Infectious Disorders - Drug Targets (Formerly Current Drug Targets - Infectious Disorders) - Volume 12, Issue 5, 2012

DNA polymerases pol IIIC and dnaE [i.e. pol IIIE] are essential for replicative DNA synthesis in low G:C Gram-positive eubacteria. Therefore, they have strong potential as targets for development of Gram-positive-selective antibacterial agents. This work has sought to extend to dnaE the recent discovery of antimicrobial agents based on pol IIICspecific dGTP analogs. Compound 324C, a member of the same dGTP analog family, was found to be a potent and selective inhibitor of isolated dnaE in vitro. Surprisingly, 324C had no inhibitory effect in either intact Bacillus subtilis cells or in permeabilized cell preparations used to assess replicative DNA synthesis directly. It is proposed that the failure of 324C in the intact cell is a consequence of two major factors: (i) its template-dependent base pairing mechanism, and (ii) a specific subordinate role which dnaE apparently plays to pol IIIC. To generate an effective dnaE-selective inhibitor of replicative DNA synthesis in Gram-positive bacteria, it will likely be necessary to develop a molecule that attacks the enzyme’s active site directly, without binding to template DNA.

Aims: Nephropathy is the leading secondary complication of metabolic syndrome. Nutritional supplement by chromium-picolinate is assumed to have renoprotective effects. However, potential toxic effects reported increase the concerns about the safety of chromium-picolinate. The experimental design aimed at determining, whether the treatment with clinically relevant doses of chromium-picolinate can harm individual oucomes through DNA damage and extensive alterations in central detoxification / cell-cycle regulating pathways in treatment of diabetes. Methods: The study was performed in a double-blind manner. Well-acknowledged animal model of db/db-mice and clinically relevant doses of chromium- picolinate were used. As an index of DNA-damage, measurement of DNA-breaks was performed using “Comet Assay”-analysis. Individual and group-specific expression patterns of SOD-1 and P53 were evaluated to get insights into central detoxification and cell-cycle regulating pathways under the treatment conditions. Results: Experimental data revealed highly individual reaction towards the treatment conditions. The highest variability of DNA-damage was monitored under the prolonged treatment with high dosage of CrPic. Expression patterns demonstrated a correlation with the subcellular imaging and dosage-dependent suppression under the chromium-picolinate treatment. Interpretation and recommendations: Population at-risk for diabetes is huge and increasing in pandemic scale. One of the reasons might be the failed attempt to prevent the disease by application of artificial supplements and drugs with hardly recognised individual risks. Consequently, a multimodal approach of integrative medicine by predictive diagnostics, targeted prevention and individually created treatment algorithms is highly desirable.

Gastric carcinogenesis, which may well extend over decades, is characterized by a slow stepwise evolution from superficial gastritis to glandular atrophy, intestinal metaplasia, dysplasia, and finally, adenocarcinoma. This sequence provides an excellent opportunity for the prevention or early detection of the events preceding development of the neoplasm. In 1994, the International Agency for Research on Cancer defined Helicobacter pylori (H. pylori) as a group I carcinogen for gastric cancer (GC). Evidence supporting a causal association has been demonstrated by epidemiological data as well as by experimental animal models. A meta-analysis has shown an higher risk (odds ratio: 1.92) of progression to GC in infected compare to uninfected subjects, that increased to a value >8 considering the surveys having a follow-up of more than 8 years. A crucial question remains whether and when precancerous lesions can reverse after H. pylori eradication. While several prospective studies have cast doubts about this reversibility others obtained opposing results. Currently, H. pylori is recognized as a necessary but insufficient cause of GC. The most accepted model of gastric carcinogenesis provides, like for other cancers, a multifactorial pathogenesis, linked with a number of initiators and other continuator agents. This review presents a multidisciplinary point of view to approaching the relationship between H. pylori infection and GC, focusing on the potential benefits of bacterial eradication in slowing down or in inducing regression of precancerous lesions.

Although Highly Active Anti-Retroviral Therapy (HAART) significantly reduced HIV/AIDS mortality, appropriate adherence level is recommended for viral suppression and therapeutic response in People Living with HIV/AIDS (PLWHA). In the most studies, adherence is defined as taking ≥95% of prescribed medications. Poor or non-adherence may lead to treatment failure and drug resistance. There is no golden standard for evaluation of adherence to medication and many measurement methods are used to assess adherence rate. Moreover, several determinants have been contemplated for adherence in different studies; however, the exact roles of some determinants are not well established. The goals of this review are to describe the adherence rates, to discuss the advantages and disadvantages of common adherence measurement methods, to examine significant correlations related to adherence and to recommend strategies for improving adherence in clinical care.

