Microbiology

Oncotarget

Oncotarget published this trending research paper on March 24, 2023 in Volume 14, entitled, “Downregulation of angulin-1/LSR induces malignancy via upregulation of EGF-dependent claudin-2 and TGF-β-dependent cell metabolism in human lung adenocarcinoma A549 cells" by researchers from the Department of Thoracic Surgery, Sapporo Medical University School of Medicine, Sapporo, Japan; Department of Cell Science, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan; Department of Respiratory Medicine and Allergology, Sapporo Medical University School of Medicine, Sapporo, Japan; Department of Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan; Department of Molecular Medicine, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan.

DOI - https://doi.org/10.18632/oncotarget.27728

Correspondence to - Takashi Kojima - ktakashi@sapmed.ac.jp

Abstract

Abnormal expression of bicellular tight junction claudins, including claudin-2 are observed during carcinogenesis in human lung adenocarcinoma. However, little is known about the role of tricellular tight junction molecule angulin-1/lipolysis-stimulated lipoprotein receptor (LSR). In the lung adenocarcinoma tissues examined in the present study, expression of claudin-2 was higher than in normal lung tissues, while angulin-1/LSR was poorly or faintly expressed. We investigated how loss of angulin-1/LSR affects the malignancy of lung adenocarcinoma cell line A549 and normal human lung epithelial (HLE) cells. The EGF receptor tyrosine kinase inhibitor AG1478 prevented the increase of claudin-2 expression induced by EGF in A549 cells. Knockdown of LSR induced expression of claudin-2 at the protein and mRNA levels and AG1478 prevented the upregulation of claudin-2 in A549 cells. Knockdown of LSR induced cell proliferation, cell migration and cell metabolism in A549 cells. Knockdown of claudin-2 inhibited the cell proliferation but did not affect the cell migration or cell metabolism of A549 cells. The TGF-β type I receptor inhibitor EW-7197 prevented the decrease of LSR and claudin-2 induced by TGF-β1 in A549 cells and 2D culture of normal HLE cells. EW-7197 prevented the increase of cell migration and cell metabolism induced by TGF-β1 in A549 cells. EW-7197 prevented the increase of epithelial permeability of FITC-4kD dextran induced by TGF-β1 in 2.5D culture of normal HLE cells. In conclusion, downregulation of angulin-1/LSR induces malignancy via EGF-dependent claudin-2 and TGF-β-dependent cell metabolism in human lung adenocarcinoma.

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Keywords - angulin-1/LSR, claudin-2, cell metabolism, malignancy, lung adenocarcinoma

About Oncotarget

Oncotarget is a primarily oncology-focused, peer-reviewed, open access journal. Papers are published continuously within yearly volumes in their final and complete form, and then quickly released to Pubmed. On September 15, 2022, Oncotarget was accepted again for indexing by MEDLINE. Oncotarget is now indexed by Medline/PubMed and PMC/PubMed.

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Angulin-1/LSR Downregulation Induces Malignancy in A549 Lung Adenocarcinoma Cells

Aging (Aging-US)

Aging-US published this trending research paper on March 1, 2023 in Volume 15, Issue 5, entitled, “Cellular senescence with SASP in periodontal ligament cells triggers inflammation in aging periodontal tissue" by researchers from the Department of Periodontology, Graduate School of Dentistry, Osaka University, Suita, Osaka, Japan.

DOI - https://doi.org/10.18632/aging.204569

Corresponding authors - Motozo Yamashita - yamashita.motozou.dent@osaka-u.ac.jp

Abstract

The direct cause of periodontitis is periodontopathic bacteria, while various environmental factors affect the severity of periodontitis. Previous epidemiological studies have shown positive correlations between aging and periodontitis. However, whether and how aging is linked to periodontal health and disease in biological processes is poorly understood. Aging induces pathological alterations in organs, which promotes systemic senescence associated with age-related disease. Recently, it has become evident that senescence at the cellular level, cellular senescence, is a cause of chronic diseases through production of various secretory factors including proinflammatory cytokines, chemokines, and matrix metalloproteinases (MMPs), which is referred to the senescence-associated secretory phenotype (SASP). In this study, we examined the pathological roles of cellular senescence in periodontitis. We found localization of senescent cells in periodontal tissue, particularly the periodontal ligament (PDL), in aged mice. Senescent human PDL (HPDL) cells showed irreversible cell cycle arrest and SASP-like phenotypes in vitro. Additionally, we observed age-dependent upregulation of microRNA (miR)-34a in HPDL cells. These results suggest that chronic periodontitis is mediated by senescent PDL cells that exacerbate inflammation and destruction of periodontal tissues through production of SASP proteins. Thus, miR-34a and senescent PDL cells might be promising therapeutic targets for periodontitis in elderly people.

