bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of Health Expenditures Determinants: A Model to Manage the Economic Burden of Cardiovascular Disease
Authors: Salvatore Fiorella Pia , Spada Alessia , Fortunato Francesca , Vrontis Demetris , Fiore Mariantonietta
Published: April 2021

The purpose of this paper is to investigate the determinants influencing the costs of cardiovascular disease in the regional health service in Italy’s Apulia region from 2014 to 2016. Data for patients with acute myocardial infarction (AMI), heart failure (HF), and atrial fibrillation (AF) were collected from the hospital discharge registry. Generalized linear models (GLM), and generalized linear mixed models (GLMM) were used to identify the role of random effects in improving the model performance. The study was based on socio-demographic variables and disease-specific variables (diagnosis-related group, hospitalization type, hospital stay, surgery, and economic burden of the hospital discharge form). Firstly, both models indicated an increase in health costs in 2016, and lower spending values for women (p < 0.001) were shown. GLMM indicates a significant increase in health expenditure with increasing age (p < 0.001). Day-hospital has the lowest cost, surgery increases the cost, and AMI is the most expensive pathology, contrary to AF (p < 0.001). Secondly, AIC and BIC assume the lowest values for the GLMM model, indicating the random effects’ relevance in improving the model performance. This study is the first that considers real data to estimate the economic burden of CVD from the regional health service’s perspective. It appears significant for its ability to provide a large set of estimates of the economic burden of CVD, providing information to managers for health management and planning.
A Randomized, Double-Blind, Placebo-Controlled Trial to Assess the Acidogenic Potential of Dental Biofilms through a Tablet Containing Weissella cibaria CMU
Authors: Kang Mi-Sun , Lee Dong-Suk , Kim Myoungsuk , Lee Seung-Ah , Nam Seoul-Hee
Published: April 2021

The possibility of preventing dental caries by taking probiotic bacterium Weissella cibaria (W. cibaria) CMU tablets to alter the pH of the dental plaque in the oral cavity was evaluated. A randomized, double-blind, placebo-controlled trial was performed on adults aged 20 years or older with 20 or more natural teeth. Ninety-two people underwent dental scaling before being randomly assigned to the experimental group (n = 49) or the control group (n = 43). Depending on the group they belonged to, W. cibaria CMU or the placebo was administered to them once daily for 8 weeks before bedtime. Twenty-four subjects were later excluded from the study because the week 8 dosing was not smoothly performed, for a final subject count of 68. The Cariview test was used to evaluate the amount of acid produced by the dental plaque to assess the risk of caries. The results showed that although there was no significant difference between the results of the two groups, the intake of the W. cibaria CMU tablets eliminated the risk of developing dental caries from acid production in the oral flora because the W. cibaria colonizes and lives in the dental plaque and the oral cavity and suppresses acids.
A Systematic Framework for Collecting Site-Specific Sampling and Survey Data to Support Analyses of Health Impacts from Land-Based Pollution in Low- and Middle-Income Countries
Authors: von Stackelberg Katherine , Williams Pamela R.D. , Sánchez-Triana Ernesto
Published: April 2021

The rise of small-scale and localized economic activities in low- and middle-income countries (LMICs) has led to increased exposures to contaminants associated with these processes and the potential for resulting adverse health effects in exposed communities. Risk assessment is the process of building models to predict the probability of adverse outcomes based on concentration-response functions and exposure scenarios for individual contaminants, while epidemiology uses statistical methods to explore associations between potential exposures and observed health outcomes. Neither approach by itself is practical or sufficient for evaluating the magnitude of exposures and health impacts associated with land-based pollution in LMICs. Here we propose a more pragmatic framework for designing representative studies, including uniform sampling guidelines and household surveys, that draws from both methodologies to better support community health impact analyses associated with land-based pollution sources in LMICs. Our primary goal is to explicitly link environmental contamination from land-based pollution associated with specific localized economic activities to community exposures and health outcomes at the household level. The proposed framework was applied to the following three types of industries that are now widespread in many LMICs: artisanal scale gold mining (ASGM), used lead-acid battery recycling (ULAB), and small tanning facilities. For each activity, we develop a generalized conceptual site model (CSM) that describes qualitative linkages from chemical releases or discharges, environmental fate and transport mechanisms, exposure pathways and routes, populations at risk, and health outcomes. This upfront information, which is often overlooked, is essential for delineating the contaminant zone of influence in a community and identifying relevant households for study. We also recommend cost-effective methods for use in LMICs related to environmental sampling, biological monitoring, survey questionnaires, and health outcome measurements at contaminated and unexposed reference sites. Future study designs based on this framework will facilitate consistent, comparable, and standardized community exposure, risk, and health impact assessments for land-based pollution in LMICs. The results of these studies can also support economic burden analyses and risk management decision-making around site cleanup, risk mitigation, and public health education.
The Commonly Utilized Natural Products during the COVID-19 Pandemic in Saudi Arabia: A Cross-Sectional Online Survey
Authors: AlNajrany Sina M. , Asiri Yousif , Sales Ibrahim , AlRuthia Yazed
Published: April 2021

