Anti-receptor Advanced Glycation End Products Decreases Inflammatory Pathways in Retinopathy Diabetics: In vivo Study

BACKGROUND: Diabetic retinopathy is an emerging microvascular complication of diabetes mellitus and a causes of blindness in individuals between ages 30 and 70 years, which is characterized by increased proliferation of blood vessels, vascular occlusion, angiogenesis, loss of pericytes from retinal capillaries, microaneurysms, retinal bleeding, increased retinal capillary permeability, thickening of capillary basal membranes, and infarcts that affect the retina, induced to permanent blindness. AIM: This study aimed to find the role of receptor advanced glycation end products (RAGE) inhibition in lowering the vascularization process which causes a decrease in retinal function on diabetic retinopathy. MATERIALS AND METHODS: This research was an in vivo experimental study. A total of 30 male Wistar rats (200 ± 20 g) were obtained from Eureka Research Laboratory (Palembang, Indonesia). Experimental animals were placed in cages under controlled conditions (12 h of light/dark cycles with temperatures of 22 ± 1°C and humidity of 40–60%), fed and drank ad libitum. White rats were induced by diabetes mellitus using alloxan at a dose of 120 mg/kgBW, intraperitoneally, accompanied by drinking 10% glucose solution for 140 days. Furthermore, experimental animals were grouped into five groups (at eight animals per group), Group 1: Normal control, Group 2: Negative control (induced diabetics retinopathy and given intravenous aquadest), Group 3: Given anti-RAGE 1 ng/mL, Group 4: Given anti-RAGE 10 ng/mL, and Group 5: Given anti-RAGE 100 ng/mL. Giving anti-RAGE was done in a single dosage and intravitreal. After the rats were sacrificed by intraperitoneal injection of 10% chloral hydrate, the evacuation of the eye’s retinal tissue was then carried out, fixed in a 4% paraformaldehyde buffer for immunohistochemistry examination of the eye’s retinal tissue. Evaluation of the expression of nuclear factor-κβ (NF-kB) and intercellular adhesion molecule-1 (ICAM-1) used Image J Software so that the percentage of NF-kB and ICAM-1 expression would be obtained. RESULTS: Negative control group showed an increase in NF-kB expression in the retinal tissue of diabetic retinopathy rats. Administration of anti-RAGE showed its potential to suppress NF-kB expression in retinal tissue of diabetic retinopathy white rats as well with an increase of anti-RAGE dose from 1 ng/mL to 100 ng/mL. Activation of NF-kB causes activation of the inflammatory cascade, which is characterized by the production of pro-inflammatory cytokines, one of which is ICAM-1. Giving anti-RAGE could suppress the expression of ICAM-1 along with an increase in anti-RAGE dose. CONCLUSION: Anti-RAGE is able to block the inflammatory process, by inhibiting the expression of NF-kB and ICAM-1 in the retinal tissue of diabetics retinopathy in white rats

TiO₂ Nanoparticles Prepared by Sol-Gel Method for Anode Application in Lithium-Ion Batteries

TiO 2 nanoparticles are prepared via sol-gel method using titanium tetraisopropoxide (TTIP) as a precursor under refluxing and controlled pH. It is found that pure anatase phase is obtained with pH 10. Further characterization studies are carried out on pure nanoparticle anatase phase by XRD, SEM, and transmission electron microscope (TEM). Their electrochemical performances as anode material in lithium-ion batteries are investigated by cyclic voltammetry, galvanostatic cycling, and rate capability measurements. A high discharge capacity of 321 mAh/g (vs. 335 mAh/g theoretical) is achieved at 1C rate. After the first galvanostatic charge/discharge cycle, voltage profiles show plateaus at 1.75 and 1.95 V versus Li at discharge and charge, respectively. High Coulombic efficiency (>99%) is maintained after 300 cycles, which makes anatase TiO 2 nanoparticles prepared by sol-gel method, a very promising material for anode application in lithium rechargeable batteries

Numerical approach of riemann-liouville fractional derivative operator

This article introduces some new straightforward and yet powerful formulas in the form of series solutions together with their residual errors for approximating the Riemann-Liouville fractional derivative operator. These formulas are derived by utilizing some of forthright computations, and by utilizing the so-called weighted mean value theorem (WMVT). Undoubtedly, such formulas will be extremely useful in establishing new approaches for several solutions of both linear and nonlinear fractionalorder differential equations. This assertion is confirmed by addressing several linear and nonlinear problems that illustrate the effectiveness and the practicability of the gained findings

