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1.
Nat Commun ; 11(1): 5077, 2020 10 08.
Artículo en Inglés | MEDLINE | ID: mdl-33033240

RESUMEN

Although substantial progress has been made in cancer biology and treatment, clinical outcomes of bladder carcinoma (BC) patients are still not satisfactory. The tumor microenvironment (TME) is a potential target. Here, by single-cell RNA sequencing on 8 BC tumor samples and 3 para tumor samples, we identify 19 different cell types in the BC microenvironment, indicating high intra-tumoral heterogeneity. We find that tumor cells down regulated MHC-II molecules, suggesting that the downregulated immunogenicity of cancer cells may contribute to the formation of an immunosuppressive microenvironment. We also find that monocytes undergo M2 polarization in the tumor region and differentiate. Furthermore, the LAMP3 + DC subgroup may be able to recruit regulatory T cells, potentially taking part in the formation of an immunosuppressive TME. Through correlation analysis using public datasets containing over 3000 BC samples, we identify a role for inflammatory cancer-associated fibroblasts (iCAFs) in tumor progression, which is significantly related to poor prognosis. Additionally, we characterize a regulatory network depending on iCAFs. These results could help elucidate the protumor mechanisms of iCAFs. Our results provide deep insight into cancer immunology and provide an essential resource for drug discovery in the future.


Asunto(s)
Fibroblastos/patología , Inflamación/patología , Análisis de Secuencia de ARN , Análisis de la Célula Individual , Vejiga Urinaria/patología , Área Bajo la Curva , Fibroblastos Asociados al Cáncer/metabolismo , Fibroblastos Asociados al Cáncer/patología , Línea Celular Tumoral , Polaridad Celular , Proliferación Celular , Citocinas/metabolismo , Variaciones en el Número de Copia de ADN/genética , Células Dendríticas/metabolismo , Redes Reguladoras de Genes , Humanos , Ligandos , Glicoproteínas de la Membrana Asociadas a los Lisosomas/metabolismo , Monocitos/patología , Células Mieloides/patología , Proteínas de Neoplasias/metabolismo , Linfocitos T Reguladores/inmunología , Microambiente Tumoral , Vejiga Urinaria/inmunología
2.
Nat Commun ; 11(1): 4966, 2020 10 02.
Artículo en Inglés | MEDLINE | ID: mdl-33009404

RESUMEN

Temporal lobe epilepsy (TLE) is the most common type of drug-resistant epilepsy in adults, with an unknown etiology. A hallmark of TLE is the characteristic loss of layer 3 neurons in the medial entorhinal area (MEA) that underlies seizure development. One approach to intervention is preventing loss of these neurons through better understanding of underlying pathophysiological mechanisms. Here, we show that both neurons and glia together give rise to the pathology that is mitigated by the amino acid D-serine whose levels are potentially diminished under epileptic conditions. Focal administration of D-serine to the MEA attenuates neuronal loss in this region thereby preventing epileptogenesis in an animal model of TLE. Additionally, treatment with D-serine reduces astrocyte counts in the MEA, alters their reactive status, and attenuates proliferation and/or infiltration of microglia to the region thereby curtailing the deleterious consequences of neuroinflammation. Given the paucity of compounds that reduce hyperexcitability and neuron loss, have anti-inflammatory properties, and are well tolerated by the brain, D-serine, an endogenous amino acid, offers new hope as a therapeutic agent for refractory TLE.


Asunto(s)
Epilepsia del Lóbulo Temporal/tratamiento farmacológico , Epilepsia del Lóbulo Temporal/patología , Serina/uso terapéutico , Animales , Astrocitos/efectos de los fármacos , Astrocitos/patología , Conducta Animal , Encéfalo/patología , Corteza Entorrinal/efectos de los fármacos , Corteza Entorrinal/patología , Gliosis/patología , Inflamación/patología , Microglía/efectos de los fármacos , Microglía/patología , Neuronas/efectos de los fármacos , Neuronas/patología , Ratas Sprague-Dawley , Serina/administración & dosificación , Serina/farmacología
3.
Molecules ; 25(20)2020 Oct 14.
Artículo en Inglés | MEDLINE | ID: mdl-33066442

