bluuebunny/crossref_metadata_2025 huggingface dataset:
Methylmercury Induces Apoptosis in Mouse C17.2 Neural Stem Cells through the Induction of OSGIN1 Expression by NRF2
Authors: Yamashita Naoya , Uchiyama Marino , Yamagata Ryota , Hwang Gi-Wook
Published: March 2024

Methylmercury is a known environmental pollutant that exhibits severe neurotoxic effects. However, the mechanism by which methylmercury causes neurotoxicity remains unclear. To date, we have found that oxidative stress-induced growth inhibitor 1 (OSGIN1), which is induced by oxidative stress and DNA damage, is also induced by methylmercury. Therefore, in this study, we investigated the relationship between methylmercury toxicity and the induction of OSGIN1 expression using C17.2 cells, which are mouse brain neural stem cells. Methylmercury increased both OSGIN1 mRNA and protein levels in a time- and concentration-dependent manner. Moreover, these increases were almost entirely canceled out by pretreatment with actinomycin D, a transcription inhibitor. Furthermore, similar results were obtained from cells in which expression of the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2) was suppressed, indicating that methylmercury induces OSGIN1 expression via NRF2. Methylmercury causes neuronal cell death by inducing apoptosis. Therefore, we next investigated the role of OSGIN1 in methylmercury-induced neuronal cell death using the activation of caspase-3, which is involved in apoptosis induction, as an indicator. As a result, the increase in cleaved caspase-3 (activated form) induced by methylmercury exposure was decreased by suppressing OSGIN1, and the overexpression of OSGIN1 further promoted the increase in cleaved caspase-3 caused by methylmercury. These results suggest, for the first time, that OSGIN1 is a novel factor involved in methylmercury toxicity, and methylmercury induces apoptosis in C17.2 cells through the induction of OSGIN1 expression by NRF2.
Skin Autofluorescence as a Potential Adjunctive Marker for Cardiovascular Risk Assessment in Type 2 Diabetes: A Systematic Review
Authors: Reurean-Pintilei Delia , Pantea Stoian Anca , Potcovaru Claudia-Gabriela , Salmen Teodor , Cinteză Delia , Stoica Roxana-Adriana , Lazăr Sandra , Timar Bogdan
Published: March 2024

Diabetes mellitus (DM), due to its long-term hyperglycemia, leads to the accumulation of advanced glycation end-products (AGEs), especially in the vessel walls. Skin autofluorescence (SAF) is a non-invasive tool that measures AGEs. DM patients have a rich dietary source in AGEs, associated with high oxidative stress and long-term inflammation. AGEs represent a cardiovascular (CV) risk factor, and they are linked with CV events. Our objective was to assess whether SAF predicts future CV events (CVE) by examining its association with other CV risk factors in patients with type 2 DM (T2DM). Additionally, we assessed the strengths and limitations of SAF as a predictive tool for CVE. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses methodology, we conducted a systematic review with CRD42024507397 protocol, focused on AGEs, T2DM, SAF, and CV risk. We identified seven studies from 2014 to 2024 that predominantly used the AGE Reader Diagnostic Optic tool. The collective number of patients involved is 8934, with an average age of 63. So, SAF is a valuable, non-invasive marker for evaluating CV risk in T2DM patients. It stands out as a CV risk factor associated independently with CVE. SAF levels are influenced by prolonged hyperglycemia, lifestyle, aging, and other chronic diseases such as depression, and it can be used as a predictive tool for CVE.
Label-Free SERS of Urine Components: A Powerful Tool for Discriminating Renal Cell Carcinoma through Multivariate Analysis and Machine Learning Techniques
Authors: Buhas Bogdan Adrian , Toma Valentin , Beauval Jean-Baptiste , Andras Iulia , Couți Răzvan , Muntean Lucia Ana-Maria , Coman Radu-Tudor , Maghiar Teodor Andrei , Știufiuc Rareș-Ionuț , Lucaciu Constantin Mihai , Crisan Nicolae
Published: March 2024

The advent of Surface-Enhanced Raman Scattering (SERS) has enabled the exploration and detection of small molecules, particularly in biological fluids such as serum, blood plasma, urine, saliva, and tears. SERS has been proposed as a simple diagnostic technique for various diseases, including cancer. Renal cell carcinoma (RCC) ranks as the sixth most commonly diagnosed cancer in men and is often asymptomatic, with detection occurring incidentally. The onset of symptoms typically aligns with advanced disease, aggressive histology, and unfavorable prognosis, and therefore new methods for an early diagnosis are needed. In this study, we investigated the utility of label-free SERS in urine, coupled with two multivariate analysis approaches: Principal Component Analysis combined with Linear Discriminant Analysis (PCA-LDA) and Support Vector Machine (SVM), to discriminate between 50 RCC patients and 44 healthy donors. Employing LDA-PCA, we achieved a discrimination accuracy of 100% using 13 principal components, and an 88% accuracy in discriminating between different RCC stages. The SVM approach yielded a training accuracy of 100%, a validation accuracy of 99% for discriminating between RCC and controls, and an 80% accuracy for discriminating between stages. The comparative analysis of raw and normalized SERS spectral data shows that while raw data disclose relative concentration variations in urine metabolites between the two classes, the normalization of spectral data significantly improves the accuracy of discrimination. Moreover, the selection of principal components with markedly distinct scores between the two classes serves to alleviate overfitting risks and reduces the number of components employed for discrimination. We obtained the accuracy of the discrimination between the RCC patients cases and healthy donors of 90% for three PCs and a linear discrimination function, and a 88% accuracy of discrimination between stages using six PCs, mitigating practically the risk of overfitting and increasing the robustness of our analysis. Our findings underscore the potential of label-free SERS of urine in conjunction with chemometrics for non-invasive and early RCC detection.
Insights into the Adolescent Cystic Fibrosis Airway Microbiome Using Shotgun Metagenomics
Authors: McDermott Gillian , Walsh Aaron , Crispie Fiona , Frost Susanna , Greally Peter , Cotter Paul D. , O’Sullivan Orla , Renwick Julie
Published: March 2024

