Green Tea (Camelia Sinensis)

Cancer

EGCG is the most studied Green tea catechin and is considered to play a crucial role in cancer-preventive and therapeutic activities. Several studies have been performed to examine the effects of EGCG on various in vitro cancer-related molecular targets and in vivo models for potential cancer chemoprevention and therapy. The overwhelming majority of these studies observed that EGCG inhibits a vast array of anticancer molecular targets and cancer-related cellular processes.[1] The following table list a few of the cancers that it has an effect on.*

Cervical cancer

Cervical cancer is the fourth most common gynaecological cancer worldwide. Although prophylactic vaccination presents the most effective method for cervical cancer prevention, chemotherapy is still the primary invasive intervention. It is urgent to exploit low-toxic natural anticancer drugs on account of high cytotoxicity and side-effects of conventional agents. As a natural product, (-)-epigallocatechin gallate (EGCG) has abilities in anti-proliferation, anti-metastasis and pro-apoptosis of cervical cancer cells. Moreover, EGCG also has pharmaceutical synergistic effects with conventional agents such as cisplatin (CDDP) and bleomycin (BLM).*

Restraining Human Papillomavirus (HPV) Oncoproteins

Since persistent infection with HPV is the prominent etiological reason in the formation of cervical cancer, seeking drugs for restraining HPV-related oncoproteins is essential. EGCG has a positive effect on suppressing HPV oncogenes and oncoproteins. E6 and E7 of HPV are two main encoded oncoproteins in cervical cancer. In conjunction with the cellular ubiquitin ligase E6AP, E6 oncoprotein could degrade tumour suppressor protein P53 via the ubiquitin-proteasome pathway; meanwhile, E7 oncoprotein could induce retinoblastoma tumour suppressor gene product pRb degradation, resulting in disrupting cell cycle regulation and inhibiting apoptosis of cervical carcinoma. Thus, restraining the expressions of E6 and E7 oncoproteins and their proteasome pathways could inhibit HPV infection and the development of cervical cancer.*

By accumulating ubiquitinated proteins and natural proteasome targets including tumour suppressor protein P27, IκB-α and Bcl-2 associated X protein (BAX) in HeLa cells, EGCG potently inhibited the degradation ability of E7 on pRb through restraining ubiquitin-proteasomal activity and suppressing tumour growth. Oestrogen also has been confirmed to play a critical role in HPV positive cervical cancer. Aromatase, as the key enzyme in oestrogen biosynthesis, could upregulate the expression of oestrogen receptor (ER). EGCG could suppress the mRNA and protein expression levels of oestrogen receptor-α (ER-α) and aromatase, hence restraining E6 and E7 expressions. As a result, EGCG indirectly inhibits the proliferation and induces the apoptosis of cervical cancer cells. Immunohistochemistry study shows a similar result in both HeLa cells and HPV immortalized cervical epithelial TCL-1 cells.*

Neurodegenerative diseases

Neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD), are led by protein misfolding resulting from amyloid protein, which is a fibrous polymer rich in β  sheets, formed by the self-assembly of proteins of different sequences, structures, and functions. EGCG could conjugate directly with natural peptides not folded to inhibit the formation of toxic intermediate products of α-synaptic nucleoprotein and amyloid protein β and form a nontoxic and disordered oligomer of these two proteins, so as to exert protective effects on nerves. In addition, protein aggregation is generally related to the reduced endogenous antioxidants, inflammation and increased iron ions, NO levels, and other related factors. The presence of ROS and RNS will intensify protein misfolding. Experimental studies have emphasized that EGCG could serve as an antioxidant and inhibit the transformation of nitrate and peroxynitrite into NO, thus decreasing ischemic neuronal damage and protecting nerve. Besides the effect on neurodegenerative diseases, EGCG is shown to inhibit the microglia mediated inflammatory response and reduce the damage of the central nervous system triggered by infrasound. In addition, EGCG can promote the healing of extrusion-damaged sciatic nerve, which may be accomplished by changing the expression of the gene controlling apoptosis.[5] *

Neuroprotective

LPS-mediated systemic inflammation plays a critical role in neurodegenerative diseases. When macrophages were treated with LPS, expression of proinflammatory cytokines (TNF-α, IL-1β, and IL-6) was induced, whereas EGCG pre-treatment of macrophages inhibited LPS-mediated induction of these cytokines. EGCG treatment of neurons inhibited LPS-induced production of ROS, suggesting that EGCG represents a potent and useful neuroprotective agent for inflammation-mediated neurological disorders.[6] *

