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Objective: Previous in vitro and in vivo studies indicated that catechins from the tea plant (Camellia sinensis) have a therapeutic effect on herpes simplex virus infections. The aim of this study was to clinically evaluate a topical proprietary formulation containing lipophilic catechins (AverTeaX, Camellix, LLC, Evans, GA, USA) on recurrent herpes labialis., Study Design: A double-blind, placebo-controlled, randomized trial with 40 participants, initially in two groups., Results: Compared with the vehicle (100% glycerin USP, CVS Pharmacies, Inc., Woonsocket, RI, USA) group, AverTeaX applied topically six to eight times daily resulted in a significant reduction in clinical episode duration (median 4.5 days vs. 9 days; P = .003) and shortened blistering and ulceration stages within an episode from a median of 3 days to 1 day (P = .0003). Median quality-of-life scores, based on a multiquestion survey, showed significant differences between the groups with respect to duration of itching, from a median of 4 days to 1 day (P = .0021), and duration until symptom free, from a median of 8 days to 4 days (P = .0016). Significant differences were not found for median scores for itching, pain, burning, swelling, bleeding, and stress. Adverse effects were not reported., Conclusion: AverTeaX formulation containing lipophilic catechins effectively inhibited herpes simplex labialis infection with clinical significance., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: Previous animal studies indicated catechins from the tea plant (Camellia sinensis) may modulate salivary function and possess a therapeutic effect for xerostomia. The objective of this study was to evaluate a natural formulation containing tea catechins in 60 patients with xerostomia, including patients with Sjögren syndrome., Study Design: This study used a double-blind, placebo-controlled, randomized design. The functional placebo contained all natural formulation ingredients and 500 mg xylitol, but without the key plant extracts., Results: After 8 weeks of therapy, the xylitol-containing placebo failed to modulate saliva output. In comparison, the catechin-containing natural formulation resulted in a statistically significant increase in unstimulated (3.8-fold) and stimulated (2.1-fold) saliva output vs baseline. The quality of life score showed a significant improvement in both groups but no significant difference between groups., Conclusions: The catechin-containing natural formula partially restored salivary function in patients with xerostomia and provided an objective improvement in saliva output, which warrants large-scale clinical trials., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: The purpose of the present study was to compare the antioxidant potential of lipophilic tea polyphenols (LTP) against the one of naturally-occurring water-soluble green tea polyphenols (GTP) in a two-stage model of diethylnitrosamine (DEN)/phenobarbital (PB)-induced hepatocarcinogenesis in Sprague-Dawley rats., Materials and Methods: GTP/LTP was given 5-times weekly by oral gavage with tea polyphenols equivalent to 0-, 40- and 400-mg/kg of body weight/day. GTP/LTP treatment was started 2 weeks prior to the initiation of DEN and continued for 30 weeks., Results: Histopathological and electron microscopic examination of liver tissue confirmed the protective effect of LTP on DEN/PB-induced liver damage and pre-carcinogenesis. LTP treatment significantly increased total antioxidant capacity (T-AOC) and glutathione peroxidase (GSH-Px) activity in liver tissues. Immunohistochemical detection of cellular nuclear factor erythroid-2-related factor-2 (Nrf2) and peroxiredoxin-6 (P6) indicated a down-regulation in Nrf2 and up-regulation of P6 expression in the liver of LTP-supplemented rats., Conclusion: The present study provides evidence for the first time, that LTP exerts significant antioxidant effects on DEN/PB-induced liver damage and hepatocarcinogenesis through elevating T-AOC levels, enhancing GSH-Px activity and inducing P6 expression in rat liver tissues., (Copyright © 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background: Green tea polyphenols (GTPs) have been proposed as promising candidates for chemoprevention. However, GTPs levels are maintained relatively low in the blood and are chemically-unstable. Lipid-soluble tea polyphenols (LTPs) are products of modified GTPs with ester linkage with fatty acids. LTPs are lipophilic and expected to provide improved absorption and utilization in the body compared with water-soluble polyphenols. The current study was designed to investigate the chemo-preventive property and the possible mechanisms of LTP action against diethylnitrosamine (DEN)-induced liver cancer in rats., Materials and Methods: Oral administration of LTPs at doses of 0, 40, and 400 mg/kg/day was initiated 2 weeks prior to DEN injection and was continued for 30 weeks. At that time point samples were collected and liver histopathological analyses were performed., Results: LTPs decreased the area and number of placental glutathione S-transferase-positive foci in liver samples of DEN-treated rats. Furthermore, LTPs counteracted DEN-induced fibrosis formation in liver. Immunohistochemical staining of rat liver showed that LTPs inhibited DEN-mediated elevations in numbers of cells positive for PCNA and 8-OHdG., Conclusion: For the first time, the present study demonstrated, that LTPs exert a chemo-preventive effect against precancerous lesions through inhibition of cellular proliferation and DNA damage in a rat liver model.

