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1.
Mol Cell ; 77(2): 213-227.e5, 2020 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-31735641

RESUMO

Macrophages form a major cell population in the tumor microenvironment. They can be activated and polarized into tumor-associated macrophages (TAM) by the tumor-derived soluble molecules to promote tumor progression and metastasis. Here, we used comparative metabolomics coupled with biochemical and animal studies to show that cancer cells release succinate into their microenvironment and activate succinate receptor (SUCNR1) signaling to polarize macrophages into TAM. Furthermore, the results from in vitro and in vivo studies revealed that succinate promotes not only cancer cell migration and invasion but also cancer metastasis. These effects are mediated by SUCNR1-triggered PI3K-hypoxia-inducible factor 1α (HIF-1α) axis. Compared with healthy subjects and tumor-free lung tissues, serum succinate levels and lung cancer SUCNR1 expression were elevated in lung cancer patients, suggesting an important clinical relevance. Collectively, our findings indicate that the secreted tumor-derived succinate belongs to a novel class of cancer progression factors, controlling TAM polarization and promoting tumorigenic signaling.


Assuntos
Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Macrófagos/metabolismo , Metástase Neoplásica/patologia , Receptores Acoplados a Proteínas G/metabolismo , Ácido Succínico/metabolismo , Células A549 , Animais , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Células HT29 , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Células MCF-7 , Macrófagos/patologia , Camundongos Endogâmicos C57BL , Células PC-3 , Transdução de Sinais/fisiologia , Microambiente Tumoral/fisiologia
2.
Nurs Health Sci ; 26(3): e13144, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39013554

RESUMO

Moderate physical activity is related to reduced mortality in hemodialysis patients. However, most hemodialysis patients have low physical activity levels for complex reasons. This study investigated the determinants of moderate-to-high physical activity levels and whether psychosocial correlates are associated with engagement in moderate-to-high physical activity among hemodialysis patients. A cross-sectional survey was conducted with 134 hemodialysis outpatients, aged 64.7 years, in three hemodialysis centers in Taiwan. Data on sociodemographics, comorbidities, lifestyles, and psychosocial correlates, including perceived benefits, barriers, and self-efficacy of physical activity, were collected. Multiple logistic regression analyses were performed. Results showed that patients with moderate-to-high physical activity levels constituted a significantly lower proportion of current smokers and had fewer perceived physical activity barriers and higher self-efficacy of physical activity compared with those with low levels. After adjusting for potential sociodemographic covariates, current employment, nonsmoking status, and high self-efficacy of physical activity were significantly associated with moderate-to-high physical activity levels. Developing strategies to improve the self-efficacy of physical activity, support employment, and enhance anti-smoking campaigns in hemodialysis patients can help them engage in moderate-to-high levels of physical activity.


Assuntos
Exercício Físico , Diálise Renal , Humanos , Estudos Transversais , Masculino , Feminino , Diálise Renal/psicologia , Diálise Renal/métodos , Diálise Renal/estatística & dados numéricos , Pessoa de Meia-Idade , Taiwan , Exercício Físico/psicologia , Exercício Físico/fisiologia , Idoso , Inquéritos e Questionários , Autoeficácia , Modelos Logísticos
3.
J Am Soc Nephrol ; 33(11): 2040-2058, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-35918145

RESUMO

BACKGROUND: Ureteral obstruction is marked by disappearance of the vasopressin-dependent water channel aquaporin-2 (AQP2) in the renal collecting duct and polyuria upon reversal. Most studies of unilateral ureteral obstruction (UUO) models have examined late time points, obscuring the early signals that trigger loss of AQP2. METHODS: We performed RNA-Seq on microdissected rat cortical collecting ducts (CCDs) to identify early signaling pathways after establishment of UUO. RESULTS: Vasopressin V2 receptor (AVPR2) mRNA was decreased 3 hours after UUO, identifying one cause of AQP2 loss. Collecting duct principal cell differentiation markers were lost, including many not regulated by vasopressin. Immediate early genes in CCDs were widely induced 3 hours after UUO, including Myc, Atf3, and Fos (confirmed at the protein level). Simultaneously, expression of NF-κB signaling response genes known to repress Aqp2 increased. RNA-Seq for CCDs at an even earlier time point (30 minutes) showed widespread mRNA loss, indicating a "stunned" profile. Immunocytochemical labeling of markers of mRNA-degrading P-bodies DDX6 and 4E-T indicated an increase in P-body formation within 30 minutes. CONCLUSIONS: Immediately after establishment of UUO, collecting ducts manifest a stunned state with broad disappearance of mRNAs. Within 3 hours, there is upregulation of immediate early and inflammatory genes and disappearance of the V2 vasopressin receptor, resulting in loss of AQP2 (confirmed by lipopolysaccharide administration). The inflammatory response seen rapidly after UUO establishment may be relevant to both UUO-induced polyuria and long-term development of fibrosis in UUO kidneys.


