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


HDAC2, Histone Deacetylase 2: Click to Expand ⟱
Source:
Type:
HDAC2 is a member of the class I histone deacetylase family that removes acetyl groups from lysine residues on histone proteins.

• This deacetylation usually promotes chromatin compaction, leading to transcriptional repression of genes involved in cell differentiation, apoptosis, and cell cycle regulation.
• HDAC2, along with its relatives HDAC1 and others, is often found as part of multiprotein corepressor complexes that regulate gene expression in both normal and cancer cells.

2. Role of HDAC2 in Cancer
• Overexpression and Dysregulation:
– In several types of cancer, HDAC2 is overexpressed or dysregulated, contributing to an altered transcriptional profile.
– Elevated HDAC2 levels can lead to the suppression of tumor suppressor genes and genes involved in cell-cycle checkpoints or apoptosis, facilitating tumor progression.

• Impact on the Tumor Microenvironment:
– HDAC2 activity influences not only tumor cells but also the surrounding stromal and immune cells, affecting inflammatory responses and immune evasion strategies.
Scientific Papers found: Click to Expand⟱
3029- RosA,    Rosmarinic Acid, a Component of Rosemary Tea, Induced the Cell Cycle Arrest and Apoptosis through Modulation of HDAC2 Expression in Prostate Cancer Cell Lines
- in-vitro, Pca, PC3 - in-vitro, Pca, DU145
TumCP↓, RA decreased the cell proliferation in cell viability assay, and inhibited the colony formation and tumor spheroid formation.
tumCV↓,
Apoptosis↑, RA induced early- and late-stage apoptosis of PC-3 and DU145 cells
HDAC2↓, RA inhibited the expression of HDAC2, as SAHA did
PCNA↓, (PCNA), cyclin D1 and cyclin E1 were downregulated by RA, whereas p21 was upregulated. In addition,
cycD1↓,
cycE↓,
P21↑,
DNAdam↑, apoptotic cells observed by DNA fragmentation were significantly increased
Casp3↑, expression of Caspase-3 was upregulated by SAHA and RA in both cell lines

3030- RosA,    Anticancer Activity of Rosmarinus officinalis L.: Mechanisms of Action and Therapeutic Potentials
- Review, Var, NA
ROS⇅, could defend against their oxidative damage of DNA, proteins, and lipids [15], although, as subsequently observed, the derivatives of rosemary are, in some conditions, capable of inducing a cytotoxic effect precisely through the release of ROS
*NRF2↑, scavenging action, RE has also been stated to control intracellular antioxidant systems, by stimulating the activation of nuclear transcription factor (Nrf)2 target genes
*GSH↑, augmenting the glutathione level, with an increase in its reduced form (GSH) compared with that of its oxidized form (GSSG)
HDAC2↓, Similar to the effects of SAHA, RA reduced cell growth and blocked cancer spheroid formation, caused the apoptosis of tumor cells, and blocked the expression of HDAC2

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,

3001- RosA,    Therapeutic Potential of Rosmarinic Acid: A Comprehensive Review
- Review, Var, NA
TumCP↓, including in tumor cell proliferation, apoptosis, metastasis, and inflammation
Apoptosis↑,
TumMeta↓,
Inflam↓,
*antiOx↑, RA is therefore considered to be the strongest antioxidant of all hydroxycinnamic acid derivatives
*AntiAge↑, , it also exerts powerful antimicrobial, anti-inflammatory, antioxidant and even antidepressant, anti-aging effects
*ROS↓, RA and its metabolites can directly neutralize reactive oxygen species (ROS) [10] and thereby reduce the formation of oxidative damage products.
BioAv↑, RA is water-soluble, and according to literature data, the efficacy of secretion of this compound in infusions is about 90%
Dose↝, Accordingly, it is possible to consume approximately 110 mg RA daily, i.e., approximately 1.6 mg/kg for adult men weighing 70 kg.
NRF2↑, liver cancer cell line, HepG2, transfected with plasmid containing ARE-luciferin gene, RA predominantly enhances ARE-luciferin activity and promotes nuclear factor E2-related factor-2 (Nrf2) translocation from cytoplasm to the nucleus
P-gp↑, and also increases MRP2 and P-gp efflux activity along with intercellular ATP level
ATP↑,
MMPs↓, RA concurrently induced necrosis and apoptosis and stimulated MMP dysfunction activated PARP-cleavage and caspase-independent apoptosis.
cl‑PARP↓,
Hif1a↓, inhibits transcription factor hypoxia-inducible factor-1α (HIF-1α) expression
GlucoseCon↓, it also suppressed glucose consumption and lactate production in colorectal cells
lactateProd↓,
Warburg↓, may suppress the Warburg effects through an inflammatory pathway involving activator of transcription-3 (STAT3) and signal transducer of interleukin (IL)-6
TNF-α↓, RA supplementation also reduced tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX-2) and IL-6 levels, and modulated p65 expression [
COX2↓,
IL6↓,
HDAC2↓, RA induced the cell cycle arrest and apoptosis in prostate cancer cell lines (PCa, PC-3, and DU145) [31]. These effects were mediated through modulation of histone deacetylases expression (HDACs), specifically HDAC2;
GSH↑, RA can also inhibit adhesion, invasion, and migration of Ls 174-T human colon carcinoma cells through enhancing GSH levels and decreasing ROS levels
ROS↓,
ChemoSen↑, RA also enhances chemosensitivity of human resistant gastric carcinoma SGC7901 cells
*BG↓, RA significantly increased insulin index sensitivity and reduced blood glucose, advanced glycation end-products, HbA1c, IL-1β, TNFα, IL-6, p-JNK, P38 mitogen-activated protein kinase (MAPK), and NF-κB levels
*IL1β↓,
*TNF-α↓,
*IL6↓,
*p‑JNK↓,
*p38↓,
*Catalase↑, The reduced activities of CAT, SOD, glutathione S-transferases (GST), and glutathione peroxidase (GPx) and the reduced levels of vitamins C and E, ceruloplasmin, and GSH in plasma of diabetic rats were also significantly recovered by RA application
*SOD↑,
*GSTs↑,
*VitC↑,
*VitE↑,
*GSH↑,
*GutMicro↑, protective effects of RA (30 mg/kg) against hypoglycemia, hyperlipidemia, oxidative stress, and an imbalanced gut microbiota architecture was studied in diabetic rats.
*cardioP↑, Cardioprotective Activity: RA also reduced fasting serum levels of vascular cell adhesion molecule 1 (VCAM-1), inter-cellular adhesion molecule 1 (ICAM-1), plasminogen-activator-inhibitor-1 (PAI-1), and increased GPX and SOD levels
*ROS↓, Finally, in H9c2 cardiac muscle cells, RA inhibited apoptosis by decreasing intracellular ROS generation and recovering mitochondria membrane potential
*MMP↓,
*lipid-P↓, At once, RA suppresses lipid peroxidation (LPO) and ROS generation, whereas in HSC-T6 cells it increases cellular GSH.
*NRF2↑, Additionally, it significantly increases Nrf2 translocation
*hepatoP↑, Hepatoprotective Activity
*neuroP↑, Nephroprotective Activity
*P450↑, RA also reduced CP-produced oxidative stress and amplified cytochrome P450 2E1 (CYP2E1), HO-1, and renal-4-hydroxynonenal expression.
*HO-1↑,
*AntiAge↑, Anti-Aging Activity
*motorD↓, A significantly delays motor neuron dysfunction in paw grip endurance tests,


