bluuebunny/crossref_metadata_2025 huggingface dataset:
Chemical-Physical Properties and Bioactivity of New Premixed Calcium Silicate-Bioceramic Root Canal Sealers
Authors: Zamparini Fausto , Prati Carlo , Taddei Paola , Spinelli Andrea , Di Foggia Michele , Gandolfi Maria Giovanna
Published: November 2022

The aim of the study was to analyze the chemical–physical properties and bioactivity (apatite-forming ability) of three recently introduced premixed bioceramic root canal sealers containing varied amounts of different calcium silicates (CaSi): a dicalcium and tricalcium silicate (1–10% and 20–30%)-containing sealer with zirconium dioxide and tricalcium aluminate (CERASEAL); a tricalcium silicate (5–15%)-containing sealer with zirconium dioxide, dimethyl sulfoxide and lithium carbonate (AH PLUS BIOCERAMIC) and a dicalcium and tricalcium silicate (10% and 25%)-containing sealer with calcium aluminate, tricalcium aluminate and tantalite (NEOSEALER FLO). An epoxy resin-based sealer (AH PLUS) was used as control. The initial and final setting times, radiopacity, flowability, film thickness, open pore volume, water absorption, solubility, calcium release and alkalizing activity were tested. The nucleation of calcium phosphates and/or apatite after 28 days aging in Hanks balanced salt solution (HBSS) was evaluated by ESEM-EDX, vibrational IR and micro-Raman spectroscopy. The analyses showed for NeoSealer Flo and AH Plus the longest final setting times (1344 ± 60 and 1300 ± 60 min, respectively), while shorter times for AH Plus Bioceramic and Ceraseal (660 ± 60 and 720 ± 60 min, respectively). Radiopacity, flowability and film thickness complied with ISO 6876/12 for all tested materials. A significantly higher open pore volume was observed for NeoSealer Flo, AH Plus Bioceramic and Ceraseal when compared to AH Plus (p < 0.05), significantly higher values were observed for NeoSealer Flo and AH Plus Bioceramic (p < 0.05). Ceraseal and AH Plus revealed the lowest solubility. All CaSi-containing sealers released calcium and alkalized the soaking water. After 28 days immersion in HBSS, ESEM-EDX analyses revealed the formation of a mineral layer that covered the surface of all bioceramic sealers, with a lower detection of radiopacifiers (Zirconium for Ceraseal and AH Plus Bioceramic, Tantalum for NeoSealer Flo) and an increase in calcium, phosphorous and carbon. The calcium phosphate (CaP) layer was more evident on NeoSealer Flo and AH Plus Bioceramic. IR and micro-Raman revealed the formation of calcium carbonate on the surface of all set materials. A thin layer of a CaP phase was detected only on AH Plus Bioceramic and NeoSealer Flo. Ceraseal did not show CaP deposit despite its highest calcium release among all the tested CaSi-containing sealers. In conclusion, CaSi-containing sealers met the required chemical and physical standards and released biologically relevant ions. Slight/limited apatite nucleation was observed in relation to the high carbonation processes.
GSK343, an Inhibitor of Enhancer of Zeste Homolog 2, Reduces Glioblastoma Progression through Inflammatory Process Modulation: Focus on Canonical and Non-Canonical NF-κB/IκBα Pathways
Authors: Scuderi Sarah Adriana , Filippone Alessia , Basilotta Rossella , Mannino Deborah , Casili Giovanna , Capra Anna Paola , Chisari Giulia , Colarossi Lorenzo , Sava Serena , Campolo Michela , Esposito Emanuela , Paterniti Irene
Published: November 2022

Glioblastoma (GB) is a tumor of the central nervous system characterized by high proliferation and invasiveness. The standard treatment for GB includes radiotherapy and chemotherapy; however, new therapies are needed. Particular attention was given to the role of histone methyltransferase enhancer of zeste-homolog-2 (EZH2) in GB. Recently, several EZH2-inhibitors have been developed, particularly GSK343 is well-known to regulate apoptosis and autophagy processes; however, its abilities to modulate canonical/non-canonical NF-κB/IκBα pathways or an immune response in GB have not yet been investigated. Therefore, this study investigated for the first time the effect of GSK343 on canonical/non-canonical NF-κB/IκBα pathways and the immune response, by an in vitro, in vivo and ex vivo model of GB. In vitro results demonstrated that GSK343 treatments 1, 10 and 25 μM significantly reduced GB cell viability, showing the modulation of canonical/non-canonical NF-κB/IκBα pathway activation. In vivo GSK343 reduced subcutaneous tumor mass, regulating canonical/non-canonical NF-κB/IκBα pathway activation and the levels of reactive oxygen species (ROS), malondialdehyde (MDA), and superoxide dismutase (SOD). Ex vivo results confirmed the anti-proliferative effect of GSK343 and also demonstrated its ability to regulate immune response through CXCL9, CXCL10 and CXCL11 expression in GB. Thus, GSK343 could represent a therapeutic strategy to counteract GB progression, thanks to its ability to modulate canonical/non-canonical NF-κB/IκBα pathways and immune response.
In Vitro and In Vivo Response of Zinc-Containing Mesoporous Bioactive Glasses in a Sheep Animal Model
Authors: Jiménez-Holguín Javier , Arcos Daniel , Lozano Daniel , Saiz-Pardo Melchor , de Pablo David , Ortega Luis , Enciso Silvia , Fernández-Tomé Blanca , Díaz-Güemes Idoia , Sánchez-Margallo Francisco Miguel , Casarrubios Laura , Portolés María Teresa , Vallet-Regí María
Published: November 2022

