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PubMed2003

Guggulsterone is a farnesoid X receptor antagonist in coactivator association assays but acts to enhance transcription of bile salt export pump.

Guggulipid is an extract of the guggul tree Commiphora mukul and has been widely used to treat hyperlipidemia in humans. The plant sterol guggulsterone (GS) is the active agent in this extract. Recent studies have shown that GS can act as an antagonist ligand for farnesoid X receptor (FXR) and decrease expression of bile acid-activated genes. Here we show that GS, although an FXR antagonist in coactivator association assays, enhances FXR agonist-induced transcription of bile salt export pump (BSEP), a major hepatic bile acid transporter. In HepG2 cells, in the presence of an FXR agonist such as chenodeoxycholate or GW4064, GS enhanced endogenous BSEP expression with a maximum induction of 400-500% that induced by an FXR agonist alone. This enhancement was also readily observed in FXR-dependent BSEP promoter activation using a luciferase reporter construct. In addition, GS alone slightly increased BSEP promoter activation in the absence of an FXR agonist. Consistent with the results in HepG2, guggulipid treatment in Fisher rats increased BSEP mRNA. Interestingly, in these animals expression of the orphan nuclear receptor SHP (small heterodimer partner), a known FXR target, was also significantly increased, whereas expression of other FXR targets including cholesterol 7alpha-hydroxylase (Cyp 7a1), sterol 12alpha-hydroxylase (Cyp 8b1), and the intestinal bile acid-binding protein (I-BABP), remained unchanged. Thus, we propose that GS is a selective bile acid receptor modulator that regulates expression of a subset of FXR targets. Guggulipid treatment in rats lowered serum triglyceride and raised serum high density lipoprotein levels. Taken together, these data suggest that guggulsterone defines a novel class of FXR ligands characterized by antagonist activities in coactivator association assays but with the ability to enhance the action of agonists on BSEP expression in vivo.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2003

Antiatherogenic effect of Caps HT2, a herbal Ayurvedic medicine formulation.

The antiatherogenic effect of a herbal formulation, Caps HT2, was evaluated as antioxidant, anticoagulant, platelet antiaggregatory, lipoprotein lipase releasing, anti-inflammatory and hypolipidaemic activity in rats. The formulation contained the methanolic extracts of selected parts of plants, Commiphora mukul, Allium sativum, Plumbago indica, Semecarpus anacardium, Hemidesmus indicus, Terminalia arjuna, Tinospora cordifolia, Withania somnifera and Ocimum sanctum. The formulation, Caps HT2 was found to scavenge superoxide and hydroxyl radicals; the IC50 required being 55.0 and 610.0 microg/ml respectively. The lipid peroxidation was found inhibited (50%) by 48.5 microg/ml of Caps HT2. The intravenous administration of the formulation (5 mg/kg) delayed the plasma recalcification time in rabbits and enhanced the release of lipoprotein lipase enzyme significantly (p < 0.001). The formulation also inhibited ADP induced platelet aggregation in vitro, which was comparable to commercial heparin. The anti-inflammatory action of the formulation was significant (p < 0.001) with acute and chronic inflammations induced by carrageenan and formalin respectively in rats. The hypolipidaemic effect of Caps HT2 was significant (p < 0.001) with the administration of the formulation, in diet-induced hyperlipidaemia of rats for a period of 30 days. Oral administration of the formulation, Caps HT2 (100, 200, 300 and 400 mg/kg) significantly raised HDL cholesterol levels. The atherogenic index and the reduction in body weight were significant indicating the effectiveness against hyperlipidaemia and obesity. All these results revealed the therapeutic potential of Caps HT2 against vascular intimal damage and atherogenesis leading to various types of cardiovascular problems.

Animals↗
PubMed2000

Efficacy of the botanical extract (myrrh), chemical insecticides and their combinations on the cotton leafworm, Spodoptera littoralis boisd (Lepidoptera : Noctuidae).

