-
International Journal of Molecular... Oct 2019Sepsis is defined as "a life-threatening organ dysfunction caused by a host's dysfunctional response to infection". Although the treatment of sepsis has developed... (Review)
Review
Sepsis is defined as "a life-threatening organ dysfunction caused by a host's dysfunctional response to infection". Although the treatment of sepsis has developed rapidly in the past few years, sepsis incidence and mortality in clinical treatment is still climbing. Moreover, because of the diverse manifestations of sepsis, clinicians continue to face severe challenges in the diagnosis, treatment, and management of patients with sepsis. Here, we review the recent development in our understanding regarding the cellular pathogenesis and the target of clinical diagnosis of sepsis, with the goal of enhancing the current understanding of sepsis. The present state of research on targeted therapeutic drugs is also elaborated upon to provide information for the treatment of sepsis.
Topics: Autophagy; Biomarkers; Blood Coagulation Disorders; Endoplasmic Reticulum Stress; Humans; Incidence; Inflammation; Mitochondrial Diseases; Neuroendocrine Cells; Sepsis; Virulence
PubMed: 31671729
DOI: 10.3390/ijms20215376 -
Seminars in Immunopathology Jul 2016The immunopathology of chronic obstructive pulmonary disease (COPD) is based on the innate and adaptive inflammatory immune responses to the chronic inhalation of... (Review)
Review
The immunopathology of chronic obstructive pulmonary disease (COPD) is based on the innate and adaptive inflammatory immune responses to the chronic inhalation of cigarette smoking. In the last quarter of the century, the analysis of specimens obtained from the lower airways of COPD patients compared with those from a control group of age-matched smokers with normal lung function has provided novel insights on the potential pathogenetic role of the different cells of the innate and acquired immune responses and their pro/anti-inflammatory mediators and intracellular signalling pathways, contributing to a better knowledge of the immunopathology of COPD both during its stable phase and during its exacerbations. This also has provided a scientific rationale for new drugs discovery and targeting to the lower airways. This review summarises and discusses the immunopathology of COPD patients, of different severity, compared with control smokers with normal lung function.
Topics: Adaptive Immunity; Autoimmunity; B-Lymphocytes; Biomarkers; Cell Communication; Cytokines; Disease Progression; Gene Expression; Humans; Immunity, Innate; Inflammation Mediators; Lymphocyte Activation; Neuroendocrine Cells; Neuropeptides; Neurotransmitter Agents; Oxidative Stress; Pulmonary Disease, Chronic Obstructive; Respiratory Mucosa; T-Lymphocyte Subsets
PubMed: 27178410
DOI: 10.1007/s00281-016-0561-5 -
Science (New York, N.Y.) Jun 2018Pulmonary neuroendocrine cells (PNECs) are rare airway epithelial cells whose function is poorly understood. Here we show that -mutant mice that have no PNECs exhibit...
Pulmonary neuroendocrine cells (PNECs) are rare airway epithelial cells whose function is poorly understood. Here we show that -mutant mice that have no PNECs exhibit severely blunted mucosal type 2 response in models of allergic asthma. PNECs reside in close proximity to group 2 innate lymphoid cells (ILC2s) near airway branch points. PNECs act through calcitonin gene-related peptide (CGRP) to stimulate ILC2s and elicit downstream immune responses. In addition, PNECs act through the neurotransmitter γ-aminobutyric acid (GABA) to induce goblet cell hyperplasia. The instillation of a mixture of CGRP and GABA in -mutant airways restores both immune and goblet cell responses. In accordance, lungs from human asthmatics show increased PNECs. These findings demonstrate that the PNEC-ILC2 neuroimmunological modules function at airway branch points to amplify allergic asthma responses.
Topics: Animals; Asthma; Basic Helix-Loop-Helix Transcription Factors; Calcitonin Gene-Related Peptide; Cytokines; Disease Models, Animal; Epithelial Cells; Female; Goblet Cells; Humans; Hyperplasia; Lung; Mice; Neuroendocrine Cells; gamma-Aminobutyric Acid
PubMed: 29599193
DOI: 10.1126/science.aan8546 -
Nature Reviews. Immunology Jun 2021The community of cells lining our airways plays a collaborative role in the preservation of immune homeostasis in the lung and provides protection from the pathogens and... (Review)
Review
The community of cells lining our airways plays a collaborative role in the preservation of immune homeostasis in the lung and provides protection from the pathogens and pollutants in the air we breathe. In addition to its structural attributes that provide effective mucociliary clearance of the lower airspace, the airway epithelium is an immunologically active barrier surface that senses changes in the airway environment and interacts with resident and recruited immune cells. Single-cell RNA-sequencing is illuminating the cellular heterogeneity that exists in the airway wall and has identified novel cell populations with unique molecular signatures, trajectories of differentiation and diverse functions in health and disease. In this Review, we discuss how our view of the airway epithelial landscape has evolved with the advent of transcriptomic approaches to cellular phenotyping, with a focus on epithelial interactions with the local neuronal and immune systems.
