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1.
Artigo em Inglês | MEDLINE | ID: mdl-31532246

RESUMO

Cisplatin is a commonly used chemotherapeutic drug for cancer treatment, but its nephrotoxicity may lead to the deterioration of renal function. Previous work was focused on cisplatin-induced acute kidney disease, whereas the mechanism of chronic kidney disease (CKD) following cisplatin chemotherapy is largely unknown. Here we have characterized the mouse model of chronic kidney defects induced by repeated low dose cisplatin treatment. We have also established a relevant cell culture model. In the animal model, C57 mice were given weekly injection of 8 mg/kg cisplatin for 4 weeks. This led to a sustained decline of kidney function. These mice showed loss of kidney mass, interstitial fibrosis, continued activation of inflammatory cytokines, and appearance of atubular glomeruli. In the cell model, BUMPT mouse proximal tubular cell line was treated 4 times with 1-2 mM cisplatin, resulting in low levels of apoptosis and the expression of fibrosis proteins and profibrotic factors. These data suggest that repeated treatment with low dose cisplatin causes long-term renal pathologies with characteristics of chronic kidney disease.

2.
J Environ Sci (China) ; 85: 138-146, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31471020

RESUMO

Arsenic (As) is an omnipresent metalloid toxicant, which has elicited serious environmental pollution and health risky problems. Previous studies have uncovered that the As exposure could also cause markedly reduction of serum triglycerides in mice. However, the regulation mechanisms are still largely unknown. The present study is aimed to elucidate the molecular mechanisms of lncRNAs in As-induced lipid metabolic disequilibrium. We demonstrated that lncRNA PU.1 AS was significantly induced in the liver of As-feed mice companied with lower serum triglycerides contents; further in vitro experiment confirmed that PU.1 AS regulated liver cells lipid accumulation by nile red fluorescence staining. Intensive mechanistic investigations illustrated that PU.1 AS could interact with EZH2 protein to regulate its downstream target gene expression, and As-induced PU.1 AS attenuated EZH2-supppressed Sirt6 expression, thereafter leading to a decreased SREBP-1c protein expression, as well as the diminished synthesis of triglycerides in hepatocytes. In conclusion, this study provided a new lncRNA-related regulatory signaling pathway participating in As-induced abnormal lipid metabolism.


Assuntos
Arsênico/metabolismo , Metabolismo dos Lipídeos/genética , Animais , Camundongos , RNA Longo não Codificante/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1 , Triglicerídeos
3.
Cell Death Dis ; 10(9): 677, 2019 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-31515472

RESUMO

Acute kidney injury (AKI) is a syndrome of abrupt loss of renal functions. The underlying pathological mechanisms of AKI remain largely unknown. BCL2-interacting protein 3 (BNIP3) has dual functions of regulating cell death and mitophagy, but its pathophysiological role in AKI remains unclear. Here, we demonstrated an increase of BNIP3 expression in cultured renal proximal tubular epithelial cells following oxygen-glucose deprivation-reperfusion (OGD-R) and in renal tubules after renal ischemia-reperfusion (IR)-induced injury in mice. Functionally, silencing Bnip3 by specific short hairpin RNAs in cultured renal tubular cells reduced OGD-R-induced mitophagy, and potentiated OGD-R-induced cell death. In vivo, Bnip3 knockout worsened renal IR injury, as manifested by more severe renal dysfunction and tissue injury. We further showed that Bnip3 knockout reduced mitophagy, which resulted in the accumulation of damaged mitochondria, increased production of reactive oxygen species, and enhanced cell death and inflammatory response in kidneys following renal IR. Taken together, these findings suggest that BNIP3-mediated mitophagy has a critical role in mitochondrial quality control and tubular cell survival during AKI.