Cystic fibrosis (CF) is an inherited genetic disorder which manifests primarily in airway disease. Recent advances in molecular technologies have unearthed the diverse polymicrobial nature of the CF airway. Numerous studies have characterised the genus-level composition of this airway community using targeted 16S rDNA sequencing. Here, we employed whole-genome shotgun metagenomics to provide a more comprehensive understanding of the early CF airway microbiome. We collected 48 sputum samples from 11 adolescents and children with CF over a 12-month period and performed shotgun metagenomics on the Illumina NextSeq platform. We carried out functional and taxonomic analysis of the lung microbiome at the species and strain levels. Correlations between microbial diversity measures and independent demographic and clinical variables were performed. Shotgun metagenomics detected a greater diversity of bacteria than culture-based methods. A large proportion of the top 25 most-dominant species were anaerobes. Samples dominated by Staphylococcus aureus and Prevotella melaninogenica had significantly higher microbiome diversity, while no CF pathogen was associated with reduced microbial diversity. There was a diverse resistome present in all samples in this study, with 57.8% agreement between shotgun metagenomics and culture-based methods for detection of resistance. Pathogenic sequence types (STs) of S. aureus, Pseudomonas aeruginosa, Haemophilus influenzae and Stenotrophomonas maltophilia were observed to persist in young CF patients, while STs of S. aureus were both persistent and shared between patients. This study provides new insight into the temporal changes in strain level composition of the microbiome and the landscape of the resistome in young people with CF. Shotgun metagenomics could provide a very useful one-stop assay for detecting pathogens, emergence of resistance and conversion to persistent colonisation in early CF disease.
Exploring the Integrated Role of miRNAs and lncRNAs in Regulating the Transcriptional Response to Amino Acids and Insulin-like Growth Factor 1 in Gilthead Sea Bream (Sparus aurata) Myoblasts
Authors: García-Pérez Isabel , Duran Bruno Oliveira Silva , Dal-Pai-Silva Maeli , Garcia de la serrana Daniel
Published: March 2024

In this study, gilthead sea bream (Sparus aurata) fast muscle myoblasts were stimulated with two pro-growth treatments, amino acids (AA) and insulin-like growth factor 1 (Igf-1), to analyze the transcriptional response of mRNAs, microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) and to explore their possible regulatory network using bioinformatic approaches. AA had a higher impact on transcription (1795 mRNAs changed) compared to Igf-1 (385 mRNAs changed). Both treatments stimulated the transcription of mRNAs related to muscle differentiation (GO:0042692) and sarcomere (GO:0030017), while AA strongly stimulated DNA replication and cell division (GO:0007049). Both pro-growth treatments altered the transcription of over 100 miRNAs, including muscle-specific miRNAs (myomiRs), such as miR-133a/b, miR-206, miR-499, miR-1, and miR-27a. Among 111 detected lncRNAs (>1 FPKM), only 30 were significantly changed by AA and 11 by Igf-1. Eight lncRNAs exhibited strong negative correlations with several mRNAs, suggesting a possible regulation, while 30 lncRNAs showed strong correlations and interactions with several miRNAs, suggesting a role as sponges. This work is the first step in the identification of the ncRNAs network controlling muscle development and growth in gilthead sea bream, pointing out potential regulatory mechanisms in response to pro-growth signals.
A Review of the Use of Native and Engineered Probiotics for Colorectal Cancer Therapy
Authors: Han Huawen , Zhang Yifan , Tang Haibo , Zhou Tuoyu , Khan Aman
Published: March 2024

Colorectal cancer (CRC) is a serious global health concern, and researchers have been investigating different strategies to prevent, treat, or support conventional therapies for CRC. This review article comprehensively covers CRC therapy involving wild-type bacteria, including probiotics and oncolytic bacteria as well as genetically modified bacteria. Given the close relationship between CRC and the gut microbiota, it is crucial to compile and present a comprehensive overview of bacterial therapies used in the context of colorectal cancer. It is evident that the use of native and engineered probiotics for colorectal cancer therapy necessitates research focused on enhancing the therapeutic properties of probiotic strains.. Genetically engineered probiotics might be designed to produce particular molecules or to target cancer cells more effectively and cure CRC patients.
Tetraselmis chuii Edible Microalga as a New Source of Neuroprotective Compounds Obtained Using Fast Biosolvent Extraction
Authors: Cokdinleyen Melis , Alvarez-Rivera Gerardo , Tejera Jose Luis González , Mendiola José A. , Valdés Alberto , Kara Huseyin , Ibáñez Elena , Cifuentes Alejandro
Published: March 2024

