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Tea catechins' affinity for human cannabinoid receptors
Abstract
Among the many known health benefits of tea catechins count anti-inflammatory and neuroprotective activities, as well as effects on the regulation of food intake. Here we address cannabimimetic bioactivity of catechin derivatives occurring in tea leaves as a possible cellular effector of these functionalities. Competitive radioligand binding assays using recombinant human cannabinoid receptors expressed in Chem-1 and CHO cells identified (-)-epigallocatechin-3-O-gallate, EGCG (K(i)=33.6 microM), (-)-epigallocatechin, EGC (K(i)=35.7 microM), and (-)-epicatechin-3-O-gallate, ECG (K(i)=47.3 microM) as ligands with moderate affinity for type 1 cannabinoid receptors, CB1. Binding to CB2 was weaker with inhibition constants exceeding 50 microM for EGC and ECG. The epimers (+)-catechin and (-)-epicatechin exhibited negligible affinities for both CB1 and CB2. It can be concluded that central nervous cannabinoid receptors may be targeted by selected tea catechins but signaling via peripheral type receptors is less likely to play a major role in vivo.
... A recent study by Dimmito et al. [73] revealed carrots (Daucus carota, L) contain a high concentration of falcarinol (FaOH), which acts as a moderate skin irritant, aggravating histamine-induced edema skin, and showed receptor affinity to both CB1 and CB2 with a CB1 antagonist profile [74]. Catechins and epi-catechin compounds in tea (Camellia sinensis L.) were found to be receptors of CB1 [75]. Furthermore, Kava Kava (Piper methysticum forster) also known as "intoxicating pepper", which is used as a traditional medicine to cure pains, headaches, convulsions, menstrual pains, and skin diseases [76], was reported to have the ability to activate the CB1 and CB2 receptors [77]. ...
The Cannabis species is one of the potent ancient medicinal plants acclaimed for its medicinal properties and recreational purposes. The plant parts are used and exploited all over the world for several agricultural and industrial applications. For many years Cannabis spp. has proven to present a highly diverse metabolomic profile with a pool of bioactive metabolites used for numerous pharmacological purposes ranging from anti-inflammatory to antimicrobial. Cannabis sativa has since been an extensive subject of investigation, monopolizing the research. Hence, there are fewer studies with a comprehensive understanding of the composition of bioactive metabolites grown in different environmental conditions, especially C. indica and a few other Cannabis strains. These pharmacological properties are mostly attributed to a few phytocannabinoids and some phytochemicals such as terpenoids or essential oils which have been tested for antimicrobial properties. Many other discovered compounds are yet to be tested for antimicrobial properties. These phytochemicals have a series of useful properties including anti-insecticidal, anti-acaricidal, anti-nematicidal, anti-bacterial, anti-fungal, and anti-viral properties. Research studies have reported excellent antibacterial activity against Gram-positive and Gram-negative multidrug-resistant bacteria as well as methicillin-resistant Staphylococcus aureus (MRSA). Although there has been an extensive investigation on the antimicrobial properties of Cannabis, the antimicrobial properties of Cannabis on phytopathogens and aquatic animal pathogens, mostly those affecting fish, remain under-researched. Therefore, the current review intends to investigate the existing body of research on metabolomic profile and anti-microbial properties whilst trying to expand the scope of the properties of the Cannabis plant to benefit the health of other animal species and plant crops, particularly in agriculture.
... Polyphenol compounds found in the leaves of teas, in several fruits and legumes, such as catechins, exhibit binding properties with CB1 and CB2 receptors in a dose-dependent manner (Korte et al., 2010). In addition, curcumin, another polyphenol that inhibits tumor growth by increasing ROS levels and the antioxidant glutathione (GSH) (Larasati et al., 2018) has been linked to a cannabinoid activity in multiple physiological systems, such as alternative treatments for inflammatory bowel disease, other digestive diseases or liver fibrosis Quezada and Cross, 2019), alone or in the presence of hemopressin (El Swefy et al., 2016). ...
The endocannabinoid system (ECS) is an important brain modulatory network. ECS regulates brain homeostasis throughout development, from progenitor fate decision to neuro- and gliogenesis, synaptogenesis, brain plasticity and circuit repair, up to learning, memory, fear, protection, and death. It is a major player in the hypothalamic-peripheral system-adipose tissue in the regulation of food intake, energy storage, nutritional status, and adipose tissue mass, consequently affecting obesity. Loss of ECS control might affect mood disorders (anxiety, hyperactivity, psychosis, and depression), lead to drug abuse, and impact neurodegenerative (Alzheimer’s, Parkinson, Huntington, Multiple, and Amyotrophic Lateral Sclerosis) and neurodevelopmental (autism spectrum) disorders. Practice of regular physical and/or mind-body mindfulness and meditative activities have been shown to modulate endocannabinoid (eCB) levels, in addition to other players as brain-derived neurotrophic factor (BDNF). ECS is involved in pain, inflammation, metabolic and cardiovascular dysfunctions, general immune responses (asthma, allergy, and arthritis) and tumor expansion, both/either in the brain and/or in the periphery. The reason for such a vast impact is the fact that arachidonic acid, a precursor of eCBs, is present in every membrane cell of the body and on demand eCBs synthesis is regulated by electrical activity and calcium shifts. Novel lipid (lipoxins and resolvins) or peptide (hemopressin) players of the ECS also operate as regulators of physiological allostasis. Indeed, the presence of cannabinoid receptors in intracellular organelles as mitochondria or lysosomes, or in nuclear targets as PPARγ might impact energy consumption, metabolism and cell death. To live a better life implies in a vigilant ECS, through healthy diet selection (based on a balanced omega-3 and -6 polyunsaturated fatty acids), weekly exercises and meditation therapy, all of which regulating eCBs levels, surrounded by a constructive social network. Cannabidiol, a diet supplement has been a major player with anti-inflammatory, anxiolytic, antidepressant, and antioxidant activities. Cognitive challenges and emotional intelligence might strengthen the ECS, which is built on a variety of synapses that modify human behavior. As therapeutically concerned, the ECS is essential for maintaining homeostasis and cannabinoids are promising tools to control innumerous targets.
... In one study, the two compounds were shown to have a direct and potent effect on cannabinoid receptors [8] , however, a separate study could not reproduce those results [3] . A number of catechins, found in tea, as well as certain plant pigments (Cyanidin and Delphinidin) have been observed to directly bind to cannabinoid receptors [9,10] , albeit at very high levels. This high-level binding affinity may be the result of nonspecific denaturation of the proteins rather than functional binding. ...
Cannabis has been cultivated and used for millennia by the human race. The original medicinal and industrial uses of cannabis were almost forgotten during the vilification during the early 20th century. However, with renewed focus, interest, and tolerance, this species has found itself in the limelight of its original purpose. Cannabinoids have become a staple in modern holistic medicine and have even found mainstream medicinal applications. Confusion has arisen over the classification of its primary compounds, cannabinoids, as well as to the presence of similar compounds in other plant species. Novel cannabinoids produced legitimately by researchers or illicitly by clandestine chemists have only added to this issue and furthered the need for unification not only in understanding, but also in terminology. This review seeks to define critical terms for cannabinoid chemistry as well provide an introduction to the variety of compounds.
... Korte and co-workers performed competition binding assays on membrane preparations of recombinant receptors, using [ 3 H]-CP55940 as radiolabelled ligand; the K i values ranging from 33.6 mM for EGCG to over 2.5 mM for (+)-catechin and (-)-epicatechin to CB1, while the receptor CB2 affinity were generally lower than that of CB1. The cannabimimetic activities can contribute in mitigation of pain, complementing a COX-2 inhibitory role and opioid receptor functionalities of catechins, also modulating food intake [135]. ...
Nowadays cardiovascular diseases (CVDs) are the major causes for the reduction of the quality of life. The endocannabinoid system is an attractive therapeutic target for the treatment of cardiovascular disorders due to its involvement in vasomotor control, cardiac contractility, blood pressure and vascular inflammation. Alteration in cannabinoid signalling can be often related to cardiotoxicity, circulatory shock, hypertension, and atherosclerosis. Plants have been the major sources of medicines until modern eras in which researchers are experiencing a rediscovery of natural compounds as novel therapeutics. One of the most versatile plant is Cannabis sativa L., containing phytocannabinoids that may play a role in the treatment of CVDs. The aim of this review is to collect and investigate several less studied plants rich in cannabinoid-like active compounds able to interact with cannabinoid system; these plants may play a pivotal role in the treatment of disorders related to the cardiovascular system.
... While, at present, tea is cultivated in more than 40 countries in the world, the major portion (90%) is produced by Asian countries [22]. Due to the presence of biologically active compounds (antitoxin, antioxidant, anti-inflammatory, antibacterial, antiviral, anti-carcinogenic, etc.) like polyphenols, amino acids and vitamins in tea [23,24], tea drinking has been promoted for centuries [25][26][27]. Controversies about the benefits and risks due to the consumption of tea are not completely absent, but the few reported toxic effects are outclassed by its countless health-promoting benefits [28]. ...
Considering the probable health risks due to radioactivity input via drinking tea, the concentrations of 226Ra, 232Th,40K and 137Cs radionuclides in the soil and the corresponding tea leaves of a large tea plantation were measured using high purity germanium (HPGe) γ-ray spectrometry. Different layers of soil and fresh tea leaf samples were collected from the Udalia Tea Estate (UTE) in the Fatickchari area of Chittagong, Bangladesh. The mean concentrations (in Bq/kg) of radionuclides in the studied soil samples were found to be 34 ± 9 to 45 ± 3 for 226Ra, 50 ± 13 to 63 ± 5 for 232Th, 245 ± 30 to 635 ± 35 for 40K and 3 ± 1 to 10 ± 1 for 137Cs, while the respective values in the corresponding tea leaf samples were 3.6±0.7 to 5.7±1.0, 2.4± 0.5 to 5.8±0.9, 132± 25 to 258±29 and
... Some polyphenols demonstrated an affinity to the human cannabinoid receptor CB1 in radioligand assays such as delphinidin (Ki: 21.3 µM) and cyanidin (Ki: 16.2 µM), whereas similar binding affinities for CB2 receptors were demonstrated also by delphinidin (Ki: 34.3 µM), cyanidin (Ki: 33.5 µM) and peonidin (Ki: 46.4 µM) [23]. Some catechins such as epigallocatechin, epigallocatechin-3-O-gallate and epicatechin-3-O-gallate were reported to modulate CB1 receptors with Ki values of 35.7 µM, 33.6 µM and 47.3 µM, respectively [24]. The flavanone glycosides miconioside B and C showed weak affinity to CB2 receptors in radioligand-binding studies [25]. ...
In this study, the aerial parts of Moricandia sinaica were evaluated for their in vivo analgesic, anti-inflammatory and antipyretic activities. The analgesic activities were examined using acetic acid-induced writhing, the hot plate test and the tail flick method. The anti-inflammatory and the antipyretic activities were evaluated using carrageenan-induced paw edema in rats and brewer's yeast-induced pyrexia in mice, respectively. The aqueous fraction of the methanol extract (MS-3) showed to be the most bioactive among the other investigated fractions. At the dose of 500 mg/kg, the fraction (MS-3) showed a significant percentage inhibition of the carrageenan-induced edema by 52.4% (p < 0.05). In addition, MS-3 exhibited a significant inhibition of acetic acid-induced writhes by 44.4% and 61.5% (p < 0.001) at 250-mg/kg and 500-mg/kg doses, respectively. At 120 min post-treatment, the rat groups treated with MS-3 displayed statistically significant reduction in rectal temperature (p < 0.001) by 1.7 • C and 2.2 • C at 250-and 500-mg/kg doses, respectively. The phytochemical composition of the fraction (MS-3) was characterized by high-performance liquid chromatography-mass spectrometry (HPLC-PDA-MS/MS). Molecular docking studies demonstrated that the polyphenols identified in MS-3 revealed good binding energy upon docking to some target proteins involved in pain response and inflammation, such as the cannabinoid receptors CB1 and CB2, the fatty acid amide hydrolase (FAAH) and the cyclooxygenase COX-1 and COX-2 enzymes. Based on the findings from the present work, it could be concluded that the aerial parts extract of M. sinaica exerts potential analgesic, anti-inflammatory and antipyretic effects in rats.
... In addition, epicatechin gallate activated nitric oxide synthase in endothelial cells through TRPV1 (Guo et al. 2015). Epicatechin gallate extracted from green tea binds to CB receptors (in particular CB1) in the central nervous system (Korte et al. 2009) and PPARγ receptor (Wu et al. 2017). Rutin (also named quercetin-3-rutinoside, sophorin, vitamin P or rutoside) is also a component that was identified in the analysis of A. andrachne leaf extract. ...
Arbutus andrachne L. is a medicinal plant that grows in Jordan and has many valuable effects. In the present study, the anti-nociceptive effect of A. andrachne methanolic leaf extract was determined in mice using thermal and chemical tests. Our findings show that different doses of A. andrachne extract reduced the number of writhings significantly compared to control group. The leaf extract also reduced the time of paw licking in the early and late phases of formalin test. In all the conducted tests, 300 mg/kg body wt. was the best effective dose. A peroxisome proliferator-activated receptor alpha (PPARα) antagonist reversed the action of the plant extract in the early phase of formalin test while antagonists of the PPARα, PPAR gamma (PPARγ) and cannabinoid 1 (CB1) receptors were responsible for abolishing its effect in the late phase of this test. Also, the extract administration increased the latency time in hot plate and tail flick, an effect that was reversed by the antagonists of PPARγ, CB1 and transient receptor potential vanilloid 1 (TRPV1). No effect was noticed for α2-adrenergic receptor antagonist in the action of A. andrachne in any of the conducted tests in this study. Furthermore, analysis of the constituents in the methanolic leaf extract using liquid chromatography mass spectrometry (LCMS) showed that the extract is rich in compounds that have anti-nociceptive and/or anti-inflammatory effects such as arbutin, rutin, linalool, linoleic acid, gallic acid, lauric acid, myristic acid, hydroquinone, β-sitosterol, ursolic acid, isoquercetin, quercetin, (+)-gallocatechin, kaempferol, α-tocopherol, myricetin 3-O-rhamnoside and catechin gallate. In conclusion, A. andrachne showed promising anti-nociceptive effects in thermal and chemical models of pain. These findings can open an avenue for natural pain relief.
