Phytochemicals and ArthritisOsteoarthritis (OA) is a condition characterised by inflammation and damage to articular cartilage and subchondral bone of synovial joints leading to loss of structure and function which causes pain, stiffness, swelling and deformity. More than 8.5 million people in the UK suffer from this degenerative disease affecting the hands, feet, spine, hips and knees in particular. According to Arthritis Research UK, the annual cost of the condition to the NHS is £5.2 billion [Arthritis research]. In 2011, more than 77,000 knee and 66,000 hip replacements were carried out due to osteoarthritis.

Over genetic predisposition, OA can be caused by mechanical factors such as obesity, trauma and bad posture but the existence of inflammation in OA, locally or systemic, is widespread [Kraus]. This explains the increase in non-weight baring joint OA [Kraus, Dahaghin, Reyes] and why large epidemiology studies have strongly linked arthritis with other lifestyle habits  which increase systemic inflammation such as smoking, factors associated with poor gut health high processed sugar, low bacteria rich foods) , lack of exercise and high meat low fruit and vegetable diets [Wang, Mc Alindon, Williams, Pattison, Hanninen].Joint discomfort and stiffness is more common amoung people after cancer treatments with studies consistently reporting the incidence as over 55%, effecting mobility and long-term quality of life [Thomas, Adelaide, Crew, Henry, Pegram].

Arthritis has a significant impact patients ability to exercise which it can lead to an exacerbation of other symptoms by restricting an individual’s ability to be physically active [Thomas, Shen].

Regular exercise can mitigate many of the risks and side effect experienced by men on Androgen Depletion Therapy (ADT), particularly weight gain, hot flushes and osteoporosis [Gardner]. Exercise after breast cancer helps reduce unwelcomed weight gain [Chlebowski], improves sleep patterns and severity of hot flushes [Thomas]. Compliance to medical interventions has been shown to be improved by supervised exercise programmes [Prasad]. Numerous prospective studies and meta-analysis have highlighted that physical activity can improve cancer-related fatigue, peripheral neuropathy, muscle weakness, thromboembolism, weight gain, loss of bone density, arthritis itself, quality of life, psychological distress, incontinence and sexual dysfunction [Fong, Irwin, Thomas Irwin, Roberts].

The goals of treatment for arthritis are to relieve pain, maintain or improve joint mobility, increase the strength of joints and to minimize the disabling effects of the disease. Simple analgesia such as paracetamol, nonsteroidal anti-inflammatory (NSAI) agents help and, if severe, agents such as opioids, duloxetine have a role, which although helpful, have significant long-term cardiovascular and gastrointestinal risks [Henry, Reddy]. Complementary measures such as Yoga and Pilates have demonstrated some effectiveness in helping to relieve joint pain and improving mobility [Haslock]. As regards other complementary therapies, phase III trials do supports the use of acupuncture [Crew-10] but benefits have been seen with nutritional interventions especially increasing phytochemical rich food intake.

How phytochemicals help arthritis

There are many reasons why fruit, herbs and vegetable intake enhance joint and general health, but their phytochemical content is certainly a significant factor [Thomas, Knekt, Thomas,].  Phytochemicals occurring naturally in plants are responsible for their colour, taste, and aroma [Thomas, Thomas]. Their regular intake is linked to a lower risk of cancer, better cancer outcomes, improved joint health and exercise performance [Powanada, Boer, Bailey, Bondon Thomas].  So, boosting their intake may have a significant role for cancer survivors by improving exercise capacity, reducing arthritis, other side effect of and improving outcomes [Wang, Bradbury, Block, Buck, pierce, Zhu, Key, Cherubini, Loito, WCRF Hu]. What’s higher intake is linked to a lower incidence of chronic degenerative disease so their regular intake may help reduce many of the conditions which are more common after cancer treatments including raised cholesterol, blood pressure, macular degeneration, dementia, stroke and heart disease [Martin, Thomas, Cherubini]. Relevant to recent events, they also may have anti-viral properties [Li, Lin, Ge, Wu, Lau, Yu]. They influence several biological pathways that are responsible for their benefit which have been described in a recent review [Thomas]  the most prominent relating to cancer, exercise and arthritis are now summarised:

Improving gut health:  Some polyphenols act as prebiotics which promote a healthy gut health microbiome, in particular plant lignans found in nuts, resveratrol in red wine, ellagitannin found in tea as well as celery, pomegranate and turmeric. These butyrate forming polyphenols they stimulate the growth of anti-inflammatory (bacteroidetes) bacteria and impair the growth of pro-inflammatory firmicutes bacteria by a number of mechanisms. They prevent adhesion of firmicutes, creating more physical space for bacteroidetes species. They preferentially feed healthy gut bacteria,  because the metabolism of polyphenols into glycans such as butyrate, are used as energy by these species but also by the host gut wall cells.  Firmicutes (bad bacteria) have less of the enzyme required to digest glycans than Bacteroidetes, so are less able to use them as food. As a result they turn to sugar as an energy source. Moreover, Firmicutes are more repressed than Bacteroidetes by the natural antibiotic properties of many polyphenols. Over time, diets low in polyphenols and high in sugar lead to firmicute overgrowth, causing inflammation, hyperplasia and dysplasia of gut cells which can lead to cancer. They damage colon’s integrity, cause “leaky gut syndrome” which allows toxins to pass into the bloodstream triggering systemic inflammation leading to a whole host of issues including low mood and arthritis which demotivates individuals from pursuing a fruitful exercise regimen [Huang, Powanda, Huag, Shen]. In the large population based Rotterdam Study cohort study an abundance of Firmicutes (unhealthy) species was found to be  associated with increased knee pain caused by  inflammation in the knee joint [Boer]. 

Weight reducing properties: In addition to improving gut health, polyphenols have other properties which can help prevent obesity [Wang]. Laboratory studies indicate that the anti-obesity effects of polyphenol-rich diets may be attributed to the ability of polyphenols such as epigallocatechin gallate (EGCG) and green tea extracts, resveratrol and curcumin, to interact directly with adipose tissues (preadipocytes, adipose stem cells, and immune cells) reducing their propensity to store energy [Siriwardhana, Chan].  Polyphenols, further mitigate the metabolic consequences associated with obesity  [Esfahani, Wang]. Finally, the reabsorption of cholesterol from the gut is increased in the presence of inflammation and decreased when the bodies inflammatory system is in a good balance [Tall]. Avoiding obesity has several benefits but more specifically for this study calorie reduction, intermittent fasting and exercise programmes that reduce obesity have been shown to help weight-baring joints by reducing mechanical strain [Winer, Muller]. In addition, obesity is also associated with changes in gastrointestinal-microbiome composition, which can lead to an increased intestinal absorption of pro-inflammatory bacterial products which aggravate joints [Brun, Winer, Berenbaum, Berenbaum]. Studies have shown that showed that the weight of mice could be changed by over 15%, just by shifting their intestinal bacteria and transplanting bacteria from the gut of obese humans has been shown to trigger obesity in mice [Marotz]. Weight reduction programmes, therefore, which also promote high polyphenol intake and healthy gut microbiome, could therefore further help joints by reducing system in inflammation and improving the gut integrity [Shouten, Felson].