Green tea polyphenol epigallocatechin gallate (EGCG) is a strong antioxidant that has previously been shown to reduce the number of plaques in HIV-infected cultured cells. Modified EGCG, palmitoyl-EGCG (p-EGCG), is of interest as a topical antiviral agent for herpes simplex virus (HSV-1) infections. This study evaluated the effect of p-EGCG on HSV-infected Vero cells. Results of cell viability and cell proliferation assays indicate that p-EGCG is not toxic to cultured Vero cells and show that modification of the green tea polyphenol epigallocatechin gallate (EGCG) with palmitate increases the effectiveness of EGCG as an antiviral agent. Furthermore, p-EGCG is a more potent inhibitor of herpes simplex virus 1 (HSV-1) than EGCG and can be topically applied to skin, one of the primary tissues infected by HSV. Viral binding assay, plaque forming assay, PCR, real-time PCR, and fluorescence microscopy were used to demonstrate that p-EGCG concentrations of 50 μM and higher block the production of infectious HSV-1 particles. p-EGCG was found to inhibit HSV-1 adsorption to Vero cells. Thus, p-EGCG may provide a novel treatment for HSV-1 infections., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Significance: Protection of glandular cells from autoimmune-induced damage would be of significant clinical benefit to Sjogren's syndrome (SS) patients. Epigallocatechin-3-gallate (EGCG) possesses anti-apoptotic, anti-inflammatory, and autoantigen-inhibitory properties., Aims: To investigate if EGCG protects against certain autoimmune-induced pathological changes in the salivary glands of the non-obese diabetic (NOD) mouse model for SS., Main Methods: Animals were provided with either water or water containing 0.2% EGCG. At the age of 8, 16 and 22 weeks, submandibular salivary gland tissue and serum samples were collected for pathological and serological analysis., Key Findings: Significant lymphocyte infiltration was observed in the salivary glands of the water-fed group at the age of 16 weeks, while the EGCG group showed reduced lymphocyte infiltration. By 22 weeks of age, water-fed animals demonstrated elevated levels of apoptotic activity within the lymphocytic infiltrates, and high levels of serum total anti-nuclear antibody, compared to EGCG-fed animals. Remarkably, proliferating cell nuclear antigen (PCNA) and Ki-67 levels in the salivary glands of water-fed NOD mice were significantly elevated in comparison to BALB/c control mice; in contrast, PCNA and Ki-67 levels in EGCG-fed NOD animals were similar to BALB/c mice. These results indicate that EGCG protects the NOD mouse submandibular glands from autoimmune-induced inflammation, and reduces serum autoantibody levels. Abnormal proliferation, rather than apoptosis, appears to be a characteristic of the NOD mouse gland that is normalized by EGCG. The evidence suggests that EGCG could be useful in delaying or managing SS-like autoimmune disorders.

The current study investigated the protective effects of green tea polyphenols (GTPP) on TBT-induced oxidative damage. The results showed that reactive oxygen species (ROS) production and malondialdehyde content of the liver in mice exposed to TBT were reduced in the GTPP-treated group compared to the untreated group. The intracellular ROS level was elevated in TBT-treated human FL cells in a time-dependent manner. Comet assay data demonstrated that the number of cells with damaged DNA in untreated mice was found to be significantly higher compared to GTPP-treated mice. Damage to the nuclei and mitochondria observed in TBT-treated mice were alleviated in mice treated with both TBT and GTPP. The results represent the first observation that GTPP were effective in reducing TBT-induced oxidative damage both in vivo and in vitro. The possible protective mechanism may be due to the powerful ability of GTPP to scavenge ROS and prevent DNA breaks. We conclude that GTPP could be an effective agent or food supplement to reduce the cytotoxicity of TBT.

