As early as 1996, Wang et al. (1996) found that hyperoside has a protective effect on myocardial ischemia/reperfusion injury. After years of follow-up studies by other scholars, the effect has been reaffirmed. Hyperoside has a protective effect on cardiomyocyte injury induced by hypoxia/reoxygenation through anti-oxidant properties. After hyperoside preconditioning, the activities of Bnip3, Bax, and caspase3 decrease, and the expression of Bcl-2 increases ( Xiao et al., 2017). Hyperoside can alleviate heart failure by inducing autophagy, inhibiting apoptosis, changing the level of apoptosis-related proteins, and promoting the autophagy of H9C2 cells induced by angiotensin II. Most importantly, hyperoside can reduce the heart/body weight ratio and the cross-sectional area of cardiomyocytes ( Guo et al., 2020). Recent studies proved that ( Wang et al., 2018b) hyperoside can also prevent cardiac hypertrophy by blocking the activation of the AKT signal pathway and protecting heart remodeling caused by pressure overload. In the model of oxidative injury induced by high glucose, hyperoside protects cardiomyocytes from oxidative stress induced by high glucose by activating PI3K/AKT/Nrf2 signal pathway ( Wang et al., 2018a). After the hyperoside intervention, cardiac function parameters of cardiomyocytes injured by ischemia-reperfusion injury obtained significant improvements. The possible mechanism is that hyperoside-activated anti-oxidant Nrf2 signal pathway and decreased the level of endoplasmic reticulum stress and oxidative stress ( Hou et al., 2016). However, some studies suggested that the protective effect of hyperoside on ischemia–reperfusion injury of isolated rat cardiomyocytes may be related to the activation of the ERK signal pathway, thus promoting the phosphorylation of extracellular signal-regulated protein kinase, improving myocardial contractile function, and reducing the myocardial infarct size ( Li et al., 2013).

The effect of hyperoside on cerebral ischemia–reperfusion injury has also been previously reported. Hyperoside was administered to rats at doses of 6.25, 12.5, and 25 mg·kg ⁻¹, which can significantly improve abnormal neurological symptoms. Among them, 12.5 and 25 mg·kg ⁻¹ significantly reduced infarct weight, inhibited the increase of MDA and NO in rats’ cerebral cortex, increased the CBF of the cerebral cortex, and protected cerebral infarction by reducing lipid peroxidation and NO ( Chen et al., 1998). Liu et al. (2012) studied primary cultured rat neurons and created ischemia–reperfusion cell model (OGDR), reporting that hyperoside could significantly reduce the damage caused by OGDR to neurons and that internal mechanisms were related to the NO signal pathway. The regulation of hyperoside may be related to the BKC a channel by activating TRPV4, reducing the concentration of Ca ²⁺ in cells, relaxing blood vessels, forming a new therapeutic target for protecting ischemic brain injury, and participating in brain protection ( Han et al., 2018).

The inhibitory effect of hyperoside on tumor has been confirmed in various human malignant tumor cells such as lung, breast, liver, prostate, colon, gastric, and similar. The important reason for the unrestricted growth of tumor cells is the loss of their active and physiological apoptotic ability. Therefore, inducing tumor cell apoptosis and inhibiting tumor cell proliferation are the main purposes of most anti-tumor drugs ( Shi et al., 2014). Hyperoside can affect tumor cells through different mechanisms of action, including depressing proliferation, promoting apoptosis, blocking cell cycle.

