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1.
Zhonghua Wei Zhong Bing Ji Jiu Yi Xue ; 33(1): 43-48, 2021 Jan.
Artículo en Chino | MEDLINE | ID: mdl-33565399

RESUMEN

OBJECTIVE: To investigate the effect and mechanism of exosomes derived from human-induced pluripotent mesenchymal stem cells (iMSC-Exos) on alveolar macrophages (AM) pyroptosis. METHODS: The exosomes in the culture supernatant of human-induced pluripotent mesenchymal stem cells (iMSC) were extracted by rotating ultrafiltration, and the extracted exosomes were identified by transmission electron microscopy, Western blotting and high-resolution adjustable resistance pulse. The rat alveolar macrophage cells (NR8383 cells) were cultured in vitro and the logarithmic growth phase cells were divided into three groups: the control group was added with an equal volume of phosphate buffered saline (PBS) in the AM supernatant; in LPS/ATP group AM cells were stimulated with 500 µg/L LPS for 23 hours and then 5 mmol/L ATP was added for 1 hour to induce pyrolysis; iMSC-Exos group was incubated with AM and 100 mg/L iMSC-Exos for 3 hours before giving LPS and ATP. The cytotoxic activity was detected by cell counting kit-8 (CCK-8) and lactate dehydrogenase (LDH) analysis, the apoptosis and the expression of caspase-1 were observed by immunofluorescence, the levels of inflammatory factors interleukins (IL-1ß and IL-18) released by AM were detected by enzyme linked immunosorbent assay (ELISA), the NOD-like receptor protein 3 (NLRP3) inflammasome pathway and the expression level of pyroptosis related protein gasdermin D (GSDMD) were detected by Western blotting. RESULTS: The extracted exosomes were observed by transmission electron microscopy as round vesicles, expressing exosomal markers CD63 and CD9 showed by Western blotting, high-resolution adjustable resistance pulse showed the average diameter of the particles was 130 nm, and could be uptaken by AM. Compared with the control group, the cell activity decreased [(0.56±0.05)% vs. (1.06±0.07)%, P < 0.01], the release of necrotic substance LDH increased (U/L: 1 218.86±22.73 vs. 188.30±1.61, P < 0.01), the expression levels of inflammatory factors increased [IL-1ß (ng/L): 958.91±32.78 vs. 194.63±5.14, IL-18 (ng/L): 870.89±21.86 vs. 288.85±24.48, both P < 0.01], and the apoptosis rate [(55.35±6.19)% vs. (12.01±1.32)%, P < 0.01] and caspase-1 expression (fluorescence intensity: 41.06±3.65 vs. 2.80±0.54, P < 0.01) elevated in the AM after LPS/ATP stimulation, suggesting that LPS combined with ATP successfully induced alveolar pyroptosis. Compared with the LPS/ATP group, AM pretreated with iMSC-Exos showed increased cell viability [(0.81±0.05)% vs. (0.56±0.05)%, P < 0.01], decreased LDH secretion (U/L: 535.05±42.55 vs. 1 218.86±22.73, P < 0.01), decreased expression of inflammatory factors [IL-1ß (ng/L): 381.82±19.50 vs. 958.91±32.78, IL-18 (ng/L): 533.77±31.54 vs. 870.89±21.86, both P < 0.01], and decreased apoptosis rate [(19.74±2.96)% vs. (55.35±6.19)%, P < 0.01] and caspase-1 expression (fluorescence intensity: 12.16±1.31 vs. 41.06±3.65, P < 0.01). At the same time, the expression of NLRP3 inflammasome pathway [NLRP3 protein (NLRP3/ß-actin): 0.62±0.06 vs. 1.89±0.11; cleaved caspase-1 protein (cleaved caspase-1/ß-actin): 0.42±0.07 vs. 1.22±0.17, both P < 0.01] and pyrolysis-related protein was significantly inhibited [GSDMD protein (GSDMD/ß-actin): 0.57±0.05 vs. 1.22±0.05, P < 0.01]. CONCLUSIONS: iMSC-Exos successfully reversed the AM pyroptosis and inflammatory factor expression induced by LPS/ATP, which may be due to the targeted inhibition of NLRP3 inflammasome pathway, suggesting that iMSC-Exos can exert anti-inflammatory effects by inhibiting the pyrolysis of AM.


Asunto(s)
Exosomas , Células Madre Mesenquimatosas , Animales , Exosomas/metabolismo , Humanos , Inflamasomas , Interleucina-1beta/metabolismo , Péptidos y Proteínas de Señalización Intracelular , Lipopolisacáridos , Macrófagos Alveolares/metabolismo , Células Madre Mesenquimatosas/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Proteínas de Unión a Fosfato , Pirólisis , Piroptosis , Ratas
2.
Zhen Ci Yan Jiu ; 46(1): 14-20, 2021 Jan 25.
Artículo en Chino | MEDLINE | ID: mdl-33559420

