Database Query Results : Betulinic acid, , JNK

BetA, Betulinic acid: Click to Expand ⟱
Features:
Betulinic acid "buh-TOO-li-nik acid" is a natural compound with antiretroviral, anti malarial, anti-inflammatory and anticancer properties. It is found in the bark of several plants, such as white birch, ber tree and rosemary, and has a complex mode of action against tumor cells.
-Betulinic acid is a naturally occurring pentacyclic triterpenoid
-vitro concentrations range from 1–100 µM, in vivo studies in rodents have generally used doses from 10–100 mg/kg
Precursor: Betulin, via oxidation at C-28
Lipophilicity: High (poor aqueous solubility)
-half-life reports vary 3-5 hrs?. Reported half-life varies by formulation and species; several studies report multi-hour systemic persistence.
BioAv -hydrophobic molecule with relatively poor water solubility.
Main Cancer action
-Direct mitochondrial targeting in cancer cells
-Minimal effect on normal cells

Key pathways
-Mitochondrial membrane permeabilization
-ROS-mediated apoptosis
-Caspase-independent death

Chemo relevance: Generally compatible, Not a redox buffer

Pathways:
- often induce ROS production
- ROS↑ related: MMP↓(ΔΨm), ER Stress↑, UPR↑, GRP78↑, Ca+2↑, Cyt‑c↑, Caspases↑, DNA damage↑, cl-PARP↑, HSP↓
- Lowers AntiOxidant defense in Cancer Cells(Often associated with reduced redox buffering capacity in tumor cells (e.g., GSH depletion); NRF2 direction model-dependent.): NRF2↓, SOD↓, GSH↓
- May Raise AntiOxidant defense in Normal Cells: NRF2↑, SOD↑, GSH↑, Catalase↑ Reports suggest relative sparing of normal cells and preservation of antioxidant capacity in some models
- lowers Inflammation : NF-kB↓(typ), COX2↓, p38↓ (context-dependent; often stress-activated), Pro-Inflammatory Cytokines : IL-1β↓, TNF-α↓, IL-6↓, IL-8↓
- inhibit Growth/Metastases : , MMPs↓, MMP2↓, MMP9↓, TIMP2, IGF-1↓, VEGF↓, ROCK1↓, FAK↓, NF-κB↓, TGF-β↓, α-SMA↓, ERK↓
- reactivate genes thereby inhibiting cancer cell growth : P53↑, HSP↓(model-dependent), Sp proteins↓,
- cause Cell cycle arrest : TumCCA↑, cyclin D1↓, CDK2↓, CDK4↓,
- inhibits Migration/Invasion : TumCMig↓, TumCI↓, FAK↓, ERK↓, EMT↓, TOP1↓,
- inhibits glycolysis (secondary to mitochondrial stress) ATP depletion : HIF-1α↓, PKM2↓, cMyc↓, GLUT1↓, LDH↓, LDHA↓, HK2↓, PFKs↓, PDKs↓, HK2↓, ECAR↓, GRP78↑(ER stress), GlucoseCon↓
- inhibits angiogenesis↓ : VEGF↓, HIF-1α↓, EGFR↓,
- inhibits Cancer Stem Cells in some studies : CSC↓, GLi1↓, β-catenin↓, OCT4↓,
- Others: PI3K↓(typ), AKT↓(typ), JAK↓, STAT↓, β-catenin↓, AMPK↓(AMPK is often activated during metabolic stress), ERK↓, JNK,
- Synergies: chemo-sensitization, chemoProtective, RadioSensitizer, Others(review target notes), Neuroprotective, Cognitive, Renoprotection, Hepatoprotective, CardioProtective,
- Selectivity: Cancer Cells vs Normal Cells

