bluuebunny/crossref_metadata_2025 huggingface dataset:
Astragaloside IV Attenuates Ocular Hypertension in a Mouse Model of TGFβ2 Induced Primary Open Angle Glaucoma
Authors: Kasetti Ramesh B. , Maddineni Prabhavathi , Kodati Bindu , Nagarajan Bhavani , Yacoub Sam
Published: November 2021

Elevated intraocular pressure (IOP) is a major risk factor in developing primary open angle glaucoma (POAG), which is the most common form of glaucoma. Transforming growth factor-beta 2 (TGFβ2) is a pro-fibrotic cytokine that plays an important role in POAG pathogenesis. TGFβ2 induced extracellular matrix (ECM) production, deposition and endoplasmic reticulum (ER) stress in the trabecular meshwork (TM) contribute to increased aqueous humor (AH) outflow resistance and IOP elevation. Drugs which alter the glaucomatous fibrotic changes and ER stress in the TM may be effective in reducing ocular hypertension. Astragaloside IV (AS.IV), a novel saponin isolated from the roots of Astragalus membranaceus, has demonstrated antifibrotic and ER stress lowering effects in various tissues during disease conditions. However, the effect of AS.IV on glaucomatous TM fibrosis, ER stress and ocular hypertension has not been studied. Primary human TM cells treated with AS.IV decreased TGFβ2 induced ECM (FN, Col-I) deposition and ER stress (KDEL, ATF4 and CHOP). Moreover, AS.IV treatment reduced TGFβ2 induced NF-κB activation and αSMA expression in TM cells. We found that AS.IV treatment significantly increased levels of matrix metalloproteases (MMP9 and MMP2) and MMP2 enzymatic activity, indicating that the antifibrotic effects of AS.IV are mediated via inhibition of NF-κB and activation of MMPs. AS.IV treatment also reduced ER stress in TM3 cells stably expressing mutant myocilin. Interestingly, the topical ocular AS.IV eye drops (1 mM) significantly decreased TGFβ2 induced ocular hypertension in mice, and this was associated with a decrease in FN, Col-1 (ECM), KDEL (ER stress) and αSMA in mouse TM tissues. Taken together, the results suggest that AS.IV prevents TGFβ2 induced ocular hypertension by modulating ECM deposition and ER stress in the TM.
Stimuli-Responsive Polymeric Nanomaterials for the Delivery of Immunotherapy Moieties: Antigens, Adjuvants and Agonists
Authors: Nagareddy Raveena , Thomas Reju George , Jeong Yong Yeon
Published: November 2021

Immunotherapy has been investigated for decades, and it has provided promising results in preclinical studies. The most important issue that hinders researchers from advancing to clinical studies is the delivery system for immunotherapy agents, such as antigens, adjuvants and agonists, and the activation of these agents at the tumour site. Polymers are among the most versatile materials for a variety of treatments and diagnostics, and some polymers are reactive to either endogenous or exogenous stimuli. Utilizing this advantage, researchers have been developing novel and effective polymeric nanomaterials that can deliver immunotherapeutic moieties. In this review, we summarized recent works on stimuli-responsive polymeric nanomaterials that deliver antigens, adjuvants and agonists to tumours for immunotherapy purposes.
Characterizing the NLRP3 Inflammasome in Mood Disorders: Overview, Technical Development, and Measures of Peripheral Activation in Adolescent Patients
Authors: Zhou Xinyang , Fernando Shehan M. , Pan Alexander Y. , Laposa Rebecca , Cullen Kathryn R. , Klimes-Dougan Bonnie , Andreazza Ana C.
Published: November 2021

The NOD-, LRR-, and pyrin-domain-containing protein 3 (NLRP3) inflammasome is a node of intracellular stress pathways and a druggable target which integrates mitochondrial stress and inflammatory cascades. While a body of evidence suggests the involvement of the NLRP3 inflammasome in numerous diseases, a lack of reliable measurement techniques highlights the need for a robust assay using small quantities of biological samples. We present a literature overview on peripheral activation of the NLRP3 inflammasome in mood disorders, then outline a process to develop and validate a robust assay to measure baseline and activated intracellular levels of “apoptosis-associated speck-like protein containing a CARD” (ASC) as a key component of an inflammatory profile in peripheral blood mononuclear cells (PBMC). A consistent association between high NLRP3 mRNA levels and relevant cytokines was seen in the literature. Using our method to measure ASC, stimulation of PBMC with lipopolysaccharide and nigericin or adenosine triphosphate resulted in microscopic identification of intracellular ASC specks, as well as interleukin 1 (IL-1) beta and caspase-1 p10 in the periphery. This was abolished by dose-dependent pre-treatment with 100 nM MCC950. We also report the use of this technique in a small pilot sample from patients with bipolar disorder and depressive disorders. The results show that levels of intracellular ASC and IL-1 beta are sensitive to change upon activation and maintained over time, which may be used to improve the detection of NLRP3 activation and guide personalized therapeutic strategy in the treatment of patients.
Genetic Biomarkers in Chronic Myeloid Leukemia: What Have We Learned So Far?
Authors: Abdulmawjood Bilal , Costa Beatriz , Roma-Rodrigues Catarina , Baptista Pedro V. , Fernandes Alexandra R.
Published: November 2021

