Yaron Gil, Asia Zubkov, Jacques Balayla, Aviad Cohen, Ishai Levin
Methotrexate administration for the treatment of tubal ectopic pregnancies has been shown to cause tubal mass enlargement. Our hypothesis was that, by administrating Methotrexate, a local necrotic reaction occurs, leading to hematoma formation and eventually fallopian tube rupture. Salpingectomy specimens were collected, analysed and divided into three equal groups: patients who received Methotrexate but who ultimately failed medical treatment, patients who had a viable ectopic pregnancy and patients with a self-resolving ectopic pregnancy that were operated due to other medical indications. The specimens were dyed using the Cleaved Caspase-3 (Asp175) Rabbit mA. Specimens were divided into three equal groups and analysed. The patients in self-resolving ectopic pregnancy group were older and had more pregnancies. Rates of apoptosis were found to be less than 1% per slide. Necrosis was not evident in any of the pathological specimens. It seems Methotrexate administration does not lead to a significant tubal necrotic reaction. Further studies are required.
{"title":"Apoptosis versus necrosis in tubal ectopic pregnancies following Methotrexate","authors":"Yaron Gil, Asia Zubkov, Jacques Balayla, Aviad Cohen, Ishai Levin","doi":"10.1111/iep.12465","DOIUrl":"10.1111/iep.12465","url":null,"abstract":"<p>Methotrexate administration for the treatment of tubal ectopic pregnancies has been shown to cause tubal mass enlargement. Our hypothesis was that, by administrating Methotrexate, a local necrotic reaction occurs, leading to hematoma formation and eventually fallopian tube rupture. Salpingectomy specimens were collected, analysed and divided into three equal groups: patients who received Methotrexate but who ultimately failed medical treatment, patients who had a viable ectopic pregnancy and patients with a self-resolving ectopic pregnancy that were operated due to other medical indications. The specimens were dyed using the Cleaved Caspase-3 (Asp175) Rabbit mA. Specimens were divided into three equal groups and analysed. The patients in self-resolving ectopic pregnancy group were older and had more pregnancies. Rates of apoptosis were found to be less than 1% per slide. Necrosis was not evident in any of the pathological specimens. It seems Methotrexate administration does not lead to a significant tubal necrotic reaction. Further studies are required.</p>","PeriodicalId":14157,"journal":{"name":"International Journal of Experimental Pathology","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2023-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/iep.12465","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9472086","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Charly Jehanno, Yann Le Page, Gilles Flouriot, Pascale Le Goff, Denis Michel
By depriving cancer cells of blood supplies of oxygen and nutrients, anti-angiogenic therapy is aimed at simultaneously asphyxiating and starving the cells. But in spite of its apparent logic, this strategy is generally counterproductive over the long term as the treatment seems to elicit malignancy. Since a defect of blood supply is expected to deprive tumours simultaneously of oxygen and nutrients naturally, we examine here these two deprivations, alone or in combination, on the phenotype and signalling pathways of moderately aggressive MCF7 cancer cells. Each deprivation induces some aspects of the aggressive and migratory phenotypes through activating several pathways, including HIF1-alpha as expected, but also SRF/MRTFA and TCF4/beta-catenin. Strikingly, the dual deprivation has strong cooperative effects on the upregulation of genes increasing the metastatic potential, such as four and a half LIM domains 2 (FHL2) and HIF1A-AS2 lncRNA, which have response elements for both pathways. Using anti-angiogenic agents as monotherapy is therefore questionable as it may give falsely promising short-term tumour regression, but could ultimately exacerbate aggressive phenotypes.
