Histology and histopathology Vol.39, nº8 (2024)

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    Transcription factor YY1 accelerates hepatic fibrosis development by activating NLRP3 inflammasome-mediated pyroptosis
    (Universidad de Murcia. Departamento de Biología Celular e Histología, 2024) Fu, Xiao; Xiao, Ping; Luo, Xin; Guo, Ninghong
    y. Hepatic fibrosis is the basis of multiple liver diseases and may eventually develop into hepatocellular carcinoma. Hepatic stellate cell (HSC) activation is a driving factor of hepatic fibrogenesis. In the liver microenvironment, liver cells and others play a crucial role in HSC activation. The liver tissues of CCl4- induced rats show excessive fibrosis, inflammation, and cell apoptosis. Yin Yang 1 (YY1) was highly expressed in hepatic fibrosis rats and TGF-β1-treated liver cells. In animal experiments, YY1 knockdown effectively attenuated CCl4-induced liver injury and pyroptosisrelated IL-1β and IL-18 expression. In cellular experiments, NLRP3 inflammasome-mediated pyroptosis was activated by TGF-β1 treatment, while YY1 knockdown significantly inhibited the activation of the NLRP3 inflammasome, pyroptosis, and the secretion of IL-1β and IL-18. In addition, our data showed that TGF-β1-treated liver cell conditional medium markedly induced HSC activation, which was rescued by YY1 knockdown in liver cells. YY1 overexpression in liver cells contributed to the activation of TGF-β1-treated liver cell conditional medium in HSCs, however, this effect of YY1 was attenuated by NLRP3 inhibition. Overall, YY1 overexpression in liver cells contributed to HSC activation by facilitating IL-1β and IL-18 production via activating NLRP3 inflammasomemediated pyroptosis, thus aggravating hepatic fibrogenesis. Our data indicate that YY1 may be a novel target for the treatment of hepatic fibrosis and associated liver diseases.
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    Expression of the HIF-1α/VEGF pathway is upregulated to protect alveolar bone density reduction in nasal-obstructed rats
    (Universidad de Murcia. Departamento de Biología Celular e Histología, 2024) Liu, Zishan; Li, Yongming
    Background. Hypoxia and mouth breathing are closely related to maxillofacial bone metabolism and are characteristic of obstructive sleep apnea-hypopnea syndrome (OSAHS). Being key factors in the hypoxia response, hypoxia-inducible factor 1α (HIF-1α) and HIF-responsive gene vascular endothelial growth factor (VEGF) are essential for bone remodeling. This study focuses on the role of the HIF-1α/VEGF pathway in alveolar bone metabolism during OSAHS. Materials and methods. 36 three-week-old male Wistar rats were divided into three groups: twelve control rats, twelve bilateral nasal obstructed (BNO) rats, twelve BNO rats treated with intraperitoneal injection of Dimethyloxalylglycine (DMOG). After two weeks, the microstructure and bone mineral density (BMD) of alveolar bone were evaluated using microcomputed tomography (micro-CT). The expressions of HIF-1α and VEGF in the alveolar bone were then assessed via immunohistochemistry staining, quantitative real-time polymerase chain reaction (qRTPCR) and Western blot. Alkaline phosphatase (ALP) staining and Alizarin red S staining were performed to evaluate osteogenesis of bone marrow-derived mesenchymal stem cells (BMSCs). Results. Significant reductions in alveolar bone density were noted in BNO rats. Bilateral nasal obstruction increased the expressions of HIF-1α and VEGF in alveolar bone. With upregulation of HIF1α/VEGF via DMOG, alveolar bone density of BNO rats increased. Furthermore, DMOG promoted the osteogenic differentiation of BMSCs by stabilizing the HIF-1α protein and increasing the expression of VEGF. Conclusion. Bilateral nasal obstruction changes alveolar bone structure and leads to a reduction in alveolar bone density. Moreover, the expression of the HIF-1α/VEGF signaling pathway increases to protect alveolar bone density reduction in BNO rats.
