TABLE 2.

Immunostimulatory and related bioactivities of Cordyceps spp.: in vitro and in vivo.

Activity	Species	Extract/Compound	In vitro/in vivo	Results	References
Immunostimulant	C. militaris (L.) Fr.	Polysaccharides	RAW264.7 macrophages	↓NO, ROS, TNF-α production, NF-κB activation and MAPKs pathways, melanoma growth	Lee and Hong (2011)
				↓NO, TNF-α and IL-1β production	Lee et al. (2010)
				↓NO, TNF-α and activates macrophages through the MAPKs and NF-κB signaling pathways	Lee et al. (2015)
	C. japonica Lloyd	Aqueous and methanol	Forced swimming performances, immobilizing stress	↑Liver enzyme activities, ↓lipid peroxidation	Shin et al. (2001)
Immunomodulatory	C. bassiana Z.Z. Li, C.R. Li, B. Huang and M.Z. Fan Z.Z. Li, C.R. Li, B. Huang and M.Z. Fan	Ethanol	LPS-activated macrophages	↓Expression of IL-12, IFN-γ	Byeon et al. (2011a)
		Butanol fraction	Molecular basis of inhibition of cytokine expression	↓IL-12 and TNF-α expression, Syk, JAK-2, and ERK	Byeon et al. (2011b)
		Methanol	HMNC proliferation	↓HMNC proliferation, EC50 = 32.5 ± 5.2 μg/ml, ↑IL-2 and IFN-γ	Weng et al. (2002)
	C. gunnii (Berk.) Berk.	Polysaccharide	Macrophage phagocytosis along with humoral and cellular immunity	↑Thymus and spleen indexes, macrophage phagocytosis, the proliferation of splenic cells, level of IFN-γ and TNF-α, ↓IL-4	Zhu et al. (2012b)
			Spleen lymphocytes proliferation, peritoneal macrophage (PMphi) phagocytosis, and CTL	↓Spleen lymphocytes proliferation, PMphi phagocytosis of neutral red and CTL	Xiao et al. (2004b)
	C. pruinosa Petch	Polysaccharide	Splenic T cell and Mphi phagocytosis	↑Proliferation of activated splenic T cell and cellular immune functions	Liu and Fei (2001)
			Renal injury in endotoxemic rats	↓Oxidative stress and inflammatory cytokines, NF-κB activation, ↑body’s cellular antioxidant defense system.	(Chiu et al., 2014)
	C. taii Z.Q. Liang and A.Y. Liu	Polysaccharides	Splenic T cell and Mphi phagocytosis	↑Proliferation of activated splenic T cell and cellular immune functions	(Liu and Fei, 2001)
	C. sinensis (Berk.) Sacc.	Adenosine and guanosine	RAW264.7 cells	↓NO, ↑IL-1β, TNF-α	(Yu et al., 2007)
		Polysaccharide	Macrophages proliferation, phagocytosis	Activation of the MAPK and NF-κB signaling pathways	(Cheong et al., 2016)
		Exopolysaccharide	B16 melanoma-bearing mice	↑Neutral red uptake capacity, spleen lymphocyte proliferation, ↓levels of Bcl-2	Zhang Q et al. (2005)
		Aqueous	Lupus-prone (NZB/NZW) F1 hybrids	↑Survival, CD8+ T cells%, ↓ proteinuria, titers of anti-double-stranded DNA antibody CD4+ T cells%	(Chen et al., 2009)
			Macrophage J774 cell	↑Phagocytosis	(Jia and Lau, 1997)
		Exopolysaccharide	Raw264.7 macrophage cell	Stimulate the release of cytokines	(Wang et al., 2011)
		Chloroquine and bafilomycin A	Bone marrow-derived dendritic cells (BM-DCs)	Activation of BM-DCs in a TLR9-dependent manner	(Xiao et al., 2010)
		Methanol	Lymphoproliferative response, natural killer cell (NK)	Inhibited blastogenesis response, NK cell activity, IL-2, and TNF-α production	(Kuo et al., 1996)