{"title":"Synergistic activation of genes promoting invasiveness by dual deprivation in oxygen and nutrients","authors":"Charly Jehanno, Yann Le Page, Gilles Flouriot, Pascale Le Goff, Denis Michel","doi":"10.1111/iep.12464","DOIUrl":"10.1111/iep.12464","url":null,"abstract":"<p>By depriving cancer cells of blood supplies of oxygen and nutrients, anti-angiogenic therapy is aimed at simultaneously asphyxiating and starving the cells. But in spite of its apparent logic, this strategy is generally counterproductive over the long term as the treatment seems to elicit malignancy. Since a defect of blood supply is expected to deprive tumours simultaneously of oxygen and nutrients naturally, we examine here these two deprivations, alone or in combination, on the phenotype and signalling pathways of moderately aggressive MCF7 cancer cells. Each deprivation induces some aspects of the aggressive and migratory phenotypes through activating several pathways, including HIF1-alpha as expected, but also SRF/MRTFA and TCF4/beta-catenin. Strikingly, the dual deprivation has strong cooperative effects on the upregulation of genes increasing the metastatic potential, such as four and a half LIM domains 2 (FHL2) and HIF1A-AS2 lncRNA, which have response elements for both pathways. Using anti-angiogenic agents as monotherapy is therefore questionable as it may give falsely promising short-term tumour regression, but could ultimately exacerbate aggressive phenotypes.</p>","PeriodicalId":14157,"journal":{"name":"International Journal of Experimental Pathology","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2023-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/iep.12464","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9125897","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sepsis remains a worldwide public health problem. This study aims to explore the role and mechanism of transcriptional factors (TFs) in sepsis-induced myocardial injury. Firstly, TF KLF13 was selected to explore its role in sepsis-induced myocardial injury. The caecal ligation and puncture (CLP) -induced sepsis mouse model was established and the septic mice were examined using standard histopathological methods. KLF13 expression was detected in the septic mouse heart and was also seen in a lipoploysaccharide (LPS) -induced cellular inflammation model. To explore this further both pro-apoptotic cleaved-caspase3/caspase3 and Bax levels and anti-apoptotic Bcl2 levels were examined, also in both models, In addition inflammatory cytokine (IL-1β, TNF-α, IL-8 and MCP-1) production and IκB-α protein level and p65 phosphorylation were examined in both septic mice and LPS-induced cells. Thus three parameters - cardiomyocyte apoptosis, inflammatory response and NF-κB pathway activation were evaluated under similar conditions. The septic mice showed significant oedema, disordered myofilament arrangement and degradation and necrosis to varying degrees in the myocardial cells. KLF13 was downregulated in both the septic mouse heart and the LPS-induced cellular inflammation model. Furthermore, both models showed abnormally increased cardiomyocyte apoptosis (increased cleaved-caspase3/caspase and Bax protein levels and decreased Bcl2 level), elevated inflammation (increased production of inflammatory cytokines) and the activated NF-κB pathway (increased p65 phosphorylation and decreased IκB-α protein level). KLF13 overexpression notably ameliorated sepsis-induced myocardial injury in vivo and in vitro. KLF13 overexpression protected against sepsis-induced myocardial injury and LPS-induced cellular inflammation and apoptosis via inhibiting the inflammatory pathways (especially NF-κB signalling) and cardiomyocyte apoptosis.
脓毒症仍然是一个全球性的公共卫生问题。本研究旨在探讨转录因子(tf)在脓毒症心肌损伤中的作用及机制。首先选取TF KLF13,探讨其在脓毒症致心肌损伤中的作用。建立盲肠结扎穿刺(CLP)致脓毒症小鼠模型,采用标准组织病理学方法对脓毒症小鼠进行检查。在脓毒症小鼠心脏中检测到KLF13表达,在脂多糖(LPS)诱导的细胞炎症模型中也可见到KLF13表达。为了进一步探讨这一点,我们检测了两种模型中促凋亡的caspase3/caspase3和Bax水平以及抗凋亡的Bcl2水平,此外,我们检测了脓毒症小鼠和lps诱导的细胞中炎症因子(IL-1β、TNF-α、IL-8和MCP-1)的产生以及i- κ b -α蛋白水平和p65磷酸化。因此,在类似的条件下,心肌细胞凋亡、炎症反应和NF-κ b通路激活三个参数被评估。脓毒症小鼠心肌细胞明显水肿,肌丝排列紊乱,不同程度降解坏死。在脓毒症小鼠心脏和lps诱导的细胞炎症模型中,KLF13均下调。此外,两种模型均表现出心肌细胞凋亡异常增加(cleaved-caspase3/ caspasase和Bax蛋白水平增加,Bcl2蛋白水平降低),炎症升高(炎症细胞因子产生增加)和NF-κB通路激活(p65磷酸化增加,i -κB -α蛋白水平降低)。KLF13过表达可显著改善脓毒症诱导的心肌损伤。KLF13过表达通过抑制炎症通路(尤其是NF-κB信号传导)和心肌细胞凋亡,对脓毒症诱导的心肌损伤和lps诱导的细胞炎症和凋亡具有保护作用。
{"title":"KLF13 overexpression protects sepsis-induced myocardial injury and LPS-induced inflammation and apoptosis","authors":"Ni Zeng, Zaijin Jian, Wenxin Zhu, Junmei Xu, Yongmei Fan, Feng Xiao","doi":"10.1111/iep.12459","DOIUrl":"10.1111/iep.12459","url":null,"abstract":"<p>Sepsis remains a worldwide public health problem. This study aims to explore the role and mechanism of transcriptional factors (TFs) in sepsis-induced myocardial injury. Firstly, TF KLF13 was selected to explore its role in sepsis-induced myocardial injury. The caecal ligation and puncture (CLP) -induced sepsis mouse model was established and the septic mice were examined using standard histopathological methods. KLF13 expression was detected in the septic mouse heart and was also seen in a lipoploysaccharide (LPS) -induced cellular inflammation model. To explore this further both pro-apoptotic cleaved-caspase3/caspase3 and Bax levels and anti-apoptotic Bcl2 levels were examined, also in