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1.
Anticancer Res ; 41(4): 2147-2155, 2021 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-33813426

RESUMEN

BACKGROUND/AIM: Inflammation-based prognostic scores are proven prognostic biomarkers in various cancers. This study aimed to identify a useful prognostic score for patients with biliary tract cancer (BTC) after surgical resection. PATIENTS AND METHODS: This retrospective study recruited 115 patients with BTC during 2010-2020. The relationship between clinicopathological variables, including various prognostic scores and overall survival (OS), was investigated using univariate and multivariate analyses. RESULTS: BTC included 58 cholangiocarcinoma, 29 gallbladder carcinoma, 16 ampullary carcinoma, and 12 perihilar cholangiocarcinoma cases. A significant difference was detected in OS of patients with a Japanese modified Glasgow prognostic score (JmGPS) 0 (n=62) and JmGPS 1 or 2 (high JmGPS) (n=53). In the multivariate analysis, tumour differentiation (p=0.014) and a high JmGPS (p=0.047) were independent prognostic factors. CONCLUSION: The high JmGPS was an independent prognostic predictor after surgical resection and was superior to other prognostic scores.


Asunto(s)
Neoplasias del Sistema Biliar/diagnóstico , Neoplasias del Sistema Biliar/cirugía , Colangiocarcinoma/diagnóstico , Colangiocarcinoma/cirugía , Inflamación/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Ampolla Hepatopancreática/metabolismo , Ampolla Hepatopancreática/patología , Ampolla Hepatopancreática/cirugía , Neoplasias de los Conductos Biliares/diagnóstico , Neoplasias de los Conductos Biliares/metabolismo , Neoplasias de los Conductos Biliares/mortalidad , Neoplasias de los Conductos Biliares/cirugía , Conductos Biliares Intrahepáticos/metabolismo , Conductos Biliares Intrahepáticos/patología , Conductos Biliares Intrahepáticos/cirugía , Neoplasias del Sistema Biliar/metabolismo , Neoplasias del Sistema Biliar/mortalidad , Biomarcadores de Tumor/metabolismo , Proteína C-Reactiva/metabolismo , Colangiocarcinoma/metabolismo , Colangiocarcinoma/mortalidad , Neoplasias del Conducto Colédoco/diagnóstico , Neoplasias del Conducto Colédoco/metabolismo , Neoplasias del Conducto Colédoco/mortalidad , Neoplasias del Conducto Colédoco/cirugía , Femenino , Neoplasias de la Vesícula Biliar/diagnóstico , Neoplasias de la Vesícula Biliar/metabolismo , Neoplasias de la Vesícula Biliar/mortalidad , Neoplasias de la Vesícula Biliar/cirugía , Humanos , Inflamación/metabolismo , Japón/epidemiología , Tumor de Klatskin/diagnóstico , Tumor de Klatskin/metabolismo , Tumor de Klatskin/mortalidad , Tumor de Klatskin/cirugía , Masculino , Persona de Mediana Edad , Periodo Posoperatorio , Valor Predictivo de las Pruebas , Pronóstico , Proyectos de Investigación , Estudios Retrospectivos , Sensibilidad y Especificidad , Análisis de Supervivencia , Resultado del Tratamiento
2.
Cell ; 184(6): 1530-1544, 2021 03 18.
Artículo en Inglés | MEDLINE | ID: mdl-33675692

RESUMEN

The prevalence of type 2 diabetes and obesity has risen dramatically for decades and is expected to rise further, secondary to the growing aging, sedentary population. The strain on global health care is projected to be colossal. This review explores the latest work and emerging ideas related to genetic and environmental factors influencing metabolism. Translational research and clinical applications, including the impact of the COVID-19 pandemic, are highlighted. Looking forward, strategies to personalize all aspects of prevention, management and care are necessary to improve health outcomes and reduce the impact of these metabolic diseases.


Asunto(s)
/epidemiología , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/terapia , Obesidad/epidemiología , Obesidad/terapia , Pandemias , Medicina de Precisión/métodos , /virología , Ritmo Circadiano , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Epigénesis Genética , Predisposición Genética a la Enfermedad , Humanos , Inflamación/inmunología , Inflamación/metabolismo , Obesidad/genética , Obesidad/metabolismo , Prevalencia , Factores de Riesgo , Termotolerancia
3.
Int Heart J ; 62(2): 396-406, 2021 Mar 30.
Artículo en Inglés | MEDLINE | ID: mdl-33731537

