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1.
J Clin Invest ; 133(14)2023 07 17.
Artículo en Inglés | MEDLINE | ID: mdl-37463446

RESUMEN

Human epidermal growth factor receptor 2-targeted (HER2-targeted) therapy is the mainstay of treatment for HER2+ breast cancer. However, the proteolytic cleavage of HER2, or HER2 shedding, induces the release of the target epitope at the ectodomain (ECD) and the generation of a constitutively active intracellular fragment (p95HER2), impeding the effectiveness of anti-HER2 therapy. Therefore, identifying key regulators in HER2 shedding might provide promising targetable vulnerabilities against resistance. In the current study, we found that upregulation of dolichyl-phosphate N-acetylglucosaminyltransferase (DPAGT1) sustained high-level HER2 shedding to confer trastuzumab resistance, which was associated with poor clinical outcomes. Upon trastuzumab treatment, the membrane-bound DPAGT1 protein was endocytosed via the caveolae pathway and retrogradely transported to the ER, where DPAGT1 induced N-glycosylation of the sheddase - ADAM metallopeptidase domain 10 (ADAM10) - to ensure its expression, maturation, and activation. N-glycosylation of ADAM10 at N267 protected itself from ER-associated protein degradation and was essential for DPAGT1-mediated HER2 shedding and trastuzumab resistance. Importantly, inhibition of DPAGT1 with tunicamycin acted synergistically with trastuzumab treatment to block HER2 signaling and reverse resistance. These findings reveal a prominent mechanism for HER2 shedding and suggest that targeting DPAGT1 might be a promising strategy against trastuzumab-resistant breast cancer.


Asunto(s)
Antineoplásicos , Neoplasias de la Mama , Humanos , Femenino , Trastuzumab/farmacología , Trastuzumab/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Transducción de Señal , Proteínas de la Membrana/metabolismo , Resistencia a Antineoplásicos , Línea Celular Tumoral , Antineoplásicos/farmacología
2.
Free Radic Biol Med ; 201: 41-54, 2023 05 20.
Artículo en Inglés | MEDLINE | ID: mdl-36924851

RESUMEN

Aberrant lipid metabolism mediated by the selective transport of fatty acids plays vital roles in cancer initiation, progression, and therapeutic failure. However, the biological function and clinical significance of abnormal fatty acid transporters in human cancer remain unclear. In the present study, we reported that solute carrier family 27 member 4 (SLC27A4) is significantly overexpressed in 21 types of human cancer, especially in the fatty acids-enriched microenvironment surrounding hepatocellular carcinoma (HCC), breast cancer, and ovarian cancer. Upregulated SLC27A4 expression correlated with shorter overall and relapse-free survival of patients with HCC, breast cancer, or ovarian cancer. Lipidomic analysis revealed that overexpression of SLC27A4 significantly promoted the selective uptake of mono-unsaturated fatty acids (MUFAs), which induced a high level of MUFA-containing phosphatidylcholine and phosphatidylethanolamine in HCC cells, consequently resulting in resistance to lipid peroxidation and ferroptosis. Importantly, silencing SLC27A4 significantly promoted the sensitivity of HCC to sorafenib treatment, both in vitro and in vivo. Our findings revealed a plausible role for SLC27A4 in ferroptosis defense via lipid remodeling, which might represent an attractive therapeutic target to increase the effectiveness of sorafenib treatment in HCC.


Asunto(s)
Carcinoma Hepatocelular , Proteínas de Transporte de Ácidos Grasos , Ferroptosis , Neoplasias Hepáticas , Femenino , Humanos , Neoplasias de la Mama , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/metabolismo , Proteínas de Transporte de Ácidos Grasos/metabolismo , Ácidos Grasos/metabolismo , Ácidos Grasos Insaturados , Ferroptosis/genética , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/metabolismo , Recurrencia Local de Neoplasia , Neoplasias Ováricas , Sorafenib/farmacología , Sorafenib/uso terapéutico , Microambiente Tumoral
3.
Adv Sci (Weinh) ; 9(31): e2201974, 2022 11.
Artículo en Inglés | MEDLINE | ID: mdl-36169100

RESUMEN

Tumor-derived extracellular vesicles (EVs) function as critical mediators in selective modulation of the microenvironment of distant organs to generate a pre-metastatic niche that facilitates organotropic metastasis. Identifying the organ-specific molecular determinants of EVs can develop potential anti-metastatic therapeutic targets. In the current study, large oncosomes (LOs), atypically large cancer-derived EVs, are found to play a crucial role in facilitating bone-tropic metastasis of hepatocellular carcinoma (HCC) cells by engineering an osteoclastic pre-metastatic niche and establishing a vicious cycle between the osteoclasts and HCC cells. Transmembrane protein, VAMP-associated protein A (VAPA), is significantly enriched on LOs surface via direct interaction with LOs marker αV-integrin. VAPA-enriched LOs-induced pre-metastatic education transforms the bone into a fertile milieu, which supports the growth of metastatic HCC cells. Mechanically, LOs-delivered VAPA integrates to plasma membrane of osteoclasts and directly interacts with and activates neural Wiskott-Aldrich syndrome protein (N-WASP) via dual mechanisms, consequently resulting in ARP2/3 complex-mediated reorganization of actin cytoskeleton in osteoclasts and osteoclastogenesis. Importantly, treatment with N-WASP inhibitor 187-1-packaged LOs (LOs/187-1) dramatically abolishes the inductive effect of VAPA-enriched LOs on pre-metastatic niche formation and precludes HCC bone metastasis. These findings reveal a plausible mechanism for bone-tropism of HCC and can represent a potential strategy to prevent HCC bone metastasis.


