bluuebunny/crossref_metadata_2025 huggingface dataset:
Absence of Detectable Radionuclides in Breast Milk in Sendai, Japan in 2012 Even by High-Sensitivity Determination: Estimated Dose among Infants after the Fukushima Nuclear Disaster
Authors: Lyu Zhaoqing , Soleman Sani Rachman , Fujitani Tomoko , Fujii Yukiko , Mahmoud Manal A. M. , Harada Kouji H.
Published: May 2021

The aim of this study was to estimate radionuclide levels in breast milk and the transferred dose to their infants in Sendai (100 km from Fukushima), Japan after the 2011 Fukushima nuclear disaster. Radionuclide concentrations were analyzed in 101 specimens of breast milk collected in 2012. Median values for minimum detectable activities were 0.39, 0.34, 1.1, 1.89, and 17.1 Bq/kg for 137Cs, 134Cs, 131I, 110mAg, and 40K, respectively. Only radionuclides from 40K were detected. To estimate potential exposure and radiocesium dose, we assumed that the samples contained each minimum detectable activity level. The mean minimum detectable activity concentrations (standard deviation) of 137Cs and 134Cs were 0.42 (0.15) and 0.37 (0.14) Bq/kg, respectively. Means of estimated dietary intakes of 137Cs and 134Cs among infants were 0.35 (0.12) and 0.31 (0.11) Bq/day, respectively. The committed effective doses of radiocesium in infants aged 3 and 12 months via breastmilk were estimated at 5.6 (2.1) and 3.3 (1.2) μSv/year, respectively. Dietary intakes of 137Cs and 134Cs in breastfeeding mothers were back-calculated at 1.9 (0.71) and 1.7 (0.65) Bq/day, respectively. The study verified no discernible exposure to radionuclides among infants. The most conservative estimates were below the Japanese internal exposure limit of 1 mSv/year.
Evaluating Exercise Progression in an Australian Cardiac Rehabilitation Program: Should Cardiac Intervention, Age, or Physical Capacity Be Considered?
Authors: Price Kym Joanne , Gordon Brett Ashley , Bird Stephen Richard , Benson Amanda Clare
Published: May 2021

Progression of prescribed exercise is important to facilitate attainment of optimal physical capacity during cardiac rehabilitation. However, it is not clear how often exercise is progressed or to what extent. This study evaluated whether exercise progression during clinical cardiac rehabilitation was different between cardiovascular treatment, age, or initial physical capacity. The prescribed exercise of sixty patients who completed 12 sessions of outpatient cardiac rehabilitation at a major Australian metropolitan hospital was evaluated. The prescribed aerobic exercise dose was progressed using intensity rather than duration, while repetitions and weight lifted were utilised to progress resistance training dose. Cardiovascular treatment or age did not influence exercise progression, while initial physical capacity and strength did. Aerobic exercise intensity relative to initial physical capacity was progressed from the first session to the last session for those with high (from mean (95%CI) 44.6% (42.2–47.0) to 68.3% (63.5–73.1); p < 0.001) and moderate physical capacity at admission (from 53.0% (50.7–55.3) to 76.3% (71.2–81.4); p < 0.001), but not in those with low physical capacity (from 67.3% (63.7–70.9) to 85.0% (73.7–96.2); p = 0.336). The initial prescription for those with low physical capacity was proportionately higher than for those with high capacity (p < 0.001). Exercise testing should be recommended in guidelines to facilitate appropriate exercise prescription and progression.
Hormonal Differences in Intimate Partner Violence Perpetrators When They Cope with Acute Stress: A Pilot Study
Authors: Romero-Martínez Ángel , Blanco-Gandía Mari-Carmen , Rodriguez-Arias Marta , Lila Marisol , Moya-Albiol Luis
Published: May 2021

Background: Only a few studies have paid attention to the ability of perpetrators of intimate partner violence (IPVAW) against women to cope with acute stress, including hormonal parameters. In fact, previous studies assessed how salivary testosterone (Tsal) and cortisol (Csal) changed after coping with an acute emotional stressor (directly related to IPVAW), and they concluded that an imbalance between the two hormones might be characteristic of these men. Nevertheless, they neglected to examine the role of other hormones, such as salivary oxytocin (OXsal), which also seemed to play an important role in behavioral regulation, and whether this response could be generalized to other types of stress not directly related to IPVAW. Methods: This study aims to assess whether IPVAW perpetrators (n = 19) present differential hormonal (Tsal, Csal, OXsal and their ratios) and psychological state (anxiety, anger, and general affect) responses when coping with an acute cognitive laboratory stressor (a set of neuropsychological tests performed in front of an expert committee) in comparison with non-violent men (n = 16). This quasi-experimental study also assessed whether the psychological state variables drive this different hormonal response. Results: Our results revealed that IPVAW perpetrators had lower Csal and higher Tsal/Csal ratio levels during the post-task period, as well as higher total levels (average) of OXsal than controls. We also found that, only in IPVAW perpetrators, high levels of baseline anxiety and negative affect were related to high rises in Csal during the stress task. Conclusions: These data present a background showing that IPVAW perpetrators and non-violent men cope differently with stress. These findings might help to identify idiosyncratic profiles of IPVAW perpetrators that can then be employed to establish their therapeutic needs. Moreover, we reinforced the importance of combining biological markers with self-reports, thus increasing the reliability of these forensic assessments.
Acute and Sub-Chronic Effects of Microplastics (3 and 10 µm) on the Human Intestinal Cells HT-29
Authors: Visalli Giuseppa , Facciolà Alessio , Pruiti Ciarello Marianna , De Marco Giuseppe , Maisano Maria , Di Pietro Angela
Published: May 2021

