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1.
J Diabetes Complications ; 33(11): 107419, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31473080

RESUMO

OBJECTIVE: Although diabetic kidney disease (DKD) has been considered as a glomerulocentric disease in the past few decades, growing evidence demonstrated that tubular damage was indispensable in its pathogenesis and progression. This study was designed to investigate the association of urinary acidification dysfunction with the progression of DKD in type 2 diabetic patients. METHODS: Here the urinary acidification functions were measured from 80 participants with renal biopsy-proven DKD. The different kinds of renal tubular transportation dysfunction were analyzed, including the dysfunction of bicarbonate reabsorption, titratable acid secretion, and ammonium secretion. In addition, patients were followed up for 17 (interquartile range, 11-32) months to evaluate the effect of urinary acidification dysfunction in the progression of DKD. RESULTS: The most common urinary acidification dysfunction was the disorder of ammonium secretion, accounting for 53.75%. The more proteinuria excretion and the lower glomerular filtration rate (GFR) were observed in the urinary titratable acid disorder group than the normal group, and the same results were obtained for ammonium secretion disorder. Urine titratable acid was positively correlated with eGFR whereas it was inversely correlated with proteinuria, serum creatinine, and BUN. Moreover, 24 h urine protein, serum creatinine, BUN and cystatin C increased from DKD stage II to stage IV, whereas the eGFR and urine titratable acid decreased in the same way. Furthermore, Kaplan-Meier analysis and Cox regression showed that the disorder of titratable acid was an independent risk factor for DKD progression. CONCLUSIONS: The dysfunction of urinary titratable acid is a potential biomarker for the severity of proteinuria, eGFR and glomerular lesions in patients with DKD. Moreover, the titratable acid disorder is an independent risk factor of the DKD progression.

2.
Biosci Trends ; 13(4): 334-341, 2019 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-31434815

RESUMO

Histone acetylation has recently been implicated in gene transcription and estradiol (E2) actions in the hypothalamus. This study aims to determine the involvement of histone acetylation in mediating E2-induced luteinizing hormone (LH) surge to understand the mechanism underlying LH surge dysfunction in female reproductive aging. Young and middle-aged female rats were ovariectomized (OVX) and treated with hormone or oil once per day for two days. At the time of the expected LH surge, blood samples were taken for LH assay. The anterior and posterior hypothalami were dissected, histone H3/H4 acetylation and histone deacetylases (HDACs) 4, -5, -10 and -11 protein expressions were measured using Western blotting. Our results show that in the young females, E2 markedly increased histone H3 acetylation while significantly reducing HDAC10 protein expression in the anterior hypothalamus. Notably, E2-induced alterations of histone H3 acetylation and HDAC10 in the anterior hypothalamus were absent in middle-aged females, associated with a reduced LH release. However, age alters histone H4 acetylation in both the anterior and posterior hypothalamus and significantly increased HDAC 4 and -5 protein expression in the anterior hypothalamus. Taken together, these data suggest that histone H3 acetylation in the anterior hypothalamus may mediate E2 regulation of LH surge and the process possibly through decreasing HDAC10. The missed responsiveness of histone H3 acetylation and HDAC10 expression to E2 in the anterior hypothalamus may contribute to LH surge failure that occurs in female reproductive aging.


Assuntos
Histonas/metabolismo , Hipotálamo Anterior/metabolismo , Hormônio Luteinizante/sangue , Acetilação , Fatores Etários , Animais , Estradiol/metabolismo , Estradiol/fisiologia , Feminino , Ratos , Ratos Sprague-Dawley
3.
Int J Endocrinol ; 2019: 1454617, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31341471

RESUMO

Background: Graves' disease (GD) is an organ-specific autoimmune disease. Accumulated data have indicated that aberrant epigenetic modifications are associated with many autoimmune disorders. However, it remains unknown whether histone methylation plays a role in the pathogenesis of GD. In the present study, we aimed to assess histone modification patterns in peripheral blood mononuclear cells (PBMCs) from GD patients. The rate (degree) of H3K4 and H3K9 methylation and the expressions of histone-modifying genes were investigated. Methods: A total of 68 GD patients and 32 healthy controls were enrolled in this study. Global histone H3K4/H3K9 methylation of PBMCs was evaluated by the EpiQuik™ global histone H3K4/H3K9 methylation assay kit. The expressions of histone methyltransferases (HMTs) and histone demethylases (HDMs) at the mRNA level were determined by real-time quantitative polymerase chain reaction. Results: Global histone H3K9 methylation in PBMCs of GD patients was significantly decreased compared with that in the healthy controls (P=0.007). The expressions of HMTs (SUV39H1 and SUV39H2) at the mRNA level were significantly decreased in PBMCs from GD patients compared with healthy controls (P<0.001), whereas the SETD1A expression at the mRNA level was significantly increased in GD patients compared with healthy controls (P=0.004). In addition, the expressions of HDMs, including JHDM2A and JMJD2A, at the mRNA level were significantly increased in GD patients compared with healthy controls (P<0.001; P=0.007). Moreover, the mRNA expression levels of JARID1A and LSD1 did not significantly differ in GD patients and healthy controls (P>0.05). Conclusions: These findings firstly suggested that the histone methylation was aberrant in PBMCs of GD patients, which could be possibly attributed to the deregulation of epigenetic modifier genes. Abnormal histone methylation modification may be involved in the pathogenesis of GD.

