Insulin requirement for the antihyperglycaemic effect of metformin.

1. Insulin-dependent diabetic BB/S rats with little or no endogenous insulin were used to determine whether insulin is required for the acute antihyperglycaemic effect of metformin (dimethylbiguanide). 2. Metformin (250 mg kg-1, intrajejunally) did not lower the hyperglycaemia in BB/S rats in the absence of exogenous insulin, but metformin increased by 69% (P < 0.05) the blood glucose-lowering effect of exogenous insulin. 3. Metformin (250 mg kg-1, intrajejunally) improved glucose disposal in rats with a normal insulin response to an intravenous glucose challenge. Plasma glucose disappearance was increased from 0.7 +/- 0.1 to 2.5 +/- 0.1% min-1 (P < 0.05). 3. When the insulin response to glucose was suppressed with somatostatin and diazoxide, metformin improved glucose disposal to a similar extent to that in rats with a normal insulin response. Plasma glucose disappearance was increased from 0.24 +/- 0.02 to 1.0 +/- 0.1% min-1 (P < 0.01). 5. The results indicate that insulin is required for the acute antihyperglycaemic effect of metformin, but the extent of this effect is not proportional to the prevailing insulin concentration.     

The effect of therapeutic hypothermia on drug metabolism and response: cellular mechanisms to organ function

INTRODUCTION: Therapeutic hypothermia is being employed clinically due to its neuro-protective benefits. Both critical illness and therapeutic hypothermia significantly affect drug disposition, potentially contributing to drug-therapy and drug-disease interactions. Currently, there is limited information on the known alterations in drug concentration and response during mild hypothermia treatment, and there is a limited understanding of the specific mechanisms that underlie alterations in drug concentrations and the potential clinical importance of these changes. AREAS COVERED: A systemic review of the effect of therapeutic hypothermia on drug metabolism, disposition and response is provided. Specifically, the clinical and preclinical evidence of the effects of therapeutic hypothermia on blood flow, specific hepatic metabolism pathways, transporter function, renal excretion, pharmacodynamics and the effects during rewarming are reviewed. EXPERT OPINION: Available evidence demonstrates that mild hypothermia decreases the clearance of a variety of drugs with apparently little change in drug-protein binding. Recent evidence suggests that the magnitude of the change is elimination route specific. Further research is needed to determine the impact of these alterations on both drug concentration and response in order to optimize the therapeutic hypothermia in this vulnerable patient population.     

Alzheimer's disease and inflammation: a review of cellular and therapeutic mechanisms

1. Of the neurodegenerative diseases that cause dementia, Alzheimer's disease (AD) is the most common. Three major pathologies characterize the disease: senile plaques, neurofibrillary tangles and inflammation. We review the literature on events contributing to the inflammation and the treatments thought to target this pathology. 2. The senile plaques of AD consist primarily of complexes of the beta-amyloid protein. This protein is central to the pathogenesis of the disease. 3. Inflammatory microglia are consistently associated with senile plaques in AD, although the classic inflammatory response (immunoglobulin and leucocyte infiltration) is absent. beta-Amyloid fragments appear to mediate such inflammatory mechanisms by activating the complement pathway in a similar fashion to immunoglobulin. 4. Epidemiological studies have identified a reduced risk of AD in patients with arthritis and in leprosy patients treated with anti-inflammatory drugs. Longitudinal studies have shown that the consumption of anti-inflammatory medications reduces the risk of AD only in younger patients (< 75 years). 5. There is a considerable body of in vitro evidence indicating that the inflammatory response of microglial cells is reduced by non-steroidal anti-inflammatory drugs (NSAID). However, no published data are available concerning the effects of these medications on brain pathology in AD. 6. Cyclo-oxygenase 2 enzyme is constitutively expressed in neurons and is up-regulated in degenerative brain regions in AD. Non-steroidal anti-inflammatory drugs may reduce this expression. 7. Platelets are a source of beta-amyloid and increased platelet activation and increased circulating beta-amyloid have been identified in AD. Anti-platelet medication (including NSAID) would prevent such activation and its potentially harmful consequences. 8. Increased levels of luminal beta-amyloid permeabilizes the blood-brain barrier (BBB) and increases vasoconstriction of arterial vessels, paralleling the alterations observed with infection and inflammation. Cerebral amyloidosis is highly prevalent in AD, compromising the BBB and vasoactivity. Anti-inflammatory medications may alleviate these problems.     

