RESUMEN
BACKGROUND: While body mass index (BMI) defines obesity as a well-established risk factor for cardiovascular disease, the paradoxical theory of BMI suggests that obesity may indeed have a favorable impact on the prognosis of cardiovascular disease. Therefore, this study aims to assess the correlation between body shape index (ABSI), which is a novel measure of obesity, and coronary heart disease (CHD) among obese individuals in the United States. METHODS: The data from the National Health and Nutrition Examination Survey (NHANES) were evaluated by us for 5046 patients. We assessed the exposure variable ABSI, which includes waist circumference (WC), height, and BMI. The outcome variable was CHD. RESULTS: The cross-sectional study included a total of 5046 obese adults aged over 20 years, with an average age (standard deviation: SD) of 49.86 (16.24) years and a male proportion of 44.57%.The odds ratio (OR) values for CHD in Model 1, Model 2, 3 were found to be 2.45 (95%CI: 2.12, 2.83), 1.53 (95%CI:1.30, 1.81) and 1.31 (95%CI:1.09, 1.56) per SD increase in ABSI, respectively. In the fully adjusted model, we designated participants in the T1 group as the reference group. Our findings indicate a significant increase in the prevalence of CHD (OR:1.82, 95%CI: 1.07-3.10) only within the T3 group. Although there is an increased prevalence of CHD (OR:1.32, 95%CI: 0.77-2.29) in the T2 group, no statistically significant difference was observed. CONCLUSIONS: The increase in ABSI is strongly associated with the rise in CHD prevalence among obese individuals in the United States.
Asunto(s)
Índice de Masa Corporal , Enfermedad Coronaria , Encuestas Nutricionales , Obesidad , Circunferencia de la Cintura , Humanos , Masculino , Femenino , Estudios Transversales , Obesidad/epidemiología , Obesidad/complicaciones , Adulto , Persona de Mediana Edad , Enfermedad Coronaria/epidemiología , Enfermedad Coronaria/etiología , Estados Unidos/epidemiología , Factores de Riesgo , Adulto Joven , Prevalencia , Anciano , EstaturaRESUMEN
BRASH syndrome is a vicious cycle of hyperkalemia and bradycardia and is an under-recognized life-threatening clinical diagnosis. It is usually initiated by hypovolemia or hyperkalemia. We report here on the case of a 92-year-old man with hypertension and heart failure who presented to the emergency department with weakness following diarrhea. He was on amlodipine, benazepril, metoprolol, furosemide and spironolactone. The patient's blood pressure was 88/53 mmHg and the serum creatinine was 241 µmol/L. Within 2 h, the patient's heart rate decreased from 58 beats per minute to 26 beats per minute, and serum potassium levels gradually increased from 6.07 mmol/L to 7.3 mmol/L. The electrocardiogram showed a junctional escape rhythm with accidental sinus capture. The diagnosis of BRASH syndrome was made based on clinical symptoms, a biochemical profile and the results of an electrocardiogram. The patient was rapidly stabilized with the administration of intravenous calcium gluconate, dextrose and insulin, 5% sodium bicarbonate, 0.9% sodium chloride, furosemide, and oral zirconium cyclosilicate. Sinus rhythm at a heart rate of 75 bpm was detected 5 h later, along with normal serum potassium levels. After 2 weeks, kidney function returned to normal. Clinicians should be alert to patients with hyperkalemia and maintain a high index of suspicion for BRASH syndrome. Timely diagnosis and comprehensive intervention are critical for better outcomes in managing patients with BRASH.
RESUMEN
Anomalous origin of the coronary artery (AOCA) in coronary arteries represent a rare congenital variation, especially when three or more openings coexist, accompanied by conditions such as myocardial infarction, acute heart failure, and severe stenosis in three vessels, making it even rarer. This study reports a rare case of a patient admitted for the first time with acute myocardial infarction. Coronary angiography revealed four openings, along with the aforementioned rare conditions. Guided by intravascular ultrasound (IVUS), treatments were administered for different lesions in various vessels. IVUS confirmed a rare case with a 1â mm extremely short left main coronary artery and three openings. The two-year follow-up results for this patient are deemed satisfactory, indicating a favorable prognosis.
RESUMEN
A specialized population of mast cells residing within epithelial layers, currently known as intraepithelial mast cells (IEMCs), was originally observed over a century ago, yet their physiological functions have remained enigmatic. In this study, we unveil an unexpected and crucial role of IEMCs in driving gasdermin C-mediated type 2 immunity. During helminth infection, αEß7 integrin-positive IEMCs engaged in extensive intercellular crosstalk with neighboring intestinal epithelial cells (IECs). Through the action of IEMC-derived proteases, gasdermin C proteins intrinsic to the epithelial cells underwent cleavage, leading to the release of a critical type 2 cytokine, interleukin-33 (IL-33). Notably, mast cell deficiency abolished the gasdermin C-mediated immune cascade initiated by epithelium. These findings shed light on the functions of IEMCs, uncover a previously unrecognized phase of type 2 immunity involving mast cell-epithelial cell crosstalk, and advance our understanding of the cellular mechanisms underlying gasdermin C activation.
