bluuebunny/crossref_metadata_2025 huggingface dataset:
Modeling the Research Landscapes of Artificial Intelligence Applications in Diabetes (GAPRESEARCH)
Authors: Vu Giang Thu , Tran Bach Xuan , McIntyre Roger S. , Pham Hai Quang , Phan Hai Thanh , Ha Giang Hai , Gwee Kenneth K. , Latkin Carl A. , Ho Roger C.M. , Ho Cyrus S.H.
Published: March 2020

The rising prevalence and global burden of diabetes fortify the need for more comprehensive and effective management to prevent, monitor, and treat diabetes and its complications. Applying artificial intelligence in complimenting the diagnosis, management, and prediction of the diabetes trajectory has been increasingly common over the years. This study aims to illustrate an inclusive landscape of application of artificial intelligence in diabetes through a bibliographic analysis and offers future direction for research. Bibliometrics analysis was combined with exploratory factor analysis and latent Dirichlet allocation to uncover emergent research domains and topics related to artificial intelligence and diabetes. Data were extracted from the Web of Science Core Collection database. The results showed a rising trend in the number of papers and citations concerning AI applications in diabetes, especially since 2010. The nucleus driving the research and development of AI in diabetes is centered around developed countries, mainly consisting of the United States, which contributed 44.1% of the publications. Our analyses uncovered the top five emerging research domains to be: (i) use of artificial intelligence in diagnosis of diabetes, (ii) risk assessment of diabetes and its complications, (iii) role of artificial intelligence in novel treatments and monitoring in diabetes, (iv) application of telehealth and wearable technology in the daily management of diabetes, and (v) robotic surgical outcomes with diabetes as a comorbid. Despite the benefits of artificial intelligence, challenges with system accuracy, validity, and confidentiality breach will need to be tackled before being widely applied for patients’ benefits.
Effects of Exercise on Biomarkers in Health and Disease: Some New Insights with Special Focus on Extreme Exercise and Healthy Ageing
Authors: Reis Victor Machado
Published: March 2020

Health conditions associated with sedentary lifestyles continue to grow [...]
Recent Trends and Future Direction of Dental Research in the Digital Era
Authors: Joda Tim , Bornstein Michael M. , Jung Ronald E. , Ferrari Marco , Waltimo Tuomas , Zitzmann Nicola U.
Published: March 2020

The digital transformation in dental medicine, based on electronic health data information, is recognized as one of the major game-changers of the 21st century to tackle present and upcoming challenges in dental and oral healthcare. This opinion letter focuses on the estimated top five trends and innovations of this new digital era, with potential to decisively influence the direction of dental research: (1) rapid prototyping (RP), (2) augmented and virtual reality (AR/VR), (3) artificial intelligence (AI) and machine learning (ML), (4) personalized (dental) medicine, and (5) tele-healthcare. Digital dentistry requires managing expectations pragmatically and ensuring transparency for all stakeholders: patients, healthcare providers, university and research institutions, the medtech industry, insurance, public media, and state policy. It should not be claimed or implied that digital smart data technologies will replace humans providing dental expertise and the capacity for patient empathy. The dental team that controls digital applications remains the key and will continue to play the central role in treating patients. In this context, the latest trend word is created: augmented intelligence, e.g., the meaningful combination of digital applications paired with human qualities and abilities in order to achieve improved dental and oral healthcare, ensuring quality of life.
Information Fusion for Cultural Heritage Three-Dimensional Modeling of Malay Cities
Authors: Mohd Noor Norzailawati , Ibrahim Illyani , Abdullah Alias , Abdullah Ahmad Afiq Aiman
Published: March 2020

Malaysia’s heritage structures are facing challenges due to rapid local development and societal challenges that threaten their cultural and artistic values. Improving conservation approaches in this context is an urgent and crucial task. The application of geo-information technologies in laser scanning, photogrammetry, and geographic information systems (GISs) has significantly improved these conservation approaches. In this study, we fused drone images and range data from a laser scanner to construct a high-resolution three-dimensional GIS city model for one traditional Malay settlement located in Malaysia. The results showed that fusing photogrammetry and laser scanning can effectively capture the architectural uniqueness of Malay buildings, including specific façade geometries on walls, roofs, and motifs. The findings show that the development of various geoinformation approaches can assist with the conservation of Malay city heritage in this region.
Real-Time 3D Imaging and Inhibition Analysis of Various Amyloid Aggregations Using Quantum Dots
Authors: Lin Xuguang , Galaqin Nuomin , Tainaka Reina , Shimamori Keiya , Kuragano Masahiro , Noguchi Taro Q. P. , Tokuraku Kiyotaka
Published: March 2020