4.
Cell Prolif ; 52(5): e12638, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31152465

RESUMO

OBJECTIVES: Terminally differentiated stratified squamous epithelial cells play an important role in barrier protection of the skin. The integrity of epidermal cells is maintained by tight regulation of proliferation and differentiation. The aim of this study was to investigate the role of epigenetic regulator H3K4me3 and its demethylase Jarid1b in the control of epithelial cell differentiation. MATERIALS AND METHODS: RT-qPCR, Western blotting and IHC were used to detect mRNA and protein levels. We analysed cell proliferation by CCK8 assay and cell migration by wound healing assay. ChIP was used to measure H3K4me3 enrichment. A chamber graft model was established for epidermal development. RESULTS: Our studies showed that H3K4me3 was decreased during epidermal differentiation. The H3K4me3 demethylase Jarid1b positively controlled epidermal cell differentiation in vitro and in vivo. Mechanistically, we found that Jarid1b substantially increased the expression of mesenchymal-epithelial transition (MET)-related genes, among which Ovol1 positively regulated differentiation gene expression. In addition, Ovol1 expression was repressed by PI3K-AKT pathway inhibitors and overexpression (O/E) of the PI3K-AKT pathway suppressor Ship1. Knockdown (KD) of Ship1 activated downstream PI3K-AKT pathway and enhanced Ovol1 expression in HaCaT. Importantly, we found that Jarid1b negatively regulated Ship1 expression, but not that of Pten, by directly binding to its promoter to modulate H3K4me3 enrichment. CONCLUSION: Our results identify an essential role of Jarid1b in the regulation of the Ship1/AKT/Ovol1 pathway to promote epithelial cell differentiation.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Histona Desmetilases com o Domínio Jumonji/metabolismo , Proteínas Nucleares/metabolismo , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas Repressoras/metabolismo , Fatores de Transcrição/metabolismo , Animais , Diferenciação Celular , Linhagem Celular , Proliferação de Células , Proteínas de Ligação a DNA/genética , Células Epidérmicas/citologia , Células Epidérmicas/metabolismo , Transição Epitelial-Mesenquimal , Histonas/metabolismo , Humanos , Histona Desmetilases com o Domínio Jumonji/antagonistas & inibidores , Histona Desmetilases com o Domínio Jumonji/genética , Masculino , Camundongos , Camundongos Nus , Proteínas Nucleares/antagonistas & inibidores , Proteínas Nucleares/genética , Fosfatidilinositol 3-Quinases/metabolismo , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatases/antagonistas & inibidores , Fosfatidilinositol-3,4,5-Trifosfato 5-Fosfatases/genética , Regiões Promotoras Genéticas , Interferência de RNA , RNA Interferente Pequeno/metabolismo , Proteínas Repressoras/antagonistas & inibidores , Proteínas Repressoras/genética , Transdução de Sinais , Fatores de Transcrição/genética
5.
Free Radic Res ; 53(7): 727-736, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31130024

RESUMO

Ischemia/reperfusion (IR) is a common cause of acute kidney injury (AKI). However, effective therapies for IR-induced AKI are lacking. Hyperoside is an active constituent in the flowers of Abelmoschus manihot (L.) Medic, which is a traditional Chinese herbal medicine for the treatment of various ischemic brain and heart diseases. Our previous study demonstrated that hyperoside inhibited adriamycin induced podocyte injury both in vivo and in vitro. The aim of this study is to investigate the effect of hyperoside in IR-induced AKI. In mice, pretreatment of hyperoside could markedly attenuate IR-induced AKI, tubular cell apoptosis, and oxidative stress in the kidneys. Meanwhile, we found hyperoside inhibited IR-induced mitochondrial fission by suppressing OMA1 mediated proteolysis of optic atrophy 1 (OPA1). Consistently, in human proximal tubular epithelial cells, hyperoside might inhibit CoCl2-induced mitochondrial fission, oxidative stress, and apoptosis by regulating OMA1-OPA1 axis. Taken together, our results support the idea that OMA1-OPA1 mediated mitochondrial fission can be used for the prevention of AKI. Hyperoside might have novel therapeutic potential in the treatment of AKI.


Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Rim/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Plantas/química , Quercetina/análogos & derivados , Traumatismo por Reperfusão/tratamento farmacológico , Apoptose , Medicamentos de Ervas Chinesas/farmacologia , Humanos , Quercetina/farmacologia , Quercetina/uso terapêutico
6.
Am J Physiol Renal Physiol ; 317(1): F107-F115, 2019 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-30995110

RESUMO

Numerous studies have demonstrated that several mechanisms, including oxidative stress, DNA damage, and inflammatory responses, are closely linked to cisplatin-induced nephrotoxicity. Adenosine, emerging as a key regulatory molecule, is mostly protective in the pathophysiology of inflammatory diseases. A previous study showed that some of the adenosine receptors led to renal protection against ischemia-reperfusion injury. However, these adenosine receptor agonists lack a useful therapeutic index due to cardiovascular side effects. We hypothesized that inhibition of adenosine kinase (ADK) might exacerbate extracellular adenosine levels to reduce cisplatin-induced renal injury. In the present study, pretreatment with the ADK inhibitor ABT-702 could markedly attenuate cisplatin-induced acute kidney injury, tubular cell apoptosis, oxidative stress, and inflammation in the kidneys. Consistent with in vivo results, inhibition of ADK suppressed cisplatin-induced apoptosis, reactive oxygen species production, and inflammation in HK2 cells. Additionally, the protective effect of ADK inhibition was abolished by A1 or A2B adenosine receptor antagonist and enhanced by A2A or A3 adenosine receptor antagonist. Collectively, the results suggest that inhibition of ADK might increase extracellular adenosine levels, which inhibited cisplatin-induced oxidative stress and inflammation via A1 and A2B adenosine receptors, finally suppressing cisplatin-induced cell apoptosis. Pharmacological therapies based on ADK will be of potential use in therapy of cisplatin-induced nephrotoxicity.

7.
Artigo em Inglês | MEDLINE | ID: mdl-30873118

RESUMO

Purpose: We investigated the effects of Traditional Chinese Medicine (TCM) on the occurrence and progression of albuminuria in patients with type 2 diabetes. Methods: In this randomized, double-blind, multicenter, controlled trial, we enrolled 600 type 2 diabetes without diabetic nephropathy (DN) or with early-stage DN. Patients were randomly assigned (1:1) to receive Liuwei Dihuang Pills (LWDH) (1.5 g daily) and Ginkgo biloba Tablets (24 mg daily) orally or matching placebos for 24 months. The primary endpoint was the change in urinary albumin/creatinine ratio (UACR) from baseline to 24 months. Results: There were 431 patients having UACR data at baseline and 24 months following-up in both groups. Changes of UACR from baseline to follow-up were not affected in both groups: -1.61(-10.24, 7.17) mg/g in the TCM group and -0.73(-7.47, 6.75) mg/g in the control group. For patients with UACR ≥30 mg/g at baseline, LWDH and Ginkgo biloba significantly reduced the UACR value at 24 months [46.21(34.96, 58.96) vs. 20.78(9.62, 38.85), P < 0.05]. Moreover, the change of UACR from baseline to follow-up in the TCM group was significant higher than that in the control group [-25.50(-42.30, -9.56] vs. -20.61(-36.79, 4.31), P < 0.05]. Conclusion: LWDH and Ginkgo biloba may attenuate deterioration of albuminuria in type 2 diabetes patients. These results suggest that TCM is a promising option of renoprotective agents for early stage of DN. Trial registration: The study was registered in the Chinese Clinical Trial Registry. (no. ChiCTR-TRC-07000037, chictr.org).

8.
Int J Endocrinol ; 2019: 7429187, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30774658

RESUMO

The objective of this study was to investigate whether IRF7 polymorphisms are associated with autoimmune thyroid diseases (AITDs). We selected three single nucleotide polymorphisms (SNPs) of IRF7, namely, rs1061501, rs1131665, and rs1061502 for genotyping using PCR-based ligase detection reaction (LDR) method in a total of 1659 participants (592 with Graves' disease, 297 with Hashimoto's thyroiditis, and 770 healthy controls). Gene-disease and genotype-clinical phenotype associations were evaluated for the three SNPs. Our results showed that the AG genotype and the minor allele G frequency of rs1131665 and rs1061502 in AITD patients were both higher than those of the controls (rs1131665: AG genotype: P = 0.017, OR = 1.968; allele G: P = 0.018, OR = 1.946; rs1061502: AG genotype: P = 0.029, OR = 1.866; allele G: P = 0.031, OR = 1.847). Subgroup analysis also showed that the AG genotype and the minor allele G frequency of rs1131665 and rs1061502 in Graves' disease patients were both higher than those of the controls (rs1131665: AG genotype: P = 0.015, OR = 2.074; allele G: P = 0.016, OR = 2.048; rs1061502: AG genotype: P = 0.034, OR = 1.919; allele G: P = 0.035, OR = 1.898). Furthermore, the allele G frequency of rs1061501 was associated with Graves' ophthalmopathy (P = 0.035, OR = 1.396). No significant difference in IRF7 polymorphisms was found between Hashimoto's thyroiditis patients and controls. Our study has revealed for the first time that IRF7 is a susceptibility gene for AITD, especially for Graves' disease and Graves' ophthalmopathy.

