Relevance of NLRP3 Inflammasome-Related Pathways in the Pathology of Diabetic Wound Healing and Possible Therapeutic Targets

Table 1

Summary of treatment strategies by modulating NLRP3 inflammasome pathways in DW.

Signal 1	Agent	Mechanism	Indicators	Diabetic wound healing	Model
	GC-AgNPs-CGP	Activate Nrf2/HO-1 and inhibit TLR4/NF-κB pathways	MDA↓, SOD↑, Nrf2↑, Nqo-1↑, HO-1↑, Keap-1↓, MMP-2↓	Improve the wound healing	CGP dressed diabetic Sprague Dawley rats
	Genistein	Improve cutaneous Nrf2-related antioxidant and reduce NF-κB-associated inflammation	NLRP3↑, ASC↑, caspase-1↑, IL-1β↑, NF-κB↓, Nrf2↑, HO-1↓	Accelerate delayed wound healing	Alloxan monohydrate induced mice
	Plumbagin	Improve antioxidant status and reduce inflammation	Nrf2↑, MMP-2↓, NF-κB↓, TNF-α↓, IL-6↓, IL-1β↓	Improve wound healing activity	STZ-induced Wistar albino rats
	Neferine	Inhibit inflammatory cytokines and Nrf2 pathway	Nrf2↑, SOD↑, CAT↑, GPx↑, NF-κB↓, TNF-a↓, IL-6↓, IL-1β↓	Promote faster wound healing	STZ-induced Wistar rats
	Rutin	Reduce oxidative stress and inflammatory response	Nrf2↑, SOD1↑, GPx↑, HO-1↑, MMP-2↓, NFκB↓, TNF-α↓, IL-6↓, IL-1β↓	Promote wound healing	STZ-induced Wistar rats
	Luteolin	Inactivate NF-κB and upregulate Nrf2	Nrf2↑, SOD1↑, GPx↑, MMP-9↓, NF-κB↓, TNF-α↓, IL-6↓, IL-1β↓	Promote wound restoration	STZ-induced rats
	Metformin	Regulate AMPK/NLRP3 inflammasome pathway	NLRP3↓, IL-1β↓, caspase-1↓, p-AMPK/AMPK↑, p-mTOR/mTOR↓, IL-10↑	Accelerate the wound healing	Sprague-Dawley rats
	Rapamycin	Inhibit mTOR/NF-κB pathways	NLRP3↓, ASC↓, caspase-1↓, mTOR phosphorylation↓, NF-κB↓	Accelerate the wound healing	THP-1-derived macrophages
	Wnt7a	Regulate high autophagic and inflammatory response	NLRP3↓, LC3A/B↓, IL-1β↓, caspase-1↓, TLR4↓, p62↓, TNF-a↓	Accelerate diabetic wound healing process	STZ-induced Sprague-Dawley rats
	Paeoniflorin	Inhibit NF-κB and NLRP3 signaling pathways	CXCR2↓, NF-κB↓, NLRP3↓, cleaved caspase-1↓	Attenuate wound inflammation and better wound healing	STZ-induced Sprague-Dawley rats
	Topical calcitriol application	Suppress NLRP3-IL-1β signaling pathway	NLRP3↓, pro-IL-1β↓, IL-1β↓, cleaved caspase-1↓, ASC↓	Promotes corneal wound healing	STZ-induced C57BL/6 mice
	MF-094	Inhibit the NLRP3 inflammasome	NLRP3↓, caspase-1 p20↓	Accelerate diabetic wound healing	STZ-induced rats
	Sulforaphane	Alleviate oxidative stress, increase proliferation and migration, decrease apoptosis	Nrf2↑, HO-1↑, NQO1↑, TGF-β1 ↑, MMP9↓	Promote diabetic wound healing	STZ-induced diabetic mice
	Cinnamaldehyde	Alleviate oxidative stress, increase proliferation and migration, decrease apoptosis	Nrf2↑ ,HO-1↑, NQO1↑, TGF-β1↑, MMP10↓	Promote diabetic wound healing	STZ-induced diabetic mice
Signal 2
	BAY 11–7, 082	Selectively inhibit NLRP3 inflammasome activity	Active caspase-1↓, IL-1β↓, IL-18↓, VEGF↑, and CXCL12↑	Improve the impaired healing pattern: a decrease time to complete skin healing	Db/db mice
	BBG	Purinergic P2X7 receptor inhibitor	Active caspase-1↓, IL-1β↓, IL-18↓, VEGF↑, and CXCL12↑	Improve the impaired healing pattern: a decreased time to complete skin healing	db/db mice
	Zol	Active K+/P2X7 receptor/ROS pathway	NLRP3↑, caspase-1↑, IL-1β↑	Impair oral socket wound healing	db/db mice
	BSP	Inhibit NLRP3 inflammasome activation	TNF-α↓, ROS↓, IL-1β↓, IL-18↓, caspase-1↓, NLRP3↓	Accelerate diabetic wound healing, suppress macrophage infiltration, and promote angiogenesis	High fat-diet feeding combined with streptozocin in C57BL/6 mice; macrophages
	YVAD	The caspase-1 inhibitor	IL-1β↓, IL-18↓, NLRP3↓	Improve wound healing	Keratinocytes and Mp
	Glyburide	Close ATP-sensitive potassium channels	IL-1β↓, IL-18↓, NLRP3↓	Improve wound healing	Keratinocytes and Mp
	Melatonin	Inhibition of NLRP3 inflammasome activation	TNF-α↓, IL-1β↓, IL-6↓, IL-8↓, NLRP3↓	Promote diabetic wound healing	Keratinocytes
	MFG-E8	Intergrin β3-limited P2X7 receptor pathways	Active caspase-1↓, IL-1β↓, IL-18↓, NLRP3↓	Improve angiogenesis and accelerates wound healing	Mfge8-/-diabetic mice, Mfge8-/-neutrophils
	Fenofibrate	Inhibition of ROS/TXNIP/NLRP3 pathway	TXNIP↓, active caspase-1↓, IL-1β↓ ,IL-18↓, NLRP3↓	Accelerate wound healing	STZ-induced diabetic mice, EPC
	NAC	A free radical scavenger	ROS↓, IL-1β↓ ,IL-18↓, caspase-1↓, NLRP3↓	Improve the wound healing	STZ-induced diabetic mice

