bluuebunny/crossref_metadata_2025 huggingface dataset:
Individual and Contextual Factors Associated with Adolescents’ Self-Perceived Need for Treatment
Authors: Lopes Roanny Torres , Neves Érick Tássio Barbosa , da Costa Dutra Laio , Firmino Ramon Targino , de Lima Larissa Chaves Morais , Paiva Saul Martins , Ferreira Fernanda Morais , Granville-Garcia Ana Flávia
Published: March 2024

The present study aimed to investigate associations between the self-perceived dental treatment need and clinical factors, familial characteristics, and school context in adolescents. A cross-sectional study was conducted with a representative sample of 746 students aged 15 to 19 years in a medium-sized city in Brazil. Data collection involved the use of a sociodemographic questionnaire, an oral health questionnaire, and the Family Adaptability and Cohesion Scales (FACES III) instrument. Clinical examinations were performed by two trained and calibrated examiners (Kappa > 0.80) using the Nyvad criteria. A robust logistic regression analysis for complex samples was performed using a multilevel approach (α = 5%). The individual factors associated with the self-perceived treatment need were dental pain (OR = 1.08; 95% CI: 1.01–1.16), the loss of the first molars (OR = 1.09; 95% CI: 1.03–1.15), and disengaged family cohesion (OR = 1.15; 95% CI: 1.01–1.31). In terms of context, attending a public school was associated with the self-perceived treatment need (OR = 1.17; 95% CI: 1.02–1.33). Thus, the individual factors of toothache, tooth loss, and a disengaged family, as well as the school context, exerted an influence on the self-perceived treatment need.
Improving Retention in Mental Health and Psychosocial Support Interventions: An Analysis of Completion Rates across a Multi-Site Trial with Refugee, Migrant, and Host Communities in Latin America
Authors: Fernández Capriles Isabella , Armijos Andrea , Angulo Alejandra , Schojan Matthew , Wainberg Milton L. , Bonz Annie G. , Tol Wietse A. , Greene M. Claire
Published: March 2024

Research on mental health and psychosocial support (MHPSS) interventions within refugee and migrant communities has increasingly focused on evaluating implementation, including identifying strategies to promote retention in services. This study examines the relationship between participant characteristics, study setting, and reasons for intervention noncompletion using data from the Entre Nosotras feasibility trial, a community-based MHPSS intervention targeting refugee, migrant, and host community women in Ecuador and Panama that aimed to promote psychosocial wellbeing. Among 225 enrolled women, approximately half completed the intervention, with varying completion rates and reasons for nonattendance across study sites. Participants who were older, had migrated for family reasons, had spent more time in the study community, and were living in Panamá (vs. Ecuador) were more likely to complete the intervention. The findings suggest the need to adapt MHPSS interventions to consider the duration of access to the target population and explore different delivery modalities including the role of technology and cellular devices as reliable or unreliable source for engaging with participants. Engaging younger, newly arrived women is crucial, as they showed lower completion rates. Strategies such as consulting scheduling preferences, providing on-site childcare, and integrating MHPSS interventions with other programs could enhance intervention attendance.
Barriers Affecting Breastfeeding Practices of Refugee Mothers: A Critical Ethnography in Saskatchewan, Canada
Authors: Hirani Shela Akbar Ali
Published: March 2024

Refugee mothers are vulnerable to cultural stereotyping and socioeconomic hardships when they migrate to a new country. This vulnerability often has a negative impact on refugee mothers’ breastfeeding practices. Saskatchewan is one of the growing provinces in Canada that has a noticeable increase in refugee population with young children and limited availability of healthcare settings with baby-friendly status. Considering existing gaps in knowledge, this critical ethnographic study aimed to explore barriers that impede the breastfeeding practices of refugee mothers in Saskatchewan. After seeking ethics approval, data were collected using multiple methods, including in-depth interviews undertaken with 27 refugee mothers with young children of age range 1 day to 24 months, a review of media communications and field observations of community-based services/facilities available to refugee mothers. Findings suggest that psychosocial barriers, healthcare barriers, environmental barriers, and maternal and child health-related barriers impede the breastfeeding practices of refugee mothers in Saskatchewan. Breastfeeding practices of refugee mothers can be promoted through healthcare support, culturally appropriate services, interpretation services in healthcare settings, implementation of baby-friendly initiatives, hospital and community-based breastfeeding campaigns, and follow-up services. Collaborative efforts by healthcare settings, healthcare providers, policymakers, public health agencies, service providers, and governments are essential to support the breastfeeding practices of refugee mothers.
Spatio-Temporal Evolution Characteristics and Influencing Factors of INGO Activities in Myanmar
Authors: Liu Sicong , Zhang Yinbao , Liu Jianzhong , Zhang Xinjia , Huang Xiaoshuang
Published: March 2024

Myanmar is among the regions with the most frequent activities of International Non-Government Organizations (INGOs). Analyzing the spatio-temporal patterns of these activities holds crucial importance for optimizing organizational coordination and enhancing governmental oversight. This study focuses on the spatio-temporal evolution characteristics and influencing factors of INGO activities in Myanmar from 2010 to 2021, utilizing spatial autocorrelation and regression analysis. The results show that the number of INGOs in Myanmar has shown a gradual slowdown in growth trends, with the number of activities exhibiting a wave-like pattern, primarily driven by spontaneous activities of INGOs. The spatial distribution of INGO activities in Myanmar is concentrated in the southern plains, with the core located in Yangon, Naypyitaw, and Loilen. Furthermore, there is significant spatial polarization in the hotspot area of INGO acticities. The hotspots followed an evolutionary path from “South Myanmar” to “North Myanmar” and then back to “South Myanmar”. INGO activities in Myanmar are more focused on the local economic level, urbanization level, medical level, education level, and total population size, providing the necessary support and services for the local society and making up for the “government malfunction” and “market malfunction”.
Emerging Molecular and Synaptic Targets for the Management of Chronic Pain Caused by Systemic Lupus Erythematosus
Authors: Weng Han-Rong
Published: March 2024