Reducing excess inflammation: Although an inflammatory response is an important part of a healthy immunity, persistent low-grade chronic inflammatory activity is associated with an increase in age-related diseases such as dementia,atherosclerosis, arthritis and cancer [Khanasari]. As mentioned above polyphenols can reduce inflammation by improving gut health and helping to reduce weight but they also have direct anti-inflammatory properties. There is a general consensus that an important mechanism for excess inflammation is caused by the body over compensation from an ailing immune system. The immune system responds to reduced T cells and natural killer cell potential (caused by aging, obesity and diabetes) by increasing pro-inflammatory cytokines via modulation of NF‐κB which in part helps maintain immunosenescence [Franceschi, Rukavina, Hoffman-Goetz]. The price for this is higher levels of pro-inflammatory cytokines such as c-reactive protein, Tumour Necrosis Factor (TNF) and interleukin-6 (IL-6) and acute phase proteins which increase concentrations of NK cells and T-cells but at the same time increase inflammatory exudates in tissues and promote cancer by excess activation of COX–2 and prostaglandins via modulation of the function of NF‐κB, [Blacklock, Zakkar, Wolpin].  Exercise are known to enhance natural killer cell activity and increase T-cell production directly reducing the need of the immune system to increase circulating inflammatory biomarkers [Nicklas, Zimmer [Martinez]. Likewise phytochemicals have been shown to inhibit NF-kappa B signalling in vitro, particularly the green tea polyphenol Epigallocatechin-3-Gallate (EGCG), quercetin, curcumin, caffeic acid, and caffeic acid phenethylester [Salminen, Carlsen]. Other anti-inflammatory mechanism of phytochemicals involve direct reduction in the prostaglandin and cox-2 pathways [Reuland Madaan].

Reducing excess oxidative stress: Phytochemicals can help protecting us oxidative genetic damage from environmental and ingested carcinogens by help regulating and arming antioxidant enzymes. Their antioxidant enhancing properties stem from an ability facilitate activation of the transcription factor NF‐E2–related factor 2 (Nrf2), which enhances an appropriate antioxidant response to damaging reactive oxidative species [Stivala, Davidosn, Juge, Dinkova‐Kostova). ROS are generated at higher levels in obesity, after eating unhealthy foods such as burnt meat, unaccustomed exercise and processes sugar or smoking. Higher systemic levels of oxidative stress have been linked to a greater risk of cancer initiation and progression [Thomas, Davies, Poljsak]. Likewise, greater levels of oxidative stress in joints has been shown to have an apoptopic effects on chondrocytes increasing cartilage degeneration [Giovannucci, Shen]. This explains why individuals with lifestyle habits which increase oxdative stress intake particularly vulnerable to arthritis and cancer (Wang, Marseglia).

It is important to differentiate polyphenols from direct antioxidants such as vitamin A and E. Although some phytochemicals could have weak direct anti-oxidant properties, in the past, this aspect has been overstated. In fact, many people previously referred to them only as anti-oxidants which is misleading and diminishes the importance of their, other biochemical properties. Unlike direct anti-oxidant vitamins A & E (highlighted below), they do not over deplete ROS levels causing anti-oxidative stress, instead they improve antioxidant efficiency and capacity when needed [Avery, Peternelj, Lotito].

Direct joint health properties: The ability of polyphenols to reduce systemic inflammation explains why consumption of these phytochemical rich foods correlates with lower pain, stiffness and reduced mobility in people with OA affected joints [Saberi Hosnijeh].  Polyphenols, in particular,  also have some direct, joint protective properties by inhibiting matrix metalloproteinase (MMPs) enzymes over production responsible for extracellular matrix (cartilage – collagen and proteoglycan aggrecan) degeneration [Dahlberg, Mitchel, Brinckerhoff]. Polyphenols also exert anti-apoptotic effects on chondrocytes in joints exposed to oxidative stress or inflammation reducing cartilage degeneration [Shen].

Tissue oxygenation and improved vascular health: Polyphenol rich foods such as celery, pomegranate, beetroot and other leafy green vegetables are rich in nitrates which, in the presence of vitamin C and polyphenols, are converted to nitric oxide (NO) rather than nitrates in meat which are converted to carcinogenic nitrosamines [Lundberg, Tannenbaum,]. These have been shown to help to improve vascular health and oxygenation [Kim-Shapiro, Raphaeolle. This explains the intake of nitrate rich foods is emerging as a potential natural strategy to enhance exercise performance (see below) and prevent pathologies associated with diminished NO bioavailability such as those associated with abnormal endothelial function including hypertension, atherosclerosis, type 2 diabetes, low mood and dementia [Hobbs, Vanhatalo, Wootton-Beard, Presley, Bailey, Bondon, D’Angelo].

Role and evidence for some nutritional supplements 

These are particularly popular amongst people with arthritis and musculoskeletal conditions. Reports from formal surveys suggest that over 70% of arthralgia suffers have used a variety of products at one stage in their illness and this figure goes over 75% among living post cancer, who also have arthralgia [Bishop, Thomas]. The charity Arthritis Research has comprehensively reviewed 30 available OTC nutritional supplements, highlighting their potential benefits but emphasizing the significant gaps in research [Arthritis research, Thomas K, Richardson, Shen, Kikuchi]. Commonly used OTC supplements include probiotic bacteria, glucosamine, chondroitin, fish oils, antioxidant vitamins A and E and a variety of polyphenol rich whole food supplements [Fox, Towheed].The available data from this report and other robust studies relating to arthritis and exercise were reviewed by the scientific committee for this study and the salient conclusion are now summarised:

Probiotic supplements: Probiotics are live microorganisms, which when administered in adequate amounts confer a health benefit on the host [WHO]. Microbes used as probiotics are derived from different genera and species and have been studied extensively for a variety of health and disease endpoints. In terms of arthritis, laboratory studies have shown that Lactobacillus acidophilus protected organs in rats with experimental arthritis by regulating the pro-inflammatory cytokines. They even protected the kidneys from simultaneous indomethacin administration  [Amdekar]. In humans, the large population based Rotterdam Study cohort study an abundance of Firmicutes (unhealthy) species was found to be  associated with increased knee pain caused by  inflammation in the knee joint [Boer]. A randomised trial from Iran found that supplementation with Lactobacillus casei improved symptoms and inflammatory cytokines in female patients with established rheumatoid arthritis for more than 1 year as compared to a group receiving placebo [Alipour]. Likewise, a  larger double-blind, placebo RCT reported that knee osteoarthtitis related pains significantly improved Lactobacillus compared to placebo daily for 6 months. They also reported that improvements in the Western Ontario and McMaster Universities Osteoarthritis Index scores (WOMAC) were strongly correlated with lower levels of C-reactive protein (CRP) [Le

Glucosamine and chondroitin: These are an amino sugar supplements made from pig or shark cartilage has been found in animal studies to delay the breakdown, and improve repair, of damaged cartilage. Glucosamine has been specifically evaluated in a RCT involving 400 women with breast cancer and did demonstrate a significant difference in pain and knee joint space [Bruyere]. However in 13 subsequent RCT, the results were mixed, and two large meta-analysis concluded there were no meaningful benefit or change clinical joint aspects of glucosamine [Wandel, Towheed]. Laboratory studies have found that chondroitin supplements reduced the activity of enzymes that break down collagen in joints in addition to their anti-inflammatory properties [Thomas K].  In humans, some of the 22 RCT versus placebo have demonstrated a benefit to regular supplementation but again two meta-analysis concluded that, no clinically meaningful benefits have been demonstrated [Reichenbach, Wandel].

Fish oils: These have been reported to improve symptoms of rheumatoid arthritis, in term of pain and lower non-steroidal intake but the evidence of a benefit for osteoarthritis lacks sufficient data [Cleland, Fortin].  More specifically an involving women experiencing arthralgia taking an aromatase inhibitor were randomised toomega 3 rich fish oils or placebo (soybean/corn oil) daily for 24 weeks and although arthralgia scores in both groups improved, there was no meaningful difference between them [Hershmann]. Of more concern, cod liver oil is very high in vitamin A and Vitamin E is often added as an anti-oxidant preservative to fish oils. The mechanism of risk are highlighted in the next paragraph.

Pomegranate (Punica granatum): The whole fruit and particularly the ground seeds are particularly rich in anthocyanins, flavonoids, gallic acid, ellagic acid, quercetin, and ellagitannins. In laboratory studies pomegranate has been shown to inhibit proliferation, markers of migration, induce apoptosis and cell adhesion in breast and prostate cancer cell lines [Wang, Rettig].  Pomegranate is a good sources of plant nitrates [Lundberg, Raphaeolle, Tannenbaum]. The ability to enhance nitrate conversion into NO levels is one of the postulated reasons why pomegranate extract (PE)  has reported joint and exercise benefits.  In one double-blind, placebo-controlled crossover study compared to placebo it achieved measurable improvements in blood flow, vessel diameter [Trexler].  Another study gave PE to fit young men and  found it enhanced, intramuscular blood flow and oxygen saturation during exercise [Roelofs]. This was supported by another randomised, double-blinded involving male, amateur cyclists, training 2 to 4 sessions per week, which reporting a statistically significant improvement in time to exhaustion and the time to reach ventilatory threshold [Torregrosa-García]. Other Intervention studies, have shown it to help muscles and joints to restore their functionality, enhance nitric oxide bioavailability and increase efficiency of oxygen usage for endurance exercisers and recovery following intensive weightlifting training sessions [Crum, Ammar].