Asunto(s)
Neoplasias Óseas , Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Osteoclastos/metabolismo , Osteoclastos/patología , Proteína Estafilocócica A , Transducción de Señal , Microambiente Tumoral
4.
Nat Commun ; 13(1): 5644, 2022 09 26.
Artículo en Inglés | MEDLINE | ID: mdl-36163134

RESUMEN

Indoleamine 2,3 dioxygenase 1 (IDO1) is an attractive target for cancer immunotherapy. However, IDO1 inhibitors have shown disappointing therapeutic efficacy in clinical trials, mainly because of the activation of the aryl hydrocarbon receptor (AhR). Here, we show a post-transcriptional regulatory mechanism of IDO1 regulated by a proteasome-associated deubiquitinating enzyme, USP14, in colorectal cancer (CRC). Overexpression of USP14 promotes tryptophan metabolism and T-cell dysfunction by stabilizing the IDO1 protein. Knockdown of USP14 or pharmacological targeting of USP14 decreases IDO1 expression, reverses suppression of cytotoxic T cells, and increases responsiveness to anti-PD-1 in a MC38 syngeneic mouse model. Importantly, suppression of USP14 has no effects on AhR activation induced by the IDO1 inhibitor. These findings highlight a relevant role of USP14 in post-translational regulation of IDO1 and in the suppression of antitumor immunity, suggesting that inhibition of USP14 may represent a promising strategy for CRC immunotherapy.


Asunto(s)
Neoplasias Colorrectales , Receptores de Hidrocarburo de Aril , Animales , Neoplasias Colorrectales/genética , Enzimas Desubicuitinizantes , Indolamina-Pirrol 2,3,-Dioxigenasa , Ratones , Complejo de la Endopetidasa Proteasomal , Receptores de Hidrocarburo de Aril/genética , Receptores de Hidrocarburo de Aril/metabolismo , Triptófano/metabolismo , Ubiquitina Tiolesterasa
5.
Cancer Res ; 81(14): 3835-3848, 2021 07 15.
Artículo en Inglés | MEDLINE | ID: mdl-34049973

RESUMEN

Mitochondrial dynamics play vital roles in the tumorigenicity and malignancy of various types of cancers by promoting the tumor-initiating potential of cancer cells, suggesting that targeting crucial factors that drive mitochondrial dynamics may lead to promising anticancer therapies. In the current study, we report that overexpression of mitochondrial fission factor (MFF), which is upregulated significantly in liver cancer-initiating cells (LCIC), promotes mitochondrial fission and enhances stemness and tumor-initiating capability in non-LCICs. MFF-induced mitochondrial fission evoked mitophagy and asymmetric stem cell division and promoted a metabolic shift from oxidative phosphorylation to glycolysis that decreased mitochondrial reactive oxygen species (ROS) production, which prevented ROS-mediated degradation of the pluripotency transcription factor OCT4. CRISPR affinity purification in situ of regulatory elements showed that T-box transcription factor 19 (TBX19), which is overexpressed uniquely in LCICs compared with non-LCICs and liver progenitor cells, forms a complex with PRMT1 on the MFF promoter in LCICs, eliciting epigenetic histone H4R3me2a/H3K9ac-mediated transactivation of MFF. Targeting PRMT1 using furamidine, a selective pharmacologic inhibitor, suppressed TBX19-induced mitochondrial fission, leading to a profound loss of self-renewal potential and tumor-initiating capacity of LCICs. These findings unveil a novel mechanism underlying mitochondrial fission-mediated cancer stemness and suggest that regulation of mitochondrial fission via inhibition of PRMT1 may be an attractive therapeutic option for liver cancer treatment. SIGNIFICANCE: These findings show that TBX19/PRMT1 complex-mediated upregulation of MFF promotes mitochondrial fission and tumor-initiating capacity in liver cancer cells, identifying PRMT1 as a viable therapeutic target in liver cancer.


