Research Progress on the Pharmacological Effects and Molecular Mechanisms of Baicalein

Baicalein, a flavonoid monomer compound isolated from the dried roots of the traditional Chinese medicinal herb Scutellaria baicalensis, serves as the primary pharmacological material basis of the herb. In recent years, with the extensive research and deepening understanding of baicalein by researchers, it is believed that baicalein has various effects including scavenging oxygen free radicals, relieving fever and pain, anti-inflammation, inhibiting neovascularization, anti-tumor, and antibacterial and antiviral properties.

1. Analgesic, Antipyretic, and Anti-inflammatory Effects

Baicalein exerts analgesic, antipyretic, and anti-inflammatory effects by interfering with signaling pathways such as NF-κB and MAPK, inhibiting the activity of nuclear factors, and suppressing the secretion and release of inflammatory factors. Baicalein blocks these signaling pathways to inhibit the infiltration of macrophages and lymphocytes, significantly reducing the mRNA expression of pro-inflammatory factors such as TNF-α, IL-1β, and monocyte chemoattractant protein. Using LPS-induced RAW264.7 cells to form an inflammatory model to study the anti-inflammatory mechanism of baicalein, it was found that baicalein inhibits COX-2 gene expression, prevents the binding of C/EBPb to DNA, and thereby inhibits the metabolism of arachidonic acid and the production of its metabolites. Baicalein significantly reduces the damage to the body caused by LPS-induced mastitis by blocking the expression of TLR4 receptors, thereby inhibiting the NF-κB pathway and reducing the activity of inflammatory factors such as TNF-α and IL-1β. Baicalein can also reduce the ascites content in rat models of severe acute pancreatitis by inhibiting the secretion of IL-6 and TNF-α, preventing pancreatic damage, and improving survival rates. In addition, in a rabbit model of phlebitis induced by the chemotherapeutic drug vinorelbine (VRB), baicalein significantly reduces the loss of vascular endothelial cells, edema, inflammatory cell infiltration, and thrombosis, and lowers serum levels of TNF-α, IL-1β, IL-6, and ICAM-1. In vitro experiments show that baicalein can reduce VRB-induced endothelial cell apoptosis, lower intracellular ROS levels, inhibit the phosphorylation of p38, and ultimately inhibit the activation of the NF-κB signaling pathway. The results indicate that baicalein can protect against VRB-induced endothelial damage in rabbit models of intravenous injection by inhibiting the production of intracellular ROS and inactivating the p38/NF-κB pathway, thereby reducing the production of pro-inflammatory cytokines.

2. Antibacterial and Antiviral Effects

Baicalein has a wide antibacterial spectrum, with a particularly significant inhibitory effect against Staphylococcus aureus. Baicalein exerts its antibacterial function by affecting bacterial membrane permeability, inhibiting protein synthesis, and influencing the activities of SDH, MDH, and DNA topoisomerase I and II. Research shows that the IC50 of baicalein's inhibitory effect on Escherichia coli is approximately 0.29 mmol/L, and the mechanism may be the inhibition of ATP synthase. The minimum inhibitory concentrations (MICs) of baicalein against Fusarium oxysporum and Candida albicans are 112 and 264 μg/mL, respectively. Baicalein inhibits Candida albicans by inhibiting the formation of its biofilm, reducing mitochondrial membrane potential, and inducing cell death. Baicalein demonstrates better antibacterial efficacy when used in combination with other antibacterial drugs. In vitro studies have shown that the combination of baicalein and ciprofloxacin can reverse the ciprofloxacin resistance of methicillin-resistant Staphylococcus aureus by inhibiting the NorA efflux pump, pyruvate kinase activity, and the bacterial SOS response, resulting in the loss of reactive oxygen species and ATP in the bacteria.

After oral administration, baicalein can rapidly be converted into baicalin in the body, exerting an inhibitory effect on the replication of influenza A virus. Baicalein has significant inhibitory effects on neuraminidase and ROS production in vitro, and in vivo, it can significantly reduce the mortality rate and improve lung parameters in mice infected with influenza A virus. Baicalein exerts its antiviral effect by inhibiting the activity of epidermal growth factor tyrosine kinase, restoring the expression of VIPmRNA in extravillous trophoblast cells, and blocking the nuclear translocation of human cytomegalovirus.

3. Anti-Tumor and Anti-Cancer Effects

Baicalein exhibits significant anti-proliferative effects on various cancer cell lines. It can arrest HCT-116 human colon cancer cells in the S phase, activate caspase 3 and caspase 9, and promote cell apoptosis. Research has found that baicalein can effectively inhibit the growth and metastasis of prostate cancer cells, and its mechanism is related to inhibiting the caveolin-1/AKT/mTOR pathway. Baicalein not only inhibits the expression of MMP-2 in a dose-dependent manner, but also powerfully resists the invasion of ovarian cancer cells, which is associated with its ability to reduce NF-κB signaling molecule activity and inhibit p38MAPK activation. The key to preventing tumor metastasis is inhibiting tumor cells from detaching from the primary tumor. Studies have shown that baicalein can inhibit the growth and migration of human breast cancer cells in a dose-dependent manner, and its inhibitory mechanism is related to inhibiting epithelial-mesenchymal transition (EMT) in breast epithelial cells while inhibiting the NF-κB signaling pathway. Baicalein can inhibit EMT in breast epithelial cells and tumorigenic activity in breast cancer cells. Baicalein inhibits TGF-b1-mediated EMT by suppressing NF-κB pathway expression levels, subsequently reducing migration and TGF-b1-mediated EMT in human breast cancer cells (MDA-MB-231 cells). Baicalein has therapeutic effects on human breast cancer MCF-7 cells, mediating cell cycle arrest mainly in the G0/G1 phase within 12 hours of treatment with baicalein, and after 12 hours, they mainly arrest in the S phase. With 200 μg/mL baicalein treatment for 24 hours, 44.9% of MCF-7 cells entered the early stage of apoptosis.