Turmeric (Curcuma longa): A perennial plant native to southern Asia originating from the ginger family. Its constituents include the three curcuminoids: curcumin (diferuloylmethane) the primary constituent and the one responsible for its vibrant yellow colour, demethoxycurcumin and bisdemethoxycurcumin, as well as volatile oils (tumerone, atlantone and zingiberone). In one notable laboratory study,  turmeric was injected intraperitoneally to rats prior to the administration of arthritis inducing toxins. The turmeric profoundly inhibited joint inflammation and peri-articular joint destruction, via de-activation of NF-kappaB which mediate joint inflammation and destruction via including chemokines, cyclooxygenase 2 and RANK. Consistent with these findings, inflammatory cell influx, joint levels of prostaglandin E(2) and peri-articular osteoclast formation were inhibited by the turmeric extract supplementation [Funk]. Turmeric polyphenols are capable of interacting with numerous molecular targets involved in inflammation [Handler, Thomas]. In humans, a crossover double blind RCT gave 50mg of turmeric, as well as other botanicals was given to participants with osteoarthritis three times daily for three months. Those taking the turmeric combination demonstrated significant improvements in pain severity and disability scores over placebo [Kulkarni]. Another study, participants with a history of joint pain were randomized participants to a placebo or a supplement containing turmeric root extract and reported an improvement in joint pain severity, improvements in the ability to perform daily activities and stiffness scores and knee pain after 8 weeks [Nieman]. Finally, a further study involving participants with arthritic pains of the knee randomly compared turmeric versus  ibuprofen per day, for 6 weeks. Although both groups’ pain levels improved when walking and climbing stairs it was significantly greater degree in the turmeric group [Kuptniratsaikul, Kulkarni].

Green tea (Camellia sinensis): The common beverage and particularly the dried whole leaf extract rich source of catechins such as epigallocatechin 3-gallate (EGCG) [Thomas, Manning, Doss, Cooper]. A number of laboratory studies, using chondrocytes derived from OA cartilage, have demonstrated that pre-incubation with tea extract, or pure EGCG, reduced pro-inflammatory cytokines such as IL-1β, TNFα, IL-6, prostaglandin E2 and COX-2 when exposed to oxidative stress [Ahmed, Singh, Samuels, Malemud]. Tea catechins, via their influence on inflammatory cytokins, blocked activation of matrix-degrading MMPs [Ahmed, Brinckerhoff, Adcocks, Vankemmelbeke]. In animals, the potential modifying effect of EGCG on arthritis was first discovered in a study in which the consumption of EGCG-containing green tea extract in drinking water ameliorated collagen-induced arthritis in mice [Haqqi]. Despite this cell line and animal data there are no significant, adequately powered prospective trial data in humans with arthritis although studies investigating other conditions in humans have confirmed an excellent safety profile [Taylor, Heck, Salahuddin, Cooper].

Broccoli, rich in the phytochemical sulforaphane (SFN) is known to be a potent  chondroprotective agent and it’s role its role in joint health has been firmly established [Kong]. In laboratory experiments it directly restore signs of cartilage destruction and in clinical studies, SFN levels in synovial fluid, within joints correlated with reduced inflammation and improved comfort.[Davison].

Boswellia serrate (Indian Frankincense): A branching tree of the family Burseraceae that grows in dry mountainous regions of India, Northern Africa and Middle East. Its resin contains a number of phytochemicals including monoterpenes, diterpenes; triterpenes; pentacyclic triterpenic acids (boswellic acids) and tetracyclic triterpenic acids [Siddiqui]. These phytochemicals, particularly the boswellic acids have wide range of microbiological effects which have potential disease modifying effects on the arthritis and other chronic conditions [Siddiqui].

In human chondrocytes, Boswellia serrata has demonstrated an ability to suppress a protein known as RANKL which induces osteoclastogenesis and potentiates apoptosis both preventing cartilage and bone reabsorption [Sengupta, Tardaka]. Boswellia has also been shown to suppress the TNF-α induced release of MMP-3 [Siddiqui, Sengupta]. A unique property of boswellic acid is its ability to inhibit leukotriene synthesis by interacting directly with or blocking translocation of the pro-inflammatory enzyme 5-lipoxygenase (5-LO) without effecting arachidonic acid [Siemoneit]. Finally, Boswellia serrata inhibits NF-kB activation from irritants such as cigarette smoke, okadaic acid which trigger TNF-α and IL-1β release or direct  exposure the these cytokines themselves [Siddiqui].

In mice with formaldehyde induced arthritis, those feed with Boswellia exhibited a >50% anti-arthritic activity both in terms of preventing arthritis development as well as those with established disease [Singh].  A similar protective effect was seen in rabbits who had arthritis induced by bovine serum albumin [Sharma]. In humans, a RCT involving 75 participants with established osteoarthritis found that, compared to placebo, those given enriched Boswellia serrata extract had improved pain and functional ability scores as well as significant reduction in synovial fluid matrix metalloproteinase-3 [Sengupta]. In another small RCT,  Boswelliacapsules three times a day for 8 weeks improved pain, knee flexion and walking distance compared to placebo [Kimmatkar]. The same dose was investigated in another trial RCT, this time involving 66 people for 6 months compared to the non-steroidal anti-inflammatory drug (NSAI) valdecoxib. Although pain, stiffness and ability to perform physical activity improved in all participants, the onset of action was slower in participants who were given boswellia.  At the end of the trial, those in the Boswellia group experienced a significant less arthritic compared to those given the NSAI with an absolute magnitude of 15%, enough to improve joint related quality of life score [Sontakke]. Other smaller and non controlled randomised trials also involving participants with rheumatoid arthritis report similar benefits [Kulkarni, Chrubasik, Chopra]. Finally a comprehensive Cochrane review concluded Bowellia reduced joint pain over placebo [Cameron]. Considering all this evidence The European Food Safety association allows a statement for Boswellia of “Helps to maintain joint health and supports joint flexibility (EFSA].

Synergistic interactions between boswellic acid in Curamin has been confirmed by the results of several studies which show the combination is more effective and safe than each other alone for OA knee pain [Kizhakedath, Haroyan, Yu]

Beetroot (Beta vulgaris rubra): This popular root vegetable is rich in several bioactive compounds including ascorbic acid, carotenoids, phenolic acids and flavonoids but is also one of the few vegetables that contain a group phytochemical pigments known as betalains. These are categorised as either betacyanin pigments that are red-violet in colour or betaxanthin pigments that are yellow-orange in colour [Clifford, Ninfali]. A number of investigations have reported betalains to have favourable anti-inflammatory and oxidative enzyme enhancing capabilities in vitro and via a variety of in vivo animal models [Vidal, Clifford, Reddy, Das, Baker]. One study group reported betanin inhibited COX-2 enzyme activity by 97%, a level comparable or greater than commonly used anti-inflammatory drugs (Ibuprofen, and Celebrex) [Clifford]. In humans, administration of betalain-rich oral capsules made from beetroot extract significantly reduced serum pro-inflammatory cytokines and helped alleviate joint pains in osteoarthritic patient. In addition, even after 10 days of supplementation (100, 70 or 35 mg per day) factors which may have an influence of cancer pathways also decreased from baseline by up to 30% tumour particularly necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6) [Pietrzkowski].

