钒化合物生物效应的化学基础和药用前景金属药物研究的化学问题

本文从非必需元素的相似性作用规律的观点，综述了钒在生理条件下的物种变化和决定其生物效应的基本化学性质，对钒化合物的类胰岛素活性、作用机制和钒抗糖尿病药物研究进行了介绍。     

糖尿病与钒

本文主要介绍糖尿病的由来、钒的化合物对糖尿病特有的治疗作用及作用机制.简要阐明钒与糖尿病的关系及当前研究的新动向.     

钒化合物的靶点蛋白及其生物效应

作为一种生物相关的金属元素,基于钒的金属化合物在糖尿病、癌症、阿尔茨海默症、神经炎症等疾病的治疗方面表现出独特的潜在应用价值。现阶段研究表明,钒发挥其生物活性主要源于钒酸根作为磷酸根类似物对细胞内磷酸转移反应的影响,及钒在细胞内经氧化还原转化产生的活性氧物质对相关信号通路的调节;而钒化合物与细胞内靶点蛋白的相互作用亦被认为是发挥其治疗作用的关键因素。本文就钒的化学性质、钒化合物与血清蛋白的结合、钒化合物对细胞内效应靶点蛋白及其作用通路的调控、细胞内金属药物靶点蛋白分析鉴定等几方面,对近年来取得的相关研究的进展进行综述,以系统性阐释钒化合物用于疾病治疗的生物活性机制,并对进一步揭示钒化合物作用机理的探索方向及其药用前景进行展望。     

氨基酸膦酸氧钒配合物的降糖活性及与DNA作用研究

研究证明钒无论体内还是体外都具有良好的降糖活性。对于胰岛素强化剂进行糖尿病的介入性治疗来说，钒配位化合物的设计合成、基团的选择、协同效应等均具有重要的意义。为了研究钒配位化合物胰岛素强化剂的活性，通过链脲霉素模型鼠进行了口服生物学实验，结果表明氨基酸膦酸氧钒配合物具有较高的体内降糖活性。通过琼脂糖凝胶电泳研究表明氨基酸膦酸氧钒配合物与DNA之间存在较强的相互作用。     

从钒化合物生物效应的多样性看其作用机制*

本文对近年来关于钒化合物不同生物效应机制的研究进展进行了总结,着重于其类胰岛素和抗癌效应的信号转导机制以及两者之间的相关性。同时,基于钒化合物对磷酸转移反应的干预以及对细胞氧化还原状态的调节,讨论了钒化合物多样化的生物效应是否具有一个共同作用机制的可能性,并提出了未来钒化合物研究方向和所面临的挑战。     

不平“钒”的金属元素*

钒是地壳中含量第21丰富元素,是人体必需的微量元素。介绍钒元素的发现、自然分布以及在人体内的循环。重点从化学结构分析钒酸盐磷酸盐的拮抗作用机制,从生化机理阐述钒化合物对激酶与磷酸酶的调节、对RNA和DNA功能的影响、对活性氧作用的影响,从人体健康视角探讨钒对治疗糖尿病和癌症及保护心血管等的潜在药理学作用。     

硒蛋白与糖尿病——硒的两面性

糖尿病是危害人类健康的全球性重大疾病,胰岛素抵抗是诱发2型糖尿病的重要因素。微量必需元素硒与人体健康密切相关,通过硒蛋白发挥多种重要生物学功能。近年来硒与糖尿病的关系引人关注,早期研究表明硒具有类胰岛素作用,可望用于防治糖尿病,但近来的人群试验和动物研究却表明硒在糖尿病发生发展中的作用具有两面性,长期补充一定剂量的硒反而增加了胰岛素抵抗和2型糖尿病的发病率。而且,硒在糖尿病发生发展中的两面性被证实与几种硒蛋白密切相关,包括谷胱甘肽过氧化物酶1(GPx1)、硒蛋白S(SelS)和硒蛋白P(SelP)等。本文结合本课题组的工作介绍了硒在糖尿病中的两面性以及硒蛋白在糖尿病发生发展中的作用,并对未来的研究方向进行了展望。     

钒化合物药用研究前景展望

本文针对钒化合物在药用研究中的挑战,结合国内外在相关领域的主要进展,从其作用机制的化学基础出发,分析了钒化合物可能的作用物种以及钒化合物所诱导产生的活性氧物种在其生物效应中的作用;同时,从疾病之间的相互联系,探讨了如何有效利用钒化合物生物效应的特点,并进一步指出钒化合物在药用研究中的前景及未来的研究策略.     

