Database Query Results : Shikonin, , neuroP

SK, Shikonin: Click to Expand ⟱
Features:
The (R)-enantiomer of alkannin is known as shikonin, and the racemic mixture of the two is known as shikalkin.
Shikonin is a naphthoquinone derivative primarily isolated from the roots of plants in the Boraginaceae family (e.g., Lithospermum erythrorhizon).
Shikonin is the main active component of a Chinese medicinal plant 'Zi Cao'
-Shikonin is a major component of zicao (purple gromwell, the dried root of Lithospermum erythrorhizon), a Chinese herbal medicine with anti-inflammatory properties
-Quinone methides (QMs) are highly reactive intermediates formed from natural compounds like shikonin
-ic50 cancer cells 1-10uM, normal cells >10uM

-known as Glycolysis inhibitor: ( inhibit pyruvate kinase M2 (PKM2*******), a key enzyme in the glycolytic pathway)

Available from mcsformulas.com Shikonin Pro Liposomal, 30 mg
Also In Glycolysis Inhibithree(100 mg PHLORIZIN,10 mg TANSHINONE IIA, 8 mg Shikonin)

-Note half-life15-30mins or 8hr?.
BioAv low, poor water solubility
Pathways:
- usually induce ROS production in cancer cells, and reduce ROS in normal cells.
- ROS↑ related: MMP↓(ΔΨm), ER Stress↑, GRP78↑, Ca+2↑, Cyt‑c↑, Caspases↑, DNA damage↑, cl-PARP↑, HSP↓,
- Lowers AntiOxidant defense in Cancer Cells: NRF2↓, TrxR↓**, SOD↓, GSH↓ Catalase↓ GPx4↓
- Raises AntiOxidant defense in Normal Cells: ROS↓, NRF2↑, SOD↑, GSH↑, Catalase↑,
- lowers Inflammation : NF-kB↓, COX2↓, p38↓, Pro-Inflammatory Cytokines : NLRP3↓, IL-1β↓, TNF-α↓, IL-6↓, IL-8↓
- inhibit Growth/Metastases : TumMeta↓, TumCG↓, EMT↓, MMPs↓, MMP2↓, MMP9↓, IGF-1↓, uPA↓, VEGF↓, FAK↓, NF-κB↓, TGF-β↓, ERK↓
- cause Cell cycle arrest : TumCCA↑, cyclin D1↓, cyclin E↓, CDK2↓, CDK4↓,
- inhibits Migration/Invasion : TumCMig↓, TumCI↓, FAK↓, ERK↓, EMT↓,
- inhibits glycolysis /Warburg Effect and ATP depletion : HIF-1α↓, PKM2↓, cMyc↓, GLUT1↓, LDH↓, LDHA↓, HK2↓, PFKs↓, PDKs↓, ECAR↓, OXPHOS↓, GRP78↑, GlucoseCon↓
- inhibits angiogenesis↓ : VEGF↓, HIF-1α↓, EGFR↓, Integrins↓,
- Others: PI3K↓, AKT↓, JAK↓, STAT↓, β-catenin↓, AMPK, ERK↓, JNK, P53↑,
- Synergies: chemo-sensitization, chemoProtective, RadioSensitizer, 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
1 PKM2-mediated aerobic glycolysis (Warburg metabolism) Energy / biomass restriction Key, repeatedly reported mechanism: shikonin suppresses PKM2 activity and PKM2-driven glycolysis in multiple tumor models, with downstream growth inhibition and apoptosis
2 ROS accumulation / oxidative stress ↑ ROS Redox overload Common upstream trigger that drives mitochondrial dysfunction and regulated cell death programs; often precedes necroptosis/apoptosis signaling
3 Necroptosis core cascade (RIPK1 → RIPK3 → MLKL) Programmed necrotic cell death Strong evidence across cancers (e.g., leukemia and nasopharyngeal carcinoma): shikonin increases RIPK1/RIPK3/MLKL expression/activation; necroptosis inhibitors can blunt the effect
4 Mitochondrial integrity (ΔΨm) Mitochondrial dysfunction ROS-linked depolarization; acts as a pivot into intrinsic apoptosis and other death programs
5 Intrinsic apoptosis (BAX/BAK → Caspase-9/3) Programmed cell death Frequently observed; often framed as ROS → mitochondrial damage → caspase-dependent apoptosis
6 PKM2/STAT3 signaling axis Reduced survival & proliferation signaling In ESCC and related models, shikonin suppresses PKM2-driven glycolysis and down-modulates STAT3 pathway activity
7 NF-κB pathway Reduced pro-survival transcription Reported as part of multi-target suppression of inflammatory/anti-apoptotic programs in several tumor models and reviews
8 PI3K–AKT (± mTOR) Growth & resistance pathway inhibition Often described as sensitizing cells to apoptosis/TRAIL; may be secondary to oxidative stress and metabolic collapse
