benzofurans and Diabetes-Mellitus

3-N-butylphthalide (NBP) is a component isolated from seeds of Chinese celery, and it was firstly approved for the treatment of ischemic stroke. With the gradual in-depth understanding of its pharmacological action, it was found that it may have potential effects on treating diabetes and its complications. This review aims to illustrate the researches on the properties of NBP and its therapeutic efficacy in diabetic related diseases. This review will discuss the results of experiments in vitro and in vivo to make progress in understanding the beneficial effects of NBP and its derivatives on diabetic complications including diabetic vascular diseases, diabetic peripheral neuropathy, diabetic brain related diseases and diabetic cataract. We will also demonstrate NBP's numerous molecular targets and interactions with multiple cellular signaling pathways such as oxidative stress, inflammatory responses, apoptosis and autophagy. NBP is proved to be a potential therapeutic approach for treating diabetic complications.

Topics: Benzofurans; Diabetes Complications; Diabetes Mellitus; Humans; Oxidative Stress

The alpha (α)-amylase is a calcium metalloenzyme that aids digestion by breaking down polysaccharide molecules into smaller ones such as glucose and maltose. In addition, the enzyme causes postprandial hyperglycaemia and blood glucose levels to rise. α-Amylase is a well-known therapeutic target for the treatment and maintenance of postprandial blood glucose elevations. Various enzymatic inhibitors, such as acarbose, miglitol and voglibose, have been found to be effective in targeting this enzyme, prompting researchers to express an interest in developing potent alpha-amylase inhibitor molecules. The review mainly focused on designing different derivatives of drug molecules such as benzofuran hydrazone, indole hydrazone, spiroindolone, benzotriazoles, 1,3-diaryl-3-(arylamino) propan-1-one, oxadiazole and flavonoids along with their target-receptor interactions, IC

Topics: 1-Deoxynojirimycin; Acarbose; alpha-Amylases; Benzofurans; Blood Glucose; Diabetes Mellitus; Drug Discovery; Flavonoids; Glycoside Hydrolase Inhibitors; Humans; Hydrazones; Hypoglycemic Agents; Indoles; Inositol; Oxadiazoles; Structure-Activity Relationship

Here we review epidemiologic studies dealing with the dietary intake and the body burden of polychlorinated dibenzo-p-dioxins (PCDDs)/polychlorinated dibenzo-furans (PCDFs)/ polychlorinated biphenyls (PCBs) in the general population, and potential adverse health effects of these substances, especially on the risk of diabetes mellitus and endometriosis, and on thyroid function and the neurodevelopment of infants. The mean or median intake of dioxin-related compounds among the general populations of various countries is lower than the maximum tolerable daily intake (TDI) set by the WHO in 1998 (4pg TEQ/kg/day). However, there have been few reports on the distribution of intake and the proportion of subjects whose exposure levels exceed the maximum TDL. At present, it remains unclear whether background exposure to dioxin-related compounds is associated with increased risk of diabetes (because of lack of longitudinal studies), endometriosis (because of lack of studies with sufficient statistical power), or altered thyroid function (because of inconsistent results on humans). Consistent results have been reported for the association between exposure to background levels of PCBs/dioxins, especially trans-placental PCBs, and defective neurodevelopment of infants in the U.S. and Europe. Thus, efforts should be made to further decrease the body burden among women of reproductive age by reducing the release of PCDDs/PCDFs/PCBs into the environment.

Topics: Benzofurans; Body Burden; Diabetes Mellitus; Diet; Endometriosis; Environmental Pollutants; Epidemiologic Methods; Female; Humans; Male; Nervous System; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins; Polymers; Pregnancy; Thyroid Gland

