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1.
EMBO J ; 2024 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-38886581

RESUMO

Endothelial cell responses to fluid shear stress from blood flow are crucial for vascular development, function, and disease. A complex of PECAM-1, VE-cadherin, VEGF receptors (VEGFRs), and Plexin D1 located at cell-cell junctions mediates many of these events. However, available evidence suggests that another mechanosensor upstream of PECAM-1 initiates signaling. Hypothesizing that GPCR and Gα proteins may serve this role, we performed siRNA screening of Gα subunits and found that Gαi2 and Gαq/11 are required for activation of the junctional complex. We then developed a new activation assay, which showed that these G proteins are activated by flow. We next mapped the Gα residues required for activation and developed an affinity purification method that used this information to identify latrophilin-2 (Lphn2/ADGRL2) as the upstream GPCR. Latrophilin-2 is required for all PECAM-1 downstream events tested. In both mice and zebrafish, latrophilin-2 is required for flow-dependent angiogenesis and artery remodeling. Furthermore, endothelial-specific knockout demonstrates that latrophilin plays a role in flow-dependent artery remodeling. Human genetic data reveal a correlation between the latrophilin-2-encoding Adgrl2 gene and cardiovascular disease. Together, these results define a pathway that connects latrophilin-dependent G protein activation to subsequent endothelial signaling, vascular physiology, and disease.

2.
Mater Horiz ; 2024 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-38700262

RESUMO

Steels exhibit distinct properties that underscore their pivotal role in critical industries, such as maritime, aerospace, automotive, petrochemical, and biomedicine. In recent times, there has been an increasing trend towards manufacturing near-net-shape steel components through various additive manufacturing (AM) modalities, utilizing intricate 3D model data. Initially, powder bed fusion (PBF) technology garnered significant attention for the fabrication of steel components. Nonetheless, arc-directed energy deposition (arc-DED), also known as wire arc additive manufacturing (WAAM) technology, is progressively gaining prominence in the AM enterprise due to its high production rate, the ability to print large-scale components, and notably, reduced capital investment. While early research on WAAM-fabricated steels primarily focused on microstructural and mechanical characteristics, there is an increasing emphasis on the corrosion performance of WAAM steel components. These components often encounter exposure to corrosive environments in their intended applications. The existing literature lacks a comprehensive review that delves into the nuanced factors influencing the corrosion behavior of WAAM-fabricated steels and the primary corrosion mechanisms governing their degradation. Therefore, this review is dedicated to exploring the corrosion properties of WAAM-fabricated steels, identifying key parameters influencing their degradation behavior. Moreover, it offers an in-depth examination and discussion of the underlying mechanisms governing corrosion-induced deterioration. Furthermore, this review meticulously scrutinizes the microstructural features and WAAM technologies, providing clarity and organization regarding details relevant to the corrosion of WAAM steel components. To conclude, the paper highlights the existing research gaps related to the corrosion of WAAM steel, delineating potential avenues for future research.

3.
Materials (Basel) ; 17(7)2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38612132

RESUMO

Ferrous alloys, particularly steels, form a specialized class of metallic materials extensively employed in industrial sectors to combat deterioration and failures caused by wear. Despite their commendable mechanical properties, steels are not immune to wear-induced degradation. In this context, surface nanocrystallization (SNC) technologies have carved a distinct niche for themselves by enabling the nanostructuring of the surface layer (with grain sizes < 100 nm). This process enhances overall mechanical properties to a level desirable for wear resistance while preserving the chemical composition. Existing literature has consistently highlighted the efficacy of various SNC methods in improving the wear resistance of ferrous alloys, positioning SNC as a promising tool to extend materials' service life in practical applications. This review provides a comprehensive examination of the SNC techniques employed in surface treatment of ferrous alloys and their impact on wear behavior. We delved into the underlying mechanisms governing wear in SNC-treated Fe-based alloys and concluded with a discussion on current challenges and future perspectives in this evolving field.

4.
Mater Horiz ; 10(12): 5391-5435, 2023 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-37789823

RESUMO

The growing demand for materials with exceptional corrosion resistance and mechanical properties in the aerospace and ocean industries has led to increased research interest in versatile alloys like nickel-aluminum bronze (NAB). NABs exhibit excellent corrosion performance due to the formation of a protective, duplex corrosion product film on the surface, which is largely influenced by their complex microstructure. While NABs are typically produced as cast or wrought products, the emergence of additive manufacturing (AM) technologies has enabled 3D printing of near-net-shape NABs with intricate geometries. This paper provides a critical review of the corrosion properties, passivity, and microstructural characteristics of conventionally produced and AMed NAB alloys, as well as the fundamental mechanisms governing their corrosion behavior under varying conditions. Additionally, it highlights the current research gap and unprecedented challenges associated with the corrosion behavior of traditional and AMed NABs.

