RESUMEN
Multiple alterations of cellular metabolism have been documented in experimental studies of autosomal dominant polycystic kidney disease (ADPKD) and are thought to contribute to its pathogenesis. To elucidate the molecular pathways and transcriptional regulators associated with the metabolic changes of renal cysts in ADPKD, we compared global gene expression data from human PKD1 renal cysts, minimally cystic tissues (MCT) from the same patients, and healthy human kidney cortical tissue samples. We found gene expression profiles of PKD1 renal cysts were consistent with the Warburg effect with gene pathway changes favoring increased cellular glucose uptake and lactate production, instead of pyruvate oxidation. Additionally, mitochondrial energy metabolism was globally depressed, associated with downregulation of gene pathways related to fatty acid oxidation (FAO), branched-chain amino acid (BCAA) degradation, the Krebs cycle, and oxidative phosphorylation (OXPHOS) in renal cysts. Activation of mTORC1 and its two target proto-oncogenes, HIF-1α and MYC, was predicted to drive the expression of multiple genes involved in the observed metabolic reprogramming (e.g., GLUT3, HK1/HK2, ALDOA, ENO2, PKM, LDHA/LDHB, MCT4, PDHA1, PDK1/3, MPC1/2, CPT2, BCAT1, NAMPT); indeed, their predicted expression patterns were confirmed by our data. Conversely, we found AMPK inhibition was predicted in renal cysts. AMPK inhibition was associated with decreased expression of PGC-1α, a transcriptional coactivator for transcription factors PPARα, ERRα, and ERRγ, all of which play a critical role in regulating oxidative metabolism and mitochondrial biogenesis. These data provide a comprehensive map of metabolic pathway reprogramming in ADPKD and highlight nodes of regulation that may serve as targets for therapeutic intervention.
Asunto(s)
Metabolismo Energético , Riñón Poliquístico Autosómico Dominante , Biología de Sistemas , Humanos , Biología de Sistemas/métodos , Riñón Poliquístico Autosómico Dominante/metabolismo , Riñón Poliquístico Autosómico Dominante/genética , Canales Catiónicos TRPP/metabolismo , Canales Catiónicos TRPP/genética , Mitocondrias/metabolismo , Mitocondrias/genética , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/genética , Fosforilación Oxidativa , Regulación de la Expresión GénicaRESUMEN
Polycystic kidney disease (PKD) is characterized by extensive cyst formation and progressive fibrosis. However, the molecular mechanisms whereby the loss/loss-of-function of Polycystin 1 or 2 (PC1/2) provokes fibrosis are largely unknown. The small GTPase RhoA has been recently implicated in cystogenesis, and we identified the RhoA/cytoskeleton/myocardin-related transcription factor (MRTF) pathway as an emerging mediator of epithelium-induced fibrogenesis. Therefore, we hypothesized that MRTF is activated by PC1/2 loss and plays a critical role in the fibrogenic reprogramming of the epithelium. The loss of PC1 or PC2, induced by siRNA in vitro, activated RhoA and caused cytoskeletal remodeling and robust nuclear MRTF translocation and overexpression. These phenomena were also manifested in PKD1 (RC/RC) and PKD2 (WS25/-) mice, with MRTF translocation and overexpression occurring predominantly in dilated tubules and the cyst-lining epithelium, respectively. In epithelial cells, a large cohort of PC1/PC2 downregulation-induced genes was MRTF-dependent, including cytoskeletal, integrin-related, and matricellular/fibrogenic proteins. Epithelial MRTF was necessary for the paracrine priming of the fibroblast-myofibroblast transition. Thus, MRTF acts as a prime inducer of epithelial fibrogenesis in PKD. We propose that RhoA is a common upstream inducer of both histological hallmarks of PKD: cystogenesis and fibrosis.
