International Journal Of Experimental Pathology[JOURNAL]
Sun
200 papers
Exosomal miR-221-3p derived from bone marrow mesenchymal stem cells alleviates endoplasmic reticulum stress-mediated apoptosis in nucleus pulposus cells via the Nrf2/HO-1 signalling pathway.
Xu G, Zhu K, Chen Z … +2 more , Li M, Zhang Z
Int J Exp Pathol · 2025 Nov · PMID 41201370 · Full text
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...
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.
Effect of pulmonary arterial hypertension on the morphology and antioxidant defence of the ventral prostate of sedentary and exercised rats.
Guimarães-Ervilha LO, Iasbik-Lima T, Soares LL … +6 more , Faria JVL, Oliveira MS, Carvalho RPR, Morais-Santos M, Natali AJ, Machado-Neves M
Int J Exp Pathol · 2025 Nov · PMID 41117296 · Full text
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 s...
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.
Correction to '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 · 2025 Nov · PMID 41108724 · Full text
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Roles of long non-coding RNAs in oesophageal cancer pathogenesis.
Jiang N, Hu B, Shu X … +3 more , Li G, Wang J, Lv C
Int J Exp Pathol · 2025 Sep · PMID 40888502 · Full text
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 c...
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 induces pulmonary fibrosis related to the aberrant sphingolipid metabolism.
Tang X, Li G, Shi L … +8 more , Liu T, Si Z, Li G, Yu W, Zhang T, Zhao Z, Zhao X, Zhao Z
Int J Exp Pathol · 2025 Sep · PMID 40884045 · Full text
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 sph...
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.
Molecular epidemiology of Epstein-Barr virus in gastric cancer patients compared to healthy control group in Shiraz, Iran.
Tabatabaie FH, Faraji S, Ansari M … +8 more , Farahani F, Vafapour Z, Abuei H, Hashemi SMA, Shokripour M, Omidifar N, Farhadi A, Sarvari J
Int J Exp Pathol · 2025 Sep · PMID 40757763 · Full text
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...
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.
The role of ketone bodies in oxidized LDL-induced cell proliferation and lipid accumulation of macrophages.
Sato A, Nemoto H, Yabuki A … +3 more , Sato G, Ogawa Y, Ohira M
Int J Exp Pathol · 2025 Jul · PMID 40448300 · Full text
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,...
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.
Role of the tendon circadian clock in tendinopathy and implications for therapeutics.
Møbjerg A, Pedersen SD, Kjaer M … +1 more , Yeung CC
Int J Exp Pathol · 2025 May · PMID 40308034 · Full text
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 mechan...
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.
Exercise combined with corticoid/omega-3 therapy positively affected skeletal and cardiac muscles in middle aged mdx mice.
Suarez PAS, Junior MM, de Carvalho SC … +3 more , Santo Neto H, Minatel E, Marques MJ
Int J Exp Pathol · 2025 May · PMID 40308028 · Full text
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 invest...
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), VO consumption, VCO 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.
Extracellular matrix: Dystroglycan interactions-Roles for the dystrophin-associated glycoprotein complex in skeletal tissue dynamics.
Hopkinson M, Pitsillides AA
Int J Exp Pathol · 2025 Mar · PMID 39923120 · Full text
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 DG...
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.
KLF9 aggravates the cardiomyocyte hypertrophy in hypertrophic obstructive cardiomyopathy through the lncRNA UCA1/p27 axis.
Ding D, Zhao G
Int J Exp Pathol · 2025 Mar · PMID 39909852 · Full text
Cardiac hypertrophy refers to an abnormal increase in the thickness of the heart muscle. Our study explores the role of Krüppel-like factor 9 (KLF9) in hypertrophic obstructive cardiomyopathy (HOCM)-induced cardiomyocyte...