Rank Pathway / Axis Cancer Cells Normal Cells TSF Primary Effect Notes / Interpretation
1 Intrinsic apoptosis (mitochondrial-mediated) ↑ mitochondria depolarization; ↑ cytochrome-c; ↑ caspase-9/3 activation ↔ limited activation (higher exposure required) R, G Execution of apoptosis Betulinic acid (BA) is well known to engage the intrinsic apoptotic cascade, typically downstream of redox and signaling perturbations.
2 ROS / redox stress ↑ ROS (P→R) ↔ basal or antioxidant adaptation in some contexts P, R Stress induction Many studies report ROS elevation in tumor cells exposed to BA; the direction and magnitude vary by cell type and exposure.
3 Mitochondrial permeability transition / ΔΨm loss ΔΨm ↓ (R→G) ↔ maintained R, G Mitochondrial failure Often observed as an early event preceding caspase activation in apoptosis studies.
4 PI3K / AKT / mTOR survival axis ↓ PI3K/AKT signaling; ↓ phospho-mTOR R, G Survival/growth suppression Betulinic acid often downregulates pro-survival kinase signaling, sensitizing cells to apoptosis and cytostasis.
5 NF-κB signaling ↓ NF-κB activity R, G Pro-survival/inflammatory transcription suppression Reduction in NF-κB activity limits pro-survival gene expression; supports sensitization to stressors.
6 MAPK re-wiring (JNK / ERK / p38) Stress-MAPK shifts; JNK/p38 often ↑; ERK context-dependent P, R Early stress signaling MAPK responses vary by model, with stress-associated p38/JNK often activated and ERK modulation variable.
7 Cell-cycle checkpoints (p21, p27, cyclins) ↑ p21/p27; ↑ G1/S or G2/M arrest G Proliferation arrest BA often induces cell-cycle blockade, slowing proliferation before apoptosis commitment.
8 Angiogenic signaling (VEGF & related) ↓ VEGF; anti-angiogenic outputs G Anti-angiogenic support Typically seen at the level of reduced pro-angiogenic factor expression or secretion in longer-term assays.
9 EMT / invasion / migration programs (MMPs) ↓ MMP2/MMP9; ↓ migration/invasion G Anti-invasive phenotype Often measured as reduced invasive capacity and decreased expression of EMT markers in later time points.
10 Autophagy modulation ↑ LC3-II; ↑ autophagic flux (model dependent) G Adaptive clearance / cell fate shift BA can modulate autophagy, which may either sensitize cells to death pathways or reflect adaptive stress responses.

Time-Scale Flag (TSF): P / R / G

  • P: 0–30 min (primary/physical-chemical effects; rapid kinase/redox signaling)
  • R: 30 min–3 hr (acute redox and stress-response activation)
  • G: >3 hr (gene-regulatory adaptation and phenotypic outcomes)


JNK, c-Jun N-terminal kinase (JNK): Click to Expand ⟱
Source:
Type:
JNK acts synergistically with NF-κB, JAK/STAT, and other signaling molecules to exert a survival function. Janus signaling promotes cancer cell survival.
JNK, or c-Jun N-terminal kinase, is a member of the mitogen-activated protein kinase (MAPK) family. It plays a crucial role in various cellular processes, including cell proliferation, differentiation, and apoptosis (programmed cell death). JNK is activated in response to various stress signals, such as UV radiation, oxidative stress, and inflammatory cytokines.
JNK activation can promote apoptosis in cancer cells, acting as a tumor suppressor. However, in other contexts, it can promote cell survival and proliferation, contributing to tumor progression.

JNK is often unregulated in cancers, leading to increased cancer cell proliferation, survival, and resistance to apoptosis. This activation is typically associated with poor prognosis and aggressive tumor behavior.