Zinc-enriched mesoporous bioactive glasses (MBGs) are bioceramics with potential antibacterial and osteogenic properties. However, few assays have been performed to study these properties in animal models. In this study, MBGs enriched with up to 5% ZnO were synthesized, physicochemically characterized, and evaluated for their osteogenic activity both in vitro and in vivo. The ZnO MBGs showed excellent textural properties despite ZnO incorporation. However, the release of Zn2+ ions inhibited the mineralization process when immersed in simulated body fluid. In vitro assays showed significantly higher values of viability and expression of early markers of cell differentiation and angiogenesis in a ZnO-content-dependent manner. The next step was to study the osteogenic potential in a sheep bone defect model. Despite their excellent textural properties and cellular response in vitro, the ZnO MBGs were not able to integrate into the bone tissue, which can be explained in terms of inhibition of the mineralization process caused by Zn2+ ions. This work highlights the need to develop nanostructured materials for bone regeneration that can mineralize to interact with bone tissue and induce the processes of implant acceptance, cell colonization by osteogenic cells, and regeneration of lost bone tissue.
An Agent-Based Model of Radiation-Induced Lung Fibrosis
Authors: Cogno Nicolò , Bauer Roman , Durante Marco
Published: November 2022

Early- and late-phase radiation-induced lung injuries, namely pneumonitis and lung fibrosis (RILF), severely constrain the maximum dose and irradiated volume in thoracic radiotherapy. As the most radiosensitive targets, epithelial cells respond to radiation either by undergoing apoptosis or switching to a senescent phenotype that triggers the immune system and damages surrounding healthy cells. Unresolved inflammation stimulates mesenchymal cells’ proliferation and extracellular matrix (ECM) secretion, which irreversibly stiffens the alveolar walls and leads to respiratory failure. Although a thorough understanding is lacking, RILF and idiopathic pulmonary fibrosis share multiple pathways and would mutually benefit from further insights into disease progression. Furthermore, current normal tissue complication probability (NTCP) models rely on clinical experience to set tolerance doses for organs at risk and leave aside mechanistic interpretations of the undergoing processes. To these aims, we implemented a 3D agent-based model (ABM) of an alveolar duct that simulates cell dynamics and substance diffusion following radiation injury. Emphasis was placed on cell repopulation, senescent clearance, and intra/inter-alveolar bystander senescence while tracking ECM deposition. Our ABM successfully replicates early and late fibrotic response patterns reported in the literature along with the ECM sigmoidal dose-response curve. Moreover, surrogate measures of RILF severity via a custom indicator show qualitative agreement with published fibrosis indices. Finally, our ABM provides a fully mechanistic alveolar survival curve highlighting the need to include bystander damage in lung NTCP models.
Adsorption Analysis of Exopolymeric Substances as a Tool for the Materials Selection of Photobioreactors Manufacture
Authors: García-Abad Lucía , Soriano-Jerez Yolanda , Cerón-García María del Carmen , Muñoz-Bonilla Alexandra , Fernández-García Marta , García-Camacho Francisco , Molina-Grima Emilio
Published: November 2022

An improved method that allows the robust characterization of surfaces is necessary to accurately predict the biofouling formation on construction materials of photobioreactors (PBR). Exopolymeric substances (EPS), such as proteins and polysaccharides, have been demonstrated to present a similar behavior to cells in terms of surface adhesion. In this work, these EPS were used to optimize parameters, such as EPS concentration or adsorption time, to evaluate accurately the adsorption capacity of surfaces and, with it, predict the biofouling formation in contact with microalgae cultures. Once the method was optimized, the characterization of seven commercial polymeric surfaces was submitted to different abrasive particles sizes, which modified the roughness of the samples, as well as protein and polysaccharide lawns, which were prepared and carried out in order to evaluate the characteristics of these substances. The characterization consisted of the determination of surface free energy, water adhesion tension, and critical tension determined from the measurement of the contact angle, roughness, surface zeta potential, and the EPS adhesion capacity of each material. This will be useful to understand the behavior of the surface in the function of its characteristics and the interaction with the solutions of EPS, concluding that the hydrophobic and smooth surfaces present good anti-biofouling characteristics.
Conjugates of Methylene Blue with Cycloalkaneindoles as New Multifunctional Agents for Potential Treatment of Neurodegenerative Disease
Authors: Bachurin Sergey O. , Shevtsova Elena F. , Makhaeva Galina F. , Aksinenko Alexey Yu. , Grigoriev Vladimir V. , Goreva Tatiana V. , Epishina Tatiana A. , Kovaleva Nadezhda V. , Boltneva Natalia P. , Lushchekina Sofya V. , Rudakova Elena V. , Vinogradova Darya V. , Shevtsov Pavel N. , Pushkareva Elena A. , Dubova Ludmila G. , Serkova Tatiana P. , Veselov Ivan M. , Fisenko Vladimir P. , Richardson Rudy J.
Published: November 2022

The development of multi-target-directed ligands (MTDLs) would provide effective therapy of neurodegenerative diseases (ND) with complex and nonclear pathogenesis. A promising method to create such potential drugs is combining neuroactive pharmacophoric groups acting on different biotargets involved in the pathogenesis of ND. We developed a synthetic algorithm for the conjugation of indole derivatives and methylene blue (MB), which are pharmacophoric ligands that act on the key stages of pathogenesis. We synthesized hybrid structures and performed a comprehensive screening for a specific set of biotargets participating in the pathogenesis of ND (i.e., cholinesterases, NMDA receptor, mitochondria, and microtubules assembly). The results of the screening study enabled us to find two lead compounds (4h and 4i) which effectively inhibited cholinesterases and bound to the AChE PAS, possessed antioxidant activity, and stimulated the assembly of microtubules. One of them (4i) exhibited activity as a ligand for the ifenprodil-specific site of the NMDA receptor. In addition, this lead compound was able to bypass the inhibition of complex I and prevent calcium-induced mitochondrial depolarization, suggesting a neuroprotective property that was confirmed using a cellular calcium overload model of neurodegeneration. Thus, these new MB-cycloalkaneindole conjugates constitute a promising class of compounds for the development of multitarget neuroprotective drugs which simultaneously act on several targets, thereby providing cognitive stimulating, neuroprotective, and disease-modifying effects.
Surface Design Options in Polymer- and Lipid-Based siRNA Nanoparticles Using Antibodies
Authors: Gabel Michael , Knauss Annkathrin , Fischer Dagmar , Neurath Markus F. , Weigmann Benno
Published: November 2022

