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Mental retardation is the main clinical manifestation of Down syndrome (DS), and neural abnormalities occur during the early embryonic period and continue throughout life. Tc1, a model mouse for DS, carries the majority part of the human chromosome 21 and has multiple neuropathy phenotypes similar to patients with DS. To explore the mechanism of early neural abnormalities of Tc1 mouse, induced pluripotent stem (iPS) cells from Tc1 mice were obtained, and genome-wide gene expression and methylation analysis were performed for Tc1 and wild-type iPS cells. Our results showed hypermethylation profiles for Tc1 iPS cells, and the abnormal genes were shown to be related to neurodevelopment and distributed on multiple chromosomes. In addition, important genes involved in neurogenesis and neurodevelopment were shown to be downregulated in Tc1 iPS cells. In short, our study indicated that genome-wide hypermethylation leads to the disordered expression of genes associated with neurodevelopment in Tc1 mice during early development. Overall, our work provided a useful reference for the study of the molecular mechanism of nervous system abnormalities in DS.
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Síndrome de Down/genética , Neurogênese/genética , Animais , Células Cultivadas , Metilação de DNA , Modelos Animais de Doenças , Humanos , Células-Tronco Pluripotentes Induzidas , CamundongosRESUMO
BACKGROUND: Liver injury is one of the most common complications during sepsis. Macrophage migration inhibitory factor (MIF) is an important proinflammatory cytokine. This study explored the role of MIF in the lipopolysaccharide (LPS)-induced liver injury through genetically manipulated mouse strains. METHODS: The model of LPS-induced liver injury was established in wild-type and Mif-knockout C57/BL6 mice. Serum levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TBil) were detected, and the expressions of MIF, tumor necrosis factor-α (TNF-α) and interleukin-1ß (IL-1ß) were measured. Liver histopathology was conducted to assess liver injury. Moreover, the inhibitions of MIF with (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester (ISO-1) and 4-iodo-6-phenylpyrimidine (4-IPP) were used to evaluate their therapeutic potential of liver injury. RESULTS: Compared with wild-type mice, the liver function indices and inflammation factors presented no significant difference in the Mif-/- mice. After 72 h of the LPS-induced liver injury, serum levels of ALT, AST, and TBil as well as TNF-α and IL-1ß were significantly increased, but the knockout of Mif attenuated liver injury and inflammatory response. In liver tissue, mRNA levels of TNF-α, IL-1ß and NF-κB p65 were remarkably elevated in LPS-induced liver injury, while the knockout of Mif reduced these levels. Moreover, in LPS-induced liver injury, the inhibitions of MIF with ISO-1 and 4-IPP alleviated liver injury and slightly attenuated inflammatory response. Importantly, compared to mice with LPS-induced liver injury, Mif knockout or MIF inhibitions significantly prolonged the survival of the mice. CONCLUSIONS: In LPS-induced liver injury, the knockout of Mif or MIF inhibitions alleviated liver injury and slightly attenuated inflammatory response, thereby prolonged the survival of the mice. Targeting MIF may be an important strategy to protect the liver from injury during sepsis.
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Doença Hepática Crônica Induzida por Substâncias e Drogas , Fatores Inibidores da Migração de Macrófagos , Sepse , Animais , Técnicas de Inativação de Genes , Lipopolissacarídeos/toxicidade , Fígado , Fatores Inibidores da Migração de Macrófagos/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator de Necrose Tumoral alfa/genéticaRESUMO
Usually, secreted or transmembrane proteins complete their three-dimension folding within endoplasmic reticulum (ER). Under the conditions of nutrient depletion, cell differentiation, or other stress statuses, misfolded or unfolded proteins aggregate within ER, and consequently cause ER stress and Unfolded Protein Response (UPR). In response to ER stress, BiP (Binding immunoglobulin protein) dissociates with IRE1a (Inositol-requiring kinase 1) and binds to unfolded proteins as a molecular chaperone in helping maintain their correct structure. Co-related to BiP's dissociation, IRE1a oglimerizes and activated its endoribonuclease domain by transautophosphorylation. Activated IRE1a then, by cleaving mRNA of Xbp1 and activating its transcription activity, triggers UPR. In this paper, in order to determine effect of BiP on transcription activity of IRE1a, we cloned promoter region of IRE1a into reporter gene analysis vector and found that BiP could upregulate promoter activity of IRE1a. Then, we constructed another 6 truncated promoter reporter vectors of IRE1a and pinpoint the core promoter activity region. Furthermore, both our RT-PCR and Western blot results showed that BiP could upregulate mRNA transcription level and protein expression level of IRE1a. Base on these findings, we can propose that, in order to alleviate ER stress caused by the misfolded or malfolded proteins, BiP could upregulate expression of IRE1a by increase its promoter activity. This study may suggest a novel signal pathway on IRE1a regulation in ER stress.
