bluuebunny/crossref_metadata_2025 huggingface dataset:
Functional and Biological Characterization of the LGR5Δ5 Splice Variant in HEK293T Cells
Authors: Kappler Matthias , Thielemann Laura , Glaß Markus , Caggegi Laura , Güttler Antje , Pyko Jonas , Blauschmidt Sarah , Gutschner Tony , Taubert Helge , Otto Sven , Eckert Alexander W. , Tavassol Frank , Bache Matthias , Vordermark Dirk , Kaune Tom , Rot Swetlana
Published: December 2024

The regulator of the canonical Wnt pathway, leucine-rich repeat-containing G protein-coupled receptor 5 (LGR5), is expressed in the stem cell compartment of several tissues and overexpressed in different human carcinomas. The isoform of the stem cell marker LGR5, named LGR5Δ5 and first described by our group, is associated with prognosis and metastasis in oral squamous cell carcinoma (OSCC) and soft tissue sarcoma (STS). In a proof-of-principle analysis, the function of LGR5Δ5 was investigated in HEK293T cells, a model cell line of the Wnt pathway, compared to full-length LGR5 (FL) expression. The CRISPR/CAS knockout of LGR5 and LGR4 (thereby avoiding the side effects of LGR4) resulted in a loss of Wnt activity that cannot be restored by LGR5Δ5 but by LGR5FL rescue. The ability to migrate was not affected by LGR5Δ5, but was reduced by LGR5FL overexpression. The CRISPR/CAS of LGR4 and 5 induced radiosensitization, which was enhanced by the overexpression of LGR5FL or LGR5Δ5. RNA sequencing analysis revealed a significant increase in the ligand R-spondin 1 (RSPO1) level by LGR5Δ5. Furthermore, LGR5Δ5 appears to be involved in the regulation of genes related to the cytoskeleton, extracellular matrix stiffness, and angiogenesis, while LGR5FL is associated with the regulation of collagens and histone proteins.
Whole-Exome Sequencing, Mutational Signature Analysis, and Outcome in Multiple Myeloma—A Pilot Study
Authors: Oelschläger Lorenz , Künstner Axel , Frey Friederike , Leitner Theo , Leypoldt Lisa , Reimer Niklas , Gebauer Niklas , Bastian Lorenz , Weisel Katja , Sailer Verena-Wilbeth , Röcken Christoph , Klapper Wolfram , Konukiewitz Björn , Murga Penas Eva Maria , Forster Michael , Schub Natalie , Ahmed Helal M. M. , Kirfel Jutta , von Bubnoff Nikolas Christian Cornelius , Busch Hauke , Khandanpour Cyrus
Published: December 2024

The complex and heterogeneous genomic landscape of multiple myeloma (MM) and many of its clinical and prognostic implications remains to be understood. In other cancers, such as breast cancer, using whole-exome sequencing (WES) and molecular signatures in clinical practice has revolutionized classification, prognostic prediction, and patient management. However, such integration is still in its early stages in MM. In this study, we analyzed WES data from 35 MM patients to identify potential mutational signatures and driver mutations correlated with clinical and cytogenetic characteristics. Our findings confirm the complex mutational spectrum and its impact on previously described ontogenetic and epigenetic pathways. They show TYW1 as a possible new potential driver gene and find no significant associations of mutational signatures with clinical findings. Further studies are needed to strengthen the role of mutational signatures in the clinical context of patients with MM to improve patient management.
SlUPA-like, a bHLH Transcription Factor in Tomato (Solanum lycopersicum), Serves as the Crosstalk of GA, JA and BR
Authors: Guo Pengyu , Cheng Xin , Wang Yunshu , Chen Guoping , Chen Xuqing , Yang Yingwu , Zhang Xiuhai , Hu Zongli
Published: December 2024

The bHLH (basic Helix–Loop–Helix) transcription factor serves as pivotal controller in plant growth and development. In a previous study, the overexpression of SlUPA-like in Solanum lycopersicum L. Ailsa Craig (AC++) altered the JA (Jasmonic acid) response and endogenous GA (Gibberellic acid) content. However, the detailed regulation mechanism was not fully explored. In the present research, we found that the overexpression of SlUPA-like influenced the accumulation of GA, JA and BR (Brassinolide). RNA-Seq data illustrated that the expression levels of genes related to these plant hormones were significantly affected. Additionally, the interaction of SlUPA-like with SlMYB21, SlMYC2 and SlDELLA was characterized by employing Y2H (Yeast Two-Hybrid) and BiFC (Bimolecular Fluorescence Complementation) assay. Furthermore, Dual-LUC (Dual-Luciferase) assay and EMSA (Electrophoretic Mobility Shift Assay) identified that SlUPA-like directly targeted the E-box motif in the promoter of SlGID2 and activated the transcription of SlGID2. These results shed light on the potential role of SlUPA-like in mediating crosstalk among multiple plant hormones and established a robust theoretical framework for further unraveling the functions of SlUPA-like transcription factors in the context of plant growth and hormone signal transduction.
Trehalose Interferes with the Photosynthetic Electron Transfer Chain of Cereibacter (Rhodobacter) sphaeroides Permeating the Bacterial Chromatophore Membrane
Authors: Venturoli Giovanni , Mamedov Mahir D. , Vitukhnovskaya Liya A. , Semenov Alexey Y. , Francia Francesco
Published: December 2024

