Table 1.

Biofunctional components, concentration, experimental/disease model and anti-inflammatory actions of Cordyceps militaris.

Bioactive Component	Dose/Disease Model	Study Type/Experimental Model	Results/Mechanism	References
Cordycepin	2.5–10 mg per kg of rat/Parkinson’s disease	In vivo/ Male Sprague-Dawley rats	Reduced neuro-inflammation, dynamin-related protein 1 (Drp1), IL-1β, IL-18 and tyrosine hydroxylase. Amplified NLRP3 inflammasome activation, ATP production, AMP-activated protein kinase and mitochondrial functions	[164]
Cordycepin	0.0005–0.008 nM/L	In vitro/ PC12 rat pheochromocytoma cell line	Improved mitochondrial functioning by increased ATP content, maintaining membrane potential, inhibiting fission protein 1(Fis1) and mitochondrial ROS levels.	[164]
Cordycepin	0–40 µg per mL/ TNF-α-induced inhibition of osteogenic differentiation in ADMSCs	In vitro/ ADMSCs	Restoration of cell proliferation and osteogenic differentiation by regulating Runx2 and Osx mRNA expressions, and NF-κB signaling via inhibition of IκBα phosphorylation.	[165]
Cordycepin	0–40 µg per mL/LPS-stimulated RAW264.7 cells	In vitro/ RAW264.7 cells	Reduced proinflammatory chemicals such as IL-1β, IL-6, TNF-α, iNOS, COX-2 and NO synthesis	[64]
C. militaris extract (WIB801C)	20, 50, 100 mg per kg of rat/Focal cerebral ischemia	In vivo/ Male Sprague-Dawley rat	Neuroprotection, inhibited MCP-1-induced microglial migration, oedema and the infiltration of ED-1-and MPO-positive inflammatory cells.	[158]
Asterina pectinifera fermented C. militaris extract (FACM)	0–40 µg per mL/LPS-induced RAW264.7 macrophages	In vitro/ RAW264.7 macrophages	Amelioration of LPS-stimulated phosphorylation levels of MAPKs (p38, JNK1/2, and ERK1/2), NO synthase expression, IL-6 and TNF-α.	[140]
Cordycepin	10, 20, 400 mg per kg of rat/ Acute lung injury, asthma.	In vivo/ Male BALB/c mice	Inhibited OVA-specific immunoglobulin (Ig) E, mucus hypersecretion, eotaxin, IL-4, -5, -13 and ICAM-1, NF-kB activation and p38-MAPK signaling cascades, recruitment of inflammatory cells in an experimental model.	[143]
Militarin Derivatives	0–100 µM/ LPS-treated RAW264.7	In vitro/ RAW264.7 cells, peritoneal macrophages	Inhibited NO production and PGE2 by downregulating p38/AP-1, IKKe/IRF-3, and Syk/NF-kB pathways	[122]
Militarin Derivatives	5–20 mg per kg in DSS-induced colitis, 5–30 mg per kg in gastritis model and ear oedema model	In vivo/ male C57BL/6 and ICR mice	Anti-inflammatory effects by reducing gastric damage (gastritis), inhibited colon size and up-regulated phospho-p38 (colitis), and inhibited ear oedema.	[122]
Cordycepin and adenosine	0, 1, 10 and 100 µg per mL/ LPS induced inflammatory response	In vitro/ Murine macrophage	Inhibition of inflammation by reducing expression of M1 chemokines (CX3CR1, RANTES) and cytokines (IL-1β, TNF-α).	[166]
Extract of C. militaris grown on soybean	5–20 mg per kg of mice/ DSS-induced colitis	In vivo/ C57BL/6 mice	Inhibited TNF-𝛼, iNOS, MMP-3, MMP-9 mRNA Expressions in colonic tissue of a colitis model.	[167]
