Natural Ingredients from Medicine Food Homology as Chemopreventive Reagents against Type 2 Diabetes Mellitus by Modulating Gut Microbiota Homoeostasis

Type 2 diabetes mellitus (T2DM) is a noteworthy worldwide public health problem. It represents a complex metabolic disorder, mainly characterized as hyperglycemia and lipid dysfunction. The gut microbiota dysbiosis has been proposed to play a role in the development of diabetes. Recently, there has been considerable interest in the use of medicine food homology (MFH) and functional food herbs (FF) to ameliorate diabetes and lead to a natural and healthy life. Hence, this review compiles some reports and findings to demonstrate that the practical use of the MFH/FF can modulate the homoeostasis of gut microbiota, thereby ameliorating the development of T2DM. The results provided useful data to support further investigation of the functional basis and application of MFH/FF to treat T2DM through maintaining intestinal homeostasis.     

Discovery of Novel and Selective G-Protein Coupled Receptor 120 (GPR120) Agonists for the Treatment of Type 2 Diabetes Mellitus

Diabetes mellitus (DM), a chronic metabolic disorder characterized by high blood glucose, not only poses a serious threat to human life and health, but also places an economic burden on society. Currently available antidiabetic pharmacological agents have some adverse effects, which have stimulated researchers to explore novel antidiabetic agents with different mechanisms of action. G-protein Coupled Receptor 120 (GPR120), also known as free fatty acid receptor 4 (FFAR4), which is activated by medium-chain and long-chain fatty acids, has emerged as an interesting potential target for the treatment of metabolic disorders. Herein, we designed and synthesized a series of novel GPR120 agonists based on the structure of TUG-891, which is susceptible to β-oxidation and loses its GPR120 agonistic activity in vivo. Among the designed compounds, 14d showed excellent agonistic activity and selectivity and could improve glucose tolerance in normal mice in a dose-dependent manner. In addition, the compound 14d displayed good antidiabetic effects in diet-induced obese (DIO) mice and elevated insulin levels. Molecular simulations illustrated that compound 14d could enter the active site of GPR120 and interact with ARG99, which plays an important role in GPR120 activation. Based on these observations, compound 14d may be a promising lead compound deserving of further biological evaluation and structural modifications.     

Determination of Plasma Amino Acid Biomarkers by High Performance Liquid Chromatography for Diagnosis of Type 2 Diabetes Mellitus

The use of the fasting plasma glucose and 2-h plasma glucose tolerance tests leads to under-diagnosis of type 2 diabetes mellitus. To explore the contribution of metabolites for diagnosis for type 2 diabetes, plasma targeted metabolites (including free amino acids, lipids, and two hepatic aminotransferases) of 95 subjects were determined by high performance liquid chromatography and routine clinical methods. Receiver operating characteristic curve analysis was employed to evaluate potential diagnosis models. Based on the processing of orthogonal partial least squares-discriminant analysis, five amino acids (lysine, aspartate acid, threonine, methionine, and alanine) and two lipids (low density lipoprotein-cholesterol and high density lipoprotein-cholesterol) were discovered as potential biomarkers of type 2 diabetes. The area under the receiver operating characteristic curve built by the combination of these biomarkers and fasting plasma glucose was 0.994, which is significantly higher than that of the latter alone (0.907). These findings indicate that simultaneous measurement of specific metabolites with fasting plasma glucose from a single blood test for screening type 2 diabetes might be a more sensitive and specific strategy and provide additional insight regarding disease pathophysiologic mechanisms.     

