Histology and histopathology Vol.40, nº3 (2025)
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- PublicationOpen AccessClinicopathologic and molecular characteristics of neuroendocrine carcinomas of the gallbladder(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2025) Tang, Hui; Jiang, Xiaojun; Zhu, Lili; Xu, Liming; Wang, Xiaoxi; Li, Hong; Gao, Feifei; Liu, Xinxin; Ren, Chuanli; Zhao, YanGallbladder neuroendocrine carcinomas (GB-NECs) are a rare subtype of malignant gallbladder cancer (GBC). The genetic and molecular characteristics of GB-NECs are rarely reported. This study aims to assess the frequency of microsatellite instability (MSI) in GB-NECs and characterize their clinicopathologic and molecular features in comparison with gallbladder adenocarcinomas (GB-ADCs). Data from six patients with primary GB-NECs and 13 with GB-ADCs were collected and reevaluated. MSI assay, immunohisto-chemistry for mismatch repair proteins (MLH1, MSH2, MSH6, and PMS2), comprehensive genomic profiling (CGP) via next-generation sequencing (NGS), and evaluation of tumor mutation burden (TMB) were conducted on these samples. The six GB-NEC cases were all female, with a mean age of 62.0±9.2 years. Of these, two cases were diagnosed as large cell neuroendocrine carcinomas (LCNECs), while the remaining four were small cell neuroendocrine carcinomas (SCNECs). Microsatellite states observed in both GB-NECs and GB-ADCs were consistently microsatellite stable (MSS). Notably, TP53 (100%, 6/6) and RB1 (100%, 6/6) exhibited the highest mutation frequency in GB-NECs, followed by SMAD4 (50%, 3/6), GNAS (50%, 3/6), and RICTOR (33%, 2/6), with RB1, GNAS, and RICTOR specifically present in GB-NECs. Immunohistochemical (IHC) assays of p53 and Rb in the six GB-NECs were highly consistent with genetic mutations detected by targeted NGS. Moreover, no statistical difference was observed in TMB between GB-NECs and GB-ADCs (p=0.864). Although overall survival in GB-NEC patients tended to be worse than in GB-ADC patients, this difference did not reach statistical significance (p=0.119). This study has identified the microsatellite states and molecular mutation features of GB-NECs, suggesting that co-mutations in TP53 and RB1 may signify a neuroendocrine inclination in GB-NECs. The IHC assay provides an effective complement to targeted NGS for determining the functional status of p53 and Rb in clinical practice.
- PublicationOpen AccessBioinformatics study of the TNFRSF1A mechanism involved in acute liver injury in sepsis through the mTOR signaling pathway(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2025) Chen, Zhidong; Tang, Kankai; Zhang, HuiObjectives. This study analyzed potential key genes involved in the mechanism of acute liver injury induced by sepsis through bioinformatics techniques, aiming to provide novel insights for the identification of early-stage sepsis-induced acute liver injury and its diagnosis. Methods. Gene chip data sets containing samples from acute liver injury induced by sepsis and control groups (GSE22009 and GSE60088) were selected from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) with |log fold change| >1 and p<0.05 were screened with the GEO2R tool, which was also used for the selection of upregulated DEGs in the chips with p<0.05. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, Gene Ontology, and protein-protein interaction (PPI) analyses were then conducted. Results were visualized using R language packages, including volcano plots, Venn diagrams, and boxplots. The intersection of candidate genes with relevant genes in the Comparative Toxicogenomics Database (CTD) was performed, and the clinical significance of these genes was explored through a literature review. A rat model of acute liver injury was developed by inducing sepsis with the cecum ligation and puncture method. Real-time PCR was performed to determine the gene expression in rat liver tissues. Results. A total of 646 upregulated DEGs were determined in GSE22009 and 146 in GSE60088. A Venn diagram was used to find the intersection of the upregulated DEGs between the two data sets, and 67 DEGs associated with sepsis-mediated acute liver damage were obtained. Enrichment analysis from the KEGG pathway showed that DEG upregulation was primarily associated with various pathways: TNF, NF-κB, IL-17, ferroptosis, mTOR, and JAK-STAT signaling pathways. DEGs resulted in three clusters and 15 candidate genes, as revealed by the PPI network and module analyses. Intersection with sepsis-induced acute liver injury-related genes in the CTD resulted in the identification of three significant differentially co-expressed genes: CXCL1, ICAM1, and TNFRSF1A. Sepsis-induced liver tissue indicated the overexpression of CXCL1, ICAM1, and TNFRSF1A mRNA, as compared with the control group (p<0.05). Conclusion. The key genes identified and related signaling pathways provided insights into the molecular mechanisms of sepsis-induced acute liver injury. In vivo studies revealed the overexpression of CXCL1, ICAM1, and TNFRSF1A mRNA in sepsis-mediated injured liver tissues, providing a theoretical basis for early diagnosis and targeted treatment research