Chronic Myeloid Leukemia (CML) is a rare malignant proliferative disease of the hematopoietic system, whose molecular hallmark is the Philadelphia chromosome (Ph). The Ph chromosome originates an aberrant fusion gene with abnormal kinase activity, leading to the buildup of reactive oxygen species and genetic instability of relevance in disease progression. Several genetic abnormalities have been correlated with CML in the blast phase, including chromosomal aberrations and common altered genes. Some of these genes are involved in the regulation of cell apoptosis and proliferation, such as the epidermal growth factor receptor (EGFR), tumor protein p53 (TP53), or Schmidt-Ruppin A-2 proto-oncogene (SRC); cell adhesion, e.g., catenin beta 1 (CTNNB1); or genes associated to TGF-β, such as SKI like proto-oncogene (SKIL), transforming growth factor beta 1 (TGFB1) or transforming growth factor beta 2 (TGFB2); and TNF-α pathways, such as Tumor necrosis factor (TNFA) or Nuclear factor kappa B subunit 1 (NFKB1). The involvement of miRNAs in CML is also gaining momentum, where dysregulation of some critical miRNAs, such as miRNA-451 and miRNA-21, which have been associated to the molecular modulation of pathogenesis, progression of disease states, and response to therapeutics. In this review, the most relevant genomic alterations found in CML will be addressed.
Bone Regeneration of a 3D-Printed Alloplastic and Particulate Xenogenic Graft with rhBMP-2
Authors: Ryu Ji-In , Yang Byoung-Eun , Yi Sang-Min , Choi Hyo-Geun , On Sung-Woon , Hong Seok-Jin , Lim Ho-Kyung , Byun Soo-Hwan
Published: November 2021

This study aimed to evaluate the bone regeneration capacity of a customized alloplastic material and xenograft with recombinant human bone morphogenetic protein-2 (rhBMP-2). We prepared hydroxyapatite (HA)/tricalcium phosphate (TCP) pure ceramic bone blocks made using a 3D printing system and added rhBMP-2 to both materials. In eight beagle dogs, a total of 32 defects were created on the lower jaws. The defective sites of the negative control group were left untreated (N group; 8 defects), and those in the positive control group were filled with particle-type Bio-Oss (P group; 12 defects). The defect sites in the experimental group were filled with 3D-printed synthetic bone blocks (3D group; 12 defects). Radiographic and histological evaluations were performed after healing periods of 6 and 12 weeks and showed no significant difference in new bone formation and total bone between the P and 3D groups. The 3D-printed custom HA/TCP graft with rhBMP-2 showed bone regeneration effects similar to that of particulate Bio-Oss with rhBMP-2. Through further study and development, the application of 3D-printed customized alloplastic grafts will be extended to various fields of bone regeneration.
Novel Hybrid Polymer Composites Based on Anthraquinone and Eco-Friendly Dyes with Potential for Use in Intelligent Packaging Materials
Authors: Masek Anna , Plota Angelika , Chrzastowska Julia , Piotrowska Małgorzata
Published: November 2021

This study aimed to present the influence of bio-based and anthraquinone dyes and their combinations on the optical properties of ethylene-propylene (EPM) composites after thermo-oxidative and climatic aging. Therefore, the chosen polymer was filled with a natural, plant-origin flavonoid—quercetin, and with two commercial anthraquinone dyes (C.I. Solvent Yellow 163 and C.I. Solvent Red 207). The manufactured polymer composites were subjected to accelerated aging tests: weathering and thermo-oxidation, respectively. Examination of the materials’ properties indicated that the combination of synthetic and natural dyes can result in better resistance to oxidizing agents and higher thermal stability of ethylene-propylene products. Moreover, color change of quercetin-containing samples due to exposure to simulated atmospheric conditions could be a promising solution for use as aging indicators in intelligent packaging materials that will inform about the ongoing degradation process. Another interesting finding is that these samples exhibited good fungistatic activity against Candida albicans yeast and Aspergillus niger mold. Overall, this novel solution based on hybrid polymer composites containing natural and commercial dyes is a more environmentally friendly alternative to traditional materials used in the plastic packaging industry with better and more desirable properties.
Both Clathrin-Mediated and Membrane Microdomain-Associated Endocytosis Contribute to the Cellular Adaptation to Hyperosmotic Stress in Arabidopsis
Authors: Wu Zheng , Fan Chengyu , Man Yi , Zhang Yue , Li Ruili , Li Xiaojuan , Jing Yanping
Published: November 2021

As sessile organisms, plants must directly deal with an often complex and adverse environment in which hyperosmotic stress is one of the most serious abiotic factors, challenging cellular physiology and integrity. The plasma membrane (PM) is the hydrophobic barrier between the inside and outside environments of cells and is considered a central compartment in cellular adaptation to diverse stress conditions through dynamic PM remodeling. Endocytosis is a powerful method for rapid remodeling of the PM. In animal cells, different endocytic pathways are activated in response to osmotic stress, while only a few reports are related to the endocytosis response pathway and involve a mechanism in plant cells upon hyperosmotic stress. In this study, using different endocytosis inhibitors, the microdomain-specific dye di-4-ANEPPDHQ, variable-angle total internal reflection fluorescence microscopy (VA-TIRFM), and confocal microscopy, we discovered that internalized Clathrin Light Chain-Green Fluorescent Protein (CLC-GFP) increased under hyperosmotic conditions, accompanied by decreased fluorescence intensity of CLC-GFP at the PM. CLC-GFP tended to have higher diffusion coefficients and a fraction of CLC-GFP molecules underwent slower diffusion upon hyperosmotic stress. Meanwhile, an increased motion range of CLC-GFP was found under hyperosmotic treatment compared with the control. In addition, the order of the PM decreased, but the order of the endosome increased when cells were in hyperosmotic conditions. Hence, our results demonstrated that clathrin-mediated endocytosis and membrane microdomain-associated endocytosis both participate in the adaptation to hyperosmotic stress. These findings will help to further understand the role and the regulatory mechanism involved in plant endocytosis in helping plants adapt to osmotic stress.
Synbiotics Alleviate Hepatic Damage, Intestinal Injury and Muscular Beclin-1 Elevation in Rats after Chronic Ethanol Administration
Authors: Chen Yi-Hsiu , Chiu Wan-Chun , Xiao Qian , Chen Ya-Ling , Shirakawa Hitoshi , Yang Suh-Ching
Published: November 2021

