RESUMEN
Intravascular neutrophils and platelets collaborate in maintaining host integrity, but their interaction can also trigger thrombotic complications. We report here that cooperation between neutrophil and platelet lineages extends to the earliest stages of platelet formation by megakaryocytes in the bone marrow. Using intravital microscopy, we show that neutrophils "plucked" intravascular megakaryocyte extensions, termed proplatelets, to control platelet production. Following CXCR4-CXCL12-dependent migration towards perisinusoidal megakaryocytes, plucking neutrophils actively pulled on proplatelets and triggered myosin light chain and extracellular-signal-regulated kinase activation through reactive oxygen species. By these mechanisms, neutrophils accelerate proplatelet growth and facilitate continuous release of platelets in steady state. Following myocardial infarction, plucking neutrophils drove excessive release of young, reticulated platelets and boosted the risk of recurrent ischemia. Ablation of neutrophil plucking normalized thrombopoiesis and reduced recurrent thrombosis after myocardial infarction and thrombus burden in venous thrombosis. We establish neutrophil plucking as a target to reduce thromboischemic events.
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Enfermedades Cardiovasculares , Infarto del Miocardio , Trombosis , Humanos , Megacariocitos , Trombopoyesis , Neutrófilos , Plaquetas/fisiologíaRESUMEN
Platelet homeostasis is essential for vascular integrity and immune defence1,2. Although the process of platelet formation by fragmenting megakaryocytes (MKs; thrombopoiesis) has been extensively studied, the cellular and molecular mechanisms required to constantly replenish the pool of MKs by their progenitor cells (megakaryopoiesis) remains unclear3,4. Here we use intravital imaging to track the cellular dynamics of megakaryopoiesis over days. We identify plasmacytoid dendritic cells (pDCs) as homeostatic sensors that monitor the bone marrow for apoptotic MKs and deliver IFNα to the MK niche triggering local on-demand proliferation and maturation of MK progenitors. This pDC-dependent feedback loop is crucial for MK and platelet homeostasis at steady state and under stress. pDCs are best known for their ability to function as vigilant detectors of viral infection5. We show that virus-induced activation of pDCs interferes with their function as homeostatic sensors of megakaryopoiesis. Consequently, activation of pDCs by SARS-CoV-2 leads to excessive megakaryopoiesis. Together, we identify a pDC-dependent homeostatic circuit that involves innate immune sensing and demand-adapted release of inflammatory mediators to maintain homeostasis of the megakaryocytic lineage.
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Células Dendríticas , Homeostasis , Megacariocitos , Trombopoyesis , Animales , Femenino , Humanos , Masculino , Ratones , Apoptosis , Plaquetas/citología , Médula Ósea , Linaje de la Célula , Proliferación Celular , Células Dendríticas/inmunología , Células Dendríticas/citología , Retroalimentación Fisiológica , Inmunidad Innata , Microscopía Intravital , Megacariocitos/citología , Megacariocitos/inmunología , Ratones Endogámicos C57BL , SARS-CoV-2/inmunología , COVID-19/inmunología , COVID-19/fisiopatología , COVID-19/virologíaRESUMEN
AIM: Recent imaging studies have found significant abnormalities in the brain's functional or structural connectivity among patients with high myopia (HM), indicating a heightened risk of cognitive impairment and other behavioral changes. However, there is a lack of research on the topological characteristics and connectivity changes of the functional networks in HM patients. In this study, we employed graph theoretical analysis to investigate the topological structure and regional connectivity of the brain function network in HM patients. METHODS: We conducted rs-fMRI scans on 82 individuals with HM and 59 healthy controls (HC), ensuring that the two groups were matched for age and education level. Through graph theoretical analysis, we studied the topological structure of whole-brain functional networks among participants, exploring the topological properties and differences between the two groups. RESULTS: In the range of 0.05 to 0.50 of sparsity, both groups demonstrated a small-world architecture of the brain network. Compared to the control group, HM patients showed significantly lower values of normalized clustering coefficient (γ) (P = 0.0101) and small-worldness (σ) (P = 0.0168). Additionally, the HM group showed lower nodal centrality in the right Amygdala (P < 0.001, Bonferroni-corrected). Notably, there is an increase in functional connectivity (FC) between the saliency network (SN) and Sensorimotor Network (SMN) in the HM group, while the strength of FC between the basal ganglia is relatively weaker (P < 0.01). CONCLUSION: HM Patients exhibit reduced small-world characteristics in their brain networks, with significant drops in γ and σ values indicating weakened global interregional information transfer ability. Not only that, the topological properties of the amygdala nodes in HM patients significantly decline, indicating dysfunction within the brain network. In addition, there are abnormalities in the FC between the SN, SMN, and basal ganglia networks in HM patients, which is related to attention regulation, motor impairment, emotions, and cognitive performance. These findings may provide a new mechanism for central pathology in HM patients.