Scientific drug design enables the production of novel agents that may be specific for individual malaria species, particularly by targeting their methods of cellular entry. Though there are practical and theoretical barriers to introducing novel agents into clinical practice, there may also be theoretical benefits to encourage further investigation of such agents, including a reduction in the rate of development of falciparum resistance. This paper discusses the potential risks and benefits such agents using the example of CCR5 blockers, drugs which are already in use for HIV treatment, but may be able to block DARC, the site of Plasmodium vivax into the human red blood cell.

The presence of DNA and RNA circulating in human plasma and serum is described. The possible sources of the DNA/RNA in blood, their ability to enter other cells and to express in the recipient cells are discussed and the relationship with metastases considered. The possible role(s) of the DNA/RNA in clinical diagnosis, in monitoring treatment and in prognosis are considered for diabetes and oncology.

Malaria, one of the most deadly diseases of our time affects more than 200 million people across the globe and is responsible for about one million deaths annually. Until recently Plasmodium falciparum has been the main cause for malarial infection in human beings but now Plasmodium knowlesi from Malaysia remains as one of the most virulent parasite spreading fast not only in Malaysia but in different parts of the world. Hence there is urgent need for the global fight to control malaria. Global malaria eradication program by use of insecticide spraying has resulted in good response in the past. Treatment of malaria infected patients with anti-malarial drugs has helped to eliminate malarial infections successfully but with increased resistance displayed by malarial parasites to these drugs there is resurgence of malaria caused both by drug resistance as well as by infection caused by new malarial species like Plasmodium knowlesi. With recent advances on molecular studies on malarial parasites it is now clear that the pineal hormone melatonin acts as a cue for growth and development of Plasmodium falciparum. Same may be true for Plasmodium knowlesi also. Hence treatment modalities that can effectively block the action of melatonin on Plasmodium species during night time by way of using either bright light therapy or use of melatonin receptor blocking can be considered as useful approaches for eliminating malarial infection in man.

Bacterial pathogens can alter global host gene expression via histone modifications and chromatin remodeling in order to subvert host responses, including those involved with innate immunity, allowing for bacterial survival. Shigella flexneri, Listeria monocytogenes, Chlamydia trachomatis, and Anaplasma phagocytophilum express effector proteins that modify host histones and chromatin structure. A. phagocytophilum modulates granulocyte respiratory burst in part by dampening transcription of several key phagocyte oxidase genes. The A. phagocytophilum protein AnkA localizes to the myeloid cell nucleus where it binds AT-rich regions in the CYBB promoter and decreases its transcription. AT-rich regions of DNA are characteristic of matrix attachment regions (MARs) which are critical for chromatin structure and transcription. MAR-binding proteins, such as SATB1, interact with histone modifying enzymes resulting in altered gene expression. With A. phagocytophilum infection, histone deacetylase 1 (HDAC1) expression is increased and histone H3 acetylation is decreased at the CYBB promoter, suggesting a role for AnkA in altering host epigenetics and modulating gene transcription, at this, and perhaps other loci. This review will focus on how bacterial pathogens alter host epigenetics, by specifically examining A. phagocytophilum AnkA cis-regulation of CYBB transcription and epigenetic changes associated with infection.

There is an increasing global trend in cardiometabolic disorders being a leading cause of morbidity and mortality. Adverse dietary habits and sedentary lifestyles contribute to cardiovascular disease (CVD) and diabetes mellitus (DM). Dietary nutrients in nuts have attracted attention in recent literature due to their beneficial effects on CVD by attenuating lipid profiles, inflammation and oxidative stress. There is well-established evidence of the pharmacological properties of micronutrients that render them therapeutically effective in chronic inflammatory diseases. Although caution should be exercised in using antioxidant supplementation, antioxidant foods as dietary components play an important role in the management of cardiometabolic disorders. There is documented evidence of disease-modifying effects of nutritional compounds with anti-inflammatory and antioxidant effects. They have specific applications in ameliorating oxidative stress- induced inflammatory diseases such as DM and CVD. It is relevant that dietary components that influence risk of DM, have similar effects on inflammatory biomarkers of cardiovascular risk. Polyphenolic compounds such as flavonoids, isoflavones, phenolic acids and lignan contribute to increased plasma antioxidant capacity, decreased oxidative stress markers and reduced total and LDL cholesterol. They modulate genes associated with metabolism, stress defence, detoxification and transporter proteins. Their antioxidant and anti-inflammatory actions have specific applications for pathologies associated with chronic low-grade systemic inflammation that underpins progression of DM and CVD. Mechanisms involved depend on the structure of the compound, redox status of the inflammatory milieu and other interactions. Bioactive phytochemicals play an important therapeutic role in attenuating oxidative damage induced by metabolic syndrome associated with atherogenic dyslipidaemia and a pro-inflammatory, pro-thrombotic state, at a sub-cellular level. It would be critical to formulate optimal proportions and their combinations for therapeutic efficacy, based on synergistic interactions. Some of these mechanisms and potential actions are discussed.