bluuebunny/crossref_metadata_2025 huggingface dataset:
Iron Accumulation and Changes in Cellular Organelles in WDR45 Mutant Fibroblasts
Authors: Lee Hye Eun , Jung Min Kyo , Noh Seul Gi , Choi Hye Bin , Chae Se hyun , Lee Jae Hyeok , Mun Ji Young
Published: October 2021

Iron overload in the brain, defined as excess stores of iron, is known to be associated with neurological disorders. In neurodegeneration accompanied by brain iron accumulation, we reported a specific point mutation, c.974-1G>A in WD Repeat Domain 45 (WDR45), showing iron accumulation in the brain, and autophagy defects in the fibroblasts. In this study, we investigated whether fibroblasts with mutated WDR45 accumulated iron, and other effects on cellular organelles. We first identified the main location of iron accumulation in the mutant fibroblasts and then investigated the effects of this accumulation on cellular organelles, including lipid droplets, mitochondria and lysosomes. Ultrastructure analysis using transmission electron microscopy (TEM) and confocal microscopy showed structural changes in the organelles. Increased numbers of lipid droplets, fragmented mitochondria and increased numbers of lysosomal vesicles with functional disorder due to WDR45 deficiency were observed. Based on correlative light and electron microscopy (CLEM) findings, most of the iron accumulation was noted in the lysosomal vesicles. These changes were associated with defects in autophagy and defective protein and organelle turnover. Gene expression profiling analysis also showed remarkable changes in lipid metabolism, mitochondrial function, and autophagy-related genes. These data suggested that functional and structural changes resulted in impaired lipid metabolism, mitochondrial disorder, and unbalanced autophagy fluxes, caused by iron overload.
A Multi-Perspective Proximity View on the Dynamic Head Region of the Ribosomal 40S Subunit
Authors: Schmitt Kerstin , Kraft Alina-Andrea , Valerius Oliver
Published: October 2021

A comparison of overlapping proximity captures at the head region of the ribosomal 40S subunit (hr40S) in Saccharomyces cerevisiae from four adjacent perspectives, namely Asc1/RACK1, Rps2/uS5, Rps3/uS3, and Rps20/uS10, corroborates dynamic co-localization of proteins that control activity and fate of both ribosomes and mRNA. Co-locating factors that associate with the hr40S are involved in (i) (de)ubiquitination of ribosomal proteins (Hel2, Bre5-Ubp3), (ii) clamping of inactive ribosomal subunits (Stm1), (iii) mRNA surveillance and vesicular transport (Smy2, Syh1), (iv) degradation of mRNA (endo- and exonucleases Ypl199c and Xrn1, respectively), (v) autophagy (Psp2, Vps30, Ykt6), and (vi) kinase signaling (Ste20). Additionally, they must be harmonized with translation initiation factors (eIF3, cap-binding protein Cdc33, eIF2A) and mRNA-binding/ribosome-charging proteins (Scp160, Sro9). The Rps/uS-BioID perspectives revealed substantial Asc1/RACK1-dependent hr40S configuration indicating a function of the β-propeller in context-specific spatial organization of this microenvironment. Toward resolving context-specific constellations, a Split-TurboID analysis emphasized the ubiquitin-associated factors Def1 and Lsm12 as neighbors of Bre5 at hr40S. These shuttling proteins indicate a common regulatory axis for the fate of polymerizing machineries for the biosynthesis of proteins in the cytoplasm and RNA/DNA in the nucleus.
Novel Insights into the Role of the Mineralocorticoid Receptor in Human Glioblastoma
Authors: Aldaz Paula , Fernández-Celis Amaya , López-Andrés Natalia , Arozarena Imanol
Published: October 2021

The majority of glioblastoma (GBM) patients require the administration of dexamethasone (DEXA) to reduce brain inflammation. DEXA activates the glucocorticoid receptor (GR), which can consequently crosstalk with the mineralocorticoid receptor (MR). However, while GR signaling is well studied in GBM, little is known about the MR in brain tumors. We examined the implication of the MR in GBM considering its interplay with DEXA. Together with gene expression studies in patient cohorts, we used human GBM cell lines and patient-derived glioma stem cells (GSCs) to assess the impact of MR activation and inhibition on cell proliferation, response to radiotherapy, and self-renewal capacity. We show that in glioma patients, MR expression inversely correlates with tumor grade. Furthermore, low MR expression correlates with poorer survival in low grade glioma while in GBM the same applies to classical and mesenchymal subtypes, but not proneural tumors. MR activation by aldosterone suppresses the growth of some GBM cell lines and GSC self-renewal. In GBM cells, the MR antagonist spironolactone (SPI) can promote proliferation, radioprotection and cooperate with DEXA. In summary, we propose that MR signaling is anti-proliferative in GBM cells and blocks the self-renewal of GSCs. Contrary to previous evidence obtained in other cancer types, our results suggest that SPI has no compelling anti-neoplastic potential in GBM.
Immortalizing Cells for Human Consumption
Authors: Soice Emily , Johnston Jeremiah
Published: October 2021

