Enhanced oxidative stress and the glycolytic switch in superficial urothelial carcinoma of urinary bladder

AbstractObjectiveTo examine whether oxidative stress and the glycolytic switch are correlated to tumor grading, tumor recurrence, and disease progression in urothelial carcinoma (UC) of the urinary bladder (UB).MethodsAll surgical specimens obtained from 27 patients (each containing their UC and normal tissues of UB) were subjected to a pathological examination by computerized tomography, and a portion of each specimen was used for the analysis of molecular biomarkers. The mRNA expression levels of pyruvate dehydrogenase kinase-1 (PDK1), hypoxia-inducible factor 1 alpha (HIF-1α), lactate dehydrogenase A (LDHA), pyruvate dehydrogenase, and glucose transporter protein 1 (Glut-1) were measured using TaqMan-based real-time quantitative polymerase chain reaction. In addition, 8-hydroxy-2-deoxyguanosine (8-OHdG) and the mitochondrial DNA (mtDNA) copy number were also determined.ResultsThe 8-OHdG content and glycolytic genes expression were higher in UC of the UB than those in the normal tissues of UB, whereas the mtDNA copy number was depleted. According to the multivariate analysis, patients with Grade 3 tumors had higher expression levels of HIF-1α, LDHA, and Glut-1 than those with Grades 1 and 2 tumors. In addition, patients with locally recurrent tumors had a higher expression of HIF-1α and LDHA than those with nonrecurrent tumors. Furthermore, patients under disease progression had higher levels of HIF-1α and PDK1 than those not under disease progression.ConclusionsUC of the UB manifested that the glycolytic phenotype would reflect the Warburg effect. We suggest that the molecular mechanism in the regulation of glycolytic switch in UC of the UB might provide a specific biomarker for the future development of cancer diagnosis

Associations of obesity and malnutrition with cardiac remodeling and cardiovascular outcomes in Asian adults:A cohort study

BackgroundObesity, a known risk factor for cardiovascular disease and heart failure (HF), is associated with adverse cardiac remodeling in the general population. Little is known about how nutritional status modifies the relationship between obesity and outcomes. We aimed to investigate the association of obesity and nutritional status with clinical characteristics, echocardiographic changes, and clinical outcomes in the general community.Methods and findingsWe examined 5,300 consecutive asymptomatic Asian participants who were prospectively recruited in a cardiovascular health screening program (mean age 49.6 ± 11.4 years, 64.8% male) between June 2009 to December 2012. Clinical and echocardiographic characteristics were described in participants, stratified by combined subgroups of obesity and nutritional status. Obesity was indexed by body mass index (BMI) (low, ≤25 kg/m2 [lean]; high, >25 kg/m2 [obese]) (WHO-recommended Asian cutoffs). Nutritional status was defined primarily by serum albumin (SA) concentration (low, ConclusionsIn our cohort study among asymptomatic community-based adults in Taiwan, we found that obese individuals with poor nutritional status have the highest comorbidity burden, the most adverse cardiac remodeling, and the least favorable composite outcome

Relation of early-stage renal insufficiency and cardiac structure and function in a large population of asymptomatic Asians: a cross-sectional cohort analysis