In terms of oxidative stress, in another study, rats were randomize to a normal diet or a diet supplemented with a dried beetroot extract for 7 days prior to being exposed to the known carcinogen reactive oxygen species carbon-tetrachloride, a well-established carcinogen and reactive oxygen, nitrogen species (RONS) generator. Those rats pre-treated with the beetroot expressed significantly lower levels of lipid peroxidation a marker of oxidative damage. Furthermore, the beetroot extracts fed rats maintained endogenous antioxidant enzyme activity (glutathione peroxidase, superoxide dismutase and catalase enzymes) at normal cellular concentrations following the oxidative insult which significantly dropped in the controls. This suggests beetroot also exhibits indirect antioxidant effects via up regulation of the antioxidant defence mechanisms [Vulić].

Cordyceps mushroom: Cordyceps militaris was originally extracted from a parasitic caterpillar fungus found in humid tropical countries but now, more commonly, cordyceps sinensis is derived from cultivated spores. Either version is rich in the phytochemical cordycepin, also known as 3-deoxyadenosine a nucleoside derivative [Won]. Various studies have focused on the pharmacological activities of cordycepin and revealed it exerted properties, such as anti-inflammatory, anti-angiogenesis, anti-aging and anti-proliferation [Kim, yoo, lee, lee, rao]. In a study in mice, a cordyceps extract significantly prolonged the exhaustive swimming time, decrease concentrations of serum lactic acid [Xu]. In humans, an 8 weeks of cordyceps supplementation (20 mg/kg/day) has been shown to improve endurance capacity, body composition, and metabolic-related biomarkers in young sedentary individuals [Liao]. In another double-blind controlled trial, 12 weeks of dried cordyceps improved lactic acid threshold and performance healthy elderly men and women [Chen]. Likewise 6 weeks of dried cordyceps extract improved oxygen uptake, aerobic capacity and ventilation function and resistance to fatigue during exercise [Yi]. An in-vitro study has found that cordycepin inhibited expression of MMP in interleukin-1 beta induced arthritis synovial fibroblasts [Noh, Wang]. A more recent study, confirmed cordyceps catabolic the gene expressions of MMP but also discovered that it protected cartilage via its ability to decrease glycosaminoglycan (GAG) release, which prevents aggrecan degradation and proteoglycan loss, both are hallmark manifestations of OA [Penfei].

Food combinations: The evaluation a capsule containing dried whole polyphenol rich foods (turmeric, green tea, broccoli and pomegranate) reported a statistically significant effect on markers of progression in men with early prostate cancer [Thomas Thomas]. A follow up study established that changes in PSA correlate with underlying tumour changes seen on diffusion weighted MRI [Thomas]. In this study men also reported an improvement in arthralgia but although non-significant using pre-determined statistical. Other interventions studies, have demonstrated benefits of concentrated polyphenol rich food supplement over placebo and non-steroidal anti-inflammatory medications for joint symptoms [Davis, Kuptniratsaikul, Kulkarni. Nieman]. In terms of exercise, to improve performance and recovery, numerous dietary intervention studies have been conducted in both armature and elite athletes . A study published in 2020 show that teh combimation of turmeric and pomegranate significantly reduced inflammation in distance runners {Tanner}


Concerns with Vitamins A and E supplements,

In the past were thought to be potentially useful nutritional elements to reduce oxidative stress but with the passage of time, significant concerns have been discovered not only for arthritis but for cancer and exercise performance. Unlike polyphenols which promote a natural adaptive increase in anti-oxidant enzymes, direct anti-oxidants (vitamin A, E and acetylcysteine) can actually block this process. So, in the long term they reduce cellular anti-oxidant enzyme activity which leads to greater oxidative stress, to such an extent they can mitigate other health benefits of exercise, increase genetic damage, impede joint and tissue repair [Teixeira, Avery, Poljsak, Eder, Ristow, Gomez-Cabera, Peternelj]. This was demonstrated in a study involving kayakers who were randomised to take an antioxidant supplement including vitamin E and beta-carotene. They show that, although antioxidant status reduced immediately after exercise by 4 weeks lipid peroxidation, muscle damage, and inflammation was worse hindering the recovery of muscle damage [Teixeira].

Vitamins A & E can also block keap 1 which interferes with the signal for nrf2 to reduce the anti-oxidant levels. As such, they cause anti-oxidant enzymes to remain elevated, even when the oxidative stress subsides [Eder, Ristow]. Combined with their ability to neutralize ROS by directly donating a hydrogen atom this can result in the mopping up of too many ROS that can lead to a state called anti-oxidative stress [Poljsak].  This can also cause tissue damage as our cells do need a certain level of ROS for normal functions such as regulating vascular tone, monitoring of oxygen tension in the control of red cell production, induction of stress response to pathogen attack [Poljsak, Ristow, Schulz, Son].

So, combining these concerns together, vitamins (E and A) supplements can delay the adaptive production of anti-oxidant enzymes when they are needed then delay their degradation when they are not needed [Poljsak, Ristow, Eder, Teixeira, Avery, Peternelj]. As a result, the time cells spend with the optimal balance is shortened compared to a standard diet which explains why there is now clinical evidence that, unless correcting a known deficiency, vitamin A & E have no benefit during exercise and can even mitigate the cancer protective benefits, reduce exercise performance and increase tissue damage [Miller, Myung, Collins, Avery, Mursu, Bjelakovic, Ionescu Poljsak, Shulz]. These concerns have been born out in clinical studies of Vitamin A & E supplements some  of which have even been linked to a higher cancer risk [Thomas, Poljsak]. For example, the ATBC showed a higher incidence of lung cancer [Albanes]; The Women’s Health Study involving patients with diabetes or cardiovascular disease showing a higher incidence of heart disease [Richardson]; The Queensland skin cancer study which reported a higher rate of recurrent skin cancers [Hercberg]; The SELECT study showing a higher incidence of prostate cancer [Klein]; the CARET Study showing an increased risk of both lung and prostate cancer [Omenn]. The vitamin A and E content of fish oils and may be one explanation why two trials have reported a link with higher prostate cancer incidence with regular use [Brasky].


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Jones AM. Dietary Nitrate Supplementation and Exercise Performance. Sports Medicine 2014;44:35–45.

Wang X, Ouyang Y, Liu J et al,  Fruit and vegetable consumption and mortality from all causes, cardiovascular disease, and cancer: systematic review and dose-response meta-analysis of prospective cohort studies. BMJ. 2014 Jul 29; 349; 4490.

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Bernardeau M, Guguen M, Vernoux JP. Beneficial lactobacilli in food and feed: long-term use, biodiversity and proposals for specific and realistic safety assessments. FEMS Microbiol Rev. 2006;30:487–513.


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Amdekar, S., Singh, V., Kumar, A., Sharma, P., & Singh, R. (2014). Lactobacillus acidophilus Protected Organs in Experimental Arthritis by Regulating the Pro-inflammatory Cytokines. Indian journal of clinical biochemistry : IJCB, 29(4), 471–478.

Alipour B, Homayouni-Rad A, Vaghef-Mehrabany E, et al. Effects of Lactobacillus casei supplementation on disease activity and inflammatory cytokines in rheumatoid arthritis patients: a randomized double-blind clinical trial. Int J Rheum Dis. 2014;17(5):519-527.

Lei M, Guo C, Wang D, Zhang C, Hua L. The effect of probiotic Lactobacillus casei Shirota on knee osteoarthritis: a randomised double-blind, placebo-controlled clinical trial. Benef Microbes. 2017;8(5):697-703. doi:10.3920/BM2016.0207.

Ryu YB, Jeong HJ, Kim JH, et al. Biflavonoids displaying SARS-CoV 3CL (pro) inhibition. Bioorg Med Chem. 2010;18:7940–7.

Berggren A, Lazou Ahrén I, Larsson N, Önning G. Randomised, double-blind and placebo-controlled study using new probiotic lactobacilli for strengthening the body immune defence against viral infections. Eur J Nutr. 2011;50(3):203-210.