RESUMEN

Endothelial injury and inflammation have been found to be essential in the pathogenesis of coronary artery disease (CAD). Circulating exosomes are of great value as novel biomarkers for CAD. However, the role of circulating exosomes in the pathogenesis of CAD remains unclear. Thus, in this study, we aimed to examine whether circulating exosomes from CAD are involved in the endothelial injury and inflammation. The serum-derived exosomes were isolated from CAD and controls using an ExoQuick reagent, and these were then quantified by measuring the protein levels using BCA methods. The uptake of exosomes by human umbilical vein endothelial cells (HUVECs) was observed by laser scanning microscope and analyzed via flow cytometry. Then, HUVECs were treated with vehicle, exosomes from CAD (CAD-exo), and controls (ctrl-exo) in the absence and presence of vascular endothelial growth factor (VEGF). Cell viability, migration, and angiogenesis were evaluated using CCK-8 assay, scratch assay, and tube formation assay. Inflammatory factors including IL-1ß, IL-6, TNF-α, ICAM-1, and VCAM-1 levels were detected via qPCR. As per our findings, no significant differences were noted in uptake of ctrl-exo and CAD-exo by HUVECs. CAD-exo suppressed cell viability in a dose-dependent manner. Compared with ctrl-exo, CAD-exo-treated HUVECs significantly suppressed migration and angiogenesis. However, CAD-exo had a stronger inhibitory effect on VEGF-induced migration and angiogenesis compared with ctrl-exo. Moreover, IL-1ß, TNF-α, and ICAM-1 were determined to be significantly upregulated in HUVECs treated with CAD-exo, but IL-6 and VCAM-1 expressions were not affected. Overall, our results suggest that CAD-exo are involved in endothelial injury and inflammation, which may, in turn, cause endothelial dysfunction and potentially promote the development of CAD.


Asunto(s)
Enfermedad de la Arteria Coronaria/sangre , Exosomas/metabolismo , Movimiento Celular , Proliferación Celular , Células Cultivadas , Enfermedad de la Arteria Coronaria/patología , Femenino , Citometría de Flujo , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Células Endoteliales de la Vena Umbilical Humana/patología , Humanos , Inflamación/metabolismo , Inflamación/patología , Masculino , Persona de Mediana Edad
4.
Nat Commun ; 12(1): 1770, 2021 03 19.
Artículo en Inglés | MEDLINE | ID: mdl-33741914

RESUMEN

Inflammation generally leads to recruitment of monocyte-derived macrophages. What regulates the fate of these cells and to what extent they can assume the identity and function of resident macrophages is unclear. Here, we show that macrophages elicited into the peritoneal cavity during mild inflammation persist long-term but are retained in an immature transitory state of differentiation due to the presence of enduring resident macrophages. By contrast, severe inflammation results in ablation of resident macrophages and a protracted phase wherein the cavity is incapable of sustaining a resident phenotype, yet ultimately elicited cells acquire a mature resident identity. These macrophages also have transcriptionally and functionally divergent features that result from inflammation-driven alterations to the peritoneal cavity micro-environment and, to a lesser extent, effects of origin and time-of-residency. Hence, rather than being predetermined, the fate of inflammation-elicited peritoneal macrophages seems to be regulated by the environment.


Asunto(s)
Diferenciación Celular/genética , Inflamación/genética , Macrófagos Peritoneales/metabolismo , Macrófagos/metabolismo , Cavidad Peritoneal/patología , Animales , Células Cultivadas , Citocinas/metabolismo , Femenino , Factor de Transcripción GATA6/genética , Factor de Transcripción GATA6/metabolismo , Perfilación de la Expresión Génica , Inflamación/metabolismo , Macrófagos/citología , Macrófagos Peritoneales/citología , Masculino , Ratones Congénicos , Ratones Endogámicos C57BL , Peritonitis/genética , Peritonitis/metabolismo
5.
Int J Mol Sci ; 22(4)2021 Feb 16.
Artículo en Inglés | MEDLINE | ID: mdl-33669352

RESUMEN

Cystic fibrosis (CF) is an inherited disorder caused by mutations in the gene encoding for the cystic fibrosis transmembrane conductance regulator (CFTR) protein, an ATP-gated chloride channel expressed on the apical surface of airway epithelial cells. CFTR absence/dysfunction results in defective ion transport and subsequent airway surface liquid dehydration that severely compromise the airway microenvironment. Noxious agents and pathogens are entrapped inside the abnormally thick mucus layer and establish a highly inflammatory environment, ultimately leading to lung damage. Since chronic airway inflammation plays a crucial role in CF pathophysiology, several studies have investigated the mechanisms responsible for the altered inflammatory/immune response that, in turn, exacerbates the epithelial dysfunction and infection susceptibility in CF patients. In this review, we address the evidence for a critical role of dysfunctional inflammation in lung damage in CF and discuss current therapeutic approaches targeting this condition, as well as potential new treatments that have been developed recently. Traditional therapeutic strategies have shown several limitations and limited clinical benefits. Therefore, many efforts have been made to develop alternative treatments and novel therapeutic approaches, and recent findings have identified new molecules as potential anti-inflammatory agents that may exert beneficial effects in CF patients. Furthermore, the potential anti-inflammatory properties of CFTR modulators, a class of drugs that directly target the molecular defect of CF, also will be critically reviewed. Finally, we also will discuss the possible impact of SARS-CoV-2 infection on CF patients, with a major focus on the consequences that the viral infection could have on the persistent inflammation in these patients.


