HealthCare

LYCOPENE AS A CANCER PREVENTING FOOD
Lycopene is often included as an ingredient in antioxidant combination supplements and is thought to contribute to risk reduction for cancer. Some studies have investigated the effects of lycopene on risk of disease, although many consider it as part of the carotenoid group and study its effects in this way.
Total cancer risk A 2002 Japanese study involving 2444 people who were
followed for 9 years found that high serum levels of lycopene, total carotenes and carotenoids were significantly and inversely associated with subsequent mortality from all causes and cancers of all sites after adjusting for gender, age and serum levels of total cholesterol, alpha-tocopherol and retinol.
In particular, there is some evidence that lycopene levels are inversely proportional to cancers of the prostate, stomach and cervix. Prostate cancer A review of 15 epidemiological studies concluded that although results are not yet definitive, overall the data suggest that increased consumption of  lycopene from tomatoes and tomato-based products may be prudent in order to reduce the risk of prostate cancer.

More specifically, five studies found a 30–40% reduction in prostate cancer risk associated with high tomato or lycopene consumption, three found a non-significant 30% reduction in risk, and seven were not supportive of an association. The largest epidemiological study was conducted by the Harvard Medical School, which assessed the diets of 47,894 volunteers and identified several foods as significantly associated with lower prostate cancer risk. They were tomato sauce, tomatoes and pizza, which are primary sources of lycopene. Additionally, consumption of more than 10 servings per week was required for protective effects to be observed.
Besides the epidemiological data on primary prevention, there are some reports of short- to medium-term clinical intervention trials with lycopene supplement or tomatoes. A small study of men with high-grade prostate intraepithelial neoplasia (HGPIN), a precursor of prostate cancer, showed that supplementation with 4 mg lycopene twice daily for 1 year had a chemopreventative effect, preventing progression of HGPIN to prostate cancer. Three of four studies found that either lycopene or tomatoes significantly reduces serum levels of prostate specific antigen (PSA). Kucuk et al conducted a randomised study involving 26 men, which found that taking a tomato oleoresin extract containing 30 mg lycopene for 3 weeks resulted in smaller prostate tumours, less involvement of surgical margins and/or extra-prostatic tissues with the cancer and less diffuse involvement of the prostate by high-grade prostatic intraepithelial neoplasia compared with controls
(Kucuk et al 2001). Additionally, plasma PSA levels were reduced. Another study  involving 32 patients with localised prostate cancer found that
consuming tomato sauce-based pasta dishes for 3 weeks (providing 30 mg
lycopene/day) reduced serum PSA levels by 17.5% and, overall, significantly reduced DNA damage in both leukocyte and prostate tissue.

A lycopene supplement for 3 months in 20 patients with metastatic hormone refractive prostate cancer (HRPC) significantly reduced PSA levels and provided relief in bone pain and lower urinary tract symptoms (Ansari & Gupta 2004). HRPC was defined as an increase in PSA levels of more than twice the normal value (0–4 ng/mL) confirmed in two consecutive determinations at 2-week intervals in the presence of castrate levelsof testosterone. In contrast, no effect on PSA levels was observed in a dose-escalating study of 36 men, which tested high doses of lycopene in biochemically relapsed prostate cancer. The doses studied were 15, 30, 45, 60, 90, and 120 mg/day taken for 1 year and significant elevations of plasma lycopene were noted at 3 months and then appeared to plateau for all six dose levels.  Stomach Cancer : Although mixed results were previously obtained from case–control studies, recent evidence is supportive of lycopene as a protective agent in stomach cancer.
2004

DEFICIENCY SIGNS AND SYMPTOMS
Although lycopene is not considered an essential nutrient, it is important for
wellbeing and optimal health. As such, deficiency signs and symptoms are unknown.

Lycopene as an ANTIOXIDANT
The many conjugated double bonds of lycopene make it a powerful antioxidant and its activity in vitro is nearly twice as great as beta-carotene .
LYCOPENE REDUCES LDL-CHOLESTEROL LEVELS AND LIPID OXIDATION
A significant 14% reduction in plasma LDL-cholesterol concentrations has been shown for a dose of 60 mg/day lycopene taken over 3 months by healthy volunteers. While the mechanism of action is unclear, in vitro testing suggests HMG-CoA reductase inhibition and enhancement of LDL receptor activity in macrophages.  Lycopene also prevents oxidation of lipids and LDL cholesterol, according to a clinical study by Agarwal & Rao .

