吡格列酮对2型糖尿病大鼠血清炎症介质和糖耐量的影响

目的探讨吡格列酮对2型糖尿病大鼠炎症因子及其糖耐量水平的影响。方法8周龄健康Wistar大鼠,用链脲菌素（STZ）加高脂肪高热卡饮食诱导2型糖尿病大鼠模型,将糖尿病大鼠随机分为2组：糖尿病组（n=10）、吡格列酮组（n=10,10mg·kg-1．d-1,灌胃）,健康Wistar大鼠作为对照组（n=10）,糖尿病组和对照组给予同体积生理盐水灌胃,8周后分别测定空腹血糖（FBG）和胰岛素水平（FINS）,进行口服葡萄糖耐量试验（OGTT）,计算胰岛素抵抗指数（HOMA。IR）,测定大鼠血清中白介素1B（IL-1B）、白介素6（IL．6）、肿瘤坏死因子α（TNF-α）、急相反应蛋白C（CRP）水平。结果FBG、FINS和HOMA-R水平,糖尿病组比对照组显著升高（P〈0．05）,而吡格列酮可以明显降低糖尿病大鼠的水平,差异有统计学意义（P〈0．05）;OGTF实验结果显示：糖尿病大鼠餐后血糖水平明显升高（P〈0．05）,吡咯列酮明显减低糖尿病大鼠餐后血糖水平差异有统计学意义（P〈0．05）;IL-1β、IL-6、TNF-α、CRP水平与正常对照组比较糖尿病组显著升高（P〈0．05）,而吡格列酮可以明显降低糖尿病大鼠的水平,差异有统计学意义（P〈0．05）。结论吡格列酮可下调血清炎症因子的表达,改善胰岛素抵抗。     

Targeting cardiac natriuretic peptides in the therapy of diabetes and obesity

Introduction: Atrial and B-type Natriuretic Peptides (NP) are cardiac hormones with potent cardiovascular and metabolic effects. They signal through the NPRA/cGMP system and are inactivated by a clearance receptor NPRC and neutral endopeptidases (NEP). Recombinant ANP and BNP are currently used as drug treatment for acute decompensated congestive heart failure. Recent literature indicate that a defective NP system is linked to obesity and predict the risk of type 2 diabetes (T2D).

Areas covered: This article reviews recent epidemiological, clinical and preclinical evidences that NP system deficiency may be causal of obesity and T2D. The molecular mechanisms of the NP pathway in several metabolic target tissues are presented. The therapeutic potential of NP in obesity and T2D is discussed.

Expert opinion: Targeting the NP pathway may offer a novel therapeutic avenue for the management of obesity and T2D. The benefit/risk of drugs increasing circulating NP levels by blocking NPRC and NEP, and/or enhancing NPRA signaling should be assessed in obese and type 2 diabetic individuals.     

Inflammatory and Metabolic Dysregulation and the 2-Year Course of Depressive Disorders in Antidepressant Users

Scarce evidence suggests that inflammatory and metabolic dysregulation predicts poor response to antidepressants, which could result in worse depression outcome. This study prospectively examined whether inflammatory and metabolic dysregulation predicted the 2-year course of depressive disorders among antidepressant users. Data were from the Netherlands Study of Depression and Anxiety, including 315 persons (18–65 years) with a current depressive disorder (major depressive disorder, dysthymia) at baseline according to the DSM-IV criteria and using antidepressants. Inflammatory (C-reactive protein, interleukin-6 (IL-6), tumor-necrosis factor-α) and metabolic (waist circumference, triglycerides, high-density lipoprotein (HDL) cholesterol, blood pressure, fasting glucose) factors were measured at baseline. Primary outcome for course of depression was indicated by whether or not a DSM-IV depressive disorder diagnosis was still/again present at 2-year follow-up, indicating chronicity of depression. Elevated IL-6, low HDL cholesterol, hypertriglyceridemia, and hyperglycemia were associated with chronicity of depression in antidepressant users. Persons showing ⩾4 inflammatory or metabolic dysregulations had a 1.90 increased odds of depression chronicity (95% CI=1.12–3.23). Among persons who recently (ie, at most 3 months) started antidepressant medication (N=103), having ⩾4 dysregulations was associated with a 6.85 increased odds of depression chronicity (95% CI=1.95–24.06). In conclusion, inflammatory and metabolic dysregulations were found to predict a more chronic course of depressive disorders among patients using antidepressants. This could suggest that inflammatory and metabolic dysregulation worsens depression course owing to reduced antidepressant treatment response and that alternative intervention treatments may be needed for depressed persons with inflammatory and metabolic dysregulation.     

