bluuebunny/crossref_metadata_2025 huggingface dataset:
Uridine Alleviates Sepsis-Induced Acute Lung Injury by Inhibiting Ferroptosis of Macrophage
Authors: Lai Kai , Song Congkuan , Gao Minglang , Deng Yu , Lu Zilong , Li Ning , Geng Qing
Published: March 2023

Uridine metabolism is extensively reported to be involved in combating oxidative stress. Redox-imbalance-mediated ferroptosis plays a pivotal role in sepsis-induced acute lung injury (ALI). This study aims to explore the role of uridine metabolism in sepsis-induced ALI and the regulatory mechanism of uridine in ferroptosis. The Gene Expression Omnibus (GEO) datasets including lung tissues in lipopolysaccharides (LPS) -induced ALI model or human blood sample of sepsis were collected. In vivo and vitro, LPS was injected into mice or administered to THP-1 cells to generate sepsis or inflammatory models. We identified that uridine phosphorylase 1 (UPP1) was upregulated in lung tissues and septic blood samples and uridine significantly alleviated lung injury, inflammation, tissue iron level and lipid peroxidation. Nonetheless, the expression of ferroptosis biomarkers, including SLC7A11, GPX4 and HO-1, were upregulated, while lipid synthesis gene (ACSL4) expression was greatly restricted by uridine supplementation. Moreover, pretreatment of ferroptosis inducer (Erastin or Era) weakened while inhibitor (Ferrostatin-1 or Fer-1) strengthened the protective effects of uridine. Mechanistically, uridine inhibited macrophage ferroptosis by activating Nrf2 signaling pathway. In conclusion, uridine metabolism dysregulation is a novel accelerator for sepsis-induced ALI and uridine supplementation may offer a potential avenue for ameliorating sepsis-induced ALI by suppressing ferroptosis.
Muscle Cell Insulin Resistance Is Attenuated by Rosmarinic Acid: Elucidating the Mechanisms Involved
Authors: Den Hartogh Danja J. , Vlavcheski Filip , Tsiani Evangelia
Published: March 2023

Obesity and elevated blood free fatty acid (FFA) levels lead to impaired insulin action causing insulin resistance in skeletal muscle, and contributing to the development of type 2 diabetes mellitus (T2DM). Mechanistically, insulin resistance is associated with increased serine phosphorylation of the insulin receptor substrate (IRS) mediated by serine/threonine kinases including mTOR and p70S6K. Evidence demonstrated that activation of the energy sensor AMP-activated protein kinase (AMPK) may be an attractive target to counteract insulin resistance. We reported previously that rosemary extract (RE) and the RE polyphenol carnosic acid (CA) activated AMPK and counteracted the FFA-induced insulin resistance in muscle cells. The effect of rosmarinic acid (RA), another polyphenolic constituent of RE, on FFA-induced muscle insulin resistance has never been examined and is the focus of the current study. Muscle cell (L6) exposure to FFA palmitate resulted in increased serine phosphorylation of IRS-1 and reduced insulin-mediated (i) Akt activation, (ii) GLUT4 glucose transporter translocation, and (iii) glucose uptake. Notably, RA treatment abolished these effects, and restored the insulin-stimulated glucose uptake. Palmitate treatment increased the phosphorylation/activation of mTOR and p70S6K, kinases known to be involved in insulin resistance and RA significantly reduced these effects. RA increased the phosphorylation of AMPK, even in the presence of palmitate. Our data indicate that RA has the potential to counteract the palmitate-induced insulin resistance in muscle cells, and further studies are required to explore its antidiabetic properties.
Development of Fluorescent Bacteria with Lux and Riboflavin Genes
Authors: Lim Sun-Joo , Choi Miae , Yun Inseop , Lee Seulgi , Chang Ny , Lee Chan-Yong
Published: March 2023

Lumazine protein from marine luminescent bacteria of Photobacterium species bind with very high affinity to the fluorescent chromophore 6,7-dimethyl-8-ribitylumazine. The light emission of bacterial luminescent systems is used as a sensitive, rapid, and safe assay for an ever-increasing number of biological systems. Plasmid pRFN4, containing the genes encoding riboflavin from the rib operon of Bacillus subtilis, was designed for the overproduction of lumazine. To construct fluorescent bacteria for use as microbial sensors, novel recombinant plasmids (pRFN4-Pp N-lumP and pRFN4-Pp luxLP N-lumP) were constructed by amplifying the DNA encoding the N-lumP gene (luxL) from P. phosphoreum and the promoter region (luxLP) present upstream of the lux operon of the gene by PCR and ligating into the pRFN4-Pp N-lumP plasmid. A new recombinant plasmid, pRFN4-Pp luxLP-N-lumP, was constructed with the expectation that the fluorescence intensity would be further increased when transformed into Escherichia coli. When this plasmid was transformed into E. coli 43R, the fluorescence intensity of transformants was 500 times greater than that of E. coli alone. As a result, the recombinant plasmid in which the gene encoding N-LumP and DNA containing the lux promoter exhibited expression that was so high as to show fluorescence in single E. coli cells. The fluorescent bacterial systems developed in the present study using lux and riboflavin genes can be utilized in the future as biosensors with high sensitivity and rapid analysis times.
Dissection of Antibody Responses of Gam-COVID-Vac-Vaccinated Subjects Suggests Involvement of Epitopes Outside RBD in SARS-CoV-2 Neutralization
Authors: Byazrova Maria , Gattinger Pia , Astakhova Ekaterina , Hofer Gerhard , Khaitov Musa , Filatov Alexander , Valenta Rudolf
Published: March 2023