CHEMOPREVENTATIVE ACTIVITY OF LYCOPENE
Anticancer activity of lycopene has been demonstrated in cell and tissue culture studies and animal tumour models. Lycopene appears to inhibit human cancer cell growth by interfering with growth factor receptor signalling and cell cycle progression without producing toxicity or apoptosis.
In vitro and in vivo evidence supports the theory that antiproliferative activity is achieved by upregulation of a gene, connexin 43, which restores direct intercellular gap junctional communication, usually deficient in many human tumours. This restoration of normal intercellular gap junctional communication is associated with decreased proliferation. Investigation using animal models also suggests that lycopene may exert its chemopreventative effects by modulating lipid peroxidation
and enhancing the activities of phase 2 enzymes, specifically those in the glutathione redox cycle.  A cell culture study using endometrial, mammary and lung human cancer cells has identified that lycopene has stronger antiproliferative activity than alpha- and beta-carotenes.
Of special significance in prostate cancer prevention is the finding that lycopene interferes with local testosterone activation by reducing the expression of 5-alphareductase I in prostate tumours in a rat model (Siler et al 2004). As a consequence, several androgen target genes in the tumours were drastically downregulated.

OTHER BENEFICIAL ACTIONS OF LYCOPENE
The Antioxidant Supplementation in the Atherosclerosis Prevention (ASAP) study showed that low plasma levels of lycopene were associated with an 18% increase in intima–media thickness (IMT) of the common carotid artery wall in men as compared with men in whom plasma levels were higher than median.

Lycopene Structure and Foods with Lycopene

Lycopene is a fat-soluble, non-provitamin A carotenoid that imparts the red colour to tomatoes, guava, rosehip, watermelon and pink grapefruit.This pigment acts as an antioxidant in the body, protecting cells against damage from the free radicals formed when body cells burn oxygen for energy. Animals and humans do not synthesise lycopene, so they must depend on dietary sources. Research shows that bioavailability of lycopene varies depending on factors such as food source, other foods in the diet, the presence of other carotenoids and dietary fat, cooking temperatures and processing.
Processing, and heating in particular, has been found to significantly increase
lycopene bioavailability, as it induces the isomerisation of lycopene from the trans- to cis-configuration. In other words, lycopene is best absorbed
from tomato products such as pastes and sauces, rather than from unprocessed fresh tomatoes. Lycopene is not produced in the body, so you can only obtain its benefits by eating foods rich in lycopene. Cooked or processed tomato products, such as spaghetti sauce, tomato juice, ketchup and pizza sauce are, by far, the major sources of lycopene in the typical American diet.

Lycopene is widely distributed in the human body and is one of the major
carotenoids found in human serum (between 21% and 43% of total carotenoids). High concentrations are found in the adrenal gland and testes, although significant amounts are also found in the liver, adipose tissue, prostate, kidney and ovaries. Lycopene has also
been detected in high concentrations in ciliary body and retinal pigment epithelium.

CHEMICAL COMPONENTS IN LYCOPENE
Lycopene is a 40-carbon acyclic carotene with 11 conjugated and 2 unconjugated double bonds, normally in the all-trans-configuration, but the double bonds are subject to isomerisation, and various cis-isomers (mainly 5, 9, 13 or 15) are found in plasma and plants. The cis-isomer has better bioavailability from foods.

FOOD SOURCES OF LYCOPENE
The richest sources of lycopene are red tomatoes and processed tomato products. Other sources include watermelon, pink grapefruit and papaya. The lycopene content of food depends on the cultivars grown and the growing conditions. It is currently estimated that daily intake from all dietary sources ranges between 0.5 and 27 mg/person/day or 0.08 and 0.45 mg/kg/day.

ANTICANCER (ANTINEOPLASTIC AND CHEMOPREVENTION) uses of Ashwagandha Studies show that withania can stimulate the production of cytotoxic T-lymphocytes in vivo and in vitro, and that it may prevent or reduce tumour growth. Withania was found in animal models to prevent
skin carcinoma induced by UVB radiation and forestomach tumours  reduce the incidence, number and size of tumours; and to counteract the associated decrease in body weight.

The withaferin A fraction appears to exert anti-angiogenic activity  and may be partly responsible for the antineoplastic effects observed in vitro and in vivo studies. The antioxidant effects aid in the prevention of DNA damage by mutagens  and this in combination with detoxifying properties, anti-inflammatory and immunomodulatory effects, determined in animal studies, are likely to contribute to its chemopreventive action.

Animal studies suggest a potential role for withania as an adjunctive treatment during chemotherapy for the prevention of drug-induced bone marrow depression. Observe— beneficial interactions are possible.

Prevention of bone marrow depression Animal studies suggest a potential role for withania as an adjunctive treatment during chemotherapy for the prevention of drug-induced bone marrow depression. The ability to stimulate stem cell proliferation has led to concerns that W. somnifera could reduce cyclophosphamide-induced toxicity and therefore reduce its
usefulness in cancer therapy. However, preliminary animal studies indicate that withania could prove to be a potent and relatively safe radiosensitiser and chemotherapeutic agent.

