bluuebunny/crossref_metadata_2025 huggingface dataset:
TRAIL-R Deficient Mice Are Protected from Neurotoxic Effects of Amyloid-β
Authors: Di Benedetto Giulia , Burgaletto Chiara , Serapide Maria Francesca , Caltabiano Rosario , Munafò Antonio , Bellanca Carlo Maria , Di Mauro Rosaria , Bernardini Renato , Cantarella Giuseppina
Published: October 2022

TRAIL, a member of TNF superfamily, is a potent inducer of neuronal death. Neurotoxic effects of TRAIL appear mediated by its death receptor TRAIL-R2/DR5. To assess the role of TRAIL/TRAIL-R2 pathway in AD-related neurodegeneration, we studied the impact of the treatment with amyloid-β (Aβ) upon cell viability and inflammation in TRAIL-R-deficient mice (TRAIL-R−/−). Here, we demonstrate that the lack of TRAIL-R2 protects from death cultured TRAIL-R−/− mouse embryonic hippocampal cells after treatment with either Aβ1-42 or TRAIL. Consistently, stereotaxic injection of Aβ1-42 resulted in blunted caspase activation, as well as in reduction of JNK phosphorylation and increased AKT phosphorylation in TRAIL-R−/− mice. Moreover, the lack of TRAIL-R2 was associated with blunted constitutive p53 expression in mice that have undergone Aβ1-42 treatment, as well as in decrease of phosphorylated forms of tau and GSK3β proteins. Likewise, TRAIL-R2 appears essential to both TRAIL and Aβ-mediated neurotoxicity and inflammation. Indeed, hippocampi of TRAIL-R−/− mice challenged with Aβ1-42, showed a slight expression of microglial (Iba-1) and astrocytic (GFAP) markers along with attenuated levels of IL-1β, TNF-α, NOS2 and COX2. In conclusion, the bulk of these results demonstrate that the constitutive lack of TRAIL-R2 is associated with a substantial reduction of noxious effects of Aβ1-42, providing further evidence on the prominent role played by TRAIL in course of Aβ-related neurodegeneration and confirming that the TRAIL system represents a potential target for innovative AD therapy.
Prevalence of Bacterial Coinfections with Vibrio harveyi in the Industrialized Flow-through Aquaculture Systems in Hainan Province: A Neglected High-Risk Lethal Causative Agent to Hybrid Grouper
Authors: Xu He , Zeng Yan-Hua , Yin Wen-Liang , Lu Hong-Bin , Gong Xiao-Xiao , Zhang Na , Zhang Xiang , Long Hao , Ren Wei , Cai Xiao-Ni , Huang Ai-You , Xie Zhen-Yu
Published: October 2022

Vibrio harveyi is one of the most serious bacterial pathogens to aquatic animals worldwide. Evidence is mounting that coinfections caused by multiple pathogens are common in nature and can alter the severity of diseases in marine animals. However, bacterial coinfections involving V. harveyi have received little attention in mariculture. In this study, the results of pathogen isolation indicated that bacterial coinfection was a common and overlooked risk for hybrid groupers (♀ Epinephelus polyphekadion × ♂ E. fuscoguttatus) reared in an industrialized flow-through pattern in Hainan Province. The artificial infection in hybrid groupers revealed that coinfections with V. harveyi strain GDH11385 (a serious lethal causative agent to groupers) and other isolated pathogens resulted in higher mortality (46.67%) than infection with strain GDH11385 alone (33.33%), whereas no mortality was observed in single infection with other pathogens. Furthermore, the intestine, liver and spleen of hybrid groupers are target organs for bacterial coinfections involving V. harveyi. Based on the infection patterns found in this study, we propose that V. harveyi may have a specific spatiotemporal expression pattern of virulence genes when infecting the host. Taken together, bacterial coinfection with V. harveyi is a neglected high-risk lethal causative agent to hybrid groupers in the industrialized flow-through aquaculture systems in Hainan Province.
Metabolic Heterogeneity of Brain Tumor Cells of Proneural and Mesenchymal Origin
Authors: Seliger Corinna , Meyer Anne-Louise , Leidgens Verena , Rauer Lisa , Moeckel Sylvia , Jachnik Birgit , Proske Judith , Dettmer Katja , Rothhammer-Hampl Tanja , Kaulen Leon D. , Riemenschneider Markus J. , Oefner Peter J. , Kreutz Marina , Schmidt Nils-Ole , Merrill Marsha , Uhl Martin , Renner Kathrin , Vollmann-Zwerenz Arabel , Proescholdt Martin , Hau Peter
Published: October 2022

Brain-tumor-initiating cells (BTICs) of proneural and mesenchymal origin contribute to the highly malignant phenotype of glioblastoma (GB) and resistance to current therapies. BTICs of different subtypes were challenged with oxidative phosphorylation (OXPHOS) inhibition with metformin to assess the differential effects of metabolic intervention on key resistance features. Whereas mesenchymal BTICs varied according to their invasiveness, they were in general more glycolytic and less responsive to metformin. Proneural BTICs were less invasive, catabolized glucose more via the pentose phosphate pathway, and responded better to metformin. Targeting glycolysis may be a promising approach to inhibit tumor cells of mesenchymal origin, whereas proneural cells are more responsive to OXPHOS inhibition. Future clinical trials exploring metabolic interventions should account for metabolic heterogeneity of brain tumors.
The TGA Transcription Factors from Clade II Negatively Regulate the Salicylic Acid Accumulation in Arabidopsis
Authors: Fonseca Alejandro , Urzúa Tomás , Jelenska Joanna , Sbarbaro Christopher , Seguel Aldo , Duarte Yorley , Greenberg Jean T. , Holuigue Loreto , Blanco-Herrera Francisca , Herrera-Vásquez Ariel
Published: October 2022