Extract of C. militaris grown on soybean	10 and 100 µg per mL/ LPS-induce RAW264.7 Cells.	In vitro/ RAW264.7 cells	Suppressed TNF-𝛼 and iNOS in a cell model	[167]
Extract (Mulberry leaves fermented with C. Militaris)	High fat diet-induce -obese mice	In vivo/ C57BL/6N male mice	Inhibited mast cell infiltration, COX-2, iNOS, IL-6, -1β, TNF-α, NF-κB. Anti-inflammatory response via the PI3K/AKT/mTOR signaling pathway.	[148]
Cordycepin	0, 10, 50 or 100 µM/ Nucleus pulposus cell and intervertebral disc organ culture inflammatory models	In vitro/ rats	Increased type-II collagen, aggrecan synthesis. Inhibited PGE2, NO, and matrix damaging enzymes (MMP-3, -13; ADAMTS-4, and -5).	[146]
C. militaris extract, fractions, ergosterol	0.1, 1, 10 and 100 µg per mL/ LPS-stimulated BV2 microglia cells	In vitro/ BV2 microglia cells	Significantly reduction in LPS induced nitric oxide.	[168]
C. militaris-fermented product extract	0.603–1.809 g per kg per day/ liver fibrosis BALB/c mice	In vivo/ Male BALB/c mice	Suppressed proinflammatory cytokines, such as TNF-α, IL-6, and NF-κB.	[151]
Cordycepin, C. militaris butanol extract	0–30 µg of Cordycepin per mL/ or 0–75 µg of extract per mL/ LPS-triggered RAW264.7 cells	In vitro/ RAW264.7 cells	Anti-inflammatory effect by inhibiting NO synthesis, NF-κB activation, iNOS, COX-2 expressions and phosphorylation of p38 and Akt.	[136]
Ergosterol palmitate; palmitic acid; ergosterol; ergosterol peroxide; 3,4-O-isopropylidene-d-mannitol; Cordycepin; d-mannitol; d-glucose	LPS/IFN-α stimulated murine peritoneal macrophage cells	In vitro/ macrophage cells	Suppressed synthesis of cytokines including IL-12 and TNF-α and NO production	[40]
Soya-cerebroside, C. militaris extract	0, 1, 5, and 10 µM/ IL-1β-induced monocytes	In vitro/ Monocyte	Reduced monocytes migration and MCP-1 expressions. Downregulated SP1 expression by activating miR-432 and inducing phosphorylation of AKT and AMPK.	[159]
Soya-cerebroside, C. militaris extract	3 and 10 mg per kg per day/ IL-1β-induced inflammatory rat model	In vivo/ Severe combined immunodeficiency	Inhibited edema and cartilage damage. Induction in CD68 and MCP-1 (a marker for monocyte/macrophages) positive cells,	[159]
Soya-cerebroside	0, 1, 5, and 10 µM/ Osteoarthritis synovial fibroblasts (OASFs)	In vitro/ humans	Decreased monocyte migration, activated AKT and AMPK signaling pathways, MCP-1 and microRNA (miR)-432 expression in OASFs.	[159]
C. militaris extract	1, 10, 100 and 1000 µg per mL/ In LPS-stimulated RAW264.7 and antigen-induced RBL-2H3 cells	In vitro/ RAW264.7 and RBL-2H3 cells	Inhibited nitrite production, iNOS, and TNF-α.	[169]
C. militaris extract	500 mg per kg of animal per day/ DSS induced acute colitis	In vivo/ BALB/c mice	Alleviated the severity of the disease in a colitis mouse model by decreasing mRNA expression of TNF- α and iNOS.	[169]
GRC, GRC-ON89A	250, 500 µg per mL/ LPS-induced Macrophages	In vitro/ RAW264.7 cells	Reduced NO production, iNOS, COX-2, and TNF-α mRNA expression, and that of MAPKs (ERK, JNK, and P38), NF-κB.	[120]
