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Bone marrow-derived cells (BMDCs) infiltrate hypoxic tumors at a pre-angiogenic state and differentiate into mature macrophages, thereby inducing pro-tumorigenic immunity. A critical factor regulating this differentiation is activation of SREBP2-a well-known transcription factor participating in tumorigenesis progression-through unknown cellular mechanisms. Here, we show that hypoxia-induced Golgi disassembly and Golgi-ER fusion in monocytic myeloid cells result in nuclear translocation and activation of SREBP2 in a SCAP-independent manner. Notably, hypoxia-induced SREBP2 activation was only observed in an immature lineage of bone marrow-derived cells. Single-cell RNA-seq analysis revealed that SREBP2-mediated cholesterol biosynthesis was upregulated in HSCs and monocytes but not in macrophages in the hypoxic bone marrow niche. Moreover, inhibition of cholesterol biosynthesis impaired tumor growth through suppression of pro-tumorigenic immunity and angiogenesis. Thus, our findings indicate that Golgi-ER fusion regulates SREBP2-mediated metabolic alteration in lineage-specific BMDCs under hypoxia for tumor progression.
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Monocitos , Neoplasias , Humanos , Monocitos/metabolismo , Médula Ósea , Colesterol/metabolismo , Proteína 2 de Unión a Elementos Reguladores de Esteroles/genética , Proteína 2 de Unión a Elementos Reguladores de Esteroles/metabolismo , HipoxiaRESUMEN
The theory of polymer dynamics describes the intermediate scattering function for a polymer molecule in terms of relaxation modes defined by normal coordinates for the corresponding coarse-grained model. However, due to the difficulty of defining the normal coordinates for arbitrary polymer molecules, it is generally challenging to express the intermediate scattering function for a polymer molecule in terms of relaxation modes. To overcome this challenge, we propose a general method to calculate the intermediate scattering function for a polymer molecule on the basis of a relaxation mode analysis approach [Takano and Miyashita, J. Phys. Soc. Jpn. 64, 3688 (1995)]. In the proposed method, relaxation modes defined by eigenfunctions in a Markov process are evaluated on the basis of the simulation results for a polymer molecule and used to calculate the intermediate scattering function for that molecule. To demonstrate the effectiveness of the present method, we simulate the dynamics of a linear polymer molecule in a dilute solution and apply it to the calculation of the intermediate scattering function for the polymer molecule. The evaluation results regarding the relaxation modes reasonably describe the intermediate scattering function on the length scale of the radius of gyration of the polymer molecule. Accordingly, we examine the contributions of the pure relaxation and oscillatory relaxation processes to the entire intermediate scattering function.
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A 51-year-old man visited to our hospital because of chest discomfort and hematemesis. He was diagnosed with Mallory-Weiss syndrome and followed in outpatient clinic. One week later, he visited our hospital again for fever and discomfort. Chest computed tomography (CT) showed a foreign body perforated in the mediastinum in the upper esophagus, and he was urgently hospitalized for surgical removal of esophageal foreign body. Before surgery he vomited the esophageal foreign body with a lot of blood. Hematemesis was stopped spontaneously and contrast-enhanced CT revealed a pseudoaneurysm in the distal aortic arch, so thoracic endovascular aortic repair (TEVAR) was performed to prevent rupture. Esophageal endoscopy found that the site of esophageal injury healed spontaneously, so the patient was followed conservatively with antibiotics. He was discharged on postoperative day 18 uneventfully. TEVAR was an effective treatment for aortic injury caused by esophageal foreign body in our case.
