Atherosclerosis (AS), a leading contributor to global cardiovascular mortality, is primarily driven by the dual pathological processes of chronic persistent inflammation and dysregulated lipid metabolism. Current clinical interventions are predominantly limited to single-target approaches (e.g., lipid-lowering therapies), which are insufficient for simultaneously modulating the two pathophysiological mechanisms and inhibiting atherosclerotic progression. Recently, combination therapeutic strategies based on multi-target and multi-organ synergistic effects have gained increasing attention in AS treatment. In this study, we developed a dual-functional nanodelivery system co-encapsulating PCSK9 inhibitor of evolocumab and natural anti-inflammatory agent of curcumin, with surface modification using macrophage membranes (Møm) and hyaluronic acid (HA). This novel design not only confers immune evasion capability to the nanocomplex but also facilitates drug accumulation in atherosclerotic lesions and hepatic tissues, thereby enabling synchronous regulation of the inflammatory microenvironment and lipid metabolic homeostasis. In vivo studies demonstrated remarkable therapeutic efficacy of this nanoformulation on atherosclerosis by effectively reducing plaque area, enhancing plaque stability and markedly ameliorating hepatic lipid accumulation. Overall, the proposed strategy, which enables multi-target and multi-organ synergistic regulation of inflammatory responses and lipid metabolism disorder, provides a promising approach for the clinical management of atherosclerosis.

Macrophages play a protective role in atherosclerosis, whereas homocysteine (Hcy) is recognized as an independent risk factor for atherosclerosis. Defects in macrophage autophagy contribute to the formation of atherosclerotic plaques, and dysregulated energy metabolism is closely linked to the process of autophagy. However, the regulation of macrophage autophagy by pyruvate dehydrogenase (PDH), a key component of the PDH complex involved in energy and metabolic homeostasis, remains poorly understood in the context of atherosclerosis induced by Hcy. In our study, proteomic profiling identifies 748 upregulated proteins and 760 downregulated proteins in Hcy-treated macrophages. KEGG pathway analysis reveals significant enrichment of differentially expressed proteins in metabolism-related pathways, including those related to the biosynthesis of amino acids, carbon metabolism, and glycolysis/gluconeogenesis. Additionally, we explore the role of PDH in mediating Hcy-induced atherosclerosis in ApoE -/- mice. The results show a marked reduction in PDH expression and activity in Hcy-treated macrophages, leading to impaired autophagy. Notably, PDH activation enhances the assembly of the autophagy initiator ULK1-FIP200-Atg13 complex through the modulation of the AMPK/mTOR signaling pathway, suggesting a potential therapeutic target for Hcy-induced atherosclerosis.

Silicosis is an occupational disease caused by inhalation of silica dust, which is hallmarked by progressive pulmonary fibrosis associated with poor prognosis. Wnt/β-catenin signaling is implicated in the development of fibrosis and is a therapeutic target for fibrotic diseases. Previous clinical studies of patients with pneumoconiosis, including silicosis, revealed an increased concentration of circulating WNT3A and DKK1 proteins and inflammatory cells in bronchoalveolar lavage compared with healthy subjects. The present study evaluated the effects of adenovirus-mediated transduction of Dickkopf-1 (Dkk1), a Wnt/β-catenin signaling inhibitor, on the development of pulmonary silicosis in mice. Consistent with previous human clinical studies, our experimental studies in mice demonstrated an aberrant Wnt/β-catenin signaling activity coinciding with increased Wnt3a and Dkk1 proteins and inflammation in lungs of silica-induced silicosis mice compared with controls. Intratracheal delivery of adenovirus expressing murine Dkk1 (AdDkk1) inhibited Wnt/β-catenin activity in mouse lungs. The adenovirus-mediated Dkk1 gene transduction demonstrated the potential to prevent silicosis development and ameliorate silica-induced lung fibrogenesis in mice, accompanied by the reduced expression of epithelia--mesenchymal transition markers and deposition of extracellular matrix proteins compared with mice treated with "null" adenoviral vector. Mechanistically, AdDkk1 is able to attenuate the lung silicosis by inhibiting a silica-induced spike in TGF-β/Smad signaling. In addition, the forced expression of Dkk1 suppressed silica-induced epithelial cell proliferation in polarized human bronchial epithelial cells. This study provides insight into the underlying role of Wnt/β-catenin signaling in promoting the pathogenesis of silicosis and is proof-of-concept that targeting Wnt/β-catenin signaling by Dkk1 gene transduction may be an alternative approach in the prevention and treatment of silicosis lung disease.