The mechanism of RNA interference (RNAi) could represent a breakthrough in the therapy of all diseases that arise from a gene defect or require the inhibition of a specific gene expression. In particular, small interfering RNA (siRNA) offers an attractive opportunity to achieve a new milestone in the therapy of human diseases. The limitations of siRNA, such as poor stability, inefficient cell uptake, and undesired immune activation, as well as the inability to specifically reach the target tissue in the body, can be overcome by further developments in the field of nanoparticulate drug delivery. Therefore, types of surface modified siRNA nanoparticles are presented and illustrate how a more efficient and safer distribution of siRNA at the target site is possible by modifying the surface properties of nanoparticles with antibodies. However, the development of such efficient and safe delivery strategies is currently still a major challenge. In consideration of that, this review article aims to demonstrate the function and targeted delivery of siRNA nanoparticles, focusing on the surface modification via antibodies, various lipid- and polymer-components, and the therapeutic effects of these delivery systems.
Shift of Choline/Betaine Pathway in Recombinant Pseudomonas for Cobalamin Biosynthesis and Abiotic Stress Protection
Authors: Balabanova Larissa , Pentekhina Iuliia , Nedashkovskaya Olga , Degtyarenko Anton , Grigorchuk Valeria , Yugay Yulia , Vasyutkina Elena , Kudinova Olesya , Seitkalieva Aleksandra , Slepchenko Lubov , Son Oksana , Tekutyeva Liudmila , Shkryl Yury
Published: November 2022

The B12-producing strains Pseudomonas nitroreducens DSM 1650 and Pseudomonas sp. CCUG 2519 (both formerly Pseudomonas denitrificans), with the most distributed pathway among bacteria for exogenous choline/betaine utilization, are promising recombinant hosts for the endogenous production of B12 precursor betaine by direct methylation of bioavailable glycine or non-proteinogenic β-alanine. Two plasmid-based de novo betaine pathways, distinguished by their enzymes, have provided an expression of the genes encoding for N-methyltransferases of the halotolerant cyanobacterium Aphanothece halophytica or plant Limonium latifolium to synthesize the internal glycine betaine or β-alanine betaine, respectively. These betaines equally allowed the recombinant pseudomonads to grow effectively and to synthesize a high level of cobalamin, as well as to increase their protective properties against abiotic stresses to a degree comparable with the supplementation of an exogenous betaine. Both de novo betaine pathways significantly enforced the protection of bacterial cells against lowering temperature to 15 °C and increasing salinity to 400 mM of NaCl. However, the expression of the single plant-derived gene for the β-alanine-specific N-methyltransferase additionally increased the effectiveness of exogenous glycine betaine almost twofold on cobalamin biosynthesis, probably due to the Pseudomonas’ ability to use two independent pathways, their own choline/betaine pathway and the plant β-alanine betaine biosynthetic pathway.
Statins as Repurposed Drugs in Gynecological Cancer: A Review
Authors: Wang Kai-Hung , Liu Chin-Hung , Ding Dah-Ching
Published: November 2022

Discovering new drugs is an expensive and time-consuming process, including target identification, bioavailability, pharmacokinetic (PK) tests, pharmacodynamic (PD) tests, toxicity profiles, recommended dosage test, and observation of the side effects, etc. Repurposed drugs could bypass some steps, starting from phase II trials, and shorten the processes. Statins, also known as HMG-CoA inhibitors (HMGCR), are commonly used to manage and prevent various cardiovascular diseases and have been shown to improve the morbidity and mortality of patients. In addition to the inhibitory effects on the production of cholesterol, the beneficial effects of statins on the prognosis and risk of various cancers are also shown. Statins not only inhibited cell proliferation, metastasis, and chemoresistance but affected the tumor microenvironment (TME). Thus, statins have great potential to be repurposed in oncology. Hence, we review the meta-analysis, cohort, and case-control studies of statins in gynecological cancers, and elucidate how statins regulate cell proliferation, apoptosis, tumor growth, and metastasis. Although the results in gynecological cancers remain controversial and the effects of different statins in different histotypes of gynecological cancers and TME are needed to elucidate further, statins are excellent candidates and worthy of being repurposed drugs in treating gynecological cancers.
Treatment of Periodontal Inflammation in Diabetic Rats with IL-1ra Thermosensitive Hydrogel
Authors: Liu Yue , Liu Chang , Wang Chang , Zhang Qian , Qu Xingyuan , Liang Chen , Si Chao , Wang Lei
Published: November 2022

