bluuebunny/crossref_metadata_2025 huggingface dataset:
Dietary Intervention through Flipped Learning as a Techno Pedagogy for the Promotion of Healthy Eating in Secondary Education
Authors: López Núñez Juan Antonio , López-Belmonte Jesús , Moreno-Guerrero Antonio-José , Marín-Marín José Antonio
Published: April 2020

Technological progress in the educational field has led to the application of active and innovative teaching methods, such as flipped learning, including in the field of dietary education. This is considered a mixed formative approach that combines face-to-face and outside the classroom education. The objective of this research was to analyze the effectiveness of flipped learning methodology on a traditional training practice in dietary training, both in the sixth grade of primary education and in the fourth level of secondary education. A quasi-experimental design was adopted with two experimental groups, two control groups and only posttest. The final sample was composed of 115 students divided into four groups, two of each educational stage mentioned. A didactic unit consisting of six sessions in all groups was applied. Two different training methodologies were followed according to the nature of the group (control-traditional; experimental-flipped learning). The results reveal that flipped learning is effective both in primary education and in secondary education, being more influential in student development in this last stage. It is concluded that the flipped learning approach has meant an improvement of the academic indicators evaluated after a diet education program.
Accessing Physical Activity and Health Disparities among Underserved Hispanic Children: The Role of Actual and Perceived Motor Competence
Authors: Zhang Tao , Lee Joonyoung , Chu Tsz Lun (Alan) , Chen Changzhou , Gu Xiangli
Published: April 2020

Promoting physical activity (PA) and eliminating health disparities among underserved minority children is a public health priority. The main purpose of this study was to examine the relationship of actual motor competence (a set of object control skills) and perceived motor competence with PA participation and health-related quality of life (HRQoL) among underserved Hispanic children who were born in the U.S. Guided by Stodden et al.’s conceptual model, we tested the direct and indirect effects (mediational model) of actual motor competence on health-related outcomes (PA and HRQoL) through perceived motor competence. Participants were 215 underserved Hispanic children (Mage = 10.55 years, SD = 0.53 [age range 10–12]; 51.6% boys), recruited from four elementary schools in the southwestern U.S., who completed validated questionnaires assessing their perceived motor competence, PA, and HRQoL. Their actual motor skills were assessed using PE MetricsTM. After examining the associations among the variables, we tested the hypothesized model using structural equation modeling (SEM; AMOS 25). The hypothesized model indicated a good fit (χ²/df = 38.427/24 = 1.60 < 5; non-normed fit index (NFI) = 0.93; comparative fit index (CFI) = 0.968; root mean square error of approximation (RMSEA) = 0.053 [0.016, 0.083]). The effect of actual motor competence on PA and HRQoL was fully mediated by perceived motor competence. The findings demonstrated the mediating role of perceived motor competence between actual motor competence and health-related outcomes (PA and HRQoL) among underserved Hispanic children. The results highlight that actual motor competence significantly predicted underserved Hispanic children’ perceived motor competence, which in turn positively predicted their PA and HRQoL. These findings have significant practical implications for future intervention strategies of randomized clinical trials in schools aimed at promoting PA and HRQoL and eliminating health disparities among underserved Hispanic children.
Individual and Environmental Factors Associated with Tobacco Smoking, Alcohol Abuse and Illegal Drug Consumption in University Students: A Mediating Analysis
Authors: Delgado-Lobete Laura , Montes-Montes Rebeca , Vila-Paz Alba , Cruz-Valiño José-Manuel , Gándara-Gafo Berta , Talavera-Valverde Miguel-Ángel , Santos-del-Riego Sergio
Published: April 2020

Substance abuse is a major and prevalent public health concern among university students. Tobacco smoking, risky alcohol behavior, and illegal drug consumption may lead to health problems and behavioral and academic issues. Several individual and environmental factors associate with substance abuse in this population, and the mediating effect of alcohol abuse in the relationship between tobacco smoking and drug consumption is yet to be explored. The purposes of this study were to evaluate the association of individual and environmental factors and substance use, and to analyze the relationship between tobacco smoking, alcohol abuse, and drug consumption, considering alcohol abuse as a possible mediator. A total of 550 Spanish undergraduate and postgraduate students completed several questionnaires regarding their smoking status, alcohol use, and drug consumption during the last six months. Bivariate and multivariate analyses were conducted to explore associations between factors. Direct, indirect and mediating effects were tested using a partial least squares approach (PLS-SEM). The results indicated that substance abuse is associated with being male, living with other students, and combined substance consumption. PLS-SEM showed a significant effect of tobacco smoking and alcohol abuse on drug consumption. Alcohol abuse plays a mediating role in the relationship between tobacco smoking and drug use.
A Qualitative Inquiry into the Human Library Approach: Facilitating Social Inclusion and Promoting Recovery
Authors: Kwan Chi Kin
Published: April 2020