Tetraselmis chuii is an EFSA-approved novel food and dietary supplement with increasing use in nutraceutical production worldwide. This study investigated the neuroprotective potential of bioactive compounds extracted from T. chuii using green biobased solvents (ethyl acetate, AcOEt, and cyclopentyl methyl ether, CPME) under pressurized liquid extraction (PLE) conditions and supercritical fluid extraction (SFE). Response surface optimization was used to study the effect of temperature and solvent composition on the neuroprotective properties of the PLE extracts, including anticholinergic activity, reactive oxygen/nitrogen species (ROS/RNS) scavenging capacity, and anti-inflammatory activity. Optimized extraction conditions of 40 °C and 34.9% AcOEt in CPME resulted in extracts with high anticholinergic and ROS/RNS scavenging capacity, while operation at 180 °C and 54.1% AcOEt in CPME yielded extracts with potent anti-inflammatory properties using only 20 min. Chemical characterization revealed the presence of carotenoids (neoxanthin, violaxanthin, zeaxanthin, α- and β-carotene) known for their anti-cholinesterase, antioxidant, and anti-inflammatory potential. The extracts also exhibited high levels of omega-3 polyunsaturated fatty acids (PUFAs) with a favorable ω-3/ω-6 ratio (>7), contributing to their neuroprotective and anti-inflammatory effects. Furthermore, the extracts were found to be safe to use, as cytotoxicity assays showed no observed toxicity in HK-2 and THP-1 cell lines at or below a concentration of 40 μg mL−1. These results highlight the neuroprotective potential of Tetraselmis chuii extracts, making them valuable in the field of nutraceutical production and emphasize the interest of studying new green solvents as alternatives to conventional toxic solvents.
The 12-Membered TNFR1 Peptide, as Well as the 16-Membered and 6-Membered TNF Peptides, Regulate TNFR1-Dependent Cytotoxic Activity of TNF
Authors: Yurkina Daria M. , Romanova Elena A. , Tvorogova Anna V. , Naydenysheva Zlata K. , Feoktistov Alexey V. , Yashin Denis V. , Sashchenko Lidia P.
Published: March 2024

Understanding the exact mechanisms of the activation of proinflammatory immune response receptors is very important for the targeted regulation of their functioning. In this work, we were able to identify the sites of the molecules in the proinflammatory cytokine TNF (tumor necrosis factor) and its TNFR1 (tumor necrosis factor receptor 1), which are necessary for the two-stage cytotoxic signal transduction required for tumor cell killing. A 12-membered TNFR1 peptide was identified and synthesized, interacting with the ligands of this receptor protein’s TNF and Tag7 and blocking their binding to the receptor. Two TNF cytokine peptides interacting with different sites of TNFR1 receptors were identified and synthesized. It has been demonstrated that the long 16-membered TNF peptide interferes with the binding of TNFR1 ligands to this receptor, and the short 6-membered peptide interacts with the receptor site necessary for the transmission of a cytotoxic signal into the cell after the ligands’ interaction with the binding site. This study may help in the development of therapeutic approaches to regulate the activity of the cytokine TNF.
The Role of Stem Cells in the Treatment of Cardiovascular Diseases
Authors: Bakinowska Estera , Kiełbowski Kajetan , Boboryko Dominika , Bratborska Aleksandra Wiktoria , Olejnik-Wojciechowska Joanna , Rusiński Marcin , Pawlik Andrzej
Published: March 2024

Cardiovascular diseases (CVDs) are the leading cause of death and include several vascular and cardiac disorders, such as atherosclerosis, coronary artery disease, cardiomyopathies, and heart failure. Multiple treatment strategies exist for CVDs, but there is a need for regenerative treatment of damaged heart. Stem cells are a broad variety of cells with a great differentiation potential that have regenerative and immunomodulatory properties. Multiple studies have evaluated the efficacy of stem cells in CVDs, such as mesenchymal stem cells and induced pluripotent stem cell-derived cardiomyocytes. These studies have demonstrated that stem cells can improve the left ventricle ejection fraction, reduce fibrosis, and decrease infarct size. Other studies have investigated potential methods to improve the survival, engraftment, and functionality of stem cells in the treatment of CVDs. The aim of the present review is to summarize the current evidence on the role of stem cells in the treatment of CVDs, and how to improve their efficacy.
Cancer Stem Cells from Definition to Detection and Targeted Drugs
Authors: Ruszkowska-Ciastek Barbara , Kwiatkowska Katarzyna , Marques-da-Silva Dorinda , Lagoa Ricardo
Published: March 2024

Cancers remain the second leading cause of mortality in the world. Preclinical and clinical studies point an important role of cancer/leukaemia stem cells (CSCs/LSCs) in the colonisation at secondary organ sites upon metastatic spreading, although the precise mechanisms for specific actions are still not fully understood. Reviewing the present knowledge on the crucial role of CSCs/LSCs, their plasticity, and population heterogeneity in treatment failures in cancer patients is timely. Standard chemotherapy, which acts mainly on rapidly dividing cells, is unable to adequately affect CSCs with a low proliferation rate. One of the proposed mechanisms of CSC resistance to anticancer agents is the fact that these cells can easily shift between different phases of the cell cycle in response to typical cell stimuli induced by anticancer drugs. In this work, we reviewed the recent studies on CSC/LSC alterations associated with disease recurrence, and we systematised the functional assays, markers, and novel methods for CSCs screening. This review emphasises CSCs’ involvement in cancer progression and metastasis, as well as CSC/LSC targeting by synthetic and natural compounds aiming at their elimination or modulation of stemness properties.
PFDN4 as a Prognostic Marker Was Associated with Chemotherapy Resistance through CREBP1/AURKA Pathway in Triple-Negative Breast Cancer
Authors: Wang Shih-Ho , Yeh Cheng-Hsi , Wu Chia-Wei , Hsu Chia-Yi , Tsai Eing-Mei , Hung Chao-Ming , Wang Yi-Wen , Hsieh Tsung-Hua
Published: March 2024