Assuntos
Túbulos Renais Coletores , Obstrução Ureteral , Ratos , Animais , Aquaporina 2/genética , Aquaporina 2/metabolismo , Obstrução Ureteral/complicações , Obstrução Ureteral/metabolismo , Poliúria/metabolismo , Rim/metabolismo , Vasopressinas , RNA Mensageiro/metabolismo , Túbulos Renais Coletores/metabolismo
4.
FASEB J ; 35(8): e21785, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34314075

RESUMO

In the present study, acute onset of severe lupus nephritis was successfully treated in mice using a new, benzamide-linked, small molecule that targets immune modulation and the NLRP3 inflammasome. Specifically, 6-(2,4-difluorophenyl)-3-(3-(trifluoromethyl)phenyl)-2H-benzo[e][1,3]oxazine-2,4(3H)-dione (Cf-02) (a) reduced serum levels of IgG anti-dsDNA, IL-1ß, IL-6, and TNF-α, (b) inhibited activation of dendritic cells and differentially regulated T cell functions, and (c) suppressed the NF-κB/NLRP3 inflammasome axis, targeting priming and activating signals of the inflammasome. Moreover, treatment with Cf-02 significantly inhibited secretion of IL-1ß in lipopolysaccharide-stimulated macrophages, but this effect was abolished by autophagy induction. These results recommend Cf-02 as a promising drug candidate for the serious renal conditions associated with systemic lupus erythematosus. Future investigations should examine whether Cf-02 may also be therapeutic in other types of chronic kidney disease involving NLRP3 inflammasome-driven signaling.


Assuntos
Autofagia/efeitos dos fármacos , Fatores Imunológicos/farmacologia , Interleucina-1beta/imunologia , Nefrite Lúpica/tratamento farmacológico , NF-kappa B/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Animais , Estudos de Casos e Controles , Células Cultivadas , Células Dendríticas , Feminino , Humanos , Macrófagos , Camundongos , Camundongos Endogâmicos C57BL , Síndrome de Sjogren
5.
J Formos Med Assoc ; 121 Suppl 1: S12-S19, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34972608

RESUMO

BACKGROUND/PURPOSE: End-stage kidney disease (ESKD) is a global burden that reflects each country's unique condition. We used the National Health Insurance Research Database (NHIRD) of Taiwan to decipher changes in the mortality and international survival rates and to determine the effectiveness of the pre-end-stage renal disease care program (pre-ESRD care program) to guide future health policies for ESKD. METHODS: We conducted a retrospective cohort analysis of the NHIRD data along with records from the catastrophic illness certificate program of ESKD patients from 2010 to 2018. RESULTS: From 2010 to 2018, the annual dialysis-related mortality rate in Taiwan increased from 10.6 to 11.8 deaths per hundred patient-years. The mortality rate for patients below 40 years appears to be decreasing, reflecting the improved quality of care for ESKD patients. Patients above 75 years showed increasing mortality, indicating the prolonged survival and aging of the ESKD population. Patients undergoing dialysis who participated in the pre-ESRD care program had a higher post-dialysis initiation life expectancy than those who did not participate. Among the program enrollees, the post-dialysis initiation life expectancy was higher in patients who had participated for more than one year. Taiwan has one of the highest ESKD patient survival rates globally. CONCLUSION: From 2010 to 2018, the reduced mortality in young patients and aging of the ESKD population might indicate that the quality of care in Taiwan for ESKD has improved. Furthermore, a better survival rate after dialysis initiation was observed in the pre-ESRD care program participants.


Assuntos
Falência Renal Crônica , Humanos , Diálise Renal , Estudos Retrospectivos , Taxa de Sobrevida , Taiwan/epidemiologia
6.
Invest New Drugs ; 39(3): 747-755, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33428079

RESUMO

Background Tirapazamine's (TPZ) tolerability after an intra-arterial (IA) injection remains unclear. We investigated TPZ's safety and tolerability in rats by first injecting into the left hepatic artery and then performing a hepatic artery ligation, which recapitulates the transarterial embolization used clinically. Research design and methods: Forty-six rats in five groups were respectively injected with 0, 0.25, 0.50, 1.0, or more than 1.5 mL IA of TPZ (0.7 mg/mL) into the left hepatic artery and then subjected to hepatic artery ligation under laparotomy. Blood samples were collected four times daily up to day 15 after which the rats were euthanized and necropsied. The toxicity profile of IA injection of TPZ followed by hepatic artery ligation was then assessed. Results No significant changes to the rats' body weight and serum total bilirubin were observed. Serum alanine aminotransferase (ALT) levels increased slightly but remained below 100 U/L one day after treatment for most rats. Three rats in Groups 3 and 4 exhibited an over two-fold transient elevation of ALT. All ALT recovered to the baseline at day 14. Liver tissues were collected on day 15 using H&E staining. One rat in Group 3 showed ischemic coagulative necrosis in its liver tissue. Other sporadic pathological changes not related to TPZ doses were observed in Groups 2, 3, 4, and 5. Conclusion TPZ by IA injection followed by embolization is tolerated up to 7 mg/kg. This finding supports the strategy of administering an IA injection of TPZ followed by trans-arterial embolization to the liver.


Assuntos
Antineoplásicos/toxicidade , Tirapazamina/toxicidade , Alanina Transaminase/sangue , Animais , Bilirrubina/sangue , Feminino , Artéria Hepática/cirurgia , Injeções Intra-Arteriais , Ligadura , Fígado/efeitos dos fármacos , Fígado/patologia , Masculino , Ratos , Hipóxia Tumoral
7.
FASEB J ; 34(7): 9498-9511, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32463165

