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1.
J Ethnopharmacol ; 282: 114574, 2022 Jan 10.
Artículo en Inglés | MEDLINE | ID: mdl-34461187

RESUMEN

ETHNOPHARMACOLOGICAL RELEVANCE: Gekko gecko is used as a traditional medicine for various diseases including respiratory disorders in northeast Asian countries, mainly Korea, Japan, and China. AIM OF THE STUDY: Allergic asthma is a chronic respiratory disease caused by an inappropriate immune response. Due to the recent spread of coronavirus disease 2019, interest in the treatment of pulmonary disorders has rapidly increased. In this study, we investigated the anti-asthmatic effects of G. gecko extract (GGE) using an established mouse model of ovalbumin-induced asthma. MATERIALS AND METHODS: To evaluate the anti-asthmatic effects of GGE, we evaluated histological changes and the responses of inflammatory mediators related to allergic airway inflammation. Furthermore, we investigated the regulatory effects of GGE on type 2 helper T (Th2) cell activation. RESULTS: Administration of GGE attenuated asthmatic phenotypes, including inflammatory cell infiltration, mucus production, and expression of Th2 cytokines. Furthermore, GGE treatment reduced Th2 cell activation and differentiation. CONCLUSIONS: These results indicate that GGE alleviates allergic airway inflammation by regulating Th2 cell activation and differentiation.


Asunto(s)
Antiasmáticos/uso terapéutico , Asma/tratamiento farmacológico , Medicina Tradicional de Asia Oriental , Moco/metabolismo , Ovalbúmina , Extractos Vegetales/uso terapéutico , Animales , Asma/inducido químicamente , Asma/patología , Líquido del Lavado Bronquioalveolar , COVID-19 , Citocinas/metabolismo , Femenino , Citometría de Flujo , Inmunoglobulina E/inmunología , Mediadores de Inflamación/metabolismo , Pulmón/patología , Ratones , Ratones Endogámicos BALB C , Pandemias , Células Th2/efectos de los fármacos , Células Th2/inmunología , Triptaminas/farmacología
2.
Int J Mol Sci ; 22(21)2021 Oct 21.
Artículo en Inglés | MEDLINE | ID: mdl-34768820

RESUMEN

Disseminated intravascular coagulation (DIC) is a severe condition characterized by the systemic formation of microthrombi complicated with bleeding tendency and organ dysfunction. In the last years, it represents one of the most frequent consequences of coronavirus disease 2019 (COVID-19). The pathogenesis of DIC is complex, with cross-talk between the coagulant and inflammatory pathways. The objective of this study is to investigate the anti-inflammatory action of ultramicronized palmitoylethanolamide (um-PEA) in a lipopolysaccharide (LPS)-induced DIC model in rats. Experimental DIC was induced by continual infusion of LPS (30 mg/kg) for 4 h through the tail vein. Um-PEA (30 mg/kg) was given orally 30 min before and 1 h after the start of intravenous infusion of LPS. Results showed that um-PEA reduced alteration of coagulation markers, as well as proinflammatory cytokine release in plasma and lung samples, induced by LPS infusion. Furthermore, um-PEA also has the effect of preventing the formation of fibrin deposition and lung damage. Moreover, um-PEA was able to reduce the number of mast cells (MCs) and the release of its serine proteases, which are also necessary for SARS-CoV-2 infection. These results suggest that um-PEA could be considered as a potential therapeutic approach in the management of DIC and in clinical implications associated to coagulopathy and lung dysfunction, such as COVID-19.


Asunto(s)
Amidas/uso terapéutico , Trastornos de la Coagulación Sanguínea/tratamiento farmacológico , Coagulación Intravascular Diseminada/tratamiento farmacológico , Etanolaminas/uso terapéutico , Ácidos Palmíticos/uso terapéutico , Sepsis/complicaciones , Amidas/química , Amidas/farmacología , Animales , Trastornos de la Coagulación Sanguínea/etiología , COVID-19/patología , COVID-19/virología , Citocinas/sangre , Citocinas/metabolismo , Modelos Animales de Enfermedad , Coagulación Intravascular Diseminada/etiología , Etanolaminas/química , Etanolaminas/farmacología , Productos de Degradación de Fibrina-Fibrinógeno/metabolismo , Lipopolisacáridos/toxicidad , Pulmón/metabolismo , Pulmón/patología , Masculino , Mastocitos/citología , Mastocitos/efectos de los fármacos , Mastocitos/metabolismo , Ácidos Palmíticos/química , Ácidos Palmíticos/farmacología , Tiempo de Tromboplastina Parcial , Tiempo de Protrombina , Ratas , Ratas Sprague-Dawley , SARS-CoV-2/aislamiento & purificación , Sepsis/patología , Serina Proteasas/metabolismo
3.
Int J Mol Sci ; 22(21)2021 Nov 06.
Artículo en Inglés | MEDLINE | ID: mdl-34769454