Disaccharide trehalose has been proven in many cases to be particularly effective in preserving the functional and structural integrity of biological macromolecules. In this work, we studied its effect on the electron transfer reactions that occur in the chromatophores of the photosynthetic bacterium Cereibacter sphaeroides. In the presence of a high concentration of trehalose, following the activation of the photochemistry by flashes of light, a slowdown of the electrogenic reactions related to the activity of the photosynthetic reaction center and cytochtome (cyt) bc1 complexes is observable. The kinetics of the third phase of the electrochromic carotenoid shift, due to electrogenic events linked to the reduction in cyt bH heme via the low-potential branch of the cyt bc1 complex and its oxidation by quinone molecule on the Qi site, is about four times slower in the presence of trehalose. In parallel, the reduction in oxidized cyt (c1 + c2) and high-potential cyt bH are strongly slowed down, suggesting that the disaccharide interferes with the electron transfer reactions of the high-potential branch of the bc1 complex. A slowing effect of trehalose on the kinetics of the electrogenic protonation of the secondary quinone acceptor QB in the reaction center complex, measured by direct electrometrical methods, was also found, but was much less pronounced. The direct detection of carbohydrate content indicates that trehalose, at high concentrations, permeates the membrane of chromatophores. The possible mechanisms underlying the observed effect of trehalose on the electron/proton transfer process are discussed in terms of trehalose’s propensity to form strong hydrogen bonds with its surroundings.
Proton-Translocating NADH–Ubiquinone Oxidoreductase: Interaction with Artificial Electron Acceptors, Inhibitors, and Potential Medicines
Authors: Grivennikova Vera G. , Gladyshev Grigory V. , Zharova Tatyana V. , Borisov Vitaliy B.
Published: December 2024

Proton-translocating NADH–ubiquinone oxidoreductase (complex I) catalyzes the oxidation of NADH by ubiquinone accompanied by the transmembrane transfer of four protons, thus contributing to the formation of a proton motive force (pmf) across the coupling membranes of mitochondria and bacteria, which drives ATP synthesis in oxidative phosphorylation. In recent years, great progress has been achieved in resolving complex I structure by means of X-ray crystallography and high-resolution cryo-electron microscopy, which has led to the formulation of detailed hypotheses concerning the molecular mechanism of coupling of the redox reaction to vectorial proton translocation. To test and probe proposed mechanisms, a comprehensive study of complex I using other methods including molecular dynamics and a variety of biochemical studies such as kinetic and inhibitory analysis is required. Due to complex I being a major electron entry point for oxidative metabolism, various mutations of the enzyme lead to the development of severe pathologies and/or are associated with human metabolic disorders and have been well documented. This review examines current information on the structure and subunit composition of complex I of eukaryotes and prokaryotes, reactions catalyzed by this enzyme, and ways to regulate them. The review also discusses biomedical aspects related to the enzyme in light of recent findings.
Mechanistic Relevance of Ventricular Arrhythmias in Heart Failure with Preserved Ejection Fraction
Authors: Bahrami Pegah , Aromolaran Kelly A. , Aromolaran Ademuyiwa S.
Published: December 2024

Heart failure with preserved ejection fraction (HFpEF) is increasing at an alarming rate worldwide, with limited effective therapeutic interventions in patients. Sudden cardiac death (SCD) and ventricular arrhythmias present substantial risks for the prognosis of these patients. Obesity is a risk factor for HFpEF and life-threatening arrhythmias. Obesity and its associated metabolic dysregulation, leading to metabolic syndrome, are an epidemic that poses a significant public health problem. More than one-third of the world population is overweight or obese, leading to an enhanced risk of incidence and mortality due to cardiovascular disease (CVD). Obesity predisposes patients to atrial fibrillation and ventricular and supraventricular arrhythmias—conditions that are caused by dysfunction in the electrical activity of the heart. To date, current therapeutic options for the cardiomyopathy of obesity are limited, suggesting that there is considerable room for the development of therapeutic interventions with novel mechanisms of action that will help normalize sinus rhythms in obese patients. Emerging candidates for modulation by obesity are cardiac ion channels and Ca-handling proteins. However, the underlying molecular mechanisms of the impact of obesity on these channels and Ca-handling proteins remain incompletely understood. Obesity is marked by the accumulation of adipose tissue, which is associated with a variety of adverse adaptations, including dyslipidemia (or abnormal systemic levels of free fatty acids), increased secretion of proinflammatory cytokines, fibrosis, hyperglycemia, and insulin resistance, which cause electrical remodeling and, thus, predispose patients to arrhythmias. Furthermore, adipose tissue is also associated with the accumulation of subcutaneous and visceral fat, which is marked by distinct signaling mechanisms. Thus, there may also be functional differences in the effects of the regional distribution of fat deposits on ion channel/Ca-handling protein expression. Evaluating alterations in their functional expression in obesity will lead to progress in the knowledge of the mechanisms responsible for obesity-related arrhythmias. These advances are likely to reveal new targets for pharmacological modulation. Understanding how obesity and related mechanisms lead to cardiac electrical remodeling is likely to have a significant medical and economic impact. Nevertheless, substantial knowledge gaps remain regarding HFpEF treatment, requiring further investigations to identify potential therapeutic targets. The objective of this study is to review cardiac ion channel/Ca-handling protein remodeling in the predisposition to metabolic HFpEF and arrhythmias. This review further highlights interleukin-6 (IL-6) as a potential target, cardiac bridging integrator 1 (cBIN1) as a promising gene therapy agent, and leukotriene B4 (LTB4) as an underappreciated pathway in future HFpEF management.
The Search for a Universal Treatment for Defined and Mixed Pathology Neurodegenerative Diseases
Authors: O’Day Danton H.
Published: December 2024

