12 pages, 1685 KB  
Article
Use of 3D Spheroid Models for the Assessment of RT Response in Head and Neck Cancer
by Marilyn Wegge 1, Rüveyda Dok 1, Ludwig J. Dubois 2 and Sandra Nuyts 1,3,*
1 Laboratory of Experimental Radiotherapy, Department of Oncology, KU Leuven, University of Leuven, 3000 Leuven, Belgium
2 The M-Lab, Department of Precision Medicine, GROW-School for Oncology and Reproduction, Maastricht University, 6229 ER Maastricht, The Netherlands
3 Department of Radiation Oncology, Leuven Cancer Institute, UZ Leuven, 3000 Leuven, Belgium
Int. J. Mol. Sci. 2023, 24(4), 3763; https://doi.org/10.3390/ijms24043763 - 13 Feb 2023
Cited by 15 | Viewed by 4232
Abstract
Radiotherapy (RT) is a key player in the treatment of head and neck cancer (HNC). The RT response, however, is variable and influenced by multiple tumoral and tumor microenvironmental factors, such as human papillomavirus (HPV) infections and hypoxia. To investigate the biological mechanisms [...] Read more.
Radiotherapy (RT) is a key player in the treatment of head and neck cancer (HNC). The RT response, however, is variable and influenced by multiple tumoral and tumor microenvironmental factors, such as human papillomavirus (HPV) infections and hypoxia. To investigate the biological mechanisms behind these variable responses, preclinical models are crucial. Up till now, 2D clonogenic and in vivo assays have remained the gold standard, although the popularity of 3D models is rising. In this study, we investigate the use of 3D spheroid models as a preclinical tool for radiobiological research by comparing the RT response of two HPV-positive and two HPV-negative HNC spheroid models to the RT response of their corresponding 2D and in vivo models. We demonstrate that HPV-positive spheroids keep their higher intrinsic radiosensitivity when compared to HPV-negative spheroids. A good correlation is found in the RT response between HPV-positive SCC154 and HPV-negative CAL27 spheroids and their respective xenografts. In addition, 3D spheroids are able to capture the heterogeneity of RT responses within HPV-positive and HPV-negative models. Moreover, we demonstrate the potential use of 3D spheroids in the study of the mechanisms underlying these RT responses in a spatial manner by whole-mount Ki-67 and pimonidazole staining. Overall, our results show that 3D spheroids are a promising model to assess the RT response in HNC. Full article
(This article belongs to the Special Issue Advances in Molecular Mechanism of Head and Neck Cancer)
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4 pages, 205 KB  
Editorial
Molecular Mechanisms of Hepatotoxicity
by Antonietta Messina * and Jean-Charles Duclos-Vallée *
UMR_S 1193, INSERM/Université Paris-Saclay, Fédération Hospitalo-Universitaire (FHU) Hépatinov, F-94807 Villejuif, France
Int. J. Mol. Sci. 2023, 24(4), 3791; https://doi.org/10.3390/ijms24043791 - 14 Feb 2023
Cited by 6 | Viewed by 4227
Abstract
Drug-induced liver injury, also known as drug-induced hepatotoxicity (DILI), is a major cause of medicine withdrawal (prescription or over-the-counter) from the market [...] Full article
(This article belongs to the Special Issue Molecular Mechanisms of Hepatotoxicity)
14 pages, 3695 KB  
Article
Development of a Propidium Monoazide-Based Viability Quantitative PCR Assay for Red Sea Bream Iridovirus Detection
by Kyung-Ho Kim, Gyoungsik Kang, Won-Sik Woo, Min-Young Sohn, Ha-Jeong Son and Chan-Il Park *
Department of Marine Biology and Aquaculture, College of Marine Science, Gyeongsang National University, 2, Tongyeonghaean-ro, Tongyeong 53064, Republic of Korea
Int. J. Mol. Sci. 2023, 24(4), 3426; https://doi.org/10.3390/ijms24043426 - 8 Feb 2023
Cited by 10 | Viewed by 4226
Abstract
Red sea bream iridovirus (RSIV) is an important aquatic virus that causes high mortality in marine fish. RSIV infection mainly spreads through horizontal transmission via seawater, and its early detection could help prevent disease outbreaks. Although quantitative PCR (qPCR) is a sensitive and [...] Read more.