Psoriasiform lesions are characterized by hyperproliferation and aberrant differentiation of epidermal keratinocytes, accompanied by inflammation, leading to a disrupted skin barrier with an abnormal stratum corneum. The expression and proteolytic processing of caspase 14, a member of the caspase family which is associated with epithelial cell differentiation, planned cell death, and barrier formation, is altered in psoriatic epidermis. We recently reported that human psoriatic tissues lack normal expression of caspase 14 [J Dermatol Sci37 (2005) 61], and caspase 14 is induced by EGCG, a green tea polyphenol (GTP), in exponentially growing normal human epidermal keratinocytes (NHEK) [J Pharmacol Exp Ther315 (2005) 805]. This suggests that GTPs may have beneficial effects on psoriasiform lesions. The current study aimed to determine whether MAPK pathways are required for GTP-induced caspase 14 expression in NHEK and if GTPs can modulate the expression of pathological markers in the psoriasiform lesions that develop in the flaky skin mouse. The results indicate that the p38 and JNK MAPK pathways are required for EGCG-induced expression of caspase 14 in NHEK. Importantly, topical application of 0.5% GTPs significantly reduced the symptoms of epidermal pathology in the flaky skin mice, associated with efficient caspase 14 processing and reduction in proliferating cell nuclear antigen levels. This suggests that GTP-activated pathways may be potential targets for novel therapeutic approaches to the treatment of some psoriasiform skin disorders.

Sjogren's syndrome (SS) is a relatively common autoimmune disorder. A key feature of SS is lymphocytic infiltration of the salivary and lacrimal glands, associated with the destruction of secretory functions of these glands. Current treatment of SS targets the symptoms but is unable to reduce or prevent the damage to the glands. We reported previously that the major green tea polyphenol (GTP) epigallocatechin-3-gallate (EGCG) inhibits autoantigen expression in normal human keratinocytes and immortalized normal human salivary acinar cells (Hsu et al. 2005). However, it is not known whether GTPs have this effect in vivo, if they can reduce lymphocytic infiltration, or protect salivary acinar cells from tumor necrosis factor-alpha (TNF-alpha)-induced cytotoxicity. Here, we demonstrate that in the NOD mouse, a model for human SS, oral administration of green tea extract reduced the serum total autoantibody levels and the autoimmune-induced lymphocytic infiltration of the submandibular glands. Further, we show that EGCG protected normal human salivary acinar cells from TNF-alpha-induced cytotoxicity. This protection was associated with specific phosphorylation of p38 MAPK, and inhibitors of the p38 MAPK pathway blocked the protective effect. In conclusion, GTPs may provide a degree of protection against autoimmune-induced tissue damage in SS, mediated in part through activation of MAPK elements.

Sjogren's syndrome (SS) is an autoimmune disorder that affects the salivary glands, leading to xerostomia, and the lacrimal glands, resulting in xerophthalmia. Secondary SS is associated with other autoimmune disorders such as systemic rheumatic diseases and systemic lupus erythematosis (SLE), which can affect multiple organs, including the epidermis. Recent studies have demonstrated that green tea polyphenols (GTPs) possess both anti-inflammatory and anti-apoptotic properties in normal human cells. Epidemiological evidence has indicated that, in comparison to the United States, the incidence of SS, clinical xerostomia and lupus is considerably lower in China and Japan, the two leading green tea-consuming countries.Thus, GTPs might be responsible, in part, for geographical differences in the incidence of xerostomia by reducing the initiation or severity of SS and lupus. Consistent with this, molecular, cellular and animal studies indicate that GTPs could provide protective effects against autoimmune reactions in salivary glands and skin. Therefore, salivary tissues and epidermal keratinocytes could be primary targets for novel therapies using GTPs. This review article evaluates the currently available research data on GTPs, focusing on their potential application in the treatment of the oral manifestations of SS and skin manifestations of SLE.