Silicosis is caused by the continuous inhalation of environmental silica dust. The repetitive exposure of silica induces airway epithelial cell injury, leads proliferative exhaustion of epithelial stem cells, ultimately results in the lung remodeling and the development of silicosis. The B-cell-specific Moloney murine leukemia virus integration site 1 (Bmi1) is a pivotal transcription factor in stem cell self-renewal and proliferation of many tissues including the lung, but its role in the airway basal cell proliferation and differentiation during the pathogenesis of silicosis in lung has yet been investigated. In this study, the function of Bmi1 in airway basal cell proliferation and differentiation in response to silica challenge was investigated in lungs of silicosis mice and primary human bronchial epithelia cells (HBECs) exposed to silica dioxide (SiO2). Results showed a decreased expression of Bmi1 protein, epithelial basal cell markers Krt14 and Krt5, club cell marker Clara cell secretory protein, and ciliated cell marker acetyl-α-tubulin in silicosis lungs, compared to healthy mice. In consistence, a persistent exposure of SiO2 reduced the capacity of cell proliferation and differentiation in HBECs, as ascertained by the reduction of differentiated epithelial cell markers and BMI1 expression, while an increased P21-positive senescent cell fraction. Moreover, an overexpression of BMI1 in HBECs reduced the SiO2-senescent cells, enhanced the potency of cell proliferation and differentiation, and increased capacity of airway epithelial regeneration in response to the persistent exposure of SiO2. These data suggest that Bmi1 is a key transcription factor engaging in maintaining the self-renewal, proliferation and differentiation of epithelial stem cells in lung during the development of silicosis disease.

Acinetobacter baumannii (A. baumannii) is a common opportunistic nosocomial pathogen, which is able to produce biofilms on the surface of indwelling medical devices, and consequentially causes severe infections in clinical settings. In order to identify genes that involved in the biofilm formation of A. baumannii, the differential expression of genes between biofilms and planktonic cells was analyzed by RNAseq assay and validated in clinical isolates. The RNAseq data showed that 264 genes were up-regulated, while 240 genes were down-regulated in the biofilms of A. baumannii. Among them, the gene encoding alcohol dehydrogenase (ADH), a known molecule of bacterial quorum sensing (QS) system that plays a key role in biofilm formation bacteria, was one of the most up-regulated gene in both reference strains and clinical isolates. Functional studies using ADH inhibitor disulfiram and activator taurine further demonstrated that the presence of disulfiram significantly inhibit the cell growth, motility and biofilm formation, paralleled by a decreased expression of QS-related genes, including AbaI, A1S_0109, and A1S_0112, in a dose-dependent manner; vice versa, the addition of ADH activator taurine, and QS molecule C12- homoserine lactone synthase (HSL) led a dose-dependent increase of bacterial growth, motility and biofilm production, along with an increased expression of QS-related genes in both reference strains and clinical isolates of A. baumannii. These results suggested that the ADH was a key molecule able to modulate the QS system and promote the biofilm formation, growth and motility in A. baumannii.