both models, In addition inflammatory cytokine (IL-1β, TNF-α, IL-8 and MCP-1) production and IκB-α protein level and p65 phosphorylation were examined in both septic mice and LPS-induced cells. Thus three parameters - cardiomyocyte apoptosis, inflammatory response and NF-κB pathway activation were evaluated under similar conditions. The septic mice showed significant oedema, disordered myofilament arrangement and degradation and necrosis to varying degrees in the myocardial cells. KLF13 was downregulated in both the septic mouse heart and the LPS-induced cellular inflammation model. Furthermore, both models showed abnormally increased cardiomyocyte apoptosis (increased cleaved-caspase3/caspase and Bax protein levels and decreased Bcl2 level), elevated inflammation (increased production of inflammatory cytokines) and the activated NF-κB pathway (increased p65 phosphorylation and decreased IκB-α protein level). KLF13 overexpression notably ameliorated sepsis-induced myocardial injury in vivo and in vitro<i>.</i> KLF13 overexpression protected against sepsis-induced myocardial injury and LPS-induced cellular inflammation and apoptosis via inhibiting the inflammatory pathways (especially NF-κB signalling) and cardiomyocyte apoptosis.</p>","PeriodicalId":14157,"journal":{"name":"International Journal of Experimental Pathology","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2022-12-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/iep.12459","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10726587","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The aim of this study was to evaluate the clinicopathological significance of autocrine motility factor receptor (AMFR) expression in a variety of human invasive micropapillary carcinomas (IMPC). AMFR expression was compared in 111 samples of a variety of human IMPCs which had intrinsic non-micropapillary components and with 26 cases of control pulmonary adenocarcinoma (CPA, carcinoma without an IMPC component) by immunohistochemistry (IHC). In the 137 cases analysed, AMFR expression was significantly elevated in the IMPC components compared to the non-IMPC components (p = .005) and normal tissues (p < .001). AMFR expression was also higher in the IMPC samples compared to their intrinsic non-IMPC components (p = .0234). Between the 69 cases of lung IMPC and 26 cases of CPA, AMFR expression was notably higher in the IMPC components than in the CPA components (p = .0455). However, there was no significant difference between the non-IMPC components in the lung and the CPA components (p = .4584). Moreover, in breast cancer, elevated AMFR expression was not significantly correlated with mixed type or pure type IMPC (p = .5969) or with age, gender, T stage, or lymph node metastasis (LNM). Between IMPC and CPA of the lung, there was no statistical significance in age, T stage, and LNM, where AMFR expression was higher in IMPC (p = .0071). Thus this study demonstrated that AMFR was overexpressed in a variety of human IMPC components compared with non-micropapillary components. This suggests that AMFR expression is a potential new prognostic indicator for different types of human IMPC, which might thus be a new therapeutic target.
{"title":"Expression of autocrine motility factor receptor (AMFR) in human breast and lung invasive micropapillary carcinomas","authors":"Jing Xu, Hongfei Ma, Qi Wang, Hui Zhang","doi":"10.1111/iep.12462","DOIUrl":"10.1111/iep.12462","url":null,"abstract":"<p>The aim of this study was to evaluate the clinicopathological significance of autocrine motility factor receptor (AMFR) expression in a variety of human invasive micropapillary carcinomas (IMPC). AMFR expression was compared in 111 samples of a variety of human IMPCs which had intrinsic non-micropapillary components and with 26 cases of control pulmonary adenocarcinoma (CPA, carcinoma without an IMPC component) by immunohistochemistry (IHC). In the 137 cases analysed, AMFR expression was significantly elevated in the IMPC components compared to the non-IMPC components (<i>p</i> = .005) and normal tissues (<i>p</i> < .001). AMFR expression was also higher in the IMPC samples compared to their intrinsic non-IMPC components (<i>p</i> = .0234). Between the 69 cases of lung IMPC and 26 cases of CPA, AMFR expression was notably higher in the IMPC components than in the CPA components (<i>p</i> = .0455). However, there was no significant difference between the non-IMPC components in the lung and the CPA components (<i>p</i> = .4584). Moreover, in breast cancer, elevated AMFR expression was not significantly correlated with mixed type or pure type IMPC (<i>p</i> = .5969) or with age, gender, T stage, or lymph node metastasis (LNM). Between IMPC and CPA of the lung, there was no statistical significance in age, T stage, and LNM, where AMFR expression was higher in IMPC (<i>p</i> = .0071). Thus this study demonstrated that AMFR was overexpressed in a variety of human IMPC components compared with non-micropapillary components. This suggests that AMFR expression is a potential new prognostic indicator for different types of human IMPC, which might thus be a new therapeutic target.