Protective effects of green tea polyphenols on human HepG2 cells against oxidative damage of fenofibrate

The aim of this work was to investigate the protective effects of green tea polyphenols on the cytotoxic effects of hypolipidemic agent fenofibrate (FF), a peroxisome proliferator (PP), in human HepG2 cells. The results showed that high concentrations of FF induced human HepG2 cell death through a mechanism involving an increase of reactive oxygen species (ROS) and intracellular reduced glutathione (GSH) depletion. These effects were partially prevented by antioxidant green tea polyphenols. The elevated expression of PP-activated receptors alpha (PPARalpha) in HepG2 cells induced by FF was also decreased by treatment with green tea polyphenols. In conclusion, this result demonstrates that oxidative stress and PPARalpha are involved in FF cytotoxicity and green tea polyphenols have a protective effect against FF-induced cellular injury. It may be beneficial for the hyperlipidemic patients who were administered the hypolipidemic drug fenofibrate to drink tea or use green tea polyphenols synchronously during their treatment.     

Cancer chemoprevention by tea polyphenols

Tea is one of the most widely consumed beverages, second only to water. Many experimental researches in laboratory animals demonstrated that tea components had an inhibitory effect on carcinogenesis at a number of organ sites. The inhibitory effects of tea against carcinogenesis have been attributed to the biologic activities of the polyphenol fraction in tea. This review summarizes experimental data on chemopreventive effects of tea polyphenols in various tumor bioassay systems. Many laboratory studies have demonstrated the inhibitory effects of green tea polyphenols, especially (-)-epigallocatechin-3-gallate (EGCG), on carcinogenesis in animals models. The majority of these studies have been conducted in mouse skin tumor models, where tea polyphenols were used either as oral feeding in drinking water or in direct local application. Most studies used 12-O-tetradecanoylphorbol-13-acetate (TPA) or ultraviolet (UV) radiation as the tumor promoter and found anticarcinogenic effects caused by green tea polyphenols. Black tea was also found to be effective, although the activity was weaker than that of green tea in some experiments. Other studies showed that black tea polyphenols-theaflavins exhibited stronger anticarcinogenic activity than did EGCG. Caffeine in tea was also important for tea to prevent tumorigenesis. The molecular mechanisms of the cancer chemopreventive effects of tea polyphenols are not completely understood. They are most likely related to the mechanisms of biochemical actions of tea polyphenols, which include antioxidative activities, modulation of xenobiotic metabolite enzymes and inhibition of tumor promotion. In addition, we have also proposed that tea polyphenols function as cancer chemopreventive agents through modulation of mitotic signal transduction. However, the molecular mechanisms involved in this modulation need further investigation.     

Tea polyphenols, their biological effects and potential molecular targets

Tea is the most popular beverage in the world, second only to water. Tea contains an infusion of the leaves from the Camellia sinensis plant rich in polyphenolic compounds known as catechins, the most abundant of which is (-)-EGCG. Although tea has been consumed for centuries, it has only recently been studied extensively as a health-promoting beverage that may act to prevent a number of chronic diseases and cancers. The results of several investigations indicate that green tea consumption may be of modest benefit in reducing the plasma concentration of cholesterol and preventing atherosclerosis. Additionally, the cancer-preventive effects of green tea are widely supported by results from epidemiological, cell culture, animal and clinical studies. In vitro cell culture studies show that tea polyphenols potently induce apoptotic cell death and cell cycle arrest in tumor cells but not in their normal cell counterparts. Green tea polyphenols were shown to affect several biological pathways, including growth factor-mediated pathway, the mitogen-activated protein (MAP) kinase-dependent pathway, and ubiquitin/proteasome degradation pathways. Various animal studies have revealed that treatment with green tea inhibits tumor incidence and multiplicity in different organ sites such as skin, lung, liver, stomach, mammary gland and colon. Recently, phase I and II clinical trials have been conducted to explore the anticancer effects of green tea in humans. A major challenge of cancer prevention is to integrate new molecular findings into clinical practice. Therefore, identification of more molecular targets and biomarkers for tea polyphenols is essential for improving the design of green tea trials and will greatly assist in a better understanding of the mechanisms underlying its anti-cancer activity.     

Distinct effects of tea catechins on 6-hydroxydopamine-induced apoptosis in PC12 cells.

