Life Extension Magazine®

Issue: Jun 2011

Green tea

History and development of radiation-protective agents.

PURPOSE: The search for ideal protective agents for use in a variety of radiation scenarios has continued for more than six decades. This review evaluates agents and procedures that have the potential to protect against acute and late effects of ionising radiation when administered either before or after radiation exposure. CONCLUSION: Over the years, extensive experimental studies of radiation-protective agents have enhanced our knowledge of radiation physics, chemistry, and biology. However, translation of agents from animal testing to use in various scenarios, such as prophylactic adjuncts in radiotherapy or post-exposure treatments for potential victims of radiation accidents/incidents, has been slow. Nevertheless, a number of compounds are now available for use in a variety of radiation situations. These include agents approved by the US Food and Drug Administration for use in reducing exposure to internal radionuclides (Prussian blue, calcium diethylenetriamene pentaacetate (DTPA) and zinc DTPA, potassium iodide) and amifostine for alleviating xerostomia associated with radiotherapy. Consensus groups have also recommended other therapies such as granulocyte colony-stimulating factor for radiation-induced neutropenia. The variety of prophylactic and therapeutic agents in the research pipeline includes those that are naturally-occurring with low toxicity, provide a long window of protection, protect normal tissue while sensitising tumours, or act via receptors and modulate biological processes such as induction of genes responsible for radioresistance. The search for agents that protect against acute and late effects of ionising radiation injury will undoubtedly continue into the future and influence other areas of radiation research.

Int J Radiat Biol. 2009 Jul;85(7):539-73

Health effects from fallout.

This paper primarily discusses health effects that have resulted from exposures received as a result of above-ground nuclear tests, with emphasis on thyroid disease from exposure to 131I and leukemia and solid cancers from low dose rate external and internal exposure. Results of epidemiological studies of fallout exposures in the Marshall Islands and from the Nevada Test Site are summarized, and studies of persons with exposures similar to those from fallout are briefly reviewed (including patients exposed to 131I for medical reasons and workers exposed externally at low doses and low dose rates). Promising new studies of populations exposed in countries of the former Soviet Union are also discussed and include persons living near the Semipalatinsk Test Site in Kazakhstan, persons exposed as a result of the Chernobyl accident, and persons exposed as a result of operations of the Mayak Nuclear Plant in the Russian Federation. Very preliminary estimates of cancer risks from fallout doses received by the United States population are presented.

Health Phys. 2002 May;82(5):726-35

A cohort study of thyroid disease in relation to fallout from nuclear weapons testing.

OBJECTIVE: To estimate individual radiation doses and current thyroid disease status for a previously identified cohort of 4,818 schoolchildren potentially exposed to fallout from detonations of nuclear devices at the Nevada Test Site between 1,951 and 1958. DESIGN: Cohort analytic study. SETTING: Communities in southwestern Utah, southeastern Nevada, and southeastern Arizona.PARTICIPANTS: Individuals who were still residing in the three-state area (n = 3,122) were reexamined in 1985 and 1986, and information on the subjects’ and their mothers’ milk and vegetable consumption during the fallout period was obtained by telephone interview (n = 3,545). After exclusions to eliminate missing data and confounding factors, 2,473 subjects were available for analysis. MAIN OUTCOME MEASURES: Individual radiation doses to the thyroid were estimated by combining consumption data with radionuclide deposition rates provided by the US Department of Energy and a survey of milk producers. Relative risk models adjusted for age, sex, and state were fitted using maximum likelihood to period prevalence data for thyroid carcinomas, neoplasms, and nodules. RESULTS: Doses ranged from 0 mGy to 4,600 mGy, and averaged 170 mGy in Utah. There was a statistically significant excess of thyroid neoplasms (benign and malignant; n = 19), with an increase in excess relative risk of 0.7% per milligray. A relative risk for thyroid neoplasms of 3.4 was observed among 169 subjects exposed to doses greater than 400 mGy. Positive but nonsignificant dose-response slopes were found for carcinomas and nodules. CONCLUSIONS: Exposure to Nevada Test Site-generated radioiodines was associated with an excess of thyroid neoplasms. The conclusions are limited by the small number of exposed individuals and the low incidence of thyroid neoplasms.

JAMA. 1993 Nov 3;270(17):2076-82

Thyroid cancer rates and 131I doses from Nevada atmospheric nuclear bomb tests: an update.

Exposure to radioactive iodine ((131)I) from atmospheric nuclear tests conducted in Nevada in the 1950s may have increased thyroid cancer risks. To investigate the long-term effects of this exposure, we analyzed data on thyroid cancer incidence (18,545 cases) from eight Surveillance, Epidemiology, and End Results (SEER) tumor registries for the period 1973-2004. Excess relative risks (ERR) per gray (Gy) for exposure received before age 15 were estimated by relating age-, birth year-, sex- and county-specific thyroid cancer rates to estimates of cumulative dose to the thyroid that take age into account. The estimated ERR per Gy for dose received before 1 year of age was 1.8 [95% confidence interval (CI), 0.5-3.2]. There was no evidence that this estimate declined with follow-up time or that risk increased with dose received at ages 1-15. These results confirm earlier findings based on less extensive data for the period 1973-1994. The lack of a dose response for those exposed at ages 1-15 is inconsistent with studies of children exposed to external radiation or (131)I from the Chernobyl accident, and results need to be interpreted in light of limitations and biases inherent in ecological studies, including the error in doses and case ascertainment resulting from migration. Nevertheless, the study adds support for an increased risk of thyroid cancer due to fallout, although the data are inadequate to quantify it.

Radiat Res. 2010 May;173(5):659-64

Oxidative Stress Resistance in Deinococcus radiodurans.

Summary: Deinococcus radiodurans is a robust bacterium best known for its capacity to repair massive DNA damage efficiently and accurately. It is extremely resistant to many DNA-damaging agents, including ionizing radiation and UV radiation (100 to 295 nm), desiccation, and mitomycin C, which induce oxidative damage not only to DNA but also to all cellular macromolecules via the production of reactive oxygen species. The extreme resilience of D. radiodurans to oxidative stress is imparted synergistically by an efficient protection of proteins against oxidative stress and an efficient DNA repair mechanism, enhanced by functional redundancies in both systems. D. radiodurans assets for the prevention of and recovery from oxidative stress are extensively reviewed here. Radiation- and desiccation-resistant bacteria such as D. radiodurans have substantially lower protein oxidation levels than do sensitive bacteria but have similar yields of DNA double-strand breaks. These findings

challenge the concept of DNA as the primary target of radiation toxicity while advancing protein damage, and the protection of proteins against oxidative damage, as a new paradigm of radiation toxicity and survival. The protection of DNA repair and other proteins against oxidative damage is imparted by enzymatic and nonenzymatic antioxidant defense systems dominated by divalent manganese complexes. Given that oxidative stress caused by the accumulation of reactive oxygen species is associated with aging and cancer, a comprehensive outlook on D. radiodurans strategies of combating oxidative stress may open new avenues for antiaging and anticancer treatments. The study of the antioxidation protection in D. radiodurans is therefore of considerable potential interest for medicine and public health.

Microbiol Mol Biol Rev. 2011 Mar;75(1):133-91

Measurement of oxidatively generated base damage in cellular DNA.