5.
Diabetes ; 72(12): 1781-1794, 2023 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-37725942

RESUMO

Insulin activates insulin receptor (IR) signaling and subsequently triggers IR endocytosis to attenuate signaling. Cell division regulators MAD2, BUBR1, and p31comet promote IR endocytosis on insulin stimulation. Here, we show that genetic ablation of the IR-MAD2 interaction in mice delays IR endocytosis, increases IR levels, and prolongs insulin action at the cell surface. This in turn causes a defect in insulin clearance and increases circulating insulin levels, unexpectedly increasing glucagon levels, which alters glucose metabolism modestly. Disruption of the IR-MAD2 interaction increases serum fatty acid concentrations and hepatic fat accumulation in fasted male mice. Furthermore, disruption of the IR-MAD2 interaction distinctly changes metabolic and transcriptomic profiles in the liver and adipose tissues. Our findings establish the function of cell division regulators in insulin signaling and provide insights into the metabolic functions of IR endocytosis. ARTICLE HIGHLIGHTS: The physiological role of IR endocytosis in insulin sensitivity remains unclear. Disruption of the IR-MAD2 interaction delays IR endocytosis and prolongs insulin signaling. IR-MAD2 controls insulin clearance and glucose metabolism. IR-MAD2 maintains energy homeostasis.


Assuntos
Resistência à Insulina , Receptor de Insulina , Animais , Masculino , Camundongos , Endocitose , Glucose/metabolismo , Homeostase , Insulina/metabolismo , Fígado/metabolismo , Receptor de Insulina/genética , Receptor de Insulina/metabolismo , Proteínas Mad2/metabolismo
6.
Int J Clin Pract ; 2023: 8966501, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36874385

RESUMO

Background: Performing spinal anesthesia with at least hemodynamic variation and complications is always challenging for anesthesiologists. In this study, we investigated the effect of ephedrine and placebo on hemodynamic changes in patients undergoing percutaneous nephrolithotomy with spinal anesthesia. Methods: This randomized, double-blind prospective clinical trial was conducted on 120 patients aged 20‒60 years with ASA (American Society of Anesthesiologists) classes I and II. Patients who were candidates for percutaneous nephrolithotomy with spinal anesthesia were divided into intervention (received 1 cc = 5 mg ephedrine) and control groups (received 1 cc normal saline). All vital parameters, including HR (heart rate) and NIBP (noninvasive blood pressure), were recorded perioperatively T0-T25) and finally at the end of surgery time (Tf). The results were analyzed by SPSS software version 23, and a P value ≤0.05 was considered significant. Results: The mean arterial pressure during surgery between T3 and T9 and the mean heart rate in times of T3-T8 in the intervention group were higher than in the control group, and this difference was statistically significant (P < 0.05). The incidence of hypotension, bradycardia, nausea, and vomiting and the amount of prescribed ephedrine, atropine, and ondansetron in the control group were higher than in the intervention group (P=0.001). Seven patients in the control group and four in the intervention group had shivering, but this difference was not statistically significant (P=0.43). Conclusion: This study showed the effectiveness of the prescription of 5 mg ephedrine two minutes before changing from the lithotomy position to the supine in maintaining hemodynamic stability, reducing hypotension, bradycardia, nausea, and vomiting, and the amount of prescribed ephedrine, atropine, and ondansetron. Trial Registrations. This trial is registered with IRCT20160430027677N22.


