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Current advances on the therapeutic potential of scutellarin: an updated review

Received date: 20 November 2023; Accepted: 18 January 2024; Published online: 4 March 2024

Abstract

Scutellarin is widely distributed in Scutellaria baicalensis, family Labiatae, and Calendula officinalis, family Asteraceae, and belongs to flavonoids. Scutellarin has a wide range of pharmacological activities, it is widely used in the treatment of cerebral infarction, angina pectoris, cerebral thrombosis, coronary heart disease, and other diseases. It is a natural product with great research and development prospects. In recent years, with in-depth research, researchers have found that wild scutellarin also has good therapeutic effects in anti-tumor, anti-inflammatory, anti-oxidation, anti-virus, treatment of metabolic diseases, and protection of kidney. The cancer treatment involves glioma, breast cancer, lung cancer, renal cancer, colon cancer, and so on. In this paper, the sources, pharmacological effects, in vivo and in vitro models of scutellarin were summarized in recent years, and the current research status and future direction of scutellarin were analyzed.

Graphical Abstract

Keywords

Scutellarin    Pharmacological action    Experimental study    Model    Mechanism    
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1 Introduction

Scutellarin is a natural flavonoid extracted from plants that can be obtained from a variety of natural plants. Scutellarin is the main active substance, not only in Erigeron plants [1], but also widely distributed in Scutellaria plants [2], Opuntia plants [3], Centaurus plants [4], and Anaphalis plants [5]. Cumulative data show that scutellarin can be isolated from a variety of plants, such as Conya sumatrensis Retz [3], Centaurea montana [4], Anaphalis sinica Hance. [5], Vernonia esculenta Hemsl. [6], Erigeron breviscapus (Vant.) Hand.-Mazz. [7], Scutellaria barbata D. Don. [8], Scutellaria baicalensis Georgi. [9], Erigeron multiradiatus [10], Conyza canadensis L. [11], Thymus mongolicus (Ronniger) Ronn. [12], Perilla frutescens (L.) Britt. [13], Rosmarinus officinalis L. [14], Juniperus rigida S. et Z. [15], Patrinia villosa [16] etc. The structure, source, and function of scutellarin are shown in Fig. 1 and Table 1.

Fig. 1

Structure and source of scutellarin

Table 1

Distribution of scutellarin

Latin name Scutellarin content (%) Extraction site Extract method References
Conyza sumatrensis (Retz.) + Dried whole herb 95% Ethanol [3]
Centaurea calcitrapa + Roots and seeds Ethanol [4]
Anaphalis sinica Hance. + Dried whole herb Ethanol [5]
Vernonia esculenta Hemsl. + Dry root Ethanol [6]
Erigeron breviscapus (Vant.) Hand. –Mazz. 0.72–2.4 Dried whole herb 80% Ethanol [7]
Scutellaria barbata D. Don. 0.21–0.33 Dried whole herb 80% Ethanol [8]
Scutellaria baicalensis Georgi 1.690 Dry root 70% Ethanol [9]
Erigeron multiradiatus 1.1 Dried whole herb 80% Ethanol [10]
Erigeron elongatus Ledeb. 1.24 Dried whole herb 80% Ethanol [10]
Erigeron lanuginosus Y. L. Chen. 0.78 Dried whole herb 80% Ethanol [10]
Erigeron acer Linn. 1.52 Dried whole herb 80% Ethanol [10]
Erigeron canadensis L. 3.2–3.4 Dried whole herb 95% Ethanol [11]
Thymus mongolicus (Ronniger) Ronn. + Dried whole herb and above-ground part 80% Ethanol [12]
Perilla frutescens (L.) Britt. + Roots, stems, leaves and fruits 80% Ethanol [13]
Rosmarinus officinalis + Dried whole herb 65% Ethanol [14]
Juniperus rigida S.et Z. + Branches and cones 70% Ethanol [15]
Patrinia villosa + Dried whole herb 60% Ethanol [16]
"+" indicates unknown content

Toxicological studies have proved that scutellarin is a slightly toxic or non-toxic natural small-molecule flavone compound, and the safe dose of LD50 value is 10 g/kg [17]. Based on the advantages of low toxicity and a wide range of sources, researchers found that scutellarin has a variety of pharmacological activities, including cardiovascular [18] and cerebrovascular diseases [19, 20], treatment of a variety of cancer therapies [21], and anti-inflammatory effects. In recent years, scutellarin played an important role in the treatment and protective effects of liver and kidney function caused by diabetes, the damage of brain, heart, liver, and kidney organs caused by alcohol, and eye diseases.

Animal models and cell models are important pharmacological research methods to evaluate drug activity and explore drug mechanisms, which usually need to be comprehensively evaluated by in vitro and in vivo methods combined with various models. Based on the study of different pharmacological activities of scutellarin in recent years, we combined the mechanism of scutellarin with in vivo and in vitro models to update the research progress of scutellarin’s pharmacological effects and look for changes and breakthroughs in recent years.

2 Pharmacological effects

2.1 Anti-cerebrovascular disease effect

Scutellarin is widely used in the clinical treatment of cerebral ischemia because of its anti-inflammatory, antioxidant, and vasodilator effects. The key feature of cerebral ischemia is that microglia in the brain evolve from a quiescent, branching morphology to an activated, unbranched, amoeboid morphology, which releases a large number of inflammatory mediators such as tumor necrosis factor-alpha (TNF-α), inter-leukin-1 beta (IL-1β), inducible nitric oxide synthase (iNOS), and other inflammatory mediators. TNF-α, IL-1β, iNOS, and reactive oxygen species (ROS), thereby exacerbating local inflammation and neuronal damage [22]. Chen et al. [23] found that scutellarin inhibited phosphorylated c-Jun N-terminal kinase (p-JNK), peripheral blood phosphorylated p38 mitogen-activated protein kinase (p-p38), and down-regulated inflammation in microglia by modulating the mitogen-activated protein kinases (MAPKs) pathway through the establishment of a permanent cerebral arterial occlusion model (MCAO). In addition, it can also significantly upregulate the expression level of extracellular signal-regulated kinase1/2 (p-ERK1/2), which can play a neuroprotective role. NIU [24] and others simulated neonatal hypoxic-ischemic disease (HIE) by culturing primary rat cerebral cortical neurons under the condition of hypoxia and glucose deficiency. After administration of scutellarin, it was found that scutellarin could inhibit neuronal death and regulate the Growth-associated protein (GAP43)-dependent pathway to promote axonal elongation of neurons, thus alleviating long-term nerve injury caused by HIE. Another study found that scutellarin can activate G-cyclase (GC) and produce cyclic guanosine monophosphate (cGMP) through endothelial-derived nitric oxide (NO), thus regulating the cGMP-dependent protein kinase (PKG) pathway [25–27]. PKG is a powerful vascular tone regulator. Activated PKG induces phosphorylation of vasodilator-stimulated phosphoprotein (Vasp), which in turn activates downstream ion channels and triggers endothelium-dependent vasodilation [28, 29]. DENG et al. found that scutellarin can repair oxidative stress injury in mice models of cerebral ischemia–reperfusion injury by down-regulating tMCAO-induced mRNA and protein expression of AR and NOX [30]. MENG et al. found that scutellarin can treat cerebral ischemia by regulating MARK, phosphatidylinositol 3 kinase (PI3K), hypoxia-inducible factor-1 (HIF-1), and other pathways, thus exerting vasorelaxation, anti-inflammatory and antioxidant effects [31]. Jia et al. [32] found through network pharmacology and experimental validation that Scutellarin exerts therapeutic effects on cerebral ischemia by activating astrocyte JAK2/STAT3 signaling, which provides a solid experimental basis for its clinical application. Xie et al. [33] found that Scutellarin exhibited antioxidant, anti-inflammatory, and neuroprotective effects in cerebral ischemia/reperfusion injury (CIRI) through PI3K/Akt pathway-mediated Nrf2 activation. Zhang et al. [34] found that scutellarin inhibits the inflammatory process through nuclear factor κ-B p65 and p38 mitogen-activated protein kinase signaling pathways and protects against brain damage in ischemically injured rats. Wang et al. [35] found that scutellarin exerts an effective effect on acute-phase ischemic brain injury by modulating neurotransmitter activity and reducing the toxicity of excitatory amino acids in neurons. M2 Microglia can exert neuroprotective effects and promote tissue repair. Chen et al. [36] found that scutellarin may directly promote the polarization of M2 microglia and their expression of neurotrophic factors. The protective effect was exerted through the inhibition of JNK and p38 signaling pathways. In addition, lucigenin promotes the polarization of M2 microglia by enhancing the ERK1/2 signaling pathway. In addition, scutellarin may also alleviate acute alcoholic brain injury by stimulating the activity of antioxidant enzymes and inhibiting the expression of syndromic factors [37]. Types of action and models of scutellarin in anti-cerebrovascular disease are showed in Table 2.