This survey focuses on the critical evaluation of the main methods that are currently available for monitoring single and complex oxidatively generated damage to cellular DNA. Among chromatographic methods, HPLC-ESI-MS/MS and to a lesser extent HPLC-ECD which is restricted to a few electroactive nucleobases and nucleosides are appropriate for measuring the formation of single and clustered DNA lesions. Such methods that require optimized protocols for DNA extraction and digestion are sensitive enough for measuring base lesions formed under conditions of severe oxidative stress including exposure to ionizing radiation, UVA light and high intensity UVC laser pulses. In contrast application of GC-MS and HPLC-MS methods that are subject to major drawbacks have been shown to lead to overestimated values of DNA damage. Enzymatic methods that are based on the use of DNA repair glycosylases in order to convert oxidized bases into strand breaks are suitable, even if they are far less specific than HPLC methods, to deal with low levels of single modifications. Several other methods including immunoassays and (32)P-postlabeling methods that are still used suffer from drawbacks and therefore are not recommended. Another difficult topic is the measurement of oxidatively generated clustered DNA lesions that is currently achieved using enzymatic approaches and that would necessitate further investigations.

Mutat Res. 2011 Feb 15

The manganese superoxide dismutase mimetic, M40403, protects adult mice from lethal total body irradiation.

Over-expression of manganese superoxide dismutase (MnSOD) protects tissues from radiation. M40403 is a stable non-peptidyl mimetic of MnSOD that crosses cell membranes and is effective in reducing experimental inflammation. Male BALB/c mice were injected intraperitoneally (i.p.) and subcutaneously (s.c.) with M40403, 30 min before 6.5, 7.5 and 8.5 Gy total body irradiation (TBI). Whereas all control injected mice died after receiving 8.5 Gy TBI by day 17, 30 day survival of mice pre-treated i.p. with 40, 30, 20 or 10 mg/kg was 100%, 90%, 81% and 25%, respectively. The Dose Reduction Factor 50/30 for animals treated with 30 mg M40403 s.c. 30 min prior to TBI was 1.41. Decreased apoptosis of the large and particularly the small bowel and marked recovery of both lymphoid and hematopoietic tissues occurred in the M40403 pre-treated animals. M40403 is effective in reducing TBI-induced tissue destruction and has potential as a new radioprotective agent.

Free Radic Res. 2010 May;44(5):529-40

Protective effects of dietary antioxidants on proton total-body irradiation-mediated hematopoietic cell and animal survival.

Abstract: Dietary antioxidants have radioprotective effects after gamma-radiation exposure that limit hematopoietic cell depletion and improve animal survival. The purpose of this study was to determine whether a dietary supplement consisting of l-selenomethionine, vitamin C, vitamin E succinate, alpha-lipoic acid and N-acetyl cysteine could improve survival of mice after proton total-body irradiation (TBI). Antioxidants significantly increased 30-day survival of mice only when given after irradiation at a dose less than the calculated LD(50/30); for these data, the dose-modifying factor (DMF) was 1.6. Pretreatment of animals with antioxidants resulted in significantly higher serum total white blood cell, polymorphonuclear cell and lymphocyte cell counts at 4 h after 1 Gy but not 7.2 Gy proton TBI. Antioxidants significantly modulated plasma levels of the hematopoietic cytokines Flt-3L and TGFbeta1 and increased bone marrow cell counts and spleen mass after TBI. Maintenance of the antioxidant diet resulted in improved recovery of peripheral leukocytes and platelets after sublethal and potentially lethal TBI. Taken together, oral supplementation with antioxidants appears to be an effective approach for radioprotection of hematopoietic cells and improvement of animal survival after proton TBI.

Radiat Res. 2009 Aug;172(2):175-86

Thyroid blockade during a radiation emergency in iodine-rich areas: effect of a stable-iodine dosage.

We examined the effect of stable iodine on thyroid gland blockade in patients with hyperthyroidism in order to make a preliminary evaluation of the appropriate dose of iodine prophylaxis in the event of a radiation emergency in Japan in which radioiodine is released to the environment. Eight patients were orally given single doses of 50 mg or 100 mg of potassium iodide, which contained 38 mg and 76 mg of iodide, respectively. Both doses significantly suppressed a thyroid uptake of (123)I for 24 h (p = 0.03). The protective effects at 24 h were 73.3% and 79.5%, respectively. No side effects were observed during the trial. The present study demonstrates that a single oral administration of 38 mg of iodide produces a thyroid-blocking effect equivalent to that of 76 mg of iodide, suggesting that a reevaluation of the stable iodine dosage during radiation emergencies in iodine-rich areas such as Japan is warranted.

J Radiat Res (Tokyo). 2004 Jun;45(2):201-4

Enhancing nuclear emergency preparedness: Vermont’s distribution program for potassium iodide.

On January 31, 2002, Vermont’s health commissioner requested potassium iodide (KI) for individuals in the 10-mile Emergency Planning Zone of the nuclear power facility. Vermont’s KI distribution program emphasized public information about the role, risks, and benefits of KI. Predistribution ensured that individuals could receive KI in a 0- to 4-hour time period, to provide maximum protection. Five months after the program began, more than 1,000 individuals had received KI, and 3,000-4,000 KI doses have been distributed in schools. Efforts are ongoing to identify barriers to participation, provide public education, and evaluate KI distribution efforts.

J Public Health Manag Pract. 2003 Sep-Oct;9(5):361-7

Free radicals in biology: oxidative stress and the effects of ionizing radiation.

The most important electron acceptor in the biosphere is molecular oxygen which, by virtue of its bi-radical nature, readily accepts unpaired electrons to give rise to a series of partially reduced species collectively known as reduced (or ‘reactive’) oxygen species (ROS). These include superoxide (O.2-), hydrogen peroxide (H2O2), hydroxyl radical (HO.) and peroxyl (ROO.) and alkoxyl (RO.) radicals which may be involved in the initiation and propagation of free radical chain reactions and which are potentially highly damaging to cells. Mechanisms have evolved to restrict and control such processes, partly by compartmentation, and partly by antioxidant defences such as chain-breaking antioxidant compounds capable forming stable free radicals (e.g. ascorbate, alpha-tocopherol) and the evolution of enzyme systems (e.g. superoxide dismutase, catalase, peroxidases) that diminish the intracellular concentration of the ROS. Although some ROS perform useful functions, the production of ROS exceeding the ability of the organism to mount an antioxidant defence results in oxidative stress and the ensuing tissue damage may be involved in certain disease processes. Evidence that ROS are involved in primary pathological mechanisms is a feature mainly of extraneous physical or chemical perturbations of which radiation is perhaps the major contributor. One of the important radiation-induced free-radical species is the hydroxyl radical which indiscriminately attacks neighbouring molecules often at near diffusion-controlled rates. Hydroxyl radicals are generated by ionizing radiation either directly by oxidation of water, or indirectly by the formation of secondary partially ROS. These may be subsequently converted to hydroxyl radicals by further reduction (‘activation’) by metabolic processes in the cell. Secondary radiation injury is therefore influenced by the cellular antioxidant status and the amount and availability of activating mechanisms. The biological response to radiation may be modulated by alterations in factors affecting these secondary mechanisms of cellular injury.

Int J Radiat Biol. 1994 Jan;65(1):27-33

Protection against ionizing radiation by antioxidant nutrients and phytochemicals.

The potential of antioxidants to reduce the cellular damage induced by ionizing radiation has been studied in animal models for more than 50 years. The application of antioxidant radioprotectors to various human exposure situations has not been extensive although it is generally accepted that endogenous antioxidants, such as cellular non-protein thiols and antioxidant enzymes, provide some degree of protection. This review focuses on the radioprotective efficacy of naturally occurring antioxidants, specifically antioxidant nutrients and phytochemicals, and how they might influence various endpoints of radiation damage. Results from animal experiments indicate that antioxidant nutrients, such as vitamin E and selenium compounds, are protective against lethality and other radiation effects but to a lesser degree than most synthetic protectors. Some antioxidant nutrients and phytochemicals have the advantage of low toxicity although they are generally protective when administered at pharmacological doses. Naturally occurring antioxidants also may provide an extended window of protection against low-dose, low-dose-rate irradiation, including therapeutic potential when administered after irradiation. A number of phytochemicals, including caffeine, genistein, and melatonin, have multiple physiological effects, as well as antioxidant activity, which result in radioprotection in vivo. Many antioxidant nutrients and phytochemicals have antimutagenic properties, and their modulation of long-term radiation effects, such as cancer, needs further examination. In addition, further studies are required to determine the potential value of specific antioxidant nutrients and phytochemicals during radiotherapy for cancer.