Fujita R, Iimuro S, Shinozaki T, Sakamaki K, Uemura Y, Takeuchi A, et al. Decreased duration of acute upper respiratory tract infections with daily intake of fermented milk: a multicenter, double‐blinded, randomized comparative study in users of day care facilities for the elderly population. American Journal of Infection Control 2013;41(12):1231‐5.

Rerksuppaphol S, Rerksuppaphol L. Randomized controlled trial of probiotics to reduce common cold in schoolchildren. Pediatrics International 2012;54(5):682‐7.

Boer, C.G., Radjabzadeh, D., Medina-Gomez, C. et al. Intestinal microbiome composition and its relation to joint pain and inflammation. Nat Commun 10, 4881 (2019).

Shi Z. “Gut Microbiota: An Important Link between Western Diet and Chronic Diseases.” Nutrients vol. 11,10 2287. 24 Sep. 2019, doi:10.3390/nu11102287


Wang Y, Hodge A, Wluka A, English D, Giles G, O’Sullivan R, et al. Effect of fruit and vegetables on knee cartilage and bone in healthy, middle‐aged subjects: a cross‐sectional study.Arthritis Res Ther2007;9:R66.

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Marseglia L,Manti S, D’Angelo G et al Oxidative Stress in Obesity: A Critical Component in Human Diseases International Journal of Molecular Sciences. 2015 Jan; 16(1)378

Juge N, Mithen RF, Traka M.Molecular basis for chemoprevention by sulforaphane: a comprehensive review.Cell Mol Life Sci2007;64:1105–27.

McAlindon TE, Jacques P, Zhang Y, Hannan MT, Aliabadi P, Weissman B, et al. Do antioxidant micronutrients protect against the development and progression of knee osteoarthritis? Arthritis Rheum1996; 39: 648– 56.

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Zakkar M, Van der Heiden K, Luong LA, Chaudhury H, Cuhlmann S, Hamdulay SS, et al.Activation of Nrf2 in endothelial cells protects arteries from exhibiting a proinflammatory state.Arterioscler Thromb Vasc Biol2009;29:1851–7.

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Wang Y,  Simpson J, Wluka A et al Meat consumption and risk of primary hip and knee joint replacement due to osteoarthritis: a prospective cohort study. BMC Musculoskelet Disord. (2011)

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Health claims for phytochemical rich foods European Safety authority EFSA Journal 2010; 8(2):1493

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Heinen MM, Hughes MC, Ibiebele TI, et al: Intake of antioxidant nutrients and the risk of skin cancer. EJC 43(18):2707-2716, 2007.

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Wandel et al  Effects of glucosamine, chondroitin, or placebo in patients with osteoarthritis of hip or knee: network meta-analysis BMJ 2010; 341, c4675

Towheed et al Glucosamine therapy for treating osteoarthritis. Cochrane Database Sys Rev 2005; 18 18;(2):CD002946.

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Thomas R, C Marshall, M Williams, L Walker Can switching to Aromatase inhibitors in tamoxifen intolerant post menopausal women improve hot flushes, toxicity, qol and mood?British Journal of Cancer (2008) 98, 1494-1499.

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Thomas R. Madeleine Williams1, Graham Smith1 Bridget Ashdown1Patient ranking of late symptoms after breast and prostate cancer and their influence on self initiated nutritional therapies – The Bedford Real World Study. Multidiscipinary Conference of Supportive Care (Adelaide). International Journal of Supportive Care, 2016

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Reference related to Boswellia:

Clifford, Tom et al. “The potential benefits of red beetroot supplementation in health and disease.” Nutrients vol. 7,4 2801-22. 14 Apr. 2015, doi:10.3390/nu7042801


Siddiqui, M Z. “Boswellia serrata, a potential antiinflammatory agent: an overview.” Indian journal of pharmaceutical sciences vol. 73,3 (2011): 255-61. doi:10.4103/0250-474X.93507

Singh, Pooja et al. “A-90 Day Gavage Safety Assessment of Boswellia serrata in Rats.” Toxicology international vol. 19,3 (2012): 273-8. doi:10.4103/0971-6580.103668

Siemoneit U, Pergola C, Jazzar B, et al. On the interference of boswellic acids with 5-lipoxygenase: Mechanistic studies in vitro and pharmacological relevance. Eur J Pharmacol. 2009; 606:246–54.

Singh GB, Atal CK. Pharmacology of an extract of Boswellia serrata. Indian J Pharmacol. 1984; 16:51.

Sharma ML, Bani S, Singh GB. Anti-arthritic activity of boswellic acids in bovine serum albumin (BSA)-induced arthritis. Int Immunopharmacol. 1989; 11:647–52.

Siddiqui MZ Boswellia Serrata, A Potential Anti-inflammatory Agent: An Overview. 2011 Indian J Pharm Sci; 73(3):255-61

Sengupta K, et al Cellular and molecular mechanisms of anti-inflammatory effect of Aflapin: a novel Boswellia serrata extract . Mol Cell Biochem. (2011)

Takada Y, et al Acetyl-11-keto-beta-boswellic acid potentiates apoptosis, inhibits invasion, and abolishes osteoclastogenesis by suppressing NF-kappa B and NF-kappa B-regulated gene expression . J Immunol. (2006)

Sengupta K, Alluri KV, Satish AR, Mishra S, Golakoti T, Sarma KVS et al. A double- blind, randomised, placebo-controlled study of the efficacy and safety of 5-LOXIN® for treatment of osteoarthritis of the knee. Arthritis Research & Therapy 2008; 10(4): 85-9.

Kulkarni R, Patki P, Jog V, Gandage S, Patwardhan B. Treatment of osteoarthritis with a herbomineral formulation: A double blind, placebo-controlled, cross-over study. J Ethnopharmacol. 1991;33:91–5.

Chopra A, Lavin P, Patwardhan B et al. Randomized double blind trial of an Ayurvedic plant derived formulation for treatment of rheumatoid arthritis. J Rheumatol. 2000;27:1365–72.

Kimmatkar N, Thawani V, Hingorani L, et al. Efficacy and tolerability of Boswellia serrata extract in treatment of osteoarthritis of knee – a randomised, double blind, placebo-controlled trial. Phytomedicine 2003;10(1):3–7

Sontakke S, Thawani V, Pimpalkhute S, Kabra P, Babhulkar S, Hingorani L. Open, randomised, controlled clinical trial of Boswellia serrata extract as compared to valdecoxib in osteoarthritis of knee. Indian Journal of Pharmacology 2007; 39:27–29.

Sengupta K, Krishnaraju AV, Vishal AA et al. Comparative efficacy and tolerability
of 5-LOXIN® and Aflapin® against osteoarthritis of the knee: a double-blind, randomised, placebo-controlled clinical study. International Journal of Medical Sciences 2010; 7(6):366–77.

Chrubasik JE, Roufogalis BD, Chrubasik S.  Evidence of effectiveness of herbal antiinflammatory drugs in the treatment of painful osteoarthritis and chronic low back pain . Phytother Res. (2007).

Cameron, Melainie, and Sigrun Chrubasik. “Oral herbal therapies for treating osteoarthritis.” The Cochrane database of systematic reviews vol. 5,5 CD002947. 22 May. 2014, doi:10.1002/14651858.CD002947.pub2

Kizhakkedath R. Clinical evaluation of a formulation containing Curcuma Longa and Boswellia Serrata extracts in the management of knee osteoarthritis. Mol Med Rep. 2013;8:1542–1548. doi: 10.3892/mmr.2013.1661. [PubMed] [CrossRef] [Google Scholar]

Haroyan, Armine et al. “Efficacy and safety of curcumin and its combination with boswellic acid in osteoarthritis: a comparative, randomized, double-blind, placebo-controlled study.” BMC complementary and alternative medicine vol. 18,1 7. 9 Jan. 2018, doi:10.1186/s12906-017-2062-z

Yu, Ganpeng et al. “Effectiveness of Boswellia and Boswellia extract for osteoarthritis patients: a systematic review and meta-analysis.” BMC complementary medicine and therapies vol. 20,1 225. 17 Jul. 2020, doi:10.1186/s12906-020-02985-6


References specific to Beetroot:

Vieira de Oliveira G, Nascimento L,  Volino-Souza MA single oral dose of beetroot-based gel does not improve muscle oxygenation parameters, but speeds up handgrip isometric strength recovery in recreational combat sports athletes. Biol Sport. 2020 Mar; 37(1): 93–99.