... Tea consumption (especially green) is potentially beneficial to health and longevity given its antioxidant, flavanols, flavonoids, polyphenols, and catechins content (Shimizu et al., 2012). It is well known that tea catechins have anti-inflammatory and neuroprotective activities, and have an affinity for cannabinoid receptors, and help to regulate food intake, which may inhibit pain, nausea, and provide calming effects (Korte et al., 2010). In recent studies, green tea may help reduce the risk of cardiovascular disease and some ____________________________________________________________________________ Email: wahid-ttc@sust.edu ...
Green tea is made from Camellia sinensis leaves that have undergone minimal oxidation during processing and helps to reduce the risk of cardiovascular disease and some forms of cancer. A study was conducted to evaluate the changes in quality characteristics of processed green tea extract for 21 days. Green tea extract was prepared in the laboratory scale with the addition of two different green tea from Kazi & Kazi (K-1) and Finlay (F-1), honey and ginger juice. The changes in total phenol content, DPPH scavenging effect, caffeine content, and sensory quality were analyzed during the storage period. The DPPH scavenging effect decreased slightly 97.17% to 84.51 % for F-1 and 97.84 % to 85.50 % for K-1 in the storage period of 7 to 21 days respectively for 50000 µg/ml concentration. For other concentration DPPH activity also decreased gradually during the storage period. Similarly the total phenol content decreased slightly from 4.13 (GAE mg/100gm) to 2.99 (GAE mg/100gm) for K-1 and 3.59 (GAE mg/100gm) to 3.0 (GAE mg/100gm) for F-1 in storage period whereas level of caffeine increased from 42.17 to 64.09 (ppm for K-1 and from 41.82 to 60.26 (ppm) for F-1 in during storage period. The sensory quality of K-1 was better than the F-1 with the score of overall acceptability 6.2 and 5.9 respectively. The study results might help to consider the quality changes of green tea extract during the storage period to introduce a green tea-based beverage.
... EGCG has undergone a phase 2 clinical trial (Torre et al. 2016). However EGCG interacts with the cannabinoid receptor 1 (CNR1) (Korte et al. 2010). ...
Growing evidence support the implication of DYRK1A in the development of cognitive deficits seen in Down syndrome (DS) and Alzheimer's disease (AD). We here demonstrate that pharmacological inhibition of brain DYRK1A is able to correct recognition memory deficits in three DS mouse models with increasing genetic complexity (Tg(Dyrk1a), Ts65Dn, Dp1Yey), all expressing an extra copy of Dyrk1a Overexpressed DYRK1A accumulates in the cytoplasm and at the synapse. Treatment of the three DS models with the pharmacological DYRK1A inhibitor Leucettine L41 leads to normalization of DYRK1A activity and corrects the novel object cognitive impairment observed in these models. Brain functional magnetic resonance imaging reveals that this cognitive improvement is paralleled by functional connectivity remodeling of core brain areas involved in learning/memory processes. The impact of Dyrk1a trisomy and L41 treatment on brain phosphoproteins was investigated by a phosphoproteomics approach, revealing the implication of synaptic (synapsin I) and cytoskeletal components involved in synaptic response and axonal organization. These results encourage the development of DYRK1A inhibitors as drug candidates to treat cognitive deficits associated with DS and AD.
... Le manque de sélectivité de ce composé rend donc difficile la compréhension des mécanismes moléculaires sous-jacents à la restauration des phénotypes observés dans les études précliniques et cliniques d'ores et déjà réalisées. Il est également important de préciser que parmi les autres cibles de l'EGCG, se trouvent les récepteurs aux cannabinoïdes CB1 (Korte et al., 2010). Or ces récepteurs sont connus pour leur rôle dans la régulation du relargage des neurotransmetteurs dans différentes aires du cerveau telles que le cortex préfrontal ou encore l'hippocampe. ...
La trisomie 21 (T21) résulte de la présence d’une extra-copie du chromosome 21 (Chr21). Parmi les gènes candidats impliqués dans les déficits cognitifs liés à la T21, DYRK1A est un des plus pertinents. Des études ont montré une corrélation entre l’augmentation de son activité kinase avec les déficits mnésiques observés dans les modèles murins de T21. Afin de comprendre les mécanismes sous-jacents aux altérations cognitives causées par son surdosage, nous avons utilisé des modèles murins sur-exprimant DYRK1A seule ou en plus d’autres gènes orthologues au Chr21, ainsi que des inhibiteurs spécifiques de DYRK1A (Leucettines) synthétisés par ManRos Therapeutics. Ici sont présentées les conséquences d’un traitement chronique avec ces Leucettines sur la cognition de ces animaux. Des analyses du phosphoprotéome de ces souris traitées ou non avec une des Leucettines, la L41, a mis en lumière des cibles et mécanismes biologiques impliqués dans les perturbations mnésiques de ces animaux. Enfin, ce projet a surtout permis de mettre en évidence un nouvel inhibiteur plus sélectif pour DYRK1A comme candidat-médicament pour l’amélioration des fonctions cognitives des porteurs de la T21.
... As the most abundant green tea (GT) constituent, EGCG has been the focus of research in relation to the reduction of morbidity and mortality because of cardiovascular disease. Several mechanisms of action have been proposed as to why EGCG may benefit cardiovascular health in humans, such as the lowering of plasma cholesterol through a reduction of cholesterol absorption [12], a decrease in cholesterol synthesis [13] and/or an increase in the cholesterol clearance rate through an up regulation of the LDL receptor [14][15][16]. Phytophospholipid complexes exhibit better pharmacokinetic and pharmacodynamic profile than conventional herbal extracts [17,18]. The present work envisaged to develop phospholipid complex of green tea extract rich in Epigallocatechin 3-gallate (EGCG) to improve the in vitro dissolution and in turn the oral bioavailability. ...
OBJECTIVE: Phospholipid complexes are formulated to improve absorption,
bioavailability and stability of herbal product. There are many herbal extracts having
excellent in-vitro activity but less in-vivo activity because of their macromolecular size
and poor aqueous/lipid solubility, which result in poor absorption and bioavailability.
Green tea polyphenol has poor oral bioavailability due to many known and unknown
reasons and is unstable in the gastrointestinal tract. There have been published reports
that encapsulating green tea polyphenols in drug delivery carrier significantly delayed
its degradation in simulated digestive fluids and leads to improved oral bioavailability.
METHODS: The present work aims in improving the GI dissolution and oral
bioavailability of green tea extract rich in Epigallocatechin-3-gallate (EGCG) by
formulating into phospholipid complex. EGCG-Phospholipid complex (EPC) was
formulated by anti-solvent evaporation method using green tea extract and
phosphatidylcholine (PC) in the ratio of 0.5:1, 0.75:1, 1:1, 1:0.75 and 1:0.5.
RESULT: EPC were characterized by solubility, particle size, drug content, %
entrapment efficacy, differential scanning calorimetry (DSC), Fourier transform
infrared spectroscopy (FTIR) and in vitro dissolution study. The results showed that the
average particle size of optimized EPC formulation was 201.96 nm. The Drug content
and Entrapment efficiency was found to be 90.57 ± 1.187 and 95.41 ± 0.898,
respectively. In vitro drug release studies revealed that the cumulative % drug release
of the optimized EPC was 98.41% at 3 hours.
CONCLUSION: Results of the physicochemical and drug release studies suggested
that EPC would serve as useful novel drug delivery system and provide improved oral
bioavailability.
... 206 Genistein has been also shown to have a 20-fold higher binding affinity to estrogen receptor β than estrogen receptor α. 207 Genistein also is 130-fold more potent than its counterpart 17β-estradiol to bind to estrogen receptor α. 207,208 It has been also shown that CNS cannabinoid receptors may be targeted by selected tea catechins (EGCG K i = 33.6 μM), but signaling via peripheral type receptors is not as likely to be important in vivo. 209 This is of particular interest because cannabinoids have the ability to activate an ER-stress related pathway that leads to the activation of autophagymediated cancer cell death and to inhibition of tumor angiogenesis and cancer cell migration. 210 However, if polyphenol-induced modulation of this intercellular trafficking/communication is truly relevant, under in vivo conditions, will depend on whether a rational correlation between bioavailability and bioefficacy can be established. ...
Natural polyphenols are organic chemicals which contain phenol units in their structures. They show anticancer properties. However, a key problem is their short half-life and low bioavailability under in vivo conditions. Still, definitively demonstrating the human benefits of isolated polyphenolic compounds (alone or in combination) using modern scientific methodology has proved challenging. The main discrepancy between experimental and clinical observations is the frequent use of non-physiologically relevant concentrations of polyphenols in mechanistic studies. Thus, it remains highly controversial how potential underlying mechanisms can be correlated with bioavailable concentrations and biological half-life. The present review analyses proposed anticancer mechanisms, in vivo reported anticancer effects, and possible mechanisms that may explain discrepancies between bioavailability and bioefficacy. Polyphenol metabolism and possible toxic-side effects are also considered. Our main conclusion emphasizes that these natural molecules (and their chemical derivatives) indeed can be very useful, not only as cancer chemopreventive agents but also in Oncotherapy.
... However, some problems with this compound remain, such as its complex pharmacokinetic properties, poor bioavailability, multiple and heterogeneous effects on signaling pathways and the degree of purity of the commercially available compound (Lambert et al., 2007;Kanwar et al., 2012;Lorenz, 2013). In addition, EGCG was found to have a low inhibitory effect on cannabinoid receptor 1 (CNR1) activity (Korte et al., 2010), which could have negative consequences for long-term treatment as the well-known rimonabant, an inverse agonist directing CNR1. Rimonabant was used as an anorectic and antiobesity drug and was removed from the market after reports of severe depression and suicide in treated people (Thomas et al., 2014). ...
Down syndrome (DS) is one of the leading causes of intellectual disability, and patients with DS face various health issues, including learning and memory deficits, congenital heart disease, Alzheimer’s disease (AD), leukemia and cancer, leading to huge medical and social costs. Remarkable advances on DS research have been made in improving cognitive function in mouse models for future therapeutic approaches in patients. Among the different approaches, DYRK1A inhibitors have emerged as promising therapeutics to reduce DS cognitive deficits. DYRK1A is a dual-specificity kinase that is overexpressed in DS and plays a key role in neurogenesis, outgrowth of axons and dendrites, neuronal trafficking and aging. Its pivotal role in the DS phenotype makes it a prime target for the development of therapeutics. Recently, disruption of DYRK1A has been found in Autosomal Dominant Mental Retardation 7 (MRD7), resulting in severe mental deficiency. Recent advances in the development of kinase inhibitors are expected, in the near future, to remove DS from the list of incurable diseases, providing certain conditions such as drug dosage and correct timing for the optimum long-term treatment. In addition the exact molecular and cellular mechanisms that are targeted by the inhibition of DYRK1A are still to be discovered.
... The trend of tea drinking has long been promoted due to its association in reducing blood cholesterol and risk of cardiovascular disease, cancer, immune disorders and Parkinson's disease (Fujita & Yamagami, 2008;Hamer, 2007;Siddiqui, Raisuddin, & Shukla, 2005). Polyphenols, amino acids and vitamins are the primary biologically active components in tea, which have been confirmed to exhibit antioxidant, antibacterial, antitoxin, antiviral, anti-inflammatory and anticancer activities (Friedman, 2007;Korte et al., 2010). ...
The purpose of this research was to establish an effective dose of gamma irradiation to eliminate any possible bacterial contamination as well as assess the levels of essential major elements [sodium (Na), potassium (K), calcium (Ca), magnesium (Mg) and iron (Fe)] present in black tea. The samples were compared to fresh tea leaves and soil from the tea gardens of two distinct tea cultivating regions (Sylhet and Moulvibazar) in Bangladesh. Maximum coliform bacterial contaminants (4.0 × 102 cfu/g) were completely eliminated following an irradiation dose of 2.5 kGy, whereas a viable bacterial load of 9.0 × 103 cfu/g was completely eliminated at 5.0 kGy. Major elements were present at higher concentrations in black tea samples originating from Sylhet compared to those from Moulvibazar. Among the analyzed elements, only Na and Fe were present at higher concentrations in the fresh tea leaves from Sylhet, whereas K, Ca and Mg were observed at higher concentrations in the tea leaves from Moulvibazar. The amount of each mineral in the black tea is acceptable for daily intake and is safe for consumption. It is concluded that black tea from Bangladesh is a rich source of minerals and could be free of microbial contamination after receiving 5.0 kGy of gamma radiation.
... Initial reports claimed that epigallocatechin 4-gallate and (-)-epigallocatechin in green tea (Camellia sinensis) bound CB 2 at high concentrations [59], but this finding was subsequently challenged [60]. Ferruginene C, a mixture of isomers from R. ferrugineum, showed weak ...
Plants have been the predominant source of medicines throughout the vast majority of human history, and remain so today outside of industrialized societies. One of the most versatile in terms of its phytochemistry is cannabis, whose investigation has led directly to the discovery of a unique and widespread homeostatic physiological regulator, the endocannabinoid system. While it had been the conventional wisdom until recently that only cannabis harbored active agents affecting the endocannabinoid system, in recent decades the search has widened and identified numerous additional plants whose components stimulate, antagonize, or modulate different aspects of this system. These include common foodstuffs, herbs, spices, and more exotic ingredients: kava, chocolate, black pepper, and many others that are examined in this review.
... These compounds have been comprehensively studied and shown to possess antioxidant, anti-inflammatory, GABAergic, glutamatergic, monoaminergic, opioidergic, and nitrergic modulatory activities and contribute to the several therapeutic benefits. For the first time, Korte et al. [54] evaluated the affinities of EGCG, ECG, EGC, (−)-epicatechin, and (+)catechin for human CB 1 and CB 2 receptors in competitive radioligand binding assays in Chem-1 and CHO cells. All the compounds, namely, EGCG ( = 33.6 mM), EGC ( = 35.7 mM), and ECG ( = 47.3 mM) exhibited binding with CB 1 and CB 2 receptors in a dose-dependent manner. ...
Globally diabetes mellitus (DM) is swiftly reaching epidemic proportions and impose major health care and socio-economic challenges that are associated with its complications. DM is considered as the major risk factor for the development of debilitating micro & macro vascular complications. Clinical studies have revealed that development of diabetic cardiomyopathy (DCM) in subjects with diabetes can occur both- dependent and independent of pre-existing increased risk factors such as poor glycemic control, hyperlipidemia, and or hypertension. Therefore, DCM represents as a major challenge for the clinical community for the prompt diagnosis and devising the treatment paradigm to combat the diabetes induced cardiac dysfunction. In Chinese traditional medical practice, heart ailments have been coped with herbal extracts. Phytochemicals bioavailability and pharmacokinetic properties are to yet be established completely in human subjects. However, tremendous progress has been made to isolate, purify the phytochemicals and characterize their effects on mitigating the development of DCM in pre-clinical models. Currently there are no approved drugs available for the treatment of DCM. In this review, we have discussed the progress made in understanding the mechanisms for the phytochemicals cardio-protective actions in the diabetic milieu and their caveats and provide future perspectives for proposing these agents to serve as prototypes in the development of drugs for the management of DCM.