4. Removal of Oxygen Free Radicals and Antioxidant Effects

Baicalein is a flavonoid inhibitor of 12-lipoxygenase that can prevent ROS accumulation by upregulating Nrf2 and inhibiting 12-lipoxygenase, thereby protecting cells from hydrogen peroxide-induced damage. Baicalein possesses phenolic hydroxyl groups, including three hydroxyl groups, which exhibit a certain degree of free radical scavenging activity. It selectively increases the content of H2O2 in tumor cells, leading to tumor cell death. Baicalein is an excellent inhibitor of xanthine oxidase and can effectively suppress the production of oxygen free radicals during ischemia-reperfusion. Therefore, baicalein can protect human fibroblasts from damage caused by oxygen free radicals, and its protective mechanism is related to the scavenging of free radicals.

5. Treatment of Diabetes and Its Complications

Diabetes can lead to reduced executive function and attention in patients, and in severe cases, cognitive impairment may occur. Baicalein significantly reduces blood glucose levels and acetylcholinesterase (AChE) activity in diabetic rat models, increases body weight and choline acetyltransferase (ChAT) activity, thus improving cognitive impairment in rats. Baicalein can delay the occurrence of diabetic complications. It significantly reduces renal tissue damage and oxidative stress in diabetic rats, likely through inhibiting NF-κB activation and reducing the expression of iNOS and TGF-β1, thereby improving structural changes in renal tissue. Baicalein significantly inhibits monocyte adhesion, TGF-β1mRNA expression, and vascular inflammation caused by high glucose. After gastric administration, baicalein can improve diabetic retinopathy, inhibit the activation of keratinocytes and inflammatory responses, thereby improving vascular function in the retina of diabetic rats and inhibiting neuronal loss.

6. Hepatoprotective Effects

Baicalein can significantly alleviate immune-mediated liver injury caused by LPS and sepsis, primarily by inhibiting the MAPKs and NF-κB pathways to reduce the levels of ALT, TNF-α, AST, and NO, and inhibiting the expression of iNOS. The mechanism may involve increasing the Bcl-1/Bax ratio, protecting liver tissue mitochondria, inhibiting the release of cytochrome C, and inhibiting the phosphorylation of IκBα, ERK, and JNK. Acetaminophen (APAP)-induced hepatotoxicity is the main cause of drug-induced liver injury. Baicalein can alleviate APAP-induced hepatotoxicity both in vitro and in vivo. The results of liver glutathione (GSH) and reactive oxygen species (ROS) formation indicate that baicalein alleviates APAP-induced oxidative stress injury in the liver. Baicalein can induce the activation of nuclear factor erythroid 2-related factor 2 (Nrf2) and increase the expression of its downstream antioxidant genes. Baicalein induces sustained phosphorylation of extracellular signal-regulated protein kinase (ERK) 1/2 and protein kinase C (PKC), and both ERK1/2 and PKC inhibitors can eliminate Nrf2 phosphorylation and subsequent activation, thereby reducing APAP-induced hepatotoxicity.

7. Gastric Protective Effects

Research indicates that baicalein exerts gastric protective effects by inhibiting the activity of related secretory proteins in the gastric mucosa. Studies using ethanol/HCl-induced ulcer mice have investigated the role of presynaptic α2 receptors, sulfhydryl (SH) compounds, nitric oxide (NO), prostaglandins (PG), and ATP-sensitive K+ (KATP) channels in the gastric protection of baicalein. The levels of reduced glutathione (GSH) and myeloperoxidase (MPO) activity in the gastric mucosa were measured. The results showed that baicalein exhibited a dose-related gastric protective effect against acidified ethanol-induced injury. Intraduodenal treatment with baicalein significantly increased gastric mucus secretion. Additionally, baicalein treatment reduced total acid secretion and increased the pH value after the pylorus, thereby exerting a protective effect.

References

[1] Tian Shuo, Hong Tao, Zhang Duo, et al. Recent Research Progress on the Pharmacological Effects and Molecular Mechanisms of Baicalein [J]. Heilongjiang Medicine, 2015, 28(06): 1195-1199.

[2] Zhu Yanan, Yang Qimei, Zhang Shuo, et al. Research Progress on the Pharmacological Effects and Mechanisms of Baicalin and Baicalein [J]. Lishizhen Medicine and Materia Medica Research, 2020, 31(04): 921-925.

About the Author

Xiaomichong, a pharmaceutical quality researcher, has been committed to pharmaceutical quality research and drug analysis method validation for a long time. Currently employed by a large domestic pharmaceutical research and development company, she is engaged in drug inspection and analysis as well as method validation.