Patients with systemic lupus erythematosus (SLE) frequently experience chronic pain due to the limited effectiveness and safety profiles of current analgesics. Understanding the molecular and synaptic mechanisms underlying abnormal neuronal activation along the pain signaling pathway is essential for developing new analgesics to address SLE-induced chronic pain. Recent studies, including those conducted by our team and others using the SLE animal model (MRL/lpr lupus-prone mice), have unveiled heightened excitability in nociceptive primary sensory neurons within the dorsal root ganglia and increased glutamatergic synaptic activity in spinal dorsal horn neurons, contributing to the development of chronic pain in mice with SLE. Nociceptive primary sensory neurons in lupus animals exhibit elevated resting membrane potentials, and reduced thresholds and rheobases of action potentials. These changes coincide with the elevated production of TNFα and IL-1β, as well as increased ERK activity in the dorsal root ganglion, coupled with decreased AMPK activity in the same region. Dysregulated AMPK activity is linked to heightened excitability in nociceptive sensory neurons in lupus animals. Additionally, the increased glutamatergic synaptic activity in the spinal dorsal horn in lupus mice with chronic pain is characterized by enhanced presynaptic glutamate release and postsynaptic AMPA receptor activation, alongside the reduced activity of glial glutamate transporters. These alterations are caused by the elevated activities of IL-1β, IL-18, CSF-1, and thrombin, and reduced AMPK activities in the dorsal horn. Furthermore, the pharmacological activation of spinal GPR109A receptors in microglia in lupus mice suppresses chronic pain by inhibiting p38 MAPK activity and the production of both IL-1β and IL-18, as well as reducing glutamatergic synaptic activity in the spinal dorsal horn. These findings collectively unveil crucial signaling molecular and synaptic targets for modulating abnormal neuronal activation in both the periphery and spinal dorsal horn, offering insights into the development of analgesics for managing SLE-induced chronic pain.
Shedding Light on Photodynamic Therapy in the Treatment of Necrobiosis Lipoidica: A Multicenter Real-Life Experience
Authors: Li Pomi Federica , Motolese Alfonso , Paganelli Alessia , Vaccaro Mario , Motolese Alberico , Borgia Francesco
Published: March 2024

Necrobiosis Lipoidica (NL) is a dermatological condition characterized by the development of granulomatous inflammation leading to the degeneration of collagen and subsequent formation of yellowish-brown telangiectatic plaques usually localized on the pretibial skin of middle-aged females. Due to its rarity and unclear etiopathogenesis, therapeutic options for NL are not well-standardized. Among them, photodynamic therapy (PDT) is an emerging tool, although its efficacy has primarily been evaluated in single case reports or small case series. This study reports the real-life experience of a cohort of NL patients treated with PDT at the Section of Dermatology of the University Hospital of Messina and Reggio-Emilia. From 2013 to 2023, 17 patients were enrolled —5 males (29%) and 12 females (71%) aged between 16 and 56 years (mean age: 42 ± 13 years), with a median duration of NL of 8 years. The overall complete clearance (>75% lesion reduction) was 29%, while the partial clearance (25–75% lesion reduction) was 59%, with 12% being non-responders. This study adds to the little amount of evidence present in the literature regarding the effectiveness of PDT in the treatment of NL. Variability in treatment responses among patients underscores the need for personalized protocols, optimizing photosensitizers, light sources, and dosimetry. The standardization of treatment protocols and consensus guidelines are essential to ensure reproducibility and comparability across studies.
The Influence of Copper and Zinc on Photosynthesis and Phenolic Levels in Basil (Ocimum basilicum L.), Borage (Borago officinalis L.), Common Nettle (Urtica dioica L.) and Peppermint (Mentha piperita L.)
Authors: Adamczyk-Szabela Dorota , Wolf Wojciech M.
Published: March 2024

This work is aimed at relationships which govern zinc and copper uptake by four popular medicinal herbs: basil (Ocimum basilicum L.), borage (Borago officinalis L.), common nettle (Urtica dioica L.) and peppermint (Mentha piperita L.). They are often grown in soils with significant copper or zinc levels. Herbs were cultivated by a pot method in controlled conditions. Manganese, iron, copper and zinc concentrations were determined by High-Resolution Continuum Source Flame Atomic Absorption Spectrometry. The efficiency of photosynthesis was estimated by measuring the chlorophyll content, water use efficiency, net photosynthesis, intercellular CO2, stomatal conductance, and transpiration rate. Phenolic compounds were determined by the Folin–Ciocalteu method. Analysis of variance showed that herbs grown in soil treated with copper exhibited a lower iron content in roots, while manganese behaved in the opposite way. The only exception was borage, where a decrease in the manganese content in roots was observed. Both copper and zinc supplementations increased the total content of phenolics, while the highest increases were observed for common nettle and basil. Peppermint and borage responded less to supplementation. In the majority of samples, zinc and copper did not significantly affect the photosynthesis. Herbal extracts from common nettle and basil had unique antioxidant properties and may be good free radical scavengers.
Molecular Mechanism of Resveratrol and Its Therapeutic Potential on Female Infertility
Authors: Podgrajsek Rebeka , Ban Frangez Helena , Stimpfel Martin
Published: March 2024