The key to the successful social inclusion of people recovering from mental illness is mutual understanding with other community members. To promote such social inclusion, the human library approach has been adopted by a group of practitioners based in Hong Kong. Through a review of this community mental health initiative, this study explores the relevance and usefulness of this approach in a mental health setting. A collaborative inquiry-based research method was adopted to explore the human library approach in practice. A practitioner inquiry group was conducted with four social workers and three peer support workers to examine their experience of running the human library. Thematic analysis and member checks were used to identify important themes. The practitioners’ reports of their experiences showed that the human library is well suited to facilitating social inclusion and promoting mental health recovery. Community members and people in recovery can benefit from participating in a human library, and the two sides can become connected through mutual understanding. However, possible risks for people in recovery were also identified. This study argues that the human library deserves consideration as an approach to facilitating social inclusion and promoting recovery. Its effectiveness and benefits are evident, especially compared with large-scale one-way intervention approaches. A clinical practice manual should be developed to inform future practitioners of the value of the human library approach in mental health settings.
Comparing Activity and Participation between Acquired Brain Injury and Spinal-Cord Injury in Community-Dwelling People with Severe Disability Using WHODAS 2.0
Authors: Yoon Seo Yeon , Leigh Ja-Ho , Lee Jieun , Kim Wan Ho
Published: April 2020

Central-nervous-system (CNS) injuries constitute a significant cause of morbidity (often resulting in long-term disability) and mortality. This cross-sectional study compared the activity and participation of community-dwelling people with severe disability from acquired brain injuries (ABI) (n = 322) and spinal-cord injuries (SCI) (n = 183) to identify risk factors related to disability. Data were collected through a questionnaire survey of community-dwelling people with severe disability attending 65 healthcare centers. The survey included the World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) and sociodemographic factors. We categorized a registered grade of disability of 1 or 2 as severe disability. WHODAS 2.0 domain and summary scores were compared between the ABI and SCI groups, and risk factors associated with disability were identified through regression analysis. ABI participants had significantly higher disability in cognition and relationships, whereas patients with SCI had higher disability in mobility (p < 0.05). Onset duration was negatively correlated with cognition, relationships, participation, and summary scores in ABI participants (p < 0.05). Neither group’s socioeconomic factors were associated with WHODA 2.0 scores. Understanding the different patterns of disability between SCI and ABI in community-dwelling people with severe disability helps establish future plans for the management of health resources.
Barriers and Facilitators to Leisure Physical Activity in Children: A Qualitative Approach Using the Socio-Ecological Model
Authors: Martínez-Andrés María , Bartolomé-Gutiérrez Raquel , Rodríguez-Martín Beatriz , Pardo-Guijarro María Jesús , Garrido-Miguel Miriam , Martínez-Vizcaíno Vicente
Published: April 2020

Despite the benefits of engaging in physical activity during their leisure time, children do not meet the recommendations on physical activity. Following the socio-ecological model as a theoretical framework, the aim of this study was to determine the barriers and facilitators that influence physical activity participation in children’s leisure time. Data collection was conducted through focus groups and individual drawings in a sample of 98 eight- to eleven-year-olds from six schools in Cuenca (Spain). Following the socio-ecological model, individual characteristics (age and sex), as well as the microsystem (parents and friends), mesosystem (timing and out-of-school schedule) and exosystem (safety and weather) influence physical activity participation. The relationships between these levels of the socio-ecological model reveal that opportunities for leisure physical activity are determined by children’s schedules. This schedule is negotiated by the family and is influenced by parents’ worries and necessities. This is the main barrier to physical activity participation due to the creation of more restrictive, sedentary schedules, especially for girls. Our results show the elements required to develop successful strategies to increase physical activity opportunities, namely, focusing on giving children the opportunity to choose activities, raising parents’ awareness of the importance of physical activity and improving the perceived safety of parks, taking into consideration the gender perspective.
Effects of Landscape Pattern Change on Water Yield and Nonpoint Source Pollution in the Hun-Taizi River Watershed, China
Authors: Zong Min , Hu Yuanman , Liu Miao , Li Chunlin , Wang Cong , Ping Xiaoying
Published: April 2020

Understanding the influence of landscape pattern changes on water yield (WYLD) and nutrient yield is a key topic for water resource management and nonpoint source (NPS) pollution reduction. The annual WYLD and NPS pollution were estimated in 2004 and 2015 with the calibrated and validated Soil and Water Assessment Tool (SWAT) in the Hun-Taizi River watershed. The impact of land use and landscape pattern changes on the annual WYLD and NPS loading changes were analyzed with a boosted regression tree (BRT) and redundancy analysis (RDA). The results showed that WYLD had a positive correlation with dry farmland and built-up area; however, a negative correlation with paddy field and water area, with the relative contribution of 42.03%, 23.79%, 17.06%, and 13.55%, respectively. The change in nutrient yield was positively correlated with changes in dry farmland, built-up area, and water area but negatively with forestland, according to the BRT model. Landscape patterns had an important influence on WYLD and NPS pollution. A large unfragmented forestland may improve water quality, while a large concentrated dry farmland results in water quality deterioration due to NPS pollution. Water quality is more likely degraded when land uses are complex and scattered with many small patches in a forestland dominated watershed.
“If I Don’t Eat Enough, I Won’t Be Healthy”. Women’s Experiences with Gestational Diabetes Mellitus Treatment in Rural and Urban South India
Authors: Kragelund Nielsen Karoline , Vildekilde Thilde , Kapur Anil , Damm Peter , Seshiah Veerasamy , Bygbjerg Ib C.
Published: April 2020

