MZe786 Rescues Cardiac Mitochondrial Activity in High sFlt-1 and Low HO-1 Environment

Hypertensive disorder in pregnancy is a major cause of maternal and perinatal mortality worldwide. Women who have had preeclampsia are at three to four times higher risk in later life of developing high blood pressure and heart disease. Soluble Flt-1 (sFlt-1) is elevated in preeclampsia and may remain high postpartum in women with a history of preeclampsia. Heme oxygenase-1 (Hmox1/HO-1) exerts protective effects against oxidative stimuli and is compromised in the placenta of pregnant women with preeclampsia. We hypothesized that sFlt-1 inhibits cardiac mitochondrial activity in HO-1 deficient mice. HO-1 haplo-insufficient mice (Hmox1+/−) were injected with adenovirus encoding sFlt-1 (Ad-sFlt-1) or control virus (Ad-CMV). Subsequently, they were treated daily with either placebo or MZe786 for six days, when the heart tissue was harvested to assess cardiac mitochondrial activity. Here, we show that the loss of HO-1 disturbed cardiac mitochondrial respiration and reduced mitochondrial biogenesis. The overexpression of sFlt-1 resulted in the inhibition of the cardiac mitochondrial activity in Hmox1+/− mice. The present study demonstrates that the hydrogen sulfide (H2S) releasing molecule, MZe786, rescues mitochondrial activity by stimulating cardiac mitochondrial biogenesis and antioxidant defense in Hmox1−/− mice and in Hmox1+/− mice exposed to a high sFlt-1 environment

MZe786, a hydrogen sulfide-releasing aspirin prevents preeclampsia in heme oxygenase-1 haplodeficient pregnancy under high soluble flt-1 environment

Preeclampsia affects one in twelve of the 130 million pregnancies a year. The lack of an effective therapeutic to prevent or treat it is responsible for an annual global cost burden of 100 billion US dollars. Preeclampsia also affects these women later in life as it is a recognised risk factor for cardiovascular disease, stroke and vascular dementia. Our laboratory demonstrated that preeclampsia is associated with high soluble fms-like tyrosine kinase 1 (sFlt-1) and low heme oxygenase-1 (HO1/Hmox1) expression. Here we sought to determine the therapeutic value of a novel H 2S-releasing aspirin (MZe786) in HO-1 haploid deficient (Hmox1 +/−) pregnant mice in a high sFlt-1 environment. Pregnant Hmox1 +/− mice were injected with adenovirus encoding sFlt-1 or control virus at gestation day E11.5. Subsequently, Hmox1 +/− dams were treated daily with a number of treatment regimens until E17.5, when maternal and fetal outcomes were assessed. Here we show that HO-1 compromised mice in a high sFlt-1 environment during pregnancy exhibit severe preeclampsia signs and a reduction in antioxidant genes. MZe786 ameliorates preeclampsia by reducing hypertension and renal damage possibly by stimulating antioxidant genes. MZe786 also improved fetal outcome in comparison with aspirin alone and appears to be a better therapeutic agent at preventing preeclampsia than aspirin alone

Hydrogen sulfide releasing molecule MZe786 inhibits soluble Flt-1 and prevents preeclampsia in a refined RUPP mouse model

An imbalance in angiogenic growth factors and poor utero-placental perfusion are strongly associated with preeclampsia. The reduced utero-placental perfusion (RUPP) model that mimics insufficient placental perfusion is used to study preeclampsia. The aim of this study was to develop a refined RUPP model in C57Bl/6 J mice to test the efficacy of MZe786 as a potential inhibitor of soluble Flt-1 for preeclampsia therapy. Murine RUPP (mRUPP) was induced through bilateral ligation of the ovarian arteries at E11.5 that resulted in typical preeclampsia symptoms including increase in mean arterial pressure (MAP), kidney injury and elevated soluble Flt-1 (sFlt-1) levels in the maternal plasma and amniotic fluid. The murine RUPP kidneys showed tubular and glomerular damage along with increased oxidative stress characterised by increased nitrotyrosine staining. The mRUPP displayed abnormal placental vascular histology, reduced expression of placental cystathionine γ-lyase (CSE), the hydrogen sulfide (H 2S) producing enzyme, and resulted in adverse fetal outcomes (FGR). Importantly, oral administration of hydrogen sulfide (H 2S)-releasing compound MZe786 from E11.5 to E17.5 successfully prevented the development of preeclampsia. Specifically, MZe786 treatment reduced maternal MAP and kidney nitrotyrosine staining and improved fetal outcome. The circulation levels of sFlt-1 were dramatically decreased in MZe786 treated animals implying that H 2S released from MZe786 offered protection by inhibiting sFlt-1 levels. MZe786 prevent preeclampsia and warrant a rapid move to randomised control clinical trial

