Database Query Results : Berberine, , ER Stress

BBR, Berberine: Click to Expand ⟱
Features:
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

Rank Pathway / Target Axis Direction Primary Effect Notes / Cancer Relevance Ref
1 AMPK → mTOR axis ↑ AMPK / ↓ mTOR signaling Metabolic stress + growth suppression In vivo/in vitro colon tumorigenesis model: berberine activates AMPK, inhibits mTOR signaling and reduces proliferation/tumorigenesis, growth suppression, autophagy, HIF-1α ↓, glycolysis ↓, berberine’s known mitochondrial/energetic effects (ref)
2 Mitochondrial dysfunction / ROS generation ↑ ROS / mitochondrial stress Upstream metabolic trigger Berberine inhibits mitochondrial function, increases ROS, and contributes to AMPK activation and downstream apoptosis (ref)
3 Mitochondrial apoptosis (cytochrome c release) ↑ cytochrome c release Intrinsic death signaling Oral cancer model: berberine reduces mitochondrial membrane potential, releases cytochrome c, activates caspase-3 (ref)
4 Intrinsic apoptosis (caspase-3 activation) ↑ caspase-3 activation Programmed cell death Same oral cancer study documents caspase-3 activation as a key execution marker (ref)
5 NF-κB signaling (p65 activation) ↓ NF-κB activation Reduced pro-survival transcription Colon cancer model reports inhibition of p65 phosphorylation; interpreted as secondary to metabolic/redox stress (ref)
6 Cell cycle control ↑ G1 arrest Proliferation blockade Prostate cancer model: berberine induces G1-phase cell cycle arrest and caspase-3–dependent apoptosis (ref)
7 Hypoxia / glycolysis signaling (HIF-1α) ↓ HIF-1α protein Warburg / glycolysis suppression Berberine suppresses mTOR and reduces HIF-1α protein expression downstream of AMPK activation (ref)
8 Angiogenesis signaling (HIF-1α → VEGF axis) ↓ VEGF signaling Reduced vascular support Lung cancer study: berberine suppresses VEGF signaling alongside HIF-1α inhibition (ref)
9 PI3K–AKT–mTOR signaling ↓ PI3K / AKT / mTOR Survival pathway suppression Gastric cancer paper: berberine represses PI3K/AKT/mTOR signaling and improves chemosensitivity (ref)
10 Migration / invasion programs ↓ migration & invasion Anti-metastatic phenotype Tongue SCC model: berberine suppresses migration and invasion with associated signaling changes (ref)
11 Telomerase (hTERT) / immortalization axis ↓ hTERT-related signaling Reduced proliferative capacity Lung cancer study includes AP-2/hTERT regulatory axis modulation by berberine (ref)
12 In vivo tumor suppression ↓ tumorigenesis Demonstrated anti-tumor effect Colon tumorigenesis model confirms reduced proliferation and tumor burden with berberine (ref)


ER Stress, endoplasmic reticulum (ER) stress signaling pathway: Click to Expand ⟱
Source:
Type:
Protein expression of ATF, GRP78, and GADD153 which is a hall marker of ER stress.
The endoplasmic reticulum (ER) stress signaling pathway plays a crucial role in maintaining cellular homeostasis and responding to various stressors, including those encountered in cancer. When cells experience stress, such as the accumulation of misfolded proteins, they activate a series of signaling pathways collectively known as the unfolded protein response (UPR). The UPR aims to restore normal function by enhancing the protein-folding capacity of the ER, degrading misfolded proteins, and, if the stress is unresolved, triggering apoptosis.
The activation of ER stress pathways can contribute to resistance against chemotherapy and targeted therapies. Cancer cells may utilize the UPR to survive treatment-induced stress, making it challenging to achieve effective therapeutic outcomes.

-ER stress-associated proteins include: phosphorylation of PERK, eIF2α, ATF4, CHOP and cleaved-caspase 12
Scientific Papers found: Click to Expand⟱
2698- BBR,    A gene expression signature-based approach reveals the mechanisms of action of the Chinese herbal medicine berberine
- Analysis, BC, MDA-MB-231
HDAC↓, Results showed that BBR may inhibit protein synthesis, histone deacetylase (HDAC), or AKT/mammalian target of rapamycin (mTOR) pathways.
Akt↓,
mTOR↓,
ER Stress↑, BBR inhibited global protein synthesis and basal AKT activity, and induced endoplasmic reticulum (ER) stress and autophagy, which was associated with activation of AMP-activated protein kinase (AMPK).
TumAuto↑,
AMPK↑,
mTOR∅, However, BBR did not alter mTOR or HDAC activities.
HDAC∅, SAHA but not BBR inhibited HDAC activity, suggesting that BBR is not an HDAC inhibitor.
ac‑α-tubulin↑, BBR induced the acetylation of α-tubulin, a substrate of HDAC6, although it did not directly inhibit HDAC activity