Topics: alpha-Amylases; Benzofurans; Chalcones; Diabetes Mellitus; Humans

Salvianolic acid B (Sal B), the Q-marker in Salvia miltiorrhiza, was proved to present an obvious anti-diabetes effect when treated as a food intake. Until now, the metabolism feature, tissue distribution and anti-diabetes mechanism of Sal B have not been fully elucidated.. The metabolites of Sal B in rats were profiled using ultrahigh-performance liquid chromatography coupled with time-of-flight mass spectrometry. The potential anti-diabetes mechanism of Sal B was predicted by network pharmacology.. A total of 31 metabolites were characterized in rats after ingestion of Sal B at a dosage of 40 mg/kg, including 1 in plasma, 19 in urine, 31 in feces, 0 in heart, 0 in liver, 0 in spleen, 1 in lung, 1 in kidney and 0 in brain. Among them, 18 metabolites were reported for the first time. Phase I reactions of hydrolysis, hydrogenation, dehydroxylation, hydroxylation, decarboxylation and isomerization, and phase II reactions of methylation were found in Sal B. Notably, decarboxylation and dehydroxylation were revealed in Sal B for the first time. The pharmacology network results showed that Sal B and its metabolites could regulate ALB, PLG, ACE, CASP3, MMP9, MMP2, MTOR, etc. The above targets were involved in insulin signaling pathway, PI3K-Akt signaling pathway, HIF-1 signaling pathway, TNF signaling pathway, etc. CONCLUSIONS: The metabolism feature of Sal B in vivo was systematically revealed, and its anti-diabetes mechanism for further pharmacological validations was predicted based on metabolite profiling and network pharmacology for the first time.

Topics: Animals; Benzofurans; Caspases; Chromatography, High Pressure Liquid; Diabetes Mellitus; Drugs, Chinese Herbal; Feces; Humans; Hypoglycemic Agents; Isomerism; Kidney; Liver; Lung; Male; Mass Spectrometry; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Network Pharmacology; Rats; Salvia miltiorrhiza

Diabetes is a chronic metabolic disease, whereas α-glucosidases are key enzymes involved in the metabolism of starch and glycogen. There is a long history of the use of mulberry leaf (the leaf of

Topics: Acarbose; alpha-Glucosidases; Benzofurans; Diabetes Mellitus; Glycogen; Glycoside Hydrolase Inhibitors; Humans; Hypoglycemic Agents; Molecular Docking Simulation; Morus; Plant Leaves; Starch

This study investigated the roles of bone morphogenetic protein-4 (BMP4) and ROS in diabetic endothelial dysfunction and explored whether Salvianolic acid B (Sal B) improved endothelial function by affecting BMP4-ROS in diabetic mice.. db/db mice were orally administrated with Sal B (10 mg/kg/day) for one week while db/m + mice were injected with adenoviral vectors delivering BMP4 (3 × 10. We first revealed the existence of a BMP4-ROS cycle in db/db mice, which stimulated p38 MAPK/JNK/caspase 3 and thus participated in endothelial dysfunction. One week-treatment or 24 h-incubation with Sal B disrupted the cycle, suppressed p38 MAPK/JNK/caspase 3 cascade, and improved endothelium-dependent relaxations (EDRs) in db/db mouse aortas. Importantly, in vivo Sal B treatment also improved flow-mediated dilatation in db/db mouse second order mesenteric arteries. Furthermore, in vivo BMP4 overexpression induced oxidative stress, stimulated p38 MAPK/JNK/caspase 3, and impaired EDRs in db/m + mouse aortas, which were all reversed by Sal B.. The present study demonstrates that Sal B ameliorates endothelial dysfunction through breaking the BMP4-ROS cycle and subsequently inhibiting p38 MAPK/JNK/caspase 3 in diabetic mice and provides evidence for the additional new mechanism underlying the benefit of Sal B against diabetic vasculopathy.

Topics: Animals; Aorta; Benzofurans; Bone Morphogenetic Protein 4; Bone Morphogenetic Proteins; Caspase 3; Diabetes Mellitus; Diabetes Mellitus, Experimental; Diabetic Angiopathies; Disease Models, Animal; Endothelial Cells; Endothelium, Vascular; Male; MAP Kinase Signaling System; Mesenteric Arteries; Mice; Mice, Inbred C57BL; Oxidative Stress; p38 Mitogen-Activated Protein Kinases; Reactive Oxygen Species; Vascular Diseases; Vasodilation

Abnormalities in angiogenesis that are associated with diabetes may contribute to vascular complications and result in disabilities and death. Furthermore, an imbalance in angiogenesis in different tissues, including the retina and kidney, can play a role in the pathogenesis of diabetic microvascular complications. Phlorotannins, such as phloroglucinol (PG) and dieckol (DK), which are found in Ecklonia cava exhibit antioxidant and anti-inflammatory activities that improve endothelial function in hypertension. However, reports on the effects of these compounds on diabetes-induced angiogenesis in vivo and in vitro are scarce. In this study, we assessed the antiangiogenic effects of PG and DK on endothelial cells treated with a high concentration of glucose to mimic angiogenesis. In addition, we sought to determine the effects of these compounds on cell proliferation, cell migration, and capillary formation. In silico docking of PG and DK into VEGFR-2 revealed their potential as therapeutic agents against angiogenesis. Further, both compounds were identified to inhibit the formation of the retinal vessel in transgenic zebrafish (flk:EGFP) embryos under high glucose conditions. These findings suggested that PG and DK derived from E. cava are potential inhibitors of angiogenesis in diabetic vascular complications and could, therefore, be used to develop angiogenic agents.