Asunto(s)
Interleucina-33 , Mastocitos , Proteínas de Unión a Fosfato , Proteínas Citotóxicas Formadoras de Poros , Animales , Ratones , Comunicación Celular/inmunología , Células Epiteliales/inmunología , Células Epiteliales/metabolismo , Interleucina-33/metabolismo , Interleucina-33/inmunología , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Péptidos y Proteínas de Señalización Intracelular/inmunología , Mastocitos/inmunología , Mastocitos/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas de Unión a Fosfato/metabolismo , Proteínas Citotóxicas Formadoras de Poros/inmunología , Proteínas Citotóxicas Formadoras de Poros/metabolismoRESUMEN
The blood-brain barrier (BBB) protects the central nervous system from infections or harmful substances1; its impairment can lead to or exacerbate various diseases of the central nervous system2-4. However, the mechanisms of BBB disruption during infection and inflammatory conditions5,6 remain poorly defined. Here we find that activation of the pore-forming protein GSDMD by the cytosolic lipopolysaccharide (LPS) sensor caspase-11 (refs. 7-9), but not by TLR4-induced cytokines, mediates BBB breakdown in response to circulating LPS or during LPS-induced sepsis. Mice deficient in the LBP-CD14 LPS transfer and internalization pathway10-12 resist BBB disruption. Single-cell RNA-sequencing analysis reveals that brain endothelial cells (bECs), which express high levels of GSDMD, have a prominent response to circulating LPS. LPS acting on bECs primes Casp11 and Cd14 expression and induces GSDMD-mediated plasma membrane permeabilization and pyroptosis in vitro and in mice. Electron microscopy shows that this features ultrastructural changes in the disrupted BBB, including pyroptotic endothelia, abnormal appearance of tight junctions and vasculature detachment from the basement membrane. Comprehensive mouse genetic analyses, combined with a bEC-targeting adeno-associated virus system, establish that GSDMD activation in bECs underlies BBB disruption by LPS. Delivery of active GSDMD into bECs bypasses LPS stimulation and opens the BBB. In CASP4-humanized mice, Gram-negative Klebsiella pneumoniae infection disrupts the BBB; this is blocked by expression of a GSDMD-neutralizing nanobody in bECs. Our findings outline a mechanism for inflammatory BBB breakdown, and suggest potential therapies for diseases of the central nervous system associated with BBB impairment.
Asunto(s)
Barrera Hematoencefálica , Encéfalo , Células Endoteliales , Gasderminas , Inflamación , Animales , Femenino , Humanos , Masculino , Ratones , Membrana Basal/metabolismo , Membrana Basal/ultraestructura , Barrera Hematoencefálica/metabolismo , Barrera Hematoencefálica/patología , Barrera Hematoencefálica/ultraestructura , Barrera Hematoencefálica/virología , Encéfalo/metabolismo , Encéfalo/patología , Encéfalo/ultraestructura , Caspasas Iniciadoras/metabolismo , Dependovirus , Células Endoteliales/metabolismo , Células Endoteliales/ultraestructura , Gasderminas/antagonistas & inhibidores , Gasderminas/metabolismo , Inflamación/patología , Inflamación/metabolismo , Klebsiella pneumoniae/fisiología , Receptores de Lipopolisacáridos/metabolismo , Lipopolisacáridos/sangre , Lipopolisacáridos/farmacología , Ratones Endogámicos C57BL , Piroptosis , Sepsis/metabolismo , Sepsis/patología , Sepsis/microbiología , Análisis de la Célula Individual , Uniones Estrechas/metabolismo , Uniones Estrechas/ultraestructuraRESUMEN
BACKGROUNDS: The role of O-GlcNAc transferase (OGT)-induced O-linked N-acetylglucosaminylation (O-GlcNAcylation) has been reported in multiple human diseases. However, its specific functions in osteoarthritis (OA) progression remain undetermined. OBJECTIVE: This study focused on the target proteins of OGT-induced O-GlcNAcylation in OA and the specific functional mechanism. METHODS: The levels of total O-GlcNAc and OGT were measured in both in vitro and in vivo OA models using western blot. The effects of OGT knockout on OA progression were detected through Safranin O staining, immunohistochemical staining and OARSI score evaluation. The effects of OGT silencing on LPS-induced chondrocyte injury were assessed by performing loss-of function assays. Co-immunoprecipitation (co-IP) was conducted to verify the effect of OGT-induced O-GlcNAcylation on the interaction between NEK7 and NLRP3. The role of OGT in modulating the O-GlcNAcylation and phosphorylation levels of NEK7 was analysed using western blot. RESULTS: The OGT-indued O-GlcNAcylation level was increased in both in vitro and in vivo OA models. Knockout of OGT mitigated OA progression in model mice. Additionally, silencing of OGT suppressed LPS-induced chondrocyte pyroptosis. Moreover, silencing of OGT inhibited the O-GlcNAcylation and enhanced the phosphorylation of NEK7 at S260 site, thereby blocking the binding of NEK7 with NLRP3. CONCLUSION: OGT-induced NEK7 O-GlcNAcylation promotes OA progression by promoting chondrocyte pyroptosis via the suppressing interaction between NEK7 and NLRP3.
