benzofurans and Obesity

Globally, people are struggling with obesity. Many effective, nonconventional methods of weight reduction, such as herbal and natural dietary supplements, are increasingly being sought. Fat burners are believed to raise metabolism, burn more calories and hasten fat loss. Despite patient perceptions that herbal remedies are free of adverse effects, some supplements are associated with severe hepatotoxicity. The present report describes a young healthy woman who presented with fulminant hepatic failure requiring emergent liver transplantation caused by a dietary supplement and fat burner containing usnic acid, green tea and guggul tree extracts. Thorough investigation, including histopathological examination, revealed no other cause of hepatotoxicity. The present case adds to the increasing number of reports of hepatotoxicity associated with dietary supplements containing usnic acid, and highlights that herbal extracts from green tea or guggul tree may not be free of adverse effects. Until these products are more closely regulated and their advertising better scrutinized, physicians and patients should become more familiar with herbal products that are commonly used as weight loss supplements and recognize those that are potentially harmful.

Topics: Adipose Tissue; Adult; Benzofurans; Camellia sinensis; Commiphora; Dietary Supplements; Hepatic Encephalopathy; Humans; Hypolipidemic Agents; Liver Failure, Acute; Liver Transplantation; Monitoring, Physiologic; Obesity; Phytotherapy; Plant Extracts; Plant Gums; Plant Preparations; Tea; Treatment Outcome; Weight Loss

To investigate the effect of fasiglifam on glycaemic control in people with type 2 diabetes mellitus (T2DM).. In total, 421 people with T2DM and glycated haemoglobin (HbA1c) ≥7.0% and ≤10.5% who had received only diet and exercise treatment for ≥12 weeks prior to screening were randomized to receive fasiglifam 25 or 50 mg or placebo. The primary efficacy endpoint was change from baseline in HbA1c at week 24.. The mean participant age was 53.5 years, mean baseline body mass index 32.3 kg/m. The data indicate that fasiglifam effectively reduced HbA1c from baseline for 24 weeks in participants with T2DM. The incidence of TEAEs was higher in the fasiglifam groups; however, the incidence of serious AEs was low overall and similar between groups. ALT elevations were observed only in the fasiglifam groups, which contributed to the decision to terminate the fasiglifam programme after completion of the present study.

Topics: Benzofurans; Body Mass Index; Chemical and Drug Induced Liver Injury; Combined Modality Therapy; Diabetes Mellitus, Type 2; Diet, Diabetic; Dose-Response Relationship, Drug; Double-Blind Method; Exercise; Female; Follow-Up Studies; Glycated Hemoglobin; Humans; Hyperglycemia; Hypoglycemia; Hypoglycemic Agents; Liver; Lost to Follow-Up; Male; Middle Aged; Obesity; Patient Dropouts; Receptors, G-Protein-Coupled; Sulfones

The effect of daily therapeutic doses of 100 mg benzbromarone (Normurat) and 2.0 g probenecid on the purine metabolism of 40 test subjects was investigated. Fasting-hyperuricemia was used as the model and particular attention paid to the mechanisms of renal elimination. Urate concentration remains under the solubility threshold when benzbromarone is administered, in contrast to medication with probenecid. The significantly greater hypouricemic effect of benzbromarone correlates with a significant rise in the excretion and clearance of uric acid in comparison to probenecid, accompanied by a stronger depression of tubular reabsorption. Serum levels, clearances and reabsorption rates demonstrate the prolonged effect of the benzofurane derivative Normurat even during strict fasting. Supplementary allantoin and urea determinations gave no indication of increased enterobacterial uricolysis. Normurat was well tolerated, side effects were not noted.

