Excessive Extracellular Matrix Deposition Research Articles

Prevalence and risk factors of left ventricular diastolic dysfunction in systemic sclerosis patients: insights from new echocardiographic parameters

Abstract Background Systemic sclerosis (SSc) is a rare autoimmune connective tissue disease characterized by excessive extracellular matrix deposition and fibrosis that can affect the skin, blood vessels, and internal organs, including the heart. Primary heart involvement in SSc refers to the presence of cardiac fibrosis, inflammation, and dysfunction in the absence of pulmonary hypertension (PH). Although PH is usually considered the major risk factor for death in SSc patients, diastolic dysfunction has been proposed as an independent predictor of mortality, which may be more robust than PH. Purpose Early identification and management of heart complications in SSc patients are crucial to prevent further deterioration and improve treatment outcomes. However, myocardial damage caused by SSc is often poorly understood, and the long-term effects and prognosis remain unknown. Methods We conducted a cross-sectional study of 69 patients (p) with SSc diagnosis evaluated between February 2022 and February 2023. We analyzed the prevalence of left ventricular diastolic dysfunction (LVDD) as recommended by the 2016 ASE/EACVI guidelines. We compared the presence of risk factors associated with LVDD and its association with other echocardiographic findings. Of the 69p, 24 (34.8%) had LVDD, 41 (59.4%) had normal diastolic function, and 4 (5.8%) had undetermined diastolic dysfunction. Older age (mean age 69.7 ± 11.2 vs 57 ± 12.8; p < 0.01), arterial hypertension (50% vs 22%; p = 0.02), higher body mass index (28.3 ± 8 vs 24.6 ± 4.5; p = 0.02), and higher NTproBNP levels (131 [64-403] vs 97 [45-163]; p = 0.047) were significantly associated with LVDD. The absence of antitopoisomerase (scl70 0% vs 22.2%; p = 0.021) and the presence of anticentromere (CENP-A 81% vs 55.6%; p = 0.05) and (CENP-B 85.7% vs 55.6%; p = 0.02) antibodies were also significantly associated with LVDD. Additionally, classical parameters of ventricular function, such as left ventricular ejection fraction (LVEF 63.5 ± 4.2 vs 63.4 ± 3.7; p = 0.9) or tricuspid annular plane systolic excursion (TAPSE 20.6 ± 2.3mm vs 21.2 ± 2.4mm; p = 0.32), were not associated with LVDD. However, impairment of the right ventricular free wall strain (-23.8 ± 4 vs -27 ± 2.8; p = 0.017), and lower left atrial strain reservoir function (27.7 ± 10 vs 38.4 ± 12.7; p = 0.05) were significantly associated with LVDD. Conclusion LVDD is highly prevalent in patients with systemic sclerosis, particularly in elderly patients with a higher body mass index and those affected by arterial hypertension. These patientes have higher values of NTproBNP. Futhermore, antitopoisomerases antibodies are less likely to be expressed and anticetromere antibodies are more likely to be expressed . These findings highlight the importance of regular cardiovascular monitoring in SSc patients and the potential value of using new echocardiographic parameters to identify those at risk for LVDD.

Role of macrophage-to-myofibroblast transition in chronic liver injury and liver fibrosis

BackgroundChronic liver injury contributes to liver fibrosis, which is characterized by the excessive deposition of extracellular matrix (ECM) components. ECM is mainly composed of myofibroblasts. Recently, macrophage-to-myofibroblasts transition (MMT), has been identified as a novel origin for myofibroblasts. However, the potential functions of MMT in chronic liver injury and liver fibrosis remain unknown.MethodsTo clarify the transformation of fibrotic cells in hepatic fibrosis, liver specimens were collected from people at different stages in the progression of hepatic fibrosis and stained with immunofluorescence. Models of hepatic fibrosis such as the CCL4 model, HFD-induced NAFLD model, MCD-induced NAFLD model and ethanol-induced AFLD model were demonstrated and were stained with immunofluorescence.ResultsHere, we uncovered macrophages underwent MMT in clinical liver fibrosis tissue samples and multiple animal models of chronic liver injury. MMT cells were found in specimens from patients with liver fibrosis on the basis of co-expression of macrophage (CD68) and myofibroblast (a-SMA) markers. Moreover, macrophages could transform into myofibroblasts in CCL4-induced liver fibrosis model, high-fat diet (HFD) and methionine-choline-deficient diet (MCD)-induced nonalcoholic fatty liver diseases (NAFLD) model, and ethanol-induced alcoholic fatty liver diseases (AFLD) model. In addition, we highlighted that MMT cells mainly had a predominant M2 phenotype in both human and experimental chronic liver injury.ConclusionsTaken together, MMT acts a crucial role in chronic liver injury and liver fibrosis.