Assuntos
Raquianestesia , Hipotensão , Nefrolitotomia Percutânea , Humanos , Efedrina , Bradicardia , Ondansetron , Estudos Prospectivos , Hemodinâmica , Atropina , Náusea
7.
Proc Natl Acad Sci U S A ; 120(4): e2217543120, 2023 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-36669104

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, in which prognosis is determined by liver fibrosis. A common variant in hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13, rs72613567-A) is associated with a reduced risk of fibrosis in NAFLD, but the underlying mechanism(s) remains unclear. We investigated the effects of this variant in the human liver and in Hsd17b13 knockdown in mice by using a state-of-the-art metabolomics approach. We demonstrate that protection against liver fibrosis conferred by the HSD17B13 rs72613567-A variant in humans and by the Hsd17b13 knockdown in mice is associated with decreased pyrimidine catabolism at the level of dihydropyrimidine dehydrogenase. Furthermore, we show that hepatic pyrimidines are depleted in two distinct mouse models of NAFLD and that inhibition of pyrimidine catabolism by gimeracil phenocopies the HSD17B13-induced protection against liver fibrosis. Our data suggest pyrimidine catabolism as a therapeutic target against the development of liver fibrosis in NAFLD.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Animais , Humanos , Camundongos , Fígado/metabolismo , Cirrose Hepática/patologia , Hepatopatia Gordurosa não Alcoólica/patologia , Pirimidinas/farmacologia , Pirimidinas/metabolismo
8.
Diabetologia ; 66(3): 567-578, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36456864

RESUMO

AIMS/HYPOTHESIS: Athletes exhibit increased muscle insulin sensitivity, despite increased intramuscular triacylglycerol content. This phenomenon has been coined the 'athlete's paradox' and is poorly understood. Recent findings suggest that the subcellular distribution of sn-1,2-diacylglycerols (DAGs) in the plasma membrane leading to activation of novel protein kinase Cs (PKCs) is a crucial pathway to inducing insulin resistance. Here, we hypothesised that regular aerobic exercise would preserve muscle insulin sensitivity by preventing increases in plasma membrane sn-1,2-DAGs and activation of PKCε and PKCθ despite promoting increases in muscle triacylglycerol content. METHODS: C57BL/6J mice were allocated to three groups (regular chow feeding [RC]; high-fat diet feeding [HFD]; RC feeding and running wheel exercise [RC-EXE]). We used a novel LC-MS/MS/cellular fractionation method to assess DAG stereoisomers in five subcellular compartments (plasma membrane [PM], endoplasmic reticulum, mitochondria, lipid droplets and cytosol) in the skeletal muscle. RESULTS: We found that the HFD group had a greater content of sn-DAGs and ceramides in multiple subcellular compartments compared with the RC mice, which was associated with an increase in PKCε and PKCθ translocation. However, the RC-EXE mice showed, of particular note, a reduction in PM sn-1,2-DAG and ceramide content when compared with HFD mice. Consistent with the PM sn-1,2-DAG-novel PKC hypothesis, we observed an increase in phosphorylation of threonine1150 on the insulin receptor kinase (IRKT1150), and reductions in insulin-stimulated IRKY1162 phosphorylation and IRS-1-associated phosphoinositide 3-kinase activity in HFD compared with RC and RC-EXE mice, which are sites of PKCε and PKCθ action, respectively. CONCLUSIONS/INTERPRETATION: These results demonstrate that lower PKCθ/PKCε activity and sn-1,2-DAG content, especially in the PM compartment, can explain the preserved muscle insulin sensitivity in RC-EXE mice.


Assuntos
Resistência à Insulina , Camundongos , Animais , Resistência à Insulina/fisiologia , Proteína Quinase C-theta/metabolismo , Proteína Quinase C-épsilon/metabolismo , Cromatografia Líquida , Fosfatidilinositol 3-Quinases/metabolismo , Camundongos Endogâmicos C57BL , Espectrometria de Massas em Tandem , Insulina/metabolismo , Músculo Esquelético/metabolismo , Triglicerídeos/metabolismo , Ceramidas/metabolismo
9.
Aging Cell ; 21(2): e13539, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35088525

