What Are the Benefits of Ivy Leaf Extract Hederagenin?

Hederagenin, a pentacyclic triterpenoid compound, is primarily derived from Chinese ivy and widely distributed in traditional Chinese herbs such as Cynanchum wilfordii, Patrinia scabiosa, Paeonia lactiflora, and Acanthopanax senticosus, among others. It is commonly found in the form of saponins or saponins [1]. Hederagenin extract is extensively studied in pharmaceutical and health-related fields due to its diverse biological activities, including antitumor, antidepressant, anti-inflammatory, and antibacterial effects. It also demonstrates potential therapeutic benefits for conditions such as depression, Alzheimer's disease, and osteoarthritis. However, its application is limited by poor oral bioavailability and low solubility. This paper provides a systematic review of the pharmacological effects and molecular mechanisms of Hederagenin, summarizing existing research to provide insights for future studies.

1 Pharmacological Effects of Ivy Extract Hederagenin

1.1 Anti-inflammatory Effects of Ivy Extract Hederagenin

Inflammation is a local and systemic pathological change primarily characterized by defensive reactions in response to pro-inflammatory factors. In normal conditions, inflammation is a natural defensive response of the body. However, prolonged excessive inflammation can lead to progressive tissue damage and become a pathogenic mechanism of diseases. The overexpression of inflammatory cytokines can cause adverse reactions in the body, such as the interleukin (IL) family and tumor necrosis factor α (TNF-α). The anti-inflammatory mechanism of Hederagenin is primarily associated with the nuclear factor κB (NF-κB) pathway. Zhang et al. [2] found that inhibiting the phosphorylation of p38 mitogen-activated protein kinase (MAPK) can suppress the activation of the transient receptor potential (TRP) channel, reduce the secretion of inflammatory factors such as IL-1β, IL-6, and TNF-α, thereby achieving an anti-inflammatory effect. Li et al. [3] suggested that the expression levels of pro-inflammatory cytokines and chemokines are associated with NF-κB, Hederagenin inhibits the NF-κB signaling pathway, reduces the expression levels of pro-inflammatory cytokines, thereby suppressing their activation, decreasing the secretion of pro-inflammatory cytokines, inhibiting the nuclear translocation of NF-κB and Smads proteins to reduce their transcriptional activity, and downregulating the downstream target molecules of the inflammatory signaling pathway, transforming growth factor β1, thereby exerting an anti-inflammatory effect.

In the study by Ma et al. [4], Hederagenin exerts its effects by regulating the Ras protein/Jun N-terminal kinase/T cell transcription factor 4 axis, downregulating the levels of inflammatory cytokines (tumor necrosis factor α and IL-6), transforming growth factor β1, and connective tissue growth factor in serum, thereby alleviating pulmonary fibrosis and inflammation in rats. Wang and Zhao [5] found that macrophage polarization and inflammatory responses are associated with the NOD-like receptor protein 3 inflammasome and NF-κB pathways. Hederagenin downregulated the expression of the NOD-like receptor protein 3 inflammasome and inhibited the phosphorylation of the NF-κB pathway, and through the NF-κB signaling pathway, it inhibited lipopolysaccharide-induced NOD-like receptor protein 3 inflammasome activation and M1-type macrophage polarization, thereby alleviating inflammatory responses, thereby exerting an anti-inflammatory effect in acute lung injury. Lee et al. [6] found that Hederagenin inhibits the NF-κB signaling pathway, reducing pro-inflammatory mediators such as nitric oxide synthase and cyclooxygenase-2, thereby alleviating inflammation.

Kim et al. [7] also demonstrated that Hederagenin exerts anti-inflammatory effects by reducing inflammatory mediators to improve alcoholic liver injury. Shen et al. [8] found that Hederagenin inhibits the tyrosine kinase 2/signal transduction and transcription activation factor (STAT)3/MAPK signaling pathway, reduce inflammatory cytokines and pro-inflammatory mediators to exert anti-inflammatory effects. Yu et al. [9] demonstrated that Hederagenin regulates the NF-κB, MAPK, and phosphoinositide-3-kinase (PI3K)/protein kinase B (Akt) pathways to reduce the expression of apoptosis markers and pro-inflammatory cytokines, downregulate the expression levels of related genes, thereby alleviating inflammatory responses. The aforementioned studies collectively indicate that Hederagenin exerts anti-inflammatory effects by influencing inflammatory cytokines through multiple pathways, with the IL family and tumor necrosis factor α potentially serving as key regulatory factors.