两种胰岛素方案治疗门诊初诊2型糖尿病患者的疗效及低血糖发生率比较

目的研究两种胰岛素方案治疗门诊初诊2型糖尿病患者的疗效及低血糖发生率。方法选取孝感市中心医院2013年3月—2014年8月84例门诊初诊2型糖尿病患者,抽签随机分为两组,其中42例采用餐前皮下注射门冬胰岛素治疗记为对照组,剩下42例采用餐前注射门冬胰岛素联合晚间注射甘精胰岛素强化治疗记为观察组。结果两组治疗后血糖相关指标比较无明显差异,不具有统计学意义(P0.05);观察组低血糖率11.90%较对照组30.95%显著较低,具有统计学意义(P0.05)。结论两种胰岛素方案治疗初诊2型糖尿病均较为有效,但早期采用强化治疗方案能有效稳定平衡血糖代谢、预防低血糖发生,可作为临床治疗初诊2型糖尿病的首选参考方法。     

The Purinergic Landscape of Type 2 Diabetes Mellitus

Adenosine triphosphate (ATP) is the key energy intermediate of cellular metabolic processes and a ubiquitous extracellular messenger. As an extracellular messenger, ATP acts at plasma membrane P2 receptors (P2Rs). The levels of extracellular ATP (eATP) are set by both passive and active release mechanisms and degradation processes. Under physiological conditions, eATP concentration is in the low nanomolar range but can rise to tens or even hundreds of micromoles/L at inflammatory sites. A dysregulated eATP homeostasis is a pathogenic factor in several chronic inflammatory diseases, including type 2 diabetes mellitus (T2DM). T2DM is characterized by peripheral insulin resistance and impairment of insulin production from pancreatic β-cells in a landscape of systemic inflammation. Although various hypoglycemic drugs are currently available, an effective treatment for T2DM and its complications is not available. However, counteracting systemic inflammation is anticipated to be beneficial. The postulated eATP increase in T2DM is understood to be a driver of inflammation via P2X7 receptor (P2X7R) activation and the release of inflammatory cytokines. Furthermore, P2X7R stimulation is thought to trigger apoptosis of pancreatic β-cells, thus further aggravating hyperglycemia. Targeting eATP and the P2X7R might be an appealing novel approach to T2DM therapy.     

Lycopene: A Potent Antioxidant for the Amelioration of Type II Diabetes Mellitus

Nutrition is of utmost importance in chronic disease management and has often been described as the cornerstone of a variety of non-communicable diseases. In particular, type II diabetes mellitus (T2DM) represents a prevalent and global public health crisis. Lycopene, a bright red carotenoid hydrocarbon found in tomatoes and other red fruits and vegetables, has been extensively studied for its biological activities and treatment efficiency in diabetes care. Epidemiological investigations indicate that lycopene has potential antioxidant properties, is capable of scavenging reactive species, and alleviates oxidative stress in T2DM patients. This review aims to summarize the characteristics and mechanisms of action of lycopene as a potent antioxidant for T2DM. In addition, the evidence demonstrating the effects of lycopene on glycemic control and oxidative stress biomarkers in T2DM are also highlighted using animal and human studies as literature approach.     

Novel GPR120 Agonists with Improved Pharmacokinetic Profiles for the Treatment of Type 2 Diabetes

GPR120 is a promising target for the treatment of type 2 diabetes (T2DM), which is activated by free fatty acids (FFAs) and stimulates the release of glucagon-like peptide-1(GLP-1). GLP-1, as an incretin, can enhance glucose-dependent secretion of insulin from pancreatic beta cells and reduce blood glucose. In this study, a series of novel GPR120 agonists were designed and synthesized to improve the stability and hydrophilicity of the phenylpropanoic acid GPR120 agonist TUG-891. Compound 11b showed excellent GPR120 agonistic activity and pharmacokinetic properties, and could reduce the blood glucose of normal mice in a dose-dependent manner. In addition, no hypoglycemic side effects were observed even at a dose of 100 mg/kg. Moreover, 11b showed good anti-hyperglycemic effects in diet-induced obese (DIO) mice. Molecular simulation illustrated that compound 11b could enter the active site of GPR120 and interact with ARG99. Taken together, the results indicate that compound 11b might be a promising drug candidate for the treatment of T2DM.     