Toxicology. 2003 Jul 15;189(1-2):1-20

Radioprotection by antioxidants.

The role of reactive oxygen species in ionizing radiation injury and the potential of antioxidants to reduce these deleterious effects have been studied in animal models for more than 50 years. This review focuses on the radioprotective efficacy and the toxicity in mice of phosphorothioates such as WR-2721 and WR-151327, other thiols, and examples of radioprotective antioxidants from other classes of agents. Naturally occurring antioxidants, such as vitamin E and selenium, are less effective radioprotectors than synthetic thiols but may provide a longer window of protection against lethality and other effects of low dose, low-dose rate exposures. Many natural antioxidants have antimutagenic properties that need further examination with respect to long-term radiation effects. Modulation of endogenous antioxidants, such as superoxide dismutase, may be useful in specific radiotherapy protocols. Other drugs, such as nimodipine, propranolol, and methylxanthines, have antioxidant properties in addition to their primary pharmacological activity and may have utility as radioprotectors when administered alone or in combination with phosphorothioates.

Ann N Y Acad Sci. 2000;899:44-60

Influence of different radioprotective compounds on radiotolerance and cell cycle distribution of human progenitor cells of granulocytopoiesis in vitro.

Ficoll-separated mononuclear cells (MNC) of cryopreserved human bone marrow were incubated with isotoxic doses of diltiazem, N-acetylcysteine (NAC), glycopolysaccharide extract of spirulina platensis (SPE), tempol, thiopental, WR2721 and WR1065. After irradiation with a single dose of 0.73 Gy, survival of granulocyte/macrophage colony-forming cells (GM-CFC) was determined at d 10-14, using an agar culture system. Diltiazem, NAC, tempol and WR1065 significantly improved radiotolerance with protection factors (PF) between 1.21 and 1.36 (n = 5, P < 0.05) at 0.73 Gy (PF-0.73 Gy). The survival curves of diltiazem (D0 = 0.88 Gy, n = 1.00), NAC (D0 = 0.92 Gy, n = 1.10), tempol (D0 = 0.99 Gy, n = 1.10), WR1065 (D0 = 0.89 Gy, n = 1.16) and control (D0 = 0.78 Gy, n = 1.00) over 0.36-2.91 Gy showed a significant radioprotective effect for D0 only for tempol (P = 0.018) and for the extrapolation number ‘n’ only in the case of NAC (P = 0.023). Cell cycle analysis of the CD34+ cell subpopulation (control-0 h: G1 = 82.7%, S = 13.7%, G2/M = 3.6%) revealed that all compounds with a significant PF-0.73 Gy also caused a significant increase in CD34+ cells in S phase up to 48 h. Within the first 24 h, only NAC (26.7 +/- 4.1%), tempol (14.3 +/- 1.0%) and possibly WR1065 (15.5 +/- 1.6%) had higher fractions of CD34+ S-phase cells compared with controls. This observation and the improvement of GM-CFC cloning efficiency indicated that only NAC was able to recruit progenitor cells in the cell cycle, whereas tempol and WR1065 possibly inhibited cell cycle progression by S and G2/M arrest. Of the radioprotectors tested, NAC, tempol and WR1065 may be suitable to support, alone or combined with cytokine therapy, accelerated haematopoietic recovery after irradiation.

Br J Haematol. 2002 Oct;119(1):244-54

Antioxidants reduce consequences of radiation exposure.

Antioxidants have been studied for their capacity to reduce the cytotoxic effects of radiation in normal tissues for at least 50 years. Early research identified sulfur-containing antioxidants as those with the most beneficial therapeutic ratio, even though these compounds have substantial toxicity when given in-vivo. Other antioxidant molecules (small molecules and enzymatic) have been studied for their capacity to prevent radiation toxicity both with regard to reduction of radiation-related cytotoxicity and for reduction of indirect radiation effects including long-term oxidative damage. Finally, categories of radiation protectors that are not primarily antioxidants, including those that act through acceleration of cell proliferation (e.g. growth factors), prevention of apoptosis, other cellular signaling effects (e.g. cytokine signal modifiers), or augmentation of DNA repair, all have direct or indirect effects on cellular redox state and levels of endogenous antioxidants. In this review we discuss what is known about the radioprotective properties of antioxidants, and what those properties tell us about the DNA and other cellular targets of radiation.

Adv Exp Med Biol. 2008;614:165-78

New paradigms in the mechanisms and management of glaucoma.

During the last 30 years, the definition of glaucoma as been revised to eliminate the inclusion of intraocular pressure. Open angle glaucoma is the second leading cause of blindness in the world, but the proportion of those with the disease who become blind is low. Diagnostic methods for glaucoma need improvement. The pathogenetic steps to loss of neurons in glaucoma are increasingly understood and non-pressure lowering therapies are on the horizon.

Eye (Lond). 2005 Dec;19(12):1241-8

Effects of Mirtogenol on ocular blood flow and intraocular hypertension in asymptomatic subjects.

PURPOSE: The most important variable risk factor for developing glaucoma is intraocular hypertension. Timely lowering of high intraocular pressure (IOP) significantly lowers the likelihood of developing glaucoma. The aim of this study was to evaluate the effects of the food supplement Mirtogenol (Mirtoselect and Pycnogenol on IOP and ocular blood flow in a product evaluation study. METHODS: Thirty-eight asymptomatic subjects with intraocular hypertension were either given Mirtogenol (20 subjects) or were not treated (18 subjects). The visual acuity, IOP, and ocular blood flow were measured at two, three, and six months. RESULTS: After two months of supplementation with Mirtogenol, the mean IOP decreased from a baseline of 25.2 mmHg to 22.2 mmHg. After three months of treatment with Mirtogenol, the IOP was significantly lowered compared to that of untreated controls (p<0.05) to 22.0 mmHg. No further improvement was found after six months. Nineteen of the twenty patients taking Mirtogenol had a decreased IOP after three months. Only marginal effects on the IOP were found in the 18 control subjects. No side effects were observed. Ocular blood flow (central retinal, ophthalmic, and posterior ciliary arteries) improved both in the systolic and diastolic components as measured by Color Doppler imaging. After three months of treatment, the improvement of ocular blood flow was significant as compared to both baseline and control group (p<0.05). CONCLUSIONS: An improved ocular blood flow may contribute to the prevention of glaucoma. The results of this study indicate that Mirtogenol may represent a safe preventative intervention for lowering the risk for developing symptomatic glaucoma by controlling IOP and improving ocular blood flow.

Mol Vis. 2008 Jul 10;14:1288-92

Mirtogenol potentiates latanoprost in lowering intraocular pressure and improves ocular blood flow in asymptomatic subjects.