Amyloidosis refers to aggregates of protein that accumulate and are deposited as amyloid fibrils into plaques. When these are detected in organs, they are the main hallmark of Alzheimer’s disease, Parkinson’s disease, and other related diseases. Recent medical advances have shown that many precursors and proteins can induce amyloidosis even though the mechanism of amyloid aggregation and the relationship of these proteins to amyloidosis remains mostly unclear. In this study, we report the real-time 3D-imaging and inhibition analysis of amyloid β (Aβ), tau, and α-synuclein aggregation utilizing the affinity between quantum dots (QD) and amyloid aggregates. We successfully visualized these amyloid aggregations in real-time using fluorescence microscopy and confocal microscopy simply by adding commercially available QD. The observation by transmission electron microscopy (TEM) showed that QD particles bound to all amyloid fibrils. The 3D-imaging with QD revealed differences between amyloid aggregates composed of different amyloid peptides that could not be detected by TEM. We were also able to quantify the inhibition activities of these proteins by rosmarinic acid, which has high activity for Aβ aggregation, from fluorescence micrographs as half-maximal effective concentrations. These imaging techniques with QD serve as quick, easy, and powerful tools to understand amyloidosis and to discover drugs for therapies.
Antimicrobial and Physicochemical Properties of Artificial Saliva Formulations Supplemented with Core-Shell Magnetic Nanoparticles
Authors: Niemirowicz-Laskowska Katarzyna , Mystkowska Joanna , Łysik Dawid , Chmielewska Sylwia , Tokajuk Grażyna , Misztalewska-Turkowicz Iwona , Wilczewska Agnieszka Z. , Bucki Robert
Published: March 2020

Saliva plays a crucial role in oral cavity. In addition to its buffering and moisturizing properties, saliva fulfills many biofunctional requirements, including antibacterial activity that is essential to assure proper oral microbiota growth. Due to numerous extra- and intra-systemic factors, there are many disorders of its secretion, leading to oral dryness. Saliva substitutes used in such situations must meet many demands. This study was design to evaluate the effect of core-shell magnetic nanoparticles (MNPs) adding (gold-coated and aminosilane-coated nanoparticles NPs) on antimicrobial (microorganism adhesion, biofilm formation), rheological (viscosity, viscoelasticity) and physicochemical (pH, surface tension, conductivity) properties of three commercially available saliva formulations. Upon the addition of NPs (20 µg/mL), antibacterial activity of artificial saliva was found to increase against tested microorganisms by 20% to 50%. NPs, especially gold-coated ones, decrease the adhesion of Gram-positive and fungal cells by 65% and Gram-negative bacteria cells by 45%. Moreover, the addition of NPs strengthened the antimicrobial properties of tested artificial saliva, without influencing their rheological and physicochemical properties, which stay within the range characterizing the natural saliva collected from healthy subjects.
Candida albicans Shields the Periodontal Killer Porphyromonas gingivalis from Recognition by the Host Immune System and Supports the Bacterial Infection of Gingival Tissue
Authors: Bartnicka Dominika , Gonzalez-Gonzalez Miriam , Sykut Joanna , Koziel Joanna , Ciaston Izabela , Adamowicz Karina , Bras Grazyna , Zawrotniak Marcin , Karkowska-Kuleta Justyna , Satala Dorota , Kozik Andrzej , Zyla Edyta , Gawron Katarzyna , Lazarz-Bartyzel Katarzyna , Chomyszyn-Gajewska Maria , Rapala-Kozik Maria
Published: March 2020

Candida albicans is a pathogenic fungus capable of switching its morphology between yeast-like cells and filamentous hyphae and can associate with bacteria to form mixed biofilms resistant to antibiotics. In these structures, the fungal milieu can play a protective function for bacteria as has recently been reported for C. albicans and a periodontal pathogen—Porphyromonas gingivalis. Our current study aimed to determine how this type of mutual microbe protection within the mixed biofilm affects the contacting host cells. To analyze C. albicans and P. gingivalis persistence and host infection, several models for host–biofilm interactions were developed, including microbial exposure to a representative monocyte cell line (THP1) and gingival fibroblasts isolated from periodontitis patients. For in vivo experiments, a mouse subcutaneous chamber model was utilized. The persistence of P. gingivalis cells was observed within mixed biofilm with C. albicans. This microbial co-existence influenced host immunity by attenuating macrophage and fibroblast responses. Cytokine and chemokine production decreased compared to pure bacterial infection. The fibroblasts isolated from patients with severe periodontitis were less susceptible to fungal colonization, indicating a modulation of the host environment by the dominating bacterial infection. The results obtained for the mouse model in which a sequential infection was initiated by the fungus showed that this host colonization induced a milder inflammation, leading to a significant reduction in mouse mortality. Moreover, high bacterial counts in animal organisms were noted on a longer time scale in the presence of C. albicans, suggesting the chronic nature of the dual-species infection.
Potential Role of Venular Amyloid in Alzheimer’s Disease Pathogenesis
Authors: Morrone Christopher D. , Bishay Jossana , McLaurin JoAnne
Published: March 2020

Insurmountable evidence has demonstrated a strong association between Alzheimer’s disease (AD) and cerebral amyloid angiopathy (CAA), along with various other cerebrovascular diseases. One form of CAA, which is the accumulation of amyloid-beta peptides (Aβ) along cerebral vessel walls, impairs perivascular drainage pathways and contributes to cerebrovascular dysfunction in AD. To date, CAA research has been primarily focused on arterial Aβ, while the accumulation of Aβ in veins and venules were to a lesser extent. In this review, we describe preclinical models and clinical studies supporting the presence of venular amyloid and potential downstream pathological mechanisms that affect the cerebrovasculature in AD. Venous collagenosis, impaired cerebrovascular pulsatility, and enlarged perivascular spaces are exacerbated by venular amyloid and increase Aβ deposition, potentially through impaired perivascular clearance. Gaining a comprehensive understanding of the mechanisms involved in venular Aβ deposition and associated pathologies will give insight to how CAA contributes to AD and its association with AD-related cerebrovascular disease. Lastly, we suggest that special consideration should be made to develop Aβ-targeted therapeutics that remove vascular amyloid and address cerebrovascular dysfunction in AD.
Biochemical Markers in Alzheimer’s Disease
Authors: Rabbito Alessandro , Dulewicz Maciej , Kulczyńska-Przybik Agnieszka , Mroczko Barbara
Published: March 2020

