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Contribution of mammalian target of rapamycin in the pathophysiology of cirrhotic cardiomyopathy

World Journal of Gastroenterology 2016年第19期22卷 4685-4694页

作者： Seyed Soheil Saeedi Saravi Mahmoud Ghazi-Khansari Shahram Ejtemaei Mehr Maliheh Nobakht Seyyedeh Elaheh Mousavi Ahmad Reza Dehpour Department of Pharmacology School of Medicine Tehran University of Medical Sciences Experimental Medicine Research center Tehran University of Medical Sciences Department of Toxicology-Pharmacology Faculty of Pharmacy Guilan University of Medical Sciences Department of Anatomy School of Medicine Iran University of Medical Sciences

AIM: To explore the role of mammalian target of rapamycin(m TOR) in the pathogenesis of cirrhotic cardiomyopathy and the potential of rapamycin to improve this pathologic ***: Male albino Wistar rats weighing 100-120 g were treated with tetrachloride carbon(CCl_4) for 8 wk to induce cirrhosis. Subsequently, animals were administered rapamycin(2 mg/kg per day). The QT_c intervals were calculated in a 5-min electrocardiogram. Then, the left ventricular papillary muscles wereisolated to examine inotropic responsiveness to β-adrenergic stimulation using a standard organ bath equipped by Powerlab system. Phosphorylated-m TOR localization in left ventricles was immunohistochemically assessed, and ventricular tumor necrosis factor(TNF)-α was measured. Western blot was used to measure levels of ventricular phosphorylated-m TOR ***: Cirrhosis was confirmed by hematoxylin and eosin staining of liver tissues, visual observation of lethargy, weight loss, jaundice, brown urine, ascites, liver stiffness, and a significant increase of spleen weight(P used a significant decrease of contractile responsiveness to isoproterenol stimulation and a significant increase in cardiac TNF-α. These findings were correlated with data from western blot and immunohistochemical studies on phosphorylated-m TOR expression in left ventricles. Phosphorylated-m TOR was significantly enhanced in cirrhotic rats, especially in the endothelium, compared to controls. Rapamycin treatment significantly increased contractile force and myocardial localization of phosphorylated-m TOR and decreased cardiac TNF-α concentration compared to cirrhotic rats with no treatment. CONCLusION: In this study, we demonstrated a potential role for cardiac m TOR in the pathophysiology of cirrhoti

关键词： Cirrhotic cardiomyopathy Rat Mammalian target of Rapamycin Rapamycin Inotropic effect

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The human and mouse sex-determining SRY genes repress the Rspo1/β-catenin signaling

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Journal of Genetics and Genomics 2009年第4期36卷 193-202页

作者： Yun-Fai Chris Lau Division of Cell and Developmental Genetics Department of Medicine VA Medical Center University of CaliforniaSan Francisco CA 94121 USA

The sex-determining region Y （SRY） is the gene on the Y chromosome responsible for switching on male sex determination during mammalian embryogenesis. In its absence, ovaries develop in the embryo. Hence, ovarian determination and differentiation is considered to be a default, or passive, developmental pathway. Recently this classical paradigm of sex determination has been challenged with the discovery of the R-spondin 1 （RSPO1） as an active ovarian determinant. Mutations of RSPO1 cause a female-to-male sex reversal. RSPO1 synergizes with WNT4 in activating an ovarian development in the bipotential gonad via the canonical Wnt signaling. Early studies showed that SRY represses such Wnt signaling, but also generated discrepancies on whether only mouse Sry is capable of inhibiting such Wnt signaling and whether both human and mouse SRY proteins are able to interact with β-catenin, the intracellular messenger responsible for executing the Wnt signals. Our studies show that both human SRY and mouse Sry are capable of repressing the Rspol/Wnt/β-catenin signaling. However, the repression activities vary among different SRY/Sry proteins and paradoxically related to the presence and/or size of an acidic/glutamine-rich domain. The HMG box of human SRY could bind directly to β-catenin while the mouse Sry binds to β-catenin via its HMG box and glutamine-rich domain. The results clarify some of the initial discrepancies, and raise the possibility that SRY interacts with β-catenin in the nucleus and represses the transcriptional activation of the Rspol/Wnt target genes involved in ovarian determination, thereby switching on testis determination.

