International Journal of Experimental Pathology最新文献

Excessive endoplasmic reticulum (ER) stress can lead to apoptosis of nucleus pulposus cells (NPCs), a hallmark of intervertebral disc degeneration (IVDD). Our study aimed to determine whether bone marrow mesenchymal stem cells (BMSCs-exos) alleviate ER stress-related NPC apoptosis through the delivery of miR-221-3p. Human NPCs were stimulated by advanced glycation end products (AGEs) for 24 h to construct a cellular model of ER stress. Exosomes were isolated from BMSCs transfected with miR-NC and miR-221-3p inhibitor and co-cultured together with AGEs in NPCs. MiR-221-3p expression in NPCs was detected by reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR). The protein levels of ER stress and apoptosis markers and nuclear factor erythroid 2 p45-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1) pathway-related molecules in NPCs were measured by western blotting and immunofluorescence staining. The Nrf2 agonist tert-butylhydroquinone (TBHQ) was used to verify whether exosomal miR-221-3p affected ER stress-mediated apoptosis by regulating the Nrf2/HO-1 pathway. MiR-221-3p expression was decreased in AGEs-stimulated NPCs, while co-culture with BMSCs-exos rescued such a decline. AGEs-induced reduction in NPC viability and elevation in cell apoptosis and ER stress were overturned by BMSCs-exos treatment, whereas miR-221-3p knockdown further antagonized these effects of BMSCs-exos. MiR-221-3p knockdown reversed the enhancement of BMSCs-exos on Nrf2 and HO-1 levels and Nrf2 nuclear translocation in AGEs-induced NPCs. Importantly, TBHQ abrogated the promotion of Exos-miR-221-3p inhibitor on ER stress and apoptosis in NPCs. BMSCs-exos reduced ER stress-mediated apoptosis in NPCs by promoting the Nrf2/HO-1 pathway through delivering miR-221-3p.

Pulmonary arterial hypertension (PAH) is a chronic disease characterized by increased pulmonary vascular resistance, right ventricular overload and systemic repercussions, including disorders in non-target organs. This study aimed to investigate the effects of PAH on the ventral prostate of adult Wistar rats, as well as the role of resistance training (RT) in modulating potential changes caused by the disease. Male rats (n = 32, 60 days old) were divided into four groups: sedentary control, sedentary PAH, RT control and PAH + RT. PAH was induced using two injections of monocrotaline, while rats were submitted to the RT protocol for a month. Afterward, the ventral prostate was collected and analysed for biometric, histopathological and oxidative parameters (CEUA 38/2021). The results showed that PAH significantly reduced the body and prostate weights and increased glandular epithelium and stroma proportions, besides causing epithelium atrophy and inflammatory infiltrates (p < .05). The activity of superoxide dismutase and catalase was lower, culminating in high levels of malondialdehyde and carbonyl proteins (p < .05). The exercise mainly influenced biometric and stereological parameters. The RT protocol minimized the negative effect of PAH regarding catalase activity, epithelium/lumen proportion and inflammatory infiltrate incidence. However, it was ineffective in restoring prostate weight and completely normalizing markers of oxidative stress. In conclusion, PAH induces significant morphofunctional changes in the ventral prostate, including oxidative damage and tissue remodelling. Although RT exerts protective effects, its benefits are limited, highlighting the need for complementary therapies to counteract PAH-induced prostate alterations fully.

Novaes RD, Gonçalves RV, Cupertino MC, Araújo BM, Rezende RM, Santos EC, Leite JPV, Matta SLP. The energy density of laser light differentially modulates the skin morphological reorganization in a murine model of healing by secondary intention. Int J Exp Pathol 2014;95(2):138–146. doi:10.1111/iep.12063

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With high morbidity and mortality internationally, oesophageal cancer is one of the most common diseases of the digestive system. The most frequent approaches to the treatment of oesophageal cancer are a combination of chemotherapy and radiation therapy. Inevitably, some individuals with oesophageal cancer fail to respond favourably to these treatments because of therapeutic resistance, with eventual unfavourable outcomes. Thus, it would be helpful if patients with oesophageal cancer learned more about the pathophysiology of the disease. Discovering early-detection biomarkers could help to identify prognostic markers. Long non-coding RNAs (lncRNAs) are endogenous RNAs with more than 200 nucleotides that do not code for proteins, and these have been recognised increasingly as being important in cancer. A few of the lncRNAs have been shown to be associated with oesophageal cancer. When target gene expression is inhibited or promoted, lncRNAs can play a role in cell growth, apoptosis and metastasis, among other functions in biology, and are aberrantly produced in oesophageal cancer. Using epithelial–mesenchymal transition (EMT), which is implicated in the occurrence, development and diagnosis of oesophageal cancer, lncRNAs may regulate the natural history of the disease. Thus in this article we have reviewed the biological and molecular mechanisms of lncRNAs, including their role as suppressors of tumours as well as in malignancy, in relationship to oesophageal cancer. Furthermore, we have extrapolated from this analysis some potential A lncRNA candidates for oesophageal cancer detection, prediction and treatment. Lastly, we debate both the potential and the difficulties about how lncRNAs may influence oesophageal cancer.

