condition found tbRes List
RosA, Rosmarinic acid: Click to Expand ⟱
Features: polyphenol
Polyphenol of many herbs - rosemary, perilla, sage mint and basil. Rosmarinic acid (RA) is predominantly found in a variety of medicinal and culinary herbs, especially those belonging to the Lamiaceae family, including rosemary (Rosmarinus officinalis), basil (Ocimum basilicum), sage (Salvia officinalis), thyme (Thymus vulgaris), and mints (Mentha spp.). In addition to the Lamiaceae family, RA is also present in plants from other families, such as Boraginaceae and Apiaceae.
-Rosmarinic acid is one of the hydroxycinnamic acids, and was initially isolated and purified from the extract of rosemary, a member of mint family (Lamiaceae)
-Its chemical structure allows it to act as a free radical scavenger by donating hydrogen atoms to stabilize ROS and free radicals.
RA’s dual nature as both a phenolic acid and a flavonoid-related compound enables it to chelate metal ions and prevent the formation of free radicals, thus interrupting oxidative chain reactions. It can modulate the activity of enzymes involved in OS, such as catalase (CAT), superoxide dismutase (SOD), and glutathione peroxidase (GPx), underscoring its potential role in preventing oxidative damage at the cellular level.
-divided as rosemary extract, carnosic acid, rosmarinic acid?

Summary:
-Capacity to chelate transition metal ions, particularly ironChelator (Fe2+) and copper (Cu2+)
-RA plus Cu(II)-induced oxidative DNA damage, which causes ROS
-rosmarinic acid (RA) as a potential inhibitor of MARK4↓ (inhibiting to tumor growth, invasion, and metastasis) activity (IC50 = 6.204 µM)

-Note half-life 1.5–2 hours.
BioAv water-soluble, rapid absorbtion
Pathways:
- varying results of ROS up or down in cancer cells. Plus a report of lowering ROS and no effect on Tumor cell viability.
However always seems to lower ROS↓ in normal cells.
- ROS↑ related: MMP↓(ΔΨm), ER Stress↑, UPR↑, Cyt‑c↑, Caspases↑, DNA damage↑, cl-PARP↑, HSP↓,
- No indication of Lowering AntiOxidant defense in Cancer Cells:
- Raises AntiOxidant defense in Normal Cells:(and perhaps even in cancer 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↓, VEGF↓, ROCK1↓, RhoA↓, NF-κB↓, ERK↓, MARK4↓
- reactivate genes thereby inhibiting cancer cell growth(weak) : HDAC2↓, DNMTs↓weak, P53↑, HSP↓,
- cause Cell cycle arrest : TumCCA↑, cyclin D1↓, cyclin E↓, CDK2↓, CDK4↓,
- inhibits Migration/Invasion : TumCMig↓, TumCI↓, ERK↓, EMT↓,
- inhibits glycolysis /Warburg Effect and ATP depletion : HIF-1α↓??, LDHA↓, PFKs↓, GRP78↑, GlucoseCon↓
- inhibits angiogenesis↓ : VEGF↓, HIF-1α↓, EGFR↓,
- inhibits Cancer Stem Cells (few references) : CSC↓, Hh↓, GLi1↓,
- Others: PI3K↓, AKT↓, STAT↓, AMPK, ERK↓, JNK,
- Synergies: chemo-sensitization, chemoProtective, RadioSensitizer, RadioProtective, Others(review target notes), Neuroprotective, Cognitive, Renoprotection, Hepatoprotective, CardioProtective,

- Selectivity: Cancer Cells vs Normal Cells


PI3K, Phosphatidylinositide-3-Kinases: Click to Expand ⟱
Source: HalifaxProj(inhibit) CGL-CS
Type:
Phosphatidylinositol 3-kinase (PtdIns3K or PI3K) is a family of enzymes that play a crucial role in cell signaling pathways, particularly in the regulation of cell growth, survival, and metabolism. The PI3K pathway is one of the most frequently altered pathways in human cancer. Inhibition of the PI3K pathway has been explored as a therapeutic strategy for cancer treatment. Several PI3K inhibitors have been developed and are currently being tested in clinical trials. These inhibitors can target specific components of the pathway, such as PI3K, AKT, or mTOR.

Class I phosphoinositide 3-kinase (PI3K)
Class III PtdIns3K
In contrast to the class III PtdIns3K as a positive regulator of autophagy, class I PI3K-AKT signaling has an opposing effect on the initiation of autophagy.