GRC, GRC-ON89A	25 mg per kg of animal/ DNFB induced allergic contact dermatitis	In vivo/ BALB/c, C57BL/6N mice models	Decreased inflammatory response such as ear swelling in an experimental model	[120]
Cordycepin	12.5, 25, 50, 100 µg per mL/ Cholecystokinin-stimulated pancreatic acinar cancer cell	In vitro/ pancreatic acinar cancer cell	Anti-inflammatory effect by down regulating NLRP3 inflammasome activation and NF-κB via AMPK.	[152]
Cordycepin	100 mg per kg of animal/ Caerulein induced acute pancreatitis	In vivo/ Male ICR mice	Augmented neutrophil infiltration and reduced edema, acinar cell vacuolization, serum amylase, lipase levels. Inhibited TNF-α, IL-1β, IL-6 by suppressing the activation of NLRP3 inflammasome and NF-κB.	[152]
C. militaris aqueous extract	1 and 2 g per kg of animal/ Cationic bovine serum albumin-induced membranous glomerulonephritis rat model	In vivo/ Wistar male rats	Amplification of total protein, serum albumin, MDA, SOD, and glutathione peroxidase. Attenuated IL-1, TNF-α, 6-keto-PGF1α, NF-κB p65. Reduced serum levels of VCAM-1, ICAM-1, and MCP-1 and urine protein serum creatinine, triglyceride, blood urea nitrogen and total cholesterol.	[144]
Extract of fruiting bodies C. militaris	500 µg per mL/ LPS-induced inflammatory response in macrophages	In vitro/ RAW264.7 Macrophages	Reduced Synthesis of IL-6, NO, and TNF-α.	[170]
Cordycepin	50, 100, and 200 g per kg / LPS-induced acute lung injury mice model	In vivo/ Male BALB/c mice	Inhibition of Nrf2 and HO-1 expressions, MDA content, IL-1β, TNF-α and NF-κB activation.	[133]
C. militaris and Rumex crispus Mixture	50 and 100 µg per mL/ LPS-induced splenocytes	Ex vivo/ splenocytes	Suppressed COX-2, iNOS, IL-1β, IL-6, TNF-α, IFN-γ) and NO synthesis	[135]
C. militaris-based nanoemulsion	25 and 50 µg per mL/ LPS-induced Macrophages	In vitro/ RAW264.7 Macrophages	Reduced expression of proinflammatory cytokines (TNF-α, IL-1β, IKKa, iNOS, IL-6, NF-kß) and NO production.	[171]
Mulberry leaves fermented with C. militaris	100, 200 and 400 μg per mL/ LPS-induced Macrophages	In vitro/ RAW264.7 Macrophages	Anti-inflammatory activity by iNOS-mediated COX-2, expression of inflammatory cytokines (IL-1β, IL-6 and TNF-α), and MAPK signaling pathway	[148]
Cordycepin	10, 50 and 100 μM/ IL-1β-stimulated human osteoarthritic chondrocytes	Ex vivo/ osteoarthritic chondrocytes	Suppressed IL-1β, PGE2, MMP-13, IL-6, iNOS, COX-2 and NO synthesis.	[145]
Cordycepin	PBMCs (Kawasaki disease patients), LPS-induced Macrophages	In vitro and Ex-Vivo/ PBMCs, macrophages	Inhibition of LPS-stimulated TNFα production in mouse macrophages and in PBMCs	[172]
Cordycepin	1, 5, 10 and 20 mg per kg/ Traumatic brain injury	In vivo/ Sprague-Dawley rats	Increased arginase 1 and IL-10. Inhibition of IL-1β, iNOS, MPO and MMP-9, and NADPH oxidase expression.	[173]