Millions of people have been vaccinated with Gam-COVID-Vac but fine specificities of induced antibodies have not been fully studied. Plasma from 12 naïve and 10 coronavirus disease 2019 (COVID-19) convalescent subjects was obtained before and after two immunizations with Gam-COVID-Vac. Antibody reactivity in the plasma samples (n = 44) was studied on a panel of micro-arrayed recombinant folded and unfolded severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) proteins and 46 peptides spanning the spike protein (S) and by immunoglobulin G (IgG) subclass enzyme-linked immunosorbent assay (ELISA). The ability of Gam-COVID-Vac-induced antibodies to inhibit binding of the receptor-binding domain (RBD) to its receptor angiotensin converting enzyme 2 (ACE2) was investigated in a molecular interaction assay (MIA). The virus-neutralizing capacity of antibodies was studied by the pseudo-typed virus neutralization test (pVNT) for Wuhan-Hu-1 and Omicron. We found that Gam-COVID-Vac vaccination induced significant increases of IgG1 but not of other IgG subclasses against folded S, spike protein subunit 1 (S1), spike protein subunit 2 (S2), and RBD in a comparable manner in naïve and convalescent subjects. Virus neutralization was highly correlated with vaccination-induced antibodies specific for folded RBD and a novel peptide (i.e., peptide 12). Peptide 12 was located close to RBD in the N-terminal part of S1 and may potentially be involved in the transition of the pre- to post-fusion conformation of the spike protein. In summary, Gam-COVID-Vac vaccination induced S-specific IgG1 antibodies in naive and convalescent subjects in a comparable manner. Besides the antibodies specific for RBD, the antibodies induced against a peptide close to the N-terminus of RBD were also associated with virus-neutralization.
Phenotypes and Molecular Mechanisms Underlying the Root Response to Phosphate Deprivation in Plants
Authors: Ren Meiyan , Li Yong , Zhu Jianshu , Zhao Keju , Wu Zhongchang , Mao Chuanzao
Published: March 2023

Phosphorus (P) is an essential macronutrient for plant growth. The roots are the main organ for nutrient and water absorption in plants, and they adapt to low-P soils by altering their architecture for enhancing absorption of inorganic phosphate (Pi). This review summarizes the physiological and molecular mechanisms underlying the developmental responses of roots to Pi starvation, including the primary root, lateral root, root hair, and root growth angle, in the dicot model plant Arabidopsis thaliana and the monocot model plant rice (Oryza sativa). The importance of different root traits and genes for breeding P-efficient roots in rice varieties for Pi-deficient soils are also discussed, which we hope will benefit the genetic improvement of Pi uptake, Pi-use efficiency, and crop yields.
Inherited Thrombocytopenia Caused by Variants in Crucial Genes for Glycosylation
Authors: Marín-Quílez Ana , Díaz-Ajenjo Lorena , Di Buduo Christian A. , Zamora-Cánovas Ana , Lozano María Luisa , Benito Rocío , González-Porras José Ramón , Balduini Alessandra , Rivera José , Bastida José María
Published: March 2023

Protein glycosylation, including sialylation, involves complex and frequent post-translational modifications, which play a critical role in different biological processes. The conjugation of carbohydrate residues to specific molecules and receptors is critical for normal hematopoiesis, as it favors the proliferation and clearance of hematopoietic precursors. Through this mechanism, the circulating platelet count is controlled by the appropriate platelet production by megakaryocytes, and the kinetics of platelet clearance. Platelets have a half-life in blood ranging from 8 to 11 days, after which they lose the final sialic acid and are recognized by receptors in the liver and eliminated from the bloodstream. This favors the transduction of thrombopoietin, which induces megakaryopoiesis to produce new platelets. More than two hundred enzymes are responsible for proper glycosylation and sialylation. In recent years, novel disorders of glycosylation caused by molecular variants in multiple genes have been described. The phenotype of the patients with genetic alterations in GNE, SLC35A1, GALE and B4GALT is consistent with syndromic manifestations, severe inherited thrombocytopenia, and hemorrhagic complications.
Imaging Mass Spectrometry for the Classification of Melanoma Based on BRAF/NRAS Mutational Status
Authors: Casadonte Rita , Kriegsmann Mark , Kriegsmann Katharina , Streit Helene , Meliß Rolf Rüdiger , Müller Cornelia S. L. , Kriegsmann Joerg
Published: March 2023

Mutations of the oncogenes v-raf murine sarcoma viral oncogene homolog B1 (BRAF) and neuroblastoma RAS viral oncogene homolog (NRAS) are the most frequent genetic alterations in melanoma and are mutually exclusive. BRAF V600 mutations are predictive for response to the two BRAF inhibitors vemurafenib and dabrafenib and the mitogen-activated protein kinase kinase (MEK) inhibitor trametinib. However, inter- and intra-tumoral heterogeneity and the development of acquired resistance to BRAF inhibitors have important clinical implications. Here, we investigated and compared the molecular profile of BRAF and NRAS mutated and wildtype melanoma patients’ tissue samples using imaging mass spectrometry-based proteomic technology, to identify specific molecular signatures associated with the respective tumors. SCiLSLab and R-statistical software were used to classify peptide profiles using linear discriminant analysis and support vector machine models optimized with two internal cross-validation methods (leave-one-out, k-fold). Classification models showed molecular differences between BRAF and NRAS mutated melanoma, and identification of both was possible with an accuracy of 87–89% and 76–79%, depending on the respective classification method applied. In addition, differential expression of some predictive proteins, such as histones or glyceraldehyde-3-phosphate-dehydrogenase, correlated with BRAF or NRAS mutation status. Overall, these findings provide a new molecular method to classify melanoma patients carrying BRAF and NRAS mutations and help provide a broader view of the molecular characteristics of these patients that may help understand the signaling pathways and interactions involving the altered genes.
Status of Phytotoxins Isolated from Necrotrophic Fungi Causing Diseases on Grain Legumes
Authors: Agudo-Jurado Francisco J. , Reveglia Pierluigi , Rubiales Diego , Evidente Antonio , Barilli Eleonora
Published: March 2023