Topics: Adolescent; Adult; Benzbromarone; Benzofurans; Fasting; Female; Humans; Male; Middle Aged; Obesity; Probenecid; Purines; Uric Acid

Inhibition of adipogenesis is an important strategy for obesity treatment. Rocaglamide-A (Roc-A) is a natural herbal medicine isolated from the genus Aglaia (family Meliaceae), which has a cyclopenta[b]benzofuran core structure. Roc-A exhibits various pharmacological effects against diverse human cancer cells. However, the exact role of Roc-A during adipogenesis in adipocytes has not been studied at all. In this study, we demonstrate that Roc-A is crucial for reducing adipogenesis via downregulating PPARγ transcriptional activity. Consistently, Western-blot and RT-PCR analyses clearly showed that Roc-A inhibits the expression of PPARγ target genes and lipogenic markers in a dose-dependent manner along with suppression of lipid accumulation, in both 3T3-L1 cells and mouse adipose-derived stem cells. Mechanistically, Roc-A significantly decreased STAT3 phosphorylation in a dose-dependent manner in 3T3-L1 adipocytes. In particular, we confirmed that Roc-A effectively suppressed the expression of genes involved in cell-cycle regulation, such as cyclin A, B, D1, and E1, early during mitotic clonal expansion in 3T3-L1 adipocytes, and this effect was abolished by the JAK2/STAT3 activator FGF2. Taken together, our results demonstrated that Roc-A reduces adipogenesis by inhibiting PPARγ transactivation and STAT3 phosphorylation and thus may serve as a therapeutic target in obesity.

Topics: Adipogenesis; Animals; Benzofurans; Mice; Obesity; PPAR gamma

Salvianolic acid B (SalB) is a polyphenolic compound in Salvia miltiorrhiza Bunge ("Danshen"), which has been largely used in Traditional Chinese Medicine for the treatment of metabolic syndrome, obesity, diabetes, among others.. This study was to investigate the effects of Salvianolic acid B (SalB) on mRNA, lncRNA and circRNA's expression profile in brown adipose tissue (BAT) of obese mice.. High-fat-diet induced obese C57BL/6J mice were treated with SalB (100 mg/kg/day) for 8 weeks. Then, BAT was harvested for RNA-Seq analysis. Differentially expressed mRNAs, lncRNAs and circRNAs were analyzed using the Illumina Hiseq 4000. Following this procedure, bioinformatic tools including Gene ontology (GO), KEGG pathway and lncRNA-mRNA co-network analysis were utilized. Finally, RT-qPCR was performed to validate the differentially expressed RNAs.. Compared with control group, 2532 mRNAs, 774 lncRNAs and 25 circRNAs were differentially expressed in SalB group. Additionally, 40 upregulated and 109 downregulated gene-related pathways were identified in the SalB group. Among them, metabolic pathways showed the highest enrichment coefficient in upregulated genes. Moreover, 54 up-regulated and 626 down-regulated coding mRNAs associated with lncRNA-Hsd11b1 and lncRNA-Vmp1.. SalB may play an anti-obesity role by adjusting the expression of mRNAs correlated with inflammatory response and energy metabolism through regulating the expression of lncRNA-Hsd11b1. The findings of this research provide new directions to study the mechanisms of SalB, and would open therapeutic avenues for the treatment of obesity.

Topics: Adipose Tissue, Brown; Animals; Benzofurans; Computational Biology; Diet, High-Fat; Down-Regulation; Energy Metabolism; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; RNA, Circular; RNA, Long Noncoding; RNA, Messenger; Salvia miltiorrhiza; Up-Regulation

Obesity is one of the world's largest health problems, and 3-N-butylphthalide (NBP), a bioactive compound in celery, has been used in dieting and weight management programs. In this study, NBP prevented high-fat-diet-induced weight gain, reduced the food efficiency ratio, altered the blood biochemical profile, and reduced the obesity-related index. NBP reduced adiposity, white fat depots, liver weight, and hepatic steatosis in obese mice. NBP ameliorated the diabetic state by decreasing glucose levels and improving glucose and insulin tolerance. NBP increased uncoupling protein-1 expression in white adipose tissue and upregulated thermogenesis by enhancing mitochondrial respiration. NBP inhibited white adipocyte development by prohibiting lipid accumulation in human adipose-derived stem cells. NBP increased free fatty acid uptake and the oxygen consumption rate in beige adipocytes. Our results suggest that NBP could be used as functional natural supplement against obesity and its associated disorders.

