Luteolin is a naturally occurring flavonoid compound that typically appears as pale yellow, needle-like crystals. It often exists in glycosylated forms in various medicinal herbs, vegetables, and fruits, including honeysuckle, perilla, basil, cabbage, cauliflower, carrots, and pomegranates. Modern pharmacological studies have demonstrated that luteolin possesses a wide range of pharmacological activities, such as anti-inflammatory, antibacterial, antioxidant, and anti-tumor effects.


Antioxidant Properties of Luteolin

Luteolin, a type of flavonoid, is a potent scavenger of reactive oxygen species (ROS), acting as both an O₂ scavenger and a singlet oxygen quencher. The antioxidant capacity of luteolin is significantly influenced by the number and position of phenolic hydroxyl groups on its B ring. The presence of a catechol group on the B ring is particularly crucial for its antioxidant activity.

Luteolin can donate hydrogen atoms to react with free radicals, forming stable compounds and preventing ROS-induced cellular damage. Moreover, it can activate nuclear factor erythroid 2-related factor 2 (Nrf2), which then translocates to the nucleus and binds to antioxidant response elements (AREs). This leads to the upregulation of antioxidant enzymes such as catalase, superoxide dismutase, glutathione peroxidase, and heme oxygenase-1, thereby reducing ROS generation.

Studies have demonstrated that luteolin can effectively scavenge ROS induced by UVA irradiation, protecting human skin fibroblasts (HSFs) and inhibiting the production of hypoxia-inducible factor-1α (HIF-1α), thus mitigating UVA-induced HSF autophagy. Additionally, luteolin has been shown to prevent hydrogen peroxide-induced cytotoxicity and apoptosis in human immortalized keratinocytes (HaCaT cells).

The antioxidant activity of luteolin is pH-dependent, with optimal activity observed at a pH range of 3-4 in acidic conditions. Compared to butylated hydroxytoluene (BHT), luteolin exhibits a stronger inhibitory effect on the formation of malondialdehyde from palm oil, indicating its superior antioxidant capacity.


Antimicrobial Properties of Luteolin

Luteolin has been shown to exhibit potent antimicrobial activity against a wide range of bacteria.

Disruption of bacterial cell wall and membrane: Experimental evidence suggests that luteolin can disrupt the integrity of bacterial cell walls and increase cell membrane permeability, leading to alterations in cell morphology.

Inhibition of DNA synthesis: Luteolin inhibits the activity of intracellular DNA topoisomerases, resulting in decreased levels of total protein and nucleic acids within the cell, thereby suppressing bacterial growth. Studies have shown that luteolin can induce morphological changes in Escherichia coli and Pseudomonas aeruginosa, with some E. coli cells exhibiting distorted or even ruptured shapes.

Activity against antibiotic-resistant bacteria: Luteolin exhibits significant activity against methicillin-resistant Staphylococcus aureus (MRSA) and can enhance the efficacy of other antibiotics such as quinolones and aminoglycosides by reducing their minimum inhibitory concentrations (MICs) and mitigating adverse effects.

pH stability: The minimum inhibitory concentration (MIC) of luteolin against Staphylococcus aureus was consistently below 0.24% within a pH range of 5.0 to 9.0, indicating strong antimicrobial activity. While the MIC tended to decrease slightly with extreme pH values, luteolin's antimicrobial activity was not significantly affected by high temperatures or short-term heat treatment.

Luteolin demonstrates a broad spectrum of antimicrobial activity and the ability to combat antibiotic resistance, making it a promising candidate for the treatment of bacterial infections, especially those caused by drug-resistant strains.


Anti-inflammatory Effects of Luteolin

Inflammation is a defensive response initiated by the body to harmful stimuli. Studies have shown that luteolin exerts potent anti-inflammatory effects, particularly in macrophages.

In vitro studies using MTT assay and cell death ELISA demonstrated that treatment with 20 μM luteolin induced morphological changes in RAW264.7 macrophages, characterized by cell shrinkage and the formation of apoptotic bodies.

In vivo studies have shown that luteolin can modulate macrophage polarization from the pro-inflammatory M1 phenotype to the anti-inflammatory M2 phenotype by upregulating signal transducer and activator of transcription 6 (STAT6) and downregulating STAT3. This shift in macrophage polarization is accompanied by a reduction in pro-inflammatory cytokines and an increase in anti-inflammatory cytokines.