Hyperoside could inhibit the survival and proliferation of hypoxia-induced non-small cell lung cancer cell line A549 in a dose-dependent manner, possibly through iron accumulation on the AMPK/HO-1 axis to combat hypoxia-induced survival and proliferation of A549 ( Chen et al., 2020). In vitro experiments revealed that hyperoside could induce autophagy and apoptosis in human non-small cell lung cancer by inhibiting the activation of the Akt/mTOR/p70S6K signaling pathway ( Fu et al., 2016). By inducing the inactivation of the NF-kB signaling pathway, activating caspase3 regulated by Bcl-2/Bax, and increasing lung cancer malignant tumor cell apoptosis, hyperoside can also inhibit lung cancer growth. Regulating caspase-3 and p53 inhibits the proliferation, migration, and invasion of lung cancer cells, promotes the expression of pro-apoptotic factors, and suppresses the expression of anti-apoptotic factors ( Liu et al., 2016; Lü, 2016). Apoptosis is closely related to the activation of p38MAPK and JNK-induced mitochondrial death pathway ( Yang et al., 2017c). Further studies proved that hyperoside mediates p38MAPK and AKT/PI3K signaling pathways, regulates the expression of genes related to migration and invasion and inhibits the invasion and migration of A549 cells ( Yang et al., 2017b). Some studies have shown that hyperoside can also work synergistically with some drugs to exert its anti-tumor effect. Hyperoside can inhibit the proliferation of A549 cells by inducing cell apoptosis and G1/S phase arrest. Let-7a-5p can inhibit the proliferation of A549 cells by blocking the cell cycle in G1/S phase. At the same time, microRNA-let-7a-5p directly regulates the expression of CCND1 in A549 cells. Hyperoside combined with let-7a-5p can effectively inhibit the proliferation of A549 cells ( Li et al., 2018a).

According to breast cancer research, hyperoside can reduce the production of ROS, inhibit the transcription activity of NF-kB and the expression of Bcl-2 and XIAP, promote the expression of Bax and cleaved caspase-3, and induce breast cancer cells MCF-7 and the apoptosis of 4T1 that can scavenge free radicals and has a cytotoxic effect on breast cancer MCF-7 cells ( Qiu et al., 2019). Hyperoside can inhibit the viability of breast cancer cells without being cytotoxic to normal breast mammary epithelial cell lines ( Agar et al., 2015). It also increases cell apoptosis and caspase-3 activity, inhibits the activation of TLR4-NF-κB signal transduction caused by paclitaxel, reduces the expression of anti-apoptotic protein Bcl-2, enhances the expression of pro-apoptotic protein Bax and pro-inflammatory cytokines IL-6, and IL-6 protein levels increase the sensitivity of paclitaxel to breast cancer cells MDA-MB-231 ( Sun et al., 2020). In other types of cancer, hyperoside can also exert its anti-cancer effect. Guo et al found that hyperoside can reduce the expression of the C-Myc gene in cervical cancer C-33A and HeLa cells and promote the expression of TFRC. To inhibit the proliferation of cervical cancer cells ( Guo et al., 2019a), hyperoside may induce the apoptosis of human endometrial RL952 cells through the Ca ²⁺-related mitochondrial apoptosis pathway, and it can induce death receptor-mediated and mitochondrial-mediated apoptosis. The apoptotic pathway induces apoptosis of HT-29 human colon cancer cells, thereby inhibiting tumor growth ( Guon and Chung, 2016; Li et al., 2012a). Hyperoside can inhibit GSH-Px and CAT mRNA expression by inducing caspase-dependent apoptosis and p53 signaling pathway and participating in the pro-apoptotic signal transduction of SW620 human colorectal cancer cells ( Zhang et al., 2017a). It can also induce apoptosis of SW579 human thyroid squamous cell carcinoma cells, partly by up-regulating Fas during apoptosis And FasL mRNA expression and down-regulating survivin protein expression to induce apoptosis ( Liu et al., 2017). Hyperoside inhibits the cycle of INS-1 and MIA PaCa-2 pancreatic cancer cells in the G2/M phase and activates caspase-3 protein expression, induces apoptosis of tumor cells, and inhibits the proliferation of osteosarcoma cells by inducing G0/G1 block in the cell cycle ( Boukes and van de Venter, 2016; Zhang et al., 2014). It may also reactivate caspase-9 and caspase-9 by inhibiting BAD phosphorylation, increase the level of p27 by up-regulating LC-II in the HL-60 AML cell line; it can induce autophagy, and enhance the apoptosis-inducing effect of As2O3 on acute myeloid leukemia cells ( Zhang et al., 2015). Hyperoside can also down-regulate β1-adrenergic receptors in rat C6 glioblastoma cells, reduce the β1AR density in the plasma membrane, and subsequently reduce downstream signal transduction, thus inhibiting the growth of tumor cells ( Jakobs et al., 2013). High glycosides use PGRMC1-dependent autophagy to induce apoptosis and cell death of ovarian cancer cells and increase tumor cells’ sensitivity to cisplatin drugs. In combination with quercetin, it can inhibit prostate cancer cells and kidney cancer by regulating microRNA-21 Cell growth and metastasis ( Li et al., 2014; Yang et al., 2015; Zhu et al., 2017).

