Natural course of obesities

Obesity is a chronic disease. At the initial phase, behavioral and environmental factors play a key role in the constitution of adipose tIssue excess. Progressively biological alterations of adipose tIssue metabolism lead to some degree of irreversibility of the disease and contribute to the development of its metabolic and cardio-vascular complications.     

Is leptin the missing link between osteoarthritis and obesity?

The contribution of leptin, as a possible link between osteoarthritis (OA) and obesity, was studied in cartilage and synovial fluid samples obtained from osteoarthritic patients. Its effect on cartilage was evaluated in rats after intraarticular injections of leptin. Leptin levels were measured in the synovial fluid samples by enzyme linked immunosorbent assay; leptin concentrations were correlated with the body mass index. Leptin was strongly expressed in osteophytes and OA cartilage, while, in normal cartilage, few chondrocytes produced leptin. The level of leptin expression was related to the grade of cartilage destruction and was in good relation with those of growth factors as IGF1 and TGFb. Studies in rats showed that intraarticular leptin injection stimulated anabolic functions of chondrocytes and induced the synthesis of leptin, IGF1 and TGFB in cartilage at both the chondrocytes and induced the synthesis of leptin, IGF1 and TGFB in cartilage at both the mRNA and protein levels. In conclusion, leptin may be a link between osteoarthritis and obesity, and may play a key role in cartilage metabolism. Leptin may contribute to the pathophysiology of OA.     

New insights from structural biology into the druggability of G protein-coupled receptors

The recent availability of X-ray structures for diverse ligand-bound Family A G protein-coupled receptors (GPCRs) in multiple conformations (inactive form with an antagonist/inverse agonist bound and active form with an agonist bound) now enables rational drug design efforts that have historically been applied to soluble enzyme targets. Here, we review properties of these GPCR binding sites, using a unique combination of calculated physicochemical properties and water energetics (GRID, WaterMap and SZMAP) to provide a new perspective and rational assessment of druggability for each GPCR target binding site. Examples are described from several well-studied enzyme systems to support this advanced structure-based approach to assessing druggability and to contrast their properties with those of GPCRs. Changes in receptor conformations between the GPCR inactive and active forms evident from the protein structures are discussed, yielding important pointers for rational drug design of antagonists and agonists and a better understanding of GPCR activation.     

Emerging insights into the molecular biology of brain metastases

One of the foremost challenges in oncology is developing improved therapies for preventing and treating metastases to the brain. Recent research in this area is bringing about a shift in the understanding of brain metastases. Previously, the occurrence and poor outcomes associated with brain metastases have been largely attributed to the exclusion of anticancer drugs from the brain by the blood-brain barrier (BBB). However, studies in multiple tumor types have also demonstrated that brain metastases have significant molecular differences from primary tumors and extracranial metastases. These molecular differences may not only promote the formation of brain metastases, but they may also contribute to these tumors' poor responsiveness to therapies. Such changes may be intrinsic to the cancer cells or driven by unique interactions with the brain microenvironment. An improved understanding of the molecular characteristics of brain metastases that contribute to their aggressive behaviors will facilitate the development of rational, more effective treatments for these tumors.     

New insights into inflammatory resolution

Acute inflammatory reactions are usually self-limiting and resolve quite rapidly with complete removal of the injurious agent and little incidence of tissue damage. Chronic inflammatory reactions, on the other hand, fail to resolve and persist for long periods of time with varying levels of tissue injury. To identify the 'stop signals' that switch off acute inflammation and that may be absent or inactivated during the development of a chronic lesion, is of enormous interest. Using the experimental model of carrageenin-induced inflammation in the rat we have identified the need for the expression of inducible cyclooxygenase and its synthesis of the cycloopentenone prostaglandins for effective resolution in this model; inhibition of this cyclooxygenase prevented exudate and inflammatory cell clearance. Herein, we describe these findings and suggest a possible mechanism by which inducible cyclooxygenase derived cyclopentenone prostaglandins may be exerting their antiinflammatory effects during resolution.     

