673 research outputs found

    Guggulsterone, an anti-inflammatory phytosterol, inhibits tissue factor and arterial thrombosis

    Get PDF
    Background: The phytosterol guggulsterone is a potent anti-inflammatory mediator with less side effects than classic steroids. This study assesses the impact of guggulsterone on tissue factor (TF) expression and thrombus formation. Methods and results: Guggulsterone inhibited TNF-α-induced endothelial TF protein expression and surface activity in a concentration-dependent manner; in contrast, dexamethasone did not affect TNF-α-induced TF expression. Guggulsterone enhanced endothelial tissue factor pathway inhibitor and impaired plasminogen activator inhibitor-1 as well as vascular cell adhesion molecule-1 protein. Real-time polymerase chain reaction revealed that guggulsterone inhibited TNF-α-induced TF mRNA expression; moreover, it impaired activation of the MAP kinases JNK and p38, while that of ERK remained unaffected. In vivo, guggulsterone inhibited TF activity and photochemical injury induced thrombotic occlusion of mouse carotid artery. Guggulsterone also inhibited TF expression, proliferation, and migration of vascular smooth muscle cells in a concentration-dependent manner. Conclusions: Guggulsterone inhibits TF expression in vascular cells as well as thrombus formation in vivo; moreover, it impairs vascular smooth muscle cell activation. Hence, this phytosterol offers novel therapeutic options, in particular in inflammatory diseases associated with an increased risk of thrombosi

    Prevention and Treatment of Head and Neck Cancer with Natural Compound Inhibitors of STAT3

    Get PDF
    Head and neck squamous cell carcinoma (HNSCC) is a commonly occurring malignancy associated with severe morbidity, persistently high mortality rates, frequent recurrence, and the appearance of second primary tumors (SPTs). A great need exists, therefore, for new therapies, including complementary and preventive approaches to treating HNSCC. Signal transducer and activator of transcription (STAT)-3, an oncogenic transcription factor, shows promise as an important therapeutic target in the treatment of HNSCC. The current study focuses on the STAT3-targeting activities of two natural compounds, guggulsterone and honokiol, and investigation of their antitumor activity in HNSCC. Guggulsterone, a compound contained in the resin of the Commiphora mukul plant, used in Indian Ayurvedic medicine, is widely available as a dietary supplement and associated with few side effects. Honokiol is a naturally-occurring compound that has been used in traditional Chinese medicine and is derived from the plant, Magnolia officinalis. Both compounds have been shown to have anticancer activity in various models and to inhibit nuclear factor kappa B (NF kappa B), an oncogenic transcription factor. NF kappa B and STAT3 interact with one another in various ways. Therefore, we hypothesized that guggulsterone and/or honokiol might be useful in targeting STAT3. Both compounds inhibited growth and invasiveness and induced apoptosis in HNSCC cell lines, in addition to decreasing levels of phosphotyrosine STAT3, and, for guggulsterone, total STAT3. Guggulsterone was also found to cause cell cycle arrest and to target hypoxia-inducible factor (HIF)-1 alpha, a potential therapeutic target whose expression is correlated with poor clinical outcome in HNSCC. Guggulsterone-induced growth inhibition relied partly on its ability to inhibit STAT3. Both compounds enhanced the activities of current HNSCC therapies and modestly inhibited tumor growth in the xenograft model of HNSCC. To test the chemopreventive potential of STAT3 and epidermal growth factor receptor (EGFR) inhibition, a study administering Guggulipid, a guggulsterone-containing nutraceutical, or erlotinib, an EGFR-targeting tyrosine kinase inhibitor (TKI) to mice treated orally with a carcinogen is currently underway. Our results so far suggest that guggulsterone and honokiol-mediated inhibition of STAT3 and guggulsterone-mediated inhibition of HIF-1 alpha provide a biologic rationale for further clinical investigation of these compounds as complementary and preventive treatments for HNSCC

    Current status of herbal and their future perspectives

    Get PDF
    Traditional medicine is the synthesis of therapeutic experience of generations of practicing physicians of indigenous systems of medicine. Throughout the history of mankind, many infectious diseases have been treated with herbals. The traditional medicine is increasingly solicited through the tradipractitioners and herbalists in the treatment of infectious diseases. Among the remedies used, plant drugs constitute an important part. A number of scientific investigations have highlighted the importance and the contribution of many plant families i.e. Asteraceae, Liliaceae, Apocynaceae, Solanaceae, Caesalpinaceae, Rutaceae, Piperaceae, Sapotaceae used as medicinal plants. Medicinal plants play a vital role for the development of new drugs (export and import diverse parts or bioactive compounds in the current market). The bioactive extract should be standardized on the basis of active compound. The bioactive extract should undergo limited safety studies

