The role of NPY in metabolic homeostasis: implications for obesity therapy

Neuropeptide Y (NPY) is a 36 amino acid amidated peptide which has now emerged as an important regulator of feeding behaviour. Upon intracerebroventricular (icv.) administration, NPY produces a pronounced feeding response in a variety of species. The actions of NPY are believed to be mediated by a family of receptor subtypes named Y1 - y6. Recent studies suggest that the Y1 and Y5 receptor subtypes are intimately involved in NPY induced feeding. This review presents preclinical data obtained with receptor subtype selective agonists and antagonists as well as findings from knockout mice. These new data suggest that NPY receptor antagonists may become an additional option for treating human obesity.     

The role of dopamine in motivation for food in humans: implications for obesity

Obesity is a major public health problem. The increasing number of obese individuals in the US adds urgency to the efforts to understand the mechanisms underlying pathological overeating. Imaging studies using positron emission tomography implicate the involvement of brain dopamine (DA) in normal and pathological food intake in humans. In normal body weight, fasting subjects, food presentation that could not be consumed was associated with increases in striatal extracellular DA, which provides evidence of an involvement of DA in non-hedonic motivational properties of food intake. In pathologically obese subjects, the authors showed reductions in striatal D2 receptor availability that were inversely associated with the weight of the subject. The involvement of the DA system in reward and reinforcement has led to the hypothesis that low brain DA activity in obese subjects predisposes them to excessive use of food. A better understanding of the role of the DA system in the motivation for food intake will help the development of better therapeutic interventions.     

The role of angiotensin in obesity and metabolic disease

Obesity is associated with increased body fat composition and elevated risk of metabolic and cardiovascular disease. The activity of the renin-angiotensin system is generally increased in obesity and experimental evidence has shown that angiotensin influences appetite and metabolism as well as mechanisms that induce adipose tissue growth and metabolism in peripheral organs. This review summarises some of the key evidence from animal and human experiments that links the renin-angiotensin system to obesity and metabolic disease. This research has been greatly aided by the continuing development of new pharmaceuticals that inhibit the renin-angiotensin system. While their primary use is in the treatment of hypertension and heart failure, a range of experimental and clinical evidence indicates their potential use in the treatment of obesity and metabolic disease.     

Effects of obesity on pharmacokinetics implications for drug therapy

Obesity is a worldwide problem, with major health, social and economic implications. The adaptation of drug dosages to obese patients is a subject of concern, particularly for drugs with a narrow therapeutic index. The main factors that affect the tissue distribution of drugs are body composition, regional blood flow and the affinity of the drug for plasma proteins and/or tissue components. Obese people have larger absolute lean body masses as well as fat masses than non-obese individuals of the same age, gender and height. However, the percentage of fat per kg of total bodyweight (TBW) is markedly increased, whereas that chrome P450 isoforms are altered, but no clear overview of drug hepatic metabolism in obesity is currently available. Pharmacokinetic studies provide differing data on renal function in obese patients. This review analyses recent publications on several classes of drugs: antibacterials, anticancer drugs, psychotropic drugs, anticonvulsants, general anaesthetics, opioid analgesics, neuromuscular blockers, beta-blockers and drugs commonly used in the management of obesity. Pharmacokinetic studies in obesity show that the behaviour of molecules with weak or moderate lipophilicity (e.g. lithium and vecuronium) is generally rather predictable, as these drugs are distributed mainly in lean tissues. The dosage of these drugs should be based on the ideal bodyweight (IBW). However, some of these drugs (e.g. antibacterials and some anticancer drugs) are partly distributed in adipose tissues, and their dosage is based on IBW plus a percentage of the patient's excess bodyweight. There is no systematic relationship between the degree of lipophilicity of markedly lipophilic drugs (e.g. remifentanil and some beta-blockers) and their distribution in obese individuals. The distribution of a drug between fat and lean tissues may influence its pharmacokinetics in obese patients. Thus, the loading dose should be adjusted to the TBW or IBW, according to data from studies carried out in obese individuals. Adjustment of the maintenance dosage depends on the observed modifications in clearance. Our present knowledge of the influence of obesity on drug pharmacokinetics is limited. Drugs with a small therapeutic index should be used prudently and the dosage adjusted with the help of drug plasma concentrations.     