Asunto(s)
N-Acetilglucosaminiltransferasas , Proteína con Dominio Pirina 3 de la Familia NLR , Osteoartritis , Humanos , Ratones , Animales , Proteína con Dominio Pirina 3 de la Familia NLR/genética , Lipopolisacáridos , Ratones Noqueados , Quinasas Relacionadas con NIMA/genéticaRESUMEN
Target tracking is an important research in the field of computer vision. Despite the rapid development of technology, difficulties still remain in balancing the overall performance for target occlusion, motion blur, etc. To address the above issue, we propose an improved kernel correlation filter tracking algorithm with adaptive occlusion judgement and model updating strategy (called Aojmus) to achieve robust target tracking. Firstly, the algorithm fuses color-naming (CN) and histogram of gradients (HOG) features as a feature extraction scheme and introduces a scale filter to estimate the target scale, which reduces tracking error caused by the variations of target features and scales. Secondly, the Aojmus introduces four evaluation indicators and a double thresholding mechanism to determine whether the target is occluded and the degree of occlusion respectively. The four evaluation results are weighted and fused to a final value. Finally, the updating strategy of the model is adaptively adjusted based on the weighted fusion value and the result of the scale estimation. Experimental evaluations on the OTB-2015 dataset are conducted to compare the performance of the Aojmus algorithm with four other comparable algorithms in terms of tracking precision, success rate, and speed. The experimental results show that the proposed Aojmus algorithm outperforms all the algorithms compared in terms of tracking precision. The Aojmus also exhibits excellent performance on attributes such as target occlusion and motion blur in terms of success rate. In addition, the processing speed reaches 74.85 fps, which also demonstrates good real-time performance.
RESUMEN
Based on a synthesized laser ultrasonic array, full matrix capture can be used to acquire data, which can then be post-processed using the total focusing method. However, this noncontact ultrasonic imaging technique has not been widely used because of the numerous artifacts in ultrasonic images and time-consuming data acquisition. To address these issues, this study proposes a post-processing algorithm, which uses the laser ultrasound directivity information to suppress the artifacts in the total focusing method's images. In particular, a weight factor is defined using the directivity information. By multiplying the image intensity of the total focusing method with this factor, the algorithm uses not only the amplitude and phase information of laser ultrasound but also its directivity information. The experimental results indicate that four types of artifacts are suppressed. Because the grating lobe artifacts can be suppressed, a larger element spacing can be used to reduce the data acquisition time.
RESUMEN
BACKGROUND: We explored the therapeutic effects of Adipose-derived mesenchymal stem cells (ADMSCs) and Synovial-derived mesenchymal stem cells (SDMSCs) on osteoarthritis (OA). METHODS: SDMSCs and ADMSCs were co-cultured with chondrocytes and stimulated with interleukin (IL)-1ß. An OA model was established on rats by intra-articular injection with ADMSCs and SDMSCs. After 8 weeks, the joint diameter difference was detected, and histological staining was used to observe the pathological changes in cartilage tissue. Enzyme-linked immunosorbent assay (ELISA) was used to detect the expressions of IL-6, tumor necrosis factor (TNF)-α and IL-1ß in joint fluid. The expressions of COL2A1, Aggrecan, Matrix metalloproteinase (MMP)-13, SOX9, IL-6, TNF-α and IL-1ß were detected by qRT-PCR and Western blotting in cartilage tissue. Reactive oxygen species (ROS) content in cells and cartilage tissues was detected by ROS kit. RESULTS: SDMSCs and ADMSCs co-cultured with chondrocytes could reduce MMP-13 expression, increase the expressions of COL2A1, Aggrecan and SOX9, as well as reverse the effects of IL-1ß on promoting ROS content and inflammatory factors levels. After the OA model was established, the injection of ADMSCs and SDMSCs reduced the differences in joint diameter and tissue lesions in OA rats. The OA model led to increased levels of IL-6, TNF-α and IL-1ß in joint fluid and cartilage tissue, while the injection of ADMSCs and SDMSCs inhibited the inflammatory factor levels in OA rats, and increased the expressions of COL2A1, Aggrecan and SOX9 in OA rats. CONCLUSION: ADMSCs and SDMSCs improve osteoarthritis in rats by reducing chondrocyte ROS and inhibiting inflammatory response.
