Differential potency of vitamin D3, folic acid and memantine in protecting against neurobehavioral alterations of scopolamine induced Alzheimer’s model in rats

Background: Alzheimer disease is the cause of 60% to 70% of cases of dementia in elderly people, it is a chronic neurodegenerative disease that usually starts slowly and worsens over time. AD is characterized by the presence of senile plaques enriched with insoluble aggregate of beta-amyloid, neurofibrillary tangles and cholinergic neuronal degeneration in the brain tissue, leading to neural dysfunction, neuroinflammation, and critical pathological perturbations.Methods: Thirty-six males were classified into control group, Alzheimer-induced model (scopolamine 2.5 mg/kg IP once daily for 21 days). Folic acid-treated group (4 mg/kg, IP) once daily for 21 days with scopolamine. Vitamin D3-treated group (42 IU/kg, SC) once daily for 21 days with scopolamine. Vitamin D3 and folic acid-treated group (vitamin D3; 42 IU/kg, SC and folic acid; 4 mg/kg, IP) once daily with scopolamine for 21 days. Memantine-treated group (20 mg/kg IP) once daily with scopolamine for 21 days.Results: Induction of Alzheimer’s showed significant decrease in brain tissue levels of BDNF, Ach, glutathione reductase and significant increase in amyloid peptide 1-42 level with significant memory impairment, significant increase of initial acquisition latency, firstt retention latency and second retention latency. While administration of folic acid, vitamin D3, memantine separately or in combination resulted insignificant increase of brain tissue levels of BDNF, Ach, glutathione reductase with significant reduction of amyloid peptide 1-42 level with significant memory improvement (significant decrease IAL, first RL and second RL). Also showed improvement of histopathological changes occurred in the brain.Conclusions: Data obtained in the present study revealed that treatment of experimentally induced alzheimer rats with folic acid or vitamin D3 or memantine separately or combined group (folic acid+vitamin D3) resulted in significant increase of brain tissue levels of BDNF, acetyl choline, glutathione reductase with significant reduction of amyloid peptide 1-42 level with significant decrease of IAL, first RL and second RL to reach the platform with improvement of histopathological changes occurred in the brain. But combined and memantine-treated groups resulted in more significant improvement than other treated groups

Synthesis and evaluation of troponoids as a new class of antibiotics

Novel antibiotics are urgently needed. The troponoids [tropones, tropolones, and α-hydroxytropolones (α-HT)] can have anti-bacterial activity. We synthesized or purchased 92 troponoids and evaluated their antibacterial activities against Staphylococcus aureus, Escherichia coli, Acinetobacter baumannii, and Pseudomonas aeruginosa. Preliminary hits were assessed for minimum inhibitory concentrations (MIC80) and cytotoxicity (CC50) against human hepatoma cells. Sixteen troponoids inhibited S. aureus/E. coli/A. baumannii growth by ≥80% growth at 50 values >50 μM. Two selected tropolones (63 and 285) inhibited 18 methicillin-resistant S. aureus (MRSA) strains with similar MIC80 values as against a reference strain. Two selected thiotropolones (284 and 363) inhibited multidrug-resistant (MDR) E. coli with MIC80 ≤30 μM. One α-HT (261) inhibited MDR-A. baumannii with MIC80 ≤30 μM. This study opens new avenues for development of novel troponoid antibiotics to address the critical need to combat MDR bacterial infections

Improvement of Subjective Well-Being by Ranolazine in Patients with Chronic Angina and Known Myocardial Ischemia (IMWELL Study)

Introduction: We aimed to assess if ranolazine would improve angina symptoms among patients with documented myocardial ischemia. Methods: Eligible subjects had chronic stable angina and at least one coronary stenosis with fractional flow reserve (FFR) ≤0.80 or at least one chronic total occlusion (CTO) without attempted revascularization. Subjects were randomized to oral ranolazine 500 mg twice daily for 1 week, then ranolazine 1000 mg twice daily for 15 weeks versus matching placebo. The primary end point was change in angina at 16 weeks as assessed by the Seattle Angina Questionnaire (SAQ). Results: Between September 2014 and January 2016, 25 subjects were randomized to ranolazine versus 25 to placebo. The most common reason for eligibility was CTO (72%), while the remainder had myocardial ischemia documented by low FFR. The mean FFR was 0.57 ± 0.12. Sixty-eight percent of subjects were on two or more anti-angina medications at baseline. Study medication was discontinued in 32% (eight of 25) of the ranolazine group versus 36% (nine of 25) of the placebo group. By intention-to-treat, 46 subjects had baseline and follow-up SAQ data completed. Ranolazine was not associated with an improvement in angina compared with placebo at 16 weeks. The results were similar among 33 subjects that completed study medication. The incidence of ischemia-driven hospitalization or catheterization was 12% (three of 25) of the ranolazine group versus 20% (five of 25) in the placebo group (p \u3e 0.05). Conclusions: In subjects with chronic stable angina and documented myocardial ischemia, ranolazine did not improve angina symptoms at 16 weeks

The partially alternating ternary sum in an associative dialgebra

The alternating ternary sum in an associative algebra, $abc - acb - bac + bca + cab - cba$, gives rise to the partially alternating ternary sum in an associative dialgebra with products $\dashv$ and $\vdash$ by making the argument $a$ the center of each term: $a \dashv b \dashv c - a \dashv c \dashv b - b \vdash a \dashv c + c \vdash a \dashv b + b \vdash c \vdash a - c \vdash b \vdash a$. We use computer algebra to determine the polynomial identities in degree $\le 9$ satisfied by this new trilinear operation. In degrees 3 and 5 we obtain $[a,b,c] + [a,c,b] \equiv 0$ and $[a,[b,c,d],e] + [a,[c,b,d],e] \equiv 0$; these identities define a new variety of partially alternating ternary algebras. We show that there is a 49-dimensional space of multilinear identities in degree 7, and we find equivalent nonlinear identities. We use the representation theory of the symmetric group to show that there are no new identities in degree 9.Comment: 14 page