The need to produce immortal, food-relevant cell lines is one of the most pressing challenges of cellular agriculture, the field which seeks to produce meat and other animal products via tissue engineering and synthetic biology. Immortal cell lines have a long and complicated story, from the first recognized immortal human cell lines taken from Henrietta Lacks, to today, where they are used to assay toxicity and produce therapeutics, to the future, where they could be used to create meat without harming an animal. Although work in immortal cell lines began more than 50 years ago, there are few existing cell lines made of species and cell types appropriate for cultured meat. Cells in cultured meat will be eaten by consumers; therefore, cultured meat cell lines will also require unique attributes not selected for in other cell line applications. Specifically, cultured meat cell lines will need to be approved as safe for consumption as food, proliferate and differentiate efficiently at industrial scales, and have desirable taste, texture, and nutrition characteristics for consumers. This paper defines what cell lines are needed, the existing methods to produce new cell lines and their limitations, and the unique considerations of cell lines used in cultured meat.
Aberrant Upregulation of Indoleamine 2,3-Dioxygenase 1 Promotes Proliferation and Metastasis of Hepatocellular Carcinoma Cells via Coordinated Activation of AhR and β-Catenin Signaling
Authors: Chen Chih-Ta , Wu Pei-Hua , Hu Chia-Chi , Nien Hsiao-Ching , Wang Jin-Town , Sheu Jin-Chuan , Chow Lu-Ping
Published: October 2021

Hepatocellular carcinoma (HCC) is the fourth most common cause of cancer-related death worldwide. Chronic liver inflammation due to hepatitis virus infection and other major effectors is a major risk factor of HCC. Indoleamine 2,3-dioxygenase 1 (IDO1), a heme enzyme highly expressed upon stimulation with proinflammatory cytokines such as interferon-γ (IFN-γ), is activated to modulate the tumor microenvironment and potentially crucial in the development of certain cancer types. Earlier studies have majorly reported an immunomodulatory function of IDO1. However, the specific role of IDO1 in cancer cells, particularly HCC, remains to be clarified. Analysis of The Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA LIHC) dataset in the current study revealed a significant correlation between IDO1 expression and HCC. We further established inducible IDO1-expressing cell models by coupling lentivirus-mediated knockdown and IFN-γ induction of IDO1 in normal and HCC cells. In functional assays, proliferation and motility-related functions of HCC cells were compromised upon suppression of IDO1, which may partially be rescued by its enzymatic product, kynurenine (KYN), while normal hepatocytes were not affected. Aryl hydrocarbon receptor (AhR), a reported endogenous KYN receptor, is suggested to participate in tumorigenesis. In mechanistic studies, IDO1 activation promoted both AhR and β-catenin activity and nuclear translocation. Immunofluorescence staining and co-immunoprecipitation assays further disclosed interactions between AhR and β-catenin. In addition, we identified a Src-PTEN-PI3K/Akt-GSK-3β axis involved in β-catenin stabilization and activation following IDO1-mediated AhR activation. IDO1-induced AhR and β-catenin modulated the expression of proliferation- and EMT-related genes to facilitate growth and metastasis of HCC cells. Our collective findings provide a mechanistic basis for the design of more efficacious IDO1-targeted therapy for HCC.
11,12 Epoxyeicosatrienoic Acid Rescues Deteriorated Wound Healing in Diabetes
Authors: Sommer Katharina , Jakob Heike , Reiche Caroline , Henrich Dirk , Sterz Jasmina , Frank Johannes , Marzi Ingo , Sander Anna Lena
Published: October 2021

Epoxyeicosatrienoic acids (EET) facilitate regeneration in different tissues, and their benefit in dermal wound healing has been proven under normal conditions. In this study, we investigated the effect of 11,12 EET on dermal wound healing in diabetes. We induced diabetes by i.p. injection of streptozotocin 2 weeks prior to wound creation on the dorsal side of the mouse ear. 11,12 EET was applied every second day on the wound, whereas the control groups received only solvent. Epithelialization was monitored every second day intravitally up to wound closure. Wounds were stained for VEGF, CD31, TGF-β, TNF-α, SDF-1α, NF-κB, and Ki-67, and fibroblasts were counted after hematoxylin-eosin stain on days 3, 6, 9, and 16 after wounding. After induction of diabetes, wounds closed on day 13.00 ± 2.20 standard deviation (SD). Local 11,12 ETT application improved wound closure significantly to day 8.40 ± 1.39 SD. EET treatment enhanced VEGF and CD31 expression in wounds on day 3. It also seemed to raise TNF-α level on all days investigated as well as TGF-β level on days 3 and 6. A decrease in NF-κB could be observed on days 9 and 16 after EET application. The latter findings were not significant. SDF-1α expression was not influenced by EET application, and Ki-67 was significantly less in the EET group on day 9 after EET application. The number of fibroblasts was significantly increased on day 9 after the 11,12 EET application. 11,12 EET improve deteriorated wound healing in diabetes by enhancing neoangiogenesis, especially in the early phase of wound healing. Furthermore, they contribute to the dissolution of the initial inflammatory reaction, allowing the crucial transition from the inflammatory to proliferative phase in wound healing.
Programming of Embryonic Development
Authors: Dahlen Carl R. , Borowicz Pawel P. , Ward Alison K. , Caton Joel S. , Czernik Marta , Palazzese Luca , Loi Pasqualino , Reynolds Lawrence P.
Published: October 2021

Assisted reproductive techniques (ART) and parental nutritional status have profound effects on embryonic/fetal and placental development, which are probably mediated via “programming” of gene expression, as reflected by changes in their epigenetic landscape. Such epigenetic changes may underlie programming of growth, development, and function of fetal organs later in pregnancy and the offspring postnatally, and potentially lead to long-term changes in organ structure and function in the offspring as adults. This latter concept has been termed developmental origins of health and disease (DOHaD), or simply developmental programming, which has emerged as a major health issue in animals and humans because it is associated with an increased risk of non-communicable diseases in the offspring, including metabolic, behavioral, and reproductive dysfunction. In this review, we will briefly introduce the concept of developmental programming and its relationship to epigenetics. We will then discuss evidence that ART and periconceptual maternal and paternal nutrition may lead to epigenetic alterations very early in pregnancy, and how each pregnancy experiences developmental programming based on signals received by and from the dam. Lastly, we will discuss current research on strategies designed to overcome or minimize the negative consequences or, conversely, to maximize the positive aspects of developmental programming.
Gene Mapping, Cloning and Association Analysis for Salt Tolerance in Rice
Authors: Fan Xiaoru , Jiang Hongzhen , Meng Lijun , Chen Jingguang
Published: October 2021

