20 pages, 2889 KiB  
Article
Microglia Impairs Proliferation and Induces Senescence In-Vitro in NGF Releasing Cells Used in Encapsulated Cell Biodelivery for Alzheimer’s Disease Therapy
by Sumonto Mitra 1,*, Ruchi Gera 1, Julia Sundheimer 1, Marine Lemee 1, Lars U. Wahlberg 2, Bengt Linderoth 3, Maria Eriksdotter 1,4,† and Homira Behbahani 1,*,†
1 Division of Clinical Geriatrics, Center for Alzheimer Research, Department of NVS, Karolinska Institutet, 141 52 Huddinge, Sweden
2 Gloriana Therapeutics, Inc., Providence, RI 02885, USA
3 Department of Clinical Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden
4 Theme Inflammation and Aging, Karolinska University Hospital, 141 86 Huddinge, Sweden
These authors supervised equally to this work.
Int. J. Mol. Sci. 2022, 23(16), 9011; https://doi.org/10.3390/ijms23169011 - 12 Aug 2022
Cited by 5 | Viewed by 3283
Abstract
There is no cure yet available for Alzheimer’s disease (AD). We recently optimized encapsulated cell biodelivery (ECB) devices releasing human mature nerve growth factor (hmNGF), termed ECB-NGF, to the basal forebrain of AD patients. The ECB-NGF delivery resulted in increased CSF cholinergic markers, [...] Read more.
There is no cure yet available for Alzheimer’s disease (AD). We recently optimized encapsulated cell biodelivery (ECB) devices releasing human mature nerve growth factor (hmNGF), termed ECB-NGF, to the basal forebrain of AD patients. The ECB-NGF delivery resulted in increased CSF cholinergic markers, improved glucose metabolism, and positive effects on cognition in AD patients. However, some ECB-NGF implants showed altered hmNGF release post-explantation. To optimize the ECB-NGF platform for future therapeutic purposes, we initiated in-vitro optimization studies by exposing ECB-NGF devices to physiological factors present within the AD brain. We report here that microglia cells can impair hmNGF release from ECB-NGF devices in-vitro, which can be reversed by transferring the devices to fresh culture medium. Further, we exposed the hmNGF secreting human ARPE-19 cell line (NGC0211) to microglia (HMC3) conditioned medium (MCM; untreated or treated with IL-1β/IFNγ/Aβ40/Aβ42), and evaluated biochemical stress markers (ROS, GSH, ΔΨm, and Alamar Blue assay), cell death indicators (Annexin-V/PI), cell proliferation (CFSE retention and Ki67) and senescence markers (SA-β-gal) in NGC0211 cells. MCMs from activated microglia reduced cell proliferation and induced cell senescence in NGC0211 cells, which otherwise resist biochemical alterations and cell death. These data indicate a critical but reversible impact of activated microglia on NGC0211 cells. Full article
(This article belongs to the Special Issue Advances in Neurodegenerative Diseases Research and Therapy)
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31 pages, 10813 KiB  
Review
Comparison of the Behavior of Perivascular Cells (Pericytes and CD34+ Stromal Cell/Telocytes) in Sprouting and Intussusceptive Angiogenesis
by Lucio Díaz-Flores 1,*, Ricardo Gutiérrez 1, Maria Pino García 2, Miriam González-Gómez 1,3, Lucio Díaz-Flores, Jr. 1, Jose Luis Carrasco 1, Juan Francisco Madrid 4 and Aixa Rodríguez Bello 5
1 Department of Basic Medical Sciences, Faculty of Medicine, University of La Laguna, 38071 Tenerife, Spain
2 Department of Pathology, Eurofins Megalab–Hospiten Hospitals, 38100 Tenerife, Spain
3 Instituto de Tecnologías Biomédicas de Canarias, University of La Laguna, 38071 Tenerife, Spain
4 Department of Cell Biology and Histology, School of Medicine, Campus of International Excellence “Campus Mare Nostrum”, IMIB-Arrixaca, University of Murcia, 30120 Murcia, Spain
5 Department of Bioquímica, Microbiología, Biología Celular y Genética, University of La Laguna, 38071 Tenerife, Spain
Int. J. Mol. Sci. 2022, 23(16), 9010; https://doi.org/10.3390/ijms23169010 - 12 Aug 2022
Cited by 18 | Viewed by 3640
Abstract
Perivascular cells in the pericytic microvasculature, pericytes and CD34+ stromal cells/telocytes (CD34+SCs/TCs), have an important role in angiogenesis. We compare the behavior of these cells depending on whether the growth of endothelial cells (ECs) from the pre-existing microvasculature is toward the interstitium with [...] Read more.