Larsen FJ, Weitzberg E, Lundberg JO, et al. Effects of dietary nitrate on oxygen cost during exercise. Acta Physiol. 2007;191:59–66.

Balsalobre-Fernardaz C, Romereo-Morelda B, Cupeiro R et al. The effects of beetroot juice supplementation on exercise economy, rating of perceived exertion and running mechanics in elite distance runners: A double-blinded, randomized study. PLos one 2018, 13(7): e0200517.

Baker R.G.; Hayden, M.S.; Ghosh, S. NF-κB, inflammation, and Metabolic Disease. Cell Metab. 
2001, 13, 11–22.

Bailey, S.J.; Winyard, P.; Vanhatalo, A. et al. Dietary nitrate supplementation reduces the O2 cost of low-intensity exercise and enhances tolerance to high-intensity exercise in humans. J. Appl. Physiol. 2009, 107, 1144–1155.

 Bondonno, C.P.; Downey, L.A.; Croft, K.D. et al. The acute effect of flavonoid-rich apples and nitrate-rich spinach on cognitive performance and mood in healthy men and women. Food Funct. 2014, 5, 849–858.


Ormsbee, M.J.; Lox, J.; Arciero, P.J. Beetroot juice and exercise performance. J. Int. Soc. Sports Nutr. 2013, 5, 27–35.


Cermak, N.M.; Gibala, M.J.; van Loon, L.J.C. Nitrate supplementation’s improvement of 10-km time-trial performance in trained cyclists. Int. J. Sports Nutr. Exerc. 2012. 22, 64–71.


Clifford T, Howatson G, Daniel J. West D et al. The Potential Benefits of Red Beetroot Supplementation in Health and Disease Nutrients 2015, 7, 2801-2822.


Das, S.; Williams, D.S.; Das, A.; Kukreja, R.C. Beet root juice promotes apoptosis in oncogenic MDA-MB-231 cells while protecting cardiomyocytes under doxorubicin treatment. J. Exp. Second. Sci. 2013, 2, 1–6.


Hobbs, D.A.; George, T.W.; Lovegrove, J.A. The effects of dietary nitrate on blood pressure and endothelial function: A review of human intervention studies. Nutr. Res. Rev. 2013, 26, 210–222.


Kapadia, G.J.; Azuine, M.A.; Rao, G.S.; Arai, T.; Iida, A.; Tokuda, H. Cytotoxic effect of the red beetroot (Beta vulgaris L.) extract compared to doxorubicin (Adriamycin) in the human prostate (PC-3) and breast (MCF-7) cancer cell lines. Anti -Cancer Agent Med. Chem. 2011, 11, 280–284.


Kapadia, G.J.; Azuine, M.A.; Sridhar, R.; Okuda, Y.; Tsuruta, A.; Ichiishi, E.; Mukainakec, T.; Takasakid, M.; Konoshimad, T.; Nishinoc, H.; et al. Chemoprevention of DMBA-induced UV-B promoted, NOR-1-induced TPA promoted skin carcinogenesis, and DEN-induced phenobarbital promoted liver tumors in mice by extract of beetroot. Pharmacol. Res. 2003, 47, 141–148.


Kim-Shapiro, D.B.; Gladwin, M.T. Mechanisms of nitrite bioactivation. Nitric Oxide 2014, 38, 


Lansley, K.E.; Winyard, P.G.; Bailey, S.J.; Vanhatalo, A.; Wilkerson, D.P.; Blackwell, J.R.; Gilchrist, M.; Benjamin, N.; Jones, A.M. Acute dietary nitrate supplementation improves cycling time trial performance. Med. Sci. Sports Exerc. 2011, 43, 1125–1131.


Lechner, J.F.; Wang, L.S.; Rocha, C.M. et alDrinking water with red beetroot food color antagonizes esophageal 
carcinogenesis in N-nitrosomethylbenzylamine-treated rats. J. Med. Food 2010, 13, 733–739.


Lundberg, J.O.; Weitzberg, E.; Gladwin, M.T. The nitrate-nitrite-nitric oxide pathway in physiology and therapeutics. Nat. Rev. 2008, 7, 156–167.


Ninfali, P.; Angelino, D. Nutritional and functional potential of Beta vulgaris cicla and rubra. Fitoterapia 2013, 89, 188–199.


[Bailey, Cermak, Vanhatalo, Lansley, Ormsbee].


Pietrzkowski, Z.; Nemzer, B.; Spórna, A.; Stalica, P.; Tresher, W.; Keller, R.; Jiminez, R.; Michalowski, T.; Wybraniec, S. Influence of betalin-rich extracts on reduction of discomfort associated with osteoarthritis. New. Med. 2010, 1, 12–17.


Presley, T.D.; Morgan, A.R.; Bechtold, E. et al. Acute effect of a high nitrate diet on brain perfusion in older adults. Nitric Oxide 2011, 24, 34–42.


Raphaeolle L, Santarelli RL, Pierre F, Corpet DE Processed meat and colorectal cancer: a review of epidemiologic and experimental evidence Nutr Cancer. 2008; 60(2): 131–144.


Reddy, M.K.; Alexander-Lindo, R.L.; Nair, M.G. Relative inhibition of lipid peroxidation, 
cyclooxygenase enzymes, and human tumor cell proliferation by natural food colors. J. Agric. Food Chem. 2005, 53, 9268–9273.


Tannenbaum SR, Wishnok JS, Leaf CD. “Inhibition of nitrosamine formation by ascorbic acid”. The American Journal of Clinical Nutrition. 1991, 53 247–250.


Vanhatalo, A.; Bailey, S.J.; Blackwell, J.R.; et al.  Acute and chronic effects of dietary nitrate supplementation on blood pressure and the physiological responses to moderate-intensity and incremental exercise. Am. J. Physiol. -Reg. I 2010, 299, 1121–1131.


Vidal, P.J.; López-Nicolás, J.M.; Gandía-Herrero, F.; García-Carmona, F. Inactivation of lipoxygenase and cyclooxygenase by natural betalains and semi-synthetic analogues. Food. Chem. 2014, 154, 246–254.


Vulić, J.J.; Ćebović, T.N.; Čanadanović-Brunet, J.M.; Ćetković, G.S.; Čanadanović, V.M.; Djilas, S.M.; Tumbas Šaponjac, V.T. In vivo and in vitro antioxidant effects of beetroot pomace extracts. J. Funct. Foods 2014, 6, 168–175.


Wootton-Beard, P.C.; Brandt, K.; Fell, D.; Warner, S.; Ryan, L. Effects of a beetroot juice with high neobetanin content on the early-phase insulin response in healthy volunteers. J. Nutr. Sci. 2011, 3, 1–9.


Lv, X.; Qiu, M.; Chen, D.; Zheng, N.; Jin, Y.; Wu, Z. Apigenin Inhibits Enterovirus 71 Replication Through Suppressing Viral IRES Activity and Modulating Cellular JNK Pathway. Antiviral Research 2014, 109, 30–41.


  1. Mafuvadze B, Benakanakere I, Lopez, F et al Apigenin prevents development of progesterone -induced mammary tumours in rats. Cancer Prevention Research, 2011; 18.


Patel  D, Shukla  S, Gupta  S. Apigenin and cancer chemoprevention: Progress, potential and promise.Int J Oncol 2007;30:233–45.


Birt  D, Hendrich  S, Wang  W. Dietary agents in cancer prevention: Flavonoids and isoflavonoid. Pharmacol Ther 2001;90:157–77.


Gupta  S, Afaq  F, Mukhtar  H Selective growth-inhibitory, cell-cycle deregulatory and apoptotic response of apigenin in normal versus human prostate carcinoma cells. Biochem Biophys Res Commun2001;287:914–20.