Due to ingestion of contaminated foods, the human gastrointestinal tract is the most likely site of exposure to microplastics (MPs) with gut barrier dysfunction and intestinal inflammation. Aimed to assess the effects induced by MPs with different granulometry (polystyrene (PS) 3 and 10 µm), we performed an in vitro study by using the human intestinal cell line HT29. As a novelty, we assessed the sub-chronic exposure extending the treatment up to 48 days simulating the in vivo situation. In the range of 100–1600 particles mL−1, both the PS suspensions had moderate cytotoxicity after 24 h with percentages of mortality between 6.7 and 21.6 for the 10 µm and 6.1 and 29.6 for the 3 µm PS. Microscopic observation highlighted a more pronounced lysosomal membrane permeabilization in HT29 exposed to PS 3µm. Reactive oxygen species production was higher in cells exposed to PS 10 µm, but sub-chronic exposure highlighted the ability of the cells to partially neutralize this effect. Comet-assay confirmed the temporary oxidative damage that was PS-induced. Overall, considering the very fast turnover of intestinal cells, the increase in cell mortality, equal to 25% and 11% for 3 and 10 µm PS-MPs for each time point, could trigger intestinal disorders due to prolonged exposure.
Improving Victimization Risk Estimation: A Geographically Weighted Regression Approach
Authors: Ramos Rafael G.
Published: May 2021

Standardized crime rates (e.g., “homicides per 100,000 people”) are commonly used in crime analysis as indicators of victimization risk but are prone to several issues that can lead to bias and error. In this study, a more robust approach (GWRisk) is proposed for tackling the problem of estimating victimization risk. After formally defining victimization risk and modeling its sources of uncertainty, a new method is presented: GWRisk uses geographically weighted regression to model the relation between crime counts and population size, and the geographically varying coefficient generated can be interpreted as the victimization risk. A simulation study shows how GWRisk outperforms naïve standardization and Empirical Bayesian Estimators in estimating risk. In addition, to illustrate its use, GWRisk is applied to the case of residential burglaries in Belo Horizonte, Brazil. This new approach allows more robust estimates of victimization risk than other traditional methods. Spurious spikes of victimization risk, commonly found in areas with small populations when other methods are used, are filtered out by GWRisk. Finally, GWRisk allows separating a reference population into segments (e.g., houses, apartments), estimating the risk for each segment even if crime counts were not provided per segment.
HSV-1 and Endogenous Retroviruses as Risk Factors in Demyelination
Authors: Bello-Morales Raquel , Andreu Sabina , Ripa Inés , López-Guerrero José Antonio
Published: May 2021

Herpes simplex virus type 1 (HSV-1) is a neurotropic alphaherpesvirus that can infect the peripheral and central nervous systems, and it has been implicated in demyelinating and neurodegenerative processes. Transposable elements (TEs) are DNA sequences that can move from one genomic location to another. TEs have been linked to several diseases affecting the central nervous system (CNS), including multiple sclerosis (MS), a demyelinating disease of unknown etiology influenced by genetic and environmental factors. Exogenous viral transactivators may activate certain retrotransposons or class I TEs. In this context, several herpesviruses have been linked to MS, and one of them, HSV-1, might act as a risk factor by mediating processes such as molecular mimicry, remyelination, and activity of endogenous retroviruses (ERVs). Several herpesviruses have been involved in the regulation of human ERVs (HERVs), and HSV-1 in particular can modulate HERVs in cells involved in MS pathogenesis. This review exposes current knowledge about the relationship between HSV-1 and human ERVs, focusing on their contribution as a risk factor for MS.
Detection of SARS-CoV-2 RNA by a Multiplex Reverse-Transcription Loop-Mediated Isothermal Amplification Coupled with Melting Curves Analysis
Authors: Oscorbin Igor P. , Shevelev Georgiy Yu. , Pronyaeva Ksenia A. , Stepanov Andrey A. , Shamovskaya Darya V. , Mishukova Olga V. , Pyshnyi Dmitrii V. , Filipenko Maksim L.
Published: May 2021

Loop-mediated isothermal amplification (LAMP) is a method of nucleic acid amplification that is more stable and resistant to DNA amplification inhibitors than conventional PCR. LAMP multiplexing with reverse transcription allows for the single-tube amplification of several RNA fragments, including an internal control sample, which provides the option of controlling all analytical steps. We developed a method of SARS-CoV-2 viral RNA detection based on multiplex reverse-transcription LAMP, with single-tube qualitative analysis of SARS-CoV-2 RNA and MS2 phage used as a control RNA. The multiplexing is based on the differences in characteristic melting peaks generated during the amplification process. The developed technique detects at least 20 copies of SARS-CoV-2 RNA per reaction on a background of 12,000 MS2 RNA copies. The total time of analysis does not exceed 40 min. The method validation, performed on 125 clinical samples of patients’ nasal swabs, showed a 97.6% concordance rate with the results of real-time (RT)-PCR assays. The developed multiplexed LAMP can be employed as an alternative to PCR in diagnostic practice to save personnel and equipment time.
Current Perspectives on the Physiological Activities of Fermented Soybean-Derived Cheonggukjang
Authors: Kim Il-Sup , Hwang Cher-Won , Yang Woong-Suk , Kim Cheorl-Ho
Published: May 2021