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Encéfalo , Imagen por Resonancia Magnética , Red Nerviosa , Humanos , Masculino , Femenino , Adulto , Imagen por Resonancia Magnética/métodos , Encéfalo/fisiopatología , Encéfalo/diagnóstico por imagen , Red Nerviosa/fisiopatología , Red Nerviosa/diagnóstico por imagen , Adulto Joven , Mapeo Encefálico/métodos , Miopía Degenerativa/fisiopatología , Descanso/fisiologíaRESUMEN
BACKGROUND: To investigate the changes and clinical significance of vascular endothelial injury markers in type 2 diabetes mellitus (T2DM) complicated with pulmonary embolism (PE). METHODS: This prospective study enrolled patients with T2DM hospitalized in one hospital from January 2021 to June 2022. Soluble thrombomodulin (sTM) (ELISA), von Willebrand factor (vWF) (ELISA), and circulating endothelial cells (CECs) (flow cytometry) were measured. PE was diagnosed by computed tomography pulmonary angiography (CTPA). RESULTS: Thirty participants were enrolled in each group. The plasma levels of sTM (151.22 ± 120.57 vs. 532.93 ± 243.82 vs. 1016.51 ± 218.00 pg/mL, P < 0.001) and vWF (9.63 ± 2.73 vs. 11.50 ± 2.17 vs. 18.02 ± 3.40 ng/mL, P < 0.001) and the percentage of CECs (0.17 ± 0.46 vs. 0.30 ± 0.08 vs. 0.56 ± 0.18%, P < 0.001) gradually increased from the control group to the T2DM group to the T2DM + PE group. sTM (OR = 1.002, 95%CI: 1.002-1.025, P = 0.022) and vWF (OR = 1.168, 95%CI: 1.168-2.916, P = 0.009) were associated with T2DM + PE. sTM > 676.68 pg/mL for the diagnosis of T2DM + PE achieved an AUC of 0.973, while vWF > 13.75 ng/mL achieved an AUC of 0.954. The combination of sTM and vWF above their cutoff points achieved an AUC of 0.993, with 100% sensitivity and 96.7% specificity. CONCLUSIONS: Patients with T2DM show endothelial injury and dysfunction, which were worse in patients with T2DM and PE. High sTM and vWF levels have certain clinical predictive values for screening T2DM accompanied by PE.
Asunto(s)
Diabetes Mellitus Tipo 2 , Embolia Pulmonar , Humanos , Células Endoteliales , Diabetes Mellitus Tipo 2/complicaciones , Factor de von Willebrand/análisis , Estudios Prospectivos , Endotelio Vascular/química , BiomarcadoresRESUMEN
CONTEXT: Panax ginseng C. A. Meyer (Araliaceae) is a famous Asian medicine. Ginsenoside Rc is a component isolated from Panax ginseng. OBJECTIVE: This study evaluates the effect of ginsenoside Rc on myocardial ischaemic injury. MATERIALS AND METHODS: Male Swiss mice were subcutaneously injected with 50 mg/kg isoproterenol once a day for three days. Ginsenoside Rc (10, 20, or 40 mg/kg) was intragastrically administered 1 h after isoproterenol injection. The mice in the control group were subcutaneously injected with normal saline and intragastrically given 0.5% CMC-Na. CK-MB and troponin T were assayed. Histopathological examination of myocardium was conducted. The expression of Nrf2, GCLC, GCLM and HO-1 in heart tissues was evaluated by Western blot. RESULTS: In myocardial ischaemic mice, ginsenoside Rc reduced the levels of CK-MB (197.1 ± 15.7, 189.9 ± 19.0, 184.0 ± 14.4 vs. 221.6 ± 27.9) and troponin T (10.3 ± 1.7, 9.5 ± 1.3, 8.7 ± 1.7 vs. 13.4 ± 2.4). Ginsenoside Rc attenuated the necrosis and inflammatory cells infiltration in myocardium. Furthermore, ginsenoside Rc not only decreased the contents of MDA, TNF-α but also increased GSH level in the heart tissues. The expression of Nrf2, GCLC, GCLM and HO-1 was significantly increased in the animals treated with ginsenoside Rc. ML385, an Nrf2 inhibitor, blocked partially the ginsenoside Rc-mediated cardioprotective effect. Ginsenoside Rc attenuated myocardial ischaemic injury in mice, which may be, in part, through its antioxidative and anti-inflammatory effects. CONCLUSIONS: This study indicated that ginsenoside Rc might be a novel candidate for treatment of myocardial ischaemia.
