Histology and histopathology Vol.39, nº8 (2024)

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Open Access
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.
Open Access
Comprehensive insights into the understanding of hypoxia in ameloblastoma
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2024) Bologna Molina, Ronell; Schuch, Lauren; Niklander, Sven Eric
Hypoxia is characterized by a disparity between supply and demand of oxygen. The association between hypoxia and head and neck tumors is a topic of significant interest. Tumors frequently encounter areas with inadequate oxygen supply, resulting in a hypoxic microenvironment. Ameloblastoma is one of the most common benign odontogenic tumors of the maxillofacial region. It is a slow-growing but locally invasive tumor with a high recurrence rate. The literature has demonstrated the correlation between hypoxia and ameloblastoma, revealing a discernible link between the heightened expression of hypoxic markers in low oxygen conditions. This association is intricately tied to the tumoral potential for invasion, progression, and malignant transformation. Hypoxia profoundly influences the molecular and cellular landscape within ameloblastic lesions. The present review sheds light on the mechanisms, implications, and emerging perspectives in understanding this intriguing association to clarify the dynamic relationship between hypoxia and ameloblastoma.
Open Access
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.
Open Access
Identification and validation of plasma AGRN as a novel diagnostic biomarker of hepatitis B Virus-related chronic hepatitis and liver fibrosis/cirrhosisy
(Universidad de Murcia. Departamento de Biología Celular e Histología, 2024) Ai, Rong; Li, Lu; Yuan, Xiwei; Zhao, Dandan; Miao, Tongguo; Guan, Weiwei; Dong, Shiming; Dong, Chen; Dou, Yao; Hou, Mengmeng; Nan, Yuemin
Objective. The aim of this study was to find novel biomarkers and develop a non-invasive, effective diagnostic model for hepatitis B Virus-related chronic hepatitis and liver fibrosis/cirrhosis. Method. Quantitative real-time polymerase chain reaction (qRT-PCR) was utilized to assess the expression of differentially expressed genes (AGRN, JAG1, CCL5, ID3, CCND1, and CAPN2) in peripheral blood mononuclear cells (PBMCs) from healthy subjects, chronic hepatitis B (CHB), and liver fibrosis/cirrhosis (LF/LC) patients. The molecular mechanisms underlying AGRN-regulated CHB were further explored and verified in LX2 cells, in which small interfering RNA (siRNA) was used to block AGRN gene expression. Finally, enzyme-linked Immunosorbent Assay (ELISA) was used to measure AGRN protein expression in 100 healthy volunteers, 100 CHB patients, and 100 LF/LC patients, and the efficacy of the diagnostic model was assessed by the Area Under the Curve (AUC). Results. AGRN mRNA displayed a steady rise in the PBMCs of normal, CHB, and LF/LC patients. Besides, AGRN expression was markedly elevated in activated LX2 cells, whereas the expression of COL1 and α-SMA decreased when AGRN was inhibited using siRNA. In addition, downregulation of AGRN can reduce the gene expression of β-catenin and c-MYC while upregulating the expression of GSK-3β. Furthermore, PLT and AGRN were used to develop a non-invasive diagnostic model (PA). To identify CHB patients from healthy subjects, the AUC of the PA model was 0.951, with a sensitivity of 87.0% and a specificity of 91.0%. The AUC of the PA model was 0.922 with a sensitivity of 82.0% and a specificity of 90.0% when differentiating between LF/LC and CHB patients. Conclusion. The current study indicated that AGRN could be a potential plasma biomarker and the established PA model could improve the diagnostic accuracy for HBV-related liver diseases.
Open Access
Quantification of eosinophil densities in the oesophagus, stomach and small bowel of adults: A review of endoscopic and surgical specimens with normal histology, Free State Province, South Africa
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2024) Budding, Liska; Duncan, Jane; Joubert, Gina; Goedhals, Jacqueline
Aim. Studies defining eosinophil densities in the gastrointestinal tract (GIT) are limited. To assess whether eosinophils are pathologically infiltrating the GIT, it is important to evaluate eosinophil densities for specific populations. Methods. A retrospective, quantitative, comparative study was conducted to determine the number of eosinophils in the oesophagus, stomach and small bowel of patients in central South Africa and to investigate whether a statistically significant difference occurred between ethnic and gender groups. Results. In total, 309 histological sections from the oesophagus, gastric corpus, gastric antrum and small intestine were sampled from male and female, African and Caucasian patients. Histology reports and review of the slides confirmed the absence of histological abnormality. The number of eosinophils in the epithelium and lamina propria were manually quantified. The eosinophil values across gender, ethnicity and location were 0-2.0/mm2 for the oesophagus, 0-53.0/mm2 for the gastric corpus and 7.1-115.3/mm2 for the small intestine. Regarding the gastric antrum, African and Caucasian females had eosinophil values of 1.0-35.7/mm2 and 0-22.4/mm2, respectively. Males had an eosinophil density of 0-31.6/mm2 in the gastric antrum. The eosinophil values in the oesophagus, gastric corpus and small bowel were not significantly different between genders and ethnic groups. The only site where ethnicity influenced the number of eosinophils was the gastric antrum, a discrepancy that cannot be explained. Conclusion. To the authors' knowledge, this is the first report on the eosinophil densities in the oesophagus, stomach and small bowel of adults in South Africa.
Open Access
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.