PI3K inhibitors include:
-Idelalisib , Copanlisib, Alpelisib
-LY294002?
-Wortmannin: potent PI3K inhibitor, has some associated toxicity.
-Quercetin:
-Curcumin
-Resveratrol
-Epigallocatechin Gallate (EGCG)
Scientific Papers found: Click to Expand⟱
3027- RosA,    Rosmarinic acid inhibits proliferation and invasion of hepatocellular carcinoma cells SMMC 7721 via PI3K/AKT/mTOR signal pathway
- in-vitro, HCC, SMMC-7721 cell
TumCP↓, RosA significantly inhibited the proliferation of SMMC-7721 cells and induced G1 arrest and apoptosis in a dose-dependent manner
TumCCA↑,
Apoptosis↑,
EMT↓, RosA might inhibit cell invasion by regulating epithelial-mesenchymal transition
TumCI↓,
PI3K↓, IGF-1 could reverse the inhibition of PI3K/AKT/mTOR signal pathway by RosA
Akt↓,
mTOR↓,
TumCMig↓, inhibition effect of migration and invasion by regulation MMPs, Vimentin and EMT.
MMPs↓,
Vim↓,

3016- RosA,    Rosmarinic Acid Inhibits Cell Growth and Migration in Head and Neck Squamous Cell Carcinoma Cell Lines by Attenuating Epidermal Growth Factor Receptor Signaling
- in-vitro, HNSCC, UM-SCC-6 - in-vitro, HNSCC, UM-SCC-10B
chemoP↓,
EGF↓, RA as an inhibitor of epidermal growth factor (EGF) st
tumCV↓, RA inhibited cell viability, migration and cellular production of ROS in HNSCC cell lines.
TumCMig↓,
ROS↓,
PI3K↓, down-regulation of the phosphatidylinositol 3-kinase Akt (PI3K/Akt) and mitogen-activated protein kinase ERK (MAPK/ERK) pathways.
Akt↓,
ERK↓,
antiOx↑, RA serves as a potent antioxidant in HNSCC
p‑EGFR↓, RA’s ability to attenuate EGFR phosphorylation

3003- RosA,    Comprehensive Insights into Biological Roles of Rosmarinic Acid: Implications in Diabetes, Cancer and Neurodegenerative Diseases
- Review, Var, NA - Review, AD, NA - Review, Park, NA
*Inflam↓, anti-inflammatory and antioxidant properties and its roles in various life-threatening conditions, such as cancer, neurodegeneration, diabetes,
*antiOx↑,
*neuroP↑,
*IL6↓, diabetic rat model treated with RA, there is an anti-inflammatory activity reported. This activity is achieved through the inhibition of the expression of various proinflammatory factors, including in IL-6, (IL-1β), tumour
*IL1β↓,
*NF-kB↓, inhibiting NF-κB activity and reducing the production of prostaglandin E2 (PGE2), nitric oxide (NO), and cyclooxygenase-2 (COX-2) in RAW 264.7 cells.
*PGE2↓,
*COX2↓,
*MMP↑, RA inhibits cytotoxicity in tumour patients by maintaining the mitochondrial membrane potential
*memory↑, amyloid β(25–35)-induced AD in rats was treated with RA, which mitigated the impairment of learning and memory disturbance by reducing oxidative stress
*ROS↓,
*Aβ↓, daily consumption of RA diminished the effect of neurotoxicity of Aβ25–35 in mice
*HMGB1↓, SH-SY5Y in vitro and ischaemic diabetic stroke in vivo, and the studies revealed that a 50 mg/kg dose of RA decreased HMGB1 expression
TumCG↓, Rosemary and its extracts have been shown to exhibit potential in inhibiting the growth of cancer cells and the development of tumours in various cancer types, including colon, breast, liver, and stomach cancer
MARK4↓, Another study reported the inhibition of Microtubule affinity regulating kinase 4 (MARK4) by RA
Zeb1↓, Fig 4 BC:
MDM2↓,
BNIP3↑,
ASC↑, Skin Cancer
NLRP3↓,
PI3K↓,
Akt↓,
Casp1↓,
E-cadherin↑, Colon Cancer
STAT3↓,
TLR4↓,
MMP↓,
ICAM-1↓,
AMPK↓,
IL6↑, PC and GC
MMP2↓,
Warburg↓,
Bcl-xL↓, CRC: Apoptosis induction caspases ↑, Bcl-XL ↓, BCL-2 ↓, Induces cell cycle arrest, Inhibition of EMT and invasion, Reduced metastasis
Bcl-2↓,
TumCCA↑,
EMT↓,
TumMeta↓,
mTOR↓, Inhibits mTOR/S6K1 pathway to induce apoptosis in cervical cancer
HSP27↓, Glioma ↓ expression of HSP27 ↑ caspase-3
Casp3↑,
GlucoseCon↓, GC: Inhibited the signs of the Warburg effect, such as high glucose consumption/anaerobic glycolysis, lactate production/cell acidosis, by inhibiting the IL-6/STAT3 pathway
lactateProd↓,
VEGF↓, ↓ angiogenic factors (VEGF) and phosphorylation of p65
p‑p65↓,
GIT1↓, PC: Increased degradation of Gli1
Foxm1↓, inhibiting FOXM1
cycD1↓, RA treatment in CRC cells inhibited proliferation-induced cell cycle arrest of the G0/G1 phase by reducing the cyclin D1 and CDK4 levels,
CDK4↓,
MMP9↓, CRC cells, and it led to a decrease in the expressions of matrix metalloproteinase (MMP)-2 and MMP-9.
HDAC2↓, PCa cells through the inhibition of HDAC2