RESUMEN

OBJECTIVE: To observe the effects of acupuncture on the behavior, serum inflammatory cytokines, hippocampal Nod-like receptor protein 3(NLRP3) inflammasome-related proteins and microglia activation in rats with intrauterine distress induced ischemia-hypoxic brain injury (HIBD), so as to explore the mechanism of acupuncture underlying treatment of HIBD by regulating hippocampal inflammation. METHODS: The HIBD model was established by clipping bilateral uterine arteries for 10 min and delaying caesarean delivery. HIBD rats were randomly divided into model group and acupuncture group according to body weight and litter factors, with 12 rats in each group. Twelve rats delivered normally were regarded as the normal group. Acupuncture was applied to bilateral "Benshen"(GB13) for 10 min, once a day for 14 consecutive days. H.E. staining was used to observe the pathological changes of hippocampus. The three chamber sociability test was used to determine the rat's social ability. The serum IL-1ß and IL-18 levels, the hippocampal expressions of NLRP3, apoptosis associated speck like protein containing CARD(ASC) and cysteinyl aspartate specific proteinase-1(Caspase-1), andionized calcium bindingadaptor molecule-1(IBA-1) were detected by ELISA,Western blot and Immunofluorescence, separately. RESULTS: Compared with the normal group, The hippocampal neurons in the model group are arranged loosely, and the cells are solidified and shrunk and the whole cells are deeply stained. The time of exploring the stranger rat in the model group was significantly reduced (P<0.01). The contents of IL-1ß and IL-18, the expressions of NLRP3, ASC, Caspase-1 and IBA-1 of the model group were higher than those of the normal group (P<0.01, P<0.05, P<0.001). Following acupuncture intervention, the cell structure of hippocampal neurons was improved, and there were fewer cases of cell solidification, atrophy, and deep staining. In comparison with the model group, the time of exploring stranger rat in the acupuncture group was significantly increased (P<0.01). The contents of IL-1ß and IL-18, the expressions of NLRP3, ASC and Caspase-1, and IBA-1 of the acupuncture group were significantly down-regulated than those of the model group (P<0.01, P<0.05). CONCLUSION: Acupuncture can effectively improve the social behavior deficits of HIBD rats,which may be related to inhibition of the expression of inflammatory response proteins NLRP3, ASC and Caspase-1 in the hippocampus, decrease the activation of microglia in the hippocampus, and reduce serum IL-1ß and IL-18, thereby alleviating inflammation.


Asunto(s)
Terapia por Acupuntura , Lesiones Encefálicas , Animales , Femenino , Hipocampo/metabolismo , Inflamación/genética , Inflamación/terapia , Interleucina-1beta/metabolismo , Embarazo , Ratas , Ratas Sprague-Dawley
3.
Nat Commun ; 12(1): 86, 2021 01 04.
Artículo en Inglés | MEDLINE | ID: mdl-33397971

RESUMEN

Inflammation and cell death are closely linked arms of the host immune response to infection, which when carefully balanced ensure host survival. One example of this balance is the tightly regulated transition from TNFR1-associated pro-inflammatory complex I to pro-death complex II. By contrast, here we show that a TRIF-dependent complex containing FADD, RIPK1 and caspase-8 (that we have termed the TRIFosome) mediates cell death in response to Yersinia pseudotuberculosis and LPS. Furthermore, we show that constitutive binding between ZBP1 and RIPK1 is essential for the initiation of TRIFosome interactions, caspase-8-mediated cell death and inflammasome activation, thus positioning ZBP1 as an effector of cell death in the context of bacterial blockade of pro-inflammatory signaling. Additionally, our findings offer an alternative to the TNFR1-dependent model of complex II assembly, by demonstrating pro-death complex formation reliant on TRIF signaling.


Asunto(s)
Interleucina-1beta/metabolismo , Lipopolisacáridos/farmacología , Proteínas de Unión al ARN/metabolismo , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismo , Proteínas Adaptadoras del Transporte Vesicular/metabolismo , Animales , Caspasa 8/metabolismo , Muerte Celular/efectos de los fármacos , Ratones Endogámicos C57BL , Unión Proteica/efectos de los fármacos , Receptores Tipo I de Factores de Necrosis Tumoral/metabolismo , Yersinia
4.
Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi ; 37(1): 84-89, 2021 Jan.
Artículo en Chino | MEDLINE | ID: mdl-33441233

RESUMEN

Chlamydia infection remains a problem for the world. Hundreds of millions of people suffer from Chlamydia-related diseases, but the specific infection mechanism is still unclear. Studies have shown that interleukins is involved in the innate immune process after Chlamydia infection. In the early stage of infection, Chlamydia, through receptor-mediated multiple signal transduction pathways, such as mitogen-activated protein kinase (MAPK), signal transducers and activators of transcription 3 (STAT3), myeloid differentiation factor 88 (MyD88) pathways, promotes the body to release a variety of pro-inflammatory interleukins, such as interleukin 1ß (IL-1ß), IL-6, IL-8 and IL-17, which inhibits Chlamydia replication and accelerates the clearance of Chlamydia. With the continuous secretion of pro-inflammatory interleukins, the body regulates immune cells to secrete anti-inflammatory interleukins, such as IL-4, IL-10 and IL-22, to reduce inflammatory reaction and tissue damage. We summarized the role of interleukins in Chlamydia infection in order to provide reference for clinical treatment.


Asunto(s)
Infecciones por Chlamydia , Chlamydia , Chlamydia/metabolismo , Humanos , Interleucina-1beta/metabolismo , Interleucinas , Factor 88 de Diferenciación Mieloide/metabolismo , Transducción de Señal
5.
Int J Nanomedicine ; 16: 471-480, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33500617

RESUMEN

Background: Doxil® (PEGylated liposomal doxorubicin, PLD) has been widely used in cancer treatment due to its excellent therapeutic efficacy, but it can simultaneously cause severe adverse effects such as hand-foot syndrome (HFS). To date, the pathophysiologic mechanism of HFS development induced by PLD administration has not been well understood. Materials and Methods: The histological features of skin lesion in PLD-induced HFS model were characterized by hematoxylin and eosin (H&E) staining and picrosirius red staining, and the induction of inflammation and apoptosis in the epidermal layer was detected by immunohistochemical and TUNEL staining. Moreover, the generation of reactive oxygen species (ROS) was determined to elucidate the potential mechanism of skin lesion in the development of HFS. Results: The administration of PLD has been demonstrated to induce the histological damage of skin tissues including the destruction of collagen fibers and the induction of severe inflammation and apoptosis of epidermal cells. The mechanism was probably attributed to the accumulation of PLD in the skin tissues during the long-term circulation and further the induction of ROS to cause the oxidative damage of keratinocytes owing to the sustained release of doxorubicin from PLD. Conclusion: The ROS generation induced by the administration of PLD has been identified to be a crucial factor in the development of HFS, which could be used as a potential therapeutic target to alleviate the HFS symptom of PLD administration.