2683- BBR,    Berberine reduces endoplasmic reticulum stress and improves insulin signal transduction in Hep G2 cells
- in-vitro, Liver, HepG2
JNK↓, while the activation of JNK was blocked
p‑PERK↓, phosphorylation both on PERK and eIF2α were inhibited in cells pretreated with berberine.
p‑eIF2α↓,
*ER Stress↓, antidiabetic effect of berberine in Hep G2 cells maybe related to attenuation of ER stress

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
TumCCA↑, Evidence has accumulated that berberine is able to induce cell cycle arrest and apoptosis in many human cancer cell lines.
Apoptosis↑,
TumCG↓, Berberine induced dose- and time-dependent irreversible inhibition of cell growth and cellular DNA synthesis
Casp3↑, induced apoptosis correlated with caspase-3 activation.
TumCCA↑, berberine induced mainly G0/G1-phase arrest
ROS↑, berberine induced reactive oxygen species (ROS) and Ca2+ production
Ca+2↑,
MMP↓, as well as the dysfunction of mitochondrial membrane potential (MMP), which were correlated with apoptosis
ER Stress↑, our data support that berberine initially induces an endoplasmic reticulum stress response based on ROS and Ca2+ production which is followed by dysfunctions of the mitochondria, resulting in apoptosis of these oral cancer HSC-3 cells.
Cyt‑c↑, Prolonged exposure of the HSC-3 cells to berberine causes increased apoptosis through reduced levels of MMP, release of cytochrome c and activation of caspase-3.

3681- BBR,    The efficacy and mechanism of berberine in improving aging-related cognitive dysfunction: A study based on network pharmacology
- in-vivo, AD, NA
*memory↑, treatment with berberine significantly improved spatial learning and memory in mice with cognitive decline induced by D-gal
*cognitive↑,
MAPK↑, core targets of berberine for improving cognitive function, include Mapk1, Src, Ctnnb1, Akt1, Pik3ca, Tp53, Jun, and Hsp90aa1.
*Akt↑,
*PI3K↑, PI3K-Akt signaling pathway and MAPK signaling pathway were significantly enriched.
*TP53↑, Tp53 and Jun expression showed a decreasing trend and were significantly lower in the BBR-H group
*Jun↓,
*HSP90↑, src, Ctnnb1, Akt1, Pik3ca, and Hsp90aa1 exhibited an increasing tendency in both the BBR-L and BBR-H groups
*neuroP↑, Akt1, Ctnnb1, Tp53, and Jun were involved in the neuroprotective actions of berberine.
*Inflam↓, pharmacological effects of BBR, including anti-inflammatory
*antiOx↑, BBR has antioxidant properties as well as protective effects against neurodegenerative diseases
*p16↓, BBR reduces the expression of P16 in brain tissue of cognitive dysfunctions mice
*ER Stress↓, inhibition of endoplasmic reticulum stress

2681- BBR,  PDT,    Berberine-photodynamic induced apoptosis by activating endoplasmic reticulum stress-autophagy pathway involving CHOP in human malignant melanoma cells
- in-vitro, Melanoma, NA
Apoptosis↑, BBR-PDT induced apoptosis via up-regulating the expression of cleaved caspase-3 protein.
cl‑Casp3↑,
LC3s↑, LC3-related autophagy level was upregulated in MMCs with BBR-PDT.
ER Stress↑, BBR-PDT activated endoplasmic reticulum (ER) stress, involving a dramatic increase in reactive oxygen species (ROS).
ROS↑,
CHOP↑, knockdown of CHOP protein expression inhibited apoptosis, autophagy and ER stress levels caused by BBR-PDT, suggesting that CHOP protein may be related to apoptosis, autophagy and ER stress in MMCs with BBR-PDT

