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Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease of unknown etiology characterized by distorted distal lung architecture, inflammation, and fibrosis. The molecular mechanisms involved in the pathophysiology of IPF are incompletely defined. Several lung cell types including alveolar epithelial cells, fibroblasts, monocyte-derived macrophages, and endothelial cells have been implicated in the development and progression of fibrosis. Regardless of the cell types involved, changes in gene expression, disrupted glycolysis, and mitochondrial oxidation, dysregulated protein folding, and altered phospholipid and sphingolipid metabolism result in activation of myofibroblast, deposition of extracellular matrix proteins, remodeling of lung architecture and fibrosis. Lipid mediators derived from phospholipids, sphingolipids, and polyunsaturated fatty acids play an important role in the pathogenesis of pulmonary fibrosis and have been described to exhibit pro- and anti-fibrotic effects in IPF and in preclinical animal models of lung fibrosis. This review describes the current understanding of the role and signaling pathways of prostanoids, lysophospholipids, and sphingolipids and their metabolizing enzymes in the development of lung fibrosis. Further, several of the lipid mediators and enzymes involved in their metabolism are therapeutic targets for drug development to treat IPF.

IntroductionDysregulated sphingolipid metabolism has been implicated in the pathogenesis of various pulmonary disorders. Nuclear sphingosine-1-phosphate (S1P) has been shown to regulate histone acetylation, and therefore could mediate pro-inflammatory genes expression.MethodsProfile of sphingolipid species in bronchoalveolar lavage fluids and lung tissue of mice challenged with Pseudomonas aeruginosa (PA) was investigated. The role of nuclear sphingosine kinase (SPHK)2 and S1P in lung inflammatory injury by PA using genetically engineered mice was determined.ResultsGenetic deletion of Sphk2, but not Sphk1, in mice conferred protection from PA-mediated lung inflammation. PA infection stimulated phosphorylation of SPHK2 and its localisation in epithelial cell nucleus, which was mediated by protein kinase C (PKC) δ. Inhibition of PKC δ or SPHK2 activity reduced PA-mediated acetylation of histone H3 and H4, which was necessary for the secretion of pro-inflammatory cytokines, interleukin-6 and tumour necrosis factor-α. The clinical significance of the findings is supported by enhanced nuclear localisation of p-SPHK2 in the epithelium of lung specimens from patients with cystic fibrosis (CF).ConclusionsOur studies define a critical role for nuclear SPHK2/S1P signalling in epigenetic regulation of bacterial-mediated inflammatory lung injury. Targeting SPHK2 may represent a potential strategy to reduce lung inflammatory pulmonary disorders such as pneumonia and CF.

Ubiquitin proteasome system was found to contribute to bone loss by regulating bone turnover and metabolism, by modulating osteoblast differentiation and bone formation as well as formation of osteoclasts that contribute to bone resorption. Muscle Ring Finger (MuRF) are novel ubiquitin ligases, which are muscle specific and have not been much implicated in the bone but have been implicated in several human diseases including heart failure and skeletal muscle atrophy. This study is aimed at understanding the role of MuRF1, MuRF2, MuRF3 and Atrogin which are distinct MuRF family proteins in bone homeostasis. Wildtype, heterozygous and homozygous mice of each of the isoforms were used and the bone microarchitecture and mechanical properties were assessed using microCT and biomechanics. MuRF1 depletion was found to alter cortical properties in both males and females, but only trabecular spacing in the females. MuRF2 depletion let to no changes in the cortical and trabecular properties but change in the strain to yield in the females. Depletion of MuRF3 led to decrease in the cortical properties in the females and increase in the trabecular properties in the males. Atrogin depletion was found to reduce cortical properties in both males and females, whereas some trabecular properties were found to be reduced in the females. Each muscle-specific ligase was found to alter the bone structure and mechanical properties in a distinct a sex-dependent manner.HighlightsMuRF1, MuRF2, MuRF3, and Atrogin-1 protein is expressed in bone.Adult MuRF1−/− femur cortical architecture is significantly increased (female > male).Adult MuRF3−/− femurs have significant alterations in cortical (female) and trabecular (male) bone.Atrogin-1−/− femurs exhibit significant changes in cortical (males and females) and decreased trabecular (male) bone.

