Histology and histopathology Vol.33, nº2 (2018)
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- PublicationOpen AccessTopically applied azaphenothiazines inhibit contact sensitivity to oxazolone in mice(Universidad de Murcia. Departamento de Biología Celular e Histología, 2018) Artym, Jolanta; Kocięba, Maja; Zaczyńska, Ewa; Zimecki, Michał; Jeleń, Małgorzata; Morak Młodawska, Beata; Pluta, Krystian; Kaleta Kuratewicz, Katarzyna; Madej, Jan P.; Kuropka, Piotr; Kuryszko, JanIn this work we investigated the efficacy of two topically applied azaphenothiazine derivatives, 9- c h l o r o - 6 - a c e t y l ami n o b u t y l q u i n o b e n z o [ 3 , 2 - b][1,4]thiazine (compound 4) and 6-chloroethylureidoethyldiquino[3,2-b;2’;3’-e][1,4]thiazine (compound 5), in the amelioration of inflammatory symptoms of contact sensitivity (CS) to oxazolone in mice, in relation to the commercial ointment Protopic® (tacrolimus), the reference drug. The compounds were administered 24 h following elicitation of CS and, 24 h later, the parameters of inflammation, such as ear edema, blood composition, leukocyte level, numbers of cells in the draining lymph nodes, histological picture of the inflamed tissue, and the morphometric analysis, were analyzed. The study showed that the effectiveness of the studied azaphenothiazines applied as a 0.1% ointment was comparable to the reference drug regarding suppression of the inflammatory process, when all the investigated histological parameters are taken into account.
- PublicationOpen AccessTime-dependent and lesion-dependent HMGB1-selective localization in brains of patients with cerebrovascular diseases(Universidad de Murcia. Departamento de Biología Celular e Histología, 2018) Umahara, Takahiko; Uchihara, Toshiki; Hirokawa, Katsuiku; Hirao, Kentaro; Shimizu, Soichiro; Hashimoto, Takao; Terasi, Hiroo; Hanyu, HaruoHigh mobility group box 1 protein (HMGB1) has multiple functions, including the maintenance of nucleosomes and the regulation of gene transcription. HMGB1 is released from activated macrophages, resulting in the induction of inflammatory cytokines. Recently, much research about the role of HMGB1 in cerebrovascular disease (CVD) has been reported. In an animal model, HMGB1 neutralization ameliorates brain infarction, there is an early release of HMGB1 from neurons, and HMGB1 antibody attenuates delayed cerebral vasospasm in experimental subarachnoid hemorrhage. It was also reported that elevation of HMGB1 in serum correlates with severity of acute intracerebral hemorrhage. However, the evidence of HMGB1 localization in brains of patients with CVD is very limited. Therefore, we investigated at autopsy the immunolocalization of HMGB1 in brains of patients with CVD (acute and chronic cerebral infarction, acute cerebral hemorrhage, subarachnoid hemorrhage). In 3 out of 10 acute cerebral infarction cases, the cytoplasm of neurons located around the ischemic core (i.e., penumbra) was positive for HMGB1. In the chronic stage of cerebral infarction, macrophages located in some ischemic regions were positive for HMGB1. Around the hematoma in the basal ganglia, HMGB1-like immunoreactivity (IR) was intense in macrophages. However, around the subarachnoid hematoma, HMGB1- like IR was not seen in the cortex. In arteries surrounded by subarachnoid hematoma, HMGB1-like IR was located in the cytoplasm of vascular smooth muscle cells. These findings, which partially differ from animal model results, may provide translational research and a basis for understanding the role of HMGB1 in brains of patients with CVD.