Molecular Docking and Dynamics Simulation of Natural Compounds from Betel Leaves (Piper betle L.) for Investigating the Potential Inhibition of Alpha-Amylase and Alpha-Glucosidase of Type 2 Diabetes

Piper betle L. is widely distributed and commonly used medicinally important herb. It can also be used as a medication for type 2 diabetes patients. In this study, compounds of P. betle were screened to investigate the inhibitory action of alpha-amylase and alpha-glucosidase against type 2 diabetes through molecular docking, molecular dynamics simulation, and ADMET (absorption, distribution, metabolism, excretion, and toxicity) analysis. The molecule apigenin-7-O-glucoside showed the highest binding affinity among 123 (one hundred twenty-three) tested compounds. This compound simultaneously bound with the two-target proteins alpha-amylase and alpha-glucosidase, with high molecular mechanics-generalized born surface area (MM/GBSA) values (ΔG Bind = −45.02 kcal mol⁻¹ for alpha-amylase and −38.288 for alpha-glucosidase) compared with control inhibitor acarbose, which had binding affinities of −36.796 kcal mol⁻¹ for alpha-amylase and −29.622 kcal mol⁻¹ for alpha-glucosidase. The apigenin-7-O-glucoside was revealed to be the most stable molecule with the highest binding free energy through molecular dynamics simulation, indicating that it could compete with the inhibitors’ native ligand. Based on ADMET analysis, this phytochemical exhibited a wide range of physicochemical, pharmacokinetic, and drug-like qualities and had no significant side effects, making them prospective drug candidates for type 2 diabetes. Additional in vitro, in vivo, and clinical investigations are needed to determine the precise efficacy of drugs.     

浅析磷酸西格列汀联合二甲双胍治疗新诊断2型糖尿病的降糖效果

目的探讨磷酸西格列汀联合二甲双胍治疗新诊断2型糖尿.病的降糖效果及对胰岛功能的保护作用。方法将2015年12月—2016年12月在广州市增城区人民医院内分泌科治疗的66例新诊断2型糖尿病患者随机分为两组,对照组单服二甲双胍治疗,观察组采用磷酸西格列汀联合二甲双胍治疗,比较两组患者的血糖及胰岛素功能。结果观察组治疗后FPG、2h PG、Hb A1c明显较对照组改善,差异有统计学意义(P<0.05);观察组治疗后HOMA-β、HOMAIR、IAI、血清APN明显较对照组改善,差异有统计学意义(P<0.05)。结论磷酸西格列汀联合二甲双胍治疗新诊断2型糖尿病效果显著,有利于血糖的平稳控制,延缓胰岛功能恶化,保护胰岛β细胞功能,具有积极的临床意义。     

pH-temperature Responsive Hydrogel-Mediated Delivery of Exendin-4 Encapsulated Chitosan Nanospheres for Sustained Therapeutic Efficacy in Type 2 Diabetes Mellitus

Type 2 Diabetes Mellitus (T2D) is a chronic, obesity-related, and inflammatory disorder characterize by insulin resistance, inadequate insulin secretion, hyperglycemia, and excessive glucagon secretion. Exendin-4 (EX), a clinically established antidiabetic medication that acts as a glucagon-like peptide-1 receptor agonist, is effective in lowering glucose levels and stimulating insulin secretion while significantly reducing hunger. However, the requirement for multiple daily injections due to EX's short half-life is a significant limitation in its clinical application, leading to high treatment costs and patient inconvenience. To address this issue, an injectable hydrogel system is developed that can provide sustained EX release at the injection site, reducing the need for daily injections. In this study, the electrospray technique is examine to form EX@CS nanospheres by electrostatic interaction between cationic chitosan (CS) and negatively charged EX. These nanospheres are uniformly dispersed in a pH-temperature responsive pentablock copolymer, which forms micelles and undergoes sol-to-gel transition at physiological conditions. Following injection, the hydrogel gradually degraded, exhibiting excellent biocompatibility. The EX@CS nanospheres are subsequently released, maintaining therapeutic levels for over 72 h compared to free EX solution. The findings demonstrate that the pH-temperature responsive hydrogel system containing EX@CS nanospheres can be a promising platform for the treatment of T2D.     

