New tricks for old drugs- praziquantel ameliorates bleomycin-induced pulmonary fibrosis in mice.

BACKGROUND: Pulmonary fibrosis is a chronic progressive disease with complex pathogenesis, short median survival time, and high mortality. There are few effective drugs approved for pulmonary fibrosis treatment. This study aimed to evaluate the effect of praziquantel (PZQ) on bleomycin (BLM)-induced pulmonary fibrosis. METHODS: In this study, we investigated the role and mechanisms of PZQ in pulmonary fibrosis in a murine model induced by BLM. Parameters investigated included survival rate, lung histopathology, pulmonary collagen deposition, mRNA expression of key genes involved in pulmonary fibrosis pathogenesis, the activity of fibroblast, and M2/M1 macrophage ratio. RESULTS: We found that PZQ improved the survival rate of mice and reduced the body weight loss induced by BLM. Histological examination showed that PZQ significantly inhibited the infiltration of inflammatory cells, collagen deposition, and hydroxyproline content in BLM-induced mice. Besides, PZQ reduced the expression of TGF-ß and MMP-12 in vivo and inhibited the proliferation of fibroblast induced by TGF-ß in vitro. Furthermore, PZQ affected the balance of M2/M1 macrophages. CONCLUSIONS: Our study demonstrated that PZQ could ameliorate BLM-induced pulmonary fibrosis in mice by affecting the balance of M2/M1 macrophages and suppressing the expression of TGF-ß and MMP-12. These findings suggest that PZQ may act as an effective anti-fibrotic agent for preventing the progression of pulmonary fibrosis.

Prediction and validation of common targets in atherosclerosis and non-small cell lung cancer influenced by atorvastatin.

BACKGROUND: Cardiovascular disease and cancer are the main causes of morbidity and mortality worldwide. Studies have shown that these two diseases may have some common risk factors. Atorvastatin is mainly used for the treatment of atherosclerosis in clinic. A large number of studies show that atorvastatin may produce anti-tumor activities. This study aimed to predict the common targets of atorvastatin against atherosclerosis and non-small cell lung cancer (NSCLC) based on network pharmacology. METHODS: The target genes of atherosclerosis and NSCLC were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The disease-target-component model map and the core network were obtained using Cytoscape 3.7.1. The MTS and wound healing assay were used to detect the effect of atorvastatin on cell viability and migration of A549 cells. The expression of potential common target genes of atorvastatin against atherosclerosis and NSCLC were confirmed in A549 cells and lung cancer tissues of patients. RESULTS: We identified 15 identical pathogenic genes, and four of which (MMP9, MMP12, CD36, and FABP4) were considered as the key target genes of atorvastatin in anti-atherosclerosis and NSCLC. The MTS and wound healing assays revealed that atorvastatin decreased A549 cells migration significantly. Atorvastatin markedly decreased the expression of MMP9, MMP12, CD36, and FABP4 in A549 cells and patients were treated with atorvastatin. CONCLUSIONS: This study demonstrated 15 common pathogenic genes in both atherosclerosis and NSCLC. And verified that MMP 9, MMP 12, CD 36 and FABP 4 might be the common target genes of atorvastatin in anti-atherosclerosis and NSCLC.

Sodium butyrate (SB) ameliorated inflammation of COPD induced by cigarette smoke through activating the GPR43 to inhibit NF-κB/MAPKs signaling pathways.

