Table 1.

Preventive and therapeutic properties of OA against various chronic diseases.

Disease	In Vitro/ In Vivo	Dose/Conc.	Model	Mechanism of Action or Outcome	References
Cancer
Breast cancer	In vitro	50, 100, 200 μM	MDA-MB-231, MCF-7	↑SIRT3, SOD2, PHD activity, ↓glycolysis, HIF-1α, mitochondrial ROS	[76]
	In vivo	100 mg/kg	MDA-MB-231 xenograft	↑SIRT3, SOD2, ↓tumor volume and mass, glycolysis, HIF-1α, hexokinase II,	[76]
	In vitro	10, 20, 40 μM	MDA-MB-231	↑E-cadherin, p27, ↓cell proliferation, CDK2, cyclin E, vimentin, N-cadherin, EMT, migration, invasion, COX-2, NF-κB, IL-6, IL-8, TNF-α	[114]
Cervical cancer	In vitro	5, 20, 80 μM	HeLa	↑Procaspase-3, procaspase-8, procaspase-9, cleaved PARP, apoptosis ↓Bcl-2, cell growth	[75]
	In vivo	40, 80 mg/kg	HeLa xenograft	↑Cleaved PARP, ↓tumor growth, Bcl-2, procaspase-3, procaspase-8, procaspase-9	[75]
Colon cancer	In vitro	200 μM/L	HT-29 cells	↑Bax, p53, PARP, procaspase-3, ROS, ↓COX-2, Bcl-2, PGE2	[118]
	In vivo	100 mg/kg	HT-29	↓Tumor, COX-2	[118]
	In vitro	100 μM/L	HCT-116	↑Caspase-3, caspase-9, Bax, ROS, Nrf2, HO-1, NQO1, ↓Bcl-2,	[56]
	In vivo	50, 100, 200 mg/kg	HCT-116 xenograft	↑Nrf-2, apoptosis, ↓tumor growth	[56]
ESCC	In vitro	10, 50 μM	TE13, ECA109	↑Apoptosis, G2/M arrest, radiosensitization, ↓cyclin B1, cdc2	[136]
Glioma	In vitro	25, 50, 75, 100, 125, 150, 175, 200 μM	U251, U118, U87	↑Autophagy, Beclin, ↓Akt, ERK Notch-1, Mcl-1	[126]
	In vitro	50 μM	C6, U251	↑Apoptosis, ↓p-Akt, β-catenin, IP3R1, p-GSK-3β	[94]
	In vivo	150 mg/kg	C6 xenograft	↑Apoptosis, ↓Akt/β-catenin, IP3R1, p-GSK-3β,	[94]
Hematological malignancies	In vitro	60 μM	K562, KU812 with M2-10B4	↑Apoptosis, ↓CXCL12/CXCR7, p-ERK, p-BAD, survivin	[130]
	In vivo	200 mg/kg	K562 xenograft	↑Apoptosis, ↓CXCR7, p-ERK, CD13+ cells	[130]
	In vitro	20 μM	HL-60, NB4	↑TNF-α sensitivity, ↓tRXRα, PI3K/Akt, NF-κB	[83]
	In vivo	80 mg/kg	AML cell xenograft	↑Survival, ↓NF-κB, AML cell population	[83]
	In vitro	10–160 μM	t (8i21)-positive kasumi-l, primary AML cells	↑C/EBPα, p21, CD11b/CD14, ↓AML 1/ETO, HDAC-1	[129]
	In vivo	200 mg/kg	NOD/SCID mice	↑Survival, ↓HDAC-1, AML1/ETO, CD45+ cells,	[129]
Hepatocellular carcinoma	In vitro	50 μM	HepG2 cells	↑Apoptosis, p53, cleaved PARP, ↓Cell viability, TS and DPD mRNA, COX-2, Bcl-2, procaspase-3	[119]
	In vivo	1000 mg/kg/day	H22 xenograft	↓Tumor growth, tumor weight	[119]
	In vitro	12.5, 25, 50 μM	SMMC-7721	↑NAG1, acetylation of C/EBPβ, ↓migration, invasion, EMT, p-SMAD2/3, TGF-β1/SMAD axis	[120]
	In vivo	200 mg/kg	SMMC-7721	↑E-cadherin, ↓pulmonary metastasis, vimentin, twist1	[120]
Kaposi’s sarcoma	In vitro	20–1000 μM	KSHVvIL-6	↑Apoptosis, PPARγ, invasion, neovascularization, ↓Prox1, VEGFR3, LYVE-1, podoplanin	[80]
Lung cancer	In vitro	40 μM	H460	↓Tregs, TGF-β, NF-κB	[134]
	In vivo	60 mg/kg	H460 xenograft	↓Tumor, Tregs, FOXP3,	[134]
	In vitro	50 μM/L	H460, A549, 95D, PC9, HCC827, H1975	↑Apoptosis, ↓tumor, XPC transcription	[135]
