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Post-translational modifications of prostaglandin-endoperoxide synthase 2 in colorectal cancer:An update

World Journal of Gastroenterology 2018年第48期24卷 5454-5461页

作者： Rafael I Jaén Patricia Prieto marta Casado Paloma martín-Sanz Lisardo Boscá department of metabolism and Physiopathology of Inflammatory Diseases Instituto de Investigaciones Biomédicas Alberto Sols (CSIC-UAM) department of Biomedicine Instituto de Biomedicina de Valencia (CSIC) Centro de investigación Biomédica en Red de enfermedades Cardiovasculares y Hepáticas y DigestivasISCⅢ unidad Asociada IIBmULPGC Universidad de las Palmas de Gran Canaria (ULPGC)

The biosynthesis of prostanoids is involved in both physiological and pathological processes. The expression of prostaglandin-endoperoxide synthase 2(PTGS2; also known as COX-2) has been traditionally associated to the onset of several pathologies, from inflammation to cardiovascular, gastrointestinal and oncologic events. For this reason, the search of selective PTGS2 inhibitors has been a focus for therapeutic interventions. In addition to the classic non-steroidal anti-inflammatory drugs, selective and specific PTGS2 inhibitors, termed coxibs, have been generated and widely used. PTGS2 activity is less restrictive in terms of substrate specificity than the homeostatic counterpart PTGS1, and it accounts for the elevated prostanoid synthesis that accompanies several pathologies. The main regulation of PTGS2 occurs at the transcription level. In addition to this, the stability of the mRnA is finely regulated through the interaction with several cytoplasmic elements, ranging from specificmicroR nAs to proteins that control mR nA degradation. moreover, the protein has been recognized to be the substrate for several post-translational modifications that affect both the enzyme activity and the targeting for degradation via proteasomal and non-proteasomal mechanisms. Among these modifications, phosphorylation, glycosylation and covalent modifications by reactive lipidic intermediates and by free radicals associated to the proinflammatory condition appear to be the main changes. Identification of these post-translational modifications is relevant to better understand the role of PTGS2 in several pathologies and to establish a correct analysis of the potential function of this protein in diseases progress. Finally, these modifications can be used as biomarkers to establish correlations with other parameters, including the immunomodulation dependent on molecular pathological epidemiology determinants, which may provide a better frame for potential therapeutic interventions.

关键词： Prostaglandins Prostaglandin-endoperoxide synthase 2 Post-translational modifications Glycosylation Colorectal cancer Inflammation

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Association between Helicobacter *** and hepatobiliary malignancies:A review

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World Journal of Gastroenterology 2015年第5期21卷 1414-1423页

作者： Fany Karina Segura-López Alfredo Güitrón-Cantú Javier Torres Hospital de Especialidades UmAE no 71 Instituto Mexicano del Seguro SocialTorreónCoahuila 27000México departamento de endoscopia Gastrointestinal Hospital de Especialidades UMAE No 71Instituto Mexicano del Seguro SocialTorreónCoahuila 2700México unidad de investigación en enfermedades Infecciosas y Parasitarias Hospital de Pediatría UMAECentro Médico Nacional Siglo XXIInstituto Mexicano del Seguro SocialMéxico CP 06720DFMéxico

Hepatobiliary cancers are highly lethal cancers that comprise a spectrum of invasive carcinomas originating in the liver hepatocellular carcinoma,the bile ducts intrahepatic cholangiocarcinoma and extrahepaticcholangiocarcinoma,the gallbladder and the ampulla of Vater(collectively known as biliary tract cancers).These tumors account for approximately 13% of all annual cancer-related deaths worldwide and for 10%-20% of deaths from hepatobiliary ***(CCA) is a devastating disease that displays a poor survival rate for which few therapeutic options are *** genetics,geographical and environmental factors,cholelithiasis,obesity,parity,and endemic infection with liver flukes have been identified as risk factors that influence the development of biliary tract *** important factors affecting the carcinogenesis of these tumors include chronic inflammation,obstruction of the bile ducts,and impaired bile *** has been suggested that CCA is caused by infection with Helicobacter species,such as Helicobacter bilis and Helicobacter hepaticus,in a manner that is similar to the reported role of Helicobacter pylori in distal gastric *** to the difficulty in culturing these Helicobacter species,molecular methods,such as polymerase chain reaction and sequencing,or immunologic assays have become the methods of choice for ***,clinical studies of benign or malignant biliary tract diseases revealed remarkable variability in the methods and the findings,and the use of uniform and validated techniques is needed.

