Natural product-based treatment potential for type 2 diabetes mellitus and cardiovascular disease

Table 1 basic characteristics of included randomized control trial studies

No.	Year	Study design	Setting	Department	Sample size	Intervention	Dose	Duration	Effect	Ref.
1	2021	Double-blind placebo	St. Michael’s Hospital, University of Toronto	Out patient’s department	24 T2DM patients	American ginseng	1 g/meal (3 g/d)	8 wk	Decrease blood glucose, HbA1c, and systolic blood pressure and increase nitric oxide	[26]
2	2020	Randomized, placebo-controlled, two-center trial	Two university-affiliated centres (St. Michael’s Hospital Toronto, Canada, and KB Merkur Hospital, Zagreb, and Croatia)		80 participants with diagnosed T2D and hypertension	American ginseng extract and Rg3- enriched Korean ginseng extract [f 1.50 g/d AG and 0.75 g/d Rg3-KRG standardized extracts (extracted to contain 75 mg of ginsenoside Rg3 and 375 mg total ginsenosides)]	2.25 g 3 times daily	12 wk	Reduce end-systolic pressure (-6.60 mmHg ± 2.50 mmHg	[27]
3	2018	Double-blinded, randomized, placebo-controlled trial	Diabetes PRAXIS Rathausallee, Duisburg, Germany	Specialized medical office for diabetology	42 hypertensive patients with T2D	Flavanol-rich cocoa	2.5 g/d	12 wk	Reduce HOMA-IR and blood cholesterol level	[28]
4	2018	Randomized, placebo-controlled trial	Iranian Diabetes Society and Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences	Out patients department	62 T2DM patients with at least one year of diabetic history	M. officinalis capsules	700 mg/d	12 wk	Reduce FBS, HbA1c, Insulin (min/mL), HOMA-b cell (%), hs-CRP (mg/L)	[29]
5	2019	Randomized, single-blind controlled trial	Shiraz Heart Center Outpatient Clinic affiliated with the Shiraz University of Medical Sciences, Shiraz, Iran	Out patients department	75 metabolic syndrome patients	Sesame oil enriched with vit E group	30 mL/d sesame oil + 400 mg vit E powder	2 wk	Reductions in serum total cholesterol, triglycerides, FBG, HOMA-IR, MDA, hs-CRP, HDL-C systolic and diastolic BP	[30]
6	2019	Randomized, double-blinded, placebo-controlled trial	Cardiology clinic affiliated to Kashan University of Medical Sciences (KAUMS), Kashan, Iran	Out patients department	90 T2D patients	Flaxseed oil and fish oil	1000 mg of flaxseed oil, as the source of omega-3 fatty acids, containing 400 mg of ALA (n = 30) or 1000 mg of fish oil containing 250 mg of EPA and 150 mg of DHA	12 wk	Reduce high-sensitivity CRP significant increase in total nitrite al antioxidant capacity	[31]
7	2020	Randomized double-blind clinical trial	Diabetes Control Center of Sabzevar Iran	Out patients department	50 participants with diagnosed T2D	N. Sativa oil	1000 mg N. Sativa oil as two capsules, each containing 500 mg N. Sativa oil, daily	8 wk	Decrease FBS, triglyceride, total cholesterol, low-density lipoprotein cholesterol, serum hs-CRP, mdaand increase in serum level of high-density lipoprotein cholesterol	[32]
8	2020	Random assignment, parallel-group, single-center, double-blind, placebo-controlled design	Nizam’s Institute of Medical Sciences, Hyderabad	Out patients department	74 T2DM patients	T. chebula	T. chebula 250 mg, T. chebula 500 mg	Twice daily for 12 wk	Improves endothelial function (reflection index), GSH, MDA, hs-CRP, total cholesterol, HDL, LDL, HbA1c	[33]
9	2020	Randomized, double-blind, placebo-controlled, cross-over intervention study	Diabetic and general medical clinics of the Prince of Wales Hospital, the teaching hospital of The Chinese University of Hong Kong, Shatin, Hong Kong	Out patients department	20 T2D patients	Bilberry (Vaccinium myrtillus L.)	1.4 g/d of extract) daily	4 wk	Improves glycaemic control by HbA1c and Random blood sugar	[34]

