Table 2 Summary of pharmacological activities of CF

Hypoglycemic activity

 Oleanolic acid

Fasting rat

Decrease plasma glucose levels. Regulate ACh release from nerve terminals to activate muscarinic M3 receptors in the pancreatic cells and increase C-peptide and insulin release

[83]

 Iridoid glycosides

STZ-induced rat as DM model

Show α-glucosidase inhibition activity in vitro and decrease serum glucose levels in vivo

[16]

 Loganin

 Morroniside

 Ursolic acid

STZ-induced mice as DM model, HepG2 cell lines

Show α-glucosidase inhibition activity in vitro. Decrease fasting blood glucose and alleviate weight loss, polydipsia, and polyphagia. Increase SOD activity and ROS scavenging activity. Attenuate aldose reductase activity and decrease MDA plasma level and renal somatic indices in mice

[14]

 Butyl morroniside

 (−)-Epicatechin-3-O-gallate

 Caftaric acid monomethyl ester

High glucose-induced BRIN-BD11 and H4IIE cell lines as in vitro DM model

Increase glucose uptake efficiency. Reduce PEPCK mRNA level and NO production. Inhibit pancreatic β-cell death

[15]

 Aqueous extract

STZ-induced rat as diabetic organs injury model

Decrease levels of glucose and TC in serum, and α-SMA expression in kidney. Improve the pathohistological injury of pancreas, kidney, lung, and liver

[13]

 Aqueous extract

Normal rat

Show α-glucosidase inhibition activity in vitro, and exhibit hypoglycemic effect via oral sucrose tolerance test in vivo

[17]

 Aqueous extract

Dexamethasone and 8-bromo-cAMP-induced BRIN-BD11 and H4IIE cell lines as in vitro DM model

Increase insulin release. Decrease PEPCK mRNA level

[18]

Nephroprotective activity

 Loganin

STZ-induced rat and high glucose-induced HK-2 as in vivo and in vitro diabetic nephropathy model

Improve renal function. Decrease CTGF level in kidney and serum via ERK signaling pathway

[23]

 Morroniside

 Loganin

 7-O-Galloyl-d-sedoheptulose

Db/db mice as obesity-associated type 2 diabetic nephropathy model

Suppress formation of AGEs and TBARS in the kidney. Reduce the production of SREBP-1&2, NF-κB p65, COX-2, and iNOS. Decrease GSH/GSSG ratio and levels of serum glucose, TC, and TG

[19]

 7-O-Galloyl-d-sedoheptulose

STZ-induced rat as diabetic nephropathy model

Decrease serum creatinine, renal glucose, and urinary protein. Reduce the production of AGE, RAGE, HO-1, intracellular glycation, CML, GA-pyridine, and TBARS

[21]

 Iridoid glycosides

STZ-induced rat as diabetic nephropathy model

Suppress over-deposition of fibronectin and laminin in the kidney. Reduce protein and mRNA levels of TGF-β1 in serum and glomeruli

[25]

 Iridoid glycosides

 Triterpene acids

Db/db mice as obesity-associated type 2 diabetic nephropathy model

Improve the histological injury of kidney and pancreas. Ameliorate the structural alterations in mesangial cells and the podocytes in the renal cortex. Inhibit ECM accumulation in the kidney. Decrease 24 h urine protein and serum levels of urea nitrogen and creatinine. Increase insulin release, and decrease fasting blood glucose and levels of TC, TG, and GSP. Attenuate food consumption, water intake, and urine volume. Reduce the production of RAGE, NF-κB, SphK1, and TGF-β

[22]

 CF extract

STZ-induced rat as diabetic nephropathy model

Inhibit AGE formation in the kidney. Attenuate hyperglycemia and proteinuria. Reduce the production of RAGE, NF-κB, TGF-β1, and CML

[20]

 Ethanol extract

High glucose-induced mesangial cells as in vitro diabetic nephropathy model

Decrease the production of Col V, FN, and IL-6

[24]

Myocardial protection activity

 Morroniside

High glucose-induced rat as diabetic cardiomyopathy model

Inhibit myocardial cell apoptosis. Elevate Bcl-2 production and decrease expressions of Bax and caspase-3

[28]

 Triterpene acids

STZ-induced rat as diabetic cardiomyopathy model

Inhibit the ventricular remodeling and regulate the systolic and diastolic function of the left ventricle. Increase insulin release and reduce serum glucose levels. Enhance GSX and SOD activity. Increase the production of calstabin 2, PLB, and SERCA2a. Decrease protein and mRNA levels of ECE, iNOS, MDA, ET-1, and propreET-1

[26]

Testis-protective activity

 Iridoid glycosides

STZ-induced rat as diabetic testicular damage model

Improve the pathohistological injury of testes and pancreas. Increase serum insulin release and decrease blood glucose levels. Alleviate weight loss, polydipsia, polyphagia, and polyuria. Increase CAT and SOD activity. Reduce the production of AGEs, RAGE, ROS, MDA, and p-p38 MAPK. Down-regulate Bax/Bcl-2 ratio and spermatogenic cell apoptosis