Perivascular cells in the pericytic microvasculature, pericytes and CD34+ stromal cells/telocytes (CD34+SCs/TCs), have an important role in angiogenesis. We compare the behavior of these cells depending on whether the growth of endothelial cells (ECs) from the pre-existing microvasculature is toward the interstitium with vascular bud and neovessel formation (sprouting angiogenesis) or toward the vascular lumen with intravascular pillar development and vessel division (intussusceptive angiogenesis). Detachment from the vascular wall, mobilization, proliferation, recruitment, and differentiation of pericytes and CD34+SCs/TCs, as well as associated changes in vessel permeability and functionality, and modifications of the extracellular matrix are more intense, longer lasting over time, and with a greater energy cost in sprouting angiogenesis than in intussusceptive angiogenesis, in which some of the aforementioned events do not occur or are compensated for by others (e.g., sparse EC and pericyte proliferation by cell elongation and thinning). The governing mechanisms involve cell–cell contacts (e.g., peg-and-socket junctions between pericytes and ECs), multiple autocrine and paracrine signaling molecules and pathways (e.g., vascular endothelial growth factor, platelet-derived growth factor, angiopoietins, transforming growth factor B, ephrins, semaphorins, and metalloproteinases), and other factors (e.g., hypoxia, vascular patency, and blood flow). Pericytes participate in vessel development, stabilization, maturation and regression in sprouting angiogenesis, and in interstitial tissue structure formation of the pillar core in intussusceptive angiogenesis. In sprouting angiogenesis, proliferating perivascular CD34+SCs/TCs are an important source of stromal cells during repair through granulation tissue formation and of cancer-associated fibroblasts (CAFs) in tumors. Conversely, CD34+SCs/TCs have less participation as precursor cells in intussusceptive angiogenesis. The dysfunction of these mechanisms is involved in several diseases, including neoplasms, with therapeutic implications. Full article
(This article belongs to the Special Issue Molecular Morphology and Function of Stromal Cells 2.0)
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16 pages, 2796 KiB  
Article
Glycosylphosphatidylinositol Mannosyltransferase Ⅰ Protects Chinese Giant Salamander, Andrias davidianus, against Iridovirus
by Jingjing Zhang 1,2, Yanlin Dai 1,2, Yuding Fan 1, Nan Jiang 1, Yong Zhou 1, Lingbing Zeng 1,2,* and Yiqun Li 1,*
1 Yangtze River Fisheries Research Institute, Chinese Academy of Fishery Sciences, Wuhan 430223, China
2 National Demonstration Center for Experimental Fisheries Science Education, Shanghai Ocean University, Shanghai 201306, China
Int. J. Mol. Sci. 2022, 23(16), 9009; https://doi.org/10.3390/ijms23169009 - 12 Aug 2022
Cited by 3 | Viewed by 1887
Abstract
Glycosylphosphatidylinositol mannosyltransferase I (GPI-MT-I) is an essential glycosyltransferase of glycosylphosphatidylinositol-anchor proteins (GPI-APs) that transfers the first of the four mannoses in GPI-AP precursors, which have multiple functions, including immune response and signal transduction. In this study, the GPI-MT-I gene that regulates GPI-AP biosynthesis [...] Read more.
Glycosylphosphatidylinositol mannosyltransferase I (GPI-MT-I) is an essential glycosyltransferase of glycosylphosphatidylinositol-anchor proteins (GPI-APs) that transfers the first of the four mannoses in GPI-AP precursors, which have multiple functions, including immune response and signal transduction. In this study, the GPI-MT-I gene that regulates GPI-AP biosynthesis in Andrias davidianus (AdGPI-MT-I) was characterized for the first time. The open reading frame (ORF) of AdGPI-MT-I is 1293 bp and encodes a protein of 430 amino acids that contains a conserved PMT2 superfamily domain. AdGPI-MT-I mRNA was widely expressed in the tissues of the Chinese giant salamander. The mRNA expression level of AdGPI-MT-I in the spleen, kidney, and muscle cell line (GSM cells) was significantly upregulated post Chinese giant salamander iridovirus (GSIV) infection. The mRNA expression of the virus major capsid protein (MCP) in AdGPI-MT-I-overexpressed cells was significantly reduced. Moreover, a lower level of virus MCP synthesis and gene copying in AdGPI-MT-I-overexpressed cells was confirmed by western blot and ddPCR. These results collectively suggest that GSIV replication in GSM cells was significantly reduced by the overexpression of the AdGPI-MT-I protein, which may contribute to a better understanding of the antiviral mechanism against iridovirus infection. Full article
(This article belongs to the Section Molecular Biology)
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15 pages, 2592 KiB  
Article
Inhibition of Vps34 and p110δ PI3K Impairs Migration, Invasion and Three-Dimensional Spheroid Growth in Breast Cancer Cells
by Marzia Di Donato, Pia Giovannelli, Antimo Migliaccio and Antonio Bilancio *
Department of Medicine Precision, “Luigi Vanvitelli”, Affiliation University of Campania, Via L. De Crecchio 7, 80138 Naples, Italy
Int. J. Mol. Sci. 2022, 23(16), 9008; https://doi.org/10.3390/ijms23169008 - 12 Aug 2022
Cited by 12 | Viewed by 2520
Abstract
Breast cancer is a heterogeneous disease that represents the most common cancer around the world; it comprises 12% of new cases according to the World Health Organization. Despite new approaches in early diagnosis and current treatment, breast cancer is still the leading cause [...] Read more.
