News and Commentaries
This page regularly presents hot news and commentaries on up-to-date and cutting-edge advances in human genome, bioinformatics, functional genomics, pharmacogenomics, drug development, healthcare and other emerging areas in biotechnology and molecular medicine. It is not so easy to catch up with publications in leading journals, news letters and over the Internet even in a limited number of fields. Efforts are being made here to make highly selective choice of papers and news reports to concisely summarize recent advances and to extract creative and innovative concepts and ideas for basic research and development in biomedicine. Hopefully, these ideas and related information are useful for finding new avenues and directions in research and development. Complementary and Alternative Medicine (06 August, 2003) CAM is big business. CAM users spend out of pocket on CAM therapies as much as on conventional medicine. New protocols are necessary to comparatively evaluate CAM, and resulting information should be made available for general public and medical professionals for their best use in human health conditions. Lactoferrin for Developing Novel Therapeutics Against Primary Infection and Inflammatory Diseases (Updated 16 January 2003;15 February 2001) Lactoferrin in the mammalian milk is an anti-infective, anti-inflammatory and immunomodulatory protein. It is non-toxic and may be orally administered. It is under intensive investigation for the development of novel therapeutics against gastritis, atopic dermatitis, inflammatory bowel diseases and epithelial tumors. Stress and Immunomodulation (Updated 12 December, 2002; 7 April, 1999) Social and psychological stress disrupts neuroendocrine-immune systems to render the body vulnerable to deleterious health conditions and to infection. Stress-reducing measures enhance active coping attitude, chance of recovery and quality of life of the individual under stress. Recent Aspects of Metastatic Cancer-Host Cross Talk and Possibility for Drug Development (20 October, 2001) Metastatic cancer-host cross talk offers distinct steps of intervention. Metastasis to the target organ appears to go through receptor/ligand mechanism. Once metastasis is established, the cancer intervention may be a totally different story than the block of metastasis process. Therefore it would be important to diagnose metastasis-prone tumors while still localized and to intervene its spread in order to achieve best kind of treatment and high probability of survival of the patient. Heparanase: A New Target for Anti-metastatic Drugs (Updated 3 September, 2001; 5 July, 1999) Heparanase emerges as a promising target for the development of ant-metastatic drugs. The enzyme is an endo-beta-D-glucuronidase that cleaves haparan sulfate peptidoglycans for metastatic cancer cells to breach extracellular marix for invasion. Elucidation of active-site residues leads to computational chemistry for novel drug development. Therapeutic Aspects of Ginkgo biloba Extracts, Flavonoid and Terpenoid Constituents (25 July, 2001) Ginkgo biloba leave extracts have been used as remedies for a variety of physiological symptoms for 6 millennia. Constituent compounds are being developed for novel treatment, ginkgo-flavonol glycosides for neurodegenerative damage caused by free radicals, ginkgolide B (terpene trilactone) for asthma, and bilobalide (sesquiterpene) for ischemia-induced damage. Ginkgo biloba compounds should be valuable therapeutics in increasingly elder population as well as additives to enhance quality of healthcare products for daily health maintenance. Drug Design Approaches: Molecular Modeling, Computational Chemistry and Combinatorial Chemistry (10 April, 2001) In the age of human genome being deciphered and 3-dimensional structures of proteins available in an increasing number, drugs may now be designed in advance guessing possible 3-dimensional shape of the targets. Virtual experiments may be performed that are cheaper, faster, and safer than real experiments, and the resulting data can help cost-effective development processes in pharmaceutical R&D. Type 2 Diabetes and Nuclear Receptors for Developing New Therapy (25 January, 2001) New venues are opening up to attack insulin resistance in type 2 diabetes. Nuclear receptors offer molecular mechanisms for designing new compounds for their activation to reduce insulin resistance, while a hormone has been discovered that is a signalling molecule for insulin resistance and increased in diet-induced and genetic forms of obesity. It is promising that downregulation of this hormone offers a new leverage to reduce insulin resistance. Regulation of Dietary Cholesterol Balance--A New Approach for Novel Cholesterol-Lowering Agents (5 January, 2001) Cholesterol is pumped out of peripheral cells, including macrophages, by reverse transporters. These transporters are upregulated by ligand-activated nuclear receptor LXR. Concomitant activation of another nuclear receptor FXR enhances P450 hydroxylase CYP7A to stimulate cholesterol metabolism to bile acid, resulting in overall lowering of serum cholesterol. This regulation of cholesterol balance may lead to innovative therapy of hyperlipidemia without inhibiting normal de novo cholesterol