Cardiac hypertrophy refers to an abnormal increase in the thickness of the heart muscle. Our study explores the role of Krüppel-like factor 9 (KLF9) in hypertrophic obstructive cardiomyopathy (HOCM)-induced cardiomyocyte hypertrophy, providing new targets for the treatment of HOCM. Cardiomyocytes were treated with isoproterenol (ISO). The levels of natriuretic peptide B (BNP)/natriuretic peptide A (ANP)/KLF9/long non-coding RNA urothelial carcinoma-associated 1 (lncRNA UCA1)/p27 were measured. Cell surface area and protein/DNA ratio were tested. The binding between KLF9 and the lncRNA UCA1 promoter and between zeste homologue 2 (EZH2) and lncRNA UCA1 was verified. The enrichment of histone H3 lysine 27 tri-methylation (H3K27me3) and EZH2 on the p27 promoter was analysed. ISO treatment increased KLF9 and lncRNA UCA1 expression and decreased p27 expression in cardiomyocytes. KLF9 knockdown inhibited ISO-induced cardiomyocyte hypertrophy, reduced ANP and BNP expression, and alleviated cardiomyocyte damage. KLF9 activated lncRNA UCA1 expression. LncRNA UCA1 recruited EZH2 to the p27 promoter region, increasing the enrichment of H3K27me3, thereby epigenetically suppressing p27 expression. LncRNA UCA1 overexpression or p27 downregulation reduced the protective effect of KLF9 downregulation on cardiomyocyte hypertrophy. In conclusion, KLF9 activates lncRNA UCA1 expression, and lncRNA UCA1 epigenetically suppresses p27 expression, thereby exacerbating cardiomyocyte hypertrophy in HOCM.
Silencing long non-coding RNA linc00689 suppresses the growth and invasion of osteosarcoma cells by targeting miR-129-5p/NUSAP1.
Zhang L, Song J, Xu X … +4 more , Sun D, Huang H, Chen Y, Zhang T
Int J Exp Pathol · 2025 Mar · PMID 39891384 · Full text
Long non-coding RNAs (lncRNAs) have been reported to play a critical role in the progression and metastasis of osteosarcoma. Recently, long intergenic non-protein coding RNA 689 (linc00689) has been shown to be involved...
Long non-coding RNAs (lncRNAs) have been reported to play a critical role in the progression and metastasis of osteosarcoma. Recently, long intergenic non-protein coding RNA 689 (linc00689) has been shown to be involved in glioma. However, the precise role of linc00689 in osteosarcoma is unknown. In this study, our data demonstrated that silencing linc00689 by siRNA markedly suppressed the proliferation, migration, invasion and epithelial-mesenchymal transition (EMT) of MG63 and SAOS-2 cells. Bioinformatics analysis and dual-luciferase reporter assay revealed that linc00689 could bind to miR-129-5p. Moreover, NUSAP1 was a target of miR-129-5p and positively regulated by linc00689. Further, NUSAP1 overexpression enhanced MG63 cell behaviour and abolished the inhibitory effects of linc00689 knockdown on the proliferation, migration, invasion and EMT of MG63 cells. In conclusion, linc00689 exerts an oncogenic role in the progression of osteosarcoma, which works via the miR-129-5p/NUSAP1 axis.
Review of methodology and re-analysis of lipidomic data focusing on specialised pro-resolution lipid mediators (SPMs) in a human model of resolving inflammation.
Homer NZM, Andrew R, Gilroy DW
Int J Exp Pathol · 2025 Feb · PMID 39713922 · Full text
Using a model of UV-killed E. coli driven dermal inflammation in healthy human volunteers, we originally reported that following inflammatory resolution there was infiltration of macrophages, which, through prostanoids i...
Using a model of UV-killed E. coli driven dermal inflammation in healthy human volunteers, we originally reported that following inflammatory resolution there was infiltration of macrophages, which, through prostanoids including prostaglandin (PG) E, imprints long-term tissue immunity. In addition to the prostanoids, data on levels of Specialised Pro-Resolution Lipid Mediators (SPMs) throughout inflammatory onset, resolution and post-resolution phases of this model were presented, but as illustrations rather than as primary data. Therefore, in response to a request for increased transparency, a subset of the original data from our human UV-killed E. coli model was re-analysed by two experts from an independent laboratory alongside a review of the methodology used. The prostanoids were detected robustly following re-analysis but the areas of the chromatographic peaks of the SPM lipid mediators were too small to yield amounts that could be reliably detected and/or quantified using community standards. Importantly, with prostanoids including PGE being robustly detected, this re-analysis does not alter the original report that post-resolution PGs imprint tissue immunity. Here we show the outcome of this re-analysis and review the biology surrounding SPMs as a result.
Identification of BCL3 as a biomarker for chondrocyte programmed cell death in osteoarthritis.
Ren J, Li R, Meng C … +2 more , Xu Y, Li C
Int J Exp Pathol · 2025 Feb · PMID 39676743 · Full text
Osteoarthritis (OA) is a condition that is widely prevalent and causes joint pain and disability, with programmed cell death (PCD) playing a role in its pathogenesis. This study aimed to identify biomarkers associated wi...