Periodontitis is a chronic inflammatory disease that is considered to be the main cause of adult tooth loss. Diabetes mellitus (DM) has a bidirectional relationship with periodontitis. Interleukin-1β (IL-1β) is an important pre-inflammatory factor, which participates in the pathophysiological process of periodontitis and diabetes. The interleukin-1 receptor antagonist (IL-1ra) is a natural inhibitor of IL-1, and the balance between IL-1ra and IL-1β is one of the main factors affecting chronic periodontitis (CP) and diabetes. The purpose of this study is to develop a drug carrier that is safe and nontoxic and can effectively release IL-1ra, which can effectively slow down the inflammation of periodontal tissues with diabetes, and explore the possibility of lowering the blood sugar of this drug carrier. Therefore, in this experiment, a temperature-sensitive hydrogel loaded with IL-1ra was prepared and characterized, and its anti-inflammatory effect in high-sugar environments in vivo and in vitro was evaluated. The results showed that the hydrogel could gel after 5 min at 37 °C, the pore size was 5–70 μm, and the cumulative release of IL-1ra reached 83.23% on the 21st day. Real-time polymerase chain reaction (qRT-PCR) showed that the expression of IL-1β, Interleukin 6 (IL-6), and tumor necrosis factor α (TNF-α) inflammatory factors decreased after the treatment with IL-1ra-loaded thermosensitive hydrogel. Histological evaluation and micro-computed tomography (Micro-CT) showed that IL-1ra-loaded thermosensitive hydrogel could effectively inhibit periodontal inflammation and reduce alveolar bone absorption in rats with diabetic periodontitis. It is worth mentioning that this hydrogel also plays a role in relieving hyperglycemia. Therefore, the temperature-sensitive hydrogel loaded with IL-1ra may be an effective method to treat periodontitis with diabetes.
Lophatherum gracile Bronghiart Suppresses Receptor Activator of Nuclear Factor Kappa-B Ligand-Stimulated Osteoclastogenesis and Prevents Ovariectomy-Induced Osteoporosis
Authors: Lee Sung-Ju , Jang Seon-A , Kim Seong Cheol , Ryuk Jin Ah , Ha Hyunil
Published: November 2022

Lophatherum gracile Bronghiart, used in traditional herbal medicine, has many biological properties including antiviral, antipyretic, antitumor, vasorelaxation, and neutrophilic inflammatory effects. However, its modulatory effects on bone metabolism have not been investigated previously. In this study, we examined the effects of a water extract of the leaves of L. gracile (WELG) on osteoclast differentiation and bone loss, and explored its underlying mechanisms. We found that WELG inhibits osteoclastogenesis by suppressing both receptor activator of nuclear factor-κB ligand (RANKL)-induced early activation of mitogen-activated protein kinases (MAPKs) and nuclear factor-κB (NF-κB)- and RANKL-induced modulation of the positive and negative regulators of osteoclastogenesis in osteoclast precursors. In vivo study demonstrated that WELG protects against bone loss, weight gain, and fat accumulation without affecting uterine atrophy in an ovariectomy-induced postmenopausal osteoporosis mice model. In addition, photochemical analysis of WELG identified active constituents known to have bone-protective effects. Overall, the results of this study suggest that WELG can be a potential candidate for therapy and prevention of postmenopausal osteoporosis.
Genetic Dissection of Phosphorus Use Efficiency and Genotype-by-Environment Interaction in Maize
Authors: Li Dongdong , Li Guoliang , Wang Haoying , Guo Yuhang , Wang Meng , Lu Xiaohuan , Luo Zhiheng , Zhu Xintian , Weiß Thea Mi , Roller Sandra , Chen Shaojiang , Yuan Lixing , Würschum Tobias , Liu Wenxin
Published: November 2022

Genotype-by-environment interaction (G-by-E) is a common but potentially problematic phenomenon in plant breeding. In this study, we investigated the genotypic performance and two measures of plasticity on a phenotypic and genetic level by assessing 234 maize doubled haploid lines from six populations for 15 traits in seven macro-environments with a focus on varying soil phosphorus levels. It was found intergenic regions contributed the most to the variation of phenotypic linear plasticity. For 15 traits, 124 and 31 quantitative trait loci (QTL) were identified for genotypic performance and phenotypic plasticity, respectively. Further, some genes associated with phosphorus use efficiency, such as Zm00001eb117170, Zm00001eb258520, and Zm00001eb265410, encode small ubiquitin-like modifier E3 ligase were identified. By significantly testing the main effect and G-by-E effect, 38 main QTL and 17 interaction QTL were identified, respectively, in which MQTL38 contained the gene Zm00001eb374120, and its effect was related to phosphorus concentration in the soil, the lower the concentration, the greater the effect. Differences in the size and sign of the QTL effect in multiple environments could account for G-by-E. At last, the superiority of G-by-E in genomic selection was observed. In summary, our findings will provide theoretical guidance for breeding P-efficient and broadly adaptable varieties.
Reliability of Computing van der Waals Bond Lengths of Some Rare Gas Diatomics
Authors: Zhang Yi-Liang , Li Bin
Published: November 2022

When the bond lengths of 11 molecules containing van der Waals bonds are optimized by 572 methods and 20 basis sets, it is found that the best mean absolute deviations (MADs) of density-functional theory (DFT) methods are 0.005 Å (shown by APFD/6-311++G**), 0.007 Å (B2PLYPD3(Full)/aug-cc-pVQZ), and 0.010 Å (revDSDPBEP86/aug-cc-pVQZ), while the best MADs of ab initio methods are 0.008 Å (BD(T)/aug-cc-pVTZ) and 0.016 Å (MP4/aug-cc-pVQZ). Moreover, the best MADs calculated by 54 selected methods in combination with 60 other basis sets (such as 6-311++G, 6-31++G(3d′f,3p′d), and UGBS1V++) are not better. Therefore, these bond lengths can be calculated with extremely high accuracy by some special methods and basis sets, and CCSD(T) is also not as good as expected because its best MAD is only 0.023 Å (CCSD(T)/aug-cc-pVQZ).
Iron Content, Iron Speciation and Phycocyanin in Commercial Samples of Arthrospira spp.
Authors: Isani Gloria , Ferlizza Enea , Bertocchi Martina , Dalmonte Thomas , Menotta Simonetta , Fedrizzi Giorgio , Andreani Giulia
Published: November 2022