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Enfermedades de la Aorta , Procedimientos Endovasculares , Cuerpos Extraños , Masculino , Humanos , Persona de Mediana Edad , Hematemesis/complicaciones , Esófago/diagnóstico por imagen , Esófago/cirugía , Enfermedades de la Aorta/cirugía , Cuerpos Extraños/complicaciones , Cuerpos Extraños/diagnóstico por imagen , Cuerpos Extraños/cirugíaRESUMEN
BACKGROUND: Poor oral health is an independent risk factor for upper-aerodigestive tract cancers, including esophageal cancer. Several studies have investigated short-term outcomes after esophagectomy and the impact of periodontal disease, but few have examined the impact of periodontal disease on long-term outcomes. The purpose of this study was to investigate the rate of periodontitis among esophagectomy patients and the prognostic value of periodontitis and its effect on prognosis after esophagectomy. METHODS: A total of 508 patients who underwent esophagectomy received oral health care from a dentist before cancer treatment at Akita University Hospital between January 2009 and December 2021. We assessed the presence and severity of the patients' periodontitis and divided them into no-periodontitis, mild periodontitis, severe periodontitis and edentulous jaw groups. We then assessed 10-year overall survival (OS) and disease-specific survival (DSS) and determined whether periodontitis was an independent prognostic factor affecting OS and DSS. RESULTS: We found that 101 (19.9%) patients had no periodontitis, 207 (40.8%) had mild periodontitis, 176 (34.6%) had severe periodontitis requiring tooth extraction, and 24 (4.7%) had edentulous jaw. Both OS and DSS were significantly poorer in the periodontitis than no-periodontitis group (p < 0.001). In detail, the edentulous jaw group had the poorest prognosis (p < 0.001). Multivariate analysis showed that periodontitis was an independent risk factor affecting OS and DSS. CONCLUSION: Esophageal cancer patients had a high prevalence of periodontitis. Moreover, the presence of periodontitis and severity of periodontitis are independent risk factors contributing to a poorer prognosis after esophagectomy.
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Neoplasias Esofágicas , Arcada Edéntula , Periodontitis , Humanos , Esofagectomía/efectos adversos , Estadificación de Neoplasias , Neoplasias Esofágicas/complicaciones , Neoplasias Esofágicas/cirugía , Pronóstico , Periodontitis/complicaciones , Periodontitis/epidemiología , Periodontitis/cirugía , Arcada Edéntula/cirugíaRESUMEN
Mitochondrial one-carbon metabolism is crucial for embryonic development and tumorigenesis, as it supplies one-carbon units necessary for nucleotide synthesis and rapid cell proliferation. However, its contribution to adult tissue homeostasis remains largely unknown. To examine its role in adult tissue homeostasis, we specifically investigated mammary gland development during pregnancy, as it involves heightened cell proliferation. We discovered that MTHFD2, a mitochondrial one-carbon metabolic enzyme, is expressed in both luminal and basal/myoepithelial cell layers, with upregulated expression during pregnancy. Using the mouse mammary tumor virus (MMTV)-Cre recombinase system, we generated mice with a specific mutation of Mthfd2 in mammary epithelial cells. While the mutant mice were capable of properly nurturing their offspring, the pregnancy-induced expansion of mammary glands was significantly delayed. This indicates that MTHFD2 contributes to the rapid development of mammary glands during pregnancy. Our findings shed light on the role of mitochondrial one-carbon metabolism in facilitating rapid cell proliferation, even in the context of the adult tissue homeostasis.
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Células Epiteliales , Glándulas Mamarias Animales , Metilenotetrahidrofolato Deshidrogenasa (NADP) , Animales , Femenino , Ratones , Embarazo , Proliferación Celular , Células Epiteliales/metabolismo , Hidrolasas/metabolismo , Glándulas Mamarias Animales/metabolismo , Ratones Transgénicos , Metilenotetrahidrofolato Deshidrogenasa (NADP)/metabolismoRESUMEN
Colorectal cancer (CRC) is caused by genetic alterations, and comprehensive sequence analyses have revealed the mutation landscapes. In addition to somatic changes, genetic variations are considered important factors contributing to tumor development; however, our knowledge on this subject is limited. Familial adenomatous polyposis coli (FAP) is an autosomal-dominant inherited disease caused by germline mutations in the adenomatous polyposis coli (APC) gene. FAP patients are classified into two major groups based on clinical manifestations: classical FAP (CFAP) and attenuated FAP (AFAP). In this study, we established 42 organoids from three CFAP patients and two AFAP patients. Comprehensive gene expression analysis demonstrated a close association between IFN/STAT signaling and the phenotypic features of FAP patients. Genetic disruption of Stat1 in the mouse model of FAP reduced tumor formation, demonstrating that the IFN/STAT pathway is causally associated with the tumor-forming potential of APC-deficient tumors. Mechanistically, STAT1 is downstream target of KRAS and is phosphorylated by its activating mutations. We found that enhanced IFN/STAT signaling in CFAP conferred resistance to MEK inhibitors. These findings reveal the crosstalk between RAS signaling and IFN/STAT signaling, which contributes to the tumor-forming potential and drug response. These results offer a rationale for targeting of IFN/STAT signaling and for the stratification of CRC patients.