Red sea bream iridovirus (RSIV) is an important aquatic virus that causes high mortality in marine fish. RSIV infection mainly spreads through horizontal transmission via seawater, and its early detection could help prevent disease outbreaks. Although quantitative PCR (qPCR) is a sensitive and rapid method for detecting RSIV, it cannot differentiate between infectious and inactive viruses. Here, we aimed to develop a viability qPCR assay based on propidium monoazide (PMAxx), which is a photoactive dye that penetrates damaged viral particles and binds to viral DNA to prevent qPCR amplification, to distinguish between infectious and inactive viruses effectively. Our results demonstrated that PMAxx at 75 μM effectively inhibited the amplification of heat-inactivated RSIV in viability qPCR, allowing the discrimination of inactive and infectious RSIV. Furthermore, the PMAxx-based viability qPCR assay selectively detected the infectious RSIV in seawater more efficiently than the conventional qPCR and cell culture methods. The reported viability qPCR method will help prevent the overestimation of red sea bream iridoviral disease caused by RSIV. Furthermore, this non-invasive method will aid in establishing a disease prediction system and in epidemiological analysis using seawater. Full article
(This article belongs to the Special Issue Recent Advances of Biochemistry and Molecular Biology of Infectious Diseases)
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20 pages, 4523 KB  
Article
Ephedra foeminea as a Novel Source of Antimicrobial and Anti-Biofilm Compounds to Fight Multidrug Resistance Phenotype
by Shurooq Ismail 1,2, Rosa Gaglione 1,3, Marco Masi 1, Srichandan Padhi 4, Amit K. Rai 4, Ghadeer Omar 2, Alessio Cimmino 1,* and Angela Arciello 1,3,*
1 Department of Chemical Sciences, University of Naples Federico II, Via Cintia 21, I-80126 Naples, Italy
2 Department of Biology and Biotechnology, An-Najah National University, Nablus 97300, Palestine
3 Istituto Nazionale di Biostrutture e Biosistemi (INBB), 00136 Rome, Italy
4 Institute of Bioresources and Sustainable Development, Imphal, Manipur 795004, India
Int. J. Mol. Sci. 2023, 24(4), 3284; https://doi.org/10.3390/ijms24043284 - 7 Feb 2023
Cited by 8 | Viewed by 4224
Abstract
Plants are considered a wealthy resource of novel natural drugs effective in the treatment of multidrug-resistant infections. Here, a bioguided purification of Ephedra foeminea extracts was performed to identify bioactive compounds. The determination of antimicrobial properties was achieved by broth microdilution assays to [...] Read more.
Plants are considered a wealthy resource of novel natural drugs effective in the treatment of multidrug-resistant infections. Here, a bioguided purification of Ephedra foeminea extracts was performed to identify bioactive compounds. The determination of antimicrobial properties was achieved by broth microdilution assays to evaluate minimal inhibitory concentration (MIC) values and by crystal violet staining and confocal laser scanning microscopy analyses (CLSM) to investigate the antibiofilm capacity of the isolated compounds. Assays were performed on a panel of three gram-positive and three gram-negative bacterial strains. Six compounds were isolated from E. foeminea extracts for the first time. They were identified by nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS) analyses as the well-known monoterpenoid phenols carvacrol and thymol and as four acylated kaempferol glycosides. Among them, the compound kaempferol-3-O-α-L-(2″,4″-di-E-p-coumaroyl)-rhamnopyranoside was found to be endowed with strong antibacterial properties and significant antibiofilm activity against S. aureus bacterial strains. Moreover, molecular docking studies on this compound suggested that the antibacterial activity of the tested ligand against S. aureus strains might be correlated to the inhibition of Sortase A and/or of tyrosyl tRNA synthase. Collectively, the results achieved open interesting perspectives to kaempferol-3-O-α-L-(2″,4″-di-E-p-coumaroyl)-rhamnopyranoside applicability in different fields, such as biomedical applications and biotechnological purposes such as food preservation and active packaging. Full article
(This article belongs to the Special Issue Advances in Antimicrobial and Macromolecules Materials)
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14 pages, 8033 KB  
Article
Specific Forms of Graphene Quantum Dots Induce Apoptosis and Cell Cycle Arrest in Breast Cancer Cells
by Tien-Hsiung Ku 1,2,3,†, Wen-Ting Shen 4, Chien-Te Hsieh 5, Grace Shiahuy Chen 3,* and Wei-Chung Shia 4,*,†
1 Department of Anesthesiology, Changhua Christian Hospital, Changhua 50050, Taiwan
2 Artificial Intelligence Development Center, Changhua Christian Hospital, Changhua 50050, Taiwan
3 Department of Applied Chemistry, Providence University, Taichung 43301, Taiwan
4 Molecular Medicine Laboratory, Department of Research, Changhua Christian Hospital, Changhua 50050, Taiwan
5 Department of Chemical Engineering and Materials Science, Yuan Ze University, Taoyuan 32003, Taiwan
† These authors contributed equally to this work.
Int. J. Mol. Sci. 2023, 24(4), 4046; https://doi.org/10.3390/ijms24044046 - 17 Feb 2023
Cited by 37 | Viewed by 4219
Abstract
Graphene quantum dots (GQDs), nanomaterials derived from graphene and carbon dots, are highly stable, soluble, and have exceptional optical properties. Further, they have low toxicity and are excellent vehicles for carrying drugs or fluorescein dyes. Specific forms of GQDs can induce apoptosis and [...] Read more.