Topics: Adipocytes; Adipose Tissue, White; Adiposity; Animals; Benzofurans; Blood Glucose; Cells, Cultured; Diet, High-Fat; Fatty Liver; Humans; Lipid Metabolism; Lipids; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Protective Agents; Thermogenesis

Salvianolic acid B (Sal B) exhibits anti-obesity activity, yet the underlying mechanism linking this effect to metabolic endotoxemia remains unexplored. For this purpose, high-fat diet-induced obese mice were orally administered with Sal B for 10 weeks. Hematoxylin/eosin staining, transmission electron microscopy, and immunohistochemical staining were used to evaluate histopathological alterations in the white adipose tissue (WAT) and/or jejunums. The expression levels of genes related to fat and cholesterol synthesis in the WAT were determined by qPCR. The composition of fecal microbiota was profiled by 16S rRNA gene pyrosequencing. Western blotting was employed to evaluate the relative protein expressions involved in lipopolysaccharide (LPS)/toll-like receptor 4 (TLR4) signaling pathway in the WAT. Treatment of obese mice with Sal B improves insulin sensitivity, attenuates body weight gain and alleviates serum levels of LPS and tumor necrosis factor alpha, which is associated with an improvement in intestinal epithelial integrity and probiotic composition as well as a reduction in Gram-negative Proteobacteria and Deferribacteres. In addition, Sal B downregulates the expressions of TLR4 and myeloid differential factor-88, as well as the phosphorylation levels of Jun N-terminal kinase, nuclear factor-kappa B p65, and an insulin receptor substrate in the WAT. In summary, Sal B may attenuate body weight gain and insulin resistance through the regulation of gut microbiota abundances and LPS/TLR4 signaling pathway in obese mice, suggesting Sal B could be a promising drug candidate for protection against obesity.

Topics: Administration, Oral; Animals; Anti-Obesity Agents; Benzofurans; Diet, High-Fat; Gastrointestinal Microbiome; Lipopolysaccharides; Mice; Mice, Obese; Obesity; Signal Transduction; Toll-Like Receptor 4; Weight Gain

Activation of free fatty acid receptors (FFAR1 and FFAR4) which are G protein-coupled receptors (GPCRs) with established (patho)physiological roles in a variety of obesity-related disorders, induce human airway smooth muscle (HASM) cell proliferation and shortening. We reported amplified agonist-induced cell shortening in HASM cells obtained from obese lung donors. We hypothesized that FFAR1 modulate excitation-contraction (EC) coupling in HASM cells and play a role in obesity-associated airway hyperresponsiveness.. In HASM cells pre-treated (30 min) with FFAR1 agonists TAK875 and GW9508, we measured histamine-induced Ca. Unexpectedly, we found that TAK875, a synthetic FFAR1 agonist, attenuated histamine-induced MLC phosphorylation and cortical tension development in HASM cells. These physiological outcomes were unassociated with changes in histamine-evoked Ca. Taken together, our findings identified the FFAR1 agonist TAK875 as a novel bronchoprotective agent that warrants further investigation to treat difficult-to-control asthma and/or airway hyperreactivity in obesity.

Topics: Adrenergic beta-2 Receptor Agonists; Benzofurans; Bronchoconstriction; Bronchodilator Agents; Cells, Cultured; Histamine; Humans; Lung; Methylamines; Muscle, Smooth; Myocytes, Smooth Muscle; Myosin Light Chains; Obesity; Phosphorylation; Propionates; Receptors, G-Protein-Coupled; Signal Transduction; Sulfones

Metabolic inflammatory damage, characterized by Toll-like receptor 4 (TLR4) signaling activation, is a major mechanism underlying lipotoxicity-induced

Topics: Animals; Benzofurans; Cell Line, Tumor; Diet, High-Fat; Inflammation; Insulin-Secreting Cells; Male; Mice; Obesity; Rats; Rats, Sprague-Dawley; Receptors, G-Protein-Coupled; Signal Transduction; Sulfones; Toll-Like Receptor 4; Transcription Factor RelA