Silicosis is a chronic fibrotic lung disease caused by the accumulation of silica dust in the distal lung. Canonical Wnt signaling and NADPH oxidase 4 (NOX4) have been demonstrated to play a crucial role in the pathogenesis of pulmonary fibrosis including silicosis. However, the underlying mechanisms of crosstalk between these two signalings are not fully understood. In the present study, we aimed to explore the interaction of Wnt/β-catenin and NOX4 of human epithelial cells in response to an exposure of silica dust. Results demonstrated an elevated expression of key components of Wnt/β-catenin signaling and NOX4 in the lungs of silicon dioxide- (SiO2-) induced silicosis mice. Furthermore, the activated Wnt/β-catenin and NOX4 signaling are accompanied by an inhibition of cell proliferation, an increase of ROS production and cell apoptosis, and an upregulation of profibrogenic factors in BEAS-2B human lung epithelial cells exposed to SiO2. A mechanistic study further demonstrated that the Wnt3a-mediated activation of canonical Wnt signaling could augment the SiO2-induced NOX4 expression and reactive oxygen species (ROS) production but reduced glutathione (GSH), while Wnt inhibitor DKK1 exhibited an opposite effect to Wnt3a. Vice versa, an overexpression of NOX4 further activated SiO2-induced Wnt/β-catenin signaling and NFE2-related factor 2 (Nrf2) antioxidant response along with a reduction of GSH, whereas the shRNA-mediated knockdown of NOX4 showed an opposite effect to NOX4 overexpression. These results imply a positive feed forward loop between Wnt/β-catenin and NOX4 signaling that may promote epithelial-mesenchymal transition (EMT) of lung epithelial cells in response to an exposure of silica dust, which may thus provide an insight into the profibrogenic role of Wnt/β-catenin and NOX4 crosstalk in lung epithelial cell injury and pathogenesis of silicosis.

An early diagnosis of interstitial lung disease (ILD) is important for guiding treatments of rheumatoid arthritis (RA)-associated ILD (RA-ILD) in clinical settings. The non-canonical Wnt signaling representative ligand Wnt5a was recently found to involve in idiopathic pulmonary fibrosis (IPF) and pathogenesis of RA. The goal of this study was to examine the clinical relevance of Wnt5a in RA-ILD. In this report, the clinical relevance of plasma Wnt5a protein was evaluated in 40 RA-ILD patients and 41 non-ILD RA cohorts. The results showed an elevated Wnt5a protein in plasmas of RA-ILD patients compared with non-ILD RA patients (p < 0.01), which was positively correlated with the plasma level of rheumatoid factor (RF). Of note, more abundant Wnt5a was also found in patients with usual interstitial pneumonia (UIP) than those with nonspecific interstitial pneumonia (NSIP) and other ILD patterns. More importantly, the disease severity was correlated with the circulating Wnt5a as ascertained by high-resolution computed tomography (HRCT)-UIP scores. The multiple-factor non-conditional logistic regression analysis further revealed that the age, RA duration, smoking and plasma Wnt5a were risk factors with clinical significance for RA-ILD. Interestingly, more Wnt5a-positive patients were identified in RA-ILD smokers relative to RA-ILD never-smokers, and longer smoking duration was strongly correlated with Wnt5a in RA-ILD patients. In consistence, ROC curve also suggested that the Wnt5a was a potential candidate biomarker for identifying patients with RA-UIP. These results demonstrate that the circulating Wnt5a may be a risk factor and potential biomarker for identifying UIP and accessing the severity and progression of ILD in RA patients.

Wnt signaling pathways are tightly controlled under a physiological condition, under which they play key roles in many biological functions, including cell fate specification and tissue regeneration. Increasing lines of evidence recently demonstrated that a dysregulated activation of Wnt signaling, particularly the Wnt/β-catenin signaling, was involved in the pathogenesis of chronic pulmonary diseases, such as chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). In this respect, Wnt signaling interacts with other cellular signaling pathways to regulate the initiation and pathogenic procedures of airway inflammation and remodeling, pulmonary myofibroblast proliferation, epithelial-to-mesenchymal transition (EMT), and development of emphysema. Intriguingly, Wnt/β-catenin signaling is activated in IPF; an inhibition of this signaling leads to an alleviation of pulmonary inflammation and fibrosis in experimental models. Conversely, Wnt/β-catenin signaling is inactivated in COPD tissues, and its reactivation results in an amelioration of airspace enlargement with a restored alveolar epithelial structure and function in emphysema models. These studies thus imply distinct mechanisms of Wnt/β-catenin signaling in the pathogenesis of these two chronic pulmonary diseases, indicating potential targets for COPD and IPF treatments. This review article aims to summarize the involvement and pathogenic roles of Wnt signaling pathways in the COPD and IPF, with a focus on the implication of Wnt/β-catenin signaling as underlying mechanisms and therapeutic targets in these two incurable diseases.