4.
World J Gastroenterol ; 25(32): 4764-4778, 2019 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-31528100

RESUMO

BACKGROUND: Non-invasive evaluation for liver fibrosis is clinically important, especially in patients with undetectable hepatitis B virus (HBV) DNA treated with nucleoside analogs. AIM: To clarify the monitoring power of hepatitis B core-related antigen (HBcrAg) for hepatic histologic changes in patients with chronic hepatitis B (CHB) treated with entecavir. METHODS: This prospective multicenter study used multiple ordinal and multivariate logistics regression analysis to assess variables associated with Ishak fibrosis score and regression for fibrosis regression, respectively, in 403 CHB patients, including 374 with entecavir for 72 weeks (291 underwent paired liver biopsy) and 29 as controls. RESULTS: Level of HBcrAg correlated negatively with liver fibrosis staging (γ = -0.357, P < 0.001) in hepatitis B e antigen (HBeAg)-positive patients, and positively with liver fibrosis staging in HBeAg-negative patients. Higher HBcrAg concentration was associated with younger age, HBeAg positive status, high HBV DNA loads, high level of hepatitis B surface antigen (HBsAg) and higher necroinflammation, but not with HBV genotype. Serum concentration of HBcrAg, basal core promoter/precore (BCP/PC) mutant, quantitation of HBsAg (qHBsAg) and platelet counts were independently associated with Ishak fibrosis score on multiple ordinal regression. HBV DNA was undetectable in 88.37% of patients treated with entecavir at week 72, while their level of HBcrAg was still detectable. A greater reduction in post-treatment HBcrAg concentration was associated with the regression of hepatic fibrosis and histological improvement. HBcrAg concentration > 6.33 log IU/mL at baseline and logarithmic reduction > 1.03 log IU/mL at week 72 were associated with a higher chance of regression of liver fibrosis and histological improvement, respectively. CONCLUSION: HBcrAg level is associated with liver fibrosis progression. HBcrAg is an excellent monitor of hepatic histological changes, especially in CHB patients treated with nucleoside analogs.

5.
Adv Exp Med Biol ; 1165: 557-584, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31399985

RESUMO

Renal fibrosis is the final common pathway of all chronic kidney diseases progressing to end-stage renal diseases. Autophagy, a highly conserved lysosomal degradation pathway, plays important roles in maintaining cellular homeostasis in all major types of kidney cells including renal tubular cells as well as podocytes, mesangial cells and endothelial cells in glomeruli. Autophagy dysfunction is implicated in the pathogenesis of various renal pathologies. Here, we analyze the pathological role and regulation of autophagy in renal fibrosis and related kidney diseases in both glomeruli and tubulointerstitial compartments. Further research is expected to gain significant mechanistic insights and discover pathway-specific and kidney-selective therapies targeting autophagy to prevent renal fibrosis and related kidney diseases.


Assuntos
Apoptose , Autofagia , Rim/citologia , Rim/patologia , Fibrose , Humanos
6.
Hepatology ; 2019 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-31298745

RESUMO

Intrahepatic cholangiocarcinoma (ICC), a type of bile duct cancer, has a high mortality rate. Gut microbiota, bile acid (BA) metabolism, and cytokines have not been characterized in patients with ICC, and better noninvasive diagnostic approaches for ICC are essential to be established. Therefore, in this study we aimed to improve our understanding of changes in gut microbiota, BA metabolism, and cytokines in patients with ICC. We found that the α-diversities and ß-diversities of ICC were highest and that the abundances of four genera (Lactobacillus, Actinomyces, Peptostreptococcaceae, and Alloscardovia) were increased in patients with ICC compared with those in patients with hepatocellular carcinoma or liver cirrhosis and in healthy individuals. The glycoursodeoxycholic acid and tauroursodeoxycholic acid (TUDCA) plasma-stool ratios were obviously increased in patients with ICC. Furthermore, the genera Lactobacillus and Alloscardovia that were positively correlated with TUDCA plasma-stool ratios were combined to discriminate ICC from the other three diseases. Vascular invasion (VI) frequently led to a poor prognosis in patients with ICC. Compared with patients with ICC without VI, patients with VI had a greater abundance of the family Ruminococcaceae, increased levels of plasma interleukin (IL)-4 and six conjugated BAs, and decreased levels of plasma IL-6 and chenodeoxycholic acid. A positive correlation between plasma taurocholic acid and IL-4 was observed in patients with ICC. Plasma TUDCA was negatively correlated with the abundance of the genus Pseudoramibacter and the survival time of patients with ICC, but had no effect on tumor size, as determined in two murine tumor models. Conclusion: In this study, we identified some biomarkers, including gut microbiota, BAs and inflammatory cytokines, for the diagnosis of ICC and prediction of VI in patients with ICC.