C5a/C5aR1 axis as a key driver promotes epithelial-to-mesenchymal transition in airway epithelial cells in silica nanoparticles-induced pulmonary fibrosis

Previous studies have shown that silica nanoparticles (SiNPs) exposure can affect the respiratory, cardiovascular, reproductive and other systems, with the lung being the primary target organ for the direct effect, causing damage with a central feature of pulmonary inflammation and fibrosis. However, the underlying mechanisms of pulmonary fibrosis due to SiNPs are not fully understood. The aim of the study was to investigate the role of complement anaphylatoxin C5a in SiNPs-induced pulmonary fibrosis. A mouse model of SiNPs-induced pulmonary fibrosis was established, and pulmonary fibrosis-related indicators, epithelial-to-mesenchymal transition (EMT), C5a/C5aR1 and high mobility group protein B1 (HMGB1) proteins were measured. An in vitro study using the human lung epithelial cell line BEAS-2B investigated whether C5a leads to epithelial-to-mesenchymal trans-differentiation. In vivo studies revealed that SiNPs-induced pulmonary fibrosis mainly manifested as EMT trans-differentiation in airway epithelial cells, which subsequently led to excessive deposition of extracellular matrix (ECM). Furthermore, we found that C5a and C5aR1 proteins were also increased in SiNPs-induced pulmonary fibrosis tissue. In vitro studies also showed that C5a directly activated HMGB1/RAGE signaling and induced EMT in BEAS-2B cells. Finally, treatment of SiNPs-exposed mice with the C5aR1 inhibitor PMX205 effectively reduced C5aR1 levels and inhibited the activation of HMGB1/RAGE signaling and the expression of EMT-related proteins, culminating in a significant alleviation of pulmonary fibrosis. Taken together, our results suggest that C5a/C5aR1 is the main signaling pathway for SiNPs-induced pulmonary fibrosis, which induces EMT in airway epithelial cells via the HMGB1/RAGE axis.

Inhalation of taraxasterol loaded mixed micelles for the treatment of idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a chronic and fatal lung disease characterized by pulmonary inflammation, oxidative stress, and excessive extracellular matrix (ECM) deposition. Current anti-fibrotic drugs for IPF treatment in the clinic lack selectivity and demonstrate unsatisfactory efficacy, highlighting the urgent necessity for a novel therapeutic strategy. Taraxasterol (TA), which has biological activities against lung injury induced by various factors, is a potential anti-IPF drug due to its anti-inflammatory, antioxidant and lung-protective effects. However, the protective effect of TA on IPF has not been confirmed, and its clinical application is limited due to its poor aqueous solubility. In this study, we demonstrated that TA could inhibit epithelial-mesenchymal transition (EMT) and migration of A549 cells by inhibiting the transforming growth factor-β1 (TGF-β1)/Smad signaling pathway. To improve the aqueous solubility and pulmonary administration performance of TA, we prepared TA loaded methoxy poly(ethylene glycol)-poly(d,l-lactide) (mPEG-PLA)/d-α-tocopheryl polyethylene glycol succinate (TPGS) mixed polymeric micelles (TA-PM). Then a MicroSprayerⓇ Aerosolizer was used to deliver TA-PM once every two days for three weeks to evaluate their therapeutic effects on bleomycin (BLM)-induced IPF mice. Our results demonstrated that inhaled TA-PM significantly inhibited BLM-induced inflammation, oxidative stress and fibrosis in lung tissue. Furthermore, TA-PM exhibited high pulmonary deposition and retention by pulmonary administration, along with a favorable safety profile. Overall, this study emphasizes the potential of inhaled TA-PM as a promising treatment for IPF, providing a new opportunity for their clinical application.