In a study to examine the neuroprotective effects of EGCG after transient middle cerebral artery occlusion. EGCG prevented the impairment of neurological function and decreased the infarct volume, compared with the vehicle group. The upregulation of TNF-α, IL-1β, and IL-6 levels caused by ischemia/reperfusion was significantly ameliorated by EGCG. EGCG also inhibited the upregulation of NF-κB, and induction of COX-2 and iNOS. Thus, EGCG may be a promising therapeutic agent for cerebral ischemia/reperfusion injury, through attenuation of inflammation.[7] *

In an autoimmune encephalomyelitis model, EGCG reduced clinical severity by limiting brain inflammation and neuronal damage, and involvement of EGCG’s control of NF-κB via its anti- oxidative effect was proposed.[8] [9] *

Inflammation

EGCG has demonstrated its anti-inflammatory effects in numerous studies related to the pathological conditions wherein inflammation is a core driving factor. In-Bae Kim et al. found that EGCG was effective in preventing IL-8 production in airway epithelial cells, limiting the degree of respiratory inflammation. IL-8 stimulates the recruitment of neutrophils and can promote the presence of reactive oxygen species (ROS). EGCG also acts as an antioxidant by reducing IκB phosphorylation to block IL-1β-induced NF-κB activation.[10] In a neuroprotection study, Orhan Aktas et al. demonstrated the ameliorative effects of EGCG on inflammation in experimental autoimmune encephalomyelitis (EAE), an animal model for the neurodegenerative disease, multiple sclerosis (MS). The therapeutic efficacy of EGCG was attributed to the inhibition of CD4+ T cell production increase in the intracellular amounts of IκB-α and the prevention of ROS formation in neurons.[11] Yan Tang et al. showed that EGCG blocked P2X4-receptor-mediated pro-inflammatory gene expression by IFN-γ in vascular endothelial cells via down-regulation of the JAK1/2 tyrosine kinase pathway.[12] These studies underline the ability of EGCG to distinctly target certain key signalling molecules to alleviate the downstream events associated with autoimmune diseases.[13] *

NF-kappa B

Beneficial effects of EGCG have been associated with the reduction of nuclear factor-kB and activator protein-1 DNA binding, suggesting that EGCG is beneficial for the treatment of reperfusion-induced myocardial damage by inhibition of the NF-kappa B and AP-1 pathway. Epigallocatechin, a green tea polyphenol, also attenuates myocardial ischemia reperfusion injury in rats. In vivo treatment with EGCG was found to reduce myocardial damage and myeloperoxidase activity. Plasma IL-6 and creatine phosphokinase levels decreased after EGCG administration.[14] *

Antioxidant

Green tea is rich in polyphenols (catechins and gallic acid, particularly), but it also contains carotenoids, tocopherols, ascorbic acid (vitamin C), minerals such as Cr, Mn, Se or Zn, and certain phytochemical compounds.[15] *

They may function indirectly as antioxidants through:-

1) inhibition of the redox-sensitive transcription factors*

2) inhibition of ‘pro-oxidant’ enzymes, such as inducible nitric oxide synthase, lipoxygenases, cyclooxygenases and xanthine oxidase*

3) induction of antioxidant enzymes, such as glutathione-S-transferases and superoxide dismutases*

Green tea polyphenols may act as either antioxidants or pro-oxidants to exert protective effects against cancer. Studies have shown that consumption of green tea can either induce oxidative stress, leading to ROS-mediated cancer cell death, or they can scavenge ROS under conditions of high oxidative stress, preventing cellular damage. Transcription factors such as NF-κκ and AP-1 regulate cancer cell survival and proliferation and may be modulated in part by ROS[16] *

Antiviral

EGCG was found to be the most potent and universal virus inhibitor among the natural catechins, directly interacting not only with various types of enveloped DNA, (+)-RNA, and (−)-RNA viruses, but also various types of cells. The 3-galloyl and 5′-OH groups appear crucial for virus inhibition activity. EGCG mainly inhibits the early stages of infections, such as attachment, entry, and membrane fusion, by interfering with either viral membrane proteins or cellular protein or both of them.[17] *

Influenza

Respiratory epithelium cells serve as the first line of defence against the influenza virus and culminate in the production of interferon (IFN), a key molecule in the antiviral innate immune response.[19] However, the virulence factors of the influenza virus can antagonize the IFN immune response and promote influenza virus infection.[20]Therefore, inducing IFN expression may be an effective strategy against the influenza virus. Although many studies have reported that EGCG has anti-influenza-virus effects[21], whether EGCG can induce IFN-λ expression in airway epithelial cells to suppress the influenza virus and related signalling pathways has not been elucidated at this stage.*

