Casp3 Cancer Research Results

Casp3, CPP32, Cysteinyl aspartate specific proteinase-3: Click to Expand ⟱

Source:

Type:

Also known as CP32.
Cysteinyl aspartate specific proteinase-3 (Caspase-3) is a common key protein in the apoptosis and pyroptosis pathways, and when activated, the expression level of tumor suppressor gene Gasdermin E (GSDME) determines the mechanism of tumor cell death.
As a key protein of apoptosis, caspase-3 can also cleave GSDME and induce pyroptosis. Loss of caspase activity is an important cause of tumor progression.
Many anticancer strategies rely on the promotion of apoptosis in cancer cells as a means to shrink tumors. Crucial for apoptotic function are executioner caspases, most notably caspase-3, that proteolyze a variety of proteins, inducing cell death. Paradoxically, overexpression of procaspase-3 (PC-3), the low-activity zymogen precursor to caspase-3, has been reported in a variety of cancer types. Until recently, this counterintuitive overexpression of a pro-apoptotic protein in cancer has been puzzling. Recent studies suggest subapoptotic caspase-3 activity may promote oncogenic transformation, a possible explanation for the enigmatic overexpression of PC-3. Herein, the overexpression of PC-3 in cancer and its mechanistic basis is reviewed; collectively, the data suggest the potential for exploitation of PC-3 overexpression with PC-3 activators as a targeted anticancer strategy.
Caspase 3 is the main effector caspase and has a key role in apoptosis. In many types of cancer, including breast, lung, and colon cancer, caspase-3 expression is reduced or absent.
On the other hand, some studies have shown that high levels of caspase-3 expression can be associated with a better prognosis in certain types of cancer, such as breast cancer. This suggests that caspase-3 may play a role in the elimination of cancer cells, and that therapies aimed at activating caspase-3 may be effective in treating certain types of cancer.
Procaspase-3 is a apoptotic marker protein.
Prognostic significance:
• High Cas3 expression: Associated with good prognosis and increased sensitivity to chemotherapy in breast, gastric, lung, and pancreatic cancers.
• Low Cas3 expression: Linked to poor prognosis and increased risk of recurrence in colorectal, hepatocellular carcinoma, ovarian, and prostate cancers.

Scientific Papers found: Click to Expand⟱

5257-

3BP,

Tumor Energy Metabolism and Potential of 3-Bromopyruvate as an Inhibitor of Aerobic Glycolysis: Implications in Tumor Treatment

Review,

Var,

Glycolysis↓, In recent years, a small molecule alkylating agent, 3-bromopyruvate (3-BrPA), being an effective glycolytic inhibitor, has shown great potential as a promising antitumor drug.
mt-OXPHOS↓, Not only it targets glycolysis process, but also inhibits mitochondrial OXPHOS in tumor cells.
HK2↓, The direct inhibition of mitochondrial HK-II isolated from the rabbit liver implanted VX2 tumor via 3-BrPA was demonstrated by Ko et al. [17].
Cyt‑c↑, -BrPA treatment resulted in an increase of cytochrome c release [59,60], along with an elevated expression of active proapoptotic caspase-3 and a decrease of antiapoptotic Bcl-2 and Mcl-1 [59]
Casp3↓,
Bcl-2↓,
Mcl-1↓,
GAPDH↓, Additionally, GAPDH was found to be inhibited by 3-BrPA in several studies
LDH↓, Recent reports showed 3-BrPA had ability to inhibit post glycolysis targets and other metabolic pathways, such as LDH, PDH, TCA cycle, and glutaminolysis
PDH↓, 3-BrPA was proven to be an inhibitor of PDH [72,73,74],
TCA↓,
GlutaM↓, this inhibition of TCA cycle can lead to the impairment of glutaminolysis due to α-KG generated from glutamine is incorporated into the TCA cycle by IDH and αKD activities
GSH↓, Indeed, a remarkable decrease of reduced glutathione (GSH) level was observed after 3-BrPA treatment in both microorganisms and various tumor cells [53,61,65].
ATP↓, 3-BrPA successfully killed AS-30D hepatocellular carcinoma (HCC) cells via the inhibition of both ATP-producing glycolysis and mitochondrial respiration [17].
mitResp↓,
ROS↑, the increase of ROS and concomitant decrease of GSH were commonly found in 3-BrPA-mediated antitumor studies [53,59,61,64,65,76,77,86,89].
ChemoSen↑, When 3-BrPA was combined with cisplatin or oxaliplatin with non-toxic low-dose, 3-BrPA strikingly enhanced the antiproliferative effects of both platinum drugs in HCT116 cells and resistant p53-deficient HCT116 cells [89].
toxicity↝, Finally, two years after the first diagnosis, the patient died due to an overload of liver function rather than the tumor itself [118].

3448-

ALA,

Alpha lipoic acid attenuates hypoxia-induced apoptosis, inflammation and mitochondrial oxidative stress via inhibition of TRPA1 channel in human glioblastoma cell line

*Inflam↓, inflammatory and oxidant effects of hypoxia were increased by activation of TRPA1, but its action on the values was decreased by the ALA treatment.
*ROS↓,
*GSH↑, through upregulation thiol redox system members [glutathione (GSH) and glutathione peroxidase (GSH-Px)] and down-regulation of mitochondrial ROS and extracellular productions.
*GPx↑,
*Casp3↓, HYPOX-induced caspase 3 and 9 activities were decreased by the ALA treatment
*Casp9↓,
*MMP↑, ALA treatment decreased HYPOX-induced mitochondrial membrane depolarization (JC-1) and intracellular ROS production levels

3550-

ALA,

Mitochondrial Dysfunction and Alpha-Lipoic Acid: Beneficial or Harmful in Alzheimer's Disease?

Review,

AD,

*antiOx↑, antioxidant and anti-inflammatory properties
*Inflam↓,
*PGE2↓, α-LA has mechanisms of epigenetic regulation in genes related to the expression of various inflammatory mediators, such PGE2, COX-2, iNOS, TNF-α, IL-1β, and IL-6
*COX2↓,
*iNOS↓,
*TNF-α↓,
*IL1β↓,
*IL6↓,
*BioAv↓, α-LA has rapid uptake and low bioavailability and the metabolism is primarily hepatic
*Ach↑, α-LA increases the production of acetylcholine [30], inhibits the production of free radicals [31], and promotes the downregulation of inflammatory processes
*ROS↓,
*cognitive↑, Studies have shown that patients with mild AD who were treated with α-LA showed a slower progression of cognitive impairment
*neuroP↑, α-LA is classified as an ideal neuroprotective antioxidant because of its ability to cross the blood-brain barrier and its uniform uptake profile throughout the central and peripheral nervous systems
*BBB↑,
*Half-Life↓, α-LA presented a mean time to reach the maximum plasma concentration (tmax) of 15 minutes and a mean plasma half-life (t1/2) of 14 minutes
*BioAv↑, LA consumption is recommended 30 minutes before or 2 hours after food intake
*Casp3↓, α-LA had an effect on caspases-3 and -9, reducing the activity of these apoptosis-promoting molecules to basal levels
*Casp9↓,
*ChAT↑, α-LA increased the expression of M2 muscarinic receptors in the hippocampus and M1 and M2 in the amygdala, in addition to ChaT expression in both regions.
*cognitive↑, α-LA acts on these apoptotic signalling pathways, leading to improved cognitive function and attenuation of neurodegeneration.
*eff↑, Based on their results, the authors suggest that treatment with α-LA would be a successful neuroprotective option in AD, at least as an adjuvant to standard treatment with acetylcholinesterase inhibitors.
*cAMP↑, The increase of cAMP caused by α-LA inhibits the release of proinflammatory cytokines, such as IL-2, IFN-γ, and TNF-α.
*IL2↓,
*INF-γ↓,
*TNF-α↓,
*SIRT1↑, Protein expression encoded by SIRT1 showed higher levels after α-LA treatment, especially in liver cells.
*SOD↑, antioxidant enzymes (SOD and GSH-Px) and malondialdehyde (MDA) were analysed by ELISA after 24 h of MCAO, which showed that the enzymatic activities were recovered and MDA was reduced in the α-LA-treated groups i
*GPx↑,
*MDA↓,
*NRF2↑, The ratio of nucleus/cytoplasmic Nrf2 was higher in the α-LA group 40 mg/kg, indicating that the activation of this factor also occurred in a dose-dependent manner

5320-

ALC,

l-Carnitine: An adequate supplement for a multi-targeted anti-wasting therapy in cancer

in-vivo,

Var,

rats

Strength↑, improved physical performance (total physical activity, mean movement velocity and total travelled distance).
*Casp3↓, Interestingly, l-carnitine treatment also decreases caspase-3 mRNA content therefore suggesting a modulation of apoptosis.
cachexia↓, concluded that l-carnitine supplementation may be a good approach for a multi-targeted therapy for the treatment of cancer-related cachexia.
*Dose↝, It is a natural compound free from toxicity up to 6 g/day in human subjects with cancer10 and up to 9 g/day i.v. in patients with acute cardiac infarction.

2637-

Api,

Apigenin Alleviates Endoplasmic Reticulum Stress-Mediated Apoptosis in INS-1 β-Cells

in-vitro,

Diabetic,

*other↝, In the present study, the anti-diabetic effect of apigenin on pancreatic β-cell insulin secretion, apoptosis, and the mechanism underlying its anti-diabetic effects, were investigated in the INS-ID β-cell line
*Insulin↑, The results showed that apigenin concentration-dependently facilitated 11.1-mM glucose-induced insulin secretion, which peaked at 30 µM
ER Stress↓, Apigenin also concentration-dependently inhibited the expression of endoplasmic reticulum (ER) stress signaling proteins
*CHOP↓, CCAAT/enhancer binding protein (C/EBP) homologous protein (CHOP) and cleaved caspase-3
*cl‑Casp3↓,
*ROS↓, In contrast, the cytoprotective effect of apigenin against oxidative stress, inflammation, apoptosis, and oxidative and ER stresses has been demonstrated in various cell types
*Inflam↓,
*TXNIP↓, expression of TXNIP, which was increased by the thapsigargin treatment, was downregulated in INS-1D cells in response to apigenin.

