Candidate For Treatment Of Diabetes Research Articles

Hepatorenal protective efficacy of flavonoids from Ocimum basilicum extract in diabetic albino rats: A focus on hypoglycemic, antioxidant, anti-inflammatory and anti-apoptotic activities

Plant derived phytochemical therapy is a bright candidate for treatment of diabetes and its associated complications. Ocimum baslicum is used as an anti-diabetic traditional medicine. Hence, the present study investigated the effect of Hail Ocimum extract (HOE) and its total flavonoids (HOETF) against hepatorenal damage in experimental diabetes induced by high-fat diet (HFD) and injection of streptozotocin (STZ) in rats. Diabetic animals were co-treated daily with HOE, HOETF or metformin (MET) as a standard anti-diabetic drug for four weeks. Compared to controls, HFD/STZ-treatment lead to significant increases in fasting blood glucose, insulin and HOMA-IR levels. Furthermore, diabetic rats had elevated hepatic (ALT and ALP) and kidney functions (urea and creatinine) biomarkers together with disturbed lipid profile and decreased PPAR-γ gene expression. Higher levels of hepatic and renal LPO and NO paralleled with lower levels of GSH and activities of antioxidant enzymes (SOD, CAT, GPx and GR) after HFD/STZ treatment. Additionally, noteworthy inflammatory and apoptotic responses were evident in both organs of diabetic rats as witnessed by augmented levels of TNF-α, IL-1b and Bax levels with declined levels of Bcl-2. Moreover, histological examination of hepatic, renal and pancreatic tissues validated the biochemical findings. On contrary, co-treatment of diabetic animals with HOE or HOETF could decrease glucose and insulin levels together with improvement of lipid markers and alleviation of hepatorenal dysfunction, oxidative injury, inflammatory and apoptotic events. Conclusively, HOE or HOETF could be a promising complementary therapeutic option for the management of diabetic hepatorenal complication owing to their antioxidant, anti-inflammatory; anti-apoptotic properties.

An efficient large-scale refolding technique for recovering biologically active recombinant human FGF-21 from inclusion bodies

Fibroblast growth factor 21 (FGF-21) is an important regulator in glycolipid metabolism that is a promising drug candidate for treatment of diabetes and obesity. However, the productivity of recombinant hFGF-21 (rhFGF-21) in Escherichia coli (E. coli) is relatively low, which limits its clinical application. To meet the clinical demand and control the production cost, rhFGF-21 proteins were expressed in inclusion bodies (IBs) form in Rosetta (DE3) by high cell density fermentation in 50-L scale. Hollow fiber membrane filtration technology was used to enrich the bacteria, wash, denature and refold the IBs in the current report. The renatured proteins were purified by two-step affinity chromatography. Authenticity of the purified rhFGF-21 was confirmed by the N-and C-terminal sequence, disulfide bond composition and molecular weight analyses. Results showed that the average target protein and recovery of rhFGF-21 expressed in IBs form of three batches were more than those of the soluble form. Both the rhFGF-21 proteins from the two forms showed equal potency in improving the glucose uptake in HepG2 cells and anti-diabetic effect in db/db mice. In this study, an efficient method for preparation of FGF-21 was established. This novel process provides an important technical basis for the large-scale production of rhFGF-21.

Tetradecyl 2,3-Dihydroxybenzoate Improves the Symptoms of Diabetic Mice by Modulation of Insulin and Adiponectin Signaling Pathways.

