Tea, Coffee and Health Benefits
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A number of epidemiological studies and clinical trials have reported the beneficial effects of both green tea and coffee on human health, including anticancer, anti-obesity, antidiabetic, antihypertensive, and hepatoprotective effects. Furthermore, these findings in humans are supported by cell-based and animal experiments. These effects have been attributed to epigallocatechin gallate (EGCG) in green tea and chlorogenic acid (CGA) in coffee, which have been proposed to function via various mechanisms of action, the most important of which appears to implicate reactive oxygen species (ROS). Both EGCG and CGA can exert conflicting dual actions as an antioxidant and a prooxidant. Their antioxidative action can scavenge ROS, leading to downregulation of nuclear factor-κB to produce various favorable effects such as anti-inflammatory effects and cancer cell apoptosis. The prooxidant actions, however, can promote the generation of ROS leading to the activation of 5’AMP-dependent protein kinase, which modulates various enzymes and factors with beneficial roles. At present, it remains unclear how EGCG and CGA can be directed to act as either a prooxidant or an antioxidant, although their cellular concentrations, the presence of metal cations such as Cu+ and Fe++, and the redox state of the cells appear to be important factors. Notably, several human studies did not report the beneficial health effects of green tea and coffee. The inconsistent results may have been caused by various confounding factors including smoking, intestinal microbiota, and genetic factors. This chapter examines the current information on these properties of green tea and coffee with the aim of improving the understanding of a way to enjoy healthy longevity.
KeywordsGreen tea Coffee Polyphenol Catechin EGCG Chlorogenic acid Human health ROS NF-κB
Aberrant crypt foci
5′-AMP-activated protein kinase
Body mass index
Chronic lymphocytic leukemia
Diastolic blood pressure
Extracellular signal-regulated kinase
Fatty acid synthase
Green coffee extract
Green tea catechin
Green tea extract
Green tea polyphenol
Hepatitis B virus
Hepatitis C virus
Hepatocyte nuclear factor
Human antigen R
Insulin-like growth factor
Insulin receptor substrate
Liver X receptor
Mitogen-activated protein kinase
Mechanistic target of rapamycin kinase
Nonalcoholic fatty liver disease
Nuclear factor-kappa B
Nitric oxide synthase
Nuclear factor, erythroid 2 like 2
Protein kinase C
Peroxisome proliferator-activated receptor
Qushi Huayu Decoction
Reactive oxygen species
Retinoid X receptor
Systolic blood pressure
Spontaneously hypertensive rats
Sterol-responsive element-binding protein
Signal transducer and activator of transcription
Type 2 diabetes mellitus
Tumor necrosis factor
Vascular endothelial growth factor
Black tea is also produced from C. sinensis through enzymic processing (sometimes called fermentation) by intrinsic enzymes and microorganisms during which catechins are polymerized to yield catechin derivatives such as theaflavin (Fig. 1) and theasinensins . It has been shown to have physiological effects similar to those of green tea, albeit with a lesser efficacy than green tea in most cases.
Coffee is also consumed worldwide and, like green tea, exerts various health-related effects. It contains about 2,000 chemicals, including caffeine, and the major polyphenols are chlorogenic acid (CGA) or 5-caffeoylquinic acid (Fig. 1) and its derivatives, which amount to about 3 g per 100 g of roasted coffee powder . A single serving of coffee provides 20–675 mg of CGAs . It should be noted that a recent analysis using ultrahigh-performance liquid chromatography showed that green tea leaves collected from public markets in Brazil contained 1.1 g of CGAs per 100 g of dried leaves .
In this review, we discuss recent evidence that supports the beneficial effects of tea and coffee consumption in relation to the mechanistic aspects of catechins and CGAs by focusing on selected diseases in which we have studied the action of green tea. Caffeine , a highly bioactive constituent contained in both tea and coffee, has been comprehensively reviewed by Temple et al.  and is discussed only briefly here. For the sake of readability, 95% confidence interval values and statistical p-values, which an original datum contains in statistical evaluation, are not presented here unless otherwise described.
2 Effects on Cancer
2.1 Effects of Tea on Cancer
2.1.1 Human Epidemiological Studies
A number of human epidemiological studies have shown that green tea exerts beneficial effects against various cancers [1, 2, 3, 4, 5, 6]. A review article by Yang et al. reported an inverse association between green/black tea consumption and cancer risk for various types of cancer including bladder, breast, colon, gastric, kidney, lung, ovarian, pancreatic, and prostate cancers in 51 of 127 case-control studies and 19 of 90 cohort studies which were carried out from 1965 to 2008 . Yuan and co-workers reviewed the results of 13 studies in which green tea consumption was associated with a significant risk reduction for breast, colorectal, gastric, esophagus, liver, lung, oral cavity, and prostate cancers in 9 studies [13, 14].
Recent studies also demonstrated the beneficial effects of tea, with some examples as follows. The European Prospective Investigation into Cancer and Nutrition study, involving 486,799 men/women for a median follow-up of 11 years, found that increased tea intake was associated with a 59% reduction in the risk of developing hepatocellular carcinoma (HCC) . The analysis of 87 datasets from 57 studies, which included a total of 49,812 subjects, showed that high tea consumption was associated with a reduced risk of oral cancer with a risk ratio (RR) of 0.72, although it had no significant effect on the risk of bladder, breast, colon, gastric, liver, lung, rectal, ovarian, pancreatic, and prostate cancers or gliomas. In a subgroup analysis of individuals in Western countries, the consumption of tea was associated with a reduced risk of bladder cancer, although the consumption of black tea was associated with an increased risk of breast cancer .
The results of a hospital-based, case-control study including 160 cases and 320 controls in China showed that the regular consumption of larger amounts of green tea (≥35 g/week) was associated with a lower risk of stomach cancer, with odds ratios (ORs) of 0.72 and 0.53, respectively. Among regular tea drinkers, lower temperature and longer interval between tea being poured and drunk also reduced the risk, suggesting that green tea was inversely associated with risk of stomach cancer .
In a study to determine the prostate cancer (PCa) risk associated with green tea and EGCG intake among Hong Kong Chinese men, data from 32 cases and 50 controls showed that habitual green tea drinking had an adjusted OR of 0.60. An inverse association was also found between intake of EGCG and PCa risk . Similarly, data from the Japan Public Health Center-Based Prospective Study showed that green tea intake may decrease the risk of advanced PCa .
A case-control study in Vietnamese men showed that after adjustment for confounding factors, increased tea consumption was associated with a reduced risk of PCa . The adjusted ORs were 0.52 and 0.30 for participants drinking 100–500 mL/day and >500 mL/day, respectively, relative to those drinking <100 mL/day. Significant inverse dose-response relationships were also observed for years of drinking and number of cups consumed daily, showing that habitual tea consumption was associated with a reduced risk of PCa. A meta-analysis of seven epidemiological studies and three randomized controlled clinical trials indicated that green tea consumption reduced the incidence of PCa with a linear dose-response effect and significantly reduced the risk of PCa risk at more than 7 cups/day .
A meta-analysis of eight studies comprising 18 independent reports on biliary tract cancer showed that tea intake reduced the risk of cancer by about 34% compared with a no-intake group. This inverse relationship was statistically significant in women but not in men . Chen et al. conducted a meta-analysis to evaluate relationships between tea intake and the risk of biliary tract cancer in 29 qualified studies. The summary OR of developing colorectal cancer for the highest versus the lowest tea consumption was 0.93. A stratified analysis revealed that tea, especially green tea, had a protective effect in female and rectal cancer patients. The dose-response analysis showed that there was a significant inverse association between an increment of 1 cup/day of tea consumption and colorectal cancer risk (OR, 0.68) in women .
A meta-analysis performed in April 2016 in a total of 18 (11 case-control and 7 cohort) studies, comprising data for 701,857 female subjects including 8,683 ovarian cancer cases, showed that tea consumption had a significant protective effect against ovarian cancer (relative risk [RR], 0.86). The relationship was confirmed after adjusting for family history of cancer (RR, 0.85), menopause status (RR, 0.85), education (RR, 0.82), body mass index (BMI) (RR, 0.85), and smoking (RR, 0.83) .
2.1.2 Clinical Studies
One of the most significant studies may be that of an Italian research group which showed that green tea catechins (GTCs) were safe and highly effective for the treatment of premalignant lesions prior to the development of PCa. Only 1 tumor was detected among a group of 30 men with precancerous lesions who received daily oral administration of 600 mg GTCs, as compared with 9 detected tumors among 30 placebo-treated male patients after 1 year . A later systematic review of 15 studies with 11 reports on the effect of green tea consumption on PCa prevention and 4 reports on the effect of green tea on treatment revealed that green tea appeared to be an effective chemopreventive agent for PCa, particularly in patients with high-grade prostate intraepithelial neoplasia, although evidence of efficacy in the treatment of PCa is currently lacking .
To investigate whether erythrocyte oxidative stress was associated with PCa and whether daily consumption of green tea improved the oxidative phenotype, Lassed et al. performed a study on 70 Algerian PCa patients and 120 age-matched healthy subjects. The results at baseline showed reduced glutathione levels and catalase activity and a high level of malondialdehyde in erythrocytes from PCa patients. The consumption of 2–3 cups of green tea per day for 6 months significantly increased glutathione concentration and catalase activity and decreased malondialdehyde concentration. Green tea also significantly decreased oxidative stress in these patients, indicating that regular consumption of green tea for a long period may prevent the development of PCa or at least delay its progression .
In a clinical trial in ten patients with stage 0 chronic lymphocytic leukemia (CLL) and ten healthy subjects administered oral green tea extract (GTE) therapy for 6 months, eight out of ten patients showed a reduction in lymphocytosis and absolute number of circulating regulatory T (Treg) cells. Only one nonresponding patient had disease progression at 5 months after the end of GTE administration and chemotherapy. These findings suggest that green tea can control lymphocytosis and prevent disease progression .
In a clinical trial in 124 subjects who were recruited and randomly assigned to low-dose GTCs (500 mg), high-dose GTCs (1,000 mg), or placebo for 3 months, urinary fumonisin B1, a carcinogen, was significantly decreased after 1 month in the high-dose group compared with the placebo group, with reduction rates of 18.95% in the low-dose group and 33.62% in the high-dose group. After a 3-month intervention, urinary levels of fumonisin B1 were reduced to 40.18% in the low-dose group and 52.6% in the high-dose group compared with both the placebo group and baseline levels. These findings suggest that supplementation with GTCs may represent a useful chemopreventive strategy for reducing co-exposure to aflatoxin B1 and fumonisin B1 .
In a randomized placebo-controlled trial, 99 women received either Polyphenon E (PPE) , a green tea polyphenol formulation primarily consisting of EGCG, or placebo once a day for 4 months. A complete response, defined as negative for high-risk human papilloma virus and normal histopathology, was noted in 17.1% and 14.6% of women in the PPE and placebo arms, respectively, showing a preferable effect of PPE .
In a phase II pharmacodynamic prevention trial of PPE, patients with bladder tumors were randomized to receive PPE containing either 800 or 1,200 mg of EGCG or placebo for 14–28 days prior to transurethral resection of the bladder tumor or cystectomy. EGCG levels in plasma and urine increased significantly, and the expression of proliferating cell nuclear antigen and clusterin was downregulated in the bladder tissues. Despite the limitations of this pilot study, the authors pointed out that the observed pharmacodynamics and desirable biological activity warranted further clinical studies of PPE in bladder cancer prevention .
In a randomized clinical trial to evaluate GTE for the prevention of metachronous colorectal polyps, 143 patients who underwent the endoscopic removal of colorectal adenomas were divided into a supplementation group (0.9 g GTE/day for 12 months) and a control group without supplementation. Follow-up colonoscopy after conducted 12 months found that the incidence of metachronous adenomas was 42.3% in the control group and 23.6% in the GTE group. The number of relapsed adenomas also decreased in the GTE group compared with that in the control group .
Although several studies have demonstrated the anticancer effects of green tea, as described above, conflicting results have also been reported [1, 4]. For example, Je and Park identified five eligible cohort studies comprising 231,870 female participants and 1,831 cases of endometrial cancer . The pooled RR of the three studies conducted in the United States, in which black tea was consumed by most people, was 1.00. These findings do not support an association between tea consumption and endometrial carcinogenesis risk. Furthermore, a meta-analysis of 25 case-control studies (15,643 patients and 30,795 controls) and 7 prospective cohort studies (1,807 cases and 443,076 participants) showed that tea consumption was not significantly associated with bladder cancer risk .
In a double-blind randomized controlled trial, subjects with primary multifocal high-grade prostatic intraepithelial neoplasia and/or atypical small acinar proliferation received 35 mg lycopene, 55 μg selenium, and 600 mg GTCs, or placebo, per day for 6 months. The results indicated that the administration of high doses of lycopene, GTCs, and selenium in men was associated with a higher incidence of PCa, suggesting that the use of these supplements should be avoided .
In a comprehensive review article, Yang and Wang concluded that the results of human studies on GTCs, mostly from small randomized clinical trials, have been inconsistent . The authors highlighted the following examples. An earlier randomized clinical trial on oral cancer prevention in China showed that a mixed tea product (3 g/day) caused a significant decrease in cancer growth, but a later phase II randomized clinical trial in the United States showed that GTE (500, 750, or 1,000 mg/m2, twice daily) for 12 weeks resulted in only potentially beneficial effects, which were not significant in reducing oral premalignant lesions. Furthermore, in spite of seemingly promising results reported in the Italian intervention study mentioned previously, a subsequent trial in Florida with a similar design showed that catechin supplementation for 6–12 months did not cause a reduction in the number of PCa cases compared with placebo .
