bluuebunny/crossref_metadata_2025 huggingface dataset:
Implications of Kynurenine Pathway Metabolism for the Immune System, Hypothalamic–Pituitary–Adrenal Axis, and Neurotransmission in Alcohol Use Disorder
Authors: Osuch Bartosz , Misztal Tomasz , Pałatyńska Kinga , Tomaszewska-Zaremba Dorota
Published: May 2024

In recent years, there has been a marked increase in interest in the role of the kynurenine pathway (KP) in mechanisms associated with addictive behavior. Numerous reports implicate KP metabolism in influencing the immune system, hypothalamic–pituitary–adrenal (HPA) axis, and neurotransmission, which underlie the behavioral patterns characteristic of addiction. An in-depth analysis of the results of these new studies highlights interesting patterns of relationships, and approaching alcohol use disorder (AUD) from a broader neuroendocrine–immune system perspective may be crucial to better understanding this complex phenomenon. In this review, we provide an up-to-date summary of information indicating the relationship between AUD and the KP, both in terms of changes in the activity of this pathway and modulation of this pathway as a possible pharmacological approach for the treatment of AUD.
Plexiform Fibromyxoma in the Stomach: Immunohistochemical Profile and Comprehensive Genetic Characterization
Authors: Di Mauro Annabella , Rega Rosalia Anna , Leongito Maddalena , Albino Vittorio , Palaia Raffaele , Gualandi Alberto , Belli Andrea , D’Arbitrio Imma , Moccia Pasquale , Tafuto Salvatore , De Chiara Annarosaria , Ottaiano Alessandro , Ferrara Gerardo
Published: May 2024

Plexiform fibromyxoma (PF), also referred to as plexiform angiomyxoid myofibroblast tumor, is an exceedingly rare mesenchymal neoplasm primarily affecting the stomach. Herein, we present a case of PF diagnosed in a 71-year-old male with a history of lung cancer, initially suspected to have a gastrointestinal stromal tumor (GIST) of the stomach, who subsequently underwent subtotal gastrectomy. The histopathological and molecular features of the tumor, including mutations in ABL1, CCND1, CSF1R, FGFR4, KDR, and MALAT1-GLI1 fusion, are elucidated and discussed in the context of diagnostic, prognostic, and therapeutic considerations.
Macrophage Migration Inhibitory Factor (MIF) and D-Dopachrome Tautomerase (DDT): Pathways to Tumorigenesis and Therapeutic Opportunities
Authors: Valdez Caroline Naomi , Sánchez-Zuno Gabriela Athziri , Bucala Richard , Tran Thuy T.
Published: May 2024

Discovered as inflammatory cytokines, MIF and DDT exhibit widespread expression and have emerged as critical mediators in the response to infection, inflammation, and more recently, in cancer. In this comprehensive review, we provide details on their structures, binding partners, regulatory mechanisms, and roles in cancer. We also elaborate on their significant impact in driving tumorigenesis across various cancer types, supported by extensive in vitro, in vivo, bioinformatic, and clinical studies. To date, only a limited number of clinical trials have explored MIF as a therapeutic target in cancer patients, and DDT has not been evaluated. The ongoing pursuit of optimal strategies for targeting MIF and DDT highlights their potential as promising antitumor candidates. Dual inhibition of MIF and DDT may allow for the most effective suppression of canonical and non-canonical signaling pathways, warranting further investigations and clinical exploration.
Blood-Based Epigenetic Age Acceleration and Incident Colorectal Cancer Risk: Findings from a Population-Based Case–Control Study
Authors: Malyutina Sofia , Chervova Olga , Maximov Vladimir , Nikitenko Tatiana , Ryabikov Andrew , Voevoda Mikhail
Published: May 2024

This study investigates the association between epigenetic age acceleration (EAA) derived from DNA methylation and the risk of incident colorectal cancer (CRC). We utilized data from a random population sample of 9,360 individuals (men and women, aged 45–69) from the HAPIEE Study who had been followed up for 16 years. A nested case–control design yielded 35 incident CRC cases and 354 matched controls. Six baseline epigenetic age (EA) measures (Horvath, Hannum, PhenoAge, Skin and Blood (SB), BLUP, and Elastic Net (EN)) were calculated along with their respective EAAs. After adjustment, the odds ratios (ORs) for CRC risk per decile increase in EAA ranged from 1.20 (95% CI: 1.04–1.39) to 1.44 (95% CI: 1.21–1.76) for the Horvath, Hannum, PhenoAge, and BLUP measures. Conversely, the SB and EN EAA measures showed borderline inverse associations with ORs of 0.86–0.87 (95% CI: 0.76–0.99). Tertile analysis reinforced a positive association between CRC risk and four EAA measures (Horvath, Hannum, PhenoAge, and BLUP) and a modest inverse relationship with EN EAA. Our findings from a prospective population-based-case-control study indicate a direct association between incident CRC and four markers of accelerated baseline epigenetic age. In contrast, two markers showed a negative association or no association. These results warrant further exploration in larger cohorts and may have implications for CRC risk assessment and prevention.
Antiplatelet Effects of Flavonoid Aglycones Are Mediated by Activation of Cyclic Nucleotide-Dependent Protein Kinases
Authors: Balykina Anna , Naida Lidia , Kirkgöz Kürsat , Nikolaev Viacheslav O. , Fock Ekaterina , Belyakov Michael , Whaley Anastasiia , Whaley Andrei , Shpakova Valentina , Rukoyatkina Natalia , Gambaryan Stepan
Published: May 2024