窦道伤口护理新见解

窦道是伤口处理难题,其处理方法也不胜枚举,全文介绍目前窦道护理的常用处理方法,并结合临床护理经验,提出见解,为临床窦道处理提供参考。     

New insights into the role of cytochrome P450 reductase (POR) in microsomal redox biology

Cytochrome P450 reductase (POR) is an essential electron transfer protein located on the endoplasmic reticulum of most cell types, and has long been appreciated for its role in cytochrome P450-mediated drug metabolism. Additional roles and electron acceptors for POR have been described, but it is largely with the recent availability of POR-null tissues that these supplemental roles for POR have been able to be explored. These studies have confirmed POR as the principal redox partner for the microsomal P450s responsible for drug and xenobiotic metabolism as well as cholesterol and bile acid synthesis, and for heme oxygenase, which catalyzes the initial step in the breakdown of heme. Surprisingly, these studies have revealed that squalene monooxygenase, an enzyme essential to cholesterol synthesis, has a second unknown redox partner in addition to POR, and that 7-dehydrocholesterol reductase, previously proposed to require POR as an electron donor, functions fully independently of POR. These studies have also helped define the role of cytochrome b₅ in P450 catalysis, and raise the question as to the extent to which POR contributes to b₅-dependent redox pathways.     

New insights into the second generation antihistamines

Second generation antihistamines are recognised as being highly effective treatments for allergy-based disease and are among the most frequently prescribed and safest drugs in the world. However, consideration of the therapeutic index or the benefit/risk ratio of the H1 receptor antagonists is of paramount importance when prescribing this class of compounds as they are used to treat non-life threatening conditions. There are many second generation antihistamines available and at first examination these appear to be comparable in terms of safety and efficacy. However, the newer antihistamines in fact represent a heterogeneous group of compounds, having markedly differing chemical structures, adverse effects, half-life, tissue distribution and metabolism, spectrum of antihistaminic properties, and varying degrees of anti-inflammatory effects. With regard to the latter, there is growing awareness that some of these compounds might represent useful adjunct medications in asthma therapy. In terms of safety issues, the current second generation grouping includes compounds with proven cardiotoxic effects and others with the potential for adverse drug interactions. Moreover, some of the second generation H1 antagonists have given cause for concern regarding their potential to cause a degree of somnolence in some individuals. It can be argued, therefore, that the present second generation grouping is too large and indistinct since this was based primarily on the concept of separating the first generation sedating compounds from nonsedating H1 antagonists. Although it is too early to talk about a third generation grouping of antihistamines, future membership of such a classification could be based on a low volume of distribution coupled with a lack of sedating effects, drug interactions and cardiotoxicity.     

New insights into mechanisms of statin-associated myotoxicity

Statin drugs represent a major improvement in the treatment of hypercholesterolemia that constitutes the main origin of atherosclerosis, leading to coronary heart disease. Besides the tremendous beneficial effects of statins, various forms of muscular toxicity (myalgia, cramp, exercise intolerance, fatigability) occur frequently. Many hypotheses were proposed to explain statin myotoxicity. The goal of this review is to highlight some of the most recent findings that can account for interpreting the pathophysiological mechanisms for statin-induced myotoxicity. Statin-induced myotoxicity appears multifactorial. Apart from the deleterious effect due to a reduction in cholesterol biosynthesis, statins have a direct effect on the respiratory chain of the mitochondria. It is proposed that mitochondrial impairment leads to a mitochondrial calcium leak that directly interferes with the regulation of sarcoplasmic reticulum calcium cycling without excluding a direct effect of statin on the sarcoplasmic reticulum. Both mitochondrial and calcium impairments may account for apoptosis process, oxidative stress, and muscle remodeling and degeneration that have been extensively reported to explain statin myotoxicity and functional symptoms described by treated patients.     

New insights into imiquimod's mechanisms of action

Imiquimod, an immune response modifier with potent antiviral and antitumor properties, has been reported to be effective in the treatment of various cutaneous neoplasms. Besides stimulating the production of pro-inflammatory cytokines through Toll-like receptors on the surface of dendritic cells of monocyte-macrophage lineage, novel antiapoptotic mechanisms have been identified.     