Cellular and molecular mechanisms of vascular injury in diabetes--part II: cellular mechanisms and therapeutic targets

Although the mechanisms by which insulin-resistance and hyperglycemia lead to cardiovascular disease are still incompletely understood, all mechanisms apparently converge on the vessel wall and the endothelium as a common disease target. Endothelial cells play a crucial role in vascular homeostasis, providing a functional barrier and modulating several signals involved in vasomotion, as well as antiplatelet, anti-inflammatory, anti-proliferative, and anti-oxidant properties of the vessel wall. Endothelial cell dysfunction occurs early in diabetes and insulin resistance states. Since atherosclerosis may result from an imbalance between the magnitude of vascular injury and the capacity of repair, a role has been recently postulated for a defective mobilization of vascular progenitors, including endothelial progenitor cells, in the pathogenesis of vascular disease. Here we summarize the evidence for such an occurrence. We also here highlight how new insights into pathways of vascular damage in diabetes may indicate new targets for preventive and treatment strategies.     

The role of AMPK-dependent pathways in cellular and molecular mechanisms of metformin: a new perspective for treatment and prevention of diseases

Inflammopharmacology - Metformin can suppress gluconeogenesis and reduce blood sugar by activating adenosine monophosphate-activated protein kinase (AMPK) and inducing small heterodimer partner...     

The Urocortins: mechanisms of cardioprotection and therapeutic potential

The study of the Urocortin family of peptides is becoming increasingly important clinically, as new discoveries have revealed that their roles in the body are extremely diverse. They range from being involved in the aetiology of affective disorders, boosting the immune system, to cardioprotection during ischaemia and reperfusion injury. Therefore, it is important to understand how these peptides become activated, how they activate different cell types and finally their intracellular signalling pathways. Such studies may enable scientists to develop clinical therapies based on their mechanism of action, which may be used to alleviate a diverse range of pathologies.     

罗格列酮联合二甲双胍治疗初发2型糖尿病疗效与安全性评价

目的探讨罗格列酮与二甲双胍联合治疗初发2型糖尿病的疗效,并评价联合用药的安全性。方法 180例初发2型糖尿病患者随机分为罗格列酮组、二甲双胍组和罗格列酮联合二甲双胍组,每组60例,分别给予罗格列酮、二甲双胍和罗格列酮＋二甲双胍,共治疗24周。观察3组糖化血红蛋白（HbA1c）、空腹血糖（FBG）、餐后2h血糖（2hBG）、胰岛素（BG）、空腹胰岛素（FINS）、胰岛素抵抗指数（HOMA-IR）、胰岛素敏感指数（HOMA-IAI）、体重指数（BMI）、总胆固醇（TC）、三酰甘油（TG）,并观察3组的不良反应情况。结果 3组治疗后FBG、2hBG、FINS、HbA1c、TC及TG均较治疗前显著下降（P〈0.05或〈0.01）;罗格列酮联合二甲双胍组FBG、2hBG、BMI较单用罗格列酮及二甲双胍显著下降（P〈0.05）,FINS较二甲双胍组显著下降（P〈0.05）;罗格列酮联合二甲双胍组HOMA-IAI升高程度较其他2组更明显（P〈0.05）。结论罗格列酮联合二甲双胍治疗初发2型糖尿病较二者单用疗效好,可作为理想的用药选择。     

Molecular and cellular mechanisms of apolipoprotein E4 neurotoxicity and potential therapeutic strategies

Apolipoprotein (apo) E is a multifunctional protein that has central roles in lipid metabolism and neurobiology. It has three common isoforms (apoE2, apoE3 and apoE4) that have different effects on lipid and neuronal homneostasis. Unlike apoE3, tie most common isoform, apoE4 is a major risk factor for Alzheimer's disease (AD). Although the mechanisms underlying the actions of apoE4 in AD pathogenesis are still poorly understood, emerging data strongly suggest that apoE4, with its multiple cellular origins and multiple structural and biophysical properties, contributes to this disease by interacting with different factors through various pathways. Thus, multiple molecular and cellular mechanisms should be considered in developing anti-AD drugs that target apoE4.     