Introduction: Interstitial lung disease (ILD) is a common, devastating pulmonary complication. An increased number of reports suggesting that biological disease modifying antirheumatic drugs (DMARDs) induced or exacerbated ILDs in rheumatoid arthritis (RA) patients has garnered increased attention.Areas covered: This article discusses ILDs induced by or exacerbated during biological therapy in RA patients. The article summarizes the efficacy and safety of a variety of licensed and off-label biologics clinically used for rheumatic diseases, focusing on the onset or exacerbation of RA-associated ILDs (RA-ILDs) in RA patients treated with biologics targeting tumor necrosis factor, CD20, interleukin 1 (IL-1) and IL-6 receptors. Additionally, the pathogenesis of RA-ILDs is discussed.Expert opinion: To some extent, the possibility of biologic-induced RA-ILDs increases the difficulty in choosing an optimal regimen for RA treatment with biological agents, as the relationship between biological therapy safety and the induction or exacerbation of RA-ILDs has not been established. A framework to assess baseline disease severity, particularly standardizing the evaluation of the pulmonary condition stage in RA patients and monitoring the outcome during the biological therapy treatment, is highly needed and may substantially help guide treatment decisions and predict the treatment benefits.

Pulmonary fibrosis is a progressive lung disease that its pathogenic mechanism currently is incompletely understood. Toll-like receptor (TLR) signaling has recently been identified as a regulator of inflammation and pulmonary fibrosis. In addition, mesenchymal stem cells (MSCs) of different origins offer a great promise in treatment of idiopathic pulmonary fibrosis (IPF). However mechanisms of pathogenic roles of TLR signaling and therapeutic effects of MSCs in the IPF remain elusive. In present study, the involvement of TLR signaling and the therapeutic role of MSCs were interrogated in MyD88-deficient mice using human placental MSCs of fetal origins (hfPMSCs). The results showed an alleviated pulmonary inflammation and fibrosis in myeloid differentiation primary response gene 88 (MyD88)-deficient mice treated with bleomycin (BLM), accompanied with a reduced TGF-β signaling and production of pro-fibrotic cytokines, including TNF-α, IL-1β. An exposure of HLF1 lung fibroblasts, A549 epithelial cells and RAW264.7 macrophages to BLM led an increased expression of key components of MyD88 and TGF-β signaling cascades. Of interest, enforced expression and inhibition of MyD88 protein resulted in an enhanced and a reduced TGF-β signaling in above cells in the presence of BLM, respectively. However, the addition of TGF-β1 showed a marginally inhibitory effect on MyD88 signaling in these cells in the absence of BLM. Importantly, the administration of hfPMSCs could significantly attenuate BLM-induced pulmonary fibrosis in mice, along with a reduced hydroxyproline (HYP) deposition, MyD88 and TGF-β signaling activation, and production of pro-fibrotic cytokines. These results may suggest an importance of MyD88/TGF-β signaling axis in the tissue homeostasis and functional integrity of lung in response to injury, which may offer a novel target for treatment of pulmonary fibrosis.

Background. Serum concentrations of soluble interleukin-7 receptor (sIL-7R) and anti-C1q antibody have recently been identified as unique serological markers for lupus nephritis (LN) in patients with systemic lupus erythematosus (SLE). In this study, we evaluated the correlation of serum sIL-7R and anti-C1q in SLE patients. Methods. Sera from 134 patients with SLE and 84 healthy cohorts were tested for levels of sIL-7R and anti-C1q antibodies in terms of ELISA. Correlations of the sIL-7R and anti-C1q autoantibodies were evaluated. Results. The serum concentrations of sIL-7R and anti-C1q antibodies were significantly higher in SLE patients and LN patients in comparison with healthy individuals/controls and SLE patients with non-LN, respectively. In addition, both sIL-7R and anti-C1q concentrations were found to significantly correlate with the SLE disease activity as evaluated by SLEDAI scores. Interestingly, the serum sIL-7R concentration was strongly correlated with the level of anti-C1q antibodies (r = 0.2871,p = 0.0008) but not statistically correlated with other serological markers, including the anti-dsDNA and complements C3 and C4 concentrations in SLE patients. Conclusion. Both serum sIL-7R and anti-C1q antibodies were strongly associated with disease activity and LN in SLE patients, suggesting that they may be reliable serological markers for identification of SLE patients with active diseases and LN.