Thus, further studies are needed to determine the chemopreventive effects of green tea, but its potentially beneficial effects are supported by Yang and Wang in a phase 2 trial in patients with early CLL where oral doses of PPE (2,000 mg twice/day) caused a sustained decline in absolute lymphocyte count and/or lymphadenopathy in the majority of patients . Furthermore, in a study to assess salivary antioxidant alterations in smokers, participants who consumed 2 cups of green tea per day (2 g of green tea dissolved in 150 mL hot water per cup) had increased levels of salivary antioxidants, suggesting that green tea may reduce the rate of oral cancer, given the likely association between oxidative stress and oral cancer .
This optimistic expectation may also be supported by a highly encouraging case report of an EGCG-based ointment (PPE/sinecatechins), approved by the US Food and Drug Administration, which was successfully used to treat anogenital warts. Rob et al. found that after application of the ointment for 10 weeks in an 11-year-old child, the warts disappeared completely without recurrence during a 12-week follow-up .
2.1.3 Laboratory Studies and Mechanism of Action
A large number of animal and cell-based experiments have indicated the anticancer effects of green tea [1, 2, 3, 4, 5, 6, 38, 39]. For black tea and oolong tea, however, fewer studies are available. Hibasami et al. reported for the first time that catechins, including EGCG, induced apoptosis or programmed cell death in cancer cells . Our research group also observed similar apoptosis-inducing actions of EGCG and has proposed that the binding of EGCG to the cell surface Fas protein is involved in its anticancer activity . Tachibana et al. found that the 67 kDa laminin receptor on the cell surface is an EGCG receptor and mediates various types of EGCG activity, including its anticancer activity . The role of the protein-binding capability of EGCG in its mechanism of action has been reviewed elsewhere by Yang et al. as well as our research group [1, 2].
The number of animal and cell-based experiments showing anticancer effects of EGCG and GTCs continues to increase, as described next. C3H/He mice (8 weeks old; n = 46) were treated with 0.05% N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) solution for 14–24 weeks. Mice in the BBN + GTP group (n = 47) were additionally treated with 0.5% GTP solution over the same period. Cytoplasmic human antigen R (HuR) expression in cancer cells increased at 14 and 24 weeks in the BBN group compared with that in the control group and was associated with increased invasion of tumor cells in muscle. However, these effects were not observed in the BBN + GTP group. GTP was independently associated with cyclooxygenase (COX)-2 and heme oxygenase (HO)-1 expression, while cytoplasmic HuR expression was associated with COX-2 and vascular endothelial growth factor (VEGF)-A levels. Expression of COX-2 and HO-1 was associated with cell proliferation while that of VEGF-A and HO-1 was associated with angiogenesis. Therefore, GTP potentially suppresses tumor cell proliferation and angiogenesis both directly and indirectly via HuR-related pathways in bladder cancer .
When the cytotoxic effects of GTPs were examined in human cell lines (MCF-7, A549, Hela, PC3, and HepG2 cells), GTPs were found to inhibit cell growth, particularly in MCF-7 cells. Mechanistic studies showed that the main modes of cell death induced by GTCs were cell cycle arrest at G1/M and G2/M and apoptosis . GTP also caused a reduction in mitochondrial membrane potential, increased the generation of reactive oxygen species (ROS) , induced DNA fragmentation, and activated caspase 3 and caspase 9 .
The cancer-preventive activity of PPE was demonstrated in an animal model of colorectal cancer induced by azoxymethane (AOM) . Dietary PPE increased the plasma and colonic levels of tea polyphenols and decreased tumor multiplicity and size. It also decreased β-catenin nuclear expression, induced apoptosis, and increased the expression of retinoid X receptor (RXR)-α, β, and γ in adenocarcinomas. These results demonstrate the inhibitory effects of orally administered PPE on colon carcinogenesis .
Posadino et al. investigated the impact of PPE on PCa cells. PPE treatment at 30 and 100 μg/mL significantly decreased cell viability and proliferation. PPE-induced cell death was associated with mitochondrial dysfunction and the downregulation of Akt activation. Cell exposure to the ROS scavenger N-acetylcysteine prevented PPE-induced ROS increase, Akt activation impairment, and cell death, indicating the causative role of ROS. In cells over-expressing Akt, PPE failed to cause ROS increase, Akt activation impairment, and cell death. Thus, PPE induced apoptotic cell death through a prooxidant rather than an antioxidant mechanism .
When estrogen receptor α-positive breast cancer T47D cells were treated with 0–80 μM EGCG, cell viability was decreased, and EGCG at 80 μM increased the gene expression of PTEN, caspase 3, and caspase 9 but decreased that of Akt. Furthermore, EGCG increased the Bax/Bcl-2 ratio of gene and protein expression and decreased the gene expression of hTERT. These findings suggest that EGCG may be a useful adjuvant therapeutic agent for the treatment of breast cancer . Chen et al. found that EGCG inhibited the spheroid formation of colorectal cancer cells as well as the expression of colorectal cancer stem cell markers, suppressed cell proliferation, and induced apoptosis. EGCG downregulated the activation of the Wnt/β-catenin pathway, supporting its potential as an anticancer agent targeting colorectal cancer stem cells through the suppression of this pathway . Aberrant expression of β-catenin is associated with the progression of various cancers, including head and neck cancer. Shin et al. found that EGCG induced apoptosis in KB and FaDu cells via the suppression of β-catenin signaling and promotion of ubiquitin-mediated 26S proteasomal degradation. These effects of EGCG were confirmed in a syngeneic mouse model .
Harati et al. found that EGCG suppressed the proliferation and viability of liposarcoma, synovial sarcoma, and fibrosarcoma cells . Cornwall et al. showed that EGCG at concentrations ranging from 25 to 100 μg/mL induced apoptosis in CLL B-cells but did not affect healthy control B-cells. They also showed that, in contrast to healthy controls, T-cells from CLL patients underwent apoptosis in the presence of EGCG. Thus, EGCG differentially induces apoptosis in CLL B- and T-cells but not in healthy B- and T-cells .
In an attempt to identify its anticancer activities against cholangiocarcinoma cells, Kwak et al. found that EGCG inhibited the growth of HuCC-T1 cells but not of human embryonic kidney 293 T cells, indicating that EGCG induced apoptosis in cancer cells without adverse effects in normal cells. EGCG inhibited the expression of mutant p53 and induced apoptotic molecular signals such as Bax/Bcl-2, caspases, and cytochrome c. EGCG also inhibited the activity of matrix metalloproteinase (MMP)-2/9, invasion, and migration. In an animal tumor xenograft model using HuCC-T1 cells, EGCG inhibited tumor growth and suppressed carcinogenic molecular signals such as Notch1, MMP-2/9, and proliferating cell nuclear antigen .
Similarly, Luo et al. showed that treatment of bladder cancer SW780 cells with EGCG resulted in the significant inhibition of cell proliferation by induction of apoptosis, without obvious toxicity to normal bladder epithelium SV-HUC-1 cells. EGCG also inhibited SW780 cell migration and invasion at 25–100 μM. EGCG induced apoptosis in SW780 cells by the activation of caspases 8, 9, and 3; Bax; Bcl-2; and PARP. Animal studies demonstrated that EGCG decreased tumor volume and weight in mice bearing SW780 tumors and downregulated the expression of nuclear factor-kappa B (NF-κB) and MMP-9 at both the protein and mRNA level in tumor and SW780 cells . As exemplified by this finding and the studies described above, EGCG exerts stronger apoptosis-inducing effects on cancerous cells than on normal cells. Our research group has also provided evidence that differentiated HL-60 cells are notably less susceptible to apoptosis than undifferentiated cells .
Interestingly, Ward et al. reported that different diets may have different effects on the action of GTE. They hypothesized that GTE would have different effects on colon carcinogenesis, body composition, and lipid metabolism in mice fed a basal diet formulated to promote health and growth (AIN93G) compared with total Western diet, which emulates the typical American diet. Mice were fed either AIN93G or the total Western diet for 18 weeks with or without GTE. The quantity of a precancerous marker, aberrant crypt foci (ACF), was nearly three times greater in AOM-treated mice fed the total Western diet than in those fed AIN93G. The consumption of GTE suppressed ACF development only in mice fed the total Western diet. Similarly, supplementation with GTE suppressed weight gain and fasted glucose level only in mice fed the total Western diet, while GTE suppressed fat mass gain in mice fed either diet, suggesting that diet is an important factor for the efficacy of GTCs .
In their review of animal and cell experiments, Yang and Wang extensively discussed the molecular mechanisms by which GTCs exert anticancer actions. For example, in tumorigenesis of the small intestine in ApcMin/+ mice, EGCG action was associated with increased levels of E-cadherin on the plasma membrane and decreased levels of nuclear β-catenin , c-Myc, phospho-Akt, and phospho-ERK1/2 in tumors . In a model of AOM-induced precancerous lesions, the inhibitory activity of PPE was associated with decreased levels of nuclear β-catenin and cyclin D1 and increased levels of RXR-α. In male C57BL/KsJ-db/db mice, the inhibition of AOM-induced ACF formation by EGCG was associated with the suppression of insulin-like growth factor 1 (IGF1) signaling. EGCG also increased the levels of IGF1 receptor (IGF1R), phospho-IGF1R, phospho-GSK3, and β-catenin in colonic mucosa. Yang and Wang further described that oral administration of 0.5% PPE or 0.044% caffeine in drinking water to tumor-bearing A/J mice inhibited the progression of lung adenomas to adenocarcinomas by enhancing apoptosis and decreasing the levels of c-Jun and phospho-ERK1/2 in adenocarcinomas.
In a study which examined the cytotoxicity of green, black, and purple tea infusions, green tea inhibited breast cancer 4TI cell proliferation to the greatest extent with an IC50: 13.12 μg/mL. Results also revealed the differential expression of apoptosis-related genes. Caspases 8, 9, 3, and 6 and 8AP2, Aifm1, Aifm2, and Apopt1 genes were significantly upregulated, indicating the process of apoptosis was initiated and executed .
In a PCa model, the antitumor action of GTC was associated with the modulation of IGF1 and IGFBP3 levels with reduced levels of phosphatidylinositol 3-kinase (PI3K) , phospho-Akt, and phospho-ERK1/2. Furthermore, GTC significantly decreased the levels of angiogenic and metastatic markers such as VEGF-A, MMP-2, and MMP-9 .
Tumor metastases are responsible for approximately 90% of all cancer-related deaths . In these events, cancer cells released from the tumor invade surrounding tissues, enter the blood vessels, and extravasate to spread to new organs through several steps including attachment to and subsequent degradation of the endothelial basement membranes . In 1992, Taniguchi et al. reported that GTCs rich in EGCG inhibited the metastasis of melanoma B16-F10 and BL6 cells in both experimental and spontaneous metastasis systems . Our research group has also observed similar effects of green tea in an animal model of metastasis .
In 2001, GTEs were demonstrated to inhibit metastasis in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice, and a later study showed that PPE was an effective chemopreventive agent in preventing metastasis of PCa in this mouse model [60, 61]. A likely molecular basis for the inhibition of metastasis by green tea and GTCs is their ability to inhibit the enzymatic activity and gene expression of MMPs . The results of our research group suggest that EGCG inhibits MMP activity by directly binding to MMPs .
Theaflavins have been shown to inhibit the growth and metastasis of HCC in an orthotopic model and a lung metastasis model. Theaflavins induced apoptosis by activating the caspase pathway, suppressing the phosphorylation of constitutive and inducible signal transducer and activator of transcription 3 (STAT3), and downregulating downstream proteins regulated by STAT3, including antiapoptotic proteins (Bcl-2 and survivin) and invasion-related proteins MMP-2 and MMP-9 .
Angiogenesis is required for many physiological processes, including embryogenesis and postnatal growth, but pathological angiogenesis is a hallmark of several diseases including cancer and subsequent metastasis. Rashidi et al. reviewed the ability of green tea constituents to suppress angiogenesis signaling, summarized the mechanism by which EGCG might act on the VEGF family of proteins, and highlighted the microRNAs affected by green tea that are involved in antiangiogenesis .
2.2 Effects of Coffee on Cancer
2.2.1 Epidemiological Studies
Some early epidemiological studies of the health effects of coffee showed that coffee consumption was associated with an increase in cancer risk . For example, Yu et al. reported that daily coffee consumption was a risk factor for renal cell carcinoma in women . However, several later studies have demonstrated the beneficial effects of coffee on cancer. A comprehensive review by Wierzejska showed that coffee consumption reduced cancer risk in 1/4 studies on bladder cancer, 10/17 studies on breast cancer, 6/9 studies on colorectal cancer, 5/5 studies on liver cancer, 2/4 studies on pancreatic cancer, and 3/4 studies on PCa, while 3/3 studies on lung cancer showed an increased risk . Since then, a growing number of studies have sought to further examine these effects, as reviewed here.
In a study of 64,603 participants with a follow-up period of up to 15 years for breast cancer, consumption of ≥4 cups/day of boiled coffee was associated with a reduced risk of cancer (hazard ratio (HR): 0.52) as compared with <1 cup/day, although no association was found for all cancer sites combined or for prostate and colorectal cancers. An increased risk of premenopausal breast cancer and a reduced risk of postmenopausal breast cancer were found for both total coffee (HR, 1.69 for premenopausal breast cancer; HR, 0.60 for postmenopausal breast cancer) and filtered coffee (HR, 1.76 for premenopausal breast cancer; HR, 0.52 for postmenopausal breast cancer). Boiled coffee was associated with an increased risk of respiratory tract cancer (HR, 1.81), a finding limited to men. The main results for less common cancer types included reduced risk for renal cell cancer with total coffee (HR, 0.30) and increased risk for pancreatic cancer for boiled coffee (HR, 2.51). These findings demonstrate that coffee has beneficial effects in certain types of cancer and that the effect may be dependent on the brewing method .