Targeting the chromatin remodeling protein BRG1 in liver fibrosis: Mechanism and translational potential

AimsLiver fibrosis is characterized by excessive deposition of extracellular matrix (ECM) proteins in the interstitia. Hepatic stellate cells (HSCs) are considered the major source for ECM-producing myofibroblasts contributing to liver fibrosis. The molecular mechanism whereby HSC-myofibroblast transition is regulated remains incompletely understood. We investigated the involvement of BRG1, a chromatin remodeling protein, in this process. MethodsRosa26-Smarca4 mice were crossed to Lrat-Cre mice to generate HSC-specific BRG1 transgenic mice. Liver fibrosis was induced by bile duct ligation (BDL) or injection with carbon tetrachloride (CCl4). ResultsWe report here that over-expression of BRG1 promoted HSC-myofibroblast transition in vitro. More importantly, the BRG1 transgenic mice displayed amplification of liver fibrogenesis, induced by BDL or CCl4 injection, compared to the wild type littermates. On the contrary, BRG1 inhibition by a small-molecule compound (PFI-3) attenuated HSC-myofibroblast transition in vitro and ameliorated liver fibrosis in a dose-dependent manner in mice. RNA-seq analysis showed that PFI-3 treatment preferentially influenced the expression of ECM genes in activated HSCs. ConclusionOur data provide strong evidence that BRG1 plays an important role in HSC-myofibroblast transition and suggest that targeting BRG1 could be considered as a reasonable strategy for the intervention of liver fibrosis.

CNS tumor stroma transcriptomics identify perivascular fibroblasts as predictors of immunotherapy resistance in glioblastoma patients

Excessive deposition of extracellular matrix (ECM) is a hallmark of solid tumors; however, it remains poorly understood which cellular and molecular components contribute to the formation of ECM stroma in central nervous system (CNS) tumors. Here, we undertake a pan-CNS analysis of retrospective gene expression datasets to characterize inter- and intra-tumoral heterogeneity of ECM remodeling signatures in both adult and pediatric CNS disease. We find that CNS lesions – glioblastoma in particular – can be divided into two ECM-based subtypes (ECMhi and ECMlo) that are influenced by the presence of perivascular stromal cells resembling cancer-associated fibroblasts (CAFs). Ligand-receptor network analysis predicts that perivascular fibroblasts activate signaling pathways responsible for recruitment of tumor-associated macrophages and promotion of cancer stemness. Our analysis reveals that perivascular fibroblasts are correlated with unfavorable response to immune checkpoint blockade in glioblastoma and poor patient survival across a subset of CNS tumors. We provide insights into new stroma-driven mechanisms underlying immune evasion and immunotherapy resistance in CNS tumors like glioblastoma, and discuss how targeting these perivascular fibroblasts may prove an effective approach to improving treatment response and patient survival in a variety of CNS tumors.

β1 integrin signaling governs necroptosis via the chromatin-remodeling factor CHD4

Fibrosis, characterized by sustained activation of myofibroblasts and excessive extracellular matrix (ECM) deposition, is known to be associated with chronic inflammation. Receptor-interacting protein kinase 3 (RIPK3), the central kinase of necroptosis signaling, is upregulated in fibrosis and contributes to tumor necrosis factor (TNF)-mediated inflammation. In bile-duct-ligation-induced liver fibrosis, we found that myofibroblasts are the major cell type expressing RIPK3. Genetic ablation of β1 integrin, the major profibrotic ECM receptor in fibroblasts, not only abolished ECM fibrillogenesis but also blunted RIPK3 expression via a mechanism mediated by the chromatin-remodeling factor chromodomain helicase DNA-binding protein 4 (CHD4). While the function of CHD4 has been conventionally linked to the nucleosome-remodeling deacetylase (NuRD) and CHD4-ADNP-HP1(ChAHP) complexes, we found that CHD4 potently repressed a set of genes, including Ripk3, with high locus specificity but independent of either the NuRD or the ChAHP complex. Thus, our data uncover that β1 integrin intrinsically links fibrotic signaling to RIPK3-driven inflammation via a novel mode of action of CHD4.

The Communication from Immune Cells to the Fibroblasts in Keloids: Implications for Immunotherapy.

