condition found tbRes List
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↓">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


NF-kB, Nuclear factor kappa B: Click to Expand ⟱
Source: HalifaxProj(inhibit)
Type:
NF-kB signaling
Nuclear factor kappa B (NF-κB) is a transcription factor that plays a crucial role in regulating immune response, inflammation, cell proliferation, and survival.
NF-κB is often found to be constitutively active in many types of cancer cells. This persistent activation can promote tumorigenesis by enhancing cell survival, proliferation, and metastasis.
Scientific Papers found: Click to Expand⟱
2226- SK,    Shikonin, a Chinese plant-derived naphthoquinone, induces apoptosis in hepatocellular carcinoma cells through reactive oxygen species: A potential new treatment for hepatocellular carcinoma
- in-vitro, HCC, HUH7 - in-vitro, HCC, Bel-7402
selectivity↑, shikonin induced apoptosis of Huh7 and BEL7402 but not nontumorigenic cells.
ROS↑, ROS generation was detected
eff↓, ROS scavengers completely inhibited shikonin-induced apoptosis, indicating that ROS play an essential role
Akt↓, downregulation of Akt and RIP1/NF-κB activity was found to be involved in shikonin-induced apoptosis
RIP1↓,
NF-kB↓,

2221- SK,    Shikonin Induces Apoptosis, Necrosis, and Premature Senescence of Human A549 Lung Cancer Cells through Upregulation of p53 Expression
- in-vitro, Lung, A549
Apoptosis↑, shikonin significantly induced cell apoptosis and reduced proliferation in a dose-dependent manner.
TumCP↓,
tumCV↓, shikonin (1–2.5 μg/mL) cause viability reduction
Necroptosis↑, while higher concentrations (5–10 μg/mL) precipitate both apoptosis and necrosis.
P53↑, via p53-mediated cell fate pathways
ROS↑, Its cytotoxic actions are largely through enhancing ROS generation to trigger caspase-dependent apoptosis and to downregulate nuclear factor-kappa B- (NF-kB-) mediated matrix metalloproteinase (MMP) expressions to reduce tumor survival and invasion
NF-kB↓,

3042- SK,    The protective effects of Shikonin on lipopolysaccharide/D -galactosamine-induced acute liver injury via inhibiting MAPK and NF-kB and activating Nrf2/HO-1 signaling pathways
- in-vivo, Nor, NA
*TNF-α↓, Our results showed that SHK treatment distinctly decreased serum TNF-a, IL-1b, IL-6 and IFN-g inflammatory cytokine production
*IL1β↓,
*IL6↓,
*IFN-γ↓,
*ALAT↓, , reduced serum ALT, AST, hepatic MPO and ROS production levels,
*AST↓,
*MPO↓,
*ROS↓,
*JNK↓, inhibited JNK1/2, ERK1/2, p38 and NF-kB (p65) phosphorylation, and suppressed IkBa phosphorylation and degradation.
*ERK↓,
*p38↓,
*NF-kB↓,
*p‑IKKα↓,
*SOD↑, SHK could dramatically increase SOD and GSH production, as well as reduce ROS production,
*GSH↑,
*HO-1↑, through up-regulating the protein expression of HO-1, Nqo1, Gclc and Gclm, which was related to the induction of Nrf2 nuclear translocation.
*NRF2↑,
*hepatoP↑,

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↝,

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.

2212- SK,    Shikonin Exerts an Antileukemia Effect against FLT3-ITD Mutated Acute Myeloid Leukemia Cells via Targeting FLT3 and Its Downstream Pathways
- in-vitro, AML, NA
FLT3↓, SHK suppresses the expression and phosphorylation of FLT3 receptors and their downstream molecules
NF-kB↓, Inhibition of the NF-κB/miR-155 pathway is an important mechanism through which SHK kills FLT3-AML cells
miR-155↓,
Diff↑, Moreover, a low concentration of SHK promotes the differentiation of AML cells with FLT3-ITD mutations.
TumCG↓, Finally, SHK could significantly inhibit the growth of MV4-11 cells in leukemia bearing mice.