Effects of the botanical extract (myrrh), Commiphora molmol, and the sublethal treatments of profenofos/chlorofluazuron, fenvalerate and pyriproxyfen on the larvae of S. littoralis were investigated. The results showed that myrrh induced the highest activity after 7 days of treatment with concentration of 10000 ppm and the percentage of mortality reached 44.4%. The chemical insecticide profenofos/chlorofluazuron appeared to be the most effective treatment, giving a mortality of 54% after one day of treatment with a concentration of 100 ppm. Different treatments showed adverse effects on pupation, emerging adults and larval duration. The highest concentration of myrrh (10000 ppm) induced 35% pupation. No pupa was obtained with profenofos/chlorofluazuron while fenvalerate and pyriproxyfen gave 13.3% at 50 ppm. At 10000 ppm of myrrh, 25% adult was emerged, also fenvalerate and pyriproxyfen decreased the emerging moth to 13.3% at 50 ppm. For control there was no larval mortality at 7 days and the percentages of pupation and adult emergence were 90%. Bioassays were also conducted to test the joint action of myrrh applied in binary mixtures with each chemical insecticide on Spodoptera larvae. Results of the bioassay of mixtures indicated antagonistic effects on larval mortality. However, combination of myrrh with profenofos/chlorofluazuron showed additive effect. Also, the degree of pupation and emerging moth varied considerably when myrrh combined with the chemical insecticides. The present work shows the strong efficacy of the botanical extract (myrrh) which could be used alone or in combination with sublethal doses of certain insecticides to control the cotton leafworm.

Animals↗
PubMed2002

A natural product that lowers cholesterol as an antagonist ligand for FXR.

Extracts of the resin of the guggul tree (Commiphora mukul) lower LDL (low-density lipoprotein) cholesterol levels in humans. The plant sterol guggulsterone [4,17(20)-pregnadiene-3,16-dione] is the active agent in this extract. We show that guggulsterone is a highly efficacious antagonist of the farnesoid X receptor (FXR), a nuclear hormone receptor that is activated by bile acids. Guggulsterone treatment decreases hepatic cholesterol in wild-type mice fed a high-cholesterol diet but is not effective in FXR-null mice. Thus, we propose that inhibition of FXR activation is the basis for the cholesterol-lowering activity of guggulsterone. Other natural products with specific biologic effects may modulate the activity of FXR or other relatively promiscuous nuclear hormone receptors.

Animals↗
PubMed2002

The hypolipidemic natural product guggulsterone acts as an antagonist of the bile acid receptor.

Ayurveda, the ancient Indian system of health care and medicine, has a well-organized materia medica in which plants form a dominant part. A key illustration of the exploitation of this knowledge toward the development of a modern drug is the isolation and characterization of two antihyperlipidemic compounds, Z-, and E-guggulsterone from the tree Commiphora mukul, the exudate of which has been traditionally used for mitigating lipid disorders. Here, we demonstrate that Z-guggulsterone and an analog, 80-574 currently in clinical trials, act as antagonists of the bile acid receptor (BAR), a member of the intracellular receptor superfamily. These compounds antagonize the activity of BAR in vitro, and in cell culture systems on promoters and endogenous target genes. In biochemical assays, they are able to displace coactivator peptides from the receptor in a dose-dependent manner. The mechanism by which they act as BAR antagonists is likely through their inability to recruit coactivator proteins, failure to release corepressor proteins from unliganded receptor, and ability to compete with BAR agonists to block coactivator recruitment. Our data suggest these compounds may mediate at least some of their effects via the BAR.

Carrier Proteins↗
PubMed1999

Ancient-modern concordance in Ayurvedic plants: some examples.

Ayurveda is the ancient (before 2500 b.c.) Indian system of health care and longevity. It involves a holistic view of man, his health, and illness. Ayurvedic treatment of a disease consists of salubrious use of drugs, diets, and certain practices. Medicinal preparations are invariably complex mixtures, based mostly on plant products. Around 1,250 plants are currently used in various Ayurvedic preparations. Many Indian medicinal plants have come under scientific scrutiny since the middle of the nineteenth century, although in a sporadic fashion. The first significant contribution from Ayurvedic materia medica came with the isolation of the hypertensive alkaloid from the sarpagandha plant (Rouwolfia serpentina), valued in Ayurveda for the treatment of hypertension, insomnia, and insanity. This was the first important ancient-modern concordance in Ayurvedic plants. With the gradual coming of age of chemistry and biology, disciplines central to the study of biologic activities of natural products, many Ayurvedic plants have been reinvestigated. Our work on Commiphora wightti gum-resin, valued in Ayurveda for correcting lipid disorders, has been described in some detail; based on these investigations, a modern antihyperlipoproteinemic drug is on the market in India and some other countries. There has also been concordance for a few other Ayurvedic crude drugs such as Asparagus racemosus, Cedrus deodara, and Psoralea corylifolia.

