Epigenetic regulation in fibrosis progress.

Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease. Recent studies have identified the key role of crosstalk between dysregulated epithelial cells, mesenchymal, immune, and endothelial cells in IPF. In addition, genetic mutations and environmental factors (e.g., smoking) have also been associated with the development of IPF. With the recent development of sequencing technology, epigenetics, as an intermediate link between gene expression and environmental impacts, has also been reported to be implicated in pulmonary fibrosis. Although the etiology of IPF is unknown, many novel therapeutic targets and agents have emerged from clinical trials for IPF treatment in the past years, and the successful launch of pirfenidone and nintedanib has demonstrated the promising future of anti-IPF therapy. Therefore, we aimed to gain an in-depth understanding of the underlying molecular mechanisms and pathogenic factors of IPF, which would be helpful for the diagnosis of IPF, the development of anti-fibrotic drugs, and improving the prognosis of patients with IPF. In this study, we summarized the pathogenic mechanism, therapeutic targets and clinical trials from the perspective of multiple cell types, gene mutations, epigenetic and environmental factors.

Research Progress in the Molecular Mechanisms, Therapeutic Targets, and Drug Development of Idiopathic Pulmonary Fibrosis

Matrix metalloproteinases inhibitors in idiopathic pulmonary fibrosis: Medicinal chemistry perspectives.

Determining the mechanism of senescence‐associated pulmonary fibrosis is crucial for designing more effective treatments for chronic lung diseases. This study aimed to determine the following: whether Sirt1 and serum vitamin D decreased with physiological aging, promoting senescence‐associated pulmonary fibrosis by activating TGF‐β1/IL‐11/MEK/ERK signaling, whether Sirt1 overexpression prevented TGF‐β1/IL‐11/MEK/ERK signaling‐mediated senescence‐associated pulmonary fibrosis in vitamin D‐deficient (Cyp27b1−/−) mice, and whether Sirt1 downregulated IL‐11 expression transcribed by TGF‐β1/Smad2 signaling through deacetylating histone at the IL‐11 promoter in pulmonary fibroblasts. Bioinformatics analysis with RNA sequencing data from pulmonary fibroblasts of physiologically aged mice was conducted for correlation analysis. Lungs from young and physiologically aged wild‐type (WT) mice were examined for cell senescence, fibrosis markers, and TGF‐β1/IL‐11/MEK/ERK signaling proteins, and 1,25(OH)2D3 and IL‐11 levels were detected in serum. Nine‐week‐old WT, Sirt1 mesenchymal transgene (Sirt1Tg), Cyp27b1−/−, and Sirt1TgCyp27b1−/− mice were observed the pulmonary function, aging, and senescence‐associated secretory phenotype and TGF‐β1/IL‐11/MEK/ERK signaling. We found that pulmonary Sirt1 and serum vitamin D decreased with physiological aging, activating TGF‐β1/IL‐11/MEK/ERK signaling, and promoting senescence‐associated pulmonary fibrosis. Sirt1 overexpression improved pulmonary dysfunction, aging, DNA damage, senescence‐associated secretory phenotype, and fibrosis through downregulating TGF‐β1/IL‐11/MEK/ERK signaling in Cyp27b1−/− mice. Sirt1 negatively regulated IL‐11 expression through deacetylating H3K9/14ac mainly at the region from −871 to −724 of IL‐11 promoter, also the major binding region of Smad2 which regulated IL‐11 expression at the transcriptional level, and subsequently inhibiting TGF‐β1/IL‐11/MEK/ERK signaling in pulmonary fibroblasts. This signaling in aging fibroblasts could be a therapeutic target for preventing senescence‐associated pulmonary fibrosis induced by vitamin D deficiency.