Asunto(s)
Apoptosis , Doxorrubicina/análogos & derivados , Síndrome Mano-Pie/etiología , Síndrome Mano-Pie/patología , Inflamación/patología , Polietilenglicoles/efectos adversos , Especies Reactivas de Oxígeno/metabolismo , Animales , Antibióticos Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Modelos Animales de Enfermedad , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Femenino , Humanos , Inflamación/tratamiento farmacológico , Interleucina-1beta/metabolismo , Interleucina-6/metabolismo , Queratinocitos/efectos de los fármacos , Polietilenglicoles/administración & dosificación , Ratas Wistar , Piel/patología
6.
Life Sci ; 269: 118987, 2021 Mar 15.
Artículo en Inglés | MEDLINE | ID: mdl-33417958

RESUMEN

AIMS: To explore the therapeutic effect of miR-129-5p carried by exosomes from Human Synovial Mesenchymal Stem Cell (HS-MSC) on osteoarthritis(OA). MATERIALS AND METHODS: The levels of miR-129-5p and high mobility group protein -1 (HMGB1) and interleukin-1ß (IL-1ß) in the joint fluid of OA patients were respectively detected via real-time quantitative reverse transcription-PCR (RT-PCR) and enzyme-linked immunosorbent assay (ELISA). IL-1ß was taken to act on chondrocytes for the establishment of OA model in vitro. Ultracentrifugation was conducted to isolate HS-MSC exosomes (HS-MSC-Exo) from the supernatant. Western blot and ELISA were carried out to measure the expression of iNOS, COX2, MMP13, Collagen 2, TLR4, NF-κB, Caspase3, Bcl-2, HMGB1 in chondrocytes. Flow cytometry was conducted to detect the apoptosis of chondrocytes. Besides, bioinformatics was employed to predict the targeted relationship between miR-129-5p and HMGB1, which was further verified via dual luciferase activity experiments. KEY FINDINGS: The results illustrated that miR-129-5p was decreased in OA patients and IL-1ß-induced chondrocytes, while HMGB1 was notably upregulated. HS-MSC-Exo rich in miR-129-5p remarkably declined the inflammatory response and apoptosis of chondrocytes, while HS-MSC-Exo deficient in miR-129-5p increased the IL-1ß-mediated inflammatory response and apoptosis of chondrocytes. In terms of mechanism, miR-129-5p targets the 3'UTR end of HMGB1 and inhibits IL-1ß-mediated upregulation of HMGB1. SIGNIFICANCE: In a word, this paper proved that miR-129-5p, existing in HS-MSC-Exo, can suppress the IL-1ß-mediated OA by inhibiting HMGB1 release.


Asunto(s)
Exosomas/metabolismo , Proteína HMGB1/metabolismo , Células Madre Mesenquimatosas/metabolismo , MicroARNs/metabolismo , Osteoartritis/metabolismo , Membrana Sinovial/metabolismo , Secuencia de Bases , Condrocitos/metabolismo , Condrocitos/patología , Femenino , Regulación de la Expresión Génica , Proteína HMGB1/genética , Humanos , Interleucina-1beta/metabolismo , Articulaciones/patología , Masculino , MicroARNs/genética , Persona de Mediana Edad , Líquido Sinovial/metabolismo
7.
J Med Chem ; 64(1): 768-781, 2021 01 14.
Artículo en Inglés | MEDLINE | ID: mdl-33440945

RESUMEN

Berberine (BBR), a traditional Chinese medicine, has therapeutic effects on a variety of inflammation-related diseases, but its direct proteomic targets remain unknown. Using activity-based protein profiling, we first demonstrated that BBR directly targets the NEK7 protein via the hydrogen bond between the 2,3-methylenedioxy and 121-arginine (R121) residues. The fact that R121 is located precisely within the key domain involved in the NEK7-NLRP3 interaction allows BBR to specifically block the NEK7-NLRP3 interaction and successively inhibit IL-1ß release, independent of the NF-κB and TLR4 signaling pathways. Moreover, BBR displays in vivo anti-inflammatory efficacy in a NEK7-dependent manner. Therefore, we consider NEK7 to be a key target of BBR in the treatment of NLRP3-related inflammatory diseases, and the development of novel NEK7-NLRP3 interaction inhibitors might be easily achieved using NEK7 as a target.


Asunto(s)
Antiinflamatorios/química , Berberina/química , Quinasas Relacionadas con NIMA/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Animales , Antiinflamatorios/metabolismo , Antiinflamatorios/farmacología , Berberina/metabolismo , Berberina/farmacología , Sitios de Unión , Humanos , Enlace de Hidrógeno , Interleucina-1beta/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Simulación del Acoplamiento Molecular , Monocitos/citología , Monocitos/efectos de los fármacos , Monocitos/metabolismo , FN-kappa B/metabolismo , Quinasas Relacionadas con NIMA/antagonistas & inhibidores , Quinasas Relacionadas con NIMA/genética , Proteína con Dominio Pirina 3 de la Familia NLR/química , Dominios y Motivos de Interacción de Proteínas/efectos de los fármacos , Interferencia de ARN , ARN Interferente Pequeño/metabolismo , Transducción de Señal/efectos de los fármacos , Relación Estructura-Actividad
8.
J Surg Res ; 257: 468-476, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-32896815

