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    المصدر: PLoS ONE, Vol 16, Iss 4, p e0250090 (2021)
    PLoS ONE

    الوصف: Background Hypofibrinolysis resulting from the up-regulation of plasminogen activator inhibitor-1 (PAI-1) usually occurs in patients with type 2 diabetes mellitus (T2DM), rendering them hypercoagulable. This study assessed the plasma antigen and activity levels of the PAI-1 enzyme in T2DM patients in a district hospital in Ghana. Methods This was a hospital-based case-control study conducted from December 2018 to May 2019 at Nkenkaasu District Hospital. Sixty subjects with T2DM (30 T2DM subjects with good glycemic control and 30 with poor glycemic control), and 30 apparently healthy blood donors were recruited into the study. Blood specimens were collected for complete blood count, lipid profile, PAI-1 Ag and PAI-1 activity levels. A pre-tested questionnaire was used to obtain demographic and clinical information. The data was analyzed using SPSS version 22.0. Results Elevated PAI-1 Ag and activity levels were observed in the T2DM subjects compared to the healthy controls, with the levels and activity significantly higher (PAI-1 Ag; p< 0.001, PAI-1 activity level; p = 0.004) in the T2DM subjects with poor glycemic control in comparison to those with good glycemic control. A significant positive correlation was observed between HbA1c and PAI-1 enzymes. PAI-1 Ag levels significantly increased along with increased total cholesterol (Β = 0.262, p = 0.033), triglyceride (Β = -0.273, p = 0.034) and HbA1c (Β = 0.419, p = 0.001). Similarly, PAI-1 activity level was associated with total cholesterol (Β = 0.325, p = 0.009), triglyceride (Β = -0.262, p = 0.042), HbA1c (Β = 0.389, p = 0.003) and VLDL-c (Β = -0.227, p = 0.029). Conclusion PAI-1 antigen/activity is enhanced in poorly controlled Ghanaian T2DM subjects. The hypercoagulable state of the affected individuals put them at higher risk of developing cardiovascular diseases. Good glycemic control to regulate plasma PAI-1 levels is essential during T2DM lifelong management. Markers of fibrinolysis should be assessed in these individuals and appropriate anticoagulants given to prevent thrombosis and adverse cardiovascular diseases.

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    المصدر: PLoS ONE
    PLoS ONE, Vol 15, Iss 3, p e0230627 (2020)

    الوصف: The gene encoding eukaryotic initiation factor 5A (EIF5A) is found in diabetes-susceptibility loci in mouse and human. eIF5A is the only protein known to contain hypusine (hydroxyputrescine lysine), a polyamine-derived amino acid formed post-translationally in a reaction catalyzed by deoxyhypusine synthase (DHPS). Previous studies showed pharmacologic blockade of DHPS in type 1 diabetic NOD mice and type 2 diabetic db/db mice improved glucose tolerance and preserved beta cell mass, which suggests that hypusinated eIF5A (eIF5AHyp) may play a role in diabetes pathogenesis by direct action on the beta cells and/or altering the adaptive or innate immune responses. To translate these findings to human, we examined tissue from individuals with and without type 1 and type 2 diabetes to determine the expression of eIF5AHyp. We detected eIF5AHyp in beta cells, exocrine cells and immune cells; however, there was also unexpected enrichment of eIF5AHyp in pancreatic polypeptide-expressing PP cells. Interestingly, the presence of eIF5AHyp co-expressing PP cells was not enhanced with disease. These data identify new aspects of eIF5A biology and highlight the need to examine human tissue to understand disease.