Alzheimer’s disease (AD) is one of the most frequent neurodegenerative diseases affecting more than 35 million people in the world, and its incidence is estimated to triple by 2050. Alzheimer’s disease is an age-related disease characterized by the progressive loss of memory and cognitive function, caused by the unstoppable neurodegeneration and brain atrophy. Current AD treatments only relieve the symptoms. The first molecular signs of the disease identified decades ago and were related to the tau neurofibrillary tangles and the β amyloid plaques. Despite the considerable progress in the diagnostic field, there is no certain knowledge of the specific biomarkers reflecting molecular mechanisms that trigger the symptoms of the disease. Therefore, there is an enormous need to find biomarkers useful for early diagnosis, before the first symptoms appear, and develop new therapeutic targets, which would guarantee improving patients’ quality of life. Researchers from all around the world are looking for biomarkers that can be identified in different biological fluids such as plasma, serum, and cerebrospinal fluid, specific for Alzheimer’s disease. In this review, we would like to resume some of the most interesting discovery in pathological mechanisms underlying Alzheimer’s disease and promising biomarkers.
Potential Therapeutic Approaches for Cerebral Amyloid Angiopathy and Alzheimer’s Disease
Authors: Tanaka Masashi , Saito Satoshi , Inoue Takayuki , Satoh-Asahara Noriko , Ihara Masafumi
Published: March 2020

Cerebral amyloid angiopathy (CAA) is a cerebrovascular disease directly implicated in Alzheimer’s disease (AD) pathogenesis through amyloid-β (Aβ) deposition, which may cause the development and progression of dementia. Despite extensive studies to explore drugs targeting Aβ, clinical benefits have not been reported in large clinical trials in AD patients or presymptomatic individuals at a risk for AD. However, recent studies on CAA and AD have provided novel insights regarding CAA- and AD-related pathogenesis. This work has revealed potential therapeutic targets, including Aβ drainage pathways, Aβ aggregation, oxidative stress, and neuroinflammation. The functional significance and therapeutic potential of bioactive molecules such as cilostazol and taxifolin have also become increasingly evident. Furthermore, recent epidemiological studies have demonstrated that serum levels of a soluble form of triggering receptor expressed on myeloid cells 2 (TREM2) may have clinical significance as a potential novel predictive biomarker for dementia incidence. This review summarizes recent advances in CAA and AD research with a focus on discussing future research directions regarding novel therapeutic approaches and predictive biomarkers for CAA and AD.
Special Issue: G Protein-Coupled Adenosine Receptors: Molecular Aspects and Beyond
Authors: Ciruela Francisco
Published: March 2020

Adenosine is a purine nucleoside present in all human cells where it plays many different physiological roles: From being a building block for nucleic acids to a key constituent of the biological energy currency ATP [...]
Exploring miR-9 Involvement in Ciona intestinalis Neural Development Using Peptide Nucleic Acids
Authors: Mercurio Silvia , Cauteruccio Silvia , Manenti Raoul , Candiani Simona , Scarì Giorgio , Licandro Emanuela , Pennati Roberta
Published: March 2020

The microRNAs are small RNAs that regulate gene expression at the post-transcriptional level and can be involved in the onset of neurodegenerative diseases and cancer. They are emerging as possible targets for antisense-based therapy, even though the in vivo stability of miRNA analogues is still questioned. We tested the ability of peptide nucleic acids, a novel class of nucleic acid mimics, to downregulate miR-9 in vivo in an invertebrate model organism, the ascidian Ciona intestinalis, by microinjection of antisense molecules in the eggs. It is known that miR-9 is a well-conserved microRNA in bilaterians and we found that it is expressed in epidermal sensory neurons of the tail in the larva of C. intestinalis. Larvae developed from injected eggs showed a reduced differentiation of tail neurons, confirming the possibility to use peptide nucleic acid PNA to downregulate miRNA in a whole organism. By identifying putative targets of miR-9, we discuss the role of this miRNA in the development of the peripheral nervous system of ascidians.
Drosophila SLC22 Orthologs Related to OATs, OCTs, and OCTNs Regulate Development and Responsiveness to Oxidative Stress
Authors: Engelhart Darcy C. , Azad Priti , Ali Suwayda , Granados Jeffry C. , Haddad Gabriel G. , Nigam Sanjay K.
Published: March 2020

The SLC22 family of transporters is widely expressed, evolutionarily conserved, and plays a major role in regulating homeostasis by transporting small organic molecules such as metabolites, signaling molecules, and antioxidants. Analysis of transporters in fruit flies provides a simple yet orthologous platform to study the endogenous function of drug transporters in vivo. Evolutionary analysis of Drosophila melanogaster putative SLC22 orthologs reveals that, while many of the 25 SLC22 fruit fly orthologs do not fall within previously established SLC22 subclades, at least four members appear orthologous to mammalian SLC22 members (SLC22A16:CG6356, SLC22A15:CG7458, CG7442 and SLC22A18:CG3168). We functionally evaluated the role of SLC22 transporters in Drosophila melanogaster by knocking down 14 of these genes. Three putative SLC22 ortholog knockdowns—CG3168, CG6356, and CG7442/SLC22A—did not undergo eclosion and were lethal at the pupa stage, indicating the developmental importance of these genes. Additionally, knocking down four SLC22 members increased resistance to oxidative stress via paraquat testing (CG4630: p < 0.05, CG6006: p < 0.05, CG6126: p < 0.01 and CG16727: p < 0.05). Consistent with recent evidence that SLC22 is central to a Remote Sensing and Signaling Network (RSSN) involved in signaling and metabolism, these phenotypes support a key role for SLC22 in handling reactive oxygen species.
Chlamydia psittaci PmpD-N Modulated Chicken Macrophage Function by Triggering Th2 Polarization and the TLR2/MyD88/NF-κB Signaling Pathway
Authors: Chu Jun , Li Xiaohui , Qu Guanggang , Wang Yihui , Li Qiang , Guo Yongxia , Hou Lei , Liu Jue , Eko Francis , He Cheng
Published: March 2020