银杏苦内酯对急性胰腺炎大鼠的治疗作用及机制

观察血小板活化因子受体特异性拮抗刘银杏苦内酯（ＢＮ５２０２１）对牛磺胆酸钠诱导的急性胰腺炎（ＡＰ）大鼠的治疗作用及其对胰腺组织丙二醛（ＭＤＡ）．ＳＯＤ和Ｃａ２＋的影响。结果表明：ＢＮ５２０２１显著降低ＡＰ大鼠死亡率，延长平均存活时间、降低血清淀粉酶活性、减轻胰组织病理损伤；显著降低胰组织Ｃａ２＋含量和ＭＤＡ含量、提高ＳＯＤ活性。提示ＢＮ５２０２１对ＡＰ大鼠有一定治疗作用，此与其抑制钙超载、清除自由基有关。     

格列美脲联合二甲双胍对老年糖尿病的治疗作用研究

目的探讨格列美脲联合二甲双胍对老年糖尿病的治疗作用。方法100例老年糖尿病患者,随机分为二甲双胍组与格列美脲联合二甲双胍组,各50例。二甲双胍组患者采取二甲双胍治疗,格列美脲联合二甲双胍组采取格列美脲联合二甲双胍治疗。比较两组疗效;空腹、餐后血糖达标时间和糖化血红蛋白降低至<6%时间;治疗前后患者血糖、血脂;不良反应发生率。结果格列美脲联合二甲双胍组总有效率为100.00%,高于二甲双胍组的82.00%,差异有统计学意义(P<0.05)。治疗后,格列美脲联合二甲双胍组患者的餐后2 h血糖、空腹血糖、总胆固醇(TC)、低密度脂蛋白胆固醇(LDL-C)均低于二甲双胍组,差异有统计学意义(P<0.05)。格列美脲联合二甲双胍组空腹、餐后血糖达标时间和糖化血红蛋白降低至<6%时间均短于二甲双胍组,差异有统计学意义(P<0.05)。格列美脲联合二甲双胍组用药期间出现腹泻症状1例(2.00%);二甲双胍组用药期间出现腹泻症状1例(2.00%),两组不良反应发生率比较,差异无统计学意义(P>0.05)。结论格列美脲联合二甲双胍治疗老年糖尿病效果确切,可有效改善血糖和血脂,且无明显不良反应,安全性高。     

二甲双胍延长寿命的作用及其作用机制

通过药理学方法来降低有机体的衰老率从而延长寿命已成为目前的研究热点之一。二甲双胍是一种用于治疗2型糖尿病的常用双胍类药物,研究显示二甲双胍可以延缓衰老并延长寿命,它可以通过激活腺苷酸活化蛋白激酶（AMPK）、抑制哺乳动物雷帕霉素靶蛋白（mTOR）及其下游相关分子发挥其抗衰老作用。本文对二甲双胍延长线虫、转基因小鼠和大鼠的寿命及其作用机制进行综述。     

二甲双胍的抗肿瘤作用

近一个世纪以来,人们逐渐认识到糖尿病与癌症的发生风险升高有关。多项研究证实[1-3],2型糖尿病患者发生乳腺癌、胰腺癌、大肠癌、子宫内膜癌等恶性肿瘤的风险增加,死亡风险高于非糖尿病患者。二甲双胍是美国糖尿病学会(American Diabetes Association,ADA)和欧洲糖尿病研究协会     

Parthanatos: mitochondrial-linked mechanisms and therapeutic opportunities

Cells die by a variety of mechanisms. Terminally differentiated cells such as neurones die in a variety of disorders, in part, via parthanatos, a process dependent on the activity of poly (ADP-ribose)-polymerase (PARP). Parthanatos does not require the mediation of caspases for its execution, but is clearly mechanistically dependent on the nuclear translocation of the mitochondrial-associated apoptosis-inducing factor (AIF). The nuclear translocation of this otherwise beneficial mitochondrial protein, occasioned by poly (ADP-ribose) (PAR) produced through PARP overactivation, causes large-scale DNA fragmentation and chromatin condensation, leading to cell death. This review describes the multistep course of parthanatos and its dependence on PAR signalling and nuclear AIF translocation. The review also discusses potential targets in the parthanatos cascade as promising avenues for the development of novel, disease-modifying, therapeutic agents.