Table 2

Types of action and models of scutellarin in anti-cerebrovascular disease

Disease model Dose Animal/cell Weight/g In vivo/in vitro References
Cerebral artery occlusion model(MCAO) 100 mg/kg Male SD rats 250–280 g In vivo [23]
100 mg/kg Male SD rats 250–280 g In vivo [32]
Cerebral artery occlusion reperfusion model (MCAO/R)
OGD/R model		 20 mg/kg (rats)
25, 50, 100 μM (cell)		 Male SD rats
HT22 cell line		 270 ± 10 g In vivo
In vitro		 [33]
Cerebral artery occlusion reperfusion model (MCAO/R) 6, 12 mg/kg SD rats – In vivo [35]
Middle cerebral artery (MCAO) 40, 80 mg/kg Male SD rats 200–220 g In vivo [34]
Cerebral artery occlusion (MCAO)
LPS-stimulated BV-2 cell model		 100 mg/kg (rats)
0.54 μM (cell)		 Adult male SD rats
BV-2 microglia		 150 ± 10 g In vivo
In vitro		 [36]
Hypoxic-ischemic encephalopathy model (HIE) 20 mg/kg
0.1–100 μmol		 Timed pregnant female SD rat primary cortical neuronal cells – In vitro [24]
Cerebral ischemia–reperfusion model (IR) 45, 90 mg/kg SD rats – In vivo [29]
Transient middle cerebral artery occlusion (tMCAO) 50, 100 mg/kg Male C57BL/6N mice 20–24 g In vivo [30]
Acute alcohol mice brain injury model 10, 25, 50 mg/kg BALB/c male mice 18‒22 g In vivo [37]

2.2 Anti-cardiovascular disease effect

Scutellarin has pharmacological effects such as slowing down heart rate, regulating myocardial contractility, dilating blood vessels, reducing cardiac preload and afterload, dilating coronary arteries, and increasing myocardial oxygen supply. It has been widely used in the clinical treatment of cardiovascular diseases. Li et al. [38] found that scutellarin mediates I/R-induced cardiomyocyte apoptosis and cardiac dysfunction by regulating the activation of Bcl-2/Bax/Caspase-3 signaling pathway, so as to improve treatment and improve ischemic heart disease. Zhou et al. [39] found that scutellarin ameliorates I/R-induced cardiomyocyte apoptosis and cardiac dysfunction by activating the Bcl-2/Bax/Caspase-3 signaling pathway via the cGAS-STING signaling pathway. Wang et al. [40] found that scutellarin protects against myocardial ischemia–reperfusion injury EPK1/2-CREB regulates mitochondrial autophagy. Fu et al. [41] found that scutellarin significantly reduced lipid levels and increased antioxidant enzymes in atherosclerotic (AS) rats by inhibiting mammalian sterile20-like kinases 1 (Mst1) phosphorylation, Yes-associated protein (YAP) phosphorylation, phosphorylation of forkhead box O3A (FOXO3a), nuclear translocation of FOXO3a, and up-regulation of protein kinase Bm (AKT) expression. Regulates downstream genes to inhibit vascular endothelial cell injury and apoptosis, thus exerting anti-AS effects. Scutellarin has also been used in the treatment of diabetic cardiomyopathy, where it can lower blood glucose, total cholesterol, triglyceride, and LDL levels, up-regulate HDL levels, down-regulate the levels of lactic dehydrogenase 1 (LDH1) and creatine kinase (CK), and promote mRNA and protein expression of autophagy-related factors Beclin-1 and Lc3-Ⅱ, and inhibit the apoptosis-related factors cysteine aspartic acid-specific protease (caspase), as well as the B-cell lymphocyte-associated X protein (BAX). Protein (BAX), and Cytochrome C (Cyt-C) mRNA and protein expression, thereby up-regulating autophagy-associated factors to promote autophagy signaling pathway and down-regulating apoptosis-associated factors to inhibit apoptosis signaling pathway, which improves the cardiac morphology and reduces apoptosis of cardiac myocytes and serves as a treatment for type 2 diabetic cardiomyopathy [42]. Huo and others [43] found that scutellarin could improve oxidative stress, inflammation, and reduce apoptosis by modulating NRF2/KEAP/ARE, TLR4/MYD88/NF-κB, and apoptosis pathways to treat and prevent myocardial injury complicated by type 2 diabetes mellitus. Qu et al. [44] used isolated rat hearts to study the effect of scutellarin on acute myocardial ischemia/reperfusion injury and found that scutellarin significantly increased the expression I/R (ischemia/reperfusion)-induced decrease in PPARγ and Nrf2 protein, and decreased the I/R-induced elevation of NF-κB protein expression to achieve cardioprotection. scutellarin- scutellarin (PAE) polylactic acid-glycidylglycolic acid (PLGA) nanoparticles (NPs) made by combining scutellarin with PLGA were able to reduce CK, LDH, and AST levels in serum, decrease apoptosis, and improve cardiac function [45]. Types and models of scutellarin action in anti-cardiovascular diseases are shown in Table 3.

Table 3

Types of action and models of scutellarin in anti-cardiovascular disease

Disease model Dose Animal/cell Weight/g In vivo/in vitro References
Ischemia/reperfusion (I/R) 20 mg/kg Male C57BL/6 mice 18-25 g in vivo [38]
DOX-induced cytotoxicity in H9c2 cells, CFs, and HUVECs 6, 12, 25, 50, 100 μM Rat H9c2 cells, CFs, and HUVECs – In vitro [39]
Myocardial ischemia–reperfusion animal model (MIR)
Myocardial ischemia–reperfusion injury cell model		 50 mg/kg (mice)
10, 30, 50,
100 μM (cell)		 Male C57BL/6 mice
H9c2 cell		 12 weeks of age In vivo
In vitro		 [40]
atherosclerosis model (AS) 6.25, 25 mg/kg Male SD rats 200–220 g In vivo [41]
Diabetes complicated cardiomyopathy model (T2DC) 100, 200 mg/kg Male SD rats 180–200 g In vivo [42]
10, 20 mg/kg Swiss mice 22 ± 3 g In vivo [43]
Isolated Langendorff rat heart model 1, 5, and 25 µg/ml Male SD rats 250–300 g In vitro [44]
rat myocardial ischemia (MI) 5 mg/kg Male SD rats 250 ± 20 g In vivo [45]

2.3 Antitumor effect

In vivo and in vitro studies have shown that scutellarin can be used for the prevention and treatment of a variety of human cancers, and the types of cancers are shown in Fig. 2. Types of action and models of scutellarin in antitumor effects are shown in Table 4.

Fig. 2

Categories of human cancers that can be prevented and treated by scutellarin

Table 4

Types of action and models of scutellarin in anti-tumor effect

Type of disease Disease model Dose Animal/cell Weight/g Positive control Dose In vivo/in vitro References
Anti-colon cancer Oxidized azo-induced colon cancer 25, 50, 100 mg/kg (mice)
60–400 μmol (cell)		 Male C57BL/6 mice
HT-29 cell		 – – – In vivo
In vitro		 [46]
Human colorectal cancer (CRC) cell lines
SW620 xenograft human tumor model in mice		 6.25, 12.5, 25, 100, 160, 200, 300, 400 μg/mL
6.4, 12.8, 25.6 mg/kg		 Human SW620, Caco2, HT29 cells
male nude mice		 –
25 g		 – – In vitro
In vivo		 [47]
Colitis-associated colorectal cancer (CAC) model 25, 50, 100 mg/kg
80, 160, 320 μM		 Male C57BL/6 mice
IEC-6 rat small in testine epithelial cells		 6 weeks
old		 GANT61 20 mg/kg In vivo
In vitro		 [48]
Anti-renal cancer Xenograft mouse model
renal cell carcinoma		 30, 60 mg/kg
30, 60, 90 μM		 Male BALB/c nude mice
ACHN, 786-O cell		 5 weeks
old		 – – In vivo
In vitro		 [49]
Anti-lung cancer Lung cancer 100, 250, 500 μM A549 cell – – – In vitro [54]
A549 xenograft nude mouse model Non-small cell lung cancer (NSCLC) 0–500 μg/mL Male BALB/c nude mice A549 cell, H1975 cell 4 weeks
old		 – – In vitro [55]
Anti-glioma cancer Glioma in situ in rats 20, 50 mg/kg Female SD rats – – – In vivo [56]
Glioma cell 10, 20, 40, 80, 160 μg/mL Glioma cell line T98G – – – In vitro [57]
Glioma cell 10 mg/mL U251, M059K, and SF-295 cell lines – 5-fluorouracil 10 mg/mL In vitro [58]
Anti-breast cancer Triple-negative breast cancer (TNBC) model 10 mg/kg Female Balb/c mice 4 weeks old – – – [59]
1, 10 mg/kg
5, 20 μM		 Female nude Balb/c mice female Balb/c mice HMMECs HUVECs 4 weeks old – – In vivo
In vitro		 [60]
Anti-esophageal squamous cell carcinoma (ESCC) Patient-derived xenograft esophageal squamous carcinoma (ESCC) esophageal squamous cell carcinoma (ESCC) model 10 mg/kg
2, 5, 10 μM		 Female mice
KYSE cell		 6–9 weeks old – – In vivo
In vitro		 [61]
Anti-pancreatic cancer Pancreatic cancer (PaCa) cell model 100 μM Human PaCa cell lines – – – In vitro [62]
Anti-hepatocellular carcinoma Pancreatic cancer cell model 2.5, 5, 10, 20, 40, 80, 100 µmol/L Mouse HCC cell line, Hepa1-6 – – – In vitro [63]

