bluuebunny/crossref_metadata_2025 huggingface dataset:
Mannan Oligosaccharides Application: Multipath Restriction From Aeromonas hydrophila Infection in the Skin Barrier of Grass Carp (Ctenopharyngodon idella)
Authors: Lu Zhiyuan , Feng Lin , Jiang Wei-Dan , Wu Pei , Liu Yang , Jiang Jun , Kuang Sheng-Yao , Tang Ling , Li Shu-Wei , Liu Xiang-An , Zhong Cheng-Bo , Zhou Xiao-Qiu
Published: October 2021

The objective of this study was to evaluate the efficacy of dietary Mannan oligosaccharides (MOS) supplementation on skin barrier function and the mechanism of on-growing grass carp (Ctenopharyngodon idella). Five hundred forty grass carp were fed for 60 days from the growing stage with six different levels of MOS diets (0, 200, 400, 600, 800, and 1,000 mg kg-1). At the end of the growth trial, the 14-day Aeromonas hydrophila challenge experiment has proceeded. The obtained data indicate that MOS could (1) decline skin lesion morbidity after being challenged by the pathogenic bacteria; (2) maintain physical barrier function via improving antioxidant ability, inhibiting excessive apoptosis, and strengthening the tight junction between the epithelial cell and the related signaling pathway (Nrf2/Keap1, p38MAPK, and MLCK); and (3) regulate immune barrier function by modulating the production of antimicrobial compound and expression of involved cytokines and the related signaling pathway (TOR and NFκB). Finally, we concluded that MOS supplementation reinforced the disease resistance and protected the fish skin barrier function from Aeromonas hydrophila infection.
Co-Expression of FOXP3FL and FOXP3Δ2 Isoforms Is Required for Optimal Treg-Like Cell Phenotypes and Suppressive Function
Authors: Sato Yohei , Liu Jessica , Lee Esmond , Perriman Rhonda , Roncarolo Maria Grazia , Bacchetta Rosa
Published: October 2021

FOXP3 is the master transcription factor in both murine and human FOXP3+regulatory T cells (Tregs), a T-cell subset with a central role in controlling immune responses. Loss of the functional Foxp3 protein inscurfymice leads to acute early-onset lethal lymphoproliferation. Similarly, pathogenic FOXP3 mutations in humans lead to immunodysregulation, polyendocrinopathy, enteropathy, and X-linked (IPEX) syndrome, which are characterized by systemic autoimmunity that typically begins in the first year of life. However, although pathogenicFOXP3mutations lead to overlapping phenotypic consequences in both systems, FOXP3 in human Tregs, but not mouse, is expressed as two predominant isoforms, the full length (FOXP3FL) and the alternatively spliced isoform, delta 2 (FOXP3Δ2). Here, using CRISPR/Cas9 to generate FOXP3 knockout CD4+T cells (FOXP3KOGFPCD4+ T cells), we restore the expression of each isoform by lentiviral gene transfer to delineate their functional roles in human Tregs. When compared to FOXP3FL or FOXP3Δ2 alone, or double transduction of the same isoform, co-expression of FOXP3FL and FOXP3Δ2 induced the highest overall FOXP3 protein expression in FOXP3KOGFPCD4+ T cells. This condition, in turn, led to optimal acquisition of Treg-like cell phenotypes including downregulation of cytokines, such as IL-17, and increased suppressive function. Our data confirm that co-expression of FOXP3FL and FOXP3Δ2 leads to optimal Treg-like cell function and supports the need to maintain the expression of both when engineering therapeutics designed to restore FOXP3 function in otherwise deficient cells.
Ductal Macrophages Predominate in the Immune Landscape of the Lactating Mammary Gland
Authors: Hassel Chervin , Gausserès Blandine , Guzylack-Piriou Laurence , Foucras Gilles
Published: October 2021

The mammary gland is unique in female mammals. Mammary tissue undergoes development and remodeling during lactation, a stage associated with high susceptibility to bacterial infections, inducing an inflammatory condition called mastitis. Although the immune response of the mammary gland has been the subject of intense research to improve prevention and treatment efficacy, the precise definition of its immune composition at this particular physiological stage is still missing. We combined single-cell RNA-Seq, flow cytometry, and three-dimensional confocal microscopy techniques to characterize the immune landscape of lactating murine mammary tissue. Macrophages dominated the immune cell repertoire and could be subdivided into at least two subsets: ductal and stromal macrophages. Ductal macrophages represented approximately 80% of the total CD45pos immune cells and co-expressed F4/80 and CD11c, with high levels of MHC class II molecules. They were strategically poised below the alveolar basal cells in contact with the myoepithelial cell network. Adaptive T and B lymphocytes were remarkably less numerous at this stage, which could explain the limited efficacy of vaccination against mastitis. These results support the view that new strategies to increase mammary immunity and prevent mastitis should be devised.
Identification of a DNA Methylation-Driven Genes-Based Prognostic Model and Drug Targets in Breast Cancer: In silico Screening of Therapeutic Compounds and in vitro Characterization
Authors: Tian Saisai , Fu Lu , Zhang Jinbo , Xu Jia , Yuan Li , Qin Jiangjiang , Zhang Weidong
Published: October 2021