Soil salinization caused by the accumulation of sodium can decrease rice yield and quality. Identification of rice salt tolerance genes and their molecular mechanisms could help breeders genetically improve salt tolerance. We studied QTL mapping of populations for rice salt tolerance, period and method of salt tolerance identification, salt tolerance evaluation parameters, identification of salt tolerance QTLs, and fine-mapping and map cloning of salt tolerance QTLs. We discuss our findings as they relate to other genetic studies of salt tolerance association.
Five Functional Aspects of the Epidermal Barrier
Authors: Lefèvre-Utile Alain , Braun Camille , Haftek Marek , Aubin François
Published: October 2021

The epidermis is a living, multilayered barrier with five functional levels, including a physical, a chemical, a microbial, a neuronal, and an immune level. Altogether, this complex organ contributes to protect the host from external aggression and to preserve its integrity. In this review, we focused on the different functional aspects.
The Role of Gut Dysbiosis in Acute-on-Chronic Liver Failure
Authors: Kim Sung-Eun , Park Ji Won , Kim Hyung Su , Jang Myoung-Kuk , Suk Ki Tae , Kim Dong Joon
Published: October 2021

Acute-on-chronic liver failure (ACLF) is an important syndrome of liver failure that has a high risk of short-term mortality in patients with chronic liver disease. The development of ACLF is associated with proinflammatory precipitating events, such as infection, alcoholic hepatitis, and intense systemic inflammation. Recently, the role of the gut microbiome has increasingly emerged in human health and disease. Additionally, the gut microbiome might have a major role in the development of liver disease. In this review, we examine evidence to support the role of gut dysbiosis in cirrhosis and ACLF. Additionally, we explore the mechanism by which the gut microbiome contributes to the development of ACLF, with a focus on alcohol-induced liver disease.
Novel Hybrid Peptide Cathelicidin 2 (1-13)-Thymopentin (TP5) and Its Derived Peptides with Effective Antibacterial, Antibiofilm, and Anti-Adhesion Activities
Authors: Guo He-Nan , Tong Yu-Cui , Wang Hui-Li , Zhang Jing , Li Zhong-Xuan , Abbas Zaheer , Yang Tian-Tian , Liu Meng-Yao , Chen Pei-Yao , Hua Zheng-Chang , Yan Xiao-Na , Cheng Qiang , Ahmat Marhaba , Wang Jun-Yong , Zhang Lu-Lu , Wei Xu-Biao , Liao Xiu-Dong , Zhang Ri-Jun
Published: October 2021

The increasing numbers of infections caused by multidrug-resistant (MDR) pathogens highlight the urgent need for new alternatives to conventional antibiotics. Antimicrobial peptides have the potential to be promising alternatives to antibiotics because of their effective bactericidal activity and highly selective toxicity. The present study was conducted to investigate the antibacterial, antibiofilm, and anti-adhesion activities of different CTP peptides (CTP: the original hybrid peptide cathelicidin 2 (1-13)-thymopentin (TP5); CTP-NH2: C-terminal amidated derivative of cathelicidin 2 (1-13)-TP5; CTPQ: glutamine added at the C-terminus of cathelicidin 2 (1-13)-TP5) by determining the minimal inhibitory concentrations (MICs), minimal bactericidal concentrations (MBCs), propidium iodide uptake, and analysis by scanning electron microscopy, transmission electron microscopy, and confocal laser scanning microscopy). The results showed that CTPs had broad-spectrum antibacterial activity against different gram-positive and gram-negative bacteria, with MICs against the tested strains varying from 2 to 64 μg/mL. CTPs at the MBC (2 × MIC 64 μg/mL) showed strong bactericidal effects on a standard methicillin-resistant Staphylococcus aureus strain ATCC 43300 after co-incubation for 6 h through disruption of the bacterial membrane. In addition, CTPs at 2 × MIC also displayed effective inhibition activity of several S. aureus strains with a 40–90% decrease in biofilm formation by killing the bacteria embedded in the biofilms. CTPs had low cytotoxicity on the intestinal porcine epithelial cell line (IPEC-J2) and could significantly decrease the rate of adhesion of S. aureus ATCC 43300 on IPEC-J2 cells. The current study proved that CTPs have effective antibacterial, antibiofilm, and anti-adhesion activities. Overall, this study contributes to our understanding of the possible antibacterial and antibiofilm mechanisms of CTPs, which might be an effective anti-MDR drug candidate.
Interactions in Ternary Aqueous Solutions of NMA and Osmolytes—PARAFAC Decomposition of FTIR Spectra Series
Authors: Kaczkowska Emilia , Panuszko Aneta , Bruździak Piotr
Published: October 2021

Intermolecular interactions in aqueous solutions are crucial for virtually all processes in living cells. ATR-FTIR spectroscopy is a technique that allows changes caused by many types of such interactions to be registered; however, binary solutions are sometimes difficult to solve in these terms, while ternary solutions are even more difficult. Here, we present a method of data pretreatment that facilitates the use of the Parallel Factor Analysis (PARAFAC) decomposition of ternary solution spectra into parts that are easier to analyze. Systems of the NMA–water–osmolyte-type were used to test the method and to elucidate information on the interactions between N-Methylacetamide (NMA, a simple peptide model) with stabilizing (trimethylamine N-oxide, glycine, glycine betaine) and destabilizing osmolytes (n-butylurea and tetramethylurea). Systems that contain stabilizers change their vibrational structure to a lesser extent than those with denaturants. Changes in the latter are strong and can be related to the formation of direct NMA–destabilizer interactions.
Exosomes as Intercellular Messengers in Hypertension
Authors: Arishe Olufunke Omolola , Priviero Fernanda , Wilczynski Stephanie A. , Webb R. Clinton
Published: October 2021

