We performed a cross sectional study on 151 patients with type 2 diabetes from the diabetes clinic of Vali Asr hospital affiliated with Tehran University of Medical Science plus 45controls.Diabetes was diagnosed according to the criteria of the American Diabetes Association which is based on glycemia [24].Exclusion criteria were smoking, pregnancy, creatinine >1.5 mg/dl or GFR< 70 cc/min, glomerulonephritis, thyroid disorders, acute infections, stroke, diabetic ketoacidosis, non-ketonic hyperosmolar diabetes, congestive heart failure, use of antioxidant and hospital admission in recent 6 months.None of the participants were on hormone replacement therapy.Controls were healthy volunteers from the patients' concomitants or hospital staffs.Healthy controls were selected from those without any known disease including type 2 diabetes, hyperlipidemia, ischemic heart disease and malignancy.Demographic and anthropometric data including age, sex, duration of diabetes, height and weight in light clothing and blood pressure in sitting position were recorded.Blood pressure was re measured twice after 5 minutes average.The body mass index (BMI; Kg/m 2 ) was calculated according to the Quetelet formula.Diet was almost similar in composition in all the studied groups.
8-iso-PGF2α is a family of PGF2α that could be offered as a non-invasive tool to represent in vivo oxidation status, as a link between oxidative milieus and vascular dysfunction.A total of 45 patients with type 2 diabetes and 45 healthy adults were studied in this cross-sectional analysis. Blood samples were collected to measure the level of lipid profile, oxidative stress, and glycemic control indices. The sensitivity and specificity of 8-iso-PGF2α as a screening test were analyzed in the cut-off range 252 - 377.5 pg/mL and the corresponding receiver operating characteristics (ROC) were plotted to assess performance of the test.8-iso-PGF2α level was significantly higher in the diabetic group (439.11 pg/mL ± 181.13 vs. 380.93 pg/mL ± 146.52). After adjustments for age, gender, and body mass index (BMI), linear regression analysis revealed that homeostasis model assessment of insulin resistance (HOMA-IR), blood pressure, fasting blood sugar (FBS), serum creatinine, insulin, oxLDL, and CRP levels are directly correlated with 8-iso-PGF2α in the 25% - 75% quartiles. Moreover, their mean levels were higher in quartiles with greater 8-iso-PGF2α levels. The cut-offs showing the best equilibrium between sensitivity and specificity approached 269.5 pg/mL with 83% and 62.5% sensitivity and specificity, respectively.Our study provides evidence for the application of serum 8-isoPGF2α in the 25 - 75% quartile ranges to screen for the severity of oxidative reactions and glycemic control in vivo without need for any further in vitro enzymatic reactions, with higher levels, reflecting more severe oxidation and poor glycemic control.
Human embryonic stem cells (hESCs) can be used to generate scalable numbers of cardiomyocytes (CMs) for studying cardiac biology, disease modelling, drug screens, and potentially for regenerative therapies. A fluorescence-based reporter line will significantly enhance our capacities to visualize the derivation, survival, and function of hESC-derived CMs. Our goal was to develop a reporter cell line for real-time monitoring of live hESC-derived CMs.We used CRISPR/Cas9 to knock a mCherry reporter gene into the MYH6 locus of hESC lines, H1 and H9, enabling real-time monitoring of the generation of CMs. MYH6:mCherry+ cells express atrial or ventricular markers and display a range of cardiomyocyte action potential morphologies. At 20 days of differentiation, MYH6:mCherry+ cells show features characteristic of human CMs and can be used successfully to monitor drug-induced cardiotoxicity and oleic acid-induced cardiac arrhythmia.We created two MYH6:mCherry hESC reporter lines and documented the application of these lines for disease modelling relevant to cardiomyocyte biology.
We aimed to study whether pulse pressure (PP) predicts the response of diabetic nephropathy to glucose-lowering treatment. Patients with uncontrolled type 2 diabetes were followed for decrease in albuminuria after insulin/oral-hypoglycemic treatment. A total of 143 patients were followed for a median time of 10.5 months in a cohort study. Fasting blood sugar and HbA1C significantly decreased, while systolic, diastolic and pulse pressures remained constant during intervention. Median albuminuria decreased from 18.4 mg/day [10-40] to 16.4 mg/day [9-28] at the end of study (p-value < 0.005). The number of patients with normo/micro/macro-albuminuria changed from 98/36/9 to 108/31/4 (p-value < 0.001). No significant difference in baseline PP (47.5 ± 1.61 vs. 45.9 ± 1.81 mmHg; p-value = 0.51) or final PP (47.0 ± 2.41 vs. 49.4 ± 2.38 mmHg; p-value = 0.47) existed between those with decreased and increased albuminuria. PP was not a significant predictor of albuminuria changes in receiver operating characteristic curve (p-value = 0.77) and regression (p-value = 0.98) analyses. Benefits of glycemic control in diabetic nephropathy are independent of PP.