PURPOSE: The dietary supplement Mirtogenol((R)) was previously shown to lower elevated intraocular pressure (IOP). We here present the effects of this supplement on IOP in comparison as well as in combination with latanoprost eye drops. METHODS: Seventy-nine patients with asymptomatic ocular hypertension were randomly assigned to three groups receiving either the supplement, or latanoprost eye drops, or both in combination. Intraocular pressure and retinal blood flow were investigated in monthly intervals over 24 weeks. RESULTS: Mirtogenol alone lowered IOP from baseline 38.1 to 29.0 mmHg after 16 weeks, with little further improvement during the following eight weeks. Latanoprost rapidly lowered IOP from baseline 37.7 to 27.2 mmHg within four weeks, without further effects thereafter. The combination of the supplement and latanoprost lowered IOP from 38.0 to 27.3 mmHg after four weeks, and further decreased IOP to 24.2 mmHg after six weeks. After 24 weeks IOP with the combination treatment (23.0 mmHg) was significantly lower than with latanoprost alone (27.2 mmHg). Mirtogenol and latanoprost individually showed comparable effects for gradually increasing central artery blood flow with treatment duration. Combination treatment showed higher systolic blood flow velocity throughout the trial period. The diastolic blood flow velocity gradually increased with treatment duration in all three groups. From twelve weeks onwards, the diastolic component with combination treatment was higher than with individual treatments. CONCLUSIONS: Mirtogenol lowered elevated IOP in patients almost as effectively as latanoprost, however, it takes much longer (24 vs 4 weeks). The combination of both was more effective for lowering IOP and the combination yielded better retinal blood flow. No serious side effects occurred during the study, apart from standard side effects in patients related to Latanoprost. These promising results warrant further research of Mirtogenol with a larger patient group.

Clin Ophthalmol. 2010 May 14;4:471-6

Current management of glaucoma and the need for complete therapy.

Glaucoma is a long-term ocular neuropathy defined by optic disc or retinal nerve fiber structural abnormalities and visual field abnormality. Primary open-angle glaucoma is the most common type of glaucoma. Currently available treatments, initiated in a stepwise process, focus on intraocular pressure (IOP) reduction, and initially include topical drug therapy (single then multidrug combinations), followed by laser then surgical treatment. Topical prostaglandin analogues or beta-adrenergic receptor blockers are first used, followed by alpha-agonists or topical carbonic anhydrase inhibitors, and infrequently, cholinergic agonists and oral therapy. Limitations to existing topical IOP-reducing medications include continued disease progression in glaucoma patients with normal IOP, treatment failure, and low rates of compliance and persistence. Therapeutic agents under investigation include neuroprotectants, which target the disease process manifested by death of retinal ganglion cells, axonal loss, and irreversible loss of vision. Neuroprotectants may be used alone or in combination with IOPreducing therapy (a treatment strategy called complete therapy). Memantine, an N-methyl-D-aspartate receptor blocker currently approved for dementia, is the neuroprotectant farthest along in the process seeking regulatory approval for glaucoma treatment and has a favorable safety profile because of its selective mechanism of action. Several other neuroprotectants are in early stage investigation. Complete therapy provides hope for improved outcomes by reducing the significant morbidity and economic consequences that occur as a result of neurodegeneration and disease progression.

Am J Manag Care. 2008 Feb;14(1 Suppl):S20-7

Neuroprotection in glaucoma - Is there a future role?

In glaucoma, the major cause of global irreversible blindness, there is an urgent need for treatment modalities that directly target the RGCs. The discovery of an alternative therapeutic approach, independent of IOP reduction, is highly sought after, due to the indirect nature and limited effectiveness of IOP lowering therapy in preventing RGC loss. Several mechanisms have been implicated in initiating the apoptotic cascade in glaucomatous retinopathy and numerous drugs have been shown to be neuroprotective in animal models of glaucoma. These mechanisms and their potential treatment include excitotoxicity, protein misfolding, mitochondrial dysfunction, oxidative stress, inflammation and neurotrophin deprivation. All of these mechanisms ultimately lead to programmed cell death with loss of RGCs. In this article we summarize the mechanisms involved in glaucomatous disease, highlight the rationale for neuroprotection in glaucoma management and review current potential neuroprotective strategies targeting RGCs from the laboratory to the clinic.

Exp Eye Res. 2010 Nov;91(5):554-66

Disease progression and the need for neuroprotection in glaucoma management.

Glaucoma, the second leading cause of worldwide blindness, is a progressive optic neuropathy characterized by a loss of retinal ganglion cells and their axons beyond typical age-related baseline loss. Diagnosis is defined by optic disc and visual field changes, and the primary goal of glaucoma treatment is to preserve vision. Proven existing therapies (ie, pharmacotherapy, laser, and surgical) focus on reduction of intraocular pressure (IOP), although elevated IOP is no longer a diagnostic feature of glaucoma. New neuroprotectant drugs are being investigated, with the goal of reducing retinal ganglion cell loss, either prophylactically or after the insult has occurred. Various treatment strategies are being evaluated, and include a neuroprotectant only, or a complete therapy approach comprised of both a neuroprotectant supplemented by an IOP-lowering therapy. Dually targeted complete therapy may directly preserve the optic nerve, decrease the risk factors that cause glaucoma damage, and reduce glaucoma-related morbidities. Neuroprotectant therapy outcomes should include functional and structural effects of disease progression and neuroprotectant therapies, as well as patient functioning and economic impact.

Am J Manag Care. 2008 Feb;14(1 Suppl):S15-9

Management of glaucoma: focus on pharmacological therapy.

Glaucoma represents a major cause of vision loss throughout the world. Primary open-angle glaucoma, the most common form of glaucoma, is a chronic, progressive disease often, though not always, accompanied by elevated intraocular pressure (IOP). In this disorder, retinal ganglion cell loss and excavation of the optic nerve head produce characteristic peripheral visual field deficits. Patients with normal-tension glaucoma present with typical visual field and optic nerve head changes, without a documented history of elevated IOP. A variety of secondary causes, such as pigment dispersion syndrome and ocular trauma, can result in glaucoma as well. Treatment of all forms of glaucoma consists of reducing IOP. With proper treatment, progression of this disease can often be delayed or prevented. Treatment options for glaucoma include medications, laser therapy and incisional surgery. Laser techniques for the reduction of IOP include argon laser trabeculoplasty and selective laser trabeculoplasty. Both techniques work by increasing outflow of aqueous humour through the trabecular meshwork. Surgical options for glaucoma treatment include trabeculectomy, glaucoma drainage tube implantation and ciliary body cyclodestruction. While each of these types of procedures is effective at lowering IOP, therapy usually begins with medications. Medications lower IOP either by reducing the production or by increasing the rate of outflow of aqueous humour within the eye. Currently, there are five major classes of drugs used for the treatment of glaucoma: (i) cholinergics (acetylcholine receptor agonists); (ii) adrenoceptor agonists; (iii) carbonic anhydrase inhibitors (CAIs); (iv) beta-adrenoceptor antagonists; and (v) prostaglandin analogues (PGAs). Treatment typically begins with the selection of an agent for IOP reduction. Although beta-adrenoceptor antagonists are still commonly used by many clinicians, the PGAs are playing an increasingly important role in the first-line therapy of glaucoma. Adjunctive agents, such as alpha-adrenoceptor agonists and CAIs are often effective at providing additional reduction in IOP for patients not controlled on monotherapy. As with any chronic disease, effective treatment depends on minimising the adverse effects of therapy and maximising patient compliance. The introduction of a variety of well tolerated and potent medications over the past few years now allows the clinician to choose a treatment regimen on an individual patient basis and thereby treat this disorder more effectively.

Drugs Aging. 2005;22(1):1-21

Current and emerging medical therapies in the treatment of glaucoma.