Breast cancer is the most common malignancy and its incidence is increasing. It is currently mainly treated by clinical chemotherapy, but chemoresistance remains poorly understood. Prefolded proteins 4 (PFDN4) are molecular chaperone complexes that bind to newly synthesized polypeptides and allow them to fold correctly to stabilize protein formation. This study aimed to investigate the role of PFDN4 in chemotherapy resistance in breast cancer. Our study found that PFDN4 was highly expressed in breast cancer compared to normal tissues and was statistically significantly associated with stage, nodal status, subclasses (luminal, HER2 positive and triple negative), triple-negative subtype and disease-specific survival by TCGA database analysis. CRISPR knockout of PFDN4 inhibited the growth of 89% of breast cancer cell lines, and the triple-negative cell line exhibited a stronger inhibitory effect than the non-triple-negative cell line. High PFDN4 expression was associated with poor overall survival in chemotherapy and resistance to doxorubicin and paclitaxel through the CREBP1/AURKA pathway in the triple-negative MDAMB231 cell line. This study provides insightful evidence for the value of PFDN4 in poor prognosis and chemotherapy resistance in breast cancer patients.
The Role of Inflammation in Lymphedema: A Narrative Review of Pathogenesis and Opportunities for Therapeutic Intervention
Authors: Bowman Catharine , Rockson Stanley G.
Published: March 2024

Lymphedema is a chronic and progressive disease of the lymphatic system characterized by inflammation, increased adipose deposition, and tissue fibrosis. Despite early hypotheses identifying lymphedema as a disease of mechanical lymphatic disruption alone, the progressive inflammatory nature underlying this condition is now well-established. In this review, we provide an overview of the various inflammatory mechanisms that characterize lymphedema development and progression. These mechanisms contribute to the acute and chronic phases of lymphedema, which manifest clinically as inflammation, fibrosis, and adiposity. Furthermore, we highlight the interplay between current therapeutic modalities and the underlying inflammatory microenvironment, as well as opportunities for future therapeutic development.
Insights into the Management of Chronic Hepatitis in Children—From Oxidative Stress to Antioxidant Therapy
Authors: Ioniuc Ileana , Lupu Ancuta , Tarnita Irina , Mastaleru Alexandra , Trandafir Laura Mihaela , Lupu Vasile Valeriu , Starcea Iuliana Magdalena , Alecsa Mirabela , Morariu Ionela Daniela , Salaru Delia Lidia , Azoicai Alice
Published: March 2024

Recent research has generated awareness of the existence of various pathophysiological pathways that contribute to the development of chronic diseases; thus, pro-oxidative factors have been accepted as significant contributors to the emergence of a wide range of diseases, from inflammatory to malignant. Redox homeostasis is especially crucial in liver pathology, as disturbances at this level have been linked to a variety of chronic diseases. Hepatitis is an umbrella term used to describe liver inflammation, which is the foundation of this disease regardless of its cause. Chronic hepatitis produces both oxidative stress generated by hepatocyte inflammation and viral inoculation. The majority of hepatitis in children is caused by a virus, and current studies reveal that 60–80% of cases become chronic, with many young patients still at risk of advancing liver damage. This review intends to emphasize the relevance of understanding these pathological redox pathways, as well as the need to update therapeutic strategies in chronic liver pathology, considering the beneficial effects of antioxidants.
MicroRNAs in Pancreatic Cancer: Advances in Biomarker Discovery and Therapeutic Implications
Authors: Madadjim Roland , An Thuy , Cui Juan
Published: March 2024

Pancreatic cancer remains a formidable malignancy characterized by high mortality rates, primarily attributable to late-stage diagnosis and a dearth of effective therapeutic interventions. The identification of reliable biomarkers holds paramount importance in enhancing early detection, prognostic evaluation, and targeted treatment modalities. Small non-coding RNAs, particularly microRNAs, have emerged as promising candidates for pancreatic cancer biomarkers in recent years. In this review, we delve into the evolving role of cellular and circulating miRNAs, including exosomal miRNAs, in the diagnosis, prognosis, and therapeutic targeting of pancreatic cancer. Drawing upon the latest research advancements in omics data-driven biomarker discovery, we also perform a case study using public datasets and address commonly identified research discrepancies, challenges, and limitations. Lastly, we discuss analytical approaches that integrate multimodal analyses incorporating clinical and molecular features, presenting new insights into identifying robust miRNA-centric biomarkers.
Bone Morphogenetic Protein 2 Enhances Porcine Beige Adipogenesis via AKT/mTOR and MAPK Signaling Pathways
Authors: Liu Jiali , Jiang Yao , Chen Chuanhe , Zhang Lilan , Wang Jiahao , Yang Chunhuai , Wu Tianwen , Yang Shulin , Tao Cong , Wang Yanfang
Published: March 2024

Bone morphogenetic protein 2 (BMP2) has been reported to regulate adipogenesis, but its role in porcine beige adipocyte formation remains unclear. Our data reveal that BMP2 is significantly induced at the early stages of porcine beige adipocyte differentiation. Additionally, supplementing rhBMP2 during the early stages, but not the late stages of differentiation, significantly enhances porcine SVF adipogenesis, thermogenesis, and proliferation. Furthermore, compared to the empty plasmid-transfected-SVFs, BMP2-overexpressed SVFs had the enhanced lipid accumulation and thermogenesis, while knockdown of BMP2 in SVFs exhibited the opposite effect. The RNA-seq of the above three types of cells revealed the enrichment of the annotation of thermogenesis, brown cell differentiation, etc. In addition, the analysis also highlights the significant enrichment of cell adhesion, the MAPK cascade, and PPARγ signaling. Mechanistically, BMP2 positively regulates the adipogenic and thermogenic capacities of porcine beige adipocytes by activating PPARγ expression through AKT/mTOR and MAPK signaling pathways.
Targeting Group 3 Medulloblastoma by the Anti-PRUNE-1 and Anti-LSD1/KDM1A Epigenetic Molecules
Authors: Bibbò Francesca , Asadzadeh Fatemeh , Boccia Angelo , Sorice Carmen , Bianco Orazio , Saccà Carmen Daniela , Majello Barbara , Donofrio Vittoria , Bifano Delfina , De Martino Lucia , Quaglietta Lucia , Cristofano Adriana , Covelli Eugenio Maria , Cinalli Giuseppe , Ferrucci Veronica , De Antonellis Pasqualino , Zollo Massimo
Published: March 2024