2.3.1 Anti-colon cancer effect

Zeng et al. [46] found that scutellarin reduced the expression levels of TNF-α and TNF-1β in mouse serum, up-regulated the expression of BAX, and down-regulated the expression level of Bcl-2 in mouse cancer tissues through down-regulation of the Wnt/β-Catenin signaling pathway, and then inhibited the proliferation and migration of HT-29 cancer cells, and induced cell apoptosis. Scutellarin is one of the active ingredients of Erigeron breviscapu (Dengzhanxixin in China) injection (EBI). By activating the necrotic RIPK3/MLKL classical signaling pathway, EBI greatly promoted intracellular ROS production, significantly inhibited the proliferation of three human colorectal cancer (CRC) cell lines, and effectively inhibited the migration and invasion of SW620 cells, thus exerting anti-tumor effects. In addition, in the SW620 xenograft mouse model, EBI significantly inhibited tumor growth and lung metastasis and effectively circumvented drug-resistant apoptosis providing a new therapeutic pathway for anti-colon cancer [47]. Scutellarin significantly ameliorated AOM/DSS-induced CAC in mice and induced apoptosis in CAC tissues by inhibiting NF κB (nuclear factor κB)-mediated inflammation and the Hedgehog signaling axis. In addition, scutellarin inhibited cell proliferation, migration, and colony formation, and induced apoptosis in SW480 cells by down-regulating the Hedgehog signaling pathway activity, and reduced NFκB-mediated inflammatory responses in TNF-α-stimulated IEC-6 cells [48].

2.3.2 Anti-renal cancer effect

Deng et al. [49] found that scutellarin enhanced the expression of phosphatase and tensin homologue (PTEN) protein, a bispecific protein phosphatase identified as a tumor suppressor in a variety of human malignant tumors, and that activated PTEN caused second messenger lipid phosphatidylinositol 3,4,5-trisphosphate (PIP3) dephosphorylates, thereby contributing to its counteracting phosphatidylinositol-3-kinase (P13K) activity and AKT phosphorylation, inhibiting the PI3K/AKT pathway, which plays an important role in tumor cell proliferation, angiogenesis, and survival, and induces apoptosis of tumor cells, stalling their cell cycle at the G0/G1 phase, thus inhibiting the proliferation and invasion of renal cancer cells, suggesting that scutellarin has the potential to be a potential drug for the treatment of renal cancer.

2.3.3 Anti-lung cancer effect

TGF-β is considered a tumor suppressor due to its strong growth inhibitory activity in a wide range of cells. The TGF-β/Smad signaling pathway plays an important role in tumor cell proliferation, differentiation, and apoptosis. However, scutellarin modulates this pathway to induce apoptosis in tumor cells, and it has been reported that scutellarin selectively reduces the survival rate of tumor cells without affecting normal cells [50–53]. He and others [54] found that scutellarin could enhance 125I-induced apoptosis and the antiproliferative effect of tumor cells through down-regulation of the AKT/mTOR pathway, which provided the possibility of its combination therapy. Sun and others [55] found that scutellarin could promote caspase-3-dependent apoptosis induced by the first-line antitumor drug cisplatin via the ERK/P53 pathway and promote cisplatin-induced cytotoxicity autophagy via the c-Met-AKT pathway, which in turn acted to reverse the unique properties of cisplatin resistance.

2.3.4 Anti-glioma cancer effect

Wang et al. [56] found that scutellarin was able to inhibit the growth of glioma, as well as the proliferation and migration of glioma cells. In addition, scutellarin could significantly reduce the expression of baculovirus inhibitor of apoptosis protein 5 (BIRC5), thereby reversing the inhibition of apoptosis in glioma cells and exerting its anti-glioma effect. Therefore, Scutellarin may become a new potential targeted drug for the treatment of gliomas. Du et al. [57] found that Scutellarin inhibited the proliferation of glioma cells by upregulating miR-15a expression. Scutellarin-induced apoptosis and cell cycle in the G2/M phase SF-295 cell line inhibited cell proliferation in a dose-dependent manner and inhibited the growth of gliomas through the p63 signaling pathway in a dose-dependent manner, which was similar but weaker than the effect of 5-fluorouracil [58].

2.3.5 Anti-breast cancer effect

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with high blood vessels and frequent metastasis. Scutellarin blocks the interaction between TNF-α and TNFR2, and inhibits the activation of RUNX1 and the production of G-CSF in endothelial cells associated with TNBC downstream, thus reducing the metastasis of TNBC [59]. Scutellarin reduces the tendency of decreased connexin expression by regulating the TNFR2-ERK1/2-EZH2 signaling pathway, which inhibits TNF-α initiated vascular endothelial barrier disruption and thus reduces TNBC metastasis [60].

2.3.6 Treatment of other tumors

AKT is a serine/threonine kinase, belonging to the AGC family, which can regulate cell proliferation and survival, and scutellarin can activate this pathway, causing tumor cells to arrest with the G2 phase, which plays a role in the treatment of esophageal squamous carcinoma [61]. Girdin is an actin-binding protein, that is involved in cancer invasion and angiogenesis, and is a prognostic biomarker. Girdin can participate in pancreatic cancer (PaCa) migration mediated by EGF signal, and SCU can inhibit cancer invasion by inhibiting Girdin, thus playing a role in anti-cancer [62]. Li et al. used an aminoethyl anisamide-targeted copolymerization approach to amplify the delivery capacity of scutellarin to facilitate the in vivo application of scutellarin in hepatocellular carcinoma (HCC) immunotherapy and demonstrated that scutellarin has the potential to trigger immunogenic cell death (ICD) in hepatocellular carcinoma HCC [63]).

2.4 Anti-diabetic effect

2.4.1 Therapeutic effect on insulin resistance

Insulin resistance (IR) is a condition in which the peripheral tissues of the body become less sensitive to insulin and is present in various metabolic disorders such as diabetes mellitus, obesity, and hypertension. IR can occur in the liver, muscle, and adipose tissues, and when the levels of insulin, free fatty acids, or glucose in them are elevated tissues produce ROS and oxidative stress, as a vicious cycle IR and oxidative stress reinforce each other and exacerbate the body damage. LUAN et al. found that scutellarin reduced insulin-dependent lipid accumulation and mRNA expression upregulated Akt phosphorylation and improved the insulin signaling pathway in HepG2 cells in vitro. Down-regulation of rapamycin-targeted protein (mTOR) phosphorylation and n-SREBP-1c protein levels in high-fat diet (HFD)-fed mice and reduction of lipid accumulation in IR and lipid metabolism disorders through mTOR-dependent pathways [64]. Gao et al. found that scutellarin could activate the AMPK-α-mediated insulin signaling pathway, which in turn up-regulated P85α, activated the PI3K/AKT pathway, and ultimately affected the expression of the glucose transporter GLUT4, which indirectly exerted a hypoglycemic and lipid-lowering effect. in addition, scutellarin could also be a multi-targeted treatment for IR through its anti-oxidative stress, but the mechanism of the synergism of scutellarin’s modulation of the AMPK pathway and the anti-oxidative stress in the treatment of IR is still unclear and needs to be further investigated [65].

2.4.2 Antidiabetic-induced retinal injury

Scutellarin has a favorable therapeutic effect on diabetes-induced endothelial cell damage and retinopathy (DR). Scutellarin reduces the expression of BCL2, BAX, and fine cYTC, and inhibits apoptosis through a mitochondria-dependent pathway to treat diabetes-induced endothelial cell damage. Scutellarin also improves the decrease in mitochondrial membrane potential with ROS overload, decreases the protein expression of superoxide dismutase (SOD), and promotes the expression of microtubule-associated protein LC3II and autophagy-related gene ATG5. In addition, scutellarin can upregulate mitogen phagocytosis by modulating the PINK1/Parkin signaling pathway, thereby exerting a protective effect against hyperglycemia-induced vascular endothelial cell injury [66]. Vascular endothelial growth factor (VEGF) is the main cause of retinal neovascularization, vascular leakage, and is a therapeutic target for anti-angiogenesis in DR. Oral administration of scutellarin attenuates microvascular dysfunction caused by hyperglycemia and hypoxia in vitro and in vivo and inhibits vascular neovascularization, which may be related to its inhibition of VEGF and its downstream proteins, p-ERK, phosphorylated adhesion plaque kinase (p-FAK), and phosphorylated tyrosine protein kinase (p-Src) activation. It is evident that scutellarin is a VEGF inhibitor and has the potential to be a therapeutic agent for diabetic microangiopathy. Li et al. [67] found induced DR cell focussing in DM rats, particularly in retinal ganglion cells (RGCs), and found that scutellarin administration significantly inhibited cell focussing in DR and explained the molecular network mechanisms involved.