173-

Api,

Apigenin-induced apoptosis is enhanced by inhibition of autophagy formation in HCT116 human colon cancer cells

in-vitro,

Colon,

HCT116

 25, 50 uM

CycB/CCNB1↓,
cDC2↓,
CDC25↓,
P53↑,
P21↑,
cl‑PARP↑, cleavage
proCasp8↓, Apigenin induced poly (ADP-ribose) polymerase (PARP) cleavage and decreased the levels of procaspase-8, -9 and -3
proCasp9↓,
proCasp3↓,

3391-

ART/DHA,

Antitumor Activity of Artemisinin and Its Derivatives: From a Well-Known Antimalarial Agent to a Potential Anticancer Drug

Review,

Var,

TumCP↓, inhibiting cancer proliferation, metastasis, and angiogenesis.
TumMeta↓,
angioG↓,
TumVol↓, reduces tumor volume and progression
BioAv↓, artemisinin has low solubility in water or oil, poor bioavailability, and a short half-life in vivo (~2.5 h)
Half-Life↓,
BioAv↑, semisynthetic derivatives of artemisinin such as artesunate, arteeter, artemether, and artemisone have been effectively used as antimalarials with good clinical efficacy and tolerability
eff↑, preloading of cancer cells with iron or iron-saturated holotransferrin (diferric transferrin) triggers artemisinin cytotoxicity
eff↓, Similarly, treatment with desferroxamine (DFO), an iron chelator, renders compounds inactive
ROS↑, ROS generation may contribute with the selective action of artemisinin on cancer cells.
selectivity↑, Tumor cells have enhanced vulnerability to ROS damage as they exhibit lower expression of antioxidant enzymes such as superoxide dismutase, catalase, and gluthatione peroxidase compared to that of normal cells
TumCCA↑, G2/M, decreased survivin
survivin↓,
BAX↑, Increased Bax, activation of caspase 3,8,9 Decreased Bc12, Cdc25B, cyclin B1, NF-κB
Casp3↓,
Casp8↑,
Casp9↑,
CDC25↓,
CycB/CCNB1↓,
NF-kB↓,
cycD1/CCND1↓, decreased cyclin D, E, CDK2-4, E2F1 Increased Cip 1/p21, Kip 1/p27
cycE/CCNE↓,
E2Fs↓,
P21↑,
p27↑,
ADP:ATP↑, Increased poly ADP-ribose polymerase Decreased MDM2
MDM2↓,
VEGF↓, Decreased VEGF
IL8↓, Decreased NF-κB DNA binding [74, 76] IL-8, COX2, MMP9
COX2↓,
MMP9↓,
ER Stress↓, ER stress, degradation of c-MYC
cMyc↓,
GRP78/BiP↑, Increased GRP78
DNAdam↑, DNA damage
AP-1↓, Decreased NF-κB, AP-1, Decreased activation of MMP2, MMP9, Decreased PKC α/Raf/ERK and JNK
MMP2↓,
PKCδ↓,
Raf↓,
ERK↓,
JNK↓,
PCNA↓, G2, decreased PCNA, cyclin B1, D1, E1 [82] CDK2-4, E2F1, DNA-PK, DNA-topo1, JNK VEGF
CDK2↓,
CDK4↓,
TOP2↓, Inhibition of topoisomerase II a
uPA↓, Decreased MMP2, transactivation of AP-1 [56, 88] NF-κB uPA promoter [88] MMP7
MMP7↓,
TIMP2↑, Increased TIMP2, Cdc42, E cadherin
Cdc42↑,
E-cadherin↑,

4278-

ART/DHA,

Artemisinin Ameliorates the Neurotoxic Effect of 3-Nitropropionic Acid: A Possible Involvement of the ERK/BDNF/Nrf2/HO-1 Signaling Pathway

in-vivo,

NA,

Rats

*IL6↓, ART effectively suppressed neuroinflammatory (IL-6) and apoptotic markers (caspase 3 and 9), increasing BDNF levels and restoring the p-ERK1/2, Nrf2, and HO-1 expression.
*Casp3↓,
*Casp9↓,
*BDNF↑,
*ERK↑,
*NRF2↑,
*HO-1↑,
*neuroP↑, ART could exert its neuroprotective effect via antioxidant, anti-inflammatory, and antiapoptotic properties with a possible involvement of the ERK/BDNF/Nrf2/HO-1 pathway.
*antiOx↑,
*Inflam↓,

3163-

Ash,

Rad,

Withaferin A, a steroidal lactone, selectively protects normal lymphocytes against ionizing radiation induced apoptosis and genotoxicity via activation of ERK/Nrf-2/HO-1 axis

*radioP↑, Withaferin A (WA) protected only normal lymphocytes, but not cancer cells, against IR-induced apoptosis
selectivity↑,
*Casp3↓, WA treatment led to significant inhibition of IR-induced caspase-3 activation and decreased IR-induced DNA damage to lymphocytes and bone-marrow cells.
*DNAdam↓,
*ROS↓, WA reduced intracellular ROS and GSH levels
*GSH↓,
*NRF2↑, WA induced pro-survival transcription factor, Nrf-2, and expression of cytoprotective genes HO-1, catalase, SOD, peroxiredoxin-2 via ERK.
*HO-1↑,
*Catalase↑,
*SOD↑,
*Prx↑,
*ERK↑, Activated ERK promotes the nuclear translocation and activity of Nrf2

3164-

Ash,

Withaferin A alleviates fulminant hepatitis by targeting macrophage and NLRP3

*hepatoP↑, Withania Somnifera, is a hepatoprotective agent
*IKKα↓, WA also inhibits inflammation by directly inhibiting IκκB activity46,47 or NLRP3 inflammasome activation in vitro in immune cells
*NLRP3↓,
*NRF2↑, WA probably protects against FH by targeting the macrophage and/or hepatocyte stress via activating NRF2, AMPKα
*AMPK↑,
*Inflam↓, Thus, WA potently protects against GalN/LPS-induced hepatotoxicity and inflammation
*Apoptosis↓, WA suppressed hepatic apoptosis in vivo
*cl‑Casp3↓, attenuate the increase of cleaved CASP3 and cleaved PARP1
*cl‑PARP1↓,
*NLRP3↓, WA prevented GalN/LPS-induced FH partially by inhibiting activation of the NLRP3 inflammasome
*ROS↓, fig 7
*ALAT↓,
*AST↓,
*GSH↑, (GSH) levels were significantly depleted by ~50% 6 h after GalN/LPS administration and were recovered to levels comparable with that of control mice by WA treatment

2618-

Ba,

Baicalein induces apoptosis by inhibiting the glutamine-mTOR metabolic pathway in lung cancer

in-vitro,

Lung,

H1299

12.5, 25, and 50 μM

in-vivo,

Lung,

A549

10, 20, and 40 μM

TumCG↓, Baicalein inhibited lung cancer xenograft tumor growth in vivo and suppressed proliferation and promoted apoptosis in lung cancer cells in vitro.
TumCP↓,
Apoptosis↑,
GLUT1↓, baicalein interacted with glutamine transporters as well as glutaminase and inhibited their activation
GLS↓,
mTOR↓, mTOR, an apoptosis-related protein and downstream target of glutamine metabolism, was also inhibited by baicalein treatment
*toxicity∅, baicalein treatment did not result in damage to the mouse organs, including the liver, heart, spleen, lung, or kidney
cl‑Casp9↓, baicalein dose-dependently suppressed the protein levels of Bax, cleaved caspase 9, and cleaved caspase 3 in H1299 and A549 cells
cl‑Casp3↓,
GSH↓, Meanwhile, the levels of glutathione (GSH), S-formylglutathione, and pyroglutamic acid in baicalein-treated A549 cells were downregulated when compared to that in control group
GlutMet↓, These findings indicate that baicalein inhibits cellular glutamine uptake, which is consistent with the findings of metabolomics studies.

2689-

BBR,

Berberine protects against glutamate-induced oxidative stress and apoptosis in PC12 and N2a cells

in-vitro,

Nor,

PC12

in-vitro,

AD,

in-vitro,

Stroke,

*ROS↓, In both cell lines, pretreatment with berberine (especially at low concentrations) significantly decreased ROS generation, lipid peroxidation, and DNA fragmentation, while improving glutathione content and SOD activity in glutamate-injured cells.
*lipid-P↓,
*DNAdam↓, Berberine significantly diminished glutamate-induced DNA fragmentation
*GSH↑,
*SOD↑,
*eff↑, This is relevant to berberine treatment in neurodegenerative disorders, such as dementia (Alzheimer’s disease), seizures, and stroke.
*cl‑Casp3↓, Berberine significantly decreased cleaved caspase-3 and bax/bcl-2 expressions in the glutamate-injured cells
*BAX↓,
*neuroP↑, the current study demonstrated that berberine exerts neuroprotective effects against glutamate-induced N2a and PC12 cytotoxicity via antioxidant and anti-apoptotic mechanisms
*Dose↝, the protective effect of berberine was more significant at lower concentrations and decreased with increasing concentration.
*Ca+2↓, Nadjafi et al demonstrated that berberine protects OLN-93 oligodendrocytes against ischemic-induced cell death by attenuating the intracellular Ca2+ overload similar to the NMDA or the AMPA/kainate receptors antagonists

2674-

BBR,

Berberine: A novel therapeutic strategy for cancer

Review,

Var,

Review,

IBD,

Inflam↓, anti-inflammatory, antidiabetic, antibacterial, antiparasitic, antidiarrheal, antihypertensive, hypolipidemic, and fungicide.
AntiCan↑, elaborated on the anticancer effects of BBR through the regulation of different molecular pathways such as: inducing apoptosis, autophagy, arresting cell cycle, and inhibiting metastasis and invasion.
Apoptosis↑,
TumAuto↑,
TumCCA↑,
TumMeta↓,
TumCI↓,
eff↑, BBR is shown to have beneficial effects on cancer immunotherapy.
eff↑, BBR inhibited the release of Interleukin 1 beta (IL-1β), Interferon gamma (IFN-γ), Interleukin 6 (IL-6), and Tumor Necrosis Factor-alpha (TNF-α) from LPS stimulated lymphocytes by acting as a dopamine receptor antagonist
CD4+↓, BBR inhibited the proliferation of CD4+ T cells and down-regulated TNF-α and IL-1 and thus, improved autoimmune neuropathy.
TNF-α↓,
IL1↓,
BioAv↓, On the other hand, P-Glycoprotein (P-gp), a secretive pump located in the epithelial cell membrane, restricts the oral bioavailability of a variety of medications, such as BBR. The use of P-gp inhibitors is a common and effective way to prevent this
BioAv↓, Regardless of its low bioavailability, BBR has shown great therapeutic efficacy in the treatment of a number of diseases.
other↓, BBR has been also used as an effective therapeutic agent for Inflammatory Bowel Disease (IBD) for several years
AMPK↑, inhibitory effects on inflammation by regulating different mechanisms such as 5′ Adenosine Monophosphate-Activated Protein Kinase (AMPK. Increase of AMPK
MAPK↓, Mitogen-Activated Protein Kinase (MAPK), and NF-κB signaling pathways
NF-kB↓,
IL6↓, inhibiting the expression of proinflammatory genes such as IL-1, IL-6, Monocyte Chemoattractant Protein 1 (MCP1), TNF-α, Prostaglandin E2 (PGE2), and Cyclooxygenase-2 (COX-2)
MCP1↓,
PGE2↓,
COX2↓,
*ROS↓, BBR protected PC-12 cells (normal) from oxidative damage by suppressing ROS through PI3K/AKT/mTOR signaling pathways
*antiOx↑, BBR therapy improved the antioxidant function of mice intestinal tissue by enhancing the levels of glutathione peroxidase and catalase enzymes.
*GPx↑,
*Catalase↑,
AntiTum↑, Besides, BBR leaves great antitumor effects on multiple types of cancer such as breast cancer,69 bladder cancer,70 hepatocarcinoma,71 and colon cancer.72
TumCP↓, BBR exerts its antitumor activity by inhibiting proliferation, inducing apoptosis and autophagy, and suppressing angiogenesis and metastasis
angioG↓,
Fas↑, by increasing the amounts of Fas receptor (death receptor)/FasL (Fas ligand), ROS, ATM, p53, Retinoblastoma protein (Rb), caspase-9,8,3, TNF-α, Bcl2-associated X protein (Bax), BID
FasL↑,
ROS↑,
ATM↑,
P53↑,
RB1↑,
Casp9↑,
Casp8↑,
Casp3↓,
BAX↑,
Bcl-2↓, and declining Bcl2, Bcl-X, c-IAP1 (inhibitor of apoptosis protein), X-linked inhibitor of apoptosis protein (XIAP), and Survivin levels
Bcl-xL↓,
IAP1↓,
XIAP↓,
survivin↓,
MMP2↓, Furthermore, BBR suppressed Matrix Metalloproteinase-2 (MMP-2), and MMP-9 expression.
MMP9↓,
CycB/CCNB1↓, Inhibition of cyclin B1, cdc2, cdc25c
CDC25↓,
CDC25↓,
Cyt‑c↑, BBR inhibited tumor cell proliferation and migration and induced mitochondria-mediated apoptosis pathway in Triple Negative Breast Cancer (TNBC) by: stimulating cytochrome c release from mitochondria to cytosol
MMP↓, decreased the mitochondrial membrane potential, and enabled cytochrome c release from mitochondria to cytosol
RenoP↑, BBR significantly reduced the destructive effects of cisplatin on the kidney by inhibiting autophagy, and exerted nephroprotective effects.
mTOR↓, U87 cell, Inhibition of m-TOR signaling
MDM2↓, Downregulation of MDM2
LC3II↑, Increase of LC3-II and beclin-1
ERK↓, BBR stimulated AMPK signaling, resulting in reduced extracellular signal–regulated kinase (ERK) activity and COX-2 expression in B16F-10 lung melanoma cells
COX2↓,
MMP3↓, reducing MMP-3 in SGC7901 GC and AGS cells
TGF-β↓, BBR suppressed the invasion and migration of prostate cancer PC-3 cells by inhibiting TGF-β-related signaling molecules which induced Epithelial-Mesenchymal Transition (EMT) such as Bone morphogenetic protein 7 (BMP7),
EMT↑,
ROCK1↓, inhibiting metastasis-associated proteins such as ROCK1, FAK, Ras Homolog Family Member A (RhoA), NF-κB and u-PA, leading to in vitro inhibition of MMP-1 and MMP-13.
FAK↓,
RAS↓,
Rho↓,
NF-kB↓,
uPA↓,
MMP1↓,
MMP13↓,
ChemoSen↑, recent studies have indicated that it can be used in combination with chemotherapy agents