Matrix metalloproteinase-14 (MMP-14) and Cathepsin-B (Cat-B) are overexpressed in glioblastoma (GBM) and not normal brain, making them promising targets for prodrug activation. We investigated a novel combination therapy using two tumor-enzyme activatable theranostic nanoprobes (TNP): TNP-MMP-14, which disrupts the blood tumor barrier via MMP-14 activation, and TNP-Cat-B, which selectively targets GBM cells through Cat-B activation. We hypothesized that combining TNP-MMP-14 and TNP-Cat-B would enhance TNP tumor accumulation and therapeutic efficacy compared to TNP-Cat-B monotherapy. Thirty NSG mice with luciferase-expressing GBM39 tumors received either TNP-MMP-14 plus TNP-Cat-B, TNP-Cat-B only, or saline. Magnetic resonance imaging (MRI) was conducted pre- and post-treatment, with T2* relaxation times analyzed using a generalized linear model. Histopathological differences were assessed using Kruskal–Wallis and Mann–Whitney tests. A Bonferroni correction was applied to account for multiple comparisons. Combination therapy significantly reduced tumor T2* relaxation times (12.98 ± 4.20 ms) compared to TNP-Cat-B monotherapy (22.49 ± 3.95 ms, p < 0.001). The apoptotic marker caspase-3 was also significantly higher in the combination group (64.46 ± 23.43 vs. 15.93 ± 5.81, p < 0.001). These findings demonstrate the potential of dual-enzyme activatable nanoparticles to enhance GBM treatment by overcoming drug delivery barriers and improving therapeutic efficacy over monotherapy.

Mechanical ventilation (MV) performed in respiratory failure patients to maintain lung function leads to ventilator-induced lung injury (VILI). This study investigates the role of sphingolipids and sphingolipid metabolizing enzymes in VILI using a rodent model of VILI and alveolar epithelial cells subjected to cyclic stretch (CS). MV (0 PEEP (Positive End Expiratory Pressure), 30 mL/kg, 4 h) in mice enhanced sphingosine-1-phosphate lyase (S1PL) expression, and ceramide levels, and decreased S1P levels in lung tissue, thereby leading to lung inflammation, injury and apoptosis. Accumulation of S1P in cells is a balance between its synthesis catalyzed by sphingosine kinase (SphK) 1 and 2 and catabolism mediated by S1P phosphatases and S1PL. Thus, the role of S1PL and SphK1 in VILI was investigated using Sgpl1+/− and Sphk1−/− mice. Partial genetic deletion of Sgpl1 protected mice against VILI, whereas deletion of SphK1 accentuated VILI in mice. Alveolar epithelial MLE-12 cells subjected to pathophysiological 18% cyclic stretch (CS) exhibited increased S1PL protein expression and dysregulation of sphingoid bases levels as compared to physiological 5% CS. Pre-treatment of MLE-12 cells with S1PL inhibitor, 4-deoxypyridoxine, attenuated 18% CS-induced barrier dysfunction, minimized cell apoptosis and cytokine secretion. These results suggest that inhibition of S1PL that increases S1P levels may offer protection against VILI.

Growing interest in the role of the immune response in Alzheimer’s Disease and related dementias (ADRD) has led to widespread use of fluid inflammatory markers in research studies. To standardize the use and interpretation of inflammatory markers in AD research, we build upon prior guidelines to develop consensus statements and recommendations to advance application and interpretation of these markers. In this roadmap paper, we propose a glossary of terms related to the immune response in the context of biomarker discovery/validation, discuss current conceptualizations of inflammatory markers in research, and recommend best practices to address key knowledge gaps. We also provide consensus principles to summarize primary conceptual, methodological, and interpretative issues facing the field: (1) a single inflammatory marker is likely insufficient to describe an entire biological cascade, and multiple markers with similar or distinct functions should be simultaneously measured in a panel; (2) association studies in humans are insufficient to infer causal relationships or mechanisms; (3) neuroinflammation displays time-dependent and disease context-dependent patterns; (4) neuroinflammatory mechanisms should not be inferred based solely on blood inflammatory marker changes; and (5) standardized reporting of CSF inflammatory marker assay validation and performance will improve incorporation of inflammatory markers into the biological AD criteria.