RESUMEN

BACKGROUND: Donation after circulatory death donors (DCD) can expand the donor pool for heart transplantation, which primarily depends on brain death donors. Ischemia and reperfusion injury are inherent to the DCD process. We hypothesize that pharmacologic inhibition of interleukin-1 (IL-1) and/or IL-18 is protective to DCD hearts. MATERIALS AND METHODS: Following clinical protocol, in-situ ischemia time in control beating-heart donor (CBD) and DCD groups was less than 5 and 40 min, respectively. Wild type (WT) C57Bl6/j, IL-1 receptor type I knockout (IL-1RI-KO), and IL-18 KO mice were used. Hearts were reanimated for 90 min on a Langendorff system with Krebs-Henseleit buffer at 37°C, to assess physiologic parameters. Recombinant IL-1 receptor antagonist (IL-1Ra) and/or IL-18 binding protein (IL-18BP) were added to the Krebs-Henseleit buffer to inhibit IL-1 and/or the IL-18 signaling, respectively. RESULTS: Developed pressure and ± dP/dt were significantly impaired in the DCD-WT group compared to CBD-WT (P ≤ 0.05). Troponin release was higher in DCD-WT groups. Functional parameters were preserved, and troponin release was significantly less in the DCD knockout groups. Heart function was improved in DCD groups treated with IL-1Ra or IL-18BP compared to the DCD-WT group. CONCLUSIONS: Heart function was significantly impaired in the DCD-WT group compared to CBD-WT. Genetic deletion or pharmacologic blockade of IL-1 or IL-18 was protective to DCD hearts.


Asunto(s)
Péptidos y Proteínas de Señalización Intercelular/uso terapéutico , Proteína Antagonista del Receptor de Interleucina 1/uso terapéutico , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Daño por Reperfusión Miocárdica/prevención & control , Obtención de Tejidos y Órganos , Animales , Muerte , Evaluación Preclínica de Medicamentos , Corazón/efectos de los fármacos , Péptidos y Proteínas de Señalización Intercelular/farmacología , Proteína Antagonista del Receptor de Interleucina 1/farmacología , Interleucina-18/antagonistas & inhibidores , Interleucina-18/genética , Interleucina-1beta/antagonistas & inhibidores , Interleucina-1beta/genética , Masculino , Ratones Noqueados , Daño por Reperfusión Miocárdica/metabolismo , Distribución Aleatoria
9.
Phytomedicine ; 81: 153423, 2021 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-33310308

RESUMEN

BACKGROUND: As a traditional and typical prescription of prominently activating blood circulation to remove blood stasis, Xuefu Zhuyu decoction (XZD) consists of 15 kinds of herbal medicine. Clinical investigations have showed that XZD could significantly promote the new hair generation of alopecia areata (AA) patients characterized by Qi stagnation and blood stasis. PURPOSE: The purpose of this study was executed to determine whether the mechanisms by which XZD stimulated newborn hair were related to its anti-inflammatory effects. METHODS: Clinical AA individuals were recruited to confirm the efficies of XZD. High performance liquid chromatography (HPLC) analysis was performed to qualitatively and quantitatively determine the contents of 15 compounds in XZD. Schrodinger molecular docking and in vivo surface plasmon resonance (SPR) techniques were used to evaluate the potential binding properties of compounds to target proteins. C3H/HeJ mice were randomly assigned to groups control, AA, and the XZD administration (6.5, 13.0 and 26.0 g/kg/d). Except for mice in control group, all the mice in the other groups were treated with a 21-day chronic unpredictable mild stress (CUMS) induced AA. Hematoxylin-eosin (H&E) staining was performed to determine the degree of pathological damage to the skin. Enzyme-linked immunosorbent assay (ELISA) was performed to detect levels of interleukin-6 (IL-6), interleukin-1 beta (IL-1ß) and tumor necrosis factor alpha (TNF-α) and in serum and skin tissues. Western blot, immunohistochemistry and quantitative reverse transcription-polymerase chain reaction (qRT-PCR) were used to examine the expression levels of IL-6, IL-1ß, TNF-α and osteopontin proteins and genes in skin tissues. RESULTS: XZD could visibly promote hair regeneration of AA patients. The potential active ingredients in XZD prescription included at least amygdalin, hydroxysafflor yellow A, kaempferide, ferulic acid, catalpol, verbascoside, ß-ecdysone, platycodin D, paeoniflorin, naringin, neohesperidin, liquiritin, glycyrrhizic acid, saikosaponin A and saikosaponin D. The results of molecular docking and SPR analysis showed that verbascoside, liquiritin, kaempferide and amygdalin showed the best potential binding properties with IL-6, IL-1ß, TNF-α and osteopontin, respectively. Pathological evaluation showed that compared with the CUMS group, the administration of XZD significantly promoted hair regeneration, evidenced by increased number of skin hair follicles in C3H/HeJ AA mice. Compared with control group, ELISA data showed that the levels of IL-6, IL-1ß and TNF-α in serum and skin tissues of CUMS induced AA mice were significantly increased, while XZD administration dramatically restrained the contents of the three pro-inflammatory factors. Western blot, immunohistochemistry, and qRT-PCR results further demonstrated that XZD administration notably down-regulated the protein and gene expression levels of osteopontin, IL-6, IL-1ß and TNF-α in comparation with CUMS group. CONCLUSION: XZD could dramatically ameliorate CUMS-induced AA damage in the skin of C3H/HeJ mice, possibly by suppressing the levels of IL-6, IL-1ß, TNF-α and osteopontin.