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Transformación Celular Neoplásica/metabolismo , Neoplasias Colorrectales/etiología , Neoplasias Colorrectales/metabolismo , Interferones/metabolismo , Factores de Transcripción STAT/metabolismo , Transducción de Señal , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Transformación Celular Neoplásica/efectos de los fármacos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/patología , Modelos Animales de Enfermedad , Resistencia a Antineoplásicos , Perfilación de la Expresión Génica , Humanos , Inmunohistoquímica , Ratones , Modelos Biológicos , Organoides , Inhibidores de Proteínas Quinasas/farmacología , Transducción de Señal/efectos de los fármacos , Técnicas de Cultivo de Tejidos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Dynamic analysis methods are important for analyzing long simulations such as folding simulations. Relaxation mode analysis, which approximately extracts slow modes and rates, has been applied in molecular dynamics (MD) simulations of protein systems. Previously, we showed that slow modes are suitable for analyzing simulations in which large conformational changes occur. Here, we applied relaxation mode analysis to folding simulations of a designed mutant of protein G, NuG2, to investigate its folding pathways. The folding simulations of NuG2 were previously performed for this mutant with Anton. In the present study, the free energy surfaces were calculated by projecting the coordinates on the axis of the slow relaxation modes obtained from relaxation mode analysis. We classified various characteristic states such as native, nativelike, intermediate, and random states and clarified two main folding pathways. In the early folding process, the first and second ß strands formed an N-terminal ß-sheet. After the early folding process, the fourth ß strand formed along the first ß strand in the same or opposite direction as the native structure; two characteristic intermediate states were identified. Finally, the intermediate structures folded to the native structure in the folding process. Relaxation mode analysis can be applied to folding simulations of complex proteins to investigate their folding processes.
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Recently, dynamic analysis methods in signal processing have been applied to the analysis of molecular dynamics (MD) trajectories of biopolymers. In the context of a relaxation mode analysis (RMA) method, based on statistical physics, it is explained why the signal-processing methods work well for the simulation trajectories of biopolymers. A distinctive difference between the RMA method and the signal-processing methods is the introduction of an additional parameter, called an evolution time parameter. This parameter enables us to better estimate the relaxation modes and rates, although it increases computational difficulty. In this paper, we propose a simple and effective extension of the RMA method, which is referred to as the positive definite RMA method, to introduce the evolution time parameter robustly. In this method, an eigenvalue problem for the time correlation matrix of physical quantities relevant to slow relaxation in a system is first solved to find the subspace in which the matrix is numerically positive definite. Then, we implement the RMA method in the subspace. We apply the method to the analysis of a 3-µs MD trajectory of a heterotrimer of an erythropoietin protein and two of its receptor proteins, and we demonstrate the effectiveness of the method.
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A model is developed for simulating entangled polymers by dissipative particle dynamics (DPD) using the segmental repulsive potential (SRP). In contrast to previous SRP models that define a single-point interaction on each bond, the proposed SRP model applies a dynamically adjustable multipoint on the bond. Previous SRP models could not reproduce the equilibrium properties of Groot and Warren's original DPD model [R. D. Groot and P. B. Warren, J. Chem. Phys. 107, 4423 (1997)] because the introduction of a single SRP induces a large excluded volume, whereas, the proposed multipoint SRP (MP-SRP) introduces a cylindrical effective excluded bond volume. We demonstrate that our MP-SRP model exhibits equilibrium properties similar to those of the original DPD polymers. The MP-SRP model parameters are determined by monitoring the number of topology violations, thermodynamic properties, and the polymer internal structure. We examine two typical DPD polymers with different bond-length distributions; one of them was used in the modified SRP model by Sirk et al. [J. Chem. Phys. 136, 134903 (2012)], whereas the other was used in the original DPD model. We demonstrate that for both polymers, the proposed MP-SRP model captures the entangled behaviors of a polymer melt naturally, by calculating the slowest relaxation time of a chain in the melt and the shear relaxation modulus. The results indicate that the proposed MP-SRP model can be applied to a variety of DPD polymers.
