Oritavancin: a new avenue for resistant Gram-positive bacteria

Oritavancin, a new semisynthetic glycopeptide has a spectrum of activity similar to vancomycin, although it exhibits potent antimicrobial activity against vancomycin-resistant staphylococci and enterococci species. It has a long-terminal half-life of 360 h, is highly protein bound and has been dosed once-daily in clinical trials. Oritavancin has been studied in complicated skin and skin structure infections where it was noninferior to the comparator group of vancomycin/cephalexin. Thus far, oritavancin has a favorable side-effect profile and appears promising in the treatment of multidrug resistant Gram-positive bacteria.     

Oritavancin: a new avenue for resistant Gram-positive bacteria

Oritavancin, a new semisynthetic glycopeptide has a spectrum of activity similar to vancomycin, although it exhibits potent antimicrobial activity against vancomycin-resistant staphylococci and enterococci species. It has a long-terminal half-life of 360 h, is highly protein bound and has been dosed once-daily in clinical trials. Oritavancin has been studied in complicated skin and skin structure infections where it was noninferior to the comparator group of vancomycin/cephalexin. Thus far, oritavancin has a favorable side-effect profile and appears promising in the treatment of multidrug resistant Gram-positive bacteria.     

Allosteric inhibition induces an open WPD-loop: a new avenue towards glioblastoma therapy

The mobility of loops around the catalytic site of a protein remains crucial to its activity. Dynamics of the WPD-loop is an essential determinant of the catalytic activity of tyrosine-protein phosphatase zeta, an implicated protein in glioblastoma cells. The WPD-loop assumes a closed conformation upon substrate binding in order to position its catalytic aspartate to participate in catalysis. Herein, we explore the impact of NAZ2329, a recently identified allosteric inhibitor of tyrosine-protein phosphatase zeta, on the atomic flexibility of the WPD-loop. The druglikeness of NAZ2329 was assessed using the SwissADME online tool. The enzymatic complex was then subjected to conformational simulations using the AMBER molecular dynamics software. Structural analysis revealed that NAZ2329 induced an open conformation of the crucial WPD-loop, consequently impeding enzyme activity even upon substrate binding. Based on the molecular interactions between NAZ2329 and tyrosine-protein phosphatase zeta, a pharmacophore model was generated to exhibit the important functional moieties of NAZ2329. These findings provide an insightful molecular and structural mechanism in targeting tyrosine-protein phosphatase zeta as a therapeutic intervention for glioblastoma. We believe that this optimized pharmacophoric model will aid in the design of improved anti-tyrosine phosphatase agents, thus allowing for increased patient adherence.

Structural mechanism of inhibition of NAZ2329 at the allosteric site of PTPRZ, with particular emphasis on the dynamics of the WPD-loop.     

Skp2 in the ubiquitin-proteasome system: A comprehensive review

The ubiquitin-proteasome system (UPS) is a complex process that regulates protein stability and activity by the sequential actions of E1, E2 and E3 enzymes to influence diverse aspects of eukaryotic cells. However, due to the diversity of proteins in cells, substrate selection is a highly critical part of the process. As a key player in UPS, E3 ubiquitin ligases recruit substrates for ubiquitination specifically. Among them, RING E3 ubiquitin ligases which are the most abundant E3 ubiquitin ligases contribute to diverse cellular processes. The multisubunit cullin-RING ligases (CRLs) are the largest family of RING E3 ubiquitin ligases with tremendous plasticity in substrate specificity and regulate a vast array of cellular functions. The F-box protein Skp2 is a component of CRL1 (the prototype of CRLs) which is expressed in many tissues and participates in multiple cellular functions such as cell proliferation, metabolism, and tumorigenesis by contributing to the ubiquitination and subsequent degradation of several specific tumor suppressors. Most importantly, Skp2 plays a pivotal role in a plethora of cancer-associated signaling pathways. It enhances cell growth, accelerates cell cycle progression, promotes migration and invasion, and inhibits cell apoptosis among others. Hence, targeting Skp2 may represent a novel and attractive strategy for the treatment of different human cancers overexpressing this oncogene. In this review article, we summarized the known roles of Skp2 both in health and disease states in relation to the UPS.     

Inhibition of the ubiquitin-proteasome activity prevents glutamate transporter degradation and morphine tolerance

Glutamate transporters play a crucial role in physiological glutamate homeostasis and neurotoxicity. Recently, we have shown that downregulation of glutamate transporters after chronic morphine exposure contributed to the development of morphine tolerance. In the present study, we examined whether regulation of the glutamate transporter expression with the proposed proteasome inhibitor MG-132 would contribute to the development of tolerance to repeated intrathecal (twice daily × 7 days) morphine administration in rats. The results showed that MG-132 (5 nmol) given intrathecally blocked morphine-induced glutamate transporter downregulation and the decrease in glutamate uptake activity within the spinal cord dorsal horn. Co-administration of morphine (15 nmol) with MG-132 (vehicle = 1 < 2.5 < 5 = 10 nmol) also dose-dependently prevented the development of morphine tolerance in rats. These findings suggest that prevention of spinal glutamate transporter downregulation may regulate the glutamatergic function that has been implicated in the development of morphine tolerance. The possible relationship between MG-132-mediated regulation of glutamate transporters, ubiquitin–proteasome system, and the cellular mechanisms of morphine tolerance is discussed in light of these findings.     