Cheonggukjang (CGJ, fermented soybean paste), a traditional Korean fermented dish, has recently emerged as a functional food that improves blood circulation and intestinal regulation. Considering that excessive consumption of refined salt is associated with increased incidence of gastric cancer, high blood pressure, and stroke in Koreans, consuming CGJ may be desirable, as it can be made without salt, unlike other pastes. Soybeans in CGJ are fermented by Bacillus strains (B. subtilis or B. licheniformis), Lactobacillus spp., Leuconostoc spp., and Enterococcus faecium, which weaken the activity of putrefactive bacteria in the intestines, act as antibacterial agents against pathogens, and facilitate the excretion of harmful substances. Studies on CGJ have either focused on improving product quality or evaluating the bioactive substances contained in CGJ. The fermentation process of CGJ results in the production of enzymes and various physiologically active substances that are not found in raw soybeans, including dietary fiber, phospholipids, isoflavones (e.g., genistein and daidzein), phenolic acids, saponins, trypsin inhibitors, and phytic acids. These components prevent atherosclerosis, oxidative stress-mediated heart disease and inflammation, obesity, diabetes, senile dementia, cancer (e.g., breast and lung), and osteoporosis. They have also been shown to have thrombolytic, blood pressure-lowering, lipid-lowering, antimutagenic, immunostimulatory, anti-allergic, antibacterial, anti-atopic dermatitis, anti-androgenetic alopecia, and anti-asthmatic activities, as well as skin improvement properties. In this review, we examined the physiological activities of CGJ and confirmed its potential as a functional food.
Isoprenoid Derivatives of Lysophosphatidylcholines Enhance Insulin and GLP-1 Secretion through Lipid-Binding GPCRs
Authors: Drzazga Anna , Kamińska Daria , Gliszczyńska Anna , Gendaszewska-Darmach Edyta
Published: May 2021

Insulin plays a significant role in carbohydrate homeostasis as the blood glucose lowering hormone. Glucose-induced insulin secretion (GSIS) is augmented by glucagon-like peptide (GLP-1), a gastrointestinal peptide released in response to ingesting nutriments. The secretion of insulin and GLP-1 is mediated by the binding of nutrients to G protein-coupled receptors (GPCRs) expressed by pancreatic β-cells and enteroendocrine cells, respectively. Therefore, insulin secretagogues and incretin mimetics currently serve as antidiabetic treatments. This study demonstrates the potency of synthetic isoprenoid derivatives of lysophosphatidylcholines (LPCs) to stimulate GSIS and GLP-1 release. Murine insulinoma cell line (MIN6) and enteroendocrinal L cells (GLUTag) were incubated with LPCs bearing geranic acid (1-GA-LPC), citronellic acid (1-CA-LPC), 3,7-dimethyl-3-vinyloct-6-enoic acid (GERA-LPC), and (E)-3,7,11-trimethyl- 3-vinyldodeca-6,10-dienoic acid (1-FARA-LPC). Respective free terpene acids were also tested for comparison. Besides their insulin- and GLP-1-secreting capabilities, we also investigated the cytotoxicity of tested compounds, the ability to intracellular calcium ion mobilization, and targeted GPCRs involved in maintaining lipid and carbohydrate homeostasis. We observed the high cytotoxicity of 1-GERA-LPC and 1-FARA-LPC in contrast 1-CA-LPC and 1-GA-LPC. Moreover, 1-CA-LPC and 1-GA-LPC demonstrated the stimulatory effect on GSIS and 1-CA-LPC augmented GLP-1 secretion. Insulin and GLP-1 release appeared to be GPR40-, GPR55-, GPR119- and GPR120-dependent.
Potential of Mesenchymal Stem Cells in the Rejuvenation of the Aging Immune System
Authors: Yeo Genieve Ee Chia , Ng Min Hwei , Nordin Fazlina Binti , Law Jia Xian
Published: May 2021

Rapid growth of the geriatric population has been made possible with advancements in pharmaceutical and health sciences. Hence, age-associated diseases are becoming more common. Aging encompasses deterioration of the immune system, known as immunosenescence. Dysregulation of the immune cell production, differentiation, and functioning lead to a chronic subclinical inflammatory state termed inflammaging. The hallmarks of the aging immune system are decreased naïve cells, increased memory cells, and increased serum levels of pro-inflammatory cytokines. Mesenchymal stem cell (MSC) transplantation is a promising solution to halt immunosenescence as the cells have excellent immunomodulatory functions and low immunogenicity. This review compiles the present knowledge of the causes and changes of the aging immune system and the potential of MSC transplantation as a regenerative therapy for immunosenescence.
Increased Expression of 11β-Hydroxysteroid Dehydrogenase Type 1 Contributes to Epidermal Permeability Barrier Dysfunction in Aged Skin
Authors: Kim Beom Jun , Lee Noo Ri , Lee Chung Hyeok , Lee Young Bin , Choe Sung Jay , Lee Solam , Hwang Hyun Jee , Kim Eunjung , Lavery Gareth G. , Shin Kyong-Oh , Park Kyungho , Choi Eung Ho
Published: May 2021