5483-

BM,

The Role of Bacopa monnieri in Alzheimer’s Disease: Mechanisms and Potential Clinical Use—A Review

Review,

AD,

*cognitive↑, Bacopa monnieri, also known as brahmi, which has gained particular popularity for its cognitive-function-enhancing properties and neuroprotective effects.
*neuroP↑,
*PI3K↑, figure 3
*Akt↑,
*GSK‐3β↓,
*tau↓,
*ROS↓,
*MMP3↓,
*Casp1↓,
*Casp3↓,
*NF-kB↓,
*TNF-α↓,
*IL6↓,

5680-

BML,

Anticancer properties of bromelain: State-of-the-art and recent trends

Review,

Var,

*Inflam↓, anticancer, anti-edema, anti-inflammatory, anti-microbial, anti-coagulant, anti-osteoarthritis, anti-trauma pain, anti-diarrhea, wound repair.
*Bacteria↓,
*Pain↓,
*Diar↓,
*Wound Healing↑,
ERK↓, Figure 1
JNK↓,
XIAP↓,
HSP27↓,
β-catenin/ZEB1↓,
HO-1↓,
lipid-P↓,
ACSL4↑,
ROS↑,
SOD↑,
Catalase↓,
GSH↓,
MDA↓,
Casp3↓,
Casp9↑,
DNAdam↑,
Apoptosis↑,
NF-kB↓,
P53↑,
MAPK↓,
APAF1↑,
Cyt‑c↓,
CD44↓,
Imm↑, Bromelain was also studied in the innate immune system, where it could enhance and sustain the process
ATG5↑,
LC3I↑,
Beclin-1↑,
IL2↓, bromelain in vitro experiments resulted in diminished amounts of IL-2, IL-6, IL-4, G-CSF, Gm-CSF, IFN-γ,
IL4↓,
IFN-γ↓,
COX2↓, proprietary bromelain extract could decrease IL-8, COX-2, iNOS, and TNF-α without affecting cell viability.
iNOS↓,
ChemoSen↑, Bromelain may increase the cytotoxicity of cisplatin in the treatment of breast cancer as reported in 2 studies with MDA-MB-231 and 4T1 Breast Tumor cell lines
RadioS↑, The size and weight of tumors in gamma-irradiated EST-bearing mice treated with bromelain decreased significantly with a significant amelioration in the histopathological examination
Dose↝, oral bromelain administration in breast cancer patients (daily up to a dose of 7800 mg)
other↓, The role of bromelain (in combination with papain, sodium selenite and Lens culinaris lectin) has been also tested as a complementary medicine on more than 600 breast cancer patients to reduce the side effects caused by the administration of the adju

5663-

BNL,

Osthole/borneol thermosensitive gel via intranasal administration enhances intracerebral bioavailability to improve cognitive impairment in APP/PS1 transgenic mice

in-vivo,

AD,

mice

*ZO-1↓, Mechanisms showed that borneol as a “courier” opened up intercellular space and loosened the tight junctions of the nasal mucosa by suppressing ZO-1 and occludin expression
*cl‑Casp3↓, Osthole assisted by borneol demonstrated significantly improved efficiency in suppressing cleaved caspase-3 expression, increasing the Bcl-2/Bax ratio
*Bax:Bcl2↓,
*MDA↓, reducing malondialdehyde levels, inhibiting neuron apoptosis, and decreasing Aβ levels by inhibiting BACE1 expression to alleviate cognitive impairment in APP/PS1 mice
*Apoptosis↓,
*Aβ↓,
*BACE↓,
*cognitive↑,
*BioAv↑, our study demonstrated that the intracerebral bioavailability of osthole profoundly improved with intranasal administration of osthole/borneol
memory↑, our study demonstrated that the intracerebral bioavailability of osthole profoundly improved with intranasal administration of osthole/borneol
P-gp↓, This may be caused by a higher dose of BO inhibiting the action of the P-gp transporter in intestinal mucosa and CYP450 metabolism in the liver.
BioEnh↑,

3507-

Bor,

Boron inhibits apoptosis in hyperapoptosis condition: Acts by stabilizing the mitochondrial membrane and inhibiting matrix remodeling

*MMP↑, n the presence of boron, there was a significant and dose-dependent increase in MMP, which inhibited mitochondrial remodeling to the condensed state and hence the release of Cyt c and initiation of apoptosis.
*Cyt‑c↓, Boron inhibits the release of mitochondrial Cyt c and activation of Casp
*Apoptosis↓, Boron inhibits apoptosis.
*Casp3↓,
*NO↓, Nitric oxide (NO) and iNOS levels decrease in boron treated hyperapoptosis cultures.
*iNOS↓,

3791-

CA,

Caffeic Acid and Diseases—Mechanisms of Action

Review,

AD,

*memory↑, Feeding hyperinsulinemic rats with caffeic acid (30 mg/kg b.w./day) for 30 weeks significantly improved their memory and learning impairments caused by a high-fat diet
*cognitive↑, caffeic acid (100 mg/kg for two weeks) significantly improved learning deficits and increased cognitive function
*p‑tau↓, pretreatment with caffeic acid (10 μg/mL) decreased the level of phosphorylated tau protein
*ROS↓, Caffeic acid (100 mg/kg for two weeks) also suppressed oxidative stress, inflammation, NF-κB-p65 protein expression, and caspase-3 activity
*Inflam↓,
*NF-kB↓,
*Casp3↓,
*lipid-P↓, caffeic acid (50 mg/kg/day) improved cognitive functions and inhibited lipid peroxidation and nitric oxide formation in the brain
*AChE↓, Caffeic acid (12 μg/mL) inhibited acetylcholinesterase and butyrylcholinesterase activity in the brain of untreated rats in vitro
*BChE↓,
*GSK‐3β↓, improves cognitive functions, probably by inhibiting NF-κB and GSK3β signaling and acetylcholinesterase and butyrylcholinesterase activity (
*5LO↓, we consider the inhibitory effect of caffeic acid on 5-lipoxygenase as another factor in protecting the brain against damage
*BDNF↓, Caffeic acid also increased the expression of brain-derived neurotrophic factor (BDNF) in stressed mice; the effect was mediated by 5-lipoxygenase inhibition
VEGF↓, the primary way how caffeic acid affects hepatocellular carcinoma in vitro is inhibiting VEGF expression
HSP70/HSPA5↓, affeic acid (20 μM) also decreased the expression of mortalin(mitochondrial 70 kDa heat shock protein),

5766-

CAPE,

A Nano-Liposomal Formulation of Caffeic Acid Phenethyl Ester Modulates Nrf2 and NF-κβ Signaling and Alleviates Experimentally Induced Acute Pancreatitis in a Rat Model

in-vivo,

Nor,

rat

*MDA↓, CAPE-loaded-NL significantly counteracted ornithine-induced elevation in serum activities of pancreatic digestive enzymes and pancreatic levels of malondialdehyde, nuclear factor kappa B (NF-κB) p65, tumor necrosis factor-alpha, nitrite/nitrate, clea
*NF-kB↓,
*p65↓,
*TNF-α↓,
*cl‑Casp3↓,
*GSR↑, pretreatment with CAPE-loaded-NL significantly reinstated the ornithine-lowered glutathione reductase activity, glutathione,
*GSH↑,
*NRF2↑, nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase-1 levels and ATP/ADP ratio, and potentiated the Bcl-2/Bax ratio in pancreatic tissue.
*HO-1↑,
*Bax:Bcl2↓,
*antiOx↑, displayed superior antioxidant, anti-inflammatory and anti-apoptotic effects compared to free CAPE oral suspension
*Inflam↓,

5907-

CAR,

Anti-proliferative and pro-apoptotic effect of carvacrol on human hepatocellular carcinoma cell line HepG-2

in-vitro,

Liver,

HepG2

TumCG↓, In this study, we showed that carvacrol inhibited HepG2 cell growth by inducing apoptosis
Apoptosis↓,
Casp3↓, activation of caspase-3, cleavage of PARP and decreased Bcl-2 gene expression
cl‑PARP↑,
Bcl-2↓,
p‑ERK↓, decreasing phosphorylation of ERK1/2 significantly in a dose-dependent manner, and activated phosphorylation of p38
p‑p38↑,
*Bacteria↓, carvacrol has been shown to exhibit anti-microbial, anti-mutagenic, anti-platelet, analgesic, anti-inflammatory, anti-angiogenic, anti-oxidant, anti-elastase, insecticidal, anti-parasitic,cell-protective, AChE inhibitor and anti-tumor activity
*AntiAg↑,
*Inflam↓,
*antiOx↑,
*AChE↓,
AntiTum↑,
MMP↓, classical apoptosis response, including decrease in mitochondrial membrane potential and increase in cytochrome c release from mitochondria, decrease in Bcl-2/Bax ratio, increase in caspase activity and cleavage of PARP and fragmentation of DNA,
Cyt‑c↑,
Bax:Bcl2↑,
Casp↑,
DNAdam↑,
selectivity↑, we found that carvacrol induced stronger effects on hepatocellular carcinoma cells compared to normal human fetal liver cells.

