Silymarin (Milk Thistle) silibinin / iNOS Cancer Research Results

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)

iNOS, Inducible nitric oxide synthase: Click to Expand ⟱

Source: HalifaxProj(block)

Type:

An enzyme that produces nitric oxide (NO) in response to inflammatory stimuli.
iNOS can promote tumor growth by enhancing blood flow and nutrient supply to tumors through vasodilation. It may also help cancer cells evade apoptosis (programmed cell death).
Immune Activation: In some contexts, NO produced by iNOS can enhance the immune response against tumors, promoting the activation of immune cells that can target and destroy cancer cells.
Inhibition of Tumor Growth: High levels of NO can induce cytotoxic effects on tumor cells, leading to reduced proliferation and increased apoptosis.

Scientific Papers found: Click to Expand⟱

3331-

SIL,

The clinical anti-inflammatory effects and underlying mechanisms of silymarin

Review,

NA,

*Inflam↓, *NF-kB↓, *NLRP3↓, *COX2↓, *iNOS↓, *neuroP↑, *p‑ERK↓, *p38↓, *MAPK↓, *EGFR↓, *ROS↓, *lipid-P?, *5LO↓,

3330-

SIL,

Mechanistic Insights into the Pharmacological Significance of Silymarin

Review,

Var,

*neuroP↑, *hepatoP↑, *cardioP↑, *antiOx↓, *NLRP3↓, *NAD↑, ROS↓, NLRP3↓, TumCMig↓, *COX2↓, *iNOS↓, *MPO↓, *AChE↓, *LDH↓, *Telomerase↓, *Fas↓,

3329-

SIL,

iNOS_expression_in_the_brain_and_Gills_of_the_hypoxic-reoxygenated_rainbow_trout_Oncorhynchus_mykis">Silymarin regulates the HIF-1 and iNOS expression in the brain and Gills of the hypoxic-reoxygenated rainbow trout (Oncorhynchus mykis)

in-vivo,

Nor,

rainbow trout

*NO↓, *MDA↓, *TAC↑, *Hif1a↓, *iNOS↓,

3328-

SIL,

Modulatory effect of silymarin on inflammatory mediators in experimentally induced benign prostatic hyperplasia: emphasis on PTEN, HIF-1α, and NF-κB

in-vivo,

BPH,

injected testosterone (3 mg/kg/day, subcutaneously (s.c.)) for 2 weeks.

Rats

*NF-kB↓, *Hif1a↓, *PTEN↑, *Weight↓, *NO↓, *IL6↓, *IL8↓, *COX2↓, *iNOS↓,

3325-

SIL,

Modulatory effect of silymarin on pulmonary vascular dysfunction through HIF-1α-iNOS following rat lung ischemia-reperfusion injury

in-vivo,

Nor,

Rats

*Inflam↓, *ROS↓, *Casp3↑, *Casp9↑, *Hif1a↓, *iNOS↓, *SOD↑, *MDA↓,

3320-

SIL,

Neuroprotective Potential of Silymarin against CNS Disorders: Insight into the Pathways and Molecular Mechanisms of Action

Review,

AD,

*hepatoP↑, *neuroP↑, *ROS↓, *β-Amyloid↓, *Inflam↓, *Aβ↓, *NF-kB↓, *TNF-α↓, *TNF-β↓, *iNOS↓, *NO↓, *COX2↓,

3319-

SIL,

Silymarin and neurodegenerative diseases: Therapeutic potential and basic molecular mechanisms

Review,

AD,

Review,

Park,

Review,

Stroke,

*neuroP↑, *ROS↓, *Inflam↓, *Apoptosis↓, *BBB?, *tau↓, *NF-kB↓, *IL1β↓, *TNF-α↓, *IL4↓, *MAPK↓, *memory↑, *cognitive↑, *Aβ↓, *ROS↓, *lipid-P↓, *GSH↑, *MDA↓, *SOD↑, *Catalase↑, *AChE↓, *BChE↓, *p‑ERK↓, *p‑JNK↓, *p‑p38↓, *GutMicro↑, *COX2↓, *iNOS↓, *TLR4↓, *neuroP↑, *Strength↑, *AMPK↑, *MMP↑, *necrosis↓, *NRF2↑, *HO-1↑,

3290-

SIL,

A review of therapeutic potentials of milk thistle (Silybum marianum L.) and its main constituent, silymarin, on cancer, and their related patents

Analysis,

Var,

hepatoP↑, chemoP↑, *lipid-P↓, *antiOx↑, tumCV↓, TumCMig↓, Apoptosis↑, ROS↑, GSH↓, Bcl-2↓, survivin↓, cycD1/CCND1↓, NOTCH1↓, BAX↑, NF-kB↓, COX2↓, LOX1↓, iNOS↓, TNF-α↓, IL1↓, Inflam↓, *toxicity↓, CXCR4↓, EGFR↓, ERK↓, MMP↓, Cyt‑c↑, TumCCA↑, RB1↑, P53↑, P21↑, p27↑, cycE/CCNE↓, CDK4↓, p‑pRB↓, Hif1a↓, cMyc↓, IL1β↓, IFN-γ↓, PCNA↓, PSA↓, CYP1A1↓,

3314-

SIL,

Silymarin: Unveiling its pharmacological spectrum and therapeutic potential in liver diseases—A comprehensive narrative review

Review,

NA,

*antiOx↑, *hepatoP↑, *Half-Life↑, *ROS↓, *GSH↑, *hepatoP↑, *lipid-P↓, *TNF-α↓, *IFN-γ↓, *IL2↓, *IL4↓, *NF-kB↓, *iNOS↓, *OATPs↓, *OCT4↓, *Inflam↓, *PGE2↓, MMPs↓, VEGF↓, angioG↓, STAT3↓, *ALAT↓, *AST↓, Dose↝,

