scholarly journals Binding Efficacy and Thermogenic Efficiency of Pungent and Nonpungent Analogs of Capsaicin

Molecules ◽  
2018 ◽  
Vol 23 (12) ◽  
pp. 3198 ◽  
Author(s):  
Padmamalini Baskaran ◽  
Kyle Covington ◽  
Jane Bennis ◽  
Adithya Mohandass ◽  
Teresa Lehmann ◽  
...  
Keyword(s):  
Hydrogen Bond ◽  
Molecular Docking ◽  
Energy Expenditure ◽  
High Fat Diet ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Docking Studies ◽  
Transient Receptor Potential Vanilloid ◽  
Metabolic Dysfunction ◽  
High Fat

(1) Background: Capsaicin, a chief ingredient of natural chili peppers, enhances metabolism and energy expenditure and stimulates the browning of white adipose tissue (WAT) and brown fat activation to counter diet-induced obesity. Although capsaicin and its nonpungent analogs are shown to enhance energy expenditure, their efficiency to bind to and activate their receptor—transient receptor potential vanilloid subfamily 1 (TRPV1)—to mediate thermogenic effects remains unclear. (2) Methods: We analyzed the binding efficiency of capsaicin analogs by molecular docking. We fed wild type mice a normal chow or high fat diet (± 0.01% pungent or nonpungent capsaicin analog) and isolated inguinal WAT to analyze the expression of thermogenic genes and proteins. (3) Results: Capsaicin, but not its nonpungent analogs, efficiently binds to TRPV1, prevents high fat diet-induced weight gain, and upregulates thermogenic protein expression in WAT. Molecular docking studies indicate that capsaicin exhibits the highest binding efficacy to TRPV1 because it has a hydrogen bond that anchors it to TRPV1. Capsiate, which lacks the hydrogen bond, and therefore, does not anchor to TRPV1. (4) Conclusions: Long-term activation of TRPV1 is imminent for the anti-obesity effect of capsaicin. Efforts to decrease the pungency of capsaicin will help in advancing it to mitigate obesity and metabolic dysfunction in humans.

Abstract 419: Metabocin TM Increases Lipolytic Pathways to Counter High Fat Diet-Induced Non-Alcoholic Fatty Liver Disease

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Baskaran Thyagarajan ◽  
Sara Cisneros ◽  
Ross Cook ◽  
Padmamalini Baskaran
Keyword(s):  
High Fat Diet ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Sirtuin 1 ◽  
Transient Receptor Potential Vanilloid ◽  
High Fat ◽  
Ppar Alpha ◽  
Alcoholic Fatty Liver ◽  
Transient Receptor ◽  
Alcoholic Fatty Liver Disease

Non-alcoholic fatty liver disease (NAFDLD) is a comorbidity of high fat diet-induced obesity. NAFLD leads to steatohepatitis and hepatic steatosis, which progress into cirrhosis and liver cancer. Currently, there is no single strategy to counter NAFLD. In our effort to understand the role of transient receptor potential vanilloid receptor in the pathophysiology of high fat diet-induced, non-alcoholic fatty liver disease, we discovered that mammalian liver expresses transient receptor potential vanilloid 1 protein and that Metabocin TM {( E )- N -[(4-hydroxy-3-methoxyphenyl) methyl]-8-methylnon-6-enamide; also know as capsaicin; an agonist of transient receptor potential vanilloid 1 channel protein} significantly prevented mice from diet-induced NAFLD. Feeding high fat diet (60% calories from fat) for 32 weeks, from the age of 6 weeks until 38 weeks, caused hypertension, hyperglycemia, glucose intolerance and hyper triglyceridemia in the wild type mice and Metabocin TM prevented these effects. Metabocin TM markedly prevented hepatic steatosis and decreased lipid accumulation in the liver. Also, Metabocin TM significantly increased the expression of lipolytic PPAR alpha, PPAR gamma co activator 1 alpha, sirtuin-1 and forkhead box protein 01, while suppressed the expression of lipogenic stearoyl CoA desaturase 1. Further, Metabocin TM increased liver lipolysis, facilitated the activation of sirtuin-1 via Ca 2+ /Calmodulin dependent protein kinase II/AMPK-dependent mechanism and induced an interaction between sirtuin-1 and PPAR alpha. Metabocin TM also increased the expression of lipin-1 (a transcriptional regulator of PPAR alpha) and mitochondrial UCP-1. Our data provide evidence for the emergence of Metabocin TM as a novel drug molecule to antagonize NAFLD and its associated pathologies.

