The incidence and mortality rate of atherosclerotic cardiovascular disease (ASCVD) is increasing yearly worldwide. Recently, a growing body of evidence has unveiled the anti-atherosclerotic properties of fisetin, a natural polyphenol compound. In this article, we reviewed the pharmacologic actions of fisetin on experimental atherosclerosis and its protective effects on disease-relevant cell types such as endothelial cells, macrophages, vascular smooth muscle cells, and platelets. Based on its profound cardiovascular actions, fisetin holds potential for clinical translation and could be developed as a potential therapeutic option for atherosclerosis and its related complications. Large-scale randomized clinical trials are warranted to ascertain the safety and efficacy of fisetin in patients with or high risk for ASCVD.

BACKGROUND: Ischemia-reperfusion injury (IRI) is a well-known ailment that can disturb organ function.
OBJECTIVE: This systematic review study investigated fisetin\'s effects and possible mechanisms in attenuating myocardial, cerebral, renal, and hepatic IRIs.
METHODS: This systematic review included studies earlier than Sep 2023 by following the PRISMA statement 2020. After determining inclusion and exclusion criteria and related keywords, bibliographic databases, such as Cochrane Library, PubMed, Web of Science, Embase, and Scopus databases, were used to search the relevant studies. Studies were imported in End- Note X8, and the primary information was recorded in Excel.
RESULTS: Fisetin reduced reactive oxygen species (ROS) generation and upregulated antioxidant enzymes, such as superoxide dismutase (SOD), glutathione (GSH), catalase (CAT), and glutathione peroxidase (GPx), in ischemic tissues. Moreover, fisetin can attenuate oxidative stress by activating phosphoinositide-3-kinase-protein kinase B/Akt (PI3K/Akt) and nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathways. Fisetin has been indicated to prevent the activation of several pro-inflammatory signaling pathways, including NF-κB (Nuclear factor kappa-light-chain-enhancer of activated B cells) and MAPKs (Mitogen-activated protein kinases). It also inhibits the production of pro-inflammatory cytokines and enzymes like tumor necrosis factor-a (TNF-α), inducible-NO synthase (iNOS), cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2), interleukin-1β (IL-1β), IL-1, and IL-6. Fisetin attenuates IRI by improving mitochondrial function, anti-apoptotic effects, promoting autophagy, and preserving tissues from histological changes induced by IRIs.
CONCLUSIONS: Fisetin, by antioxidant, anti-inflammatory, mitochondrial protection, promoting autophagy, and anti-apoptotic properties, can reduce cell injury due to myocardial, cerebral renal, and hepatic IRIs without any significant side effects.

As secondary plant metabolites, polyphenols are abundant in fruits and vegetables. They are in high demand because of their many health benefits. However, their low bioavailability makes them complex compounds to use for therapeutic purposes. Due to the limited solubility of phytocompounds, dietary supplements made from them may only be partially effective. Such molecules include fisetin, found in strawberries, and have shown great promise in treating Alzheimer\'s disease and cancer. Unfortunately, because of their limited water solubility, low absorption, and poor bioavailability, the assistance of nanotechnology is required to allow them to fulfil their potential fully. Here, we provide evidence that nanodelivery methods and structure modifications can improve fisetin bioavailability, which is linked to improvements in therapeutic efficacy. An open question remains as to which nanocarrier should be chosen to meet the abovementioned requirements and be able to enhance fisetin\'s therapeutic potential to treat a particular disease.

Neurological diseases place a substantial burden on public health and have a serious impact on the quality of life of patients. Despite the multifaceted pathological process involved in the occurrence and development of these neurological diseases, each disease has its own unique pathological characteristics and underlying molecular mechanisms which trigger their onset. Thus, it is unlikely to achieve effective treatment of neurological diseases by means of a single approach. To this end, we reason that it is pivotal to seek an efficient strategy that implements multitherapeutic targeting and addresses the multifaceted pathological process to overcome the complex issues related to neural dysfunction. In recent years, natural medicinal plant-derived monomers have received extensive attention as new neuroprotective agents for treatment of neurological disorders. Fisetin, a flavonoid, has emerged as a novel potential molecule that enhances neural protection and reverses cognitive abnormalities. The neuroprotective effects of fisetin are attributed to its multifaceted biological activity and multiple therapeutic mechanisms associated with different neurological disorders. In this review article, we summarize recent research progression regarding the pharmacological effects of fisetin in treating several neurological diseases and the potential mechanisms.

