Effects of Epac1 on Diabetic Retinal Inflammation

An ever-growing body of research suggests that inflammation is one of the primary causes of diabetic retinopathy, as the inflammation can lead to insulin resistance. Beta-adrenergic receptor agonists can reduce the inflammation in human retinal endothelial cells (HRECs), but are not a viable treatment due to systemic effects. Epac1 lies downstream of beta-adrenergic receptor signaling, and it may have the capability to reduce inflammation by acting as an alternative pathway for beta-adrenergic receptor agonists to block inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1B). We hypothesized that the Epac1 agonist will decrease cytokine levels, leading to improved insulin signal transduction in the retina. HRECs were grown in normal (5mM) or high glucose (25mM). Some cells were not treated with the Epac1 agonist and serve as controls. Western blotting was done using primary antibodies for total and phosphorylated insulin receptor substrate-1 (IRS-1), insulin receptor (IR) and Akt, as well as beta actin as a control for loading. Anti-Rabbit IgG/HRP was used for secondary antibodies. ELISA analyses were done for protein levels of TNF-alpha and IL-1B. We are not done with data analyses, but we expect to find that Epac1 will increase insulin receptor and Akt phosphorylation, while reducing TNF-alpha and IL-1B levels

Rapamycin Attenuates Cardiac Fibrosis in Experimental Uremic Cardiomyopathy by Reducing Marinobufagenin Levels and Inhibiting Downstream Pro-Fibrotic Signaling

Background: Experimental uremic cardiomyopathy causes cardiac fibrosis and is causally related to the increased circulating levels of the cardiotonic steroid, marinobufagenin (MBG), which signals through Na/K‐ATPase. Rapamycin is an inhibitor of the serine/threonine kinase mammalian target of rapamycin (mTOR) implicated in the progression of many different forms of renal disease. Given that Na/K‐ATPase signaling is known to stimulate the mTOR system, we speculated that the ameliorative effects of rapamycin might influence this pathway. Methods and Results: Biosynthesis of MBG by cultured human JEG‐3 cells is initiated by CYP27A1, which is also a target for rapamycin. It was demonstrated that 1 μmol/L of rapamycin inhibited production of MBG in human JEG‐2 cells. Male Sprague‐Dawley rats were subjected to either partial nephrectomy (PNx), infusion of MBG, and/or infusion of rapamycin through osmotic minipumps. PNx animals showed marked increase in plasma MBG levels (1025±60 vs 377±53 pmol/L; PPP Conclusions: Rapamycin treatment in combination with MBG infusion significantly attenuated cardiac fibrosis. Our results suggest that rapamycin may have a dual effect on cardiac fibrosis through (1) mTOR inhibition and (2) inhibiting MBG‐mediated profibrotic signaling and provide support for beneficial effect of a novel therapy for uremic cardiomyopathy

Identification of a pool of non-pumping Na/K-ATPase

Recent studies have ascribed many non-pumping functions to the Na/K-ATPase. Here, we present experimental evidence demonstrating that over half of the plasma membrane Na/KATPase in LLC-PK1 cells is performing cellular functions other than ion pumping. This “non-pumping” pool of Na/K-ATPase, like the pumping pump, binds ouabain. Depletion of either cholesterol or caveolin-1 moves some of the “non-pumping” Na/KATPase into the pumping pool. Graded knock-down of the 1 subunit of the Na/K-ATPase eventually results in loss of this “non-pumping” pool while preserving the pumping pool. Our prior studies indicate that a loss of the non-pumping pool is associated with a loss of receptor function as evidenced by the failure of ouabain administration to induce the activation of Src and/or ERK. Therefore, our new findings suggest that a substantial amount of surface-expressed Na/K-ATPase, at least in some types of cells, may function as non-canonical ouabain-binding receptors

Carbonylation Modification Regulates Na/K-AT PaseSignaling and Salt Sensitivity: A Review and a Hypothesis

Na/K-ATPase signaling has been implicated in different physiological and pathophysiological conditions. Accumulating evidence indicates that oxidative stress not only regulates the Na/K-ATPase enzymatic activity, but also regulates its signaling and other functions. While cardiotonic steroids (CTS)-induced increase in reactive oxygen species (ROS) generation is an intermediate step in CTS-mediated Na/K-ATPase signaling, increase in ROS alone also stimulates Na/K-ATPase signaling. Based on literature and our observations, we hypothesize that ROS have biphasic effects on Na/K-ATPase signaling, transcellular sodium transport, and urinary sodium excretion. Oxidative modulation, in particular site specific carbonylation of the Na/K-ATPase α1 subunit, is a critical step in proximal tubular Na/K-ATPase signaling and decreased transcellular sodium transport leading to increases in urinary sodium excretion. However, once this system is overstimulated, the signaling, and associated changes in sodium excretion are blunted. This review aims to evaluate ROS-mediated carbonylation of the Na/K-ATPase, and its potential role in the regulation of pump signaling and sodium reabsorption in the renal proximal tubule (RPT)