BackgroundFew studies have addressed early-stage kidney disease and preclinical cardiac structural and functional abnormalities from a large-scale Asian population. Further, the extent to which measures of myocardial function and whether these associations may vary by testing various formulas of renal insufficiency remains largely unexplored.ObjectiveTo explore the associations among renal function, proteinuria, and left ventricular (LV) structural and diastolic functional alterations.DesignA cross-sectional, retrospective cohort study.SettingRegistered data from a cardiovascular health screening program at MacKay Memorial Hospital from June 2009 to December 2012.ParticipantsAsymptomatic individuals.MeasurementsRenal function was evaluated in terms of estimated glomerular filtration rate (eGFR) by both MDRD and CKD-EPI formulas and severity of proteinuria, which were further related to cardiac structure, diastolic function (including LV e’ by tissue Doppler), and circulating N-terminal pro-brain natriuretic peptide (NT-proBNP) level.ResultsAmong 4942 participants (65.8% men, mean age 49.4 ± 11.2 years), the mean CKD-EPI/MDRD eGFR was 90.6 ± 15.7 and 88.5 ± 16.9 ml/min/1.73m2, respectively. Lower eGFR, estimated either by the MDRD or CKD-EPI method, and higher proteinuria were significantly associated with lower LV e’ and higher NT-proBNP (all p<0.05) even after adjusting for clinical covariates. In general, lower eGFR estimated by CKD-EPI and MDRD displayed similar impacts on worsening e’ and NT-proBNP, rather than E/e’, in multivariate models. Finally, lower LV e’ or higher composite diastolic score, rather than E/e’, demonstrated remarkable interaction with eGFR level estimated by either CKD-EPI or MDRD on circulating NT-proBNP level (p interaction <0.05).LimitationsProteinuria was estimated using a urine dipstick rather than more accurately by the urine protein-to-creatinine ratio. Also, pertaining drug history and clinical hard outcomes were lacking.ConclusionBoth clinical estimate of renal insufficiency by eGFR or proteinuria, even in a relatively early clinical stage, were tightly linked to impaired cardiac diastolic relaxation and circulating NT-proBNP level. Elevation of NT-proBNP with worsening renal function may be influenced by impaired myocardial relaxation

Association of Female Menopause With Atrioventricular Mechanics and Outcomes

BACKGROUND: Despite known sex differences in cardiac structure and function, little is known about how menopause and estrogen associate with atrioventricular mechanics and outcomes. OBJECTIVE: To study how, sex differences, loss of estrogen in menopause and duration of menopause, relate to atrioventricular mechanics and outcomes. METHODS: Among 4051 asymptomatic adults (49.8 ± 10.8 years, 35%women), left ventricular (LV) and left atrial (LA) mechanics were assessed using speckle-tracking. RESULTS: Post-menopausal (vs. pre-menopausal) women had similar LV ejection fraction but reduced GLS, reduced PALS, increased LA stiffness, higher LV sphericity and LV torsion (all p < 0.001). Multivariable analysis showed menopause to be associated with greater LV sphericity (0.02, 95%CI 0.01, 0.03), higher indexed LV mass (LVMi), lower mitral e’, lower LV GLS (0.37, 95%CI 0.04–0.70), higher LV torsion, larger LA volume, worse PALS (∼2.4-fold) and greater LA stiffness (0.028, 95%CI 0.01–0.05). Increasing years of menopause was associated with further reduction in GLS, markedly worse LA mechanics despite greater LV sphericity and higher torsion. Lower estradiol levels correlated with more impaired LV diastolic function, impaired LV GLS, greater LA stiffness, and increased LV sphericity and LV torsion (all p < 0.05). Approximately 5.5% (37/669) of post-menopausal women incident HF over 2.9 years of follow-up. Greater LV sphericity [adjusted hazard ratio (aHR) 1.04, 95%CI 1.00–1.07], impaired GLS (aHR 0.87, 95%CI 0.78–0.97), reduced peak left atrial longitudinal strain (PALS, aHR 0.94, 95%CI 0.90–0.99) and higher LA stiffness (aHR 10.5, 95%CI 1.69–64.6) were independently associated with the primary outcome of HF hospitalizations in post-menopause. Both PALS < 23% (aHR:1.32, 95%CI 1.01–3.49) and GLS < 16% (aHR:5.80, 95%CI 1.79–18.8) remained prognostic for the incidence of HF in post-menopausal women in dichotomous analyses, even after adjusting for confounders. Results were consistent with composite outcomes of HF hospitalizations and 1-year all-cause mortality as well. CONCLUSION: Menopause was associated with greater LV/LA remodeling and reduced LV longitudinal and LA function in women. The cardiac functional deficit with menopause and lower estradiol levels, along with their independent prognostic value post-menopause, may elucidate sex differences in heart failure further