Optimization,Biopharmaceutical Profile and Therapeutic Efficacy of Pioglitazone-loaded PLGA-PEG Nanospheres as a Novel Strategy for Ocular Inflammatory Disorders

Purpose

The main goal of this study was to encapsulate Pioglitazone (PGZ), in biodegradable polymeric nanoparticles as a new strategy for the treatment of ocular inflammatory processes.

Methods

To improve their biopharmaceutical profile for the treatment of ocular inflammatory disorders, nanospheres (NSs) of PGZ were formulated by factorial design with poly (lactic-co-glycolic acid) polyethylene glycol (PLGA-PEG). Interactions drug-polymer have been carried out by spectroscopic (X-ray spectroscopy, FTIR) and thermal methods (DSC). The PGZ-NSs were tested for their in vitro release profile, cytotoxicity, and ocular tolerance (HET-CAM® test); ex vivo corneal permeation, and in vivo inflammatory prevention and bioavailability.

Results

The optimized system showed a negative surface charge of ?13.9 mV, an average particle size (Z_av) of around 160 nm, a polydispersity index (PI) below 0.1, and a high encapsulation efficiency (EE) of around 92%. According to the DSC results, the drug was incorporated into the NSs polymeric matrix. The drug release was sustained for up to 14 h. PGZ-NSs up to 10 μg/ml exhibited no retinoblastoma cell toxicity. The ex vivo corneal and scleral permeation profiles of PGZ-NSs showed that retention and permeation through the sclera were higher than through the cornea. Ocular tolerance in vitro and in vivo demonstrated the non-irritant character of the formulation.

Conclusion

The in vivo anti-inflammatory efficacy of developed PGZ-NSs indicates this colloidal system could constitute a new approach to prevent ocular inflammation.

     

Accumulation of PEG-liposomes in the Inflamed Colon of Rats: Potential for Therapeutic and Diagnostic Targeting of Inflammatory Bowel Diseases

Therapeutic intervention in inflammatory bowel diseases (IBDs) is often associated with severe toxicity related to the nonspecific and ubiquitous interaction of drugs with the organs and tissues. In order to prevent side effects from aggressive and prolonged treatment with glucocorticoids and immunosuppressive agents, preferential accumulation of these potent drugs in diseased tissue is desired. In this work, we report that liposomes show a remarkable tendency to accumulate in inflamed colon of rats with experimental colitis. The disposition of liposomes was monitored by labeling them with Tc-99m followed by gamma camera imaging, and determining biodistribution of radioactivity in various organs. The images showed distinct accumulation of radioactivity in the colon of rats with colitis, while the abdomen of normal rats was conspicuously free of any visible radioactivity. Although images acquired 4 h after Tc-99m-liposome injection were clear enough for diagnostic indication, the real potential of liposomes for drug delivery was evident in 24 h images where the major organs of liposome accumulation were dwarfed by intense colon activity in animals with colitis. On necropsy, 13.5% ± 5.48 of the activity accumulated in the inflamed colon as compared to only 0.1% in the normal colon, giving a target-to-nontarget ratio of 135. The blood borne radioactivity was 9% ± 2.12 (colitis) and 25.7% ± 4.27 (normal), indicating that the decrease in circulating liposomes is associated with an increase in liposome accumulation in the inflammatory site. The other two major organs that accumulated liposomes were spleen (10.7% normal vs. 11% colitis) and liver (8% normal vs. 10.1% colitis). In conclusion, this study demonstrates the innate propensity of liposomes to accumulate in the sites of inflammation and potential of liposomes loaded with therapeutic drugs or diagnostic agents for targeting colitis.     

基于卓越计划的制药工程专业课程与实践体系探讨

卓越工程师教育培养计划是我国高等工程教育的重大教学改革项目,其目的是面向工业界、面向世界、面向未来培养造就一大批创新能力强、适应经济社会发展需要的卓越工程师。我校是医药类院校中唯一实施卓越计划的试点高校,以中国药科大学制药工程专业卓越计划的实施为例,从专业课程与实践教学体系两方面,探讨了制药工程卓越人才的培养模式。     

Psychosocial Interventions for Adults with Severe Mental Illnesses and Co-Occurring Substance Use Disorders

Abstract

A growing body of research supports the effectiveness of integrated treatment for people with co-occurring severe mental illness and substance use disorders (dual disorders), but the effects of specific interventions are less clear. This review focuses on the effects of specific psychosocial interventions for dual disorders, including individual, group, and family modalities, as well as structural (e.g., case management model), procedural (e.g., contingency management), residential, and rehabilitation (e.g., vocational) interventions, with an emphasis on randomized controlled trials. Controlled research on specific individual interventions has focused mainly on motivation enhancement approaches for clients in the earlier stages of treatment, and has reported improved retention in treatment and substance abuse outcomes. Group interventions have been most extensively studied, with findings indicating that a variety of different treatment approaches specifically designed for dual disorder clients (e.g., emphasizing education, motivational enhancement, cognitive-behavioral counseling) are more effective at improving substance abuse outcomes than no group treatment or standard 12-Step approaches. Structural studies suggest that increasing the intensity of integrated dual disorder treatment produces only modest benefits. Residential dual disorder programs show great promise, especially for clients who are homeless and without psychosocial supports. Research on family therapy, procedural interventions, or rehabilitation is too premature at this time to draw any conclusions, although promising results have emerged in each area. Future avenues for research on specific interventions for dual disorders are considered.     