Growing evidence has suggested that hyperoside has anti-inflammatory, anti-oxidant stress, anti-swelling, anti-bacterial and anti-viral effects in vivo and in vitro. Due to the anti-inflammatory effect, hyperoside is commonly applied in the treatment of a variety of inflammatory-related diseases.

Hyperoside can inhibit the release of lipopolysaccharide (LPS)-mediated HMGB1 and HMGB1-mediated cytoskeletal rearrangement and inhibit the HMGB1 signaling pathway to treat vasculitis ( Ku et al., 2015). Zhou et al. (2018) explored the effects of hyperoside on inflammation and apoptosis of human umbilical vein endothelial cells induced by endotoxin. They found that 20 μg/L and 50 μg/L hyperoside could significantly increase the survival rate of human umbilical vein endothelial cells induced by LPS. In addition, hyperoside could decrease the mRNA expression of IL-1β, IL-6, TNF-α, and iNOS in umbilical vein endothelial cells in a dose-and time-dependent manner. Furthermore, some studies showed that hyperoside could inhibit vascular inflammation mediated by TNF-α, which is characterized by the drop of VCAM-1 expression in vascular smooth muscle cells and the adhesion ability of monocytes to vascular smooth muscle cells, where hyperoside (10, 50, 100 μmol/L) dose-dependently inhibited the proliferation and migration of human RAFLSs induced by LPS, reduced the production of TNF-α, IL-6, IL-1 and MMP-9 in LPS-stimulated cells and inhibited lipopolysaccharide. Moreover, it induced p65 and IκBα phosphorylation, lipopolysaccharide-induced p65 nuclear translocation, and NF-κB DNA adhesion at 3 weeks after administration, thus significantly reducing the clinical score of collagen-induced arthritis (CIA) in mice, reduced synovial hyperplasia, inflammatory cell infiltration, and cartilage damage ( Fan et al., 2017; Jang et al., 2018; Jin et al., 2016; Yang et al., 2017a). In another study, hyperoside significantly inhibited the loss of cell viability and the increase in endothelial Ca ²⁺ content and apoptosis in HUVEC induced by H2O2, and reduced B-cell lymphoma (Bcl)-2 related X Protein (Bax). It also cleaved caspase-3 and phosphorylated p38 mRNA expression levels while increasing the mRNA expression of Bcl-2 in H2O2-induced HUVEC, thus indicating that it has a certain anti-H ₂O ₂-induced HUVEC apoptosis effect, as well as a key role in preventing cardiovascular diseases ( Hao et al., 2016). Hyperoside could decrease skin inflammation by inhibiting inflammatory pathways and repairing DNA damage ( Kurt-Celep et al., 2020). Animal experiments demonstrated that hyperoside could lower TNF-α and IL-1β in rat cerebral ischemia-reperfusion injury models and play an anti-inflammatory role ( He et al., 2019). Hyperoside also has a protective effect on ovalbumin-induced allergic airway inflammation in mice by decreasing the levels of IL-4, IL-5, IL-1β, and IgE and reducing inflammatory cell infiltration ( Ye et al., 2017).

Hyperoside can selectively block the activation of AIM2 and NLRC4 inflammatory bodies and inhibit inflammatory response. In vitro experiments illustrated that hyperoside inhibited the production of TNF-α and IL-1β and inhibited the activation of AKT, NF-κB, and extracellular regulated kinase (ERK1/2) that are mediated by HMGB1 in lipopolysaccharide-induced vascular endothelial cells ( Jung et al., 2012). In rat peritoneal macrophages, hyperoside inhibited the expression of pro-inflammatory cytokines and iNOS, and significantly decreased the levels of inflammatory cytokines such as TNF-α and IL-6 ( Kim et al., 2011). Hyperoside can also be applied to treat allergic inflammation aggravated by TSLP, thus reducing the expression of IL-1β, IL-6, and their mRNA, down-regulating Ca ²⁺/RIP2/Caspase-1/NF-κB signal pathway and inhibiting the level of TSLP in human mast cell lines ( Han et al., 2014).