Objectives: The utilization rate of herbal and dietary supplements among the Saudi population is reported to be high. However, the utilization rate and types of herbal and dietary supplements during the COVID-19 pandemic are largely unknown. Methods: This was an online questionnaire-based cross-sectional study that used convenience sampling and social media platforms (Telegram®, Twitter®, and WhatsApp®) to disseminate a 12-item questionnaire across the Saudi general public aged 18 years and above. The questionnaire inquired about the sociodemographic characteristics (e.g., age, gender, education, geographical location), presence of chronic health conditions and the use of prescription medications, awareness of the viral nature of COVID-19 infection and its common symptoms, and the commonly utilized herbal and/or dietary supplements. Results: Sixty-four percent of the 1473 participants reported using herbal and/or dietary supplements for the purpose of boosting their immune system to prevent COVID-19 infection. In addition, 88.2% of the respondents were misinformed about the manifestation of COVID-19 symptoms. Most of the participants were Saudi (91.9%), aged 49 years and younger (83%), female (52%), and healthy (81%). Honey (46%), lemon (45%), ginger (36%), vitamin C (32%), black seed (26%), garlic (26%), and turmeric (19%) were the most commonly used herbal and/or dietary supplements by the participants. Saudi nationals (OR = 1.67, 95% CI: 1.08 to 2.6, p = 0.02), older adults (OR = 1.30, 95% CI:1.10 to 1.55, p = 0.002), and those taking prescription medications had higher odds of using dietary and/or herbal supplements (OR = 3.31, 95% CI: 2.61 to 4.18, p < 0.0001). Conclusion: The utilization rate of herbal and dietary supplements among the Saudi public during the COVID-19 pandemic is high. Future studies should examine the impact of different public awareness campaigns aimed at improving the public knowledge of the risk and benefits associated with the use of different commonly utilized herbal and dietary products identified in this study.
Examining the Availability and Accessibility of Rehabilitation Services in a Rural District of South Africa: A Mixed-Methods Study
Authors: Magaqa Qhayiya , Ariana Proochista , Polack Sarah
Published: April 2021

Introduction: Rehabilitation services aim to optimise individuals’ functioning and reduce disability. However, people with disabilities, who represent a key population of users of rehabilitation services, continue to have unmet needs for rehabilitation services that include the provision of assistive devices. This paper examines the availability and accessibility of rehabilitation services in a rural district of South Africa in order to explore why unmet needs for rehabilitation services persist. Methods: All nine district hospitals in a rural district of South Africa were included in the study. Rehabilitation services capacity was assessed by examining the available assistive devices, consumables and human resources at the level of the health facility. Data collection was conducted using the Global Co-operative Assistive Technology [GATE] Assistive Products List, AT2030’s ATScale priority list and the South African National Catalogue of Commodities for Primary Health Care Facilities. Descriptive statistics were then used for the analysis. For the qualitative component, semi-structured interviews were conducted with adults with physical disabilities at household level to explore barriers to accessing assistive device inclusive rehabilitation services and the consequences thereof in the same rural district. An interview guide based on the WHO health system building blocks was used. Thematic content analysis guided the analysis of the interview transcripts. Findings: The findings of the research demonstrate that rehabilitation service capacity in the district was constrained as a result of low availability of assistive devices [2–22%] and consumables [2–47%], as well as, possibly, a shortage of rehabilitation providers [n = 30] with an unequal distribution across health facilities [n = 9]. In addition, people with physical disabilities reported poor referral pathways, financial constraints, transport and road consideration and equipment unavailability as barriers to accessing rehabilitation services. Moreover, these barriers to access predisposed individuals to finance-, health- and person-related harm. Conclusion: Rehabilitation service availability is constrained by a lack of service capacity in rural South Africa. In addition, the rehabilitation services in district hospitals are not adequately accessible because of existing barriers to enable key populations to achieve optimised functioning.
Increased Incidence of Premenstrual Syndrome in Females with Palmar Hyperhidrosis
Authors: Cheng Chun-An , Liang Yu-Cheng , Chang Yin-Han , Cheng Chun-Gu , Chung Chi-Hsiang , Chien Wu-Chien
Published: April 2021

Background: Premenstrual syndrome (PMS) is a common disorder affecting the quality of life of women of reproductive age. In a previous study, sex hormone imbalances and alterations in autonomic function were present in PMS, with parasympathetic dysfunction and sympathetic overactivity during the late luteal phase. Palmar hyperhidrosis (PH) presents with oversweating, heat and emotional stimulation, sympathetic hyperactivity and parasympathetic hypofunction. We hypothesized that the incidence of PMS is increased in females with PH. Methods: Data were retrieved from the Taiwanese National Health Insurance Database. The patients with PH were identified by the International Classification of Disease, 9th Revision, Clinical Modification (ICD-9-CM) disease code 780.8. Female patients matched by age and index day were used as the control group. The incidence of PMS was considered an outcome by the ICD-9-CM disease code 625.4. The factors related to PMS were analyzed by Cox regression. Results: The adjusted hazard ratio for the incidence of PMS was 1.276 (95% confidence interval: 1.05–1.488) in females with PH. Conclusions: This study found a positive correlation between PMS and female PH patients. Patients and physicians must understand the relationship of PMS with autonomic function alterations and other risk factors to prevent this problematic disorder.
Development and Implementation of ‘Just Right’ Physical Behavior in Industrial Work Based on the Goldilocks Work Principle—A Feasibility Study
Authors: Lerche Anders Fritz , Mathiassen Svend Erik , Rasmussen Charlotte Lund , Straker Leon , Søgaard Karen , Holtermann Andreas
Published: April 2021