... These compounds have been comprehensively studied and shown to possess antioxidant, anti-inflammatory, GABAergic, glutamatergic, monoaminergic, opioidergic, and nitrergic modulatory activities and contribute to the several therapeutic benefits. For the first time, Korte et al. [54] evaluated the affinities of EGCG, ECG, EGC, (−)-epicatechin, and (+)catechin for human CB 1 and CB 2 receptors in competitive radioligand binding assays in Chem-1 and CHO cells. All the compounds, namely, EGCG ( = 33.6 mM), EGC ( = 35.7 mM), and ECG ( = 47.3 mM) exhibited binding with CB 1 and CB 2 receptors in a dose-dependent manner. ...
The cannabinoid molecules are derived from
Cannabis sativa
plant which acts on the cannabinoid receptors types 1 and 2 (CB
1
and CB
2
) which have been explored as potential therapeutic targets for drug discovery and development. Currently, there are numerous cannabinoid based synthetic drugs used in clinical practice like the popular ones such as nabilone, dronabinol, and Δ
9
-tetrahydrocannabinol mediates its action through CB
1
/CB
2
receptors. However, these synthetic based
Cannabis
derived compounds are known to exert adverse psychiatric effect and have also been exploited for drug abuse. This encourages us to find out an alternative and safe drug with the least psychiatric adverse effects. In recent years, many phytocannabinoids have been isolated from plants other than
Cannabis
. Several studies have shown that these phytocannabinoids show affinity, potency, selectivity, and efficacy towards cannabinoid receptors and inhibit endocannabinoid metabolizing enzymes, thus reducing hyperactivity of endocannabinoid systems. Also, these naturally derived molecules possess the least adverse effects opposed to the synthetically derived cannabinoids. Therefore, the plant based cannabinoid molecules proved to be promising and emerging therapeutic alternative. The present review provides an overview of therapeutic potential of ligands and plants modulating cannabinoid receptors that may be of interest to pharmaceutical industry in search of new and safer drug discovery and development for future therapeutics.
... It exists in two epimeric forms, (+)gallocatechin and (-)-gallocatechin or ent-gallocatechin. This compound had been shown to have moderate affinity for the human cannabinoid receptor (Korte et al., 2010), which may contribute to the health benefits found by consuming green tea (Camellia sinensis). It is reported to exhibit antimetastatis, anticancer, immunoprotective, antiviral, anti-Alzheimer's disease, osteoclastogeneses property, among others (Ko et al., 2009). ...
The global forestry industry after experiencing a market downturn during the past decade has now aimed its
vision towards the integrated biorefinery. New business models and strategies are constantly being explored
to re-invent the global wood and pulp/paper industry through sustainable resource exploitation. The goal is to
produce diversified, innovative and revenue generating product lines using on-site bioresources (wood and
tree residues). The most popular product lines are generally produced from wood fibers (biofuels, pulp/paper,
biomaterials, and bio/chemicals). However, the bark and other tree residues like foliage that constitute forest
wastes, still remain largely an underexploited resource from which extractives and phytochemicals can be
harnessed as by-products (biopharmaceuticals, food additives and nutraceuticals, biopesticides, cosmetics).
Commercially, Populus (poplar) tree species including hybrid varieties are cultivated as a fast growing bioenergy crop, but can also be utilized to produce bio-based chemicals. This reviewidentifies and underlines the potential of natural products (phytochemicals) from Populus species that could lead to new business ventures in biorefineries and contribute to the bioeconomy. In brief, this review highlights the importance of by-products/co-products in forest industries, methods that can be employed to extract and purify poplar phytochemicals, the potential pharmaceutical and other uses of N160 phytochemicals identified frompoplar species – their chemical structures, properties and bioactivities, the challenges and limitations of utilizing poplar phytochemicals, and potential commercial opportunities. Finally, the overall discussion and conclusion are made considering the recent biotechnological advances in phytochemical research to indicate the areas for future commercial applications from poplar tree species.
... In addition to the properties described above, green tea and its components may exert neuroprotective effects through a variety of other mechanisms. These include green tea extract-and L-theaninemediated regulation of the secretion of stress hormones that influence cognitive function, including corticosterone [119,120]; EGCG-mediated reduction of amyloid-induced mitochondrial dysfunction [121]; inhibition of glutamate dehydrogenase [122,123], 3,4-dihydroxyphenylalanine decarboxylase [124], and histone acetyltransferase [125]; inhibition of fatty acid synthase by catechins [126,127]; interactions between catechin derivatives and opioid/cannabinoid receptors [128,129]; and L-theanine-mediated modulation of glutamatergic [130], GABAergic [131], dopaminergic [132], and serotoninergic neurotransmission in the brain [132][133][134]. Caffeine is also a psychoactive ingredient of green tea [76] and this stimulates cholinergic neurons by acting as a non-selective antagonist of adenosine A1 and A2A receptors [135]. ...
The prevalence of cognitive dysfunction, and particularly dementia, is increasing rapidly among older adults worldwide. There is currently no cure for dementia. In this situation, pharmaceutical and non-pharmaceutical combination therapies capable of preventing or slowing the progression of cognitive dysfunction are important. Nutritional intervention provides an important non-pharmaceutical approach in clinical practice. Green tea has the potential to contribute to this nutritional approach. Experimental studies in vitro and in vivo have suggested that green tea and its components could affect cognition via several potential mechanisms; these include its antioxidant and anti-inflammatory properties, protein kinase C activation, and acetylcholinesterase inhibition. Although several epidemiological and interventional studies in humans have suggested an association between tea consumption and cognition, not all studies have reported consistent findings. The present review summarizes experimental studies of the mechanisms involved in these effects and clinical studies of green tea consumption and cognition. This review provides a basis for the development of an evidence-based approach to the use of green tea and its ingredients in individuals with cognitive dysfunction.
... Epigallocatechin gallate, [(2R, 3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)chroman-3-yl] 3,4,5-trihydroxybenzoate also known as epigallocatechin-3-gallate is the ester of epigallocatechin and gallic acid and is a type of catechin. It has been the subject of a number of studies investigating its potential use as a therapeutic for a broad range of disorders, which includes HIV [5][6][7][8], Cancer [9][10][11][12], Chronic fatigue syndrome [13][14][15], Sjögren's syndrome [16], Endometriosis [17], Spinal muscular atrophy [18], Neurodegeneration [19][20], Cannabinoid 1 receptor, CB1 receptor Activity [21], Periapical lesions [22], Cerebrovascular insult [23]. ...
Rosuvastatin Calcium is a statin used extensively for the treatment of dyslipidemia, hypercholesterolemia and hypertriglyceridemia. Like all statins, Rosuvastatin can possibly cause myopathy and rhabdomyolysis. It was reported that statin induced the expression of atrogin-1, a key gene involved in skeletal muscle atrophy. In this process the function of mitochondria play a vital role in limiting the atrophy. Epigallocatechin gallate promotes mitochondrial biogenesis and thereby prevents the atrophy caused by statin. Similarly, Epigallocatechin gallate can also helps in reducing the LDL cholesterol. Both Rosuvastatin Calcium and Epigallocatechin gallate has a poor bioavailability and it can be improved by the use of nanoparticles. Nanoparticles were filled in hard gelatin capsules along with Microcrystalline Cellulose, Colloidal Silicon Dioxide, Magnesium Trisilicate and Magnesium Stearate. The ratio of Colloidal Silicon Dioxide, Magnesium Trisilicate and Magnesium Stearate was studied using two level Factorial design. The final product is stable and provides a sustained release for 24 hours. The combination proved to be promising with improved efficacy and reduced side effects. Please cite this article in press as Ramkumar Ponnuraj et al. Formulation and Development of Capsules Containing Rosuvastatin Calcium Nanoparticles and Epigallocatechin Gallate Nanoparticles. Indo American Journal of Pharm Research.2015:5(06).
... It exists in two epimeric forms, (+)gallocatechin and (-)-gallocatechin or ent-gallocatechin. This compound had been shown to have moderate affinity for the human cannabinoid receptor (Korte et al., 2010), which may contribute to the health benefits found by consuming green tea (Camellia sinensis). It is reported to exhibit antimetastatis, anticancer, immunoprotective, antiviral, anti-Alzheimer's disease, osteoclastogeneses property, among others (Ko et al., 2009). ...
... Finally, it is noteworthy that some natural dietary antioxidant polyphenols display significant affinity for human cannabinoid receptors, acting as antagonists/inverse agonists (Gertsch et al., 2008;Korte et al., 2009Korte et al., , 2010. ...
... Cyanidin and delphinidin, two anthocyanidins found in a wide range of plants, have micromolar affinities for CB 1 [162]. Epigallocatechin-3-O-gallate, the most abundant catechin in tea, also has micromolar affinities for CB 1 [163]. ...
The "classic" endocannabinoid (eCB) system includes the cannabinoid receptors CB1 and CB2, the eCB ligands anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and their metabolic enzymes. An emerging literature documents the "eCB deficiency syndrome" as an etiology in migraine, fibromyalgia, irritable bowel syndrome, psychological disorders, and other conditions. We performed a systematic review of clinical interventions that enhance the eCB system-ways to upregulate cannabinoid receptors, increase ligand synthesis, or inhibit ligand degradation.
We searched PubMed for clinical trials, observational studies, and preclinical research. Data synthesis was qualitative. Exclusion criteria limited the results to 184 in vitro studies, 102 in vivo animal studies, and 36 human studies. Evidence indicates that several classes of pharmaceuticals upregulate the eCB system, including analgesics (acetaminophen, non-steroidal anti-inflammatory drugs, opioids, glucocorticoids), antidepressants, antipsychotics, anxiolytics, and anticonvulsants. Clinical interventions characterized as "complementary and alternative medicine" also upregulate the eCB system: massage and manipulation, acupuncture, dietary supplements, and herbal medicines. Lifestyle modification (diet, weight control, exercise, and the use of psychoactive substances-alcohol, tobacco, coffee, cannabis) also modulate the eCB system.
Few clinical trials have assessed interventions that upregulate the eCB system. Many preclinical studies point to other potential approaches; human trials are needed to explore these promising interventions.
... Fukuda et al. reported that the pigments of green tea leaves had the potential to protect against dioxin toxicity through the suppression of aryl hydrocarbon receptor transformation (36). Moreover, EGCG has been suggested to exert binding properties with human cannabinoid receptors and focal adhesion kinase and insulin-like growth factor-I receptors (37,38). Thus, GTE may prevent the down-regulation of muscarinic receptors in CYP-treated bladders by affecting cholinergic neuronal activity. ...
The aim of this study was to characterize pharmacological effects of gosha-jinki-gan (GJG) and green tea extract (GTE), on urodynamic parameters, bladder receptors, and urinary cytokines in rats with cyclophosphamide (CYP)-induced cystitis. Urodynamic parameters in CYP-treated rats were measured using the cystometric method. Muscarinic and purinergic receptors in rat tissues were measured by radioreceptor assays. Urinary cytokine levels were measured with ELISA kits. GJG and GTE were orally administered to rats once a day for 7 days. The GJG treatment significantly ameliorated changes in urodynamic parameters in CYP-treated rats. Similar treatment with GTE slightly attenuated changes in urodynamic parameters. The maximal number of binding sites for [(3)H]NMS and [(3)H]αβ-MeATP in the bladder was significantly lower in CYP-treated rats than in sham rats. Such a reduction in receptor density was significantly attenuated by the GJG treatment. GTE treatment also significantly attenuated the down-regulation of muscarinic receptors, but not P2X receptors in bladders of rats with CYP-induced cystitis. The elevation in urinary cytokine levels in CYP-treated rats was effectively attenuated by GJG treatment. The elevation in cytokine levels in CYP-treated rats was alleviated by GTE treatment. In conclusion, GJG may be a pharmacologically useful plant extract for cystitis.
... EGC is one of the major composites of the green tea polyphenols which is less studied and the behavioral action of it in different provided experimental environments is poorly understood. EGC has been shown to have moderate affinity to the human cannabinoid receptor, which may contribute to the health benefits found by consuming green tea (18) . ...
Chlorpyriphos (CP) is one of the most widely used organophosphate insecticides for crops such as cotton, corn, almonds, and fruit trees including oranges and apples. It is known
to cause various classes of neurotoxicity, reproductive and developmental toxicity, acute toxicity, asthma, and endocrine disruption. (-)-Epigallocatechin (EGC), one of the major
constituents of green tea, a flavan-3-ol type of chemical compound possessing a catechin and a gallate residue was tested for its efficacy to protect CP-induced cytotoxicity in the present
study. The antioxidant potential of EGC was determined by DPPHw radical scavenging assay, and XTT assay was performed to determine the cytoprotective effect by exposing the
MDA-MB-435S (Human breast carcinoma) cells simultaneously to CP and EGC. Results obtained confirmed the free radical scavenging activity of EGC, and a concentration
dependent decrease in CP-induced cytotoxicity until a threshold level of 50 μg/ml. The study concludes that EGC can effectively prevent CP-induced cytotoxicity and could be used
to counteract harmful effects of CP which is an environmental pollutant.
... Hence, neither trans-resveratrol nor curcumin interact functionally with the CB1 receptor, despite the fact that these compounds appear to share the ability of the CB1 receptor inverse agonist, rimonabant, to induce weight loss in mice. More recently, catechin-derivatives were shown to bind to human cannabinoid receptors rather non-selectively at high mM concentrations (Korte et al., 2010). Among these, epigallocatechin 3-gallate and (-)-epigallocatechin (Table 1) were reported to bind to the CB1 receptor with Ki values of 33.6 and 35.7 mM respectively. ...
It is intriguing that during human cultural evolution man has detected plant natural products that appear to target key protein receptors of important physiological systems rather selectively. Plants containing such secondary metabolites usually belong to unique chemotaxa, induce potent pharmacological effects and have typically been used for recreational and medicinal purposes or as poisons. Cannabis sativa L. has a long history as a medicinal plant and was fundamental in the discovery of the endocannabinoid system. The major psychoactive Cannabis constituent Δ ⁹ ‐tetrahydrocannabinol (Δ ⁹ ‐THC) potently activates the G‐protein‐coupled cannabinoid receptor CB 1 and also modulates the cannabinoid receptor CB 2 . In the last few years, several other non‐cannabinoid plant constituents have been reported to bind to and functionally interact with CB receptors. Moreover, certain plant natural products, from both Cannabis and other plants, also target other proteins of the endocannabinoid system, such as hydrolytic enzymes that control endocannabinoid levels. In this commentary we summarize and critically discuss recent findings.