Cancer is a disease in which repeated rounds of mutations cause uncontrolled growth of cells, which prospers at the expense of their neighbor cells and then eventually leads to the destruction of the whole cellular community. Chemopreventive drugs either prevent DNA damage, which results in malignancy, or they stop or reverse the division of premalignant cells with DNA damage, which inhibits the growth of cancer. There is an obvious need for an alternate strategy given the ongoing rise in cancer incidence, the ineffectiveness of traditional chemotherapies to control cancer, and the excessive toxicity of chemotherapies. From antiquity to date, the saga of the usage of plants as medicine has been the mainstay among people worldwide. In recent years, extensive studies have been conducted on medicinal plants, spices, and nutraceuticals, as these have gained much popularity in reducing the risk of several cancer types in humans. Extensive studies on cell culture systems and animal models have demonstrated that various medicinal plants and nutraceuticals from various natural resources and their products, such as major polyphenolic constituents, flavones, flavonoids, antioxidants, etc, provide considerable protection against many cancer types. As shown in the literatures, the major aim of studies conducted is to develop preventive/therapeutic agents which can induce apoptosis in cancer cells without affecting normal cells. Projects are going on worldwide to find better ways to eradicate the disease. The study of phytomedicines has shed new light on this topic as research to date has proven that they have antiproliferative and apoptotic capabilities that will aid in the development of novel cancer prevention options. Dietary substances, such as Baicalein, Fisetin, and Biochanin A have shown that they have an inhibitory effect on cancer cells, suggesting that they may work as chemopreventive agents. This review discusses the chemopreventive and anticancer mechanisms of such reported natural compounds.

As the worldwide population progresses in age, there is an increasing need for effective treatments for age-associated musculoskeletal conditions such as osteoporosis and osteoarthritis (OA). Fisetin, a natural flavonoid, has garnered attention as a promising pharmaceutical option for treating or delaying the progression of osteoporosis and OA. However, there is no systematic review of the effects of fisetin on bone and cartilage. The aim of this review is to report the latest evidence on the effects of fisetin on bone and cartilage, with a focus on clinical significance. The PubMed, Embase, and Cochrane Library databases were searched up to December 9th 2021 to evaluate the effects of fisetin on bone and cartilage in in vitro studies and in vivo preclinical animal studies. The risk of bias, quality, study design, sample characteristics, dose and duration of fisetin treatment, and outcomes of the 13 eligible studies were analyzed in this systematic review. Qualitative evaluation was conducted for each study due to differences in animal species, cell type, created disease model, dose and duration of fisetin treatment, and time between intervention and assessment among the eligible studies. The beneficial effects of fisetin on osteoporosis have been demonstrated in in vitro and in vivo preclinical studies across animal species. Similarly, the beneficial effects of fisetin on OA have been demonstrated in in vivo preclinical animal studies, but the reports on OA are still limited. Fisetin, a natural supplement can be use in orthobiologics treatment, as adjuvant to orthopaedic surgery, to improve clinical outcome.

Diet plays a crucial role in homeostasis maintenance. Plants and spices containing flavonoids have been widely used in traditional medicine for thousands of years. Flavonols present in our diet may prevent cancer initiation, promotion and progression by modulating important enzymes and receptors in signal transduction pathways related to proliferation, differentiation, apoptosis, inflammation, angiogenesis, metastasis and reversal of multidrug resistance. The anticancer activity of fisetin has been widely documented in numerous in vitro and in vivo studies. This review summarizes the worldwide, evidence-based research on the activity of fisetin toward various types of cancerous conditions, while describing the chemopreventive and therapeutic effects, molecular targets and mechanisms that contribute to the observed anticancer activity of fisetin. In addition, this review synthesized the results from preclinical studies on the use of fisetin as an anticancer agent. Based on the available literature, it might be suggested that fisetin has a bioactive potential to become a complementary drug in the prevention and treatment of cancerous conditions. However, more in-depth research is required to validate current data, so that this compound or its derivatives can enter the clinical trial phase.