Asunto(s)
Carcinógenos/metabolismo , Transformación Celular Neoplásica/genética , Epigenómica/métodos , Neoplasias Hepáticas/genética , Dinámicas Mitocondriales/genética , Humanos
6.
Adv Sci (Weinh) ; 8(4): 2001961, 2021 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-33643786

RESUMEN

The incidence of bone metastases in hepatocellular carcinoma (HCC) has increased prominently over the past decade owing to the prolonged overall survival of HCC patients. However, the mechanisms underlying HCC bone-metastasis remain largely unknown. In the current study, HCC-secreted lectin galactoside-binding soluble 3 (LGALS3) is found to be significantly upregulated and correlates with shorter bone-metastasis-free survival of HCC patients. Overexpression of LGALS3 enhances the metastatic capability of HCC cells to bone and induces skeletal-related events by forming a bone pre-metastatic niche via promoting osteoclast fusion and podosome formation. Mechanically, ubiquitin ligaseRNF219-meidated α-catenin degradation prompts YAP1/ß-catenin complex-dependent epigenetic modifications of LGALS3 promoter, resulting in LGALS3 upregulation and metastatic bone diseases. Importantly, treatment with verteporfin, a clinical drug for macular degeneration, decreases LGALS3 expression and effectively inhibits skeletal complications of HCC. These findings unveil a plausible role for HCC-secreted LGALS3 in pre-metastatic niche and can suggest a promising strategy for clinical intervention in HCC bone-metastasis.

7.
Nat Commun ; 10(1): 3761, 2019 08 21.
Artículo en Inglés | MEDLINE | ID: mdl-31434880

RESUMEN

The mechanisms underlying how cells subjected to genotoxic stress reestablish reduction-oxidation (redox) homeostasis to scavenge genotoxic stress-induced reactive oxygen species (ROS), which maintains the physiological function of cellular processes and cell survival, remain unclear. Herein, we report that, via a TCF-independent mechanism, genotoxic stress induces the enrichment of ß-catenin in chromatin, where it forms a complex with ATM phosphorylated-JDP2 and PRMT5. This elicits histone H3R2me1/H3R2me2s-induced transcriptional activation by the recruitment of the WDR5/MLL methyltransferase complexes and concomitant H3K4 methylation at the promoters of multiple genes in GSH-metabolic cascade. Treatment with OICR-9429, a small-molecule antagonist of the WDR5-MLL interaction, inhibits the ß-catenin/JDP2/PRMT5 complex-reestablished GSH metabolism, leading to a lethal increase in the already-elevated levels of ROS in the genotoxic-agent treated cancer cells. Therefore, our results unveil a plausible role for ß-catenin in reestablishing redox homeostasis upon genotoxic stress and shed light on the mechanisms of inducible chemotherapy resistance in cancer.


Asunto(s)
Daño del ADN/fisiología , Glutatión/metabolismo , Proteína-Arginina N-Metiltransferasas/metabolismo , Proteínas Represoras/metabolismo , beta Catenina/metabolismo , Células A549 , Animales , Compuestos de Bifenilo/farmacología , Línea Celular Tumoral , Cromatina , Dihidropiridinas/farmacología , Femenino , Glutatión/efectos de los fármacos , N-Metiltransferasa de Histona-Lisina/metabolismo , Histonas/metabolismo , Homeostasis , Humanos , Ratones , Ratones Endogámicos NOD , Ratones SCID , Proteína de la Leucemia Mieloide-Linfoide/metabolismo , Neoplasias/metabolismo , Regiones Promotoras Genéticas , Dominios y Motivos de Interacción de Proteínas/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Activación Transcripcional
8.
Zhongguo Dang Dai Er Ke Za Zhi ; 10(2): 173-8, 2008 Apr.
Artículo en Zh | MEDLINE | ID: mdl-18433541

RESUMEN

OBJECTIVE: To investigate the effects of astragalus on tubulointerstitial lesions in rats with IgA nephropathy (IgAN) and to explore the possible mechanism. METHODS: Twenty-eight Sprague-Dawley rats were randomly assigned to three groups. The rat model of IgA nephropathy was induced by intragastric administration of bovine serum albumin and injections of LPS and CC14. Six weeks later, the rats with IgAN were randomly treated with oral astragalus (3 g/kg/d, for 6 weeks) or normal saline. Normal control rats which were not subjected to IgAN were treated with normal saline. The number of urinary erythrocytes and urinary protein and B-D-N-Acetyl glucosaminidase (NAG) contents were determined by Pan-automatic biochemistry analyzing meter. Expression of monocyte chemotactic protein-1 (MCP-1) and nuclear factor-kappa B (NF-kappaB) in tubulointerstitial tissues were analyzed by immunohistochemistry. A semiquantitative score was used to evaluate the degree of renal pathologic lesions. RESULTS: The number of urinary erythrocytes (74.02+/-16.58 / microL vs 383.23+/-4.94 /microL) and urinary protein (13.88+/-4.94 vs 59.82+/-14.73 mg/L) and NAG contents (2.84+/-0.31 vs 5.24+/-0.80 U/L) in the astragalus-treated IgAN rats decreased remarkably compared with those in the IgAN rats without astragalus treatment (P<0.01). Expression of the NF-kappaB and MCP-1 in the renal tissues in the IgAN rats without astragalus treatment was significantly higher than that in the astragalus-treated IgAN rats and normal control rats (P<0.01). There were significant differences in the scores of renal pathologic lesions between the IgAN rats with or without astragalus treatment (6.03+/-0.46 vs 10.57+/-1.23; P<0.01). CONCLUSIONS: Astragalus can decrease the number of urinary erythrocytes and urinary protein and NAG contents, and relieves tubulointerstitial lesions, possibly through the down-regulation of NF-kappaB and MCP-1 expression in rats with IgAN.


