Table 1.

In vitro and in vivo studies of Hsd and Hst for disease treatment.

Biological activities	Disease	Flavanone	In Vitro Models	In Vivo Models	Mechanism	Reference
Antioxidant	Arthritis	Hsd		Rheumatoid arthritis rats	Reduce the levels of catalase, nitric oxide and free radicals.	[140]
	Postmenopausal osteoporosis	Hst	RANKL-induced RAW 264.7 cells	Ovariectomized mice	Inhibit Jnk mediated Irf-3/c-Jun activation.	[141]
	Postmenopausal osteoporosis	Hst		Ovariectomized rats	Regulate bone morphogenetic protein pathway and osteopontin expression	[142]
	Genotoxicity	Hsd		Cyclophosphamide-induced mice	Reduce the frequency of MnPCE and increased proliferation on bone marrow cellularity that affected by CP.	[143]
	Cardiovascular Remodeling	Hsd		l-arginine methyl ester-induced rats	Down-regulation of TGF-β1 and TNF-R1 protein expression	[99]
	Metabolic Syndrome	Hsd	Bovine aortic endothelial cells		Stimulate phosphorylation of Src, Akt, AMP kinase, endothelial NO synthase to produce NO.	[144]
	Cardiomyocyte apoptosis	Hst	LPS-induced H9C2 cells		Downregulate the protein expression of Bax, upregulated the expression of Bcl-2 and attenuated the phosphorylation level of JNK	[145]
	Protect cardiomyocytes	Hsd		Senescent rats	Enhance the activity of enzyme antioxidants	[37]
	Myocardial ischemia reperfusion	Hsd		Experimentally-induced rats	Increase tissue nitrite, antioxidant level and Reduce inflammation, arrhythmias and apoptosis	[146]
	Metabolic syndrome and insulin resistance	Hsd		ISO-induced rats	Reduce levels of plasma cholesterol, LDL-C, VLDL-C, TG, FFA	[1]
	hypercholesterolemia and fatty liver	Hsd		High-cholesterol diet-induced rats	Inhibit synthesis and absorption of cholesterol and regulate the expression of mRNA for RBP, C-FABP, H-FABP	[147]
	Cognitive impairment	Hsd		APP/PS1 mice	Reduce the levels of ROS, LPO, protein carbonyl, 8-OHdG, increasing the activities of HO-1, SOD, catalase, GSH-Px	[148]
	Diabetes Depression	Hsd		Streptozotocin-induced diabetic rats	Enhancement of Glo-1 and activation of the Nrf2/ARE pathway	[149]
	Acute lung inflammation	Hsd		Ventilator-induced lung injury mice	Reduce recruitment of inflammatory cells to the airways and the formation of CCL-2 and IL-12	[150]
	Acute lung injury	Hst		LPS-induced ALI mice	(1)Inhibit MAPK activation, regulate Iκβ degradation, block the interaction MD2 and its co-receptor TLR4 (2)Associated with the TLR4-MyD88-NF-κβ pathway.	[151] [152] [153]
	Acute gastric injury	Hsd		Streptozotocin and nicotinamide-induced rats	Increase antioxidant defense capacity through the induction of HO-1 via ERK/Nrf2 pathway.	[154]
	Hepatotoxicity Nephrotoxicity	Hsd		Paclitaxel-induced rats	Amendment of Nrf2/HO-1 and caspase-3/Bax/Bcl-2 signaling pathways.	[155]
	Renal injury	Hsd		Aluminum-induced rats	Inhibit the MMP-9-related signaling pathway activated by ALCL3.	[138]
	Renal injury	Hsd		sodium fluoride-induced rats	Inhibit PI3K/Akt/mTOR pathway.	[156]
Anti-inflammatory	Postmenopausal osteoporosis	Hsd		Ovariectomized mice Ovariectomized rats	Inhibition of osteoclast superoxide reduces bone Resorption.	[157] [158] [159]
	Osteoporosis	Hst	RANKL-induced Murine macrophage cells	LPS-induced mice	(1)Inhibit activation of NF-κβ and MAPK signaling (2)Scavenger active oxygens (3)Activate the Nrf2/HO-1 signaling pathway.	[160]
	Cardiac hypertrophy	Hsd		Isoproterenol-induced rats	Interfering with NF‐κB signaling via JNK phosphorylation	[161]
	Hypertensive	Hsd		Spontaneously hypertensive rats	Improving NO bioavailability in endothelial cells.	[162]
	Hypertensive	Hsd	Human umbilical vein endothelial cells	Spontaneously hypertensive rats	Stimulate CaMKII/p38 MAPK/MasR expression and CaMKII/eNOS/NO production	[163]
	Parkinson's Disease	Hsd		6-OHDA-induced mice	Attenuate the striatal levels of proinflammatory cytokines tumor necrosis factor-α, interferongamma, interleukin-1β, interleukin-2, interleukin-6	[164]
