scholarly journals The PNUTS-PP1 axis regulates endothelial aging and barrier function via SEMA3B suppression

2020 ◽  
Author(s):  
Noelia Lozano-Vidal ◽  
Laura Stanicek ◽  
Diewertje I. Bink ◽  
Veerle Kremer ◽  
Alyson W. MacInnes ◽  
...  
Keyword(s):  
Barrier Function ◽  
Health Care Systems ◽  
Multiorgan Failure ◽  
Cell Aging ◽  
Binding Motif ◽  
Loss Of Function ◽  
Nuclear Targeting ◽  
Age Related ◽  
Care Systems

ABSTRACTAge-related diseases pose great challenges to health care systems worldwide. During aging, endothelial senescence increases the risk for cardiovascular disease. Recently, it was described that Phosphatase 1 Nuclear Targeting Subunit (PNUTS) has a central role in cardiomyocyte aging and homeostasis. Here, we determined the role of PNUTS in endothelial cell aging. We confirmed that PNUTS is repressed in senescent endothelial cells (ECs). Moreover, PNUTS silencing elicits several of the hallmarks of endothelial aging: senescence, reduced angiogenesis and loss of barrier function. To validate our findings in vivo, we generated an endothelial-specific inducible PNUTS-deficient mouse line (Cdh5-CreERT2;PNUTSfl/fl), termed PNUTSEC-KO. Two weeks after PNUTS deletion, PNUTSEC-KO mice presented severe multiorgan failure and vascular leakage. We showed that the PNUTS binding motif for protein phosphatase 1 (PP1) is essential to maintain endothelial barrier function. Transcriptomic analysis of PNUTS-silenced HUVECs and lungs of PNUTSEC-KO mice revealed that the PNUTS-PP1 axis tightly regulates the expression of semaphorin 3B (SEMA3B). Indeed, silencing of SEMA3B completely restored barrier function after PNUTS loss-of-function. These results reveal a pivotal role for PNUTS in endothelial homeostasis through a PP1-SEMA3B downstream pathway that provides a potential target against the effects of aging in ECs.

scholarly journals Clinical Evolution of New Delhi Metallo-β-Lactamase (NDM) Optimizes Resistance under Zn(II) Deprivation

2017 ◽  
Vol 62 (1) ◽  
Author(s):  
Guillermo Bahr ◽  
Luisina Vitor-Horen ◽  
Christopher R. Bethel ◽  
Robert A. Bonomo ◽  
Lisandro J. González ◽  
...  
Keyword(s):  
Cellular Localization ◽  
Health Care Systems ◽  
Catalytic Efficiency ◽  
Catalytic Performance ◽  
System Response ◽  
New Delhi ◽  
Content Type ◽  
Carbapenem Resistant ◽  
Care Systems

ABSTRACTCarbapenem-resistantEnterobacteriaceae(CRE) are rapidly spreading and taking a staggering toll on all health care systems, largely due to the dissemination of genes coding for potent carbapenemases. An important family of carbapenemases are the Zn(II)-dependent β-lactamases, known as metallo-β-lactamases (MBLs). Among them, the New Delhi metallo-β-lactamase (NDM) has experienced the fastest and widest geographical spread. While other clinically important MBLs are soluble periplasmic enzymes, NDMs are lipoproteins anchored to the outer membrane in Gram-negative bacteria. This unique cellular localization endows NDMs with enhanced stability upon the Zn(II) starvation elicited by the immune system response at the sites of infection. Since the first report of NDM-1, new allelic variants (16 in total) have been identified in clinical isolates differing by a limited number of substitutions. Here, we show that these variants have evolved by accumulating mutations that enhance their stability or the Zn(II) binding affinityin vivo, overriding the most common evolutionary pressure acting on catalytic efficiency. We identified the ubiquitous substitution M154L as responsible for improving the Zn(II) binding capabilities of the NDM variants. These results also reveal that Zn(II) deprivation imposes a strict constraint on the evolution of this MBL, overriding the most common pressures acting on catalytic performance, and shed light on possible inhibitory strategies.

scholarly journals Transient non-integrative nuclear reprogramming promotes multifaceted reversal of aging in human cells

2019 ◽  
Author(s):  
Tapash Jay Sarkar ◽  
Marco Quarta ◽  
Shravani Mukherjee ◽  
Alex Colville ◽  
Patrick Paine ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Human Fibroblasts ◽  
Human Cells ◽  
Cellular Aging ◽  
Epigenetic Reprogramming ◽  
Epigenetic Clock ◽  
Nuclear Reprogramming ◽  
Loss Of Function ◽  
Age Related