Inactive cortisone is converted into active cortisol by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). Excessive levels of active glucocorticoids could deteriorate skin barrier function; barrier impairment is also observed in aged skin. In this study, we aimed to determine whether permeability barrier impairment in the aged skin could be related to increased 11β-HSD1 expression. Aged humans (n = 10) showed increased cortisol in the stratum corneum (SC) and oral epithelium, compared to young subjects (n = 10). 11β-HSD1 expression (as assessed via immunohistochemical staining) was higher in the aged murine skin. Aged hairless mice (56-week-old, n = 5) manifested greater transepidermal water loss, lower SC hydration, and higher levels of serum inflammatory cytokines than the young mice (8-week-old, n = 5). Aged 11β-HSD1 knockout mice (n = 11), 11β-HSD1 inhibitor (INHI)-treated aged wild type (WT) mice (n = 5) and young WT mice (n = 10) exhibited reduced SC corticosterone level. Corneodesmosome density was low in WT aged mice (n = 5), but high in aged 11β-HSD1 knockout and aged INHI-treated WT mice. Aged mice exhibited lower SC lipid levels; this effect was reversed by INHI treatment. Therefore, upregulation of 11β-HSD1 in the aged skin increases the active-glucocorticoid levels; this suppresses SC lipid biosynthesis, leading to impaired epidermal permeability barrier.
Multi-Omics Model Applied to Cancer Genetics
Authors: Pettini Francesco , Visibelli Anna , Cicaloni Vittoria , Iovinelli Daniele , Spiga Ottavia
Published: May 2021

In this review, we focus on bioinformatic oncology as an integrative discipline that incorporates knowledge from the mathematical, physical, and computational fields to further the biomedical understanding of cancer. Before providing a deeper insight into the bioinformatics approach and utilities involved in oncology, we must understand what is a system biology framework and the genetic connection, because of the high heterogenicity of the backgrounds of people approaching precision medicine. In fact, it is essential to providing general theoretical information on genomics, epigenomics, and transcriptomics to understand the phases of multi-omics approach. We consider how to create a multi-omics model. In the last section, we describe the new frontiers and future perspectives of this field.
Molecular Alterations in Gastric Intestinal Metaplasia
Authors: Jonaitis Paulius , Kupcinskas Limas , Kupcinskas Juozas
Published: May 2021

Gastric cancer (GC) remains one of the most common causes of mortality worldwide. Intestinal metaplasia (IM) is one of the preneoplastic gastric lesions and is considered an essential predisposing factor in GC development. Here we present a review of recent most relevant papers to summarize major findings on the molecular alterations in gastric IM. The latest progress in novel diagnostic methods allows scientists to identify various types of molecular alterations in IM, such as polymorphisms in various genes, changes in the expression of micro-RNAs and long noncoding RNAs, and altered microbiome profiles. The results have shown that some of these alterations have strong associations with IM and a potential to be used for screening, treatment, and prognostic purposes; however, one of the most important limiting factors is the inhomogeneity of the studies. Therefore, further large-scale studies and clinical trials with standardized methods designed by multicenter consortiums are needed. As of today, various molecular alterations in IM could become a part of personalized medicine in the near future, which would help us deliver a personalized approach for each patient and identify those at risk of progression to GC.
Assessment of a Small Molecule Synthetic Lignan in Enhancing Oxidative Balance and Decreasing Lipid Accumulation in Human Retinal Pigment Epithelia
Authors: Dhingra Anuradha , Sharp Rachel C. , Kim Taewan , Popov Anatoliy V. , Ying Gui-Shuang , Pietrofesa Ralph A. , Park Kyewon , Christofidou-Solomidou Melpo , Boesze-Battaglia Kathleen
Published: May 2021

Visual function depends on the intimate structural, functional and metabolic interactions between the retinal pigment epithelium (RPE) and the neural retina. The daily phagocytosis of the photoreceptor outer segment tips by the overlaying RPE provides essential nutrients for the RPE itself and photoreceptors through intricate metabolic synergy. Age-related retinal changes are often characterized by metabolic dysregulation contributing to increased lipid accumulation and peroxidation as well as the release of proinflammatory cytokines. LGM2605 is a synthetic lignan secoisolariciresinol diglucoside (SDG) with free radical scavenging, antioxidant and anti-inflammatory properties demonstrated in diverse in vitro and in vivo inflammatory disease models. In these studies, we tested the hypothesis that LGM2605 may be an attractive small-scale therapeutic that protects RPE against inflammation and restores its metabolic capacity under lipid overload. Using an in vitro model in which loss of the autophagy protein, LC3B, results in defective phagosome degradation and metabolic dysregulation, we show that lipid overload results in increased gasdermin cleavage, IL-1 β release, lipid accumulation and decreased oxidative capacity. The addition of LGM2605 resulted in enhanced mitochondrial capacity, decreased lipid accumulation and amelioration of IL-1 β release in a model of defective lipid homeostasis. Collectively, these studies suggest that lipid overload decreases mitochondrial function and increases the inflammatory response, with LGM2605 acting as a protective agent.
Changes in the Content of Organic Acids and Expression Analysis of Citric Acid Accumulation-Related Genes during Fruit Development of Yellow (Passiflora edulis f. flavicarpa) and Purple (Passiflora edulis f. edulis) Passion Fruits
Authors: Zhang Xiaoxue , Wei Xiaoxia , Ali Muhammad Moaaz , Rizwan Hafiz Muhammad , Li Binqi , Li Han , Jia Kaijie , Yang Xuelian , Ma Songfeng , Li Shaojia , Chen Faxing
Published: May 2021