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Although nonstructural dysfunction of a bioprosthesis caused by pannus formation or native valve attachment has been well described, structural valve deterioration( SVD) caused by calcification or tear of a bioprosthesis, especially a bovine pericardial valve, is very rare in the tricuspid position. We report a case of redo tricuspid valve surgery for SVD 14 years after tricuspid valve replacement( TVR) using a Carpentier-Edwards Perimount (CEP) pericardial valve. A 71-year-old woman was referred to our hospital because of exertional dyspnea and pre-syncope. She had undergone mitral valve replacement with a St. Jude Medical mechanical valve and TVR with a CEP pericardial valve 14 years previously. Transthoracic echocardiography revealed tricuspid valve stenosis with a mean trans-tricuspid valve pressure gradient (TVPG) of 7.3 mmHg. Redo TVR using a CEP Magna Mitral Ease valve was performed under cardiac arrest. Severe calcification was observed on the ventricular side of the leaflets of the explanted valve. The mean TVPG decreased to 3.2 mmHg after surgery, and the patient's postoperative course was uneventful.
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Calcinosis , Prótesis Valvulares Cardíacas , Válvula Mitral/patología , Válvula Tricúspide/cirugía , Anciano , Animales , Bovinos , Electrocardiografía , Femenino , Humanos , Válvula Mitral/trasplante , Factores de Tiempo , Trasplante Heterólogo , Válvula Tricúspide/fisiopatologíaRESUMEN
PURPOSE: This study aimed to examine the risk factors for severe postoperative tricuspid regurgitation (TR) in patients undergoing mitral valve surgery. We also studied the effects of prophylactic tricuspid valve repair (TVR) on severe postoperative TR. METHODS: We retrospectively studied 125 patients without severe TR who underwent mitral valve surgery from 1987 to 2006. Patients did not undergo TVR before 1998 (the early period, n = 54). In 1998 (the late period, n = 71), patients with a preoperative tricuspid annular diameter of ≥35 mm underwent TVR using an annuloplasty ring (n = 52). RESULTS: In the analysis of the early period, the rates of freedom from severe TR at 10 and 20 years after surgery were 76 and 59 %, respectively. A multivariate analysis identified moderate preoperative TR as a significant risk factor for severe TR. In the late period, none of the 52 patients who underwent TVR developed severe TR. However, 4/19 patients who did not undergo TVR developed severe TR, and all of these four patients had a preoperative tricuspid annular diameter of ≤35 mm. CONCLUSIONS: Moderate preoperative TR is a significant risk factor for severe postoperative TR in patients undergoing mitral valve surgery. The aggressive application of TVR can prevent severe postoperative TR; however, tricuspid annular dilatation might not be a good indicator for TVR.
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Anuloplastia de la Válvula Cardíaca/métodos , Válvula Mitral/cirugía , Complicaciones Posoperatorias/prevención & control , Insuficiencia de la Válvula Tricúspide/prevención & control , Válvula Tricúspide/cirugía , Adulto , Anciano , Dilatación Patológica , Femenino , Humanos , Masculino , Persona de Mediana Edad , Periodo Preoperatorio , Estudios Retrospectivos , Factores de Riesgo , Índice de Severidad de la Enfermedad , Válvula Tricúspide/patologíaRESUMEN
BACKGROUND: Poor oral health is a risk factor for causing upper aerodigestive tract tumors, including esophageal cancer. Our aim was to determine the periodontitis rate in our cohort of esophageal cancer patients. We also analyzed whether preoperative dental examination and care reduces the likelihood of severe pneumonia after esophagectomy. STUDY DESIGN: Between 2003 and 2014, 529 esophageal cancer patients received esophagectomy at Akita University Hospital. We studied 232 patients who had preoperative dental examinations and care (dental care group) retrospectively and assessed the severity of their periodontitis. The dental care group was compared to 297 patients who did not have preoperative dental care (control group) with respect to the incidence of severe pneumonia after esophagectomy. RESULTS: Ninety-one patients (39.2%) in the dental care group were diagnosed with slight periodontitis and 69 (29.7%) were diagnosed with severe periodontitis. Among all the patients, 69 patients (13.0%) were diagnosed with grade 3B postoperative severe pneumonia. The dental care group had a significantly lower incidence of severe pneumonia than the control group. Moreover, multivariable logistic regression analysis revealed that anastomotic leakage, preoperative dental care, gender and %VC were correlated significantly with the occurrence of postoperative severe pneumonia. CONCLUSION: Preoperative dental examination and care by a dentist are essential to reduce the likelihood of postoperative severe pneumonia in esophageal cancer patients.