Topics: Angiogenesis Inhibitors; Animals; Animals, Genetically Modified; Benzofurans; Diabetes Mellitus; Dose-Response Relationship, Drug; Endothelial Cells; Glucose; Humans; Phaeophyceae; Phloroglucinol; Protein Structure, Tertiary; Zebrafish

Pharmacophore mapping and molecular docking can be synergistically integrated to improve the drug design and discovery process. A rational strategy, combiphore approach, derived from the combined study of Structure and Ligand based pharmacophore has been described to identify novel GPR40 modulators.. DISCOtech module from Discovery studio was used for the generation of the Structure and Ligand based pharmacophore models which gave hydrophobic aromatic, ring aromatic and negative ionizable as essential pharmacophoric features. The generated models were validated by screening active and inactive datasets, GH scoring and ROC curve analysis. The best model was exposed as a 3D query to screen the hits from databases like GLASS (GPCR-Ligand Association), GPCR SARfari and Mini-Maybridge. Various filters were applied to retrieve the hit molecules having good drug-like properties. A known protein structure of hGPR40 (pdb: 4PHU) having TAK-875 as ligand complex was used to perform the molecular docking studies; using SYBYL-X 1.2 software.. Clustering both the models gave RMSD of 0.89. Therefore, the present approach explored the maximum features by combining both ligand and structure based pharmacophore models. A common structural motif as identified in combiphore for GPR40 modulation consists of the para-substituted phenyl propionic acid scaffold. Therefore, the combiphore approach, whereby maximum structural information (from both ligand and biological protein) is explored, gives maximum insights into the plausible protein-ligand interactions and provides potential lead candidates as exemplified in this study.

Topics: Allosteric Regulation; Benzofurans; Blood Glucose; Crystallography, X-Ray; Diabetes Mellitus; Drug Design; Drug Discovery; Humans; Hydrophobic and Hydrophilic Interactions; Hypoglycemic Agents; Insulin; Ligands; Molecular Docking Simulation; Quantitative Structure-Activity Relationship; Receptors, G-Protein-Coupled; Sulfones

Topics: Animals; Benzofurans; Diabetes Mellitus; Erectile Dysfunction; Humans; Indoles; Male; Penile Erection; Rats

Death-associated protein kinase-related apoptosis-inducing kinase-2 (DRAK2) is a serine/threonine kinase that plays a key role in a wide variety of cell death signaling pathways. Inhibition of DRAK2 was found to efficiently protect islet β-cells from apoptosis and hence DRAK2 inhibitors represent a promising therapeutic strategy for the treatment of diabetes. Only very few chemical entities targeting DRAK2 are currently known. We carried out a high throughput screening and identified compound 4 as a moderate DRAK2 inhibitor with an IC

Topics: Apoptosis; Apoptosis Regulatory Proteins; B-Lymphocytes; Benzofurans; Cells, Cultured; Diabetes Mellitus; Drug Discovery; Humans; Inhibitory Concentration 50; Islets of Langerhans; Protective Agents; Protein Serine-Threonine Kinases; Structure-Activity Relationship

Diabetes affects an increasing number of patients worldwide and is responsible for a significant rise in healthcare expenses. Imaging of β-cells bears the potential to contribute to an improved understanding, diagnosis, and development of new treatment options for diabetes. Here, we describe the first small molecule fluorescent probe targeting the free fatty acid receptor 1 (FFAR1/GPR40). This receptor is highly expressed on β-cells, and was up to now unexplored for imaging purposes. We designed a novel probe by facile modification of the selective and potent FFAR1 agonist TAK-875. Effective and specific binding of the probe was demonstrated using FFAR1 overexpressing cells. We also successfully labeled FFAR1 on MIN6 and INS1E cells, two widely used β-cell models, by applying an effective amplification protocol. Finally, we showed that the probe is capable of inducing insulin secretion in a glucose-dependent manner, thus demonstrating that functional activity of the probe was maintained. These results suggest that our probe represents a first important step to successful β-cell imaging by targeting FFAR1. The developed probe may prove to be particularly useful for in vitro and ex vivo studies of diabetic cellular and animal models to gain new insights into disease pathogenesis.