Fungal phytotoxins can be defined as secondary metabolites toxic to host plants and are believed to be involved in the symptoms developed of a number of plant diseases by targeting host cellular machineries or interfering with host immune responses. As any crop, legumes can be affected by a number of fungal diseases, causing severe yield losses worldwide. In this review, we report and discuss the isolation, chemical, and biological characterization of fungal phytotoxins produced by the most important necrotrophic fungi involved in legume diseases. Their possible role in plant–pathogen interaction and structure–toxicity relationship studies have also been reported and discussed. Moreover, multidisciplinary studies on other prominent biological activity conducted on reviewed phytotoxins are described. Finally, we explore the challenges in the identification of new fungal metabolites and their possible applications in future experiments.
Molecular Imprinting of Benzylpiperazine: A Comparison of the Self-Assembly and Semi-Covalent Approaches
Authors: Wright Kathleen M. , Bowyer Michael C. , McCluskey Adam , Holdsworth Clovia I.
Published: March 2023

Molecularly imprinted polymers (MIPs) for benzylpiperazine (BZP, 1), an illicit designer drug, were developed by using both self-assembly and semi-covalent approaches. From an array of potential functional monomers (FMs) and using a combination of pre-synthetic interaction studies (by molecular modelling and NMR analysis) and binding assays, the highest performing self-assembly 1-MIPs were confirmed to result from methacrylic acid (7) as FM, ethylene glycol dimethacrylate (EGDMA) or trimethylolpropane trimethacrylate (TRIM) as crosslinkers and chloroform as the porogen and rebinding solvent at template (T): FM ratios of 1:1 and 1:2, giving imprinting factors (IF) 3 to 7. The semi-covalent 1-MIPs were designed using benzylpiperazine (4-vinylphenyl) carbamate (16) as the template–monomer adduct in combination with either EDGMA or TRIM. Our comparative analysis showed the semi-covalent polymers to have a stronger affinity for 1 (significantly lower Kd values and higher IFs) and faster uptake than the self-assembly systems. Both approaches have comparable cross-reactivity: marginal to low against cocaine (17) and morphine (18) and high against ephedrine (19) and phenylpiperazine (20). They also have comparable selectivity: highly selective towards 1 against 17, moderate against 18 and non-selective against 19. EGDMA-based self-assembly MIPs displayed a greater imprinting effect (higher IFs and NIP-to-MIP Kd ratios) than TRIM-based MIPs, while the TRIM-based semi-covalent MIP outperformed its EGDMA-based equivalent. By virtue of its modest selectivity against the test illicit drugs, 1-MIPs could potentially be used as a dummy MIP for the broad-based capture and enrichment of illicit drug blends for subsequent laboratory analysis.
Do We Preserve Tumor Control Probability (TCP) in FLASH Radiotherapy? A Model-Based Analysis
Authors: Liew Hans , Mein Stewart , Tessonnier Thomas , Abdollahi Amir , Debus Jürgen , Dokic Ivana , Mairani Andrea
Published: March 2023

Reports of concurrent sparing of normal tissue and iso-effective treatment of tumors at ultra-high dose-rates (uHDR) have fueled the growing field of FLASH radiotherapy. However, iso-effectiveness in tumors is often deduced from the absence of a significant difference in their growth kinetics. In a model-based analysis, we investigate the meaningfulness of these indications for the clinical treatment outcome. The predictions of a previously benchmarked model of uHDR sparing in the “UNIfied and VERSatile bio response Engine” (UNIVERSE) are combined with existing models of tumor volume kinetics as well as tumor control probability (TCP) and compared to experimental data. The potential TCP of FLASH radiotherapy is investigated by varying the assumed dose-rate, fractionation schemes and oxygen concentration in the target. The developed framework describes the reported tumor growth kinetics appropriately, indicating that sparing effects could be present in the tumor but might be too small to be detected with the number of animals used. The TCP predictions show the possibility of substantial loss of treatment efficacy for FLASH radiotherapy depending on several variables, including the fractionation scheme, oxygen level, and DNA repair kinetics. The possible loss of TCP should be seriously considered when assessing the clinical viability of FLASH treatments.
Towards a Better Understanding of the Complexities of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome and Long COVID
Authors: Tate Warren P. , Walker Max O. M. , Peppercorn Katie , Blair Anna L. H. , Edgar Christina D.
Published: March 2023

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex condition arising in susceptible people, predominantly following viral infection, but also other stressful events. The susceptibility factors discussed here are both genetic and environmental although not well understood. While the dysfunctional physiology in ME/CFS is becoming clearer, understanding has been hampered by different combinations of symptoms in each affected person. A common core set of mainly neurological symptoms forms the modern clinical case definition, in the absence of an accessible molecular diagnostic test. This landscape has prompted interest in whether ME/CFS patients can be classified into a particular phenotype/subtype that might assist better management of their illness and suggest preferred therapeutic options. Currently, the same promising drugs, nutraceuticals, or behavioral therapies available can be beneficial, have no effect, or be detrimental to each individual patient. We have shown that individuals with the same disease profile exhibit unique molecular changes and physiological responses to stress, exercise and even vaccination. Key features of ME/CFS discussed here are the possible mechanisms determining the shift of an immune/inflammatory response from transient to chronic in ME/CFS, and how the brain and CNS manifests the neurological symptoms, likely with activation of its specific immune system and resulting neuroinflammation. The many cases of the post viral ME/CFS-like condition, Long COVID, following SARS-CoV-2 infection, and the intense research interest and investment in understanding this condition, provide exciting opportunities for the development of new therapeutics that will benefit ME/CFS patients.
Cytogenetic Damage Induced by Radioiodine Therapy: A Follow-Up Case Study
Authors: Khvostunov Igor K. , Nasonova Elena , Krylov Valeriy , Rodichev Andrei , Kochetova Tatiana , Shepel Natalia , Korovchuk Olga , Kutsalo Polina , Shegai Petr , Kaprin Andrei
Published: March 2023