DNA methylation is a vital epigenetic change that regulates gene transcription and helps to keep the genome stable. The deregulation hallmark of human cancer is often defined by aberrant DNA methylation which is critical for tumor formation and controls the expression of several tumor-associated genes. In various cancers, methylation changes such as tumor suppressor gene hypermethylation and oncogene hypomethylation are critical in tumor occurrences, especially in breast cancer. Detecting DNA methylation-driven genes and understanding the molecular features of such genes could thus help to enhance our understanding of pathogenesis and molecular mechanisms of breast cancer, facilitating the development of precision medicine and drug discovery. In the present study, we retrospectively analyzed over one thousand breast cancer patients and established a robust prognostic signature based on DNA methylation-driven genes. Then, we calculated immune cells abundance in each patient and lower immune activity existed in high-risk patients. The expression of leukocyte antigen (HLA) family genes and immune checkpoints genes were consistent with the above results. In addition, more mutated genes were observed in the high-risk group. Furthermore, a in silico screening of druggable targets and compounds from CTRP and PRISM databases was performed, resulting in the identification of five target genes (HMMR, CCNB1, CDC25C, AURKA, and CENPE) and five agents (oligomycin A, panobinostat, (+)-JQ1, voxtalisib, and arcyriaflavin A), which might have therapeutic potential in treating high-risk breast cancer patients. Further in vitro evaluation confirmed that (+)-JQ1 had the best cancer cell selectivity and exerted its anti-breast cancer activity through CENPE. In conclusion, our study provided new insights into personalized prognostication and may inspire the integration of risk stratification and precision therapy.
Pyroptosis in the Retinal Neurovascular Unit: New Insights Into Diabetic Retinopathy
Authors: Meng Chunren , Gu Chufeng , He Shuai , Su Tong , Lhamo Thashi , Draga Deji , Qiu Qinghua
Published: October 2021

Diabetic retinopathy (DR) is prevalent among people with long-term diabetes mellitus (DM) and remains the leading cause of visual impairment in working-aged people. DR is related to chronic low-level inflammatory reactions. Pyroptosis is an emerging type of inflammatory cell death mediated by gasdermin D (GSDMD), NOD-like receptors and inflammatory caspases that promote interleukin-1β (IL-1β) and IL-18 release. In addition, the retinal neurovascular unit (NVU) is the functional basis of the retina. Recent studies have shown that pyroptosis may participate in the destruction of retinal NVU cells in simulated hyperglycemic DR environments. In this review, we will clarify the importance of pyroptosis in the retinal NVU during the development of DR.
Microbiota Signals Suppress B Lymphopoiesis With Aging in Mice
Authors: Krambs Joseph R. , Monlish Darlene A. , Gao Feng , Schuettpelz Laura G. , Link Daniel C.
Published: October 2021

Aging is associated with significant changes in hematopoiesis that include a shift from lymphopoiesis to myelopoiesis and an expansion of phenotypic hematopoietic stem cells (HSCs) with impaired self-renewal capacity and myeloid-skewed lineage differentiation. Signals from commensal flora support basal myelopoiesis in young mice; however, their contribution to hematopoietic aging is largely unknown. Here, we characterize hematopoiesis in young and middle-aged mice housed under specific pathogen free (SPF) and germ-free (GF) conditions. The marked shift from lymphopoiesis to myelopoiesis that develops during aging of SPF mice is mostly abrogated in GF mice. Compared with aged SPF mice, there is a marked expansion of B lymphopoiesis in aged GF mice, which is evident at the earliest stages of B cell development. The expansion of phenotypic and functional HSCs that occurs with aging is similar in SPF and GF mice. However, HSCs from young GF mice have increased lymphoid lineage output, and the aging-associated expansion of myeloid-biased HSCs is significantly attenuated in GF mice. Consistent with these data, RNA expression profiling of phenotypic HSCs from aged GF mice show enrichment for non-myeloid biased HSCs. Surprisingly, the RNA expression profiling data also suggest that inflammatory signaling is increased in aged GF HSCs compared with aged SPF HSCs. Collectively, these data suggest that microbiota-related signals suppress B lymphopoiesis at multiple stages of development and contribute to the expansion of myeloid-biased HSCs that occurs with aging.
Dermatomyositis With Anti-MDA5 Antibodies: Bioclinical Features, Pathogenesis and Emerging Therapies
Authors: Nombel Anaïs , Fabien Nicole , Coutant Frédéric
Published: October 2021

Anti-MDA5 dermatomyositis is a rare systemic autoimmune disease, historically described in Japanese patients with clinically amyopathic dermatomyositis and life-threatening rapidly progressive interstitial lung disease. Subsequently, the complete clinical spectrum of the disease was enriched by skin, articular and vascular manifestations. Depending on the predominance of these symptoms, three distinct clinical phenotypes with different prognosis are now defined. To date, the only known molecular component shared by the three entities are specific antibodies targeting MDA5, a cytosolic protein essential for antiviral host immune responses. Several biological tools have emerged to detect these antibodies, with drawbacks and limitations for each of them. However, the identification of this highly specific serological marker of the disease raises the question of its role in the pathogenesis. Although current knowledge on the pathogenic mechanisms that take place in the disease are still in their enfancy, several lines of evidence support a central role of interferon-mediated vasculopathy in the development of skin and lung lesions, as well as a possible pathogenic involvement of anti-MDA5 antibodies. Here, we review the clinical and biological evidences in favor of these hypothesis, and we discuss the contribution of emerging therapies that shed some light on the pathogenesis of the disease.
The Corrosion Behavior of N80 Steel in Multiple Thermal Fluid Environment Containing O2 and CO2
Authors: Lin Xueqiang , Luo Xiaokang , Liu Wei , Chen Yufan , Pang Bo , Guo Yi , He Qingkun
Published: October 2021