Resveratrol is a polyphenol present in various plant sources. Studies have reported numerous potential health benefits of resveratrol, exhibiting anti-aging, anti-inflammatory, anti-microbial, and anti-carcinogenic activity. Due to the reported effects, resveratrol is also being tested in reproductive disorders, including female infertility. Numerous cellular, animal, and even human studies were performed with a focus on the effect of resveratrol on female infertility. In this review, we reviewed some of its molecular mechanisms of action and summarized animal and human studies regarding resveratrol and female infertility, with a focus on age-related infertility, polycystic ovary syndrome, and endometriosis.
Generating Concentration Gradients across Membranes for Molecular Dynamics Simulations of Periodic Systems
Authors: Shinn Eric Joon , Tajkhorshid Emad
Published: March 2024

The plasma membrane forms the boundary between a living entity and its environment and acts as a barrier to permeation and flow of substances. Several computational means of calculating permeability have been implemented for molecular dynamics (MD) simulations-based approaches. Except for double bilayer systems, most permeability studies have been performed under equilibrium conditions, in large part due to the challenges associated with creating concentration gradients in simulations utilizing periodic boundary conditions. To enhance the scientific understanding of permeation and complement the existing computational means of characterizing membrane permeability, we developed a non-equilibrium method that enables the generation and maintenance of steady-state gradients in MD simulations. We utilize PBCs advantageously by imposing a directional bias to the motion of permeants so that their crossing of the boundary replenishes the gradient, like a previous study on ions. Under these conditions, a net flow of permeants across membranes may be observed to determine bulk permeability by a direct application of J=PΔc. In the present study, we explore the results of its application to an exemplary O2 and POPC bilayer system, demonstrating accurate and precise permeability measurements. In addition, we illustrate the impact of permeant concentration and the choice of thermostat on the permeability. Moreover, we demonstrate that energetics of permeation can be closely examined by the dissipation of the gradient across the membrane to gain nuanced insights into the thermodynamics of permeability.
Multidisciplinary Approach to the Diagnosis of Idiopathic Interstitial Pneumonias: Focus on the Pathologist’s Key Role
Authors: Lucà Stefano , Pagliuca Francesca , Perrotta Fabio , Ronchi Andrea , Mariniello Domenica Francesca , Natale Giovanni , Bianco Andrea , Fiorelli Alfonso , Accardo Marina , Franco Renato
Published: March 2024

Idiopathic Interstitial Pneumonias (IIPs) are a heterogeneous group of the broader category of Interstitial Lung Diseases (ILDs), pathologically characterized by the distortion of lung parenchyma by interstitial inflammation and/or fibrosis. The American Thoracic Society (ATS)/European Respiratory Society (ERS) international multidisciplinary consensus classification of the IIPs was published in 2002 and then updated in 2013, with the authors emphasizing the need for a multidisciplinary approach to the diagnosis of IIPs. The histological evaluation of IIPs is challenging, and different types of IIPs are classically associated with specific histopathological patterns. However, morphological overlaps can be observed, and the same histopathological features can be seen in totally different clinical settings. Therefore, the pathologist’s aim is to recognize the pathologic–morphologic pattern of disease in this clinical setting, and only after multi-disciplinary evaluation, if there is concordance between clinical and radiological findings, a definitive diagnosis of specific IIP can be established, allowing the optimal clinical–therapeutic management of the patient.
Interaction between Oligodendrocytes and Interneurons in Brain Development and Related Neuropsychiatric Disorders
Authors: Liu Yingqi , Yuan Jie , Dong Yuhao , Jiang Sufang , Zhang Ming , Zhao Xianghui
Published: March 2024

A variety of neurological and psychiatric disorders have recently been shown to be highly associated with the abnormal development and function of oligodendrocytes (OLs) and interneurons. OLs are the myelin-forming cells in the central nervous system (CNS), while interneurons are important neural types gating the function of excitatory neurons. These two types of cells are of great significance for the establishment and function of neural circuits, and they share similar developmental origins and transcriptional architectures, and interact with each other in multiple ways during development. In this review, we compare the similarities and differences in these two cell types, providing an important reference and further revealing the pathogenesis of related brain disorders.
Immune Cytolytic Activity and Strategies for Therapeutic Treatment
Authors: Agioti Stephanie , Zaravinos Apostolos
Published: March 2024

Intratumoral immune cytolytic activity (CYT), calculated as the geometric mean of granzyme-A (GZMA) and perforin-1 (PRF1) expression, has emerged as a critical factor in cancer immunotherapy, with significant implications for patient prognosis and treatment outcomes. Immune checkpoint pathways, the composition of the tumor microenvironment (TME), antigen presentation, and metabolic pathways regulate CYT. Here, we describe the various methods with which we can assess CYT. The detection and analysis of tumor-infiltrating lymphocytes (TILs) using flow cytometry or immunohistochemistry provide important information about immune cell populations within the TME. Gene expression profiling and spatial analysis techniques, such as multiplex immunofluorescence and imaging mass cytometry allow the study of CYT in the context of the TME. We discuss the significant clinical implications that CYT has, as its increased levels are associated with positive clinical outcomes and a favorable prognosis. Moreover, CYT can be used as a prognostic biomarker and aid in patient stratification. Altering CYT through the different methods targeting it, offers promising paths for improving treatment responses. Overall, understanding and modulating CYT is critical for improving cancer immunotherapy. Research into CYT and the factors that influence it has the potential to transform cancer treatment and improve patient outcomes.
An Alternative Application of Magnetic-Activated Cell Sorting: CD45 and CD235a Based Purification of Semen and Testicular Tissue Samples
Authors: Czétány Péter , Balló András , Márk László , Török Attila , Szántó Árpád , Máté Gábor
Published: March 2024