</p>","PeriodicalId":14157,"journal":{"name":"International Journal of Experimental Pathology","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2022-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/iep.12462","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9280721","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ras homologue family member C (RhoC) is an oncogene in diverse types of human cancers, whereas its regulatory mechanisms involving macrophage polarization is rarely investigated. This study is designed to explore the regulatory role of RhoC in colon cancer and the underlying molecular mechanisms involving macrophage polarization. We detected RhoC expression by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot, and analysed the biological function of RhoC knockdown in CC cells by the MTT, wound healing and transwell assay. Macrophage polarization-associated markers, genes associated with migration, phosphatase and tensin homologue (PTEN) and forkhead box O (FOXO) were determined by qRT-PCR and western blot. The xenograft tumour mouse model was used to assess the role of RhoC in vivo. RhoC is highly expressed in CC cells. The cell viability, invasion and migration abilities of CC cells were reduced by knockdown of RhoC. RhoC knockdown promoted M1 polarization, inhibited M2 polarization and decreased levels of genes associated with migration (matrix metalloproteinase-2 and matrix metalloproteinase-9). Silencing of RhoC inhibited tumour growth and expression of genes associated with migration in the xenografted model. In addition, silencing of RhoC promoted PTEN/FOXO1 expression, and PTEN inhibitor (SF1670) reversed the inhibitory effects of RhoC silencing. We demonstrated that silencing of RhoC reduced CC cells invasion and migration, and tumour growth by suppressing M2 macrophage polarization via regulating the PTEN/FOXO1 pathway.
{"title":"Silencing of RhoC induces macrophage M1 polarization to inhibit migration and invasion in colon cancer via regulating the PTEN/FOXO1 pathway","authors":"Bin Yang, Lihua Wang, Zhiying Tian","doi":"10.1111/iep.12460","DOIUrl":"10.1111/iep.12460","url":null,"abstract":"<p>Ras homologue family member C (RhoC) is an oncogene in diverse types of human cancers, whereas its regulatory mechanisms involving macrophage polarization is rarely investigated. This study is designed to explore the regulatory role of RhoC in colon cancer and the underlying molecular mechanisms involving macrophage polarization. We detected RhoC expression by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot, and analysed the biological function of RhoC knockdown in CC cells by the MTT, wound healing and transwell assay. Macrophage polarization-associated markers, genes associated with migration, phosphatase and tensin homologue (PTEN) and forkhead box O (FOXO) were determined by qRT-PCR and western blot. The xenograft tumour mouse model was used to assess the role of RhoC in vivo. RhoC is highly expressed in CC cells. The cell viability, invasion and migration abilities of CC cells were reduced by knockdown of RhoC. RhoC knockdown promoted M1 polarization, inhibited M2 polarization and decreased levels of genes associated with migration (matrix metalloproteinase-2 and matrix metalloproteinase-9). Silencing of RhoC inhibited tumour growth and expression of genes associated with migration in the xenografted model. In addition, silencing of RhoC promoted PTEN/FOXO1 expression, and PTEN inhibitor (SF1670) reversed the inhibitory effects of RhoC silencing. We demonstrated that silencing of RhoC reduced CC cells invasion and migration, and tumour growth by suppressing M2 macrophage polarization via regulating the PTEN/FOXO1 pathway.</p>","PeriodicalId":14157,"journal":{"name":"International Journal of Experimental Pathology","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2022-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/iep.12460","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9280723","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Túlio de Almeida Hermes, Rafael Dias Mâncio, Daniela Sayuri Mizobutti, Aline Barbosa Macedo, Larissa Akemi Kido, Valéria Helena Alves Cagnon Quitete, Elaine Minatel
Duchenne muscular dystrophy (DMD) is the most severe and frequent form of muscular dystrophy. The mdx mouse is one of the most widely used experimental models to understand aspects of the biology of dystrophic skeletal muscles and the mechanisms of DMD. Oxidative stress and apoptosis are present in early stages of the disease in mdx mice. The high production of reactive oxygen species (ROS) causes activation of apoptotic death regulatory proteins due to DNA damage and breakdown of nuclear and mitochondrial membranes. The quadriceps (QUA) muscle of the mdx mouse is a good tool to study oxidative events. Previous studies have demonstrated that cilostazol exerts an anti-oxidant effect by decreasing the production of reactive oxygen species (ROS). The present study aimed to evaluate the ability of cilostazol to modulate oxidative stress and apoptosis in the QUA muscle of mdx mice. Fourteen-day-old mdx mice received cilostazol or saline for 14 days. C57BL/10 mice were used as a control. In the QUA muscle of mdx mice, cilostazol treatment decreased ROS production (−74%), the number of lipofuscin granules (−47%), lipid peroxidation (−11%), and the number of apoptotic cells (−66%). Thus cilostazol showed anti-oxidant and anti-apoptotic action in the QUA muscle of mdx mice.
