Pharmacological Actions, Molecular Mechanisms, Pharmacokinetic Progressions, and Clinical Applications of Hydroxysafflor Yellow A in Antidiabetic Research

Table 1

Summary of pharmacological effects and mechanisms of HSYA on diabetes and diabetes complications.

Disease	Species/strains	Effective dose/concentration	Route	Positive control	Intervention time	Main improved results	Mechanisms/pathways	Reference
Diabetes	HFD- and STZ-induced T2DM rats	120 mg/kg	i.g.	Metformin as positive control	8 weeks	Pancreatic β-cell apoptosis↓, FBG↓, IR↓, TG↓, TC↓, LDLC↓, glycogen synthase↑, hepatic glycogen↑	Regulation on glycolipid metabolism via PI3K/Akt pathway	[13]
Diabetes	HG-induced rat INS-1 insulinoma cells (pancreatic β-cells)	800 μM		N-Acetylcysteine as oxidative stress scavenger control	72 hours	Pancreatic β-cell apoptosis↓, ROS↓, MDA↓, CAT↑, GSH-px↑, SOD↑	Antioxidative effects via JNK/c-jun pathway	[18]
Diabetic nephropathy	HFD- and STZ-induced T2DM rats	120 mg/kg	i.g.		8 weeks	Scr↓, UN↓, TG↓, TC↓, LDLC↓, FBG↓, TNF-α↓, LDH↓, FFA↓, MDA↓, SOD↑	Antioxidative and anti-inflammation effects	[16]
Diabetic nephropathy	HG-induced mice MPC-5 podocyte cells and HG-induced mice RAW264.7 cells	100 μM, 200 μM		Kaempferol as positive control	24 hours	Podocyte apoptosis↓; In podocytes: TNF-α↓, IL-1β↓; In RAW264.7 cells: TNF-α↓, iNOS↓, IL-1β↓ CD206↑, Arg-1↑	Anti-inflammation effects directly on podocyte cells and indirectly via macrophage polarization	[14]
Diabetic vascular injury	HG-induced HUVECs	10 μM, 25 μM, 50 μM			24, 48, and 72 hours	HUVEC hyperpermeability↓, HUVEC apoptosis↓, VCAM-1↓, ICAM-1↓, E-selectin↓, NOX4↓, ROS↓, H2O2↓	Anti-inflammation effects via the NOX4 pathway	[19]
Diabetic vascular injury	Methylglyoxal-induced HBMECs	10, 50, and 100 μM			24 hours	HBMEC apoptosis↓, caspase-3↓, AGEs↓	Antiglycation effects	[20]
Diabetic wound	STZ-induced T1DM rats	2 mg/mL	vs ext	Hydrogel as positive control	30 days	Wound closure↑, granulation tissue formation↑, collagen disposition↑, secretion of VEGF↑, TGF-β1↑		[17]
Diabetic wound	HUVECs and LPS-induced RAW264.7 cells	0.4, 0.8, and 1.6 mM			60 and 96 hours	NO production↓, HEK migration↑, HUVEC tube formation↑	Anti-inflammation effects	[17]
Diabetic obesity	3T3-L1 preadipocytes and adipocytes	100 mg/L			24 hours	PPARγ2 promoter activities↑, PPARγ2↑	Increasing the expression of insulin signaling pathway-related genes	[21]

Abbreviations: T1DM: type 1 diabetes mellitus; T2DM: type 2 diabetes mellitus; HFD: high-fat diet; STZ: streptozotocin; FBG: fasting blood glucose; IR: insulin resistance; TG: triglyceride; TC: total cholesterol; LDLC: low-density lipoprotein cholesterol; DN: diabetic nephropathy; ROS: reactive oxygen species; SOD: superoxide dismutase; CAT: catalase; GSH-px: glutathione peroxidase; MDA: malondialdehyde; Scr: serum creatinine; UN: urea nitrogen; LDH: lactate dehydrogenase; FFA: free fatty acids; NOX4: NADPH oxidase 4; H₂O₂: hydrogen peroxide; HG: high glucose; HBMECs: human brain microvascular endothelial cells; HUVECs: human umbilical vein endothelial cells; VCAM-1: vascular cell adhesion molecule-1; ICAM-1: intercellular adhesion molecule-1; iNOS: inducible nitric oxide synthase; TNF-α: tumor necrosis factor-α; CD206: mannose receptor; Arg-1: arginase-1; IL-1β: interleukin-1β; LPS: lipopolysaccharide; AGEs: advanced glycation end-products; VEGF: vascular growth factors; TGF-β1: transforming growth factor-β1; NO: nitric oxide; HEKs: human epithelial keratinocytes; PPARγ2: peroxisome proliferator-activated receptor-γ2.