Cigarette smoke is the primary cause of Chronic Obstructive Pulmonary Disorder (COPD). Cigarette smoke extract (CSE)-induced oxidative damage of the lungs results in mitochondrial dysfunction and apoptosis of epithelium. Mitochondrial cardiolipin (CL) present in the inner mitochondrial membrane plays an important role in mitochondrial function, wherein its fatty acid composition is regulated by lysocardiolipin acyltransferase (LYCAT). In this study, we investigated the role of LYCAT expression and activity in mitochondrial oxidative stress, mitochondrial dynamics, and lung epithelial cell apoptosis. LYCAT expression was increased in human lung specimens from smokers, and cigarette smoke-exposed-mouse lung tissues. Cigarette smoke extract (CSE) increased LYCAT mRNA levels and protein expression, modulated cardiolipin fatty acid composition, and enhanced mitochondrial fission in the bronchial epithelial cell line, BEAS-2B in vitro. Inhibition of LYCAT activity with a peptide mimetic, attenuated CSE-mediated mitochondrial (mt) reactive oxygen species (ROS), mitochondrial fragmentation, and apoptosis, while MitoTEMPO attenuated CSE-induced MitoROS, mitochondrial fission and apoptosis of BEAS-2B cells. Collectively, these findings suggest that increased LYCAT expression promotes MitoROS, mitochondrial dynamics and apoptosis of lung epithelial cells. Given the key role of LYCAT in mitochondrial cardiolipin remodeling and function, strategies aimed at inhibiting LYCAT activity and ROS may offer an innovative approach to minimize lung inflammation caused by cigarette smoke.

Sphingosine-1-phosphate (S1P), a bioactive lipid mediator, is generated from sphingosine by sphingosine kinases (SPHKs) 1 and 2 and is metabolized to ∆2-hexadecenal (∆2-HDE) and ethanolamine phosphate by S1P lyase (S1PL) in mammalian cells. We have recently demonstrated the activation of nuclear SPHK2 and the generation of S1P in the nucleus of lung epithelial cells exposed to Pseudomonas aeruginosa. Here, we have investigated the nuclear localization of S1PL and the role of ∆2-HDE generated from S1P in the nucleus as a modulator of histone deacetylase (HDAC) activity and histone acetylation. Electron micrographs of the nuclear fractions isolated from MLE-12 cells showed nuclei free of ER contamination, and S1PL activity was detected in nuclear fractions isolated from primary lung bronchial epithelial cells and alveolar epithelial MLE-12 cells. Pseudomonasaeruginosa-mediated nuclear ∆2-HDE generation, and H3/H4 histone acetylation was attenuated by S1PL inhibitors in MLE-12 cells and human bronchial epithelial cells. In vitro, the addition of exogenous ∆2-HDE (100–10,000 nM) to lung epithelial cell nuclear preparations inhibited HDAC1/2 activity, and increased acetylation of Histone H3 and H4, whereas similar concentrations of S1P did not show a significant change. In addition, incubation of ∆2-HDE with rHDAC1 generated five different amino acid adducts as detected by LC-MS/MS; the predominant adduct being ∆2-HDE with lysine residues of HDAC1. Together, these data show an important role for the nuclear S1PL-derived ∆2-HDE in the modification of HDAC activity, histone acetylation, and chromatin remodeling in lung epithelial cells.

Alzheimer's disease (AD) affects women more frequently and more severely than men, but the biological mechanisms underlying these sex differences remain poorly understood. This review integrates recent findings from neuroscience, immunology, endocrinology, and genetics to explore how sex steroid hormones, particularly estrogen, shape neuroimmune responses and influence AD risk. We highlight the pivotal roles of microglia and astrocytes, whose inflammatory and neuroprotective actions are modulated by hormonal fluctuations across the female lifespan, including pregnancy, menopause, and menopausal hormone replacement therapy. Key genetic risk factors, such as apolipoprotein E ε4, show sex‐specific effects on glial activation, tau pathology, and cognitive decline. Furthermore, life‐stage transitions, especially menopause, intersect with changes in brain metabolism, immune signaling, and epigenetic regulation, increasing susceptibility to neurodegeneration in women. We propose a framework for sex‐aware, personalized approaches to AD prevention and treatment. By integrating hormone–immune interactions with genetic and glial biology, this review emphasizes the critical need for sex‐specific models in AD research. Highlights Women develop greater tauopathy, with more cognitive and clinical consequences in Alzheimer's disease (AD). Glial activation is adapted by estrogens to shape vulnerability or resilience to AD. Sex differences in innate and adaptive immunity could contribute to AD progression. Effects of menopausal hormone therapy on immunity in AD remain understudied. Future studies to explore sex differences in immune function during AD are needed. Conceptual framework for sex‐specific Alzheimer's disease (AD) risk. Sex differences in AD vulnerability arise from the intersection of multiple biological systems. Fluctuations in sex hormones across reproductive life stages (e.g., pregnancy, menopause) shape long‐term neuroendocrine tone. These hormonal shifts influence immune modulation, including both peripheral and central immune activity, particularly in glial cells such as microglia and astrocytes. Concurrently, genetic architecture, including sex‐interacting variants such as apolipoprotein E ε4, modifies susceptibility to AD pathology. The dynamic interplay among these systems contributes to a sex‐specific trajectory of AD risk, with distinct implications for disease onset, progression, and therapeutic response in women. (Figure created with BioRender.)