Cyanobacteria are characterized by high iron content. In this research, we collected ten commercial samples of Arthrospira spp. sold as food supplement to determine iron content and assess whether iron speciation showed variability among samples and changed respect to A. platensis grown in controlled conditions. Particular attention was also paid to phycocyanin, as an iron-binding protein. In six of the ten samples, 14 essential and non-essential trace elements were analysed using ICP-MS. Iron content measured in samples using atomic absorption spectrometry (AAS) varied from 353 (sample S5) to 1459 (sample S7) µg g−1 dry weight and was in the range of those reported by other authors in commercial supplements. Iron speciation was studied using size exclusion chromatography followed by the analysis of the collected fraction for the determination of iron by AAS and for protein separation using SDS-PAGE. Overlapping chromatographic profiles were obtained for total proteins, phycocyanin and iron, although quantitative differences were evidenced among the samples analysed. In most samples, iron was mainly bound to ligands with high molecular mass; however, in four samples iron was also bound to ligands with low molecular mass. In fractions containing the most relevant iron burden, the principal protein was phycocyanin, confirming its role as an iron-binding protein in commercial samples.
In Vivo Preclinical Assessment of β-Amyloid–Affine [11C]C-PIB Accumulation in Aluminium-Induced Alzheimer’s Disease-Resembling Hypercholesterinaemic Rat Model
Authors: Képes Zita , Barkóczi Alexandra , Szabó Judit P. , Kálmán-Szabó Ibolya , Arató Viktória , Jószai István , Deák Ádám , Kertész István , Hajdu István , Trencsényi György
Published: November 2022

Aluminum (Al) excess and hypercholesterinaemia are established risks of Alzheimer’s disease (AD). The aim of this study was to establish an AD-resembling hypercholesterinaemic animal model—with the involvement of 8 week and 48 week-old Fischer-344 rats—by Al administration for the safe and rapid verification of β-amyloid-targeted positron emission tomography (PET) radiopharmaceuticals. Measurement of lipid parameters and β-amyloid–affine [11C]C-Pittsburgh Compound B ([11C]C-PIB) PET examinations were performed. Compared with the control, the significantly elevated cholesterol and LDL levels of the rats receiving the cholesterol-rich diet support the development of hypercholesterinaemia (p ≤ 0.01). In the older cohort, a notably increased age-related radiopharmaceutical accumulation was registered compared to in the young (p ≤ 0.05; p ≤ 0.01). A monotherapy-induced slight elevation of mean standardised uptake values (SUVmean) was statistically not significant; however, adult rats administered a combined diet expressed remarkable SUVmean increment compared to the adult control (SUVmean: from 0.78 ± 0.16 to 1.99 ± 0.28). One and two months after restoration to normal diet, the cerebral [11C]C-PIB accumulation of AD-mimicking animals decreased by half and a third, respectively, to the baseline value. The proposed in vivo Al-induced AD-resembling animal system seems to be adequate for the understanding of AD neuropathology and future drug testing and radiopharmaceutical development.
Significance of Antioxidants on Aging and Neurodegeneration
Authors: Tchekalarova Jana , Tzoneva Rumiana
Published: November 2022

The hallmark of aging is an organism’s difficulty to maintain proper homeostasis, leading to a disrupted balance between the endogenous antioxidant system and the production of free radicals, a progressive inflammatory process, and increased susceptibility to (neurodegenerative diseases [...]
Enhanced Resistance to Sclerotinia sclerotiorum in Brassica rapa by Activating Host Immunity through Exogenous Verticillium dahliae Aspf2-like Protein (VDAL) Treatment
Authors: Jiang Shufang , Zheng Weiwei , Li Zewei , Tan Jingru , Wu Meifang , Li Xinyuan , Hong Seung-Beom , Deng Jianyu , Zhu Zhujun , Zang Yunxiang
Published: November 2022

Sclerotinia stem rot caused by Sclerotinia sclerotiorum is one of the most destructive diseases in Brassica rapa. Verticillium dahliae Aspf2-like protein (VDAL) is a secretory protein of V. dahliae which has been shown to enhance the resistance against fungal infections in several plants. Nonetheless, the molecular mechanisms of VDAL-primed disease resistance are still poorly understood. In this study, we performed physiological, biochemical, and transcriptomic analyses of Brassica rapa in order to understand how VDAL confers resistance to S. sclerotiorumn infections in plants. The results showed that foliar application of VDAL significantly reduced the plaque area on leaves inoculated with S. sclerotiorum. It also enhanced antioxidant capacity by increasing activities of superoxide dismutase (SOD), peroxidase (POD), peroxidase (APX), glutathione reductase (GR), protoporphyrinogen oxidase (PPO), and defense-related enzymes β-1,3-glucanase and chitinase during the infection periods. This occurred in parallel with significantly reduced relative conductivity at different periods and lower malondialdehyde (MDA) content as compared to sole S. sclerotiorum inoculation. Transcriptomic analysis showed a total of 146 (81 up-regulated and 65 down-regulated) differentially expressed genes (DEGs) in VDAL-treated leaves compared to the control. The most enriched three Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were the mitogen–activated protein kinase (MAPK) signaling pathway, plant hormone signal transduction, and plant-pathogen interaction, all of which were associated with plant immunity. DEGs associated with MAPK and hormone signal transduction pathways were ethylene response sensor ERS2, EIN3 (Ethylene Insensitive3)-binding F-box protein 2 (EBF2), ethylene-responsive transcription factor ERF94, MAPK 9 (MKK9), protein phosphatase 2C (PP2C37), auxin-responsive proteins (AUX/IAA1 and 19), serine/threonine-protein kinase CTR1, and abscisic acid receptors (PLY 4 and 5). Among the DEGs linked with the plant–pathogen interaction pathway were calmodulin-like proteins (CML5, 24, 27), PTI1-like tyrosine protein kinase 3 (Pti13) and transcription factor MYB30, all of which are known to play key roles in pathogen-associated molecular pattern (PAMP)-triggered immunity and effector-triggered immunity (ETI) for hypersensitive response (HR), cell wall reinforcement, and stomatal closure in plants. Overall, VDLA treatment triggered repression of the auxin and ABA signaling pathways and de-repression of the ethylene signaling pathways in young B. rapa seedlings to increase plant innate immunity. Our results showed that VDAL holds great potential to enhance fungal disease resistance in B. rapa crop.
C Type Natriuretic Peptide Receptor Activation Inhibits Sodium Channel Activity in Human Aortic Endothelial Cells by Activating the Diacylglycerol-Protein Kinase C Pathway
Authors: Yu Ling , Nouri Mohammad-Zaman , Liu Lauren P. , Bala Niharika , Denslow Nancy D. , LaDisa John F. , Alli Abdel A.
Published: November 2022