Enteropeptidase is a serine protease localized on the duodenal brush border that catalyzes the conversion of inactive trypsinogen into active trypsin, thereby regulating protein breakdown in the gut. We evaluated the effects of SCO-792, a novel enteropeptidase inhibitor, in mice.. In vivo inhibition of enteropeptidase was evaluated via an oral protein challenge. Pharmacological effects were evaluated in normal mice, in diet-induced obese (DIO) mice and in obese and diabetic ob/ob mice.. A single oral administration of SCO-792 inhibited plasma branched-chain amino acids (BCAAs) in an oral protein challenge test in mice, indicating in vivo inhibition of enteropeptidase. Repeated treatment with SCO-792 induced reduction in food intake and decrease in body weight in DIO and ob/ob mice. Plasma FGF21 levels were increased in SCO-792-treated DIO mice, an observation that was probably independent of reduction in food intake. Hyperglycaemia was markedly improved in SCO-792-treated ob/ob mice. A hyperinsulinaemic-euglycaemic clamp study revealed improved muscle insulin sensitivity in SCO-792-treated ob/ob mice. SCO-792 also improved plasma and liver lipid profiles and decreased plasma alanine transaminase, suggesting a potential treatment for liver diseases. Dietary supplementation with essential amino acids attenuated the effect of SCO-792 on reduction in food intake and decrease in body weight in normal mice, suggesting a pivotal role for enteropeptidase in these biological phenomena.. SCO-792 inhibited enteropeptidase in vivo, reduced food intake, decreased body weight, increased insulin sensitivity, improved glucose and lipid control, and ameliorated liver parameters in mouse models with obesity and/or diabetes. SCO-792 may exhibit similar effects in patients.

Topics: Animals; Aspartic Acid; Benzofurans; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Disease Models, Animal; Enteropeptidase; Insulin; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Serine Proteinase Inhibitors; Small Molecule Libraries

Obesity-induced metabolic dysfunctions increase the risk for vascular diseases, including type II diabetes and stroke. Managing obesity is of interest to address the worldwide health problem; however, the role of genetic variability in human obesity development and specific targets for obesity-related metabolic disease have not been thoroughly studied. A SNP in the brain-derived neurotropic factor (

Topics: Animals; Benzofurans; Brain-Derived Neurotrophic Factor; CD36 Antigens; Cell Differentiation; Diet, High-Fat; Insulin Resistance; Intra-Abdominal Fat; Male; Methionine; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Obese; Mutation; Obesity; Valine

Activating transcription factor 3 (Atf3) has been previously demonstrated to impact obesity and metabolism. However, a metabolic role of Atf3 in mice remains debatable. We investigated the role of Atf3 in mice and further investigated Atf3 expression as a therapeutic target for obesity and metabolic diseases. Atf3 knockout (KO) mice fed with a high fat diet (HFD) aggravated weight gain and impaired glucose metabolism compared to littermate control wild type (WT) mice. Atf3 KO aged mice fed with a chow diet (CD) for longer than 10 months also displayed increased body weight and fat mass compared to WT aged mice. We also assessed requirements of Atf3 in a phytochemical mediated anti-obese effect. Effect of sulfuretin, a previously known phytochemical Atf3 inducer, in counteracting weight gain and improving glucose tolerance was almost completely abolished in the absence of Atf3, indicating that Atf3 induction can be a molecular target for preventing obesity and metabolic diseases. We further identified other Atf3 small molecule inducers that exhibit inhibitory effects on lipid accumulation in adipocytes. These data highlight the role of Atf3 in obesity and further suggest the use of chemical Atf3 inducers for prevention of obesity and metabolic diseases.

Topics: Activating Transcription Factor 3; Aging; Animals; Anti-Obesity Agents; Benzofurans; Body Weight; Diet, High-Fat; Flavonoids; Glucose Intolerance; Metabolic Diseases; Mice, Knockout; Molecular Targeted Therapy; Obesity