RESUMO

Mitochondrial aldehyde dehydrogenase 2 (ALDH2) is an enzyme that detoxifies aldehydes by converting them to carboxylic acids. ALDH2 deficiency is known to increase oxidative stress. Increased oxidative stress plays a pivotal role in abdominal aortic aneurysm (AAA) pathogenesis. Reactive oxygen species (ROS) promote degradation of the extracellular matrix (ECM) and vascular smooth muscle cell (VSMC) apoptosis. Reducing oxidative stress by an ALDH2 activator could have therapeutic potential for limiting AAA development. We hypothesized that ALDH2 deficiency could increase the risk for AAA by decreasing ROS elimination and that an ALDH2 activator could provide an alternative option for AAA treatment. The National Center for Biotechnology (NCBI) Gene Expression Omnibus (GEO) database was used. Human aortic smooth muscle cells (HASMCs) were used for the in vitro experiments. Gene-targeted ALDH2*2 KI knock-in mice on a C57BL/6J background and apolipoprotein E knockout (ApoE KO) mice were obtained. An animal model of AAA was constructed using osmotic minipumps to deliver 1000 ng/kg/min angiotensin II (AngII) for 28 days. Patients with AAA had significantly lower ALDH2 expression levels than normal subjects. ALDH2*2 KI mice were susceptible to AngII administration, exhibiting significantly increased AAA incidence rates and increased aortic diameters. Alda-1, an ALDH2 activator, reduced AngII-induced ROS production, NF-kB activation, and apoptosis in HASMCs. Alda-1 attenuated AngII-induced aneurysm formation and decreased aortic expansion in ApoE KO mice. We concluded that ALDH2 deficiency is associated with the development of AAAs in humans and a murine disease model. ALDH2 deficiency increases susceptibility to AngII-induced AAA formation by attenuating anti-ROS effects and increasing VSMC apoptosis and vascular inflammation. Alda-1 was shown to attenuate the progression of experimental AAA in a murine model.


Assuntos
Aldeído-Desidrogenase Mitocondrial/fisiologia , Aneurisma da Aorta Abdominal/prevenção & controle , Apoptose , Inflamação/prevenção & controle , Músculo Liso Vascular/imunologia , Substâncias Protetoras , Espécies Reativas de Oxigênio/metabolismo , Animais , Aneurisma da Aorta Abdominal/imunologia , Aneurisma da Aorta Abdominal/metabolismo , Aneurisma da Aorta Abdominal/patologia , Modelos Animais de Doenças , Feminino , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/imunologia , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Músculo Liso Vascular/metabolismo , Músculo Liso Vascular/patologia , Estresse Oxidativo
8.
FASEB J ; 33(11): 12565-12575, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31461385

RESUMO

Acute mountain sickness (AMS) occurs in up to 25% of unacclimatized persons who ascend to 3000 m and can result in high-altitude pulmonary edema (HAPE). MicroRNAs (miRs) can regulate gene expression at the post-transcriptional level. Hypoxia selectively disrupts endothelial tight junction complexes through a hypoxia-inducible factor-1α (HIF-1α)-dependent mechanism. Though increased HIF-1α expression is associated with adaptation and protection from AMS development in the early stage of hypoxia, a downstream effector of HIF-1α, VEGF, can induce overzealous endothelial barrier dysfunction, increase vascular permeability, and ultimately result in HAPE and high-altitude cerebral edema. We hypothesized that the fine-tuning of downstream effectors by miRs is paramount for the preservation of endothelial barrier integrity and the prevention of vascular leakage. We found that several miRs were up-regulated in healthy volunteers who were subjected to a 3100-m height. By reviewing the literature and using online bioinformatics prediction software, we specifically selected miR-424 for further investigation because it can modulate both HIF-1α and VEGF. Hypoxia-induced miR-424 overexpression is HIF-1α dependent, and miR-424 stabilized HIF-1α, decreased VEGF expression, and promoted vascular endothelial cadherin phosphorylation. In addition, hypoxia resulted in endothelial barrier dysfunction with increased permeability; miR-424 thus attenuated hypoxia-induced endothelial cell senescence and apoptosis. miR-322 knockout mice were susceptible to hypoxia-induced pulmonary vascular leakage. miR-322 mimics improved hypoxia-induced pulmonary vascular leakage in vivo. We conclude that several miRs were up-regulated in healthy adult volunteers subjected to hypobaric hypoxemia. miR-424/322 could modulate the HIF-1α-VEGF axis and prevent hypoxia-induced pulmonary vascular leakage under hypoxic conditions.-Tsai, S.-H., Huang, P.-H., Tsai, H.-Y., Hsu, Y.-J., Chen, Y.-W., Wang, J.-C., Chen, Y.-H., Lin, S.-J. Roles of the hypoximir microRNA-424/322 in acute hypoxia and hypoxia-induced pulmonary vascular leakage.


Assuntos
Doença da Altitude/metabolismo , Edema Encefálico/metabolismo , Permeabilidade Capilar , Células Endoteliais da Veia Umbilical Humana/metabolismo , Hipóxia/metabolismo , Pneumopatias/metabolismo , MicroRNAs/metabolismo , Doença Aguda , Doença da Altitude/patologia , Animais , Edema Encefálico/patologia , Feminino , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Hipóxia/patologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Pneumopatias/patologia , Masculino , Camundongos , Camundongos Knockout , Estudos Prospectivos , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/biossíntese
9.
Nephrol Dial Transplant ; 35(1): 74-85, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31065699