Immunomodulatory and antioxidant	C. militaris (L.) Fr.	Polysaccharides	Cyclophosphamide-induced immunosuppression	↑Spleen lymphocyte activity, macrophage function, SOD, catalase, GPx, and TAOC level and the spleen and thymus indices, ↓MDA level	Wang M et al. (2012)
		Polysaccharides	Viscera index, leukocyte count, differential leukocyte count, IgG levels	Upregulated the expression of TNF-α, IFN-γ, and IL-1β mRNA, ↑spleen and thymus indices, the spleen lymphocyte activity, the total quantity of white blood cells, and IgG function, ↓MDA	(Liu et al., 2016)
Immunosuppressive	C. gunnii (Berk.) Berk.	Polysaccharide	Cytotoxic T lymphocytes	Inhibiting cellular immunologic and humoral immunologic function	(Xiao et al., 2004a)
Anti-inflammatory	C. bassiana Z.Z. Li, C.R. Li, B. Huang and M.Z. Fan	1,9-Dimethylguanine	Reporter gene assay and mRNA analysis	Blockade of luciferase activity caused by NF-κB and AP-1, suppress the mRNA levels of COX-2 and TNF-α	(Suh et al., 2017)
		Butanol fraction	LPS-induced inflammation in RAW 264.7 cells	↓NO, iNOS, COX-2, IκB, MAPKs activation, JNK, and p38 phosphorylation	(Yoon et al., 2017)
		4-Isopropyl-2,6-bis(1-phenylethyl) phenol	LPS and sodium nitroprusside treated RAW264.7 cells	↓NO and ROS production, mRNA expression, NF-κB activation	(Yang et al., 2015b)
		Aqueous	LPS-treated RAW264.7 cells.	↓COX-2, IL-12, and iNOS, Syk kinase activity ↑IL-10	(Yang et al., 2017)
		Butanol fraction		↓NO and ROS production, and IκB/NF-κB pathway, JNK, and p38 activation	Kim T W et al. (2014)
	C. cicadae S.Z. Shing	Ergosterol peroxide	Human T cells	↓T-cell proliferation, IL-2, IL-4, IL-10, and IFN-γ, AP-1 proteins expression	(Kuo et al., 2003)
		N6-(2-Hydroxyethyl) adenosine	LPS-induced pro-inflammatory	↓TLR4-mediated NF-κB signaling pathway	(Lu et al., 2015)
			CCl4-induced liver fibrosis	↓BUN and SCr levels, IL-12 and TNF-α expression, TGF-β1/CTGF	(Kim et al., 2018)
	C. guangdongensis T.H. Li, Q.Y. Lin and B. Song	Aqueous	Chronic bronchitis caused by tobacco smoking	↓Bronchial lesions and inflammatory cell infiltration	(Yan et al., 2014)
	C. militaris (L.) Fr.	Aqueous	Dextran sodium sulfate-induced acute colitis	Attenuated body weight loss, diarrhea, gross bleeding, ↓epithelial damage, loss of goblet cells, loss of crypts, infiltration of inflammatory cells	(Han et al., 2011)
		Cordycerebroside A soyacerebroside I and glucocerebroside	RAW264.7 macrophages	↓Accumulation of pro-inflammatory iNOS and COX-2 protein expression	(Chiu et al., 2016b)
	C. pruinosa Petch		RAW264.7 macrophage cells	↓ NO production, TNF-α, ROS, IL-6, iNOS, phosphorylation of p65/p50	Kim H G et al. (2014)
		Methanol		↓IL-1β, TNF-α, COX-2, iNOS, NF-κB activation	(Kim et al., 2003)
Anti-inflammatory and anti-cancer	C. militaris (L.) Fr.	Cordycepin	LPS/IFN-γ-stimulated macrophages and colon 205, PC-3, and HepG2 cells	↓NO, TNF-α and IL-12 production, IC50 = 7.5, 6.3, and 7.6 μg/ml	(Rao et al., 2010)
Antioxidant	C. cicadae S.Z. Shing	Water-soluble polysaccharides	Total reducing power and scavenging activities	IC50= 28.99 μg/ml (DPPH scavenging), 0.19 and 0.30 mg/m L mg/ml (hydroxyl and superoxide anion radicals)	(Song et al., 2018)
	C. formosana Kobayasi & Shimizu	Aqueous	DPPH and ROS scavenging	Strong antioxidant capability	Wang Y W et al. (2015)