Effects of egg and vitamin A supplementation on hemoglobin, retinol status and physical growth levels of primary and middle school students in

Lack of protein and vitamin A influences the growth of student in impoverished mountain areas. The aim of the study was to assess the effects of egg and vitamin A supplementation on hemoglobin, serum retinol and anthropometric indices of 10-18 years old students of a low socioeconomic status. A total number of 288 students from four boarding schools were randomly selected by using cluster sampling method in Chongqing, and they were assigned into supplement group and control group non-randomly. Students in supplement group received a single 200,000 international units vitamin A and 1 egg/day (including weekends) for 6 months. The control group did not receive any supplementation. We measured hemoglobin, serum retinol and height and weight at baseline and after supplementation. The supplementation increased the mean hemoglobin concentration by 7.13 g/L compared with 1.38 g/L in control group (p<0.001), the mean serum retinol concentration by 0.31 μmol/L compared with 0.09 μmol/L in the control group (p=0.005), the mean height-for-age z score by 0.05 compared with 0.03 in the control group (p=0.319), the mean weight-for-age z score by 0.05 compared with -0.12 in the control group (p<0.001). Our results revealed that egg and vitamin A supplementation is an effective, convenient, and practical method to improve the levels of hemoglobin, serum retinol and prevent the deterioration of growth in terms of weight for primary and middle school students from outlying poverty-stricken areas. Our intervention did not have a beneficial effect on linear growth

Application and Evaluation of [Tc]-Labeled Peptide Nucleic Acid Targeting in Breast Cancer Imaging

It has been reported that dysregulation of microRNA-155 expression and function is associated with tumorigenesis, growth, tumor subtypes, invasion, and poor survival rates. Peptide nucleic acid (PNA), an artificially synthesized nucleic acid mimic, has been applied for molecular diagnosis. In this study, a PNA sequence that undergoes complementary binding to miR-155 was labeled with 99m Tc to evaluate whether the tracer could visualize the expression of miR-155 in breast cancer. Both antisense PNA (anti-PNA, fully complementary bound to human mature miR-155 , referred to as “anti-PNA-155”) and mismatched PNA (referred to as “mis-PNA”) single strands containing 23-mer were synthesized. The relative expression of miR-155 in MCF-7 cells and tumors was higher than that in MDA-MB-231 cells and tumors. Single-photon emission computed tomography (SPECT) scan showed that radioactivity mainly accumulated in kidney. MCF-7 tumors, but not MDA-MB-231 tumors, were clearly visualized after [ 99m Tc]anti-PNA-155 injection. MCF-7 tumors were less visible when coinjected with 100-fold excess of anti-PNA-155 or injected with [ 99m Tc]mis-PNA, which suggested specific binding. Biodistribution study results were consistent with SPECT imaging. We successfully demonstrated that [ 99m Tc]anti-PNA-155 could visualize miR-155 expression in vivo, suggesting it may be a promising probe applied in breast cancer

Long-term outcomes of surgical or endovascular treatment of adult with midaortic syndrome: A single-center retrospective study over a 14-year periodCentral MessagePerspective

Objective: Midaortic syndrome is a rare clinical condition that has been mainly studied in juveniles through case reports and series. This study aims to report the anatomic characteristics and long-term outcomes of 41 adult patients with midaortic syndrome who received open surgical treatment or endovascular treatment over a 14-year period. Methods: A consecutive cohort of 41 adult patients diagnosed with midaortic syndrome at our center between January 2008 and November 2021 were enrolled in the study. Patients’ baseline and anatomic characteristics were collected and analyzed. Primary follow-up outcomes included death and reintervention. Other follow-up outcomes included hypertension and complications. Results: The study enrolled 41 adult patients with midaortic syndrome with a mean age of 37.5 ± 13.4 years. Twenty-five patients received open surgical treatment, and 16 patients received endovascular treatment. Isolated infrarenal lesions were more likely to be found in the endovascular treatment group (P = .005), whereas patients with multiple (P = .002) or intravisceral involvement (P = .001) were more likely to be found in the open surgical treatment group. The open surgical treatment group was more likely to have a lower postoperative peak systolic pressure gradient (P = .020). The 5- and 10-year reintervention-free survivals were 87.7% and 71.7% in the open surgical treatment group and 92.3% and 79.1% in the endovascular treatment group, respectively. Conclusions: Both open surgical treatment and endovascular treatment showed satisfactory long-term efficacy outcomes for adult patients with midaortic syndrome. Given the patients’ relatively young age and long life expectancy, strict and regular lifelong follow-up is necessary