Sulfuretin is a natural flavonoid found in the plant Rhus verniciflua STOKES. The plant has been traditionally used as medicinal agent for antiviral, cathartic, diaphoretic, anti-rheumatic and sedative activities in East Asia. In this study we isolated and identified sulfuretin from R. verniciflua and investigated its anti-adipogenic activity against 3T3-L1 preadipocytes cells. We evaluated the effects of sulfuretin on the adipogenic transcription factors like peroxisome proliferator-activated receptor γ (PPARγ), CCAAT/enhancer-binding protein α (C/EBPα), fatty acid synthase (FAS), Fabp4, adiponectin and zinc fingerprint protein (Zfp) 521 by gene expression (real-time QPCR) and Western blot analysis. Sulfuretin treatment at Day 0 and 2 showed significant reduction of lipid production in 3T3-L1 cells in concentration dependent manner. Gene expression analysis (real-time PCR) revealed that sulfuretin inhibited the both major adipogenic factors (C/EBPα, C/EBPβ and PPARγ) and minor adipogenic factors (sterol regulatory element-binding protein (SREBP1c), adiponectin, FAS, Fabp4, Zfp423, and Ebf1). Western blot analysis showed the increased expression of β-catenin and suppression of PPARγ after sulfuretin treatment. Overall, sulfuretin is a natural flavonoid having potent anti-adipogenic activity through the suppression of major adipogenic factors C/EBPα, C/EBPβ and PPARγ, which initiate adipogenesis.

Topics: 3T3-L1 Cells; Adipocytes; Adipogenesis; Adipose Tissue; Animals; Anti-Obesity Agents; Benzofurans; beta Catenin; CCAAT-Enhancer-Binding Proteins; DNA-Binding Proteins; Flavonoids; Gene Expression; Mice; Obesity; Phytotherapy; Plant Extracts; PPAR gamma; Rhus; Sterol Regulatory Element Binding Protein 1; Transcription Factors

In this study, hot-water extracts (HW) from roots of Vitis thunbergii var. taiwaniana (VTT-R) were shown to lower levels of lipid accumulation significantly (P < 0.01 or 0.001) compared to the control in 3T3-L1 adipocytes. The VTT-R-HW (40 mg/kg) interventions concurrent with a high-fat (HF) diet in C57BL/6 mice over a 5 eek period were shown to reduce body weights significantly (P < 0.05) compared to those of mice fed a HF diet under the same food-intake regimen. The (+)-ε-viniferin isolated from VTT-R-HW was shown to reduce the size of lipid deposits significantly compared to the control (P < 0.05 or 0.001) in 3T3-L1 adipocytes, and dose-dependent 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitions showed that the 50% inhibitory concentration was calculated to be 96 μM. The two-stage (+)-ε-viniferin interventions (10 mg/kg, day 1 to day 38; 25 mg/kg, day 39 to day 58) were shown to lower mice body weights significantly (P < 0.05 or 0.001), the weight ratio of mesenteric fat, blood glucose, total cholesterol, and low-density lipoprotein compared to that of the HF group under the same food-intake regimen but without concurrent VTT-R-HW interventions. It might be possible to use VTT-R-HW or (+)-ε-viniferin as an ingredient in the development of functional foods for weight management, and this will need to be investigated further.

Topics: Animals; Benzofurans; Blood Glucose; Cholesterol; Diet, High-Fat; Humans; Male; Mice; Mice, Inbred C57BL; Molecular Structure; Obesity; Plant Extracts; Plant Roots; Stilbenes; Vitis

Ethanol extracts (Et) from the stem (S) and leaf (L) of Vitis thunbergii var. taiwaniana (VTT) were used to investigate yeast α-glucosidase and porcine kidney dipeptidyl peptidase-IV (DPP-IV) inhibitory activities. Both VTT-Et showed complete α-glucosidase inhibition at 0.1 mg/mL; VTT-S-Et and VTT-L-Et showed 26 and 11% DPP-IV inhibition, respectively, at 0.5 mg/mL. The VTT-Et interventions (20 and 50 mg/kg) resulted in improvements in impaired glucose tolerance of diet-induced obese rats. (+)-Hopeaphenol, (+)-vitisin A, and (-)-vitisin B were isolated from the ethyl acetate fractions of S-Et and showed yeast α-glucosidase inhibition (IC50 = 18.30, 1.22, and 1.02 μM) and porcine kidney DPP-IV inhibition (IC50 = 401, 90.75, and 15.3 μM) compared to acarbose (6.39 mM) and sitagliptin (47.35 nM), respectively. Both (+)-vitisin A and (-)-vitisin B showed mixed noncompetitive inhibition against yeast α-glucosidase and porcine kidney DPP-IV, respectively. These results proposed that VTT extracts might through inhibitions against α-glucosidase and DPP-IV improve the impaired glucose tolerance in diet-induced obese rats.

