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1.
Theranostics ; 11(4): 1970-1981, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33408792

RESUMO

The binding between the immune checkpoints, programmed cell death ligand 1 (PD-L1) and programmed cell death 1 (PD-1), compromises T-cell-mediated immune surveillance. Immune checkpoint therapy using immune checkpoint inhibitors (ICIs) to block PD-L1 on cancer cell membrane or PD-1 on activated T cell membrane can restore antitumor function of T cell. However, the intracellular expression of PD-L1 and its active redistribution to cancer cell membrane may impair the therapeutic benefits of ICIs. To address this issue, herein we develop a nanodrug (MS NPs) capable of reducing PD-L1 expression and enhancing antitumor effects. Methods: The nanodrug was self-assembled from immunoadjuvant metformin (Met, an old drug) and anticancer agent 7-ethyl-10-hydroxycamptothecin (SN38) via hydrogen bonds and electrostatic interactions. A series of experiments, including the characterization of MS NPs, the validation of MS NPs-mediated down-regulation of PD-L1 expression and in vitro therapeutic effect, the MS NPs-mediated in vivo chemo-immunotherapy and tumor metastasis inhibition were carried out. Results: Different from ICIs that conformationally block PD-L1 on cancer cell membrane, MS NPs directly reduced the PD-L1 level via metformin to achieve immunotherapy. Therefore, MS NPs showed enhanced chemo-immunotherapy effect than its counterparts. MS NPs were also effective in inhibiting tumor metastasis by remodeling the extracellular matrix and restoring immune surveillance. Additionally, no obvious toxicity was observed in major organs from MS NPs-treated mice and a high survival rate of mice was obtained after MS NPs treatment. Conclusion: We have designed nanodrug MS NPs by self-assembly of the immunoadjuvant Met and the anticancer agent SN38 for combined immunotherapy and chemotherapy. MS NPs might break the deadlock of antibody-based ICIs in immunotherapy, and repurposing old drug might provide a new perspective on the development of novel ICIs.

2.
Brain Behav ; : e01969, 2020 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-33242234

RESUMO

INTRODUCTION: The relationship between poststroke fatigue (PSF) and serum Cystatin C (Cys-C) levels in hypertensive intracerebral hemorrhage (HICH) patients has not been determined. In this study, we investigated the association between serum Cys-C levels and PSF in HICH patients. METHODS: A total of 125 patients with HICH were enrolled. Fatigue assessment was performed 6 months after HICH onset. The presence of PSF was defined as Fatigue Severity Scale (FSS) of 4 or more. Serum Cys-C levels were measured within 24 hr after admission. The correlation between FSS score and Cys-C level was analyzed by Spearman's correlation. Receiver operating characteristic (ROC) curves for PSF were calculated using Cys-C values. RESULTS: Of enrolled 125 patients in the study, 36.0% who developed PSF were divided to the PSF group, which had higher Cys-C levels compared with the no-PSF group. There was significant positive correlation between FSS score and serum Cys-C level. Receiver operating characteristic curves for PSF revealed an area under the curve of 0.86 for Cys-C. High admission Cys-C (>0.75mg/L) yielded specificity of 93.7%, positive predictive value of 87.5%, and negative predictive value of 88.2%. In multivariate analysis, Cys-C increased by 1 mg/dl (0.1 mg/L), and the risk of PSF in patients increased by 2.55 times (odds ratio = 2.55, 95% CI: 1.65-3.95, p < .001). CONCLUSIONS: High Cys-C levels have predictive value for PSF and can be used as one screening indicator for PSF occurrence.