关键词： Helicobacter bilis Helicobacter hepaticus Helicoba

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IKKβ overexpression together with a lack of tumour suppressor genes causes ameloblastic odontomas in mice

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International Journal of Oral Science 2020年第1期12卷 31-39页

作者： Angustias Page Ana Bravo Cristian Suarez-Cabrera Raquel Sanchez-Baltasar marta Oteo miguel Angel morcillo mLlanos Casanova Jose CSegovia manuel navarro Angel Ramirez molecular Oncology Unit.Centro de investigaciones energéticas Medioambientales y Tecnológicas(CIEMAT)MadridSpain Instituto de investigación 12 de Octubre i+12 MadridSpain Centro de investigación Biomédica en Red de Cáncer(CIBEROnC) MadridSpain department of Anatomy Animal Production and Veterinary Clinical SciencesLaboratory of Pathology Phenotyping of Genetically Engineered MiceFaculty of Veterinary MedicineUniversity of Santiago de CompostelaLugoSpain Biomedical Applications and Pharmacokinetics Unit Centro de Investigaciones EnergéticasMedioambientales y Tecnológicas(CIEMAT)MadridSpain Hematopoietic Innovative Therapies Division.Centro de investigaciones energéticas Medioambientales y Tecnológicas(CIEMAT).Centro de Investigación Biomédica en Red de Enfermedades Raras(CIBERER)MadridSpain unidad mixta de Terapias Avanzadas Fundación Instituto de Investigaciones Sanitarias Fundación Jiménez DíazMadridSpain

Odontogenic tumours are a heterogeneous group of lesions that develop in the oral cavity region and are characterized by the formation of tumoural structures that differentiate as teeth. Due to the diversity of their histopathological characteristics and clinical behaviour, the classification of these tumours is still under debate. Alterations in morphogenesis pathways such as the Hedgehog,mAPK and WnT/β-catenin pathways are implicated in the formation of odontogenic lesions, but the molecular bases of many of these lesions are still unknown. In this study, we used genetically modified mice to study the role of IKKβ(a fundamental regulator of nF-κB activity and many other proteins) in oral epithelial cells and odontogenic tissues. Transgenic mice overexpressing IKKβ in oral epithelial cells show a significant increase in immune cells in both the oral epithelia and oral submucosa. They also show changes in the expression of several proteins and mi RnAs that are important for cancer development. Interestingly, we found that overactivity of IKKβ in oral epithelia and odontogenic tissues, in conjunction with the loss of tumour suppressor proteins(p53, or p16 and p19), leads to the appearance of odontogenic tumours that can be classified as ameloblastic odontomas, sometimes accompanied by foci of secondary ameloblastic carcinomas. These tumours show nF-κB activation and increased β-catenin *** findings may help to elucidate the molecular determinants of odontogenic tumourigenesis and the role of IKKβ in the homoeostasis and tumoural transformation of oral and odontogenic epithelia.

关键词： IKKβ tumour suppressor

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Commitment of human mesenchymal stromal cells to skeletal lineages is independent of their morphogenetic capacity

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World Journal of Stem Cells 2023年第7期15卷 701-712页

作者： Jessica Cristina marín-Llera Damián García-García Estefania Garay-Pacheco Victor Adrian Cortes-morales Juan Jose montesinos-montesinos Jesus Chimal-monroy medicina Genómica y Toxicología Ambiental Instituto de Investigaciones BiomédicasUniversidad Nacional Autónoma de MéxicoCoyoacan 04510Mexico Laboratorio de Células Troncales mesenquimales Unidad de Investigación Médica en Enfermedades OncológicasHospital de Oncología Centro Medico Nacional Siglo XXIInstituto Mexicano del Seguro SocialMexico City 06720Mexico departamento de medicina Genómica y Toxicología Ambiental Instituto de Investigaciones BiomédicasUniversidad Nacional Autónoma de MéxicoCoyoacan 04510Mexico

