bluuebunny/crossref_metadata_2025 huggingface dataset:
Physicians’ Perspectives on the Implementation of the Second Opinion Directive in Germany—An Exploratory Sequential Mixed-Methods Study
Authors: May Susann , Bruch Dunja , Muehlensiepen Felix , Ignatyev Yuriy , Neugebauer Edmund , Ronckers Cecile , von Peter Sebastian
Published: June 2022

A new Second Opinion Directive (SOD) was introduced in Germany in December 2018 for hysterectomy, tonsillotomy, and tonsillectomy to support shared decision making and to avoid unnecessary surgeries. Owing to its recent implementation, evidence and insights regarding outcomes and challenges encountered with the SOD are lacking, notably from the physicians’ perspective. To assess this, we undertook an exploratory sequential mixed-methods design with an initial qualitative phase followed by a quantitative evaluation. A qualitative analysis of 22 interviews with specialists in gynecology and otorhinolaryngology was followed by a statistical analysis of a survey of 136 physicians in those disciplines. The specialists expressed a generally positive opinion of the new SOD, emphasizing the aspects of patient orientation, support in decision making, and patient safety. However, they also highlighted the following structural problems regarding the SOD implementation: In addition to an increased organisational effort, the specialists criticised the SOD with regard to its implementation in rural regions with a low availability of specialists for referral. Barriers that impede the implementation of the current directive, such as the adaptation of the qualifying requirements for authorized second opinion physicians, as well as the inclusion of relevant indications, need focused consideration to obtain better alignment with everyday practice.
Retrospective Analysis of Treatment Outcomes of Maxillary Sinusitis Associated with Medication-Related Osteonecrosis of the Jaw
Authors: Otsuru Mitsunobu , Hayashida Saki , Morishita Kota , Murata Maho , Soutome Sakiko , Sasaki Miho , Takagi Yukinori , Sumi Misa , Umeda Masahiro
Published: June 2022

Although maxillary sinusitis often occurs in patients with medication-related osteonecrosis of the jaw (MRONJ) of the upper jaw, there have been few reports on the treatment and outcomes for maxillary sinusitis associated with maxillary MRONJ. This study aimed to retrospectively investigate the treatment outcomes of maxillary sinusitis in patients with MRONJ of the upper jaw. There were 34 patients diagnosed with maxillary MRONJ and sinusitis by preoperative computed tomography who underwent surgery in our institution between January 2011 and December 2019. Age, sex, primary disease, stage of MRONJ, class and administration period of an antiresorptive agent, corticosteroid administration, preoperative leukocyte count and serum albumin level, periosteal reaction, sinusitis grade, maxillary sinus surgical procedure, and treatment outcomes of MRONJ and sinusitis were examined. There were 7 male and 27 female patients (average age, 74.7 years). Complete healing of MRONJ was obtained in 29 of 34 patients (85.3%). Maxillary sinusitis resolved or improved in 21 patients (61.8%) but did not change or worsen in 13 patients (38.2%). We found that complete resection of necrotic bone with intraoperative irrigation of the maxillary sinus may provide good treatment outcomes for maxillary sinusitis associated with MRONJ, although our findings were not statistically significant owing to the small number of patients.
A Macro-Level Association of Vaccination Rate with the Number of Confirmed COVID-19 Cases in the United States and Japan
Authors: Noda Hiroyuki
Published: June 2022

Aiming to evaluate a macro-level association of vaccination rate as well as booster vaccination rate with the number of confirmed COVID-19 cases in the United States and Japan, a cross-sectional study was conducted using data in each jurisdiction. Data on the total number of people who were fully vaccinated as of the end of December 2021, data on the total number of people who have received a booster dose as of the end of March 2022 and data on the cumulative number of confirmed COVID-19 cases were obtained from the website of the national governments. A generalized regression model was used to examine the association. This study showed that a higher vaccination rate was associated with a lower number of confirmed COVID-19 cases per year in 2021 for both the United States and Japan. The number of confirmed COVID-19 cases per 1000 population per year (95% confidence intervals) as a 1% increment of the vaccination rate was −0.74 (−1.29, −0.20), p = 0.007 for the United States and −1.48 (−1.95, −1.00), p < 0.0001 for Japan. A similar association was observed for the booster vaccination rate in 2022, although the association was attenuated in a multivariable model, particularly for the United States. This study provided macro-level evidence that vaccination may reduce the number of confirmed COVID-19 cases.
Comparing Mental Health, Wellbeing and Flourishing in Undergraduate Students Pre- and during the COVID-19 Pandemic
Authors: Graham Marien Alet , Eloff Irma
Published: June 2022

There has been a preponderance of studies on student mental health, wellbeing and flourishing during the COVID-19 pandemic. Few studies have compared data on student mental health and wellbeing before and during the pandemic. The purpose of the current study was to compare mental health and wellbeing in undergraduate students before and during the COVID-19 pandemic. Survey research was conducted with three groups of undergraduate students (n = 905) from diverse scientific fields at a large, urban university in South Africa. Data was collected by means of electronic surveys, combining full-scale items from three instruments, the Mental Health Continuum Short Form, the Flourishing Scale and the Fragility of Happiness Scale. Data was analysed by the Statistical Package for the Social Sciences (SPSS), the Analysis of Moment Structures (AMOS) and R software. The results indicate that while the mental health and wellbeing of students declined during the pandemic concerning their perceived ability to contribute to society, having supportive and rewarding social relationships and them being engaged and interested in their daily activities, it also improved in terms of their perceived ability to manage their daily lives (environmental mastery), being challenged to grow (personal growth) and in terms of their views that society was becoming better (social growth/actualisation).
Microbial Contamination and Public Health: An Overview
Authors: Tropea Alessia
Published: June 2022