	In vivo	50 mg/kg	H460 xenografts	↑Cisplatin sensitivity, ↓tumor growth, Ki67, PCNA, XPC expression	[135]
Skin cancer	In vitro	20 μM	JB6P+	↓Transformation, inflammation, SHCBP1, NF-κB p65, IL-1β, IL-6, IL-18, TNF-α, COX-2, iNOS,	[137]
	In vivo	40 mg/kg	DMBA/TPA mice	↓SHCBP1, IL-1β, IL-4, IL-6, IL-18, TNF-α, NLRP3, PCNA tumorigenesis, incidence rate, tumor multiplicity, epidermal thickness	[137]
Cardiovascular diseases
Cardioprotective effects	In vivo	40 mg/kg	C57BL/6 mice	↑Body weight, SIRT1, cAMP/protein kinase A, improved contractile function, Nrf2, HO-1, NQO1, Bcl-2, ↓plasma and cardiac CK-MB, LDH, LVEDP, 4-HNE, nitrotyrosine, gp91phox, NADPH oxidase 4, p47phox, p67phox, IL-6, IL-1β, MMP-2, MMP-9, p-IκBα, caspase 3/7 activity, PARP activity, apoptosis	[143]
Endotoxemia	In vivo	10, 20 μM	Sprague-Dawley rats	↑Coronary flow, LVDP ↓CPP	[55]
Hind limb ischemia	In vivo	10 mg/kg/day	C57BL/6 mice	↑VEGFA, Ang-2, FGF-2, PDGF-BB, angiogenesis, perfusion recovery, regeneration of myocytes ↓IL-1β, tissue injury, ischemia, apoptosis of myocytes	[153]
Chronic liver diseases
Acute liver injury	In vivo	60 mg/kg	C57 BL/6 mice	↑IL-1Ra, HGF, EGF, PCNA positive cells, survival, ↓IL-1β, IL-6, TNF-α, necrotic areas	[69]
	In vivo	15, 30, 60 mg/kg	BALB/c mice	↑Nrf 2, HO-1, ↓AST, ALT, TNF-α, MDA, MPO activity, NF-κB, TLR4, necrosis	[159]
ALD	In vitro	10–100 μM	LO2 cells	↑YAP, ↓AST, ALT, LDH, p21, p16 and HMGA1	[169]
	In vivo	30 mg/kg	ICR mice	↑YAP, ↓AST, ALT, ALP, lipid vacuolation	[169]
	In vitro	10, 20, 40 μM	LO2 cells	↑Mfn2, PGC-1α, ↓LDH, IL-1β, IL-18, caspase-1, NF-κB, ROS, NLRP3 inflammasome	[77]
	In vivo	40 mg/kg	ICR mice	↓Inflammation, lipid accumulation, ALT, ALP, AST	[77]
Hepatic steatosis	In vitro	10, 20, 40 μM	LO2 cells	↑CPT1, PPARα, PPARγ, ↓lipid droplet accumulation, HIF-1α, apoptosis, SREBP1, FAS, SCD1	[59]
	In vivo	30 mg/kg	ICR mice	↓ Apoptosis, ALT, AST, ALP, IL-6, IL-8, TNF-α	[59]
Hepatic fibrosis	In vitro	20, 30, 40 μM	HSCs	↑LC3-B, Atg3, Atg4, Atg5, Atg7, Atg9, beclin, Atg12, Atg14, ↓α-SMA, desmin, α1collagen, fibronectin, TGF-β, TNF-α, p62	[162]
	In vivo	20, 30, 40 mg/kg	ICR mice	↑LC3-B, Atg5, beclin1, ↓AST, ALT, ALP, α-SMA, α1collagen, fibronectin, PDGF-βR, TGF-βR1, p62, fibrosis lesions, necrosis, inflammation	[162]
	In vitro	20, 30, 40 μM	HSCs	↓Hexokinase II, LDH-A, PFK1, PKM2, actin stress fibers, p-MLC2, contraction	[163]
	In vivo	40 mg/kg	ICR mice	↓Liver injury, glycolysis, α-SMA, α1collagen, fibronectin, ALT, AST, TBIL, IBIL, p-MLC2	[163]
	In vitro	20, 30, 40 μM	HSC	↑SLC7A11, GSH, lipid droplet content, retinol, cholesterol, triglyceride ↓ATGL, α-SMA, α1collagen, fibronectin, desmin, ROS	[79]
	In vivo	20 mg/kg	C57BL/6	↑Antioxidant activity, ↓liver fibrosis, collagen deposition lipid droplet content, retinol, cholesterol, triglyceride, α-SMA, collagen I	[79]
	In vitro	20, 30, 40 μM	HSC	↑Autophagy, Atg5, Atg12, beclin, LC3B, ↓ NF-κB, NLRP3, TNF-α, IL-1β, p-PI3K, p-Akt p-mTOR, ROS, p62, IL-1β, IL-4, IL-6, IL18, TNF-α, IFNγ	[92]