The role of oxidative stress in cardiovascular diseases, malignant tumors, liver and kidney injury, and autoimmune diseases has been extensively verified. Hyperoside has a protective effect on oxidative stress and apoptosis of granulosa cells induced by H ₂O ₂, which is potentially exerted by reducing the expression of Bax and up-regulating the expression of Bcl-2 in granulosa cells ( Wang et al., 2019). After intraperitoneal injection of hyperoside (50 mg/kg/d) into the rat model of ischemia–reperfusion injury, the activity of malondialdehyde decreased, the activity of superoxide dismutase and glutathione peroxidase increased, the expression of heme oxygenase-1 and NADPH quinone oxidoreductase-1 increased, and the apoptosis index decreased. Hyperoside could remarkably reduce the levels of ALT and AST after reperfusion and reduce the histological injury score ( Shi et al., 2019). Similarly, polyphenols in the lotus chamber, including hyperoside and other compounds, were also reported to display strong anti-oxidant and anti-proliferation activity and to have the ability to effectively scavenge many kinds of free radicals such as superoxide anion ( Shen et al., 2019).

In a rat model of cerebral ischemia–reperfusion injury, He et al. ( Kurt-Celep et al., 2020) found that hyperoside could increase the levels of SOD, MDA, and GSH-Px, improve the total anti-oxidant capacity of the rat brain, and inhibit oxidative stress and anti-apoptosis. Gao et al. (2019) applied Saccharomyces cerevisiae as a model to study the anti-oxidant activity of hyperoside, revealing that hyperoside can reduce the level of intracellular reactive oxygen species and lipid peroxidation, and improve cell survival rate. Chen et al. (2019) proposed that hyperoside improves the activity of free radical scavenging (or power reduction) in a dose-dependent manner and has an anti-oxidant role through the REDOX reaction and covalent pathway of lyophilized water extract and phenolic components of Hyalocin. Hyperoside promotes the expansion of cord blood hematopoietic cells in vitro by reducing the level of intracellular ROS. The expansion ability of cord blood hematopoietic cells that are pretreated with hyperoside (1 μM) was 54.9±9.6 times higher than that of the control group (42.0±8.1 times), which was a noticeable difference ( Zhang et al., 2018a). Hyperoside exerts a protective effect on apoptosis of retinal pigment epithelial cells by inhibiting blue light-induced poly ADP-ribose polymerase cleavage and complement C3 activation of PARP ( Kim et al., 2018). Similarly, hyperoside has a protective effect on oxidative damage and cytotoxicity of renal cells simulated by oxalate, and the ability of hyperoside to enhance endogenous antioxidation and detoxification may be closely related to Nrf2/HO-1/NQO1 pathway ( Chen et al., 2018b). In vitro experiments revealed that hyperoside could enhance the activity of anti-oxidant enzyme SOD/CAT/GSH-Px ( Zou et al., 2017).

Yang et al. (2016) demonstrated that hyperoside protects melanocytes from oxidative damage by inhibiting p38 phosphorylation and mitochondrial apoptosis signals and activating AKT, which provides vital value for the treatment of vitiligo. By inducing an endogenous oxidation system, hyperoside up-regulates the level of Nrf2 and the binding activity of anti-oxidant response elements and increases the expression of HO-1 mRNA and protein in a time- and dose-dependent manner ( Park et al., 2016). Additionally, hyperoside in hawthorn extract has been shown to have an immunomodulatory effect through its antioxidant activity, including spleen cells, NK cells, CTL cells, and macrophages; however, the specific mechanism remained unclear ( Mustapha et al., 2016). Li et al. (2012b) argued that the underlying mechanism might be correlated with the activation of the ERK signal pathway. According to a recent study, hyperoside can attenuate H ₂O ₂-induced oxidative stress damage in L02 cells by inhibiting the KAP1-activated NRF2-ARE signal pathway and increasing serine kinase-3β to inhibit phosphorylation ( Xing et al., 2015). The anti-oxidant activity of hyperoside is also reflected in its inhibitory effect on cell injury induced by H ₂O ₂ that up-regulates the expression of HO-1 and increases the activity of heme oxygenase-1 through the interaction of Keap1-Nrf2-ARE signal pathway ( Xing et al., 2011). Hyperoside depends on the regulation of NMDA receptors of NR2A and NR2B, and significantly attenuates NMDA-induced neuronal apoptosis and prevents neuronal injury ( Zhang et al., 2010). Previous studies revealed that H2O2 could induce apoptosis of hamster lung fibroblasts (V79-4). Through the intervention of hyperoside, the activity of antioxidant enzymes in V79-4 cells significantly increases, while the content of reactive oxygen species obviously decreases ( Piao et al., 2008).

