Fisetin alleviates cerebral ischemia/reperfusion injury by regulating Sirt1/Foxc1/Ubqln1 pathway-mediated proteostasis.

BACKGROUND: Cerebral ischemia/reperfusion injury (IRI) is pathologically associated with protein damage. The flavonoid fisetin has good therapeutic effects on cerebral IRI. However, the role of fisetin in regulating protein damage during cerebral IRI development remains unclear. This study investigated the pharmacological effects of fisetin on protein damage during cerebral IRI progression and defined the underlying mechanism of action. METHODS: In vivo and in vitro models of cerebral IRI were established by middle cerebral artery occlusion/reperfusion (MACO/R) and oxygen-glucose deprivation/reperfusion (OGD/R) treatment, respectively. Triphenyl tetrazolium chloride staining was performed to detect cerebral infarct size, and the modified neurologic severity score was used to examine neurological deficits. LDH activity and protein damage were assessed using kits. HT22 cell vitality and apoptosis were examined using CCK-8 assay and TUNEL staining, respectively. Interactions between Foxc1, Ubqln1, Sirt1, and Ezh2 were analyzed using CoIP, ChIP and/or dual-luciferase reporter gene assays. RESULTS: Fisetin alleviated protein damage and ubiquitinated protein aggregation and neuronal death caused by MCAO/R and OGD/R. Ubqln1 knockdown abrogated the inhibitory effect of fisetin on OGD/R-induced protein damage, ubiquitinated protein aggregation, and neuronal death in HT22 cells. Further experiments demonstrated that Foxc1 functions as a transcriptional activator of Ubqln1 and that Sirt1 promotes Foxc1 expression by deacetylating Ezh2 and inhibiting its activity. Furthermore, Sirt1 knockdown abrogated fisetin-mediated biological effects on OGD/R-treated HT22 cells. CONCLUSION: Fisetin improved proteostasis during cerebral IRI by regulating the Sirt1/Foxc1/Ubqln1 signaling axis. Our findings strongly suggest that fisetin-mediated inhibition of protein damage after ischemic stroke is a part of the mechanism through which fisetin is neuroprotective in cerebral IRI.

Genotoxic and Cytotoxic Activity of Fisetin on Glioblastoma Cells.

BACKGROUND/AIM: Fisetin is a yellow-coloring flavonoid that can be found in a wide variety of plants, vegetables, and fruits, such as strawberries, apples, and grapes. It has been shown to have biological activity by targeting different pathways regulating survival and death and to bear antioxidant and anti-inflammatory activity. Fisetin was shown to be cytotoxic on different cancer cell lines and has the ability to kill therapy-induced senescent cancer cells. The aim of the study was to investigate the DNA damaging and cytotoxic potential of fisetin and its ability to enhance the killing effect of temozolomide on glioblastoma cells. MATERIALS AND METHODS: We used LN229 glioblastoma cells and measured survival and apoptosis by flow cytometry, DNA strand breaks by the alkaline comet and γH2AX assay, and the DNA damage response by western blot analysis. RESULTS: Fisetin was cytotoxic on glioblastoma cells, inducing apoptosis. In the dose range of 40-80 µM it also induced DNA damage, as measured by the alkaline comet and γH2AX assay, and triggered DNA damage response, as revealed by p53 activation. Furthermore, fisetin enhanced the genotoxic effect of methyl methanesulfonate, presumably due to inhibition of DNA repair processes. When administered together with temozolomide, the first-line therapeutic for glioblastoma, it enhanced cell death, reduced the yield of senescent cells following treatment and exhibited senolytic activity on glioblastoma cells. CONCLUSION: Data show that high-dose fisetin has a genotoxic potential and suggest that, harnessing the cytotoxic and senolytic activity of the flavonoid, it may enhance the effect of anticancer drugs and eliminate therapy-induced senescent cells. Therefore, it may be useful for adjuvant cancer therapy, including glioblastoma, which is worth to be studied in clinical trials.

Effects of Nanoparticle-Mediated Dihydromyricetin to Diabetic Wounds: An In Vivo Study.