5901-

CAR,

Neuroprotective role of carvacrol in ischemic brain injury: a systematic review of preclinical evidence and proposed TRPM7 involvement

Review,

Stroke,

*neuroP↑, improved neurological scores when carvacrol was given before or shortly after injury.
*ROS↓, studies showed reduced oxidative damage (MDA, 4-HNE), increased antioxidant enzymes (SOD, CAT, GPx), lower apoptosis (cleaved caspase-3), and variable changes in TRPM7 expression.
*MDA↓,
*4-HNE↓,
*SOD↑,
*Catalase↑,
*GPx↑,
*Apoptosis↓,
*cl‑Casp3↓,
*TRPM7⇅, variable changes in TRPM7 expression
*BBB↓, Natural products such as carvacrol can cross the blood-brain barrier and have been reported to inhibit TRPM7 in vitro
*TRPM7↓,

5943-

Cela,

Celastrol: A Spectrum of Treatment Opportunities in Chronic Diseases

Review,

Arthritis,

Review,

IBD,

Review,

AD,

Review,

Park,

*other↝, The most abundant and promising bioactive compound derived from the root of this plant is celastrol, also called tripterine, which possess a broad range of biological activities
*other↝, TW is generally used in the treatment of Crohn’s disease (CD) in China.
*CRP↓, Inflammatory parameters, including c-reactive protein (CRP), also decreased
*eff↝, Etanercept plus TW had an equivalent therapeutic effect to that of Etanercept plus MTX and were both well tolerated
*other↑, TW in human kidney transplantation (26). Rejection occurred in 4.1% of patients treated with TW versus 24.5% of control patients, showing efficacy in the prevention of renal allograph rejection
*CXCR4↓, celastrol decreases hypoxia-induced FLS invasion by inhibiting HIF-1α-mediated CXCR4 transcription
*IL1β↓, Authors have shown that it decreases the production of IL-1β, IL-6, IL-17, IL-18, and TNF by SIC cells harvested from arthritic rats
*IL6↓,
*IL17↓,
*IL18↓,
*TNF-α↓,
*MMP9↓, celastrol reduces MMP-9 production, which limits bone damage
*PGE2↓, celastrol suppresses LPS-induced expression of PEG2 via the downregulation of COX-1 and COX-2 activation
*COX1↓,
*COX2↓,
*PI3K↓, associated with a decrease in PI3K/Akt pathway
*Akt↓,
*other↑, Remarkably, this bone-protective property of celastrol in arthritic models is further supported by studies performed in cancer models
TumCCA↑, celastrol induces cell cycle arrest, apoptosis, and autophagy by the activation of reactive oxygen species (ROS)/c-Jun N-terminal kinases (JNK) signaling pathway
Apoptosis↑,
ROS↑,
JNK↑,
TumAuto↑, celastrol is still able to induce autophagy through HIF/BNIP3 activation
Hif1a↓, The inhibitory effect of celastrol on angiogenesis is mediated by the suppression of HIF-1α,
BNIP3↝,
HSP90↓, The inhibition of HSP90 by celastrol
Fas↑, activation of Fas/Fas ligand pathway in non-small-cell lung cancer
FasL↑,
ETC↓, inhibition of mitochondrial respiratory chain (MRC) complex I
VEGF↓, This inhibition of HIF-1α leads to the decrease of its target genes, such as the VEGF
angioG↓, Angiogenesis Inhibition
RadioS↑, celastrol can overcome tumor resistance to radiotherapy in prostate (129) and lung cancer cells
*neuroP↑, celastrol is a promising neuroprotective agent in animal models of neurodegenerative diseases, such as Parkinson disease (149), Huntington disease (149–151), Alzheimer disease
*HSP70/HSPA5↑, his induction of HSP70 by celastrol explains its beneficial effects not only in neurodegenerative disorders but also in inflammatory diseases.
*ROS↓, celastrol protects human dopaminergic cells from injury and apoptosis and prevents ROS generation and mitochondrial membrane potential loss
*MMP↑,
*Cyt‑c↓, It inhibits cytochrome c release, Bax/Bcl-2 alterations, caspase-9/3 activation, and p38 MAPK activation
*Casp3↓,
*Casp9↓,
*MAPK↓,
*Dose⇅, Authors discuss that it seems to have a narrow therapeutic window, and suggest that it may have a biphasic effect with protective properties at low concentrations and toxic effects at higher concentrations.
*HSPs↑, induces a set of HSPs (HSP27, 32, and 70) in rat cerebral cortical cultures, which are selectively impacted during the progression of this disease
BioAv↓, Due to this poor water solubility, celastrol has low bioavailability. oral administration of celastrol in rats results in ineffective absorption into the systemic circulation, with an absolute bioavailability of 17.06%
Dose↝, narrow therapeutic window of dose together with the occurrence of adverse effects. Our own data showed in vivo that the doses of 2.5 and 5 μg/g/day are effective and non-toxic in the treatment of arthritis in rats;

6017-

CGA,

Therapeutic Potential of Chlorogenic Acid in Chemoresistance and Chemoprotection in Cancer Treatment

Review,

Var,

AntiCan↑, Chlorogenic acid (5-caffeoylquinic acid, CGA), found in plants and vegetables, is promising in anticancer mechanisms.
*chemoP↑, CGA can overcome resistance to conventional chemotherapeutics and alleviate chemotherapy-induced toxicity by scavenging free radicals effectively.
TNF-α↓, CGA reduces inflammation levels in renal tissues by down-regulating tumor necrosis factor-alpha (TNF-α) and cyclooxygenase-2 (COX-2),
COX2↓,
IL6↓, Moreover, CGA exhibits a protective effect against 5-FU-induced ovarian tissue damage, reducing Interleukin 6 (IL-6) levels;
eff↑, CGA suppresses the expression of Programmed Cell Death Ligand 1 (PD-L1) on cancer cells, boosting the antitumor effect of the anti-PD-1 antibody and enhancing anticancer immunotherapy
PD-L1↓,
*cognitive↓, CGA, have shown promise in preventing cognitive dysfunction and suppressing amyloid β plaques
*Aβ↓,
*TAC↑, hyperlipidemic patients who ingested 200 mL of Mate tea (12.5 mg/mL) daily experienced a significant increase in serum total antioxidant status and the enzymatic activity of superoxide dismutase (SOD),
*SOD↑,
*eff↑, In blueberry jam production, the high-temperature processing of blueberries with sucrose promoted the formation of 11 CGA derivatives
*eff↑, roasting process (170 to 200 °C/10 to 30 min) of coffee beans promotes CGA transformation to four chlorogenic acid lactones
ChemoSen↑, CGA was found to increase the sensitivity of hepatocellular carcinoma cells to 5-FU treatment
tumCV↓, CGA was shown to collaborate by significantly reducing cell viability and growth through induction of apoptosis, attributed to inhibition of extracellular signal-regulated kinases (ERKs)
Apoptosis↑,
ERK↓,
chemoP↑, Protective Role of Chlorogenic Acid against Toxicity Induced by Chemotherapy
*GPx↑, figure4
*GSTs↑,
*GSH↑,
*SOD↑,
*Catalase↑,
*ROS↓,
*lipid-P↓,
*MDA↓,
*Casp3↓,
*HO-1↓,
cardioP↑, reported the cardioprotective effect of CGA against doxorubicin-induced cardiotoxicity in female Swiss albino mice.
radioP↑, The radioprotective potential of CGA against γ-radiation-induced chromosomal damage in male albino Swiss mice was initially demonstrated in 1993.

6010-

CGA,

The Biological Activity Mechanism of Chlorogenic Acid and Its Applications in Food Industry: A Review

Review,

Nor,

*antiOx↑, mainly shown as anti-oxidant, liver and kidney protection, anti-bacterial, anti-tumor, regulation of glucose metabolism and lipid metabolism, anti-inflammatory, protection of the nervous system,
*hepatoP↑,
*RenoP↑,
AntiTum↑,
*glucose↝,
*Inflam↓,
*neuroP↑,
*ROS↓, ↓Active oxygen (ROS) , ↓Keap1,↑Nrf2, ↑SOD, ↑CAT, ↑Glutathione Peroxidase (GSH-Px), ↑Glutathione (GSH), ↓MDA
*Keap1↓,
*NRF2↑,
*SOD↑,
*Catalase↑,
*GPx↑,
*GSH↑,
*MDA↓,
*p‑ERK↑, ↑ERK1/2 phosphorylation
*GRP78/BiP↑, ↑Glucose regulatory protein 78 (GRP78)
*CHOP↑, ↑C/EBP homologous protein (CHOP)
*GRP94↑, ↑Glucose Regulatory Protein 94 (GRP94)
*Casp3↓, ↓Caspase-9/Caspase-3
*Casp9↓,
*HGF/c-Met↑, ↑Hepatocyte Growth Factor (HGF)
*TNF-α↓, ↓Tumor Necrosis Factor-α (TNF-α)/Interferonγ (IFN-γ)
*TLR4↓, ↓TLR4
*MAPK↓, ↓MAPK signal pathway
*IL1β↓, ↓Interleukin 1β (IL-1β)/Interleukin 6 (IL-6)
*iNOS↓, ↓Inducible Nitric Oxide Synthase (iNOS)
TCA↓, ↓Tricarboxylic acid cycle (TCA) ↓Glycolysis
Glycolysis↓,
Bcl-2↓, ↓Anti-apoptotic gene Bcl-2/Bcl-XL
BAX↑, ↑Pro-apoptotic gene Bax/Bcl-XS/Bad
MAPK↑, ↑p38 mitogen-activated protein kinase (p38 MAPK)
JNK↑, ↑c-Jun N-terminal Kinase (JNK)
CSCs↓, ↓Stem cell marker genes Nanog, POU5F1, Sox2, CD44, Oct4
Nanog↓,
SOX2↓,
CD44↓,
OCT4↓,
P53↑, ↑P53
P21↑, ↑p21
*SOD1↑, ↑CuZnSOD (SOD1)/MnSOD (SOD2)
*AGEs↓, ↓Glycosylation end products (AGEs)
*GLUT2↑, ↑Glucose Transporter 2 (GLUT2)
*HDL↑, ↑High-density lipoprotein (HDL)
*Fas↓, ↓Fatty acid synthase (FAS)
*HMG-CoA↓, ↓β-hydroxy-β-methylglutamyl-CoA (HMG-CoA) reductase
*NF-kB↓, ↑NF-κB signaling pathway
*HO-1↓, ↑Nrf2/HO-1 signaling pathway
*COX2↓, ↓Cyclooxygenase-2 (COX-2)
*TLR4↓, ↓Toll-like receptor 4 (TLR4)
*BioAv↑, One route may be immediate absorption in the stomach or upper gastrointestinal tract, and the other route may be slowly absorbed throughout the small intestine.
*BioAv↝, It indicates that the bioavailability of CGA is closely related to the metabolic capacity of the organism's gut flora
TumCP↓, CGA also inhibits the proliferation, migration, and invasion of cancer cells.
TumCMig↓,
TumCI↓,

2807-

CHr,

Evidence-based mechanistic role of chrysin towards protection of cardiac hypertrophy and fibrosis in rats

in-vivo,

Nor,

Wistar rats

*antiOx↑, antioxidant, anti-inflammatory, anti-fibrotic and anti-apoptotic
Inflam↓,
*cardioP↑, Pre-treatment with chrysin of 60 mg/kg reversed the ISO-induced damage to myocardium and prevent cardiac hypertrophy and fibrosis through various anti-inflammatory, anti-apoptotic, antioxidant and anti-fibrotic pathways
*GSH↑, CHY at the highest dose (60 mg/kg) significantly bolstered the antioxidant status :GSH, SOD and CAT
*SOD↑,
*Catalase↑,
*GAPDH↑, significant increase in GAPDH levels was observed in CHYP group in comparison with normal group
*BAX↓, Decrease in apoptotic (Bax), increase in anti-apoptotic (Bcl-2)
*Bcl-2↑,
*PARP↓, expression of downstream signalling proteins, that is, PARP, cytochrome-C and caspase-3 were following the similar pattern. however at CHY 60 mg/kg treatment group, the levels were remarkably (P < 0·001) reduced.
*Cyt‑c↓,
*Casp3↓,
*NOX4↓, Whereas, lower levels of Nox-4 and higher levels of Nrf-2, HO-1 and HSP-70 were observed in CHYP group
*NRF2↑,
*HO-1↑,
*HSP70/HSPA5↑,

3624-

Cro,

Crocus Sativus L. (Saffron) in Alzheimer's Disease Treatment: Bioactive Effects on Cognitive Impairment