Flavonoid aglycones are secondary plant metabolites that exhibit a broad spectrum of pharmacological activities, including anti-inflammatory, antioxidant, anticancer, and antiplatelet effects. However, the precise molecular mechanisms underlying their inhibitory effect on platelet activation remain poorly understood. In this study, we applied flow cytometry to analyze the effects of six flavonoid aglycones (luteolin, myricetin, quercetin, eriodictyol, kaempferol, and apigenin) on platelet activation, phosphatidylserine externalization, formation of reactive oxygen species, and intracellular esterase activity. We found that these compounds significantly inhibit thrombin-induced platelet activation and decrease formation of reactive oxygen species in activated platelets. The tested aglycones did not affect platelet viability, apoptosis induction, or procoagulant platelet formation. Notably, luteolin, myricetin, quercetin, and apigenin increased thrombin-induced thromboxane synthase activity, which was analyzed by a spectrofluorimetric method. Our results obtained from Western blot analysis and liquid chromatography–tandem mass spectrometry demonstrated that the antiplatelet properties of the studied phytochemicals are mediated by activation of cyclic nucleotide-dependent signaling pathways. Specifically, we established by using Förster resonance energy transfer that the molecular mechanisms are, at least partly, associated with the inhibition of phosphodiesterases 2 and/or 5. These findings underscore the therapeutic potential of flavonoid aglycones for clinical application as antiplatelet agents.
Exposure of Bladder Cancer Cells to Blue Light (λ = 453 nm) in the Presence of Riboflavin Synergistically Enhances the Cytotoxic Efficiency of Gemcitabine
Authors: Sturm Sofia , Niegisch Günter , Windolf Joachim , Suschek Christoph V.
Published: May 2024

Non-muscle invasive bladder cancer is a common tumour in men and women. In case of resistance to the standard therapeutic agents, gemcitabine can be used as off-label instillation therapy into the bladder. To reduce potential side effects, continuous efforts are made to optimise the therapeutic potential of drugs, thereby reducing the effective dose and consequently the pharmacological burden of the medication. We recently demonstrated that it is possible to significantly increase the therapeutic efficacy of mitomycin C against a bladder carcinoma cell line by exposure to non-toxic doses of blue light (453 nm). In the present study, we investigated whether the therapeutically supportive effect of blue light can be further enhanced by the additional use of the wavelength-specific photosensitiser riboflavin. We found that the gemcitabine-induced cytotoxicity of bladder cancer cell lines (BFTC-905, SW-1710, RT-112) was significantly enhanced by non-toxic doses of blue light in the presence of riboflavin. Enhanced cytotoxicity correlated with decreased levels of mitochondrial ATP synthesis and increased lipid peroxidation was most likely the result of increased oxidative stress. Due to these properties, blue light in combination with riboflavin could represent an effective therapy option with few side effects and increase the success of local treatment of bladder cancer, whereby the dose of the chemotherapeutic agent used and thus the chemical load could be significantly reduced with similar or improved therapeutic success.
Plasma Redox Balance in Advanced-Maternal-Age Pregnant Women and Effects of Plasma on Umbilical Cord Mesenchymal Stem Cells
Authors: Grossini Elena , Aquino Carmen Imma , Venkatesan Sakthipriyan , Troìa Libera , Tizzoni Eleonora , Fumagalli Federica , Ferrante Daniela , Vaschetto Rosanna , Remorgida Valentino , Surico Daniela
Published: May 2024

Pregnancy at advanced maternal age (AMA) is a condition of potential risk for the development of maternal–fetal complications with possible repercussions even in the long term. Here, we analyzed the changes in plasma redox balance and the effects of plasma on human umbilical cord mesenchymal cells (hUMSCs) in AMA pregnant women (patients) at various timings of pregnancy. One hundred patients and twenty pregnant women younger than 40 years (controls) were recruited and evaluated at various timings during pregnancy until after delivery. Plasma samples were used to measure the thiobarbituric acid reactive substances (TBARS), glutathione and nitric oxide (NO). In addition, plasma was used to stimulate the hUMSCs, which were tested for cell viability, reactive oxygen species (ROS) and NO release. The obtained results showed that, throughout pregnancy until after delivery in patients, the levels of plasma glutathione and NO were lower than those of controls, while those of TBARS were higher. Moreover, plasma of patients reduced cell viability and NO release, and increased ROS release in hUMSCs. Our results highlighted alterations in the redox balance and the presence of potentially harmful circulating factors in plasma of patients. They could have clinical relevance for the prevention of complications related to AMA pregnancy.
Extracellular Vesicles in Environmental Toxicological Studies: Association between Urinary Concentrations of Phthalate Metabolites and Exosomal miRNA Expression Profiles
Authors: Cocci Paolo , Bondi Danilo , Santangelo Carmen , Pietrangelo Tiziana , Verratti Vittore , Cichelli Angelo , Caprioli Giovanni , Nzekoue Franks Kamgang , Nguefang Manuella Lesly Kouamo , Sagratini Gianni , Mosconi Gilberto , Palermo Francesco Alessandro
Published: May 2024