Asunto(s)
Planta del Astrágalo , Quimiocina CCL2/análisis , Glomerulonefritis por IGA/tratamiento farmacológico , Túbulos Renales/patología , Factor de Transcripción ReIA/análisis , Animales , Glomerulonefritis por IGA/metabolismo , Glomerulonefritis por IGA/patología , Inmunohistoquímica , Ratas , Ratas Sprague-Dawley
9.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 32(1): 82-7, 2007 Feb.
Artículo en Zh | MEDLINE | ID: mdl-17344593

RESUMEN

OBJECTIVE: To explore the effect and possible mechanism of catechin microcapsulation on the repair of DNA damage in glumreular mesangial cells (GMCs) induced by H2O2. METHODS: According to H2O2 concentration, the experiment GMCs were divided into 6 groups: a control group, 50 micromol/L group, 100 micromol/L group, 150 micromol/L group, 200 micromol/L group and 250 micromol/L group. Each group was sub-divided into 3 groups: 6 h group, 12 h group and 24 h group, in order to determining the optimum dose and the best time of detecting the DNA damage in GMCs. The cultured cells were divided into 8 groups as follows: the NS control group, the H2O2 group, the catechin groups (the final concentrations were 10.0, 15.0, and 20.0 mg/L respectively) and the various catechin microcapsulation groups (the final concentrations were 10.0, 15.0, and 20.0 mg/L respectively). At the end of the experiment, hydroxy radical (OH), malonydialdehyde (MDA) and total superoxide dismutase (tSOD) concentration of supernadant in GMCs were determined by biochemistry assay, the repair of DNA damage in GMCs were detected by single cell gel electrophoresis assay. RESULTS: (1)At 6th h, H2O2 of 100 micromoL/L could cause the DNA damage of GMCs, and H2O2 of 150 micromol/L could result in DNA damage significantly. (2) No difference was found in the comet span of GMCs DNA in the catechin group and catechin microcapsulation group of different concentrations, while the DNA comet tail-long in the catechin microcapsulation group was shorter than that of the catechin group(all P(s)<0.05), and the fluorescence intensity of tail in the catechin microcapsulation group was lower than that of the catechin group(all P(s)<0.01). (3)When the concentration of catechin was 10.0 mg/L, no statistical significance was obtained in the concentration of dOH-, MDA and tSOD between the catechin microcapsulation group and the catechin group; while dOH- and MDA concentrations were lower, and the tSOD was higher in the catechin microcapsulation group than that in the catechin group when the concentration of catechin was 15.0 mg/L and 20.0 mg/L(all P(s)<0.05). CONCLUSION: Catechin microcapsulation can enhance the GMCs ability of repairing DNA damage,which may be due to elevating the capacity of its anti-oxidation by catechin microcapsulation.


Asunto(s)
Catequina/farmacología , Daño del ADN/efectos de los fármacos , Reparación del ADN/efectos de los fármacos , Peróxido de Hidrógeno/toxicidad , Células Mesangiales/efectos de los fármacos , Animales , Cápsulas , Células Cultivadas , Ensayo Cometa , Relación Dosis-Respuesta a Droga , Radical Hidroxilo/metabolismo , Malondialdehído/metabolismo , Células Mesangiales/metabolismo , Células Mesangiales/patología , Ratas , Superóxido Dismutasa/metabolismo
10.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 32(1): 174-8, 2007 Feb.
Artículo en Zh | MEDLINE | ID: mdl-17344613

RESUMEN

OBJECTIVE: To evaluate the clinical and pathological features of 94 children suffering from IgA nephropathy (IgAN) while estimating the prevalent situation in Hunan province. METHODS: To summarize the annual number of hospitalized children, those with kidney diseases, those accepted biopsy, and those confirmed as IgAN in both Xiangya Hospital and Second Xiangya Hospital undertaking kidney biopsy in Hunan province during 1995 and 2004. RESULTS: In the past 10 years, as the hospitalized population in both hospitals accrued to 9.98% each year. The rate of 7.5% was seen in those with kidney diseases. Among whom 56.3% accepted kidney biopsy and 94 of them were confirmed as IgAN. Hematuria was the main clinical presentation, seen in 71 cases, accounting to 76%, and even to 98% after excluding those with nephrotic syndrome and isolating proteinuria type of IgAN. Inflammation infiltration (91%), renal tubule degeneration (81%), and renal interstitial fibrosis (31%) were the major pathological features of 94 children, especially in nephrotic syndrome IgAN. CONCLUSION: The number of children with IgAN synchronously accrues as hospitalized population, those with kidney diseases, and those by kidney biopsy. Hematuria is the major symptom. To routinely perform urine analysis and kidney biopsy in asymptomatic hematuria may improve the diagnosis. Inflammation infiltration, renal tubule degeneration, and renal interstitial fibrosis are the major pathological features in IgAN children, especially in nephrotic syndrome IgAN, probably relating to continuous proteinuria. Early control of proteinuria may delay or decrease renal tubule fibrosis.