Breast cancer is a heterogeneous disease that represents the most common cancer around the world; it comprises 12% of new cases according to the World Health Organization. Despite new approaches in early diagnosis and current treatment, breast cancer is still the leading cause of death for cancer mortality. New targeted therapies against key signalling transduction molecules are required. Phosphoinositide 3-kinase (PI3K) regulates multiple biological functions such as proliferation, survival, migration, and growth. It is well established that PI3K isoform-selective inhibitors show fewer toxic side effects compared to broad spectrum inhibition of PI3K (pan-PI3K inhibitors). Therefore, we tested the PI3K p110δ-selective inhibitor, IC87114, and Vps34-selective inhibitor, Vps34-IN1, on the breast cancer cell lines MCF-7 and MDA-MB-231, representing hormone-responsive and triple-negative breast cancer cells, respectively. Our data show that both inhibitors decreased migration of MCF-7 and MDA-MB-231 cells, and Vps34 also significantly impacted MCF-7 cell proliferation. Three-dimensional (3D) in vitro culture models show that IC87114 and Vps34-IN1 treatment reduced the growth of MCF-7 and MDA-MB-231 cells in 3D tumour spheroid cultures. This study identifies IC87114 and Vps34-IN1 as potential therapeutic approaches in breast cancer. Full article
(This article belongs to the Special Issue Phosphoinositides and Downstream Signalling Molecules 2.0)
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3 pages, 183 KiB  
Editorial
Molecular Mechanisms Underlying Stress Response and Resilience
by Kazunori Kageyama 1,* and Takahiro Nemoto 2
1 Department of Endocrinology and Metabolism, Hirosaki University Graduate School of Medicine, 5 Zaifu-cho, Hirosaki, Aomori 036-8562, Japan
2 Department of Bioregulatory Science (Physiology), Nippon Medical School, Tokyo 113-8602, Japan
Int. J. Mol. Sci. 2022, 23(16), 9007; https://doi.org/10.3390/ijms23169007 - 12 Aug 2022
Cited by 5 | Viewed by 1963
Abstract
A variety of stressors induce various physiological responses by modulating sympathetic, neuroendocrine, and behavioral systems [...] Full article
(This article belongs to the Special Issue Molecular Mechanisms Underlying Stress Response and Resilience)
24 pages, 1293 KiB  
Review
Making the Rounds: Exploring the Role of Circulating Tumor DNA (ctDNA) in Non-Small Cell Lung Cancer
by Misty Dawn Shields 1,†, Kevin Chen 2,†, Giselle Dutcher 3, Ishika Patel 4 and Bruna Pellini 5,6,*
1 Department of Internal Medicine, Division of Hematology/Oncology, Indiana University School of Medicine, Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, IN 46202, USA
2 Department of Radiation Oncology, Division of Cancer Biology, Washington University School of Medicine, St. Louis, MO 63110, USA
3 Department of Medicine, Division of Solid Tumor Oncology, University Hospitals Seidman Cancer Center, Case Western Reserve University, Cleveland, OH 44106, USA
4 Department of Public Health, University of South Florida, 12902 Magnolia Drive, Tampa, FL 33612, USA
5 Department of Thoracic Oncology, Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA
6 Department of Oncologic Sciences, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA
These authors contributed equally to this work.
Int. J. Mol. Sci. 2022, 23(16), 9006; https://doi.org/10.3390/ijms23169006 - 12 Aug 2022
Cited by 39 | Viewed by 9185
Abstract
Advancements in the clinical practice of non-small cell lung cancer (NSCLC) are shifting treatment paradigms towards increasingly personalized approaches. Liquid biopsies using various circulating analytes provide minimally invasive methods of sampling the molecular content within tumor cells. Plasma-derived circulating tumor DNA (ctDNA), the [...] Read more.