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Atención Odontológica , Neoplasias Esofágicas/cirugía , Esofagectomía/efectos adversos , Periodontitis/complicaciones , Neumonía/etiología , Cuidados Preoperatorios , Anciano , Neoplasias Esofágicas/complicaciones , Neoplasias Esofágicas/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Neumonía/prevención & control , Factores Protectores , Estudios Retrospectivos , Factores de Riesgo , Índice de Severidad de la Enfermedad , Extracción DentalRESUMEN
We report a case of large anterior septal perforation (40×20 mm) immediately following repair of ventricular septal perforation( 9×9 mm) with the infarction exclusion technique. The large perforation was successfully repaired through a left ventriculotomy with a combined double patch/cone-shaped patch technique. This technique can be effective not only in cases of large laceration of ventricular septum as a consequence of inappropriate repair but also of large septal perforation with extensive fragility of the septal myocardium.
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Procedimientos Quirúrgicos Cardíacos , Anciano de 80 o más Años , Angiografía , Ecocardiografía , Femenino , Humanos , Resultado del Tratamiento , Rotura Septal Ventricular/diagnóstico por imagen , Rotura Septal Ventricular/cirugíaRESUMEN
A 52-year-old woman was admitted to our hospital for acute right hemi-paresis, left homonymous hemianopia, and fever. Magnetic resonance imaging of the brain showed multiple cerebral infarctions and transesophageal echocardiography (TEE) revealed a vegetation on the posterior leaflet of her mitral valve. Mitral valve repair was performed under a diagnosis of infective endocarditis (IE). Further multiple cerebral infarctions occurred on the 11th postoperative day, resulting in left hemiplegia and dysarthria. TEE revealed vegetations on her mitral valve and mitral valve replacement (MVR) was performed. Microscopic examination of the resected valve showed mild lymphocytic infiltration, but no bacterial or fungal organisms were detected. On the 66th day after the initial surgery, she developed deep vein thrombosis and acute pulmonary embolism. Abdominal computed tomography showed a huge ovarian tumor, and TEE demonstrated vegetations on the left atrial wall, the aortic valve, and the mechanical valve immobilizing one of the leaflets. The patient was finally diagnosed as having Trousseau syndrome caused by an ovarian tumor and non-bacterial thrombotic endocarditis( NBTE). Three months after the initial operation, redo MVR was performed and aortic valve vegetations were removed. Four days later, the ovarian cancer was resected. Her postoperative course was uneventful and she was discharged on foot on the 143rd day after the initial operation. NBTE caused by malignancy is rare but must be considered when managing endocarditis.
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Endocarditis/etiología , Válvula Mitral/cirugía , Neoplasias Ováricas/complicaciones , Procedimientos Quirúrgicos Cardíacos , Infarto Cerebral/etiología , Femenino , Humanos , Persona de Mediana Edad , Complicaciones Posoperatorias , Reoperación , Síndrome , Trombosis/etiologíaRESUMEN
It is important to extract reaction coordinates or order parameters from protein simulations in order to investigate the local minimum-energy states and the transitions between them. The most popular method to obtain such data is principal component analysis, which extracts modes of large conformational fluctuations around an average structure. We recently applied relaxation mode analysis for protein systems, which approximately estimates the slow relaxation modes and times from a simulation and enables investigations of the dynamic properties underlying the structural fluctuations of proteins. In this study, we apply this relaxation mode analysis to extract reaction coordinates for a system in which there are large conformational changes such as those commonly observed in protein folding/unfolding. We performed a 750-ns simulation of chignolin protein near its folding transition temperature and observed many transitions between the most stable, misfolded, intermediate, and unfolded states. We then applied principal component analysis and relaxation mode analysis to the system. In the relaxation mode analysis, we could automatically extract good reaction coordinates. The free-energy surfaces provide a clearer understanding of the transitions not only between local minimum-energy states but also between the folded and unfolded states, even though the simulation involved large conformational changes. Moreover, we propose a new analysis method called Markov state relaxation mode analysis. We applied the new method to states with slow relaxation, which are defined by the free-energy surface obtained in the relaxation mode analysis. Finally, the relaxation times of the states obtained with a simple Markov state model and the proposed Markov state relaxation mode analysis are compared and discussed.