Gestational diabetes mellitus (GDM) is associated with a range of adverse pregnancy outcomes as well as increased risk of future type 2 diabetes and cardiovascular disease. In India, 10%–35% of pregnant women develop GDM. In this study, we investigated women’s experiences with the dietary and pharmaceutical treatment for GDM in rural and urban Tamil Nadu, India. Semi-structured interviews were conducted with 19 women diagnosed with GDM. Data were analyzed using qualitative content analysis. Three overall aspects were discovered with several sub-aspects characterizing women’s experiences: emotional challenges (fear and apprehension for the baby’ health and struggling to accept a treatment seen as counterintuitive to being safe and healthy), interpersonal challenges (managing treatment in the near social relations and social support, and coordinating treatment with work and social life), and health system-related challenges (availability and cost of treatment, interaction with health care providers). Some aspects acted as barriers. However, social support and positive, high-quality interactions with health care providers could mitigate some of these barriers and facilitate the treatment process. Greater efforts at awareness creation in the social environment and systemic adjustments in care delivery targeting the individual, family, community and health system levels are needed in order to ensure that women with GDM have the opportunity to access treatment and are enabled and motivated to follow it as well.
Development and Psychometric Properties of the Pressure Injury Prevention Knowledge Questionnaire in Spanish Nurses
Authors: López-Franco María Dolores , Parra-Anguita Laura , Comino-Sanz Inés María , Pancorbo-Hidalgo Pedro L.
Published: April 2020

Pressure injuries (PIs) are a major health problem with severe implications for patients. Professionals who care for people at risk should have high knowledge about PIs prevention. The actual knowledge can be measured using different tools, but we have found no questionnaire to measure the knowledge on PIs prevention developed and validated for Spanish-speaking countries. The aim of this study was to develop a questionnaire in Spanish to measure the knowledge about PIs prevention based on current international guidelines. Content validity was evaluated by 12 experts in wound care. A convenience sample of 438 nursing professionals from Spain participated to evaluate the questionnaire using item analysis, Rasch model, and known-groups validity. The PI Prevention Knowledge (PIPK) questionnaire shows good discrimination and difficulty indices. The 31-item PIPK shows good fit and reliability of 0.98 for items and 0.72 for people; also, it has enough evidence for construct validity. Because the questionnaire has been developed based on the recommendations from international guidelines, the English version of this questionnaire could be used in further studies to test its psychometric properties.
Dimensions of the Complexity of Health Interventions: What Are We Talking about? A Review
Authors: Trompette Justine , Kivits Joëlle , Minary Laetitia , Alla François
Published: April 2020

Many recommendations and innovative approaches are available for the development and evaluation of complex health interventions. We investigated the dimensions of complexity described in health research and how these descriptions may affect the adopted research methodology (e.g., the choice of designs and methods). We used a mixed method approach to review the scientific literature evaluating complex interventions in the health field. Of 438 articles identified, 179 were subjected to descriptive analysis and 48 to content analysis. The three principal dimensions of complexity were: stakeholder characteristics, intervention multimodality and context. Recognition of such dimensions influenced the methodological choices made during evaluation of the interventions with their use of designs and methods, which aimed to address the complexity. We analysed not only how researchers view complexity but also the effects of such views on researcher practices. Our results highlight the need for clarification of what complexity means and to consider complexity when deciding how to evaluate research interventions.
The Effects of Human BDH2 on the Cell Cycle, Differentiation, and Apoptosis and Associations with Leukemia Transformation in Myelodysplastic Syndrome
Authors: Yang Wen-Chi , Lin Sheng-Fung , Wang Shu-Chen , Tsai Wan-Chi , Wu Chun-Chieh , Wu Shih-Chi
Published: April 2020

Iron overload is related to leukemia transformation in myelodysplastic syndrome (MDS) patients. Siderophores help to transport iron. Type 2-hydroxybutyrate dehydrogenase (BDH2) is a rate-limiting factor in the biogenesis of siderophores. Using qRT-PCR, we analyze BDH2mRNA expression in the bone marrow (BM) of 187 MDS patients, 119 de novo acute myeloid leukemia (AML) patients, and 43 lymphoma patients with normal BM. Elevated BDH2mRNA expression in BM is observed in MDS patients (n = 187 vs. 43, normal BM; P = 0.009), and this is related to ferritin levels. Patients with higher BDH2 expression show a greater risk of leukemia progression (15.25% vs. 3.77%, lower expression; P = 0.017) and shorter leukemia-free-survival (medium LFS, 9 years vs. 7 years; P = 0.024), as do patients with a ferritin level ≥350 ng/mL. Additionally, we investigate the mechanisms related to the prognostic ability of BDH2 by using BDH2-KD THP1. The cell cycle analysis, surface markers, and special stain studies indicate that BDH2-KD induces differentiation and decreases the growth rate of THP1 cells, which is associated with the retardation of the cell cycle. Moreover, many genes, including genes related to mitochondrial catabolism, oncogenes, tumor suppressor genes, and genes related to cell differentiation and proliferation influence BDH2-KD THP1 cells. Herein, we demonstrate that BDH2 is involved in cell cycle arrest and the inhibition of differentiation in malignant cells. Furthermore, the high BDH2 expression in MDS patients could be suggestive of a poor prognostic factor. This study provides a foundation for further research on the roles of BDH2 and iron metabolism in the pathogenesis of MDS.
Optimization of a High-Throughput 384-Well Plate-Based Screening Platform with Staphylococcus aureus ATCC 25923 and Pseudomonas aeruginosa ATCC 15442 Biofilms
Authors: Gilbert-Girard Shella , Savijoki Kirsi , Yli-Kauhaluoma Jari , Fallarero Adyary
Published: April 2020