钒胰岛素样作用研究进展

对钒酸盐的胰岛素作用的研究进行了综述，着重介绍了钒对糖尿病动物的降血糖作用及其机理的探讨。     

微量元素对控制糖尿病大鼠动脉Ⅳ型胶原沉积的实验研究

探讨了微量元素对糖尿病（DM）大鼠动脉Ⅳ型胶原沉积的影响。链脲佐菌素（STZ）诱导动物模型，经胃灌注微量元素后检测大鼠血糖及用免疫组化方法检测动脉Ⅳ型胶原水平。结果表明，微量元素钒，铬，硒能显著降低糖尿病大鼠血糖水平，减少Ⅳ型胶原沉积。抽示微量元素对糖尿病血管病变的发生有预防作用。     

Solanum anguivi Lam. Fruits: Their Potential Effects on Type 2 Diabetes Mellitus

Type 2 diabetes mellitus (T2DM) is a complex metabolic disorder of glucose homeostasis associated with a status of insulin resistance, impaired insulin signaling, β-cell dysfunction, impaired glucose and lipid metabolism, sub-clinical inflammation, and increased oxidative stress. Consuming fruits and vegetables rich in phytochemicals with potential antidiabetic effects may prevent T2DM and/or support a conservative T2DM treatment while being safer and more affordable for people from low-income countries. Solanum anguivi Lam. fruits (SALF) have been suggested to exhibit antidiabetic properties, potentially due to the presence of various phytochemicals, including saponins, phenolics, alkaloids, ascorbic acid, and flavonoids. For the saponin fraction, antidiabetic effects have already been reported. However, it remains unclear whether this is also true for the other phytochemicals present in SALF. This review article covers information on glucose homeostasis, T2DM pathogenesis, and also the potential antidiabetic effects of phytochemicals present in SALF, including their potential mechanisms of action.     

UHPLC-MS-Based Serum and Urine Metabolomics Reveals the Anti-Diabetic Mechanism of Ginsenoside Re in Type 2 Diabetic Rats

Panax ginseng was employed in the treatment of “Xiao-Ke” symptom, which nowadays known as diabetes mellitus, in traditional Chinese medicine for more than a thousand years. Ginsenoside Re was the major pharmacologic ingredient found abundantly in ginseng. However, the anti-diabetic of Ginsenoside Re and its underlying mechanism in metabolic level are still unclear. Serum and urine metabolomic method was carried out to investigate the anti-diabetic pharmacological effects and the potential mechanism of Ginsenoside Re on high-fat diet combined streptozotocin-induced type 2 diabetes mellitus (T2DM) rats based on ultra-high-performance liquid chromatography coupled with quadrupole exactive orbitrap mass spectrometry (UHPLC-Q-Exactive Orbitrap/MS). Serum and urine samples were collected from the control group (CON), T2DM group, metformin (MET) treatment group, and ginsenoside Re treatment group after intervention. The biochemical parameters of serum were firstly analyzed. The endogenous metabolites in serum and urine were detected by UHPLC-MS. The potential metabolites were screened by multivariate statistical analysis and identified by accurate mass measurement, MS/MS, and metabolite databases. The anti-diabetic-related metabolites were analyzed by KEGG metabolic pathway, and its potential mechanism was discussed. The treatment of ginsenoside Re significantly reduced the blood glucose and serum lipid level improved the oxidative stress caused by T2DM. Biochemical parameters (urea nitrogen, uric acid) showed that ginsenoside Re could improve renal function in T2DM rats. Respective 2 and 6 differential metabolites were found and identified in serum and urine of ginsenoside Re compared with T2DM group and enriched in KEGG pathway. Metabolic pathways analysis indicated that the differential metabolites related to T2DM were mainly involved in arachidonic acid metabolism, Vitamin B6, steroid hormone biosynthesis, and bile secretion metabolic pathways. This study verified the anti-diabetic and anti-oxidation effects of ginsenoside Re, elaborated that ginsenoside Re has a good regulation of the metabolic disorder in T2DM rats, which could promote insulin secretion, stimulated cannabinoid type 1 receptor (CB₁), and CaMKK β to activate AMPK signaling pathway, inhibited insulin resistance, and improved blood glucose uptake and diabetic nephropathy, so as to play the role of anti-diabetic.     

Anti-diabetic effects of a series of vanadium dipicolinate complexes in rats with streptozotocin-induced diabetes