Diabetic wound is one of the serious complications of diabetes, and the wound is persistent and easily recurring, which seriously endangers the health and life of patients. How to effectively promote the healing of diabetic wounds has been a hot spot and difficult area of clinical research. Some previous studies have shown that dihydromyricetin has the effects of regulating blood glucose, controlling the severity, and inhibiting scarring. In the present study, we used polylactic-co-glycolic acid nanoparticles as a carrier to load dihydromyricetin to make drug-loaded nanoparticles and applied them dropwise (200 µL) to diabetic mice wounds by topical application to observe the healing and scar formation of diabetic wounds. We found that the healing rate of the diabetic mice was faster and the scar formation was less obvious. In addition, the elevated blood glucose level and weight loss of the mice in the treatment group were also reduced. Therefore, nanoparticle-mediated dihydromyricetin may be an effective treatment for diabetic wounds.

A novel flavonol-polysaccharide from Tamarix chinensis alleviates influenza A virus-induced acute lung injury. Evidences for its mechanism of action.

BACKGROUND: Tamarix chinensis Lour. is a Chinese medicine used for treating inflammation-related diseases and its crude polysaccharides (MBAP90) exhibited significant anticomplement activities in vitro. PURPOSE: To obtain anticomplement homogenous polysaccharides from MBAP90 and explore its therapeutic effects and potential mechanism on influenza A virus (IAV)-induced acute lung injury (ALI). METHODS: Anticomplement activity-guided fractionation of the water-soluble crude polysaccharides from the leaves and twigs of T. chinensis were performed by diethylaminoethyl-52 (DEAE-52) cellulose and gel permeation columns to yield a homogeneous polysaccharide MBAP-5, which was further characterized using ultra-high-performance liquid chromatography-ion trap tandem mass spectrometry (UPLC-IT-MS) and nuclear magnetic resonance (NMR) analysis. In vitro, the anticomplement activity of MBAP-5 through classical pathway was measured using a hemolytic test. The therapeutic effects of MBAP-5 on ALI were evaluated in H1N1-infected mice. H&E staining, enzyme linked immunosorbent assay (ELISA), immunohistochemistry, and western blot were used to systematically access lung histomorphology, inflammatory cytokines, degree of complement component 3c, 5aR, and 5b-9 (C3c, C5aR, and C5b-9) deposition, and inflammasome signaling pathway protein expressions in lung tissues. RESULTS: MBAP-5 was a novel flavonol-polysaccharide with the molecular weight (Mw) of 153.6 kDa. Its structure was characterized to process a backbone of →4)-α-D-GlcpA-(1→, →6)-α-D-Glcp-(1→, →3,4)-α-D-Glcp-(1→, →3,4,6)-α-D-Glcp-(1→, and →4,6)-ß-D-Glcp-(1→, as well as branches of α-L-Araf-(1→ and ß-D-Galp-(1→. Particularly, O-3 of →3,4,6)-α-D-Glcp-(1→ was substituted by quercetin. In vitro assay showed that MBAP-5 had a potent anticomplement activity with a CH50 value of 102 ± 4 µg/ml. Oral administration of MBAP-5 (50 and 100 mg/kg) effectively attenuated the H1N1-induced pulmonary injury in vivo by reducing pulmonary edema, virus replication, and inflammatory responses. Mechanistically, MBAP-5 inhibited the striking deposition and contents of complement activation products (C3c, C5aR, and C5b-9) in the lung. Toll-like receptor 4 (TLR4) /transcription factor nuclear factor κB (NF-κB) signaling pathway was constrained by MBAP-5 treatment. In addition, MBAP-5 could suppress activation of the inflammasome pathways, including Nod-like receptor pyrin domain 3 (NLRP3), cysteinyl aspartate specific proteinase-1/12 (caspase-1/12), apoptosis­associated speck­like protein (ASC), gasdermin D (GSDMD), interleukin (IL)-1ß, and IL-18 expressions. CONCLUSIONS: A novel flavonol-polysaccharide MBAP-5 isolated from T. chinensis demonstrated a therapeutic effect against ALI induced by IAV attack. The mechanism might be associated with inhibition of complement system and inflammasome pathways activation.