    Virucidal Effect of Guggulsterone Isolated from Commiphora gileadensis

    Get PDF
    Commiphora gileadensis, locally known as becham, is a plant used in traditional Arabian medicine for treating headache, constipation, stomach, joint pain, and inflammatory disorders. Several studies have reported its antibacterial properties; however, no study has demonstrated its antiviral activity. This study aimed to evaluate the antiviral activity of C. gileadensis as well as to isolate its active compound and investigate its mode of action. This activity was evaluated using 4 viruses, herpes simplex virus type 2 (HSV-2), respiratory syncytial virus type B (RSV‑B), coxsackie virus B type 3, and adenovirus type 5 by performing the plaque reduction assay and the 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays for enveloped and nonenveloped viruses, respectively. The methanol extract of C. gileadensis leaves only showed antiviral activity against enveloped viruses with a selectivity index of 11.19 and 10.25 for HSV-2 and RSV‑B, respectively. The study of the mechanism underlying antiviral activity demonstrated a virucidal effect by direct contact with these target viruses. The active compound, isolated using bio-guided assays involving TLC, was identified as guggulsterone by HPLC-diode array detection coupled with electrospray ionization mass spectrometry. Guggulsterone is an antagonist of the bile acid receptor and a modulator of cholesterol metabolism; however, its antimicrobial properties have been reported for the first time in this study

    PHYSICO-CHEMICAL ANALYSIS AND IMPACT OF DIFFERENT SHODHANA METHODS ON GUGGULU

    Get PDF
    Objective: Guggulu is one of the important Dravya (drug) used in Ayurvedic formulations since ancient time which means “Protection against diseases”. Ashuddhaguggulu has physical and chemical impurities which need to be eliminated before using in formulation by Shodhana. The present study was conducted to evaluate and compare the effect of different Shodhana methods i.e., Dolayantra Shodhana and dissolving Shodhana on properties of Guggulu by employing various physic-chemical and chromatographic methods. Method: Physicochemical screening was done by evaluating ash, Acid Insoluble Ash, Loss on Drying, Water Soluble Extractive and Alcohol Soluble Extractive. Chromatographic analysis was performed to estimate guggulsterone (E and Z) content, using High Performance Liquid Chromatography (HPLC). Result: The Physico-chemical studies showed decrease in LOD, Ash and Acid Insoluble Ash content and increase in extractive values such as Alcohol Soluble Extractive of Guggulu after Shodhana process. The HPTLC analysis showed significant change in guggulsterone (E and Z) content in Guggulu after Shodhana process Conclusion: This study helps to understand the effect of different Shodhana methods on the efficacy of drug. In this study, we established qualitative profile of Shodhit Guggulu in terms of physicochemical parameters and phytochemical content by HPLC

    A Validated High Performance Thin Layer Chromatographic Method for Simultaneous Estimation of Berberine Chloride and Guggulsterone Z in Herbal Formulation

    Get PDF
    A simple, precise, and robust high-performance thin layer chromatography (HPTLC) method was developed and validated for the determination of berberine chloride and guggulsterone Z in herbal formulation. Chromatographic separation was achieved on aluminium plates precoated with silica gel G60F254 as the stationary phase and toluene-acetonitrile-formic acid (5:3:0.5 v/v/v) as the mobile phase. Densitometric evaluation was carried out at 264 nm. The present method was validated according to ICH guidelines. The Rf value of berberine chloride and guggulsterone Z was found to be 0.40 ± 0.02 and 0.68 ± 0.02, respectively. The response in terms of peak area was found to be linear over the concentration range of 100-500 ng/spot for berberine chloride and 200-1000 ng/spot for guggulsterone Z with regression coefficient value greater than 0.995 for both the phytoconstituents. The method was validated by determining its accuracy, precision, robustness, specificity and system suitability. The method was found to be accurate, precise and robust to carry out the simultaneous estimation of berberine chloride and guggulsterone Z. The developed method was successfully applied for the simultaneous estimation of berberine chloride and guggulsterone Z in herbal formulation

    Guggulsterone Targets Smokeless Tobacco Induced PI3K/Akt Pathway in Head and Neck Cancer Cells

    Get PDF
    Epidemiological association of head and neck cancer with smokeless tobacco (ST) emphasizes the need to unravel the molecular mechanisms implicated in cancer development, and identify pharmacologically safe agents for early intervention and prevention of disease recurrence. Guggulsterone (GS), a biosafe nutraceutical, inhibits the PI3K/Akt pathway that plays a critical role in HNSCC development. However, the potential of GS to suppress ST and nicotine (major component of ST) induced HNSCC remains unexplored. We hypothesized GS can abrogate the effects of ST and nicotine on apoptosis in HNSCC cells, in part by activation of PI3K/Akt pathway and its downstream targets, Bax and Bad.Our results showed ST and nicotine treatment resulted in activation of PI3K, PDK1, Akt, and its downstream proteins--Raf, GSK3β and pS6 while GS induced a time dependent decrease in activation of PI3K/Akt pathway. ST and nicotine treatment also resulted in induction of Bad and Bax phosphorylation, increased the association of Bad with 14-3-3ζresulting in its sequestration in the cytoplasm of head and neck cancer cells, thus blocking its pro-apoptotic function. Notably, GS pre-treatment inhibited ST/nicotine induced activation of PI3K/Akt pathway, and inhibited the Akt mediated phosphorylation of Bax and Bad.In conclusion, GS treatment not only inhibited proliferation, but also induced apoptosis by abrogating the effects of ST/nicotine on PI3K/Akt pathway in head and neck cancer cells. These findings provide a rationale for designing future studies to evaluate the chemopreventive potential of GS in ST/nicotine associated head and neck cancer