The C-type natriuretic peptide receptor (NPRC) is expressed in many cell types and binds all natriuretic peptides with high affinity. Ligand binding results in the activation or inhibition of various intracellular signaling pathways. Although NPRC ligand binding has been shown to regulate various ion channels, the regulation of endothelial sodium channel (EnNaC) activity by NPRC activation has not been studied. The objective of this study was to investigate mechanisms of EnNaC regulation associated with NPRC activation in human aortic endothelial cells (hAoEC). EnNaC protein expression and activity was attenuated after treating hAoEC with the NPRC agonist cANF compared to vehicle, as demonstrated by Western blotting and patch clamping studies, respectively. NPRC knockdown studies using siRNA’s corroborated the specificity of EnNaC regulation by NPRC activation mediated by ligand binding. The concentration of multiple diacylglycerols (DAG) and the activity of protein kinase C (PKC) was augmented after treating hAoEC with cANF compared to vehicle, suggesting EnNaC activity is down-regulated upon NPRC ligand binding in a DAG-PKC dependent manner. The reciprocal cross-talk between NPRC activation and EnNaC inhibition represents a feedback mechanism that presumably is involved in the regulation of endothelial function and aortic stiffness.
Advances in Targeted Immunotherapy for Hepatobiliary Cancers
Authors: Ruff Samantha M. , Shannon Alexander H. , Pawlik Timothy M.
Published: November 2022

Cancer of the hepatobiliary system can be divided into primary liver cancer and biliary tract cancer (BTC), which includes hepatocellular carcinoma (HCC), cholangiocarcinoma (CCA), and gallbladder cancer (GBC). These aggressive cancers often present at an advanced stage or among patients with poorly preserved liver function. The primary treatment for HCC and BTC when diagnosed early is surgical resection, but given the high rate of recurrence and often advanced stage at diagnosis, many patients will require systemic therapy. Unfortunately, even with systemic therapy, long-term survival is poor. The immune system plays an important role in preventing cancer progression. The unique immune environment of the liver and subsequent alterations to the immune microenvironment by tumor cells to create a favorable microenvironment plays a key role in the progression of HCC and BTC. Due to the paucity of effective systemic therapies and distinctive immune environment of the liver, research and clinical trials are investigating the use of immunotherapy in HCC and BTC. This review will focus on current immunotherapies and emerging data for the treatment of HCC and BTC.
The Farnesoid X Receptor as a Master Regulator of Hepatotoxicity
Authors: Rausch Magdalena , Samodelov Sophia L. , Visentin Michele , Kullak-Ublick Gerd A.
Published: November 2022

The nuclear receptor farnesoid X receptor (FXR, NR1H4) is a bile acid (BA) sensor that links the enterohepatic circuit that regulates BA metabolism and elimination to systemic lipid homeostasis. Furthermore, FXR represents a real guardian of the hepatic function, preserving, in a multifactorial fashion, the integrity and function of hepatocytes from chronic and acute insults. This review summarizes how FXR modulates the expression of pathway-specific as well as polyspecific transporters and enzymes, thereby acting at the interface of BA, lipid and drug metabolism, and influencing the onset and progression of hepatotoxicity of varying etiopathogeneses. Furthermore, this review article provides an overview of the advances and the clinical development of FXR agonists in the treatment of liver diseases.
MUC1 Tissue Expression and Its Soluble Form CA15-3 Identify a Clear Cell Renal Cell Carcinoma with Distinct Metabolic Profile and Poor Clinical Outcome
Authors: Lucarelli Giuseppe , Rutigliano Monica , Loizzo Davide , di Meo Nicola Antonio , Lasorsa Francesco , Mastropasqua Mauro , Maiorano Eugenio , Bizzoca Cinzia , Vincenti Leonardo , Battaglia Michele , Ditonno Pasquale
Published: November 2022