1748- RosA,    The Role of Rosmarinic Acid in Cancer Prevention and Therapy: Mechanisms of Antioxidant and Anticancer Activity
- Review, Var, NA
AntiCan↑, RA exhibits significant potential as a natural agent for cancer prevention and treatment
*BioAv↝, Various factors, including its lipophilic nature, stability in the gastrointestinal tract, and interactions with food, can significantly influence its absorption
*CardioT↓, RA attenuated these effects by reducing ROS levels, indicating its potential role as a cardioprotective agent during chemotherapy.
*Iron↓, Another significant mechanism antioxidant activity of RA is its capacity to chelate transition metal ions, particularly iron (Fe2+) and copper (Cu2+), which can catalyze the formation of highly reactive hydroxyl radicals through the Fenton reaction.
*ROS↓, forming stable complexes with Fe2+ and Cu2+, thus inhibiting their pro-oxidant activity.
*SOD↑, SOD, CAT, and GPx, play crucial roles in neutralizing ROS and maintaining cellular redox homeostasis. RA upregulates the expression and activity of these enzymes
*Catalase↑,
*GPx↑,
*NRF2↑, activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, a primary regulator of the antioxidant response
MARK4↓, Anwar’s study demonstrated that RA inhibited MARK4 activity in MDA-MB-231 breast cancer cells, resulting in dose-dependent apoptosis
MMP9↓, RA effectively inhibited cancer cell invasion and migration by reducing matrix metalloproteinase-9 (MMP-9) activity
TumCCA↑, caused cell cycle arrest
Bcl-2↓, RA downregulates Bcl-2 expression and upregulates Bax, thereby promoting apoptosis
BAX↑,
Apoptosis↑,
E-cadherin↑, promoting E-cadherin expression, while downregulating N-cadherin and vimentin
N-cadherin↓,
Vim↓,
Gli1↓, induced apoptosis by downregulating Gli1, a key component of the Hedgehog signaling pathway,
HDAC2↓, RA induced apoptosis by modulating histone deacetylase 2 (HDAC2) expression
Warburg↓, anti-Warburg effect of RA in colorectal carcinoma
Hif1a↓, RA inhibits hypoxia-inducible factor-1 alpha (HIF-1α) and downregulates miR-155
miR-155↓,
p‑PI3K↑, RA has been shown to upregulate p-PI3K, protecting cells through the PI3K/Akt pathway,
ROS↑, RA, induces significant ROS generation in A549 cells, which triggers both apoptosis and autophagy.
*IronCh↑, RA’s dual nature as both a phenolic acid and a flavonoid-related compound enables it to chelate metal ions and prevent the formation of free radicals,

3006- RosA,    Rosmarinic acid attenuates glioblastoma cells and spheroids’ growth and EMT/stem-like state by PTEN/PI3K/AKT downregulation and ERK-induced apoptosis
- in-vitro, GBM, U87MG - in-vitro, GBM, LN229
TumCG↓, Rosmarinic acid (RA) reduced the glioma growth and motility in 2D- and 3D-cultures
EMT↓, RA suppressed epithelial-mesenchymal transition and stem-cell property in spheroids.
SIRT1↓, RA downregulated SIRT1/FOXO1/NF-κB axis independently of p53 or PTEN function.
FOXO1↓,
NF-kB↓,
angioG↓, RA dose-dependently reduced angiogenesis and intracellular ROS levels, suppressed glioma growth,
ROS↓,
PTEN↓, RA also inhibited the PTEN/PI3K/AKT pathway in U-87MG cells.
PI3K↓,
Akt↓,
*Inflam↓, anti-inflammatory, antimicrobial, cardioprotective, hepatoprotective, neuroprotective, antidiabetic, and especially anticancer effects (
*cardioP↑,
*hepatoP↑,
*neuroP↑,
Warburg↓, suppresses Warburg effect