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Endorribonucleases/genética , Endorribonucleases/metabolismo , Regulação da Expressão Gênica , Proteínas de Choque Térmico/metabolismo , Regiões Promotoras Genéticas , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , Transcrição Gênica , Chaperona BiP do Retículo Endoplasmático , Ordem dos Genes , Genes Reporter , Vetores Genéticos/genética , Humanos , Ativação Transcricional , TransfecçãoRESUMO
Introduction: Down syndrome (DS) is the most common genetic condition that causes intellectual disability in humans. The molecular mechanisms behind the DS phenotype remain unclear. Therefore, in this study, we present new findings on its molecular mechanisms through single-cell RNA sequencing. Methods: Induced pluripotent stem cells (iPSCs) from the patients with DS and the normal control (NC) patients were differentiated into iPSCs-derived neural stem cells (NSCs). Single-cell RNA sequencing was performed to achieve a comprehensive single-cell level differentiation roadmap for DS-iPSCs. Biological experiments were also performed to validate the findings. Results and Discussion: The results demonstrated that iPSCs can differentiate into NSCs in both DS and NC samples. Furthermore, 19,422 cells were obtained from iPSC samples (8,500 cells for DS and 10,922 cells for the NC) and 16,506 cells from NSC samples (7,182 cells for DS and 9,324 cells for the NC), which had differentiated from the iPSCs. A cluster of DS-iPSCs, named DS-iPSCs-not differentiated (DSi-PSCs-ND), which had abnormal expression patterns compared with NC-iPSCs, were demonstrated to be unable to differentiate into DS-NSCs. Further analysis of the differentially expressed genes revealed that inhibitor of differentiation family (ID family) members, which exhibited abnormal expression patterns throughout the differentiation process from DS-iPSCs to DS-NSCs, may potentially have contributed to the neural differentiation of DS-iPSCs. Moreover, abnormal differentiation fate was observed in DS-NSCs, which resulted in the increased differentiation of glial cells, such as astrocytes, but decreased differentiation into neuronal cells. Furthermore, functional analysis demonstrated that DS-NSCs and DS-NPCs had disorders in axon and visual system development. The present study provided a new insight into the pathogenesis of DS.