7.
Artif Cells Nanomed Biotechnol ; 47(1): 3067-3071, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31349749

RESUMO

Long non coding RNAs (lncRNAs) are important in the occurrence and development of various cancers. They have been considered to participate in many processes of diseases. In this study, we aimed at investigating expression level and clinical significance of lncRNA X91348 in hepatocellular carcinoma (HCC). The expression of X91348 in tissue and serum samples from patients with HCC and from healthy people was detected through quantitative real-time polymerase chain reaction (qRT-PCR). X91348 expression was decreased in patients with HCC compared with healthy controls no matter in tissue or serum samples. The relationship between X91348 expression and clinicopathologic characteristics was analysed. The result demonstrated that tumour size, HBsAg and Child-Pugh were vital influencing factors for X91348 expression, which revealed X91348 may be involved in the progress of HCC. Kaplan-Meier analysis was used to evaluate overall survival of patients with different expressions of X91348. Finally, prognostic value of X91348 in HCC was assessed via cox regression analysis. X91348 was proved to be closely related to the prognosis of HCC. Taken together, the down-regulation of X91348 could be an independent diagnostic and prognostic indicator for HCC.

8.
Cell Rep ; 28(2): 554-566.e4, 2019 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-31291588

RESUMO

G-protein-coupled receptors (GPCRs) constitute the largest superfamily of cell surface signaling proteins. However, the molecular mechanisms underlying their cell surface delivery after synthesis remain poorly understood. Here, we screen the TBC domain-containing proteins, putative Rab GTPase-activating proteins (GAPs), in the intracellular trafficking of GPCRs and identify several TBC proteins that activity-dependently regulate the anterograde transport, en route from the endoplasmic reticulum to the Golgi or from the Golgi to the cell surface, of several prototypic GPCR members without affecting other plasma membrane proteins. We also show that TBC1D6 functions as a GAP for Rab26, physically associates with Rab26, and attenuates Rab26 interaction with GPCRs. Furthermore, both overexpression and depletion of TBC1D6 inhibit the post-Golgi traffic of GPCRs. These data demonstrate important roles of the TBC proteins in forward trafficking of nascent GPCRs and reveal regulatory mechanisms of GPCR targeting to the functional destination.

9.
Artigo em Inglês | MEDLINE | ID: mdl-31339772

RESUMO

Ischemia-reperfusion-induced acute kidney injury (IR-AKI) favors mitochondrial permeability transition pore (mPTP) opening and subsequent cell death. Cyclophilin D (CypD) is an essential component of the mPTP, and recent findings implicate the p53-CypD complex in cell death. To evaluate the role of p53-CypD following IR-AKI, we tested the hypothesis that the p53-CypD complex mediates renal tubular cell apoptosis in IR-AKI via mPTP opening. The expression of p53 and cleaved caspase-3 was significantly increased in rats subjected to IR-AKI compared with the normal control and sham-operated control. The underlying mechanisms were determined using an in vitro model of ATP-depletion. The inhibition of mPTP opening using the CypD inhibitor cyclosporin A or a siRNA for p53 in ATP-depleted HK-2 cells prevented mitochondrial membrane depolarization and reduced apoptosis. Furthermore, p53 binds to CypD in ATP-depleted HK-2 cells. These results suggest that the p53-CypD complex mediates renal tubular cell apoptosis in IR-AKI via mPTP opening.

10.
J Cell Physiol ; 234(12): 23202-23215, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31215650

RESUMO

Breast cancer (BC) is the most prevalent malignant cancer in the world, is the leading cause of cancer-related death female. Recently, there is accumulating evidence that long noncoding RNAs (lncRNAs) might as an important role in the progression of BC. (epithelial-mesenchymal transition (EMT) is considered to play a vital role in tumor cells migration and invasion. Nevertheless, the entire biological mechanisms and functions of lncRNAs in tumor migration, invasion, and EMT remain uncertain. In the present research, we observed that the expression of lncRNA AC073284.4 was downregulated in BC paclitaxel-resistant (PR) cells (MCF-7/PR) and tissues. Bioinformatics analysis predicted that miR-18b-5p was a direct target of AC073284.4, which has been validated by dual-luciferase reporter gene assay. We further proved that AC073284.4 could directly bind to miR-18b-5p and relieve the suppression for dedicator of cytokinesis protein 4 (DOCK4). Furthermore, the underlying functional experiments demonstrated that AC073284.4 might sponge miR-18b-5p to attenuate the invasion, metastasis, and EMT of BC cell through upregulating DOCK4 expression. In summary, AC073284.4 might serve as a competing endogenous RNA (ceRNA) in BC progression via modulating miR-18b-5p/DOCK4 axis, which weakens EMT and migration of BC. These results suggesting that AC073284.4 might function as a potential novel diagnostic biomarker in the progression of BC.