Asunto(s)
Células Madre Mesenquimatosas , Osteoartritis , Agrecanos/genética , Agrecanos/metabolismo , Agrecanos/farmacología , Animales , Condrocitos , Humanos , Interleucina-6/metabolismo , Células Madre Mesenquimatosas/metabolismo , Osteoartritis/terapia , Ratas , Especies Reactivas de Oxígeno/metabolismo , Especies Reactivas de Oxígeno/farmacología , Especies Reactivas de Oxígeno/uso terapéutico , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
OBJECTIVE: To explore suitable treatment strategies for patients with coronary heart disease and atrial fibrillation after percutaneous coronary intervention (PCI) via systematically analyzing and comparing the clinical efficacy of dual antithrombotic therapy (DAT) and triple antithrombotic therapy (TAT). METHODS: Pubmed, Embase and Cochrane Library databases were searched. The literature from the database establishment to August 2022 was reviewed by 2 researchers separately according to the inclusion and exclusion criteria and the method recommended by the Cochrane Collaboration. The data was extracted for quality assessment. The primary endpoints of the study were safety endpoints and efficacy endpoints, the former includes major bleeding events and the latter includes mortality, myocardial infarction, stent thrombosis and stroke. RevMan5.4 software was used for meta-analysis. RESULTS: There were 11 studies were included for the meta-analysis, 5 observational studies and 6 randomized controlled trials. The number of patients included was 2,4032, of which 13818 (57.5%) received DAT and 9483 (39.5%) received TAT. Our analyses indicated that compared with TAT treatment, DAT significantly reduced the incidence of major bleeding (OR=0.71, 95% CI [0.61, 0.83], P<0.0001) and the incidence of minor bleeding (OR=0.61, 95% CI [0.50, 0.75], P<0.00001). Subgroup analysis showed that DAT with novel oral anticoagulants (NOACs) reduced major bleeding (OR=0.64, 95% CI [0.54, 0.76], P<0.00001) and the incidence of minor bleeding (OR=0.56, 95% CI [0.45, 0.69], P<0.00001), but DAT with vitamin K antagonists (VKAs) was not significantly different from TAT in major bleeding (OR=1.20, 95% CI [0.82, 1.75], P=0.35) and minor bleeding (OR=1.15, 95% CI [0.64, 2.05], P=0.64). CONCLUSIONS: DAT with NOACs has a higher safety profile against bleeding in patients with atrial fibrillation after PCI. DAT with VKAs was similar to TAT in terms of antithrombotic effect and incidence of bleeding.
RESUMEN
PURPOSE: MicroRNAs play an important role in osteosarcoma (OS) development and progress. Although miR-1253 was considered as a tumor-inhibitor in some cancers, it's function in the OS is not clear. METHODS: In our study, we examined the expression of miR-1253 in OS cells and osteoblast cells using quantitative real-time PCR. The proliferation of OS cells was measured by BrdU assay, and we performed transwell to detect migration and invasion of OS cells. Meanwhile, EMT proteins were tested by western blot. We used Bioinformatics to predict the target genes of miR-1253 and found out Matrix metalloproteinases9 (MMP9) was one of that. The direct combination between miR-1253 and MMP9 was verified by double luciferase reporting experiment. Quantitative real-time PCR and western blot were used to detect the expression of MMP9. RESULTS: We found that the expression level of miR-1253 in OS cells was significantly lower than that in osteoblast cells. Overexpression of miR-1253 could significantly inhibit OS cell proliferation, migration, invasion and EMT. And then, MMP9 was predicted as a downstream target of miR-1253 by Bioinformatics analysis. Further experiments showed that miR-1253 could reduce the protein level of MMP9 by directly binding to the 3'-UTR of MMP9. Afterward, we performed a rescue experiment, in which both MMP9 and miR-1253 were overexpressed. Compared with the groups overexpressed miR-1253 alone, cell proliferation, migration and invasion in co-overexpression groups were improved. CONCLUSIONS: In summary, these results suggested that miR-1253 down-regulated in OS cells, and could suppress the proliferation, migration and invasion of OS cells. Its molecular regulatory mechanism was that inhibits the expression of the downstream target gene MMP9 by directly binding, thus affect OS cell functions. Therefore, miR-1253 has the potential to become a biomarker and therapeutic target for OS therapy.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Neoplasias Óseas/patología , Regulación Neoplásica de la Expresión Génica , MicroARNs/genética , Osteosarcoma/patología , Apoptosis , Biomarcadores de Tumor/genética , Neoplasias Óseas/genética , Neoplasias Óseas/metabolismo , Movimiento Celular , Proliferación Celular , Humanos , Metaloproteinasa 9 de la Matriz/genética , Metaloproteinasa 9 de la Matriz/metabolismo , Osteosarcoma/genética , Osteosarcoma/metabolismo , Células Tumorales CultivadasRESUMEN