Food contamination with microbial agents can take place at any stage of the food chain, from farm to fork. For this reason, good hygienic and manufacturing practices must be followed along the entire food chain to prevent microbiological food contamination due to microbes which can cause high incidence of morbidity and mortality among consumers. Recent research have been focused on the implementation of innovative technologies for enhancing the quality and safety of food without compromising its organoleptic and nutritional characteristics. Studies should be addressed to the development of simple, less expensive, and fast tests for monitoring and controlling microbial food contamination, as well as to the development of new food manufacturing processes.
Innovative Application of Diathermy in Orthodontics: A Case Report
Authors: Cirulli Nunzio , Inchingolo Alessio Danilo , Patano Assunta , Ceci Sabino , Marinelli Grazia , Malcangi Giuseppina , Coloccia Giovanni , Montenegro Valentina , Di Pede Chiara , Ciocia Anna Maria , Barile Giuseppe , Mancini Antonio , Palmieri Giulia , Azzollini Daniela , Rapone Biagio , Nucci Ludovica , Bordea Ioana Roxana , Scarano Antonio , Lorusso Felice , Tartaglia Gianluca Martino , Maspero Cinzia , Nuzzolese Manuel , Cardarelli Filippo , Di Venere Daniela , Inchingolo Angelo Michele , Dipalma Gianna , Inchingolo Francesco
Published: June 2022

Introduction: Several strategies have been proposed in the literature to accelerate tooth movement, many of which are invasive and have numerous side effects, such as surgical techniques (corticotomy and piezocision technique). This research investigates to what extent diathermy can accelerate the orthodontic alignment phase. Materials and Methods: A patient with lower teeth crowding index of the same magnitude was selected. The orthodontic treatment with Nickel–Titanium (NiTi) thermal arc 0.015 in the lower arch was performed, associated with a weekly application of diathermy using the intraoral handpiece. The total duration of treatment was three weeks. During each session, an intraoral transducer was employed to stimulate the hard and soft tissues of the left dental hemiarch, which was also orthodontically aligned like the right one. Results: Comparing the tooth movements of four elements of the two hemiarchies, it was found that, overall, the two teeth examined on the treated side underwent a more significant number of changes than on the untreated side, although not by a significant amount. Conclusions: The use of diathermy, according to the authors, is a non-invasive approach that may speed up the orthodontic alignment phase and reduce treatment duration, resulting in a lower risk of caries, gingival recessions, root resorptions, and patient compliance improvement, without side effects. Further studies and an adequate sample size will be needed to confirm the findings.
Analyzing Trajectories of Acute Cigarette Reduction Post-Introduction of an E-Cigarette Using Ecological Momentary Assessment Data
Authors: Guttentag Alexandra , Tseng Tuo-Yen , Shelley Donna , Kirchner Thomas
Published: June 2022

Electronic cigarettes (ECs) may hold great potential for helping smokers transition off combustible cigarettes (CCs); however, little is known about the patterns that smokers follow when using an EC as a CC-substitute in order to ultimately reduce and quit smoking. Our primary aim in this study was to evaluate whether common patterns of CC use exist amongst individuals asked to substitute an EC for at least half of the CCs they would normally smoke. These patterns may elucidate the immediate switching and reduction behaviors of individuals using ECs as a reduction/cessation tool. This analysis uses data from a randomized controlled trial of 84 adult smokers assigned to receive either 4.5% nicotine or placebo (0% nicotine) EC. Participants were advised to use the EC to help them reach a 50% reduction in cigarettes-per-day (CPD) within 3 weeks. Longitudinal trajectory analysis was used to identify CPD reduction classes amongst the sample; participants clustered into four distinct, linear trajectories based on daily CC use during the 3-week intervention. Higher readiness to quit smoking, prior successful quit attempts, and lower baseline CC consumption were associated with assignment into “more successful” CC reduction classes. ECs may be a useful mechanism to promote CC reduction. This study demonstrates that a fine-grained trajectory approach can be applied to examine switching patterns in the critical first weeks of an attempt.
Toward a Theory of the Underpinnings and Vulnerabilities of Structural Racism: Looking Upstream from Disease Inequities among People Who Use Drugs
Authors: Friedman Samuel R. , Williams Leslie D. , Jordan Ashly E. , Walters Suzan , Perlman David C. , Mateu-Gelabert Pedro , Nikolopoulos Georgios K. , Khan Maria R. , Peprah Emmanuel , Ezell Jerel
Published: June 2022

Structural racism is increasingly recognized as a key driver of health inequities and other adverse outcomes. This paper focuses on structural racism as an “upstream” institutionalized process, how it creates health inequities and how structural racism persists in spite of generations of efforts to end it. So far, “downstream” efforts to reduce these health inequities have had little success in eliminating them. Here, we attempt to increase public health awareness of structural racism and its institutionalization and sociopolitical supports so that research and action can address them. This paper presents both a theoretic and an analytic approach to how structural racism contributes to disproportionate rates of HIV/AIDS and related diseases among oppressed populations. We first discuss differences in disease and health outcomes among people who use drugs (PWUD) and other groups at risk for HIV from different racial and ethnic populations. The paper then briefly analyzes the history of racism; how racial oppression, class, gender and other intersectional divisions interact to create health inequities; and how structural racism is institutionalized in ways that contribute to disease disparities among people who use drugs and other people. It examines the processes, institutions and other structures that reinforce structural racism, and how these, combined with processes that normalize racism, serve as barriers to efforts to counter and dismantle the structural racism that Black, indigenous and Latinx people have confronted for centuries. Finally, we discuss the implications of this analysis for public health research and action to undo racism and to enhance the health of populations who have suffered lifetimes of racial/ethnic oppression, with a focus on HIV/AIDS outcomes.
The Effect of Outdoor Environmental Exposure on Readmission Rates for Children and Adolescents with Asthma—A Systematic Review
Authors: Smaller Lisa , Batra Mehak , Erbas Bircan
Published: June 2022