Keloids are a type of fibrotic disease characterized by excessive collagen production and extracellular matrix (ECM) deposition. The symptoms of pain and itching and frequent recurrence after treatment significantly impact the quality of life and mental health of patients. A deeper understanding of the pathogenesis of keloids is crucial for the development of an effective therapeutic approach. Fibroblasts play a central role in the pathogenesis of keloids by producing large amounts of collagen fibers. Recent evidence indicates that keloids exhibit high immune cell infiltration, and these cells secrete cytokines or growth factors to support keloid fibroblast proliferation. This article provides an update on the knowledge regarding the keloid microenvironment based on recent single-cell sequencing literature. Many inflammatory cells gathered in keloid lesions, such as macrophages, mast cells, and T lymphocytes, indicate that keloids may be an inflammatory skin disease. In this review, we focus on the communication from immune cells to the fibroblasts and the potential of immunotherapy for keloids. We hope that this review will trigger interest in investigating keloids as an inflammatory disease, which may open up new avenues for drug development by targeting immune mediators.

Therapeutic targets of fibrosis: Translational advances and current challenges.

In a physiological context, the extracellular matrix (ECM) provides an important scaffold for organs. Dysregulation of ECM in disease conditions, characterised by excess deposition of connective tissue and extracellular matrix in response to a pathological insult, is a key driver of disease progression in multiple organs. The resultant fibrosis is predominantly an irreversible process and directly contributes to, and exacerbates, dysfunction of an affected organ. This is particularly paramount in the kidney, liver, heart and lung. A hybrid Joint Meeting of NC-IUPHAR and British Pharmacological Society was held in Paris and via a webinar in November 2020, when two successive sessions were devoted to translational advances in fibrosis as a therapeutic target. On the upsurge of response to these sessions, the concept of a special themed issue on this topic emerged, and is entitled Translational Advances in Fibrosis as a Therapeutic Target. In this special issue, we seek to provide an up-to-date account of the diverse molecular mechanisms and causal role that fibrosis plays in disease progression (contributing to, and exacerbating, dysfunction of affected organs). Recent developments in the understanding of molecular targets involved in fibrosis, and how their actions can be manipulated therapeutically, are included.

The molecular mechanisms of extracellular matrix-derived hydrogel therapy in idiopathic pulmonary fibrosis models

Idiopathic Pulmonary Fibrosis (IPF) is a progressively debilitating lung condition characterized by oxidative stress, cell phenotype shifts, and excessive extracellular matrix (ECM) deposition. Recent studies have shown promising results using decellularized ECM-derived hydrogels produced through pepsin digestion in various lung injury models and even a human clinical trial for myocardial infarction. This study aimed to characterize the composition of ECM-derived hydrogels, assess their potential to prevent fibrosis in bleomycin-induced IPF models, and unravel their underlying molecular mechanisms of action. Porcine lungs were decellularized and pepsin-digested for 48 h. The hydrogel production process, including visualization of protein molecular weight distribution and hydrogel gelation, was characterized. Peptidomics analysis of ECM-derived hydrogel contained peptides from 224 proteins. Probable bioactive and cell-penetrating peptides, including collagen IV, laminin beta 2, and actin alpha 1, were identified. ECM-derived hydrogel treatment was administered as an early intervention to prevent fibrosis advancement in rat models of bleomycin-induced pulmonary fibrosis. ECM-derived hydrogel concentrations of 1 mg/mL and 2 mg/mL showed subtle but noticeable effects on reducing lung inflammation, oxidative damage, and protein markers related to fibrosis (e.g., alpha-smooth muscle actin, collagen I). Moreover, distinct changes were observed in macroscopic appearance, alveolar structure, collagen deposition, and protein expression between lungs that received ECM-derived hydrogel and control fibrotic lungs. Proteomic analyses revealed significant protein and gene expression changes related to cellular processes, pathways, and components involved in tissue remodeling, inflammation, and cytoskeleton regulation. RNA sequencing highlighted differentially expressed genes associated with various cellular processes, such as tissue remodeling, hormone secretion, cell chemotaxis, and cytoskeleton engagement. This study suggests that ECM-derived hydrogel treatment influence pathways associated with tissue repair, inflammation regulation, cytoskeleton reorganization, and cellular response to injury, potentially offering therapeutic benefits in preventing or mitigating lung fibrosis.