Advancements in the clinical practice of non-small cell lung cancer (NSCLC) are shifting treatment paradigms towards increasingly personalized approaches. Liquid biopsies using various circulating analytes provide minimally invasive methods of sampling the molecular content within tumor cells. Plasma-derived circulating tumor DNA (ctDNA), the tumor-derived component of cell-free DNA (cfDNA), is the most extensively studied analyte and has a growing list of applications in the clinical management of NSCLC. As an alternative to tumor genotyping, the assessment of oncogenic driver alterations by ctDNA has become an accepted companion diagnostic via both single-gene polymerase chain reactions (PCR) and next-generation sequencing (NGS) for advanced NSCLC. ctDNA technologies have also shown the ability to detect the emerging mechanisms of acquired resistance that evolve after targeted therapy. Furthermore, the detection of minimal residual disease (MRD) by ctDNA for patients with NSCLC after curative-intent treatment may serve as a prognostic and potentially predictive biomarker for recurrence and response to therapy, respectively. Finally, ctDNA analysis via mutational, methylation, and/or fragmentation multi-omic profiling offers the potential for improving early lung cancer detection. In this review, we discuss the role of ctDNA in each of these capacities, namely, for molecular profiling, treatment response monitoring, MRD detection, and early cancer detection of NSCLC. Full article
(This article belongs to the Special Issue Liquid Biopsies in Oncology)
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17 pages, 2541 KiB  
Article
Characterization of Adherent-Invasive Escherichia coli (AIEC) Outer Membrane Proteins Provides Potential Molecular Markers to Screen Putative AIEC Strains
by Waleska Saitz 1,†, David A. Montero 2,3,†, Mirka Pardo 1, Daniela Araya 1, Marjorie De la Fuente 2, Marcela A. Hermoso 2,4, Mauricio J. Farfán 5, Daniel Ginard 6, Ramon Rosselló-Móra 7, Dave A. Rasko 8,9, Felipe Del Canto 1,* and Roberto M. Vidal 1,10,*
1 Programa de Microbiología y Micología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile
2 Programa de Inmunología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile
3 Centro Integrativo de Biología y Química Aplicada (CIBQA), Universidad Bernardo O’Higgins, Santiago 8370993, Chile
4 Department of Gastroenterology and Hepatology, University Medical Center Groningen (UMCG), University of Groningen, 9712 Groningen, The Netherlands
5 Departamento de Pediatría y Cirugía Infantil Oriente, Hospital Dr. Luis Calvo Mackenna, Facultad de Medicina, Universidad de Chile, Santiago 7500539, Chile
6 Department of Gastroenterology and Palma Health Research Institute, Hospital Universitario Son Espases, 07120 Palma de Mallorca, Spain
7 Grupo de Microbiología Marina, Instituto Mediterráneo de Estudios Avanzados (IMEDEA; CSIC-UIB), 07190 Esporles, Illes Balears, Spain
8 Institute for Genome Sciences, University of Maryland School of Medicine, Baltimore, MD 21201, USA
9 Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA
10 Instituto Milenio de Inmunología e Inmunoterapia, Facultad de Medicina, Universidad de Chile, Santiago 8380453, Chile
These authors contributed equally to this work.
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Int. J. Mol. Sci. 2022, 23(16), 9005; https://doi.org/10.3390/ijms23169005 - 12 Aug 2022
Cited by 10 | Viewed by 3182
Abstract
Adherent-invasive E. coli (AIEC) is a pathotype associated with the etiopathogenesis of Crohn’s disease (CD), albeit with an as-yet unclear role. The main pathogenic mechanisms described for AIEC are adherence to epithelial cells, invasion of epithelial cells, and survival and replication within macrophages. [...] Read more.
Adherent-invasive E. coli (AIEC) is a pathotype associated with the etiopathogenesis of Crohn’s disease (CD), albeit with an as-yet unclear role. The main pathogenic mechanisms described for AIEC are adherence to epithelial cells, invasion of epithelial cells, and survival and replication within macrophages. A few virulence factors have been described as participating directly in these phenotypes, most of which have been evaluated only in AIEC reference strains. To date, no molecular markers have been identified that can differentiate AIEC from other E. coli pathotypes, so these strains are currently identified based on the phenotypic characterization of their pathogenic mechanisms. The identification of putative AIEC molecular markers could be beneficial not only from the diagnostic point of view but could also help in better understanding the determinants of AIEC pathogenicity. The objective of this study was to identify molecular markers that contribute to the screening of AIEC strains. For this, we characterized outer membrane protein (OMP) profiles in a group of AIEC strains and compared them with the commensal E. coli HS strain. Notably, we found a set of OMPs that were present in the AIEC strains but absent in the HS strain. Moreover, we developed a PCR assay and performed phylogenomic analyses to determine the frequency and distribution of the genes coding for these OMPs in a larger collection of AIEC and other E. coli strains. As result, it was found that three genes (chuA, eefC, and fitA) are widely distributed and significantly correlated with AIEC strains, whereas they are infrequent in commensal and diarrheagenic E. coli strains (DEC). Additional studies are needed to validate these markers in diverse strain collections from different geographical regions, as well as investigate their possible role in AIEC pathogenicity. Full article
(This article belongs to the Section Molecular Biology)
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22 pages, 2499 KiB  
Review
Microfluidic Approaches for Affinity-Based Exosome Separation
by Eike K. Theel 1 and Sebastian P. Schwaminger 1,2,*
1 Bioseparation Engineering Group, School of Engineering and Design, Technical University of Munich, Boltzmannstraße 15, 85748 Garching bei München, Germany
2 Division of Medicinal Chemistry, Otto Loewi Research Center, Medical University of Graz, Neue Stiftingtalstraße 6, 8010 Graz, Austria
Int. J. Mol. Sci. 2022, 23(16), 9004; https://doi.org/10.3390/ijms23169004 - 12 Aug 2022
Cited by 35 | Viewed by 5681
Abstract
As a subspecies of extracellular vesicles (EVs), exosomes have provided promising results in diagnostic and theranostic applications in recent years. The nanometer-sized exosomes can be extracted by liquid biopsy from almost all body fluids, making them especially suitable for mainly non-invasive point-of-care (POC) [...] Read more.