Green tea polyphenols have aroused considerable attention in recent years for preventing oxidative stress related diseases including cancer, cardiovascular disease, and degenerative disease. Neurodegenerative diseases are cellular redox status dysfunction related diseases. The present study investigated the different effects of the five main components of green tea polyphenols on 6-hydroxydopamine (6-OHDA)-induced apoptosis in PC12 cells, the in vitro model of Parkinson's disease (PD). When the cells were treated with five catechins respectively for 30 min before exposure to 6-OHDA, (-)-epigallocatechins gallate (EGCG) and (-)-epicatechin gallate (ECG) in 50-200 microM had obvious concentration-dependent protective effects on cell viability, while (-)-epicatechin (EC), (+)-catechin ((+)-C), and (-)-epigallocatechin (EGC) had almost no protective effects. The five catechins also showed the same pattern described above of the different effects against 6-OHDA-induced cell apoptotic characteristics as analyzed by cell viability, fluorescence microscopy, flow cytometry, and DNA fragment electrophoresis methods. The present results indicated that 200 microM EGCG or ECG led to significant inhibition against typical apoptotic characteristics of PC12 cells, while other catechins had little protective effect against 6-OHDA-induced cell death. Therefore, the classified protective effects of the five catechins were in the order ECG> or = EGCG>EC> or = (+)-C>EGC. The antiapoptotic activities appear to be structurally related to the 3-gallate group of green tea polyphenols. The present data indicate that EGCG and ECG might be potent neuroprotective agents for PD.     

Protective effects of green tea polyphenols and their major component, (-)-epigallocatechin-3-gallate (EGCG), on 6-hydroxydopamine-induced apoptosis in PC12 cells

Green tea polyphenols exert a wide range of biochemical and pharmacological effects, and have been shown to possess antimutagenic and anticarcinogenic properties. Oxidative stress is involved in the pathogenesis of Parkinson's disease. However, although green tea polyphenols may be expected to inhibit the progression of Parkinson's disease on the basis of their known antioxidant activity, this has not previously been established. In the present study, we evaluated the neuroprotective effects of green tea polyphenols in the Parkinson's disease pathological cell model. The results show that the natural antioxidants have significant inhibitory effects against apoptosis induced by oxidative stress. 6-Hydroxydopamine (6-OHDA)-induced apoptosis in catecholaminergic PC12 cells was chosen as the in vitro model of Parkinson's disease in our study. Apoptotic characteristics of PC12 cells were assessed by MTT assay, flow cytometry, fluorescence microscopy and DNA fragmentation. Green tea polyphenols and their major component, EGCG at a concentration of 200 microM, exert significant protective effects against 6-OHDA-induced PC12 cell apoptosis. EGCG is more effective than the mixture of green tea polyphenols. The antioxidant function of green tea polyphenols may account for this neuroprotective effect. The present study supports the notion that green tea polyphenols have the potential to be effective as neuropreventive agents for the treatment of neurodegenerative diseases.     

Antimutagenic and anticarcinogenic activity of tea polyphenols

Tea is the most popular beverage, consumed by over two thirds of the world's population. Tea is processed differently in different parts of the world to give green (20%), black (78%) or oolong tea (2%). Green tea is consumed mostly in Japan and China. The antimutagenic and anticarcinogenic activities of green tea are extensively examined. The chemical components of green and black tea are polyphenols, which include EC, ECG, EGC, EGCG and TFs. This article reviews the epidemiological and experimental studies on the antimutagenicity and anticarcinogenicity of tea extracts and tea polyphenols. In Japan, an epidemiological study showed an inverse relationship between habitual green tea drinking and the standardized mortality rates for cancer. Some cohort studies on Chanoyu (Japanese tea ceremony) women teachers also showed that their mortality ratio including deaths caused by malignant neoplasms were surprisingly low. The antimutagenic activity against various mutagens of tea extracts and polyphenols including ECG and EGCG has been demonstrated in microbial systems (Salmonella typhimurium and Escherichia coli), mammalian cell systems and in vivo animal tests. The anticarcinogenic activity of tea phenols has been shown in experimental animals such as rats and mice, in transplantable tumors, carcinogen-induced tumors in digestive organs, mammary glands, hepatocarcinomas, lung cancers, skin tumors, leukemia, tumor promotion and metastasis. The mechanisms of antimutagenesis and anticarcinogenesis of tea polyphenols suggest that the inhibition of tumors may be due to both extracellular and intracellular mechanisms including the modulation of metabolism, blocking or suppression, modulation of DNA replication and repair effects, promotion, inhibition of invasion and metastasis, and induction of novel mechanisms.     