The burden of asthma readmission for children and adolescents is approximately 10% worldwide. Research has been synthesised for behavioural and indoor impacts; however, no such synthesis has been conducted for outdoor environmental exposures. This systematic review aims to evaluate and synthesise the impact the outdoor environment has on readmission rates for children or adolescents with asthma. We conducted a systematic search of seven databases and hand searched reference lists of articles published up until 18 January 2021. There were 12 out of 392 studies eligible for inclusion. Overall, most studies showed that outdoor environments impact on readmission; however, the strength of association is seen to be stronger in a particular subpopulation of each study depending on the exposure investigated. The evidence for the association between outdoor environmental exposure and readmission rates for children or adolescents with asthma is increasing; however, it is complicated by potential confounders such as socioeconomic factors, ethnicity, indoor air pollutants, and other behavioural factors. Further research is required to differentiate between them. Additionally, further studies need to be undertaken in further countries other than the United States of America to understand the full relationship.
Association between Gut Microbiota and Body Composition in Japanese General Population: A Focus on Gut Microbiota and Skeletal Muscle
Authors: Sugimura Yoshikuni , Kanda Akira , Sawada Kaori , Wai Kyi Mar , Tanabu Asano , Ozato Naoki , Midorikawa Tatsuyuki , Hisada Takayoshi , Nakaji Shigeyuki , Ihara Kazushige
Published: June 2022

This study aimed to investigate the gut microbial genera associated with skeletal muscle mass, using a large-scale survey from the standpoint of preventing sarcopenia. A total of 848 participants were included in the analysis. The mean (SD) ages of men (n = 353) and women (n = 495) were 50.0 (12.9) years and 50.8 (12.8) years, respectively. Body composition was assessed using appendicular skeletal muscle mass/body weight (ASM/BW), ASM, and BW. Additionally, the relationship between gut microbial genera and body composition was analyzed. The means (SD) of ASM/BW were 34.9 (2.4) % in men and 29.4 (2.9) % in women. Blautia and Bifidobacterium were positively associated with ASM/BW only in men (Blautia: β = 0.0003, Bifidobacterium: β = 0.0001). However, Blautia was negatively associated with BW (β = −0.0017). Eisenbergiella was positively associated with ASM/BW (β = 0.0209) and negatively associated with BW (β = −0.0769) only in women. Our results indicate that Blautia, Bifidobacterium and Eisenbergiella, which are positively associated with ASM/BW, might help increase skeletal muscle mass. ASM/BW may clarify the relationship between gut microbiota and skeletal muscle mass without being affected by obesity or excess body fat mass.
Differences in Time Perspectives Measured under the Dramatically Changing Socioeconomic Conditions during the Ukrainian Political Crises in 2014/2015
Authors: Senyk Oksana , Abramov Volodymyr , Bedan Viktoriia , Bunas Alina , Hrechkosii Marharyta , Lutsenko Olena , Mandzyk Tetiana , Wittmann Marc
Published: June 2022

The characteristics of the individual’s time perspective in relation to changes in social, economic, and political conditions are of major conceptual interest. We assessed the time orientations of 1588 Ukrainian students living in two different regions (western and south-eastern Ukraine) with the Zimbardo Time Perspective Inventory (ZTPI) before (2010–2013) and during (2014–2016) the socioeconomic, political, and military crises which started in 2014, eight years before the war in 2022. We applied ANOVAs with the ZTPI dimensions as dependent variables and the period of testing (precrisis, postcrisis) as an independent variable for the two Ukrainian regions separately. The time perspectives of residents in the region most distant from the war zone (western), who positively assessed the change in the political situation around 2014, increased in the future time orientation and decreased in the present-fatalistic, past-positive, and 333 present-hedonistic time orientations. The time perspectives of residents in the regions closest to the war zone (southeastern) decreased in the future and increased in the past-negative and present-fatalistic time orientations, reflecting their negative judgments of the events. It is not the crisis itself, but the specific social, economic, and political factors and evaluations which define the time perspectives, which are flexible and adjust to changes during extreme life circumstances.
Dietary Copper Deficiency Leads to Changes in Gene Expression Indicating an Increased Demand for NADH in the Prefrontal Cortex of the Rat’s Brain
Authors: Cendrowska-Pinkosz Monika , Ostrowska-Lesko Marta , Ognik Katarzyna , Krauze Magdalena , Juskiewicz Jerzy , Dabrowska Anna , Szponar Jaroslaw , Mandziuk Slawomir
Published: June 2022

Copper is an essential element to brain cells as it is a cofactor and a structural component of various enzymes involved in energy metabolism pathways. Accumulating evidence points to the pivotal role of copper deficiency in neurodegeneration resulting from impaired copper homeostasis. Despite the indisputable role of copper in mitochondrial respiration, its homeostasis regulation in the brain tissue remains unclear. The assessment of changes in the expression of genes encoding key pathways of energy metabolism can greatly benefit further studies exploring copper’s role in neurodegeneration. Using a rat model, we investigate whether the replacement of the inorganic form of copper with metallic nanoparticles containing copper or complete deprivation of copper from the diet have an impact on the expression of genes involved in energy metabolism in the prefrontal cortex of the rats’ brain. Herein, we indicate that removing inorganic copper from the normal standard diet or the replacement with copper nanoparticles can lead to programmed energy metabolism changes. It can be recognized that some of these changes indicate an increased demand for NADH in the prefrontal cortex of the rat’s brain, probably as a result of adaptation effect.
Gas-Plasma-Activated Water Impact on Photo-Dependent Dormancy Mechanisms in Nicotiana tabacum Seeds
Authors: Grainge Giles , Nakabayashi Kazumi , Iza Felipe , Leubner-Metzger Gerhard , Steinbrecher Tina
Published: June 2022

