The aim of the study was to determine the feasibility of the Vitellaria paradoxa nutshell as a new medicinal resource for treating diabetes. A total of forty-one compounds were identified by HPLC-DAD-Q-TOF-MS and phytochemical methods in V. paradoxa nutshell methanol extract. Based on HPLC fingerprints, four characteristic constituents were quantified and the origin of twenty-eight V. paradoxa nutshells from seven sub-Saharan countries was compared, which were classified into three groups with chemometric method. Twenty-eight samples contained high total phenolic content, and exhibited moderate-higher antioxidant activity and strong α-glucosidase inhibitory activity. Furthermore, all fractions and isolated compounds were evaluated for their antioxidant and α-glucosidase inhibitory activities, and α-glucosidase inhibitory action mechanism of four characteristic constituents including protocatechuic acid, 3, 5, 7-trihydroxycoumarin, (2R, 3R)-(+)-taxifolin and quercetin was investigated via molecular docking method, which were all stabilized by hydrogen bonds with α-glucosidase. The study provided an effective approach to waste utilization of V. paradoxa nutshell, which would help to resolve waste environmental pollution and provide a basis for developing potential herbal resource for treating diabetes.
Africa South of the Sahara ; Chromatography, High Pressure Liquid ; Diabetes Mellitus ; drug therapy ; enzymology ; Glycoside Hydrolase Inhibitors ; chemistry ; pharmacology ; Humans ; Hypoglycemic Agents ; chemistry ; pharmacology ; Molecular Docking Simulation ; Plant Extracts ; chemistry ; pharmacology ; Plants, Medicinal ; chemistry ; Sapotaceae ; chemistry ; alpha-Glucosidases ; metabolism

Calpain activation contributes to hyperglycemia-induced endothelial dysfunction and apoptosis. This study was designed to investigate the role of calpain inhibition in improving diabetic erectile dysfunction (ED) in mice. Thirty-eight-week-old male C57BL/6J mice were divided into three groups: (1) nondiabetic control group, (2) diabetic mice + vehicle group, and (3) diabetic mice + MDL28170 (an inhibitor of calpain) group. Type 1 diabetes was induced by intraperitoneal injection of streptozotocin at 60 mg kg^-1 body weight for 5 consecutive days. Thirteen weeks later, diabetic mice were treated with MDL28170 or vehicle for 4 weeks. The erectile function was assessed by electrical stimulation of the cavernous nerve. Penile tissues were collected for measurement of calpain activity and the endothelial nitric oxide synthase (eNOS)-nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) pathway. Terminal deoxynucleotidyl transferase 2'-deoxyuridine 5'-triphosphate nick end labeling (TUNEL) staining was used to evaluate apoptosis. Caspase-3 expression and activity were also measured to determine apoptosis. Our results showed that erectile function was enhanced by MDL28170 treatment in diabetic mice compared with the vehicle diabetic group. No differences in calpain-1 and calpain-2 expressions were observed among the three groups. However, calpain activity was increased in the diabetic group and reduced by MDL28170. The eNOS-NO-cGMP pathway was upregulated by MDL28170 treatment in diabetic mice. Additionally, MDL28170 could attenuate apoptosis and increase the endothelium and smooth muscle levels in corpus cavernosum. Inhibition of calpain could improve erectile function, probably by upregulating the eNOS-NO-cGMP pathway and reducing apoptosis.
Animals ; Apoptosis/drug effects* ; Calpain/antagonists & inhibitors* ; Cyclic GMP/biosynthesis* ; Diabetes Complications/drug therapy* ; Diabetes Mellitus, Experimental/complications* ; Dipeptides/therapeutic use* ; Endothelium/metabolism* ; Enzyme Inhibitors/therapeutic use* ; Erectile Dysfunction/etiology* ; In Situ Nick-End Labeling ; Male ; Mice ; Mice, Inbred C57BL ; Muscle, Smooth/metabolism* ; Nitric Oxide Synthase Type III/biosynthesis* ; Penis/enzymology* ; Up-Regulation

OBJECTIVEThe current study was designed to evaluate the various antioxidant potentials and inhibitory effects of phenolic-rich leaf extracts of Bridelia ferruginea (BF) on the in vitro activities of some key enzymes involved in the metabolism of carbohydrates.