Topics: alpha-Glucosidases; Animals; Benzofurans; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucose Intolerance; Glycoside Hydrolase Inhibitors; Kinetics; Male; Obesity; Phenols; Plant Extracts; Plant Leaves; Rats; Rats, Wistar; Saccharomyces cerevisiae; Stilbenes; Swine; Vitis

Red wines are thought to be one of the major dietary sources of trans-resveratrol. The beneficial effects of t-resveratrol against metabolic disorders have been well characterized, however, red wines also contain various resveratrol derivatives whose health benefits have not been completely elucidated. In this report, we investigated ε-viniferin, a resveratrol dimer, which is present at comparable concentrations to t-resveratrol in red wines, and has higher anti-adipogenesis activity in 3T3-L1 cells. In addition, ε-viniferin was more effective than t-resveratrol in its anti-obesity and anti-inflammatory effects in high-fat diet fed mice. These results suggested ε-viniferin may be one of the active ingredients against metabolic disorders in red wines, in addition to t-resveratrol.

Topics: 3T3 Cells; Adipogenesis; Animals; Anti-Obesity Agents; Benzofurans; Diet, High-Fat; Dimerization; Dose-Response Relationship, Drug; Male; Mice; Mice, Inbred C57BL; Obesity; Resveratrol; Stilbenes; Treatment Outcome

Lithospermic acid B (LAB), an active component isolated from Salvia miltiorrhiza radix, has been reported to have antioxidant effects. We examined the effects of LAB on the prevention of diabetic retinopathy in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, an animal model of type 2 diabetes.. LAB (10 or 20 mg/kg) or normal saline were given orally once daily to 24-week-old male OLETF rats for 52 weeks. At the end of treatment, fundoscopic findings, vascular endothelial growth factor (VEGF) expression in the eyeball, VEGF levels in the ocular fluid, and any structural abnormalities in the retina were assessed. Glucose metabolism, serum levels of high-sensitivity C-reactive protein (hsCRP), monocyte chemotactic protein-1 (MCP1), and tumor necrosis factor-alpha (TNFα) and urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels were also measured. Treatment with LAB prevented vascular leakage and basement membrane thickening in retinal capillaries in a dose-dependent manner. Insulin resistance and glucose intolerance were significantly improved by LAB treatment. The levels of serum hsCRP, MCP1, TNFα, and urinary 8-OHdG were lower in the LAB-treated OLETF rats than in the controls.. Treatment with LAB had a preventive effect on the development of diabetic retinopathy in this animal model, probably because of its antioxidative effects and anti-inflammatory effects.

Topics: 8-Hydroxy-2'-Deoxyguanosine; Animals; Antioxidants; Benzofurans; C-Reactive Protein; Chemokine CCL2; Deoxyguanosine; Depsides; Diabetic Retinopathy; Glucose; Glucose Intolerance; Insulin Resistance; Male; Obesity; Rats; Rats, Long-Evans; Tumor Necrosis Factor-alpha; Vascular Endothelial Growth Factor A

Obesity contributes to the development of cardiometabolic disorders such as type 2 diabetes, fatty liver disease and cardiovascular disease. Salvianolic acid B (Sal B) is a molecule derived from the root of Salvia miltiorrhiza (Danshen), which is a traditional Chinese medicine that is widely used to treat cardiovascular diseases. However, the role of Sal B in obesity and obesity-related metabolic disorders is unknown. In this study, we aimed to investigate the effects of Sal B on high-fat diet-induced obesity and determine the possible mechanisms involved.. Male C57BL/6J mice fed a high-fat diet for 12 weeks received a supplement of Sal B (100 mg/kg/day) by gavage for a further 8 weeks. These mice were compared to control mice fed an un-supplemented high-fat diet. 3T3-L1 preadipocytes were used in vitro studies.. Sal B administration significantly decreased body weight, white adipose tissue weight, adipocyte size and lipid (triglyceride and total cholesterol) levels in obese mice. Eight weeks of Sal B administration also improved the intraperitoneal glucose tolerance test (IPGTT) and intraperitoneal insulin tolerance test (IPITT) scores in high-fat diet-induced obese mice. In 3T3-L1 preadipocytes that were cultured in vitro and induced to differentiate, Sal B reduced the accumulation of lipid droplets and lipid content in a dose-dependent manner. Immunoblotting indicated that Sal B decreased peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT/enhancer binding protein α (C/EBPα) expression but increased the expression of GATA binding protein 2 and 3 (GATA 2, GATA 3) both in vivo and in vitro.. Our data suggest that Sal B may reduce obesity and obesity-related metabolic disorders by suppressing adipogenesis. The effects of Sal B in adipose tissue may be related to its action on PPARγ, C/EBPα, GATA-2 and GATA-3.