The risk of toxicity attributable to radioiodine therapy (RIT) remains a subject of ongoing research, with a whole-body dose of 2 Gy proposed as a safe limit. This article evaluates the RIT-induced cytogenetic damage in two rare differentiated thyroid cancer (DTC) cases, including the first follow-up study of a pediatric DTC patient. Chromosome damage in the patient’s peripheral blood lymphocytes (PBL) was examined using conventional metaphase assay, painting of chromosomes 2, 4, and 12 (FISH), and multiplex fluorescence in situ hybridization (mFISH). Patient 1 (female, 1.6 y.o.) received four RIT courses over 1.1 years. Patient 2 (female, 49 y.o.) received 12 courses over 6.4 years, the last two of which were examined. Blood samples were collected before and 3–4 days after the treatment. Chromosome aberrations (CA) analyzed by conventional and FISH methods were converted to a whole-body dose accounting for the dose rate effect. The mFISH method showed an increase in total aberrant cell frequency following each RIT course, while cells carrying unstable aberrations predominated in the yield. The proportion of cells containing stable CA associated with long-term cytogenetic risk remained mostly unchanged during follow-up for both patients. A one-time administration of RIT was safe, as the threshold of 2 Gy for the whole-body dose was not exceeded. The risk of side effects projected from RIT-attributable cytogenetic damage was low, suggesting a good long-term prognosis. In rare cases, such as the ones reviewed in this study, individual planning based on cytogenetic biodosimetry is strongly recommended.
Respiratory Health Effects of In Vivo Sub-Chronic Diesel and Biodiesel Exhaust Exposure
Authors: Landwehr Katherine R. , Mead-Hunter Ryan , O’Leary Rebecca A. , Kicic Anthony , Mullins Benjamin J. , Larcombe Alexander N.
Published: March 2023

Biodiesel, which can be made from a variety of natural oils, is currently promoted as a sustainable, healthier replacement for commercial mineral diesel despite little experimental data supporting this. The aim of our research was to investigate the health impacts of exposure to exhaust generated by the combustion of diesel and two different biodiesels. Male BALB/c mice (n = 24 per group) were exposed for 2 h/day for 8 days to diluted exhaust from a diesel engine running on ultra-low sulfur diesel (ULSD) or Tallow or Canola biodiesel, with room air exposures used as control. A variety of respiratory-related end-point measurements were assessed, including lung function, responsiveness to methacholine, airway inflammation and cytokine response, and airway morphometry. Exposure to Tallow biodiesel exhaust resulted in the most significant health impacts compared to Air controls, including increased airway hyperresponsiveness and airway inflammation. In contrast, exposure to Canola biodiesel exhaust resulted in fewer negative health effects. Exposure to ULSD resulted in health impacts between those of the two biodiesels. The health effects of biodiesel exhaust exposure vary depending on the feedstock used to make the fuel.
Natriuretic Peptides: It Is Time for Guided Therapeutic Strategies Based on Their Molecular Mechanisms
Authors: Gallo Giovanna , Rubattu Speranza , Autore Camillo , Volpe Massimo
Published: March 2023

Natriuretic peptides (NPs) are the principal expression products of the endocrine function of the heart. They exert several beneficial effects, mostly mediated through guanylate cyclase-A coupled receptors, including natriuresis, diuresis, vasorelaxation, blood volume and blood pressure reduction, and regulation of electrolyte homeostasis. As a result of their biological functions, NPs counterbalance neurohormonal dysregulation in heart failure and other cardiovascular diseases. NPs have been also validated as diagnostic and prognostic biomarkers in cardiovascular diseases such as atrial fibrillation, coronary artery disease, and valvular heart disease, as well as in the presence of left ventricular hypertrophy and severe cardiac remodeling. Serial measurements of their levels may be used to contribute to more accurate risk stratification by identifying patients who are more likely to experience death from cardiovascular causes, heart failure, and cardiac hospitalizations and to guide tailored pharmacological and non-pharmacological strategies with the aim to improve clinical outcomes. On these premises, multiple therapeutic strategies based on the biological properties of NPs have been attempted to develop new targeted cardiovascular therapies. Apart from the introduction of the class of angiotensin receptor/neprilysin inhibitors to the current management of heart failure, novel promising molecules including M-atrial natriuretic peptide (a novel atrial NP-based compound) have been tested for the treatment of human hypertension with promising results. Moreover, different therapeutic strategies based on the molecular mechanisms involved in NP regulation and function are under development for the management of heart failure, hypertension, and other cardiovascular conditions.
Aminooxy Click Modification of a Periodate-Oxidized Immunoglobulin G: A General Approach to Antibody–Drug Conjugates with Dye-Mediated Expeditious Stoichiometry Control
Authors: Sapozhnikova Ksenia A. , Gulyak Evgeny L. , Brylev Vladimir A. , Misyurin Vsevolod A. , Oreshkov Sergey D. , Alexeeva Anastasiya V. , Ryazantsev Dmitry Yu. , Simonova Maria A. , Ryabukhina Ekaterina V. , Popova Galina P. , Tikhonova Nataliya A. , Lyzhko Natalia A. , Barmashov Alexander E. , Misyurin Andrey V. , Ustinov Alexey V. , Alferova Vera A. , Korshun Vladimir A.
Published: March 2023