The purpose of this study was to investigate the beneficial effects of synbiotics on liver damage, intestinal health, and muscle loss, and their relevance in rats with chronic ethanol feeding. Thirty Wistar rats fed with a control liquid diet were divided into control and synbiotics groups, which were respectively provided with water or synbiotics solution (1.5 g/kg body weight/day) for 2 weeks. From the 3rd to 8th week, the control group was divided into a C group (control liquid diet + water) and an E group (ethanol liquid diet + water). The synbiotics group was separated in to three groups, SC, ASE, and PSE. The SC group was given a control liquid diet with synbiotics solution; the ASE group was given ethanol liquid diet with synbiotics solution, and the PSE group was given ethanol liquid diet and water. As the results, the E group exhibited liver damage, including increased AST and ALT activities, hepatic fatty changes, and higher CYP2E1 expression. Intestinal mRNA expressions of occludin and claudin-1 were significantly decreased and the plasma endotoxin level was significantly higher in the E group. In muscles, beclin-1 was significantly increased in the E group. Compared to the E group, the PSE and ASE groups had lower plasma ALT activities, hepatic fatty changes, and CYP2E1 expression. The PSE and ASE groups had significantly higher intestinal occludin and claudin-1 mRNA expressions and lower muscular beclin-1 expression when compared to the E group. In conclusion, synbiotics supplementation might reduce protein expression of muscle protein degradation biomarkers such as beclin-1 in rats with chronic ethanol feeding, which is speculated to be linked to the improvement of intestinal tight junction and the reduction of liver damage.
Differential Response of Leafminer Flies Liriomyza trifolii (Burgess) and Liriomyza sativae (Blanchard) to Rapid Cold Hardening
Authors: Iqbal Junaid , Zhang Xiao-Xiang , Chang Ya-Wen , Du Yu-Zhou
Published: November 2021

Rapid cold hardening (RCH) is a rapid and critical adaption of insects to sudden temperature changes but is often overlooked or underestimated as a component of survival. Thus, interspecific comparisons of RCH are needed to predict how phenotypes will adapt to temperature variability. RCH not only enhances cold survival but also protects against non-lethal cold injury by preserving essential functions such as locomotion, reproduction, and energy balance. This study investigated the difference in basal cold tolerance and RCH capacity of L. trifolii and L. sativae. In both species, the cold tolerance of pupae was significantly enhanced after short-term exposure to moderately cold temperatures. The effect of RCH last for 4 h in L. sativae but only 2 h in L. trifolii. Interestingly, L. trifolii adults had a RCH response but L. sativae adults failed to acclimate. Short-term acclimation also lowered the supercooling point significantly in the pupae of both species. Based on these results, we propose a hypothesis that these differences will eventually affect their competition in the context of climate change. This study also provides the basis for future metabolomic and transcriptomic studies that may ultimately uncover the underlying mechanisms of RCH and interspecific competition between L. trifolii and L. sativae.
Evaluating the Efficacy of 30 Different Essential Oils against Varroa destructor and Honey Bee Workers (Apis mellifera)
Authors: Hýbl Marian , Bohatá Andrea , Rádsetoulalová Iva , Kopecký Marek , Hoštičková Irena , Vaníčková Alena , Mráz Petr
Published: November 2021

Essential oils and their components are generally known for their acaricidal effects and are used as an alternative to control the population of the Varroa destructor instead of synthetic acaricides. However, for many essential oils, the exact acaricidal effect against Varroa mites, as well as the effect against honey bees, is not known. In this study, 30 different essential oils were screened by using a glass-vial residual bioassay. Essential oils showing varroacidal efficacy > 70% were tested by the complete exposure assay. A total of five bees and five mites were placed in the Petri dishes in five replications for each concentration of essential oil. Mite and bee mortality rates were assessed after 4, 24, 48, and 72 h. The LC50 values and selectivity ratio (SR) were calculated. For essential oils with the best selectivity ratio, their main components were detected and quantified by GC-MS/MS. The results suggest that the most suitable oils are peppermint and manuka (SR > 9), followed by oregano, litsea (SR > 5), carrot, and cinnamon (SR > 4). Additionally, these oils showed a trend of the increased value of selective ratio over time. All these oils seem to be better than thymol (SR < 3.2), which is commonly used in beekeeping practice. However, the possible use of these essential oils has yet to be verified in beekeeping practice.
To the Theory of Unsteady Thermal Conductivity Caused by the Hot Core of the Earth
Authors: Gladkov Sergey O.
Published: November 2021

A solution is given to the spatial-temporary distribution of temperature in the volume of the Earth, due to the specified power of the thermal radiation of the hot core. An estimate is made of the maximum possible cooling time of the core.
Effect of Electrolytic Manganese Residue in Fly Ash-Based Cementitious Material: Hydration Behavior and Microstructure
Authors: Wang Yaguang , Zhang Na , Ren Yongyu , Xu Yingtang , Liu Xiaoming
Published: November 2021

