American Journal of Pathology

Aging is associated with non-resolving inflammation and tissue dysfunction. Resolvin D2 (RvD2) is a pro-resolving ligand that acts through the G-protein coupled receptor (GPCR) called GPR18. Unbiased RNA sequencing revealed increased Gpr18 expression in macrophages from old mice, and in livers from elderly humans, which was associated with increased steatosis and fibrosis in middle-aged (MA) and old mice. MA mice that lack GPR18 on myeloid cells had exacerbated steatosis and hepatic fibrosis, which was associated with a decline in Mac2+ macrophages...

A gradual decline in renal function occurs even in healthy aging individuals. In addition to aging, per se, concurrent metabolic syndrome and hypertension, which are common in the aging population, can induce mitochondrial dysfunction and inflammation, which collectively contribute to age-related kidney dysfunction and disease. This study examined the role of the nuclear hormone receptors, the estrogen-related receptors (ERRs), in regulation of age-related mitochondrial dysfunction and inflammation. The ERRs were decreased in both aging human and mouse kidneys and were preserved in aging mice with lifelong caloric restriction (CR)...

No abstract text is available yet for this article.

The pathophysiology of long-recognized hematological abnormalities in Ebola virus disease (EVD) is unknown. From limited human sampling (of peripheral blood), it has been postulated that emergency hematopoiesis plays a role in severe EVD, but the systematic characterization of the bone marrow (BM) has not occurred in human disease or in nonhuman primate models. In a lethal rhesus macaque (RhM) model of EVD, sternal BMs from eighteen RhMs were characterized after intramuscular exposure to Ebola virus (EBOV) Kikwit as compared to uninfected controls (n=3)...

Perturbations in lipid and protein homeostasis induce endoplasmic reticulum (ER) stress in metabolic-dysfunction-associated steatotic liver disease (MASLD), formerly known as nonalcoholic fatty liver disease (NAFLD). Lipotoxic and proteotoxic stress can activate the unfolded protein response (UPR) transducers: Inositol Requiring Enzyme1α, PKR-like ER Kinase and Activating Transcription Factor 6α. Collectively, these pathways induce expression of genes that encode functions to resolve the protein folding defect and ER stress by increasing the protein folding capacity of the ER and degradation of misfolded proteins...

We have previously shown that five growth factors (Factors) [i.e. insulin, fibroblast growth factor-2 (FGF-2), stem cell factor (SCF), interleukin-3 (IL-3), and stromal-derived factor-1 alpha (SDF-1α)] in combination are necessary for human ECs to undergo tube morphogenesis, a process requiring both lumen formation and sprouting behavior. Here, we investigate why they are required by subdividing the Factors into 4 separate groups: Insulin only, Insulin + FGF-2, no FGF-2 (all Factors but without FGF-2), and all Factors...

Pregnancy-related problems have been linked to impairments in maternal uterine spiral artery (SpA) remodelling. The mechanisms underlying this association are still unclear, as are whether hyperandrogenism and insulin resistance - the two common manifestations of polycystic ovary syndrome (PCOS) - affect uterine SpA remodelling. This study verified previous work in which exposure to 5-dihydrotestosterone (DHT) and insulin (INS) in rats during pregnancy resulted in hyperandrogenism, insulin intolerance, and higher foetal mortality...

No abstract text is available yet for this article.

The gut microbiota was initially thought to develop into a stable, adult-like profile during early postnatal life. The formation of the gut microbiota during early life has been shown to contribute to healthy growth and has lifelong implications for host health. Adolescence, the developmental period between childhood and adulthood, is a critical window for healthy growth and maturation. The composition of the gut microbiota in adolescents is distinct from that of children and adults, which supports the premise that the gut microbiota continues to develop during adolescence toward an adult-like profile...

Renal fibrosis is a pathological process that leads to irreversible renal failure without effective treatment. Epithelial-to-mesenchymal transition (EMT) plays a key role in the pathogenesis of renal fibrosis. Herein, we found that tubular aberrant expression of Interleukin (IL)-11 is critically involved in renal fibrosis. IL-11 and its receptor IL-11Rα1 were significantly induced in unilateral ureteral obstruction (UUO) kidneys and were mainly expressed by renal tubular epithelial cells (RTECs), co-localised with transforming growth factor (TGF)-β1...