Design and Synthesis of Novel Arctigenin Analogues for the Amelioration of Metabolic Disorders

相似文献   

Potential Relevance of Bell-Shaped and U-Shaped Dose-Responses for the Therapeutic Targeting of Angiogenesis in Cancer

Tumor angiogenesis, the growth of new blood vessels into tumors, facilitates tumor growth and thus represents an attractive therapeutic target. Numerous experimental angiogenesis inhibitors have been characterised and subsequently trialled in patients. Some of these agents have failed to show any substantial activity in patients. In contrast, others have been more successful, but even these provide only a few months extra patient survival. Recent work has focused on understanding the effects of anti-angiogenic agents on tumor biology and has revealed a number of new findings that may help to explain the limited efficacy of angiogenesis inhibitors. Herein, I review the evidence that hormetic dose-responses (i.e. bell-shaped and U-shaped dose-response curves) are often observed with anti-angiogenic agents. Agents reported to exhibit these types of dose-response include: 5-fluorouracil, ATN-161, bortezomib, cisplatin, endostatin, enterostatin, integrin inhibitors, interferon-α, plasminogen activator-1 (PAI-1), rapamycin, rosiglitazone, statins, thrombospondin-1, TGF-α1 and TGF-α3. Hormesis may also be relevant for drugs that target the vascular endothelial growth factor (VEGF) signalling pathway and for metronomic chemotherapy. Here I argue that hormetic dose-responses present a challenge for the clinical translation of several anti-angiogenic agents and discuss how these problems might be circumvented.     

联合疗法治疗女性外阴上皮内非瘤样病变临床观察

目的探讨高强度聚焦超声（HIFU）配合专用药物治疗女性外阴上皮内非瘤样病变的效果。方法将2006年1月～2011年1月在济南军区总医院妇产科就诊的女性外阴上皮内非瘤样病变376例分为两组,HIFU组75例,单独应用HIFU治疗,联合疗法组301例,采用HIFU联合局部专用药物治疗。以同期56例单纯应用传统药物治疗的同类疾病患者为对照组。设立＂外阴瘙痒评分法＂、＂外阴白色病变面积计算法＂、＂四象限比较法＂和＂四度皮肤弹性评估法＂判定疗效。结果①HIFU组与联合疗法组对控制各类外阴上皮内非瘤样病变瘙痒症状的疗效显著优于对照组（P〈0.05）,联合疗法组疗效更佳（P〈0.05）。②HIFU组与联合疗法组控制白色病变的总有效率均高于对照组（P〈0.05）。HIFU组、联合疗法组治疗后白色病变面积与本组治疗前比较显著减小（P〈0.01）。③HIFU组、联合疗法组符合外阴皮肤弹性不良标准的患者治疗后外阴局部皮肤弹性评分与治疗前比较差异均有统计学意义（P〈0.05,P〈0.01）,HIFU组、联合疗法组外阴局部皮肤弹性改善总有效率均显著高于对照组（P〈0.05）,联合疗法组疗效更佳（P〈0.05）。结论 HIFU联合局部专用药物治疗女性外阴上皮内非瘤样病变,对瘙痒症状、外阴局部皮肤弹性的改善及减小白色病变面积效果满意,并具有治疗方便、安全无创的优势。     

Metabolic and Pharmacological Properties of Rutin,a Dietary Quercetin Glycoside,for Treatment of Inflammatory Bowel Disease

Purpose Orally administered rutin reportedly ameliorates 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis of rats. We investigated the metabolic and pharmacological properties of rutin underlying the rutin-mediated amelioration of the rat colitis.Methods Apparent partition coefficients of rutin and its aglycone quercetin were compared. The biochemical/chemical stability of rutin was examined in the contents of various segments of gastrointestinal tracts of rats. Inflammatory indices were determined in the colitis rats after oral administration of rutin or rectal administration of quercetin. In human colon epithelial cells, the effect of quercetin on tumor necrosis factor-alpha (TNF-α)-induced nuclear factor kappa B (NFκB) activation was examined.Results The sugar residue in rutin greatly lowered the apparent partition coefficient and was rapidly deglycosylated to liberate quercetin in the cecal contents, whereas it was stable in the contents of the upper intestine. Not only oral administration of rutin but also rectal administration of quercetin remarkably ameliorated TNBS-induced colitis rats, indicating that quercetin liberated from rutin is therapeutically active. Furthermore, quercetin dose-dependently inhibited an inflammatory signal TNF-α-dependent NFκB activation.Conclusions Our data suggest that rutin acted as a quercetin deliverer to the large intestine and its anti-inflammatory action in TNBS-induced colitis rats may be through quercetin-mediated inhibition of TNF-α-induced NFκB activation.     