Osteoarthritis (OA) is a condition that is widely prevalent and causes joint pain and disability, with programmed cell death (PCD) playing a role in its pathogenesis. This study aimed to identify biomarkers associated with PCD in OA and explore their potential roles. Three RNA-sequencing datasets (GSE114007, GSE51588 and GSE220243) related to OA were analysed. Differential expression and weighted gene co-expression network identified key differentially expressed PCD-related genes (DE-PRMGs). Potential biomarkers were identified and validated through receiver operating characteristic (ROC) curves, correlation analyses, gene set enrichment analysis, single-cell expression and RT-qPCR. A total of 45 DE-PRMGs were identified, affecting pathways like TNF signalling and RNA degradation. BCL3, TREM2 and NRP2 were prioritized as potential OA biomarkers, which are associated with ribosome function and immune cell infiltration and potentially linked to PCD. The functional role of one of the molecules identified, BCL3, was explored further using a cell model of inflammation induced chondrocytes. BCL3 was significantly down regulated in OA samples from the public dataset and clinical samples analysed by RT-qPCR. BCL3 overexpression reduced apoptosis in chondrocytes stimulated with inflammatory cytokines. Thus the functional studies highlighted the anti-apoptotic role of BCL3 in chondrocytes and provide new insights into OA pathogenesis with potential for future therapeutic development.
Perinatal exposure to lead alters male reproductive behaviour and immunoreactivity of androgen and oestrogen receptors in the brain.
Arteaga-Silva M, Vigueras-Villaseñor RM, Guillen-Herrera G … +6 more , Landero-Huerta DA, Contreras-García IJ, Montes S, Ríos C, Limón-Morales O, Rojas-Castañeda JC
Int J Exp Pathol · 2025 Feb · PMID 39676704 · Full text
Lead (Pb) exposure during perinatal development alters testosterone (T) concentrations and delays puberty in children and laboratory rodents. In addition, exposure to the metal during adult life decreases T and libido in...
Lead (Pb) exposure during perinatal development alters testosterone (T) concentrations and delays puberty in children and laboratory rodents. In addition, exposure to the metal during adult life decreases T and libido in men and affects male reproductive behaviour (MRB) in rats. MRB is regulated by various brain nuclei including the medial preoptic area (MPOa) and the medial amygdala (MeA), in which T and oestradiol (E) act through their respective androgen (AR) and oestrogen (ER) receptors. However, the mechanism by which MRB is affected by Pb exposure is not known. The objectives of the present study were to evaluate whether perinatal Pb exposure affects MRB and the number of cells immunoreactive to AR and ERα in the MPOa and the MeA. Male Wistar rats exposed to Pb (320 ppm) in drinking water from the beginning of pregnancy until weaning were used. The experimental group experienced significant alterations in MRB, an important decrease in T and E concentrations, and a significant increase in Pb concentrations in the blood, MPOa (hypothalamus) and MeA. In addition, in the studied areas the number of cells immunoreactive to AR and ERα, or detected using the Nissl technique, decreased significantly. These results show that perinatal exposure to Pb alters MRB. This event may be related to a decrease in both the concentrations of sex hormones and the number of cells that express their receptors as well as in the neuronal Nissl staining population. This ultimately affects the quality of life of the individual.
Histomorphometric analysis of excisional cutaneous wounds with different diameters in an animal model.
Staianov J, Struz JMR, Vieira RV … +4 more , Luiz RM, Zarpelon-Schutz AC, Teixeira KN, Bernardi-Wenzel J
Int J Exp Pathol · 2024 Dec · PMID 39439085 · Full text
The skin wound model in rats is a fundamental stage in preclinical trials, but there is a lack of standardization in these trials regarding the initial wound area, making analysis and comparison between studies difficult...
The skin wound model in rats is a fundamental stage in preclinical trials, but there is a lack of standardization in these trials regarding the initial wound area, making analysis and comparison between studies difficult. Therefore, this study evaluates the healing progression of excisional skin lesions of varying diameters in Wistar rats, aiming to identify the optimal wound size for monitoring treatment effects on wound healing. Excisions of 0.8, 1.5, 2.0 and 3.0 cm in diameter were made on the back of the animals. Thirty animals were used per treatment and evaluated on days 3, 7, 10, 14 and 21 after surgery. The lesions were cleaned daily with saline solution until they were completely closed. The 0.8 cm group showed complete repair on D14, while in the other groups, the wounds persisted until day 21, with a reddened surface and no complete epidermal coverage, but with greater keratinization and presence of appendages in the 1.5 cm lesions. Therefore, as a standardization model for creating skin wounds, we suggest using 1.5 or 2.0 cm excisions, considering that 0.8 cm wounds close very early and 3.0 cm wounds, although behaving similarly to 2.0 cm wounds, are more invasive for the animals. The 1.5 cm model proved to be suitable for closure within 21 days. When evaluating a product intended to accelerate wound healing, 2.0 cm lesions are recommended to assess the effectiveness of the treatment.