Salicylic acid (SA) is a hormone that modulates plant defenses by inducing changes in gene expression. The mechanisms that control SA accumulation are essential for understanding the defensive process. TGA transcription factors from clade II in Arabidopsis, which include the proteins TGA2, TGA5, and TGA6, are known to be key positive mediators for the transcription of genes such as PR-1 that are induced by SA application. However, unexpectedly, stress conditions that induce SA accumulation, such as infection with the avirulent pathogen P. syringae DC3000/AvrRPM1 and UV-C irradiation, result in enhanced PR-1 induction in plants lacking the clade II TGAs (tga256 plants). Increased PR-1 induction was accompanied by enhanced isochorismate synthase-dependent SA production as well as the upregulation of several genes involved in the hormone’s accumulation. In response to avirulent P. syringae, PR-1 was previously shown to be controlled by both SA-dependent and -independent pathways. Therefore, the enhanced induction of PR-1 (and other defense genes) and accumulation of SA in the tga256 mutant plants is consistent with the clade II TGA factors providing negative feedback regulation of the SA-dependent and/or -independent pathways. Together, our results indicate that the TGA transcription factors from clade II negatively control SA accumulation under stress conditions that induce the hormone production. Our study describes a mechanism involving old actors playing new roles in regulating SA homeostasis under stress.
A New Phospholipase D from Moritella sp. JT01: Biochemical Characterization, Crystallization and Application in the Synthesis of Phosphatidic Acid
Authors: Wang Fanghua , Mao Xuejing , Deng Fuli , Cui Ruiguo , Li Lilang , Liu Siyu , Yang Bo , Lan Dongming , Wang Yonghua
Published: October 2022

A new phospholipase D from marine Moritella sp. JT01 (MsPLD) was recombinantly expressed and biochemically characterized. The optimal reaction temperature and pH of MsPLD were determined to be 35 °C and 8.0. MsPLD was stable at a temperature lower than 35 °C, and the t1/2 at 4 °C was 41 days. The crystal structure of apo-MsPLD was resolved and the functions of a unique extra loop segment on the enzyme activity were characterized. The results indicated that a direct deletion or fastening of the extra loop segment by introducing disulfide bonds both resulted in a complete loss of its activity. The results of the maximum insertion pressure indicated that the deletion of the extra loop segment significantly decreased MsPLD’s interfacial binding properties to phospholipid monolayers. Finally, MsPLD was applied to the synthesis of phosphatidic acid by using a biphasic reaction system. Under optimal reaction conditions, the conversion rate of phosphatidic acid reached 86%. The present research provides a foundation for revealing the structural–functional relationship of this enzyme.
Yeast-Fermented Rapeseed Meal Extract Is Able to Reduce Inflammation and Oxidative Stress Caused by Escherichia coli Lipopolysaccharides and to Replace ZnO in Caco-2/HTX29 Co-Culture Cells
Authors: Taranu Ionelia , Pistol Gina Cecilia , Anghel Andrei Cristian , Marin Daniela , Bulgaru Cristina
Published: October 2022

(1) The present study tested in vitro the capacity of a fermented rapeseed meal extract to reduce medicinal ZnO, which will be banned at the EU level from 2023 onwards because of its potential to cause environmental pollution and the development of Zn resistance in gut bacteria. Rapeseed meal could be an important ZnO substitute as it has antioxidant/radical scavenging properties due to its content of bioactive compounds (e.g., polyphenols). (2) Protein array and flow cytometry were used to detect apoptosis, oxidative stress production, and inflammatory and signaling-related molecules in Caco-2 and goblet HT29-MTX co-culture cells challenged with Escherichia coli lipopolysaccharides and treated with ZnO and FRSM. (3) LPS induced cell death (21.1% vs. 12.7% in control, p < 0.005); apoptosis (16.6%); ROS production; and overexpression of biomarkers related to inflammation (63.15% cytokines and 66.67% chemokines), oxidative stress, and signaling proteins when compared to untreated cells. ZnO was effective in counteracting the effect of LPS, and 73.68% cytokines and 91.67% of chemokines were recovered. FRSM was better at restoring normal protein expression for 78.94% of cytokines, 91.67% of chemokines, and 61.11% of signaling molecules. FRSM was able to mitigate negative effects of LPS and might be an alternative to ZnO in pig diets.
Improved Adipose Tissue Function after Single Anastomosis Duodeno-Ileal Bypass with Sleeve-Gastrectomy (SADI-S) in Diet-Induced Obesity
Authors: Becerril Sara , Tuero Carlota , Cienfuegos Javier A. , Rodríguez Amaia , Catalán Victoria , Ramírez Beatriz , Valentí Víctor , Moncada Rafael , Unamuno Xabier , Gómez-Ambrosi Javier , Frühbeck Gema
Published: October 2022

Bariatric surgery has been recognized as the safest and most effective procedure for controlling type 2 diabetes (T2D) and obesity in carefully selected patients. The aim of the present study was to compare the effects of Sleeve Gastrectomy (SG) and Single Anastomosis Duodenoileal Bypass with SG (SADI-S) on the metabolic profile of diet-induced obese rats. A total of 35 four-week-old male Wistar rats were submitted to surgical interventions (sham operation, SG and SADI-S) after 4 months of being fed a high-fat diet. Body weight, metabolic profile and the expression of molecules involved in the control of subcutaneous white (SCWAT), brown (BAT) and beige (BeAT) adipose tissue function were analyzed. SADI-S surgery was associated with significantly decreased amounts of total fat pads (p < 0.001) as well as better control of lipid and glucose metabolism compared to the SG counterparts. An improved expression of molecules involved in fat browning in SCWAT and in the control of BAT and BeAT differentiation and function was observed following SADI-S. Together, our findings provide evidence that the enhanced metabolic improvement and their continued durability after SADI-S compared to SG rely, at least in part, on the improvement of the BeAT phenotype and function.
Atomic Scale Optimization Strategy of Al-Based Layered Double Hydroxide for Alkali Stability and Supercapacitors
Authors: Jing Chuan , Shu Kai , Sun Qing , Zheng Jiayu , Zhang Shuijie , Liu Xin , Yao Kexin , Zhou Xianju , Liu Xiaoying
Published: October 2022