Targeting NAMPT for Therapeutic Intervention in Cancer and Inflammation: Structure‐Based Drug Design and Biological Screening

Nicotinamide phosphoribosyltransferase (NAMPT) is a rate limiting enzyme that plays an important role in the synthesis of nicotinamide adenine dinucleotide (NAD) via a salvage pathway. Along with a role in bioenergetics, NAMPT regulates the activity of proteins such as SIRT‐1 that utilize NAD as a cofactor. As NAD metabolism is usually high in diseased conditions, it has been hypothesized and proven that NAMPT is over expressed in various cancers and inflammatory disorders. Inhibitors targeting NAMPT could therefore be useful in treating disorders arising from aberrant NAMPT signalling. In this study, inhibitors against NAMPT were designed using an energy‐based pharmacophore strategy and evaluated for efficacy in cellular assays. Besides reducing cellular pools of NAD and NMN, NAMPT inhibitors decreased concentrations of reactive oxygen species as well as mRNA levels of TNFα and IL6, thereby implicating their potential in alleviating the inflammatory process. In addition, reduced NAD levels corroborated with an induction of apoptosis in prostate cancer cell lines.     

Preparation and Evaluation of 99mTc‐labeled anti‐CD11b Antibody Targeting Inflammatory Microenvironment for Colon Cancer Imaging

CD11b, an active constituent of innate immune response highly expressed in myeloid‐derived suppressor cells (MDSCs), can be used as a marker of inflammatory microenvironment, particularly in tumor tissues. In this research, we aimed to fabricate a ^99mTc‐labeled anti‐CD11b antibody as a probe for CD11b⁺ myeloid cells in colon cancer imaging with single‐photon emission computed tomography (SPECT). In situ murine colon tumor model was established in histidine decarboxylase knockout (Hdc^?/?) mice by chemicals induction. ^99mTc‐labeled anti‐CD11b was obtained with labeling yields of over 30% and radiochemical purity of over 95%. Micro‐SPECT/CT scans were performed at 6 h post injection to investigate biodistributions and targeting of the probe. In situ colonic neoplasma as small as 3 mm diameters was clearly identified by imaging; after dissection of the animal, anti‐CD11b immunofluorescence staining was performed to identify infiltration of CD11b+ MDSCs in microenvironment of colonic neoplasms. In addition, the images displayed intense signal from bone marrow and spleen, which indicated the origin and migration of CD11b⁺ MDSCs in vivo, and these results were further proved by flow cytometry analysis. Therefore, ^99mTc‐labeled anti‐CD11b SPECT displayed the potential to facilitate the diagnosis of colon tumor in very early stage via detection of inflammatory microenvironment.     

Therapeutic promises of leukocyte elastase and macrophage metalloelastase inhibitors for the treatment of pulmonary emphysema

The fibrous protein elastin, which comprises an appreciable percentage of all protein content in some tissues, such as arteries, some ligaments, and the lungs, can be hydrolysed or otherwise destroyed by a select group of enzymes classified as elastases. To date four elastases are known, three of which are human: human leukocyte elastase (HLE), pancreatic elastase II (PE-II) and macrophage metalloelastase (MME, MMP-12). Human leukocyte and pancreatic elastases are both serine proteinases (i.e., having a catalytic triad corresponding to Ser¹⁹⁵, Asp¹⁰² and His⁵⁷ of chymotrypsin). However, macrophage metalloelastase is a member of the matrix metalloproteinase family (MMPs, matrixins), which contain a zinc atom at the catalytic site. Imbalances in the levels or regulation of tissue or cellular proteases are thought to manifest themselves in various disease states. In order to prevent self-inflicted tissue damage due to over expression of enzymes, numerous endogenous inhibitors directed against proteolytic enzymes exist. In the case of human leukocyte elastase the primary endogenous inhibitor is ₁-proteinase inhibitor (₁-PI). In the case of the MMPs the endogenous inhibitors are the tissue inhibitors of metalloproteinases (TIMPs). Both of these natural inhibitors are proteins. Because of the liabilities of proteins as drugs, low molecular weight inhibitors may be useful as therapeutic agents as a replacement to ₁-PI and TIMPs. Since HLE and MME have been implicated in the pathogenesis of pulmonary emphysema, inhibitors of these enzymes should have beneficial effects for the treatment of this chronic disease. This report reviews inhibitors of HLE that have appeared in the patent literature since 1997 as well as patents that specifically claim MME inhibition.