Abstract 394: Posttranslational Modification Of Klf5 Mediates Metabolic Dysfunction And Vascular Disease In Metabolic Syndrome

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Yumiko Oishi ◽  
Ichiro Manabe ◽  
Kazuyuki Tobe ◽  
Takashi Kadowaki ◽  
Ryozo Nagai
Keyword(s):  
Skeletal Muscle ◽  
Metabolic Syndrome ◽  
Energy Expenditure ◽  
Posttranslational Modifications ◽  
High Fat Diet ◽  
Metabolic Diseases ◽  
C2c12 Myotubes ◽  
Metabolic Dysfunction ◽  
High Fat ◽  
Increased Risk

We have previously shown that a zinc finger transcription factor, Krüppel-like factor 5 (KLF5), plays an important role in pathogenesis of cardiovascular diseases, such as atherosclerosis. KLF5 heterozygous knockout ( KLF5 +/ − ) mice exhibited much less neointima formation, cardiac hypertrophy and fibrosis. We also found that expression of KLF5 correlated with a higher incidence of restenosis following PCI and the SNP located within the KLF5 promoter was associated with an increased risk of hypertension in man. Interestingly, KLF5 is also expressed in metabolic tissues such as adipose tissue, skeletal muscle, and pancreatic β-cells. Thus, we hypothesized that KLF5 might play a role in metabolic diseases. To test this, KLF5 +/ − mice were fed with high-fat diet. Although KLF5 +/ − mice ate more food than wild-type littermates, they were resistant to high-fat diet-induced obesity and protected from dyslipidemia, glucose intolerance and hepatic steatosis, indicating that KLF5 + /− mice were less susceptible to metabolic syndrome. The systemic O 2 consumption and expression of genes involved in energy expenditure in skeletal muscle were increased in KLF5 + /− mice, demonstrating enhanced energy expenditure, which partly explains the phenotype. Knocking down KLF5 by siRNA increased expression levels of UCP2/3 and CPT-1b in C2C12 myotubes, suggesting that KLF5 may inhibit energy expenditure-related genes. Chromatin immunoprecipitation and coimmunoprecipitation assays showed that KLF5 interacted with corepressors, such as SMRT and NCoR, and strongly inhibited the UCP and CPT-1b promoters. We found that this inhibitory activity of KLF5 depended on its SUMOylation. When KLF5 was deSUMOylated, it activated the promoters. These data demonstrate that KLF5 acts as a molecular switch for energy expenditure and the posttranslational modifications of KLF5 including SUMOylation turns on/off the switch function of KLF5. Given that KLF5 also controls tissue remodeling in response to external stress, KLF5 may mediate metabolic dysfunction and atherosclerosis in metabolic syndrome. Our findings also suggest that the posttranscriptional modification of KLF5 is an attractive novel therapeutic target.

scholarly journals Investigating the Multitarget Mechanism of Traditional Chinese Medicine Prescription for Cancer-Related Pain by Using Network Pharmacology and Molecular Docking Approach

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Jinyuan Chang ◽  
Lixing Liu ◽  
Yaohan Wang ◽  
Yutong Sui ◽  
Hao Li ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Receptor Potential ◽  
Binding Activity ◽  
Mitogen Activated Protein Kinase ◽  
Network Pharmacology ◽  
Transient Receptor Potential Vanilloid ◽  
Mitogen Activated Protein ◽  
Transient Receptor