Seeds sense temperature, nutrient levels and light conditions to inform decision making on the timing of germination. Limited light availability for photoblastic species results in irregular germination timing and losses of population germination percentage. Seed industries are therefore looking for interventions to mitigate this risk. A growing area of research is water treated with gas plasma (GPAW), in which the formed solution is a complex consisting of reactive oxygen and nitrogen species. Gas plasma technology is widely used for sterilisation and is an emerging technology in the food processing industry. The use of the GPAW on seeds has previously led to an increase in germination performance, often attributed to bolstered antioxidant defence mechanisms. However, there is a limited understanding of how the solution may influence the mechanisms that govern seed dormancy and whether photoreceptor-driven germination mechanisms are affected. In our work, we studied how GPAW can influence the mechanisms that govern photo-dependent dormancy, isolating the effects at low fluence response (LFR) and very low fluence response (VLFR). The two defined light intensity thresholds affect germination through different phytochrome photoreceptors, PHYB and PHYA, respectively; we found that GPAW showed a significant increase in population germination percentage under VLFR and further described how each treatment affects key physiological regulators.
Fabrication of CL-20/HMX Cocrystal@Melamine–Formaldehyde Resin Core–Shell Composites Featuring Enhanced Thermal and Safety Performance via In Situ Polymerization
Authors: Duan Binghui , Lu Xianming , Mo Hongchang , Tan Bojun , Wang Bozhou , Liu Ning
Published: June 2022

Safety concerns remain a bottleneck for the application of 2,4,6,8,10,12-hexanitro- 2,4,6,8,10,12-hexaazaisowurtzitane (CL-20)/1,3,5,7-tetranitro-1,3,5,7-tetrazacyclooctane (HMX) cocrystal. Melamine–formaldehyde (MF) resin was chosen to fabricate CL-20/HMX cocrystal-based core–shell composites (CH@MF composites) via a facile in situ polymerization method. The resulted CH@MF composites were comprehensively characterized, and a compact core–shell structure was confirmed. The effects of the shell content on the properties of the composites were explored as well. As a result, we found that, except for CH@MF–2 with a 1% shell content, the increase in shell content led to a rougher surface morphology and more close-packed structure. The thermal decomposition peak temperature improved by 5.3 °C for the cocrystal enabled in 1.0 wt% MF resin. Regarding the sensitivity, the CH@MF composites exhibited a significantly reduced impact and friction sensitivity with negligible energy loss compared with the raw cocrystal and physical mixtures due to the cushioning and insulation effects of the MF coating. The formation mechanism of the core–shell micro-composites was further clarified. Overall, this work provides a green, facile and industrially potential strategy for the desensitization of energetic cocrystals. The CH@MF composites with high thermal stability and low sensitivity are promising to be applied in propellants and polymer-bonded explosive (PBX) formulations.
Effect of Psilocybin and Ketamine on Brain Neurotransmitters, Glutamate Receptors, DNA and Rat Behavior
Authors: Wojtas Adam , Bysiek Agnieszka , Wawrzczak-Bargiela Agnieszka , Szych Zuzanna , Majcher-Maślanka Iwona , Herian Monika , Maćkowiak Marzena , Gołembiowska Krystyna
Published: June 2022

Clinical studies provide evidence that ketamine and psilocybin could be used as fast-acting antidepressants, though their mechanisms and toxicity are still not fully understood. To address this issue, we have examined the effect of a single administration of ketamine and psilocybin on the extracellular levels of neurotransmitters in the rat frontal cortex and reticular nucleus of the thalamus using microdialysis. The genotoxic effect and density of glutamate receptor proteins was measured with comet assay and Western blot, respectively. An open field test, light–dark box test and forced swim test were conducted to examine rat behavior 24 h after drug administration. Ketamine (10 mg/kg) and psilocybin (2 and 10 mg/kg) increased dopamine, serotonin, glutamate and GABA extracellular levels in the frontal cortex, while psilocybin also increased GABA in the reticular nucleus of the thalamus. Oxidative DNA damage due to psilocybin was observed in the frontal cortex and from both drugs in the hippocampus. NR2A subunit levels were increased after psilocybin (10 mg/kg). Behavioral tests showed no antidepressant or anxiolytic effects, and only ketamine suppressed rat locomotor activity. The observed changes in neurotransmission might lead to genotoxicity and increased NR2A levels, while not markedly affecting animal behavior.
High-Mobility Group Box 1 Inhibitor BoxA Alleviates Neuroinflammation-Induced Retinal Ganglion Cell Damage in Traumatic Optic Neuropathy
Authors: Peng Jingyi , Jin Jiayi , Su Wenru , Shao Wanwen , Li Weihua , Li Zhiquan , Yu Huan , Zheng Yongxin , Zhong Liuxueying
Published: June 2022