The liver is the largest lymph-producing organ. In cirrhotic patients, lymph production significantly increases concomitant with lymphangiogenesis. The aim of this study was to determine the mechanism of lymphangiogenesis in liver and its implication in liver fibrosis. Liver biopsies from portal hypertensive patients with portal-sinusoidal vascular disease(PSVD)(n=22) and liver cirrhosis(n=5) were evaluated for hepatic lymphatic vessels(LVs) comparing with controls(n=9, n=6, respectively). For mechanistic studies, rats with partial portal vein ligation(PPVL) and bile duct ligation(BDL) were used...

A growing body of evidence suggests de novo lipogenesis (DNL) as a key metabolic pathway adopted by cancers to fuel tumorigenic processes. While increased DNL has also been reported in hepatocellular carcinoma (HCC), understanding on molecular mechanisms driving DNL remains limited. In the present study, we investigated the functional role of sortilin, a member of the vacuolar protein sorting 10 protein (Vps10p) receptor family, in HCC. Sortilin was overexpressed in HCC and associated with poorer survival outcome...

Through accurate proliferation rate quantification, an appropriate treatment for breast cancer may be devised. Pathologists use breast tissue biopsy glass slides stained with hematoxylin and eosin to obtain grading information. However, this manual evaluation may lead to high costs and ineffectiveness because diagnosis depends on the facility and the pathologists' insights and experiences. A convolutional neural network is considered feasible as a computer-based observer to improve clinicians' capacity in grading breast cancer...

Bronchopulmonary dysplasia (BPD, also called chronic lung disease of immaturity) afflicts approximately one-third of all extremely premature infants causing lifelong lung damage. There is no effective treatment other than supportive care. Retinopathy of prematurity (ROP), which irreversibly impairs vision, is common in BPD, suggesting related pathogenesis, but specific mechanisms of BPD and ROP are obscure. A neonatal mouse hyperoxic model of coincident BPD and retinopathy was used to screen for candidate mediators, which revealed that granulocyte colony-stimulating factor (G-CSF/CSF3) was significantly upregulated in mouse lung lavage fluid and plasma at postnatal day 14 in response to hyperoxia...

Chronic kidney disease (CKD) is characterized by the accumulation of uremic toxins and renal tubular damage. Tryptophan-derived uremic toxins [indoxyl sulfate (IS) and kynurenine (Kyn)] are well-characterized tubulotoxins. Emerging evidence suggests that transmembrane and Ig domain-containing 1 (TMIGD1) protects tubular cells and promotes survival. However, the direct molecular mechanism(s) underlying how these two opposing pathways crosstalk remains unknown. We posited that IS and Kyn mediate tubular toxicity through TMIGD1 and the loss of TMIGD1 augments tubular injury...

Severe dry eye (SDE) can cause grievous damage of the ocular surface and result in vision impairment and even blindness. To investigate the fate of limbal stem cells in SDE and the underlying mechanism, we established an SDE rat model by removing the extra orbital and infraorbital lacrimal glands and maintained it in a low-humidity environment. One month after the operation, aqueous tear secretion dramatically reduced, blood vessels invaded into the central cornea, and inflammatory cells infiltrated into the limbal stroma...

Tissue inhibitors of metalloproteinases (TIMPs) are a conserved family of proteins that were originally identified as cytokine-like erythroid growth factors. Subsequently, TIMPs were characterized as endogenous inhibitors of Matrixin proteinases. These proteinases are the primary mediators of extracellular matrix turnover in pathologic conditions such as cancer invasion and metastasis. Thus, TIMPs were immediately recognized as important regulators of tissue homeostasis. However, TIMPs also demonstrate unique biological activities that are independent of metalloproteinase regulation...

The histopathologic distinction of lung adenocarcinoma (LADC) subtypes is subject to high interobserver variability, which can compromise the optimal assessment of patient prognosis. Therefore, this study developed convolutional neural networks capable of distinguishing LADC subtypes and predicting disease-specific survival, according to the recently established LADC tumor grades. Consensus LADC histopathologic images were obtained from 17 expert pulmonary pathologists and one pathologist in training. Two deep learning models (AI-1 and AI-2) were trained to predict eight different LADC classes...

No abstract text is available yet for this article.

Despite the fact that ∼70% of bladder cancers are non-invasive and have high recurrence rates, early stage disease is understudied. The relative lack of models to validate the contribution of molecular drivers of bladder tumorigenesis is a significant issue. While mutations in PIK3CA are frequent in human bladder cancer, an in vivo model for understanding their contribution to bladder tumorigenesis is unavailable. Therefore, a Upk2-Cre/Pik3caH1047R mouse model expressing one or two R26-Pik3caH1047R alleles in a urothelium-specific manner was created...