Phthalates are chemical compounds, mainly used as additives in plastics, which are known to induce harmful impacts to the environment and human health due to their ability to act as hormone-mimics. Few studies have been reported on the relationship between human exposure to phthalates and the level of circulating microRNAs (miRs), especially those miRs encapsulated in extracellular vesicles/exosomes or exosome-like vesicles (ELVs). We examined the relationship of ELV-miR expression patterns and urine of adult men with five phthalate metabolites (i.e., mono isobutyl phthalate, mono-n-butyl phthalate, mono benzyl phthalate, mono-(2-ethyl-5-oxohexyl) phthalate, mono-(2-ethylhexyl) phthalate) to identify potential biomarkers and relevant pathways. We found significant positive associations which were further confirmed by multivariable analysis. Overall, our analyses showed that the Σ phthalate metabolite concentration was associated with a significant increase in the expression level of two miRs found in ELV: miR-202 and miR-543. Different pathways including cancer and immune-related responses were predicted to be involved in this relationship. Analyzing the specific downstream target genes of miR-202 and miR-543, we identified the phosphatase and tensin homolog (PTEN) as the key gene in several converging pathways. In summary, the obtained results demonstrate that exposure to environmental phthalates could be related to altered expression profiles of specific ELV-miRs in adult men, thereby demonstrating the potential of miRs carried by exosomes to act as early effect biomarkers.
In Vivo Pro-Inflammatory Effects of Silver Nanoparticles on the Colon Depend on Time and Route of Exposure
Authors: Grodzicki Wojciech , Dziendzikowska Katarzyna , Gromadzka-Ostrowska Joanna , Wilczak Jacek , Oczkowski Michał , Kopiasz Łukasz , Sapierzyński Rafał , Kruszewski Marcin , Grzelak Agnieszka
Published: May 2024

Nanosilver is a popular nanomaterial, the potential influence of which on humans is of serious concern. Herein, we exposed male Wistar rats to two regimens: a repeated oral dose of 30 mg/kg bw silver nanoparticles (AgNPs) over 28 days and a single-dose injection of 5 mg/kg bw of AgNPs. At three different time points, we assessed antioxidant defense, oxidative stress and inflammatory parameters in the colon, as well as toxicity markers in the liver and plasma. Both experimental scenarios showed increased oxidative stress and inflammation in the colon. Oral administration seemed to be linked to increased reactive oxygen species generation and lipid peroxidation, while the effects induced by the intravenous exposure were probably mediated by silver ions released from the AgNPs. Repeated oral exposure had a more detrimental effect than the single-dose injection. In conclusion, both administration routes had a similar impact on the colon, although the underlying mechanisms are likely different.
The Evolving Landscape of Flowcytometric Minimal Residual Disease Monitoring in B-Cell Precursor Acute Lymphoblastic Leukemia
Authors: Verbeek Martijn W. C. , van der Velden Vincent H. J.
Published: May 2024

Detection of minimal residual disease (MRD) is a major independent prognostic marker in the clinical management of pediatric and adult B-cell precursor Acute Lymphoblastic Leukemia (BCP-ALL), and risk stratification nowadays heavily relies on MRD diagnostics. MRD can be detected using flow cytometry based on aberrant expression of markers (antigens) during malignant B-cell maturation. Recent advances highlight the significance of novel markers (e.g., CD58, CD81, CD304, CD73, CD66c, and CD123), improving MRD identification. Second and next-generation flow cytometry, such as the EuroFlow consortium’s eight-color protocol, can achieve sensitivities down to 10−5 (comparable with the PCR-based method) if sufficient cells are acquired. The introduction of targeted therapies (especially those targeting CD19, such as blinatumomab or CAR-T19) introduces several challenges for flow cytometric MRD analysis, such as the occurrence of CD19-negative relapses. Therefore, innovative flow cytometry panels, including alternative B-cell markers (e.g., CD22 and CD24), have been designed. (Semi-)automated MRD assessment, employing machine learning algorithms and clustering tools, shows promise but does not yet allow robust and sensitive automated analysis of MRD. Future directions involve integrating artificial intelligence, further automation, and exploring multicolor spectral flow cytometry to standardize MRD assessment and enhance diagnostic and prognostic robustness of MRD diagnostics in BCP-ALL.
The Role of Regulatory T Cells and Their Therapeutic Potential in Hypertensive Disease of Pregnancy: A Literature Review
Authors: Headen Kyle , Jakaite Vaidile , Mesaric Vita Andreja , Scotta Cristiano , Lombardi Giovanna , Nicolaides Kypros H. , Shangaris Panicos
Published: May 2024

Hypertensive disorders of pregnancy (HDP), including preeclampsia (PE) and gestational hypertension (GH), are major causes of maternal and foetal morbidity and mortality. This review elucidates the role of regulatory T cells (Tregs) in the immunological aspects of HDP and explores their therapeutic potential. Tregs, which play a critical role in maintaining immune homeostasis, are crucial in pregnancy to prevent immune-mediated rejection of the foetus. The review highlights that Tregs contribute to immunological adaptation in normal pregnancy, ensuring foetal acceptance. In contrast, HDP is associated with Treg dysfunction, which is marked by decreased numbers and impaired regulatory capacity, leading to inadequate immune tolerance and abnormal placental development. This dysfunction is particularly evident in PE, in which Tregs fail to adequately modulate the maternal immune response against foetal antigens, contributing to the pathophysiology of the disorder. Therapeutic interventions aiming to modulate Treg activity represent a promising avenue for HDP management. Studies in animal models and limited clinical trials suggest that enhancing Treg functionality could mitigate HDP symptoms and improve pregnancy outcomes. However, given the multifactorial nature of HDP and the intricate regulatory mechanisms of Tregs, the review explores the complexities of translating in vitro and animal model findings into effective clinical therapies. In conclusion, while the precise role of Tregs in HDP is still being unravelled, their central role in immune regulation during pregnancy is indisputable. Further research is needed to fully understand the mechanisms by which Tregs contribute to HDP and to develop targeted therapies that can safely and effectively harness their regulatory potential for treating hypertensive diseases of pregnancy.
Myokine Secretion following an Aerobic Exercise Intervention in Individuals with Type 2 Diabetes with or without Exercise Resistance
Authors: Garneau Léa , Mulvihill Erin E. , Smith Steven R. , Sparks Lauren M. , Aguer Céline
Published: May 2024