Traumatic optic neuropathy (TON) is a significant cause of vision loss and irreversible blindness worldwide. It is defined as retinal ganglion cell death and axon degeneration caused by injury. Optic nerve crush (ONC), a well-validated model of TON, activates retinal microglia and initiates neuroinflammation. High-mobility group box 1 (HMGB1), a non-histone chromosomal binding protein in the nucleus of eukaryotic cells, is an important inducer of microglial activation and pro-inflammatory cytokine release. The purpose of this study was to examine the protective effects and mechanism of the HMGB1 inhibitor BoxA to neuroinflammation-induced retinal ganglion cells (RGCs) damage in traumatic optic neuropathy. For that purpose, an optic nerve crush model was established in C57BL/6J mice at 10–12 weeks. Model mice received an intravitreal injection of PBS and the HMGB1 inhibitor BoxA. Our data demonstrated that HMGB1 expression increased after optic nerve crush. Retinal ganglion cell function and morphology were damaged, and retinal ganglion cell numbers were reduced after optic nerve crush. Intravitreal injection of BoxA after ONC can alleviate damage. Furthermore, BoxA reduced microglial activation and expression levels of nuclear factor κB (NF-kB), nucleotide-binding domain, leucine-rich repeat containing protein 3 (NLRP3), and apoptosis-associated speck-like protein containing a CARD (ASC) in experimental ONC mice. In summary, HMGB1 mediates NLRP3 inflammasome via NF-kB to participate in retinal inflammatory injury after ONC. Thus, intravitreal injection of BoxA has potential therapeutic benefits for the effective treatment of RGC death to prevent TON.
New Borane-Protected Derivatives of α-Aminophosphonous Acid as Anti-Osteosarcoma Agents: ADME Analysis and Molecular Modeling, In Vitro Studies on Anti-Cancer Activities, and NEP Inhibition as a Possible Mechanism of Anti-Proliferative Activity
Authors: Mizerska-Kowalska Magdalena , Sowa Sylwia , Donarska Beata , Płaziński Wojciech , Sławińska-Brych Adrianna , Tomasik Aleksandra , Ziarkowska Anna , Łączkowski Krzysztof Z. , Zdzisińska Barbara
Published: June 2022

Many organophosphorus compounds (OPs), especially various α-aminophosphonates, exhibit anti-cancer activities. They act, among others, as inhibitors of the proteases implicated in cancerogenesis. Thesetypes of inhibitors weredescribed, e.g., for neutral endopeptidase (NEP) expressed in different cancer cells, including osteosarcoma (OS). The aim of the present study isto evaluate new borane-protected derivatives of phosphonous acid (compounds 1–7) in terms of their drug-likeness properties, anti-osteosarcoma activities in vitro (against HOS and Saos-2 cells), and use as potential NEP inhibitors. The results revealed that all tested compounds exhibited the physicochemical and ADME properties typical for small-molecule drugs. However, compound 4 did not show capability of blood–brain barrier penetration (Lipiński and Veber rules;SwissAdme tool). Moreover, the α-aminophosphonite-boranes (compounds 4–7) exhibited stronger anti-proliferative activity against OS cells than the other phosphonous acid-borane derivatives (compounds 1–3),especially regarding HOS cells (MTT assay). The most promising compounds 4 and 6 induced apoptosis through the activation of caspase 3 and/or cell cycle arrest at the G2 phase (flow cytometry). Compound 4 inhibited the migration and invasiveness of highly aggressive HOS cells (wound/transwell and BME-coated transwell assays, respectively). Additionally, compound 4 and, to a lesser extent, compound 6 inhibited NEP activity (fluorometric assay). This activity of compound 4 was involved in its anti-proliferative potential (BrdU assay). The present study shows that compound 4 can be considered a potential anti-osteosarcoma agent and a scaffold for the development of new NEP inhibitors.
Lethality of Zinc Oxide Nanoparticles Surpasses Conventional Zinc Oxide via Oxidative Stress, Mitochondrial Damage and Calcium Overload: A Comparative Hepatotoxicity Study
Authors: Pei Xingyao , Jiang Haiyang , Xu Gang , Li Cun , Li Daowen , Tang Shusheng
Published: June 2022

Zinc oxide nanoparticles (ZnO NPs) with high bioavailability and excellent physicochemical properties are gradually becoming commonplace as a substitute for conventional ZnO materials. The present study aimed to investigate the hepatotoxicity mechanism of ZnO NPs and traditional non-nano ZnO particles, both in vivo and in vitro, and identify the differences in their toxic effects. The results showed that the extent and conditions of zinc ion release from ZnO NPs were inconsistent with those of ZnO. The RNA-seq results revealed that the expression quantity of differentially expressed genes (DEGs) and differentially expressed transcripts (DETs) affected by ZnO NPs was more than in ZnO, and the overall differences in genes or transcripts in the ZnO NPs group were more pronounced than in the ZnO group. Furthermore, the cell inactivation, oxidative stress, mitochondrial damage, and intracellular calcium overload induced by ZnO NPs were more serious than ZnO in HepG2 cells. Moreover, compared with traditional ZnO, the rat liver damage induced by ZnO NPs was more significant, with evidence of higher AST and ALT levels, weaker antioxidant capacity, and more serious histopathological damage (p < 0.05). In summary, the hepatotoxicity of ZnO NPs was more serious than that of conventional ZnO, which is helpful to understand the hepatotoxicity mechanism of Zn compounds in different states and improve the risk assessment of novel nano ZnO products in a variety of applications.
Liposomal Formulations of a New Zinc(II) Complex Exhibiting High Therapeutic Potential in a Murine Colon Cancer Model
Authors: Ribeiro Nádia , Albino Melissa , Ferreira Andreia , Escrevente Cristina , Barral Duarte , Pessoa João , Reis Catarina , Gaspar Maria , Correia Isabel
Published: June 2022