Magnetic activated cell sorting (MACS) is a well-known sperm selection technique, which is able to remove apoptotic spermatozoa from semen samples using the classic annexinV based method. Leukocytes and erythrocytes in semen samples or in testicular tissue processed for in vitro fertilization (IVF) could exert detrimental effects on sperm. In the current study, we rethought the aforementioned technique and used magnetic microbeads conjugated with anti-CD45/CD235a antibodies to eliminate contaminating leukocytes and erythrocytes from leukocytospermic semen samples and testicular tissue samples gained via testicular sperm extraction (TESE). With this technique, a 15.7- and a 30.8-fold reduction could be achieved in the ratio of leukocytes in semen and in the number of erythrocytes in TESE samples, respectively. Our results show that MACS is a method worth to reconsider, with more potential alternative applications. Investigations to find molecules labeling high-quality sperm population and the development of positive selection procedures based on these might be a direction of future research.
Arginine Supplementation in MELAS Syndrome: What Do We Know about the Mechanisms?
Authors: Barros Camila D. S. , Coutinho Aryane , Tengan Celia H.
Published: March 2024

MELAS syndrome, characterized by mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes, represents a devastating mitochondrial disease, with the stroke-like episodes being its primary manifestation. Arginine supplementation has been used and recommended as a treatment for these acute attacks; however, insufficient evidence exists to support this treatment for MELAS. The mechanisms underlying the effect of arginine on MELAS pathophysiology remain unclear, although it is hypothesized that arginine could increase nitric oxide availability and, consequently, enhance blood supply to the brain. A more comprehensive understanding of these mechanisms is necessary to improve treatment strategies, such as dose and regimen adjustments; identify which patients could benefit the most; and establish potential markers for follow-up. This review aims to analyze the existing evidence concerning the mechanisms through which arginine supplementation impacts MELAS pathophysiology and provide the current scenario and perspectives for future investigations.
Comprehensive Molecular Profiling of NPM1-Mutated Acute Myeloid Leukemia Using RNAseq Approach
Authors: Petiti Jessica , Pignochino Ymera , Schiavon Aurora , Giugliano Emilia , Berrino Enrico , Giordano Giorgia , Itri Federico , Dragani Matteo , Cilloni Daniela , Lo Iacono Marco
Published: March 2024

Acute myeloid leukemia (AML) is a complex hematologic malignancy with high morbidity and mortality. Nucleophosmin 1 (NPM1) mutations occur in approximately 30% of AML cases, and NPM1-mutated AML is classified as a distinct entity. NPM1-mutated AML patients without additional genetic abnormalities have a favorable prognosis. Despite this, 30–50% of them experience relapse. This study aimed to investigate the potential of total RNAseq in improving the characterization of NPM1-mutated AML patients. We explored genetic variations independently of myeloid stratification, revealing a complex molecular scenario. We showed that total RNAseq enables the uncovering of different genetic alterations and clonal subtypes, allowing for a comprehensive evaluation of the real expression of exome transcripts in leukemic clones and the identification of aberrant fusion transcripts. This characterization may enhance understanding and guide improved treatment strategies for NPM1mut AML patients, contributing to better outcomes. Our findings underscore the complexity of NPM1-mutated AML, supporting the incorporation of advanced technologies for precise risk stratification and personalized therapeutic strategies. The study provides a foundation for future investigations into the clinical implications of identified genetic variations and highlights the importance of evolving diagnostic approaches in leukemia management.
Neurodevelopmental Disruptions in Children of Preeclamptic Mothers: Pathophysiological Mechanisms and Consequences
Authors: González-Rojas Andrea , Valencia-Narbona Martina
Published: March 2024

Preeclampsia (PE) is a multisystem disorder characterized by elevated blood pressure in the mother, typically occurring after 20 weeks of gestation and posing risks to both maternal and fetal health. PE causes placental changes that can affect the fetus, particularly neurodevelopment. Its key pathophysiological mechanisms encompass hypoxia, vascular and angiogenic dysregulation, inflammation, neuronal and glial alterations, and disruptions in neuronal signaling. Animal models indicate that PE is correlated with neurodevelopmental alterations and cognitive dysfunctions in offspring and in humans, an association between PE and conditions such as cerebral palsy, autism spectrum disorder, attention deficit hyperactivity disorder, and sexual dimorphism has been observed. Considering the relevance for mothers and children, we conducted a narrative literature review to describe the relationships between the pathophysiological mechanisms behind neurodevelopmental alterations in the offspring of PE mothers, along with their potential consequences. Furthermore, we emphasize aspects pertinent to the prevention/treatment of PE in pregnant mothers and alterations observed in their offspring. The present narrative review offers a current, complete, and exhaustive analysis of (i) the pathophysiological mechanisms that can affect neurodevelopment in the children of PE mothers, (ii) the relationship between PE and neurological alterations in offspring, and (iii) the prevention/treatment of PE.
Human Rad51 Protein Requires Higher Concentrations of Calcium Ions for D-Loop Formation than for Oligonucleotide Strand Exchange
Authors: Renodon-Corniere Axelle , Mikawa Tsutomu , Kuwabara Naoyuki , Ito Kentaro , Levitsky Dmitri , Iwasaki Hiroshi , Takahashi Masayuki
Published: March 2024