Asunto(s)
Células Epiteliales , Enfermedades Renales Poliquísticas , Canales Catiónicos TRPP , Proteína de Unión al GTP rhoA , Animales , Humanos , Ratones , Citoesqueleto/metabolismo , Células Epiteliales/metabolismo , Células Epiteliales/patología , Fibrosis , Ratones Endogámicos C57BL , Enfermedades Renales Poliquísticas/metabolismo , Enfermedades Renales Poliquísticas/patología , Enfermedades Renales Poliquísticas/genética , Proteína de Unión al GTP rhoA/metabolismo , Transactivadores/metabolismo , Canales Catiónicos TRPP/metabolismo , Canales Catiónicos TRPP/genéticaRESUMEN
Magnesium hydroxide (Mg(OH)2), as a green halogen-free flame retardant, has attracted significant attention in the field of flame retardant composite materials. In addition to conventional indicators such as purity and whiteness, Mg(OH)2 is required to take the form of regular hexagonal sheets to ensure the dispersion of composite materials. We use irregular large particles of Mg(OH)2 prepared by the magnesium factory in western Qinghai as raw materials to study the influence of alkali metal ions K+ and Na+ mainly present in salt lakes on the physicochemical properties of Mg(OH)2. The products were characterized via X-ray diffraction, scanning electron microscopy, automatic nitrogen physical adsorption apparatus, and other modern characterization techniques. Results show that alkali metal ions K+ and Na+ considerably influence the crystal surface polarity, particle size, and morphology of the prepared Mg(OH)2. The mechanism analysis shows that the presence of K+ and Na+ alters the dissolution, recrystallization, and growth characteristics of Mg(OH)2. This study provides theoretical support for the realization of high-performance Mg(OH)2 using salt lake resources and demonstrates the value for promoting the large-scale industrial application of the salt lake industry.
RESUMEN
Metabolic reprogramming is a driver of autosomal dominant polycystic kidney disease (ADPKD) progression and a potential therapeutic intervention route. We showed before that the AMP-associated protein kinase (AMPK) activator salsalate attenuates cystic disease progression. Here, we aim to study the early, direct effects of short salsalate treatment in adult-onset conditional Pkd1 deletion mice. Cystic mice were treated with salsalate for two weeks, after which NMR metabolomics and RNA sequencing analyses were performed. Pkd1 deletion resulted in clear metabolomic dysregulation. Short salsalate treatment has small, but significant, effects, reverting acetylcarnitine and phosphocholine concentrations back to wildtype levels, and showing associations with altered purine metabolism. RNA sequencing revealed that short salsalate treatment, next to restoring energy metabolism toward wildtype levels, also affects cell proliferation and inflammation, in PKD. We show that salsalate positively affects major dysregulated processes in ADPKD: energy metabolism, cell proliferation, and inflammation, providing more insights into its working mechanisms.
RESUMEN
This retrospective study aimed to evaluate whether anti-glycoproteins (GPs) autoantibodies can be used as predictors of response to high-dose dexamethasone combined with rituximab (DXM-RTX) in the treatment of primary immune thrombocytopenia (ITP) patients. One-hundred twenty-six ITP patients were included and retrospectively analyzed, 66.7% of anti-GPIb/IX and 65.9% of anti-GPIIb/IIIa autoantibodies. Results showed that overall response (OR) and complete response (CR) rates of patients without anti-GPIb/IX autoantibodies to DXM-RTX were significantly higher than those with anti-GPIb/IX autoantibodies at 4 weeks (OR: 73.8% vs. 47.6%, CR: 50.0% vs. 26.2%; P < 0.05) and 6 months (OR: 71.4% vs. 45.2%, CR: 42.9% vs. 25.0%; P < .05). Furthermore, patients with anti-GPIb/IX single-positivity exhibited higher resistance to DXM-RTX than patients with anti-GPIIb/IIIa single-positivity at 4 weeks (OR: 37.5% vs. 78.3%; P < .05) and 6 months (OR: 29.2% vs. 78.3%; P < .05). Multivariable logistic regression analysis revealed that anti-GPIb/IX autoantibodies and megakaryocytes were associated with the OR rate of patients at both 4 weeks and 6 months, and anti-GPIb/IX autoantibodies at 4 weeks represented the only significant factor affecting OR rate with DXM-RTX (F = 9.128, P = .003). Therefore, platelet anti-GPIb/IX autoantibodies might predict poor response to DXM-RTX in ITP patients.