As a subspecies of extracellular vesicles (EVs), exosomes have provided promising results in diagnostic and theranostic applications in recent years. The nanometer-sized exosomes can be extracted by liquid biopsy from almost all body fluids, making them especially suitable for mainly non-invasive point-of-care (POC) applications. To achieve this, exosomes must first be separated from the respective biofluid. Impurities with similar properties, heterogeneity of exosome characteristics, and time-related biofouling complicate the separation. This practical review presents the state-of-the-art methods available for the separation of exosomes. Furthermore, it is shown how new separation methods can be developed. A particular focus lies on the fabrication and design of microfluidic devices using highly selective affinity separation. Due to their compactness, quick analysis time and portable form factor, these microfluidic devices are particularly suitable to deliver fast and reliable results for POC applications. For these devices, new manufacturing methods (e.g., laminating, replica molding and 3D printing) that use low-cost materials and do not require clean rooms are presented. Additionally, special flow routes and patterns that increase contact surfaces, as well as residence time, and thus improve affinity purification are displayed. Finally, various analyses are shown that can be used to evaluate the separation results of a newly developed device. Overall, this review paper provides a toolbox for developing new microfluidic affinity devices for exosome separation. Full article
(This article belongs to the Special Issue Nanotechnology-Based Drug Delivery Systems for Cancer Therapy)
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23 pages, 3084 KiB  
Review
Upconversion Nanostructures Applied in Theranostic Systems
by Chao Lu 1, Etienne Joulin 1, Howyn Tang 2, Hossein Pouri 1 and Jin Zhang 1,2,*
1 Department of Chemical and Biochemical Engineering, University of Western Ontario, London, ON N6A 5B9, Canada
2 School of Biomedical Engineering, University of Western Ontario, London, ON N6A 5B9, Canada
Int. J. Mol. Sci. 2022, 23(16), 9003; https://doi.org/10.3390/ijms23169003 - 12 Aug 2022
Cited by 11 | Viewed by 4458
Abstract
Upconversion (UC) nanostructures, which can upconvert near-infrared (NIR) light with low energy to visible or UV light with higher energy, are investigated for theranostic applications. The surface of lanthanide (Ln)-doped UC nanostructures can be modified with different functional groups and bioconjugated with biomolecules [...] Read more.
Upconversion (UC) nanostructures, which can upconvert near-infrared (NIR) light with low energy to visible or UV light with higher energy, are investigated for theranostic applications. The surface of lanthanide (Ln)-doped UC nanostructures can be modified with different functional groups and bioconjugated with biomolecules for therapeutic systems. On the other hand, organic molecular-based UC nanostructures, by using the triplet-triplet annihilation (TTA) UC mechanism, have high UC quantum yields and do not require high excitation power. In this review, the major UC mechanisms in different nanostructures have been introduced, including the Ln-doped UC mechanism and the TTA UC mechanism. The design and fabrication of Ln-doped UC nanostructures and TTA UC-based UC nanostructures for theranostic applications have been reviewed and discussed. In addition, the current progress in the application of UC nanostructures for diagnosis and therapy has been summarized, including tumor-targeted bioimaging and chemotherapy, image-guided diagnosis and phototherapy, NIR-triggered controlled drug releasing and bioimaging. We also provide insight into the development of emerging UC nanostructures in the field of theranostics. Full article
(This article belongs to the Special Issue Emerging Nanotechnologies for Drug Delivery and Tissue Regeneration)
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19 pages, 3302 KiB  
Article
Ethyl Vinyl Ketone Activates K+ Efflux to Regulate Stomatal Closure by MRP4-Dependent eATP Accumulation Working Upstream of H2O2 Burst in Arabidopsis
by Junqing Gong, Lijuan Yao, Chunyang Jiao, Zhujuan Guo, Shuwen Li, Yixin Zuo and Yingbai Shen *
1 National Engineering Research Center of Tree Breeding and Ecological Restoration, College of Biological Sciences and Technology, Beijing Forestry University, No. 35, Qinghua East Road, Beijing 100083, China
These authors contributed equally to this work.