关键词： SRY sex determination R-spondin 1 canonical Wnt signaling β-catenin protein interaction

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Nanomaterials incorporated ultrasound contrast agents for cancer theranostics

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Cancer Biology & Medicine 2016年第3期13卷 313-324页

作者： Lei Fu Heng-Te Ke College of Pharmaceutical Sciences Soochow University center of Systems Medicine Chinese Academy of Medical Sciences Suzhou Institute of Systems Medicine

Nanotechnology provides various nanomaterials with tremendous functionalities for cancer diagnostics and ***, theranostics has been developed as an alternative strategy for efficient cancer treatment through combination of imaging diagnosis and therapeutic interventions under the guidance of diagnostic results. Ultrasound(us) imaging shows unique advantages with excellent features of real-time imaging, low cost, high safety and portability, making us contrast agents(UCAs)an ideal platform for construction of cancer theranostic agents. This review focuses on the development of nanomaterials incorporated multifunctional UCAs serving as theranostic agents for cancer diagnostics and therapeutics, via conjugation of superparamagnetic iron oxide nanoparticles(SPIOs), Cu S nanoparticles, DNA, si RNA, gold nanoparticles(GNPs), gold nanorods(GNRs), gold nanoshell(GNS), graphene oxides(GOs), polypyrrole(PPy) nanocapsules, Prussian blue(PB) nanoparticles and so on to different types of UCAs. The cancer treatment could be more effectively and accurately carried out under the guidance and monitoring with the help of the achieved theranostic agents. Furthermore, nanomaterials incorporated theranostic agents based on UCAs can be designed and constructed by demand for personalized and accurate treatment of cancer, demonstrating their great potential to address the challenges of cancer heterogeneity and adaptation, which can provide alternative strategies for cancer diagnosis and therapeutics.

关键词： Cancer theranostics ultrasound contrast agents nanomaterials nanomedicine

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Targeting late SV40 factor: Is the achilles heel of hepatocarcinogenesis revealed?

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World Journal of Gastroenterology 2012年第46期18卷 6709-6711页

作者： Amir Shlomai Institute of Gastroenterology and Liver Diseases Tel-Aviv Sourasky Medical Center and Sackler Faculty of Medicine Tel-Aviv University

Hepatocellular carcinoma (HCC) is a dreadful cancer and a major cause of death among patients with chronic liver disease and cirrhosis. The apparent alterations in a diversity of intracellular pathways found in HCC has set the rational for developing molecular-directed drugs that simultaneously inhibit multiple pathways, such as the multi-kinase inhibitor Sorafenib. However, recently this concept has been challenged by showing that HCC is heavily dependent on a single oncogene designated late SV-40 factor (LSF), a transcription factor that is over-expressed in liver cancer cells and that its expression is strongly correlated with tumor grade and aggressiveness. Furthermore, using an intensive screening for drugs that inhibit LSF activity, grant et al have found a molecule designated factor quinolinone inhibitor 1 that can specifically block the ability of LSF to bind its target promoters, resulting in a massive death of HCC cells both in vitro and in vivo. The innovative findings of HCC representing "oncogene addiction" to LSF and the ability of a single molecule to block the activity of this oncogene resulting in tumor abolishment are encouraging and provide us with the hope that the "Achilles heel" of HCC has been found.

关键词： Oncogene addiction Hepatocellular carcinoma Late SV40 factor Transcription factor Multikinase inhibit

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P2X7 receptor antagonism in amyotrophic lateral sclerosis

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Neural Regeneration Research 2017年第5期12卷 749-750页

作者： Ronald Sluyter Rachael Bartlett Diane Ly Justin J.Yerbury School of Biological Sciences and center for medical and Molecular Bioscience University of Wollongong Wollongong NSW Australia Illawarra Health and medical Research Institute NSW Wollongong Australia

Amyotrophic lateral sclerosis（ALS）is a rapidly progressive disorder characterized by the degeneration and subsequent loss of upper and lower motor neurons,resulting in reduced muscle function and paralysis（Mathis et al.,2017）.Current therapies are limited to the oral administration of riluzole,which improves survival by only 3 months（Mathis et al.,2017）.Thus,

关键词： BBG SOD

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Mind-body control:a new perspective on motor neuron function

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Signal Transduction and Targeted Therapy 2024年第9期9卷 3557-3559页