The pseudocapacitor material is easily decomposed when immersed in alkaline solution for a long time. Hence, it is necessary to find a strategy to improve the alkali stability of pseudocapacitor materials. In addition, the relationship between alkali stability and electrochemical performance is still unclear. In this work, a series of Al-based LDH (Layered double hydroxide) and derived Ni/Co-based sulfides are prepared, and corresponding alkali stability and electrochemical performance are analyzed. The alkali stability of CoAl LDH is so poor and can be improved effectively by doping of Ni. Ni1Co2S4 and Ni2Co1Al LDH exhibit an outstanding alkali stability, and Ni2Co1S4 exhibits an extremely poor alkali stability. The variable valence state of Co element and the solubility of Al in alkali solution are the fundamental reasons for the poor alkali stability of CoAl LDH and Ni2Co1S4. Ni2Co1S4 showed an outstanding electrochemical performance in a three-electrode system, which is better than that of Ni1Co2S4, indicating that there is no direct correlation between alkali stability and electrochemical properties. Sulfidation improved the electrical conductivity and electrochemical activity of electrode materials, whereas alkali etching suppressed the occurrence of the electrochemical reaction. Overall, this work provides a clear perspective to understand the relationship between alkali stability and electrochemical properties.
Prolonged Exposure to High Temperature Inhibits Shoot Primary and Root Secondary Growth in Panax ginseng
Authors: Hong Jeongeui , Geem Kyoung Rok , Kim Jaewook , Jo Ick-Hyun , Yang Tae-Jin , Shim Donghwan , Ryu Hojin
Published: October 2022

High temperature is one of the most significant abiotic stresses reducing crop yield and quality by inhibiting plant growth and development. Global warming has recently increased the frequency of heat waves, which negatively impacts agricultural fields. Despite numerous studies on heat stress responses and signal transduction in model plant species, the molecular mechanism underlying thermomorphogenesis in Panax ginseng remains largely unknown. Here, we investigated the high temperature response of ginseng at the phenotypic and molecular levels. Both the primary shoot growth and secondary root growth of ginseng plants were significantly reduced at high temperature. Histological analysis revealed that these decreases in shoot and root growth were caused by decreases in cell elongation and cambium stem cell activity, respectively. Analysis of P. ginseng RNA-seq data revealed that heat-stress-repressed stem and root growth is closely related to changes in photosynthesis, cell wall organization, cell wall loosening, and abscisic acid (ABA) and jasmonic acid (JA) signaling. Reduction in both the light and dark reactions of photosynthesis resulted in defects in starch granule development in the storage parenchymal cells of the main tap root. Thus, by combining bioinformatics and histological analyses, we show that high temperature signaling pathways are integrated with crucial biological processes that repress stem and root growth in ginseng, providing novel insight into the heat stress response mechanism of P. ginseng.
Study of Biological Activities and ADMET-Related Properties of Salicylanilide-Based Peptidomimetics
Authors: Pindjakova Dominika , Pilarova Eliska , Pauk Karel , Michnova Hana , Hosek Jan , Magar Pratibha , Cizek Alois , Imramovsky Ales , Jampilek Josef
Published: October 2022

A series of eleven benzylated intermediates and eleven target compounds derived from salicylanilide were tested against Staphylococcus aureus ATCC 29213 and Enterococcus faecalis ATCC 29212 as reference strains and against three clinical isolates of methicillin-resistant S. aureus (MRSA) and three isolates of vancomycin-resistant E. faecalis. In addition, the compounds were evaluated against Mycobacterium tuberculosis H37Ra and M. smegmatis ATCC 700084. The in vitro cytotoxicity of the compounds was assessed using the human monocytic leukemia cell line THP-1. The lipophilicity of the prepared compounds was experimentally determined and correlated with biological activity. The benzylated intermediates were found to be completely biologically inactive. Of the final eleven compounds, according to the number of amide groups in the molecule, eight are diamides, and three are triamides that were inactive. 5-Chloro-2-hydroxy-N-[(2S)- 4-(methylsulfanyl)-1-oxo-1-{[4-(trifluoromethyl)phenyl]amino}butan-2-yl]benzamide (3e) and 5-chloro-2-hydroxy-N-[(2S)-(4-methyl-1-oxo-1-{[4-(trifluoromethyl)phenyl]amino)pentan-2-yl)benzamide (3f) showed the broadest spectrum of activity against all tested species/isolates comparable to the used standards (ampicillin and isoniazid). Six diamides showed high antistaphylococcal activity with MICs ranging from 0.070 to 8.95 μM. Three diamides showed anti-enterococcal activity with MICs ranging from 4.66 to 35.8 μM, and the activities of 3f and 3e against M. tuberculosis and M. smegmatis were MICs of 18.7 and 35.8 μM, respectively. All the active compounds were microbicidal. It was observed that the connecting linker between the chlorsalicylic and 4-CF3-anilide cores must be substituted with a bulky and/or lipophilic chain such as isopropyl, isobutyl, or thiabutyl chain. Anticancer activity on THP-1 cells IC50 ranged from 1.4 to >10 µM and increased with increasing lipophilicity.
Insights into the Metabolic Response of Lactiplantibacillus plantarum CCFM1287 upon Patulin Exposure
Authors: Wei Chaozhi , Zhang Chuan , Gao Yuhang , Yu Leilei , Zhao Jianxin , Zhang Hao , Chen Wei , Tian Fengwei
Published: October 2022