3.
Artigo em Inglês | MEDLINE | ID: mdl-33236952

RESUMO

Upregulating the expression of long non-coding RNA LINC00982 controlled cell proliferation in gastric cancer, but the regulatory molecular mechanisms are yet to be expounded. We here aimed to elaborate how LINC00982 regulated the malignancy of gastric cancer cells. RT-qPCR and Western blot analysis were used to detect the expression of LINC00982 and CTSF in gastric cancer tissues and cells. Modulatory effect of LINC00982 on gastric cancer cells was assessed by CCK-8, colony formation, Transwell migration and invasion assays. The relationship between LINC00982, HEY1 and CTSF was examined by RIP, luciferase assay, and ChIP, and their interaction in the regulation of gastric cancer cellular functions was analyzed by performing gain-of-function and rescue assays. The nude mouse model of tumor formation was developed to examine the effects of LINC00982 on tumorigenesis. LINC00982 was lowly expressed in gastric cancer tissues, while its overexpression impaired the proliferative, migratory and invasive properties of gastric cancer cells. Furthermore, LINC00982 could bind to transcription factor HEY1 and inhibited its expression. Through blocking the binding of HEY1 to CTSF promoter. LINC00982 promoted the expression of CTSF. Overexpression of HEY1 or inhibition of CTSF could reverse the anti-tumor effects of LINC00982 on gastric cancer, which were further demonstrated in vivo. Taken together, LINC00982 acted as a tumor suppressor in gastric cancer, which is therefore suggested to be a potential anti-tumor target for gastric cancer.

4.
PeerJ ; 8: e9780, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32879807

RESUMO

Background: Monochasma savatieri is an endangered hemiparasitic medicinal plant with a variety of antioxidant, antimicrobial and anti-inflammatory properties. Despite the urgent need to understand the parasitic biology of M. savatieri, parasite-host associations have long been neglected in studies of M. savatieri. Methods: We conducted a pot cultivation experiment to analyze changes in the growth traits, physiological performance and anatomical structures of M. savatieri grown with the potential host Gardenia jasminoides E., before and after the establishment of the parasite-host association. Results: Prior to the establishment of the parasite-host association, the presence of the host had no significant effect on the maximum root length, leaf indexes or total dry weight of M. savatieri seedlings, but had significant positive effect on seedling height, number of roots or number of haustoria. When it was continuously grown without a host, M. savatieri growth was rather slow. The establishment of the parasite-host association enhanced the growth of M. savatieri, and higher levels of photosynthetic pigments, increased antioxidant enzyme activity and lower malondialdehyde accumulation were observed in M. savatieri with an established parasite-host association. Furthermore, an analysis of the anatomical structures of M. savatieri showed that the establishment of the parasite-host association enabled better development of the seedling vegetative organs than that in seedlings without parasite-host associations. Conclusions: Our study demonstrates the physiological and anatomical changes that occurred in M. savatieri after connection with a host and suggests that the enhanced growth and development of M. savatieri were highly dependent on the parasite-host association.

5.
iScience ; 23(9): 101446, 2020 Aug 10.
Artigo em Inglês | MEDLINE | ID: mdl-32829287

RESUMO

Identification of safe and effective compounds to increase or activate UCP1 expression in brown or white adipocytes remains a potent therapeutic strategy to combat obesity. Here we reported that, glyburide, one of the FDA-approved drugs currently used to treat type 2 diabetes, can significantly enhance UCP1 expression in both brown and white adipocytes. Glyburide-fed mice exhibited a clear resistance to high-fat diet-induced obesity, reduced blood triglyceride level, and increased UCP1 expression in brown adipose tissue. Moreover, in situ injection of glyburide to inguinal white adipose tissue remarkably enhanced UCP1 expression and increased thermogenesis. Further mechanistic studies indicated that the glyburide effect in UCP1 expression in adipocytes was KATP channel independent but may involve the regulation of the Ca2+-Calcineurin-NFAT signal pathway. Overall, our findings revealed the significant effects of glyburide in regulating UCP1 expression and thermogenesis in adipocytes, which can be potentially repurposed to treat obesity.

