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| ISL is a distinct natural chalcone, chemically identified as 2′,4′,4-trihydroxychalcone, found particularly in licorice species such as Glycyrrhiza spp.ISL has substantial preclinical evidence involving anticancer, anti-inflammatory, antioxidant, metabolic, and neuroprotective effects. Reported anticancer actions include inhibition of proliferation, angiogenesis, EMT, invasion, and metastasis, with induction of apoptosis, cell-cycle arrest, autophagy, or ferroptosis depending on the model. Frequently reported pathways include PI3K/AKT/mTOR, NF-κB, STAT3, MAPK, Wnt/β-catenin, Nrf2, and Src signalling. Isoliquiritigenin — isoliquiritigenin (ISL; 2′,4′,4-trihydroxychalcone) is a naturally occurring polyphenolic chalcone found particularly in licorice roots from Glycyrrhiza species. It is formally classified as a flavonoid-family chalcone rather than an isoflavone. ISL is a pleiotropic experimental bioactive compound with anticancer, anti-inflammatory, metabolic, antioxidant/pro-oxidant, and neuroprotective activities. Anticancer effects are strongly model- and concentration-dependent, and clinically relevant systemic exposure to unconjugated ISL is substantially more limited than the micromolar concentrations commonly used in cell culture. ISL also has weak phytoestrogenic activity and can interact with estrogen receptors. Primary mechanisms (ranked):
Bioavailability / PK relevance: Oral ISL undergoes substantial intestinal absorption barriers and rapid phase-II metabolism, particularly glucuronidation. Animal studies report oral bioavailability of roughly 20–34%, but circulating parent ISL is transient and extensively converted to conjugated metabolites. Human pharmacokinetic studies of licorice-containing Kampo preparations confirm detectable ISL exposure but at levels substantially below many experimental cancer-cell concentrations. Low aqueous solubility and rapid metabolism have driven development of nanoparticles, micelles, SMEDDS, and structural derivatives to improve exposure. In-vitro vs systemic exposure relevance: Many anticancer experiments use approximately 10–100+ µM ISL, whereas parent-compound concentrations achieved after conventional oral botanical exposure are generally much lower because of rapid intestinal glucuronidation and systemic metabolism. Consequently, direct translation of high-micromolar in-vitro cytotoxicity to oral supplementation is poor. Some lower-concentration receptor, enzyme, inflammatory, and metabolic effects may be more pharmacologically plausible. Clinical evidence status: Preclinical. Extensive cell-culture and multiple animal xenograft studies support anticancer activity, but ISL itself is not an established cancer treatment and there is no convincing randomized human anticancer efficacy evidence. Human studies primarily provide pharmacokinetic information from multi-component licorice/Kampo preparations rather than therapeutic evaluation of purified ISL. Drug-interaction potential involving CYP and UGT enzymes and weak estrogenic activity warrant caution. Isoliquiritigenin Cancer-Relevant Mechanisms
Alzheimer’s disease relevance: ISL has meaningful but still preclinical AD relevance. In Aβ42-stimulated microglia, it activates NRF2 while suppressing NF-κB, inflammatory cytokines, nitric oxide, and oxidative injury, indirectly protecting neuronal cells. More recent mouse evidence reports improved cognition together with reduced tau phosphorylation, oxidative stress, mitochondrial dysfunction, neuronal loss, and synaptic impairment. Evidence remains limited to cellular and animal models; there is no established human AD therapeutic evidence. Primary AD mechanisms (ranked):
Isoliquiritigenin Alzheimer’s-Relevant Mechanisms
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| In all eukaryotic cells, intracellular Ca2+ levels are maintained at low resting concentrations (approximately 100 nM) by the activity of the major Ca2+ extrusion system, the plasma membrane Ca2+-ATPase (PMCA), which exchanges extracellular protons (H+) for cytosolic Ca2+. Indeed, sustained elevation of [Ca2+]C in the form of overload, saturating all Ca2+-dependent effectors, prolonged decrease in [Ca2+]ER, causing ER stress response, and high [Ca2+]M, inducing mitochondrial permeability transition (MPT), are considered to be pro-death factors. In cancer the Ca2+-handling toolkit undergoes profound remodelling (figure 1) to favour activation of Ca2+-dependent transcription factors, such as the nuclear factor of activated T cells (NFAT), c-Myc, c-Jun, c-Fos that promote hypertrophic growth via induction of the expression of the G1 and G1/S phase transition cyclins (D and E) and associated cyclin-dependent kinases (CDK4 and CDK2). Thus, cancer cells may evade apoptosis through decreasing calcium influx into the cytoplasm. This can be achieved by either downregulation of the expression of plasma membrane Ca2+-permeable ion channels or by reducing the effectiveness of the signalling pathways that activate these channels. Such protective measures would largely diminish the possibility of Ca2+ overload in response to pro-apoptotic stimuli, thereby impairing the effectiveness of mitochondrial and cytoplasmic apoptotic pathways. Voltage-Gated Calcium Channels (VGCCs): Overexpression of VGCCs has been associated with increased tumor growth and metastasis in various cancers, including breast and prostate cancer. Store-Operated Calcium Entry (SOCE): SOCE mechanisms, such as STIM1 and ORAI1, are often upregulated in cancer cells, contributing to enhanced cell survival and proliferation. High intracellular calcium levels are associated with increased cell proliferation and migration, leading to a poorer prognosis. Calcium signaling can also influence hormone receptor status, affecting treatment responses. Increased Ca²⁺ signaling is associated with advanced disease and metastasis. Patients with higher CaSR expression may have a worse prognosis due to enhanced tumor growth and resistance to apoptosis. -Ca2+ is an important regulator of the electric charge distribution of bio-membranes. |
| 7764- | ISL, | Licorice Extract Isoliquiritigenin Increased Cytosol Calcium and Induced Apoptosis in Colon Cancer Cells via Transient Receptor Potential Vanilloid‐1 |
| - | in-vitro, | CRC, | HT-29 | - | in-vitro, | CRC, | HCT116 |
Query results interpretion may depend on "conditions" listed in the research papers. Such Conditions may include : -low or high Dose -format for product, such as nano of lipid formations -different cell line effects -synergies with other products -if effect was for normal or cancerous cells
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