Patulin (PAT) is a common mycotoxin in the food industry, and is found in apple products in particular. Consumption of food or feed contaminated with PAT can cause acute or chronic toxicity in humans and animals. Lactiplantibacillus plantarum CCFM1287 is a probiotic strain that effectively degrades PAT in PBS and food systems. In this study, it was found that the concentration of PAT (50 mg/L) in MRS medium decreased by 85.09% during the first stages of CCFM1287 growth, and this change was consistent with the first-order degradation kinetic model. Meanwhile, the regulation of oxidative stress by L. plantarum CCFM1287 in response to PAT exposure and metabolic changes that occur during PAT degradation were investigated. The degree of intracellular damage was attenuated after 16 h of exposure compared to 8 h. Meanwhile, metabolomic data showed that 30 and 29 significantly different metabolites were screened intracellularly in the strain after 8 h and 16 h of PAT stress at 50 mg/L, respectively. The results of pathway enrichment analysis suggested that the purine metabolic pathway was significantly enriched at both 8 h and 16 h. However, as is consistent with the performance of the antioxidant system, the changes in Lactiplantibacillus diminished with increasing time of PAT exposure. Therefore, this study helps to further explain the mechanism of PAT degradation by L. plantarum CCFM1287.
Novel Biomarkers and Therapeutic Targets for Melanoma
Authors: Sabag Noa , Yakobson Alexander , Retchkiman Meir , Silberstein Eldad
Published: October 2022

Malignant melanoma is one of the most common cancers in the world. In the disease’s early stages, treatment involves surgery, in advanced stages however, treatment options were once scarce. There has been a paradigm shift in advanced melanoma treatment with the introduction of immunotherapy and targeted therapies. Understanding the molecular pathways and their pathologic counterparts helped identifying specific biomarkers that lead to the development of specific targeted therapies. In this review we briefly present some of these markers and their relevance to melanoma treatment.
Bioengineering Approaches to Fight against Orthopedic Biomaterials Related-Infections
Authors: Barros Joana , Monteiro Fernando Jorge , Ferraz Maria Pia
Published: October 2022

One of the most serious complications following the implantation of orthopedic biomaterials is the development of infection. Orthopedic implant-related infections do not only entail clinical problems and patient suffering, but also cause a burden on healthcare care systems. Additionally, the ageing of the world population, in particular in developed countries, has led to an increase in the population above 60 years. This is a significantly vulnerable population segment insofar as biomaterials use is concerned. Implanted materials are highly susceptible to bacterial and fungal colonization and the consequent infection. These microorganisms are often opportunistic, taking advantage of the weakening of the body defenses at the implant surface–tissue interface to attach to tissues or implant surfaces, instigating biofilm formation and subsequent development of infection. The establishment of biofilm leads to tissue destruction, systemic dissemination of the pathogen, and dysfunction of the implant/bone joint, leading to implant failure. Moreover, the contaminated implant can be a reservoir for infection of the surrounding tissue where microorganisms are protected. Therefore, the biofilm increases the pathogenesis of infection since that structure offers protection against host defenses and antimicrobial therapies. Additionally, the rapid emergence of bacterial strains resistant to antibiotics prompted the development of new alternative approaches to prevent and control implant-related infections. Several concepts and approaches have been developed to obtain biomaterials endowed with anti-infective properties. In this review, several anti-infective strategies based on biomaterial engineering are described and discussed in terms of design and fabrication, mechanisms of action, benefits, and drawbacks for preventing and treating orthopaedic biomaterials-related infections.
Receptor for Advanced Glycation End-Products Promotes Activation of Alveolar Macrophages through the NLRP3 Inflammasome/TXNIP Axis in Acute Lung Injury
Authors: Lenga Ma Bonda Woodys , Fournet Marianne , Zhai Ruoyang , Lutz Jean , Blondonnet Raiko , Bourgne Céline , Leclaire Charlotte , Saint-Béat Cécile , Theilliere Camille , Belville Corinne , Bouvier Damien , Blanchon Loïc , Berger Marc , Sapin Vincent , Jabaudon Matthieu
Published: October 2022

The roles of thioredoxin-interacting protein (TXNIP) and receptor for advanced glycation end-products (RAGE)-dependent mechanisms of NOD-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome-driven macrophage activation during acute lung injury are underinvestigated. Cultured THP-1 macrophages were treated with a RAGE agonist (S100A12), with or without a RAGE antagonist; cytokine release and intracytoplasmic production of reactive oxygen species (ROS) were assessed in response to small interfering RNA knockdowns of TXNIP and NLRP3. Lung expressions of TXNIP and NLRP3 and alveolar levels of IL-1β and S100A12 were measured in mice after acid-induced lung injury, with or without administration of RAGE inhibitors. Alveolar macrophages from patients with acute respiratory distress syndrome and from mechanically ventilated controls were analyzed using fluorescence-activated cell sorting. In vitro, RAGE promoted cytokine release and ROS production in macrophages and upregulated NLRP3 and TXNIP mRNA expression in response to S100A12. TXNIP inhibition downregulated NLRP3 gene expression and RAGE-mediated release of IL-1β by macrophages in vitro. In vivo, RAGE, NLRP3 and TXNIP lung expressions were upregulated during experimental acute lung injury, a phenomenon being reversed by RAGE inhibition. The numbers of cells expressing RAGE, NLRP3 and TXNIP among a specific subpopulation of CD16+CD14+CD206- (“pro-inflammatory”) alveolar macrophages were higher in patients with lung injury. This study provides a novel proof-of-concept of complex RAGE–TXNIP–NLRP3 interactions during macrophage activation in acute lung injury.
Hepatocyte-Derived Prostaglandin E2-Modulated Macrophage M1-Type Polarization via mTOR-NPC1 Axis-Regulated Cholesterol Transport from Lysosomes to the Endoplasmic Reticulum in Hepatitis B Virus x Protein-Related Nonalcoholic Steatohepatitis
Authors: Lan You , Qian Bo , Huang Hai-Yan , Wang Pan , Li Ting , Yuan Qi , Zhang Han-Yu , Lin Yu-Chun , Lin Zhong-Ning
Published: October 2022