Electrolytic manganese residue (EMR) is a solid waste with a main mineralogical composition of gypsum. It is generated in the production of metal manganese by the electrolysis process. In this research, EMR, fly ash, and clinker were blended to make fly ash-based cementitious material (FAC) to investigate the effect of EMR on strength properties, hydration behavior, microstructure, and environmental performance of FAC. XRD, TG, and SEM studied the hydration behavior of FAC. The pore structure and [SiO4] polymerization degree were characterized by MIP and 29Si NMR, respectively. The experimental results indicate that FAC shows excellent mechanical properties when the EMR dosage is 10%. Moderate content of sulfate provided by EMR can promote hydration reaction of FAC, and it shows a denser pore structure and higher [SiO4] polymerization degree in this case. Heavy metal ions derived from EMR can be adsorbed in the hydration products of FAC to obtain better environmental properties. This paper presents an AFt covering model for the case of excessive EMR in FAC, and it importantly provides theoretical support for the recycling of EMR in cementitious materials.
Study of the Interfacial Bond Behavior between CFRP Grid–PCM Reinforcing Layer and Concrete via a Simplified Mechanical Model
Authors: Dai Huijuan , Wang Bo , Zhang Jiawei , Zhang Junlei , Uji Kimitaka
Published: November 2021

This paper presents the results of pull-out tests conducted to investigate the interfacial bond behavior between a carbon-fiber-reinforced polymer (CFRP) grid–polymer cement mortar (PCM) reinforcing layer and existing concrete, and proposes a simplified mechanical model to further study the interface bond mechanism. Four specimens composed of a CFRP grid, PCM, and concrete were tested. The influence of the type of CFRP grid and the grid interval on the interface bond behavior was discussed. The failure patterns, maximum tensile loads, and CFRP grid strains were obtained. The change process of interface bond stress was investigated based on the grid strain analysis. In addition, the simplified mechanical model and finite element model (FEM) were emphatically established, and the adaptability of the simplified mechanical model was validated through the comparative analysis between the FEM results and the test results. The research results indicate that a CFRP grid with a larger cross-sectional area and smaller grid interval could effectively improve the interface bond behavior. The tensile stress was gradually transferred from the loaded edge to the free edge in the CFRP grid. The interface bond behavior was mainly dependent on the anchorage action of the CFRP grid in the PCM, and the bond action between the PCM and the concrete. The FEM results were consistent with the test results, and the simplified mechanical model with nonlinear springs could well describe the interface bond mechanism between the CFRP grid–PCM reinforcing layer and concrete.
Fixed-Bed Modification of Zeolitic Tuffs and Their Application for Cr(VI) Removal
Authors: Warchoł Jolanta Karolina , Sobolewska Paulina , Tylus Włodzimierz , Petrus Roman
Published: November 2021

Natural clinoptilolite tuff (CL) and chabazite-clinoptilolite tuff (CH) were modified in fixed-bed column by immobilization of hexadecyltrimethylammonium bromide (HDTMA-Br), then investigated as a sorbent for inorganic anions of Cr(VI). The proposed modification technique combined with surfactant solution batching allows minimizing the surfactant loses through foaming and crystallization and creation of stable organic coverage. The HDTMA loading depended on the mineral composition of the zeolitic tuff, the topology of its external surface, and process conditions. The maximum surface coverage was obtained by gradually dosing surfactant solution in the smallest volume of batches and corresponded up to 100% and 182% of external cation exchange capacity (ECEC) for mono and double layer coverage, respectively. In case of mono layer coverage, modification proceeds until the exhaustion of surfactant in supply solution, while in the double layer one, until equilibrium of HDTMA concentration in both zeolitic and liquid phases was established. The efficiency of Cr(VI) uptake by prepared surface modified zeolites (SMZs) increased with increasing of HDTMA loading. In the case of mono layer SMZs, the capacities of CH-HDTMA and CL-HDTMA were 10.3 and 5.4 mg/g, respectively, while in the case of double layer SMZs, the amount of Cr uptake on CH-HDTMA and CL-HDTMA were 16.8 and 15 mg/g, respectively. Ion exchange is the predominant mechanism of Cr(VI) sorption but it takes place only if modification resulted in at least partial double layer coverage. The XPS analysis reveals Cr(VI) reduction to a less-toxic Cr(III) by the electron donating N-containing groups and by reaction with Fe+2 ions on the zeolite external surface.
Mechanical Properties of Recycled Aggregate Concretes Containing Silica Fume and Steel Fibres
Authors: Jahandari Soheil , Mohammadi Masoud , Rahmani Aida , Abolhasani Masoumeh , Miraki Hania , Mohammadifar Leili , Kazemi Mostafa , Saberian Mohammad , Rashidi Maria
Published: November 2021

In this study, the impact of steel fibres and Silica Fume (SF) on the mechanical properties of recycled aggregate concretes made of two different types of Recycled Coarse Aggregates (RCA) sourced from both low- and high-strength concretes were evaluated through conducting 60 compressive strength tests. The RCAs were used as replacement levels of 50% and 100% of Natural Coarse Aggregates (NCA). Hook-end steel fibres and SF were also used in the mixtures at the optimised replacement levels of 1% and 8%, respectively. The results showed that the addition of both types of RCA adversely affected the compressive strength of concrete. However, the incorporation of SF led to compressive strength development in both types of concretes. The most significant improvement in terms of comparable concrete strength and peak strain with ordinary concrete at 28 days was observed in the case of using a combination of steel fibres and SF in both recycled aggregate concretes, especially with RCA sourced from high strength concrete. Although using SF slightly increased the elastic modulus of both recycled aggregate concretes, a substantial improvement in strength was observed due to the reinforcement with steel fibre and the coexistence of steel fibre and SF. Moreover, existing models to predict the elastic modulus of both non-fibrous and fibrous concretes are found to underestimate the elastic modulus values. The incorporation of SF changed the compressive stress-strain curves for both types of RCA. The addition of steel fibre and SF remarkably improved the post-peak ductility of recycled aggregates concretes of both types, with the most significant improvement observed in the case of RCA sourced from a low-strength parent concrete. The existing model to estimate the compressive stress-strain curve for steel fibre-reinforced concrete with natural aggregates was found to reasonably predict the compressive stress-strain behaviour for steel fibres-reinforced concrete with recycled aggregate.
Research on Task-Service Network Node Matching Method Based on Multi-Objective Optimization Model in Dynamic Hyper-Network Environment
Authors: Zhang Cheng-lei , Liu Jia-jia , Han Hu , Wang Xiao-jie , Yuan Bo , Zhuang Shen-le , Yang Kang
Published: November 2021