The predominant neurodegenerative diseases, Alzheimer’s disease, Parkinson’s disease, dementia with Lewy Bodies, Huntington’s disease, amyotrophic lateral sclerosis, and frontotemporal dementia, are rarely pure diseases but, instead, show a diversity of mixed pathologies. At some level, all of them share a combination of one or more different toxic biomarker proteins: amyloid beta (Aβ), phosphorylated Tau (pTau), alpha-synuclein (αSyn), mutant huntingtin (mHtt), fused in sarcoma, superoxide dismutase 1, and TAR DNA-binding protein 43. These toxic proteins share some common attributes, making them potentially universal and simultaneous targets for therapeutic intervention. First, they all form toxic aggregates prior to taking on their final forms as contributors to plaques, neurofibrillary tangles, Lewy bodies, and other protein deposits. Second, the primary enzyme that directs their aggregation is transglutaminase 2 (TGM2), a brain-localized enzyme involved in neurodegeneration. Third, TGM2 binds to calmodulin, a regulatory event that can increase the activity of this enzyme threefold. Fourth, the most common mixed pathology toxic biomarkers (Aβ, pTau, αSyn, nHtt) also bind calmodulin, which can affect their ability to aggregate. This review examines the potential therapeutic routes opened up by this knowledge. The end goal reveals multiple opportunities that are immediately available for universal therapeutic treatment of the most devastating neurodegenerative diseases facing humankind.
Characterization of Biopolymer Hydrogels Prepared with Water Exposed to Indirect Plasma Treatment
Authors: Król-Kilińska Żaneta , Kulig Dominika , Zimoch-Korzycka Anna , Reszke Edward , Bobak Łukasz , Jurić Slaven , Jarmoluk Andrzej
Published: December 2024

This study aimed to evaluate the influence of indirect-plasma-treated water (IPTW) in the preparation of hydrogels. Three commonly used natural, biodegradable polymers with the ability to form gels were selected: gelatin, carrageenan, and sodium alginate. The pH, gelling temperature, texture profile, swelling degree, and color of hydrogels were evaluated, and the polymers were subjected to Fourier-transform infrared (FTIR) spectroscopy. The morphology of the hydrogels was investigated using Scanning Electron Microscopy (SEM). Additionally, the physiochemical properties of the water media, which were distilled water (DW) and IPTW, were analyzed. The results indicated that the gels prepared using IPTW were characterized by a lower pH, higher hardness and lower gelation temperature. After 48 h of swelling ratio (SR) testing, gelatin and alginate hydrogels made with IPTW were characterized by lower SR, while an inverse relationship was found in the case of SR of carrageenan gels. The FTIR analysis confirmed changes in the water binding ability. The use of IPTW also significantly affected the microstructure of the tested materials. A statistically significant change in the color of IPTW gel samples was also noted. The results showed that IPTW induces physicochemical changes in hydrogels, which can lead to the enhancement of their practical applications.
Therapeutic Drug Monitoring of Low Methotrexate Doses for Drug Exposure and Adherence Assessment—Pre-Analytical Variables, Bioanalytical Issues, and Current Clinical Applications
Authors: Kocur Arkadiusz , Mikulska Aleksandra , Moczulski Mateusz , Pawiński Tomasz
Published: December 2024

Methotrexate (MTX) is an antifolic agent used in the first line of anti-inflammatory disease treatment and some oncologic issues. The metabolism of MTX is rapid, and the MTX concentration in the blood is not significant 24 h after administration. Unlike this, methotrexate polyglutamates (MTXPGs) can be informative biomarkers of drug exposure. It is widely concluded that MTXPG retention in red blood cells (RBCs) is related to appropriate efficacy, drug exposure, and toxicity during treatment. Therefore, the mentioned biomarker may be appropriately used for the PK/PD monitoring of low-dose MTX (LDMTX) treatment. The presented review study aimed to review published studies about MTX determination in clinical practice, including pre-analytical variability, bioanalytical considerations, and clinical applications of the methods for pharmacotherapy supporting target populations. In total, 14 papers from the field of bioanalytics have been included in the main review. For each phase of an analytical process, the best practises and main findings were defined as guidelines for proper analytical method optimisation, validation, and standard operation procedure implementation in clinical practice. The presented study is the first comprehensive review of MTX and its methods of metabolite determination to account for pre-analytical, analytical, and post-analytical phases concerning the TDM process.
Exploring the Link Between Psoriasis and Adipose Tissue: One Amplifies the Other
Authors: Di Caprio Roberta , Nigro Ersilia , Di Brizzi Eugenia Veronica , Buononato Dario , Mallardo Marta , Tancredi Vittorio , Daniele Aurora , Balato Anna
Published: December 2024

Psoriasis and obesity, while distinct, are inter-related inflammatory conditions. Adipose tissue (AT)-derived mediators could be pathogenically active in triggering and/or amplifying psoriatic skin inflammation and, vice versa, skin inflammation could drive increased adiposity that triggers the development of several chronic conditions. Gaining insight into their intricate relationship could be essential for effective management and treatment. The aim of this study was to determine (i) the pathogenic role of psoriasis-signature cytokines in contributing to AT metabolism and (ii) the role of AT-derived mediators in triggering and/or amplifying skin inflammation. For this reason, firstly, whole AT was treated with IL-17 and TNF-α, alone or in combination, to investigate their effects on the expression and production of adipokines and inflammatory factors. IL-17 and TNF-α were able to induce an additive or synergistic effect on AT-derived mediators. In order to assess the effects on the skin of inflamed AT by psoriasis-signature cytokines, ex vivo skin organ culture was performed and an increase in several inflammatory mediators was observed. These findings confirm that psoriasis and obesity amplify each other’s inflammatory processes and understanding this mutual exacerbation could lead to more effective therapeutic strategies that address both skin inflammation and AT metabolism.
Therapeutic Potential of a Natural Blend of Aronia melancarpa, Lonicera caerulea, and Echinacea purpurea Extracts in Treating Upper Respiratory Tract Infections: Preliminary Clinical and In Vitro Immunomodulatory Insights
Authors: Zima Katarzyna , Sochocka Marta , Ochnik Michał , Khaidakov Barbara , Lemke Krzysztof , Kowalczyk Paulina
Published: December 2024

