bluuebunny/crossref_metadata_2025 huggingface dataset:
The Forms of the Lectin Tff2 Differ in the Murine Stomach and Pancreas: Indications for Different Molecular Functions
Authors: Znalesniak Eva B. , Laskou Aikaterini , Salm Franz , Haupenthal Katharina , Harder Sönke , Schlüter Hartmut , Hoffmann Werner
Published: April 2023

The lectin TFF2 belongs to the trefoil factor family (TFF). This polypeptide is typically co-secreted with the mucin MUC6 from gastric mucous neck cells, antral gland cells, and duodenal Brunner glands. Here, TFF2 fulfills a protective function by forming a high-molecular-mass complex with the MUC6, physically stabilizing the mucus barrier. In pigs and mice, and slightly in humans, TFF2 is also synthesized in the pancreas. Here, we investigated the murine stomach, pancreas, and duodenum by fast protein liquid chromatography (FPLC) and proteomics and identified different forms of Tff2. In both the stomach and duodenum, the predominant form is a high-molecular-mass complex with Muc6, whereas, in the pancreas, only low-molecular-mass monomeric Tff2 was detectable. We also investigated the expression of Tff2 and other selected genes in the stomach, pancreas, and the proximal, medial, and distal duodenum (RT-PCR analysis). The absence of the Tff2/Muc6 complex in the pancreas is due to a lack of Muc6. Based on its known motogenic, anti-apoptotic, and anti-inflammatory effects, we propose a protective receptor-mediated function of monomeric Tff2 for the pancreatic ductal epithelium. This view is supported by a report that a loss of Tff2 promotes the formation of pancreatic intraductal mucinous neoplasms.
Molecular Ultrasound Imaging Depicts the Modulation of Tumor Angiogenesis by Acetylsalicylic Acid
Authors: Mueller-Diesing Flurin , Lederle Wiltrud , Rix Anne , Koletnik Susanne , Doleschel Dennis , Snelting Maximilian , Gremse Felix , Kiessling Fabian
Published: April 2023

Acetylsalicylic acid (ASA) is a well-established drug for heart attack and stroke prophylaxis. Furthermore, numerous studies have reported an anti-carcinogenic effect, but its exact mechanism is still unknown. Here, we applied VEGFR-2-targeted molecular ultrasound to explore a potential inhibitory effect of ASA on tumor angiogenesis in vivo. Daily ASA or placebo therapy was performed in a 4T1 tumor mouse model. During therapy, ultrasound scans were performed using nonspecific microbubbles (CEUS) to determine the relative intratumoral blood volume (rBV) and VEGFR-2-targeted microbubbles to assess angiogenesis. Finally, vessel density and VEGFR-2 expression were assessed histologically. CEUS indicated a decreasing rBV in both groups over time. VEGFR-2 expression increased in both groups up to Day 7. Towards Day 11, the binding of VEGFR-2-specific microbubbles further increased in controls, but significantly (p = 0.0015) decreased under ASA therapy (2.24 ± 0.46 au vs. 0.54 ± 0.55 au). Immunofluorescence showed a tendency towards lower vessel density under ASA and confirmed the result of molecular ultrasound. Molecular US demonstrated an inhibitory effect of ASA on VEGFR-2 expression accompanied by a tendency towards lower vessel density. Thus, this study suggests the inhibition of angiogenesis via VEGFR-2 downregulation as one of the anti-tumor effects of ASA.
3D-Cultured Adipose-Derived Stem Cell Spheres Using Calcium-Alginate Scaffolds for Osteoarthritis Treatment in a Mono-Iodoacetate-Induced Rat Model
Authors: Lin Yu-Ying , Kuan Che-Yung , Chang Chia-Tien , Chuang Ming-Hsi , Syu Wan-Sin , Zhang Kai-Ling , Lee Chia-Hsin , Lin Po-Cheng , Dong Guo-Chung , Lin Feng-Huei
Published: April 2023

Osteoarthritis (OA) is a degenerative disease that causes pain, cartilage deformation, and joint inflammation. Mesenchymal stem cells (MSCs) are potential therapeutic agents for OA treatment. However, the 2D culture of MSCs could potentially affect their characteristics and functionality. In this study, calcium-alginate (Ca-Ag) scaffolds were prepared for human adipose-derived stem cell (hADSC) proliferation with a homemade functionally closed process bioreactor system; the feasibility of cultured hADSC spheres in heterologous stem cell therapy for OA treatment was then evaluated. hADSC spheres were collected from Ca-Ag scaffolds by removing calcium ions via ethylenediaminetetraacetic acid (EDTA) chelation. In this study, 2D-cultured individual hADSCs or hADSC spheres were evaluated for treatment efficacy in a monosodium iodoacetate (MIA)-induced OA rat model. The results of gait analysis and histological sectioning showed that hADSC spheres were more effective at relieving arthritis degeneration. The results of serological and blood element analyses of hADSC-treated rats indicated that the hADSC spheres were a safe treatment in vivo. This study demonstrates that hADSC spheres are a promising treatment for OA and can be applied to other stem cell therapies or regenerative medical treatments.
Long-Term Transcriptomic Changes and Cardiomyocyte Hyperpolyploidy after Lactose Intolerance in Neonatal Rats
Authors: Anatskaya Olga V. , Runov Andrey L. , Ponomartsev Sergey V. , Vonsky Maxim S. , Elmuratov Artem U. , Vinogradov Alexander E.
Published: April 2023

