bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effect of ouabain on calcium signaling in rodent brain: A systematic review of in vitro studies
Authors: Leite Jacqueline Alves , Pôças Elisa , Maia Gisele Silva , Barbosa Leandro , Quintas Luis Eduardo M. , Kawamoto Elisa Mitiko , Silva Maria Luiza Correia da , Scavone Cristoforo , de Carvalho Luciana E. Drumond 
Published: August 2022

The Na+/K+-ATPase is an integral membrane ion pump, essential to maintaining osmotic balance in cells in the presence of cardiotonic steroids; more specifically, ouabain can be an endogenous modulator of the Na+/K+-ATPase. Here, we conducted a systematic review of the in vitro effects of cardiotonic steroids on Ca2+ in the brain of rats and mice. Methods: The review was carried out using the PubMed, Virtual Health Library, and EMBASE databases (between 12 June 2020 and 30 June 2020) and followed the guidelines described in the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA). Results: in total, 829 references were identified in the electronic databases; however, only 20 articles were considered, on the basis of the inclusion criteria. The studies demonstrated the effects of ouabain on Ca2+ signaling in synaptosomes, brain slices, and cultures of rat and mouse cells. In addition to the well-known cytotoxic effects of high doses of ouabain, resulting from indirect stimulation of the reverse mode of the Na+/Ca2+ exchanger and increased intracellular Ca2+, other effects have been reported. Ouabain-mediated Ca2+ signaling was able to act increasing cholinergic, noradrenergic and glutamatergic neurotransmission. Furthermore, ouabain significantly increased intracellular signaling molecules such as InsPs, IP3 and cAMP. Moreover treatment with low doses of ouabain stimulated myelin basic protein synthesis. Ouabain-induced intracellular Ca2+ increase may promote the activation of important cell signaling pathways involved in cellular homeostasis and function. Thus, the study of the application of ouabain in low doses being promising for application in neurological diseases.Systematic Review Registration:https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020204498, identifier CRD42020204498.
Identification of a potential diagnostic signature for postmenopausal osteoporosis via transcriptome analysis
Authors: Zeng Rui , Ke Tian-Cheng , Ou Mao-Ta , Duan Li-Liang , Li Yi , Chen Zhi-Jing , Xing Zhi-Bin , Fu Xiao-Chen , Huang Cheng-Yu , Wang Jing 
Published: August 2022

Purpose: We aimed to establish the transcriptome diagnostic signature of postmenopausal osteoporosis (PMOP) to identify diagnostic biomarkers and score patient risk to prevent and treat PMOP.Methods: Peripheral blood mononuclear cell (PBMC) expression data from PMOP patients were retrieved from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were screened using the “limma” package. The “WGCNA” package was used for a weighted gene co-expression network analysis to identify the gene modules associated with bone mineral density (BMD). Least absolute shrinkage and selection operator (LASSO) regression was used to construct a diagnostic signature, and its predictive ability was verified in the discovery cohort. The diagnostic values of potential biomarkers were evaluated by receiver operating characteristic curve (ROC) and coefficient analysis. Network pharmacology was used to predict the candidate therapeutic molecules. PBMCs from 14 postmenopausal women with normal BMD and 14 with low BMD were collected, and RNA was extracted for RT-qPCR validation.Results: We screened 2420 differentially expressed genes (DEGs) from the pilot cohort, and WGCNA showed that the blue module was most closely related to BMD. Based on the genes in the blue module, we constructed a diagnostic signature with 15 genes, and its ability to predict the risk of osteoporosis was verified in the discovery cohort. RT-qPCR verified the expression of potential biomarkers and showed a strong correlation with BMD. The functional annotation results of the DEGs showed that the diagnostic signature might affect the occurrence and development of PMOP through multiple biological pathways. In addition, 5 candidate molecules related to diagnostic signatures were screened out.Conclusion: Our diagnostic signature can effectively predict the risk of PMOP, with potential application for clinical decisions and drug candidate selection.
Inhibition of adenylyl cyclase 1 by ST034307 inhibits IP3-evoked changes in sino-atrial node beat rate
Authors: Bose Samuel J. , Read Matthew J. , Akerman Emily , Capel Rebecca A. , Ayagama Thamali , Russell Angela , Terrar Derek A. , Zaccolo Manuela , Burton Rebecca A. B. 
Published: August 2022