Lipidomic profiling of plasma free fatty acids in type-1 diabetes highlights specific changes in lipid metabolism

This research was funded by the British Heart Foundation [grant numbers PG/15/9/31270, FS/15/42/3155].Type-1 diabetes mellitus (T1DM) is associated with metabolic changes leading to alterations in glucose and lipid handling. While T1DM- associated effects on many major plasma lipids have been characterised, such effects on plasma free fatty acids (FFA) have not been fully examined. Using gas chromatography-mass spectrometry, we measured the plasma concentrations of FFA species in individuals with T1DM (n=44) and age/sex-matched healthy controls (n=44). Relationships between FFA species and various parameters were evaluated. Plasma concentrations of myristate (14:0), palmitoleate (16:1), palmitate (16:0), linoleate (18:2), oleate (18:1c9), cis-vaccenate (18:1c11), eicosapentaenoate (20:5), arachidonate (20:4) and docosahexanoate (22:6) were reduced in the T1DM group (p<0.0001 for all, except p=0.0020 for eicosapentaenoate and p=0.0068 for arachidonate); α-linolenate (18:3) and dihomo-γ- linolenate (20:3) concentrations were unchanged. Saturated/unsaturated FFA ratio, n-3/n-6 ratio, de novo lipogenesis index (palmitate (main lipogenesis product)/linoleate (only found in diet)) and elongase index (oleate/palmitoleate) were increased in the T1DM group (p=0.0166, p=0.0089, p<0.0001 and p=0.0008 respectively). The stearoyl-CoA desaturase 1 (SCD1) index 1 (palmitoleate/palmitate) and index 2 (oleate/stearate) were reduced in T1DM (p<0.0001 for all). The delta-(5)- desaturase (D5D) index (arachidonate/dihomo-γ-linolenate) was unchanged. Age and sex had no effect on plasma FFA concentrations in T1DM, while SCD1 index 1 was positively correlated (p=0.098) and elongase index negatively correlated with age (p=0.0363). HbA1c was negatively correlated with all plasma FFAs concentrations measured except α- linolenate and dihomo-γ-linolenate. Correlations were observed between plasma FFAs and cholesterol and HDL, but not LDL or diabetes duration. Collectively, these results aid our understanding of T1DM and its effects on lipid metabolism.Publisher PDFPeer reviewe

Interplay between the glassy transition and granular superconductivity in organic materials

It is known that some (BEDT-TTF)2X layered organic superconductors undergo a glassy transition near 80 K. Our purpose is to exploit quenched disorder to get new insights on both the superconducting state (T < 12 K) and the glassy transition by studying the superconducting properties as functions of annealing time (ta) and temperature (Ta) around 80 K. The main results on the fully deuterated kappa-(BEDT-TTF)2Cu[N(CN)2]Br compound are: 1) The data can be described by a percolation cluster model. 2) At short time scales, the clusters grow with ta following a power law. 3) At large time scales the clusters grow toward a thermodynamic state following a stretched exponential law in (1 - exp(-(t/tau)beta)with beta varying from about 0.5 to 1 in our Ta range (65 - 110 K). 4) The relaxation time follows an Arrhenius law tau(T)=tau0exp(U/T) with U around 2660 K and 1/tau0 around 2x1013 s-1. 5) The asymptotic magnetization fits with a scaling law with Tg around 55K and n around 3.2. The results are consistent with a Ising spin-glass-like model.Comment: 17 pages; 4 figure

Changes in plasma free fatty acids in obese patients before and after bariatric surgery highlight alterations in lipid metabolism

This work was supported by the British Heart Foundation (grant ref: FS/20/3/34956).Obesity is a complex disease that increases an individual’s risk of developing other diseases and health-related problems. A common feature is dyslipidemia characterized by increased levels of plasma lipids, which include non-esterified fatty acids (NEFAs). The role of NEFAs in obesity-related morbidity is interesting as NEFAs constitute a reservoir of metabolic energy, are principal components of cell membranes and are precursors for signalling molecules. Bariatric surgery promotes sustained weight loss in severely obese patients, reducing the incidence and severity of co-morbidities. In this study we measure changes in circulating NEFA species in plasma samples taken from 25 obese individuals before and 9 months after Roux-en-Y gastric bypass surgery. The mean weight of the cohort reduced by 29.2% from 149.0±25.1 kg pre-surgery to 105.5±19.8 kg post-surgery and the BMI by 28.2% from 51.8±6.3 kg/m2 pre-surgery to 37.2±5.4 kg/m2. Mean glycated haemoglobin (HbA1c) reduced from 6.5±1.3% to 5.5±0.5%, consistent with the intervention leading to improved glycaemic control, particularly in those who were dysglycemic prior to surgery. Total and LDL cholesterol concentrations were markedly reduced following surgery. Concentrations of seven NEFAs were found to decrease 9 months after surgery compared to pre-surgery levels: myristate, palmitoleate, palmitate, linoleate, oleate, stearate and arachidonate. Bariatric surgery led to increased lipogenesis and elongase activity and decreased stearoyl-CoA desaturase 1 activity. This study thus highlights metabolic changes that take place following gastric bypass surgery in severely obese patients.Publisher PDFPeer reviewe

