Article

Relationships between cyclic AMP levels and lipolysis in fat cells after isoproterenol and forskolin stimulation

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Abstract

Using the flask-incubated fat cell system, alterations in glycerol release (lipolysis) and cAMP accumulation were determined after incubation with isoproterenol or forskolin. These agents caused concentration-dependent increases in both cAMP accumulation and lipolysis. The maximum responses to forskolin for each variable were greater than the corresponding responses to isoproterenol. The maximum responses to isoproterenol for both cAMP accumulation and glycerol release were increased by the presence of either adenosine deaminase or theophylline. Under these conditions, high concentrations of isoproterenol continued to increase cAMP accumulation while having no further effect on lipolysis. These results support the concept that the maximum response to isoproterenol alone was limited by the accumulation of cAMP within the cells. The maximum response to isoproterenol in the presence of either theophylline or adenosine deaminase (and to forskolin) was limited by some step in the lipolytic process distal to cAMP accumulation. The relationships between cAMP levels and lipolysis for isoproterenol and forskolin were found to be different. A 6-fold increase in cAMP levels was sufficient to maximally increase lipolysis with isoproterenol, whereas the maximum lipolytic response to forskolin was associated with a 20-fold increase in cAMP levels. A plot of log cAMP vs. glycerol release resulted in linear relationships for both drugs. The slope of the line for isoproterenol was significantly greater than that for forskolin. At any given concentration of cAMP the corresponding lipolytic response was greater for isoproterenol than for forskolin.

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... Forskolin, a bioactive compound of Coleus forskohlii, enhances adenylate cyclase enzyme activity, thereby increasing intracellular cyclic adenosine monophosphate (cAMP) concentration [6]. Increased intracellular cAMP levels elevate hormone-sensitive lipase enzyme activity by the activation of protein kinase A, resulting in promoting lipolysis in mature adipocytes [7][8][9]. In addition to lipolysis, cAMP also involves the regulation of adipocyte differentiation. ...
... The regulation of adipocyte differentiation and lipolysis in differentiated adipocytes can control the adipocyte size [2]. It has been demonstrated that forskolin is able to promote lipolysis in mature adipocytes by the activation of hormone-sensitive lipase enzyme activity [7][8][9]. Here, we further demonstrated forskolin could attenuate the adipocyte differentiation of murine mesenchymal stem cells. Thus, forskolin administration may regulate adipocyte differentiation and lipolysis in the adipose tissue of high-fat diet-fed mice, resulting in the reduction of fat cell diameter. ...
... The effects of forskolin on lipolysis by increased cellular cAMP concentration and activation of hormone-sensitive lipase enzyme activity in differentiated adipocytes have been well-studied [7][8][9]. The elevation of cellular cAMP concentration also positively regulates the early program of differentiation [23,24]. ...
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The purpose of this study was to investigate the effects of forskolin on body weight, glucose metabolism and fat cell diameter in high-fat diet-induced obese mice. Four-week-old male mice (C57BL/6) were randomly assigned to 1 of 3 treatment groups: a high-fat diet plus 5% dimethyl sulfoxide (vehicle), high-fat diet plus 2 mg/kg of forskolin (dissolved in 5% dimethyl sulfoxide) and high-fat diet plus 4 mg/kg of forskolin (dissolved in 5% dimethyl sulfoxide). Forskolin or dimethyl sulfoxide was administered intraperitoneally every two days. The results indicated that no significant difference was observed in the body weight, feed intake and serum lipid parameters among groups at 20 weeks of age. The blood glucose levels were significantly reduced in the groups treated with 2 mg/kg of forskolin before glucose tolerance test. Forskolin administration linearly decreased blood glucose levels of high-fat diet-fed mice at 90 min and total area under curve (AUC) after insulin tolerance test. The subcutaneous adipocyte diameter was significantly reduced in the groups treated with 2 mg/kg of forskolin. Forskolin administration linearly reduced the gonadal adipocyte diameter of high-fat diet-fed mice. Forskolin significantly reduced the differentiation of murine mesenchymal stem cells into adipocytes and this was accompanied by a decrease in intracellular triglyceride content and an increase in glycerol concentration in the culture medium. The subcutaneous adipocyte diameter, gonadal adipocyte diameter and total AUC of insulin tolerance test were moderately negatively correlated with the concentration of forskolin in the high-fat diet-induced obese model. These results demonstrate that forskolin can regulate glucose metabolism and reduce fat cell diameter of high-fat diet-fed mice and inhibit the adipocyte differentiation of murine mesenchymal stem cells.
... It has been documented that forskolin increases the rate of lipolysis via cyclic adenosine monophosphate (cAMP) accumulation by mechanisms independent of hormonal stimulation both in vitro [18,19] and in animal models [20,21]. Furthermore, forskolin also directly activates hormone sensitive lipase by phosphorylation of protein kinase A resulting in further lipolysis and release of free fatty acids [19]. ...
... Forskolin is extracted from the tuberous roots of the plant and thus far, C. forskohlii is the only species known to contain significant amounts of the bioactive component [17]. It has been documented that forskolin increases the rate of lipolysis via cyclic adenosine monophosphate (cAMP) accumulation by mechanisms independent of hormonal stimulation both in vitro [18,19] and in animal models [20,21]. Furthermore, forskolin also directly activates hormone sensitive lipase by phosphorylation of protein kinase A resulting in further lipolysis and release of free fatty acids [19]. ...
... It has been documented that forskolin increases the rate of lipolysis via cyclic adenosine monophosphate (cAMP) accumulation by mechanisms independent of hormonal stimulation both in vitro [18,19] and in animal models [20,21]. Furthermore, forskolin also directly activates hormone sensitive lipase by phosphorylation of protein kinase A resulting in further lipolysis and release of free fatty acids [19]. Limited human studies have indicated that supplementation with C. forskohlii extract elicits favorable changes to body composition. ...
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Limited studies have shown that Coleus forskohlii extract may aid in weight management. This randomized, double blind placebo-controlled clinical study assessed the effects of supplementation with C. forskohlii extract on key markers of obesity and metabolic parameters in overweight and obese individuals. Thirty participants completed the trial and they were randomly assigned to receive either 250 mg of C. forskohlii extract (n = 15) or a placebo twice daily for 12 weeks. All participants were advised to follow a hypocaloric diet throughout the study. Body weight, body mass index (BMI), waist and hip circumference, and waist to hip ratio, were monitored fortnightly. Dietary intake was assessed at the baseline and weeks 4, 8 and 12. Appetite was assessed using visual analogue scales and blood samples were analyzed for plasma lipids, ghrelin, leptin, glucose and insulin at the baseline and end of the intervention. Significant reductions to waist and hip circumference (p = 0.02; p = 0.01, respectively) were recorded in both experimental and placebo groups after the 12 week intervention. Furthermore, high density lipoprotein-cholesterol (HDL-C) was significantly increased (p = 0.01) in both groups. The experimental group showed a favorable improvement in insulin concentration and insulin resistance (p = 0.001; 0.01 respectively) compared to the placebo group. These findings suggest that C. forskohlii extract in conjunction with a hypocaloric diet may be useful in the management of metabolic risk factors.
... CFE has been used for centuries in Ayurvedic medicine to treat various diseases of the cardiovascular, respiratory and central nervous systems. 18) CFE contains a diterpene compound, forskolin, which has been shown to activate adenylate cyclase 19) to enhance lipolysis and fat loss in cell culture 20) and human studies. 21,22) Based on the action of forskolin, CFE is generally standardized at 10% forskolin for use in dietary supplements. ...
... CFE contains forskolin, an active compound shown to activate adenylate cyclase 19) to enhance lipolysis and fat loss in cell culture. 20) The enhanced lipolysis by forskolin is thought to be the underlying mechanism of the weight-loss effect of CFE. However, there are inconsistencies in the weight-loss effect observed in human studies. ...