Medulloblastoma (MB) is a highly malignant childhood brain tumor. Group 3 MB (Gr3 MB) is considered to have the most metastatic potential, and tailored therapies for Gr3 MB are currently lacking. Gr3 MB is driven by PRUNE-1 amplification or overexpression. In this paper, we found that PRUNE-1 was transcriptionally regulated by lysine demethylase LSD1/KDM1A. This study aimed to investigate the therapeutic potential of inhibiting both PRUNE-1 and LSD1/KDM1A with the selective inhibitors AA7.1 and SP-2577, respectively. We found that the pharmacological inhibition had a substantial efficacy on targeting the metastatic axis driven by PRUNE-1 (PRUNE-1-OTX2-TGFβ-PTEN) in Gr3 MB. Using RNA seq transcriptomic feature data in Gr3 MB primary cells, we provide evidence that the combination of AA7.1 and SP-2577 positively affects neuronal commitment, confirmed by glial fibrillary acidic protein (GFAP)-positive differentiation and the inhibition of the cytotoxic components of the tumor microenvironment and the epithelial–mesenchymal transition (EMT) by the down-regulation of N-Cadherin protein expression. We also identified an impairing action on the mitochondrial metabolism and, consequently, oxidative phosphorylation, thus depriving tumors cells of an important source of energy. Furthermore, by overlapping the genomic mutational signatures through WES sequence analyses with RNA seq transcriptomic feature data, we propose in this paper that the combination of these two small molecules can be used in a second-line treatment in advanced therapeutics against Gr3 MB. Our study demonstrates that the usage of PRUNE-1 and LSD1/KDM1A inhibitors in combination represents a novel therapeutic approach for these highly aggressive metastatic MB tumors.
Early Movement Restriction Affects FNDC5/Irisin and BDNF Levels in Rat Muscle and Brain
Authors: Dupuis Orlane , Girardie Julien , Van Gaever Mélanie , Garnier Philippe , Coq Jacques-Olivier , Canu Marie-Hélène , Dupont Erwan
Published: March 2024

Interaction with the environment appears necessary for the maturation of sensorimotor and cognitive functions in early life. In rats, a model of sensorimotor restriction (SMR) from postnatal day 1 (P1) to P28 has shown that low and atypical sensorimotor activities induced the perturbation of motor behavior due to muscle weakness and the functional disorganization of the primary somatosensory and motor cortices. In the present study, our objective was to understand how SMR affects the muscle–brain dialogue. We focused on irisin, a myokine secreted by skeletal muscles in response to exercise. FNDC5/irisin expression was determined in hindlimb muscles and brain structures by Western blotting, and irisin expression in blood and cerebrospinal fluid was determined using an ELISA assay at P8, P15, P21 and P28. Since irisin is known to regulate its expression, Brain-Derived Neurotrophic Factor (BDNF) levels were also measured in the same brain structures. We demonstrated that SMR increases FNDC5/irisin levels specifically in the soleus muscle (from P21) and also affects this protein expression in several brain structures (as early as P15). The BDNF level was increased in the hippocampus at P8. To conclude, SMR affects FNDC5/irisin levels in a postural muscle and in several brain regions and has limited effects on BDNF expression in the brain.
Difference of Cerebrospinal Fluid Biomarkers and Neuropsychiatric Symptoms Profiles among Normal Cognition, Mild Cognitive Impairment, and Dementia Patient
Authors: Hsu Ching-Chi , Wang Shiow-Ing , Lin Hong-Chun , Lin Eric S. , Yang Fan-Pei , Chang Ching-Mao , Wei James Cheng-Chung
Published: March 2024