Back to the future: targeting the extracellular matrix to treat systemic sclerosis.

Fibrosis is the excessive deposition of a stable extracellular matrix (ECM); fibrotic tissue is composed principally of highly crosslinked type I collagen and highly contractile myofibroblasts. Systemic sclerosis (SSc) is a multisystem autoimmune connective tissue disease characterized by skin and organ fibrosis. The fibrotic process has been recognized in SSc for >40 years, but drugs with demonstrable efficacy against SSc fibrosis in ameliorating the lung involvement have only recently been identified. Unfortunately, these treatments are ineffective at improving the skin score in patients with SSc. Previous clinical trials in SSc have largely focused on the cross-purposing of anti-inflammatory drugs and the use of immunosuppressive drugs from the transplantation field, which address inflammatory and/or autoimmune processes. Limited examination has taken place of specific anti-fibrotic agents developed through their ability to directly target the ECM in SSc by, for example, alleviating the persistent matrix stiffness and mechanotransduction that might be required for both the initiation and maintenance of fibrosis, including in SSc. However, because of the importance of the ECM in the SSc phenotype, attempts have now been made to identify drugs that specifically target the ECM, including some drugs that are currently under consideration for the treatment of cancer.

Co-delivery of pirfenidone and siRNA in ZIF-based nanoparticles for dual inhibition of hepatic stellate cell activation in liver fibrotic therapy

Hepatic fibrosis, as a destructive liver disease, occurs due to activated hepatic stellate cells (HSCs) producing excessive extracellular matrix deposition. If left untreated, it could further deteriorate into cirrhosis and hepatoma with high morbidity and mortality. Currently, to break the dilemma of poor targeting efficiency on HSCs and limited effect of monotherapy, it is urgent to explore a precise and efficient treatment against liver fibrosis. In the present work, a novel multifunctional nanoplatform based on vitamin A (VA) modified zeolitic imidazolate framework-8 (ZIF-8) nanoparticles was designed for co-delivery of chemical drug (Pirfenidone) and genetic drug (TGF-β1 siRNA) to achieve HSCs targeting mediated synergistic chemo-gene therapy against liver fibrosis. With the large specific surface area and acid-responsive degradation characteristics, ZIF-8 nanoparticles have great advantages to achieve high loading efficiency of Pirfenidone and enable acid-reactive drug release. After complexing siRNA, the prepared chemo-gene drug co-delivered nanocomplex (GP@ZIF-VL) proved excellent serum stability and effectively protected siRNA from degradation. Importantly, in vitro cell uptake and in vivo biodistribution demonstrated that VA functionalization markedly enhanced the delivery efficiency of GP@ZIF-VL nanocomplex into HSCs. As expected, GP@ZIF-VL significantly reduced extracellular matrix deposition and ameliorated hepatic fibrosis, as evidenced by decreased levels of liver enzymes in serum and a reduction in the hydroxyproline content in liver tissue. Therefore, GP@ZIF-VL nanocomplex displayed a bright future on the treatment of liver fibrosis with HSCs-targeting mediated chemo-gene synergetic therapy.

Voltage-dependent anion channel 1 (VDAC1) overexpression alleviates cardiac fibroblast activation in cardiac fibrosis via regulating fatty acid metabolism

Cardiac fibrosis is characterized by the excessive deposition of extracellular matrix in the myocardium with cardiac fibroblast activation, leading to chronic cardiac remodeling and dysfunction. However, little is known about metabolic alterations in fibroblasts during cardiac fibrosis, and there is a lack of pharmaceutical treatments that target metabolic dysregulation. Here, we provided evidence that fatty acid β-oxidation (FAO) dysregulation contributes to fibroblast activation and cardiac fibrosis. With transcriptome, metabolome, and functional assays, we demonstrated that FAO was downregulated during fibroblast activation and cardiac fibrosis, and that perturbation of FAO reversely affected the fibroblast-to-myofibroblast transition. The decrease in FAO may be attributed to reduced long-chain fatty acid (LCFA) uptake. Voltage-dependent anion channel 1 (VDAC1), the main gatekeeper of the outer mitochondrial membrane (OMM), serves as the transporter of LCFA into the mitochondria for further utilization and has been shown to be decreased in myofibroblasts. In vitro, the addition of exogenous VDAC1 was shown to ameliorate cardiac fibroblast activation initiated by transforming growth factor beta 1 (TGF-β1) stimuli, and silencing of VDAC1 displayed the opposite effect. A mechanistic study revealed that VDAC1 exerts a protective effect by regulating LCFA uptake into the mitochondria, which is impaired by an inhibitor of carnitine palmitoyltransferase 1A. In vivo, AAV9-mediated overexpression of VDAC1 in myofibroblasts significantly alleviated transverse aortic constriction (TAC)-induced cardiac fibrosis and rescued cardiac function in mice. Finally, we treated mice with the VDAC1-derived R-Tf-D-LP4 peptide, and the results showed that R-Tf-D-LP4 prevented TAC-induced cardiac fibrosis and dysfunction in mice. In conclusion, this study provides evidence that VDAC1 maintains FAO metabolism in cardiac fibroblasts to repress fibroblast activation and cardiac fibrosis and suggests that the VDAC1 peptide is a promising drug for rescuing fibroblast metabolism and repressing cardiac fibrosis.