Lipid metabolic dysregulation and liver inflammation have been reported to be associated with nonalcoholic steatohepatitis (NASH), but the underlying mechanisms remain unclear. Hepatitis B virus x protein (HBx) is a risk factor for NASH. Based on metabolomic and transcriptomic screens and public database analysis, we found that HBx-expressing hepatocyte-derived prostaglandin E2 (PGE2) induced macrophage polarization imbalance via prostaglandin E2 receptor 4 (EP4) through in vitro, ex vivo, and in vivo models. Here, we revealed that the M1-type polarization of macrophages induced by endoplasmic reticulum oxidoreductase-1-like protein α (ERO1α)-dependent endoplasmic reticulum stress was associated with the HBx-related hepatic NASH phenotype. Mechanistically, HBx promoted Niemann–Pick type C1 (NPC1)/oxysterol-binding protein-related protein 5 (ORP5)-mediated cholesterol transport from the lysosome to the endoplasmic reticulum via mammalian target of rapamycin (mTOR) activation. This study provides a novel basis for screening potential biomarkers in the macrophage mTOR–cholesterol homeostasis–polarization regulatory signaling pathway and evaluating targeted interventions for HBx-associated NASH.
Molecular Mechanisms Underlying Pathological and Therapeutic Roles of Pericytes in Atherosclerosis
Authors: Dabravolski Siarhei A. , Markin Alexander M. , Andreeva Elena R. , Eremin Ilya I. , Orekhov Alexander N. , Melnichenko Alexandra A.
Published: October 2022

Pericytes are multipotent mesenchymal stromal cells playing an active role in angiogenesis, vessel stabilisation, maturation, remodelling, blood flow regulation and are able to trans-differentiate into other cells of the mesenchymal lineage. In this review, we summarised recent data demonstrating that pericytes play a key role in the pathogenesis and development of atherosclerosis (AS). Pericytes are involved in lipid accumulation, inflammation, growth, and vascularization of the atherosclerotic plaque. Decreased pericyte coverage, endothelial and pericyte dysfunction is associated with intraplaque angiogenesis and haemorrhage, calcification and cholesterol clefts deposition. At the same time, pericytes can be used as a novel therapeutic target to promote vessel maturity and stability, thus reducing plaque vulnerability. Finally, we discuss recent studies exploring effective AS treatments with pericyte-mediated anti-atherosclerotic, anti-inflammatory and anti-apoptotic effects.
Oxidative Stress and DNA Damage Markers in Colorectal Cancer
Authors: Acevedo-León Delia , Monzó-Beltrán Lidia , Pérez-Sánchez Laura , Naranjo-Morillo Eva , Gómez-Abril Segundo Ángel , Estañ-Capell Nuria , Bañuls Celia , Sáez Guillermo
Published: October 2022

Oxidative stress (OS) and inflammation are known to play an important role in chronic diseases, including cancer, and specifically colorectal cancer (CRC). The main objective of this study was to explore the diagnostic potential of OS markers in patients with CRC, which may translate into an early diagnosis of the disease. To do this, we compared results with those in a group of healthy controls and assessed whether there were significant differences. In addition, we explored possible correlations with the presence of tumors and tumor stage, with anemia and with inflammatory markers used in clinical practice. The study included 80 patients with CRC and 60 healthy controls. The following OS markers were analyzed: catalase (CAT), reduced glutathione (GSH) and oxidized glutathione (GSSG) in serum; and 8-oxo-7,8-dihydro-2′-deoxyguanosine (8-oxodG) and F2-isoprotanes in urine (F2-IsoPs). Tumor markers (CEA and CA 19.9), anemia markers (hemoglobin, hematocrit and medium corpuscular volume) and inflammatory markers (leukocytes, neutrophils, N/L index, platelets, fibrinogen, C-reactive protein, CRP and IL-6) were also determined. Comparison of means between patients and controls revealed highly significant differences for all OS markers, with an increase in the prooxidant markers GSSG, GSSG/GSH ratio, 8-oxodG and F2-IsoPs, and a decrease in the antioxidant markers CAT and GSH. Tumor and inflammatory markers (except CRP) correlated positively with GSSG, GSSG/GSH ratio, 8-oxodG and F2-IsoPs, and negatively with CAT and GSH. In view of the results obtained, OS markers may constitute a useful tool for the early diagnosis of CRC patients.
Saccharomyces cerevisiae as a Model System for Eukaryotic Cell Biology, from Cell Cycle Control to DNA Damage Response
Authors: Vanderwaeren Laura , Dok Rüveyda , Voordeckers Karin , Nuyts Sandra , Verstrepen Kevin J.
Published: October 2022

The yeast Saccharomyces cerevisiae has been used for bread making and beer brewing for thousands of years. In addition, its ease of manipulation, well-annotated genome, expansive molecular toolbox, and its strong conservation of basic eukaryotic biology also make it a prime model for eukaryotic cell biology and genetics. In this review, we discuss the characteristics that made yeast such an extensively used model organism and specifically focus on the DNA damage response pathway as a prime example of how research in S. cerevisiae helped elucidate a highly conserved biological process. In addition, we also highlight differences in the DNA damage response of S. cerevisiae and humans and discuss the challenges of using S. cerevisiae as a model system.
Genome-Wide Analysis of the MYB-Related Transcription Factor Family in Pepper and Functional Studies of CaMYB37 Involvement in Capsaicin Biosynthesis
Authors: Liu Yi , Zhang Zhishuo , Fang Ke , Shan Qingyun , He Lun , Dai Xiongze , Zou Xuexiao , Liu Feng
Published: October 2022