Upper respiratory tract infections (URTIs) are a prevalent health issue, causing considerable morbidity. Despite the availability of conventional treatments, there is an increasing interest in natural products due to their potential antiviral and immunomodulatory benefits. This study aims to evaluate the efficacy of an ELA blend (E—Echinacea purpurea, L—Lonicera cerulea, A—Aronia melanocarpa) in preventing and alleviating the symptoms of URTIs. Additionally, the study examines the blend’s antiviral and immunomodulatory effects both in vitro and through a clinical trial. A randomized, double-blind, placebo-controlled trial involved 61 participants prone to URTIs, with a 60-day treatment and follow-up period. A placebo group later received the ELA blend for 60 days. The ELA blend significantly reduced the incidence of URTIs during the observation period (2 vs. 8; p = 0.044) and, in particular, throat-related symptoms (8 vs. 16; p = 0.038). Analyses of PBMCs showed that baseline production of the cytokines IFN-γ (p = 0.020), IL-1β (p = 0.004), IL-2(p < 0.001), IL-6 (p < 0.001), and TNF-α (p < 0.001) increased after ELA blend treatment. Moreover, the ELA blend modulated cytokine production in response to PHA-L stimulation, decreasing IFN-γ (p = 0.008) and IL-2 (p = 0.012) while increasing IL-1β (p = 0.005). Following R848 stimulation, the ELA blend enhanced the production of INF-α (p = 0.012) and IL-2 (p = 0.025), and decreased IL-1β (p < 0.001), IL-6 (p < 0.001), and TNF-α (p = 0.049). The blend suppressed VSV replication and significantly increased cytokine levels, with IFN-γ increasing by 98 pg/mL (p = 0.002), IL-1β rising by 233.0 pg/mL (p = 0.004), and TNF-α showing an increase of 2905 pg/mL (p = 0.002). These findings highlight the ELA blend’s potential to alleviate URTI symptoms, modulate inflammatory and antiviral immune responses, and inhibit viral replication. Further investigations should aim to validate these findings through large-scale studies, and explore the ELA blend’s long-term safety and efficacy in diverse populations. Additionally, research should investigate optimal dosing strategies and explore potential synergistic effects with conventional treatments to maximize clinical outcomes. Trial registration: retrospectively registered under NCT06020001.
Beyond Calories: Individual Metabolic and Hormonal Adaptations Driving Variability in Weight Management—A State-of-the-Art Narrative Review
Authors: Theodorakis Nikolaos , Kreouzi Magdalini , Pappas Andreas , Nikolaou Maria
Published: December 2024

The global rise in obesity underscores the need for effective weight management strategies that address individual metabolic and hormonal variability, moving beyond the simplistic “calories in, calories out” model. Body types—ectomorph, mesomorph, and endomorph—provide a framework for understanding the differences in fat storage, muscle development, and energy expenditure, as each type responds uniquely to caloric intake and exercise. Variability in weight outcomes is influenced by factors such as genetic polymorphisms and epigenetic changes in hormonal signaling pathways and metabolic processes, as well as lifestyle factors, including nutrition, exercise, sleep, and stress. These factors impact the magnitude of lipogenesis and myofibrillar protein synthesis during overfeeding, as well as the extent of lipolysis and muscle proteolysis during caloric restriction, through complex mechanisms that involve changes in the resting metabolic rate, metabolic pathways, and hormonal profiles. Precision approaches, such as nutrigenomics, indirect calorimetry, and artificial-intelligence-based strategies, can potentially leverage these insights to create individualized weight management strategies aligned with each person’s unique metabolic profile. By addressing these personalized factors, precision nutrition offers a promising pathway to sustainable and effective weight management outcomes. The main objective of this review is to examine the metabolic and hormonal adaptations driving variability in weight management outcomes and explore how precision nutrition can address these challenges through individualized strategies.
Chiral Amino Acids Mediate Mitochondria-Dependent Apoptosis of Human Proximal Tubular Epithelial Cells Under Oxidative Stress
Authors: Lu Ying , Zhang Yang , Jin Zhaoyang , Cui Shuaishuai , Wu Li , He Yujian
Published: December 2024

Amino acids are the basic structural units of life, and their intake levels affect disease and health. In the case of renal disease, alterations in amino acid metabolism can be used not only as a clinical indicator of renal disease but also as a therapeutic strategy. However, the biological roles and molecular mechanisms of natural chiral amino acids in human proximal tubular epithelial cells (HK-2) remain unclear. In this study, cell viability assays revealed that chiral acidic amino acids (Glu and Asp) and aromatic amino acids (Trp and Phe) inhibited cell growth. The molecular mechanisms indicated that cell growth was closely related to ROS levels. Specifically, chiral Glu, Asp, Trp, and Phe induced oxidative stress and mitochondria-dependent apoptosis in HK-2 cells. This was manifested by elevated levels of intracellular ROS, 8-OHdG, and MDA, increased activities of antioxidant enzymes CAT, SOD, and GPx, decreased mitochondrial membrane potential, increased cytoplasmic Ca2+ concentration, and cell acidification. The expression levels of apoptosis-related molecules Caspase-9, Caspase-3, Cyt-C, and Bax were increased, and the expression level of anti-apoptotic molecule Bcl-2 was decreased. Moreover, L-Glu, D-Asp, L-Trp, and D-Phe exhibited a more pronounced inhibition of cell growth and elicited more substantial alterations in gene expression compared to the other configurations.
Effects of Brassinosteroid on the Physiological Changes on Two Varieties of Tea Plants Under Salt Stress
Authors: Zhang Zhuolu , Ma Xiru , Tang Dandan , Chen Yiduo , Chen Guo , Zou Juanfen , Tan Liqiang , Tang Qian , Chen Wei
Published: December 2024