	C. gunnii (Berk.) Berk.	Polysaccharide	D-galactose-induced	↓LPO, GPx, ↑SOD, catalase	(Zhu et al., 2009)
				↓MDA, GPx, ↑SOD	(Zhu et al., 2011)
	C. japonica Lloyd	Aqueous and methanol	TBA reactant assay	↑Cytosolic SOD, catalase, and GSH-px, ↓MDA	(Shin et al., 2001)
		Ethanol	DPPH	IC50 = 163 μg/ml, ↑SOD, catalase	(Jung et al., 2009)
	C. jiangxiensis Z.Q. Liang, A.Y. Liu & Yong C. Jiang	Polysaccharide	DPPH	EC50 = 18.06 mg/ml	(Xiao et al., 2011)
	C. kyushuensis A. Kawam.	Methanol	Scavenging effect on hydroxyl radical	IC50 = 1.5–4.8 mg/ml	(Zhang et al., 2015)
	C. militaris (L.) Fr.	Polysaccharides	DPPH, hydroxyl and superoxide radical	Strong antioxidant capability	Chen X et al. (2013)
		Methanol		↓LPO also scavenge reducing power and free radicals.	(Reis et al., 2013)
	C. pruinosa Petch	Polysaccharide	DPPH, hydroxyl, and superoxide radical	↓LPO also scavenge reducing power and free radicals.	(Lu et al., 2016)
	C. sinensis (Berk.) Sacc.	Polysaccharide	PC12 cells against hydrogen peroxide-induced injury	↑SOD, GSH, ↓MDA	(Gu et al., 2003)
		Aqueous and ethanol	DPPH, hydroxyl, and superoxide radical	↓LPO, scavenge reducing power and free radicals	(Yamaguchi et al., 2000a)
		Exopolysaccharide	Trolox equivalent antioxidant	35–40 μmol Trolox/g	(Leung et al., 2009)
Antioxidant and Immunoenhancing	C. taii Z.Q. Liang and A.Y. Liu	Polysaccharides	D-galactose-induced aging	Superoxide anion-free radical (EC50 = 2.04–2.49 mg/ml), ↑ SOD, catalase, GSH, ↓MDA	(Xiao et al., 2012b)
Free radical scavenging	C. bassiana Z.Z. Li, C.R. Li, B. Huang and M.Z. Fan	Methanol	DPPH radical inhibition	47.7% scavenging activity of stage 3	(Hyun et al., 2013)
Anti-tumor	C. sinensis (Berk.) Sacc.	Methanol	K562, Jurkat, WM-1341, HL-60, and RPMI-8226 cells	10–40% at 10 μg/ml inhibitor to the proliferation	(Bok et al., 1999)
		Polysaccharide	U937 cells	78–83% growth inhibition rate, ↑IFN-γ, and TNF-α	(Chen et al., 1997)
		Cordycepin	K562, Vero, Wish, Calu-1, and Raji tumor cell lines	Significantly inhibited	(Kuo et al., 1994)
	C. japonica Lloyd	Ethanol	Sarcoma-180 tumor cells	↑Phagocytosis and acid phosphatase activity	(Shin et al., 2003)
	C. gunnii (Berk.) Berk.	Polysaccharide	S180 cells	Stronger inhibition at 800 μg/ml	(Zhu et al., 2016a)
			K562 cell	56.65% tumor inhibition ratio	(Zhu et al., 2012a)
			H22 cell	45.3% tumor inhibition ratio	Zhu Z-Y et al. (2014)
			K562 cells	69.92% tumor inhibition ratio	(Zhu et al., 2013)
		Selenium enriched polysaccharide	SKOV-3 cells	Stimulate apoptosis through p53-Bax-caspase pathway	(Sun et al., 2018)
		Polysaccharide	S180 cell	85% tumor inhibition ratio	(Zhu et al., 2016b)
	C. cicadae S.Z. Shing	Ethanol	SGC-7901 cells	↓Proliferation of SGC-7901 cells, ↑calpain-1, caspase-12, and caspase-9 expression	(Xie et al., 2019)
Anti-tumor and antimetastatic	C. taii Z.Q. Liang and A.Y. Liu	Chloroform	A549 and SGC-7901 cells	IC50 = 30.2 and 65.7 μg/ml, ↑GPx	Liu R M et al. (2015)
Anti-cancer	C. cicadae S.Z. Shing	Aqueous	MHCC97H human hepatocellular carcinoma cells	↓MHCC97H cells growth via G2/M cell cycle arrest	Wang H et al. (2014)