The corrosion behavior of N80 steel in Multiple thermal fluid environment containing O2 and CO2 was analyzed by Scanning Electron Microscopy (SEM), Energy-dispersive Spectrometry (EDS) and X-ray Diffraction (XRD) techniques. The results showed that, the corrosion products formed on N80 steel showed double layer structure. The outer layer are loose and porous, providing little protection. The inner layer are mainly FeCO3 crystals, and a small amount of Fe2O3 and FeOOH composition. The formation of Fe oxide on the inner layer of the film destroyed the integrity of the inner layer, resulting in localized corrosion. During the development of pitting, Cl− is enriched only at the tip of the pitting hole, which is the main cause of pitting corrosion and eventually leads to the formation of dendritic localized corrosion. The difference between internal and external potentials, the O2 concentration and the decrease of pH in the pitting holes combined to increase the corrosion process.
Oxic and Anoxic Organic Polymer Degradation Potential of Endophytic Fungi From the Marine Macroalga, Ecklonia radiata
Authors: Perkins Anita K. , Rose Andrew L. , Grossart Hans-Peter , Rojas-Jimenez Keilor , Barroso Prescott Selva K. , Oakes Joanne M.
Published: October 2021

Cellulose and chitin are the most abundant polymeric, organic carbon source globally. Thus, microbes degrading these polymers significantly influence global carbon cycling and greenhouse gas production. Fungi are recognized as important for cellulose decomposition in terrestrial environments, but are far less studied in marine environments, where bacterial organic matter degradation pathways tend to receive more attention. In this study, we investigated the potential of fungi to degrade kelp detritus, which is a major source of cellulose in marine systems. Given that kelp detritus can be transported considerable distances in the marine environment, we were specifically interested in the capability of endophytic fungi, which are transported with detritus, to ultimately contribute to kelp detritus degradation. We isolated 10 species and two strains of endophytic fungi from the kelp Ecklonia radiata. We then used a dye decolorization assay to assess their ability to degrade organic polymers (lignin, cellulose, and hemicellulose) under both oxic and anoxic conditions and compared their degradation ability with common terrestrial fungi. Under oxic conditions, there was evidence that Ascomycota isolates produced cellulose-degrading extracellular enzymes (associated with manganese peroxidase and sulfur-containing lignin peroxidase), while Mucoromycota isolates appeared to produce both lignin and cellulose-degrading extracellular enzymes, and all Basidiomycota isolates produced lignin-degrading enzymes (associated with laccase and lignin peroxidase). Under anoxic conditions, only three kelp endophytes degraded cellulose. We concluded that kelp fungal endophytes can contribute to cellulose degradation in both oxic and anoxic environments. Thus, endophytic kelp fungi may play a significant role in marine carbon cycling via polymeric organic matter degradation.
Correlation Between Microbial Diversity and Volatile Flavor Compounds of Suan zuo rou, a Fermented Meat Product From Guizhou, China
Authors: Wang Hanyu , Su Wei , Mu Yingchun , Zhao Chi
Published: October 2021

Suan zuo rou (SZR), a traditional fermented meat from Guizhou province, China, is loved by local people for its unique flavor and nutritional value. However, the microbial communities and related flavor characteristics of SZR from different regions of Guizhou are unclear. We studied the correlation between the microbial communities and the physicochemical properties and volatile flavor compounds (VFCs) of 15 SZR samples from three regions in Guizhou province. The microbial community structure of SZR was determined by high-throughput sequencing and VFCs were identified by headspace-solid phase microextraction combined with gas chromatography-mass spectrometry. The results indicated that the microbial communities of SZR varied among the regions, as evidenced by the relative abundance of Weissella, Staphylococcus, Brochothrix, Kazachstania, and Debaryomces. There were also significant differences in pH, water activity, NaCl, and total volatile basic nitrogen (P < 0.05). Based on orthogonal projections to latent structures and Pearson’s correlation coefficient, we showed that Wickerhamomyces, Kazachstania, Lactobacillus, Weissella, Brochothrix, Debaryomyces, Staphylococcus, Pediococcus, Pichia, Candida, and Leuconostoc were highly correlated with 48 VFCs (| ρ| > 0.8, P < 0.05). Redundancy analysis showed that most of the dominant bacteria were positively related to water activity, whereas Lactobacillus was positively related with pH, and negatively related with total volatile basic nitrogen.
Contamination Issue in Viral Metagenomics: Problems, Solutions, and Clinical Perspectives
Authors: Jurasz Henryk , Pawłowski Tomasz , Perlejewski Karol
Published: October 2021

We describe the most common internal and external sources and types of contamination encountered in viral metagenomic studies and discuss their negative impact on sequencing results, particularly for low-biomass samples and clinical applications. We also propose some basic recommendations for reducing the background noise in viral shotgun metagenomic (SM) studies, which would limit the bias introduced by various classes of contaminants. Regardless of the specific viral SM protocol, contamination cannot be totally avoided; in particular, the issue of reagent contamination should always be addressed with high priority. There is an urgent need for the development and validation of standards for viral metagenomic studies especially if viral SM protocols will be more widely applied in diagnostics.
Boosting Synergistic Effects of Short Antimicrobial Peptides With Conventional Antibiotics Against Resistant Bacteria
Authors: Wu Chih-Lung , Peng Kuang-Li , Yip Bak-Sau , Chih Ya-Han , Cheng Jya-Wei
Published: October 2021