SummaryAging is characterized by a gradual loss of function occurring at the molecular, cellular, tissue and organismal levels1-3. At the chromatin level, aging is associated with the progressive accumulation of epigenetic errors that eventually lead to aberrant gene regulation, stem cell exhaustion, senescence, and deregulated cell/tissue homeostasis3. The technology of nuclear reprogramming to pluripotency, through over-expression of a small number of transcription factors, can revert both the age and the identity of any cell to that of an embryonic cell by driving epigenetic reprogramming2,4,5. Recent evidence has shown that transient transgenic reprogramming can ameliorate age-associated hallmarks and extend lifespan in progeroid mice6. However, it is unknown how this form of ‘epigenetic rejuvenation’ would apply to physiologically aged cells and, importantly, how it might translate to human cells. Here we show that transient reprogramming, mediated by transient expression of mRNAs, promotes a rapid reversal of both cellular aging and of epigenetic clock in human fibroblasts and endothelial cells, reduces the inflammatory profile in human chondrocytes, and restores youthful regenerative response to aged, human muscle stem cells, in each case without abolishing cellular identity. Our method, that we named Epigenetic Reprogramming of Aging (ERA), paves the way to a novel, potentially translatable strategy for ex vivo cell rejuvenation treatment. In addition, ERA holds promise for in vivo tissue rejuvenation therapies to reverse the physiological manifestations of aging and the risk for the development of age-related diseases.

scholarly journals LncRNA KCNQ1OT1 attenuates sepsis-induced myocardial injury via regulating miR-192-5p/XIAP axis

2020 ◽  
Vol 245 (7) ◽  
pp. 620-630 ◽  
Author(s):  
Fangyuan Sun ◽  
Weifang Yuan ◽  
Hao Wu ◽  
Gang Chen ◽  
Yuxia Sun ◽  
...  
Keyword(s):  
Myocardial Injury ◽  
Myocardial Dysfunction ◽  
Health Care Systems ◽  
Cardiac Injury ◽  
Convincing Evidence ◽  
Luciferase Reporter ◽  
H9c2 Cardiomyocytes ◽  
Care Systems

Myocardial dysfunction is a prime cause of death in sepsis. This study is to delve into the function of lncRNA KCNQ1OT1 in myocardial injury induced by sepsis. Sepsis-induced myocardial injury model in rat was initiated by intraperitoneally injecting of LPS (10 mg/kg) in vivo, and cardiomyocyte H9c2 was treated with LPS to mimic sepsis in vitro. KCNQ1OT1 and miR-192-5p expressions were detected by qRT-PCR. The cell viability was probed with CCK-8 experiment and the apoptosis of the cardiomyocytes was tested using flow cytometry analysis. Western blot was operated to determine apoptosis-related proteins expressions. ELISA was used to evaluate the levels of TNF-α, IL-6, and IL-1β. Bioinformatics analysis, RT-PCR, dual luciferase reporter assay, and RNA immunoprecipitation experiment were utilized to detect the interrelation of genes. Herein, we proved that KCNQ1OT1 was considerably down-regulated, whereas miR-192-5p was markedly increased in myocardial tissues of septic rats. KCNQ1OT1 interrelated with miR-192-5p, and negatively modulated its expression levels. Overexpression of KCNQ1OT1 or the transfection of miR-192-5p inhibitors greatly facilitated the viability and impeded the apoptosis of H9c2 cardiomyocytes. miR-192-5p paired with the 3ʹUTR of XIAP, and repressed its protein expression, and XIAP was modulated positively by KCNQ1OT1. In conclusion, our work indicates that down-regulation of KCNQ1OT1 advances cardiac injury through regulating miR-192-5p/XIAP axis during sepsis. Impact statement Sepsis-induced cardiomyopathy remains to be a major challenge to health care systems around the globe. There are no known therapies currently available that can cure the disease. This study provides convincing evidence that KCNQ1OT1 could attenuate sepsis-mediated myocardial injury. We further demonstrate that the beneficial function of KCNQ1OT1 was achieved by regulating the miR-192-5p/XIAP axis. We therefore found a new mechanism of cardioprotective effect of KCNQ1OT1, one which also offers a novel theoretical basis for the therapy of sepsis-induced cardiomyopathy.

scholarly journals The PDZ Binding Motif of Human Papillomavirus Type 16 E6 Induces PTPN13 Loss, Which Allows Anchorage-Independent Growth and Synergizes with Ras for Invasive Growth

2007 ◽  
Vol 82 (5) ◽  
pp. 2493-2500 ◽  
Author(s):  
William C. Spanos ◽  
Andrew Hoover ◽  
George F. Harris ◽  
Shu Wu ◽  
Guinevere L. Strand ◽  
...  
Keyword(s):  
Human Papillomavirus ◽  
Tyrosine Phosphatase ◽  
Binding Motif ◽  
Ras Signaling ◽  
Invasive Growth ◽  
Dependent Manner ◽  
Loss Of Function ◽  
Hpv16 E6 ◽  
Anchorage Independent Growth