RESUMO

Mild uncoupling of oxidative phosphorylation is an intrinsic property of all mitochondria and may have evolved to protect cells against the production of damaging reactive oxygen species. Therefore, compounds that enhance mitochondrial uncoupling are potentially attractive anti-aging therapies; however, chronic ingestion is associated with a number of unwanted side effects. We have previously developed a controlled-release mitochondrial protonophore (CRMP) that is functionally liver-directed and promotes oxidation of hepatic triglycerides by causing a subtle sustained increase in hepatic mitochondrial inefficiency. Here, we sought to leverage the higher therapeutic index of CRMP to test whether mild mitochondrial uncoupling in a liver-directed fashion could reduce oxidative damage and improve age-related metabolic disease and lifespan in diet-induced obese mice. Oral administration of CRMP (20 mg/[kg-day] × 4 weeks) reduced hepatic lipid content, protein kinase C epsilon activation, and hepatic insulin resistance in aged (74-week-old) high-fat diet (HFD)-fed C57BL/6J male mice, independently of changes in body weight, whole-body energy expenditure, food intake, or markers of hepatic mitochondrial biogenesis. CRMP treatment was also associated with a significant reduction in hepatic lipid peroxidation, protein carbonylation, and inflammation. Importantly, long-term (49 weeks) hepatic mitochondrial uncoupling initiated late in life (94-104 weeks), in conjugation with HFD feeding, protected mice against neoplastic disorders, including hepatocellular carcinoma (HCC), in a strain and sex-specific manner. Taken together, these studies illustrate the complex variation of aging and provide important proof-of-concept data to support further studies investigating the use of liver-directed mitochondrial uncouplers to promote healthy aging in humans.


Assuntos
Carcinoma Hepatocelular , Resistência à Insulina , Neoplasias Hepáticas , Animais , Carcinoma Hepatocelular/metabolismo , Dieta Hiperlipídica/efeitos adversos , Feminino , Fígado/metabolismo , Neoplasias Hepáticas/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo
10.
J Mater Eng Perform ; 30(9): 6618-6629, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34092989

RESUMO

This study aims to investigate the effects of annealing, quenching, and tempering (Q&T) heat treatments on the microstructure, crystallographic orientation, and electrochemical performance of a wall shaped 420 martensitic stainless steel part fabricated by wire arc additive manufacturing technology. The formation of a martensitic matrix with delta ferrite in the as-printed sample, islands of spherical chromium carbides embedded in a ferritic matrix in annealed sample, and intergranular chromium-rich carbides along the primary austenite grain boundaries in addition to intra-lath Fe-rich carbides in the quenching and tempering heat treated sample were detected. To characterize the corrosion performance of the fabricated samples, open circuit potential, potentiodynamic polarization, and electrochemical impedance spectroscopy tests were performed on all samples in aerated 3.5 wt.% NaCl electrolyte at room temperature. The corrosion morphology of the as-printed sample was characterized by localized corrosion attacks adjacent to the delta ferrite phase, while severe pitting occurred in the annealed sample due to the high susceptibility of ferritic matrix-carbide interface to pitting. In contrast to the as-printed and annealed sample, the electrochemical performance of the quenched and subsequently tempered samples was found to be significantly improved, ascribed to elimination of the chromium depleted regions adjacent to the delta ferrite phase, and enhanced protectiveness of the passive film on the alloy's surface.

11.
J Educ Health Promot ; 9: 224, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33062757

RESUMO

INTRODUCTION: The performance of the emergency department (ED) as one of the main parts of hospitals, have a great impact on the performance of the whole-hospital. In Iran, the official education program of this discipline was started in 2001 and has expanded in most medical universities. Given the unprecedentedness of emergency medicine (EM), there are limited studies about this specialty. Thus, this study aims to explore the status, role, and performance of Iranian EM specialists. MATERIALS AND METHODS: This qualitative study was conducted using content analysis of 19 semi-structured interviews with EM specialists and key informant. Purposive sampling was conducted, and some teaching and nonstate hospitals in different geographic regions of Tehran city were selected. Conducting interviews continued until reaching the data saturation. Thematic analysis was employed. Extracted themes were reviewed and confirmed by some of the participants. RESULTS: The study results were categorized within five main themes; included the role of ED from EM specialists' viewpoint, EM specialists' viewpoint on their discipline, performance of EM specialists (including medical, managerial, and economic performance), and role of EM specialists in patient satisfaction; and opportunities and challenges of EM specialists. CONCLUSION: Overall, the study findings highlighted the effectiveness and positive medical, managerial and economic impacts of EM in Iran, inside and beyond hospitals. However, the study addressed significant opportunities some solvable challenges in educational, professional and economic domains, and interdisciplinary relationships. Further studies are recommended for comprehensive exploring viewpoint of other disciplines and stakeholders.