Organic acids are key components that determine the taste and flavor of fruits and play a vital role in maintaining fruit quality and nutritive value. In this study, the fruits of two cultivars of passion fruit Yellow (Passiflora edulis f. flavicarpa) and purple (Passiflora edulis f. edulis) were harvested at five different developmental stages (i.e., fruitlet, green, veraison, near-mature and mature stage) from an orchard located in subtropical region of Fujian Province, China. The contents of six organic acids were quantified using ultra-performance liquid chromatography (UPLC), activities of citric acid related enzymes were determined, and expression levels of genes involved in citric acid metabolism were measured by quantitative real-time PCR (qRT-PCR). The results revealed that citric acid was the predominant organic acid in both cultivars during fruit development. The highest citric acid contents were observed in both cultivars at green stage, which were reduced with fruit maturity. Correlation analysis showed that citrate synthase (CS), cytosolic aconitase (Cyt-ACO) and cytosolic isocitrate dehydrogenase (Cyt-IDH) may be involved in regulating citric acid biosynthesis. Meanwhile, the PeCS2, PeACO4, PeACO5 and PeIDH1 genes may play an important role in regulating the accumulation of citric acid. This study provides new insights for future elucidation of key mechanisms regulating organic acid biosynthesis in passion fruit.
Human Polymerase δ-Interacting Protein 2 (PolDIP2) Inhibits the Formation of Human Tau Oligomers and Fibrils
Authors: Kasho Kazutoshi , Krasauskas Lukas , Smirnovas Vytautas , Stojkovič Gorazd , Morozova-Roche Ludmilla A. , Wanrooij Sjoerd
Published: May 2021

A central characteristic of Alzheimer’s disease (AD) and other tauopathies is the accumulation of aggregated and misfolded Tau deposits in the brain. Tau-targeting therapies for AD have been unsuccessful in patients to date. Here we show that human polymerase δ-interacting protein 2 (PolDIP2) interacts with Tau. With a set of complementary methods, including thioflavin-T-based aggregation kinetic assays, Tau oligomer-specific dot-blot analysis, and single oligomer/fibril analysis by atomic force microscopy, we demonstrate that PolDIP2 inhibits Tau aggregation and amyloid fibril growth in vitro. The identification of PolDIP2 as a potential regulator of cellular Tau aggregation should be considered for future Tau-targeting therapeutics.
The Role of PGC1α in Alzheimer’s Disease and Therapeutic Interventions
Authors: Mota Bibiana C. , Sastre Magdalena
Published: May 2021

The peroxisome proliferator-activated receptor co-activator-1α (PGC1α) belongs to a family of transcriptional regulators, which act as co-activators for a number of transcription factors, including PPARs, NRFs, oestrogen receptors, etc. PGC1α has been implicated in the control of mitochondrial biogenesis, the regulation of the synthesis of ROS and inflammatory cytokines, as well as genes controlling metabolic processes. The levels of PGC1α have been shown to be altered in neurodegenerative disorders. In the brains of Alzheimer’s disease (AD) patients and animal models of amyloidosis, PGC1α expression was reduced compared with healthy individuals. Recently, it was shown that overexpression of PGC1α resulted in reduced amyloid-β (Aβ) generation, particularly by regulating the expression of BACE1, the rate-limiting enzyme involved in the production of Aβ. These results provide evidence pointing toward PGC1α activation as a new therapeutic avenue for AD, which has been supported by the promising observations of treatments with drugs that enhance the expression of PGC1α and gene therapy studies in animal models of AD. This review summarizes the different ways and mechanisms whereby PGC1α can be neuroprotective in AD and the pre-clinical treatments that have been explored so far.
Antibody-Based Therapeutics for Atherosclerosis and Cardiovascular Diseases
Authors: Ji Eunhye , Lee Sahmin
Published: May 2021

Cardiovascular disease is the leading cause of death worldwide, and its prevalence is increasing due to the aging of societies. Atherosclerosis, a type of chronic inflammatory disease that occurs in arteries, is considered to be the main cause of cardiovascular diseases such as ischemic heart disease or stroke. In addition, the inflammatory response caused by atherosclerosis confers a significant effect on chronic inflammatory diseases such as psoriasis and rheumatic arthritis. Here, we review the mechanism of action of the main causes of atherosclerosis such as plasma LDL level and inflammation; furthermore, we review the recent findings on the preclinical and clinical effects of antibodies that reduce the LDL level and those that neutralize the cytokines involved in inflammation. The apolipoprotein B autoantibody and anti-PCSK9 antibody reduced the level of LDL and plaques in animal studies, but failed to significantly reduce carotid inflammation plaques in clinical trials. The monoclonal antibodies against PCSK9 (alirocumab, evolocumab), which are used as a treatment for hyperlipidemia, lowered cholesterol levels and the incidence of cardiovascular diseases. Antibodies that neutralize inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-17, and IL-12/23) have shown promising but contradictory results and thus warrant further research.
IDO and CD40 May Be Key Molecules for Immunomodulatory Capacity of the Primed Tonsil-Derived Mesenchymal Stem Cells
Authors: Lee Hyun-Joo , Jung Harry , Kim Dong-Kyu
Published: May 2021