Int. J. Mol. Sci. 2022, 23(16), 9002; https://doi.org/10.3390/ijms23169002 - 12 Aug 2022
Cited by 10 | Viewed by 2394
Abstract
Plants regulate stomatal mobility to limit water loss and improve pathogen resistance. Ethyl vinyl ketone (evk) is referred to as a reactive electrophilic substance (RES). In this paper, we found that evk can mediate stomatal closure and that evk-induced stomatal closure by increasing [...] Read more.
Plants regulate stomatal mobility to limit water loss and improve pathogen resistance. Ethyl vinyl ketone (evk) is referred to as a reactive electrophilic substance (RES). In this paper, we found that evk can mediate stomatal closure and that evk-induced stomatal closure by increasing guard cell K+ efflux. To investigate the role of eATP, and H2O2 in evk-regulated K+ efflux, we used Arabidopsis wild-type (WT), mutant lines of mrp4, mrp5, dorn1.3 and rbohd/f. Non-invasive micro-test technology (NMT) data showed that evk-induced K+ efflux was diminished in mrp4, rbohd/f, and dorn1.3 mutant, which means eATP and H2O2 work upstream of evk-induced K+ efflux. According to the eATP content assay, evk stimulated eATP production mainly by MRP4. In mrp4 and mrp5 mutant groups and the ABC transporter inhibitor glibenclamide (Gli)-pretreated group, evk-regulated stomatal closure and eATP buildup were diminished, especially in the mrp4 group. According to qRT-PCR and eATP concentration results, evk regulates both relative gene expressions of MRP4/5 and eATP concentration in rbohd/f and WT group. According to the confocal data, evk-induced H2O2 production was lower in mrp4, mrp5 mutants, which implied that eATP works upstream of H2O2. Moreover, NADPH-dependent H2O2 burst is regulated by DORN1. A yeast two-hybrid assay, firefly luciferase complementation imaging assay, bimolecular fluorescence complementation assay, and pulldown assay showed that the interaction between DORN1 and RBOHF can be realized, which means DORN1 may control H2O2 burst by regulating RBOHF through interaction. This study reveals that evk-induced stomatal closure requires MRP4-dependent eATP accumulation and subsequent H2O2 accumulation to regulate K+ efflux. Full article
(This article belongs to the Section Molecular Plant Sciences)
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13 pages, 1007 KiB  
Review
miRNA in Ischemic Heart Disease and Its Potential as Biomarkers: A Comprehensive Review
by Amanda Shen-Yee Kong 1, Kok-Song Lai 2, Swee-Hua Erin Lim 2, Sivakumar Sivalingam 3, Jiun-Yan Loh 4,* and Sathiya Maran 1,*
1 School of Pharmacy, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway, Subang Jaya 47500, Malaysia
2 Health Sciences Division, Abu Dhabi Women’s College, Higher Colleges of Technology, Abu Dhabi 41012, United Arab Emirates
3 Department of Cardiacvascular and Thoracic Surgery, National Heart Institute, 145, Jalan Tun Razak, Kuala Lumpur 50400, Malaysia
4 Centre of Research for Advanced Aquaculture (CORAA), UCSI University, Cheras, Kuala Lumpur 56000, Malaysia
Int. J. Mol. Sci. 2022, 23(16), 9001; https://doi.org/10.3390/ijms23169001 - 12 Aug 2022
Cited by 18 | Viewed by 3448
Abstract
Ischemic heart disease (IHD) constitutes the leading global cause of mortality and morbidity. Although significant progress has been achieved in the diagnosis, treatment, and prognosis of IHD, more robust diagnostic biomarkers and therapeutic interventions are still needed to circumvent the increasing incidence of [...] Read more.
Ischemic heart disease (IHD) constitutes the leading global cause of mortality and morbidity. Although significant progress has been achieved in the diagnosis, treatment, and prognosis of IHD, more robust diagnostic biomarkers and therapeutic interventions are still needed to circumvent the increasing incidence of IHD. MicroRNAs (miRNAs) are critical regulators of cardiovascular function and are involved in various facets of cardiovascular biology. While the knowledge of the role of miRNAs in IHD as diagnostic biomarkers has improved, research emphasis on how miRNAs can be effectively used for diagnosis and prognosis of IHD is crucial. This review provides an overview of the biology, therapeutic and diagnostic potential, as well as the caveats of using miRNAs in IHD based on existing research. Full article
(This article belongs to the Special Issue MicroRNA in Cardiac Health and Disease)
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20 pages, 3455 KiB  
Article
The IRE1α–XBP1s Arm of the Unfolded Protein Response Activates N-Glycosylation to Remodel the Subepithelial Basement Membrane in Paramyxovirus Infection
by Yingxin Zhao 1,*, Dianhua Qiao 2, Melissa Skibba 2 and Allan R. Brasier 2,3,*
1 Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555-1060, USA
2 Department of Medicine, School of Medicine and Public Health (SMPH), University of Wisconsin-Madison, Madison, WI 53705, USA
3 Institute for Clinical and Translational Research (ICTR), University of Wisconsin-Madison, Madison, WI 53705, USA
Int. J. Mol. Sci. 2022, 23(16), 9000; https://doi.org/10.3390/ijms23169000 - 12 Aug 2022
Cited by 9 | Viewed by 2422
Abstract
Respiratory syncytial virus (RSV) causes severe lower respiratory tract infections (LRTI) associated with decreased pulmonary function, asthma, and allergy. Recently, we demonstrated that RSV induces the hexosamine biosynthetic pathway via the unfolded protein response (UPR), which is a pathway controlling protein glycosylation and [...] Read more.