2.4.3 Antidiabetic-induced liver and kidney damage

Fan et al. [68] found that scutellarin may ameliorate T2DM liver injury by inhibiting hepatocyte apoptosis in vitro and in vivo. Huang et al. [69] found that scutellarin was effective in ameliorating various features of diabetic nephropathy (DN) in vivo, including proteinuria, glomerular dilatation, accumulation of tethered matrix, renal fibrosis, and podocyte injury, by modulating the TGF-β1 signaling pathway and its interaction with the Erk and Wnt/β-linker pathways. Scutellarin plays an important role in the treatment of diabetes and its complications, and types of action and models informations are showed in Table 5.

Table 5

Types of action and models of scutellarin in anti-diabetic effect

Type of disease Disease model Dose Animal/cell Weight/g Positive control Dose In vivo/in vitro References
Anti-insulin resistance High fat-diet-fed (HFD)mice 50 mg/kg Male C57BL/6 J mice
HepG2 cells		 7 weeks old – – In vivo [63]
High-fat diet (HFD) mice
PA-treated HepG2 cells		 50, 150 mg/kg
10, 30, 50 μM		 Male C57BL/6 mice
HepG2 cells		 6–8 weeks old Metform-in 200 mg/kg In vivo
In vitro		 [64]
Anti-diabetic-induced retinal injury High glucose (HG)-induced injury to human umbilical vein endothelial cells (HUVEC) 3, 10, 30 μM HUVECs cell – – – In vitro [66]
Diabetic retinopathy model (DR) 50 mg/kg Male SD rats Adult – – In vivo [67]
Antidiabetic-induced liver damage Type 2 Diabetes Model (T2DM)
Human LO2 hepatocytes		 50, 10, 200 mg/kg
0.1, 0.2, 0.4, 0.8, 1.0 mmol/L		 SD rats
LO2 cells		 60–180 g Rosiglita-zone 5 mg/kg In vivo
In vitro		 [68]
Antidiabetic-induced kidney damage Diabetic nephropathy (DN) mice 10, 40 mg/kg Male C57BL/6 J mice 8 weeks old Empaglif-lozin 20 mg/kg, In vivo [69]

2.5 Therapeutic role in Alzheimer’s disease

Alzheimer’s disease (AD) is a neurodegenerative disease associated with aging, characterized by progressive memory impairment, and cognitive and social decline. At present, there is no drug to cure this disease. As for the pathogenesis of AD, it is widely assumed that amyloid (Aβ) aggregates and is accompanied by the production of neurotoxic ROS. In addition, gene mutation, abnormal phosphorylation of tau protein, neuroinflammation, cholinergic injury, and imbalance of neurovascular lesions are also causes of AD. Scutellarin binds to Aβ-42 receptors in the brain, effectively inhibits the generation of Aβ oligomers and fibers, attenuates its induced neurotoxicity and reduces the expression of phosphorylated Tau protein, increases the expression levels of superoxide dismutase and acetylcholine, inhibits the expression levels of ROS and pro-inflammatory factors TNF-α and IL-6, and attenuates neuroinflammation. It also antagonizes Aβ-induced expression of anti-apoptotic protein Bcl2, inhibits expression of pro-apoptotic protein Bax and cleaved caspase 3, reduces apoptosis, and alleviates AD [70–73]. Defective mitochondrial bioenergetics and its resulting low glucose metabolism are key pathophysiologic regulators that promote neurodegeneration, Sheng et al. [74] found that scutellarin rescue mitochondrial damage by improving mitochondrial glucose oxidation via the Pdk-Pdc axis and that active components that ameliorate mitochondrial bioenergetic deficiencies may be valuable in the treatment of neurological disorders. Microglia are essential for the development and homeostasis of the neonatal central nervous system (CNS). Types of action and models of scutellarin in the treatment of Alzheimer’s diseases are showed in Table 6.

Table 6

Types of action and models of scutellarin in Alzheimer’s disease

Disease model Dose Animal/cell Weight/g In vivo/in vitro References
Mouse hippocampal neuronal L-Glu-damaged HT22 cells 20 mg/kg
5, 15 μM		 Male Balb/c mice
HT22 cell line		 20–24 g In vivo
In vitro		 [70]
Brain Aβ amyloidosis model 50 mg/kg
2.5, 5, 10 µM		 Half male and half female C57BL/6 mice
SH-SY5Y cell line		 Age-matching In vivo
In vitro		 [71]
Rodent model of AD 50 mg/kg
0, 5, 10, 15, 30 μg/mL		 Wistar rats
Rat PC12 cell		 200 g In vitro
In vivo		 [72]
Chronic cerebral hypoperfusion induced by permanent bilateral common carotid artery occlusion (pBCAO) 10, 30 mg/kg Male SD rats 280–300 g In vivo [73]
Chronic cerebral hypoperfusion (CCH) model 100 mg/kg Male SD rats 200 ± 10 g In vivo [74]

2.6 Anti-inflammatory effect

As a natural small molecule, scutellarin has good anti-inflammatory activity and can be used in the prevention and treatment of pneumonia, arthritis, and neuroinflammation. scutellarin can inhibit the inflammatory response by modulating the NF-ĸb/NLRP3 pathway, which exerts an antagonistic effect [75]. Lipopolysaccharide (LPS) is a common inflammatory factor that activates the inflammatory sensory protein caspase-11 and produces an inflammatory response. Scutellarin induces Ser/Thr phosphorylation of caspase-11 at PKA-specific sites, which counteracts the activation of caspase11 and antagonizes the inflammatory response caused by LPS [76]. Cerebrovascular diseases are often accompanied by neuroinflammation, which can lead to increased morbidity and mortality. In the central nervous system, microglia are resident innate immune cells Neuroinflammation is regulated by microglia, which play a dual role in the developing brain, both neuroprotective and neurotoxic. Activated microglia release inflammatory factors such as TNF-α, IL-1β, and NO, which further stimulate microglia activation and promote the accumulation of pro-inflammatory mediators, ultimately leading to neuronal death and exacerbating brain damage. Scutellarin can inhibit the production of inflammatory factors by regulating the AKT/NF-κB and p38/JNK pathways, which in turn inhibits microglia activation to alleviate neuroinflammation [77]. In addition, it has been shown that scutellarin can also alleviate and treat osteoarthritis by modulating the NF-ĸB pathway [78]. Yang et al. [79] found that scutellarin significantly reduced subchondral bone loss and cartilage degeneration in a mouse model of cartilage injury in medial meniscus (DMM) destabilization and in ovariectomy (OVX)-induced mouse subchondral bone loss. By inhibiting interleukin 1β-induced extracellular matrix degradation of cartilage NF-κB/mitogen-activated protein kinase (NF-κB/MAPK) signaling pathway. Li et al. [80] found that scutellarin attenuated complete Freund’s adjuvant (CFA)-induced rheumatoid arthritis (RA) in mice by modulating the Keap1/Nrf2/HO-1 pathway, and the results provide preliminary evidence for the treatment of arthritis with Scutellarin. Ulcerative colitis (UC) is an inflammatory bowel disease of unknown etiology that lacks effective treatments, Aksit et al. [81] found that scutellarin may prevent UC by downregulating pro-inflammatory cytokines and inhibiting apoptosis and oxidative stress. Types of action and models of scutellarin in anti-inflammatory effects are shown in Table 7.

Table 7

Types of action and models of scutellarin in anti-inflammatory and antioxidant effect

Type of disease Disease model Dose Animal/cell Weight/g Positive control Dose In vivo/in vitro References
Anti-inflammatory Idiopathic pulmonary fibrosis (IPF) 30, 60, 90 mg/kg Male BAL/bc mice 20–30 g – – In vivo [75]
LPS-induced depression animal model 15, 30, 45 mg/kg Adult male SD rats 200–220 g Fluoxetine – In vivo [76]
LPS-induced mouse model of osteoarthritis
LPS-induced		 50, 100 mg/kg
12.5, 25, 50 μmol/L		 Female C57BL/6 mice
Murine J774A.1 macrophage cell line		 6–8 weeks old – – In vivo
In vitro		 [77]
Osteoarthritis model (OA) mice
Medial meniscus (DMM) model		 50 mg/kg
0, 15, 30, 60 mM		 C57BL/6 mice
measured chondrocyte		 2 weeks old – – In vivo [78]
DMM model mice
medial meniscus (DMM) model		 25, 50 mg/kg
0, 1.56, 3.12, 6.25, 12.5, 25, 50, 100 and 200 μM		 female C57/BL mice
Mouse ATDC5 cells		 18–22 g – – In vivo
In vitro		 [79]
Rheumatoid arthritis model (RA) 20 mg/kg Male C57BL/6 mice 25–30 g Leflunomide 4 mg/kg In vivo [80]
Acetic acid-induced ulcerative colitis (UC) Model 20 mg/kg Adult male SD rats 250–320 g Sulfasalazine
TUNEL-positive cells		 100 mg/kg In vivo [81]
Anti-oxidant H2O2-induced oxidative damage of cells 25, 50, 100 μM ARPE-19 cell – – – In vitro [83]

2.7 Antioxidant effect

The presence of phenolic hydroxyl groups in the chemical structure of scutellarin provides hydrogen atoms to exert antioxidant effects. Scutellarin can effectively scavenge a variety of free radicals such as 1,1-diphenyl-2-trinitrophenylhydrazine (DPPH), 2,2ʹ-biamine-bis-(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS+), and superoxide anion (O2–), and mitigate the damage caused by the accumulation of free radicals on the body [82]. Hu et al. found that scutellarin could antagonize the effects of H2O2-induced damage to the retina in the mouse retina by culturing H2O2-induced damage to the retina in the mouse retina cells (APRE-19), and after administration of scutellarin, they found that it could antagonize the H2O2-induced increase in BAX expression and decrease in bcl-2 expression, which in turn decreased the expression of ROS, MDA, SOD, and GSH, reduced oxidative damage, and increased the survival rate of APRE-19 [83]. Types of action and models of scutellarin in antioxidan effect is shown in Table 7.

