RESUMO
BACKGROUND: The association between homocysteine (Hcy) and IgA nephropathy (IgAN) is not well understood. We aimed to investigate the relationship between Hcy and clinicopathologic features in IgAN patients. METHODS: A total of 337 IgAN patients and 150 sex- and age- matched healthy controls were enrolled in this single-center retrospective study. According to Hcy ≤ 10 µmol/L or > 10 µmol/L, patients were divided into low and high Hcy groups. Multivariate logistic regression was performed to explore the risk factors for elevated Hcy. RESULTS: Serum Hcy was higher in IgAN patients than in healthy controls [11.6 (9.1,15.3) vs. 8.8 (7.5,10.6) µmol/L, P < 0.001], unanimously in the subgroup of 156 patients with a normal estimated glomerular filtration rate (eGFR) (≥ 90 ml/min/1.73 m2) [9.9 (7.6,12.4) vs. 8.8 (7.5,10.6) µmol/L, P < 0.001]. Compared to the low Hcy group, serum creatinine (Scr), blood urine nitrogen (BUN), uric acid (UA), endocapillary hypercellularity (E) and tubular atrophy/interstitial fibrosis lesion (T) were higher in the high Hcy group. Hcy levels were positively correlated with Scr, BUN, UA, 24-h urine protein, and E and T lesions, but negatively correlated with eGFR and superoxide dismutase (SOD). In the subgroup with normal eGFR, patients with higher Hcy were persistent with higher Scr, BUN and T lesions. A multivariate logistic regression model showed that the risk of elevated Hcy in patients with pathological T increased by 2.87-fold. T lesions could better predict high Hcy, with an odds ratio (OR) of 14.20 in the subgroup with normal eGFR. CONCLUSIONS: Pathologic T was an independent risk factor associated with elevated Hcy, especially at the early stage of IgAN.
Assuntos
Glomerulonefrite por IGA/sangue , Glomerulonefrite por IGA/patologia , Homocisteína/sangue , Túbulos Renais/patologia , Adulto , Feminino , Glomerulonefrite por IGA/diagnóstico , Humanos , Masculino , Estudos RetrospectivosRESUMO
The TGFß (transforming growth factor ß)/SMAD and NF-κB (nuclear factor κB) signalling pathways play a key role in hypertensive nephropathy. The present study examined whether targeting these pathways by SMAD7, a downstream inhibitor of both pathways, blocks AngII (angiotensin II)-induced hypertensive kidney disease in mice. A doxycycline-inducible SMAD7-expressing plasmid was delivered into the kidney by a non-invasive ultrasound-microbubble technique before and after AngII infusion. Results showed that pre-treatment with SMAD7 prevented AngII-induced progressive renal injury by inhibiting an increase in proteinuria and serum creatinine while improving the glomerular filtration rate. Similarly, treatment with SMAD7 in the established hypertensive nephropathy at day 14 after AngII infusion halted the progressive renal injury. These preventive and therapeutic effects of SMAD7 on hypertensive kidney injury were associated with inhibition of AngII-induced up-regulation of SMURF2 (SMAD-specific E3 ubiquitin protein ligase 2) and Sp1 (specificity protein 1), blockade of TGFß/Smad3-mediated renal fibrosis and suppression of NF-κB-driven renal inflammation. Moreover, overexpression of SMAD7 also prevented AngII-induced loss of renal miR-29b, an miRNA with an inhibitory role in both TGFß/Smad3 and NF-κB pathways. In conclusion, SMAD7 may be a therapeutic agent for AngII-mediated hypertensive nephropathy. Inhibition of the Sp1/SMAD3/NF-κB/miR-29b regulatory network may be a mechanism by which SMAD7 inhibits hypertensive nephropathy.