The delineation of biomarkers and neuropsychiatric symptoms across normal cognition, mild cognitive impairment (MCI), and dementia stages holds significant promise for early diagnosis and intervention strategies. This research investigates the association of neuropsychiatric symptoms, evaluated via the Neuropsychiatric Inventory (NPI), with cerebrospinal fluid (CSF) biomarkers (Amyloid-β42, P-tau, T-tau) across a spectrum of cognitive states to enhance diagnostic accuracy and treatment approaches. Drawing from the National Alzheimer’s Coordinating Center’s Uniform Data Set Version 3, comprising 977 individuals with normal cognition, 270 with MCI, and 649 with dementia. To assess neuropsychiatric symptoms, we employed the NPI to understand the behavioral and psychological symptoms associated with each cognitive category. For the analysis of CSF biomarkers, we measured levels of Amyloid-β42, P-tau, and T-tau using the enzyme-linked immunosorbent assay (ELISA) and Luminex multiplex xMAP assay protocols. These biomarkers are critical in understanding the pathophysiological underpinnings of Alzheimer’s disease and its progression, with specific patterns indicative of disease stage and severity. This study cohort consists of 1896 participants, which is composed of 977 individuals with normal cognition, 270 with MCI, and 649 with dementia. Dementia is characterized by significantly higher NPI scores, which are largely reflective of mood-related symptoms (p < 0.001). In terms of biomarkers, normal cognition shows median Amyloid-β at 656.0 pg/mL, MCI at 300.6 pg/mL, and dementia at 298.8 pg/mL (p < 0.001). Median P-tau levels are 36.00 pg/mL in normal cognition, 49.12 pg/mL in MCI, and 58.29 pg/mL in dementia (p < 0.001). Median T-tau levels are 241.0 pg/mL in normal cognition, 140.6 pg/mL in MCI, and 298.3 pg/mL in dementia (p < 0.001). Furthermore, the T-tau/Aβ-42 ratio increases progressively from 0.058 in the normal cognition group to 0.144 in the MCI group, and to 0.209 in the dementia group (p < 0.001). Similarly, the P-tau/Aβ-42 ratio also escalates from 0.305 in individuals with normal cognition to 0.560 in MCI, and to 0.941 in dementia (p < 0.001). The notable disparities in NPI and CSF biomarkers among normal, MCI and Alzheimer’s patients underscore their diagnostic potential. Their combined assessment could greatly improve early detection and precise diagnosis of MCI and dementia, facilitating more effective and timely treatment strategies.
Smelling TNT: Trends of the Terminal Nerve
Authors: Ruqa Wael Abu , Pennacchia Fiorenza , Rusi Eqrem , Zoccali Federica , Bruno Giuseppe , Talarico Giuseppina , Barbato Christian , Minni Antonio
Published: March 2024

There is very little knowledge regarding the terminal nerve, from its implications in the involvement and pathogenesis of certain conditions, to its embryological origin. With this review, we try to summarize the most important evidence on the terminal nerve, aiming to clarify its anatomy and the various functions attributed to it, to better interpret its potential involvement in pathological processes. Recent studies have also suggested its potential role in the control of human reproductive functions and behaviors. It has been hypothesized that it plays a role in the unconscious perception of specific odors that influence autonomic and reproductive hormonal systems through the hypothalamic–pituitary–gonadal axis. We used the PubMed database and found different articles which were then selected independently by three authors. We found 166 articles, of which, after careful selection, only 21 were analyzed. The terminal nerve was always thought to be unimportant in our body. It was well studied in different types of animals, but few studies have been completed in humans. For this reason, its function remains unknown. Studies suggest a possible implication in olfaction due to the anatomical proximity with the olfactive nerve. Others suggest a more important role in reproduction and sexual behaviors. New emerging information suggests a possible role in Kallmann syndrome and COVID-19.
Metabolic Profiling as an Approach to Differentiate T-Cell Acute Lymphoblastic Leukemia Cell Lines Belonging to the Same Genetic Subgroup
Authors: Alabed Husam B. R. , Pellegrino Roberto Maria , Buratta Sandra , Lema Fernandez Anair Graciela , La Starza Roberta , Urbanelli Lorena , Mecucci Cristina , Emiliani Carla , Gorello Paolo
Published: March 2024

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive tumor mainly affecting children and adolescents. It is driven by multiple genetic mutations that together define the leukemic phenotype. Interestingly, based on genetic alterations and/or deregulated expression, at least six genetic subgroups have been recognized. The TAL/LMO subgroup is one of the most represented genetic subgroups, characterizing 30–45% of pediatric T-ALL cases. The study of lipid and metabolic profiles is increasingly recognized as a valuable tool for comprehending the development and progression of tumors. In this study, metabolic and lipidomic analysis via LC/MS have been carried out on four T-ALL cell lines belonging to the TAL/LMO subgroup (Jurkat, Molt-4, Molt-16, and CCRF-CEM) to identify new potential metabolic biomarkers and to provide a subclassification of T-ALL cell lines belonging to the same subgroup. A total of 343 metabolites were annotated, including 126 polar metabolites and 217 lipid molecules. The statistical analysis, for both metabolic and lipid profiles, shows significant differences and similarities among the four cell lines. The Molt-4 cell line is the most distant cell line and CCRF-CEM shows a high activity in specific pathways when compared to the other cell lines, while Molt-16 and Jurkat show a similar metabolic profile. Additionally, this study highlighted the pathways that differ in each cell line and the possible enzymes involved using bioinformatic tools, capable of predicting the pathways involved by studying the differences in the metabolic profiles. This experiment offers an approach to differentiate T-ALL cell lines and could open the way to verify and confirm the obtained results directly in patients.
Biocompatibility of Synechococcus sp. PCC 7002 with Human Dermal Cells In Vitro
Authors: Fuchs Benedikt , Mert Sinan , Kuhlmann Constanze , Taha Sara , Birt Alexandra , Nickelsen Jörg , Schenck Thilo Ludwig , Giunta Riccardo Enzo , Wiggenhauser Paul Severin , Moellhoff Nicholas
Published: March 2024

