Insights into the Progression of Labile Hb A1c to Stable Hb A1c via a Mechanistic Assessment of 2,3-Bisphosphoglycerate Facilitation of the Slow Nonenzymatic Glycation Process

Nonenzymatic glycation (NEG) of human hemoglobin (Hb A) consists of initial non covalent, reversible steps involving glucose and amino acid residues, which may also involve effector reagent(s) in the formation of labile Hb A_1c (the conjugate acid of the Schiff base). Labile Hb A_1c can then undergo slow, largely irreversible, formation of stable Hb A_1c (the Amadori product). Stable Hb A_1c is measured to assess diabetic progression after labile Hb A_1c removal. This study aimed to increase the understanding of the distinctions between labile and stable Hb A_1c from a mechanistic perspective in the presence of 2,3-bisphosphoglycerate (2,3-BPG). 2,3-Bisphosphoglycerate is an effector reagent that reversibly binds in the Hb A_1c pocket and modestly enhances overall NEG rate. The deprotonation of C2 on labile Hb A_1c in the formation of the Amadori product was previously proposed to be rate-limiting. Computational chemistry was used here to identify the mechanism(s) by which 2,3-BPG facilitates the deprotonation of C2 on labile Hb A_1c. 2,3-Bisphosphoglycerate is capable of abstracting protons on C2 and the α-nitrogen of labile Hb A_1c and can also deprotonate water and/or amino acid residues, therefore preparing these secondary reagents to deprotonate labile Hb A_1c. Parallel reactions not leading to an Amadori product were found that include formation of the neutral Schiff base, dissociation of glucose from the protein, and cyclic glycosylamine formation. These heretofore under appreciated parallel reactions may help explain both the selective removal of labile from stable Hb A_1c and the slow rate of NEG.     

In vitro activity of EDTA and TOL-463 against Neisseria gonorrhoeae

Neisseria gonorrhoeae quickly develops drug resistance. Time-kill curves revealed that EDTA and TOL-463 inhibit growth similar to penicillin, ciprofloxacin, and azithromycin. Furthermore, synergistic and additive antimicrobial interactions occurred when EDTA and TOL-463 were combined with penicillin or azithromycin, respectively, suggesting that further investigations into these unconventional antimicrobials may be advantageous.     

Effects of topical tranexamic acid during open reduction and internal fixation of acetabular fractures: A retrospective study

ObjectiveThe aim of this study was to assess the effect of topical tranexamic acid on blood loss and transfusion rates in acetabular fracture surgery.MethodsThe medical records of 61 patients who underwent open reduction and internal fixation for acetabular fracture between 2012 and 2015 were retrospectively reviewed. The patients were divided into two groups: Group I consisted of 31 patients (19 men and 12 women, mean age: 52 ± 19 years) who received intraoperatively a topical tranexamic acid solution of 3 g and Group 2 consisted of 30 control patients (17 men and 13 women, mean age: 48 ± 24 years) who received only 0.9% saline solution. The groups were compared based on their intraoperative blood loss, Postoperative drain output at 24 and 48 h, and postoperative hemoglobin levels, and transfusion rates.ResultsThe mean intraoperative blood loss was 410 ± 100 ml in Group 1, compared to 570 ml ± 160 ml of the control group (p < 0.05). The postoperative drain output after 24 h was 210 ± 70 ml in Group 1 compared to 330 ± 90 ml of the control group (p < 0.05). The drain output at 48 h was (50 ± 20 ml) in group 1 compared to 90 ± 40 ml of the control group (p < 0.05). The transfusion rate was significantly low group 1 (42%) than the control group (97%). Hemoglobin drop was again significantly less in tranexamic acid group (2.1 ± 1.1) than the control group (3.2 ± 1.3). The nadir postoperative hemoglobin was higher in the Group 1 (10.4 ± 1.5) than the control group (9.2 ± 1.3).ConclusionTopical administration of tranexamic acid reduces intraoperative and postoperative blood loss in acetabular fracture surgery, decreasing transfusion rates.Level of EvidenceLevel III, Therapeutic Study.     