The mechanisms and therapeutic potential of long noncoding RNA NEAT1 in fibrosis.

Fibrosis is the excess deposition of extracellular matrix involved in the pathogenesis of chronic diseases and finally leads to the disruption of tissue architecture and failure of organ function. Long noncoding RNAs (lncRNAs) are a class of RNAs with lengths greater than 200 nucleotides and do not code proteins, which regulate gene expression at multiple levels. Nuclear-enriched abundant transcript 1 (NEAT1) is a long noncoding RNA that is widely expressed in mammalian cells and known as essential architectural scaffold for the formation of paraspeckles. Recently, the accumulating studies demonstrated that lncRNA NEAT1 was remarkable upregulated in the development of fibrosis in different organs, such as liver fibrosis, renal fibrosis, cardiac fibrosis, and lung fibrosis. More importantly, knockdown of NEAT1 remarkably alleviated fibrosis in vitro and in vivo. In this review, we summarized current studies of NEAT1 in fibrosis and hopefully aid in a better understanding of the mechanisms of fibrosis and the potential of NEAT1 as novel therapeutic target for fibrosis.

Silibinin Downregulates Types I and III Collagen Expression via Suppression of the mTOR Signaling Pathway.

Keloid scars are fibro-proliferative conditions characterized by abnormal fibroblast proliferation and excessive extracellular matrix deposition. The mammalian target of the rapamycin (mTOR) pathway has emerged as a potential therapeutic target in keloid disease. Silibinin, a natural flavonoid isolated from the seeds and fruits of the milk thistle, is known to inhibit the mTOR signaling pathway in human cervical and hepatoma cancer cells. However, the mechanisms underlying this inhibitory effect are not fully understood. This in vitro study investigated the effects of silibinin on collagen expression in normal human dermal and keloid-derived fibroblasts. We evaluated the effects of silibinin on the expressions of collagen types I and III and assessed its effects on the suppression of the mTOR signaling pathway. Our findings confirmed elevated mTOR phosphorylation levels in keloid scars compared to normal tissue specimens. Silibinin treatment significantly reduced collagen I and III expressions in normal human dermal and keloid-derived fibroblasts. These effects were accompanied by the suppression of the mTOR signaling pathway. Our findings suggest the potential of silibinin as a promising therapeutic agent for preventing and treating keloid scars. Further studies are warranted to explore the clinical application of silibinin in scar management.

Tangeretin attenuates bleomycin-induced pulmonary fibrosis by inhibiting epithelial-mesenchymal transition via the PI3K/Akt pathway.