Objective To investigate the effect of oxidative stress preconditioning on the oxidative stress-induced damage of bone marrow mesenchymal stem cells (BMSCs). Methods BMSCs were isolated and cultured by density gradient centrifugation combined with adherence method. The cells were divided into three groups: control group (control medium), oxidative damage group (treated with 1000 µmol/L H2O2 for 24 hours), and preconditioning group (preincubated with 50 µmol/L H2O2 for 8 hours before treatment with 1000 µmol/L H2O2 for 24 hours). DCFH-DA staining was used to analyze the level of reactive oxygen species (ROS). Mitochondrial membrane potential was measured by JC-1 staining. DNA damage was detected by TUNEL. Malondialdehyde (MDA) content was detected by thiobarbituric acid (TBA) method, and superoxide dismutase (SOD) activity was detected by water soluble tetrazolium-1 (WST-1) assay. CCK-8 assay was used to detect cell viability and flow cytometry to detect cell apoptosis. Results Compared with the oxidative damage group, the preconditioning group had reduced ROS level, reduced DNA damage, higher mitochondrial membrane potential, significantly decreased MDA content, increased SOD activity, increased cell viability, and significantly decreased apoptosis. Conclusion Oxidative stress preconditioning can enhance the anti-oxidative stress ability of BMSCs and promote its survival under oxidative stress.
Asunto(s)
Células Madre Mesenquimatosas , Apoptosis , Células de la Médula Ósea , Peróxido de Hidrógeno/toxicidad , Malondialdehído , Estrés Oxidativo , Especies Reactivas de OxígenoRESUMEN
BACKGROUND: Light penetration in deeper tissue is impeded by the skin scattering properties, which significantly limits the clinical applications of light in medical diagnosis and therapy. To overcome this problem, skin optical clearing methods using different optical clearing agents (OCAs) have been extensively developed to clear the dermis tissue. It is critically important to remove the outmost stratum corneum (SC) before the OCAs were applied for optical clearing, since the SC works as a natural barrier to the OCAs. For this, a controllable approach for the SC disruption through physical or chemical methods is highly required for enhanced skin optical clearing. METHODS: Salicylic acid (SA) was combined with OCAs as a rapid skin optical clearing method to create a transparent window within 5 min. The clearing efficacy of this method was demonstrated by using dorsal skin model of mice. In addition, the intensity variations of vessel gray images and diffuse reflectance (DR) spectra were used to quantify the optical clearing efficacy, which were acquired by a low-cost self-built white light imaging system and optical fiber spectrometer, respectively. RESULTS: Within a specific action time of the OCAs to the skin tissue, the enhanced images of the deeper blood vessels were obtained through the removal of the SC. It takes 5 min for the skin to turn transparent and 15 min to visualize the microvascular morphology for naked eyes. Furthermore, the intensity of blood vessel gray images was identified to be an evaluation parameter for quantifying the optical clearing efficacy. CONCLUSIONS: An efficient and easy-to-handle method for enhanced skin optical clearing was established by combining SA with OCAs, which could boost the clinical applications of light in medical diagnosis and therapy.
Asunto(s)
Fotoquimioterapia , Ácido Salicílico , Animales , Ratones , Imagen Óptica , Fotoquimioterapia/métodos , Fármacos Fotosensibilizantes , Ácido Salicílico/farmacología , Piel/diagnóstico por imagen , Tomografía Computarizada por Rayos XRESUMEN
Cytotoxic lymphocyte-mediated immunity relies on granzymes. Granzymes are thought to kill target cells by inducing apoptosis, although the underlying mechanisms are not fully understood. Here, we report that natural killer cells and cytotoxic T lymphocytes kill gasdermin B (GSDMB)-positive cells through pyroptosis, a form of proinflammatory cell death executed by the gasdermin family of pore-forming proteins. Killing results from the cleavage of GSDMB by lymphocyte-derived granzyme A (GZMA), which unleashes its pore-forming activity. Interferon-γ (IFN-γ) up-regulates GSDMB expression and promotes pyroptosis. GSDMB is highly expressed in certain tissues, particularly digestive tract epithelia, including derived tumors. Introducing GZMA-cleavable GSDMB into mouse cancer cells promotes tumor clearance in mice. This study establishes gasdermin-mediated pyroptosis as a cytotoxic lymphocyte-killing mechanism, which may enhance antitumor immunity.