The “Welcome to Medicare” Visit: A Missed Opportunity for Cancer Screening Among Women?

On January 1, 2005, Medicare began covering a “Welcome to Medicare” visit (WMV) for new enrollees with fee-for-service (FFS) Medicare (Parts A and B). The new benefit was expected to increase demand for mammography and Pap tests among women transitioning onto Medicare. This study examined whether Medicare's coverage of a WMV influenced the use of mammography and Pap tests among women aged 65 and 66 years with FFS Medicare

Listeria monocytogenes exploits efferocytosis to promote cell-to-cell spread

Efferocytosis, the process by which dying/dead cells are removed by phagocytosis, plays an important role in development, tissue homeostasis and innate immunity1. Efferocytosis is mediated, in part, by receptors that bind to exofacial phosphatidylserine (PS) on cells or cellular debris after loss of plasma membrane asymmetry. Here we show that a bacterial pathogen, Listeria monocytogenes (Lm), can exploit efferocytosis to promote cell-to-cell spread during infection. These bacteria can escape the phagosome in host cells using the pore-forming toxin Listeriolysin O (LLO) and two phospholipases C2. Expression of the cell surface protein ActA allows Lm to activate host actin regulatory factors and undergo actin-based motility in the cytosol, eventually leading to formation of actin-rich protrusions at the cell surface. We show that protrusion formation is associated with plasma membrane damage due to LLO’s pore-forming activity. LLO also promotes the release of bacteria-containing protrusions from the host cell, generating membrane-derived vesicles with exofacial PS. The PS-binding receptor TIM-4 contributes to efficient cell-to-cell spread by Lm in macrophages in vitro and growth of these bacteria is impaired in TIM-4−/− mice. Thus, Lm promotes its dissemination in a host by exploiting efferocytosis. Our study suggests that PS-targeted therapeutics may be useful in the fight against infections by Lm and other bacteria that utilize similar strategies of cell-to-cell spread during infection

Systems analysis reveals a transcriptional reversal of the mesenchymal phenotype induced by SNAIL-inhibitor GN-25

Abstract Background HMLEs (HMLE-SNAIL and Kras-HMLE, Kras-HMLE-SNAIL pairs) serve as excellent model system to interrogate the effect of SNAIL targeted agents that reverse epithelial-to-mesenchymal transition (EMT). We had earlier developed a SNAIL-p53 interaction inhibitor (GN-25) that was shown to suppress SNAIL function. In this report, using systems biology and pathway network analysis, we show that GN-25 could cause reversal of EMT leading to mesenchymal-to-epithelial transition (MET) in a well-recognized HMLE-SNAIL and Kras-HMLE-SNAIL models. Results GN-25 induced MET was found to be consistent with growth inhibition, suppression of spheroid forming capacity and induction of apoptosis. Pathway network analysis of mRNA expression using microarrays from GN-25 treated Kras-HMLE-SNAIL cells showed an orchestrated global re-organization of EMT network genes. The expression signatures were validated at the protein level (down-regulation of mesenchymal markers such as TWIST1 and TWIST2 that was concurrent with up-regulation of epithelial marker E-Cadherin), and RNAi studies validated SNAIL dependent mechanism of action of the drug. Most importantly, GN-25 modulated many major transcription factors (TFs) such as inhibition of oncogenic TFs Myc, TBX2, NR3C1 and led to enhancement in the expression of tumor suppressor TFs such as SMAD7, DD1T3, CEBPA, HOXA5, TFEB, IRF1, IRF7 and XBP1, resulting in MET as well as cell death. Conclusions Our systems and network investigations provide convincing pre-clinical evidence in support of the clinical application of GN-25 for the reversal of EMT and thereby reducing cancer cell aggressiveness