Porcine respiratory disease complex (PRDC) is a common syndrome in the modern swine industry worldwide, and its pathogenesis remains unclear to date. Our study aimed to investigate PRDC-induced pulmonary fibrosis and sphingolipid metabolism, and their relationship. Mouse and cell line (A549 and 3D4/21) models exposed to bleomycin and/or transforming growth factor-β1 (TGF-β1) were developed. Histopathological and immunohistochemical staining, colorimetry, lipidomics analysis and pharmacologic intervention assays were used to analyse lung fibrosis and sphingolipid profiles. PRDC was validated by the presence of alveolar epithelial cell (AEC) injury and hyperplasia, inflammatory infiltrates, asymmetric macrophage polarization and mast cell phenotypic changes, TGF-β1 and fibroblast growth factor 2 (FGF-2) overproduction, extensive collagen deposition, foci of fibroblast/myofibroblast with stress fibres (α-SMA, γ-SMA and γ2 actin), cell interaction with increasing frequency, proliferation, apoptosis and autophagy dysregulation, and mucin 6 release—all of which are characteristics of pulmonary fibrosis. Based on the sphingolipidomics and pharmacologic interventions data—the dysregulated sphingolipids, including sphingomyelin (SM), ceramide (Cer), sphingosine-1-phosphate (S1P) and cerebroside (Cb), possibly due to serine palmitoyltransferase (SPT; SPTLC1), ceramide synthase (CerS; CerS2, CerS4), sphingomyelin synthase (SMS; SMS1), neutral sphingomyelinase (NSMase), acid sphingomyelinase (ASMase; SMPDL3B) and sphingosine kinase (SphK; SphK1, SphK2), were found to be closely related to pulmonary fibrosis. Furthermore, d18:1 24:1 SM and 18:1 S1P may be conserved biomarkers and tiamulin fumarate (TF) changes have anti-fibrotic activity. Overall, PRDC induces pulmonary fibrosis, related to the aberrant sphingolipid metabolism, where conserved sphingolipid biomarkers and anti-fibrotic candidates have been found.

Gastric cancer (GC) is the third leading cause of cancer-related mortality worldwide. The Epstein–Barr virus (EBV) may play a role in certain cases of GC. Therefore, this study aimed to investigate the prevalence of EBV in the gastric tissue of both gastric cancer patients and non-cancer patients in Shiraz, Iran. In this cross-sectional study, 159 formalin-fixed paraffin-embedded (FFPE) tissues from gastric cancer patients and 137 from non-cancer patients were assessed. All samples were assessed using PCR on the β-globin gene. The nested PCR method was used to investigate the presence of the EBNA-1-EBV gene. The results were analysed using chi-squared statistical tests. The mean age of the GC group and the control group was 62.08 ± 13.45 and 63.97 ± 9.13. In the GC and control groups, 33.33% (53/159) and 35.04% (48/137) were female. The results showed that in the cancer group, 1.88% (3/159) of tissue samples were positive for EBV, while this statistic was 22.62% (31/137) for non-cancer samples (p < .0001). All EBV-positive cancer patients were female with a mean age of 64.66 ± 7.37 while in the control group, 20.83% (10/48) of females and 23.59% (21/89) of males were positive for EBV, which was not statistically significant (p = .832). The low frequency of EBV infection in GC tissue might indicate the ‘hit and run’ mechanism of EBV in GC carcinogenesis. Additionally, the abundance of B lymphocytes in the inflamed samples of the healthy control group might influence the high frequency of EBV in this group. More investigations are recommended to verify these results.