ABSTRACT The human papillomavirus (HPV) oncogene E6 has been shown to perform multiple functions (p53 degradation, telomerase activation, etc.) that play a role in oncogenic transformation. Beyond known E6 functions, an undefined mechanism that allows cellular invasion requires the E6 PDZ binding motif (PDZBM). Here, we show that HPV type 16 (HPV16) E6 interacts with and induces loss of a protein tyrosine phosphatase (PTPN13) in a PDZBM-dependent manner. PTPN13 loss induced either by the presence of E6 or by a short hairpin RNA strategy allows for anchorage-independent growth (AIG) and synergy with a known oncogene, Rasv12, resulting in invasive growth in vivo. Restoring PTPN13 expression reverses AIG in cells lacking PTPN13. A genomic analysis of colorectal carcinoma has identified an association between PTPN13 loss-of-function mutations and aberrant Ras signaling. Our findings support this correlation and provide methods for further evaluation of the mechanisms by which PTPN13 loss/Ras expression leads to invasive growth, the results of which will be important for treatment of HPV-related and non-HPV cancer.

Role of estrogen in the management of COVID – 19 in females

2020 ◽  
Vol 10 (3) ◽  
pp. 67-70
Author(s):  
Keerthi Chadam Venkatesulu ◽  
Shaik Habeeb Jan ◽  
Harika Sree Gaddam
Keyword(s):  
Health Care Systems ◽  
Treatment Options ◽  
Adverse Outcomes ◽  
Older Individuals ◽  
Therapeutic Benefits ◽  
Age Related ◽  
Disease Condition ◽  
Care Systems ◽  
The Difference

With the increase, the spread of COVID-19 its effect can be seen on health care systems seek innovative treatment ways as the need of the hour. The suspected leading cause of COVID-19 is due to the response to inflammations and the cytokine storm, which majorly damages the lung tissue. The difference in response to the vaccine can be seen due to different sex. Moreover, age-related decrease in sex steroid hormones like Estrogen as well as testosterone can promote pro-inflammatory raise in older individuals which in turn increases the risk of COVID-19 related adverse outcomes. Such sex hormones have the capacity of mitigating inflammatory response and can also provide promising therapeutic benefits for patients suffering from COVID-19. Moreover, over above the effects of on any ERS, these drugs showed useful ancillary properties. Most showed to highlight broader roles in mitigating viral replication by the ER-independent mechanisms as mentioned. Data simplifies ER modulation an apt pharmacological approach for restricting storm and thus prevents the inflammation due to COVID-19. Mainly the application of or tissue-selective estrogen complex can provide a pharmacological response. Such treatment options can be fruitful for both sexes in the early phase of such disease condition to prevent further progression of the disease to severe forms.

User Diversity as a Challenge for the Integration of Medical Technology into Future Smart Home Environments

2012 ◽  
pp. 553-582 ◽  
Author(s):  
Wiktoria Wilkowska ◽  
Martina Ziefle
Keyword(s):  
Medical Technology ◽  
Health Care Systems ◽  
Home Environments ◽  
Medical Technologies ◽  
Technology Generation ◽  
Age Related ◽  
Medical Sector ◽  
Care Systems ◽  
And Gender

Facing the growing aging population in many countries of the world, healthcare-related technologies become increasingly important, representing a possible solution to the soaring overstrained health care systems and dwindling number of caregivers. Though a user-centred and sensible integration of medical technology in home environments is highly challenging, especially when focusing on the group of old and frail users. Their specific needs and wants, their (dis)abilities and limitations have to be carefully considered, in order to reach full acceptance and a successful rollout of e-health applications in home environments. As the knowledge about acceptance in the medical sector is still limited, an elaborate research is needed in order to understand and respect aged persons’ specific demands. In an empirical approach, the role of age, technology generation, technical expertise, and gender are determining for the acceptance of medical technologies. As the acceptance of medical technologies might be also biased by social norms and the way aging and age-related consequences are evaluated within a society, individual ageing concepts as well as economic and educational levels were considered for the evaluation of the perceived benefits and drawbacks of medical technologies. Outcomes show the importance of understanding users’ needs and wants in order to develop user-centred medical technology concepts and to allow a successful rollout.

scholarly journals Curculigoside Ameliorates Bone Loss by Influencing Mesenchymal Stem Cell Fate in Aging Mice

2021 ◽  
Vol 9 ◽  
Author(s):  
Na Wang ◽  
Ziyi Li ◽  
Shilun Li ◽  
Yukun Li ◽  
Liu Gao ◽  
...  
Keyword(s):  
Stem Cell ◽  
Bone Loss ◽  
Cell Fate ◽  
Cell Lineage ◽  
Binding Motif ◽  
Osteoporosis Therapy ◽  
Senile Osteoporosis ◽  
Age Related