In this study, tracheal epithelial cells (BEAS-2B) were used as an model to investigate EGCG’s anti-IAV effects and mechanisms. The results confirmed that EGCG can induce IFN-λ2 expression through p38 MAPK signalling pathway, but not through the ERK and JNK signalling pathways. It was also found that IFN-λ2 neutralizing antibody attenuated the role of EGCG inhibiting the expression of H1N1 nucleoprotein (NP) gene and protein. These findings provide some insight into the mechanisms behind EGCG’s anti-IAV (H1N1) activity.*

Combining these new findings with other research results, EGCG not only inhibits influenza viral replication by damage to the physical properties of the viral envelope and partial inhibition of the neuraminidase (NA) surface glycoprotein[22] but also anti-IAV by inducing IFN-λ2 expression. A recent study demonstrated that EGCG could treat acute lung injury induced by swine influenza virus (H9N2) through 67LR/Tollip-downregulated TLR4 protein levels, decreased MPO activity and inflammatory cytokine levels.[23] These findings suggest that EGCG can fight influenza viruses through a variety of mechanisms.[24]*

Atherosclerosis

Aberrant chronic inflammation and excess accumulation of lipids play a pivotal role in the occurrence and progression of atherosclerosis. (-)-Epigallocatechin-3-gallate (EGCG), the major catechins in green tea, displayed anti-atherosclerotic properties in vivo and in vitro. However, the effects and underlying mechanism of EGCG on atherosclerosis remain unclear.*

EGCG administration markedly attenuated atherosclerotic plaque formation in HFD-fed ApoE-/- mice, which were accompanied by increased plasma interleukin-10 (IL-10) level and decreased plasma IL-6 and tumour necrosis factor-α (TNF-α) levels. In addition, EGCG modulated high-fat-induced dyslipidaemia, evidencing by decreased total cholesterol (TC) and low-density lipoprotein levels and increased high-density lipoprotein level. Meanwhile, EGCG treatment alleviated high-fat-mediated liver lipid accumulation and decreased liver TC and triglyceride. Mechanistically, EGCG significantly modulated high-fat-induced hepatic tetratricopeptide repeat domain protein 39B (TTC39B) expression and its related genes (Lxrβ, Abcg5, Abcg8, Abca1, Srebf1, Scd1, Scd2, Fas, Elovl5, Mylip) expression in liver from ApoE-/- mice. Notably, EGCG remarkably induced hepatic liver X receptor α (LXRα) and LXRβ expression and inhibited both precursor and mature sterol regulatory element binding transcription factor-1 (SREBP-1) expression. Conclusion: Taken together, our data for the first time suggested that TTC39B was involved in EGCG-mediated anti-atherosclerotic effects through modulation of LXR/SREBP-1 pathway.[25]*

Myocardial ischemia

Epigallocatechin-3-gallate (EGCG) is the most prominent catechin in green tea. EGCG has been shown to modulate numerous molecular targets in the setting of inflammation and cancer, particularly the effects of EGCG in myocardial reperfusion injury. Male Wistar rats were subjected to myocardial ischemia (30 min) and reperfusion (up to 2 h). Rats were treated with EGCG (10 mg/kg intravenously) or with vehicle at the end of the ischemia period followed by a continuous infusion (EGCG 10 mg/kg/h) during the reperfusion period. In vehicle-treated rats, extensive myocardial injury was associated with tissue neutrophil infiltration as evaluated by myeloperoxidase activity, and elevated levels of plasma creatine phosphokinase. Vehicle-treated rats also demonstrated increased plasma levels of interleukin-6. These events were associated with cytosol degradation of inhibitor kappa B-alpha, activation of Ikappa B kinase, phosphorylation of c-Jun, and subsequent activation of nuclear factor-kappa B and activator protein-1 in the infarcted heart. In vivo treatment with EGCG reduced myocardial damage and myeloperoxidase activity. Plasma IL-6 and creatine phosphokinase levels decreased after EGCG administration. This beneficial effect of EGCG was associated with reduction of nuclear factor-kB and activator protein-1 DNA binding. The results suggest that EGCG is beneficial for the treatment of reperfusion-induced myocardial damage by inhibition of the NF-kappa B and AP-1 pathway.*