Longitudinal transcriptomic and genetic landscape of radiotherapy response in canine melanoma

Canine malignant melanoma (MM) is a highly aggressive tumour with a low survival rate and represents an ideal spontaneous model for the human counterpart. Considerable progress has been recently obtained, but the therapeutic success for canine melanoma is still challenging. Little is known about the mechanisms beyond pathogenesis and melanoma development, and the molecular response to radiotherapy has never been explored before. A faster and deeper understanding of cancer mutational processes and developing mechanisms are now possible through next generation sequencing technologies. In this study, we matched whole exome and transcriptome sequencing in four dogs affected by MM at diagnosis and at disease progression to identify possible genetic mechanisms associated with therapy failure. According to previous studies, a genetic similarity between canine MM and its human counterpart was observed. Several somatic mutations were functionally related to MAPK, PI3K/AKT and p53 signalling pathways, but located in genes other than BRAF, RAS and KIT. At disease progression, several mutations were related to therapy effects. Natural killer cell-mediated cytotoxicity and several immune-system-related pathways resulted activated opening a new scenario on the microenvironment in this tumour. In conclusion, this study suggests a potential role of the immune system associated to radiotherapy in canine melanoma, but a larger sample size associated with functional studies are needed

Mitochondrial pyruvate carrier inhibitors improve metabolic parameters in diet-induced obese mice

The mitochondrial pyruvate carrier (MPC) is an inner mitochondrial membrane complex that plays a critical role in intermediary metabolism. Inhibition of the MPC, especially in liver, may have efficacy for treating type 2 diabetes mellitus. Herein, we examined the antidiabetic effects of zaprinast and 7ACC2, small molecules which have been reported to act as MPC inhibitors. Both compounds activated a bioluminescence resonance energy transfer-based MPC reporter assay (reporter sensitive to pyruvate) and potently inhibited pyruvate-mediated respiration in isolated mitochondria. Furthermore, zaprinast and 7ACC2 acutely improved glucose tolerance in diet-induced obese mice in vivo. Although some findings were suggestive of improved insulin sensitivity, hyperinsulinemic-euglycemic clamp studies did not detect enhanced insulin action in response to 7ACC2 treatment. Rather, our data suggest acute glucose-lowering effects of MPC inhibition may be due to suppressed hepatic gluconeogenesis. Finally, we used reporter sensitive to pyruvate to screen a chemical library of drugs and identified 35 potentially novel MPC modulators. Using available evidence, we generated a pharmacophore model to prioritize which hits to pursue. Our analysis revealed carsalam and six quinolone antibiotics, as well as 7ACC1, share a common pharmacophore with 7ACC2. We validated that these compounds are novel inhibitors of the MPC and suppress hepatocyte glucose production and demonstrated that one quinolone (nalidixic acid) improved glucose tolerance in obese mice. In conclusion, these data demonstrate the feasibility of therapeutic targeting of the MPC for treating diabetes and provide scaffolds that can be used to develop potent and novel classes of MPC inhibitors

A Patient-Derived Cell Atlas Informs Precision Targeting of Glioblastoma

Glioblastoma (GBM) is a malignant brain tumor with few therapeutic options. The disease presents with a complex spectrum of genomic aberrations, but the pharmacological consequences of these aberrations are partly unknown. Here, we report an integrated pharmacogenomic analysis of 100 patient-derived GBM cell cultures from the human glioma cell culture (HGCC) cohort. Exploring 1,544 drugs, we find that GBM has two main pharmacological subgroups, marked by differential response to proteasome inhibitors and mutually exclusive aberrations in TP53 and CDKN2A/B. We confirm this trend in cell and in xenotransplantation models, and identify both Bcl-2 family inhibitors and p53 activators as potentiators of proteasome inhibitors in GBM cells, We can further predict the responses of individual cell cultures to several existing drug classes, presenting opportunities for drug repurposing and design of stratified trials. Our functionally profiled biobank provides a valuable resource for the discovery of new treatments for GBM.Patrik Johansson, Cecilia Krona and Soumi Kundu share first authorship</p

Essential versus accessory aspects of cell death: recommendations of the NCCD 2015

Cells exposed to extreme physicochemical or mechanical stimuli die in an uncontrollable manner, as a result of their immediate structural breakdown. Such an unavoidable variant of cellular demise is generally referred to as ‘accidental cell death’ (ACD). In most settings, however, cell death is initiated by a genetically encoded apparatus, correlating with the fact that its course can be altered by pharmacologic or genetic interventions. ‘Regulated cell death’ (RCD) can occur as part of physiologic programs or can be activated once adaptive responses to perturbations of the extracellular or intracellular microenvironment fail. The biochemical phenomena that accompany RCD may be harnessed to classify it into a few subtypes, which often (but not always) exhibit stereotyped morphologic features. Nonetheless, efficiently inhibiting the processes that are commonly thought to cause RCD, such as the activation of executioner caspases in the course of apoptosis, does not exert true cytoprotective effects in the mammalian system, but simply alters the kinetics of cellular demise as it shifts its morphologic and biochemical correlates. Conversely, bona fide cytoprotection can be achieved by inhibiting the transduction of lethal signals in the early phases of the process, when adaptive responses are still operational. Thus, the mechanisms that truly execute RCD may be less understood, less inhibitable and perhaps more homogeneous than previously thought. Here, the Nomenclature Committee on Cell Death formulates a set of recommendations to help scientists and researchers to discriminate between essential and accessory aspects of cell death