Role of Stem Cells in Orthopaedic Surgery: Theoretical Survey

This study aims at analyzing the Stem cell application is a burgeoning field of medicine that is likely to influence the future of orthopaedic surgery. Stem cells are associated with great promise and great controversy. For the orthopaedic surgeon, stem cells may change the way that orthopaedic surgery is practiced and the overall approach of the treatment of musculoskeletal disease. Stem cells may change the field of orthopaedics from a field dominated by surgical replacements and reconstructions to a field of regeneration and prevention. This review will introduce the basic concepts of stem cells pertinent to the orthopaedic surgeon and proceed with a more in depth discussion of current developments in the study of stem cells in orthopaedic surgery. Keywords: Stem cell, orthopaedic, surgery

Association Between Lipid Profile and Diabetic Foot Ulcer

Diabetic foot ulcer is a serious disabling consequence of Diabetes Mellitus. They are characterized by the breakdown of skin and underlying tissues in the feet, and are a major cause of lower limb amputations. Various risk factors have been identified for the development of diabetic foot ulcers, including poor glycemic control, peripheral neuropathy, peripheral arterial disease, and impaired wound healing. it is considered that the lipid profile is one of many factors that contribute to the formation and progression of diabetic foot ulcers. To stratify the incidence of diabetic foot ulcers (DFUs), biomarkers are required. The aim of this review is to assess the relationship between the risk of DFU and lipid profile in diabetic patients

The Hippo component YAP localizes in the nucleus of human papilloma virus positive oropharyngeal squamous cell carcinoma

Background: HPV infection causes cervical cancer, mediated in part by the degradation of Scribble via the HPV E6 oncoprotein. Recently, Scribble has been shown to be an important regulator of the Hippo signaling cascade. Deregulation of the Hippo pathway induces an abnormal cellular transformation, epithelial to mesenchymal transition, which promotes oncogenic progression. Given the recent rise in oropharyngeal HPV squamous cell carcinoma we sought to determine if Hippo signaling components are implicated in oropharyngeal squamous cell carcinoma. Methods: Molecular and cellular techniques including immunoprecipiations, Western blotting and immunocytochemistry were used to identify the key Hippo pathway effector Yes-Associated Protein (YAP)1. Oropharyngeal tissue was collected from CO2 laser resections, and probed with YAP1 antibody in tumor and pre-malignant regions of HPV positive OPSCC tissue. Results: This study reveals that the Scribble binding protein Nitric Oxide Synthase 1 Adaptor Protein (NOS1AP) forms a complex with YAP. Further, the NOS1APa and NOS1APc isoforms show differential association with activated and non-activated YAP, and impact cellular proliferation. Consistent with deregulated Hippo signaling in OPSCC HPV tumors, we see a delocalization of Scribble and increased nuclear accumulation of YAP1 in an HPV-positive OPSCC. Conclusion: Our preliminary data indicates that NOS1AP isoforms differentially associate with YAP1, which, together with our previous findings, predicts that loss of YAP1 enhances cellular transformation. Moreover, YAP1 is highly accumulated in the nucleus of HPV-positive OPSCC, implying that Hippo signaling and possibly NOS1AP expression are de-regulated in OPSCC. Further studies will help determine if NOS1AP isoforms, Scribble and Hippo components will be useful biomarkers in OPSCC tumor biology

Impostor phenomenon among urologists in Saudi Arabia

Impostor phenomenon (IP) is the persistent inability to believe that one’s success is deserved or has been legitimately achieved due to one’s efforts or skills. It is associated with burnout, anxiety and depression and can negatively impact the lives of the affected individuals. This study aimed to determine the prevalence of IP among urologists in Saudi Arabia. A cross-sectional study was conducted among practicing urologists and urologists-in-training in Saudi Arabia between November and December 2022. A self-administered questionnaire comprising questions on the sociodemographic characteristics and the Clance impostor phenomenon scale (CIPS) was distributed through email to all registered urologists in the Saudi Commission for Health Specialties database. A total of 155 urologists (143 men and 12 women) were enrolled in this study. The majority of the urologists (44.5%) were consultants, and the prevalence of the impostor phenomenon in this study was 27.7%. Nearly half of the urologists (49.7%) presented moderate levels of the phenomenon, 23.9% of the urologists demonstrated high levels, and 20.6% presented low levels. Only 5.8% of the urologists showed intense levels of the phenomenon. The phenomenon was significantly more prevalent among those in training (p = 0.010) and less prevalent among those with a subspecialty in endourology (p = 0.016). The prevalence of the impostor phenomenon among urologists was 27.7%. It was more commonly seen in resident urologists, and those with a subspecialty in endourology were less likely to be affected by this phenomenon