Fisetin ameliorates fibrotic kidney disease in mice via inhibiting ACSL4-mediated tubular ferroptosis.

Kidney fibrosis is the hallmark of chronic kidney disease (CKD) progression, whereas no effective anti-fibrotic therapies exist. Recent evidence has shown that tubular ferroptosis contributes to the pathogenesis of CKD with persistent proinflammatory and profibrotic responses. We previously reported that natural flavonol fisetin alleviated septic acute kidney injury and protected against hyperuricemic nephropathy in mice. In this study, we investigated the therapeutic effects of fisetin against fibrotic kidney disease and the underlying mechanisms. We established adenine diet-induced and unilateral ureteral obstruction (UUO)-induced CKD models in adult male mice. The two types of mice were administered fisetin (50 or 100 mg·kg-1·d-1, i.g.) for 3 weeks or 7 days, respectively. At the end of the experiments, the mice were euthanized, and blood and kidneys were gathered for analyzes. We showed that fisetin administration significantly ameliorated tubular injury, inflammation, and tubulointerstitial fibrosis in the two types of CKD mice. In mouse renal tubular epithelial (TCMK-1) cells, treatment with fisetin (20 µM) significantly suppressed adenine- or TGF-ß1-induced inflammatory responses and fibrogenesis, and improved cell viability. By quantitative real-time PCR analysis of ferroptosis-related genes, we demonstrated that fisetin treatment inhibited ferroptosis in the kidneys of CKD mice as well as in injured TCMK-1 cells, as evidenced by decreased ACSL4, COX2, and HMGB1, and increased GPX4. Fisetin treatment effectively restored ultrastructural abnormalities of mitochondrial morphology and restored the elevated iron, the reduced GSH and GSH/GSSG as well as the increased lipid peroxide MDA in the kidneys of CKD mice. Notably, abnormally high expression of the ferroptosis key marker ACSL4 was verified in the renal tubules of CKD patients (IgAN, MN, FSGS, LN, and DN) as well as adenine- or UUO-induced CKD mice, and in injured TCMK-1 cells. In adenine- and TGF-ß1-treated TCMK-1 cells, ACSL4 knockdown inhibited tubular ferroptosis, while ACSL4 overexpression blocked the anti-ferroptotic effect of fisetin and reversed the cytoprotective, anti-inflammatory, and anti-fibrotic effects of fisetin. In summary, we reveal a novel aspect of the nephroprotective effect of fisetin, i.e. inhibiting ACSL4-mediated tubular ferroptosis against fibrotic kidney diseases.

Fisetin suppresses ferroptosis through Nrf2 and attenuates intervertebral disc degeneration in rats.

Low back pain, primarily caused by intervertebral disc degeneration (IVDD), lacks effective pharmacological treatments. Oxidative stress has been identified as a significant contributor to IVDD. This study aims to establish an in vitro model of IVDD induced by oxidative stress and identify potential therapeutic agents and their underlying mechanisms. By screening the natural product library, fisetin emerged as the most promising compound in suppressing cell death induced by oxidative stress in nucleus pulposus cells (NPCs). Furthermore, our investigation revealed that the cell death induced by oxidative stress was predominantly associated with ferroptosis, and fisetin demonstrated the ability to inhibit ferroptosis in NPCs. Mechanistic exploration suggested that the impact of fisetin on ferroptosis may be mediated through the Nrf2/HO-1 (Nuclear factor erythroid 2-related factor 2/heme oxygenase-1) axis. Notably, the in vivo study demonstrated that fisetin could alleviate IVDD in rats. These findings highlight fisetin as a potential therapeutic option for IVDD and implicate the involvement of the Nrf2/HO-1 pathway in its mechanism of action.

Role of Fisetin in Selected Malignant Neoplasms in Women.