A universal approach to the construction of antibody–drug conjugates (ADCs) has been developed. It relies on periodate oxidation of naturally present glycans of immunoglobulin G, followed by oxime ligation and, optionally, copper(I)-catalyzed alkyne-azide cycloaddition for conjugation with a toxic payload. The introduction of highly absorbing cyanine dyes into the linker allows for facile determination of the drug–antibody ratio. We applied this methodology to the synthesis of cytotoxic conjugates of an antibody against the tumor-associated antigen PRAME with doxorubicin and monomethyl auristatin E (MMAE). The resultant conjugates retained their affinity to a large extent, yet their cytotoxicity in vitro varied dramatically: while the doxorubicin-based conjugate did not produce any effect on cells, the MMAE-based one demonstrated specific activity against PRAME-expressing cancer cell lines. Importantly, the latter conjugate constitutes the first reported example of a PRAME-targeting ADC.
Excess Enthalpies for Binary Mixtures of the Reactive System Acetic Acid + n-Butanol + n-Butyl Acetate + Water: Brief Data Review and Results at 313.15 K and Atmospheric Pressure
Authors: Golikova Alexandra , Shasherina Anna , Anufrikov Yuri , Misikov Georgii , Toikka Maria , Zvereva Irina , Toikka Alexander
Published: March 2023

The data on molar excess enthalpies, HmE, for the binary mixtures acetic acid + n-butanol, acetic acid + n-butyl acetate and n-butanol + n-butyl acetate at 313.15 K and atmospheric pressure were obtained with use of the C80 isothermal mixing calorimeter (Setaram). The correlation of the data was carried out using the NRTL model and Redlich–Kister equation. A comparative analysis with the literature data on all available binary subsystems of the quaternary system was carried out. Other thermodynamic properties (Cp,mE, SmE, ΔmixSm, GmE and ΔmixGm) of the binary systems were estimated using literature data and well-known formulas of classical thermodynamics.
TRIM21 Expression as a Prognostic Biomarker for Progression-Free Survival in HNSCC
Authors: von Bernuth Amelie , Ribbat-Idel Julika , Klapper Luise , Jagomast Tobias , Rades Dirk , Leichtle Anke , Pries Ralph , Bruchhage Karl-Ludwig , Perner Sven , Offermann Anne , Sailer Verena , Idel Christian
Published: March 2023

Patients with head and neck squamous cell carcinoma (HNSCC) continue to have a rather poor prognosis. Treatment-related comorbidities have negative impacts on their quality of life. TRIM21 is a cytosolic E3 ubiquitin ligase that was initially described as an autoantigen in autoimmune diseases and later associated with the intracellular antiviral response. Here, we investigated the role of TRIM21 as a biomarker candidate for HNSCC in predicting tumor progression and patient survival. We analyzed TRIM21 expression and its association with clinical-pathological parameters in our HNSCC cohort using immunohistochemistry. Our HNSCC cohort included samples from 419 patients consisting of primary tumors (n = 337), lymph node metastases (n = 156), recurrent tumors (n = 54) and distant metastases (n = 16). We found that cytoplasmic TRIM21 expression was associated with the infiltration of immune cells into primary tumors. In addition, TRIM21 expression was significantly higher in primary tumors than in lymph node metastases, and increased TRIM21 expression was correlated with shorter progression-free survival in HNSCC patients. These results suggest that TRIM21 could be a new biomarker for progression-free survival.
Prognostic Value of Monocarboxylate Transporter 1 Overexpression in Cancer: A Systematic Review
Authors: Silva Ana , Cerqueira Mónica Costa , Rosa Beatriz , Sobral Catarina , Pinto-Ribeiro Filipa , Costa Marta Freitas , Baltazar Fátima , Afonso Julieta
Published: March 2023

Energy production by cancer is driven by accelerated glycolysis, independently of oxygen levels, which results in increased lactate production. Lactate is shuttled to and from cancer cells via monocarboxylate transporters (MCTs). MCT1 works both as an importer and an extruder of lactate, being widely studied in recent years and generally associated with a cancer aggressiveness phenotype. The aim of this systematic review was to assess the prognostic value of MCT1 immunoexpression in different malignancies. Study collection was performed by searching nine different databases (PubMed, EMBASE, ScienceDirect, Scopus, Cochrane Library, Web of Science, OVID, TRIP and PsycINFO), using the keywords “cancer”, “Monocarboxylate transporter 1”, “SLC16A1” and “prognosis”. Results showed that MCT1 is an indicator of poor prognosis and decreased survival for cancer patients in sixteen types of malignancies; associations between the transporter’s overexpression and larger tumour sizes, higher disease stage/grade and metastasis occurrence were also frequently observed. Yet, MCT1 overexpression correlated with better outcomes in colorectal cancer, pancreatic ductal adenocarcinoma and non-small cell lung cancer patients. These results support the applicability of MCT1 as a biomarker of prognosis, although larger cohorts would be necessary to validate the overall role of MCT1 as an outcome predictor.
Advances and New Perspectives in Plant-Microbe Interactions
Authors: Baslam Marouane
Published: March 2023

Plants, due to their sessile nature, are constantly exposed to a myriad of microorganisms [...]
Hematological Parameters and Procalcitonin as Discriminants between Bacterial Pneumonia-Induced Sepsis and Viral Sepsis Secondary to COVID-19: A Retrospective Single-Center Analysis
Authors: Moisa Emanuel , Dutu Madalina , Corneci Dan , Grintescu Ioana Marina , Negoita Silvius
Published: March 2023