- PublicationOpen AccessThe role of tumor-associated macrophage in breast cancer biology(Universidad de Murcia. Departamento de Biología Celular e Histología, 2018) Choi, Junjeong; Gyamfi, Jones; Jang, Haerin; Koo, Ja SeungBreast cancer is the most commonly diagnosed malignant tumor in women worldwide and contributes significantly as the primary cause of female cancer related mortality. Hence, research is focused on discovering new and effective treatment targets. The breast tumor microenvironment (TME) comprising of recruited host stromal cells and tumor cells, has recently emerged as an important player in tumor progression, with the potential for future treatment. The TME comprises immune system elements (such as macrophages and lymphocytes), cells composing blood vessel, fibroblast, myofibroblast, mesenchymal stem cells, adipocytes and extracellular matrix (ECM). Among these cells, tumor-associated macrophages (TAM) are the prominent components of TME in breast cancers. Macrophages exhibit a high plasticity in response to various external signals and participate in innate and adoptive immune responses to control numerous factors of TME. Depending on the microenvironmental signal present, macrophages are polarized into two distinct phenotypes, the classically activated (M1) or the alternative activated (M2) macrophages. Tumor-associated macrophages (TAMs) closely resemble the M2-polarized. Clinicopathological studies have suggested that TAM accumulation in tumors correlates with a poor clinical outcome. In human breast carcinomas, high TAM density correlates with poor prognosis. Over the years, studies into the role of TAMs in breast cancer progression have identified TAMs to be capable of inducing angiogenesis, remodelling the tumor extracellular matrix to aid invasion, modelling breast cancer cells to evade host immune system and recruiting immunosuppressive leukocytes to the tumor microenvironment. Along with these functions, the potential role for TAMs in activation of breast cancer stem cells (CSC) has also emerged. Thus, TAMs in breast cancer can enhance cancer cell invasion by degrading the ECM, stimulate tumor vascularization and angiogenesis and suppress the antitumor functions of cytotoxic T cells resulting in poor prognosis for patients. These observations make TAMs an attractive target for therapeutic intervention by targeting various aspects of their function. This review discusses the mechanisms responsible for TAM recruitment and highlights the roles of TAMs in regulating tumor angiogenesis, invasion, metastasis, immunosuppression, and chemotherapeutic resistance. Finally, the potential for TAM-targeted therapy as a promising novel strategy is also discussed.
- PublicationOpen AccessMicroRNAs regulate APOBEC gene expression(Universidad de Murcia. Departamento de Biología Celular e Histología, 2018) Cao, Wei; Wu, WeiApolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) is a family of evolutionarily conserved cytidine deaminases, encoded by eleven genes located in the human genome. APOBECs play key roles in innate immunity through their ability to mutagenize viral DNA and restrict viral replication. Recent cancer genomics revealed APOBEC3 subtype-mediated APOBEC-signature mutations are common in a broad spectrum of human cancers. The pervasive APOBEC3 activation in the host genome which converts cytosine to uracile during RNA editing has been suggested to depend on ATR/chk1 pathways. In this review, we highlight how microRNAs interact with the APOBEC gene family and post-transcriptionally regulate APOBEC gene expression, and we speculate how targeting specific microRNAs may reduce host genome mutagenesis via inactivation of APOBEC deaminases.
- PublicationOpen AccessIn vitro differentiation of primordial germ cells and oocyte-like cells from stem cells(Universidad de Murcia. Departamento de Biología Celular e Histología, 2018) Costa, José J.N.; Souza, Glaucinete B.; Soares, Maria A.A.; Ribeiro, Regislane P.; van den Hurk, Robert; Silva, José R.V.Infertility is the result of failure due to an organic disorder of the reproductive organs, especially their gametes. Recently, much progress has been made on generating germ cells, including oocytes, from various types of stem cells. This review focuses on advances in female germ cell differentiation from different kinds of stem cells, with emphasis on embryonic stem cells, adult stem cells, and induced pluripotent stem cells. The advantages and disadvantages of the derivation of female germ cells from several types of stem cells are also highlighted, as well as the ability of stem cells to generate mature and functional female gametes. This review shows that stem cell therapies have opened new frontiers in medicine, especially in the reproductive area, with the possibility of regenerating fertility.
- PublicationOpen AccessToxicity of malathion at early life stages of the Senegalese sole, Solea senegalensis (Kaup, 1858): notochord and somatic disruptions(Universidad de Murcia. Departamento de Biología Celular e Histología, 2018) Ortiz Delgado, Juan B.; Scala, Emanuele; Arellano, Juana M.; Úbeda Manzanaro, María; Sarasquete, CarmenThe toxicity of malathion to Solea senegalensis was studied in a static renewal bioassay for 24, 48 and 72 h, with toxicant concentrations ranging from 1.56 until 100 µgL-1. The LC50 values of malathion for 48 and 72-h was 63.5 (95% C.I: 50.83-79.34) and 22.94 (95% C.I: 17.16-30.68) µgL-1 respectively. The survival of larvae was non-affected by exposure to malathion at concentrations up to 25 µgL-1 (24 h NOEC), 6.25 µgL-1 (48 h NOEC) and <1.6 µgL-1 (72 h NOEC). At the end of the experiment, surviving larvae from concentrations smaller than the 72h-LC50 were chosen to study morphological changes during malathion exposure. Results revealed a strong disruption in the notochord and trunk musculature integrity as a result of toxicant exposure. Noticeable changes in the composition and reduction of collagen fibers from the perinotochordal connective sheath and perimysium were clearly detected. The trunk musculature was also altered, showing a general disorganization of fibers. Moreover, malathion exposure provoked pericardial and yolk-sac oedemas and histopathological alterations in some other organ- systems and tissues (i.e. liver, pancreas, intestine).