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Antioxidantes , Panax , Animales , Antiinflamatorios/farmacología , Antioxidantes/farmacología , Ginsenósidos , Isoproterenol , Masculino , Ratones , Factor 2 Relacionado con NF-E2/metabolismo , Panax/metabolismo , Troponina TRESUMEN
Platelet plays an important role in the progression of atherosclerosis. Recently it has been reported that myocardial infarction (MI) triggers megakaryopoiesis and thrombopoiesis in the bone marrow and leads to increased circulating platelets, which might contribute to the aggravation of atherosclerosis. However, the underlying mechanisms remain unclear. Here, we analyzed post-MI bone marrow tissue and found that MI induced an upregulation of bone marrow NOD-like Receptor Protein 3 (NLRP3) and subsequent secretion of IL-1ß, an essential stimulator of megakaryopoiesis. Targeting NLRP3 using a specific inhibitor MCC950 reduced bone marrow IL-1ß expression. Using bone marrow whole-mount immunofluorescence staining combined with flow cytometry, we demonstrated that MCC950 reduced megakaryocyte cellularity and maturity, and effectively attenuated the excessive platelet production after MI. Importantly, mice subjected to MI treated with MCC950 showed a higher survival rate compared with the only MI group. Taken together, this study shows that bone marrow NLRP3-IL-1ß signal regulates megakaryocyte development and platelet production after myocardial infarction. It provides a new hint that pharmacological inhibition of NLRP3 might become a potential therapeutic approach for controlling excessive thrombopoiesis after MI.
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Médula Ósea/metabolismo , Inflamasomas/metabolismo , Interleucina-1beta/metabolismo , Megacariocitos/metabolismo , Infarto del Miocardio/fisiopatología , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Trombopoyesis/fisiología , Animales , Plaquetas/efectos de los fármacos , Plaquetas/metabolismo , Citometría de Flujo , Furanos/farmacología , Indenos/farmacología , Inflamasomas/efectos de los fármacos , Masculino , Ratones Endogámicos C57BL , Proteína con Dominio Pirina 3 de la Familia NLR/antagonistas & inhibidores , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Sulfonamidas/farmacología , Análisis de Supervivencia , Trombopoyesis/efectos de los fármacosRESUMEN
CONTEXT: Panax ginseng C.A. Meyer (Araliaceae) has cardioprotective effects. Ginsenosides are responsible for most of the pharmacological activities of ginseng. OBJECTIVE: This study investigates the effect of ginsenoside Rg2 on myocardial fibrosis in myocardial ischaemia rats. MATERIALS AND METHODS: Male Wistar rats were divided into control, isoproterenol, ginsenoside Rg2 (5, 20 mg/kg) groups (n = 8). The rats were subcutaneously injected with isoproterenol (5 mg/kg) or normal saline (control group) once daily for 7 days. The animals were intragastrically treated with ginsenoside Rg2 or 0.5% CMC-Na (control and isoproterenol groups) daily for 28 days. At day 28, cardiac function, myocardial fibrosis, and TGF-ß1/Smad signalling pathway were evaluated. RESULTS: Compared with myocardial ischaemic rats, ginsenoside Rg2 at doses of 5, 20 mg/kg abated partially the augment of LVEDP (8.9 ± 1.3 vs. 7.5 ± 0.7, 7.2 ± 1.0 mmHg) and the decreases of the LVSP (96.75 ± 13.2 vs. 118.3 ± 19.4, 124.3 ± 21.3 mmHg), the + dp/dt (2142.8 ± 309.3 vs. 2598.6 ± 404.0, 2661.5 ± 445.2 mmHg/s), and the -dp/dt (1996.3 ± 306.3 vs. 2476.6 ± 289.7, 2509.6 ± 353.1 mmHg/s). Ginsenoside Rg2 (9.2 ± 0.9%, 8.5 ± 0.8%) alleviated myocardial fibrosis when compared with the isoproterenol group (10.1 ± 1.0%), which was accompanied by suppressed TGF-ß1/Smad signalling in heart tissues. CONCLUSIONS: Ginsenosides from ginseng possess the property of alleviating myocardial fibrosis, improving cardiac function after myocardial ischaemia. Ginsenosides may be promising agents for improving the outcomes of patients with myocardial ischaemia.