Human Rad51 protein (HsRad51)-promoted DNA strand exchange, a crucial step in homologous recombination, is regulated by proteins and calcium ions. Both the activator protein Swi5/Sfr1 and Ca2+ ions stimulate different reaction steps and induce perpendicular DNA base alignment in the presynaptic complex. To investigate the role of base orientation in the strand exchange reaction, we examined the Ca2+ concentration dependence of strand exchange activities and structural changes in the presynaptic complex. Our results show that optimal D-loop formation (strand exchange with closed circular DNA) required Ca2+ concentrations greater than 5 mM, whereas 1 mM Ca2+ was sufficient for strand exchange between two oligonucleotides. Structural changes indicated by increased fluorescence intensity of poly(dεA) (a poly(dA) analog) reached a plateau at 1 mM Ca2+. Ca2+ > 2 mM was required for saturation of linear dichroism signal intensity at 260 nm, associated with rigid perpendicular DNA base orientation, suggesting a correlation with the stimulation of D-loop formation. Therefore, Ca2+ exerts two different effects. Thermal stability measurements suggest that HsRad51 binds two Ca2+ ions with KD values of 0.2 and 2.5 mM, implying that one step is stimulated by one Ca2+ bond and the other by two Ca2+ bonds. Our results indicate parallels between the Mg2+ activation of RecA and the Ca2+ activation of HsRad51.
Necrosis Links Neurodegeneration and Neuroinflammation in Neurodegenerative Disease
Authors: Homma Hidenori , Tanaka Hikari , Fujita Kyota , Okazawa Hitoshi
Published: March 2024

The mechanisms of neuronal cell death in neurodegenerative disease remain incompletely understood, although recent studies have made significant advances. Apoptosis was previously considered to be the only mechanism of neuronal cell death in neurodegenerative diseases. However, recent findings have challenged this dogma, identifying new subtypes of necrotic neuronal cell death. The present review provides an updated summary of necrosis subtypes and discusses their potential roles in neurodegenerative cell death. Among numerous necrosis subtypes, including necroptosis, paraptosis, ferroptosis, and pyroptosis, transcriptional repression-induced atypical cell death (TRIAD) has been identified as a potential mechanism of neuronal cell death. TRIAD is induced by functional deficiency of TEAD-YAP and self-amplifies via the release of HMGB1. TRIAD is a feasible potential mechanism of neuronal cell death in Alzheimer’s disease and other neurodegenerative diseases. In addition to induction of cell death, HMGB1 released during TRIAD activates brain inflammatory responses, which is a potential link between neurodegeneration and neuroinflammation.
Biology and Toxicology of Gametes, Embryos, and Cancer Cells in Reproductive Systems
Authors: Kang Minju , Kim Byeongseok , Choi Youngsok
Published: March 2024

Reproduction is the important process of transmitting one’s genetic information to the next generation [...]
The Reduced Gut Lachnospira Species Is Linked to Liver Enzyme Elevation and Insulin Resistance in Pediatric Fatty Liver Disease
Authors: Tsai Ching-Chung , Chiu Min-Hsi , Kek Ho-Poh , Yang Ming-Chun , Su Yu-Tsun , Liu Hsien-Kuan , Wu Ming-Shiang , Yeh Yao-Tsung
Published: March 2024

The objective of this study was to investigate gut dysbiosis and its metabolic and inflammatory implications in pediatric metabolic dysfunction-associated fatty liver disease (MAFLD). This study included 105 children and utilized anthropometric measurements, blood tests, the Ultrasound Fatty Liver Index, and fecal DNA sequencing to assess the relationship between gut microbiota and pediatric MAFLD. Notable decreases in Lachnospira spp., Faecalibacterium spp., Oscillospira spp., and Akkermansia spp. were found in the MAFLD group. Lachnospira spp. was particularly reduced in children with MAFLD and hepatitis compared to controls. Both MAFLD groups showed a reduction in flavone and flavonol biosynthesis sequences. Lachnospira spp. correlated positively with flavone and flavonol biosynthesis and negatively with insulin levels and insulin resistance. Body weight, body mass index (BMI), and total cholesterol levels were inversely correlated with flavone and flavonol biosynthesis. Reduced Lachnospira spp. in children with MAFLD may exacerbate insulin resistance and inflammation through reduced flavone and flavonol biosynthesis, offering potential therapeutic targets.
Ferroptosis: Frenemy of Radiotherapy
Authors: Kerkhove Lisa , Geirnaert Febe , Dufait Inès , De Ridder Mark
Published: March 2024

Recently, it was established that ferroptosis, a type of iron-dependent regulated cell death, plays a prominent role in radiotherapy-triggered cell death. Accordingly, ferroptosis inducers attracted a lot of interest as potential radio-synergizing drugs, ultimately enhancing radioresponses and patient outcomes. Nevertheless, the tumor microenvironment seems to have a major impact on ferroptosis induction. The influence of hypoxic conditions is an area of interest, as it remains the principal hurdle in the field of radiotherapy. In this review, we focus on the implications of hypoxic conditions on ferroptosis, contemplating the plausibility of using ferroptosis inducers as clinical radiosensitizers. Furthermore, we dive into the prospects of drug repurposing in the domain of ferroptosis inducers and radiosensitizers. Lastly, the potential adverse effects of ferroptosis inducers on normal tissue were discussed in detail. This review will provide an important framework for subsequent ferroptosis research, ascertaining the feasibility of ferroptosis inducers as clinical radiosensitizers.
Tumor Microenvironment: Cellular Interaction and Metabolic Adaptations
Authors: Benvenuto Monica , Focaccetti Chiara
Published: March 2024