2680- BBR,  PDT,    Photodynamic therapy-triggered nuclear translocation of berberine from mitochondria leads to liver cancer cell death
- in-vitro, Liver, HUH7
TumCD↑, blue light irradiation (488 nm). The results showed that berberine rapidly translocated from the mitochondria to the nucleus upon light exposure, ultimately inducing cell death in SNU449 and Huh7 cells.
ROS↑, Additionally, we observed a significant increase in reactive oxygen species, linking the phototoxic effects to oxidative stress
TumCCA↑, indicating cell cycle arrest following treatment with berberine and PDT
ER Stress↑, Western blotting confirmed that ER stress was significantly induced

2679- BBR,    Berberine Improves Behavioral and Cognitive Deficits in a Mouse Model of Alzheimer’s Disease via Regulation of β-Amyloid Production and Endoplasmic Reticulum Stress
- in-vivo, AD, NA
*cognitive↑, berberine could improve cognitive deficits in the triple-transgenic mouse model of Alzheimer’s disease (3 × Tg AD) mice.
PERK↓, berberine treatment may inhibit PERK/eIF2α signaling-mediated BACE1 translation, thus reducing Aβ production and resultant neuronal apoptosis
*eIF2α↓,
*neuroP↑, berberine may have neuroprotective effects, via attenuation of ER stress and oxidative stress.
*ER Stress↓,
*ROS↓,

2677- BBR,    Liposome-Encapsulated Berberine Alleviates Liver Injury in Type 2 Diabetes via Promoting AMPK/mTOR-Mediated Autophagy and Reducing ER Stress: Morphometric and Immunohistochemical Scoring
- in-vivo, Diabetic, NA
*hepatoP↑, berberine (Lip-BBR) to aid in ameliorating hepatic damage and steatosis, insulin homeostasis, and regulating lipid metabolism in type 2 diabetes (T2DM)
*LC3II↑, Lip-BBR treatment promoted autophagy via the activation of LC3-II and Bclin-1 proteins and activated the AMPK/mTOR pathway in the liver tissue of T2DM rats.
*Beclin-1↑,
*AMPK↑,
*mTOR↑,
*ER Stress↓, It decreased the endoplasmic reticulum stress by limiting the CHOP, JNK expression, oxidative stress, and inflammation.
*CHOP↓,
*JNK↓,
*ROS↓,
*Inflam↓,
*BG↓, Oral supplementation of diabetic rats either by Lip-BBR or Vild, 10 mg/kg of each, significantly (p < 0.001) lowered the blood glucose levels of tested diabetic rats compared to the diabetic group.
*SOD↑, when the diabetic rats received Lip-BBR, the decrements were less pronounced compared to the diabetic group by 1.16 fold, 2.52 fold, and 67.57% for SOD, GPX, and CAT, respectively.
*GPx↑,
*Catalase↑,
*IL10↑, Treatment of the diabetic rats with Lip-BBR significantly (p < 0.001) elevated serum IL-10 levels by 37.01% compared with diabetic rats.
*IL6↓, Oral supplementation of Lip-BBR could markedly (p < 0.0001) reduce the elevated serum levels of IL-6 and TNF-α when it is used as a single treatment by 55.83% and 49.54%,
*TNF-α↓,
*ALAT↓, ALT, AST, and ALP in the diabetic group were significantly higher (p < 0.0001) by 88.95%, 81.64%, and 1.8 fold, respectively, compared with those in the control group, but this was reversed by the treatment with Lip-BBR
*AST↓,
*ALP↓,

2676- BBR,    Berberine protects rat heart from ischemia/reperfusion injury via activating JAK2/STAT3 signaling and attenuating endoplasmic reticulum stress
- in-vivo, Nor, NA - in-vivo, CardioV, NA
*cardioP↑, Pretreatment with BBR significantly reduced MI/R-induced myocardial infarct size, improved cardiac function, and suppressed myocardial apoptosis and oxidative damage.
*ROS↓,
*ER Stress↓, pretreatment with BBR suppressed MI/R-induced ER stress
*p‑PERK↓, evidenced by down-regulating the phosphorylation levels of myocardial PERK and eIF2α and the expression of ATF4 and CHOP in heart tissues.
*p‑eIF2α↓,
*ATF4↓,
CHOP↓,
*JAK2↑, Pretreatment with BBR also activated the JAK2/STAT3 signaling pathway in heart tissues
*STAT3↑,
*UPR↓, Therefore, reducing excessive UPR, also referred to as ER stress, is of great importance in ameliorating MI/R injury.