Asunto(s)
Alopecia Areata/tratamiento farmacológico , Antiinflamatorios no Esteroideos/farmacología , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/farmacología , Cabello/efectos de los fármacos , Alopecia Areata/etiología , Alopecia Areata/patología , Animales , Antiinflamatorios no Esteroideos/química , Citocinas/química , Citocinas/metabolismo , Femenino , Cabello/crecimiento & desarrollo , Folículo Piloso/efectos de los fármacos , Humanos , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Masculino , Ratones Endogámicos C3H , Simulación del Acoplamiento Molecular , Regeneración/efectos de los fármacos , Piel/efectos de los fármacos , Piel/metabolismo , Piel/patología , Resonancia por Plasmón de Superficie , Factor de Necrosis Tumoral alfa/metabolismo , Adulto Joven
10.
Gene ; 766: 145149, 2021 Jan 15.
Artículo en Inglés | MEDLINE | ID: mdl-32971185

RESUMEN

BACKGROUND: Crosstalk between posterior cruciate ligament fibroblasts (PCLfs) and synoviocytes (SCs) significantly modifies the homeostatic balance of the extracellular matrix (ECM) and appears to post a prominent affection for wound healing of PCL. Interleukin-1ß (IL-1ß) is regarded as a critical factor in acute inflammatory events during ligament injury. METHODS: In order to confirm the capability of SCs the response of lysyl oxidases (LOXs) and matrix metalloproteinases (MMPs) to IL-1ß, the complex cues of the joint cavity following PCL injury were simulated and the effect of IL-1ß on the expression of LOXs and MMPs in PCLfs were investigated. PCLfs in both the mono- and co-culture conditions were treated with IL-1ß. Cell lysates were collected from the PCLfs and LOXs and MMP-1, 2, 3 expression quantified using quantitative real-time PCR and western bolting. RESULTS: The results indicated that injury alone elevated the expression of LOXs and MMP-1, 2 and 3. But IL-1ß significantly decreased the LOX, LOXL1, and LOXL3 expression, and simultaneously increased MMP-1, 2 and 3 expressions in injured PCLfs. Furthermore, co-culture further suppressed LOXs, but stimulated MMP-1, 2 and 3 expressions when subjected to both mechanical injury and IL-1ß treatment. This possibly suggests that a number of soluble factors are secreted that act as mediators that amplify the response of SCs. CONCLUSION: The results indicated that the SCs could affect the IL-1ß-induction of LOXs inhibition and MMPs accumulation, which may be the underlying mechanism of the the poor healing response following PCL injury.


Asunto(s)
Fibroblastos/metabolismo , Interleucina-1beta/metabolismo , Metaloproteinasas de la Matriz/metabolismo , Proteína-Lisina 6-Oxidasa/metabolismo , Sinoviocitos/metabolismo , Células Cultivadas , Técnicas de Cocultivo/métodos , Matriz Extracelular/metabolismo , Humanos , Membrana Sinovial/metabolismo , Cicatrización de Heridas/fisiología
11.
Cell Prolif ; 54(2): e12973, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33382502

RESUMEN

OBJECTIVES: NLRP3 inflammasome is a critical part of the innate immune system and plays an important role in a variety of inflammatory diseases. However, the effects of NLRP3 inflammasome on periodontitis have not been fully studied. MATERIALS AND METHODS: We used ligature-induced periodontitis models of NLRP3 knockout mice (NLRP3KO ) and their wildtype (WT) littermates to compare their alveolar bone phenotypes. We further used Lysm-Cre/RosanTnG mouse to trace the changes of Lysm-Cre+ osteoclast precursors in ligature-induced periodontitis with or without MCC950 treatment. At last, we explored MCC950 as a potential drug for the treatment of periodontitis in vivo and in vitro. RESULTS: Here, we showed that the number of osteoclast precursors, osteoclast differentiation and alveolar bone loss were reduced in NLRP3KO mice compared with WT littermates, by using ligature-induced periodontitis model. Next, MCC950, a specific inhibitor of the NLRP3 inflammasome, was used to inhibit osteoclast precursors differentiation into osteoclast. Further, we used Lysm-Cre/RosanTnG mice to demonstrate that MCC950 decreases the number of Lysm-Cre+ osteoclast precursors in ligature-induced periodontitis. At last, treatment with MCC950 significantly suppressed alveolar bone loss with reduced IL-1ß activation and osteoclast differentiation in ligature-induced periodontitis. CONCLUSION: Our findings reveal that NLRP3 regulates alveolar bone loss in ligature-induced periodontitis by promoting osteoclastic differentiation.


Asunto(s)
Pérdida de Hueso Alveolar/patología , Diferenciación Celular , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Osteoclastos/citología , Periodontitis/patología , Pérdida de Hueso Alveolar/metabolismo , Pérdida de Hueso Alveolar/prevención & control , Animales , Diferenciación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Compuestos Heterocíclicos de 4 o más Anillos/farmacología , Compuestos Heterocíclicos de 4 o más Anillos/uso terapéutico , Inflamasomas/efectos de los fármacos , Inflamasomas/metabolismo , Interleucina-1beta/metabolismo , Lipopolisacáridos/farmacología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Osteoclastos/metabolismo , Osteogénesis/efectos de los fármacos , Periodontitis/tratamiento farmacológico , Periodontitis/etiología , Células Madre/citología , Células Madre/metabolismo , Sulfonas/farmacología , Sulfonas/uso terapéutico
12.
Ecotoxicol Environ Saf ; 207: 111306, 2021 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-32949934

RESUMEN

Although studies have demonstrated that fine particulate matter (PM2.5) induces ocular surface damage, PM2.5 exposure causes cornea toxicity is not entirely clear. The aim of this study is to investigate the role of the nod-like receptor family pyrin domain containing three (NLRP3) inflammasome-mediated pyroptosis in PM2.5-related corneal toxicity. Human corneal epithelial cells (HCECs) were exposed to different concentrations of PM2.5, and the cell viability, expressions of NLRP3 inflammasome mediated pyroptosis axis molecules and intracellular reactive oxygen species (ROS) formation were measured in HCECs. Animal experiments were undertaken to topically apply PM2.5 suspension to mouse eyes for three months and the pyroptosis related molecules in the mouse corneas were measured. RESULTS: Our results showed a dose-dependent decrease of HCEC viability in the PM2.5-treated cells. NLRP3 inflammasome-mediated pyroptosis axis (NLRP3, ASC, GSDMD, caspase-1, IL-1ß, and IL-18) were activated in the PM2.5-treated HCECs, accompanied by increased ROS formation. Further in vivo study confirmed the activation of this pathway in the mouse corneas exposed to PM2.5. In conclusion, this study provids novel evidence that PM2.5 induces corneal toxicity by triggering cell pyroptosis.