Asunto(s)
Granzimas/metabolismo , Células Asesinas Naturales/inmunología , Proteínas de Neoplasias/metabolismo , Proteínas Citotóxicas Formadoras de Poros/metabolismo , Piroptosis/inmunología , Linfocitos T Citotóxicos/enzimología , Animales , Granzimas/química , Células HEK293 , Humanos , Interferón gamma , Ratones , Ratones Endogámicos BALB C , Ratones Transgénicos , Proteínas de Neoplasias/química , Proteínas de Neoplasias/genética , Neoplasias/inmunología , Neoplasias/patología , Proteínas Citotóxicas Formadoras de Poros/química , Proteínas Citotóxicas Formadoras de Poros/genética , Dominios Proteicos , ProteolisisRESUMEN
Antibacterial autophagy (xenophagy) is an important host defense, but how it is initiated is unclear. Here, we performed a bacterial transposon screen and identified a T3SS effector SopF that potently blocked Salmonella autophagy. SopF was a general xenophagy inhibitor without affecting canonical autophagy. S. Typhimurium ΔsopF resembled S. flexneri ΔvirAΔicsB with the majority of intracellular bacteria targeted by autophagy, permitting a CRISPR screen that identified host V-ATPase as an essential factor. Upon bacteria-caused vacuolar damage, the V-ATPase recruited ATG16L1 onto bacteria-containing vacuole, which was blocked by SopF. Mammalian ATG16L1 bears a WD40 domain required for interacting with the V-ATPase. Inhibiting autophagy by SopF promoted S. Typhimurium proliferation in vivo. SopF targeted Gln124 of ATP6V0C in the V-ATPase for ADP-ribosylation. Mutation of Gln124 also blocked xenophagy, but not canonical autophagy. Thus, the discovery of SopF reveals the V-ATPase-ATG16L1 axis that critically mediates autophagic recognition of intracellular pathogen.
Asunto(s)
Proteínas Relacionadas con la Autofagia/metabolismo , Proteínas Bacterianas/genética , Macroautofagia , Salmonella/metabolismo , ATPasas de Translocación de Protón Vacuolares/metabolismo , Factores de Virulencia/genética , ADP-Ribosilación , Proteínas Relacionadas con la Autofagia/deficiencia , Proteínas Relacionadas con la Autofagia/genética , Proteínas Bacterianas/metabolismo , Sistemas CRISPR-Cas/genética , Edición Génica , Células HeLa , Humanos , Proteínas Asociadas a Microtúbulos/metabolismo , Unión Proteica , Salmonella/patogenicidad , Sistemas de Secreción Tipo III/metabolismo , ATPasas de Translocación de Protón Vacuolares/genética , Factores de Virulencia/metabolismoRESUMEN
OBJECTIVE: To report the surgical procedures and efficacy of using medial plantar venous flap for the repair of soft tissue defects of the fingers. METHODS: From March 2010 to April 2012, medial plantar venous flaps were harvested to repair the wounds of 31 fingers in 29 cases. Among them, there were 13 middle fingers with defects at the tips in 11 cases, 7 fingers with defects in the dorsal part in 7 cases, and 11 fingers with defects in the finger pulp in 11 cases. The size of the defects ranged from 1.2cm×1.5 cm to 2.5cm × 3.5cm. Medial plantar venous flaps of 1.5cm × 2cm - 3×4 cm were harvested. Full-thickness skin grafts were adopted for the donor areas. RESULTS: All 31 flaps survived, except for 1 flap with arterial crisis and 2 cases with venous crisis. These conditions were timely corrected by secondary anastomosis of artery and vein and the flaps survived. The wounds and the donor areas achieved healing by the first intention. All grafted skins survived. Postoperative follow-up was conducted for 26 fingers in 24 cases for 4-12 months, excluding 5 cases with lost follow-up. The dorsal part of the damaged fingers had normal morphology, and the skin color and texture were similar to those of the normal skin. After the repair of defects in the fingertip and pulp, fingerprints appeared, and the protective sensation was restored. CONCLUSION: The soft tissue defects of the fingers can be satisfactorily repaired with medial plantar venous flap, and little damage is caused to the donor area. This method is proven effective for the repair of soft tissue defects of the fingers.