Plant extracts have been widely used as topical applications for wound-healing, anti-aging, and disease treatments. Examples of these include ginkgo biloba, echinacea, ginseng, grape seed, green tea, lemon, lavender, rosemary, thuja, sarsaparilla, soy, prickly pear, sagebrush, jojoba, aloe vera, allantoin, feverwort, bloodroot, apache plume, and papaya. These plants share a common character: they all produce flavonoid compounds with phenolic structures. These phytochemicals are highly reactive with other compounds, such as reactive oxygen species and biologic macromolecules, to neutralize free radicals or initiate biological effects. A short list of phenolic phytochemicals with promising properties to benefit human health includes a group of polyphenol compounds, called catechins, found in green tea. This article summarizes the findings of studies using green tea polyphenols as chemopreventive, natural healing, and anti-aging agents for human skin, and discusses possible mechanisms of action.

Epigallocatechin-3-gallate (EGCG), the most abundant polyphenol in green tea, exerts chemopreventive effects by selectively inducing apoptosis in tumor cells. In contrast, EGCG accelerates terminal differentiation in normal human epidermal keratinocytes (NHEK) mediated partially by up-regulation of p57/KIP2, a cyclin-dependent kinase inhibitor that confers growth arrest and differentiation. However, it is unclear if EGCG modulates caspase 14, a unique regulator of epithelial cell terminal differentiation associated with cornification. Here, we examined the effect of EGCG on caspase 14 expression in NHEK and correlated the protein and mRNA expression of p57/KIP2 with those of caspase 14 in either normal keratinocytes or p57/KIP2-expressing tumor cells (OSC2, an oral squamous cell carcinoma cell line). Additionally, paraffin-embedded normal and untreated psoriatic (aberrant keratinization) skin sections from humans were assessed for caspase 14 by immunohistochemistry. In NHEK, EGCG induced the expression of caspase 14 mRNA and protein levels within a 24-h period. The expression of p57/KIP2 in OSC2 cells was adequate to induce caspase 14 in the absence of EGCG; this induction of caspase 14 was down-regulated by transforming growth factor-beta1. In human psoriatic skin samples, caspase 14 staining in the upper epidermis was reduced, especially in nuclear areas. These results suggest that, in addition to p57/KIP2, EGCG-induced terminal differentiation of epidermal keratinocytes involves up-regulation of caspase 14. Further understanding of how EGCG modulates cellular differentiation may be useful in developing green tea preparations for selected clinical applications.

The green tea polyphenol (-)-epigallocatechin-3-gallate (EGCG) possesses promising anticancer potential. Although in vivo studies unveiled the metabolic routes and pharmacokinetics of EGCG and showed no adverse effects, in vitro studies at high concentrations demonstrated oxidative stress. EGCG causes differential oxidative environments in tumor versus normal epithelial cells, but the roles that EGCG, hydrogen peroxide (H2O2), and intracellular catalase play in the epithelial system are largely unknown. The current study employed enzyme activity assays, reactive oxygen species quantification, and immunoblotting to investigate whether EGCG-induced differential effects correlate with levels of key antioxidant enzymes and H2O2. It was found that normal human keratinocytes with high catalase activity are least susceptible to H2O2, whereas H2O2 caused significant cytotoxicity in oral carcinoma cell lines. However, the EGCG-induced differential effects could not be duplicated by H2O2 alone. The addition of exogenous catalase failed to completely prevent the EGCG-induced cytotoxicity and rescue the EGCG-induced growth arrest in the tumor cells. The antioxidant N-acetyl-L-cysteine rescued the tumor cells from H2O2-induced damage only, but not from EGCG-induced mitochondrial damage. Finally, alterations in catalase or superoxide dismutase activities were not observed upon EGCG exposure. In conclusion, although endogenous catalase may play a role in response to H2O2-induced cytotoxicity, the EGCG-induced cytotoxic effects on tumor cells mainly result from sources other than H2O2.