Background: Tonsil-derived mesenchymal stem cells (T-MSCs) were reported to have suppressive effect on T cells, yet much remains unknown about the underlying mechanisms supporting this effect. We investigated the underlying mechanism of the immunomodulatory effect of T-MSCs on immune cell proliferation and cytokine production. Methods: We isolated T-MSCs from human palatine tonsil and evaluated the immunomodulatory capacity using RT-PCR, ELISA, and flow cytometry. Additionally, we assessed the expression of various soluble factors and several costimulatory molecules to detect the priming effect on T-MSCs. Results: T-MSCs significantly inhibited the immune cell proliferation and cytokine expression (TNF-α and IFN-γ) in the direct co-culture, but there was no suppressive effect in indirect co-culture. Additionally, we detected a remarkably higher expression of indoleamine 2,3-dioxygenase (IDO) in the primed T-MSCs having co-expression CD40. Moreover, immune cells or CD4+ T cells showed lower TNF-α, IFN-γ, and IL-4 expression when the primed T-MSC were added; whereas those findings were reversed when the inhibitor for IDO (not IL-4) or CD40 were added. Furthermore, T-bet and GATA3 levels were significantly decreased in the co-cultures of the primed T-MSCs and CD4+ T cells; whereas those findings were reversed when we added the neutralizing anti-CD40 antibody. Conclusions: Primed T-MSCs expressing IDO and CD40 may have immunomodulatory capacity via Th1-mediated and Th2-mediated immune response.
Sialic Acid-Siglec Axis in Human Immune Regulation, Involvement in Autoimmunity and Cancer and Potential Therapeutic Treatments
Authors: Gianchecchi Elena , Arena Andrea , Fierabracci Alessandra
Published: May 2021

Siglecs are sialic acid-binding immunoglobulin-like lectins. Most Siglecs function as transmembrane receptors mainly expressed on blood cells in a cell type-specific manner. They recognize and bind sialic acids in specific linkages on glycoproteins and glycolipids. Since Sia is a self-molecule, Siglecs play a role in innate immune responses by distinguishing molecules as self or non-self. Increasing evidence supports the involvement of Siglecs in immune signaling representing immune checkpoints able to regulate immune responses in inflammatory diseases as well as cancer. Although further studies are necessary to fully understand the involvement of Siglecs in pathological conditions as well as their interactions with other immune regulators, the development of therapeutic approaches that exploit these molecules represents a tremendous opportunity for future treatments of several human diseases, as demonstrated by their application in several clinical trials. In the present review, we discuss the involvement of Siglecs in the regulation of immune responses, with particular focus on autoimmunity and cancer and the chance to target the sialic acid-Siglec axis as novel treatment strategy.
Histone Deacetylase Inhibitors Ameliorate Morphological Defects and Hypoexcitability of iPSC-Neurons from Rubinstein-Taybi Patients
Authors: Alari Valentina , Scalmani Paolo , Ajmone Paola Francesca , Perego Sara , Avignone Sabrina , Catusi Ilaria , Lonati Paola Adele , Borghi Maria Orietta , Finelli Palma , Terragni Benedetta , Mantegazza Massimo , Russo Silvia , Larizza Lidia
Published: May 2021

Rubinstein-Taybi syndrome (RSTS) is a rare neurodevelopmental disorder caused by mutations in CREBBP or EP300 genes encoding CBP/p300 lysine acetyltransferases. We investigated the efficacy of the histone deacetylase inhibitor (HDACi) Trichostatin A (TSA) in ameliorating morphological abnormalities of iPSC-derived young neurons from P149 and P34 CREBBP-mutated patients and hypoexcitability of mature neurons from P149. Neural progenitors from both patients’ iPSC lines were cultured one week with TSA 20 nM and, only P149, for 6 weeks with TSA 0.2 nM, in parallel to neural progenitors from controls. Immunofluorescence of MAP2/TUJ1 positive cells using the Skeletonize Image J plugin evidenced that TSA partially rescued reduced nuclear area, and decreased branch length and abnormal end points number of both 45 days patients’ neurons, but did not influence the diminished percentage of their neurons with respect to controls. Patch clamp recordings of TSA-treated post-mitotic P149 neurons showed complete/partial rescue of sodium/potassium currents and significant enhancement of neuron excitability compared to untreated replicas. Correction of abnormalities of P149 young neurons was also affected by valproic acid 1 mM for 72 h, with some variation, with respect to TSA, on the morphological parameter. These findings hold promise for development of an epigenetic therapy to attenuate RSTS patients cognitive impairment.
Application of Immunohistochemistry in the Pathological Diagnosis of Liver Tumors
Authors: Takahashi Yoshihisa , Dungubat Erdenetsogt , Kusano Hiroyuki , Ganbat Dariimaa , Tomita Yasuhiko , Odgerel Sarandelger , Fukusato Toshio
Published: May 2021

Although radiological diagnostics have been progressing, pathological diagnosis remains the most reliable method for diagnosing liver tumors. In some cases, definite pathological diagnosis cannot be obtained by histological evaluation alone, especially when the sample is a small biopsy; in such cases, immunohistochemical staining is very useful. Immunohistochemistry is the most frequently used technique for molecular pathological diagnosis due to its broad application, ease of performance and evaluation, and reasonable cost. The results occasionally reflect specific genetic mutations. The immunohistochemical markers of hepatocellular carcinoma include those of hepatocellular differentiation—such as hepatocyte paraffin 1 and arginase-1—and those of malignant hepatocytes—such as glypican-3, heat shock protein 70, and glutamine synthetase (GS). To classify the subtypes of hepatocellular adenoma, examination of several immunohistochemical markers, such as liver fatty acid-binding protein, GS, and serum amyloid A, is indispensable. Immunohistochemical staining for GS is also important for the diagnosis of focal nodular hyperplasia. The representative immunohistochemical markers of intrahepatic cholangiocarcinoma include cytokeratin (CK) 7 and CK19. In this article, we provide an overview of the application of immunohistochemistry in the pathological diagnosis of liver tumors referring to the association with genetic alterations. Furthermore, we aimed to explain the practical points in the differential diagnosis of liver tumors by immunohistochemical staining.
Molecular Genetics of Conjunctival Melanoma and Prognostic Value of TERT Promoter Mutation Analysis
Authors: van Poppelen Natasha M. , van Ipenburg Jolique A. , van den Bosch Quincy , Vaarwater Jolanda , Brands Tom , Eussen Bert , Magielsen Frank , Dubbink Hendrikus J. , Paridaens Dion , Brosens Erwin , Naus Nicole , de Klein Annelies , Kiliç Emine , Verdijk Robert M.
Published: May 2021

