condition found tbRes List
HNK, Honokiol: Click to Expand ⟱
Features:
Honokiol is a Lignan isolated from bark, seed cones and leaves of trees of Magnolia species. Honokiol was traditionally used for anxiety and stroke treatment, as well as the alleviation of flu symptoms.
-considered to have antioxidant properties
-low oral bioavailability and difficulty in intravenous administration
-the development of various formulations of honokiol, including microemulsion, liposomes, nanoparticles and micelle copolymers have successfully solved the problem of low water solubility.

Pathways:
-Inhibit NF-κB activation
-Downregulate STAT3 signalin
-Inhibiting the PI3K/Akt pathway,
-Inhibition of mTOR
-Influences various MAPK cascades—including ERK, JNK, and p38
-Inhibition of EGFR
-Inhibiting Notch pathway (CSCs)
-GPx4 inhibit
-Can induce ER stress in cancer cells, which contributes to the activation of unfolded protein response (UPR) pathways
-Disrupt the mitochondrial membrane potential in cancer cells.
-Reported to increase ROS production in cancer cells
-Can exhibit antioxidant properties in normal cells. - has some inhibitor activity but Not classified as HDAC inhibitor as weaker and may work more indirectly.
- is well-known in the research community for its role in activating SIRT3

-Note half-life 40–60 minutes
BioAv
Pathways:
- induce ROS production in cancer cells, and typically lowers ROS in normal cells
- ROS↑ related: MMP↓(ΔΨm), ER Stress↑, GRP78↑, Ca+2↑, Cyt‑c↑, Caspases↑, DNA damage↑, cl-PARP↑, HSP↓ Prx
- Raises AntiOxidant defense in Normal Cells: ROS↓, NRF2↑, SOD↑, GSH↑, Catalase↑,
- lowers Inflammation : NF-kB↓, COX2↓, Pro-Inflammatory Cytokines : IL-1β↓, TNF-α↓, IL-6↓,
- inhibit Growth/Metastases : TumMeta↓, TumCG↓, EMT↓, MMPs↓, MMP2↓, MMP9↓, VEGF↓, ROCK1↓, RhoA↓, NF-κB↓, CXCR4↓, ERK↓
- reactivate genes thereby inhibiting cancer cell growth : HDAC↓, EZH2↓, P53↑, HSP↓,
- cause Cell cycle arrest : TumCCA↑, cyclin D1↓, cyclin E↓, CDK2↓, CDK4↓, CDK6↓,
- inhibits Migration/Invasion : TumCMig↓, TumCI↓, ERK↓, EMT↓,
- inhibits glycolysis and ATP depletion : HIF-1α↓, cMyc↓, GLUT1↓, LDH↓, LDHA↓, HK2↓, PDKs↓, ECAR↓, OXPHOS↓, GRP78↑, GlucoseCon↓
- inhibits angiogenesis↓ : VEGF↓, HIF-1α↓, Notch↓, EGFR↓,
- inhibits Cancer Stem Cells : CSC↓, CD133↓, β-catenin↓, sox2↓, nestin↓, OCT4↓,
- Others: PI3K↓, AKT↓, JAK↓, STAT↓, Wnt↓, β-catenin↓, AMPK, ERK↓, JNK, TrxR**, - Shown to modulate the nuclear translocation of SREBP-2 (related to cholesterol).
- Synergies: chemo-sensitization, chemoProtective, RadioSensitizer, RadioProtective, Others(review target notes), Neuroprotective, Cognitive, Renoprotection, Hepatoprotective, CardioProtective,

- Selectivity: Cancer Cells vs Normal Cells


ERK, ERK signaling: Click to Expand ⟱
Source:
Type:
MAPK3 (ERK1)
ERK proteins are kinases that activate other proteins by adding a phosphate group. An overactivation of these proteins causes the cell cycle to stop.
The extracellular signal-regulated kinase (ERK) signaling pathway is a crucial component of the mitogen-activated protein kinase (MAPK) signaling cascade, which plays a significant role in regulating various cellular processes, including proliferation, differentiation, and survival. high levels of phosphorylated ERK (p-ERK) in tumor samples may indicate active ERK signaling and could correlate with aggressive tumor behavior