RESUMEN

On 11 March 2020, the World Health Organization (WHO) declared a pandemic due to the spread of COVID-19 from Wuhan, China, causing high mortality rates all over the world. The related disease, which mainly affects the lungs, is responsible for the onset of Diffuse Alveolar Damage (DAD) and a hypercoagulability state, frequently leading to Severe Acute Respiratory Syndrome (SARS) and multiorgan failure, particularly in old and severe-critically ill patients. In order to find effective therapeutic strategies, many efforts have been made aiming to shed light on the pathophysiology of COVID-19 disease. Moreover, following the late advent of vaccination campaigns, the need for the comprehension of the pathophysiology of the fatal, although rare, thrombotic adverse events has become mandatory as well. The achievement of such purposes needs a multidisciplinary approach, depending on a correct interpretation of clinical, biochemical, biomolecular, and forensic findings. In this scenario, autopsies have helped in defining, on both gross and histologic examinations, the main changes to which the affected organs undergo and the role in assessing whether a patient is dead "from" or "with" COVID-19, not to mention whether the existence of a causal link exists between vaccination and thrombotic adverse events. In the present work, we explored the role of postmortem immunohistochemistry, and the increasingly used ancillary technique, in helping to understand the mechanism underlying the pathophysiology of both COVID-19 disease and COVID-19 vaccine-related adverse and rare effects.


Asunto(s)
Vacunas contra la COVID-19/efectos adversos , COVID-19/patología , Trombosis/etiología , Autopsia , COVID-19/prevención & control , COVID-19/virología , Vacunas contra la COVID-19/administración & dosificación , Citocinas/metabolismo , Endotelio/metabolismo , Endotelio/patología , Humanos , Inmunohistoquímica , SARS-CoV-2/aislamiento & purificación
4.
Comput Math Methods Med ; 2021: 6021763, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34754326

RESUMEN

Background: Oxidative stress, inflammation, and nucleus pulposus cells (NPCs) apoptosis are involved in pathogenesis of intervertebral disc (IVD) degeneration (IVDD). Dimethyl fumarate (DMF) has been found to effectively depress oxidative stress and inflammation via the Nrf2 pathway. Hence, this project was designed to explore the underlying mechanisms of how DMF protects NPCs from damage by LPS challenge. Methods and Results: CCK8 assay and flow cytometry of apoptosis indicated that DMF treatment attenuated LPS-induced NPC damage. Western blot analysis demonstrated that DMF enhanced the expressions of nuclear factor-erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) in LPS-challenged NPCs. DMF treatment significantly decreased the accumulation of ROS, downregulated inflammatory cytokines (p-NF-κB, IL-1ß, and TNF-α), and ER stress-associated apoptosis proteins (Bip, calpain-1, caspase-12, caspase-3, and Bax) in LPS-challenged NPCs. The level of antiapoptotic protein Bcl-2 was promoted by DMF treatment in LPS-challenged NPCs. Glutathione (GSH) assay showed that DMF treatment improved reduced to oxidized glutathione ratio in LPS-challenged NPCs. Furthermore, the results of western blot analysis indicated that in LPS-challenged NPCs, DMF treatment ameliorated the elevated levels of matrix degradation enzymes (MMP-13, aggrecanase 1) and type I collagen and the reduced levels of matrix composition (type II collagen and ACAN). However, Nrf2 knockdown abolished these protective effects of DMF. Conclusion: Our data suggested that treatment with DMF mitigated LPS-induced oxidative stress, inflammation, and ER stress-associated apoptosis in NPCs via the Nrf2/HO-1 signaling pathway, thus reliving LPS-induced dysfunction of NPCs, which offered a novel potential pharmacological treatment strategy for IVDD.


Asunto(s)
Dimetilfumarato/farmacología , Hemo-Oxigenasa 1/metabolismo , Degeneración del Disco Intervertebral/tratamiento farmacológico , Degeneración del Disco Intervertebral/metabolismo , Factor 2 Relacionado con NF-E2/agonistas , Núcleo Pulposo/efectos de los fármacos , Núcleo Pulposo/metabolismo , Antioxidantes/farmacología , Apoptosis/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Biología Computacional , Citocinas/metabolismo , Citoprotección/efectos de los fármacos , Estrés del Retículo Endoplásmico/efectos de los fármacos , Humanos , Inflamación/tratamiento farmacológico , Degeneración del Disco Intervertebral/patología , Lipopolisacáridos/toxicidad , Núcleo Pulposo/patología , Estrés Oxidativo/efectos de los fármacos , Transducción de Señal/efectos de los fármacos
5.
Braz Dent J ; 32(3): 65-74, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34755791