Topics: Animals; Apoptosis; Cellular Microenvironment; Circadian Rhythm; Epithelial Cells; Genetic Markers; Humans; Immunologic Memory; Mice; Models, Immunological; Neuroendocrine Cells; Neuroimmunomodulation; RNA-Seq; Respiratory Mucosa; Single-Cell Analysis
PubMed: 33442032
DOI: 10.1038/s41577-020-00477-9 -
Communications Biology Dec 2020Neuroendocrine prostate cancer is one of the most aggressive subtypes of prostate tumor. Although much progress has been made in understanding the development of...
Neuroendocrine prostate cancer is one of the most aggressive subtypes of prostate tumor. Although much progress has been made in understanding the development of neuroendocrine prostate cancer, the cellular architecture associated with neuroendocrine differentiation in human prostate cancer remain incompletely understood. Here, we use single-cell RNA sequencing to profile the transcriptomes of 21,292 cells from needle biopsies of 6 castration-resistant prostate cancers. Our analyses reveal that all neuroendocrine tumor cells display a luminal-like epithelial phenotype. In particular, lineage trajectory analysis suggests that focal neuroendocrine differentiation exclusively originate from luminal-like malignant cells rather than basal compartment. Further tissue microarray analysis validates the generality of the luminal phenotype of neuroendocrine cells. Moreover, we uncover neuroendocrine differentiation-associated gene signatures that may help us to further explore other intrinsic molecular mechanisms deriving neuroendocrine prostate cancer. In summary, our single-cell study provides direct evidence into the cellular states underlying neuroendocrine transdifferentiation in human prostate cancer.
Topics: Aged; Aged, 80 and over; Biopsy; Carcinoma, Neuroendocrine; Cell Line, Tumor; Computational Biology; Epithelial-Mesenchymal Transition; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Male; Neuroendocrine Cells; Prostatic Neoplasms; Single-Cell Analysis; Transcriptome
PubMed: 33328604
DOI: 10.1038/s42003-020-01476-1 -
Cell Reports Aug 2016Small cell lung carcinoma (SCLC) is a high-grade pulmonary neuroendocrine tumor. The transcription factors ASCL1 and NEUROD1 play crucial roles in promoting malignant...
Small cell lung carcinoma (SCLC) is a high-grade pulmonary neuroendocrine tumor. The transcription factors ASCL1 and NEUROD1 play crucial roles in promoting malignant behavior and survival of human SCLC cell lines. Here, we find that ASCL1 and NEUROD1 identify heterogeneity in SCLC, bind distinct genomic loci, and regulate mostly distinct genes. ASCL1, but not NEUROD1, is present in mouse pulmonary neuroendocrine cells, and only ASCL1 is required in vivo for tumor formation in mouse models of SCLC. ASCL1 targets oncogenic genes including MYCL1, RET, SOX2, and NFIB while NEUROD1 targets MYC. ASCL1 and NEUROD1 regulate different genes that commonly contribute to neuronal function. ASCL1 also regulates multiple genes in the NOTCH pathway including DLL3. Together, ASCL1 and NEUROD1 distinguish heterogeneity in SCLC with distinct genomic landscapes and distinct gene expression programs.
Topics: Animals; Basic Helix-Loop-Helix Transcription Factors; Cell Line, Tumor; Female; Gene Expression; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Male; Mice; Neuroendocrine Cells; Neuroendocrine Tumors; Oncogenes; Proto-Oncogene Proteins c-myc; Small Cell Lung Carcinoma; Transcription Factors
PubMed: 27452466
DOI: 10.1016/j.celrep.2016.06.081 -
Neuron Jun 2019How general anesthesia (GA) induces loss of consciousness remains unclear, and whether diverse anesthetic drugs and sleep share a common neural pathway is unknown....
How general anesthesia (GA) induces loss of consciousness remains unclear, and whether diverse anesthetic drugs and sleep share a common neural pathway is unknown. Previous studies have revealed that many GA drugs inhibit neural activity through targeting GABA receptors. Here, using Fos staining, ex vivo brain slice recording, and in vivo multi-channel electrophysiology, we discovered a core ensemble of hypothalamic neurons in and near the supraoptic nucleus, consisting primarily of neuroendocrine cells, which are persistently and commonly activated by multiple classes of GA drugs. Remarkably, chemogenetic or brief optogenetic activations of these anesthesia-activated neurons (AANs) strongly promote slow-wave sleep and potentiates GA, whereas conditional ablation or inhibition of AANs led to diminished slow-wave oscillation, significant loss of sleep, and shortened durations of GA. These findings identify a common neural substrate underlying diverse GA drugs and natural sleep and reveal a crucial role of the neuroendocrine system in regulating global brain states. VIDEO ABSTRACT.
