 pathways and suppression of anti-apoptotic signals, which further shows the benefits of the use of fistein as a therapeutic agent in prostate cancer.
Breast cancer deaths rank highest among all cancer-related deaths in women. While there have been more recent breakthroughs in treatment and preventative options, these often only target certain patients, and certain groups do not benefit, particularly those with triple-negative breast cancer and those with a significant cancer cell burden. As with other cancer lines, the PI3K/Akt/mTOR pathway appears to have a significant impact on the development of malignant forms of breast cancer. Fisetin, through regulation at various levels of these pathways, induces cancer cell suicide, reduces the viability of cancer cells and inhibits the proliferative activity of mutant cells (7), which may offer an alternative therapeutic option to women who don’t benefit from currently offered therapies.
Another common risk of cancer is related to the skin changes due to UV irradiation. In a 2015 study on mice exposed to UVB radiation, fisetin was found to block chemical mediators of inflammation and reduce the capacity of inflammatory cells to infiltrate into exposed sites. The topical fisetin treatment used in this research also shown to have the potential to decrease DNA damage within the skin cells exposed to UVB, which may have antitumor effects (8).
As an antioxidant, fisetin is able to help the body to manage the effect that free radicals may have on fats, amino acids, carbohydrates and nucleic acids, preventing their oxidation from damaging other tissues.
One of the most significant is fisetin’s binding capacity to phospholipids. Phospholipids have a polar head and hydrophobic tail, with a region in between that allows for binding of other compounds. It’s this binding region that is easily available for free radicals to attach, which causes an unstable phospholipid molecule, leaving it vulnerable to oxidation. Fisetin is also more likely to bind to this site, which prevents the binding of free radicals.
Lipid peroxidation is one of the greatest risks that leads to coronary artery disease, particularly as a result of the oxidation of low density lipoproteins (LDL). It’s this peroxidation of LDL that causes it to become sticky, leading to it accumulating along the endothelial cells of the artery walls. This sticky accumulation of cholesterol and other immune cells causes atherosclerosis that, when it is significant enough, can cause complete occlusion of the artery, which stops blood flow and can result in an ischaemic heart attack.
Research shows that fistein may protect from endothelial dysfunction as a result of oxidation of LDL cholesterol via the extracellular signal regulated kinase-5 (Erk-5) pathway, which is a transcriptional activator and regulator of endothelial cells (ECs) homeostasis. Upregulation of this pathway improves endothelial markers which reduces endothelial dysfunction (9), it reduces the effects of inflammation and offers overall cardioprotective benefits.
Fisetin can protect from cardiovascular events in another way: reducing the serious effects that a heart attack may have on the overall function of the cardiovascular system. In a study on rats, researchers fed one group of them with fisetin before inducing a heart attack over a span of 2 days with a toxic chemical. When researchers assessed the damage to their cardiovascular system, it was found that fisetin had normalised all biochemical parameters that were supposed to be abnormal following the inflammatory and oxidative stress that the heart attack and chemical had caused. The conclusion of the study was thus that it was the role of fistein in stabilizing the free radical membrane activity due to its potent antioxidant properties (10).
Treatment of heart attack typically takes the approach of rapidly increasing oxygenation of the tissue that has been affected by ischaemia due to the infarction. While this approach is essential to prevent necrosis of the tissue, there is a high risk of development of free radicals (reactive oxygen species), which further exacerbates the tissue injury. It leads to a phenomenon called ischaemic reperfusion injury.
A study to evaluate the treatment for both MI and IRI in zebrafish indicated that fisetin may reduce the serious effects of both. In a subsequent study, this time conducted on mammalian cardiac cells, fisetin enhanced the activity of cardiac tissue that had been affected by the infarction, it protected against DNA damage by reactive oxygen species and overall prevented cell suicide. The researchers thus concluded that clinical trials should be conducted as a means to evaluate these potential therapeutic properties of fisetin in humans (11).
Fisetin has been shown to improve the risk of neuronal cell death as a result of increased cellular stress. This has serious therapeutic implications in brain health as it may improve neurotrophic activity, which has an influence on learning and memory. A study conducted in rats showed that by activating specific signalling pathways within the central nervous system, fisetin could be useful in treating CNS disorders via regulating of the ERK and cAMP pathways. Fisetin improves long-term potentiation of neural pathways in the hippocampal areas of rats, which enhances their object recognition and thus was concluded to facilitate learning and memory (12).