RESUMEN

The activation of NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) inflammasome and/or its components is associated with the physio-pathogenesis of many respiratory diseases including asthma, COPD (chronic obstructive pulmonary disease), SARS Cov-2 (severe acute respiratory syndrome coronavirus 2), and in several autoimmune diseases. Hibiscus noldeae Baker f. has been widely reported to be traditionally used in the treatment of different ailments, some of which are of inflammatory background such as asthma, wounds, headache, etc. However, the claims have not been supported by evidence at the molecular and functional levels. Here, we report on the bio-guided fractionation of H. noldeae and assessment of the inhibitory properties of some fractions and purified compounds on NLRP3 inflammasome and Interleukin 6 (IL-6). The activation of the NLRP3 inflammasome was determined by detecting the activity of caspase-1 and the production of Interleukin 1ß (IL-1ß) in Lipopolysaccharide (LPS) and ATP-stimulated Tamm-Horsfall Protein 1 (THP-1) macrophages, while the production of IL-6 was studied in LPS-stimulated RAW264.7 mouse macrophages. It was observed that hexane and ethyl acetate fractions of the crude extract of the aerial parts of H. noldeae, as well as caffeic acid, isoquercetin, and ER2.4 and ER2.7 fractions revealed significant inhibitory effects on Caspase-1 activities, and on IL-1ß and IL-6 production. The ER2.4 and ER2.7 fractions downregulated the production of IL-1ß and IL-6, in a similar range as the caspase-1 inhibitor AC-YVAD-CHO and the drug Dexamethasone, both used as controls, respectively. Overall, our work does provide the very first scientific based evidence for Hibiscus noldeae anti-inflammatory effects and widespread use by traditional healers in Rwanda for a variety of ailments.


Asunto(s)
Antiinflamatorios/farmacología , Hibiscus/química , Inflamasomas/efectos de los fármacos , Inflamación/tratamiento farmacológico , Interleucina-6/antagonistas & inhibidores , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Extractos Vegetales/farmacología , Animales , Inflamasomas/inmunología , Inflamasomas/metabolismo , Inflamación/inmunología , Inflamación/metabolismo , Inflamación/patología , Interleucina-6/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Macrófagos/metabolismo , Ratones , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Células RAW 264.7
4.
Nat Commun ; 11(1): 4596, 2020 09 14.
Artículo en Inglés | MEDLINE | ID: mdl-32929083

RESUMEN

Earlier studies indicate that either the canonical or non-canonical pathways of inflammasome activation have a limited role on malaria pathogenesis. Here, we report that caspase-8 is a central mediator of systemic inflammation, septic shock in the Plasmodium chabaudi-infected mice and the P. berghei-induced experimental cerebral malaria (ECM). Importantly, our results indicate that the combined deficiencies of caspases-8/1/11 or caspase-8/gasdermin-D (GSDM-D) renders mice impaired to produce both TNFα and IL-1ß and highly resistant to lethality in these models, disclosing a complementary, but independent role of caspase-8 and caspases-1/11/GSDM-D in the pathogenesis of malaria. Further, we find that monocytes from malaria patients express active caspases-1, -4 and -8 suggesting that these inflammatory caspases may also play a role in the pathogenesis of human disease.


Asunto(s)
Caspasa 8/metabolismo , Inflamación/patología , Malaria Cerebral/enzimología , Animales , Encéfalo/patología , Caspasa 1/metabolismo , Células Dendríticas/metabolismo , Activación Enzimática , Matriz Extracelular/metabolismo , Regulación de la Expresión Génica , Humanos , Interferón gamma/metabolismo , Interleucina-1beta/metabolismo , Lipopolisacáridos , Malaria Cerebral/genética , Ratones Endogámicos C57BL , Monocitos/metabolismo , Plasmodium chabaudi/fisiología , Bazo/metabolismo , Receptores Toll-Like/metabolismo
5.
Nat Commun ; 11(1): 4766, 2020 09 21.
Artículo en Inglés | MEDLINE | ID: mdl-32958778

RESUMEN

Germline telomere maintenance defects are associated with an increased incidence of inflammatory diseases in humans, yet whether and how telomere dysfunction causes inflammation are not known. Here, we show that telomere dysfunction drives pATM/c-ABL-mediated activation of the YAP1 transcription factor, up-regulating the major pro-inflammatory factor, pro-IL-18. The colonic microbiome stimulates cytosolic receptors activating caspase-1 which cleaves pro-IL-18 into mature IL-18, leading to recruitment of interferon (IFN)-γ-secreting T cells and intestinal inflammation. Correspondingly, patients with germline telomere maintenance defects exhibit DNA damage (γH2AX) signaling together with elevated YAP1 and IL-18 expression. In mice with telomere dysfunction, telomerase reactivation in the intestinal epithelium or pharmacological inhibition of ATM, YAP1, or caspase-1 as well as antibiotic treatment, dramatically reduces IL-18 and intestinal inflammation. Thus, telomere dysfunction-induced activation of the ATM-YAP1-pro-IL-18 pathway in epithelium is a key instigator of tissue inflammation.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas de Ciclo Celular/metabolismo , Inflamación/patología , Telómero/patología , Proteínas Adaptadoras Transductoras de Señales/antagonistas & inhibidores , Proteínas Adaptadoras Transductoras de Señales/genética , Animales , Antibacterianos/uso terapéutico , Proteínas de la Ataxia Telangiectasia Mutada/antagonistas & inhibidores , Proteínas de la Ataxia Telangiectasia Mutada/metabolismo , Caspasa 1/metabolismo , Proteínas de Ciclo Celular/antagonistas & inhibidores , Proteínas de Ciclo Celular/genética , Niño , Colon/metabolismo , Colon/microbiología , Colon/patología , Enfermedades Gastrointestinales/patología , Microbioma Gastrointestinal/efectos de los fármacos , Microbioma Gastrointestinal/fisiología , Humanos , Inflamación/tratamiento farmacológico , Inflamación/metabolismo , Inflamación/microbiología , Interleucina-18/genética , Interleucina-18/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patología , Ratones , Ratones Mutantes , Fosforilación , Precursores de Proteínas/genética , Precursores de Proteínas/metabolismo , Transducción de Señal , Telomerasa/genética , Telomerasa/metabolismo
6.
Open Biol ; 10(9): 200160, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32961074