This article is part of a themed issue on Cannabinoids. To view the editorial for this themed issue visit http://dx.doi.org/10.1111/j.1476‐5381.2010.00831.x
Natural pigments are important sources for the screening of bioactive lead compounds. This article reviewed the chemistry and therapeutic potentials of over 570 colored molecules from plants, fungi, bacteria, insects, algae, and marine sources. Moreover, related biological activities, advanced extraction, and identification approaches were reviewed. A variety of biological activities, including cytotoxicity against cancer cells, antioxidant, anti-inflammatory, wound healing, anti-microbial, antiviral, and anti-protozoal activities, have been reported for different pigments. Considering their structural backbone, they were classified as naphthoquinones, carotenoids, flavonoids, xanthones, anthocyanins, benzotropolones, alkaloids, terpenoids, isoprenoids, and non-isoprenoids. Alkaloid pigments were mostly isolated from bacteria and marine sources, while flavonoids were mostly found in plants and mushrooms. Colored quinones and xanthones were mostly extracted from plants and fungi, while colored polyketides and terpenoids are often found in marine sources and fungi. Carotenoids are mostly distributed among bacteria, followed by fungi and plants. The pigments isolated from insects have different structures, but among them, carotenoids and quinone/xanthone are the most important. Considering good manufacturing practices, the current permitted natural colorants are: Carotenoids (canthaxanthin, β-carotene, β-apo-8'-carotenal, annatto, astaxanthin) and their sources, lycopene, anthocyanins, betanin, chlorophyllins, spirulina extract, carmine and cochineal extract, henna, riboflavin, pyrogallol, logwood extract, guaiazulene, turmeric, and soy leghemoglobin.
Neurodegenerative and neuropsychiatric diseases are increasingly affecting individuals' quality of life, thus increasing their cost to social and health systems. These diseases have overlapping mechanisms, such as oxidative stress, protein aggregation, neuroinflammation, neurotransmission impairment, mitochondrial dysfunction, and excitotoxicity. Currently, there is no cure for neurodegenerative diseases, and the available therapies have adverse effects and low efficacy. For neuropsychiatric disorders, such as depression, the current therapies are not adequate to one-third of the patients, the so-called treatment-resistant patients. So, searching for new treatments is fundamental. Medicinal plants appear as a strong alternative and complement towards new treatment protocols, as they have been used for health purposes for thousands of years. Thus, the main goal of this review is to revisit the neuroprotective potential of some of the most predominant medicinal plants (and one fungus) used in traditional Chinese medicine (TCM), focusing on their proven mechanisms of action and their chemical compositions, to give clues on how they can be useful against neurodegeneration progression.
The endocannabinoid system (ECS), a conserved physiological system emerged as a novel pharmacological target for its significant role and potential therapeutic benefits ranging from neurological diseases to cancer. Among both, CB1 and CB2R types, CB2R have received attention for its pharmacological effects as antioxidant, anti-inflammatory, immunomodulatory and antiapoptotic that can be achieved without causing psychotropic adverse effects through CB1R. The ligands activate CB2R are of endogenous, synthetic and plant origin. In recent years, β-caryophyllene (BCP), a natural bicyclic sesquiterpene in cannabis as well as non-cannabis plants, has received attention due to its selective agonist property on CB2R. BCP has been well studied in a variety of pathological conditions mediating CB2R selective agonist property. The focus of the present manuscript is to represent the CB2R selective agonist mediated pharmacological mechanisms and therapeutic potential of BCP. The present narrative review summarizes insights into the CB2R-selective pharmacological properties and therapeutic potential of BCP such as cardioprotective, hepatoprotective, neuroprotective, nephroprotective, gastroprotective, chemopreventive, antioxidant, anti-inflammatory, and immunomodulator. The available evidences suggest that BCP, can be an important candidate of plant origin endowed with CB2R selective properties that may provide a pharmacological rationale for its pharmacotherapeutic application and pharmaceutical development like a drug. Additionally, given the wide availability in edible plants and dietary use, with safety, and no toxicity, BCP can be promoted as a nutraceutical and functional food for general health and well-being. Further, studies are needed to explore pharmacological and pharmaceutical opportunities for therapeutic and preventive applications of use of BCP in human diseases.
Flavonoids are polyphenolic phytochemicals produced in fruits, nuts and vegetables and dietary consumption of these structurally diverse compounds is associated with multiple health benefits including increased lifespan, decreased cardiovascular problems and low rates of metabolic diseases. Preclinical studies with individual flavonoids demonstrate that these compounds exhibit anti-inflammatory and anticancer activities and they enhance the immune system. Their effectiveness in both chemoprevention and chemotherapy is associated with their targeting of multiple genes/pathways including nuclear receptors, the aryl hydrocarbon receptor (AhR), kinases, receptor tyrosine kinases and G protein-coupled receptors. However, despite the remarkable preclinical activities of flavonoids, their clinical applications have been limited and this is due, in part, to problems in drug delivery and poor bioavailability and these problems are being addressed. Further improvements that will expand clinical applications of flavonoids include mechanism-based precision medicine approaches which will identify critical mechanisms of action of individual flavonoids with optimal activities that can be used in combination therapies.
Extracts from Cannabis species have aided the discovery of the endocannabinoid signaling system (ECSS) and phytocannabinoids that possess broad therapeutic potential. Whereas the reinforcing effects of C. sativa are largely attributed to CB1 receptor agonism by Δ9-tetrahydrocannabinol (Δ9-THC), the observed medicinal effects of Cannabis arise from the combined actions of various compounds. In addition to compounds bearing a classical cannabinoid structure, naturally occurring fatty acid amides and esters resembling anandamide and 2-arachidonoyl glycerol isolated from non- Cannabis species are also valuable tools for studying ECSS function. This review highlights the potential of plant-based secondary metabolites from Cannabis and unrelated species as ECSS modulators.
The presence of GPRCs in plants is still a question of debate. While G-protein coupled signalling exists, the signalling cycle is typically not activated by seven transmembrane-spanning receptors. By contrast, many plant secondary metabolites are known to affect human GPRCs. Some are very specific for a single type of receptor; however, many others act on more than one type, albeit with often strongly different affinities.
Opioid receptors (ORs), μOR, δOR, κOR and ORL1 mediate numerous signaling cascades, most importantly, through the modulation of ion channels. Research demonstrates the role of OR mediated signal transduction in treating pain, cancer, neurodegenerative disorders and cardiac insults. Yet, the primary application of drugs that modulate ORs is analgesia. Current opioids like morphine that are mainly μOR orthosteric agonists attract many undesirable side-effects (constipation, urinary retention, respiratory depression and hypotension) and the existing modus operandi against these is the inclusion of a μOR antagonist (for example. naloxone) which itself produces side-effects. As such, there is a current thrust to delineate the anti-nociceptive pathways mediated by ORs from the pathways involved in their induction of debilitating side-effects, in order to develop enhanced lead molecules. This review discusses the effects of natural products on the OR-induced signaling cascades and compares these to current synthetic leads and drugs. Important to these discussions is the complexity of OR signaling which involves OR trafficking, de- and re-sensitization, homo- and hetero-dimerization, the type of ligand binding (agonist, antagonist, reverse antagonist, orthosteric and allosteric agonist and antagonist in the context of biased agonism) and reasons for dysregulation that primarily occur because of inter-individual variations. Our current understanding of the different forms of ORs has expanded, thus introducing the concept of allosterism, which is also discussed. The authors present possible combination therapies to be explored towards developing the 'Holy Grail' of analgesics, for example, ignavine, the natural μOR positive allosteric modulator (PAM) with codeine and the natural fascaplysin, a balanced agonist with fentanyl. There remain many gaps in natural products research on ORs, more so on ORL1 and δ- and ҡ receptors. Furthermore, additional exploration of ORs' modulation is needed for ameliorating other associated disease conditions of global concern.
Humans perceive physical information about the surrounding environment through their senses. This physical information is registered by a collection of highly evolved and finely tuned molecular sensory receptors. A multitude of bioactive, structurally diverse ligands have evolved in nature that bind these molecular receptors. The complex, dynamic interactions between the ligands and the receptors lead to changes in our sensory perception or mood. Here, we review our current knowledge of natural products and their derived analogues that interact specifically with human G protein-coupled receptors, ion channels, and nuclear hormone receptors to modulate the sensations of taste, smell, temperature, pain, and itch, as well as mood and its associated behaviour. We discuss the molecular and structural mechanisms underlying such interactions and highlight cases where subtle differences in natural product chemistry produce drastic changes in functional outcome. We also discuss cases where a single compound triggers complex sensory or behavioural changes in humans through multiple mechanistic targets. Finally, we comment on the therapeutic potential of the reviewed area of research and draw attention to recent technological developments in genomics, metabolomics, and metabolic engineering that allow us to tap the medicinal properties of natural product chemistry without taxing nature.
The organized tightly regulated signaling relays engaged by the cannabinoid receptors (CBs) and their ligands, G proteins and other effectors, together constitute the endocannabinoid system (ECS). This system governs many biological functions including cell proliferation, regulation of ion transport and neuronal messaging. This review will firstly examine the physiology of the ECS, briefly discussing some anomalies in the relay of the ECS signaling as these are consequently linked to maladies of global concern including neurological disorders, cardiovascular disease and cancer. While endogenous ligands are crucial for dispatching messages through the ECS, there are also commonalities in binding affinities with copious exogenous ligands, both natural and synthetic. Therefore, this review provides a comparative analysis of both types of exogenous ligands with emphasis on natural products given their putative safer efficacy and the role of Δ9-tetrahydrocannabinol (Δ9-THC) in uncovering the ECS. Efficacy is congruent to both types of compounds but noteworthy is the effect of a combination therapy to achieve efficacy without the unideal side-effects. An example is Sativex that displayed promise in treating Huntington's disease (HD) in preclinical models allowing for its transition to current clinical investigation. Despite the in vitro and preclinical efficacy of Δ9-THC to treat neurodegenerative ailments, its psychotropic effects limit its clinical applicability to treating feeding disorders. We therefore propose further investigation of other compounds and their combinations such as the triterpene, α,β-amyrin that exhibited greater binding affinity to CB1 than CB2 and was more potent than Δ9-THC and the N-alkylamides that exhibited CB2 selective affinity, the latter can be explored towards peripherally exclusive ECS modulation. The synthetic CB1 antagonist, Rimonabant was pulled from market for the treatment of diabetes, however its analogue SR144528 maybe an ideal lead molecule towards this end and HU-210 and Org27569 are also promising synthetic small molecules.
Marco ist 23 Jahre alt. Nach dem Abitur hat er ein Pädagogikstudium begonnen, das er durch einen Nebenjob in einem Zeitschriftenladen finanziert. Cannabis konsumiert er seit acht Jahren, zunächst nur auf Partys mit Freunden, dann aber zunehmend auch alleine daheim. Mittlerweile raucht er täglich mehrere Male, in der Regel beginnt er gleich nach dem Aufstehen damit den Tag. Häufig schläft er dann gleich wieder ein, sodass es ihm teilweise schwerfällt, Termine an der Uni einzuhalten. Auch auf der Arbeitsstelle gibt es Probleme. Aufgrund von Unpünktlichkeit wurde er mehrmals abgemahnt. Durch den Cannabiskonsum ist er sehr lethargisch geworden.
Rosuvastatin Calcium is a statin used extensively for the treatment of dyslipidemia,
hypercholesterolemia and hypertriglyceridemia. As reported statin induced the expression of
atrogin-1, a key gene involved in skeletal muscle atrophy [1] and hence Rosuvastatin can
possibly cause myopathy and rhabdomyolysis. In this process the function of mitochondria
play a vital role in limiting the atrophy. Epigallocatechin gallate promotes mitochondrial
biogenesis [2] and thereby prevents the atrophy caused by statin. Similarly, Epigallocatechin
gallate can also helps in reducing the LDL cholesterol. Both Rosuvastatin Calcium and
Epigallocatechin gallate have a poor bioavailability and it can be improved by the use of
nanoparticles. Nanoparticles were filled in hard gelatin capsules along with Microcrystalline
Cellulose, Colloidal Silicon Dioxide, Magnesium Trisilicate and Magnesium Stearate. The
ratio of Colloidal Silicon Dioxide, Magnesium Trisilicate and Magnesium Stearate was
studied using two level Factorial design. The final product is stable and provides a sustained
release for 24 hours. The combination proved to be promising with improved efficacy and
reduced side effects.
The therapeutic use of Cannabis dates back to ancient times and this plant has been used for centuries as remedy for a large number of diseases. Today it is well known that biological activity of Cannabis is related to the endocannabinoid system (ECS), a complex signaling network that comprises classical cannabinoid receptors (CB1 and CB2), arachidonic acid-derived ligands, and enzymes degrading the endocannabinoids anandamide and 2-arachidonoyl glycerol, namely fatty acid amide hydrolase and monoacylglycerol lipase. The modulation of the ECS activity turned out to be a therapeutic promise in a wide range of diseases. A problem to the development of Cannabis and cannabinoid medications is the psychoactive property of natural or synthetic agonists, mediated by CB1 receptor. This review deals with the literature analysis of the important biological activities of Cannabis and the efforts aimed to the discovery of natural and nonnatural selective cannabinoids.
Epigallocatechin gallate is a type of catechin has many therapeutic advantages, but its scope is limited due to its poor bioavailability. Most of the ingested Epigallocatechin gallate apparently does not get into the blood, since absorption takes place in the small gut and substantial quantities pass from the small intestine to the large intestine, where it undergoes further degradation by the action of local microbiota [1-4]. Chitosan, a polymer of linear polysaccharide, enhances transport of drug across epithelial surfaces and is biocompatible and biodegradable. The aim of this study is to formulate and characterize Epigallocatechin gallate loaded Chitosan nanoparticles prepared by ionic-gelation method. This increases the abosorption and bioavailaility of Epigallocatechin gallate. The resulting nanoparticles tend to aggregate in biological fluid which can be minimized by addition of poloxamer 188. The nanoparticles obtained were evaluated for percentage yield of drug, drug entrapment efficiency, particle size and morphology using scanning electron microscopy (SEM), compatibility studies using Fourier-Transform infrared spectroscopy (FTIR) and Differential scanning calorimetry (DSC) and in vitro release kinetics. Among the four different ratios of drug to polymer, 1:0.5 ratio showed high drug loading and encapsulation efficiency. The resulting nanoparticles were spherical in shape with a smooth surface. The particle size range was 197.84 ± 21.45 nm to 385.45 ± 15.87 nm. The prepared nanoparticles proved to be promising dosage form of Epigallocatechin gallate, with improved bioavailability. Please cite this article in press as Ramkumar Ponnuraj et al. Formulation And Characterization of Epigallocatechin Gallate Nanoparticles. Indo American Journal of Pharm Research.2015:5(01).