Graphene quantum dots (GQDs), nanomaterials derived from graphene and carbon dots, are highly stable, soluble, and have exceptional optical properties. Further, they have low toxicity and are excellent vehicles for carrying drugs or fluorescein dyes. Specific forms of GQDs can induce apoptosis and could be used to treat cancers. In this study, three forms of GQDs (GQD (nitrogen:carbon = 1:3), ortho-GQD, and meta-GQD) were screened and tested for their potential to inhibit breast cancer cell (MCF-7, BT-474, MDA-MB-231, and T-47D) growth. All three GQDs decreased cell viability after 72 h of treatment and specifically affected breast cancer cell proliferation. An assay for the expression of apoptotic proteins revealed that p21 and p27 were up-regulated (1.41-fold and 4.75-fold) after treatment. In particular, ortho-GQD-treated cells showed G2/M phase arrest. The GQDs specifically induced apoptosis in estrogen receptor-positive breast cancer cell lines. These results indicate that these GQDs induce apoptosis and G2/M cell cycle arrest in specific breast cancer subtypes and could potentially be used for treating breast cancers. Full article
(This article belongs to the Special Issue Theranostic Ultrasound Contrast Agents in Medical Applications)
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15 pages, 1507 KB  
Article
Molecular Signature of Biological Aggressiveness in Clear Cell Sarcoma of the Kidney (CCSK)
by Michele Fiore 1,†, Alberto Taddia 2,†, Valentina Indio 3, Salvatore Nicola Bertuccio 2, Daria Messelodi 2, Salvatore Serravalle 4, Jessica Bandini 4, Filippo Spreafico 5, Daniela Perotti 6, Paola Collini 7, Andrea Di Cataldo 8, Gianandrea Pasquinelli 2, Francesca Chiarini 9, Maura Fois 4, Fraia Melchionda 4,*, Andrea Pession 2,10,‡ and Annalisa Astolfi 2,*,‡
1 Orthopaedics and Traumatology Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
2 Department of Medical and Surgical Sciences, DIMEC, University of Bologna, 40138 Bologna, Italy
3 Department of Veterinary Medical Sciences, University of Bologna, Ozzano dell’Emilia, 40064 Bologna, Italy
4 Pediatric Oncology and Hematology “Lalla Seràgnoli”, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
5 Pediatric Oncology Unit, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy
6 Molecular Bases of Genetic Risk and Genetic Testing Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy
7 Soft Tissue Tumor Pathology Unit, Advanced Diagnostics Department, Fondazione IRCCS Istituto Nazionale Dei Tumori, 20133 Milan, Italy
8 Department of Clinical and Experimental Medicine, Unit of Pediatric Hematology and Oncology, University of Catania, 95124 Catania, Italy
9 Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy
10 Division of Pediatrics, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
† These authors contributed equally to this work.
‡ These authors contributed equally to this work.
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Int. J. Mol. Sci. 2023, 24(4), 3743; https://doi.org/10.3390/ijms24043743 - 13 Feb 2023
Cited by 10 | Viewed by 4209
Abstract
Clear cell sarcoma of the kidney (CCSK) is a rare pediatric renal tumor with a worse prognosis than Wilms’ tumor. Although recently, BCOR internal tandem duplication (ITD) has been found as a driver mutation in more than 80% of cases, a deep molecular [...] Read more.
Clear cell sarcoma of the kidney (CCSK) is a rare pediatric renal tumor with a worse prognosis than Wilms’ tumor. Although recently, BCOR internal tandem duplication (ITD) has been found as a driver mutation in more than 80% of cases, a deep molecular characterization of this tumor is still lacking, as well as its correlation with the clinical course. The aim of this study was to investigate the differential molecular signature between metastatic and localized BCOR-ITD-positive CCSK at diagnosis. Whole-exome sequencing (WES) and whole-transcriptome sequencing (WTS) were performed on six localized and three metastatic BCOR-ITD-positive CCSKs, confirming that this tumor carries a low mutational burden. No significant recurrences of somatic or germline mutations other than BCOR-ITD were identified among the evaluated samples. Supervised analysis of gene expression data showed enrichment of hundreds of genes, with a significant overrepresentation of the MAPK signaling pathway in metastatic cases (p < 0.0001). Within the molecular signature of metastatic CCSK, five genes were highly and significantly over-expressed: FGF3, VEGFA, SPP1, ADM, and JUND. The role of FGF3 in the acquisition of a more aggressive phenotype was investigated in a cell model system obtained by introducing the ITD into the last exon of BCOR by Crispr/Cas9 gene editing of the HEK-293 cell line. Treatment with FGF3 of BCOR-ITD HEK-293 cell line induced a significant increase in cell migration versus both untreated and scramble cell clone. The identification of over-expressed genes in metastatic CCSKs, with a particular focus on FGF3, could offer new prognostic and therapeutic targets in more aggressive cases. Full article
(This article belongs to the Special Issue Molecular Research on Rare Cancers and Metabolic Diseases)
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22 pages, 4600 KB  
Article
Cell Uptake of Steroid-BODIPY Conjugates and Their Internalization Mechanisms: Cancer Theranostic Dyes
by Ana F. Amendoeira 1,2,†, André Luz 1,2,†, Ruben Valente 1,2, Catarina Roma-Rodrigues 1,2, Hasrat Ali 3, Johan E. van Lier 3, Fernanda Marques 4, Pedro V. Baptista 1,2,* and Alexandra R. Fernandes 1,2,*
1 Associate Laboratory i4HB, Institute for Health and Bioeconomy, NOVA School of Science and Technology, 2819-516 Caparica, Portugal
2 UCIBIO—Applied Molecular Biosciences Unit, Department of Life Sciences, NOVA School of Science and Technology, 2819-516 Caparica, Portugal
3 Department of Nuclear Medicine and Radiobiology, Faculty of Medicine and Health Sciences, University of Sherbrooke, Sherbrooke, QC J1H5N4, Canada
4 Centro de Ciências e Tecnologias Nucleares, Departamento de Engenharia e Ciências Nucleares, Instituto Superior Técnico, Universidade de Lisboa, Estrada Nacional 10, km 139.7, 2695-066 Bobadela, Portugal
† These authors contributed equally to this work.