BACKGROUND: The primary therapeutic strategy in managing ischemic heart diseases is to restore the perfusion of the myocardial ischemic area by surgical methods that often result in an unavoidable injury called ischemia-reperfusion injury (IR). Fisetin is an effective flavonoid with antioxidant and anti-inflammatory properties, proven to be cardioprotective against IR injury in both in-vitro and invivo models, apart from its promising health benefits against cancer, diabetes, and neurodegenerative ailments.
OBJECTIVE: The potential of fisetin in attenuating myocardial IR is inconclusive as the effectiveness of fisetin needs more understanding in terms of its possible target sites and underlying different mechanisms. Considering the surge in recent scientific interests in fisetin as a pharmacological agent, this review not only updates the existing preclinical and clinical studies with fisetin and its underlying mechanisms but also summarizes its possible targets during IR protection.
METHODS: We performed a literature survey using search engines Pubmed, PMC, Science direct, Google, and research gate published across the years 2006-2021. The relevant studies were extracted from the databases with the combinations of the following keywords and summarized: myocardial ischemia-reperfusion injury, natural products, flavonoid, fisetin, PI3K, JAK-STAT, Nrf2, PKC, JNK, autophagy.
RESULTS: Fisetin is reported to be effective in attenuating IR injury by delaying the clotting time, preserving the mitochondrial function, reducing oxidative stress, and inhibiting GSK 3β. But it failed to protect diseased cardiomyocytes challenged to IR. As discussed in the current review, fisetin not only acts as a conventional antioxidant and anti-inflammatory agent to exert its biological effect but may also exert modulatory action on the cellular metabolism and adaptation via direct action on various signalling pathways that comprise PI3K, JAK-STAT, Nrf2, PKC, JNK, and autophagy. Moreover, the dosage of fisetin and co-morbidities like diabetes and obesity are found to be detrimental factors for cardioprotection.
CONCLUSIONS: For further evaluation and smooth clinical translation of the fisetin molecule in IR treatment, researchers should pay close attention to the potential of fisetin to possibly alter the key cardioprotective pathways and dosage, as the efficacy of fisetin is tissue and cell type-specific and varies with different doses.

Prostate and bladder cancer represent the two most frequently diagnosed genito-urinary malignancies. Diet has been implicated in both prostate and bladder cancer. Given their prolonged latency and high prevalence rates, both prostate and bladder cancer represent attractive candidates for dietary preventive measures, including the use of nutritional supplements. Flavonols, a class of flavonoids, are commonly found in fruit and vegetables and are known for their protective effect against diabetes and cardiovascular diseases. Furthermore, a higher dietary intake of flavonols was associated with a lower risk of both bladder and prostate cancer in epidemiological studies. In this systematic review, we gathered all available evidence supporting the anti-cancer potential of selected flavonols (kaempferol, fisetin and myricetin) against bladder and prostate cancer. A total of 21, 15 and 7 pre-clinical articles on bladder or prostate cancer reporting on kaempferol, fisetin and myricetin, respectively, were found, while more limited evidence was available from animal models and epidemiological studies or clinical trials. In conclusion, the available evidence supports the potential use of these flavonols in prostate and bladder cancer, with a low expected toxicity, thus providing the rationale for clinical trials that explore dosing, settings for clinical use as well as their use in combination with other pharmacological and non-pharmacological interventions.

Aging and the emergence of age-associated illnesses are one of the major challenges of our present society. Alzheimer\'s disease (AD) is closely associated with aging and is defined by increasing memory loss and severe dementia. Currently, there are no therapy options available that halt AD progression. This work investigates three hallmarks of the disease (autophagy, neuroinflammation, and senescence) and systematically analyzes if there is a beneficial effect from three substances derived from food sources, the so called \"nutraceuticals\" epigallocatechin gallate, fisetin, and spermidine, on these hallmarks. The results imply a positive outlook for the reviewed substances to qualify as a novel treatment option for AD. A combination of nutraceutical substances and other preventive measures could have significant clinical impact in a multi-layered therapy approach to counter AD.