Review,

AD,

*AChE↓, aqueous and methanolic saffron extract presented a moderate activity as AChE inhibitor (up to 30%),
*memory↑, f 50-200 mg/kg of crocin enhanced memory impairment
*cognitive↑, crocin (30 mg/kg) for 3 weeks significantly improved cognitive impairment caused by intracerebroventricular injection of STZ,
*MDA↑, improved cognitive tasks and produced a significant decrease of malondialdehyde (MDA) levels and increase of total thiol content and glutathione peroxidase (GPx) activity in STZ-lesioned rats
*Thiols↑,
*GPx↑,
*antiOx↑, crocetin is only one and strong antioxidant, providing protection in rescuing cell viability, blocking reactive oxygen species (ROS) production and reducing caspase-3 activation
*ROS↓, crocin can prevent oxidative stress damage to hippocampus, memory and learning impairments
*Casp3↓,
*neuroP↑, neuroprotective effects of crocin against AD
*SOD↑, increase the levels of glutathione peroxidase, superoxide dismutase, acetylcholine and choline acetyltransferase,
*Ach↑,
*ChAT↑,
*BBB↑, shown that crocetin, able to pass through BBB, inhibits fibril Aβ formation,
*Aβ↓,
*tau↓, inhibitory effects of crocin on tau protein neurofibrillary tangles in AD.
*cognitive↑, (15 mg twice a day) or a capsule of placebo (two capsules a day) for 16 weeks. The results of this study indicated that saffron produces a significant improvement in cognitive performance
*Inflam↓, anticholinergic, anti-inflammatory and antioxidant features

3630-

Cro,

Crocin Improves Cognitive Behavior in Rats with Alzheimer's Disease by Regulating Endoplasmic Reticulum Stress and Apoptosis

in-vivo,

AD,

Rats

*memory↑, learning and memory abilities of AD rats were significantly decreased, which was significantly rescued by resveratrol and crocin.
*Bcl-2↑, Bcl2 in PFC and hippo of AD model group was significantly decreased (P<0.01), while those of Bax, Caspase3, GRP78, and CHOP were significantly increased .Resveratrol and crocin could significantly reverse
*BAX↓,
*Casp3↓,
*GRP78/BiP↓,
*CHOP↓,
*Dose↝, We also reported that the higher dose (40 mg/kg and 80 mg/kg) of crocin performed significantly better than lower dose (20 mg/kg), but no difference was found between 40 mg/kg and 80 mg/kg crocin

3631-

Cro,

Investigation of the neuroprotective effects of crocin via antioxidant activities in HT22 cells and in mice with Alzheimer's disease

in-vitro,

AD,

HT22

in-vivo,

AD,

mice

*ROS↓, suppressed intracellular reactive oxygen species (ROS) accumulation and Ca2+ overload compared with untreated cells.
*Ca+2↓, crocin strongly inhibited the overload of Ca2+ compared with the l-Glu-damaged HT22 cells,
*BAX↓, crocin significantly decreased the expression levels of Bax, Bad and cleaved caspase-3
*BAD↓,
*Casp3↓,
*cognitive↑, crocin substantially improved the cognition and memory abilities of the mice as measured by their coordination of movement in an open field test,
*memory↑,
*Aβ↓, Crocin improved cognitive abilities of AD mice, and reduced Aβ deposition in their brains
*GPx↑, crocin was able to reduce the Aβ1-42 content in the mouse brains, increase the levels of glutathione peroxidase, superoxide dismutase, acetylcholine and choline acetyltransferase,
*SOD↑,
*ChAT↑,
*Ach↑,
*AChE↓, and reduce the levels of ROS and acetylcholinesterase in the serum, cerebral cortex and hypothalamus compared with untreated mice.
*ROS↓,
*p‑Akt↑, crocin upregulated the phosphorylation levels of Akt and mTOR in 24-h l-Glu-exposed cells.
*p‑mTOR↑,
*neuroP↑, crocin-mediated neuroprotection of l-Glu-damaged HT22 cells.

3580-

CUR,

Curcumin Acts as Post-protective Effects on Rat Hippocampal Synaptosomes in a Neuronal Model of Aluminum-Induced Toxicity

in-vivo,

AD,

rat

*ROS↓, curcumin post-treatment significantly improved oxidative damage and morphological alterations, and suppressed cytochrome c and caspase 3 activities
*Cyt‑c↓,
*Casp3↓,
*neuroP↑, curcumin had more therapeutic effects than protective effects in AlCI3-induced neurotoxicity.

461-

CUR,

Curcumin inhibits prostate cancer progression by regulating the miR-30a-5p/PCLAF axis

in-vitro,

Pca,

PC3

10, 20, 30, 40 and 50 µM, 12, 24 and 48 h

in-vitro,

Pca,

DU145

TumCP↓,
TumCMig↓,
TumCI↓,
Apoptosis↑,
miR-30a-5p↑,
PCLAF↓,
Bcl-2↓,
Casp3↓,
BAX↑,
cl‑Casp3↑,

452-

CUR,

Curcumin downregulates the PI3K-AKT-mTOR pathway and inhibits growth and progression in head and neck cancer cells

vitro+vivo,

HNSCC,

SCC9

0, 25, 10, 5, 2.5, 1.25 and 0.75 μM, 24 and 48 h

41uM

vitro+vivo,

HNSCC,

FaDu

vitro+vivo,

HNSCC,

HaCaT

TumCCA↑, arrested cell cycle at phase G2 /M
PI3k/Akt/mTOR↓,
Casp3↑,
EGFR↓, 0.18 fold
EGF↑, Curcumin induced a noticeable increase in the expression of EGF (11.3-fold change)
PRKCG↑, 13.2 fold
p‑Akt↓,
p‑mTOR↓,
RPS6KA1↓, 0.17 fold
EIF4E↓, 0.18 fold
proCasp3↓,

2818-

CUR,

Novel Insight to Neuroprotective Potential of Curcumin: A Mechanistic Review of Possible Involvement of Mitochondrial Biogenesis and PI3/Akt/ GSK3 or PI3/Akt/CREB/BDNF Signaling Pathways

Review,

AD,

*neuroP↑, Curcumin's protective functions against neural cell degeneration due to mitochondrial dysfunction and consequent events such as oxidative stress, inflammation, and apoptosis in neural cells have been documented
*ROS↓, studies show that curcumin exerts neuroprotective effects on oxidative stress.
*Inflam↓,
*Apoptosis↓,
*cognitive↑, cognitive performance to receive the title of neuroprotective
*cardioP↑, Studies have shown that curcumin can induce cell regeneration and defense in multiple organs such as the brain, cardiovascular system,
other↑, It has been shown that chronic use of curcumin in patients with neurodegenerative disorder can cause gray matter volume increase
*COX2↓, Curcumin also decreased the brain protein levels and activity of cyclooxygenase 2 (COX-2)
*IL1β↓, inhibition of IL-1β and TNF-α production, and enhancement of Nf-Kβ inhibition
*TNF-α↓,
NF-kB↓,
*PGE2↓, hronic curcumin therapy has shown a significant decrease in lipopolysaccharide (LPS)-induced elevation of brain prostaglandin E2 (PGE2) synthesis in rats
*iNOS↓, curcumin pretreatment decreased NOS activity in the ischemic rat model
*NO↓, curcumin has been shown to decrease NOS expression and NO production in rat brain tissue
*IL2↓, IL-2 is a cytokine that is anti-inflammatory. Numerous studies have shown that curcumin increases the secretion of IL-2
*IL4↓, curcumin reduced levels of IL-4
*IL6↓, Numerous studies have shown that curcumin in neurodegenerative events attenuates IL-6 production
*INF-γ↓, curcumin reduced the production of INF-γ, as pro-inflammatory cytokine
*GSK‐3β↓, Furthermore, previous findings have confirmed that inhibition of GSK-3β or CREB activation by curcumin has reduced the production of pro-inflammatory mediators under different conditions
*STAT↓, Inhibition of GSK-3β by curcumin has been found to result in reduced STAT activation
*GSH↑, chronic curcumin therapy increased glutathione levels in primary cultivated rat cerebral cortical cells
*MDA↓, multiple doses of 5, 10, 40 and 60 mg/kg) in rodents will inhibit neurodegenerative agent malicious effects, and reduce the amount of MDA and lipid peroxidation in brain tissue
*lipid-P↓,
*SOD↑, Curcumin induces increased production of SOD, glutathione peroxidase (GPx), CAT, and glutathione reductase (GR) activating antioxidant defenses
*GPx↑,
*Catalase↑,
*GSR↓,
*LDH↓, Curcumin decreased lactate dehydrogenase, lipoid peroxidation, ROS, H2O2 and inhibited Caspase 3 and 9
*H2O2↓,
*Casp3↓,
*Casp9↓,
*NRF2↑, ncreased mitochondrial uncoupling protein 2 and increased mitochondrial biogenesis. Nuclear factor-erythroid 2-related factor 2 (Nrf2)
*AIF↓, Curcumin treatment decreased the number of AIF positive nuclei 24 h after treatment in the hippocampus,
*ATP↑, curcumin in hippocampal cells induced an increase in mitochondrial mass leading to increased production of ATP with major improvements in mitochondrial efficiency

3206-

EGCG,

Insights on the involvement of (-)-epigallocatechin gallate in ER stress-mediated apoptosis in age-related macular degeneration

Review,

AMD,

*Ca+2↓, EGCG restores [Ca2+]i homeostasis by decreasing ROS production through inhibition of prohibitin1 which regulate ER-mitochondrial tether site and inhibit apoptosis.
*ROS↓,
*Apoptosis↓,
*GRP78/BiP↓, EGCG downregulated GRP78, CHOP, PERK, ERO1α, IRE1α, cleaved PARP, cleaved caspase 3, caspase 12 and upregulated expression of calnexinin MRPE cells
*CHOP↓,
*PERK↓,
*IRE1↓,
*p‑PARP↓,
*Casp3↓,
*Casp12↓,
*ER Stress↓,
*UPR↓, EGCG mitigates ER stress; maintain calcium homeostasis and inhibition of UPR to control the progression of AMD.

3723-

Gb,

Can We Use Ginkgo biloba Extract to Treat Alzheimer’s Disease? Lessons from Preclinical and Clinical Studies

Review,

AD,

*memory↑, GBE displayed generally consistent anti-AD effects in animal experiments, and it might improve AD symptoms in early-stage AD patients after high doses and long-term administration.
*antiOx↑, Antioxidant properties
*Casp3↓, ↓caspase-3
*APP↓, ↓APP
*AChE↓, ↓AChE activity
*Aβ↓, ↓Aβ oligomers
*5HT↑, ↑5-HT in the striatum
*SOD↓, ↓SOD ↓MDA ↓NO
*MDA↓,
*NO↓,
*GSH↑, ↓SOD ↑GSH ↓MDA
*Bcl-2↑, ↑Bcl-2 ↓Bax
*BAX↑,
*TNF-α↓, ↓TNF-α, IL-1β, ccl-2, iNOS, and IL-10
*IL1β↑,
*iNOS↓,
*IL10↓,
*p‑tau↓, ↓tau phosphorylation
*ROS↓, ↓ROS
*MAOB↓, ↓MAO-B enzyme activity
*cognitive↑, A total of 819 patients who had been diagnosed with AD, or that had AD-like symptoms, received lower SKT scores after GBE treatment for 12 to 24 weeks
*neuroP↑, Neuroprotective Mechanism Analysis
*Apoptosis↓, GBE Inhibits Cell Apoptosis

4236-

H2,

Neuroprotective effects of hydrogen inhalation in an experimental rat intracerebral hemorrhage model

in-vivo,

Stroke,

Forty-five 8-week-old male Sprague-Dawley rats

*neuroP↑, H2 gas administration exerted a neuroprotective effect against early brain injury after ICH through anti-inflammatory, neuroprotective, anti-apoptotic, and antioxidative activity.
*Inflam↓,
*antiOx↑,
*BDNF↑, neuroprotective benefits of hydrogen inhalation might owe to down-regulation of caspase-3-related apoptotic signaling, and upregulation of BDNF expression related
*Casp3↓,