Int. J. Mol. Sci. 2023, 24(4), 3600; https://doi.org/10.3390/ijms24043600 - 10 Feb 2023
Cited by 6 | Viewed by 4209
Abstract
Estradiol-BODIPY linked via an 8-carbon spacer chain and 19-nortestosterone- and testosterone-BODIPY linked via an ethynyl spacer group were evaluated for cell uptake in the breast cancer cell lines MCF-7 and MDA-MB-231 and prostate cancer cell lines PC-3 and LNCaP, as well as in [...] Read more.
Estradiol-BODIPY linked via an 8-carbon spacer chain and 19-nortestosterone- and testosterone-BODIPY linked via an ethynyl spacer group were evaluated for cell uptake in the breast cancer cell lines MCF-7 and MDA-MB-231 and prostate cancer cell lines PC-3 and LNCaP, as well as in normal dermal fibroblasts, using fluorescence microscopy. The highest level of internalization was observed with 11β-OMe-estradiol-BODIPY 2 and 7α-Me-19-nortestosterone-BODIPY 4 towards cells expressing their specific receptors. Blocking experiments showed changes in non-specific cell uptake in the cancer and normal cells, which likely reflect differences in the lipophilicity of the conjugates. The internalization of the conjugates was shown to be an energy-dependent process that is likely mediated by clathrin- and caveolae-endocytosis. Studies using 2D co-cultures of cancer cells and normal fibroblasts showed that the conjugates are more selective towards cancer cells. Cell viability assays showed that the conjugates are non-toxic for cancer and/or normal cells. Visible light irradiation of cells incubated with estradiol-BODIPYs 1 and 2 and 7α-Me-19-nortestosterone-BODIPY 4 induced cell death, suggesting their potential for use as PDT agents. Full article
(This article belongs to the Special Issue Hormone Receptors and Signaling in Breast Cancer)
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23 pages, 8278 KB  
Article
Extracellular Vesicle Treatment Alleviates Neurodevelopmental and Neurodegenerative Pathology in Cortical Spheroid Model of Down Syndrome
by Natalie Baker Campbell 1, Yesha Patel 2, Tara L. Moore 1,3, Maria Medalla 1,3 and Ella Zeldich 1,3,*
1 Department of Anatomy & Neurobiology, Boston University Chobanian & Avedesian School of Medicine, Boston University, Boston, MA 02118, USA
2 Commonwealth Honors College, University of Massachusetts Amherst, Amherst, MA 01003, USA
3 Center for Systems Neuroscience, Boston University, Boston, MA 02115, USA
Int. J. Mol. Sci. 2023, 24(4), 3477; https://doi.org/10.3390/ijms24043477 - 9 Feb 2023
Cited by 6 | Viewed by 4209
Abstract
Down syndrome (DS), or trisomy 21, is manifested in a variety of anatomical and cellular abnormalities resulting in intellectual deficits and early onset of Alzheimer’s disease (AD) with no effective treatments available to alleviate the pathologies associated with the disorder. The therapeutic potential [...] Read more.