LINKED ARTICLES

This article is part of a themed issue on Mitochondrial Pharmacology: Energy, Injury & Beyond. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2014.171.issue-8     

The cellular mechanisms involved in the vasodilator effect of nebivolol on the renal artery

Nebivolol is known as a highly selective beta1-adrenoceptor antagonist. Based on the reported vasodilator effect of nebivolol, we examined the cellular mechanisms by which the drug induces renal artery vasodilation, an issue of potential relevance for condition associated with high blood pressure. To this purpose, myograph and patch-clamp techniques were used. Small mouse renal arteries were placed in the myograph chamber, and after the optimal concentration for the vasodilator effect of nebivolol was established (50 microM), the arteries were further investigated to assess the potential contribution of nitric oxide (NO) and of Ca2+ ions to the nebivolol-induced effect, by exposing the arteries to the specific inhibitors such as N(G)-nitro-L-arginine methylester (L-NAME, 100 microM), ethylenglycol-bis-(beta-amino-ethylen ester) N,N'-tetraacetic acid (EGTA, 4 microM) and thapsigargin (1 microM). The expression of NO synthase was evaluated by the Western-blot technique. Using myograph and patch-clamp techniques applied on intact renal artery, we investigated the role of beta2-adrenoceptors, of myoendothelial junctions and of Ca(2+)-activated K+ channels in the vasodilatory effects of nebivolol, using 100 microM butoxamine, 40 microM 18 beta-glycyrrhetinic acid, 1 mM tetraethylammonium, and 100 nM iberiotoxin, respectively. The results showed that the cellular mechanisms of the vasodilator effect of nebivolol on the renal artery entail (i) activation of the endothelial beta2-adrenoceptor, (ii) participation of [Ca2+]i, (iii) increase in NO and eNOS, and (iv) activation of Ca(2+)-activated K+ channels. The cellular mechanisms underlying vasodilator effect of nebivolol on the artery explain the favorable effect of this drug in hypertension.     

Tyrosine phosphatases: cellular functions and therapeutic potential

Proper control of protein tyrosine phosphorylation, a post-translational modification that is critical for cell growth and differentiation, is accomplished through the actions of protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). Alterations in the activity of either of these enzymes can result in improper protein tyrosine phosphorylation which can lead to oncogenic transformation of cells. This review summarises recent advances in the identification and characterisation of protein tyrosine phosphatases and the patent literature related to these advances.     

The role of neuroinflammation in neuropathic pain: mechanisms and therapeutic targets

Neuroinflammation is a proinflammatory cytokine-mediated process that can be provoked by systemic tissue injury but it is most often associated with direct injury to the nervous system. It involves neural-immune interactions that activate immune cells, glial cells and neurons and can lead to the debilitating pain state known as neuropathic pain. It occurs most commonly with injury to peripheral nerves and involves axonal injury with Wallerian degeneration mediated by hematogenous macrophages. Therapy is problematic but new trials with anti-cytokine agents, cytokine receptor antibodies, cytokine-signaling inhibitors, and glial and neuron stabilizers provide hope for future success in treating neuropathic pain.     

Chemopreventive and therapeutic effects of nimbolide in cancer: The underlying mechanisms

Cancer chemoprevention is a strategy taken to block, reverse or retard the multistep process of carcinogenesis, including the blockage of its vital morphogenetic milestones viz. normal–preneoplasia–neoplasia–metastasis. Naturally occurring phytochemicals are becoming increasingly popular over synthetic drugs for several reasons, including safety, efficacy and easy availability. Nimbolide, a triterpene derived from the leaves and flowers of neem, is widely used in traditional medical practices for treating various human ailments. The neem limonoid exhibits multiple pharmacological effects among which its anticancer activity is the most promising. The preclinical and mechanistic studies carried over the decades have shown that nimbolide inhibits tumorigenesis and metastasis without any toxicity and unwanted side effects. Nimbolide exhibits anticancer activity through selective modulation of multiple cell signaling pathways linked to inflammation, survival, growth, invasion, angiogenesis and metastasis. The present review highlights the current knowledge on molecular targets that contribute to the observed anticancer activity of nimbolide related to (i) inhibition of carcinogenic activation and induction of antioxidant and carcinogen detoxification enzymes, (ii) induction of growth arrest and apoptosis; and (iii) suppression of proinflammatory signaling pathways related to cancer progression.     