RESUMEN

This study investigated the effect of three commercial calcium silicate-based materials (CSBM) on cytotoxicity and pro-and anti-inflammatory cytokines production in cultured human periodontal ligament stem cells (hPDLSCs). Culture of hPDLSCs was established and characterized. Extracts of Bio-C Sealer (Angelus, Londrina, PR, Brazil), MTA Fillapex (Angelus, Londrina, PR, Brazil) and PBS Cimmo HP (Cimmo Soluções em Saúde, Pouso Alegre, MG, Brazil) were prepared by placing cement specimens (5 x 3 mm) in culture medium. Then, the extracts were serially two-fold diluted (1, 1:2, 1:4, 1:8, 1:16) and inserted into the cell-seeded wells for 24, 48 and 72 h for MTT assays. TNF-α and IL-10 cytokines were quantified by ELISA at 24h-cell supernatants. Data were analyzed by ANOVA and Tukey's test (α = 0.05). All CSBM exhibited some cytotoxicity that varied according to extract concentration and time of evaluation. MTA Fillapex presented the highest cytotoxic effects with significant reduction of metabolic activity/cell viability when compared to Bio-C Sealer and Cimmo HP®. TNF-α was significantly upregulated by the three tested cements (p < 0.05) while only MTA Fillapex significantly upregulated IL-10 in comparison to control. Taken collectively, the results showed that PBS Cimmo HP®, Bio-C Sealer and MTA Fillapex present mild and transient cytotoxicity and slightly induced TNF-α production. MTA Fillapex upregulated IL-10 release by hPDLSCs.


Asunto(s)
Compuestos de Calcio/efectos adversos , Ligamento Periodontal , Materiales de Obturación del Conducto Radicular/efectos adversos , Silicatos/efectos adversos , Células Madre/efectos de los fármacos , Compuestos de Aluminio , Citocinas/metabolismo , Humanos , Ensayo de Materiales , Óxidos , Ligamento Periodontal/citología
7.
JAMA Netw Open ; 4(11): e2133090, 2021 11 01.
Artículo en Inglés | MEDLINE | ID: mdl-34779847

RESUMEN

Importance: Antidepressant use may be associated with reduced levels of several proinflammatory cytokines suggested to be involved with the development of severe COVID-19. An association between the use of selective serotonin reuptake inhibitors (SSRIs)-specifically fluoxetine hydrochloride and fluvoxamine maleate-with decreased mortality among patients with COVID-19 has been reported in recent studies; however, these studies had limited power due to their small size. Objective: To investigate the association of SSRIs with outcomes in patients with COVID-19 by analyzing electronic health records (EHRs). Design, Setting, and Participants: This retrospective cohort study used propensity score matching by demographic characteristics, comorbidities, and medication indication to compare SSRI-treated patients with matched control patients not treated with SSRIs within a large EHR database representing a diverse population of 83 584 patients diagnosed with COVID-19 from January to September 2020 and with a duration of follow-up of as long as 8 months in 87 health care centers across the US. Exposures: Selective serotonin reuptake inhibitors and specifically (1) fluoxetine, (2) fluoxetine or fluvoxamine, and (3) other SSRIs (ie, not fluoxetine or fluvoxamine). Main Outcomes and Measures: Death. Results: A total of 3401 adult patients with COVID-19 prescribed SSRIs (2033 women [59.8%]; mean [SD] age, 63.8 [18.1] years) were identified, with 470 receiving fluoxetine only (280 women [59.6%]; mean [SD] age, 58.5 [18.1] years), 481 receiving fluoxetine or fluvoxamine (285 women [59.3%]; mean [SD] age, 58.7 [18.0] years), and 2898 receiving other SSRIs (1733 women [59.8%]; mean [SD] age, 64.7 [18.0] years) within a defined time frame. When compared with matched untreated control patients, relative risk (RR) of mortality was reduced among patients prescribed any SSRI (497 of 3401 [14.6%] vs 1130 of 6802 [16.6%]; RR, 0.92 [95% CI, 0.85-0.99]; adjusted P = .03); fluoxetine (46 of 470 [9.8%] vs 937 of 7050 [13.3%]; RR, 0.72 [95% CI, 0.54-0.97]; adjusted P = .03); and fluoxetine or fluvoxamine (48 of 481 [10.0%] vs 956 of 7215 [13.3%]; RR, 0.74 [95% CI, 0.55-0.99]; adjusted P = .04). The association between receiving any SSRI that is not fluoxetine or fluvoxamine and risk of death was not statistically significant (447 of 2898 [15.4%] vs 1474 of 8694 [17.0%]; RR, 0.92 [95% CI, 0.84-1.00]; adjusted P = .06). Conclusions and Relevance: These results support evidence that SSRIs may be associated with reduced severity of COVID-19 reflected in the reduced RR of mortality. Further research and randomized clinical trials are needed to elucidate the effect of SSRIs generally, or more specifically of fluoxetine and fluvoxamine, on the severity of COVID-19 outcomes.