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Cardiotónicos/farmacología , Ginsenósidos/farmacología , Isquemia Miocárdica/tratamiento farmacológico , Panax/química , Animales , Cardiotónicos/administración & dosificación , Cardiotónicos/aislamiento & purificación , Relación Dosis-Respuesta a Droga , Fibrosis/tratamiento farmacológico , Fibrosis/patología , Ginsenósidos/administración & dosificación , Ginsenósidos/aislamiento & purificación , Isoproterenol/farmacología , Masculino , Isquemia Miocárdica/fisiopatología , Ratas , Ratas Wistar , Transducción de Señal/efectos de los fármacos , Proteínas Smad/metabolismo , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
Colorectal carcinoma (CRC) recurrence is often accompanied by metastasis. Most metastasis undergo through epithelial-mesenchymal transition (EMT). Studies showed that retinol X receptor alpha (RXRα) and 20(S)-Protopanaxadiol (PPD) have anti-tumour effects. However, the anti-metastasis effect of 20(S)-PPD and the effect of RXRα on EMT-induced metastasis are few studies on. Therefore, the role of RXRα and 20(S)-PPD in CRC cell metastasis remains to be fully elucidated. RXRα with clinicopathological characteristics and EMT-related expression in clinical samples were examined. Then, RXRα and EMT level in SW480 and SW620 cells, overexpressed and silenced RXRα in SW620 cells and SW480 cells, respectively, were evaluated. Finally, 20(S)-PPD effect on SW620 and SW480 cells was evaluated. The results showed that a lower RXRα expression in cancer tissues, and a moderate negative correlation between RXRα and N stage, and tended to higher level of EMT. SW480 and SW620 cells had the highest and lowest RXRα expression among four CRC cell lines. SW480 had lower EMT level than SW620. Furthermore, 20(S)-PPD increased RXRα and inhibited EMT level in SW620 cell. Finally, 20(S)-PPD cannot restore SW480 cells EMT level to normal when RXRα silencing. These findings suggest that 20(S)-PPD may inhibit EMT process in CRC cells by regulating RXRα expression.
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Neoplasias Colorrectales/metabolismo , Transición Epitelial-Mesenquimal/efectos de los fármacos , Receptor alfa X Retinoide/metabolismo , Sapogeninas/farmacología , Adulto , Anciano , Animales , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Modelos Animales de Enfermedad , Transición Epitelial-Mesenquimal/genética , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Receptor alfa X Retinoide/genéticaRESUMEN
Atherosclerosis is still the major cause of morbidity and mortality all over the world. Recently, it has been reported increased levels of tissue iron increase the risk of atherosclerosis. However, the detailed mechanism of iron-induced atherosclerosis progression is barely known. Here, we used apoE-deficient mice models to investigate the effects of low iron diet (<0 mg iron carbonyl/kg), high iron diet (25,000 mg iron carbonyl/kg) on atherosclerosis in vivo. As exhibited, we observed that CD68 was significant enriched by high iron diet in apoE-deficient mice. In addition, transforming growth factor ß, tumor necrosis factor α, interleukin 6 (IL-6), IL-23, IL-10, and IL-1ß levels were also greatly induced by high iron diet. Then, we found that the iron load promoted the inflammation response in macrophages. Moreover, macrophage polarization is a process by which macrophage can express various functional programs in activating macrophages. Here, we observed that iron-load macrophages were polarized toward a proinflammatory macrophage phenotype. The polarization of M1 macrophage was promoted by ferric ammonium citrate (FAC) in bone marrow derived macrophages (BMDMs). Furthermore, ECAR and cellular OCR in BMDM with or without FAC was examined. As shown, BMDM indicated with 50 µM FAC showed a significant increase in basic state and maximal ECAR in contrast to the control group. However, there was no significant difference in OCR. This indicated that the glycolysis was involved in the polarization of M1 macrophage triggered by iron-load. In conclusion, we indicated that the iron load exacerbates the progression of atherosclerosis via inducing inflammation and enhancing glycolysis in macrophages.
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Aterosclerosis/patología , Glucólisis , Inflamación/patología , Hierro/efectos adversos , Macrófagos/metabolismo , Índice de Severidad de la Enfermedad , Animales , Aterosclerosis/complicaciones , Polaridad Celular , Femenino , Compuestos Férricos/efectos adversos , Inflamación/complicaciones , Macrófagos/patología , Masculino , Ratones Endogámicos C57BL , FenotipoRESUMEN
Long noncoding RNA UCA1 has exerted a significant effect in cardiovascular disease. The biological role of UCA1 in atherosclerosis is unclear. Our study was to identify the potential mechanisms in the progression of atherosclerosis. Here, we observed that ox-LDL increased UCA1 expression greatly in THP-1 cells. Knockdown of UCA1 greatly inhibited CD36 expression, a crucial biomarker in atherosclerosis. Meanwhile, 20 µg/ml ox-LDL induced foam cell formation, which can be reversed by downregulation of UCA1. In addition, TC and TG levels induced by ox-LDL was rescued by UCA1 small interfering RNA. Accumulating studies have indicated that oxidative stress contributes to atherosclerosis progression. Here, we also found that reactive oxygen species, MDA, and THP-1 cell apoptosis were restrained by decreased of UCA1 with an increase of the superoxide dismutase activity. Moreover, miR-206 was predicted as a target of UCA1 and knockdown of UCA1 was able to repress miR-206 expression. Furthermore, overexpression of miR-206 inhibited oxidative stress process and it was reversed by UCA1 upregulation in vitro. In conclusion, we indicated that UCA1 sponged miR-206 to exacerbate atherosclerosis events induced by ox-LDL in THP-1 cells.