Many cardiovascular diseases originate from growth retardation, inflammation, and malnutrition during early postnatal development. The nature of this phenomenon is not completely understood. Here we aimed to verify the hypothesis that systemic inflammation triggered by neonatal lactose intolerance (NLI) may exert long-term pathologic effects on cardiac developmental programs and cardiomyocyte transcriptome regulation. Using the rat model of NLI triggered by lactase overloading with lactose and the methods of cytophotometry, image analysis, and mRNA-seq, we evaluated cardiomyocyte ploidy, signs of DNA damage, and NLI-associated long-term transcriptomic changes of genes and gene modules that differed qualitatively (i.e., were switched on or switched off) in the experiment vs. the control. Our data indicated that NLI triggers the long-term animal growth retardation, cardiomyocyte hyperpolyploidy, and extensive transcriptomic rearrangements. Many of these rearrangements are known as manifestations of heart pathologies, including DNA and telomere instability, inflammation, fibrosis, and reactivation of fetal gene program. Moreover, bioinformatic analysis identified possible causes of these pathologic traits, including the impaired signaling via thyroid hormone, calcium, and glutathione. We also found transcriptomic manifestations of increased cardiomyocyte polyploidy, such as the induction of gene modules related to open chromatin, e.g., “negative regulation of chromosome organization”, “transcription” and “ribosome biogenesis”. These findings suggest that ploidy-related epigenetic alterations acquired in the neonatal period permanently rewire gene regulatory networks and alter cardiomyocyte transcriptome. Here we provided first evidence indicating that NLI can be an important trigger of developmental programming of adult cardiovascular disease. The obtained results can help to develop preventive strategies for reducing the NLI-associated adverse effects of inflammation on the developing cardiovascular system.
The Control of the Crossover Localization in Allium
Authors: Kudryavtseva Natalia , Ermolaev Aleksey , Pivovarov Anton , Simanovsky Sergey , Odintsov Sergey , Khrustaleva Ludmila
Published: April 2023

Meiotic crossovers/chiasmata are not randomly distributed and strictly controlled. The mechanisms behind crossover (CO) patterning remain largely unknown. In Allium cepa, as in the vast majority of plants and animals, COs predominantly occur in the distal 2/3 of the chromosome arm, while in Allium fistulosum they are strictly localized in the proximal region. We investigated the factors that may contribute to the pattern of COs in A. cepa, A. fistulosum and their F1 diploid (2n = 2x = 8C + 8F) and F1 triploid (2n = 3x = 16F + 8C) hybrids. The genome structure of F1 hybrids was confirmed using genomic in situ hybridization (GISH). The analysis of bivalents in the pollen mother cells (PMCs) of the F1 triploid hybrid showed a significant shift in the localization of COs to the distal and interstitial regions. In F1 diploid hybrid, the COs localization was predominantly the same as that of the A. cepa parent. We found no differences in the assembly and disassembly of ASY1 and ZYP1 in PMCs between A. cepa and A. fistulosum, while F1 diploid hybrid showed a delay in chromosome pairing and a partial absence of synapsis in paired chromosomes. Immunolabeling of MLH1 (class I COs) and MUS81 (class II COs) proteins showed a significant difference in the class I/II CO ratio between A. fistulosum (50%:50%) and A. cepa (73%:27%). The MLH1:MUS81 ratio at the homeologous synapsis of F1 diploid hybrid (70%:30%) was the most similar to that of the A. cepa parent. F1 triploid hybrid at the A. fistulosum homologous synapsis showed a significant increase in MLH1:MUS81 ratio (60%:40%) compared to the A. fistulosum parent. The results suggest possible genetic control of CO localization. Other factors affecting the distribution of COs are discussed.
Autoreactivity against Denatured Type III Collagen Is Significantly Decreased in Serum from Patients with Cancer Compared to Healthy Controls
Authors: Jensen Christina , Drobinski Patryk , Thorlacius-Ussing Jeppe , Karsdal Morten A. , Bay-Jensen Anne-Christine , Willumsen Nicholas
Published: April 2023

Autoantibodies have the potential as cancer biomarkers as they may associate with the outcome and immune-related adverse events (irAEs) following immunotherapy. Cancer and other fibroinflammatory diseases, such as rheumatoid arthritis (RA), are associated with excessive collagen turnover leading to collagen triple helix unfolding and denaturation with exposure of immunodominant epitopes. In this study, we aimed to investigate the role of autoreactivity against denatured collagen in cancer. A technically robust assay to quantify autoantibodies against denatured type III collagen products (anti-dCol3) was developed and then measured in pretreatment serum from 223 cancer patients and 33 age-matched controls. Moreover, the association between anti-dCol3 levels and type III collagen degradation (C3M) and formation (PRO-C3) was investigated. Anti-dCol3 levels were significantly lower in patients with bladder (p = 0.0007), breast (p = 0.0002), colorectal (p < 0.0001), head and neck (p = 0.0005), kidney (p = 0.005), liver (p = 0.030), lung (p = 0.0004), melanoma (p < 0.0001), ovarian (p < 0.0001), pancreatic (p < 0.0001), prostate (p < 0.0001), and stomach cancers (p < 0.0001) compared to controls. High anti-dCol3 levels were associated with type III collagen degradation (C3M, p = 0.0002) but not type III collagen formation (PRO-C3, p = 0.26). Cancer patients with different solid tumor types have downregulated levels of circulating autoantibodies against denatured type III collagen compared to controls, suggesting that autoreactivity against unhealthy type III collagen may be important for tumor control and eradication. This autoimmunity biomarker may have the potential for studying the close relationship between autoimmunity and cancer.
Secretory and Membrane-Associated Biomarkers of Mast Cell Activation and Proliferation
Authors: Parente Roberta , Giudice Valentina , Cardamone Chiara , Serio Bianca , Selleri Carmine , Triggiani Massimo
Published: April 2023