Down syndrome (DS), or trisomy 21, is manifested in a variety of anatomical and cellular abnormalities resulting in intellectual deficits and early onset of Alzheimer’s disease (AD) with no effective treatments available to alleviate the pathologies associated with the disorder. The therapeutic potential of extracellular vesicles (EVs) has emerged recently in relation to various neurological conditions. We have previously demonstrated the therapeutic efficacy of mesenchymal stromal cell-derived EVs (MSC-EVs) in cellular and functional recovery in a rhesus monkey model of cortical injury. In the current study, we evaluated the therapeutic effect of MSC-EVs in a cortical spheroid (CS) model of DS generated from patient-derived induced pluripotent stem cells (iPSCs). Compared to euploid controls, trisomic CS display smaller size, deficient neurogenesis, and AD-related pathological features, such as enhanced cell death and depositions of amyloid beta (Aβ) and hyperphosphorylated tau (p-tau). EV-treated trisomic CS demonstrated preserved size, partial rescue in the production of neurons, significantly decreased levels of Aβ and p-tau, and a reduction in the extent of cell death as compared to the untreated trisomic CS. Together, these results show the efficacy of EVs in mitigating DS and AD-related cellular phenotypes and pathological depositions in human CS. Full article
(This article belongs to the Special Issue Therapeutic Mechanisms of Stem Cells and Exosomes for Geriatric Disease)
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12 pages, 3363 KB  
Article
Studies on the Oxidation of Aromatic Amines Catalyzed by Trametes versicolor Laccase
by Ivan Bassanini 1,*, Simone Grosso 1, Chiara Tognoli 1,2, Giovanni Fronza 3 and Sergio Riva 1,*
1 Istituto di Scienze e Tecnologie Chimiche-SCITEC, Consiglio Nazionale delle Ricerche, Via Mario Bianco 9, 20131 Milan, Italy
2 Dipartimento di Scienze Farmaceutiche, Università degli Studi di Milano, Via Mangiagalli 25, 20133 Milan, Italy
3 Istituto di Scienze e Tecnologie Chimiche-SCITEC, Consiglio Nazionale delle Ricerche, Via Luigi Mancinelli 7, 20131 Milan, Italy
Int. J. Mol. Sci. 2023, 24(4), 3524; https://doi.org/10.3390/ijms24043524 - 9 Feb 2023
Cited by 8 | Viewed by 4204
Abstract
The bio-oxidation of a series of aromatic amines catalyzed by T. versicolor laccase has been investigated exploiting either commercially available nitrogenous substrates [(E)-4-vinyl aniline and diphenyl amine] or ad hoc synthetized ones [(E)-4-styrylaniline, (E)-4-(prop-1-en-1-yl)aniline and (E [...] Read more.
The bio-oxidation of a series of aromatic amines catalyzed by T. versicolor laccase has been investigated exploiting either commercially available nitrogenous substrates [(E)-4-vinyl aniline and diphenyl amine] or ad hoc synthetized ones [(E)-4-styrylaniline, (E)-4-(prop-1-en-1-yl)aniline and (E)-4-(((4-methoxyphenyl)imino)methyl)phenol]. At variance to their phenolic equivalents, the investigated aromatic amines were not converted into the expected cyclic dimeric structures under T. versicolor catalysis. The formation of complex oligomeric/polymeric or decomposition by-products was mainly observed, with the exception of the isolation of two interesting but unexpected chemical skeletons. Specifically, the biooxidation of diphenylamine resulted in an oxygenated quinone-like product, while, to our surprise, in the presence of T. versicolor laccase (E)-4-vinyl aniline was converted into a 1,2-substited cyclobutane ring. To the best of our knowledge, this is the first example of an enzymatically triggered [2 + 2] olefin cycloaddition. Possible reaction mechanisms to explain the formation of these products are also reported. Full article
(This article belongs to the Special Issue Biotechnological Applications of Oxidoreductases)
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14 pages, 10532 KB  
Article
Head and Neck Cancer Patients’ Survival According to HPV Status, miRNA Profiling, and Tumour Features—A Cohort Study
by Ivana Šimić 1, Ksenija Božinović 2, Nina Milutin Gašperov 1, Mario Kordić 3,4, Ena Pešut 1, Luka Manojlović 5, Magdalena Grce 1, Emil Dediol 3,* and Ivan Sabol 1,*
1 Laboratory for Molecular Virology and Bacteriology, Ruđer Bošković Institute, 10000 Zagreb, Croatia
2 Laboratory for Cell Biology and Signalling, Ruđer Bošković Institute, 10000 Zagreb, Croatia
3 Department of Maxillofacial Surgery, Clinical Hospital Dubrava, 10000 Zagreb, Croatia
4 Department of Maxillofacial Surgery, Clinical Hospital Mostar, 88000 Mostar, Bosnia and Herzegovina
5 Clinical Department of Pathology and Cytology, Clinical Hospital Dubrava, 10000 Zagreb, Croatia
Int. J. Mol. Sci. 2023, 24(4), 3344; https://doi.org/10.3390/ijms24043344 - 7 Feb 2023
Cited by 14 | Viewed by 4204
Abstract
Head and neck cancers (HNC) are a heterogeneous group of tumours mainly associated with tobacco and alcohol use and human papillomavirus (HPV). Over 90% of all HNC are squamous cell carcinomas (HNSCC). Sample material from patients diagnosed with primary HNSCC (n = [...] Read more.