Asunto(s)
Glomerulonefritis por IGA/patología , Riñón/patología , Adolescente , Biopsia con Aguja , Niño , Preescolar , China/epidemiología , Femenino , Glomerulonefritis por IGA/complicaciones , Glomerulonefritis por IGA/epidemiología , Hematuria/diagnóstico , Hematuria/etiología , Hospitalización/estadística & datos numéricos , Humanos , Masculino
11.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 32(6): 938-40, 2007 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-18182707

RESUMEN

OBJECTIVE: To investigate the efficacy and adverse effect of mycophenolate mofetil (MMF) in the treatment of frequently relapsing nephrotic syndrome in children. METHODS: The study population consisted of 37 children (24 simple nephrotic syndrome and 13 nephritis-type syndrome) suffering from frequently relapsing nephrotic syndrome. Patients received 20-30 mg/(kg d) of MMF in conjunction with 1 mg/(kg d) prednisone for 3-6 months. RESULTS: Out of 24 patients suffered from simple nephrotic syndrome, 17 patients (70.8%) with complete relief, 4 patients (16.7%) with partial relief and 3 patients (12.5%) with non-relief, whereas out of 13 patients suffered from nephritis-type syndrome 6 patients (46.2%) with complete relief, 3 patients (23.1%) with partial relief and 4 patients (30.7%) with non-relief. Eight patients with Minimal Change Disease (MCD) achieved complete relief. Of 23 patients with Mesangial Proliferative Glomerulonephritis (MsPGN) or Membranoproliferative Glomerulonephritis (MPGN), complete relief was observed in 17 patients (73.9%), partial relief in 4 patients (17.4%) and non-relief in 2 patients. CONCLUSION: These Results suggest that MMF has better efficacy against simple renal disease than against nephritis-type syndrome, and MMF may be more suitable for the treatment of frequently relapsing nephrotic syndrome characterized by proliferative lesions.


Asunto(s)
Ácido Micofenólico/análogos & derivados , Síndrome Nefrótico/tratamiento farmacológico , Adolescente , Niño , Preescolar , Femenino , Humanos , Inmunosupresores/efectos adversos , Inmunosupresores/uso terapéutico , Masculino , Ácido Micofenólico/efectos adversos , Ácido Micofenólico/uso terapéutico , Recurrencia , Resultado del Tratamiento
12.
Zhongguo Dang Dai Er Ke Za Zhi ; 9(2): 117-21, 2007 Apr.
Artículo en Zh | MEDLINE | ID: mdl-17448305

RESUMEN

OBJECTIVE: To investigate the clinicopathologic characteristics of childhood renal diseases. METHODS: A retrospective analysis of 1316 renal biopsies performed over the past 20 years was performed. RESULTS: Of the 1316 patients, 383 (29.09% ) were diagnosed as nephrotic syndrome, 291 (22.00%) as acute nephritis syndrome, 224 (17.21%) as isolated hematuria, 209(15.87%) as purpura nephritis, and 96 (7.30% ) as hepatitis B virus-associated nephritis . Mesangial proliferation was the most common pathological change (756 cases; 57.45%), followed by IgA nephropathy (113 cases; 8.59%), endothelial capillary proliferation(112 cases; 8.51%), membranous nephropathy (66 cases; 5.02%), and various minor and minimal changes (59 cases; 4.48%). Alport syndrome, congenital nephrotic syndrome, thin basement membrane nephropathy, fibrillary glomerulopathy disease, and Fabry disease were confirmed by electronic microscopy. IgA, IgM and C1q nephropathy were definitely diagnosed using immune histochemistry or immunofluorescent. A diagnosis of primary glomerular disease was made in 69.53% of the cases (915 cases); secondary glomerular disease was noted in 26.14% (344 cases). Of the 915 cases of primary glomerular disease, 375 (41.0%) had nephrotic syndrome. Secondary glomerular disease due to purura nephritis was common (209/344; 60.8%). CONCLUSIONS: Primiary glomerular disease predominates in children. Nephrotic syndrome is the most common clinical diagnosis. Mesangial proliferation is the most common pathological patterns in children with renal disease.