The aim of this study was exploration of the genetic background of conjunctival melanoma (CM) and correlation with recurrent and metastatic disease. Twenty-eight CM from the Rotterdam Ocular Melanoma Study group were collected and DNA was isolated from the formalin-fixed paraffin embedded tissue. Targeted next-generation sequencing was performed using a panel covering GNAQ, GNA11, EIF1AX, BAP1, BRAF, NRAS, c-KIT, PTEN, SF3B1, and TERT genes. Recurrences and metastasis were present in eight (29%) and nine (32%) CM cases, respectively. TERT promoter mutations were most common (54%), but BRAF (46%), NRAS (21%), BAP1 (18%), PTEN (14%), c-KIT (7%), and SF3B1 (4%) mutations were also observed. No mutations in GNAQ, GNA11, and EIF1AX were found. None of the mutations was significantly associated with recurrent disease. Presence of a TERT promoter mutation was associated with metastatic disease (p-value = 0.008). Based on our molecular findings, CM comprises a separate entity within melanoma, although there are overlapping molecular features with uveal melanoma, such as the presence of BAP1 and SF3B1 mutations. This warrants careful interpretation of molecular data, in the light of clinical findings. About three quarter of CM contain drug-targetable mutations, and TERT promoter mutations are correlated to metastatic disease in CM.
Modulation of Cellular Response to Different Parameters of the Rotating Magnetic Field (RMF)—An In Vitro Wound Healing Study
Authors: Jedrzejczak-Silicka Magdalena , Kordas Marian , Konopacki Maciej , Rakoczy Rafał
Published: May 2021

Since the effect of MFs (magnetic fields) on various biological systems has been studied, different results have been obtained from an insignificant effect of weak MFs on the disruption of the circadian clock system. On the other hand, magnetic fields, electromagnetic fields, or electric fields are used in medicine. The presented study was conducted to determine whether a low-frequency RMF (rotating magnetic field) with different field parameters could evoke the cellular response in vitro and is possible to modulate the cellular response. The cellular metabolic activity, ROS and Ca2+ concentration levels, wound healing assay, and gene expression analyses were conducted to evaluate the effect of RMF. It was shown that different values of magnetic induction (B) and frequency (f) of RMF evoke a different response of cells, e.g., increase in the general metabolic activity may be associated with the increasing of ROS levels. The lower intracellular Ca2+ concentration (for 50 Hz) evoked the inability of cells to wound closure. It can be stated that the subtle balance in the ROS level is crucial in the wound for the effective healing process, and it is possible to modulate the cellular response to the RMF in the context of an in vitro wound healing.
Extracellular Vesicles as a Therapeutic Tool for Kidney Disease: Current Advances and Perspectives
Authors: Corrêa Raphael Rodrigues , Juncosa Estela Mancheño , Masereeuw Rosalinde , Lindoso Rafael Soares
Published: May 2021

Extracellular vesicles (EVs) have been described as important mediators of cell communication, regulating several physiological processes, including tissue recovery and regeneration. In the kidneys, EVs derived from stem cells have been shown to support tissue recovery in diverse disease models and have been considered an interesting alternative to cell therapy. For this purpose, however, several challenges remain to be overcome, such as the requirement of a high number of EVs for human therapy and the need for optimization of techniques for their isolation and characterization. Moreover, the kidney’s complexity and the pathological process to be treated require that EVs present a heterogeneous group of molecules to be delivered. In this review, we discuss the recent advances in the use of EVs as a therapeutic tool for kidney diseases. Moreover, we give an overview of the new technologies applied to improve EVs’ efficacy, such as novel methods of EV production and isolation by means of bioreactors and microfluidics, bioengineering the EV content and the use of alternative cell sources, including kidney organoids, to support their transfer to clinical applications.
Glycosylation Biomarkers Associated with Age-Related Diseases and Current Methods for Glycan Analysis
Authors: Paton Beatrix , Suarez Manuel , Herrero Pol , Canela Núria
Published: May 2021

Ageing is a complex process which implies the accumulation of molecular, cellular and organ damage, leading to an increased vulnerability to disease. In Western societies, the increase in the elderly population, which is accompanied by ageing-associated pathologies such as cardiovascular and mental diseases, is becoming an increasing economic and social burden for governments. In order to prevent, treat and determine which subjects are more likely to develop these age-related diseases, predictive biomarkers are required. In this sense, some studies suggest that glycans have a potential role as disease biomarkers, as they modify the functions of proteins and take part in intra- and intercellular biological processes. As the glycome reflects the real-time status of these interactions, its characterisation can provide potential diagnostic and prognostic biomarkers for multifactorial diseases. This review gathers the alterations in protein glycosylation profiles that are associated with ageing and age-related diseases, such as cancer, type 2 diabetes mellitus, metabolic syndrome and several chronic inflammatory diseases. Furthermore, the review includes the available techniques for the determination and characterisation of glycans, such as liquid chromatography, electrophoresis, nuclear magnetic resonance and mass spectrometry.
A Comprehensive Review: Sphingolipid Metabolism and Implications of Disruption in Sphingolipid Homeostasis
Authors: Quinville Brianna M. , Deschenes Natalie M. , Ryckman Alex E. , Walia Jagdeep S.
Published: May 2021