Asunto(s)
Antidepresivos , COVID-19/mortalidad , Fluoxetina , Fluvoxamina , Inhibidores de la Captación de Serotonina , Índice de Severidad de la Enfermedad , Adulto , Anciano , Antidepresivos/farmacología , COVID-19/metabolismo , Citalopram/farmacología , Citocinas/metabolismo , Femenino , Fluoxetina/farmacología , Fluvoxamina/farmacología , Humanos , Masculino , Persona de Mediana Edad , Medicamentos bajo Prescripción , Estudios Retrospectivos , Riesgo , SARS-CoV-2 , Inhibidores de la Captación de Serotonina/farmacología , Sertralina , Estados Unidos
8.
Sci Rep ; 11(1): 21849, 2021 11 08.
Artículo en Inglés | MEDLINE | ID: mdl-34750472

RESUMEN

The huge worldwide demand for vaccines targeting SARS-CoV-2 has necessitated the continued development of novel improved formulations capable of reducing the burden of the COVID-19 pandemic. Herein, we evaluated novel protein subunit vaccine formulations containing a resistin-trimerized spike antigen, SmT1. When combined with sulfated lactosyl archaeol (SLA) archaeosome adjuvant, formulations induced robust antigen-specific humoral and cellular immune responses in mice. Antibodies had strong neutralizing activity, preventing viral spike binding and viral infection. In addition, the formulations were highly efficacious in a hamster challenge model reducing viral load and body weight loss even after a single vaccination. The antigen-specific antibodies generated by our vaccine formulations had stronger neutralizing activity than human convalescent plasma, neutralizing the spike proteins of the B.1.1.7 and B.1.351 variants of concern. As such, our SmT1 antigen along with SLA archaeosome adjuvant comprise a promising platform for the development of efficacious protein subunit vaccine formulations for SARS-CoV-2.


Asunto(s)
Adyuvantes Inmunológicos/química , Antígenos Arqueales/química , Vacunas contra la COVID-19/uso terapéutico , Lípidos/química , Animales , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Peso Corporal , COVID-19/terapia , Chlorocebus aethiops , Cricetinae , Citocinas/metabolismo , Femenino , Humanos , Inmunidad Celular , Inmunidad Humoral , Inmunización Pasiva , Mesocricetus , Ratones , Ratones Endogámicos C57BL , Pruebas de Neutralización , Péptidos/química , Dominios Proteicos , SARS-CoV-2 , Receptores Toll-Like/inmunología , Células Vero , Carga Viral
9.
Science ; 374(6568): eabe6723, 2021 11 05.
Artículo en Inglés | MEDLINE | ID: mdl-34735226

RESUMEN

A diverse group of antimicrobial proteins (AMPs) helps protect the mammalian intestine from varied microbial challenges. We show that small proline-rich protein 2A (SPRR2A) is an intestinal antibacterial protein that is phylogenetically unrelated to previously discovered mammalian AMPs. In this study, SPRR2A was expressed in Paneth cells and goblet cells and selectively killed Gram-positive bacteria by disrupting their membranes. SPRR2A shaped intestinal microbiota composition, restricted bacterial association with the intestinal surface, and protected against Listeria monocytogenes infection. SPRR2A differed from other intestinal AMPs in that it was induced by type 2 cytokines produced during helminth infection. Moreover, SPRR2A protected against helminth-induced bacterial invasion of intestinal tissue. Thus, SPRR2A is a distinctive AMP triggered by type 2 immunity that protects the intestinal barrier during helminth infection.


Asunto(s)
Proteínas Ricas en Prolina del Estrato Córneo/metabolismo , Microbioma Gastrointestinal , Bacterias Grampositivas/fisiología , Mucosa Intestinal/metabolismo , Intestinos/microbiología , Nematospiroides dubius , Infecciones por Strongylida/inmunología , Animales , Carga Bacteriana , Membrana Celular/metabolismo , Permeabilidad de la Membrana Celular , Proteínas Ricas en Prolina del Estrato Córneo/genética , Citocinas/metabolismo , Susceptibilidad a Enfermedades , Células Caliciformes/metabolismo , Humanos , Inmunidad Innata , Mucosa Intestinal/microbiología , Listeria monocytogenes/fisiología , Listeriosis/microbiología , Ratones , Viabilidad Microbiana , Células de Paneth/metabolismo , Proteínas Citotóxicas Formadoras de Poros/genética , Proteínas Citotóxicas Formadoras de Poros/metabolismo , Infecciones por Strongylida/metabolismo , Infecciones por Strongylida/microbiología
10.
Immunity ; 54(11): 2444-2446, 2021 11 09.
Artículo en Inglés | MEDLINE | ID: mdl-34758335

RESUMEN

Maternal infection during pregnancy increases the offspring's risk of developing neurodevelopmental disorders. While IL-6 is involved, the mechanism by which IL-6 and other cytokines affect developing neural circuits is unknown. In this issue of Immunity, Mirabella et al. (2021) show that the pro-inflammatory cytokine IL-6 specifically increases synaptogenesis in immature excitatory neurons through downstream neuronal STAT3-dependent transcriptional regulation of Rgs4.