Role of ARC NPY neurons in energy homeostasis

Neuropeptide Y (NPY) is one of the most abundant and widely distributed neurotransmitters in the mammalian brain and appears to be an important regulatory peptide in both the central and peripheral nervous systems. The arcuate nucleus (ARC) is the major site of expression for NPY within neurons in the hypothalamus. The most noticeable effect of NPY is the stimulation of feeding. To date, six NPY receptor subtypes have been cloned and pharmacologically characterized, and there is evidence for further NPY receptor subtypes. The recent isolation and cloning of a rat NPY receptor with the required pharmacology for the feeding response, called the Y(5) receptor, has led to the suggestion that this is the "feeding" receptor. There is, however, still controversy as to whether the Y(5) receptor represents the true "feeding" receptor, since selective Y(1) receptor antagonists are capable of antagonizing NPY-induced hyperphagia. It also is possible that another, as yet unidentified, NPY receptor subtype(s) may mediate the effects of NPY on energy balance. The potency and behavioral specificity of NPY on feeding and its ability to induce obesity, together with the evidence that ARC-NPY neurons operate homeostatically to counteract energy deficits, all suggest that the ARC-PVN projection is important in regulating energy balance. The next few years will tell us whether or not these important physiological lessons will be successfully translated into a safe and effective form of therapy for human obesity.     

The role of beta-amyloid protein in synaptic function: implications for Alzheimer's disease therapy

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive and irreversible loss of memory and other cognitive functions. Substantial evidence based on genetic, neuropathological and biochemical data has established the central role of beta-amyloid protein (betaAP) in this pathology. Although the precise etiology of AD is not well understood yet, strong evidence for some of the molecular events that lead to progressive brain dysfunction and neurodegeneration in AD has been afforded by identification of biochemical pathways implicated in the generation of betaAP, development of transgenic models exhibiting progressive disease pathology and by data on the effects of betaAP at the neuronal network level. However, the mechanisms by which betaAP causes cognitive decline have not been determined, nor is it clear if the degree of dementia correlates in time with the degree of neuronal loss. Hence, it is of interest to understand the biochemical processes involved in the mechanisms of betaAP-induced neurotoxicity and the mechanisms involved in electrophysiological effects of this protein on different parameters of synaptic transmission and on neuronal firing properties. In this review we analyze recent evidence suggesting a complex role of betaAP in the molecular events that lead to progressive loss of function and eventually to neurodegeneration in AD as well as the therapeutic implications based on betaAP metabolism inhibition.     

The MCM complex: its role in DNA replication and implications for cancer therapy

The MCM complex controls the once per cell cycle DNA replication in eukaryotic cells. In a process known as DNA replication licensing, it primes chromatin for DNA replication by binding origins of DNA replication during the late M to early G1 phase of the cell cycle. Activated by S phase promoting protein kinases, the origin-bound MCM complexes unwind the double stranded DNA at the origins, recruit DNA polymerases and initiate DNA synthesis. Coupled with the initiation of DNA replication in the S phase, the MCM complexes move away from replication origins as a component of the DNA replication fork, likely serving as DNA helicases. Their departure deprives replication origins the ability to re-initiate DNA replication for the reminder of the cell cycle. Because of its vital role in genome duplication in proliferating cells, deregulation of the MCM function results in chromosomal defects that may contribute to tumorigenesis. The MCM proteins are highly expressed in malignant human cancers cells and pre-cancerous cells undergoing malignant transformation. They are not expressed in differentiated somatic cells that have been withdrawn from the cell cycle. Therefore, these proteins are ideal diagnostic markers for cancer and promising targets for anti-cancer drug development. In this article, I will overview the structures and functions of the MCM complex with an effort to integrate insights from recent biochemical and structural studies. Discussions will also cover activities and structures of the complex that may be useful for the development of drug screens.     