Type 2 diabetes (T2D) is characterized by muscle metabolic dysfunction that exercise can minimize, but some patients do not respond to an exercise intervention. Myokine secretion is intrinsically altered in patients with T2D, but the role of myokines in exercise resistance in this patient population has never been studied. We sought to determine if changes in myokine secretion were linked to the response to an exercise intervention in patients with T2D. The participants followed a 10-week aerobic exercise training intervention, and patients with T2D were grouped based on muscle mitochondrial function improvement (responders versus non-responders). We measured myokines in serum and cell-culture medium of myotubes derived from participants pre- and post-intervention and in response to an in vitro model of muscle contraction. We also quantified the expression of genes related to inflammation in the myotubes pre- and post-intervention. No significant differences were detected depending on T2D status or response to exercise in the biological markers measured, with the exception of modest differences in expression patterns for certain myokines (IL-1β, IL-8, IL-10, and IL-15). Further investigation into the molecular mechanisms involving myokines may explain exercise resistance with T2D; however, the role in metabolic adaptations to exercise in T2D requires further investigation.
Melatonin Enhances Neural Differentiation of Adipose-Derived Mesenchymal Stem Cells
Authors: Romano Ivana Roberta , D’Angeli Floriana , Gili Elisa , Fruciano Mary , Lombardo Giuseppe Angelo Giovanni , Mannino Giuliana , Vicario Nunzio , Russo Cristina , Parenti Rosalba , Vancheri Carlo , Giuffrida Rosario , Pellitteri Rosalia , Lo Furno Debora
Published: May 2024

Adipose-derived mesenchymal stem cells (ASCs) are adult multipotent stem cells, able to differentiate toward neural elements other than cells of mesodermal lineage. The aim of this research was to test ASC neural differentiation using melatonin combined with conditioned media (CM) from glial cells. Isolated from the lipoaspirate of healthy donors, ASCs were expanded in a basal growth medium before undergoing neural differentiation procedures. For this purpose, CM obtained from olfactory ensheathing cells and from Schwann cells were used. In some samples, 1 µM of melatonin was added. After 1 and 7 days of culture, cells were studied using immunocytochemistry and flow cytometry to evaluate neural marker expression (Nestin, MAP2, Synapsin I, GFAP) under different conditions. The results confirmed that a successful neural differentiation was achieved by glial CM, whereas the addition of melatonin alone did not induce appreciable changes. When melatonin was combined with CM, ASC neural differentiation was enhanced, as demonstrated by a further improvement of neuronal marker expression, whereas glial differentiation was attenuated. A dynamic modulation was also observed, testing the expression of melatonin receptors. In conclusion, our data suggest that melatonin’s neurogenic differentiation ability can be usefully exploited to obtain neuronal-like differentiated ASCs for potential therapeutic strategies.
The Inhibition of TREK-1 K+ Channels via Multiple Compounds Contained in the Six Kamikihito Components, Potentially Stimulating Oxytocin Neuron Pathways
Authors: Miyano Kanako , Nonaka Miki , Sakamoto Masahiro , Murofushi Mika , Yoshida Yuki , Komura Kyoko , Ohbuchi Katsuya , Higami Yoshikazu , Fujii Hideaki , Uezono Yasuhito
Published: May 2024

Oxytocin, a significant pleiotropic neuropeptide, regulates psychological stress adaptation and social communication, as well as peripheral actions, such as uterine contraction and milk ejection. Recently, a Japanese Kampo medicine called Kamikihito (KKT) has been reported to stimulate oxytocin neurons to induce oxytocin secretion. Two-pore-domain potassium channels (K2P) regulate the resting potential of excitable cells, and their inhibition results in accelerated depolarization that elicits neuronal and endocrine cell activation. We assessed the effects of KKT and 14 of its components on a specific K2P, the potassium channel subfamily K member 2 (TREK-1), which is predominantly expressed in oxytocin neurons in the central nervous system (CNS). KKT inhibited the activity of TREK-1 induced via the channel activator ML335. Six of the 14 components of KKT inhibited TREK-1 activity. Additionally, we identified that 22 of the 41 compounds in the six components exhibited TREK-1 inhibitory effects. In summary, several compounds included in KKT partially activated oxytocin neurons by inhibiting TREK-1. The pharmacological effects of KKT, including antistress effects, may be partially mediated through the oxytocin pathway.
Exploring the Antiviral Potential of Natural Compounds against Influenza: A Combined Computational and Experimental Approach
Authors: Perovic Vladimir , Stevanovic Kristina , Bukreyeva Natalya , Paessler Slobodan , Maruyama Junki , López-Serrano Sergi , Darji Ayub , Sencanski Milan , Radosevic Draginja , Berardozzi Simone , Botta Bruno , Mori Mattia , Glisic Sanja
Published: May 2024