Article
We examined CYP induction and recovery at various doses of Coleus forskohlii extract (CFE) to assess potential drug interactions by a mechanism involving intestinal CYP. Mice were administered diets with various doses of CFE up to 0.5% (equivalent to 700–800 mg/kg body weight) for 2 weeks, then CFE was withdrawn for 3 d. Changes in CYP activities and mRNA expression in the small intestine and liver were then evaluated. CFE induced CYP in the small intestine at a higher dose compared to the liver; CYP3A was induced at 0.5% and 0.005% CFE in the small intestine and liver, respectively. There was no sex difference in CFE dose for CYP induction. CYP induction quickly reverted after withdrawal of CFE, especially for CYP3A, in the small intestine; whereas, a gradual recovery was observed in the liver. In conclusion, CFE induced CYP in the small intestine and liver; however, a higher dose of CFE was needed for the small intestine. Moreover, the induction was soon recovered, suggesting actual interactions of CFE with prescription drugs are unlikely to occur through CYP in the small intestine. Graphical Abstract Fullsize Image
... CFE has been used for centuries in Ayurvedic medicine to treat various diseases of the cardiovascular, respiratory, and central nervous systems 8 . CFE contains a diterpene compound, forskolin, which has been shown to activate adenylate cyclase 9 to enhance lipolysis and fat loss in cell culture 10 and human studies 11 . CFE generally contains 10 forskolin in dietary supplements; however, besides forskolin, there is no standardization of compounds in CFE as a dietary supplement. ...
... CFE is a popular herbal ingredient in weight-loss supplements, and the weight-loss effect is attributed to the action of forskolin, which activates adenylate cyclase 9 and enhances lipolysis and fat loss 10 . We previously reported that CFE induced hepatic CYP and fatty liver in mice, while pure forskolin did not 12,13 . ...
Article
Coleus forskohlii extract (CFE), a popular weight-loss herbal product, induces hepatic cytochrome P450 (CYP) and fatty liver in mice; however, its main bioactive ingredient, forskolin, does not show such effects. To ensure the safety of CFE as a dietary supplement, identification of the compounds implicated in the induction of hepatic CYP and fatty liver is required. In this study, we separated a crude CFE extract into 5 fractions (Fr.) by column chromatography and administered the fractions to mice for one week to assess their ability to induce CYP and fatty liver. CYP induction was detected for all fractions, indicating that many compounds may be involved in CYP induction, while fatty liver was only detected for Fr. 2. Further isolation and purification of Fr. 2 by column chromatography identified 14-deoxycoleon U as a major compound and crocetin dialdehyde as a pigment compound. An in vivo mouse study revealed that crocetin dialdehyde had no effect on the liver and, as 14-deoxycoleon U was the major compound in Fr. 2, it is likely that the active compound inducing fatty liver in CFE is 14-deoxycoleon U. These findings will facilitate the preparation of standardized safe CFE ingredients for dietary supplements. graphical abstract Fullsize Image
... Currently, CFE has received attention as a popular herbal ingredient for weight-loss products, because CFE contains a diterpene compound, forskolin. This compound has been shown to activate adenylate cyclase [6,7] to enhance lipolysis and fat loss in studies performed in cell culture [8,9], rat [10], and human [11,12]. In our previous studies, we observed that CFE induced hepatic cytochrome P450 (CYP) while also inducing fatty liver in mice, although these induction events were not seen with forskolin alone [13,14]. ...
... An overflow of fatty acid derived from lipolysis has been proposed to be the main cause of the excess accumulation of triglyceride observed in hepatic steatosis [23]. The forskolin in CFE is thought to enhance lipolysis due to activation of adenylate cyclase [8,9]. Therefore, enhanced lipolysis by forskolin is implicated as a source of increased fatty acid, leading to enhanced triglyceride synthesis in the liver. ...
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Coleus forskohlii extract (CFE), an herbal ingredient, is used for weight-loss products. CFE's alleged efficacy is attributed to forskolin. However, CFE has been shown to induce fatty liver in mice, with components other than forskolin playing a part in this effect. The present study addressed the underlying mechanism of CFE-induced fatty liver by analyzing changes in CFE-treated mice of lipid concentrations and of the levels of mRNAs encoding enzymes and transcription factors known to be related to fatty liver. Mice were fed a diet containing 0, 0.3 and 1% CFE for 2 weeks. CFE at 1% clearly induced fatty liver, as demonstrated by histological examination and confirmed by increases in triglyceride concentrations in liver. However, treated mice did not exhibit elevation in plasma levels of non-esterified fatty acids. Comprehensive analysis of liver mRNA levels revealed accumulation of multiple transcripts, including mRNAs encoding enzymes acetyl-CoA carboxylase and long-chain elongase; transcription factor peroxisome proliferator-activated receptor gamma (PPARγ); and lipid-droplet-associated fat-specific protein 27 (Fsp27). These findings suggest that the de novo synthesis and accumulation of triglyceride in the liver, through the enhanced expression of specific lipogenic mRNAs, is a major underlying mechanism of fatty liver induction by CFE.
... Elevations of cyclic AMP concentrations stimulate lipolysis in adipocytes, and thus this process is intimately connected with changes in adenylate cyclase activity [10,11]. However, in a number of model systems of obesity, alterations in adipocyte catecholamine-stimulated lipolysis have been noted [12][13][14][15][16]. ...
... In the Zucker rat, obesity occurs as a result of a single gene defect, although the nature of this remains to be determined [29,30]. Nevertheless, this defect leads to a marked decrease in hormone-stimulated lipolysis in the obese rats [14], a process controlled by the cyclic AMP-dependent activation and phosphorylation of hormone-sensitive triacylglycerol lipase [10]. ...
Article
Attenuated maximal activations by forskolin, Mn+. NaF or guanosine 5'-[gamma-thio]triphosphate (GTP[S]) were noted for adenylate cyclase activity in adipocytes from obese (fa/fa) Zucker rats compared with their lean (Fa/Fa) littermates. GTP[S] achieved half-maximal activation of adenylate cyclase at some 10-fold lower concentrations in membranes from lean animals compared with those from obese. Levels of the 42 and 45 kDa forms of Gs were some 40-50% lower in membranes from obese animals, and levels of Gi-1 and Gi-3 were some 62-65% lower. No differences in levels of Gi-2 alpha-subunits or G-protein beta-subunits were observed. Gi function, as assessed by inhibiting forskolin-stimulated adenylate cyclase, achieved by prostaglandin E1, nicotinate and phenylisopropyladenosine, was similar in membranes from both lean and obese animals. Levels of beta-adrenoceptors were some 50% lower in membranes from obese animals. It is suggested that the attenuated activation of adenylate cyclase by stimulatory ligands in membranes from obese animals may be caused by decreases in both Gs and receptors, and that this may contribute to the attenuated lipolytic response seen in adipocytes from such animals.
... Significant and variable amounts of endogenous adenosine can be released from cultured adipocytes, confounding lipolysis assays (19). ADA circumvents this problem by eliminating endogenous adenosine, thereby decreasing inter-assay variability (20) but also enhancing lipolysis (21,22). As expected, ADA increased basal and stimulated rates of lipolysis in both wild type and mutant WAT (Fig. 2C). ...
... The following observations from previous studies suggest the existence of a compartmentalized apparatus mediating lipolytic stimulation. (i) At any given intracellular cAMP concentration, the lipolytic response from catecholamines is greater than that from forskolin, a nonspecific adenylate cyclase activator (21,22,37). Hence, low concentrations of isoproterenol (ϳ10 nM) can stimulate lipolysis without measurably altering overall cAMP levels, whereas low concentrations of forskolin (0.1-1.0 M) increase intracellular cAMP levels without affecting lipolysis (37). ...
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Targeted disruption of the RIIbeta subunit of protein kinase A (PKA) produces lean mice that resist diet-induced obesity. In this report we examine the effects of the RIIbeta knockout on white adipose tissue physiology. Loss of RIIbeta is compensated by an increase in the RIalpha isoform, generating an isoform switch from a type II to a type I PKA. Type I holoenzyme binds cAMP more avidly and is more easily activated than the type II enzyme. These alterations are associated with increases in both basal kinase activity and the basal rate of lipolysis, possibly contributing to the lean phenotype. However, the ability of both beta(3)-selective and nonspecific beta-adrenergic agonists to stimulate lipolysis is markedly compromised in mutant white adipose tissue. This defect was found in vitro and in vivo and does not result from reduced expression of beta-adrenergic receptor or hormone-sensitive lipase genes. In contrast, beta-adrenergic stimulated gene transcription remains intact, and the expression of key genes involved in lipid metabolism is normal under both fasted and fed conditions. We suggest that the R subunit isoform switch disrupts the subcellular localization of PKA that is required for efficient transduction of signals that modulate lipolysis but not for those that mediate gene expression.