In recent years, bacterial infections have become a main concern following the spread of antimicrobial resistance. In addition, bacterial biofilms are known for their high tolerance to antimicrobials and they are regarded as a main cause of recalcitrant infections in humans. Many efforts have been deployed in order to find new antibacterial therapeutic options and the high-throughput screening (HTS) of large libraries of compounds is one of the utilized strategies. However, HTS efforts for anti-biofilm discovery remain uncommon. Here, we miniaturized a 96-well plate (96WP) screening platform, into a 384-well plate (384WP) format, based on a sequential viability and biomass measurements for the assessment of anti-biofilm activity. During the assay optimization process, different parameters were evaluated while using Staphylococcus aureus and Pseudomonas aeruginosa as the bacterial models. We compared the performance of the optimized 384WP platform to our previously established 96WP-based platform by carrying out a pilot screening of 100 compounds, followed by the screening of a library of 2000 compounds to identify new repurposed anti-biofilm agents. Our results show that the optimized 384WP platform is well-suited for screening purposes, allowing for the rapid screening of a higher number of compounds in a run in a reliable manner.
Heterogeneity of Integrin αIIbβ3 Function in Pediatric Immune Thrombocytopenia Revealed by Continuous Flow Cytometry Analysis
Authors: Martyanov Alexey , Morozova Daria , Sorokina Maria , Filkova Aleksandra , Fedorova Daria , Uzueva Selima , Suntsova Elena , Novichkova Galina , Zharkov Pavel , Panteleev Mikhail , Sveshnikova Anastasia
Published: April 2020

Immune thrombocytopenia (ITP) is an autoimmune condition primarily induced by the loss of immune tolerance to the platelet glycoproteins. Here we develop a novel flow cytometry approach to analyze integrin αIIbβ3 functioning in ITP in comparison with Glanzmann thrombasthenia (GT) (negative control) and healthy pediatric donors (positive control). Continuous flow cytometry of Fura-Red-loaded platelets from whole hirudinated blood was used for the characterization of platelet responses to conventional activators. Calcium levels and fibrinogen binding were normalized to ionomycin-induced responses. Ex vivo thrombus formation on collagen was observed in parallel-plate flow chambers. Platelets from all ITP patients had significantly higher cytosolic calcium concentration in the quiescent state compared to healthy donors (15 ± 5 nM vs. 8 ± 5 nM), but calcium increases in response to all activators were normal. Clustering analysis revealed two subpopulations of ITP patients: the subgroup with high fibrinogen binding (HFB), and the subgroup with low fibrinogen binding (LFB) (8% ± 5% for LFB vs. 16% ± 3% for healthy donors in response to ADP). GT platelets had calcium mobilization (81 ± 23 nM), fibrinogen binding (5.1% ± 0.3%) and thrombus growth comparable to the LFB subgroup. Computational modeling suggested phospholipase C-dependent platelet pre-activation for the HFB subgroup and lower levels of functional integrin molecules for the LFB group.
A Comprehensive Proteomic and Phosphoproteomic Analysis of Retinal Pigment Epithelium Reveals Multiple Pathway Alterations in Response to the Inflammatory Stimuli
Authors: Song Juha , Han Dohyun , Lee Heonyi , Kim Da Jung , Cho Joo-Youn , Park Jae-Hak , Seok Seung Hyeok
Published: April 2020

Overwhelming and persistent inflammation of retinal pigment epithelium (RPE) induces destructive changes in the retinal environment. However, the precise mechanisms remain unclear. In this study, we aimed to investigate RPE-specific biological and metabolic responses against intense inflammation and identify the molecular characteristics determining pathological progression. We performed quantitative analyses of the proteome and phosphoproteome of the human-derived RPE cell line ARPE-19 after treatment with lipopolysaccharide (LPS) for 45 min or 24 h using the latest isobaric tandem-mass tags (TMTs) labeling approach. This approach led to the identification of 8984 proteins, of which 261 showed a 1.5-fold change in abundance after 24 h of treatment with LPS. A parallel phosphoproteome analysis identified 20,632 unique phosphopeptides from 3207 phosphoproteins with 3103 phosphorylation sites. Integrated proteomic and phosphoproteomic analyses showed significant downregulation of proteins related to mitochondrial respiration and cell cycle checkpoint, while proteins related to lipid metabolism, amino acid metabolism, cell-matrix adhesion, and endoplasmic reticulum (ER) stress were upregulated after LPS stimulation. Further, phosphorylation events in multiple pathways, including MAPKK and Wnt/β-catenin signalings, were identified as involved in LPS-triggered pathobiology. In essence, our findings reveal multiple integrated signals exerted by RPE under inflammation and are expected to give insight into the development of therapeutic interventions for RPE disorders.
Genetic Dissection of Hypertrophic Cardiomyopathy with Myocardial RNA-Seq
Authors: Gao Jun , Collyer John , Wang Maochun , Sun Fengping , Xu Fuyi
Published: April 2020