Topics: Anesthesia, General; Anesthetics, General; Animals; Dexmedetomidine; Electroencephalography; Electromyography; Electrophysiological Phenomena; Hypnotics and Sedatives; Hypothalamus; Isoflurane; Ketamine; Mice; Neuroendocrine Cells; Neurons; Optogenetics; Patch-Clamp Techniques; Propofol; Proto-Oncogene Proteins c-fos; Sleep; Sleep, Slow-Wave; Supraoptic Nucleus
PubMed: 31006556
DOI: 10.1016/j.neuron.2019.03.033 -
Theranostics 2024Neuroendocrine prostate cancer (NEPC) typically implies severe lethality and limited treatment options. The precise identification of NEPC cells holds paramount...
Neuroendocrine prostate cancer (NEPC) typically implies severe lethality and limited treatment options. The precise identification of NEPC cells holds paramount significance for both research and clinical applications, yet valid NEPC biomarker remains to be defined. Leveraging 11 published NE-related gene sets, 11 single-cell RNA-sequencing (scRNA-seq) cohorts, 15 bulk transcriptomic cohorts, and 13 experimental models of prostate cancer (PCa), we employed multiple advanced algorithms to construct and validate a robust NEPC risk prediction model. Through the compilation of a comprehensive scRNA-seq reference atlas (comprising a total of 210,879 single cells, including 66 tumor samples) from 9 multicenter datasets of PCa, we observed inconsistent and inefficient performance among the 11 published NE gene sets. Therefore, we developed an integrative analysis pipeline, identifying 762 high-quality NE markers. Subsequently, we derived the NE cell-intrinsic gene signature, and developed an R package named NEPAL, to predict NEPC risk scores. By applying to multiple independent validation datasets, NEPAL consistently and accurately assigned NE feature and delineated PCa progression. Intriguingly, NEPAL demonstrated predictive capabilities for prognosis and therapy responsiveness, as well as the identification of potential epigenetic drivers of NEPC. The present study furnishes a valuable tool for the identification of NEPC and the monitoring of PCa progression through transcriptomic profiles obtained from both bulk and single-cell sources.
Topics: Male; Humans; Neuroendocrine Cells; Prostatic Neoplasms; Prostate; Gene Expression Profiling; Transcriptome
PubMed: 38250042
DOI: 10.7150/thno.92336 -
Frontiers in Endocrinology 2021
Topics: Animals; Cell Communication; Disease; Gene Regulatory Networks; Health; Hormones; Humans; Immune System; Nerve Net; Neuroendocrine Cells; Neuroimmunomodulation; Neurotransmitter Agents
PubMed: 34552560
DOI: 10.3389/fendo.2021.718893 -
Neuroendocrinology 2023Extracellular vesicles (EVs) are membrane-enclosed nanoparticles that contain various biomolecules, including nucleic acids, proteins and lipids, and are manufactured... (Review)
Review
Extracellular vesicles (EVs) are membrane-enclosed nanoparticles that contain various biomolecules, including nucleic acids, proteins and lipids, and are manufactured and released by virtually all cell types. There is evidence that EVs are involved in intercellular communication, acting in an autocrine, paracrine or/and endocrine manner. EVs are released by the cells of the central nervous system (CNS), including neurons, astrocytes, oligodendrocytes and microglia, and have the ability to cross the blood-brain barrier (BBB) and enter the systemic circulation. Neuroendocrine cells are specialized neurons that secrete hormones directly into blood vessels, such as the hypophyseal portal system or the systemic circulation, a process that allows neuroendocrine integration to take place. In mammals, neuroendocrine cells are widely distributed throughout various anatomic compartments, with the hypothalamus being a central neuroendocrine integrator. The hypothalamus is a key part of the stress system (SS), a highly conserved neuronal/neuroendocrine system aiming at maintaining systemic homeostasis when the latter is threatened by various stressors. The central parts of the SS are the interconnected hypothalamic corticotropin-releasing hormone (CRH) and the brainstem locus caeruleus-norepinephrine (LC-NE) systems, while their peripheral parts are, respectively, the pituitary-adrenal axis and the sympathetic nervous/sympatho-adrenomedullary systems (SNS-SAM) as well as components of the parasympathetic nervous system (PSNS). During stress, multiple CNS loci show plasticity and undergo remodeling, partly mediated by increased glutamatergic and noradrenergic activity, and the actions of cytokines and glucocorticoids, all regulated by the interaction of the hypothalamic-pituitary-adrenal (HPA) axis and the LC-NE/SNS-SAM systems. In addition, there are peripheral changes due to the increased secretion of stress hormones and pro-inflammatory cytokines in the context of stress-related systemic (para)inflammation. We speculate that during stress, central and peripheral, cellular and molecular alterations take place, with some of them generated, communicated, and spread via the release of stress-induced neural/neuroendocrine cell-derived EVs.
Topics: Animals; Hypothalamo-Hypophyseal System; Neurosecretory Systems; Adrenocorticotropic Hormone; Norepinephrine; Extracellular Vesicles; Cytokines; Pituitary-Adrenal System; Stress, Physiological; Corticotropin-Releasing Hormone; Mammals
PubMed: 36137504
DOI: 10.1159/000527182