RESUMO

BACKGROUND: Renal tubulointerstitial lesions (TILs), a key pathological hallmark for chronic kidney disease to progress to end-stage renal disease, feature renal tubular atrophy, interstitial mononuclear leukocyte infiltration and fibrosis in the kidney. Our study tested the renoprotective and therapeutic effects of compound K (CK), as described in our US patent (US7932057B2), on renal TILs using a mouse unilateral ureteral obstruction (UUO) model. METHODS: Renal pathology was performed and renal draining lymph nodes were subjected to flow cytometry analysis. Mechanism-based experiments included the analysis of mitochondrial dysfunction, a model of tubular epithelial cells (TECs) under mechanically induced constant pressure (MICP) and tandem mass tags (TMT)-based proteomics analysis. RESULTS: Administration of CK ameliorated renal TILs by reducing urine levels of proinflammatory cytokines, and preventing mononuclear leukocyte infiltration and fibrosis in the kidney. The beneficial effects clearly correlated with its inhibition of: (i) NF-κB-associated priming and the mitochondria-associated activating signals of the NLRP3 inflammasome; (ii) STAT3 signalling, which in part prevents NLRP3 inflammasome activation; and (iii) the TGF-ß-dependent Smad2/Smad3 fibrotic pathway, in renal tissues, renal TECs under MICP and/or activated macrophages, the latter as a major inflammatory player contributing to renal TILs. Meanwhile, TMT-based proteomics analysis revealed downregulated renal NLRP3 inflammasome activation-associated signalling pathways in CK-treated UUO mice. CONCLUSIONS: The present study, for the first time, presents the potent renoprotective and therapeutic effects of CK on renal TILs by targeting the NLRP3 inflammasome and STAT3 signalling.


Assuntos
Ginsenosídeos/farmacologia , Inflamassomos/efeitos dos fármacos , Mitocôndrias/patologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Nefrite Intersticial/tratamento farmacológico , Obstrução Ureteral/tratamento farmacológico , Animais , Inflamassomos/metabolismo , Rim/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , NF-kappa B/metabolismo , Nefrite Intersticial/metabolismo , Nefrite Intersticial/patologia , Transdução de Sinais/efeitos dos fármacos , Proteína Smad2/metabolismo , Proteína Smad3/metabolismo , Obstrução Ureteral/metabolismo , Obstrução Ureteral/patologia
10.
Br J Clin Pharmacol ; 86(11): 2204-2216, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32337738

RESUMO

AIMS: Evidence on acute respiratory failure (ARF) from antipsychotics is scant, and only 1 population-based study examined this drug safety issue in chronic obstructive pulmonary disease patients. Antipsychotics have been frequently prescribed off-label in adults, but whether antipsychotic use carries an increased ARF risk among adult patients is uncertain. METHODS: We adopted a nested case-control study analysing 716 493 adults aged ≥20 years, identified from the Taiwan nationwide healthcare claims records between January 2000 and December 2013. Among the study cohort, 7084 adults with ARF and 12,785 disease risk scored-matched randomly selected controls were analysed. Multivariable logistic regression models were employed to estimate odds ratios of ARF with antipsychotic usages. RESULTS: Current, recent, and recent past use of antipsychotics was associated with a 2.33-fold (95% confidence interval [CI] = 2.06-2.64), 1.79-fold (95% CI = 1.43-2.25) and 1.41-fold (95% CI = 1.20-1.66) increased risk of ARF, respectively, compared with nonuse, while antipsychotics discontinued >90 days carried no risk. A dose-dependent association was observed with current therapy of antipsychotics (test for trend, P < .001), in which antipsychotic use at >1 defined daily dose yielded the highest risk of 6.53-fold (95% CI = 3.33-12.79). The findings were robust to using carbamazepine as an active comparator. CONCLUSION: Antipsychotic use was associated with an increased risk of ARF in adult patients. The risk was dose-dependent and markedly higher with current use of antipsychotic agents at doses of 1 defined daily dose and above, <10% of this cohort. Physicians should be vigilant about any respiratory symptoms in patients currently receiving antipsychotics at such dose.


Assuntos
Antipsicóticos , Insuficiência Respiratória , Adulto , Antipsicóticos/efeitos adversos , Estudos de Casos e Controles , Humanos , Insuficiência Respiratória/induzido quimicamente , Insuficiência Respiratória/epidemiologia , Fatores de Risco , Taiwan/epidemiologia
11.
Arterioscler Thromb Vasc Biol ; 39(3): 432-445, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30626205

RESUMO

Objective- Vascular smooth muscle cell (VSMC) transformation to an osteochondrogenic phenotype is an initial step toward arterial calcification, which is highly correlated with cardiovascular disease-related morbidity and mortality. TLR2 (Toll-like receptor 2) plays a pathogenic role in the development of vascular diseases, but its regulation in calcification of arteries and VSMCs remains unclear. We postulate that TLR2-mediated inflammation participates in mediating atherosclerotic arterial calcification and VSMC calcification. Approach and Results- We found that ApoE-/- Tlr2-/- genotype in mice suppressed high-fat diet-induced atherosclerotic plaques formation during initiation but progressively lost its preventative capacity, compared with ApoE-/- mice. However, TLR2 deficiency prohibited high-fat diet-induced advanced atherosclerotic calcification, chondrogenic metaplasia, and OPG (osteoprotegerin) downregulation in the calcified lesions. Incubation of VSMCs in a calcifying medium revealed that TLR2 agonists significantly increased VSMC calcification and chondrogenic differentiation. Furthermore, TLR2 deficiency suppressed TLR2 agonist-mediated VSMC chondrogenic differentiation and consequent calcification, which were triggered via the concerted actions of IL (interleukin)-6-mediated RANKL (receptor activator of nuclear factor κB ligand) induction and OPG suppression. Inhibition experiments with pharmacological inhibitors demonstrated that IL-6-mediated RANKL induction is signaled by p38 and ERK1/2 (extracellular signal-regulated kinase 1/2) pathways, whereas the OPG is suppressed via NF-κB (nuclear factor κB) dependent signaling mediated by ERK1/2. Conclusions- We concluded that on ligand binding, TLR2 activates p38 and ERK1/2 signaling to selectively modulate the upregulation of IL-6-mediated RANKL and downregulation of OPG. These signaling pathways act in concert to induce chondrogenic transdifferentiation of VSMCs, which in turn leads to vascular calcification during the pathogenesis of atherosclerosis.