Being the green gold of the future, cyanobacteria have recently attracted considerable interest worldwide. This study investigates the adaptability and biocompatibility of the cyanobacterial strain Synechococcus sp. PCC 7002 with human dermal cells, focusing on its potential application in biomedical contexts. First, we investigated the adaptability of Synechococcus PCC 7002 bacteria to human cell culture conditions. Next, we evaluated the biocompatibility of cyanobacteria with common dermal cells, like 3T3 fibroblasts and HaCaT keratinocytes. Therefore, cells were directly and indirectly cocultured with the corresponding cells, and we measured metabolic activity (AlamarBlue assay) and proliferation (cell count and PicoGreen assay). The lactate dehydrogenase (LDH) assay was performed to determine the cytotoxic effect of cyanobacteria and their nutrition medium on human dermal cells. The cyanobacteria exhibited exponential growth under conventional human cell culture conditions, with the temperature and medium composition not affecting their viability. In addition, the effect of illumination on the proliferation capacity was investigated, showing a significant impact of light exposure on bacterial growth. The measured oxygen production under hypoxic conditions demonstrated a sufficient oxygen supply for further tissue engineering approaches depending on the number of bacteria. There were no significant adverse effects on human cell viability and growth under coculture conditions, whereas the LDH assay assessed signs of cytotoxicity regarding 3T3 fibroblasts after 2 days of coculturing. These negative effects were dismissed after 4 days. The findings highlight the potential of Synechococcus sp. PCC 7002 for integration into biomedical approaches. We found no cytotoxicity of cyanobacteria on 3T3 fibroblasts and HaCaT keratinocytes, thus paving the way for further in vivo studies to assess long-term effects and systemic reactions.
Evolution of a Human-Specific De Novo Open Reading Frame and Its Linked Transcriptional Silencer
Authors: Delihas Nicholas
Published: March 2024

In the human genome, two short open reading frames (ORFs) separated by a transcriptional silencer and a small intervening sequence stem from the gene SMIM45. The two ORFs show different translational characteristics, and they also show divergent patterns of evolutionary development. The studies presented here describe the evolution of the components of SMIM45. One ORF consists of an ultra-conserved 68 amino acid (aa) sequence, whose origins can be traced beyond the evolutionary age of divergence of the elephant shark, ~462 MYA. The silencer also has ancient origins, but it has a complex and divergent pattern of evolutionary formation, as it overlaps both at the 68 aa ORF and the intervening sequence. The other ORF consists of 107 aa. It develops during primate evolution but is found to originate de novo from an ancestral non-coding genomic region with root origins within the Afrothere clade of placental mammals, whose evolutionary age of divergence is ~99 MYA. The formation of the complete 107 aa ORF during primate evolution is outlined, whereby sequence development is found to occur through biased mutations, with disruptive random mutations that also occur but lead to a dead-end. The 107 aa ORF is of particular significance, as there is evidence to suggest it is a protein that may function in human brain development. Its evolutionary formation presents a view of a human-specific ORF and its linked silencer that were predetermined in non-primate ancestral species. The genomic position of the silencer offers interesting possibilities for the regulation of transcription of the 107 aa ORF. A hypothesis is presented with respect to possible spatiotemporal expression of the 107 aa ORF in embryonic tissues.
Synthetic Derivatives of Natural ent-Kaurane Atractyligenin Disclose Anticancer Properties in Colon Cancer Cells, Triggering Apoptotic Cell Demise
Authors: Badalamenti Natale , Maggio Antonella , Fontana Gianfranco , Bruno Maurizio , Lauricella Marianna , D’Anneo Antonella
Published: March 2024

The antitumor activity of different ent-kaurane diterpenes has been extensively studied. Several investigations have demonstrated the excellent antitumor activity of synthetic derivatives of the diterpene atractyligenin. In this research, a series of new synthetic amides and their 15,19-di-oxo analogues obtained from atractyligenin by modifying the C-2, C-15, and C-19 positions were designed in order to dispose of a set of derivatives with different substitutions at the amidic nitrogen. Using different concentrations of the obtained compounds (10–300 μM) a reduction in cell viability of HCT116 colon cancer cells was observed at 48 h of treatment. All the di-oxidized compounds were more effective than their alcoholic precursors. The di-oxidized compounds had already reduced the viability of two colon cancer cells (HCT116 and Caco-2) at 24 h when used at low doses (2.5–15 μM), while they turned out to be poorly effective in differentiated Caco-2 cells, a model of polarized enterocytes. The data reported here provide evidence that di-oxidized compounds induced apoptotic cell death, as demonstrated by the appearance of condensed and fragmented DNA in treated cells, as well as the activation of caspase-3 and fragmentation of its target PARP-1.
Genome-Wide Identification and Expression Profiling of Velvet Complex Transcription Factors in Populus alba × Populus glandulosa
Authors: Hao Yuanyuan , Yan Xiaojing , Li Quanzi
Published: March 2024

The discovery of new genes with novel functions is a major driver of adaptive evolutionary innovation in plants. Especially in woody plants, due to genome expansion, new genes evolve to regulate the processes of growth and development. In this study, we characterized the unique VeA transcription factor family in Populus alba × Populus glandulosa, which is associated with secondary metabolism. Twenty VeA genes were characterized systematically on their phylogeny, genomic distribution, gene structure and conserved motif, promoter binding site, and expression profiling. Furthermore, through ChIP-qPCR, Y1H, and effector-reporter assays, it was demonstrated that PagMYB128 directly regulated PagVeA3 to influence the biosynthesis of secondary metabolites. These results provide a basis for further elucidating the function of VeAs gene in poplar and its genetic regulation mechanism.
Diversity, Complexity, and Specificity of Bacterial Lipopolysaccharide (LPS) Structures Impacting Their Detection and Quantification
Authors: Dardelle Flavien , Phelip Capucine , Darabi Maryam , Kondakova Tatiana , Warnet Xavier , Combret Edyta , Juranville Eugenie , Novikov Alexey , Kerzerho Jerome , Caroff Martine
Published: March 2024

