Protective Effect and Possible Mechanisms of Artemisinin and Its Derivatives for Diabetic Nephropathy: A Systematic Review and Meta-Analysis in Animal Models

Table 1

Basic characteristics of included studies.

Study	Species (sex; ), age/weight	Model		Experimental group	Control group	Administration/duration	Outcomes	Intergroup differences
		Establish	Modeling standard
Han et al., 2019	db/db mice (male, 6/6), 8 weeks/NM	Spontaneous diabetes	NM	Regular diet supplemented with artemether, 670 mg/kg/d	Regular diet	By free access to the diets, 12 weeks	(1) Protein excretion; (2) Body weight; (3) FPG; (4) Catalase↓; (5) SOD2↓; (6) PGC-1α↑; (7) PDK1↑; (8) PDH↑; (9) MPC2↑; (10) MPC1↑; (11) PDP1↑; (12) Renal pathology	(1); (2); (3); (4); (5); (6); (7); (8); (9); (10); (11)
Liang et al., 2020 (A)	SD rats (male, 20/10), NM/180-220 g	SIJ STZ (60 mg/kg)		Artesunate, 50, 100 mg/kg/d	Same volume of NS	By intragastric, 3 weeks	(1) Bun; (2) SCr; (3) KI; (4) TGF-β1↓; (5) SMAD↓; (6) AMPK↑; (7) LC3 II↑; (8) Renal pathology	(1); (2); (3); (4); (5); (6); (7)
Liang et al., 2020 (B)	SD rats (male, 31/10), 8 weeks/200-220 g	SIJ STZ (55 mg/kg)	;	Dihydroartemisinin, 10, 20, 40 g/kg/d	Same volume of NS	By intragastric, 8 weeks	(1) Bun; (2) SCr; (3) Microalbuminuria; (4) Body weight; (5) TGF-β1↓; (6) SMAD3↓; (7) p- SMAD3↓; (8) Fibronectin↓; (9) E-cadherin↑	(1); (2); (3); (4); (5); (6); (7); (8); (9)
Lin, 2018	SD rats (male, 30/10), NM/180-220 g			Artemisinin suspended in 0.5% sodium CMC, 25, 50, and 75 mg/kg/d	NS, 10 ml/kg/d	By intragastric, 12 weeks	(1) Proteinuria; (2) Body weight; (3) FPG; (4) KI; (5) TGF-β1↓; (6) RhoA↓; (7) ROCK1↓; (8) α-SMA↓; (9) E-cadherin↑; (10) Renal pathology	(1); (2); (3); (4); (5); (6); (7); (8); (9)
Nie et al., 2015 (A)	SD rats (male, 18/6), 6–8 weeks/180-220 g	(40 mg/kg)	; of the original volume;	Artesunate, 10, 20, and 30 mg/kg/d	NM	By intragastric, 8 weeks	(1) Bun; (2) SCr; (3) Proteinuria; (4) Body weight; (5) FPG; (6) KI; (7) MCP-1↓; (8) TNF-α↓; (9) TLR4↓; (10) Renal pathology	(1); (2); (3); (4); (5); (6); (7); (8); (9)
Nie et al., 2015 (B)	SD rats (male, 18/6), 6–8 weeks/180-220 g	(40 mg/kg)	; of the original volume;	Artesunate, 10, 20, and 30 mg/kg/d	NM	By intragastric, 8 weeks	(1) Bun; (2) SCr; (3) Proteinuria; (4) FPG; (5) MCP-1↓; (6) TNF-α↓; (7) Renal pathology	(1); (2); (3); (4); (5); (6)
Nie et al., 2015 (C)	SD rats (male, 16/8), 6–8 weeks/180-220 g	(30 mg/kg)	; of the original volume;	Artesunate, 10 and 30 mg/kg/d	NS, 10 mg/kg/d	By intragastric, 12 weeks	(1) Bun; (2) SCr; (3) Proteinuria; (4) Body weight; (5) FPG; (6) KI; (7) IL-8↓; (8) TLR4↓	(1); (2); (3); (4); (5); (6); (7); (8)