60例非胰岛素依赖型糖尿病人发铬分析

用ＤＣＴ直读光谱仪测定了６０例非胰岛素依赖型糖尿病人发铬微量元素。铬（Ⅲ）含量低于对照组。具有生物活性的铬（Ⅲ）有机化合物－葡萄糖耐受因子（ＧＴＦ）是胰岛素的“协同激素”。铬（Ⅲ）含量降低，葡萄糖耐量受损，可导致胰岛素作用降低，影响糖元的合成与代谢。提示铬的测定对非胰岛素依赖型糖尿病早期诊断及治疗有一定的临床价值。     

Therapeutic Screening of Herbal Remedies for the Management of Diabetes

The study of diabetes mellitus (DM) patterns illustrates increasingly important facts. Most importantly, they include oxidative stress, inflammation, and cellular death. Up to now, there is a shortage of drug therapies for DM, and the discovery and the development of novel therapeutics for this disease are crucial. Medicinal plants are being used more and more as an alternative and natural cure for the disease. Consequently, the objective of this review was to examine the latest results on the effectiveness and protection of natural plants in the management of DM as adjuvant drugs for diabetes and its complex concomitant diseases.     

2型糖尿病患者血清钙镁与甲状腺激素含量变化及临床意义

为了监测 2型糖尿病人血清钙、镁和甲状腺激素含量 ,分析其临床意义及相关性 ,应用放射免疫分析法测定了 1 1 5例 2型糖尿病及 1 5 0例健康人血清甲状腺激素含量。同时用美国杜邦RXL自动生化仪测定了其血清钙、镁含量。结果表明 ,在 2型糖尿病伴有明显并发症者血镁、FT3水平明显降低 (P <0 0 5 ) ,钙镁两种元素与甲状腺激素水平无明显相关性。 2型糖尿病患者适当补镁对预防其并发症是有益的 ,测定FT3 等可作为判断 2型糖尿病严重程度和估计预后的参考指标。     

Lignin as a Natural Carrier for the Efficient Delivery of Bioactive Compounds: From Waste to Health

Lignin is a fascinating aromatic biopolymer with high valorization potentiality. Besides its extensive value in the biorefinery context, as a renewable source of aromatics lignin is currently under evaluation for its huge potential in biomedical applications. Besides the specific antioxidant and antimicrobial activities of lignin, that depend on its source and isolation procedure, remarkable progress has been made, over the last five years, in the isolation, functionalization and modification of lignin and lignin-derived compounds to use as carriers for biologically active substances. The aim of this review is to summarize the current state of the art in the field of lignin-based carrier systems, highlighting the most important results. Furthermore, the possibilities and constraints related to the physico–chemical properties of the lignin source will be reviewed herein as well as the modifications and processing required to make lignin suitable for the loading and release of active compounds.     

Identification of Natural Compounds as Inhibitors of Pyruvate Kinase M2 for Cancer Treatment

The reliance of tumor cells on aerobic glycolysis is one of the emerging hallmarks of cancer. Pyruvate kinase M2 (PKM2), an important enzyme of glycolytic pathway, is highly expressed in a number of cancer cells. Tumor cells heavily depend on PKM2 to fulfill their divergent energetic and biosynthetic requirements, suggesting it as novel drug target for cancer therapies. Based on this context, we performed enzymatic-assay-based screening of the in-house phenolic compounds library for the identification of PKM2 inhibitors. This screening identified silibinin, curcumin, resveratrol, and ellagic acid as potential inhibitors of PKM2 with IC₅₀ values of 0.91 µM, 1.12 µM, 3.07 µM, and 4.20 µM respectively. For the determination of Ki constants and the inhibition type of hit compounds, Lineweaver–Burk graphs were plotted. Silibinin and ellagic acid performed the competitive inhibition of PKM2 with Ki constants of 0.61 µM and 5.06 µM, while curcumin and resveratrol were identified as non-competitive inhibitors of PKM2 with Ki constants of 1.20 µM and 7.34 µM. The in silico screening of phenolic compounds against three binding sites of PKM2 provided insight into the binding pattern and functionally important amino residues of PKM2. Further, the evaluation of cytotoxicity via MTT assay demonstrated ellagic acid as potent inhibitor of cancer cell growth (IC₅₀ = 20 µM). These results present ellagic acid, silibinin, curcumin, and resveratrol as inhibitors of PKM2 to interrogate metabolic reprogramming in cancer cells. This study has also provided the foundation for further research to validate the potential of identified bioactive entities for PKM2 targeted-cancer therapies.     