METHODSIn this study, BF leaf free and bound phenolic-rich extracts were used. We quantified total phenolic and flavonoid contents, and evaluated several antioxidant activities using assays for ferric reducing antioxidant power, total antioxidant activity (phosphomolybdenum reducing ability), 1,1-diphenyl-2-picrylhydrazyl and thiobarbituric acid reactive species. Also, extracts were tested for their ability to inhibit α-amylase and α-glucosidase activity.

RESULTSThe total phenolic and total flavonoid contents in the free phenolic extract of BF were significantly greater than in the bound phenolic extract. Also, all the antioxidant activities considered were significantly greater in the free phenolic extract than in the bound phenolic extract. In the same vein, the free phenolic-rich extract had a significantly higher percentage inhibition against α-glucosidase activity (IC = 28.5 µg/mL) than the bound phenolic extract (IC = 340.0 µg/mL). On the contrary, the free phenolic extract (IC = 210.0 µg/mL) had significantly lower inhibition against α-amylase than the bound phenolic-rich extract (IC = 190.0 µg/mL).

CONCLUSIONThe phenolic-rich extracts of BF leaves showed antioxidant potentials and inhibited two key carbohydrate-metabolizing enzymes in vitro.

Animals ; Antioxidants ; chemistry ; pharmacology ; Diabetes Mellitus, Type 2 ; enzymology ; metabolism ; Enzyme Inhibitors ; chemistry ; pharmacology ; Glycoside Hydrolase Inhibitors ; chemistry ; pharmacology ; Humans ; Iron ; adverse effects ; Magnoliopsida ; chemistry ; Oxidative Stress ; drug effects ; Pancreas ; drug effects ; enzymology ; metabolism ; Phenols ; chemistry ; pharmacology ; Plant Extracts ; chemistry ; pharmacology ; Rats ; Swine ; alpha-Amylases ; antagonists & inhibitors ; chemistry ; alpha-Glucosidases ; chemistry

INTRODUCTIONThis study was designed and conducted to evaluate the effects of vitamin A, C and E supplementation, and omega-3 fatty acid supplementation on the activity of paraoxonase and arylesterase in an experimental model of diabetes mellitus.

METHODSA total of 64 male Sprague Dawley® rats, each weighing 250 g, were randomly distributed into four groups: (a) normal control; (b) diabetic control; (c) diabetic with vitamin A, C and E supplementation; and (d) diabetic with omega-3 fatty acid supplementation. The animals were anaesthetised after four weeks of intervention, and paraoxonase and arylesterase activity in blood plasma, and liver and heart homogenates were measured.

RESULTSArylesterase activity in the heart and liver homogenates was significantly lower in the diabetic control group than in the normal control group (p < 0.01). Vitamin A, C and E supplementation, and omega-3 fatty acid supplementation significantly increased liver arylesterase activity (p < 0.05). No significant change was observed in paraoxonase activity and other investigated factors.

CONCLUSIONVitamin A, C and E, or omega-3 fatty acid supplementation were found to increase liver arylesterase activity in streptozotocin-induced diabetic rats. These supplements may be potential agents for the treatment of diabetes mellitus complications.

Animals ; Aryldialkylphosphatase ; metabolism ; Ascorbic Acid ; pharmacology ; Carboxylic Ester Hydrolases ; metabolism ; Diabetes Mellitus, Experimental ; diet therapy ; metabolism ; Dietary Supplements ; Fatty Acids, Omega-3 ; pharmacology ; Liver ; enzymology ; Male ; Myocardium ; enzymology ; Rats ; Rats, Sprague-Dawley ; Vitamin A ; pharmacology ; Vitamins ; pharmacology

UNLABELLEDOCTOBER: To explore the effects of the glucagon-like peptide 1 (GLP-1) liraglutide on the penile erectile function of rats with diabetic erectile dysfunction (DED) by observing the impact of liraglutide on the expression of eNOS in the corpus cavernosum of diabetic rats.

METHODSWe randomly divided 30 six-week-old male SD rats into a normal control (n = 10) and an experimental group (n = 20) , established models of diabetes mellitus (DM) in the experimental rats, and subdivided them into a DM (n = 8) and a GLP-1 group (n = 8) to receive intramuscular injection of normal saline and liraglutide at 5 mg per kg of the body weight per day, respectively. After 12 weeks of intervention, we obtained the levels of FPG, FINS, TG, TC, HDL-C, LDL-C, testosterone, and IL-6 and the indexes of Homa-IR and Homa-β, detected the expressions of Akt/p-Akt and eNOS/p-eNOS in the corpus cavernosum by Western blot, and compared the erectile function between different groups.