6.
Angew Chem Int Ed Engl ; 59(46): 20411-20416, 2020 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-32743842

RESUMO

Efforts have been devoted to achieving a highly efficient artificial synthesis of ammonia (NH3 ). Reported herein is a novel Fe-MoS2 catalyst with Fe atomically dispersed onto MoS2 nanosheets, imitating natural nitrogenase, to boost N2 electroreduction into NH3 at room temperature. The Fe-MoS2 nanosheets exhibited a faradic efficiency of 18.8 % with a yield rate of 8.63 µg NH 3 mgcat. -1 h-1 for NH3 at -0.3 V versus the reversible hydrogen electrode. The mechanism study revealed that the electroreduction of N2 was promoted and the competing hydrogen evolution reaction was suppressed by decorating the edge sites of S in MoS2 with the atomically dispersed Fe, resulting in high catalytic performance for the electroreduction of N2 into NH3 . This work provides new ideas for the design of catalysts for N2 electroreduction and strengthens the understanding about N2 activation over Mo-based catalysts.

7.
Nat Metab ; 2(5): 447-460, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32694659

RESUMO

The rhythmic regulation of transcriptional processes is intimately linked to lipid homeostasis, to anticipate daily changes in energy access. The Rev-erbα-HDAC3 complex was previously discovered to execute the rhythmic repression of lipid genes; however, the epigenetic switch that turns on these genes is less clear. Here, we show that genomic recruitment of MRG15, which is encoded by the mortality factor on chromosome 4 (MORF4)-related gene on chromosome 15, displays a significant diurnal rhythm and activates lipid genes in the mouse liver. RNA polymerase II (Pol II) recruitment and histone acetylation correspond to MRG15 binding, and the rhythm is impaired upon MRG15 depletion, establishing MRG15 as a key modulator in global rhythmic transcriptional regulation. MRG15 interacts with the nuclear receptor LRH-1, rather than with known core clock proteins, and is recruited to genomic loci near lipid genes via LRH-1. Blocking of MRG15 by CRISPR targeting or by the FDA-approved drug argatroban, which is an antagonist to MRG15, attenuates liver steatosis. This work highlights MRG15 as a targetable master regulator in the rhythmic regulation of hepatic lipid metabolism.


Assuntos
Proteínas Cromossômicas não Histona/genética , Proteínas Cromossômicas não Histona/metabolismo , Epigênese Genética/genética , Epigênese Genética/fisiologia , Metabolismo dos Lipídeos/genética , Metabolismo dos Lipídeos/fisiologia , Fígado/metabolismo , Transativadores/genética , Transativadores/metabolismo , Animais , Arginina/análogos & derivados , Arginina/farmacologia , Arginina/uso terapêutico , Linhagem Celular , Ritmo Circadiano , Epigênese Genética/efeitos dos fármacos , Epigenômica , Fígado Gorduroso/tratamento farmacológico , Teste de Tolerância a Glucose , Histonas/metabolismo , Humanos , Metabolismo dos Lipídeos/efeitos dos fármacos , Fígado/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Ácidos Pipecólicos/farmacologia , Ácidos Pipecólicos/uso terapêutico , RNA Polimerase II/metabolismo , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Sulfonamidas/farmacologia , Sulfonamidas/uso terapêutico
8.
BMC Infect Dis ; 20(1): 435, 2020 Jun 22.
Artigo em Inglês | MEDLINE | ID: mdl-32571239