Atrial arrhythmias, such as atrial fibrillation (AF), are a major mortality risk and a leading cause of stroke. The IP3 signalling pathway has been proposed as an atrial-specific target for AF therapy, and atrial IP3 signalling has been linked to the activation of calcium sensitive adenylyl cyclases AC1 and AC8. We investigated the involvement of AC1 in the response of intact mouse atrial tissue and isolated guinea pig atrial and sino-atrial node (SAN) cells to the α-adrenoceptor agonist phenylephrine (PE) using the selective AC1 inhibitor ST034307. The maximum rate change of spontaneously beating mouse right atrial tissue exposed to PE was reduced from 14.5% to 8.2% (p = 0.005) in the presence of 1 μM ST034307, whereas the increase in tension generated in paced left atrial tissue in the presence of PE was not inhibited by ST034307 (Control = 14.2%, ST034307 = 16.3%; p &gt; 0.05). Experiments were performed using isolated guinea pig atrial and SAN cells loaded with Fluo-5F-AM to record changes in calcium transients (CaT) generated by 10 μM PE in the presence and absence of 1 μM ST034307. ST034307 significantly reduced the beating rate of SAN cells (0.34-fold decrease; p = 0.003) but did not inhibit changes in CaT amplitude in response to PE in atrial cells. The results presented here demonstrate pharmacologically the involvement of AC1 in the downstream response of atrial pacemaker activity to α-adrenoreceptor stimulation and IP3R calcium release.
Recent advances on development of p21-activated kinase 4 inhibitors as anti-tumor agents
Authors: Li Yang , Lu Qing , Xie Chenghu , Yu Yiming , Zhang Ao 
Published: August 2022

The p21-activated kinase 4 (PAK4) is a member of the PAKs family. It is overexpressed in multiple tumor tissues. Pharmacological inhibition of PAK4 attenuates proliferation, migration, and invasion of cancer cells. Recent studies revealed that inhibition of PAK4 sensitizes immunotherapy which has been extensively exploited as a new strategy to treat cancer. In the past few years, a large number of PAK4 inhibitors have been reported. Of note, the allosteric inhibitor KPT-9274 has been tested in phase Ⅰ clinic trials. Herein, we provide an update on recent research progress on the PAK4 mediated signaling pathway and highlight the development of the PAK4 small molecular inhibitors in recent 5 years. Meanwhile, challenges, limitations, and future developmental directions will be discussed as well.
S-3′-hydroxy-7′, 2′, 4′-trimethoxyisoxane, a novel ferroptosis inducer, promotes NSCLC cell death through inhibiting Nrf2/HO-1 signaling pathway
Authors: Chen Jing , Zhou Songlin , Zhang Xian , Zhao Huange 
Published: August 2022

Background: Ferroptosis is a newly discovered and promising non-apoptotic programmed cell death (PCD), and inducing ferroptosis in cancer cells could open up a novel avenue for drug screening and cancer therapy. S-3′-hydroxy-7′, 2′, 4′-trimethoxyisoxane (ShtIX), a new isoflavane compound, has been reported to possess cytotoxicity in non-small cell lung cancer (NSCLC). The aim of this research is to explore the ShtIX-induced cell death form and its underlying molecular mechanism in NSCLC cells.Methods: Cell proliferation, cell cycle arrest, and cell death tests were used to assess the ability of ShtIX to kill NSCLC cells. Iron metabolism, Fe2+ content, reactive oxygen species (ROS) production, lipid peroxide (MDA) level, glutathione (GSH) level, and glutathione peroxidase 4 (GPX4) level were used to determine ferroptosis caused by ShtIX. We employed western blot, quantitative real-time PCR, and Nrf2 interference in NSCLC cells to investigate the roles of Nrf2/HO-1 in ShtIX-induced ferroptosis. In a xenograft nude mouse model, the anticancer efficacy of ShtIX and the function of ferroptosis were studied.Results: Our research shows that ShtIX can selectively kill NSCLC cells while sparing normal cells and that ShtIX-induced cell death can be efficiently reversed by the ferroptosis inhibitors and the iron chelator, but not by other cell death inhibitors. After cells were treated with ShtIX, there was an increase in Fe2+ content and lipid peroxidation accumulation, as well as a drop in GSH and GPX4 levels, all of which are indicators of ferroptosis. ShtIX also reduced the expression of Nrf2 and HO-1, and genetic Nrf2 silencing in NSCLC enhanced the effect of ShtIX-induced ferroptosis. Additionally, ShtIX retards tumor growth and induced ferroptosis through Nrf2/HO-1 signal pathway in the A549 xenograft model, whereas Fer-1 lessens the anticancer effect.Conclusion: This work provided the evidence that ShtIX caused ferroptosis in NSCLC cells, and inhibiting the Nrf2/HO-1 pathway can considerably exacerbate the effect of ShtIX-induced ferroptosis. The study establishes ShtIX as a promising natural ferroptosis inducer for the treatment of NSCLC.
Exploring potential antidiabetic and anti-inflammatory flavonoids from Euphorbia humifusa with an integrated strategy
Authors: Rakotondrabe Tojofaniry Fabien , Fan Minxia , Guo Mingquan 
Published: August 2022