EEk singaling is frequently activated and is often associated with aggressive tumor behavior, treatment resistance, and poor outcomes.
Scientific Papers found: Click to Expand⟱
2885- HNK,    Honokiol: a novel natural agent for cancer prevention and therapy
NF-kB↓, Honokiol targets multiple signaling pathways including nuclear factor kappa B (NF-κB), signal transducers and activator of transcription 3 (STAT3), epidermal growth factor receptor (EGFR) and mammalian target of rapamycin (m-TOR)
STAT3↓,
EGFR↓,
mTOR↓,
BioAv↝, honokiol has revealed a desirable spectrum of bioavailability after intravenous administration in animal models, thus making it a suitable agent for clinical trials
Inflam↓, inflammation, proliferation, angiogenesis, invasion and metastasis.
TumCP↓,
angioG↓,
TumCI↓,
TumMeta↓,
cSrc↓, STAT3 inhibition by honokiol has also been correlated with the repression of upstream protein tyrosine kinases c-Src, JAK1 and JAK2
JAK1↓,
JAK2↓,
ERK↓, by inhibiting ERK and Akt pathways (31) or by upregulation of PTEN
Akt↓,
PTEN↑,
ChemoSen↑, Chemopreventive/ chemotherapeutic effects of honokiol in various malignancies: preclinical studies
chemoP↑,
COX2↓, honokiol was found to inhibit UVB-induced expression of cyclooxygenase-2, prostaglandin E2, proliferating cell nuclear antigen and pro-inflammatory cytokines, such as TNF-α, interleukin (IL)-1β and IL-6 in the skin
PGE2↓,
TNF-α↓,
IL1β↓,
IL6↓,
Casp3↑, release of caspases-3, -8 and -9as well as poly (ADP-ribose) polymerase (PARP) cleavage and p53 activation upon honokiol treatment that led to DNA fragmentation
Casp8↑,
Casp9↑,
cl‑PARP↑,
DNAdam↑,
Cyt‑c↑, translocation of cytochrome c to cytosol in human melanoma cell lines
RadioS↑, liposomal honokiol for 24 h showed a higher radiation enhancement ratio (~ two-fold) as compared to the radiation alone,
RAS↓, Honokiol also caused suppression of Ras activation
BBB↑, honokiol could effectively cross BBB and BCSFB and inhibit brain tumor growth
BioAv↓, Due to the concerns about poor aqueous solubility, liposomal formulations of honokiol have been developed and tested for their pharmacokinetics
Half-Life↝, In another comparative study, plasma honokiol concentrations was maintained above 30 and 10 μg/mL for 24 and 48 hours, respectively, in liposomal honokiol-treated mice, whereas it fell quickly (less than 5 μg/mL) by 12 hours in free honokiol-treated
Half-Life↝, free honokiol has poor GIT absorption, bio-transformed in liver to mono-glucuronide honokiol and sulphated mono-hydroxyhonokiol, ~ 50% is secreted in bile, ~ 60-65% plasma protein bound with elimination half life of (t1/2) of 49.05 – 56.24 minutes.
toxicity↓, These studies suggest that honokiol either alone or as a part of magnolia bark extract does not induce toxicity in animal models and thus could be clinically safe