Asunto(s)
Córnea/efectos de los fármacos , Células Epiteliales/efectos de los fármacos , Inflamasomas/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Material Particulado/toxicidad , Piroptosis/efectos de los fármacos , Animales , Caspasa 1/metabolismo , Línea Celular , Supervivencia Celular/efectos de los fármacos , Córnea/patología , Células Epiteliales/inmunología , Células Epiteliales/metabolismo , Células Epiteliales/patología , Humanos , Inflamación , Interleucina-18/metabolismo , Interleucina-1beta/metabolismo , Ratones , Especies Reactivas de Oxígeno/metabolismo
13.
J Med Chem ; 64(1): 871-889, 2021 01 14.
Artículo en Inglés | MEDLINE | ID: mdl-33332136

RESUMEN

The NLRP3 inflammasome is a critical component of innate immunity, which defends internal and external threats. However, inappropriate activation of the NLRP3 inflammasome induces various human diseases. In this study, we discovered and synthesized a series of tetrahydroquinoline inhibitors of NLRP3 inflammasome. Among these analogues, compound 6 exhibited optimal NLRP3 inhibitory activity. In vitro studies indicated that compound 6 directly bound to the NACHT domain of NLRP3 but not to protein pyrin domain (PYD) or LRR domain, inhibited NLRP3 ATPase activity, and blocked ASC oligomerization, thereby inhibiting NLRP3 inflammasome assembly and activation. Compound 6 specifically inhibited the NLRP3 inflammasome activation, but had no effect on the activation of NLRC4 or AIM2 inflammasomes. Furthermore, in the dextran sulfate sodium (DSS)-induced colitis mouse model, compound 6 exhibited significant anti-inflammatory activity through inhibiting NLRP3 inflammasome in vivo. Therefore, our study provides a potent NLRP3 inflammasome inhibitor, which deserves further structural optimization as a novel therapeutic candidate for NLRP3-driven diseases.


Asunto(s)
Antiinflamatorios/uso terapéutico , Colitis/tratamiento farmacológico , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Quinolinas/química , Animales , Antiinflamatorios/química , Antiinflamatorios/metabolismo , Línea Celular , Supervivencia Celular/efectos de los fármacos , Colitis/inducido químicamente , Colitis/patología , Sulfato de Dextran/toxicidad , Diseño de Fármacos , Femenino , Humanos , Concentración 50 Inhibidora , Interleucina-1beta/metabolismo , Lipopolisacáridos/farmacología , Ratones , Ratones Endogámicos C57BL , Monocitos/citología , Monocitos/efectos de los fármacos , Monocitos/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Quinolinas/metabolismo , Quinolinas/uso terapéutico , Especies Reactivas de Oxígeno/metabolismo , Relación Estructura-Actividad
14.
Nat Commun ; 11(1): 6343, 2020 12 11.
Artículo en Inglés | MEDLINE | ID: mdl-33311467

RESUMEN

D-mannose is a monosaccharide approximately a hundred times less abundant than glucose in human blood. Previous studies demonstrated that supraphysiological levels of D-mannose inhibit tumour growth and stimulate regulatory T cell differentiation. It is not known whether D-mannose metabolism affects the function of non-proliferative cells, such as inflammatory macrophages. Here, we show that D-mannose suppresses LPS-induced macrophage activation by impairing IL-1ß production. In vivo, mannose administration improves survival in a mouse model of LPS-induced endotoxemia as well as decreases progression in a mouse model of DSS-induced colitis. Phosphomannose isomerase controls response of LPS-activated macrophages to D-mannose, which impairs glucose metabolism by raising intracellular mannose-6-phosphate levels. Such alterations result in the suppression of succinate-mediated HIF-1α activation, imposing a consequent reduction of LPS-induced Il1b expression. Disclosing an unrecognized metabolic hijack of macrophage activation, our study points towards safe D-mannose utilization as an effective intervention against inflammatory conditions.


Asunto(s)
Interleucina-1beta/metabolismo , Activación de Macrófagos/efectos de los fármacos , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Manosa/metabolismo , Manosa/farmacología , Animales , Diferenciación Celular/efectos de los fármacos , Línea Celular , Colitis/metabolismo , Colitis/patología , Regulación de la Expresión Génica , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Inflamación/metabolismo , Interleucina-1beta/genética , Lipopolisacáridos/efectos adversos , Manosafosfatos/metabolismo , Redes y Vías Metabólicas/efectos de los fármacos , Metabolómica , Monocitos/metabolismo
15.
PLoS Pathog ; 16(12): e1009107, 2020 12.
Artículo en Inglés | MEDLINE | ID: mdl-33338061

RESUMEN

Mycolactone, a lipid-like toxin, is the major virulence factor of Mycobacterium ulcerans, the etiological agent of Buruli ulcer. Its involvement in lesion development has been widely described in early stages of the disease, through its cytotoxic and immunosuppressive activities, but less is known about later stages. Here, we revisit the role of mycolactone in disease outcome and provide the first demonstration of the pro-inflammatory potential of this toxin. We found that the mycolactone-containing mycobacterial extracellular vesicles produced by M. ulcerans induced the production of IL-1ß, a potent pro-inflammatory cytokine, in a TLR2-dependent manner, targeting NLRP3/1 inflammasomes. We show our data to be relevant in a physiological context. The in vivo injection of these mycolactone-containing vesicles induced a strong local inflammatory response and tissue damage, which were prevented by corticosteroids. Finally, several soluble pro-inflammatory factors, including IL-1ß, were detected in infected tissues from mice and Buruli ulcer patients. Our results revisit Buruli ulcer pathophysiology by providing new insight, thus paving the way for the development of new therapeutic strategies taking the pro-inflammatory potential of mycolactone into account.