12.
Prehosp Disaster Med ; 35(5): 588-591, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32638682

RESUMO

Flood is the most common natural hazard in Iran, which annually affects the environment and human lives. On March 25, 2019 in Shiraz-Iran, following a heavy rainfall, the occurrence of a flash flood caused an extensive number of deaths, injuries, and vehicle demolitions in a short time. Evidence suggests that man-made causes of the incident, including unsustainable urban development and lack of early warning services, have played a more influential role compared with its natural causes. This study has attempted to substantiate that understanding disaster risks, as the first priority of Sendai Framework for Disaster Risk Reduction (SFDRR) 2015-2030, directly impacts the decisions and actions of policymakers, local authorities, and the public. To provide more safety, mitigation, and disaster risk reduction, attention should primarily be paid on making a cultural paradigm shift through providing sufficient training in developing appropriate disaster risk perception in the community at large.


Assuntos
Planejamento em Desastres , Inundações , Medição de Risco/métodos , Monitoramento Ambiental , Humanos , Irã (Geográfico) , Modelos Teóricos , Fatores de Risco
13.
Materials (Basel) ; 13(12)2020 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-32575808

RESUMO

Wire arc additive manufacturing (WAAM) is known to induce a considerable microstructural inhomogeneity and anisotropy in mechanical properties, which can potentially be minimized by adopting appropriate post-printing heat treatment. In this paper, the effects of two heat treatment cycles, including hardening and normalizing on the microstructure and mechanical properties of a WAAM-fabricated low-carbon low-alloy steel (ER70S-6) are studied. The microstructure in the melt pools of the as-printed sample was found to contain a low volume fraction of lamellar pearlite formed along the grain boundaries of polygonal ferrite as the predominant micro-constituents. The grain coarsening in the heat affected zone (HAZ) was also detected at the periphery of each melt pool boundary, leading to a noticeable microstructural inhomogeneity in the as-fabricated sample. In order to modify the nonuniformity of the microstructure, a normalizing treatment was employed to promote a homogenous microstructure with uniform grain size throughout the melt pools and HAZs. Differently, the hardening treatment contributed to the formation of two non-equilibrium micro-constituents, i.e., acicular ferrite and bainite, primarily adjacent to the lamellar pearlite phase. The results of microhardness testing revealed that the normalizing treatment slightly decreases the microhardness of the sample; however, the formation of non-equilibrium phases during hardening process significantly increased the microhardness of the component. Tensile testing of the as-printed part in the building and deposition directions revealed an anisotropic ductility. Although normalizing treatment did not contribute to the tensile strength improvement of the component, it suppressed the observed anisotropy in ductility. On the contrary, the hardening treatment raised the tensile strength, but further intensified the anisotropic behavior of the component.

14.
Nature ; 579(7798): 279-283, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32132708

RESUMO

Although it is well-established that reductions in the ratio of insulin to glucagon in the portal vein have a major role in the dysregulation of hepatic glucose metabolism in type-2 diabetes1-3, the mechanisms by which glucagon affects hepatic glucose production and mitochondrial oxidation are poorly understood. Here we show that glucagon stimulates hepatic gluconeogenesis by increasing the activity of hepatic adipose triglyceride lipase, intrahepatic lipolysis, hepatic acetyl-CoA content and pyruvate carboxylase flux, while also increasing mitochondrial fat oxidation-all of which are mediated by stimulation of the inositol triphosphate receptor 1 (INSP3R1). In rats and mice, chronic physiological increases in plasma glucagon concentrations increased mitochondrial oxidation of fat in the liver and reversed diet-induced hepatic steatosis and insulin resistance. However, these effects of chronic glucagon treatment-reversing hepatic steatosis and glucose intolerance-were abrogated in Insp3r1 (also known as Itpr1)-knockout mice. These results provide insights into glucagon biology and suggest that INSP3R1 may represent a target for therapies that aim to reverse nonalcoholic fatty liver disease and type-2 diabetes.


Assuntos
Glucagon/farmacologia , Gluconeogênese/efeitos dos fármacos , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Fígado/efeitos dos fármacos , Acetilcoenzima A/metabolismo , Tecido Adiposo/efeitos dos fármacos , Animais , Diabetes Mellitus Tipo 2/fisiopatologia , Ativação Enzimática/efeitos dos fármacos , Glucagon/sangue , Receptores de Inositol 1,4,5-Trifosfato/genética , Lipase/metabolismo , Lipólise/efeitos dos fármacos , Lipólise/genética , Camundongos Knockout , Mitocôndrias/efeitos dos fármacos , Hepatopatia Gordurosa não Alcoólica/fisiopatologia , Oxirredução/efeitos dos fármacos
15.
Sci Rep ; 10(1): 3069, 2020 02 20.
Artigo em Inglês | MEDLINE | ID: mdl-32080237