2894- HNK,    Pharmacological features, health benefits and clinical implications of honokiol
- Review, Var, NA - Review, AD, NA
*BioAv↓, HNK showed poor aqueous solubility due to phenolic hydroxyl groups forming intramolecular hydrogen bonds and poor solubility in water (
*neuroP↑, HNK has the accessibility to reach the neuronal tissue by crossing the BBB and showing neuroprotective effects
*BBB↑,
*ROS↓, fig 2
*Keap1↑,
*NRF2↑,
*Casp3↓,
*SIRT3↑,
*Rho↓,
*ERK↓,
*NF-kB↓,
angioG↓,
RAS↓,
PI3K↓,
Akt↓,
mTOR↓,
*memory↑, oral administration of HNK (1 mg/kg) in senescence-accelerated mice prevents age-related memory and learning deficits
*Aβ↓, in Alzheimer’s disease, HNK significantly reduces neurotoxicity of aggregated Ab
*PPARγ↑, Furthermore, the expression of PPARc and PGC1a was increased by HNK, suggesting its beneficial impact on energy metabolism
*PGC-1α↑,
NF-kB↓, activation of NFjB was suppressed by HNK via suppression of nuclear translocation and phosphorylation of the p65 subunit and further instigated apoptosis by enhancing TNF-a
Hif1a↓, HNK has anti-oxidative properties and can downregulate the HIF-1a protein, inhibiting hypoxia- related signaling pathways
VEGF↓, renal cancer, via decreasing the vascular endothelial growth factor (VEGF) and heme-oxygenase-1 (HO-1)
HO-1↓,
Foxm1↓, HNK interaction with the FOXM1 oncogenic transcription factor inhibits cancer cells
p27↑, HNK treatment upregulates the expression of CDK inhibitor p27 and p21, whereas it downregulates the expression of CDK2/4/6 and cyclin D1/2
P21↑,
CDK2↓,
CDK4↓,
CDK6↓,
cycD1↓,
Twist↓, HNK averted the invasion of urinary bladder cancer cells by downregulating the steroid receptor coactivator, Twist1 and Matrix metalloproteinase-2
MMP2↓,
Rho↑, By activating the RhoA, ROCK and MLC signaling, HNK inhibits the migration of highly metastatic renal cell carcinoma
ROCK1↑,
TumCMig↓,
cFLIP↓, HNK can be used to suppress c-FLIP, the apoptosis inhibitor.
BMPs↑, HNK treatment increases the expression of BMP7 protein
OCR↑, HNK might increase the oxygen consumption rate while decreasing the extracellular acidification rate in breast cancer cells.
ECAR↓,
*AntiAg↑, It also suppresses the platelet aggregation
*cardioP↑, HNK is an attractive cardioprotective agent because of its strong antioxidative properties
*antiOx↑,
*ROS↓, HNK treatment reduced cellular ROS production and decreased mitochondrial damage in neonatal rat cardiomyocytes exposed to hypoxia/reoxygenation
P-gp↓, The expres- sion of P-gp at mRNA and protein levels is reduced in HNK treatment on human MDR and MCF-7/ADR breast cancer cell lines

1153- HNK,    Honokiol Eliminates Glioma/Glioblastoma Stem Cell-Like Cells via JAK-STAT3 Signaling and Inhibits Tumor Progression by Targeting Epidermal Growth Factor Receptor
- in-vitro, GBM, U251 - in-vitro, GBM, U87MG - in-vivo, NA, NA
tumCV↓,
Apoptosis↑,
TumCMig↓,
TumCI↓,
Bcl-2↓,
EGFR↓,
CD133↓,
Nestin↓,
Akt↓,
ERK↓,
Casp3↑,
p‑STAT3↓,
TumCG↓, in vivo