... Pro-lipolytic effect of Forskolin was reportedly mediated by cAMP accumulation (Allen et al., 1986;Litosch et al., 1982). ...
Article
Ethnopharmacological relevance Phyto-preparations and phyto-compounds, by their natural origin, easy availability, cost-effectiveness, and fruitful traditional uses based on accumulated experiences, have been extensively explored to mitigate the global burden of obesity. Aim of this review The review aimed to analyse and critically summarize the prospect of future anti-obesity drug leads from the extant array of phytochemicals for mitigation of obesity, using adipose related targets (adipocyte formation, lipid metabolism, and thermogenesis) and non-adipose targets (hepatic lipid metabolism, appetite, satiety, and pancreatic lipase activity). Phytochemicals as inhibitors of adipocyte differentiation, modulators of lipid metabolism, and thermogenic activators of adipocytes are specifically discussed with their non-adipose anti-obesogenic targets. Materials and methods PubMed, Google Scholar, Scopus, and SciFinder were accessed to collect data on traditional medicinal plants, compounds derived from plants, their reported anti-obesity mechanisms, and therapeutic targets. The taxonomically accepted name of each plant in this review has been vetted from “The Plant List” (www.theplantlist.org) or MPNS (http://mpns.kew.org). Results Available knowledge of a large number of phytochemicals, across a range of adipose and non-adipose targets, has been critically analysed and delineated by graphical and tabular depictions, towards mitigation of obesity. Neuro-endocrinal modulation in non-adipose targets brought into sharp dual focus, both non-adipose and adipose targets as the future of anti-obesity research. Numerous phytochemicals (Berberine, Xanthohumol, Ursolic acid, Guggulsterone, Tannic acid, etc.) have been found to be effectively reducing weight through lowered adipocyte formation, increased lipolysis, decreased lipogenesis, and enhanced thermogenesis. They have been affirmed as potential anti-obesity drugs of future because of their effectiveness yet having no threat to adipose or systemic insulin sensitivity. Conclusion Due to high molecular diversity and a greater ratio of benefit to risk, plant derived compounds hold high therapeutic potential to tackle obesity and associated risks. This review has been able to generate fresh perspectives on the anti-diabetic/anti-hyperglycemic/anti-obesity effect of phytochemicals. It has also brought into the focus that many phytochemicals demonstrating in vitro anti-obesogenic effects are yet to undergo in vivo investigation which could lead to potential phyto-molecules for dedicated anti-obesity action.
... 13,14 It increases intracellular levels of cAMP in essentially all kinds of cells, including ECs, SMCs and leucocytes. Forskolin is known for its lipolysis function 15,16 and is available as a health product. The role of FSK in vascular remodelling remains to be defined. ...
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Neointimal formation and atherogenesis are major vascular complications following percutaneous coronary intervention, and there is lack of pharmacological therapy. This study was aimed to examine the effect of forskolin (FSK), a cyclic adenosine monophosphate (cAMP)‐elevating agent, on vascular response to angioplasty wire injury and on atherogenesis in mice. Forskolin treatment reduced neointima formation at 7 and 28 days after wire injury. Early morphometrics of the injured vessels revealed that FSK treatment enhanced endothelial repair and reduced inflammatory cell infiltration. In vitro treatment of primary aortic cells with FSK, at 3‐100 μmol/L, increased endothelial cell proliferation, whereas FSK, at 30‐100 μmol/L, inhibited smooth muscle cell proliferation. FSK inhibited lipopolysaccharide‐induced leucocyte‐endothelial interaction in vitro and in vivo. In a mouse model of atherosclerosis driven by dyslipidaemia and hypertension, FSK administration increased endothelial repair and reduced atherosclerotic plaque formation, without affecting blood pressure, plasma lipids or aortic aneurysms formation. In summary, FSK, at doses relevant to human therapeutic use, protects against neointimal hyperplasia and atherogenesis, and this is attributable to its activities on pro‐endothelial repair and anti‐inflammation. This study raises a potential of clinical use of FSK as an adjunct therapy to prevent restenosis and atherosclerosis after percutaneous coronary intervention.
... Increased cAMP synthesis by CFE may be associated with enhancement of cAMP-dependent lipolysis in the adipose tissue. It has been reported that forskolin induces cAMP accumulation and lipolysis in fat cells isolated from rat adipose tissue (20,21). In addition, CFE suppressed body weight gain and lipid accumulation by ovariectomy in rats (22). ...
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Obesity is one of the main causes of non-alcoholic steatohepatitis (NASH), which is associated with impaired liver functions including drug metabolism. Coleus forskohlii extract (CFE) is a popular ingredient of weight loss dietary supplements in Japan. In this study, we examined the effect of CFE on the treatment of NASH. C57BL/6 mice (male, 10-wk-old) were fed a NASH diet (high-fat, low-methionine, and choline-deficient diet) for 12 wk to establish NASH. Then, we examined the effect of 0.5% (w/w) CFE in diet during diet-treatment (change to control diet) and/or treadmill-exercise (45 min at 20 m/min, 5 d/wk) to improve NASH for 3 wk. After experimental period, lipids profiles and liver functional markers in the blood, and hepatic lipid content and major CYP subtype mRNA expression and activity in liver were measured. Diet-treatment, but not exercise decreased liver weight and hepatic lipid contents in NASH induced mice. CFE attenuated the effects of diet-treatment which reduced liver weight, even though body weight and adipose tissue weight were reduced. Further, CFE significantly increased liver microsomal CYP1A1, CYP1A2, CYP2C, and CYP3A activities in each condition, and CYP inductions were greater in diet-treatment group compared to those in exercise group. These results suggest that taking CFE should be avoided during diet-treatment of NASH, especially in patients under medication.
... FSK has also been shown to counteract the decreased response of fat cells to epinephrine, associated with aging. FSK also accelerates lipolysis through the activation of hormonesensitive lipase [54]. It is primarily via the increased synthesis of cyclic AMP that C. Forskohlii may exert its medicinal influences on a significant number of common health conditions. ...
... There is a possibility that disease state or the drugs used may have independently caused diarrhea. The functional component of CFE, forskolin, has been shown to activate adenylate cyclase and increase the production of cAMP [22], to enhance lipolysis in fat cells [23,24] and in human studies [14,25,26]. However, it is suggested that the increased levels of cAMP in the intestine, caused by CFE, could lead to the secretion of water, which would manifest as diarrhea [14], and a similar mechanism of action has been observed for the cholera toxin [27]. ...
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The formulations of the functional ingredients of dietary supplements was studied with a small number of subjects, with a particular focus on their effectiveness, but not enough to evaluate their safety. In this regard, the reevaluation and estimation of the safe use of marketed products, with regards to their adverse event (AE) frequencies, are important. To address this issue, a post-marketing nationwide online survey was conducted for the herbal ingredient Coleus forskohlii extract (CFE), a popular weight-loss ingredient. The questionnaire included product names, adherence to the claimed amount, and AE experiences. The safe intake amount was estimated by the relationship between the claimed amount of CFE and the frequencies of AEs of each product. The number of users who experienced AEs was 75 (10.5% of all users). Gastrointestinal symptoms accounted for 92.0% (n = 69) of all AEs, and diarrhea alone accounted for 81.3% (n = 61). The amount of CFE was significantly associated with the occurrence of diarrhea (p = 0.005). The fitted curve showed that the safe intake amount of CFE was less than 250 mg/day; however, considering its effectiveness, 500 mg/day of CFE might be acceptable. In conclusion, nationwide online surveys of users enable us to confirm and reevaluate the safety of herbal supplements.
... Estimation of Ca, Na and K was carried out by flame photometer. Molybdenum blue and indo-phenol blue methods were applied for the determination of P and N, respectively, using a spectrophotometer (Bear, 1975;Allen et al., 1986). ...