[27]

Antioxidant activity

 Morroniside

Hydrogen peroxide-induced SH-SY5Y cell line as in vitro neurodegenerative disorder model

Suppress intracellular accumulation of Ca²⁺. Increase SOD activity and reduce the loss of MMP. Inhibit cytotoxicity

[29]

 Morroniside

High ambient glucose-induced endothelial cell injury model

Attenuate cellular morphological damage. Repair cell cycle progression and improve cell viability

[35]

 Ursolic acid

Hydrogen peroxide-induced HEI-OC1 cell line as in vitro inner ear diseases model

Increase antioxidant enzymes expressions, e.g., CAT and GPX. Suppress lipid peroxidation

[32]

 5-Hydroxymethylfurfural

High glucose-induced HUVECs as in vitro oxidative stress model

Decrease levels of ROS, IL-8, JNK1, and JNK2/3. Increase P-Akt production

[34]

 Total saponins

STZ-induced rat as a diabetic oxidative stress model

Regulate NO release and endothelium-dependent relaxation on the mesenteric artery. Reduce blood glucose levels

[30]

 Aqueous extract

Hypoxanthine and xanthine oxidase-induced bovine PAECs as in vitro oxidative stress model

Regulate GSH redox cycle. Increase the intracellular GSH production and the activity of GSH peroxidase and GSH disulfide reductase. Reduce the intracellular level of GSH disulfide. Increase CAT and SOD activity and inhibit the production of hydrogen peroxide and superoxide anion

[31]

 Ethanol extract

LPS-induced RAW 264.7 macrophage cells as in vitro oxidative stress model

Attenuate xanthine oxidase activity and ROS production. Induce the production of antioxidant enzymes, e.g., CAT, GSX, Cu/Zn-SOD, and Mn-SOD

[33]

Anti-inflammatory activity

 Cornuside

TNF-α-induced HUVECs as in vitro inflammation model

Decrease the production of ICAM-1, VCAM-1, MCP-1, and NF-κB. Inhibit NF-κB p65 translocation

[36]

 Cornuside

LPS-induced RAW 264.7 macrophage cells as in vitro inflammation model

Decrease the production of COX-2, iNOS, PGE₂, NO, IL-1β, IL-6, and TNF-α. Suppress the translocation of NF-κB p65, the phosphorylation and degradation of IκB-α, and the phosphorylation of ERK1/2, JNK1/2, and p38

[38]

 Aqueous extract

LPS-induced RAW 264.7 macrophage cells as in vitro inflammation model

Decrease protein and mRNA levels of COX-2 and iNOS. Reduce PGE₂ and NO production

[37]

Anticancer activity

 Aqueous extract

HSC-2, HSC-3, HSC-4, Ca9-22, NA cell lines as in vitro oral squamous cell carcinoma model

Produce broad radical peak under alkaline condition and increase the cytotoxicity and superoxide anion scavenging activity of vitamin C

[39]

 Aqueous extract

E2-induced MCF-7 cell line as in vitro ER⁺ human mammary carcinoma model

Inhibit cell line anchorage-independent growth and reduce the mitogenically inert metabolite E3 formation

[40]

 Aqueous extract

Parental ER⁺ MCF-7 cell line as in vitro human mammary carcinoma model

Suppress cell line anchorage-independent growth and induce G1 or G2/M arrest and apoptosis. Increase anti-proliferative E2 metabolites production

[41]

 Aqueous extract

HepG2, SKHep1 and PLC/PRF/5 cell lines as in vitro hepatocellular carcinoma model

Inhibit cell proliferation. Exhibit free radicals scavenging activity and suppress lipid peroxidation and xanthine oxidase production

[42]

Neuroprotective activity

 Cornuside

 1,2,3-Tri-O-galloyl-β-d-glucose

 1,2,3,6-Tetra-O-galloyl-β-d-glucose

 Tellimagrandin I

 Tellimagrandin II

 Isoterchebin

In vitro enzyme activities assay

Exhibit synergetic inhibitory activities against BACE1 and ChE

[45]

 Morroniside

MCAO-induced rat as focal cerebral ischemia model

Decrease the infarction volume and improve neurological function. Increase GSH expression and SOD activity. Decrease the production and activity of MDA and caspase-3 in ischemic cortex tissues

[47]

 5-Hydroxymethylfurfural

Hydrogen peroxide-induced rat hippocampal neurons as in vitro neurodegenerative disorder model

Enhance Bcl-2 production and suppress expressions of Bax, caspase-3, and p53

[84]

 Iridoid glycosides

MCAO-induced rat as focal cerebral ischemia model

Improve neurological function. Increase the number of BrdU-positive cells and nestin-positive cells in the subventricular zone, and the number of new mature neurons and blood vessels in the striatum. Increase protein and mRNA levels of VEGF and Flk-1