A promising therapeutic window and cost-effectiveness are just two of the potential advantages of using naturally derived drugs. Fisetin (3,3',4',7-tetrahydroxyflavone) is a natural flavonoid of the flavonol group, commonly found in fruit and vegetables. In recent years, fisetin has gained wide attention across the scientific community because of its broad spectrum of pharmacological properties, including cytotoxic activity against most abundant cancers. By stimulating or inhibiting selected molecular targets or biochemical processes, fisetin could affect the reduction of metastasis or cancer progression, which indicates its chemotherapeutic or chemopreventive role. In this review, we have summarized the results of studies on the anticancer effects of fisetin on selected female malignancies, both in in vitro and in vivo tests, i.e., breast, cervical, and ovarian cancer, published over the past two decades. Until now, no article dedicated exclusively to the action of fisetin on female malignancies has appeared. This review also describes a growing number of nanodelivery systems designed to improve the bioavailability and solubility of this natural compound. The reported low toxicity and activity of fisetin on cancer cells indicate its valuable potential, but large-scale clinical trials are urgently needed to assess real chemotherapeutic efficacy of this flavonoid.

Research progress of dihydromyricetin in the treatment of diabetes mellitus.

Diabetic Mellitus (DM), a chronic metabolic disorder disease characterized by hyperglycemia, is mainly caused by the absolute or relative deficiency of insulin secretion or decreased insulin sensitivity in target tissue cells. Dihydromyricetin (DMY) is a flavonoid compound of dihydroflavonol that widely exists in Ampelopsis grossedentata. This review aims to summarize the research progress of DMY in the treatment of DM. A detailed summary of related signaling induced by DMY are discussed. Increasing evidence implicates that DMY display hypoglycemic effects in DM via improving glucose and lipid metabolism, attenuating inflammatory responses, and reducing oxidative stress, with the signal transduction pathways underlying the regulation of AMPK or mTOR/autophagy, and relevant downstream cascades, including PGC-1α/SIRT3, MEK/ERK, and PI3K/Akt signal pathways. Hence, the mechanisms underlying the therapeutic implications of DMY in DM are still obscure. In this review, following with a brief introduction of the absorption, metabolism, distribution, and excretion characteristics of DMY, we summarized the current pharmacological developments of DMY as well as possible molecular mechanisms in the treatment of DM, aiming to push the understanding about the protective role of DMY as well as its preclinical assessment of novel application.

Therapeutic Potential and Molecular Mechanisms of the Multitargeted Flavonoid Fisetin.

Flavonoids effectively treat cancer, inflammatory disorders (cardiovascular and nervous systems), and oxidative stress. Fisetin, derived from fruits and vegetables, suppresses cancer growth by altering cell cycle parameters that lead to cell death and angiogenesis without affecting healthy cells. Clinical trials are needed in humans to prove the effectiveness of this treatment for a wide range of cancers. According to the results of this study, fisetin can be used to prevent and treat a variety of cancers. Despite early detection and treatment advances, cancer is the leading cause of death worldwide. We must take proactive steps to reduce the risk of cancer. The natural flavonoid fisetin has pharmacological properties that suppress cancer growth. This review focuses on the potential drug use of fisetin, which has been extensively explored for its cancer-fighting ability and other pharmacological activities such as diabetes, COVID-19, obesity, allergy, neurological, and bone disorders. Researchers have focused on the molecular function of fisetin. In this review, we have highlighted the biological activities against chronic disorders, including cancer, metabolic illnesses, and degenerative illnesses, of the dietary components of fisetin.

Fisetin derivatives exhibit enhanced anti-inflammatory activity and modulation of endoplasmic reticulum stress.

Inflammation and endoplasmic reticulum (ER) stress are often hand in hand in the context of chronic disease. Both are activated upon perceived disturbances in homeostasis, being deleterious when intensely or chronically activated. Fisetin (FST) is a dietary flavonol that is known to possess multiple relevant bioactivities, raising the question of its potential health benefits and even its use in novel pharmacological approaches against ER stress and inflammation. To attain this prospect, some limitations to this molecule, namely its poor bioavailability and solubility, must be addressed. In an attempt to improve the biological properties of the parent molecule, we have synthesized a set of FST derivatives. These new molecules were tested along with the original compound for their ability to mitigate the activation of the signaling pathways underlying inflammation and ER stress. By reducing LPS-induced nuclear factor-kappa B (NF-κB) activation, cytokine release, inflammasome activation and reactive oxygen species (ROS) generation, FST has proven to be effective against the onset of inflammation. The molecule also decreases the activation of the unfolded protein response (UPR), as evidenced by the reduced expression of relevant UPR-related genes upon ER stress induction. Some of the tested derivatives are novel inhibitors of targets associated to inflammation and ER stress signaling, in some cases more potent than the parent compound. Furthermore, the reduced cytotoxicity of some of these molecules enabled the use of higher concentrations than that of FST, resulting in the observation of enhanced bioactivities.