RESUMO

BACKGROUND: The aseptic meningitis caused by varicella zoster virus (VZV) reactivation was less described in the literature, most of which were detected by means of polymerase chain reaction. The authors presented 4 adult immunocompetent patients with acute aseptic meningitis with VZV infection diagnosed by next-generation sequencing (NGS). CASE PRESENTATION: Four patients were admitted to the hospital with headache and fever between March 2018 and August 2019. The median ages were 37 years (range 22-52 years). The median symptoms onset to clinic time was 3.5 days (range 3-6 days). Two patients had signs of meningeal irritation. Rash occurred after the meningitis symptoms in 1 patient (time from meningitis symptoms to rash, 2 days). No other sign or symptom was reported. The brain Magnetic resonance imaging and electroencephalography were normal in all patients. Cerebrospinal fluid (CSF) samples were obtained at a median of 4 days (range 3-7 days) from the meningitis symptoms onset. Opening pressure of lumbar puncture after admission were high in these cases (median 256 mm H2O; range 165-400 mm H2O). White blood cell counts and protein levels were significantly elevated in CSF samples (median 317 × 10^6/L, range 147-478 × 10^6/L; median 1.41 g/L, range 0.57-1.79 g/L). The cytology of CSF demonstrated a lymphocytic pleocytosis, and most multinuclear cells. The culture of CSF was negative for all 4 cases, while T-cell spot test was positive for 2 cases, who were administrated with anti-tuberculosis treatment for suspicious tuberculous meningitis. NGS of CSF (the Vision Medical Research Institute) detected specific sequences of VZV in the 4 cases within 72 h after admission. The inappropriate treatment were stopped while acyclovir were continued intravenously for 10-14 days. All patients recovered completely. CONCLUSIONS: VZV is an infectious agent that causes aseptic meningitis in immunocompetent adults and could not be accompanied by skin manifestations. The NGS of CSF is a rapid detection for the identification and differentiation of meningitis in patients, which is of great importance for providing the rapid and accurate diagnosis and the targeted antimicrobial therapy for central nervous system infection.


Assuntos
Líquido Cefalorraquidiano/virologia , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Meningite Asséptica/etiologia , Meningite Viral/etiologia , Infecção pelo Vírus da Varicela-Zoster/complicações , Aciclovir/uso terapêutico , Adulto , Antivirais/uso terapêutico , Líquido Cefalorraquidiano/citologia , Exantema/etiologia , Exantema/virologia , Herpesvirus Humano 3/genética , Humanos , Imagem por Ressonância Magnética , Masculino , Meningite Asséptica/diagnóstico , Meningite Asséptica/tratamento farmacológico , Meningite Viral/diagnóstico por imagem , Pessoa de Meia-Idade , Infecção pelo Vírus da Varicela-Zoster/diagnóstico por imagem , Infecção pelo Vírus da Varicela-Zoster/tratamento farmacológico , Adulto Jovem
9.
Mol Med Rep ; 22(1): 155-164, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32377739

RESUMO

Data for p53 mutation in prostate cancer in The Cancer Genome Atlas database revealed that >85% of p53 mutations occurred in the p53 DNA binding domain. These mutations not only severely damage the function of the p53 protein, but also reduce the disease­free survival of patients. Peroxisome proliferator­activated receptor γ coactivator­1α (PGC­1α) is involved in the regulation of mitochondrial function and is highly expressed in prostate cancer PC3 and DU145 cells with p53 deletion or mutation. However, whether p53 negatively regulates PGC­1α in prostate cancer cells remains to be elucidated. In the present study, p53 overexpression was induced in prostate cancer PC3 cells. Subsequently, the expression levels of PGC­1α and alterations to mitochondrial function were assessed. Moreover, PGC­1α was activated in prostate cancer PC3 cells using ZLN005 to investigate alterations to mitochondrial function and cell apoptosis. The present study revealed that p53 decreased the expression and nuclear localization of the PGC­1α protein and induced mitochondrial dysfunction. Activation of PGC­1α partially reversed p53­mediated mitochondrial dysfunction. Inhibition of the p53/PGC­1α pathway on mitochondrial biogenesis and fission­/fusion­associated gene and protein expression were associated with mitochondrial dysfunction. p53/PGC­1α­mediated mitochondrial dysfunction promoted apoptosis of PC3 prostate cancer cells. The results indicated that PGC­1α is an essential target of p53­induced apoptosis in prostate cancer cells and indicated that targeting PGC­1α may provide a new therapeutic strategy for prostate cancer.