Topics: Animals; Benzofurans; Diabetes Mellitus; Fluorescent Dyes; HEK293 Cells; Humans; Insulin; Insulin Secretion; Insulin-Secreting Cells; Mice; Molecular Imaging; Rats; Receptors, G-Protein-Coupled; Structure-Activity Relationship; Sulfones

Previous studies reported that exposure to dioxins was associated with an increased risk of various diseases in general populations.. The aim of this study was to examine the association between levels of dioxins in blood and allergic and other diseases.. We conducted a cross-sectional study on 1,063 men and 1,201 women (aged 15-76 years), who were living throughout Japan and not occupationally exposed to dioxins, during 2002-2010. In fasting blood samples, polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), and dioxin-like PCBs (DL-PCBs) were analyzed by isotope dilution high-resolution gas chromatography/mass spectrometry. We obtained information on life style and self-reported history of diseases using a questionnaire. Blood pressure, blood levels of hemoglobin A1c, and serum lipids were also measured. Multiple logistic regression models were used to analyze the association between dioxin levels in blood and various diseases.. Toxic equivalents of PCDDs/PCDFs and total dioxins showed significant inverse dose-response relationships with atopic dermatitis, after adjustments for potential confounders. The highest quartile for total dioxins had an adjusted odds ratio of 0.26 (95 % confidence interval 0.08-0.70) compared to the reference group (first quartile). The odds ratios for hypertension, diabetes mellitus, hyperlipidemia, gout in men, and gynecologic diseases in women significantly increased with increasing toxic equivalents of PCDDs/PCDFs, DL-PCBs, and total dioxins in blood.. The present findings suggest that background exposure to dioxins was associated with reduced risk of atopic dermatitis. The results also support the idea that low-level exposure to dioxins is associated with an increased risk of diabetes, hypertension, and hyperlipidemia.

Topics: Adolescent; Adult; Aged; Benzofurans; Cross-Sectional Studies; Dermatitis, Atopic; Diabetes Mellitus; Environmental Exposure; Female; Humans; Hyperlipidemias; Hypertension; Japan; Life Style; Male; Middle Aged; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins; Surveys and Questionnaires; Young Adult

The present work investigates protein tyrosine phosphatase 1B (PTP1B) and the α-glucosidase inhibitory activities of two edible brown algae, Ecklonia stolonifera and Eisenia bicyclis, as well as in their isolated phlorotannins. Since the individual extracts and fractions showed significant inhibitory activities, column chromatography was performed to isolate six phlorotannins, phloroglucinol (1), dioxinodehydroeckol (2), eckol (3), phlorofurofucoeckol-A (4), dieckol (5), and 7-phloroeckol (6). Phlorotannins 3-6 were potent and noncompetitive PTP1B inhibitors with IC(50) values ranging from 0.56 to 2.64 µM; 4-6 exhibited the most potent α-glucosidase inhibition with IC(50) values ranging from 1.37 to 6.13 µM. Interestingly, 4 and 6 were noncompetitive, while 5 exhibited competitive inhibition in an α-glucosidase assay. E. stolonifera and E. bicyclis as well as their isolated phlorotannins therefore possessed marked PTP1B and α-glucosidase inhibitory activities; this could lead to opportunities in the development of therapeutic agents to control the postprandial blood glucose level and thereby prevent diabetic complications.

Topics: alpha-Glucosidases; Benzofurans; Blood Glucose; Complex Mixtures; Diabetes Mellitus; Dioxins; Enzyme Inhibitors; Glycoside Hydrolase Inhibitors; Humans; Hyperglycemia; Hypoglycemic Agents; Kinetics; Magnetic Resonance Spectroscopy; Phaeophyceae; Phloroglucinol; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Solutions; Spectrophotometry; Tannins; Yeasts

In an investigation of (-)-Cercosporamide derivatives with a plasma glucose-lowering effect, we found that N-benzylcarboxamide derivative 4 was a partial agonist of PPARgamma. A SAR study of the substituents on carboxamide nitrogen afforded the N-(1-naphthyl)methylcarboxamide derivative 23 as the most potent selective PPARgamma modulator. An X-ray crystallography study revealed that compound 23 bounded to the PPARgamma ligand binding domain in a unique way without any interaction with helix12. Compound 23 displayed a potent plasma glucose-lowering effect in db/db mice without the undesirable increase in body fluid and heart weight that is typically observed when PPARgamma full agonists are administrated.