Health fairs: An avenue for colon health promotion in the community.

Colon cancer is the number two cause of cancer deaths in both men and women in the United States. Colon cancer is 90% treatable if diagnosed early, yet only 41% of Americans over age 50 who should be screened have been. Two of the reasons why so many people are not screened include the lack of public awareness about colorectal cancer and the need for regular screening, and the lack of social support for discussion of the "disease down there." GI nurses can use hospital, community, and university health fairs as an opportunity to educate their communities on the prevention of and screening for colon cancer. Suggestions are given on how to: be included in a health fair, set up the booth, obtain information to distribute, develop a display of educational materials, "hook" the audience, and educate attendees on a cancer prevention diet and exercise program. The American Cancer Society Screening Guidelines and factors that increase colon cancer risk are listed. A colon cancer screening questionnaire is included for attendees to take home, complete, and discuss with their private physicians. A health fair is presented as a fun way to promote the prevention of and screening for colon cancer.     

ATH-3, a new gene for atherosclerosis in the mouse

Mice derived from resistant A/J (A) and susceptible C57BL/6J (B) strains have been used to study the genetics of diet-induced atherosclerosis. A comparison of lesion scores between the parental strains, the F1 offspring of A x B and B x A matings and the offspring of (B x A)F1 hybrids backcrossed to either parent strain, indicates that a single major gene with alleles for resistance and susceptibility is responsible for the difference in response of A/J and C57BL/6J mice to a high fat, high cholesterol diet. By comparing the strain distribution pattern of susceptibility with known genetic markers in 30 A x B and B x A recombinant inbred (RI) strains, this gene, designated Ath-3, has been mapped close to a coat colour gene, c, on chromosome 7. Although a single gene may be primarily responsible for the difference in susceptibility to diet-induced atherosclerosis in these mice, the results of the breeding experiments indicate that its expression is probably modified by one or more additional genes.     

Community service: an avenue for nursing power

Directing volunteer nursing expertise and services can greatly benefit the community, the nursing profession, and the nurse. This article presents concepts of power from a nursing perspective and the benefits of directing nursing expertise into a community.     

A shot of good cholesterol: synthetic HDL, a new intervention for atherosclerosis

One of the American Heart Association's Top 10 Research Advances for the Treatment of Heart Disease is the use of a synthetic form of high-density lipoprotein (HDL) to reduce coronary atherosclerosis (JAMA. 2003;290:2292-2300). While HDL has not been a target for therapy for dyslipidemias, new insight into the major protein component of HDL, apolipoprotein A-I, may lead to new therapies. Apolipoprotein A-I was recently found to be a better predictor of cardiovascular events than is low-density lipoprotein (Am Heart J. 2003;146:227-233; J Intern Med. 2004;255:188-205). This article reviews the recent study by Nissen and colleagues describing the finding of a genetic mutation in HDL in some persons in Italy and the subsequent development of a synthetic form of HDL to be used as an infusion to successfully target atherosclerotic lesions (JAMA. 2003;290:2292-2300). In addition, controversies related to HDL cholesterol as a target for therapy are reviewed. Implications for nursing research, education, and practice are also described.     

Connexins: new genes in atherosclerosis

Atherosclerosis, the main cause of death and disability in adult populations of industrialized societies, is a multifactorial progressive process involving a variety of pathogenic mechanisms. Our current view on the pathogenesis of the disease implies complex patterns of interactions between a dysfunctional endothelium, leukocytes, and activated smooth muscle cells in which cytokines and growth factors are known to play a crucial role. Apart from paracrine cell-to-cell signalling, a role for gap junction-mediated intercellular communication in the development of the disease has been recently suggested. Gap junction channels result from the docking of two hemichannels or connexons, formed by the hexameric assembly of connexins, and directly connect the cytoplasm of adjacent cells. In this review, we summarize existing evidence implicating connexins in atherosclerosis. Indeed, the expression pattern of vascular connexins is altered during atherosclerotic plaque formation. In addition, changes in connexin expression or gap junctional communication have been observed in vascular cells in vitro by disturbances in blood flow, cholesterol, inflammatory cytokines, and growth factors. Furthermore, genetically modifying connexin expression affects the course of the atherosclerotic process in mouse models of the disease. Finally, the involvement of connexins in treatment of atherosclerotic disease will be discussed.