3-Oxodapagliflozin as a Potent and Highly Selective SGLT2 Inhibitor for the Treatment of Type 2 Diabetes

Structural modifications of 3-OH in the glucose moiety of dapagliflozin（1）, an approved potent sodium-dependent glucose transporter 2（SGLT2） inhibitor, led to 3-oxodapagliflozin（16）, a highly potent and more selective SGLT2 inhibitor[IC50（hSGLT1）/IC50（hSGLT2）=2851 for compound 16 vs. 843 for compound 1]. 3-Oxodapagliflozin（16） exhibited in vitro（IC50=1.0nmol/L against hSGLT2 for compound 16 vs. 1.3 nmol/L for compound 1） and in vivo activities comparable to those of dapagliflozin（1）. The bioactivities of 3-oxodapagliflozin （16） warrant its further evaluation as a promising SGLT2 inhibitor for the treatment of type 2 diabetes.     

Phytochemical Profiling,Isolation, and Pharmacological Applications of Bioactive Compounds from Insects of the Family Blattidae Together with Related Drug Development

In traditional Chinese medicine (TCM), insects from the family Blattidae have a long history of application, and their related active compounds have excellent pharmacological properties, making them a prominent concern with significant potential for medicinal and healthcare purposes. However, the medicinal potential of the family Blattidae has not been fully exploited, and many problems must be resolved urgently. Therefore, a comprehensive review of its chemical composition, pharmacological activities, current research status, and existing problems is necessary. In order to make the review clearer and more systematic, all the contents were independently elaborated and summarized in a certain sequence. Each part started with introducing the current situation or a framework and then was illustrated with concrete examples. Several pertinent conclusions and outlooks were provided after discussing relevant key issues that emerged in each section. This review focuses on analyzing the current studies and utilization of medicinal insects in the family Blattidae, which is expected to provide meaningful and valuable relevant information for researchers, thereby promoting further exploration and development of lead compounds or bioactive fractions for new drugs from the insects.     

Computational Study of Asian Propolis Compounds as Potential Anti-Type 2 Diabetes Mellitus Agents by Using Inverse Virtual Screening with the DIA-DB Web Server,Tanimoto Similarity Analysis,and Molecular Dynamic Simulation

Propolis contains a wide range of pharmacological activities because of their various bioactive compounds. The beneficial effect of propolis is interesting for treating type-2 diabetes mellitus (T2DM) owing to dysregulation of multiple metabolic processes. In this study, 275 of 658 Asian propolis compounds were evaluated as potential anti-T2DM agents using the DIA-DB web server towards 18 known anti-diabetes protein targets. More than 20% of all compounds could bind to more than five diabetes targets with high binding affinity (<−9.0 kcal/mol). Filtering with physicochemical and pharmacokinetic properties, including ADMET parameters, 12 compounds were identified as potential anti-T2DM with favorable ADMET properties. Six of those compounds, (2R)-7,4′-dihydroxy-5-methoxy-8-methylflavone; (RR)-(+)-3′-senecioylkhellactone; 2′,4′,6′-trihydroxy chalcone; alpinetin; pinobanksin-3-O-butyrate; and pinocembrin-5-methyl ether were first reported as anti-T2DM agents. We identified the significant T2DM targets of Asian propolis, namely retinol-binding protein-4 (RBP4) and aldose reductase (AKR1B1) that have important roles in insulin sensitivity and diabetes complication, respectively. Molecular dynamic simulations showed stable interaction of selected propolis compounds in the active site of RBP4 and AKR1B1. These findings suggest that Asian propolis compound may be effective for treatment of T2DM by targeting RBP4 and AKR1B1.