Assuntos
Hipertensão Renal/terapia , Nefrite/terapia , Proteína Smad7/genética , Angiotensina II , Animais , Modelos Animais de Doenças , Técnicas de Transferência de Genes , Terapia Genética , Hipertensão Renal/induzido quimicamente , Hipertensão Renal/genética , Imuno-Histoquímica , Interleucina-1beta/metabolismo , Rim/efeitos dos fármacos , Rim/patologia , Nefropatias/induzido quimicamente , Nefropatias/patologia , Nefropatias/prevenção & controle , Macrófagos/patologia , Masculino , Camundongos , Camundongos Endogâmicos , NF-kappa B/metabolismo , Nefrite/induzido quimicamente , Nefrite/genética , Reação em Cadeia da Polimerase em Tempo Real , Transdução de Sinais , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Monocyte chemoattractant protein-1 (MCP-1) and its receptor CC chemokine receptor 2 (CCR2) play a major role in inflammation and proliferation of cancers. We investigated a possible association between polymorphisms in MCP-1 and CCR2 genes (MCP-1 -2518A/G and CCR2 190G/A or V64I) and the risk as well as prognosis of renal cell carcinoma (RCC). Genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism in 416 RCC cases and 458 age-matched healthy controls. Frequency of MCP-1 2518GG genotype for cases and controls was 0.384 and 0.286, respectively; individuals carrying the GG genotype had a 1.89-fold increased risk of RCC than those with AA genotype (95 % confidence interval [CI] 1.24-2.81, p = 0.002; data were adjusted for age and sex). Frequency of CCR2 190AA (64I/64I) genotype for cases and controls was 0.175 and 0.076, respectively; subjects having AA genotype had a 2.68-fold increased risk of RCC compared to those with the wild-type GG genotype (95 %CI 1.71-4.17, p = 4.3 × 10(-6); data were adjusted for age and sex). When analyzing the survival rate of RCC, patients with MCP-1 -2518GG genotype revealed significantly shorter survival time compared to cases with MCP-1 -2518AA and AG genotypes (p = 0.003). Similarly, RCC cases carrying CCR2 190AA genotype showed significantly shorter survival rate than patients with GG or GA genotypes (p < 0.001). These data suggested that MCP-1 -2518A/G and CCR2 190G/A polymorphisms are new risk factors for RCC and could be used as prognostic markers for this malignancy.
Assuntos
Carcinoma de Células Renais/genética , Quimiocina CCL2/genética , Neoplasias Renais/genética , Polimorfismo de Nucleotídeo Único , Receptores CCR2/genética , Idoso , Substituição de Aminoácidos , Carcinoma de Células Renais/mortalidade , Carcinoma de Células Renais/secundário , Estudos de Casos e Controles , Feminino , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Estimativa de Kaplan-Meier , Neoplasias Renais/mortalidade , Neoplasias Renais/patologia , Masculino , Pessoa de Meia-Idade , PrognósticoRESUMO
BACKGROUND: There is no comprehensive treatment method for hepatocellular carcinoma (HCC); hence, research and development are still focused on systemic therapies, including drugs. Sinikangai fang (SNKAF) decoction, a classic Chinese herbal prescription, has been widely used to treat liver cancer. However, there is no research on its core active component and target. METHODS: Mouse models were established to measure the anticancer effect of SNKAF decoction on HCC. Further, we investigated the effect of SNKAF decoction on inhibition of hepatoma cells proliferation using cell viability, cloning and invasion assays in vitro. The components of SNKAF were collected from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database and TCM@Taiwan database. Metabolomic analysis was used to identify the potential genes and pathways in HCC treated with SNKAF decoction. Then, the expression of phosphoinositide 3-kinase (PI3K), Akt, P53, FoxO proteins of the potential signal pathways were detected using Western blot. RESULTS: The animal experiments showed that SNKAF decoction inhibited tumor growth (P < 0.05) and induced no weight loss in the mice. In vitro data showed that HCCLM3 and MHCC97H cell proliferation was inhibited by SNKAF serum in a time- and concentration dependent manner. Further combined analysis network pharmacology with metabonomics showed that 217 target genes overlapped. The core target genes included BCL2, MCL1, Myc, PTEN, gsk3b, CASP9, CREB1, MDM2, pt53 and CCND1. Cancer-associated pathways were largely involved in SNKAF mechanisms, including P53, FoxO, and PI3K/Akt signaling pathways, which are closely related to induced-tumor cell apoptosis. In addition, Western bolt verified that 10% SNKAF serum significantly affected the main proteins of PI3K/Akt/P53/FoxO signaling pathway in both cell lines. CONCLUSION: SNKAF decoction-containing serum inhibited HCCLM3 and MHCC97H cell proliferation, migration, invasion, and induced-tumor cell apoptosis in-vivo. We confirmed that SNKAF decoction is a promising alternative treatments for HCC patients.
