Histology and histopathology Vol.33, nº1 (2018)
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- PublicationOpen AccessCisplatin induced apoptosis of ovarian cancer A2780s cells by activation of ERK/p53/PUMA signals(Universidad de Murcia. Departamento de Biología Celular e Histología, 2018) Song, Hao; Wei, Mei; Liu, Wenfen; Shen, Shulin; Li, Jiaqun; Wang, LimingCisplatin (CDDP) is one of the most effective anticancer agents widely used in the treatment of solid tumors, including ovarian cancer. It is generally considered as a cytotoxic drug which kills cancer cells by causing DNA damage, and subsequently inducing apoptosis in cancer cells. However, the underlying mechanisms leading to cell apoptosis remain obscure. In this study, the signaling pathways involved in CDDPinduced apoptosis were examined using CDDP-sensitive ovarian cancer A2780s cells. A2780s cells were treated with CDDP (1.5-3 μg/ml) for 6h, 12h and 24h. Using siRNA targeting P53 and PUMA, and a selective MEK inhibitor, PD98059 to examine the relation between ERK1/2 activation, p53 and PUMA expression after exposure to CDDP, and the effect on CDDP-induced apoptosis. The results shown that treatment of A2780s cells with CDDP (3 μg/ml) for 6-24h induced apoptosis, resulting in the activation of extracellular signalregulated kinase 1/2 (ERK1/2) and accumulation of p53 and PUMA (p53 upregulated modulator of apoptosis) protein. Knockdown of P53 or PUMA by siRNA transfection blocked CDDP-induced apoptosis. Inhibition of ERK1/2 using PD98059, a selective MEK inhibitor, blocked the apoptotic cell death but prevented CDDP-induced accumulation of p53 and PUMA. Knockdown of P53 by siRNA transfection also blocked CDDP-induced accumulation of PUMA. We therefore concluded that CDDP activated ERK1/2 and inducedp53-dependent PUMA upregulation, resulting in triggering apoptosis in A2780s cells. Our study clearly demonstrates that the ERK1/2/p53/PUMA axis is related to CDDP-induced cell death in A2780s cells.
- PublicationOpen AccessZoledronate promotes bone formation by blocking osteocyte-osteoblast communication during bone defect healing(Universidad de Murcia. Departamento de Biología Celular e Histología, 2018) Cui, Pingping; Liu, Hongrui; Sun, Jing; Amizuka, Norio; Sun, Qinfeng; Li, MinqiNitrogen-containing bisphosphonates (NBPs) are potent antiresorptive drugs and their actions on osteoclasts have been studied extensively. Recent studies have suggested that N-BPs also target bone-forming cells. However, the precise mechanism of N-BPs in osteoblasts is paradoxical, and the specific role of osteocytes is worthy of in-depth study. Here, we investigated the cellular mechanisms of N-BPs regulating bone defect healing by zoledronate (ZA). Bone histomorphometry confirmed an increase in new bone formation by systemic ZA administration. ZA induced more alkaline phosphatase-positive osteoblasts and tartrate-resistant acid phosphatase-positive osteoclasts residing on the bone surface. Inexplicably, ZA increased SOST expression in osteocytes embedded in the bone matrix, which was not compatible with the intense osteoblast activity on the bone surface. ZA induced heterogeneous osteocytes and disturbed the distribution of the osteocytic-canalicular system (OLCS). Furthermore, according to the degree of OLCS regularity, dentin matrix protein 1 reactivity had accumulated around osteocytes in the ZA group, but it was distributed evenly in the OLCS of the control group. The control group showed a dense array of the gap junction protein connexin 43. However, connexin 43 was extremely sparse after ZA administration. In summary, ZA treatment reduces gap junction connections and blocks cellular communication between osteocytes and osteoblasts. Retaining SOST expression in osteocytes leads to activation of the Wnt signaling pathway and subsequent bone formation.