9 Stress MAPKs (JNK / p38) Pro-death stress signaling Common downstream response to ROS; can reinforce apoptosis and other death outcomes
10 Ferroptosis-related axis (lipid peroxidation; GPX4) ↑ lipid perox / ↓ GPX4 Iron-dependent oxidative death Reported prominently for acetylshikonin (a shikonin derivative): ROS-associated lipid peroxidation with reduced GPX4 expression alongside RIPK1/RIPK3/MLKL activation
11 Endoplasmic reticulum stress (UPR / ERS) Proteotoxic stress signaling Frequently mentioned in leukemia-focused mechanism summaries and broader reviews as contributory to growth arrest and death
12 Multiple regulated death programs (apoptosis / necroptosis / ferroptosis / pyroptosis) ↑ (context-dependent) Broader cell-death engagement Recent reviews emphasize that shikonin can engage several programmed cell death modalities depending on cell context and dosing
Rank Pathway / Target Axis Direction Primary Effect Notes / Cancer Relevance Ref
1 PKM2-mediated aerobic glycolysis (Warburg metabolism) ↓ PKM2 activity / ↓ glycolysis Energy & biomass restriction Demonstrates shikonin (and analogs) inhibit cancer glycolysis, reducing glucose consumption/lactate production via PKM2 targeting (ref)
2 PKM2 → STAT3 signaling axis ↓ PKM2-driven signaling / ↓ STAT3 pathway Reduced survival & proliferation ESCC study: shikonin suppresses PKM2-mediated aerobic glycolysis and regulates PKM2/STAT3 signaling (ref)
3 Necroptosis (RIPK1 → RIPK3 → MLKL) ↑ RIPK1/RIPK3/MLKL Programmed necrotic cell death Nasopharyngeal carcinoma: shikonin induces necroptosis with upregulation of RIPK1/RIPK3/MLKL (with ROS involvement) (ref)
4 ROS accumulation ↑ ROS Oxidative stress trigger Colon cancer model: shikonin increases intracellular ROS; ROS functions upstream of apoptosis (ref)
5 Mitochondrial apoptosis (Caspase-9/3) ↑ Caspase-9/3 Programmed cell death Same colon cancer study shows shikonin increases caspase-3 and caspase-9 activity (mitochondria-mediated apoptosis) (ref)
6 ER stress / UPR (PERK → eIF2α → CHOP) Proteotoxic stress apoptosis signaling Colon cancer: shikonin-induced apoptosis mediated by PERK/eIF2α/CHOP ER-stress pathway (ref)
7 Autophagic flux (autophagosome–lysosome completion) ↓ autophagic flux (blocked) ROS + apoptosis amplification Colorectal cancer: shikonin induces ROS and apoptosis by inhibiting autophagic flux (ref)
8 NF-κB signaling ↓ NF-κB activity Reduced pro-survival transcription Pancreatic cancer xenograft/mechanistic study: shikonin suppresses NF-κB activity and NF-κB–regulated gene products (ref)
9 PI3K–AKT–mTOR (stemness / chemoresistance axis) ↓ PI3K/AKT/mTOR Reduced survival & stemness Chemoresistant lung cancer CSC context: shikonin attenuates PI3K–Akt–mTOR pathway and reduces cancer stemness (ref)
10 Cell cycle control (p21; G2/M arrest) ↑ p21 / ↑ G2/M arrest Proliferation block Gastric cancer (AGS): shikonin induces cell-cycle arrest linked to p21 regulation (ref)
11 Invasion / metastasis programs (NF-κB-linked) ↓ invasion Anti-invasive phenotype Reports shikonin inhibits tumor invasion via down-regulation of NF-κB–related mechanisms in a high-metastatic tumor model (ref)
12 Chemosensitization via glycolysis suppression ↓ glycolysis / ↑ cisplatin sensitivity Combination benefit NSCLC: shikonin inhibits glycolysis and sensitizes cells to cisplatin (explicitly connecting metabolic suppression to chemosensitization) (ref)


neuroP, neuroprotective: Click to Expand ⟱
Source:
Type:
Neuroprotective refers to the ability of a substance, intervention, or strategy to preserve the structure and function of nerve cells (neurons) against injury or degeneration.
-While cancer and neurodegenerative processes might seem distinct, there is significant overlap in terms of treatment-related neurotoxicity, shared molecular mechanisms, and the potential for therapies that provide neuroprotection during cancer treatment.