Head and neck cancers (HNC) are a heterogeneous group of tumours mainly associated with tobacco and alcohol use and human papillomavirus (HPV). Over 90% of all HNC are squamous cell carcinomas (HNSCC). Sample material from patients diagnosed with primary HNSCC (n = 76) treated with surgery as primary treatment at a single centre were assessed for HPV genotype, miR-9-5p, miR-21-3p, miR-29a-3p and miR-100-5p expression levels. Clinical and pathological data were collected from medical records. Patients were enrolled between 2015 and 2019 and followed-up until November 2022. Overall survival, disease-specific survival and disease-free survival were assessed and correlated with clinical, pathological, and molecular data. Kaplan-Meier and Cox proportional hazard regression was used to assess different risk factors. In the study, male gender, HPV-negative HNSCC (76.3%) mostly located in the oral region (78.9%) predominated. Most patients had stage IV cancer (47.4%), and the overall survival rate was 50%. HPV was found not to affect survival, indicating that in this population, classic risk factors predominate. The presence of both perineural and angioinvasion was strongly associated with survival in all analyses. Of all miRNAs assessed, only upregulation of miR-21 was consistently shown to be an independent predictor of poor prognosis and may thus serve as a prognostic biomarker in HNSCC. Full article
(This article belongs to the Special Issue Human Papillomavirus and Head and Neck Cancer - Molecular Research)
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27 pages, 8818 KB  
Article
Genistein and Procyanidin B2 Reduce Carcinogen-Induced Reactive Oxygen Species and DNA Damage through the Activation of Nrf2/ARE Cell Signaling in Bronchial Epithelial Cells In Vitro
by Tharindu L. Suraweera 1, J. P. Jose Merlin 1, Graham Dellaire 2, Zhaolin Xu 2,3 and H. P. Vasantha Rupasinghe 1,2,*
1 Department of Plant, Food, and Environmental Sciences, Faculty of Agriculture, Dalhousie University, Truro, NS B2N 2R8, Canada
2 Department of Pathology, Faculty of Medicine, Dalhousie University, Halifax, NS B3H 4H7, Canada
3 QEII Health Sciences Centre, Division of Anatomical Pathology and Cytopathology, Nova Scotia Health Authority, Halifax, NS B3H 1V8, Canada
Int. J. Mol. Sci. 2023, 24(4), 3676; https://doi.org/10.3390/ijms24043676 - 12 Feb 2023
Cited by 31 | Viewed by 4202
Abstract
Cancer is one of the leading causes of death worldwide. Chemotherapy and radiation therapy are currently providing the basis for cancer therapies, although both are associated with significant side effects. Thus, cancer prevention through dietary modifications has been receiving growing interest. The potential [...] Read more.
Cancer is one of the leading causes of death worldwide. Chemotherapy and radiation therapy are currently providing the basis for cancer therapies, although both are associated with significant side effects. Thus, cancer prevention through dietary modifications has been receiving growing interest. The potential of selected flavonoids in reducing carcinogen-induced reactive oxygen species (ROS) and DNA damage through the activation of nuclear factor erythroid 2 p45 (NF-E2)-related factor (Nrf2)/antioxidant response element (ARE) pathway was studied in vitro. Dose-dependent effects of pre-incubated flavonoids on pro-carcinogen 4-[(acetoxymethyl)nitrosamino]-1-(3-pyridyl)-1-butanone (NNKAc)-induced ROS and DNA damage in human bronchial epithelial cells were studied in comparison to non-flavonoids. The most effective flavonoids were assessed for the activation of Nrf2/ARE pathway. Genistein, procyanidin B2 (PCB2), and quercetin significantly suppressed the NNKAc-induced ROS and DNA damage. Quercetin significantly upregulated the phosphorylated protein kinase B/Akt. PCB2 significantly upregulated the activation of Nrf2 and Akt through phosphorylation. Genistein and PCB2 significantly upregulated the phospho-Nrf2 nuclear translocation and catalase activity. In summary, genistein and PCB2 reduced the NNKAc-induced ROS and DNA damage through the activation of Nrf2. Further studies are required to understand the role of dietary flavonoids on the regulation of the Nrf2/ARE pathway in relation to carcinogenesis. Full article
(This article belongs to the Special Issue Cancer Targeted Small Molecules)
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27 pages, 908 KB  
Review
Matrix Metalloproteinases in Cardioembolic Stroke: From Background to Complications
by Anna Wysocka 1,*, Jacek Szczygielski 2,3, Marta Kopańska 4, Joachim M. Oertel 3 and Andrzej Głowniak 5
1 Department of Internal Medicine and Internal Nursing, Faculty of Health Sciences, Medical University of Lublin, 20-093 Lublin, Poland
2 Department of Neurosurgery, Institute of Medical Sciences, University of Rzeszów, 35-310 Rzeszów, Poland
3 Department of Neurosurgery, Saarland University Medical Center, Saarland University Faculty of Medicine, 66421 Homburg, Saar, Germany
4 Department of Physiology, Institute of Medical Sciences, University of Rzeszów, 35-310 Rzeszów, Poland
5 Department of Cardiology, Medical University of Lublin, 20-954 Lublin, Poland
Int. J. Mol. Sci. 2023, 24(4), 3628; https://doi.org/10.3390/ijms24043628 - 11 Feb 2023
Cited by 16 | Viewed by 4201
Abstract
Matrix metalloproteinases (MMPs) are endopeptidases participating in physiological processes of the brain, maintaining the blood–brain barrier integrity and playing a critical role in cerebral ischemia. In the acute phase of stroke activity, the expression of MMPs increase and is associated with adverse effects, [...] Read more.