	C. formosana Kobayasi & Shimizu	Aqueous	A549 lung cancer, MDA-mb-231 breast cancer, Huh7 liver cancer, and HL-60 leukemia cells	IC50 = 1.0 mg/ml (A549 cells), IC50 = 0.53 mg/ml (MDA-mb-231 cells), IC50 = 0.44 mg/ml (Huh7 cells), IC50 = 0.19 mg/ml (HL-60 cells), ↓breast tumor size	Wang J et al. (2014)
	C. kyushuensis A. Kawam.		U937 and K562 cells	IC50 = 31.23 μg/ml and 62.5 μg/ml	(Zhao et al., 2018)
	C. jiangxiensis Z.Q. Liang, A.Y. Liu & Yong C. Jiang	Chloroform	Gastric adenocarcinoma cell line SGC-7901	IC50 = 10 μg/ml, ↑ caspase-3 activity	(Xiao et al., 2006)
	C. militaris (L.) Fr.	Curdlan	Dendritic cell maturation	↑ CD40, CD80, CD86, MHC-I, MHC-II molecules, IL-12, IL-1β, TNF-α, IFN-αβ expression, phosphorylation of ERK, p38, JNK, and NF-κB, p50/p65	Kim H S et al. (2010)
	C. taii Z.Q. Liang and A.Y. Liu	Cytochalasin	95-D, A-549 and HL-7702 cells	IC50 = 3.67–4.04 μM	(Li et al., 2015)
	C. sphecocephala (Klotzsch ex Berk.) Berk. and M.A. Curtis	Polysaccharides	HepG2, SKN-SH cells	Activation of caspase-3, and modulation of Bcl-2 and Bax	(Oh et al., 2008)
Cytotoxicity	C. bifusispora O.E. Erikss.	Methanol	CHO cells	Cell death ratio (4.14 ± 0.25) at 4,000 μg/ml concentration, LD50 > 8.0 g/kg	(Lu et al., 2013)
	C. cicadae Shing.	Beauvericin, beauvericin A, beauvericin E, and beauvericin J	HepG2 and HepG2/ADM cells	IC50 = 2.40 ± 0.37 to 14.48 ± 1.68 μM.	Wang J et al. (2014)
	C. formosana Kobayasi & Shimizu	Rugulosin and skyrin	CHO cells	Rugulosin and skyrin LD50 = 18.3 ± 0.2 and 103.7 ± 5.9 μg/ml	(Lu et al., 2014)
	C. jiangxiensis Z.Q. Liang, A.Y. Liu & Yong C. Jiang	Jiangxienone	SGC-7901 cell and A549 cell	IC50 = 1.38–2.93 μM	(Xiao et al., 2012a)
			HGC-27	DNA damage response pathway	(Lü et al., 2014)
	C. pruinosa Petch	Cordycepol C, cordycol	HeLa and HepG2	IC50 = 12–33 μg/ml	(Sun et al., 2013)
		Butanol fraction	HeLa	Caspase-3- and -9-dependent apoptosis, ↑proteolytic cleavage of PARP and release of cytochrome c, ↓Bcl-2/Bax protein ratio	Kim H G et al. (2010)
Anti-diabetic	C. cicadae S.Z. Shing	Crude polysaccharide	Alloxan-induced diabetic	↓Blood glucose, TC, TG, LDL, MDA, urea, CREA, ALT, AST, and ALP. ↑body weights, HDL, SOD, GSH	(Zhang et al., 2018)
	C. japonica Lloyd	Methanol	STZ-induced diabetes	↓serum glucose, glucose tolerance up to 3 h	(Shim et al., 2000)
	C. militaris (L.) Fr.	Cordycepin	Alloxan-induced	↓Blood glucose, TC, TG, LDL, MDA, urea, CREA, ALT, AST, and ALP. ↑body weights, HDL, SOD GSH	(Ma et al., 2015)
Antimicrobial	C. cicadae S.Z. Shing	Hydroalcoholic	Agar well diffusion method	Damage bacterial cell wall and membranes, ↑cell permeability	(Zhang et al., 2017)
Antibacterial	C. heteropoda Kobayasi	Cicadapeptins I and II	Agar disk/diffusion assays	Inhibition zones against Bacillus cereus (13 and 12 mm) and B. subtilis (13 and 11 mm), Escherichia coli (16 mm for both peptides)	(Krasnoff et al., 2005)
Antifungal		Cicadapeptins I and II	Potato dextrose agar plates	Botrytis cinereal (11 mm zones) showed inhibitory activity	(Krasnoff et al., 2005)
	C. dipterigena Berk. and Broome	Cordycepsidone A	Gibberella fujikuroi	Strong and dose-dependent activity	(Varughese et al., 2012)