Cognition Disorders↗
PubMed2003

Herbs for serum cholesterol reduction: a systematic view.

OBJECTIVES: To systematically review the clinical evidence for herbal medicinal products in the treatment of hypercholesterolemia. STUDY DESIGN: A systematic review of randomized clinical trials of herbal medicinal products used to lower serum cholesterol. Systematic literature searches were conducted in 6 electronic data-bases. The reference lists of all papers and our files were searched for more relevant publications. Experts in the field and manufacturers of identified herbal medicinal products were contacted for published and unpublished data. No language restrictions were imposed. OUTCOMES MEASURED: All randomized clinical trials of serum cholesterol reduction, in which mono-preparations of herbal medicinal products were administered as supplements to human subjects, were included. RESULTS: Twenty-five randomized clinical trials involving 11 herbal medicinal products were identified. Guggul (Commiphora mukul), fenugreek (Trigonella foenum-graecum), red yeast rice, and artichoke (Cynara scolymus) have been most extensively studied and have demonstrated reductions in total serum cholesterol levels of between10% and 33%. The methodological quality as assessed by the Jadad score was less than 3 (maximum, 5) for 13 of the 25 trials. CONCLUSIONS: Many herbal medicinal products have potential hypocholesterolemic activity and encouraging safety profiles. However, only a limited amount of clinical research exists to support their efficacy. Further research is warranted to establish the value of these extracts in the treatment of hypercholesterolemia.

Cholesterol↗
PubMed1994

Ethnobotany and research on medicinal plants in India.

Vast ethnobotanical knowledge exists in India from ancient time. Since the 1950s the study of ethnobotany has intensified; 10 books and 300 papers have been published. Our work over four decades, both in the field and literary studies, has resulted in a dictionary of Indian folk-medicine and ethnobotany that includes 2532 plants. India has about 45,000 plant species; medicinal properties have been assigned to several thousand. About 2000 figure frequently in the literature; indigenous systems commonly employ 500. Despite early (4500-1500 BC) origins and a long history of usage, in the last two centuries Ayurveda has received little official support and hence less attention from good medical practitioners and researchers. Much work is now being done on the botany, pharmacognosy, chemistry, pharmacology and biotechnology of herbal drugs. The value of ethnomedicine has been realized; work is being done on psychoactive plants, household remedies and plants sold by street drug vendors. Statistical methods are being used to assess the credibility of claims. Some recent work in drug development relates to species of Commiphora (used as a hypolipidaemic agent), Picrorhiza (which is hepatoprotective), Bacopa (used as a brain tonic), Curcuma (antiinflammatory) and Asclepias (cardiotonic). A scrutiny of folk claims found 203 plants for evaluation. Less well known ethnomedicines have been identified that are used to treat intestinal, joint, liver and skin diseases.

India↗
PubMed1998

Role of Lipistat in protection against isoproterenol induced myocardial necrosis in rats: a biochemical and histopathological study.

A test drug (Lipistat) comprising of equal-proportions of extracts of Terminalia arjuna, Inula racemosa Hook, latex of Commiphora mukul, in three different doses (225 mg/kg; 350 mg/kg; 450 mg/kg) were administered orally daily for 6 days a week for 60 days in rats. Thereafter, the rats were subjected to isoproterenol (ISO) induced (85 mg/kg, s.c. for 2 days) myocardial necrosis. Gross and microscopic examinations (histopathology) were done along with estimations of myocardial tissue high energy phosphates (HEP) stores and lactate content. Gross examination showed significant (P < 0.05) cardioprotection in Lipistat treated animals. On microscopic examination no statistically significant reduction in myocardial damage by 350 and 450 mg/kg of Lipistat were observed although loss of myocardial HEP stores and accumulation of lactate were significantly prevented. The results of the present study suggest the potential usefulness of Lipistat in the prevention of ischemic heart disease.

Adenosine Triphosphate↗
PubMed1998

Botanical influences on cardiovascular disease.