Abbreviation: GC-AgNPs-CGP: gallocatechin-silver nanoparticle-impregnated cotton gauze patches; Nrf2: nuclear factor erythroid-2-related factor; HO-1: heme oxygenase 1; TLR4: Toll-like receptor 4; NF-κB: nuclear factor kappa-B; MDA: malonaldehyde; SOD: superoxide dismutase; Nqo-1:NADPH quinone oxidoreductase-1; Keap-1: Kelch-like ECH-associated protein 1; MMP-2: matrix metalloproteinase-2; NLRP3: Nod-like receptor protein 3; ASC: apoptosis-associated speck-like protein containing; IL-1β: interleukin-1; STZ: streptozocin; TNF-α: tumor necrosis factor-alpha; IL-6: interleukin-6; GPx: glutathione peroxidases; MMP-9: matrix metalloproteinase-9; AMPK: adenosine monophosphate-activated protein kinase; mTOR: mechanistic target of rapamycin; IL-10: interleukin-10; LC3A/B: microtubule-associated protein 1A/1B-light chain 3; TLR4: Toll-like receptor 4; CXCR2: C-X-C motif chemokine receptor 2; Mp: macrophage; VEGF: vascular endothelial growth factor; TGF-β1: transforming growth factor beta1; MMP10: matrix metalloproteinase-10; CXCL12: chemokine C-X-C motif ligand 12; ROS: reactive oxygen species; IL-18: interleukin-18; P2X7: BBG: brilliant blue G; Zol: zoledronate; BSP: Bletilla striata polysaccharide; YVAD: Tyr-Val-Ala-Asp; MFG-E8: milk fat globule epidermal growth factor VIII; NAC: N-acetylcysteine; TXNIP: thioredoxin-interacting protein.