The global spread of antibiotic-resistant infections has meant that there is an urgent need to develop new antimicrobial alternatives. In this study, we developed a strategy to boost and/or synergize the activity of conventional antibiotics by combination with antimicrobial peptides tagged with the bulky non-natural amino acid β-naphthylalanine (Nal) to their N- or C-terminus. A checkerboard method was used to evaluate synergistic effects of the parent peptide and the Nal-tagged peptides. Moreover, boron-dipyrro-methene labeled vancomycin was used to characterize the synergistic mechanism of action between the peptides and vancomycin on the bacterial strains. These Nal-tagged antimicrobial peptides also reduced the antibiotic-induced release of lipopolysaccharide from Gram-negative bacteria by more than 99.95%. Our results demonstrate that Nal-tagged peptides could help in developing antimicrobial peptides that not only have enhanced antibacterial activities but also increase the synergistic effects with conventional antibiotics against antibiotic-resistant bacteria.
Essential Genes of Vibrio anguillarum and Other Vibrio spp. Guide the Development of New Drugs and Vaccines
Authors: Bekaert Michaël , Goffin Nikki , McMillan Stuart , Desbois Andrew P.
Published: October 2021

Essential genes in bacterial pathogens are potential drug targets and vaccine candidates because disrupting their function is lethal. The development of new antibiotics, in addition to effective prevention measures such as vaccination, contributes to addressing the global problem of bacterial antibiotic resistance. The aim of this present study was to determine the essential genes of Vibrio anguillarum, a bacterial pathogen of aquatic animals, as a means to identify putative targets for novel drugs and to assist the prioritisation of potential vaccine candidates. Essential genes were characterised by a Tn-seq approach using the TnSC189 mariner transposon to construct a library of 52,662 insertion mutants. In total, 329 essential genes were identified, with 34.7% found within the core genome of this species; each of these genes represents a strong potential drug target. Seven essential gene products were predicted to reside in the cell membrane or be released extracellularly, thus serving as putative vaccine candidates. Comparison to essential gene data from five other studies of Vibrio species revealed 13 proteins to be conserved across the studies, while 25 genes were specific to V. anguillarum and not found to be essential in the other Vibrio spp. This study provides new information on the essential genes of Vibrio species and the methodology may be applied to other pathogens to guide the development of new drugs and vaccines, which will assist efforts to counter antibiotic resistance.
Phosphorylation Regulates CIRBP Arginine Methylation, Transportin-1 Binding and Liquid-Liquid Phase Separation
Authors: Lenard Aneta J. , Hutten Saskia , Zhou Qishun , Usluer Sinem , Zhang Fangrong , Bourgeois Benjamin M. R. , Dormann Dorothee , Madl Tobias
Published: October 2021

Arginine-glycine(-glycine) (RG/RGG) regions are highly abundant in RNA-binding proteins and involved in numerous physiological processes. Aberrant liquid-liquid phase separation (LLPS) and stress granule (SGs) association of RG/RGG regions in the cytoplasm have been implicated in several neurodegenerative disorders. LLPS and SG association of these proteins is regulated by the interaction with nuclear import receptors, such as transportin-1 (TNPO1), and by post-translational arginine methylation. Strikingly, many RG/RGG proteins harbour potential phosphorylation sites within or close to their arginine methylated regions, indicating a regulatory role. Here, we studied the role of phosphorylation within RG/RGG regions on arginine methylation, TNPO1-binding and LLPS using the cold-inducible RNA-binding protein (CIRBP) as a paradigm. We show that the RG/RGG region of CIRBP is in vitro phosphorylated by serine-arginine protein kinase 1 (SRPK1), and discovered two novel phosphorylation sites in CIRBP. SRPK1-mediated phosphorylation of the CIRBP RG/RGG region impairs LLPS and binding to TNPO1 in vitro and interferes with SG association in cells. Furthermore, we uncovered that arginine methylation of the CIRBP RG/RGG region regulates in vitro phosphorylation by SRPK1. In conclusion, our findings indicate that LLPS and TNPO1-mediated chaperoning of RG/RGG proteins is regulated through an intricate interplay of post-translational modifications.
From Neurodevelopmental to Neurodegenerative Disorders: The Vascular Continuum
Authors: Ouellette Julie , Lacoste Baptiste
Published: October 2021

Structural and functional integrity of the cerebral vasculature ensures proper brain development and function, as well as healthy aging. The inability of the brain to store energy makes it exceptionally dependent on an adequate supply of oxygen and nutrients from the blood stream for matching colossal demands of neural and glial cells. Key vascular features including a dense vasculature, a tightly controlled environment, and the regulation of cerebral blood flow (CBF) all take part in brain health throughout life. As such, healthy brain development and aging are both ensured by the anatomical and functional interaction between the vascular and nervous systems that are established during brain development and maintained throughout the lifespan. During critical periods of brain development, vascular networks remodel until they can actively respond to increases in neural activity through neurovascular coupling, which makes the brain particularly vulnerable to neurovascular alterations. The brain vasculature has been strongly associated with the onset and/or progression of conditions associated with aging, and more recently with neurodevelopmental disorders. Our understanding of cerebrovascular contributions to neurological disorders is rapidly evolving, and increasing evidence shows that deficits in angiogenesis, CBF and the blood-brain barrier (BBB) are causally linked to cognitive impairment. Moreover, it is of utmost curiosity that although neurodevelopmental and neurodegenerative disorders express different clinical features at different stages of life, they share similar vascular abnormalities. In this review, we present an overview of vascular dysfunctions associated with neurodevelopmental (autism spectrum disorders, schizophrenia, Down Syndrome) and neurodegenerative (multiple sclerosis, Huntington’s, Parkinson’s, and Alzheimer’s diseases) disorders, with a focus on impairments in angiogenesis, CBF and the BBB. Finally, we discuss the impact of early vascular impairments on the expression of neurodegenerative diseases.
The Nuclear Function of IL-33 in Desensitization to DNA Damaging Agent and Change of Glioma Nuclear Structure
Authors: Chung Yu-Han , Qian Qiu , Huang Hsin-Ying , Chiu Wen-Tai , Yang Chung-Shi , Tzeng Shun-Fen
Published: October 2021