Assuntos
Aterosclerose/patologia , Calcinose/metabolismo , Calcinose/patologia , Condrogênese/fisiologia , Interleucina-6/fisiologia , Sistema de Sinalização das MAP Quinases , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/metabolismo , Osteoprotegerina/biossíntese , Ligante RANK/biossíntese , Receptor 2 Toll-Like/fisiologia , Animais , Doenças da Aorta/etiologia , Doenças da Aorta/genética , Doenças da Aorta/patologia , Doenças da Aorta/prevenção & controle , Apolipoproteínas E/deficiência , Aterosclerose/etiologia , Aterosclerose/genética , Aterosclerose/prevenção & controle , Calcinose/genética , Células Cultivadas , Colesterol na Dieta/toxicidade , Dieta Hiperlipídica/efeitos adversos , Gorduras na Dieta/toxicidade , Regulação da Expressão Gênica , Masculino , Camundongos , Camundongos Endogâmicos C57BL , NF-kappa B/metabolismo , Osteoprotegerina/genética , Ligante RANK/genética , Distribuição Aleatória
12.
J Ren Nutr ; 30(3): 200-207, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-31704188

RESUMO

OBJECTIVE: Vitamin D has been demonstrated to lessen proteinuria severity in chronic kidney disease (CKD). Compared with healthy populations, patients with CKD may have lower serum levels of 1,25-dihydroxy vitamin D (1,25-(OH)2 D) and 25-hydroxy vitamin D (25-(OH) D). We investigated the effect of  oral low-dose active vitamin D (calcitriol at 0.25 µg, 3 times weekly) on urinary protein excretion. DESIGN AND METHODS: We conducted a nonblinded and non-placebo-controlled study. In total, 60 patients with CKD (average estimated glomerular filtration rate of >15 mL/min) who received a stable dose of angiotensin receptor blocker (ARB) or angiotensin-converting enzyme inhibitor (ACEI) were enrolled in this 24-week study. We randomly assigned these patients to the vitamin D group (oral calcitriol at 0.25 µg 3 times weekly with an ACEI or ARB) or the control group (ACEI or ARB). Change in the urine protein/creatinine ratio (uPCR) was the primary endpoint in this study. RESULTS: The mean baseline uPCRs of the 2 groups were comparable (1.84 ± 0.83 g/g vs. 2.02 ± 0.97 g/g, control vs. vitamin D group; P = .46). After the 24-week treatment, the uPCRs were significantly lower than the baseline values in the vitamin D group (1.35 ± 0.64 g/g; P < .05) but not in the control group. The values of uPCR decreased significantly at 8, 16, and 24 weeks (P < .05 vs. baseline) in the vitamin D group. The values of uPCRs were significantly lower in the vitamin D group than in the control group at 8, 16, and 24 weeks (P < .05). A positive correlation was discovered between reduction in uPCRs at 24-week and baseline 25-(OH) D serum level in the vitamin D group (r = 0.738, P < .001). CONCLUSION: Supplementary low-dose active vitamin D could reduce proteinuria in CKD patients with low serum 25-(OH) D levels.


Assuntos
Insuficiência Renal Crônica , Deficiência de Vitamina D , Antagonistas de Receptores de Angiotensina/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Calcitriol , Humanos , Proteinúria/tratamento farmacológico , Insuficiência Renal Crônica/complicações , Insuficiência Renal Crônica/tratamento farmacológico , Vitamina D , Deficiência de Vitamina D/complicações , Deficiência de Vitamina D/tratamento farmacológico , Vitaminas/uso terapêutico
13.
Am J Physiol Renal Physiol ; 317(5): F1342-F1349, 2019 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-31509008

RESUMO

Bacterial infection has long been recognized to contribute to struvite urinary stone deposition; however, its contribution to the development of chronic kidney stones has not been extensively investigated. In the present study, we hypothesized another possible method of bacteria contributing to the formation of calcium oxalate (CaOx) that accounts for the biggest part of the kidney stone. Bacteria may play important roles by influencing renal Ca2+-related ion channel activities, resulting in chronic inflammation of the kidney along with rapid aggregation of stones. We examined the correlation among infection-promoted CaOx kidney stones and alterations in Ca2+-related ion channels in an animal model with experimentally induced Proteus mirabilis and foreign body infection. After the bladder was infected for 7 days, the data demonstrated that stones were presented and induced severe renal tubular breakage as well as altered levels of monocyte chemoattractant protein-1, cyclooxygenase-2, osteopontin, and transient receptor potential vanilloid member 5 expression, reflecting responses of kidney ion channels. Monocyte chemoattractant protein-1, osteopontin, and transient receptor potential vanilloid member 5 expression was significantly downregulated over time, indicating the chronic inflammation phase of the kidney and accelerated aggregation of CaOx crystals, respectively, whereas cyclooxygenase-2 exhibited no differences. These results indicated that bacterial infection is considerably correlated with an alteration in renal Ca2+-related ion channels and might support specific and targeted Ca2+-related ion channel-based therapeutics for urolithiasis and related inflammatory renal damage.