Over a decade of intense research in the field of obesity has led to the knowledge that chronic, excessive adipose tissue expansion leads to an increase in the risk for CVD, type 2 diabetes mellitus and cancer. This is primarily thought to stem from the low-grade, systemic inflammatory response syndrome that characterises adipose tissue in obesity, and this itself is thought to arise from the complex interplay of factors including metabolic endotoxaemia, increased plasma NEFA, hypertrophic adipocytes and localised hypoxia. Plasma concentrations of vitamins and antioxidants are lower in obese individuals than in the non-obese, which is hypothesised to negatively affect the development of inflammation and disease in obesity. This paper provides a review of the current literature investigating the potential of nutraceuticals to ameliorate the development of oxidative stress and inflammation in obesity, thereby limiting the onset of obesity complications. Research has found nutraceuticals able to positively modulate the activity of adipocyte cell lines and further positive effects have been found in other aspects of pathogenic obesity. While their ability to affect weight loss is still controversial, it is clear that they have a great potential to reverse the development of overweight and obesity-related comorbidities; this, however, still requires much research especially that utilising well-structured randomised controlled trials.
Obesity and cardiometabolic risk continue to be major public health concerns. A better understanding of the physiopathological mechanisms leading to obesity may help to identify novel therapeutic targets. The endocannabinoid system discovered in the early 1990s is believed to influence body weight regulation and cardiometabolic risk factors. This article aims to review the literature on the endocannabinoid system including the biological roles of its major components, namely, the cannabinoid receptors, their endogenous ligands the endocannabinoids and the ligand-metabolising enzymes. The review also discusses evidence that the endocannabinoid system constitutes a new physiological pathway occurring in the central nervous system and peripheral tissues that has a key role in the control of food intake and energy expenditure, insulin sensitivity, as well as glucose and lipid metabolism. Based on the important finding that there is a close association between obesity and the hyperactivity of the endocannabinoid system, interest in blocking stimulation of this pathway to aid weight loss and reduce cardiometabolic risk factor development has become an important area of research. Among the pharmacological strategies proposed, the antagonism of the cannabinoid receptors has been particularly investigated and several clinical trials have been conducted. One challenging pharmacological task will be to target the endocannabinoid system in a more selective, and hence, safe way. As the management of obesity also requires lifestyle modifications in terms of healthy eating and physical activity, the targeting of the endocannabinoid system may represent a novel approach for a multifactorial therapeutic strategy.
Although considerable experimental and animal evidence shows that green tea may possess potent activities of neuroprotection, neurorescue, and amyloid precursor protein processing that may lead to cognitive enhancement, no human data are available.
The objective was to examine the association between green tea consumption and cognitive function in humans.
We analyzed cross-sectional data from a community-based Comprehensive Geriatric Assessment (CGA) conducted in 2002. The subjects were 1003 Japanese subjects aged > or =70 y. They completed a self-administered questionnaire that included questions about the frequency of green tea consumption. We evaluated cognitive function by using the Mini-Mental State Examination with cutoffs of <28, <26, and <24 and calculated multivariate-adjusted odds ratios (ORs) of cognitive impairment.
Higher consumption of green tea was associated with a lower prevalence of cognitive impairment. At the <26 cutoff, after adjustment for potential confounders, the ORs for the cognitive impairment associated with different frequencies of green tea consumption were 1.00 (reference) for < or =3 cups/wk, 0.62 (95% CI: 0.33, 1.19) for 4-6 cups/wk or 1 cup/d, and 0.46 (95% CI: 0.30, 0.72) for > or =2 cups/d (P for trend = 0.0006). Corresponding ORs were 1.00 (reference), 0.60 (95% CI: 0.35, 1.02), and 0.87 (95% CI: 0.55, 1.38) (P for trend = 0.33) for black or oolong tea and 1.00 (reference), 1.16 (95% CI: 0.78, 1.73), and 1.03 (95% CI: 0.59, 1.80) (P for trend = 0.70) for coffee. The results were essentially the same at cutoffs of <28 and <24.
A higher consumption of green tea is associated with a lower prevalence of cognitive impairment in humans.
Osteoporosis is a major health problem in postmenopausal women. Evidence suggests the importance of oxidative stress in bone metabolism and bone loss. Tea consumption may be beneficial to osteoporosis due to its antioxidant capability. However, lack of objective data characterizing tea consumption has hindered the precise evaluation of the association between tea ingestion and bone mineral density in previous questionnaire-based epidemiological studies. On the other hand, although published studies suggest that Tai Chi (TC) exercise can benefit bone health and may reduce oxidative stress, all studies were conducted using a relatively healthy older population, instead of a high-risk one such as osteopenic postmenopausal women. Therefore, this study was designed to test an intervention including green tea polyphenol (GTP) and TC exercise for feasibility, and to quantitatively assess their individual and interactive effects on postmenopausal women with osteopenia.
One hundred and forty postmenopausal women with osteopenia (defined as bone mineral density T-score at the spine and/or hip between 1 to 2.5 SD below the reference database) were randomly assigned to 4 treatment arms: (1) placebo group receiving 500 mg medicinal starch daily, (2) GTP group receiving 500 mg of GTP per day, (3) placebo+TC group receiving both placebo treatment and TC training (60-minute group exercise, 3 times per week), and (4) GTP+TC group receiving both GTP and TC training for 24 weeks. The outcome measures were bone formation biomarker (serum bone alkaline phosphatase), bone resorption biomarker (serum tartrate resistant acid phosphatase), and oxidative DNA damage biomarker (urinary 8-hydroxy-2'-deoxyguanosine). All outcome measures were determined at baseline, 4, 12, and 24 weeks. Urinary and serum GTP concentrations were also determined at baseline, 4, 12, and 24 weeks for bioavailability. Liver function was monitored monthly for safety. A model of repeated measurements with random effect error terms was applied. Traditional procedures such as ANCOVA, chi-squared analysis, and regression were used for comparisons.
We present the rationale, design, and methodology of a placebo-controlled randomized trial to investigate a new complementary and alternative medicine strategy featuring a dietary supplement and a mind-body exercise for alleviating bone loss in osteopenic postmenopausal women.
Proteomic studies on anticancer activity of Green Tea Catechins (specifically EGCG) are suggesting a large set of protein targets that may directly interact with EGCG and alter the physiology of diseased cells, including cancer. Of notice, benign cells are usually left untouched. Lipid rafts have been recently recognized as signal processing hubs and suggested to be involved in drug uptake by means of endocytosis. These findings are suggesting new insights on the molecular mechanisms of anticancer drugs action. In the membrane, EGCG is hijacked by the laminin receptor (LamR), a lipid raft protein. Similar to aplidin and edelfosin, EGCG alters membrane domains composition also preventing EGF binding to EGFR, imerization of EGFR and relocation of phosphorylated EGFR to lipid rafts. In vitro studies have recently shown that EGCG also binds both DNA and RNA in GpC-rich regions. This event may importantly affect genes function. Moreover, EGCG was shown to inhibit telomerase, topoisomerase II and DNA methyltransferase 1 (DNMT1), thus ultimately affecting chromatin maintenance and remodeling. But another important alternative pathway besides interaction with specific proteins may play an important role in EGCG action: direct targeting of bioactive membrane platforms, lipid rafts. Structural alteration of the platforms deeply impact (and often inactivates) important pathways involving MAP kinases. The key issue is that, important and specific differences in lipid rafts composition have been found in transformed versus benign cells and apoptotic versus non-apoptotic cells. We suggest here that the anticancer activity of Green Tea Catechins against different kind of cancers may find an explanation in direct targeting of lipid rafts by EGCG.
'Benifuuki', a tea (Camellia Sinensis L.) cultivar in Japan, is rich in anti-allergic epigallocatechin-3-O-(3-O-methyl) gallate (EGCG3''Me). 'Benifuuki' green tea and simultaneous addition of ginger extract remarkably suppressed cytokine (TNF-alpha and MIP-1alpha) secretion from mouse bone marrow-derived mast cells after antigen stimulation and, as expected, suppressed delay-type allergy. After drinking 'benifuuki' green tea containing 43.5 mg of EGCG and 8.5 mg of EGCG3''Me, the AUC (area under the drug concentration time curve; min mug/ml) of EGCG was 6.72 +/- 2.87 and EGCG3''Me was 8.48 +/- 2.54 in healthy human volunteers. Though the dose of EGCG was 5.1 times the dose of EGCG3''Me, the AUC of EGCG3''Me was higher than that of EGCG. A double blind clinical study on subjects with Japanese cedar pollinosis was carried out. At the 11th week after starting the study, in the most severe cedar pollen scattering period, symptoms, i.e., blowing the nose and itching eyes, were significantly relieved in the 'benifuuki' intake group compared with the placebo group, and blowing the nose, itching eyes and nasal symptom score, and at the 11th and 13th weeks, stuffy nose, throat pain and the nasal symptom medication score were significantly relieved in the 'benifuuki' containing ginger extract group compared with the placebo group. These results suggested that over one consecutive month, drinking 'benifuuki' green tea was useful to reduce some of the symptoms from Japanese cedar pollinosis, and did not affect any normal immune response in subjects with seasonal rhinitis, and the ginger extract enhanced the effect of 'benifuuki' green tea.
Endocannabinoids act as retrograde messengers that, by inhibiting neurotransmitter release via presynaptic CB(1) cannabinoid receptors, regulate the functionality of many synapses. In addition, the endocannabinoid system participates in the control of neuron survival. Thus, CB(1) receptor activation has been shown to protect neurons from acute brain injury as well as in neuroinflammatory conditions and neurodegenerative diseases. Nonetheless, some studies have reported that cannabinoids can also exert neurotoxic actions. Cannabinoid neuroprotective activity relies on the inhibition of glutamatergic neurotransmission and on other various mechanisms, and is supported by the observation that the brain overproduces endocannabinoids upon damage. Coupling of neuronal CB(1) receptors to cell survival routes such as the phosphatidylinositol 3-kinase/Akt and extracellular signal-regulated kinase pathways may contribute to cannabinoid neuroprotective action. These pro-survival signals occur, at least in part, by the cross-talk between CB(1) receptors and growth factor tyrosine kinase receptors. Besides promoting neuroprotection, a role for the endocannabinoid system in the control of neurogenesis from neural progenitors has been put forward. In addition, activation of CB(2) cannabinoid receptors on glial cells may also participate in neuroprotection by limiting the extent of neuroinflammation. Altogether, these findings support that endocannabinoids constitute a new family of lipid mediators that act as instructive signals in the control of neuron survival.
In this study, we investigated the effects of the major green tea polyphenol, (-)-epigallocatechin-3-gallate (EGCG), on high-fat-induced obesity, symptoms of the metabolic syndrome, and fatty liver in mice. In mice fed a high-fat diet (60% energy as fat), supplementation with dietary EGCG treatment (3.2 g/kg diet) for 16 wk reduced body weight (BW) gain, percent body fat, and visceral fat weight (P < 0.05) compared with mice without EGCG treatment. The BW decrease was associated with increased fecal lipids in the high-fat-fed groups (r(2) = 0.521; P < 0.05). EGCG treatment attenuated insulin resistance, plasma cholesterol, and monocyte chemoattractant protein concentrations in high-fat-fed mice (P < 0.05). EGCG treatment also decreased liver weight, liver triglycerides, and plasma alanine aminotransferase concentrations in high-fat-fed mice (P < 0.05). Histological analyses of liver samples revealed decreased lipid accumulation in hepatocytes in mice treated with EGCG compared with high-fat diet-fed mice without EGCG treatment. In another experiment, 3-mo-old high-fat-induced obese mice receiving short-term EGCG treatment (3.2 g/kg diet, 4 wk) had decreased mesenteric fat weight and blood glucose compared with high-fat-fed control mice (P < 0.05). Our results indicate that long-term EGCG treatment attenuated the development of obesity, symptoms associated with the metabolic syndrome, and fatty liver. Short-term EGCG treatment appeared to reverse preexisting high-fat-induced metabolic pathologies in obese mice. These effects may be mediated by decreased lipid absorption, decreased inflammation, and other mechanisms.
Marijuana and many of its constituent cannabinoids influence the central nervous system (CNS) in a complex and dose-dependent manner. Although CNS depression and analgesia are well documented effects of the cannabinoids, the mechanisms responsible for these and other cannabinoid-induced effects are not so far known. The hydrophobic nature of these substances has suggested that cannabinoids resemble anaesthetic agents in their action, that is, they nonspecifically disrupt cellular membranes. Recent evidence, however, has supported a mechanism involving a G protein-coupled receptor found in brain and neural cell lines, and which inhibits adenylate cyclase activity in a dose-dependent, stereoselective and pertussis toxin-sensitive manner. Also, the receptor is more responsive to psychoactive cannabinoids than to non-psychoactive cannabinoids. Here we report the cloning and expression of a complementary DNA that encodes a G protein-coupled receptor with all of these properties. Its messenger RNA is found in cell lines and regions of the brain that have cannabinoid receptors. These findings suggest that this protein is involved in cannabinoid-induced CNS effects (including alterations in mood and cognition) experienced by users of marijuana.
The major active ingredient of marijuana, delta 9-tetrahydrocannabinol (delta 9-THC), has been used as a psychoactive agent for thousands of years. Marijuana, and delta 9-THC, also exert a wide range of other effects including analgesia, anti-inflammation, immunosuppression, anticonvulsion, alleviation of intraocular pressure in glaucoma, and attenuation of vomiting. The clinical application of cannabinoids has, however, been limited by their psychoactive effects, and this has led to interest in the biochemical bases of their action. Progress stemmed initially from the synthesis of potent derivatives of delta 9-THC, and more recently from the cloning of a gene encoding a G-protein-coupled receptor for cannabinoids. This receptor is expressed in the brain but not in the periphery, except for a low level in testes. It has been proposed that the nonpsychoactive effects of cannabinoids are either mediated centrally or through direct interaction with other, non-receptor proteins. Here we report the cloning of a receptor for cannabinoids that is not expressed in the brain but rather in macrophages in the marginal zone of spleen.