Mast cells (MCs) are immune cells distributed in many organs and tissues and involved in the pathogenesis of allergic and inflammatory diseases as a major source of pro-inflammatory and vasoactive mediators. MC-related disorders are heterogeneous conditions characterized by the proliferation of MC within tissues and/or MC hyper-reactivity that leads to the uncontrolled release of mediators. MC disorders include mastocytosis, a clonal disease characterized by tissue MC proliferation, and MC activation syndromes that can be primary (clonal), secondary (related to allergic disorders), or idiopathic. Diagnosis of MC disorders is difficult because symptoms are transient, unpredictable, and unspecific, and because these conditions mimic many other diseases. Validation of markers of MC activation in vivo will be useful to allow faster diagnosis and better management of MC disorders. Tryptase, being the most specific MC product, is a widely used biomarker of proliferation and activation. Other mediators, such as histamine, cysteinyl leukotrienes, and prostaglandin D2, are unstable molecules and have limitations in their assays. Surface MC markers, detected by flow cytometry, are useful for the identification of neoplastic MC in mastocytosis but, so far, none of them has been validated as a biomarker of MC activation. Further studies are needed to identify useful biomarkers of MC activation in vivo.
In Vitro and In Vivo Effects of the Combination of Polypurine Reverse Hoogsteen Hairpins against HER-2 and Trastuzumab in Breast Cancer Cells
Authors: López-Aguilar Ester , Fernández-Nogueira Patricia , Fuster Gemma , Carbó Neus , Ciudad Carlos J. , Noé Véronique
Published: April 2023

Therapeutic oligonucleotides are powerful tools for the inhibition of potential targets involved in cancer. We describe the effect of two Polypurine Reverse Hoogsteen (PPRH) hairpins directed against the ERBB2 gene, which is overexpressed in positive HER-2 breast tumors. The inhibition of their target was analyzed by cell viability and at the mRNA and protein levels. The combination of these specific PPRHs with trastuzumab was also explored in breast cancer cell lines, both in vitro and in vivo. PPRHs designed against two intronic sequences of the ERBB2 gene decreased the viability of SKBR-3 and MDA-MB-453 breast cancer cells. The decrease in cell viability was associated with a reduction in ERBB2 mRNA and protein levels. In combination with trastuzumab, PPRHs showed a synergic effect in vitro and reduced tumor growth in vivo. These results represent the preclinical proof of concept of PPRHs as a therapeutic tool for breast cancer.
Can Electronegative LDL Act as a Multienzymatic Complex?
Authors: Benitez Sonia , Puig Núria , Rives José , Solé Arnau , Sánchez-Quesada José Luis
Published: April 2023

Electronegative LDL (LDL(−)) is a minor form of LDL present in blood for which proportions are increased in pathologies with increased cardiovascular risk. In vitro studies have shown that LDL(−) presents pro-atherogenic properties, including a high susceptibility to aggregation, the ability to induce inflammation and apoptosis, and increased binding to arterial proteoglycans; however, it also shows some anti-atherogenic properties, which suggest a role in controlling the atherosclerotic process. One of the distinctive features of LDL(−) is that it has enzymatic activities with the ability to degrade different lipids. For example, LDL(−) transports platelet-activating factor acetylhydrolase (PAF-AH), which degrades oxidized phospholipids. In addition, two other enzymatic activities are exhibited by LDL(−). The first is type C phospholipase activity, which degrades both lysophosphatidylcholine (LysoPLC-like activity) and sphingomyelin (SMase-like activity). The second is ceramidase activity (CDase-like). Based on the complementarity of the products and substrates of these different activities, this review speculates on the possibility that LDL(−) may act as a sort of multienzymatic complex in which these enzymatic activities exert a concerted action. We hypothesize that LysoPLC/SMase and CDase activities could be generated by conformational changes in apoB-100 and that both activities occur in proximity to PAF-AH, making it feasible to discern a coordinated action among them.
Fish Models for Exploring Mitochondrial Dysfunction Affecting Neurodegenerative Disorders
Authors: Otsuka Takayoshi , Matsui Hideaki
Published: April 2023

Neurodegenerative disorders are characterized by the progressive loss of neuronal structure or function, resulting in memory loss and movement disorders. Although the detailed pathogenic mechanism has not been elucidated, it is thought to be related to the loss of mitochondrial function in the process of aging. Animal models that mimic the pathology of a disease are essential for understanding human diseases. In recent years, small fish have become ideal vertebrate models for human disease due to their high genetic and histological homology to humans, ease of in vivo imaging, and ease of genetic manipulation. In this review, we first outline the impact of mitochondrial dysfunction on the progression of neurodegenerative diseases. Then, we highlight the advantages of small fish as model organisms, and present examples of previous studies regarding mitochondria-related neuronal disorders. Lastly, we discuss the applicability of the turquoise killifish, a unique model for aging research, as a model for neurodegenerative diseases. Small fish models are expected to advance our understanding of the mitochondrial function in vivo, the pathogenesis of neurodegenerative diseases, and be important tools for developing therapies to treat diseases.
KNOX Genes Were Involved in Regulating Axillary Bud Formation of Chrysanthemum × morifolium
Authors: Yang Qingqing , Cong Tianci , Yao Yicen , Cheng Tangren , Yuan Cunquan , Zhang Qixiang
Published: April 2023

