Aberrant basement membrane production by HSCs in MASLD is attenuated by the bile acid analog INT-767.

Background: The farnesoid X receptor (FXR) is a leading therapeutic target for metabolic dysfunction-associated steatohepatitis (MASH)-related fibrosis. INT-767, a potent FXR agonist, has shown promise in preclinical models. We aimed to define the mechanisms of INT-767 activity in experimental MASH and dissect cellular and molecular targets of FXR agonism in human disease.

Application of a High-Content Screening Assay Utilizing Primary Human Lung Fibroblasts to Identify Antifibrotic Drugs for Rapid Repurposing in COVID-19 Patients.

Lung imaging and autopsy reports among COVID-19 patients show elevated lung scarring (fibrosis). Early data from COVID-19 patients as well as previous studies from severe acute respiratory syndrome, Middle East respiratory syndrome, and other respiratory disorders show that the extent of lung fibrosis is associated with a higher mortality, prolonged ventilator dependence, and poorer long-term health prognosis. Current treatments to halt or reverse lung fibrosis are limited; thus, the rapid development of effective antifibrotic therapies is a major global medical need that will continue far beyond the current COVID-19 pandemic.

The oncogene Gankyrin is expressed in testicular cancer and contributes to cisplatin sensitivity in embryonal carcinoma cells.

Background: Testicular germ cell cancer (TGCC) develops from pre-malignant germ neoplasia in situ (GCNIS) cells. GCNIS originates from fetal gonocytes (POU5F1/MAGE-A4), which fail to differentiate to pre-spermatogonia (POU5F1/MAGE-A4) and undergo malignant transformation. Gankyrin is an oncogene which has been shown to prevent POU5F1 degradation and specifically interact with MAGE-A4 in hepatocellular carcinoma (HCC) cells.

Augmentation of Human Monocyte Responses to Lipopolysaccharide by the Protein S and Mer/Tyro3 Receptor Tyrosine Kinase Axis.

Resolution of the inflammatory response requires coordinated regulation of pro- and anti-inflammatory mediator production, together with clearance of recruited inflammatory cells. Many different receptors have been implicated in phagocytosis of apoptotic cells (efferocytosis), including Mer, a receptor tyrosine kinase that can mediate recognition and subsequent internalization of apoptotic cells. In this manuscript, we examine the expression and function of the Tyro3/Axl/Mer (TAM) family of receptors by human monocytes.

Neutrophils induce macrophage anti-inflammatory reprogramming by suppressing NF-κB activation.

Apoptotic cells modulate the function of macrophages to control and resolve inflammation. Here, we show that neutrophils induce a rapid and sustained suppression of NF-κB signalling in the macrophage through a unique regulatory relationship which is independent of apoptosis. The reduction of macrophage NF-κB activation occurs through a blockade in transforming growth factor β-activated kinase 1 (TAK1) and IKKβ activation.

The "Phagocytic Synapse" and Clearance of Apoptotic Cells.

Apoptosis and subsequent phagocytic clearance of apoptotic cells is important for embryonic development, maintenance of tissues that require regular cellular renewal and innate immunity. The timely removal of apoptotic cells prevents progression to secondary necrosis and release of cellular contents, preventing cellular stress and inflammation. In addition, altered phagocyte behavior following apoptotic cell contact and phagocytosis engages an anti-inflammatory phenotype, which impacts upon development and progression of inflammatory and immune responses.

Glycogen synthase kinase-3β modulation of glucocorticoid responsiveness in COPD.

In chronic obstructive pulmonary disease (COPD), oxidative stress regulates the inflammatory response of bronchial epithelium and monocytes/macrophages through kinase modulation and has been linked to glucocorticoid unresponsiveness. Glycogen synthase-3β (GSK3β) inactivation plays a key role in mediating signaling processes upon reactive oxygen species (ROS) exposure. We hypothesized that GSK3β is involved in oxidative stress-induced glucocorticoid insensitivity in COPD.

Oxidants induce a corticosteroid-insensitive phosphorylation of histone 3 at serine 10 in monocytes.

Oxidative stress enhances inflammation and reduces the effectiveness of corticosteroids, but the inflammatory signalling pathways induced by oxidants remain ill-defined. Phosphorylation of histone 3 at serine 10 (H3-Pser10) marks out a subset of inflammatory genes for transcription, several of which are induced in oxidant-associated inflammation. However, the influence of oxidants or of corticosteroids on this modification remains unknown.

Functional characterisation of human pulmonary monocyte-like cells in lipopolysaccharide-mediated acute lung inflammation.

Background: We have previously reported the presence of novel subpopulations of pulmonary monocyte-like cells (PMLC) in the human lung; resident PMLC (rPMLC, HLA-DR(+)CD14(++)CD16(+)cells) and inducible PMLC (iPMLC, HLA-DR(+)CD14(++)CD16(-) cells). iPMLC are significantly increased in bronchoalveolar lavage (BAL) fluid following inhalation of lipopolysaccharide (LPS). We have carried out the first functional evaluation of PMLC subpopulations in the inflamed lung, following the isolation of these cells, and other lineages, from BAL fluid using novel and complex protocols.

Technical advance: autofluorescence-based sorting: rapid and nonperturbing isolation of ultrapure neutrophils to determine cytokine production.