People living with hypertension have a higher risk of developing heart diseases, and hypertension remains a top cause of mortality. In hypertension, some detrimental changes occur in the arterial wall, which include physiological and biochemical changes. Furthermore, this disease is characterized by turbulent blood flow, increased fluid shear stress, remodeling of the blood vessels, and endothelial dysfunction. As a complex disease, hypertension is thought to be caused by an array of factors, its etiology consisting of both environmental and genetic factors. The Mosaic Theory of hypertension states that many factors, including genetics, environment, adaptive, neural, mechanical, and hormonal perturbations are intertwined, leading to increases in blood pressure. Long-term efforts by several investigators have provided invaluable insight into the physiological mechanisms responsible for the pathogenesis of hypertension, and these include increased activity of the sympathetic nervous system, overactivation of the renin–angiotensin–aldosterone system (RAAS), dysfunction of the vascular endothelium, impaired platelet function, thrombogenesis, vascular smooth muscle and cardiac hypertrophy, and altered angiogenesis. Exosomes are extracellular vesicles released by all cells and carry nucleic acids, proteins, lipids, and metabolites into the extracellular environment. They play a role in intercellular communication and are involved in the pathophysiology of diseases. Since the discovery of exosomes in the 1980s, numerous studies have been carried out to understand the biogenesis, composition, and function of exosomes. In this review, we will discuss the role of exosomes as intercellular messengers in hypertension.
Towards Understanding the Chemical Structure Modification of EVA Copolymer upon MAPLE Processing of Thin Films
Authors: Niemczyk Agata , Brajnicov Simona , Satulu Veronica , Baranowska Jolanta , Mitu Bogdana , Dinescu Maria
Published: October 2021

A series of coatings from poly(ethylene-co-vinyl acetate) (EVA) were obtained using the matrix-assisted pulsed laser evaporation (MAPLE) technique. By changing the process parameters, i.e., laser fluence and EVA co-polymer concentration in the target, coatings with various morphologies and topographies were produced. The evaluation of the film structure was based on an analysis of optical and atomic force microscopy and profilometry measurements. A detailed chemical structure investigation, conducted based on Fourier transform infrared (FTIR) and X-ray photoelectron spectroscopy (XPS) spectra, revealed that although the general structure was preserved, some alterations of ethylene (Et) and vinyl acetate (VAc) blocks took place. The most noticeable change was in the ester group that was transformed into ketone and carboxyl groups; nevertheless, some changes in the aliphatic main chain were also present. The chemical structure changes in EVA coatings took place regardless of the process parameters used. The use of chloroform as a solvent to dissolve the EVA copolymer was indicated as a possible reason of the changes as well as the tendency of EVA macromolecules to form clusters. Nevertheless, due to low level of structure alteration, it has been shown that the MAPLE technique can be successfully used to obtain coatings from polymers with more complex structures, which are soluble in a limited number of solvents.
Statin-Associated Myopathy: Emphasis on Mechanisms and Targeted Therapy
Authors: Vinci Pierandrea , Panizon Emiliano , Tosoni Letizia Maria , Cerrato Carla , Pellicori Federica , Mearelli Filippo , Biasinutto Chiara , Fiotti Nicola , Di Girolamo Filippo Giorgio , Biolo Gianni
Published: October 2021

Hyperlipidemia is a major risk factor for cardiovascular morbidity and mortality. Statins are the first-choice therapy for dyslipidemias and are considered the cornerstone of atherosclerotic cardiovascular disease (ASCVD) in both primary and secondary prevention. Despite the statin-therapy-mediated positive effects on cardiovascular events, patient compliance is often poor. Statin-associated muscle symptoms (SAMS) are the most common side effect associated with treatment discontinuation. SAMS, which range from mild-to-moderate muscle pain, weakness, or fatigue to potentially life-threatening rhabdomyolysis, are reported by 10% to 25% of patients receiving statin therapy. There are many risk factors associated with patient features and hypolipidemic agents that seem to increase the risk of developing SAMS. Due to the lack of a “gold standard”, the diagnostic test for SAMS is based on a clinical criteria score, which is independent of creatine kinase (CK) elevation. Mechanisms that underlie the pathogenesis of SAMS remain almost unclear, though a high number of risk factors may increase the probability of myotoxicity induced by statin therapy. Some of these, related to pharmacokinetic properties of statins and to concomitant therapies or patient characteristics, may affect statin bioavailability and increase vulnerability to high-dose statins.
Effect of NSAIDs Supplementation on the PACAP-, SP- and GAL-Immunoreactive Neurons in the Porcine Jejunum
Authors: Brzozowska Marta , Jana Barbara , Całka Jarosław
Published: October 2021