RESUMO

Low blood phosphate (Pi) reduces muscle function in hypophosphatemic disorders. Which Pi transporters are required and whether hormonal changes due to hypophosphatemia contribute to muscle function is unknown. To address these questions we generated a series of conditional knockout mice lacking one or both house-keeping Pi transporters Pit1 and Pit2 in skeletal muscle (sm), using the postnatally expressed human skeletal actin-cre. Simultaneous conditional deletion of both transporters caused skeletal muscle atrophy, resulting in death by postnatal day P13. smPit1-/-, smPit2-/- and three allele mutants are fertile and have normal body weights, suggesting a high degree of redundance for the two transporters in skeletal muscle. However, these mice show a gene-dose dependent reduction in running activity also seen in another hypophosphatemic model (Hyp mice). In contrast to Hyp mice, grip strength is preserved. Further evaluation of the mechanism shows reduced ERK1/2 activation and stimulation of AMP kinase in skeletal muscle from smPit1-/-; smPit2-/- mice consistent with energy-stress. Similarly, C2C12 myoblasts show a reduced oxygen consumption rate mediated by Pi transport-dependent and ERK1/2-dependent metabolic Pi sensing pathways. In conclusion, we here show that Pit1 and Pit2 are essential for normal myofiber function and survival, insights which may improve management of hypophosphatemic myopathy.


Assuntos
Fibras Musculares Esqueléticas/citologia , Fibras Musculares Esqueléticas/metabolismo , Proteínas Cotransportadoras de Sódio-Fosfato Tipo III/metabolismo , Fator de Transcrição Pit-1/metabolismo , Alelos , Animais , Linhagem Celular , Sobrevivência Celular , Transporte de Elétrons , Metabolismo Energético , Força da Mão , Camundongos Knockout , Modelos Biológicos , Células Musculares/metabolismo , Necrose , Consumo de Oxigênio , Fosfatos/metabolismo , Proteínas Cotransportadoras de Sódio-Fosfato Tipo III/deficiência , Fator de Transcrição Pit-1/deficiência
16.
Cancer Metab ; 7: 10, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31867105

RESUMO

BACKGROUND: Obesity confers an increased risk and accelerates the progression of multiple tumor types in rodents and humans, including both breast and colon cancer. Because sustained weight loss is rarely achieved, therapeutic approaches to slow or prevent obesity-associated cancer development have been limited, and mechanistic insights as to the obesity-cancer connection have been lacking. METHODS: E0771 breast tumors and MC38 colon tumors were treated in vivo in mice and in vitro with two mechanistically different insulin-lowering agents, a controlled-release mitochondrial protonophore (CRMP) and sodium-glucose cotransporter-2 (SGLT2) inhibitors, and tumor growth and glucose metabolism were assessed. Groups were compared by ANOVA with Bonferroni's multiple comparisons test. RESULTS: Dapagliflozin slows tumor growth in two mouse models (E0771 breast cancer and MC38 colon adenocarcinoma) of obesity-associated cancers in vivo, and a mechanistically different insulin-lowering agent, CRMP, also slowed breast tumor growth through its effect to reverse hyperinsulinemia. In both models and with both agents, tumor glucose uptake and oxidation were not constitutively high, but were hormone-responsive. Restoration of hyperinsulinemia by subcutaneous insulin infusion abrogated the effects of both dapagliflozin and CRMP to slow tumor growth. CONCLUSIONS: Taken together, these data demonstrate that hyperinsulinemia per se promotes both breast and colon cancer progression in obese mice, and highlight SGLT2 inhibitors as a clinically available means of slowing obesity-associated tumor growth due to their glucose- and insulin-lowering effects.

17.
Cell Rep ; 28(3): 759-772.e10, 2019 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-31315053

RESUMO

Mechanisms coordinating pancreatic ß cell metabolism with insulin secretion are essential for glucose homeostasis. One key mechanism of ß cell nutrient sensing uses the mitochondrial GTP (mtGTP) cycle. In this cycle, mtGTP synthesized by succinyl-CoA synthetase (SCS) is hydrolyzed via mitochondrial PEPCK (PEPCK-M) to make phosphoenolpyruvate, a high-energy metabolite that integrates TCA cycling and anaplerosis with glucose-stimulated insulin secretion (GSIS). Several strategies, including xenotopic overexpression of yeast mitochondrial GTP/GDP exchanger (GGC1) and human ATP and GTP-specific SCS isoforms, demonstrated the importance of the mtGTP cycle. These studies confirmed that mtGTP triggers and amplifies normal GSIS and rescues defects in GSIS both in vitro and in vivo. Increased mtGTP synthesis enhanced calcium oscillations during GSIS. mtGTP also augmented mitochondrial mass, increased insulin granule number, and membrane proximity without triggering de-differentiation or metabolic fragility. These data highlight the importance of the mtGTP signal in nutrient sensing, insulin secretion, mitochondrial maintenance, and ß cell health.


