518 research outputs found
Repression of hypoxia-inducible factor-1 contributes to increased mitochondrial reactive oxygen species production in diabetes
Background: Excessive production of mitochondrial reactive oxygen species (ROS) is a central mechanism for the development of diabetes complications. Recently, hypoxia has been identified to play an additional pathogenic role in diabetes. In this study, we hypothesized that ROS overproduction was secondary to the impaired responses to hypoxia due to the inhibition of hypoxia-inducible factor-1 (HIF-1) by hyperglycemia. Methods: The ROS levels were analyzed in the blood of healthy subjects and individuals with type 1 diabetes after exposure to hypoxia. The relation between HIF-1, glucose levels, ROS production and its functional consequences were analyzed in renal mIMCD-3 cells and in kidneys of mouse models of diabetes. Results: Exposure to hypoxia increased circulating ROS in subjects with diabetes, but not in subjects without diabetes. High glucose concentrations repressed HIF-1 both in hypoxic cells and in kidneys of animals with diabetes, through a HIF prolyl-hydroxylase (PHD)-dependent mechanism. The impaired HIF-1 signaling contributed to excess production of mitochondrial ROS through increased mitochondrial respiration that was mediated by Pyruvate dehydrogenase kinase 1 (PDK1). The restoration of HIF-1 function attenuated ROS overproduction despite persistent hyperglycemia, and conferred protection against apoptosis and renal injury in diabetes. Conclusions: We conclude that the repression of HIF-1 plays a central role in mitochondrial ROS overproduction in diabetes and is a potential therapeutic target for diabetic complications. These findings are timely since the first PHD inhibitor that can activate HIF-1 has been newly approved for clinical use. Funding: This work was supported by grants from the Swedish Research Council, Stockholm County Research Council, Stockholm Regional Research Foundation, Bert von Kantzows Foundation, Swedish Society of Medicine, Kung Gustaf V:s och Drottning Victorias Frimurarestifelse, Karolinska Institute's Research Foundations, Strategic Research Programme in Diabetes, and Erling-Persson Family Foundation for S-B.C.; grants from the Swedish Research Council and Swedish Heart and Lung Foundation for T.A.S.; and ERC consolidator grant for M.M.Peer reviewe
The Impact of the COVID-19 Pandemic on Women's Perinatal Mental Health: Preliminary Data on the Risk of Perinatal Depression/Anxiety from a National Survey in Italy
Increasing evidence suggests that during the COVID-19 pandemic, anxiety and depression during the perinatal period increased. The aim of the study is to estimate the prevalence of risk for both maternal depression and anxiety among women attending 18 healthcare centres in Italy during the SARS-COV-2 pandemic and to investigate the psychosocial risks and protective factors associated. It was divided into a retrospective phase (2019, 2020, and the first nine months of 2021) and a prospective phase (which began in November 2021 and it is still ongoing), which screened 12,479 and 2349 women, respectively, for a total of 14,828 women in the perinatal period. To evaluate the risk of anxiety and depression, the General Anxiety Disorder-7 (GAD-7), the Edinburgh Postnatal Depression Scale (EPDS), and an ad hoc form were used to collect sociodemographic variables. In the prospective study, the average age of the women is 31 (range 18-52) years. Results showed that the percentage of women who had EPDS score â„9 increased from 11.6% in 2019 to 25.5% in the period ranging from November 2021 to April 2022. In logistic regression models, the variables associated with the risk of depression at a level â€0.01 include having economic problems (OR 2.16) and not being able to rely on support from relatives or friends (OR 2.36). Having the professional status of the housewife is a lower risk (OR 0.52). Those associated with the risk of anxiety include being Italian (OR 2.97), having an education below secondary school level (OR 0.47), having some or many economic problems (OR 2.87), being unable to rely on support from relatives or friends (OR 2.48), and not having attended an antenatal course (OR 1.41). The data from this survey could be useful to determine the impact of the SARS-COV-2 pandemic on women and to establish a screening program with common and uniformly applied criteria which are consistent with national and international women's mental health programs
Multidifferential study of identified charged hadron distributions in -tagged jets in proton-proton collisions at 13 TeV
Jet fragmentation functions are measured for the first time in proton-proton
collisions for charged pions, kaons, and protons within jets recoiling against
a boson. The charged-hadron distributions are studied longitudinally and
transversely to the jet direction for jets with transverse momentum 20 GeV and in the pseudorapidity range . The