Branching is an important agronomic and economic trait in cut chrysanthemums. The axillary meristem (AM) formation of the axillary buds of cut chrysanthemums has a decisive role in its branching characteristics. However, little is known about the regulation mechanism of axillary meristem formation in chrysanthemums at the molecular level. Members of the Homeobox gene family especially genes belonging to the class I KNOX branch play a key role in regulating the axillary bud growth and development processes of plants. In this study, three genes belonging to the class I KNOX branch, CmKNAT1, CmKNAT6, and CmSTM were cloned from chrysanthemums, and their functions in regulating axillary bud formation were examined. The subcellular localization test showed that these three KNOX genes were expressed in the nucleus, so all of them might function as transcription factors. The results of the expression profile analysis showed that these three KNOX genes were highly expressed in the AM formation stage of axillary buds. Overexpression of KNOX genes result in a wrinkled leaf phenotype in tobacco and Arabidopsis, which may be related to the excessive division of leaf cells, resulting in the proliferation of leaf tissue. Furthermore, overexpression of these three KNOX genes enhances the regeneration ability of tobacco leaves, indicating that these three KNOX genes may participate in the regulation of cell meristematic ability, thus promoting the formation of buds. In addition, the results of fluorescence quantitative testing showed that these three KNOX genes may promote the formation of chrysanthemum axillary buds by promoting the cytokinin pathway while inhibiting the auxin and gibberellin pathways. In conclusion, this study demonstrated that CmKNAT1, CmKNAT6, and CmSTM genes were involved in regulating axillary bud formation of Chrysanthemum × morifolium and preliminarily revealed the molecular mechanism of their regulation of AM formation. These findings may provide a theoretical basis and candidate gene resources for genetic engineering breeding of new varieties of cut chrysanthemums without lateral branches.
Efficacy of Essential Oils in Relieving Cancer Pain: A Systematic Review and Meta-Analysis
Authors: Corasaniti Maria Tiziana , Bagetta Giacinto , Morrone Luigi Antonio , Tonin Paolo , Hamamura Kengo , Hayashi Takafumi , Guida Francesca , Maione Sabatino , Scuteri Damiana
Published: April 2023

Over 80% of patients affected by cancer develops cancer-related pain, one of the most feared consequences because of its intractable nature, particularly in the terminal stage of the disease. Recent evidence-based recommendations on integrative medicine for the management of cancer pain underline the role of natural products. The present systematic review and meta-analysis aims at appraising for the first time the efficacy of aromatherapy in cancer pain in clinical studies with different design according to the most updated Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) 2020 recommendations. The search retrieves 1002 total records. Twelve studies are included and six are eligible for meta-analysis. The present study demonstrates significant efficacy of the use of essential oils in the reduction of the intensity of pain associated with cancer (p < 0.00001), highlighting the need for earlier, more homogeneous, and appropriately designed clinical trials. Good certainty body of evidence is needed for effective and safe management of cancer-related pain using essential oils by establishment of a step-by-step preclinical-to-clinical pathway to provide a rational basis for clinical use in integrative oncology. PROSPERO registration: CRD42023393182.
Neurotrophins: Expression of Brain–Lung Axis Development
Authors: Manti Sara , Xerra Federica , Spoto Giulia , Butera Ambra , Gitto Eloisa , Di Rosa Gabriella , Nicotera Antonio Gennaro
Published: April 2023

Neurotrophins (NTs) are a group of soluble growth factors with analogous structures and functions, identified initially as critical mediators of neuronal survival during development. Recently, the relevance of NTs has been confirmed by emerging clinical data showing that impaired NTs levels and functions are involved in the onset of neurological and pulmonary diseases. The alteration in NTs expression at the central and peripheral nervous system has been linked to neurodevelopmental disorders with an early onset and severe clinical manifestations, often named "synaptopathies" because of structural and functional synaptic plasticity abnormalities. NTs appear to be also involved in the physiology and pathophysiology of several airway diseases, neonatal lung diseases, allergic and inflammatory diseases, lung fibrosis, and even lung cancer. Moreover, they have also been detected in other peripheral tissues, including immune cells, epithelium, smooth muscle, fibroblasts, and vascular endothelium. This review aims to provide a comprehensive description of the NTs as important physiological and pathophysiological players in brain and lung development.
PARP1 Activation Induces HMGB1 Secretion Promoting Intestinal Inflammation in Mice and Human Intestinal Organoids
Authors: Vitali Roberta , Mancuso Anna Barbara , Palone Francesca , Pioli Claudio , Cesi Vincenzo , Negroni Anna , Cucchiara Salvatore , Oliva Salvatore , Carissimi Claudia , Laudadio Ilaria , Stronati Laura
Published: April 2023