synthesis. Cytochrome P450 Enzymes and Nuclear Receptors for Metabolism of Steroids and Xenobiotics --- New Venues for Novel Drug Development (1 August, 2000) Nuclear receptor PXR serves as a sensor for xenobiotics and induce their metabolism. This mechanism offers a molecular basis of drug-drug interaction, and of possible reduction of prescribed drugs. Other nuclear receptors exhibit regulation of cholesterol balance and serum glucose level in type 2 diabetes. Rice Genome Sequencing and Genetically-Modified Rice (6 April, 2000) Rice genome (430 million base-pairs) is the largest so far sequenced, and nearly 30,000 genes were found. The sequence data is a rich source for useful genes to be multiplied in genetically-modified rice to enhance rice production with low cost and to enrich nutrients. Initial attempts were made to enrich rice grains with provitamin A (b-carotene) to meet vitamin A deficiency in human population dependent on rice as the main food stuff. Recent Advances in Cyclooxygenase-2 (Cox-2) Inhibitors: Novel Drugs for Rheumatoid Arthritis and Cancer (20 January, 2000) Cox-2 mediates production of prostaglandins responsible for pain, inflammation and fever, and is induced by diverse inflammatory stimulations. Cox-2 selective inhibitors with few undesirable side effects are now being developed as anticancer agents as well as novel drugs for the treatment of rheumatoid arthritis. Protein Tyrosine Kinases Are New Targets For Novel Therapeutics (15 December, 1999) Protein tyrosine kinases are involved in the signal transduction pathways, tumorigenesis and other physiological functions, and they are major targets for drug development. A specific inhibitor of these enzymes is promising as a novel drug for chronic myelogenous leukemia, and a small, nonpeptidyl agonist of insulin activates insulin receptor kinase, mimicks in vivo function of insulin, and is potentially an orally active antidiabetic agent. Promising Targets to Combat Alzheimer's Disease (5 November/3 December, 1999) Amyloid_beta is the primary component in Alzheimerﾕs disease brains. A beta-secretase is now cloned, and together with gamma-secretase and presenilin proteins, these enzymes present promising new targets to develop drugs to combat Alzheimerﾕs disease that world-wide has 20 million patients. Recent Advances in Pharmacomimetics Development (20 October, 1999) The advent of genomics and bioinformatics reinforce the development of peptide mimetics that are agonists and antagonists of specific active domains of target molecules involved in disease occurrence. Nonpeptidyl mimetics are also designed based on the structures of peptide counterparts, isolated from natural sources, and synthesized through breakthrough technology. Recent discoveries are described on mimetic inhibitors (nuclear factor of activated T cells, angiotensin I converting enzyme, rheumatoid arthritis-associated factor, cell division pathway), and mimetic agonists (interleukin-4, erythropoietin, insulin, heparin). Apoptosis Inhibitors As a New Class of Tumor Progression Factors (5 October, 1999) A new class of apoptosis-regulating proteins termed FLIP have been found recently to possess apoptosis-inhibiting activity by blocking caspase-8. FLIP is highly expressed in apoptosis-resistant tumors and being viewed as a means for tumors to escape from T-cell dependent immunity against them. It is likely that FLIP constitutes a new class of tumor progression factors. Temporary Inhibition of p53 for Reduced Side Effects in Anticancer Therapy (10 September, 1999) What are possible determinants of severe side effects in cancer chemotherapy and radiation therapy? To explore the notion that temporary suppression of p53 might be a workable therapeutic strategy to prevent damage of normal tissues during anticancer treatment and to result in reduced side effects, a chemical inhibitor of p53 was characterized for its effects in vitro and in vivo. The p53 inhibitor protected mice from lethal irradiation, and together with other findings, might be useful for reducing the side effects of cancer therapy and other type of stress associated with p53 induction. Transport of Plasma Lipoproteins and New Targets for Drug Development (30 August, 1999) Elevated plasma levels of apolipoprotein B (apoB)-containing lipoproteins (low density lipoproteins=LDL) constitute a major risk factor for the development of coronary heart disease. High density lipoprotein (HDL, "good" cholesterol) deficiency also presents a high risk of coronary disease. The study of inherited diseases now reveal the regulatory mechanisms of these plasma lipoproteins. In rare abetalipoproteinemia, 97-kDa subunit of microsomal triglyceride-transfer protein is mutated recessively leading to the virtual absence of LDL in plasma, whereas in Tangier disease the gene ABC1 on chromosome 9q22-31, encoding a member of the ATP-binding cassette (ABC) transporter, is mutated causing a defect in HDL metabolism and transport. These findings offer new targets for developing drugs that protect against heart attack. Blockade of Signal Transduction through MAP Kinase Pathway Presents a Novel Potential Anti-cancer Agents (15 August, 1999) The screening by in vitro cascade assay system for identifying small-molecule inhibitors of the mitogen-activated