Database Query Results : Silymarin (Milk Thistle) silibinin, , JNK

SIL, Silymarin (Milk Thistle) silibinin: Click to Expand ⟱

Features:

Silymarin (Milk Thistle) Flowering herb related to daisy and ragweed family.
Silibinin (INN), also known as silybin is the major active constituent of silymarin, a standardized extract of the milk thistle seeds.
-a flavonoid combination of 65–80% of seven flavolignans; the most important of these include silybin, isosilybin, silychristin, isosilychristin, and silydianin. Silybin is the most abundant compound in around 50–70% in isoforms silybin A and silybin B

-Note half-life 6hrs?.
BioAv not soluble in water, low bioAv (1%). 240mg yielded only 0.34ug/ml plasma level. oral administration of SM (equivalent to 120 mg silibinin), total (unconjugated + conjugated) silibinin concentration in plasma was 1.1–1.3 μg/mL, so can not achieve levels used in most in-vitro studies.
Pathways:
- results for both inducing and reducing ROS in cancer cells. In normal cell seems to consistently lower ROS. Reports show both ROS↑ and ROS↓ in cancer models; systemic pro-oxidant effects may require higher exposures than typical oral dosing, but local or combination contexts may differ. (level in GUT could be much higher (800uM).
- ROS↑ related: MMP↓(ΔΨm), Ca+2↑, Cyt‑c↑, Caspases↑, DNA damage↑, cl-PARP↑,
- Raises AntiOxidant defense in Normal Cells: ROS↓, NRF2↑, SOD↑, GSH↑, Catalase↑,
- lowers Inflammation : NF-kB↓, COX2↓, p38↓(context-dependent; often stress-activated), Pro-Inflammatory Cytokines : NLRP3↓, IL-1β↓, TNF-α↓, IL-6↓, IL-8↓
- inhibit Growth/Metastases : TumMeta↓, TumCG↓, EMT↓, MMPs↓, MMP2↓, MMP9↓, TIMP2, uPA↓, VEGF↓, FAK↓, NF-κB↓, CXCR4↓, TGF-β↓, α-SMA↓, ERK↓
- reactivate genes thereby inhibiting cancer cell growth : HDAC↓, DNMTs↓, P53↑, HSP↓,
- cause Cell cycle arrest : TumCCA↑, cyclin D1↓, cyclin E↓, CDK2↓, CDK4↓,
- inhibits Migration/Invasion : TumCMig↓, TumCI↓, TNF-α↓, FAK↓, ERK↓, EMT↓,
- inhibits glycolysis and ATP depletion : HIF-1α↓, PKM2↓, cMyc↓, GLUT1↓, LDH↓, LDHA↓, HK2↓, PFKs↓, GRP78↑(ER stress), Glucose↓, GlucoseCon↓
- inhibits angiogenesis↓ : VEGF↓, HIF-1α↓, Notch↓, PDGF↓, EGFR↓,
- inhibits Cancer Stem Cells : CSC↓, Hh↓, GLi1↓, β-catenin↓, Notch2↓, OCT4↓,
- Others: PI3K↓, AKT↓, JAK↓, STAT↓, Wnt↓, β-catenin↓, AMPK, ERK↓, JNK, - SREBP (related to cholesterol).
- Synergies: chemo-sensitization, chemoProtective, RadioSensitizer, RadioProtective, 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	ROS / redox buffering + mitochondrial protection	Often ↑ stress susceptibility; can support apoptosis when survival signaling is blocked	↓ oxidative stress; mitochondrial protection	P, R, G	Context-selective redox modulation	Silymarin is classically cytoprotective/antioxidant in normal tissues (notably liver), while in tumors it can weaken pro-survival adaptation and increase vulnerability to stressors and therapy.