Asunto(s)
Interleucina-6 , Neurogénesis , Citocinas/metabolismo , Femenino , Humanos , Neuronas/metabolismo , Embarazo , Factor de Transcripción STAT3/metabolismo
11.
Front Immunol ; 12: 748417, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34804033

RESUMEN

Rationale: Myocardial injury associates significantly and independently with mortality in COVID-19 patients. However, the pathogenesis of myocardial injury in COVID-19 remains unclear, and cardiac involvement by SARS-CoV-2 presents a major challenge worldwide. Objective: This histological and immunohistochemical study sought to clarify the pathogenesis and propose a mechanism with pathways involved in COVID-19 myocardial injury. Methods and Results: Postmortem minimally invasive autopsies were performed in six patients who died from COVID-19, and the myocardium samples were compared to a control group (n=11). Histological analysis was performed using hematoxylin-eosin and toluidine blue staining. Immunohistochemical (IHC) staining was performed using monoclonal antibodies against targets: caspase-1, caspase-9, gasdermin-d, ICAM-1, IL-1ß, IL-4, IL-6, CD163, TNF-α, TGF-ß, MMP-9, type 1 and type 3 collagen. The samples were also assessed for apoptotic cells by TUNEL. Histological analysis showed severe pericardiocyte interstitial edema and higher mast cells counts per high-power field in all COVID-19 myocardium samples. The IHC analysis showed increased expression of caspase-1, ICAM-1, IL-1ß, IL-6, MMP-9, TNF-α, and other markers in the hearts of COVID-19 patients. Expression of caspase-9 did not differ from the controls, while gasdermin-d expression was less. The TUNEL assay was positive in all the COVID-19 samples supporting endothelial apoptosis. Conclusions: The pathogenesis of COVID-19 myocardial injury does not seem to relate to primary myocardiocyte involvement but to local inflammation with associated interstitial edema. We found heightened TGF-ß and interstitial collagen expression in COVID-affected hearts, a potential harbinger of chronic myocardial fibrosis. These results suggest a need for continued clinical surveillance of patients for myocardial dysfunction and arrythmias after recovery from the acute phase of COVID-19.


Asunto(s)
COVID-19/metabolismo , Lesiones Cardíacas/metabolismo , SARS-CoV-2 , Anciano , Apoptosis , Biopsia , COVID-19/patología , Caspasa 1/metabolismo , Colágeno/metabolismo , Citocinas/metabolismo , Femenino , Lesiones Cardíacas/patología , Humanos , Inmunohistoquímica , Molécula 1 de Adhesión Intercelular/metabolismo , Masculino , Metaloproteinasa 9 de la Matriz/metabolismo , Miocardio/metabolismo , Miocardio/patología
12.
Sci Rep ; 11(1): 20793, 2021 10 21.
Artículo en Inglés | MEDLINE | ID: mdl-34675240

RESUMEN

In Europe, multiple waves of infections with SARS-CoV-2 (COVID-19) have been observed. Here, we have investigated whether common patterns of cytokines could be detected in individuals with mild and severe forms of COVID-19 in two pandemic waves, and whether machine learning approach could be useful to identify the best predictors. An increasing trend of multiple cytokines was observed in patients with mild or severe/critical symptoms of COVID-19, compared with healthy volunteers. Linear Discriminant Analysis (LDA) clearly recognized the three groups based on cytokine patterns. Classification and Regression Tree (CART) further indicated that IL-6 discriminated controls and COVID-19 patients, whilst IL-8 defined disease severity. During the second wave of pandemics, a less intense cytokine storm was observed, as compared with the first. IL-6 was the most robust predictor of infection and discriminated moderate COVID-19 patients from healthy controls, regardless of epidemic peak curve. Thus, serum cytokine patterns provide biomarkers useful for COVID-19 diagnosis and prognosis. Further definition of individual cytokines may allow to envision novel therapeutic options and pave the way to set up innovative diagnostic tools.


Asunto(s)
COVID-19/sangre , COVID-19/epidemiología , Citocinas/sangre , Anciano , Biomarcadores/sangre , Prueba de COVID-19 , Estudios de Casos y Controles , Citocinas/metabolismo , Análisis Discriminante , Femenino , Humanos , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Italia/epidemiología , Aprendizaje Automático , Masculino , Persona de Mediana Edad , Pandemias , Análisis de Regresión , SARS-CoV-2
13.
Molecules ; 26(20)2021 Oct 14.
Artículo en Inglés | MEDLINE | ID: mdl-34684784

RESUMEN

This work investigated the preparation, characterization, antioxidant, and anti-inflammation capacities of Flammulina velutipes polyphenols (FVP) and fermented FVP (FFVP). The results revealed that the new syringic acid, accounting for 22.22%, was obtained after fermentation (FFVP). FFVP exhibits higher antioxidant and anti-inflammation activities than FVP, enhancing cell viability and phagocytosis, inhibiting the secretion of NO and ROS, and reducing the inflammatory response of RAW264.7 cells. This study revealed that FFVP provides a theoretical reference for in-depth study of its regulatory mechanisms and further development of functional antioxidants that are applicable in the food and health industry.