1.2 Neuroprotective effects of Hederagenin, an extract from ivy

Based on the biological characteristics of Hederagenin, it can be inferred that Hederagenin may play an important role in neuroprotection. Yu et al. [9] found that Hederagenin is associated with the mixed lineage enzyme 3 signaling pathway in brain ischemia/reperfusion injury, Hederagenin can inhibit the activation of the mixed lineage enzyme 3 signaling pathway and activate the NF-κB and mitogen-activated protein kinase-Jun amino-terminal kinase pathways, thereby exerting its neuroprotective effects by reducing inflammatory responses and inhibiting neuronal apoptosis following cerebral ischemia/reperfusion injury. Additionally, Hederagenin reduces infarct volume after cerebral ischemia/reperfusion injury, effectively improves neurological dysfunction, and provides significant neuroprotective effects.

Lin et al. [10] suggested that the neuroprotective effects of Hederagenin, an extract from ivy, are associated with the PI3K/Akt pathway, by activating Akt and its downstream targets forkhead box protein O3a, glycogen synthase kinase 3β phosphorylation, thereby reducing corticosterone-induced neuronal damage. Hederagenin can also increase the expression of brain-derived neurotrophic factor, activate the forkhead box protein O3a/PI3K/Akt pathway, prevent neuronal damage, exerting its neuroprotective and antidepressant effects. Liang et al. [11] suggested that the antidepressant effect of Hederagenin may be related to enhanced neurotransmitter levels, as Hederagenin may regulate the serotonin gene system, particularly influencing gene expression to exert antidepressant effects.

Wu et al. [12] suggested that neurodegenerative diseases are associated with proteins that tend to aggregate and misfold. They found that Hederagenin, an extract from ivy, can activate autophagy through the adenosine monophosphate-activated protein kinase-rapamycin target protein signaling pathway, thereby enhancing autophagy to promote protein degradation and clear aggregated misfolded proteins, thus exerting its neuroprotective effects. Additionally, Xie et al. [13] found that the expression of EB (TFEB), an important transcription factor regulating the expression of genes associated with lysosomes and autophagy, can be up-regulated by Hederagenin. Hederagenin induces autophagy through the peroxisome proliferator-activated receptor α/TFEB pathway, thereby promoting the degradation of β-amyloid. HD may exert its neuroprotective effects by inducing autophagy and through mechanisms related to the peroxisome proliferator-activated receptor α/TFEB pathway to alleviate Alzheimer's disease.

In summary, the neuroprotective effects of Hederagenin are associated with multiple signaling pathways, and its ability to mitigate disease pathology by promoting cellular autophagy warrants further investigation. Whether Hederagenin can achieve effective doses in humans merits further consideration. In future studies, incorporating Hederagenin into lipid-based nanomedicine formulations may represent a stable and effective drug delivery approach.

1.3 Antitumor Effects of Hederagenin

Hederagenin has been demonstrated to possess broad potential antitumor effects both in vitro and in vivo, with studies spanning various types of tumors, including colorectal cancer, head and neck cancer, lung cancer, breast cancer, prostate cancer, and cervical cancer. Liu et al. [14] found that Hederagenin can upregulate the expression of Bcl-2-related X protein (Bax), an important regulator of apoptosis in the B-lymphoma 2 (Bcl-2) family, downregulate Bcl-2, Bcl-2, and survival protein expression. Hederagenin also increased the expression of caspase-9 and caspase-3, which are associated with the intrinsic apoptosis pathway, and promoted the cleavage of cytochrome C, leading to apoptosis. This suggests that Hederagenin induces apoptosis in colon cancer cells through the mitochondrial pathway.