Neuroprotective	C. cicadae S.Z. Shing	Polysaccharides, adenosine	Glutamate-induced PC12 cells	↑Cell survival rate, GPx, SOD, Bcl-2/Bax ratio, ↓ROS and Ca2+, ERK, p38, and JNK expression	(Olatunji et al., 2016)
		Butanol fraction	Glutamate-induced PC12 cells	↓ROS accumulation, GSH-Px, and SOD levels	(Wang et al., 2018)
Antiviral	C. guangdongensis T.H. Li, Q.Y. Lin and B. Song	Aqueous	Influenza virus H9N2	↓Pulmonary index by 22.1%	(Yan et al., 2010)
Antimalarial	C. brunnearubra BCC 1395	Ethyl acetate	Malarial parasite plasmodium falciparum K1	IC50 = 18 μM	(Isaka et al., 2007a)
Cannabinoid receptors CB1 and CB2 (agonistic)	C. annullata Kobayasi & Shimizu	Ethyl acetate	HEK293 cells	15.5–75.5% inhibition	(Asai et al., 2012)
Anti-proliferative	C. bassiana Z.Z. Li, C.R. Li, B. Huang and M.Z. Fan	Ethanol	VSMC and carotid artery of balloon-injured rats	↓VSMC proliferation and ↑ERK 1/2 phosphorylation	(Jin et al., 2016)
Anti-trypanosomal	C. cardinalis G.H. Sung & Spatafora	Methanol	Against trypanosoma brucei	IC50 = 8.63 μg/ml	(Umeyama et al., 2014)
Anti-fibrotic	C. cicadae S.Z. Shing	Ergosterol peroxide	NRK-49 F cell line	Blockage of TGF-β1-stimulated phosphorylation of ERK1/2, p38 and JNK pathway, ↓ TGF-β1-induced fibroblasts	Zhu R et al. (2014)
Anti-atopic dermatitis	C. bassiana Z.Z. Li, C.R. Li, B. Huang and M.Z. Fan	Butanol fraction	Topical use of DNFB in NC/Nga mice	Blockade of histamine release, IgE production, IL-4, and IFN-γ secretion	Wu G et al. (2011)
Pro-apoptotic		4-Isopropyl-2-(1-phenylethyl) aniline	MDA-MB-231, HeLa, and C6 glioma cells	↓Proliferation of MDA-mb-231, HeLa, and C6 glioma cells, reduced the phosphorylation of STAT3, Src, and PI3K/p85	Kim M S et al. (2015)
Antitubercular	Ophiocordyceps Communis Hywel-Jones and Samson	Cordycommunin	Mycobacterium tuberculosis H37Ra	MIC = 15μM, weak cytotoxicity to kB cells	(Haritakun et al., 2010)
Anti-fatigue	C. guangdongensis T.H. Li, Q.Y. Lin and B. Song	Ethanol	Forced swimming	↓Blood lactic acid levels	(Yan et al., 2013)
Protein tyrosine phosphatase inhibitor	C. gracilioides Kobayasi	Terreusinone A, pinophilin C and cryptosporioptide A	PTP1B, SHP2, CDC25B, LAR and SHP1 enzyme	IC50 = 3.4–50 μg/ml	(Wei et al., 2015)
Antihyperlipidemic	C. militaris (L.) Fr.	Polysaccharides	HFD-induced	↓Blood and liver lipid, ↑SGPT, and antioxidant activity	Wang L et al. (2015)
Renoprotective	C. pruinosa Petch	Whole broth	LPS-induced renal cell injury	↓RBF and GFR, ED-1, GRP78, Beclin-1 autophagy and TUNEL apoptosis, ↑blood leukocyte counts, plasma blood urea nitrogen and creatinine level	Wu M F et al. (2011)
Anti-HIV-1		Cordysobin	HIV-1 reverse transcriptase	IC50 = 8.2 × 10–3 μM	Wang S X et al. (2012)
Renoprotective		Cyclosporine A	Cyclosporine-induced renal tubule dysfunction	↓Apoptosis, caspase-3 activation, ↑magnesium reabsorption channels TRMP6 and TRMP7	(Chyau et al., 2014)
Anti-asthmatic	C. sphecocephala (Klotzsch ex Berk.) Berk. and M.A. Curtis	Culture filtrate	Ovalbumin-induced asthmatic mice	↓IL-4, IL-13, and IL-25 expression and undesirable immune responses	(Heo et al., 2010)
Antiaging	C. sinensis (Berk.) Sacc.	Aqueous	D-galactose-induced aging	↑SOD, catalase, GSH, ↓MDA, monoamine oxidase	Chen et al. (1997)