Several botanicals, including Crataegus oxycantha, Terminalia arjuna, Inula racemosa, and Astragalus membranaceus, have been found to have therapeutic benefit for the treatment of cardiovascular disease. Crataegus oxycantha has been used traditionally as a cardiac tonic and current uses include treatment for angina, hypertension, arrhythmias, and congestive heart failure. Animal studies have also indicated that Crataegus extracts may also have potential use as anti-ischemic and lipid-lowering agents. The bark of the Terminalia arjuna tree has a long history of use as a cardiac tonic as well, and has been indicated in the treatment of coronary artery disease, heart failure, hypercholesterolemia and for relief of anginal pain. Additionally, it has been found to have antibacterial and antimutagenic properties. Inula racemosa, also known as Pushkarmoola, is another traditional Ayurvedic botanical that has potential cardioprotective benefit. In human trials, a combination of Inula racemosa and Commiphora mukul was shown to be superior to nitroglycerin in reducing the chest pain and dyspnea associated with angina. Astragalus membranaceus, a Chinese herb, is often used as a "Qi tonifier" and has been studied for its therapeutic benefit in treatment of ischemic heart disease, myocardial infarction, heart failure, and relief of anginal pain. Clinical studies have indicated that its in vitro antioxidant activity is the mechanism by which it affords its cardioprotective benefit.

Antioxidants↗
PubMedDate not supplied

Stimulation of low density lipoprotein receptor activity in liver membrane of guggulsterone treated rats.

Chronic feeding of guggulsterone to rats showed hypolipidaemic activity in blood serum and liver membrane lipids. The decrease in serum cholesterol is associated with enhanced uptake of LDL by the liver through receptor mediated endocytosis, located on the surface of the cell membrane. In the present communication it has been shown that membranes prepared from liver of guggulsterone treated rats exhibit up to 87% increase in binding sites for human 125I-LDL. Significant decrease in lipid levels of serum as well as of membrane were observed. Lipid lowering activity of the drug in relation to LDL catabolism and other possible mechanisms have been explained.

Administration, Oral↗
PubMed2000

Syntheses and biological evaluation of 3-substituted amino-1-aryl-6-hydroxy-hex-2-ene-1-ones as antioxidant and hypolipidemic agents.

A new series of compounds belonging to 3-substituted amino-1-aryl-6-hydroxy-hex-2-ene-1-ones (4-12a-e) have been synthesized and evaluated for antioxidant and hypolipidemic activities. Amongst all the synthesized compounds, seven compounds, namely 5b, 5d, 6e, 8a, 8b, 10b and 11a, exhibit better antioxidant activity than probucol. Two compounds, 5d and 10b, have been evaluated in detail for antioxidant and hypolipidemic activities and show comparable activity profile to that of probucol and guggulipid. From the present study it may be postulated that the mechanism of action of these compounds could be through activation of lecithin cholesterol acyltransferase (LCAT), liver lipolytic activity, increased faecal bile acid secretion and inhibition of hepatic cholesterol biosynthesis.

Alkenes↗
PubMed1994

Nodulocystic acne: oral gugulipid versus tetracycline.

Twenty patients with nodulocystic acne were randomly allocated to one of two treatment schedules: 1) Tetracycline 500 mg or 2) Tab. Gugulipid (equivalent to 25 mg guggulsterone). Both were taken twice daily for 3 months, and both produced a progressive reduction in the lesions in the majority of patients. With tetracycline, the percentage reduction in the inflammatory lesions was 65.2% as compared to 68% with gugulipid; on comparison, this difference was statistically insignificant (P > 0.05). Follow-up at 3 months showed a relapse in 4 cases on tetracyline and 2 cases on gugulipid. An interesting observation was that the patients with oily faces responded remarkably better to gugulipid.

Acne Vulgaris↗
PubMed2002

Efficacy of azithromycin, praziquantel and mirazid in treatment of cryptosporidiosis in school children.

The study was conducted at a primary school in Abis 8 village. 88 children aged eleven years consented to participate in the present study. After fecal examination, 43 (48.8%) cases were found infected with Cryptosporidium. The mean oocysts number per high power field (HPF) ranged from (1.6-48 oocysts/HPF). Azitbromycin, praziquantel (PZQ) and mirazid were given to 13, 16 and 14 infected children respectively. Three weeks after treatment, azithromycin and praziquantel gave cure rates of 91% and 56.2% respectively with a percent reduction of oocysts in stools of 99% for azithromycin and 71.5% for PZQ. Mirazid was not effective. All the three drugs were well tolerated. It was concluded that azithromycin is highly effective in the treatment of children with cryptosporidiosis: PZQ decreases the infection rate and intensity.

Animals↗