Bletilla striata Polysaccharide Promotes Diabetic Wound Healing Through Inhibition of the NLRP3 Inflammasome

Abstract

The aim of this study was to evaluate the therapeutic effects of Bletilla striata polysaccharide (BSP) on wound healing in diabetes mellitus (DM) and to explore the underlying mechanisms. DM mouse models were induced by high fat-diet feeding combined with low-dose streptozocin injection. To establish diabetic foot ulcer (DFU) models, DM mice were wounded on the dorsal surface. Subsequently, mice were treated with vehicle or BSP for 12 days and wound healing was monitored. The effects of BSP on the production of interleukin-1β (IL-1β), tumor necrosis factor-α, macrophages infiltration, angiogenesis, the activation of nucleotide-binding and oligomerization (NACHT) domain, leucine-rich repeat (LRR), and pyrin domain (PYD)-containing protein 3 (NLRP3) inflammasome, and insulin sensitivity in wound tissues were subsequently evaluated. Separated- and cultured- bone marrow-derived macrophages (BMDMs) and cardiac microvascular endothelial cells (CMECs) were isolated from mice and used to investigate the effects of BSP on cell viability, reactive oxygen species (ROS) generation, NLRP3 inflammasome activation and insulin sensitivity in vitro following exposure to high glucose (HG). BSP administration accelerated diabetic wound healing, suppressed macrophage infiltration, promoted angiogenesis, suppressed NLRP3 inflammasome activation, decreased IL-1β secretion, and improved insulin sensitivity in wound tissues in DM mice. In vitro, co-treatment with BSP protected against HG-induced ROS generation, NLRP3 inflammasome activation, and IL-1β secretion in BMDMs, and improved cell viability and decreased ROS levels in CMECs. Moreover, in HG exposed BMDMs-CMECs cultures, BSP treatment suppressed NLRP3 inflammasome activation and IL-1β secretion in BMDMs, and improved cell viability and insulin sensitivity in CMECs. Furthermore, treatment with IL-1β almost completely suppressed the beneficial effects of BSP on the NLRP3 inflammasome, IL-1β secretion, and insulin sensitivity in HG-treated BMDMs-CMECs. BSP promotes DFU healing through inhibition of the HG-activated NLRP3 inflammasome.

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

“…Oxidative Medicine and Cellular Longevity 9 Oxidative Medicine and Cellular Longevity Persistent NLRP3 activation in macrophages disrupts the transformation of the inflammatory M1 phenotype to M2 phenotype, which results in delayed healing of DW [57]. Treatment with Bletilla striata polysaccharide, the main active ingredient of Bletilla striata, promotes wound healing by suppressing the NLRP3 inflammasome, and as a result, induces a switch from the proinflammatory M1 phenotype towards the prohealing M2 phenotype [132]. The external use of glibenclamide can show similar pharmacological effects by inhibiting NLRP3 inflammasome activity and reducing the expression of inflammatory factors to downregulate the MI phenotype and upregulate the M2 phenotype [48].…”

Botanical Drugs in Traditional Chinese Medicine With Wound Healing Properties

“…In RAW264.7 cells, BRP (5–200 μg/ml) stimulated the expression of iNOS, TNF-α, and IL-1β in concentration-dependent manner ( Diao et al, 2008 ). A recent study conducted in the diabetic mouse model found that 5% BRP solution (50 μl) treatment once daily could accelerate the diabetic wound healing via inhibiting the high glucose-activated NLRP3 inflammasome ( Zhao et al, 2021 ). Additionally, BRP could also be used for the treatment of oral ulcer ( Liao et al, 2019 ).…”

Therapeutic Effect and Mechanism of Negative Pressure Wound Therapy with Huoxue Shengji Decoction Instillation for Chronic Skin Ulcers

“…The main components including Astragalus membranaceus [ 22 , 23 ], Salvia miltiorrhiza [ 24 ], and Safflower [ 25 ] and their extracts or monomers demonstrated the ability to upregulate the expression of VEGF/VEGFR2 in HUVECs and promote angiogenesis in vitro. The extracts or monomers of Angelica dahurica [ 26 ], Frankincense [ 27 ], Myrrh [ 28 ], and Bletilla striata [ 29 ] also showed antibacterial and anti-inflammatory effects in promoting wound healing. This is consistent with the theory of traditional Chinese medicine.…”