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BACKGROUND: Serum protein induced by vitamin K absence or antagonist-II (PIVKA-II) is a promising biomarker for hepatocellular carcinoma (HCC) surveillance. AIM: To identify the contributing factors related to the abnormal elevation of PIVKA-II level and assess their potential influence on the performance of PIVKA-II in detecting HCC. METHODS: This study retrospectively enrolled in 784 chronic liver disease (CLD) patients and 267 HCC patients in Mengchao Hepatobiliary Hospital of Fujian Medical University from April 2016 to December 2019. Logistic regression and the area under the receiver operating characteristic curve (AUC) were used to evaluate the influencing factors and diagnostic performance of PIVKA-II for HCC, respectively. RESULTS: Elevated PIVKA-II levels were independently positively associated with alcohol-related liver disease, serum alkaline phosphatase (ALP), and total bilirubin (TBIL) for CLD patients and aspartate aminotransferase (AST) and tumor size for HCC patients (all P < 0.05). Serum PIVKA-II were significantly lower in patients with viral etiology, ALP ≤ 1 × upper limit of normal (ULN), TBIL ≤ 1 × ULN, and AST ≤ 1 × ULN than in those with nonviral disease and abnormal ALP, TBIL, or AST (all P < 0.05), but the differences disappeared in patients with early-stage HCC. For patients with TBIL ≤ 1 × ULN, the AUC of PIVKA-II was significantly higher compared to that in patients with TBIL > 1 × ULN (0.817 vs 0.669, P = 0.015), while the difference between ALP ≤ 1 × ULN and ALP > 1 × ULN was not statistically significant (0.783 vs 0.729, P = 0.398). These trends were then more prominently perceived in subgroups of patients with viral etiology and HBV alone. CONCLUSION: Serum PIVKA-II has better performance in detecting HCC at an early stage for CLD patients with normal serum TBIL.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/diagnóstico , Carcinoma Hepatocelular/etiologia , Neoplasias Hepáticas/patologia , Estudos Retrospectivos , alfa-Fetoproteínas/metabolismo , Biomarcadores , Protrombina , Bilirrubina , Biomarcadores TumoraisRESUMO
Pathogenic variants of zinc finger C4H2-type containing (ZC4H2) on the X chromosome cause a group of genetic diseases termed ZC4H2-associated rare disorders (ZARD), including Wieacker-Wolff Syndrome (WRWF) and Female-restricted Wieacker-Wolff Syndrome (WRWFFR). In the current study, a de novo c.352C>T (p.Gln118*) mutation in ZC4H2 (NM_018684.4) was identified in a female neonate born with severe arthrogryposis multiplex congenita (AMC) and Pierre-Robin sequence (cleft palate and micrognathia). Plasmids containing the wild-type (WT), mutant-type (MT) ZC4H2, or GFP report gene (N) were transfected in 293T cell lines, respectively. RT-qPCR and western blot analysis showed that ZC4H2 protein could not be detected in the 293T cells transfected with MT ZC4H2. The RNA seq results revealed that the expression profile of the MT group was similar to that of the N group but differed significantly from the WT group, indicating that the c.352C>T mutation resulted in the loss of function of ZC4H2. Differentially expressed genes (DEGs) enrichment analysis showed that c.352C>T mutation inhibited the expression levels of a series of genes involved in the oxidative phosphorylation pathway. Subsequently, expression levels of ZC4H2 were knocked down in neural stem cells (NSCs) derived from induced pluripotent stem cells (iPSCs) by lentiviral-expressed small hairpin RNAs (shRNAs) against ZC4H2. The results also demonstrated that decreasing the expression of ZC4H2 significantly reduced the growth of NSCs by affecting the expression of genes related to the oxidative phosphorylation signaling pathway. Taken together, our results strongly suggest that ZC4H2 c.352C>T (p.Gln118*) mutation resulted in the loss of protein function and caused WRWFFR.
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Códon sem Sentido , Proteínas Nucleares , Animais , Apraxias , Proteínas de Transporte/genética , Contratura , Feminino , Doenças Genéticas Ligadas ao Cromossomo X , Peptídeos e Proteínas de Sinalização Intracelular/genética , Atrofia Muscular , Proteínas Nucleares/genética , Oftalmoplegia , FenótipoRESUMO
BACKGROUND: Acute pancreatitis (AP) is an inflammatory disease in which the regulatory pathway is complex and not well understood. Soluble suppression of tumorigenicity 2 (sST2) protein receptor functions as a decoy receptor for interleukin (IL)-33 to prevent IL-33/suppression of tumorigenicity 2L (ST2L)-pathway-mediated T helper (Th)2 immune responses. AIM: To investigate the role of sST2 in AP. METHODS: We assessed the association between sST2 and severity of AP in 123 patients enrolled in this study. The serum levels of sST2, C-reactive protein (CRP) and Th1- and Th2-related cytokines, including interferon (IFN)-γ, tumor necrosis factor (TNF)-α, IL-2, IL-4, IL-5 and IL-13, were measured by highly sensitive ELISA, and the severity of AP in patients was evaluated by the 2012 Atlanta Classification Criteria. RESULTS: Serum sST2 levels were significantly increased in AP patients, and further, these levels were significantly elevated in severe AP (SAP) patients compared to moderately severe AP (MSAP) and mild AP (MAP) patients. Logistic regression showed sST2 was a predictor of SAP [odds ratio (OR): 1.003 (1.001-1.006), P = 0.000]. sST2 cutoff point was 1190 pg/mL, and sST2 above this cutoff was associated with SAP. sST2 was also a predictor of any organ failure and mortality during AP [OR: 1.006 (1.003-1.009), P = 0.000, OR: 1.002 (1.001-1.004), P = 0.012, respectively]. Additionally, the Th1-related cytokines IFN-γ and TNF-α in the SAP group were higher and the Th2-related cytokine IL-4 in the SAP group was significantly lower than those in MSAP and MAP groups. CONCLUSION: sST2 may be used as a novel inflammatory marker in predicting AP severity and may regulate the function and differentiation of IL-33/ST2-mediated Th1 and Th2 Lymphocytes in AP homeostasis.