The technical limitations of isolating neutrophils without contaminating leukocytes, while concurrently minimizing neutrophil activation, is a barrier to determining specific neutrophil functions. We aimed to assess the use of FACS for generating highly pure quiescent neutrophil populations in an antibody-free environment. Peripheral blood human granulocytes and murine bone marrow-derived neutrophils were isolated by discontinuous Percoll gradient and flow-sorted using FSC/SSC profiles and differences in autofluorescence.

Flavones induce neutrophil apoptosis by down-regulation of Mcl-1 via a proteasomal-dependent pathway.

Neutrophil apoptosis and subsequent nonphlogistic clearance by surrounding phagocytes are key to the successful resolution of neutrophilic inflammation, with dysregulated apoptosis reported in multiple human inflammatory diseases. Enhancing neutrophil apoptosis has proresolution and anti-inflammatory effects in preclinical models of inflammation. Here we investigate the ability of the flavones apigenin, luteolin, and wogonin to induce neutrophil apoptosis in vitro and resolve neutrophilic inflammation in vivo.

Mechanisms of corticosteroid resistance in severe asthma and chronic obstructive pulmonary disease (COPD).

Inhaled glucocorticoids, also know as corticosteroids (ICS), revolutionized the treatment of asthma by suppressing airways inflammation and ICS therapy now forms the basis of treatment of asthma of all severities. More recently and usually in combination with a long-acting β-agonist (LABA), ICS use has been established in the treatment of chronic obstructive pulmonary disease (COPD). In asthma, ICS improves asthma control, lung function and prevents exacerbations, including hospital admissions and probably decreases mortality.

Cigarette Smoke Exposure Alters mSin3a and Mi-2alpha/beta Expression; implications in the control of pro-inflammatory gene transcription and glucocorticoid function.

Background: The key co-repressor complex components HDAC-2, Mi-2alpha/beta and mSin3a are all critical to the regulation of gene transcription. HDAC-2 function is impaired by oxidative stress in a PI3Kdelta dependant manner which may be involved in the chronic glucocorticoid insensitive inflammation in the lungs of COPD patients. However, the impact of cigarette smoke exposure on the expression of mSin3a and Mi2alpha/beta and their role in glucocorticoid responsiveness is unknown.

Overcoming reduced glucocorticoid sensitivity in airway disease: molecular mechanisms and therapeutic approaches.

There is a considerable and growing unmet medical need in respiratory disease concerning effective anti-inflammatory therapies for conditions such as severe asthma, chronic obstructive pulmonary disease and cystic fibrosis. These diseases share a predominant characteristic of an enhanced and uncontrolled inflammatory response in the lungs, which contributes to disease progression, hospitalization and mortality. These diseases are poorly controlled by current anti-inflammatory therapies including glucocorticoids, which are otherwise effective in many other inflammatory conditions or in milder disease such as asthma.

A role for phosphoinositol 3-kinase delta in the impairment of glucocorticoid responsiveness in patients with chronic obstructive pulmonary disease.

Background: Glucocorticoid function is markedly impaired in the lungs of patients with chronic obstructive pulmonary disease (COPD). This reduction in glucocorticoid sensitivity might be due to an oxidant-mediated increase in phosphoinositol 3-kinase (PI3K) delta signaling.

Objective: We sought to determine the role of PI3Kdelta in the reduced glucocorticoid responsiveness in patients with COPD.

Fixed airflow obstruction due to asthma or chronic obstructive pulmonary disease: 5-year follow-up.

Background: Both smokers and patients with asthma can experience fixed airflow obstruction, which is associated with distinctive patterns of airway pathology. The influence of fixed airflow obstruction on the prognosis of these patients is unknown.

Objective: We sought to investigate lung function decline and exacerbations in a 5-year prospective study of subjects with fixed airflow obstruction due to asthma or chronic obstructive pulmonary disease (COPD).

Cigarette smoke regulates VEGFR2-mediated survival signaling in rat lungs.

Background: Vascular endothelial growth factor (VEGF) and VEGF receptor 2 (VEGFR2)-mediated survival signaling is critical to endothelial cell survival, maintenance of the vasculature and alveolar structure and regeneration of lung tissue. Reduced VEGF and VEGFR2 expression in emphysematous lungs has been linked to increased endothelial cell death and vascular regression. Previously, we have shown that CS down-regulated the VEGFR2 and its downstream signaling in mouse lungs.

Inhibition of PI3Kdelta restores glucocorticoid function in smoking-induced airway inflammation in mice.

Rationale: There is an increasing prevalence of reduced responsiveness to glucocorticoid therapy in severe asthma and chronic obstructive pulmonary disease (COPD). The molecular mechanism of this remains unknown. Recent studies have shown that histone deacetylase activity, which is critical to glucocorticoid function, is altered by oxidant stress and may be involved in the development of glucocorticoid insensitivity.

Curcumin restores corticosteroid function in monocytes exposed to oxidants by maintaining HDAC2.

Oxidative stress as a result of cigarette smoking is an important etiologic factor in the pathogenesis of chronic obstructive pulmonary disease (COPD), a chronic steroid-insensitive inflammatory disease of the airways. Histone deacetylase-2 (HDAC2), a critical component of the corticosteroid anti-inflammatory action, is impaired in lungs of patients with COPD and correlates with disease severity. We demonstrate here that curcumin (diferuloylmethane), a dietary polyphenol, at nanomolar concentrations specifically restores cigarette smoke extract (CSE)- or oxidative stress-impaired HDAC2 activity and corticosteroid efficacy in vitro with an EC(50) of approximately 30 nM and 200 nM, respectively.