BACKGROUnD mesenchymal stromal cells(mSCs)are multipotent cell populations obtained from fetal and adult *** share some characteristics with limb bud mesodermal cells such as differentiation potential into osteogenic,chondrogenic,and tenogenic lineages and an embryonic mesodermal *** mSCs differentiate into skeletal-related lineages in vitro,they have not been shown to selforganize into complex skeletal structures or connective tissues,as in the *** this work,we demonstrate that the expression of molecular markers to commit mSCs to skeletal lineages is not sufficient to generate skeletal elements in *** To evaluate the potential of mSCs to differentiate into skeletal lineages and generate complex skeletal structures using the recombinant limb(RL)*** We used the experimental system of RLs from dissociated-reaggregated human placenta(PL)and umbilical cord blood(UCB)*** being harvested and reaggregated in a pellet,cultured cells were introduced into an ectodermal cover obtained from an early chicken limb ***,this filled ectoderm was grafted into the back of a donor chick *** these conditions,the cells received and responded to the ectoderm’s embryonic signals in a spatiotemporal manner to differentiate and pattern into skeletal *** response to differentiation and morphogenetic signals was evaluated by quantitative poly-merase chain reaction,histology,immunofluorescence,scanning electron microscopy,and in situ *** We found that human PL-mSCs and UCB-mSCs constituting the RLs expressed chondrogenic,osteogenic,and tenogenic molecular markers while differentially committing into limb lineages but could not generate complex structures in ***-RL from PL or UCB were committed early to chondrogenic ***,the UCB-RL osteogenic commitment was favored,although preferentially to a tenogenic cell *** findings suggest that the commitment of mSCs to differentiate int

关键词： Human mesenchymal stromal cells Recombinant limbs mesenchymal stromal cell morphogene-sis mesenchymal stromal cell in vivo differentiation Skeletal tissues

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Occult hepatitis B virus infection among mexican human immunodeficiency virus-1-infected patients

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World Journal of Gastroenterology 2014年第37期20卷 13530-13537页

作者： ma Teresa Alvarez-muoz Angelica maldonado-Rodriguez Othon Rojas-montes Rocio Torres-Ibarra Fernanda Gutierrez-Escolano Guillermo Vazquez-Rosales Alejandro Gomez Onofre muoz Javier Torres Rosalia Lira unidad de investigacion medica en enfermedades Infecciosas y Parasitarias Hospital de PediatriaCentro Medico Nacional Siglo XXIInstituto Mexicano del Seguro Social Clinica de Hepatitis Hospital de Infectologia Centro Médico Nacional La Raza Hospital General Regional no.72 IMSS unidad de investigacion medica en enfermedades Infecciosas y Parasitarias Hospital de PediatriaCentro Medico Nacional Siglo XXIInstituto Mexi-cano del Seguro Social Hospital Infantil de mexico "Federico Gomez"

AIm: To determine the frequency of occult hepatitis B infection (OHBI) in a group of human immunodeficiency virus (HIV)-1+/ hepatitis B surface antigen negative (HBsAg)- patients from mexico.

关键词： Hepatitis B virus Occult hepatitis B virus infection Human immunodeficiency virus Hepatitis B surface antigen negative Risk factors molecular diagnostics

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Is the combination of immunotherapy with conventional chemotherapy the key to increase the efficacy of colorectal cancer treatment?

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World Journal of Gastrointestinal Oncology 2023年第2期15卷 251-267页

作者： Jonadab E Olguin monica G mendoza-Rodriguez C Angel Sanchez-Barrera Luis I Terrazas Laboratorio nacional en Salud Diagnóstico Molecular y Efecto Ambiental en Enfermedades Crónico-degenerativasFacultad de Estudios Superiores IztacalaUniversidad Nacional Autónoma de MéxicoTlalnepantla 54090Estado de MexicoMexico unidad de Biomedicina Facultad de Estudios Superiores IztacalaUniversidad Nacional Autónoma de MéxicoTlalnepantla 54090Estado de MexicoMexico

Colorectal cancer(CRC) is among the most prevalent and deadly neoplasms worldwide. According to GLOBOCAn predictions, its incidence will increase from 1.15 million CRC cases in 2020 to 1.92 million cases in 2040. Therefore, a better understanding of the mechanisms involved in CRC development is necessary to improve strategies focused on reducing the incidence, prevalence,and mortality of this oncological pathology. Surgery, chemotherapy, and radiotherapy are the main strategies for treating CRC. The conventional chemotherapeutic agent utilized throughout the last four decades is 5-fluorouracil, notwithstanding its low efficiency as a single therapy. In contrast, combining 5-fluorouracil therapy with leucovorin and oxaliplatin or irinotecan increases its efficiency. However, these treatments have limited and temporary solutions and aggressive side effects. Additionally, most patients treated with these regimens develop drug resistance, which leads to disease progression. The immune response is considered a hallmark of cancer;thus, the use of new strategies and methodologies involving immune molecules, cells, and transcription factors has been suggested for CRC patients diagnosed in stages Ⅲ and Ⅳ. despite the critical advances in immunotherapy, the development and impact of immune checkpoint inhibitors on CRC is still under investigation because less than 25% of CRC patients display an increased 5-year survival. The causes of CRC are diverse and include modifiable environmental factors(smoking, diet, obesity, and alcoholism), individual genetic mutations, and inflammation-associated bowel diseases. Due to these diverse causes, the solutions likely cannot be generalized. Interestingly, new strategies, such as single-cell multiomics, proteomics, genomics, flow cytometry, and massive sequencing for tumor microenvironment analysis, are beginning to clarify the way forward. Thus,the individual mechanisms involved in developing the CRC microenvironment, their causes, and t