10.
Eur J Med Chem ; 193: 112221, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32222663

RESUMO

Heparanase (HPSE)-directed tumor progression plays a crucial role in mediating tumor-host crosstalk and priming the tumor microenvironment, leading to tumor growth, metastasis and chemo-resistance. HPSE-mediated breakdown of structural heparan sulfate (HS) networks in the extracellular matrix (ECM) and basement membranes (BM) directly facilitates tumor growth and metastasis. Lysosome HPSE also induces multi-drug resistance via enhanced autophagy. Therefore, HPSE inhibitors development has become an attractive topic to block tumor growth and metastasis or eliminate drug resistance. In this review, we summarize HPSE inhibitors applied experimentally and clinically according to interaction with the binding sites of HPSE and participation of growth factors. The antitumor activity and structure-activity relationship (SAR) are also emphasized.


Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Glucuronidase/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/química , Produtos Biológicos/química , Produtos Biológicos/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/química , Glucuronidase/metabolismo , Humanos , Neoplasias/metabolismo , Oligossacarídeos/química , Oligossacarídeos/farmacologia , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia
11.
J Am Chem Soc ; 142(5): 2129-2133, 2020 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-31955575

RESUMO

Labile heme (LH) is an important signaling molecule in virtually all organisms. However, specifically detecting LH remains an outstanding challenge. Herein, by learning from the bioactivation mechanism of artemisinin, we have developed the first LH-responsive small-molecule fluorescent probe, HNG, based on a 4-amino-1,8-naphthalimide (NG) fluorophore. HNG showed high selectivity for LH without interference from hemin, protein-interacting heme, and zinc protoporphyrin. Using HNG, the changes of LH levels in live cells were imaged, and a positive correlation of LH level with the degree of hemolysis was uncovered in hemolytic mice. Our study not only presents the first molecular probe for specific LH detection but also provides a strategy to construct probes with high specificity through a bioinspired approach.

12.
Neurosurg Rev ; 2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-31953781

RESUMO

Atorvastatin therapy in chronic subdural hematoma patients has attracted more and more clinical attention. To evaluate the efficacy of atorvastatin in the treatment of chronic subdural hematoma. A systematic literature search was performed in the PubMed, Embase, and Cochrane Library databases; related controlled trials comparing the efficacy of atorvastatin in the treatment of chronic subdural hematoma published from inception to December 2018 were collected. We used Cochrane risk of bias method to evaluate the quality of the included studies. Meta-analysis was used to analyze the included data by RevMan 5.3 software. Of the 53 retrieved studies, 6 trials were included. Results of meta-analysis showed that compared with chronic subdural hematoma patients without atorvastatin treatment, both in patients who have had surgery and those who have not, atorvastatin were effective in reducing the incidence of recurrence requires surgery (OR = 0.30, 95% CI 0.19-0.48, P < 0.00001). And improve the recovery rate of neurological function of patients (OR = 1.75, 95% CI 1.08-2.83, P = 0.02). This meta-analysis suggests that patients with chronic subdural hematoma can improve their prognosis after receiving atorvastatin. Additionally, the neurological function recovery appears to be improving by atorvastatin.

13.
Ciênc. rural (Online) ; 50(3): e20190649, 2020. tab, graf
Artigo em Inglês | LILACS-Express | LILACS | ID: biblio-1089557

RESUMO

ABSTRACT: Monochasma savatieri Franch. ex Maxim is a perennial, parasitic herb used in traditional Chinese medicine and its wild resources have decreased sharply in recent years due to destructively harvesting and habitat destruction. Haustorium formation is a key event of parasites, but the concentrations of haustorium-inducing factors vary with species and cultivation conditions. In this study, we investigated the effects of the 2,6-dimethoxy-p-benzoquinone (DMBQ) concentration and cultivation density on the growth traits, haustorium formation and biomass of M. savatieri in the absence of a host plant. The results showed that both the DMBQ concentration and cultivation density regulated growth traits, haustorium formation and biomass in M. savatieri. The number of haustoria was significantly positively correlated with seedling height, maximum root length, the number of root tips and total dry weight. Membership function analysis revealed an overall greater increase in growth traits, haustorium formation and biomass when M. savatieri was treated with 10 μmol·L-1DMBQ and grew solitarily. These results offer an understanding of growth in M. savatieri influenced by the DMBQ concentration and cultivation density, which may aid in the establishment of a comprehensive cultivation system for M. savatieri or similar plants.