Introduction: Glaucoma is a disease of the eye in which the optic nerve and retinal ganglion cells (RGCs) are injured, leading to the loss of the peripheral visual field and eventually to profound vision loss and blindness. Glaucoma is usually characterized by an increase in intraocular pressure (IOP), which is treated with ocular hypotensive drugs. However, both RGC apoptosis and optic nerve atrophy, due to glaucoma, can occur independently of IOP. Areas covered: This review discusses several current and emerging treatments for glaucoma. Current research is updating the known properties of a number of drugs now used to treat glaucoma. Some drugs may offer neuroprotection, not only reducing vision loss, but restoring injured or compromised RGCs and optic nerve cells. Several molecules now under development aim to lower IOP primarily by enhancing aqueous drainage through conventional pathways of the trabecular meshwork and Schlemm’s canal. Gene transfer models are being investigated, and a murine-derived neurotrophic growth factor (NGF) seems to offer the promise of actually restoring visual function in some patients. Drugs that are already widely used are being re-branded in preservative-free formulations. Expert opinion: The ultimate goal in glaucoma research is to find new compounds that will not only normalize IOP, but also arrest or even reverse apoptotic damage to the optic nerve and RGCs to slow the rate of progression of the disease so that it will not interfere with the patient’s ability to see and his/her quality of life. This should be obtained with affordable costs, minimal side effects and a reasonable schedule.

Expert Opin Emerg Drugs. 2011 Apr 7

Resveratrol prevents the expression of glaucoma markers induced by chronic oxidative stress in trabecular meshwork cells.

Elevated intraocular pressure (IOP) constitutes the best characterized risk for primary open-angle glaucoma (POAG). Elevated IOP is believed to result from an increase in aqueous humor outflow resistance at the level of the trabecular meshwork (TM)/Schlemm’s canal. Malfunction of the TM in POAG is associated with the expression of markers for inflammation, cellular senescence, oxidative damage, and decreased cellularity. Current POAG treatments rely on lowering IOP, but there is no therapeutic approach available to delay the loss of function of the TM in POAG patients. We evaluated the effects of chronic administration of the dietary supplement resveratrol on the expression of markers for inflammation, oxidative damage, and cellular senescence in primary TM cells subjected to chronic oxidative stress (40% O2). Resveratrol treatment effectively prevented increased production of intracellular reactive oxygen species (iROS) and inflammatory markers (IL1alpha, IL6, IL8, and ELAM-1), and reduced expression of the senescence markers sa-beta-gal, lipofuscin, and accumulation of carbonylated proteins. Furthermore, resveratrol exerted antiapoptotic effects that were not associated with a decrease in cell proliferation. These results suggest that resveratrol could potentially have a role in preventing the TM tissue abnormalities observed in POAG.

Food Chem Toxicol. 2009 Jan;47(1):198-204

Protective effects of bilberry (Vaccinium myrtillus L.) extract against endotoxin-induced uveitis in mice.

Endotoxin-induced uveitis (EIU), a useful animal model of ocular inflammation, is induced by injection of lipopolysacharide (LPS). These experiments showed that the nitric oxide (NO) level significantly increased in the whole eye homogenate of BALB/C mice 24 h after footpad injection of LPS at a dosage of 100 mg/mouse. However, the elevated NO level was significantly reduced by oral administration of bilberry extract (containing 42.04% anthocyanins) at dosages of 50, 100, and 200 mg/kg/day for 5 days before the LPS injection. In addition, bilberry extract decreased malondialdehyde (MDA) level and increased oxygen radical absorbance capacity (ORAC) level, glutathione (GSH) level, vitamin C level, and total superoxide dismutase (SOD) and glutathione peroxidase (GPx) activities. Moreover, bilberry extract increased expression of copper/zinc superoxide dismutase (CuZnSOD), manganese superoxide dismutase (MnSOD), and GPx mRNA. Taken together, bilberry extract showed protective effects against EIU, whereas the effects of bilberry extract (100 and 200 mg/kg/day, 5 days) were dose-dependent. In conclusion, these results provide new evidence to elucidate the beneficial effects of bilberry extract on eye health.

J Agric Food Chem. 2010 Apr 28;58(8):4731-6

Influence of facial skin attributes on the perceived age of Caucasian women.

BACKGROUND AND OBJECTIVE: The facial appearance of a person does not always reflect the chronological age; some people look younger or older than they really are. Many studies have described the changes in skin properties (colour, wrinkles, sagging, micro relief, etc.) with age, but few of them have analysed their influence on the perceived age. The primary objective of this study was to assess the contribution of individual skin attributes of the face on the perceived age of Caucasian women. Secondary objectives were to assess the influence of age and gender of graders with regard to the age perception. SUBJECTS AND METHOD: A random sample of 173 subjects of 20 to 74 years of age was taken from a database of more than 5,000 healthy Caucasian women. A trained grader performed visual assessment of facial skin attributes (using a visual analogue scale), and a front face photograph was taken from each subject. Photographs were shown to 48 graders (20 men and 28 women, aged 22-64 years) who were asked to estimate the age of the subjects. Graders were classified as young (less than 35 years), middle age (35-50 years) and seniors (older than 50 years). Partial Least Square regression models were built to predict the chronological and the perceived age from the measured facial individual attributes. The contribution of each attribute within the regression model enabled to measure the relevance of this attribute with regards to age prediction. RESULTS: The eye area and the skin colour uniformity were the main attributes related to perceived age. For age prediction, older graders’ estimations were more driven by lips border definition shape and eyes opening, whereas younger graders’ (older than 50 years) estimations were more driven by dark circles, nasolabial fold and brown spots. There were statistically significant differences in graders’ age perception between gender and among age ranges. Our findings suggest that female graders are more accurate than male, and younger graders (under 35 years) are more accurate than older (over 50 years) to predict Caucasian women age from facial photographs. CONCLUSIONS: Different skin attributes influence the estimation of age. These attributes have a different weight in the evaluation of the perceived age, depending on the age and of the observer. The most important attributes to estimate age are eyes, lips and skin colour uniformity.

J Eur Acad Dermatol Venereol. 2008 Aug;22(8):982-91

Overview of current thoughts on facial volume and aging.

Facial aging is a dynamic process involving the aging of soft tissue and bony structures. Much is known in regards to how the face loses volume as the soft tissue structures age. Epidermal thinning and the decrease in collagen cause skin to lose its elasticity. Loss of fat, coupled with gravity and muscle pull, leads to wrinkling and the formation of dynamic lines. The aging process has also been shown to affect the facial bones. Multiple studies suggest that the bony aging of the orbit and midface is a process primarily of contraction and morphologic change. This loss of bony volume and projection may contribute to the aged appearance. In this review, we will demonstrate how specific soft tissue and bony aspects of the face change with age in both genders and what impact these structural changes may have on overall facial aesthetics.

Facial Plast Surg. 2010 Oct;26(5):350-5

Photoprotection beyond ultraviolet radiation—effective sun protection has to include protection against infrared A radiation-induced skin damage.

Solar radiation is well known to damage human skin, for example by causing premature skin ageing (i.e. photoageing). We have recently learned that this damage does not result from ultraviolet (UV) radiation alone, but also from longer wavelengths, in particular near-infrared radiation (IRA radiation, 760-1,440 nm). IRA radiation accounts for more than one third of the solar energy that reaches human skin. While infrared radiation of longer wavelengths (IRB and IRC) does not penetrate deeply into the skin, more than 65% of the shorter wavelength (IRA) reaches the dermis. IRA radiation has been demonstrated to alter the collagen equilibrium of the dermal extracellular matrix in at least two ways: (a) by leading to an increased expression of the collagen-degrading enzyme matrix metalloproteinase 1, and (b) by decreasing the de novo synthesis of the collagen itself. IRA radiation exposure therefore induces similar biological effects to UV radiation, but the underlying mechanisms are substantially different, specifically, the cellular response to IRA irradiation involves the mitochondrial electron transport chain. Effective sun protection requires specific strategies to prevent IRA radiation-induced skin damage.

Skin Pharmacol Physiol. 2010;23(1):15-7

Nutrition and aging skin: sugar and glycation.