What is the context?The safety and efficacy of high-dose dexamethasone combined with rituximab (DXM-RTX) in the treatment of primary immune thrombocytopenia (ITP) are gradually recognized; however, there still needs to be an adequate clinical trial to predict its efficacy. Autoantibodies against platelet glycoproteins (GPs) are proven to be associated with a variety of therapeutic responses in ITP. Such as anti-GPIb/IX autoantibodies predict poor response to intravenous immunoglobulin G therapy and rhTPO therapy in ITP patients. Therefore, a retrospective study was needed to verify whether anti-GP autoantibodies can expect a response to DXM-RTX therapy in ITP patients.What is new?This study identified that anti-GPIb/IX autoantibodies were a predictive factor for poor response to DXM-RTX in ITP patients. It mainly manifested in the following aspects: (1) Overall response (OR) and complete response (CR) rates of patients without anti-GPIb/IX autoantibodies to DXM-RTX were significantly higher than those with anti-GPIb/IX autoantibodies at four weeks and six months. (2) Multivariable logistic regression analysis revealed that anti-GPIb/IX autoantibodies at both four weeks and six months were associated with the OR rate of patients.What is the impact?Our study suggests that ITP patients with anti-GPIb/IX positive autoantibodies respond poorly to DXM-RTX therapy. Platelet anti-GPIb/IX autoantibodies might predict poor response to DXM-RTX therapy in ITP patients.
Asunto(s)
Púrpura Trombocitopénica Idiopática , Humanos , Estudios Retrospectivos , Rituximab/farmacología , Rituximab/uso terapéutico , Púrpura Trombocitopénica Idiopática/tratamiento farmacológico , Autoanticuerpos , Complejo GPIIb-IIIa de Glicoproteína Plaquetaria , Dexametasona/farmacología , Dexametasona/uso terapéuticoRESUMEN
AIM: Neoadjuvant chemotherapy (NAC) plays an important role in the treatment and prognosis of breast cancer. The early identification of patients who can truly benefit from preoperative NAC is crucial in clinical practice. The purpose of this study was to explore whether the ultrasound features and clinical characteristics combined with tumor-infiltrating lymphocyte(TIL) levels can improve the performance of predicting NAC efficacy in breast cancer patients. MATERIAL AND METHODS: In this retrospective study, 202 invasive breast cancer patients who underwent NAC followed by surgery were included. The baseline ultrasound features were reviewed by two radiologists. Miller-Payne Grading (MPG) was used to assess pathological response, and MPG 4-5 was defined as major histologic responders (MHR). Multivariable logistic regression analysis was used to evaluate independent predictors for MHR and build the prediction models. The receiver operating characteristic (ROC) curve was used to evaluate the performance of the models. RESULTS: Of the 202 patients, 104 patients achieved MHR and 98 patients achieved non-MHR. Multivariate logistic regression analysis showed the US size (p=0.042), molecular subtypes (p=0.001), TIL levels (p<0.001), shape (p=0.030), and posterior features (p=0.018) were independent predictors for MHR. The model combined the US features, clinical characteristics, and TIL levels had a better performance with an area under the curve (AUC) of 0.811, a sensitivity of 0.663, and a specificity of 0.847. CONCLUSION: The model combined US features, clinical characteristics, and TIL levels had a better performance in predicting pathological response to NAC in breast cancer.
Asunto(s)
Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Resultado del Tratamiento , Terapia Neoadyuvante , Linfocitos Infiltrantes de Tumor/patología , Estudios RetrospectivosRESUMEN
Background: Autosomal dominant polycystic kidney disease (ADPKD) is the most common genetic disorder and an important cause of end stage renal disease (ESRD). Tolvaptan (a V2R antagonist) is the first disease modifier drug for treatment of ADPKD, but also causes severe polyuria. AMPK activators have been shown to attenuate cystic kidney disease. Methods: In this study, we tested the efficacy of the combined administration of salsalate (a direct AMPK activator) and tolvaptan using clinically relevant doses in an adult-onset conditional Pkd1 knock-out (KO) mouse model. Results: Compared to untreated Pkd1 mutant mice, the therapeutic effects of salsalate were similar to that of tolvaptan. The combined treatment tended to be more effective than individual drugs used alone, and was associated with improved kidney survival (p < 0.0001) and reduced kidney weight to body weight ratio (p < 0.0001), cystic index (p < 0.001) and blood urea levels (p < 0.001) compared to untreated animals, although the difference between combination and single treatments was not statistically significant. Gene expression profiling and protein expression and phosphorylation analyses support the mild beneficial effects of co-treatment, and showed that tolvaptan and salsalate cooperatively attenuated kidney injury, cell proliferation, cell cycle progression, inflammation and fibrosis, and improving mitochondrial health, and cellular antioxidant response. Conclusion: These data suggest that salsalate-tolvaptan combination, if confirmed in clinical testing, might represent a promising therapeutic strategy in the treatment of ADPKD.