Sirt1 overexpression improves senescence‐associated pulmonary fibrosis induced by vitamin D deficiency through downregulating IL‐11 transcription

BACKGROUND
Matrix metalloproteinases (MMPs), also known as metalloproteinases, are enzymes that degrade proteins and require the presence of active metal atoms. There are more than 20 types of MMPs, and they promote cell migration through the proteolytic degradation of extracellular basement. MMPs are upregulated in cancers and inflamed regions. MMPs have three conservation regions: pro-MMP, catalysis, and hemopexin. Through these domains, MMPs cleave matrixes and cell-cell barriers. Consequently, MMPs cleave the whole extracellular matrix (ECM). In other words, they decompose most of the components related to the ECM, in their roles as key enzymes in cellular and pathophysiological events in the body.


INTRODUCTION
Zn2+-containing endo-type peptidases directly degrade and remodel the ECM region in the progression of various diseases. MMPs are frequently found in abnormal disease status of inflammatory responses, periodontal lesion, inflammatory pulmonary lesion, arteriosclerotic smooth muscles, arthritis, and tumor metastasis and invasion. They are also known to participate in aging processes-such as wrinkle formation-by destroying collagen in the dermis. In particular, the onset of diseases via the MMP-dependent inflammatory response is caused by the breakdown of proteins in the ECM and the basement membranous region, which are the supporting structures of cells.


METHODS
This review describes the developments in the research examining the general and selective inhibitors for MMP associated with various human diseases over the past 20 years in terms of structure remodeling, substrate-recognizing specificities, and pharmacological applicability.


RESULTS
Among two similar types of MMPs, MMP-2 is known as gelatinase-A with a 72 kDa, while MMP-9 is termed as gelatinase-B with a 92 kDa. Both of these play a key role in this action. Therefore, both enzymatic expression levels coincide during the onset and progression of diseases. Endogenous tissue inhibitors of matrix metalloproteinases (TIMPs) are highly specific for each MMP inhibitor type. The intrinsic factors regulate various MMP types by inhibiting the onset of various diseases mediated by MMP-dependent or independent inflammatory responses. The MMP-9 and MMP-2 enzyme activity related to the prognosis of diseases associated with the inflammatory response are selectively inhibited by TIMP1 and TIMP2, respectively. The major pathogenesis of MMP-mediated diseases is related to the proliferation of inflammatory cells in various human tissues, which indicates their potential to diagnose or treat these diseases. The discovery of a substance that inhibits MMPs would be very important for preventing and treating various MMP-dependent diseases.


CONCLUSION
Considerable research has examined MMP inhibitors, but most of these have been synthetic compounds. Research using natural products as MMP inhibitors has only recently become a subject of interest. This review intends to discuss recent research trends regarding the physiological properties, functions, and therapeutic agents related to MMPs.

Physiological Properties, Functions, and Trends in the Matrix Metalloproteinase Inhibitors in Inflammation-Mediated Human Diseases.

Objectives Idiopathic pulmonary fibrosis (IPF) is marked by the excessive accumulation of extracellular matrix, which participates in a variety of chronic diseases or injuries and seriously threatens human health. Due to the side effects of clinical drugs, there is still a need to develop novel and less toxic drugs to treat pulmonary fibrosis. Materials and methods SKLB-YTH-60 was developed through computer-aided drug design, de novo synthesis and high-throughput screening. We employed the bleomycin (BLM)-induced lung fibrosis animal models and used TGF-β1 to induce the epithelial-mesenchymal transition (EMT) of A549 cells in vitro. Meanwhile, the protein expression of collagen I and the α-smooth muscle actin (α-SMA), E-cadherin, p-FGFR1, p-PLCγ, p-Smad2/3 and p-Erk1/2 was detected by western blot. Results YTH-60 has obvious anti-proliferative activity on fibroblasts and A549 cells. Moreover, YTH-60 could impair the EMT of A549 cells and suppressed fibrosis by inhibiting FGFR and TGF-β/Smad-dependent pathways. Intraperitoneal administration of preventive YTH-60 could significantly reduce the degree of fibrosis in mice and regulate the imbalance of the immune microenvironment. In addition, we observed that therapeutic YTH-60 treatment attenuated fibrotic changes in mice during the period of fibrosis. Importantly, YTH-60 has shown an acceptable oral bioavailability (F = 17.86%) and appropriate eliminated half-life time (T1/2 = 8.03 hours). Conclusions Taken together, these preclinical evaluations suggested that YTH-60 could be a promising drug candidate for treating IPF.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/cpr.13081

A novel multikinase inhibitor SKLB-YTH-60 ameliorates inflammation and fibrosis in bleomycin-induced lung fibrosis mouse models.