2.8 Antiviral effect

Modern studies have shown that scutellarin has some antiviral activity. Its antiviral pharmacological action is a specific manifestation of the purgative and detoxifying action in classical Chinese medicine [84]. Details of scutellarin’s antiviral activity were reported as research progressed. Wang et al. [85] found that scutellarin significantly inhibited the activities of sortase A (SrtA) and caseinolytic peptidase P (ClpP) of methicillin-resistant Staphylococcus aureus (MRSA) strain USA300 by screening hundreds of compounds, fluorescence quenching assay and molecular docking results showed that scutellarin directly binds to SrtA molecules, and also inhibits hemolytic activity of Staphylococcus aureus (SA) by inhibiting Hla expression in a SrtA-independent way. It can also inhibit the hemolytic activity of SrtA by suppressing the expression of Hla in a SrtA-independent manner. Therefore, the combination of scutellarin with vancomycin has the effect of preventing MRSA invasion of A549 cells and pneumonia in mice.

2.9 Protect the liver and kidney

Scutellarin may be a promising drug for the prevention of liver and renal injury. Miao et al. [86] established a model of CCL4-induced hepatic injury in mice and found that scutellarin exerted potential CCl4-induced hepatic injury by inhibiting the CYP2E1 and IĸBα/NF-ĸB pathways, modulating the intestinal microbiota, and endogenous metabolites involved in lipid metabolism and bile acid homeostasis, and exerting potential hepatoprotective effects. Scutellarin can play a protective role in renal protection. Dai et al. found that Scutellarin activated Nrf2 signaling protects the kidney from ischemia/reperfusion-induced oxidative damage by reducing inflammatory factors through up-regulation of the HO-1 pathway as revealed in vivo and in vitro experiments [87]. Acute renal injury (AKI) has a high mortality and morbidity. The oxidative stress induced in the kidneys after acute and excessive alcohol intake leads to acute kidney injury (AKI), resulting in causing severe swelling and damage groups of tubular epithelial cells with glomerular atrophy, necrosis, and inflammatory infiltration. Yang et al. found that langoustine exerts a protective effect against AKI through anti-inflammation and antioxidant activity [88]. Shahmohammadi et al. found that scutellarin can inhibit acute renal injury induced by regulating Nrf2/PPAR-c/PGC-1a/NF-kB/TLR4 [89].

2.10 Other effects

Scutellarin also has pharmacological activities such as treatment of glaucoma, liver protection, kidney protection, and hyperuricemia. Zhu et al. established a mouse model of glaucoma and found that scutellarin could maintain the retinal structure and visual function of mice when intraocular pressure was elevated, suggesting that scutellarin is a potentially novel neurotherapeutic agent used in the treatment of glaucoma [90]. Li et al. found that scutellarin reduced renal injury and lowered the glomerular filtration rate in hyperuricemic mice (HN), which may be alleviated by a regulatory mechanism of extracellular cellular communication network factor 1 (CCN1) on the activation of NLRP3 inflammatory vesicles [91]. Duan et al. found that scutellarin inhibited the onset and duration of convulsions and reduced the severity of PTZ-induced seizures in mice by modulating changes in the levels of gamma-aminobutyric acid (GABA), glutamate, and dopamine, as well as the activities of Ca2+ ATPase and Na+ K+ ATPase [92]. Types of action and models of scutellarin in other effects are shown in Table 8.

Table 8

Types of action and models of scutellarin in other effects

Type of disease Disease model Dose Animal/cell Weight/g Positive control Dose In vivo/in vitro References
Anti-viral Mice pneumonia model Mice pneumonia model Male and female C57BL/6 J mice 6–8 weeks old – – In vitro [85]
Protect liver injury BALB/c mice were injected with CCl4 0.03, 0.06, and 0.12 mmol/kg BALB/c mice 18–22 g Bifendate 0.4 mmol/kg In vivo [86]
Protect renal injury I/R-AKI model 50 mg/kg
20 μM		 Male Wistar rats
Human renal tubular epithelial cells (HK-2)		 250–300 g – – In vivo
In vitro		 [87]
Alcohol-induced AKI model 10, 25, 50 mg/kg Male BALB/c mice 18–22 g Icariin 60 mg/kg In vivo [88]
LPS-instigated model of AKI 25, 50, 100 ml/kg C57BL/6 mice 18–22 g – – In vivo [89]
Glaucoma treatment Injected with hydrogel into chronic IOP elevation 300 mg/kg C57BL/6 J mice 15–18 weeks – – In vivo [90]
Anti-hyperuricemia Hyperuricemia nephropathy (HV) 20 mg/kg C57BL/6 mice 25–27 g – – In vivo [91]
Anti-convulsant Pentylenetetrazol (PTZ) kindling epilepsy model 10, 20 mg/kg Male Swiss mice 30 g Diazepam 5 mg/kg In vivo [92]

3 Conclusion

Scutellarin is a slightly toxic or non-toxic natural small-molecule flavone compound with good effects against cardiovascular and cerebrovascular diseases, anti-tumor, anti-insulin resistance, anti-virus, anti-diabetic complications, anti-Alzheimer’s disease, liver and renal protection, with a complex mechanism of action involving numerous targets and signaling pathways, and scutellarin exerts these therapeutic effects mainly related to its anti-inflammatory, antioxidant, apoptosis-regulating, and vasodilating effects, but the current study was not specific enough and in-depth enough to explain the link between each target, pathway, and disease as a whole, and was unable to connect them to form a holistic mechanistic network, which requires a more in-depth study [93]. In addition, through the collection of animal or cell models in the article, it is found that most experimental results are only preliminary results, and most results lack positive control, which is a lack of reference for the clinical application of candidate drugs. Commonly used drugs, oral and intravenous injections in the formulations based on scutellarin are the mainstream of the current formulation research, among which the injectable products include breviscapine injection, Deng zhan hua Injection, breviscapine sodium chloride injection, breviscapine dextrose injection, the first two of which are more widely used in clinical applications [94].

It has been proved that scutellarin can be used in combination with other drugs to enhance therapeutic efficacy. Therefore, combining scutellarin with other drugs has a promising application prospect. Cocrystallization and nanoformulation technology occupy an important proportion in new drug development, and co-crystallization of scutellarin with other drugs for combination therapy may be a potential way of new drug development. In addition, cocrystallization and nanoformulation can also help to improve the problems of poor stability, poor water solubility, low oral bioavailability, and short in vivo half-life of scutellarin, which has a good prospect for research and development.

As a natural small molecule, scutellarin has good prospects for clinical application and is a potential therapeutic agent for tumors, atherosclerosis, cardiac and cerebral ischemic injuries, diabetic microangiopathy, hyperuricemia, and anti-Alzheimer’s disease, etc. However, the current study is not deep enough, and more pharmacological mechanisms of action need to be further explored. Network pharmacology is an interdisciplinary subject between bioinformatics and pharmacology. With the breakthrough of artificial intelligence and other fields, it can better improve the efficiency of research and provide support for the mechanism exploration of candidate natural small molecules.

Notes

Acknowledgements

The authors are thankful to National Science Foundation of China (Grant No.22278443), the Key R&D Program of Shan Dong Province (Grant No. 2021ZDSYS26), CAMS Innovation Fund for Medical Sciences (Grant No. 2022-I2M-1-015), Chinese Pharmacopoeia Commission Drug Standard Promoting Fund (Grant No. 2023Y11), Inde-pendent Innovation and Achievement Transformation Plan Project of Zaozhuang City (Grant No. 2202GH15), the Xinjiang Uygur Autonomous Region Innovation Environment Construction Special Fund and Technology Innovation Base Construction Key Laboratory Open Project (Grant No. 2022D04016), National Natural Science Foundation of China (Grant No. 882141204), and CAMS Innovation Fund for Medical Sciences (Grant No. 2022-I2M-1-005) for financial support. Fig. 2 was created with BioRender.com.