Matrix metalloproteinases (MMPs) are endopeptidases participating in physiological processes of the brain, maintaining the blood–brain barrier integrity and playing a critical role in cerebral ischemia. In the acute phase of stroke activity, the expression of MMPs increase and is associated with adverse effects, but in the post-stroke phase, MMPs contribute to the process of healing by remodeling tissue lesions. The imbalance between MMPs and their inhibitors results in excessive fibrosis associated with the enhanced risk of atrial fibrillation (AF), which is the main cause of cardioembolic strokes. MMPs activity disturbances were observed in the development of hypertension, diabetes, heart failure and vascular disease enclosed in CHA2DS2VASc score, the scale commonly used to evaluate the risk of thromboembolic complications risk in AF patients. MMPs involved in hemorrhagic complications of stroke and activated by reperfusion therapy may also worsen the stroke outcome. In the present review, we briefly summarize the role of MMPs in the ischemic stroke with particular consideration of the cardioembolic stroke and its complications. Moreover, we discuss the genetic background, regulation pathways, clinical risk factors and impact of MMPs on the clinical outcome. Full article
(This article belongs to the Special Issue Advances in Molecular Mechanisms of Stroke)
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19 pages, 4540 KB  
Article
Melatonin Alleviates Chromium Toxicity in Maize by Modulation of Cell Wall Polysaccharides Biosynthesis, Glutathione Metabolism, and Antioxidant Capacity
by Xiaoxiao Yang 1, Jianhong Ren 2, Xinyue Lin 1, Zhenping Yang 3, Xiping Deng 1,4,5,* and Qingbo Ke 1,4,5,*
1 College of Life Sciences, Northwest A&F University, Yangling 712100, China
2 College of Life Sciences, Shanxi Agricultural University, Taigu 030800, China
3 College of Agronomy, Shanxi Agricultural University, Taigu 030800, China
4 State Key Laboratory of Soil Erosion and Dryland Farming on the Loess Plateau, Institute of Soil and Water Conservation, Northwest A&F University, Yangling 712100, China
5 Institute of Soil and Water Conservation, Chinese Academy of Sciences and Ministry of Water Resources, Yangling 712100, China
Int. J. Mol. Sci. 2023, 24(4), 3816; https://doi.org/10.3390/ijms24043816 - 14 Feb 2023
Cited by 43 | Viewed by 4200
Abstract
Melatonin, a pleiotropic regulatory molecule, is involved in the defense against heavy metal stress. Here, we used a combined transcriptomic and physiological approach to investigate the underlying mechanism of melatonin in mitigating chromium (Cr) toxicity in Zea mays L. Maize plants were treated [...] Read more.
Melatonin, a pleiotropic regulatory molecule, is involved in the defense against heavy metal stress. Here, we used a combined transcriptomic and physiological approach to investigate the underlying mechanism of melatonin in mitigating chromium (Cr) toxicity in Zea mays L. Maize plants were treated with either melatonin (10, 25, 50 and 100 μM) or water and exposed to 100 μM K2Cr2O7 for seven days. We showed that melatonin treatment significantly decreased the Cr content in leaves. However, the Cr content in the roots was not affected by melatonin. Analyses of RNA sequencing, enzyme activities, and metabolite contents showed that melatonin affected cell wall polysaccharide biosynthesis, glutathione (GSH) metabolism, and redox homeostasis. During Cr stress, melatonin treatment increased cell wall polysaccharide contents, thereby retaining more Cr in the cell wall. Meanwhile, melatonin improved the GSH and phytochelatin contents to chelate Cr, and the chelated complexes were then transported to the vacuoles for sequestration. Furthermore, melatonin mitigated Cr-induced oxidative stress by enhancing the capacity of enzymatic and non-enzymatic antioxidants. Moreover, melatonin biosynthesis-defective mutants exhibited decreased Cr stress resistance, which was related to lower pectin, hemicellulose 1, and hemicellulose 2 than wild-type plants. These results suggest that melatonin alleviates Cr toxicity in maize by promoting Cr sequestration, re-establishing redox homeostasis, and inhibiting Cr transport from the root to the shoot. Full article
(This article belongs to the Special Issue The Role of Melatonin in Plants 2.0)
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Graphical abstract

14 pages, 2128 KB  
Communication
Effects of Usnic Acid to Prevent Infections by Creating a Protective Barrier in an In Vitro Study
by Rebecca Galla 1,2,†, Sara Ferrari 1,†, Sara Ruga 1, Beatrice Mantuano 1, Giorgia Rosso 1, Stelvio Tonello 3, Luigi Rosa 4, Piera Valenti 4 and Francesca Uberti 1,2,*
1 Laboratory of Physiology, Department of Translational Medicine, University of Piemonte Orientale, Via Solaroli 17, 28100 Novara, Italy
2 Noivita Srls, Spin-Off UPO, Via Alfieri 3, 28100 Novara, Italy
3 Laboratory of Immuno Rheumatology-Internal Medicine, Department of Translational Medicine, CAAD Center for Allergic and Autoimmune Disease, Via Solaroli 17, 28100 Novara, Italy
4 Department of Public Health and Infectious Diseases, University of Rome La Sapienza, Piazzale Aldo Moro, 5, 00185 Rome, Italy
† These authors contributed equally to this work.
