Letters in Drug Design & Discovery - Volume 3, Issue 9, 2006

Recent studies have identified a novel role for gut-derived peptides in the physiological regulation of appetite and body weight. This data is reviewed and the potential of peptide hormones, particularly ghrelin, PYY, GLP-1 and oxyntomodulin, as therapies for anorexia and obesity is explored.

In addition to CD4 and chemokine receptors glycosyl phosphatidylinositol-anchored proteins (GPIAPs) have been involved in the regulation of the human immunodeficiency virus (HIV) life cycle. In this article we will review the mechanisms underlying the anti-HIV activities regulated by GPI-APs and their ligands. Understanding how GPI-APs finely regulate HIV infection and replication may unravel novel and complementary strategies to combat and control HIV infection.

Though urinalysis is recognized as the criterion measure of recent drug use, oral fluid (OF) testing has emerged as a viable alternative with greater serviceability. Despite its emergence, research gaps remain. This essay summarizes the OF literature in social science settings and provides recommendations for future OF drug testing research.

Identification of naturally occurring compounds as potential anti-cancer chemotherapy drugs is a prominent research area. Simple dietary isothiocyanates have a spectrum of cellular targets including effects on ATP binding cassette (ABC) transporters, which mediate resistance to chemotherapy. Recent investigations have identified complex compounds, containing an isothiocyanate, which may be more specific inhibitors of ABC transporters.

A set of 24 descriptors consisting of quantum and chemical descriptors have been used to model binding constant (logK) of the benzene sulfonamides to human CAII. Simple as well as multiple regression have indicated that MNC (most negative charge) is the most dominating parameter to be used in modeling log K. Excellent results are obtained in multi-parametric regression. The results are critically discussed using a variety of statistics, which indicated that the hydrophobic term (log P) is not essential to yield excellent models.

With nanofabricated microfluidic systems, we studied the migration behaviors of two cell lines in vitro. Cells were allowed to migrate through areas of 15 mm in height, containing a microfluidic channel of 15 mm (height) by 15 mm (width) and 45 mm to 1cm in length. We observed that cells left their monolayer origin as individual cells to enter the entrance of the channel. After migration through the channel, the daughter cells resulting from the first division migrated away from each other to form two colonies. When each of the two colonies expanded into 32-cell colonies, the colonies disassociated into multiple small colonies. Our results indicate that cells can actively break off from the monolayer, and the dissociation of cells from each other is highly regulated. Future gene expression profiling study on cells prior and post disassociation should reveal genes that regulate the disassociation of cells from the monolayer. These genes are potential candidate genes which regulate cancer cells to leave the original tumor and become the metastasis. We demonstrated here that a microfluidic system can be a powerful means to study cell disassociation, which is a first step of cancer metastasis. Our system can be easily converted to an inexpensive high throughput device to screen drugs for inhibiting metastasis in the pharmaceutical industry.

Agrobacterium tumefaciens is a Gram-negative rod able to induce crown-gall-like tumors in the potato discs. The cytotoxicity of extracts from Tabebuia and Xetospongia spp. was evaluated using this model. Two out of the six extracts tested (dichloromethane- and partial methanol-soluble extracts of Xetospongias spp.) showed the highest biological activity.

The therapeutic efficacy of most pharmacological agents is generally established first in rodents and then in humans. To better extrapolate the effects of pharmacological agents in rodents to humans it is important to know how similar (or dissimilar) systems are between rodents and humans. This review examines the differences in the localization of the noradrenergic receptors in the hippocampus of humans and rodents. The differences in receptor localization could have major implications for the actions (or side effects) of noradrenergic agents in humans.

The relationship between the use of anti-hypertensive drugs and cancer risk remains controversial.The main objective of this study was to assess the effects of beta-blocker use on cancer risk. Methods:In a cohort of 839 patients with cardiovascular disease, followed up prospectively for a mean of 10years, we compared the risk of cancer in subjects who had and had not received beta-blockers. We estimated therelative risk of cancer associated with beta-blocker use with a Cox model adjusted for sex and age. The use ofbeta-blockers and the duration of exposure to the drug were analyzed as time-dependent variables. We alsocalculated standardized incidence ratios (SIR) from the corresponding age- and sex-adjusted cancer incidencesin the French general population. Results: A total of 326 beta-blocker users and 513 subjects on other treatments were included in the cohort.During the follow-up period, corresponding to 8,466 person-years, 15 incident cancer cases occurred in beta-blocker users and 59 occurred in patients who had never used beta-blockers. The Cox model estimated theoverall relative risk of cancer at 0.51 (95% confidence interval [CI]: 0.29-0.90) in the beta-blocker users,compared with those who had never used beta-blockers (p= 0.02), with a 6% decrease per year of use (95% CI:1%-12%p= 0.03). The corresponding SIR ratio between these two groups was 0.44 (CI: 0.24-0.76) Conclusion: In this cohort, beta-blocker treatments appeared to decrease the risk of cancer significantly.However, this result should be interpreted with caution, as biases inherent in this type of epidemiologicalstudy cannot be totally excluded.

Cell death by apoptosis is a fundamental mechanism for the maintenance of tissue homeostasis, activated to get rid of excess, damaged, or infected cells. It may be induced by several stimuli such as growth factor withdrawal, oxidative stress, drugs, or humoral mediators such as cytokines. The present study is focused on the cytotoxic activity of TNFα, a pleiotropic cytokine that promotes a variety of biological effects. TNFα cytotoxicity depends on the cell type and state. Although apoptosis (or type I cell death) has long been considered as the paradigm, various observations have stressed the possibility that TNFα-induced cell death may also develop with other features. Particularly interesting, in this regard, is the possibility that TNFα effects include stimulation of autophagy and/or induction of autophagic (type II) cell death. Aim of the present study has been to investigate if TNFα-induced death in cell types of different origin can bemodulated by interference with the autophagic process. The work has been performed on U937 (lymphoid), HT-29 (colon carcinoma), L929 (fibrosarcoma) and HTC (hepatoma) cell lines. All of them undergo apoptosis orapoptosis-like death in response to TNFα alone (U937, L929), or combined with transcription or translationinhibitors (HT-29, HTC). However, when TNFα is coupled with 3-methyladenine, a well known inhibitor of theautophagic process, the various cell lines show different behaviors: HTC cells are partially protected fromTNFα-induced death, whereas HT-29, L929 and U937 cells are sensitized, albeit to varying degrees, since thepercentage of apoptotic cells is higher than in cultures exposed to the cytokine alone. These results show that 3-methyladenine can modulate TNFα-induced death both positively and negatively,depending on the cell type. Moreover, they are consistent with the view that modulation of autophagy can berelevant to the design of therapeutic strategies aimed to reduce excess apoptosis, such as that occurring inacute hepatitis, or to enhance cell death in pathologies characterized by defective apoptosis, such as cancer.

Asthma is a chronic inflammatory disease of the airways associated with variable airflow obstruction and increased responsiveness to a variety of stimuli. Arachidonic acid metabolites play an important role in the pathophysiology of asthma and in this review we examine the major products of the lipoxygenase and cycloxygenase pathways, their effects on the airways and the current strategies used to target them.