Asunto(s)
Úlcera de Buruli/inmunología , Inflamación/inmunología , Interleucina-1beta/inmunología , Macrólidos/inmunología , Animales , Úlcera de Buruli/metabolismo , Úlcera de Buruli/patología , Vesículas Extracelulares/metabolismo , Humanos , Inflamación/metabolismo , Inflamación/microbiología , Interleucina-1beta/metabolismo , Macrólidos/metabolismo , Macrólidos/toxicidad , Ratones , Ratones Endogámicos C57BL , Mycobacterium ulcerans
16.
Zhonghua Nan Ke Xue ; 26(8): 740-744, 2020 Aug.
Artículo en Chino | MEDLINE | ID: mdl-33377738

RESUMEN

Objective: To study the effect of Qiangjing Tablets (QJT) on the secretion of the inflammatory cytokines IL-1ß and TNF-ɑ from Sertoli cells in infertile mice based on the microenvironment of spermatogenesis. METHODS: We isolated and cultured mouse Sertoli cells, established the model of Ureaplasma urealyticum (UU) infection in the cells, and treated the cells with QJT at the concentrations of 2.5%, 5% and 10% in the serum. After modeling, we determined the contents of IL-1ß and TNF-ɑ in the supernatant of the cells by ELISA and examined the effect of QJT on the secretion of the inflammatory factors from the Sertoli cells by analyzing the dose-effect and time-effect relationships of the drug. RESULTS: In comparison with the blank control, the UU-infected Sertoli cells showed significantly increased secretion of IL-1ß and TNF-ɑ (P < 0.05), the former reaching the peak value in 12 hours and the latter in 24 hours, followed by a downward trend. The secretion of IL-1ß was remarkably inhibited in the 5% and 10% QJT groups (P < 0.05) and that of TNF- ɑ in the 10% QJT group compared with those in the UU infection model group (P < 0.05). CONCLUSIONS: The secretion of IL-1ß and TNF-ɑ is significantly increased in the UU-infected Sertoli cells, and that of IL-1ß negatively correlated with time. QJT-containing serum can inhibit the secretion of IL-1ß and TNF-ɑ from Sertoli cells, and the inhibitory effect of IL-1 ß is most significant at 5% and 10% and that of TNF- ɑ at 10%.


Asunto(s)
Medicamentos Herbarios Chinos/farmacología , Interleucina-1beta/metabolismo , Células de Sertoli/efectos de los fármacos , Espermatogénesis/efectos de los fármacos , Factor de Necrosis Tumoral alfa/metabolismo , Animales , Células Cultivadas , Masculino , Ratones , Células de Sertoli/metabolismo , Comprimidos
17.
Front Immunol ; 11: 583373, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33149733

RESUMEN

Coronaviruses (CoVs) are members of the genus Betacoronavirus and the Coronaviridiae family responsible for infections such as severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and more recently, coronavirus disease-2019 (COVID-19). CoV infections present mainly as respiratory infections that lead to acute respiratory distress syndrome (ARDS). However, CoVs, such as COVID-19, also present as a hyperactivation of the inflammatory response that results in increased production of inflammatory cytokines such as interleukin (IL)-1ß and its downstream molecule IL-6. The inflammasome is a multiprotein complex involved in the activation of caspase-1 that leads to the activation of IL-1ß in a variety of diseases and infections such as CoV infection and in different tissues such as lungs, brain, intestines and kidneys, all of which have been shown to be affected in COVID-19 patients. Here we review the literature regarding the mechanism of inflammasome activation by CoV infection, the role of the inflammasome in ARDS, ventilator-induced lung injury (VILI), and Disseminated Intravascular Coagulation (DIC) as well as the potential mechanism by which the inflammasome may contribute to the damaging effects of inflammation in the cardiac, renal, digestive, and nervous systems in COVID-19 patients.


Asunto(s)
Caspasa 1/metabolismo , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/patología , Síndrome de Liberación de Citoquinas/patología , Inflamasomas/inmunología , Neumonía Viral/inmunología , Neumonía Viral/patología , Betacoronavirus/inmunología , Coagulación Intravascular Diseminada/patología , Humanos , Inflamación/patología , Interleucina-1beta/metabolismo , Pandemias , Síndrome Respiratorio Agudo Grave/patología , Lesión Pulmonar Inducida por Ventilación Mecánica/patología
18.
J Toxicol Sci ; 45(11): 673-680, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33132241

RESUMEN

The epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) have been approved for non-small cell lung cancer. Although EGFR TKIs are less toxic than traditional cytotoxic therapies, they cause many severe idiosyncratic drug reactions. Reactive metabolites can cause cellular damage with the release of danger-associated molecular patterns (DAMPs), which is thought to be involved in immune activation. Inflammasomes can be activated by DAMPs, and this may be a common mechanism by which DAMPs initiate an immune response. We tested the ability of afatinib, dacomitinib, erlotinib, gefitinib, and osimertinib to induce the release of DAMPs that activate inflammasomes. Human hepatocarcinoma functional liver cell-4 (FLC-4) cells were used for bioactivation of drugs, and the detection of inflammasome activation was performed with the human macrophage cell line, THP-1 cells. Gefitinib is known to be oxidized to a reactive iminoquinone metabolite. We found that the supernatant from the incubation of gefitinib with FLC-4 cells for 7 days led to increased caspase-1 activity and production of IL-1ß by THP-1 cells. In the supernatant of FLC-4 cells with gefitinib, the heat shock protein (HSP) 40, 70 and 90 were significantly increased. In addition, activated THP-1 cells secreted high mobility group box 1 (HMGB1) protein. These results support the hypothesis that the reactive iminoquinone metabolite can cause the release of DAMPs from hepatocytes, which in turn, can activate inflammasomes. Inflammasome activation may be an important step in the activation of the immune system by gefitinib, which in some patients, can cause immune-related adverse events.