The effects of oral treatment of rats with streptozotocin-induced diabetes with a range of vanadium dipicolinate complexes (Vdipic) and derivatives are reviewed. Structure–reactivity relationships are explored aiming to correlate properties such as stability, to their insulin-enhancing effects. Three types of modifications are investigated; first, substitutions on the aromatic ring, second, coordination of a hydroxylamido group to the vanadium, and third, changes in the oxidation state of the vanadium ion. These studies allowed us to address the importance of coordination chemistry, and redox chemistry, as modes of action. Dipicolinate was originally chosen as a ligand because the dipicolinatooxovanadium(V) complex (V5dipic), is a potent inhibitor of phosphatases. The effect of vanadium oxidation state (3, 4 or 5), on the insulin-enhancing properties was studied in both the Vdipic and VdipicCl series. Effects on blood glucose, body weight, serum lipids, alkaline phosphatase and aspartate transaminase were selectively monitored. Statistically distinct differences in activity were found, however, the trends observed were not the same in the Vdipic and VdipicCl series. Interperitoneal administration of the Vdipic series was used to compare the effect of administration mode. Correlations were observed for blood vanadium and plasma glucose levels after V5dipic treatment, but not after treatment with corresponding V4dipic and V3dipic complexes. Modifications of the aromatic ring structure with chloride, amine or hydroxyl groups had limited effects. Global gene expression was measured using Affymetrix oligonucleotide chips. All diabetic animals treated with hydroxyl substituted V5dipic (V5dipicOH) and some diabetic rats treated with vanadyl sulfate had normalized hyperlipidemia yet uncontrolled hyperglycemia and showed abnormal gene expression patterns. In contrast to the normal gene expression profiles previously reported for some diabetic rats treated with vanadyl sulfate, where both hyperlipidemia and hyperglycemia were normalized. Modification of the metal, changing the coordination chemistry to form a hydroxylamine ternary complex, had the most influence on the anti-diabetic action. Vanadium absorption into serum was determined by atomic absorption spectroscopy for selected vanadium complexes. Only diabetic rats treated with the ternary V5dipicOH hydroxylamine complex showed statistically significant increases in accumulation of vanadium into serum compared to diabetic rats treated with vanadyl sulfate. The chemistry and physical properties of the Vdipic complexes correlated with their anti-diabetic properties. Here, we propose that compound stability and ability to interact with cellular redox reactions are key components for the insulin-enhancing activity of vanadium compounds. Specifically, we found that the most overall effective anti-diabetic Vdipic compounds were obtained when the compound administered had an increased coordination number in the vanadium complex.     

Bioactive Agent Discovery from the Natural Compounds for the Treatment of Type 2 Diabetes Rat Model

Diabetes mellitus is a well-known chronic metabolic disease that poses a long-term threat to human health and is characterized by a relative or absolute lack of insulin, resulting in hyperglycemia. Type 2 diabetes mellitus (T2DM) typically affects many metabolic pathways, resulting in β-cell dysfunction, insulin resistance, abnormal blood glucose levels, inflammatory processes, excessive oxidative reactions, and impaired lipid metabolism. It also leads to diabetes-related complications in many organ systems. Antidiabetic drugs have been approved for the treatment of hyperglycemia in T2DM; these are beneficial for glucose metabolism and promote weight loss, but have the risk of side effects, such as nausea or an upset stomach. A wide range of active components, derived from medicinal plants, such as alkaloids, flavonoids, polyphenol, quinones, and terpenoids may act as alternative sources of antidiabetic agents. They are usually attributed to improvements in pancreatic function by increasing insulin secretions or by reducing the intestinal absorption of glucose. Ease of availability, low cost, least undesirable side effects, and powerful pharmacological actions make plant-based preparations the key player of all available treatments. Based on the study of therapeutic reagents in the pathogenesis of humans, we use the appropriate animal models of T2DM to evaluate medicinal plant treatments. Many of the rat models have characteristics similar to those in humans and have the advantages of ease of genetic manipulation, a short breeding span, and access to physiological and invasive testing. In this review, we summarize the pathophysiological status of T2DM rat models and focus on several bioactive compounds from herbal medicine with different functional groups that exhibit therapeutic potential in the T2DM rat models, in turn, may guide future approach in treating diabetes with natural drugs.     

Recent discovery of plant-derived anti-diabetic natural products

Covering: 2005 to 2010. This review covers recent discoveries of anti-diabetic compounds. Diabetes mellitus (DM) is a complex disease affecting patients' daily life and elevating patients' risk of developing other diseases. There are several forms of diabetes, including type-1 diabetes (insulin-dependent), type-2 diabetes (noninsulin-dependent), and gestational diabetes. Type-2 diabetes is the most common form and the patient population with type-2 DM rises every year. Current treatments meet some but not all patients' needs. Therefore, new anti-diabetic drugs are in great demand. Traditional herbal medicine provides a rich source for new drug discovery. In this review, recent discoveries of anti-diabetic compounds have been summarized according to their chemical structures and mechanisms of action. Anti-diabetic plant extracts, many of which have been used and marketed as dietary supplements, were also included and discussed, and are classified according to the positive control used in the anti-diabetic animal studies. New anti-diabetic natural products found in the recent patent literature are also summarized.     