RESULTSThe frequency and rate of penile erection were significantly lower in the DM group than in the GLP-1 and normal control groups (P < 0.05) and also lower in the GLP-1 group than in the normal controls (P < 0.05). Immunofluorescence staining showed the expression of eNOS mainly in the cytoplasm of the cavernosal vessels and sinusoidal endothelial cells, markedly lower in the DM and GLP-1 groups than in the normal rats (P < 0.05), but higher in the GLP-1 than in the DM group (P < 0.05). The level of eNOS/p-eNOS in the penile tissue was significantly decreased in the DM and GLP-1 groups in comparison with the normal controls (P < 0.01 or P < 0.05), while that of p-eNOS was markedly increased in the GLP-1 group as compared with the DM group (P < 0.05). No statistically significant differences were observed in the Akt level among the three groups of animals (P > 0.05). The expression of p-Akt was remarkably reduced in the DM and GLP-1 groups in comparison with the control rats (P < 0.01 or P < 0.05), but higher in the GLP-1 than in the DM group (P < 0.05).

CONCLUSIONGLP-1 can protect the function of endothelial cells in the corpus cavernosum and improve the erectile function of DED rats by regulating the Akt/ eNOS signaling pathway, which indicates that GLP-1 could be an important option for the treatment and prevention of DED.

Animals ; Blotting, Western ; Diabetes Mellitus, Experimental ; Erectile Dysfunction ; drug therapy ; enzymology ; Hypoglycemic Agents ; pharmacology ; Liraglutide ; pharmacology ; Male ; Nitric Oxide Synthase Type III ; metabolism ; Penile Erection ; drug effects ; Penis ; drug effects ; enzymology ; physiopathology ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Testosterone ; blood

OBJECTIVETo investigate the role of integrin-linked kinase (ILK) signaling pathway in the skin lesions and wound healing in diabetic rats.

METHODSThirty-six SD rats were divided into diabetic wound group (D) and non-diabetic wound group (N) according to the random number table, with 18 rats in each group. 10 g/L streptozocin (60 mg/kg) was intraperitoneally injected in rats in group D, while the rats in group N were given same quantity of sodium citrate buffer. Two weeks after successful reproduction of diabetic model of rats in group D, two full-thickness skin of an area of 2 cm × 2 cm was resected on both sides of back of rats in the two groups. Wounds of three rats of each group were photographed and examined on post injury day (PID) 1, 3, 7, 10, 14, and 21, and the wound healing rates were calculated. The non-injured skin and wound tissue (central part) on back of three rats of the rest 15 rats in the two groups were harvested on PID 3, 7, 10, 14, and 21, respectively. Morphology of the non-injured skin tissue was observed with HE staining, and the thickness of full-thickness skin and epidermis were measured. The mRNA expression levels of ILK, protein kinase B (Akt), and glycogen synthase kinase-3β (GSK-3β) in non-injured skin tissue were determined with real-time fluorescent quantitative RT-PCR. The protein expression levels of ILK, Akt, phosphorylated Akt, GSK-3β, and phosphorylated GSK-3β in non-injured skin tissue, and ILK, phosphorylated Akt in wound tissue were assessed with Western blotting. Data were processed with two independent-sample t test, one-way analysis of variance, SNK test and analysis of variance of factorial design.