Ketone bodies (KBs), which include β-hydroxybutyric acid (β-HB) and acetoacetic acid (AcAc), play critical roles in organismal energy homeostasis; however, their effects on atherosclerosis remain unknown. In this study, we investigated the role of β-HB and AcAc on proliferation and lipid accumulation in macrophages by the uptake of oxidized LDL (Ox-LDL), causing the formation of atherosclerotic plaques, using mouse macrophage J774A.1 cells. Both β-HB and AcAc reduced cell proliferation, and AcAc increased lipid accumulation in Ox-LDL-treated J774A.1 cells. Western blotting showed that Ox-LDL decreased the protein expression of two KB-specific receptors, GPR41 and GPR43, both of which are known as potent modulators of inflammation, but had negligible effects on that of the β-HB-specific GPR109A in the cells. These results suggest that Ox-LDL may induce inflammatory responses by decreasing the protein expression of GPR41 and GPR43 in macrophages, and that AcAc, but not β-HB, may exacerbate Ox-LDL-caused atherosclerosis.

Exercise has an important impact on skeletal muscle quality, emerging as an adjuvant therapy to ameliorate muscle inflammation and fibrosis in Duchenne muscular dystrophy (DMD). The aim of the present study was to investigate the benefit of exercise alone or in association with corticoid and omega-3 therapy in the middle aged mdx mouse model of DMD, Mdx mice (12 months of age) performed treadmill exercise (12.4 m/min, for 15 min, twice a week) for 4 weeks. Exercised mdx received deflazacort (1.2 mg/kg; gavage) alone or combined with omega-3 (300 mg/kg; gavage). Sedentary mdx, C57BL/10 and exercised mdx received mineral oil and served as control. At the endpoint (14 months of age), muscle function, respiratory function, electrocardiography (ECG), blood markers of myonecrosis (creatine kinase, CK; alanine aminotransferase, ALT; and aspartate aminotransferase, AST), muscle biomarkers of inflammation and fibrosis (western blot), area of fibrosis and histopathology of tibialis anterior, biceps brachii and diaphragm muscles were evaluated. Exercise and exercise-associated therapies improved behavioural activity (open field), muscle function (grip strength, four limb hanging test, hanging wire test and rotarod), VO₂ consumption, VCO₂ production and ECG. Functional benefits correlated with reduced myonecrosis (decreased CK, ALT, AST) and fibrosis. The muscles studied showed a reduction in inflammation biomarkers (NF-κB, IL-6 and TNF-α) and fibrosis (TGF-β and fibronectin) and an increase in calsequestrin (calcium buffering protein) and PGC1-α (muscle integrity marker). In conclusion, exercise alone or associated with corticosteroid/omega-3 therapy benefited limb, diaphragm and cardiac dystrophic muscles in middle-aged mdx mice.

Tendinopathy or tendon overuse injury is a major clinical problem for individuals and has a significant socio-economic cost. Its pathophysiology is not yet fully understood and involves multiple factors, including mechanical, cellular and molecular factors. The circadian rhythm has been shown to be a major regulator of extracellular matrix (ECM) homeostasis in several connective tissues, including tendon. Very recently, the human patellar tendon has been established as a peripheral clock tissue that exhibits dampening with chronic tendinopathy, and this has important translational and clinical relevance. This review summarises what is currently known about the role of the tendon circadian clock in collagen and tendon ECM homeostasis and proposes a role for circadian clock disruption in tendinopathy. A better understanding of the mechanisms that regulate tendon clock synchronisation could guide the development of new therapeutic strategies for managing tendon overuse injuries.

Contributions made by the dystrophin-associated glycoprotein complex (DGC) to cell–cell and cell-extracellular matrix (ECM) interactions are vital in development, homeostasis and pathobiology. This review explores how DGC functions may extend to skeletal pathophysiology by appraising the known roles of its major ECM ligands, and likely associated DGC signalling pathways, in regulating cartilage and bone cell behaviour and emergent skeletal phenotypes. These considerations will be contextualised by highlighting the potential of studies into the role of the DGC in isolated chondrocytes, osteoblasts and osteoclasts, and by fuller deliberation of skeletal phenotypes that may emerge in very young mice lacking vital, yet diverse core elements of the DGC. Our review points to roles for individual DGC components—including the glycosylation of dystroglycan itself—beyond the establishment of membrane stability which clearly accounts for severe muscle phenotypes in muscular dystrophy. It implies that the short stature, low bone mineral density, poor bone health and greater fracture risk in these patients, which has been attributed due to primary deficiencies in muscle-evoked skeletal loading, may instead arise due to primary roles for the DGC in controlling skeletal tissue (re)modelling.