A population-based prospective cohort study of >215,000 men and women in Hawaii and California with an 18-year follow-up period showed that high levels of coffee consumption were associated with reduced risk of incident HCC and chronic liver disease mortality. Compared with non-coffee drinkers, those who drank 2–3 cups/day had a 38% reduction in risk for HCC (RR, 0.62), while those who drank ≥4 cups/day had a 41% reduction in HCC risk (RR, 0.59). Compared with non-coffee drinkers, participants who consumed 2–3 cups of coffee/day had a 46% reduction in risk of death from chronic liver disease (RR, 0.54), and those who drank ≥4 cups/day had a 71% reduction (RR, 0.29). These findings suggested that coffee consumption reduces the risk of HCC and chronic liver disease in multiethnic US populations .
A study of 738 middle-aged Japanese patients with adenoma and 697 controls showed that high coffee consumption was associated with a reduced risk of adenoma. A multivariate-adjusted OR for the highest versus lowest quartile of coffee intake was 0.67, suggesting a protective effect of coffee drinking on colon adenoma, a precursor of colon cancer .
Results from a Danish case-control study from 1995 through 1999 showed that both coffee (OR, 0.90 per cup/day) and total caffeine consumption from coffee and tea combined (OR, 0.93 per 100 mg/day) decreased the risk of ovarian cancer .
The results of the European Prospective Investigation into Cancer and Nutrition study in a total of 335,060 women from 1992 to 2000 indicated that higher caffeinated coffee intake may be associated with a lower risk of postmenopausal breast cancer, with a null association in the case of decaffeinated coffee .
A prospective study of breast cancer in the Swedish Women’s Lifestyle and Health study of 42,099 female participants suggested that coffee consumption and caffeine intake were inversely associated with the overall risk of breast cancer and of estrogen receptor-positive/prolactin-negative breast cancer .
In a case-control study, during and 6 months after adjuvant chemotherapy, 953 patients with stage III colon cancer prospectively answered questionnaires which included the dietary intake of caffeinated coffee , decaffeinated coffee , and non-herbal tea. The results showed that patients who consumed ≥4 cups/day of total coffee had an adjusted HR of 0.58 for colon cancer recurrence or mortality, compared with nondrinkers. The daily consumption of ≥4 cups of caffeinated coffee resulted in reduced cancer recurrence or mortality risk (HR, 0.48), while decaffeinated coffee was not associated with cancer outcome .
In a prospective cohort study in 307 patients over 4 years, the risk of colorectal tumor recurrence was significantly lower (OR, 0.21) in patients who consumed >3 cups of coffee/day compared with those who did not consume coffee. In a sub-analysis of tumor location, OR of colorectal tumor recurrence in the proximal colon showed a tendency toward reduction as coffee consumption increased; however, increased coffee consumption significantly increased colorectal tumor recurrence in the distal colon .
A meta-analysis with a total of 1,534,039 participants from 13 published studies showed that the RR of total coffee consumption and endometrial cancer was 0.80. A stronger inverse association between coffee intake and cancer incidence was found in patients who had never received hormone therapy (RR, 0.60) and subjects with a BMI ≥25 kg/m2 (RR, 0.57). The overall RR for caffeinated and decaffeinated coffee was 0.66 and 0.77, respectively. Endometrial cancer risk decreased by 5% for every 1 cup of daily coffee intake, 7% for every 1 cup of daily caffeinated coffee intake, 4% for every 1 cup of daily decaffeinated coffee intake, and 4% for every 100 mg of daily caffeine intake. These findings suggest that coffee and caffeine may reduce the incidence of endometrial cancer and that these effects may be modified by BMI and history of hormone therapy .
A systematic review and meta-analysis of nine observational studies with a total of 927,173 study participants showed that the pooled RR for melanoma among regular coffee drinkers was 0.75 compared with controls. The pooled RR for melanoma among decaffeinated coffee drinkers was, however, not statistically significant .
A systematic review and meta-analysis of prospective cohort studies including 12 studies on HCC (3,414 cases) and 6 studies on chronic liver disease (1,463 cases) found that the summary RRs for HCC were 0.66 for regular, 0.78 for low, and 0.50 for high coffee consumption, respectively. The summary RRs for chronic liver disease were 0.62 for regular, 0.72 for low, and 0.35 for high consumption and 0.74 for an increment of 1 cup/day. These findings indicate an inverse relation between coffee consumption and the risk of HCC and chronic liver disease .
In a meta-analysis of observational studies published until February 2016, the intake of caffeinated coffee was inversely associated with nonmelanoma skin cancer risk (summary RR, 0.82 for those in the highest versus lowest category of intake), as was the intake of caffeine (summary RR, 0.86). In a subgroup analysis, these associations were limited to the basal cell cancer histotype. There was no association between decaffeinated coffee intake and summary RR, suggesting that caffeine may contribute to the risk reduction .
A meta-analysis of 9 cohort and 13 case-control studies involving 7,631 cases and 1,019,693 controls reported a summary RR for gastric cancer of 0.94 for the highest category of coffee consumption compared with the lowest category and 0.93 for coffee drinkers compared with nondrinkers. The pooled RRs for the population consuming <1 cup/day, 1–2 cups/day, and 3–4 cups/day compared with that of nondrinkers were 0.95, 0.92, and 0.88, respectively, indicating that an increase in coffee consumption was associated with a decreased risk of gastric cancer .
Another meta-analysis of the cohort and case-control studies reported a summary RR for nonmelanoma skin cancer of 0.96 for 1 cup of coffee, 0.92 for 1–2 cups, 0.89 for 2–3 cups, and 0.81 for >3 cups/day, respectively. The results suggest that caffeinated coffee might have dose-dependent chemopreventive effects against basal cell carcinoma .
The results of a study of 18 cohorts, involving 2,272,642 participants and 2,905 cases, and of 8 case-control studies, involving 1,825 cases and 4,652 controls, showed that increased consumption of caffeinated coffee and, to a lesser extent, decaffeinated coffee was associated with reduced risk of HCC, including in patients with preexisting liver disease. An extra intake of 2 cups/day of coffee was associated with a 35% reduction in the risk of HCC .
However, several studies have failed to demonstrate the beneficial effects of coffee, as exemplified by the following studies. A cohort study with 560,356 participants in the UK Million Women Study found no significant association between endometrial cancer risk and consumption of coffee . In a systematic meta-analysis of 2,803 cases and 503,234 controls in ten independent studies, Chen et al. found that coffee consumption was significantly associated with the increased risk of laryngeal carcinoma (RR : 1.47) .
A meta-analysis of 9 prospective cohort studies involving 1,250,825 participants and 3,027 gastric cancer cases demonstrated that coffee consumption was not associated with overall gastric cancer risk and that it may even be a risk factor for gastric cardia cancer .
A meta-analysis of 17 studies (5 cohort and 12 case-control studies) involving 12,276 cases and 102,516 controls showed that coffee intake was associated with an increased risk of lung cancer. Particularly over the past 5 years, studies have consistently indicated that lung cancer risk is significantly increased by 47% in the population with the highest category intake of coffee compared to that with the lowest category intake .
In a large population-based case-control study in Italy, no association was observed between regular coffee consumption and any type of leukemia . A meta-analysis of 12 case-control studies, comprising a total of 3,649 cases and 5,705 controls, showed that high maternal coffee consumption was associated with increased risk of acute lymphoblastic leukemia (OR, 1.43) and acute myeloid leukemia (OR, 2.52) in children. The finding indicates a detrimental association between maternal coffee consumption and childhood leukemia risk .
A multicentric case-control study on 690 bladder cancer cases and 665 hospital controls conducted in Italy between 2003 and 2014 showed that decaffeinated coffee, tea, cola, and energy drinks were not related to bladder cancer risk . A meta-analysis of 13 prospective cohort studies with 20 independent reports involving 3,368 patients with gastric cancer and 1,372,811 participants during a follow-up period ranging from 4.3 to 8 years did not support the hypothesis that coffee consumption was associated with the reduced risk of gastric cancer and even indicated an increased risk of gastric cancer for participants in the United States .
The results of a population-based prospective cohort study in Japan on 89,555 people aged 45–74 years showed no clear association between coffee consumption and biliary tract, gallbladder, or extrahepatic bile duct cancer . Furthermore, based on the meta-analysis of five cohort studies and nine case-control studies, Akter et al. concluded that the evidence was insufficient to support that coffee drinking increased or decreased the risk of colorectal cancer .
These conflicting results may have been caused by several confounding factors, including the methods of quantifying coffee consumption, coffee temperature, cigarette smoking, alcohol consumption, and differences in genetic and environmental factors such as race, sex, age, intestinal microbiota, and lifestyle as in the case of tea consumption [1, 2, 92].
2.2.2 Clinical Studies
A total of 31 men and 33 women were randomly assigned to two groups with two intervention periods of 2 weeks separated by a washout period of 8 weeks, and they consumed 1,000 mL of cafetière (French press) coffee daily or no coffee . The results showed that unfiltered coffee significantly increased the glutathione content in the colorectal mucosa by 8% and in plasma by 15%. Unfiltered coffee did not influence the colorectal mucosal proliferation rate, but appeared to cause an increase in detoxification capacity and antimutagenic properties in the colorectal mucosa by increasing the glutathione concentration. Thus, the findings suggest a possible reduction of colon cancer risk by coffee consumption.
A controlled intervention trial with a crossover design in which 38 participants consumed 800 mL coffee or water daily over 5 days demonstrated that the proportion of DNA migration attributable to the formation of oxidized purines was decreased by 12.3% after coffee intake. However, other biochemical parameters including the total antioxidant levels in plasma, glutathione concentrations in blood, and superoxide dismutase and glutathione peroxidase activity in lymphocytes were not markedly altered. These results indicate that coffee consumption prevents the endogenous formation of oxidative DNA damage in humans .
A clinical trial in which ten participants consumed 1 L of unfiltered coffee/day over 5 days showed a weak induction of glutathione S-transferase (GST) and a threefold increase in the induction of placental-type GST in blood, whereas the level of GST-α was not altered . Although serum cholesterol levels were increased without statistical significance, other clinical parameters (creatinine, alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase), which are markers for organ damage, were not altered. In a similar trial with seven participants who consumed 1 L coffee/day over 3 days, a significant threefold induction of placental-type GST was observed. The effects were identical between filtered and unfiltered coffee, indicating that caffeine concentration was not responsible for this result. In a further trial, the consumption of unfiltered coffee (1 L/day for 5 days) resulted in a 45% reduction effect. These findings show that coffee induces placental-type GST, which may confer protection against chemical carcinogenesis .
However, a placebo-controlled intervention trial on 160 healthy human subjects who consumed 3 or 5 cups of coffee per day for 8 weeks showed that blood pressure, oxidation of DNA and lipids, blood glucose level, insulin , cholesterol , triglycerides , and inflammatory markers were unchanged, although a slight elevation of serum creatinine level and a significant elevation of serum γ-glutamyl transaminase level were observed in the 5 cups/day group. These findings indicated that there was no detectable effect, either beneficial or harmful, of coffee consumption on human health . Given the conflicting results of these clinical studies, further studies are warranted to understand the relationship between coffee and cancer.
2.2.3 Laboratory Studies and Mechanism of Action
Numerous cell-based and animal experiments have demonstrated the anticancer effects of CGAs, the most common polyphenols found in coffee.
A cell-based experiment found that CGA inhibited the viability of colon cancer HCT116 and HT29 cells. CGA induced ROS production and cell cycle arrest at the S phase and suppressed the activation of ERK. These events may lead to a reduction in viability of cancer cells and suggest that CGA is a potential treatment for colorectal cancer. Deka et al. found that CGA killed MDAMB-231 and MCF-7 breast cancer cells with an IC50 of about 76 and 53 μg/mL, respectively. CGA bound to protein kinase C (PKC) with a dissociation constant of about 29 μM and caused the translocation of PKC from the cytosol to the plasma membrane, leading to cell cycle arrest at the G1 phase. CGA induced apoptosis through a mitochondrial pathway which involves a reduction in mitochondrial potential and the release of cytochrome c into the cytosol .
Salomone et al. reviewed the effects of coffee and its components in experimental models of liver cancer. Coffee exerted beneficial effects, including a reduction in preneoplastic lesions in an aflatoxin-induced liver cancer model, a reduction in tumor growth and metastasis in hepatoma-bearing rats, and a reduction in the incidence of liver tumors in an aminopyrine-sodium nitrite-induced cancer model. Regarding the mechanism of action of coffee and CGA, the authors highlighted the antioxidant effects associated with nuclear factor, erythroid 2 like 2 (Nrf2) signaling, the activation of which leads to (1) the induction of enzymes involved in xenobiotic detoxification processes and cellular antioxidant defenses; (2) the induction of gene expression of hepatic and intestinal NAD(P)H/quinone oxidoreductase 1, GST class α1, intestinal uridine-5′-diphosphoglucose-glucuronosyl transferase 1A6, and the glutamate cysteine ligase catalytic subunit; (3) the induction of the transcription of several UDP-glucuronosyltransferases in hepatoma cells; and (4) an increase in hepatic superoxide dismutase, catalase, and glutathione peroxidase activity .