The Impact Of Oral Health Education And Preventive Measures On Dental Caries And Periodontal Diseases

Oral problems, including dental caries, periodontal diseases, and tooth loss, are significant global public health concerns. This is due to the fact that inadequate oral health has extensive impacts on general health and quality of life. In improving oral health, especially in developing countries, there are obstacles that need to be addressed. It is crucial to enhance public health programs worldwide by implementing efficient preventative measures against diseases and simultaneously boosting oral health. Frequently, collective actions are employed for the purpose of oral health education. These actions often involve delivering lectures utilizing various materials such as flipcharts, videos, PowerPoint presentations, as well as implementing other activities like supervised teeth brushing and topical fluoride application. This paper aimed to review the impact of oral health education and preventive measures on dental caries and periodontal diseases

Transcriptomics-based characterization of the toxicity of ZnO nanoparticles against chronic myeloid leukemia cells

Introduction: Zinc oxide nanoparticles (ZnO NPs) have recently attracted attention as potential anti-cancer agents. To the best of our knowledge, the toxicity of ZnO NPs against human chronic myeloid leukemia cells (K562 cell line) has not been studied using transcriptomics approach. Objective: The goals of this study were to evaluate the capability of ZnO NPs to induce apoptosis in human chronic myeloid leukemia cells (K562 cells) and to investigate the putative mechanisms of action. Methods: We used viability assay and flowcytometry coupled with Annexin V-FITC and propidium iodide to investigate the toxicity of ZnO NPs on K562 cells and normal peripheral blood mononuclear cells. Next we utilized a DNA microarray-based transcriptomics approach to characterize the ZnO NPs-induced changes in the transcriptome of K562 cells. Results: ZnO NPs exerted a selective toxicity (mainly by apoptosis) on the leukemic cells (p≤ 0.005) and altered their transcriptome; 429 differentially expressed genes (DEGs) with fold change (FC)≥ 4 and p≤ 0.008 with corrected p≤ 0.05 were identified in K562 cells post treatment with ZnO NPs. The over-expressed genes were implicated in “response to zinc”, “response to toxic substance” and “negative regulation of growth” (corrected p≤ 0.05). In contrast, the repressed genes positively regulated “cell proliferation”, “cell migration”, “cell adhesion”, “receptor signaling pathway via JAK-STAT” and “phosphatidylinositol 3-kinase signaling” (corrected p≤ 0.05). Lowering the FC to ≥ 1.5 with p≤ 0.05 and corrected p≤ 0.1 showed that ZnO NPs over-expressed the anti-oxidant defense system, drove K562 cells to undergo mitochondrial-dependent apoptosis, and targeted NF-κB pathway. Conclusion: Taken together, our findings support the earlier studies that reported anti-cancer activity of ZnO NPs and revealed possible molecular mechanisms employed by ZnO NPs to induce apoptosis in K562 cells

Oral semaglutide adequate glycaemia control with safe cardiovascular ‎profile

BackgroundType 2 diabetes is a chronic and progressive disease that ‎associated with series complication such as major adverse ‎cardiovascular events. Adequate glycaemic control proven ‎to reduce this risk. Orally administered semaglutide ‎promising medication in managing patient with type 2 ‎diabetes.‎AimsTo assess the cardiovascular safety and efficacy of semaglutide, a recently approved glucagon-like peptide 1 receptor agonist (GLP-1 RA) for type 2 diabetes.Methods Pub Med, ‎Google Scholar, and EBSCO ‎ databases were ‎systematically search for relevant articles. The terms‎ diabetes‎, Glucagon-like peptide, semaglutide‎ were used. Out of hundred twenty-two records, only ‎four fulfilled ‎the inclusion criteria.Results Four placebo-controlled studies with oral semaglutide ‎were included. Single study concern about the cardiovascular safety of oral semaglutide ‎and showed that, ‎compared with placebo, semaglutide ‎ was not associated ‎with increased in the cardiovascular events. On the other ‎hand, the remaining trials shown that, semaglutide ‎ can ‎effectively control the blood glucose as evident by ‎reduction in HA1c.ConclusionOral semaglutide can effectively and safely lower blood glucose without increase in the major adverse ‎cardiovascular events‎‎ (MACE).