Topics: Animals; Benzofurans; Crystallography, X-Ray; Diabetes Mellitus; Glucose; Humans; Hyperglycemia; Hypoglycemic Agents; Male; Mice; Models, Molecular; PPAR gamma

The aim of this study was to investigate the protective effect of dl-3-n-butylphthalide (NBP) on chronic brain injury caused by diabetes.. A group of diabetic Sprague-Dawley rats was orally treated with NBP for 6 weeks. In this study, we examined glial reactivity in hippocampus of streptozotocin (STZ)-induced diabetic rats by determining the expression of glial fibrillary acidic protein (GFAP) and CD11b. We also examined anti-apoptosis protein, vascular endothelial growth factor (VEGF) and key apoptosis enzyme, caspase-3, expression by immunohistochemistry.. We found that GFAP, CD11b, VEGF (685.1 +/- 35.5 cells/mm(2) in diabetic rats versus 320.6 +/- 21.9 cells/mm(2) in control rats, p<0.05, n=5) and VEGF(+)-caspase-3(+) (393.4 +/- 24.2 cells/mm(2) versus 135.8 +/- 12.0 cells/mm(2) in control rats, p<0.05, n=5) immunostaining increased in the hippocampus of diabetic rats; However, treatment with NBP resulted in an obvious reduction of GFAP and CD11b-immunoreactive gliocytes in hippocampus. VEGF expression was up-regulated (837.2 +/- 20.1 cells/mm(2), n=5), while the caspase-3 expression was reduced (240.0 +/- 15.1 cells/mm(2), n=5) in the NBP-treated diabetes mellitus-NBP rats.. These results suggest that diabetes causes increased glial reactivity, apoptosis and compensatory VEGF expression, and NBP may have a protective effect for diabetic brain damage through enhancing VEGF expression to inhibit caspase-3 mediated apoptosis.

Topics: Animals; Apoptosis; Benzofurans; Cerebral Arteries; Diabetes Mellitus; Diabetes Mellitus, Experimental; Disease Models, Animal; Gliosis; Hippocampus; Male; Neurons; Neuroprotective Agents; Rats; Rats, Sprague-Dawley; Stroke; Up-Regulation; Vascular Endothelial Growth Factor A

The aim of this research was to formulate Marsupsin-phospholipid complex (M-P Complex) in attempt to increase the bioavailability of marsupsin and to characterize this new formulation along with its evaluation. Marsupsin-phospholipid complex was formulated by mechanical dispersion method. In this new formulation, complex formation was confirmed by carrying out transmission electron microscopy (TEM), IR, (1)H-NMR and RP-HPLC analysis. TEM showed M-P Complex diameter range of 0.05-0.5 microm. The entrapment efficiency of M-P Complex was found to be 44%. In vitro release study revealed its first order release profile. Mean blood serum concentration vs time curve of marsupsin was of first order after oral administration of M-P Complex in albino rabbits which clearly showed remarkably increased bioavailability of M-P Complex than standardized marsupsin. The average value of C(max) and T(max) of M-P Complex were found to be 3.02 mg/ml and 10.2 h, respectively. Hence the findings demonstrate that complexing marsupsin with phospholipids results in better oral bioavailability and improved biological response than free form of standardized marsupsin.