New insights into the Ca2+-ATPases that contribute to cadmium tolerance in yeast

Cadmium (Cd²⁺) is a toxic heavy metal which triggers several toxic effects in eukaryotes, including neurotoxicity and impaired calcium metabolism. In the model organism Saccharomyces cerevisiae, the best characterized pathway for Cd²⁺ detoxification involves conjugation with glutathione (GSH) and subsequent transport to vacuoles by Ycf1p, an ATPase homologous to human MRP1 (Multidrug resistance associated protein 1). However, Cd²⁺ tolerance also can be mediated by Pmr1p, a Ca²⁺ pump located in the Golgi membrane, possibly through to the secretory pathway. Herein, we showed that inactivation of the PMR1 gene, alone or simultaneously with YCF1, delayed initial Cd²⁺ capture compared to wild-type (WT) cells. In addition, Cd²⁺ treatment altered the expression profile of yeast internal Ca²⁺ transporters; specifically, PMC1 gene expression is induced substantially by the metal in WT cells, and this induction is stronger in mutants lacking YCF1. Taken together, these results indicate that, in addition to Pmr1p, the vacuolar Ca²⁺-ATPase Pmc1p also helps yeast cells cope with Cd²⁺ toxicity. We propose a model where Pmc1p and Pmr1p Ca²⁺-ATPase function in cooperation with Ycf1p to promote Cd²⁺ detoxification.     

New insights into seaweed polyphenols on glucose homeostasis

Abstract

Context: Polyphenol-rich marine macroalgae are gaining dietary importance due to their influence over diabetes mellitus and the role as a vital source of high-value nutraceuticals. Their assorted beneficial effects on human health include competitive inhibition of digestive enzymes, varying the activity of hepatic glucose-metabolizing enzymes, lowering the plasma glucose levels, and lipid peroxidation, delaying the aging process.

Objective: In this paper, we review the health beneficial effects of polyphenols and phlorotannins from brown seaweeds with special emphasis on their inhibitory effects on carbohydrate-metabolizing enzymes.

Methods: A survey of literature from databases such as Sciencedirect, Scopus, Pubmed, Springerlink, and Google Scholar from the year 1973 to 2013 was done to bring together the information relating to drug discovery from brown seaweeds as a source for diabetes treatment.

Results: Over the past two decades, 20 different bioactive polyphenols/phlorotannins have been isolated and studied from 10 different brown algae. Discussion of the positive effect on the inhibition of enzymes metabolizing carbohydrates in both in vitro and in vivo experiments are included.

Conclusion: Despite the recent advancements in isolating bioactive compounds from seaweeds with potential health benefit or pharmaceutical behavior, studies on the polyphenol effectiveness on glucose homeostasis in human beings are very few in response to their functional characterization. Added research in this area is required to confirm the close connection of polyphenol rich seaweed-based diet consumption with glucose homeostasis and the exciting possibility of prescribing polyphenols to treat the diabetes pandemic.     

New insights into molecular targets for urinary incontinence

Urinary incontinence (UI) is a disease affecting quality of life of 200 million patients worldwide. It is characterized by involuntary loss of urine. The factors involved are cystitis, detrusor hyperreflexia, spinal injury, benign prostatic hyperplasia, etc. The surge in the number of reviews on this subject indicates the amount of research devoted to this field. The prevalence is increasing at an alarming rate but unfortunately, only a few medications are currently available for this condition. There are peripheral as well as central targets including cholinergic, vanilloid, prostaglandin, kinin, calcium channel, cannabinoid, serotonin, and GABA-receptors, which act by different mechanisms to treat different types of incontinence. Drugs acting on the central nervous system (CNS) increase urinary bladder capacity, volume, or pressure threshold for micturition reflex activation while peripherally acting drugs decrease the amplitude of micturition contraction and residual volume. Anticholinergic drugs specifically M3 receptor antagonists are the first choice but have frequent side effects such as dry mouth, CNS disturbances, etc. Therefore, there is a need to understand the biochemical pathways that control urinary dysfunction to determine the potential to which they can be exploited in the treatment of this condition. This article reviews the central and peripheral molecular targets and the potential therapeutic approaches to the treatment of UI.     

Transglutaminase: New insights into gelatin nanoparticle cross-linking

Gelatin nanoparticles (GNPs) have demonstrated to be beneficial as a biodegradable and biocompatible delivery system. So far, nanoparticles prepared by the two-step desolvation technique were subsequently cross-linked by glutaraldehyde to guarantee storage stability. Although in vivo and in vitro toxicological studies have not revealed any glutaraldehyde related undesired effects, an alternative to chemical cross-linking could ease future clinical use in humans. Therefore, the recombinant enzyme microbial transglutaminase was used to examine its cross-linking abilities in nanoparticle production. Various process parameters, such as incubation time, temperature, medium, pH and the particle purification were evaluated regarding their impact on particle size and its distribution. Cross-linking reactions were best at 25°C using an ion-free solvent at a neutral pH and have been terminated after 12?h. Preliminary storage stability testing indicated adequate consistency of particle size and particle distribution making transglutaminase a potential candidate for glutaraldehyde substitution in future GNP production.