Asunto(s)
Antiinflamatorios/uso terapéutico , Fibrosis Quística/tratamiento farmacológico , Inflamación/tratamiento farmacológico , Animales , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Antiinflamatorios/farmacología , Azitromicina/farmacología , Azitromicina/uso terapéutico , /tratamiento farmacológico , Cannabinoides/farmacología , Cannabinoides/uso terapéutico , Fibrosis Quística/complicaciones , Fibrosis Quística/metabolismo , Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Eicosanoides/metabolismo , Humanos , Inflamación/complicaciones , Inflamación/metabolismo , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Roscovitina/farmacología , Roscovitina/uso terapéutico , Transducción de Señal/efectos de los fármacos , Timalfasina/farmacología , Timalfasina/uso terapéutico
6.
J Coll Physicians Surg Pak ; 30(1): S7-S10, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33650415

RESUMEN

OBJECTIVE: To determine the effects of tocilizumab (TCZ) on inflammatory markers, laboratory indices; and short-term outcome in patients with severe COVID-19. STUDY DESIGN: Cross-sectional analytical study. Place and Duration of the Study: Hayatabad Medical Complex, Peshawar, Pakistan from 10th June till 31st August 2020. METHODOLOGY: Fifty-four patients with severe COVID-19 fulfilled the inclusion criteria and were included. All patients had received TCZ (4 mg/kg) in addition to standard treatment. Serum C-reactive protein (CRP), lactate dehydrogenase (LDH), D-dimer levels, full blood count, and liver function tests (LFTs) were checked before and 24 hours after receiving TCZ. Short-term outcome, defined as survival at day 28, was determined from hospital record/telephonic contact. Paired t-test was employed to assess the statistical significance of mean differences between the pre- and post-TCZ variables, considering a p-value of <0.05 as significant. RESULTS: Overall, the mean pre- and post-TCZ CRP was 18.7 ± 10.7 and 10.2 ± 8.6 mg/dl (p <0.001). It was 18.0 ± 10.3 and 10.3 ± 8.8 mg/dl (p=0.003) in survivors; and 19.4 ± 11.4 and 10.2 ± 8.7 mg/dl (p=0.005) in non-survivors, respectively. Overall, mean D-dimer level decreased from 12.5 ± 23 to 10.3 ± 12.2 µg/ml following TCZ (p=0.643); it decreased from 15.8 ± 29.8 to 11.4 ± 10.6 µg/ml (p=0.612) in survivors; and 9.0 ± 12.8 to 9.2 ± 14.1 µg/ml (p=0.961) in non-survivors, respectively. There were no significant differences in the pre- and post-TCZ LDH levels overall and between the groups. The 28-day mortality was 46.3%. CONCLUSION: Tocilizumab results in a significant reduction in CRP, while mean change in LDH and D-dimers was not substantial. The mean change in inflammatory markers did not predict survival. Key Words: Tocilizumab, COVID-19, Biomarkers, Outcome, Mortality.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Citocinas/metabolismo , Inflamación/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/metabolismo , /metabolismo , Estudios Transversales , Humanos , Persona de Mediana Edad , Pakistán/epidemiología , Pandemias , Estudios Retrospectivos , Sobrevivientes
7.
Methods Mol Biol ; 2269: 167-174, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33687679

RESUMEN

Three-dimensional (3D) cell cultures combining multipotent mesenchymal stromal cells (MSC), tendon extracellular matrix scaffolds, and mechanical stimulation by a bioreactor have been used to induce tenogenic differentiation in vitro. Yet, these conditions alone do not mimic the environment of acute inflammatory tendon disease adequately, thus the results of such studies are not representatives for tendon regeneration after acute injury. In this chapter, we describe two different approaches to introduce inflammatory stimuli, comprising co-culture with leukocytes and supplementation with the cytokines IL-1 ß and TNF-α. The presented in vitro model of inflammatory tendon disease could be used to study musculoskeletal pathophysiology and regeneration in more depth.


Asunto(s)
Células Madre Mesenquimatosas/metabolismo , Modelos Biológicos , Tendinopatía/metabolismo , Tendones/metabolismo , Andamios del Tejido/química , Animales , Humanos , Inflamación/metabolismo , Inflamación/patología , Interleucina-1beta/metabolismo , Células Madre Mesenquimatosas/patología , Tendinopatía/patología , Tendones/patología , Factor de Necrosis Tumoral alfa/metabolismo
8.
Methods Mol Biol ; 2291: 317-332, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33704761

RESUMEN

Shiga toxin-producing Escherichia coli (STEC) and the related pathogen enteropathogenic Escherichia coli (EPEC) use a type III secretion system to translocate effector proteins into host cells to modulate inflammatory signaling pathways during infection. Here we describe the procedures to investigate effector-driven modulation of host inflammatory signaling pathways in mammalian cells where bacterial effectors are ectopically expressed or in cell lines infected with STEC or EPEC. We focus on the TNF-induced NF-κB response by examining IκBα degradation by immunoblot and p65 nuclear localization in addition to using an NF-κB-dependent luciferase reporter and cytokine secretion assays. These methods can be adapted for examining effector-mediated modulation of other inflammatory stimuli and host signaling pathways.