Numerous studies indicated that hyperoside has a neuroprotective effect. Hyperoside has a protective effect on human dopaminergic neurons, and it can inhibit 6-hydroxydopamine induced oxidative stress of dopaminergic neurons by activating Nrf2/HO-1 signal. It can also improve the loss of neuronal vitality, lactate dehydrogenase release, excessive accumulation of ROS, and abnormal mitochondrial membrane potential induced by 6-OHDA ( Ramesh et al., 2018). Most importantly, hyperoside treatment activates nuclear erythroid 2-related factor 2 that is the upstream molecule of heme oxygenase-1. Simultaneously, Nrf2-dependent HO-1 signal activation is a potential target for preventing and treating Parkinson’s disease ( Kwon et al., 2019).

Amyloid protein, which is thought to have an important role in Alzheimer’s disease’s pathogenesis, produces neurotoxicity by destroying the blood-brain barrier ( Kumaran et al., 2018). Liu et al. (2018b) stated that hyperoside could alleviate the damage of a blood-brain barrier induced by Aβ1–42 and may be a potential drug for AD treatment. Furthermore, hyperoside can reverse mitochondrial dysfunction induced by Aβ25-35, inhibit its toxicity and apoptosis, and protect primary cultured cortical neurons by regulating PI3K/AKT/Bad/BclXL pathway ( Zeng et al., 2011). Based on the in vitro ischemia model of hypoxia–glucose deprivation–reperfusion injury, it was obvious that hyperoside has a protective effect on primary cultured cortical neurons against OGD-R injury and that NO signal pathway is involved in this regulatory process ( Liu et al., 2012).

As the most important detoxification organ of the human body, the metabolism of most drugs depends on the liver, and liver injury caused by drugs is inevitable. Paracetamol is widely used in clinics due to its good antipyretic and analgesic effect; however, liver injury caused by acetaminophen is unavoidable. In vitro experiments proved that hyperoside could effectively reduce the indexes of acute liver injury induced by acetaminophen. The possible mechanisms of ALT, AST, and ALP are related to hyperoside that can increase the level of glutathione and reduce the content of ROS ( Jiang et al., 2019). Xie et al. (2016) proposed that Hyperoside accelerates the harmless metabolism of APAP by inhibiting the activity of CYP2E1 and increasing the expression and activity of detoxifying enzymes Sults and UGTS.

Hyperoside has a protective effect on liver fibrosis and liver injury induced by heart failure in rats, such as the decrease of hydroxyproline content and liver fibrosis area, the decrease of ALT, AST, and ALP levels, and the relief of hepatocyte edema and vacuolar degeneration ( Guo et al., 2019b). By inhibiting inflammation and strengthening the anti-oxidant defense system, the protein and mRNA expression of iNOS, COX-2, and TNF-α are inhibited ( Choi et al., 2011). Recently, Wang et al. (2016) suggested that hyperoside can effectively inhibit the DNA binding activity of transcription factor NF-κB, change the expression of apoptosis-related genes regulated by it, and induce HSC apoptosis in hepatic stellate cells to reduce hepatic fibrosis.

Diabetic nephropathy is one of the diabetic microvascular complications. Early selective loss of glomerular permeability has an essential role in the pathogenesis of microalbuminuria in diabetic nephropathy. Oral administration of hyperoside to 30 mg/kg/day DN mice for 4 weeks can significantly reduce microalbumin excretion and glomerular filtration but has no significant effect on glucose metabolism and lipid metabolism ( Zhang et al., 2016a). Moreover, hyperoside may delay the progression of diabetic nephropathy by down regulating the phosphorylation levels of p38MAPK, IL-β, and pERK1/2 in glomerular Mesangial cells of diabetic rats and reducing the expression of TGF-κ1 and AGE/RAGE binding ( Kim et al., 2016). Hyperoside can inhibit the activity of heparanase gene promoter and heparanase expression induced by ROS or high glucose in podocytes ( An et al., 2017).