Assuntos
Canais de Cálcio/metabolismo , Cálculos Renais/metabolismo , Urolitíase/metabolismo , Animais , Regulação da Expressão Gênica , Imunidade Inata , Rim/patologia , Infecções por Proteus/complicações , Proteus mirabilis , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Estruvita , Bexiga Urinária/patologia , Urolitíase/etiologia
14.
BMC Nephrol ; 20(1): 300, 2019 08 05.
Artigo em Inglês | MEDLINE | ID: mdl-31382928

RESUMO

BACKGROUND: A chronic inflammatory state is a prominent feature in patients with end-stage renal disease (ESRD). Nuclear factor-kappa B (NF-κB) is a transcription factor that regulates the expression of genes involved in inflammation. Some genetic studies have demonstrated that the NF-κB genetic mutation could cause kidney injury and kidney disease progression. However, the association of a gene polymorphism in the transcription factor binding site of NF-κB with kidney disease is not clear. METHODS: We used the Taiwan Biobank database, the University of California, Santa Cruz, reference genome, and a chromatin immunoprecipitation sequencing database to find single nucleotide polymorphisms (SNPs) at potential binding sites of NF-κB. In addition, we performed a case-control study and genotyped 847 patients with ESRD and 846 healthy controls at Tri-Service General Hospital from 2015 to 2016. Furthermore, we used the ChIP assay to identify the binding activity of different genotypes and used Luciferase reporter assay to examine the function of the rs9395890 polymorphism. RESULT: The results of biometric screening in the databases revealed 15 SNPs with the potential binding site of NF-κB. Genotype distributions of rs9395890 were significantly different in ESRD cases and healthy controls (P = 0.049). The ChIP assay revealed an approximately 1.49-fold enrichment of NF-κB of the variant type TT when compared to that of the wild-type GG in rs9395890 (P = 0.027; TT = 3.20 ± 0.16, GT = 2.81 ± 0.20, GG = 1.71 ± 0.18). The luciferase reporter assay showed that the NF-κB binding site activity in T allele was slightly higher than that in G allele, though it is not significant. CONCLUSIONS: Our findings indicate that rs9395890 is associated with susceptibility to ESRD in Taiwan population.


Assuntos
Falência Renal Crônica/genética , NF-kappa B/genética , Polimorfismo de Nucleotídeo Único , Idoso , Alelos , Sítios de Ligação/genética , Estudos de Casos e Controles , Sequenciamento de Cromatina por Imunoprecipitação/métodos , Feminino , Genes Reporter , Genótipo , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Falência Renal Crônica/metabolismo , Luciferases/genética , Masculino , NF-kappa B/metabolismo , Alinhamento de Sequência , Taiwan
15.
J Vasc Surg ; 68(6S): 72S-81S.e1, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-29290496

RESUMO

BACKGROUND: Rupture of abdominal aortic aneurysm (AAA) is one of the leading causes of sudden death among the elderly. Most incidental AAAs are below the threshold for intervention at the time of detection; however, there is no evidence that commonly used cardiovascular drugs have clinical beneficial effects on AAA progression. Therefore, in addition to current cardiovascular risk-reducing treatments, an adjunctive medical therapy targeting the regulation of extracellular matrix metabolism is still required in the clinical setting. Fucoidan is an extract of brown seaweed and a sulfated polysaccharide. Emerging evidence suggests that fucoidan has potential cardiovascular applications. Numerous investigations of fucoidan in diseases of the cardiovascular system have mainly focused on its pleiotropic anti-inflammatory effects. Specifically, fucoidan has been shown to have matrix metalloproteinase (MMP)-reducing effects in several studies. We aimed to evaluate the beneficial effect of fucoidan on aneurysmal growth in a murine model of aortic aneurysm and further provide a rationale for using fucoidan as a medical adjunctive therapy. METHODS: A murine model of angiotensin II (Ang II)-induced AAA was used to assess the therapeutic effects of fucoidan on AAA growth in vivo. The characteristics and quantification of AAAs were determined in situ. Human umbilical vein endothelial cells were used for studying the involved pathways in vitro. Western blotting was used to detect the involved signaling pathways both in vivo and in vitro. RESULTS: Treatment with fucoidan significantly reduced the incidence of AAA formation. Administration of fucoidan significantly attenuated Ang II-induced aortic expansion from 1.56 ± 0.76 mm to 1.09 ± 0.30 mm. Administration of fucoidan significantly suppressed MMP-2 and MMP-9 activities and reduced the grade of elastin degradation in vivo. In vitro, we found that fucoidan could ameliorate the Ang II-induced phosphorylation of c-Jun N-terminal kinase and nuclear factor κB p65, and it further reduced MMP and reactive oxygen species production. CONCLUSIONS: Fucoidan inhibits the progression of experimental AAA growth through the attenuation of proinflammatory nuclear factor κB and c-Jun N-terminal kinase activation. Fucoidan could be a potential medical adjunctive therapy for small AAAs.


