American Journal of Pathology最新文献

Hepatoblastoma (HB), the most common pediatric liver cancer, often dysregulates the Wnt/β-catenin, Hippo and/or NFE2L2/NRF2 pathways. Pairwise combinations of oncogenically active forms of the terminal transcription factors of these pathways, namely β-catenin (B), YAP (Y) and NRF2 (N) generate HBs in mice, with the triple combination (B+Y+N) being particularly potent. Each tumor group alters the expression of thousands of B-,Y- and N-driven unique and common target genes. Identifying those most responsible for transformation is thus of paramount importance as it might reveal new mechanistic insights and therapeutic opportunities. Transcriptional profiling of >60 murine HBs has previously revealed a common set of 22 "BYN genes" that are similarly deregulated in all cases. Most are associated with multiple "Cancer Hallmarks" and their expression levels often correlate with survival in human HBs, hepatocellular carcinomas and other cancers. Among the most down-regulated of these is Gas1, which encodes a glycosylphosphatidylinositol (GPI)-linked outer membrane protein. We show here that restoring Gas1 expression impairs B+Y+N-driven HB tumor growth in vivo and in HB-derived immortalized BY and BYN cell lines in vitro in a manner than requires membrane anchoring of the protein via its GPI moiety. Our findings implicate Gas1 as a proximal mediator of HB pathogenesis and validate the BYN gene set as deserving of closer additional scrutiny in future studies.

Cor pulmonale, a condition marked by right ventricular (RV) dysfunction, is frequently associated with chronic obstructive pulmonary disease (COPD) and significantly worsens COPD prognosis. Despite its clinical relevance, the development of effective treatments is hindered by the lack of animal models that accurately replicate the complex interplay between COPD and cor pulmonale. This study introduces a novel rat model combining cigarette smoke (CS) exposure with left pulmonary artery ligation (LPAL) to better mimic the pathophysiological features of COPD-cor pulmonale. Pulmonary function tests revealed impaired lung function, and histological assessments indicated emphysematous changes and inflammatory infiltration, consistent with COPD pathology. Furthermore, the model exhibited hallmarks of cor pulmonale, including right ventricular hypertrophy, fibrosis, and capillary rarefaction, alongside hemodynamic alterations indicative of pulmonary hypertension. This study's findings underscore the potential of the LPAL+CS rat model to advance understanding of COPD-cor pulmonale pathophysiology and facilitate the development of targeted therapeutics.

Duchenne muscular dystrophy (DMD) is a lethal, progressive skeletal and cardiac myopathy. Cardiomyopathy is the leading cause of death in DMD patients but the molecular basis for heart failure is incompletely understood. Like humans, in the mdx mouse model of DMD cardiac function is impaired after the onset of skeletal muscle pathology. Dysregulation of Klotho gene regulation in dystrophic skeletal muscles occurs at disease onset affecting pathogenesis. Whether Klotho is protective against dystrophin-deficient cardiomyopathy is unknown. Here, we showed that expression of a Klotho transgene prevented deficits in left ventricular ejection fraction and fractional shortening in mdx mice. Improvements in cardiac performance were associated with reductions in adverse cardiac remodeling, cardiac myocyte hypertrophy and fibrosis. In addition, mdx mice expressed high concentrations of plasma fibroblast growth factor 23 (FGF23) and expression was increased locally in hearts. The cardioprotective effects of Klotho were not associated with differences in renal function or serum biochemistries, but transgene expression prevented increased expression of plasma FGF23 and cardiac Fgf23 mRNA expression. Cardiac reactive oxygen species, oxidative damage, mitochondrial damage, and apoptosis were reduced in transgenic hearts. Our findings also showed that FGF23 stimulates hypertrophic growth in dystrophic neonatal mouse ventricular myocytes in vitro, which was inhibited by co-stimulation with soluble Klotho. Taken together, these results demonstrate that Klotho prevented dystrophic cardiac remodeling and improved function.

Alcohol-associated liver disease (ALD) is a significant global health concern and a leading cause of liver disease-related deaths. However, the treatment options are limited due to the lack of animal models that accurately replicate ALD pathogenesis. An ideal ALD animal model should have pathological characteristics similar to those of human ALD, with a clear pathological process and ease of drug intervention. Over the years, researchers have focused on developing ideal ALD preclinical animal models by testing various methods, such as ad libitum drinking water with ethanol, acute, single large doses of ethanol gavage, multiple alcohol gavages in a short period, the Lieber-DeCarli liquid diet feeding model, the intragastric infusion model, and the Gao-binge model. With the increasing occurrence of obesity and metabolic dysfunction-associated steatotic liver disease, a new category of metabolic and alcohol-associated liver disease (MetALD) is also emerging. Studies have investigated the combined effects of a high-fat diet combined with binge alcohol or drinking water containing ethanol to mimic MetALD. In addition to mice, other species such as rats, guinea pigs, zebrafish, and non-human primates have also been tested to establish ALD preclinical models. This review aims to summarize current animal ALD models, particularly the emerging MetALD models, with the hope of providing a valuable reference for establishing more effective animal models in ALD studies in the future.

