benzofurans and Weight-Gain

While the alteration of I. LSL 60101 was administered in adult male Sprague-Dawley rats daily during 16 days (doses of 10 and 20 mg/kg, ip) and its antidepressant-like potential was assessed through the course of treatment in the forced-swim test, novelty-suppressed feeding test and two-bottle choice test (sucrose preference). The regulation of several key neuroplasticity markers (i.e., FADD, p-ERK1/2, ERK1/2, p-JNK1/2, JNK1/2, mBDNF) was evaluated 24-h post-treatment by western blot analysis in the right hippocampus and the proliferation of neural progenitors was quantified in the left hippocampus by immunohistochemistry.. The results showed that LSL 60101 did not induce an antidepressant-like effect over the course of treatment in any of the behavioral tests conducted, and it did not alter any of the hippocampal neuroplasticity markers evaluated.. These results add to the existing literature by suggesting that not all I

Topics: Anhedonia; Animals; Antidepressive Agents; Benzofurans; Feeding Behavior; Hippocampus; Imidazoles; Imidazoline Receptors; Male; Neural Stem Cells; Neuronal Plasticity; Rats; Rats, Sprague-Dawley; Swimming; Weight Gain

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

Prenylation of bioactive natural compounds has been postulated to be able to enhance the utilization rate and affinity of the compounds with cell membranes, thus promote their bioactivities. Coumestrol, isolated from Medicago sativa, has been known as a phytoestrogen which has bone health benefits. In our previous work, psoralidin, a prenylated coumestrol, was proved to have a higher ability than coumestrol to promote bone formation and to attenuate resorption in vitro. However, it remains to be investigated whether psoralidin will have stronger bone health benefits than coumestrol. In the current study, psoralidin was isolated from Psoralea corylifolia L. and the osteotropic activities of coumestrol and psoralidin were compared in ovariectomized (OVX) rats. Both coumestrol and psoralidin were found to suppress OVX-induced bone loss in vivo, as shown by improved total bone mineral content (t-BMC) or density (t-BMD) and mineral apposition rate, bone biomechanical properties, microstructure and trabecular bone formation, enhanced osteogenic differentiation but suppressed adipogenic differentiation of bone marrow stromal cells (BMSCs), and activation of PI3K/Akt axis and downstream factors such as GSK3β/β-catenin and Nrf-2/HO-1. However, psoralidin was shown to have higher activities than coumestrol in the above measurements/indices. Our findings demonstrate that psoralidin, as a novel anti-osteoporosis candidate, could suppress bone loss in OVX rats and have better osteoprotective effects than coumestrol, which may be related to the presence of the isopentenyl group in psoralidin.

Topics: Adipogenesis; Animals; Antioxidants; Benzofurans; Biomarkers; Biomechanical Phenomena; Bone Density; Bone Remodeling; Calcification, Physiologic; Coumarins; Coumestrol; Estradiol; Female; Mesenchymal Stem Cells; Minerals; Osteoclasts; Osteogenesis; Ovariectomy; Oxidation-Reduction; Pentanes; Phosphatidylinositol 3-Kinases; Protective Agents; Proto-Oncogene Proteins c-akt; Rats, Sprague-Dawley; Signal Transduction; Tartrate-Resistant Acid Phosphatase; Uterus; Weight Gain

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

The aim of this study was to determine the contamination of broiler chicken with polychlorinated dibenzodioxins and dibenzofurans (PCDD/Fs) after feeding either uncontaminated feed or feed contaminated with 1, 2 or 4 ng/kg toxic equivalents (TEQ). The feed was mixed with pure substances of PCDD/Fs to get the intended contamination. Ten groups of seven 1-day-old chickens each were housed in special cages for broiler fattening. The fattening period lasted for 6 weeks. The contaminated feed was given for either 2, 4, or 6 weeks, one group received uncontaminated feed (control group). After slaughtering the edible parts of the chickens breast and leg including the skin were homogenized. Body weight gain and feed conversion (kg feed/kg body weight gain) were in the normal range (final weight 1.98+/-0.07 kg; feed conversion 1.74+/-0.03). One kilogram edible tissue contained an average of 21.2+/-4.1% of the total TEQ-intake in all groups. The PCDD/Fs residues in the edible tissues significantly correlated with the amount of PCDD/Fs-intake (r=0.99; Pearson correlation). There was no decrease in dioxin residues (% of total PCDD/Fs intake) after a 2 or 4 weeks withdrawal period. The results of this trial predict that a threshold value of 2 pg/g chicken fat can be met if the PCDD/Fs content in chicken feed is not higher than 0.4 ng/kg.