Asunto(s)
Enfermedades Renales/patología , Riñón/patología , Adolescente , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Glomérulos Renales/patología , Masculino , Insuficiencia Renal/patología , Estudios Retrospectivos
13.
Zhongguo Dang Dai Er Ke Za Zhi ; 9(2): 125-8, 2007 Apr.
Artículo en Zh | MEDLINE | ID: mdl-17448307

RESUMEN

OBJECTIVE: To investigate the role of mast cells in the development of renal interstitial fibrosis in children with Henoch-Schonlein purpura nephritis (HSPN) and possible mechanisms. METHODS: Paraffin-embedded renal biopsy tissue sections from 20 children with HSPN were examined for the levels of tryptase-beta and transforming growth factor-beta1 (TGF-beta1) by immunohistochemical staining. Mast cells were counted by toluidine blue staining. Masson staining was used to assess the level of renal interstitial fibrosis and renal histopathological scores. Normal renal tissue sections from 5 nephrectomized children for nephroma were used as control group. RESULTS: The percentages of positive tryptase-beta cellsand mast cells and the TGF-beta1 expression in the HSPN group were significantly higher than those in the control group (P < 0.05). The percentages of positive tryptase-beta cells and mast cells and the TGF-beta1 expression in renal tissue were positively correlated with the glomeruli histopathological score (r =0.940, 0.920, 0.937, respectively; P < 0.05) and were also positively correlated with the histopathological score of renal interstitium (r=0.903, 0.859, 0.948, respectively; P < 0.05). The level of renal interstitial fibrosis was positively correlated with the percentages of positive tryptase-beta cells and mast cells and the expression of TGF-beta1 (r =0.790, 0.766, 0.858, respectively; P < 0.05). There was a positive correlation between the percentages of positive tryptase-beta cells and mast cells (r =0.941, P < 0.05), between the percentage of positive tryptase-beta cells and the TGF-beta1 expression (r =0.897, P < 0.05) and between the percentage of positive mast cells and the TGF-beta1 expression (r=0.942, P < 0.05). CONCLUSIONS: Tubulointerstitial mast cell infiltration is associated with the development of renal interstitial fibrosis in children with HSPN. Mast cells together with TGF-beta1 and mast cell-derived tryptase-beta may be involved in the development of the renal interstitial fibrosis in HSPN.


Asunto(s)
Vasculitis por IgA/patología , Riñón/patología , Mastocitos/fisiología , Nefritis/patología , Adolescente , Niño , Femenino , Fibrosis , Humanos , Vasculitis por IgA/metabolismo , Riñón/química , Masculino , Factor de Crecimiento Transformador beta1/análisis , Triptasas/análisis
14.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 31(1): 138-40, 2006 Feb.
Artículo en Zh | MEDLINE | ID: mdl-16562696

RESUMEN

OBJECTIVE: To investigate the eliminating ability of catechin to eliminate O2-* and *OH. METHODS: The ability of catechin to clear away O2-* and *OH was respectively measured by faintness chemiluminescence and spin trapping assay. RESULTS: IC50 that catechin eliminated O2-* and *OH was 6.16, 0.59 g/mL respectively, and the eliminating ability of catechin was much stronger than that of the extract from liquorice, rosemary, grape pip, giant knotweed and ginkgo leaf. CONCLUSION: Compared with several important natural plants of antioxidants, the eliminating ability of cathechin is the best.


Asunto(s)
Catequina/farmacología , Depuradores de Radicales Libres/farmacología , Antioxidantes/farmacología , Radical Hidroxilo/metabolismo , Mediciones Luminiscentes , Superóxidos/metabolismo
15.
Zhongguo Dang Dai Er Ke Za Zhi ; 8(4): 275-8, 2006 Aug.
Artículo en Zh | MEDLINE | ID: mdl-16923355

RESUMEN

OBJECTIVE: To investigate the pathological changes of liver in children with hepatitis B virus associated glomerulonephritis (HBV-GN). METHODS: Thirteen children with HBV-GN (aged from 2-14 years) underwent renal and liver biopsy. The biopsy findings were analyzed. RESULTS: Different degrees of hepatic lesions were seen in all of the 13 patients, mild lesions accounting for 69.2% (9/13). HBSAg positive was the most common in the liver tissue [76.9% (10/13)]. Among the renal lesions, membranous glomerulopathy accounted for 69.2%( 9/13), followed by membranoproliferative glomerulonephritis 30.8% (4/13). HBsAg and HBcAg positive were presented in all patients' kidney tissues. HBV antigens were detected in stroma between nephric tubule in all samples. Four patients presented with HBcAg positive in both live and kidneys. CONCLUSIONS: The children with HBV-GN couple with liver lesions. The severity of the renal lesions is not always accord with that of the liver lesions. The appearance of HBcAg in both kidneys and liver indicates severe lesions of the two organs. It is suggested that a liver-kidney holistic treatment is necessary for children with HBV-GN.


