Modulatory effect of caffeic acid in alleviating diabetes and associated complications

Table 1 Protective effects of caffeic acid and derivatives in diabetes and associated complications

Type of study/condition	Dose	Mode of action	Ref.
STZ-induced diabetic mice	Topical administration of propolis at 20 μL	Healing of human DFU	[79]
	CAPE at 5 μmol/kg and 10 μmol/kg	Increased wound contraction and re-epithelialization by reducing oxidative stress	[80,81]
Diabetic mice with DFU	Topical application of propolis	Stimulated VEGF and activated NO/cGMP pathway	[82,83]
Diabetic mice with renal damage	CA at 5%	Decreased AGEs, IL-1b, and IL-6, and reduced activity of renal AR and SDH.	[92]
STZ-induced diabetic mice, nephropathy	CA at 10-50 mg/kg	Modulation of autophagy pathway	[93]
	CA at 40 mg/kg	Improved renal parameters, and downregulated the expression of miR-636	[94]
	CAPE and CAPE-pNO2 at 20 μmol/kg/d	Inhibited inflammation through the Akt/NF-κB pathway and prevented renal fibrosis through the TGF-β/Smad pathway	[95]
Diabetes induced in HUVECs	CAPE treatment at 3-10 μM	Reduced VEGF-induced angiogenesis	[96]
STZ-induced diabetic rats, retinopathy	CAF6 and CAF12 at 250 mM	Modulation of ERK1/2 and protein kinase-B/Akt signaling pathways	[98]
STZ-induced diabetic rats, neuropathy	CAPE at 10 μM/kg/d	Inhibition of iNOS enzyme	[102]
Alloxan-induced diabetic mice, CVD	CA at 50 mg/kg	Reduced atherogenic indices such as TG, LDL-c, VLDL-c, and TC	[53]
	CA at 2%	Improved glycemic control and lipid metabolism, increased plasma antithrombin-III and protein C activities, and decreased MDA, IL-β, IL-6, and TNF-α levels	[34]
STZ-induced T1D rat model, CVD	CAPA at 3 and 15 mg/kg	Reduced myocardial infarction and amelioration of cardiac dysfunction	[103]

STZ: Streptozotocin; DFU: Diabetic foot ulcer; CAPE: Caffeic acid phenethyl ester; VEGF: Vascular endothelial growth factor; NO: Nitric oxide; cGMP: Cyclic guanosine monophosphate; CA: Caffeic acid; AGEs: Advanced glycation end products; IL: Interleukin; AR: Aldol reductase; SDH: Sorbitol dehydrogenase;CAPE-pNO2: Caffeic acid para-nitro phenethyl ester; NF-κB: Nuclear factor-κB; TGF-β: Transforming growth factor-β; HUVECs: Human umbilical vein endothelial cells; ERK: Extracellular signal regulated kinase; iNOS: Inducible nitric oxide synthase; TG: Triacylglycerol; LDL-c: Low density lipoprotein cholesterol; VLDL-c: Very low-density lipoprotein cholesterol; TC: Total cholesterol; T1D: Type1 diabetes; MDA: Malondialdehyde; TNF-α: Tumor necrosis factor-α; CVD: Cardiovascular disorder;CAPA: Caffeic acid phenethyl amide.

Table 2 List of clinical trials conducted on propolis against diabetes mellitus

Number	Treatment	Condition	Outcome	ClinicalTrials.gov Identifier, phase, and status of trial
1	Propolis 300 mg twice a day for 12 wk	Type 2 DM	Propolis administration modified the glycemic control in patients with type 2 DM	ClinicalTrials.gov
				Identifier: NCT03416127
				Phase: 2
				Status: Completed
2	Propolis 400 mg for 6 mo, after performing scaling and root planing	Type 2 DM, periodontitis	Improvement in HbA1c, FPG, serum CML, and changes in periodontal parameters	ClinicalTrials.gov
				Identifier: NCT02794506
				Phase: 4
				Status: Completed
3	Propolis spray at the site of injury	Diabetic foot ulcer	Propolis possesses anti-inflammatory and antioxidant effects and its topical application is well tolerated, improving the healing of human diabetic foot ulcer	ClinicalTrials.gov
				Identifier: NCT03649243
				Phase: Not applicable
				Status: Completed

DM: Diabetes mellitus, HbA1c: Hemoglobin A1c, FPG: Fasting plasma glucose, CML: Carboxymethyllysine.