2	Intrinsic apoptosis (mitochondria → caspases)	↑ apoptosis signaling; ↑ caspase activation	↔ minimal activation	G	Cell death execution	Common downstream outcome in cancer models: apoptosis increases after earlier signaling/redox shifts and/or checkpoint disruption.
3	Cell-cycle control (cyclins/CDKs; checkpoints)	↑ arrest (G1/S or G2/M depending on model)	↔	G	Cytostasis	Typically observed as reduced proliferation with checkpoint engagement; timing usually later than kinase phosphorylation changes.
4	NF-κB inflammatory transcription	↓ NF-κB activity; ↓ inflammatory/pro-survival tone	↔ or protective anti-inflammatory effect	R, G	Anti-inflammatory / anti-survival transcription	NF-κB suppression can reduce tumor-promoting inflammation and blunt stress-adaptive survival programs.
5	JAK/STAT3 axis (incl. PD-L1 / immune escape programs in some models)	↓ STAT3 signaling (context); may ↓ PD-L1 in certain tumor contexts	↔	R, G	Reduced survival + immune-evasion signaling	Reported to attenuate STAT3-driven tumor programs and, in some contexts, reduce immune-suppressive signaling (model dependent).
6	PI3K → AKT → mTOR survival / growth signaling	↓ PI3K/AKT/mTOR signaling (context)	↔	R, G	Growth/survival suppression	Reduced PI3K/AKT/mTOR tone increases sensitivity to apoptosis and can reinforce cell-cycle arrest.
7	MAPK re-wiring (ERK/p38/JNK balance)	Stress-MAPK shifts; ERK tone often reduced or re-patterned	↔	P, R, G	Signal reprogramming	Early phosphorylation shifts can precede later gene-expression changes; exact ERK direction is model and dose dependent.
8	Angiogenesis (VEGF and angiogenic factors)	↓ VEGF / angiogenesis outputs	↔	G	Anti-angiogenic support	Typically reflected in reduced pro-angiogenic expression/secretion and angiogenesis-related phenotypes over longer windows.
9	EMT / invasion / migration programs (incl. TGF-β/Smad-associated EMT in some systems)	↓ EMT markers; ↓ migration/invasion	↔	G	Anti-invasive phenotype	Often presents as restoration of epithelial markers and suppression of migration/invasion assays; commonly a later phenotype-level outcome.
10	Xenobiotic handling (Phase I/II enzymes; cytoprotection / chemoprevention framing)	May alter carcinogen activation/detox balance	↑ detox / cytoprotection against xenobiotics	G	Chemopreventive protection	A key “dual strategy” theme: protection of normal tissue from toxins/therapy while modulating tumor response pathways.
11	Drug resistance / efflux (MDR phenotype; P-gp-related resistance in some models)	May ↓ functional MDR and ↑ chemo sensitivity (context)	↔	R, G	Chemo-sensitization support	Reported synergy with chemotherapy in resistant tumor settings; transporter direction can be context-specific, so present as “reported to reduce functional resistance” rather than a universal single-transporter claim.
12	Immune microenvironment signaling (cytokines / macrophage recruitment in some models)	May ↓ pro-tumor cytokine programs and recruitment signals (context)	↔	G	Anti-inflammatory tumor microenvironment shift	Immune-modulatory effects are increasingly discussed, but they are more model-dependent and typically show on longer time scales.