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Pancreatite , Doença Aguda , Biomarcadores , Citocinas , Humanos , Proteína 1 Semelhante a Receptor de Interleucina-1 , Interleucina-13 , Pancreatite/diagnóstico , Índice de Gravidade de DoençaRESUMO
Background and Aim: Glioblastoma multiforme (GBM) is a highly aggressive brain malignancy that lacks reliable treatments. Resveratrol possesses anti-cancer effects, but its activity against glioblastoma cells is variable for unknown reasons. One mechanism through which anti-cancer drugs exert their effects is oxidative damage caused by increased reactive oxygen species (ROS) production. Thus, the present study examined the relationship between oxidative stress and sensitivity to resveratrol in glioblastoma cells. Methods: Two GBM cell lines (U251 and LN428) were exposed to 100 µM resveratrol for 48 h, and proliferation and apoptosis were assessed. ROS generation was evaluated using 2'-7'-dichlorodihydrofluorescein diacetate-based flow cytometry and fluorescent microscopy. Immunocytochemical staining and western blotting were conducted at regular intervals to profile the expression patterns of superoxide dismutase-2 (SOD2), catalase, caspase-9, caspase-3, and sulfotransferases (SULTs) in untreated and resveratrol-treated GBM cells. Results: Resveratrol-treated U251 cells, but not resveratrol-treated LN428 cells, exhibited remarkable growth arrest and extensive apoptosis accompanied by elevated intracellular ROS levels and attenuated SOD2 and catalase expression. Mitochondrial impairment and more distinct increases in the expression of activated caspase-9 and caspase-3 were detected in U251 cells following resveratrol treatment. The levels of resveratrol metabolic enzymes (SULT1A1 and SULT1C2) were lower in U251 cells than in LN428 cells. Conclusions: Resveratrol increased ROS generation and induced oxidation-related cellular lesions in U251 cells by activating an ROS-related mitochondrial signal pathway. The levels of SULTs and ROS may indicate the therapeutic outcomes of resveratrol treatment in GBM.