{"title":"Cilostazol attenuates oxidative stress and apoptosis in the quadriceps muscle of the dystrophic mouse experimental model","authors":"Túlio de Almeida Hermes, Rafael Dias Mâncio, Daniela Sayuri Mizobutti, Aline Barbosa Macedo, Larissa Akemi Kido, Valéria Helena Alves Cagnon Quitete, Elaine Minatel","doi":"10.1111/iep.12461","DOIUrl":"10.1111/iep.12461","url":null,"abstract":"<p>Duchenne muscular dystrophy (DMD) is the most severe and frequent form of muscular dystrophy. The mdx mouse is one of the most widely used experimental models to understand aspects of the biology of dystrophic skeletal muscles and the mechanisms of DMD. Oxidative stress and apoptosis are present in early stages of the disease in mdx mice. The high production of reactive oxygen species (ROS) causes activation of apoptotic death regulatory proteins due to DNA damage and breakdown of nuclear and mitochondrial membranes. The quadriceps (QUA) muscle of the mdx mouse is a good tool to study oxidative events. Previous studies have demonstrated that cilostazol exerts an anti-oxidant effect by decreasing the production of reactive oxygen species (ROS). The present study aimed to evaluate the ability of cilostazol to modulate oxidative stress and apoptosis in the QUA muscle of mdx mice. Fourteen-day-old mdx mice received cilostazol or saline for 14 days. C57BL/10 mice were used as a control. In the QUA muscle of mdx mice, cilostazol treatment decreased ROS production (−74%), the number of lipofuscin granules (−47%), lipid peroxidation (−11%), and the number of apoptotic cells (−66%). Thus cilostazol showed anti-oxidant and anti-apoptotic action in the QUA muscle of mdx mice.</p>","PeriodicalId":14157,"journal":{"name":"International Journal of Experimental Pathology","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2022-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/iep.12461","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10736136","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Amanda Harduim Valduga, Daniela Sayuri Mizobuti, Fernanda dos Santos Rapucci Moraes, Rafael Dias Mâncio, Luis Henrique Rapucci Moraes, Túlio de Almeida Hermes, Aline Barbosa Macedo, Elaine Minatel
There is strong cross-talk between abnormal intracellular calcium concentration, high levels of reactive oxygen species (ROS) and an exacerbated inflammatory process in the dystrophic muscles of mdx mice, the experimental model of Duchenne muscular dystrophy (DMD). In this study, we investigated effects of Idebenone, a potent anti-oxidant, on oxidative stress markers, the anti-oxidant defence system, intracellular calcium concentrations and the inflammatory process in primary dystrophic muscle cells from mdx mice. Dystrophic muscle cells were treated with Idebenone (0.05 μM) for 24 h. The untreated mdx muscle cells were used as controls. The MTT assay showed that Idebenone did not have a cytotoxic effect on the dystrophic muscle cells. The Idebenone treatment was able to reduce the levels of oxidative stress markers, such as H2O2 and 4-HNE, as well as decreasing intracellular calcium influx in the dystrophic muscle cells. Regarding Idebenone effects on the anti-oxidant defence system, an up-regulation of catalase levels, glutathione reductase (GR), glutathione peroxidase (GPx) and superoxide dismutase (SOD) activity was observed in the dystrophic muscle cells. In addition, the Idebenone treatment was also associated with reduction in inflammatory molecules, such as nuclear factor kappa-B (NF-κB) and tumour necrosis factor (TNF) in mdx muscle cells. These outcomes supported the use of Idebenone as a protective agent against oxidative stress and related signalling mechanisms involved in dystrophinopathies, such as DMD.
