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Salvianolic acid B attenuates inflammation and prevent pathologic fibrosis by inhibiting CD36-mediated activation of the PI3K-Akt signaling pathway in frozen shoulder [dataset 1]

ABSTRACT: Frozen shoulder (FS) is characterized by pain and limited range of motion (ROM). Inflammation and fibrosis are accepted as main pathologic processes associated with the development of FS. However, the intrinsic mechanisms underlying pathologic fibrosis remain unclear. We aimed to elucidate the key molecules involved in pathologic fibrosis and explore new therapeutic targets for FS. Synovial fibroblasts isolated from patient biopsies were identified using immunofluorescence. Western blotting, RT-qPCR, cell adhesion tests, and would-healing assays were used to evaluate the fibrosis-related functions of synovial fibroblasts. Elevated cluster of differentiation 36 (CD36) expression was detected in FS using western blotting and immunohistochemistry. Salvianolic acid b (SaB) inhibited CD36, blocking synovial fibroblast-induced inflammation and fibrosis. Our RNA-seq data showed that knocking down CD36 dramatically impaired the capacity of synovial fibroblasts for cell adhesion and that the PI3K-Akt signaling pathway may be crucial to the fibrotic process of FS. By up-regulating CD36 and inhibiting the phosphorylation of Akt, we demonstrated that CD36 promotes pathologic fibrosis by activating the PI3k-Akt pathway. Finally, rats treated with SaB had improved ROM and less collagen fiber deposition than the FS model group. Conclusions: SaB attenuates inflammation and inhibited the CD36-mediated activation of the PI3K-Akt signaling pathway to block pathologic fibrosis of FS in in vitro and in vivo models.

ORGANISM(S): Homo sapiens

PROVIDER: GSE238052 | GEO | 2023/07/24

REPOSITORIES: GEO

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Project description:Background: Loss of motion and arthrofibrosis after anterior cruciate ligament reconstruction (ACLR) can be a devastating complication for athletes. The cellular and molecular pathogenesis of arthrofibrosis is poorly understood, limiting prevention and treatment options. Synovial inflammation may contribute to post-ACLR arthrofibrosis. Hypothesis/Purpose: We hypothesized that higher synovial immune cell infiltration and inflammatory/catabolic gene expression patterns at the time of ACLR would correlate with poorer motion-related outcomes. Study Design: Case Series Methods: Patients aged 10-18 undergoing primary ACLR were enrolled in a prospective pilot study, and synovial tissue biopsies were obtained during ACLR. Flow cytometry and single cell RNA-sequencing explored synovial cell types/frequencies and gene expression. Principle component analysis followed by clustering grouped patients into distinct immunophenotypes based on their synovial cell composition. Clinical follow-up with knee range of motion (ROM), need for lysis of adhesions, and patient reported outcome measures were collected and compared between immunophenotypes. Results: Enrolled patients (n = 17) underwent ACLR at a median of 37 days post-injury. Analysis revealed three distinct immunophenotypes. Type 1 comprised patients with the longest time between injury and surgery and the lowest hematopoietic and T cell infiltration. Types 2 and 3 had similar times between injury and surgery, and Type 2 had intermediate while Type 3 had the highest hematopoietic and T cell percentages. Type 3 was associated with worse ROM at 2- and 6-weeks post-op; T cell prevalence and ROM were inversely correlated at those time points. The only patient requiring lysis of adhesions for arthrofibrosis was in Type 3. Conclusion: Synovial immune infiltration after ACL injury shows variability between patients that clusters into three immunophenotypes correlating with early ROM and the risk of arthrofibrosis. T cell recruitment and infiltration was the strongest factor correlated with ROM outcomes and presents an exciting venue for future research on post-ACLR arthrofibrosis.

Project description:Aim: Inflammation and fibrosis have been shown to be critical factors in heart failure (HF) progression. Calycosin (Cal) is the major active component of Radix astragali and has been widely used to treat inflammation in clinical practice. However, whether Cal could ameliorate myocardial infarction (MI)-induced inflammation and fibrosis and precise mechanisms remain uncertain. The aim of this study is to explore the role of Cal in HF and to clarify the underlying mechanisms. Methods: For in vivo experiments, rats underwent left anterior descending (LAD) artery ligation for HF model, and the cardioprotective effects of Cal were measured by echocardiographic assessment and histological examination. RNA-seq approach was applied to explore potential differential genes and pathways. For further mechanistic study, pro-inflammatory conditioned media (CM)-induced H9C2 cells injury model and TGFβ-stimulated cardiac fibroblasts model were applied to determine the regulatory mechanisms of Cal. Results: In vivo experiment, echocardiography results showed that Cal significantly improved heart function. GO and Reactome enrichment revealed that inflammation and fibrosis pathway are involved in Cal-treated group. KEGG enrichment indicated that PI3K-AKT pathway is enriched in the Cal-treated group. Further experiments proved that Cal alleviated cardiomyocyte inflammatory responses evidenced by down-regulating the expressions of phosphorylated IκB kinase α/β (p-IKKα/β), phosphorylated nuclear factor kapa B (p-NFκB) and tumor necrosis factor α (TNFα). Besides, Cal effectively attenuated cardiac fibrosis through the inhibitions of expressions and depositions of collagen I and collagen III. In vitro experiments, the phosphatidylinositol 3 kinase (PI3K) inhibitor LY294002 could abrogate the anti-inflammation and anti-fibrosis therapeutic effects of Cal, demonstrating that the cardio-protective effects of Cal were mediated through upregulations of PI3K and serine/threonine kinase (AKT). Conclusion: Cal improves cardiac function against HF by inhibiting cardiomyocytes inflammation and fibroblasts fibrosis via activation of the PI3K-AKT pathway.

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Salvianolic acid B attenuates inflammation and prevent pathologic fibrosis by inhibiting CD36-mediated activation of the PI3K-Akt signaling pathway in frozen shoulder [dataset 1]

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