Asunto(s)
Traumatismos de los Dedos/cirugía , Procedimientos de Cirugía Plástica/métodos , Colgajos Quirúrgicos/cirugía , Adulto , Femenino , Pie , Humanos , Masculino , Persona de Mediana Edad , Procedimientos de Cirugía Plástica/instrumentación , Trasplante de Piel/métodos , Traumatismos de los Tejidos Blandos/cirugía , Colgajos Quirúrgicos/irrigación sanguínea , Cicatrización de Heridas , Adulto JovenRESUMEN
Immune recognition of pathogen-associated molecular patterns (PAMPs) by pattern recognition receptors often activates proinflammatory NF-κB signalling1. Recent studies indicate that the bacterial metabolite D-glycero-ß-D-manno-heptose 1,7-bisphosphate (HBP) can activate NF-κB signalling in host cytosol2-4, but it is unclear whether HBP is a genuine PAMP and the cognate pattern recognition receptor has not been identified. Here we combined a transposon screen in Yersinia pseudotuberculosis with biochemical analyses and identified ADP-ß-D-manno-heptose (ADP-Hep), which mediates type III secretion system-dependent NF-κB activation and cytokine expression. ADP-Hep, but not other heptose metabolites, could enter host cytosol to activate NF-κB. A CRISPR-Cas9 screen showed that activation of NF-κB by ADP-Hep involves an ALPK1 (alpha-kinase 1)-TIFA (TRAF-interacting protein with forkhead-associated domain) axis. ADP-Hep directly binds the N-terminal domain of ALPK1, stimulating its kinase domain to phosphorylate and activate TIFA. The crystal structure of the N-terminal domain of ALPK1 and ADP-Hep in complex revealed the atomic mechanism of this ligand-receptor recognition process. HBP was transformed by host adenylyltransferases into ADP-heptose 7-P, which could activate ALPK1 to a lesser extent than ADP-Hep. ADP-Hep (but not HBP) alone or during bacterial infection induced Alpk1-dependent inflammation in mice. Our findings identify ALPK1 and ADP-Hep as a pattern recognition receptor and an effective immunomodulator, respectively.
Asunto(s)
Azúcares de Adenosina Difosfato/inmunología , Burkholderia cenocepacia , Citosol , Inmunidad Innata , Moléculas de Patrón Molecular Asociado a Patógenos/inmunología , Proteínas Quinasas/metabolismo , Yersinia pseudotuberculosis , Azúcares de Adenosina Difosfato/metabolismo , Animales , Infecciones por Burkholderia/enzimología , Infecciones por Burkholderia/inmunología , Infecciones por Burkholderia/patología , Burkholderia cenocepacia/genética , Burkholderia cenocepacia/inmunología , Burkholderia cenocepacia/metabolismo , Sistemas CRISPR-Cas , Cristalografía por Rayos X , Citocinas/biosíntesis , Citosol/enzimología , Citosol/inmunología , Disacáridos/metabolismo , Activación Enzimática , Femenino , Edición Génica , Factores Inmunológicos/inmunología , Factores Inmunológicos/metabolismo , Inmunomodulación , Inflamación/enzimología , Inflamación/inmunología , Inflamación/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Modelos Moleculares , FN-kappa B/metabolismo , Moléculas de Patrón Molecular Asociado a Patógenos/metabolismo , Yersinia pseudotuberculosis/genética , Yersinia pseudotuberculosis/inmunología , Yersinia pseudotuberculosis/metabolismoRESUMEN
SUMMARY OBJECTIVE To report the surgical procedures and efficacy of using medial plantar venous flap for the repair of soft tissue defects of the fingers. Methods From March 2010 to April 2012, medial plantar venous flaps were harvested to repair the wounds of 31 fingers in 29 cases. Among them, there were 13 middle fingers with defects at the tips in 11 cases, 7 fingers with defects in the dorsal part in 7 cases, and 11 fingers with defects in the finger pulp in 11 cases. The size of the defects ranged from 1.2cm×1.5 cm to 2.5cm × 3.5cm. Medial plantar venous flaps of 1.5cm × 2cm - 3×4 cm were harvested. Full-thickness skin grafts were adopted for the donor areas. RESULTS All 31 flaps survived, except for 1 flap with arterial crisis and 2 cases with venous crisis. These conditions were timely corrected by secondary anastomosis of artery and vein and the flaps survived. The wounds and the donor areas achieved healing by the first intention. All grafted skins survived. Postoperative follow-up was conducted for 26 fingers in 24 cases for 4-12 months, excluding 5 cases with lost follow-up. The dorsal part of the damaged fingers had normal morphology, and the skin color and texture were similar to those of the normal skin. After the repair of defects in the fingertip and pulp, fingerprints appeared, and the protective sensation was restored. CONCLUSION The soft tissue defects of the fingers can be satisfactorily repaired with medial plantar venous flap, and little damage is caused to the donor area. This method is proven effective for the repair of soft tissue defects of the fingers.