Wang et al. ( Wu et al., 2018) proposed that Huangkui capsule and its active ingredient hyperoside could improve the proteinuria and renal dysfunction of the mouse model of early diabetic nephropathy, reduce glomerular basement membrane thickening, glomerular hypertrophy and mesangial dilatation, and alleviate the pathological changes of early DN by inhibiting Akt/mTOR/p70S6K signal activity, which was consistent with results reported in another study ( Cai et al., 2017). Huangkui capsule significantly improves the renal function of rats with chronic renal failure induced by adenine and significantly inhibits Scr, BUN, UP, p-ERK1/2, α-SMA, and similar. It was recently reported that hyperoside could alleviate D-galactose-induced renal injury and delay renal aging by inhibiting AMPK-ULK1 signal-mediated autophagy ( Liu et al., 2018a). Hyperoside can block ADR-induced mitochondrial division and improve renal injury in both ADR-induced nephrotic mice and cultured human podocytes ( Chen et al., 2017).

Further studies revealed that hyperoside could alleviate glomerulosclerosis and improve renal function in diabetic nephropathy mice, which may be related to its promotion of the expression of MMP-2 and MMP-9 and the inhibition of the expression of TIMP-1 and Col IV, FN ( Zhang et al., 2016b). Yan et al. (2014) proposed the renal fibrosis model of Wistar rats based on unilateral ureteral obstruction, reporting that the combination of hyperoside and quercetin (H:Q=1:1) could significantly inhibit the expression of smooth muscle actin and fibronectin in Mesangial cells induced by interleukin-1β (IL-1β), thus effectively interfering with the progression of renal fibrosis. As the main active component of total flavonoids of Abelmoschus, hyperoside could inhibit caspase-3 and caspase-8 expression induced by advanced glycation end product, reduce podocyte apoptosis induced by sAGEs and prevent renal injury ( Lei et al., 2012). Furthermore, the combination of hyperoside and quercetin (20 mg/kg/day) can inhibit the formation of calcium oxalate stones induced by ethylene glycol in rats and significantly increase catalase levels superoxide dismutase ( Zhu et al., 2014).

Hyperoside, which decreases the levels of MC3T3-E1 phosphorylated Jun N-terminal kinases and p38 induced by H ₂O ₂ in osteoblasts, has a protective effect on MC3T3-E1 of osteoblasts induced by hydrogen peroxide ( Qi et al., 2020). Hyperoside can induce MC3T3-E1 differentiation of mouse preosteoblasts, and it participates in the process of promoting and inhibiting osteoclast formation ( Hou et al., 2020).

After an artificial joint replacement, joint aseptic loosening often occurs, which maybe related to titanium particles’ effect on osteoblast apoptosis and autophagy. Hyperoside effectively intervenes by improving the vitality and proliferation of MC3T3-E1 cells to protect MC3T3-E1 cells from titanium particles. At the same time, the activation of the TWEEP-p38 pathway is involved in this repair process ( Zhang and Zhang, 2019). Further studies revealed that hyperoside has an anti-osteoporotic effect on ovariectomized mice, which may be correlated with its inhibition of TRAF6-mediated RANKL/RANK/NF-κB signal pathway and the increase of OPG/RANKL value ( Chen et al., 2018a). Artemisia annua extracts’ active components include chlorogenic acid, hyperoside, and artemisia lactone, which together inhibit osteoclast differentiation and bone resorption-related acidification that is partly achieved by down-regulating the interaction between V-ATPase and TRAF6 to reduce acidification ( Lee et al., 2017). Hyperoside reduces the expression of osteopontin, sclerosin, TNF, and IL6, thereby reducing osteoblastic activity ( Nash et al., 2016).