Asunto(s)
Glomerulonefritis/patología , Hepatitis B/complicaciones , Hígado/patología , Adolescente , Niño , Preescolar , Femenino , Hepatitis B/patología , Antígenos del Núcleo de la Hepatitis B/análisis , Humanos , Riñón/patología , Masculino
17.
Zhong Nan Da Xue Xue Bao Yi Xue Ban ; 30(5): 597-600, 2005 Oct.
Artículo en Zh | MEDLINE | ID: mdl-16320598

RESUMEN

OBJECTIVE: To investigate the difference of Pax2 and P53 expressions in children with primary nephritic syndrome (PNS) and the effect of Pax2 on glucocorsteroid (GC)-resistance. METHODS: Renal Pax2 and P53 expressions in children with PNS (40 patients) were detected by immunohistochemistry. A semiquantitative score was used to evaluate the injury degree of the glomeruli and the tubulointerstitium, and correlation analysis was done among Pax2, P53 and pathologic score. RESULTS: Pax2 and P53 expressions were not found in the control group. Pax2 expression of renal tubule epithelia exsisted in children with PNS and there was weak or no expression of Pax2 in the podocytes. Pax2 expressions in the proximal tubule and the distal tubule in the GC-resistant group were more intense than those in the GC-intensive group (P <0.01). The more the Pax2 expression in the tubule, the more abnormal structure such as dilation and atrophy. Pax2 expression in the tubule epithelia was positively correlated with pathologic score of tubulointerstitium (P < 0.01). There was no P53 expression in the GC-intensive group, but there exsisted P53 expression in parts of the patients from the GC-resistant group, mainly distributing in the renal tubular epithelia. P53 expression was positively correlated with P53 expression and the pathologic score of tubulointerstitium (P < 0.01). CONCLUSION: Over-expression of Pax2 in the renal tubule epithelia may improve P53 expression to a certain degree, which may aggravate the lesion of the renal tubule. It may be one of the mechanisms resulting in GC-resistant in children with PNS.


Asunto(s)
Resistencia a Medicamentos , Glucocorticoides/uso terapéutico , Síndrome Nefrótico/tratamiento farmacológico , Síndrome Nefrótico/metabolismo , Factor de Transcripción PAX2/biosíntesis , Adolescente , Niño , Preescolar , Femenino , Humanos , Masculino , Factor de Transcripción PAX2/genética , Proteína p53 Supresora de Tumor/biosíntesis , Proteína p53 Supresora de Tumor/genética
18.
World J Pediatr ; 8(2): 156-63, 2012 May.
Artículo en Inglés | MEDLINE | ID: mdl-22573426

RESUMEN

BACKGROUND: The subcapsular transplantation of metanephric mesenchymal cells (MMCs) may be a new therapeutic approach for the treatment of acute tubular necrosis (ATN). To investigate this hypothesis and provide evidence for its possible use in the clinic, we evaluated the nephroprotective effects of transplanting MMCs into the renal subcaspsule of rats with ATN induced by gentamicin. METHODS: MMCs were expanded in culture. After gentamicin-induced ATN was established, fluorescently-labeled cells were transplanted and traced in kidney tissues by fluorescence microscopy. Serum creatinine (Cr), urea nitrogen (BUN), and N-acetyl-b-D-glucosaminidase (NAG) levels were determined at different time points. Kidney pathology was studied by hematoxylin-eosin staining. Apoptosis was examined by the TUNEL assay. RESULTS: In the MMCs-treated group, the mortality rate decreased; BUN, Cr, and NAG levels peaked at 8 days, and were significantly lower than those in the other groups at 11 and 14 days. RIMM-18 cells locally recruited through precise tropism to sites of injury had the ability to migrate into the tubuli from the renal subcapsule. Damage to the cell-treated kidneys was reduced. The pathologic lesion scores of tubular damage reached the highest values at 8 days in the treated kidneys and 11 days in the untreated ones. The apoptotic index showed that the peaks of apoptosis occurred at earlier stages of the injury process in cell-treated than in untreated kidney and thereafter declined in a time-dependent manner. CONCLUSION: The subcapsular transplantation of MMCs could ameliorate renal function and repair kidney injury.


Asunto(s)
Necrosis Tubular Aguda/cirugía , Trasplante de Células Madre Mesenquimatosas , Animales , Femenino , Gentamicinas/administración & dosificación , Riñón/citología , Necrosis Tubular Aguda/inducido químicamente , Ratas , Ratas Sprague-Dawley
19.
Zhonghua Er Ke Za Zhi ; 46(1): 55-60, 2008 Jan.
Artículo en Zh | MEDLINE | ID: mdl-18353241