Asunto(s)
Escherichia coli Enteropatógena/metabolismo , Infecciones por Escherichia coli/metabolismo , Escherichia coli Shiga-Toxigénica/metabolismo , Transducción de Señal , Factor de Transcripción ReIA/metabolismo , Animales , Línea Celular , Escherichia coli Enteropatógena/patogenicidad , Infecciones por Escherichia coli/patología , Humanos , Inflamación/metabolismo , Inflamación/microbiología , Inhibidor NF-kappaB alfa/metabolismo , Escherichia coli Shiga-Toxigénica/patogenicidad
9.
Life Sci ; 273: 119290, 2021 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-33662430

RESUMEN

The current study examined the role of sex differences in the development of risk factors associated with obesity and its comorbidities using models that differ in their susceptibility to develop obesity, obesity-resistant S5B/Pl (S5B) and obesity-prone Osborne-Mendel (OM) rats. Male and female rats were fed a low fat or high fat diet (HFD) and markers of metabolic syndrome (MetSyn) and expression of inflammatory cytokines/chemokines in visceral and subcutaneous adipose depots were measured. We hypothesized that male and female OM and S5B rats would exhibit differential responses to the consumption of HFD and that females, regardless of susceptibility to develop obesity, would display decreased obesity-related risk factors. Results suggested that consumption of HFD increased adiposity and fasting glucose levels in male OM and S5B rats, decreased circulating adiponectin levels in male S5B rats, and increased body weight and triglyceride levels in male OM rats. The consumption of HFD increased body weight and adiposity in female OM rats, not female S5B rats. Overall, female rats did not meet criteria for MetSyn, while male rats consuming HFD met criteria for MetSyn. Visceral and subcutaneous adipose tissue inflammation was higher in male rats. In visceral adipose tissue, HFD consumption differentially altered expression of cytokines in male and female S5B and OM rats. These findings suggest that resistance to obesity in males may be overridden by chronic consumption of HFD and lead to increased risk for development of obesity-related comorbidities, while female rats appear to be protected from the adverse effects of HFD consumption.


Asunto(s)
Tejido Adiposo/patología , Biomarcadores/metabolismo , Dieta Alta en Grasa/efectos adversos , Inflamación/patología , Síndrome Metabólico/patología , Obesidad/complicaciones , Tejido Adiposo/metabolismo , Animales , Peso Corporal , Femenino , Inflamación/etiología , Inflamación/metabolismo , Leptina/metabolismo , Masculino , Síndrome Metabólico/etiología , Síndrome Metabólico/metabolismo , Ratas , Factores Sexuales , Aumento de Peso
10.
Life Sci ; 273: 119295, 2021 May 15.
Artículo en Inglés | MEDLINE | ID: mdl-33667522

RESUMEN

AIMS: Dipeptidyl peptidase-4 (DPP-4) has been involved in the pathogenesis of inflammatory bowel diseases (IBD), yet the underlying mechanisms remain inconclusive. The present study aimed to investigate the potential of linagliptin, a potent/selective DPP-4 inhibitor with marked anti-inflammatory actions, to attenuate trinitrobenzene sulfonic acid (TNBS)-evoked colitis in rats; an experimental model of IBD, and the implicated molecular mechanisms. This may add to the clinical utility of linagliptin for the management of patients with coexisting IBD and diabetes mellitus. Notably, no former studies have linked JAK2/STAT3, HMGB1/NF-κB, and Nrf2/HO-1 signaling in TNBS-evoked colitis. MATERIALS AND METHODS: Western blotting and ELISA were used to determine the levels of target signals. KEY FINDINGS: Administration of linagliptin (1.5 mg/kg; p.o.) mitigated the colitis severity via diminishing the disease activity index, colon weight/length ratio, and macroscopic scores. Linagliptin also lowered the colonic histologic scores and leukocyte invasion. Notably, linagliptin inhibited the colonic DPP-4 activity and upregulated the expression of intestinotrophic GLP-2 without incurring hypoglycemia in animals. Linagliptin curbed inflammation through the suppression of colonic IL-6, TNF-α, and myeloperoxidase and upregulation of IL-10. It also inhibited the IL-6/JAK2/STAT3 pathway via downregulating p-JAK2/JAK2 and p-STAT3/STAT3 protein expression and HMGB1/RAGE/NF-κB cascade through lowering HMGB1, RAGE, and p-NF-κB p65/NF-κB p65 protein expression. In the context of mucosal oxidative stress, linagliptin diminished lipid peroxides and augmented GSH, GPx, and total antioxidant capacity. It also activated Nrf2/HO-1 pathway via upregulating Nrf2 and HO-1 protein expression. SIGNIFICANCE: Linagliptin shows a promise for the management of IBD via targeting IL-6/JAK2/STAT3, HMGB1/RAGE/NF-κB, and Nrf2/HO-1 pathways.