Protective effects of betulinic acid on intestinal mucosal injury induced by cyclophosphamide in mice

BackgroundBetulinic acid (BA) is a plant-derived pentacyclic triterpenoid with a variety of biological activities. The purpose of this study was to assess the potential protective role of BA against intestinal mucosal injury induced by cyclophosphamide (CYP) treatment.MethodsMice were pretreated with BA daily (0.05, 0.5, and 5.0 mg/kg) for 14 days, then injected intraperitoneally with CYP (50 mg/kg) for 2 days.ResultsBA pretreatment reduced the contents of malondialdehyde (MDA) and glutathione (GSH), decreased the activity of superoxide dismutase (SOD) in small intestine, increased villus hight/crypt depth ratio and restored the morphology of intestinal villi in CYP-induced mice. Moreover, BA pretreatment could significantly down-regulate the levels of pro-inflammatory cytokines interleukin-5 (IL-5), IL-17, IL-12 (P70) and tumor necrosis factor α (TNF-α), reduced production of chemokines macrophage inflammatory protein-1α (MIP-1α), macrophage inflammatory protein-1β (MIP-1β) and regulated upon activation, normal T-cell expressed and secreted (RANTES), and enhanced the levels of anti-inflammatory such as IL-2 and IL-10 in serum, and decreased the mRNA expressions of IL-1β and TNF-α in intestine of CYP-induced mice. Furthermore, RT-PCR demonstrated that BA improved intestinal physical and immunological barrier in CYP-stimulated mice by enhancing the mRNA expressions of zonula occluden 1 (ZO-1) and Claudin-1.ConclusionsBA might be considered as an effective agent in the amelioration of the intestinal mucosal resulting from CYP treatment.     

Anti-atherosclerotic action of GW9508 – Free fatty acid receptors activator – In apoE-knockout mice

BackgroundIn the past two decades, enhanced understanding of the biology of G-protein-coupled receptors (GPRs) has led to the identification of several such receptors as novel targets for free fatty acids (FFAs). Two GPRs, FFAR1 and FFAR4, have received special attention in the context of chronic inflammatory diseases, thanks to their anti-inflammatory activities.MethodsThe present study investigates the influence of prolonged treatment with GW9508 – agonist of FFAR1 and FFAR4 – on the development of atherosclerosis plaque in apoE-knockout mice, using morphometric and molecular methods.ResultsGW9508 administration has led to the reduction of atheroscletoric plaque size in an apoE-knockout mice model. Moreover, a FFAR1/FFAR4 agonist reduced the content of macrophages by almost 20%, attributed by immunohistochemical phenotyping to the pro-inflammatory M1-like activation state macrophages.ConclusionsProlonged administration of GW9508 resulted in significant amelioration of atherogenesis, providing evidence that the strategy based on macrophage phenotype switching toward an M2-like activation state via stimulation of FFAR1/FFAR4 receptors holds promise for a new approach to the prevention or treatment of atherosclerosis.     

Dissected Aorta Repair Through Stent Implantation trial: Canadian results

Objectives

We describe the Canadian results of the Ascyrus Medical Dissection Stent (AMDS), a novel partially uncovered aortic arch hybrid graft implanted antegrade during hypothermic circulatory arrest to promote true lumen expansion and enhance aortic remodeling.

Targeting the PI3K/AKT/mTOR pathway in biliary tract cancers: A review of current evidences and future perspectives

Biliary tract cancers (BTCs) are a group of invasive neoplasms, with increasing incidence and dismal prognosis. In advanced disease, the standard of care is represented by first-line chemotherapy with cisplatin and gemcitabine. In subsequent lines, no clear recommendations are currently available, highlighting the need for novel therapeutic approaches.The PI3K/AKT/mTOR pathway is a core regulator of cell metabolism, growth and survival, and is involved in BTCs carcinogenesis and progression. Mutations, gene copy number alterations and aberrant protein phosphorylation of PI3K, AKT, mTOR and PTEN have been thoroughly described in BTCs and correlate with poor survival outcomes.Several pre-clinical evidences state the efficacy of PI3K/AKT/mTOR pathway inhibitors in BTCs, both in vitro and in vivo. In the clinical setting, initial studies with rapamycin analogs have shown interesting activity with an acceptable toxicity profile. Novel strategies evaluating AKT and PI3K inhibitors have risen serious safety concerns, pointing out the need for improved patient selection and increased target specificity for the clinical development of these agents, both alone and in combination with chemotherapy.This review extensively describes the role of the PI3K/AKT/mTOR pathway in BTCs and examines the rationale of its targeting in these tumors, with particular focus on clinical activity, toxicities and perspectives on further development of PI3K/AKT/mTOR pathway inhibitors.