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BACKGROUND: Acute lung injury (ALI) is a common and life-threatening complication of severe acute pancreatitis (SAP). There are currently limited effective treatment options for SAP and associated ALI. Calycosin (Cal), a bioactive constituent extracted from the medicinal herb Radix Astragali exhibits potent anti-inflammatory properties, but its effect on SAP and associated ALI has yet to be determined. AIM: To identify the roles of Cal in SAP-ALI and the underlying mechanism. METHODS: SAP was induced via two intraperitoneal injections of L-arg (4 g/kg) and Cal (25 or 50 mg/kg) were injected 1 h prior to the first L-arg challenge. Mice were sacrificed 72 h after the induction of SAP and associated ALI was examined histologically and biochemically. An in vitro model of lipopolysaccharide (LPS)-induced ALI was established using A549 cells. Immunofluorescence analysis and western blot were evaluated in cells. Molecular docking analyses were conducted to examine the interaction of Cal with HMGB1. RESULTS: Cal treatment substantially reduced the serum amylase levels and alleviated histopathological injury associated with SAP and ALI. Neutrophil infiltration and lung tissue levels of neutrophil mediator myeloperoxidase were reduced in line with protective effects of Cal against ALI in SAP. Cal treatment also attenuated the serum levels and mRNA expression of pro-inflammatory cytokines tumor necrosis factor-α, interleukin-6, IL-1ß, HMGB1 and chemokine (CXC motif) ligand 1 in lung tissue. Immunofluorescence and western blot analyses showed that Cal treatment markedly suppressed the expression of HMGB1 and phosphorylated nuclear factor-kappa B (NF-κB) p65 in lung tissues and an in vitro model of LPS-induced ALI in A549 cells suggesting a role for HGMB1 in the pathogenesis of ALI. Furthermore, molecular docking analysis provided evidence for the direct interaction of Cal with HGMB1. CONCLUSION: Cal protects mice against L-arg-induced SAP and associated ALI by attenuating local and systemic neutrophil infiltration and inflammatory response via inhibition of HGMB1 and the NF-κB signaling pathway.
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Lesão Pulmonar Aguda , Proteína HMGB1 , Pancreatite , Doença Aguda , Lesão Pulmonar Aguda/induzido quimicamente , Lesão Pulmonar Aguda/tratamento farmacológico , Animais , Inflamação/tratamento farmacológico , Isoflavonas , Lipopolissacarídeos/toxicidade , Pulmão , Camundongos , Simulação de Acoplamento Molecular , NF-kappa B , Pancreatite/induzido quimicamente , Pancreatite/complicações , Pancreatite/tratamento farmacológicoRESUMO
Acute pancreatitis (AP) is a common serious acute condition of the digestive system that remains a clinical challenge. Severe acute pancreatitis (SAP) in particular is characterized by high morbidity and mortality. The present study was designed to investigate the protective effect of Galangin (Gal), a natural flavonol obtained from lesser galangal, on L-arginine-induced SAP in mice and in AR42J cells. Amylase and lipase activities were measured and the histopathology of the pancreas, lung, and kidney was evaluated. Inflammation and oxidative stress were assessed using ELISA, western blotting, RT-PCR, and immunohistochemistry. Gal was shown to reduce proinflammatory cytokine production and reactive oxygen species (ROS) generation in vivo and in vitro. L-arginine treatment reduced the expression of components of the nuclear factor E2-related factor 2 (Nrf2) signaling pathway and the downstream protein heme oxygenase-1 (HO-1) in mice, whereas Gal increased their expression. Furthermore, the Nrf2/HO-1 pathway inhibitor brusatol prevented the anti-inflammatory and antioxidant effects of Gal in mice with SAP. Taken together, our results imply that Gal has protective effects in L-arginine-induced SAP that are induced by the upregulation of the Nrf2/HO-1 pathway, which has anti-inflammatory and antioxidant effects. Thus, Gal may represent a promising treatment for SAP.