The polymorphic membrane protein D (PmpD) is a highly conserved outer membrane protein which plays an important role in pathogenesis during Chlamydia psittaci infection. In this study, we evaluated the ability of the N-terminus of PmpD (PmpD-N) to modulate the functions of chicken macrophages and the signaling pathway(s) involved in PmpD-N-induced Toll-like receptors (TLRs), as well as interleukin (IL)-6 and IL-10 cytokine secretions. Thus, HD11 macrophages were treated with exogenous and intracellular PmpD-N of C. psittaci. The chlamydial growth was evaluated by enumeration of chlamydial loads in the infected macrophages. The phagocytic function of macrophages following PmpD-N treatment was detected by fluorescein-labeled Escherichia coli (E. coli). The concentration of nitric oxide (NO) secreted by HD11 macrophages was measured by the amount of NO2- in the culture supernatant using the Griess method. The cytokine secretions were assessed using multiplex cytokine ELISA kits. Expression levels of TLRs, myeloid differentiation factor 88 (MyD88), and nuclear factor kappa B (NF-κB) were analyzed by a Western blotting assay, as well as a luciferase assay, while NF-κB p65 nuclear translocation was assessed by confocal microscopy. The nuclear translocation of the transcription factor NF-κB was confirmed by evaluating its ability to combine with the corresponding promoter using the electrophoretic mobility shift assay (EMSA). After treatment with exogenous or endogenous PmpD-N, chlamydial loads and phagocytic functions were reduced significantly compared with those of the plasmid vector group, while NO secretions were reduced significantly compared with those of the lipopolysaccharide (LPS) treatment. Stimulation of HD11 cells with PmpD-N provoked the secretion of the Th2 cytokines, IL-6, and IL-10 and upregulated the expression of TLR2, TLR4, MyD88, and NF-κB. Furthermore, inhibition of TLR2, MyD88, and NF-κB in HD11 cells significantly decreased IL-6 and IL-10 cytokine levels, while NO production and phagocytosis increased significantly, strongly suggesting their involvement in PmpD-N-induced Th2 cytokine secretion and macrophage dysfunction. Our data indicate that C. psittaci PmpD-N inhibited macrophage functions by activating the Th2 immune response and the TLR2/MyD88/NF-κB signaling pathway.
3-Iodothyronamine and Derivatives: New Allies Against Metabolic Syndrome?
Authors: Rutigliano Grazia , Bandini Lavinia , Sestito Simona , Chiellini Grazia
Published: March 2020

In the two decades since its discovery, a large body of evidence has amassed to highlight the potential of 3-iodothyronamine (T1AM) as an antiobesity drug, whose pleiotropic signaling actions profoundly impact energy metabolism. In the present review, we recapitulate the most relevant properties of T1AM, including its structural and functional relationship to thyroid hormone, its endogenous levels, molecular targets, as well as its genomic and non-genomic effects on metabolism elicited in experimental models after exogenous administration. The physiological and pathophysiological relevance of T1AM in the regulation of energy homeostasis and metabolism is also discussed, along with its potential therapeutic applications in metabolic disturbances. Finally, we examine a number of T1AM analogs that have been recently developed with the aim of designing novel pharmacological agents for the treatment of interlinked diseases, such as metabolic and neurodegenerative disorders, as well as additional synthetic tools that can be exploited to further explore T1AM-dependent mechanisms and the physiological roles of trace amine-associated receptor 1 (TAAR1)-mediated effects.
The Impact of Natural Compounds on S-Shaped Aβ42 Fibril: From Molecular Docking to Biophysical Characterization
Authors: Muscat Stefano , Pallante Lorenzo , Stojceski Filip , Danani Andrea , Grasso Gianvito , Deriu Marco Agostino
Published: March 2020

The pursuit for effective strategies inhibiting the amyloidogenic process in neurodegenerative disorders, such as Alzheimer’s disease (AD), remains one of the main unsolved issues, and only a few drugs have demonstrated to delay the degeneration of the cognitive system. Moreover, most therapies induce severe side effects and are not effective at all stages of the illness. The need to find novel and reliable drugs appears therefore of primary importance. In this context, natural compounds have shown interesting beneficial effects on the onset and progression of neurodegenerative diseases, exhibiting a great inhibitory activity on the formation of amyloid aggregates and proving to be effective in many preclinical and clinical studies. However, their inhibitory mechanism is still unclear. In this work, ensemble docking and molecular dynamics simulations on S-shaped Aβ42 fibrils have been carried out to evaluate the influence of several natural compounds on amyloid conformational behaviour. A deep understanding of the interaction mechanisms between natural compounds and Aβ aggregates may play a key role to pave the way for design, discovery and optimization strategies toward an efficient destabilization of toxic amyloid assemblies.
Correlative Monitoring of Immune Activation and Tissue Damage in Malignant Melanoma—An Algorithm for Identification of Tolerance Breakage During Immune Checkpoint Inhibitor Therapy of Cancer
Authors: Wahl Renate U. , Leijs Marike , Araujo Arturo , Rübben Albert
Published: March 2020