杜氏肌营养不良症(DMD)实验模型mdx小鼠的细胞内钙浓度异常、活性氧(ROS)水平升高和炎症过程加剧之间存在强烈的串扰。在这项研究中,我们研究了强效抗氧化剂伊地苯酮对mdx小鼠原发性营养不良肌肉细胞氧化应激标志物、抗氧化防御系统、细胞内钙浓度和炎症过程的影响。以依地苯酮(0.05 μM)处理肌营养不良细胞24 h。以未处理的mdx肌细胞为对照。MTT试验表明,依地苯酮对肌营养不良细胞无细胞毒作用。依地苯酮治疗能够降低氧化应激标志物(如H2O2和4-HNE)的水平,并减少营养不良肌肉细胞内钙的内流。关于依地苯酮对抗氧化防御系统的影响,在营养不良的肌肉细胞中观察到过氧化氢酶、谷胱甘肽还原酶(GR)、谷胱甘肽过氧化物酶(GPx)和超氧化物歧化酶(SOD)活性的上调。此外,依地苯酮治疗还与mdx肌细胞中核因子κ b (NF-κB)和肿瘤坏死因子(TNF)等炎症分子的减少有关。这些结果支持使用依地苯酮作为抗氧化应激的保护剂,以及与肌营养不良病(如DMD)相关的信号机制。
{"title":"Protection of dystrophic muscle cells using Idebenone correlates with the interplay between calcium, oxidative stress and inflammation","authors":"Amanda Harduim Valduga, Daniela Sayuri Mizobuti, Fernanda dos Santos Rapucci Moraes, Rafael Dias Mâncio, Luis Henrique Rapucci Moraes, Túlio de Almeida Hermes, Aline Barbosa Macedo, Elaine Minatel","doi":"10.1111/iep.12463","DOIUrl":"10.1111/iep.12463","url":null,"abstract":"<p>There is strong cross-talk between abnormal intracellular calcium concentration, high levels of reactive oxygen species (ROS) and an exacerbated inflammatory process in the dystrophic muscles of mdx mice, the experimental model of Duchenne muscular dystrophy (DMD). In this study, we investigated effects of Idebenone, a potent anti-oxidant, on oxidative stress markers, the anti-oxidant defence system, intracellular calcium concentrations and the inflammatory process in primary dystrophic muscle cells from <i>mdx</i> mice. Dystrophic muscle cells were treated with Idebenone (0.05 μM) for 24 h. The untreated <i>mdx</i> muscle cells were used as controls. The MTT assay showed that Idebenone did not have a cytotoxic effect on the dystrophic muscle cells. The Idebenone treatment was able to reduce the levels of oxidative stress markers, such as H<sub>2</sub>O<sub>2</sub> and 4-HNE, as well as decreasing intracellular calcium influx in the dystrophic muscle cells. Regarding Idebenone effects on the anti-oxidant defence system, an up-regulation of catalase levels, glutathione reductase (GR), glutathione peroxidase (GPx) and superoxide dismutase (SOD) activity was observed in the dystrophic muscle cells. In addition, the Idebenone treatment was also associated with reduction in inflammatory molecules, such as nuclear factor kappa-B (NF-κB) and tumour necrosis factor (TNF) in mdx muscle cells. These outcomes supported the use of Idebenone as a protective agent against oxidative stress and related signalling mechanisms involved in dystrophinopathies, such as DMD.</p>","PeriodicalId":14157,"journal":{"name":"International Journal of Experimental Pathology","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2022-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/iep.12463","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10736137","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-12-01DOI: 10.33696/pathology.3.039
A. Finall, D. James, M. Quintela-Vazquez, RS Conlan
Introduction: Endometrioid and clear cell carcinomas of the ovary are the most common subtypes of epithelial malignancy arising from endometriosis and are often termed endometriosis-associated ovarian carcinomas (EAOCs). There is a paucity of experimental evidence in the medical literature regarding the role of long non-coding ribonucleic acid (RNA) gene expression in the pathogenesis of these carcinomas. Purpose: There is a need to develop understanding of the pathogenesis of these carcinomas for neoplastic risk stratification in endometriosis and to develop novel diagnostic biomarkers. Clear cell carcinoma of the ovary, in particular, has a poor prognosis as a result of resistance to standard platinum-based chemotherapy. Methods: RNAseq datasets from EAOCs were downloaded from Gene Expression Omnibus (GEO) and compared with normal ovarian control sequences using a customized bioinformatic pipeline. Results: We found 88 differentially expressed non-coding RNA molecules present in both endometrioid and clear cell carcinoma types compared with controls. A further 117 were specifically differentially expressed in the endometrioid carcinoma group and 128 in clear cell carcinoma samples alone. Genes of interest for further study from the 88 shared set in both EAOC types include CASC9, RP4-561L24.3, SLC2A1-AS1, LUCAT1, XIST, CASC15, and MIR99AHG. These genes appear to influence ferroptosis as a common pathway. Conclusions: Alterations in the ferroptosis pathway may be a key event in development of EAOC in ovarian endometriosis patients. Further work is required to elucidate the function of the candidate RNA genes identified in this study by in-vitro, cell line and cultured organoid experiments. These candidate RNA gene biomarkers have potential clinical utility in early diagnosis, risk stratification of endometriosis, and post-surgical monitoring.