Background: Tetradecyl 2,3-dihydroxybenzoate (ABG-001) derived from Chinese medicine, gentiana regescens Franch is a leading compound with NGF mimic effect, it can induce neurite outgrowth of PC12 cells via the IGF-1/PI3K/ERK signaling pathway. Thus, we inferred that this compound had anti-diabetic effect and used streptozocin (STZ)-induced diabetic mice to indicate it.Methods: ABG-001 was synthesized with 2,3-dihydroxybenzoic acid and tetradecyl alcohol under certain reaction conditions. STZ-induced diabetic mice were used to investigate anti-diabetic effect. Oral glucose tolerance test, insulin tolerance test, RT-PCR, Western blot, ELISA assays and histological section were performed to do the analysis of action mechanism.Results: ABG-001 showed anti-diabetic effect in STZ-induced diabetic mice. In diabetic mice, the anti-diabetic effect of ABG-001 at a dose of 20 mg/kg was equal with metformin at a dose of 140 mg/kg. Moreover, glucose tolerance and insulin sensitivity were significantly improved on diabetic mice. The plasma insulin, adiponectin and leptin were notably increased, whereas glucagon remarkably decreased. The gene expressions of adiponectin and leptin in adipose tissue, glucose transporter 4 and adiponectin receptor 1 in liver and gastrocnemius, ADR2 in hypothalamus and pancreas were obviously increased.Conclusion: ABG-001 exerts antidiabetic effects via modulation of insulin and adiponectin signaling pathways. This new type of molecule could be a promising drug candidate for treatment of diabetes.

Glucose-responsive biopolymer nanoparticles prepared by co-assembly of concanavalin A and amylopectin for insulin delivery

The development of glucose-responsive biopolymer nanocarriers for self-regulated insulin delivery is significant in the treatment of diabetes. In this work, for the first time, we have developed a new approach to prepare glucose-responsive biopolymer nanoparticles co-assembled by concanavalin A (Con A) and amylopectin. The influence of the Con A-amylopectin mass ratio, incubation time, pH, and ionic strength on the characteristics of the obtained nanoparticles was investigated. Under optimal conditions, the biopolymer nanoparticles were spherical with diameters of 100–300nm. The results of fluorimetry indicated that the conformation of Con A was changed with the combination of a different concentration of amylopectin. The Fourier transform infrared (FTIR) spectra of biopolymer nanoparticles indicated that the nanoparticles were formed through the interaction between Con A and amylopectin. Insulin could be embedded into nanoparticles, and the encapsulation efficiency of insulin was approximately 69.73%. The loading capacity of insulin was up to 17%. The insulin-release rate for nanoparticles in 3mg/ml glucose media increased 2.23 times that of nanoparticles in the absence of glucose. Thus, the developed biopolymer nanoparticles with underlying glucose-sensitive behavior are excellent candidates for treatment of diabetes.

Mosquitocidal, Antimalarial and Antidiabetic Potential of Musa paradisiaca-Synthesized Silver Nanoparticles: In Vivo and In Vitro Approaches

The development of pathogens and parasites resistant to synthetic drugs has created the need for developing alternative approaches to fight vector-borne diseases. In this research, we fabricated green-synthesized silver nanoparticles (AgNP) using Musa paradisiaca stem extract as a reducing and stabilizing agent. AgNP showed plasmon resonance reduction under UV–Vis spectrophotometry, SEM and XRD highlighted that they were crystalline in nature with face centered cubic geometry. The FTIR spectrum of AgNP exhibited main peaks at 464.74, 675.61, 797.07, 1059.42, 1402.58, 1639.69, 2115.61 and 3445.75 cm−1. AgNP showed growth inhibition activity against bacteria and fungi of public health relevance. AgNP were a valuable candidate for treatment of diabetes in STZ-treated rat by normalizing glucose, galactose and insulin. AgNP were toxic against larvae and pupae of the malaria vector Anopheles stephensi, with LC50 of 3.642 (I), 5.497 (II), 8.561 (III), 13.477 (IV), and 17.898 ppm (pupae), respectively. Furthermore, the antiplasmodial activity of nanoparticles was evaluated against CQ-resistant (CQ-r) and CQ-sensitive (CQ-s) strains of Plasmodium falciparum, IC50 were 84.22 μg/ml (CQ-s) and 89.24 μg/ml (CQ-r), while chloroquine IC50 were 86 μg/ml (CQ-s) and 91 μg/ml (CQ-r). Overall, we add knowledge on the multipurpose effectiveness of green-fabricated nanoparticles in medicine and parasitology, which can be potentially helpful to develop newer and safer antiplasmodial agents and vector control tools.