作者： Maria-Luise Petrovic-Erfurth Albena Jordanova Molecular Neurogenomics Group VIB Center for Molecular NeurologyVIB2610 AntwerpBelgium Molecular Neurogenomics Group Department of Biomedical SciencesUniversity of Antwerp2610 AntwerpBelgium Molecular Medicine center Department of Medical Chemistry and BiochemistryMedical University-Sofia1431 SofiaBulgaria

A recent study published in Nature1 used an optogeneticallyactivated behavioral paradigm in fruit flies to demonstrate that individual motor neurons command their target muscles in a biased manner to execute body movements,based on the mechanosensory feedback preceding the *** finding contradicts the current postulate that activation of a specific motor neuron would always result in a pre-determined fixed muscle response,adding important new perspectives in the fields of neurobiology,biomechanics,and *** a dancing ballerina executes her turns,she typically controls her head position and fixes her gaze on a single orientation *** spotting technique helps her to maintain balance and to prevent dizziness during her complex *** how is this mind-body control achieved from a neurobiological point of view?

关键词： execute individual maintain

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Establishment of organoid models for pancreatic ductal adenocarcinoma and screening of individualized therapy strategy

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Animal Models and Experimental Medicine 2023年第5期6卷 409-418页

作者： Miaomiao Gong Han Meng Dengxu Tan Peng Li Jing Qin Qingling An Changhong Shi Jiaze An Division of Cancer Biology Laboratory Animal CenterFourth Military Medical UniversityXi'anChina School of Basic medical Sciences Medical College of Yan'an UniversityYananChina Animal Experiment center Guangzhou University of Chinese MedicineGuangzhouChina Department of Hepatobiliary and Pancreaticosplenic Surgery Xijing HospitalFourth Military Medical UniversityXi'anChina

Background:Patients with pancreatic ductal adenocarcinoma(PDAC)who undergo surgical resection and receive effective chemotherapy have the best chance for longterm ***,because of the heterogeneity of pancreatic cancer,it is difficult to find a personalized treatment strategy for *** are ideal preclinical models for personalized ***,we explore the cultivation conditions and construction methods of PDAC organoid models to screen the individualized therapy ***:Fresh PDAC tissues from surgical resection were collected and digested with digestive enzymes;then the tumor cells were embedded in Matrigel with a suitable medium to establish the PDAC organoid *** genetic stability of the organoids was analyzed using whole exon sequencing;hematoxylin and eosin staining and immunohistochemistry of organoids were performed to analyze their consistency with the pathological morphology of the patient's tumor tissue;After 2 days of organoid culture,we selected four commonly used clinical chemotherapy drugs for single or combined treatment to analyze drug ***:Two cases of PDAC organoid models were successfully established,and the results of their pathological characteristics and exome sequencing were consistent with those of the patient's tumor *** PDAC organoids showed more sensitivity to gemcitabine and cisplatin,and the combined treatment was more effective than ***:Both organoids better retained the pathological characteristics,genomic stability,and heterogeneity with the original *** PDAC organoids exhibited different sensitivities to the same ***,this study provided ideal experimental models for screening individualized therapy strategy for patients with PDAC.

关键词： 3D culture individualized therapy organoid pancreatic ductal adenocarcinoma

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Non-invasive digestion monitoring with an FDA-cleared wearable biosensor:further validation for use in tracking food ingestion

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Gastroenterology Report 2021年第5期9卷 475-477,I0003页

作者： Erica R.Cohen Mayra Lopez Brennan M.R.Spiegel Christopher V.Almario Karsh Division of Gastroenterology and Hepatology Cedars-Sinai Medical CenterLos AngelesCAUSA Cedars-Sinai center for Outcomes Research and Education(CS-CORE) Los AngelesCAUSA Division of Health Services Research Cedars-Sinai Medical CenterLos AngelesCAUSA Department of Health Policy and Management UCLA Fielding School of Public HealthLos AngelesCAUSA Division of Informatics Cedars-Sinai Medical CenterLos AngelesCAUSA

Introduction Obesity affects one-third of the us population and accounts for$200 billion/year in expenditures[1].Diet and exercise form the cornerstone of management,yet are often ineffective[2].Mobile health applications(mHealth apps)can augment traditional strategies;Gill and Panda[3]demonstrated that obese patients can modify their eating behavior and lose weight using an mHealth app to track food *** promising,these apps typically require active data input and currently lack passively collected,physiologic input to support sustained behavior change.