Respiratory syncytial virus (RSV) causes severe lower respiratory tract infections (LRTI) associated with decreased pulmonary function, asthma, and allergy. Recently, we demonstrated that RSV induces the hexosamine biosynthetic pathway via the unfolded protein response (UPR), which is a pathway controlling protein glycosylation and secretion of the extracellular matrix (ECM). Because the presence of matrix metalloproteinases and matricellular growth factors (TGF) is associated with severe LRTI, we studied the effect of RSV on ECM remodeling and found that RSV enhances the deposition of fibronectin-rich ECM by small airway epithelial cells in a manner highly dependent on the inositol requiring kinase (IRE1α)–XBP1 arm of the UPR. To understand this effect comprehensively, we applied pharmacoproteomics to understand the effect of the UPR on N-glycosylation and ECM secretion in RSV infection. We observe that RSV induces N-glycosylation and the secretion of proteins related to ECM organization, secretion, or proteins integral to plasma membranes, such as integrins, laminins, collagens, and ECM-modifying enzymes, in an IRE1α–XBP1 dependent manner. Using a murine paramyxovirus model that activates the UPR in vivo, we validate the IRE1α–XBP1-dependent secretion of ECM to alveolar space. This study extends understanding of the IRE1α–XBP1 pathway in regulating N-glycosylation coupled to structural remodeling of the epithelial basement membrane in RSV infection. Full article
(This article belongs to the Special Issue Extracellular Matrix in Development and Disease 3.0)
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20 pages, 808 KiB  
Review
The Link between Gut Microbiota and Hepatic Encephalopathy
by Sung-Min Won, Ki Kwang Oh, Haripriya Gupta, Raja Ganesan, Satya Priya Sharma, Jin-Ju Jeong, Sang Jun Yoon, Min Kyo Jeong, Byeong Hyun Min, Ji Ye Hyun, Hee Jin Park, Jung A. Eom, Su Been Lee, Min Gi Cha, Goo Hyun Kwon, Mi Ran Choi, Dong Joon Kim and Ki Tae Suk *
Institute for Liver and Digestive Diseases, Hallym University College of Medicine, Chuncheon 24253, Korea
Int. J. Mol. Sci. 2022, 23(16), 8999; https://doi.org/10.3390/ijms23168999 - 12 Aug 2022
Cited by 37 | Viewed by 9678
Abstract
Hepatic encephalopathy (HE) is a serious complication of cirrhosis that causes neuropsychiatric problems, such as cognitive dysfunction and movement disorders. The link between the microbiota and the host plays a key role in the pathogenesis of HE. The link between the gut microbiome [...] Read more.
Hepatic encephalopathy (HE) is a serious complication of cirrhosis that causes neuropsychiatric problems, such as cognitive dysfunction and movement disorders. The link between the microbiota and the host plays a key role in the pathogenesis of HE. The link between the gut microbiome and disease can be positively utilized not only in the diagnosis area of HE but also in the treatment area. Probiotics and prebiotics aim to resolve gut dysbiosis and increase beneficial microbial taxa, while fecal microbiota transplantation aims to address gut dysbiosis through transplantation (FMT) of the gut microbiome from healthy donors. Antibiotics, such as rifaximin, aim to improve cognitive function and hyperammonemia by targeting harmful taxa. Current treatment regimens for HE have achieved some success in treatment by targeting the gut microbiota, however, are still accompanied by limitations and problems. A focused approach should be placed on the establishment of personalized trial designs and therapies for the improvement of future care. This narrative review identifies factors negatively influencing the gut–hepatic–brain axis leading to HE in cirrhosis and explores their relationship with the gut microbiome. We also focused on the evaluation of reported clinical studies on the management and improvement of HE patients with a particular focus on microbiome-targeted therapy. Full article
(This article belongs to the Special Issue Liver–Gut Axis 2.0)
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25 pages, 992 KiB  
Review
Microbe Related Chemical Signalling and Its Application in Agriculture
by Nur Wahida Abdul Hamid and Kalaivani Nadarajah *
Department of Biological Sciences and Biotechnology, Faculty of Science and Technology, Universiti Kebangsaan Malaysia, Bangi 43600, Malaysia
Int. J. Mol. Sci. 2022, 23(16), 8998; https://doi.org/10.3390/ijms23168998 - 12 Aug 2022
Cited by 27 | Viewed by 4231
Abstract
The agriculture sector has been put under tremendous strain by the world’s growing population. The use of fertilizers and pesticides in conventional farming has had a negative impact on the environment and human health. Sustainable agriculture attempts to maintain productivity, while protecting the [...] Read more.