The influenza A virus nonstructural protein 1 (NS1), which is crucial for viral replication and immune evasion, has been identified as a significant drug target with substantial potential to contribute to the fight against influenza. The emergence of drug-resistant influenza A virus strains highlights the urgent need for novel therapeutics. This study proposes a combined theoretical criterion for the virtual screening of molecular libraries to identify candidate NS1 inhibitors. By applying the criterion to the ZINC Natural Product database, followed by ligand-based virtual screening and molecular docking, we proposed the most promising candidate as a potential NS1 inhibitor. Subsequently, the selected natural compound was experimentally evaluated, revealing measurable virus replication inhibition activity in cell culture. This approach offers a promising avenue for developing novel anti-influenza agents targeting the NS1 protein.
Urinary L-FABP as an Early Biomarker for Pediatric Acute Kidney Injury Following Cardiac Surgery with Cardiopulmonary Bypass: A Systematic Review and Meta-Analysis
Authors: Wilnes Bruno , Castello-Branco Beatriz , Branco Bárbara Castello , Sanglard André , Vaz de Castro Pedro Alves Soares , Simões-e-Silva Ana Cristina
Published: May 2024

Acute kidney injury (AKI) following surgery with cardiopulmonary bypass (CPB-AKI) is common in pediatrics. Urinary liver-type fatty acid binding protein (uL-FABP) increases in some kidney diseases and may indicate CPB-AKI earlier than current methods. The aim of this systematic review with meta-analysis was to evaluate the potential role of uL-FABP in the early diagnosis and prediction of CPB-AKI. Databases Pubmed/MEDLINE, Scopus, and Web of Science were searched on 12 November 2023, using the MeSH terms “Children”, “CPB”, “L-FABP”, and “Acute Kidney Injury”. Included papers were revised. AUC values from similar studies were pooled by meta-analysis, performed using random- and fixed-effect models, with p < 0.05. Of 508 studies assessed, nine were included, comprising 1658 children, of whom 561 (33.8%) developed CPB-AKI. Significantly higher uL-FABP levels in AKI versus non-AKI patients first manifested at baseline to 6 h post-CPB. At 6 h, uL-FABP correlated with CPB duration (r = 0.498, p = 0.036), postoperative serum creatinine (r = 0.567, p < 0.010), and length of hospital stay (r = 0.722, p < 0.0001). Importantly, uL-FABP at baseline (AUC = 0.77, 95% CI: 0.64–0.89, n = 365), 2 h (AUC = 0.71, 95% CI: 0.52–0.90, n = 509), and 6 h (AUC = 0.76, 95% CI: 0.72–0.80, n = 509) diagnosed CPB-AKI earlier. Hence, higher uL-FABP levels associate with worse clinical parameters and may diagnose and predict CPB-AKI earlier.
Differential Colonization and Mucus Ultrastructure Visualization in Bovine Ileal and Rectal Organoid-Derived Monolayers Exposed to Enterohemorrhagic Escherichia coli
Authors: Kawasaki Minae , Ambrosini Yoko M.
Published: May 2024

Enterohemorrhagic Escherichia coli (EHEC) is a critical public health concern due to its role in severe gastrointestinal illnesses in humans, including hemorrhagic colitis and the life-threatening hemolytic uremic syndrome. While highly pathogenic to humans, cattle, the main reservoir for EHEC, often remain asymptomatic carriers, complicating efforts to control its spread. Our study introduces a novel method to investigate EHEC using organoid-derived monolayers from adult bovine ileum and rectum. These polarized epithelial monolayers were exposed to EHEC for four hours, allowing us to perform comparative analyses between the ileal and rectal tissues. Our findings mirrored in vivo observations, showing a higher colonization rate in the rectum compared with the ileum (44.0% vs. 16.5%, p < 0.05). Both tissues exhibited an inflammatory response with increased expression levels of TNF-a (p < 0.05) and a more pronounced increase of IL-8 in the rectum (p < 0.01). Additionally, the impact of EHEC on the mucus barrier varied across these gastrointestinal regions. Innovative visualization techniques helped us study the ultrastructure of mucus, revealing a net-like mucin glycoprotein organization. While further cellular differentiation could enhance model accuracy, our research significantly deepens understanding of EHEC pathogenesis in cattle and informs strategies for the preventative measures and therapeutic interventions.
Unveiling the Potential of Natural Compounds: A Comprehensive Review on Adipose Thermogenesis Modulation
Authors: Shin Jaeeun , Lee Yeonho , Ju Seong Hun , Jung Young Jae , Sim Daehyeon , Lee Sung-Joon
Published: May 2024

The process of adipocyte browning has recently emerged as a novel therapeutic target for combating obesity and obesity-related diseases. Non-shivering thermogenesis is the process of biological heat production in mammals and is primarily mediated via brown adipose tissue (BAT). The recruitment and activation of BAT can be induced through chemical drugs and nutrients, with subsequent beneficial health effects through the utilization of carbohydrates and fats to generate heat to maintain body temperature. However, since potent drugs may show adverse side effects, nutritional or natural substances could be safe and effective as potential adipocyte browning agents. This review aims to provide an extensive overview of the natural food compounds that have been shown to activate brown adipocytes in humans, animals, and in cultured cells. In addition, some key genetic and molecular targets and the mechanisms of action of these natural compounds reported to have therapeutic potential to combat obesity are discussed.
Knowing Our Enemy in the Antimicrobial Resistance Era: Dissecting the Molecular Basis of Bacterial Defense Systems
Authors: Martínez Mario , Rizzuto Irene , Molina Rafael
Published: May 2024