To study the intake of catechins in the Dutch population and to assess the relation between catechin intake and other dietary factors. Catechins, dietary components that belong to the flavonoid family, potentially protect against chronic diseases such as cancer and cardiovascular diseases. Catechins are the major components of tea, but they are present in many other plant foods as well.
Data were used from a nationwide dietary survey carried out in 1998 among a representative sample of 6200 Dutch men and women aged 1-97y. Dietary data were collected using a 2 day dietary record method.
The average daily catechin intake was 50 mg (s.d. 56 mg/day). Catechin intake increased with age, and the intake was higher in women (60 mg/day) than in men (40 mg/day). Tea was the main catechin source in all age groups, whereas chocolate was second in children, and apples and pears were second in adults and elderly. Catechin intake was lower in smokers than in non-smokers, and increased with socio-economic status. A high intake was associated with a high intake of fiber (r = 0.20), vitamin C (r = 0.17) and beta-carotene (r = 0.10).
Catechins are quantitatively important bioactive components of the daily diet, which should be taken into account when studying the relation between diet and chronic diseases. Catechin intake is only moderately associated with the intake of other nutrients, but much stronger with certain health behaviours such as smoking.
Tea consumption has been associated with reduced risk of both cancer and cardiovascular disease in population studies, but clinical data demonstrating bioavailability of the individual catechins and other polyphenolic components of tea are limited. This study assessed the apparent bioavailability of the prominent catechins from black tea in humans drinking tea throughout the day. After 5 d of consuming a low flavonoid diet, subjects drank a black tea preparation containing 15.48, 36.54, 16.74, and 31.14 mg of (-)-epigallocatechin (EGC), (-)-epicatechin (EC), (-)-epigallocatechin gallate (EGCG) and (-)-epicatechin gallate (ECG), respectively, at four time points (0, 2, 4 and 6 h). Blood, urine and fecal specimens were collected over a 24- to 72-h period and catechins were quantified by HPLC with coularray detection. Plasma concentrations of EGC, EC and EGCG increased significantly relative to baseline (P < 0.05). Plasma EGC, EC and EGCG peaked after 5 h, whereas ECG peaked at 24 h. Urinary excretion of EGC and EC, which peaked at 5 h, was increased relative to baseline amounts (P < 0.05) and fecal excretion of all four catechins was increased relative to baseline (P < 0.05). Approximately 1.68% of ingested catechins were present in the plasma, urine and feces, and the apparent bioavailability of the gallated catechins was lower than the nongallated forms. Thus, catechins were bioavailable. However, unless they are rapidly metabolized or sequestered, the catechins appeared to be absorbed in amounts that were small relative to intake.
Several G protein-coupled receptors function within lipid rafts plasma membrane microdomains, which may be important in limiting
signal transduction. Here we show that treatment of rat C6 glioma cells with the raft disruptor methyl-β-cyclodextrin (MCD)
doubles the binding efficiency (i.e. the ratio between maximum binding and dissociation constant) of type-1 cannabinoid receptors (CB1R), which belong to the
rhodopsin family of G protein-coupled receptors. In parallel, activation of CB1R by the endogenous agonist anandamide (AEA)
leads to ∼3-fold higher [35S]GTPγS binding in MCD-treated cells than in controls, and CB1R-dependent signaling via adenylate cyclase, and p42/p44 MAPK
is almost doubled by MCD. Unlike CB1R, the other AEA-binding receptor TRPV1, the AEA synthetase NAPE-PLD, and the AEA hydrolase
FAAH are not modulated by MCD, whereas the activity of the AEA membrane transporter (AMT) is reduced to ∼50% of the controls.
We also show that MCD reduces dose-dependently AEA-induced apoptosis in C6 cells but not in human CHP100 neuroblastoma cells,
which mirror the endocannabinoid system of C6 cells but are devoid of CB1R. MCD reduces also cytochrome c release from mitochondria of C6 cells, and this effect is CB1R-dependent and partly mediated by activation of p42/p44 MAPK.
Altogether, the present data suggest that lipid rafts control CB1R binding and signaling, and that CB1R activation underlies
the protective effect of MCD against apoptosis.
Tea catechins, (-)-epicatechin (EC), (-)-epigallocatechin (EGC), (-)-epicatechin gallate (ECG), and (-)-epigallocatechin gallate (EGCG), have been shown to be epimerized to (-)-catechin (C), (-)-gallocatechin (GC), (-)-catechin gallate (CG), and (-)-gallocatechin gallate (GCG), respectively, during heat treatment. In this study, we examined the effect of tea catechins rich in ECG and EGCG and heat-treated tea catechins rich in CG and GCG on postprandial hypertriacylglycerolemia in rats. Both tea catechins and heat-treated tea catechins suppressed postprandial hypertriacylglycerolemia. Lymphatic recovery of (14)C-trioleoylglycerol in rats cannulated in the thoracic duct was delayed by the administration of tea catechins and heat-treated tea catechins. Tea catechins and heat-treated tea catechins had the same effect on all variables tested. These catechin preparations dose-dependently inhibited the activity of pancreatic lipase in vitro. When purified catechins were used, only those with a galloyl moiety inhibited the activity of pancreatic lipase. These results suggest that catechins with a galloyl moiety suppress postprandial hypertriacylglycerolemia by slowing down triacylglycerol absorption through the inhibition of pancreatic lipase. Because postprandial hypertriacylglycerolemia is a risk factor for coronary heart disease, our results suggest that catechins with a galloyl moiety may prevent this disease.
The chemical composition of the chromatography 63 subfraction (63SF) from the ethyl acetate soluble fraction of the crude extract of Croton celtidifolius bark presented a high content of total proanthocyanidins (75.0+/-2.3%). HPLC analysis of 63SF revealed a dimeric profile (e.g.catechin-(4alpha-->8)-catechin and gallocatechin-(4alpha-->8)-catechin) and polymeric proanthocyanidins. In pharmacological investigations, 63SF administered intraperitoneally exhibited dose-dependent antinociceptive activity against several chemical stimuli, including the intraperitoneal injection of acetic acid (ID50 (the dose of 63SF which was able to reduce the nociceptive response by 50% relative to the control value)=0.9 (0.5-1.6)) and the intraplantar injection of capsaicin (ID50=13.0 (10.0-17.0)), glutamate (ID50=4.0 (2.0-7.0)) and formalin (ID50 first phase=36.0 (24.0-53.0) and late phase=11.0 (8.0-14.0)). 63SF administered orally exhibited an antinociceptive effect in the formalin test (ID50 first phase=125.0 (89.0-177.0) and late phase=65.0 (33.0-95.0)). In the same test, 63SF was effective when given soon after the first phase, as well as exhibiting therapeutic activity. Furthermore, 63SF was effective in models of thermal nociception including tail-flick and hot-plate tests. When the mice were treated in the neonatal period with capsaicin, the antinociceptive effect of 63SF in the first phase of the formalin test was abolished, but pretreatment with naltrexone did not change the antinociceptive effect of 63SF. Together, these results provide evidence that 63SF exerted a pronounced systemic antinociception against chemical (acetic acid, formalin, glutamate and capsaicin tests) and thermal (hot-plate and tail-flick tests) nociceptive models of pain in mice at a dose that did not interfere with the locomotor activity. The mechanism by which this sub-fraction produced antinociception remains unclear, but it is unlikely to involve the activation of the opioid system. However, unmyelinated C-fibres sensitive to treatment with capsaicin are likely to participate in antinociception caused by 63SF.
Obesity is a metabolic disorder resulting from imbalance between metabolizable energy intake and energy expenditure. It is known to be a strong risk factor for lifestyle-related diseases. Here, we investigated the effects of long-term intake of tea catechins (Cat) in combination with regular exercise (Ex) on the development of obesity in C57BL/6 mice.
We compared body weight, adipose tissue mass, plasma parameters and beta-oxidation activity in mice fed a low-fat diet (5% triglyceride (TG); LF), a high-fat diet (30% TG; HF), a HF diet supplemented with 0.5% (w/w) tea Cat, a HF diet in addition to swimming Ex or a HF diet plus 0.5% tea Cat in addition to swimming Ex (Cat+Ex) for 15 weeks. Oxygen consumption and respiratory quotients were measured using indirect calorimetry.
Tea-Cat intake in combination with swimming Ex suppressed HF diet-induced body-weight gain by 18 and 22%, respectively, compared to Ex and tea-Cat intake on their own. Visceral fat accumulation and the development of hyperinsulinemia and hyperleptinemia were also reduced in the HF+Cat+Ex group. Muscular beta-oxidation activity in this group was 69 and 52% higher, respectively, than that in the HF and HF+Cat groups. Lipid oxidation, determined using indirect calorimetry, was higher in the HF+Cat+Ex group, suggesting increased lipid utilization at the individual level.
These results indicate that intake of tea Cat, together with regular Ex helps to reduce diet-induced obesity. This effect might be attributed, at least in part, to the activation of whole-body energy metabolism.
We assessed the effect of ingestion of green tea (GT) extract along with a low-energy diet (LED) on resting energy expenditure (REE), substrate oxidation and body weight as GT has been shown to increase energy expenditure and fat oxidation in the short term in both animals and people. Forty-six overweight women (BMI 27 center dot 6 (sd 1 center dot 8) kg/m(2)) were fed in energy balance from day 1 to day 3, followed by a LED with GT (1125 mg tea catechins +225 mg caffeine/d) or placebo (PLAC) from day 4 to day 87. Caffeine intake was standardised to 300 mg/d. Energy expenditure was measured on days 4 and 32. Reductions in weight (4 center dot 19 (sd 2 center dot 0) kg PLAC, 4 center dot 21 (sd 2 center dot 7) kg GT), BMI, waist:hip ratio, fat mass and fat-free mass were not statistically different between treatments. REE as a function of fat-free mass and fat mass was significantly reduced over 32 d in the PLAC group (P < 0 center dot 05) but not in the GT group. Dietary restraint increased over time (P < 0 center dot 001) in both groups, whereas disinhibition and general hunger decreased (P < 0 center dot 05). The GT group became more hungry over time and less thirsty, and showed increased prospective food consumption compared with PLAC (P < 0 center dot 05). Taken together, the ingestion of GT along with a LED had no additional benefit for any measures of body weight or body composition. Although the decrease in REE as a function of fat-free mass and fat mass was not significant with GT treatment, whereas it was with PLAC treatment, no significant effect of treatment over time was seen, suggesting that a robust limitation of REE reduction during a LED was not achieved by GT.
Background: Epidemiological studies suggested that consumption of fruit and vegetables may protect against stroke. The hypothesis that dietary antioxidant vitamins and flavonoids account for this observation is investigated in a prospective study. Methods: A cohort of 552 men aged 50 to 69 years was examined in 1970 and followed up for 15 years. Mean nutrient and food intake was calculated from crosscheck dietary histories taken in 1960, 1965, and 1970. The association between antioxidants, selected foods, and stroke incidence was assessed by Cox proportional hazards regression analysis. Adjustment was made for confounding by age, systolic blood pressure, serum cholesterol, cigarette smoking, energy intake, and consumption of fish and alcohol. Results: Forty-two cases of first fatal or nonfatal stroke were documented Dietary flavonoids (mainly quercetin) were inversely associated with stroke incidence after adjustment for potential confounders, including antioxidant vitamins. The relative risk (RR) of the highest vs the lowest quartile of flavonoid intake (greater than or equal to 28.6 mg/d vs <18.3 mg/d) was 0.27 (95% confidence interval [CI], 0.11 to 0.70). A lower stroke risk was also observed for the highest quartile of beta-carotene intake (RR, 0.54; 95% CI, 0.22 to 1.33). The intake of vitamin C and vitamin E was not associated with stroke risk. Black tea contributed about 70% to flavonoid intake. The RR for a daily consumption of 4.7 cups or more of tea vs less than 2.6 cups of tea was 0.31 (95% CI, 0.12 to 0.84). Conclusions: The habitual intake of flavonoids and their major source (tea) may protect against stroke.
(-)-Epigallocatechin gallate (EGCG) has a sedative effect acting through γ-aminobutyric acid (GABA)A receptors in the brain, but it is unclear what structural components of the molecule are necessary for its action. To investigate the necessity of the galloyl group on the sedation induced by EGCG, the effect of EGCG was compared with (-)-epigallocatechin (EGC) in which the galloyl group is removed from EGCG. Intracerebroventricular (i.c.v.) injection of EGC, as well as EGCG, induced, and the effect of EGC were blocked by the GABAA receptor antagonist picrotoxin. It is concluded that catechins have a sedative effect acting through GABAA receptors under an acute stress condition irrespective of the presence of the galloyl group.
A theoretical analysis has been made of the relationship between the inhibition constant (KI) of a substance and the (I50) value which expresses the concentration of inhibitor required to produce 50 per cent inhibition of an enzymic reaction at a specific substrate concentration. A comparison has been made of the relationships between KI and I50 for monosubstrate reactions when noncompetitive or uncompetitive inhibition kinetics apply, as well as for bisubstrate reactions under conditions of competitive, noncompetitive and uncompetitive inhibition kinetics. Precautions have been indicated against the indiscriminate use of I50 values in agreement with the admonitions previously described in the literature. The analysis described shows KI does not equal I50 when competitive inhibition kinetics apply; however, KI is equal to I50 under conditions of either noncompetitive or uncompetitive kinetics.
Green tea and black tea (BT) contain gallated [(-)-epigallocatechin-3-gallate (EGCG), (-)-epicatechin-3-gallate] and nongallated [(-)-epicatechin, (-)-epigallocatechin (EGC)] tea polyphenols (PP). During BT production, PP undergo oxidation and form larger polymers such as theaflavins (THE) and thearubigins, which contribute to the health benefit of BT. This article gives an overview of the role of chemical characteristics and endogenous metabolism of tea PP and their bioavailability in humans and describes attempts to increase their bioavailability. At pH close to neutral, EGCG and EGC form homo- and heterodimers generating hydrogen peroxide. To confirm the pH instability of EGCG, EGC, and THE in cell culture medium, their antiproliferative activity was determined in the presence and absence of catalase. The antiproliferative activity in LNCaP prostate cancer cells was decreased when incubated with catalase prior to EGCG, EGC, and THE treatment. In addition, new findings demonstrated that the formation of methyl-EGC increased the stability at neutral pH compared with EGC. Approaches to increase the bioavailability of flavan-3-ols are reviewed, which include the administration of tea in combination with fruit juices, coadministration with piperine, and peracetylation of EGCG. Future intervention studies will need to focus on the bioactivity not only of green tea and BT PP but also of their metabolites and biotransformation products.