C. militaris fruiting bodies extract	4 g per kg/ OVA sensitized airway inflammatory mice model	In vivo/ BALB/c mice	Inhibited asthmatic airway inflammation and blocked bronchoconstriction mediators-leukotrienes	[97]
C. militaris, C. militaris fermented Haliotis discus hannai (HFCM-5)	50, 100 and 200 µg per mL/ LPS-induced Macrophages	In vitro/ RAW264.7 Macrophages	Decreased proinflammatory cytokines, TNF-α and IL-6 in a concentration-dependent manner. In addition, showed nitric oxide inhibitory activity.	[174]
Cordycepin	50 and 100 μM/ Palmitic acid and oleic acid in inflammation in Hepatocytes	In vitro/ hepatocytes	Attenuated the increased expression of inflammatory genes (TNF-α, IL-1β, Cxcl10, Ccl2 and Ccl5)	[121]
Cordycepin	100 and 200 mg per kg/ Lipotoxic model), nonalcoholic steatohepatitis	In vivo/ Mice	Suppressed inflammatory genes (IL-1β, Cxcl2, Cxcl10, Ccl2, and Ccl5), activation of NF-κB signaling, and inflammatory cell infiltration. Anti-inflammatory effects through AMPK pathways	[121]
Spent mushroom (C. militaris)	0.5, 1 and 1.5 g per kg/	In vitro/ pigs	Improved health conditions. Inhibition of IL-1β and TNF-α.	[175]
Fermented cultured C. militaris (GRC-SC11)	0–300 µg per mL/ allergic model (RBL-2H3 cells)	In vitro/ RBL-2H3	IL-4 and TNF-α inhibition	[176]
Cordycepin	2 g per liter in drinking water/ LPS stimulated animals	In vivo/ Male broilers (Ross 308)	Inhibition of COX-2 and iNOS	[123]
C. militaris powder	3, 1.5, and 0.5 g powder per individual/	In vivo/ Humans	Suppressed inflammatory cytokines including EGF, eotaxin, fractalkine, IP-10, IL-1α, -6, -8, IFN-α2, -γ, MIP-1α, -1β, GRO, G-CSF, GM-CSF, MCP-1, sCD40L, TGF-α, VEGF	[137]

Abbreviations: 1-fluoro-2,4-dinitrofluorobenzene: DNFB; Adipose-derived mesenchymal stem cells: ADMSCs; Cordyceps militaris grown on germinated Rhynchosia nulubilis: GRC; Cyclooxygenase 2: COX-2; Dextran sodium sulfate-induced: DSS; Epidermal growth factor: EGF; Fibroblast growth factor-2: FGF-2; Granulocyte-colony stimulating factor: G-CSF; Granulocyte-macrophage colony-stimulating factor: GM-CSF; GRC: fermented with Pediococcus pentosaceus ON89A isolated from onion hexane extract: GRC-ON89A; Growth regulated oncogene: GRO; Interferon-α2 (IFN-α2), IFN-γ; Heme oxygenase-1: HO-1; IFN-γ inducible protein 10: IP-10; Inducible NO synthase: iNOS; Intercellular adhesion molecule 1: ICAM-1; Interleukin-1α: (IL)-1α, IL-1β, IL-1ra, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12(p40), IL-12(p70), IL-13, IL-15, IL-17; Lipopolysaccharide: LPS; Macrophage inflammatory protein-1α: (MIP)-1α, MIP-1β; Macrophage-derived chemokine: MDC; Malondialdehvde: MDA; Monocyte chemoattractant protein-1: (MCP)-1, MCP-3; Monocyte chemoattractant protein-1: MCP-1; Nuclear factor erythroid 2–related factor 2: Nrf2; Nuclear factor-κB: NF-κB; Mitogen -activated protein kinases: MAPKs; Ovalbumin: OVA; Peripheral Blood Mononuclear Cells: PBMCs; Transforming growth factor-α: TGF-α; Tumor necrosis factor alpha: TNF-α; Tumor necrosis factor-α: (TNF)-α, TNF-β; Vascular endothelial growth factor: VEGF; Vascular adhesion molecule 1: VCAM-1.