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

Mitochondrial physiology

As the knowledge base and importance of mitochondrial physiology to evolution, health and disease expands, the necessity for harmonizing the terminology concerning mitochondrial respiratory states and rates has become increasingly apparent. The chemiosmotic theory establishes the mechanism of energy transformation and coupling in oxidative phosphorylation. The unifying concept of the protonmotive force provides the framework for developing a consistent theoretical foundation of mitochondrial physiology and bioenergetics. We follow the latest SI guidelines and those of the International Union of Pure and Applied Chemistry (IUPAC) on terminology in physical chemistry, extended by considerations of open systems and thermodynamics of irreversible processes. The concept-driven constructive terminology incorporates the meaning of each quantity and aligns concepts and symbols with the nomenclature of classical bioenergetics. We endeavour to provide a balanced view of mitochondrial respiratory control and a critical discussion on reporting data of mitochondrial respiration in terms of metabolic flows and fluxes. Uniform standards for evaluation of respiratory states and rates will ultimately contribute to reproducibility between laboratories and thus support the development of data repositories of mitochondrial respiratory function in species, tissues, and cells. Clarity of concept and consistency of nomenclature facilitate effective transdisciplinary communication, education, and ultimately further discovery

Isolation and Characterization of a Novel Strain of Mesenchymal Stem Cells from Mouse Umbilical Cord: Potential Application in Cell-Based Therapy

<div><p>Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) have recently been recognized as a potential source for cell-based therapy in various preclinical animal models, such as Parkinson’s disease, cerebral ischemia, spinal cord injury, and liver failure; however, the precise cellular and molecular mechanisms underlying the beneficial outcomes remain under investigation. There is a growing concern regarding rejection and alteration of genetic code using this xenotransplantation approach. In this study, a novel strain of murine MSCs derived from the umbilical cord of wild-type and green fluorescent protein (GFP) transgenic mice have been successfully isolated, expanded, and characterized. After 10 passages, the mUC-MSCs developed a rather homogeneous, triangular, spindle-shaped morphology, and were sub-cultured up to 7 months (over 50 passages) without overt changes in morphology and doubling time. Cell surface markers are quite similar to MSCs isolated from other tissue origins as well as hUC-MSCs. These mUC-MSCs can differentiate into osteoblasts, adipocytes, neurons, and astrocytes <i>in vitro</i>, as well as hematopoietic lineage cells <i>in vivo</i>. mUC-MSCs also possess therapeutic potential against two disease models, focal ischemic stroke induced by middle cerebral artery occlusion (MCAo) and acute hepatic failure. Subtle differences in the expression of cytokine-related genes exist between mUC-MSCs and hUC-MSCs, which may retard and jeopardize the advance of cell therapy. Allografts of these newly established mUC-MSCs into various mouse disease models may deepen our insights into the development of more effective cell therapy regimens.</p> </div

Isolation of novel MSCs from mouse umbilical cord.

<p>(A) Mouse UC-MSCs isolated from GFP transgenic mice at passage numbers 0 (Div 4) and 10 (P10). mUC-MSCs displayed the triangular, spindle-shaped, and fibroblast-like morphology at P10. (B) Growth Kinetics of mUC-MSCs. Cumulative cell number was counted at each passage. (C) The population doubling time pattern of mUC-MSCs from passage 10 to passage 50. (D) RT-PCR analysis of the pluripotency-associated genes in mUC-MSCs. Lane 1, mES cells; lane 2, germ cells from testis; lane 3, mUC-MSCs from heterogeneous populations (Mix); land 4-5, mUC-MSCs derived from different single colony. Scale bar = 50 µm.</p

Immunophenotype antigen profile of mUC-MSCs.

<p>Cells of passage number 12–20 were labeled with PE- or APC-conjugated antibodies against the indicated antigens, and analyzed by flow cytometry. Hematopoietic cells markers, including CD2, CD3, CD5, CD11b, CD19, CD45, CD117, Gr-1, and TER-119; mesenchymal stem cells markers, including CD13, CD29, CD44, CD49e, and Sca-1; and mES cells marker, SSEA-1, were used. The respective isotype control was displayed as an open histogram (dark gray line), and specific antibody was displayed as a filled histogram (green).</p