RESUMEN

Coronavirus disease 2019 (COVID-19) has swept the world, unlike any other pandemic in the last 50 years. Our understanding of the disease has evolved rapidly since the outbreak; disease prognosis is influenced mainly by multi-organ involvement. Acute respiratory distress syndrome, heart failure, renal failure, liver damage, shock and multi-organ failure are strongly associated with morbidity and mortality. The COVID-19 disease pathology is plausibly linked to the hyperinflammatory response of the body characterized by pathological cytokine levels. The term 'cytokine storm syndrome' is perhaps one of the critical hallmarks of COVID-19 disease severity. In this review, we highlight prominent cytokine families and their potential role in COVID-19, the type I and II interferons, tumour necrosis factor and members of the Interleukin family. We address various changes in cellular components of the immune response corroborating with changes in cytokine levels while discussing cytokine sources and biological functions. Finally, we discuss in brief potential therapies attempting to modulate the cytokine storm.


Asunto(s)
Infecciones por Coronavirus/patología , Síndrome de Liberación de Citoquinas/patología , Citocinas/sangre , Neumonía Viral/patología , Betacoronavirus/inmunología , Síndrome de Liberación de Citoquinas/sangre , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Humanos , Inflamación/patología , Pandemias
7.
PLoS Pathog ; 16(9): e1008811, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32903274

RESUMEN

Damage-associated molecular patterns (DAMPs) are endogenous molecules activating the immune system upon release from injured cells. Here we show that the IFI16 protein, once freely released in the extracellular milieu of chronically inflamed tissues, can function as a DAMP either alone or upon binding to lipopolysaccharide (LPS). Specifically, using pull-down and saturation binding experiments, we show that IFI16 binds with high affinity to the lipid A moiety of LPS. Remarkably, IFI16 DAMP activity is potentiated upon binding to subtoxic concentrations of strong TLR4-activating LPS variants, as judged by TLR4-MD2/TIRAP/MyD88-dependent IL-6, IL-8 and TNF-α transcriptional activation and release in stimulated monocytes and renal cells. Consistently, using co-immunoprecipitation (co-IP) and surface plasmon resonance (SPR) approaches, we show that IFI16 is a specific TLR4-ligand and that IFI16/LPS complexes display a faster stimulation turnover on TLR4 than LPS alone. Altogether, our findings point to a novel pathomechanism of inflammation involving the formation of multiple complexes between extracellular IFI16 and subtoxic doses of LPS variants, which then signal through TLR4.


Asunto(s)
Inflamación/inmunología , Neoplasias Renales/inmunología , Leucemia/inmunología , Lipopolisacáridos/metabolismo , Proteínas Nucleares/metabolismo , Fosfoproteínas/metabolismo , Receptor Toll-Like 4/metabolismo , Humanos , Inflamación/metabolismo , Inflamación/patología , Neoplasias Renales/metabolismo , Neoplasias Renales/patología , Leucemia/metabolismo , Leucemia/patología , Factor 88 de Diferenciación Mieloide/metabolismo , FN-kappa B/metabolismo , Transducción de Señal , Células Tumorales Cultivadas
8.
Cytokine ; 136: 155256, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-32866898

RESUMEN

The COVID-19 pandemic has rapidly spread around the world with significant morbidity and mortality in a subset of patients including the elderly. The poorer outcomes are associated with 'cytokine storm-like' immune responses, otherwise referred to as 'hyperinflammation'. While most of the infected individuals show minimal or no symptoms and recover spontaneously, a small proportion of the patients exhibit severe symptoms characterized by extreme dyspnea and low tissue oxygen levels, with extensive damage to the lungs referred to as acute respiratory distress symptom (ARDS). The consensus is that the hyperinflammatory response of the host is akin to the cytokine storm observed during sepsis and is the major cause of death. Uncertainties remain on the factors that lead to hyperinflammatory response in some but not all individuals. Hyperinflammation is a common feature in different viral infections such as dengue where existing low-titer antibodies to the virus enhances the infection in immune cells through a process called antibody-dependent enhancement or ADE. ADE has been reported following vaccination or secondary infections with other corona, Ebola and dengue virus. Detailed analysis has shown that antibodies to any viral epitope can induce ADE when present in sub-optimal titers or is of low affinity. In this review we will discuss ADE in the context of dengue and coronavirus infections including Covid-19.