We describe an innovative approach for identification of tolerance breakage during immune checkpoint inhibitor therapy in malignant melanoma. Checkpoint inhibitor therapy enhances the immunologic clearance of cancer by suppressing pathways which induce immune suppression and tolerance. We posit that by analyzing temporal correlations of key markers of immune activation and tissue damage it would be possible to detect the onset of anticancer immune reaction as well as of immunologic adverse effects which might become crucial for optimization as well as safety of immune checkpoint inhibitor treatment. We analyzed time courses of routine laboratory values of serum tumor markers as well as of markers of immune activation in 17 patients with metastasized malignant melanoma receiving checkpoint inhibition and weekly laboratory controls. A parallel serum level increase of interleukin-6 and the tumor marker S100B could be identified in 13 patients, suggesting that the onset of tolerance breakage under checkpoint inhibition may be identified and measured. Immune-related adverse events in the patients were also accompanied by a peak of IL-6. In six patients, the onset of a putative anticancer immune reaction and the beginning of immunologic adverse events occurred in the same treatment cycle; in six patients the immunologic adverse reactions took place in separate cycles.
Regulating Divergent Transcriptomes through mRNA Splicing and Its Modulation Using Various Small Compounds
Authors: Fujita Ken-ichi , Ishizuka Takaki , Mitsukawa Mizuki , Kurata Masashi , Masuda Seiji
Published: March 2020

Human transcriptomes are more divergent than genes and contribute to the sophistication of life. This divergence is derived from various isoforms arising from alternative splicing. In addition, alternative splicing regulated by spliceosomal factors and RNA structures, such as the RNA G-quadruplex, is important not only for isoform diversity but also for regulating gene expression. Therefore, abnormal splicing leads to serious diseases such as cancer and neurodegenerative disorders. In the first part of this review, we describe the regulation of divergent transcriptomes using alternative mRNA splicing. In the second part, we present the relationship between the disruption of splicing and diseases. Recently, various compounds with splicing inhibitor activity were established. These splicing inhibitors are recognized as a biological tool to investigate the molecular mechanism of splicing and as a potential therapeutic agent for cancer treatment. Food-derived compounds with similar functions were found and are expected to exhibit anticancer effects. In the final part, we describe the compounds that modulate the messenger RNA (mRNA) splicing process and their availability for basic research and future clinical potential.
Recent Advances in Practical Methods for Liver Cell Biology: A Short Overview
Authors: Torres Sandra , Abdullah Zeinab , Brol Maximilian J , Hellerbrand Claus , Fernandez Mercedes , Fiorotto Romina , Klein Sabine , Königshofer Philipp , Liedtke Christian , Lotersztajn Sophie , Nevzorova Yulia A. , Schierwagen Robert , Reiberger Thomas , Uschner Frank Erhard , Tacke Frank , Weiskirchen Ralf , Trebicka Jonel
Published: March 2020

Molecular and cellular research modalities for the study of liver pathologies have been tremendously improved over the recent decades. Advanced technologies offer novel opportunities to establish cell isolation techniques with excellent purity, paving the path for 2D and 3D microscopy and high-throughput assays (e.g., bulk or single-cell RNA sequencing). The use of stem cell and organoid research will help to decipher the pathophysiology of liver diseases and the interaction between various parenchymal and non-parenchymal liver cells. Furthermore, sophisticated animal models of liver disease allow for the in vivo assessment of fibrogenesis, portal hypertension and hepatocellular carcinoma (HCC) and for the preclinical testing of therapeutic strategies. The purpose of this review is to portray in detail novel in vitro and in vivo methods for the study of liver cell biology that had been presented at the workshop of the 8th meeting of the European Club for Liver Cell Biology (ECLCB-8) in October of 2018 in Bonn, Germany.
Defects in Galactose Metabolism and Glycoconjugate Biosynthesis in a UDP-Glucose Pyrophosphorylase-Deficient Cell Line Are Reversed by Adding Galactose to the Growth Medium
Authors: Durrant Christelle , Fuehring Jana I. , Willemetz Alexandra , Chrétien Dominique , Sala Giusy , Ghidoni Riccardo , Katz Abram , Rötig Agnès , Thelestam Monica , Ermonval Myriam , Moore Stuart E. H.
Published: March 2020

UDP-glucose (UDP-Glc) is synthesized by UGP2-encoded UDP-Glc pyrophosphorylase (UGP) and is required for glycoconjugate biosynthesis and galactose metabolism because it is a uridyl donor for galactose-1-P (Gal1P) uridyltransferase. Chinese hamster lung fibroblasts harboring a hypomrphic UGP(G116D) variant display reduced UDP-Glc levels and cannot grow if galactose is the sole carbon source. Here, these cells were cultivated with glucose in either the absence or presence of galactose in order to investigate glycoconjugate biosynthesis and galactose metabolism. The UGP-deficient cells display < 5% control levels of UDP-Glc/UDP-Gal and > 100-fold reduction of [6-3H]galactose incorporation into UDP-[6-3H]galactose, as well as multiple deficits in glycoconjugate biosynthesis. Cultivation of these cells in the presence of galactose leads to partial restoration of UDP-Glc levels, galactose metabolism and glycoconjugate biosynthesis. The Vmax for recombinant human UGP(G116D) with Glc1P is 2000-fold less than that of the wild-type protein, and UGP(G116D) displayed a mildly elevated Km for Glc1P, but no activity of the mutant enzyme towards Gal1P was detectable. To conclude, although the mechanism behind UDP-Glc/Gal production in the UGP-deficient cells remains to be determined, the capacity of this cell line to change its glycosylation status as a function of extracellular galactose makes it a useful, reversible model with which to study different aspects of galactose metabolism and glycoconjugate biosynthesis.
Stem Cell Signaling Pathways in the Small Intestine
Authors: Takahashi Toshio , Shiraishi Akira
Published: March 2020