Side effects associated with nonsteroidal anti-inflammatory drugs (NSAIDs) treatment are a serious limitation of their use in anti-inflammatory therapy. The negative effects of taking NSAIDs include abdominal pain, indigestion nausea as well as serious complications such as bleeding and perforation. The enteric nervous system is involved in regulation of gastrointestinal functions through the release of neurotransmitters. The present study was designed to determine, for the first time, the changes in pituitary adenylate cyclase-activating polypeptide (PACAP), substance P (SP) and galanin (GAL) expression in porcine jejunum after long-term treatment with aspirin, indomethacin and naproxen. The study was performed on 16 immature pigs. The animals were randomly divided into four experimental groups: control, aspirin, indomethacin and naproxen. Control animals were given empty gelatin capsules, while animals in the test groups received selected NSAIDs for 28 days. Next, animals from each group were euthanized. Frozen sections were prepared from collected jejunum and subjected to double immunofluorescence staining. NSAIDs supplementation caused a significant increase in the population of PACAP-, SP- and GAL-containing enteric neurons in the porcine jejunum. Our results suggest the participation of the selected neurotransmitters in regulatory processes of the gastrointestinal function and may indicate the direct toxic effect of NSAIDs on the ENS neurons.
Pharmacogenetics of Drug-Resistant Epilepsy (Review of Literature)
Authors: Smolarz Beata , Makowska Marianna , Romanowicz Hanna
Published: October 2021

Pharmacogenomic studies in epilepsy are justified by the high prevalence rate of this disease and the high cost of its treatment, frequent drug resistance, different response to the drug, the possibility of using reliable methods to assess the control of seizures and side effects of antiepileptic drugs. Candidate genes encode proteins involved in pharmacokinetic processes (drug transporters, metabolizing enzymes), pharmacodynamic processes (receptors, ion channels, enzymes, regulatory proteins, secondary messengers) and drug hypersensitivity (immune factors). This article provides an overview of the literature on the influence of genetic factors on treatment in epilepsy.
Histone Modification in NSCLC: Molecular Mechanisms and Therapeutic Targets
Authors: Bajbouj Khuloud , Al-Ali Abeer , Ramakrishnan Rakhee K. , Saber-Ayad Maha , Hamid Qutayba
Published: October 2021

Lung cancer is the leading cause of cancer mortality in both genders, with non-small cell lung cancer (NSCLC) accounting for about 85% of all lung cancers. At the time of diagnosis, the tumour is usually locally advanced or metastatic, shaping a poor disease outcome. NSCLC includes adenocarcinoma, squamous cell carcinoma, and large cell lung carcinoma. Searching for novel therapeutic targets is mandated due to the modest effect of platinum-based therapy as well as the targeted therapies developed in the last decade. The latter is mainly due to the lack of mutation detection in around half of all NSCLC cases. New therapeutic modalities are also required to enhance the effect of immunotherapy in NSCLC. Identifying the molecular signature of NSCLC subtypes, including genetics and epigenetic variation, is crucial for selecting the appropriate therapy or combination of therapies. Epigenetic dysregulation has a key role in the tumourigenicity, tumour heterogeneity, and tumour resistance to conventional anti-cancer therapy. Epigenomic modulation is a potential therapeutic strategy in NSCLC that was suggested a long time ago and recently starting to attract further attention. Histone acetylation and deacetylation are the most frequently studied patterns of epigenetic modification. Several histone deacetylase (HDAC) inhibitors (HDIs), such as vorinostat and panobinostat, have shown promise in preclinical and clinical investigations on NSCLC. However, further research on HDIs in NSCLC is needed to assess their anti-tumour impact. Another modification, histone methylation, is one of the most well recognized patterns of histone modification. It can either promote or inhibit transcription at different gene loci, thus playing a rather complex role in lung cancer. Some histone methylation modifiers have demonstrated altered activities, suggesting their oncogenic or tumour-suppressive roles. In this review, patterns of histone modifications in NSCLC will be discussed, focusing on the molecular mechanisms of epigenetic modifications in tumour progression and metastasis, as well as in developing drug resistance. Then, we will explore the therapeutic targets emerging from studying the NSCLC epigenome, referring to the completed and ongoing clinical trials on those medications.
Melatonin Confers Plant Cadmium Tolerance: An Update
Authors: Gu Quan , Wang Chuyan , Xiao Qingqing , Chen Ziping , Han Yi
Published: October 2021

Cadmium (Cd) is one of the most injurious heavy metals, affecting plant growth and development. Melatonin (N-acetyl-5-methoxytryptamine) was discovered in plants in 1995, and it is since known to act as a multifunctional molecule to alleviate abiotic and biotic stresses, especially Cd stress. Endogenously triggered or exogenously applied melatonin re-establishes the redox homeostasis by the improvement of the antioxidant defense system. It can also affect the Cd transportation and sequestration by regulating the transcripts of genes related to the major metal transport system, as well as the increase in glutathione (GSH) and phytochelatins (PCs). Melatonin activates several downstream signals, such as nitric oxide (NO), hydrogen peroxide (H2O2), and salicylic acid (SA), which are required for plant Cd tolerance. Similar to the physiological functions of NO, hydrogen sulfide (H2S) is also involved in the abiotic stress-related processes in plants. Moreover, exogenous melatonin induces H2S generation in plants under salinity or heat stress. However, the involvement of H2S action in melatonin-induced Cd tolerance is still largely unknown. In this review, we summarize the progresses in various physiological and molecular mechanisms regulated by melatonin in plants under Cd stress. The complex interactions between melatonin and H2S in acquisition of Cd stress tolerance are also discussed.
PR-619, a General Inhibitor of Deubiquitylating Enzymes, Diminishes Cisplatin Resistance in Urothelial Carcinoma Cells through the Suppression of c-Myc: An In Vitro and In Vivo Study
Authors: Hsu Fu-Shun , Lin Wei-Chou , Kuo Kuan-Lin , Chiu Yen-Ling , Hsu Chen-Hsun , Liao Shih-Ming , Dong Jun-Ren , Liu Shing-Hwa , Chang Shih-Chen , Yang Shao-Ping , Chen Yueh-Tang , Chang Ruei-Je , Huang Kuo-How
Published: October 2021