E. humifusa Willd, a monoecious annual plant, native to Eastern Asia, has been traditionally attributed to the treatment and prevention of miscellaneous diseases, including diabetes mellitus and its associated complications. Earlier studies have supported this species’ pharmacological efficacies including its antibacterial, antidiabetic, and anti-inflammatory properties. Even so, the underlying bioactive components with their mechanisms of action associated with its antidiabetic and anti-inflammatory effects remain elusive. The preamble in vitro assessments of the crude extract and its different fractions revealed that the n-butanol fraction (EHNB) exhibited the best activity, which was subsequently subjected to a rapid screening of candidate ligands through bio-affinity ultrafiltration with the two enzyme targets: α-glucosidase (α-Glu) and cycloxygenase-2 (COX-2) combined with UPLC/QTOF-MS. As a result, 7 compounds were identified from EHNB, among them, vitexin and astragalin were screened out as the most active ligand compounds. Vitexin showed great specific binding (SB) affinity values of 1.26 toward α-Glu and 1.32 toward COX-2, while astragalin showed 1.32 and 1.36, respectively. The docking simulation results exhibited strong interactions of vitexin and astragalin with the key residues of the enzyme targets, suggesting their possible mechanisms of action. The in vitro antidiabetic validation revealed noticeable half-maximal inhibitory effects (IC50) of 36.38 ± 3.06 µM for vitexin and 42.47 ± 4.13 µM for astragalin, much better than that of the positive drug acarbose (109.54 ± 14.23 µM). Similarly, these two compounds showed the inhibitory activity against COX-2 with the half-maximal inhibitory effects (IC50) at 27.91 ± 1.74 µM and 49.05 ± 1.49 µM, respectively. Therefore, these two flavonoid compounds (vitexin and astragalin) were speculated as potential antidiabetic and anti-inflammatory compounds from E. humifusa. Taken together, the integrated strategy applied to E. humifusa led to the fast identification of two potential double-acting flavonoids and enlightened its antidiabetic and anti-inflammatory uses. Besides these findings, the integrated strategy in this study could also be used to facilitate the rapid discovery and development of active candidates from other traditional herbal medicines against multi-drug targets and to aid in revealing their mechanisms of action for their traditional uses.
Dipolarization-induced energetic electron precipitation during continuously active periods and isolated substorms
Authors: Shukhtina M. A. , Sergeev V. A. , Rogov D. D. 
Published: August 2022

Recently we proposed a spatio-temporal model of auroral absorption for isolated substorms based on linear prediction filter technique, which describes the precipitation effects as a sum of properly weighted and time-delayed contributions of short dipolarizations/injections inferred from magnetic MPB index. Here we apply a similar approach to a more general and practically important type of continuous activity including substorms clusters, which is accompanied by intense energetic electron precipitation lasting for many hours and may affect ozone concentration and climate. Unexpectedly, in spite of very different geophysical background, the derived precipitation response to unit-scale injection appeared almost identical to that obtained for isolated substorms. Significant part of absorption variance during active non-storm periods turns out to be the result of superposition of previous injections with short memory less than 4 h. Our results indicate that, while the injection efficiency is roughly the same, large difference in precipitated fluxes and ionospheric response between two different types of activity is mostly provided by a more frequent appearance and increased intensities of dipolarizations/injections during active periods. In both event types dipolarizations are the decisive factor which determines energetic electron precipitation.
Malat1 deficiency prevents hypoxia-induced lung dysfunction by protecting the access to alveoli
Authors: Sallé-Lefort Sandrine , Miard Stéphanie , Henry Cyndi , Arias-Reyes Christian , Marcouiller François , Beaulieu Marie-Josée , Aubin Sophie , Lechasseur Ariane , Jubinville Éric , Marsolais David , Morissette Mathieu C. , Joseph Vincent , Soliz Jorge , Bossé Ynuk , Picard Frédéric 
Published: August 2022