Asunto(s)
Colitis/tratamiento farmacológico , Hipoglucemiantes/farmacología , Inflamación/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Linagliptina/farmacología , Ácido Trinitrobencenosulfónico/toxicidad , Animales , Colitis/inducido químicamente , Colitis/metabolismo , Colitis/patología , Citocinas/genética , Citocinas/metabolismo , Inflamación/inducido químicamente , Inflamación/metabolismo , Inflamación/patología , Enfermedades Inflamatorias del Intestino/inducido químicamente , Enfermedades Inflamatorias del Intestino/metabolismo , Enfermedades Inflamatorias del Intestino/patología , Janus Quinasa 2/genética , Janus Quinasa 2/metabolismo , Masculino , FN-kappa B/genética , FN-kappa B/metabolismo , Oxidación-Reducción , Ratas , Ratas Wistar , Factor de Transcripción STAT3/genética , Factor de Transcripción STAT3/metabolismo , Transducción de Señal
11.
Molecules ; 26(4)2021 Feb 23.
Artículo en Inglés | MEDLINE | ID: mdl-33672225

RESUMEN

Alzheimer's, Parkinson's, and multiple sclerosis are neurodegenerative diseases related by neuronal degeneration and death in specific areas of the central nervous system. These pathologies are associated with neuroinflammation, which is involved in disease progression, and halting this process represents a potential therapeutic strategy. Evidence suggests that microglia function is regulated by A1 and A2A adenosine receptors (AR), which are considered as neuroprotective and neurodegenerative receptors, respectively. The manuscript's aim is to elucidate the role of these receptors in neuroinflammation modulation through potent and selective A1AR agonists (N6-cyclopentyl-2'- or 3'-deoxyadenosine substituted or unsubstituted in 2 position) and A2AAR antagonists (9-ethyl-adenine substituted in 8 and/or in 2 position), synthesized in house, using N13 microglial cells. In addition, the combined therapy of A1AR agonists and A2AAR antagonists to modulate neuroinflammation was evaluated. Results showed that A1AR agonists were able, to varying degrees, to prevent the inflammatory effect induced by cytokine cocktail (tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, and interferon (IFN)-γ), while A2AAR antagonists showed a good ability to counteract neuroinflammation. Moreover, the effect achieved by combining the two most effective compounds (1 and 6) in doses previously found to be non-effective was greater than the treatment effect of each of the two compounds used separately at maximal dose.


Asunto(s)
Agonistas del Receptor de Adenosina A1/farmacología , Antagonistas del Receptor de Adenosina A2/farmacología , Inflamación/tratamiento farmacológico , Receptor de Adenosina A1/metabolismo , Receptores de Adenosina A2/metabolismo , Animales , Células Cultivadas , Inflamación/metabolismo , Ratones
12.
Front Immunol ; 12: 627579, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33692801

RESUMEN

An important manifestation of severe COVID-19 is the ARDS-like lung injury that is associated with vascular endothelialitis, thrombosis, and angiogenesis. The intravascular innate immune system (IIIS), including the complement, contact, coagulation, and fibrinolysis systems, which is crucial for recognizing and eliminating microorganisms and debris in the body, is likely to be involved in the pathogenesis of COVID-19 ARDS. Biomarkers for IIIS activation were studied in the first 66 patients with COVID-19 admitted to the ICU in Uppsala University Hospital, both cross-sectionally on day 1 and in 19 patients longitudinally for up to a month, in a prospective study. IIIS analyses were compared with biochemical parameters and clinical outcome and survival. Blood cascade systems activation leading to an overreactive conjunct thromboinflammation was demonstrated, reflected in consumption of individual cascade system components, e.g., FXII, prekallikrein, and high molecular weight kininogen and in increased levels of activation products, e.g., C4d, C3a, C3d,g, sC5b-9, TAT, and D-dimer. Strong associations were found between the blood cascade systems and organ damage, illness severity scores, and survival. We show that critically ill COVID-19 patients display a conjunct activation of the IIIS that is linked to organ damage of the lung, heart, kidneys, and death. We present evidence that the complement and in particular the kallikrein/kinin system is strongly activated and that both systems are prognostic markers of the outcome of the patients suggesting their role in driving the inflammation. Already licensed kallikrein/kinin inhibitors are potential drugs for treatment of critically ill patients with COVID-19.


Asunto(s)
/inmunología , Inflamación/inmunología , Sistema Calicreína-Quinina/inmunología , Trombosis/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/metabolismo , Coagulación Sanguínea , /virología , Enfermedad Crítica , Femenino , Fibrinólisis/inmunología , Humanos , Inmunidad Innata , Inflamación/metabolismo , Inflamación/patología , Inflamación/virología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , /metabolismo , /virología , Índice de Severidad de la Enfermedad , Adulto Joven
13.
Nat Neurosci ; 24(3): 343-354, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33558694

RESUMEN

Aberrant inflammation in the CNS has been implicated as a major player in the pathogenesis of human neurodegenerative disease. We developed a new approach to derive microglia from human pluripotent stem cells (hPSCs) and built a defined hPSC-derived tri-culture system containing pure populations of hPSC-derived microglia, astrocytes, and neurons to dissect cellular cross-talk along the neuroinflammatory axis in vitro. We used the tri-culture system to model neuroinflammation in Alzheimer's disease with hPSCs harboring the APPSWE+/+ mutation and their isogenic control. We found that complement C3, a protein that is increased under inflammatory conditions and implicated in synaptic loss, is potentiated in tri-culture and further enhanced in APPSWE+/+ tri-cultures due to microglia initiating reciprocal signaling with astrocytes to produce excess C3. Our study defines the major cellular players contributing to increased C3 in Alzheimer's disease and presents a broadly applicable platform to study neuroinflammation in human disease.