11.
Proc Natl Acad Sci U S A ; 116(27): 13394-13403, 2019 Jul 02.
Artigo em Inglês | MEDLINE | ID: mdl-31213542

RESUMO

Increased glycolysis in the lung vasculature has been connected to the development of pulmonary hypertension (PH). We therefore investigated whether glycolytic regulator 6-phosphofructo-2-kinase/fructose-2, 6-bisphosphatase (PFKFB3)-mediated endothelial glycolysis plays a critical role in the development of PH. Heterozygous global deficiency of Pfkfb3 protected mice from developing hypoxia-induced PH, and administration of the PFKFB3 inhibitor 3PO almost completely prevented PH in rats treated with Sugen 5416/hypoxia, indicating a causative role of PFKFB3 in the development of PH. Immunostaining of lung sections and Western blot with isolated lung endothelial cells showed a dramatic increase in PFKFB3 expression and activity in pulmonary endothelial cells of rodents and humans with PH. We generated mice that were constitutively or inducibly deficient in endothelial Pfkfb3 and found that these mice were incapable of developing PH or showed slowed PH progression. Compared with control mice, endothelial Pfkfb3-knockout mice exhibited less severity of vascular smooth muscle cell proliferation, endothelial inflammation, and leukocyte recruitment in the lungs. In the absence of PFKFB3, lung endothelial cells from rodents and humans with PH produced lower levels of growth factors (such as PDGFB and FGF2) and proinflammatory factors (such as CXCL12 and IL1ß). This is mechanistically linked to decreased levels of HIF2A in lung ECs following PFKFB3 knockdown. Taken together, these results suggest that targeting PFKFB3 is a promising strategy for the treatment of PH.

12.
Am J Pathol ; 189(9): 1744-1762, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31199920

RESUMO

Alcoholic fatty liver disease is often complicated by other pathologic insults, such as viral infection or high-fat diet. Autophagy plays a homeostatic role in the liver but can be compromised by alcohol, high-fat diet, or viral infection, which in turn affects the disease process caused by these etiologies. To understand the full impact of autophagy modulation on alcohol-induced liver injury, several genetic models of autophagy deficiency, which have different levels of functional alterations, were examined after acute binge or chronic-plus-binge treatment. Mice given alcohol with either mode and induced with deficiency in liver-specific Atg7 shortly after the induction of Atg7 deletion had elevated liver injury, indicating the protective role of autophagy. Constitutive hepatic Atg7-deficient mice, in which Atg7 was deleted in embryos, were more susceptible with chronic-plus-binge but not with acute alcohol treatment. Constitutive hepatic Atg5-deficient mice, in which Atg5 was deleted in embryos, were more susceptible with acute alcohol treatment, but liver injury was unexpectedly improved with the chronic-plus-binge regimen. A prolonged autophagy deficiency may complicate the hepatic response to alcohol treatment, likely in part due to endogenous liver injury. The complexity of the relationship between autophagy deficiency and alcohol-induced liver injury can thus be affected by the timing of autophagy dysfunction, the exact autophagy gene being affected, and the alcohol treatment regimen.