1637-

HCA,

OLST,

Orlistat and Hydroxycitrate Ameliorate Colon Cancer in Rats: The Impact of Inflammatory Mediators

in-vivo,

Colon,

32 mg/kg/day(or)+(135 mg/kg/day(HCA)

rats

TumVol↓, Administration of orlistat and HCA improved the measured markers of a colon tumor
OS↑, orlistat and hydroxycitrate (135 mg/kg/day) decreased ACF incidence and mortality rate in the groups treated with DMH and/or HFD.
*IL6↓, orlistat and hydroxycitrate show decreased IL-6
*NF-kB↓, co-treatment of orlistat and hydroxycitrate record a significant reduction in the NF-kB
*eff↑, protective effects of orlistat and hydroxycitrate (HCA) against dimethylhydrazine (DMH) and high-fat diet (HFD)-i
*Casp3↓, rats supplemented with orlistat and hydroxycitrate show a decrease in the caspase-3 tissue content
*TNF-α↓, orlistat and hydroxycitrate administration to the treated rats substantially reduced the colonic TNF-α tissue
*Catalase↑, orlistat and hydroxycitrate show an increase in the colonic CAT content
*NO↓, orlistat and hydroxycitrate show a significant reduction in the colonic NO content
*ROS↓, orlistat and hydroxycitrate can potentially ameliorate the pathological lesions in the colon and reducing oxidative stress, inflammation, and apoptosis which are considered critical mechanisms for preventing colon cancer
*Inflam↓,
*Apoptosis↓,

4238-

HNK,

Neuropharmacological potential of honokiol and its derivatives from Chinese herb Magnolia species: understandings from therapeutic viewpoint

Review,

AD,

NA,

Park,

*BDNF↑, honokiol treatment led to an improvement in plasma BDNF levels.
*hepatoP↑, prevented liver damage by reducing transaminase levels (ALT and AST), liver OS, and TNF-α activity in mice challenged with LPS.
*ALAT↓,
*AST↓,
*TNF-α↓,
*SIRT3↑, 0.5, 1, 2, 5, 10 and 20 μM Enhanced SIRT3 expression, reduced Aβ levels
*Aβ↓,
*Apoptosis↓, Honokiol exhibited a dose-dependent reduction in hippocampal neural apoptosis, ROS generation, and decline in the membrane potential of mitochondria caused by AβO
*ROS↓,
*MMP↑,
*Ca+2↓, Dose-dependent reduction of ROS, suppression of intracellular Ca elevation, and inhibition of caspase-3 activity
*Casp3↓,
*Ach↑, Increased extracellular acetylcholine release to 165.5 ± 5.78% of the basal level
*PPARγ↑, Increased the expression of PPARγ and PGC1α
*PGC-1α↑,
*motorD↑, Improvement of motor dysfunction due to reversal of nigrostriatal dopaminergic neuronal loss
*TNF-α↓, Attenuated the levels of ROS, TNF-α, and IL-1β in both the in vivo and in vitro
*IL1β↓,

2868-

HNK,

Honokiol: A review of its pharmacological potential and therapeutic insights

Review,

Var,

Review,

Sepsis,

*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 eIF2Î±, 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) 786â0 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

2894-

HNK,

Pharmacological features, health benefits and clinical implications of honokiol

Review,

Var,

Review,

AD,

*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/CCND1↓,
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

4212-

Hup,

Huperzine A Alleviates Oxidative Glutamate Toxicity in Hippocampal HT22 Cells via Activating BDNF/TrkB-Dependent PI3K/Akt/mTOR Signaling Pathway

in-vitro,

Nor,

HT22

*ROS↓, 10 μM HupA for 24 h significantly protected HT22 from cellular damage and suppressed the generation of ROS.
*p‑Akt↓, HupA dramatically prevented the down-regulations of p-Akt, p-mTOR, and p-p70s6 kinase in HT22 cells under oxidative toxicity
*p‑mTOR↓,
*p‑p70S6↓,
*BDNF↑, the protein levels of BDNF and p-TrkB were evidently enhanced after co-treatment with HupA and glutamate in HT22 cells.
*Apoptosis↓, Cellular apoptosis was significantly suppressed (decreased caspase-3 activity and enhanced Bcl-2 protein level) after HupA treatment.
*Casp3↓,
*Bcl-2↑,

2351-

lamb,

Anti-Warburg effect via generation of ROS and inhibition of PKM2/β-catenin mediates apoptosis of lambertianic acid in prostate cancer cells

in-vitro,

Pca,

DU145

in-vitro,

Pca,

PC3

proCasp3↓, LA exerted cytotoxicity, increased sub G1 population and attenuated the expression of pro-Caspase3 and pro-poly (ADP-ribose) polymerase (pro-PARP) in DU145 and PC3 cells
proPARP↓,
LDHA↓, LA reduced the expression of lactate dehydrogenase A (LDHA), glycolytic enzymes such as hexokinase 2 and pyruvate kinase M2 (PKM2) with reduced production of lactate in DU145 and PC3 cells
Glycolysis↓,
HK2↓,
PKM2↓,
lactateProd↓,
p‑STAT3↓, inhibited the expression of p-STAT3, cyclin D1, C-Myc, β-catenin, and p-GSK3β with the decrease of nuclear translocation of p-PKM2
cycD1/CCND1↓,
cMyc↓,
β-catenin/ZEB1↓,
p‑GSK‐3β↓,
ROS↑, LA generated ROS in DU145 and PC3
eff↓, while ROS scavenger NAC (N-acetyl L-cysteine) blocked the ability of LA to reduce p-PKM2, PKM2, β-catenin, LDHA, and pro-caspase3 in DU145 cells.

4292-

LT,

Luteolin for neurodegenerative diseases: a review

Review,

AD,

Review,

Park,

Review,

MS,

Review,

Stroke,

*Inflam↓, luteolin, showing significant anti-inflammatory, antioxidant, and neuroprotective activity.
*antiOx↑,
*neuroP↑,
*BioAv↝, To increase the bioavailability of luteolin, several delivery methods have been developed; the most thoroughly studied include lipid carriers like liposomes and nanoformulations
*BBB↑, luteolin given intraperitoneally (ip) to mice can readily cross the blood-brain barrier (BBB) and enter the brain
*TNF-α↓, nhibiting pro-inflammatory mediators such as cyclooxygenase-2 (COX-2), nitric oxide (NO), TNF-α, IL-β, IL-6, IL-8, IL-31, and IL-33 in several in vitro models of AD
*IL1β↓,
*IL6↓,
*IL8↓,
*IL33↓,
*NF-kB↓, inhibition of the NF-кB pathway
*BACE↓, leads to the inhibition of a downstream target– β-site amyloid precursor protein cleaving enzyme (BACE1), which is a key mediator in forming Aβ fibrils in AD pathology
*ROS↓, anti-oxidant activity mainly by reducing ROS levels and increasing SOD activity in in vitro models of AD
*SOD↑,
*HO-1↑, increase the expression of antioxidant enzymes such as heme oxygenase-1 (HO-1) via the nuclear factor erythroid 2–related factor 2/ antioxidant responsive element (Nrf-2/ARE) complex activation
*NRF2↑,
*Casp3↓, reducing the levels of caspase-3 and − 9 and improving the B-cell lymphoma protein 2/Bcl-2-associated X protein (Bcl-2/Bax) ratio, as it was reported in in vitro models of AD
*Casp9↑,
*Bax:Bcl2↓,
*UPR↑, enhancing the unfolded protein response (UPR) pathway, leading to an increase in endoplasmic reticulum (ER) chaperone GRP78 and a decrease in the expression of UPR-targeted pro-apoptotic genes via the MAPK pathway.
*GRP78/BiP↑,
*Aβ↓, evidence that suggests that luteolin can directly influence the formation of Aβ plaques by selectively inhibiting the activity of N-acetyl-α-galactosaminyltransferase (ppGalNAc-T) isoforms
*GSK‐3β↓, inactivating the glycogen synthase kinase-3 alpha (GSK-3α) isoform, suppressing Aβ and promoting tau disaggregation
*tau↓,
*CREB↑, luteolin promoted phosphorylation and activation of cAMP response element-binding protein (CREB) leading to the increased miR-132 expression, and eventually neurite outgrowth in PC12 cells
*ATP↑, ROS production was decreased by 40%, MMP levels were restored close to control N2a levels (202%), and ATP levels were improved by 444%).
*cognitive↑, protective effect of luteolin against cognitive dysfunction was also reported in the streptozotocin
*BloodF↑, Luteolin increased regional cerebral blood flow values, alleviated the leakage of the lumen of vessels, and protected the integrity of BBB
*BDNF↑, increasing the level of brain-derived neurotrophic factor (BDNF) and tyrosine kinase receptor (TrkB) expression in the cerebral cortex
*TrkB↑,
*memory↑, luteolin supplementation significantly ameliorated memory and cognitive deficits in 3 × Tg-AD mice.
*PPARγ↑, attenuated mitochondrial dysfunction via peroxisome proliferator-activated receptor gamma (PPARγ) activation.
*eff↑, combination of luteolin with another compound– l-theanine (an amino acid found in tea) also improved AD-like symptoms in the Aβ25–35-treated rats

2907-

LT,

Protective effect of luteolin against oxidative stress‑mediated cell injury via enhancing antioxidant systems

in-vitro,

Nor,

Chinese hamster lung fibroblasts (V79-4)

*ROS↓, Intracellular ROS levels and damage to cellular components such as lipids and DNA in H2O2-treated cells were significantly decreased by luteolin pretreatment.
*Casp9↓, Luteolin suppressed active caspase-9 and caspase-3 levels while increasing Bcl-2 expression and decreasing Bax protein levels.
*Casp3↓,
*Bcl-2↑,
*BAX↓,
*GSH↑, luteolin restored levels of glutathione that was reduced in response to H2O2.
*SOD↑, luteolin enhanced the activity and protein expressions of superoxide dismutase, catalase, glutathione peroxidase, and heme oxygenase-1.
*Catalase↑,
*GPx↑,
*HO-1↑,
*antiOx↑, upregulating antioxidant enzymes.
*lipid-P↓, protective effect of luteolin against lipid peroxidation
*p‑γH2AX↓, showed that luteolin pretreatment diminished expression levels of phospho-H2A.X in H2O2-exposed cells
eff↑, promising therapeutic agent for management and treatment of conditions such as COPD and pulmonary fibrosis.