RESUMEN
BACKGROUND: Inflammation has been implicated in the progressive exacerbation of valvular atrial fibrillation (VAF) and thrombogenesis. This study aimed to analyze the association of systemic inflammation as measured by six indices with left atrial thrombus (LAT) in patients with VAF. METHODS: This comparative cross-sectional analytical study included 434 patients with VAF. Logistic regression analysis was used to assess the predictive value of LAT using six inflammation indices: neutrophil-to-lymphocyte ratio, monocyte-to-lymphocyte ratio (MLR), white blood cell-to-mean platelet volume ratio, neutrophil-to-mean platelet volume ratio, systemic immune inflammation index, and systemic inflammation response index. Receiver operating characteristic curves were plotted, and the area under these curves (AUC) were calculated to evaluate the discriminative ability of the indices. RESULTS: Transesophageal echocardiography revealed LAT in 143 (32.9%) patients. All six indices reflected a positive correlation with C-reactive protein levels. Multivariate logistic analysis revealed that these indices were independent predictors of LAT, and MLR appeared to perform best (odds ratio 12.006 [95% confidence interval (CI) 3.404-42.347]; P < 0.001; AUC 0.639 [95% CI 0.583-0.694]; P < 0.001). CONCLUSIONS: Selected inflammatory indices were significantly and independently associated with LAT among patients with VAF.
Asunto(s)
Fibrilación Atrial , Cardiopatías , Trombosis , Humanos , Estudios Transversales , Factores de Riesgo , Cardiopatías/complicaciones , Trombosis/diagnóstico por imagen , Trombosis/etiología , Ecocardiografía Transesofágica , Inflamación/diagnóstico , Inflamación/complicacionesRESUMEN
BACKGROUND: Age- and height-adjusted total kidney volume is currently considered the best prognosticator in patients with autosomal dominant polycystic kidney disease. We tested the ratio of urinary epidermal growth factor and monocyte chemotactic peptide 1 for the prediction of the Mayo Clinic Imaging Classes. METHODS: Urinary epidermal growth factor and monocyte chemotactic peptide 1 levels were measured in two independent cohorts (discovery, n = 74 and validation set, n = 177) and healthy controls (n = 59) by immunological assay. Magnetic resonance imaging parameters were used for total kidney volume calculation and the Mayo Clinic Imaging Classification defined slow (1A-1B) and fast progressors (1C-1E). Microarray and quantitative gene expression analysis were used to test epidermal growth factor and monocyte chemotactic peptide 1 gene expression. RESULTS: Baseline ratio of urinary epidermal growth factor and monocyte chemotactic peptide 1 correlated with total kidney volume adjusted for height (r = - 0.6, p < 0.001), estimated glomerular filtration rate (r = 0.69 p < 0.001), discriminated between Mayo Clinic Imaging Classes (p < 0.001), and predicted the variation of estimated glomerular filtration rate at 10 years (r = - 0.51, p < 0.001). Conditional Inference Trees identified cut-off levels of the ratio of urinary epidermal growth factor and monocyte chemotactic peptide 1 for slow and fast progressors at > 132 (100% slow) and < 25.76 (89% and 86% fast, according to age), with 94% sensitivity and 66% specificity (p = 6.51E-16). Further, the ratio of urinary epidermal growth factor and monocyte chemotactic peptide 1 at baseline showed a positive correlation (p = 0.006, r = 0.36) with renal outcome (delta-estimated glomerular filtration rate per year, over a mean follow-up of 4.2 ± 1.2 years). Changes in the urinary epidermal growth factor and monocyte chemotactic peptide 1 were mirrored by gene expression levels in both human kidney cysts (epidermal growth factor: - 5.6-fold, fdr = 0.001; monocyte chemotactic peptide 1: 3.1-fold, fdr = 0.03) and Pkd1 knock-out mouse kidney (Egf: - 14.8-fold, fdr = 2.37E-20, Mcp1: 2.8-fold, fdr = 6.82E-15). CONCLUSION: The ratio of urinary epidermal growth factor and monocyte chemotactic peptide 1 is a non-invasive pathophysiological biomarker that can be used for clinical risk stratification in autosomal dominant polycystic kidney disease.