Hypertrophic cardiomyopathy (HCM) is an inherited disorder of the myocardium, and pathogenic mutations in the sarcomere genes myosin heavy chain 7 (MYH7) and myosin-binding protein C (MYBPC3) explain 60%–70% of observed clinical cases. The heterogeneity of phenotypes observed in HCM patients, however, suggests that novel causative genes or genetic modifiers likely exist. Here, we systemically evaluated RNA-seq data from 28 HCM patients and 9 healthy controls with pathogenic variant identification, differential expression analysis, and gene co-expression and protein–protein interaction network analyses. We identified 43 potential pathogenic variants in 19 genes in 24 HCM patients. Genes with more than one variant included the following: MYBPC3, TTN, MYH7, PSEN2, and LDB3. A total of 2538 protein-coding genes, six microRNAs (miRNAs), and 1617 long noncoding RNAs (lncRNAs) were identified differentially expressed between the groups, including several well-characterized cardiomyopathy-related genes (ANKRD1, FHL2, TGFB3, miR-30d, and miR-154). Gene enrichment analysis revealed that those genes are significantly involved in heart development and physiology. Furthermore, we highlighted four subnetworks: mtDNA-subnetwork, DSP-subnetwork, MYH7-subnetwork, and MYBPC3-subnetwork, which could play significant roles in the progression of HCM. Our findings further illustrate that HCM is a complex disease, which results from mutations in multiple protein-coding genes, modulation by non-coding RNAs and perturbations in gene networks.
High Expression of miR-34a Associated with Less Aggressive Cancer Biology but Not with Survival in Breast Cancer
Authors: Tokumaru Yoshihisa , Katsuta Eriko , Oshi Masanori , Sporn Judith C. , Yan Li , Le Lan , Matsuhashi Nobuhisa , Futamura Manabu , Akao Yukihiro , Yoshida Kazuhiro , Takabe Kazuaki
Published: April 2020

Most breast cancer (BC) patients succumb to metastatic disease. MiR-34a is a well-known tumor suppressive microRNA which exerts its anti-cancer functions by playing a role in p53, apoptosis induction, and epithelial-mesenchymal transition (EMT) suppression. Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) and The Cancer Genome Atlas (TCGA) cohorts were used to test our hypothesis that miR-34a high BCs translate to less aggressive cancer biology and better survival in large cohorts. There was no association between miR-34a expression levels and clinicopathological features of BC patients except for HER2 positivity. MiR-34a high expressing tumors were associated with lower Nottingham pathological grades and lower MKI67 expression. In agreement, high miR-34a tumors demonstrated lower GSVA scores of cell cycle and cell proliferation-related gene sets. High miR-34a tumors enriched the p53 pathway and apoptosis gene sets. Unexpectedly, high miR-34a tumors also associated with elevated EMT pathway score and ZEB1 and two expressions. MiR-34a expression did not associate with any distant metastasis. Further, high miR-34a tumors did not associate with better survival compared with miR-34a low tumors. In conclusion, the clinical relevance of miR-34a high expressing tumors was associated with suppressed cell proliferation, enhanced p53 pathway and apoptosis, but enhanced EMT and these findings did not reflect better survival outcomes in large BC patient cohorts.
Protein Arginine Methyltransferase 1 (PRMT1) Selective Inhibitor, TC-E 5003, Has Anti-Inflammatory Properties in TLR4 Signaling
Authors: Kim Eunji , Jang Jiwon , Park Jae Gwang , Kim Kyung-Hee , Yoon Keejung , Yoo Byong Chul , Cho Jae Youl
Published: April 2020

Protein arginine methyltransferase 1 (PRMT1) is the most predominant PRMT and is type I, meaning it generates monomethylarginine and asymmetric dimethylarginine. PRMT1 has functions in oxidative stress, inflammation and cancers, and modulates diverse diseases; consequently, numerous trials to develop PRMT1 inhibitors have been attempted. One selective PRMT1 inhibitor is N,N′-(Sulfonyldi-4,1-phenylene)bis(2-chloroacetamide), also named TC-E 5003 (TC-E). In this study, we investigated whether TC-E regulated inflammatory responses. Nitric oxide (NO) production was evaluated by the Griess assay and the inflammatory gene expression was determined by conducting RT-PCR. Western blot analyzing was carried out for inflammatory signaling exploration. TC-E dramatically reduced lipopolysaccharide (LPS)-induced NO production and the expression of inflammatory genes (inducible NO synthase (iNOS), cyclooxygenase (COX)-2, tumor necrosis factor (TNF)-α and interleukin (IL)-6) as determined using RT-PCR. TC-E downregulated the nuclear translocation of the nuclear factor (NF)-κB subunits p65 and p50 and the activator protein (AP)-1 transcriptional factor c-Jun. Additionally, TC-E directly regulated c-Jun gene expression following LPS treatment. In NF-κB signaling, the activation of IκBα and Src was attenuated by TC-E. Taken together, these data show that TC-E modulates the lipopolysaccharide (LPS)-induced AP-1 and NF-κB signaling pathways and could possibly be further developed as an anti-inflammatory compound.
Pharmacogenomics of Cognitive Dysfunction and Neuropsychiatric Disorders in Dementia
Authors: Cacabelos Ramon
Published: April 2020

Symptomatic interventions for patients with dementia involve anti-dementia drugs to improve cognition, psychotropic drugs for the treatment of behavioral disorders (BDs), and different categories of drugs for concomitant disorders. Demented patients may take >6–10 drugs/day with the consequent risk for drug–drug interactions and adverse drug reactions (ADRs >80%) which accelerate cognitive decline. The pharmacoepigenetic machinery is integrated by pathogenic, mechanistic, metabolic, transporter, and pleiotropic genes redundantly and promiscuously regulated by epigenetic mechanisms. CYP2D6, CYP2C9, CYP2C19, and CYP3A4/5 geno-phenotypes are involved in the metabolism of over 90% of drugs currently used in patients with dementia, and only 20% of the population is an extensive metabolizer for this tetragenic cluster. ADRs associated with anti-dementia drugs, antipsychotics, antidepressants, anxiolytics, hypnotics, sedatives, and antiepileptic drugs can be minimized by means of pharmacogenetic screening prior to treatment. These drugs are substrates, inhibitors, or inducers of 58, 37, and 42 enzyme/protein gene products, respectively, and are transported by 40 different protein transporters. APOE is the reference gene in most pharmacogenetic studies. APOE-3 carriers are the best responders and APOE-4 carriers are the worst responders; likewise, CYP2D6-normal metabolizers are the best responders and CYP2D6-poor metabolizers are the worst responders. The incorporation of pharmacogenomic strategies for a personalized treatment in dementia is an effective option to optimize limited therapeutic resources and to reduce unwanted side-effects.
Immunological Mechanisms in Inflammation-Associated Colon Carcinogenesis
Authors: Hirano Takehiro , Hirayama Daisuke , Wagatsuma Kohei , Yamakawa Tsukasa , Yokoyama Yoshihiro , Nakase Hiroshi
Published: April 2020