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

P: 0–30 min (primary/physical–chemical effects; rapid signaling / phosphorylation shifts)
R: 30 min–3 hr (redox signaling + acute stress-response signaling)
G: >3 hr (gene-regulatory adaptation and phenotype-level 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⟱

3319-

SIL,

Silymarin and neurodegenerative diseases: Therapeutic potential and basic molecular mechanisms

Review,

AD,

Review,

Park,

Review,

Stroke,

*neuroP↑, Silymarin can be used as a neuroprotective therapy against AD, PD and CI
*ROS↓, Silymarin prohibit oxidative stress, pathologic protein aggregation.
*Inflam↓, Silymarin inhibit neuroinflammation, apoptosis, and estrogenic receptor modulation.
*Apoptosis↓,
*BBB?, Silymarin, as a polyphenolic complex, can cross the blood-brain barrier (BBB)
*tau↓, inhibitory action of Silibinin on tau protein phosphorylation in the hippocampus and cortical region of the brain could describe an important neuro-protective effect against AD progression
*NF-kB↓, inhibiting the NF-ÎºB pathway leading to attenuating the activity of NF-ÎºB (
*IL1β↓, inhibition of inflammatory responses such as IL-1Î² and TNF-Î± mRNA gene
*TNF-α↓,
*IL4↓, enhance the production of IL-4 in the hippocampal region
*MAPK↓, down-regulation of MAPK activation
*memory↑, Silibinin exhibited its beneficial effect on improvement of memory impairment in rats
*cognitive↑, Silymarin was able to alleviated the impairment in cognitive, learning and memory ability caused by AÎ² aggravation through making a reduction in oxidative stress in the hippocampal region
*Aβ↓,
*ROS↓,
*lipid-P↓, eduction in lipid peroxidation, controlling the GSH levels and then cellular anti-oxidant status improvement,
*GSH↑,
*MDA↓, Silymarin could reduce MDA content and significantly increased the reduced activity level of antioxidant enzyme, including SOD, CAT and GSH in the brain tissue induced by aluminum
*SOD↑,
*Catalase↑,
*AChE↓, Silibinin/ Silymarin, as a strong suppressor of AChE and BChE activity, exerted a positive effect against AD symptoms via increasing the ACh level in the brain
*BChE↓,
*p‑ERK↓, Silibinin could inhibit increased level of phosphorylated ERK, JNK and p38 (p-ERK, p-JNK and p-p38, respectively
*p‑JNK↓,
*p‑p38↓,
*GutMicro↑, demonstrated in APP/PS1 transgenic mice model of AD which was associated with controlling of the gut microbiota by both Silymarin and Silibinin
*COX2↓, Inhibition of the NF-ÎºB pathway/ expression, Inhibition of IL-1Î², TNF-Î±, COX_2 and iNOS level/ expression
*iNOS↓,
*TLR4↓, suppress TLR4 pathways and then subsequently diminished elevated level of TNF-Î± and up-regulated percentage of NF-ÎºB mRNA expression
*neuroP↑, neuro-protective mechanisms on cerebral ischemia (CI)
*Strength↑, Silymarin decreased the loss of grip strength in the experimental rats
*AMPK↑, In SH-SY5Y cells, Silibinin blocked OGD/re-oxygenation- induced neuronal degeneration via AMPK activation as well as suppression in both ROS production and MMP reduction and even reduced neuronal apoptosis and necrosis.
*MMP↑,
*necrosis↓,
*NRF2↑, Silymarin up-regulated Nrf-2/HO-1 signaling (Yuan et al., 2017
*HO-1↑,

3315-

SIL,

Silymarin alleviates docetaxel-induced central and peripheral neurotoxicity by reducing oxidative stress, inflammation and apoptosis in rats

in-vivo,

Nor,

rats

neuroP↑, Silymarin protects against the brain and sciatic nerve injuries induced by docetaxel.
*NRF2↑, Silymarin activates Nrf2/HO-1, and suppresses Bax/Bcl2 signaling.
*HO-1↑,
*lipid-P↓, SLM significantly decreased brain lipid peroxidation level and ameliorated brain glutathione (GSH), superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) activities in DTX-administered rats
*GSH↑,
*SOD↑,
*Catalase↑,
*GPx↑,
*NF-kB↓, SLM attenuated levels of nuclear factor kappa B (NF-κB), tumor necrosis factor-α (TNF-α),
*TNF-α↓,
*JNK↓, decreased the expression of c-Jun N-terminal kinase (JNK) in the sciatic nerve
*Bcl-2↑, SLM markedly up-regulated the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 (HO-1) and B-cell lymphoma-2 (Bcl-2) and downregulated the expression of Bcl-2 associated X protein (Bax) in the brain
*BAX↑,

3293-

SIL,

Silymarin (milk thistle extract) as a therapeutic agent in gastrointestinal cancer