The Goldilocks Work Principle expresses that productive work should be redesigned to comprise physical behaviors of different intensities in a composition promoting workers’ health and fitness. This study is the first to assess the feasibility of redesigning work in an industrial setting according to the Goldilocks Work Principle. We recruited workers (n = 20) from a brewery in Denmark, and we conducted a participatory 16-week intervention including a workshop and two consultations. The workshop aimed to support the workers in modifying their work, while the consultations assisted the eventual implementation. Feasibility was evaluated as per three aspects: (1) developing modifications of work, (2) implementing these modifications, and (3) changing physical behavior and self-reported fatigue, pain and energy. The three aspects were addressed through records completed by the workers, measurements of workers’ physical behavior and intensity during ‘control’ workdays (i.e., usual work) and ‘intervention’ workdays (i.e., modified work), and self-reported fatigue, pain and energy level following both types of workday. Five modifications to work were developed, and three of these five modifications were implemented. To some extent, physical behavior and intensity changed as intended during ‘intervention’ workdays compared to ‘control’ workdays. Workers were also less fatigued, had less pain, and had more energy after ‘intervention’ workdays. These results suggest that it is feasible to develop and implement modified work based on the Goldilocks Work Principle among industrial workers. However, we also identified several barriers to the implementation of such modifications.
The Double Mediating Effect of Social Isolation and Emotional Support on Feelings of Entrapment and Motivation for Recovery among Korean Alcoholic Inpatients
Authors: Lee Joo-Young , An Jae-Sun , Suh Kyung-Hyun
Published: April 2021

This study identified the relationship between feeling of entrapment and motivation for change among hospitalized alcoholic patients and examined the double mediating effect model of social isolation and emotional support on this relationship. The study participants were 101 male and female alcoholic patients hospitalized at C hospital, which specializes in alcohol treatment at I city in Korea. PROCESS Macro 3.5 Model 6 was used for analyses of double mediating effects. The results revealed that entrapment and social isolation were negatively correlated with motivation for recovery of alcoholic inpatients, whereas emotional support was positively correlated with it. In a sequential double mediation model for motivation to change in alcoholic inpatients, the direct effects of social isolation and entrapment were not significant. However, the sequential indirect effect of social isolation and emotional support on entrapment and motivation for recovery among alcoholic inpatients was significant. These results suggest that making alcoholic inpatients not feel socially isolated by providing them with emotional support or through other means of assistance by practitioners or family members is important for their recovery from alcohol use disorder.
High-Fat Diet Aggravates Cerebral Infarct, Hemorrhagic Transformation and Neuroinflammation in a Mouse Stroke Model
Authors: Grisotto Coline , Taïlé Janice , Planesse Cynthia , Diotel Nicolas , Gonthier Marie-Paule , Meilhac Olivier , Couret David
Published: April 2021

Background: Stroke in context of type 2 diabetes (T2D) is associated with a poorer outcome than in non-diabetic conditions. We aimed at creating a new reproducible mouse model of stroke in impaired glucose tolerance conditions induced by high-fat diet. Methods: Adult C57BL6 mice were fed for 2 months with either normal diet (ND) or high-fat diet (HFD). We used a model of Middle Cerebral Artery Occlusion (MCAO) for 90 min. Oral Glucose Tolerance Test (OGTT) and Insulin Tolerance Test (ITT) were used to assess pre-diabetic status. Brain infarct volume, hemorrhagic transformation (HT) as well as systemic and cerebral inflammatory markers were evaluated. Results: HFD was associated with an increased body weight and glycemia following OGTT. The HFD group presented a significant increase in brain infarct volume (38.7 (IQR 30–46.7%) vs. 28.45 (IQR 21–30%); p = 0.016) and HT (HFD: 2 (IQR 1–5) vs. ND: 0 (IQR 0–1); p = 0.012) and higher levels of IL-6 and MCP-1 in infarcted hemisphere compared to the ND group. Conclusion: Two months of HFD in adult mice were sufficient to alter the lipid profile and the control of hyperglycemia. These metabolic perturbations were significantly associated with increased infarct volume and hemorrhagic complications.
The Distribution of GPR17-Expressing Cells Correlates with White Matter Inflammation Status in Brain Tissues of Multiple Sclerosis Patients
Authors: Angelini Jacopo , Marangon Davide , Raffaele Stefano , Lecca Davide , Abbracchio Maria
Published: April 2021

In multiple sclerosis (MS), oligodendrocyte precursor cells (OPCs) are recruited to the site of injury to remyelinate damaged axons; however, in patients this process is often ineffective due to defects in OPC maturation. The membrane receptor GPR17 timely regulates the early stages of OPC differentiation; however, after reaching its highest levels in immature oligodendrocytes, it has to be downregulated to allow terminal maturation. Since, in several animal models of disease GPR17 is upregulated, the aim of this work was to characterize GPR17 alterations in MS patients. We developed immunohistochemistry and immunofluorescence procedures for the detection of GPR17 in human tissues and stained post-mortem MS brain lesions from patients with secondary progressive MS and control subjects. The inflammatory activity in each lesion was evaluated by immunohistochemistry for the myelin protein MOG and the HLA antigen to classify them as active, chronic inactive or chronic active. Hence, we assessed the distribution of GPR17-positive cells in these lesions compared to normal appearing white matter (NAWM) and white matter (WM) of control subjects. Our data have shown a marked increase of GPR17-expressing oligodendroglial cells accumulating at NAWM, in which moderate inflammation was also found. Furthermore, we identified two distinct subpopulations of GPR17-expressing oligodendroglial cells, characterized by either ramified or rounded morphology, that differently populate the WM of healthy controls and MS patients. We concluded that the coordinated presence of GPR17 in OPCs at the lesion sites and inflamed NAWM areas suggests that GPR17 could be exploited to support endogenous remyelination through advanced pharmacological approaches.
Amyloid Aggregates of Smooth-Muscle Titin Impair Cell Adhesion
Authors: Bobylev Alexander G. , Fadeev Roman S. , Bobyleva Liya G. , Kobyakova Margarita I. , Shlyapnikov Yuri M. , Popov Daniil V. , Vikhlyantsev Ivan M.
Published: April 2021