Asunto(s)
Antiinflamatorios/química , Antiinflamatorios/farmacología , Antioxidantes/química , Antioxidantes/farmacología , Flammulina/química , Polifenoles/química , Polifenoles/farmacología , Animales , Productos Biológicos/química , Productos Biológicos/farmacología , Supervivencia Celular/efectos de los fármacos , Citocinas/metabolismo , Fermentación , Inflamasomas/antagonistas & inhibidores , Ratones , Microscopía Electrónica de Rastreo , FN-kappa B/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Óxido Nítrico/metabolismo , Fagocitosis/efectos de los fármacos , Células RAW 264.7 , Especies Reactivas de Oxígeno/metabolismo , Transducción de Señal/efectos de los fármacos
14.
Molecules ; 26(20)2021 Oct 14.
Artículo en Inglés | MEDLINE | ID: mdl-34684794

RESUMEN

Luohuazizhu suppository is a Traditional Chinese Medicine used in clinic to treat cervicitis, which is prepared from Callicarpa nudiflora Hook. et Arn (C. nudiflora), an herbal Chinese medicine named Luohuazizhu. This study aimed to figure out the active constituents of C. nudiflora and the potential mechanism for its anti-cervicitis effect. The ethanol extract in C. nudiflora (CNE) and the different fractions of CNE extracted by petroleum ether (CNE-p), dichloromethane (CNE-d), and n-butanol (CNE-b) were tested in vivo for their anti-cervicitis effects. Then the isolated compounds from the CNE-p were tested in vitro for their anti-inflammatory activities. The results displayed that CNE-p, CNE-d, and CNE-b exhibited adequate anti-cervicitis effects, with CNE-p showing the highest efficacy. Further experiment demonstrated that CNE-p could significantly inhibit the expression of NLRP3 in vitro. Six diterpenoids obtained from the CNE-p showed the ability to regulate inflammatory factor levels in vitro. Among these compounds, compounds 1 (callicarpic acid A) and 2 (syn-3,4-seco-12S-hydroxy-15,16-epoxy-4(18),8(17),3(16),14(15)-labdatetraen-3-oic acid) were the most effective agents, and they also inhibited the expression level of NLRP3 in vitro. The results confirmed that C. nudiflora has significant anti-cervicitis effects and the diterpenoids were most likely to be its active components. These data provide scientific support for the clinic usage of Luohuazizhu suppository and the development of new agents in treating cervicitis.


Asunto(s)
Callicarpa/química , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Fitoquímicos/farmacología , Cervicitis Uterina/tratamiento farmacológico , Animales , Antiinflamatorios/aislamiento & purificación , Antiinflamatorios/farmacología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Diterpenos/aislamiento & purificación , Diterpenos/farmacología , Femenino , Humanos , Medicina China Tradicional , Ratones , Simulación del Acoplamiento Molecular , Proteína con Dominio Pirina 3 de la Familia NLR/química , Fitoquímicos/aislamiento & purificación , Extractos Vegetales/farmacología , Plantas Medicinales/química , Células RAW 264.7 , Ratas , Ratas Sprague-Dawley , Cervicitis Uterina/metabolismo , Cervicitis Uterina/patología
15.
Cells ; 10(10)2021 09 26.
Artículo en Inglés | MEDLINE | ID: mdl-34685525

RESUMEN

The coronavirus disease 2019 (COVID-19) is related to enhanced production of NETs, and autoimmune/autoinflammatory phenomena. We evaluated the proportion of low-density granulocytes (LDG) by flow cytometry, and their capacity to produce NETs was compared with that of conventional neutrophils. NETs and their protein cargo were quantified by confocal microscopy and ELISA. Antinuclear antibodies (ANA), anti-neutrophil cytoplasmic antibodies (ANCA) and the degradation capacity of NETs were addressed in serum. MILLIPLEX assay was used to assess the cytokine levels in macrophages' supernatant and serum. We found a higher proportion of LDG in severe and critical COVID-19 which correlated with severity and inflammatory markers. Severe/critical COVID-19 patients had higher plasmatic NE, LL-37 and HMGB1-DNA complexes, whilst ISG-15-DNA complexes were lower in severe patients. Sera from severe/critical COVID-19 patients had lower degradation capacity of NETs, which was reverted after adding hrDNase. Anti-NET antibodies were found in COVID-19, which correlated with ANA and ANCA positivity. NET stimuli enhanced the secretion of cytokines in macrophages. This study unveils the role of COVID-19 NETs as inducers of pro-inflammatory and autoimmune responses. The deficient degradation capacity of NETs may contribute to the accumulation of these structures and anti-NET antibodies are related to the presence of autoantibodies.