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Keywords - aging, cellular senescence, periodontitis, periodontal ligament, SASP, microRNAs, SIRT1

About Aging-US

Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways.

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Cellular Senescence Triggers Inflammation in Aging Periodontal Tissue

Ariel K. Frame, PhD Candidate in the Neuroscience program at Western University, London, Canada, discusses a research paper he co-authored that was published by Aging (Aging-US) in Volume 15, Issue 4, entitled, “Aging and memory are altered by genetically manipulating lactate dehydrogenase in the neurons or glia of flies.”

DOI - https://doi.org/10.18632/aging.204565

Corresponding authors - Ariel K. Frame - aframe@uwo.ca, and Robert C. Cumming - rcummin5@uwo.ca

Abstract

The astrocyte-neuron lactate shuttle hypothesis posits that glial-generated lactate is transported to neurons to fuel metabolic processes required for long-term memory. Although studies in vertebrates have revealed that lactate shuttling is important for cognitive function, it is uncertain if this form of metabolic coupling is conserved in invertebrates or is influenced by age. Lactate dehydrogenase (Ldh) is a rate limiting enzyme that interconverts lactate and pyruvate. Here we genetically manipulated expression of Drosophila melanogaster lactate dehydrogenase (dLdh) in neurons or glia to assess the impact of altered lactate metabolism on invertebrate aging and long-term courtship memory at different ages. We also assessed survival, negative geotaxis, brain neutral lipids (the core component of lipid droplets) and brain metabolites. Both upregulation and downregulation of dLdh in neurons resulted in decreased survival and memory impairment with age. Glial downregulation of dLdh expression caused age-related memory impairment without altering survival, while upregulated glial dLdh expression lowered survival without disrupting memory. Both neuronal and glial dLdh upregulation increased neutral lipid accumulation. We provide evidence that altered lactate metabolism with age affects the tricarboxylic acid (TCA) cycle, 2-hydroxyglutarate (2HG), and neutral lipid accumulation. Collectively, our findings indicate that the direct alteration of lactate metabolism in either glia or neurons affects memory and survival but only in an age-dependent manner.

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Keywords - aging, astrocyte-neuron lactate shuttle (ANLS), lactate, lactate dehydrogenase, dLdh, Drosophila melanogaster, glia, long-term memory, courtship conditioning

About Aging-US

Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways.

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Behind the Study: Aging and Memory Altered in Neurons or Glia of Flies

Aging-US published this research paper on February 27, 2023 in Volume 15, Issue 5, entitled, "Age-related methylation changes in the human sperm epigenome" by researchers from the Institute of Human Genetics, Julius Maximilians University, Würzburg, Germany; Department of Bioinformatics, Julius Maximilians University, Würzburg, Germany; Platform Degenerative Diseases, German Primate Center, Leibniz Institute for Primate Research, Göttingen and German Center for Cardiovascular Research, Partner Site Göttingen, Göttingen, Germany; Fertility Center, Wiesbaden, Germany.

DOI - https://doi.org/10.18632/aging.204546

Corresponding author - Thomas Haaf - thomas.haaf@uni-wuerzburg.de

Abstract

Advanced paternal age is associated with increased risks for reproductive and offspring medical problems. Accumulating evidence suggests age-related changes in the sperm epigenome as one underlying mechanism. Using reduced representation bisulfite sequencing on 73 sperm samples of males attending a fertility center, we identified 1,162 (74%) regions which were significantly (FDR-adjusted) hypomethylated and 403 regions (26%) being hypermethylated with age. There were no significant correlations with paternal BMI, semen quality, or ART outcome. The majority (1,152 of 1,565; 74%) of age-related differentially methylated regions (ageDMRs) were located within genic regions, including 1,002 genes with symbols. Hypomethylated ageDMRs were closer to transcription start sites than hypermethylated DMRs, half of which reside in gene-distal regions. In this and conceptually related genome-wide studies, so far 2,355 genes have been reported with significant sperm ageDMRs, however most (90%) of them in only one study. The 241 genes which have been replicated at least once showed significant functional enrichments in 41 biological processes associated with development and the nervous system and in 10 cellular components associated with synapses and neurons. This supports the hypothesis that paternal age effects on the sperm methylome affect offspring behaviour and neurodevelopment. It is interesting to note that sperm ageDMRs were not randomly distributed throughout the human genome; chromosome 19 showed a highly significant twofold enrichment with sperm ageDMRs. Although the high gene density and CpG content have been conserved, the orthologous marmoset chromosome 22 did not appear to exhibit an increased regulatory potential by age-related DNA methylation changes.