  3. 3

    المصدر: PLoS ONE
    PLoS ONE, Vol 13, Iss 5, p e0196352 (2018)

    الوصف: Introduction Neonatal inflammation, mediated in part through Toll-like receptor (TLR) and inflammasome signaling, contributes to adverse outcomes including organ injury. Pentoxifylline (PTX), a phosphodiesterase inhibitor which potently suppresses cytokine production in newborn cord blood, is a candidate neonatal anti-inflammatory agent. We hypothesized that combinations of PTX with other anti-inflammatory agents, the steroid dexamethasone (DEX) or the macrolide azithromycin (AZI), may exert broader, more profound and/or synergistic anti-inflammatory activity towards neonatal TLR- and inflammasome-mediated cytokine production. Methods Whole newborn and adult blood was treated with PTX (50–200 μM), DEX (10−10–10−7 M), or AZI (2.5–20 μM), alone or combined, and cultured with lipopolysaccharide (LPS) (TLR4 agonist), R848 (TLR7/8 agonist) or LPS/adenosine triphosphate (ATP) (inflammasome induction). Supernatant and intracellular cytokines, signaling molecules and mRNA were measured by multiplex assay, flow cytometry and real-time PCR. Drug interactions were assessed based on Loewe's additivity. Results PTX, DEX and AZI inhibited TLR- and/or inflammasome-mediated cytokine production in newborn and adult blood, whether added before, simultaneously or after TLR stimulation. PTX preferentially inhibited pro-inflammatory cytokines especially TNF. DEX inhibited IL-10 in newborn, and TNF, IL-1β, IL-6 and interferon-α in newborn and adult blood. AZI inhibited R848-induced TNF, IL-1β, IL-6 and IL-10, and LPS-induced IL-1β and IL-10. (PTX+DEX) synergistically decreased LPS- and LPS/ATP-induced TNF, IL-1β, and IL-6, and R848-induced IL-1β and interferon-α, while (PTX+AZI) synergistically decreased induction of TNF, IL-1β, and IL-6. Synergistic inhibition of TNF production by (PTX+DEX) was especially pronounced in newborn vs. adult blood and was accompanied by reduction of TNF mRNA and enhancement of IL10 mRNA. Conclusions Age, agent, and specific drug-drug combinations exert distinct anti-inflammatory effects towards TLR- and/or inflammasome-mediated cytokine production in human newborn blood in vitro. Synergistic combinations of PTX, DEX and AZI may offer benefit for prevention and/or treatment of neonatal inflammatory conditions while potentially limiting drug exposure and toxicity.

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    المصدر: PLoS ONE, Vol 13, Iss 11, p e0207065 (2018)
    PLoS ONE

    الوصف: Aims Increased proinsulin (PI) compared to C-peptide (CP) concentrations have been reported, both prior to type 1 diabetes mellitus (T1D) onset, as well as early in disease. In this pilot study, we sought to define the normal PI secretion in a healthy cohort and compare this to a local T1D cohort and a separate well-defined nationally representative T1D cohort with measurable CP. Methods Thirteen healthy subjects and 12 T1D subjects with T1D >3 years from the local T1D cohort completed mixed meal tolerance tests (MMTT) with PI and CP measured over 90 and 240 minutes. The change in CP (maximum versus baseline, ΔCP) during MMTT in the T1D Exchange T1D cohort was stratified according to non-fasting PI concentrations, based on a fasting PI threshold, as defined by the healthy control group. Results The maximum fasting PI in the control group was 6 pmol/L. Individuals from the T1D Exchange with a non-fasting PI ≥ 6 pmol/L had a lower ΔCP during a MMTT, compared to those with a PI < 6 pmol/L. While only three individuals from the local T1D cohort had measurable CP and PI during the MMTT, those with a greater ΔCP had lower PI secretion. Conclusion While all T1D subjects from the T1D Exchange secreted measurable non-fasting PI, those with a greater non-fasting PI demonstrated a decrease in ΔCP during the MMTT. PI may be preferentially secreted compared to CP in some individuals with long standing T1D.

