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Pathophysiology and multi-target prevention strategies for cyclophosphamide-induced bladder injury.

Cyclophosphamide (CYP) is a cornerstone alkylating agent in oncology, autoimmune diseases, and hematopoietic stem cell transplantation, but its clinical use is often limited by bladder toxicity. This toxicity is primarily caused by acrolein, a reactive CYP metabolite that accumulates in urine and initiates urothelial injury. Barrier disruption allows toxicants to penetrate, amplifying oxidative stress, inflammation, neurogenic inflammation, and sensory sensitization. Persistent or severe damage can lead to detrusor dysfunction, interstitial remodeling, fibrosis, and a range of conditions, incl

Inflammaging in periodontal, periapical, and malignancy-associated disease: drivers of alveolar bone loss and repair.

BACKGROUND: Aging significantly impacts bone metabolism through altered osteoblast/osteoclast dynamics, reduced stem cell regeneration, and chronic inflammaging. This narrative review explores how these age-related changes influence alveolar bone loss and regeneration in the oral cavity. METHODS: The review investigates key mechanisms-including immunosenescence and inflammasome activation-across three specific pathological contexts: (1) periodontitis, (2) periapical bone resorption, and (3) malignancy-associated osteolysis. Preclinical and clinical evidence were integrated to analyze the bone

Microglia as Double-Edged Players in Ischemic Stroke.

Stroke has long been a leading cause of death and long-term disability worldwide. In recent years, more and more research has revealed that microglial responses to ischemic injury are highly heterogeneous and exhibit dynamic evolution over time, across brain regions, and under different metabolic states. This endows microglia with a dual regulatory role in both neurotoxicity and neuroprotection after ischemia: on one hand, they drive inflammatory responses, exacerbating secondary neuronal damage, blood-brain barrier disruption, and synaptic loss; on the other hand, they orchestrate debris clea

Disulfiram Attenuates Adenine-Induced Renal Fibrosis by Modulating Inflammatory and Immunometabolic Responses.

Chronic kidney disease (CKD) is partly driven by excessive innate immune activation, which contributes to progressive renal injury and fibrosis. Disulfiram (DSF), an approved treatment for alcohol dependence, has recently emerged as an inhibitor of innate immune responses such as pyroptosis. In this study, we investigated whether DSF attenuates kidney injury in adenine-induced nephropathy and explored the underlying mechanisms. DSF treatment markedly ameliorated kidney injury in adenine-induced nephropathy, accompanied by suppression of inflammatory cell infiltration and inflammasome- and pyro

NLRP3/GSDMD-dependent neutrophil extracellular traps exacerbate microglia-mediated neuroinflammation following traumatic brain injury.

Traumatic brain injury (TBI) induces profound neuroinflammation, leading to secondary brain damage and neurological dysfunction. Emerging evidence highlights the critical role of neutrophil extracellular traps (NETs) in amplifying inflammatory responses after injury. This study investigates the involvement of the NLRP3 inflammasome and gasdermin D (GSDMD) in regulating NET formation and subsequent microglia-mediated neuroinflammation after TBI. Using a male mouse model of TBI, we demonstrate that activation of the NLRP3/GSDMD axis significantly enhances NET release from neutrophils. These NETs

Inflammation in Cardiomyopathies: Cellular Mechanisms Across Cardiac Phenotype.

Cardiomyopathies are traditionally classified by structural and genetic phenotypes, but emerging evidence highlights chronic myocardial inflammation as a pivotal driver of disease progression across different etiologies. This review synthesizes the current literature on the cellular and molecular inflammatory mechanisms underlying hypertrophic cardiomyopathy, Anderson-Fabry disease, cardiac amyloidosis, arrhythmogenic cardiomyopathy, and dilated cardiomyopathy. Across these distinct conditions, endogenous triggers such as metabolic substrates, misfolded amyloid fibrils, mechanical stress, or v

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… Damage-associated molecular patterns (DAMPs) engage pattern-recognition receptors, such as Toll-like receptors, thereby activating core signaling pathways, including NF-κB and the NLRP3 inflammasome. … The innate immune system provides the initial, non-specific defense through pattern-recognition receptors and inflammasomes—particularly NLRP3—which amplify inflammation via cytokines such as IL-1β and IL-18. …

Macrophage ACAT1 Aggravates Alcohol-Associated Liver Disease by Inducing Mitochondrial Damage and NLRP3 Activation.