- PublicationOpen AccessClinicopathological and molecular features of genome-stable colorectal cancers(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2025) Jin, Lingyan; Jin, Hye Yeong; Kim, Younghoon; Cho, Nam Yun; Bae, Jeong Mo; Kim, Jung Ho; Han, Sae Won; Kim, TaeYou; Kang, Gyeong HoonColorectal cancers (CRCs) are traditionally divided into those with either chromosomal instability (CIN) or microsatellite instability (MSI). By utilizing TCGA data, the Laird team found a subset of CRCs, namely, genome-stable CRCs (GS CRCs), which lack both CIN and MSI. Although the molecular features of GS CRCs have been described in detail, the clinicopathological features are not well defined. A total of 437 CRCs were analyzed for copy number variation (CNV) statuses in eight genes (ARID1A, EGFR, FGFR1, KDM5B, MYBL2, MYC, SALL4, and SETDB1) using droplet-digital PCR. CRCs that showed CNV in ≤ one gene and no MSI were defined as GS-like CRCs. Clinicopathological and molecular features of GS-like CRCs were compared with those of CIN-like CRCs. GS-like CRCs comprised 4.6% of CRCs and showed a predilection toward the proximal colon, lower nuclear optical density, KRAS mutation, PIK3CA mutation, and aberrant expression of KRT7. Survival analysis showed no significant difference between the three subgroups. Through our study, the GS-like subtype was found to comprise a minor proportion of CRCs and have proclivity toward a proximal bowel location, hypochromatic tumor nuclei, aberrant KRT7 expression, and a high frequency of KRAS and PIK3CA mutations.
- PublicationOpen AccessRole of acupuncture in improving the outcome of sepsis-induced lung injury(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2025) Li, Peng; Li, Fangfang; Chen, Si; Ma, Qiulei; Wang, Jie; Ma, Bingquan; Xu, JinObjective. The purpose of this study was to investigate the effect of serum exosomes of mice after acupuncture (acu-exo) on acute lung injury (ALI) in sepsis in vitro and in vivo. Methods. Serum exosomes (acu-exo) of normal mice were prepared after acupuncture. Lipopolysaccharide (LPS) was used to establish the model of ALI in vivo and in vitro. Immunohistochemistry, western blot, and immunofluorescence were used to evaluate the mechanism of acu-exo on ALI. P2X7 knockout mice and P2X7 siRNA were used to verify the mechanism. Results. Compared with normal mice, serum exosomes were significantly increased in normal mice after acupuncture. The results showed that P2X7 was increased in the lung of septic mice as compared with the WT group. It was also found that the increase in NLRP3 and NF-κB was accompanied by the activation of P2X7. Increased P2X7 led to activation of the P2X7 receptor causing mitochondrial dysfunctions in lung tissue of septic mice. Knockout of P2X7 or silenced P2X7 markedly decreased NLRP3 and NF-κB and led to mitochondrial function recovery in lung tissue of sepsis. At the same time, acu-exo significantly restored the above changes in the lung tissue of septic mice. Conclusions. Inhibition of P2X7 led to mito-chondrial function recovery of lung tissue by inhibiting NLRP3 and NF-κB. At the same time, acu-exo could improve ALI by decreasing NLRP3 and NF-κB activation
- PublicationOpen AccessElectroacupuncture pretreatment inhibits ferroptosis and inflammation after middle cerebral artery occlusion in rats by activating Nrf2(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2025) Pu, Yanpeng; Cheng, Jingyan; Wang, Zhenya; Zhang, Jingbo; Liang, Fajun; Zhang, Xianbao; Zheng, Zhijun; Yin, Miaomiao; Wang, ZhenObjective. Electroacupuncture (EA) pretreatment can effectively increase the tolerance of the brain to ischemic stroke. The mechanism of ischemic tolerance induced by EA is related to Nrf2, but its specific mechanism has not been elucidated. This paper was designed to explore the effect of EA pretreatment on brain injury and the related mechanisms. Methods. Rats were pretreated with EA before middle cerebral artery occlusion (MCAO) modeling. The symptoms of neurological deficit and the volume of cerebral infarction were measured. The levels of inflammatory factors, oxidative stress-related factors, LPO, ROS, and Fe2+ were evaluated by the corresponding kits. Cell apoptosis was determined through TUNEL staining. The mRNA expression of inflammatory factors was examined by RT-qPCR, and the protein expression of ferroptosis-related factors, pyroptosis-related proteins, Keap1, Nrf2, HO-1, and NQO1 by western blotting. Results. EA pretreatment improved the symptoms of neurological deficit and reduced the volume of cerebral infarction. EA pretreatment significantly inhibited oxidative stress, inflammatory response, ferroptosis, pyroptosis, and apoptosis in brain tissues of MCAO rats. Mechanistically, EA pretreatment could activate Nrf2 expression and reduce Keap1 expression. Conclusion. EA pretreatment reduced inflammation and oxidative stress and inhibited ferroptosis by activating Nrf2 expression, ultimately delaying the development of ischemic stroke.
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