9.
Arterioscler Thromb Vasc Biol ; 38(12): 2780-2792, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30571174

RESUMO

Objective- Monocyte-derived foam cells are one of the key players in the formation of atherosclerotic plaques. Adenosine receptors and extracellular adenosine have been demonstrated to modulate foam cell formation. ADK (adenosine kinase) is a major enzyme regulating intracellular adenosine levels, but its functional role in myeloid cells remains poorly understood. To enhance intracellular adenosine levels in myeloid cells, ADK was selectively deleted in novel transgenic mice using Cre-LoxP technology, and foam cell formation and the development of atherosclerotic lesions were determined. Approach and Results- ADK was upregulated in macrophages on ox-LDL (oxidized low-density lipoprotein) treatment in vitro and was highly expressed in foam cells in atherosclerotic plaques. Atherosclerotic mice deficient in ADK in myeloid cells were generated by breeding floxed ADK (ADKF/F) mice with LysM-Cre (myeloid-specific Cre recombinase expressing) mice and ApoE-/- (apolipoprotein E deficient) mice. Mice absent ADK in myeloid cells exhibited much smaller atherosclerotic plaques compared with controls. In vitro assays showed that ADK deletion or inhibition resulted in increased intracellular adenosine and reduced DNA methylation of the ABCG1 (ATP-binding cassette transporter G1) gene. Loss of methylation was associated with ABCG1 upregulation, enhanced cholesterol efflux, and eventually decreased foam cell formation. Conclusions- Augmentation of intracellular adenosine levels through ADK knockout in myeloid cells protects ApoE-/- mice against atherosclerosis by reducing foam cell formation via the epigenetic regulation of cholesterol trafficking. ADK inhibition is a promising approach for the treatment of atherosclerotic diseases.


Assuntos
Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/genética , Adenosina Quinase/deficiência , Aorta/enzimologia , Doenças da Aorta/prevenção & controle , Aterosclerose/prevenção & controle , Epigênese Genética , Células Espumosas/enzimologia , Camundongos Knockout para ApoE , Membro 1 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Adenosina Quinase/genética , Animais , Aorta/patologia , Doenças da Aorta/enzimologia , Doenças da Aorta/genética , Doenças da Aorta/patologia , Aterosclerose/enzimologia , Aterosclerose/genética , Aterosclerose/patologia , Células Cultivadas , Colesterol/metabolismo , Metilação de DNA , Modelos Animais de Doenças , Feminino , Células Espumosas/patologia , Masculino , Camundongos Endogâmicos C57BL , Placa Aterosclerótica , Transdução de Sinais
10.
Medicine (Baltimore) ; 97(48): e13302, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30508917

RESUMO

BACKGROUND: In chronic liver diseases, cirrhosis ranks as the 14th highest death cause worldwide, developing into decompensated cirrhosis. A potential and feasible technique in assessing cardiac function is urgent. This study explores if the Doppler myocardial performance (Tei) index combined with the plasma B-type natriuretic peptide (BNP) levels can assess cardiac function in patients with decompensated cirrhosis. METHODS: A total of 140 individuals were selected in the study and were classified into 3 groups: control group (n = 40, healthy individuals), compensated cirrhosis group (n = 50), and decompensated cirrhosis group (n = 50). Plasma BNP levels, alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), and albumin (ALB) were identified by an enzyme-linked immunosorbent assay (ELISA). The correlation of Tei index between left ventricle (LV) and right ventricle (RV) as well as plasma BNP levels with cardiac function was assessed using a Pearson test analysis. All patients were subjected to this experiment for 1 year to analyze the relationship between Tei index and plasma BNP levels in prognosis of decompensated cirrhosis patients. RESULTS: Patients with decompensated cirrhosis showed significantly elevated levels of ALT, AST, and TBIL level in contrary to a reduced ALB level. Cirrhosis patients also showed a significantly reduced ejection fraction (ET) index, but an increase in isovolumetric contraction time (ICT), isovolumetric relaxation time (IRT), Tei index, and plasma BNP levels in comparison to healthy individuals. ICT, IRT, Tei index, and plasma BNP levels were elevated in decompensated cirrhotic patients as opposed to compensated cirrhotic patients. These results indicate a positive correlation of both Tei index and plasma BNP levels with cirrhosis and its progression. Tei index and plasma BNP levels are positively associated with Child-Pugh classification and negatively correlated with both cardiac function and prognosis in patients suffering from decompensated cirrhosis. CONCLUSION: The study provided evidence supporting the correlation of Tei index and plasma BNP levels in decompensated cirrhotic patients with cardiac function, highlighting a potential value for evaluation.


Assuntos
Ecocardiografia Doppler , Cirrose Hepática/sangue , Cirrose Hepática/diagnóstico por imagem , Peptídeo Natriurético Encefálico/sangue , Biomarcadores/sangue , Progressão da Doença , Feminino , Seguimentos , Coração/diagnóstico por imagem , Coração/fisiopatologia , Humanos , Cirrose Hepática/mortalidade , Masculino , Pessoa de Meia-Idade , Prognóstico
11.
Artigo em Inglês | MEDLINE | ID: mdl-30356900