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Anti-Inflamatórios/farmacologia , Antioxidantes/farmacologia , Flavonoides/farmacologia , Heme Oxigenase (Desciclizante)/metabolismo , Heme Oxigenase-1/metabolismo , Proteínas de Membrana/metabolismo , Fator 2 Relacionado a NF-E2/metabolismo , Pâncreas/efeitos dos fármacos , Pancreatite/prevenção & controle , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/patologia , Injúria Renal Aguda/prevenção & controle , Lesão Pulmonar Aguda/metabolismo , Lesão Pulmonar Aguda/patologia , Lesão Pulmonar Aguda/prevenção & controle , Animais , Linhagem Celular , Modelos Animais de Doenças , Mediadores da Inflamação/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Rim/patologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos Endogâmicos C57BL , Estresse Oxidativo , Pâncreas/enzimologia , Pâncreas/patologia , Pancreatite/enzimologia , Pancreatite/patologia , Ratos , Índice de Gravidade de Doença , Transdução de SinaisRESUMO
OBJECTIVE: To investigate the factors associated with the occurrence of transplant renal artery stenosis (TRAS). METHODS: A retrospective analysis was conducted in 26 recipients who developed TRAS and 40 concurrent renal recipients without TRAS. We also conducted a nested case-control study in 14 patients with TRAS (TRAS-SD group) and another 14 non-TRAS recipients who received the allograft from the same donor (non-TRAS-SD group). RESULTS: Compared with those in the concurrent recipients without TRAS, acute rejection (AR) occurred at a significantly higher incidence (P=0.004) and the warm ischemia time (WIT) was significantly longer (P=0.015) and the level of high?density lipoprotein cholesterol (HDL--C) significantly lower (P=0.009) in the recipients with TRAS. Logistic regression analysis suggested that AR (P=0.007) and prolonged WIT (P=0.046) were risk factors of TRAS while HDL-C (P=0.022) was the protective factor against TRAS. In recent years early diagnosis of TRAS had been made in increasing cases, the interval from transplantation to TRAS diagnosis became shortened steadily, and the recipients tended to have higher estimated glomerular filtration rate at the time of TRAS diagnosis. CONCLUSION: Apart from the surgical technique, AR and prolonged WIT are also risk factors of TRAS while a high HDL-C level is the protective factor against TRAS. The improvement of the diagnostic accuracy by ultrasound is the primary factor contributing to the increased rate of early TRAS diagnosis in recent years.
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HDL-Colesterol/sangue , Transplante de Rim/efeitos adversos , Obstrução da Artéria Renal/fisiopatologia , Estudos de Casos e Controles , Rejeição de Enxerto/fisiopatologia , Humanos , Fatores de Proteção , Estudos Retrospectivos , Resultado do Tratamento , Isquemia QuenteRESUMO
Trisomy 21 is the most common chromosomal disorder and underlies Down syndrome. Epigenetics, such as DNA methylation and post-translational histone modifications, plays a vital role in Down syndrome. However, the functions of epigenetics-related long noncoding RNAs (lncRNAs), found to have an impact on neural diseases such as Alzheimer's disease, remain unknown in Down syndrome. In this study, we analyzed the RNA sequencing data from Down syndrome-induced pluripotent stem cells (iPSCs) and normal iPSCs. A large number of lncRNAs were identified differentially expressed in Down syndrome-iPSCs. Notably, stronger perturbation was shown in the expression of lncRNAs compared to protein coding genes (Kolmogorov-Smirnov test, P<0.05), suggesting that lncRNAs play more important roles in Down syndrome. Through gene set enrichment analysis and bi-clustering, we also found that most of the differential expressed lncRNAs were closely associated with mitochondrial functions (e.g. mitochondrion organization, P=3.21×10-17; mitochondrial ATP synthesis coupled electron transport, P=1.73×10-19 and mitochondrial membrane organization, P=4.04×10-8). PCR-array and qRT-PCR results revealed that almost all genes related to mitochondria were down-regulated in Down syndrome-iPSCs, implying that mitochondria were dysfunctional in Down syndrome (e.g. ATP5B, Fold Change=-8.2317; COX6A1, Fold Change=-12.7788 and SLC25A17, Fold Change=-22.1296). All in all, our study indicated that a stronger perturbation of lncRNAs expression may lead to the dysfunction of mitochondria in Down syndrome.