Glioma, the most common subtype of primary brain tumor, is an aggressive and highly invasive neurologically tumor among human cancers. Interleukin-33 (IL-33) is considered as a dual functional cytokine, an alarmin upon tissue damage and a nuclear chromatin-associated protein. Despite that, IL-33 is known to foster the formation of the inflammatory tumor microenvironment and facilitate glioma progression, evidence showing nuclear IL-33 function is still poor. In this study using lentivirus-mediated IL-33 gene knockdown (IL33KD) and IL-33 overexpression (IL33oe) in rat C6 glioma cells and human glioma cell lines (U251MG and U87MG), we found that IL33oe-glioma cells had resistance to the insults of the alkylating agent, temozolomide (TMZ), possibly because of the increased expression of DNA repair genes (i.e., BRCA1, BRCA2, Rad51, FANCB, and FANCD) in IL33oe-glioma cells. Alternatively, examination of glioma nuclear shape from transmission electron microscopy (TEM) imaging analysis and immunofluorescence for histone protein H2A staining showed that IL33KD attenuated the abnormal cancerous nuclear characteristic, such as indentation, long clefts, and multiple nucleoids. Yet, IL33oe promoted the changes in glioma nuclear shapes, such as the formation of multiple lobes. We further found that histone proteins, H2A and H3, were reduced in IL33KD glioma cells. The non-histone DNA-binding nucleoproteins, the high mobility group A1 (HMGA1) and HMGA2, were also downregulated by IL33KD. In contrast, IL33oe increased H2A and H3 proteins and HMGA1 and HMGA2 in glioma cells. Altogether, the upregulation of nuclear IL-33 expression was along with an increase in the expression of DNA repair genes, contributing to the desensitization of glioma cells to DNA damaging agents. Moreover, nuclear IL-33 proteins in cooperation with chromatin-associated proteins regulate glioma nuclear structure, which might be crucial for glioma progression and malignancy.
Endoplasmic Reticulum-Based Calcium Dysfunctions in Synucleinopathies
Authors: Kovacs Gergo , Reimer Lasse , Jensen Poul Henning
Published: October 2021

Neuronal calcium dyshomeostasis has been associated to Parkinson's disease (PD) development based on epidemiological studies on users of calcium channel antagonists and clinical trials are currently conducted exploring the hypothesis of increased calcium influx into neuronal cytosol as basic premise. We reported in 2018 an opposite hypothesis based on the demonstration that α-synuclein aggregates stimulate the endoplasmic reticulum (ER) calcium pump SERCA and demonstrated in cell models the existence of an α-synuclein-aggregate dependent neuronal state wherein cytosolic calcium is decreased due to an increased pumping of calcium into the ER. Inhibiting the SERCA pump protected both neurons and an α-synuclein transgenicC. elegansmodel. This models two cellular states that could contribute to development of PD. First the prolonged state with reduced cytosolic calcium that could deregulate multiple signaling pathways. Second the disease ER state with increased calcium concentration. We will discuss our hypothesis in the light of recent papers. First, a mechanistic study describing how variation in the Inositol-1,4,5-triphosphate (IP3) kinase B (ITPKB) may explain GWAS studies identifying the ITPKB gene as a protective factor toward PD. Here it was demonstrated that how increased ITPKB activity reduces influx of ER calcium to mitochondria via contact between IP3-receptors and the mitochondrial calcium uniporter complex in ER-mitochondria contact, known as mitochondria-associated membranes (MAMs). Secondly, it was demonstrated that astrocytes derived from PD patients contain α-synuclein accumulations. A recent study has demonstrated how human astrocytes derived from a few PD patients carrying the LRRK2-2019S mutation express more α-synuclein than control astrocytes, release more calcium from ER upon ryanodine receptor (RyR) stimulation, show changes in ER calcium channels and exhibit a decreased maximal and spare respiration indicating altered mitochondrial function in PD astrocytes. Here, we summarize the previous findings focusing the effect of α-synuclein to SERCA, RyR, IP3R, MCU subunits and other MAM-related channels. We also consider how the SOCE-related events could contribute to the development of PD.
Identification of a Rare EGFR T790I Mutation in Lung Adenocarcinoma Sensitive to Osimertinib
Authors: Wang Yu , Liu Songtao , Feng Alei , Luo Huan , Hu Jinwei , Wang Kai , Dong Wei
Published: October 2021