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Keywords - aging, ART outcome, DNA methylation, male germ cells, paternal age effect, human sperm epigenome

About Aging-US

Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways.

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Age-Related Methylation Changes in the Human Sperm Epigenome

Aging-US published this research paper as the cover for Volume 15, Issue 5, entitled, "AAV1.NT-3 gene therapy prevents age-related sarcopenia" by researchers from the Center for Gene Therapy, The Abigail Wexner Research Institute, Nationwide Children’s Hospital, Columbus, OH; Department of Pediatrics and Neurology, Nationwide Children’s Hospital and The Ohio State University, Columbus, OH; Department of Pathology and Laboratory Medicine, Nationwide Children’s Hospital, Columbus, OH.

DOI - https://doi.org/10.18632/aging.204577

Corresponding author - Zarife Sahenk - zarife.sahenk@nationwidechildrens.org

Abstract

Sarcopenia is progressive loss of muscle mass and strength, occurring during normal aging with significant consequences on the quality of life for elderly. Neurotrophin 3 (NT-3) is an important autocrine factor supporting Schwann cell survival and differentiation and stimulating axon regeneration and myelination. NT-3 is involved in the maintenance of neuromuscular junction (NMJ) integrity, restoration of impaired radial growth of muscle fibers through activation of the Akt/mTOR pathway. We tested the efficacy of NT-3 gene transfer therapy in wild type (WT)-aged C57BL/6 mice, a model for natural aging and sarcopenia, via intramuscular injection 1 × 1011 vg AAV1.tMCK.NT-3, at 18 months of age. The treatment efficacy was assessed at 6 months post-injection using run to exhaustion and rotarod tests, in vivo muscle contractility assay, and histopathological studies of the peripheral nervous system, including NMJ connectivity and muscle. AAV1.NT-3 gene therapy in WT-aged C57BL/6 mice resulted in functional and in vivo muscle physiology improvements, supported by quantitative histology from muscle, peripheral nerves and NMJ. Hindlimb and forelimb muscles in the untreated cohort showed the presence of a muscle- and sex-dependent remodeling and fiber size decrease with aging, which was normalized toward values obtained from 10 months old WT mice with treatment. The molecular studies assessing the NT-3 effect on the oxidative state of distal hindlimb muscles, accompanied by western blot analyses for mTORC1 activation were in accordance with the histological findings. Considering the cost and quality of life to the individual, we believe our study has important implications for management of age-related sarcopenia.

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Keywords - aging, sarcopenia, gene therapy, NT-3, muscle remodeling

About Aging-US

Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways.

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AAV1.NT-3 Gene Therapy Prevents Age-Related Sarcopenia

Oncotarget published this trending editorial perspective in Volume 14, entitled, “Leakage? or Secretion? Unconventional protein secretion in cancer" by researchers Kohji Yamada and Kiyotsugu Yoshida from the Department of Biochemistry, Jikei University School of Medicine, Minato-ku, Tokyo, Japan. 

DOI - https://doi.org/10.18632/oncotarget.28368 (PDF Download)

Correspondence to - Kohji Yamada -  kyamada@jikei.ac.jp, and  Kiyotsugu Yoshida -  kyoshida@jikei.ac.jp

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Keywords - unconventional protein secretion, cancer, endoplasmic reticulum

About Oncotarget

Oncotarget is a primarily oncology-focused, peer-reviewed, open access journal. Papers are published continuously within yearly volumes in their final and complete form, and then quickly released to Pubmed. On September 15, 2022, Oncotarget was accepted again for indexing by MEDLINE. Oncotarget is now indexed by Medline/PubMed and PMC/PubMed.

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Leakage? Or Secretion? Unconventional Protein Secretion in Cancer

Oncotarget published this editorial in Volume 14, entitled, “Unlocking the potential of molecular-driven stratification for osteosarcoma treatment and prognosis" by researchers from the INSERM U1015, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France; Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Campus, Université Paris-Saclay, Villejuif, France.

DOI - https://doi.org/10.18632/oncotarget.28364

Correspondence to - Antonin Marchais -  ANTONIN.MARCHAIS@gustaveroussy.fr

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Keywords - multiomics, osteosarcoma, bone sarcoma, stratification

About Oncotarget

Oncotarget is a primarily oncology-focused, peer-reviewed, open access journal. Papers are published continuously within yearly volumes in their final and complete form, and then quickly released to Pubmed. On September 15, 2022, Oncotarget was accepted again for indexing by MEDLINE. Oncotarget is now indexed by Medline/PubMed and PMC/PubMed.