关键词： Colorectal cancer Immunotherapy checkpoint inhibitors Chemotherapy Immunotherapy Immune response

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Oral Pharmacokinetics of mirodenafil in mexican Healthy Volunteers

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Pharmacology & Pharmacy 2014年第1期5卷 112-116页

作者： miriam del Carmen Carrasco-Portugal Francisco Javier Flores-murrieta Juan Gerardo Reyes-García noemí Santos-Caballero Landsteiner Scientific S.A. de C.V. México DF México Sección de Estudios de Posgrado e investigación Escuela Superior de Medicina Instituto Politécnico Nacional México DF México unidad de investigación en Farmacología Insituto Nacional de Enfermedades Respiratorias “Ismael Cosio Villegas” México DF México unidad de investigación en Farmacología Insituto Nacional de Enfermedades Respiratorias “Ismael Cosio Villegas” México DF México Sección de Estudios de Posgrado e investigación Escuela Superior de Medicina Instituto Politécnico Nacional México DF México

mirodenafil is a 5-phosphodiesterase inhibitor that is currently marketed in Korea for the treatment of erectile dysfunction;however, no information in other populations is available. It has been described that mirodenafil is metabolized by CYP3A4, a metabolic pathway in which interethnic differences have been reported. The purpose of this study was to characterize the oral pharmacokinetics of mirodenafil in mexicans. Seventeen male healthy volunteers were enrolled in this study. After an overnight fast, volunteers received an oral 100 mg dose and blood samples were collected at selected times during 24 h. Plasma was stored frozen and analyzed by an HPLC method. Pharmacokinetic parameters obtained were: Cmax 331.129 ± 32.689 ng/mL, tmax 1.574 ± 0.293 h, AUC24h 883.293 ± 104.088 ng·h/mL, AUC￥ 976.477 ± 108.812 ng·h/mL and t1/2 1.807 ± 0.171 h. Parameter values observed in this study are similar to those reported in Koreans. Since efficacy and safety studies of mirodenafil have been conducted in Koreans, it is expected that dosage regime to employ in mexicans should be similar to the approved for Korean population.

关键词： Erectile Dysfunction Healthy Volunteers mexican mirodenafil Pharmacokinetic

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Impact of STAT-signaling pathway on cancer-associated fibroblasts in colorectal cancer and its role in immunosuppression

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World Journal of Gastrointestinal Oncology 2024年第5期16卷 1705-1724页

作者： Damián Sánchez-Ramírez mónica G mendoza-Rodríguez Omar R Alemán Fernando A Candanedo-González miriam Rodríguez-Sosa Juan Josémontesinos-montesinos mauricio Salcedo Ismael Brito-Toledo Felipe Vaca-Paniagua Luis I Terrazas unidad de investigacion en Biomedicina Facultad de Estudios Superiores IztacalaUniversidad Nacional Autonoma de MexicoTlalnepantla 54090Estado de MexicoMexico department of Biology Facultad de QuimicaUniversidad Nacional Autonoma de MexicoCiudad UniversitariaMexico City 04510Mexico department of Pathology National Medical Center Century XXIInstituto Mexicano del Seguro SocialMexico City 06720Mexico Laboratorio de Células Troncales mesenquimales Unidad de Investigación Médica en Enfermedades OncológicasHospital de Oncología Centro Medico Nacional Siglo XXIInstituto Mexicano del Seguro SocialMexico City 06720Mexico unidad de investigacion en Biomedicina y Oncologia Genomica Instituto Mexciano del Seguro SocialMexico City 07300Mexico Servicio de Colon y Recto Hospital de Oncología Centro Medico Nacional Siglo XXIInstituto Mexicano del Seguro SocialMexico City 06720Mexico Laboratorio nacional en Salud Facultad de Estudios Superiores IztacalaUniversidad Nacional Autónoma de MéxicoTlalnepantla 54090Estado de MexicoMexico

Colorectal cancer(CRC)remains one of the most commonly diagnosed and deadliest types of cancer *** displays a desmoplastic reaction(DR)that has been inversely associated with poor prognosis;less DR is associated with a better *** reaction generates excessive connective tissue,in which cancer-associated fibroblasts(CAFs)are critical cells that form a part of the tumor *** are directly involved in tumorigenesis through different ***,their role in immunosuppression in CRC is not well understood,and the precise role of signal transducers and activators of transcription(STATs)in mediating CAF activity in CRC remains *** the myriad chemical and biological factors that affect CAFs,different cytokines mediate their function by activating STAT signaling ***,the harmful effects of CAFs in favoring tumor growth and invasion may be modulated using STAT ***,we analyze the impact of different STATs on CAF activity and their immunoregulatory role.