data sample was collected with the LHCb experiment at a center-of-mass energy
of 13 TeV, corresponding to an integrated luminosity of 1.64 fb. Triple
differential distributions as a function of the hadron longitudinal momentum
fraction, hadron transverse momentum, and jet transverse momentum are also
measured for the first time. This helps constrain transverse-momentum-dependent
fragmentation functions. Differences in the shapes and magnitudes of the
measured distributions for the different hadron species provide insights into
the hadronization process for jets predominantly initiated by light quarks.Comment: All figures and tables, along with machine-readable versions and any
supplementary material and additional information, are available at
https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-013.html (LHCb
public pages
Study of the decay
The decay is studied
in proton-proton collisions at a center-of-mass energy of TeV
using data corresponding to an integrated luminosity of 5
collected by the LHCb experiment. In the system, the
state observed at the BaBar and Belle experiments is
resolved into two narrower states, and ,
whose masses and widths are measured to be where the first uncertainties are statistical and the second
systematic. The results are consistent with a previous LHCb measurement using a
prompt sample. Evidence of a new
state is found with a local significance of , whose mass and width
are measured to be and , respectively. In addition, evidence of a new decay mode
is found with a significance of
. The relative branching fraction of with respect to the
decay is measured to be , where the first
uncertainty is statistical, the second systematic and the third originates from
the branching fractions of charm hadron decays.Comment: All figures and tables, along with any supplementary material and
additional information, are available at
https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-028.html (LHCb
public pages
Measurement of the ratios of branching fractions and
The ratios of branching fractions
and are measured, assuming isospin symmetry, using a
sample of proton-proton collision data corresponding to 3.0 fb of
integrated luminosity recorded by the LHCb experiment during 2011 and 2012. The
tau lepton is identified in the decay mode
. The measured values are
and
, where the first uncertainty is
statistical and the second is systematic. The correlation between these
measurements is . Results are consistent with the current average
of these quantities and are at a combined 1.9 standard deviations from the
predictions based on lepton flavor universality in the Standard Model.Comment: All figures and tables, along with any supplementary material and
additional information, are available at
https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-039.html (LHCb
public pages
Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries
Abstract
Background
Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres.
Methods
This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and lowâmiddle-income countries.
Results
In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of âsingle-useâ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for lowâmiddle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia.
Conclusion
This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both highâ and lowâmiddleâincome countries
Effetti dell'ipossia e iperglicemia sulla bioenergetica cellulare
Mitochondria have a central role in energy supply in cells, ROS production and apoptosis and have been implicated in several human disease and mitochondrial dysfunctions in hypoxia have been related with disorders like Type II Diabetes, Alzheimer Disease, inflammation, cancer and ischemia/reperfusion in heart.
When oxygen availability becomes limiting in cells, mitochondrial functions are modulated to allow biologic adaptation. Cells exposed to a reduced oxygen concentration readily respond by adaptive mechanisms to maintain the physiological ATP/ADP ratio, essential for their functions and survival. In the beginning, the AMP-activated protein kinase (AMPK) pathway is activated, but the responsiveness to prolonged hypoxia requires the stimulation of hypoxia-inducible factors (HIFs).
In this work we report a study of the mitochondrial bioenergetics of primary cells exposed to a prolonged hypoxic period . To shine light on this issue we examined the bioenergetics of fibroblast mitochondria cultured in hypoxic atmospheres (1% O2) for 72 hours. Here we report on the mitochondrial organization in cells and on their contribution to the cellular energy state. Our results indicate that prolonged hypoxia cause a significant reduction of mitochondrial mass and of the quantity of the oxidative phosphorylation complexes. Hypoxia is also responsible to damage mitochondrial complexes as shown after normalization versus citrate synthase activity.