RESUMEN

OBJECTIVE: To study the regulattory effect of Astragalus membranaceus on immune disturbance of the rats with IgA nephropathy. METHODS: Rats IgA nephropathy (IgAN) model was duplicated by oral feeding of bovine serum albumin (BSA), subcutaneous injection of carbon tetrachloride (CCl4) and injection of lipopolysaccharide (LSP) into vena caudalis. The rats were divided into three groups randomly for the normal, IgAN model group and the group treated with Astragalus membranaceus (treatment group). The treatment group was given the Astragalus membranaceus granules via intragastric administratsion, the normal group and the IgAN model group were given the equal amount of aqua destillata by gastric perfusion. The rats were examined for albuminuria, hematuria and pathological changes of renal tissue and the distribution of TGF-beta and interleukin-5 in renal tissue was determined by immunohistochemistry and the IFN-gamma and IL-4 of cytokine of Th1 and Th2 types were detected in rats IgA nephropathy model by sandwich enzyme linked immunosorbent assay (ELISA). RESULTS: (1) The hematuria in rats with IgA nephropathy significantly increased compared with normal control group and Astragalus treatment group (P < 0.05). There was significant increase in albuminuria in rats with IgA nephropathy, compared with normal control group and astragalus treatment group (P < 0.01). (2) The pathological change of glomerular mesangium, renal tubules and renal interstitia became serious in rats IgA nephropathy model when compared with normal control group and astragalus treatment group. Immumofluorescence showed renal IgA density in rats IgA nephropathy model was significantly higher than that in the normal control group (P < 0.001) and astragalus treatment group (P < 0.001). (3) The result of immuno histochemistry showed that there was only weak expression of TGF-beta and interleukin 5 in normal renal tissue. The expression of TGF-beta and interleukin 5 in IgA nephropathy model was significantly stronger than those in normal control group (P < 0.05) and astragalus treatment group (P < 0.05). (4) The serum IL-4 levels were (33.74 +/- 7.52) pg/ml in rats IgA nephropathy model, significantly higher than that in normal control group (2.36 +/- 0.85) pg/ml and astragalus treatment group (3.24 +/- 1.13) pg/ml. The IFN-gamma level in serum of rats IgA nephropathy model was (18.79 +/- 3.80) pg/ml, which was significantly higher than that in normal control group (46.53 +/- 5.56) pg/ml and astragalus treatment group (41.28 +/- 2.95) pg/ml. CONCLUSIONS: The astragalus could lower the level of hematuria and 24 hours-albuminuria of the IgAN model, and amelioratse the change of the renal pathology and reduce the deposit of IgA in glomerular mesangium. The possible mechanism of the effect is that astragalus could regulate the derangement of Th1, Th2, accordingly could improve the level of IL-4 and IFN-gamma in the serum and diminish the expression of cytokine Th2 TGF-beta1 and IL-5 of the renal tissue, and thereby could postpone the development of IgAN.


Asunto(s)
Astragalus propinquus/química , Astragalus propinquus/inmunología , Medicamentos Herbarios Chinos/farmacología , Glomerulonefritis por IGA/inmunología , Factor de Crecimiento Transformador beta1/farmacología , Animales , Bovinos , Interleucina-4/farmacología , Interleucina-5/farmacología , Túbulos Renales/efectos de los fármacos , Ratas , Factor de Crecimiento Transformador beta/inmunología
20.
Zhonghua Er Ke Za Zhi ; 45(7): 494-7, 2007 Jul.
Artículo en Zh | MEDLINE | ID: mdl-17953803

RESUMEN

OBJECTIVE: To investigate fibronectin synthesis in SD rat mesangial cells after transforming growth factor-beta1 (TGF-beta1) is silenced by the short interfering RNA (siRNA) expressed by reconstructed pGEFP-C1 vectors. METHODS: Depending upon the 538th - 556th (A) and 895th - 913th (B) nucleotides of rat TGF-beta1 gene, a nucleotide (A or B) was constructed into a small hairpin nucleotide which was separately (A or B) or together (A plus B) inserted into a pGEFP-C1 vector with three reconstructed pGEFP-C1 vectors separately expressing the siRNAs for A or/and B. TGF-beta1 and fibronectin were dynamically investigated for their interrelationship by ELISA in the supernatant and RT-PCR in their extracted total RNA. RESULTS: The siRNA hairpin-like molecules were constructed according to the 538th - 556th nucleotides of rat TGF-beta1 gene were able to markedly silence the expression of TGF-beta1 mRNA (P < 0.01) and protein (P < 0.01) at 48 h. Lipfectamin 2000 transfection stimulated the peak secretion of fibronectin at 24 h in the control and the experimental group whose TGF-beta1 was not silenced, but the silence of TGF-beta1 in both experimental groups delayed the top values of fibronectin to 48 h (P < 0.01). CONCLUSION: The silence of TGF-beta1 by siRNA decreased the fibronectin expression, but the latter was possibly not completely TGF-dependent.


Asunto(s)
Fibronectinas/metabolismo , Células Mesangiales/efectos de los fármacos , Interferencia de ARN/efectos de los fármacos , ARN Interferente Pequeño/farmacología , Factor de Crecimiento Transformador beta1/genética , Animales , Células , Células Cultivadas , Células Mesangiales/metabolismo , Interferencia de ARN/fisiología , ARN Mensajero/metabolismo , Ratas , Ratas Sprague-Dawley , Factor de Crecimiento Transformador beta1/química
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