In order to reduce the cost of manufacturing and service for the Cloud 3D printing (C3DP) manufacturing grid, to solve the problem of resources optimization deployment for no-need preference under circumstance of cloud manufacturing, consider the interests of enterprises which need Cloud 3D printing resources and cloud platform operators, together with QoS and flexibility of both sides in the process of Cloud 3D printing resources configuration service, a task-service network node matching method based on Multi-Objective optimization model in dynamic hyper-network environment is built for resource allocation. This model represents interests of the above-mentioned two parties. In addition, the model examples are solved by modifying Mathematical algorithm of Node Matching and Evolutionary Solutions. Results prove that the model and the algorithm are feasible, effective and stable.
Calculation and AFM Experimental Research on Slip Friction for Unlubricated Spherical Contact with Roughness Effect
Authors: Zhu Shengguang , Ni Liyong
Published: November 2021

Previous research on friction calculation models has mainly focused on static friction, whereas sliding friction calculation models are rarely reported. In this paper, a novel sliding friction model for realizing a dry spherical flat contact with a roughness effect at the micro/nano scale is proposed. This model yields the sliding friction by the change in the periodic substrate potential, adopts the basic assumptions of the Greenwood–Williamson random contact model about asperities, and assumes that the contact area between a rigid sphere and a nominal rough flat satisfies the condition of interfacial friction. It subsequently employs a statistical method to determine the total sliding friction force, and finally, the feasibility of this model presented is verified by atomic force microscopy friction experiments. The comparison results show that the deviations of the sliding friction force and coefficient between the theoretical calculated values and the experimental values are in a relatively acceptable range for the samples with a small plasticity index (Ψ≤1).
Protective Effects of L-Theanine on IPEC-J2 Cells Growth Inhibition Induced by Dextran Sulfate Sodium via p53 Signaling Pathway
Authors: Zhang Longlin , Ma Mengmeng , Li Zhengyi , Zhang Haihan , He Xi , Song Zehe
Published: November 2021

L-theanine is a nonprotein amino acid found in tea leaves and has been widely used as a safe food additive in beverages or foods because of its varied bioactivities. The aim of this study was to reveal the in vitro gastrointestinal protective effects of L-theanine in DSS-induced intestinal porcine enterocyte (IPEC-J2) cell models using molecular and metabolic methods. Results showed that 2.5% dextran sulfate sodium (DSS) treatment inhibited the cell proliferation of IPEC-J2 and blocked the normal operation of the cell cycle, while L-theanine pretreatment significantly preserved these trends to exert protective effects. L-theanine pre-treatment also up-regulated the EGF, CDC2, FGF2, Rb genes and down-regulated p53, p21 proliferation-related mRNA expression in DSS-treated cells, in accompany with p53 signaling pathway inhibition. Meanwhile, metabolomics analysis revealed that L-theanine and DSS treated IPEC-J2 cells have different metabolomic profiles, with significant changes in the key metabolites involved in pyrimidine metabolism and amino acid metabolism, which play an important role in nucleotide metabolism. In summary, L-theanine has a beneficial protection in DSS-induced IPEC-J2 cells via promoting proliferation and regulating metabolism disorders.
Salicylic Acid and Risk of Colorectal Cancer: A Two-Sample Mendelian Randomization Study
Authors: Nounu Aayah , Richmond Rebecca , Stewart Isobel , Surendran Praveen , Wareham Nicholas , Butterworth Adam , Weinstein Stephanie , Albanes Demetrius , Baron John , Hopper John , Figueiredo Jane , Newcomb Polly , Lindor Noralane , Casey Graham , Platz Elizabeth , Marchand Loïc , Ulrich Cornelia , Li Christopher , van Dujinhoven Fränzel , Gsur Andrea , Campbell Peter , Moreno Víctor , Vodicka Pavel , Vodickova Ludmila , Amitay Efrat , Alwers Elizabeth , Chang-Claude Jenny , Sakoda Lori , Slattery Martha , Schoen Robert , Gunter Marc , Castellví-Bel Sergi , Kim Hyeong-Rok , Kweon Sun-Seog , Chan Andrew , Li Li , Zheng Wei , Bishop D. , Buchanan Daniel , Giles Graham , Gruber Stephen , Rennert Gad , Stadler Zsofia , Harrison Tabitha , Lin Yi , Keku Temitope , Woods Michael , Schafmayer Clemens , Van Guelpen Bethany , Gallinger Steven , Hampel Heather , Berndt Sonja , Pharoah Paul , Lindblom Annika , Wolk Alicja , Wu Anna , White Emily , Peters Ulrike , Drew David , Scherer Dominique , Bermejo Justo , Brenner Hermann , Hoffmeister Michael , Williams Ann , Relton Caroline
Published: November 2021