Comparative antimutagenic and anticlastogenic effects of green tea and black tea: a review

Tea is the most popular beverage next to water, consumed by over two-thirds of the world's population. It is processed in different ways in different parts of the world to give green, black or oolong tea. Experimental studies have demonstrated the significant antimutagenic and anticlastogenic effects of both green and black tea and its polyphenols in multiple mutational assays. In the present review, we have attempted to evaluate and update the comparative antimutagenic and anticlastogenic effects of green tea, black tea and their polyphenols in different test systems, based on available literature. Existing reports have suggested that the protective effects of black tea is as good as green tea, however, more studies on black tea and its polyphenols are needed before a final conclusion can be made.     

(−)-Epigallocatechin gallate suppresses the cytotoxicity induced by trichothecene mycotoxins in mouse cultural macrophages

Trichothecene mycotoxins are toxic secondary metabolites produced by a number of fungi including Fusarium species, which adversely affect lymphocytes. Deoxynivalenol (DON) and HT-2 toxin (HT-2) belong to the trichothecene group of mycotoxins and the occurrence of cereals and foodstuffs with these compounds are serious health problems. The aim of this study was to examine the effect of (−)-epigallocatechin gallate (EGCG), one of the main components in green tea catechins, on DON- or HT-2-induced cytotoxicity in mouse macrophages. EGCG had protective effects against the trichothecene-induced cytotoxicities of both mycotoxins. Additionally, EGCG suppressed the DON-induced activation of caspase-3/7, which is an indicator of apoptosis. These results indicate that EGCG might be useful in protection against DON- or HT-2-induced cell death, suggesting that EGCG could contribute to reducing the toxicities of trichothecenes.     

Green tea polyphenols enhance sodium nitroprusside-induced neurotoxicity in human neuroblastoma SH-SY5Y cells

Oxidative stress is a main mediator in nitric oxide (NO) -induced neurotoxicity and has been implicated in the pathogenesis of many neurodegenerative disorders. Green tea polyphenols are usually expected as potent chemo-preventive agents due to their ability of scavenging free radicals and chelating metal ions. However, not all the actions of green tea polyphenols are necessarily beneficial. In the present study, we demonstrated that higher-concentration green tea ployphenols significantly enhanced the neurotoxicity by treatment of sodium nitroprusside (SNP), a nitric oxide donor. SNP induced apoptosis in human neuroblastoma SH-SY5Y cells in a concentration and time-dependent manner, as estimated by cell viability assessment, FACScan analysis and DNA fragmentation assay, whereas treatment with green tea polyphenols alone had no effect on cell viability. Pre-treatment with lower-dose green tea polyphenols (50 and 100 microm) had only a slightly deleterious effect in the presence of SNP, while higher-dose green tea polyphenols (200 and 500 microm) synergistically damaged the cells severely. Further research showed that co-incubation of green tea polyphenols and SNP caused loss of mitochondrial membrane potential, depletion of intracellular GSH and accumulation of reactive oxygen species, and exacerbated NO-induced neuronal apoptosis via a Bcl-2 sensitive pathway.     

The antioxidant and pro-oxidant activities of green tea polyphenols: A role in cancer prevention

Green tea (Camellia sinensis) is rich in catechins, of which (−)-epigallocatechin-3-gallate (EGCG) is the most abundant. Studies in animal models of carcinogenesis have shown that green tea and EGCG can inhibit tumorigenesis during the initiation, promotion and progression stages. Many potential mechanisms have been proposed including both antioxidant and pro-oxidant effects, but questions remain regarding the relevance of these mechanisms to cancer prevention. In the present review, we will discuss the redox chemistry of the tea catechins and the current literature on the antioxidant and pro-oxidative effects of the green tea polyphenols as they relate to cancer prevention. We report that although the catechins are chemical antioxidants which can quench free radical species and chelate transition metals, there is evidence that some of the effects of these compounds may be related to induction of oxidative stress. Such pro-oxidant effects appear to be responsible for the induction of apoptosis in tumor cells. These pro-oxidant effects may also induce endogenous antioxidant systems in normal tissues that offer protection against carcinogenic insult. This review is meant point out understudied areas and stimulate research on the topic with the hope that insights into the mechanisms of cancer preventive activity of tea polyphenols will result.     