Gu-tong formula (GTF) has achieved good curative effects in the treatment of cancer-related pain. However, its potential mechanisms have not been explored. We used network pharmacology and molecular docking to investigate the molecular mechanism and the effective compounds of the prescription. Through the analysis and research in this paper, we obtained 74 effective compounds and 125 drug-disease intersection targets to construct a network, indicating that quercetin, kaempferol, and β-sitosterol were possibly the most important compounds in GTF. The key targets of GTF for cancer-related pain were Jun proto-oncogene (JUN), mitogen-activated protein kinase 1 (MAPK1), and RELA proto-oncogene (RELA). 2204 GO entries and 148 pathways were obtained by GO and KEGG enrichment, respectively, which proved that chemokine, MAPK, and transient receptor potential (TRP) channels can be regulated by GTF. The results of molecular docking showed that stigmasterol had strong binding activity with arginine vasopressin receptor 2 (AVPR2) and C-X3-C motif chemokine ligand 1 (CX3CL1) and cholesterol was more stable with p38 MAPK, prostaglandin-endoperoxide synthase 2 (PTGS2), and transient receptor potential vanilloid-1 (TRPV1). In conclusion, the therapeutic effect of GTF on cancer-related pain is based on the comprehensive pharmacological effect of multicomponent, multitarget, and multichannel pathways. This study provides a theoretical basis for further experimental research in the future.

Hypoglycemic activity of 6-bromoembelin and vilangin in high-fat diet fed-streptozotocin-induced type 2 diabetic rats and molecular docking studies

Life Sciences ◽  
2016 ◽  
Vol 153 ◽  
pp. 100-117 ◽  
Author(s):  
Antony Stalin ◽  
Santiagu Stephen Irudayaraj ◽  
Gopalsamy Rajiv Gandhi ◽  
Kedike Balakrishna ◽  
Savarimuthu Ignacimuthu ◽  
...  
Keyword(s):  
Molecular Docking ◽  
High Fat Diet ◽  
Docking Studies ◽  
Diabetic Rats ◽  
Hypoglycemic Activity ◽  
High Fat ◽  
Molecular Docking Studies ◽  
Type 2 Diabetic

scholarly journals Ion channels alterations in the forebrain of high-fat diet fed rats

2021 ◽  
Vol 65 (s1) ◽  
Author(s):  
Proshanta Roy ◽  
Ilenia Martinelli ◽  
Michele Moruzzi ◽  
Federica Maggi ◽  
Consuelo Amantini ◽  
...  
Keyword(s):  
Ion Channels ◽  
Western Blot ◽  
High Fat Diet ◽  
Transient Receptor Potential ◽  
Trp Channels ◽  
Receptor Potential ◽  
Acid Oxidation ◽  
Standard Diet ◽  
High Fat ◽  
Qrt Pcr

Evidence suggests that transient receptor potential (TRP) ion channels dysfunction significantly contributes to the physiopathology of metabolic and neurological disorders. Dysregulation in functions and expression in genes encoding the TRP channels cause several inherited diseases in humans (the so-called ‘TRP channelopathies’), which affect the cardiovascular, renal, skeletal, and nervous systems. This study aimed to evaluate the expression of ion channels in the forebrain of rats with diet-induced obesity (DIO). DIO rats were studied after 17 weeks under a hypercaloric diet (high-fat diet, HFD) and were compared to the control rats with a standard diet (CHOW). To determine the systemic effects of HFD exposure, we examined food intake, fat mass content, fasting glycemia, insulin levels, cholesterol, and triglycerides. qRT-PCR, Western blot, and immunochemistry analysis were performed in the frontal cortex (FC) and hippocampus (HIP). After 17 weeks of HFD, DIO rats increased their body weight significantly compared to the CHOW rats. In DIO rats, TRPC1 and TRPC6 were upregulated in the HIP, while they were downregulated in the FC. In the case of TRPM2 expression, instead was increased both in the HIP and in the FC. These could be related to the increase of proteins and nucleic acid oxidation. TRPV1 and TRPV2 gene expression showed no differences both in the FC and HIP. In general, qRT-PCR analyses were confirmed by Western blot analysis. Immunohistochemical procedures highlighted the expression of the channels in the cell body of neurons and axons, particularly for the TRPC1 and TRPC6. The alterations of TRP channel expression could be related to the activation of glial cells or the neurodegenerative process presented in the brain of the DIO rat highlighted with post synaptic protein (PSD 95) alterations. The availability of suitable animal models may be useful for studying possible pharmacological treatments to counter obesity-induced brain injury. The identified changes in DIO rats may represent the first insight to characterize the neuronal alterations occurring in obesity. Further investigations are necessary to characterize the role of TRP channels in the regulation of synaptic plasticity and obesity-related cognitive decline.