Asunto(s)
Riñón Poliquístico Autosómico Dominante , Animales , Humanos , Ratones , Progresión de la Enfermedad , Factor de Crecimiento Epidérmico/genética , Riñón , Monocitos/patología , Riñón Poliquístico Autosómico Dominante/diagnóstico por imagen , Riñón Poliquístico Autosómico Dominante/genéticaRESUMEN
OBJECTIVES: Tumor-infiltrating lymphocytes (TILs) have emerged as an efficient biomarker predicting treatment response and prognosis of breast cancer (BC). This study aimed to evaluate the association between conventional ultrasound and contrast-enhanced ultrasound (CEUS) imaging features with TIL levels in invasive BC patients. METHODS: We retrospectively included 267 women with invasive BC who had undergone conventional ultrasound and CEUS. Patients were divided into low (≤10%) and high (>10%) TIL groups. Conventional ultrasound and CEUS features were analyzed by two sonographers. The associations between the TIL levels and imaging features were evaluated. RESULTS: Of the 267 patients, 122 with high TILs and 145 with low TIL levels. High TIL tumors were more likely to have a circumscribed margin, oval or round shape, and enhanced posterior echoes on ultrasonography (p < 0.05). In contrast, low TIL tumors were more likely to have an irregular shape, un-circumscribed, indistinct and spiculated margin (p < 0.05). In CEUS, high TIL tumors showed a more regular shape, clearer margin, more homogeneous enhancement and higher peak intensity (PI) value (p < 0.05). Logistic analysis indicated that shape, posterior features, PI, and enhanced homogeneity were independent predictors for high TIL tumors. The model combined the four independent predictors have a moderate performance in predicting high TIL tumors with AUC 0.79, sensitivity 0.72, and specificity 0.78. CONCLUSIONS: Conventional ultrasound and CEUS features were associated with TIL levels in invasive BC. Consequently, the results suggested that preoperative conventional ultrasound and CEUS may be a useful noninvasive imaging biomarker for individualized treatment decisions.
Asunto(s)
Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/diagnóstico por imagen , Neoplasias de la Mama/patología , Linfocitos Infiltrantes de Tumor/patología , Estudios Retrospectivos , Ultrasonografía , PronósticoRESUMEN
Autosomal dominant polycystic kidney disease (ADPKD) is the most common Mendelian kidney disease, affecting approximately one in 1,000 births and accounting for 5% of end-stage kidney disease in developed countries. The pathophysiology of ADPKD is strongly linked to metabolic dysregulation, which may be secondary to defective polycystin function. Overweight and obesity are highly prevalent in patients with ADPKD and constitute an independent risk factor for progression. Recent studies have highlighted reduced AMP-activated protein kinase (AMPK) activity, increased mammalian target of rapamycin (mTOR) signaling, and mitochondrial dysfunction as shared pathobiology between ADPKD and overweight/obesity. Notably, mTOR and AMPK are two diametrically opposed sensors of energy metabolism that regulate cell growth and proliferation. However, treatment with the current generation of mTOR inhibitors is poorly tolerated due to their toxicity, making clinical translation difficult. By contrast, multiple preclinical and clinical studies have shown that pharmacological activation of AMPK provides a promising approach to treat ADPKD. In this narrative review, we summarize the pleiotropic functions of AMPK as a regulator of cellular proliferation, macromolecule metabolism, and mitochondrial biogenesis, and discuss the potential for pharmacological activation of AMPK to treat ADPKD and obesity-related kidney disease.