Tan, 2014	SD rats (male,20/10), NM/NM			Artesunate, 25 and 50 mg/kg/d	Same volume of distilled water	By intragastric, 6 weeks	(1) Microalbuminuria; (2) FPG; (3) KI; (4) TGF-β1↓; (5) CTGF↓; (6) Renal pathology	(1); (2); (3); (4); (5)
Wang et al., 2019	C57BL/6J mice (male,6/6), 7-8 weeks/22-26 g	Continuous intraperitoneal injections STZ (55 mg/kg)	NM	Regular diet supplemented with artemether, 670 mg/kg/d	Regular diet	By free access to the diets, 8 weeks	(1) Protein excretion; (2) FPG; (3) p-p27^kip↓; (4) p-MEK1/2↓; (5) p-Erk1/2↓; (6) p-Akt↓; (7) p-mTOR↓; (8) p70S6K↓; (9) S6RP↓; (10) Catalase↑; (11) SOD2↑; (12) PDK1↓; (13) PGC-1α↑; (14) MPC1↑; (15) PDH↑; (16) Renal pathology	(1); (2); (3); (4); (5); (6); (7); (8); (9); (10); (11); (12); (13); (14); (15); (16)
Xiang et al., 2019	SD rats (male, 6/6), NM/250-300 g	SIJ STZ (60 mg/kg)	; of the original volume; before modeling	Artemisinin, 300 mg/kg/d	Same volume of NS	By intragastric, 4 weeks	(1) Bun; (2) SCr; (3) Proteinuria; (4) FPG; (5) ID1↓; (6) IGFBP1↑; (7) Cdkn1a↓; (8) HMGCS2↓; (9) Rarres2↓; (10) Sult1a1↑; (11) Pigr↑; (12) Steap4↑; (13) Renal pathology	(1); (2); (3); (4); (5); (6); (7); (8); (9); (10); (11); (12)
Yang and Zhang, 2017	Wistar rats (male, 40/20), NM/200-260 g	(30 mg/kg)		Artesunate, 10 and 30 mg/kg/d	NS, 1 ml/kg/d	By intragastric, 8 weeks	(1) Bun; (2) SCr; (3) Proteinuria; (4) Body weight; (5) FPG; (6) KI; (7) IL-8↓; (8) TLR4↓	(1); (2); (3); (4); (5); (6); (7); (8)
Zhang et al., 2014 (A)	SD rats (male, 6/6), NM/180-220 g	SIJ STZ (65 mg/kg)		Artemisinin suspended in DMSO, 75 mg/kg/d	Same volume of DMSO	By SIJ, 6 weeks	(1) Bun; (2) SCr; (3) Protein excretion; (4) Body weight; (5) FPG; (6) KI; (7) PDGF-B↓; (8) Renal pathology	(1); (2); (3); (4); (5); (6); (7)
Zhang et al., 2014 (B)	SD rats (male, 6/6), NM/180-220 g	SIJ STZ (65 mg/kg)		Artemisinin suspended in DMSO, 75 mg/kg/d	Same volume of DMSO	By SIJ, 6 weeks	(1) Bun; (2) SCr; (3) Protein excretion; (4) Body weight; (5) FPG; (6) KI; (7) PKC↓; (8) Renal pathology	(1); (2); (3); (4); (5); (6); (7)
Zhang et al., 2014 (C)	SD rats (male, 6/6), NM/180-220 g	SIJ STZ (65 mg/kg)		Artemisinin suspended in DMSO, 75 mg/kg/d	Same volume of DMSO	By SIJ, 6 weeks	(1) Bun; (2) SCr; (3) Protein excretion (4) Body weight; (5) FPG; (6) KI; (7) MMP-2↑; (8) TIMP-2↓; (9) Fibronectin↓; (10) Col4A1↓; (11) Renal pathology	(1); (2); (3); (4); (5); (6); (7); (8); (9); (10)
Zhang et al., 2020	SD rats (male, 33/10), 5-6 weeks/160-200 g	SIJ STZ (55 mg/kg)		Artemisinin suspended in 0.5% sodium CMC, 25, 50, and 75 mg/kg/d	Same volume of 0.5% SCC	By intragastric, 8 weeks	(1) Bun; (2) SCr; (3) Protein excretion; (4) Body weight; (5) FPG; (6) KI; (7) TGF-β1↓; (8) Nrf2↑; (9) HO-1↑; (10) NQO-1↑; (11) MDA↓; (12) T-SOD↑; (13) GSH-Px↑; (14) Renal pathology	(1); (2); (3); (4); (5); (6); (7); (8); (9); (10); (11); (12); (13)