Extracellular High-mobility group box 1 (HMGB1) contributes to the pathogenesis of inflammatory disorders, including inflammatory bowel diseases (IBD). Poly (ADP-ribose) polymerase 1 (PARP1) has been recently reported to promote HMGB1 acetylation and its secretion outside cells. In this study, the relationship between HMGB1 and PARP1 in controlling intestinal inflammation was explored. C57BL6/J wild type (WT) and PARP1−/− mice were treated with DSS to induce acute colitis, or with the DSS and PARP1 inhibitor, PJ34. Human intestinal organoids, which are originated from ulcerative colitis (UC) patients, were exposed to pro-inflammatory cytokines (INFγ + TNFα) to induce intestinal inflammation, or coexposed to cytokines and PJ34. Results show that PARP1−/− mice develop less severe colitis than WT mice, evidenced by a significant decrease in fecal and serum HMGB1, and, similarly, treating WT mice with PJ34 reduces the secreted HMGB1. The exposure of intestinal organoids to pro-inflammatory cytokines results in PARP1 activation and HMGB1 secretion; nevertheless, the co-exposure to PJ34, significantly reduces the release of HMGB1, improving inflammation and oxidative stress. Finally, HMGB1 release during inflammation is associated with its PARP1-induced PARylation in RAW264.7 cells. These findings offer novel evidence that PARP1 favors HMGB1 secretion in intestinal inflammation and suggest that impairing PARP1 might be a novel approach to manage IBD.
COVID-19 Biomarkers at the Crossroad between Patient Stratification and Targeted Therapy: The Role of Validated and Proposed Parameters
Authors: Rizzi Manuela , D’Onghia Davide , Tonello Stelvio , Minisini Rosalba , Colangelo Donato , Bellan Mattia , Castello Luigi Mario , Gavelli Francesco , Avanzi Gian Carlo , Pirisi Mario , Sainaghi Pier Paolo
Published: April 2023

Clinical knowledge about SARS-CoV-2 infection mechanisms and COVID-19 pathophysiology have enormously increased during the pandemic. Nevertheless, because of the great heterogeneity of disease manifestations, a precise patient stratification at admission is still difficult, thus rendering a rational allocation of limited medical resources as well as a tailored therapeutic approach challenging. To date, many hematologic biomarkers have been validated to support the early triage of SARS-CoV-2-positive patients and to monitor their disease progression. Among them, some indices have proven to be not only predictive parameters, but also direct or indirect pharmacological targets, thus allowing for a more tailored approach to single-patient symptoms, especially in those with severe progressive disease. While many blood test-derived parameters quickly entered routine clinical practice, other circulating biomarkers have been proposed by several researchers who have investigated their reliability in specific patient cohorts. Despite their usefulness in specific contexts as well as their potential interest as therapeutic targets, such experimental markers have not been implemented in routine clinical practice, mainly due to their higher costs and low availability in general hospital settings. This narrative review will present an overview of the most commonly adopted biomarkers in clinical practice and of the most promising ones emerging from specific population studies. Considering that each of the validated markers reflects a specific aspect of COVID-19 evolution, embedding new highly informative markers into routine clinical testing could help not only in early patient stratification, but also in guiding a timely and tailored method of therapeutic intervention.
Membrane Lesions and Reduced Life Span of Red Blood Cells in Preeclampsia as Evidenced by Atomic Force Microscopy
Authors: Giosheva Ina , Strijkova Velichka , Komsa-Penkova Regina , Krumova Sashka , Langari Ariana , Danailova Avgustina , Taneva Stefka G. , Stoyanova Tanya , Topalova Lora , Gartchev Emil , Georgieva Galya , Todinova Svetla
Published: April 2023

Preeclampsia (PE) presents with maternal de novo hypertension and significant proteinuria and is one of the leading causes of maternal and perinatal morbidity and mortality with unknown etiology. The disease is associated with inflammatory vascular response and severe red blood cell (RBC) morphology changes. This study examined the nanoscopic morphological changes of RBCs from PE women versus normotensive healthy pregnant controls (PCs) and non-pregnant controls (NPCs) applying atomic force microscopy (AFM) imaging. The results revealed that the membrane of fresh PE RBCs differed significantly from healthy ones by the presence of invaginations and protrusions and an increased roughness value (Rrms) (4.7 ± 0.8 nm for PE vs. 3.8 ± 0.5 nm and 2.9 ± 0.4 nm for PCs and NPCs, respectively). PE-cells aging resulted in more pronounced protrusions and concavities, with exponentially increasing Rrms values, in contrast to the controls, where the Rrms parameter decreased linearly with time. The Rrms, evaluated on a 2 × 2 µm2 scanned area, for senescent PE cells (13 ± 2.0 nm) was significantly higher (p < 0.01) than that of PCs (1.5 ± 0.2 nm) and NPCs (1.9 ± 0.2 nm). Furthermore, the RBCs from PE patients appeared fragile, and often only ghosts were observed instead of intact cells at 20–30 days of aging. Oxidative-stress simulation on healthy cells led to RBC membrane features similar to those observed for PE cells. The results demonstrate that the most pronounced effects on RBCs in PE patients are related to impaired membrane homogeneity and strongly altered roughness values, as well as to vesiculation and ghost formation in the course of cell aging.
Genome-Wide Analysis of the SNARE Family in Cultivated Peanut (Arachis hypogaea L.) Reveals That Some Members Are Involved in Stress Responses
Authors: Lu Chaoxia , Peng Zhenying , Liu Yiyang , Li Guowei , Wan Shubo
Published: April 2023