An altered metabolism is involved in the development of clear cell renal carcinoma (ccRCC). MUC1 overexpression has been found to be associated with advanced disease and poor prognosis. In this study, we evaluated the metabolomic profile of human ccRCC, according to MUC1 expression, and integrated it with transcriptomic data. Moreover, we analyzed the role of MUC1 in sustaining ccRCC aggressiveness and the prognostic value of its soluble form CA15-3. Integrated metabolomic and transcriptomic analysis showed that MUC1-expressing ccRCC was characterized by metabolic reprogramming involving the glucose and lipid metabolism pathway. In addition, primary renal cancer cells treated with a small interfering RNA targeting MUC1 (siMUC1) migrated and proliferated at a slower rate than untreated cancer cells. After cisplatin treatment, the death rate of cancer cells treated with siMUC1 was significantly greater than that of untreated cells. Kaplan–Meier curves showed significant differences in CSS and PFS among groups of patients with high versus low levels of CA15-3. In a multivariate analysis, CA15-3 was an independent adverse prognostic factor for cancer-specific and progression-free survival. In conclusion, MUC1 expressing ccRCC is characterized by a particular metabolic reprogramming. The inhibition of MUC1 expression decreases cell motility and viability and improves cisplatin susceptibility, suggesting that this pathway can regulate de novo chemotherapy resistance in ccRCC.
Amyloidogenesis: What Do We Know So Far?
Authors: Alraawi Zeina , Banerjee Nayan , Mohanty Srujana , Kumar Thallapuranam Krishnaswamy Suresh
Published: November 2022

The study of protein aggregation, and amyloidosis in particular, has gained considerable interest in recent times. Several neurodegenerative diseases, such as Alzheimer’s (AD) and Parkinson’s (PD) show a characteristic buildup of proteinaceous aggregates in several organs, especially the brain. Despite the enormous upsurge in research articles in this arena, it would not be incorrect to say that we still lack a crystal-clear idea surrounding these notorious aggregates. In this review, we attempt to present a holistic picture on protein aggregation and amyloids in particular. Using a chronological order of discoveries, we present the case of amyloids right from the onset of their discovery, various biophysical techniques, including analysis of the structure, the mechanisms and kinetics of the formation of amyloids. We have discussed important questions on whether aggregation and amyloidosis are restricted to a subset of specific proteins or more broadly influenced by the biophysiochemical and cellular environment. The therapeutic strategies and the significant failure rate of drugs in clinical trials pertaining to these neurodegenerative diseases have been also discussed at length. At a time when the COVID-19 pandemic has hit the globe hard, the review also discusses the plausibility of the far-reaching consequences posed by the virus, such as triggering early onset of amyloidosis. Finally, the application(s) of amyloids as useful biomaterials has also been discussed briefly in this review.
Overexpression of a Senescence-Related Gene CpSRG1 from Wintersweet (Chimonanthus praecox) Promoted Growth and Flowering, and Delayed Senescence in Transgenic Arabidopsis
Authors: Cao Yinzhu , Li Guixiang , Wang Xia , Huang Renwei , Luo Jianghui , Li Mingyang , Liu Daofeng , Sui Shunzhao
Published: November 2022

Plant senescence is a complex process that is controlled by developmental regulation and genetic programs. A senescence-related gene CpSRG1, which belongs to the 2OG-Fe(II) dioxygenase superfamily, was characterized from wintersweet, and the phylogenetic relationship of CpSRG1 with homologs from other species was investigated. The expression analysis by qRT-PCR (quantitative real-time PCR) indicated that CpSRG1 is abundant in flower organs, especially in petals and stamens, and the highest expression of CpSRG1 was detected in stage 6 (withering period). The expression patterns of the CpSRG1 gene were further confirmed in CpSRG1pro::GUS (β-glucuronidase) plants, and the activity of the CpSRG1 promoter was enhanced by exogenous Eth (ethylene), SA (salicylic acid), and GA3 (gibberellin). Heterologous overexpression of CpSRG1 in Arabidopsis promoted growth and flowering, and delayed senescence. Moreover, the survival rates were significantly higher and the root lengths were significantly longer in the transgenic lines than in the wild-type plants, both under low nitrogen stress and GA3 treatment. This indicated that the CpSRG1 gene may promote the synthesis of assimilates in plants through the GA pathway, thereby improving growth and flowering, and delaying senescence in transgenic Arabidopsis. Our study has laid a satisfactory foundation for further analysis of senescence-related genes in wintersweet and wood plants. It also enriched our knowledge of the 2OG-Fe(II) dioxygenase superfamily, which plays a variety of important roles in plants.
Harnessing Normal and Engineered Mesenchymal Stem Cells Derived Exosomes for Cancer Therapy: Opportunity and Challenges
Authors: Ahmadi Mahdi , Mahmoodi Monireh , Shoaran Maryam , Nazari-Khanamiri Fereshteh , Rezaie Jafar
Published: November 2022

There remains a vital necessity for new therapeutic approaches to combat metastatic cancers, which cause globally over 8 million deaths per year. Mesenchymal stem cells (MSCs) display aptitude as new therapeutic choices for cancer treatment. Exosomes, the most important mediator of MSCs, regulate tumor progression. The potential of harnessing exosomes from MSCs (MSCs-Exo) in cancer therapy is now being documented. MSCs-Exo can promote tumor progression by affecting tumor growth, metastasis, immunity, angiogenesis, and drug resistance. However, contradictory evidence has suggested that MSCs-Exo suppress tumors through several mechanisms. Therefore, the exact association between MSCs-Exo and tumors remains controversial. Accordingly, the applications of MSCs-Exo as novel drug delivery systems and standalone therapeutics are being extensively explored. In addition, engineering MSCs-Exo for targeting tumor cells has opened a new avenue for improving the efficiency of antitumor therapy. However, effective implementation in the clinical trials will need the establishment of standards for MSCs-Exo isolation and characterization as well as loading and engineering methods. The studies outlined in this review highlight the pivotal roles of MSCs-Exo in tumor progression and the promising potential of MSCs-Exo as therapeutic drug delivery vehicles for cancer treatment.
Characterization of a Glycolipid Synthase Producing α-Galactosylceramide in Bacteroides fragilis
Authors: Caballé Marc , Faijes Magda , Planas Antoni
Published: November 2022