RESUMEN
Immune thrombocytopenia (ITP), characterized by decreased platelet counts, is a complex immune-mediated disorder with unelucidated pathogenesis. Accumulating evidence shows that T cell-mediated platelet destruction is one crucial process during the progression of ITP. Here, we attempted to identify core genes in peripheral blood-derived T-cells of chronic ITP through the analysis of microarray data (GSE43179) and clinical verification, with the aim to further understand the pathogenesis and progression of ITP. Compared with healthy controls, 97 differentially expressed genes (DEGs), including 63 up-regulated and 34 down-regulated were identified in ITP patients. Functional enrichment analysis showed that the DEGs were mainly enriched in innate immune response, inflammatory response, and IL-17 signaling pathway. Among the DEGs, top 15 hub genes ranked by degree score were identified via protein-protein interaction (PPI) network and were further confirmed by quantitative reverse transcription PCR (qRT-PCR). Among top 15 hub genes, the expression levels of 14 DEGs like TLR4, S100A8, S100A9, and S100A12 were significantly up-regulated, while one DEG IFNG was down-regulated in ITP patients. Noticeably, TLR4 exhibited the highest degree score, and S100A8 had the largest fold change in qRT-PCR analysis. Altogether, our results suggested that the pathogenesis and progression of ITP are related with multiple immune-related pathways, and that TLR4 and S100A8 are likely to play crucial roles.
Asunto(s)
Perfilación de la Expresión Génica , Púrpura Trombocitopénica Idiopática , Biología Computacional/métodos , Perfilación de la Expresión Génica/métodos , Humanos , Mapas de Interacción de Proteínas/genética , Púrpura Trombocitopénica Idiopática/genética , Linfocitos T , Receptor Toll-Like 4/genéticaRESUMEN
BACKGROUND: To discuss the clinical features of a patient with hereditary hemorrhagic telangiectasia (HHT). METHODS: The clinical data of one patient with HHT are retrospectively analysed. In addition, we review the relevant literature. RESULTS: A 32-year-old male patient was admitted to the hematology outpatient department of our hospital and presented with intermittent epistaxis for 24 years. In recent years, he was diagnosed with iron deficiency anemia. The nasal endoscopic examination showed telangiectasia at the front of the right-middle turbinate and the left nasal cavity. He had ENG genetic mutation positivity. CONCLUSIONS: Patients with HHT may suffer from many complications, including bleeding, anemia, iron deficiency, and high-output heart failure. These patients may have telangiectasias and arteriovenous malformations in various organs.
Asunto(s)
Anemia , Malformaciones Arteriovenosas , Telangiectasia Hemorrágica Hereditaria , Adulto , Malformaciones Arteriovenosas/complicaciones , Malformaciones Arteriovenosas/diagnóstico por imagen , Epistaxis/complicaciones , Humanos , Masculino , Estudios Retrospectivos , Telangiectasia Hemorrágica Hereditaria/complicaciones , Telangiectasia Hemorrágica Hereditaria/diagnóstico , Telangiectasia Hemorrágica Hereditaria/genéticaRESUMEN
Diffuse large B-cell lymphoma (DLBCL) is one of the most common causes of cancer death worldwide, and responds poorly to the existing treatments. Thus, identifying novel therapeutic targets of DLBCL is urgently needed. In this study, we found that T-lymphokine-activated killer cell-originated protein kinase (TOPK) was highly expressed in DLBCL cells and tissues. Data from the GEPIA database also indicated that TOPK was highly expressed in DLBCL tissues. The high expression levels of proteins were identified via Western blots and immunohistochemistry (IHC). TOPK knockdown inhibited cell growth and induced apoptosis of DLBCL cells with 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2 H-tetrazolium (MTS) and flow cytometry. Further experiments demonstrated that acetylshikonin, a compound that targeted TOPK, could attenuate cell growth and aggravate cell apoptosis through TOPK/extracellular signal-regulated kinase (ERK)-1/2 signaling, as shown by MTS, flow cytometry and Western blots. In addition, we demonstrated that TOPK modulated the effect of acetylshikonin on cell proliferation and apoptosis in U2932 and OCI-LY8 cells using MTS, flow cytometry and Western blots. Taken together, the present study suggests that acetylshikonin suppresses the growth of DLBCL cells by attenuating TOPK signaling, and the targeted inhibition of TOPK by acetylshikonin may be a promising approach for the treatment of DLBCL.