2675- BBR,    The therapeutic effects of berberine against different diseases: A review on the involvement of the endoplasmic reticulum stress
- Review, Var, NA
*Inflam↓, including anti-inflammatory, antioxidative, anti-apoptotic, antiproliferative, and antihypertensive.
*antiOx↑,
*ER Stress↓, BBR can decrease apoptosis and inflammation following different pathological conditions, which might be mediated by targeting ER stress pathways.
*cardioP↑, protective potential of BBR against several diseases, such as metabolic disorders, cancer, intestinal diseases, cardiovascular, liver, kidney, and central nervous system diseases, in both in vivo and in vitro studies.
*RenoP↑,
*hepatoP↑,

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
tumCV↓,
ROS↑,
Ca+2↑,
ER Stress↑,
eff↓, administration of the antioxidants, N-acetylcysteine and glutathione, reversed berberine-induced apoptosis
Bax:Bcl2↑,
MMP↓,
Casp9↑,
Casp3↑,
cl‑PARP↑,


* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 11

Pathway results for Effect on Cancer / Diseased Cells:


Redox & Oxidative Stress ⓘ

ROS↑, 4,  

Mitochondria & Bioenergetics ⓘ

MMP↓, 2,  

Core Metabolism/Glycolysis ⓘ

AMPK↑, 1,  

Cell Death ⓘ

Akt↓, 1,   Apoptosis↑, 2,   Bax:Bcl2↑, 1,   Casp3↑, 2,   cl‑Casp3↑, 1,   Casp9↑, 1,   Cyt‑c↑, 1,   JNK↓, 1,   MAPK↑, 1,   TumCD↑, 1,  

Transcription & Epigenetics ⓘ

tumCV↓, 1,  

Protein Folding & ER Stress ⓘ

CHOP↓, 1,   CHOP↑, 1,   p‑eIF2α↓, 1,   ER Stress↑, 5,   PERK↓, 1,   p‑PERK↓, 1,  

Autophagy & Lysosomes ⓘ

LC3s↑, 1,   TumAuto↑, 1,  

DNA Damage & Repair ⓘ

cl‑PARP↑, 1,  

Cell Cycle & Senescence ⓘ

TumCCA↑, 3,  

Proliferation, Differentiation & Cell State ⓘ

HDAC↓, 1,   HDAC∅, 1,   mTOR↓, 1,   mTOR∅, 1,   TumCG↓, 1,  

Migration ⓘ

Ca+2↑, 2,   ac‑α-tubulin↑, 1,  

Drug Metabolism & Resistance ⓘ

eff↓, 1,  
Total Targets: 32

Pathway results for Effect on Normal Cells:


Redox & Oxidative Stress ⓘ

antiOx↑, 2,   Catalase↑, 1,   GPx↑, 1,   ROS↓, 3,   SOD↑, 1,  

Core Metabolism/Glycolysis ⓘ

ALAT↓, 1,   AMPK↑, 1,  

Cell Death ⓘ

Akt↑, 1,   JNK↓, 1,  

Protein Folding & ER Stress ⓘ

CHOP↓, 1,   eIF2α↓, 1,   p‑eIF2α↓, 1,   ER Stress↓, 6,   HSP90↑, 1,   p‑PERK↓, 1,   UPR↓, 1,  

Autophagy & Lysosomes ⓘ

Beclin-1↑, 1,   LC3II↑, 1,  

DNA Damage & Repair ⓘ

p16↓, 1,   TP53↑, 1,  

Proliferation, Differentiation & Cell State ⓘ

Jun↓, 1,   mTOR↑, 1,   PI3K↑, 1,   STAT3↑, 1,  

Angiogenesis & Vasculature ⓘ

ATF4↓, 1,  

Immune & Inflammatory Signaling ⓘ

IL10↑, 1,   IL6↓, 1,   Inflam↓, 3,   JAK2↑, 1,   TNF-α↓, 1,  

Clinical Biomarkers ⓘ

ALAT↓, 1,   ALP↓, 1,   AST↓, 1,   BG↓, 1,   IL6↓, 1,   TP53↑, 1,  

Functional Outcomes ⓘ

cardioP↑, 2,   cognitive↑, 2,   hepatoP↑, 2,   memory↑, 1,   neuroP↑, 2,   RenoP↑, 1,  
Total Targets: 42

Scientific Paper Hit Count for: ER Stress, endoplasmic reticulum (ER) stress signaling pathway
11 Berberine
2 Photodynamic Therapy
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

Filter Conditions: Pro/AntiFlg:%  IllCat:%  CanType:%  Cells:%  prod#:41  Target#:103  State#:%  Dir#:%
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