protein (MAP) kinase pathway led to the discovery of small-molecule inhibitors of human colon carcinoma. The blockers of phosphorylation are new types of anticancer agents, and being nontoxic, cytostatic, and oral in some of them may open a new avenue for the development of antitumor drugs. Snippets Come Of Age: Common Disease-Common Variant (CD-CV) Hypothesis (26 July, 1999) In molecular medicine, a major goal is to understand the role of common genetic variants in association with, and in susceptibility or resistance to, common diseases and pharmacogenetic traits. Single nucleotide polymorphisms (SNPs) are being surveyed in the coding region of human genome in the notion of common disease-common variant. Significant variation in nucleotide diversity was seen across genes that might be polulation- and/or individual-specific. Erythropoietin (EPO) Mimicry (1 July/20 May, 1999) Activation of transmembrane receptors for cytokines occurs when oligomerization of receptor chains is induced by binding of a protein ligand (cytokine) to a specific ligand-binding domain on the receptor. Thus activation of receptors by small, peptidyl molecules might make it possible to develop cytokine mimetics that may replace natural counterparts that are now on the market for therapy. This is illustrated here for erythropoietin (EPO). Fetal Tolerance: Positive Defence from Within (16 June, 1999) During pregnancy a semiallogeneic fetus survives as maternal T cells acquire a transient state of tolerance specific for paternal alloantigens. Several lines of mechanistic evidence indicate that this is because tryptophan required for T cell proliferation is degraded by specific induction of indoleamine 2,3-dioxygenase (IDO) in macrophages, and that results in fetal tolerance. This positive immunological defence by fetus itself against attack from maternal T cells may be more significant than the placental barrier from maternal lymphocytes. Alternative Agriculture: Molecular Approaches to Produce Recombinant Proteins and to Isolate Novel Compounds (8 June, 1999) A large quantity of recombinant proteins (monoclonal antibodies, etc) may now be produced in the plant cost-effectively for therapeutic use. The plant is also viewed as unexplored source for the isolation of novel biologically active compounds. Transcriptional Repressor and Regulation of Cell Cycle Reentry (7 March, 1999) The E2F family of proteins is required to establish the correct cell cycle-dependent transcription of genes that direct the process of cell division (progression from the G1 to the S phase of the cell cycle). These proteins are activators or repressors, dependent on other protein factors they bind. A new E2F-6 protein recently cloned appears to a transcriptional repressor that inhibits genes required for the cell to reenter into the cell cycle thus keeps the cell in G0 phase. Peptidic and Nonpeptidic Mimicry: An Ultimate Approach for Drug Development (25 February, 1999) Recent advances in the concept and technology of molecular modeling lead to innovative and perhaps ultimate approaches to the development of new drugs, as agonists and antagonists. Peptidic and nonpeptidic mimetics have been developed for (peptidic): erythropoietin, tumor necrosis factor-alpha, and cyclin-dependent kinase 2, and for (nonpeptidic): granulocyte colony-stimulating factor and somatostatin (nonpeptidic). Virulence Factors As Targets For Vaccine And Therapy Against Drug-Resistant Pathogens (10 February, 1999) Vancomycin-resistant Staphylococcus aureus is a serious problem and methods for prevention and treatment of drug-resistant infections are needed in the clinical arena. An RNA molecule, RNAIII, regulates the synthesis of the virulence factors and induced by RNAIII-activating protein. It is now reported that once vaccinated with RNAIII-activating protein, mice were protected from drug-resistant S. aureus to indicate a possible alternative prevention method. Cost of Drug Development (20 January, 1999 ) Due to the astronomically increasing costs associated with bringing a new drug to market; full commercial success is possible only for a minority of products. The pharmaceutical industry is thus, prone to take risk-averse strategies and deficit reduction. Conversely, innovative research in a venture company is an acceptable risk and leads to a "discovery" industry in the name and form of biotechnology companies. If the approach to drug discovery is risk-averse and traditional in its concept then even a major pharmaceutical company would be disqualified as an inventor and forced to play only a limited role. Transgenic Production Of Human Proteins For Therapeutic Use (8 January, 1999) Human proteins for therapeutic use have been produced by extraction from tissues and plasma and by recombinant technology from mammalian and microbial cells that oftentimes sacrificed cost effectiveness for a large scale production of pure, native and stable proteins. As transgenic technology makes considerable progress, so called "animal factory" has now made it possible to produce a large amount of human serum proteins and monoclonal antibodies for therapeutic use at economically feasible cost without virus and prion contamination. Environmental Endocrine-Disrupting Chemicals (Endocrine Disrupters) (15 