RESUMO

Background: IL-36α is involved in the pathogenesis of a variety of autoimmune diseases, but the relationship between IL-36α and Graves' disease (GD) has rarely investigated. In the present study, we aimed to explore the expression of IL-36α and elucidate the potential role of IL-36α in GD. Methods: The expression of IL-36α mRNA in peripheral blood mononuclear cells (PBMCs) from 32 newly diagnosed GD patients, 15 refractory GD patients and 30 normal controls (NC) was examined using quantitative real-time polymerase chain reaction (qRT-PCR). The level of IL-36α in serum from 46 newly diagnosed GD patients, 10 refractory GD patients and 24 NC was measured using enzyme linked immunosorbent assay (ELISA). The percentage of CD4+IL-36α+T cells was detected by flow cytometry. PBMCs from newly diagnosed GD patients and NC group were cultured in the presence or absence of recombinant human IL-36α, and the expression levels of IFN-γ, TNF-α, IL-6, and IL-17A in culture supernatant were detected by cytokine array. Results: The expression of IL-36α mRNA in newly diagnosed GD patients was significantly higher than that in NC group (P = 0.019). IL-36α mRNA expression was positively associated with thyrotropin receptor antibody (TRAb) (P = 0.004, r = 0.498) in newly diagnosed GD patients. The level of IL-36α in serum from newly diagnosed GD patients was significantly higher than that in refractory GD patients and NC group (P = 0.01; P = 0.007). The percentage of CD4+IL-36α+T cells in newly diagnosed GD patients was significantly higher than that in NC group (P = 0.030). In GD group, recombinant human IL-36α stimulation resulted in the increase of INF-γ, TNF-α, IL-6 and IL-17A (P = 0.015; P = 0.016; P = 0.039; P = 0.017). Conclusion: IL-36α and CD4+IL-36α+T cells may be involved in the pathogenesis of GD by promoting the production of Th1, Th2, and Th17 cytokines.

12.
Front Physiol ; 9: 1195, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30319431

RESUMO

Hyperglycemia induces glomerular hyper-filtration, which contributes to the development of diabetic nephropathy (DN), a condition that remains a challenge for treatment. The present study investigated the effect of Xiao-Shen-Formula (XSF) used for treatment of renal injury in type 1 DN mice model induced by streptozotocin (STZ) and its underlying mechanism in cultured human glomerular endothelial cell (hGECs). Studies were performed using control, diabetic DN, DN treated with XSF groups (1 g/kg/d, LXSF or 3 g/kg/d, HXSF) for 6 weeks and hGECs were post-treated with mice serum containing HXSF (MS-HXSF) and arginase inhibitor (ABH, 100 µM) in high glucose medium. HXSF treatment restored STZ-induced renal hyper-filtration, glomerulosclerosis, renal microvascular remodeling and the increased levels of systemic reactive oxidative species and inflammatory cytokines, accompanied by preventing the decreased expression of glomerular heparin sulfate and the increased levels of cortical heparanase and argianse2 protein and arginase activity. In hGECs study, MS-HXSF ameliorated the enhancement in arginase activity, the protein/mRNA expression of heparanase, mRNA levels of vascular cell adhesion molecule-1, intercellular adhesion molecule-1, monocyte chemoattractant protein-1 and permeability of hGECs monolayers as well as the depression of nitric oxide production. Besides all these protective effects, XSF blunted the mRNA expression of TNF-α in vivo and vitro studies as well, which was not changed by the post-treatment of ABH or HXSF plus ABH. This study demonstrated that the protective effect of XSF might be related with vascular prevention, anti-inflammation and anti-oxidation through intervening multi-targets including glomerular endothelial arginase-heparanase signaling pathway in DN model.

13.
Complement Ther Med ; 40: 120-125, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30219436

RESUMO

OBJECTIVE: To evaluate the impact to oxidative stress, atherosclerosis and macrovascular disease by two proprietary herbal medicines including Ginkgo Leaf Tablets and Liuwei Dihuang Pills in type 2 diabetes. METHODS: The recruited 140 type 2 diabetes were randomly divided into the treatment group and control group which were both received basic diabetic management including anti-hyperglycemia, anti-hypertension, life style adjustment and health education etc. Additionally, the treatment group was given both Ginkgo Leaf Tablets and Liuwei Dihuang Pills while the control group was given placebos of Ginkgo Leaf Tablets and Liuwei Dihuang Pills. The relative clinical indexes about macrovascular events occurrence, atherosclerosis degree(IMT levels), oxidative stress in vivo(plasma carboxymethyl lysine(CML) and 8-isoprostane(8-IsoP) levels), plasma glucose, plasma lipid, blood pressure, other drugs usage situations and so on of two groups before and after consecutive 36-month treatment were accurately collected and statistically analyzed. RESULTS: There were no significant differences of cardiovascular disease, cerebrovascular disease, IMT levels, plasma CML and 8-IsoP levels between the two groups before treatment. After 36-month treatment, the plasma CML and 8-IsoP levels of treatment group were both significantly lower than control group (CML: 312.4 ± 90.4 ng/ml versus 463.5 ± 97.2 ng/ml, P < 0.0001; 8-IsoP: 23.7 ± 9.5 pg/ml versus 62.6 ± 16.1 pg/ml, P < 0.0001) although this improvement was not shared with IMT and macrovascular events. CONCLUSION: Ginkgo Leaf Tablets and Liuwei Dihuang Pills are beneficial to oxidative stress which plays important role in diabetic atherosclerosis and macrovascular complications. The preventive and therapeutic values of herbal medicines will be proved in further diabetic complication researches.


Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Extratos Vegetais/uso terapêutico , Idoso , Biomarcadores/sangue , Pressão Sanguínea/efeitos dos fármacos , Diabetes Mellitus Tipo 2/sangue , Dinoprosta/análogos & derivados , Dinoprosta/sangue , Medicamentos de Ervas Chinesas/farmacologia , Feminino , Humanos , Lisina/análogos & derivados , Lisina/sangue , Masculino , Pessoa de Meia-Idade , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia
14.
Exp Physiol ; 103(12): 1618-1632, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30204276

RESUMO

NEW FINDINGS: What is the central question of this study? What is the role of hypothalamic DNA methylation in the development of polycystic ovary syndrome (PCOS) and the response to electro-acupuncture treatment. What is the main finding and its importance? Global DNA methylation and expression of DNA methyltransferases (DNMTs) were increased in PCOS-like rats, and electro-acupuncture (EA) decreased global DNA methylation and DNMT3b expression. Pyrosequencing showed that the DNA methylation of some PCOS candidate genes was changed in the PCOS and PCOS+EA groups, suggesting that hypothalamic DNA methylation plays an important role in the development of PCOS and in mediating the effects of electro-acupuncture treatment. ABSTRACT: Polycystic ovary syndrome (PCOS) is a common reproductive and endocrine disease of unknown aetiology. Recently, epigenetic studies focusing on DNA methylation in PCOS have received much attention, but the mechanisms are still unclear. In the present study, we used the 5α-dihydrotestosterone-induced PCOS-like rat model and treated the rats with electro-acupuncture (EA). Rats were randomly divided into four groups - controls, diet-induced obesity, PCOS and PCOS+EA. We examined the reproductive, metabolic and behavioural phenotypes, validated the effect of EA, and explored the role of hypothalamic DNA methylation by analysing the methylation of global DNA and selected candidate genes. The PCOS rats presented with reproductive dysfunctions such as lack of regular oestrous cyclicity, metabolic disorders such as increased body weight and insulin resistance, and depression and anxiety-like behaviours. EA improved the reproductive functions, decreased body weight and improved experimental depressive behaviour. Furthermore, global DNA methylation and the expression of DNA methyltransferases (DNMTs) were increased in PCOS rats compared to the control group, and EA decreased the global DNA methylation and the expression of DNMT3b. In addition, pyrosequencing showed that the DNA methylation of certain CpG sites in targeted genes (Plcg1, Camk2b, Esr2 and Pgr) was increased in the PCOS group, but the DNA methylation of Camk2b and Ar was decreased after EA treatment. These results indicate that hypothalamic DNA methylation might be correlated with the development of PCOS and that EA has an effect on hypothalamic DNA methylation in PCOS rats.


Assuntos
Metilação de DNA/genética , Di-Hidrotestosterona/farmacologia , Hipotálamo/metabolismo , Síndrome do Ovário Policístico/induzido quimicamente , Síndrome do Ovário Policístico/genética , Terapia por Acupuntura/métodos , Animais , Peso Corporal/genética , Ilhas de CpG/genética , Eletroacupuntura/métodos , Feminino , Resistência à Insulina/genética , Ratos , Ratos Wistar
15.
Biomed Res Int ; 2018: 7959707, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29992164

RESUMO

Background: To date, studies have shown that polymorphisms in an autophagy-related gene, IRGM, are linked with different diseases, especially autoimmune diseases. The present study aimed to examine the roles of IRGM polymorphisms in autoimmune thyroid diseases (AITD). Methods: Three polymorphisms in IRGM gene (rs10065172, rs4958847, and rs13361189) were genotyped in 1569 participants (488 with Graves' disease, 292 with Hashimoto's thyroiditis, and 789 healthy controls) using PCR-based ligase detection reaction method. Gene-disease associations were evaluated for the three SNPs. Results: T allele of rs10065172, A allele of rs4958847, and C allele of rs13361189 were all higher in Graves' disease patients than controls, and the ORs were OR = 1.207 (P = 0.022), OR = 1.207 (P = 0.027), and OR = 1.200 (P = 0.027), respectively. After adjusting for sex and age, rs10065172 and rs13361189 were still associated with GD under both the allele model and dominant model, and the adjusted ORs for rs10065172 were 1.20 (P = 0.033) and 1.33 (P = 0.024), while the adjusted ORs for rs13361189 were 1.19 (P = 0.042) and 1.33 (P = 0.026), respectively. No significant difference was found between Hashimoto's thyroiditis patients and controls. Haplotype analysis found that CTA frequency was distinguishingly higher in Graves' disease patients (OR = 1.195, P = 0.030). The frequency of TCG haplotype was distinguishingly lower in AITD and Graves' disease patients (OR = 0.861, P = 0.044; OR = 0.816, P = 0.017). Conclusions: Our study reveals IRGM as a susceptibility gene of AITD and Graves' disease for the first time.