The role played by the endocannabinoid system in the regulation of energy balance is currently generating a great amount of interest among several groups of investigators. This interest in large part comes from the urgent need to develop anti-obesity and anti-cachexia drugs around target systems (such as the endocannabinoid system), which appears to be genuinely involved in energy balance regulation. When activated, the endocannabinoid system favors energy deposition through increasing energy intake and reducing energy expenditure. This system is activated in obesity and following food deprivation, which further supports its authentic function in energy balance regulation. The cannabinoid receptor type 1 (CB1), one of the two identified cannabinoid receptors, is expressed in energy-balance brain structures that are also able to readily produce or inactivate N-arachidonoyl ethanolamine (anandamide) and 2-arachidonoylglycerol (2AG), the most abundantly formed and released endocannabinoids. The brain action of endocannabinoid system on energy balance seems crucial and needs to be delineated in the context of the homeostatic and hedonic controls of food intake and energy expenditure. These controls require the coordinated interaction of the hypothalamus, brainstem and limbic system and it appears imperative to unravel those interplays. It is also critical to investigate the metabolic endocannabinoid system while considering the panoply of functions that the endocannabinoid system fulfills in the brain and other tissues. This article aims at reviewing the potential mechanisms whereby the brain endocannabinoid system influences the regulation energy balance.
Various studies have reported on the neuroprotective effects of polyphenols, widely present in food, beverages, and natural products. For example, we have shown that resveratrol, a polyphenol enriched in red wine and other foods such as peanuts, protects hippocampal cells against beta-amyloid (Abeta)-induced toxicity, a key protein involved in the neuropathology of Alzheimer disease. This effect involves, at least in part, the capacity of resveratrol to activate the phosphorylation of delta isoform of protein kinase C (PKC-delta). The neuroprotective action of resveratrol is shared by piceatannol, a stilbene derivative, as well as by tea-derived catechin gallate esters. The thioflavin T assay indicated that all these polyphenols inhibited the formation of Abeta fibrils, suggesting that this action likely also contributes to their neuroprotective effects. Binding and autoradiographic studies revealed that the effects of polyphenols might involve specific binding sites that are particularly enriched in the choroid plexus in the rat brain. Interestingly, the choroid plexus secretes transthyretin, a protein that has been shown to modulate Abeta aggregation and that may be critical to the maintenance of normal learning capacities in aging. Taken together, these data suggest that polyphenols target multiple enzymes/proteins, leading to their neuroprotective actions, possibly through action via specific plasma membrane binding sites.
Green tea (epigallocatechin gallate + caffeine) and protein each were shown to improve body weight maintenance after weight loss.
We investigated the effect of a green tea-caffeine mixture added to a high-protein (HP) diet on weight maintenance (WM) after body weight loss in moderately obese subjects.
A randomized, placebo-controlled, double-blind parallel trial was conducted in 80 overweight and moderately obese subjects [age (mean +/- SD): 44 +/- 2 y; body mass index (BMI; in kg/m(2)): 29.6 +/- 2.0] matched for sex, age, BMI, height, body mass, and with a habitually low caffeine intake. A very-low-energy diet intervention during 4 wk was followed by 3 mo of WM; during the WM period, the subjects received a green tea-caffeine mixture (270 mg epigallocatechin gallate + 150 mg caffeine/d) or placebo, both in addition to an adequate protein (AP) diet (50-60 g protein/d) or an HP diet (100-120 g protein/d).
Subjects lost 7.0 +/- 1.6 kg, or 8.2 +/- 2.0%, body weight (P < 0.001). During the WM phase, WM, resting energy expenditure, and fat-free mass (FFM) increased relatively in both the HP groups and in the AP + green tea-caffeine mixture group (P < 0.05), whereas respiratory quotient and body fat mass decreased, all compared with the AP + placebo group. Satiety increased only in both HP groups (P < 0.05). The green tea-caffeine mixture was only effective with the AP diet.
The green tea-caffeine mixture, as well as the HP diet, improved WM independently through thermogenesis, fat oxidation, sparing FFM, and, for the HP diet, satiety; a possible synergistic effect failed to appear.
Epigallocatechin gallate (EGCG) is a major green tea polyphenol with pronounced antioxidative activity. The effects of EGCG on lifespan and stress resistance in wild-type N2 and transgenic strains of Caenorhabditis elegans [ HSP-16.2/GFP, MEV-1(KN1), FEM-1(HC17)] were investigated. The expression of HSP-16.2 (induced by the pro-oxidant juglone) and the intracellular levels of H (2)O (2) were inhibited by EGCG treatment. Daily administration of 220 muM EGCG increased the mean lifespan by 10.14 % and 14.27 % in N2 and FEM-1(HC17) strains, respectively, and 55 muM EGCG increased the mean lifespan in MEV-1(KN1) by 16.11 %. The survival rate was also increased under lethal oxidative stress by 65.05 %. These findings suggest that the increased mean lifespan and stress resistance in C. ELEGANS apparently depend, among other factors, on the antioxidant properties of EGCG.
We investigated the effects of continuous ingestion of a catechin-rich beverage in patients with type 2 diabetes who were not receiving insulin (Ins) therapy in a double-blind controlled study. The participants ingested green tea containing either 582.8 mg of catechins (catechin group; n = 23) or 96.3 mg of catechins (control group; n = 20) per day for 12 weeks. At week 12, the decrease in waist circumference was significantly greater in the catechin group than in the control group. Adiponectin, which is negatively correlated with visceral adiposity, increased significantly only in the catechin group. Although the increase in Ins at week 12 was significantly greater in the catechin group than in the control group, no apparent difference was noted between the two groups in glucose and hemoglobin A(1c). In patients treated with insulinotropic agents, the increase in Ins at week 12 was significantly greater in the catechin group than in the control group. This significant increase in Ins levels was observed only in the catechin group. In the catechin group receiving other treatments, Ins levels remained unchanged. In addition, in patients treated with insulinotropic agents, the decrease in hemoglobin A(1c) at week 12 was significantly greater in the catechin group than in the control group. These results suggest that a catechin-rich beverage might have several therapeutic uses: in the prevention of obesity; in the recovery of Ins-secretory ability; and, as a way to maintain low hemoglobin A(1c) levels in type 2 diabetic patients who do not yet require Ins therapy.
Ten healthy human subjects consumed 500 mL of Choladi green tea, containing 648 mumol of flavan-3-ols after which plasma and urine were collected over a 24 h period and analysed by HPLC-MS. Plasma contained a total of ten metabolites, in the form of O-methylated, sulphated and glucuronide conjugates of (epi)catechin and (epi)gallocatechin, with 29-126 nM peak plasma concentrations (C(max)) occurring 1.6-2.3 h after ingestion, indicative of absorption in the small intestine. Plasma also contained unmetabolised (-)-epigallocatechin-3-gallate and (-)-epicatechin-3-gallate with respective C(max) values of 55 and 25 nM. Urine excreted 0-24 h after consumption of green tea contained 15 metabolites of (epi)catechin and (epi)gallocatechin, but (-)-epigallocatechin-3-gallate and (-)-epicatechin-3-gallate were not detected. Overall flavan-3-ol metabolite excretion was equivalent to 8.1% of intake, however, urinary (epi)gallocatechin metabolites corresponded to 11.4% of (epi)gallocatechin ingestion while (epi)catechin metabolites were detected in amounts equivalent to 28.5% of (epi)catechin intake. These findings imply that (epi)catechins are highly bioavailable, being absorbed and excreted to a much greater extent than most other flavonoids. It is also evident that flavan-3-ol metabolites are rapidly turned over in the circulatory system and as a consequence C(max) values are not an accurate quantitative indicator of the extent to which absorption occurs.
and purpose Green tea consumption is inversely associated with death from stroke. The purpose of the present study was to assess whether it is inversely associated with subsequent stroke incidence and whether this association is preserved even with roasted tea leaves.
In 1998, 6358 Japanese adults (2087 men and 4271 women) aged 40-89 years without a history of stroke or heart disease completed a lifestyle questionnaire, including consumption of green tea or roasted tea. By the end of 2003, 110 stroke events (59 cerebral infarction events, 34 cerebral haemorrhage events, 15 subarachnoidal haemorrhage events and two stroke events of unspecified subtype) had been documented. Cox proportional hazards regression analysis was used to calculate the multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (95% CIs) for total stroke events, cerebral infarction events and cerebral haemorrhage events according to consumption categories of green tea and roasted tea.
A considerably lower risk was observed for total stroke incidence in both the middle (multivariable HR, 0.43; 95% CI, 0.25-0.74; P = 0.002) and the high (multivariable HR, 0.41; 95% CI, 0.24-0.70; P = 0.001) categories of green tea consumption. This inverse association was consistent even when cerebral infarction and cerebral haemorrhage were analysed separately. The consumption of roasted tea was not associated with stroke risk.
Green tea consumption is associated with a reduced risk of total stroke incidence, cerebral infarction and cerebral haemorrhage.
Chemical antioxidant activity assays are used extensively to evaluate the potential bioactivity of plant foods and their phytochemical constituents, but they do not mimic the complexity of biological systems. The cellular antioxidant activity (CAA) activity assay was developed to be a more biologically relevant model to measure antioxidant activity. Structure-activity relationships of flavonoids have been determined in many chemistry antioxidant activity assays, and they vary with the protocols. The objective of this study was to determine structure-activity relationships of selected flavonoids in the CAA assay. The structures that conferred flavonoids with the most antioxidant activity in the CAA assay were a 3',4'- o-dihydroxyl group in the B-ring, a 2,3-double bond combined with a 4-keto group in the C-ring, and a 3-hydroxyl group. Isoflavones had no cellular antioxidant activity. Flavanols with a galloyl moiety had higher antioxidant activity than those without, and a B-ring 3',4',5'-trihydroxyl group further improved their efficacy. ORAC values for flavonoids were not related to their CAA values. Knowledge of structure-activity relationships in the CAA assay may be helpful in assessing potential in vivo antioxidant activity of flavonoids.
Albino-Swiss male mice were tested in the hot plate test. Oligomeric procyjanidin (OL-1), rutin, quercetin, hyperoside and vitexin rhamnoside were administered intraperitoneally in doses 3.5 and 10 mg/kg. It was found that OL-1, rutin and hyperoside but not vitexin rhamnoside exert analgesic action, whereas quercetin even decreases the pain threshold level. The mechanism of the analgesic action of flavonoids remains to be explained.
[3H]CP-55,940, a high-affinity cannabinoid receptor ligand, was used for in vitro binding and autoradiography in peripheral tissues in the rat. Specific cannabinoid receptor binding was found to be restricted to components of the immune system, i.e., spleen, lymph nodes and Peyer's patches. Displacement studies showed that this binding is identical (similar Kd and structure-activity profile) to that in brain. Cannabinoid receptors in the immune system are confined to B lymphocyte-enriched areas, i.e., the marginal zone of the spleen, cortex of the lymph nodes and nodular corona of Peyer's patches. Specific binding is absent in T lymphocyte-enriched areas, such as the thymus and periarteriolar lymphatic sheaths of the spleen. Certain macrophage-enriched areas, i.e., liver and lung, lack specific binding. Thus, the single peripheral cell type that may contain cannabinoid receptors is the B lymphocyte. Numerous sites have dense binding that could not be displaced by excess unlabeled drug. These nonspecific sites were found in the liver, adrenal glands and sebaceous glands, which are high in fat content, and in the heart, pancreas, components of the male and female reproductive systems and the epithelium of the esophagus. Thus, the highly lipophilic nature of cannabinoids does not appear to be the sole determinant of nonspecific binding. The data suggest that cannabinoids may exert specific receptor-mediated actions on the immune system of rats. Perhaps, also at high concentrations, cannabinoids exert membrane effects at sites where they are sequestered nonspecifically.
Epidemiological studies suggested that consumption of fruit and vegetables may protect against stroke. The hypothesis that dietary antioxidant vitamins and flavonoids account for this observation is investigated in a prospective study.
A cohort of 552 men aged 50 to 69 years was examined in 1970 and followed up for 15 years. Mean nutrient and food intake was calculated from cross-check dietary histories taken in 1960, 1965, and 1970. The association between antioxidants, selected foods, and stroke incidence was assessed by Cox proportional hazards regression analysis. Adjustment was made for confounding by age, systolic blood pressure, serum cholesterol, cigarette smoking, energy intake, and consumption of fish and alcohol.
Forty-two cases of first fatal or nonfatal stroke were documented. Dietary flavonoids (mainly quercetin) were inversely associated with stroke incidence after adjustment for potential confounders, including antioxidant vitamins. The relative risk (RR) of the highest vs the lowest quartile of flavonoid intake ( > or = 28.6 mg/d vs <18.3 mg/d) was 0.27 (95% confidence interval [CI], 0.11 to 0.70). A lower stroke risk was also observed for the highest quartile of beta-carotene intake (RR, 0.54; 95% CI, 0.22 to 1.33). The intake of vitamin C and vitamin E was not associated with stroke risk. Black tea contributed about 70% to flavonoid intake. The RR for a daily consumption of 4.7 cups or more of tea vs less than 2.6 cups of tea was 0.31 (95% CI, 0.12 to 0.84).
The habitual intake of flavonoids and their major source (tea) may protect against stroke.
The effects of quercetin, flavone, catechin and chrysin on the naloxone-precipitated withdrawal contracture of the acute morphine-dependent guinea-pig ileum have been investigated in-vitro.
After 4 min in-vitro exposure to morphine a strong contracture of guinea-pig isolated ileum was observed after the addition of naloxone. All the flavonoids, injected 10 min before morphine at concentrations between 10−7 and 10−5 M, were capable of blocking naloxone-induced contracture after exposure to morphine in a concentration-dependent fashion. IC50 values calculated for quercetin, flavone, catechin and chrysin were 2.7 times 10−6, 7.3 times 10−7, 8.5 times 10−7 and 5.3 times 10−6 M, respectively.
These results suggest that flavonoids might play an important role in the control of morphine withdrawal.
Several catechin compounds were examined for their ability to induce apoptosis in human histiocytic lymphoma U937 cells. Catechins with a pyrogallol-type structure in a B-ring induced apoptosis and a 3-O-gallate group in cis-relationship to the B ring enhanced the activity. Catechins without a pyrogallol-type structure in a molecule lacked activity. These data suggest the important role of the 5'(3')-hydroxyl group in the B-ring and that a pyrogallol-type structure in a molecule is a minimum requirement for apoptosis induction by catechin compounds.