Review,

Var,

hepatoP↑, Silymarin has been shown to protect the liver in both experimental models and clinical studies.
TumMeta↓, In addition to its anti-metastatic activity, silymarin has also been reported to exhibit anti-inflammatory activity
Inflam↓,
chemoP↑, The chemoprotective effects of silymarin and silibinin (its major constituent) suggest they could be applied to reduce the side effects and increase the anti-cancer effects of chemotherapy and radiotherapy in various cancer types, especially in GC
radioP↑,
Half-Life↝, silibinin showed a 6-h half-life
*GSTs↑, Oral administration of silibinin leads to an increase in glutathione S-transferase (GST) and quinone reductase (QR) activity in the liver, stomach, lungs, small bowel, and skin, in a time- and dose-dependent manner
p‑JNK↑, Silymarin significantly up-regulated the levels of phosphorylated (p)-JNK, Bax, and p-p38, and cleaved poly-ADP ribose polymerase (PARP), while it down-regulated Bcl-2 and p-ERK1/2 expression, in a dose-dependent manner.
BAX↑,
p‑p38↑,
cl‑PARP↑,
Bcl-2↓,
p‑ERK↓,
TumVol↓, Silymarin (100 mg/kg) decreased the tumor volume in an AGS xenograft mouse model and increased apoptosis in the tumors.
eff↑, resveratrol, lycopene, sulforaphane, or silybinin have been shown to have anti-tumor activity, along with relatively low-toxicity to normal cells. Therefore they could be used in combination
TumCCA↑, Silibinin induced apoptosis and cell cycle arrest in G2/M phase in MGC803 cells
STAT3↓, Silybinin down-regulated p-STAT3 protein expression and also its downstream genes (such as Mcl-1, survivin, Bcl-xL, and STAT3).
Mcl-1↓,
survivin↓,
Bcl-xL↓,
Casp3↑, Silibinin increased caspase-3 and caspase-9 mRNA and protein expression levels.
Casp9↑,
eff↑, Therefore, the anti-cancer activity of silibinin might be enhanced by HDAC inhibitors
CXCR4↓, Silymarin significantly induced apoptosis and decreased the expression level of CXCR-4 in HepG2 cells in a concentration-dependent manner.
Dose↝, It has been shown to be tolerated by patients at a large dose (700 mg) thrice per day over six months

3304-

SIL,

Silymarin induces inhibition of growth and apoptosis through modulation of the MAPK signaling pathway in AGS human gastric cancer cells

in-vitro,

GC,

AGS

0, 20, 40, 60, 80, 100 and 120 µg/ml for 24 h

in-vivo,

NA,

100 mg/kg silymarin injection group mice

BAX↑, Silymarin increased the expression of Bax, phosphorylated (p)-JNK and p-p38, and cleaved poly-ADP ribose polymerase, and decreased the levels of Bcl-2 and p-ERK1/2 in a concentration-dependent manner.
p‑JNK↑,
p‑p38↑,
cl‑PARP↑,
Bcl-2↓,
p‑ERK↓,
TumVol↓, Silymarin (100 mg/kg) significantly decreased the AGS tumor volume and increased apoptosis
Apoptosis↑,
tumCV↓,

3305-

SIL,

Silymarin inhibits proliferation of human breast cancer cells via regulation of the MAPK signaling pathway and induction of apoptosis