Various amyloid aggregates, in particular, aggregates of amyloid β-proteins, demonstrate in vitro and in vivo cytotoxic effects associated with impairment of cell adhesion. We investigated the effect of amyloid aggregates of smooth-muscle titin on smooth-muscle-cell cultures. The aggregates were shown to impair cell adhesion, which was accompanied by disorganization of the actin cytoskeleton, formation of filopodia, lamellipodia, and stress fibers. Cells died after a 72-h contact with the amyloid aggregates. To understand the causes of impairment, we studied the effect of the microtopology of a titin-amyloid-aggregate-coated surface on fibroblast adhesion by atomic force microscopy. The calculated surface roughness values varied from 2.7 to 4.9 nm, which can be a cause of highly antiadhesive properties of this surface. As all amyloids have the similar structure and properties, it is quite likely that the antiadhesive effect is also intrinsic to amyloid aggregates of other proteins. These results are important for understanding the mechanisms of the negative effect of amyloids on cell adhesion.
In Vitro Characterization of Human CD24hiCD38hi Regulatory B Cells Shows CD9 Is Not a Stable Breg Cell Marker
Authors: Mohd Jaya Fatin N. , Garcia Sergio G. , Borras Francesc E. , Guerrero Dolores , Chan Godfrey C. F. , Franquesa Marcella
Published: April 2021

Regulatory B (Breg) cells are endowed with immune suppressive functions. Various human and murine Breg subtypes have been reported. While interleukin (IL)-10 intracellular staining remains the most reliable way to identify Breg cells, this technique hinders further essential functional studies. Recent findings suggest that CD9 is an effective surface marker of murine IL-10 competent Breg cells. However, the stability of CD9 and its relevance as a unique marker for human Breg cells, which have been widely characterized as CD24hiCD38hi, have not been investigated. Here, we demonstrate that CD9 expression is sensitive to in vitro B cell stimulations. CD9 expression could either be re-expressed or downregulated in purified CD9-negative B cells and CD9-positive B cells, respectively. We found no significant differences in the Breg differentiation capacity of the CD9-negative and CD9-positive B cells. Furthermore, CD9-positive B cells co-express CD40 and CD86, suggesting their nature as B cell activation or co-stimulatory molecules, rather than regulatory ones. Therefore, we report the relatively unstable CD9 as a distinct surface molecule, indicating the need for further research for a more reliable marker to purify human Breg cells.
DNA Methylation of the Angiotensinogen Gene, AGT, and the Aldosterone Synthase Gene, CYP11B2 in Cardiovascular Diseases
Authors: Takeda Yoshimichi , Demura Masashi , Yoneda Takashi , Takeda Yoshiyu
Published: April 2021

Angiotensinogen (AGT) and aldosterone play key roles in the regulation of blood pressure and are implicated in the pathogenesis of cardiovascular diseases. DNA methylation typically acts to repress gene transcription. The aldosterone synthase gene CYP11B2 is regulated by angiotensin II and potassium. DNA methylation negatively regulates AGT and CYP11B2 expression and dynamically changes in response to continuous promoter stimulation of each gene. High salt intake and excess circulating aldosterone cause DNA demethylation around the CCAAT-enhancer-binding-protein (CEBP) sites of the ATG promoter region, thereby converting the phenotype of AGT expression from an inactive to an active state in visceral adipose tissue and heart. A close association exists between low DNA methylation at CEBP-binding sites and increased AGT expression in salt-sensitive hypertensive rats. Salt-dependent hypertension may be partially affected by increased cardiac AGT expression. CpG dinucleotides in the CYP11B2 promoter are hypomethylated in aldosterone-producing adenomas. Methylation of recognition sequences of transcription factors, including CREB1, NGFIB (NR4A1), and NURR1 (NR4A2) diminish their DNA-binding activity. The methylated CpG-binding protein MECP2 interacts directly with the methylated CYP11B2 promoter. Low salt intake and angiotensin II infusion lead to upregulation of CYP11B2 expression and DNA hypomethylation in the adrenal gland. Treatment with the angiotensin II type 1 receptor antagonist decreases CYP11B2 expression and leads to DNA hypermethylation. A close association between low DNA methylation and increased CYP11B2 expression are seen in the hearts of patients with hypertrophic cardiomyopathy. These results indicate that epigenetic regulation of both AGT and CYP11B2 contribute to the pathogenesis of cardiovascular diseases.
On Iron Metabolism and Its Regulation
Authors: Vogt Anne-Cathrine S. , Arsiwala Tasneem , Mohsen Mona , Vogel Monique , Manolova Vania , Bachmann Martin F.
Published: April 2021