子宫内膜样癌和卵巢透明细胞癌是由子宫内膜异位症引起的上皮恶性肿瘤中最常见的亚型,通常被称为子宫内膜异位症相关性卵巢癌(EAOCs)。关于长链非编码核糖核酸(RNA)基因表达在这些癌的发病机制中的作用,医学文献中缺乏实验证据。目的:有必要进一步了解子宫内膜异位症的发病机制,并开发新的诊断生物标志物。特别是卵巢透明细胞癌,由于对标准铂类化疗有耐药性,预后较差。方法:从Gene Expression Omnibus (GEO)下载EAOCs的RNAseq数据集,并使用定制的生物信息学管道与正常卵巢对照序列进行比较。结果:与对照组相比,我们在子宫内膜样癌和透明细胞癌中发现了88种差异表达的非编码RNA分子。另有117个在子宫内膜样癌组中特异性表达,128个在透明细胞癌样本中单独表达。在这两种EAOC类型共有的88个基因集中,需要进一步研究的基因包括CASC9、RP4-561L24.3、SLC2A1-AS1、LUCAT1、XIST、CASC15和MIR99AHG。这些基因似乎是影响铁下垂的共同途径。结论:铁下垂途径的改变可能是卵巢子宫内膜异位症患者EAOC发展的关键事件。进一步的工作需要通过体外、细胞系和培养的类器官实验来阐明本研究中鉴定的候选RNA基因的功能。这些候选RNA基因生物标志物在子宫内膜异位症的早期诊断、风险分层和术后监测方面具有潜在的临床应用价值。
{"title":"Differential Expression of Long Non-coding Ribonucleic Acid (RNA) Genes in Endometriosis-associated Ovarian Cancer (EAOC): A Pilot Meta-analysis for Pathological Insights and Potential Diagnostic Biomarker Identification","authors":"A. Finall, D. James, M. Quintela-Vazquez, RS Conlan","doi":"10.33696/pathology.3.039","DOIUrl":"https://doi.org/10.33696/pathology.3.039","url":null,"abstract":"Introduction: Endometrioid and clear cell carcinomas of the ovary are the most common subtypes of epithelial malignancy arising from endometriosis and are often termed endometriosis-associated ovarian carcinomas (EAOCs). There is a paucity of experimental evidence in the medical literature regarding the role of long non-coding ribonucleic acid (RNA) gene expression in the pathogenesis of these carcinomas.\u0000Purpose: There is a need to develop understanding of the pathogenesis of these carcinomas for neoplastic risk stratification in endometriosis and to develop novel diagnostic biomarkers. Clear cell carcinoma of the ovary, in particular, has a poor prognosis as a result of resistance to standard platinum-based chemotherapy.\u0000Methods: RNAseq datasets from EAOCs were downloaded from Gene Expression Omnibus (GEO) and compared with normal ovarian control sequences using a customized bioinformatic pipeline.\u0000Results: We found 88 differentially expressed non-coding RNA molecules present in both endometrioid and clear cell carcinoma types compared with controls. A further 117 were specifically differentially expressed in the endometrioid carcinoma group and 128 in clear cell carcinoma samples alone. Genes of interest for further study from the 88 shared set in both EAOC types include CASC9, RP4-561L24.3, SLC2A1-AS1, LUCAT1, XIST, CASC15, and MIR99AHG. These genes appear to influence ferroptosis as a common pathway.\u0000Conclusions: Alterations in the ferroptosis pathway may be a key event in development of EAOC in ovarian endometriosis patients. Further work is required to elucidate the function of the candidate RNA genes identified in this study by in-vitro, cell line and cultured organoid experiments. These candidate RNA gene biomarkers have potential clinical utility in early diagnosis, risk stratification of endometriosis, and post-surgical monitoring.","PeriodicalId":14157,"journal":{"name":"International Journal of Experimental Pathology","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87051825","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-12-01DOI: 10.33696/pathology.3.040
Daniel Molano Franco, R. Masclans Joan, X. Nuvials, Mario Gómez, Cesar Enciso, M. Villabon, Edgar Beltran, M. Pérez, G. Ramírez, Andres Gomez, Luis Escobar, Andres Villa, Cristian Arias-Reyes, J. Soliz
Background. COVID-19 patients in intensive care units suffer from bacterial/fungal superinfections. However, the incidence and cause of such superinfections in high-altitude hospitals remain poorly investigated. Objectives. The aim of this study was to evaluate the frequency of bacterial/fungal superinfection in patients with COVID-19 hospitalized in the intensive care unit (ICU) of the Hospital Universitario San José de Bogotá, Colombia, located at an altitude of 2,651 meters above sea level (high altitude). The impact of corticosteroids on the development of infection was also evaluated. Methods. The cohort included 279 patients, of which 188 (67.4%) were male, 116 (42.3%) were treated with dexamethasone, and 48 (17.2%) were diagnosed with superinfection. A retrospective descriptive cohort study was performed to evaluate the association between bacterial/fungal superinfection frequency, corticosteroid treatment, mechanical ventilation, and mortality rate. Results. Our results showed that bacteremia was the most frequent diagnosis (n=20; 41.6%) of patients with superinfection, followed by pulmonary superinfection (n=17; 35.4%). The most frequently identified causative agents of superinfection were K. pneumoniae (n=23; 26.1%), C. albicans (n=10; 11.4%) and P. aeruginosa (n=8; 9.1%). Moreover, our results showed no association between corticosteroid treatment (or the use of empiric antibiotic treatment) and mortality. However, we found a significant association between bacterial/fungal superinfection and the number of days on mechanical ventilation. However, bacterial/fungal superinfection showed no impact on the mortality rate. Conclusions. We conclude that bacterial/fungal superinfection in ICU highland patients with SARS-CoV-2 treated at Hospital Universitario San José in Bogotá, Colombia, increases mainly in proportion to the time required for mechanical ventilation.