Topics: Animal Feed; Animals; Benzofurans; Chickens; Dioxins; Dose-Response Relationship, Drug; Drug Residues; Food Contamination; Humans; Meat; Polychlorinated Dibenzodioxins; Soil Pollutants; Weight Gain

Chronic administration of the tricyclic antidepressant clomipramine to neonatal rats from postnatal days 8 to 21 is reported to induce several behavioral changes in adult life, and it may serve as an animal model of human depressive disorder. Findings include increased immobility time in the forced swim test and locomotor hyperactivity in the open field test. Clomipramine is a serotonergic reuptake inhibitor, which suggests that altered development of the serotonergic system could account for the observed behavioral changes in the adult rat. The present study was carried out with a selective serotonin reuptake inhibitor (SSRI) to investigate whether the serotonin system, in particular, is involved in the neonatal animal model. The substance, Lu 10-134-C (LU), was characterized in monoamine reuptake and receptor binding assays and found to be an SSRI. Rats received LU during postnatal days 8 to 21 (2.5-15 mg/kg b. i.d.), and they were assessed in open field, forced swim and social interaction tests at the age of 4 months. Behavior of LU-treated rats and saline controls did not differ in the open field and social interaction tests. However, in the forced swim tests LU-treated neonates showed prolonged immobility time compared with saline controls. In conclusion, chronic LU treatment during neonatal life produces long-term changes in the forced swim test, but not in the open field and social interaction tests. The behavioral changes in the forced swim test suggest that the central serotonergic system may be involved in the putative neonatal animal model of depression.

Topics: Animals; Animals, Newborn; Benzofurans; Butylamines; Depression; Disease Models, Animal; Female; Male; Mice; Motor Activity; Rats; Rats, Wistar; Receptors, Serotonin; Selective Serotonin Reuptake Inhibitors; Swimming; Weight Gain

A 1-year chronic toxicity study was conducted in which rhesus monkeys (4/sex/dose) were given daily doses of 0, 3, 10, or 25 mg zatosetron/kg by nasogastric intubation. Clinical signs of toxicity characterized by salivation, diarrhea or soft stools, and/or emesis occurred in animals that received 10 or 25 mg/kg of zatosetron. One monkey in the high-dose group and one in the middle-dose group died as a result of intratracheal administration of the compound. The death of another monkey in the high-dose group was associated with an unexpectedly high (3-fold the mean plasma Cmax value in surviving females in this group) plasma level of zatosetron as indicated by postmortem analysis of heart blood. Animals of both sexes in all treatment groups gained weight at a slightly reduced rate when compared to control monkeys. Depressed appetite occurred in some monkeys in all treatment groups but was most evident in those receiving 25 mg/kg. Evaluation of ECG's indicated that treatment with zatosetron did not produce any rhythm or conduction disturbances. However, there was a mild increase in the Q-Tc interval throughout the treatment period at 4 hours postdosing in monkeys in the middle- and high-dose groups and a slight increase prior to dosing in animals in the high-dose group. Mean plasma Cmax and AUC(0-24 hr) values on Day 360 were dose proportional for zatosetron and for the N-demethylated metabolite in both sexes over the dose range tested. The mean t1/2 (elimination phase) for the plasma disappearance of zatosetron ranged from 3.4 to 7.2 hr in males and from 2.3 to 6.8 hr in females. Hematology, urinalysis, and clinical chemistry parameters were unaffected by treatment. There were no treatment-related gross or microscopic alterations or changes in organ weights. With the exception of mild effects on body weight gain, there was no evidence of chronic toxicity in monkeys given 3 mg/kg zatosetron daily for 1 year.