Glycolipids are complex molecules involved in important cellular processes. Among them, the glycosphingolipid α-galactosylceramide has proven to be of interest in biomedicine for its immunostimulatory capabilities. Given its structural requirements, the use of ceramide glycosyltransferase enzymes capable of synthesizing this molecule under in vivo or in vitro conditions is a potential production strategy. Several GT4 enzymes from Bacteroides fragilis were considered as potential candidates in addition to the known BF9343_3149, but only this one showed glycolipid synthase activity. The enzyme was expressed as a SUMO fusion protein to produce soluble protein. It is a non-processive glycosyltransferase that prefers UDP-Gal over UDP-Glc as a donor substrate, and maximum activity was found at pH 7.3 and around 30–35 °C. It does not require metal cations for activity as other GT4 enzymes, but Zn2+ inactivates the enzyme. The reaction occurs when the ceramide lipid acceptor is solubilized with BSA (100% conversion) but not when it is presented in mixed micelles, and anionic lipids do not increase activity, as in other membrane-associated glycolipid synthases. Further protein engineering to increase stability and activity can make feasible the enzymatic synthesis of α-GalCer for biomedical applications.
Quantitative Transcriptome Analysis of Purified Equine Mast Cells Identifies a Dominant Mucosal Mast Cell Population with Possible Inflammatory Functions in Airways of Asthmatic Horses
Authors: Akula Srinivas , Riihimäki Miia , Waern Ida , Åbrink Magnus , Raine Amanda , Hellman Lars , Wernersson Sara
Published: November 2022

Asthma is a chronic inflammatory airway disease and a serious health problem in horses as well as in humans. In humans and mice, mast cells (MCs) are known to be directly involved in asthma pathology and subtypes of MCs accumulate in different lung and airway compartments. The role and phenotype of MCs in equine asthma has not been well documented, although an accumulation of MCs in bronchoalveolar lavage fluid (BALF) is frequently seen. To characterize the phenotype of airway MCs in equine asthma we here developed a protocol, based on MACS Tyto sorting, resulting in the isolation of 92.9% pure MCs from horse BALF. We then used quantitative transcriptome analyses to determine the gene expression profile of the purified MCs compared with total BALF cells. We found that the MCs exhibited a protease profile typical for the classical mucosal MC subtype, as demonstrated by the expression of tryptase (TPSB2) alone, with no expression of chymase (CMA1) or carboxypeptidase A3 (CPA3). Moreover, the expression of genes involved in antigen presentation and complement activation strongly implicates an inflammatory role for these MCs. This study provides a first insight into the phenotype of equine MCs in BALF and their potential role in the airways of asthmatic horses.
Tree Genetic Engineering, Genome Editing and Genomics
Authors: Fladung Matthias , Kersten Birgit
Published: November 2022

In this Special Issue [...]
Airway Smooth Muscle Cell Mitochondria Damage and Mitophagy in COPD via ERK1/2 MAPK
Authors: Fang Lei , Zhang Ming , Li Junling , Zhou Liang , Tamm Michael , Roth Michael
Published: November 2022

Chronic obstructive pulmonary disease (COPD) is characterized by irreversible deterioration of the airway wall. Cigarette smoking is the major trigger, and in vitro studies showed that cigarette smoke extract (CSE) induced mitophagy in airway epithelial cells via oxidative stress, but this mechanism was not studied in airway smooth muscle cells (ASMCs). Primary ASMCs isolated from COPD patients or non-disease donors were investigated for CSE-induced remodeling and mitochondria structure. Proteins were assessed by Western blots for remodeling: collagen type-I, α-smooth muscle actin (α-SMA) and fibronectin; autophagy: beclin-1, protein62 (p62), light chain (LC)3A/B; mitochondria activity: mitochondrially encoded cytochrome c oxidase II & -IV (MTCO2, MTCO4), peroxisome proliferator activated receptor gamma coactivator 1α (PGC-1α); lysosomes: early endosome antigen 1, lysosome activated membrane protein 1; and cell signaling: extracellular signal regulated kinase (ERK1/2). Lysotracker and Mitotracker were used to monitor mitochondria morphology and organelle co-localization. Compared with controls, untreated COPD ASMCs showed lower collagen type-I and α-SMA expressions, but increased fibronectin levels. CSE further downregulated collagen type-I and α-SMA expression, but upregulated fibronectin. CSE decreased PGC-1α, MTCO2, and MTCO4, but increased beclin-1, p62, and LC3. CSE upregulated mitophagy and lysosomes activity via ERK1/2 phosphorylation. In vitro, cigarette smoke induced the deterioration of ASMCs, which might explain the tissue loss and structural remodeling in COPD bronchi. The results suggest that preventing exceeded mitophagy in ASMCs might present a novel therapeutic target for COPD.
G Protein-Coupled Receptors Regulated by Membrane Potential
Authors: David Dekel , Bentulila Ziv , Tauber Merav , Ben-Chaim Yair
Published: November 2022

G protein-coupled receptors (GPCRs) are involved in a vast majority of signal transduction processes. Although they span the cell membrane, they have not been considered to be regulated by the membrane potential. Numerous studies over the last two decades have demonstrated that several GPCRs, including muscarinic, adrenergic, dopaminergic, and glutamatergic receptors, are voltage regulated. Following these observations, an effort was made to elucidate the molecular basis for this regulatory effect. In this review, we will describe the advances in understanding the voltage dependence of GPCRs, the suggested molecular mechanisms that underlie this phenomenon, and the possible physiological roles that it may play.