Fisetin, 3,3′4′7-4 hydroxyflavonoids, is a compound extracted from natural plants and has pharmacological effects against different pathological processes.
Epidemiological studies have shown that regular consumption of flavonoid-containing fruits and vegetables reduces the risk of cardiovascular disease, inflammatory diseases, neurodegenerative diseases, and cancer.
The concentration of fisetin in food ranges from 2 to 160 μg/g. High levels are found in strawberries, apples and persimmons. People get about 0.4 mg of fisetin per day from their meals.
Fisetin is also abundant in various legume trees and shrubs. At present, there are not many studies on fisetin, and fisetin has not yet been used clinically. This article will review its mechanism of action to develop its potential therapeutic value.
Studies have shown that it has a therapeutic effect on neurological abnormalities, cardiovascular disease, diabetes, obesity, lung disease, immune disease, cancer and other inflammatory diseases.
1 Physical and chemical properties
Fisetin, also known as fisetin, fisetin, fisetin, fisetin, is a yellow bioactive pigment. Molecular formula C15H10O6, molar mass 286.2363 g/mol, density 1.688 g/mL, decomposition point 330 ℃, soluble in ethanol, acetone, acetic acid, hydroxide alkali solution.
The solubility in ethanol is about 5 mg/mL, and it crystallizes into yellow needle-like crystals in dilute ethanol. It is highly soluble (about 30 mg/mL) in dimethyl sulfoxide at 25 °C, insoluble in water and ether. , benzene, chloroform and petroleum ether. It exhibits dark green fluorescence in dilute sodium hydroxide ethanol solution.
2 Antioxidant effect
Oxidative stress refers to the excessive production of reactive oxygen species and reactive nitrogen species in the body, a serious imbalance between the body's oxidation and antioxidant systems, resulting in the accumulation of reactive oxygen species (ROS) in the body or cells and causing cytotoxicity, resulting in tissue damage. .
Under pathological conditions, excessive ROS can cause a chain reaction of oxidative damage, aggravate the damage of oxidative stress to proteins, nucleic acids and lipids, resulting in the destruction and abnormal regulation of the structure, physiology and metabolic mechanisms of cells and tissues, resulting in the occurrence of whole organism pathology. Physiological changes.
The dissociation energy and dipole moment of the hydroxyl bond in the fisetin molecule indicate that fisetin has strong antioxidant capacity and can scavenge free radicals. Fisetin prevents the oxidation of low-density lipoprotein cholesterol (LDL-C), in part by reducing CD36 gene expression in macrophages, possibly helping to improve atherosclerosis.
Fisetin has been shown to protect peroxide donors, induce extracellular signal-regulated kinase (ERK1/2)/c-myc phosphorylation, increase nuclear nf-2-related factor-2 (Nrf2), glutamate esterase As well as glutathione (GSH) levels, improve cell viability.
Studies have shown that fisetin is tightly bound to the hydrophilic head and hydrophobic tail of phospholipids, the binding area is easily utilized by free radicals, and acts as a reaction site for the antioxidant activity of fisetin, inhibiting lipid peroxidation.
3 Anti-inflammatory effects
Among the 13 flavonoids tested, fisetin was the most potent inhibitor of hexosaminidase secretion and inhibited the production of inflammatory cytokines. In addition, it can activate mitogen-activated protein kinases (MAPKs) and inhibit the transcriptional activation of nuclear factor kappa B (NF-κB) by reducing the phosphorylation of p38, extracellular regulated protein kinase (ERK) and stress-activated protein kinase , enhances the phosphorylation and degradation of nuclear NF-κB inhibitor α.
Fisetin inhibits mast cell activation by inhibiting cell-cell interactions, reducing the amount of cell surface antigen CD40 and intercellular adhesion molecule-1 (ICAM-1), and downregulating NF-κB and MAPKs pathways.
Studies have shown that fisetin treatment can inhibit allergic inflammation by reducing the expression of thymic stromal lymphopoietin mRNA and the secretion of IL-4, IL-5, and IL-13 [6].
During the acute response, inflammatory cytokines (IL-4, IL-5, and IL-13) are produced, IgE is increased, and fisetin reduces the production of these inflammatory mediators, eosinophils, and mast cells.
Kim et al[7] found in the study that fisetin at a dose of 250 mg/kg per day for 8-15 d in NC/Nga mice with specific inflammation could significantly improve the skin symptoms of the mice and reduce the number of skin lesions on the ears and dorsal skin. The infiltration of eosinophils, mast cells, CD4+ T and CD8+ T cells essentially inhibits macrophage-mediated inflammatory responses by blocking major NF-κB regulatory enzymes.