Article
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THE FAMILY Lamiaceae (Labiatae) contains several genera, such as sage (Salvia), mint (Mentha) and basil (Ocimum) with a rich diversity of ethno botanical uses. It has an important role as a source of medicinal and aromatic compounds of commercial importance. Medicinal plants represent an important health and economic component of biodiversity. It is essential to make the complete inventory of the medicinal component of the flora of any country for conservation and sustainable use. The conservation of the threatened and endangered medicinal species in the wild is indispensable. Therefore, protein, isozymes, RAPD and ISSR markers were employed for molecular characterization, variability evaluation and genetic relationships of 12 Lamiaceae species collected from various areas Taif region, Saudi Arabia. All biochemical and molecular markers revealed high polymorphism percentages among the studied genotypes. The UPGMA clusters result indicated that all genotypes could be distinguished by these markers. The polymorphism information obtained through biochemical and molecular analyses may also help for further studies of other Lamiaceae genotypes in Saudi Arabia.
... Traditionally, the roots have been used as condiments in pickles, for preparation of pickles. Forskolin has positive effect against a wide range of conditions such as asthma, glaucoma, hypertension, hair loss, cancer, and obesity [310][311][312][313][314]. C. forskohlii extract (standardized to contain 95% forskolin) is potentially useful in skin care formulations, particularly as a conditioning age. ...
Article
Autism is a prototypical form of pervasive developmental disorder (PDD), characterized by complex behavioural impairments detectable as early as 18-36 months of age with severe abnormalities in communications, social awareness and skills, and the presence of restrictive and stereotyped patterns of behaviors, interests, and activities. In addition to these core symptoms, there are few other behavior disturbances which are commonly seen in the autistic individuals, such as anxiety, depression, sleeping and eating disturbances, attention issues, temper tantrums, motor disabilities and aggression or self-injury. Propionic acid (PPA) on oral and intraventricular injection of PPA in rodents mimics the behavioural and biochemical abnormalities observed in autism patients. Increased PPA levels may interfere with overall cellular metabolism in tricarboxylic acid cycle where it interferes with the conversion of succinyl co-A to succinate for generation of FADH2 in electron transport chain complex II further impairs the ATP synthesis. Extracellular signals regulate various intracellular neuroprotective functions through secondary messenger’s cyclic AMP (cAMP) that subsequently activate target enzymes Protein kinase A (PKA) & activate cyclic AMP responsive element binding protein (CREB) which regulate and protects various toxic damage in brain. Forskolin (FSK) (also called Coleonol) Coleus forskohlii Briq. (Lamiaceae), major pharmacological mechanism of action is linked to its direct action on adenyl cyclase (AC) enzyme which results in the increase intracellular cAMP/PKA/CREB pathway further responsible for various neuroprotective mechanisms. It is first time designed to investigate the protective and therapeutic potency of FSK in AC/cAMP/PKA mediated CREB activation in intraventricular PPA induced autism in rats
... Benth.), a member of the family Lamiaceae, is an ancient root drug in Ayurvedic materia medica10. Forskolin showed positive effects against a wide range of conditions such as asthma[11], glaucoma[12] , hypertension [13,14], cancer [15] , heart diseases [16], diabetes [17] and obesity [18]. It also showed increase in the rate of sensory nerve regeneration in freezelesioned sciatic nerves [19], stimulation of water and cation permeability in aquaporin 1 water channels [20] and direct alteration of gating of a single class of voltage-dependent potassium channels from a clonal pheochromocytoma (PC12) cell line independent of adenylate cyclase activation [21]. ...
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Coleus forskohlii is an important ancient root drug of Indian origin, commonly known as gander in indian ayurvedic system of medicine. A lot of research work has been done on Coleus forskohlii regarding various cardiovascular disorders but no work has been done to find out its cardioprotective activity. Wistar albino rats were divided into five main groups having 5 animal each: Group 1 termed as Normal control (NC) received 0.5ml of normal saline throughout experimental period and served as control. Group 2 termed as Isoprenaline group (ISO) received 0.5ml of normal saline for 28 day and received Isoprenaline (85mg/kg, s.c.) on 29th and 30th day at an interval of 24 hours. Group 3 termed as Standard group (STD) received Metoprolol (pure) (10 mg/kg/day, p.o.) for 28 day and received Isoprenaline (85mg/kg, s.c.) on 29th and 30th day at an interval of 24 hours. Group 4 termed as Test group 1 (TG 1) & Group 5 termed as Test group 2 (TG 2) received Coleus forskohlii (50 mg/kg/day, p.o.) (100 mg/kg/day, p.o.) for 28 day and received Isoprenaline (85mg/kg, s.c.) on 29th and 30th day at an interval of 24 hours respectively. The experiment was terminated on 31st day and animal were sacrificed by cervical decapitation after an overnight fast. Blood was collected for estimation of biochemical parameter and heart was dissected out for grading, heart/weight ratio and histopathological examination.the the level of marker enzyme in serum as AST, ALT, LDH, CK, Troponin-I were significantly decreased (P<0.001) in rats pretreated with Coleus forskohlii when compared to that of group which received isoprenaline alone. Further, histopathological examination showed the reduction of necrosis, edema and inflammation following Coleus forskohlii pretreatment. Based on present findings, it is concluded that Coleus forskohliil may be a potential preventive and therapeutic agent against the myocardial necrosis associated ischemic heart disease.
... Therefore, Coleus forskohlii extract (CFE) standardized to 10 (w/w) forskolin is generally used as an ingredient in dietary supplements. Currently, CFE is used worldwide as a weight loss dietary supplement, because forskolin has been shown to increase both c-AMP accumulation and lipolysis in fat cells 6), 7) , and CFE reduces fat accumulation in ovariectomized rats 8) and decreases body fat in overweight women and obese men 9), 10) . ...
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This in vivo study in rats evaluated whether Coleus forskohlii extract (CFE) taken orally interacted with tolbutamide, a hypoglycemic drug metabolized by CYP2C enzymes. Rats were fed 0%, 0.3%, 1% (w/w) CFE diet for 2 weeks, followed by 0% CFE diet for 1 day. They were then given 40 mg/kg tolbutamide by intragastric gavage. Blood glucose level was determined up to 6 h after tolbutamide administration. CFE treatment increased total CYP content and various CYP subtypes in the liver. In particular, increases in activity and protein expression were noted for the CYP2B, CYP2C, and CYP3A subtypes. CFE treatment dose-dependently attenuated both the hypoglycemic action of tolbutamide at 6 h and the plasma concentration of tolbutamide. The activity of (S)-warfarin 7-hydroxylase, a CYP2C enzyme was negatively correlated with plasma tolbutamide level, which also showed a negative correlation with the reduction of blood glucose level. These results indicate that CFE induced hepatic CYPs in rats and attenuated the hypoglycemic action of tolbutamide via a hepatic CYP2C-mediated mechanism.
... Theoretically, an increase in cAMP induced by forskolin will enhance lipolysis leading to elevated fat degradation and physiological fat utilization, and thus promote fat and weight loss. It has been shown that forskolin increases both cAMP accumulation and lipolysis in fat cells (6,7), and CFE standardized with forskolin reduces fat accumulation in ovariectomised rats (8) and induces favorable effects on body fat in overweight women and obese men (9,10). ...
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From studies in mice, we have reported that Coleus forskohlii extract (CFE), a popular herbal weight-loss ingredient, markedly induced hepatic drug metabolizing enzymes, especially cytochrome P450 (CYP), and interacted with co-administered drugs. This study was designed to examine how the induction of drug metabolizing enzymes by CFE was influenced by different levels of macronutrients in the diet. Mice were fed a non-purified diet or semi-purified diet with and without CFE (0.3-0.5%) for 14-18 d, and changes in the ratio of liver weight to body weight, an indicator of hepatic CYP induction, and hepatic drug metabolizing enzymes were analyzed. The ratio of liver weight to body weight, content and activities of CYPs, and activity of glutathione S-transferase were higher in a semi-purified standard diet (AIN93G formula) group than in high sucrose (62.9%) and high fat (29.9%) diet groups. Different levels of protein (7%, 20%, and 33%) in the diets did not influence CFE-induced CYP induction or increase the ratio of liver weight to body weight. The effect of CFE on the ratio of liver weight to body weight was higher with a semi-purified diet than with a non-purified diet, and was similar between dietary administration and intragastric gavage when the CFE dose and the diet were the same. There was a positive correlation between CFE-induced CYP induction and the content of starch in the diets, suggesting that dietary starch potentiates CFE-induced CYP induction in mice. The mechanism of enhanced CYP induction remains unclear.
