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| Berberine — Berberine is a protoberberine/isoquinoline alkaloid natural product found in plants such as Coptis, Berberis, and Phellodendron. It is a small-molecule phytochemical with pleiotropic metabolic, anti-inflammatory, and anticancer signaling effects rather than a single highly selective target profile. Its standard abbreviation is BBR. In oncology it is best classified as a multitarget natural-product lead compound and adjunct-sensitizer candidate, with strong preclinical evidence but no established standard anticancer regulatory use. Its translational profile is shaped by very low conventional oral bioavailability, extensive first-pass metabolism, broad tissue distribution, and substantial context dependence between cancer-cell pro-death effects and normal-cell cytoprotective redox effects. Primary mechanisms (ranked):
Bioavailability / PK relevance: Conventional oral berberine has poor systemic bioavailability, often cited as below 1% in animal studies, because of limited absorption, P-glycoprotein efflux, first-pass intestinal/hepatic metabolism, and self-aggregation. Human exposure is usually in the low ng/mL plasma range with conventional dosing, while multiple metabolites may contribute to activity. Tissue distribution can exceed plasma levels, but PK remains a major clinical translation constraint. In-vitro vs systemic exposure relevance: Many anticancer in-vitro studies use roughly 10–100 µM, commonly around 20–50 µM, which usually exceeds readily achievable conventional plasma exposure after standard oral dosing. Therefore, direct translation of cell-culture potency to systemic monotherapy expectations is limited unless local gut exposure, tissue accumulation, metabolite contribution, formulation enhancement, or combination use is specifically relevant. Clinical evidence status: Strong preclinical and mechanistic evidence; limited early human oncology/chemoprevention evidence; no established phase III anticancer efficacy standard and no mainstream regulatory approval as an anticancer drug. Current clinical relevance is best viewed as investigational and adjunct-oriented rather than proven standalone oncology therapy. Berberine is a chemical found in some plants like European barberry, goldenseal, goldthread, Oregon grape, phellodendron, and tree turmeric. Berberine is a bitter-tasting and yellow-colored chemical.Coptis (commonly referring to Coptidis Rhizoma, a traditional Chinese medicinal herb) contains bioactive alkaloids (most notably berberine and coptisine) that have been studied for their pharmacological effects—including their influence on reactive oxygen species (ROS) and related pathways. – Berberine is known for its relatively low oral bioavailability, often cited at less than 1%. This low bioavailability is mainly due to poor intestinal absorption and active efflux by transport proteins such as P-glycoprotein. – Despite the low bioavailability, berberine is still pharmacologically active, and its metabolites may also contribute to its overall effects. • Effective Dosage in Studies – Many clinical trials or preclinical studies use dosages in the range of 500 to 1500 mg per day, typically administered in divided doses. – Therefore, to obtain a bioactive dose of berberine, supplementation in a standardized extract form is necessary. -IC50 in cancer cell lines: Approximately 10–100 µM (commonly around 20–50 µM in many models) -IC50 in normal cell lines: Generally higher (often above 100 µM), although this can vary with cell type - In vivo studies: Dosing regimens in animal models generally range from about 50 to 200 mg/kg - very effective AChE inhibitor (Alzheimers) - Berberine may enhance the effects of blood-thinning medications like warfarin and aspirin. -Note half-life reports vary 2.5-90hrs?. -low solubility of apigenin in water : BioAv Pathways: - induce ROS production - ROS↑ related: MMP↓(ΔΨm), ER Stress↑, Ca+2↑, Cyt‑c↑, Caspases↑, DNA damage↑, UPR↑, cl-PARP↑, HSP↓ - Lowers AntiOxidant defense in Cancer Cells: NRF2↓, GSH↓ - Raises AntiOxidant defense in Normal Cells: NRF2↑, SOD↑, GSH↑, Catalase↑, - lowers Inflammation : NF-kB↓, COX2↓, p38↓, Pro-Inflammatory Cytokines : IL-1β↓, TNF-α↓, IL-6↓, IL-8↓ - PI3K/AKT(Inhibition), JAK/STATs, Wnt/β-catenin, AMPK, MAPK/ERK, and JNK. - inhibit Growth/Metastases : , MMPs↓, MMP2↓, MMP9↓, IGF-1↓, uPA↓, VEGF↓, ROCK1↓, FAK↓, RhoA↓, NF-κB↓, CXCR4↓, TGF-β↓, α-SMA↓, ERK↓ - reactivate genes thereby inhibiting cancer cell growth : HDAC↓, DNMT1↓, EZH2↓, P53↑, HSP↓ - cause Cell cycle arrest : TumCCA↑, cyclin D1↓, cyclin E↓, CDK2↓, CDK4↓, CDK6↓, - inhibits Migration/Invasion : TumCMig↓, TumCI↓, FAK↓, ERK↓, - inhibits glycolysis /Warburg Effect and ATP depletion : HIF-1α↓, PKM2↓, cMyc↓, GLUT1↓, LDH↓, LDHA↓, HK2↓, PFKs↓, PDKs↓, Glucose↓, GlucoseCon↓ - inhibits angiogenesis↓ : VEGF↓, HIF-1α↓, Notch↓, FGF↓, PDGF↓, EGFR↓, Integrins↓, - inhibits Cancer Stem Cells : CSC↓, Hh↓, GLi1↓, CD133↓, β-catenin↓, n-myc↓, sox2↓, notch2↓, nestin↓, OCT4↓, - Others: PI3K↓, AKT↓, JAK↓, STAT↓, Wnt↓, β-catenin↓, AMPK↓, α↓, ERK↓, JNK, - Synergies: chemo-sensitization, chemoProtective, RadioSensitizer, RadioProtective, Others(review target notes), Neuroprotective, Cognitive, Renoprotection, Hepatoprotective, CardioProtective, - Selectivity: Cancer Cells vs Normal Cells
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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. |
| 2689- | BBR, | Berberine protects against glutamate-induced oxidative stress and apoptosis in PC12 and N2a cells |
| - | in-vitro, | Nor, | PC12 | - | in-vitro, | AD, | NA | - | in-vitro, | Stroke, | NA |
| 2684- | BBR, | Berberine is a Novel Mitochondrial Calcium Uniporter Inhibitor that Disrupts MCU‐EMRE Assembly |
| - | in-vivo, | Nor, | NA |
| 5177- | BBR, | Berberine induces apoptosis in human HSC-3 oral cancer cells via simultaneous activation of the death receptor-mediated and mitochondrial pathway |
| - | in-vitro, | Oral, | HMC3 |
| 1379- | BBR, | Berberine derivative DCZ0358 induce oxidative damage by ROS-mediated JNK signaling in DLBCL cells |
| - | in-vitro, | lymphoma, | NA |
| 2670- | BBR, | Berberine: A Review of its Pharmacokinetics Properties and Therapeutic Potentials in Diverse Vascular Diseases |
| - | Review, | Var, | NA |
| 1402- | BBR, | Berberine-induced apoptosis in human glioblastoma T98G cells is mediated by endoplasmic reticulum stress accompanying reactive oxygen species and mitochondrial dysfunction |
| - | in-vitro, | GBM, | T98G |
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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