Asunto(s)
Acrecentamiento Dependiente de Anticuerpo/inmunología , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/veterinaria , Peritonitis Infecciosa Felina/inmunología , Inflamación/patología , Pandemias/veterinaria , Neumonía Viral/inmunología , Neumonía Viral/veterinaria , Dengue Grave/inmunología , Animales , Gatos , Citocinas/metabolismo
10.
Medicine (Baltimore) ; 99(38): e22241, 2020 Sep 18.
Artículo en Inglés | MEDLINE | ID: mdl-32957369

RESUMEN

BACKGROUND: Quercetin, a major flavonol, wildly exists in plantage, which has been reported to have an anti-apoptosis and anti-inflammation effects on vascular endothelial cells, but its underlying molecular mechanisms remain unclear. OBJECTIVE: The aim of this study was to investigate the mechanisms of how quercetin inhibits tumor necrosis factor alpha (TNF-α) induced human umbilical vein endothelial cells (HUVECs) apoptosis and inflammation. METHODS AND RESULTS: HUVECs were preconditioned with quercetin for 18 hours, and subsequently treated with TNF-α for 6 hours to induce apoptosis. The expression of intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), E-selectin, ß-actin mRNA was then detected by RT-PCR. Flow cytometry was used to estimate the apoptosis rates, and the expression of activator protein 1 (AP-1) and nuclear factor kappa B (NF-κB) was measured by Western blot. TNF-α induced elevated apoptosis rates and upregulation of VCAM-1, ICAM-1, and E-selectin were meaningfully reduced in HUVECs by pretreatment with quercetin. In addition, quercetin also inhibited the activation of AP-1and NF-κB. CONCLUSION: Results indicate that quercetin could suppress TNF-α induced apoptosis and inflammation by blocking NF-κB and AP-1 signaling pathway in HUVECs, which might be one of the underlying mechanisms in treatment of coronary heart disease.


Asunto(s)
Antiinflamatorios/farmacología , Apoptosis/efectos de los fármacos , Células Endoteliales de la Vena Umbilical Humana/citología , Inflamación/prevención & control , FN-kappa B/metabolismo , Quercetina/farmacología , Factor de Transcripción AP-1/metabolismo , Regulación hacia Abajo , Selectina E/metabolismo , Humanos , Inflamación/metabolismo , Inflamación/patología , Molécula 1 de Adhesión Intercelular/metabolismo , Transducción de Señal , Factor de Necrosis Tumoral alfa/farmacología , Molécula 1 de Adhesión Celular Vascular/metabolismo
11.
Mol Cell ; 80(1): 43-58.e7, 2020 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-32937100

RESUMEN

Immune cell function depends on specific metabolic programs dictated by mitochondria, including nutrient oxidation, macromolecule synthesis, and post-translational modifications. Mitochondrial adaptations have been linked to acute and chronic inflammation, but the metabolic cues and precise mechanisms remain unclear. Here we reveal that histone deacetylase 3 (HDAC3) is essential for shaping mitochondrial adaptations for IL-1ß production in macrophages through non-histone deacetylation. In vivo, HDAC3 promoted lipopolysaccharide-induced acute inflammation and high-fat diet-induced chronic inflammation by enhancing NLRP3-dependent caspase-1 activation. HDAC3 configured the lipid profile in stimulated macrophages and restricted fatty acid oxidation (FAO) supported by exogenous fatty acids for mitochondria to acquire their adaptations and depolarization. Rather than affecting nuclear gene expression, HDAC3 translocated to mitochondria to deacetylate and inactivate an FAO enzyme, mitochondrial trifunctional enzyme subunit α. HDAC3 may serve as a controlling node that balances between acquiring mitochondrial adaptations and sustaining their fitness for IL-1ß-dependent inflammation.


Asunto(s)
Ácidos Grasos/metabolismo , Histona Desacetilasas/metabolismo , Inflamación/metabolismo , Interleucina-1beta/metabolismo , Mitocondrias/metabolismo , Adulto , Animales , Caspasa 1/metabolismo , Femenino , Humanos , Inflamación/patología , Metabolismo de los Lípidos , Masculino , Ratones Endogámicos C57BL , Ratones Noqueados , Persona de Mediana Edad , Mitocondrias/ultraestructura , Subunidad alfa de la Proteína Trifuncional Mitocondrial/metabolismo , Células Mieloides/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Oxidación-Reducción , Fosforilación Oxidativa , Adulto Joven
12.
Adv Exp Med Biol ; 1274: 71-99, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32894508