Bokyung Sung, Hae Young Chung, Nam Deuk Kim Role of Apigenin in Cancer Prevention via the Induction of Apoptosis and Autophagy J Cancer Prev. 2016 Dec; 21(4): 216–226.


Reference related to Turmeric (Curcumin):


White B, Judkins DZ. Clinical Inquiry. Does turmeric relieve inflammatory conditions? J Fam Pract. 2011 Mar;60(3):155-6.


Curcumin counteracts the proliferative effect of estradiol and induces apoptosis in cervical cancer cells.Singh M, Singh N. Mol Cell Biochem. 2011 Jan; 347(1-2):1-11. Epub 2010 Oct 13.


Lopresti AL, Maes M, Maker GL, Hood SD, Drummond PD (2014) Curcumin for the treatment of major depression a randomised, double- blind placebo controlled study. J Affect Disord 167: 368-375.


Jurenka JS. Anti-inflammatory properties of curcumin,  major constituent of Curcuma longa: a review of preclinical and clinical research. Altern Med Rev. 2009 Jun;14(2):141-53. Review. Erratum in: Altern Med Rev. 2009 Sep;14(3):277.


Funk JL1, Frye JB, Oyarzo JN et al Efficacy and mechanism of action of turmeric supplements in the treatment of experimental arthritis 2006. Arthritis Rheum. 54(11):3452-64.


Kulkarni RR, Patki PS, Jog VP, et al. Treatment of osteoarthritis with a herbomineral formulation: a double-blind, placebo controlled, cross-over study. J Ethnopharmacol 1991;33:91-95.


Nieman DC, Shanely RA, Luo B, Dew D, Meaney MP, Sha W A commercialized dietary supplement alleviates joint pain in community adults: a double-blind, placebo-controlled community trial. Nutr J. 2013 Nov 25; 12(1):154. Epub 2013 Nov 25.


KuptniratsaikulV,ThanakhumtornS,ChinswangwatanakulP,Wattanamongkonsil L, Thamlikitkul V. Efficacy and safety of Curcuma domestica extracts in patients with knee osteoarthritis. Journal of Alternative and Complementary Medicine 2009; 15(8):891–97.


Belcaro G, Cesarone MR, Dugall M et al. Curcumin-phosphatidylcholine complex, for the complementary management of osteoarthritis. Panminerva Med 2010;52:55-62.


Shoba G, Joy D, Joseph T, et al. Influence of piperine on the pharmacokinetics of curcumin in animals and human volunteers. Planta Med 1998;64:353-356.


Lao CD, Ruffin MT 4th, Normolle D. Dose escalation of a curcuminoid formulation. BMC Complement Altern Med. 2006 Mar 17;6:10.


Cheng AL, Hsu CH, Lin JK, et al. Phase I clinical trial of curcumin, a chemopreventive agent, in patients with high-risk or pre-malignant lesions. Anticancer Res. 2001;21(4B):2895-2900.


Sharma RA, Steward WP, Gescher AJ. Pharmacokinetics and pharmacodynamics of curcumin. Adv Exp Med Biol. 2007;595:453-70.


Shah BH, et al (1999). Inhibitory effect of curcumin, on platelet-activating factor through inhibition of thromboxane formation and Ca2+ signaling. Biochem Pharmacol., 58(7): 1167–72.


Davis JM1, Murphy EA, Carmichael MD, et al. Curcumin effects on inflammation and performance recovery following eccentric exercise-induced muscle damage. Am J Physiol Regul Integr Comp Physiol. 2007; 292(6): 2168-73.


Huang WC, Chiu WC, Chuang HL et al. Effect of curcumin supplementation on physiological fatigue and physical performance in mice. Nutrients. 2015 Jan 30;7(2):905-21.


Somasundaram S, Edmund NA, Moore DT, Small GW, Shi YY, Orlowski RZ. Curcumin inhibits chemotherapy-induced apoptosis in models of cancer. Cancer Res. 2002;62(13):3868-75.


Zhang HN, Yu CX, Chen WW and Young CY (2007). Curcumin down regulates gene NKX3.1 in prostate cancer cell lines (LNcaP). Acta Pharmacologica Sinica, 28 (3): 423-430.


Srivastava KC, Bordia A and Verma SK (1995). Curcumin, a major component of food spice turmeric (Curcuma longa) inhibits aggregation and alters eicosanoid metabolism in human blood platelets. Prostaglandins Leukot Essent Fatty Acids, 52(4): 223-227.


Steward WP and Gescher AG (2008). Curcurmin in cancer management: Recent results of analogue design and clinical studies. Molecular Nutrition & Food Research, 52(9): 1005-1009.


Khafif A, Schantz SP, Chou TC and Sacks PG (1998). Quantitation of chemoprotective synergism between green tea extract and curcurmin. Carcinogenesis, 19(3); 419-424.


Sengupta K, Krishnaraju AV, Vishal AA et al. Comparative efficacy and tolerability
of 5-LOXIN® and Aflapin® against osteoarthritis of the knee: a double-blind, randomised, placebo-controlled clinical study. International Journal of Medical Sciences 2010; 7(6):366–77.

Chrubasik JE, Roufogalis BD, Chrubasik S.  Evidence of effectiveness of herbal anti-inflammatory drugs in the treatment of painful osteoarthritis and chronic low back pain . Phytother Res. (2007).


Lupi S, et al Mutagenicity evaluation with Ames test of hydro-alcoholic solution of terpenes . J Prev Med Hyg. (2009)



Reference related to Green tea:


Ota N, Soga S, Shimotoyodome A. Daily consumption of tea catechins improves aerobic capacity in healthy male adults: a randomized double-blind, placebo-controlled, crossover trial. Biosci Biotechnol Biochem. 2016;80(12):2412-2417.

Manning J, Roberts JC. Analysis of catechin content of commercial green tea products. J Herb Pharmacother. 2003;3:19–32. doi: 10.1300/J157v03n03_03.

Jówko E, Długołęcka B, Makaruk B, Cieśliński I. The effect of green tea extract supplementation on exercise- induced oxidative stress parameters in male sprinters. European Journal of Nutrition. 2015;54(5):783-791

Machado ÁS, da Silva W, Souza MA, Carpes FP. Green tea extract preserves neuromuscular activation and muscle damage markers in athletes under cumulative fatigue. Frontiers in physiology 2018;17(9):1137

Cooper R, Morre DJ, Morre DM. Medicinal benefits of green tea: part I. Review of noncancer health benefits. J Altern Complement Med. 2005;11:521–528. doi: 0.1089/acm.2005.11.521

Doss MX, Potta SP, Hescheler J, Sachinidis A. Trapping of growth factors by catechins: a possible therapeutical target for prevention of proliferative diseases. J Nutr Biochem. 2005;16:259–266. doi: 10.1016/j.jnutbio.2004.11.003.

Singh R, Ahmed S, Malemud CJ, Goldberg VM, Haqqi TM. Epigallocatechin-3-gallate selectively inhibits interleukin-1beta-induced activation of mitogen activated protein kinase subgroup c-Jun N-terminal kinase in human osteoarthritis chondrocytes. J Orthop Res. 2003;21:102–109. doi: 10.1016/S0736-0266(02)00089-X.

Ahmed S, Wang N, Lalonde M, Goldberg VM, Haqqi TM. Green tea polyphenol epigallocatechin-3-gallate (EGCG) differentially inhibits interleukin-1 beta-induced expression of matrix metalloproteinase-1 and -13 in human chondrocytes. J Pharmacol Exp Ther. 2004;308:767–773. doi: 10.1124/jpet.103.059220.

Ahmed S, Rahman A, Hasnain A, et al. Green tea polyphenol epigallocatechin-3-gallate inhibits the IL-1 beta-induced activity and expression of cyclooxygenase-2 and nitric oxide synthase-2 in human chondrocytes. Free Radic Biol Med. 2002;33:1097–1105. doi: 10.1016/S0891-5849(02)01004-3.