Network pharmacology identifies fisetin as a treatment for osteoporosis that activates the Wnt/ß-catenin signaling pathway in BMSCs.

BACKGROUND: Although fisetin may exist widely in many natural herbs, its anti-OP mechanism is still unclear. The aim of this study is to explore the molecular anti-osteoporosis (OP) mechanism of fisetin based on network pharmacology and cell experiments. METHODS: The target of fisetin was extracted by the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP). The targets of OP were obtained by DisGeNET, GeneCards and the Comparative Toxicogenomics Database, and the targets of fisetin in OP were screened by cross-analysis. The protein-protein interaction (PPI) network was constructed by STRING, and the core targets were obtained. We performed gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses on common targets via the Database for Annotation, Visualization and Integrated Discovery. Finally, an in vitro cell experiment was used to verify the anti-OP effect and mechanism of fisetin. RESULTS: There are 44 targets of fisetin related to the treatment of OP. The PPI results suggest that CTNNB1, CCND1, TP53, JUN, and AKT1 are the core targets. A total of 259 biological process, 57 molecular function and 26 cell component terms were obtained from GO enrichment analysis. The results of KEGG pathway enrichment analysis suggested that fisetin treatment of OP may be related to the Wnt signaling pathway, estrogen signaling pathway, PI3K-Akt signaling pathway and other signaling pathways. In vitro cell experiments showed that fisetin significantly increased the expression levels of ALP, collagen I, osteopontin and RUNX2 in bone marrow mesenchymal stem cells (BMSCs) (p < 0.05). Fisetin also increased the gene expression levels of Wnt3 and ß-catenin (CTNNB1) in BMSCs, which indicates that fisetin can regulate the Wnt/ß-catenin signaling pathway and promote the osteogenic differentiation of BMSCs. CONCLUSIONS: Fisetin acts on multiple targets and pathways in the treatment of OP; mechanistically, it regulates the Wnt/ß-catenin signaling pathway, which promotes the osteogenic differentiation of BMSCs and maintains bone homeostasis. The results of this study provide a theoretical basis for further study on the complex anti-OP mechanism of fisetin.

Antiproliferative Mechanisms of a Polyphenolic Combination of Kaempferol and Fisetin in Triple-Negative Breast Cancer Cells.

Herein, we investigate the combinatorial therapeutic effects of naturally occurring flavonoids kaempferol (K) and fisetin (F) on triple-negative breast cancer (TNBC: MDA-MB-231 cell line). Dose-dependent MTT assay results show that K and F exhibited cytotoxicity in MDA-MB-231 cells at 62 and 75 µM (IC50), respectively, after 24 h. However, combined K + F led to 40% and more than 50% TNBC cell death observed at 10 and 20 µM, respectively, which revealed the synergistic association of both. The combination of K and F was determined to be more effective in inhibiting cell viability than either of the agents alone. The morphological changes associated with significant apoptotic cell death were observed under a fluorescent microscope, strongly supporting the synergistic association between K and F. We also proposed that combining the effects of both polyphenols, as opposed to their individual effects, would increase their in vitro efficacy. Furthermore, we assessed the cell death pathway by the combinational treatment via reactive oxygen species-induced DNA damage and the mitochondrially mediated apoptotic pathway. This study reveals the prominent synergistic role of phytochemicals, which helps in elevating the therapeutic efficacy of dietary nutrients and that anticancer effects may be a result of nutrients that act in concert.

Flavonols in Action: Targeting Oxidative Stress and Neuroinflammation in Major Depressive Disorder.