Bacterial and viral sepsis induce alterations of all hematological parameters and procalcitonin is used as a biomarker of infection and disease severity. Our aim was to study the hematological patterns associated with pulmonary sepsis triggered by bacteria and Severe Acute Respiratory Syndrome–Coronavirus–type-2 (SARS-CoV-2) and to identify the discriminants between them. We performed a retrospective, observational study including 124 patients with bacterial sepsis and 138 patients with viral sepsis. Discriminative ability of hematological parameters and procalcitonin between sepsis types was tested using receiver operating characteristic (ROC) analysis. Sensitivity (Sn%), specificity (Sp%), positive and negative likelihood ratios were calculated for the identified cut-off values. Patients with bacterial sepsis were older than patients with viral sepsis (p < 0.001), with no differences regarding gender. Subsequently to ROC analysis, procalcitonin had excellent discriminative ability for bacterial sepsis diagnosis with an area under the curve (AUC) of 0.92 (cut-off value of >1.49 ng/mL; Sn = 76.6%, Sp = 94.2%), followed by RDW% with an AUC = 0.87 (cut-off value >14.8%; Sn = 80.7%, Sp = 85.5%). Leukocytes, monocytes and neutrophils had good discriminative ability with AUCs between 0.76–0.78 (p < 0.001), while other hematological parameters had fair or no discriminative ability. Lastly, procalcitonin value was strongly correlated with disease severity in both types of sepsis (p < 0.001). Procalcitonin and RDW% had the best discriminative ability between bacterial and viral sepsis, followed by leukocytes, monocytes and neutrophils. Procalcitonin is a marker of disease severity regardless of sepsis type.
Transcriptomic Analysis of CRISPR/Cas9-Mediated PARP1-Knockout Cells under the Influence of Topotecan and TDP1 Inhibitor
Authors: Dyrkheeva Nadezhda S. , Malakhova Anastasia A. , Zakharenko Aleksandra L. , Okorokova Larisa S. , Shtokalo Dmitriy N. , Pavlova Sophia V. , Medvedev Sergey P. , Zakian Suren M. , Nushtaeva Anna A. , Tupikin Alexey E. , Kabilov Marsel R. , Khodyreva Svetlana N. , Luzina Olga A. , Salakhutdinov Nariman F. , Lavrik Olga I.
Published: March 2023

Topoisomerase 1 (TOP1) is an enzyme that regulates DNA topology and is essential for replication, recombination, and other processes. The normal TOP1 catalytic cycle involves the formation of a short-lived covalent complex with the 3′ end of DNA (TOP1 cleavage complex, TOP1cc), which can be stabilized, resulting in cell death. This fact substantiates the effectiveness of anticancer drugs—TOP1 poisons, such as topotecan, that block the relegation of DNA and fix TOP1cc. Tyrosyl-DNA phosphodiesterase 1 (TDP1) is able to eliminate TOP1cc. Thus, TDP1 interferes with the action of topotecan. Poly(ADP-ribose) polymerase 1 (PARP1) is a key regulator of many processes in the cell, such as maintaining the integrity of the genome, regulation of the cell cycle, cell death, and others. PARP1 also controls the repair of TOP1cc. We performed a transcriptomic analysis of wild type and PARP1 knockout HEK293A cells treated with topotecan and TDP1 inhibitor OL9-119 alone and in combination. The largest number of differentially expressed genes (DEGs, about 4000 both up- and down-regulated genes) was found in knockout cells. Topotecan and OL9-119 treatment elicited significantly fewer DEGs in WT cells and negligible DEGs in PARP1-KO cells. A significant part of the changes caused by PARP1-KO affected the synthesis and processing of proteins. Differences under the action of treatment with TOP1 or TDP1 inhibitors alone were found in the signaling pathways for the development of cancer, DNA repair, and the proteasome. The drug combination resulted in DEGs in the ribosome, proteasome, spliceosome, and oxidative phosphorylation pathways.
Spectroscopic Study of Five-Coordinated Thermal Treated Alumina Formation: FTIR and NMR Applying
Authors: Mashkovtsev Maxim , Tarasova Nataliia , Baksheev Evgeniy , Rychkov Vladimir , Zhuravlev Nikolai , Solodovnikova Polina , Galiaskarova Maria
Published: March 2023

This work represents research into materials designed to improve the environment. The study was carried out on aluminum hydroxide xerogels and alumina catalysts obtained by the Controlled Double Jet Precipitation (CDJP) process at different pH values. It has been shown that the pH of the CDJP process determines the content of aluminum-bound nitrate ions in the aluminum hydroxide. These ions are removed at a higher temperature than the decomposition of ammonium nitrate. The high content of aluminum-bound nitrate ions determines the structural disorder of the alumina and the high content of the penta-coordinated alumina catalyst.
Identification of the Constituents of Ethyl Acetate Fraction from Smilax china L. and Determination of Xanthine Oxidase Inhibitory Properties
Authors: Li Xin , Liu Shanshan , Jin Weili , Zhang Wenkai , Zheng Guodong
Published: March 2023

The aim of this work was to investigate the xanthine oxidase (XO)-inhibitory activity of ethanol extracts from Smilax china L. and to identify the active compounds in the ethyl acetate (EtOAc) fraction. Extraction of ethanol extracts from Smilax china L. and then ethanol extracts were concentrated, and the polyphenolic compounds were extracted with petroleum ether (PE), chloroform, EtOAc, n-butanol (n-BuOH), and residual ethanol fractions. Their effects on XO activity were then compared separately. The polyphenolic components of the EtOAc fraction were identified by HPLC and HPLC–mass spectrometry (HPLC-MS) analysis. Kinetic analysis demonstrated that all these extracts showed XO-inhibitory properties, and among them the EtOAc fraction had the strongest inhibitory effect (IC50 = 101.04 μg/mL). The inhibitory constant (Ki) of the EtOAc fraction on XO activity was 65.20 μg/mL, showing excellent inhibition on XO in the competitive mode. Sixteen compounds were identified from the EtOAc fraction. The study demonstrates that the EtOAc fraction of Smilax china L. may be a potential functional food to inhibit XO activity.
Pivotal Role of Intestinal Microbiota and Intraluminal Metabolites for the Maintenance of Gut–Bone Physiology
Authors: Grüner Niklas , Ortlepp Anna Lisa , Mattner Jochen
Published: March 2023