Sphingolipids are a specialized group of lipids essential to the composition of the plasma membrane of many cell types; however, they are primarily localized within the nervous system. The amphipathic properties of sphingolipids enable their participation in a variety of intricate metabolic pathways. Sphingoid bases are the building blocks for all sphingolipid derivatives, comprising a complex class of lipids. The biosynthesis and catabolism of these lipids play an integral role in small- and large-scale body functions, including participation in membrane domains and signalling; cell proliferation, death, migration, and invasiveness; inflammation; and central nervous system development. Recently, sphingolipids have become the focus of several fields of research in the medical and biological sciences, as these bioactive lipids have been identified as potent signalling and messenger molecules. Sphingolipids are now being exploited as therapeutic targets for several pathologies. Here we present a comprehensive review of the structure and metabolism of sphingolipids and their many functional roles within the cell. In addition, we highlight the role of sphingolipids in several pathologies, including inflammatory disease, cystic fibrosis, cancer, Alzheimer’s and Parkinson’s disease, and lysosomal storage disorders.
Mechanisms of Nausea and Vomiting: Current Knowledge and Recent Advances in Intracellular Emetic Signaling Systems
Authors: Zhong Weixia , Shahbaz Omar , Teskey Garrett , Beever Abrianna , Kachour Nala , Venketaraman Vishwanath , Darmani Nissar A.
Published: May 2021

Nausea and vomiting are common gastrointestinal complaints that can be triggered by diverse emetic stimuli through central and/or peripheral nervous systems. Both nausea and vomiting are considered as defense mechanisms when threatening toxins/drugs/bacteria/viruses/fungi enter the body either via the enteral (e.g., the gastrointestinal tract) or parenteral routes, including the blood, skin, and respiratory systems. While vomiting is the act of forceful removal of gastrointestinal contents, nausea is believed to be a subjective sensation that is more difficult to study in nonhuman species. In this review, the authors discuss the anatomical structures, neurotransmitters/mediators, and corresponding receptors, as well as intracellular emetic signaling pathways involved in the processes of nausea and vomiting in diverse animal models as well as humans. While blockade of emetic receptors in the prevention of vomiting is fairly well understood, the potential of new classes of antiemetics altering postreceptor signal transduction mechanisms is currently evolving, which is also reviewed. Finally, future directions within the field will be discussed in terms of important questions that remain to be resolved and advances in technology that may help provide potential answers.
C3 Deficiency Leads to Increased Angiogenesis and Elevated Pro-Angiogenic Leukocyte Recruitment in Ischemic Muscle Tissue
Authors: Götz Philipp , Braumandl Anna , Kübler Matthias , Kumaraswami Konda , Ishikawa-Ankerhold Hellen , Lasch Manuel , Deindl Elisabeth
Published: May 2021

The complement system is a potent inflammatory trigger, activator, and chemoattractant for leukocytes, which play a crucial role in promoting angiogenesis. However, little information is available about the influence of the complement system on angiogenesis in ischemic muscle tissue. To address this topic and analyze the impact of the complement system on angiogenesis, we induced muscle ischemia in complement factor C3 deficient (C3−/−) and wildtype control mice by femoral artery ligation (FAL). At 24 h and 7 days after FAL, we isolated the ischemic gastrocnemius muscles and investigated them by means of (immuno-)histological analyses. C3−/− mice showed elevated ischemic damage 7 days after FAL, as evidenced by H&E staining. In addition, angiogenesis was increased in C3−/− mice, as demonstrated by increased capillary/muscle fiber ratio and increased proliferating endothelial cells (CD31+/BrdU+). Moreover, our results showed that the total number of leukocytes (CD45+) was increased in C3−/− mice, which was based on an increased number of neutrophils (MPO+), neutrophil extracellular trap formation (MPO+/CitH3+), and macrophages (CD68+) displaying a shift toward an anti-inflammatory and pro-angiogenic M2-like polarized phenotype (CD68+/MRC1+). In summary, we show that the deficiency of complement factor C3 increased neutrophil and M2-like polarized macrophage accumulation in ischemic muscle tissue, contributing to angiogenesis.
Tumor Immune Microenvironment and Immunosuppressive Therapy in Hepatocellular Carcinoma: A Review
Authors: Oura Kyoko , Morishita Asahiro , Tani Joji , Masaki Tsutomu
Published: May 2021

Liver cancer has the fourth highest mortality rate of all cancers worldwide, with hepatocellular carcinoma (HCC) being the most prevalent subtype. Despite great advances in systemic therapy, such as molecular-targeted agents, HCC has one of the worst prognoses due to drug resistance and frequent recurrence and metastasis. Recently, new therapeutic strategies such as cancer immunosuppressive therapy have prolonged patients’ lives, and the combination of an immune checkpoint inhibitor (ICI) and VEGF inhibitor is now positioned as the first-line therapy for advanced HCC. Since the efficacy of ICIs depends on the tumor immune microenvironment, it is necessary to elucidate the immune environment of HCC to select appropriate ICIs. In this review, we summarize the findings on the immune microenvironment and immunosuppressive approaches focused on monoclonal antibodies against cytotoxic T lymphocyte-associated protein 4 and programmed cell death protein 1 for HCC. We also describe ongoing treatment modalities, including adoptive cell transfer-based therapies and future areas of exploration based on recent literature. The results of pre-clinical studies using immunological classification and animal models will contribute to the development of biomarkers that predict the efficacy of immunosuppressive therapy and aid in the selection of appropriate strategies for HCC treatment.