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Aterosclerosis/genética , Lipoproteínas LDL/genética , MicroARNs/genética , ARN Largo no Codificante/genética , Apoptosis/genética , Aterosclerosis/patología , Antígenos CD36/genética , Línea Celular , Células Espumosas/metabolismo , Células Espumosas/patología , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Lipoproteínas LDL/farmacología , Macrófagos/efectos de los fármacos , Monocitos/efectos de los fármacos , Estrés Oxidativo/genética , ARN Largo no Codificante/antagonistas & inhibidores , ARN Interferente Pequeño/genéticaRESUMEN
After myocardial infarction (MI), increased platelet number and size are inversely related to the outcomes of patients. Our previous study confirmed an excessive thrombopoiesis taking place in the bone marrow after MI. However, the mechanisms remain unknown. It has been reported that the sympathetic stimulation by noise or exercise can promote megakaryocyte (MK) producing platelets which is mediated by α2-adrenoceptor. Here, using whole-mount staining combined with western blotting and ELISA assay, we vividly showed an activation of the bone marrow sympathetic nervous system (SNS) after MI. Interestingly, we observed a direct spatial attachment between MKs and the sympathetic nerves. The administration of α-adrenoceptor antagonist, phentolamine or prazosin, could effectively attenuate post-MI MK cellularity and maturity, and alter the distribution of MK away from the bone marrow vessels. Surprisingly, the antagonists did not suppress the final stage of platelet formation. MI mice treated with phentolamine or prazosin showed elevating circulating platelets comparable as those treated with PBS as the control. Together, this study demonstrated that the activation of bone marrow SNS after MI regulates megakaryocyte expansion but not platelet production. Therefore, targeting sympathetic activation might become a novel approach for controlling post-MI bone marrow MK development, but other approaches are still needed to effectively reduce the platelet numbers.
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Médula Ósea/inervación , Megacariocitos/patología , Infarto del Miocardio/fisiopatología , Sistema Nervioso Simpático/fisiopatología , Animales , Plaquetas/patología , Médula Ósea/fisiopatología , Masculino , Ratones Endogámicos C57BL , Recuento de PlaquetasRESUMEN
Platelet, apart from its classic role of homeostasis, serves also as a crucial immune cell component that contributes to the aggravation of atherosclerosis. It has been reported that myocardial infarction (MI) triggers leukocytosis in the bone marrow and spleen, which accelerates post-MI atherosclerosis. However, it remains unclear whether thrombopoiesis is also enhanced after MI. Here, using flow cytometry and bone marrow whole-mount immunofluorescence staining combined with three-dimensional (3D) reconstruction, we for the first time demonstrated an enhanced thrombopoiesis and megakaryopoiesis in a mouse model of coronary artery ligation as a mimic of MI. We showed that MI leads to increasing number of peripheral platelets, as well as elevating number and larger size of bone marrow MKs. We also observed more proplatelets and fragmented MKs, and a closer spatial distribution of MK populations to the bone marrow vascular niche after MI. This study provides direct evidence that MI induces bone marrow megakaryocyte proliferation, maturation and platelet production. It opens a new scope that targeting platelet production might become a novel therapeutic approach for attenuating post-MI atherosclerosis.