In addition, fisetin also reduced IL-5, IL-13, tumor necrosis factor (TNF-α), inhibited by activating lymph node CD4+ T cells and increasing IL-10 production? The production of interferon and IL-4, in addition, inhibits the activation of NF-κB by reducing the phosphorylation level of p65 .
Fisetin inhibits leukocyte infiltration and migration in septic mice and inhibits the expression of endothelial protein C receptor involved in vascular inflammation.
At the same time, it also inhibited the production of TNF-α and IL-1β and the activation of protein kinase B (AKT), NF-κB and ERK1/2 in human umbilical vein endothelial cells.
Studies have shown that fisetin inhibits high glucose-induced vascular inflammation, vascular permeability, leukocyte adhesion and migration, expression of cell adhesion molecules, ROS formation and activation of NF-κB.
4 Anti-tumor effect
Fisetin rapidly interferes with cancer cell mitosis in a protein-dependent manner. It causes chromosomes to separate prematurely, preventing cancer cells from successfully completing the replication process. Fisetin has antiproliferative properties on several tumor cells, it has potential value in cancer prevention and treatment, may reduce angiogenesis, and inhibit tumor growth by inhibiting urokinase plasminogen activator.
Fisetin has many biological effects, one of which is the inhibition of topoisomerase II, resulting in genotoxicity, resulting in DNA double-strand breaks.
Analysis of cell culture studies found that fisetin treatment affected the localization and phosphorylation of several mitotic proteins, disrupted spindle formation, and resulted in the failure of cell division and reduced cell viability.
Fisetin induces cell death in various cancer cell lines. Studies have shown that fisetin-mediated antiproliferative and proapoptotic effects are specific to cancer cells, whereas normal cells are much less affected by fisetin treatment.
5 Anti-diabetic effects
Experimental studies have found that fisetin reduces blood sugar levels in diabetic animals by enhancing glycolysis, inhibiting glycogen production and increasing glycogen storage.
Diabetic rats fed fisetin for 1 month had significantly lower blood glucose levels, increased insulin levels, and reduced glycosylated hemoglobin, with similar metabolic changes to those treated with gliclazide .
Fisetin achieves these effects by participating in the modulation of carbohydrate metabolism-related enzymes. In liver and kidney tissues, fisetin enhances the activities of hexokinase, pyruvate kinase and lactate dehydrogenase in the glycolytic pathway, conversely it inhibits glucose-6-phosphate during gluconeogenesis Enzyme, fructose-1,6-bisphosphatase and glucose-6-phosphate dehydrogenase activities.
Fisetin treatment also affects hepatic glycogen metabolism in diabetic rats, promotes hepatic glycogen synthesis and inhibits its decomposition.
In addition to modulating pro-inflammatory cytokines, fisetin has been found to reduce vascular inflammation in diabetes, and recent studies have shown that fisetin affects some of the pathophysiological processes involved in the formation of vascular inflammation, including decreased vascular permeability and decreased leukocyte migration and adhesion and ROS generation. Fisetin may also play a role in relieving or reducing common complications of diabetes mellitus, which is closely related to abnormal lipoprotein metabolism.
A recent study showed that treatment of streptozotocin-induced diabetic rats with fisetin kept LDL-C and very low-density lipoprotein cholesterol (VLDL-C) levels within the normal range, while increasing high Levels of density lipoprotein cholesterol (HDL-C).
Data from in vivo studies show that fisetin inhibits high glucose-induced overexpression of ICAM-1, vascular cell adhesion molecule-1, and E-selectin in endothelial cells, a result that reduces the effect of human monocytes on human umbilical veins Adhesion of endothelial cells.
Complications frequently occur in diabetic patients due to macromolecular glycosylation and high glucose toxicity in multiple organs. Fisetin can activate glyoxalase 1 and reduce the content of glycated hemoglobin, which can reduce renal hypertrophy and proteinuria in diabetic rats.
Eye complications of diabetes often include cataracts. A recent study showed that feeding diabetic rats with fisetin reduced the severity of their cataracts and delayed the onset of late complications.
In addition, in recent years, fisetin acts on C-aminobutyric acid A receptors in the spinal cord of type 1 diabetic rats, and research on its therapeutic effect on diabetic neuropathy has also followed.
6 Neuroprotective effects
Experimental studies have shown that fisetin is the most effective neuroprotective flavonoid that regulates intracellular signaling to promote cell survival.
Fisetin is the most potent of all flavonoids to induce axonal growth and pc-12 cell differentiation by activating the Ras-ERK signaling pathway, especially the activation of ERK. Maher et al [15] found that fisetin could improve the memory of mice by activating ERK and inducing phosphorylation of cAMP response element binding protein.