RESUMEN

Bioactive lipid mediators resulting from the metabolism of polyunsaturated fatty acids (PUFA) are controlled by many pathways that regulate the levels of these mediators and maintain homeostasis to prevent disease. PUFA metabolism is driven primarily through three pathways. Two pathways, the cyclooxygenase (COX) and lipoxygenase (LO) enzymatic pathways, form metabolites that are mostly inflammatory, while the third route of metabolism results from the oxidation by the cytochrome P450 enzymes to form hydroxylated PUFA and epoxide metabolites. These epoxygenated fatty acids (EpFA) demonstrate largely anti-inflammatory and beneficial properties, in contrast to the other metabolites formed from the degradation of PUFA. Dysregulation of these systems often leads to chronic disease. Pharmaceutical targets of disease focus on preventing the formation of inflammatory metabolites from the COX and LO pathways, while maintaining the EpFA and increasing their concentration in the body is seen as beneficial to treating and preventing disease. The soluble epoxide hydrolase (sEH) is the major route of metabolism of EpFA. Inhibiting its activity increases concentrations of beneficial EpFA, and often disease states correlate to mutations in the sEH enzyme that increase its activity and decrease the concentrations of EpFA in the body. Recent approaches to increasing EpFA include synthetic mimics that replicate biological activity of EpFA while preventing their metabolism, while other approaches focus on developing small molecule inhibitors to the sEH. Increasing EpFA concentrations in the body has demonstrated multiple beneficial effects in treating many diseases, including inflammatory and painful conditions, cardiovascular disease, neurological and disease of the central nervous system. Demonstration of efficacy in so many disease states can be explained by the fundamental mechanism that EpFA have of maintaining healthy microvasculature and preventing mitochondrial and endoplasmic reticulum stress. While there are no FDA approved methods that target the sEH or other enzymes responsible for metabolizing EpFA, current clinical efforts to test for efficacy by increasing EpFA that include inhibiting the sEH or administration of EpFA mimics that block metabolism are in progress.


Asunto(s)
Enfermedades Cardiovasculares/tratamiento farmacológico , Estrés del Retículo Endoplásmico , Ácidos Grasos/metabolismo , Inflamación/tratamiento farmacológico , Mitocondrias/patología , Terapia Molecular Dirigida , Manejo del Dolor , Enfermedades Cardiovasculares/metabolismo , Estrés del Retículo Endoplásmico/efectos de los fármacos , Humanos , Inflamación/patología , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Dolor
13.
Lancet Oncol ; 21(9): e419-e430, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32888471

RESUMEN

Notable advances have been achieved in the treatment of cancer since the advent of immunotherapy, and immune checkpoint inhibitors have shown clinical benefit across a wide variety of tumour types. Nevertheless, most patients still progress on these treatments, highlighting the importance of unravelling the underlying mechanisms of primary resistance to immunotherapy. A well described biomarker of non-responsiveness to immune checkpoint inhibitors is the absence or low presence of lymphocytes in the tumour microenvironment, so-called cold tumours. There are five mechanisms of action that have the potential to turn cold tumours into so-called hot and inflamed tumours, hence increasing the tumour's responsiveness to immunotherapy-increasing local inflammation, neutralising immunosuppression at the tumour site, modifying the tumour vasculature, targeting the tumour cells themselves, or increasing the frequency of tumour-specific T cells. In this Review, we discuss preclinical data that serves as the basis for ongoing immunotherapy clinical trials for the treatment of non-immunoreactive tumours, as well as reviewing clinical and translational data where available. We explain how improving our understanding of the underlying mechanisms of primary resistance to immunotherapy will help elucidate an increasingly granular view of the tumour microenvironment cellular composition, functional status, and cellular localisation, with the goal of further therapy refinement.


Asunto(s)
Resistencia a Antineoplásicos/inmunología , Inmunoterapia/efectos adversos , Inflamación/terapia , Neoplasias/terapia , Microambiente Tumoral/efectos de los fármacos , Antineoplásicos Inmunológicos/inmunología , Antineoplásicos Inmunológicos/uso terapéutico , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/antagonistas & inhibidores , Quinasa 1 Reguladora del Ciclo Celular (Checkpoint 1)/inmunología , Ensayos Clínicos como Asunto , Humanos , Inmunidad Celular/inmunología , Inflamación/inmunología , Inflamación/patología , Linfocitos/efectos de los fármacos , Linfocitos/inmunología , Neoplasias/inmunología , Neoplasias/patología , Microambiente Tumoral/inmunología
14.
Zhonghua Wei Chang Wai Ke Za Zhi ; 23(9): 896-903, 2020 Sep 25.
Artículo en Chino | MEDLINE | ID: mdl-32927515