Author contributions

Conceptualization and study design: LZ, YL, GD and YX; literature review and collection: YX, GS, YT and SY; writing—original draft preparation: YX, GS, YT, WZ; figures and tables: YX, GS; review and editing: YX, WZ, LZ, YL and GD. All authors have read and agreed to the published version of the manuscript. The author(s) read and approved the final manuscript.

Funding

This funding was supported by National Science Foundation of China (22278443); the Key R&D Program of Shan Dong Province (2021ZDSYS26); Chinese Academy of Medical Sciences Initiative for Innovative Medicine (2022-I2M-1-015, 2022-I2M-1-005);Chinese Pharmacopoeia Commission Drug Standard Promoting Fund (2023Y11); Jiangsu Provincial Agricultural Science and Technology Independent Innovation Fund (2202GH15); Special Fund for Scientific Innovation Strategy-Construction of High-level Academy of Agriculture Science (2022D04016); National Natural Science Foundation of China (882141204).

Availability of data and materials

The data supporting the findings of this study are available upon reasonable request from the corresponding author.

Declarations

Competing interests

The authors declare that they have no conflict of interest.

References

  1. 1.
    Qu J, Wang Y, Luo G. Determination of scutellarin in Erigeron breviscapus extract by liquid chromatography-tandem mass spectrometry. J Chromatogr A. 2001;919(2): 437-41. CrossRef PubMed Google Scholar
  2. 2.
    Malikov V, Yuldashev M. Phenolic compounds of plants of the Scutellaria Genus. Distribution, structure, and properties. Chem Nat Compd. 2002;38(5): 473-519. CrossRef PubMed Google Scholar
  3. 3.
    Xin C, Su Y, Guo L, et al. Phenolic constituents from Conyza sumatrensis. Biochem Syst Ecol. 2008;36(3): 216-8. CrossRef PubMed Google Scholar
  4. 4.
    Formisano C, Rigano D, et al. Flavonoids in Subtribe Centaureinae (Cass) Dumort (Tribe Cardueae, Asteraceae): distribution and13C-NMR Spectral Data. Chem Biodivers. 2012;9: 2096-158. CrossRef PubMed Google Scholar
  5. 5.
    Hua Y, Wang H. Chemical Components of Anaphalis sinica Hance. J Chin Chem Soc-Taip. 2004;51(2): 409-15. CrossRef PubMed Google Scholar
  6. 6.
    Hasibuan P, Harahap U, Sitorus P, et al. The anticancer activities of Vernonia amygdalina Delile. Leaves on 4T1 breast cancer cells through phosphoinositide 3-kinase (PI3K) pathway. Heliyon. 2020;6(7): e04449. CrossRef PubMed Google Scholar
  7. 7.
    Liu C, Gao M, Guo B. Plant regeneration of Erigeron breviscapus (vant.) Hand. Mazz. and its chromatographic fingerprint analysis for quality control. Plant Cell Rep. 2008;27(1): 39-45. CrossRef PubMed Google Scholar
  8. 8.
    Wang A, Cheng G. Determination of Scutellarin in Herba scutellariae Barbata by HPLC. Guangzhou Chem Ind. 2017;45(07): 94–5+113. PubMed Google Scholar
  9. 9.
    Hong C, Chen J, Lu M, et al. Simultaneous determination of scutellarin and baicalin in the flowers of Scutellaria Baicalensis Georgi by HPLC. Chin J Mod Appl Pharm. 2020;37(11): 1320-3. PubMed Google Scholar
  10. 10.
    Hu Y, Zhang H, Zhang Z. Determination flavonoids and scutellarin in herbs of Erigeron genu. Chin J Pharm Ana. 2005;25(01): 21-3. PubMed Google Scholar
  11. 11.
    Liu H, Liu B, Wang G, et al. Studies on the chemical constituents from Conyza canadensis. Chin Med Mat. 2011;34(05): 718-20. PubMed Google Scholar
  12. 12.
    Fan S, Sui H, Chen X, et al. Determination of phenolic parts in Thymusquinquecostatus Celak by HPLC and UV-Vis. J Beijing Univ TCM. 2019;42(10): 854-61. PubMed Google Scholar
  13. 13.
    Gaihre Y, Tsuge K, Hamajima H, et al. The contents of polyphenols in Perilla frutescens (L.) Britton var frutescens (Egoma) leaves are determined by vegetative stage, spatial leaf position, and timing of harvesting during the day. J Oleo Sci. 2021;70(6): 855-59. CrossRef PubMed Google Scholar
  14. 14.
    Cattaneo L, Cicconi R, Mignogna G, et al. Anti-proliferative effect of Rosmarinus officinalis L. extract on human melanoma A375 cells. PLoS ONE. 2015;10(7): e0132439. CrossRef PubMed Google Scholar
  15. 15.
    Pisarev D, Novikov O, Novikova M, et al. Flavonoid composition of Juniperus oblonga Bieb. Bull Exp Biol Med. 2011;150(6): 714-7. CrossRef PubMed Google Scholar
  16. 16.
    Han X, Wang S, Yang X, et al. Analysis of plasma migration components in Patrinia villosa (Thunb.) Juss. effective parts by UPLC-Q-TOF-MS. Biomed Chromatogr. 2020;34(1): e4701. CrossRef PubMed Google Scholar
  17. 17.
    Wang X, Wei L, Wang L, et al. Scutellarin potentiates vancomycin against lethal pneumonia caused by methicillin-resistant Staphylococcus aureus through dual inhibition of sortase A and caseinolytic peptidase P. Biochem Pharmacol. 2022;199: 114982. CrossRef PubMed Google Scholar
  18. 18.
    Fang H, Zhao X, Zhang M, et al. Beneficial effects of flavonoids on cardiovascular diseases by influencing NLRP3 inflammasome. Inflammopharmacology. 2023;31: 1-15. CrossRef PubMed Google Scholar
  19. 19.
    Xu H, Wang E, Chen F, et al. Neuroprotective phytochemicals in experimental ischemic stroke: mechanisms and potential clinical applications. Oxid Med Cell Longev. 2021;2021: 1-45. PubMed Google Scholar
  20. 20.
    Bangar A, Khan H, Kaur A, et al. Understanding mechanistic aspect of the therapeutic role of herbal agents on neuroplasticity in cerebral ischemic-reperfusion injury. J Ethnopharmacol. 2023, 117153. PubMed Google Scholar
  21. 21.
    Tuli H, Bhushan S, Kumar A, et al. Autophagy Induction by Scutellaria Flavones in Cancer: Recent Advances. Pharmaceuticals. 2023;16(2): 302. CrossRef PubMed Google Scholar
  22. 22.
    Subedi L, Gaire B. Phytochemicals as regulators of microglia/macrophages activation in cerebral ischemia. Pharmacol Res. 2021;165: 105419. CrossRef PubMed Google Scholar
  23. 23.
    Chen H, Jia W, Li H, et al. Scutellarin exerts anti-inflammatory effects in activated microglia/brain macrophage in cerebral ischemia and in activated BV-2 microglia through regulation of MAPKs signaling pathway. Neuromolecular Med. 2020;22(2): 264-77. CrossRef PubMed Google Scholar
  24. 24.
    Niu R, Xiong L, Zhou H, et al. Scutellarin ameliorates neonatal hypoxic-ischemic encephalopathy associated with GAP43-dependent signaling pathway. Chin Med. 2021;16(1): 105. CrossRef PubMed Google Scholar
  25. 25.
    Hung Y, Liu Y, Wu B, et al. Cinaciguat prevents postnatal closure of ductus arteriosus by vasodilation and anti-remodeling in neonatal rats. Front Physiol. 2021;12: 661171. CrossRef PubMed Google Scholar
  26. 26.
    Lorigo M, Quintaneiro C, Maia C, et al. UV-B filter octylmethoxycinnamate impaired the main vasorelaxant mechanism of humanumbilical artery. Chemosphere. 2021;277: 130302. CrossRef PubMed Google Scholar
  27. 27.
    Abdallah H, Hassan N, El-Halawany A, et al. Major flavonoids from Psiadia punctulata produce vasodilation via activation of endothelial dependent NO signaling. J Adv Res. 2020;24: 273-9. CrossRef PubMed Google Scholar
  28. 28.
    Shen Z, Zhang Z, Wang X, et al. VEGFB-VEGFR1 ameliorates Ang II-induced cardiomyocyte hypertrophy through Ca2+-mediated PKG I pathway. J Cell Biochem. 2018;119(2): 1511-20. CrossRef PubMed Google Scholar
  29. 29.
    Chen Y, Chen C, Li M, et al. Scutellarin reduces cerebral ischemia reperfusion injury involving in vascular endothelium protection and PKG signal. Nat Prod Bioprospect. 2021;11(6): 659-70. CrossRef PubMed Google Scholar
  30. 30.