Estimated glomerular filtration rate (EGFR)-sensitive mutations are extremely important for targeted treatment strategies in lung cancer. Osimertinib can effectively inhibit the activity of EGFR-sensitive mutations, including the T790M mutation. However, the efficiency of osimertinib for rare mutation types of T790 is unclear. Here, we report the case of a Chinese patient with lung adenocarcinoma (LADC) harboring a T790I mutation who achieved significant benefits from osimertinib treatment.
Plasmatic Exosome Number and Size Distinguish Prostate Cancer Patients From Healthy Individuals: A Prospective Clinical Study
Authors: Logozzi Mariantonia , Mizzoni Davide , Di Raimo Rossella , Giuliani Alessandro , Maggi Martina , Sciarra Alessandro , Fais Stefano
Published: October 2021

There is a urgent need for valuable strategy in early and less invasive diagnosis for cancer. Preliminary data have shown that the plasmatic levels of exosomes increase in cancer condition. This study investigates the relevance of plasmatic levels and size distribution of exosomes in 42 individuals with no signs of urological disease (CTR) as compared to 65 prostate cancer patients (PCa). It was used Nanoparticle Tracking Analysis (NTA), a highly reliable and sensitive method for exosomes characterization and quantification. The relation structure among the NTA-derived parameters was assessed by means of Principal Component Analysis, which allowed detecting the global discriminant power of NTA test in terms of Receiver Operating Characteristic (ROC) curve and the selection of cut-off thresholds. The results showed that PCa had significantly higher plasmatic levels of exosomes and that the exosomes were smaller in size as compared to the CTR; the values reached 89% sensitivity and 71% specificity, in distinguishing PCa from CTR. These results propose a new exosome-based non-invasive clinical approach for the clinical follow-up of prostate cancer undergoing surgical treatment; in addition this method may be developed as a new screening test for prostate cancer’s early diagnosis. While this clinical study was performed in prostate cancer, it may represent a proof of concept extendable to virtually all cancers, as it is suggested by both pre-clinical evidence and clinical data obtained with different technical approaches.
m6A Modification in Non-Coding RNA: The Role in Cancer Drug Resistance
Authors: Chen Chen , Guo Yuying , Guo Yaxin , Wu Xiaoke , Si Chaohua , Xu Yanxin , Kang Qiaozhen , Sun Zhenqiang
Published: October 2021

Cancer drug resistance has always been a major difficulty in cancer therapy. In the face of drug pressure, resistant cancer cells show complex molecular mechanisms including epigenetic changes to maintain survival. Studies prove that cancer cells exhibit abnormal m6A modification after acquiring drug resistance. m6A modification in the target RNA including non-coding RNA can be a controller to determine the fate and metabolism of RNA by regulating their stability, subcellular localization, or translation. In particular, m6A-modified non-coding RNA plays multiple roles in multiple drug-resistant cancer cells, which can be a target for cancer drug resistance. Here, we provide an overview of the complex regulatory mechanisms of m6A-modified non-coding RNA in cancer drug resistance, and we discuss its potential value and challenges in clinical applications.
Comparative Analyses of Two Established Scores to Assess the Stability of Spinal Bone Metastases Before and After Palliative Radiotherapy
Authors: Bostel Tilman , Akbaba Sati , Wollschläger Daniel , Klodt Tristan , Oebel Laura , Mayer Arnulf , Drabke Sophia , Sprave Tanja , Debus Jürgen , Förster Robert , Rief Harald , Rühle Alexander , Grosu Anca-Ligia , Schmidberger Heinz , Nicolay Nils H.
Published: October 2021

Background and Purpose

To compare two validated spinal instability scores regarding the stabilizing effects and skeletal-related events (SREs) of palliative radiotherapy (RT) in patients with spinal bone metastases (SBM).

Materials and Methods

Two hundred eighty-two osteolytic SBM of lung or breast cancer patients were analyzed for stability before and following RT based on the Spinal Instability Neoplastic Score (SINS) or the Taneichi score. Score concordance was quantified by absolute agreement and Cohen’s kappa coefficient. SREs were defined as fractures or local progression after RT. OS was quantified as the time between the start of RT and death from any cause.

Results

At 3 and 6 months after RT, 35 and 50% of initially unstable SBM were re-stabilized according to SINS in patients still alive. Corresponding Taneichi score-based stabilization proportions were 25 and 46%, respectively. Comparison of both stability scores showed high absolute agreement for all time-points (range 71–78%, kappa range 0.35–0.44). SRE occurred more frequently in initially unstable SBM compared to stable SBM according to SINS (14 vs. 5%), but no such association could be shown for the Taneichi-based instability criterion. Poor general condition of patients was negatively associated with SINS-measured re-stabilization after 6 months, but no predictive factor for re-stabilization could be found for the Taneichi score.

Conclusions

Despite the relatively high agreement between both stabilization scores, the SINS should be considered the standard for future studies on the stabilization effects of RT in SBM.
Genomic Landscape in Neoplasm-Like Stroma Reveals Distinct Prognostic Subtypes of Pancreatic Ductal Adenocarcinoma
Authors: Jiang Jiahong , Xu Yaping , Chang Lianpeng , Ru Guoqing , Xia Xuefeng , Yang Ling , Yi Xin , Chen Zheling , Huang Dong-Sheng , Yang Liu
Published: October 2021