Green tea polyphenols (GTPPs) are considered beneficial to human health, especially as chemopreventive agents. Recently, cytotoxic reactive oxygen species (ROS) were identified in tumor and certain normal cell cultures incubated with high concentrations of the most abundant GTPP, (-)-epigallocatechin-3-gallate (EGCG). If EGCG also provokes the production of ROS in normal epithelial cells, it may preclude the topical use of EGCG at higher doses. The current study examined the oxidative status of normal epithelial, normal salivary gland, and oral carcinoma cells treated with EGCG, using ROS measurement and catalase and superoxide dismutase activity assays. The results demonstrated that high concentrations of EGCG induced oxidative stress only in tumor cells. In contrast, EGCG reduced ROS in normal cells to background levels. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and 5-bromodeoxyuridine incorporation data were also compared between the two oral carcinoma cell lines treated by EGCG, which suggest that a difference in the levels of endogenous catalase activity may play an important role in reducing oxidative stress provoked by EGCG in tumor cells. It is concluded that pathways activated by GTPPs or EGCG in normal epithelial versus tumor cells create different oxidative environments, favoring either normal cell survival or tumor cell destruction. This finding may lead to applications of naturally occurring polyphenols to enhance the effectiveness of chemo/radiation therapy to promote cancer cell death while protecting normal cells.

The most abundant green tea polyphenol, epigallocatechin-3-gallate (EGCG), was found to induce differential effects between tumor cells and normal cells. Nevertheless, how normal epithelial cells respond to the polyphenol at concentrations for which tumor cells undergo apoptosis is undefined. The current study tested exponentially growing and aged primary human epidermal keratinocytes in response to EGCG or a mixture of the four major green tea polyphenols. EGCG elicited cell differentiation with associated induction of p57/KIP2 within 24 h in growing keratinocytes, measured by the expression of keratin 1, filaggrin, and transglutaminase activity. Aged keratinocytes, which exhibited low basal cellular activities after culturing in growth medium for up to 25 days, renewed DNA synthesis and activated succinate dehydrogenase up to 37-fold upon exposure to either EGCG or the polyphenols. These results suggest that tea polyphenols may be used for treatment of wounds or certain skin conditions characterized by altered cellular activities or metabolism.

Induction of apoptosis by green tea polyphenols has been observed in various tumor cell systems, but whether green tea polyphenol-induced apoptosis requires caspase 3 for execution has not been confirmed. We previously reported that green tea polyphenol-induced apoptosis involved Apaf-1 accumulation and caspase 3 activation in the cytosol. In the current study, tumor cells either with deleted caspase 3 gene or expressing wild-type caspase 3 were treated with increasing concentrations of green tea polyphenol(s), followed by morphological analysis and caspase 3 activity assay. The caspase 3 null parental cell line was further examined in comparison with a well-characterized, caspase 3 wild type oral carcinoma cell line by MTT assay and BrdU incorporation assay. The results demonstrated that, while the mitochondrial function gradually declined to insignificant levels, caspase 3 null cells did not undergo apoptosis, which suggested that green tea polyphenol-induced apoptosis is a mitochondria-targeted, caspase 3-executed mechanism.

Green tea has been a popular beverage for many centuries. Only recently, however, has the anti-cancer power of green tea constituents been unveiled. Green tea polyphenols are found to induce apoptosis (programmed cell death) in many types of tumor cells, including oral cancer cells. However, mechanisms that enable normal cells to evade the apoptotic effect still are not understood. In this study, cell growth and invasion assays combined with apoptosis assays were used to examine the effects of green tea extracts, green tea polyphenols, and the most potent green tea polyphenol, (-)-epigallocatechin-3-gallate (EGCG), on normal human keratinocytes and oral carcinoma cells. The results showed that green tea and its constituents selectively induce apoptosis only in oral carcinoma cells, while EGCG was able to inhibit the growth and invasion of oral carcinoma cells. These differential responses to green tea and its constituents between normal and malignant cells were correlated with the induction of p57, a cell cycle regulator. These data suggest that the chemopreventive effects of green tea polyphenols may involve a p57 mediated survival pathway in normal epithelial cells, while oral carcinoma cells undergo an apoptotic pathway. Therefore, regular consumption of green tea could be beneficial in the prevention of oral cancer.