Chili pepper is an important economic vegetable worldwide. MYB family gene members play an important role in the metabolic processes in plant growth and development. In this study, 103 pepper MYB-related members were identified and grouped into nine subfamilies according to phylogenetic relationships. Additionally, a total of 80, 20, and 37 collinear gene pairs were identified between pepper and tomato, pepper and Arabidopsis, and tomato and Arabidopsis, respectively. We performed promoter cis-element analysis and showed that CaMYB-related members may be involved in multiple biological processes such as growth and development, secondary metabolism, and circadian rhythm regulation. Expression pattern analysis indicated that CaMYB37 is significantly more enriched in fruit placenta, suggesting that this gene may be involved in capsaicin biosynthesis. Through VIGS, we confirmed that CaMYB37 is critical for the biosynthesis of capsaicin in placenta. Our subcellular localization studies revealed that CaMYB37 localized in the nucleus. On the basis of yeast one-hybrid and dual-luciferase reporter assays, we found that CaMYB37 directly binds to the promoter of capsaicin biosynthesis gene AT3 and activates its transcription, thereby regulating capsaicin biosynthesis. In summary, we systematically identified members of the CaMYB-related family, predicted their possible biological functions, and revealed that CaMYB37 is critical for the transcriptional regulation of capsaicin biosynthesis. This work provides a foundation for further studies of the CaMYB-related family in pepper growth and development.
Wheat Flour-Based Edible Films: Effect of Gluten on the Rheological Properties, Structure, and Film Characteristics
Authors: Wang Jing , Sun Xinyu , Xu Xingfeng , Sun Qingjie , Li Man , Wang Yanfei , Xie Fengwei
Published: October 2022

This work investigates the structure, rheological properties, and film performance of wheat flour hydrocolloids and their comparison with that of a wheat starch (WS)–gluten blend system. The incorporation of gluten could decrease inter-chain hydrogen bonding of starch, thereby reducing the viscosity and solid-like behavior of the film-forming solution and improving the frequency-dependence, but reducing the surface smoothness, compactness, water vapor barrier performance, and mechanical properties of the films. However, good compatibility between starch and gluten could improve the density of self-similar structure, the processability of the film-forming solution, and film performance. The films based on wheat flours showed a denser film structure, better mechanical properties, and thermal stability that was no worse than that based on WS–gluten blends. The knowledge gained from this study could provide guidance to the development of other flour-based edible packaging materials, thereby promoting energy conservation and environmental protection.
Quantitative Proteomics of Medium-Sized Extracellular Vesicle-Enriched Plasma of Lacunar Infarction for the Discovery of Prognostic Biomarkers
Authors: Datta Arnab , Chen Christopher , Gao Yong-Gui , Sze Siu Kwan
Published: October 2022

Lacunar infarction (LACI), a subtype of acute ischemic stroke, has poor mid- to long-term prognosis due to recurrent vascular events or incident dementia which is difficult to predict using existing clinical data. Herein, we aim to discover blood-based biomarkers for LACI as a complementary prognostic tool. Convalescent plasma was collected from forty-five patients following a non-disabling LACI along with seventeen matched control subjects. The patients were followed up prospectively for up to five years to record an occurrence of adverse outcome and grouped accordingly (i.e., LACI-no adverse outcome, LACI-recurrent vascular event, and LACI-cognitive decline without any recurrence of vascular events). Medium-sized extracellular vesicles (MEVs), isolated from the pooled plasma of four groups, were analyzed by stable isotope labeling and 2D-LC-MS/MS. Out of 573 (FDR < 1%) quantified proteins, 146 showed significant changes in at least one LACI group when compared to matched healthy control. A systems analysis revealed that major elements (~85%) of the MEV proteome are different from the proteome of small-sized extracellular vesicles obtained from the same pooled plasma. The altered MEV proteins in LACI patients are mostly reduced in abundance. The majority of the shortlisted MEV proteins are not linked to commonly studied biological processes such as coagulation, fibrinolysis, or inflammation. Instead, they are linked to oxygen-glucose deprivation, endo-lysosomal trafficking, glucose transport, and iron homeostasis. The dataset is provided as a web-based data resource to facilitate meta-analysis, data integration, and targeted large-scale validation.
Minicircle Delivery to the Neural Retina as a Gene Therapy Approach
Authors: Staurenghi Federica , McClements Michelle E. , Salman Ahmed , MacLaren Robert E.
Published: October 2022

Non-viral gene therapy has the potential to overcome several shortcomings in viral vector-based therapeutics. Methods of in vivo plasmid delivery have developed over recent years to increase the efficiency of non-viral gene transfer, yet further improvements still need to be made to improve their translational capacity. Gene therapy advances for inherited retinal disease have been particularly prominent over the recent decade but overcoming physical and physiological barriers present in the eye remains a key obstacle in the field of non-viral ocular drug delivery. Minicircles are circular double-stranded DNA vectors that contain expression cassettes devoid of bacterial DNA, thereby limiting the risks of innate immune responses induced by such elements. To date, they have not been extensively used in pre-clinical studies yet remain a viable vector option for the treatment of inherited retinal disease. Here, we explore the potential of minicircle DNA delivery to the neural retina as a gene therapy approach. We consider the advantages of minicircles as gene therapy vectors as well as review the challenges involved in optimising their delivery to the neural retina.
3β-Corner Stability by Comparative Molecular Dynamics Simulations
Authors: Rudnev Vladimir R. , Nikolsky Kirill S. , Petrovsky Denis V. , Kulikova Liudmila I. , Kargatov Anton M. , Malsagova Kristina A. , Stepanov Alexander A. , Kopylov Arthur T. , Kaysheva Anna L. , Efimov Alexander V.
Published: October 2022