RESUMO OBJETIVO Relatar os procedimentos cirúrgicos e a eficácia do uso de retalhos plantares mediais venosos para reparo de defeitos de tecidos moles dos dedos. METODOLOGIA De março de 2010 a abril de 2012, foram colhidos retalhos plantares mediais venosos para reparar ferimentos de 31 dedos em 29 casos. Entre eles, 13 dedos médios com defeitos nas pontas em 11 casos, 7 dedos com defeitos na parte dorsal em 7 casos e 11 dedos com defeitos na polpa digital em 11 casos. O tamanho dos defeitos variava de 1,2 cm × 1,5 cm a 2,5 cm × 3,5 cm. Foram colhidos retalhos plantares mediais venosos de 1,5 cm × 2 cm a 3 cm × 4 cm. Foram adotados enxertos de pele de espessura total na área doadora. RESULTADOS Todos os 31 retalhos sobreviveram, com exceção de 1 retalho com crise arterial e 2 casos com crise venosa. Esses problemas foram corrigidos a tempo com anastomoses secundárias das artérias e veias e os retalhos sobreviveram. Os ferimentos e áreas doadoras atingiram cicatrização por primeira intenção. Todos os enxertos de pele sobreviveram. Foi realizado acompanhamento pós-operatório em de 26 dedos em 24 casos por 4 a 12 meses, sendo que dos casos tratados 5 não tiveram acompanhamento. As partes dorsais dos dedos lesionados apresentaram morfologia normal, com cor e textura da pele muito similares a da pele normal. Após o reparo dos defeitos nas pontas e polpas digitais, impressões digitais apareceram e a sensação protetora foi restaurada. CONCLUSÃO Os defeitos de tecido mole dos dedos podem ser reparados de forma satisfatória com retalhos plantares mediais venosos, com poucos danos à área doadora. Este método mostrou se eficaz para o reparo de defeitos de tecido mole dos dedos.
Asunto(s)
Humanos , Masculino , Femenino , Adulto , Adulto Joven , Colgajos Quirúrgicos/cirugía , Procedimientos de Cirugía Plástica/métodos , Traumatismos de los Dedos/cirugía , Colgajos Quirúrgicos/irrigación sanguínea , Cicatrización de Heridas , Trasplante de Piel/métodos , Traumatismos de los Tejidos Blandos/cirugía , Procedimientos de Cirugía Plástica/instrumentación , Pie , Persona de Mediana EdadRESUMEN
Objective To investigate the effect of miR-125b on the aerobic glycolysis of osteosarcoma HOS cells and its underlying mechanism. Methods Real-time quantitative PCR was performed to detect the expression of miR-125b in HOSB normal human osteoblast cells and HOS osteosarcoma cells. The glucose uptake rate was assessed with 3H-2 deoxyglucose (3H-2DG) and lactate production was tested with the kits to observe the effect of miR-125b-mimics on the aerobic glycolysis of osteosarcoma HOS cells. Hexokinase-2 (HK2) protein was detected by Western blot analysis. Dual luciferase reporter gene assay was used to determine whether HK2 was the direct target of miR-125b. Results Compared with HOSB normal human osteoblast cells, the expression of miR-125b was significantly lower in HOS cells. The glucose uptake and lactate production were downregulated in HOS cells transfected with miR-125b-mimics. Aerobic glycolysis of HOS cells was markedly inhibited. Protein level of HK2 was significantly inhibited in HOS cells transfected with miR-125b-mimics. Luciferase assay indicated that HK2 was the direct target of miR-125b. Conclusion miR-125b is down-regulated in HOS cells, and it inhibits the aerobic glycolysis of HOS cells by directly regulating the expression of HK2.
Asunto(s)
Regulación Neoplásica de la Expresión Génica , Glucólisis/genética , Hexoquinasa/genética , MicroARNs/genética , Regiones no Traducidas 3'/genética , Secuencia de Bases , Línea Celular , Línea Celular Tumoral , Regulación hacia Abajo , Hexoquinasa/metabolismo , Humanos , Osteosarcoma/genética , Osteosarcoma/metabolismo , Osteosarcoma/patología , Homología de Secuencia de Ácido NucleicoRESUMEN
Pyroptosis is a form of cell death that is critical for immunity. It can be induced by the canonical caspase-1 inflammasomes or by activation of caspase-4, -5 and -11 by cytosolic lipopolysaccharide. The caspases cleave gasdermin D (GSDMD) in its middle linker to release autoinhibition on its gasdermin-N domain, which executes pyroptosis via its pore-forming activity. GSDMD belongs to a gasdermin family that shares the pore-forming domain. The functions and mechanisms of activation of other gasdermins are unknown. Here we show that GSDME, which was originally identified as DFNA5 (deafness, autosomal dominant 5), can switch caspase-3-mediated apoptosis induced by TNF or chemotherapy drugs to pyroptosis. GSDME was specifically cleaved by caspase-3 in its linker, generating a GSDME-N fragment that perforates membranes and thereby induces pyroptosis. After chemotherapy, cleavage of GSDME by caspase-3 induced pyroptosis in certain GSDME-expressing cancer cells. GSDME was silenced in most cancer cells but expressed in many normal tissues. Human primary cells exhibited GSDME-dependent pyroptosis upon activation of caspase-3 by chemotherapy drugs. Gsdme-/- (also known as Dfna5-/-) mice were protected from chemotherapy-induced tissue damage and weight loss. These findings suggest that caspase-3 activation can trigger necrosis by cleaving GSDME and offer new insights into cancer chemotherapy.