Patients with chronic inflammatory bowel diseases are at an increased risk of developing colitis-associated cancer (CAC). Chronic inflammation positively correlates with tumorigenesis. Similarly, the cumulative rate of incidence of developing CAC increases with prolonged colon inflammation. Immune signaling pathways, such as nuclear factor (NF)-κB, prostaglandin E2 (PGE2)/cyclooxygenase-2 (COX-2), interleukin (IL)-6/signal transducer and activator of transcription 3 (STAT3), and IL-23/T helper 17 cell (Th17), have been shown to promote CAC tumorigenesis. In addition, gut microbiota contributes to the development and progression of CAC. This review summarizes the signaling pathways involved in the pathogenesis following colon inflammation to understand the underlying molecular mechanisms in CAC tumorigenesis.
Molecular Drug Discovery of Single Ginsenoside Compounds as a Potent Bruton’s Tyrosine Kinase Inhibitor
Authors: Lee Keun Woo , Lee Woong Hee , Han Baek-Soo , Lee Jin Ha , Doo Eun Kyung , Kim Jeong-Hwan
Published: April 2020

Bruton’s tyrosine kinase (BTK) is known as a direct regulator of inflammasome, which is an intracellular target to therapeutically modulate innate immunity. Although there is great interest in developing small molecule-based drugs with BTK inhibition, there are only a few drugs available in the market, due to the difficulty of drug discovery and the potential side effects. To select suitable drug compounds to inhibit BTK signaling, molecular drug screening bioassay processes of single ginsenosides integrated with in silico molecular simulation were performed. The experimental results for the ginsenoside compositions (Rb2 and Rb3) exhibited showed that they effectively suppressed the activity of BTK expression in a rational agreement with molecular docking calculations of the compounds against the BTK binding site. They implemented a possible inhibiting effect of BTK signaling through increasing their molecular affinity for targeting BTK, enabling them to be useful in treating BTK-mediated diseases.
The Molecular and Mechanistic Insights Based on Gut–Liver Axis: Nutritional Target for Non-Alcoholic Fatty Liver Disease (NAFLD) Improvement
Authors: Ji Yun , Yin Yue , Sun Lijun , Zhang Weizhen
Published: April 2020

Non-alcoholic fatty liver disease (NAFLD) is recognized as the most frequent classification of liver disease around the globe. Along with the sequencing technologies, gut microbiota has been regarded as a vital factor for the maintenance of human and animal health and the mediation of multiple diseases. The modulation of gut microbiota as a mechanism affecting the pathogenesis of NAFLD is becoming a growing area of concern. Recent advances in the communication between gut and hepatic tissue pave novel ways to better explain the molecular mechanisms regarding the pathological physiology of NAFLD. In this review, we recapitulate the current knowledge of the mechanisms correlated with the development and progression of NAFLD regulated by the gut microbiome and gut–liver axis, which may provide crucial therapeutic strategies for NAFLD. These mechanisms predominantly involve: (1) the alteration in gut microbiome profile; (2) the effects of components and metabolites from gut bacteria (e.g., lipopolysaccharides (LPS), trimethylamine-N-oxide (TMAO), and N,N,N-trimethyl-5-aminovaleric acid (TMAVA)); and (3) the impairment of intestinal barrier function and bile acid homeostasis. In particular, the prevention and therapy of NAFLD assisted by nutritional strategies are highlighted, including probiotics, functional oligosaccharides, dietary fibers, ω-3 polyunsaturated fatty acids, functional amino acids (L-tryptophan and L-glutamine), carotenoids, and polyphenols, based on the targets excavated from the gut–liver axis.
Cannabidiol and Other Non-Psychoactive Cannabinoids for Prevention and Treatment of Gastrointestinal Disorders: Useful Nutraceuticals?
Authors: Martínez Vicente , Iriondo De-Hond Amaia , Borrelli Francesca , Capasso Raffaele , del Castillo María Dolores , Abalo Raquel
Published: April 2020

Cannabis sativa is an aromatic annual flowering plant with several botanical varieties, used for different purposes, like the production of fibers, the production of oil from the seeds, and especially for recreational or medical purposes. Phytocannabinoids (terpenophenolic compounds derived from the plant), include the well-known psychoactive cannabinoid Δ9-tetrahydrocannabinol, and many non-psychoactive cannabinoids, like cannabidiol. The endocannabinoid system (ECS) comprises of endocannabinoid ligands, enzymes for synthesis and degradation of such ligands, and receptors. This system is widely distributed in the gastrointestinal tract, where phytocannabinoids exert potent effects, particularly under pathological (i.e., inflammatory) conditions. Herein, we will first look at the hemp plant as a possible source of new functional food ingredients and nutraceuticals that might be eventually useful to treat or even prevent gastrointestinal conditions. Subsequently, we will briefly describe the ECS and the general pharmacology of phytocannabinoids. Finally, we will revise the available data showing that non-psychoactive phytocannabinoids, particularly cannabidiol, may be useful to treat different disorders and diseases of the gastrointestinal tract. With the increasing interest in the development of functional foods for a healthy life, the non-psychoactive phytocannabinoids are hoped to find a place as nutraceuticals and food ingredients also for a healthy gastrointestinal tract function.
Functional Lipids in Autoimmune Inflammatory Diseases
Authors: Cas Michele Dei , Roda Gabriella , Li Feng , Secundo Francesco
Published: April 2020