in-vitro,

BC,

MDA-MB-231

0, 25, 50, 75, 100, 150 or 200 µg/ml silymarin for 24 h

in-vitro,

BC,

MCF-7

in-vivo,

NA,

mice

TumCP↓, Silymarin decreased the viability and proliferation of MDA-MB-231 and MCF-7 cells in a concentration-dependent manner.
tumCV↓,
BAX↑, Silymarin increased the levels of Bax, cleaved poly-ADP ribose polymerase, cleaved caspase-9 and phosphorylated (p-)JNK, and decreased the levels of Bcl-2, p-P38 and p-ERK1/2.
cl‑PARP↑,
Casp9↑,
p‑JNK↑,
Bcl-2↓,
p‑p38↓,
p‑ERK↓,
*toxicity∅, In mice treated with silymarin for 3 weeks (25 and 50 mg/kg), MCF-7 tumor growth was inhibited without organ toxicity
Dose↝, cell viability increased to 110% @ low dose 25ug/ml before dropping see figure 1
*hepatoP↑, silymarin is used as a healthy functional food in recognition of the hepatoprotective effects and has been reported the various effects such as inflammation (750 mg/kg/day), antioxidants (150 mg/kg−1) and anti-cancer
Inflam↓,
AntiCan↑,

3301-

SIL,

Critical review of therapeutic potential of silymarin in cancer: A bioactive polyphenolic flavonoid

Review,

Var,

Inflam↓, graphical abstract
TumCCA↑,
Apoptosis↓,
TumMeta↓,
TumCG↓,
angioG↓,
chemoP↑, The chemo-protective effects of silymarin and silibinin propose that they could be applied to decrease the side effects and increase the anti-tumor effects of chemotherapy and radiotherapy in different types of cancers.
radioP↑,
p‑ERK↓, fig 2
p‑p38↓,
p‑JNK↓,
P53↑,
Bcl-2↓,
Bcl-xL↓,
TGF-β↓,
MMP2↓,
MMP9↓,
E-cadherin↑,
Wnt↓,
Vim↓,
VEGF↓,
IL6↓,
STAT3↓,
*ROS↓,
IL1β↓,
PGE2↓,
CDK1↓, Causes cell cycle arrest by down-regulating CDK1, cyclinB1, survivin, Bcl-xl, Mcl-1 and activating caspase 3 and caspase 9,
CycB/CCNB1↓,
survivin↓,
Mcl-1↓,
Casp3↑,
Casp9↑,
cMyc↓, Silibinin treatment diminishes c-MYC
COX2↓, Silibinin considerably down-regulated the expression of COX-2, HIF-1α, VEGF, Ang-2, Ang-4, MMP-2, MMP-9, CCR-2 and CXCR-4
Hif1a↓,
CXCR4↓,
CSCs↓, HCT-116 cells, Induction of apoptosis, suppression of migration, elimination of CSCs. Attenuation of EMT via decreased expression of N- cadherin and vimentin and increased expression of (E-cadherin).
EMT↓,
N-cadherin↓,
PCNA↓, Decrease in PCNA and cyclin D1 level.
cycD1/CCND1↓,
ROS↑, Hepatocellular carcinoma: Silymarin nanoemulsion reduced the cell viability and increased ROS intensity and chromatin condensation.
eff↑, Silymarin + Curcumin
eff↑, Silibinin + Metformin
eff↑, Silibinin + 1, 25-vitamin D3
HER2/EBBR2↓, Significant down regulation of HER2 by 150 and 250 µM of silybin after 24, 48 and 72 h.

3296-

SIL,

Silibinin induces oral cancer cell apoptosis and reactive oxygen species generation by activating the JNK/c-Jun pathway

