11β-Hydroxysteroid dehydrogenase type 1The main components of metabolic syndrome obesity, insulin resistance, hypertension and dyslipidemia have become prevalent worldwide, and excess glucocorticoid levels have been implicated in patients with these symptoms. Numerous rodent studies steroide con meno effetti collaterali demonstrated the potential use of 11beta-HSD1 inhibitors as treatment for the components of metabolic syndrome and limited clinical data in humans have shown 11beta-HSD1 inhibition to improve glucose levels, insulin sensitivity and lipid profiles. Many organizations have 11beta hydroxysteroid dehydrogenase inhibitor active in dehydtogenase 11beta-HSD1 academic and patent literature, and two previous articles from this journal have reviewed disclosures through August To summarize the 11beta hydroxysteroid dehydrogenase inhibitor patent literature and progress in defining the utility of small molecule 11beta-HSD1 inhibitors. This review covers the recent 11beta-HSD1 patent literature and clinical activity ranging from late through the end of
11beta-hydroxysteroid dehydrogenase type 1 inhibitors: a review of recent patents. - PubMed - NCBI
Curcumin reduced serum glucose, cholesterol, triglyceride, low density lipoprotein levels in high-fat-diet-induced obese rats. December 7, ; Accepted: October 17, ; Published: This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors have declared that no competing interests exist.
Glucocorticoids GCs have a wide range of physiological and pharmacological roles in mammalian functions . Excessive GCs under conditions such as stress and Cushing's syndrome cause a spectrum of clinical features, including metabolic syndrome . GCs increase glucose output in the liver, induce fat accumulation, dampen glucose-dependent insulin sensitivity in the adipose tissue, thus increasing the risks of metabolic syndrome .
One of chemicals is curcumin Fig. In this study, we investigated the therapeutic efficacy of curcumin for high-fat-diet HFD -induced metabolic syndrome in a rat model, and we also screened 12 curcumin analogues Fig. Human liver and kidney microsomes were purchased from Gentest Woburn, MA. Curcumin analogues were synthesized by coupling the appropriate aldehyde with acetone, or cyclopentanone or cyclohexanone in an alkaline medium, respectively as described  , .
The melting points and spectroscopic analysis such as NMR and mass spectroscopy were performed. For example, the reaction of 5-bromofuranaldehyde with three respective ketones in alkaline medium was performed to generate these compounds as previously described  , .
Rats were euthanized by CO2, and livers, testes and kidneys were collected. Rat liver, testis and kidney microsomes were prepared as described previously . In brief, rat liver and kidney were homogenized in 0.
Purified rat Leydig cells were obtained from day-old Sprague-Dawley rats by collagenase digestion of the testes followed by Percoll density centrifugation of the cell suspension, according to the previously described method .
Adult rat Leydig cells were harvested from the Percoll gradient at a band at 1. The Escherichia coli transformants carrying an insert were selected by colony hybridization, and a clone with the insert in the correct orientation relative to the vector T7 promoter was identified by restriction mapping. In brief, each assay tube contained 25 nM substrate 11DHC for rat or cortisone for human , spiked with 30, cpm their respective 3 Hketo-steroid in the PBS buffer.
At the end of reaction, the reaction was stopped by adding 2 ml ice-cold ether. The steroids were extracted, and the organic layer was dried under nitrogen. In brief, the assay tubes contained 25 nM substrate 11DHC for rat or cortisone for human , spiked with 30, cpm their respective 3 Hketo-steroid, 0. The percentage conversion of CORT to 11DHC or cortisol to cortisone was calculated by dividing the radioactive counts identified as 11keto-steroids by the total counts.
The mode of inhibition was assayed by adding various concentrations of steroid substrates in the presence of an inhibitor as described .
Thirty male Sprague-Dawley rats body weight — g were randomly divided into three groups: Rats were gavaged with vehicle 0. By the end of curcumin treatment, rats were euthanized. The body, liver, kidney and testis weights were recorded.
Sera were used for measurement of serum glucose, and lipid analysis. Lineweaver-Burk plot was used for the mode of inhibition. Data were subjected to analysis by one-way ANOVA followed by Tukey's multiple comparisons testing to identify significant differences between groups when three were calculated. We further used intact cells to screen curcumin derivatives Fig. Thiophenyl 1,4-pentadieneone compounds 4 and 6 were among the most potent inhibitors Table 1 and Fig.
Compound 4 [ 1E,4E -1,5-bis 3-methylthiophenyl penta-1,4-dienone] was Compound 6 [ 1E,4E -1,5-bis thiophenyl penta-1,4-dienone] was There are clear structure-activity responses for these compounds.
During the two-month treatment, there were no adverse effects found in HFD and curcumin treatment groups. Curcumin reduced HFD-induced increase of body weight gain and liver weight after two months of treatment. As shown in Fig. Elevation of GCs, such as in Cushing's syndrome, is closely associated with the pathogenesis of metabolic syndrome, including insulin resistance, central obesity, hyperglycaemia and dyslipidaemia .
Over-expression of Hsd11b1 in mouse liver also caused insulin-resistance, hypertension and fatty liver without obesity . In addition, Hsd11b1 null mice were resistant to HFD-induced insulin resistance, obesity and dyslipidaemia . Although HFD did not increase serum glucose level, the curcumin treatment also reduced serum glucose level Fig. Apparently, many reports have been documented about curcumin in regard to its beneficial effects on metabolic disorders in various animal models.
Several earlier studies conducted in rats demonstrated that curcumin lowered serum and liver cholesterol levels  , . In diabetic rats fed with either normal or high fat diet, curcumin also remarkably reduced serum cholesterol and Tg levels .
A clinical report showed that oral doses of up to mg of curcumin failed to reach detectable serum level . However, within 1 h of oral administration, higher doses of curcumin up to 8 g rendered its peak levels of about 0.
Unlike curcumin, these compounds are more metabolically stable because of mono-carbonyl group . Whether the compound is more effective than curcumin in the treatment of metabolic syndrome is worthy to be tested in the future. Indeed, BVT was evaluated in vivo in the hyperglycemic KKAy mouse model, and the results demonstrated that the compound significantly lowered blood glucose level .
Compared to these compounds, our curcumin derivatives among the potent inhibitors within the nanomolar range. There is a clear structure activity response S. The newly characterized compound 4 and 6 possesses IC 50 in mid-nanomolar range and an up to fold increase efficacy compared to the parent compound curcumin. The enhanced activity and selectivity seems to be conferred by thiophenyl pentacyclic ring structure in compound 4, 6 and The effects of curcumin on body weight, the weights of liver, testis and kidney were recorded.
We also thank Dr. Conceived and designed the experiments: Click through the PLOS taxonomy to find articles in your field. March 22, Copyright: Introduction Glucocorticoids GCs have a wide range of physiological and pharmacological roles in mammalian functions . Structures of curcumin and its pentadienone analogues. Chemistry Curcumin analogues were synthesized by coupling the appropriate aldehyde with acetone, or cyclopentanone or cyclohexanone in an alkaline medium, respectively as described  , .
Preparation of microsomes Rats were euthanized by CO2, and livers, testes and kidneys were collected. Animal treatment Thirty male Sprague-Dawley rats body weight — g were randomly divided into three groups: Physiological parameters, serum glucose and lipid profiles after curcumin treatment During the two-month treatment, there were no adverse effects found in HFD and curcumin treatment groups.
Acknowledgments We thank Dr. Author Contributions Conceived and designed the experiments: View Article Google Scholar 2. Clin Sci Lond View Article Google Scholar 3. View Article Google Scholar 4. View Article Google Scholar 5. View Article Google Scholar 6.
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