Open Access
Role of mitochondria in neonatal hypoxic-ischemic encephalopathy
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2024) Kong, Weijing; Lu, Cheng
Neonatal hypoxic-ischemic encephalopathy, an important cause of death as well as long-term disability in survivors, is caused by oxygen and glucose deprivation, and limited blood flow. Following hypoxic-ischemic injury in the neonatal brain, three main biochemical damages (excitotoxicity, oxidative stress, and exacerbated inflammation) are triggered. Mitochondria are involved in all three cascades. Mitochondria are the nexus of metabolic pathways to offer most of the energy that our body needs. Hypoxic-ischemic injury affects the characteristics of mitochondria, including dynamics, permeability, and ATP production, which also feed back into the process of neonatal hypoxic-ischemic encephalopathy. Mito-chondria can be a cellular hub in inflammation, which is another main response of the injured neonatal brain. Some treatments for neonatal hypoxic-ischemic encephalopathy affect the function of mitochondria or target mitochondria, including therapeutic hypothermia and erythropoietin. This review presents the main roles of mitochondria in neonatal hypoxic-ischemic encephalopathy and discusses some potential treatments directed at mitochondria, which may foster the development of new therapeutic strategies for this encephalopathy
Open Access
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.
Open Access
CBP-mediated FOXO4 acetylation facilitates postmenopausal osteoporosis (PMO) progression through the inhibition of the Wnt/β-catenin signaling pathway
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2024) Huang, Qiubo; Wang, Jiang
FOXO4 was previously identified as a potential biomarker and therapeutic target for postmenopausal osteoporosis (PMO) using bioinformatic analysis, but its specific function and molecular mechanism in the progression of osteoporosis was not reported. The current study was designed to investigate the biological function and underlying mechanism of FOXO4 in PMO. Our results showed that FOXO4 expression was significantly upregulated in the serum samples of PMO patients, which was also negatively correlated with the expression of osteogenesis genes (OCN and ALP). In addition, FOXO4 depletion alleviated osteoporosis by facilitating osteogenic differentiation and inhibiting adipogenic differentiation in human bone marrow mesenchymal stem cells (hBMSCs). Overexpression of FOXO4 exerted the opposite effects on the osteogenic/adipogenic differentiation in hBMSCs. Moreover, FOXO4 knockdown activated the Wnt/β-catenin signaling whereas the inhibition of Wnt/β-catenin signaling overturned the effects of FOXO4 deficiency on osteoporosis. Furthermore, FOXO4 upregulation in PMO was caused by CBP-induced acetylation. In summary, our data demonstrated that FOXO4 was a potent biomarker for PMO and mediated the balance between osteogenesis and adipogenesis in hBMSCs by regulating Wnt/β-catenin signaling
Open Access
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.
Open Access
The multiple facets of the club cell in the pulmonary epithelium
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2024) López Valdez, Nelly; Rojas Lemus, Marcela; Bizarro-Nevares, Patricia; González Villalva, Adriana Elizabeth; Casarrubias Tabarez, Brenda; Cervantes Valencia, María Eugenia; Ustarroz-Cano, Martha; Morales Ricardes, Guadalupe; Mendoza Martínez, Shamir; Guerrero Palomo, Gabriela; Fortoul, Teresa I.
The non-ciliated bronchiolar cell, also referred to as “club cell”, serves as a significant multifunctional component of the airway epithelium. While the club cell is a prominent epithelial type found in rodents, it is restricted to the bronchioles in humans. Despite these differences, the club cell's importance remains undisputed in both species due to its multifunctionality as a regulatory cell in lung inflammation and a stem cell in lung epithelial regeneration. The objective of this review is to examine different aspects of club cell morphology and physiology in the lung epithelium, under both normal and pathological conditions, to provide a comprehensive understanding of its importance in the respiratory system.
Open Access
Impact of maternal stress on metabolism and penile morphology in young offspring rats
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2024) Macedo, Carolinne; Monnerat, Juliana; Lucchetti, Bianca; Teixeira, Gabriel; Mentzinger, Juliana; Rocha, Helena; Medeiros, Renata; Rocha, Natália; Souza, Diogo de; Sampaio, Francisco; Gregorio, Bianca M.
Exposure to prolonged stress in pregnancy and/or lactation can lead to the future development of diseases. We aimed to study the effects of maternal stress on the biometry, metabolism, and penile morphology of young Wistar rats. Animals were divided into two experimental groups: Control Group (C) - pups from control mothers, without any intervention (n=5); and Chronic Stress Group (S) - pups from mothers who suffered variable stress in the third week of pregnancy (14th to 21st day; n=5). Food intake and body mass of the pups (n=10, in the C group and n=9 in the S group) were checked; at euthanasia (three months old), fat deposits and penis were removed. At birth and weaning, S animals were lighter than C animals, [-33.72% (p=0.0422) and -17.07% (p=0.0018)], respectively. However, the final body mass and body mass delta showed no differences. Food intake and fat deposits also did not differ. However, the S group was hyperglycemic at 30 and 60 days of life [+20.59% (p=0.0042) and +14.56% (p=0.0079), respectively], despite the glycemia measured at 90 days showing no difference between groups. Penile areas and surface densities of the corpora cavernosa components were similar between groups. The results indicate that maternal stress is an important metabolic programmer, which generates low birth weight and accelerated recovery of body mass after birth (catch-up). However, in an early analysis (90 days of life), exposure to gestational stress did not change the morphology of the offspring's penis in adulthood.

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