Salt stress is one of the abiotic stresses affecting crop quality and yield, and the application of exogenous brassinosteroids (BRs) can be used in response to salt stress. However, the function of BR in tea plants under salt stress remains to be elucidated. This study investigated the effects of exogenous spraying of BR on the malondialdehyde, soluble sugar, soluble protein, and antioxidant enzyme activities in tea plants under salt stress and explored the expression changes in genes related to the synthesis pathways of proline and secondary metabolites (flavonoids and theanine). The results show that 200 mM NaCl solution inhibits the physiology of tea plants, but 0.2 mg/L BR could partially reduce the damage by increasing photosynthetic pigments, osmoregulatory substances (such as soluble sugar, soluble protein, and proline), and the activity of antioxidant enzymes (including peroxidase, catalase, and superoxide dismutase), while decreasing the malondialdehyde content in salt-stressed leaves. The qRT-PCR experiment also shows that the genes related to the synthesis pathways of proline and secondary metabolites (flavonoids and theanine) were upregulated under salt stress, and the proline degradation genes were downregulated, thus promoting the accumulation of proline under salt stress in both varieties. When tea plants were subjected to salt stress, the expression of genes related to the synthesis of secondary metabolites was regulated accordingly to resist salt stress. Moreover, spraying BR had an obvious effect on improving the salt tolerance of tea plants. Therefore, exploring a way to improve the salt tolerance of tea trees provides a reference for the subsequent study of its salt tolerance mechanism, which is of great significance for expanding the introduction area of tea trees, increasing the planting area of tea trees, and improving the yield and quality of tea.
Assessment of IL-8, RANTES, MIG, MCP-1, IP-10, and IL-12p70 and Their Association with Anxiety and Quality of Life in Patients with Chronic Kidney Disease or After Kidney Transplantation
Authors: Furtak Gabriela , Lerch Natalia , Kozłowski Mateusz , Tkacz Piotr , Piekara Emilia , Łagódka Maria , Durys Damian , Gutowska Izabela , Widecka Krystyna , Marchelek-Myśliwiec Małgorzata , Żwierełło Wojciech , Cymbaluk-Płoska Aneta
Published: December 2024

Anxiety is a subjective feeling of fear in response to stressful or threatening situations. Chronic diseases (such as chronic kidney disease) or the state after kidney transplantation are such situations and they may result in a decreased quality of life. The main aim of this research was to evaluate if the proteins IL-8, RANTES, MIG, MCP-1, IP-10, and IL-12p70 could be indicators of higher levels of anxiety or decreased quality of life in chronically ill women. The assessment was conducted using the STAI and SF-36 questionnaires and with the measurement of listed proteins from the patient’s blood sample. The study group consisted of 107 women—101 patients from the Nephrological Clinic and 6 from the Dialysis Center. Both of the facilities are part of University Clinical Hospital No. 2 in Szczecin. Statistical analysis was performed using JASP software (JASP 0.18.3 version). Anxiety levels and quality of life correlations between STAI and SF-36 scores and individual variables were assessed. Logistic regression models were performed for both questionnaire outcomes: SF-36 and STAI. Lower quality of life was found in the group with a higher IL-8 concentration compared to the group of women with a lower IL-8 concentration. A positive weak correlation was found between a decreased quality of life and IL-8 and RANTES. A higher RANTES level increases the odds of a lower quality of life. This study shows that special care should be provided for chronically ill women (especially with CKD or after KTx) with a higher RANTES or IL-8 concentration. They would highly benefit from close monitoring of their mental health.
β-Cell Deletion of Hypoxia-Inducible Factor 1α (HIF-1α) Increases Pancreatic β-Cell Susceptibility to Streptozotocin
Authors: Yu Josephine , Lalwani Amit , Gunton Jenny E.
Published: December 2024

Type 1 diabetes (T1D) is caused by the immune-mediated loss of pancreatic β-cells. Hypoxia-inducible factor 1α (HIF-1α) is a transcription factor which is crucial for cellular responses to low oxygen. Here, we investigate the role of β-cell HIF-1α in β-cell death and diabetes after exposure to multiple low-dose streptozotocin (MLDS). MDLS triggers auto-immunity in susceptible animal models, such as non-obese diabetic (NOD) mice. These experiments used a novel mouse model with β-cell-specific deletion of HIF-1α on a NOD background (BIN mice). Mice were given 20 mg/kg MLDS for 5 consecutive days. Following MLDS, 100% of BIN mice developed frank diabetes versus 33% of floxed-control (FC) littermates and 17% of NOD controls (p < 0.001). BIN mice had obvious loss of β-cell mass (p < 0.0001) and increased necrotic areas within islets (p < 0.001). To confirm that diabetes was T1D, adoptive transfers of splenocytes from diabetic BIN and FC mice were performed on NOD-SCID (Severe Combined ImmunoDeficiency) recipients. All mice receiving BIN-splenocytes developed frank diabetes, confirming that MLDS induced true T1D. Interestingly, diabetes developed significantly faster in BIN-adoptive transfer mice compared to mice which developed diabetes after receiving an FC-adoptive transfer. These studies demonstrate the importance of β-cell HIF-1α in the preservation of β-cell mass and avoidance of auto-immunity.
Epstein–Barr Virus BRRF1 Induces Butyrophilin 2A1 in Nasopharyngeal Carcinoma NPC43 Cells via the IL-22/JAK3-STAT3 Pathway
Authors: Liu Yue , Lui Ka Sin , Ye Zuodong , Chen Luo , Cheung Allen Ka Loon
Published: December 2024