Scientific Papers found: Click to Expand⟱
3050- SK,    Systemic administration of Shikonin ameliorates cognitive impairment and neuron damage in NPSLE mice
- in-vivo, Nor, NA
*Inflam↓, Shikonin relieved the progression of NPSLE by suppressing neuroinflammation.
*neuroP↑, Shikonin repaired the loss of neuronal synapses in NPSLE mice.
*cognitive↑, Shikonin ameliorates cognitive impairment

3049- SK,    Shikonin Attenuates Chronic Cerebral Hypoperfusion-Induced Cognitive Impairment by Inhibiting Apoptosis via PTEN/Akt/CREB/BDNF Signaling
- in-vivo, Nor, NA - NA, Stroke, NA
*neuroP↑, Shikonin (SK) exerts neuroprotective effects
*p‑PTEN↓, SK administration reversed the upregulation of p-PTEN and the downregulation of p-Akt, p-CREB, and BDNF
*p‑Akt↑,
*Bcl-2↑, SK treatment upregulated the expression of bcl-2 and downregulated the expression of bax, thereby elevating the bcl-2/bax ratio.
*BAX↓,
*cognitive↑, , consequently improving cognitive impairment.
*BDNF↑, Western blot analysis showed higher p-PTEN and lower p-Akt, p-CREB, and BDNF expression in the vehicle group than in the sham group.

3040- SK,    Pharmacological Properties of Shikonin – A Review of Literature since 2002
- Review, Var, NA - Review, IBD, NA - Review, Stroke, NA
*Half-Life↝, One study using H-shikonin in mice showed that shikonin was rapidly absorbed after oral and intramuscular administration, with a half-life in plasma of 8.79 h and a distribution volume of 8.91 L/kg.
*BioAv↓, shikonin is generally used in creams and ointments, that is, oil-based preparations; indeed, its insolubility in water is usually the cause of its low bioavailability
*BioAv↑, 200-fold increase in the solubility, photostability, and in vitro permeability of shikonin through the formation of a 1 : 1 inclusion complex with hydroxypropyl-β-cyclodextrin.
*BioAv↑, 181-fold increase in the solubility of shikonin in aqueous media in the presence of β-lactoglobulin at a concentra- tion of 3.1 mg/mL
*Inflam↓, anti-inflammatory effect of shikonin
*TNF-α↓, shikonin inhibited TNF-α production in LPS-stimulated rat primary macrophages as well as NF-κB translocation from the cytoplasm to the nucleus.
*other↑, authors found that treatment with shikonin prevented the shortening of the colorectum and decreased weight loss by 5 % while improving the ap- pearance of feces and preventing bloody stools.
*MPO↓, MPO activity was reduced as well as the expression of COX-2, the activation of NF-κB and that of STAT3.
*COX2↓,
*NF-kB↑,
*STAT3↑,
*antiOx↑, Antioxidant Effects of Shikonin
*ROS↓, radical scavenging activity of shikonin
*neuroP↑, shown to exhibit a neuroprotective effect against the damage caused by ischemia/reperfusion in adult male Kunming mice
*SOD↑, it also attenuated neuronal damage and the upregulation of superoxide dismutase, catalase, and glutathione peroxidase activities while reducing the glutathione/glutathione disulfide ratio.
*Catalase↑,
*GPx↑,
*Bcl-2↑, shikonin upregulated Bcl-2, downregulated Bax and prevented cell nuclei from undergoing morphological changes typical of apoptosis.
*BAX↓,
cardioP↑, Two different studies have suggested a possible cardioprotective effect of shikonin that would be related to its anti-inflammatory and antioxidant effects.
AntiCan↑, A wide spectrum of anticancer mechanisms of action have been described for shikonin:
NF-kB↓, suppression of NF-κB-regulated gene products [44],
ROS↑, ROS generation [46],
PKM2↓, inhibition of tumor-specific pyruvate kinase-M2 [47,48]
TumCCA↑, cell cycle arrest [49]
Necroptosis↑, or induction of necroptosis [50],
Apoptosis↑, shikonin at 1 μM induced caspase-dependent apoptosis in U937 cells after 6 h with an increase in DNA fragmentation, intracellular ROS, low mitochondrial membrane potential
DNAdam↑,
MMP↓,
Cyt‑c↑, At 10 μM, shikonin induced a greater release of cytochrome c from the mitochondria and of lactate dehydrogenase,
LDH↝,