In vivo anti-diabetic activity of derivatives of isoliquiritigenin and liquiritigenin

Isoliquiritigenin (ISL), a chalcone and liquiritigenin (LTG), a flavonoid found in licorice roots and several other plants. ISL displays antioxidant, anti-inflammatory, antitumor and hepatoprotective activities whereas LTG is an estrogenic compound, acts as an agonist selective for the β-subtype of the oestrogen receptor. Both the phenolics were isolated from the rhizomes of Glycyrrhiza glabra. Five derivatives from ISL and four derivatives from LTG were synthesized. All the compounds were established by extensive spectroscopic analyses and screened through oral glucose tolerance test to gain preliminary information regarding the antihyperglycemic effect in normal Swiss albino male mice. ISL (1), ISL derivatives 3, 4, 5, 7 and LTG derivatives 9 and 10 showed significant blood glucose lowering effect. The structure–activity relationship indicated that the presence of ether and ester groups in ISL and LTG analogues are important for exhibiting the activity. Compounds 1, 4 and 10 were selected for in vivo antidiabetic activity and found to be potential candidates for treatment of diabetes. It is the first report on antidiabetic activity of ISL derivative 4 and LTG derivative 10.

Evaluation of Hypoglycemic and Antioxidative Effects of Synthesized Peptide MC62

Diabetes mellitus has been considered as a major health problem in the world today. This study aimed to investigate the hypoglycemic and antioxidative effects of peptide MC62 which was synthesized by solid-phase peptide synthesis method against diabetes induced by streptozotocin. MC62 was administered daily and injected intraperitoneally to the diabetic mice at a dose of 1μmol/kg body weight for 20days. The levels of fasting blood glucose and HbA1C, pancreatic islet damage, and associated changes in antioxidative activities were evaluated in streptozotocin-induced diabetic mice used the exenatide as positive control. After the administration of MC62 together with exenatide for 20days, the elevated fasting blood glucose and HbA1C levels were reduced, and antioxidative activities were restored. It was confirmed with the histological finding that MC62 prevented the islet from damage in diabetic mice. This indicated that MC62 can prevent mice from hyperglycemia which may be associated with oxidative stress. It also suggested that MC62 could be used as a safe alternative hypoglycemic candidate for treatment of diabetes.

Regulation of oxidative stress and somatostatin, cholecystokinin, apelin gene expressions by ghrelin in stomach of newborn diabetic rats

The aim of the study was to determine whether ghrelin treatment has a protective effect on gene expression and biochemical changes in the stomach of newborn streptozotocin (STZ) induced diabetic rats. In this study, four groups of Wistar rats were used: control, ghrelin control, diabetic and diabetic+ghrelin. The rats were sacrificed after four weeks of treatment for diabetes. The gene expressions of: somatostatin, cholecystokinin, apelin and the altered active caspase-3, active caspase-8, proliferating cell nuclear antigen, were investigated in the pyloric region of the stomach and antioxidant parameters were measured in all the stomach. Although ghrelin treatment to diabetic rats lowered the stomach lipid peroxidation levels, the stomach glutathione levels were increased. Exogenous ghrelin caused an increased activities of stomach catalase, superoxide dismutase, glutathione reductase and glutathione peroxidase in diabetic rats. Numbers of somatostatin, cholecystokinin and proliferating cell nuclear antigen immunoreactive cells decreased in the diabetic+ghrelin group compared to the diabetic group. Apelin mRNA expressions were remarkably less in the diabetic+ghrelin rats than in diabetic rats. The results may indicate that ghrelin treatment has a protective effect to some extent on the diabetic rats. This protection is possibly accomplished through the antioxidant activity of ghrelin observed in type 2 diabetes. Consequently exogenous ghrelin may be a candidate for therapeutic treatment of diabetes.