A previous experimental study in mice showed that hyperoside could exert an antidepressant effect through the monoaminergic system and up-regulation of brain-derived neurotrophic factor ( Wang et al., 2016b). Hyperoside also has an antidepressant effect on CNS after intraperitoneal administration ( Liu et al., 2019b). The main active components of Apocynum venetum leaves include hyperoside and isoquercitrin. Recent studies proved that the antidepressant effect of Apocynum venetum leaf extract (AVLE) on rats exposed to CUMS is similar to that of fluoxetine (10 mg/kg), which may be related to its up-regulation of hippocampal BDNF level and the inhibition of hippocampal neuronal apoptosis and oxidative stress ( Li et al., 2018b; Orzelska-Górka et al., 2019). Gong et al. (2017) proposed that hyperoside can increase the expression of brain-derived neurotrophic factor BDNF in the hippocampus of rats induced by chronic mild stress, thus reversing the cognitive impairment caused by CMS and improving cognitive function. In the in vitro model of depression induced by corticosterone, hyperoside reduces the expression of BDNF and CREB genes up-regulated by Ca ²⁺ through cAMP-CREB signaling pathway, which protects PC12 cells from corticosterone-induced neurotoxicity. The cellular mechanism of hyperoside protecting PC12 cells from corticosterone-induced neurotoxicity is closely correlated with the cAMP signaling pathway ( Zheng et al., 2012). In the FST model, hyperoside displayed strong antidepressant activity by mediating and activating D2-like receptors through the dopaminergic system ( Haas et al., 2011). It has recently been proposed that the extract of Hawthorn fruit can improve memory impairment in mice with Alzheimer’s disease induced by β-amyloid protein. Different from the general drug action, CPE can block the accumulation of Aβ in a concentration-dependent manner ( Lee et al., 2019).

Hu et al. ( Liu et al., 2012) agreed that Hawthorn ethanol extract containing hyperoside could affect lipid metabolism and significantly reduce the levels of triglyceride, total cholesterol, and low-density lipoprotein cholesterol in hyperlipidemic rats. Totally, 15 lipid metabolites, including threonine, aspartic acid, and glutamine, were identified as potential biomarkers of hyperlipidemia. Berkoz ( Hu et al., 2019) discovered that hyperoside could inhibit the transformation of early fat to mature fat as 10 μM hyperoside has an inhibitory effect in the late stage of adipogenesis, 5 μM hyperoside has an anti-lipid effect in the early stage of adipogenesis, and high dose hyperoside could reduce lipid accumulation in mature adipocytes, while low dose hyperoside could inhibit adipogenesis. Zhang et al. ( Berkoz, 2019) proved that hyperoside extracted from Zanthoxylum bungeanum leaves also have a certain lipid-lowering effect and can reduce LDL-C and increase HDL-C.

Platelet aggregation and thrombosis are the common pathogenesis of many vascular diseases, so anticoagulation and inhibition of platelet aggregation are the focus of many new drug researches and development. Although there are few reports on the anti-platelet effect of hyperoside, this does not negate its role in the vascular system. A simultaneous experiment in vivo and in vitro revealed that ( Lee et al., 2019) hyperoside could inhibit platelet aggregation induced by collagen or thrombin in vitro, while it had enhanced antithrombotic effect in the model of arterial thrombosis and pulmonary embolism in vivo. Both isorhamnetin-3 murine O-galactose and hyperoside in water celery extract could inhibit the activity of thrombin and activator FXa and partially prolong activated thromboplastin time and plasma prothrombin time (PT). At the same time, both of them could inhibit the production of plasminogen activator inhibitor-1 induced by TNF-α; however, the anticoagulant effect and fibrinolytic activity of hyperoside were lower than those of isorhamnetin-3 murine O-galactose ( Ku et al., 2014). In the model of vascular smooth muscle cells cultured with oxidized low-density lipoprotein in vitro, hyperoside could inhibit the proliferation of vascular smooth muscle cells through the oxLDL-LOX-1-ERK pathway and the activation of VSMCs and ERK ( Zhang et al., 2017b).

The above-reported studies on the pharmacological effects of various aspects of hyperoside revealed that hyperoside has many pharmacological properties, different mechanisms of action, and different dosages in the treatment of various diseases. The pharmacological mechanism of hyperoside, its effect on the different cells or animals, and the dosage are summarized in Table 1 and Figure 3.