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Plaquetas/fisiología , Megacariocitos/citología , Infarto del Miocardio/fisiopatología , Trombopoyesis , Animales , Proliferación Celular , Masculino , Células Progenitoras de Megacariocitos/fisiología , Megacariocitos/fisiología , Ratones Endogámicos C57BL , Infarto del Miocardio/patologíaRESUMEN
BACKGROUND: Cultured epithelial cells transplantation is a known surgical technique for vitiligo. OBJECTIVE: To evaluate the factors influencing efficacy and safety of cultured epithelial cells transplantation in 9-month follow-up. METHODS: Demographic, clinical, and repigmentation outcomes were reviewed for patients with facial segmental vitiligo who had undergone cultured epithelial cells transplantation from November 2013 to July 2015 at the clinic of the Department of Dermatology, Huashan Hospital, China. RESULTS: Twenty-eight patients who had undergone cultured epithelial cells transplantation were included. A satisfactory result (>50% repigmentation) was achieved in 79% patients with facial segmental vitiligo in 9 months. The treatment effect was significantly different in 6th month (Pâ=â0.032), 9th month (Pâ=â0.006) compared with 3rd month. Disease stability did significantly affect repigmentation outcome in 9th month (Zâ=â2.113, Pâ=â0.035). No significant difference was observed between single segmental type versus mixed type (Zâ=â1.081, Pâ=â0.280). Adverse effects were nearly absent. CONCLUSION: Cultured epithelial cells transplantation is a relatively safe and effective therapy for facial segmental stable vitiligo patients.
Asunto(s)
Trasplante de Células/métodos , Células Cultivadas/trasplante , Células Epiteliales/trasplante , Cara/fisiopatología , Vitíligo , Humanos , Vitíligo/fisiopatología , Vitíligo/terapiaRESUMEN
Objective: To explore the active substances and targets of Danbie Capsules in Endometriosis therapy. Methods: This study was conducted through TCMSP and published literature screened and obtained 183 active substances of Danbie Capsules, combined and intersected with Endometriosis target genes collected and screened in the GEO database, obtained 24 target genes for Endometriosis treatment, and mapped the target network map of Danbie Capsules active substances against Endometriosis. The network was analyzed with the aid of Cytoscape version 3.9.1. With the aid of the platform of the STRING data analysis, PPI network analysis was conducted on 24 anti-Endometriosis targets of the Danbie Capsules. Results: The research results obtained three critical active substances, namely, Quercetin, ß-sitosterol, and Luteolin. Seven critical targets were identified, and two representative genes (TP53 and AKT1) have been verified in Macromolecular docking and immunohistochemical verification. Conclusion: The active substances of Danbie Capsules in the treatment of Endometriosis are Quercetin, ß-sitosterol and Luteolin, and the main targets are TP53 and AKT1.
RESUMEN
AIM: Animals exhibit physiological changes designed to eliminate the perceived danger, provoking similar symptoms of fever. However, a high-grade fever indicates poor clinical outcomes. Caspase11 (Casp11) is involved in many inflammatory diseases. Whether Casp11 leads to fever remains unclear. In this study, we investigate the role of the preoptic area of the hypothalamus (PO/AH) microglia Casp11 in fever. METHODS: We perform experiments using a rat model of LPS-induced fever. We measure body temperature and explore the functions of peripheral macrophages and PO/AH microglia in fever signaling by ELISA, immunohistochemistry, immunofluorescence, flow cytometry, macrophage depletion, protein blotting, and RNA-seq. Then, the effects of macrophages on microglia in a hyperthermic environment are observed in vitro. Finally, adeno-associated viruses are used to knockdown or overexpress microglia Casp11 in PO/AH to determine the role of Casp11 in fever. RESULTS: We find peripheral macrophages and PO/AH microglia play important roles in the process of fever, which is proved by macrophage and microglia depletion. By RNA-seq analysis, we find Casp11 expression in PO/AH is significantly increased during fever. Co-culture and conditioned-culture simulate the induction of microglia Casp11 activation by macrophages in a non-contact manner. Microglia Casp11 knockdown decreases body temperature, pyrogenic factors, and inflammasome, and vice versa. CONCLUSION: We report that Casp11 drives fever. Mechanistically, peripheral macrophages transmit immune signals via cytokines to microglia in PO/AH, which activate the Casp11 non-canonical inflammasome. Our findings identify a novel player, the microglia Casp11, in the control of fever, providing an explanation for the transmission and amplification of fever immune signaling.