    Deng M, Sun J, Peng L, et al. Scutellarin acts on the AR-NOX axis to remediate oxidative stress injury in a mouse model of cerebral ischemia/reperfusion injury. Phytomedicine. 2022;103: 154214. CrossRef PubMed Google Scholar
  31. 31.
    Meng Z, Wu J, Zhu Y, et al. Revealing the common mechanisms of scutellarin in angina pectoris and ischemic stroke treatment via a network pharmacology Approach. Chin J Integr Med. 2021;27(1): 62-9. CrossRef PubMed Google Scholar
  32. 32.
    Jia Q, Chen H, Qi Z, et al. Network pharmacology to explore the mechanism of scutellarin in the treatment of brain ischaemia and experimental verification of JAK2/STAT3 signalling pathway. Sci Rep-Uk. 2023;13(1): 1-11. CrossRef PubMed Google Scholar
  33. 33.
    Xie X, Wang F, Ge W, et al. Scutellarin attenuates oxidative stress and neuroinflammation in cerebral ischemia/reperfusion injury through PI3K/Akt-mediated Nrf2 signaling pathways. Eur J Pharmacol. 2023;957: 175979. CrossRef PubMed Google Scholar
  34. 34.
    Zhang Y, Zhang Z, Wang J, et al. Scutellarin alleviates cerebral ischemia/reperfusion by suppressing oxidative stress and inflammatory responses via MAPK/NF‐κB pathways in rats. Environ Toxicol. 2022;37(12): 2889-96. CrossRef PubMed Google Scholar
  35. 35.
    Wang C, Liu Y, Liu X, et al. Scutellarin alleviates ischemic brain injury in the acute phase by affecting the activity of neurotransmitters in neurons. Molecules. 2023;28(7): 3181. CrossRef PubMed Google Scholar
  36. 36.
    Chen H, Yang L, Zhang X, et al. Scutellarin acts via MAPKs pathway to promote M2 polarization of microglial cells. Mol Neurobiol. 2023;60(8): 4304-23. CrossRef PubMed Google Scholar
  37. 37.
    Zhang T, Wang K, Fan H, et al. Ameliorative effect of scutellarin on acute alcohol brain injury in mice. J Zhejiang Univ-Sc B. 2022;23(3): 258-64. CrossRef PubMed Google Scholar
  38. 38.
    Li J, Song Z , Hou X. Scutellarin ameliorates ischemia/reperfusion injury induced cardiomyocyte apoptosis and cardiac dysfunction via inhibition of the cGAS STING pathway. Exp Ther Med. 2023;25(4): 1-9. CrossRef PubMed Google Scholar
  39. 39.
    Zhou L, Han Y, Yang Q, et al. Scutellarin attenuates doxorubicin-induced oxidative stress, DNA damage, mitochondrial dysfunction, apoptosis and autophagy in H9c2 cells, cardiac fibroblasts and HUVECs. Toxicol In Vitro. 2022;82: 105366. CrossRef PubMed Google Scholar
  40. 40.
    Wang W, Liu X, Ding Y, et al. Scutellarin Protects Myocardial Ischemia-Reperfusion Injury ERK1/2-CREB Regulated Mitophagy. Pharmacogn Mag. 2023, 09731296231199860. PubMed Google Scholar
  41. 41.
    Fu Y, Sun S, Sun H, et al. Scutellarin exerts protective effects against atherosclerosis in rats by regulating the Hippo-FOXO3A and PI3K/AKT signaling pathways. J Cell Physiol. 2019;234(10): 18131-45. CrossRef PubMed Google Scholar
  42. 42.
    Su Y, Fan X, Li S, et al. Scutellarin Improves Type 2 Diabetic Cardiomyopathy by Regulating Cardiomyocyte Autophagy and Apoptosis. Dis Markers. 2022;2022: 3058354. CrossRef PubMed Google Scholar
  43. 43.
    Huo Y, Mijiti A, Cai R, et al. Scutellarin alleviates type 2 diabetes (HFD/low dose STZ)-induced cardiac injury through modulation of oxidative stress, inflammation, apoptosis and fibrosis in mice. Hum Exp Toxicol. 2021;40(12): S460-74. CrossRef PubMed Google Scholar
  44. 44.
    Qu D, Feng P, Zhang X, et al. Effects of scutellarin on acute myocardial ischemia/reperfusion injury in isolated rat heart. Eur J Inflamm. 2023;21: 1721727X231192289. CrossRef PubMed Google Scholar
  45. 45.
    Yang L, Li Z, Fang J. Scutellarin Alleviates Diabetic Retinopathy via the Suppression of Nucleotide-Binding Oligomerization Domain (NOD)-Like Receptor Pyrin Domain Containing Protein 3 Inflammasome Activation. Curr Eye Res. 2023, 1-8. PubMed Google Scholar
  46. 46.
    Zeng S, Chen L, Sun Q, et al. Scutellarin ameliorates colitis-associated colorectal cancer by suppressing Wnt/β-catenin signaling cascade. Eur J Pharmacol. 2021;906: 174253. CrossRef PubMed Google Scholar
  47. 47.
    Guo X, Li R, Cui J, et al. Induction of RIPK3/MLKL-mediated necroptosis by Erigeron breviscapus injection exhibits potent antitum or effect. Front Pharmacol. 2023;14: 1219362. CrossRef PubMed Google Scholar
  48. 48.
    Zeng S, Tan L, Sun Q, et al. Suppression of colitis-associated colorectal cancer by scutellarin through inhibiting Hedgehog signaling pathway activity. Phytomedicine. 2022;98: 153972. CrossRef PubMed Google Scholar
  49. 49.
    Deng W, Han W, Fan T, et al. Scutellarin inhibits human renal cancer cell proliferation and migration via upregulation of PTEN. Bio med Pharmacother. 2018;107: 1505-13. CrossRef PubMed Google Scholar
  50. 50.
    Derynck R, Budi E. Specificity, versatility, and control of TGF-β family signaling. Sci Signal. 2019;12(570): eaav5183. CrossRef PubMed Google Scholar
  51. 51.
    David C, Massagué J. Contextual determinants of TGFβ action in development, immunity and cancer. Nat Rev Mol Cell Biol. 2018;19(7): 419-35. CrossRef PubMed Google Scholar
  52. 52.
    Yao Y, Yuan Y, Lu Z, et al. Effects of Nervilia fordii Extract on Pulmonary Fibrosis Through TGF-β/Smad Signaling Pathway. Front Pharmacol. 2021;12: 659627. CrossRef PubMed Google Scholar
  53. 53.
    Zhang G, Chen W, Li X, et al. Scutellarin-induced A549 cell apoptosis depends on activation of the transforming growth factor-β1/smad2/ROS/caspase-3 pathway. Open Life Sci. 2021;16(1): 961-8. CrossRef PubMed Google Scholar
  54. 54.
    He G, Xing D, Jin D, et al. Scutellarin improves the radiosensitivity of non-small cell lung cancer cells to iodine-125 seeds via downregulating the AKT/mTOR pathway. Thorac Cancer. 2021;12(17): 2352-9. CrossRef PubMed Google Scholar
  55. 55.
    Sun C, Zhu Y, Li X, et al. Scutellarin Increases Cisplatin-Induced Apoptosis and Autophagy to Overcome Cisplatin Resistance in Non-small Cell Lung Cancer via ERK/p53 and c-met/AKT Signaling Pathways. Front Pharmacol. 2018;9: 92. CrossRef PubMed Google Scholar
  56. 56.
    Wang F, Bao M, Xu J, et al. Scutellarin inhibits the glioma cell proliferation by downregulating BIRC5 to promote cell apoptosis. J Cell Mol Med. 2023;27(14): 1975-87. CrossRef PubMed Google Scholar
  57. 57.
    Du J, Li J, Tan J, et al. Scutellarin inhibits glioma cell proliferation by up-regulating miR-15a expression. Am J Transl Res. 2023;15(3): 2156. PubMed Google Scholar
  58. 58.
    Chen Y, Li W. Scutellarin inhibits glioblastoma growth in a dose-dependent manner by suppressing the p63 signaling pathway. Dose-Response. 2023;21(3): 15593258231197101. CrossRef PubMed Google Scholar
  59. 59.
    Mei X, Ouyang H, Zhang H, et al. Scutellarin suppresses the metastasis of triple-negative breast cancer via targeting TNFα/TNFR2-RUNX1-triggered G-CSF expression in endothelial cells. Biochem Pharmacol. 2023;217: 115808. CrossRef PubMed Google Scholar
  60. 60.
    Mei X, Zhang J, Jia W, et al. Scutellarin suppresses triple-negative breast cancer metastasis by inhibiting TNFα-induced vascular end othelial barrier breakdown. Acta Pharmacol Sin. 2022;43(10): 2666-77. CrossRef PubMed Google Scholar
  61. 61.
    Liu F, Zu X, Xie X, et al. Scutellarin Suppresses Patient-Derived Xenograft Tumor Growth by Directly Targeting AKT in Esophageal Squamous Cell Carcinoma. Cancer Prev Res (Phila). 2019;12(12): 849-60. CrossRef PubMed Google Scholar
  62. 62.
    Hayashi Y, Maysuo Y, Denda Y, et al. Girdin regulates both migration and angiogenesis in pancreatic cancer cell lines. Oncol Rep. 2023;50(3): 1-14. CrossRef PubMed Google Scholar
  63. 63.