Asunto(s)
Medios de Cultivo/efectos adversos , Gefitinib/efectos adversos , Hepatocitos , Inflamasomas/inmunología , Activación de Macrófagos/efectos de los fármacos , Inhibidores de Proteínas Quinasas/efectos adversos , Células THP-1/inmunología , Alarminas/metabolismo , Caspasa 1/metabolismo , Línea Celular , Gefitinib/metabolismo , Proteína HMGB1/metabolismo , Humanos , Interleucina-1beta/metabolismo , Inhibidores de Proteínas Quinasas/metabolismo , Quinonas/efectos adversos , Quinonas/metabolismo , Células THP-1/metabolismo
19.
Chem Biol Interact ; 331: 109278, 2020 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-33038329

RESUMEN

Only in the last decade the long-term consequences of sepsis started to be studied and even less attention has been given to the treatment of psychological symptoms of sepsis survivors. It is estimated that 60% of sepsis survivors have psychological disturbances, including depression, anxiety, and cognitive impairment. Although the causative factors remain largely poorly understood, blood-brain barrier (BBB) disturbances, neuroinflammation, and oxidative stress have been investigated. Therefore, we sought to explore if the immunomodulatory and antioxidant selenocompound 3-[(4-chlorophenyl)selanyl]-1-methyl-1H-indole (CMI) would be able to ameliorate long-term behavioral and biochemical alterations in sepsis survivors male Swiss mice. CMI treatment (1 mg/kg, given orally for seven consecutive days) attenuated depression- and anxiogenic-like behaviors and cognitive impairment present one month after the induction of sepsis (lipopolysaccharide, 5 mg/kg intraperitoneally). Meantime, CMI treatment modulated the number of neutrophils and levels of reactive species in neutrophils, lymphocytes, and monocytes. In addition, peripheral markers of liver and kidneys dysfunction (AST, ALT, urea, and creatinine) were reduced after CMI treatment in post-septic mice. Notably, CMI treatment to non-septic mice did not alter AST, ALT, urea, and creatinine levels, indicating the absence of acute hepatotoxicity and nephrotoxicity following CMI treatment. Noteworthy, CMI ameliorated BBB dysfunction induced by sepsis, modulating the expression of inflammation-associated genes (NFκB, IL-1ß, TNF-α, IDO, COX-2, iNOS, and BDNF) and markers of oxidative stress (reactive species, nitric oxide, and lipid peroxidation levels) in the prefrontal cortices and hippocampi of mice. In conclusion, we unraveled crucial molecular pathways that are impaired in post-septic mice and we present CMI as a promising therapeutic candidate aimed to manage the long-lasting behavioral alterations of sepsis survivors to improve their quality of life.


Asunto(s)
Conducta Animal , Indoles/química , Estrés Oxidativo , Sepsis/patología , Animales , Ansiedad/tratamiento farmacológico , Ansiedad/etiología , Conducta Animal/efectos de los fármacos , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Disfunción Cognitiva/tratamiento farmacológico , Disfunción Cognitiva/etiología , Ciclooxigenasa 2/genética , Ciclooxigenasa 2/metabolismo , Depresión/tratamiento farmacológico , Depresión/etiología , Depresión/patología , Modelos Animales de Enfermedad , Indoles/farmacología , Indoles/uso terapéutico , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Riñón/efectos de los fármacos , Riñón/metabolismo , Lipopolisacáridos/toxicidad , Hígado/efectos de los fármacos , Hígado/metabolismo , Locomoción/efectos de los fármacos , Masculino , Ratones , Neutrófilos/citología , Neutrófilos/metabolismo , Estrés Oxidativo/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Sepsis/complicaciones
20.
Niger J Clin Pract ; 23(10): 1345-1355, 2020 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-33047690

RESUMEN

Background: Several studies have demonstrated an association between obesity, periodontitis, and exercise. Aims: This study aimed to investigate the effects of regular exercise on obese women with periodontal disease, using serum, saliva, and gingival crevicular fluid (GCF) samples. A before-after study design was adopted to evaluate the effects of 12 weeks of regular exercise on obese women grouped according to periodontal status, without a control group (no exercise). The study sample comprised of 15 patients without periodontitis (NP group) and 10 patients with chronic periodontitis (CP group), from whom periodontal parameters were measured and serum, saliva, and GCF samples were collected. Body mass index (BMI), anthropometric measurements, somatotype-motoric tests, and maximal oxygen consumption (VO2max) were recorded at baseline and after exercise. Subjects and Methods: Med Calc was used for statistical analysis. Results: After exercise, a significant decrease in BMI and a significant increase in VO2max were observed in both groups. A significant decrease in probing depth and clinical attachment loss, serum leptin, GCF tumor necrosis factor-α(TNF-α) and leptin, and a significant increase in GCF resistin were observed in the CP group. A significant decrease in serum TNF-α and leptin levels and a significant increase in serum resistin and GCF TNF-α, leptin, resistin, and adiponectin levels were observed in the NP group. Significant correlations between bleeding on probing and levels of interleukin-1ß and leptin in GCF were observed in the CP group. Conclusions: This study showed that regular exercise exerts different impacts with respect to clinical and biochemical aspects of periodontal and systemic conditions in obese women.


Asunto(s)
Adipoquinas/metabolismo , Periodontitis Crónica/complicaciones , Periodontitis Crónica/metabolismo , Ejercicio Físico/fisiología , Líquido del Surco Gingival/química , Obesidad/complicaciones , Saliva/química , Adipoquinas/sangre , Adulto , Índice de Masa Corporal , Estudios de Casos y Controles , Periodontitis Crónica/sangre , Femenino , Humanos , Interleucina-1beta/sangre , Interleucina-1beta/metabolismo , Persona de Mediana Edad , Obesidad/sangre , Obesidad/metabolismo , Bolsa Periodontal/metabolismo , Resistina/sangre , Resistina/metabolismo , Factor de Necrosis Tumoral alfa/sangre , Factor de Necrosis Tumoral alfa/metabolismo
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