2919-

LT,

Luteolin as a potential therapeutic candidate for lung cancer: Emerging preclinical evidence

Review,

Var,

RadioS↑, it can be used as an adjuvant to radio-chemotherapy and helps to ameliorate cancer complications
ChemoSen↑,
chemoP↑,
*lipid-P↓, ↓LPO, ↑CAT, ↑SOD, ↑GPx, ↑GST, ↑GSH, ↓TNF-α, ↓IL-1β, ↓Caspase-3, ↑IL-10
*Catalase↑,
*SOD↑,
*GPx↑,
*GSTs↑,
*GSH↑,
*TNF-α↓,
*IL1β↓,
*Casp3↓,
*IL10↑,
NRF2↓, Lung cancer model ↓Nrf2, ↓HO-1, ↓NQO1, ↓GSH
HO-1↓,
NQO1↓,
GSH↓,
MET↓, Lung cancer model ↓MET, ↓p-MET, ↓p-Akt, ↓HGF
p‑MET↓,
p‑Akt↓,
HGF/c-Met↓,
NF-kB↓, Lung cancer model ↓NF-κB, ↓Bcl-XL, ↓MnSOD, ↑Caspase-8, ↑Caspase-3, ↑PARP
Bcl-2↓,
SOD2↓,
Casp8↑,
Casp3↑,
PARP↑,
MAPK↓, LLC-induced BCP mouse model ↓p38 MAPK, ↓GFAP, ↓IBA1, ↓NLRP3, ↓ASC, ↓Caspase1, ↓IL-1β
NLRP3↓,
ASC↓,
Casp1↓,
IL6↓, Lung cancer model ↓TNF‑α, ↓IL‑6, ↓MuRF1, ↓Atrogin-1, ↓IKKβ, ↓p‑p65, ↓p-p38
IKKα↓,
p‑p65↓,
p‑p38↑,
MMP2↓, Lung cancer model ↓MMP-2, ↓ICAM-1, ↓EGFR, ↓p-PI3K, ↓p-Akt
ICAM-1↓,
EGFR↑,
p‑PI3K↓,
E-cadherin↓, Lung cancer model ↑E-cadherin, ↑ZO-1, ↓N-cadherin, ↓Claudin-1, ↓β-Catenin, ↓Snail, ↓Vimentin, ↓Integrin β1, ↓FAK
ZO-1↑,
N-cadherin↓,
CLDN1↓,
β-catenin/ZEB1↓,
Snail↓,
Vim↑,
ITGB1↓,
FAK↓,
p‑Src↓, Lung cancer model ↓p-FAK, ↓p-Src, ↓Rac1, ↓Cdc42, ↓RhoA
Rac1↓,
Cdc42↓,
Rho↓,
PCNA↓, Lung cancer model ↓Cyclin B1, ↑p21, ↑p-Cdc2, ↓Vimentin, ↓MMP9, ↑E-cadherin, ↓AIM2, ↓Pro-caspase-1, ↓Caspase-1 p10, ↓Pro-IL-1β, ↓IL-1β, ↓PCNA
Tyro3↓, Lung cancer model ↓TAM RTKs, ↓Tyro3, ↓Axl, ↓MerTK, ↑p21
AXL↓,
CEA↓, B(a)P induced lung carcinogenesis ↓CEA, ↓NSE, ↑SOD, ↑CAT, ↑GPx, ↑GR, ↑GST, ↑GSH, ↑Vitamin E, ↑Vitamin C, ↓PCNA, ↓CYP1A1, ↓NF-kB
NSE↓,
SOD↓,
Catalase↓,
GPx↓,
GSR↓,
GSTs↓,
GSH↓,
VitE↓,
VitC↓,
CYP1A1↓,
cFos↑, Lung cancer model ↓Claudin-2, ↑p-ERK1/2, ↑c-Fos
AR↓, ↓Androgen receptor
AIF↑, Lung cancer model ↑Apoptosis-inducing factor protein
p‑STAT6↓, ↓p-STAT6, ↓Arginase-1, ↓MRC1, ↓CCL2
p‑MDM2↓, Lung cancer model ↓p-PI3K, ↓p-Akt, ↓p-MDM2, ↑p-P53, ↓Bcl-2, ↑Bax
NOTCH1↓, Lung cancer model ↑Bax, ↑Cleaved-caspase 3, ↓Bcl2, ↑circ_0000190, ↓miR-130a-3p, ↓Notch-1, ↓Hes-1, ↓VEGF
VEGF↓,
H3↓, Lung cancer model ↑Caspase 3, ↑Caspase 7, ↓H3 and H4 HDAC activities
H4↓,
HDAC↓,
SIRT1↓, Lung cancer model ↑Bax/Bcl-2, ↓Sirt1
ROS↑, Lung cancer model ↓NF-kB, ↑JNK, ↑Caspase 3, ↑PARP, ↑ROS, ↓SOD
DR5↑, Lung cancer model ↑Caspase-8, ↑Caspase-3, ↑Caspase-9, ↑DR5, ↑p-Drp1, ↑Cytochrome c, ↑p-JNK
Cyt‑c↑,
p‑JNK↑,
PTEN↓, Lung cancer model 1/5/10/30/50/80/100 μmol/L ↑Cleaved caspase-3, ↑PARP, ↑Bax, ↓Bcl-2, ↓EGFR, ↓PI3K/Akt/PTEN/mTOR, ↓CD34, ↓PCNA
mTOR↓,
CD34↓,
FasL↑, Lung cancer model ↑DR 4, ↑FasL, ↑Fas receptor, ↑Bax, ↑Bad, ↓Bcl-2, ↑Cytochrome c, ↓XIAP, ↑p-eIF2α, ↑CHOP, ↑p-JNK, ↑LC3II
Fas↑,
XIAP↓,
p‑eIF2α↑,
CHOP↑,
LC3II↑,
PD-1↓, Lung cancer model ↓PD-L1, ↓STAT3, ↑IL-2
STAT3↓,
IL2↑,
EMT↓, Luteolin exerts anticancer activity by inhibiting EMT, and the possible mechanisms include the inhibition of the EGFR-PI3K-AKT and integrin β1-FAK/Src signaling pathways
cachexia↓, luteolin could be a potential safe and efficient alternative therapy for the treatment of cancer cachexi
BioAv↑, A low-energy blend of castor oil, kolliphor and polyethylene glycol 200 increases the solubility of luteolin by a factor of approximately 83
*Half-Life↝, ats administered an intraperitoneal injection of luteolin (60 mg/kg) absorbed it rapidly as well, with peak levels reached at 0.083 h (71.99 ± 11.04 μg/mL) and a prolonged half-life (3.2 ± 0.7 h)
*eff↑, Luteolin chitosan-encapsulated nano-emulsions increase trans-nasal mucosal permeation nearly 6-fold, drug half-life 10-fold, and biodistribution of luteolin in brain tissue 4.4-fold after nasal administration

4231-

Lut,

Luteolin and its antidepressant properties: From mechanism of action to potential therapeutic application

Review,

AD,

*PSD95↑, upregulating the expression of synaptophysin, postsynaptic density protein 95, brain-derived neurotrophic factor, B cell lymphoma protein-2, superoxide dismutase, and glutathione S-transferase; and decreasing the expression of malondialdehyde, caspa
*BDNF↑,
*SOD↑,
*GSTA1↑,
*MDA↑,
*Casp3↓,
*Mood↑, antidepressant effects of luteolin are mediated by various mechanisms, including anti-oxidative stress, anti-apoptosis, anti-inflammation, anti-endoplasmic reticulum stress, dopamine transport, synaptic protection, hypothalamic–pituitary–adrenal axi
*antiOx↑,
*Apoptosis↓,
*Inflam↓,
*ER Stress↓,

3531-

Lyco,

Lycopene attenuates the inflammation and apoptosis in aristolochic acid nephropathy by targeting the Nrf2 antioxidant system

in-vivo,

Nor,

rats

*NRF2↑, After LYC intervened in the body, it activated Nrf2 nuclear translocation and its downstream HO-1 and NQO1 antioxidant signaling pathways
*HO-1↑, Lycopene activates Nrf2-HO-1 antioxidant pathway to inhibit oxidative stress injury induced by AAI exposure in NRK52E cells
*NQO1↑,
*ROS↓, LYC inhibited ROS production by renal tubular epithelial cells, and alleviated mitochondrial damage.
*mtDam↓,
*Bcl-2↑, LYC was able to up-regulate the expression of Bcl-2, down-regulate Bax expression and inhibit the activation of cleaved forms of Caspase-9 and Caspase-3, which finally attenuated the apoptosis
*BAX↓,
*Casp9↓,
*Casp3↓,
*Apoptosis↓,
*RenoP↑, Interestingly, there was a significant improvement in damaged renal tissue in mice with AAN after lycopene intervention
*lipid-P↓, lycopene significantly decreased the expression of AAI-induced lipid peroxidation product (MDA), and increased the expression of antioxidant enzyme systems (T-AOC, SOD, and GSH-PX)
*SOD↑,
*GPx↑,
*Inflam↓, Lycopene improves inflammatory responses in the kidneys of AAN mice
*TNF-α↓, TNF-α, IL-6, IL-10, was increased and the expression of IL-12 was decreased in the kidneys of model mice compared with the control group. However, LYC intervention reversed the expression of these genes in a dose-dependent manner
*IL6↓,
*IL10↓,

3263-

Lyco,

Lycopene protects against myocardial ischemia-reperfusion injury by inhibiting mitochondrial permeability transition pore opening

in-vitro,

Nor,

H9c2

in-vitro,

Stroke,

*Apoptosis↓, LP pretreatment significantly increased cell viability, reduced myocardial infarct size and decreased the apoptosis rate.
*MMP↑, decrease of ΔΨm were attenuated by LP and the expressions of cytochrome c, APAF-1, cleaved caspase-9 and cleaved caspase-3 were also decreased by LP
*Cyt‑c↓,
*APAF1↓,
*cl‑Casp9↓,
*cl‑Casp3↓,
*Bcl-2↑, LP treatment markedly increased Bcl-2 expression, decreased Bax expression and the Bax/Bcl-2 ratio.
*BAX↓,
cardioP↑, myocardial ischemia-reperfusion injury (MIRI). LP protects against MIRI by inhibiting MPTP opening, partly through the modulation of Bax and Bcl-2.

1777-

MEL,

Melatonin as an antioxidant: under promises but over delivers

Review,

NA,

*ROS↓, uncommonly effective in reducing oxidative stress under a remarkably large number of circumstances
*Fenton↓, reportedly chelates transition metals, which are involved in the Fenton/Haber-Weiss reactions
*antiOx↑, credible evidence to suggest that melatonin should be classified as a mitochondria-targeted antioxidant
*toxicity∅, uncommonly high-safety profile of melatonin also bolsters this conclusion.
*GPx↑, melatonin was found to stimulate antioxidative enzymes including glutathione peroxidase and glutathione reductase
*GSR↑,
*GSH↑, melatonin upregulates the synthesis of glutathione
*NO↓, neutralize nitrogen-based toxicants, i.e., nitric oxide
*Iron↓, Melatonin chelates both iron (III) and iron (II), which is the form that participates in the Fenton reaction to generate the hydroxyl radical
*Copper↓, copper-chelating ability of melaton
*IL1β↓, significant reductions in plasma cardiac troponin 1, interleukin 1 beta, inducible nitric oxide synthase (iNOS) and caspase 3 due to melatonin
*iNOS↓,
*Casp3↓,
*BBB↑, melatonin readily crosses the blood-brain barrier;
*RenoP↑, Published reports haveshown that the lung,231, 232 liver, 233- 235 kidney,236 pancreas,237 intestine,238 urinary bladder,239,240 corpus cavernosum,241 skeletal muscle242, 243 spinal cord244, 245 and stem cells246 are alsoprotected by melatonin.
chemoP↑, Melatonin has not been found to interfere with the efficacy of prescription drugs. Doxorubicin, if given it in combination with melatonin may allow the use of a larger dose with greater efficacy.
*Ca+2↝, Moreover, melatonin regulates free Ca2+ movement intracellularly
eff↑, elatonin was found to exaggerate the cancer inhibiting actions of pitavastatin270 and pravastatin271 against breast cancer in experimental studies
*PKCδ?, major targets by which melatonin reduces methamphetamine-related neuronal damage is due to the inhibition of the PKCδ gene
ChemoSen↑, at least some cases melatonin reduces the toxicity of these pharmacological agents in normal cells256, 289, 290 while enhancing the cancer-killing actions (also, see below) of conventional chemotherapeutic agents.256, 291-293
eff↑, TRAIL was combined with melatonin for the treatment of A172 and U87 human glioblastoma cells, however, apoptotic cell death was greatly exaggerated over that caused by TRAIL alone
Akt↓, in GBM: observed effect was related to a modulation of protein kinase c which reduced Akt activation resulting in a rise in death receptor 5 (DR5) levels;
DR5↑,
selectivity↑, The pro-oxidant action of melatonin is common in cancer cells while in normal cells the indoleamine is a powerful antioxidant.
ROS↑, cancer cells
eff↑, human lung adenocarcinoma cells (SK-LV-1) showed that melatonin also increased their sensitivity to the chemotherapy, cisplatin.