Asunto(s)
Enfermedad de Alzheimer/metabolismo , Complemento C3/metabolismo , Microglía/metabolismo , Células Madre Pluripotentes/patología , Enfermedad de Alzheimer/patología , Astrocitos/metabolismo , Astrocitos/patología , Hematopoyesis/fisiología , Humanos , Inflamación/metabolismo , Inflamación/patología , Microglía/patología , Modelos Biológicos , Neuronas/metabolismo , Neuronas/patología
14.
Aging (Albany NY) ; 13(4): 4794-4810, 2021 02 11.
Artículo en Inglés | MEDLINE | ID: mdl-33591951

RESUMEN

Coronavirus disease 2019 (COVID-19)-associated coagulation dysfunction is gaining attention. In particular, dynamic changes in the D-dimer level may be related to disease progression. Here, we explored whether elevated D-dimer level was related to multiple organ failure and a higher risk of death. This study included 158 patients with COVID-19 who were admitted to the intensive care unit (ICU) at Jinyintan Hospital in Wuhan, China between January 20, 2020 and February 26, 2020. Clinical and laboratory data were collected. The relationship between D-dimer elevation and organ dysfunction was analyzed, as were dynamic changes in inflammation and lipid metabolism. Approximately 63.9% of patients with COVID-19 had an elevated D-dimer level on ICU admission. The 14 day ICU mortality rate was significantly higher in patients with a high D-dimer level than in those with a normal D-dimer level. Patients with a D-dimer level of 10-40µg/mL had similar organ function on ICU admission to those with a D-dimer level of 1.5-10µg/mL. However, patients with higher levels of D-dimer developed organ injuries within 7 days. Furthermore, significant differences in inflammation and lipid metabolism markers were observed between the two groups. In conclusion, the D-dimer level is closely related to COVID-19 severity and might influence the likelihood of rapid onset of organ injury after admission.


Asunto(s)
/sangre , Productos de Degradación de Fibrina-Fibrinógeno/análisis , Inflamación/sangre , Insuficiencia Multiorgánica/sangre , Anciano , Biomarcadores/sangre , /metabolismo , China/epidemiología , Progresión de la Enfermedad , Femenino , Humanos , Inflamación/etiología , Inflamación/metabolismo , Unidades de Cuidados Intensivos , Metabolismo de los Lípidos , Masculino , Persona de Mediana Edad , Insuficiencia Multiorgánica/etiología , Insuficiencia Multiorgánica/metabolismo , Estudios Retrospectivos , Factores de Riesgo , /aislamiento & purificación
15.
Stem Cell Reports ; 16(3): 428-436, 2021 03 09.
Artículo en Inglés | MEDLINE | ID: mdl-33581053

RESUMEN

We document here that intensive care COVID-19 patients suffer a profound decline in hemoglobin levels but show an increase of circulating nucleated red cells, suggesting that SARS-CoV-2 infection either directly or indirectly induces stress erythropoiesis. We show that ACE2 expression peaks during erythropoiesis and renders erythroid progenitors vulnerable to infection by SARS-CoV-2. Early erythroid progenitors, defined as CD34-CD117+CD71+CD235a-, show the highest levels of ACE2 and constitute the primary target cell to be infected during erythropoiesis. SARS-CoV-2 causes the expansion of colony formation by erythroid progenitors and can be detected in these cells after 2 weeks of the initial infection. Our findings constitute the first report of SARS-CoV-2 infectivity in erythroid progenitor cells and can contribute to understanding both the clinical symptoms of severe COVID-19 patients and how the virus can spread through the circulation to produce local inflammation in tissues, including the bone marrow.


Asunto(s)
/virología , Células Precursoras Eritroides/virología , Eritropoyesis/fisiología , /patogenicidad , /metabolismo , Animales , Línea Celular , Chlorocebus aethiops , Células Precursoras Eritroides/metabolismo , Humanos , Inflamación/metabolismo , Inflamación/virología , Células Vero
16.
Stem Cell Reports ; 16(3): 437-445, 2021 03 09.
Artículo en Inglés | MEDLINE | ID: mdl-33631122

RESUMEN

COVID-19 is a transmissible respiratory disease caused by a novel coronavirus, SARS-CoV-2, and has become a global health emergency. There is an urgent need for robust and practical in vitro model systems to investigate viral pathogenesis. Here, we generated human induced pluripotent stem cell (iPSC)-derived lung organoids (LORGs), cerebral organoids (CORGs), neural progenitor cells (NPCs), neurons, and astrocytes. LORGs containing epithelial cells, alveolar types 1 and 2, highly express ACE2 and TMPRSS2 and are permissive to SARS-CoV-2 infection. SARS-CoV-2 infection induces interferons, cytokines, and chemokines and activates critical inflammasome pathway genes. Spike protein inhibitor, EK1 peptide, and TMPRSS2 inhibitors (camostat/nafamostat) block viral entry in LORGs. Conversely, CORGs, NPCs, astrocytes, and neurons express low levels of ACE2 and TMPRSS2 and correspondingly are not highly permissive to SARS-CoV-2 infection. Infection in neuronal cells activates TLR3/7, OAS2, complement system, and apoptotic genes. These findings will aid in understanding COVID-19 pathogenesis and facilitate drug discovery.