Epstein–Barr virus is highly associated with nasopharyngeal carcinoma (NPC) with genes expressed for tumor transformation or maintenance of viral latency, but there are certain genes that can modulate immune molecules. Butyrophilin 2A1 (BTN2A1) is an important activating protein for presenting phosphoantigens for recognition by Vγ9Vδ2 T cells to achieve antitumor activities. We have previously shown that Vγ9Vδ2 T cells achieve efficacy against NPC when BTN2A1 and BTN3A1 are upregulated by stimulating EBV gene expression, particularly LMP1. While BTN3A1 can be induced by the LMP1-mediated IFN-γ/JNK/NLRC5 pathway, the viral gene that can regulate BTN2A1 remains elusive. We showed that BTN2A1 expression is directly mediated by EBV BRRF1, which can trigger the BTN2A1 promoter and downstream JAK3-STAT3 pathway in NPC43 cells, as shown by RNA-seq data and verified via inhibitor experiments. Furthermore, BRRF1 downregulated IL-22 binding protein (IL-22RA2) to complement the EBNA1-targeting probe (P4)-induced IL-22 expression. Therefore, this study elucidated a new mechanism of stimulating BTN2A1 expression in NPC cells via the EBV gene BRRF1. The JAK3-STAT3 pathway could act in concordance with IL-22 to enhance the expression of BTN2A1, which likely leads to increased tumor cell killing by Vγ9Vδ2 T cells for enhanced potential as immunotherapy against the cancer.
Genome-Wide Identification of the SlSET Gene Family and the Function of SlSET6 Under Salt Stress
Authors: Yang Xueying , Gao Yan , Zhu Chengyu , Li Xin , Gao Yuliang , Li Kuihua
Published: December 2024

A comprehensive genome-wide identification of SET-domain-containing genes in Solanum lycopersicum (tomato) has revealed 46 members. Phylogenetic analysis showed that these SET genes, along with those from Arabidopsis thaliana and Oryza sativa, are divided into five subfamilies, with Subfamilies II and V being the largest. Motif and domain analyses identified 15 conserved motifs and revealed the presence of pre-SET and post-SET domains in several genes, suggesting functional diversification. Gene structure analysis further demonstrated variation in exon–intron organization, likely contributing to differential gene regulation. Promoter analysis identified cis-acting elements related to light responsiveness, plant growth, hormones, and stress, implicating SET genes in various biological processes. RNA-seq and qRT-PCR data revealed distinct expression patterns of SlSET genes under salt stress, with several genes showing significant upregulation, indicating their potential role in stress tolerance. In particular, SlSET6 silencing using VIGS reduced tomato’s tolerance to salt stress, leading to higher lipid peroxidation, reduced antioxidant enzyme activity, and decreased proline content, further confirming its critical role in salt stress response. These findings provide valuable insights into the functional diversity, evolutionary history, and stress-related roles of SET domain genes in tomato, with potential applications for crop improvement strategies.
Genome-Wide Identification and Characterization of GRAS Transcription Factor Family in Cultivated Hybrid Sugarcane ZZ1 (Saccharum officinarum) and Their Role in Development and Stress
Authors: Wen Hao , Wang Lidan , Gong Yuqing , Zhang Yu , Zhao Tingting , Feng Cuilian , Wang Jungang , Lin Jishan
Published: December 2024

GRAS gene family plays multifunctional roles in plant growth, development, and resistance to various biotic and abiotic stresses, belonging to the plant-specific transcription factor (TF) family. In this study, a genome-wide survey and systematic analysis of the GRAS family in cultivated hybrid sugarcane ZZ1 (Saccharum officinarum) with economic and industrial importance was carried out. We identified 747 GRAS genes with complete structural domains and classified these into 11 subfamilies by phylogenetic analyses, exhibiting a diverse range of molecular weight and isoelectric points, thereby indicating a broad structural and functional spectrum. Analysis of Protein motif and gene structure revealed a conserved yet variable arrangement of motifs within the GRAS TFs, suggesting its potential for diverse functional roles. Furthermore, the identification of numerous cis-regulatory elements by GRAS TFs promoter sequence analysis, implying their complex regulation in response to environmental and physiological signals. Tertiary structure predictions analyses using AlphaFold3 highlighted the structural flexibility and conservation within the GRAS family, with disordered regions potentially contributing to their functional versatility. Weighted Gene Co-expression Network Analysis (WGCNA) provided insights into the potential roles of ShGRAS21A in sugarcane’s response to smut infection. This comprehensive investigation of the GRAS family in ZZ1 not only uncovers their structural diversity but also sheds light on their potential regulatory roles in plant growth, development, and stress response. The findings contribute to a deeper understanding of GRAS TFs functions and lay the groundwork for future studies on their role in sugarcane improvement and disease resistance.
Oleanolic Acid Modulates DNA Damage Response to Camptothecin Increasing Cancer Cell Death
Authors: Mazzarotti Giulio , Cuomo Maria , Ragosta Maria Carmen , Russo Andrea , D’Angelo Margherita , Medugno Annamaria , Napolitano Giuseppe Maria , Iannuzzi Carmelina Antonella , Forte Iris Maria , Camerlingo Rosa , Burk Sharon , Errichiello Francesco , Frusciante Luigi , Forino Martino , Campitiello Maria Rosaria , De Laurentiis Michelino , Giordano Antonio , Alfano Luigi
Published: December 2024