Iron is a critical metal for several vital biological processes. Most of the body’s iron is bound to hemoglobin in erythrocytes. Iron from senescent red blood cells is recycled by macrophages in the spleen, liver and bone marrow. Dietary iron is taken up by the divalent metal transporter 1 (DMT1) in enterocytes and transported to portal blood via ferroportin (FPN), where it is bound to transferrin and taken up by hepatocytes, macrophages and bone marrow cells via transferrin receptor 1 (TfR1). While most of the physiologically active iron is bound hemoglobin, the major storage of most iron occurs in the liver in a ferritin-bound fashion. In response to an increased iron load, hepatocytes secrete the peptide hormone hepcidin, which binds to and induces internalization and degradation of the iron transporter FPN, thus controlling the amount of iron released from the cells into the blood. This review summarizes the key mechanisms and players involved in cellular and systemic iron regulation.
Combined Transcriptomic and Proteomic Analysis of Perk Toxicity Pathways
Authors: Popovic Rebeka , Celardo Ivana , Yu Yizhou , Costa Ana C. , Loh Samantha H. Y. , Martins L. Miguel
Published: April 2021

In Drosophila, endoplasmic reticulum (ER) stress activates the protein kinase R-like endoplasmic reticulum kinase (dPerk). dPerk can also be activated by defective mitochondria in fly models of Parkinson’s disease caused by mutations in pink1 or parkin. The Perk branch of the unfolded protein response (UPR) has emerged as a major toxic process in neurodegenerative disorders causing a chronic reduction in vital proteins and neuronal death. In this study, we combined microarray analysis and quantitative proteomics analysis in adult flies overexpressing dPerk to investigate the relationship between the transcriptional and translational response to dPerk activation. We identified tribbles and Heat shock protein 22 as two novel Drosophila activating transcription factor 4 (dAtf4) regulated transcripts. Using a combined bioinformatics tool kit, we demonstrated that the activation of dPerk leads to translational repression of mitochondrial proteins associated with glutathione and nucleotide metabolism, calcium signalling and iron-sulphur cluster biosynthesis. Further efforts to enhance these translationally repressed dPerk targets might offer protection against Perk toxicity.
Bioinformatic Prediction of an tRNASec Gene Nested inside an Elongation Factor SelB Gene in Alphaproteobacteria
Authors: Mukai Takahito
Published: April 2021

In bacteria, selenocysteine (Sec) is incorporated into proteins via the recoding of a particular codon, the UGA stop codon in most cases. Sec-tRNASec is delivered to the ribosome by the Sec-dedicated elongation factor SelB that also recognizes a Sec-insertion sequence element following the codon on the mRNA. Since the excess of SelB may lead to sequestration of Sec-tRNASec under selenium deficiency or oxidative stress, the expression levels of SelB and tRNASec should be regulated. In this bioinformatic study, I analyzed the Rhizobiales SelB species because they were annotated to have a non-canonical C-terminal extension. I found that the open reading frame (ORF) of diverse Alphaproteobacteria selB genes includes an entire tRNASec sequence (selC) and overlaps with the start codon of the downstream ORF. A remnant tRNASec sequence was found in the Sinorhizobium melilotiselB genes whose products have a shorter C-terminal extension. Similar overlapping traits were found in Gammaproteobacteria and Nitrospirae. I hypothesized that once the tRNASec moiety is folded and processed, the expression of the full-length SelB may be repressed. This is the first report on a nested tRNA gene inside a protein ORF in bacteria.
From Channels to Canonical Wnt Signaling: A Pathological Perspective
Authors: Muccioli Silvia , Brillo Valentina , Chieregato Leonardo , Leanza Luigi , Checchetto Vanessa , Costa Roberto
Published: April 2021

Wnt signaling is an important pathway mainly active during embryonic development and controlling cell proliferation. This regulatory pathway is aberrantly activated in several human diseases. Ion channels are known modulators of several important cellular functions ranging from the tuning of the membrane potential to modulation of intracellular pathways, in particular the influence of ion channels in Wnt signaling regulation has been widely investigated. This review will discuss the known links between ion channels and canonical Wnt signaling, focusing on their possible roles in human metabolic diseases, neurological disorders, and cancer.
Genome-Wide Analysis, Evolutionary History and Response of ALMT Family to Phosphate Starvation in Brassica napus
Authors: Din Ismail , Ullah Ihteram , Wang Wei , Zhang Hao , Shi Lei
Published: April 2021

Low phosphorus (P) availability is one of the major constraints to plant growth, particularly in acidic soils. A possible mechanism for enhancing the use of sparsely soluble P forms is the secretion of malate in plants by the aluminum-activated malate transporter (ALMT) gene family. Despite its significance in plant biology, the identification of the ALMT gene family in oilseed rape (Brassica napus; B. napus), an allotetraploid crop, is unveiled. Herein, we performed genome-wide identification and characterization of ALMTs in B. napus, determined their gene expression in different tissues and monitored transcriptional regulation of BnaALMTs in the roots and leaves at both a sufficient and a deficient P supply. Thirty-nine BnaALMT genes were identified and were clustered into five branches in the phylogenetic tree based on protein sequences. Collinearity analysis revealed that most of the BnaALMT genes shared syntenic relationships among BnaALMT members in B. napus, which suggested that whole-genome duplication (polyploidy) played a major driving force for BnaALMTs evolution in addition to segmental duplication. RNA-seq analyses showed that most BnaALMT genes were preferentially expressed in root and leaf tissues. Among them, the expression of BnaC08g13520D, BnaC08g15170D, BnaC08g15180D, BnaC08g13490D, BnaC08g13500D, BnaA08g26960D, BnaC05g14120D, BnaA06g12560D, BnaC05g20630D, BnaA07g02630D, BnaA04g15700D were significantly up-regulated in B. napus roots and leaf at a P deficient supply. The current study analyzes the evolution and the expression of the ALMT family in B. napus, which will help in further research on their role in the enhancement of soil P availability by secretion of organic acids.
The Emerging Regulatory Role of Circular RNAs in Periodontal Tissues and Cells
Authors: Jiao Kexin , Walsh Laurence J. , Ivanovski Sašo , Han Pingping
Published: April 2021