The superfamily of soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins mediates membrane fusion during vesicular transport between endosomes and the plasma membrane in eukaryotic cells, playing a vital role in plant development and responses to biotic and abiotic stresses. Peanut (Arachis hypogaea L.) is a major oilseed crop worldwide that produces pods below ground, which is rare in flowering plants. To date, however, there has been no systematic study of SNARE family proteins in peanut. In this study, we identified 129 putative SNARE genes from cultivated peanut (A. hypogaea) and 127 from wild peanut (63 from Arachis duranensis, 64 from Arachis ipaensis). We sorted the encoded proteins into five subgroups (Qa-, Qb-, Qc-, Qb+c- and R-SNARE) based on their phylogenetic relationships with Arabidopsis SNAREs. The genes were unevenly distributed on all 20 chromosomes, exhibiting a high rate of homolog retention from their two ancestors. We identified cis-acting elements associated with development, biotic and abiotic stresses in the promoters of peanut SNARE genes. Transcriptomic data showed that expression of SNARE genes is tissue-specific and stress inducible. We hypothesize that AhVTI13b plays an important role in the storage of lipid proteins, while AhSYP122a, AhSNAP33a and AhVAMP721a might play an important role in development and stress responses. Furthermore, we showed that three AhSNARE genes (AhSYP122a, AhSNAP33a and AhVAMP721) enhance cold and NaCl tolerance in yeast (Saccharomyces cerevisiae), especially AhSNAP33a. This systematic study provides valuable information about the functional characteristics of AhSNARE genes in the development and regulation of abiotic stress responses in peanut.
The Duration of Oxygen and Glucose Deprivation (OGD) Determines the Effects of Subsequent Reperfusion on Rat Pheochromocytoma (PC12) Cells and Primary Cortical Neurons
Authors: Singh Ayesha , Chen Ruoli
Published: April 2023

Reperfusion is the fundamental treatment for ischaemic stroke; however, many ischaemic stroke patients cannot undergo reperfusion treatment. Furthermore, reperfusion can cause ischaemic reperfusion injuries. This study aimed to determine the effects of reperfusion in an in vitro ischaemic stroke model—oxygen and glucose deprivation (OGD) (0.3% O2)—with rat pheochromocytoma (PC12) cells and cortical neurons. In PC12 cells, OGD resulted in a time-dependent increase in cytotoxicity and apoptosis, and reduction in MTT activity from 2 h onwards. Reperfusion following shorter periods (4 and 6 h) of OGD recovered apoptotic PC12 cells, whereas after 12 h, OGD increased LDH release. In primary neurons, 6 h OGD led to significant increase in cytotoxicity, reduction in MTT activity and dendritic MAP2 staining. Reperfusion following 6 h OGD increased the cytotoxicity. HIF-1a was stabilised by 4 and 6 h OGD in PC12 cells and 2 h OGD onwards in primary neurons. A panel of hypoxic genes were upregulated by the OGD treatments depending on the duration. In conclusion, the duration of OGD determines the mitochondrial activity, cell viability, HIF-1a stabilization, and hypoxic gene expression in both cell types. Reperfusion following OGD of short duration is neuroprotective, whereas OGD of long duration is cytotoxic.
The Role of Neurons in Human Health and Disease
Authors: Akay Yasemin M.
Published: April 2023

Neurons are the functional units of the nervous system [...]
Deficiency of AP1 Complex Ap1g1 in Zebrafish Model Led to Perturbation of Neurodevelopment, Female and Male Fertility; New Insight to Understand Adaptinopathies
Authors: Mignani Luca , Facchinello Nicola , Varinelli Marco , Massardi Elena , Tiso Natascia , Ravelli Cosetta , Mitola Stefania , Schu Peter , Monti Eugenio , Finazzi Dario , Borsani Giuseppe , Zizioli Daniela
Published: April 2023

In vertebrates, two homologous heterotetrameric AP1 complexes regulate the intracellular protein sorting via vesicles. AP-1 complexes are ubiquitously expressed and are composed of four different subunits: γ, β1, μ1 and σ1. Two different complexes are present in eukaryotic cells, AP1G1 (contains γ1 subunit) and AP1G2 (contains γ2 subunit); both are indispensable for development. One additional tissue-specific isoform exists for μ1A, the polarized epithelial cells specific to μ1B; two additional tissue-specific isoforms exist for σ1A: σ1B and σ1C. Both AP1 complexes fulfil specific functions at the trans-Golgi network and endosomes. The use of different animal models demonstrated their crucial role in the development of multicellular organisms and the specification of neuronal and epithelial cells. Ap1g1 (γ1) knockout mice cease development at the blastocyst stage, while Ap1m1 (μ1A) knockouts cease during mid-organogenesis. A growing number of human diseases have been associated with mutations in genes encoding for the subunits of adaptor protein complexes. Recently, a new class of neurocutaneous and neurometabolic disorders affecting intracellular vesicular traffic have been referred to as adaptinopathies. To better understand the functional role of AP1G1 in adaptinopathies, we generated a zebrafish ap1g1 knockout using CRISPR/Cas9 genome editing. Zebrafish ap1g1 knockout embryos cease their development at the blastula stage. Interestingly, heterozygous females and males have reduced fertility and showed morphological alterations in the brain, gonads and intestinal epithelium. An analysis of mRNA profiles of different marker proteins and altered tissue morphologies revealed dysregulated cadherin-mediated cell adhesion. These data demonstrate that the zebrafish model organism enables us to study the molecular details of adaptinopathies and thus also develop treatment strategies.
Gamma-Hemolysin Components: Computational Strategies for LukF-Hlg2 Dimer Reconstruction on a Model Membrane
Authors: Paternoster Costanza , Tarenzi Thomas , Potestio Raffaello , Lattanzi Gianluca
Published: April 2023

