On the Existence of Positive Solutions of Resonant and Nonresonant Multipoint Boundary Value Problems for Third-Order Nonlinear Differential Equations

Positive solutions for a kind of third-order multipoint boundary value problem under the non-resonant conditions and the resonant conditions are considered. In the nonresonant case, by using Leggett-Williams fixed-point theorem, the existence of at least three positive solutions is obtained. In the resonant case, by using Leggett-Williams norm-type theorem due to O’Regan and Zima, existence result of at least one positive solution is established. The results obtained are valid and new for the problem discussed. Two examples are given to illustrate the main results

Neutralizing Effects of Small Molecule Inhibitors and Metal Chelators on Coagulopathic Snake Venom Toxins.

Animal-derived antivenoms are the only specific therapies currently available for the treatment of snake envenoming, but these products have a number of limitations associated with their efficacy, safety and affordability for use in tropical snakebite victims. Small molecule drugs and drug candidates are regarded as promising alternatives for filling the critical therapeutic gap between snake envenoming and effective treatment. In this study, by using an advanced analytical technique that combines chromatography, mass spectrometry and bioassaying, we investigated the effect of several small molecule inhibitors that target phospholipase A (varespladib) and snake venom metalloproteinase (marimastat, dimercaprol and DMPS) toxin families on inhibiting the activities of coagulopathic toxins found in snake venoms. The venoms of , , and , which are known for their potent haemotoxicities, were fractionated in high resolution onto 384-well plates using liquid chromatography followed by coagulopathic bioassaying of the obtained fractions. Bioassay activities were correlated to parallel recorded mass spectrometric and proteomics data to assign the venom toxins responsible for coagulopathic activity and assess which of these toxins could be neutralized by the inhibitors under investigation. Our results showed that the phospholipase A-inhibitor varespladib neutralized the vast majority of anticoagulation activities found across all of the tested snake venoms. Of the snake venom metalloproteinase inhibitors, marimastat demonstrated impressive neutralization of the procoagulation activities detected in all of the tested venoms, whereas dimercaprol and DMPS could only partially neutralize these activities at the doses tested. Our results provide additional support for the concept that combinations of small molecules, particularly the combination of varespladib with marimastat, serve as a drug-repurposing opportunity to develop new broad-spectrum inhibitor-based therapies for snakebite envenoming

Varespladib Inhibits the Phospholipase A 2 and Coagulopathic Activities of Venom Components from Hemotoxic Snakes

Phospholipase A2 (PLA2) enzymes are important toxins found in many snake venoms, and they can exhibit a variety of toxic activities including causing hemolysis and/or anticoagulation. In this study, the inhibiting effects of the small molecule PLA2 inhibitor varespladib on snake venom PLA2s was investigated by nanofractionation analytics, which combined chromatography, mass spectrometry (MS), and bioassays. The venoms of the medically important snake species Bothrops asper, Calloselasma rhodostoma, Deinagkistrodon acutus, Daboia russelii, Echis carinatus, Echis ocellatus, and Oxyuranus scutellatus were separated by liquid chromatography (LC) followed by nanofractionation and interrogation of the fractions by a coagulation assay and a PLA2 assay. Next, we assessed the ability of varespladib to inhibit the activity of enzymatic PLA2s and the coagulopathic toxicities induced by fractionated snake venom toxins, and identified these bioactive venom toxins and those inhibited by varespladib by using parallel recorded LC-MS data and proteomics analysis. We demonstrated here that varespladib was not only capable of inhibiting the PLA2 activities of hemotoxic snake venoms, but can also effectively neutralize the coagulopathic toxicities (most profoundly anticoagulation) induced by venom toxins. While varespladib effectively inhibited PLA2 toxins responsible for anticoagulant effects, we also found some evidence that this inhibitory molecule can partially abrogate procoagulant venom effects caused by different toxin families. These findings further emphasize the potential clinical utility of varespladib in mitigating the toxic effects of certain snakebites

C1q/TNF-Related Protein 3 Prevents Diabetic Retinopathy via AMPK-Dependent Stabilization of Blood–Retinal Barrier Tight Junctions

Background The impairment of the inner blood–retinal barrier (iBRB) increases the pathological development of diabetic retinopathy (DR), a severe complication in diabetic patients. Identifying approaches to preserving iBRB integrity and function is a significant challenge in DR. C1q/tumor necrosis factor-related protein-3 (CTRP3) is a newly discovered adipokine and a vital biomarker, predicting DR severity. We sought to determine whether and how CTRP3 affects the pathological development of non-proliferative diabetic retinopathy (NPDR). Methods To clarify the pathophysiologic progress of the blood–retinal barrier in NPDR and explore its potential mechanism, a mouse Type 2 diabetic model of diabetic retinopathy was used. The capillary leakage was assessed by confocal microscope with fluorescent-labeled protein in vivo. Furthermore, the effect of CTRP3 on the inner blood–retinal barrier (iBRB) and its molecular mechanism was clarified. Results The results demonstrated that CTRP3 protects iBRB integrity and resists the vascular permeability induced by DR. Mechanistically, the administration of CTRP3 activates the AMPK signaling pathway and enhances the expression of Occludin and Claudin-5 (tight junction protein) in vivo and in vitro. Meanwhile, CTRP3 improves the injury of human retinal endothelial cells (HRMECs) induced by high glucose/high lipids (HG/HL), and its protective effects are AMPK-dependent. Conclusions In summary, we report, for the first time, that CTRP3 prevents diabetes-induced retinal vascular permeability via stabilizing the tight junctions of the iBRB and through the AMPK-dependent Occludin/Claudin-5 signaling pathway, thus critically affecting the development of NPDR