Topics: Animals; Benzofurans; Cresols; Diabetes Mellitus; Diffusion; Drug Carriers; Drug Compounding; Drug Evaluation, Preclinical; Hypoglycemic Agents; Materials Testing; Phospholipids; Rabbits; Rats; Treatment Outcome

The Escambia Wood Treating Company (ETC) Superfund site, Pensacola, FL, is contaminated with polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDD/F), benzo(a)pyrene, lead and arsenic from pentachlorophenol (PCP), creosote, and other compounds used to treat utility poles and foundation pilings. Although ETC's operations ceased in 1982, soils in the areas surrounding the facility continue to exhibit elevated levels of contaminants attributable to ETC operations. In July 2000, individuals who may have been affected by contamination from the ETC site, including current and former residents and former workers and their household members were invited to participate in a study, which included a health and exposure history and routine blood analysis. We also conducted a toxicological health evaluation of a subset of these eligible workers/residents by analyzing serum levels of 17 PCDD/F congeners. Members of the ETC cohort exhibited elevated serum PCDD/F relative to the general population, and congener profiles in members of the cohort reflected patterns commonly observed in persons exposed to PCP. Hypertension prevalence in the cohort was found to correlate with PCDD/F levels, although no other significant relationships were identified with monitored health indices.

Topics: Adolescent; Adult; Age Factors; Aged; Aged, 80 and over; Benzofurans; Diabetes Mellitus; Dibenzofurans, Polychlorinated; Environmental Monitoring; Environmental Pollutants; Epidemiological Monitoring; Female; Florida; Humans; Hypertension; Industrial Waste; Liver Function Tests; Male; Middle Aged; Neoplasms; Polychlorinated Dibenzodioxins

The main objective of this study was to establish background levels of serum PCDD/Fs and biochemistry of residents living near municipal waste incinerators (MWIs) which had been operating between 1 and 8 years, and also to examine the association between the serum PCDD/Fs levels and health outcomes of interest. Information on medical history, life-style, and dietary habits was obtained by questionnaire interview. Significantly elevated levels of glucose and blood urea nitrogen (BUN) were found in those with low to high serum PCDD/Fs levels (p<0.05), and PCDD/Fs levels were found to be positively associated with glucose levels, and marginally with GGT levels even after adjusting for age, sex, BMI and smoking status. Although no conclusive findings on health disorder were associated with the accumulation of serum PCDD/Fs in our study participants, we suggest that the current biochemistry examinations only reflect partially the physiological change in glucose modulation and liver function. However, the low serum PCDD/Fs level does not seem to be sufficient in eliciting pathological process for diabetes or liver-related diseases. The findings suggest that the human body's biochemistry functions such as liver and glucose modulation were affected by PCDD/Fs exposure at even these low serum PCDD/Fs levels found in the general population. Other biochemical functions therefore should be further analyzed, especially for hormone-related and immune functions.

Topics: Adolescent; Adult; Aged; Arrhythmias, Cardiac; Benzofurans; Blood Glucose; Diabetes Mellitus; Dibenzofurans, Polychlorinated; Environmental Monitoring; Environmental Pollutants; Epidemiological Monitoring; Female; gamma-Glutamyltransferase; Headache; Humans; Hypothyroidism; Incineration; Male; Middle Aged; Polychlorinated Dibenzodioxins; Taiwan

Impaired wound healing is a well-documented phenomenon in experimental and clinical diabetes. Experimental evidence suggests that a defect in vascular endothelial growth factor (VEGF) regulation might be associated with wound-healing disorders. We studied the involvement of lipid peroxidation in the pathogenesis of altered VEGF expression in diabetes-related healing deficit by using an incisional skin-wound model produced on the back of female diabetic C57BL/KsJ db+/ db+ mice and their normal (db+/+m) littermates. Animals were then randomized to the following treatment: raxofelast (15 mg.kg(-1).day(-1) i.p.), an inhibitor of lipid peroxidation, or its vehicle (DMSO/NaCl 0.9%, 1:1 vol: vol). The animals were killed on different days (3, 6, and 12 days after skin injury), and the wounded skin tissues were used for histological evaluation, for analysis of conjugated dienes (CDs), as an index of lipid peroxidation and wound breaking strength. Furthermore, we studied the time course of VEGF mRNA expression throughout the skin-repair process (3, 6, and 12 days after skin injury), by means of reverse transcriptase-polymerase chain reaction, as well as the mature protein in the wounds. Diabetic mice showed impaired wound healing with delayed angiogenesis, low breaking strength, and increased wound CD content when compared with their normal littermates. In healthy control mice, a strong induction of VEGF mRNA was found between day 3 and day 6 after injury, while no significant VEGF mRNA expression was observed at day 12 after injury. In contrast, VEGF mRNA levels, after an initial increase (day 3), were significantly lower in diabetic mice than in normal littermates, and light induction of VEGF mRNA expression was also present at day 12 after injury. Similarly, the wound content of the angiogenic factor was markedly changed in diabetic mice. Administration of raxofelast did not modify the process of wound repair in normal mice, but significantly improved the impaired wound healing in diabetic mice through the stimulation of angiogenesis, re-epithelization, and synthesis and maturation of extracellular matrix. Moreover, raxofelast treatment significantly reduced wound CD levels and increased the breaking strength of the wound. Lastly, the inhibition of lipid peroxidation restored the defect in VEGF expression during the process of skin repair in diabetic mice and normalized the VEGF wound content. The current study provides evidence that lipid peroxidation inhibiti