ASHWAGANDHA WITHANIA SOMNIFERA as an ANXIOLYTIC AND ANTIDEPRESSANT
Animal studies have found glycowithanolides to exert anxiolytic effects comparable to those of lorazepam, and antidepressant effects comparable to those of the antidepressant drug, imipramine.

CARDIOPROTECTIVE PROPERTIES OF ASHWAGANDHA WITHANIA SOMNIFERA
Cardioprotective effects have been noted in animal studies , significantly reducing myocardial injury after ischaemia and reperfusion. The alkaloids are considered to be sedative and reduce blood pressure and heart rate . The withanolides have a chemical structure similar to cardiac glycosides and have demonstrated mild ionotropic and chronotropic effects on the heart .

THYROID MODULATING USES OF ASHWAGANDHA WITHANIA SOMNIFERA
An in vivo study reported that daily administration of W. somnifera root extract enhanced serum T4 concentration (Panda & Kar 1998, 1999).

ASHWAGANDHA WITHANIA SOMNIFERA AS A SEXUAL ENHANCER
Traditionally used for this purpose, one double-blind clinical trial found that a dose of 3 g taken daily for 1 year improved the sexual performance of 71.4% of healthy aging males . Alternatively, animal studies have indicated that very high doses (3000 mg/kg) result in reduced sexual performance .
HEPATOPROTECTIVE BENEFITS OF ASHWAGANDHA WITHANIA SOMNIFERA
Animal studies have demonstrated hepatoprotective effects  and that withania inhibits phase I, and activates phase II and antioxidant enzymes in the liver .

CLINICAL USES OF ASHWAGANDHA WITHANIA SOMNIFERA
Overall, W. somnifera has not undergone significant scientific investigation in
humans, therefore much of its use is based on pharmacological effects demonstrated in experimental models or traditional usage. In practice, it is often used in herbal combination treatments.

ASHWAGANDHA WITHANIA SOMNIFERA BENEFITS IN  STRESS ADAPTATION

The pharmacological effects of the herb, which have been well established in animal studies, provide a theoretical basis for its use in situations characterised by stress . More specifically, oral administration of an aqueous, standardised extract of W. somnifera (in a dose extrapolated from the human dose) has been found to offer protection against experimentally induced biological, physical and chemical stressors . In one in-vivo study, plasma cortisol levels and adrenal weight were significantly lower, while liver weight increased. To date, controlled studies are unavailable to determine and clarify whether these effects are also significant in humans.
(For more information see ‘Clinical note— Allostasis and adaptation to stress’ in the Siberian ginseng monograph.)
ANTI ANXIETY BENEFITS OF ASHWAGANDHA WITHANIA SOMNIFERA
Although controlled studies are lacking, the herb’s pharmacological effects, such as its GABA-mimetic activity (Mehta et al 1991) and ability to lower cortisol levels  provide a theoretical basis for its use in anxiety states. One
study used a herbal combination treatment known as Geriforte, which contains primarily W. somnifera. The product was taken by 34 subjects with anxiety neurosis, and after 12 weeks significant reductions in the frequency, duration and intensity of symptoms were observed .

ANAEMIA ALLEVIATING BENEFITS OF ASHWAGANDHA WITHANIA SOMNIFERA

The herb is used in the treatment of iron deficiency anaemia due to its effects on haemopoeisis and natural iron content . This use has been supported by studies showing increased haemoglobin levels in children, induced by withania.

Medicinal Properties of ASHWAGANDHA HERB

Ashwagandha as an Antioxidant : Withania exerts an indirect antioxidant action in vivo . Daily administration of W. somnifera root extract increases hepatic glucose-6-phosphatase activity and decreases hepatic lipid peroxidation, most likely by increasing the activity of endogenous antioxidant enzymes.  In vitro W. somnifera inhibits both the lipid peroxidation and the protein oxidative modification induced by copper. In animal studies the antioxidant actions have been proposed as a possible mechanism for withania preventing the negative effects of stroke induced by middle cerebral artery occlusion .

ASHWAGANDHA - WITHANIA SOMNIFERA - INCREASES HAEMATOPOIESIS
Animal trials indicate the Ashwagandha - Withania Somnifera  increases haemoglobin and red blood cell levels and increases haematopoiesis. The iron content of the herb may further contribute to its role in red blood cell formation.