in-vitro,

Oral,

Ca9-22

 0, 50, 100, 200 μM silibinin for 48 h

in-vivo,

Oral,

YD10B

TumCP↓, Silibinin effectively suppressed YD10B and Ca9-22 cell proliferation and colony formation in a dose-dependent manner.
TumCCA↑, Moreover, it induced cell cycle arrest in the G0/G1 phase, apoptosis, and ROS generation in these cells.
ROS↑,
SOD1↓, silibinin downregulated SOD1 and SOD2 and triggered the JNK/c-Jun pathway in oral cancer cells.
SOD2↓,
*JNK↑, inducing apoptosis, G0/G1 arrest, ROS generation, and activation of the JNK/c-Jun pathway.
toxicity?, Silibinin significantly inhibited xenograft tumor growth in nude mice, with no obvious toxicity.
TumCMig↓, Silibinin inhibits oral cancer cell migration and invasion
TumCI↓,
N-cadherin↓, silibinin downregulated N-cadherin and vimentin expression and upregulated E-cadherin expression in YD10B and Ca9-22 cells
Vim↓,
E-cadherin↑,
EMT↓, Together, these results indicate that silibinin inhibits the migration and invasion of oral cancer cells by suppressing the EMT.
P53↑, silibinin significantly induced the expression of p53, cleaved caspase-3, cleaved PARP, and Bax, and downregulated the expression of the anti-apoptotic marker protein Bcl-2
cl‑Casp3↑,
cl‑PARP↑,
BAX↑,
Bcl-2↓,
SOD↓, silibinin inhibits SOD expression, induces ROS production, and activates the JNK/c-Jun pathway in oral cancer cells.

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 7

Pathway results for Effect on Cancer / Diseased Cells:

Pathway results for Effect on Normal Cells:

Redox & Oxidative Stress ⓘ

Catalase↑, 2, GPx↑, 1, GSH↑, 2, GSTs↑, 1, HO-1↑, 2, lipid-P↓, 2, MDA↓, 1, NRF2↑, 2, ROS↓, 3, SOD↑, 2,

Mitochondria & Bioenergetics ⓘ

MMP↑, 1,

Core Metabolism/Glycolysis ⓘ

AMPK↑, 1,

Cell Death ⓘ

Apoptosis↓, 1, BAX↑, 1, Bcl-2↑, 1, iNOS↓, 1, JNK↓, 1, JNK↑, 1, p‑JNK↓, 1, MAPK↓, 1, necrosis↓, 1, p‑p38↓, 1,

Proliferation, Differentiation & Cell State ⓘ

p‑ERK↓, 1,

Barriers & Transport ⓘ

BBB?, 1,

Immune & Inflammatory Signaling ⓘ

COX2↓, 1, IL1β↓, 1, IL4↓, 1, Inflam↓, 1, NF-kB↓, 2, TLR4↓, 1, TNF-α↓, 2,

Synaptic & Neurotransmission ⓘ

AChE↓, 1, BChE↓, 1, tau↓, 1,

Protein Aggregation ⓘ

Aβ↓, 1,

Clinical Biomarkers ⓘ

GutMicro↑, 1,

Functional Outcomes ⓘ

cognitive↑, 1, hepatoP↑, 1, memory↑, 1, neuroP↑, 2, Strength↑, 1, toxicity∅, 1,
Total Targets: 42

Scientific Paper Hit Count for: JNK, c-Jun N-terminal kinase (JNK)

7 Silymarin (Milk Thistle) silibinin

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#:154  Target#:168  State#:%  Dir#:%
  wNotes=on  sortOrder:rid,rpid

Database Query Results : Silymarin (Milk Thistle) silibinin, , JNK

Pathway results for Effect on Cancer / Diseased Cells:

Redox & Oxidative Stress ⓘ

Core Metabolism/Glycolysis ⓘ

Cell Death ⓘ

Kinase & Signal Transduction ⓘ

Transcription & Epigenetics ⓘ

DNA Damage & Repair ⓘ

Cell Cycle & Senescence ⓘ

Proliferation, Differentiation & Cell State ⓘ

Migration ⓘ

Angiogenesis & Vasculature ⓘ

Immune & Inflammatory Signaling ⓘ

Drug Metabolism & Resistance ⓘ

Clinical Biomarkers ⓘ

Functional Outcomes ⓘ

Pathway results for Effect on Normal Cells:

Redox & Oxidative Stress ⓘ

Mitochondria & Bioenergetics ⓘ

Core Metabolism/Glycolysis ⓘ

Cell Death ⓘ

Proliferation, Differentiation & Cell State ⓘ

Barriers & Transport ⓘ

Immune & Inflammatory Signaling ⓘ

Synaptic & Neurotransmission ⓘ

Protein Aggregation ⓘ

Clinical Biomarkers ⓘ

Functional Outcomes ⓘ

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