When G422 glioma cells were injected subcutaneously into the right flank of ICR mice in a xenograft model experiment and the mice were intraperitoneally administered either CGA or vehicle daily for 2 weeks, CGA inhibited glioblastoma growth. Moreover, CGA increased the population of CD11c-positive M1 macrophages and decreased the distribution of CD206-positive M2 macrophages in tumor tissue via the promotion of STAT1 activation and inhibition of STAT6 activation, respectively, suggesting its therapeutic potential for the reduction of glioma growth .
CGA was also shown to have therapeutic effects in breast cancer, brain tumors, lung cancer, colon cancer, and chronic myelogenous leukemia. Suggested mechanisms of action of CGA include (1) the induction of GSK-3 β and APC genes; (2) the inhibition of the β-catenin gene; (3) the inhibition of activator protein-1, NF-κB, and MAPKs; and (4) the induction of phase 2 detoxifying enzyme activity .
The bark of Odina wodier is one of the Indian tribes for treating inflammatory disorders, and its major constituent is CGA. Ojha et al. demonstrated that both the methanol extract of bark and CGA exerted significant anti-inflammatory activity, inhibiting the expression of tumor necrosis factor (TNF-α) , interleukin (IL)-1β , IL-6, and IL-12. The expression of murine TLR4, NF-κBp65, MyD88, iNOS, and COX-2 molecules was also reduced in CGA-treated groups. These findings suggest that CGA can inhibit inflammation by downregulating the TLR4/MyD88/NF-κB signaling pathway. Through these activities, CGA may be beneficial for the prevention of chronic inflammatory diseases including cardiovascular diseases, diabetes, and cancer .
In contrast, Choi et al. found that neither caffeine, caffeic acid, nor CGA showed any cytotoxicity against colon adenocarcinoma HT-29 cells, while a coffee diterpene, kahweol, did .
Cancer metastasis may be prevented by coffee polyphenols . Weng and Yen reviewed several studies to show anti-invasive and anti-metastasis activities of dietary phenolic compounds including CGA and caffeic acid in various cancer cells such as hepatoma Hep3B and SKHep1 cells, glioma U-87 cells, prostate cancer PC3 cells, fibrosarcoma HT1080 cells, and colon adenocarcinoma CT26 cells . The authors concluded that the daily consumption of natural dietary components that are rich in phenolics could be beneficial for the prevention of cancer metastasis.
2.3 Simultaneous Evaluation of the Anticancer Effects of Tea and Coffee
Examples of the simultaneous evaluation of the effects of tea and coffee on human cancer riska
Biliary tract cancer
Nonmelanoma skin cancer
All cancers combined
The results of a Danish case-control study indicated that both coffee and total caffeine consumption from coffee and tea combined decreased the risk of ovarian cancer, while no relationship was observed between tea consumption and ovarian cancer risk .
In a middle-aged Japanese population, Budhathoki et al. found that high coffee consumption was associated with a reduced risk of colorectal adenoma, with a multivariate-adjusted OR of 0.67 for the highest versus the lowest quartile of coffee intake, indicating a protective effect of coffee drinking against colon adenoma, a precursor of colon cancer. Green tea intake was not found to be associated with colorectal adenoma risk .
A systematic meta-analysis of 2,803 cases and 503,234 controls in ten independent studies, including case-control and cohort studies, showed that tea drinking was not associated with laryngeal carcinoma. However, coffee consumption was positively associated with laryngeal carcinoma (RR, 1.47) .
A cohort study with 560,356 participants in the UK Million Women Study found no significant association between endometrial cancer risk and the consumption of either tea or coffee .
The prospective study of breast cancer in the Swedish Women’s Lifestyle and Health study among 42,099 female participants suggested that coffee consumption and caffeine intake reduced the risk of both overall and estrogen receptor-positive/prolactin-negative breast cancer, while tea consumption increased the risk .
A multicenter case-control study on 690 bladder cancer cases and 665 hospital controls conducted in Italy between 2003 and 2014 showed that consumption of decaffeinated coffee, tea, cola, and energy drinks was not related to bladder cancer risk .
In a meta-analysis of observational studies reported up to February 2016, intake of both caffeinated coffee and caffeine was inversely associated with nonmelanoma skin cancer risk (summary RR, 0.82). In a subgroup analysis, these associations were limited to the basal cell cancer histotype. There was no association between intake of decaffeinated coffee and green tea and nonmelanoma skin cancer risk .
A meta-analysis of 12 case-control studies, comprising a total of 3,649 cases and 5,705 controls, showed that high maternal coffee consumption was associated with increased risk of acute lymphoblastic leukemia (OR, 1.43) and acute myeloid leukemia (OR, 2.52). On the contrary, low-to-moderate tea consumption was inversely associated with overall leukemia (OR, 0.85), although the trend was not significant. These findings indicate the detrimental association between maternal coffee consumption and childhood leukemia risk. In contrast, an inverse association was found with tea, implying that other micronutrients contained in this beverage could potentially counterbalance the deleterious effects of caffeine .
The results of a population-based prospective cohort study in Japan on 89,555 people aged 45–74 years showed no clear association between coffee consumption and biliary tract, gallbladder, or extrahepatic bile duct cancer. However, the findings suggested that high green tea consumption might lower the risk of biliary tract cancer .
In a large population-based case-control study in Italy, no association was observed between regular coffee consumption and any type of leukemia. A small protective effect of tea intake was found among myeloid malignancies, which was more evident among acute myeloid leukemia (OR, 0.68) .
In a study of 97,334 eligible individuals, 10,399 developed cancers including 145 head and neck, 99 esophageal, 136 stomach, 1137 lung, 1703 breast, 257 endometrial, 162 ovarian, 3037 prostate, 318 kidney, 398 bladder, 103 glioma, and 106 thyroid cancers. Coffee intake was not associated with the risk of all cancers combined, whereas tea drinking was associated with an overall decreased risk of cancer (RR, 0.95 for 1 cup-increment/day versus <1 cup/day). For endometrial cancer, a decreased risk was observed for coffee intake (RR, 0.69) of ≥2 cups/day .
A Japanese cohort study with 106,324 subjects (50,438 men and 55,886 women) found a significant inverse association between coffee consumption and brain tumor risk in both total subjects (≥3 cups/day; HR: 0.47) and in women (≥3 cups/day; HR: 0.24) . No association was observed between green tea and brain tumor risk. A prospective cohort study with 18,815 subjects aged 40–69 years showed that coffee consumption may reduce the risk of liver cancer regardless of hepatitis C virus (HCV) or hepatitis B virus (HBV) infection status, whereas green tea may not .
Thus, there are conflicting results related to the effects of both tea and coffee in a variety of human cancers. These differences may have arisen from several confounding factors, including the method of quantifying tea consumption, tea temperature, cigarette smoking, alcohol consumption, and differences in genetic and environmental factors such as race, sex, age, and lifestyle [1, 2, 6, 92]. In addition, caffeine consumption is an important factor to be adjusted for. Intestinal microbiota and genetic polymorphisms may also have influenced the effects of coffee in these studies . The differences in results between human and animal experiments may have been due to different doses of tea and coffee .
3 Effects on Metabolic Syndrome and Related Disorders
3.1 Effects of Green Tea on Metabolic Syndrome
3.1.1 Epidemiological Studies
Metabolic syndrome (MetS) is diagnosed based on variables related to the five components of obesity, blood triglycerides, high-density lipoprotein (HDL) cholesterol, systemic hypertension , and fasting glucose. Any agent that exerts beneficial effects on these components may potentially prevent MetS . Several human studies have suggested that tea is one such agent.
Grosso et al. conducted a cross-sectional survey among 1,889 inhabitants in Sicily, southern Italy, and found that tea consumption was inversely associated with MetS (OR, 0.51) after adjusting for all covariates. Although no direct association between caffeine intake and MetS or its components was observed, tea and coffee were significantly related to reduced OR of MetS. Similarly, results from a cross-sectional population-based survey including 8,821 adults of the Polish arm of the Health, Alcohol and Psychosocial Factors in Eastern Europe cohort study showed that a high consumption of tea was inversely related to MetS, and the analysis stratified by gender revealed a significant association for men but not for women. After adjusting for potential confounding factors, tea consumption was inversely associated with MetS (OR, 0.79) .
In a comprehensive review, Yang et al. provided several examples of reports, including two epidemiological studies to demonstrate the mitigating effects of tea on MetS . One example is the study by Vernarelli and Lambert in 6,472 US adults. Hot tea consumption was inversely associated with obesity, mean waist circumference, and BMI and also increased HDL cholesterol and reduced blood triglyceride levels in women [7, 92]. It should be noted that these associations were not observed with iced tea consumption.
In contrast, some studies did not show a beneficial effect of tea on MetS [7, 92]. For example, a cross-sectional study by Tsubono and Tsugane found no association between green tea intake and serum lipid levels . An epidemiological study on 1,902 Japanese men and women showed no correlation between green tea intake and MetS, since green tea consumption did not influence blood pressure, abdominal circumference, fasting plasma glucose, or lipid levels . The results of a cross-sectional study that enrolled 554 adults in Tokushima, Japan, showed that green tea consumption was not associated with the prevalence of MetS. Thus, epidemiological studies have provided conflicting results, which may have resulted from various factors as discussed above. Further studies are therefore required to determine whether there is an association between tea consumption and MetS .
3.1.2 Clinical Studies
Legeay et al. reviewed six human intervention studies and found that EGCG was associated with decreased BMI (three cases), body weight (four cases), low-density lipoprotein (LDL) cholesterol (five cases), blood pressure (three cases), triglycerides (two cases), and blood glucose (two cases) . In one of these studies, a randomized, double-blind trial in 115 women with central obesity, significant weight loss, from 76.8 kg to 75.7 kg, was observed as well as decreased BMI and waist circumference after 12 weeks of high-dose EGCG treatment, with a consistent trend of reduced total cholesterol and decreased LDL plasma levels .
Amiot et al. conducted a systematic review of dietary polyphenols on subjects with MetS and summarized the effects of green tea and pu-erh tea extracts in ten studies . These studies showed significant improvements in BMI (eight cases), weight circumference (seven cases), blood pressure (one case), LDL cholesterol (five cases), triglycerides (four cases), and blood glucose (two cases) in subjects with MetS. One example showed that in older adults with MetS, the consumption of 3 cups of green tea per day for 60 days was effective in inducing weight loss and reducing both BMI and waist circumference .
3.1.3 Laboratory Studies and Mechanism of Action
A number of experiments using animal models and cultured cells have demonstrated the beneficial effects of tea consumption on MetS and its components and underlying molecular mechanism. For example, a study to evaluate the effect of GTE on drug-induced weight gain and metabolic abnormalities in rats found that GTE exerted protective effects against obesity, partially due to its lowering effect on leptin . In this study, GTE significantly decreased body weight gain and average food and water intake, improved the lipid profile and fasting blood glucose levels, and decreased hyperleptinemia and hypertension in this animal model.
A study using a rat model of benign prostatic hyperplasia accompanied with MetS induced by a high-fat diet (HFD) combined with testosterone injection demonstrated that orally administered EGCG decreased the levels of glucose, total cholesterol, triglycerides, insulin-like growth factors, and inflammatory cytokines, normalized the activities of antioxidant enzymes, and increased the prostatic expression of insulin-like growth factor-binding protein-3 and peroxisome proliferator-activated receptors (PPARs) .
Yang et al. have described two major mechanisms of action for tea: one is the action of tea constituents in the gastrointestinal tract in decreasing the digestion and absorption of macronutrients or by altering the gut microbiota , and the other is that produced by tea constituents following systemic absorption, namely, the inhibition of anabolism and stimulation of catabolism in liver, muscle, adipose, and other tissues . GTCs may decrease the digestion and absorption of nutrients through the inhibition of pancreatic lipase, phospholipases, and lipid transporters to reduce body weight gain. Furthermore, green tea consumption can increase the proportion of favorable intestinal bacteria such as Bifidobacterium species .
Yang et al. have proposed the “AMPK hypothesis,” in which the activation of 5’AMP-activated protein kinase (AMPK) is the main mechanism by which EGCG and other catechins influence energy metabolism to alleviate MetS . AMPK activated by phosphorylation can decrease the expression of enzymes involved in gluconeogenesis, such as phosphoenolpyruvate carboxykinase (PEPCK) ; lipogenesis, such as fatty acid synthase (FASN) ; adipogenesis; and protein synthesis, such as homolog of target of rapamycin (mTOR), and increase the expression of those involved in lipolysis, such as acyl-CoA dehydrogenase (ACAD). Activated AMPK can also modulate the expression of transcription factors such as HNF, SREBP, PPAR-α, and PPAR-γ . Through the activation of AMPK, GTCs can activate the ERK1/2-PPAR-γ-adiponectin pathway, leading to a reduction in fat deposits in HFD-fed rats .
3.2 Effects of Green Tea on Obesity
3.2.1 Epidemiological Studies
A limited number of epidemiological studies on obesity are available to date. Some of these studies have indicated a beneficial effect of tea on obesity . For example, Vernarelli and Lambert found an inverse association between hot tea consumption and obesity as a component of MetS, as described above .
3.2.2 Clinical Studies
Several clinical studies have demonstrated a beneficial effect of tea on obesity [92, 115]. For example, in a meta-analysis of 11 studies which met the inclusion criteria, Hursel et al. found that GTCs significantly decreased body weight and also significantly maintained body weight after a period of weight loss .
A clinical trial in which 240 Japanese subjects with visceral fat-type obesity ingested green tea containing 583 mg of catechins (catechin group) or 96 mg of catechins (control) per day for 12 weeks found that decreases in body weight, BMI, body fat ratio, body fat mass, waist circumference, hip circumference, visceral fat area, and subcutaneous fat area were greater in the catechin group than in the control group .