HIF-1α plays a pivotal role in wound healing, and its expression in the multistage process of normal wound healing has been well characterized, it is necessary for cell motility, expression of angiogenic growth factor and recruitment of endothelial progenitor cells. We studied hypoxia in the pathological status of diabetes and complications of diabetes and we evaluated the combined effect of hyperglycemia and hypoxia on human dermal ïŹbroblasts (HDFs) and human dermal micro-vascular endothelial cells (HDMECs) that were grown in high glucose, low glucose concentrations and mannitol as control for the osmotic challenge.I mitocondri hanno un ruolo fondamentale nella produzione di energia nella cellula, ma sono coinvolti anche in altri processi tra cui la produzione di ROS e lâapoptosi. Disfunzioni del metabolismo mitocondriale sono state associate a diversi disordini, tra cui: diabete di tipo II, malattia si Alzheimer, infiammazione, cancro ed ischemia cardiaca.
Quando i livelli di ossigeno nella cellula diventano limitanti, la funzione mitocondriale viene modulata per consentire lâadattamento biologico. La via dellâAMP- activated protein kinase (AMPK) ha il compito di monitorare lo stato energetico della cellula mantenendo i livelli fisioligici di ATP/ADP. In seguito allâesposizione prolungata in ambiente ipossico, lâattivazione di HIF-1 eâ in grado di upregolare diversi geni coinvolti nella sopravvivenza cellulare a basse concentrazioni di ossigeno. In questo lavoro, eâ stata valutata la bioenergetica mitocondriale in fibroblasti primari coltivati a basse concentrazioni di ossigeno (1 % O2) per 72 ore; in particolare, abbiamo preso in considerazione lâorganizzazione mitocondriale nella cellula e il loro contributo nel mantenere lo stato energetico cellulare. I nostri risultati indicano che lâesposizione prolungata allâipossia causa una significativa riduzione della massa mitocondriale e della quantitaâ dei complessi della fosforilazione ossidativa, nonostante le cellule siano in grado di mantenere i livelli intracellulari di ATP. Inoltre abbiamo studiato lâipossia nel contesto patologico del diabete ed in particolare delle complicanze del diabete.
Eâ noto che lâiperglicemia e lâipossia, dovuta ad ischemia a danni vascolari, hanno un ruolo importante nellâinsorgenza delle complicanze del diabete.
HIF-1α rappresenta uno stimolo nella rigenerazione delle ferite, in quanto stimola la vascolarizzazione e la migrazione dei cheranociti ed eâ stato ipotizzato che le cellule perdano la capacitaâ di adattarsi e rispondere allâipossia quando sono coltivate in presenza di elevate concentrazioni di glucosio (>25 mM). Abbiamo valutato il ruolo della destabilizzazione di HIF-1α nella produzione di ROS, considerati i principali responsabili della progressione del diabete
Mitochondrial respiratory chain supercomplex I-III in physiology and pathology
Recent investigations by native gel electrophoresis showed the existence of
supramolecular associations of the respiratory complexes, confirmed by electron
microscopy analysis and single particle image processing. Flux control analysis
demonstrated that Complex I and Complex III in mammalian mitochondria kinetically
behave as a single unit with control coefficients approaching unity for each
component, suggesting the existence of substrate channeling within the supercomplex.
The formation of this supramolecular unit largely depends on the lipid
content and composition of the inner mitochondrial membrane. The function of the
super-complexes appears not to be restricted to kinetic advantages in electron
transfer: we discuss evidence on their role in the stability and assembly of the
individual complexes, particularly Complex I, and in preventing excess oxygen
radical formation. There is increasing evidence that disruption of the super-complex
organization leads to functional derangements responsible for pathological changes,
as we have found in K-ras-transformed fibroblasts. Biochimica et Biophysica Acta
1797 (2010) 633â64
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