Asunto(s)
Autoinmunidad , COVID-19/sangre , COVID-19/inmunología , Trampas Extracelulares/inmunología , Inmunidad Humoral , Inflamación , Neutrófilos/inmunología , Anticuerpos Antinucleares , Péptidos Catiónicos Antimicrobianos/sangre , Autoanticuerpos/metabolismo , Estudios Transversales , Citocinas/metabolismo , Citocinas/farmacología , Citometría de Flujo , Granulocitos/metabolismo , Proteína HMGB1/sangre , Voluntarios Sanos , Humanos , Microscopía Confocal , Monocitos/citología , Neutrófilos/citología , SARS-CoV-2 , Ubiquitinas/farmacología
16.
Cells ; 10(10)2021 10 03.
Artículo en Inglés | MEDLINE | ID: mdl-34685626

RESUMEN

The data currently available on how the immune system recognises the SARS-CoV-2 virus is growing rapidly. While there are structures of some SARS-CoV-2 proteins in complex with antibodies, which helps us understand how the immune system is able to recognise this new virus; however, we lack data on how T cells are able to recognise this virus. T cells, especially the cytotoxic CD8+ T cells, are critical for viral recognition and clearance. Here we report the X-ray crystallography structure of a T cell receptor, shared among unrelated individuals (public TCR) in complex with a dominant spike-derived CD8+ T cell epitope (YLQ peptide). We show that YLQ activates a polyfunctional CD8+ T cell response in COVID-19 recovered patients. We detail the molecular basis for the shared TCR gene usage observed in HLA-A*02:01+ individuals, providing an understanding of TCR recognition towards a SARS-CoV-2 epitope. Interestingly, the YLQ peptide conformation did not change upon TCR binding, facilitating the high-affinity interaction observed.


Asunto(s)
COVID-19/inmunología , COVID-19/virología , Epítopos de Linfocito T/química , Antígeno HLA-A2/inmunología , Receptores de Antígenos de Linfocitos T/inmunología , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus/química , Linfocitos T CD8-positivos/citología , Cristalografía por Rayos X , Citocinas/metabolismo , Epítopos/química , Antígeno HLA-A2/química , Humanos , Mutación , Péptidos/química , Unión Proteica , Desnaturalización Proteica , Pliegue de Proteína , Resonancia por Plasmón de Superficie , Linfocitos T Citotóxicos/inmunología
17.
Cells ; 10(10)2021 10 14.
Artículo en Inglés | MEDLINE | ID: mdl-34685733

RESUMEN

Basophils and mast cells are among the principal inducers of Th2 responses and have a crucial role in allergic and anti-parasitic protective immunity. Basophils can function as antigen-presenting cells that bind antigens on their surface and boost humoral immune responses, inducing Th2 cell differentiation. Their depletion results in lower humoral memory activation and greater infection susceptibility. Basophils seem to have an active role upon immune response to SARS-CoV-2. In fact, a coordinate adaptive immune response to SARS-CoV-2 is magnified by basophils. It has been observed that basophil amount is lower during acute disease with respect to the recovery phase and that the grade of this depletion is an important determinant of the antibody response to the virus. Moreover, mast cells, present in a great quantity in the nasal epithelial and lung cells, participate in the first immune response to SARS-CoV-2. Their activation results in a hyperinflammatory syndrome through the release of inflammatory molecules, participating to the "cytokine storm" and, in a longer period, inducing pulmonary fibrosis. The literature data suggest that basophil counts may be a useful prognostic tool for COVID-19, since their reduction is associated with a worse prognosis. Mast cells, on the other hand, represent a possible therapeutic target for reducing the airway inflammation characteristic of the hyperacute phase of the disease.


Asunto(s)
Basófilos/citología , COVID-19/inmunología , COVID-19/fisiopatología , Mastocitos/citología , Inmunidad Adaptativa , Animales , COVID-19/sangre , Diferenciación Celular , Citocinas/metabolismo , Granulocitos/citología , Humanos , Hipersensibilidad/metabolismo , Sistema Inmunológico , Inmunidad Humoral , Inmunidad Innata , Inflamación , Macrófagos/citología , Ratones , SARS-CoV-2 , Células Th17/citología , Células Th2/citología
18.
Nat Immunol ; 22(11): 1367-1374, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34686862