3010- RosA,    Exploring the mechanism of rosmarinic acid in the treatment of lung adenocarcinoma based on bioinformatics methods and experimental validation
- in-vitro, Lung, A549 - in-vivo, NA, NA
TumCG↓, RosA could inhibit the growth of transplanted tumors in nude mice bearing tumors of lung cancer cells, reduce the positive expression of Ki67 in lung tumor tissue, and hinder the proliferation of lung tumor cells.
Ki-67↓,
FABP4↑, Upregulated expression of PPARG and FABP4 by activating the PPAR signaling pathway increases the level of ROS in lung tumor tissues and promotes apoptosis of lung tumor cells.
PPARα↑,
ROS↑, RosA increases ROS levels in lung tumor tissues and induces apoptosis
Apoptosis↑,
MMP9↓, In addition, RosA can also reduce the expression of MMP-9 and IGFBP3, inhibit the migration and invasion of lung tumor tissue cells.
IGFBP3↓,
MMP2↓, In addition, RosA down-regulated the expression of MMP-9 and MMP2, regulated epithelial-mesenchymal transition to inhibit cell invasion, and slow down tumor development.
EMT↓,
TumCI↓,
PI3K↓, his study also confirmed that RosA down-regulated the expression of the PI3K/AKT/mTOR pathway-related proteins
Akt↓,
mTOR↓,
Gli1↓, Xiang Zhou et al. [28] reported that RosA inhibited the growth of PDAC tumors by inhibiting Gli1.
PPARγ↑, Upregulated expression of PPARG
Cyt‑c↑, figure 7


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

Results for Effect on Cancer/Diseased Cells:
Akt↓,5,   AMPK↓,1,   angioG↓,1,   AntiCan↑,1,   antiOx↑,1,   Apoptosis↑,3,   ASC↑,1,   BAX↑,1,   Bcl-2↓,2,   Bcl-xL↓,1,   BNIP3↑,1,   Casp1↓,1,   Casp3↑,1,   CDK4↓,1,   chemoP↓,1,   cycD1↓,1,   Cyt‑c↑,1,   E-cadherin↑,2,   EGF↓,1,   p‑EGFR↓,1,   EMT↓,4,   ERK↓,1,   FABP4↑,1,   Foxm1↓,1,   FOXO1↓,1,   GIT1↓,1,   Gli1↓,2,   GlucoseCon↓,1,   HDAC2↓,2,   Hif1a↓,1,   HSP27↓,1,   ICAM-1↓,1,   IGFBP3↓,1,   IL6↑,1,   Ki-67↓,1,   lactateProd↓,1,   MARK4↓,2,   MDM2↓,1,   miR-155↓,1,   MMP↓,1,   MMP2↓,2,   MMP9↓,3,   MMPs↓,1,   mTOR↓,3,   N-cadherin↓,1,   NF-kB↓,1,   NLRP3↓,1,   p‑p65↓,1,   PI3K↓,5,   p‑PI3K↑,1,   PPARα↑,1,   PPARγ↑,1,   PTEN↓,1,   ROS↓,2,   ROS↑,2,   SIRT1↓,1,   STAT3↓,1,   TLR4↓,1,   TumCCA↑,3,   TumCG↓,3,   TumCI↓,2,   TumCMig↓,2,   TumCP↓,1,   tumCV↓,1,   TumMeta↓,1,   VEGF↓,1,   Vim↓,2,   Warburg↓,3,   Zeb1↓,1,  
Total Targets: 69

Results for Effect on Normal Cells:
antiOx↑,1,   Aβ↓,1,   BioAv↝,1,   cardioP↑,1,   CardioT↓,1,   Catalase↑,1,   COX2↓,1,   GPx↑,1,   hepatoP↑,1,   HMGB1↓,1,   IL1β↓,1,   IL6↓,1,   Inflam↓,2,   Iron↓,1,   IronCh↑,1,   memory↑,1,   MMP↑,1,   neuroP↑,2,   NF-kB↓,1,   NRF2↑,1,   PGE2↓,1,   ROS↓,2,   SOD↑,1,  
Total Targets: 23

Scientific Paper Hit Count for: PI3K, Phosphatidylinositide-3-Kinases
6 Rosmarinic acid
Filter Conditions: Pro/AntiFlg:%  IllCat:%  CanType:%  Cells:%  prod#:142  Target#:252  State#:%  Dir#:%
  wNotes=on  sortOrder:rid,rpid

 

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