Salicylic acid (SA) has observationally been shown to decrease colorectal cancer (CRC) risk. Aspirin (acetylsalicylic acid, that rapidly deacetylates to SA) is an effective primary and secondary chemopreventive agent. Through a Mendelian randomization (MR) approach, we aimed to address whether levels of SA affected CRC risk, stratifying by aspirin use. A two-sample MR analysis was performed using GWAS summary statistics of SA (INTERVAL and EPIC-Norfolk, N = 14,149) and CRC (CCFR, CORECT, GECCO and UK Biobank, 55,168 cases and 65,160 controls). The DACHS study (4410 cases and 3441 controls) was used for replication and stratification of aspirin-use. SNPs proxying SA were selected via three methods: (1) functional SNPs that influence the activity of aspirin-metabolising enzymes; (2) pathway SNPs present in enzymes’ coding regions; and (3) genome-wide significant SNPs. We found no association between functional SNPs and SA levels. The pathway and genome-wide SNPs showed no association between SA and CRC risk (OR: 1.03, 95% CI: 0.84–1.27 and OR: 1.08, 95% CI: 0.86–1.34, respectively). Results remained unchanged upon aspirin use stratification. We found little evidence to suggest that an SD increase in genetically predicted SA protects against CRC risk in the general population and upon stratification by aspirin use.
Characterization of Individualized Glycemic Excursions during a Standardized Bout of Hypoglycemia-Inducing Exercise and Subsequent Hypoglycemia Treatment—A Pilot Study
Authors: Brož Jan , Campbell Matthew D. , Urbanová Jana , Nunes Marisa A. , Brunerová Ludmila , Rahelić Dario , Janíčková Žďárská Denisa , Taniwall Arian , Brabec Marek , Berka Vojtěch , Michalec Juraj , Polák Jan
Published: November 2021

The glycemic response to ingested glucose for the treatment of hypoglycemia following exercise in type 1 diabetes patients has never been studied. Therefore, we aimed to characterize glucose dynamics during a standardized bout of hypoglycemia-inducing exercise and the subsequent hypoglycemia treatment with the oral ingestion of glucose. Ten male patients with type 1 diabetes performed a standardized bout of cycling exercise using an electrically braked ergometer at a target heart rate (THR) of 50% of the individual heart rate reserve, determined using the Karvonen equation. Exercise was terminated when hypoglycemia was reached, followed by immediate hypoglycemia treatment with the oral ingestion of 20 g of glucose. Arterialized blood glucose (ABG) levels were monitored at 5 min intervals during exercise and for 60 min during recovery. During exercise, ABG decreased at a mean rate of 0.11 ± 0.03 mmol/L·min−1 (minimum: 0.07, maximum: 0.17 mmol/L·min−1). During recovery, ABG increased at a mean rate of 0.13 ± 0.05 mmol/L·min−1 (minimum: 0.06, maximum: 0.19 mmol/L·min−1). Moreover, 20 g of glucose maintained recovery from hypoglycemia throughout the 60 min postexercise observation window.
Baseline Predictors of Adherence in a Randomised Controlled Trial of a New Group Psychological Intervention for People with Recurrent Binge Eating Episodes Associated to Overweight or Obesity
Authors: Mannan Haider , Palavras Marly Amorim , Claudino Angélica , Hay Phillipa
Published: November 2021

Purpose: Understanding the high rate of treatment adherence in trials of people with eating disorders is important as it can compromise the quality of the trials. In clinical practice, it may also contribute to illness chronicity, relapse, and costs. Thus, we investigated factors associated with adherence to a new treatment HAPIFED, which integrates cognitive behavioural therapy having extended sessions with body weight loss therapy compared to cognitive behavioural therapy with extended sessions alone, for individuals with Bulimia Nervosa or Binge Eating Disorder or other eating disorders comorbid with overweight or obesity. Methods: In total, 98 participants having bulimia nervosa, binge eating disorder and other specified and unspecified eating disorders were recruited with 50 randomised to HAPIFED and 48 to the control intervention CBT-E, all administered in groups of up to 10 participants. An investigator external to the site conducted the random allocation, which was concealed from the statistician involved in the analysis, and known only to the therapists until the finalization of the 12-month follow-up after the end of active treatment. Three scenarios in the timeline treatment of a total of 30 sessions were assessed: 33% or 60% or 75% of presence. Mixed-effects logistic regression analysis was performed to find the correlates of adherence after adjusting for clustering by number of group participants. To account for heterogeneity by types of eating disorders in the sample, the latter variable was considered as a control factor in the models. A subgroup analysis was performed for those with binge eating disorder as this was the largest (N = 66) eating disorder group. Results: None of the six variables—frequency of binge eating episodes, purging, eating disorder symptom severity, weight, illness duration and mental health-related quality of life—significantly predicted adherence at 33%, but longer illness duration predicted higher treatment adherence at both 60% and 75% presence of the interventions. Also for 75% presence, higher body weight predicted lower treatment adherence. For the subgroup analysis, those having higher illness duration had significantly higher odds of treatment adherence for 60% and 75% of the sessions. Conclusions: Higher adherence due to late treatment completion was associated with longer binge eating illness length and a lower body weight. More research is needed to recognize factors that may interfere with engagement in treatments aiming to avoid early dropout.
Targeting Oxidative Stress, NLRP3 Inflammasome, and Autophagy by Fraxetin to Combat Doxorubicin-Induced Cardiotoxicity
Authors: Kabel Ahmed M. , Salama Samir A. , Adwas Almokhtar A. , Estfanous Remon S.
Published: November 2021