Asunto(s)
Antraquinonas/farmacología , Linfoma de Células B Grandes Difuso , Quinasas de Proteína Quinasa Activadas por Mitógenos/genética , Animales , Línea Celular Tumoral , Proliferación Celular/genética , Quinasas MAP Reguladas por Señal Extracelular/genética , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Femenino , Humanos , Tejido Linfoide/patología , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/patología , Ratones , Ratones Desnudos , Persona de Mediana Edad , Quinasas de Proteína Quinasa Activadas por Mitógenos/metabolismo , Transducción de Señal/genética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Cardiovascular disease (CVD) is a chronic disease and causes the highest rate of death globally. CVD-related deaths account for 80% of all deaths in low and middle-income countries, such as China. Crocetin (CT), a carotenoid phytoconstituent already confirm their anti-inflammatory and antioxidant effects in various diseases animal models. In the study, we make effort to access the cardio-protective effect of Crocetin against vitamin D3 and high fat induced atherosclerosis in rats and scrutinize the underlying mechanism. Sprague Dawley (SD) rats were used in this study and rats were divided into different groups and high fat diet and vitamin D was used for induction the atherosclerosis. The rats were received oral administration of crocetin (5, 10 and 15 mg/kg) and simvastatin (0.5 mg/kg) until 30 days. At the end of the experimental period, lipid, cardiac markers, anti-inflammatory, antioxidant, pro-inflammatory cytokines and atherogenic index were estimated. The mRNA expression of Intercellular adhesion molecule-1 (ICAM-1), Monocyte Chemoattractant Protein-1 (MCP-1) and vascular cell adhesion molecule 1 (VCAM-1) in aortic tissue of the atherosclerotic rats. Crocetin significantly reduced the aortic membrane thickness and platelet aggregation rates. Crocetin also dose-dependently reduced total cholesterol (TC), very low-density lipoprotein (VLDL), triacylglycerol (TG), low-density lipoprotein (LDL) and augmented the level of high-density lipoprotein (HDL) level. Additionally, Crocetin significantly (p < 0.001) abridged the level of malonaldehyde (MDA) and augmented the level of superoxide dismutase (SOD), catalase (CAT), reduced glutathione (GSH) and glutathione peroxidase (GPx). Furthermore, Crocetin significantly (p < 0.001) dose-dependently reduced the levels of pro-inflammatory cytokines and inflammatory mediators. Crocetin attenuated mRNA expression of VCAM-1, ICAM-1 and MCP-1. Crocetin had anti-atherosclerosis and cardio-protective effects on vitamin D3 and high fat induced atherosclerosis in rats through anti-inflammatory and antioxidant mechanisms.
Asunto(s)
Antiinflamatorios , Antioxidantes , Aterosclerosis/etiología , Aterosclerosis/prevención & control , Carotenoides/administración & dosificación , Carotenoides/farmacología , Colecalciferol/efectos adversos , Dieta Alta en Grasa/efectos adversos , Fitoterapia , Vitamina A/análogos & derivados , Administración Oral , Animales , Antioxidantes/metabolismo , Aorta/metabolismo , Aorta/patología , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/metabolismo , Quimiocina CCL2/metabolismo , Citocinas/metabolismo , Modelos Animales de Enfermedad , Mediadores de Inflamación/metabolismo , Molécula 1 de Adhesión Intercelular/metabolismo , Metabolismo de los Lípidos/efectos de los fármacos , Ratas Sprague-Dawley , Molécula 1 de Adhesión Celular Vascular/metabolismo , Vitamina A/administración & dosificación , Vitamina A/farmacologíaRESUMEN
Our understanding of the mechanisms responsible for the progression of chronic kidney disease (CKD) is incomplete. Microarray analysis of kidneys at 4 and 7 weeks of age in Col4a3-/- mice, a model of progressive nephropathy characterized by proteinuria, interstitial fibrosis, and inflammation, revealed that Follistatin-like-1 (Fstl1) was one of only four genes significantly overexpressed at 4 weeks of age. mRNA levels for the Fstl1 receptors, Tlr4 and Dip2a, increased in both Col4a-/- mice and mice subjected to unilateral ureteral obstruction (UUO). RNAscope® (Advanced Cell Diagnostics, Newark CA, USA) localized Fstl1 to interstitial cells, and in silico analysis of single cell transcriptomic data from human kidneys showed Fstl1 confined to interstitial fibroblasts/myofibroblasts. In vitro, FSTL1 activated AP1 and NFκB, increased collagen I (COL1A1) and interleukin-6 (IL6) expression, and induced apoptosis in cultured kidney cells. FSTL1 expression in the NEPTUNE cohort of humans with focal segmental glomerulosclerosis (FSGS), membranous nephropathy (MN), and IgA nephropathy (IgAN) was positively associated with age, eGFR, and proteinuria by multiple linear regression, as well as with interstitial fibrosis and tubular atrophy. Clinical disease progression, defined as dialysis or a 40 percent reduction in eGFR, was greater in patients with high baseline FSTL1 mRNA levels. FSTL1 is a fibroblast-derived cytokine linked to the progression of experimental and clinical CKD.