RESUMEN

Objective: At present, the modified NIH classification commonly used in clinical practice is still insufficient for assessing the risk of postoperative recurrence in some patients with intermediate-high risk gastrointestinal stromal tumors (GIST). Through exploring risk factors for recurrence of intermediate-high risk GIST, this study establishes a predictive model for recurrence with more convenience and more precision in order to guide adjuvant therapy for intermediate-high risk GIST patients. Methods: A retrospective case-control study was carried out. Clinical and pathological data of 432 GIST patients who did not receive preoperative targeted treatment, underwent complete resection in the Union Hospital of Tongji Medical College of Huazhong University of Science and Technology from January 2005 to June 2018, and were diagnosed as intermediate- or high-risk based on modified NIH classification by postopertive pathology, were retrospectively analyzed. Cox regression model was used to idenitify independent risk factors of recurrence, and a recurrence risk scoring model was established. The receiver operating characteristic curve (ROC curve), consistency index (C-index) and calibration curve were used to evaluate the accuracy of the scoring model in predicting the recurrence of moderate-risk and high-risk GIST patients. Results: Among 432 GIST patients, 332 were diagnosed as high-risk and 100 as moderate-risk; 237 were males and 195 females with average age of (57.4±12.4) years. Of 432 patients, 211 cases (48.8%) had fibrinogen (FIB) >3.5 g/L; 85 cases (19.7%) had platelet to lymphocyte ratio (PLR)>272.5; 122 cases (28.2%) had neutrophil to lymphocyte ratio (NLR) > 4.2; 102 cases (23.6%) had systemic inflammatory reaction index (SIRI)> 2.7; 198 cases (45.8%) had tumor long diameter >8 cm and 108 cases (25.0%) had mitotic counts > 8/50 HPF. Cox multivariable analysis showed that FIB (HR=1.789, 95% CI: 1.058-3.027, P=0.030), PLR (HR=1.862, 95% CI: 1.067-3.249, P=0.029), SIRI (HR=1.790, 95% CI: 1.039-3.084, P=0.036), tumor long diameter (HR=1.970, 95% CI: 1.105-2.925, P=0.017) and mitotic counts (HR=2.187, 95% CI:1.211-3.950, P=0.009) were independent risk factors for recurrence in patients with middle-risk and high-risk GIST. These 5 factors were included in the risk scoring model, which was given a weight score of 58 points, 62 points, 58 points, 63 points, and 78 points, respectively. Patients with a total score of ≤ 78 points were classified as moderate-risk recurrence (group I), those of 78 to 136 points as high-risk recurrence (group II) and those of >136 points as very high-risk recurrence (group III). ROC curve showed that the area under the curve (AUC) of the scoring model was 0.730 and the C-index was 0.724 (95% CI:0.687-0.787). The calibration curves and the Kaplan-Meier curves of patients in the three groups revealed that this model had a good predictive accuracy. Conclusions: For intermediate-risk and high-risk GIST patients, the preoperative FIB >3.5 g/L, PLR > 272.5 and SIRI > 2.7 are independent risk factors of recurrence after surgery. The recurrence risk scoring model established by combining tumor long diameter, mitotic counts, FIB, PLR and SIRI can effectively predict the risk of postoperative recurrence and metastasis in moderate-risk and high-risk GIST patients.


Asunto(s)
Fibrinógeno/análisis , Neoplasias Gastrointestinales/sangre , Tumores del Estroma Gastrointestinal/sangre , Inflamación/sangre , Recurrencia Local de Neoplasia/sangre , Anciano , Estudios de Casos y Controles , Terapia Combinada , Femenino , Neoplasias Gastrointestinales/diagnóstico , Neoplasias Gastrointestinales/patología , Neoplasias Gastrointestinales/terapia , Tumores del Estroma Gastrointestinal/diagnóstico , Tumores del Estroma Gastrointestinal/patología , Tumores del Estroma Gastrointestinal/terapia , Humanos , Inflamación/diagnóstico , Inflamación/patología , Inflamación/terapia , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/diagnóstico , Recurrencia Local de Neoplasia/patología , Recurrencia Local de Neoplasia/terapia , Valor Predictivo de las Pruebas , Pronóstico , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo
15.
J Nutr Health Aging ; 24(7): 685-691, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32744561

RESUMEN

A new coronavirus, called SARS-CoV-2, was identified in Wuhan, China, in December 2019. The SARS-CoV-2 spread very rapidly, causing a global pandemic, Coronavirus Disease 2019 (COVID-19). Older adults have higher peak of viral load and, especially those with comorbidities, had higher COVID-19-related fatality rates than younger adults. In this Perspective paper, we summarize current knowledge about SARS-CoV-2 and aging, in order to understand why older people are more affected by COVID-19. We discuss about the possibility that the so-called "immunosenescence" and "inflammaging" processes, already present in a fraction of frail older adults, could allow the immune escape of SARS-CoV-2 leading to COVID-19 serious complications. Finally, we propose to use geroscience approaches to the field of COVID-19.


Asunto(s)
Envejecimiento , Betacoronavirus , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/virología , Geriatría , Neumonía Viral/epidemiología , Neumonía Viral/virología , Virología , Anciano , Envejecimiento/inmunología , Envejecimiento/patología , Humanos , Inflamación/inmunología , Inflamación/patología , Pandemias
16.
Nat Commun ; 11(1): 4076, 2020 08 14.
Artículo en Inglés | MEDLINE | ID: mdl-32796851

RESUMEN

Group 3 innate lymphoid cells (ILC3) are an important regulator for immunity, inflammation and tissue homeostasis in the intestine, but how ILC3 activation is regulated remains elusive. Here we identify a new circular RNA (circRNA) circKcnt2 that is induced in ILC3s during intestinal inflammation. Deletion of circKcnt2 causes gut ILC3 activation and severe colitis in mice. Mechanistically, circKcnt2, as a nuclear circRNA, recruits the nucleosome remodeling deacetylase (NuRD) complex onto Batf promoter to inhibit Batf expression; this in turn suppresses Il17 expression and thereby ILC3 inactivation to promote innate colitis resolution. Furthermore, Mbd3-/-Rag1-/- and circKcnt2-/-Rag1-/- mice develop severe innate colitis following dextran sodium sulfate (DSS) treatments, while simultaneous deletion of Batf promotes colitis resolution. In summary, our data support a function of the circRNA circKcnt2 in regulating ILC3 inactivation and resolution of innate colitis.