Doxorubicin belongs to the class of anthracycline antibiotics that is widely used in the treatment protocols of a wide range of malignancies. The major deleterious effect of doxorubicin use is the possible occurrence of cardiotoxicity. This study aimed to delineate the possible effects of targeting oxidative stress, NLRP3 inflammasome, and autophagy by fraxetin on doxorubicin-induced cardiac dysfunction in rats. In a model of doxorubicin-induced cardiotoxicity, the effects of different doses of fraxetin were assessed by determination of biochemical, histopathological, immunohistochemical, and electron microscopic changes. Fraxetin, in a dose-dependent manner, was found to have the ability to mitigate the harmful effects of oxidative stress and inflammation on myocardial muscles with significant decrease in NLRP3 inflammasome, augmentation of autophagy, and amelioration of the apoptotic signaling pathways. In addition, fraxetin, in a dose-dependent manner, had the ability to combat the echocardiographic, histopathological, immunohistochemical, and electron microscopic changes induced by doxorubicin in cardiomyocytes. As a result, fraxetin may be put into consideration as a new adjuvant line of therapy on the way to mitigate doxorubicin-induced cardiotoxicity.
Discovery and Development of Inhibitors of the Plasmodial FNT-Type Lactate Transporter as Novel Antimalarials
Authors: Nerlich Cornelius , Epalle Nathan H. , Seick Philip , Beitz Eric
Published: November 2021

Plasmodium spp. malaria parasites in the blood stage draw energy from anaerobic glycolysis when multiplying in erythrocytes. They tap the ample glucose supply of the infected host using the erythrocyte glucose transporter 1, GLUT1, and a hexose transporter, HT, of the parasite’s plasma membrane. Per glucose molecule, two lactate anions and two protons are generated as waste that need to be released rapidly from the parasite to prevent blockage of the energy metabolism and acidification of the cytoplasm. Recently, the missing Plasmodium lactate/H+ cotransporter was identified as a member of the exclusively microbial formate–nitrite transporter family, FNT. Screening of an antimalarial compound selection with unknown targets led to the discovery of specific and potent FNT-inhibitors, i.e., pentafluoro-3-hydroxy-pent-2-en-1-ones. Here, we summarize the discovery and further development of this novel class of antimalarials, their modes of binding and action, circumvention of a putative resistance mutation of the FNT target protein, and suitability for in vivo studies using animal malaria models.
Simultaneous Quantification of Propylthiouracil and Its N-β-d Glucuronide by HPLC-MS/MS: Application to a Metabolic Study
Authors: Li Min , He Qingfeng , Yao Li , Wang Xiaofeng , Tang Zhijia , Zhu Xiao , Lin Hai-Shu , Xiang Xiaoqiang
Published: November 2021

Propylthiouracil (PTU) is commonly prescribed for the management of hyperthyroidism and thyrotoxicosis. Although the exact mechanism of action is not fully understood, PTU is associated with hepatoxicity in pediatric population. Glucuronidation mediated by uridine 5′-diphospho-glucuronosyltransferases (UGTs), which possess age-dependent expression, has been proposed as an important metabolic pathway of PTU. To further examine the metabolism of PTU, a reliable HPLC-MS/MS method for the simultaneous quantification of PTU and its N-β-D glucuronide (PTU-GLU) was developed and validated. The chromatographic separation was achieved on a ZORBAX Extend-C18 column (2.1 × 50 mm, 1.8 μm) through gradient delivery of a mixture of formic acid, methanol and acetonitrile. The electrospray ionization (ESI) was operated in its negative ion mode while PTU and PTU-GLU were detected by multiple reaction monitoring (MRM). This analytical method displayed excellent linearity, sensitivity, accuracy, precision, recovery and stability while its matrix effect and carry-over were insignificant. Subsequently, the in vitro metabolism of PTU was assessed and UGT1A9 was identified as an important UGT isoform responsible for the glucuronidation of PTU. The information obtained from this study will facilitate future mechanistic investigation on the hepatoxicity of PTU and may optimize its clinical application.
The Influence of Domain Permutations of an Albumin-Binding Domain-Fused HER2-Targeting Affibody-Based Drug Conjugate on Tumor Cell Proliferation and Therapy Efficacy
Authors: Yin Wen , Xu Tianqi , Altai Mohamed , Oroujeni Maryam , Zhang Jie , Vorobyeva Anzhelika , Vorontsova Olga , Vtorushin Sergey V. , Tolmachev Vladimir , Gräslund Torbjörn , Orlova Anna
Published: November 2021

Human epidermal growth factor receptor 2 (HER2) is a clinically validated target for breast cancer therapy. Previously, a drug-fused HER2-targeting affinity protein construct successfully extended the survival of mice bearing HER2-expressing xenografts. The aim of this study was to evaluate the influence of the number and positioning of the protein domains in the drug conjugate. Seven HER2-targeting affibody-based constructs, including one or two affibody molecules (Z) with or without an albumin-binding domain (ABD), namely Z, Z-ABD, ABD-Z, Z-Z, Z-Z-ABD, Z-ABD-Z, and ABD-Z-Z, were evaluated on their effects on cell growth, in vivo targeting, and biodistribution. The biodistribution study demonstrated that the monomeric constructs had longer blood retention and lower hepatic uptake than the dimeric ones. A dimeric construct, specifically ABD-Z-Z, could stimulate the proliferation of HER2 expressing SKOV-3 cells in vitro and the growth of tumors in vivo, whereas the monomeric construct Z-ABD could not. These two constructs demonstrated a therapeutic effect when coupled to mcDM1; however, the effect was more pronounced for the non-stimulating Z-ABD. The median survival of the mice treated with Z-ABD-mcDM1 was 63 days compared to the 37 days for those treated with ABD-Z-Z-mcDM1 or for the control animals. Domain permutation of an ABD-fused HER2-targeting affibody-based drug conjugate significantly influences tumor cell proliferation and therapy efficacy. The monomeric conjugate Z-ABD is the most promising format for targeted delivery of the cytotoxic drug DM1.
Antidepressants and Circadian Rhythm: Exploring Their Bidirectional Interaction for the Treatment of Depression
Authors: Silva Soraia , Bicker Joana , Falcão Amílcar , Fortuna Ana
Published: November 2021