Asunto(s)
Encéfalo/virología , Células Madre Pluripotentes Inducidas/virología , Pulmón/virología , Células-Madre Neurales/virología , Organoides/virología , /patogenicidad , Apoptosis/fisiología , Encéfalo/metabolismo , Células Cultivadas , Proteínas del Sistema Complemento/metabolismo , Células Epiteliales/metabolismo , Células Epiteliales/virología , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Inflamación/metabolismo , Inflamación/virología , Pulmón/metabolismo , Células-Madre Neurales/metabolismo , Neuronas/metabolismo , Neuronas/virología , Organoides/metabolismo , Serina Endopeptidasas/metabolismo , Transducción de Señal/fisiología , Células Madre/metabolismo , Células Madre/virología
17.
Life Sci ; 271: 119187, 2021 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-33577858

RESUMEN

Alzheimer's disease (AD) is the most common cause of dementia and is set to rise in prevalence as the global trends in population aging. The extracellular deposition of amyloid protein (Aß) and the intracellular formation of neurofibrillary tangles in the brain have been recognized as the two core pathologies of AD. Over the past decades, the presence of neuroinflammation in the brain has been documented as the third core pathology of AD. In recent years, emerging evidence demonstrated that the purinergic receptor P2X7 (P2X7R) serves a critical role in microglia responses and neuroinflammation. Besides, targeting P2X7R by genetic or pharmacological strategies attenuates the symptoms and pathological changes of AD models, and P2X7R has been recognized as a promising therapeutic target for AD. In this review, we summarized the recent evidence concerning the roles of P2X7R in neuroinflammation and implications in AD pathogenesis.


Asunto(s)
Enfermedad de Alzheimer/metabolismo , Encéfalo/metabolismo , Mediadores de Inflamación/metabolismo , Receptores Purinérgicos P2X7/metabolismo , Enfermedad de Alzheimer/patología , Animales , Encéfalo/patología , Humanos , Inflamación/metabolismo , Inflamación/patología , Microglía/metabolismo , Microglía/patología
18.
Am J Pathol ; 191(3): 575-583, 2021 03.
Artículo en Inglés | MEDLINE | ID: mdl-33608067

RESUMEN

Central nervous system (CNS) lymphoma is an extranodal non-Hodgkin B-cell lymphoma characterized by malignant lymph tissue arising in the brain or spinal cord, associated with inflammation and blood-brain barrier (BBB) disruption. Although BBB disruption is known to occur in patients with CNS lymphoma, a direct link between these two has not been shown. Herein, abundant deposition of the blood coagulation protein fibrinogen around B-cell lymphoma was detected in CNS lymphoma patients and in the CNS parenchyma in an orthotopic mouse model. Functional enrichment analysis of unbiased cerebrospinal fluid proteomics of CNS B-cell lymphoma patients showed that coagulation protein networks were highly connected with tumor-associated biological signaling pathways. In vivo two-photon imaging demonstrated that lymphoma growth was associated with BBB disruption, and in vitro experiments identified a role for fibrinogen in promoting lymphoma cell adhesion. Overall, these results identify perivascular lymphoma clustering at sites of fibrinogen deposition, and suggest that fibrinogen may be a target for pharmacologic intervention in metastatic B-cell lymphoma associated with BBB disruption.


Asunto(s)
Adhesión Celular , Neoplasias del Sistema Nervioso Central/patología , Fibrinógeno/metabolismo , Inflamación/patología , Linfocitos/patología , Linfoma de Células B/patología , Animales , Transporte Biológico , Neoplasias del Sistema Nervioso Central/etiología , Neoplasias del Sistema Nervioso Central/metabolismo , Modelos Animales de Enfermedad , Fibrinógeno/genética , Humanos , Inflamación/etiología , Inflamación/metabolismo , Linfocitos/metabolismo , Linfoma de Células B/etiología , Linfoma de Células B/metabolismo , Masculino , Ratones , Ratones Desnudos
19.
Life Sci ; 270: 119143, 2021 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-33539913

