Schisandrin B Attenuates Diabetic Cardiomyopathy by Targeting MyD88 and Inhibiting MyD88‐Dependent Inflammation

Abstract

Diabetes manifests as chronic inflammation and leads to the development diabetic cardiomyopathy (DCM). Targeting key proteins in inflammatorysignaling may provide new therapy for DCM. In this study, the authors explore the pharmacological effects and mechanisms of Schisandrin B (Sch B), a natural compound with anti-inflammatory activity against DCM. It is shown that Sch B prevents high-level glucose (HG)-induced hypertrophic and fibrotic responses in cultured cardiomyocytes. RNA sequencing and inflammatory qPCR microarray show that Sch B mainly affects myeloid differentiation primary response 88 (MyD88)-dependent inflammatory gene expression in HG-challenged cardiomyocytes. Further studies indicate that Sch B directly binds to and inhibits MyD88 activation, but does not alter MyD88-independent Toll-like receptor signaling in vivo and in vitro. Inhibiting or silencing MyD88 is associated with reduced levels of HG-induced inflammatory cytokines and myocardial injuries in vitro. Treatment of type 1 and type 2 diabetic mice with Sch B protects heart function, reduces myocardial injuries, and decreases secretion of inflammatory cytokines. Cardiomyocyte-specific MyD88 knockout also protects mice against cardiac inflammation and injury in type 1 diabetic mice. In conclusion, these studies show that cardiomyocyte MyD88 plays an apathogenetic role in DCM and Sch B specifically targets MyD88 to reduce inflammatory DCM.

The essential role of glutamine metabolism in diabetic cardiomyopathy: A review

“…[47] Additionally, interventions targeting the interaction between MyD88 and TLR4 or inhibiting MyD88 itself have shown promise in safeguarding cardiac tissues in both type 1 and type 2 diabetic murine models, effectively preventing the activation of the MyD88-dependent proinflammatory signaling pathway. [48] The activation of nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 inflammasome plays a crucial role in the development of DCM, as evidenced by previous studies. [49][50][51][52][53][54] These studies have demonstrated that hyperglycemia can activate NLRP3, subsequently activating caspase-1.…”

“…[47] Additionally, interventions targeting the interaction between MyD88 and TLR4 or inhibiting MyD88 itself have shown promise in safeguarding cardiac tissues in both type 1 and type 2 diabetic murine models, effectively preventing the activation of the MyD88-dependent proinflammatory signaling pathway. [48]…”

A LC-MS/MS Method for Quantifying the Schisandrin B and Exploring Its Intracellular Exposure Correlating Antitumor Effect

“…Sch.B has a core structure of dibenzocyclooctadiene, which inhibited efflux of chemotherapeutic drug and restored the intracellular drug accumulation by inhibiting P-glycoprotein and mutidrug resistance protein 1 [ 29 , 30 ]. In addition, Sch.B was reported to protect myocardial cell through interacting with the TIR domain of MyD88 in the cytoplasm and inhibiting MyD88-independent inflammation to attenuate diabetic cardiomyopathy [ 31 ]. The spatial distribution of Sch.B may have a critical role in exerting its effects, and further studies are needed to connect the spatial exposure levels of Sch.B inside the cells with the anticancer effect.…”

Progress in the treatment of diabetic cardiomyopathy, a systematic review

“…85 In recent years, extensive research has shown that certain herbal extracts have potential therapeutic effects on DCM. [86][87][88][89][90][91] For instance, Schisandrin B has been found to alleviate DCM by targeting MyD88 and inhibiting MyD88-dependent inflammation. 86 Paeonol promotes OPA1-mediated mitochondrial fusion through the activation of the CK2α-Stat3 pathway, thus mitigating mitochondrial oxidative stress to protect the heart.…”

“…In recent years, extensive research has shown that certain herbal extracts have potential therapeutic effects on DCM 86–91 . For instance, Schisandrin B has been found to alleviate DCM by targeting MyD88 and inhibiting MyD88‐dependent inflammation 86 .…”