2211- SK,    Shikonin mitigates ovariectomy-induced bone loss and RANKL-induced osteoclastogenesis via TRAF6-mediated signaling pathways
- in-vivo, ostP, NA
*BMD↑, Shikonin prevented bone loss by inhibiting osteoclastogenesis in vitro and improving bone loss in ovariectomized mice in vivo.
*p‑NF-kB↓, shikonin inhibited the phosphorylation of inhibitor of NF-κB (IκB), P50, P65, extracellular regulated protein kinases (ERK), c-Jun N-terminal kinase (JNK), and P38.
*p‑p50↓, by inhibiting phosphorylation of P65, P50, and IkB protein.
*p‑p65↓,
*p‑ERK↓, shikonin blocked the MAPK pathway via preventing phosphorylation of ERK, JNK, and P38
*p‑cJun↓,
*p‑p38↓,

2210- SK,    Shikonin inhibits the cell viability, adhesion, invasion and migration of the human gastric cancer cell line MGC-803 via the Toll-like receptor 2/nuclear factor-kappa B pathway
- in-vitro, BC, MGC803
TumCA↓, Shikonin (1 μm) inhibited significantly the adhesion, invasion and migratory ability of MGC-803 cells.
TumCI↓,
TumCMig↓,
MMP2↓, matrix metalloproteinases (MMP)-2, MMP-7, TLR2 and p65 NF-κB
MMP7↓,
TLR2↓,
p65↓,
NF-kB↓,
eff↑, In addition, the co-incubation of Shikonin and anti-TLR2/MG-132 has a significant stronger activity than anti-TLR2 or MG-132 alone.
ROS↑, Shikonin-induced ROS generation

2209- SK,    Shikonin inhibits tumor invasion via down-regulation of NF-κB-mediated MMP-9 expression in human ACC-M cells
- in-vitro, adrenal, ACC-M
MMP9↓, MMP-9 were significantly suppressed by increasing Shikonin concentrations.
NF-kB↓, down-regulation of MMP-9 appeared to be via the inactivation of NF-κB as the treatment with Shikonin suppressed the protein level of phosphate-IkBa
IKKα↓,

2200- SK,    Shikonin inhibits the growth of anaplastic thyroid carcinoma cells by promoting ferroptosis and inhibiting glycolysis
- in-vitro, Thyroid, CAL-62 - in-vitro, Thyroid, 8505C
NF-kB↓, SKN inhibits the expression of NF-κB,GPX4,TXNRD1,PKM2,GLUT1.
GPx4↓,
TrxR1↓, TXNRD1
PKM2↓,
GLUT1↓,
Glycolysis↓, inhibiting glycolysis in ATC cells.
Ferroptosis↑, SKN in inducing intracellular ferroptosis
GlucoseCon↓, Measurements of glucose uptake after 1, 3, and 5 μM concentrations of SKN treatment for 24 h showed a decrease in both cells
lactateProd↓, Lactate production in the cells decreased with the rise of SKN treatment concentration
ROS↑, cellular ROS increased significantly with the rise in SKN concentration

2197- SK,    Shikonin derivatives for cancer prevention and therapy
- Review, Var, NA
ROS↑, This compound accumulates in the mitochondria, which leads to the generation of reactive oxygen species (ROS), and deregulates intracellular Ca2+ levels.
Ca+2↑,
BAX↑, shikonin alone by increasing the expression of the pro-apoptotic Bax protein and decreasing the expression of the anti-apoptotic Bcl2 protein
Bcl-2↓,
MMP9↓, This treatment also inhibited metastasis by decreasing the expression of MMP-9 and NF-kB p65 without affecting MMP-2 expression.
NF-kB↓,
PKM2↓, Figure 4
Hif1a↓,
NRF2↓,
P53↑,
DNMT1↓,
MDR1↓,
COX2↓,
VEGF↓,
EMT↓,
MMP7↓,
MMP13↓,
uPA↓,
RIP1↑,
RIP3↑,
Casp3↑,
Casp7↑,
Casp9↑,
P21↓,
DFF45↓,
TRAIL↑,
PTEN↑,
mTOR↓,
AR↓,
FAK↓,
Src↓,
Myc↓,
RadioS↑, shikonin acted as a radiosensitizer because of the high ROS production it induced.

2193- SK,    Shikonin Suppresses Lymphangiogenesis via NF-κB/HIF-1α Axis Inhibition
- in-vitro, Nor, HMVEC-dLy
*NF-kB↓, shikonin decreased nuclear factor-kappaB (NF-κB) activation
*Hif1a↓, reduced both mRNA and protein levels of hypoxia-inducible factor-1 (HIF-1)α.
other↓, shikonin inhibits lymphangiogenesis in vitro by interfering the NF-κB/HIF-1α pathway and involves in suppression of VEGF-C and VEGFR-3 mRNA expression.