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Síndrome de Down/genética , Síndrome de Down/patologia , Perfilação da Expressão Gênica , Mitocôndrias/genética , RNA Longo não Codificante/genética , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismoRESUMO
OBJECTIVE: To investigate the optimal time window for intervention of BK virus (BKV) replication and its effect on the outcomes of kidney transplant recipients (KTRs). METHODS: A retrospective analysis of the clinical data and treatment regimens was conducted among KTRs whose urine BKV load was ≥1.0×104 copies/mL following the operation between April, 2000 and April, 2015. KTRs with urine BKV load <1.0×104 copies/mL matched for transplantation time served as the control group. RESULTS: A total of 54 recipients positive for urine BKV were included in the analysis. According to urine BKV load, the recipients were divided into 3 groups: group A with urine BKV load of 1.0×104-1.0×107 copies/mL (n=22), group B with urine BKV load >1.0×107 copies/mL (n=24), and group C with plasma BKV load ≥1.0×104 copies/mL (n=8); 47 recipients were included in the control group. During the follow-up for 3.2-34.5 months, the urine and plasma BKV load was obviously lowered after intervention in all the 54 BKV-positive recipients (P<0.05). Eighteen (81.82%) of the recipients in group A and 19 (79.17%) in group B showed stable or improved estimated glomerular filtration rate (eGFR) after the intervention; in group C, 4 recipients (50%) showed stable eGFR after the intervention. In the last follow-up, the recipients in groups A and B showed similar eGFR with the control group (P>0.05), but in group C, eGFR was significantly lower than that of the control group (P=0.001). The recipients in group A and the control group had the best allograft outcome with stable or improved eGFR. CONCLUSION: Early intervention of BKV replication (urine BKV load ≥1.0×104 copies/mL) in KTRs with appropriate immunosuppression reduction can be helpful for stabilizing the allograft function and improving the long-term outcomes.
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By targeting a new binding region at the interface between αß-tubulin heterodimers at the colchicine binding site, we designed a series of 7-substituted 1-methyl-1,4-dihydroindeno[1,2-c]pyrazoles as potential tubulin polymerization inhibitors. Among the compounds synthesized, 2-(6-ethoxy-3-(3-ethoxyphenylamino)-1-methyl-1,4-dihydroindeno[1,2-c]pyrazol-7-yloxy)acetamide 6a and 2-(6-ethoxy-3-(3-ethoxyphenylamino)-1-methyl-1,4-dihydroindeno[1,2-c]pyrazol-7-yloxy)-N-hydroxyacetamide 6n showed noteworthy low nanomolar potency against HepG2, Hela, PC3, and MCF-7 cancer cell lines. In mechanism studies, 6a inhibited tubulin polymerization and disorganized microtubule in A549 cells by binding to tubulin colchicine binding site. 6a arrested A549 cells in G2/M phase that was related to the alterations in the expression of cyclin B1 and p-cdc2. 6a induced A549 cells apoptosis through the activation of caspase-3 and PARP. In addition, 6a inhibited capillary tube formation in a concentration-dependent manner. In nonsmall cell lung cancer xenografts mouse model, 6a suppressed tumor growth by 59.1% at a dose of 50 mg/kg (ip) without obvious toxicity, indicating its in vivo potential as anticancer agent.
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Antineoplásicos/farmacologia , Colchicina/metabolismo , Desenho de Fármacos , Pirazóis/farmacologia , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Sítios de Ligação/efeitos dos fármacos , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Colchicina/química , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Camundongos Nus , Modelos Moleculares , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Pirazóis/síntese química , Pirazóis/química , Relação Estrutura-Atividade , Tubulina (Proteína)/química , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/químicaRESUMO
Tumor vasculature is an important target in cancer treatment. Two distinct vasculartargeting therapeutic strategies are applied to attack cancer cells indirectly. The antiangiogenic approach intervenes in the neovascularization processes and blocks the formation of new blood vessels, while th e antivascular approach targets the established tumor blood vessels, making vascular shutdown and resulting in rapid haemorrhagic necrosis and tumor cell death. A number of compounds with diverse structural scaffolds have been designed to target tumor vasculature and they are called vascular disrupting agents (VDAs). The biological or ligand-directed VDAs utilize antibodies, peptides or growth factors to deliver toxins or pro-coagulants or proapoptotic affectors to tumor-related blood vessels, while the small-molecule VDAs selectively target tumor blood vessels and have little effects on the normal endothelium. Among the small-molecule VDAs, the tubulin colchicine binding site inhibitors have been extensively studied and many of them have entered the clinical trials, including CA-4P, CA-1P, AVE8062, OXi4503, CKD-516, BNC105P, ABT-751, CYT- 997, ZD6126, NPI-2358, MN-029 and EPC2407. This review makes a summary of the small-molecule VDAs in clinical developments and highlights some potential VDA leads or candidates for the treatment of tumors.