Background: Pulmonary fibrosis (PF) is a terminal pathological change in a variety of lung diseases characterized by excessive deposition of extracellular matrix, for which effective treatment is lacking. Tangeretin (Tan), a flavonoid derived from citrus, has been shown to have a wide range of pharmacological effects. This study aimed to investigate the role and potential mechanisms of Tan on pulmonary fibrosis. Methods: A model of pulmonary fibrosis was established by administering bleomycin through tracheal drip, followed by administering Tan or pirfenidone through gavage. HE and Masson staining were employed to assess the extent of pulmonary fibrosis. Subsequently, Western blot, enzyme-linked immunosorbent assay (ELISA), RNA sequencing, and immunohistochemistry techniques were employed to uncover the protective mechanism of Tan in PF mice. Furthermore, A549 cells were stimulated with TGF-β1 to induce epithelial-mesenchymal transition (EMT) and demonstrate the effectiveness of Tan in mitigating PF. Results: Tan significantly ameliorated bleomycin-induced pulmonary fibrosis, improved fibrotic pathological changes, and collagen deposition in the lungs, and reduced lung inflammation and oxidative stress. The KEGG pathway enrichment analysis revealed a higher number of enriched genes in the PI3K/Akt pathway. Additionally, Tan can inhibit the EMT process related to pulmonary fibrosis. Conclusion: Taken together, the above research results indicate that Tan suppresses inflammation, oxidative stress, and EMT in BLM-induced pulmonary fibrosis via the PI3K/Akt pathway and is a potential agent for the treatment of pulmonary fibrosis.

Exploratory study of an anti-PD-L1/TGF-β antibody, TQB2858, in patients with refractory or recurrent osteosarcoma and alveolar soft part sarcoma: a report from Chinese sarcoma study group (TQB2858-Ib-02)

Background Novel and effective immunotherapies are required for refractory or recurrent sarcomas. Transforming growth factor-beta (TGF-β) is a diverse regulatory and fibrogenic protein expressed in multiple sarcoma tumors that promotes epithelial-mesenchymal transition and excessive deposition of extracellular matrix. This study evaluated the efficacy and safety of the anti-PD-L1/TGF-β antibody TQB2858 in patients with refractory osteosarcoma and alveolar soft part sarcoma (ASPS).MethodsThis single-arm phase 1b exploratory study included patients with refractory osteosarcoma or ASPS who had previously undergone at least two lines of systemic therapy. Patients were administered 1200 mg of TQB2858 once every 3 weeks. The primary endpoint was objective response rate (ORR), with null and alternative hypotheses of ORR ≤5% and ≥20%, respectively. Exploratory biomarker analyses using immunohistochemistry (IHC) staining (for PD-L1 and TGF-β) were performed on pre-treatment tumor samples.ResultsEleven eligible patients were included in this study. TQB2858 did not demonstrate evidence of efficacy as 0/5 osteosarcomas had any objective response, while 2/6 ASPS showed a partial response. The median progression-free survivals were 1.51 (1.38, Not Evaluable) and 2.86 (1.38, Not Evaluable) months for the osteosarcoma and ASPS groups, respectively. None of the administered cycles met the criteria for unacceptable toxicity. Other Grade 3 toxicities included abnormal liver function and elevation of γ-glutamyl transferase. IHC analysis revealed that functional enrichment in the TGF-β pathway or PD-L1 was not associated with treatment outcomes.ConclusionsThe combination of PD-L1 and TQB2858 did not significantly improve the ORR in patients with recurrent osteosarcoma. However, it improved immunogenic responses in ASPS, even after progression upon anti-PD-1/PD-L1 therapy, with an acceptable safety profile. IHC profiling with pathway enrichment analysis may not have any predictive value for survival outcomes.Trial registrationProspectively registered in the Ethical Review Committee of Peking University People’s Hospital. The trial registration number is 2021PHA105-001 and 2021PHA140-001 and the registration date was March 2, 2022.ClinicalTrials.gov Identifier CTR20213001 and CTR20220390

Transcription factor c-Maf drives macrophages to promote hypertrophic scar formation.