Green tea polyphenols for prostate cancer chemoprevention: A translational perspective

Every year nearly 200,000 men in the United States are diagnosed with prostate cancer (PCa), and another 29,000 men succumb to the disease. Within certain regions of the world population based studies have identified a possible role for green tea in the prevention of certain cancers, especially PCa. One constituent in particular, epigallocatechin-3-gallate also known as EGCG has been shown in cell culture models to decrease cell viability and promote apoptosis in multiple cancer cell lines including PCa with no effect on non-cancerous cell lines. In addition, animal models have consistently shown that standardized green tea polyphenols when administered in drinking water delay the development and progression of PCa. Altogether, three clinical trials have been performed in PCa patients and suggest that green tea may have a distinct role as a chemopreventive agent. This review will present the available data for standardized green tea polyphenols in regard to PCa chemoprevention that will include epidemiological, mechanism based studies, safety, pharmacokinetics, and applicable clinical trials. The data that has been collected so far suggests that green tea may be a promising agent for PCa chemoprevention and further clinical trials of participants at risk of PCa or early stage PCa are warranted.     

Antioxidative effects of green tea polyphenols on free radical initiated and photosensitized peroxidation of human low density lipoprotein

Antioxidative effects of the main polyphenolic components extracted from green tea leaves, i.e. (-)-epicatechin (EC), (-)-epigallocatechin (EGC), (-)-epicatechin gallate (ECG), (-)-epigallocatechin gallate (EGCG) and gallic acid (GA), against free radical initiated peroxidation of human low density lipoprotein (LDL) were studied. The peroxidation was initiated either thermally by a water-soluble initiator 2,2'-azobis(2-amidinopropane hydrochloride) (AAPH), or photochemically by a triplet sensitizer benzophenone (BP). The reaction kinetics was monitored by the uptake of oxygen and the depletion of alpha-tocopherol (TOH) presented in the native LDL. Kinetic analysis of the antioxidation process demonstrates that these green tea polyphenols are effective antioxidants against both AAPH-initiated and BP-photosensitized LDL peroxidation. The antioxidative action of the green tea polyphenols includes trapping the initiating and/or propagating peroxyl radicals with the activity sequence EC>EGCG>ECG>EGC>GA for the AAPH initiated peroxidation, and reducing the alpha-tocopheroxyl radical to regenerate alpha-tocopherol with the activity sequence of ECG>EC>EGCG>EGC>GA and ECG>EGCG>GA>EC>EGC for the AAPH-initiated and BP-photosensitized peroxidations respectively.     

Green tea and skin cancer: photoimmunology, angiogenesis and DNA repair

Human skin is constantly exposed to numerous noxious physical, chemical and environmental agents. Some of these agents directly or indirectly adversely affect the skin. Cutaneous overexposure to environmental solar ultraviolet (UV) radiation (290-400 nm) has a variety of adverse effects on human health, including the development of melanoma and nonmelanoma skin cancers. Therefore, there is a need to develop measures or strategies, and nutritional components are increasingly being explored for this purpose. The polyphenols present in green tea (Camellia sinensis) have been shown to have numerous health benefits, including protection from UV carcinogenesis. (-)-Epigallocatechin-3-gallate (EGCG) is the major and most photoprotective polyphenolic component of green tea. In this review article, we have discussed the most recent investigations and mechanistic studies that define and support the photoprotective efficacy of green tea polyphenols (GTPs) against UV carcinogenesis. The oral administration of GTPs in drinking water or the topical application of EGCG prevents UVB-induced skin tumor development in mice, and this prevention is mediated through: (a) the induction of immunoregulatory cytokine interleukin (IL) 12; (b) IL-12-dependent DNA repair following nucleotide excision repair mechanism; (c) the inhibition of UV-induced immunosuppression through IL-12-dependent DNA repair; (d) the inhibition of angiogenic factors; and (e) the stimulation of cytotoxic T cells in a tumor microenvironment. New mechanistic information strongly supports and explains the chemopreventive activity of GTPs against photocarcinogenesis.     