4147-

MF,

PEMFs Restore Mitochondrial and CREB/BDNF Signaling in Oxidatively Stressed PC12 Cells Targeting Neurodegeneration

in-vitro,

AD,

PC12

PC12 cells exposed to hydrogen peroxide (H2O2)

*ROS↓, PEMF treatment significantly counteracted H2O2- and Aβ-induced cytotoxicity by restoring cell viability, reducing reactive oxygen species production, and improving catalase activity.
*Catalase↑,
*MMP↑, PEMFs preserved the mitochondrial membrane potential and decreased caspase-3 activation and chromatin condensation
*Casp3↓,
*p‑ERK↓, Mechanistically, PEMFs inhibited ERK phosphorylation and enhanced cAMP levels, CREB phosphorylation, and BDNF expression
*cAMP↑,
*p‑CREB↑,
*BDNF↑,
*neuroP↑, PEMFs modulate multiple stress response systems, promoting neuroprotection under oxidative and amyloidogenic conditions.

506-

MF,

doxoR,

Pulsed Electromagnetic Field Stimulation Promotes Anti-cell Proliferative Activity in Doxorubicin-treated Mouse Osteosarcoma Cells

in-vitro,

OS,

LM8

5 mT, 200 Hz

x2 fold improved

The IC50 for combined PEMF and doxorubicin was about 2-fold lower than that of doxorubicin alone, suggesting that PEMF enhanced the antiproliferative activity of doxorubicin.

TumCP↓,
p‑CHK1↓, reducing the increased expression of total IĸB and phosphorylated-CHK1 induced by doxorubicin
Ca+2↑, caused by PEMF alone
Casp3↓, PEMF stimulation significantly reduced the enhancement of caspase 3/7 activity by doxorubicin at 24 h
Casp7↓, PEMF stimulation significantly reduced the enhancement of caspase 3/7 activity by doxorubicin at 24 h
p‑BAD↓,
ChemoSen↑, Our results indicate that combination of PEMF and doxorubicin could be a novel chemotherapeutic strategy.

Showing Research Papers: 1 to 50 of 80
Page 1 of 2 Next

* indicates research on normal cells as opposed to diseased cells
Total Research Paper Matches: 80

Pathway results for Effect on Cancer / Diseased Cells:

Pathway results for Effect on Normal Cells:

Redox & Oxidative Stress ⓘ

4-HNE↓, 1, antiOx↑, 16, Catalase↑, 12, Copper↓, 1, Fenton↓, 1, GPx↑, 13, GSH↓, 1, GSH↑, 13, GSR↓, 1, GSR↑, 2, GSTA1↑, 1, GSTs↑, 2, H2O2↓, 1, HDL↑, 1, HO-1↓, 2, HO-1↑, 8, Iron↓, 1, Keap1↓, 1, Keap1↑, 1, lipid-P↓, 7, MDA↓, 8, MDA↑, 2, NOX4↓, 1, NQO1↑, 1, NRF2↑, 12, Prx↑, 1, ROS↓, 32, SIRT3↑, 2, SOD↓, 1, SOD↑, 16, SOD1↑, 1, TAC↑, 1, Thiols↑, 1,

Mitochondria & Bioenergetics ⓘ

AIF↓, 1, ATP↑, 2, Insulin↑, 1, MMP↑, 6, mtDam↓, 1, PGC-1α↑, 2,

Core Metabolism/Glycolysis ⓘ

ALAT↓, 3, AMPK↑, 1, cAMP↑, 2, CREB↑, 1, p‑CREB↑, 1, GAPDH↑, 1, glucose↝, 1, GLUT2↑, 1, HMG-CoA↓, 1, LDH↓, 1, NADPH↓, 1, PPARγ↑, 3, SIRT1↑, 1,

Cell Death ⓘ

Akt↓, 1, Akt↑, 1, p‑Akt↓, 1, p‑Akt↑, 1, APAF1↓, 1, Apoptosis↓, 13, BAD↓, 1, BAX↓, 7, BAX↑, 1, Bax:Bcl2↓, 3, Bcl-2↑, 7, Casp1↓, 1, Casp12↓, 1, Casp3↓, 32, cl‑Casp3↓, 7, Casp9↓, 8, Casp9↑, 1, cl‑Casp9↓, 1, Cyt‑c↓, 5, Fas↓, 1, HGF/c-Met↑, 1, iNOS↓, 6, MAPK↓, 2,

Kinase & Signal Transduction ⓘ

p‑p70S6↓, 1,

Transcription & Epigenetics ⓘ

Ach↑, 4, other↑, 2, other↝, 3,

Protein Folding & ER Stress ⓘ

CHOP↓, 3, CHOP↑, 1, ER Stress↓, 2, GRP78/BiP↓, 2, GRP78/BiP↑, 2, GRP94↑, 1, HSP70/HSPA5↑, 2, HSPs↑, 1, IRE1↓, 1, PERK↓, 1, UPR↓, 1, UPR↑, 1,

DNA Damage & Repair ⓘ

DNAdam↓, 2, PARP↓, 1, p‑PARP↓, 1, cl‑PARP1↓, 1, p‑γH2AX↓, 1,

Proliferation, Differentiation & Cell State ⓘ

ERK↓, 1, ERK↑, 2, p‑ERK↓, 1, p‑ERK↑, 1, GSK‐3β↓, 4, p‑mTOR↓, 1, p‑mTOR↑, 1, PI3K↓, 1, PI3K↑, 1, STAT↓, 1, TRPM7↓, 1, TRPM7⇅, 1,

Migration ⓘ

5LO↓, 1, AntiAg↑, 2, APP↓, 1, Ca+2↓, 4, Ca+2↝, 1, MMP3↓, 1, MMP9↓, 1, PKCδ?, 1, p‑Rac1↓, 1, Rho↓, 1, TXNIP↓, 1, ZO-1↓, 1,

Angiogenesis & Vasculature ⓘ

NO↓, 5,

Barriers & Transport ⓘ

BBB↓, 1, BBB↑, 5, P-gp↓, 1,

Immune & Inflammatory Signaling ⓘ

COX1↓, 1, COX2↓, 5, CRP↓, 1, CXCR4↓, 1, IKKα↓, 1, IKKα↑, 1, IL10↓, 3, IL10↑, 1, IL17↓, 1, IL18↓, 1, IL1β↓, 8, IL1β↑, 1, IL2↓, 2, IL33↓, 1, IL4↓, 1, IL6↓, 9, IL8↓, 1, INF-γ↓, 2, Inflam↓, 18, NF-kB↓, 8, p65↓, 1, PGE2↓, 4, TLR4↓, 2, TNF-α↓, 15,

Synaptic & Neurotransmission ⓘ

5HT↑, 1, AChE↓, 5, BChE↓, 1, BDNF↓, 1, BDNF↑, 7, ChAT↑, 3, PSD95↑, 1, tau↓, 3, p‑tau↓, 2, TrkB↑, 1,

Protein Aggregation ⓘ

AGEs↓, 1, Aβ↓, 8, BACE↓, 2, MAOB↓, 1, NLRP3↓, 2,

Drug Metabolism & Resistance ⓘ

BioAv↓, 2, BioAv↑, 3, BioAv↝, 2, Dose⇅, 1, Dose↝, 3, eff↑, 7, eff↝, 1, Half-Life↓, 1, Half-Life↝, 1,

Clinical Biomarkers ⓘ

ALAT↓, 3, ALP↓, 1, AST↓, 3, BloodF↑, 1, CRP↓, 1, IL6↓, 9, LDH↓, 1,

Functional Outcomes ⓘ

cardioP↑, 4, chemoP↑, 1, cognitive↓, 1, cognitive↑, 11, hepatoP↑, 4, memory↑, 7, Mood↑, 1, motorD↑, 1, neuroP↑, 17, Pain↓, 1, radioP↑, 1, RenoP↑, 4, toxicity∅, 2, Wound Healing↑, 1,

Infection & Microbiome ⓘ

Bacteria↓, 2, Diar↓, 1,
Total Targets: 195

Scientific Paper Hit Count for: Casp3, CPP32, Cysteinyl aspartate specific proteinase-3

8 Thymoquinone
5 Curcumin
4 Propolis -bee glue
4 Shikonin
3 Crocetin
3 Honokiol
3 Luteolin
3 Magnetic Fields
3 Quercetin
2 Alpha-Lipoic-Acid
2 Apigenin (mainly Parsley)
2 Artemisinin
2 Ashwagandha(Withaferin A)
2 Berberine
2 Carvacrol
2 Chlorogenic acid
2 Lycopene
2 Silymarin (Milk Thistle) silibinin
2 Chemotherapy
1 3-bromopyruvate
1 Acetyl-l-carnitine
1 Radiotherapy/Radiation
1 Baicalein
1 Bacopa monnieri
1 Bromelain
1 borneol
1 Boron
1 Caffeic acid
1 Caffeic Acid Phenethyl Ester (CAPE)
1 Celastrol
1 Chrysin
1 EGCG (Epigallocatechin Gallate)
1 Ginkgo biloba
1 Hydrogen Gas
1 HydroxyCitric Acid
1 Orlistat
1 Huperzine A/Huperzia serrata
1 lambertianic acid
1 Lutein
1 Melatonin
1 doxorubicin
1 Naringin
1 Phenylbutyrate
1 Piperine
1 Piperlongumine
1 Resveratrol
1 Rosmarinic acid
1 Taurine
1 Cisplatin
1 Vitamin D3

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#:%  Target#:42  State#:%  Dir#:1
  wNotes=on  sortOrder:rid,rpid

Casp3 Cancer Research Results

Pathway results for Effect on Cancer / Diseased Cells:

Redox & Oxidative Stress ⓘ

Mitochondria & Bioenergetics ⓘ

Core Metabolism/Glycolysis ⓘ

Cell Death ⓘ

Transcription & Epigenetics ⓘ

Protein Folding & ER Stress ⓘ

Autophagy & Lysosomes ⓘ

DNA Damage & Repair ⓘ

Cell Cycle & Senescence ⓘ

Proliferation, Differentiation & Cell State ⓘ

Migration ⓘ

Angiogenesis & Vasculature ⓘ

Barriers & Transport ⓘ

Immune & Inflammatory Signaling ⓘ

Protein Aggregation ⓘ

Hormonal & Nuclear Receptors ⓘ

Drug Metabolism & Resistance ⓘ

Clinical Biomarkers ⓘ

Functional Outcomes ⓘ

Pathway results for Effect on Normal Cells:

Redox & Oxidative Stress ⓘ

Mitochondria & Bioenergetics ⓘ

Core Metabolism/Glycolysis ⓘ

Cell Death ⓘ

Kinase & Signal Transduction ⓘ

Transcription & Epigenetics ⓘ

Protein Folding & ER Stress ⓘ

DNA Damage & Repair ⓘ

Proliferation, Differentiation & Cell State ⓘ

Migration ⓘ

Angiogenesis & Vasculature ⓘ

Barriers & Transport ⓘ

Immune & Inflammatory Signaling ⓘ

Synaptic & Neurotransmission ⓘ

Protein Aggregation ⓘ

Drug Metabolism & Resistance ⓘ

Clinical Biomarkers ⓘ

Functional Outcomes ⓘ

Infection & Microbiome ⓘ

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