Scientific Papers found: Click to Expand⟱
2743- BetA,    Betulinic acid and the pharmacological effects of tumor suppression
- Review, Var, NA
ROS↓, BA improves the level of reactive oxygen species (ROS) production and alters the mitochondrial membrane potential gradient, followed by the release of cytochrome c (Cyt c), which causes the mitochondrial-mediated apoptosis of tumor cells via a caspas
MMP↓,
Cyt‑c↑,
Apoptosis↑,
TumCCA↑, BA can inhibit cancer cell growth and proliferation via cell cycle arrest
Sp1/3/4↓, BA, can inhibit the protein expression of Sp1, Sp2 and Sp4 through the microRNA (miR)-27a-ZBTB10-Sp1 axis
STAT3↓, BA can downregulate the activation of STAT3 through the upregulation of Src homology 2 domain-containing phosphatase 1 (SHP-1)
NF-kB↓, NF-κB can be inhibited by reducing the activation of inhibitor of NF-κB (IκBα) kinase (IKKβ) and phosphorylation of IκBα with BA
EMT↓, nvasion and metastasis of malignancies is prevented via epithelial-mesenchymal transition (EMT) and inhibition of topoisomerase I
TOP1↓,
MAPK↑, BA leads to the activation, via phosphorylation, of pro-apoptotic MAPK proteins, P38 and SAP/JNK, the formation of ROS and the upregulation of caspase
p38↑,
JNK↑,
Casp↑,
Bcl-2↓, BA downregulates Bcl-2 and upregulates the Bax gene in HeLa cell lines
BAX↑,
VEGF↓, BA can decrease the expression of VEGF via Sp proteins, thus having an antiangiogenic role
LAMs↓, BA suppresses the expression of lamin B1 in pancreatic cancer cells

2758- BetA,    Betulinic Acid Attenuates Oxidative Stress in the Thymus Induced by Acute Exposure to T-2 Toxin via Regulation of the MAPK/Nrf2 Signaling Pathway
- in-vivo, Nor, NA
*ROS↓, protective effects and mechanisms of BA in blocking oxidative stress caused by acute exposure to T-2 toxin in the thymus of mice was studied.
*MDA↓, BA pretreatment reduced ROS production, decreased the MDA content, and increased the content of IgG in serum and the levels of SOD and GSH in the thymus.
*SOD↑,
*GSH↑,
*p‑p38↓, BA downregulated the phosphorylation of the p38, JNK, and ERK proteins, while it upregulated the expression of the Nrf2 and HO-1 proteins in thymus tissues.
*p‑JNK↓,
*p‑ERK↓,
*NRF2↑,
*HO-1↑,
*MAPK↓, suppressing the MAPK signaling pathway.
*heparanase↑, BA also showed protective activities against alcohol-induced liver damage and dexamethasone-induced spleen and thymus oxidative damage, and these protective effects were related to the antioxidant capacity of BA
*antiOx↑, BA Increased T-2 Toxin-Induced Thymus Antioxidative Capacity