There are also studies showing that fisetin can promote the survival of nerve cells through enhanced proteasome activity after neurotrophic factor extraction, which means that it can also act as a neurotrophic factor. In addition, fisetin effectively protected the rat central nervous system originating from nerve cells (HT-22 cells) from glutamate toxicity and hypoglycemia by altering the metabolism of GSH, and it also prevented ROS by scavenging Hydrogen oxide damages neurons.
Treatment with fisetin inhibited glioblastoma invasion and suppressed the expression of a multifunctional gene family whose anti-invasive effects were associated with induction of ERK phosphorylation in such cells. Serotonin and norepinephrine levels in the prefrontal cortex and hippocampus of the depressed mice were increased, and monoamine oxidase activity in the brain was inhibited after treatment with fisetin.
The experiment was performed by intraperitoneal injection of fisetin at a dose of 30 mg/kg. As a result, an average of 8.23 ng of fisetin was detected in the brain tissue of the mice, and the ischemic areas of the striatum and the cerebral cortex of the restored mice were recovered. The cell structure of the mice played a certain role, while the control group injected the same dose of distilled water into the abdominal cavity of the mice had no such effect.
In a rabbit model of cerebral thromboembolism, fisetin significantly reduced behavioral deficits after stroke in rabbits, which will provide evidence for a novel treatment for stroke.
Pro-inflammatory factors COX-2 and MMP-9 from brain tumor cells and their microvascular endothelial cells increase the damage to the blood-brain barrier, and can inhibit the formation of capillary-like structures after application of fisetin. Tahanian et al. Inhibits Cox-2 and MMP-9 activity and protein and mRNA expression.
Aluminum is a potent environmental neurotoxin that affects brain function by activating astrocytes, microglia, and related inflammatory responses.
Aluminum chloride has been implicated in an increase in lipid peroxides (LPO), a decrease in superoxide dismutase (SOD), GSH, and glutathione thioltransferase (GST), and fisetin treatment increases rat brain Levels of antioxidants SOD, GST and GSH in tissues (cortex and hippocampus), decreased levels of LPO.
In addition, studies have shown that fisetin protects PC-12 cells from damage by ROS and induces phosphorylation of ERK, p38, and AKT in PC-12 cells.
After feeding mice with fisetin, the content of aluminum chloride can be reduced, which reverses the damage of aluminum chloride on cognitive memory, thereby reducing the neurotoxic effect.
At the same time, it also inhibited the activity of astrocytes and microglia, thereby reducing the production of pro-inflammatory factors such as TNF-α, IL-1β and inducible nitric oxide synthase induced by aluminum chloride. It also ameliorated aluminum chloride-induced neurotoxicity and neuroinflammation-induced morphological abnormalities.
7 Anti-atherosclerotic effect
It was previously believed that dyslipidemia was the sole cause of atherosclerosis, but now there is increasing evidence that a maladaptive chronic inflammatory response also plays an important role in the initiation and progression of atherosclerosis. important role.
Recent findings suggest that neutrophils are also involved in regulating the occurrence of arteriosclerosis. In addition, IL-1β, IL-6, TNF-α, P-selectin and lipoxygenase also promote the formation of arteriosclerosis.
Experimental and clinical studies have demonstrated that anti-inflammatory and immunomodulatory therapies reduce the risk of cardiovascular disease and atherosclerosis. Phagocytic cells engulf LDLs to form foam cells, and the accumulation of foam cells leads to the formation of atherosclerotic plaques.
Studies have shown that fisetin has antioxidant properties and can inhibit the oxidation of LDLs [27]. Fisetin inhibits copper-dependent LDL-C oxidation, inhibits macrophage CD36 receptor expression by reducing mRNA expression, and subsequently prevents oxidized LDLs from binding to the class B scavenger receptor CD36 on macrophages.
8 Summary
Fisetin, as a traditional Chinese medicine extracted from natural plants, has a wide range of economic and Medicinal value, thought to have health-promoting effects.
Recently, it has attracted much attention for its beneficial effects on diabetes, atherosclerosis, obesity and abnormal lipid metabolism. Currently, Fisetin is being further studied.
In order to apply the pharmacological potential of fisetin to the clinic, it is necessary to design well-designed animal experiments, conduct reliable analysis, further establish its pharmacological effects and its clinical feasibility, and lead the way for future clinical trials. Improving or curing certain diseases provides more feasible strategies to help some disease management methods to find more innovative adjuvant or monotherapy treatments to improve patient outcomes.
It is expected to be practically applied in clinical treatment as a novel, efficient and economical drug.
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