Intestinal microbiota, and their mutual interactions with host tissues, are pivotal for the maintenance of organ physiology. Indeed, intraluminal signals influence adjacent and even distal tissues. Consequently, disruptions in the composition or functions of microbiota and subsequent altered host–microbiota interactions disturb the homeostasis of multiple organ systems, including the bone. Thus, gut microbiota can influence bone mass and physiology, as well as postnatal skeletal evolution. Alterations in nutrient or electrolyte absorption, metabolism, or immune functions, due to the translocation of microbial antigens or metabolites across intestinal barriers, affect bone tissues, as well. Intestinal microbiota can directly and indirectly alter bone density and bone remodeling. Intestinal dysbiosis and a subsequently disturbed gut–bone axis are characteristic for patients with inflammatory bowel disease (IBD) who suffer from various intestinal symptoms and multiple bone-related complications, such as arthritis or osteoporosis. Immune cells affecting the joints are presumably even primed in the gut. Furthermore, intestinal dysbiosis impairs hormone metabolism and electrolyte balance. On the other hand, less is known about the impact of bone metabolism on gut physiology. In this review, we summarized current knowledge of gut microbiota, metabolites and microbiota-primed immune cells in IBD and bone-related complications.
Exploring the Potential of Vine Shoots as a Source of Valuable Extracts and Stable Lignin Nanoparticles for Multiple Applications
Authors: Pereira Ana Rita , Costa Carina , Mateus Nuno , de Freitas Victor , Rodrigues Alírio , Oliveira Joana
Published: March 2023

Large amounts of vine shoots are generated every year during vine pruning. This residue still presents many of the compounds found in the original plant, including low molecular weight phenolic compounds and structural compounds such as cellulose, hemicellulose, and lignin. For wine-producing regions, the challenge is to develop alternatives that will increase the value of this residue. This work proposes the full valorization of vine shoots, focusing on the extraction of lignin by mild acidolysis for the preparation of nanoparticles. The effect of the pretreatment solvents (ethanol/toluene, E/T, and water/ethanol, W/E), on the chemical and structural features of lignin, was evaluated. The chemical analysis suggests similar composition and structure regardless of the pretreatment solvent, although lignin isolated after pretreatment of biomass with E/T showed a higher content of proanthocyanidins (11%) compared with W/E (5%). Lignin nanoparticles (LNPs) presented an average size ranging from 130–200 nm and showed good stability for 30 days. Lignin and LNPs showed excellent antioxidant properties (half maximal inhibitory concentration, IC50 0.016–0.031 mg/mL) when compared to commercial antioxidants. In addition, extracts resulting from biomass pretreatment showed antioxidant activity, with W/E presenting a lower IC50 (0.170 mg/mL) than E/T (0.270 mg/mL), correlated with the higher polyphenol content of W/E, with (+)-catechin and (−)-epicatechin being the main compounds detected. Overall, this work shows that the pre-treatment of vine shoots with green solvents can yield (i) the production of high-purity lignin samples with antioxidant properties and (ii) phenolic-rich extracts, promoting the integral reuse of this byproduct and contributing to sustainability.
Integrated Analysis of DNA Methylation and Gene Expression in Porcine Placental Development
Authors: Tan Baohua , Zhou Chen , Zang Xupeng , Zhao Xinming , Xiao Liyao , Zeng Jiekang , Hong Linjun , Wu Zhenfang , Gu Ting
Published: March 2023

Proper placental development is crucial for the conceptus to grow and survive, because the placenta is responsible for transporting nutrients and oxygen from the pregnant female to the developing fetus. However, the processes of placental morphogenesis and fold formation remain to be fully elucidated. In this study, we used whole-genome bisulfite sequencing and RNA sequencing to produce a global map of DNA methylation and gene expression changes in placentas from Tibetan pig fetuses 21, 28, and 35 days post-coitus. Substantial changes in morphology and histological structures at the uterine–placental interface were revealed via hematoxylin–eosin staining. Transcriptome analysis identified 3959 differentially expressed genes (DEGs) and revealed the key transcriptional properties in three stages. The DNA methylation level in the gene promoter was negatively correlated with gene expression. We identified a set of differentially methylated regions associated with placental developmental genes and transcription factors. The decrease in DNA methylation level in the promoter was associated with the transcriptional activation of 699 DEGs that were functionally enriched in cell adhesion and migration, extracellular matrix remodeling, and angiogenesis. Our analysis provides a valuable resource for understanding the mechanisms of DNA methylation in placental development. The methylation status of different genomic regions plays a key role in establishing transcriptional patterns from placental morphogenesis to fold formation.
Quantum-Chemical Prediction of Molecular and Electronic Structure of Carbon-Nitrogen Chemical Compound with Unusual Ratio Atoms: C(N20)
Authors: Mikhailov Oleg V. , Chachkov Denis V.
Published: March 2023

Using various versions of quantum-chemical calculation, namely four versions of density functional theory (DFT), (DFT B3PW91/TZVP, DFT M06/TZVP, DFT B3PW91/Def2TZVP, and DFT M06/Def2TZVP) and two versions of the MP method (MP2/TZVP and MP3/TZVP), the existence possibility of the carbon-nitrogen-containing compound having an unusual M: nitrogen ratio of 1:20, unknown for these elements at present, was shown. Structural parameters data are presented; it was noted that, as may be expected, CN4 grouping has practically a tetrahedral structure, and the chemical bond lengths formed by nitrogen atoms and a carbon atom in the frameworks of each of the calculation methods indicated above are equal to each other. Thermodynamical parameters, NBO analysis data, and HOMO/LUMO images for this compound are also presented. A good agreement between the calculated data obtained using the above three quantum-chemical methods was noticed, too.
New Insights into the Role of Synovial Fibroblasts Leading to Joint Destruction in Rheumatoid Arthritis
Authors: Matsuda Kotaro , Shiba Naoto , Hiraoka Koji
Published: March 2023