Lipids are apolar small molecules known not only as components of cell membranes but also, in recent literature, as modulators of different biological functions. Herein, we focused on the bioactive lipids that can influence the immune responses and inflammatory processes regulating vascular hyperreactivity, pain, leukocyte trafficking, and clearance. In the case of excessive pro-inflammatory lipid activity, these lipids also contribute to the transition from acute to chronic inflammation. Based on their biochemical function, these lipids can be divided into different families, including eicosanoids, specialized pro-resolving mediators, lysoglycerophospholipids, sphingolipids, and endocannabinoids. These bioactive lipids are involved in all phases of the inflammatory process and the pathophysiology of different chronic autoimmune diseases such as rheumatoid arthritis, multiple sclerosis, type-1 diabetes, and systemic lupus erythematosus.
On Top of the Alveolar Epithelium: Surfactant and the Glycocalyx
Authors: Ochs Matthias , Hegermann Jan , Lopez-Rodriguez Elena , Timm Sara , Nouailles Geraldine , Matuszak Jasmin , Simmons Szandor , Witzenrath Martin , Kuebler Wolfgang M.
Published: April 2020

Gas exchange in the lung takes place via the air-blood barrier in the septal walls of alveoli. The tissue elements that oxygen molecules have to cross are the alveolar epithelium, the interstitium and the capillary endothelium. The epithelium that lines the alveolar surface is covered by a thin and continuous liquid lining layer. Pulmonary surfactant acts at this air-liquid interface. By virtue of its biophysical and immunomodulatory functions, surfactant keeps alveoli open, dry and clean. What needs to be added to this picture is the glycocalyx of the alveolar epithelium. Here, we briefly review what is known about this glycocalyx and how it can be visualized using electron microscopy. The application of colloidal thorium dioxide as a staining agent reveals differences in the staining pattern between type I and type II alveolar epithelial cells and shows close associations of the glycocalyx with intraalveolar surfactant subtypes such as tubular myelin. These morphological findings indicate that specific spatial interactions between components of the surfactant system and those of the alveolar epithelial glycocalyx exist which may contribute to the maintenance of alveolar homeostasis, in particular to alveolar micromechanics, to the functional integrity of the air-blood barrier, to the regulation of the thickness and viscosity of the alveolar lining layer, and to the defence against inhaled pathogens. Exploring the alveolar epithelial glycocalyx in conjunction with the surfactant system opens novel physiological perspectives of potential clinical relevance for future research.
A Strategy for Personalized Treatment of iPS-Retinal Immune Rejections Assessed in Cynomolgus Monkey Models
Authors: Fujii Shota , Sugita Sunao , Futatsugi Yoko , Ishida Masaaki , Edo Ayaka , Makabe Kenichi , Kamao Hiroyuki , Iwasaki Yuko , Sakaguchi Hirokazu , Hirami Yasuhiko , Kurimoto Yasuo , Takahashi Masayo
Published: April 2020

Recently, we successfully transplanted an autograft, or major histocompatibility complex (MHC)-matched allografts, from induced-pluripotent-stem-cell-derived retinal pigment epithelial (iPSC-RPE) cells in patients with age-related macular degeneration. However, there was an issue regarding immune rejection after transplantation. In this study, we established a preoperational in vitro “drug–lymphocytes–grafts immune reaction (Drug-LGIR)” test to determine the medication for immune rejection using host immunocompetent cells (lymphocytes) and transplant cells (target iPSC-RPE cells) together with different medications. The adequacy of the test was assessed by in vivo transplantation in monkey models together with medication based on in vitro data. In the results of Drug-LGIR tests, some drugs exhibited significant suppression of RPE cell-related allogeneic reactions, while other drugs did not, and the efficacy of each drug differed among the recipient monkeys. Based on the results of Drug-LGIR, we applied cyclosporine A or local steroid (triamcinolone) therapy to two monkeys, and successfully suppressed RPE-related immune rejections with RPE grafts, which survived without any signs of rejection under drug administration. We propose that our new preoperational in vitro Drug-LGIR test, which specifies the most efficacious medication for each recipient, is useful for controlling immune attacks with personalized treatment for each patient after retinal transplantation.
Increase in Efficacy of Checkpoint Inhibition by Cytokine-Induced-Killer Cells as a Combination Immunotherapy for Renal Cancer
Authors: Dehno Mojgan Naghizadeh , Li Yutao , Weiher Hans , Schmidt-Wolf Ingo G.H.
Published: April 2020