RESUMO: Monochasma savatieri Franch. O ex Maxim é uma erva parasitária aperene usada na medicina tradicional chinesa suas fontes diminuíram acentuadamente nos últimos anos devido à colheita destrutiva e à destruição de habitats e condições de sobrevivência no campo. Neste estudo, investigamos os efeitos da concentração de 2,6-dimetoxi-p-benzoquinona (DMBQ) e densidade de cultivo sobre as características de crescimento, formação de haustório e biomassa de M. savatieri na ausência de uma planta hospedeira. Os resultados mostraram que a concentração de DMBQ e a densidade de cultivo regularam as características de crescimento, a formação de haustório e a biomassa em M. savatieri. O número de haustórios foi significativamente correlacionado positivamente com a altura das plântulas, comprimento máximo das raízes, número de pontas das raízes e peso seco total. Revelou também um aumento geral nas características de crescimento, formação de haustório e biomassa quando M. savatieri foi tratado com 10 μmol • L-1DMBQ e cresceu solitariamente. Esses resultados oferecem uma compreensão do crescimento de M. savatieri influenciado pela concentração de DMBQ e densidade de cultivo, o que pode ajudar no estabelecimento de um sistema abrangente de cultivo para plantas similares de M. savatierior.

14.
Biochem Biophys Res Commun ; 517(2): 272-277, 2019 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-31349969

RESUMO

QT interval prolongation and depolarization of resting membrane potential (RMP) were found in acute myocardial infarction (MI) which is involved in the arrhythmogenic mechanism and raising the risk to initiate torsade de pointes. However, clinical anti-arrhythmic agents that primarily act on QT interval and RMP are not currently available. Our objective was to determine whether Apelin, an endogenous peptide ligand of receptor APJ, affects QT interval and RMP and underlying mechanisms. To test this viewpoint, mice were subjected to MI by ligating the left main coronary artery and Apelin was applied through tail vein at 5 min prior coronary occlusion in tested group. Compared to MI group, pretreatment of Apelin (15 µg/kg) shortened QTc and QT interval induced by MI, significantly elevated RMP and shortened action potential duration (APD) by increased IK1 currents recorded using whole-cell patch technique from cardiomyocytes underwent MI. In cultured neonatal mouse cardiomyocytes, Apelin (1 µmol/L) restored hypoxia-induced Kir2.1 down-regulation, which was abolished by IP3K inhibitor LY-294002. Additionally, Apelin elicited a time-dependent increase in phosphorylation of Akt leading to increase in PI3-kinase activity. These results showed that Apelin enhanced IK1/Kir2.1 currents via IP3K pathway as by rescue ischemia- and hypoxia-induced RMP depolarization and prolongation of QT interval, which may prevent or cure acute ischemic-mediated arrhythmias. This study brings new information to anti-arrhythmic theories and provides a potential target for the clinical management of acute ischemia-related arrhythmias.

15.
Nano Lett ; 19(8): 4965-4973, 2019 Aug 14.
Artigo em Inglês | MEDLINE | ID: mdl-31298859

RESUMO

The biggest challenge of potassium-ion batteries (KIBs) application is to develop high-performance electrode materials to accommodate the potassium ions large size. Herein, by rational design, we carbonize three-dimensional (3D) ordered macroporous ZIF-8 to fabricate 3D interconnected nitrogen-doped hierarchical porous carbon (N-HPC) that shows excellent rate performance (94 mAh g-1 at 10.0 A g-1), unprecedented cycle stability (157 mA g-1 after 12000 cycles at 2.0 A g-1), and superior reversible capacity (292 mAh g-1 at 0.1 A g-1). The 3D hierarchical porous structure diminishes the diffusion distance for both ions/electrons, while N-doping improves the reactivity and electronic conductivity via producing more defects. In addition, the bicontinuous structure possesses a large specific surface area, decreasing the current density, again improving the rate performance. In situ Raman spectra analysis confirms the potassiation and depotassiation in the N-HPC are highly reversible processes. The galvanostatic intermittent titration measurement and first-principles calculations reveal that the interconnected macropores are more beneficial to the diffusion of the K+. This 3D interpenetrating structure demonstrates a superiority for energy storage applications.