Colorectal cancer is the second leading cause of cancer-related mortality. Many current therapies rely on chemotherapeutic agents with poor specificity for tumor cells. The clinical success of cisplatin has prompted the research and design of a huge number of metal-based complexes as potential chemotherapeutic agents. In this study, two zinc(II) complexes, [ZnL2] and [ZnL(AcO)], where AcO is acetate and L is an organic compound combining 8-hydroxyquinoline and a benzothiazole moiety, were developed and characterized. Analytical and spectroscopic studies, namely, NMR, FTIR, and UV-Vis allowed us to establish the complexes’ structures, demonstrating the ligand-binding versatility: tetradentate in [ZnL(AcO)] and bidentate in [ZnL2]. Complexes were screened in vitro using murine and human colon cancer cells cultured in 2D and 3D settings. In 2D cells, the IC50 values were <22 µM, while in 3D settings, much higher concentrations were required. [ZnL(AcO)] displayed more suitable antiproliferative properties than [ZnL2] and was chosen for further studies. Moreover, based on the weak selectivity of the zinc-based complex towards cancer cell lines in comparison to the non-tumorigenic cell line, its incorporation in long-blood-circulating liposomes was performed, aiming to improve its targetability. The resultant optimized liposomal nanoformulation presented an I.E. of 76% with a mean size under 130 nm and a neutral surface charge and released the metal complex in a pH-dependent manner. The antiproliferative properties of [ZnL(AcO)] were maintained after liposomal incorporation. Preliminary safety assays were carried out through hemolytic activity that never surpassed 2% for the free and liposomal forms of [ZnL(AcO)]. Finally, in a syngeneic murine colon cancer mouse model, while free [ZnL(AcO)] was not able to impair tumor progression, the respective liposomal nanoformulation was able to reduce the relative tumor volume in the same manner as the positive control 5-fluorouracil but, most importantly, using a dosage that was 3-fold lower. Overall, our results show that liposomes were able to solve the solubility issues of the new metal-based complex and target it to tumor sites.
Hypercholesterolemia Negatively Regulates P2X7-Induced Cellular Function in CD4+ and CD8+ T-Cell Subsets from B6 Mice Fed a High-Fat Diet
Authors: Hutteau-Hamel Tom , Mellouk Amine , Trainel Nicolas , Cassard Anne-Marie , Bobé Pierre
Published: June 2022

We have previously showed that plasma membrane cholesterol and GM1 ganglioside content are responsible for the opposite sensitivity of mouse leukemic T cells to ATP. We also reported that the sensitivity of CD4+ and CD8+ T cells to ATP depends on their stage of differentiation. Here, we show that CD4+ and CD8+ T cells from B6 mice express different levels of membrane GM1 and P2X7 but similar levels of cholesterol. Thus, in CD4+ T cells, membrane cholesterol content negatively correlated with ATP/P2X7-induced CD62L shedding but positively correlated with pore formation, phosphatidylserine externalization, and cell death. By contrast, in CD8+ T cells, cholesterol, GM1, and P2X7 levels negatively correlated with all these ATP/P2X7-induced cellular responses. The relationship between cholesterol and P2X7-induced cellular responses was confirmed by modulating cholesterol levels either ex vivo or through a high-fat diet. Membrane cholesterol enrichment ex vivo led to a significant reduction in all P2X7-induced cellular responses in T cells. Importantly, diet-induced hypercholesterolemia in B6 mice was also associated with decreased sensitivity to ATP in CD4+ and CD8+ T cells, highlighting the relationship between cholesterol intake and the amplitudes of P2X7-induced cellular responses in T cells.
Polypeptides Isolated from Lactococcus lactis Alleviates Lipopolysaccharide (LPS)-Induced Inflammation in Ctenopharyngodon idella
Authors: Li Pei , Xu Youqing , Cao Yupo , Ding Zhaokun
Published: June 2022

The main purpose of the present study was to evaluate the anti-inflammatory activity of Lactococcus lactis BL52 and isolate active substances responsible for anti-inflammatory activity. Head-kidney (HK) macrophages were used for in vitro bioassay-guided isolation, and the structure of the two peptides was identified by mass spectrometry analysis. Lipopolysaccharide (LPS)-induced inflammatory responses in Ctenopharyngodon idella were also examined to evaluate the in vivo anti-inflammatory activity of active substances. Two active peptides were isolated by HPLC from L. lactis BL52, and an in vitro anti-inflammatory assay demonstrated that peptide ALBL1 and ALBL2 dose-dependently inhibited LPS-induced inflammatory cytokines TNF-α, IL-6, and IL-1β and inflammatory factors NO and PGE 2 production in macrophages (p < 0.05). After being treated with 20 mg/Kg peptide ALBL1 and ALBL2, the expression levels of TNF-α, IL-6, IL-1β, NO, and PGE 2 were significantly inhibited (p < 0.05). Results from the in vivo test showed that when the concentration of peptide ALBL1 and ALBL2 reached 30 mg/Kg, the LPS-induced upregulations of TNF-α, IL-6, IL-1β, NO, and PGE 2 were prevented. In addition, peptide ALBL1 and ALBL2 blocked the expression of Toll-like receptor 2 (TLR2) and then suppressed the phosphorylation of nuclear transcription factor-kappa B (NF-κB) p65 and degradation inhibitor of IκBα. Moreover, C. idella treated with peptide ALBL1 and ALBL2 can relieve pathological inflammatory responses caused by LPS. These results suggest that the anti-inflammatory properties of peptide ALBL1 and ALBL2 might be a result from the inhibition of IL-6, IL-1β, and TNF-α expressions through the downregulation of Toll2/NF-κB signaling pathways.
Deferiprone: A Forty-Year-Old Multi-Targeting Drug with Possible Activity against COVID-19 and Diseases of Similar Symptomatology
Authors: Kontoghiorghes George J.
Published: June 2022