scholarly journals Anti-Obesity and Lipid Lowering Activity of Bauhiniastatin-1 is Mediated Through PPAR-γ/AMPK Expressions in Diet-Induced Obese Rat Model

2021 ◽  
Vol 12 ◽  
Author(s):  
Reddy Sankaran Karunakaran ◽  
Oruganti Lokanatha ◽  
Ganjayi Muni Swamy ◽  
Chintha Venkataramaiah ◽  
Muppuru Muni Kesavulu ◽  
...  
Keyword(s):  
Molecular Docking ◽  
High Fat Diet ◽  
Docking Studies ◽  
Lipid Lowering ◽  
High Fat ◽  
Down Regulation ◽  
Binding Interactions ◽  
Molecular Docking Studies ◽  
Ppar Γ ◽  
Group I

Objective: To evaluate the therapeutic efficacy and underlying molecular mechanisms of Bauhiniastatin-1 (BSTN1) to alleviate adiposity in diet-induced obese rodent model and in 3T3-L1 cells.Methods: BSTN1 was purified and confirmed through HPLC. In-vitro experiments such as MTT assay, Oil Red-O (ORO) stain, cellular lipid content, glycerol release and RT-PCR analysis were performed in 3T3-L1 cells in the presence and absence of BSTN1. In animal experiments, rats were divided into Group-I: normal pellet diet-fed, Group-II: HFD-fed, Groups-III, IV and V: HFD-fed BSTN1 (1.25, 2.5, and 5 mg/kg.b.wt./day/rat)-treated and Group-VI: HFD-fed Orlistat-treated. The rats were fed either normal diet or high fat diet (HFD) for 18 weeks and water ad-libitum. BSTN1 was orally administered from 13th week onwards to the selected HFD-fed groups. Body composition parameters, biochemical assays, histopathology examination and western blot analysis were performed to identify the predicted targets related to obesity. Molecular docking studies threw light on the binding interactions of BSTN1 against PPAR-γ, FAS and AMPK.Results: BSTN1 at 20 μM significantly (p < 0.001) inhibited adipocyte differentiation and lipid accumulation in 3T3-L1 cells. A conspicuous down-regulation in the mRNA expression levels of PPAR-γ, FAS and SREBP1 was observed but AMPK expression remained unchanged in BSTN1 treated 3T3-L1 cells. A substantial decrease in body weight gain, fat percent, total body fat, serum and liver lipid profile (except high-density lipoprotein), glucose, insulin and insulin resistance in BSTN1 treated rats was noticed in a dose dependent manner. In BSTN1 (5 mg/kg.b.wt.)-treated groups significantly (p < 0.01) elevated plasma adiponectin level but reduced leptin level as well as fall in serum AST and ALT were noticed. Further, the disturbed structural integrity and architecture of adipose and hepatic tissues due to high fat diet feeding were considerably recovered with BSTN1 treatment. Down-regulation in the protein expression level of PPAR-γ and activation of AMPK through phosphorylation was observed in BSTN1 treated rats than the untreated. Molecular docking studies revealed strong binding interactions of BSTN1 against PPAR-γ and AMPK and thus supported the experimental results.Conclusion: Taken together, the results suggest that BSTN1 could be a promising pharmacological molecule in the treatment of obesity and dyslipidemia.

Activation of Transient Receptor Potential Vanilloid 3 Channel Suppresses Adipogenesis

Endocrinology ◽  
2015 ◽  
Vol 156 (6) ◽  
pp. 2074-2086 ◽  
Author(s):  
Sin Ying Cheung ◽  
Yu Huang ◽  
Hiu Yee Kwan ◽  
Hau Yin Chung ◽  
Xiaoqiang Yao
Keyword(s):  
Transient Receptor Potential ◽  
Receptor Potential ◽  
In Vivo Studies ◽  
Transient Receptor Potential Vanilloid ◽  
Peroxisome Proliferator ◽  
High Fat ◽  
High Fat Diets ◽  
Transient Receptor ◽  
Fat Diets