Cisplatin-based chemotherapy is the standard treatment for bladder urothelial carcinoma (UC). Most patients experience chemoresistance, the primary cause of treatment failure, which leads to disease relapse. The underlying mechanism of chemoresistance involves reduced apoptosis. In this study, we investigated the antitumor effect of the deubiquitylating enzyme inhibitor PR-619 in cisplatin-resistant bladder UC. Deubiquitinase (ubiquitin-specific protease 14 (USP14) and USP21) immunohistochemical staining demonstrated that deubiquitination is related to chemoresistance in patients with metastatic UC and may be a target for overcoming chemoresistance. Cytotoxicity and apoptosis were assessed using fluorescence-activated flow cytometry and a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium assay, and PR-619 was found to enhance the cytotoxic and apoptotic effects of cisplatin in cisplatin-resistant T24/R cells. Mitigated cisplatin chemoresistance was associated with the concurrent suppression of c-Myc expression in T24/R cells. Moreover, the expression of c-Myc was upregulated in human bladder UC specimens from patients with chemoresistance. Experiments in a xenograft nude mouse model confirmed that PR-619 enhanced the antitumor effects of cisplatin. These results are promising for the development of therapeutic strategies to prevent UC chemoresistance through the combined use of chemotherapeutic agents/deubiquitination inhibitors (PR-619) by targeting the c-Myc pathway.
The Role of Oxidative Stress in Sarcoidosis
Authors: Fois Sara Solveig , Canu Sara , Fois Alessandro Giuseppe
Published: October 2021

Sarcoidosis is a rare, systemic inflammatory disease whose diagnosis and management can pose a challenge for clinicians and specialists. Scientific knowledge on the molecular pathways that drive its development is still lacking, with no standardized therapies available and insufficient strategies to predict patient outcome. In recent years, oxidative stress has been highlighted as an important factor in the pathogenesis of sarcoidosis, involving several enzymes and molecules in the mechanism of the disease. This review presents current data on the role of oxidative stress in sarcoidosis and its interaction with inflammation, as well as the application of antioxidative therapy in the disease.
Monte Carlo Simulation of Double-Strand Break Induction and Conversion after Ultrasoft X-rays Irradiation
Authors: Hsiao Ya-Yun , Chen Fang-Hsin , Chan Chun-Chieh , Tsai Ching-Chih
Published: October 2021

This paper estimates the yields of DNA double-strand breaks (DSBs) induced by ultrasoft X-rays and uses the DSB yields and the repair outcomes to evaluate the relative biological effectiveness (RBE) of ultrasoft X-rays. We simulated the yields of DSB induction and predicted them in the presence and absence of oxygen, using a Monte Carlo damage simulation (MCDS) software, to calculate the RBE. Monte Carlo excision repair (MCER) simulations were also performed to calculate the repair outcomes (correct repairs, mutations, and DSB conversions). Compared to 60Co γ-rays, the RBE values for ultrasoft X-rays (titanium K-shell, aluminum K-shell, copper L-shell, and carbon K-shell) for DSB induction were respectively 1.3, 1.9, 2.3, and 2.6 under aerobic conditions and 1.3, 2.1, 2.5, and 2.9 under a hypoxic condition (2% O2). The RBE values for enzymatic DSBs were 1.6, 2.1, 2.3, and 2.4, respectively, indicating that the enzymatic DSB yields are comparable to the yields of DSB induction. The synergistic effects of DSB induction and enzymatic DSB formation further facilitate cell killing and the advantage in cancer treatment.
Tryptophan: A Unique Role in the Critically Ill
Authors: Kanova Marcela , Kohout Pavel
Published: October 2021

Tryptophan is an essential amino acid whose metabolites play key roles in diverse physiological processes. Due to low reserves in the body, especially under various catabolic conditions, tryptophan deficiency manifests itself rapidly, and both the serotonin and kynurenine pathways of metabolism are clinically significant in critically ill patients. In this review, we highlight these pathways as sources of serotonin and melatonin, which then regulate neurotransmission, influence circadian rhythm, cognitive functions, and the development of delirium. Kynurenines serve important signaling functions in inter-organ communication and modulate endogenous inflammation. Increased plasma kynurenine levels and kynurenine-tryptophan ratios are early indicators for the development of sepsis. They also influence the regulation of skeletal muscle mass and thereby the development of polyneuromyopathy in critically ill patients. The modulation of tryptophan metabolism could help prevent and treat age-related disease with low grade chronic inflammation as well as post intensive care syndrome in all its varied manifestations: cognitive decline (including delirium or dementia), physical impairment (catabolism, protein breakdown, loss of muscle mass and tone), and mental impairment (depression, anxiety or post-traumatic stress disorder).
Diabetes in Humans Activates Pancreatic Stellate Cells via RAGE in Pancreatic Ductal Adenocarcinoma
Authors: Uchida Chiaki , Mizukami Hiroki , Hara Yutaro , Saito Takeshi , Umetsu Satoko , Igawa Akiko , Osonoi Sho , Kudoh Kazuhiro , Yamamoto Yasuhiko , Yamamoto Hiroshi , Yagihashi Soroku , Hakamada Kenichi
Published: October 2021