3310-

SIL,

Silymarin attenuates paraquat-induced lung injury via Nrf2-mediated pathway in vivo and in vitro

in-vitro,

Lung,

A549

Inflam↓, MPO↓, NO↓, iNOS↓, ROS↓, MDA↑, SOD↑, Catalase↑, GPx↑, NRF2↑, HO-1↑, NADPH↑,

3309-

SIL,

Silymarin as a Natural Antioxidant: An Overview of the Current Evidence and Perspectives

Review,

NA,

*ROS↓, *IronCh↑, *MMP↑, *NRF2↑, *Inflam↓, *hepatoP↑, *HSPs↑, *Trx↑, *SIRT2↑, *GSH↑, *ROS↑, *NADPH↓, *iNOS↓, *NF-kB↓, *BioAv↓, *Dose↝, *BioAv↑,

Showing Research Papers: 1 to 11 of 11

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

Pathway results for Effect on Cancer / Diseased Cells:

Functional Outcomes ⓘ

chemoP↑, 1, hepatoP↑, 1,
Total Targets: 57

Pathway results for Effect on Normal Cells:

Redox & Oxidative Stress ⓘ

antiOx↓, 1, antiOx↑, 2, Catalase↑, 1, GSH↑, 3, HO-1↑, 1, lipid-P?, 1, lipid-P↓, 3, MDA↓, 3, MPO↓, 1, NRF2↑, 2, ROS↓, 7, ROS↑, 1, SOD↑, 2, TAC↑, 1, Trx↑, 1,

Metal & Cofactor Biology ⓘ

IronCh↑, 1,

Mitochondria & Bioenergetics ⓘ

MMP↑, 2,

Core Metabolism/Glycolysis ⓘ

ALAT↓, 1, AMPK↑, 1, LDH↓, 1, NAD↑, 1, NADPH↓, 1, SIRT2↑, 1,

Cell Death ⓘ

Apoptosis↓, 1, Casp3↑, 1, Casp9↑, 1, Fas↓, 1, iNOS↓, 9, p‑JNK↓, 1, MAPK↓, 2, necrosis↓, 1, p38↓, 1, p‑p38↓, 1, Telomerase↓, 1,

Protein Folding & ER Stress ⓘ

HSPs↑, 1,

Proliferation, Differentiation & Cell State ⓘ

p‑ERK↓, 2, OCT4↓, 1, PTEN↑, 1,

Migration ⓘ

5LO↓, 1,

Angiogenesis & Vasculature ⓘ

EGFR↓, 1, Hif1a↓, 3, NO↓, 3,

Barriers & Transport ⓘ

BBB?, 1, OATPs↓, 1,

Immune & Inflammatory Signaling ⓘ

COX2↓, 5, IFN-γ↓, 1, IL1β↓, 1, IL2↓, 1, IL4↓, 2, IL6↓, 1, IL8↓, 1, Inflam↓, 6, NF-kB↓, 6, PGE2↓, 1, TLR4↓, 1, TNF-α↓, 3, TNF-β↓, 1,

Synaptic & Neurotransmission ⓘ

AChE↓, 2, BChE↓, 1, tau↓, 1,

Protein Aggregation ⓘ

Aβ↓, 2, NLRP3↓, 2, β-Amyloid↓, 1,

Drug Metabolism & Resistance ⓘ

BioAv↓, 1, BioAv↑, 1, Dose↝, 1, Half-Life↑, 1,

Clinical Biomarkers ⓘ

ALAT↓, 1, AST↓, 1, EGFR↓, 1, GutMicro↑, 1, IL6↓, 1, LDH↓, 1,

Functional Outcomes ⓘ

cardioP↑, 1, cognitive↑, 1, hepatoP↑, 5, memory↑, 1, neuroP↑, 5, Strength↑, 1, toxicity↓, 1, Weight↓, 1,
Total Targets: 81

Scientific Paper Hit Count for: iNOS, Inducible nitric oxide synthase

11 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#:159  State#:%  Dir#:1
  wNotes=0  sortOrder:rid,rpid

Silymarin (Milk Thistle) silibinin / iNOS Cancer Research Results

Pathway results for Effect on Cancer / Diseased Cells:

Redox & Oxidative Stress ⓘ

Mitochondria & Bioenergetics ⓘ

Core Metabolism/Glycolysis ⓘ

Cell Death ⓘ

Transcription & Epigenetics ⓘ

DNA Damage & Repair ⓘ

Cell Cycle & Senescence ⓘ

Proliferation, Differentiation & Cell State ⓘ

Migration ⓘ

Angiogenesis & Vasculature ⓘ

Immune & Inflammatory Signaling ⓘ

Protein Aggregation ⓘ

Drug Metabolism & Resistance ⓘ

Clinical Biomarkers ⓘ

Functional Outcomes ⓘ

Pathway results for Effect on Normal Cells:

Redox & Oxidative Stress ⓘ

Metal & Cofactor Biology ⓘ

Mitochondria & Bioenergetics ⓘ

Core Metabolism/Glycolysis ⓘ

Cell Death ⓘ

Protein Folding & ER Stress ⓘ

Proliferation, Differentiation & Cell State ⓘ

Migration ⓘ

Angiogenesis & Vasculature ⓘ

Barriers & Transport ⓘ

Immune & Inflammatory Signaling ⓘ

Synaptic & Neurotransmission ⓘ

Protein Aggregation ⓘ

Drug Metabolism & Resistance ⓘ

Clinical Biomarkers ⓘ

Functional Outcomes ⓘ

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