Immune modulation

The epigallocatechin gallate fraction of green tea extract (EGTE) was examined on its effects on the innate and adaptive immune responses by measuring phagocytic and natural killer (NK) cell activity, as well as antigen-specific proliferation, cytolysis, cytokine secretion, and antibody production. The data shows that EGTE administration increased NK cell cytolysis and peritoneal cell phagocytosis, as well as splenocyte proliferation and secretion of IL-2 and IFN-g. Of note, EGTE treatment decreased the production antigen-specific IgE via increased the proportion of CD4+ CD25+ regulatory T lymphocytes in the spleen, suggesting that EGTE may play a role in regulating the allergic response.*

Cognition and Mood

Catechins are generally absorbed in the small intestine and then redistributed to the organs and the brain by crossing the blood brain barrier.[26] [27] The impairment of learning and memory abilities can be attributed to the oxidative injury in the hippocampus. Since EGCG is a compound with a high antioxidative activity, it was suggested that it is able to counteract increased oxidative stress and to restore learning and memory abilities by blocking the progressive increase in systolic blood pressure and enhancing endothelial functions. However, to date, this could be only proven by means of rodent models which applied 100 mg/kg bw for 28 days.[28] *

A rat study of Chen et al. provides comparable findings in terms of stress, but a different mechanism behind them. The ingestion of EGCG and green tea polyphenols in general resulted in an improvement of cognitive performance induced by stress. The two systems hypothalamic-pituitary-adrenal axis and sympathetic nervous system are involved in the regulation of stress response. When the hypothalamic-pituitary-adrenal axis is activated by psychological stress, an increased release of glucocorticoids can be observed.[29] Chen et al. found increased cortisol levels in plasma when rats were stressed by means of escaping tasks. Moreover, EGCG was able to improve the cognitive performance by decreasing the glucocorticoid and increasing catecholamine and plasma 5-hydroxytryptamine levels. Catecholamines consist of dopamine, epinephrine, and norepinephrine, which are associated with the modulation of cognitive performance and mood states. It was also observed that the norepinephrine and dopamine and therefore the cognitive impairment increased even further when the rats were not able to cope with the intensity and duration of the stress.[30] However, Gu et al. stated that glucocorticoids levels were not significantly changed by EGCG and suggested that learning and memory deficits were not related to glucocorticoids. They assumed that the ingestion of EGCG affects the complete impaired autophagic flux (measure of autophagic degradation activity), which is associated with cognitive dysfunctions such as Alzheimer’s disease.[31] *

Soung et al. used levels of thiobarbituric acid reactive substances (TBARS) and reactive oxygen species (ROS) as indices to access the degree of oxidative stress and alterations in the brain cytoarchitecture and cognition in a study with rats. Increased stress levels resulted in an increased concentration of free radicals and hippocampal neuron oxidative injury, which in turn induced a de- cline in memory abilities. In detail, the ingestion of EGCG led to a reduction of the hippocampal oxidative state, an increase of loco-motor activities, and a reduction of cognitive impairment.[32] *

Brown et al. suggested that EGCG has affinities for the benzodiazepine binding sites of gamma-Aminobutyric acid (GABA) which influences the regulation of anxiolytic activity.[33] EGCG was also found to modulate GABAergic systems to reduce stress-mediated effects.[34] By means of electroencephalography (EEG) measurements, it is possible to investigate different activities occurring at different locations. EGCG was found to increase alpha and theta activities, which are attributed to relaxation, quiet wakefulness, and mindfulness. Furthermore, it was observed that EGCG improves endothelial functions by enhancing the nitric oxide status, which is often related to cognitive functions such as memory, and learning abilities.[35] *

Park et al. investigated the reversing effect of EGCG on caffeine-induced precursors of anxiety. The ingestion of caffeine resulted in a release of dopamine. Simultaneously and consequently, it induces anxiogenesis, depending on the individual sensitivity. Increased ratios between small slow and fast waves are indices for an increased anxiogenic frontal cortical activity and reduced frontal cortical control.[36] The ratio is also used to predict psychological behaviours such as fear, attention, and cognitive performance.[37] [38] EGCG was observed to counteract anxiogenesis as measured by psychological tests in combination with these wave ratios. [39] *

Wightman et al. applied in their intervention study a combination of near-infrared spectroscopy (NIRS) and demanding tasks. They observed significantly reduced oxygenated and total haemoglobin concentration, cerebral blood flow in the frontal cortex, and heart rates after the administration of 135 mg EGCG. The modulation of cerebral blood flow parameters was associated with changes in cognition and mood.[40] [41] *