Pancreatic stellate cells (PSCs) mainly consist of cancer-associating fibroblasts in pancreatic ductal adenocarcinoma (PDAC). The receptor for advanced glycation end products (RAGE) is implicated in the pathophysiology of diabetic complications. Here, we studied the implication of RAGE in PSC activation in PDAC. The activation of cultured mouse PSCs was evaluated by qPCR. The induction of epithelial mesenchymal transition (EMT) in PDAC cell lines was assessed under stimulation with culture supernatant from activated PSCs. A total of 155 surgically resected PDAC subjects (83 nondiabetic, 18 with ≦3-years and 54 with >3-years history of diabetes) were clinicopathologically evaluated. A high-fat diet increased the expression of activated markers in cultured PSCs, which was abrogated by RAGE deletion. Culture supernatant from activated PSCs facilitated EMT of PDAC cells with elevation of TGF−β and IL−6, but not from RAGE−deleted PSCs. Diabetic subjects complicated with metabolic syndrome, divided by cluster analysis, showed higher PSC activation and RAGE expression. In such groups, PDAC cells exhibited an EMT nature. The complication of metabolic syndrome with diabetes significantly worsened disease−free survival of PDAC subjects. Thus, RAGE in PSCs can be viewed as a new promoter and a future therapeutic target of PDAC in diabetic subjects with metabolic syndrome.
Multicomponent Approach to the Synthesis of 4-(1H-indol-3-yl)-5-(4-methoxyphenyl)furan-2(5H)-one
Authors: Komogortsev Andrey N. , Lichitsky Boris V. , Melekhina Valeriya G.
Published: October 2021

A simple one-pot approach was developed for the synthesis of furan-2(5H)-one derivative containing indole fragments. This method includes the telescoped multicomponent reaction of indole, 4-methoxyphenylglyoxal, and Meldrum’s acid. The synthetic utility of the prepared furan-2(5H)-one was demonstrated by condensation with 4-methoxybenzaldehyde. The advantages of this method include the employment of readily accessible starting materials, atom economy, process simplicity, and the easy isolation of the target products. The structure of the synthesized furanones was confirmed by 1H and 13C-NMR spectroscopy and high-resolution mass spectrometry with electrospray ionization (ESI-HRMS).
Strength Parameters of Clay Brick Walls with Various Directions of Force
Authors: Nowak Rafał , Kania Tomasz , Derkach Valery , Orłowicz Romuald , Halaliuk Anton , Ekiert Ewa , Jaworski Rafał
Published: October 2021

The study analyzes the anisotropy effect for ceramic masonry based on experimental tests of samples made of 25 × 12 × 6.5 cm3 solid brick elements with compressive strength fb = 44.1 MPa and cement mortar with compressive strength fm = 10.9 MPa. The samples were loaded in a single plane with a joint angle that varied from the horizontal plane. The load was applied in a vertical direction. The samples were loaded at angles of 90°, 67.5°, 45°, 22.5°, and 0° toward the bed joints. The most unfavourable cases were determined. It was observed that the anisotropy of the masonry significantly influences the load-bearing capacity of the walls depending on the angle of the compressive stresses trajectory. Approximation curves and equations for compressive strength, Young’s modulus, and Poisson’s coefficient were proposed. It was observed that Young’s modulus and Poisson’s ratio will also change depending on the trajectory of compressive stresses as a function of the joint angle. Experimental tests allowed to determine the failure mechanism in prepared specimens. The study allowed to estimate the masonry strength with the load acting at different angles toward the bed joints.
Black Talc-Based TiO2/ZnO Composite for Enhanced UV-Vis Photocatalysis Performance
Authors: Shuai Huan , Wang Jiao , Wang Xianguang , Du Gaoxiang
Published: October 2021

Herein, using black talc as a carrier, a ternary black talc-TiO2/ZnO composite photocatalyst was prepared by the sol-gel method, and the effect of the black talc on the hetero-structure properties of the TiO2 and ZnO was systematically studied. The prepared composite photocatalyst showed an excellent degradation performance of the pollutant, where black talc plays an important role in promoting the interface interaction by enhancing the contact area between the TiO2 and ZnO. Moreover, the free carbon element doping in black talc favors the formation of more oxygen vacancies, thereby improving the response as a photocatalyst in visible light. In addition, the carbon in the black talc can also adsorb organic pollutants and enrich the surroundings of the photocatalyst with pollutants, so it further improves the catalytic efficiency of the photocatalyst. Under UV irradiation, the degradation rate of Rhodamine B on black talc-TiO2/ZnO was found 3.3 times higher than that of black talc-TiO2 with good stability.
Increasing the Efficiency of a Spintronic THz Emitter Based on WSe2/FeCo
Authors: Khusyainov Dinar , Guskov Andrey , Ovcharenko Sergei , Tiercelin Nicolas , Preobrazhensky Vladimir , Buryakov Arseniy , Sigov Alexander , Mishina Elena
Published: October 2021

We report an increase in terahertz (THz) radiation efficiency due to FeCo/WSe2 structures in the reflection geometry. This can be attributed to an absorption increase in the alloy FeCo layer at the input FeCo/WSe2 interface due to constructive interference, as well as to the backward transport of hot carriers from FeCo to WSe2. In contrast to the transmission geometry, the THz generation efficiency in the reflection is much less dependent on the magnetic layer thickness. Our results suggest a cheap and efficient way to improve the characteristics of THz spintronic emitters with the conservation of a full set of their important properties.
Clinical Evaluation of Dental Implants with a Double Acid-Etched Surface Treatment: A Cohort Observational Study with Up to 10-Year Follow-Up
Authors: Santos Marino Juan , Cortés-Bretón Brinkmann Jorge , García-Gil Ignacio , Martínez-Rodríguez Natalia , Fraile Javier Flores , Barona Dorado Cristina , Martínez-González José María
Published: October 2021