Microvascular responsiveness in obesity: implications for therapeutic intervention

Obesity has detrimental effects on the microcirculation. Functional changes in microvascular responsiveness may increase the risk of developing cardiovascular complications in obese patients. Emerging evidence indicates that selective therapeutic targeting of the microvessels may prevent life-threatening obesity-related vascular complications, such as ischaemic heart disease, heart failure and hypertension. It is also plausible that alterations in adipose tissue microcirculation contribute to the development of obesity. Therefore, targeting adipose tissue arterioles could represent a novel approach to reducing obesity. This review aims to examine recent studies that have been focused on vasomotor dysfunction of resistance arteries in obese humans and animal models of obesity. Particularly, findings in coronary resistance arteries are contrasted to those obtained in other vascular beds. We provide examples of therapeutic attempts, such as use of statins, ACE inhibitors and insulin sensitizers to prevent obesity-related microvascular complications. We further identify some of the important challenges and opportunities going forward. LINKED ARTICLES: This article is part of a themed section on Fat and Vascular Responsiveness. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue-3.     

The role of neuropeptide Y in energy homeostasis

When administered into the brain, NPY acts at Y1 and Y5 receptors to increase food intake. The response occurs with a short latency and is quite robust, such that exogenous NPY is generally considered to be the most potent of a growing list of orexigenic compounds that act in the brain. The role of endogenous NPY is not so straightforward, however. Evidence from diverse types of experiments suggests that rather than initiating behavioral eating per se, endogenous NPY elicits autonomic responses that prepare the individual to better cope with consuming a calorically large meal.     

Acid ceramidase upregulation in prostate cancer: role in tumor development and implications for therapy

Bioactive sphingolipids, such as ceramide, sphingosine and sphingosine-1-phosphate are known bio-effector molecules which play important roles in various aspects of cancer biology including cell proliferation, growth arrest, apoptosis, metastasis, senescence and inflammation. Therefore, enzymes involved in ceramide metabolism are gaining recognition as being critical regulators of cancer cell growth and/or survival. We previously observed that the ceramide metabolizing enzyme, acid ceramidase (AC) is upregulated in tumor tissues. Studies have now concluded that this creates a dysfunctional ceramide pathway, which is responsible for tumor progression and resistance to chemotherapy and radiation. This suggests that development of small-molecule drugs that inhibit AC enzyme activity is a promising approach for improving standard cancer therapy and patient’s clinical outcomes.     

减重手术治疗肥胖症近期疗效的分析

目的 探讨减重手术治疗肥胖症的临床疗效及其安全性.方法 回顾分析14例行腹腔镜袖状胃切除术(LSG)及腹腔镜胃转流术(LGBP)治疗肥胖症病人的临床资料,随访时间6个月.结果 14例手术均在腹腔镜下顺利完成,无中转开腹和术中并发症发生.经过术后6个月随访,14例病人术后1、3、6个月腹围、体质量及体质量指数较术前均不断下降,均差异有统计学意义(P<0.01).术后1、3及6个月额外体质量减轻百分率分别为(43.90±13.16)%,(67.62±18.21)%,(86.66±22.05)%.高脂血症、高血压及2 型糖尿病等肥胖相关并发症发生率显著降低(P<0.05).结论 LSG和LGBP治疗肥胖症及其合并症短期内安全有效,远期疗效有待进一步随访及观察.     

Investigating the cellular targets of HIV protease inhibitors: implications for metabolic disorders and improvements in drug therapy

The use of HIV protease inhibitors (PIs) may be associated with serious adverse side effects that include fat tissue redistribution, hyperlipidemia, and insulin resistance. The etiology of this toxic metabolic syndrome (commonly referred to as 'HIV lipodystrophy syndrome') remains to be elucidated. The interpretation of available clinical data on this subject is complicated in part by the pervasiveness of potential confounding factors that cannot be easily eliminated or adequately controlled. Numerous investigators have examined the effects of PIs on cellular processes in model systems amenable to extensive experimental manipulations; the present review primarily focuses on these efforts. The ultimate goal is the unambiguous identification of discrete cellular targets being surreptitiously impacted by PIs. SREBP and Glut4 are discussed as candidate target molecules in this context. The identification of cellular factors interacting with PIs represents a necessary first step in devising rational strategies for improvement in drug therapy.     