	NeuroinflammationMemory Impairments	Hst	LPS-induced HT-22 cells BV2 cells	LPS-induced mice	Through the NF-κβ signaling pathway reduced the protein expression level of TNF-α and IL-1β cytokines	[165]
	Ischemic stroke	Hst		Middle cerebral artery occlusion mice	Inhibit the TLR4-NF-κβ pathway	[166]
	Temporal lobe epilepsy	Hst		Kainic acid-induced mice	Inhibit the expression of pro-inflammatory molecules	[167]
	Parkinson's Disease	Hsd		OHDA-induced zebrafish	Downregulated the kinases lrrk2 and gsk3β along with casp3, casp9, polg	[168]
	Asthma	Hsd		HDM-induced mice	Decrease subepithelial fibrosis, smooth muscle hypertrophy in airways, lung atelectasis to ameliorating airway structural remodeling	[169]
	Lung injury	Hsd	Acrolein-induced LLC cells	Acrolein-induced mice	Attenuate the expression levels of the activated forms of p38,p53, JNK	[170]
	Peptic ulcers	Hsd		Indomethacin-induced rats	Increase COX-2 and GSH expression	[171]
	Peptic ulcers	Hsd		Stress or ethanol-induced rats	Reduce neutrophil migration and strengthen the mucus barrier close to the mucosa	[172]
	Cholestasis	Hsd	FXR-suppressed HepaRG cells.	FXR-suppressed HepaRG mice	Activate farnesoid X receptor (FXR)	[173]
	Acute renal injury	Hsd		Cisplatin-induced rats	Attenuate caspase-3 and DNA damag.	[135]
	Hepatotoxicity	Hsd		Acetaminophen-induced rats	(1)Increase GSH, GST, SOD, GPx levels and deplete MDA level. (2)Elevate TNF-α and lower the levels of interleukin IL-4.	[174]
	Testicular and kidney damage	Hsd		Carbon tetrachloride-induced rats	Repaire renal and testicular architecture and suppress NF-κβ immunoexpression.	[175]
	Renal injury	Hsd		Colistin-induced rats	Decrease the levels of MDA and inflammatory parameters and Increase GSH, SOD, CAT, GSH-Px levels.	[136]
	Acute kidney injury	Hst		Cisplatin-induced rats	Activate Nrf2, and attenuate the MAPK signaling pathway.	[176]
Anticancer	Osteosarcoma	Hsd	MG-63 cells	BALB/c mice	Inhibition of cell migration and invasion, cell cycle arrest and induction of mitochondrial-mediated apoptosis.	[177]
	Glioma	Hsd		C6 glioma cells graft rats	Inhibit the proliferation of cerebrally implanted C6 glioma and involves suppression of HIF-1α/VEGF pathway	[178]
	Lung cancer	Hsd	NSCLC A549 cells		(1)Induce apoptosis through the mitochondrial apoptotic pathway and induced G0/G1 arrest. (2)inhibite the migratory and invasive capabilities of lung cancer cells by the mediation of the SDF-1/CXCR-4 signaling cascade.	[58] [179]
	Lung cancer	Hsd	Cisplatin-induced A549 cells		Decrease the expression of P-gp and increased the intracellular accumulation of the P-gp substrate, rhodamine 123	[180]
	Lung cancer	Hsd	LLC cells	Lung carcinoma mice	Increase pinX1 protein expression.	[181]
	Gastric cancer	Hsd		MNNG-induced rats	Activate autophagy and the PI3K/AKT pathway.	[182]
	Esophageal cancer	Hst	Eca109 cells	Human xenograft tumor nude mice	Depletion of GSH, accumulation of ROS, increase of cleaved caspase-9 and cleaved caspase-3	[183]
	Ehrlich ascites carcinoma	Hsd		Ehrlich ascites carcinoma (EAC) mice	Down-regulate Bcl2 and Stimulate Caspase3 and Bax genes expression	[184]
	Liver cancer	Hsd		DEN/CCl4-induced rats	Activate Nrf2/ARE/HO-1 and PPARγ pathways.	[185]
	Gastric cancer	Hsd		Xenograft tumor nude mice	Activate the mitochondrial pathway by increasing the ROS.	[129]
	Urinary-bladder carcinogenesis	Hsd		N-butyl-N-nitrosamine-induced mice	Decrease cell proliferation by the induction of cell differentiation.	[186]
Antimicrobial	Severe acute respiratory syndrome coronavirus 2 infection	Hsd	SARS-CoV-2 Spike Protein S1 Subunit-Induced A549 cells		Attenuated inflammasome machinery protein expressions (NLRP3, ASC, Caspase-1), as well as inactivated the Akt/MAPK/AP-1 pathway.	[187]
		Hst	ATCC CRL-1739 cells	ATCC 49503 ATCC 43504 ATCC 51932 ATCC700392	(1)block the expression of genes involved in H. pylori's transcriptional (rpoA, rpoB, rpoD, rpoN) and replication (dnaE, dnaN, dnaQ, holB) machinery. (2)reduce the expression of genes involved in H. pylori adhesion and motility (sabA, alpA, alpB, hpaA, hopZ)	[188]