Drug resistance is a major challenge in cancer therapy, and the expression of efflux pumps such as P-glycoprotein (P-gp, ABCB1) often correlates with poor prognosis in various tumors, including glioblastoma (GB). Considering that different roles for these proteins have been established in the biology of various tumors, this study aimed to investigate the functions of P-gp in GB-derived cells by evaluating its survival, migratory, and apoptosis-regulating capabilities, as well as its potential as a liquid biopsy biomarker. P-gp expression was diminished via siRNA to determine its exact role in GB biology. The P-gp mRNA levels were evaluated by using quantitative real-time RT-PCR. With respect to liquid biopsy, circulating cell-free RNA was extracted from plasma belonging to patients diagnosed with GB, and P-gp levels were compared with matching tumor tissues using digital PCR. P-gp silencing significantly decreased viability, increased apoptosis, and enhanced chemotherapy sensitivity in GB cells, although it did not affect migratory patterns. Finally, P-gp expression levels in circulating cell-free RNA from patients with GB matched tumor tissue, whereas healthy volunteers appeared to bear no circulating P-gp. Taken together, the results indicate that P-gp affects GB tumor biology beyond its known role in drug resistance and could integrate a broader molecular signature for future diagnosis via liquid biopsy.

Acute lung injury (ALI) is a clinically common disease with high mortality, characterized by tissue damage caused by excessive activation of inflammation. TRIM7 is an E3 ligase that plays an important role in regulating viral infection, tumor progression, and innate immune response. Its function in ALI is unclear, however. In this study, lipopolysaccharide (LPS) was used to stimulate C57BL/6j mice and HULEC-5a cells to establish ALI models in vivo and in vitro. The results showed that TRIM7 expression was down-regulated during ALI. Furthermore, overexpressing TRIM7 in HULEC-5a cells relieved cell damage and inflammatory activation induced by LPS stimulation. TRIM7 knockdown has the opposite effect. Trim7-overexpressing mice were established by endotracheal injection of adeno-associated virus 6-Trim7 virus in vivo; the ALI model was then induced by LPS stimulation. We showed that overexpression of TRIM7 could alleviate lung tissue injury, pulmonary interstitial hemorrhage, increased alveolar and vascular permeability, inflammatory cell infiltration, and secretion of inflammatory factors induced by LPS stimulation. Mechanistically, TRIM7 has been shown to inhibit the expression of NOD-, LRR- and pyrin domain-containing 3 (NLRP3) and activation of the NLRP3 inflammasome. The regulatory effect of TRIM7 on ALI depends on the NLRP3 inflammasome. This investigation for the first time shows the inhibitory effect of TRIM7 on ALI and activation of the NLRP3 inflammasome, providing new targets and ideas for the mechanism research and treatment of ALI.

Alzheimer disease (AD) is the most common type of dementia and one of the leading causes of death in elderly patients. The number of patients with AD in the United States is projected to double by 2060. Thus, understanding modifiable risk factors for AD is an urgent public health priority. In parallel with the number of patients with AD, the number of cancer survivors is estimated to increase significantly, and up to 80% of cancer patients treated with chemotherapy will develop cognitive deficits, termed chemotherapy-related cognitive impairment. This review discusses biologically plausible pathways underlying both disorders, with the goal of understanding why a proportion of chemotherapy patients may be at higher risk of developing AD. Highlighted are the E4 allele of the apolipoprotein E gene, neuroinflammation, oxidative stress, DNA damage, mitochondrial dysfunction, neuronal and synaptic loss, cellular senescence, brain-derived neurotrophic factor signaling, white matter damage, blood-brain barrier/vascular dysfunction, tau pathology, and transposable element reactivation.

The importance of complex systems has become increasingly evident in recent years. The nervous system is one such example, with neural networks sitting at the intersection of complex networks and biology. A particularly exciting feature is the resilience of complex systems. For example, the ability of the nervous system to perform even in the face of challenges that include neuronal loss, neuroinflammation, protein accumulation, axonal disruptions, and metabolic stress is an intriguing and exciting line of investigation. In neurodegenerative diseases, neural network resilience is responsible for the time between the earliest disease-linked changes and clinical symptom onset and disease diagnosis. In this way, connectivity resilience of neurons within the complex network of cells that make up the nervous system has significant implications. This review provides an overview of relevant concepts related to complex systems with a focus on the connectivity of the nervous system. It discusses the development of the neural network and how a delicate balance determines how this complex system responds to injury, with examples illustrating maladaptive plasticity. The review then addresses the implications of these concepts, methods to understand brain connectivity and neural networks, and recent research efforts aimed at understanding neurodegeneration from this perspective. This study aims to provide foundational knowledge and an overview of current research directions in this evolving and exciting area of neuroscience.

Idiopathic pulmonary fibrosis (IPF) and other progressive fibrotic interstitial lung diseases have limited treatment options. Fibroblasts are key effector cells that sense matrix stiffness through conformation changes in mechanically sensitive receptors, leading to activation of downstream profibrotic pathways. Here, we investigate the role of Piezo2, a mechanosensitive ion channel, in human and mouse lung fibrosis, and its function in myofibroblast differentiation in primary human lung fibroblasts (HLFs). Human samples from patients with IPF and mouse tissue from bleomycin-induced pulmonary fibrosis was assessed. Primary HLFs from nonfibrotic donors were grown on substrates of different stiffness to induce myofibroblast differentiation and treated with a Piezo2 inhibitor. Piezo2 expression is up-regulated in tissue from patients with IPF and in fibrotic mouse lung tissue. Additionally, interrogation of published single-cell RNA-sequencing data showed that Piezo2 is expressed in the profibrotic Cthrc1⁺ fibroblast subpopulation. Myofibroblast differentiation was increased in HLFs grown on substrates with fibrotic levels of stiffness compared with that seen in softer substrates. Piezo2 inhibition reduced stiffness-induced expression α-smooth muscle actin and fibronectin in HLFs. Piezo2 expression is elevated in fibrotic lung disease in both patients and rodents, and its presence is key in the differentiation of fibroblasts to the profibrotic myofibroblasts. Blocking Piezo2 may play a key role in fibrosis and, thus, be a novel therapeutic approach to treat pulmonary fibrosis.