The effect of sugars on aging skin is governed by the simple act of covalently cross-linking two collagen fibers, which renders both of them incapable of easy repair. Glucose and fructose link the amino acids present in the collagen and elastin that support the dermis, producing advanced glycation end products or “AGEs.” This process is accelerated in all body tissues when sugar is elevated and is further stimulated by ultraviolet light in the skin. The effect on vascular, renal, retinal, coronary, and cutaneous tissues is being defined, as are methods of reducing the glycation load through careful diet and use of supplements.

Clin Dermatol. 2010 Jul-Aug;28(4):409-11

What causes dark circles under the eyes?

Dark circles under the eyes (DC) are defined as bilateral, round, homogeneous pigment macules on the infraorbital regions. Despite its significant prevalence, there are a few published studies about its pathogenesis. DC are caused by multiple etiologic factors that include dermal melanin deposition, postinflammatory hyperpigmentation secondary to atopic or allergic contact dermatitis, periorbital edema, superficial location of vasculature, and shadowing due to skin laxity. The purpose of this review is to discuss some of the available evidences about the anatomic features that could explain dark circles and the proposed treatments for this unpleasant condition.

J Cosmet Dermatol. 2007 Sep;6(3):211-5

In vitro and in vivo evaluation of topical delivery and potential dermal use of soy isoflavones genistein and daidzein.

Genistein, daidzein, and glycitein are soy isoflavones. These compounds can be used to protect the skin from oxidative stress induced by UVB radiation. To this end, the feasibility of skin absorption of soy isoflavones was evaluated in the present study. As assayed by flow cytometry, UVB-induced H(2)O(2) production in keratinocytes was inhibited by genistein and daidzein, confirming that these two compounds can act as free radical scavengers when keratinocytes are photodamaged. Glycitein showed no protective activity against photodamage. The effects of vehicles on the in vitro topical delivery from saturated solutions such as aqueous buffers and soybean oil were investigated. The isoflavones in a non-ionized form (pH 6) showed higher skin deposition compared to the ionized form (pH 10.8). Soybean oil reduced the isoflavone amount retained in the skin, especially for genistein. Genistein generally exhibited greater skin absorption than did daidzein. However, daidzein permeation was enhanced when an aglycone mixture was used as the active ingredient. An eutectic effect was proposed as the enhancing mechanism. In vivo skin deposition showed a linear correlation with the in vitro results. The safety profiles suggested no or only negligible stratum corneum disruption and skin erythema by topical application of soy isoflavones. It was concluded that topical delivery may serve as a potent route for soy isoflavones against photoaging and photodamage.

Int J Pharm. 2008 Nov 19;364(1):36-44

Non-sunscreen photoprotection: antioxidants add value to a sunscreen.

The association between ultraviolet radiation (UVR) exposure and both skin cancer and photo-aging is well documented. In addition to the conventional organic-chemical and physical-mineral type sunscreens, other non-sunscreen protective strategies have been developed. These include topically applied botanical extracts and other antioxidants as well as topical DNA repair enzymes. Standard terms of photoprotection such as sun protection factor (SPF) do not accurately reflect the photoprotection benefits of these materials. For example, in spite of minimal SPF, tea extract containing polyphenols such as (-)-epigallocatechin-3-gallate (EGCG) has been shown to protect against UV-induced DNA damage and immune suppression, in part through its ability to reduce oxidative stress and inhibit NF-kB. The addition of botanical antioxidants and vitamins C and E to a broad-spectrum sunscreen may further decrease UV-induced damage compared with sunscreen alone. These agents have been shown to enhance protection against UV-induced epidermal thickening, overexpression of MMP-1and MMP-9, and depletion of CD1a(+) Langerhans cells. Non-sunscreen materials such as botanical extracts, antioxidants, and DNA repair enzymes can contribute value when applied topically to human skin in vivo.

J Investig Dermatol Symp Proc. 2009 Aug;14(1):56-9

Topical application of green and white tea extracts provides protection from solar-simulated ultraviolet light in human skin.

BACKGROUND: Tea polyphenols have been found to exert beneficial effects on the skin via their antioxidant properties. AIMS: We sought to determine whether topical application of green tea or white tea extracts would prevent simulated solar radiation-induced oxidative damages to DNA and Langerhans cells that may lead to immune suppression and carcinogenesis. METHODS: Skin samples were analysed from volunteers or skin explants treated with white tea or green tea after UV irradiation. In another group of patients, the in vivo immune protective effects of green and white tea were evaluated using contact hypersensitivity to dinitrochlorobenzene. RESULTS: Topical application of green and white tea offered protection against detrimental effects of UV on cutaneous immunity. Such protection is not because of direct UV absorption or sunscreen effects as both products showed a sun protection factor of 1. There was no significant difference in the levels of protection afforded by the two agents. Hence, both green tea and white tea are potential photoprotective agents that may be used in conjunction with established methods of sun protection.

Exp Dermatol. 2009 Jun;18(6):522-6

Pomegranate as a cosmeceutical source: pomegranate fractions promote proliferation and procollagen synthesis and inhibit matrix metalloproteinase-1 production in human skin cells.

Pomegranate (Punica granatum) is an ancient fruit with exceptionally rich ethnomedical applications. The peel (pericarp) is well regarded for its astringent properties; the seeds for conferring invulnerability in combat and stimulating beauty and fertility. Here, aqueous fractions prepared from the fruit’s peel and fermented juice and lipophilic fractions prepared from pomegranate seeds were examined for effects on human epidermal keratinocyte and human dermal fibroblast function. Pomegranate seed oil, but not aqueous extracts of fermented juice, peel or seed cake, was shown to stimulate keratinocyte proliferation in monolayer culture. In parallel, a mild thickening of the epidermis (without the loss of ordered differentiation) was observed in skin organ culture. The same pomegranate seed oil that stimulated keratinocyte proliferation was without effect on fibroblast function. In contrast, pomegranate peel extract (and to a lesser extent, both the fermented juice and seed cake extracts) stimulated type I procollagen synthesis and inhibited matrix metalloproteinase-1 (MMP-1; interstitial collagenase) production by dermal fibroblasts, but had no growth-supporting effect on keratinocytes. These results suggest heuristic potential of pomegranate fractions for facilitating skin repair in a polar manner, namely aqueous extracts (especially of pomegranate peel) promoting regeneration of dermis, and pomegranate seed oil promoting regeneration of epidermis.

J Ethnopharmacol. 2006 Feb 20;103(3):311-8

Dietary compound ellagic acid alleviates skin wrinkle and inflammation induced by UV-B irradiation.

Ellagic acid, a polyphenol compound present in berries and pomegranate, has received attention as an agent that may have potential bioactivities preventing chronic diseases. This study examined photoprotective effects of ellagic acid on collagen breakdown and inflammatory responses in UV (ultraviolet)-B irradiated human skin cells and hairless mice. Ellagic acid attenuated the UV-B-induced toxicity of HaCaT keratinocytes and human dermal fibroblasts. Non-toxic ellagic acid markedly prevented collagen degradation by blocking matrix metalloproteinase production in UV-B-exposed fibroblasts. Anti-wrinkle activity of ellagic acid was further investigated in hairless mice exposed to UV-B, in which it attenuated UV-B-triggered skin wrinkle formation and epidermal thickening. Topical application of 10 micromol/l ellagic acid diminished production of pro-inflammatory cytokines IL-1beta and IL-6, and blocked infiltration of inflammatory macrophages in the integuments of SKH-1 hairless mice exposed to UV-B for 8 weeks. In addition, this compound mitigated inflammatory intracellular cell adhesion molecule-1 expression in UV-B-irradiated keratinocytes and photoaged mouse epidermis. These results demonstrate that ellagic acid prevented collagen destruction and inflammatory responses caused by UV-B. Therefore, dietary and pharmacological interventions with berries rich in ellagic acid may be promising treatment strategies interrupting skin wrinkle and inflammation associated with chronic UV exposure leading to photoageing.