2735- BetA,    Betulinic acid as apoptosis activator: Molecular mechanisms, mathematical modeling and chemical modifications
- Review, Var, NA
mt-Apoptosis↑, BA and analogues (BAs) have been known to exhibit potential antitumor action via provoking the mitochondrial pathway of apoptosis
Casp↑, cytosolic caspase activation
p38↑, inhibition of pro-apoptotic p38, MAPK and SAP/JNK kinases [8],
MAPK↓,
JNK↓,
VEGF↓, decreased expression of pro-apoptotic proteins and vascular endothelial growth factor (VEGF)
AIF↑, BA was recognized to trigger the process of apoptosis in human metastatic melanoma cells (Me-45) by releasing apoptosis inducing factor (AIF) and cytochrome c (Cyt C) through mitochondrial membrane
Cyt‑c↑,
ROS↑, BA also stimulates the increased production of reactive oxygen species (ROS) that is considered a stress factor involved in initiating mitochondrial membrane permeabilization
Ca+2↑, Moreover, the calcium overload and thereby ATP depletion are other stress factors causing enhanced inner mitochondrial membrane permeability via nonspecific pores formation
ATP↓,
NF-kB↓, BA has also known to be involved in activation of nuclear factor kappa B (NF-κB) that is responsible for apoptosis induction in variety of cancer cells
ATF3↓, According to Zhang et al. [14], BA stimulates apoptosis through the suppression of cyclic AMP-dependent transcription factor ATF-3 and NF-κB pathways and downregulation of p53 gene.
TOP1↓, inhibition of topoisomerases
VEGF↓, ecreased expression of vascular endothelial growth (VEGF) and the anti-apoptotic protein surviving in LNCaP prostate cancer cells.
survivin↓,
Sp1/3/4↓, selective proteasome-dependent targeted degradation of transcription factors specificity proteins (Sp1, Sp3, and Sp4), which generally regulate VEGF and survivin expression and highly over-expressed in tumor conditions
MMP↓, perturbed mitochondrial membrane potential
ChemoSen↑, BA can support as sensitizer in combination therapy to enhance the anticancer effects with minimum side effects.
selectivity↑, Normal human fibroblasts [41], peripheral blood lymphoblasts [41], melanocytes [32] and astrocytes [30] were found to be resistant to BA in vitro
BioAv↓, The clinical use of BA is seriously challenging due to high hydrophobicity which subsequently causes poor bioavailability
BioAv↑, A BA-loaded oil-in-water nanoemulsion was developed using phospholipase-catalyzed modified phosphatidylcholine as emulsifier in an ultrasonicator [120].
BioAv↑, Aqueous solubility of BA may also be increased through grinding with hydrophilic polymers (polyethylene glycol, polyvinylpyrrolidone, arabinogalactan) [121,122].
BioAv↑, Subsequently, for further improvement in biocompatibility, a technique of nanotube coating was employed with four biopolymers i.e. polyethylene glycol (PEG), chitosan, tween 20 and tween 80.
BioAv↑, Similarly, BA-coated silver nanoparticles displayed an improved antiproliferative and antimigratory activity, particularly against melanoma cells (A375: murine melanoma cells)


* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 3

Pathway results for Effect on Cancer / Diseased Cells:


Redox & Oxidative Stress

ATF3↓, 1,   ROS↓, 1,   ROS↑, 1,  

Mitochondria & Bioenergetics

AIF↑, 1,   ATP↓, 1,   MMP↓, 2,  

Cell Death

Apoptosis↑, 1,   mt-Apoptosis↑, 1,   BAX↑, 1,   Bcl-2↓, 1,   Casp↑, 2,   Cyt‑c↑, 2,   JNK↓, 1,   JNK↑, 1,   MAPK↓, 1,   MAPK↑, 1,   p38↑, 2,   survivin↓, 1,  

Kinase & Signal Transduction

Sp1/3/4↓, 2,  

Cell Cycle & Senescence

TumCCA↑, 1,  

Proliferation, Differentiation & Cell State

EMT↓, 1,   STAT3↓, 1,   TOP1↓, 2,  

Migration

Ca+2↑, 1,   LAMs↓, 1,  

Angiogenesis & Vasculature

VEGF↓, 3,  

Immune & Inflammatory Signaling

NF-kB↓, 2,  

Drug Metabolism & Resistance

BioAv↓, 1,   BioAv↑, 4,   ChemoSen↑, 1,   selectivity↑, 1,  
Total Targets: 31

Pathway results for Effect on Normal Cells:


Redox & Oxidative Stress

antiOx↑, 1,   GSH↑, 1,   HO-1↑, 1,   MDA↓, 1,   NRF2↑, 1,   ROS↓, 1,   SOD↑, 1,  

Cell Death

p‑JNK↓, 1,   MAPK↓, 1,   p‑p38↓, 1,  

Proliferation, Differentiation & Cell State

p‑ERK↓, 1,  

Migration

heparanase↑, 1,  
Total Targets: 12

Scientific Paper Hit Count for: JNK, c-Jun N-terminal kinase (JNK)
3 Betulinic acid
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#:42  Target#:168  State#:%  Dir#:%
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