Endotoxins are toxic lipopolysaccharides (LPSs), extending from the outer membrane of Gram-negative bacteria and notorious for their toxicity and deleterious effects. The comparison of different LPSs, isolated from various Gram-negative bacteria, shows a global similar architecture corresponding to a glycolipid lipid A moiety, a core oligosaccharide, and outermost long O-chain polysaccharides with molecular weights from 2 to 20 kDa. LPSs display high diversity and specificity among genera and species, and each bacterium contains a unique set of LPS structures, constituting its protective external barrier. Some LPSs are not toxic due to their particular structures. Different, well-characterized, and highly purified LPSs were used in this work to determine endotoxin detection rules and identify their impact on the host. Endotoxin detection is a major task to ensure the safety of human health, especially in the pharma and food sectors. Here, we describe the impact of different LPS structures obtained under different bacterial growth conditions on selective LPS detection methods such as LAL, HEK-blue TLR-4, LC-MS2, and MALDI-MS. In these various assays, LPSs were shown to respond differently, mainly attributable to their lipid A structures, their fatty acid numbers and chain lengths, the presence of phosphate groups, and their possible substitutions.
Different Levels of Therapeutic Strategies to Recover the Microbiome to Prevent/Delay Acute Lymphoblastic Leukemia (ALL) or Arrest Its Progression in Children
Authors: Aronica Tommaso Silvano , Carella Miriam , Balistreri Carmela Rita
Published: March 2024

Changes in the components, variety, metabolism, and products of microbiomes, particularly of the gut microbiome (GM), have been revealed to be closely associated with the onset and progression of numerous human illnesses, including hematological neoplasms. Among the latter pathologies, there is acute lymphoblastic leukemia (ALL), the most widespread malignant neoplasm in pediatric subjects. Accordingly, ALL cases present a typical dysfunctional GM during all its clinical stages and resulting inflammation, which contributes to its progression, altered response to therapy, and possible relapses. Children with ALL have GM with characteristic variations in composition, variety, and functions, and such alterations may influence and predict the complications and prognosis of ALL after chemotherapy treatment or stem cell hematopoietic transplants. In addition, growing evidence also reports the ability of GM to influence the formation, growth, and roles of the newborn’s hematopoietic system through the process of developmental programming during fetal life as well as its susceptibility to the onset of onco-hematological pathologies, namely ALL. Here, we suggest some therapeutic strategies that can be applied at two levels of intervention to recover the microbiome and consequently prevent/delay ALL or arrest its progression.
Newborn Screening for Inborn Errors of Metabolism by Next-Generation Sequencing Combined with Tandem Mass Spectrometry
Authors: Tang Chengfang , Li Lixin , Chen Ting , Li Yulin , Zhu Bo , Zhang Yinhong , Yin Yifan , Liu Xiulian , Huang Cidan , Miao Jingkun , Zhu Baosheng , Wang Xiaohua , Zou Hui , Han Lianshu , Feng Jizhen , Huang Yonglan
Published: March 2024

The aim of this study was to observe the outcomes of newborn screening (NBS) in a certain population by using next-generation sequencing (NGS) as a first-tier screening test combined with tandem mass spectrometry (MS/MS). We performed a multicenter study of 29,601 newborns from eight screening centers with NBS via NGS combined with MS/MS. A custom-designed panel targeting the coding region of the 142 genes of 128 inborn errors of metabolism (IEMs) was applied as a first-tier screening test, and expanded NBS using MS/MS was executed simultaneously. In total, 52 genes associated with the 38 IEMs screened by MS/MS were analyzed. The NBS performance of these two methods was analyzed and compared respectively. A total of 23 IEMs were diagnosed via NGS combined with MS/MS. The incidence of IEMs was approximately 1 in 1287. Within separate statistical analyses, the positive predictive value (PPV) for MS/MS was 5.29%, and the sensitivity was 91.3%. However, for genetic screening alone, the PPV for NGS was 70.83%, with 73.91% sensitivity. The three most common IEMs were methylmalonic academia (MMA), primary carnitine deficiency (PCD) and phenylketonuria (PKU). The five genes with the most common carrier frequencies were PAH (1:42), PRODH (1:51), MMACHC (1:52), SLC25A13 (1:55) and SLC22A5 (1:63). Our study showed that NBS combined with NGS and MS/MS improves the performance of screening methods, optimizes the process, and provides accurate diagnoses.
Advancing Sustainable COVID-19 Diagnosis: Integrating Artificial Intelligence with Bioinformatics in Chest X-ray Analysis
Authors: Louati Hassen , Louati Ali , Lahyani Rahma , Kariri Elham , Albanyan Abdullah
Published: March 2024

Responding to the critical health crisis triggered by respiratory illnesses, notably COVID-19, this study introduces an innovative and resource-conscious methodology for analyzing chest X-ray images. We unveil a cutting-edge technique that marries neural architecture search (NAS) with genetic algorithms (GA), aiming to refine the architecture of convolutional neural networks (CNNs) in a way that diminishes the usual demand for computational power. Leveraging transfer learning (TL), our approach efficiently navigates the hurdles posed by scarce data, optimizing both time and hardware utilization—a cornerstone for sustainable AI initiatives. The investigation leverages a curated dataset of 1184 COVID-positive and 1319 COVID-negative chest X-ray images, serving as the basis for model training, evaluation, and validation. Our methodology not only boosts the precision in diagnosing COVID-19 but also establishes a pioneering standard in the realm of eco-friendly and effective healthcare technologies. Through comprehensive comparative analyses against leading-edge models, our optimized solutions exhibit significant performance enhancements alongside a minimized ecological impact. This contribution marks a significant stride towards eco-sustainable medical imaging, presenting a paradigm that prioritizes environmental stewardship while adeptly addressing modern healthcare exigencies. We compare our approach to state-of-the-art architectures through multiple comparative studies.