钒酰腙配合物的合成、结构及生物活性

以酰腙为配体钒的单核、双核配合物因其结构丰富、生物活性多样而引起广泛关注。目前该领域新配合物的合成、表征和生物活性的研究甚为活跃。本文回顾了近年来钒酰腙配合物的研究状况,主要从以下三个方面进行综述：(1)钒酰腙配合物的合成方法;(2)此类配合物的配位模式;(3)一些单、双核钒酰腙配合物抗变形虫,抗肿瘤,类胰岛素,抑制Na⁺, K⁺-ATP酶,与DNA作用的生物活性。文中着重阐述了钒酰腙化合物的结构和生物活性之间的关系。此外,还提出了钒酰腙配合物研究领域的不足之处并对其今后发展方向进行了展望。     

Glucose-lowering A ivity of Amino Acid- phosphonic Acid Oxovanadium Complexes and Its Interaction with DNA

Vanadium has well-documented lowering glucose properties both in vitro and in vivo. The design of new oxovanadium（IV） coordination compounds, intended for use as insulin-enhancing agents in the treatment of diabetes mellitus, can potentially benefit from a synergistic approach, in which the whole complex has more than an additive effect from its component parts. Biological testing with oxovanadium（IV） organic phosphonic acid, for insulin-enhancing potential included acute administration, by oral gavage in streptozotocin （STZ） diabetic rats. The complexes of oxovanadium（IV） amino acid-N-phosphonic acid exhibit higher lowering glucose activity in vivo. The interaction of the complexes of oxovanadium（IV） amino acid-N-phosphonic acid with DNA was investigated by agarose gel electrophoresis. The results indicated that these complexes have strong interaction with DNA.     

Stevioside Attenuates Insulin Resistance in Skeletal Muscle by Facilitating IR/IRS-1/Akt/GLUT 4 Signaling Pathways: An In Vivo and In Silico Approach

Type-2 diabetes mellitus (T2DM), the leading global health burden of this century majorly develops due to obesity and hyperglycemia-induced oxidative stress in skeletal muscles. Hence, developing novel drugs that ameliorate these pathological events is an immediate priority. The study was designed to analyze the possible role of Stevioside, a characteristic sugar from leaves of Stevia rebaudiana (Bertoni) on insulin signaling molecules in gastrocnemius muscle of obesity and hyperglycemia-induced T2DM rats. Adult male Wistar rats rendered diabetic by administration of high fat diet (HFD) and sucrose for 60 days were orally administered with SIT (20 mg/kg/day) for 45 days. Various parameters were estimated including fasting blood glucose (FBG), serum lipid profile, oxidative stress markers, antioxidant enzymes and expression of insulin signaling molecules in diabetic gastrocnemius muscle. Stevioside treatment improved glucose and insulin tolerances in diabetic rats and restored their elevated levels of FBG, serum insulin and lipid profile to normalcy. In diabetic gastrocnemius muscles, Setvioside normalized the altered levels of lipid peroxidase (LPO), hydrogen peroxide (H₂O₂) and hydroxyl radical (OH*), antioxidant enzymes (CAT, SOD, GPx and GSH) and molecules of insulin signaling including insulin receptor (IR), insulin receptor substrate-1 (IRS-1) and Akt mRNA levels. Furthermore, Stevioside enhanced glucose uptake (GU) and oxidation in diabetic muscles by augmenting glucose transporter 4 (GLUT 4) synthesis very effectively in a similar way to metformin. Results of molecular docking analysis evidenced the higher binding affinity with IRS-1 and GLUT 4. Stevioside effectively inhibits oxidative stress and promotes glucose uptake in diabetic gastrocnemius muscles by activating IR/IRS-1/Akt/GLUT 4 pathway. The results of the in silico investigation matched those of the in vivo study. Hence, Stevioside could be considered as a promising phytomedicine to treat T2DM.     

Anti-Diabetic Potential of Plant-Based Pentacyclic Triterpene Derivatives: Progress Made to Improve Efficacy and Bioavailability

Diabetes mellitus (DM) results from the inability of the pancreas to produce sufficient insulin or weakened cellular response to the insulin produced, which leads to hyperglycemia. Current treatments of DM focus on the use of oral hypoglycemic drugs such as acarbose, alpha-glucose inhibitors, sulphonylureas, thiazolidinediones, and biguanides to control blood glucose levels. However, these medications are known to have various side effects in addition to their bioavailability, efficacy, and safety concerns. These drawbacks have increased interest in the anti-diabetic potential of plant-derived bioactive compounds such as oleanolic and maslinic acids. Although their efficacy in ameliorating blood glucose levels has been reported in several studies, their bioavailability and efficacy remain of concern. The current review examines the anti-diabetic effects of oleanolic, maslinic, asiatic, ursolic, and corosolic acids and their derivatives, as well as the progress made thus far to enhance their bioavailability and efficacy. The literature for the current review was gathered from leading academic databases—including Google Scholar and PubMed—the key words listed below were used. The literature was searched as widely and comprehensively as possible without a defined range of dates.