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Fiebre , Inflamasomas , Microglía , Animales , Masculino , Ratas , Caspasas/metabolismo , Caspasas/genética , Fiebre/metabolismo , Inflamasomas/metabolismo , Macrófagos/metabolismo , Microglía/metabolismo , Área Preóptica/metabolismo , Ratas WistarRESUMEN
BACKGROUND: It has been reported that the induction of heme oxygenase-1 (HO-1) mediated by ß1-adrenergic receptor inhibits high mobility group box 1 protein (HMGB1) release and increases the survival rate in cecal ligation and puncture-induced septic mice. The present study aimed to investigate whether dobutamine, a selective ß1-adrenergic receptor agonist, could inhibit HMGB1 release via ß1-adrenergic receptor-mediated HO-1 induction and attenuate myocardial ischemia/reperfusion (I/R) injury in rats. MATERIALS AND METHODS: Anesthetized male rats were pretreated with dobutamine (5 or 10 µg. Kg-1. min-1, intravenous) before ischemia in the absence and/or presence of LY294002 (0.3 mg/Kg), a phosphatidylinositol 3-kinase (PI3K)< inhibitor; SB203580 (1 mg/Kg), a p38 mitogen-activated-protein kinase (P38 mitogen-activated-protein kinase [p38 MAPK]) inhibitor, and zinc protoporphyrin IX ([ZnPPIX], 10 mg/Kg), a HO-1 inhibitor, respectively, and then subjected to ischemia for 30 min followed by reperfusion for 4 h. The myocardial I/R injury and oxidative stress were assessed. Likewise, the expressions of HO-1 protein, nuclear factor kappa B (NF-κB) p65, and HMGB1 were measured by Western blot analysis. RESULTS: Dobutamine significantly and dose-dependently attenuated myocardial I/R injury, reduced oxidative stress, and caused the induction of HO-1, the reduction of NF-κB activation and HMGB1 over expression. However, all the effects caused by dobutamine were significantly reversed by the presence of LY294002, SB203580, and ZnPPIX, respectively. CONCLUSIONS: The present study demonstrated that dobutamine mediated the induction of HO-1 by selectively stimulating ß1-adrenergic receptor via PI3K and p38 MAPK, which inhibited HMGB1 release and attenuated rat myocardial I/R injury in vivo.
Asunto(s)
Agonistas de Receptores Adrenérgicos beta 1/uso terapéutico , Dobutamina/uso terapéutico , Proteína HMGB1/antagonistas & inhibidores , Hemo-Oxigenasa 1/metabolismo , Daño por Reperfusión Miocárdica/prevención & control , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Agonistas de Receptores Adrenérgicos beta 1/farmacología , Animales , Cromonas/farmacología , Modelos Animales de Enfermedad , Dobutamina/farmacología , Inhibidores Enzimáticos/farmacología , Proteína HMGB1/efectos de los fármacos , Proteína HMGB1/metabolismo , Corazón/efectos de los fármacos , Corazón/fisiopatología , Hemo-Oxigenasa 1/efectos de los fármacos , Imidazoles/farmacología , Masculino , Morfolinas/farmacología , Daño por Reperfusión Miocárdica/metabolismo , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Fosfatidilinositol 3-Quinasas/efectos de los fármacos , Protoporfirinas/farmacología , Piridinas/farmacología , Ratas , Ratas Sprague-Dawley , Proteínas Quinasas p38 Activadas por Mitógenos/efectos de los fármacosRESUMEN
Myocardial ischemia-reperfusion (MI/R) injury occurs when coronary blood supply is impaired and then re-established, leading to additional injury to the myocardial tissue, including mitochondria oxidative stress and apoptosis. Ginsenoside Rc is one of the main protopanaxadiol-type saponins, and there has been relatively little research on it. Despite research confirming that ginsenoside Rc regulates mitochondrial functions, its potential benefits against MI/R injury have not been explored. In this study, we examined the protective effects of ginsenoside Rc in MI/R injury, along with its underlying mechanisms, using an in vitro H9c2 cell model of oxygen-glucose deprivation/reoxygenation (OGD/R) and an in vivo rat model of MI/R injury. Prior to this, the H9c2 cells or rats were exposed to ginsenoside Rc with or without SIRT1 small interfering RNA (siRNA) or the selective SIRT1 inhibitor EX527. The results showed that after MI/R (or OGD/R) injury, ginsenoside Rc had a cardioprotective effect; improved cardiac function (or cell survival); reduced myocardial infarct size; decreased levels of creatine kinase-MB, cardiac troponin I, and lactate dehydrogenase (LDH) in the serum (or LDH release into culture medium); reduced cardiomyocyte apoptosis; and attenuated mitochondrial oxidative damage. Ginsenoside Rc pre-treatment also upregulated the anti-apoptotic protein Bcl-2 while downregulating the pro-apoptotic proteins Bax and cleaved caspase-3. Furthermore, the cardioprotective effect of ginsenoside Rc was concomitant with upregulated SIRT1 expression and downregulated Ac-FOXO1 expression. SIRT1 siRNA or SIRT1 inhibitor EX527 abolished the cardioprotective effects of ginsenoside Rc by inhibiting the SIRT1 signaling pathway. In conclusion, our findings demonstrate that ginsenoside Rc ameliorated MI/R injury by reducing mitochondrial oxidative stress and apoptosis, at least in part, by activating SIRT1.