16.
Epilepsy Res ; 154: 139-143, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31151073

RESUMO

PURPOSE: Valproic acid (VPA) is frequently used in the treatment of epilepsy. The adverse effects of VPA include hyperammonemia (HA) which is characterized by abnormally elevated blood ammonia level. Carbamoyl-Phosphate Synthase 1 (CPS1) is an enzyme catalyzing the initial step of removing ammonia from blood. Studies have demonstrated that the CPS1 polymorphism rs1047891-A allele carriers were susceptible to VPA-induced HA. However, the evidences remained controversial. In this study, we sought to validate the association between rs1047891 and VPA-induced HA by combining the association results from previous studies together. METHODS: We first conducted a systematic meta-analysis to determine whether rs1047891 was statistically significant. Then, we further evaluated the pleiotropic effects of rs1047891 using published genome-wide association studies (GWAS) and UKBB results. A conditional analysis was conducted to investigate whether the association between rs1047891 and VPA-induced HA was mediated by cardiovascular or renal disease risk factors or vice versa. RESULTS: The allelic, dominant and recessive ORs of rs1047891-A were all significant in our fixed-effect meta-analysis. In GWAS catalog and UKBB data, rs1047891 was associated with basal metabolic rate, adiposity and hematology traits, cardiovascular and renal disease risk factors. We further proved that plasma HDL cholesterol and homocysteine level, in addition to eGFR by serum creatinine, were associated with VPA-induced HA risk independently from rs1047891 polymorphism. CONCLUSION: In conclusion, the SNP rs1047891 was associated with VPA-induce HA among epilepsy patients. Meanwhile, plasma HDL cholesterol and homocysteine level had independent effects from it.

17.
Artigo em Inglês | MEDLINE | ID: mdl-30906280

RESUMO

Fibroblast growth factor 1 (FGF1) is reported to be expressed in the testis. How FGF1 affects stem Leydig cell development remains unclear. Here, we report the effects of FGF1 on rat stem Leydig cell development in an ethane dimethane sulfonate (EDS)-treated model. FGF1 (100 ng/testis) significantly increased serum testosterone level, increased PCNA-positive Leydig cell percentage and Leydig cell number, but down-regulated the expression of Lhcgr, Star, Cyp11a1, Hsd3b1, Cyp17a1, and Hsd11b1 in Leydig cells per se, after its daily intratesticular injection from post-EDS day 14 for 14 days. Primary culture of the seminiferous tubules showed that FGF1 stimulated EdU incorporation to stem Leydig cells but blocked the differentiation into the Leydig cell lineage, possibly via FGFR1-mediated mechanism. In conclusion, FGF1 promotes stem Leydig cell proliferation but blocks its differentiation.

18.
Cell Rep ; 26(4): 884-892.e4, 2019 01 22.
Artigo em Inglês | MEDLINE | ID: mdl-30673611

RESUMO

DNA variants in the SLC16A11 coding region were identified to be strongly associated with type 2 diabetes (T2DM) in a Mexican population. Previous studies suggested that these variants disrupt SLC16A11 function and therefore proposed to revive SLC16A11 levels or activity to achieve therapeutic benefit. However, with knockout mouse models, here we show that Slc16a11 depletion has no significant metabolic defects. Further studies demonstrate that reconstitution of the mutant, but not the wild-type Slc16a11, in the liver of knockout mice causes more triglyceride accumulation and induction of insulin resistance via upregulation of lipin 1, suggesting gaining of aberrant functions of the mutant protein that affects lipid metabolism. Our findings offer a different explanation to the function of these diabetic variants, challenging the concept of enhancing SLC16A11 function to treat T2DM. The contradictory results by our and previous studies suggest that how the SLC16A11 locus contributes to human metabolism warrants further investigation.