One of the areas of interest in the use of fisetin is in its ability to reduce the rate of age-related cognitive decline. Fisetin has been found across varying cell lines to prevent neuronal dysfunction and preserve brain health in different species. This may have serious implications in the treatment of some of the most common neurological diseases of our time, including Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, stroke, depression and even the neurological implications associated with diabetes.
Fisetin has been researched in its ability to influence learning and memory, and with Alzheimer’s disease (AD) being one of the most common forms of dementia affecting cognitive function, the role of fisetin is a critical one in the effects it may have on possibly the most devastating neurological diseases of the 21st century. Current therapies for AD provide only supportive effects, with moderate improvements in memory, however, without effect on the progression of the disease (13). Also, due to the complex nature of the disease, and multiple dysfunctional pathways that are involved in its progression, it is difficult for one therapeutic strategy to be developed with a single target in mind. Natural compounds, such as fisetin, however, which have an array of biological actions, may act on many of the pathways and so, are proposed as having a greater impact on both the prevention and progression of the disease.
Fisetin has been tested in mice to determine whether oral administration may change the pathological processes associated with AD, including those affecting behaviour. While there was no effect on physiologically normal mice when they were provided with finestin, those that had AD and received the finestin intervention behaved almost indistinguishable from the normal mice. When recall was tested, the fisetin-fed AD mice also showed clear improvement in memory.
When tested in 12 months, these same finestin-fed AD mice performed with continued indistinction from the physiologically normal mice, which included reduced social anxiety, showing both improved cognition and neuropsychiatric behaviours (14).
While old age is the greatest risk factor for Alheimer’s disease, there are additional factors that need to be considered as influencing the overall risk of AD development. One environmental factor, exposure to the heavy metal lead, which is widespread in the environment, may damage the nervous system and result in cognitive deficits that are as a result of inflammation, oxidative stress and neuronal cell apoptosis. Lead has been found to act via the AMPK/SIRT1 pathway, modulating the activation of its response, which results in neuroinflammation.
Fisetin may attenuate the effects of lead-induced deficits in learning and memory. When tested in mice, compared to the control group, fisetin-fed animals who had been exposed to lead improved behaviors and showed a significant reduction in the learning and memory deficits brought about by lead exposure. Inflammatory levels were lower in the fisetin-fed mice, with notable differences in the production of inflammatory cytokines in the treatment group. The expression of NEP, a protein that helps to remove AB proteins that accumulate, was severely decreased in the control group of lead-exposed mice, however, in the fisetin-treated mice, expression was far higher (15).
Fisetin also reduced apoptosis of neuronal tissue as a result of lead exposure, and there was significantly lower toxicity noticed in the brains of the treatment group, with reduced production of tau and AB-protein accumulation and deposition.
Fistein may also provide a therapeutic target for depression. Studies in two mouse models shows that during behavioral tests, fisetin may inhibit immobility time. In addition, higher doses of fisetin attenuated the effects of induced hypothermia and improved the release of serotonin and noradrenaline, which had antidepressant-like effects on the animals (16).
One of the major concerns for stroke is neuronal cell death as a result of increased oxidative stress in the brain that most commonly develops in conjunction with arteriosclerosis. Fisetin may reduce oxidative damage owing to its antioxidant activity, which reduces the behavioural deficits that are common following a stroke.
One of the most common degenerative diseases associated with ageing is osteoarthritis (OA). It is widely associated with inflammation, in particular, production of the IL-1b inflammatory compound, and fisetin has been shown to possess anti-inflammatory effects.
In a 2017 study in mice with OA, fisetin was either given on its own or with a combined inhibitor of SIRT1, called sirtinol. Not only did the intervention of fisetin on its own inhibit the production of IL-1b, it was determined that a wide variety of other inflammatory molecules were also inhibited at the same time. With fisetin inhibiting IL-1b, there was also a marked decrease in the degradation of collagen, where collagen loss is a critical part of the disease etiology of OA.
In a 2019 study, the aim was to evaluate the effect of fistein on the progression of arthritis induced by an adjuvant in rats and to determine the mechanisms involved in immunomodulation of the disease. Adjuvant induced arthritis causes paw swelling and arthritic effects in the animals. Both lipid peroxidation