Exp Dermatol. 2010 Aug;19(8):e182-90

Effects of green tea and EGCG on cardiovascular and metabolic health.

Since ancient times green tea has been considered a health-promoting beverage. In recent years, scientists throughout the world have investigated the potential benefits of green tea and its most abundant catechin, epigallocatechin gallate (EGCG). The anti-cancer effects of green tea and EGCG were the focus of early research, and encouraging data from in vitro, animal model, and human studies have emerged. Due to the dominant role of cardiovascular disease and the dramatic rise of obesity and type 2 diabetes mellitus as major and interlinked healthcare problems, green tea and EGCG are increasingly being investigated in these areas. Dose-response relationships observed in several epidemiological studies have indicated that pronounced cardiovascular and metabolic health benefits can be obtained by regular consumption of 5-6 or more cups of green tea per day. Furthermore, intervention studies using similar amounts of green tea, containing 200-300 mg of EGCG, have demonstrated its usefulness for maintaining cardiovascular and metabolic health. Additionally, there are numerous in vivo studies demonstrating that green tea and EGCG exert cardiovascular and metabolic benefits in these model systems. Therefore, green tea and EGCG can be regarded as food components useful for the maintenance of cardiovascular and metabolic health. To prove the effectiveness for disease prevention or treatment, several multi-center, long-term clinical studies investigating the effects of one precisely-defined green tea product on cardiovascular and metabolic endpoints would be necessary. The aim of this manuscript is to provide an overview of the research investigating the effects of green tea and green tea catechins on cardiovascular and metabolic health.

J Am Coll Nutr. 2007 Aug;26(4):373S-388S

Metabolism of green tea catechins: an overview.

Green tea is one of the most popular beverages worldwide. Its major components include (-)-epicatechin ((-)-EC), (-)-epicatechin-3-gallate (ECG) (-)-epigallocatechin (EGC) and (-)-epigallocatechin-3-gallate (EGCG). It has demonstrated strong antioxidative, anti-inflammatory and anti-cancerous properties and attracted a great deal of interest over last several years. However, there is some discrepancy between the results from human pidemiological studies and cultured cell and animal models. Two reasons for its limited in vivo activities have been considered: metabolism and bioavailability. Recent studies have demonstrated that green tea catechins undergo methylation, glucuronidation and sulfation in in vitro systems and in animals and in humans. It has been also found that efflux transporters Pgp, MRP1 and MRP2 play roles in the absorption and excretion of green tea catechins. Several processes including intestinal metabolism, microbial metabolism, hepatic metabolism and chemical degradation have been found to be involved in the fate of green tea, and to be responsible for its low availability in animals, and most likely also in humans. Pharmacokinetics, absorption, distribution, drug metabolism and excretion properties of green tea provide a better understanding for its in vivo activities. In this article, drug metabolism and microbial metabolism of green tea catechins in in vitro systems and in animals and in humans will be reviewed. It also covers the factors affecting their biotransformation and bioavailability: drug-drug inhibitory and inductive interactions of phase I and phase II enzymes, inhibition of non-drug-metabolizing enzymes, transporters, chemical instability, epimerization and interindividual variability.

Curr Drug Metab. 2006 Oct;7(7):755-809

Nutraceutical antioxidants as novel neuroprotective agents.

A variety of antioxidant compounds derived from natural products (nutraceuticals) have demonstrated neuroprotective activity in either in vitro or in vivo models of neuronal cell death or neurodegeneration, respectively. These natural antioxidants fall into several distinct groups based on their chemical structures: (1) flavonoid polyphenols like epigallocatechin 3-gallate (EGCG) from green tea and quercetin from apples; (2) non-flavonoid polyphenols such as curcumin from turmeric and resveratrol from grapes; (3) phenolic acids or phenolic diterpenes such as rosmarinic acid or carnosic acid, respectively, both from rosemary; and (4) organosulfur compounds including the isothiocyanate, L-sulforaphane, from broccoli and the thiosulfonate allicin, from garlic. All of these compounds are generally considered to be antioxidants. They may be classified this way either because they directly scavenge free radicals or they indirectly increase endogenous cellular antioxidant defenses, for example, via activation of the nuclear factor erythroid-derived 2-related factor 2 (Nrf2) transcription factor pathway. Alternative mechanisms of action have also been suggested for the neuroprotective effects of these compounds such as modulation of signal transduction cascades or effects on gene expression. Here, we review the literature pertaining to these various classes of nutraceutical antioxidants and discuss their potential therapeutic value in neurodegenerative diseases.

Molecules. 2010 Nov 3;15(11):7792-814

Comparative Evaluation of Different Doses of Green Tea Extract Alone and in Combination with Sulfasalazine in Experimentally Induced Inflammatory Bowel Disease in Rats.

BACKGROUND: The exact etiopathology of inflammatory bowel disease is still unclear. Most of the therapies present are directed towards symptomatic improvement. Surgical therapy in the form of restorative proctocolectomy is reserved for the terminal stage disease, which is unresponsive to medical therapy. The present study was conducted to evaluate the effect of green tea in experimentally induced inflammatory bowel disease. METHODS: A total of 36 animals were included in the study. The animals were divided into five groups (n = 6): Group I-Vehicle (ethanol), group II-TNBS + ethanol, group III-green tea-treated group was divided into two sub-groups on the basis of different doses: group IIIA-TNBS + green tea (35 mg/kg), group IIIB-TNBS + green tea (70 mg/kg), group IV-TNBS + sulfasalazine (360 mg/kg), group V-TNBS + sulfasalazine (360 mg/kg) + green tea (least effective dose found in group III). After completion of 2 weeks of treatment, the rats were killed under ether anesthesia by cervical dislocation for assessment of intestinal inflammation, histological analysis, myeloperoxidase assay, malondialdehyde assay, and TNF- estimation. RESULTS: The study showed that green tea alone and in combination with sulfasalazine reduced inflammatory changes induced by tri nitro benzene sulfonic acid in rats. This reduction is associated with reduced malondialdehyde, lipid peroxidation, and TNF-. This correlates well with both gross morphological and histopathological scores. CONCLUSIONS: The authors concluded that a combination of green tea extract with sulfasalazine showed greater efficacy than single drug treatment.

Dig Dis Sci. 2010 Nov 17

TLR4 signaling inhibitory pathway induced by green tea polyphenol epigallocatechin-3-gallate through 67-kDa laminin receptor.

Epigallocatechin-3-gallate (EGCG), a major active polyphenol of green tea, has been shown to downregulate inflammatory responses in macrophages; however, the underlying mechanism has not been understood. Recently, we identified the 67-kDa laminin receptor (67LR) as a cell-surface EGCG receptor that mediates the anticancer action of EGCG at physiologically relevant concentrations (0.1-1 microM). In this study, we show the molecular basis for the downregulation of TLR4 signal transduction by EGCG at 1 microM in macrophages. Anti-67LR Ab treatment or RNA interference-mediated silencing of 67LR resulted in abrogation of the inhibitory action of EGCG on LPS-induced activation of downstream signaling pathways and target gene expressions. Additionally, we found that EGCG reduced the TLR4 expression through 67LR. Interestingly, EGCG induced a rapid upregulation of Toll-interacting protein (Tollip), a negative regulator of TLR signaling, and this EGCG action was prevented by 67LR silencing or anti-67LR Ab treatment. RNA interference-mediated silencing of Tollip impaired the TLR4 signaling inhibitory activity of EGCG. Taken together, these findings demonstrate that 67LR plays a critical role in mediating anti-inflammatory action of a physiologically relevant EGCG, and Tollip expression could be modulated through 67LR. These results provide a new insight into the understanding of negative regulatory mechanisms for the TLR4 signaling pathway and consequent inflammatory responses that are implicated in the development and progression of many chronic diseases.