In a mouse model of acute gouty arthritis induced by monosodium urate, luteolin significantly reduced ankle joint swelling and serum levels of pro-inflammatory cytokines such as IL-1β, IL-17, IL-6, and TNF-α. Furthermore, luteolin inhibited the expression of NF-κB and HMGB1, suggesting that it exerts its anti-inflammatory effects by suppressing the HMGB1-NF-κB signaling pathway.

At the molecular level, luteolin inhibits the phosphorylation and activation of IκB kinase β (IKKβ), thereby suppressing NF-κB activation and reducing the expression of pro-inflammatory cytokines like TNF-α and IL-6.

In conclusion, luteolin exhibits potent anti-inflammatory effects through multiple mechanisms and holds promise as a therapeutic agent for various inflammatory diseases.



Anti-Tumor Effects

In recent years, extensive research has been conducted on the effects of luteolin on tumors. Its anti-tumor mechanisms are relatively complex, involving both direct inhibition of tumor cell growth and proliferation, as well as other pathways that ultimately suppress tumor progression.

Inhibition of Tumor Cell Proliferation.Studies have shown that luteolin can suppress the proliferation of colon cancer cells by interfering with the expression of glycogen synthase kinase (GSK-3), β-catenin, and cyclin D1. Research on the effects of luteolin on human breast cancer cells (MCF-7) has revealed that its inhibitory effects on MCF-7 cells are both time-dependent and concentration-dependent.Cell cycle analysis indicates that luteolin primarily arrests cell growth in the S phase of the cell cycle. By examining 10 metabolites, including D-ribose, D-galactose, and phosphoric acid, researchers hypothesize that luteolin’s mechanism for inhibiting cell proliferation involves blocking enzyme activity in the pentose phosphate metabolic pathway.

Induction of Tumor Cell Apoptosis. Research on human liver cancer cells (HepG2) has shown that luteolin can induce apoptosis, as detected by flow cytometry. Analysis revealed that luteolin decreases the levels of iASPP within HepG2 cells while increasing the levels of pro-apoptotic proteins such as p53 and ASPP2.

Furthermore, experimental results confirmed that luteolin has a significant pro-apoptotic effect and cell cycle arrest on the non-small cell lung cancer cell line A549. The mechanism is related to the upregulation of JNK phosphorylation, which activates the mitochondrial apoptosis pathway, while simultaneously inhibiting NF-κB nuclear translocation, preventing its transcriptional activity.

Anti-Tumor Metastasis Effect. After treatment with luteolin, the secretion of MMP-9 in ovarian cancer cell line HO-8910PM decreased, and the expression of ERK2 protein was significantly reduced. This may be the primary mechanism by which tumor cell invasion and motility in vitro decrease in a dose-dependent manner. Luteolin inhibits the expression of β3 integrin, preventing epithelial cancer cell epithelial-to-mesenchymal transition (EMT), while slowing down the growth rate of A431 epidermal tumor cells. It also reduces the potential invasiveness of malignant melanoma cells by reversing the EMT process.

Sensitizing Effect on Radiotherapy and Chemotherapy. Luteolin can act as a sensitizer for radiotherapy and chemotherapy. When used in combination with chemotherapy drugs, it can increase the sensitivity of tumors to these drugs and enhance the ability of the drugs to induce apoptosis in tumor cells.


Other Pharmacological Effects of Luteolin

Luteolin has been shown to exhibit a wide range of pharmacological activities beyond its anti-inflammatory and anti-cancer properties.

Cardioprotective effects: Luteolin significantly increases the contractility of the left ventricle in rats in a dose-dependent manner (P < 0.05). The underlying mechanism may involve upregulation of the transcription factor SP1, leading to enhanced transcription of the sarcoplasmic reticulum Ca2+-ATPase (SERCA2a) gene, thereby mitigating myocardial ischemia-reperfusion injury.

Vasodilatory and renoprotective effects: Luteolin can decrease intracellular calcium concentrations, resulting in the dilation of constricted renal arteries and subsequent reduction in blood pressure. These findings suggest that luteolin may be beneficial for the treatment of renal hypertension.

Anti-allergic effects: Luteolin has demonstrated anti-allergic properties, making it a potential therapeutic agent for conditions such as asthma and dry skin itching.

Neuroprotective effects: Luteolin has been shown to enhance learning and memory functions, suggesting potential neuroprotective effects.

In summary, luteolin exhibits a wide range of pharmacological activities beyond its well-known anti-inflammatory and anti-cancer properties. These findings suggest that luteolin may have therapeutic potential for various diseases, including cardiovascular diseases, hypertension, allergies, and neurological disorders.