	In vivo	20, 30, 40 mg/kg	C57BL/6	↓ NF-κB, α-SMA, IL-1β, IL-4, IL-6, IL18, TNF-α, IFNγ	[92]
	In vitro	20, 30, 40 μM	LSECs	↓VEGF-A, angiogenesis	[256]
	In vivo	40 mg/kg	ICR mice	↓VEGF-A, Ang-2, CD31, HIF-1α	[256]
	In vitro	20, 30, 40 μM	HSC	↑Cleaved caspase-9, cleaved caspase-3, cleaved PARP, p51, p21, p27, S-phase arrest, Bax, collagen degradation, MMP-9, ATF4, p-PERK, cleaved ATF6, ↓Fibrogenesis, PDGF-β, TGF-β, EGFR, cyclin A, cyclin E, CDK-2, Bcl-2, collagen synthesis, TIMP-2, α-SMA, collagen I	[165]
	In vivo	20, 30, 40 mg/kg	ICR mice	↑ERS pathway, IL-6, IL18, TNF-α, AST, ALT	[165]
Inflammatory diseases
Allergic asthma	In vitro	0.1, 0.3, 1, 3, 10, 30 μM	RBL-2H3 mast cells	↓β-Hexosaminidase release, antigen-induced degranulation	[70]
	In vivo	5 mg/kg	Female BALB/c mice	↓IFNγ, IL-2, IL-4, IL-5, IL-13, eosinophils, inflammation score, mucin	[70]
	In vivo	15, 30, 60 mg/kg	BALB/c mice	↓ IgE, p-IκB, p-NF-κB, IL-4, IL-5, IL-13, airway hyporesponsiveness, inflammatory cells infiltration, thickening of alveolar wall	[183]
Inflammatory bowel disease	In vivo	50 mg/kg	BALB/c mice	↓Inflammation, IL-1β, IL-6, IL-17, TNF- α, Muc2, IFNγ	[189]
	In vivo	100, 200 Mg/kg	BALB/c mice	↓Distribution of CD11b+ inflammatory cells and F4/80+ macrophages, MPO, iNOS, NLRP3, IL-1β, IL-6, TNF- α, p65	[190]
Lung inflammation	In vitro	50, 100, 150 μM	BEAS-2B and RAW 2647 cells	↑Nrf2, GSH, HO-1, ↓TNF-α, IL-1β	[143]
	In vivo	15, 30, 60 mg/kg	C57BL/6	↑GR activity, GSH, ↓interstitial edema, infiltrated immune cells, alveolar wall thickness, TNF α, IL-1β, MCP-1, 3-nitrotyrosine, 8-OHdG, 8-isoprostane	[143]
Rheumatoid arthritis	In vitro	1, 4, 16 μM	FLS cells	↑IL-10, ↓IL-1β, IL-6, p-ERK, p-MAPK, p65	[202]
	In vivo	10 mg/kg	DBA/1 mice with CIA	↑Tregs ↓total IgG, IgG1, IgG2a, IgG2b, IL-1β, IL-6, IL-17, TNF-α, arthritis score, swelling, joint inflammation, Th17 cells	[202]
Osteoarthritis	In vitro	2.5, 5, 10, 20, 50 μM	Chondrocytes	↓IL-1β, MMP-13, ADAMTS-5, NO, PGE2, ALP IL-6, TNF-α, NF-κB, RUNX-2, collagen X, β-catenin	[196]
	In vivo	10 mg/kg	OA-induced mice model	↓OARSI score	[196]
	In vitro	2–128 μM	Chondrocytes	↓NOS, cox-2, MMP-3, MMP-13, ERK1/2, PI3K/Akt	[72]
Obesity	In vitro	25, 50, 75 μM	3T3-L1 pre-adipocytes	↓Lipid accumulation, adipogenesis, PPARγ, C/EBPα	[225]
Neurological diseases
ADHD	In vivo	5, 10 mg/kg	SHR, WKY	↓Drinking attempts, drinking frequency, dopamine reuptake	[209]
Alzheimer’s disease	In vitro	10, 50, 100 μM	PC12 cells	↓Ca2+, Bax, iNOS, cleaved caspase-8, cleaved PARP-1, TNF-α, NO, PGE2, p-IκBα, cox-2, p-NF-κB, p-p38, p-JNK, ROS, apoptosis, cell cycle arrest,	[71]
Memory impairment	In vivo	5 mg/kg	ICR mice	↑ChAT, ↓Nissl bodies, OX-42 positive cells, GFAP positive cells, iNOS, spontaneous alteration behavior, micro glial cell activation, lipid peroxidation	[218]

↑—Increase/Upregulation; ↓—Decrease/Downregulation.