  5. 5

    المصدر: PLoS ONE, Vol 14, Iss 8, p e0220650 (2019)
    PLoS ONE

    مصطلحات موضوعية: Eotaxin, Vascular Endothelial Growth Factor A, Physiology, Maternal Health, Pregnancy in Diabetics, Blood Pressure, Pathology and Laboratory Medicine, Vascular Medicine, Biochemistry, Epithelium, chemistry.chemical_compound, 0302 clinical medicine, Endocrinology, Pregnancy, Animal Cells, Immune Physiology, Blood plasma, Medicine and Health Sciences, Insulin, Immune Response, Innate Immune System, Multidisciplinary, Interleukin, Obstetrics and Gynecology, Body Fluids, Gestational diabetes, Vascular endothelial growth factor, Blood, Hypertension, Cytokines, Carbohydrate Metabolism, Medicine, Female, medicine.symptom, Cellular Types, Anatomy, Research Article, Adult, medicine.medical_specialty, Endocrine Disorders, Science, Immunology, 030209 endocrinology & metabolism, Inflammation, Carbohydrate metabolism, Blood Plasma, Proinflammatory cytokine, 03 medical and health sciences, Signs and Symptoms, Diagnostic Medicine, Hypertensive Disorders in Pregnancy, Internal medicine, medicine, Diabetes Mellitus, Humans, Diabetic Endocrinology, Vascular Endothelial Growth Factor Receptor-1, business.industry, Interleukin-6, Tumor Necrosis Factor-alpha, Interleukin-8, Biology and Life Sciences, Endothelial Cells, Epithelial Cells, Cell Biology, Molecular Development, medicine.disease, Hormones, Diabetes, Gestational, Biological Tissue, Diabetes Mellitus, Type 1, chemistry, Metabolic Disorders, Immune System, 030221 ophthalmology & optometry, Women's Health, business, Developmental Biology

    الوصف: The aim of this study was to determine the action of molecules in carbohydrate metabolism disorders during pregnancy. The concentration of different types of cytokines and vascular endothelial growth factor (VEGF) in the plasma were measured in 4 groups of women: Group I, normal pregnancy (n = 10); Group II, patients with gestational DM (n = 12); Group III, pregnant patients with preexisting DM (n = 16); and Group IV, diabetic non-pregnant women (n = 22). The plasma VEGF concentration was significantly higher in the women in Group IV than in other groups (P

  6. 6

    المصدر: PLoS ONE, Vol 14, Iss 7, p e0219064 (2019)
    PLoS ONE

    مصطلحات موضوعية: 0301 basic medicine, Vaginal Diseases, Endometriosis, Artificial Gene Amplification and Extension, Peritoneal Diseases, Endometrium, Biochemistry, Polymerase Chain Reaction, Epithelium, chemistry.chemical_compound, 0302 clinical medicine, Animal Cells, Medicine and Health Sciences, Small interfering RNAs, media_common, Uterine Diseases, Staining, 030219 obstetrics & reproductive medicine, Multidisciplinary, Obstetrics and Gynecology, Cell Staining, Middle Aged, Immunohistochemistry, 3. Good health, Nucleic acids, medicine.anatomical_structure, Plasminogen activator inhibitor-1, Medicine, Female, Anatomy, Cellular Types, medicine.symptom, Research Article, Adult, medicine.medical_specialty, media_common.quotation_subject, Science, Urology, Research and Analysis Methods, Young Adult, 03 medical and health sciences, Dysmenorrhea, Uterine cancer, Plasminogen Activator Inhibitor 1, Genetics, medicine, Humans, Non-coding RNA, Molecular Biology Techniques, Immunohistochemistry Techniques, Molecular Biology, Menstrual cycle, Biology and life sciences, business.industry, Pelvic pain, Uterus, Reproductive System, Dysmenorrhoea, Epithelial Cells, Cell Biology, medicine.disease, Gene regulation, Histochemistry and Cytochemistry Techniques, Rectal Diseases, Biological Tissue, 030104 developmental biology, chemistry, Specimen Preparation and Treatment, Immunologic Techniques, Women's Health, RNA, Gene expression, Stromal Cells, business, Plasminogen activator, Menstrual Abnormalities