2214- SK,    Shikonin Attenuates Cochlear Spiral Ganglion Neuron Degeneration by Activating Nrf2-ARE Signaling Pathway
- in-vitro, Nor, NA
*NRF2↑, shikonin can increase the expression of Nrf2 and its downstream molecules HO-1 and NQO1, thereby enhancing the antioxidant capacity of SGNs and SGSs
*HO-1↑,
*NQO1↑,
*antiOx↑,
*neuroP↑, shikonin pretreatment has a defensive effect on auditory nerve damage.
*ROS↓, shikonin pretreatment can also significantly reduce the high levels of reactive oxygen species (ROS) and malondialdehyde (MDA) in SGNs caused by ouabain, and increase the levels of superoxide dismutase (SOD) and reduced glutathione (GSH) expression
*MDA↓,
*SOD↑,
GSH↑,

2213- SK,    Shikonin attenuates cerebral ischemia/reperfusion injury via inhibiting NOD2/RIP2/NF-κB-mediated microglia polarization and neuroinflammation
- in-vivo, Stroke, NA
*neuroP↑, Shikonin treatment significantly reduced brain infarction volume and improved neurological function in MCAO/R rats.
*Inflam↓, Shikonin treatment significantly reduced microglial proinflammatory phenotype and levels of proinflammatory markers (inducible-NO synthase (iNOS), tumor necrosis factor-alpha (TNF-α),
*iNOS↓,
*TNF-α↓,
*IL1β↓, interleukin-1 beta (IL-1β), and IL-6), increased microglial anti-inflammatory phenotype and levels of anti-inflammatory markers (Arginase-1 (Arg1), transforming growth factor-beta (TGF-β), and IL-10),
*IL6↓,
*ARG↑,
*TGF-β↑,
*IL10↑,
*NF-kB↓, reversed the expression of Nucleotide-binding oligomerization domain 2 (NOD2) and phosphorylation receptor interacting protein 2 (p-RIP2), and suppressed nuclear factor kappa-B (NF-κB) signaling activation in the ischemic penumbra regions.
*eff↓, Furthermore, overexpression of NOD2 markedly attenuated the neuroprotective effects of Shikonin treatment in MCAO/R rats.


* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 5

Pathway results for Effect on Cancer / Diseased Cells:


Redox & Oxidative Stress

GSH↑, 1,   ROS↑, 1,  

Mitochondria & Bioenergetics

MMP↓, 1,  

Core Metabolism/Glycolysis

LDH↝, 1,   PKM2↓, 1,  

Cell Death

Apoptosis↑, 1,   Cyt‑c↑, 1,   Necroptosis↑, 1,  

DNA Damage & Repair

DNAdam↑, 1,  

Cell Cycle & Senescence

TumCCA↑, 1,  

Immune & Inflammatory Signaling

NF-kB↓, 1,  

Clinical Biomarkers

LDH↝, 1,  

Functional Outcomes

AntiCan↑, 1,   cardioP↑, 1,  
Total Targets: 14

Pathway results for Effect on Normal Cells:


Redox & Oxidative Stress

antiOx↑, 2,   Catalase↑, 1,   GPx↑, 1,   HO-1↑, 1,   MDA↓, 1,   MPO↓, 1,   NQO1↑, 1,   NRF2↑, 1,   ROS↓, 2,   SOD↑, 2,  

Cell Death

p‑Akt↑, 1,   BAX↓, 2,   Bcl-2↑, 2,   iNOS↓, 1,  

Transcription & Epigenetics

other↑, 1,  

Proliferation, Differentiation & Cell State

p‑PTEN↓, 1,   STAT3↑, 1,  

Migration

ARG↑, 1,   TGF-β↑, 1,  

Immune & Inflammatory Signaling

COX2↓, 1,   IL10↑, 1,   IL1β↓, 1,   IL6↓, 1,   Inflam↓, 3,   NF-kB↓, 1,   NF-kB↑, 1,   TNF-α↓, 2,  

Synaptic & Neurotransmission

BDNF↑, 1,  

Drug Metabolism & Resistance

BioAv↓, 1,   BioAv↑, 2,   eff↓, 1,   Half-Life↝, 1,  

Clinical Biomarkers

IL6↓, 1,  

Functional Outcomes

cognitive↑, 2,   neuroP↑, 5,  
Total Targets: 35

Scientific Paper Hit Count for: neuroP, neuroprotective
5 Shikonin
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#:150  Target#:1105  State#:%  Dir#:%
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