Rheumatoid arthritis (RA), one of the most common autoimmune diseases, is characterized by multiple-joint synovitis with subsequent destruction of bone and cartilage. The excessive autoimmune responses cause an imbalance in bone metabolism, promoting bone resorption and inhibiting bone formation. Preliminary studies have revealed that receptor activator of NF-κB ligand (RANKL)-mediated osteoclast induction is an important component of bone destruction in RA. Synovial fibroblasts are the crucial producers of RANKL in the RA synovium; novel analytical techniques, primarily, single-cell RNA sequencing, have confirmed that synovial fibroblasts include heterogeneous subsets of both pro-inflammatory and tissue-destructive cell types. The heterogeneity of immune cells in the RA synovium and the interaction of synovial fibroblasts with immune cells have recently received considerable attention. The current review focused on the latest findings regarding the crosstalk between synovial fibroblasts and immune cells, and the pivotal role played by synovial fibroblasts in joint destruction in RA.
Genetic Networks of Alzheimer’s Disease, Aging, and Longevity in Humans
Authors: Balmorez Timothy , Sakazaki Amy , Murakami Shin
Published: March 2023

Human genomic analysis and genome-wide association studies (GWAS) have identified genes that are risk factors for early and late-onset Alzheimer’s disease (AD genes). Although the genetics of aging and longevity have been extensively studied, previous studies have focused on a specific set of genes that have been shown to contribute to or are a risk factor for AD. Thus, the connections among the genes involved in AD, aging, and longevity are not well understood. Here, we identified the genetic interaction networks (referred to as pathways) of aging and longevity within the context of AD by using a gene set enrichment analysis by Reactome that cross-references more than 100 bioinformatic databases to allow interpretation of the biological functions of gene sets through a wide variety of gene networks. We validated the pathways with a threshold of p-value < 1.00 × 10−5 using the databases to extract lists of 356 AD genes, 307 aging-related (AR) genes, and 357 longevity genes. There was a broad range of biological pathways involved in AR and longevity genes shared with AD genes. AR genes identified 261 pathways within the threshold of p < 1.00 × 10−5, of which 26 pathways (10% of AR gene pathways) were further identified by overlapping genes among AD and AR genes. The overlapped pathways included gene expression (p = 4.05 × 10−11) including ApoE, SOD2, TP53, and TGFB1 (p = 2.84 × 10−10); protein metabolism and SUMOylation, including E3 ligases and target proteins (p = 1.08 × 10−7); ERBB4 signal transduction (p = 2.69 × 10−6); the immune system, including IL-3 and IL-13 (p = 3.83 × 10−6); programmed cell death (p = 4.36 × 10−6); and platelet degranulation (p = 8.16 × 10−6), among others. Longevity genes identified 49 pathways within the threshold, of which 12 pathways (24% of longevity gene pathways) were further identified by overlapping genes among AD and longevity genes. They include the immune system, including IL-3 and IL-13 (p = 7.64 × 10−8), plasma lipoprotein assembly, remodeling and clearance (p < 4.02 × 10−6), and the metabolism of fat-soluble vitamins (p = 1.96 × 10−5). Thus, this study provides shared genetic hallmarks of aging, longevity, and AD backed up by statistical significance. We discuss the significant genes involved in these pathways, including TP53, FOXO, SUMOylation, IL4, IL6, APOE, and CEPT, and suggest that mapping the gene network pathways provide a useful basis for further medical research on AD and healthy aging.
Impaired Cardiovascular Parameters in Resistance Training Practitioners Who Take Ergogenic Aids
Authors: Bavaresco Gambassi Bruno , Gonçalves e Silva Daniela Conceição Gomes , Sá Camila Almeida , Bezerra Roberto Rodrigues , de Freitas Cleilson Barbosa , Costa Marcelo Silva , Marques Paulo Roberto da Silva , da Silva Pedro Paulo Ramos , Guimarães Manoel Pereira , Almeida Fabiano de Jesus Furtado , Leite Richard Diego , Sobral Filho Dário Celestino , Schwingel Paulo Adriano
Published: March 2023

Background: Although there are studies on blood pressure (BP) and autonomic cardiac control (ACC) impairments caused by ergogenic aids, research has scarcely addressed this analysis during sleep. This study analyzed BP and ACC during sleep and wake periods in three groups of resistance training (RT) practitioners: ergogenic aid non-users, thermogenic supplement (TS) self-users, and anabolic-androgenic steroid (AAS) self-users. Methods: RT practitioners were selected for the Control Group (CG; n = 15), TS self-users Group (TSG; n = 15), and AAS self-users Group (AASG; n = 15). All individuals underwent cardiovascular Holter monitoring (BP, ACC) during sleep and wake periods. Results: The maximum systolic BP (SBP) during sleep was higher in AASG (p < 0.01) than CG (p < 0.001). CG had lower mean diastolic BP (DBP) than TSG (p < 0.01) and lower mean SBP (p = 0.009) than the other groups. Additionally, CG had higher values (p < 0.01) than TSG and AASG for SDNN and pNN50 during sleep. HF, LF, and LF/HF ratio values during sleep were statistically different in CG (p < 0.001) from the other groups. Conclusions: Our findings demonstrate that high doses of TS and AAS can impair cardiovascular parameters during sleep in RT practitioners who take ergogenic aids.