    الوصف: PurposeDeep infiltrating endometriosis (DIE) is defined as an endometriotic lesion penetrating to a depth of >5 mm and is associated with pelvic pain, but the underlying mechanisms are unclear. Our objective is to investigate whether plasminogen activator inhibitor-1 expression (PAI-1) in endometriotic tissues is increased in women with DIE.MethodsIn this blinded in vitro study, immunohistochemistry and Histoscore were used to examine the expression of PAI-1 in glandular epithelium (GECs) and stroma (SCs) in a total of 62 women: deep infiltrating uterosacral/rectovaginal endometriosis (DIE; n = 13), ovarian endometrioma (OMA; n = 14), superficial peritoneal uterosacral/cul-de-sac endometriosis (SUP; n = 23), uterine (eutopic) endometrium from women with endometriosis (UE; n = 6), and non-endometriosis eutopic endometrium (UC; n = 6). The following patient characteristics were also collected: age, American Fertility Society stage, hormonal suppression, phase of menstrual cycle, dysmenorrhea score and deep dyspareunia score.ResultsPAI-1 expression in GECs and SCs of the DIE group was significantly higher than that of SUP group (p = 0.01, p = 0.01, respectively) and UE group (p = 0.03, p = 0.04, respectively). Interestingly, increased PAI-1 expression in GECs and SCs was also significantly correlated with increased dysmenorrhea (r = 0.38, p = 0.01; r = 0.34, p = 0.02, respectively).ConclusionsWe found higher expression of PAI-1 in DIE, and an association between PAI-1 and worse dysmenorrhea.

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    المصدر: PLoS ONE, Vol 14, Iss 7, p e0219164 (2019)
    PLoS ONE

    الوصف: PurposeTo explore the relationships between vessel density (VD) in the retinal vascular plexuses with the thickness and structural changes of their corresponding retinal layers in patients with diabetic retinopathy (DR).MethodsRetrospective analysis of 17 eyes of 17 Type 1 diabetes (T1D) patients with severe non-proliferative or proliferative DR and no current or past macular edema. Seventeen age- and sex-matched healthy subjects were included as controls. Using optical coherence tomography (OCT) and OCT-angiography (OCTA), VD was measured in the superficial vascular plexus (SVP) and deep vascular complex (DVC) that includes the intermediate (ICP) and deep capillary plexuses (DCP), and compared to the retinal thickness (RT) of the inner (from the inner limiting membrane to the inner plexiform layer) and intermediate (inner nuclear and outer plexiform layer) retinal layers. The correlation between the inner and intermediate RT and the VD of the corresponding vascular networks (SVP and DVC, respectively) was assessed. All OCT and OCTA examinations were performed using the RTVue XR Avanti (Optovue, Fremont, CA).ResultsThe inner RT and VD in all plexuses were significantly reduced in T1D patients compared to healthy subjects. The capillary drop-out patterns were polygonal and well-defined in the SVP while the ICP and DCP showed a more diffuse capillary rarefaction and a VD that varied in the same proportion. The inner RT significantly correlated with VD in the SVP (r = 0.71 in healthy subjects and r = 0.62 in T1D patients, p ConclusionsIn T1D subjects, OCTA allowed observing different capillary drop-out patterns in the SVP and in the ICP-DCP, with different structural changes in the corresponding retinal layers, suggesting that they should be considered as distinct anatomical and functional entities.