Topics: Animals; Appetite; Benzofurans; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Dose-Response Relationship, Drug; Electrocardiography; Female; Macaca mulatta; Male; Serotonin Antagonists; Weight Gain

The potency of 2,3,4,7,8-pentachlorodibenzofuran (P5CDF) and of three defined 2,3,7,8-TCDD-free mixtures of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDDs/PCDFs) to induce cleft palates in NMRI mice was studied. The data were compared with a dose-response curve for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). The slope of the dose-response curve for P5CDF was the same as for TCDD. However, application of the International-TCDD-Toxic-Equivalency (I-TE) factor (NATO/CCMS 1988) of 0.5 overestimated the potency of the pentachlorinated congener about 2.5-fold under these experimental conditions, suggesting 0.2 as a TE factor. When assessing the cleft palate frequency on the basis of I-TEs and the weight of the substances, the potencies of the two PCDF mixtures studied were also clearly overestimated. This result was not substantially changed when using the TE factor of 0.2 for P5CDF. For the PCDD mixture studied, the cleft palate-inducing potency found largely agreed with the prediction when applying the I-TE factors. According to our data, the use of TE factors as calculated by the UBA/BGA (1985) or the NATO/CCMS (1988) are both conservative when attempting to assess the cleft palate incidence induced by PCDF mixtures in mice.

Topics: Animals; Benzofurans; Cleft Palate; Dose-Response Relationship, Drug; Drug Combinations; Female; Liver; Mice; Organ Size; Polychlorinated Dibenzodioxins; Polymers; Pregnancy; Risk Factors; Teratogens; Weight Gain

We investigated the role of thyroid hormone in the postnatal development of Ca2+ transport activity of sarcoplasmic reticulum in skeletal muscle (m. gastrocnemius-plantaris). With a Ca2+-stat method using the fluorescent dye fura 2 as Ca2+ indicator, we determined the oxalate-supported maximal Ca2+ uptake activity of sarcoplasmic reticulum in whole muscle homogenates from neonatal rats. Expressed per g tissue wet wt, the activity increased nearly 10-fold during the first 8 weeks after birth, following which time a plateau was reached. This development was absent in hypothyroid pups, in which the level of Ca2+ uptake activity remained constant at 10% of the normal adult value for at least 8 weeks. When the mothers were given 0.05% propylthiouracil in the drinking water 1 week before parturition, these pups ceased to grow after 4 weeks, had a reduced muscle protein content and a characteristic cretinous appearance. The effects of hypothyroidism could be reversed by T3 treatment (0.5 micrograms/100 g BW, daily) starting 1 or 6 weeks after birth. Treatment with bovine GH (0.1 or 0.5 IU/100 g BW; daily) starting on day 5 stimulated body growth, particularly of muscle, but was without effect on the failing development of Ca2+ uptake activity. The postnatal rise in citrate synthase and succinate dehydrogenase activities was impaired in the hypothyroid group, but lactate dehydrogenase and creatine kinase activities rose continuously, although at a reduced rate. T3 treatment also reversed these effects of propylthiouracil. At the higher dosage used bovine GH appeared to stimulate the accumulation of creatine kinase. We conclude that the failing postnatal development of sarcoplasmic reticulum Ca2+ transport activity in hypothyroidism is not secondary to the absence of GH, nor is it part of a general, indiscriminate effect, but, rather, that it indicates an absolute requirement of thyroid hormone for this particular aspect of muscle differentiation.

Topics: Animals; Benzofurans; Biological Transport; Calcium; Citrate (si)-Synthase; Creatine Kinase; Cytosol; Female; Fluorescent Dyes; Fura-2; Growth Hormone; Hypothyroidism; L-Lactate Dehydrogenase; Mitochondria; Muscle Development; Muscles; Pregnancy; Propylthiouracil; Rats; Rats, Inbred Strains; Sarcoplasmic Reticulum; Succinate Dehydrogenase; Thyroid Hormones; Triiodothyronine; Weight Gain