... 8,9 A separate study found that anthocyanosides contained in the leaf and stem bark of Vaccinium myrtillus exert a direct effect on the retina, including the alteration of local enzymatic reactions and enhancement of the recovery of rhodopsin. 10 Allen et al. 11 showed the effect of 1% topical application of forskolin, an extract of Coleus forskohli, on ocular pressure. He suggested that a cAMP elevating effect of the forskolin might be responsible for its action in lowering intra-ocular pressure. ...
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Aqueous crude cold-water extract from the fruiting body of the culinary-medicinal oyster mushroom Pleurotus ostreatus was assessed for activity against increased intra-ocular pressure (IOP) in mice. A 0.1% dexamethasone instillation was used to raise the intra-ocular pressure in the animals above the 21-mmHg threshold limit. The extract has intrinsic anti-hypertensive properties that are dose dependent. A comparison analysis indicated that 150 mg/mL of the crude extract produced 57.69% reduction in the intra-ocular pressure, while doses of 100 mg/ mL and 200 mg/mL produced 44.78% and 70.03% IOP reduction, respectively, compared with timolol maleate with 57.69%. The results were significant at 0.05 confidence limit (p < 0.05) when compared to a placebo and therefore support its use for the treatment of increased intra-ocular pressure.
... In vitro and animal studies demonstrate li- polysis in fat cells is stimulated by forskolin 17,29,30 via activation of adenylate cyclase and increased levels of cAMP. In a study involving 34 women, researchers discovered adipocytes from morbidly obese women have decreased adenylate cyclase activity, compared to adipocytes from normal weight women. ...
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Forskolin is the first pharmaceutical drug and product derived from a plant to be approved in India by the DCGI in 2006. Forskolin (7beta-acetoxy-8, 13-epoxy-1a, 6β, 9a-trihydroxy-labd-14-en-11-one) is a diterpenoid isolated from plant Coleus forskohlii (Lamiaceae). It is a lipid-soluble compound that can penetrate cell membranes and stimulates the enzyme adenylate cyclase which, in turn, stimulates ciliary epithelium to activate cyclic adenosine monophosphate, which decreases intraocular pressure (IOP) by reducing aqueous humor inflow. The topical application of forskolin is capable of reducing IOP in rabbits, monkeys, and humans. In its drug interactions, forskolin may act synergistically with epinephrine, ephedrine and pseudoephedrine. Whereas the effects of anti-clotting medications like warfarin, clopidogre, aspirin, anoxaparin, etc., may be enhanced by forskolin. Forskolin is contraindicated in the medications for people with ulcers as forskolin may increase acid level. Forskolin has a very good shelf-life of five years. Recently, its Ophthalmic inserts and in situ gels for sustained and delayed-release drug delivery systems were tested in New Zealand Albino Rabbits for its antiglaucoma efficacy. This drug review explains Forskolin as a drug, its antiglaucoma potential and recent findings of forskolin as an antiglaucoma agent. The literature search method used for this review was different databases and search engines like PubMed, International Pharmaceutical Abstracts, Google, Medicinal and Aromatic Plants (MAPA).
... [21][22][23] Thus, it is likely that AKAPs participate in the lipolytic reaction in adipocytes. Interestingly, it has been reported that lower concentrations of cAMP are required for activation of lipolysis by ␤-ADR agonists than by forskolin [24][25][26] and that the relationship between cAMP concentration and lipolysis differs depending on which subtype of ␤-ADR is stimulated. 27 It has been argued that these differences between cAMP concentration and lipolysis may be indicative of a "compartmentalization" of cAMP within cells. ...
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The lipolytic reaction in adipocytes is one of the most important reactions in the management of bodily energy reserves, and dysregulation of this reaction may contribute to the symptoms of Type 2 diabetes mellitus. Yet, progress on resolving the molecular details of this reaction has been relatively slow. However, recent developments at the molecular level begin to paint a clearer picture of lipolysis and point to a number of unanswered questions. While HSL has long been known to be the rate-limiting enzyme of lipolysis, the mechanism by which HSL attacks the droplet lipids is not yet firmly established. Certainly, the immunocytochemical evidence showing the movement of HSL to the lipid droplet upon stimulation leaves little doubt that this translocation is a key aspect of the lipolytic reaction, but whether or not HSL phosphorylation contributes to the translocation, and at which site(s), is as yet unresolved. It will be important to establish whether there is an activation step in addition to the translocation reaction. The participation of perilipin A is indicated by the findings that this protein can protect neutral lipids within droplets from hydrolysis, but active participation in the lipolytic reaction is yet to be proved. Again, it will be important to determine whether mutations of serine residues of PKA phosphorylation sites of perilipins prevent lipolysis, and whether such modifications abolish the physical changes in the droplet surfaces that accompany lipolysis.
... Forskolin has a unique property of activating almost all hormone sensitive adenylate cyclase enzymes in a biological system (De Souza and Shah, 1888). Forskolin is reported to be useful in the treatment of asthma (Lichey et al., 1984), glaucoma (Caprioli, 1984), hypertension (Dubey et al., 1981; De Souza et al., 2006), cancer (Agarwal and Parks, 1983; Bhat et al., 1993; Li and Wang, 2006), heart diseases (Kramer et al., 1987), diabetes (Ammon and Muller, 1984; Gold et al., 1988), and obesity (Allen, 1986). It also showed inhibition of platelet activating factor (Nourshargh and Hoult, 1986), increase in the rate of sensory nerve regeneration in freeze-lesioned sciatic nerves (Kilmer and Carlsen, 1984), stimulation of water and cation permeability in aquaporin 1 water channels (Yool et al., 1996) and direct alteration of gating of a single class of voltage-dependent potassium channels from a clonal pheochromocytoma (PC12) cell line independent of adenylate cyclase activation (Hoshi et al., 1988). ...
... Forskolin showed positive effects against a wide range of conditions such as asthma (Lichey et al.,1984), glaucoma (Caprioli and Sears, 1983), hypertension (Dubey et al., 1981;De Souza et al., 2006), cancer (Agarwal and Parks, 1983;Li and Wang, 2006), heart diseases (Kramer et al., 1987), diabetes (Ammon et al.,1984;Gold et al., 1988) and obesity (Allen et al., 1986). It also showed inhibition of platelet activating factor (Nourshargh and Hoult, 1986;Dde-Chaffoy De et al., 1987), increase in the rate of sensory nerve regeneration in freeze-lesioned sciatic nerves (Kilmer and Carlsen, 1984), stimulation of water and cation permeability in aquaporin 1 water channels (Yool et al.,1996) and direct alteration of gating of a single class of voltage-dependent potassium channels from a clonal pheochromocytoma (PC12) cell line independent of adenylate cyclase activation (Hoshi et al., 1988). ...
... ). Terpenoids were found to be present in C. forskohlii (Table 1), forskolin, a labdane diterpene (7-Acetoxy-8,13-epoxy-1, 6, 9- trihydroxy-labd-14-ene-11-one) isolated from C. forskohlii (Bhat et al., 1977; Saleem et al., 2005), was observed to activate adenyl cyclases resulting in an increase in cAMP (Seamon and Daly, 1981; Rupp et al., 1986).The mechanisms of interaction of forskolin were studied in detail (Zhang et al., 1997; Tesmer et al., 1997; Tang and Gilman, 1995). Forskolin showed positive effects against a wide range of conditions such as asthma (Lichey et al., 1984), glaucoma (Caprioli and Sears, 1983), hypertension (Dubey et al., 1981), cancer (Agarwal and Parks, 1983), heart diseases (Kramer et al., 1987), diabetes (Ammon and Müller, 1984) and obesity (Allen et al., 1986). It also showed inhibition of platelet activating factor (Nourshargh and Hoult, 1986), increase in the rate of sensory nerve regeneration in freeze-lesioned sciatic nerves (Kilmer and Carlsen, 1984), stimulation of water and cation permeability in Aquaporin 1 water channels (Yool et al., 1996) and direct alteration of getting a single class of voltage-dependent potassium channels from a clonal pheochromocytoma (PC12) cell line independent of adenylate cyclase activation (Hoshi et al., 1988). ...