T2DM: Type 2 diabetes mellitus; N. Sativa: Nigella Sativa; T. chebula: Terminalia chebula; M. officinalis: Melissa officinalis; EPA: Eicosapentaenoic acid; DHA: Docosahexaenoic acid; FBS: Fasting blood sugar; HbA1c: Hemoglobin; HOMA-IR: Homeostatic model assessment of insulin resistance; hs-CRP: Highly sensitive C-reactive protein; HDL-C: High-density lipoprotein; BP: Blood pressure; GSH: Glutathione; MDA: Malondialdehyde; LDL: Low-density lipoprotein.

Table 2 Antiglycation activity of natural compounds isolated from plant extract

No.	Plant species	Natural products	Role/mechanism	Ref.
1	Chrysanthemum morifolium	Chlorogenic acid, flavonoid glucoside, and aglycone	Antihyperglycemic, scavenges free radicals and metals, traps reactive carbonyl species	[69,70]
2	Chrysanthemum indicum	Caffeic acid, luteolin, and kaempferol	Antioxidant, anti-inflammatory, protects protein structure	[69,70]
3	Erigeron annuus	Quinic acid derivatives, such as 3,5-di-O-caffeoyl-epi-quinic acid	Inhibition of RLAR (rat lens aldose reductase), AGEs formation, AGEs/BSA cross-linking, and cataract genesis	[69]
4	Cinnamomum verum	Catechin, epicatechin, and procyanidin B2	Antioxidant, DPPH scavenger; traps methylglyoxal, protects protein structure	[69,70]
5	Allium sativum		Strong antioxidants and free radical scavengers, inhibiting CML formation	[69]
6	Ilex paraguariensis	Chlorogenic acid	Antihyperglycemic, scavenges free radicals and metals, traps reactive carbonyl species	[69]
7	Rosmarinus officinalis	Rosmarinic acid, carnosic acid, and carnosol	Antioxidant activity and antiglycation properties	[69]
8	Camellia sinensis	Epigallocatechin, 3-O-gallate (EGCG) and (-)-epicatechin 3-O-gallate (ECG)	Strong antioxidant properties and inhibits the accumulation of CML and CEL and the activation of RAGE	[69]
9	Ginkgo biloba	24% flavonoids and 6% terpenoids	Inhibit the RAGE activation in microvascular endothelial cells induced by hypoxic and hypoglycemic conditions	[69]
10	Garcinia mangostana	Catechins, procyanidins, anthocyanin, and xanthones, such as α-mangostin	Antioxidant, DPPH scavenger; traps methylglyoxal, protects protein structure	[69,70]
11	Thymus vulgaris	Flavonoids quercetin, eriodictyol, 5,6,4′-trihydroxy-7,8,3′-trimethoxyflavone, and cirsilineol	Suppressed the levels of AGEs formation	[69,70]
12	Aralia taibaiensis	Triterpenoid saponin	Potent inhibition of the late glycation and the formation of AGEs	[69]
13	Cuminum cyminum	Sesquiterpenoids, monoterpenoids, and chalcone derivatives	Antiglycation properties	[69]

EGCG: Epigallocatechin gallate; AGFs: Advanced glycated end products; ECG: Epicatechin 3-O-gallate; RLAR: Rat lens aldose reductase; BSA: Bovine serum albumin; DPPH: 2,2-diphenyl-1-picrylhydrazy; CML: Carboxy methyl lysine; CEL: Carboxy ethyl lysine; RAGE: Receptor of advanced glycation end products; DPPH: 2,2-diphenyl-1-picrylhydrazy.