Targeting DNA damage response (DDR) pathways represents one of the principal approaches in cancer therapy. However, defects in DDR mechanisms, exhibited by various tumors, can also promote tumor progression and resistance to therapy, negatively impacting patient survival. Therefore, identifying new molecules from natural extracts could provide a powerful source of novel compounds for cancer treatment strategies. In this context, we investigated the role of oleanolic acid (OA), identified in fermented Aglianico red grape pomace, in modulating the DDR in response to camptothecin (CPT), an inhibitor of topoisomerase I. Specifically, we found that OA can influence the choice of DNA repair pathway upon CPT treatment, shifting the repair process from homologous recombination gene conversion to single-strand annealing. Moreover, our data demonstrate that combining sub-lethal concentrations of OA with CPT enhances the efficacy of topoisomerase I inhibition compared to CPT alone. Overall, these findings highlight a new role for OA in the DDR, leading to a more mutagenic DNA repair pathway and increased sensitivity in the HeLa cancer cell line.
Fingerprinting of Volatile Organic Compounds in Old and Commercial Apple Cultivars by HS-SPME GC/GC-ToF-MS
Authors: Szymczak Kamil , Nawrocka Justyna , Bonikowski Radosław
Published: December 2024

Flavor is the most important feature consumers use to examine fruit ripeness, and it also has an important influence on taste sensation. Nowadays, more and more consumers pay much attention not only to the appearance but also to the fruit’s aroma. Exploiting the potential of headspace solid-phase microextraction (HS-SPME) combined with sensitive two-dimensional gas chromatography and the time-of-flight mass spectrometry (GC/GC-ToF-MS) method within 30 old/traditional cultivars of apples (Malus domestica Borkh) coming from the same germplasm and 7 modern/commercial cultivars, 119 volatile organic compounds (VOCs) were identified. The largest group was esters (53), followed by alcohols (20), aldehydes (17), ketones (10), and acids (10). The richest volatile profile was ‘Grochówka’, with 61 VOCs present. The results revealed a visible difference based on VOC levels and profiles between the different apple cultivars, as well as visible similarities within the same cultivar coming from different farms. Based on a PCA, the commercial cultivars were separated into 7 clusters, including (1) ‘Gala’, (2) ‘Melrose’, (3) ‘Red Prince’, (4) ‘Lobo’, (5) ‘Ligol’, and (6) ‘Szampion’. The results of this study indicate that the profile of volatile compounds may be a useful tool for distinguishing between commercial and old apple cultivars, as well as for the varietal classification of apples from different locations. The developed method can also be used to identify other fruit varieties and origins based on their VOC composition. This may prove to be particularly valuable in the case of establishing a Protected Designation of Origin or Protected Geographical Indication.
Epicatechin Influence on Biochemical Modification of Human Erythrocyte Metabolism and Membrane Integrity
Authors: Russo Annamaria , Patanè Giuseppe Tancredi , Laganà Giuseppina , Cirmi Santa , Ficarra Silvana , Barreca Davide , Giunta Elena , Tellone Ester , Putaggio Stefano
Published: December 2024

Red blood cells (RBCs) are the main cells of the blood, perform numerous functions within the body and are in continuous contact with endogenous and exogenous molecules. In this context, the study aims to investigate the effect of epicatechin (EC) (flavan-3-ols) on the erythrocytes, analyzing the protective effect of the molecule and the action exerted on metabolism and RBC membrane. The effect of EC on RBC viability has been evaluated through the change in hemolysis and methemoglobin, assessing caspase 3 activity and performing a cytofluorometric analysis. Next, the impact of the molecule on RBC metabolism was assessed by measuring anion flux kinetics, ATP production, and phosphatase activity. Finally, an evaluation of the potential protection against different stressors was performed. Our results show no detrimental effects of EC on RBCs (no change in hemolysis or methemoglobin and no caspase 3 activation recorded); rather, a protective effect was recorded given the reduction in hemolysis induced by hydrogen peroxide treatment and temperature increase. The increase in anion exchange and intracellular ATP values, with the inhibition of phosphatase PTP1B activity, highlights several biochemical alterations induced by EC. The present results contribute to clarifying the influence of EC on RBCs, confirming the beneficial effects of catechins.
Experimental Myopia Results in Peripapillary Ganglion Cell and Astrocyte Reorganization with No Functional Implications During Early Development
Authors: Ablordeppey Reynolds Kwame , Lin Carol Ren , Srinivas Miduturu , Benavente-Perez Alexandra
Published: December 2024