- PublicationOpen AccessMorphological alterations in the hippocampus of the Ts65Dn mouse model for Down syndrome correlate with structural plasticity markers(Universidad de Murcia. Departamento de Biología Celular e Histología, 2018) Villarroya, Olga; Ballestín, Raúl; López Hidalgo, Rosa; Mulet, Maria; Blasco Ibáñez, José Miguel; Crespo, Carlos; Nacher, Juan; Gilabert Juan, Javier; Varea, EmilioDown syndrome (DS) is the most common chromosomal aneuploidy. Although trisomy on chromosome 21 can display variable phenotypes, there is a common feature among all DS individuals: the presence of intellectual disability. This condition is partially attributed to abnormalities found in the hippocampus of individuals with DS and in the murine model for DS, Ts65Dn. To check if all hippocampal areas were equally affected in 4-5 month adult Ts65Dn mice, we analysed the morphology of dentate gyrus granule cells and cornu ammonis pyramidal neurons using Sholl method on Golgi-Cox impregnated neurons. Structural plasticity has been analysed using immunohistochemistry for plasticity molecules followed by densitometric analysis (Brain Derived Neurotrophic Factor (BDNF), Polysialylated form of the Neural Cell Adhesion Molecule (PSA-NCAM) and the Growth Associated Protein 43 (GAP43)). We observed an impairment in the dendritic arborisation of granule cells, but not in the pyramidal neurons in the Ts65Dn mice. When we analysed the expression of molecules related to structural plasticity in trisomic mouse hippocampus, we observed a reduction in the expression of BDNF and PSA-NCAM, and an increment in the expression of GAP43. These alterations were restricted to the regions related to dentate granule cells suggesting an interrelation. Therefore the impairment in dendritic arborisation and molecular plasticity is not a general feature of all Down syndrome principal neurons. Pharmacological manipulations of the levels of plasticity molecules could provide a way to restore granule cell morphology and function.
- PublicationOpen AccessMitotic index matter: how to improve the assessment of mitosis in order to better classify G2 breast cancer and luminal A category(Universidad de Murcia. Departamento de Biología Celular e Histología, 2018) del Sordo, Rachele; Ferri, Ivana; Pireddu, Anjuta; Colella, Renato; Sidoni, AngeloG2 ductal infiltrating carcinomas are a heterogeneous group of tumours with ambiguous clinical significance. This is because G2 carcinomas are almost always the largest category and poorly reproducible. Mitotic count (MC) is one of the causes of poor histological grading reproducibility. The phosphoistone H3 (PPH3) antibody improves identification of mitotic figures. The aim of our study is to demonstrate whether using a new histological grading system based on PPH3 immunostaining to assess MC can re-stratify G2 category. We selected 100 cases of G2 invasive carcinoma. The mitotic score was accurately reevaluated performing MC on PPH3 immunostained sections. 21/100 G2 cases (21%) showed the same mitotic score both with hematoxilin and eosin (H&E) and PPH3 while 79 cases (79%) with PPH3 shifted to a higher mitotic score. After re-grading the 100 G2 cases based on the assessment of mitotic score with PPH3 only 53 cases (53%) were confirmed as G2, while 47 cases (47%) had shifted to G3. Finally we reclassified early tumours in the surrogate molecular subtype according to the 2013 St. Gallen Conference criteria and found that 13/40 cases (33%) classified as luminal A were G3 with the PPH3 mitotic score and could benefit from chemotherapy. In conclusion, PPH3 improving MC gives a better categorization by halving the G2 group. In particular, applied to the surrogate subtype luminal A breast cancer it identified cases that could benefit from adjuvant cytotoxic chemotherapy.
- PublicationOpen AccessThe role of endothelial lipase in lipid metabolism, inflammation and cancer(Universidad de Murcia. Departamento de Biología Celular e Histología, 2018) Yu, Justine E; Han, Shu Yan; Wolfson, Benjamin; Zhou, QunEndothelial lipase (LIPG) plays a critical role in lipoprotein metabolism, cytokine expression, and the lipid composition of cells. Thus far, the extensive investigations of LIPG have focused on its mechanisms and involvement in metabolic syndromes such as atherosclerosis. However, recent developments have found that LIPG plays a role in cancer. This review summarizes the field of LIPG study. We focus on the role of LIPG in lipid metabolism and the inflammatory response, and highlight the recent insights in its involvement in tumor progression. Finally, we discuss the potential of targeting LIPG in therapeutic strategies.