The need for preparing new strategies for the design of emergency drug therapies against COVID-19 and similar diseases in the future is rather urgent, considering the high rate of morbidity and especially mortality associated with COVID-19, which so far has exceeded 18 million lives. Such strategies could be conceived by targeting the causes and also the serious toxic side effects of the diseases, as well as associated biochemical and physiological pathways. Deferiprone (L1) is an EMA- and FDA-approved drug used worldwide for the treatment of iron overload and also other conditions where there are no effective treatments. The multi-potent effects and high safety record of L1 in iron loaded and non-iron loaded categories of patients suggests that L1 could be developed as a “magic bullet” drug against COVID-19 and diseases of similar symptomatology. The mode of action of L1 includes antiviral, antimicrobial, antioxidant, anti-hypoxic and anti-ferroptotic effects, iron buffering interactions with transferrin, iron mobilizing effects from ferritin, macrophages and other cells involved in the immune response and hyperinflammation, as well as many other therapeutic interventions. Similarly, several pharmacological and other characteristics of L1, including extensive tissue distribution and low cost of production, increase the prospect of worldwide availability, as well as many other therapeutic approach strategies involving drug combinations, adjuvant therapies and disease prevention.
Early Postoperative Immunothrombosis of Bioprosthetic Mitral Valve and Left Atrium: A Case Report
Authors: Kostyunin Alexander , Glushkova Tatiana , Stasev Alexander , Mukhamadiyarov Rinat , Velikanova Elena , Bogdanov Leo , Sinitskaya Anna , Asanov Maxim , Ovcharenko Evgeny , Barbarash Leonid , Kutikhin Anton
Published: June 2022

A 72-year-old female patient with mixed rheumatic mitral valve disease and persistent atrial fibrillation underwent mitral valve replacement and suffered from a combined thrombosis of the bioprosthetic valve and the left atrium as soon as 2 days post operation. The patient immediately underwent repeated valve replacement and left atrial thrombectomy. Yet, four days later the patient died due to the recurrent prosthetic valve and left atrial thrombosis which both resulted in an extremely low cardiac output. In this patient’s case, the thrombosis was notable for the resistance to anticoagulant therapy as well as for aggressive neutrophil infiltration and release of neutrophil extracellular traps (NETs) within the clot, as demonstrated by immunostaining. The reasons behind these phenomena remained unclear, as no signs of sepsis or contamination of the BHV were documented, although the patient was diagnosed with inherited thrombophilia that could impede the fibrinolysis. The described case highlights the hazard of immunothrombosis upon valve replacement and elucidates its mechanisms in this surgical setting.
EST79232 and EST79376, Two Novel Sigma-1 Receptor Ligands, Exert Neuroprotection on Models of Motoneuron Degeneration
Authors: Gaja-Capdevila Núria , Hernández Neus , Yeste Sandra , Reinoso Raquel F. , Burgueño Javier , Montero Ana , Merlos Manuel , Vela José M. , Herrando-Grabulosa Mireia , Navarro Xavier
Published: June 2022

Motor neuron diseases (MNDs) include sporadic and hereditary neurological disorders characterized by progressive degeneration of motor neurons (MNs). Sigma-1 receptor (Sig-1R) is a protein enriched in MNs, and mutations on its gene lead to various types of MND. Previous studies have suggested that Sig-1R is a target to prevent MN degeneration. In this study, two novel synthesized Sig-1R ligands, coded EST79232 and EST79376, from the same chemical series, with the same scaffold and similar physicochemical properties but opposite functionality on Sig-1R, were evaluated as neuroprotective compounds to prevent MN degeneration. We used an in vitro model of spinal cord organotypic cultures under chronic excitotoxicity and two in vivo models, the spinal nerve injury and the superoxide dismutase 1 (SOD1)G93A mice, to characterize the effects of these Sig-1R ligands on MN survival and modulation of glial reactivity. The antagonist EST79376 preserved MNs in vitro and after spinal nerve injury but was not able to improve MN death in SOD1G93A mice. In contrast, the agonist EST79232 significantly increased MN survival in the three models of MN degeneration evaluated and had a mild beneficial effect on motor function in SOD1G93A mice. In vivo, Sig-1R ligand EST79232 had a more potent effect on preventing MN degeneration than EST79376. These data further support the interest in Sig-1R as a therapeutic target for neurodegeneration.
Exercise Training Enhances BDNF/TrkB Signaling Pathway and Inhibits Apoptosis in Diabetic Cerebral Cortex
Authors: Cheng Shiu-Min , Lee Shin-Da
Published: June 2022