Topics: Animals; Benzofurans; Diabetes Mellitus; Endothelial Growth Factors; Female; Lipid Peroxides; Lymphokines; Mice; Mice, Inbred C57BL; Neovascularization, Physiologic; Skin; Tensile Strength; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors; Vitamin E; Wound Healing; Wounds and Injuries

Insulin resistance in the liver and peripheral tissues, together with a pancreatic cell defect, are the common causes of Type 2 diabetes. It is now appreciated that insulin resistance can result from a defect in the insulin receptor signaling system, at a site post binding of insulin to its receptor. Protein tyrosine phosphatases (PTPases) have been shown to be negative regulators of the insulin receptor. Inhibition of PTPases may be an effective method in the treatment of Type 2 diabetes. We have identified two novel series of benzofuran/benzothiophene biphenyl oxo-acetic acids and sulfonyl-salicylic acids as potent inhibitors of PTP1B with good oral antihyperglycemic activity. To assist in the design of these inhibitors, crystallographic studies have attempted to identify enzyme inhibitor interactions. Resolution of crystal complexes has suggested that the inhibitors bind to the enzyme active site and are held in place through hydrogen bonding and van der Waals interactions formed within two hydrophobic pockets. In the oxo-acetic acid series, hydrophobic substitutents at position-2 of the benzofuran/benzothiophene biphenyl framework interacted with Phe182 of the catalytic site and were very critical to the intrinsic activity of the molecule. The hydrophobic region of the catalytic-site pocket was exploited and taken advantage by hydrophobic substituents at either the alpha-carbon or the ortho aromatic positions of the oxo-acetic acid moiety. Similar ortho aromatic substitutions on the salicylic acid-type inhibitors had no effect, primarily due to the different orientation of these inhibitors in the catalytic site. The most active inhibitors of both series inhibited recombinant human PTP1B with phosphotyrosyl dodecapeptide TRDI(P)YETD(P)Y(P)YRK as the source of the substrate with IC(50) values in the range of 20-50 nM. Compound 68 was one of the most active compounds in vivo, normalizing plasma glucose levels at the 25 mg/kg dose (po) and the 1 mg/kg dose (ip). Compound 68 was also selective against several other PTPases.

Topics: Administration, Oral; Animals; Benzofurans; Blood Glucose; Catalytic Domain; Crystallography, X-Ray; Diabetes Mellitus; Enzyme Inhibitors; Humans; Hydrogen Bonding; Hypoglycemic Agents; Mice; Models, Molecular; Phenylpropionates; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Protein Tyrosine Phosphatases; Structure-Activity Relationship; Thiophenes

A 62 year old man developed a neuropathy after several months of treatment with amiodarone. The clinical picture was atypical in that it associated a polyradiculoneuritis with cell-protein dissociation and an axial and peripheral cerebellar syndrome. Pathology of muscle and nerve showed dense inclusions in Schwann cell cytoplasm and in pericytes, highly suggestive of fat inclusions. Discontinuation of amiodarone therapy resulted in a slow regression of disorders. Diabetes mellitus developed. Several pathogenic hypotheses are proposed.

Topics: Amiodarone; Benzofurans; Cerebellar Diseases; Coronary Disease; Diabetes Mellitus; Humans; Lipids; Lysosomes; Male; Middle Aged; Muscles; Peripheral Nerves; Polyradiculoneuropathy; Schwann Cells

Topics: Adult; Benzofurans; Blood Glucose; Blood Sedimentation; Colchicine; Creatinine; Diabetes Mellitus; Electrocardiography; Fatty Liver; Female; Gout; Humans; Hyperlipidemias; Hypertension; Lipids; Liver Function Tests; Male; Middle Aged; Uric Acid