Kim et al. [15] similarly revealed that Hederagenin activates the mitochondrial-driven intrinsic apoptosis pathway, significantly inducing apoptosis in head and neck cancer cells. The mechanism involves inhibiting the nuclear factor E2-related factor 2 (Nrf2)-antioxidant response element (SREBP) antioxidant pathway, activating p53 protein in head and neck cancer cells, promoting reactive oxygen species (ROS) production, and increasing glutathione consumption, thereby promoting apoptosis in cisplatin-resistant head and neck cancer cells. Wang et al. [16] found that Hederagenin inhibits autophagy and disrupts the autophagy flux in lung cancer cells by inhibiting lysosomal acidification, leading to impaired reactive oxygen species clearance. Additionally, autophagy is an important mechanism for drug resistance, and Hederagenin can increase the resistance and cytotoxicity of paclitaxel and cisplatin.

Dai et al. [17] suggested that Hederagenin, an extract from ivy, inhibits the proliferation, invasion, and migration of glioma cells, which is associated with orphan nuclear factor receptor transcription factors. Hederagenin exerts its antitumor effects by inhibiting orphan nuclear factor receptors, thereby suppressing the downstream PI3K/Akt signaling pathway. Zhao Zhenxia et al. [18] also demonstrated the effects of hederagenin on the PI3K/Akt signaling pathway, finding that the relative expression levels of PI3K and Akt genes and proteins in prostate cancer cells were negatively correlated with increasing hederagenin levels. Additionally, hederagenin upregulates the important apoptosis regulator Bax and downregulates Bcl-2, indicating that Hederagenin inhibits the PI3K/Akt signaling pathway, thereby affecting the activation of its downstream target proteins, suppressing cell proliferation, invasion, and migration, and promoting tumor cell apoptosis to exert its antitumor effects.

In a study by Fang Lihua et al. [19] on cervical cancer, the antitumor mechanism of Hederagenin, an extract from ivy, was found to promote the induction of a cascading reaction of the caspase family in cervical cancer cells, leading to apoptosis. It also reduced the phosphorylation level of STAT3 in cervical cancer cells, inhibiting the activation of the STAT3 signaling pathway and affecting cell proliferation and pro-apoptotic effects. Zuo Fang et al. [20] found that Hederagenin also exhibits antitumor effects in breast cancer. Hederagenin exerts its antiproliferative effects by inhibiting the expression of proliferating cell nuclear antigen protein, reducing Bcl-2 expression, increasing Bax expression to promote apoptosis, and lowering matrix metalloproteinase-9 expression to inhibit the invasive ability of breast cancer cells MCF-7.

Zheng Yi et al. [21] demonstrated that Hederagenin inhibits the migration and invasion of thyroid cancer cells through the PCAT19/microRNA-4319 pathway, primarily regulating Twist protein, Snail protein, N-cadherin, and E-cadherin in the epithelial-mesenchymal transition. Additionally, it can also inhibit cell proliferation by blocking the G0/G1 phase of thyroid cancer cells. In summary, due to the diverse mechanisms of action of Hederagenin in inhibiting various types of tumors, which involve multiple targets and pathways, it demonstrates effective anti-tumor effects, including inducing apoptosis and autophagy.

2 Pharmacological effects of Hederagenin derivatives from ivy extracts

Due to the low oral bioavailability of Hederagenin, research on Hederagenin derivatives holds significant potential. Numerous derivatives have been designed and synthesized based on Hederagenin. Among these, studies on α-Hederagenin are particularly extensive. As a natural bioactive molecule, α-Hederagenin exhibits broad-spectrum antitumor effects [22].