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Tannins, phlobatannins, saponins, flavonoids, terpenoids, cardiac glycosides and alkaloids distribution in Coleus forskohlii belonging to the family Lamiaceae a well known medicinal plant in India was examined. Qualitative analysis carried out on this plant shows that terpenoids, tannins, flavonoids, phlobatannins, saponins and cardiac glycosides were present in C. forskohlii. The phytochemical constituents with respect to the role of this plant in traditional medicine treatment have well been established. Forskolin, a diterpene compound is the active principle of the C. forskohlii. Histochemical test was done to locate the forskolin in roots and tubers of C. forskohlii. Forskolin was found in the cells of cork, cortex, medullary rays and xylem in roots and tubers of C. forskohlii. These yellowish and reddish-brown masses are of diagnostic importance for this drug plant and can be used for its characterization.
... The mechanisms of interaction of forskolin were studied in detail (Zhang et al., 1997; Tesmer et al., 1997; Tang and Gilman, 1995). Forskolin showed positive effects against a wide range of conditions such as asthma (Lichey et al., 1984), glaucoma (Caprioli and Sears, 1983), hypertension (Dubey et al., 1981), cancer (Agarwal and Parks, 1983), heart diseases (Kramer et al., 1987), diabetes (Ammon and Müller, 1984) and obesity (Allen et al., 1986). It also showed inhibition of platelet activating factor (Nourshargh and Hoult, 1986) and increase in the rate of sensory nerve regeneration in freeze-lesioned sciatic nerves (Kilmer and Carlsen, 1984). ...
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Antioxidant status of different parts of Coleus forskohlii including roots, stem, leaves and tubers was analyzed. For the enzymatic antioxidant properties, the activities of superoxide dismutase, peroxidase, polyphenol oxidase and catalase were significantly higher (P < 0.05) in tubers than in the leaves, roots and stem. Among the non-enzymatic antioxidants, except for the chlorophyll and lycopene content, the reducing power and chelating abilities on Fe2+, 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical-scavenging activity, total phenol, flavonoids and �-carotene were significantly higher (P < 0.05) in tubers than in the leaves, roots and stem, respectively. The tubers possessed significantly rich sources of both enzymatic and non-enzymatic antioxidants besides their medicinal properties.
... Theoretically, an increase in cAMP by forskolin will enhance lipolysis leading to elevation of fat degradation and fat usage in the body and therefore promote fat and weight loss. In fact, Allen et al. (1986)and Okuda et al. (1992) reported forskolin-induced increases in both cAMP accumulation and lipolysis in fat cells. Han et al. (2005) showed that CFE reduced fat accumulation in ovariectomized rats. ...
Article
Coleus forskohlii root extract (CFE) is popular for use as a weight loss dietary supplement. In this study, the influence of standardized CFE containing 10% active component forskolin on the hepatic drug metabolizing system was investigated to evaluate the safety through its drug interaction potential. Male ICR mice were fed AIN93G-based diets containing 0-5% CFE or 0.05% pure forskolin for 2-3 weeks. Intake of two different sources of 0.5% CFE significantly increased the relative liver weight, total content of hepatic cytochrome P450 (CYP) and induced CYPs (especially 2B, 2C, 3A types) and glutathione S-transferase (GST) activities. CFE significantly increased mRNA expression of CYPs and GST with dose related responses. However, unlike the CFE, intake of 0.05% pure forskolin was found to be associated with only weak induction in CYP3A and GST activities with no significant increases in relative liver weight, total hepatic content or other CYPs activities. The inductions of CYPs and GST by CFE were observed at 1 week of feeding and rapidly recovered by discontinuation of CFE. These results indicated the induction potential of CFE on CYPs, and that this effect was predominantly due to other, as yet unidentified constituents, and not forskolin contained in CFE.
... This characteristic of forskolin led to its extensive use as a biochemical tool to increase intracellular cAMP concentration. Forskolin's ability to elevate cAMP has been shown to be of benefit as it stimulates lipolysis by promoting the breakdown of stored fats in animal (Okuda et al. 1992) and human fat cells (Litosch et al. 1982;Allen et al. 1986). Theoretically, levels of cAMP increased by forskolin will enhance lipolysis leading to elevation of fat degradation and fat usage in the body and therefore promote fat and weight loss. ...
Article
A rapid reverse-phase HPLC method with evaporative light scattering detection (ELSD) was developed for the determination of forskolin in weight loss multi-herbals products. The analysis was performed by water-acetonitrile gradient elution at a temperature of 40 degrees C and a flow rate of 1.0 mL/min. The evaporator tube temperature of ELSD was set at 35 degrees C, and with the nebulizing gas flow-rate (pressure) of 3.0 bar. The method was validated for linearity, accuracy, precision and limits of detection (LOD) and quantification (LOQ). Good linear relationships were obtained with correlation coefficients exceeding 0.9995. The average recovery of forskolin ranged from 99.4% to 100.4% with RSDs below 3%. The percent relative standard deviations (%RSD) of intra- and inter-day precision varied by less than 2.1%. LOD and LOQ were 0.95 microg/ml and 3.21 microg/ml, respectively. The validated ELSD method permits a shorter determination time without compromising accuracy and demonstrates that it can be used for quantification of forskolin incorporated in multi-herbal solid oral dosage forms.
... Some other studies also indicated the inconsistencies observed when the intracellular cAMP levels are correlated with lipolysis. They demonstrated that the cAMP concentration required to reach maximum lipolysis was higher for forskolin than for isoproterenol in digitonin-permeabilized adipocytes [141] and in intact adipocytes [142], as well as in isolated rat fat cells [143,144]. A similar observation was made by Schimmel [145] in hamster white adipocytes, who also reported that isoproterenol potentiation of forskolinʼs lipolytic action was not accompanied by increasing the cAMP content and persisted in the absence of extracellular K + , even though the lipolytic response to isoproterenol alone was absent in K + -free media. ...
Article
Plectranthus barbatus andr. is one of the most important species of the genus Plectranthus L' Herit. (Lamiaceae), with a wide variety of traditional medicinal uses in Hindu and Ayurvedic traditional medicine as well as in the folk medicine of Brazil, tropical Africa and China. The plant has therefore been an attractive target for intensive chemical and pharmacological studies up to now. This review presents data about the phytochemistry, ethnobotanical uses and pharmacology of Plectranthus barbatus as well as the pharmacology of its constituents. In addition to essential oil, abietane diterpenoids and 8,13-epoxy-labd-14-en-11-one diterpenoids are the main constituents found in Plectranthus barbatus. The major ethnobotanical uses are for intestinal disturbance and liver fatigue, respiratory disorders, heart diseases and certain nervous system disorders. Forskolin as one of the major constituents with its unique adenylyl cyclase activation that underlies the wide range of pharmacological properties could explain the different traditional uses of Plectranthus barbatus. Forskolin is involved in a number of patented pharmaceutical preparations used as over-the-counter drugs for the treatment of several ailments. However, the water-insoluble nature of forskolin limits its clinical usefulness. Forskolin thus served as a prototype for the development of 6-(3-dimethylaminopropionyl)forskolin hydrochloride (NKH477) as a potent water-soluble forskolin derivative that finds use in the therapy for a number of diseases especially of the cardiovascular system.
... Forskolin (Figure 1), a labdane diterpenoid, is considered the active secondary metabolite because of its ability to activate the enzyme adenylate cyclase (2). Recent research has shown that forskolin has positive effects against a wide range of conditions such as asthma, glaucoma, hypertension, hair loss, cancer, and obesity (3)(4)(5)(6)(7)(8)(9). It also inhibits the platelet-activating factor (PAF; 10). ...
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A rapid method was developed for the evaluation of forskolin in Coleus forskohlii Briq. (Lamiaceae). Forskolin was quantitated in the root and stem of dried C. forskohlii and in 17 market products by reversed-phase liquid chromatography (LC) with a photodiode array detector at 210 nm. The temperature was held constant at 30 degrees C, and the retention time of forskolin was approximately 6.8 min. The samples were extracted with acetonitrile by sonication. The precision of the method was confirmed by a standard deviation < 5.0% (n = 3), and forskolin recovery was 99.1%. Limit of detection was 1.5 microg/mL, and the response was linear through zero from 6.3 to 630 microg/mL with a correlation coefficient (R2) of 0.9998. Identity of the marker compound was confirmed by an LC/mass spectrometry experiment. The method was successful in the qualitative and quantitative evaluation of the marker compound in C. forskohlii plant material and in market products claiming to contain C. forskohlii.