Assuntos
Proteínas de Ligação ao GTP/genética , Predisposição Genética para Doença , Doença de Graves/genética , Doença de Hashimoto/genética , Adulto , Alelos , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/genética , Autofagia , Estudos de Casos e Controles , China , Feminino , Frequência do Gene , Doença de Graves/diagnóstico , Doença de Hashimoto/diagnóstico , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Doenças da Glândula Tireoide
16.
Cell Physiol Biochem ; 45(5): 1787-1796, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29510406

RESUMO

BACKGROUND/AIMS: The IKZF3 gene encodes a zinc-finger protein that plays an important role in the proliferation and differentiation of B lymphocytes. Autoimmune thyroid diseases (AITDs), mainly include Graves' disease (GD) and Hashimoto's thyroiditis (HT), are probably caused by the aberrant proliferation of B cells. The objective of this study was to explore the association between IKZF3 polymorphisms and AITDs. METHODS: We examined 915 AITD patients (604 GD and 311 HT) and 814 healthy controls. IKZF3 variants (rs2941522, rs907091, rs1453559, rs12150079 and rs2872507) were tested by PCR-ligase detection reaction. RESULTS: It was manifested that that the minor alleles of the five loci increased susceptibility to GD (p<0.05 for rs2941522, and p<0.01 for rs907091, rs1453559, rs12150079 and rs2872507) but in HT patients, these loci showed no significant difference compared with controls. Similarly, the genotype distributions of GD patients manifested obvious differences in all these loci compared with the control group, whereas no statistical differences were observed between HT patients and controls. Furthermore, bioinformatics tools were used to analyze rs1453559, rs12150079 and rs907091. These variants were believed to be the transcription regulator. CONCLUSION: It is the first time we reported the association between the IKZF3 polymorphisms and GD, indicating that IKZF3 gene tends to bean important risk factor for the development of GD.


Assuntos
Doenças Autoimunes/genética , Doença de Graves/genética , Fator de Transcrição Ikaros/genética , Doenças da Glândula Tireoide/genética , Adulto , Alelos , Doenças Autoimunes/patologia , Sequência de Bases , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Genótipo , Doença de Graves/patologia , Doença de Hashimoto/genética , Doença de Hashimoto/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Doenças da Glândula Tireoide/patologia , Adulto Jovem
17.
Arch Virol ; 163(7): 1779-1793, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29541846

RESUMO

Five epidemic waves of human infection with influenza A (H7N9) virus have emerged in China since spring 2013. We previously described the epidemiological characterization of the fifth wave in Jiangsu province. In this study, 41 H7N9 viruses from patients and live-poultry markets were isolated and sequenced to further elucidate the genetic features of viruses of the fifth wave in Jiangsu province. Phylogenetic analysis revealed substantial genetic diversity in the internal genes, and 18 genotypes were identified from the 41 H7N9 virus strains. Furthermore, our data revealed that 41 isolates from Jiangsu contained the G186V and Q226L/I mutations in their haemagglutinin (HA) protein, which may increase the ability of these viruses to bind the human receptor. Four basic amino acid insertions were not observed in the HA cleavage sites of 167 H7N9 viruses from Jiangsu, which revealed that highly pathogenic avian influenza (HPAI) H7N9 viruses did not spread to Jiangsu province in the fifth wave. These findings revealed that multiple genotypes of H7N9 viruses co-circulated in the fifth wave in Jiangsu province, which indicated that the viruses have undergone ongoing evolution with genetic mutation and reassortment. Our study highlights the need to constantly monitor the evolution of H7N9 viruses and reinforce systematic influenza surveillance of humans, birds, and pigs in China.


Assuntos
Subtipo H7N9 do Vírus da Influenza A/genética , Influenza Humana/epidemiologia , Influenza Humana/virologia , Animais , China/epidemiologia , Epidemias , Variação Genética , Genoma Viral , Genótipo , Glicoproteínas de Hemaglutininação de Vírus da Influenza/genética , Humanos , Subtipo H7N9 do Vírus da Influenza A/isolamento & purificação , Subtipo H7N9 do Vírus da Influenza A/patogenicidade , Subtipo H7N9 do Vírus da Influenza A/fisiologia , Influenza Aviária/epidemiologia , Influenza Aviária/transmissão , Influenza Aviária/virologia , Influenza Humana/transmissão , Mutação , Filogenia , Aves Domésticas/virologia , Doenças das Aves Domésticas/epidemiologia , Doenças das Aves Domésticas/transmissão , Doenças das Aves Domésticas/virologia , Vírus Reordenados/genética
18.
Horm Metab Res ; 50(2): 117-123, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29401539