Bacteria and their phage adversaries are engaged in an ongoing arms race, resulting in the development of a broad antiphage arsenal and corresponding viral countermeasures. In recent years, the identification and utilization of CRISPR–Cas systems have driven a renewed interest in discovering and characterizing antiphage mechanisms, revealing a richer diversity than initially anticipated. Currently, these defense systems can be categorized based on the bacteria’s strategy associated with the infection cycle stage. Thus, bacterial defense systems can degrade the invading genetic material, trigger an abortive infection, or inhibit genome replication. Understanding the molecular mechanisms of processes related to bacterial immunity has significant implications for phage-based therapies and the development of new biotechnological tools. This review aims to comprehensively cover these processes, with a focus on the most recent discoveries.
Mesenchymal Stem/Progenitor Cells and Their Derivates in Tissue Regeneration—Part II
Authors: Klimczak Aleksandra
Published: May 2024

During the last three decades, mesenchymal stem/stromal cells (MSCs) were extensively studied, and are mainly considered within the setting of their regenerative and immunomodulatory properties in tissue regeneration [...]
Availability of Receptors for Advanced Glycation End-Products (RAGE) Influences Differential Transcriptome Expression in Lungs from Mice Exposed to Chronic Secondhand Smoke (SHS)
Authors: Curtis Katrina L. , Chang Ashley , Van Slooten Ryan , Cooper Christian , Kirkham Madison N. , Armond Thomas , deBernardi Zack , Pickett Brett E. , Arroyo Juan A. , Reynolds Paul R.
Published: May 2024

The receptor for advanced glycation end-products (RAGE) has a central function in orchestrating inflammatory responses in multiple disease states including chronic obstructive pulmonary disease (COPD). RAGE is a transmembrane pattern recognition receptor with particular interest in lung disease due to its naturally abundant pulmonary expression. Our previous research demonstrated an inflammatory role for RAGE following acute exposure to secondhand smoke (SHS). However, chronic inflammatory mechanisms associated with RAGE remain ambiguous. In this study, we assessed transcriptional outcomes in mice exposed to chronic SHS in the context of RAGE expression. RAGE knockout (RKO) and wild-type (WT) mice were delivered nose-only SHS via an exposure system for six months and compared to control mice exposed to room air (RA). We specifically compared WT + RA, WT + SHS, RKO + RA, and RKO + SHS. Analysis of gene expression data from WT + RA vs. WT + SHS showed FEZ1, Slpi, and Msln as significant at the three-month time point; while RKO + SHS vs. WT + SHS identified cytochrome p450 1a1 and Slc26a4 as significant at multiple time points; and the RKO + SHS vs. WT + RA revealed Tmem151A as significant at the three-month time point as well as Gprc5a and Dynlt1b as significant at the three- and six-month time points. Notable gene clusters were functionally analyzed and discovered to be specific to cytoskeletal elements, inflammatory signaling, lipogenesis, and ciliogenesis. We found gene ontologies (GO) demonstrated significant biological pathways differentially impacted by the presence of RAGE. We also observed evidence that the PI3K-Akt and NF-κB signaling pathways were significantly enriched in DEGs across multiple comparisons. These data collectively identify several opportunities to further dissect RAGE signaling in the context of SHS exposure and foreshadow possible therapeutic modalities.
The Mediterranean Diet, Its Microbiome Connections, and Cardiovascular Health: A Narrative Review
Authors: Abrignani Vincenzo , Salvo Andrea , Pacinella Gaetano , Tuttolomondo Antonino
Published: May 2024

The Mediterranean diet (MD), rich in minimally processed plant foods and in monounsaturated fats but low in saturated fats, meat, and dairy products, represents one of the most studied diets for cardiovascular health. It has been shown, from both observational and randomized controlled trials, that MD reduces body weight, improves cardiovascular disease surrogates such as waist-to-hip ratios, lipids, and inflammation markers, and even prevents the development of fatal and nonfatal cardiovascular disease, diabetes, obesity, and other diseases. However, it is unclear whether it offers cardiovascular benefits from its individual components or as a whole. Furthermore, limitations in the methodology of studies and meta-analyses have raised some concerns over its potential cardiovascular benefits. MD is also associated with characteristic changes in the intestinal microbiota, mediated through its constituents. These include increased growth of species producing short-chain fatty acids, such as Clostridium leptum and Eubacterium rectale, increased growth of Bifidobacteria, Bacteroides, and Faecalibacterium prausnitzii species, and reduced growth of Firmicutes and Blautia species. Such changes are known to be favorably associated with inflammation, oxidative status, and overall metabolic health. This review will focus on the effects of MD on cardiovascular health through its action on gut microbiota.
Vitamin D Attenuates Fibrotic Properties of Fibrous Dysplasia-Derived Cells for the Transit towards Osteocytic Phenotype
Authors: Kim Ha-Young , Shim Jung-Hee , Kim Baek-Kyu , Heo Chan-Yeong
Published: May 2024

Fibrous dysplasia (FD) poses a therapeutic challenge due to the dysregulated extracellular matrix (ECM) accumulation within affected bone tissues. In this study, we investigate the therapeutic potential of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) in managing FD by examining its effects on FD-derived cells in vitro. Our findings demonstrate that 1,25(OH)2D3 treatment attenuates the pro-fibrotic phenotype of FD-derived cells by suppressing the expression of key pro-fibrotic markers and inhibiting cell proliferation and migration. Moreover, 1,25(OH)2D3 enhances mineralization by attenuating pre-osteoblastic cellular hyperactivity and promoting maturation towards an osteocytic phenotype. These results offer valuable insights into potential treatments for FD, highlighting the role of 1,25(OH)2D3 in modulating the pathological properties of FD-derived cells.
Dietary Black Soldier Fly (Hermetia illucens)—Dipterose-BSF—Enhanced Zebrafish Innate Immunity Gene Expression and Resistance to Edwardsiella tarda Infection
Authors: Nishiguchi Haruki , Suryadi Ibnu Bangkit Bioshina , Ali Muhammad Fariz Zahir , Miura Chiemi , Miura Takeshi
Published: May 2024