- PublicationOpen AccessMembranes derived from human umbilical cord Wharton's jelly stem cells as novel bioengineered tissue-like constructs(Universidad de Murcia. Departamento de Biología Celular e Histología, 2018) Jaimes Parra, B.D.; Garzon, I.; Carriel, V.; Durand Herrera, D.; Martín Piedra, M.A.; García, J.M.; Sánchez Quevedo, M.C.; Alaminos, M.; Campos, A.Cell-derived matrices were recently described as novel biomaterials generated by human cells allowed to grow and synthetize their own extracellular matrix in culture. In the present work, we generated and evaluated a novel tissue-like substitute (WDM) consisting of a membrane derived from cultured human Wharton’s jelly stem cells. WDM were evaluated ex vivo and in vivo by histochemistry and immunohistochemistry for several mesenchymal cell markers and fibrillar and non-fibrillar extracellular matrix components. Results show that WDM were heterogeneous and consisted of dense cell-poor areas surrounded by cell-rich zones with abundant HWJSC. Histological analyses demonstrated that cell-poor areas were very rich in fibrillar and non-fibrillar extracellular matrix components such as collagen and proteoglycans, and cells in the WDM were highly viable and mostly PCNA-positive. HWJSC in the WDM expressed all markers of this cell type, including CD90, CD105, pan cytokeratin and CK8. In vivo analysis showed that the WDM was highly biocompatible and grafting this membrane in the muscle of laboratory rats was not associated to increased inflammation, necrosis, tumorigenesis or other side effects, while cells properly integrated at the damage site and showed high proliferation index. These results suggest that the structure and composition of the extracellular matrix of these novel WDM could reproduce the situation of native human tissues and that WDM implanted in vivo are highly biocompatible and rapidly integrate in the host tissues. For these reasons, we hypothesize that WDM could be used in regenerative medicine protocols.
- PublicationOpen AccessExpression of p53 and selected proliferative markers (Ki-67, MCM3, PCNA, and topoisomerase IIα) in borderline ovarian tumors: Correlation with clinicopathological features(Universidad de Murcia. Departamento de Biología Celular e Histología, 2018) Ciepliński, Klaudiusz; Jóźwik, Maciej; Semczuk Sikora, Anna; Gogacz, Marek; Lewkowicz, Dorota; Ignatov, Atanas; Semczuk, AndrzejBackground. The expression of p53 has been studied not only in primary human ovarian carcinomas, but also in borderline ovarian tumors, however, the results were discordant. Expression patterns of proteins involved in cell proliferation and apoptosis have been investigated in various human neoplasms, including female genital tract neoplasms. Objective. The aim of this investigation was to assess the staining pattern and immunolocalization of p53 and selected proliferative markers (Ki-67, MCM3, PCNA, and topoisomerase IIα) in borderline ovarian tumors (BOTs). Design. The study group consisted of 42 women who underwent pelvic surgery between 2006-2015. The median patients’ age was 46 years. The immunoperoxidase technique was employed using antibodies against p53, Ki-67, MCM3, PCNA, and topoisomerase IIα. Results. For p53, nuclear expression was observed in BOTs, however, cytoplasmatic immunoreactivity was also detected. Altogether, 25 (60%) tumors demonstrated positive p53 immunostaining, including overexpression found in 6 (14%). There were no significant differences in p53 expression between subgroups of clinicopathological variables. Immunoexpression of Ki-67, MCM3, PCNA, and topoisomerase IIα was nuclear. Ki67 expression was positive in 12 (29%) cases and there was a trend towards a relationship between patients’ age and Ki-67 staining (P=0.08). Interestingly, a significantly higher Ki-67 expression was found in tumors of ≥10 cm in diameter compared to smaller tumors (P=0.008). MCM3 expression was detected in 38 (90%) tumors, and PCNA expression in 28 (67%), yet none of clinico-pathological factors was related to them. Topoisomerase IIα expression was present in 14 (33%) cases and, interestingly, its significantly higher expression was observed in BOTs of ≥10 cm in diameter compared to smaller tumors (P=0.008). Moreover, Spearman’s correlation revealed highly significant positive associations between Ki-67 and topoisomerase IIα (R=0.403, P=0.008) and Ki-67 and MCM3 (R=0.469, P=0.001). Conclusions. We report a high positive immunostaining rate for p53, suggesting a role of TP53 alterations in the development of BOTs in humans. The new finding of higher topoisomerase IIα immunostaining positivity in BOTs of ≥10 cm may be clinically relevant and requires further studies on larger patient groups.