Asunto(s)
Daño por Reperfusión Miocárdica , Ratas , Animales , Daño por Reperfusión Miocárdica/tratamiento farmacológico , Daño por Reperfusión Miocárdica/genética , Daño por Reperfusión Miocárdica/metabolismo , Sirtuina 1/genética , Sirtuina 1/metabolismo , Apoptosis , Estrés Oxidativo , ARN Interferente Pequeño/metabolismo , Miocitos CardíacosRESUMEN
Carbon tetrachloride (CCl4)-induced lipid peroxidation associated with hepatic oxidative stress and cell death is an important mechanism of acute liver injury (ALI). Ginsenoside Rd is considered an active ingredient of ginseng. Evidence suggests that ginsenoside Rd may improve ischaemic stroke, nerve damage, cancer and other diseases involving apoptosis, inflammation, oxidative stress, mitochondrial injury and autophagy. However, the effects of ginsenoside Rd on CCl4-induced ALI and its underlying mechanisms are still unclear. In this study, 0.25% CCl4 was injected intraperitoneally in mice to establish a CCl4-induced ALI model. In the Rd treatment group, Rd (10, 20[Formula: see text]mg/kg) doses were injected intraperitoneally 1[Formula: see text]h before and 23[Formula: see text]h after CCl4 administration. Ferroptosis inducer imidazole ketone erastin (IKE) was injected intraperitoneally 4[Formula: see text]h before CCl4 administration to explore the mechanism. The blood and liver were collected 24[Formula: see text]h after CCl4 administration to investigate the effect and mechanism of ginsenoside Rd on CCl4-induced ALI. Our results showed that ginsenoside Rd inhibited CCl4-induced ALI in mice. Ginsenoside Rd also downregulated CCl4-induced serum and liver iron, 4-hydroxynonenal, and 8-hydroxy-2 deoxyguanosine levels. Furthermore, it upregulated glutathione and glutathione peroxidase 4 levels. In addition, ginsenoside Rd downregulated the expression of cGAS and STING. Subsequently, the ferroptosis inducer imidazole ketone erastin significantly reversed the hepatoprotective effect and influence of ginsenoside Rd with regard to the indicators mentioned above. Our study confirmed that ginsenoside Rd ameliorated CCl4-induced ALI in mice, which was related to the reduction of ferroptosis. Simultaneously, the ginsenoside Rd-mediated inhibition of the cGAS/STING pathway contributed to its antiferroptosis effect. In conclusion, our results suggested that ginsenoside Rd inhibited ferroptosis via the cGAS/STING pathway, thereby protecting mice from CCl4-induced ALI. These results suggested ginsenoside Rd may be used as a potential intervention treatment against CCl4-induced ALI.
Asunto(s)
Isquemia Encefálica , Enfermedad Hepática Inducida por Sustancias y Drogas , Ferroptosis , Accidente Cerebrovascular , Ratones , Animales , Isquemia Encefálica/metabolismo , Hígado/metabolismo , Estrés Oxidativo , Nucleotidiltransferasas/metabolismo , Nucleotidiltransferasas/farmacología , Tetracloruro de Carbono/efectos adversos , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Enfermedad Hepática Inducida por Sustancias y Drogas/etiología , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismoRESUMEN
[This corrects the article DOI: 10.3389/fmed.2022.851808.].
RESUMEN
Aim: The objective of this study was to examine changes in functional connectivity (FC) in the hippocampus among patients with high myopia (HM) compared to healthy controls (HCs) through the utilization of seed-based functional connectivity (FC) analysis. Methods: Resting-state functional magnetic resonance imaging (fMRI) was conducted on a sample of 82 patients diagnosed with high myopia (HM) and 59 HCs. The two groups were matched based on age, weight and other relevant variables. Using seed-based FC analysis to detect alterations in hippocampal FC patterns in HM patients and HCs. Furthermore, a correlation analysis was performed to examine the associations between the mean functional connectivity (FC) signals in various brain regions of patients with HM and their corresponding clinical manifestations. Results: The FC values in the left temporal pole-temporal gyrus (L-TPOsup), right hippocampus (R-HIP), left medial temporal gyrus (L-MTG) and left hippocampus in HM patients were significantly lower than those of healthy subjects. In the left temporal pole-superior temporal gyrus (L-TPOsup), right orbital part of middle frontal gyrus (RO-MFG), left fusiform gyrus (L-FG), left cerebellum superior (L-Cbe6), left middle temporal gyrus (L-MTG), right thalamus (R-THA), and right hippocampus, FC values were also significantly lower. Conclusion: Brain dysfunction was observed in various regions of the HM patients, suggesting the existence of neurobiological alterations that could lead to impairments in visual cognition, movement, emotional processing, and visual memory.