The Wnt signaling pathway plays a key role in many biological aspects, such as cellular proliferation, tissue regeneration, embryonic development, and other systemic effects. Under a physiological condition, it is tightly controlled at different layers and arrays, and a dysregulated activation of this signaling has been implicated into the pathogenesis of various human disorders, including autoimmune diseases. Despite the fact that therapeutic interventions are available for ameliorating disease manifestations, there is no curative therapy currently available for autoimmune disorders. Increasing lines of evidence have suggested a crucial role of Wnt signaling during the pathogenesis of many autoimmune diseases; in addition, some of microRNAs (miRNAs), a class of small, noncoding RNA molecules capable of transcriptionally regulating gene expression, have also recently been demonstrated to possess both physiological and pathological roles in autoimmune diseases by regulating the Wnt signaling pathway. This review summarizes currently our understanding of the pathogenic roles of Wnt signaling in several major autoimmune disorders and miRNAs, those targeting Wnt signaling in autoimmune diseases, with a focus on the implication of the Wnt signaling as potential biomarkers and therapeutic targets in immune diseases, as well as miRNA-mediated regulation of Wnt signaling activation in the development of autoimmune diseases.

The increasing incidence of pulmonary inflammation and lung cancer, as well as exacerbation of pre-existing chronic lung diseases by exposure to airborne pollutants, e.g., particulate matter and cigarette smoke, is becoming a major public health concern in the world. However, the exact mechanisms of pulmonary injury from exposure to these airborne insults have not been fully elucidated. Nevertheless, accumulating evidence suggests that microRNAs (miRNAs) may play a unique role in the regulation of airborne agent-induced lung inflammation and carcinogenesis. Since epigenetic modifications are heritable and reversible, this may provide a new insight into the relationship of miRNAs and environmental pollution-related lung disorders. The aim of this review was to update our existing knowledge regarding the mechanisms by which airborne pollutants altering miRNA profiles in the lung, specifically for cigarette smoke and airborne particulate matter, and the potential biological roles of miRNAs in the initiation of pulmonary inflammation and lung cancer, as well as the regulation of underlying genetic susceptibility to these environmental stressors.

Lung is a complex organ lined with epithelial cells. In order to maintain its homeostasis and normal functions following injuries caused by varied extraneous and intraneous insults, such as inhaled environmental pollutants and overwhelming inflammatory responses, the respiratory epithelium normally undergoes regenerations by the proliferation and differentiation of region-specific epithelial stem/progenitor cells that resided in distinct niches along the airway tree. The importance of local epithelial stem cell niches in the specification of lung stem/progenitor cells has been recently identified. Studies using cell differentiating and lineage tracing assays, in vitro and/or ex vivo models, and genetically engineered mice have suggested that these local epithelial stem/progenitor cells within spatially distinct regions along the pulmonary tree contribute to the injury repair of epithelium adjacent to their respective niches. This paper reviews recent findings in the identification and isolation of region-specific epithelial stem/progenitor cells and local niches along the airway tree and the potential link of epithelial stem cells for the development of lung cancer.