ASHWAGANDHA - WITHANIA SOMNIFERA's IMMUNOMODULATION EFFECTS
Animal studies have shown immunomodulating effects of withania, including an increase in white blood cell, platelet and neutrophil counts, increases in IFN-gamma and IL-2 and a reduction in TNF. In vitro, increased nitric oxide production by macrophages has also been reported. Withaferin A and withanolide D may cause immunosuppression, but other factors have
immunostimulant effects .

ANTIBACTERIAL AND ANTIFUNGAL ACTIVITY OF ASHWAGANDHA - WITHANIA SOMNIFERA

Animal and in vitro studies have shown antibacterial effects against Staphylococcus aureus, Listeria monocytogenes, Bacillus anthracis, Bacillus subtilis, Salmonella enteridis  and Salmonella typhimurium (Owais et al 2005). The methanol and hexane extracts of both the leaves and the roots have potent antibacterial activity against S. typhimurium and Escherichia coli ; and the steroidal withanolides from the related species W. coagulens have been found to have antifungal activity against Allescheria boydii, Aspergillus niger, Curvularia lunata, Drechslera rostrata, Epidermophyton floccosum, Microsporum canis, Nigrospora oryzae, Pleurotus ostreatus and Stachybotrys atra.

ANTI-INFLAMMATORY ACTIVITY OF ASHWAGANDHA - WITHANIA SOMNIFERA

The withanolides (steroidal lactones) are considered to have anti-inflammatory effects. Several withanolides exert selective COX-2 enzyme inhibition  and withania has been found to decrease alpha-2-
macroglobulin, a liver-synthesised plasma protein that increases during inflammation . A reduction in the erythrocyte sedimentation rate has
also been noted in a double-blind clinical trial of 50–59 year old males.

The name ashwagandha (one of the common names for this
herb) comes from the sanskrit meaning ‘horse-like smell’. Apparently, this name not only refers to the smell of the herb but also its strengthening and
aphrodisiac qualities. It is often referred to as ‘Indian ginseng’ because it is used in much the same way in Ayurvedic medicine as Panax ginseng in TCM, although it is considered less stimulating.

Ashwagandha (and a variety of spellings including ashvagandha, ashwaganda, asvagandha), Ayurvedic ginseng, Indian ginseng, winter cherry
BOTANICAL NAME/FAMILY Withania somnifera (family Solanaceae)
Sometimes confused with Physalis alkekengi, also known as winter cherry.

Primarily root, although berry, leaves and bark of Ashwagandha are used.
Chemical components of Ashwagandha include Steroidal lactones (withanolides, withaferin A), alkaloids (including withanine, somniferine, isopelietierine, anaferine, tropine, pseudotropine), flavonoids, saponins,
sitoindosides,  iron, choline, acylsteryl glucosides, coumarins (scopoletin and aesculetin), triterpene (beta-amyrin), phytosterols (stigmasterol and beta-sitosterol) and essential oils (ipuranol, withaniol).

Main beneficial actions of Ashwagandha is as an  Adaptogen (MODULATES STRESS RESPONSES) Withania has been shown to attenuate the negative effects of chronic stress in rats, including hyperglycaemia, glucose intolerance, increase in plasma corticosteroid levels, gastric ulcerations, male sexual dysfunction, cognitive deficits, immunosuppression and mental depression. Animal trials have shown that a withanolide-free hydrosoluble fraction of withania reduces the stress response induced both chemically and physically.
Ashwagandha also  suppresses stress-induced increases in dopamine receptors in the corpus striatum and acts as a GABA-mimetic agent by binding to GABA receptors . Animal studies also suggest an ability to reduce adrenal weight and plasma cortisol levels ( thus potentially protecting against the negative effects of elevated cortisol levels in chronic stress and allostasis.
Nervous System Activity of Ashwagandha : Cognitive enhancement Memory enhancement has been confirmed by animal studies and appears to be mediated by a cholinergic effect. Increased cortical muscarinic acetylcholine receptor capacity has been observed in animals and humans with extracts of withania.  Several withanolides exert calcium antagonistic ability, together with anticholinesterase activity, by inhibiting butyrylcholinesterase and acetylcholinesterase enzymes . The presence of choline in the herb may also contribute to the production of acetylcholine and further increase cholinergic effects. Neuroprotective Several animal studies indicate the potential for protection of neurons , including protection from neuronal injury in Parkinson’s disease  and promotion of dendrite formation.
One possible explanation is due to the antioxidant properties of withania
In animal models of haloperidol-induced dyskinesia (chewing movements, tongue protrusion and buccal tremors), the reported benefits of withania appear to be due to its antioxidant rather than GABA-mimetic action . In vitro results suggest that withanolide A is able to reconstruct neuronal
networks, including axons, dendrites, pre- and postsynapses, in the neurons.