On the Existence of Positive Solutions of Resonant and Nonresonant Multipoint Boundary Value Problems for Third-Order Nonlinear Differential Equations

Positive solutions for a kind of third-order multipoint boundary value problem under the non-resonant conditions and the resonant conditions are considered. In the nonresonant case, by using Leggett-Williams fixed-point theorem, the existence of at least three positive solutions is obtained. In the resonant case, by using Leggett-Williams norm-type theorem due to O'Regan and Zima, existence result of at least one positive solution is established. The results obtained are valid and new for the problem discussed. Two examples are given to illustrate the main results

Changes in physicochemical profiles and quality of apple juice treated by ultrafiltration and during its storage

Effects of various factors, such as membrane materials, molecular weight cutoff, transmembrane pressure (TMP), and cross flow rate (CFR) on flux and physicochemical properties of apple juice during ultrafiltration and storage have been investigated. Clarity, color, total phenols, total proteins, total sugars, total soluble solids (TSS), pH, and some specific polyphenols of juices were evaluated. Results show that at conditions of PES-10 kDa, CFR 30 L/hr, and TMP 0.75 MPa, a clarified juice obtained with color 0.15 A, clarity 96.94%T, TSS 9.55 °Brix, pH 4.2, and total phenols, total proteins, and total sugars were 64.12 and 13.20 μg/ml and 50.70 mg/ml, respectively. Chlorogenic acid, epicatechin, phloridzin, catechin, and caffeic acid decreased differently from 32.63, 17.33, 3.25, 7.58, and 0.75 μg/ml to 17.24, 12.38, 1.79, 5.27, and 0.25 μg/ml, respectively. Storage in refrigeration for 4 weeks, clarity, total sugars, and total phenols reduced by 2.5%, 6.4%, and 16.6%, respectively, while TSS increased by 3.1%

Coix lachryma-jobi extract ameliorates inflammation and oxidative stress in a complete Freund’s adjuvant-induced rheumatoid arthritis model

Context: Adlay seed [Job’s tears, Coix lachryma-jobi L. var. ma-yuen Stapf (Poaceae)] is a Traditional Chinese Medicine, which has been investigated to treat inflammatory diseases and rheumatism. Objective: This study evaluates the ameliorative effects of adlay seed extract (ASE) in a complete Freund’s adjuvant (CFA)-induced rheumatoid arthritis (RA) rats. Materials and methods: The RA Sprague–Dawley rat model was induced and randomly divided into six groups with or without ASE treatment (50, 100 or 200 mg/kg). After 28 d administration, the symptoms, biochemical parameters and molecular mechanisms were investigated. Results: The values of paw oedema, PGE2 and MMP-3 decreased from 1.46 ± 0.04 to 0.66 ± 0.07 cm3, from 126.2 ± 11.48 to 79.71 ± 6.8 pg/mL and from 142.7 ± 8.36 to 86.51 ± 5.95 ng/mL, respectively; the values of body weight increased from 177.25 ± 5.94 to 205 ± 6.52 g in HASE group. In addition, treatment of ASE reduced the levels of pro-inflammatory cytokines (IL-1β, TNF-α, IL-6, MCP-1), and increased the activities of antioxidant enzyme (GSH-Px, SOD, and CAT). Furthermore, ASE could suppress the mRNA expression of COX-2 and CHI3L1 and improve the mRNA expression of CAT and GPx-1 in ankle tissues of RA rats. Discussion and conclusions: For the first time, our results indicated ASE exerts anti-RA effects via inhibiting pro-inflammatory factors and alleviating oxidative stress. Our finding sheds light on the research and development of anti-RA functional foods from adlay seed

Dietary Available Phosphorus Affected Growth Performance, Body Composition, and Hepatic Antioxidant Property of Juvenile Yellow Catfish Pelteobagrus fulvidraco

An 8-week feeding trial was carried out with juvenile yellow catfish to study the effects of dietary available phosphorus (P) on growth performance, body composition, and hepatic antioxidant property. Six pellet diets were formulated to contain graded available P levels at 0.33, 0.56, 0.81, 1.15, 1.31, and 1.57% of dry matter, respectively. Triplicate tanks with each tank containing 60 juveniles (3.09 ± 0.03 g) were fed one of the six experimental diets for 8 weeks. Specific growth rate, feeding rate, and protein efficiency ratio were significantly higher at 0.81% dietary available P. Efficiency of P utilization distinctly decreased with increasing P level. Body lipid content significantly decreased while body ash and feces P content significantly increased with increasing P level. Quadratic regression analysis indicated that vertebrae P content was maximized at 1.21% dietary available P. Fish fed 1.57% dietary available P had highest activity of hepatic superoxide dismutase and catalase and malonaldehyde content. In conclusion, decreasing dietary available P increased P utilization efficiency and body lipid content while decreased vertebrae P content. Juvenile yellow catfish were subjected to oxidative damage under the condition of high dietary P content (1.57%), and the damage could not be eradicated by their own antioxidant defense system