Hypertrophic scar (HS) is caused by the abnormal proliferation of fibroblasts and excessive deposition of extracellular matrix (ECM). Emerging evidence demonstrates that c-Maf positive M2 macrophages were mainly located in the hypertrophic scar tissues of proliferative phase. But whether c-Maf positive M2 macrophages can promote hypertrophic scar formation through modulating hypertrophic scar fibroblasts remains elusive. The aim of this study is to investigate the effects of c-Maf positive M2 macrophages on the biological behaviors and functions of hypertrophic scar fibroblasts and the potential mechanism. HE and Masson trichrome staining were used to examine the histological features of human hypertrophic scar. Immunofluorescence staining was employed to label and quantify the c-Maf+ /CD68+ M2 macrophages. CCK8, wound healing, and transwell assays were utilized to test the effects of c-Maf overexpressed M2 macrophages or the cell culture supernatants on the proliferation and migration of hypertrophic scar derived fibroblasts (HFBs) and normal skin derived fibroblasts (NFBs). Western blot and qPCR were harnessed to test the expressions of COL1, COL3, and α-SMA in the co-cultivated fibroblasts and TGF-β1 in the c-Maf overexpressed M2 macrophages. Increased number of c-Maf+ /CD68+ M2 macrophages were found in HS in contrast to the normal skin (NS). Elevated proliferation and migration were observed in the HFBs or NFBs co-cultured with c-Maf overexpressed macrophages or the cell culture supernatants. A higher mRNA and protein expressions of COL1, COL3, and α-SMA were recorded in the HFBs co-cultured with c-Maf overexpressed macrophages or treated with its culture supernatants. In addition, augmented mRNA and protein expressions of TGF-β1 were also investigated in the c-Maf overexpressed macrophages. c-Maf positive macrophages promote hypertrophic scar formation through regulating HFBs proliferation, migration, and ECM deposition via the secreted TGF-β1.

Multi-omics analysis reveals the mechanism of action of ophiopogonin D against pulmonary fibrosis

BackgroundIdiopathic pulmonary fibrosis (IPF) is a chronic and progressive lung disease with limited therapeutic strategies. Therefore, there is an urgent need to search for safe and effective drugs to treat this condition. Ophiopogonin D (OP-D), a steroidal saponin compound extracted from ophiopogon, possesses various pharmacological properties, including anti-inflammatory, antioxidant, and antitumor effects. However, the potential pharmacological effect of OP-D on pulmonary fibrosis remains unknown. PurposeThe aim of this study was to investigate whether OP-D can improve pulmonary fibrosis and to explore its mechanism of action. MethodsThe effect of OP-D on pulmonary fibrosis was investigated in vitro and in vivo using a mouse model of IPF induced by bleomycin and an in vitro model of human embryonic lung fibroblasts induced by transforming growth factor-β1 (TGF-β1). The mechanism of action of OP-D was determined using multi-omics techniques and bioinformatics. ResultsOP-D attenuated epithelial-mesenchymal transition and excessive deposition of extracellular matrix in the lungs, promoted the apoptosis of lung fibroblasts, and blocked the differentiation of lung fibroblasts into myofibroblasts. The multi-omics techniques and bioinformatics analysis revealed that OP-D blocked the AKT/GSK3β pathway, and the combination of a PI3K/AKT inhibitor and OP-D was effective in alleviating pulmonary fibrosis. ConclusionThis study demonstrated for the first time that OP-D can reduce lung inflammation and fibrosis. OP-D is thus a potential new drug for the prevention and treatment of pulmonary fibrosis.

Pathway from Acute Kidney Injury to Chronic Kidney Disease: Molecules Involved in Renal Fibrosis.

Acute kidney injury (AKI) is one of the main conditions responsible for chronic kidney disease (CKD), including end-stage renal disease (ESRD) as a long-term complication. Besides short-term complications, such as electrolyte and acid-base disorders, fluid overload, bleeding complications or immune dysfunctions, AKI can develop chronic injuries and subsequent CKD through renal fibrosis pathways. Kidney fibrosis is a pathological process defined by excessive extracellular matrix (ECM) deposition, evidenced in chronic kidney injuries with maladaptive architecture restoration. So far, cited maladaptive kidney processes responsible for AKI to CKD transition were epithelial, endothelial, pericyte, macrophage and fibroblast transition to myofibroblasts. These are responsible for smooth muscle actin (SMA) synthesis and abnormal renal architecture. Recently, AKI progress to CKD or ESRD gained a lot of interest, with impressive progression in discovering the mechanisms involved in renal fibrosis, including cellular and molecular pathways. Risk factors mentioned in AKI progression to CKD are frequency and severity of kidney injury, chronic diseases such as uncontrolled hypertension, diabetes mellitus, obesity and unmodifiable risk factors (i.e., genetics, older age or gender). To provide a better understanding of AKI transition to CKD, we have selected relevant and updated information regarding the risk factors responsible for AKIs unfavorable long-term evolution and mechanisms incriminated in the progression to a chronic state, along with possible therapeutic approaches in preventing or delaying CKD from AKI.