Periodontitis is a chronic complex inflammatory disease associated with a destructive host immune response to microbial dysbiosis, leading to irreversible loss of tooth-supporting tissues. Regeneration of functional periodontal soft (periodontal ligament and gingiva) and hard tissue components (cementum and alveolar bone) to replace lost tissues is the ultimate goal of periodontal treatment, but clinically predictable treatments are lacking. Similarly, the identification of biomarkers that can be used to accurately diagnose periodontitis activity is lacking. A relatively novel category of molecules found in oral tissue, circular RNAs (circRNAs) are single-stranded endogenous, long, non-coding RNA molecules, with covalently circular-closed structures without a 5’ cap and a 3’ tail via non-classic backsplicing. Emerging research indicates that circRNAs are tissue and disease-specific expressed and have crucial regulatory functions in various diseases. CircRNAs can function as microRNA or RNA binding sites or can regulate mRNA. In this review, we explore the biogenesis and function of circRNAs in the context of the emerging role of circRNAs in periodontitis pathogenesis and the differentiation of periodontal cells. CircMAP3K11, circCDK8, circCDR1as, circ_0062491, and circ_0095812 are associated with pathological periodontitis tissues. Furthermore, circRNAs are expressed in periodontal cells in a cell-specific manner. They can function as microRNA sponges and can form circRNA–miRNA–mRNA networks during osteogenic differentiation for periodontal-tissue (or dental pulp)-derived progenitor cells.
Species-Specific Regulation of TRPM2 by PI(4,5)P2 via the Membrane Interfacial Cavity
Authors: Barth Daniel , Lückhoff Andreas , Kühn Frank J. P.
Published: April 2021

The human apoptosis channel TRPM2 is stimulated by intracellular ADR-ribose and calcium. Recent studies show pronounced species-specific activation mechanisms. Our aim was to analyse the functional effect of phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2), commonly referred to as PIP2, on different TRPM2 orthologues. Moreover, we wished to identify the interaction site between TRPM2 and PIP2. We demonstrate a crucial role of PIP2, in the activation of TRPM2 orthologues of man, zebrafish, and sea anemone. Utilizing inside-out patch clamp recordings of HEK-293 cells transfected with TRPM2, differential effects of PIP2 that were dependent on the species variant became apparent. While depletion of PIP2 via polylysine uniformly caused complete inactivation of TRPM2, restoration of channel activity by artificial PIP2 differed widely. Human TRPM2 was the least sensitive species variant, making it the most susceptible one for regulation by changes in intramembranous PIP2 content. Furthermore, mutations of highly conserved positively charged amino acid residues in the membrane interfacial cavity reduced the PIP2 sensitivity in all three TRPM2 orthologues to varying degrees. We conclude that the membrane interfacial cavity acts as a uniform PIP2 binding site of TRPM2, facilitating channel activation in the presence of ADPR and Ca2+ in a species-specific manner.
Tunable Mechanical and Electrical Properties of Coaxial Electrospun Composite Nanofibers of P(VDF-TrFE) and P(VDF-TrFE-CTFE)
Authors: Lam Tu-Ngoc , Ma Chia-Yin , Hsiao Po-Han , Ko Wen-Ching , Huang Yi-Jen , Lee Soo-Yeol , Jain Jayant , Huang E-Wen
Published: April 2021

The coaxial core/shell composite electrospun nanofibers consisting of relaxor ferroelectric P(VDF-TrFE-CTFE) and ferroelectric P(VDF-TrFE) polymers are successfully tailored towards superior structural, mechanical, and electrical properties over the individual polymers. The core/shell-TrFE/CTFE membrane discloses a more prominent mechanical anisotropy between the revolving direction (RD) and cross direction (CD) associated with a higher tensile modulus of 26.9 MPa and good strength-ductility balance, beneficial from a better degree of nanofiber alignment, the increased density, and C-F bonding. The interfacial coupling between the terpolymer P(VDF-TrFE-CTFE) and copolymer P(VDF-TrFE) is responsible for comparable full-frequency dielectric responses between the core/shell-TrFE/CTFE and pristine terpolymer. Moreover, an impressive piezoelectric coefficient up to 50.5 pm/V is achieved in the core/shell-TrFE/CTFE composite structure. Our findings corroborate the promising approach of coaxial electrospinning in efficiently tuning mechanical and electrical performances of the electrospun core/shell composite nanofiber membranes-based electroactive polymers (EAPs) actuators as artificial muscle implants.
Genes Implicated in Familial Parkinson’s Disease Provide a Dual Picture of Nigral Dopaminergic Neurodegeneration with Mitochondria Taking Center Stage
Authors: Franco Rafael , Rivas-Santisteban Rafael , Navarro Gemma , Pinna Annalisa , Reyes-Resina Irene
Published: April 2021