Currently, α-Hederagenin exhibits antitumor effects against various cancers, including colorectal cancer, gastric cancer, lung cancer, and liver cancer. Further studies have explored the relationship between α-Hederagenin and hypoxia-mediated drug resistance in colorectal cancer cells. Results indicate that high expression of Bcl-2 in hypoxic colorectal cancer cells is a key factor influencing drug resistance [23-25]. α-Hederagenin can inhibit Akt phosphorylation and reduce Bcl-2 expression under hypoxic conditions, thereby inhibiting the Akt/Bcl-2 pathway to overcome colorectal cancer cell resistance, showing promise as a novel adjuvant for reversing colorectal cancer cell resistance. Wang et al. [26] found that α-Hederagenin blocks gastric cancer cells in the G1 phase, reduce cell proliferation, and increase reactive oxygen species levels by activating the mitochondrial pathway, thereby accelerating glutathione consumption to induce apoptosis.

Fang et al. [27] demonstrated that α-Hederagenin activates Sirtuin 6 protein, a key regulator of energy metabolism, inhibits the expression of hypoxia-inducible factor 1α and c-Myc genes associated with glycolysis regulation, and reduce the expression of glycolysis-related proteins, thereby inhibiting the growth of lung cancer cells. Wu et al. [28] found that α-Hederagenin modulates the redox system through the glutathione synthase/glutathione/glutathione peroxidase 2 axis, triggering apoptosis and ferroptosis, inducing lipid peroxidation and mitochondrial oxidative stress in non-small cell lung cancer cells, enhancing the chemotherapeutic sensitivity to cisplatin, and exhibiting synergistic effects when used in combination with cisplatin [29-30].

Chen et al. [31] discovered a new mechanism of α-Hederagenin associated with the Hippo signaling pathway, α-Hederagenin upregulates the phosphorylation of the upstream kinase of Yes-related protein (Yes-related protein) and L-type amino acid transporter through the Hippo signaling pathway, thereby inhibiting the phosphorylation and nuclear translocation of Yes-related protein, and ultimately suppressing the proliferation of hepatocellular carcinoma cells and inducing apoptosis. This finding may provide new insights for the treatment of hepatocellular carcinoma and lay a foundation for further research.

Cao et al. [32] demonstrated that α-Hederagenin can inhibit PAF/PTAFR pathway-mediated migration and invasion responses, primarily by reducing the expression of matrix metalloproteinase 9 and matrix metalloproteinase 2, while also lowering STAT3 expression to reduce liver cancer cell stem cell characteristics, ultimately achieving an antitumor effect by inhibiting the migration and invasion of hepatocellular carcinoma cells, providing a new therapeutic strategy for hepatocellular carcinoma. In a study by Ren Jingyu et al. [33], α-Hederagenin activated the p38 and Jun N-terminal kinase signaling pathways to induce apoptosis in esophageal squamous cell carcinoma cells by increasing reactive oxygen species levels, while inhibiting the proliferation and migration of esophageal squamous cell carcinoma cells.

3 Summary and Outlook

Ivy extract Hederagenin exhibits a wide range of pharmacological effects, particularly in anti-inflammatory and antitumor activities. In terms of anti-inflammatory effects, it can inhibit inflammatory factors and inflammatory infiltration, protecting the body from excessive inflammatory damage. In antitumor activities, Hederagenin can induce cell apoptosis and cell cycle arrest, reduce ATP production, and influence cell autophagy, proliferation, invasion, and metastasis. In fact, these mechanisms are believed to be closely associated with the uncontrolled growth of tumor cells, making them potentially valuable targets for drug intervention. Based on these studies, Hederagenin may serve as a potential anticancer candidate and can be combined with other drugs to enhance drug synergism, improve the sensitivity of traditional chemotherapy drugs, and reduce drug resistance.

Experimental evidence demonstrates that the anti-cancer activity of α-Hederagenin, a derivative of Hederagenin extracted from ivy, exhibits significant potential. In terms of mechanism of action, α-Hederagenin exerts anti-cancer effects by inducing tumor cell apoptosis and ferroptosis, inhibiting cell proliferation, and suppressing metastasis. Based on the pharmacological characteristics exhibited by Hederagenin, Hederagenin and its derivatives possess certain clinical medicinal value, particularly in the areas of antitumor and anti-drug resistance, and hold research potential. Further experiments are needed to clarify the antitumor effects of Hederagenin and its derivatives and their molecular mechanisms.

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