Myopic eye growth induces mechanical stretch, which can lead to structural and functional retinal alterations. Here, we investigated the effect of lens-induced myopic growth on the distribution of retinal ganglion cells (RGCs), glial fibrillary acidic protein (GFAP) expression and intensity, and peripapillary retinal nerve fiber layer (ppRNFL) thickness in common marmosets (Callithrix jacchus) induced with myopia continuously for six months, using immunohistochemistry and spectral-domain optical coherence tomography. We also explored the relationship between cellular structural parameters and the photopic negative response (PhNR) using full-field electroretinography. Marmosets induced with myopia for six months developed axial myopia, had a thinner ppRNFL, reduced peripapillary ganglion cell (≈20%) and astrocyte density (≈42%), increased panretinal GFAP expression (≈42%) and nasal mid-periphery staining intensity (≈81%) compared to age-matched controls. Greater degrees of myopia and vitreous elongation were associated with reduced peripapillary RGCs and astrocyte density, and increased GFAP expression and intensity. These cellular structural changes did not show a significant relationship with the features of the PhNR, which remained unchanged. The outcomes of this study suggest that myopia induces a reorganization of the peripapillary inner retina at the cellular level that may not result in measurable functional repercussions at this stage of myopia development.
Immune Response Elicited by Recombinant Adenovirus-Delivered Glycoprotein B and Nucleocapsid Protein UL18 and UL25 of HSV-1 in Mice
Authors: Zhang Haobo , Li Qi , Liao Yun , Ma Danjing , Zeng Fengyuan , Zhang Zhenxiao , Yu Li , Yue Rong , Li Xinghang , Liao Yuansheng , Li Dandan , Jang Guorun , Zhao Heng , Zhao Xin , Zheng Huiwen , Li Heng , Liu Longding , Zhang Ying
Published: December 2024

Due to the complex pathogenic and immune escape mechanisms of herpes simplex virus type 1 (HSV-1), especially the failure of induced immune responses to block the initial cell-to-cell transmission of the virus from skin cells to neurons, the body struggles to establish effective prevention and control methods, resulting in the failure of currently developed vaccines. Previous studies have highlighted the crucial roles of surface glycoproteins and nucleocapsid proteins in activating the body’s immune defense system against HSV-1 infection. In this study, recombinant adenoviruses were used as vectors to generate adenoviruses carrying the nucleocapsid protein genes UL18 and UL25, as well as the surface glycoprotein gene gB. This approach aimed to mimic the protein expression process that occurs following viral infection of the host and to investigate the immune response characteristics induced by UL18, UL25, and gB proteins. The findings revealed that UL18, UL25, and gB proteins could all trigger the expression of genes associated with innate immune responses; however, the specific genes induced varied in type and level. Furthermore, all three proteins were capable of promoting the proliferation of CD8+ T cells in the lymph nodes. Notably, only UL18 and gB could elicit a Th1 cell immune response. Interestingly, among these proteins, only UL18 could also induce a relatively higher IL-4 level, indicating a Th2 cell immune response. In addition to cellular immunity, all three proteins stimulated the production of specific IgG antibodies. Notably, UL18 induced higher and more sustained levels of specific IgG antibodies in mice. By contrast, only glycoprotein gB induced lower levels of neutralizing antibodies in mice. Moreover, when these mice were challenged with HSV-1, the co-immunization with UL18 and gB provided better protection than gB alone. In conclusion, HSV-1 surface glycoproteins and nucleocapsid proteins exhibit differences in their ability to induce innate and adaptive immunity in the body, suggesting potential avenues for vaccine design by leveraging their complementary advantages.
Synthesis, Properties and Applications of Lanthanide and Actinide Molecular Compounds
Authors: Maria Leonor , Marçalo Joaquim
Published: December 2024

Lanthanides and actinides have unique physical and chemical properties, and their compounds continue to be extensively studied on a fundamental level during the search for applications that range from energy production and related environmental issues to the life sciences [...]
Characterization of a Low-Shrinkage, Light-Curable Dental Nanocomposite Containing 3-(Methacryloyloxy) Propyltrimethoxysilane (MPTMS) as a Coupling Agent for Dental Restorative Materials
Authors: Hussein Ammar Ali , Mutar Mohammed Ali , Ficai Anton
Published: December 2024

This project intends to develop restorative dental nanomaterial composites that are light-curable and show minimal shrinkage. Such nanocomposites are improved via employing 2,2-bis[4(2-hydroxy-3-methacryloylpropyloxy) phenyl] propane (Bis-GMA) with the unsaturated monomers bisphenol A dimethacrylate, N,N-dimethylacetamide (DMA), ethylene glycol (EG), and methacrylic acid (MAA) and loading them with SiO2, ZrO2, or hydroxyapatite (HA) as nanofillers of 10–30 nm. The first step was to create and characterize these novel dental materials. 1,6-hexanediol methacrylate (HDOMA) was used as a cross-linking agent. The composites based on Bis-GMA and HDOMA with a mass ratio of 40/20 were loaded with 2.5, 5.0, 7.5, 10.0, 12.5, and 15.0 wt.% of the fillers mentioned above. Photopolymerization was induced by a system of photoinitiation based on Camphorquinone/2- (Diethyl amino) ethyl acrylate (CQ/DMAEMA). The nanofillers were treated with 3-(methacryloyloxy) propyltrimethoxysilane (MPTMS) at a ratio of 1.5, 2.5, as well as 3.5%wt. compared to the filler) and a silane coupling agent to increase bonding between the phases and reduce the tendency of agglomerations. SEM images displayed the adhesion between the matrix and the three functionalized nanofillers. FTIR was used to prove the functionalization of the nanofillers by silanization with MPTMS. According to the polymer matrix, two different series of dental nanocomposites were obtained. The compressive strength of dental nanocomposites treated with 2.5 wt.% MPTMS was considerably more significant than those treated with 1.5 and 3.5%wt. MPTMS. Compressive strength (CS) and volumetric shrinkage (VS) were examined as examples of physicochemical properties. This improved nanocomposite was tested for its suitability as a dental restorative material and found to have low shrinkage and high strength.