Catechins, compounds that belong to the flavonoid class, are potentially beneficial to human health. To enable epidemiological evaluation of these compounds, data on their contents in foods are required. HPLC with UV and fluorescence detection was used to determine the levels of (+)-catechin, (-)-epicatechin, (+)-gallocatechin (GC), (-)-epigallocatechin (EGC), (-)-epicatechin gallate (ECg), and (-)-epigallocatechin gallate (EGCg) in 24 types of fruits, 27 types of vegetables and legumes, some staple foods, and processed foods commonly consumed in The Netherlands. Most fruits, chocolate, and some legumes contained catechins. Levels varied to a large extent: from 4.5 mg/kg in kiwi fruit to 610 mg/kg in black chocolate. (+)-Catechin and (-)-epicatechin were the predominant catechins; GC, EGC, and ECg were detected in some foods, but none of the foods contained EGCg. The data reported here provide a base for the epidemiological evaluation of the effect of catechins on the risk for chronic diseases.
The aim of this study was to determine which type of diet contributes most to plasma concentration of (+)-catechin, a naturally occurring antioxidant flavonoid. Consecutive subjects (n=180) were screened. A blood sample was collected after a fasting period and (+)-catechin measurement in plasma was performed by high-performance liquid chromatography (HPLC) method using fluorescence detection. Dietary consumption of the last evening meal was assessed by a dietary recall method. Taking fruit, vegetable and wine consumption into account, four types of diet were identified. After adjustment for confounding factors, concentration of (+)-catechin in plasma was three-fold higher in diet with fruit and vegetable but without wine (449.5 microg/l), and four-fold higher in diet with wine but without vegetable and fruit (598.5 microg/l) in comparison to diet without fruit, vegetable and wine (131.6 microg/l). When the consumption of vegetable, fruit and wine was combined, the concentration was the highest (637.1 microg/l) (P<0. 001). Vegetable, fruit and wine were the major determinants of plasma (+)-catechin concentration (P<0.001). This study demonstrates that the highest plasma concentration of (+)-catechin was observed in subjects consuming fruit, vegetable and wine, and its antioxidant and antiaggregant activity could partly explain the relative protection against coronary heart disease (CHD).
Sixteen flavonoids including flavonols, flavones, flavanonol and catechins, and five aromatic compounds were examined for their ability to scavenge superoxide radical (O2-*) generated enzymatically in a xanthin-xanthinoxidase system and non-enzymatically in a phenazine methosulfate-NADH system. Pyrogallol, gallic acid and its ester, were much more efficient in scavenging O2-* than catechol. The superiority of pyrogallol over catechol in the flavonoidal nucleus is apparent from the much higher O2-* scavenging activity of myricetin and epigallocatechin, which contain 3',4',5'-trihydroxyl substitution in the B-ring, compared to quercetin and epicatechin, which contain 3',4'-dihydroxyl substitution, respectively. The strong O2-* scavenging ability of pyrogallol appears to function even in the A-ring, as in baicalein, and also in the form of a pyrogalloyl ester at the C-3 position in the C-ring, as in epicatechin gallate and epigallocatechin gallate. It can be concluded that the pyrogallol moiety is an active component of flavonoids for displaying high O2-* scavenging activity. Flavonoids and aromatics were also examined to correlate their O2-* scavenging activity with their oxidizability, which was measured on the basis of electrochemical redox potential and the reducing ability of the Cu2+ ion. Aromatics such as pyrogallol, gallic acid and its ester, and flavonoids such as baicalein, epicatechin gallate and epigallocatechin gallate, in which the O2-* scavenging activity is enhanced by the presence of a pyrogallol moiety which does not belong to the B-ring, reduced the correlation between the higher O2-* scavenging activity and the lower redox potential. The O2-* scavenging activity was well correlated with the Cu2+ reducing ability of flavonoids and aromatics.
Epidemiological studies have suggested that the consumption of green tea provides protection against stomach cancer. Fractionation of green tea extract, guided by antiproliferative activity against human stomach cancer (MK-1) cells, has resulted in the isolation of six active flavan-3-ols, epicatechin (EC), epigallocatechin (EGC), epigallocatechin gallate (EGCg), gallocatechin (GC), epicatechin gallate (ECg), gallocatechin gallate (GCg), together with inactive glycosides of kaempferol and quercetin. Among the six active flavan-3-ols, EGCg and GCg showed the highest activity, EGC, GC, ECg followed next, and the activity of EC was lowest. These data suggest that the presence of the three adjacent hydroxyl groups (pyrogallol or galloyl group) in the molecule would be a key factor for enhancing the activity. Since reactive oxygen species play an important role in cell death induction, radical scavenging activity was evaluated using the DPPH (1,1-diphenyl-2-picrylhydrazyl) radical. The order of scavenging activity was ECg > or = EGCg > or = EGC > or = GC > or = EC. The compounds having a galloyl moiety showed more potent activity. The contribution of the pyrogallol moiety in the B-ring to the scavenging activity seemed to be less than that of the galloyl moiety.
The neuroprotective effects of theanine and catechins contained in green tea are discussed. Although the death of cultured rat cortical neurons was induced by the application of glutamic acid, this neuronal death was suppressed with exposure to theanine. The death of hippocampal CA1 pyramidal neurons caused by transient forebrain ischemia in the gerbil was inhibited with the ventricular preadministration of theanine. The neuronal death of the hippocampal CA3 region by kainate was also prevented by the administration of theanine. Theanine has a higher binding capacity for the AMPA/kainate receptors than for NMDA receptors, although the binding capacity in all cases is markedly less than that of glutamic acid. The results of the present study suggest that the mechanism of the neuroprotective effect of theanine is related not only to the glutamate receptor but also to other mechanisms such as the glutamate transporter, although further studies are needed. One of the onset mechanisms for arteriosclerosis, a major factor in ischemic cerebrovascular disease, is probably the oxidative alteration of low-density lipoprotein (LDL) by active oxygen species. The oxidative alterations of LDL were shown to be prevented by tea catechins. Scavenging of *O(2)(-) was also exhibited by tea catechins. The neuroprotective effects of theanine and catechins contained in green tea are a focus of considerable attention, and further studies are warranted.
Increasing interest in the health benefits of tea has led to the inclusion of tea extracts in dietary supplements and functional foods. However, epidemiologic evidence regarding the effects of tea consumption on cancer and cardiovascular disease risk is conflicting. While tea contains a number of bioactive chemicals, it is particularly rich in catechins, of which epigallocatechin gallate (EGCG) is the most abundant. Catechins and their derivatives are thought to contribute to the beneficial effects ascribed to tea. Tea catechins and polyphenols are effective scavengers of reactive oxygen species in vitro and may also function indirectly as antioxidants through their effects on transcription factors and enzyme activities. The fact that catechins are rapidly and extensively metabolized emphasizes the importance of demonstrating their antioxidant activity in vivo. In humans, modest transient increases in plasma antioxidant capacity have been demonstrated following the consumption of tea and green tea catechins. The effects of tea and green tea catechins on biomarkers of oxidative stress, especially oxidative DNA damage, appear very promising in animal models, but data on biomarkers of in vivo oxidative stress in humans are limited. Larger human studies examining the effects of tea and tea catechin intake on biomarkers of oxidative damage to lipids, proteins, and DNA are needed.
Members of the Prevotella intermedia group possess protein tyrosine phosphatase (PTPase). The purpose of this study was to investigate the effects of catechin derivatives from Japanese green tea on the activity of PTPase in P. intermedia and related organisms. Multilocus enzyme electrophoresis of alkaline phosphatase derived from P. intermedia, Prevotella nigrescens, Prevotella pallens and Porphyromonas gingivalis revealed a species-specific migration pattern. Among the tea catechin derivatives tested, (-)-epigallocatechin gallate (EGCg), similar to orthovanadate, a specific inhibitor for PTPase, was effective in inhibiting the PTPase activity in P. intermedia at 0.5 microm, and related species at 5 microm. The results suggested that the inhibitory effect observed is due to the presence of galloyl moiety in the structure. In contrast, neither the green tea catechins nor orthovanadate inhibited the phosphatase activity in P. gingivalis, suggesting that this organism possessed a different family of alkaline phosphatase.
Tea is one of the most frequently consumed beverages in the world. It is rich in polyphenols, a group of compounds that exhibit numerous biochemical activities. Green tea is not fermented and contains more catechins than black tea or oolong tea. Although clinical evidence is still limited, the circumstantial data from several recent studies suggest that green tea polyphenols may promote health and reduce disease occurrence, and possibly protect against Parkinson’s disease and other neurodegenerative diseases.
Green tea polyphenols have demonstrated neuroprotectant activity in cell cultures and animal models, such as the prevention of neurotoxin-induced cell injury. The biological properties of green tea polyphenols reported in the literature include antioxidant actions, free radical scavenging, iron-chelating properties, 3H-dopamine and 3H-methyl-4-phenylpyridine uptake inhibition, catechol-O-methyl-transferase activity reduction, protein kinase C or extracellular signal-regulated kinases signal pathway activation, and cell survival/cell cycle gene modulation. All of these biological effects may benefit patients with Parkinson’s disease.
Despite numerous studies in recent years, the understanding of the biological activities and health benefits of green tea polyphenols is still very limited. Further in-depth studies are needed to investigate the safety and efficacy of green tea in humans and to determine the different mechanisms of green tea in neuroprotection.
In the course of searching for BACE1 (beta-secretase) inhibitors from natural products, the ethyl acetate soluble fraction of green tea, which was suspected to be rich in catechin content, showed potent inhibitory activity. (-)-Epigallocatechin gallate, (-)-epicatechin gallate, and (-)-gallocatechin gallate were isolated with IC(50) values of 1.6 x 10(-6), 4.5 x 10(-6), and 1.8 x 10(-6) M, respectively. Seven additional authentic catechins were tested for a fundamental structure-activity relationship. (-)-Catechin gallate, (-)-gallocatechin, and (-)-epigallocatechin significantly inhibited BACE1 activity with IC(50) values of 6.0 x 10(-6), 2.5 x 10(-6), and 2.4 x 10(-6) M, respectively. However, (+)-catechin, (-)-catechin, (+)-epicatechin, and (-)-epicatechin exhibited about ten times less inhibitory activity. The stronger activity seemed to be related to the pyrogallol moiety on C-2 and/or C-3 of catechin skeleton, while the stereochemistry of C-2 and C-3 did not have an effect on the inhibitory activity. The active catechins inhibited BACE1 activity in a non-competitive manner with a substrate in Dixon plots.
Tea has recently attracted a great deal of attention for its beneficial health effects. Green tea polyphenols inhibit the production of arachidonic acid metabolites and leukotrienes resulting in decreased inflammatory responses. In the present study, the effect of green tea extract (GTE) on lipopolysaccharide (LPS)-induced thermal and behavioural hyperalgesia in mice and the possible involvement of the cyclooxygenase pathway in this paradigm was evaluated. GTE (25 mg/kg, i.p.), nimesulide (2 mg/kg, i.p.) and rofecoxib (2 mg/kg, i.p.) significantly attenuated LPS-induced thermal and behavioural hyperalgesia but per se did not modify any of the behavioural effects. Concurrent administration of a subeffective dose of GTE (10 mg/kg, i.p.) and rofecoxib (2 mg/kg, i.p.) or nimesulide (2 mg/kg, i.p.) significantly potentiated the antinociceptive effect of GTE in both LPS-induced thermal and behavioural hyperalgesia with nimesulide showing a more pronounced enhancing effect. Thus it can be concluded that GTE attenuates LPS-induced central and peripheral hyperalgesia by selective inhibition of cyclooxygenase-2 enzyme.
Tea, in the form of green or black tea, is one of the most widely consumed beverages in the world. Extracts of tea leaves also are sold as dietary supplements. However, with the increasing interest in the health properties of tea and a significant rise in scientific investigation, this review covers recent findings on the medicinal properties and noncancer health benefits of both green and black tea. In Part II, a review of anticancer properties of green tea extracts is presented. Green tea contains a unique set of catechins that possess biological activity in antioxidant, anti-angiogenesis, and antiproliferative assays potentially relevant to the prevention and treatment of various forms of cancer. Although there has been much focus on the biological properties of the major tea catechin epigallocatechin gallate (EGCg) and its antitumor properties, tea offers other health benefits; some due to the presence of other important constituents. Characteristics unrelated to the antioxidant properties of green and black teas may be responsible for tea's anticancer activity and improvement in cardiac health and atherosclerosis. Theanine in green tea may play a role in reducing stress. Oxidized catechins (theaflavins in black tea) may reduce cholesterol levels in blood. Synergistic properties of green tea extracts with other sources of polyphenolic constituents are increasingly recognized as being potentially important to the medicinal benefits of black and green teas. Furthermore, due to presumed antioxidant and antiaging properties, tea is now finding its way into topical preparations. Each of these aspects is surveyed.
Diabetic neuropathic pain is an important microvascular complication, and morphine has been demonstrated to be ineffective in this condition. Therefore the present study was designed to investigate the modulatory effect of green tea extract (GTE) on the decreased antinociceptive effect of morphine in diabetic mice. The tail withdrawal test was performed for measurement of the nociceptive threshold in both streptozotocin (STZ)-injected and control mice. Four weeks after administration of STZ, antinociception of morphine (5 mg/kg, s.c.) alone or in combination with GTE (25, 50, and 100 mg/kg, i.p.) was measured. Experimental diabetes markedly decreased the antinociceptive effect of morphine. The decrement in morphine response was significantly attenuated by GTE administration. When GTE (25 mg/kg) and a nitric oxide (NO) inhibitor, L-N(G)-nitroarginine methyl ester (L-NAME) (10 mg/kg, i.p), were co-administered along with morphine (5 mg/kg, s.c) in diabetic mice, the antinociceptive action of morphine was significantly increased as compared with the GTE + morphine-treated diabetic group, but the increased antinociceptive action was significantly attenuated by administration of an NO precursor, L-arginine (100 mg/kg, i.p), instead of L-NAME. Plasma nitrite concentrations were estimated using the Griess reagent. Diabetes significantly increased the plasma nitrite levels that were attenuated by GTE administration. When GTE (25 mg/kg) and L-NAME (10 mg/kg, i.p) were co-administered along with morphine (5 mg/kg, s.c) in diabetic mice, the plasma nitrite levels were significantly decreased as compared with the GTE + morphine alone-treated diabetic group, but the decreased plasma nitrite levels were significantly reversed by administration of L-arginine (100 mg/kg) instead of L-NAME. It may be concluded that increased NO formation may be responsible for the decreased antinociceptive effect of morphine in diabetic mice and that GTE restored the antinociceptive effect of morphine by inhibition of NO production. The results of the present study indicate the possibility of adding GTE as an adjuvant in the treatment of diabetic neuropathic pain.