Zhou et al., 2014 (A)	SD rats (male, 5/5), NM/180-220 g	SIJ STZ (65 mg/kg)		Artemisinin suspended in DMSO, 300 mg/kg/d	Same volume of DMSO	By SIJ, 4 weeks	(1) AP-1↓; (2) Renal pathology	(1)
Zhou et al., 2014 (B)	SD rats (male, 5/5), NM/180-220 g	SIJ STZ (65 mg/kg)		Artemisinin suspended in DMSO, 300 mg/kg/d	Same volume of DMSO	By SIJ, 4 weeks	(1) c-Jun↓; (2) c-Fos↓; (3) Renal pathology	(1); (2)
Zhou et al., 2014 (C)	SD rats (male, 5/5), NM/180-220 g	SIJ STZ (65 mg/kg)		Artemisinin suspended in DMSO, 300 mg/kg/d	Same volume of DMSO	By SIJ, 4 weeks	(1) NF-κB↓; (2) Renal pathology	(1)

Abbreviations: AMPK: AMP-activated protein kinase; BG: blood glucose; BUN: blood urea nitrogen; Cdkn1a: cyclin dependent kinase inhibitor 1A; Col4A1: collagen type IV alpha-1 chain; CTGF: connective tissue growth factor; DMSO: dimethyl sulfoxide; Erk: extracellular signal-regulated kinase; FPG: fasting plasma glucose; GSH-Px: glutathione peroxidase; HFD: high-fat diet; Hmgcs2: 3-hydroxy-3-methylglutaryl-CoA synthase 2; HO-1: heme oxygenase-1; Id1: inhibitor of DNA binding 1; Igfbp1: insulin like growth factor binding protein 1; IL-8: interleukin-8; KI: kidney index; LC3 II: microtubule-associated proteins 1A/1B light chain 3B type II; MAPK: mitogen-activated protein kinase; MCP-1: monocyte chemoattractant protein-1; MDA: malondialdehyde; MPC1 & MPC2: mitochondrial pyruvate carrier 1 & 2; MMP-2: matrix metallopeptidase-2; NF-κB: nuclear factor kappa B; NM: not mentioned; NQO-1: NAD(P)H quinone oxidoreductase-1; Nrf2: nuclear factor erythroid 2-related factor 2; NS: normal saline; p-Akt: phospho-protein kinase B; p-mTOR: phospho-mammalian target of rapamycin; PGC-1α: peroxisome proliferator-activated receptor γ coactivator-1α; PDGF-B: platelet-derived growth factor-B; PDH: pyruvate dehydrogenase; PDP1:pyruvate dehydrogenase phosphatase 1; PDK1: pyruvate dehydrogenase kinase 1; Pigr: polymeric immunoglobulin receptor; PKC: protein kinase C; Rarres2: retinoic acid receptor responder 2; RhoA: ras-homolog gene family, member A; ROCK1: rho-associated coiled-coil containing protein kinase 1; SCr: serum creatinine; SD rats: Sprague Dawley rats; SIJ: single intraperitoneal injection; SOD: superoxide dismutase; α-SMA: α-smooth muscle actin; STZ: streptozotocin; sodium CMC: sodium carboxymethyl cellulose; Sult1a1: sulfotransferase 1A1; Steap4: six-transmembrane epithelial antigen of prostate 4; TGF-β1: transforming growth factor-β1; TIMP-2: tissue inhibitor of metalloproteinase-2; TLR4: toll-like receptor 4; TNF-α: tumor necrosis factor-α; T-SOD: total superoxide dismutase. Compared with the control group, ↓ indicates reduction while ↑ indicates increase.