Abstract The present study shows that activation of the transient receptor potential vanilloid 3 channel (TRPV3) suppresses adipocyte differentiation. We also found that a major functional catechin compound in green tea and cocoa, (−)-epicatechin, exerts antiadipogenic effects in the adipocytes through direct activation of TRPV3. TRPV3 was detected in the 3T3-L1 adipocytes using immunohistochemistry and semiquantitative PCR. TRPV3 activation by activators (−)-epicatechin and diphenylborinic anhydride was determined using live cell fluorescent Ca2+ imaging and patch-clamp electrophysiology. Using RNA interference, immunoblotting, and Oil red O staining, we found that the TRPV3 agonists prevented adipogenesis by inhibiting the phosphorylation of insulin receptor substrate 1, the downstream phosphoinositide 3-kinase/Akt/forkhead box protein O1 axis, and the expression of the adipogenic genes peroxisome proliferator–activated receptor γ and CCAAT/enhancer-binding protein α. TRPV3 overexpression hindered adipogenesis in the 3T3-L1 cells. In vivo studies showed that chronic treatment with the TRPV3 activators prevented adipogenesis and weight gain in the mice fed on high-fat diets. Moreover, TRPV3 expression was reduced in the visceral adipose tissue from mice fed on high-fat diets and obese (ob/ob) and diabetic (db/m+) mice. In conclusion, our study illustrates the antiadipogenic role of TRPV3 in the adipocytes.

scholarly journals Synthesis of a 1,2,3-bistriazole derivative of embelin and evaluation of its effect on high-fat diet fed-streptozotocin-induced type 2 diabetes in rats and molecular docking studies

2020 ◽  
Vol 96 ◽  
pp. 103579 ◽  
Author(s):  
Antony Stalin ◽  
Subramani Kandhasamy ◽  
Balakrishnan Senthamarai Kannan ◽  
Rama Shanker Verma ◽  
Savarimuthu Ignacimuthu ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Molecular Docking ◽  
High Fat Diet ◽  
Docking Studies ◽  
High Fat ◽  
Molecular Docking Studies

scholarly journals Desensitization of TRPV1 Involved in the Antipruritic Effect of Osthole on Histamine-Induced Scratching Behavior in Mice

2021 ◽  
Vol 2021 ◽  
pp. 1-10
Author(s):  
Niuniu Yang ◽  
Ying Ju ◽  
Delun Huang ◽  
Kunhong Ling ◽  
Han Jin ◽  
...  
Keyword(s):  
Molecular Docking ◽  
Receptor Agonist ◽  
Transient Receptor Potential ◽  
Calcium Influx ◽  
Receptor Potential ◽  
Binding Pocket ◽  
Transient Receptor Potential Vanilloid ◽  
Dependent Manner ◽  
Drg Neurons ◽  
Histamine H4 Receptor

Osthole has been isolated from the fruits of Cnidium monnieri (L.) Cusson, which has been used in Chinese traditional medicine to treat pruritic disorders for a long time. However, the antipruritic mechanism of osthole is not fully understood. In the present study, using calcium imaging, molecular docking, and animal scratching behavior, we analyzed the pharmacological effects of osthole on transient receptor potential vanilloid 1 (TRPV1). The results showed that osthole significantly induced calcium influx in a dose-dependent manner in dorsal root ganglion (DRG) neurons. Osthole-induced calcium influx was inhibited by AMG9810, an antagonist of TRPV1. Osthole and the TRPV1 agonist capsaicin-induced calcium influx were desensitized by pretreatment with osthole. Furthermore, molecular docking results showed that osthole could bind to TRPV1 with a hydrogen bond by anchoring to the amino acid residue ARG557 in the binding pocket of TRPV1. In addition, TRPV1 is a downstream ion channel for the histamine H1 and H4 receptors to transmit itch signals. Osthole attenuated scratching behavior induced by histamine, HTMT (histamine H1 receptor agonist), and VUF8430 (histamine H4 receptor agonist) in mice. These results suggest that osthole inhibition of histamine-dependent itch may be due to the activation and subsequent desensitization of TRPV1 in DRG neurons.

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