Dietary management using immunostimulants to protect fish health and prevent bacterial infection is widely practiced. Many insect species possess various bioactive substances that can improve animal health. We previously identified several bioactive polysaccharides derived from insects, including dipterose-BSF from black soldier fly (Hermetia illucens) larvae; this can stimulate innate immunity in mammalian macrophage RAW264.7 cells. However, the effect of dietary dipterose-BSF on the immune system of teleosts remains unclear. Here, we analyzed the immune status of zebrafish (Danio rerio) after 14 days of dietary inclusion of dipterose-BSF (0.01, 0.1, and 1 µg/g), followed by an immersion challenge using Edwardsiella tarda. To identify changes in the transcriptional profile induced by dipterose-BSF, we performed RNA-sequencing analyses of the liver and intestine. Differentially expressed genes were investigated, with both organs showing several upregulated genes, dominated by nuclear factor and tumor necrosis factor family genes. Gene Ontology analysis revealed several terms were significantly higher in the experimental group compared with the control group. Challenge tests suggested that dietary dipterose-BSF had some positive effects on disease resistance in fish, but these effects were not pronounced.
Concept of a Peripheral-Free Electrified Monorail System (PEMS) for Flexible Material Handling in Intralogistics
Authors: Sperling Marvin , Kurschilgen Timo , Schumacher Pietro
Published: May 2024

With the emergence of Industry 4.0 in intralogistics, the need for flexible material handling solutions is increasing. While conventional conveyor systems are often too inflexible to meet changing requirements. Automated guided vehicles offer an answer, additional solutions are required for companies relying on already busy and crowded shop floors. This paper presents a concept for a periphery-free electrified monorail system (PEMS) that enables flexible material transport with minimal floor requirements. The PEMS is based on classic electrified monorail technology, and requires no additional peripheral devices within the rail system. Installation and maintenance costs are kept to a minimum through simplified branching elements and a battery-powered energy supply for the vehicles. The modular design of the rail elements further allows transport on standardized Euro-pallets. Moreover, a taxonomy for evaluating the passivity of branching elements of electrified monorail systems is introduced. The functionality of the PEMS was validated by conducting real experiments using a prototype, The results show that the PEMS provides high flexibility in terms of layout design and usage, allowing for fast adaption to the changing requirements of intralogistics.
Total Hip Replacement with a Fully Hydroxyapatite-Coated Shortened Stem: Five- to Thirteen-Year Follow-Up Results
Authors: Marqués López Fernando , Pares Alfonso Ivet , Donaire Hoyas Daniel , Ruiz Morales Gregorio , Tey Pons Marc , Lizano Díez Xavier , León García Alfonso
Published: May 2024

Background: Shortened femoral stems aim to mimic the biomechanical performance of traditional stems while preserving more bone and minimizing soft tissue damage. Our objective is to assess the outcomes of patients treated with a shortened stem (Furlong Evolution, JRI Orthopaedics, Sheffield, UK) to analyze the implant’s efficacy and survivorship. Methods: This retrospective observational study included all patients aged 18 to 70 undergoing uncemented shortened stem total hip replacement at Hospital del Mar between 2010 and 2018. Hip function and pain were assessed with the Merle d’Aubigné–Postel scale and visual analog scale, respectively. A radiographic analysis measured stem and cup orientation, leg length discrepancy, stem subsidence, and radiolucencies around the cup. Perioperative complications, prosthetic failures, and reoperations were documented. Results: A total of 109 patients (74 male, 35 female) of a mean age of 51.8 ± 8.8 years were included. The average follow-up was 91 ± 17.4 months. Radiographically, 71 (65.1%) of the stems had been inserted at the appropriate angulation (±3°), and 102 (93.6%) of the cups had been placed in the Lewinnek safety zone. Leg length discrepancy was observed in 19 (17.4%) cases. The mean Merle d’Aubigné–Postel score improved from 13.1 ± 1.39 preoperatively to 17.8 ± 0.49 at 6 months postoperatively (p < 0.001). Merle d’Aubigné–Postel subscales also reflected a statistically significant improvement (p < 0.001). The mean pain score 12 months postoperatively was 0.52 ± 1.22, with 95.4% of patients declaring themselves satisfied or highly satisfied. The expected 13-year survival according to a Kaplan–Meier analysis was 100% in the absence of infection and 91.3% if revision for any cause is taken as a survival endpoint. Conclusions: The shortened stem under analysis provides excellent functional results and long-term survival rates.
Nodular/Keloidal Scleroderma with No Systemic Involvement—A Case Report and a Review of the Literature
Authors: Trufin Ioana Irina , Ungureanu Loredana , Halmágyi Salomea-Ruth , Apostu Adina Patricia , Șenilă Simona Corina
Published: May 2024