The tumor microenvironment (TME) plays a critical role in cancerogenesis [...]
The Effect of a Rotating Magnetic Field on the Regenerative Potential of Platelets
Authors: Cecerska-Heryć Elżbieta , Goszka Małgorzata , Gliźniewicz Marta , Grygorcewicz Bartłomiej , Serwin Natalia , Stodolak Patrycja , Słodzińska Weronika , Birger Radosław , Polikowska Aleksandra , Budkowska Marta , Rakoczy Rafał , Dołęgowska Barbara
Published: March 2024

Platelets are actively involved in tissue injury site regeneration by producing a wide spectrum of platelet-derived growth factors such as PDGF (platelet-derived growth factor), IGF-1 (insulin-like growth factor), TGF-β1 (transforming growth factor β), FGF (fibroblast growth factor), etc. A rotating magnetic field (RMF) can regulate biological functions, including reduction or induction regarding inflammatory processes, cell differentiation, and gene expression, to determine the effect of an RMF on the regenerative potential of platelets. The study group consisted of 30 healthy female and male volunteers (n = 15), from which plasma was collected. A portion of the plasma was extracted and treated as an internal control group. Subsequent doses of plasma were exposed to RMF at different frequencies (25 and 50 Hz) for 1 and 3 h. Then, the concentrations of growth factors (IGF-1, PDGF-BB, TGF-β1, and FGF-1) were determined in the obtained material by the ELISA method. There were statistically significant differences in the PDGF-BB, TGF-β1, IGF-1, and FGF-1 concentrations between the analyzed groups. The highest concentration of PDGF-BB was observed in the samples placed in RMF for 1 h at 25 Hz. For TGF-β1, the highest concentrations were obtained in the samples exposed to RMF for 3 h at 25 Hz and 1 h at 50 Hz. The highest concentrations of IGF-1 and FGF-1 were shown in plasma placed in RMF for 3 h at 25 Hz. An RMF may increase the regenerative potential of platelets. It was noted that female platelets may respond more strongly to RMF than male platelets.
Special Issue “Epigenetics in Neurodegenerative Diseases”
Authors: Agostini Simone , Mancuso Roberta
Published: March 2024

Epigenetic mechanisms inducing phenotypic changes without altering the DNA genome are increasingly recognized as key factors modulating gene expression and, consequently, cell functions [...]
Mechanochemical Approach to Obtaining a Multicomponent Fisetin Delivery System Improving Its Solubility and Biological Activity
Authors: Rosiak Natalia , Tykarska Ewa , Cielecka-Piontek Judyta
Published: March 2024

In this study, binary amorphous solid dispersions (ASDs, fisetin-Eudragit®) and ternary amorphous solid inclusions (ASIs, fisetin-Eudragit®-HP-β-cyclodextrin) of fisetin (FIS) were prepared by the mechanochemical method without solvent. The amorphous nature of FIS in ASDs and ASIs was confirmed using XRPD (X-ray powder diffraction). DSC (Differential scanning calorimetry) confirmed full miscibility of multicomponent delivery systems. FT-IR (Fourier-transform infrared analysis) confirmed interactions that stabilize FIS’s amorphous state and identified the functional groups involved. The study culminated in evaluating the impact of amorphization on water solubility and conducting in vitro antioxidant assays: 2,2-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid)—ABTS, 2,2-diphenyl-1-picrylhydrazyl—DPPH, Cupric Reducing Antioxidant Capacity—CUPRAC, and Ferric Reducing Antioxidant Power—FRAP and in vitro neuroprotective assays: inhibition of acetylcholinesterase—AChE and butyrylcholinesterase—BChE. In addition, molecular docking allowed for the determination of possible bonds and interactions between FIS and the mentioned above enzymes. The best preparation turned out to be ASI_30_EPO (ASD fisetin-Eudragit® containing 30% FIS in combination with HP-β-cyclodextrin), which showed an improvement in apparent solubility (126.5 ± 0.1 µg∙mL−1) and antioxidant properties (ABTS: IC50 = 10.25 µg∙mL−1, DPPH: IC50 = 27.69 µg∙mL−1, CUPRAC: IC0.5 = 9.52 µg∙mL−1, FRAP: IC0.5 = 8.56 µg∙mL−1) and neuroprotective properties (inhibition AChE: 39.91%, and BChE: 42.62%).
Overexpression of GmPAP4 Enhances Symbiotic Nitrogen Fixation and Seed Yield in Soybean under Phosphorus-Deficient Condition
Authors: Sun Xi , Zhang Huantao , Yang Zhanwu , Xing Xinzhu , Fu Zhao , Li Xihuan , Kong Youbin , Li Wenlong , Du Hui , Zhang Caiying
Published: March 2024