As a main component of the tumor microenvironment, the stroma is critical in development, progression, and metastasis of pancreatic ductal adenocarcinoma (PDAC). The genomic status and its relationship of neoplastic and stromal components remain unclear in PDAC. We performed targeted sequencing for 1,021 cancer-suspected genes on parallel microdissected stromal and neoplastic components from 50 operable PDAC patients. Clonality analysis of mutations was conducted to reconstruct the evolutionary trajectory, and then molecular subtypes were established. Multi-lineage differentiation potential and mesenchymal transformation of KRAS-mutant cell line Panc1 were evaluated using RT-PCR and immunofluorescence staining. In this study, 39 (78.0%) were genomically altered in stroma, with KRAS (71.8%), TP53 (61.5%), and CDKN2A (23.1%) as the most commonly mutated genes. The majority of stromal mutations (89.8%) were detected in matched neoplastic components. Patients with KRAS/TP53-mut stroma demonstrated a higher tumor cell fraction (TCF) than did those with wild-type (WT) stroma (p = 0.0371, p = 0.0014). In both components, mutants KRAS and TP53 often occurred as clonal events, and the allele frequencies presented linear correlation in the same specimen. All neoplasm-like stroma (characterized with all or initial neoplastic clones and driver events in stroma) harbored KRAS or TP53 mutations. Neoplasm-like and KRAS-mutant stroma was associated with shorter disease-free survival. It is a new finding for the existence of driver gene mutations in PDAC stroma. These data suggest that genomic features of stromal components may serve as prognostic biomarkers in resectable PDAC and might help to guide a more precise treatment paradigm in therapeutic options.
Kaempferia galanga L.: Progresses in Phytochemistry, Pharmacology, Toxicology and Ethnomedicinal Uses
Authors: Wang Si-Yu , Zhao Hui , Xu Hong-Tao , Han Xiao-Dong , Wu Yun-Shan , Xu Fang-Fang , Yang Xiao-Bo , Göransson Ulf , Liu Bo
Published: October 2021

K. galanga is an aromatic medicinal herb. It is locally to India and distributed in China, Myanmar, Indonesia, Malaysia, and Thailand. K. galanga is a Traditional Chinese Herb Medicine (TCHM), which has been applied to treat cold, dry cough, toothaches, rheumatism, hypertension and so on. In addition, it has been used widely as spices since its highly aromas. The aim of this review is to compile and update the current progresses of ethnomedicinal uses, phytochemistry, pharmacology and toxicology of K. galanga. All the data on K. galanga were based on different classical literary works, multiple electronic databases including SciFinder, Web of Science, PubMed, etc. The results showed that ninety-seven compounds have been identified from rhizome of K. galanga, including terpenoids, phenolics, cyclic dipeptides, flavonoids, diarylheptanoids, fatty acids and esters. Modern pharmacology studies revealed that extracts or secondary metabolites of the herb possessed anti-inflammatory, anti-oxidant, anti-tumorous, anti-bacterial, and anti-angiogenesis effects, which were closely related to its abundant ethnomedicinal uses. In conclusion, although previous research works have provided various information of K. galanga, more in-depth studies are still necessary to systemically evaluate phytochemistry, pharmacological activities, toxicity and quality control of this herb.
Phillyrin Prevents Neuroinflammation-Induced Blood–Brain Barrier Damage Following Traumatic Brain Injury via Altering Microglial Polarization
Authors: Jiang Qian , Wei Ding , He Xuejun , Gan Chao , Long Xiaobing , Zhang Huaqiu
Published: October 2021

Background: Phillyrin (Phi) is the main polyphenolic compound found in Forsythia suspensa. Recent studies have revealed that Phi has potent antioxidative and anti-inflammatory effects. However, whether Phi could relieve blood–brain barrier (BBB) damage following traumatic brain injury (TBI) remains unknown.

Materials and Methods: Lipopolysaccharide (LPS) was used to activate primary microglia, which were then treated with different doses of Phi or the peroxisome proliferator–activated receptor-gamma (PPARγ) antagonist (GW9662). CCK-8 assay was used for evaluating cell viability, and the cytokines (including IL-1β, IL-6, TNFα, IL-4, IL-10, and TGFβ), microglial phenotypic markers (iNOS, COX2, and CD86 for “M1” polarization; Arg1, Ym1, and CD206 for “M2” polarization), PPARγ, and NF-κB were determined by RT-PCR, Western blot, or cellular immunofluorescence. Primary cultured mouse brain microvascular endothelial cells (BMECs) were stimulated by the condition medium (CM) from microglia. The cell viability, angiogenesis, and tight junction of BMECs were determined via CCK-8 assay, tube formation assay, and Western blot (for detecting MMP3, MMP9, ZO1, claudin-5, and occludin). Furthermore, the mouse TBI model was constructed and treated with Phi and/or GW9662. The BBB integrity was evaluated by H&E staining, Evans blue staining, and tissue immunofluorescence.

Results: Phi markedly restrained the pro-inflammatory (“M1” state) cytokines and promoted anti-inflammatory (“M2” polarization) cytokines in LPS-mediated microglia. Phi mitigated “M1” polarization and promoted “M2” polarization of microglia via enhancing PPARγ and inhibiting the NF-κB pathway. The PPARγ antagonist GW9662 significantly repressed Phi-mediated anti-inflammatory effects. Meanwhile, Phi enhanced the viability, tube formation ability, and cell junction of BMECs. In the TBI mouse model, Phi promoted “M2” polarization, whereas it repressed the “M1” polarization of microglia. In addition, Phi reduced TBI-mediated BBB damage. However, the protective effects of Phi were reversed mainly by GW9662 treatment.