Medical therapy for obesity

Obesity results from a prolonged small positive energy imbalance, and treatment needs to reverse this imbalance. Many different diets have been tried to treat obesity, and weight loss occurs with all of them. There is currently no evidence that supports the superiority of one macronutrient composition for diets over any other. The principal effect seems to be the degree of adherence to the prescribed calorie reduction. Obesity drugs have been developed that tap brain mechanisms for controlling feeding and the gastrointestinal tract and its peptides. Orlistat blocks intestinal lipase and produces modest weight loss. Sibutramine is a serotonin-norepinephrine reuptake inhibitor that has a warning on its label from the US Food and Drug Administration because of cardiovascular risk. Its marketing has been suspended in Europe. Several drug combinations are on the horizon for treatment of obesity.     

The eotaxins in asthma and allergic inflammation: implications for therapy

Evidence is emerging for an important role for the CC chemokines, particularly the eotaxins, in the pathogenesis of asthmatic and allergic inflammation. This article reviews the evidence for this involvement and describes new approaches to therapeutics that are evolving as a result.     

The role of phosphodiesterases in schizophrenia : therapeutic implications

Recent studies have suggested that currently available antipsychotic medications, while useful in treating some aspects of schizophrenia, still possess considerable limitations. Improving the treatment of negative symptoms and cognitive dysfunction, and decreasing adverse effects remain significant challenges. Many new drug strategies have been proposed in recent years and increasing evidence suggests that members of the phosphodiesterase (PDE) gene family may play a role in the aetiology or treatment of schizophrenia. PDEs are key enzymes responsible for the degradation of the second messengers cAMP (3',5'-cyclic adenosine monophosphate) and cGMP (3',5'-cyclic guanosine monophosphate). Mammalian PDEs are composed of 21 genes and are categorized into 11 families based on sequence homology, enzymatic properties and sensitivity to pharmacological inhibitors. Representatives from most families have been identified in the brain by the presence of protein or RNA, and numerous studies suggest that PDEs play an important role in the regulation of intracellular signalling downstream of receptor activation in neurons. Insights into the multiple brain processes to which PDEs contribute are emerging from the phenotype of genetically engineered mice that lack activity of specific PDEs (knockout mice), as well as from in vitro and in vivo studies with PDE inhibitors.This article provides a brief overview of recent studies implicating PDE inhibition, focusing on PDE4 and PDE10, as targets for treating the positive, negative or cognitive symptoms associated with schizophrenia.     

Pharmacists' role in targeted cancer therapy in Australia and implications for pharmacy education

Objectives

To investigate the pharmacists'' role in providing targeted therapies to patients and its implications for pharmacy education.

Methods

Nine pharmacy faculty members, 12 clinical pharmacists, and 4 oncologists from across Australia and New Zealand participated in semistructured interviews, which were analysed using the framework method.

Results

Education about targeted therapies was seen as being important, although content about pharmacodiagnostic tests was taught inconsistently among 7 universities. Issues including funding, clinical and diagnostic validity of tests, and time taken for turnaround of tests were perceived as impediments to the acceptance by clinicians of the utility of pharmacodiagnostic tests.

Conclusions

Pharmacists may be the ideal professionals to interpret test results and provide counselling for patients to assist them in compliance with targeted cancer therapies. Pharmacy education in cancer therapies is critical to training pharmacists who can assist patients in the correct use of these therapies.     

肾脏在血糖调节中的重要作用

肾脏是人体最重要的排泄器官，在调节水、电解质和酸碱平衡方面起着举足轻重的作用。肾脏对葡萄糖处理的失调可能是导致2型糖尿病血糖紊乱的重要机制之一。因此，抑制肾脏对葡萄糖的重吸收作用成为治疗2型糖尿病新靶点。