This study explored the mechanisms by which the stability of super-secondary structures of the 3β-corner type autonomously outside the protein globule are maintained in an aqueous environment. A molecular dynamic (MD) study determined the behavioral diversity of a large set of non-homologous 3β-corner structures of various origins. We focused on geometric parameters such as change in gyration radius, solvent-accessible area, major conformer lifetime and torsion angles, and the number of hydrogen bonds. Ultimately, a set of 3β-corners from 330 structures was characterized by a root mean square deviation (RMSD) of less than 5 Å, a change in the gyration radius of no more than 5%, and the preservation of amino acid residues positioned within the allowed regions on the Ramachandran map. The studied structures retained their topologies throughout the MD experiments. Thus, the 3β-corner structure was found to be rather stable per se in a water environment, i.e., without the rest of a protein molecule, and can act as the nucleus or “ready-made” building block in protein folding. The 3β-corner can also be considered as an independent object for study in field of structural biology.
Diversity of Extracellular Vesicles in Human Follicular Fluid: Morphological Analysis and Quantification
Authors: Neyroud Anne-Sophie , Chiechio Regina Maria , Moulin Gregory , Ducarre Solène , Heichette Claire , Dupont Aurélien , Budzynski Mathieu , Even-Hernandez Pascale , Faro Maria Jose Lo , Yefimova Marina , Marchi Valérie , Ravel Célia
Published: October 2022

The oocyte microenvironment constituted by the follicular fluid (FF) is a key for the optimal development of female gametes. Its composition reflects the physiological state of the ovarian follicle. The particularity of FF is to contain a huge diversity of extracellular vesicles specific to women, in the same way as seminal plasma in men. Here, we described and compared morphological aspects of broad subcategories of human FF-related Extracellular Vesicles (EVs). EVs participate in physiological and pathological processes and have potential applications in diagnostics or therapeutics. EVs isolated from FF are involved in different biological functions related to follicular growth, oocyte maturation, and embryo development. However, knowledge on the morphology of FF-derived EVs is limited, mainly due to their sub-micrometer size and to intrinsic limitations in methods applied for their characterization. The aim of this study was to provide a comprehensive morphological description of EVs from FF of healthy subjects and quantification. EVs separation was realized by centrifugation, with comparison of the EV yield obtained from differential centrifugation and one-step ultracentrifugation. Cryo-Transmission Electron Microscopy was used to reveal the morphology, size, and phenotype of EVs. Dynamic Light Scattering (DLS) and Nanoparticle Tracking Analysis (NTA) were used to quantify and analyze the size distribution for each centrifugation step. We performed a comprehensive inventory of human follicular fluid EVs. We show that human FF contains a huge diversity of EVs. This study brings novel insights on EVs from normal FF and provides a reference for further studies of EVs in ovarian diseases.
bHLH010/089 Transcription Factors Control Pollen Wall Development via Specific Transcriptional and Metabolic Networks in Arabidopsis thaliana
Authors: Lai Zesen , Wang Jianzheng , Peng Shi-Qing , Chang Fang
Published: October 2022

The pollen wall is a specialized extracellular cell wall that protects male gametophytes from various environmental stresses and facilitates pollination. Here, we reported that bHLH010 and bHLH089 together are required for the development of the pollen wall by regulating their specific downstream transcriptional and metabolic networks. Both the exine and intine structures of bhlh010 bhlh089 pollen grains were severely defective. Further untargeted metabolomic and transcriptomic analyses revealed that the accumulation of pollen wall morphogenesis-related metabolites, including polysaccharides, glyceryl derivatives, and flavonols, were significantly changed, and the expression of such metabolic enzyme-encoding genes and transporter-encoding genes related to pollen wall morphogenesis was downregulated in bhlh010 bhlh089 mutants. Among these downstream target genes, CSLB03 is a novel target with no biological function being reported yet. We found that bHLH010 interacted with the two E-box sequences at the promoter of CSLB03 and directly activated the expression of CSLB03. The cslb03 mutant alleles showed bhlh010 bhlh089–like pollen developmental defects, with most of the pollen grains exhibiting defective pollen wall structures.
TCGA Molecular Prognostic Groups of Endometrial Carcinoma: Current Knowledge and Future Perspectives
Authors: Arciuolo Damiano , Travaglino Antonio , Raffone Antonio , Raimondo Diego , Santoro Angela , Russo Daniela , Varricchio Silvia , Casadio Paolo , Inzani Frediano , Seracchioli Renato , Mollo Antonio , Mascolo Massimo , Zannoni Gian Franco
Published: October 2022