背景。重症监护病房的COVID-19患者患有细菌/真菌超感染。然而,在高海拔地区的医院中,这种重复感染的发生率和原因调查仍然很少。本研究的目的是评估位于海拔2651米(高海拔)的哥伦比亚圣何塞大学医院(Universitario San joss de bogot)重症监护病房(ICU)的COVID-19患者细菌/真菌重复感染的频率。同时还评价了皮质类固醇对感染发展的影响。279例患者,其中男性188例(67.4%),地塞米松治疗116例(42.3%),重复感染48例(17.2%)。进行了一项回顾性描述性队列研究,以评估细菌/真菌重复感染频率、皮质类固醇治疗、机械通气和死亡率之间的关系。我们的结果显示,菌血症是最常见的诊断(n=20;41.6%),其次是肺部重复感染(n=17;35.4%)。最常见的重复感染病原体是肺炎克雷伯菌(n=23;26.1%),白色念珠菌(n=10;11.4%)和铜绿假单胞菌(n=8;9.1%)。此外,我们的结果显示皮质类固醇治疗(或经验性抗生素治疗的使用)与死亡率之间没有关联。然而,我们发现细菌/真菌重复感染与机械通气天数之间存在显著关联。然而,细菌/真菌重复感染对死亡率没有影响。结论。我们得出结论,在哥伦比亚波哥大圣何塞大学医院收治的重症监护室高原SARS-CoV-2患者的细菌/真菌重复感染主要与机械通气所需时间成正比。
{"title":"The Duration of Mechanical Ventilation is the Main Cause of Bacterial/Fungal Superinfection in Critically Ill Patients with COVID-19 at Altitude","authors":"Daniel Molano Franco, R. Masclans Joan, X. Nuvials, Mario Gómez, Cesar Enciso, M. Villabon, Edgar Beltran, M. Pérez, G. Ramírez, Andres Gomez, Luis Escobar, Andres Villa, Cristian Arias-Reyes, J. Soliz","doi":"10.33696/pathology.3.040","DOIUrl":"https://doi.org/10.33696/pathology.3.040","url":null,"abstract":"Background. COVID-19 patients in intensive care units suffer from bacterial/fungal superinfections. However, the incidence and cause of such superinfections in high-altitude hospitals remain poorly investigated.\u0000\u0000Objectives. The aim of this study was to evaluate the frequency of bacterial/fungal superinfection in patients with COVID-19 hospitalized in the intensive care unit (ICU) of the Hospital Universitario San José de Bogotá, Colombia, located at an altitude of 2,651 meters above sea level (high altitude). The impact of corticosteroids on the development of infection was also evaluated.\u0000\u0000Methods. The cohort included 279 patients, of which 188 (67.4%) were male, 116 (42.3%) were treated with dexamethasone, and 48 (17.2%) were diagnosed with superinfection. A retrospective descriptive cohort study was performed to evaluate the association between bacterial/fungal superinfection frequency, corticosteroid treatment, mechanical ventilation, and mortality rate.\u0000\u0000Results. Our results showed that bacteremia was the most frequent diagnosis (n=20; 41.6%) of patients with superinfection, followed by pulmonary superinfection (n=17; 35.4%). The most frequently identified causative agents of superinfection were K. pneumoniae (n=23; 26.1%), C. albicans (n=10; 11.4%) and P. aeruginosa (n=8; 9.1%). Moreover, our results showed no association between corticosteroid treatment (or the use of empiric antibiotic treatment) and mortality. However, we found a significant association between bacterial/fungal superinfection and the number of days on mechanical ventilation. However, bacterial/fungal superinfection showed no impact on the mortality rate. \u0000\u0000Conclusions. We conclude that bacterial/fungal superinfection in ICU highland patients with SARS-CoV-2 treated at Hospital Universitario San José in Bogotá, Colombia, increases mainly in proportion to the time required for mechanical ventilation.","PeriodicalId":14157,"journal":{"name":"International Journal of Experimental Pathology","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"79726177","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
{"title":"British Society for Matrix Biology Spring 2022 Meeting","authors":"","doi":"10.1111/iep.12454","DOIUrl":"https://doi.org/10.1111/iep.12454","url":null,"abstract":"","PeriodicalId":14157,"journal":{"name":"International Journal of Experimental Pathology","volume":null,"pages":null},"PeriodicalIF":3.0,"publicationDate":"2022-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"71967045","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}