Article
The effect of inoculation with arbuscular mycorrhizal fungi Claroideoglomus claroideum on Coleus forskohlii (Willd.) Briq. plants propagated by seeds or in vitro, and subsequently exposed to drought stress has been studied. Stress tolerance and yield stability are closely related to coping with oxidative stress, which occurs at prolonged water deprivation.The plants inoculated with Claroideoglomus claroideum were grown in well-watered and drought-stressed conditions. The parameters of the inoculation with arbuscular mycorrhizal fungi (root colonization, total and easy-extractable-glomalin-related soil proteins, acid and alkaline phosphatases in roots and soil) and antioxidant activity (enzyme and non-enzyme parameters) were evaluated. In the inoculation of in vitro and in vivo propagated Coleus forskohlii (Willd.) Briq.with arbuscular mycorrizal fungi (AMF), an increase in the growth parameters, the activity of enzymes with antioxidant capacity and the content of total phenols and flavonoids and water- and lipid-soluble metabolites with antioxidant capacity were recorded compared with non inoculated plants. The results showed that arbuscular mycorrhizal fungi Claroideoglomus claroideum activate plants’ antioxidant system, leading to reduced oxidative stress damage. The reduction in oxidative stress markers (hydrogen peroxide, malondialdehyde and proline) content as a result of AMF inoculation was higher in adapted in vitro propagated plants compared to in vivo plants. The same trend is observed in drought stressed plants. When grown in water-deficient conditions, adapted micro-propagated plants showed higher plant growth parameters such as shoot height, root length, plant biomass, antioxidant activity, and lower levels of oxidative stress markers, suggesting that they are more resistant to drought than the individuals which were grown from seeds.
Chapter
Diterpene forskolin is the active constituent derived from the roots of Coleus forskohlii. It is endowed for its versatile pharmacological properties. Forskolin is the only plant-derived compound known to stimulate the enzyme adenylate cyclase and subsequently effecting cyclic AMP (cAMP) synthesis. Because of its broad range of activity in signal transduction reactions, the cAMP is known as the “second messenger.” In the current chapter, some of the pharmacological properties including antiobesity, antidiabetic, antithrombotic, antioxidant, anti-inflammatory activity, asthma, glaucoma, heart disorders, hypertension, and anticancer activity of C. forskohlii and forskolin are discussed in detail.Keywords Coleus forskohlii ForskolinAntiobesityAntidiabeticAntithromboticGlaucomaAsthmaHeart disordersAnticancer
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Andrographis echioides leaves powdered sample was extracted through consecutive hot percolation method by selective sequential soxhlet extraction using ethanol, chloroform, acetone, petroleum ether, and water respectively. The crude extract was subjected to qualitative and quantitative phytochemical analysis and therapeutically active phytoconstituents identified in each extracts. Alkaloids, flavonoids, saponin, tannin, terpenoids, coumarins, glycosides, steroids and phenolic compounds are found in Andrographis echioides leaves extracts. Total flavonoids content is high percentage and alkaloids, terpenoids, tannins and steroids found in less proportion in the study plant. LC-MS analyses indicate the presence of numerous novel pharmacologically important phytochemical compounds, therapeutically active major (peaks) phytocompounds are identified.
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Drug-herb interaction is a major concern for the safety use of herbal products. In our previous mice study, we found that Coleus forskohlii extract (CFE) markedly induced hepatic cytochrome P450 (CYP), especially CYP2B, 2C and 3 A type at the dose added to weight loss supplements. Also, we showed that forskolin, an active constituent in CFE, was not involved in the CYP induction in vivo. The present study was designed to estimate the compounds inducing CYP. CFE was fractionated into 4 (diethyl ether-, ethyl acetate-, acetone-, the remainder), and the effect of those fractions on CYP was examined in two systems: test materials were fed to mice for 2 weeks (in vivo system), and those were directly added to CYP3A enzyme assay (in vitro system). It was found that CYP inducing activity in vivo was mainly distributed in the diethyl ether-fraction, which also showed a direct inhibition of CYP3A activity in vitro. The water soluble fraction showed neither CYP induction in vivo nor CYP3A inhibition in vitro. It was also suggested the existence of several compounds inducing CYP, some of which was eliminated during the fractionation procedure. CFE-induced CYP induction in vivo was well correlated with an increase in liver weight, and was related to direct inhibition of CYP enzyme activity in vitro. Combination of these characteristics would be useful for further study to identify the active constituents in CFE materials that induce CYP.
Article
Obesity is a major health problem. We investigated the effects of forskolin and rolipram in the diet of animals in which obesity had been induced. We used 50 female albino Wistar rats that were assigned randomly into five groups as follows: group 1, control; group 2, high fat diet; group 3, high fat diet + forskolin; group 4, high fat diet + rolipram; and group 5, high fat diet + rolipram + forskolin. The rats were fed for 10 weeks and rolipram and forskolin were administered during last two weeks. The animals were sacrificed and blood samples were obtained. Serum cAMP, cGMP and free fatty acids (FFA) levels were measured using ELISA assays. We also measured weight gain during the 10 week period. cAMP and FFA levels of groups 3, 4 and 5 were significantly higher than those of groups 1 and 2. We found no significant differences in serum cGMP levels among the groups. The weight gain in groups 3, 4 and 5 was significantly less than for group 2. We also found that the weight gain in group 5 was significantly less than in groups 3 and 4. We found that both forskolin and rolipram stimulated lipolysis and inhibited body weight increase by increasing cAMP levels. Also, combination therapy using the two agents may be more effective in preventing diet induced obesity than either agent alone. We found also that these agents did not effect cellular cGMP levels in diet induced obesity.
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Adenosine is an endogenous metabolite that is released from all tissues and cells including liver, pancreas, muscle and fat, particularly under stress, intense exercise, or during cell damage. The role of adenosine in glucose homeostasis has been attributed to its ability to regulate, through its membrane receptors, processes such as insulin secretion, glucose release and clearance, glycogenolysis, and glycogenesis. Additionally, adenosine and its multiple receptors have been connected to lipid metabolism by augmenting insulin-mediated inhibition of lipolysis, and the subsequent increase in free fatty acids and glycerol levels. Furthermore, adenosine was reported to control liver cholesterol synthesis, consequently affecting plasma levels of cholesterol and triglycerides, and the amount of fat tissue. Alterations in the balance of glucose and lipid homeostasis have implications in both cardiovascular disease and diabetes. The ability of different adenosine receptors to activate and inhibit the same signaling cascades has made it challenging to study the influence of adenosine, adenosine analogs and their receptors in health and disease. This review focuses on the role and significance of different adenosine receptors in mediating the effect of adenosine on glucose and lipid homeostasis. J. Cell. Physiol. © 2013 Wiley Periodicals, Inc.
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Objectives: This study aimed to determine whether Coleus forskohlii extract (CFE) influences the anticoagulant action of warfarin in mice in vivo and its relationship with hepatic cytochrome P450 (CYP). Methods: Mice were fed various doses of CFE standardised with 10% forskolin in a normal diet for one week, or in protein diets containing 7% and 20% casein (low and normal) for four weeks. They were then administered with warfarin by gavage on the last two days of the treatment regimen, and blood coagulation parameters, as well as hepatic CYP, were analysed at 18 h after the last dose. Direct interaction between CFE and forskolin with CYP2C was evaluated in vitro. Key findings: CFE dose dependently increased hepatic total CYP content and S-warfarin 7-hydroxylase activity at a dietary level of ≥0.05%. Warfarin-induced anticoagulation was attenuated by CFE in parallel with CYP induction. The findings were similar in mice fed diets containing CFE and different ratios of protein. CFE directly inhibited CYP2C activity in mouse and human liver microsomes in vitro, whereas forskolin was only slightly inhibitory. Conclusions: CFE attenuates the anticoagulant action of warfarin by inducing hepatic CYP2C; thus, caution is required with the combination of warfarin and dietary supplements containing CFE.