13.
Mol Med Rep ; 20(1): 261-269, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31115539

RESUMO

MicroRNAs (miRNAs) are frequently reported to be aberrantly expressed in non­small cell lung cancer (NSCLC) and are closely associated with aggressive tumor phenotypes. Hence, identification of cancer­related miRNAs in NSCLC may be helpful for improving the cure rate of NSCLC treatments. miR­889 has been demonstrated to be a novel cancer­associated miRNA that is aberrantly expressed and plays an important role in esophageal squamous cell carcinoma and hepatocellular carcinoma. However, the exact functions and precise molecular mechanisms through which miR­889 affects NSCLC progression are still unknown. In the present study, we report for the first time that miR­889 expression is low in NSCLC tissues and cell lines. Clinically, low miR­889 expression was found to be correlated with the TNM stage and distant metastasis in NSCLC patients. Functionally, miR­889 overexpression suppressed the proliferation and invasiveness of NSCLC cells in vitro and decreased NSCLC xenograft tumor growth in mice. Furthermore, TGF­ß­activated kinase 1­binding protein 1 (TAB1) was confirmed as a direct target gene of miR­889 in NSCLC cells. TAB1 was revealed to be overexpressed in NSCLC tissue samples and was inversely correlated with miR­889 levels. Moreover, a TAB1 knockdown had effects similar to that of miR­889 overexpression, whereas restoration of TAB1 expression counteracted the actions of miR­889 in NSCLC cells. Overall, the present results indicated that miR­889 inhibits the aggressive behaviors of NSCLC by directly targeting TAB1 mRNA, thus highlighting the importance of the miR­889/TAB1 pathway in the malignant progression of NSCLC.

15.
Theranostics ; 9(9): 2712-2726, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31131063

RESUMO

The molecular mechanism underlying the transition of acute kidney injury (AKI) to chronic kidney disease (CKD) induced by vancomycin (VAN) remains largely unknown. Methods: The mice model of VAN drives AKI to CKD was developed to investigate the role and molecular mechanism of epidermal growth factor receptor (EGFR). The EGF receptor mutant (Wa-2) mice and gefitinib were used to inactivation of EGFR. The homeodomain interacting protein kinase 2 (HIPK2) siRNA was applied to silence of HIPK2. Human proximal tubular epithelial cells (HK-2) were used to explore the molecular regulation methanism of EGFR. ChIp analysis was used to investigate if STAT3 interaction with the promoter of HIPK2. Results: A novel VAN-induced AKI mouse model was established for the first time. Moreover, the expression levels collagen I&IV, α-SMA, p-EGFR and the expression of HIPK2 proteins were upregulated in this model. Interestingly, AKI caused by VAN was markedly attenuated in waved-2 mice at the early stage, as evidenced by the suppression of renal dysfunction, renal cell apoptosis and caspase3 activation. In the latter stage, renal fibrosis and inflammation were significantly ameliorated in Wa-2 mice, accompanied by the downregulation of profibrotic molecules and F4/80. Besides, the expression levels of HIPK2 and p-STAT3 were suppressed in Wa-2 mice during VAN-induced transition of AKI to CKD. In addition, renal fibrosis and inflammation, profibrotic molecules, and EGFR/STAT3/HIPK2 signaling were ameliorated by gefitinib treatment after VAN-induced AKI. These results were consistent with the findings of Wa-2 mice. EGFR/STAT3 signaling mediated VAN-induced HIPK2 expression in HK-2 cells. ChIp analysis revealed that STAT3 directly bound to the promoter region of HIPK2. Finally, inhibition of HIPK2 attenuated the VAN drove the progression of AKI to CKD. Conclusion: These data suggest that EGFR plays an important role in VAN-driven progression of AKI to CKD.

16.
Medicine (Baltimore) ; 98(19): e15535, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31083204

RESUMO

RATIONALE: Interdigitating dendritic cell sarcoma (IDCS) is an extremely rare disease originating from dendritic cells (DCs). There are few cases report interdigitating dendritic cell sarcoma of spleen along with their pathological characteristics and treatment. PATIENT CONCERNS: Here we report a case of IDCS in 53-year-old female who presented spleen enlargement and thrombocytopenia. DIAGNOSES: The patient underwent surgical resection of spleen, and the pathology confirmed IDCS. INTERVENTIONS: She received surgical resection of spleen and one cycle of chemotherapy (ABVD with ifosfamide and oxaliplatin) after surgery. OUTCOMES: She died of severe hepatic failure caused by chemotherapy. DISCUSSION: IDCS is a rare disease with insufficient treatment guidelines. We adopted chemotherapy of ABVD with ifosfamide and oxaliplatin which showed no improvement but led to life-threatening liver damage.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Sarcoma de Células Dendríticas Interdigitantes/terapia , Falência Hepática/induzido quimicamente , Neoplasias Esplênicas/terapia , Bleomicina/efeitos adversos , Dacarbazina/efeitos adversos , Sarcoma de Células Dendríticas Interdigitantes/diagnóstico , Sarcoma de Células Dendríticas Interdigitantes/patologia , Doxorrubicina/efeitos adversos , Evolução Fatal , Feminino , Humanos , Pessoa de Meia-Idade , Baço/patologia , Esplenectomia , Neoplasias Esplênicas/diagnóstico , Neoplasias Esplênicas/patologia , Vimblastina/efeitos adversos
17.
Am J Physiol Renal Physiol ; 317(1): F116-F123, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31091124