Assuntos
Angiotensina II , Anti-Inflamatórios/farmacologia , Aorta Abdominal/efeitos dos fármacos , Aneurisma da Aorta Abdominal/prevenção & controle , Proteínas Quinases JNK Ativadas por Mitógeno/antagonistas & inibidores , Polissacarídeos/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Fator de Transcrição RelA/antagonistas & inibidores , Animais , Aorta Abdominal/enzimologia , Aorta Abdominal/patologia , Aneurisma da Aorta Abdominal/induzido quimicamente , Aneurisma da Aorta Abdominal/enzimologia , Aneurisma da Aorta Abdominal/patologia , Células Cultivadas , Colagenases/metabolismo , Modelos Animais de Doenças , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/enzimologia , Humanos , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Fosforilação , Transdução de Sinais/efeitos dos fármacos , Fator de Transcrição RelA/metabolismo , Remodelação Vascular/efeitos dos fármacos
16.
Circ Res ; 119(2): 222-36, 2016 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-27151398

RESUMO

RATIONALE: Systemic inflammation has emerged as a key pathophysiological process that induces multiorgan injury and causes serious human diseases. Endothelium is critical in maintaining cellular and inflammatory homeostasis, controlling systemic inflammation, and progression of inflammatory diseases. We postulated that endothelium produces and releases endogenous soluble factors to modulate inflammatory responses and protect against systemic inflammation. OBJECTIVE: To identify endothelial cell-released soluble factors that protect against endothelial barrier dysfunction and systemic inflammation. METHODS AND RESULTS: We found that conditioned medium of endothelial cells inhibited cyclooxgenase-2 and interleukin-6 expression in macrophages stimulated with lipopolysaccharide. Analysis of conditioned medium extracts by liquid chromatography-mass spectrometry showed the presence of 5-methoxytryptophan (5-MTP), but not other related tryptophan metabolites. Furthermore, endothelial cell-derived 5-MTP suppressed lipopolysaccharide-induced inflammatory responses and signaling in macrophages and endotoxemic lung tissues. Lipopolysaccharide suppressed 5-MTP level in endothelial cell-conditioned medium and reduced serum 5-MTP level in the murine sepsis model. Intraperitoneal injection of 5-MTP restored serum 5-MTP accompanied by the inhibition of lipopolysaccharide-induced endothelial leakage and suppression of lipopolysaccharide- or cecal ligation and puncture-mediated proinflammatory mediators overexpression. 5-MTP administration rescued lungs from lipopolysaccharide-induced damages and prevented sepsis-related mortality. Importantly, compared with healthy subjects, serum 5-MTP level in septic patients was decreased by 65%, indicating an important clinical relevance. CONCLUSIONS: We conclude that 5-MTP belongs to a novel class of endothelium-derived protective molecules that defend against endothelial barrier dysfunction and excessive systemic inflammatory responses.


Assuntos
Anti-Inflamatórios/sangue , Endotélio Vascular/metabolismo , Endotoxemia/sangue , Endotoxemia/prevenção & controle , Triptofano/análogos & derivados , Idoso , Idoso de 80 Anos ou mais , Animais , Feminino , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Inflamação/sangue , Inflamação/prevenção & controle , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Triptofano/sangue
17.
J Am Soc Nephrol ; 28(7): 2022-2037, 2017 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-28179433

RESUMO

IL-36 cytokines are proinflammatory and have an important role in innate and adaptive immunity, but the role of IL-36 signaling in renal tubulointerstitial lesions (TILs), a major prognostic feature of renal inflammation and fibrosis, remains undetermined. In this study, increased IL-36α expression detected in renal biopsy specimens and urine samples from patients with renal TILs correlated with renal function impairment. We confirmed the increased expression of IL-36α in the renal tubular epithelial cells of a mouse model of unilateral ureteral obstruction (UUO) and related cell models using mechanically induced pressure, oxidative stress, or high mobility group box 1. In contrast, the kidneys of IL-36 receptor (IL-36R) knockout mice exhibit attenuated TILs after UUO. Compared with UUO-treated wild-type mice, UUO-treated IL-36 knockout mice exhibited markedly reduced NLRP3 inflammasome activation and macrophage/T cell infiltration in the kidney and T cell activation in the renal draining lymph nodes. In vitro, recombinant IL-36α facilitated NLRP3 inflammasome activation in renal tubular epithelial cells, macrophages, and dendritic cells and enhanced dendritic cell-induced T cell proliferation and Th17 differentiation. Furthermore, deficiency of IL-23, which was diminished in IL-36R knockout UUO mice, also reduced renal TIL formation in UUO mice. In wild-type mice, administration of an IL-36R antagonist after UUO reproduced the results obtained in UUO-treated IL-36R knockout mice. We propose that IL-36 signaling contributes to the pathogenesis of renal TILs through the activation of the NLRP3 inflammasome and IL-23/IL-17 axis.