Article
Coleus forskohlii root extract (CFE) represented by its bioactive constituent 'forskolin' is popularly used as a natural weight-lowering product, but the association of its use with liver-related risks is very limited. In the present study, the effect of standardized CFE with 10% forskolin on liver function of mice was examined. Mice were given 0-5% CFE in an AIN93G-based diet for 3-5 weeks. Food intake, body weights, relative organ weights and liver marker enzymes [aspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP)] combined with histophatological analysis were assessed. CFE (0-0.5%) only had minimal effects on food intake and body weight whereas a significant difference was observed in mice receiving the highest dose (5% CFE). The extract 0.05-5% dose-dependently decreased visceral fat weight by between 16% and 63%, and a dose-dependent several folds increase was observed in liver weights and plasma AST, ALT and ALP activities with quick onset apparent after only 1 week of 0.5% CFE intake. The hepatic effect persisted throughout the 3-weeks course but was restored towards normalization within 1 week after withdrawal of treatment. Liver histology of mice fed 0.5% CFE for 3 weeks showed hepatocyte hypertrophy and fat deposition. In contrast, none of the hepatic responses measured were altered when mice were given a diet containing pure forskolin alone at the dose corresponding to its content in 0.5% CFE. The present study clearly indicated that forskolin was not involved in the CFE-induced hepatotoxicity and was caused by other unidentified constituents in CFE which warrants further studies. Copyright © 2012 John Wiley & Sons, Ltd.
Article
The stimulatory effect of Mn2+ (1.5-fold), forskolin (1.6-fold) and low (1 microM) concentrations of GTP (1.9-fold) on the adenylyl cyclase of adipocyte membranes from obese, diabetic CBA/Ca mice was markedly enhanced compared to that seen using membranes prepared from their lean littermates. In contrast, receptor-mediated stimulation, achieved with either isoprenaline or secretin was reduced and that by glucagon abolished in membranes from diabetic animals. The levels of expression of alpha-subunits of Gi-1, Gi-2 and Gi-3 were reduced to some 49, 76 and 54%, respectively, in membranes from diabetic animals compared with those from normal animals. Levels of G-protein beta-subunits and Gs alpha-subunits were similar. Receptor-mediated inhibition of adenylate activity elicited by either nicotinic acid or prostaglandin E1 (PGE1) was of a similar magnitude in membranes from normal and diabetic animals but the inhibitory action of N6-(L-2-phenylisopropyl)adenosine (PIA) was greater in membranes from diabetic animals by about 30%. Gi function was similarly evident in membranes from both lean and diabetic animals, as assessed using low concentrations of guanylyl 5'-imidodiphosphate to inhibit forskolin-stimulated adenylyl cyclase activity. However, assessing Gi function using GTP showed marked dissimilarities in that the elevated GTP concentrations expected to occur physiologically were incapable of reversing the stimulation achieved at low concentrations of GTP in membranes from diabetic but not normal animals. The adipocytes of CBA/Ca mice, as do other animal models of insulin resistance, show lesions in adenylyl cyclase regulation, Gi function and G-protein expression.
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Triglyceride mobilization and adenylyl cyclase activation in adipocytes from Wistar rats, lean Zucker (Fa/?) rats, obese Zucker (fa/fa) rats and humans were investigated in concentration-response studies with (-)-isoprenaline and the atypical beta 3-adrenoceptor selective agonist BRL 37344. Maximum FFA production by both agonists was identical in Wistar rat and lean Zucker rat adipocytes, while obese Zucker rat adipocytes and human adipocytes produced significantly less FFA, especially with BRL 37344. Maximum adenylyl cyclase activation by (-)-isoprenaline was similar for all types of adipocyte ghosts, whereas BRL 37344 was a partial agonist in all cases with the lowest intrinsic activity in human adipocytes. For (-)-isoprenaline the relationship between cAMP and lipolysis was steepest with Wistar rat adipocytes, followed by human and lean Zucker rat adipocytes, while obese Zucker rat cells showed a shallow relationship. For BRL 37344, the relationship was very steep and similar for all four adipocyte types, despite the marked differences in maximal lipolysis and cyclic AMP production. The results strongly argue in favour of cyclic AMP compartmentalization, the activity ratio between the functional and the non-functional compartment being least favourable in obese Zucker rat adipocytes. The atypical beta 3-adrenoceptor agonist BRL 37344 very efficiently directs the generated cyclic AMP into the functional compartment in all four adipocytes types investigated.
Article
Both vascular relaxation and cAMP accumulation mediated by beta adrenergic agonists declines with increasing age. We have developed a method to measure the biologically relevant cAMP bound to the regulatory subunits of cAMP-dependent protein kinase in rat aorta. In homogenates of rat aorta, binding of [3H]cAMP was saturable with a Kd of 8.0 +/- 1.5 nM; the dissociation of [3H]cAMP from the binding sites was comprised of fast and slow components at 4 degrees C. Endogenous cAMP binding in aortas stimulated with isoproterenol (10(-5) M) or forskolin (10(-5) M) was quantitated by radioimmunoassay. Compared to basal values, isoproterenol increased cAMP binding by 37% (P less than 0.05) in aortas from young animals (5-6 weeks) but had essentially no effect on binding in older animals (9-11 months). In contrast, forskolin, which causes full relaxation in aortas from older rats, equally elevated bound cAMP values in aortas in the two age groups. In addition, the ratio of total cAMP binding sites to cAMP-dependent protein kinase catalytic activity was 45% higher in aortas from the older rats, suggesting that there were proportionately more regulatory subunits in those vessels. The deficit in isoproterenol-stimulated cAMP binding in vascular smooth muscle in older animals may in part explain the loss in relaxation mediated by beta adrenergic agonists.
Article
In isolated rat adipocytes incubated in the absence of insulin, 2',5'-dideoxyadenosine blocked the increase in total adenosine 3',5'-cyclic monophosphate (cAMP) accumulation due to beta 1- or beta 3-catecholamine agonists and forskolin without affecting their stimulation of lipolysis. The inhibition of cAMP accumulation by 2',5'-dideoxyadenosine was not reflected in the total cytosolic cAMP-dependent protein kinase A activity, suggesting that the inhibition of cAMP occurred in cellular compartments distinct from those involved in the regulation of bulk protein kinase A activity. However, there was a good correlation between effects of lipolytic agents on cytosolic protein kinase A activity in fat cell extracts and lipolysis. Furthermore, it was possible to see an inhibition of the increase due to beta-agonists in cAMP accumulation, protein kinase A activity, and lipolysis by 2',5'-dideoxyadenosine in the presence of insulin. These data suggest that the readily measurable accumulation of cAMP seen with catecholamines in the absence of insulin is in a compartment separate from that involved in protein kinase A activation.
Article
Lipolysis in rat white adipocytes is stimulated by beta-adrenergic agonists. Phorbol 12-myristate 13-acetate (PMA) attenuated the receptor-mediated lipolysis by causing a shift of the dose-response curve to the higher concentrations of norepinephrine and isoproterenol. Although the adipocytes possess beta1-, beta2-, and beta3-adrenergic receptor subtypes, the effect of PMA was observed only when a beta1-agonist (dobutamine) was used. No lipolysis-attenuating effect of PMA was found when cells were exposed to a beta2-agonist (procaterol) and beta3-agonists (BRL 37344 and CL 316243), or to forskolin and 8-bromo cAMP. CGP 20712A (beta1-antagonist) efficiently inhibited lipolysis by norepinephrine, isoproterenol, and dobutamine, but did not affect lipolysis by the beta2- and beta3-agonists. ICI 118551 (beta2-antagonist) had no significant effect on lipolysis by the beta-agonists examined. CGP 20712A abolished the lipolysis-attenuating effect of PMA, but ICI 118551 did not. The protein kinase C (PKC) inhibitors, GF 109203X or Gö 6976, suppressed the effect of PMA. Pretreatment of adipocytes with PMA for 6 h caused downregulation of conventional and novel PKCs in association with a decrease in the lipolysis-attenuating effect of PMA. These results indicate that conventional and novel PKCs attenuate lipolysis mediated by beta-adrenergic receptors, probably through inhibition of the beta1-adrenergic receptor system.
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