RESUMO
OBJECTIVE: To investigate the effects of urine protein on the renal tubular-interstitial fibrosis in the patients with lupus nephritis (LN). METHODS: Protein was isolated and purified from the urine of six patients with primary LN, 1 male and 5 females, aged 27.4, and incubated with renal tubular cells of the line HK-2 for 0, 1, 2, 12, 24, or 48 h respectively. The mRNA expressions of transforming growth factor beta1(TGF-beta1), collagen I (COL I), and alpha-smooth muscle actin (alpha-SMA) in the HK-2 cells were detected by RT-PCR, and the. protein expressions of TGF-beta1, COL I, and alpha-SMA were detected with Western blotting and indirect immunofluorescence. RESULTS: The urine protein from the LN patients dose-and time-dependently increased the mRNA and protein expressions of TGF-beta1, COL I, and alpha-SMA in the HK-2 cells. The TGF-beta1 mRNA level 48 h after incubation was 0.39 +/- 0.03, significantly higher than that at the beginning of incubation (0.27 +/- 0.02, P < 0.01), and the TGF-beta1 protein level 48 h after incubation was 0.37 +/- 0.03, 1.7 times that at the beginning of incubation (0.27 +/- 0.04, P < 0.01). The COL I mRNA level 48 h after incubation was 0.38 +/- 0.02, significantly higher than the baseline level (0.22 +/- 0.03, P < 0.01); and the COL I protein level 48 h after incubation was 0.44 +/- 0.03, significantly higher than the baseline level (0.19 +/- 0.02, P < 0.01). The alpha-SMA mRNA level 48 h after incubation was 0.66 +/- 0.04, significantly higher than the baseline level (0.44 +/- 0.03, P < 0.01), and the alpha-SMA protein level 48 h after incubation was 0.43 +/- 0.02, significantly higher than the baseline level (0.24 +/- 0.03, P < 0.01). CONCLUSION: Urine protein may play an important role in the renal tubular-interstitial fibrosis by inducing the production of extracellular matrix and phenotype change in HK-2 cells.
Assuntos
Transdiferenciação Celular/efeitos dos fármacos , Colágeno Tipo I/metabolismo , Células Epiteliais/efeitos dos fármacos , Nefrite Lúpica/urina , Proteínas/farmacologia , Actinas/genética , Actinas/metabolismo , Adulto , Western Blotting , Linhagem Celular , Colágeno Tipo I/genética , Relação Dose-Resposta a Droga , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Feminino , Expressão Gênica/efeitos dos fármacos , Humanos , Túbulos Renais/citologia , Nefrite Lúpica/metabolismo , Masculino , Proteínas/isolamento & purificação , Proteinúria/metabolismo , Proteinúria/urina , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fatores de Tempo , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismoRESUMO
OBJECTIVE: To study the clinical effect of combined treatment with gamma-globulin, corticosteroids, immunosuppressor and Chinese medicines on systemic lupus erythematosus (SLE) patients characterized by hypoplastic bone marrow (HBM). METHODS: Nineteen patients were randomly assigned to two groups, the treated group (10 cases) received combined therapy of prednisone and cyclophosphamide (CTX) plus Chinese medicine Langchuang Recipe after being treated impactively with gamma-globulin. The control group (9 cases) was treated with prednisone and CTX. Changes of hypoplastic bone marrow, peripheral white blood cell (WBC), complement C3, 24 h urinary protein excretion, and lupus activity index (LAI) were observed, and a follow-up was carried out for one year. RESULTS: After one-month treatment, the bone marrow hypoplasia was relieved significantly in the treated group (P < 0.05, P < 0.01), showing an improvement superior to that in the control group (P < 0.05, P < 0.01); after three months treatment, the level of complement C3 increased (P < 0.01), while the 24 h urinary protein excretion and LAI decreased in the treated group (P < 0.05), showing significant difference as compared with those in the control group (P < 0.05, P < 0.01). In the follow-up period, 3 cases withdrew from the trial because of infection and 4 cases manifested full moon-face and acne in the control group, while no adverse reaction was found in the treated group. CONCLUSION: Treatment with integrated Chinese and Western medicine could effectively improve bone marrow hypoplasia, alleviate the clinical symptoms, suppress the activity of lupus in patients, and reduce the adverse reaction of treatment, showing a superiority to the treatment with prednisone combining with CTX.
Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Síndromes Mielodisplásicas/tratamento farmacológico , Prednisona/uso terapêutico , Adulto , Ciclofosfamida/uso terapêutico , Quimioterapia Combinada , Feminino , Humanos , Lúpus Eritematoso Sistêmico/complicações , Masculino , Síndromes Mielodisplásicas/complicações , Fitoterapia , Resultado do Tratamento , gama-Globinas/uso terapêuticoRESUMO
OBJECTIVE: To investigate potential mechanism underlying lipo-prostaglandin E1 (PGE1) in treatment of patients with chronic glomerulonephritis. METHODS: The recommended dose of 20 microg lipo-PGE1 for treatment of chronic glomerulonephritis was as a daily dose by continuous intravenous infusion or intravenous injection for 4 weeks. The levels of interleukin-1 (IL- 1), tumor necrosis factor-alpha (TNF-alpha), blood urea nitrogen (BUN), serum creatinine (SCr) and clearance of creatinine (CCr) were measured before and after treatment. RESULTS: After treatment with lipo-PGE1, levels of IL-1, TNF-alpha, BUN and SCr were lower than those before treatment (all P<0.01), but CCr values were higher than those before treatment (P<0.05). CONCLUSION: Lipo-PGE1 can reduce the renal inflammatory response and improve the renal function in the patients with chronic glomerulonephritis.
Assuntos
Alprostadil/uso terapêutico , Glomerulonefrite/tratamento farmacológico , Adolescente , Adulto , Nitrogênio da Ureia Sanguínea , Creatinina/sangue , Feminino , Glomerulonefrite/sangue , Humanos , Interleucina-1/sangue , Rim/patologia , Rim/fisiopatologia , Masculino , Resultado do Tratamento , Fator de Necrose Tumoral alfa/análise , Vasodilatadores/uso terapêuticoRESUMO
Smad7 is an inhibitory Smad and plays a protective role in obstructive and diabetic kidney disease. However, the role and mechanisms of Smad7 in hypertensive nephropathy remains unexplored. Thus, the aim of this study was to investigate the role and regulatory mechanisms of Smad7 in ANG II-induced hypertensive nephropathy. Smad7 gene knockout (KO) and wild-type (WT) mice received a subcutaneous infusion of ANG II or control saline for 4 weeks via osmotic mini-pumps. ANG II infusion produced equivalent hypertension in Smad7 KO and WT mice; however, Smad7 KO mice exhibited more severe renal functional injury as shown by increased proteinuria and reduced renal function (both p<0.05) when compared with Smad7 WT mice. Enhanced renal injury in Smad7 KO mice was associated with more progressive renal fibrosis with elevated TGF-ß/Smad3 signalling. Smad7 KO mice also showed more profound renal inflammation including increased macrophage infiltration, enhanced IL-1ß and TNF-α expression, and a marked activation of NF-κB signaling (all p<0.01). Further studies revealed that enhanced ANG II-mediated renal inflammation and fibrosis in Smad7 KO mice were also associated with up-regulation of Sp1 but downregulation of miR-29b expression. Taken together, the present study revealed that enhanced Sp1-TGF-ß1/Smad3-NF-κB signaling and loss of miR-29 may be mechanisms by which deletion of Smad7 promotes ANG II-mediated renal fibrosis and inflammation. Thus, Smad7 may play a protective role in ANG II-induced hypertensive kidney disease.