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Potential of Molecular-Driven Stratification for Osteosarcoma Treatment and Prognosis

Aging-US published this trending research paper in Volume 15, Issue 4, entitled, "Aging and memory are altered by genetically manipulating lactate dehydrogenase in the neurons or glia of flies" by researchers from the Department of Biology, Western University, London, Canada; Department of Biology, Indiana University, Bloomington, IN.

DOI - https://doi.org/10.18632/aging.204565

Corresponding authors - Ariel K. Frame - aframe@uwo.ca, and Robert C. Cumming - rcummin5@uwo.ca

Abstract

The astrocyte-neuron lactate shuttle hypothesis posits that glial-generated lactate is transported to neurons to fuel metabolic processes required for long-term memory. Although studies in vertebrates have revealed that lactate shuttling is important for cognitive function, it is uncertain if this form of metabolic coupling is conserved in invertebrates or is influenced by age. Lactate dehydrogenase (Ldh) is a rate limiting enzyme that interconverts lactate and pyruvate. Here we genetically manipulated expression of Drosophila melanogaster lactate dehydrogenase (dLdh) in neurons or glia to assess the impact of altered lactate metabolism on invertebrate aging and long-term courtship memory at different ages. We also assessed survival, negative geotaxis, brain neutral lipids (the core component of lipid droplets) and brain metabolites. Both upregulation and downregulation of dLdh in neurons resulted in decreased survival and memory impairment with age. Glial downregulation of dLdh expression caused age-related memory impairment without altering survival, while upregulated glial dLdh expression lowered survival without disrupting memory. Both neuronal and glial dLdh upregulation increased neutral lipid accumulation. We provide evidence that altered lactate metabolism with age affects the tricarboxylic acid (TCA) cycle, 2-hydroxyglutarate (2HG), and neutral lipid accumulation. Collectively, our findings indicate that the direct alteration of lactate metabolism in either glia or neurons affects memory and survival but only in an age-dependent manner.

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Keywords - aging, astrocyte-neuron lactate shuttle (ANLS), lactate, lactate dehydrogenase, dLdh, Drosophila melanogaster, glia, long-term memory, courtship conditioning

About Aging-US

Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways.

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Genetic Manipulation of Lactate Dehydrogenase Alters Memory and Aging in Flies

Aging-US published this research paper in Volume 15, Issue 4, entitled, "Isoform-specific effects of neuronal repression of the AMPK catalytic subunit on cognitive function in aged mice" by researchers from the Department of Internal Medicine-Gerontology and Geriatric Medicine, Wake Forest University School of Medicine, Winston-Salem, NC; Department of Physiology and Pharmacology, Wake Forest University School of Medicine, Winston-Salem, NC; Department of Neurobiology and Anatomy, Wake Forest University School of Medicine, Winston-Salem, NC.

DOI - https://doi.org/10.18632/aging.204554

Corresponding author - Tao Ma - tma@wakehealth.edu

Abstract

AMP-activated protein kinase (AMPK) functions as a molecular sensor that plays a critical role in maintaining cellular energy homeostasis. Dysregulation of the AMPK signaling has been linked to synaptic failure and cognitive impairments. Our recent study demonstrates abnormally increased AMPK activity in the hippocampus of aged mice. The kinase catalytic subunit of AMPK exists in two isoforms α1 and α2, and their specific roles in aging-related cognitive deficits are unknown. Taking advantage of the unique transgenic mice (AMPKα1/α2 cKO) recently developed by our group, we investigated how isoform-specific suppression of the neuronal AMPKα may contribute to the regulation of cognitive and synaptic function associated with aging. We found that aging-related impairment of long-term object recognition memory was improved with suppression of AMPKα1 but not AMPKα2 isoform. Moreover, aging-related spatial memory deficits were unaltered with suppression of either AMPKα isoform. Biochemical experiments showed that the phosphorylation levels of the eukaryotic initiation factor 2 α subunit (eIF2α) were specifically decreased in the hippocampus of the AMPKα1 cKO mice. We further performed large-scale unbiased proteomics analysis and revealed identities of proteins whose expression is differentially regulated with AMPKα isoform suppression. These novel findings may provide insights into the roles of AMPK signaling pathway in cognitive aging.

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Keywords - AMPK, aging, protein synthesis, learning and memory, proteomics

About Aging-US

Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways.

Please visit our website at https://www.Aging-US.com​​ and connect with us:

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