2073- HNK,    Honokiol induces apoptosis and autophagy via the ROS/ERK1/2 signaling pathway in human osteosarcoma cells in vitro and in vivo
- in-vitro, OS, U2OS - in-vivo, NA, NA
TumCD↑, honokiol caused dose-dependent and time-dependent cell death in human osteosarcoma cells
TumAuto↑, death induced by honokiol were primarily autophagy and apoptosis.
Apoptosis↑,
TumCCA↑, honokiol induced G0/G1 phase arrest,
GRP78/BiP↑, elevated the levels of glucose-regulated protein (GRP)−78, an endoplasmic reticular stress (ERS)-associated protein
ROS↑, increased the production of intracellular reactive oxygen species (ROS)
eff↓, In contrast, reducing production of intracellular ROS using N-acetylcysteine, a scavenger of ROS, concurrently suppressed honokiol-induced cellular apoptosis, autophagy, and cell cycle arrest.
p‑ERK↑, honokiol stimulated phosphorylation of extracellular signal-regulated kinase (ERK)1/2.
selectivity↑, human fibroblasts showed strong resistance to HNK, the IC50 values for which were 118.9 and 71.5 μM
Ca+2↑, HNK increased intracellular Ca2+ in both HOS and U2OS cells
MMP↓, mitochondrial membrane potential (MMP) sharply decreased following HNK treatment
Casp3↑, HNK markedly activated caspase-3, caspase-9
Casp9↑,
cl‑PARP↑, led to PARP cleavage
Bcl-2↓, expression of Bcl-2, Bcl-xl, and survivin was found to be decreased
Bcl-xL↓,
survivin↓,
LC3B-II↑, HNK increased the level of LC3B-II and Atg5 in HOS and U2OS cells.
ATG5↑,
TumVol↓, HNK at doses of 40 mg/kg resulted in significant decrease in tumor volume and weight, after 7 days of drug administration
TumW↓,
ER Stress↑, ER stress can trigger ROS production through release of calcium

2868- HNK,    Honokiol: A review of its pharmacological potential and therapeutic insights
- Review, Var, NA - Review, Sepsis, NA
*P-gp↓, reduction in the expression of defective proteins like P-glycoproteins, inhibition of oxidative stress, suppression of pro-inflammatory cytokines (TNF-α, IL-10 and IL-6),
*ROS↓,
*TNF-α↓,
*IL10↓,
*IL6↓,
eIF2α↑, Bcl-2, phosphorylated eIF2α, CHOP,GRP78, Bax, cleaved caspase-9 and phosphorylated PERK
CHOP↑,
GRP78/BiP↑,
BAX↑,
cl‑Casp9↑,
p‑PERK↑,
ER Stress↑, endoplasmic reticulum stress and proteins in apoptosis in 95-D and A549 cells
Apoptosis↑,
MMPs↓, decrease in levels of matrix metal-mloproteinases, P-glycoprotein expression, the formation of mammosphere, H3K27 methyltransferase, c-FLIP, level of CXCR4 receptor,pluripotency-factors, Twist-1, class I histone deacetylases, steroid receptor co
cFLIP↓,
CXCR4↓,
Twist↓,
HDAC↓,
BMPs↑, enhancement in Bax protein, and (BMP7), as well as interference with an activator of transcription 3 (STAT3), (mTOR), (EGFR), (NF-kB) and Shh
p‑STAT3↓, secreased the phosphorylation of STAT3
mTOR↓,
EGFR↓,
NF-kB↓,
Shh↓,
VEGF↓, induce apoptosis, and regulate the vascular endothelial growth factor-A expression (VEGF-A)
tumCV↓, human glioma cell lines (U251 and U-87 MG) through inhibition of colony formation, glioma cell viability, cell migration, invasion, suppression of ERK and AKT signalling cascades, apoptosis induction, and reduction of Bcl-2 expression.
TumCMig↓,
TumCI↓,
ERK↓,
Akt↓,
Bcl-2↓,
Nestin↓, increased the Bax expression, lowered the CD133, EGFR, and Nesti
CD133↓,
p‑cMET↑, HKL through the downregulating the phosphorylation of c-Met phosphorylation and stimulation of Ras,
RAS↑,
chemoP↑, Cheng and coworker determined the chemopreventive role of HKL against the proliferation of renal cell carcinoma (RCC) 786‑0 cells through multiple mechanism
*NRF2↑, , HKL also effectively activate the Nrf2/ARE pathway and reverse this pancreatic dysfunction in in vivo and in vitro model
*NADPH↓, (HUVECs) such as inhibition of NADPH oxidase activity, suppression of p22 (phox) protein expression, Rac-1 phosphorylation, reactive oxygen species production, inhibition of degradation of Ikappa-B-alpha, and suppression of activity of of NF-kB
*p‑Rac1↓,
*ROS↓,
*IKKα↑,
*NF-kB↓,
*COX2↓, Furthermore, HKL treatment the inhibited cyclooxygenase (COX-2) upregulation, reduces prostaglandin E2 production, enhanced caspase-3 activity reduction
*PGE2↓,
*Casp3↓,
*hepatoP↑, compound also displayed hepatoprotective action against oxidative injury in tert-butyl hydroperoxide (t-BHP)-injured AML12 liver cells in in vitro model
*antiOx↑, compound reduces the level of acetylation on SOD2 to stimulate its antioxidative action, which results in reduced reactive oxygen species aggregation in AML12 cells
*GSH↑, HKL prevents oxidative damage induced by H2O2 via elevating antioxidant enzymes levels which includes glutathione and catalase and promotes translocation and activation transcription factor Nrf2
*Catalase↑,
*RenoP↑, imilarly, the compound protects renal reperfusion/i-schemia injury (IRI) in adult male albino Wistar rats via reducing theactivities of serum alkaline phosphatase (ALP), aspartate aminotrans- ferase (AST) and alanine aminotransferase (ALT)
*ALP↓,
*AST↓,
*ALAT↓,
*neuroP↑, Several reports and works have shown that HKL displays some neuroprotective properties
*cardioP↑, Cardioprotection
*HO-1↑, the expression level of heme oxygenase-1 (HO-1)was remarkably up-regulated and miR-218-5p was significantly down-regulated in septic mice treated with HKL
*Inflam↓, anti-inflammatory action of HKL at dose of 10 mg/kg in the muscle layer of mice