BACKGROUND: Alcohol-associated liver disease (ALD) is a major cause of advanced liver disease, with limited effective clinical interventions, highlighting an urgent need for new therapeutic targets. Acyl-CoA:cholesterol acyltransferase 1 (ACAT1) is a key cholesterol-metabolizing acyltransferase that catalyzes the esterification of free cholesterol into cholesteryl esters. It is highly expressed predominantly in macrophages and participates in the regulation of macrophage functions. Nevertheless, its role and underlying mechanism in alcoholic liver injury remain largely unclear. RESULTS: We ob

Daidzein protected against sepsis-induced acute lung injury by suppressing pyroptosis via activation of estrogen receptor-β.

Sepsis-induced acute lung injury (SI-ALI) carries an extremely high mortality rate. Daidzein is a natural phytoestrogen with anti-inflammatory properties. Estrogen receptor β (ERβ) is a potential target for inflammatory regulation. However, whether Daidzein protects against cecal ligation and puncture (CLP)-induced ALI by targeting ERβ remains unclear. In this study, we established SI-ALI models in vivo and in vitro, and employed transcriptomics, metabolomics, molecular docking, dynamics simulation and pharmacological intervention. We found that Daidzein markedly alleviated CLP-induced ALI. Da

SIRT1 Activation Ameliorates Neuroinflammation and Cognitive Impairment in a Murine SAE Model and is Associated with the Nrf2/GPX4 Pathway.

Sepsis-associated encephalopathy (SAE) is a devastating condition with high mortality and cognitive sequelae, yet no effective treatments. This study investigates the neuroprotective potential of selective Sirtuin 1 (SIRT1) activation using the synthetic agonist SRT1720 in a male C57BL/6 J murine model of SAE. Transcriptomic profiling of the hippocampus revealed a specific disruption in glutathione and arachidonic acid metabolism pathways, indicating a metabolic priming for ferroptosis. We demonstrate that SIRT1 activation improves survival and ameliorates cognitive deficits by concurrently at

RACK1 in host immune response to infections: molecular mechanisms and therapeutic potentials.

The global healthcare system faces increasing threats from emerging and re-emerging pathogens. Current understanding of host-pathogen interactions and underlying immune mechanisms remains incomplete, which hinders the development of effective diagnostic tools and therapeutic strategies. The receptor for activated C kinase 1 (RACK1) is a multifunctional scaffolding protein that integrates diverse signaling pathways, modulates translation, and regulates key cellular processes. Despite accumulating evidence implicating RACK1 in host immune response to infections, its multifaceted roles and mechan

Enteropathogenic bacteria evade ROCK-driven epithelial cell extrusion.

Diverse pathogen-encoded virulence factors disable apoptosis, pyroptosis or necroptosis, the host cell death programs that remove infected cells1. In the intestine, the extrusion of infected cells into the lumen for elimination provides an additional layer of host defence, but no virulence mechanisms that target the cytoskeletal changes required are known2. Here we show that the Escherichia coli ubiquitin ligase NleL is an inhibitor of intestinal epithelial cell (IEC) extrusion, targeting caspase-4, ROCK1 and ROCK2 for proteasomal degradation. Genetic deletion of Rock1 and Rock2 from cultured

Mapping the anatomical and transcriptional landscape of early human fetal ovary development.

The complex genetic mechanisms underlying human ovary development can give rise to clinical phenotypes if disrupted, such as Primary (or Premature) Ovarian Insufficiency and Differences of Sex Development. We combine single-nuclei RNA sequencing, bulk RNA sequencing, and micro-focus computed tomography to elucidate the anatomy and transcriptional landscape of the human fetal ovary across key developmental timepoints (Carnegie Stage 22 until 20 weeks post conception). We show the marked growth and distinct morphological changes within the fetal ovary at the critical timepoint of germ cell expan

Parkinson's disease-associated alterations in DNA methylation and hydroxymethylation in human brain.

Epigenetic mechanisms mediate interactions between aging, genetics, and environmental factors in sporadic Parkinson's disease (PD). While multiple studies have explored DNA modifications in PD, few focus on 5-hydroxymethylcytosine (5hmc), which is important in the central nervous system and sensitive to environmental exposures. Existing studies have not differentiated between 5-methylcytosine (5mc) and 5hmc or have analyzed them separately. In this study, we modeled 5mc and 5hmc data simultaneously. We identified 108 cytosines with significant PD-associated shifts between these marks in an enr

The Role of Gut-Brain Axis in Modulating the Impact of Sterile Inflammation on Neuroimmune Responses in Neurodegenerative Diseases - Alzheimer's Disease and Parkinson's Disease.