Afatinib as a Potential Therapeutic Option for Patients With NSCLC With EGFR G724S

Introduction: EGFR G724S has been described to mediate resistance to first- and third-generation EGFR tyrosine kinase inhibitors (TKIs). In vitro experiments have provided compelling evidence that G724S retains sensitivity for afatinib. Nevertheless, limited data have reported the clinical efficacy of afatinib in patients with NSCLC harboring G724S mutation. Methods: We identified 52 patients with NSCLC with EGFR G724S from an inhouse database and comprehensively profiled their concurrent mutation statuses. Treatments and clinical outcomes were also collected. Results: Of 52 G724S-positive patients, 39 harbored concomitant EGFR exon 19 deletion (19del), and all 37 of the 39 patients who had available clinical data were detected with a G724S mutation after receiving EGFR TKIs. A rare variant of 19del E746_S752delinsV co-occurred with G724S the most frequently (n = 29), whereas 7 of 10 patients with concomitant EGFR exon 20 mutation were TKI treatment naive. S768I was the most common mutation in exon 20 (n = 7). One patient harbored a concomitant EGFR exon 21 mutation, and two lacked co-occurring EGFR mutations. A total of 23 patients provided valid clinical outcome data, of whom eight were treated with afatinib after the emergence of G724S, whereas 15 received non-afatinib treatment (alternative EGFR TKI, chemotherapy, or best supportive care). The disease control rate in afatinib-treated patients (n = 8) reached 100% with a median progression-free survival of 4.5 months, significantly longer than that of non–afatinib-treated (n = 15, 1.7 mo, hazard ratio [HR] = 0.32, p = 0.037) and alternative EGFR TKI-treated (n = 11, 1.8 mo, HR = 0.28, p = 0.042) patients. In the subset who had progressed on osimertinib, afatinib also yielded a superior progression-free survival (6.2 mo) than non-afatinib therapies (1.0 mo, HR = 0.04, p = 0.005) and alternative EGFR TKIs (1.8 mo, HR = 0.06, p = 0.033). Analysis of acquired mutations at afatinib progression revealed re-emergence of EGFR T790M or MET amplification as the potential mechanism of afatinib resistance. Conclusions: EGFR G724S emerges as a resistant mutation against EGFR TKI preferentially in the context of a rare variant of 19del, whereas it might mediate differential mechanisms in the context of exon 20 mutation. We also found that afatinib could be a potential therapeutic option for patients with NSCLC with G724S

Mapping the intellectual structure of the research of omalizumab in chronic spontaneous urticaria: A bibliometric analysis

Background: The guidelines for treating chronic spontaneous urticaria (CSU) recommend using the IgE-targeted biologic omalizumab in patients with antihistamine-refractory disease. Objective: Our aim was to present a bibliometric review of publications related to omalizumab and CSU over the past 2 decades. Methods: Relevant publications from 2003 to 2022 were extracted from the Science Citation Index-Expanded (SCI-EXPANDED) database in the Web of Science Core Collection database as of January 8, 2023. We utilized CiteSpace (version 6.1.R3), VOSviewer (version 1.6.18), and the R package (version 4.2.1) to analyze and visualize the data. The R package bibliometrix (version 4.2.1) was also used. Results: Between 2003 and 2022, a total of 566 articles on omalizumab and CSU were published. Since 2014, there has been a rapid increase in publication output. According to the collaboration network, the most influential country, institute, and scholar were the United States, Charité Universitätsmedizin Berlin, and Marcus Maurer, respectively. The study identified the Journal of Allergy and Clinical Immunology: In Practice as the most productive journal and the Journal of Allergy and Clinical Immunology as the most cocited journal. The analysis of key words revealed the presence of high-frequency terms such as angioedema, IgE, treatment, anti-IgE, asthma, and atopic dermatitis. Moreover, recent studies in this area have concentrated mainly on biomarkers, dupilumab, and coronavirus 2019 (COVID-19). Conclusion: There has been a growing interest in the use of omalizumab in CSU in recent years. The current trending topics in this research are the identification of biomarkers and the development of new mAbs for the treatment of CSU