Asunto(s)
Colitis/inmunología , Colitis/metabolismo , Linfocitos/metabolismo , Canales de potasio activados por Sodio/metabolismo , ARN Circular/metabolismo , Animales , Colitis/patología , Proteínas de Unión al ADN/genética , Modelos Animales de Enfermedad , Femenino , Proteínas de Homeodominio/genética , Homeostasis , Humanos , Inmunidad Innata , Inflamación/inmunología , Inflamación/patología , Intestinos/patología , Ratones , Ratones Endogámicos C57BL , Ratones Endogámicos ICR , Ratones Noqueados , Canales de potasio activados por Sodio/genética , ARN Circular/genética , ARN no Traducido/genética , ARN no Traducido/metabolismo , Factores de Transcripción/genética
17.
Nat Commun ; 11(1): 3984, 2020 08 07.
Artículo en Inglés | MEDLINE | ID: mdl-32770009

RESUMEN

The epsin family of endocytic adapter proteins are widely expressed, and interact with both proteins and lipids to regulate a variety of cell functions. However, the role of epsins in atherosclerosis is poorly understood. Here, we show that deletion of endothelial epsin proteins reduces inflammation and attenuates atherosclerosis using both cell culture and mouse models of this disease. In atherogenic cholesterol-treated murine aortic endothelial cells, epsins interact with the ubiquitinated endoplasmic reticulum protein inositol 1,4,5-trisphosphate receptor type 1 (IP3R1), which triggers proteasomal degradation of this calcium release channel. Epsins potentiate its degradation via this interaction. Genetic reduction of endothelial IP3R1 accelerates atherosclerosis, whereas deletion of endothelial epsins stabilizes IP3R1 and mitigates inflammation. Reduction of IP3R1 in epsin-deficient mice restores atherosclerotic progression. Taken together, epsin-mediated degradation of IP3R1 represents a previously undiscovered biological role for epsin proteins and may provide new therapeutic targets for the treatment of atherosclerosis and other diseases.


Asunto(s)
Proteínas Adaptadoras del Transporte Vesicular/metabolismo , Aterosclerosis/metabolismo , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Proteolisis , Proteínas Adaptadoras del Transporte Vesicular/química , Animales , Aorta/metabolismo , Aorta/patología , Aterosclerosis/patología , Calcio/metabolismo , Colesterol/metabolismo , Células Endoteliales/metabolismo , Femenino , Eliminación de Gen , Células HEK293 , Homeostasis , Humanos , Inflamación/patología , Masculino , Ratones Noqueados , Unión Proteica , Dominios Proteicos , Ubiquitinación
18.
Open Biol ; 10(8): 200208, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32847471

RESUMEN

COVID-19 management guidelines have largely attributed critically ill patients who develop acute respiratory distress syndrome, to a systemic overproduction of pro-inflammatory cytokines. Cardiovascular dysfunction may also represent a primary phenomenon, with increasing data suggesting that severe COVID-19 reflects a confluence of vascular dysfunction, thrombosis and dysregulated inflammation. Here, we first consolidate the information on localized microvascular inflammation and disordered cytokine release, triggering vessel permeability and prothrombotic conditions that play a central role in perpetuating the pathogenic COVID-19 cascade. Secondly, we seek to clarify the gateways which SARS-CoV-2, the causative COVID-19 virus, uses to enter host vascular cells. Post-mortem examinations of patients' tissues have confirmed direct viral endothelial infection within several organs. While there have been advances in single-cell RNA sequencing, endothelial cells across various vascular beds express low or undetectable levels of those touted SARS-CoV-2 entry factors. Emerging studies postulate alternative pathways and the apicobasal distribution of host cell surface factors could influence endothelial SARS-CoV-2 entry and replication. Finally, we provide experimental considerations such as endothelial polarity, cellular heterogeneity in organoids and shear stress dynamics in designing cellular models to facilitate research on viral-induced endothelial dysfunctions. Understanding the vascular underpinning of COVID-19 pathogenesis is crucial to managing outcomes and mortality.