关键词： Cancer-associated fibroblasts Signal transducer and activator of transcription signaling Colorectal cancer Immunity Immunosuppression

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Preclinical models of idiosyncratic drug-induced liver injury(iDILI):moving towards prediction

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Acta Pharmaceutica Sinica B 2021年第12期11卷 3685-3726页

作者： Antonio Segovia-Zafra Daniel E.Di Zeo-Sanchez Carlos Lopez-Gomez Zeus Perez-Valdes Eduardo Garcıa-Fuentes Raul J.Andrade m.Isabel Lucena marina Villanueva-Paz unidad de Gestio´n Clı´nica de Gastroenterologı´a Servicio de Farmacologıa ClınicaInstituto de Investigacio´n Biomedica de Malaga-IBIMAHospital Universitario Virgen de la VictoriaUniversidad de MalagaMalaga 29071Spain Centro de investigacion Biomedica en Red en el Area Tematica de enfermedades Hepaticas y Digestivas(CIBERehd) Madrid 28029Spain Platform ISCIII de ensayos Clınicos UICEC-IBIMAMalaga 29071Spain unidad de Gestion Clınica de Aparato Digestivo Instituto de Investigacion Biomedica de Malaga(IBIMA)Hospital Universitario Virgen de la VictoriaMalaga 29010Spai

Idiosyncratic drug-induced liver injury(iDILI) encompasses the unexpected harms that prescription and non-prescription drugs,herbal and dietary supplements can cause to the *** remains a major public health problem and a major cause of drug *** the lack of biomarkers for iDILI prediction,diagnosis and prognosis,searching new models to predict and study mechanisms of iDILI is *** of the major limitations of iDILI preclinical assessment has been the lack of correlation between the markers of hepatotoxicity in animal toxicological studies and clinically significant ***,major advances in the understanding of iDILI susceptibility and pathogenesis have come from the study of well-phenotyped iDILI ***,there are many gaps for explaining all the complexity of iDILI susceptibility and ***,there is a need to optimize preclinical human in vitro models to reduce the risk of iDILI during drug ***,the current experimental models and the future directions in iDILI modelling are thoroughly discussed,focusing on the human cellular models available to study the pathophysiological mechanisms of the disease and the most used in vivo animal iDILI *** also comment about in silico approaches and the increasing relevance of patient-derived cellular models.

关键词： Drug-induced liver injury Preclinical models mechanisms Oxidative stress mitochondrial damage Immune response Personalized medicine

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Cardiovascular assessment in liver transplant for nonalcoholic steatohepatitis patients:What we do,what we should do

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World Journal of Hepatology 2017年第15期9卷 697-703页

作者： Yolanda Sanchez-Torrijos Javier Ampuero manuel Romero-Gómez unidad Intercentros de Aparato Digestivo Hospitales Universitarios Virgen del Rocio-Virgen Macarena Instituto de Biomedicina de Sevilla Centro de investigación Biomédica en Red de enfermedades Hepáticas y Digestivas(CIBERehd)

non-alcoholic fatty liver disease(nAFLD) is increasing considerably due to the current lifestyle,which means that it is becoming one of the main indications for liver *** the other hand,there is a strong association between nAFLD and cardiovascular *** has been evidenced in many studies revealing a higher presence of carotid plaques or carotid intima-media thickness,leading to cardiovascular events and,ultimately,*** to the liver transplant guidelines,screening for heart disease in transplant candidates should be performed by electrocardiogram and transthoracic echocardiography while a stress echocardiogram should be reserved for those with more than two cardiovascular risk factors or greater than 50 years ***,there are no specific recommendations in nAFLD patients requiring a liver transplantation,despite its well-known cardiovascular risk *** studies have shown that these patients probably require a more exhaustive assessment and a global approach including other specialists such as cardiologists or ***,the incidence of cardiovascular disease is also increased in nAFLD patients in the post-transplantation period in comparison with other etiologies,because of the pre-existent risk factors together with the immunosuppressive ***,an early intervention on the lifestyle and the individualized selection of the immunosuppressive regimen could lead to a modification of the cardiovascular risk factors in nAFLD patients requiring a liver transplantation.

关键词： Cardiovascular risk non-alcoholic fatty liver disease non-alcoholic steatohepatitis Pre-transplant assessment Liver transplantation

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