Assuntos
Trifosfato de Adenosina/metabolismo , Glucose/metabolismo , Guanosina Trifosfato/metabolismo , Células Secretoras de Insulina/metabolismo , Insulina/metabolismo , Mitocôndrias/metabolismo , Succinato-CoA Ligases/metabolismo , Animais , Diferenciação Celular/genética , Linhagem Celular , Proliferação de Células/genética , Ciclo do Ácido Cítrico/genética , Homeostase , Humanos , Secreção de Insulina/genética , Secreção de Insulina/fisiologia , Células Secretoras de Insulina/enzimologia , Células Secretoras de Insulina/ultraestrutura , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microscopia Eletrônica de Transmissão , Mitocôndrias/enzimologia , Mitocôndrias/ultraestrutura , Membranas Mitocondriais/metabolismo , Fosforilação Oxidativa , Fosfoenolpiruvato Carboxiquinase (ATP)/metabolismo , Regulação para Cima
18.
Int J Health Plann Manage ; 34(4): e1495-e1509, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31309603

RESUMO

OBJECTIVE: Iran, as one of the most disaster-prone countries in the world, is exposed to a wide range of hazards. Hence, the health sector should be prepared to deal with the consequences of emergencies. This study aimed to explore Iranian disaster management status and to identify the necessary characteristics of successful incident commanders in this field. METHODS: A qualitative content analysis was designed using in-depth semi-structured interviews with 30 commanders and experts, selected by purposeful sampling, who had first-hand experiences in managing health disasters. Field notes, formal institutional reports, and photos were employed as well. Verbatim transcribed interviews and other data sources were analyzed using constant comparison method. Ethical issues were considered carefully throughout the study process. RESULTS: Two main themes were developed: The first theme, "limbo situation," as expression of the problem describes inadequacies and complexities of disaster management in Iranian health sector, including seven categories. The second theme was "effective disaster leadership" consisting of "commanders' traits" and "commanders' competencies" as subthemes. CONCLUSIONS: The study demonstrated the chaotic feature of disaster management in Iran and probably some other developing countries, with crucial and unclear role of field commanders. Working under stress, time pressure, uncertainty, and management of paradoxes needs timely and on-field decision making. This study revealed that Iranian health sector incident commanders should be transformational leaders with the ability of influencing subordinate staff and have Janusian thinking skills for overcoming the existing limbo situation.


Assuntos
Atenção à Saúde/organização & administração , Desastres , Liderança , Adulto , Planejamento em Desastres/organização & administração , Humanos , Entrevistas como Assunto , Irã (Geográfico) , Pessoa de Meia-Idade
20.
Materials (Basel) ; 11(9)2018 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-30200418

RESUMO

Creation of hydrophobic and superhydrophobic surfaces has attracted broad attention as a promising solution for protection of metal surfaces from corrosive environments. This work investigates the capability of nanosecond fiber laser surface texturing followed by a low energy coating in the fabrication of hydrophobic 17-4 PH stainless steel surfaces as an alternative to the ultrashort lasers previously utilized for hydrophobic surfaces production. Laser texturing of the surface followed by applying the hydrophobic coating resulted in steady-state contact angles of up to 145°, while the non-textured coated base metal exhibited the contact angle of 121°. The microstructure and compositional analysis results confirmed that the laser texturing process neither affects the microstructure of the base metal nor causes elemental loss from the melted regions during the ultrafast melting process. However, the electrochemical measurements demonstrated that the water-repelling property of the surface did not contribute to the anticorrosion capability of the substrate. The resultant higher corrosion current density, lower corrosion potential, and higher corrosion rate of the laser textured surfaces were ascribed to the size of fabricated surface micro-grooves, which cannot retain the entrapped air inside the hierarchical structure when fully immersed in a corrosive medium, thus degrading the material's corrosion performance.

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