Sepsis is characterized by high mortality and a complicated pathological mechanism. Macrophages play a crucial role in the initiation and progression of sepsis-associated acute respiratory distress syndrome (ARDS). Macrophage functional states and polarization phenotype have been significantly influenced by metabolic programming. This review delineates the metabolic reprogramming of macrophages from the initial ‘metabolic storm’ to subsequent ‘immune paralysis’ in sepsis-associated ARDS. It focuses on the interplay between macrophage polarization (classical activated macrophages (M1) and alternative activated macrophages (M2) phenotypes) and key metabolic pathways, including glycolysis and oxidative phosphorylation (OXPHOS). Furthermore, it explains the molecular mechanism underlying the metabolic pattern’s influence on macrophage and lung tissue damage. The final section of this review focuses on the therapeutic implications of bone marrow mesenchymal stem cells (BMMSCs) and myeloid-derived suppressor cells (MDSCs), which alter macrophage metabolic reprogramming. Based on the latest progress, this article aims to provide a comprehensive theoretical framework and cli Based on recent advances, nical guidance for immunometabolic therapy in sepsis-associated ARDS.

Alveolar macrophages (AMs), a type of immune cell, display remarkable plasticity and manifest diverse responses to stimuli by differentiating into distinct subgroups. These phenotypically distinct macrophage subtypes are primarily categorized as either classically activated or inflammatory (M1) macrophages, or alternatively activated or anti-inflammatory (M2) macrophages, the differentiation of which is underpinned by a complex regulatory network. Despite their crucial contribution to the pathobiology of acute lung injury/acute respiratory distress syndrome (ALI/ARDS), the research on AMs is currently limited. This study therefore aims to establish a comprehensive theoretical framework delineating the pathogenic role of AMs in ALI/ARDS, facilitating deeper mechanistic understanding of disease initiation and progression in ALI/ARDS and ultimately identifying novel therapeutic targets.

Gestational diabetes mellitus (GDM) constitutes a significant contributor to maternal and fetal morbidity, which is observed to be associated with future risks of offspring health. Nevertheless, it is essential to acknowledge that observational findings may be susceptible to residual confounding and bias. To investigate the association of GDM with offspring health, a genome-wide genetic association study employing Mendelian Randomization (MR) is conducted between May 31 and November 30, 2023. The inverse-variance-weighted (IVW) is utilized in the primary analysis stage. The study data of the majority patients are European ancestry, which are sourced from the IEU open genome-wide association study project. Genetically predicted GDM is associated with an increased risk of various short- and long-term health problem in offspring. For fetal and neonatal conditions, GDM is linked to an elevated risk of preterm delivery [ odd ratio (OR) = 1.150, false discovery rate (FDR)-adjusted P_IVW = 0.009] and placental disorders (OR = 2.143, FDR-adjusted P_IVW = 0.028). In respiratory diseases, it is associated with a higher likelihood of influenza (OR = 1.175, FDR-adjusted P_IVW = 0.008), bacterial pneumonia (OR = 1.141, FDR-adjusted P_IVW = 0.008), congenital malformations of the respiratory system (OR = 1.673, FDR-adjusted P_IVW = 0.033), influenza with pneumonia (OR = 1.078, FDR-adjusted P_IVW = 0.008), and need for non-invasive ventilation (OR = 1.265, FDR-adjusted P_IVW = 0.028). In terms of neurodevelopmental and psychiatric outcomes, GDM is linked to a higher risk of cerebral palsy (OR = 1.721, FDR-adjusted P_IVW = 0.008). For urinary conditions, GDM increases the risk of acute tubulo-interstitial nephritis (OR = 1.098, FDR-adjusted P_IVW = 0.008). No association is identified between genetically predicted GDM and major digestive diseases, such as gastroesophageal reflux, or cardiovascular conditions in offspring. The findings of this study provide genetic evidence supporting an association between GDM and higher risk of offspring diseases. This supports classification of GDM as risk factors for short- and long-term offspring health.

Acute respiratory distress (ARDS) caused by sepsis is a critical inflammatory condition with high mortality rates in clinical settings. The gut-lung axis plays a crucial role in regulating the immune response in both the intestinal and pulmonary environments, significantly impacting the development of ARDS. Immunometabolic reprogramming, a fundamental regulator of immune cell function, has recently been shown to profoundly affect the activity of macrophages and endothelial cells (ECs), as well as their crosstalk, thereby shaping the pathogenesis of ARDS. While a great deal has been learned about the potential inflammatory pathways involved, few clinically actionable therapies are available in part due to an incomplete understanding of gut-lung crosstalk in their shared ecosystem of cells and molecules. The current review systematically advances novel insights into the immunometabolic reprogramming that influences macrophage-ECs interactions via sepsis-induced ARDS, with a specific regard to the gut-lung axis. Here, we summarize the key biochemical pathways that control immune cell phenotypes and endothelial function, review the latest experimental evidence for their intercellular crosstalk, and describe the molecular targets that might be targeted to inform therapeutic strategies. Integrating the current evidence, this review seeks to provide a comprehensive theoretical framework and novel methods for the precise treatment of sepsis-associated ARDS, which could be beneficial to clinical practices and patients’ prognoses.

The Integrator complex plays essential roles in RNA polymerase II (RNAPII) transcription termination and RNA processing. Here, we identify INTS6, a subunit of the Integrator complex, as a novel gene associated with neurodevelopmental disorders (NDDs). Through analysis of large NDD cohorts and international collaborations, we identified 23 families harboring monoallelic likely gene-disruptive or de novo missense variants in INTS6. Phenotypic characterization revealed shared features, including language and motor delays, autism, intellectual disability, and sleep disturbances. Using a nervous-system conditional KO (cKO) mouse model, we show that Ints6 deficiency disrupts early neurogenesis, cortical lamination, and synaptic development. Ints6 cKO mice had a thickened ventricular zone/subventricular zone, thinning of the cortical plate, reduced neuronal differentiation, and increased apoptosis in cortical layer 6. Behavioral assessments of heterozygous mice revealed deficits in social novelty preference, spatial memory, and hyperactivity, mirroring phenotypes observed in individuals with INTS6 variants. Molecular analyses further revealed that INTS6 deficiency alters RNAPII dynamics, disrupts transcriptional regulation, and impairs synaptic gene expression. Treatment with a CDK9 inhibitor (CDK9i) reduced RNAPII phosphorylation, thereby limiting its binding to target genes. Notably, CDK9i reversed neurosphere overproliferation and rescued the abnormal dendritic spine phenotype caused by Ints6 deficiency. This work advances understanding of INTS-related NDD pathogenesis and highlights potential therapeutic targets for intervention.