The gamma-hemolysin protein is one of the most common pore-forming toxins expressed by the pathogenic bacterium Staphylococcus aureus. The toxin is used by the pathogen to escape the immune system of the host organism, by assembling into octameric transmembrane pores on the surface of the target immune cell and leading to its death by leakage or apoptosis. Despite the high potential risks associated with Staphylococcus aureus infections and the urgent need for new treatments, several aspects of the pore-formation process from gamma-hemolysin are still unclear. These include the identification of the interactions between the individual monomers that lead to the formation of a dimer on the cell membrane, which represents the unit for further oligomerization. Here, we employed a combination of all-atom explicit solvent molecular dynamics simulations and protein–protein docking to determine the stabilizing contacts that guide the formation of a functional dimer. The simulations and the molecular modeling reveal the importance of the flexibility of specific protein domains, in particular the N-terminus, to drive the formation of the correct dimerization interface through functional contacts between the monomers. The results obtained are compared with the experimental data available in the literature.
SM22α Deletion Contributes to Neurocognitive Impairment in Mice through Modulating Vascular Smooth Muscle Cell Phenotypes
Authors: Xu Xin , Liu Xiao-Qin , Liu Xin-Long , Wang Xu , Zhang Wen-Di , Huang Xiao-Fu , Jia Fang-Yue , Kong Peng , Han Mei
Published: April 2023

Considerable evidence now indicates that cognitive impairment is primarily a vascular disorder. The depletion of smooth muscle 22 alpha (SM22α) contributes to vascular smooth muscle cells (VSMCs) switching from contractile to synthetic and proinflammatory phenotypes in the context of inflammation. However, the role of VSMCs in the pathogenesis of cognitive impairment remains undetermined. Herein, we showed a possible link between VSMC phenotypic switching and neurodegenerative diseases via the integration of multi-omics data. SM22α knockout (Sm22α−/−) mice exhibited obvious cognitive impairment and cerebral pathological changes, which were visibly ameliorated by the administration of AAV-SM22α. Finally, we confirmed that SM22α disruption promotes the expression of SRY-related HMG-box gene 10 (Sox10) in VSMCs, thereby aggravating the systemic vascular inflammatory response and ultimately leading to cognitive impairment in the brain. Therefore, this study supports the idea of VSMCs and SM22α as promising therapeutic targets in cognitive impairment to improve memory and cognitive decline.
Severe Trauma-Induced Coagulopathy: Molecular Mechanisms Underlying Critical Illness
Authors: Zanza Christian , Romenskaya Tatsiana , Racca Fabrizio , Rocca Eduardo , Piccolella Fabio , Piccioni Andrea , Saviano Angela , Formenti-Ujlaki George , Savioli Gabriele , Franceschi Francesco , Longhitano Yaroslava
Published: April 2023

Trauma remains one of the leading causes of death in adults despite the implementation of preventive measures and innovations in trauma systems. The etiology of coagulopathy in trauma patients is multifactorial and related to the kind of injury and nature of resuscitation. Trauma-induced coagulopathy (TIC) is a biochemical response involving dysregulated coagulation, altered fibrinolysis, systemic endothelial dysfunction, platelet dysfunction, and inflammatory responses due to trauma. The aim of this review is to report the pathophysiology, early diagnosis and treatment of TIC. A literature search was performed using different databases to identify relevant studies in indexed scientific journals. We reviewed the main pathophysiological mechanisms involved in the early development of TIC. Diagnostic methods have also been reported which allow early targeted therapy with pharmaceutical hemostatic agents such as TEG-based goal-directed resuscitation and fibrinolysis management. TIC is a result of a complex interaction between different pathophysiological processes. New evidence in the field of trauma immunology can, in part, help explain the intricacy of the processes that occur after trauma. However, although our knowledge of TIC has grown, improving outcomes for trauma patients, many questions still need to be answered by ongoing studies.
Revealing the Meissner Corpuscles in Human Glabrous Skin Using In Vivo Non-Invasive Imaging Techniques
Authors: Infante Victor Hugo Pacagnelli , Bennewitz Roland , Klein Anna Lena , Meinke Martina C.
Published: April 2023

The presence of mechanoreceptors in glabrous skin allows humans to discriminate textures by touch. The amount and distribution of these receptors defines our tactile sensitivity and can be affected by diseases such as diabetes, HIV-related pathologies, and hereditary neuropathies. The quantification of mechanoreceptors as clinical markers by biopsy is an invasive method of diagnosis. We report the localization and quantification of Meissner corpuscles in glabrous skin using in vivo, non-invasive optical microscopy techniques. Our approach is supported by the discovery of epidermal protrusions which are co-localized with Meissner corpuscles. Index fingers, small fingers, and tenar palm regions of ten participants were imaged by optical coherence tomography (OCT) and laser scan microscopy (LSM) to determine the thickness of the stratum corneum and epidermis and to count the Meissner corpuscles. We discovered that regions containing Meissner corpuscles could be easily identified by LSM with an enhanced optical reflectance above the corpuscles, caused by a protrusion of the strongly reflecting epidermis into the stratum corneum with its weak reflectance. We suggest that this local morphology above Meissner corpuscles has a function in tactile perception.
From Transgenesis to Genome Editing in Crop Improvement: Applications, Marketing, and Legal Issues
Authors: Marone Daniela , Mastrangelo Anna Maria , Borrelli Grazia Maria
Published: April 2023