As mentioned previously, Yang et al. provided several examples of studies that indicated the preventive effect of tea on MetS through the mitigation of obesity . Similarly, a systematic review by Amiot et al. reported the beneficial effects of green tea on BMI . In a literature search, Ferreira et al. found that six out of eight randomized intervention studies showed a beneficial effect of green tea on obesity, such as a reduction in body weight and body fat, while two studies did not .
Green tea may also be useful in the treatment of obesity, as suggested by Suliburska et al. . In their randomized, double-blind, placebo-controlled study, 46 obese patients were randomly assigned to receive either 379 mg of green tea extract or placebo daily for 3 months. They found that 3 months of GTE supplementation decreased BMI, waist circumference, and the levels of total cholesterol, LDL cholesterol, and triglycerides.
By contrast, a randomized controlled trial showed that two kinds of Japanese brand green tea did not affect body weight, although they did show an LDL cholesterol-lowering effect .
3.2.3 Laboratory Studies
The molecular mechanisms for the anti-obesity effects of green tea have been presented in many studies, as described in above section. A comprehensive article published by Huang et al. in 2014 reviewed the anti-obesity effects of green tea in human and laboratory studies and summarized the mechanisms of action of GTC. These included (1) interference with energy absorption and metabolism to inhibit the proliferation of preadipocytes and induce apoptosis in the preadipocyte and matured adipocyte; (2) inhibition of preadipocyte differentiation and the adipogenesis of maturing adipocytes; (3) inhibition of the activity of gastrointestinal digestive enzymes, luminal emulsification, and micellar solubilization of lipids; (4) interference with the uptake and intracellular processing of lipids and secretion of chylomicrons in enterocytes; (5) enhancement of fecal excretion; (6) downregulation of hepatic gene expression of lipogenic enzymes and related transcription factors; (7) upregulation of hepatic mRNA levels of β-oxidation genes; (8) stimulation of fatty acid oxidation and glucose uptake in skeletal muscle; (9) stimulation of the gene expression of lipolysis and fatty acid oxidation-related genes in adipose tissue; and (10) suppression of glucose intake and gene expression of lipogenesis-related genes in adipose tissue . Many of these actions may be explained by the “AMPK hypothesis” of Yang et al. [7, 107] (see Fig. 2).
A recent cell-based experiment also provided one possible mechanism. In adipocytes differentiated from C3H10T1/2 cells and immortalized preadipocytes in vitro, EGCG reduced the triglyceride content. While EGCG did not affect protein kinase A signaling or brown adipocyte marker expression in adipocytes, it did increase autophagy and reduce mitochondrial membrane potential and intracellular ATP levels. Although mTOR signaling was not upregulated by EGCG treatment, AMPK phosphorylation was induced and lipophagy was activated. These results indicated that EGCG upregulated autophagic lipolysis in adipocytes, supporting the therapeutic potential of EGCG as a caloric restriction mimetic to prevent obesity and obesity-related metabolic diseases . AMPK activation by EGCG was also demonstrated in the brown adipose tissue of diet-induced obese mice .
For black tea, detailed information is available in the review article by Pan et al. .
3.3 Effects of Green Tea on Hypertension
3.3.1 Epidemiological Studies
As compared with clinical studies, less information is available for epidemiological cohort studies on the antihypertensive effect of tea/green tea. In a cross-sectional epidemiological study of Singaporean Chinese residents aged ≥40 years, consumption of green tea at least 150 mL per week was associated inversely with hypertension risk (OR, 0.63). Drinking combination of green tea and British tea was associated with higher reduction in the risk of hypertension (OR, 0.58), suggesting that consumption of tea lowers the risk of hypertension . By contrast, a study of the population-based prospective cohort that recruited 63,257 Chinese aged 45–74 years and residing in Singapore found that daily drinkers of green tea/black tea had slight increase in the hypertension risk, but these risk estimates were attenuated and became nonsignificant after adjustment for caffeine .
3.3.2 Clinical Studies
Several studies have demonstrated the beneficial effects of tea on blood pressure. For example, a meta-analysis of 10 studies (834 participants) published from 1946 to September 27, 2013, showed statistically significant reductions in systolic blood pressure (SBP, mean differences −2.36 mmHg) and diastolic blood pressure (DBP, mean differences −1.77 mmHg) with tea consumption in individuals within the prehypertensive and hypertensive blood pressure ranges . Similarly, a meta-analysis of 14 randomized controlled trials in 971 participants found that green tea or GTE supplementation caused a small but significant reduction in blood pressure .
A crossover, randomized, double-blind, placebo-controlled clinical trial in 20 middle-aged women found that GTE supplementation for 4 weeks resulted in a significant decrease in SBP compared with placebo, but not in DBP .
In contrast to reports describing the favorable effect of green tea on hypertension, several studies did not show such an effect. For example, Suliburska et al. found that daily supplementation of 379 mg of GTE for 3 months had no effect on blood pressure in a randomized, double-blind, placebo-controlled study in 46 obese patients, although the supplementation decreased BMI, waist circumference, and the levels of total cholesterol, LDL cholesterol, and triglycerides .
3.3.3 Laboratory Studies
Several laboratory studies have shown the favorable effects of green tea on hypertension and cardiovascular disease (CVD). For example, Yi et al. found that EGCG delayed the progression of hypertension in spontaneously hypertensive rats (SHR) . SHR have higher mean arterial pressure, plasma pro-inflammatory cytokines, and circulating norepinephrine levels compared with normotensive control rats and also manifest increased NF-κB activity and higher levels of the subunit of NAD(P)H oxidase, ROS, and pro-inflammatory cytokines and lower levels of IL-10 in the hypothalamic paraventricular nucleus. The bilateral hypothalamic paraventricular nucleus infusion of EGCG (20 μg/hour) for 4 weeks improved these parameters in SHR, and the involvement of ROS and NF-κB activity in the mechanism of action of EGCG was suggested  (see Fig. 3).
In another experiment in rats fed a high-NaCl diet, supplementation with GTE was shown to reduce blood pressure, concentration of TNF-α, and antioxidant status compared with a control group that did not receive GTE .
Kluknavsky et al. found that subchronic (−)-epicatechin (EC) (Fig. 1) significantly prevented the development of hypertension, increased the total antioxidant capacity of blood, and decreased blood nitrotyrosine concentration in young SHR. In the aorta, EC significantly increased nitric oxide (NO) synthase (NOS) activity and elevated NO-dependent vasorelaxation . These findings suggest that a pathway involving ROS and NF-κB is associated with the antihypertensive activity of EGCG.
In addition, the direct action of EGCG on angiotensin I-converting enzyme (ACE) may also mediate its antihypertensive effect. Takagaki and Nanjo demonstrated that EGCG and its metabolites produced by intestinal bacteria showed inhibitory activity against ACE and that a single oral intake of metabolites decreased SBP in SHR . A molecular docking mechanism may explain the potential of EGCG as a new class of ACE inhibitors. Further chemical modification via fragment modification guided by structure and ligand-based computational methodologies may lead to the discovery of better inhibitors as clinical candidates .
3.4 Effects of Green Tea on Diabetes
3.4.1 Epidemiological Studies
Many epidemiological studies have reported the antidiabetic effects of tea and GTE . For example, Panagiotakos et al. reported that long-term tea intake reduced levels of fasting blood glucose and was associated with a lower prevalence of diabetes. In a cohort of 937 older adults living on Mediterranean islands, the consumption of 1–2 cups/day of green tea and/or black tea was associated with 70% lower odds of developing type 2 diabetes mellitus (T2DM ), irrespective of age, sex, body mass, smoking, physical activity status, dietary habits, and other clinical characteristics . In a literature review of the antidiabetic effects of tea, Fu et al. identified six, ten, and one epidemiological studies published from 2006 to 2016 showing the beneficial effects of green tea, black tea, and oolong tea, respectively .
However, several epidemiological studies failed to demonstrate antidiabetic effects [92, 142]. For example, Pham et al. found a rather positive association between green tea consumption and insulin resistance in 1,440 participants aged 18–69 years . Thus, further studies are necessary to confirm the antidiabetic effects of tea in human subjects.
3.4.2 Clinical Studies
A number of intervention studies have reported the antidiabetic effect of green tea . For example, a randomized controlled trial conducted in 66 Japanese T2DM patients found that daily ingestion of GTE containing 544 mg catechins for 2 months caused significant reductions in hemoglobin A1c (HbA1c) levels and DBP . Similarly, a 2-month intervention study in 60 patients with mild hyperglycemia showed that the daily ingestion of GTE decreased the HbA1c level, although other biomarkers were unaffected .
In a randomized, double-blind, placebo-controlled trial performed in 92 Taiwanese subjects, the ingestion of 500 mg GTE three times a day for 16 weeks ameliorated the expression levels of an insulin resistance marker and the secretion of glucagon-like peptide-1 in T2DM patients . In a double-blind randomized intervention study in nondiabetic overweight or obese male subjects in the United Kingdom, Brown et al. found that twice-daily ingestion of 400 mg EGCG for 8 weeks resulted in reduced DBP, although no significant effects on glucose tolerance, insulin sensitivity, or insulin secretion were observed .
In a randomized, double-blind study in 42 diabetic subjects with a urinary albumin-creatinine ratio >30 mg/g, patients were randomly assigned to two groups to receive either GTP containing 800 mg of EGCG (17 patients with T2DM and 4 with type 1 diabetes) or placebo (21 patients with T2DM) for 12 weeks. The results indicated that GTP reduced the urinary albumin-creatinine ratio by 41%, while the placebo group had a 2% increase, suggesting that GTP may reduce the risk of diabetic nephropathy .
In contrast, several intervention studies found no beneficial effects of green tea on diabetes. For example, a double-blind, placebo-controlled, randomized multiple-dose (0, 350, or 750 mg catechins and theaflavins for 3 months) study conducted in the United States showed no effect on the level of HbA1c in patients with a medical history of diabetes of more than 6 months . A crossover randomized controlled trial in southern Sweden showed that no glucose or insulin-lowering effects were demonstrated by the consumption of 300 mL of green tea or water .
Furthermore, a meta-analysis of randomized controlled trials found that the consumption of green tea did not decrease the levels of fasting plasma glucose, fasting serum insulin, hemoglobin HbA1c, or the insulin resistance index in populations at risk of T2DM . Thus, clinical trials in humans on the effects of green tea in diabetes have demonstrated conflicting results. The discrepancy may be explained as discussed in the previous section.
3.4.3 Laboratory Studies and Mechanism of Action
Multiple studies using cultured cells and laboratory animals have demonstrated the antidiabetic effects of green tea and GTCs [92, 152].The underlined mechanisms include (1) inhibition of α-amylase and α-glucosidase activity, (2) inhibition of glucose absorption in the small intestine, (3) protection of pancreatic β-cells, (4) improvement of insulin sensitivity in peripheral organs, and (5) inhibition of glucose production from noncarbohydrates such as amino acids in the liver, known as gluconeogenesis .
Inhibition of α-amylase and α-glucosidase results in reduced glucose production leading to the prevention and suppression of diabetes by impeding the rise in blood sugar levels [92, 152]. Similarly, the inhibition of glucose absorption in the small intestine suppresses the increase in blood sugar levels [92, 152]. Improvements in insulin sensitivity would result in the rapid suppression of blood glucose levels by promoting glucose uptake by peripheral tissues. Green tea ingredients such as EGCG have exhibited insulin-like activity in terms of increased glucose uptake . EGCG may also protect insulin-secreting pancreatic β-cells from injury since EGCG protected IL-1β and interferon (IFN)-γ -mediated cytotoxicity in an insulinoma cell line, presumably through the inhibition of NF-κB activation  (see Fig. 3).
Several studies have reported inhibitory effects of EGCG on gluconeogenesis. EGCG exhibited insulin-like activity by suppressing the gene expression of gluconeogenic enzymes, glucose-6-phosphatase (G6Pase), and phosphoenolpyruvate carboxykinase . One of the proposed mechanisms is the suppression of transcription factor, hepatocyte nuclear factor-4α (HNF4α) expression by EGCG, leading to a decrease in expression of these gluconeogenic enzymes and resulting in diminished glucose production [2, 92]. The suppressive action of EGCG on HNF4α expression may be explained by its prooxidative activity to generate ROS, leading to the activation of AMPK which is known to inhibit HNF4α expression [2, 4] (see Fig. 2). Collins et al. postulated that ROS was involved in the activation of AMPK by EGCG and the suppression of hepatic gluconeogenesis .
In addition, several other mechanisms have been proposed for the antidiabetic activity of tea. These include (1) improvement of endothelial dysfunction, (2) modulation of cytokine expression, and (3) amelioration of insulin resistance, as reviewed by Fu et al. . These authors pointed out the involvement of GTCs in the modulation of gene expression under its antidiabetic effects . GTE may increase the mRNA levels of glucose transporter family proteins. EGCG can also attenuate the formation of advanced glycation end products; activate Nrf2, which regulates the expression of antioxidant proteins protecting against oxidative damage; and inhibit the expression of the AGE receptor. Green tea decreases the expression of receptor activator of NF-κB and pro-inflammatory cytokine TNF-α in a rat model of diabetes and increases anti-inflammatory cytokine IL-10. EGCG may also suppress the expression of genes related to inflammation such as IL-1β, TNF-α, IL-6, CD11s, CD18, and MCP-1 in adipose tissues in another animal model  (see Fig. 3).
3.5 Effects of Coffee on Metabolic Syndrome and Related Disorders
3.5.1 Epidemiological Studies
Hino et al. conducted a population-based health check in 1999 and found that all components of MetS (blood pressure, waist circumference, fasting plasma glucose, and lipid profiles) except for HDL cholesterol were inversely related to the consumption of coffee but not of green tea after adjusting for confounding factors .