Cigarette smoke is recognized as a major trigger for individuals with chronic obstructive pulmonary disease (COPD), leading to an amplified inflammatory response. The onset and progression of COPD are affected by multiple environmental and genetic risk factors, such as inflammatory mechanisms, oxidative stress, and an imbalance between proteinase and antiprotease. As a result, conventional drug therapies often have limited effectiveness. This study aimed to investigate the anti-inflammatory effect of sodium butyrate (SB) in COPD and explore its molecular mechanism, thereby deepening our understanding of the potential application of SB in the treatment of COPD. In our study, we observed an increase in the mRNA and protein expressions of inflammatory factors interleukin-1beta (IL-1ß), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), Matrix metallopeptidase 9 (MMP9) and MMP12 in both NR8383 cell and rat models of COPD. However, these expressions were significantly reduced after SB treatment. Meanwhile, SB treatment effectively decreased the phosphorylation levels of nuclear transcription factor-kappa B (NF-κB) p65, c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK) and inhibited the nuclear translocation of these proteins in the COPD cells, leading to a reduction in the expression of various inflammatory cytokines. Additionally, SB also inhibited the expression level of the Nod-like receptor pyrin domain 3 (NLRP3) inflammasome, which consists of NLRP3, apoptosis-associated speck-like protein (ASC), and Caspase-1 in the cigeratte smoke extract (CSE)-stimulated cells. Our results showed that CSE down-regulated the mRNA levels of G-protein-coupled receptor 43 (GPR43) and GPR109A, while SB only up-regulated the expression of GPR43 and had no effect on GPR109A. Moreover, additional analysis demonstrated that the knockdown of GPR43 diminishes the anti-inflammatory effects of SB. It is evident that siRNA-mediated knockdown of GPR43 prevented the reduction in mRNA expression of IL-1ß, IL-6, TNF-α, MMP9, and MMP12, as well as the expression of phosphorylated proteins NF-κB p65, JNK, and p38 MAPKs with SB treatment. These findings revealed a SB/GPR43 mediated pathway essential for attenuating pulmonary inflammatory responses in COPD, which may offer potential new treatments for COPD.

Efficient chemosensitizing and antimetastatic combinations of a naturally occurring trans-ferulic acid with different chemotherapies on an in vitro hepatocellular carcinoma model.

Trans-ferulic acid (TFA) is a polyphenolic compound present in many dietary supplements. The aim of this study was to get better chemotherapeutic outcomes through treatment protocols for human hepatocellular carcinoma (HCC). This study focused on the exploration of the in vitro influence of a combination of TFA with 5-fluorouracil (5-FU), doxorubicin (DOXO), and cisplatin (CIS) on HepG2 cell line. Treatment with 5-FU, DOXO, and CIS alone down-regulated oxidative stress and alpha-fetoprotein (AFP), and decreased cell migration through the depression of metalloproteinases (MMP-3, MMP-9, and MMP-12) expression. Co-treatment with TFA synergized the effects of these chemotherapies by decreased MMP-3, MMP-9, and MMP-12 expression, and gelatinolytic activity of both MMP-9 and MMP-2 in cancer cells. TFA significantly reduced the elevated levels of AFP and NO, and depressed cell migration ability (metastasis) in HepG2 groups. Co-treatment with TFA elevated the chemotherapeutic potency of 5-FU, DOXO, and CIS in managing HCC.

Matrix metalloproteinase-12 produced by Ly6Clow macrophages prolongs the survival after myocardial infarction by preventing neutrophil influx.

BACKGROUND: Various immune cells are involved in different phases of cardiac repair after myocardial infarction (MI). Especially, Ly6Clow M2-like macrophages (Ly6Clo macrophages) are vital for cardiac repair after MI. However, the molecular mechanisms how Ly6Clo macrophages promote wound healing after MI are still largely unknown. METHODS AND RESULTS: Transcriptome analysis of Ly6Clo macrophages and Ly6Chigh M1-like macrophages (Ly6Chi macrophages) harvested from the infarcted heart revealed that Ly6Clo macrophages highly expressed matrix metalloproteinase (MMP)-12 mRNA compared to Ly6Chi macrophages. MMP-12 expression was enhanced in the infarcted heart and preferentially observed in Ly6Clo macrophages. Importantly, the survival rate and cardiac function after MI were significantly impaired in MMP-12-deficient (mmp12-/-) mice compared with those in wild-type mice. In addition, the extent of myocardial fibrosis and the number of myofibroblasts in the infarct area were decreased in mmp12-/- mice. MMP-9 expression and neutrophils, which are the major cellular source of MMP-9, in the infarcted heart were increased in mmp12-/- mice. Moreover, mRNA expression of neutrophil-attracting chemokines including CXCL1, CXCL2, and CXCL5 was significantly higher in mmp12-/- mice. Consistently, treatment with anti-CXCR2 antibody significantly decreased neutrophil numbers and MMP-9 expression in the infarcted heart in mmp12-/- mice. Finally, the administration of recombinant MMP-12 into the infarcted heart decreased neutrophil numbers in the infarcted heart and promoted wound healing in both wild-type mice and mmp12-/- mice. CONCLUSION: MMP-12 produced by Ly6Clo macrophages improves the survival after MI possibly through the promotion of wound healing by reducing neutrophil infiltration.