The biotechnological approaches of transgenesis and the more recent eco-friendly new breeding techniques (NBTs), in particular, genome editing, offer useful strategies for genetic improvement of crops, and therefore, recently, they have been receiving increasingly more attention. The number of traits improved through transgenesis and genome editing technologies is growing, ranging from resistance to herbicides and insects to traits capable of coping with human population growth and climate change, such as nutritional quality or resistance to climatic stress and diseases. Research on both technologies has reached an advanced stage of development and, for many biotech crops, phenotypic evaluations in the open field are already underway. In addition, many approvals regarding main crops have been granted. Over time, there has been an increase in the areas cultivated with crops that have been improved through both approaches, but their use in various countries has been limited by legislative restrictions according to the different regulations applied which affect their cultivation, marketing, and use in human and animal nutrition. In the absence of specific legislation, there is an on-going public debate with favorable and unfavorable positions. This review offers an updated and in-depth discussion on these issues.
Reduction in CgA-Derived CST Protein Level in HTR-8/SVneo and BeWo Trophoblastic Cell Lines Caused by the Preeclamptic Environment
Authors: Bralewska Michalina , Pietrucha Tadeusz , Sakowicz Agata
Published: April 2023

One of the most dangerous complications of pregnancy is preeclampsia (PE), a disease associated with a high risk of maternal and fetal mortality and morbidity. Although its etiology remains unknown, the placenta is believed to be at the center of ongoing changes. One of the hormones produced by the placenta is chromogranin A (CgA). Thus far, its role in pregnancy and pregnancy-related disorders is enigmatic, yet it is known that both CgA and its derived peptide catestatin (CST) are involved in the majority of the processes that are disturbed in PE, such as blood pressure regulation or apoptosis. Therefore, in this study, the influence of the preeclamptic environment on the production of CgA using two cell lines, HTR-8/SVneo and BeWo, was investigated. Furthermore, the capacity of trophoblastic cells to secrete CST to the environment was tested, as well as the correlation between CST and apoptosis. This study provided the first evidence that CgA and CST proteins are produced by trophoblastic cell lines and that the PE environment has an impact on CST protein production. Furthermore, a strong negative correlation between CST protein level and apoptosis induction was found. Hence, both CgA and its derived peptide CST may play roles in the complex process of PE pathogenesis.
Unpacking the Complexities of a Silent Killer
Authors: Yamanouchi Dai
Published: April 2023

An abdominal aortic aneurysm (AAA) is a life-threatening condition that affects millions of people worldwide [...]
Ce–Metal–Organic Framework-Derived CeO2–GO: An Efficient Electrocatalyst for Oxygen Evolution Reaction
Authors: Nagajyothi Patnamsetty Chidanandha , Pavani Krishnapuram , Ramaraghavulu Rajavaram , Shim Jaesool
Published: April 2023

The oxygen evolution reaction (OER) is a crucial half-reaction in water splitting. However, this reaction is kinetically sluggish owing to the four-electron (4 e−) transfer process. Therefore, the development of low-cost, stable, highly efficient, and earth-abundant electrocatalysts for the OER is highly desirable. Metal oxides derived from metal–organic frameworks (MOFs) are among the most efficient electrocatalysts for the OER. Herein, Ce–MOF-derived CeO2/graphene oxide (GO) composites were successfully prepared using a facile method. The composites with 0, 25, 50, and 100 mg GO were named CeO2, CeO2–GO-1, CeO2–GO-2, and CeO2–GO-3, respectively. The physicochemical characteristics of the electrocatalysts were assessed using several analytical techniques, including X-ray diffraction (XRD), scanning electron microscopy (SEM), high-resolution transmission electron microscopy (HR-TEM), X-ray photoelectron spectroscopy (XPS), and Brunauer–Emmett–Teller (BET) analysis. The TEM results revealed that the CeO2 had a sheet-like morphology and that a GO layer was noticeable in the synthesized CeO2–GO-3 composite. The characterization results confirmed the formation of impurity-free CeO2–GO composites. The OER activity and stability were measured using cyclic voltammetry (CV), linear sweep voltammetry (LSV), chronoamperometry (CA), and electrochemical impedance spectroscopy (EIS). The CeO2–GO-3 electrocatalyst has a smaller Tafel slope (176 mV·dec−1) and lower overpotential (240 mV) than the other electrocatalysts. In addition, it exhibited high cyclic stability for up to 10 h. Therefore, the inexpensive CeO2–GO-3 electrocatalyst is a promising OER candidate.
Keggin Heteropolyacid Salt Catalysts in Oxidation Reactions: A Review
Authors: da Silva Marcio Jose , Rodrigues Alana Alves , Lopes Neide Paloma Gonçalves
Published: April 2023

Keggin heteropolyacids (HPAs) are metal–oxygen clusters with strong Bronsted acidity. The conversion of HPAs to metal salts can result in Lewis acidity, improving their performance in oxidation reactions. In this review, the main routes for the synthesis of Keggin-type heteropolyacids salts, as well their use as catalysts in oxidation processes of a plethora of substrates, such as monoterpenes, olefins, aldehydes, terpene alcohols, and aromatics, are described. Green reactants such as hydrogen peroxide and molecular oxygen are used as oxidants. These reactions are of interest to several industries because they can be used to produce drugs, additives, fragrances, and fine chemicals. The high efficiency of Keggin HPA with green oxidants contributes to a reduction in the environmental impact of these processes, as preconize the principles of green chemistry. Moreover, Keggin HPAs can be converted to bifunctional catalysts by the modification of their structure, total or partial replacement of their protons with Lewis acid metal cations, or the introduction of these cations into the Keggin anion structure, replacing the addenda atoms (i.e., W and Mo). Aspects linked to the synthesis and characterization of these catalysts are discussed herein, with emphasis on infrared spectroscopy and powder XRD patterns. The most recent advances achieved in the development of catalytic oxidation systems based on Keggin HPA salts are also addressed.