Dietary intervention with iron and black tea infusion in reducing cytotoxicity of arsenic

The relative efficacy of infusion of black tea leaf, Camellia sinensis (Linn.) O. Kuntze, (Theaceae), and iron as freshly prepared aqueous solution of ferrous sulphate in reducing the cytotoxic effects of arsenic, was tested in bone marrow cells of laboratory bred Swiss albino mice. Ferrous sulphate and tea given alone did not induce chromosomal breakage to any appreciable extent. Tea decreased chromosome damage induced by arsenic to a significant extent, while the addition of ferrous sulphate did not alter the protective action of tea against arsenic. Such protection against arsenic cytotoxicity by prolonged dietary administration of black tea infusion--a common routine beverage--is of importance in view of widespread exposure of human populations to arsenic damage through drinking water from tubewells in Eastern India and Bangladesh.     

Cellular thiols status and cell death in the effect of green tea polyphenols in Ehrlich ascites tumor cells.

Epidemiological studies suggest that the consumption of green tea may help prevent cancers in humans, and also breast and prostate cancers in animal models are reduced by green tea, and several mechanisms have been proposed for these effects. In this study the relationship between cellular sulfhydryl (SH) groups and the cytotoxicity of green tea polyphenols in Ehrlich ascites tumor cells was examined. It was found that in the presence of green tea extract (GTE) (100 microg/ml) and one of its polyphenolic components, epigallocatechin (EGC; 100 microM), both cellular non-protein (GSH) and protein-sulfhydryl (PSH) levels were significantly decreased and this was associated with a decrease in cell viability. Replenishing the thiol levels by using N-acetylcysteine (NAC) caused a recovery in cell viability, but this recovery was dependent on the time of thiol replenishment in the presence of EGC (initial 15 min). These results identify SH groups as a novel target of green tea polyphenols cytotoxicity in tumor cells, and a regulatory role for green tea in terms of reducing sulfhydryls in tumor inhibition.     

Green tea polyphenols inhibit cognitive impairment induced by chronic cerebral hypoperfusion via modulating oxidative stress

Responses to oxidative stress contribute to damage caused by chronic cerebral hypoperfusion, which is characteristic of certain neurodegenerative diseases. We used a rat model of chronic cerebral hypoperfusion to determine whether green tea polyphenols, which are potent antioxidants and free radical scavengers, can reduce vascular cognitive impairment and to investigate their underlying mechanisms of action. Different doses of green tea polyphenols were administered orally to model rats from 4 to 8 weeks after experimentally induced cerebral hypoperfusion, and spatial learning and memory were assessed using the Morris water maze. Following behavioral testing, oxygen free radical levels and antioxidative capability in the cortex and hippocampus were measured biochemically. The levels of lipid peroxidation and oxidative DNA damage were assessed by immunohistochemical staining for 4-hydroxynonenal and 8-hydroxy-2′-deoxyguanosine, respectively. Rats that received green tea polyphenols 400 mg/kg per day had better spatial learning and memory than saline-treated rats. Green tea polyphenols 400 mg/kg per day were found to scavenge oxygen free radicals, enhance antioxidant potential, decrease lipid peroxide production and reduce oxidative DNA damage. However, green tea polyphenols 100 mg/kg per day had no significant effects, particularly in the cortex. This study suggests that green tea polyphenols 400 mg/kg per day improve spatial cognitive abilities following chronic cerebral hypoperfusion and that these effects may be related to the antioxidant effects of these compounds.     

The green tea polyphenol (-)-epigallocatechin gallate attenuates beta-amyloid-induced neurotoxicity in cultured hippocampal neurons.