Major depressive disorder is one of the most common mental illnesses that highly impairs quality of life. Pharmacological interventions are mainly focused on altered monoamine neurotransmission, which is considered the primary event underlying the disease's etiology. However, many other neuropathological mechanisms that contribute to the disease's progression and clinical symptoms have been identified. These include oxidative stress, neuroinflammation, hippocampal atrophy, reduced synaptic plasticity and neurogenesis, the depletion of neurotrophic factors, and the dysfunction of the hypothalamic-pituitary-adrenal (HPA) axis. Current therapeutic options are often unsatisfactory and associated with adverse effects. This review highlights the most relevant findings concerning the role of flavonols, a ubiquitous class of flavonoids in the human diet, as potential antidepressant agents. In general, flavonols are considered to be both an effective and safe therapeutic option in the management of depression, which is largely based on their prominent antioxidative and anti-inflammatory effects. Moreover, preclinical studies have provided evidence that they are capable of restoring the neuroendocrine control of the HPA axis, promoting neurogenesis, and alleviating depressive-like behavior. Although these findings are promising, they are still far from being implemented in clinical practice. Hence, further studies are needed to more comprehensively evaluate the potential of flavonols with respect to the improvement of clinical signs of depression.

Dihydromyricetin suppresses inflammatory injury in microglial cells to improve neurological behaviors of Alzheimer's disease mice via the TLR4/MD2 signal.

AIM: We analyzed the role and mechanism of dihydromyricetin (DHM) in suppressing inflammatory injury in microglial cells via targeting MD2. METHODS: In vitro, BV2 cells were used as the objects of study to induce inflammatory injury with LPS + ATP, then the cell apoptosis level was identified, inflammatory factor levels were measured by ELISA, TLR4 and MD2 were stained with fluorescence staining, and protein expression was determined using Western-blot (WB) assay. Afterwards, MD2 expression was knocked down n BV2 cells to construct the BV2-MD2-/- cell line, so as to detect the role of DHM on BV2-MD2-/-. Moreover, the binding of DHM to MD2 was analyzed via mall molecule-protein docking and pull-down assays. In-vivo, wild-type (WT) C67BL/6 mice and APP/PS1 (AD) mice were used as the objects of study, which were intervened with DHM to detect the changes in mouse cognition. In addition, the pathological changes of brain tissues were analyzed with H&E staining. In addition, the inflammatory factor and protein levels in brain tissues were also detected. RESULTS: DHM suppressed inflammatory injury in BV2 cells, reduced the cell apoptosis rate and inflammatory factor levels, and suppressed the level of TLR4 and MD2. After MD2 knockdown, DHM was unable to further suppress BV2 cell injury. Results of small molecule-protein docking and pull-down assays suggested that DHM bound to MD2 to suppress the formation of TLR4 complex. In AD mice, DHM improved the cognitive disorder in mice, suppressed inflammatory injury in brain tissues and lowered the expression of TLR4 protein. CONCLUSION: DHM targeted MD2 to suppress the formation of TLR4 protein complex, thereby suppressing inflammatory injury in microglial cells and improving the cognition in AD mice.

Optimization of the Transdermal Delivery System in Astilbin Microemulsion with Improved Stability and Anti-psoriatic Activity.

BACKGROUND: Astilbin is a promising candidate drug for psoriasis. However, the poor solubility and stability limited its clinical application. PURPOSE: The present work aimed to develop a stable microemulsion of astilbin formulation and evaluate its effect in vitro and in vivo. METHODS: Oil phase, surfactants, and cosurfactants were screened using solubility and stability of astilbin as the index. The central composite experiment design and response surface methodology analysis were adopted to optimize microemulsion parameters. The particle size, zeta potential, polydispersity index, viscosity, drug content, encapsulation, transmission electron microscopy (TEM), and stability of the optimized microemulsion were evaluated. Then, the drug release and anti-psoriasis effects were evaluated in a mouse model induced by imiquimod. RESULTS: The optimum formulation contained Labrafil M 1944 Cs (10.12%), Polyoxyethylene Castor Oil 35 (37.41%), propylene glycol (12.47%), water (40%), and gallic acid (2.9%), and the average particle size was 14.71 nm. The permeability of astilbin from the optimized astilbin-gallic acid microemulsion in 24 hr was 4.39 times higher compared with the astilbin's microemulsion. The content of astilbin in astilbin-gallic acid microemulsion remained unchanged after being stored at 25°C for 4 months compared with astilbin aqueous (3 h) and astilbin microemulsion (185 h). Compared with the model group, the optimized formulation decreased the PASI score and Baker score by 49% and 73%, respectively, which showed a favorable anti-psoriasis effect. Moreover, there was no difference in the anti-psoriasis effect between the optimized group and the positive control. CONCLUSION: These results indicated that the astilbin-gallic acid microemulsion might be a potential topical drug used for the treatment of psoriasis.