关键词：生物传感器消化功能食物摄入

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Potential hydrodynamic origin of frictional transients in sliding mesothelial tissues

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Friction 2013年第2期1卷 163-177页

作者： Stephen H.LORING James P.BUTLER Department of Anesthesia Critical Care and Pain MedicineBeth Israel Deaconess Medical Center and Harvard Medical SchoolBoston MA 02215USA Department of Medicine Division of Sleep MedicineBrigham and Women’s Hospital and Harvard Medical SchoolBoston MA 02215USA

Steady-state and transient variations in frictional force observed in tribological experiments of mesothelial tissues sliding in lubricant were analyzed with a mathematical model to test the hypothesis that such phenomena are manifestations of elastohydrodynamic lubrication and,importantly,do not require physical contact between the sliding *** model incorporates three phenomena characteristic of elastohydrodynamic lubrication:thinning of the liquid layer between sliding surfaces under a normal load(“squeeze-out”),thickening of the liquid layer due to hydrodynamic pumping,and smoothing of the elastic surfaces caused by hydrodynamic pressure *** in soft mesothelial tissues sliding in lubricant showed variations in steady state friction with velocity,load,and lubricant *** non-steady sliding,the decay rate of frictional transients at the start of rotation varied with velocity,the amplitudes of these transients varied with the preceding periods without rotation,and frictional force varied during sinusoidal *** simulations were qualitatively similar to experimental results,supporting these *** lubricant viscosity increased lubricating layer thickness and lowered friction at low speeds and increased friction at high speeds,supporting hydrodynamic *** conclude that the frictional variations seen with sliding mesothelial tissues are consistent with elastohydrodynamic lubrication without contact between the sliding surfaces.

关键词： pleural space breathing pericardium lubrication model

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Regulation of immune-related diseases by multiple factors: a meeting report of 2017 International Workshop of the Chinese Academy of medical Sciences Initiative for Innovative Medicine on Tumor Immunology

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Acta Pharmaceutica Sinica B 2017年第4期7卷 532-540页

作者： Bing Cui Xuetao Cao Weiping Zou Yonghong Wan Ning Wang Yaohe Wang Pingping Li Fang Hua Yuying Liu Xiaowei Zhang Ke Li Xiaoxi Lv Bo Huang Zhuowei Hu State Key Laboratory of Bioactive Substance and Function of Natural Medicines Institute of Materia MedicaChinese Academy of Medical Sciences and Peking Union Medical College National Key Laboratory of medical Molecular Biology Department of ImmunologyInstitute of Basic Medical SciencesPeking Union Medical CollegeChinese Academy of Medical Sciences Department of Surgery University of Michigan School of Medicine The University of Michigan Comprehensive Cancer center University of Michigan Graduate Programs in Immunology and Tumor Biology University of Michigan Department of Pathology and Molecular Medicine Mc Master Immunology Research CentreMc Master University Department of Mechanical Science and Engineering University of Illinois at Urbana-Champaign Laboratory for Cellular Biomechanics and Regenerative Medicine Department of Biomedical EngineeringSchool of Life Science and TechnologyHuazhong University of Science and Technology center for Molecular Oncology Barts Cancer InstituteQueen Mary University of London School of Basic medical Sciences Academy of Medical SciencesZhengzhou University Sino-British Research Centre for Molecular Oncology National Center for International Research in Cell and Gene TherapyZhengzhou University Diabetes Research center of Chinese Academy of medical Sciences Institute of Medicinal Biotechnology Chinese Academy of Medical Sciences and Peking Union Medical College Clinical Immunology center Chinese Academy of Medical Sciences Department of Biochemistry&Molecular Biology Tongji Medical CollegeHuazhong University of Science&Technology

Immune cells play key roles in cancer and chronic inflammatory disease. A better understanding of the mechanisms and risks will help develop novel target therapies. At the 2017 International Workshop of the Chinese Academy of medical Sciences Initiative for Innovative Medicine on Tumor Immunology held in Beijing, China, on May 12, 2017, a number of speakers reported new findings and ongoing studies on immune-related diseases such as cancer, fibrotic disease, diabetes, and others. A considerably insightful overview was provided on cancer immunity, tumor microenvironments,and new immunotherapy for cancer. In addition, chronic inflammatory diseases were discussed. These findings may offer new insights into targeted immunotherapy.

关键词： Tumor Immunology Chromatin Exosomes Microparticles Vaccines Oxidative stress Dormancy Protein quality control Inflammation

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