RESUMO

Stress granules (SGs) are a type of cytoplasmic structures formed in eukaryotic cells upon cell stress, which mainly contain RNA-binding proteins and RNAs. The formation of SGs is generally regarded as a mechanism for cells to survive a harsh insult. However, little is known about SG formation and function in kidneys. To address this, we applied different kinds of stressors to cultured proximal tubular cells as well as a short period of ischemia-reperfusion to mouse kidneys. It was found that glycolytic inhibitors such as 2-deoxy-d-glucose and 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one induced SG formation within 30 min in these cells. Similarly, SGs were induced by inhibitors of mitochondrial respiration such as sodium azide and CCCP. Renal ischemia-reperfusion induced SG formation in the cells of proximal tubules. To test the role of SGs, we stably knocked down G3bp1, a SG core protein, in renal tubular cells by shRNA viral transduction. As expected, knockdown of G3bp1 largely disrupted the assembly of SGs. After azide or cisplatin treatment, more dead cells were found in knockdown cells compared with controls, accompanied by increases in cleaved/active caspase-3. Reintroduction of exogenous G3bp1 into knockdown cells could rescue the cell death phenotype. Taken together, our data provide the first evidence of SG formation in renal tubular cells during metabolic stress and acute kidney injury. SGs are formed to protect proximal tubular cells under these conditions. Modulation of SG biogenesis may provide a novel approach to lessen the severity of renal diseases.

18.
Chemosphere ; 231: 378-384, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31141740

RESUMO

Dechlorane plus (DP) is found widely in environmental media. Determining DP concentrations in dust and hair and identifying relationships between the concentrations in dust and hair could improve our understanding of the effects of DP in humans. DP concentrations in 48 hair samples from male and female students and in 30 indoor dust samples from dormitories and classrooms used by the students were determined. The objective was to determine the difference of DP concentration between indoor dust and hair, and to explore the effect of DP in dust on DP in hair of male and female students. The mean DP concentration was significantly higher in male dormitory dust than female dormitory dust, and the estimated DP dose through exposure to dust was also significantly higher for males than females. However, the mean DP concentration was significantly higher for hair from females than from males. The median DP fanti was significantly lower for hair than dust, indicating DP may be stereoselectively metabolized by humans. The median DP fanti was significantly higher for hair from females than from males, indicating DP may be metabolized differently by males and females. Human serum albumin preferred combination with anti-DP, rather than syn-DP. DP in indoor dust was not a major direct source of the DP in the hair, meaning DP in hair mainly came from within the body. There may be significant differences in DP, particularly anti-DP, metabolism in males and females.


Assuntos
Poeira/análise , Monitoramento Ambiental , Poluentes Ambientais/análise , Retardadores de Chama/análise , Cabelo/química , Hidrocarbonetos Clorados/análise , Compostos Policíclicos/análise , Feminino , Habitação , Humanos , Isomerismo , Masculino
19.
Autophagy ; : 1-21, 2019 May 22.
Artigo em Inglês | MEDLINE | ID: mdl-31066324