The ability of stem cells to divide and differentiate is necessary for tissue repair and homeostasis. Appropriate spatial and temporal mechanisms are needed. Local intercellular signaling increases expression of specific genes that mediate and maintain differentiation. Diffusible signaling molecules provide concentration-dependent induction of specific patterns of cell types or regions. Differentiation of adjacent cells, on the other hand, requires cell–cell contact and subsequent signaling. These two types of signals work together to allow stem cells to provide what organisms require. The ability to grow organoids has increased our understanding of the cellular and molecular features of small “niches” that modulate stem cell function in various organs, including the small intestine.
Cardiovascular Changes Related to Metabolic Syndrome: Evidence in Obese Zucker Rats
Authors: Martinelli Ilenia , Tomassoni Daniele , Moruzzi Michele , Roy Proshanta , Cifani Carlo , Amenta Francesco , Tayebati Seyed Khosrow
Published: March 2020

Metabolic syndrome (MetS) is a predictor of cardiovascular diseases, commonly associated with oxidative stress and inflammation. However, the pathogenic mechanisms are not yet fully elucidated. The aim of the study is to evaluate the oxidative status and inflammation in the heart of obese Zucker rats (OZRs) and lean Zucker rats (LZRs) at different ages. Morphological and morphometric analyses were performed in the heart. To study the oxidative status, the malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), protein oxidation, and antioxidant enzymes were measured in plasma and heart. To elucidate the inflammatory markers involved, immunohistochemistry and Western blot were performed for cellular adhesion molecules and proinflammatory cytokines. OZRs were characterized by hypertension, hyperlipidemia, hyperglycemia, and insulin resistance. The obesity increased MDA and decreased the activities of superoxide dismutase (SOD) in plasma as well as in the heart, associated with cardiomyocytes hypertrophy. OxyBlot in plasma and in heart showed an increase of oxidativestate proteins in OZRs. Vascular cell adhesion molecule-1, interleukin-6, and tumor necrosis factor-α expressions in OZRs were higher than those of LZRs. However, these processes did not induce apoptosis or necrosis of cardiomyocytes. Thus, MetS induces the lipid peroxidation and decreased antioxidant defense that leads to heart tissue changes and coronary inflammation.
Macrophage-Secreted Lipocalin-2 Promotes Regeneration of Injured Primary Murine Renal Tubular Epithelial Cells
Authors: Urbschat Anja , Thiemens Anne-Kathrin , Mertens Christina , Rehwald Claudia , Meier Julia K. , Baer Patrick C. , Jung Michaela
Published: March 2020

Lipocalin-2 (Lcn-2) is rapidly upregulated in macrophages after renal tubular injury and acts as renoprotective and pro-regenerative agent. Lcn-2 possesses the ability to bind and transport iron with high affinity. Therefore, the present study focuses on the decisive role of the Lcn-2 iron-load for its pro-regenerative function. Primary mouse tubular epithelial cells were isolated from kidney tissue of wildtype mice and incubated with 5 µM Cisplatin for 24 h to induce injury. Bone marrow-derived macrophages of wildtype and Lcn-2−/− mice were isolated and polarized with IL-10 towards an anti-inflammatory, iron-release phenotype. Their supernatants as well as recombinant iron-loaded holo-Lcn-2 was used for stimulation of Cisplatin-injured tubular epithelial cells. Incubation of tubular epithelial cells with wildtype supernatants resulted in less damage and induced cellular proliferation, whereas in absence of Lcn-2 no protective effect was observed. Epithelial integrity as well as cellular proliferation showed a clear protection upon rescue experiments applying holo-Lcn-2. Notably, we detected a positive correlation between total iron amounts in tubular epithelial cells and cellular proliferation, which, in turn, reinforced the assumed link between availability of Lcn-2-bound iron and recovery. We hypothesize that macrophage-released Lcn-2-bound iron is provided to tubular epithelial cells during toxic cell damage, whereby injury is limited and recovery is favored.
UbcH10 a Major Actor in Cancerogenesis and a Potential Tool for Diagnosis and Therapy
Authors: Presta Ivan , Novellino Fabiana , Donato Annalidia , La Torre Domenico , Palleria Caterina , Russo Emilio , Malara Natalia , Donato Giuseppe
Published: March 2020