The four TCGA-based molecular prognostic groups of endometrial carcinoma (EC), i.e., POLE-mutant, mismatch repair (MMR)-deficient, p53-abnormal, and “no specific molecular profile” (NSMP), have recently been integrated into ESGO-ESTRO-ESP guidelines. The POLE-mutant and MMR-deficient groups are associated with high mutational load, morphological heterogeneity, and inflammatory infiltration. These groups are frequent in high-grade endometrioid, undifferentiated/dedifferentiated, and mixed histotypes. POLE-mutant ECs show good prognosis and do not require adjuvant treatment, although the management of cases at stage >II is still undefined. MMR-deficient ECs show intermediate prognosis and are currently substratified based on clinicopathological variables, some of which might not have prognostic value. These groups may benefit from immunotherapy. P53-mutant ECs are typically high-grade and often morphologically ambiguous, accounting for virtually all serous ECs, most carcinosarcomas and mixed ECs, and half of clear-cell ECs. They show poor prognosis and are treated with chemoradiotherapy; a subset may benefit from HER2 inhibitors or PARP inhibitors. The NSMP group is the most frequent TCGA group; its prognosis is highly variable and affected by clinicopathological/molecular factors, most of which are still under evaluation. In conclusion, the TCGA classification has improved diagnosis, risk stratification, and management of EC. Further studies are needed to resolve the points of uncertainty that still exist.
Mechanisms Underlining Inflammatory Pain Sensitivity in Mice Selected for High and Low Stress-Induced Analgesia—The Role of Endocannabinoids and Microglia
Authors: Poznanski Piotr , Giebultowicz Joanna , Durdzinska Justyna , Kocki Tomasz , Sacharczuk Mariusz , Bujalska-Zadrozny Magdalena , Lesniak Anna
Published: October 2022

In this work we strived to determine whether endocannabinoid system activity could account for the differences in acute inflammatory pain sensitivity in mouse lines selected for high (HA) and low (LA) swim-stress-induced analgesia (SSIA). Mice received intraplantar injections of 5% formalin and the intensity of nocifensive behaviours was scored. To assess the contribution of the endocannabinoid system, mice were intraperitoneally (i.p.) injected with rimonabant (0.3–3 mg/kg) prior to formalin. Minocycline (45 and 100 mg/kg, i.p.) was administered to investigate microglial activation. The possible involvement of the endogenous opioid system was investigated with naloxone (1 mg/kg, i.p.). Cannabinoid receptor types 1 and 2 (Cnr1, Cnr2) and opioid receptor subtype (Oprm1, Oprd1, Oprk1) mRNA levels were quantified by qPCR in the structures of the central nociceptive circuit. Levels of anandamide (AEA) and 2-arachidonoylglycerol (2-AG) were measured by liquid chromatography coupled with the mass spectrometry method (LC-MS/MS). In the interphase, higher pain thresholds in the HA mice correlated with increased spinal anandamide and 2-AG release and higher Cnr1 transcription. Downregulation of Oprd1 and Oprm1 mRNA was noted in HA and LA mice, respectively, however no differences in naloxone sensitivity were observed in either line. As opposed to the LA mice, inflammatory pain sensitivity in the HA mice in the tonic phase was attributed to enhanced microglial activation, as evidenced by enhanced Aif1 and Il-1β mRNA levels. To conclude, Cnr1 inhibitory signaling is one mechanism responsible for decreased pain sensitivity in HA mice in the interphase, while increased microglial activation corresponds to decreased pain thresholds in the tonic inflammatory phase.
An Insight into Molecular Targets of Breast Cancer Brain Metastasis
Authors: Kaleem Mohammed , Dalhat Mahmood Hassan , Azmi Lubna , Asar Turky Omar , Ahmad Wasim , Alghanmi Maimonah , Almostadi Amal , Zughaibi Torki A. , Tabrez Shams
Published: October 2022

Brain metastasis is one of the major reasons of death in breast cancer (BC) patients, significantly affecting the quality of life, physical activity, and interdependence on several individuals. There is no clear evidence in scientific literature that depicts an exact mechanism relating to brain metastasis in BC patients. The tendency to develop breast cancer brain metastases (BCBMs) differs by the BC subtype, varying from almost half with triple-negative breast cancer (TNBC) (HER2− ER− PR−), one-third with HER2+ (human epidermal growth factor receptor 2-positive, and around one-tenth with luminal subclass (ER+ (estrogen positive) or PR+ (progesterone positive)) breast cancer. This review focuses on the molecular pathways as possible therapeutic targets of BCBMs and their potent drugs under different stages of clinical trial. In view of increased numbers of clinical trials and systemic studies, the scientific community is hopeful of unraveling the underlying mechanisms of BCBMs that will help in designing an effective treatment regimen with multiple molecular targets.
Impact of Acetate versus Citrate Dialysates on Intermediary Metabolism—A Targeted Metabolomics Approach
Authors: Broseta José Jesús , Roca Marta , Rodríguez-Espinosa Diana , López-Romero Luis Carlos , Gómez-Bori Aina , Cuadrado-Payán Elena , Devesa-Such Ramón , Soldevila Amparo , Bea-Granell Sergio , Sánchez-Pérez Pilar , Hernández-Jaras Julio
Published: October 2022

Acetate is widely used as a dialysate buffer to avoid the precipitation of bicarbonate salts. However, even at low concentrations that wouldn’t surpass the metabolic capacity of the Krebs tricarboxylic acid (TCA) cycle, other metabolic routes are activated, leading to undesirable clinical consequences by poorly understood mechanisms. This study aims to add information that could biologically explain the clinical improvements found in patients using citrate dialysate. A unicentric, cross-over, prospective targeted metabolomics study was designed to analyze the differences between two dialysates, one containing 4 mmol/L of acetate (AD) and the other 1 mmol/L of citrate (CD). Fifteen metabolites were studied to investigate changes induced in the TCA cycle, glycolysis, anaerobic metabolism, ketone bodies, and triglyceride and aminoacidic metabolism. Twenty-one patients completed the study. Citrate increased during the dialysis sessions when CD was used, without surpassing normal values. Other differences found in the next TCA cycle steps showed an increased substrate accumulation when using AD. While lactate decreased, pyruvate remained stable, and ketogenesis was boosted during dialysis. Acetylcarnitine and myo-inositol were reduced during dialysis, while glycerol remained constant. Lastly, glutamate and glutarate decreased due to the inhibition of amino acidic degradation. This study raises new hypotheses that need further investigation to understand better the biochemical processes that dialysis and the different dialysate buffers induce in the patient’s metabolism.