November, 1998) Endocrine disrupters are of considerable public concern and interest at this moment. As chemicals that could influence endocrine systems pervade the environment, their full implications for public health and environmental integrity may not be captured simply by labelling estrogenic chemicals as disrupters. The risk assessment could well be a difficult endeavor, as the endpoints of endocrine disruption may not be determined easily. Dendritic Cells and Nature of T-Cell Help (27 October, 1998) CD8+ cytotoxic T-cells (CTLs) are differentiated from naive CD8+ T cells by the participation of CD4+ T-helper cells but the nature of this 'help' was unknown. It is now reported that T-helper cells first 'condition' dendritic cells that in turn prime CTLs. CD40 signalling is important in this activation process and may also be involved in atherogenesis. Drugs Emerging to Replace Aspirin and As Anti-Cancer Agents (7 October, 1998) Aspirin is the only nonsteroidal anti-inflammatory drug that covalently modifies (acetylates) cyclooxygenases (Cox-1 and Cox-2). The side effects of aspirin arises from Cox-1 modification. Cox-2-specific aspirin derivatives (inhibitors) are now synthesized and soon to be on the market. A very interesting recent development is that Cox-2-specific inhibitors may as well be effective anti-colon cancer agents as they regulate angiogenesis induced by colon cancer cells. Phagocytosis and Resolution of Inflammation (21 September, 1998) The rapid uptake of apoptotic cells into adjacent phagocytic cells is a critical process in tissue remodeling, regulation of the immune response, or resolution of inflammation. This phagocytosis seems to be a quiet process that does not lead to production of inflammatory mediators in macrophages. Macrophages ingest neutrophils and eosinophils that are converged at the site of inflammation and emigrate to the draining lymph nodes. Mechanistically, plasma membrane glycoprotein CD14 and a cell-migration protein are suggested to be important for this specific ingestion of apoptotic cells. Molecular Beacons For Analysis of Single Base-Pair Change: Simple Detection of Drug Resistance in Mycobacterium tuberculosis (11 September, 1998) Molecular beacons are a new type of reporters designed to detect short regions of DNA accurately, rapidly and simply. Molecular beacons here are single stranded DNA (25- to 30-mer) that possesses a loop complementary to the target sequence (H526Y mutation) of rpoB gene that gives rifampin resistance to M. tuberculosis. The assay was entirely in sealed PCR tubes and simple to perform and interpret, and importantly inexpensive for field test of the drug resistance. Similar molecular beacons should be used to detect common mutations for any physiologic aberrations and pathogenesis. HIV-1 Evolution and Chemokine Receptor Genotypes-Implication for AIDS Progression (25 August, 1998) Initial infection with HIV-1 is mediated by macrophage-tropic viruses and around the time of transition to AIDS; T cell-tropic viruses emerge due to phenotypic switch that are highly cytopathic. Specific immune responses are enhanced by the productive infection with M-tropic viruses, but blocked by T-tropic ones. Thus, when cytokine receptor CCR5 (more recently CCR2, also) that is a coreceptor with CD4 for HIV-1 and required for productive infection is mutated or missing, there results strong protection against virus transmission and/or a delay in disease progression. Functional Genomics and DNA Chips (25 July, 1998)As a post-genomics study, expression genetics of the genome dubbed as "functional genomics" has recently inspired the invention of several important techniques and their successful application for the analysis of differential gene expression in cells and tissues. The DNA chip is one that is very large-scale cDNA microarrays and used to analyze the expression of entire yeast genes in minimal and rich media. ESTs (expressed sequence tags) are also used for the comparative study of gene expression in cancer cells. These techniques are useful for the screening of anticancer agents. Nuclear Receptors--Orphan Receptors (10 July, 1998) Lipophilic ligands (steroid hormones, thyroid hormones, vitamin D3) bind to nuclear receptors to exert transcriptional stimulation. Among 47 nuclear receptor genes so far identified, only a few of the ligands for these nuclear receptors are known thus those without cogante ligands identified are termed as "orphan receptors. As the hormone is a most specific biological molecule, chances are that still unidentified ligands for orphan receptors are involved in essential physiological processes, aberration of which would lead to specific diseases. Pharmacogenomics:
Single Nucleotide Polymorphisms (SNPs) and
Personalized
Medicines
(9
June, 1998)
Pharmacogenomics is a field of molecular study of
genetic factors and genome-based backgrounds that
determine drug efficacy and toxicity in different
individuals. The analysis and accumulation of SNPs
in human genomes of different races should produce
fine SNP maps to assess the effects of genetic
polymorphisms on drug potency, kinetics and
toxicity, the information of which would lead to
personalized regimens in clinical
treatment.
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