Several FDA approved small molecule anti-cancer drugs contain indazole scaffolds. Here, we report the design, synthesis and biological evaluation of a series of indazole derivatives. In vitro antiproliferative activity screening showed that compound 2f had potent growth inhibitory activity against several cancer cell lines (IC50 = 0.23–1.15 μM). Treatment of the breast cancer cell line 4T1 with 2f inhibited cell proliferation and colony formation. 2f dose-dependently promoted the apoptosis of 4T1 cells, which was connected with the upregulation of cleaved caspase-3 and Bax, and downregulation of Bcl-2. 2f also decreased the mitochondrial membrane potential and increased the levels of reactive oxygen species (ROS) in 4T1 cells. Additionally, treatment with 2f disrupted 4T1 cells migration and invasion, and the reduction of matrix metalloproteinase metalloproteinase-9 (MMP9) and increase of tissue inhibitor matrix metalloproteinase 2 (TIMP2) were also observed. Moreover, 2f could suppress the growth of the 4T1 tumor model without obvious side effects in vivo. Taken together, these results identified 2f as a potential small molecule anti-cancer agent.

/pdf/synthesis-and-biological-evaluation-of-indazole-derivatives-2zt2gf3kvn.pdf

Synthesis and biological evaluation of indazole derivatives as anti-cancer agents

Liver fibrosis is an excessive wound‐healing response governed by activated hepatic stellate cells (HSCs). To date, there is no drug available for liver fibrosis. Although ferulic acid (FA) has multiple pharmacological functions, its anti‐hepatic fibrosis activity is weak. Based on the activity modification of the FA structure, we synthesized a series of phenylacrylic derivatives and found a superior compound, FA11. In this study, we investigated its antifibrotic effect and mechanism.

An oral phenylacrylic acid derivative suppressed hepatic stellate cell activation and ameliorated liver fibrosis by blocking TGF‐β1 signalling

Liver fibrosis is characterized by the excessive deposition of extracellular matrix components and results from chronic liver injury. At present, there is no approved drug for the treatment of liver fibrosis by the Food and Drug Administration. Here, we have reported a series of novel compounds with phenacrylanilide scaffolds that potently inhibit the transfer growth factor β1 (TGF-β1)-induced activation of LX-2, a hepatic stellate cell (HSC) line. Among them, compound 42 suppressed TGF-β1-induced upregulation of fibrotic markers (α-SMA and fibronectin) and showed excellent safety in vitro. Furthermore, in a carbon tetrachloride (CCl4) -induced liver fibrosis model, 42 at a dose of 30 mg/kg/day through oral administration for 3 weeks effectively improved liver function, restored damaged liver structures, and reduced collagen deposition, with a greater effect than Tranilast. In addition, epithelial-mesenchymal transition (EMT) is inhibited by compound 42 in the process of fibrosis. Meanwhile, the imbalanced immune microenvironment could also be effectively reversed. More interestingly, compound 42 prolongs the survival of CCl4 mice and ameliorates CCl4-induced injury to spleen, kidney, lung and heart. Altogether, these results suggest that 42 could be a potential drug candidate for the treatment of liver fibrosis. 

Lin Yue

Papers

A novel multikinase inhibitor SKLB-YTH-60 ameliorates inflammation and fibrosis in bleomycin-induced lung fibrosis mouse models.

Matrix metalloproteinases inhibitors in idiopathic pulmonary fibrosis: Medicinal chemistry perspectives.

Synthesis and biological evaluation of indazole derivatives as anti-cancer agents

An oral phenylacrylic acid derivative suppressed hepatic stellate cell activation and ameliorated liver fibrosis by blocking TGF‐β1 signalling

Discovery and evaluation of phenacrylanilide derivatives as novel potential anti-liver fibrosis agents.