2188- SK,    Molecular mechanism of shikonin inhibiting tumor growth and potential application in cancer treatment
- Review, Var, NA
ROS↑, their induction of reactive oxygen species production, inhibition of EGFR and PI3K/AKT signaling pathway activation, inhibition of angiogenesis and induction of apoptosis and necroptosis
EGFR↓,
PI3K↓,
Akt↓,
angioG↓,
Apoptosis↑,
Necroptosis↑,
GSH↓, leading to the increased consumption of reduced glutathione (GSH) and increased Ca2+ concentration in the cells and destroying the mitochondrial membrane potential.
Ca+2↓,
MMP↓,
ERK↓, 24 h of treatment with shikonin, ERK 1/2 and AKT activities were significantly inhibited, and p38 activity was upregulated, which ultimately led to pro-caspase-3 cleavage and triggered the apoptosis of GC cells.
p38↑,
proCasp3↑,
eff↓, pretreated with the ROS scavengers NAC and GSH before treatment with shikonin, the production of ROS was significantly inhibited, the cytotoxicity of shikonin was attenuated
VEGF↓, shikonin can inhibit the expression of VEGF
FOXO3↑, Activated FOXO3a/EGR1/SIRT1 signaling
EGR1↑,
SIRT1↑,
RIP1↑, Upregulation of RIP1 and RIP3
RIP3↑,
BioAv↓, limitations caused by its poor water solubility, it has a short half-life and nonselective biological distribution
NF-kB↓, Shikonin can also prevent the activation of NF-κB by AKT and then downregulate the expression of Bcl-xl,
Half-Life↓, due to the limitations caused by its poor water solubility, it has a short half-life and nonselective biological distribution.


* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 13

Results for Effect on Cancer/Diseased Cells:
Akt↓,2,   angioG↓,1,   AntiCan↑,1,   Apoptosis↑,3,   AR↓,1,   BAX↑,1,   Bcl-2↓,1,   BioAv↓,1,   Ca+2↓,1,   Ca+2↑,1,   cardioP↑,1,   Casp3↑,1,   proCasp3↑,1,   Casp7↑,1,   Casp9↑,1,   COX2↓,1,   Cyt‑c↑,1,   DFF45↓,1,   Diff↑,1,   DNAdam↑,1,   DNMT1↓,1,   eff↓,2,   eff↑,1,   EGFR↓,1,   EGR1↑,1,   EMT↓,1,   ERK↓,1,   FAK↓,1,   Ferroptosis↑,1,   FLT3↓,1,   FOXO3↑,1,   GlucoseCon↓,1,   GLUT1↓,1,   Glycolysis↓,1,   GPx4↓,1,   GSH↓,1,   Half-Life↓,1,   Hif1a↓,1,   IKKα↓,1,   lactateProd↓,1,   LDH↝,1,   MDR1↓,1,   miR-155↓,1,   MMP↓,2,   MMP13↓,1,   MMP2↓,1,   MMP7↓,2,   MMP9↓,2,   mTOR↓,1,   Myc↓,1,   Necroptosis↑,3,   NF-kB↓,9,   NRF2↓,1,   other↓,1,   P21↓,1,   p38↑,1,   P53↑,2,   p65↓,1,   PI3K↓,1,   PKM2↓,3,   PTEN↑,1,   RadioS↑,1,   RIP1↓,1,   RIP1↑,2,   RIP3↑,2,   ROS↑,7,   selectivity↑,1,   SIRT1↑,1,   Src↓,1,   TLR2↓,1,   TRAIL↑,1,   TrxR1↓,1,   TumCA↓,1,   TumCCA↑,1,   TumCG↓,1,   TumCI↓,1,   TumCMig↓,1,   TumCP↓,1,   tumCV↓,1,   uPA↓,1,   VEGF↓,2,  
Total Targets: 81

Results for Effect on Normal Cells:
ALAT↓,1,   antiOx↑,1,   ARG↑,1,   AST↓,1,   BAX↓,1,   Bcl-2↑,1,   BioAv↓,1,   BioAv↑,2,   BMD↑,1,   Catalase↑,1,   p‑cJun↓,1,   COX2↓,1,   eff↓,1,   ERK↓,1,   p‑ERK↓,1,   GPx↑,1,   GSH↑,1,   Half-Life↝,1,   hepatoP↑,1,   Hif1a↓,1,   HO-1↑,1,   IFN-γ↓,1,   p‑IKKα↓,1,   IL10↑,1,   IL1β↓,2,   IL6↓,2,   Inflam↓,2,   iNOS↓,1,   JNK↓,1,   MPO↓,2,   neuroP↑,2,   NF-kB↓,3,   NF-kB↑,1,   p‑NF-kB↓,1,   NRF2↑,1,   other↑,1,   p38↓,1,   p‑p38↓,1,   p‑p50↓,1,   p‑p65↓,1,   ROS↓,2,   SOD↑,2,   STAT3↑,1,   TGF-β↑,1,   TNF-α↓,3,  
Total Targets: 45

Scientific Paper Hit Count for: NF-kB, Nuclear factor kappa B
13 Shikonin
Filter Conditions: Pro/AntiFlg:%  IllCat:%  CanType:%  Cells:%  prod#:150  Target#:214  State#:%  Dir#:%
  wNotes=on  sortOrder:rid,rpid

 

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