Lung cancer is a leading cause of cancer mortality worldwide. Several molecular pathways underlying mechanisms of this disease have been partly elucidated, among which the epidermal growth factor receptor (EGFR) pathway is one of the well-known signaling cascades that plays a critical role in tumorigenesis. Dysregulation of the EGFR signaling is frequently found in lung cancer. The strategies to effectively inhibit EGFR signaling pathway have been mounted for developing anticancer therapeutic agents. However, most anti-EGFR-targeted agents fail to repress cancer progression because of developing drug-resistance. Therefore, studies of the mechanisms underpinning the resistance toward anti-EGFR agents may provide important findings for lung cancer treatment using anti-EGFR therapies. Recently, increasing numbers of miRNAs are correlated with the drug resistance of lung cancer cells to anti-EGFR agents, indicating that miRNAs may serve as novel targets and/or promising predictive biomarkers for anti-EGFR therapy. In this paper, we summarize the emerging role of miRNAs as regulators to modulate the EGFR signaling and the resistance of lung cancer cells to anti-EGFR therapy. We also highlight the evidence supporting the use of miRNAs as biomarkers for response to anti-EGFR agents and as novel therapeutic targets to circumvent the resistance of lung cancer cells to EGFR inhibitors.

UNLABELLED Effects of ICAM-1 antisense oligonucleotide on the renal tubulointerstitium in mice with unilateral ureteral obstruction. BACKGROUND To extend our previous study of the therapy of the renal lesions of unilateral ureteral obstruction (UUO) in mice by an inhibitor of intercellular adhesion molecule-1 (ICAM-1), we investigated the blocking effects of ICAM-1 antisense oligonucleotides (ASONs) on the ICAM-1 expression in mouse kidney. METHODS First, ICAM-1 ASON was transducted into mouse renal tubular epithelial cells to investigate the effects of ICAM-1 ASON in vitro. Second, fluorescein isothiocyanate (FITC)-labeled ICAM-1 ASON was injected intravenously to determine the distribution of the ASON in vivo. Third, the expression of ICAM-1 in kidney and the changes of renal morphology were observed to investigate the therapeutic effects of ICAM-1 ASON on the UUO mice in vivo. RESULTS The expressions of ICAM-1 in the epithelial cells induced by interleukin-1beta were inhibited by ICAM-1 ASON at the dosages of 100 and 200 nmol/L. Twenty-four hours after an introvenous injection with FITC-labeled ICAM-1 ASON, the highest level of fluorescein was detected within the proximal tubules in mouse kidney. Results of immunohistology and Northern blot showed that the ICAM-1 expression was markedly reduced in the obstructed kidney after treatment with ICAM-1 ASON. The ASON also alleviated the infiltration of inflammatory cells and accumulation of the extracellular matrix in the tubulointerstitium of UUO mice without apparent side effects. CONCLUSION Our data demonstrate that ICAM-1 ASON is taken up primarily by the proximal tubular cells of mouse kidney. ICAM-1 ASON can selectively inhibit the ICAM-1 expression of the renal tubular cells both in vitro and in vivo.

OBJECTIVE: To determine the distribution of ICAM-1 antisense oligonucleotides (ASON) in kidney following intravenous administration of the ASON and to investigate its inhibition effect on the ICAM-1 expression in kidney with inflammation. METHOD: The phosphorothioate ICAM-1 ASON was synthesized and labeled with FITC. ICAM-1 ASON was given to NIH mice by intravenous injection at the dose of 1 mg·kg -1 or 10 mg·kg -1. The distribution of FITC-labeled ICAM-1 ASON in kidney were determined under fluorescent microscope. The expressions of ICAM-1 mRNA in the kidney of the mice were examined by Northern blotting. RESULTS: 1, The highest level of fluorescein was detected within the proximal tubules in the kidney at 24 hours after infection of ICAM-1 ASON. 2, There was no difference in distribution and amount of ICAM-1 ASON whether it was administered with or without liposome-DOTAP. 3, In the unilateral ureteral obstruction (UUO) mice, the distribution and the level of ICAM-1 ASON in the obstructed kidney were not different from those of the normal kidney. 4, The expression of ICAM-1 protein and ICAM-1 mRNA in the obstructed kidney were inhibited markedly by ICAM-1 ASON. CONCLUSION: After systemic administration, ICAM-1 ASON may be taken up primarily by the proximal tubular cells of the mouse kidney. The distribution and the inhibition effects of ICAM-1 ASON were idential by intravenous injection at the dose of 1 mg·kg -1 or 10 mg·kg -1.