Hypoxia is common in lung diseases and a potent stimulator of the long non-coding RNA Metastasis-Associated Lung Adenocarcinoma Transcript 1 (MALAT1). Herein, we investigated the impact of Malat1 on hypoxia-induced lung dysfunction in mice. Malat1-deficient mice and their wild-type littermates were tested after 8 days of normoxia or hypoxia (10% oxygen). Hypoxia decreased elastance of the lung by increasing lung volume and caused in vivo hyperresponsiveness to methacholine without altering the contraction of airway smooth muscle. Malat1 deficiency also modestly decreased lung elastance but only when tested at low lung volumes and without altering lung volume and airway smooth muscle contraction. The in vivo responsiveness to methacholine was also attenuated by Malat1 deficiency, at least when elastance, a readout sensitive to small airway closure, was used to assess the response. More impressively, in vivo hyperresponsiveness to methacholine caused by hypoxia was virtually absent in Malat1-deficient mice, especially when hysteresivity, a readout sensitive to small airway narrowing heterogeneity, was used to assess the response. Malat1 deficiency also increased the coefficient of oxygen extraction and decreased ventilation in conscious mice, suggesting improvements in gas exchange and in clinical signs of respiratory distress during natural breathing. Combined with a lower elastance at low lung volumes at baseline, as well as a decreased propensity for small airway closure and narrowing heterogeneity during a methacholine challenge, these findings represent compelling evidence suggesting that the lack of Malat1 protects the access to alveoli for air entering the lung.
The application of artificial gravity in medicine and space
Authors: Isasi Eugenia , Isasi Maria E. , van Loon Jack J. W. A. 
Published: August 2022

Gravity plays a crucial role in physiology. The lack of gravity, like in long duration spaceflight missions, cause pathologies in e.g., the musculoskeletal system, cardiovascular deconditioning, immune system deprivation or brain abnormalities, to just mention a few. The application of artificial gravity through short-arm human centrifugation (SAHC) has been studied as a possible countermeasure to treat spaceflight deconditioning. However, hypergravity protocols applied by using SAHC have also been used to treat different, ground-based pathologies. Such gravitational therapies have been applied in Uruguay for more than four decades now. The aim of this overview is to summarize the most important findings about the effects of gravitational therapy in different, mainly vascular based pathologies according to the experience in the Gravitational Therapy Center and to discuss the current research in the field of hypergravity applications in medicine but also as multisystem countermeasure for near weightlessness pathologies. New insight is needed on the use of hypergravity in medicine and space research and application.
Effects of chains squat training with different chain load ratio on the explosive strength of young basketball players’ lower limbs
Authors: Jiang Dongting , Xu Gang 
Published: August 2022

The purpose of this study was to explore the effects of the chain squat training (CST) with different chain load ratio (0, 10%, 20% and 30%) on the explosive power of the lower limbs of adolescent male basketball players. Forty-four youth basketball players (age 15.48 ± 0.81 years, body mass 78.86 ± 12.04 kg, height 184.95 ± 6.71 cm) were randomly allocated to one of the four groups: traditional squat training (TST), 10% chains squat training (10% CST), 20% chains squat training (20% CST), and 30% chains squat training (30% CST). Training interventions were performed 2 times per week for 6 weeks, and at the week before (Pre) and after (Post) the 6-week CST program with different chain load ratio, the no-step vertical jump, standing long jump, 15 m shuttle run, 1 R M squat and 30 m sprint test were performed. A 4 (group) × 2 (time) repeated measures analysis of variances (ANOVA) was calculated to show the scatter of each variable, and the Bonferroni’s post-hoc test was used for multiple comparisons, in addition the partial eta-squared (η2) was calculated as an estimate of the ES. Significant time × group interaction was noticed for the no-step vertical jump (p&lt; 0.001; η2= 0.611), standing long jump (p&lt; 0.001; η2= 0.490) and 1 R M squat (p&lt; 0.01; η2= 0.333) indicating that better improvements appear in CST compared to TST. However, significant time × group interaction was noted for 15 m shuttle run (p&lt; 0.001; η2= 0.428), in favor of TST compared to CST. In addition, the improvements in 30 m sprint were similar between all groups. In conclusion, CST with more chain load has better training effects on lower limb explosive strength and maximum strength, based on the improvement in 1 R M squat and jumping performance. Besides, compared with TST, CST with more chain load might not help to develop better velocity adaptation at higher range of movement.
Rural-urban differences in prevalence of and risk factors for refractive errors among school children and adolescents aged 6–18 years in Dalian, China
Authors: Wang Yachen , Liu Lei , Lu Zhili , Qu Yiyin , Ren Xianlong , Wang Jiaojiao , Lu Yan , Liang Wei , Xin Yue , Zhang Nan , Jin Lin , Wang Lijing , Song Jian , Yu Jian , Zhao Lijun , Ma Xiang , Zhang Lijun 
Published: August 2022