Scientific evidence that circadian rhythms affect pharmacokinetics and pharmacodynamics has highlighted the importance of drug dosing-time. Circadian oscillations alter drug absorption, distribution, metabolism, and excretion (ADME) as well as intracellular signaling systems, target molecules (e.g., receptors, transporters, and enzymes), and gene transcription. Although several antidepressant drugs are clinically available, less than 50% of depressed patients respond to first-line pharmacological treatments. Chronotherapeutic approaches to enhance the effectiveness of antidepressants are not completely known. Even so, experimental results found until this day suggest a positive influence of drug dosing-time on the efficacy of depression therapy. On the other hand, antidepressants have also demonstrated to modulate circadian rhythmicity and sleep–wake cycles. This review aims to evidence the potential of chronotherapy to improve the efficacy and/or safety of antidepressants. It includes pre-clinical and clinical studies that demonstrate the relevance of determining the most appropriate time of administration for antidepressant drugs. In parallel, their positive influence on the resynchronization of disrupted circadian rhythms is also herein discussed. It is expected that this review will promote the investigation of chronotherapy for the treatment of depression, contribute to a better understanding of the relationship between antidepressants and circadian rhythms, and consequently promote the development of new therapeutics.
Rearranged Copolyurea Networks for Selective Carbon Dioxide Adsorption at Room Temperature
Authors: Nam Junsik , Jeon Eunkyung , Moon Su-Young , Park Ji-Woong
Published: November 2021

Copolyurea networks (co-UNs) were synthesized via crosslinking polymerization of a mixture of tetrakis(4-aminophenyl)methane (TAPM) and melamine with hexamethylene diisocyanate (HDI) using the organic sol-gel polymerization method. The subsequent thermal treatment of between 200 and 400 °C induced the sintering of the powdery polyurea networks to form porous frameworks via urea bond rearrangement and the removal of volatile hexamethylene moieties. Incorporating melamine into the networks resulted in a higher nitrogen content and micropore ratio, whereas the overall porosity decreased with the melamine composition. The rearranged network composed of the tetraamine/melamine units in an 80:20 ratio showed the highest carbon dioxide adsorption quantity at room temperature. The results show that optimizing the chemical structure and porosity of polyurea-based networks can lead to carbon dioxide adsorbents working at elevated temperatures.
Syntheses and Characteristics of Urushiol-Based Waterborne UV-Cured Wood Coatings
Authors: Chang Chia-Wei , Liao Jyun-Ya , Lu Kun-Tsung
Published: November 2021

The manufacture and properties of waterborne UV-cured coatings (WUV coatings) by acetone process based on urushiol for wood finishing were investigated. Firstly, epoxide urushiol (EU) was prepared by reacting urushiol with epichlorohydrin. Secondly, the EU was reacted with acrylic acid to obtain acrylic epoxide urushiol (AEU). Next, the prepolymers were synthesized by the reaction of AEU, 2,2-Bis(hydroxymethyl)propionic acid (DMPA), and isophorone diisocyanate (IPDI) and hexamethylene diisocyanate (HDI), respectively, using acetone as a solvent. The prepolymers were further neutralized by triethylamine (TEA) to obtain ionomers and dispersed in the water. After removing the acetone by vacuum distillation, the polyurethane dispersions (PUDs) were obtained. Finally, the WUV coatings were performed by adding a photoinitiator (Irgacure 2959). The products in the synthesized processes and the properties of the WUV coatings were examined. The results showed that the EU, AEU, prepolymers, and ionomers could be synthesized stably. The PUDs synthesized by the IPDI and HDI had a similar solid content of 25.2% and 26.2%, and similar pH values of 7.8 and 7.6. However, the IPDI-containing PUD displayed lower viscosity, smaller particle size, and a more even polydispersity index. The IPDI-containing WUV film displayed a higher hardness, gloss, and lightfastness. The HDI-containing WUV film possessed superior impact resistance. Both IPDI-containing and HDI-containing WUV films showed excellent adhesion, bending resistance, and mass retention, and demonstrated a potential for wood finishing.
Efficient Film Fabrication and Characterization of Poly(3,4-ethylenedioxythiophene):Poly(styrenesulfonate) (PEDOT:PSS)-Metalloporphine Nanocomposite and Its Application as Semiconductor Material
Authors: Sánchez-Vergara María Elena , Hamui Leon , González-Verdugo Daniela , Cosme Ismael
Published: November 2021

The use of composite films with semiconductor behavior is an alternative to enhance the efficiency of optoelectronic devices. Composite films of poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) and metalloporphines (MPs; M = Co, Cu, Pd) have been prepared by spin-coating. The PEDOT:PSS-MP films were treated with isopropanol (IPA) vapor to modify the polymer structure from benzoid to quinoid. The quinoid structure promotes improvements in the optical and electrical behavior of films. The composite films’ morphology and structure were characterized using infrared and Raman spectroscopy, scanning electron microscopy (SEM), and atomic force microscopy (AFM). Composite films were analyzed for their optical behavior by ultraviolet-visible spectroscopy: at λ < 450 nm, the films become transparent, indicating the capacity to be used as transparent electrodes in optoelectronic devices. At λ ≥ 450 nm, the absorbance in the films increased significantly. The CoP showed an 8 times larger current density compared to the CuP. A light induced change in the J-V curves was observed, and it is larger for the CoP. The conductivity values yielded between 1.23 × 102 and 1.92 × 103 Scm−1 and were higher in forward bias.