UNASSIGNED: Engeletin (ENG) is a natural flavonoid compound known for its diverse physiological and pharmacological effects, such as anti-inflammatory, antioxidant, and immunomodulatory properties. It has garnered significant attention as a promising candidate for drug development.
UNASSIGNED: This article aims to comprehensively review the clinical application, pharmacological action, and potential mechanisms of ENG, while exploring its prospects in clinical pharmacology.
UNASSIGNED: We conducted a systematic search of PubMed, Science Direct, Google Scholar, Web of Science, Scopus, and MEDLINE for a thorough review of high-quality articles on the source, extraction, and application of ENG, or the primary active ingredient for improving bodily injuries.
UNASSIGNED: ENG exhibits significant potential in treating a variety of diseases across different systems, attributed to its anti-inflammatory, antioxidant, anti-tumor, and metabolic regulatory activities. These effects are linked to direct or indirect interactions with multiple pathways involving key molecules upstream and downstream.
UNASSIGNED: While ENG shows promise, its development requires further exploration. Future studies should focus on elucidating its mechanisms of action, identifying targets through clinical studies, and optimizing compounds for drug development. These research directions are crucial for advancing the development and application of flavonoids. This review underscores the significant research potential of ENG, paving the way for its application in diverse clinical settings.

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.

The consumption of foods that are rich in phenolic compounds has chemopreventive effects on many cancers, including breast cancer, ovarian cancer, and endometrial cancer. A wide spectrum of their health-promoting properties such as antioxidant, anti-inflammatory, and anticancer activities, has been demonstrated. This paper analyzes the mechanisms of the anticancer action of selected common flavonols, including kemferol, myricetin, quercetin, fisetin, galangin, isorhamnetin, and morin, in preclinical studies, with particular emphasis on in vitro studies in gynecological cancers and breast cancer. In the future, these compounds may find applications in the prevention and treatment of gynecological cancers and breast cancer, but this requires further, more advanced research.

Mono- and poly-O-methylated flavonols and their glycoside derivatives belong to the group of natural plant polyphenols with a wide spectrum of pharmacological activities. These compounds are known for their antioxidant, antimutagenic, hepatoprotective, antidiabetic, and antilipogenic properties. Additionally, they inhibit carcinogenesis and cancer development. Having in mind the multidirectional biological activity of methylated flavonols, we would like to support further study on their health-promoting activities; in this review we summarized the most recent reports on syringetin and some of its structural analogues: laricitrin, ayanin, and isorhamnetin. Natural sources and biological potential of these substances were described based on the latest research papers.

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.

Flavonoids seem to have hormone-like and anti-hormone properties so that the consumption of flavonoids may have potential effects on hormone-related cancers (HRCs), but the findings have been inconsistent so far. This meta-analysis was aimed to explore the association between flavonoids intake and HRCs risk among observational studies.
Qualified articles, published on PubMed, EMBASE, and China National Knowledge Infrastructure (CNKI) from January 1999 to March 2022 and focused on relationships between flavonoids (total, subclass of and individual flavonoids) and HRCs (breast, ovarian, endometrial, thyroid, prostate and testicular cancer), were retrieved for pooled analysis. Random effects models were performed to calculate the pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs). Funnel plots and Begg\'s/Egger\'s test were used to evaluate the publication bias. Subgroup analyses and sensitivity analyses were conducted to explore the origins of heterogeneity.
All included studies were rated as medium or high quality. Higher consumption of flavonols (OR = 0.85, 95% CI: 0.76-0.94), flavones (OR = 0.85, 95% CI: 0.77-0.95) and isoflavones (OR = 0.87, 95% CI: 0.82-0.92) was associated with a decreased risk of women-specific cancers (breast, ovarian and endometrial cancer), while the higher intake of total flavonoids was linked to a significantly elevated risk of prostate cancer (OR = 1.11, 95% CI: 1.02-1.21). A little evidence implied that thyroid cancer risk was augmented with the higher intake of flavones (OR = 1.24, 95% CI: 1.03-1.50) and flavanones (OR = 1.31, 95% CI: 1.09-1.57).
The present study suggests evidence that intake of total flavonoids, flavonols, flavones, flavanones, flavan-3-ols and isoflavones would be associated with a lower or higher risk of HRCs, which perhaps provides guidance for diet guidelines to a certain extent.
This protocol has been registered on PROSPERO with registration number CRD42020200720 .

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.

Flavonoids are an important class of natural polyphenolic compounds reported to exert beneficial effects in cardiovascular and metabolic diseases, cancer, autoimmune and neurological disorders. Flavonoids possess potential antioxidant, anti-inflammatory, antiapoptotic and immuno-modulation properties. Intriguingly, the importance of flavonoids in different neurological disorders is gaining more attention due to the safety, better pharmacokinetic profile and blood-brain barrier penetration, cost-effectiveness and readiness for clinical uses/trials. Many in vitro and in vivo research studies have established the neuroprotective mechanism of flavonoids in the central nervous system (CNS) diseases. The present review summarizes the benefits of various classes of flavonoids (flavones, flavonols, flavanones, anthocyanidins, isoflavones, flavanols), chemical nature, classification, their occurrence and distribution, pharmacokinetics and bioavailability. The manuscript also presents available evidences relating to the role of flavonoids in regulating key signaling pathways such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway, mitogen-activated protein kinase (MAPK) pathway, Janus kinase and signal transducer and activator of transcription proteins (JAK/STAT) pathway, Toll-like receptors (TLR) pathway, nuclear factor erythroid 2-related factor 2 (Nrf2) pathway and cAMP response element-binding protein (CREB) pathway involved in neuroinflammation associated with major neurological disorders. Literature search was conducted using electronic databases like Google Scholar, Scopus, PubMed central, Springer search and Web of science. Chemical structures used in the present analysis were drawn using Chemdraw Professional 15.0 software. This collective information provides comprehensive knowledge on disease pathways and therapeutic benefits of flavonoids in neurological disorders, druggability and future scope for research.