Topics: 3T3-L1 Cells; Animals; Benzofurans; Diet, High-Fat; Hyperlipidemias; Male; Mice; Mice, Inbred C57BL; Obesity; PPAR gamma; Weight Gain

Topics: Animals; Benzofurans; Circadian Rhythm; CLOCK Proteins; Cyclopropanes; Efficiency; Humans; Melatonin; Obesity; Sleep; Suprachiasmatic Nucleus

Excess glucocorticoids promote visceral obesity and insulin resistance. The main regulator of intracellular glucocorticoid levels are 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1), which converts inactive glucocorticoid into bioactive glucocorticoid such as cortisol in humans and corticosterone in rodents; therefore, the inhibition of 11β-HSD1 has considerable therapeutic potential for metabolic diseases including obesity and diabetes. Benzofuran is a key structure in many biologically active compounds such as benzbromarone, malibatol A and (+)-liphagal. The aim of this study was to investigate the inhibitory effect of benzofuran derivatives on 11β-HSD1 in mesenteric adipose tissue from rodents. 11β-HSD1 activity was determined by incubation of rat mesenteric adipose tissue microsomes in the presence of reduced nicotinamide adenine dinucleotide phosphate (NADPH) with and without benzofuran derivatives (Compounds 1-14). The corticosterone produced was measured by HPLC. More than 40% of 11β-HSD1 inhibition was observed in Compounds 1, 5, 7 and 8. Moreover, Compounds 7 and 8 inhibited the 11β-HSD1 activity in adipose microsomes dose- and time-dependently, as well as in 3T3-L1 adipocytes. Compounds 7 and 8 did not inhibit 11β-HSD type 2 (11β-HSD2), whereas Compounds 1 and 5 inhibited 11β-HSD2 by 18.7% and 56.3%, respectively. Further, a kinetic study revealed that Compounds 7 and 8 acted as non-competitive inhibitors of 11β-HSD1. Ki (nmol/h/mg protein) values of Compounds 7 and 8 were 17.5 and 24.0, respectively, with IC50 (µM) of 10.2 and 25.6, respectively. These data indicate that Compounds 7 and 8 are convincing candidates for seed compounds as specific inhibitors of 11β-HSD1 and have the potential to be developed as anti-obesity drugs.

Topics: 11-beta-Hydroxysteroid Dehydrogenase Type 1; 3T3-L1 Cells; Animals; Benzofurans; Corticosterone; Dose-Response Relationship, Drug; Intra-Abdominal Fat; Male; Mesentery; Metabolic Diseases; Mice; Microsomes; NADP; Obesity; Rats; Rats, Wistar

Polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), mono-ortho and non-ortho polychlorinated biphenyls (dioxin-like PCBs) were determined in samples of human fat tissue from nine Italian obese patients. The toxicity equivalent (TEQ) values ranged from 9 to 25 pg TEQ g(-1) lipid (WHO-TEF values, 2005 [Van den Berg, M., Birnbaum, L.S., Denison, M., De Vito, M., Farland, W., Feeley, M., Fiedler, H., Hakansson, H., Hanberg, A., Haws, L., Rose, M., Safe, S., Schrenk, D., Tohyama, C., Tritscher, A., Tuomisto, J., Tysklind, M., Walker, N., Peterson, R.E., 2006. The 2005 World Health Organization reevaluation of human and mammalian Toxic Equivalency Factors for dioxins and dioxin-like compounds. Toxicol. Sci. 93, 223-241]), the contribution of dioxin-like PCBs was more than 30% of the total TEQ values. The obese body burdens varied from 6 to 11 ng TEQ kg(-1) body weight (BW), exceeding the estimated steady-state body burden 5 ng TEQ kg(-1) BW, based on lipid adjusted serum concentrations from several populations in the mid-1990s, calculated in the risk assessment US EPA document.