The mechanism of nigral dopaminergic neuronal degeneration in Parkinson’s disease (PD) is unknown. One of the pathological characteristics of the disease is the deposition of α-synuclein (α-syn) that occurs in the brain from both familial and sporadic PD patients. This paper constitutes a narrative review that takes advantage of information related to genes (SNCA, LRRK2, GBA, UCHL1, VPS35, PRKN, PINK1, ATP13A2, PLA2G6, DNAJC6, SYNJ1, DJ-1/PARK7 and FBXO7) involved in familial cases of Parkinson’s disease (PD) to explore their usefulness in deciphering the origin of dopaminergic denervation in many types of PD. Direct or functional interactions between genes or gene products are evaluated using the Search Tool for the Retrieval of Interacting Genes/Proteins (STRING) database. The rationale is to propose a map of the interactions between SNCA, the gene encoding for α-syn that aggregates in PD, and other genes, the mutations of which lead to early-onset PD. The map contrasts with the findings obtained using animal models that are the knockout of one of those genes or that express the mutated human gene. From combining in silico data from STRING-based assays with in vitro and in vivo data in transgenic animals, two likely mechanisms appeared: (i) the processing of native α-syn is altered due to the mutation of genes involved in vesicular trafficking and protein processing, or (ii) α-syn mutants alter the mechanisms necessary for the correct vesicular trafficking and protein processing. Mitochondria are a common denominator since both mechanisms require extra energy production, and the energy for the survival of neurons is obtained mainly from the complete oxidation of glucose. Dopamine itself can result in an additional burden to the mitochondria of dopaminergic neurons because its handling produces free radicals. Drugs acting on G protein-coupled receptors (GPCRs) in the mitochondria of neurons may hopefully end up targeting those receptors to reduce oxidative burden and increase mitochondrial performance. In summary, the analysis of the data of genes related to familial PD provides relevant information on the etiology of sporadic cases and might suggest new therapeutic approaches.
Simultaneous Use of ROCK Inhibitors and EP2 Agonists Induces Unexpected Effects on Adipogenesis and the Physical Properties of 3T3-L1 Preadipocytes
Authors: Ida Yosuke , Watanabe Megumi , Ohguro Hiroshi , Hikage Fumihito
Published: April 2021

To elucidate the additive effects of an EP2 agonist, omidenepag (OMD) or butaprost (Buta) on the Rho-associated coiled-coil-containing protein kinase (ROCK) inhibitor, ripasudil (Rip) on adipose tissue, two- or three-dimension (2D or 3D) cultures of 3T3-L1 cells were analyzed by lipid staining, the mRNA expression of adipogenesis-related genes, extracellular matrix (ECM) molecules including collagen (Col) -1, -4 and -6, and fibronectin (Fn), and the sizes and physical properties of 3D organoids, as measured by a micro-squeezer. The results indicate that adipogenesis induced (1) an enlargement of the 3D organoids; (2) a substantial enhancement in lipid staining as well as the expression of the Pparγ, Ap2 and Leptin genes; (3) a significant softening of the 3D organoids, the effects of which were all enhanced by Rip except for Pparγ expression; and (4) a significant downregulation in Col1 and Fn, and a significant upregulation in Col4, Col6, the effects of which were unchanged by Rip. When adding the EP2 agonist to Rip, (1) the sizes of the 3D organoids were reduced substantially; (2) lipid staining was increased (OMD), or decreased (Buta); (3) the stiffness of the 3D organoids was substantially increased in Buta; (4-1) the expression of Pparγ was suppressed (2D, OMD) or increased (2D, Buta), and the expressions of Ap2 were downregulated (2D, 3D) and Leptin was increased (2D) or decreased (3D), (4-2) all the expressions of four ECM molecules were upregulated in 2D (2D), and in 3D, the expression of Col1, Col4 was upregulated. The collective findings reported herein indicate that the addition of an EP2 agonist, OMD or Buta significantly but differently modulate the Rip-induced effects on adipogenesis and the physical properties of 2D and 3D cultured 3T3-L1 cells.
A Soluble Epoxide Hydrolase Inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) Urea, Ameliorates Experimental Autoimmune Encephalomyelitis
Authors: Jonnalagadda Deepa , Wan Debin , Chun Jerold , Hammock Bruce D. , Kihara Yasuyuki
Published: April 2021

Polyunsaturated fatty acids (PUFAs) are essential FAs for human health. Cytochrome P450 oxygenates PUFAs to produce anti-inflammatory and pain-resolving epoxy fatty acids (EpFAs) and other oxylipins whose epoxide ring is opened by the soluble epoxide hydrolase (sEH/Ephx2), resulting in the formation of toxic and pro-inflammatory vicinal diols (dihydroxy-FAs). Pharmacological inhibition of sEH is a promising strategy for the treatment of pain, inflammation, cardiovascular diseases, and other conditions. We tested the efficacy of a potent, selective sEH inhibitor, 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU), in an animal model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE). Prophylactic TPPU treatment significantly ameliorated EAE without affecting circulating white blood cell counts. TPPU accumulated in the spinal cords (SCs), which was correlated with plasma TPPU concentration. Targeted lipidomics in EAE SCs and plasma identified that TPPU blocked production of dihydroxy-FAs efficiently and increased some EpFA species including 12(13)-epoxy-octadecenoic acid (12(13)-EpOME) and 17(18)-epoxy-eicosatrienoic acid (17(18)-EpETE). TPPU did not alter levels of cyclooxygenase (COX-1/2) metabolites, while it increased 12-hydroxyeicosatetraenoic acid (12-HETE) and other 12/15-lipoxygenase metabolites. These analytical results are consistent with sEH inhibitors that reduce neuroinflammation and accelerate anti-inflammatory responses, providing the possibility that sEH inhibitors could be used as a disease modifying therapy, as well as for MS-associated pain relief.
Histone Methylation Regulation in Neurodegenerative Disorders
Authors: Basavarajappa Balapal S. , Subbanna Shivakumar
Published: April 2021