The role of serum albumin in the metabolism of Boc5: Molecular identification, species differences and contribution to plasma metabolism

Boc5, the first nonpeptidic agonist of Glucagon-like peptide-1 receptor, has been recognized as a potential candidate for treatment of diabetes. However, the metabolic behaviors of this novel molecule in both human and experimental animals remain unclear. This study aimed to explore the metabolic behaviors of Boc5 in biological preparations from human, pig and rat. Boc5 was found to be very stable in liver microsomes of human, pig and rat, but it can be degraded to two metabolites in plasma from all three species, via the successive hydrolysis of the C-22 esters. Chemical inhibition studies using selective esterase inhibitors and assays with purified enzymes suggested that Boc5 hydrolysis in human was totally mediated by human serum albumin (HSA) rather than esterases. ESI-TOF-MS/MS analysis revealed that Lys525 of HSA could be modified by treatment with Boc5, strongly suggesting the pseudo-esterase activity of albumin. Studies on species differences in this albumin-mediated metabolism showed large species differences in degradation rate of Boc5, the half lives of Boc5 in plasma from three various species varied from 23.5 h to 83.1h, but they were much closer to the half lives of Boc5 in corresponding serum albumins, implying the predominant role of serum albumin in plasma metabolism of Boc5. Additionally, the effects of various ligands including fatty acids and several drugs with unambiguous binding sites on HSA, on the pseudo-esterase activity of HSA, were also investigated using both experimental and molecular modelling studies. These results showed that the binding of various ligands to HSA could significantly affect the pseudo-esterase activity of HSA towards Boc5, due to the ligand-induced conformation changes of HSA.

Polyhydroxylated Macrolides from Seimatosporium discosioides and Their Effects on the Activation of Peroxisome Proliferator-Activated Receptor Gamma

Two new polyhydroxylated macrolides, seimatopolides A (1) and B (2), were isolated from an EtOAc extract of Seimatosporium discosioides culture medium. The structures of the new compounds were established on the basis of spectroscopic analysis, including 1D and 2D NMR, and their absolute configurations were determined using the modified Mosher's method. Seimatopolides A (1) and B (2) activated peroxisome proliferator-activated receptor (PPAR)-γ with EC(50) values of 1.15 and 11.05 μM, respectively. The expression of PPAR-γ target genes in HepG2 hepatocytes was significantly altered; in particular, expression of the gluconeogenic genes glucose-6-phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK) was reduced upon stimulation with 1, supporting the proposal that compound 1 is both a PPAR-γ agonist and a possible therapeutic candidate for treatment of diabetes.

Liposomal formulations of glucagon-like peptide-1: Improved bioavailability and anti-diabetic effect

Glucagon-like peptide-1 (GLP-1), an incretin hormone, is recognized to be potent drug candidate for treatment of diabetes, however its clinical application has been highly limited, because of rapid enzymatic degradation by dipeptidyl-peptidase IV. To protect GLP-1 from enzymatic degradation and improve pharmacological effects, liposomal formulations of GLP-1 were prepared using three types of lyophilized empty liposomes such as anionic, neutral and cationic liposomes. Electron microscopic and dynamic light scattering experiments indicated the uniform size distribution of GLP-1-loaded liposomes with mean diameter of 130–210 nm, and inclusion of GLP-1 did not affect the dispersibility and morphology of each liposome. Of all liposomal formulations tested, anionic liposomal formulation exhibited the highest encapsulation efficiency of GLP-1 (ca. 80%). In intraperitoneal glucose tolerance testing in rats, marked improvement of hypoglycemic effects were observed in anionic liposomal formulation of GLP-1 (100 nmol/kg) with 1.7-fold higher increase of insulin secretion, as compared to GLP-1 solution. In pharmacokinetic studies, intravenous administration of anionic liposomal formulation of GLP-1 (100 nmol/kg) resulted in 3.6-fold higher elevation of serum GLP-1 level as compared to GLP-1 injection. Upon these findings, anionic liposomal formulation of GLP-1 would provide the improved pharmacokinetics and insulinotropic action, possibly leading to efficacious anti-diabetic medication.

A Brake Becomes an Accelerator: PTP1B—A New Therapeutic Target for Breast Cancer

The protein tyrosine phosphatase PTP1B, previously recognized for its role in downregulating insulin and leptin signaling, has now been shown to function as a positive regulator of signaling events associated with breast tumorigenesis. Inhibitors of PTP1B that have been developed as drug candidates for treatment of diabetes and obesity may offer new avenues for the treatment of breast cancer.