This study aimed to clarify the therapeutic effects of exercise training on neural BDNF/TrkB signaling and apoptotic pathways in diabetic cerebral cortex. Thirty-six male C57BL/6JNarl mice were randomly divided into three groups: control (CON-G), diabetic group (DM-G, 100 mg/kg streptozotocin, i.p.), and diabetic with exercise training group (DMEX-G, Swim training for 30 min/day, 5 days/week). After 12 weeks, H&E staining, TUNEL staining, and Western blotting were performed to detect the morphological changes, neural apoptosis, and protein levels in the cerebral cortex. The Bcl2, BclxL, and pBad were significant decreased in DM-G compared with CON-G, whereas they (excluded the Ras and pRaf1) were increased in DMEX-G. In addition, interstitial space and TUNEL(+) apoptotic cells found increased in DM-G with increases in Fas/FasL-mediated (FasL, Fas, FADD, cleaved-caspase-8, and cleaved-caspase-3) and mitochondria-initiated (tBid, Bax/Bcl2, Bak/BclxL, Bad, Apaf1, cytochrome c, and cleaved-caspase-9) apoptotic pathways. However, diabetes-induced neural apoptosis was less in DMEX-G than DM-G with observed raises in the BDNF/TrkB signaling pathway as well as decreases in Fas/FasL-mediated and mitochondria-initiated pathways. In conclusion, exercise training provided neuroprotective effects via enhanced neural BDNF/TrkB signaling pathway and prevent Fas/FasL-mediated and mitochondria-initiated apoptotic pathways in diabetic cerebral cortex.
Kidney-Specific CAP1/Prss8-Deficient Mice Maintain ENaC-Mediated Sodium Balance through an Aldosterone Independent Pathway
Authors: Ehret Elodie , Jäger Yannick , Sergi Chloé , Mérillat Anne-Marie , Peyrollaz Thibaud , Anand Deepika , Wang Qing , Ino Fréderique , Maillard Marc , Kellenberger Stephan , Gautschi Ivan , Szabo Roman , Bugge Thomas H. , Vogel Lotte K. , Hummler Edith , Frateschi Simona
Published: June 2022

The serine protease prostasin (CAP1/Prss8, channel-activating protease-1) is a confirmed in vitro and in vivo activator of the epithelial sodium channel ENaC. To test whether proteolytic activity or CAP1/Prss8 abundance itself are required for ENaC activation in the kidney, we studied animals either hetero- or homozygous mutant at serine 238 (S238A; Prss8cat/+ and Prss8cat/cat), and renal tubule-specific CAP1/Prss8 knockout (Prss8PaxLC1) mice. When exposed to varying Na+-containing diets, no changes in Na+ and K+ handling and only minor changes in the expression of Na+ and K+ transporting protein were found in both models. Similarly, the α- or γENaC subunit cleavage pattern did not differ from control mice. On standard and low Na+ diet, Prss8cat/+ and Prss8cat/cat mice exhibited standard plasma aldosterone levels and unchanged amiloride-sensitive rectal potential difference indicating adapted ENaC activity. Upon Na+ deprivation, mice lacking the renal CAP1/Prss8 expression (Prss8PaxLC1) exhibit significantly decreased plasma aldosterone and lower K+ levels but compensate by showing significantly higher plasma renin activity. Our data clearly demonstrated that the catalytic activity of CAP1/Prss8 is dispensable for proteolytic ENaC activation. CAP1/Prss8-deficiency uncoupled ENaC activation from its aldosterone dependence, but Na+ homeostasis is maintained through alternative pathways.
A Transcriptomic Response to Lactiplantibacillus plantarum-KCC48 against High-Fat Diet-Induced Fatty Liver Diseases in Mice
Authors: Soundharrajan Ilavenil , Karnan Muthusamy , Jung Jeong-Sung , Lee Kyung-Dong , Lee Jeong-Chae , Ramesh Thiyagarajan , Kim Dahye , Choi Ki-Choon
Published: June 2022

The most prevalent chronic liver disorder in the world is fatty liver disease caused by a high-fat diet. We examined the effects of Lactiplantibacillus plantarum-KCC48 on high-fat diet-induced (HFD) fatty liver disease in mice. We used the transcriptome tool to perform a systematic evaluation of hepatic mRNA transcripts changes in high-fat diet (HFD)-fed animals and high-fat diet with L. plantarum (HFLPD)-fed animals. HFD causes fatty liver diseases in animals, as evidenced by an increase in TG content in liver tissues compared to control animals. Based on transcriptome data, 145 differentially expressed genes (DEGs) were identified in the liver of HFD-fed mice compared to control mice. Moreover, 61 genes were differentially expressed in the liver of mice fed the HFLPD compared to mice fed the HFD. Additionally, 43 common DEGs were identified between HFD and HFLPD. These genes were enriched in metabolic processes, retinol metabolism, the PPAR signaling pathway, fatty acid degradation, arachidonic metabolism, and steroid hormone synthesis. Taking these data into consideration, it can be concluded that L. plantarum-KCC48 treatment significantly regulates the expression of genes involved in hepatosteatosis caused by HFD, which may prevent fatty liver disease.
Neuroprotective Effects of VEGF in the Enteric Nervous System
Authors: Hecking Ines , Stegemann Lennart Norman , Theis Verena , Vorgerd Matthias , Matschke Veronika , Stahlke Sarah , Theiss Carsten
Published: June 2022

Although the enteric nervous system (ENS) functions largely autonomously as part of the peripheral nervous system (PNS), it is connected to the central nervous system (CNS) via the gut–brain axis. In many neurodegenerative diseases, pathological changes occur in addition to gastrointestinal symptoms, such as alpha-synuclein aggregates in Parkinson’s disease, which are found early in the ENS. In both the CNS and PNS, vascular endothelial growth factor (VEGF) mediates neuroprotective and neuroregenerative effects. Since the ENS with its close connection to the microbiome and the immune system is discussed as the origin of neurodegenerative diseases, it is necessary to investigate the possibly positive effects of VEGF on enteric neurons. Using laser microdissection and subsequent quantitative RT-PCR as well as immunohistochemistry, for the first time we were able to detect and localize VEGF receptor expression in rat myenteric neurons of different ages. Furthermore, we demonstrate direct neuroprotective effects of VEGF in the ENS in cell cultures. Thus, our results suggest a promising approach regarding neuroprotection, as the use of VEGF (may) prevent neuronal damage in the ENS.