Using the PubMed, Embase, Scopus, and Science Direct databases, Yesil et al. found that four out of six human studies showed an inverse association between coffee consumption and the risk of MetS, although two studies showed no such association in a cohort consisting of young persons with a low prevalence of MetS .
In addition, the following studies reported beneficial effects of coffee. From May 2009 to December 2010, a cross-sectional survey was conducted on 1,889 inhabitants living in Sicily, southern Italy. As a result, coffee consumption (OR, 0.43) was found to be associated inversely with MetS after adjusting for all covariates. No association was observed between caffeine intake and MetS. Triglycerides were inversely associated with the consumption of espresso coffee. Thus, coffee consumption was demonstrated to have a reduced OR for MetS .
Results from a cross-sectional population-based survey including 8,821 adults showed that high coffee drinkers had lower BMI, waist circumference, SBP and DBP, and triglycerides and higher HDL cholesterol than those drinking < 1 cup/day. After adjusting for potential confounding factors, higher coffee consumption was demonstrated to be inversely associated with MetS (OR, 0.75) .
A Mendelian randomization study with 93,179 individuals from two large general population cohorts found that in a cross-sectional analysis, there was a lower risk of MetS with higher coffee intake. Compared with individuals with no coffee intake, ORs for MetS were 0.91, 0.89, 0.88, 0.83, 0.84, and 0.89 for 0.1–1, 1.1–2, 2.1–3, 3.1–4, 4.1–5, and >5 cups/day, respectively .
Shang et al. conducted a meta-analysis of 11 studies published between January 1999 and May 2015 with a total of 159,805 participants to determine the association between coffee intake and MetS risk. The aggregated result for the highest versus lowest category of coffee consumption was 0.872, suggesting that coffee consumption was associated with a reduced risk of MetS . A cross-sectional study of a random sample of 5,146 participants aged ≥20 years found that moderate drinkers had 17% lower odds of developing MetS compared with nondrinkers. Tea consumption was related to some components, but not to MetS in general .
Although these findings appear to show beneficial effects of coffee on MetS, caution should be taken as coffee, particularly instant coffee mix, may have a potentially harmful effect arising from the excessive intake of sugar and powdered creamer .
3.5.2 Clinical Studies
Several clinical studies on the effect of coffee and CGAs have been reported. Patti et al. evaluated the impact of a natural supplement, Kepar, which contains several plant extracts such as curcuma longa, silymarin, guggul, CGAs, and inulin, in 78 patients with MetS. Although Kepar exerted beneficial effects on body weight, BMI, and waist circumference, fasting glucose and total cholesterol levels, further studies are required to verify whether CGAs indeed contribute to these effects .
Santana-Gálvez et al. reviewed several clinical trials to evaluate the effects of CGA on the prevention and treatment of obesity and hypertension, which are the component disorders of MetS. These studies are discussed in the Sects 3.6.2 and 3.7.2 .
3.5.3 Laboratory Studies and Mechanism of Action
Many studies have evaluated the effect of CGA on MetS or associated disorders, including obesity, dyslipidemia, diabetes, and hypertension. Santana-Galvez et al. reviewed the literature and found the beneficial effects of CGA on MetS and its components .
Similarly, Yesil and Yilmaz identified three animal studies on the effects of coffee on MetS and five on the risk of fatty liver infiltration. All showed a protective effect of coffee against the development of MetS and nonalcoholic fatty liver disease (NAFLD) .
In a study investigating the effects of Colombian coffee extract in an animal model of MetS, rats were fed a corn starch-rich diet, whereas two other groups were given a high-carbohydrate, HFD with 25% fructose in drinking water for 16 weeks. The high-carbohydrate, HFD group showed the symptoms of MetS leading to cardiovascular remodeling and NAFLD. Colombian coffee extract supplementation attenuated the impaired glucose tolerance, hypertension, cardiovascular remodeling, and NAFLD without affecting abdominal obesity and dyslipidemia. This study suggests that Colombian coffee extract can attenuate diet-induced changes in the structure and function of the heart and the liver without changing abdominal fat deposition .
Tsumura-Suzuki obese diabetic mice are a newly developed MetS model which spontaneously exhibits obesity, diabetes, hyperlipidemia, and nonalcoholic steatohepatitis with liver nodules. When animals were divided into two coffee intake groups (with and without caffeine), coffee intake did not affect obesity and hyperlipidemia . However, coffee intake caused various degrees of improvement in pancreatic β-cell damage and steatohepatitis with liver carcinogenesis. Most of the effects were likely caused by a synergistic effect of caffeine with other components such as polyphenols, and the anti-fibrotic effects of coffee appeared to be attributable to the polyphenols rather than the caffeine .
Ma et al. conducted two sets of experiments. In one experiment, 6-week-old C57BL/6 mice were fed regular chow or HFD for 15 weeks with twice-weekly intraperitoneal injection of CGA (100 mg/kg) or vehicle. In another experiment, obese mice (average weight of 50 g) received intraperitoneal injection of CGA (100 mg/kg, twice a week) or vehicle for 6 weeks. CGA significantly inhibited the development of diet-induced obesity but did not affect body weight in the obese mice. CGA treatment also curbed HFD-induced hepatic steatosis and insulin resistance; suppressed the hepatic expression of PPAR-γ, Cd36, Fabp4, and Mgat1 genes; and attenuated inflammation in the liver and white adipose tissue accompanied by a decrease in mRNA levels of macrophage marker genes including F4/80, Cd68, Cd11b, Cd11c, and TNF-α, Mcp-1, and Ccr-2 encoding inflammatory proteins. These results suggest that CGA is a potent compound for preventing diet-induced obesity and obesity-related MetS .
Santana-Galvez et al. proposed a possible mechanism of action for CGA, whereby it may act as an antioxidant to reduce ROS, which stimulate inflammation leading to fat accumulation, weight gain, and insulin resistance (see Fig. 3). The antioxidative activity of CGA may also stimulate NO production , leading to an improvement in endothelial function and blood pressure. CGA may also improve lipid metabolism by downregulating transcriptional factors such as LXRα and PPAR and the gene expression of enzymes such as FASN, acetyl-CoA carboxylase (ACC), and HMGCR and by upregulating PPAR-α, adiponectin , and AMPK phosphorylation  (see Fig. 2).
Although these studies support a beneficial effect of CGA in MetS, others failed to show such effects. For example, in a controlled dietary intervention of over 12 weeks in which male C57BL/6 mice were divided into three groups: (i) normal diet, (ii) HFD, and (iii) HFD plus CGA (1 g/kg of diet), Mubarak et al. found that CGA supplementation in mice fed HFD did not reduce body weight compared with mice fed HFD alone. CGA caused increased insulin resistance compared with mice fed HFD and led to reduced phosphorylation of AMPK and ACC-β, a downstream target of AMPK in the liver. The livers of mice fed an HFD supplemented with CGA had a higher lipid content and more steatosis relative to mice fed an HFD, indicating impaired fatty acid oxidation. This study suggests that CGA supplementation in HFD does not protect against the characteristics of MetS in diet-induced obese mice .
3.6 Effects of Coffee on Obesity
3.6.1 Epidemiological Studies
Few studies have been published on the effect of coffee on obesity. The result of cross-sectional analyses in a Mendelian randomization study showed that higher coffee intake of up to 4 cups/day was associated with a lower risk of obesity. Compared with individuals with no coffee intake, ORs were 0.82, 0.86, 0.86, 0.83, 0.95, and 1.02 for 0.1–1, 1.1–2, 2.1–3, 3.1–4, 4.1–5, and >5 cups/day, respectively . A study on 137 patients with NAFLD and 108 controls found that coffee consumption was inversely associated with insulin resistance and obesity .
3.6.2 Clinical Studies
Several clinical studies have reported the effects of coffee or CGAs on obesity. In a meta-analysis of randomized clinical trials, Onakpoya et al. found a significant reduction (−2.47 kg) in body weight in a green coffee extract-treated group compared with placebo. The magnitude of the effect was moderate, and there was significant heterogeneity among the studies. The authors summarized that the results from these trials were promising but that the studies were of poor methodological quality. More rigorous trials are thus required to assess the usefulness of green coffee extract as a weight-loss tool .
In a randomized controlled trial, overweight men with a mild-to-moderate elevation of fasting plasma glucose were randomly allocated to a 16-week intervention of the consumption of 5 cups of caffeinated (n = 17) or decaffeinated (n = 15) instant coffee per day or no coffee (n = 13). The results indicated that waist circumference decreased by 1.5 cm in the caffeinated coffee group, increased by 1.3 cm in the decaffeinated coffee group and decreased by 0.6 cm in the non-coffee group. Body weight at 16 weeks showed a similar pattern; the corresponding changes from baseline were −1.1 kg, 0.5 kg, and −0.6 kg, respectively. The authors proposed that the decreases in the caffeinated coffee group were attributable to caffeine, which increases thermogenesis and fat oxidation .
In a review article, Santana-Gálvez et al. listed two clinical studies showing the effect of CGA on obesity . One study was a randomized, double-blind, 12-week study in 30 overweight people. The result indicated that the average loss in body weight among subjects who consumed CGA-enriched coffee was 5.4 kg, while that in the normal instant coffee groups was 1.7 kg, suggesting a beneficial effect of CGA on body weight reduction . Another study was a placebo-controlled, double-blind, crossover intervention study in 18 healthy male subjects in which those who consumed 185 mL of a test beverage with or without CGAs (329 mg) per day for 4 weeks showed no effects on body weight, BMI, or body fat, although a significantly higher postprandial energy expenditure was observed in the CGA group compared with the control group . Thus, further studies are required to determine the effects of coffee and CGAs on obesity.
3.6.3 Laboratory Studies and Mechanism of Action
A number of laboratory studies have provided evidence for the anti-obesity effect of coffee and its mechanism of action. Hsu et al. found that the addition of coffee phenols to culture medium decreased the cell growth of 3T3-L1 preadipocytes . The IC50 values of CGA, gallic acid, o-coumaric acid, and m-coumaric acid on the preadipocytes were 72.3, 43.3, 48.2, and 49.2 μM, respectively. A relationship analysis indicated that there was a linear correlation between the influence of phenolic acids on cell growth and their antioxidant activity. The treatment of preadipocytes with CGA, o-coumaric acid, and m-coumaric acid caused cell cycle arrest in the G1 phase. These results suggest that coffee phenols have anti-obesity effects .
When C57BL/6 J mice were fed a control diet, HFD, or HFD supplemented with 0.5–1.0% coffee polyphenols (CPP) for 2–15 weeks, CPP supplementation reduced body weight gain, abdominal and liver fat accumulation, and infiltration of macrophages into adipose tissues. The mRNA levels of sterol regulatory element-binding protein (SREBP) -1c, ACC-1 and -2, stearoyl-CoA desaturase-1, and pyruvate dehydrogenase kinase-4 in the liver were also significantly lower in CPP-fed mice than in HFD and control mice (see Fig. 2). Similarly, CPP suppressed the expression of these molecules in Hepa 1-6 cells, concomitant with an increase in microRNA-122. Structure-activity relationship studies of nine quinic acid derivatives isolated from CPP suggested that CGA and di-caffeoylquinic acids were active substances in the beneficial effects of CPP in these cells. Furthermore, CPP and 5-CQA decreased the nuclear active form of SREBP-1, ACC activity, and cellular malonyl-CoA levels. These findings indicate that CPP enhances energy metabolism and reduces lipogenesis by downregulating SREBP-1c and related molecules, leading to the suppression of body fat accumulation .
When a commercially available supplement composed of cocoa, coffee, green tea, and garcinia which contains 196 mg/g of total polyphenols and 4.0 mg/g of EGCG was given to high-energy diet (HED)-induced obese rats, a reduction was observed in the levels of free fatty acids, triglycerides, total cholesterol, LDL-C, and LDL-C/HDL-C, AST, ALT, and ketone bodies in serum as well as hepatic triglycerides and total cholesterol content, while the levels of HDL-C in serum and lipase activity in fat tissues increased compared with the HED group. These results suggest that the supplement stimulated lipid metabolism in HED-induced obese rats through fat mobilization from adipose tissue .
When hyperlipidemia was induced in Wistar rats using HFD, the animals given CGA complex from green coffee bean, CGA7 (50, 100, and 150 mg/kg body weight), showed decreased triglycerides and free fatty acid levels in plasma and the liver compared with the control group. CGA7 administration led to the activation of AMPK and a subsequent increase in the levels of carnitine palmitoyltransferase 1 and a decrease in ACC acetyl-CoA carboxylase (ACC) activity (see Fig. 2). These results suggest that CGA7 complex may be suitable as an active ingredient in nutrition for obesity management .
Maki et al. found that coffee intake significantly suppressed HFD-induced metabolic changes such as increased body weight and the accumulation of adipose tissue and the upregulation of glucose, free fatty acid, total cholesterol, and insulin levels in the blood. In the early phase of adipogenesis, 3T3-L1 cells treated with coffee extract displayed delayed cell cycle entry into the G2/M phase, termed as mitotic clonal expansion. Coffee extract also inhibited the activation of CCAAT/enhancer-binding protein β (C/EBP-β) by preventing its phosphorylation by ERK and suppressed adipogenesis-related events such as mitotic clonal expansion and C/EBP-β activation through the downregulation of insulin receptor substrate 1 (IRS1) . The stability of the IRS1 protein was markedly decreased by treatment with coffee extract, due to proteasomal degradation. These results showed an anti-adipogenic function for coffee intake and identified IRS1 as a novel target for coffee extract in adipogenesis .