Malignant transformation is a multistep process in which several molecular entities become dysregulated and result in dysfunction in the regulation of cell proliferation. In past years, scientists have gradually dissected the pathways involved in the regulation of the cell cycle. The mitotic ubiquitin-conjugating enzymes UbcH10, has been extensively studied since its cloning and characterization and it has been identified as a constantly overexpressed factor in many types of cancer. In this paper, we have reviewed the literature about UbcH10 in human cancer, pointing out the association between its overexpression and exacerbation of cancer phenotype. Moreover, many recalled studied demonstrated how immunohistochemistry or RT-PCR analysis can distinguish normal tissues and benign lesions from malignant neoplasms. In other experimental studies, many of the consequences of UbcH10 overexpression, such as increased proliferation, metastasizing, cancer progression and resistance to anticancer drugs are reversed through gene silencing techniques. In recent years, many authors have defined UbcH10 evaluation in cancer patients as a useful tool for diagnosis and therapy. This opinion is shared by the authors who advertise how it would be useful to start using in clinical practice the notions acquired about this important moleculein the carcinogenesis of many human malignancies.
Genome-Wide Association Mapping for Heat Stress Responsive Traits in Field Pea
Authors: Tafesse Endale G. , Gali Krishna K. , Lachagari V.B. Reddy , Bueckert Rosalind , Warkentin Thomas D.
Published: March 2020

Environmental stress hampers pea productivity. To understand the genetic basis of heat resistance, a genome-wide association study (GWAS) was conducted on six stress responsive traits of physiological and agronomic importance in pea, with an objective to identify the genetic loci associated with these traits. One hundred and thirty-five genetically diverse pea accessions from major pea growing areas of the world were phenotyped in field trials across five environments, under generally ambient (control) and heat stress conditions. Statistical analysis of phenotype indicated significant effects of genotype (G), environment (E), and G × E interaction for all traits. A total of 16,877 known high-quality SNPs were used for association analysis to determine marker-trait associations (MTA). We identified 32 MTAs that were consistent in at least three environments for association with the traits of stress resistance: six for chlorophyll concentration measured by a soil plant analysis development meter; two each for photochemical reflectance index and canopy temperature; seven for reproductive stem length; six for internode length; and nine for pod number. Forty-eight candidate genes were identified within 15 kb distance of these markers. The identified markers and candidate genes have potential for marker-assisted selection towards the development of heat resistant pea cultivars.
Indole-3-Carbinol Derivative DIM Mitigates Carbon Tetrachloride-Induced Acute Liver Injury in Mice by Inhibiting Inflammatory Response, Apoptosis and Regulating Oxidative Stress
Authors: Munakarmi Suvesh , Chand Lokendra , Shin Hyun Beak , Jang Kyu Yun , Jeong Yeon Jun
Published: March 2020

3,3′-Diindolylmethane (DIM), a metabolic product of indole-3-carbinol extracted from cruciferous vegetables exhibits anti-inflammatory and anti-cancer properties. Earlier, the product has been demonstrated to possess anti-fibrotic properties; however, its protective effects on liver injury have not been clearly elucidated. In this study, we postulated the effects and molecular mechanisms of action of DIM on carbon tetrachloride (CCl4)-induced liver injury in mice. Acute liver injury was induced by a single intraperitoneal administration of CCl4 (1 ml/kg) into mice. DIM was injected via subcutaneous route for three days at various doses (2.5, 5 and 10 mg/kg) before CCl4 injection. Mice were sacrificed and serum was collected for quantification of serum transaminases. The liver was collected and weighed. Treatment with DIM significantly reduced serum transaminases levels (AST and ALT), tumor necrosis factor-α (TNF-α) and reactive oxygen species (ROS). CCl4- induced apoptosis was inhibited by DIM treatment by the reduction in the levels of cleaved caspase-3 and Bcl2 associated X protein (Bax). DIM treated mice significantly restored Cytochrome P450 2E1, nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) expression in CCl4 treated mice. In addition, DIM downregulated overexpression of hepatic nuclear factor kappa B (NF-κB) and inhibited CCl4 mediated apoptosis. Our results suggest that the protective effects of DIM against CCl4- induced liver injury are due to the inhibition of ROS, reduction of pro-inflammatory mediators and apoptosis.
Cryptides Identified in Human Apolipoprotein B as New Weapons to Fight Antibiotic Resistance in Cystic Fibrosis Disease
Authors: Gaglione Rosa , Cesaro Angela , Dell’Olmo Eliana , Di Girolamo Rocco , Tartaglione Luca , Pizzo Elio , Arciello Angela
Published: March 2020

Chronic respiratory infections are the main cause of morbidity and mortality in cystic fibrosis (CF) patients, and are characterized by the development of multidrug resistance (MDR) phenotype and biofilm formation, generally recalcitrant to treatment with conventional antibiotics. Hence, novel effective strategies are urgently needed. Antimicrobial peptides represent new promising therapeutic agents. Here, we analyze for the first time the efficacy of three versions of a cryptide identified in human apolipoprotein B (ApoB, residues 887-922) towards bacterial strains clinically isolated from CF patients. Antimicrobial and anti-biofilm properties of ApoB-derived cryptides have been analyzed by broth microdilution assays, crystal violet assays, confocal laser scanning microscopy and scanning electron microscopy. Cell proliferation assays have been performed to test cryptide effects on human host cells. ApoB-derived cryptides have been found to be endowed with significant antimicrobial and anti-biofilm properties towards Pseudomonas and Burkholderia strains clinically isolated from CF patients. Peptides have been also found to be able to act in combination with the antibiotic ciprofloxacin, and they are harmless when tested on human bronchial epithelial mesothelial cells. These findings open interesting perspectives to cryptide applicability in the treatment of chronic lung infections associated with CF disease.
PPARs as Metabolic Regulators in the Liver: Lessons from Liver-Specific PPAR-Null Mice
Authors: Wang Yaping , Nakajima Takero , Gonzalez Frank J. , Tanaka Naoki
Published: March 2020