Senile osteoporosis is characterized by increased bone loss and fat accumulation in marrow. Curculigoside (CCG) is the major bioactive component of Curculigo orchioides, which has been used as anti-osteoporosis therapy for elder patients since antiquity. We aimed to investigate the underlying mechanisms by which CCG regulated the bone-fat balance in marrow of aging mice. In our study, CCG treatment was identified to interfere with the stem cell lineage commitment both in vivo and in vitro. In vivo, CCG promoted the transcriptional co-activator with PDZ-binding motif (TAZ) expression to reverse age-related bone loss and marrow adiposity. In vitro, proper concentration of CCG upregulated TAZ expression to increase osteogenesis and decrease adipogenesis of bone marrow mesenchymal stem cells (BMSCs). This regulating effect was discounted by TAZ knockdown or the use of MEK-ERK pathway inhibitor, UO126. Above all, our study confirmed the rescuing effects of CCG on the differential shift from adipogenesis to osteogenesis of BMSCs in aging mice and provided a scientific basis for the clinical use of CCG in senile osteoporosis.

The Challenges of Treating Neovascular Age-Related Macular Degeneration

2021 ◽  
Author(s):  
Marlene Hollaus ◽  
Wolf Bühl ◽  
Ursula Schmidt-Erfurth ◽  
Stefan Sacu
Keyword(s):  
Health Care ◽  
Macular Degeneration ◽  
Vision Loss ◽  
Health Care Systems ◽  
Developed Countries ◽  
Modern Medicine ◽  
Age Related Macular Degeneration ◽  
Age Related ◽  
Effective Form ◽  
Care Systems

AbstractAge-related macular degeneration (AMD) is one of the main causes of visual impairment and blindness in patients over 60 years in developed countries. Whilst no effective form of therapy is available for the dry form of AMD, intravitreal application of anti-VEGF substances is able to prevent the progression of neovascular AMD (nAMD) in most cases. Aside from the drugs ranibizumab, aflibercept and brolucizumab, other agents such as bevacizumab are often used off-label in order to save expense. The treatment intervals have also been refined, so as to reduce the burden on patients and health care systems. After fixed injection intervals, the pro re nata-regimen has been developed. Each month, it is decided whether the patient receives intravitreal injections based on fixed criteria. In the treat and extend-protocol, patients receive injections on each visit, but the intervals between injections vary due to the clinical outcomes. The observe-and-plan regime allows scheduling of the injection intervals in blocks, for three consecutive injections at a time. However, results of real-world studies were not able to reproduce those obtained in the pivotal studies. A high number of visits and fear of the injection procedure impose a burden on patients, that is mostly accepted due to fear of vision loss. Caregivers also complain of loss of productivity and income from having to provide regular support to patients. Health care systems worldwide are affected by increasing treatment numbers and the costs involved. The treatment of nAMD constitutes an achievement for modern medicine. However, despite the challenges, it must be evaluated and reviewed repeatedly in order to provide the best therapy for patients.

A Review of DNA and Histone Methylation Alterations in the New Era of Diagnosis and Treatment of Retinal Diseases

2020 ◽  
Vol 20 ◽  
Author(s):  
Faezeh Maroufi ◽  
Seyed Ahmad Rasoulinejad
Keyword(s):  
Dna Methylation ◽  
Histone Methylation ◽  
Health Care Systems ◽  
Expression Patterns ◽  
Age Related Macular Degeneration ◽  
Epigenetic Therapy ◽  
Retinal Diseases ◽  
Severe Visual Loss ◽  
Age Related ◽  
Care Systems

: Epigenetics has an important role in gene regulation and other cellular processes. DNA methylation, as one of the main mechanisms of epigenetics, is a type of post-replication modifications. Aberrant DNA methylation can alter gene expression patterns; so, plays a considerable role in the pathogenesis of many diseases. DNA methylation alterations in promoter of specific genes can be used for diagnosis and proprietary targets for treatment that known as “biomarker”. Early diagnosis and prevention may be possible by these biomarkers. According to the recent studies, DNA methylation abnormalities have an important role in retinogenesis and pathogenesis of retinal diseases. Retinal diseases are the main cause of blindness and severe visual loss in the world and will continue to increase. Also, they inflict enormous burden on society and health care systems. Therefore, it is important to focus on the better recognition and prevention of retinal diseases, and fining new targets for treatment. DNA methylation lionized as attractive therapeutic targets due to its reversibility. Epigenetic therapy has a high potency in treatment of retinal diseases. Here, we reviewed the DNA and histone methylation alterations in common retinal diseases, focusing on age-related macular degeneration (AMD), diabetic retinopathy, retinal detachment (RD), retinitis pigmentosa, retinal aging and retinoblastoma, and then we surveyed some new approaches of epigenetic therapy in retinal disorders.

Sign in / Sign up

Export Citation Format

Share Document