Although these results indicate the favorable effects of coffee and/or its extract in obesity, several other studies do not support these findings. For example, Cheong et al. carried out a study in which C57BL6 mice were randomly divided into the following experimental groups: (i) normal diet, (ii) HFD, or (iii) HFD supplemented with 0.5% w/w GCE rich in CGA. The results showed that groups (ii) and (iii) displayed MetS symptoms more profoundly than group (i) and that GCE did not attenuate HFD-induced obesity, glucose intolerance, insulin resistance, or systemic oxidative stress .
3.7 Effects of Coffee on Hypertension
3.7.1 Epidemiological Studies
A meta-analysis of 7 cohorts including 205,349 individuals showed a 9% significant decreased risk of hypertension per 7 cups of coffee per day in a nonlinear analysis, while in a linear dose-response association, there was a 1% decreased risk of hypertension for each additional cup of coffee per day. The analysis also suggested smoking as an important confounder .
In contrast, a large prospective study during 112,935 person-years of follow-up in 5,566 cases of incident hypertension showed that neither caffeinated coffee nor caffeine intake was associated with mean SBP or DBP but that decaffeinated coffee intake was associated with a small but clinically irrelevant decrease in mean DBP. Decaffeinated coffee intake was not associated with mean SBP. Thus, no antihypertension effects were demonstrated, but caffeinated coffee, decaffeinated coffee, and caffeine appeared not to be risk factors for hypertension in postmenopausal women .
A cross-sectional study conducted in 2012 among 1,164 individuals aged ≥63 years showed that among the 715 hypertensive participants, those consuming ≥3 cups of coffee per day showed higher 24-hour SBP and DBP than non-coffee drinkers. Compared with non-coffee drinkers, ORs for uncontrolled BP among those consuming 1, 2, and ≥3 cups of coffee/day were 1.95, 1.41, and 2.55, respectively .
3.7.2 Clinical Studies
Santana-Gálvez et al. reviewed human studies on the effects of CGA on blood pressure and found that CGA or coffee extracts reduced SBP and DBP in three out of four human intervention studies . In a similar approach, Tajik et al. found that five out of six human intervention studies showed favorable effects on blood pressure . One example is the report by Revuelta-Iniesta and Al-Dujaili, who conducted a randomized pilot crossover study in healthy subjects. The results indicated that green coffee consumption reduced SBP, arterial elasticity, BMI, and abdominal fat .
3.7.3 Laboratory Studies and Mechanism of Action
Several studies have demonstrated the beneficial effects of CGA on blood pressure and suggested the underlying molecular mechanisms. Suzuki et al. demonstrated that a single ingestion of CGA (30–600 mg/kg) reduced blood pressure in SHR, an effect that was blocked by the administration of an NOS inhibitor, N(G)-nitro-L-arginine methyl ester. When SHR were fed diets containing 0.5% CGA for 8 weeks (approximately 300 mg/kg per day), the development of hypertension was inhibited. The authors proposed, as the underlying mechanism, that dietary CGA reduces oxidative stress and improves NO bioavailability by inhibiting the excessive production of ROS in the vasculature, leading to the attenuation of endothelial dysfunction, vascular hypertrophy, and hypertension in this animal model .
Zhao et al. summarized that CGA may exert an antihypertension effect through (1) inhibition of NAD(P)H oxidase expression and activity, leading to reduction in free radical production; (2) direct free radical scavenging; (3) stimulation of NO production by the endothelial-dependent pathway; and (4) inhibition of ACE in the plasma and possibly also in the organs and tissues. The anti-inflammatory effects of CGA may also contribute to the effect .
3.8 Effects of Coffee on Diabetes
3.8.1 Epidemiological Studies
Ding et al. conducted a systematic review and meta-analysis of 28 prospective studies with 1,109,272 participants and 45,335 cases of T2DM for coffee consumption and disease risk. The results showed that compared with no or rare coffee consumption, RR for diabetes was 0.92, 0.85, 0.79, 0.75, 0.71, and 0.67 for 1–6 cups/day, respectively. Thus, the decreases in RRs for every 1 cup/day were 9% for caffeinated coffee consumption and 6% for decaffeinated coffee consumption, indicating that the consumption of both types of coffee is inversely associated with the risk of T2DM .
Based on three large cohort studies of men and women in the United States, Bhupathiraju et al. found that coffee consumption was associated with a lower risk of T2DM. During 1,663,319 person-years of follow-up, participants who increased their coffee consumption by >1 cup/day over a 4-year period had an 11% lower risk of T2DM in the subsequent 4 years compared with those who made no changes in consumption. Participants who decreased their coffee intake by >1 cup/day had a 17% higher risk for T2DM .
In another study in 90,317 US adults, where 8,718 deaths occurred during 805,644 person-years of follow-up from 1998 through 2009, coffee drinkers had a lower HR for several diseases, including diabetes, compared with nondrinkers .
Nordestgaard et al. conducted a Mendelian randomization study among 93,179 individuals from two large general population cohorts. The results indicated that higher coffee intake was associated with a lower risk of obesity, MetS, and T2DM. However, per-allele meta-analyzed ORs for T2DM were in the range of 0.98–1.01, indicating that there was no genetic evidence to support corresponding causal relationships .
In 2001–2002, a random sample of 1,514 men and 1,528 women was selected to participate in a study in the Athens metropolitan area in Greece. This 10-year follow-up study showed that individuals who consumed ≥250 mL of coffee had 54% lower odds of developing diabetes compared with abstainers, indicating the significance of long-term habitual coffee drinking in the onset of diabetes. The inverse association between habitual coffee drinking and diabetes was suggested to be mediated by serum amyloid-A levels .
A cross-sectional study in a large Brazilian cohort of 12,586 middle-aged and older individuals provided evidence of a protective effect of coffee on the risk of adult-onset diabetes. The results showed 23% and 26% lower odds of diabetes among those consuming coffee 2–3 and >3 times per day, respectively, compared with those reporting no or almost no consumption of coffee. An inverse association was also found for 2-hour post-load glucose but not for fasting glucose concentrations, suggesting the action of coffee on postprandial glucose homeostasis .
A population-based cohort study over a follow-up period of 4 years was conducted to examine the association between habitual coffee intake and the risk of T2DM and to determine whether this association varied by genetic polymorphisms related to T2DM. The results on 4,077 Korean adults aged 40–69 years with a normal glucose level at baseline showed an inverse association between coffee intake and the combined risk of T2DM and prediabetes. This inverse association was found among individuals with the GT/TT of IGF2BP2 rs4402960, GG/GC of CDKAL1 rs7754840, or CC of KCNJ11 rs5215 polymorphisms, which are known to be related to T2DM in East Asians .
The European Prospective Investigation into Cancer and Nutrition-Potsdam study involving 27,548 middle-aged participants found that coffee consumption was inversely associated with diacyl-phosphatidylcholine and liver injury markers in both sexes and positively associated with certain acyl-alkyl-phosphatidylcholines in women. Coffee consumption showed an inverse relationship with C-reactive protein in women and with triglycerides and phenylalanine in men. These findings may partly explain the inverse association between long-term coffee consumption and T2DM risk .
A population-based cohort study on first-trimester coffee and tea intake and risk of gestational diabetes among 71,239 nondiabetic women with singleton pregnancies showed that moderate first-trimester coffee and tea intake was not associated with the risk of gestational diabetes and possibly may have a protective effect .
A recent review article based on review papers from in vivo, ex vivo, and in vitro experimental studies in animals and human tissues as well as epidemiological studies reported a reduced risk of developing T2DM in regular coffee drinkers of 3–4 cups a day. The effects were proposed as attributable to CGAs and caffeine .
In a cross-sectional epidemiological study aimed to investigate the mechanism of the association of coffee with liver injury, caffeinated coffee showed a significant inverse association with ALT, AST, and NAFLD liver fat score but not with fetuin-A , another liver injury marker. However, there was no significant association between decaffeinated coffee intake and markers of liver injury . These results indicate a beneficial impact of caffeinated coffee on liver morphology and/or function and suggest that this relationship may mediate the inverse association of coffee with risk of T2DM .
By reviewing the literature, Chrysant concluded that coffee consumption has either neutral or beneficial effects on blood pressure, CVD, heart failure, cardiac arrhythmias, and diabetes, and that the established concept that coffee consumption is a risk factor for hypertension, heart disease, or diabetes is no longer warranted, although some caution should be exercised in vulnerable populations .
3.8.2 Clinical Studies
Santana-Gálvez et al. reviewed clinical trials to evaluate the effects of CGA on MetS-related diseases and found that five studies showed beneficial effects on diabetes . One such study was a randomized crossover trial for the effects of 12 g decaffeinated coffee, 1 g CGA, and placebo (1 g mannitol) on glucose and insulin concentrations during a 2-hour oral glucose tolerance test in 15 overweight men. The results indicated that CGA ingestion significantly reduced blood glucose and insulin concentrations .
3.8.3 Laboratory Studies and Mechanism of Action
Evidence has been accumulating to support the beneficial effects of CGA on diabetes in cell-based and animal experiments. A comprehensive review by Meng et al. indicated that CGA stimulated glucose uptake in murine adipocytes and L6 muscle cells and inhibited G6Pase in hepatic cells . It also reported that more than ten animal experiments found favorable effects of CGA such as improvement in blood glucose levels, glucose tolerance, and insulin resistance and inhibition of α-glucosidase , together with AMPK activation and the upregulation of hepatic PPAR-α  (see Fig. 2).
Similarly, a recent review of five animal studies found that CGA had beneficial effects in diabetes through a reduction in the levels of blood glucose and HbA1c, prevention of the development of sugar cataracts, acceleration of wound healing, and inhibition of hepatic G6Pase levels .
In an experiment in which female db/db mice were administered 80 mg/kg/day CGA by lavage for 12 weeks, the percentage of body fat and the fasting plasma HbA1c level decreased compared with that in the control group; transforming growth factor-β1 protein expression and aldose reductase activity in the kidney also decreased, while the adiponectin level in visceral adipose increased. CGA significantly upregulated phospho-AMPK in the liver and skeletal muscle and downregulated G6Pase in the liver, while upregulating GLUT4 (see Fig. 2). Thus, CGA lowered the levels of fasting plasma glucose and HbA1c during late diabetes and improved kidney fibrosis through the modulation of adiponectin receptor signaling pathways in db/db mice .
Several other investigations also demonstrated the beneficial effects of CGA in diabetes. For example, in a study aimed to investigate whether short-term treatment with plant polyphenols, including CGA, could improve endothelial dysfunction related to diabetes, streptozotocin -induced diabetic mice received CGA (0.03 mmol/kg/day) by injection for 5 days. This treatment improved the NO components of relaxation without the normalization of acetylcholine-stimulated NO production. In addition, CGA treatment suppressed the acetylcholine-stimulated level of thromboxane B2 in aortas from streptozotocin-induced diabetic mice. Thus, the treatment caused basal NO production and a prompt improvement in endothelial function in diabetic mice, which may involve the normalization of thromboxane B2 levels but not NO production under acetylcholine stimulation .
In an animal experiment to evaluate the effects of CGA on diabetic auditory pathway impairment, CGA was shown to prevent the progression of auditory pathway dysfunction caused by diabetes. The study also found that CGA may aid in the recovery from outer hair cell and otic hair cell damage. Thus, CGA appears to have beneficial effects in the management of diabetic sensorineural auditory dysfunction .
There is a possibility that CGA can protect kidney function against oxidative stress in diabetic nephropathy. Ye et al. showed that CGA decreased the levels of blood glucose, blood urea nitrogen, and serum creatinine in a rat model of diabetic nephropathy. CGA increased the activity of superoxide dismutase, glutathione peroxidase, and catalase and decreased the level of lipid peroxidation. Immunohistochemical analysis showed that CGA downregulated COX-2 protein expression in renal tissues. In addition, CGA blocked the expression of activating transcription factor-6 and C/EBP homology protein as well as the phosphorylation of eukaryotic initiation factor 2α and double-stranded RNA-activated protein kinase-like endoplasmic reticulum kinase. These findings suggest that CGA attenuates oxidative stress in diabetic nephropathy, leading to modulation of the endoplasmic reticulum signaling pathway .
In alloxan-induced diabetic rats, oral administration of aqueous infusions of Artemisia herba-alba Asso and Ajuga iva Schreber, used in folk medicine, was shown to reduce blood glucose levels. Since A. herba-alba infusion contains CGA as the main compound, CGA may contribute to this effect .
On the other hand, some studies did not show the beneficial effects of CGA in diabetes. For example, in a study using 3T3-L1 cells, coffee was shown to reduce the accumulation of lipids during adipocytic differentiation of these cells, which may explain the antidiabetic action of coffee. Coffee also inhibited expression of PPAR-γ, a transcription factor which upregulates the differentiation of adipocytes. However, CGA showed no effect on PPAR-γ gene expression, suggesting that CGA does not contribute to the antidiabetic activity of coffee .
In a study aimed to determine whether bioactive substances in coffee increase insulin secretion from β-cells and improve insulin sensitivity in skeletal muscle cells, cafestol and caffeic acid but not CGA were found to increase insulin secretion, both acutely and chronically .
3.9 Comparison of the Effects of Tea and Coffee in Simultaneous Studies on Metabolic Syndrome and Related Disorders
A cross-sectional epidemiological study among Singaporean Chinese residents aged ≥40 years reported that drinking at least 150 mL green tea per week was associated with lower hypertension risk (OR, 0.63). Drinking a combination of green tea and British tea was associated with a higher reduction in the risk of hypertension (OR, 0.58). In contrast, consumption of coffee (OR, 1.44–1.46) was found to be a potential risk factor for hypertension .