Conclusion: Phi prevents BBB damage via inhibiting the neuroinflammation of microglia through the PPARγ/NF-κB pathway, which provides a potential therapeutic drug against TBI.
The Function of microRNAs in Pulmonary Embolism: Review and Research Outlook
Authors: Luo Mingyao , Du Mingyuan , Shu Chang , Liu Sheng , Li Jiehua , Zhang Lei , Li Xin
Published: October 2021

Pulmonary embolism (PE) is a common pathologic condition that frequently occurs in patients with deep venous thrombosis. Severe PE may critically suppress cardiopulmonary function, thereby threatening the life of patients. Chronic pulmonary hypertension caused by PE may lead to deterioration of respiratory dysfunction, resulting in complete disability. MicroRNAs (miRNAs) are a group of abundantly expressed non-coding RNAs that exert multiple functions in regulating the transcriptome via post-transcriptional targeting of mRNAs. Specifically, miRNAs bind to target mRNAs in a matching mechanism between the miRNA seed sequence and mRNA 3ʹ UTR, thus modulating the transcript stability or subsequent translation activity by RNA-induced silencing complex. Current studies have reported the function of miRNAs as biomarkers of PE, revealing their mechanism, function, and targetome in venous thrombophilia. This review summarizes the literature on miRNA functions and downstream mechanisms in PE. We conclude that various related miRNAs play important roles in PE and have great potential as treatment targets. For clinical application, we propose that miRNA biomarkers combined with traditional biomarkers or miRNA signatures generated from microchips may serve as a great predictive tool for PE occurrence and prognosis. Further, therapies targeting miRNAs or their upstream/downstream molecules need to be developed more quickly to keep up with the progress of routine treatments, such as anticoagulation, thrombolysis, or surgery.
Klotho as Potential Autophagy Regulator and Therapeutic Target
Authors: Zhou Hongjing , Pu Shiyun , Zhou Houfeng , Guo Yuanxin
Published: October 2021

The protein Klotho can significantly delay aging, so it has attracted widespread attention. Abnormal downregulation of Klotho has been detected in several aging-related diseases, such as Alzheimer’s disease, kidney injury, cancer, chronic obstructive pulmonary disease (COPD), vascular disease, muscular dystrophy and diabetes. Conversely, many exogenous and endogenous factors, several drugs, lifestyle changes and genetic manipulations were reported to exert therapeutic effects through increasing Klotho expression. In recent years, Klotho has been identified as a potential autophagy regulator. How Klotho may contribute to reversing the effects of aging and disease became clearer when it was linked to autophagy, the process in which eukaryotic cells clear away dysfunctional proteins and damaged organelles: the abovementioned diseases involve abnormal autophagy. Interestingly, growing evidence indicates that Klotho plays a dual role as inducer or inhibitor of autophagy in different physiological or pathological conditions through its influence on IGF-1/PI3K/Akt/mTOR signaling pathway, Beclin 1 expression and activity, as well as aldosterone level, which can help restore autophagy to beneficial levels. The present review examines the role of Klotho in regulating autophagy in Alzheimer’s disease, kidney injury, cancer, COPD, vascular disease, muscular dystrophy and diabetes. Targeting Klotho may provide a new perspective for preventing and treating aging-related diseases.
Thyroid Hormone Plays an Important Role in Cardiac Function: From Bench to Bedside
Authors: Yamakawa Hiroyuki , Kato Tomoko S. , Noh Jaeduk Yoshimura , Yuasa Shinsuke , Kawamura Akio , Fukuda Keiichi , Aizawa Yoshiyasu
Published: October 2021

Thyroid hormones (THs) are synthesized in the thyroid gland, and they circulate in the blood to regulate cells, tissues, and organs in the body. In particular, they exert several effects on the cardiovascular system. It is well known that THs raise the heart rate and cardiac contractility, improve the systolic and diastolic function of the heart, and decrease systemic vascular resistance. In the past 30 years, some researchers have studied the molecular pathways that mediate the role of TH in the cardiovascular system, to better understand its mechanisms of action. Two types of mechanisms, which are genomic and non-genomic pathways, underlie the effects of THs on cardiomyocytes. In this review, we summarize the current knowledge of the action of THs in the cardiac function, the clinical manifestation and parameters of their hemodynamics, and treatment principles for patients with hyperthyroid- or hypothyroid-associated heart disease. We also describe the cardiovascular drugs that induce thyroid dysfunction and explain the mechanism underlying the thyroid toxicity of amiodarone, which is considered the most effective antiarrhythmic agent. Finally, we discuss the recent reports on the involvement of thyroid hormones in the regulation of myocardial regeneration and metabolism in the adult heart.
The Effect of Gender and Sex Hormones on Cardiovascular Disease, Heart Failure, Diabetes, and Atrial Fibrillation in Sleep Apnea
Authors: Hegner Philipp , Lebek Simon , Maier Lars Siegfried , Arzt Michael , Wagner Stefan
Published: October 2021

Sleep apnea is a highly prevalent disorder with increasing impact on healthcare systems worldwide. Previous studies have been conducted primarily with male subjects, and prevalence and severity of sleep apnea in women are underestimated. Recent clinical and basic science evidence increasingly points to different mechanisms in men and women with sleep-disordered breathing (SDB). SDB is associated with a variety of comorbidities, including cardiovascular disease, heart failure, diabetes, and atrial fibrillation. In this review, we discuss sex-dependent mechanisms of SDB in select associated conditions to sharpen our clinical understanding of these sex-dependent inherent differences.