[46]

 Iridoid glycosides

Fimbria-fornix transected rat as cerebral ischemia model

Decrease neuron loss in the hippocampus and improve memory deficits. Increase the production of BDNF, NGF, Bcl-2, SYP, Trk A, and GAP-43, and decrease the production of Bax and Cyt c

[49]

 7R-O-Methyl-morroniside

 7S-O-Methyl-morroniside

 7-O-Butyl-morroniside

 Loganin

 Morroniside

Glutamate-induced HT22 cell lines as in vitro hippocampal cell injury

Improve cell viability

[43]

 Iridoid glycosides

Mycobacterium tuberculosis and guinea-pig myelin basic protein-induced experimental autoimmune encephalomyelitis rat as multiple sclerosis model

Increase the number of mature oligodendrocytes and reduce the number of oligodendrocyte progenitor cells. Inhibit the process of T cell entry to the central nervous system and attenuate microglia activation. Increase BDNF expression and decrease phosphorylation of JAK/STAT1/3 and inflammatory cytokines production, e.g., IL-1β, IFN-γ, TNF-α

[48]

 Iridoid glycosides

Mycobacterium tuberculosis and myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis mouse as multiple sclerosis model

Decrease BDNF and NGF loss in the spinal cord

[50]

 Aqueous extract

PC 12 cell lines

Increase cell neurite outgrowth. Inhibit extracellular Ca²⁺ influx, and protein and mRNA levels of STIM1

[44]

Hepatoprotective activity

 5-Hydroxymethylfurfural

Hydrogen peroxide-induced L02 cell lines as in vitro hepatitis model

Promote S phase into G2/M phase and recover cell cycle to normal. Reduce NO production and caspase-4 activity and inhibit hepatocyte apoptosis

[51]

 5-Hydroxymethylfurfural

Hydrogen peroxide-induced L02 cell lines as in vitro hepatitis model

Improve hepatocyte morphology and reduce caspase-3&9 expressions

[52]

 5-Hydroxymethylfurfural

d-Galactosamine/TNF-α-induced L02 cell lines as in vitro acute liver injury model

Inhibit hepatocyte apoptosis. Increase Bcl-2 production and decrease intracellular Ca²⁺ level and production of ATF4, Bax, CHOP, PERK, and p-eIF2α

[53]

 7-O-Galloyl-d-sedoheptulose

Db/db mice as obesity-associated type 2 diabetic liver injury model

Improve hepatic histological damage and decrease serum levels of ALT, AST, and blood glucose. Attenuate water intake, food consumption, and body weight gain. Decrease the production of AP-1, NF-κB p65, IL-6, TNF-α, ICAM-1, MCP-1, AGEs, RAGE, GA-pyridine, pentosidine, CEL, CMA, CML, leptin, resistin, p-ERK1/2, and p-JNK

[54]

 Ethanol extract

Acetaminophen-induced mice as liver injury model

Increase levels of CAT, HO-1, and SOD. Suppress lipid peroxidation

[55]

Improving osteoporosis activity

 Sweroside

Rat osteoblasts and human MG-63 cell lines

Stimulate the osteocalcin secretion. Increase cell proliferation and inhibit apoptotic cell death. Increase ALP activity

[56]

 CF extract

RANKL-induced mice BMDM as in vitro osteoclast differentiation model

Suppress osteoclast differentiation. Reduce protein and mRNA levels of c-Fos, NFATc1, OSCAR, and TRAP. Inhibit phosphorylation of p-38 and c-JNK and degradation of I-κB

[57]

Promoting melanogenesis activity

 Methanol extract

Melan-a cell lines

Increase the production and activity of tyrosinase. Increase MITF-M mRNA level and TRP-1&2 production

[58]

Immunomodulatory activity

 Aqueous extract

C57BL/6 mice are transplanted with a skin graft from Balb/C donors

Prolong skin allograft survival. Reduce the number of graft-infiltrating T cells and inhibit their proliferation. Decrease intracellular IL-12 expression by intragraft DCs and IFN-γ expression by graft-infiltrating T cells. Reduce intragraft IL-12 mRNA level

[59]

Lung-protective activity

 Oleanolic acid

 Ursolic acid

Epidermal growth factor—and phorbol ester‐induced NCI‐H292 cell lines as in vitro airway diseases model

Decrease protein and mRNA levels of MUC5AC mucin

[60]

 Aqueous extract

Ovalbumin-induced BALB/c mice as allergic asthma model

Inhibit eosinophil infiltration and ameliorate allergic airway inflammation and airway hyperresponsiveness. Decrease the production of IL-5&13 and OVA-specific IgE

[61]

Vasorelaxation activity

 Cornuside

Phenylephrine-contracted rat aorta and HUVEC

Dilate vascular smooth muscle in the rat and increase cGMP production in vitro

[62]

Antiviral activity

 Aqueous extract

CVA16 infected Vero cells as in vitro HFMD model

Inhibit CVA16 replication

[63]