Topics: Adipose Tissue; Benzofurans; Body Burden; Body Weight; Dibenzofurans, Polychlorinated; Environmental Exposure; Environmental Pollutants; Female; Humans; Male; Obesity; Polychlorinated Biphenyls; Polychlorinated Dibenzodioxins; Soil Pollutants

The use of complementary and alternative medicine (CAM) in developed countries has increased significantly over the years. Among the most popular are the weight loss supplements or "fat burners." Liver failure due to these popular remedies has been widely recognized. Usnic acid has been an ingredient of dietary supplements that cause liver failure. Its hepatotoxicity has not been recognized because it is usually mixed with other ingredients that are presumably hepatotoxic. We describe a case of a 28-yr-old woman who presented with fulminant liver failure requiring orthotopic liver transplantation, after taking pure usnic acid for weight loss. This is the first report on fulminant liver failure associated with the ingestion of pure usnic acid. A discussion about hepatotoxicity of the different compounds of dietary supplements is presented. This is a reminder for the clinicians about the potential side effects of CAM.

Topics: Adult; Benzofurans; Dietary Supplements; Female; Follow-Up Studies; Humans; Liver Failure; Liver Transplantation; Obesity; Risk Assessment; Weight Loss

Topics: Adult; Benzofurans; Chemical and Drug Induced Liver Injury; Diet, Reducing; Dietary Supplements; Drugs, Chinese Herbal; Ephedra sinica; Female; Humans; Male; Middle Aged; Obesity; Plant Preparations

Hypertension is commonly accompanied by obesity, hyperlipidemia, and insulin resistance in humans, a cluster of abnormalities known as metabolic syndrome X. With the notable exception of inhibitors of the renin-angiotensin system, which have mildly beneficial effects on insulin resistance, most antihypertensive agents worsen one or more components of metabolic syndrome X. Second-generation centrally acting antihypertensive agents such as rilmenidine and moxonidine have mixed effects on components of metabolic syndrome X, which might reflect in part actions on two different receptors: I(1)-imidazoline and alpha(2)-adrenergic. Using a rat model of metabolic syndrome X, we sought to separate the influence of these two receptors on glucose and lipid metabolism by using selective antagonists. Rilmenidine and moxonidine acutely raised glucose and lowered insulin, thereby further worsening glucose tolerance. These effects were entirely mediated by alpha(2)-adrenergic receptors. Rilmenidine and moxonidine also lowered glucagon, an effect that was mediated solely by I(1)-imidazoline receptors since it was potentiated by alpha(2)-blockade, but eliminated in the presence of I(1)-antagonists. Lowering of triglyceride and cholesterol levels followed the same pattern as glucagon, implicating I(1)-imidazoline receptors in lipid-lowering actions. Chronic treatment with moxonidine reproduced the beneficial effects on glucagon and lipids while the acute hyperglycemic response did not persist. Thus, alpha(2)-adrenergic receptors mediate an acute deterioration of glucose tolerance, whereas in contrast I(1)-imidazoline receptors appear to mediate the persistent long-term improvements in glucose tolerance. The therapeutic action of I(1)-imidazoline agonists may be primarily mediated through reduced glucagon secretion.

Topics: Adrenergic alpha-Antagonists; Animals; Antihypertensive Agents; Benzofurans; Blood Pressure; Disease Models, Animal; Female; Glucagon; Glucose; Glucose Tolerance Test; Humans; Imidazoles; Imidazoline Receptors; Lipid Metabolism; Male; Metabolic Syndrome; Obesity; Oxazoles; Rats; Rats, Inbred SHR; Receptors, Adrenergic, alpha-2; Receptors, Drug; Rilmenidine; Yohimbine