Nodular or keloidal scleroderma is a rare condition with unclear cause and sporadic mentions in the medical literature. It was first recognized in the 19th century, yet its classification is still debated due to the limited number of reported cases. This rare variant of scleroderma is associated with either progressive systemic sclerosis or localized morphea. Clinically, it presents with asymptomatic nodules or plaques, resembling spontaneous keloid formation, often found on the trunk and proximal extremities. Recent literature reviews show a predominance of women with a mean age of 44 years. Diagnosis relies on clinical and histopathological findings, which usually show overlapping features of both scleroderma and true keloids, secondarily to an excessive fibrosing reaction attributed to collagen formation. We present an unusual case of a 70-year-old female patient who displayed the coexistence of two distinct subtypes of morphea (nodular/keloidal and linear), and exclusive skin involvement, which contrasts with the typical presentation of nodular/keloidal scleroderma, often associated with organ-specific disease. However, recent publications have diverged from previous ones regarding systemic sclerosis, with no systemic involvement reported between 2018 and 2024, which we evaluated in our descriptive literature review. With less than 50 cases reported in total, our case underlines the importance of recognizing this rare disease, ensuring appropriate evaluation, treatment, and follow-up.
Natural Climate Protection through Peatland Rewetting: A Future for the Rathsbruch Peatland in Germany
Authors: Schneider Petra , Fauk Tino , Mihai Florin-Constantin , Junker Harald , Ettmer Bernd , Lüderitz Volker
Published: May 2024

Draining peatlands to create agricultural land has been the norm in Europe, but in the context of climate change and the loss of biodiversity, these rich ecosystems may reactivate their functions as greenhouse gas sinks and retreat spaces for animals and plants. Against this background, the National Moor Rewetting Strategy was put into effect in Germany in 2023, together with the Natural Climate Protection Action Plan. This article examines the methodology of peatland rewetting from scientific, administrative, social, and technical perspectives. The article focuses on an example of moor rewetting in central Germany: the Rathsbruch moor near the municipality of Zerbst, Saxony-Anhalt. To illustrate the importance of rewetting projects for degraded peatlands, five scenarios with different target soil water levels were considered, and the associated greenhouse gas emissions were calculated for a period of five years. For the planning solution, an estimate of the medium-to-long-term development of the habitat types was made based on current use and the dynamics typical of the habitat. The results for the Rathsbruch moor area showed that increasing the water level in steps of 1, 0.8, or 0.5 m has no significant influence on reducing the CO2 emissions situation, while a depth of 0.3 m has a slight influence. When the water was raised to 0.1 m below the surface (Scenario 5), a significant CO2 reduction was observed. The calculated avoided CO2 costs due to environmental damage show that the environmental benefits multiply with every decimeter of water level increase. The rising groundwater levels and extensification favor the establishment of local biotopes. This means that two of the biggest man-made problems (extinction of species and climate change) can be reduced. Therefore, this research is applicable to the development and planning of recultivation work at municipal and regional levels in Germany and beyond within the framework of EU restoration policy.
Is the Suppliance of L2 Inflectional Morphology Subject to Covert Contrasts? An Analysis of the Production of L2 English Third Person Singular Agreement by L1 Bengali Speakers
Authors: Ingham Jacqueline
Published: May 2024

The cause(s) of missing inflectional morphology in obligatory contexts by adult speakers of second language (L2) English is subject to ongoing discussion. Whatever the specific theory, however, the apparent asymmetrical production of the morpheme ‘-s’ in the marking of number on plural nouns versus that on third person singular agreement has to be accounted for. This study adopts the theoretical approach put forward by the Prosodic Transfer Hypothesis, whereby the prosodic representation of inflectional morphology in the first language (L1) can, to some extent, account for differences in the suppliance of inflectional morphology in L2 English within and across L1s. It is in this context that the production of third person singular agreement, and, for contrastive purposes, number on plural nouns, by L1 Bengali speakers of L2 English, is considered in relation to available prosodic representation in the L1, as well as against phonological processes attested in L1 acquisition. More specifically, with respect to covert contrasts. An inspection of spectrograms from instances of the apparent omission of inflection by L1 Bengali speakers of L2 English at Beginner to Intermediate proficiency levels does not, however, indicate that learners are covertly supplying agreement on the third person singular (or plural number on nouns). This finding does not necessarily rule out the occurrence of covert contrasts in L2 production of inflectional morphology; alternative techniques may detect a systematic difference between bare verbs and non-audible (to the listener) inflection.
Dimensional Stability of Additively Manufactured Dentate Maxillary Diagnostic Casts in Biobased Model Resin
Authors: Demirel Münir , Diken Türksayar Almira Ada , Petersmann Sandra , Spintzyk Sebastian , Donmez Mustafa Borga
Published: May 2024

This study aimed to evaluate the dimensional stability of maxillary diagnostic casts fabricated from a biobased model resin, which consists of 50% renewable raw materials for sustainable production, a model resin, and stone, over one month. A master maxillary stone cast was digitized with a laboratory scanner to generate a reference file. This master cast was also scanned with an intraoral scanner to additively manufacture casts with a biobased model resin (BAM) and a model resin (AM). Polyvinylsiloxane impressions of the master cast were also made and poured in type III stone (CV) (n = 8). The same laboratory scanner was used to digitize each model one day (T0), 1 week (T1), 2 weeks (T2), 3 weeks (T3), and 4 weeks (T4) after fabrication. Deviations from the reference file were calculated with an analysis software and analyzed with generalized linear model analysis (α = 0.05). The interaction between the material and the time point affected measured deviations (p < 0.001). Regardless of the time point, CV had the lowest and AM had the highest deviations (p < 0.001). BAM mostly had lower deviations at T0 and mostly had higher deviations at T4 (p ≤ 0.011). AM had the highest deviations at T4 and then at T3, whereas it had the lowest deviations at T0 (p ≤ 0.002). The measured deviations of CV increased after each time point (p < 0.001). BAM casts had deviations within the previously reported clinically acceptable thresholds over one month and had acceptable dimensional stability. Therefore, tested biobased resin may be a viable alternative for the sustainable manufacturing of maxillary diagnostic casts that are to be used clinically.