Determination of osteopontin in monitoring retinal damage in metabolic syndrome.
D'Amico R, Siracusa R, Cordaro M … +6 more , Fusco R, Interdonato L, Franco GA, Cuzzocrea S, Di Paola R, Impellizzeri D
Int J Exp Pathol · 2024 Dec · PMID 39397270 · Full text
Metabolic syndrome (MetS) is becoming an increasing public health challenge. Many of the individual components of MetS are associated with ocular changes, but it is not yet clear what the association is. It is known that...
Metabolic syndrome (MetS) is becoming an increasing public health challenge. Many of the individual components of MetS are associated with ocular changes, but it is not yet clear what the association is. It is known that MetS can lead to diabetes and hence its consequences such as retinopathy. Osteopontin (OPN) is a phosphoglycoprotein that appears to be implicated in diabetic retinopathy. Given the involvement of OPN in retinal damage, the aim of this research was to evaluate OPN expression and its variation over time in a model of MetS induced by 30% fructose consumption for 1, 2 and 3 months. The weight of the animals and the consumption of food and fructose/water were evaluated during the experiment. The results showed a time-dependent increase in weight and liquid consumption in animals treated with fructose, while there was no significant difference in food consumption. Subsequently, the biochemical parameters confirmed that the animals treated with fructose, over time, underwent alterations like those found in patients with MetS. We then moved on to the evaluation of OPN and microglia. In both cases, we observed a time-dependent increase in OPN and Iba-1 in fructose consumption. Furthermore, the results showed a gradual loss of ZO-1 and occludin levels over time. Thus identification of OPN in patients with MetS could be used as an early marker of retinal damage, and this could help to prevent the complications related to the progression of this pathology.
Enhanced hepatoprotective effects of empagliflozin and vitamin D dual therapy against metabolic dysfunction-associated steatohepatitis in mice by boosted modulation of metabolic, oxidative stress, and inflammatory pathways.
Farrash WF, Idris S, Elzubier ME … +14 more , Khidir EBA, Aslam A, Mujalli A, Almaimani RA, Obaid AA, El-Readi MZ, Alobaidy MA, Salaka A, Shakoori AM, Saleh AM, Minshawi F, Samkari JA, Alshehre SM, Refaat B
Int J Exp Pathol · 2024 Dec · PMID 39397269 · Full text
Although single treatment with sodium-glucose cotransporter-2 inhibitors (SGLT2i) or vitamin D (VD) inhibited metabolic dysfunction-associated steatohepatitis (MASH) development in diabetic patients, their combination ha...
Although single treatment with sodium-glucose cotransporter-2 inhibitors (SGLT2i) or vitamin D (VD) inhibited metabolic dysfunction-associated steatohepatitis (MASH) development in diabetic patients, their combination has not been explored previously. Hence, this study investigated the hepatoprotective effects of SGLT2i (empagliflozin) and/or VD against MASH in type 2 diabetic mice. Forty Mice were assigned into negative (NC) and positive (PC) controls, SGLT2i, VD, and SGLT2i + VD groups. All animals, except the NC group, received high-fructose/high-fat diet (8 weeks) followed by diabetes induction. Diabetic mice then received another cycle of high-fructose/high-fat diet (4 weeks) followed by 8 weeks of treatment (five times/week) with SGLT2i (5.1 mg/kg/day) and/or VD (410 IU/Kg/day). The PC group demonstrated hyperglycaemia, dyslipidaemia, elevated liver enzymes, and increased non-alcoholic fatty liver disease activity score (NAS) with fibrosis. Hepatic glucose transporting molecule (SGLT2) with lipogenesis (SREBP-1/PPARγ), oxidative stress (MDA/HO), inflammation (IL1β/IL6/TNF-α), fibrosis (TGF-β1/α-SMA), and apoptosis (TUNEL/Caspase-3) markers alongside the PI3K/AKT/mTOR pathway increased in the PC group. Conversely, hepatic insulin-dependent glucose transporter (GLUT4), lipolytic (PPARα/INSIG1), antioxidant (GSH/GPx1/SOD1/CAT), and anti-inflammatory (IL-10) molecules with the inhibitor of PI3K/AKT/mTOR pathway (PTEN) decreased in the PC group. Whilst SGLT2i monotherapy outperformed VD, their combination showed the best attenuation of hyperglycaemia, dyslipidaemia, and fibrosis with the strongest modulation of hepatic glucose-transporting and lipid-regulatory molecules, PI3K/AKT/mTOR pathway, and markers of oxidative stress, inflammation, fibrosis, and apoptosis. This study is the first to reveal boosted hepatoprotection for SGLT2i and VD co-therapy against diabetes-induced MASH, possibly via enhanced metabolic control and modulation of hepatic PI3K/AKT/mTOR, anti-inflammatory, anti-oxidative, and anti-fibrotic pathways.