Legume crops establish symbiosis with nitrogen-fixing rhizobia for biological nitrogen fixation (BNF), a process that provides a prominent natural nitrogen source in agroecosystems; and efficient nodulation and nitrogen fixation processes require a large amount of phosphorus (P). Here, a role of GmPAP4, a nodule-localized purple acid phosphatase, in BNF and seed yield was functionally characterized in whole transgenic soybean (Glycine max) plants under a P-limited condition. GmPAP4 was specifically expressed in the infection zones of soybean nodules and its expression was greatly induced in low P stress. Altered expression of GmPAP4 significantly affected soybean nodulation, BNF, and yield under the P-deficient condition. Nodule number, nodule fresh weight, nodule nitrogenase, APase activities, and nodule total P content were significantly increased in GmPAP4 overexpression (OE) lines. Structural characteristics revealed by toluidine blue staining showed that overexpression of GmPAP4 resulted in a larger infection area than wild-type (WT) control. Moreover, the plant biomass and N and P content of shoot and root in GmPAP4 OE lines were also greatly improved, resulting in increased soybean yield in the P-deficient condition. Taken together, our results demonstrated that GmPAP4, a purple acid phosphatase, increased P utilization efficiency in nodules under a P-deficient condition and, subsequently, enhanced symbiotic BNF and seed yield of soybean.
Metabolome and Transcriptome Analysis Revealed the Pivotal Role of Exogenous Melatonin in Enhancing Salt Tolerance in Vitis vinifera L.
Authors: Zhang Qiunan , Gao Ruiqi , Wu Di , Wang Xiao , Liu Yang , Gao Yanqiang , Guan Le
Published: March 2024

Vitis vinifera L. possesses high economic value, but its growth and yield are seriously affected by salt stress. Though melatonin (MT) has been widely reported to enhance tolerance towards abiotic stresses in plants, the regulatory role melatonin plays in resisting salt tolerance in grapevines has scarcely been studied. Here, we observed the phenotypes under the treatment of different melatonin concentrations, and then transcriptome and metabolome analyses were performed. A total of 457 metabolites were detected in CK- and MT-treated cell cultures at 1 WAT (week after treatment) and 4 WATs. Exogenous melatonin treatment significantly increased the endogenous melatonin content while down-regulating the flavonoid content. To be specific, the melatonin content was obviously up-regulated, while the contents of more than a dozen flavonoids were down-regulated. Auxin response genes and melatonin synthesis-related genes were regulated by the exogenous melatonin treatment. WGCNA (weighted gene coexpression network analysis) identified key salt-responsive genes; they were directly or indirectly involved in melatonin synthesis and auxin response. The synergistic effect of salt and melatonin treatment was investigated by transcriptome analysis, providing additional evidence for the stress-alleviating properties of melatonin through auxin-related pathways. The present study explored the impact of exogenous melatonin on grapevines’ ability to adapt to salt stress and provided novel insights into enhancing their tolerance to salt stress.
Optimal Intermittent Administration Interval of Abaloparatide for Bone Morphogenetic Protein-Induced Bone Formation in a Rat Spinal Fusion Model
Authors: Abe Tetsutaro , Miyazaki Masashi , Sako Noriaki , Kanezaki Shozo , Tsubouchi Yuta , Kaku Nobuhiro
Published: March 2024

Both bone morphogenetic protein 2 (BMP-2) and abaloparatide are used to promote bone formation. However, there is no consensus about their optimal administration. We investigated the optimal administration theory for the pairing of BMP-2 and abaloparatide in a rat spinal fusion model. Group I was only implanted in carriers and saline. Carriers with 3 µg of recombinant human BMP-2 (rhBMP-2) were implanted in other groups. Abaloparatide injections were administered three times a week for group III (for a total amount of 120 µg/kg in a week) and six times a week for group IV (for a total amount of 120 µg/kg in a week) after surgery. They were euthanized 8 weeks after the surgery, and we explanted their spines at that time. We assessed them using manual palpation tests, radiography, high-resolution micro-computed tomography (micro-CT), and histological analysis. We also analyzed serum bone metabolism markers. The fusion rate in Groups III and IV was higher than in Group I, referring to the manual palpation tests. Groups III and IV recorded greater radiographic scores than those in Groups I and II, too. Micro-CT analysis showed that Tbs. Sp in Groups III and IV was significantly lower than in Group I. Tb. N in Group IV was significantly higher than in Group I. Serum marker analysis showed that bone formation markers were higher in Groups III and IV than in Group I. On the other hand, bone resorption markers were lower in Group IV than in Group I. A histological analysis showed enhanced trabecular bone osteogenesis in Group IV. Frequent administration of abaloparatide may be suitable for the thickening of trabecular bone structure and the enhancement of osteogenesis in a rat spinal fusion model using BMP-2 in insufficient doses.
Exploring the Gut–Mitochondrial Axis: p66Shc Adapter Protein and Its Implications for Metabolic Disorders
Authors: da C. Pinaffi-Langley Ana Clara , Melia Elizabeth , Hays Franklin A.
Published: March 2024

This review investigates the multifaceted role of the p66Shc adaptor protein and the gut microbiota in regulating mitochondrial function and oxidative stress, and their collective impact on the pathogenesis of chronic diseases. The study delves into the molecular mechanisms by which p66Shc influences cellular stress responses through Rac1 activation, Forkhead-type transcription factors inactivation, and mitochondria-mediated apoptosis, alongside modulatory effects of gut microbiota-derived metabolites and endotoxins. Employing an integrative approach, the review synthesizes findings from a broad array of studies, including molecular biology techniques and analyses of microbial metabolites’ impacts on host cellular pathways. The results underscore a complex interplay between microbial metabolites, p66Shc activation, and mitochondrial dysfunction, highlighting the significance of the gut microbiome in influencing disease outcomes through oxidative stress pathways. Conclusively, the review posits that targeting the gut microbiota-p66Shc–mitochondrial axis could offer novel therapeutic strategies for mitigating the development and progression of metabolic diseases. This underscores the potential of dietary interventions and microbiota modulation in managing oxidative stress and inflammation, pivotal factors in chronic disease etiology.
Adult Neurogenesis of Teleost Fish Determines High Neuronal Plasticity and Regeneration
Authors: Pushchina Evgeniya Vladislavovna , Kapustyanov Ilya Alexandovich , Kluka Gleb Gennadievich
Published: March 2024