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Simulación de Dinámica Molecular , Oligopéptidos/metabolismo , Solventes/química , Temperatura de Transición , Agua/química , Cadenas de Markov , Análisis de Componente Principal , Conformación Proteica , Pliegue de Proteína , SolucionesRESUMEN
Fifteen consecutive prosthetic valve endocarditis (PVE) patients were operated from March 2009 to September 2014. The average age of patients was 68 years ( range 49 to 82) and 7 patients were male. The interval between initial surgery and reoperation was 62.4 months(range 2.6 to 340.9). Seven of these cases(47%) developed PVE within the 1st year after surgery were defined as early PVE. All microorganisms isolated from blood cultures in early PVE were Staphylococcus species. Generally, the infective prosthetic valve was removed 1st, then all infective tissues were excised from the periannular cavity. A new prosthetic valve was replaced in supra-annular fashion. One patient who had a severe discontinuity between the most part of left ventricle and aorta necessitated a root replacement. One patient in aortic PVE, needed an additional patch-plasty of anterior mitral leaflet. The mean cardiopulmonary bypass and aortic clamping times were 250 minutes( range 132 to 426) and 165 minutes( range 117 to 309), respectively. Four patients needed permanent pacemaker implanted for complete A-V block. Five patients had transient acute renal failure, and 1 required dialysis could be weaned at 40 post operative day. Average postoperative hospital stay was 39 days (range 21 to 108), and the operative mortality was 0%. The postoperative follow up was 3.1 years( range 0.6 to 6.0), all patients were doing well without re-infection and heart failure except 1 patient died by non-cardiac disease.
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Endocarditis Bacteriana/cirugía , Prótesis Valvulares Cardíacas , Infecciones Estafilocócicas/cirugía , Anciano , Anciano de 80 o más Años , Endocarditis Bacteriana/microbiología , Femenino , Prótesis Valvulares Cardíacas/efectos adversos , Implantación de Prótesis de Válvulas Cardíacas , Humanos , Masculino , Persona de Mediana Edad , Reoperación , Resultado del TratamientoRESUMEN
We investigated the effects of zoledronate (ZA) and compressive force, separately and in combination, on the proliferation and differentiation of human gingival fibroblasts (HGFs) to verify the mechanism underlying medication-related osteonecrosis of the jaw (MRONJ). The addition of 100 µM ZA markedly inhibited cell proliferation. Expression of type I collagen, fibroblast growth factor 2, and connective tissue growth factor genes, was decreased by ZA and compressive force. Similar results were observed for collagen expression by using Sirius red staining. These results, together with clinical findings that MRONJ is more common in cases with excessive mechanical stress on the oral mucosa, suggest that bisphosphonates such as ZA and mechanical stress may act in conjunction as risk factors for the development of MRONJ by affecting homeostasis of the oral mucosal tissues, including HGFs.
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Osteonecrosis de los Maxilares Asociada a Difosfonatos , Conservadores de la Densidad Ósea , Humanos , Ácido Zoledrónico/farmacología , Ácido Zoledrónico/metabolismo , Difosfonatos/efectos adversos , Encía , Fibroblastos/metabolismo , Proliferación Celular , Conservadores de la Densidad Ósea/efectos adversosRESUMEN
Neuroinflammation has been gaining attention as one of the potential causes of neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis in recent years. The suppression of excessive proinflammatory responses is expected to be a target for the treatment and prevention of neurodegenerative diseases. Collapsin response mediator protein 4 (CRMP4) is involved in cytoskeleton-associated axonal guidance in the developing brain. Recently, the involvement of CRMP4 in several pathological conditions, including inflammation induced by lipopolysaccharide (LPS), a widely used inflammatory molecule, has been reported. However, the role of CRMP4 in LPS-induced inflammation in vivo remains largely unknown. In this study, we generated microglia-specific CRMP4 knockout mice for the first time and examined the role of CRMP4 in an LPS-induced brain inflammation model. We found that microglia after LPS injection in substantia nigra was significantly reduced in Crmp4-/- mice compared to Crmp4+/+mice. The increased expression of IL-10 in striatum samples was downregulated in Crmp4-/- mice. A significant reduction in Iba1 expression was also observed in microglia-specific Crmp4 knockout mice compared with that in control mice. In contrast, the expression of IL-10 did not change in these mice, whereas arginase 1 (Arg1) expression was significantly suppressed. These results demonstrate the involvement of CRMP4 in LPS-induced inflammation in vivo, that CRMP4 suppresses microglial proliferation in a cell-autonomous manner.