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

Results for Effect on Cancer/Diseased Cells:
Akt↓,1,   AMPK↓,1,   AntiCan↑,1,   Apoptosis↑,3,   ASC↑,1,   ATP↑,1,   BAX↑,1,   Bcl-2↓,2,   Bcl-xL↓,1,   BioAv↑,1,   BNIP3↑,1,   Casp1↓,1,   Casp3↑,2,   CDK4↓,1,   ChemoSen↑,1,   COX2↓,1,   cycD1↓,2,   cycE↓,1,   DNAdam↑,1,   Dose↝,1,   E-cadherin↑,2,   EMT↓,1,   Foxm1↓,1,   GIT1↓,1,   Gli1↓,1,   GlucoseCon↓,2,   GSH↑,1,   HDAC2↓,5,   Hif1a↓,2,   HSP27↓,1,   ICAM-1↓,1,   IL6↓,1,   IL6↑,1,   Inflam↓,1,   lactateProd↓,2,   MARK4↓,2,   MDM2↓,1,   miR-155↓,1,   MMP↓,1,   MMP2↓,1,   MMP9↓,2,   MMPs↓,1,   mTOR↓,1,   N-cadherin↓,1,   NLRP3↓,1,   NRF2↑,1,   P-gp↑,1,   P21↑,1,   p‑p65↓,1,   cl‑PARP↓,1,   PCNA↓,1,   PI3K↓,1,   p‑PI3K↑,1,   ROS↓,1,   ROS↑,1,   ROS⇅,1,   STAT3↓,1,   TLR4↓,1,   TNF-α↓,1,   TumCCA↑,2,   TumCG↓,1,   TumCP↓,2,   tumCV↓,1,   TumMeta↓,2,   VEGF↓,1,   Vim↓,1,   Warburg↓,3,   Zeb1↓,1,  
Total Targets: 68

Results for Effect on Normal Cells:
AntiAge↑,2,   antiOx↑,2,   Aβ↓,1,   BG↓,1,   BioAv↝,1,   cardioP↑,1,   CardioT↓,1,   Catalase↑,2,   COX2↓,1,   GPx↑,1,   GSH↑,2,   GSTs↑,1,   GutMicro↑,1,   hepatoP↑,1,   HMGB1↓,1,   HO-1↑,1,   IL1β↓,2,   IL6↓,2,   Inflam↓,1,   Iron↓,1,   IronCh↑,1,   p‑JNK↓,1,   lipid-P↓,1,   memory↑,1,   MMP↓,1,   MMP↑,1,   motorD↓,1,   neuroP↑,2,   NF-kB↓,1,   NRF2↑,3,   p38↓,1,   P450↑,1,   PGE2↓,1,   ROS↓,4,   SOD↑,2,   TNF-α↓,1,   VitC↑,1,   VitE↑,1,  
Total Targets: 38

Scientific Paper Hit Count for: HDAC2, Histone Deacetylase 2
5 Rosmarinic acid
Filter Conditions: Pro/AntiFlg:%  IllCat:%  CanType:%  Cells:%  prod#:142  Target#:984  State#:%  Dir#:%
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