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Antineoplásicos/farmacologia , Colchicina/farmacologia , Neoplasias/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Moduladores de Tubulina/farmacologia , Tubulina (Proteína)/metabolismo , Antineoplásicos/química , Sítios de Ligação/efeitos dos fármacos , Colchicina/química , Humanos , Neoplasias/metabolismo , Neovascularização Patológica/metabolismo , Moduladores de Tubulina/químicaRESUMO
In Traditional Chinese Medicine (TCM), tongue diagnosis (TD) has been an important diagnostic method for the last 3000 years. Tongue coating can be used as a very sensitive marker to determine the progress of chronic gastritis. Therefore, the scientific, qualitative, and quantitative study for the pathophysiologic basis of tongue coating (TC) emerged as a major direction for the objective research of TD. In our current report, we used GC/MS technology to determine the potential changes of metabolites and identify special metabolic biomarkers in the TC of H. pylori infected chronic gastritis patients. Four discriminative metabolites were identified by GC/MS between the TC of H. pylori infection (G + H) and without H. pylori infection (G - H) patients: ethylene, cephaloridine, γ-aminobutyric acid, and 5-pyroglutamic acid, indicating that changes in amino acid metabolism are possibly involved in the formation of TC, and the amino acid metabolites are part of the material components of TC in G + H patients.
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In this article, we describe a comprehensive management program for hypertension (HTN), based on the experience of leading cardiovascular centers in China. This comprehensive approach, adhering to a number of core principles, includes diagnosis and therapeutic interventions. Therapeutic management includes lifestyle changes, risk factor management and pharmacological intervention and should allow reliable lowering blood pressure (BP). Additional paragraphs discuss the relationship between paroxysmal atrial fibrillation (PAF), and HTN.
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The phosphoinositide 3-kinases (PI3Ks) are lipid kinases that play a central role in control of cell growth, proliferation, migration, survival and angiogenesis, and drive the progression of tumors by activating phosphoinositidedependent kinase, protein kinase B (Akt) and the mammalian target of rapamycin (mTOR). The PI3K/Akt/mTOR pathway has been shown to play an important role in cancer and has become an important target for anticancer drug development. An interest in targeting two important points along this critical signaling pathway has spurred the development of dual PI3K/mTOR inhibitors that could both prevent cancer cell proliferation and induce programmed cell death (apoptosis) by fully suppressing Akt activation. This review summarizes the developments of a diversity of small molecule dual PI3K/mTOR inhibitors in recent 10 years, with an emphasis on their structural features, the relevant biological activities, and the structure-activity relationships (SARs).
Assuntos
Inibidores de Fosfoinositídeo-3 Quinase , Inibidores de Proteínas Quinases/química , Bibliotecas de Moléculas Pequenas/química , Serina-Treonina Quinases TOR/antagonistas & inibidores , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Humanos , Fosfatidilinositol 3-Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Relação Estrutura-Atividade , Serina-Treonina Quinases TOR/metabolismoRESUMO
The main objective of the current study was to develop a universal method for a protein binding assay of complicated herbal components, and to investigate the possible relationship between compound polarity and protein binding using Schisadra lignans as an example. Firstly, the rat, dog and human plasma were spiked with three different concentrations of Schisandra chinensis extract (SLE), and ultramicrofiltration was used to obtain the unbound ingredients. Secondly, thirty-one Schisandra lignans in total plasma and ultrafiltered fluid were measured by LC-IT-TOFMS. Lastly, a relative exposure approach, which entailed calculating the relative concentrations of each Schisandra lignan from the corresponding calibration equation created from the calibration samples spiked with the stock solution of SLE, was applied in order to overcome the absence of authentic standards. The results showed that Schisandra lignans exhibited a high capability to bind with plasma protein, furthermore, the protein binding ratio of the lignan components increased proportionally with their individual chromatographic retention time, which indicated that the ratio of protein binding of lignans might increase accordingly with decreasing polarity. This study suggested that the compound polarity might be an important factor affecting the plasma protein binding of herbal components.