Advances achieved with molecular biology and genomics technologies have permitted investigators to discover epigenetic mechanisms, such as DNA methylation and histone posttranslational modifications, which are critical for gene expression in almost all tissues and in brain health and disease. These advances have influenced much interest in understanding the dysregulation of epigenetic mechanisms in neurodegenerative disorders. Although these disorders diverge in their fundamental causes and pathophysiology, several involve the dysregulation of histone methylation-mediated gene expression. Interestingly, epigenetic remodeling via histone methylation in specific brain regions has been suggested to play a critical function in the neurobiology of psychiatric disorders, including that related to neurodegenerative diseases. Prominently, epigenetic dysregulation currently brings considerable interest as an essential player in neurodegenerative disorders, such as Alzheimer’s disease (AD), Parkinson’s disease (PD), Huntington’s disease (HD), Amyotrophic lateral sclerosis (ALS) and drugs of abuse, including alcohol abuse disorder, where it may facilitate connections between genetic and environmental risk factors or directly influence disease-specific pathological factors. We have discussed the current state of histone methylation, therapeutic strategies, and future perspectives for these disorders. While not somatically heritable, the enzymes responsible for histone methylation regulation, such as histone methyltransferases and demethylases in neurons, are dynamic and reversible. They have become promising potential therapeutic targets to treat or prevent several neurodegenerative disorders. These findings, along with clinical data, may provide links between molecular-level changes and behavioral differences and provide novel avenues through which the epigenome may be targeted early on in people at risk for neurodegenerative disorders.
In Vitro Cytotoxicity of Trastuzumab (Tz) and Se-Trastuzumab (Se-Tz) against the Her/2 Breast Cancer Cell Lines JIMT-1 and BT-474
Authors: Bapat Priyanka , Sewell Debalina Goswami , Boylan Mallory , Sharma Arun K. , Spallholz Julian E.
Published: April 2021

Her/2+ breast cancer accounts for ~25% mortality in women and overexpression of Her/2 leads to cell growth and tumor progression. Trastuzumab (Tz) with Taxane is the preferred treatment for Her/2+ patients. However, Tz responsive patients often develop resistance to Tz treatment. Herein, redox selenides (RSe-) were covalently linked to Tz using a selenium (Se)-modified Bolton–Hunter Reagent forming Seleno-Trastuzumab (Se-Tz; ~25 µgSe/mg). Se-Tz was compared to Tz and sodium selenite to assess the viability of JIMT-1 and BT-474 cells. Comparative cell viability was examined by microscopy and assessed by fluorometric/enzymatic assays. Se-Tz and selenite redox cycle producing superoxide (O2•−) are more cytotoxic to Tz resistant JIMT-1 and Tz sensitive BT-474 cells than Tz. The results of conjugating redox selenides to Tz suggest a wider application of this technology to other antibodies and targeting molecules.
Intrinsically Connected: Therapeutically Targeting the Cathepsin Proteases and the Bcl-2 Family of Protein Substrates as Co-regulators of Apoptosis
Authors: Soond Surinder M. , Kozhevnikova Maria V. , Savvateeva Lyudmila V. , Townsend Paul A. , Zamyatnin Andrey A.
Published: April 2021

Taken with the growing importance of cathepsin-mediated substrate proteolysis in tumor biology and progression, the focus and emphasis placed on therapeutic design and development is coming into fruition. Underpinning this approach is the invariable progression from the direction of fully characterizing cathepsin protease members and their substrate targets, towards targeting such an interaction with tangible therapeutics. The two groups of such substrates that have gained much attention over the years are the pro- and anti- apoptotic protein intermediates from the extrinsic and intrinsic signaling arms of the apoptosis pathway. As proteins that are central to determining cellular fate, some of them present themselves as very favorable candidates for therapeutic targeting. However, considering that both anti- and pro- apoptotic signaling intermediates have been reported to be downstream substrates for certain activated cathepsin proteases, therapeutic targeting approaches based on greater selectivity do need to be given greater consideration. Herein, we review the relationships shared by the cathepsin proteases and the Bcl-2 homology domain proteins, in the context of how the topical approach of adopting ‘BH3-mimetics’ can be explored further in modulating the relationship between the anti- and pro- apoptotic signaling intermediates from the intrinsic apoptosis pathway and their upstream cathepsin protease regulators. Based on this, we highlight important future considerations for improved therapeutic design.
Insulin Signaling as a Therapeutic Target in Glaucomatous Neurodegeneration
Authors: Al Hussein Al Awamlh Sara , Wareham Lauren K. , Risner Michael L. , Calkins David J.
Published: April 2021

Glaucoma is a multifactorial disease that is conventionally managed with treatments to lower intraocular pressure (IOP). Despite these efforts, many patients continue to lose their vision. The degeneration of retinal ganglion cells (RGCs) and their axons in the optic tract that characterizes glaucoma is similar to neurodegeneration in other age-related disorders of the central nervous system (CNS). Identifying the different molecular signaling pathways that contribute to early neuronal dysfunction can be utilized for neuroprotective strategies that prevent degeneration. The discovery of insulin and its receptor in the CNS and retina led to exploration of the role of insulin signaling in the CNS. Historically, insulin was considered a peripherally secreted hormone that regulated glucose homeostasis, with no obvious roles in the CNS. However, a growing number of pre-clinical and clinical studies have demonstrated the potential of modulating insulin signaling in the treatment of neurodegenerative diseases. This review will highlight the role that insulin signaling plays in RGC neurodegeneration. We will focus on how this pathway can be therapeutically targeted to promote RGC axon survival and preserve vision.