PurposeTo assess the prevalence of refractive errors (REs) in school children aged 6–18 years in urban and rural settings in Dalian, Northeast of China.MethodsThis is a school-based cross-sectional survey using multi-stage randomization technique. Six- to eighteen-year-old school children from elementary schools, junior and senior high schools from a rural area and an urban area in Dalian were included in December 2018. All subjects underwent a comprehensive questionnaire and eye examination.ResultsA total of 4,522 school children with 6–18 years of age were investigated. The age, gender-adjusted prevalence of myopia, and anisometropia were 82.71 and 7.27% among the urban students as compared to 71.76% and 5.41% among the rural ones (OR = 1.80, 95 % CI = 1.53 - 2.11,P&lt; 0.001; OR = 1.29, 95 % CI = 1.00–1.67,P= 0.049), respectively. The hyperopia was less common in urban students than in rural ones (5.63vs. 10.21%; OR = 0.54, 95 % CI: 0.43–0.67,P&lt; 0.001). However, there was no significant difference in prevalence of astigmatism between urban (46.07%) and rural (44.69%) participants (OR = 0.96, 95 % CI: 0.84–1.10,P= 0.559). The differences on prevalence of REs were attributed to different social-demographic and physiologic factors.ConclusionsThe students from urban settings are more likely to have myopia and anisometropia but less likely to have hyperopia than their rural counterparts. Although considerable attention had been paid to controlling REs, it is necessary to further consider the urban-rural differences in REs.
Factors promoting collaboration between community sports leaders and guardians in urban areas of Japan: A cross-sectional study
Authors: Hosokawa Yoshino , Yako-Suketomo Hiroko , Ishii Kaori , Oka Koichiro 
Published: August 2022

BackgroundCommunity sports leaders (CSLs) are expected to play an important role in promoting regional sports in Japan. Increased opportunities for CSLs to work in schools and engage with guardians could encourage middle-aged adults to participate in regional sports activities. However, few CSLs work with guardians, and there is no evidence regarding what CSL characteristics encourage collaboration. The present study aimed to ascertain the aspects of coordination for CSLs collaborating with guardians in urban areas.MethodsA self-administered questionnaire survey was mailed to all 1,489 CSLs through 59 municipalities using the CSL out of 62 in Tokyo, Japan, from July to November 2021. The questionnaire covered sociodemographic data, variables related to CSL activities, coordination functions, and experience collaborating with guardians. We conducted a binomial logistic regression analysis using experience collaborating with guardians as the dependent variable, coordination function as the explanatory variable, and gender, age, residence duration, years of CSL experience, and the number of activities as covariates.ResultsThe analyzed sample comprised 478 CSLs. Binomial logistic regression analysis revealed a significant relationship between experience collaborating with guardians and the coordination function of internal/external CSL organizations, such as participation in non-CSL community activities, experience teaching and supporting their own children's sports, activity initiatives, number of times they used the school gymnasium, awareness of the regional sports plan, and cooperation with the chairman of the neighborhood association.ConclusionsCollaboration with guardians was related to CSL's individual experience engaging in regional sports from parenting and community collaboration, such as participation in non-CSL community activities and their relationship with the chairman of the neighborhood association. CSL activities may have the potential to encourage middle-aged adults to participate in regional sports.