Asunto(s)
Betacoronavirus/metabolismo , Infecciones por Coronavirus/patología , Células Endoteliales/patología , Inflamación/patología , Neumonía Viral/patología , Trombosis/patología , Permeabilidad Capilar/fisiología , Comorbilidad , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/mortalidad , Síndrome de Liberación de Citoquinas/inmunología , Síndrome de Liberación de Citoquinas/patología , Citocinas/sangre , Células Endoteliales/virología , Humanos , Pandemias , Peptidil-Dipeptidasa A/metabolismo , Neumonía Viral/inmunología , Neumonía Viral/mortalidad , Síndrome de Dificultad Respiratoria del Adulto/inmunología , Síndrome de Dificultad Respiratoria del Adulto/patología , Índice de Severidad de la Enfermedad , Internalización del Virus
19.
Yonsei Med J ; 61(8): 660-669, 2020 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-32734729

RESUMEN

PURPOSE: Neonatal hypoxic ischemic encephalopathy (HIE) is an essential factor underlying neonatal death and disability. This study sought to explore the role of miR-146b-5p in regulating neonatal HIE. MATERIALS AND METHODS: In vitro and in vivo HIE models were established in PC12 cells and 10-day neonatal Sprague Dawley rats, respectively. Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to assess miR-146b-5p expression and inflammatory factors [interleukin (IL)-6 and tumor necrosis factor (TNF)-α] in brain lesions and PC12 cells, while enzyme-linked immunosorbent assay was employed to detect the expression of oxidative stress factors (SOD and GSH-Px). Gain- and loss-assays of miR-146b-5p were conducted to verify its role in modulating the viability and apoptosis of PC12 cells under oxygen-glucose deprivation (OGD) treatment. Expression of TLR4, IRAK1, TRAF6, TAK1, and NF-κB were examined by qRT-PCR and/or Western blot. Dual luciferase activity assay was conducted to identify relationships between miR-146b-5p and IRAK1. RESULTS: In the HIE models, significant oxidative stress and inflammatory responses emerged upon upregulation of TLR4/IRAK1/TRAF6/TAK1/NF-κB signaling. Overexpression of miR-146b-5p greatly inhibited OGD-induced PC12 cell injury, inflammatory responses, and oxidative stress. Inhibiting miR-146b-5p, however, had the opposite effects. IRAK1 was found to be a target of miR-146b-5p, and miR-146b-5p overexpression suppressed the activation of IRAK1/TRAF6/TAK1/NF-κB signaling. CONCLUSION: This study demonstrated that miR-146b-5p overexpression alleviates HIE-induced neuron injury by inhibiting the IRAK1/TRAF6/TAK1/NF-κB pathway.


Asunto(s)
Hipoxia-Isquemia Encefálica/genética , Quinasas Asociadas a Receptores de Interleucina-1/metabolismo , Quinasas Quinasa Quinasa PAM/metabolismo , MicroARNs/metabolismo , FN-kappa B/metabolismo , Transducción de Señal , Factor 6 Asociado a Receptor de TNF/metabolismo , Animales , Animales Recién Nacidos , Apoptosis/genética , Secuencia de Bases , Modelos Animales de Enfermedad , Regulación hacia Abajo/genética , Glucosa/deficiencia , Inflamación/patología , MicroARNs/genética , Estrés Oxidativo , Oxígeno , Células PC12 , Ratas , Ratas Sprague-Dawley , Factor de Necrosis Tumoral alfa/metabolismo
20.
Diagn Pathol ; 15(1): 103, 2020 Aug 14.
Artículo en Inglés | MEDLINE | ID: mdl-32799894

RESUMEN

BACKGROUND: The world is currently witnessing a major devastating pandemic of Coronavirus disease-2019 (COVID-19). This disease is caused by a novel coronavirus named Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). It primarily affects the respiratory tract and particularly the lungs. The virus enters the cell by attaching its spike-like surface projections to the angiotensin-converting enzyme-2 (ACE-2) expressed in various tissues. Though the majority of symptomatic patients have mild flu-like symptoms, a significant minority develop severe lung injury with acute respiratory distress syndrome (ARDS), leading to considerable morbidity and mortality. Elderly patients with previous cardiovascular comorbidities are particularly susceptible to severe clinical manifestations. BODY: Currently, our limited knowledge of the pathologic findings is based on post-mortem biopsies, a few limited autopsies, and very few complete autopsies. From these reports, we know that the virus can be found in various organs but the most striking tissue damage involves the lungs resulting almost always in diffuse alveolar damage with interstitial edema, capillary congestion, and occasional interstitial lymphocytosis, causing hypoxia, multiorgan failure, and death. A few pathology studies have also reported intravascular microthrombi and pulmonary thrombembolism. Although the clinical presentation of this disease is fairly well characterized, knowledge of the pathologic aspects remains comparatively limited. CONCLUSION: In this review, we discuss clinical, pathologic, and genomic features of COVID-19, review current hypotheses regarding the pathogenesis, and briefly discuss the clinical characteristics. We also compare the salient features of COVID-19 with other coronavirus-related illnesses that have posed significant public health issues in the past, including SARS and the Middle East Respiratory Syndrome (MERS).


Asunto(s)
Betacoronavirus , Infecciones por Coronavirus/patología , Neumonía Viral/patología , Neumonía Viral/virología , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/virología , Humanos , Inflamación/patología , Inflamación/virología , Pandemias , Peptidil-Dipeptidasa A/metabolismo
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