RESUMO

Previous studies have shown associations of polymorphisms in the tumor necrosis factor (TNF) receptor super family member 1A (TNFRSF1A) gene with several groups of inflammatory and autoimmune related diseases, but associations of TNFRSF1A polymorphisms with autoimmune thyroid diseases (AITD), mainly including two sub-types of Hashimoto's thyroiditis (HT) and Graves' disease (GD), in the Chinese Han population is unclear. A case-control study of 1812 subjects (965 AITD patients and 847 unrelated healthy controls) was conducted to assess AITD associations with five single nucleotide polymorphisms (SNPs), including rs4149576, rs4149577, rs4149570, rs1800693, and rs767455 in the TNFRSF1A gene locus. Genotyping was performed and evaluated using the platform of ligase detection reaction. No significant difference was observed in the allele and genotype frequencies between HT or GD patients and controls in any of the five SNPs in the TNFRSF1A gene (all p values >0.05). However, a moderate association of rs4149570 with HT was found after adjusting for age and gender [odds ratio (OR)=1.40, p=0.03]. No obvious difference was found in the haplotype distribution of any of the five SNPs in the TNFRSF1A gene between the AITD patients and controls. These data suggest that these five SNPs in the TNFRSF1A gene are not associated with AITD in the Chinese Han population, but rs4149570 shows a weak association with HT after adjusting for gender and age.


Assuntos
Doenças Autoimunes/genética , Predisposição Genética para Doença , Polimorfismo de Nucleotídeo Único/genética , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Doenças da Glândula Tireoide/genética , Adulto , Estudos de Casos e Controles , Feminino , Frequência do Gene/genética , Haplótipos/genética , Humanos , Desequilíbrio de Ligação/genética , Masculino , Razão de Chances
19.
Endocr Connect ; 7(1): 220-231, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29233816

RESUMO

BACKGROUND: Type 2 diabetes is a risk factor for testosterone deficiency and impaired sex steroid status. Some studies also investigated the association of testosterone level with diabetes risk in men, but reported controversial findings. To clarify this issue, we conducted a systematic review and meta-analysis. METHODS: PubMed, EMBASE and Web of Science were searched for eligible cohort or nested case-control studies published up to August 15, 2017. Meta-analysis was used to calculate the pooled relative risk (RR) of type 2 diabetes associated with higher testosterone level. RESULTS: Thirteen cohort or nested case-control studies with 16,709 participants were included. Meta-analysis showed that higher total testosterone level could significantly decrease the risk of type 2 diabetes in men (RR = 0.65; 95% CI 0.50-0.84; P = 0.001), and higher free testosterone level could also decrease the risk of type 2 diabetes in men (RR = 0.94; 95% CI 0.90-0.99; P = 0.014). After excluding two studies that did not calculate RRs by quartiles of testosterone levels, both higher total testosterone and free testosterone levels could decrease the risk of type 2 diabetes in men, and the pooled RRs were 0.62 (95% CI 0.51-0.76; P < 0.001) and 0.77 (95% CI 0.61-0.98; P = 0.03), respectively. CONCLUSION: This meta-analysis suggests that higher testosterone level can significantly decrease the risk of type 2 diabetes in men. Therefore, combined with previous researches, the findings above suggest a reverse-causality scenario in the relation between testosterone deficiency and risk of type 2 diabetes in men.

20.
Mol Cell Endocrinol ; 470: 14-25, 2018 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-28478303

RESUMO

Heparanase degrades heparan sulfate in glomerular basement membrane (GBM) and plays an important role in diabetic nephropathy (DN). However, its regulating mechanisms remain to be deciphered. Our present study showed that the major advanced glycation endproducts (AGEs), CML-BSA, significantly increased heparanase expression in cultured podocytes and the effect was blocked by the receptor for advanced glycation endproducts (RAGE) knockdown, antibody and antagonist. In addition, NF-κB p65 phosphorylation was elevated and the increased heparanase expression and secretion upon CML-BSA could be attenuated by NF-κB inhibitor PDTC. Mechanistically, CML-BSA activated heparanase promoter through p65 directly binding to its promoter. Furthermore, the in vivo study showed that serum and renal cortex AGEs levels, glomerular p65 phosphorylation and heparanase expression were significantly increased in DN mice. Taken together, our data suggest that AGEs and RAGE interaction increases podocyte heparanase expression by activating NF-κB signal pathway, which is involved in GBM damages of DN.


Assuntos
Glucuronidase/metabolismo , NF-kappa B/metabolismo , Podócitos/metabolismo , Receptor para Produtos Finais de Glicação Avançada/metabolismo , Transdução de Sinais , Animais , Sequência de Bases , Bovinos , Nefropatias Diabéticas/metabolismo , Nefropatias Diabéticas/patologia , Nefropatias Diabéticas/fisiopatologia , Glucuronidase/genética , Produtos Finais de Glicação Avançada/sangue , Produtos Finais de Glicação Avançada/metabolismo , Proteína HMGB1/metabolismo , Córtex Renal/metabolismo , Córtex Renal/patologia , Lisina/análogos & derivados , Lisina/metabolismo , Camundongos Endogâmicos C57BL , Fosforilação , Regiões Promotoras Genéticas/genética , Ligação Proteica , Proteinúria/complicações , Proteínas S100/metabolismo , Soroalbumina Bovina/metabolismo , Fator de Transcrição RelA/metabolismo , Regulação para Cima/genética
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