    Hypolipidemic agent Z-guggulsterone: metabolism interplays with induction of carboxylesterase and bile salt export pump

    Get PDF
    Z-Guggulsterone is a major ingredient in the Indian traditional hypolipidemic remedy guggul. A study in mice has established that its hypolipidemic effect involves the farnesoid X receptor (FXR), presumably by acting as an antagonist of this receptor. It is generally assumed that the antagonism leads to induction of cytochrome P450 7A1 (CYP7A1), the rate-limiting enzyme converting free cholesterol to bile acids. In this study, we tested whether Z-guggulsterone indeed induces human CYP7A1. In addition, the expression of cholesteryl ester hydrolase CES1 and bile salt export pump (BSEP) was monitored. Contrary to the general assumption, Z-guggulsterone did not induce CYP7A1. Instead, this phytosterol significantly induced CES1 and BSEP through transactivation. Z-Guggulsterone underwent metabolism by CYP3A4, and the metabolites greatly increased the induction potency on BSEP but not on CES1. BSEP induction favors cholesterol elimination, whereas CES1 involves both elimination and retention (probably when excessively induced). Interestingly, clinical trials reported the hypolipidemic response rates from 18% to 80% and showed that higher dosages actually increased VLDL cholesterol. Our findings predict that better hypolipidemic outcomes likely occur in individuals who have a relatively higher capacity of metabolizing Z-guggulsterone with moderate CES1 induction, a scenario possibly achieved by lowering the dosing regimens

    Bile Acids Induce Cdx2 Expression Through the Farnesoid X Receptor in Gastric Epithelial Cells

    Get PDF
    Clinical and experimental studies showed that the reflux of bile into the stomach contributes to the induction of intestinal metaplasia of the stomach and gastric carcinogenesis. Caudal-type homeobox 2 (Cdx2) plays a key role in the exhibition of intestinal phenotypes by regulating the expression of intestine-specific genes such as goblet-specific gene mucin 2 (MUC2). We investigated the involvement of the farnesoid X receptor (FXR), a nuclear receptor for bile acids, in the chenodeoxycholic acid (CDCA)-induced expression of Cdx2 and MUC2 in normal rat gastric epithelial cells (RGM-1 cells). RGM-1 cells were treated with CDCA or GW4064, an FXR agonist, in the presence or absence of guggulsterone, an FXR antagonist. CDCA induced dose-dependent expression of Cdx2 and MUC2 at both the mRNA and protein levels. The maximum stimulation of Cdx2 and MUC2 mRNA induced by CDCA was observed at 3 h and by 6 h, respectively. GW4064 also induced expression of these molecules. The effects of CDCA and GW4064 on expression of Cdx2 and MUC2 were abolished by guggulsterone. These findings suggest that bile acids may induce gastric intestinal metaplasia and carcinogenesis through the FXR

    Guggulsterone-Mediated Enhancement of Radiosensitivity in Human Tumor Cell Lines

    Get PDF
    Purpose: To observe the effect of guggulsterone (GS) on the radiation response in human cancer cell lines. Materials and methods: The radiation response of cancer cells treated with GS was observed by cell survival studies, cell growth assay, NF-κB activity assay, western blotting of some key growth promoting receptors, the DNA repair protein γH2AX, and flow cytometry for DNA analyses. Results: GS inhibited radiation induced NF-κB activation and enhanced radiosensitivity in the pancreatic cell line, PC-Sw. It reduced both cell cycle movement and cell growth. GS reduced ERα protein in MCF7 cells and IGF1-Rβ protein in colon cancer cells and pancreatic cancer cells and inhibited DNA double strand break (DSB) repair following radiation. Conclusion: GS induced radiation sensitization may be due to several different mechanisms including the inhibition of NF-κB activation and reductions in IGF1-Rβ. In addition, GS induced γH2AX formation, primarily in the S-phase, indicates that DNA DSB's in the S-phase may be another reason for GS induced radiosensitivity. ERα down-regulation in response to GS suggests that it can be of potential use in the treatment of estrogen positive tumors that are resistant to tamoxifen
    corecore