RESUMEN

Group 2 innate lymphoid cells (ILC2s) represent innate homologs of type 2 helper T cells (TH2) that participate in immune defense and tissue homeostasis through production of type 2 cytokines. While T lymphocytes metabolically adapt to microenvironmental changes, knowledge of human ILC2 metabolism is limited, and its key regulators are unknown. Here, we show that circulating 'naive' ILC2s have an unexpected metabolic profile with a higher level of oxidative phosphorylation (OXPHOS) than natural killer (NK) cells. Accordingly, ILC2s are severely reduced in individuals with mitochondrial disease (MD) and impaired OXPHOS. Metabolomic and nutrient receptor analysis revealed ILC2 uptake of amino acids to sustain OXPHOS at steady state. Following activation with interleukin-33 (IL-33), ILC2s became highly proliferative, relying on glycolysis and mammalian target of rapamycin (mTOR) to produce IL-13 while continuing to fuel OXPHOS with amino acids to maintain cellular fitness and proliferation. Our results suggest that proliferation and function are metabolically uncoupled in human ILC2s, offering new strategies to target ILC2s in disease settings.


Asunto(s)
Proliferación Celular , Citocinas/metabolismo , Metabolismo Energético , Inmunidad Innata , Activación de Linfocitos , Enfermedades Mitocondriales/metabolismo , Células Th2/metabolismo , Aminoácidos de Cadena Ramificada/metabolismo , Arginina/metabolismo , Estudios de Casos y Controles , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Metabolismo Energético/efectos de los fármacos , Humanos , Inmunidad Innata/efectos de los fármacos , Interleucina-33/farmacología , Activación de Linfocitos/efectos de los fármacos , Mitocondrias/metabolismo , Enfermedades Mitocondriales/diagnóstico , Enfermedades Mitocondriales/inmunología , Fenotipo , Células Th2/efectos de los fármacos , Células Th2/inmunología
19.
Cell Transplant ; 30: 9636897211049814, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-34689578

RESUMEN

During the past 18 months as the world dealt with the COVID-19 pandemic, articles published in Cell Transplantation (CT) voiced unique perspectives on the disease which have since been supported by additional research. Intrigued by the variability in COVID-19 severity, CT authors explored the influence of variants in angiotensin-converting enzyme 2 (ACE2) and the transmembrane serine protease 2 (TMPRSS2) genes, as well as the role of androgen receptors on disease development. Mesenchymal stem cells (MSC) were offered up as a potential COVID-19 therapy because of their immune modulating characteristics and successful use in other acute respiratory diseases. Two CT author groups gave proof of principle when hospitalized COVID-19 patients were infused with MSC after no other interventions seemed to work. MSC treatment reduced disease severity and shortened hospitalization stays. Lastly, CT authors speculated why we are still in the midst of a pandemic and the consequences of disillusioned comfort as we face new emerging variants that may undermine all we have accomplished thus far.


Asunto(s)
COVID-19/inmunología , COVID-19/terapia , Células Madre Mesenquimatosas/citología , Serina Endopeptidasas/genética , Enzima Convertidora de Angiotensina 2/metabolismo , Investigación Biomédica , Trasplante de Células , Citocinas/metabolismo , Hospitalización , Humanos , Sistema Inmunológico , Células Madre Mesenquimatosas/metabolismo , Peptidil-Dipeptidasa A/genética , Publicaciones , Receptores Androgénicos/metabolismo , Estudios Retrospectivos , SARS-CoV-2 , Índice de Severidad de la Enfermedad
20.
PLoS Pathog ; 17(10): e1009928, 2021 10.
Artículo en Inglés | MEDLINE | ID: mdl-34695164

RESUMEN

Non-specific protective effects of certain vaccines have been reported, and long-term boosting of innate immunity, termed trained immunity, has been proposed as one of the mechanisms mediating these effects. Several epidemiological studies suggested cross-protection between influenza vaccination and COVID-19. In a large academic Dutch hospital, we found that SARS-CoV-2 infection was less common among employees who had received a previous influenza vaccination: relative risk reductions of 37% and 49% were observed following influenza vaccination during the first and second COVID-19 waves, respectively. The quadrivalent inactivated influenza vaccine induced a trained immunity program that boosted innate immune responses against various viral stimuli and fine-tuned the anti-SARS-CoV-2 response, which may result in better protection against COVID-19. Influenza vaccination led to transcriptional reprogramming of monocytes and reduced systemic inflammation. These epidemiological and immunological data argue for potential benefits of influenza vaccination against COVID-19, and future randomized trials are warranted to test this possibility.


Asunto(s)
COVID-19/inmunología , Protección Cruzada/fisiología , Inmunidad Innata/fisiología , Vacunas contra la Influenza/administración & dosificación , COVID-19/epidemiología , COVID-19/prevención & control , Citocinas/inmunología , Citocinas/metabolismo , Regulación hacia Abajo , Imidazoles/inmunología , Incidencia , Vacunas contra la Influenza/inmunología , Países Bajos/epidemiología , Personal de Hospital , Poli I-C/inmunología , Proteómica , Factores de Riesgo , Análisis de Secuencia de ARN
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