Cytokine-induced killer (CIK) cells are heterogeneous, major histocompatibility complex (MHC)-unrestricted T lymphocytes that have acquired the expression of several natural killer (NK) cell surface markers following the addition of interferon gamma (IFN-γ), OKT3 and interleukin-2 (IL-2). Treatment with CIK cells demonstrates a practical approach in cancer immunotherapy with limited, if any, graft versus host disease (GvHD) toxicity. CIK cells have been proposed and tested in many clinical trials in cancer patients by autologous, allogeneic or haploidentical administration. The possibility of combining them with specific monoclonal antibodies nivolumab and ipilimumab will further expand the possibility of their clinical utilization. Initially, phenotypic analysis was performed to explore CD3, CD4, CD56, PD-1 and CTLA-4 expression on CIK cells and PD-L1/PD-L2 expression on tumor cells. We further treated CIK cells with nivolumab and ipilimumab and measured the cytotoxicity of CIK cells cocultured to renal carcinoma cell lines, A-498 and Caki-2. We observed a significant decrease in viability of renal cell lines after treating with CIK cells (p < 0.0001) in comparison to untreated renal cell lines and anti-PD-1 or anti-CTLA-4 treatment had no remarkable effect on the viability of tumor cells. Using CCK-8, Precision Count Beads™ and Cell Trace™ violet proliferation assays, we proved significant increased proliferation of CIK cells in the presence of a combination of anti-PD-1 and anti-CTLA-4 antibodies compared to untreated CIK cells. The IFN-γ secretion increased significantly in the presence of A-498 and combinatorial blockade of PD-1 and CTLA-4 compared to nivolumab or ipilimumab monotreatment (p < 0.001). In conclusion, a combination of immune checkpoint inhibition with CIK cells augments cytotoxicity of CIK cells against renal cancer cells.
Fingolimod Modulates Dendritic Architecture in a BDNF-Dependent Manner
Authors: Patnaik Abhisarika , Spiombi Eleonora , Frasca Angelisa , Landsberger Nicoletta , Zagrebelsky Marta , Korte Martin
Published: April 2020

The brain-derived neurotrophic factor (BDNF) plays crucial roles in both the developing and mature brain. Moreover, alterations in BDNF levels are correlated with the cognitive impairment observed in several neurological diseases. Among the different therapeutic strategies developed to improve endogenous BDNF levels is the administration of the BDNF-inducing drug Fingolimod, an agonist of the sphingosine-1-phosphate receptor. Fingolimod treatment was shown to rescue diverse symptoms associated with several neurological conditions (i.e., Alzheimer disease, Rett syndrome). However, the cellular mechanisms through which Fingolimod mediates its BDNF-dependent therapeutic effects remain unclear. We show that Fingolimod regulates the dendritic architecture, dendritic spine density and morphology of healthy mature primary hippocampal neurons. Moreover, the application of Fingolimod upregulates the expression of activity-related proteins c-Fos and pERK1/2 in these cells. Importantly, we show that BDNF release is required for these actions of Fingolimod. As alterations in neuronal structure underlie cognitive impairment, we tested whether Fingolimod application might prevent the abnormalities in neuronal structure typical of two neurodevelopmental disorders, namely Rett syndrome and Cdk5 deficiency disorder. We found a significant rescue in the neurite architecture of developing cortical neurons from Mecp2 and Cdkl5 mutant mice. Our study provides insights into understanding the BDNF-dependent therapeutic actions of Fingolimod.
Hyaluronan-Metal Gold Nanoparticle Hybrids for Targeted Tumor Cell Therapy
Authors: Sanfilippo Vanessa , Caruso Viviana Carmela Linda , Cucci Lorena Maria , Inturri Rosanna , Vaccaro Susanna , Satriano Cristina
Published: April 2020

In this study, a novel multifunctional nanoplatform based on core-shell nanoparticles of spherical gold nanoparticles (AuNPs) capped with low and high molecular weight (200 and 700 kDa) hyaluronic acid (HA), was assembled via a green, one-pot redox synthesis method at room temperature. A multitechnique characterization approach by UV-visible spectroscopy, dynamic light scattering and atomic force microscopy pointed to the effective ‘surface decoration’ of the gold nanoparticles by HA, resulting in different grafting densities of the biopolymer chains at the surface of the metal nanoparticle, which in turn affected the physicochemical properties of the nanoparticles. Specifically, the spectral features of the gold plasmonic peak (and the related calculated optical size), the hydrodynamic diameter and the nanoparticle stability were found to depend on the molecular weight of the HA. The CD44-targeting capability of HA-functionalized gold nanoparticles was tested in terms of antibacterial activity and cytotoxicity. An enhanced inhibitory activity against both Gram-negative Escherichia coli and Gram-positive Staphylococcus aureus was found, with a HA molecular weight (MW)-dependent trend for the HA-capped AuNPs compared to the bare, glucose-capped AuNPs. Cell viability assays performed on two CD44-positive cell models, namely normal human umbilical vein endothelial (HUVEC) and prostate tumor (PC-3) cells, in comparison with neuroblastoma cells (SH-SY5Y), which do not express the CD44 receptor, demonstrated an increased cytotoxicity in neuroblastoma compared to prostate cancer cells upon the cellular treatments by HA–AuNP compared to the bare AuNP, but a receptor-dependent perturbation effect on cytoskeleton actin and lysosomal organelles, as detected by confocal microscopy. These results highlighted the promising potentialities of the HA-decorated gold nanoparticles for selective cytotoxicity in cancer therapy. Confocal microscopy imaging of the two human tumor cell models demonstrated a membrane-confined uptake of HA-capped AuNP in the cancer cells that express CD44 receptors and the different perturbation effects related to molecular weight of HA wrapping the metallic core of the plasmonic nanoparticles on cellular organelles and membrane mobility.