Opioids: cellular mechanisms of tolerance and physical dependence

Morphine and other opioids are used and abused for their analgesic and rewarding properties. Tolerance to these effects develops over hours/days to weeks, as can physical and psychological dependence. Despite much investigation, the precise cellular mechanisms underlying opioid tolerance and dependence remain elusive. Recent studies examining mu-opioid receptor desensitization and trafficking have revealed several potential mechanisms for acute receptor regulation. Other studies have reported changes in many other proteins that develop during chronic opioid treatment or withdrawal and such changes may be partly responsible for the cellular and synaptic adaptations to prolonged opioid exposure. While these studies have added to our knowledge of the cellular processes participating in opioid tolerance and dependence, the challenge remains to integrate these observations into a coherent explanation of the complex changes observed in whole animals chronically exposed to opioids.     

The transmissible spongiform encephalopathies: pathogenic mechanisms and strategies for therapeutic intervention

Primary neurodegenerative diseases tend to be intractable and largely affect the elderly. There is rarely the opportunity to identify individuals at risk and the appearance of clinical symptoms usually signifies the occurrence of irreversible neurological damage. This situation describes sporadic Creutzfeldt-Jakob disease which occurs world-wide, affecting one person per million per annum. The epidemic of bovine spongiform encephalopathy in the UK in the 1980s and the subsequent causal appearance of variant Creutzfeldt-Jakob disease in young UK residents in the 1990s has refocused attention on this whole group of diseases, known as the transmissible spongiform encephalopathies or prion diseases. The potentially lengthy incubation period of variant Creutzfeldt-Jakob disease, including perhaps an obligate peripheral phase, prior to neuroinvasion, marks variant Creutzfeldt-Jakob disease out as different from sporadic Creutzfeldt-Jakob disease. The formal possibility of detecting individuals infected with the bovine spongiform encephalopathy agent during this asymptomatic peripheral phase provides a strong incentive for the development of therapies for transmissible spongiform encephalopathies. This review focuses on recent advances in the understanding of the pathogenesis of these diseases, with particular reference to in vitro and animal model systems. Such systems have proved invaluable in the identification of potential therapeutic strategies that either specifically target the prion protein or more generally target peripheral pathogenesis. Furthermore, recent experiments in animal models suggest that even after neuroinvasion there may be pharmacological avenues to explore that might retard or even halt the degenerative process.     

Anti-atherosclerotic effect of geniposidic acid in a rabbit model and related cellular mechanisms

Abstract

Context: Geniposidic acid, one of the main active ingredients in Gardenia jasminoides J. Ellis (Rubiaceae), may also possess important pharmacological activities for cardiovascular disorders similar to other derivatives, such as geniposide.

Objective: To evaluate its anti-atherosclerosis (anti-AS) effect, the related pharmacological activities and possible cellular mechanisms were studied.

Materials and methods: Thirty rabbits were randomly divided into normal control group, model control group, and geniposidic acid subgroups. In the AS model, its effects on the intima/media thickness ratio and aortic morphology were observed. In the study of primary cultured endothelial cells (ECs) and human umbilical artery smooth muscle cells (HUASMCs), its activities on both ECs and HUASMCs proliferation, HUASMCs' migration were also studied.

Results: Compared with the model control group, the plaque area, intima/media thickness ratio, and intimal foam cells number in geniposidic acid (80, 160, and 240?mg/kg) subgroups were significantly improved (p?<?0.05). By HE staining, the activities of geniposidic acid on relieving ECs shedding and improving aortic morphology disorders were also demonstrated. From the results of CCK-8 testing, only 100?μg/ml geniposidic acid performed significant inhibition on SMC proliferation. The relative IC₅₀ of geniposidic acid on SMC inhibition was 87.73?μg/ml. Geniposide acid also showed promotion effect on ECs proliferation, and the related ED₅₀ of geniposidic acid was 86.05?μg/ml. Besides, only 50 and 100?μg/ml geniposidic acid showed obvious inhibition on SMC migration from the upper chamber (p?<?0.05).

Discussion and conclusion: The effects of geniposidic acid on protecting vascular endothelium and reversing plaque formation in an atherosclerotic model were demonstrated.