2869- HNK,    Nature's neuroprotector: Honokiol and its promise for Alzheimer's and Parkinson's
- Review, AD, NA - Review, Park, NA
*neuroP↑, neuroprotective, anti-oxidant, anti-apoptotic, neuromodulating, anti-inflammatory, and many more qualities, honokiol,
*Inflam↓,
*motorD↑, degradation of dopaminergic neurons in Parkinson's disease and improving motor function.
*Aβ↓, Alzheimer's disease, honokiol showed promise in lowering the production of amyloid-beta (Aβ) plaques, phosphorylating tau, and enhancing cognitive performance
*p‑tau↓,
*cognitive↑,
*memory↑, prevented Acetylcholinesterase activity from elevation as well as improved acetylcholine levels, and improved learning, and memory deficits via increased ERK1/2 and Akt phosphorylation
*ERK↑,
*p‑Akt↑,
*PPARγ↑, honokiol has been reported to elevate PPARγ levels in APPswe/PS1dE9 mice as PPARγ is related to ani-inflammatory
*PGC-1α↑, honokiol boosted the expression of PGC1α and PPARγ
*MMP↑, as well as reduced elevated mitochondrial membrane potential and mitochondrial ROS
*mt-ROS↓,
*SIRT3↑, Honokiol has been found as a dual SIRT-3 activator and PPAR-γ agonist that reduced oxidative stress markers within cells and changed the AMPK pathway
*IL1β↓, honokiol prevented restraint stress-induced cognitive dysfunction by reducing the hippocampus's production of IL-1β, TNF-α, glucose-regulated protein (GRP78), and C/EBP homologous protein (CHOP)
*TNF-α↓,
*GRP78/BiP↓,
*CHOP↓,
*NF-kB↓, Additionally, the neuroprotective benefits of honokiol in mice with Aβ-induced learning and memory impairment have been attributed to the inactivation of NF-κB
*GSK‐3β↓, Treatment of honokiol in PC12 cells resulted in reduced GSK-3β and induced β-catenin which effectively showed the neuroprotective and anti-oxidant effect in AD therapy
*β-catenin/ZEB1↑,
*Ca+2↓, , anti-apoptotic effect via reduced caspase 3 levels, and protected membrane injury by reduced calcium level has been investigated in PC12 cells of AD models
*AChE↓, protective effects by serving as an antioxidant, reduced AchE levels, repaired neurofibrillary tangles, reduced NF-kB which downregulates Aβ plaque
*SOD↑, fig1
*Catalase↑,
*GPx↑,


* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 6

Results for Effect on Cancer/Diseased Cells:
Akt↓,4,   angioG↓,2,   Apoptosis↑,3,   ATG5↑,1,   BAX↑,1,   BBB↑,1,   Bcl-2↓,3,   Bcl-xL↓,1,   BioAv↓,1,   BioAv↝,1,   BMPs↑,2,   Ca+2↑,1,   Casp3↑,3,   Casp8↑,1,   Casp9↑,2,   cl‑Casp9↑,1,   CD133↓,2,   CDK2↓,1,   CDK4↓,1,   CDK6↓,1,   cFLIP↓,2,   chemoP↑,2,   ChemoSen↑,1,   CHOP↑,1,   p‑cMET↑,1,   COX2↓,1,   cSrc↓,1,   CXCR4↓,1,   cycD1↓,1,   Cyt‑c↑,1,   DNAdam↑,1,   ECAR↓,1,   eff↓,1,   EGFR↓,3,   eIF2α↑,1,   ER Stress↑,2,   ERK↓,3,   p‑ERK↑,1,   Foxm1↓,1,   GRP78/BiP↑,2,   Half-Life↝,2,   HDAC↓,1,   Hif1a↓,1,   HO-1↓,1,   IL1β↓,1,   IL6↓,1,   Inflam↓,1,   JAK1↓,1,   JAK2↓,1,   LC3B-II↑,1,   MMP↓,1,   MMP2↓,1,   MMPs↓,1,   mTOR↓,3,   Nestin↓,2,   NF-kB↓,3,   OCR↑,1,   P-gp↓,1,   P21↑,1,   p27↑,1,   cl‑PARP↑,2,   p‑PERK↑,1,   PGE2↓,1,   PI3K↓,1,   PTEN↑,1,   RadioS↑,1,   RAS↓,2,   RAS↑,1,   Rho↑,1,   ROCK1↑,1,   ROS↑,1,   selectivity↑,1,   Shh↓,1,   STAT3↓,1,   p‑STAT3↓,2,   survivin↓,1,   TNF-α↓,1,   toxicity↓,1,   TumAuto↑,1,   TumCCA↑,1,   TumCD↑,1,   TumCG↓,1,   TumCI↓,3,   TumCMig↓,3,   TumCP↓,1,   tumCV↓,2,   TumMeta↓,1,   TumVol↓,1,   TumW↓,1,   Twist↓,2,   VEGF↓,2,  
Total Targets: 91

Results for Effect on Normal Cells:
AChE↓,1,   p‑Akt↑,1,   ALAT↓,1,   ALP↓,1,   AntiAg↑,1,   antiOx↑,2,   AST↓,1,   Aβ↓,2,   BBB↑,1,   BioAv↓,1,   Ca+2↓,1,   cardioP↑,2,   Casp3↓,2,   Catalase↑,2,   CHOP↓,1,   cognitive↑,1,   COX2↓,1,   ERK↓,1,   ERK↑,1,   GPx↑,1,   GRP78/BiP↓,1,   GSH↑,1,   GSK‐3β↓,1,   hepatoP↑,1,   HO-1↑,1,   IKKα↑,1,   IL10↓,1,   IL1β↓,1,   IL6↓,1,   Inflam↓,2,   Keap1↑,1,   memory↑,2,   MMP↑,1,   motorD↑,1,   NADPH↓,1,   neuroP↑,3,   NF-kB↓,3,   NRF2↑,2,   P-gp↓,1,   PGC-1α↑,2,   PGE2↓,1,   PPARγ↑,2,   p‑Rac1↓,1,   RenoP↑,1,   Rho↓,1,   ROS↓,4,   mt-ROS↓,1,   SIRT3↑,2,   SOD↑,1,   p‑tau↓,1,   TNF-α↓,2,   β-catenin/ZEB1↑,1,  
Total Targets: 52

Scientific Paper Hit Count for: ERK, ERK signaling
6 Honokiol
Filter Conditions: Pro/AntiFlg:%  IllCat:%  CanType:%  Cells:%  prod#:94  Target#:105  State#:%  Dir#:%
  wNotes=on  sortOrder:rid,rpid

 

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