epidemic in the 21st century. Twin and family studies have revealed a strong genetic component of T2DM, and a number of candidate genes such as the peroxisome proliferator-activated receptor g (PPARg) and CAPN10, have been identified in human populations. Previous studies also indicate that body mass index, dietary factors (e.g. fat/vegetable intake, high/low glycemic-load diet), as well as lifestyle variables (e.g. sedentary behavior, prolonged television viewing) are associated with an increased risk of T2DM. Therefore, the interaction between genetic and dietary/lifestyle factors may play a central role in the pathogenesis of T2DM. In this review, we focus on the PPAR pathway to illustrate how molecular variants of genes belonging to this pathway may respond differently to various dietary signals on the risk of T2DM, because they serve as nutrient sensors. The key molecules involved in this pathway include PPARa, which plays a significant role in the regulation of nutrient metabolism especially fatty acid oxidation, PPARg, which is primarily expressed in adipose tissue where it stimulates adipogenesis and lipogenesis, and PPARg coactivator 1a (PGC-1a), which is involved in regulation of gluconeogenesis. Drugs that target PPARg - thiazolidinedione (TZD), have now been widely used in the treatment of T2DM. We’ll delineate in detail how genetic variants of molecules in the PPAR pathway may modify the response to TZD in T2DM patients.
[Back
to top] Telomeres, Senescence and Longevity: The Role
of Oxidative Stress and Antioxidants
Gabriele C. Saretzki
Considerable evidence shows that accumulation of oxidative damage to various cellular macromolecules may be causally associated with cellular senescence and different age-related degenerative diseases.
Telomeres are nucleoprotein structures that protect the ends of linear chromosomes. Telomeres in human somatic cells shorten with each cell division. The amount of shortening is largely dependent on the amount of oxidative stress and genetically determined antioxidant properties. Intervention experiments have shown that lowering oxidative stress can reduce telomere shortening. That identifies telomeres as excellent biomarkers for oxidative stress and the antioxidant capacity of a cellular system or organism.
The analysis of the mechanisms responsible for aging and longevity in different animal systems from nematodic worms to rodents have demonstrated a clear correlation between the capability of an organism to cope with oxidative stress and its life span. Caloric restriction experiments and the characterisation of the insulin metabolism enhanced our understanding of the aging process substantially.
Powerful synthetic mimetics of antioxidant enzymes have been developed recently. Their use has been shown to decrease oxidative load in models for different degenerative diseases and seems encouraging for further pharmacologic intervention into aging and age-related diseases.
[Back to top] Pharmacogenetic Studies
of Psychotropic Drug-Induced Adverse Effects
Shih-Jen Tsai and Chen-Jee Hong
Psychotropic drugs, like antipsychotics, antidepressants, mood stabilizers and anxiolytics, are effective for alleviation of certain psychiatric symptoms, however, the adverse-effects (AEs) associated with these psychotic medications may limit their use, and even cause serious outcomes. Individual differences in psychotropic-related Aes suggest that genetic components may play a major role. During the past 10-15 years, dramatic advances in molecular biology have led to the modern era of pharmacogenetics, with variability in drug response, which includes both therapeutic benefits and AEs, attributed to genetic factors discovered in different populations. Thus, identification of the genetic variations that influence drug-related AEs will facilitate pre-treatment selection and development of drugs that are safe for individual patients, based on their idiosyncratic pharmacogenetic profile. We review recent pharmacogenetic investigations of psychotropic-related AEs, proposing several recommendations for future study of psychotropic-induced AEs.