J Immunol. 2010 Jul 1;185(1):33-45

Consumption of green tea causes rapid increase in plasma antioxidant power in humans.

Green tea contains polyphenolic antioxidants that have shown anticarcinogenic properties in animal and in vitro experimental studies. Current data regarding absorption and bioavailability of tea antioxidants in humans, however, are conflicting. In this study, plasma and urine antioxidant power after ingestion of green tea was measured using the ferric reducing/antioxidant power (FRAP) assay (US patent pending) to assess absorption, systemic distribution, and renal excretion of green tea antioxidants in healthy adults. Results showed that absorption of green tea antioxidants was rapid, with peak increase in plasma FRAP of around 4% at 40 minutes after ingestion: mean increase was 44 +/- 9 (SE) mumol/l. Excretion of polyphenolic antioxidants was also fast, peaking at 60-90 minutes, with significant correlation between urinary FRAP values and urinary total phenolic concentrations (r = 0.845, p < 0.001). In control studies, no increase in plasma or urine FRAP values was seen after intake of water. Although the amount of antioxidants absorbed was relatively small and the increase in plasma antioxidant power was of short duration, results demonstrate that some potentially anticarcinogenic polyphenolic antioxidants in green tea enter the systemic circulation soon after ingestion and cause a significant increase in plasma antioxidant status. This increase may, in turn, lower oxidative damage to DNA and so decrease risk of cancer.

Nutr Cancer. 1999;34(1):83-7

Pharmacokinetics and safety of green tea polyphenols after multiple-dose administration of epigallocatechin gallate and polyphenon E in healthy individuals.

PURPOSE: Green tea and green tea polyphenols have been shown to possess cancer preventive activities in preclinical model systems. In preparation for future green tea intervention trials, we have conducted a clinical study to determine the safety and pharmacokinetics of green tea polyphenols after 4 weeks of daily p.o. administration of epigallocatechin gallate (EGCG) or Polyphenon E (a defined, decaffeinated green tea polyphenol mixture). In an exploratory fashion, we have also determined the effect of chronic green tea polyphenol administration on UV-induced erythema response. EXPERIMENTAL DESIGN: Healthy participants with Fitzpatric skin type II or III underwent a 2-week run-in period and were randomly assigned to receive one of the five treatments for 4 weeks: 800 mg EGCG once/day, 400 mg EGCG twice/day, 800 mg EGCG as Polyphenon E once/day, 400 mg EGCG as Polyphenon E twice/day, or a placebo once/day (8 subjects/group). Samples were collected and measurements performed before and after the 4-week treatment period for determination of safety, pharmacokinetics, and biological activity of green tea polyphenol treatment. RESULTS: Adverse events reported during the 4-week treatment period include excess gas, upset stomach, nausea, heartburn, stomach ache, abdominal pain, dizziness, headache, and muscle pain. All of the reported events were rated as mild events. For most events, the incidence reported in the polyphenol-treated groups was not more than that reported in the placebo group. No significant changes were observed in blood counts and blood chemistry profiles after repeated administration of green tea polyphenol products. There was a >60% increase in the area under the plasma EGCG concentration-time curve after 4 weeks of green tea polyphenol treatment at a dosing schedule of 800 mg once daily. No significant changes were observed in the pharmacokinetics of EGCG after repeated green tea polyphenol treatment at a regimen of 400 mg twice daily. The pharmacokinetics of the conjugated metabolites of epigallocatechin and epicatechin were not affected by repeated green tea polyphenol treatment. Four weeks of green tea polyphenol treatment at the selected dose and dosing schedule did not provide protection against UV-induced erythema. CONCLUSIONS: We conclude that it is safe for healthy individuals to take green tea polyphenol products in amounts equivalent to the EGCG content in 8-16 cups of green tea once a day or in divided doses twice a day for 4 weeks. There is a >60% increase in the systemic availability of free EGCG after chronic green tea polyphenol administration at a high daily bolus dose (800 mg EGCG or Polyphenon E once daily).

Clin Cancer Res. 2003 Aug 15;9(9):3312-9

Bioavailability and antioxidant activity of tea flavanols after consumption of green tea, black tea, or a green tea extract supplement.

BACKGROUND: Green and black tea polyphenols have been extensively studied as cancer chemopreventive agents. Many in vitro experiments have supported their strong antioxidant activity. Additional in vivo studies are needed to examine the pharmacokinetic relation of absorption and antioxidant activity of tea polyphenols administered in the form of green or black tea or tea extract supplements. OBJECTIVE: The purpose of this study was to compare the pharmacokinetic disposition of tea polyphenols and their effect on the antioxidant capacity in plasma 8 h after a bolus consumption of either green tea, black tea, or a green tea extract supplement. DESIGN: Thirty healthy subjects were randomly assigned to 3 different sequences of green tea, black tea, or a green tea extract supplement in a 3 x 3 crossover design with a 1-wk washout period in between treatments. RESULTS: Flavanol absorption was enhanced when tea polyphenols were administered as a green tea supplement in capsule form and led to a small but significant increase in plasma antioxidant activity compared with when tea polyphenols were consumed as black tea or green tea. All 3 interventions provided similar amounts of (-)-epigallocatechin-3-gallate. CONCLUSIONS: Our observations suggest that green tea extract supplements retain the beneficial effects of green and black tea and may be used in future chemoprevention studies to provide a large dose of tea polyphenols without the side effects of caffeine associated with green and black tea beverages.

Am J Clin Nutr. 2004 Dec;80(6):1558-64

Green tea and cancer prevention.

Extracts of green tea and green tea polyphenols have exhibited inhibitory effects against the formation and development of tumors at different organ sites in animals. These include animal models for skin, lung, oral cavity, esophagus, stomach, intestine, colon, liver, pancreas, bladder, mammary gland, and prostate cancers. In addition to suppressing cell proliferation, promoting apoptosis, and modulating signaling transduction, green tea polyphenols, especially (-)-epigallocatechin-3-gallate, also inhibit cell invasion, angiogenesis, and metastasis. This article reviews data on the cancer preventive activities of green tea polyphenols, possible mechanisms involved, and the relationship between green tea consumption and human cancer risk.

Nutr Cancer. 2010;62(7):931-7

Phase I study of green tea extract in patients with advanced lung cancer.

PURPOSE: Epidemiologic studies suggest that consumption of green tea may have a protective effect against the development of several cancers. Preclinical studies of green tea and its polyphenolic components have demonstrated antimutagenic and anticarcinogenic activity, and inhibition of growth of tumor cell lines and animal tumor models, including lung cancer. Green tea may also have chemopreventive properties, and enhancement of cytotoxicity of chemotherapeutic agents has been demonstrated. This trial was designed to determine the maximum tolerated dose (MTD) of green tea extract (GTE) in patients with advanced lung cancer. METHODS: A total of 17 patients with advanced lung cancer were registered to receive once-daily oral dosing of GTE at a starting dose of 0.5 g/m2 per day, with an accelerated dose-escalation scheme. RESULTS: On this schedule, the MTD of GTE was 3 g/m2 per day, and at this dose, GTE was well tolerated with no grade 3 or 4 toxicity seen. Dose-limiting toxicities were diarrhea, nausea and hypertension. No objective responses were seen in this trial. Seven patients had stable disease ranging from 4 to 16 weeks; no patient remained on therapy longer than 16 weeks due to the development of progressive disease. CONCLUSIONS: This study suggests that while relatively nontoxic at a dose of 3 g/m2 per day, GTE likely has limited activity as a cytotoxic agent, and further study of GTE as a single-agent in established malignancies may not be warranted. Further studies should focus on the potential chemopreventive and chemotherapy-enhancing properties of GTE.

Cancer Chemother Pharmacol. 2005 Jan;55(1):33-8