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    Heraclenin promotes the osteogenic differentiation of bone marrow stromal cells by activating the RhoA/ROCK pathway
    (Universidad de Murcia. Departamento de Biología Celular e Histología, 2024) Yu, Zuguang; Yuan, Jun; Yu, Yuanyuan
    Background. Osteoporosis is a devastating skeletal disease, the pathogenesis of which is related to abnormal bone metabolism, featured by the imbalance between osteoblastic bone formation and osteoclastic bone resorption. Stem cell-based therapies have been demonstrated to improve osteoporosis treatment. Previously, the linear furanocoumarin heraclenin was reported to enhance osteoblast differentiation and mineralization in mouse mesenchymal stem cells (MSCs), suggesting its potential for osteogenic differentiation and bone regeneration. Our study was designed to confirm the promotive role of heraclenin on osteogenic differentiation of human bone MSCs (BMSCs) and explore the underlying mechanisms. Methods. Human BMSCs were treated for 24, 48, and 72h with heraclenin (5, 10, 20, 40, and 80 μM), and cell viability was determined by Cell Counting Kit-8 (CCK-8) assay. To further evaluate the cytotoxicity of heraclenin, cell suspension obtained from BMSCs treated with heraclenin (5, 10, and 20 μM) for 72h was subjected to a MUSE™ cell analyzer for cell viability and count assay. BMSCs were incubated in osteogenic induction medium for 7 days. Then, osteogenic differentiation and mineralization of BMSCs were assessed through alkaline phosphatase (ALP) and Alizarin Red S staining. The expression of osteogenesis markers including ALP, osteocalcin (OCN), osterix (OSX), and runt-related transcription factor 2 (RUNX2) was detected via reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blotting. The effects of heraclenin on the RhoA/ROCK pathway were estimated through western blotting. Y27632, the ROCK inhibitor, was used to confirm the role of the RhoA/ROCK pathway in heraclenin-mediated osteogenic differentiation of BMSCs. Results. Heraclenin (5-80 μM) was non-toxic on human BMSCs. Heraclenin treatment (5-20 μM) dosedependently enhanced ALP activity and calcium deposition. Furthermore, heraclenin promoted ALP, OCN, OSX, and RUNX2 mRNA and protein expression. Mechanically, heraclenin treatment increased RhoA and ROCK1 mRNA expression, stimulated the translocation of ROCK from the cytosolic to the membrane fraction, and elevated the protein levels of phosphorylated cofilin (p-cofilin) and active RhoA. Additionally, treatment with Y-27632 overturned the promotion of heraclenin on ALP activity, calcium deposition, the expression of osteogenesis markers, and the RhoA/ROCK signaling pathway. Conclusion. Heraclenin facilitates the osteogenic differentiation of human BMSCs through the activation of the RhoA/ROCK pathway.
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    Melan-A expression in non-melanocytic carcinoma: A potential diagnostic pitfall
    (Universidad de Murcia. Departamento de Biología Celular e Histología, 2024) Zuo, Linwei; You, Huiyan; Cai, Zhe; Liao, Shousheng; Lu, Xiangtong; Li, Lixiang; Huang, Wenyong
    Background. Melan-A/MART-1 is a melanocytic differentiation marker recognized as an antigen on melanoma cells. It is a useful diagnostic marker for pathologists in the diagnosis of melanocytic tumors. However, we recently found that Melan-A can be expressed in some non-melanocytic carcinomas that are rarely reported in the literature. Methods. We analyzed the expression of Melan-A in 87 non-melanocytic carcinoma tissue samples by immunohistochemistry. Marker positivity was defined as ≥10% positive tumor cells. Results. In 87 non-melanocytic carcinoma tissue samples, Melan-A was positive in six (6.89%) cases, of which four (66.7%) were male and two (33.3%) were female, with a mean age of 60 years (range 21-82 years). Five (83.3%) of the Melan-A-positive cases had distant metastases. Compared with Melan-A negative cases, Melan-A positive non-melanocytic carcinomas were significantly associated with poor prognosis (P=0.0023). Conclusions. Melan-A expression is relatively rare in non-melanocytic carcinoma cases. This report highlights a potential diagnostic pitfall in the diagnosis of melanoma, urges pathologists to exercise caution in cases of Melan-A positivity, and illustrates the need for an immunohistochemical marker panel to avoid misdiagnosis.
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    Expression and hypermethylation of JAM and EPB41L3 in cervical squamous cell carcinoma: Clinical significance and applications
    (Universidad de Murcia. Departamento de Biología Celular e Histología, 2024) Gu, Yun; Chu, Chengzhuo; Yuan, Bei; Wang, Jiandong; Pan, Shiyang
    This study aimed to explore the expression and hypermethylation of EPB41L3 and JAM3 in cervical squamous cell carcinoma (CSCC) and to investigate their clinical significance. JAM3 and EPB41L3 mRNA expression was analyzed using a public database, and protein expression was detected using immunohistochemistry. The methylation status of JAM3 and EPB41L3 was detected in CSCC tissues and cervical cytological specimens using a quantitative methylation-specific PCR (qMSP). JAM3 and EPB41L3 mRNA were downregulated in CSCC. The JAM3 protein was positively detected in 39.4% of CSCC tissues and frequently expressed in those with lower FIGO stage and no lymph node metastasis. EPB41L3 was expressed in 18.9% of CSCC tissues. The hypermethylation of JAM3 was detected in 52.3% of CSCC tissues and related to higher FIGO stage and lymph node metastasis. EPB41L3 hypermethylation was detected in 72.7% of CSCC tissues and related to older ages and lymph node metastasis. In cervical cytological specimens, no methylation of JAM3 and EPB41L3 was found in normal or inflamed cervical epithelial cells. The methylation of JAM3 was detected in 0%, 8.3%, and 6.3% of ASCUS, LSIL, and HSIL samples, while EPB41L3 was detected in 12.5%, 42.9%, and 71.4%, respectively. The sensitivity of the combination of JAM3 and EPB41L3 methylation detection in ASCUS, LSIL, and HSIL was 8.3%, 15.6%, and 85.7%, respectively. The specificity of the combination of JAM3 and EPB41L3 methylation detection was 100%. Downregulation of JAM3 and EPB41L3 by hypermethylation was detected in CSCC. JAM3 and EPB41L3 hypermethylation are potential biomarkers for cervical cancer screening.