RESUMO

Ischemic preconditioning (IPC) affords tissue protection in organs including kidneys; however, the underlying mechanism remains unclear. Here we demonstrate an important role of macroautophagy/autophagy (especially mitophagy) in the protective effect of IPC in kidneys. IPC induced autophagy in renal tubular cells in mice and suppressed subsequent renal ischemia-reperfusion injury (IRI). The protective effect of IPC was abolished by pharmacological inhibitors of autophagy and by the ablation of Atg7 from kidney proximal tubules. Pretreatment with BECN1/Beclin1 peptide induced autophagy and protected against IRI. These results suggest the dependence of IPC protection on renal autophagy. During IPC, the mitophagy regulator PINK1 (PTEN induced putative kinase 1) was activated. Both IPC and BECN1 peptide enhanced mitolysosome formation during renal IRI in mitophagy reporter mice, suggesting that IPC may protect kidneys by activating mitophagy. We further established an in vitro model of IPC by inducing 'chemical ischemia' in kidney proximal tubular cells with carbonyl cyanide 3-chlorophenylhydrazone (CCCP). Brief treatment with CCCP protected against subsequent injury in these cells and the protective effect was abrogated by autophagy inhibition. In vitro IPC increased mitophagosome formation, enhanced the delivery of mitophagosomes to lysosomes, and promoted the clearance of damaged mitochondria during subsequent CCCP treatment. IPC also suppressed mitochondrial depolarization, improved ATP production, and inhibited the generation of reactive oxygen species. Knockdown of Pink1 suppressed mitophagy and reduced the cytoprotective effect of IPC. Together, these results suggest that autophagy, especially mitophagy, plays an important role in the protective effect of IPC. Abbreviations: ACTB: actin, beta; ATG: autophagy related; BNIP3: BCL2 interacting protein 3; BNIP3L/NIX: BCL2 interacting protein 3 like; BUN: blood urea nitrogen; CASP3: caspase 3; CCCP: carbonyl cyanide 3-chlorophenylhydrazone; COX4I1: cytochrome c oxidase subunit 4I1; COX8: cytochrome c oxidase subunit 8; DAPI: 4',6-diamidino-2-phenylindole; DNM1L: dynamin 1 like; EGFP: enhanced green fluorescent protein; EM: electron microscopy; ER: endoplasmic reticulum; FC: floxed control; FIS1: fission, mitochondrial 1; FUNDC1: FUN14 domain containing 1; H-E: hematoxylin-eosin; HIF1A: hypoxia inducible factor 1 subunit alpha; HSPD1: heat shock protein family D (Hsp60) member 1; IMMT/MIC60: inner membrane mitochondrial protein; IPC: ischemic preconditioning; I-R: ischemia-reperfusion; IRI: ischemia-reperfusion injury; JC-1: 5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolylcarbocyanine iodide; KO: knockout; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; mito-QC: mito-quality control; mRFP: monomeric red fluorescent protein; NAC: N-acetylcysteine; PINK1: PTEN induced putative kinase 1; PPIB: peptidylprolyl isomerase B; PRKN: parkin RBR E3 ubiquitin protein ligase; ROS: reactive oxygen species; RPTC: rat proximal tubular cells; SD: standard deviation; sIPC: simulated IPC; SQSTM1/p62: sequestosome 1; TOMM20: translocase of outer mitochondrial membrane 20; TUNEL: terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling.

20.
Cancer Res ; 79(15): 3837-3850, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31088832

RESUMO

MYCN amplification drives the development of neuronal cancers in children and adults. Given the challenge in therapeutically targeting MYCN directly, we searched for MYCN-activated metabolic pathways as potential drug targets. Here we report that neuroblastoma cells with MYCN amplification show increased transcriptional activation of the serine-glycine-one-carbon (SGOC) biosynthetic pathway and an increased dependence on this pathway for supplying glucose-derived carbon for serine and glycine synthesis. Small molecule inhibitors that block this metabolic pathway exhibit selective cytotoxicity to MYCN-amplified cell lines and xenografts by inducing metabolic stress and autophagy. Transcriptional activation of the SGOC pathway in MYCN-amplified cells requires both MYCN and ATF4, which form a positive feedback loop, with MYCN activation of ATF4 mRNA expression and ATF4 stabilization of MYCN protein by antagonizing FBXW7-mediated MYCN ubiquitination. Collectively, these findings suggest a coupled relationship between metabolic reprogramming and increased sensitivity to metabolic stress, which could be exploited as a strategy for selective cancer therapy. SIGNIFICANCE: This study identifies a MYCN-dependent metabolic vulnerability and suggests a coupled relationship between metabolic reprogramming and increased sensitivity to metabolic stress, which could be exploited for cancer therapy.See related commentary by Rodriguez Garcia and Arsenian-Henriksson, p. 3818.


Assuntos
Neuroblastoma , Serina , Vias Biossintéticas , Carbono , Linhagem Celular Tumoral , Criança , Glicina , Humanos , Proteína Proto-Oncogênica N-Myc
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