  8. 8

    المصدر: PLoS ONE, Vol 12, Iss 2, p e0171076 (2017)
    PLoS ONE

    الوصف: Background The factors influencing the prognosis of acute kidney injury (AKI) were analyzed in a group of elderly AKI patients to determine the markers of early prognosis. Methods A total of 258 patients were screened, and 201 patients were enrolled in the study. Eventually, 184 AKI patients were included in the study, including 79 elderly AKI patients (≥60 years old). During one year of follow-up, renal function changes were observed, and the risk factors that influenced the prognosis of AKI were analyzed. Results When AKI occurred, the urine kidney injury molecule-1 (uKIM-1) level was significantly higher in the progressive deterioration of renal function group than in the renal function stable group. The ROC curve analysis revealed that the area under the curve for poor progressive deterioration of renal function as predicted by the uKIM-1 level was 0.681. At a cutoff point of 2.46 ng/mg, the sensitivity was 71.9% and the specificity was 70.0%. In elderly AKI patients, uKIM-1 levels exceeding 2.46 ng/mg were positively associated with poor kidney prognosis. Conclusions Elderly AKI patients are at risk of developing progressive deterioration of renal function. In elderly AKI patients, the high uKIM-1 level may predict the prognosis of kidney function and may be used as an early screening indicator of poor kidney prognosis.

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    المصدر: PLoS ONE, Vol 13, Iss 5, p e0197994 (2018)
    PLoS ONE

    الوصف: Purpose Osteoblasts and adipocytes are derived from mesenchymal stem cells. An imbalance in the differentiation of these lineages could affect the preservation of bone integrity. Several studies have suggested the importance of this imbalance in the pathogenesis of osteoporosis after kidney transplant (KT), but the role of bone marrow adiposity in this process is not well known, and if the treatment with the anti-absorptive (zoledronic acid-ZA) drugs could attenuate bone loss. Thus, our objective was compare bone marrow adiposity, osteoblasts and osteocytes before and after KT, verify an association between bone remodeling process (Turnover, Volume, and Mineralization—TMV classification), the osteocyte sclerostin expression to evaluate if there is a role of Wnt pathway, as well as the effect of ZA on these cells. Methods We studied 29 new living-donor KT patients. One group received ZA at the time of KT plus cholecalciferol for twelve months, and the other group received only cholecalciferol. Bone biopsies were performed at baseline and after 12 months of treatment. Histomorphometric evaluation was performed in bone and bone marrow adipocytes. Sclerostin (Scl) expression in osteocytes was evaluated by immunohistochemistry. Results Some bone marrow adiposity parameters were increased before KT. After KT, some of them remained increased and they worsened with the use of ZA. In the baseline, lower bone Volume and Turnover, were associated with increased bone marrow adiposity parameters (some of them). After KT, both groups showed the same associations. Osteocyte Scl expression after KT decreased with the use of ZA. We observed also an inverse association between bone adiposity parameters and lower osteocyte sclerostin expression 12 months after KT. Conclusion In conclusion, the present study suggests that KT fails to normalize bone marrow adiposity, and it even gets worse with the use of ZA. Moreover, bone marrow adiposity is inversely associated with bone Volume and Turnover, which seems to be accentuated by the antiresorptive therapy.

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    المصدر: PLoS ONE, Vol 13, Iss 2, p e0192419 (2018)
    PLoS ONE

    الوصف: Introduction Exposure to air pollution impairs aspects of endothelial function such as flow-mediated dilation (FMD). Outdoor exercisers are frequently exposed to air pollution, but how exercising in air pollution affects endothelial function and how these effects are modified by exercise intensity are poorly understood. Objectives Therefore, the purpose of this study was to determine the effects of low-intensity and high-intensity cycling with diesel exhaust (DE) exposure on FMD, blood pressure, plasma nitrite and nitrate (NOx) and endothelin-1. Methods Eighteen males performed 30-minute trials of low or high-intensity cycling (30% and 60% of power at VO2peak) or a resting control condition. For each subject, each trial was performed once while breathing filtered air (FA) and once while breathing DE (300ug/m3 of PM2.5, six trials in total). Preceding exposure, immediately post-exposure, 1 hour and 2 hours post-exposure, FMD, blood pressure and plasma endothelin-1 and NOx concentrations were measured. Data were analyzed using repeated-measures ANOVA and linear mixed model. Results Following exercise in DE, plasma NOx significantly increased and was significantly greater than FA (p