RESUMEN

Osteoarthritis (OA) is the joint pain and dysfunction syndrome caused by severe joint degeneration. The overproduced inflammatory mediators contribute greatly to OA development. It is reported that long non-coding RNA (lncRNA) takes part in many inflammatory diseases. Here, we mainly explored the function of lncRNA SNHG14 in OA process and its specific mechanisms. An OA rat model was induced by destabilizing the medial meniscus (DMM) and IL-1ß (5 ng/mL) was used to mediate an OA cell model in particular chondrocytes (AC). Gain- or loss-of functional assays of SNHG14 and miR-124-3p were carried out to explore their roles in OA development. The experimental statistics illustrated that lncRNA SNHG14 and IL-1ß mRNA expression were both increased in OA tissues, while miR-124-3p was lowly-expressed. Linear regression analysis showed that SNHG14 and miR-124-3p had negative relationship in the OA tissues. In the in vitro experiments, downregulation of lncRNA SNHG14 promoted the proliferation of IL-1ß-treated AC and inhibited cell apoptosis and COX-2, iNOS, TNF-α, IL-6 expression. Moreover, lncRNA SNHG14 inhibited miR-124-3p expression as a miRNA sponge. MiR-124-3p targeted the 3'non-translated region (3'UTR) of FSTL-1 and TLR4 and inhibited their expressions. Also, the in vivo experiments confirmed that knocking down SNHG14 relieved the progression of OA in rats via inhibiting inflammatory responses. In conclusion, this study confirmed that downregulation of lncRNA SNHG14 inhibits FSTL-1-mediated activation of NLRP3 and TLR4/NF-κB signalling pathway activation by targeting miR-124-3p, thus attenuating inflammatory reactions in OA.


Asunto(s)
MicroARNs/genética , Osteoartritis/genética , ARN Largo no Codificante/genética , Adulto , Animales , Apoptosis , China , Condrocitos/metabolismo , Femenino , Proteínas Relacionadas con la Folistatina/genética , Proteínas Relacionadas con la Folistatina/metabolismo , Humanos , Inflamación/metabolismo , Interleucina-1beta , Masculino , MicroARNs/metabolismo , Persona de Mediana Edad , FN-kappa B/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Osteoartritis/metabolismo , ARN Largo no Codificante/metabolismo , Ratas , Ratas Sprague-Dawley , Transducción de Señal , Receptor Toll-Like 4/metabolismo
20.
Mol Aspects Med ; 77: 100943, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-33551236

RESUMEN

The health of the individual and the population in general is the result of interaction between genetics and various environmental factors, of which diet/nutrition is the most important. The focus of this paper is on the association of high n-6 PUFA or low n-3 PUFA due to genetic variation and/or dietary intake, with changes in specialized pro-resolving mediators (SPMs), cytokine storm, inflammation-resolution and Covid-19. Human beings evolved on a diet that was balanced in the n-6 and n-3 essential fatty acids with a ratio of n-6/n-3 of 1-2/1 whereas today this ratio is 16/1. Such a high ratio due to high amounts of n-6 fatty acids leads to a prothrombotic and proinflammatory state and is associated with obesity, diabetes, cardiovascular disease, and some forms of cancer. In addition to the high intake of n-6 fatty acids that increases inflammation there is genetic variation in the biosynthesis of n-6 linoleic acid (LA) to arachidonic acid (ARA) and of linolenic (ALA) to eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). Present day humans have two common FADS haplotypes that differ dramatically in their ability to generate long-chain fatty acids. The more efficient, evolutionary derived haplotype increases the efficiency of synthesizing essential long-chain fatty acids from precursors and could have provided an advantage in environments with limited access to dietary long-chain fatty acids ARA, EPA and DHA. In the modern world this haplotype has been associated with lifestyle-related diseases, such as cardiovascular disease, obesity, diabetes, all of which are characterized by increased levels of inflammation. African Americans and Latino populations have increased susceptibility and higher death rates from SARS-CoV-2 than whites. These populations are characterized by increased numbers of persons (about 80%) that are fast metabolizers, leading to increased production of ARA, as well as poor intake of fruits and vegetables. The combinations of fast metabolism and high n-6 intake increases their inflammatory status and possibly susceptibility of SARS-CoV-2. In vitro and human studies indicate that the specialized pro-resolving mediators (SPM) produced from the n-3, EPA and DHA influence the resolution of inflammation, allowing the tissues to return to function and homeostasis. The SPMs each counter-regulate cytokine storms, as well as proinflammatory lipid mediators via NFκB and inflammasome down regulation and reduce the proinflammatory eicosanoids produced from ARA. The nutritional availability of dietary n-3 fatty acids from marine oils enriched with SPM intermediate precursors, along with increasing local biosynthesis of SPMs to functional concentrations may be an approach of value during SARS-CoV2 infections, as well as in prevention, and shortening their recovery from infections. It is evident that populations differ in their genetic variants and their frequencies and their interactions with the food they eat. Gene-nutrient interactions is a very important area of study that provides specific dietary advice for individuals and subgroups within a population in the form of Precision Nutrition. Nutritional science needs to focus on Precision Nutrition, genetic variants in the population and a food supply composed of Nutrients that have been part of our diet throughout evolution, which is the diet that our genes are programmed to respond.


Asunto(s)
/dietoterapia , /genética , /metabolismo , Ácidos Docosahexaenoicos/metabolismo , Eicosanoides/metabolismo , Ácido Eicosapentaenoico/análogos & derivados , Ácido Eicosapentaenoico/metabolismo , Ácidos Grasos Esenciales/metabolismo , Ácidos Grasos Omega-3/metabolismo , Predisposición Genética a la Enfermedad/genética , Haplotipos , Humanos , Inflamación/dietoterapia , Inflamación/genética , Inflamación/metabolismo , Ácido Linoleico/metabolismo , ARN Viral/genética , ARN Viral/metabolismo , /patogenicidad
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