TABLE 2.

Immunomodulatory mechanism and research progress of natural products

Name	Effect	Research phase	System for experiment	Drug dosage regimen	Reference
ASP	Increases CD4+/CD8+ ratio in spleen tissue; balances Th1/Th2 drift; improves thymus index and enhances the immune function	Preclinical study (animal level)	Lewis lung cancer cells in model mice	Model group, cisplatin group (3 mg/kg), APS high, medium, and low dose groups (400, 200, and 100 mg/kg), with 10 mice in each group.	(Liu et al., 2021)
ASP	Accelerates DTH and NK cells activity, and increased IL‐2, IL‐4, IL‐10, and IFN‐γ level in serum	Preclinical study (animal level)	Immunosuppressed mice induced by cyclophosphamide	Immunosuppressive mice were intraperitoneally injected with high, medium, and low doses (20, 13, and 7 mg/kg) of Lentinan and ASP membranaceus solution (0.5 ml/animal) for 5 consecutive days.	(Yan, Li, Li, Yu, & Yu, 2012)
ASP	Inhibits the expression of type M1 macrophage surface marker CD16/32 + L.	Preclinical study (in vitro)	EAE model in C57BL/6 female mice	Splenocytes were taken on the ninth day after immunization and cultured with high (0.2 mg/ml) and low (0.1 mg/ml) doses of ASP for 48 h	(Liu et al., 2021)
ASP	Improves the CD4+, and CD4+/CD8+ ratio, as well as immune function.	Clinical study (RCT)	Advanced ovarian epithelial cancer (patients)	70 patients with advanced epithelial ovarian cancer were treated with paclitaxel albumin binding and lobaplatin in the control group, and ASP in the experimental group for 4 consecutive cycles.	(Yan & Liu, 2021)
ASP	Increases CD3+, CD4+, and CD4+/CD8+; inhibits fatigue, and inflammation.	Clinical study (RCT)	NSCLC patients with qi deficiency syndrome	Among 75 patients with NSCLC Qi deficiency syndrome, the combined treatment group was added with Astragalus Polysaccharide for injection (250 mg per day), 10 days as a cycle.	(Zhang et al., 2018).
CA	Enhances the lethality of NK cells; promotes the proliferation of splenocytes stimulated by LPS; activates splenic B cells, enhances the host humoral immune response, and significantly promotes the secretion of CTL cells.	Preclinical study (in vitro)	Immunomodulatory effect of phenolic compounds	0, 100, 300, or 500 mM caffeic acid was added to the complete RPMI medium, and all immune effector cells were incubated at 37C for another 48 h	(Kilani‐Jaziri et al., 2017)
CA	Reversibly inhibits LPS‐induced oxidative stress by down‐regulating NF‐κB‐dependent pro‐inflammatory gene, as well as reduce TNF‐α and IL‐6.	Preclinical study (animal level)	LSP‐induced neuroinflammation in mice	Caffeic acid (30 mg/kg) and imipramine (15 mg/kg) were administered orally 1 h before LPS (1.5 mg/kg) test. Behavioral assessment was performed 3 h after LPS injection.	(Mallik et al., 2016)
CFDs	Caffeic acid derivatives can be aligned with COVID‐19's M‐pro and Nsp15 target	Preclinical study	COVID‐19	None	(Adem et al., 2021)
CAPE	Binds to SARS‐CoV‐2 Mpro	Preclinical study	COVID‐19	None	(Kumar, Dhanjal, Kaul, Wadhwa, & Sundar, 2021)
CAPE	Inhibit NF kappa B, and down regulate TNF‐α, IL‐1 β, and other proinflammatory cytokines	Preclinical study (animal level)	Liver injury induced by cigarette smoke (in rats)	21 male Wistar rats, rats in group II were exposed to cigarette smoke and rats in group III were exposed to cigarette smoke and injected with Cape every day. For 60 day experimental period.	(Pekmez et al., 2007)
CA	Has good curative effect on ITP, and the incidence of adverse reactions is low and mild	Clinical study (RCT)	Primary immune thrombocytopenia (ITP)	103 ITP patients in three centers were divided into two groups. PLT patients in group A took 300 mg CA tablets orally every day for 12 weeks.	(Qin, Wei, Hou, Zhao, & Shen, 2015)
CA	Coffee consumption seems to have beneficial effects on subclinical inflammation and HDL cholesterol.	Clinical trial	Coffee consumption person	Habitual coffee drinkers (n = 47) avoided drinking coffee for 1 month; they consumed 4 cups of filtered coffee/day in the second month and 8 cups of filtered coffee/day (150 ml/cup) in the third month.	(Kempf et al., 2010)
Res	Plays an immunomodulatory role in immunodeficient mice and inhibit type IV hypersensitivity in normal mice.	Preclinical study (animal level)	Immunosuppressive model mice	After sterile intraperitoneal injection of CY 80 mg/kg, the immune function decreased significantly after 5 days, and then gavage according to the high, medium, and low dose groups of res (10, 5, and 2.5 mg per kg body weight per day).	(Gao et al., 2003)
Res	Resveratrol supplementation reduced the expression of ACE2 (about 40%) and leptin (about 30%) in human adipose tissue	Clinical study (RCT)	ACE2 expression (SARS‐COV‐2)	11 obese men were injected with 150 mg/day placebo or trans resveratrol (30 and 150 days) and verified by analyzing free and bound resveratrol in plasma.	(de Ligt et al., 2021)
Res	Decreases CSF MMP9, increases MDC, IL‐4, and FGF‐2, regulates neuroinflammation and induces adaptive immunity.	Clinical study (RCT)	Neuroinflammation/Alzheimer’s disease	Mild to moderate Alzheimer’s disease (AD) subjects (n = 119) were treated with SIRT1 activator resveratrol (up to 1 g orally, twice daily) for 52 weeks	(Moussa et al., 2017)

Abbreviations: DB, double blind; Res: Resveratrol; RCT, randomized controlled trial.