The agriculture sector has been put under tremendous strain by the world’s growing population. The use of fertilizers and pesticides in conventional farming has had a negative impact on the environment and human health. Sustainable agriculture attempts to maintain productivity, while protecting the environment and feeding the global population. The importance of soil-dwelling microbial populations in overcoming these issues cannot be overstated. Various processes such as rhizospheric competence, antibiosis, release of enzymes, and induction of systemic resistance in host plants are all used by microbes to influence plant-microbe interactions. These processes are largely founded on chemical signalling. Producing, releasing, detecting, and responding to chemicals are all part of chemical signalling. Different microbes released distinct sorts of chemical signal molecules which interacts with the environment and hosts. Microbial chemicals affect symbiosis, virulence, competence, conjugation, antibiotic production, motility, sporulation, and biofilm growth, to name a few. We present an in-depth overview of chemical signalling between bacteria-bacteria, bacteria-fungi, and plant-microbe and the diverse roles played by these compounds in plant microbe interactions. These compounds’ current and potential uses and significance in agriculture have been highlighted. Full article
(This article belongs to the Special Issue Advances and New Perspectives in Plant-Microbe Interactions)
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18 pages, 4072 KiB  
Article
12/15-Lipoxygenase Regulation of Diabetic Cognitive Dysfunction Is Determined by Interfering with Inflammation and Cell Apoptosis
by Qi Chen 1,2,†, Qixue Zheng 1,†, Yang Yang 3, Ying Luo 1, Hong Wang 1, Huan Li 1, Lu Yang 1, Congli Hu 1, Jiahua Zhang 1, Yuke Li 1, Hui Xia 1, Zhihao Chen 1, Jie Ma 1, Xiaoyan Tian 1 and Junqing Yang 1,*,‡
1 Chongqing Key Laboratory of Biochemistry and Molecular Pharmacology, Department of Pharmacology, Chongqing Medical University, Chongqing 400016, China
2 Pharmacy Department of Guizhou Provincial People’s Hospital, Guiyang 550002, China
3 Department of Pharmacology, Chongqing Health Center for Women and Children, Chongqing 400016, China
These authors contributed equally to this work.
Department of Pharmacology, Chongqing Medical University, Chongqing 400016, China.
Int. J. Mol. Sci. 2022, 23(16), 8997; https://doi.org/10.3390/ijms23168997 - 12 Aug 2022
Cited by 10 | Viewed by 3009
Abstract
This study aimed to discuss the role of 12/15-lipoxygenase (12/15-LOX) regulation involved in diabetes cognitive dysfunction. First, Mini Mental State Examination (MMSE) test was used to evaluate cognitive ability in diabetic patients and normal controls. The plasma test showed that the plasma level [...] Read more.
This study aimed to discuss the role of 12/15-lipoxygenase (12/15-LOX) regulation involved in diabetes cognitive dysfunction. First, Mini Mental State Examination (MMSE) test was used to evaluate cognitive ability in diabetic patients and normal controls. The plasma test showed that the plasma level of 12/15-LOX in patients with MMSE scores below 27 was significantly increased compared with that of the normal group. Second, 12/15-LOX inhibitor was administered to diabetic rats. Behavioral tests, biochemistry, enzyme-linked immunosorbent assays, and Western blotting were used in this study. We found that the levels of fasting and random blood glucose increased rapidly in diabetic rats, the levels of triglycerides and total cholesterol in the diabetic group increased, and insulin levels decreased significantly. In the Morris water maze test, the escape latency was prolonged, and the crossing times decreased in the diabetic group. Under the microscope, the apoptosis of hippocampal neurons in diabetic rats increased significantly. The levels of TNF-α, IL-6 and 12-hydroxyindoleic acid (12(S)-HETE) significantly increased, and the protein expression of 12/15-LOX, p38 MAPK, Aβ1-42, caspase-3, caspase-9 and cPLA2 increased, while that of Bcl-2 decreased. However, the use of 12/15-LOX inhibitor reversed these results. Third, 12/15-LOX shRNA and p38MAPK inhibitor were administered to HT22 cells in high-glucose medium. The results of the cell experiment were consistent with those of the animal experiment. Our results indicated that the 12/15-LOX pathway participates in diabetic brain damage by activating p38MAPK to promote inflammation and neuronal apoptosis, and intervention 12/15-LOX can improve diabetic cognitive dysfunction. Full article
(This article belongs to the Special Issue Molecular Signals and Genetic Regulations of Neurological Disorders)
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