Peroxisome proliferator-activated receptor (PPAR) α, β/δ, and γ modulate lipid homeostasis. PPARα regulates lipid metabolism in the liver, the organ that largely controls whole-body nutrient/energy homeostasis, and its abnormalities may lead to hepatic steatosis, steatohepatitis, steatofibrosis, and liver cancer. PPARβ/δ promotes fatty acid β-oxidation largely in extrahepatic organs, and PPARγ stores triacylglycerol in adipocytes. Investigations using liver-specific PPAR-disrupted mice have revealed major but distinct contributions of the three PPARs in the liver. This review summarizes the findings of liver-specific PPAR-null mice and discusses the role of PPARs in the liver.
Resvega Alleviates Hydroquinone-Induced Oxidative Stress in ARPE-19 Cells
Authors: Bhattarai Niina , Korhonen Eveliina , Toppila Maija , Koskela Ali , Kaarniranta Kai , Mysore Yashavanthi , Kauppinen Anu
Published: March 2020

Retinal pigment epithelial (RPE) cells maintain homeostasis at the retina and they are under continuous oxidative stress. Cigarette smoke is a prominent environmental risk factor for age-related macular degeneration (AMD), which further increases the oxidant load in retinal tissues. In this study, we measured oxidative stress and inflammatory markers upon cigarette smoke-derived hydroquinone exposure on human ARPE-19 cells. In addition, we studied the effects of commercial Resvega product on hydroquinone-induced oxidative stress. Previously, it was observed that Resvega induces autophagy during impaired protein clearance in ARPE-19 cells, for which it has the potential to alleviate pro-inflammatory pathways. Cell viability was determined while using the lactate dehydrogenase (LDH) and the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays, and the cytokine levels were measured using the enzyme-linked immunosorbent assay (ELISA). Reactive oxygen species (ROS) production were measured using the 2′,7′-dichlorofluorescin diacetate (H2DCFDA) probe. Hydroquinone compromised the cell viability and increased ROS production in ARPE-19 cells. Resvega significantly improved cell viability upon hydroquinone exposure and reduced the release of interleukin (IL)-8 and monocytic chemoattractant protein (MCP)-1 from RPE cells. Resvega, N-acetyl-cysteine (NAC) and aminopyrrolidine-2,4-dicarboxylic acid (APDC) alleviated hydroquinone-induced ROS production in RPE cells. Collectively, our results indicate that hydroquinone induces cytotoxicity and increases oxidative stress through NADPH oxidase activity in RPE cells, and resveratrol-containing Resvega products prevent those adverse effects.
Pic-Producing Escherichia coli Induces High Production of Proinflammatory Mediators by the Host Leading to Death by Sepsis
Authors: Dutra Itaynara L. , Araújo Lorena G. , Assunção Raissa G. , Lima Yago A. , Nascimento Johnny R. , Vale André A. M. , Alves Patrícia C. S. , Trovão Liana O. , Santos Ana Carolina M. , Silva Rosa M. , Silva Lucilene A. , Maciel Márcia C. G. , de Sousa Eduardo M. , Elias Waldir P. , Nascimento Flávia R. F. , Abreu Afonso G.
Published: March 2020

Escherichia coli is an important pathogen responsible for a variety of diseases. We have recently shown that Pic, a serine protease secreted by E. coli, mediates immune evasion by the direct cleavage of complement molecules. The aim of this study was to investigate the action of a Pic-producing bacteria in a murine model of sepsis. Mice were infected with Pic-producing E. coli (F5) or F5∆pic mutant. Animal survival was monitored for five days, and a subset of mice was euthanized after 12 h for sample acquisition. The inoculation of Pic-producing bacteria induced 100% death within 24 h. The colony forming units count in the organs was significantly higher in F5. Hematological analysis showed a decrease of total leukocytes. Nitric oxide and cytokines were detected in serum, as well as on peritoneal lavage of the F5 group in higher levels than those detected in the other groups. In addition, immunophenotyping showed a decrease of activated lymphocytes and macrophages in the F5 group. Therefore, Pic represents an important virulence factor, allowing the survival of the bacterium in the bloodstream and several organs, as well as inducing a high production of proinflammatory mediators by the host, and concomitantly a cellular immunosuppression, leading to sepsis and death.
Session RPE Breakpoints Corresponding to Intensity Thresholds in Elite Open Water Swimmers
Authors: Ieno Cristian , Baldassarre Roberto , Quagliarotti Claudio , Bonifazi Marco , Piacentini Maria Francesca
Published: March 2020

This study aims to assess the correspondence between session rating of perceived exertion (sRPE) breakpoints with both the first lactate threshold (LT1) and the second lactate threshold (LT2) in elite open water swimmers (OWS). Six elite OWS of the National Olympic Team specialized in distances between 5 and 25 km participated to the study. OWS performed a set of 6 times 500 m incremental swimming step test during which blood lactate concentration (BLC), split time (ST), stroke frequency (SF), and rating of perceived exertion (RPE) were collected. To assess the corresponding breakpoints, we considered LT1 as the highest workload not associated with rise in BLC and LT2 as the increase of 2mM above LT1. According to the LT1 and LT2, the identified zones were: Z1 ≤3, Z2 between 4 and 6, Z3 ≥ 7. In conclusion, the intensity zones determined for OWS resulted different from what previously reported for other endurance disciplines.