Ahmed S, Pakozdi A, Koch AE. Regulation of interleukin-1β-induced chemokine production and matrix metalloproteinase 2 activation by epigallocatechin-3-gallate in rheumatoid arthritis synovial fibroblasts. Arthritis Rheum. 2006;54:2393–2401. doi: 10.1002/art.22023.

Adcocks C, Collin P, Buttle DJ. Catechins from green tea (Camellia sinensis) inhibit bovine and human cartilage proteoglycan and type II collagen degradation in vitro. J Nutr. 2002;132:341–346.

Vankemmelbeke MN, Jones GC, Fowles C, Ilic MZ, Handley CJ, Day AJ, Knight CG, Mort JS, Buttle DJ. Selective inhibition of ADAMTS-1, -4 and -5 by catechin gallate esters. Eur J Biochem. 2003;270:2394–2403. doi: 10.1046/j.1432-1033.2003.03607.x.

Goo HC, Hwang YS, Choi YR, Cho HN, Suh H. Development of collagenase-resistant collagen and its interaction with adult human dermal fibroblasts. Biomaterials. 2003;24:5099–5113. doi: 10.1016/S0142-9612(03)00431-9.

Haqqi TM, Anthony DD, Gupta S, Ahmad N, Lee MS, Kumar GK, Mukhtar H. Prevention of collagen-induced arthritis in mice by a polyphenolic fraction from green tea. Proc Natl Acad Sci USA. 1999;96:4524–4529. doi: 10.1073/pnas.96.8.4524.

Salahuddin Ahmed Green tea polyphenol epigallocatechin 3-gallate in arthritis: progress and promise Arthritis Res Ther. 2010; 12(2): 208. 2010.  doi:  10.1186/ar2982

Ogunleye AA, Xue F, Michels KB: Green tea and breast cancer risk of recurrence: A meta-analysis. Breast Cancer Res Treat 119(2):477, 2010

Jatoi A, Ellison N, Burch PA, et al. A phase II trial of green tea in the treatment of patients with androgen independent metastatic prostate carcinoma. Cancer. 2003 Mar 15;97(6):1442-6.

Pisters KM, Newman RA, Coldman B, et al. Phase I trial of oral green tea extract in adult patients with solid tumors. J Clin Oncol. 2001 Mar 15;19(6):1830-8.

Taylor JR and Wilt VM. Probable antagonism of warfarin by green tea. Ann Pharmacother. 1999 Apr;33(4):426-8.

Wu AH, Yu MCl: Tea, hormone-related cancers and endogenous hormone levels. Mol. Nutr. Food Res 50(2):160-169, 2006

Sun CL, Yuan JM, Koh WP, et al: Green tea and cancer risk: The Singapore Chinese Health Study. Carcinogenesis 28(10):2143-2148, 2007


References related to pomegranate:

Kumar D, Basu S, Parija L et al Curcumin and Ellagic acid synergistically induce ROS generation, DNA damage, p53 accumulation and apoptosis in HeLa cervical carcinoma cells. Biomed Pharmacother. 2016;81:31-37. doi: 10.1016/j.biopha.2016.03.037.

Pantuck AJ, Leppert JT, Zomorodian N, et al: Phase II study of pomegranate juice for men with rising PSA following surgery or radiation for prostate cancer. J Urol 173:225–226, 2005

Paller CJ, Ye X, WozniakPJ, et al: A randomised phase II study of pomegranate extract for men with rising PSA following initial therapy for localized prostate cancer. Prostate Cancer and Prostatic Diseases 16:50-55, 2013

Rettig MB, Heber D, An J, et al: Pomegranate extract inhibits androgen independent prostate cancer growth through a nuclear factor-κβ-dependent mechanism. Mol Cancer Ther 7:2662-2671, 2008

Lansky EP, Jiang W, Mo H, et al: Possible synergistic prostate cancer suppression by anatomically discrete pomegranate fractions. Invest New Drugs 23:11-20, 2005

Malik A, Afaq F, Sarfaraz S, et al: Pomegranate fruit juice for chemoprevention and chemotherapy of prostate cancer. Proc Natl Acad Sci USA. 102:14813–14818, 2005

Khan N, Mukhtar H: Pomegranate inhibits growth of primary lung tumors in mice. Cancer Res 67:3475-3482, 2007

Choi C, Liao Y, Wu S, et al: The structure of pomegranate has no hormonal component. Mass Spec Food Chem 96:4, 562, 2006


Overdevest E, Wouters J Kevin H et al ,  Citrus Flavonoid Supplementation Improves Exercise Performance in Trained Athletes. J Sports Sci Med. 2018 Mar; 17(1): 24–30.


Chondroprotective effects of pomegranate juice on monoiodoacetate-induced osteoarthritis of the knee joint of mice. J Nutr Biochem. 2012 Nov;23(11):1367-77.


Shen CL, Smith BJ, Lo DF et al Dietary polyphenols and mechanisms of osteoarthritis Phytother Res. 2010;24(2):182-5.


Wang L, Alcon A, Yuan H, Ho J, Li QJ, Martins-Green M. Cellular and molecular mechanisms of pomegranate juice-induced anti-metastatic effect on prostate cancer cells. Integr Biol (Camb) 2011; 3: 742–754.


Roelofs EJ, Smith-Ryan AE, Trexler ET et al Effects of pomegranate extract on blood flow and vessel diameter after high-intensity exercise in young, healthy adults. Eur J Sport Sci. 2017 Apr; 17(3):317-325.


Torregrosa-García A, Ávila-Gandía V, Luque-Rubia AJ et al. Pomegranate Extract Improves Maximal Performance of Trained Cyclists after an Exhausting Endurance Trial: A Randomised Controlled Trial. Nutrients. 2019 Mar 28; 11(4).


Urbaniak A, Basta P, Ast K, Wołoszyn A, Kuriańska-Wołoszyn J, Latour E, Skarpańska-Stejnborn A. J Int Soc Sports Nutr. 2018 Jul 24; 15(1):35.


Chondroprotective effects of pomegranate juice on monoiodoacetate-induced osteoarthritis of the knee joint of mice. J Nutr Biochem. 2012 Nov;23(11):1367-77.


Shen CL, Smith BJ, Lo DF et al Dietary polyphenols and mechanisms of osteoarthritis Phytother Res. 2010;24(2):182-5.


Wang L, Alcon A, Yuan H, Ho J, Li QJ, Martins-Green M. Cellular and molecular mechanisms of pomegranate juice-induced anti-metastatic effect on prostate cancer cells. Integr Biol (Camb) 2011; 3: 742–754.


Choi C, Kim JK, Choi SH, et al. Identification of steroid hormones in pomegranate (Punica granatum) using HPLC and GC mass spectrometry. Food Chemistry 2006; 96: 562–571.


Hadipour-Jahromy M, Mozaffari-Kermani R. Pomegranate protects subchondral bone and cartilage from arthritis inducing chemicals. Phytother Res. 2010;24(2):182-5.


Hadipour-Jahromy M, Mozaffari-Kermani R. Pomegranate protects subchondral bone and cartilage from arthritis inducing chemicals. Phytother Res. 2010;24(2):182-5.


Trexler E, Smith-Ryan A, Melvin M. Effects of pomegranate extract on blood flow and running time to exhaustion. Appl Physiol Nutr Metab. 2014; 39(9): 1038-42


Other references:


aThomas R, Yang D, Zollaman C. Phytochemicals in Cancer Management. Current Research in Compl and Alt therapy.  2017, 105 (01), pp 2-8.


bThomas R,  Butler E, Macchi F and Williams M. Phytochemicals in cancer prevention and management? BJMP 2015, 8 (2), pp 1-9.


cThomas R, Williams M, Sharma H, et al. A double-blind, placebo-controlled randomised trial evaluating the effect of a polyphenol-rich whole food supplement on PSA progression in men with prostate cancer–the U.K. NCRN Pomi-T study. Prostate Cancer Prostatic Dis. 2014 17(2):180.


Baker J, Horton S, Robertson J et al Nurturing Sport Expertise: Factors Influencing the Development of Elite Athlete. J Sports Sci Med. 2003; 2(1): 1–9.