Background and objectives: The main purpose of this study was to evaluate the survival and success rates of dental implants with a double acid-etched surface treatment with evaluation times up to 10 years post-loading. Materials and Methods: This study was conducted at a hospital oral surgery and implantology unit. It included 111 dental implants with a double acid-etched surface. Three groups were created: Group 1 (1–3 years loading), Group 2 (3–5 years loading), and Group 3 (over 5 years loading). Probing depth, resonance frequency analysis (ISQ value), and marginal bone loss were evaluated. Results: The data obtained underwent statistical analysis. Overall, 78 patients were included in the study, who received, in total, 111 dental implants, all replacing single teeth. Mean probing depth was 3.03 mm and mean ISQ was 65.54. Regarding marginal bone loss, in Group 1, 67.6% of implants did not undergo any thread loss, in Group 2, 48.3%, and in Group 3, 59.6%; 59.10% of all implants did not present thread loss with a mean bone loss of 0.552 mm. The implant survival rate was 99.1%, and the success rate was 96.37%. Conclusions: Implants with a double acid-etched surface showed excellent success rates in terms of marginal bone loss, ISQ, and probing depth after up to 10 years of loading, making them a clinically predictable treatment option. Future studies are needed to compare this implant surface with other types in different restorative situations.
Feasibility Study of Cooling a Bulk Acoustic Wave Resonator by Nanoparticle Enhanced Phase Change Material
Authors: Abdollahzadeh Jamalabadi Mohammad Yaghoub
Published: October 2021

In the current study, the coupling of a cooling problem with the electromagnetic resonance of a bulk acoustic wave (BAW) material is investigated. As well, a new cooling method by the addition of nanoparticles to a phase change material surrounding the BAW resonator is presented. To solve the governing equations of piezoelectric charge and momentum balance, thermal balance, and fluid flow a code with the method of finite element is introduced. After validation of various features of the code with melting profile, heat generation, charge curve, and dispersion curve with benchmarks, the eigenfrequency analysis of the system is done. The thermal behavior of the system at first mode and various boundary conditions are studied. As well, the effect of nanoparticles in fastening the cooling of the BAW resonator is demonstrated.
Oyster-Derived Tyr-Ala (YA) Peptide Prevents Lipopolysaccharide/D-Galactosamine-Induced Acute Liver Failure by Suppressing Inflammatory, Apoptotic, Ferroptotic, and Pyroptotic Signals
Authors: Siregar Adrian S. , Nyiramana Marie Merci , Kim Eun-Jin , Cho Soo Buem , Woo Min Seok , Lee Dong Kun , Hong Seong-Geun , Han Jaehee , Kang Sang Soo , Kim Deok Ryong , Choi Yeung Joon , Kang Dawon
Published: October 2021

Models created by the intraperitoneal injection of lipopolysaccharide (LPS) and D-galactosamine (D-GalN) have been widely used to study the pathogenesis of human acute liver failure (ALF) and drug development. Our previous study reported that oyster (Crassostrea gigas) hydrolysate (OH) had a hepatoprotective effect in LPS/D-GalN-injected mice. This study was performed to identify the hepatoprotective effect of the tyrosine-alanine (YA) peptide, the main component of OH, in a LPS/D-GalN-injected ALF mice model. We analyzed the effect of YA on previously known mechanisms of hepatocellular injury in the model. LPS/D-GalN-injected mice showed inflammatory, apoptotic, ferroptotic, and pyroptotic liver injury. The pre-administration of YA (10 mg/kg or 50 mg/kg) significantly reduced the liver damage factors. The hepatoprotective effect of YA was higher in the 50 mg/kg YA pre-administered group than in the 10 mg/kg YA pre-administered group. These results showed that YA had a hepatoprotective effect by reducing inflammation, apoptosis, ferroptosis, and pyroptosis in the LPS/D-GalN-injected ALF mouse model. We suggest that YA can be used as a functional peptide for the prevention of acute liver injury.
Enhanced HIFU Theranostics with Dual-Frequency-Ring Focused Ultrasound and Activatable Perfluoropentane-Loaded Polymer Nanoparticles
Authors: Chen Junjie , Nan Zhezhu , Zhao Yubo , Zhang Lei , Zhu Hongrui , Wu Daocheng , Zong Yujin , Lu Mingzhu , Ilovitsh Tali , Wan Mingxi , Yan Kai , Feng Yi
Published: October 2021

High-intensity focused ultrasound (HIFU) has been widely used in tumor ablation in clinical settings. Meanwhile, there is great potential to increase the therapeutic efficiency of temporary cavitation due to enhanced thermal effects and combined mechanical effects from nonlinear vibration and collapse of the microbubbles. In this study, dual-frequency (1.1 and 5 MHz) HIFU was used to produce acoustic droplet vaporization (ADV) microbubbles from activatable perfluoropentane-loaded polymer nanoparticles (PFP@Polymer NPs), which increased the therapeutic outcome of the HIFU and helped realize tumor theranostics with ultrasound contrast imaging. Combined with PFP@Polymer NPs, dual-frequency HIFU changed the shape of the damage lesion and reduced the acoustic intensity threshold of thermal damage significantly, from 216.86 to 62.38 W/cm2. It produced a nearly 20 °C temperature increase in half the irradiation time and exhibited a higher tumor inhibition rate (84.5% ± 3.4%) at a low acoustic intensity (1.1 MHz: 23.77 W/cm2; 5 MHz: 0.35 W/cm2) in vitro than the single-frequency HIFU (60.2% ± 11.9%). Moreover, compared with the traditional PFP@BSA NDs, PFP@Polymer NPs showed higher anti-tumor efficacy (81.13% vs. 69.34%; * p < 0.05) and better contrast-enhanced ultrasound (CEUS) imaging ability (gray value of 57.53 vs. 30.67; **** p < 0.0001), probably benefitting from its uniform and stable structure. It showed potential as a highly efficient tumor theranostics approach based on dual-frequency HIFU and activatable PFP@Polymer NPs.