Abstract Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has led to a global health crisis, and yet our understanding of the disease pathophysiology and potential treatment options remains limited. SARS-CoV-2 infection occurs through binding and internalization of the viral spike protein to angiotensin converting enzyme 2 (ACE2) on the host cell membrane. Lethal complications are caused by damage and failure of vital organs that express high levels of ACE2, including the lungs, the heart and the kidneys. Here, we established a high-throughput drug screening strategy to identify therapeutic candidates that reduce ACE2 levels in human embryonic stem cell (hESC) derived cardiac cells. Drug target analysis of validated hit compounds, including 5 alpha reductase inhibitors, revealed androgen signaling as a key modulator of ACE2 levels. Treatment with the 5 alpha reductase inhibitor dutasteride reduced ACE2 levels and internalization of recombinant spike receptor binding domain (Spike-RBD) in hESC-derived cardiac cells and human alveolar epithelial cells. Finally, clinical data on coronavirus disease 2019 (COVID-19) patients demonstrated that abnormal androgen states are significantly associated with severe disease complications and cardiac injury as measured by blood troponin T levels. These findings provide important insights on the mechanism of increased disease susceptibility in male COVID-19 patients and identify androgen receptor inhibition as a potential therapeutic strategy.
(Stem Cell Reports 10, 848–859; March 13, 2018) The authors wish to make the following corrections to Figures 5C and S4G of this article. The authors declare that these mistakes do not affect the results and conclusions of the study. In Figure 5C, the image designated as belonging to the group “Medium” (row 1, column 2) was an incorrect image put in by mistake. This has now been replaced in the figure below with the correct merge image. In Figure S4G, the image designated as belonging to the group “ALCAM-” (row 1, column 3) was also an incorrect image put in by mistake. This has now been replaced in the figure below with the correct merge image as well.Figure S4. ALCAM+ Cells Promote Tissue Repair and AngiogenesisView Large Image Figure ViewerDownload Hi-res image Download (PPT) Prospective Isolation of ISL1+ Cardiac Progenitors from Human ESCs for Myocardial Infarction TherapyGhazizadeh et al.Stem Cell ReportsMarch 1, 2018In BriefIn this article, Salekdeh and colleagues show that ISL1+ cardiac progenitors can be purified from a heterogeneous population of hESC-derived cardiomyocytes using ALCAM. Transplantation of multipotent ISL1+/ALCAM+ progenitors enhances tissue recovery, restores cardiac function, and improves angiogenesis in a rat model of myocardial infarction, based on cardiac MRI and histology. Full-Text PDF Open Access
Abstract Drug-induced toxicity is one of the leading reasons new drugs fail clinical trials. Machine learning models that predict drug toxicity from molecular structure could help researchers prioritize less toxic drug candidates. However, current toxicity datasets are typically small and limited to a single organ system (e.g., cardio, renal, or liver). Creating these datasets often involved time-intensive expert curation by parsing drug label documents that can exceed 100 pages per drug. Here, we introduce UniTox 1 , a unified dataset of 2,418 FDA-approved drugs with drug-induced toxicity summaries and ratings created by using GPT-4o to process FDA drug labels. UniTox spans eight types of toxicity: cardiotoxicity, liver toxicity, renal toxicity, pulmonary toxicity, hematological toxicity, dermatological toxicity, ototoxicity, and infertility. This is, to the best of our knowledge, the largest such systematic human in vivo database by number of drugs and toxicities, and the first covering nearly all FDA-approved medications for several of these toxicities. We recruited clinicians to validate a random sample of our GPT-4o annotated toxicities, and UniTox’s toxicity ratings concord with clinician labelers 87–96% of the time. Finally, we benchmark a graph neural network trained on UniTox to demonstrate the utility of this dataset for building molecular toxicity prediction models.
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