Assuntos
Inflamassomos/fisiologia , Interleucina-17/fisiologia , Interleucina-1/fisiologia , Interleucina-23/fisiologia , Rim/patologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/fisiologia , Nefrite/etiologia , Transdução de Sinais , Animais , Fibrose/etiologia , Humanos , Camundongos , Obstrução Ureteral/etiologia
18.
Am J Physiol Renal Physiol ; 312(3): F398-F406, 2017 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-27927649

RESUMO

Chronic kidney disease (CKD) is associated with increased cardiovascular mortality, and vascular smooth muscle cell (VSMC) dysfunction plays a pivotal role in uremic atherosclerosis. Axl signaling is involved in vascular injury and is highly expressed in VSMCs. Recent reports have shown that cilostazol, a phosphodiesterase type 3 inhibitor (PDE3), can regulate various stages of the atherosclerotic process. However, the role of cilostazol in uremic vasculopathy remains unclear. This study aimed to identify the effect of cilostazol in VSMCs in the experimental CKD and to investigate whether the regulatory mechanism occurs through Axl signaling. We investigated the effect of P-cresol and cilostazol on Axl signaling in A7r5 rat VSMCs and the rat and human CKD models. From the in vivo CKD rats and patients, aortic tissue exhibited significantly decreased Axl expression after cilostazol treatment. P-cresol increased Axl, proliferating of cell nuclear antigen (PCNA), focal adhesion kinase (FAK), and matrix metalloproteinase-2 (MMP-2) expressions, decreased caspase-3 expression, and was accompanied by increased cell viability and migration. Cilostazol significantly reversed P-cresol-induced Axl, downstream gene expressions, and cell functions. Along with the increased Axl expression, P-cresol activated PLCγ, Akt, and ERK phosphorylation and cilostazol significantly suppressed the effect of P-cresol. Axl knockdown significantly reversed the expressions of P-cresol-induced Axl-related gene expression and cell functions. Cilostazol with Axl knockdown have additive changes in downstream gene expression and cell functions in P-cresol culture. Both in vitro and in vivo experimental CKD models elucidate a new signal transduction of cilostazol-mediated protection against uremic toxin-related VSMCs dysfunction and highlight the involvement of the Axl signaling and downstream pathways.


Assuntos
Músculo Liso Vascular/efeitos dos fármacos , Miócitos de Músculo Liso/efeitos dos fármacos , Inibidores da Fosfodiesterase 3/farmacologia , Proteínas Proto-Oncogênicas/metabolismo , Receptores Proteína Tirosina Quinases/metabolismo , Transdução de Sinais/efeitos dos fármacos , Tetrazóis/farmacologia , Uremia/tratamento farmacológico , Doenças Vasculares/prevenção & controle , Animais , Linhagem Celular , Movimento Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Cilostazol , Cresóis/toxicidade , Modelos Animais de Doenças , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Humanos , Masculino , Músculo Liso Vascular/enzimologia , Músculo Liso Vascular/fisiopatologia , Miócitos de Músculo Liso/enzimologia , Fosfolipase C gama/metabolismo , Fosforilação , Proteínas Proto-Oncogênicas c-akt/metabolismo , Interferência de RNA , Ratos , Ratos Wistar , Transfecção , Uremia/enzimologia , Uremia/genética , Uremia/fisiopatologia , Doenças Vasculares/enzimologia , Doenças Vasculares/genética , Doenças Vasculares/fisiopatologia , Receptor Tirosina Quinase Axl
19.
Basic Res Cardiol ; 112(5): 58, 2017 09 04.
Artigo em Inglês | MEDLINE | ID: mdl-28871329

RESUMO

Atrial fibrillation (AF) is associated with atrial fibrosis. Inhibition of atrial fibrosis might be a plausible approach for AF prevention and therapy. This study is designed to evaluate the potential role of CD44, a membrane receptor known to regulate fibrosis, and its related signaling in the pathogenesis of atrial fibrosis and AF. Treatment of cultured rat atrial fibroblasts with transforming growth factor-ß (TGF-ß, a key mediator of atrial fibrosis) led to a higher expression of hyaluronan (HA), CD44, STAT3, and collagen (a principal marker of fibrosis) than that of ventricular fibroblasts. In vivo, TGF-ß transgenic mice and AF patients exhibited a greater expression of HA, CD44, STAT3, and collagen in their atria than wild-type mice and sinus rhythm subjects, respectively. Treating TGF-ß transgenic mice with an anti-CD44 blocking antibody resulted in a lower expression of STAT3 and collagen in their atria than those with control IgG antibody. Programmed stimulation triggered less AF episodes in TGF-ß transgenic mice treated with anti-CD44 blocking antibody than in those with control IgG. Blocking CD44 signaling with anti-CD44 antibody and mutated CD44 plasmids attenuated TGF-ß-induced STAT3 activation and collagen expression in cultured atrial fibroblasts. Deletion and mutational analysis of the collagen promoter along with chromatin immunoprecipitation demonstrated that STAT3 served as a vital transcription factor in collagen expression. TGF-ß-mediated HA/CD44/STAT3 pathway plays a crucial role in the development of atrial fibrosis and AF. Blocking CD44-dependent signaling may be a feasible way for AF management.


Assuntos
Fibrilação Atrial/metabolismo , Remodelamento Atrial , Átrios do Coração/metabolismo , Receptores de Hialuronatos/metabolismo , Fator de Transcrição STAT3/metabolismo , Fator de Crescimento Transformador beta1/metabolismo , Animais , Fibrilação Atrial/patologia , Fibrilação Atrial/fisiopatologia , Fibrilação Atrial/prevenção & controle , Células Cultivadas , Colágeno Tipo I/genética , Colágeno Tipo I/metabolismo , Modelos Animais de Doenças , Fibroblastos/metabolismo , Fibroblastos/patologia , Fibrose , Átrios do Coração/patologia , Átrios do Coração/fisiopatologia , Frequência Cardíaca , Receptores de Hialuronatos/genética , Ácido Hialurônico/metabolismo , Masculino , Camundongos Endogâmicos DBA , Camundongos Transgênicos , Ratos Wistar , Fator de Transcrição STAT3/genética , Transdução de Sinais , Fator de Crescimento Transformador beta1/genética
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