Int. J. Mol. Sci. 2023, 24(4), 3695; https://doi.org/10.3390/ijms24043695 - 12 Feb 2023
Cited by 4 | Viewed by 4199
Abstract
Nasal sprays are medical devices useful for preventing infection and the subsequent spread of airborne pathogens. The effectiveness of these devices depends on the activity of chosen compounds which can create a physical barrier against viral uptake as well as incorporate different substances [...] Read more.
Nasal sprays are medical devices useful for preventing infection and the subsequent spread of airborne pathogens. The effectiveness of these devices depends on the activity of chosen compounds which can create a physical barrier against viral uptake as well as incorporate different substances with antiviral activity. Among antiviral compounds, UA, a dibenzofuran derived from lichens, has the mechanical ability to modify its structure by creating a branch capable of forming a protective barrier. The mechanical ability of UA to protect cells from virus infection was investigated by analyzing the branching capacity of UA, and then the protection mechanism in an in vitro model was also studied. As expected, UA at 37 °C was able to create a barrier confirming its ramification property. At the same time, UA was able to block the infection of Vero E6 and HNEpC cells by interfering with a biological interaction between cells and viruses as revealed also by the UA quantification. Therefore, UA can block virus activity through a mechanical barrier effect without altering the physiological nasal homeostasis. The findings of this research could be of great relevance in view of the growing alarm regarding the spread of airborne viral diseases. Full article
(This article belongs to the Collection State-of-the-Art Bioactives and Nutraceuticals in Italy)
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18 pages, 3635 KB  
Article
Converging Role for REEP1/SPG31 in Oxidative Stress
by Valentina Naef 1, Maria C. Meschini 1, Alessandra Tessa 1, Federica Morani 2, Debora Corsinovi 2,3, Asahi Ogi 1, Maria Marchese 1, Michela Ori 2, Filippo M. Santorelli 1 and Stefano Doccini 1,*
1 Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Stella Maris Foundation, 56128 Pisa, Italy
2 Department of Biology, University of Pisa, 56126 Pisa, Italy
3 Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy
Int. J. Mol. Sci. 2023, 24(4), 3527; https://doi.org/10.3390/ijms24043527 - 9 Feb 2023
Cited by 7 | Viewed by 4197
Abstract
Mutations in the receptor expression-enhancing protein 1 gene (REEP1) are associated with hereditary spastic paraplegia type 31 (SPG31), a neurological disorder characterized by length-dependent degeneration of upper motor neuron axons. Mitochondrial dysfunctions have been observed in patients harboring pathogenic variants in REEP1, [...] Read more.
Mutations in the receptor expression-enhancing protein 1 gene (REEP1) are associated with hereditary spastic paraplegia type 31 (SPG31), a neurological disorder characterized by length-dependent degeneration of upper motor neuron axons. Mitochondrial dysfunctions have been observed in patients harboring pathogenic variants in REEP1, suggesting a key role of bioenergetics in disease-related manifestations. Nevertheless, the regulation of mitochondrial function in SPG31 remains unclear. To elucidate the pathophysiology underlying REEP1 deficiency, we analyzed in vitro the impact of two different mutations on mitochondrial metabolism. Together with mitochondrial morphology abnormalities, loss-of-REEP1 expression highlighted a reduced ATP production with increased susceptibility to oxidative stress. Furthermore, to translate these findings from in vitro to preclinical models, we knocked down REEP1 in zebrafish. Zebrafish larvae showed a significant defect in motor axon outgrowth leading to motor impairment, mitochondrial dysfunction, and reactive oxygen species accumulation. Protective antioxidant agents such as resveratrol rescued free radical overproduction and ameliorated the SPG31 phenotype both in vitro and in vivo. Together, our findings offer new opportunities to counteract neurodegeneration in SPG31. Full article
(This article belongs to the Special Issue Mitochondrial Dysfunction: A Metabolic, Cardiovascular, Neurodegenerative and Neuromuscular Issue)
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