Thrombospondins: Conserved mediators and modulators of metazoan extracellular matrix.
Adams JC
Int J Exp Pathol · 2024 Oct · PMID 39267379 · Full text
This review provides a personal overview of significant scientific developments in the thrombospondin field during the course of my career. Thrombospondins are multidomain, multimeric, calcium-binding extracellular glyco...
This review provides a personal overview of significant scientific developments in the thrombospondin field during the course of my career. Thrombospondins are multidomain, multimeric, calcium-binding extracellular glycoproteins with context-specific roles in tissue organisation. They act at cell surfaces and within ECM to regulate cell phenotype and signalling, differentiation and assembly of collagenous ECM, along with tissue-specific roles in cartilage, angiogenesis and synaptic function. More recently, intracellular, homeostatic roles have also been identified. Resolution of structures for the major domains of mammalian thrombospondins has facilitated major advances in understanding thrombospondin biology from molecule to tissue; for example, in illuminating molecular consequences of disease-causing coding mutations in human pseudoachrondroplasia. Although principally studied in vertebrates, thrombospondins are amongst the most ancient of animal ECM proteins, with many invertebrates encoding a single thrombospondin and the thrombospondin gene family of vertebrates originating through gene duplications. Moreover, thrombospondins form one branch of a thrombospondin superfamily that debuted at the origin of metazoans. The super-family includes additional sub-groups, present only in invertebrates, that differ in N-terminal domain organisation, share the distinctive TSP C-terminal region domain architecture and, to the limited extent studied to date, apparently contribute to tissue development and organisation. Finally, major lines of translational research are discussed, related to fibrosis; TSP1, TSP2 and inhibition of angiogenesis; and the alleviation of chronic cartilage tissue pathologies in pseudoachrondroplasia.
Renal protective roles of macrophage matrix metalloproteinase-12 in mice with obstructed kidneys.
Hanai S, Nakagomi D, Suzuki K … +2 more , Nakajima H, Furuya F
Int J Exp Pathol · 2024 Oct · PMID 39164934 · Full text
Matrix metalloproteinase (MMP)-12 has been reported to have diverse functions, including regulation of immune reactions and anti-inflammatory effects, but the potential roles of MMP-12 in kidney injury have not been full...
Matrix metalloproteinase (MMP)-12 has been reported to have diverse functions, including regulation of immune reactions and anti-inflammatory effects, but the potential roles of MMP-12 in kidney injury have not been fully elucidated. This study aimed to determine whether MMP-12 contributes to tubulointerstitial injury in a unilateral ureteric obstruction (UUO) model. MMP-12-deficient (MMP-12) mice and C57BL/6J mice as controls (MMP-12) were subjected to UUO and analysed 7 days after UUO. To analyse the functions of MMP-12 on monocytes/macrophages, we generated MMP-12-deficient, irradiated, chimeric mice (BM-MMP-12) and performed UUO. Bone marrow-derived macrophages (BMDMs) were isolated from both groups of mice and used for investigations. MMP-12 mice showed exacerbation of macrophage accumulation and interstitial fibrosis in the UUO-kidney compared with control mice. BM-MMP-12 mice also showed exacerbation of kidney injury. UUO induced accumulation of Ly6C macrophages in MMP-12 mice compared with control mice. Increases in inflammatory cytokine (tumour necrosis factor α, interleukin [IL]-1β, IL-6) levels from BMDMs after lipopolysaccharide stimulation were higher in MMP-12 mice than in MMP-12 mice. MMP-12 may play protective roles against kidney injury by UUO in mice, decreasing inflammatory cytokines from BMDMs and macrophage accumulation.
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