Previous evidence has indicated that the neuronal toxicity of amyloid beta (betaA) protein is mediated through oxygen free radicals and can be attenuated by antioxidants and free radical scavengers. Recent studies have shown that green tea polyphenols reduced free radical-induced lipid peroxidation. The purpose of this study was to investigate whether (-)-epigallocatechin gallate (EGCG) would prevent or reduce the death of cultured hippocampal neuronal cells exposed to betaA because EGCG has a potent antioxidant property as a green tea polyphenol. Following exposure of the hippocampal neuronal cells to betaA for 48 hours, a marked hippocampal neuronal injuries and increases in malondialdehyde (MDA) level and caspase activity were observed. Co-treatment of cells with EGCG to betaA exposure elevated the cell survival and decreased the levels of MDA and caspase activity. Proapoptotic (p53 and Bax), Bcl-XL and cyclooxygenase (COX) proteins have been implicated in betaA-induced neuronal death. However, in this study the protective effects of EGCG seem to be independent of the regulation of p53, Bax, Bcl-XL and COX proteins. Taken together, the results suggest that EGCG has protective effects against betaA-induced neuronal apoptosis through scavenging reactive oxygen species, which may be beneficial for the prevention of Alzheimer's disease.     

Natural antioxidants for neurodegenerative diseases

The author reviews the studies on the preventing effects of natural antioxidants, such as vitamins E and C, flavonoids, and polyphenols on neurodegenerative diseases, especially summarizing the results on the protective effect of ginkgo biloba extract on neuron cells, preventing effects of green tea polyphenols on apoptosis of PC12 cells (Parkinson’s disease model), preventing effects of genestien on amyloid-β-induced apoptosis of hippocampal neuronal cells (Alzhemer’s disease model), and preventing effect of Crataegus flavonoids on ischemic-reperfusion damage to the brain of the Mongolian gerbil (stroke model) in the laboratory.     

Antiangiogenic mechanisms of diet-derived polyphenols

Accumulating evidence demonstrates that polyphenols in natural products are beneficial against human lethal diseases such as cancer and metastasis. The underlying mechanisms of anti-cancer effects are complex. Recent studies show that several polyphenols, including epigallocatechin-3-gallate (EGCG) in green tea and resveratrol in red wine, inhibit angiogenesis when administrated orally. These polyphenols have direct effects on suppression of angiogenesis in several standard animal angiogenesis models. Because angiogenesis is involved in many diseases such as cancer, diabetic retinopathy and chronic inflammations, the discovery of these polyphenols as angiogenesis inhibitors has shed light on the health beneficial mechanisms of natural products, which are rich in these molecules. At the molecular level, recent studies have provided important information on how these molecules inhibit endothelial cell growth. Perhaps the greatest therapeutic advantage of these small natural molecules over large protein compounds is that they can be administrated orally without causing severe side effects. It is anticipated that more polyphenols in natural products will be discovered as angiogenesis inhibitors and that these natural polyphenols could serve as leading structures in the discovery of more potent, synthetic angiogenesis inhibitors.     

Farnesol ameliorates massive inflammation, oxidative stress and lung injury induced by intratracheal instillation of cigarette smoke extract in rats: an initial step in lung chemoprevention

Cigarette smoke toxicants are well known for their debilitating effects on lungs. Cigarette smoke toxicities cause various respiratory disorders including pulmonary emphysema, chronic obstructive pulmonary disease (COPD), pulmonary fibrosis and cancer. Farnesol, an isoprenoid, is known to possess anti-inflammatory and chemopreventive properties. In this study we report the protective efficacy of farnesol against massive lung inflammation, oxidative stress and consequent injuries caused by cigarette smoke toxicants. Farnesol was administered by gavage (50 and 100 mg/kg b.wt. in corn oil) one time daily for 7 days. On day 7 lung injuries were induced by intratracheal instillation of aqueous cigarette smoke extract (CSE). LDH, total cell count, total protein, phospholipid content and MDA formation were measured in bronchoalveolar lavage fluid (BALF). In lung tissue H2O2 content, reduced glutathione (GSH), glutathione reductase (GR), glutathione peroxidase (GPx) and catalase activities were evaluated. Prophylactic treatment with farnesol significantly shows lung protection by lowering the levels of LDH, total cell count, total protein and MDA in BALF. Farnesol maintained the phospholipid content of BALF in a positive manner. In lung tissue it positively modulated the CSE altered activities of GR, GPx and catalase. There was a marked increase in GSH content and decrease in H2O2 content of lung tissue by farnesol administration. Histopathological findings correlate with cellular and biochemical parameters of the lungs and potentiate the protective role of farnesol against CSE induced lung inflammation and injuries. These results suggest a potent role of farnesol in protection of lung against cigarette smoke toxicants induced lung injuries.