RESULTS(1) After injury, the wound scabs of rats in group N were dry, and red granulation tissue with no excretion were seen when the scabs fell off, and the wound healed fast. After injury, excretion under the wound scabs of rats in group D was seen, and the scabs easily fell off with exposure of pink granulation tissue with much excretion, and the wounds healed slowly. Except for PID 3, the wound healing rate of rats in group D was significantly lower than that in group N on other PIDs (with t values from 3.858 to 13.738, P<0.05 or P<0.01). (2) On PID 3, the hair follicles and blood vessels in the non-injured skin tissue of rats in group N were rich, and the epidermis was composed of stratified cells in form of basal cells and keratinocyte, and the hair follicles and blood vessels in the non-injured skin tissue of rats in group D were scarce, and the epidermis was nearly composed of one-layer of cells. The thickness of full-thickness skin and epidermis of non-injured skin tissue of rats in group N was similar from PID 3 to 21, and the thickness of full-thickness skin and epidermis of non-injured skin tissue of rats in group D on PID 3 was respectively (1 074 ± 66) and (15.1 ± 3.8) μm, and they gradually thinned out to (785 ± 122) and (9.7 ± 2.1) μm on PID 21, respectively. The thickness of full-thickness skin and epidermis of non-injured skin tissue of rats in group N were significantly thicker than those in group D on each PID (with t values from 4.620 to 23.549, P values below 0.001). (3) From PID 3 to 21, the mRNA expression levels of ILK and Akt in non-injured skin tissue of rats in group D were significantly lower than those in group N (with t values respectively 4.779 and 3.440, P values below 0.05), the mRNA expression levels of GSK-3β in non-injured skin tissue of rats were similar in two groups (t=0.363, P>0.05). (4) From PID 3 to 21, the protein expression levels of ILK, Akt and phosphorylated Akt in non-injured skin tissue of rats in group D were significantly lower than those in group N (with t values from 2.630 to 6.209, P<0.05 or P<0.01); the protein expression levels of GSK-3β in non-injured skin tissue of rats in two groups were similar (t=0.652, P>0.05); the protein expression level of phosphorylated GSK-3β in non-injured skin tissue of rats in group D was significantly higher than that in group N (t=4.131, P<0.001). The protein expression levels of ILK in wound tissue of rats in two groups were similar on each PID (with t values from 0.381 to 2.440, P values above 0.05). Except for PID 3, the protein expression levels of phosphorylated Akt in wound tissue of rats in group N were significantly higher than that in group D on other PIDs (with t values from 4.091 to 20.555, P<0.05 or P<0.01). From PID 3 to 21, the protein expression levels of ILK in wound tissue and non-injured skin tissue of rats in group N were similar (F=2.522, P>0.05), and the protein expression level of phosphorylated Akt in wound tissue was significantly higher than that in non-injured skin tissue (F=117.329, P<0.001); the protein expression levels of ILK in wound tissue and non-injured skin tissue of rats in group D were similar (F=1.337, P>0.05), and the protein expression level of phosphorylated Akt in wound tissue was significantly higher than that in non-injured skin tissue (F=184.120, P<0.001).

CONCLUSIONSThe skin lesion of diabetic rats may be related to the declined expression levels of ILK, Akt and phosphorylated Akt in the ILK signaling pathway. The refractory healing of wound in diabetic rats may be related to the declined expression level of phosphorylated Akt.

Animals ; Diabetes Mellitus, Experimental ; enzymology ; Glycogen Synthase Kinase 3 ; metabolism ; Glycogen Synthase Kinase 3 beta ; Phosphorylation ; Protein-Serine-Threonine Kinases ; metabolism ; Proto-Oncogene Proteins c-akt ; metabolism ; Rats ; Rats, Sprague-Dawley ; Signal Transduction ; Skin ; injuries ; Wound Healing

The present study aimed at determining whether berberine can enhance the antidiabetic effects and alleviate the adverse effects of canagliflozin in diabetes mellitus. Streptozotocin-induced diabetic mice were introduced, and the combined effects of berberine and canagliflozin on glucose metabolism and kidney functions were investigated. Our results showed that berberine combined with canagliflozin (BC) increased reduction of fasting and postprandial blood glucose, diet, and water intake compared with berberine or canagliflozin alone. Interestingly, BC showed greater decrease in blood urea nitrogen and creatinine levels and lower total urine glucose excretion than canagliflozin alone. In addition, BC showed increased phosphorylated 5' AMP-activated protein kinase (pAMPK) expression and decreased tumor necrosis factor alpha (TNFα) levels in kidneys, compared with berberine or canagliflozin alone. These results indicated that BC was a stronger antidiabetic than berberine or canagliflozin alone with less negative side effects on the kidneys in the diabetic mice. The antidiabetic effect was likely to be mediated by synergically promoting the expression of pAMPK and reducing the expression of TNFα in kidneys. The present study represented the first report that canagliflozin combined with berberine was a promising treatment for diabetes mellitus. The exact underlying mechanisms of action should be investigated in future studies.
AMP-Activated Protein Kinases ; metabolism ; Animals ; Berberine ; administration & dosage ; Blood Glucose ; metabolism ; Canagliflozin ; administration & dosage ; adverse effects ; Diabetes Mellitus, Experimental ; drug therapy ; metabolism ; Drug Therapy, Combination ; Drugs, Chinese Herbal ; administration & dosage ; Humans ; Hypoglycemic Agents ; administration & dosage ; Insulin ; metabolism ; Kidney ; drug effects ; enzymology ; metabolism ; Male ; Mice ; Streptozocin