A population-based prospective cohort study among 63,257 Singapore Chinese aged 45–74 years found that, compared to those who drank 1 cup of coffee/day, the HRs were 0.87 for <1 cup/week drinkers and 0.93 for ≥3 cups/day drinkers. Compared to <1 cup/week drinkers, daily drinkers of black or green tea had a slight nonsignificant increase in risk, after adjustment for caffeine. Compared with the lowest caffeine intake (<50 mg/day) group, the highest caffeine intake (≥300 mg/day) group had a 16% increase in risk .
In a study of the effects of tea and coffee consumption in cardiovascular diseases and risk factors such as hypertension, hyperglycemia, and hyperlipidemia, Di Lorenzo et al. concluded that data from the clinical literature showed that tea consumption reduced some risk factors, especially in overweight people and obese subjects. For coffee, the results were controversial and did not allow conclusions to be drawn .
4 Effects on Liver Disease
4.1 Effects of Green Tea on Liver Disease
4.1.1 Epidemiological Studies
Several human studies have indicated that GTC has beneficial effects in liver diseases such as hepatitis, hepatoma, and liver fibrosis . In a meta-analysis of studies published from 1995 to 2014, Yin et al. found that there was a significant reduction in the risk of liver disease with GTC intake. RRs were 0.74, 0.65, 0.57, 0.56, and 0.49 for hepatocellular carcinoma, liver steatosis, hepatitis, liver cirrhosis, and chronic liver disease, respectively .
A retrospective cross-sectional study on 1,018 patients with NAFLD, HCV, and HBV infection found that patients who drank ≥2 cups of coffee per day had a lower liver stiffness, which is indicative of less fibrosis and inflammation , but that tea consumption had no effect .
4.1.2 Clinical Studies
Only a few studies have examined the effects of green tea in liver disease. In a clinical experiment on nine cases of intractable chronic hepatitis C with a high viral load of >850 kIU/mL, Sameshima et al. found that combination therapy of 6 g of green tea powder/day and interferon/ribavirin showed 3.5-fold efficacy compared with interferon/ribavirin therapy alone . This result and that of another clinical trial in which a single 400 mg oral dose of EGCG was safe and well tolerated by all 11 patients with hepatitis C and detectable viremia strongly encourage further studies .
4.1.3 Laboratory Studies and Mechanism of Action
Several cell-based and animal experiments demonstrated the hepatoprotective effects of EGCG . For example, our research group showed that consumption of an EGCG-rich green tea beverage reduced liver damage in rats with galactosamine-induced hepatitis . Administration of the beverage restored the plasma levels of inflammatory factors TNF-α and IL-1β and their hepatic expression upregulated by galactosamine. Similarly, in concanavalin A-induced hepatitis mice, oral administration of EGCG (10 or 30 mg/kg) twice daily for 10 days prior to concanavalin A injection was associated with decreased immunoreaction and pathological damage by reducing inflammatory factors, such as TNF-α, IL-6, IFN-γ, and IL-1β (see Fig. 3). EGCG also exhibited antiapoptotic and anti-autophagic effects by inhibiting the expression of proapoptotic protein BNIP3 through the IL-6/JAKs/STAT3 pathway .
Steinmann et al. reviewed the antiviral and antibacterial activities of EGCG against human pathogens including HBV, HCV, human immunodeficiency virus, and influenza A virus. In most of the studies, EGCG exhibited antiviral properties within physiological concentrations in vitro . The actions of EGCG were suggested as being mediated through (1) the inhibition of viral entry by interference with binding to target cells, (2) the inhibition of integrase and reverse transcriptase, (3) the destruction of virions by binding to CD4 and interference with gp120 binding, (4) the inactivation of virus particles, (5) the inhibition of intracellular virus growth and viral protease, (6) the alteration of physical integrity of virus particles, and (7) the suppression of viral replication via modulation of cellular redox milieu . One of the studies reviewed by the authors showed that HCV infection was suppressed by EGCG in Huh7.5.1 cells infected with the JFH1-GFP chimeric virus when monitored for HCV RNA and protein expression levels. The inhibitory mechanism was proposed to involve the suppressive effects of EGCG on both the HCV entry and RNA replication steps. In addition, 50 and 25 μM EGCG was shown to eliminate HCV from cell cultures after two and five passages, respectively .
Xu et al. demonstrated that EGCG inhibited transcription of the HBV promoter in HEK293 cells co-transfected with expression plasmids of farnesoid X-activated receptor-α and RXR-α, suggesting that EGCG, as an antagonist of farnesoid X-activated receptor-α in liver cells, has the potential to be employed as an effective anti-HBV agent .
Green tea is generally considered to be safe for human health. However, a considerable number of reports have described hepatotoxicity related to GTE. For example, Navarro et al. found that since 2006, there have been more than 50 reports of clinically apparent acute liver injury with jaundice attributed to GTE . The illness was generally self-limiting, but fatal instances have been reported in up to 10% of cases, typically among those who presented with acute hepatocellular injury and jaundice. These authors pointed out that in most reports of GTE hepatotoxicity , the human dose of EGCG (generally less than 12 mg/kg daily) did not appear to be excessive or in the range that might have direct toxicity (estimated for humans to be 30–90 mg/kg), suggesting that liver injury associated with GTE is an idiosyncratic reaction, typical of conventional drug-induced liver injury. Naturally, the excessive consumption of catechin supplements should be avoided.
A recent investigation by Wang et al. suggested that melatonin may be useful for preventing the potential adverse effects of EGCG in its application for MetS alleviation and body weight reduction . Future studies may explore effective ways to prevent or reduce the possible adverse effects of tea constituents.
4.2 Effects of Coffee on Liver Disease
4.2.1 Epidemiological Studies
Coffee intake may exert beneficial effects in the liver. In population studies among persons with an unknown diagnosis of liver disease, greater coffee intake was associated with lower risk of cirrhosis, chronic liver disease, and HCC . In a large prospective study of patients with chronic hepatitis C and advanced liver disease who had failed to achieve a sustained virological response with peginterferon plus ribavirin treatment, Freedman et al. found an inverse association between coffee intake and liver disease progression. Drinkers of ≥3 cups of coffee/day had a 53% lower risk of liver disease progression than non-coffee drinkers. In contrast, no association was observed for the consumption of black or green tea .
Yesil et al. identified two cross-sectional studies and three case-control studies investigating the association between coffee consumption and the risk of NAFLD. All of these studies suggest a reduced risk of NAFLD associated with coffee drinking .
4.2.2 Clinical Studies
Wadhawan and Anand reviewed the literature for an association between coffee and liver disease and provided clinical evidence of the benefit of coffee consumption in hepatitis B and C, as well as in NAFLD . Coffee consumption was associated with an improvement in liver enzymes such as ALT and AST, especially in individuals at risk for liver disease. Coffee intake of ≥2 cups/day in patients with preexisting liver disease was shown to be associated with lower incidence of fibrosis and cirrhosis, lower HCC rates, and decreased mortality . Similarly, Wijarnpreecha et al. found a significantly decreased risk of NAFLD among coffee drinkers and significantly decreased risk of liver fibrosis among patients with NAFLD who drank coffee on a regular basis .
A study to examine whether or not coffee consumption was associated with lower serum aminotransferases in the general Korean population and in those at high risk for hepatic disease showed that the proportions of individuals with elevated AST were 32.5%, 33.1%, and 26.7% in subjects who drank coffee <1, 1, and ≥2 times/day, respectively. The ORs for elevated ALT and AST were significantly lower in subjects who drank ≥2 cups of coffee/day than in those who drank <1 cup/day. Thus, higher coffee consumption may be associated with lower risk of liver disease .
4.2.3 Laboratory Studies and Mechanism of Action
Twenty-five male 129/Sv mice were administered CGA, and an ɑ-naphthylisothiocyanate (ANI) challenge was performed at 75 mg/kg on day 4 after treatment. CGA almost totally attenuated the resulting drug-induced liver damage and cholestasis compared with the untreated group. A dose of 50 mg/kg of CGA significantly prevented drug-induced changes in serum levels of ALT, alkaline phosphatases, total bile acid, direct bilirubin, indirect bilirubin (5.3-, 6.3-, 18.8-, 158-, 41.4-fold, respectively), and AST (4.6-fold). Expression of the altered bile acid metabolism and transport-related genes was normalized by treatment with CGA. The expression of IL-6, TNF-α, and suppressor of cytokine signaling 3 was found to be significantly decreased (1.2-fold, 11.0-fold, and 4.4-fold, respectively) in the CGA/ANI group. Western blotting revealed that CGA inhibited the activation and expression of signal transducer and activator of transcription 3 and NF-κB. These data suggest that CGA inhibits both ANI-induced intrahepatic cholestasis and liver injury by downregulating STAT3 and NF-κB signaling  (see Fig. 3).
Feng et al. examined the impact of the Chinese herbal medicine Qushi Huayu Decoction (QHD) and its active components (geniposide and CGA) on the NAFLD liver transcriptome and gut microbiota using NAFLD rats. Increased expression of genes required for glutathione production and decreased expression of genes required for lipid synthesis were observed in NAFLD livers treated with QHD and CGA. CGA treatment decreased serum lipopolysaccharide , which could be explained by reduced mucosal damage in the colon of CGA-treated rats. In addition, the results suggested an increased abundance of Treg cell-inducing bacteria, which stimulated Treg cell activity in the CGA-treated colon, which in turn downregulated inflammatory signals, improved gut barrier function, and consequently reduced hepatic exposure to microbial products. These findings suggested that QHD simultaneously enhanced the hepatic antioxidative mechanism, decreased hepatic lipid synthesis, and promoted Treg cell-inducing microbiota in the gut .
Watanebe et al. found that coffee intake did not affect obesity or hyperlipidemia in TSOD mice, but that it did cause various degrees of improvement in pancreatic β-cell damage and steatohepatitis with liver carcinogenesis. Most of the effects appeared to be caused by a synergistic effect between caffeine and other components such as polyphenols. The anti-fibrotic effects of coffee were likely attributable to the polyphenols rather than to caffeine .
Arauz et al. examined the hepatoprotective properties of coffee and caffeine in a model of chronic bile duct ligation in Wistar rats. Western blot assays showed decreased protein expression levels of transforming growth factor-β1, connective tissue growth factor, α-smooth muscle actin, and collagen 1 in the coffee- and caffeine-treated ligation groups compared with untreated rats. Similarly, coffee decreased the mRNA levels of these proteins. The results indicated that coffee prevented bile duct ligation-induced liver cirrhosis by attenuating the oxidant processes, blocking hepatic stellate cell activation, and downregulating the main pro-fibrotic molecules involved in extracellular matrix deposition .
The beneficial effects of coffee in liver disease have also been supported by a recent review by Salomone et al. . The authors described that in experimental models of fibrosis, caffeine inhibited hepatic stellate cell activation by blocking adenosine receptors and may favorably impact angiogenesis and hepatic hemodynamics, while CGA suppressed liver fibrogenesis and carcinogenesis by reducing oxidative stress and counteracting steatogenesis through the modulation of glucose and lipid homeostasis in the liver.
In contrast, Aoyagi et al. reported that CGA did not contribute to the coffee’s suppressive effect on PPAR-γ gene expression. They observed that coffee reduced the accumulation of lipids during the adipocytic differentiation of 3T3-L1 cells and that 5% coffee decreased the accumulation of lipids by about 50% compared with control. Coffee inhibited the expression of PPAR-γ, a transcription factor that controls the differentiation of adipocytes, and reduced the expression of other differentiation marker genes aP2, adiponectin, C/EBP-α, GLUT-4, and lipoprotein lipase (LPL) during adipocyte differentiation (see Fig. 2). Major bioactive constituents of coffee extracts such as CGA, caffeine, trigonelline, and caffeic acid showed no effect on PPAR-γ gene expression. The inhibitory activity of coffee was found to be produced by the roasting of coffee beans .
Multiple human studies have shown that both green tea and coffee exert beneficial effects in human diseases, and most animal and cell-based experiments support these outcomes. Clearly, GTCs and coffee CGAs are implicated in these activities. Several mechanisms of action have been proposed, among which the involvement of ROS appears to be the most prominent. Two conflicting actions have been proposed: GTCs and CGAs can either scavenge ROS or promote its generation. The scavenging of ROS results in the inhibition of NF-κB activity, leading to the modulation of cytokines and apoptosis-related factors to yield various favorable outcomes such as anti-inflammatory effects and the induction of apoptosis in cancer cells (Fig. 3) [4, 5 ]. It is also possible that the generation of ROS results in the activation of AMPK, leading to the modulation of various enzymes and factors with roles in health promotion (Fig. 2) [4, 107]. In addition, AMPK activation has been suggested to downregulate NF-κB (Fig. 2), leading to modulation shown in Fig. 3 [224, 225].
At present, no explanation is available for these dual actions of GTCs and CGAs, although some conditions may direct them to act as either prooxidant or antioxidant agents. These conditions include their concentrations, the presence of cations such as Cu+ and Fe++, cellular concentrations of antioxidants and oxidoreductive enzymes, and the cellular redox state [4, 107]. These issues remain to be resolved in future studies.
Furthermore, conflicting results in human studies have also been reported. The reasons for these inconsistencies include incomplete adjustment for confounding factors and lack of necessary questions in questionnaires, such as the temperature of tea or coffee, intestinal microbiota, and genetic factors. Nevertheless, we may expect the overall favorable effects of green tea and coffee consumption to promote healthy longevity in view of the growing of evidence presented in this chapter.
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