    Li L, Zou Y, Wang L, et al. Nanodelivery of scutellarin induces immunogenic cell death for treating hepatocellular carcinoma. Int J Pharmaceut. 2023, 123114. PubMed Google Scholar
  64. 64.
    Luan H, Huo Z, Zhao Z, et al. Scutellarin, a modulator of mTOR, attenuates hepatic insulin resistance by regulating hepatocyte lipid metabolism via SREBP‐1c suppression. Phytotherapy research. 2020;34(6): 1455-66. CrossRef PubMed Google Scholar
  65. 65.
    Gao L, Tang H, Zeng Q, et al. The anti-insulin resistance effect of scutellarin may be related to antioxidant stress and AMPKα activation in diabetic mice. Obes Res Clin Pract. 2020;14(4): 368-74. CrossRef PubMed Google Scholar
  66. 66.
    Xi J, Rong Y, Zhao Z, et al. Scutellarin ameliorates high glucose-induced vascular endothelial cells injury by activating PINK1/Parkin-mediated mitophagy. J Ethnopharmacol. 2021;271: 113855. CrossRef PubMed Google Scholar
  67. 67.
    Li N, Guo XL, Xu M, et al. Network pharmacology mechanism of Scutellarin to inhibit RGC pyroptosis in diabetic retinopathy. Sci Rep-Uk. 2023;13(1): 6504. CrossRef PubMed Google Scholar
  68. 68.
    Fan X, Wang Y, Li X, et al. Scutellarin alleviates liver injury in type 2 diabetic mellitus by suppressing hepatocyte apoptosis in vitro and in vivo. Chin Herb Med. 2023;15: 542-8. PubMed Google Scholar
  69. 69.
    Huang B, Han R, Tan H, et al. Scutellarin ameliorates diabetic nephropathy via TGF-β1 signaling pathway. Biol Pharm Bull. 2023. CrossRef PubMed Google Scholar
  70. 70.
    Hu X, Teng S, He J, et al. Pharmacological basis for application of scutellarin in Alzheimer’s disease: antioxidation and antiapoptosis. Mol Med Rep. 2018;18(5): 4289-96. PubMed Google Scholar
  71. 71.
    Zeng Y, Cui Y, Gu J, et al. Scutellarin mitigates Aβ-induced neurotoxicity and improves behavior impairments in AD mice. Molecules. 2018;23(4): 869. CrossRef PubMed Google Scholar
  72. 72.
    Huang X, Xu Y, Sui X, et al. Scutellarein suppresses Aβ-induced memory impairment via inhibition of the NF-κB pathway in vivo and in vitro. Oncol Lett. 2019;17(6): 5581-9. PubMed Google Scholar
  73. 73.
    Shin J, Kweon K, Kim D, et al. Scutellarin ameliorates learning and memory deficit via suppressing β-amyloid formation and microglial activation in rats with chronic cerebral hypoperfusion. Am J Chin Med. 2018;46(6): 1203-23. CrossRef PubMed Google Scholar
  74. 74.
    Sheng N, Zhang Z, Zheng H, et al. Scutellarin rescued mitochondrial damage through ameliorating mitochondrial glucose oxidation via the Pdk-Pdc axis. Adv Sci. 2023;10: 2303584. CrossRef PubMed Google Scholar
  75. 75.
    Peng L, Wen L, Shi QF, et al. Scutellarin ameliorates pulmonary fibrosis through inhibiting NF-κB/NLRP3-mediated epithelial-mesenchymal transition and inflammation. Cell Death Dis. 2020;11(11): 978. CrossRef PubMed Google Scholar
  76. 76.
    Bian H, Wang G, Huang J, et al. Scutellarin protects against lipopolysaccharide-induced behavioral deficits by inhibiting neuroinflammation and microglia activation in rats. Int Immunopharmacol. 2020;88: 106943. CrossRef PubMed Google Scholar
  77. 77.
    Ye J, Zeng B, Zhong M, et al. Scutellarin inhibits caspase-11 activation and pyroptosis in macrophages via regulating PKA signaling. Acta Pharm Sin B. 2021;11(1): 112-26. CrossRef PubMed Google Scholar
  78. 78.
    Luo Z, Hu Z, Bian Y, et al. Scutellarin attenuates the IL-1β-induced inflammation in mouse chondrocytes and prevents osteoarthritic progression. Front Pharmacol. 2020;11: 107. CrossRef PubMed Google Scholar
  79. 79.
    Yang H, Wang Z, Wang L, et al. Scutellarin ameliorates osteoarthritis by protecting chondrocytes and subchondral bone microstructure by inactivating NF-κB/MAPK signal transduction. Biomed Pharmacother. 2022;155: 113781. CrossRef PubMed Google Scholar
  80. 80.
    Li J, Wang Q, Zhang X. Scutellarin alleviates complete freund’s adjuvant-induced rheumatoid arthritis in mice by regulating the Keap1/Nrf2/HO-1 pathway. Biocell. 2023;47(6): 1307-16. CrossRef PubMed Google Scholar
  81. 81.
    Aksit H, Aksit D, Altun E. Protective effects of scutellarin in experimental colitis in rats. Biotech Histochem. 2023;6(98): 432-44. CrossRef PubMed Google Scholar
  82. 82.
    Liu Q, Li X, Ouyang X, et al. Dual effect of glucuronidation of a pyrogallol-type phytophenol antioxidant: a comparison between scutellarein and scutellarin. Molecules. 2018;23(12): 3225. CrossRef PubMed Google Scholar
  83. 83.
    Hu X, Wu X, Zhao B, et al. Scutellarin protects human retinal pigment epithelial cells against hydrogen peroxide (H2O2)-induced oxidative damage. Cell Biosci. 2019;9: 12. CrossRef PubMed Google Scholar
  84. 84.
    Wang L, Song J, Liu A, et al. Research progress of the antiviral bioactivities of natural flavonoids. Nat Prod Bioprospect. 2020;10: 271-83. CrossRef PubMed Google Scholar
  85. 85.
    Wang X, Wei L, Wang L, et al. Scutellarin potentiates vancomycin against lethal pneumonia caused by methicillin-resistant Staphylococcus aureus through dual inhibition of sortase A and caseinolytic peptidase P. Biochem Pharmacol. 2022;199: 114982. CrossRef PubMed Google Scholar
  86. 86.
    Miao Z, Lai Y, Zhao Y, et al. Protective property of scutellarin against liver injury induced by carbon tetrachloride in mice. Front Pharmacol. 2021;12: 710692. CrossRef PubMed Google Scholar
  87. 87.
    Dai J, Li C, Zhao L, et al. Scutellarin protects the kidney from ischemia/reperfusion injury by targeting Nrf2. Nephrology. 2022;27(8): 690-700. CrossRef PubMed Google Scholar
  88. 88.
    Yang Q, Wang Y, Chen H, et al. Protective activities of scutellarin against alcohol-induced acute kidney injury. Chem Biodivers. 2022;19(11): e202200254. CrossRef PubMed Google Scholar
  89. 89.
    Shahmohammadi A, Golchoobian R, Mirahmadi S, et al. Scutellarin alleviates lipopolysaccharide-provoked septic nephrotoxicity via attenuation of inflammatory and oxidative events and mitochondrial dysfunction. Immunopharm Immunot. 2023;45(3): 295-303. CrossRef PubMed Google Scholar
  90. 90.
    Zhu J, Sainulabdeen A, Akers K, et al. Oral scutellarin treatment ameliorates retinal thinning and visual deficits in experimental glaucoma. Front Med (Lausanne). 2021;8: 681169. CrossRef PubMed Google Scholar
  91. 91.
    Li G, Guan C, Xu L, et al. Scutellarin ameliorates renal injury via increasing CCN1 expression and suppressing NLRP3 inflammasome activation in hyperuricemic mice. Front Pharmacol. 2020;11: 584942. CrossRef PubMed Google Scholar
  92. 92.
    Duan J, Wang J, Zhao Q, et al. Anti-convulsant effects of scutellarein in a PTZ kindling model in mice. Pharmacogn Mag. 2023. CrossRef PubMed Google Scholar
  93. 93.
    Wang L, Ma Q. Clinical benefits and pharmacology of scutellarin: a comprehensive review. Pharmacol Therapeut. 2018;190: 105-27. CrossRef PubMed Google Scholar
  94. 94.
    Li X, Sun S, Jiang G. Research progress on quality control of breviscapine in injection form. Mod Chin Med. 2020;22(06): 971-8. PubMed Google Scholar

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Authors and Affiliations

  1. 1. Beijing City Key Laboratory of Drug Target and Screening Research, National Center for Pharmaceutical Screening, Institute of Materia Medica, Chinese Academy of Medical Sciences, and Peking Union Medical College, Beijing 100050, China
  2. 2. Beijing City Key Laboratory of Polymorphic Drugs, Center of Pharmaceutical Polymorphs, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
  3. 3. Pharmaceutical College of Henan University, Kaifeng 475004, China
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