Table 1.

Application of RSV in various diseases

Disease categories	Diseases	Species	Routes and doses	Results	Biological functions of RSV	References
Autoimmune diseases	Type 1 diabetes (T1D)	Humans (N=13)	Oral/ RSV capsules (1 g/d)	RSV showed strong antidiabetic and antioxidant effects by significantly decreasing fasting blood sugar (FBS) and hemoglobin A1c (HbA1c) in patients with T1D.	Antidiabetic Antioxidant	[43]
	Systemic lupus erythematosus (SLE)	BALB/c inbred strain of mice (N=100; pristane-induced SLE murine model)	Intraperitoneal injection/ RSV (25 mg/kg; 50 mg/kg) and bio-enhancer piperine (2.5 mg/kg; 5 mg/kg)	The combination of RSV and piperine significantly reduced the expression of related factors of SEL, but did not affect the level of antibodies.	Antioxidant Anti-inflammatory	[44]
	Inflammatory bowel diseases (IBD)	C57BL/6 WT and Nrf2−/−mice (induced by dextran sulfate sodium); Human colon cancer LS174T and Caco2 cells	Intraperitoneal injection/ Imine RSV Analog 2-Methoxyl-3,6-Dihydroxyl-IRA (C33); RSV (200 mg/kg)	The derivative C33 modified by RSV showed stronger anti-inflammatory effect, and effectively improved IBD by activating Nrf2 signaling pathway in-vivo and in-vitro.	Anti-inflammatory	[45]
	Autoimmune encephalomyelitis (AE)	C57BL/6 mice	Intraperitoneal injection/ RSV (10 mg/kg; 25 mg/kg; 50 mg/kg)	RSV reduced oxidative stress and inflammation in EAE mice to protect the integrity of blood-brain barrier.	Antioxidant Anti-inflammatory	[46]
Neurodegenerative diseases	Alzheimer disease (AD)	Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs); Tg2576 Swedish transgenic AD mice	Passage 3 hUC-MSCs were cultured in media with 2.5 µM RSV, and intravenously delivered the suspension of hUC-MSCs to AD mice (1×106 cells/ 200μl saline solution)	RSV-treated hUC-MSCs showed a significant neuroinflammatory inhibitory effect that inhibited MAPKs, p38, and other signal pathways in AD mice by interacting with astrocytes and microglia.	Antioxidant Anti-inflammatory	[47]
	Parkinson disease (PD)	Mice (N=24; induced by neurotoxin MPTP)/ Human neuroblastoma cell line SH‐SY5Y	Intragastric administration of RSV (50 mg/kg) for mice/ SH‐SY5Y were cultured in media with 500 mM MPTP and 50 mM RSV	RSV promoted the expression of miR‐129, increased the number of TH+ cells, and inhibited the expression of MALAT1 and SNCA by regulated MALAT1/miR‐129/SNCA signaling pathway, thus protecting neurons and preventing PD.	Neuroprotective	[48]
	Amyotrophic lateral sclerosis (ALS)	ALS-MSCs (BM-MSCs derived from ALS patients)	BM-MSCs were cultured in media with 1 µM RSV for 12 hours	RSV activates SIRT1/AMPK signaling pathway of ALS-MSCs to improve the functional recovery effect of ALS-MSCs.	Neuroprotective Anti-inflammatory Anti-apoptosis	[49]
Cancer	Lung cancer (LC)	Human small-cell LC (SCLC) H446 cell line	H446 cells were cultured in media with RSV (40 µg/ml)	RSV inhibited the survival of human SCLC H446 cells, and promoted apoptosis by inhibiting PI3K/Akt/c-Myc signaling pathway.	Anticancer Antioxidant	[50]
	Pancreatic cancer (PC)	Human pancreatic stellate cells (PSCs)/ KPC mice	PSCs were cultured in media with 50 µM RSV/ KPC mice were treated with 50 mg/kg RSV	RSV blocked the interaction between PSCs and PC cells, and thus inhibited malignant proliferation of PC cells by inhibiting the activation of hypoxia-induced PSCs.	Anticancer Antioxidant	[51]
	Colon cancer	Human colon cancer cell lines SW480 and SW620/ BalB/c (nu/nu) mice	SW480 and SW620 cells transfected with siAKT1 were established in EMT model by using epidermal growth factor. (50 ng/ml)/ Tail vein injection EMT to BalB/c (nu/nu) mice/ Intragastric administration of RSV for mice (150 mg/kg)	RSV inhibited malignant colon cancer by reversing Epithelial-Mesenchymal Transition (EMT) via the AKT/GSK-3β/Snail signaling pathway.	Anticancer Antioxidant	[52]
	Breast cancer	MDA231 cells/ Nude mice	MDA231 cells were cultured in media with RSV/ MDA231 cells were transplanted into the fat pad of nude mice breast/ Intraperitoneal injection of RSV (100 mg/kg)	RSV inhibited malignant MDA-MB-231 human breast cancer by reversing Epithelial-Mesenchymal Transition (EMT) via the TGF-β1 signaling pathway.	Anticancer Antioxidant	[53]
Cardiovascular diseases	Atherosclerosis (AS)	ApoE−/−mice/ CD4+T cells(from the spleen of C57BL/6 mice)	Intragastric administration of RSV (5 mg/kg) for mice/ CD4+T cells were cultured in media with RSV (20, 40, 80 µM)	RSV effectively alleviated AS caused by HFD, concomitant with LPS in ApoE−/−mice/ RSV inhibited the activation of CD4+T cells.	Antioxidant Anti-inflammatory	[54]
	Hypertension	Spontaneously hypertensive rats (SHRs)	Intragastric administration of RSV (50 mg/kg) for rats	RSV attenuated the development of high blood pressure in SHRs by inhibiting the expression of Giα proteins.	Antioxidant	[55]
	Myocardial ischemia	C57BL/6J mice	Intragastric administration of RSV (320 mg/kg) for mice	RSV protected mouse heart injury induced by ischemia in-vivo, and NRCM injury induced by hypoxia in-vitro by regulating Sirt1/p53-mediated cell senescence, and inhibiting NLRP3 inflammasome activation.	Antioxidant Anti-inflammatory Anti-apoptosis	[56]
Infectious disease	Helicobacter pylori	clinical H. pylori/ G. mellonella larvae	H. pylori strains were cultured in media with RSV (100 µL)/ G. mellonella larvae were injected with 10 µL of H. pylori	RSV derivatives significantly reduced the colony movement ability and biofilm formation of H. pylori.	Antimicrobial	[57]
	Staphylococcus aureus	S. aureus/ A549 human lung epithelial cells (ATCC CCL 185)	S. aureus strains were cultured in media with RSV/ ATCC CCL 185 were cultured in media with treated strain of S. aureus	RSV effectively inhibited the expression of Hla and alleviated the cell damage of ATCC CCL 185 co-cultured by bacteria.	Anti-apoptosis	[58]