Despite strict pre- and post-transplantation screening, the incidence of new-onset diabetes after transplantation (NODAT) remains as high as 60%. This complication affects the risk of cardiovascular events and patient and graft survival rates. Thus, reducing the impact of NODAT could improve overall transplant success. The pathogenesis of NODAT is multifactorial, and both modifiable and nonmodifiable risk factors have been implicated. Monitoring and controlling the blood glucose profile, implementing multidisciplinary care, performing lifestyle modifications, using a modified immunosuppressive regimen, administering anti-metabolite agents, and taking a conventional antidiabetic approach may diminish the incidence of NODAT. In addition to these preventive strategies, inhibition of dipeptidyl peptidase-4 (DPP4) by the gliptin family of drugs has recently gained considerable interest as therapy for type 2 diabetes mellitus and NODAT. This review focuses on the role of DPP4 inhibitors and discusses recent literature regarding management of NODAT.
Animals ; Blood Glucose/drug effects/metabolism ; Diabetes Mellitus/diagnosis/*drug therapy/enzymology/etiology ; Dipeptidyl Peptidase 4/*metabolism ; Dipeptidyl-Peptidase IV Inhibitors/*therapeutic use ; Humans ; Organ Transplantation/*adverse effects ; Risk Assessment ; Risk Factors ; Treatment Outcome

Aging ; genetics ; metabolism ; Animals ; Diabetes Mellitus ; enzymology ; metabolism ; Humans ; Longevity ; genetics ; physiology ; Neoplasms ; enzymology ; metabolism ; Neurodegenerative Diseases ; enzymology ; metabolism ; Obesity ; enzymology ; metabolism ; Sirtuins ; genetics ; metabolism

INTRODUCTIONDiabetes mellitus induces microangiopathic changes that lead to endothelial dysfunction. This study investigated the effect of Xiaokening, a type of Chinese compound medicine, on the mesenteric arteriolar endothelial cell function of diabetic rats and its underlying mechanism.

METHODSDiabetes mellitus was induced in rat models via intraperitoneal injection of 60 mg/kg streptozotocin and observed over three weeks. Mesenteric arterioles, which were isolated in a cannulated and pressurised state, were incubated with intravascular injections of 1, 3 or 5 g/L Xiaokening for 24, 48 or 72 hours. The effects of Xiaokening on the release of nitric oxide (NO) on the mesenteric arterioles were detected under shear stress of 1, 10 and 20 dyn/cm(2). Biochemical methods were used to determine the activities of superoxide dismutase (SOD) and xanthine oxidase (XO). The expressions of endothelial NO synthase (eNOS), SOD and XO in the mesenteric arterioles were assessed using Western blot.

RESULTSCompared to normal rat arterioles, less NO was released in the mesenteric arterioles of diabetic rats. Xiaokening was found to have a concentration- and time-dependent effect on NO release; when the shear stress was increased, there was a gradual increase in the release of NO. Compared to normal arterioles, the expression of eNOS in the mesenteric arterioles of diabetic rats was lower. Incubation with Xiaokening increased SOD activity and expression, and decreased XO activity and expression in the mesenteric arterioles of the diabetic rats.

CONCLUSIONXiaokening was able to significantly increase NO release and improve the endothelial function of mesenteric arterioles through antioxidative mechanisms.

Animals ; Antioxidants ; chemistry ; Arterioles ; enzymology ; Diabetes Mellitus, Experimental ; drug therapy ; Dose-Response Relationship, Drug ; Drugs, Chinese Herbal ; pharmacology ; Endothelial Cells ; drug effects ; Injections, Intraperitoneal ; Male ; Nitric Oxide ; metabolism ; Nitric Oxide Synthase Type III ; metabolism ; Oxygen ; metabolism ; Rats ; Rats, Sprague-Dawley ; Streptozocin ; Superoxide Dismutase ; metabolism ; Xanthine Oxidase ; metabolism