Studying the properties of neural stem progenitor cells (NSPCs) in a fish model will provide new information about the organization of neurogenic niches containing embryonic and adult neural stem cells, reflecting their development, origin cell lines and proliferative dynamics. Currently, the molecular signatures of these populations in homeostasis and repair in the vertebrate forebrain are being intensively studied. Outside the telencephalon, the regenerative plasticity of NSPCs and their biological significance have not yet been practically studied. The impressive capacity of juvenile salmon to regenerate brain suggests that most NSPCs are likely multipotent, as they are capable of replacing virtually all cell lineages lost during injury, including neuroepithelial cells, radial glia, oligodendrocytes, and neurons. However, the unique regenerative profile of individual cell phenotypes in the diverse niches of brain stem cells remains unclear. Various types of neuronal precursors, as previously shown, are contained in sufficient numbers in different parts of the brain in juvenile Pacific salmon. This review article aims to provide an update on NSPCs in the brain of common models of zebrafish and other fish species, including Pacific salmon, and the involvement of these cells in homeostatic brain growth as well as reparative processes during the postraumatic period. Additionally, new data are presented on the participation of astrocytic glia in the functioning of neural circuits and animal behavior. Thus, from a molecular aspect, zebrafish radial glia cells are seen to be similar to mammalian astrocytes, and can therefore also be referred to as astroglia. However, a question exists as to if zebrafish astroglia cells interact functionally with neurons, in a similar way to their mammalian counterparts. Future studies of this fish will complement those on rodents and provide important information about the cellular and physiological processes underlying astroglial function that modulate neural activity and behavior in animals.
Birinapant Reshapes the Tumor Immunopeptidome and Enhances Antigen Presentation
Authors: Zhang Weiyan , Sun Shenghuan , Zhu Wenyuan , Meng Delan , Hu Weiyi , Yang Siqi , Gao Mingjie , Yao Pengju , Wang Yuhao , Wang Qingsong , Ji Jianguo
Published: March 2024

Birinapant, an antagonist of the inhibitor of apoptosis proteins, upregulates MHCs in tumor cells and displays a better tumoricidal effect when used in combination with immune checkpoint inhibitors, indicating that Birinapant may affect the antigen presentation pathway; however, the mechanism remains elusive. Based on high-resolution mass spectrometry and in vitro and in vivo models, we adopted integrated genomics, proteomics, and immunopeptidomics strategies to study the mechanism underlying the regulation of tumor immunity by Birinapant from the perspective of antigen presentation. Firstly, in HT29 and MCF7 cells, Birinapant increased the number and abundance of immunopeptides and source proteins. Secondly, a greater number of cancer/testis antigen peptides with increased abundance and more neoantigens were identified following Birinapant treatment. Moreover, we demonstrate the existence and immunogenicity of a neoantigen derived from insertion/deletion mutation. Thirdly, in HT29 cell-derived xenograft models, Birinapant administration also reshaped the immunopeptidome, and the tumor exhibited better immunogenicity. These data suggest that Birinapant can reshape the tumor immunopeptidome with respect to quality and quantity, which improves the presentation of CTA peptides and neoantigens, thus enhancing the immunogenicity of tumor cells. Such changes may be vital to the effectiveness of combination therapy, which can be further transferred to the clinic or aid in the development of new immunotherapeutic strategies to improve the anti-tumor immune response.
Rel Family Transcription Factor NFAT5 Upregulates COX2 via HIF-1α Activity in Ishikawa and HEC1a Cells
Authors: Okumura Toshiyuki , Raja Xavier Janet P. , Pasternak Jana , Yang Zhiqi , Hang Cao , Nosirov Bakhtiyor , Singh Yogesh , Admard Jakob , Brucker Sara Y. , Kommoss Stefan , Takeda Satoru , Staebler Annette , Lang Florian , Salker Madhuri S.
Published: March 2024

Nuclear factor of activated T cells 5 (NFAT5) and cyclooxygenase 2 (COX2; PTGS2) both participate in diverse pathologies including cancer progression. However, the biological role of the NFAT5-COX2 signaling pathway in human endometrial cancer has remained elusive. The present study explored whether NFAT5 is expressed in endometrial tumors and if NFAT5 participates in cancer progression. To gain insights into the underlying mechanisms, NFAT5 protein abundance in endometrial cancer tissue was visualized by immunohistochemistry and endometrial cancer cells (Ishikawa and HEC1a) were transfected with NFAT5 or with an empty plasmid. As a result, NFAT5 expression is more abundant in high-grade than in low-grade endometrial cancer tissue. RNA sequencing analysis of NFAT5 overexpression in Ishikawa cells upregulated 37 genes and downregulated 20 genes. Genes affected included cyclooxygenase 2 and hypoxia inducible factor 1α (HIF1A). NFAT5 transfection and/or treatment with HIF-1α stabilizer exerted a strong stimulating effect on HIF-1α promoter activity as well as COX2 expression level and prostaglandin E2 receptor (PGE2) levels. Our findings suggest that activation of NFAT5—HIF-1α—COX2 axis could promote endometrial cancer progression.