The Potential Role of Fisetin, a Flavonoid in Cancer Prevention and Treatment.

Cancer is a main culprit and the second-leading cause of death worldwide. The current mode of treatment strategies including surgery with chemotherapy and radiation therapy may be effective, but cancer is still considered a major cause of death. Plant-derived products or their purified bioactive compounds have confirmed health-promoting effects as well as cancer-preventive effects. Among these products, flavonoids belong to polyphenols, chiefly found in fruits, vegetables and in various seeds/flowers. It has been considered to be an effective antioxidant, anti-inflammatory and to play a vital role in diseases management. Besides these activities, flavonoids have been revealed to possess anticancer potential through the modulation of various cell signaling molecules. In this regard, fisetin, a naturally occurring flavonoid, has a confirmed role in disease management through antioxidant, neuro-protective, anti-diabetic, hepato-protective and reno-protective potential. As well, its cancer-preventive effects have been confirmed via modulating various cell signaling pathways including inflammation, apoptosis, angiogenesis, growth factor, transcription factor and other cell signaling pathways. This review presents an overview of the anti-cancer potential of fisetin in different types of cancer through the modulation of cell signaling pathways based on in vivo and in vitro studies. A synergistic effect with anticancer drugs and strategies to improve the bioavailability are described. More clinical trials need to be performed to explore the anti-cancer potential and mechanism-of-action of fisetin and its optimum therapeutic dose.

Molecular mechanisms and promising role of dihydromyricetin in cardiovascular diseases.

Vine tea, a Chinese herbal medicine, is widely used in traditional Asian medicine to treat common health problems. Dihydromyricetin (DMY) is the main functional flavonoid compound extracted from vine tea. In recent years, preclinical studies have focused on the potential beneficial effects of dihydromyricetin, including glucose metabolism regulation, lipid metabolism regulation, neuroprotection, and anti-tumor effects. In addition, DMY may play a role in cardiovascular disease by resisting oxidative stress and participating in the regulation of inflammation. This review is the first review that summaries the applications of dihydromyricetin in cardiovascular diseases, including atherosclerosis, myocardial infarction, myocardial hypertrophy, and diabetic cardiomyopathy. We also clarified the underlying mechanisms and signaling pathways involved in the above process. The aim of this review is to provide a better understanding and quick overview for future researches of dihydromyricetin in the field of cardiovascular diseases, and more detailed and robust researches are needed for evaluation and reference.

The effects of fisetin on bone and cartilage: A systematic review.

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.

Molecular mechanism and therapeutic significance of dihydromyricetin in nonalcoholic fatty liver disease.

The prevalence of nonalcoholic fatty liver disease (NAFLD) has been steadily increasing, and it has become one of the most prevalent chronic liver diseases worldwide. Recent studies have shown that dihydromyricetin (DHM) is influential in treating NAFLD. The purpose of this review was to describe how DHM prevents and treats NAFLD and its potential mechanisms through an in-depth summary of preclinical in vitro and in vivo studies. A brief overview of DHM's potential role in NAFLD involves regulation of lipid/glucose metabolism, possibly via anti-inflammatory or sirtuin-dependent mechanisms. For NAFLD, there is currently no effective and approved medication for therapy. DHM has the characteristics of liver protection, antioxidation, anti-inflammatory and apoptosis-regulatory benefits, which provides a new idea for the treatment of NAFLD. With the increasing interest in utilizing natural products to prevent and control liver diseases, our work aims to provide new ideas for the treatment of NAFLD and accelerate its translation from bench to bedside.