Asunto(s)
Factores de Crecimiento de Fibroblastos/metabolismo , Proteínas Relacionadas con la Folistatina/metabolismo , Insuficiencia Renal Crónica/metabolismo , Animales , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Cadena alfa 1 del Colágeno Tipo I , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Factores de Crecimiento de Fibroblastos/genética , Proteínas Relacionadas con la Folistatina/genética , Ratones , Ratones Noqueados , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Insuficiencia Renal Crónica/genética , Insuficiencia Renal Crónica/patología , Receptor Toll-Like 4/genética , Receptor Toll-Like 4/metabolismoRESUMEN
Herein, metastable spheroidal vaterite calcium carbonate (CaCO3) was prepared using a simple ultrasound technique. The fabricated material comprises an irregular nanoparticle aggregate when steamed ammonia liquid waste, that is, (CaCl2) and (NH4)2CO3, is used as the raw material at atmospheric temperature, without any surfactants. The effects of ultrasound amplitude, probe immersion depth, and solution volume on particle properties were investigated. The obtained samples were identified and characterized by X-ray diffraction, Fourier transform infrared spectroscopy, scanning electron microscopy, and the Brunauer-Emmett-Teller technique. Our experiments show that the probe immersion depth and the reaction volume are the key parameters that impact the diameter size and size distribution of the fabricated spheroidal vaterite CaCO3 particles. The ultrasound amplitude considerably affected the particle size and the specific surface area. A possible formation mechanism for pure vaterite is proposed herein, which suggests that simple vaterite CaCO3 is formed owing to the special properties of steamed ammonia liquid waste and the synergistic effects of the ultrasonic system. This study may provide a new method for vaterite CaCO3 synthesis.
RESUMEN
BACKGROUND AND OBJECTIVES: Progression of autosomal dominant polycystic kidney disease (ADPKD) is highly variable. On average, protein-truncating PKD1 mutations are associated with the most severe kidney disease among all mutation classes. Here, we report that patients with protein-truncating PKD1 mutations may also have mild kidney disease, a finding not previously well recognized. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: From the extended Toronto Genetic Epidemiologic Study of Polycystic Kidney Disease, 487 patients had PKD1 and PKD2 sequencing and typical ADPKD imaging patterns by magnetic resonance imaging or computed tomography. Mayo Clinic Imaging Classification on the basis of age- and height-adjusted total kidney volume was used to assess their cystic disease severity; classes 1A or 1B were used as a proxy to define mild disease. Multivariable linear regression was performed to test the effects of age, sex, and mutation classes on log-transformed height-adjusted total kidney volume and eGFR. RESULTS: Among 174 study patients with typical imaging patterns and protein-truncating PKD1 mutations, 32 (18%) were found to have mild disease on the basis of imaging results (i.e., Mayo Clinic Imaging class 1A-1B), with their mutations spanning the entire gene. By multivariable analyses of age, sex, and mutation class, they displayed mild disease similar to patients with PKD2 mutations and Mayo Clinic Imaging class 1A-1B. Most of these mildly affected patients with protein-truncating PKD1 mutations reported a positive family history of ADPKD in preceding generations and displayed significant intrafamilial disease variability. CONCLUSIONS: Despite having the most severe mutation class, 18% of patients with protein-truncating PKD1 mutations had mild disease on the basis of clinical and imaging assessment. PODCAST: This article contains a podcast at https://www.asn-online.org/media/podcast/CJASN/2021_02_18_CJN11100720_final.mp3.