BACKGROUND: Emerging evidence has demonstrated the important role of gut microbiota in host physiology, affecting host immunity. The gut-brain axis has been identified between the central nervous system and the gut microbiota, indicating bidirectional communication between the two systems. SUMMARY: Microbial imbalance (in other words, gut dysbiosis) can lead to chronic systemic inflammation, resulting in neuroinflammation as an example of sterile inflammation. Three major pathways in causing neuroinflammation from chronic systemic inflammation by the gut microbiota via the gut-brain axis are

1,8-Cineole alleviates spinal cord injury by inhibiting microglial pyroptosis via the P38 MAPK and PI3K/AKT/NLRP3 signaling pathways to protects neurons.

Following spinal cord injury (SCI), pyroptosis plays a significant role in regulating neuroinflammation during the secondary phase of injury. Although 1,8-cineole possesses anti-inflammatory effects, its role in SCI and underlying molecular mechanisms remains unclear. This study revealed that 1,8-cineole promoted motor function recovery in spinal cord-injured rats, reduced NLRP3 inflammasome-mediated microglial pyroptosis and activation, enhanced neuronal regeneration, and suppressed neuronal apoptosis and glial scar formation. Network pharmacology analysis showed that 1,8-cineole targets the

TLR9 decreases FOXO3 expression to prevent excessive inflammation in macrophage activation syndrome.

Adult-onset Still's disease (AOSD) is characterized by an overwhelming inflammatory response and hyperactivation of monocytes/macrophages, which may cause macrophage activation syndrome (MAS). Here, we demonstrate the forkhead box protein O3 (FOXO3), a transcriptional factor downregulated by interferon, as an important regulator of inflammation in AOSD-MAS. FOXO3 expression is downregulated in monocytes/PBMCs from patients with AOSD, especially in those developing MAS. A negative correlation between FOXO3 expression with disease activity and inflammatory level is identified. FOXO3 downregulati

Crystalline killer: the molecular cascade of silica toxicity from inflammation to fibrosis.

PURPOSE OF REVIEW: Silicosis, a progressive fibrotic lung disease caused by inhalation of crystalline silica, is resurging due to increased exposure in high-risk industries such as engineered stone fabrication. Characterised by asymptomatic onset and delayed diagnosis, it remains a major occupational health concern. This review synthesises current understanding of silica-induced lung injury, highlighting the physicochemical properties of silica that drive its biological reactivity and persistence in the lung. RECENT FINDINGS: Silica deposition induces lysosomal rupture, oxidative stress, and

[The immunopathology of asthma].

Type 2 (T2) high asthma, characterized by T2 markers such as eosinophilia, is driven by type 2 innate lymphoid cells (ILC2) and allergen-activated T helper (Th2) cells. Epithelial-derived cytokines called alarmins, IL-33, TSLP, IL-25 and TL1A, acting on dendritic cells and ILC2, are key in driving both allergic and non-allergic T2 high asthma. Alarmins are produced in response to allergens, pathogens, pollutants etc. Cytokines produced by Th2 cells and ILC2 cause the immunopathology of asthma including eosinophilia, mast cell activation, goblet cell hyperplasia and fibrosis, which in turn caus

The microbial metabolite trimethylamine N-oxide and the kidney diseases.

Trimethylamine N-oxide (TMAO), a metabolite, is a co-metabolite produced by both gut microbiota and livers, originating from foods rich in choline or carnitine. Emerging evidence suggests that TMAO may play a role in the pathogenesis of various kidney diseases, including acute kidney injury and chronic kidney disease. Research has demonstrated that heightened levels of TMAO are correlated with a heightened likelihood of kidney disease advancement and cardiovascular incidents among individuals with chronic kidney disease. Furthermore, TMAO has been observed to stimulate inflammation, oxidative

Discovery of Potent, Allosteric GSTO1 Covalent Inhibitors with a New Binding Mode.

GSTO1 activates the NLRP3 inflammasome by deglutathionylating NEK7 at Cys253, driving proinflammatory responses. Using PRM-based targeted mass spectrometry, we identified compound A1 as a covalent GSTO1 inhibitor modifying Cys32. Ligand-based optimization generated analogues with diverse activities; among them, A13 exhibited moderate target engagement (kinact/KI = 226 M-1·s-1), excellent cysteine selectivity confirmed by desthiobiotin iodoacetamide (DBIA)- and alkyne-based ABPP, and superior metabolic stability in human liver microsomes. High-resolution crystal structures revealed an unexpecte