- PublicationOpen AccessA qualitative comparison of ten tissue clearing techniques(Universidad de Murcia. Departamento de Biología Celular e Histología, 2018) Orlich, Michael; Kiefer, FriedemannThe understanding of spatially complex biological systems is greatly aided by the availability of high resolution information on their tissue architecture, as is provided by optical sectioning microscopy like confocal and light sheet microscopy. In addition, genetically encoded fluorescent reporter proteins reveal tissue architecture without the need for staining procedures. Owing to opacity caused by scattering and absorption, light microscopy in tissue is limited to thin tissue layers of a few micrometers traditionally provided by histological sections. Aiming to allow deeper imaging, during the last decade massive efforts to develop tissue clearing protocols produced a flurry of novel clearing techniques for whole organ visualization, now available to microscopists. In particular, new tissue clearing methods were developed that avoid the use of organic solvents, aiming to retain the integrity of genetically encoded fluorescent proteins. So far, these methods have not been directly compared and selection of the right technique can be a non-trivial task. Here, we have aimed to compare different tissue clearing approaches side by side in a standardized manner. We provide qualitative data on their clearing capability of mouse brain, lung, heart, kidney and muscle, as well as embryos and fetuses at the developmental stages E10.5, E12.5 and E15.5 and discuss possible applications.
- PublicationOpen AccessImmunohistochemical expression profiles of mucin antigens in salivary gland mucoepidermoid carcinoma: MUC4- and MUC6-negative expression predicts a shortened survival in the early postoperative phase(Universidad de Murcia. Departamento de Biología Celular e Histología, 2018) Honjo, Kie; Hiraki, Tsubasa; Higashi, Michiyo; Noguchi, Hirotsugu; Nomoto, Mitsuharu; Yoshimura, Takuya; Batra, Surinder K.; Yonezawa, Suguru; Semba, Ichiro; Nakamura, Norifumi; Tanimoto, Akihide; Yamada, SohsukeIn mucoepidermoid carcinoma (MEC), the most common salivary gland carcinoma, there is a lack of novel prognostic markers, but post-operative early recurrence strongly affects the clinical course and a poor outcome. It is critical to predict which MEC patients are prone to develop recurrence/metastases. Mucins play pivotal roles in influencing cancer biology, thus affecting cell differentiation, adhesion, carcinoma invasion, aggressiveness and/or metastatic potential. Our aim is to elucidate the significance of expression profiles for mucins, particularly MUC4 and MUC6, and their correlations with various clinicopathological features and recurrence in salivary gland MECs. We performed immunohistochemical analyses on patients with surgically resected primary MEC using antibodies against mucin core proteins MUC4/8G7 and MUC6/CLH5 in 73 paraffin-embedded samples. Recurrence was noted in 15 of 73 (20.5%) patients. MUC4 or MUC6 expression was considered to be negative when <30% or 0% of the MEC cells showed positive staining, respectively. MUC4- and/or MUC6- negative expression respectively and variably showed a significant relationship to pathological tumor high-grade, the presence of lymphovascular invasion, lymph node metastasis and/or tumor-related death. In addition, MUC4 showed significantly negative co-expression with MUC6. Kaplan-Meier analyses revealed that not only single MUC4/6-negative expression but also the combination of both predicted significantly shorter disease-free and disease-specific survivals in MECs, especially within the first two years postoperatively. Therefore, each mucin plays a pivotal role in the pathogenesis of MEC progression. The detection of MUC4 and/or MUC6 might be a powerful parameter in the clinical management of MECs in the early postsurgical phase.