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Lipopolisacáridos , Ratones Noqueados , Microglía , Proteínas del Tejido Nervioso , Enfermedades Neuroinflamatorias , Animales , Lipopolisacáridos/farmacología , Microglía/metabolismo , Microglía/efectos de los fármacos , Proteínas del Tejido Nervioso/metabolismo , Proteínas del Tejido Nervioso/genética , Ratones , Enfermedades Neuroinflamatorias/metabolismo , Enfermedades Neuroinflamatorias/inducido químicamente , Inflamación/metabolismo , Inflamación/inducido químicamente , Interleucina-10/metabolismo , Sustancia Negra/metabolismo , Sustancia Negra/efectos de los fármacos , Ratones Endogámicos C57BL , Cuerpo Estriado/metabolismo , Cuerpo Estriado/efectos de los fármacos , Masculino , Proteínas de Microfilamentos/metabolismo , Arginasa/metabolismoRESUMEN
The transcription factor SRY-related HMG box 9 (Sox9) is essential for chondrogenesis. Mutations in and around SOX9 cause campomelic dysplasia (CD) characterized by skeletal malformations. Although the function of Sox9 in this context is well studied, the mechanisms that regulate Sox9 expression in chondrocytes remain to be elucidated. Here, we have used genome-wide profiling to identify 2 Sox9 enhancers located in a proximal breakpoint cluster responsible for CD. Enhancer activity of E308 (located 308 kb 5' upstream) and E160 (located 160 kb 5' upstream) correlated with Sox9 expression levels, and both enhancers showed a synergistic effect in vitro. While single deletions in mice had no apparent effect, simultaneous deletion of both E308 and E160 caused a dwarf phenotype, concomitant with a reduction of Sox9 expression in chondrocytes. Moreover, bone morphogenetic protein 2-dependent chondrocyte differentiation of limb bud mesenchymal cells was severely attenuated in E308/E160 deletion mice. Finally, we found that an open chromatin region upstream of the Sox9 gene was reorganized in the E308/E160 deletion mice to partially compensate for the loss of E308 and E160. In conclusion, our findings reveal a mechanism of Sox9 gene regulation in chondrocytes that might aid in our understanding of the pathophysiology of skeletal disorders.
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Displasia Campomélica , Diferenciación Celular , Condrocitos , Condrogénesis , Factor de Transcripción SOX9 , Factor de Transcripción SOX9/metabolismo , Factor de Transcripción SOX9/genética , Animales , Condrocitos/metabolismo , Ratones , Displasia Campomélica/genética , Displasia Campomélica/patología , Displasia Campomélica/metabolismo , Condrogénesis/genética , Diferenciación Celular/genética , Elementos de Facilitación Genéticos/genética , Cromatina/metabolismo , Cromatina/genética , Regulación del Desarrollo de la Expresión Génica , Ratones Noqueados , Proteína Morfogenética Ósea 2/metabolismo , Proteína Morfogenética Ósea 2/genética , Humanos , Desarrollo Óseo/genéticaRESUMEN
For the development of a rechargeable metal-air battery, which is expected to become one of the most widely used batteries in the future, slow kinetics of discharging and charging reactions at the air electrode, i.e., oxygen reduction reaction (ORR) and oxygen evolution reaction (OER), respectively, are the most critical problems. Here we report that Ruddlesden-Popper-type layered perovskite, RP-LaSr3Fe3O10 (n = 3), functions as a reversible air electrode catalyst for both ORR and OER at an equilibrium potential of 1.23 V with almost no overpotentials. The function of RP-LaSr3Fe3O10 as an ORR catalyst was confirmed by using an alkaline fuel cell composed of Pd/LaSr3Fe3O10-2x(OH)2x·H2O/RP-LaSr3Fe3O10 as an open circuit voltage (OCV) of 1.23 V was obtained. RP-LaSr3Fe3O10 also catalyzed OER at an equilibrium potential of 1.23 V with almost no overpotentials. Reversible ORR and OER are achieved because of the easily removable oxygen present in RP-LaSr3Fe3O10. Thus, RP-LaSr3Fe3O10 minimizes efficiency losses caused by reactions during charging and discharging at the air electrode and can be considered to be the ORR/OER electrocatalyst for rechargeable metal-air batteries.