Assuntos
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Mutação com Ganho de Função , Resistência à Insulina/genética , Transportadores de Ácidos Monocarboxílicos , Triglicerídeos , Animais , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Diabetes Mellitus Tipo 2/patologia , Células HEK293 , Humanos , Camundongos , Camundongos Knockout , Transportadores de Ácidos Monocarboxílicos/genética , Transportadores de Ácidos Monocarboxílicos/metabolismo , Fosfatidato Fosfatase/genética , Fosfatidato Fosfatase/metabolismo , Triglicerídeos/genética , Triglicerídeos/metabolismo
19.
J Neurol Sci ; 397: 174-178, 2019 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-30641247

RESUMO

BACKGROUND: Prasugrel as a second generation P2Y12 adenosine diphosphate receptor antagonist which in the cerebral aneurysms with Endovascular treatment have become more emphasized. OBJECTIVE: To compare the efficacy and safety of prasugrel therapy for intracranial aneurysms with endovascular treatment. METHODS: The databases of PubMed, Embase, Cochrane Library databases and China Biology Medicine disc were retrieved with computers for collecting controlled trials about the comparison in the efficacy and safety of prasugrel and clopidogrel published from inception to September 2018. At the same time, the reference materials of included literature were retrieved manually. After rigorous evaluation on literature quality, the eligible data of the trials was extracted and given a Meta-analysis by applying RevMan5.3 software. RESULTS: Of the 96 studies identified, 7 trials were included. Results of meta-analysis showed that compared with patients receiving clopidogrel treatment, novel platelet P2Y12 receptor inhibitor prasugrel were effective in reducing the incidence of thromboembolic events (OR = 0.19, 95%CI: 0.08-0.45, P = .0001), but did not increase the risk of hemorrhagic complication (OR = 1.00, 95%CI: 0.53-1.89, P = 1.00), and the PRU (OR = 0.19, 95%CI: 0.08-0.45, P = .0001) and Percentage inhibition of platelet (MN = 37.05, 95%CI: 33.37-40.73, P < .00001) were controlled in a better range. CONCLUSION: In antiplatelet therapy after aneurysmal interventional therapy, the second generation of P2Y12 adenosine receptor antagonist prasugrel can significantly reduce the risk of thrombosis without increasing the risk of bleeding.


Assuntos
Procedimentos Endovasculares , Aneurisma Intracraniano/terapia , Inibidores da Agregação de Plaquetas/uso terapêutico , Cloridrato de Prasugrel/uso terapêutico , Humanos , Aneurisma Intracraniano/tratamento farmacológico , Inibidores da Agregação de Plaquetas/efeitos adversos , Cloridrato de Prasugrel/efeitos adversos , Resultado do Tratamento
20.
Anal Chem ; 91(4): 2727-2733, 2019 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-30663316

RESUMO

Nanoscale metal-organic frameworks (NMOFs) have been applied for biomedical sensing in recent years. However, it is still a great challenge to construct a highly efficient NMOFs fluorescent probe for sensing in a biological system, with high signal-to-noise ratio, photostability, and deep tissue penetration. Herein, for the first time, we report the two-photon metal-organic framework (TP-MOF) as a sensing platform. The design of TP-MOF is based on NMOFs incorporating a target-responsive two-photon organic moiety through click chemistry. PCN-58, as a model building block, was covalently modified with a small-molecule probe for H2S or Zn2+ as model analytes. TP-MOF probes retain the fluorescence-responsive properties of the TP organic moiety and possess excellent photostability and selectivity, as well as biocompatibility. Benefiting from the near-infrared (∼820 nm) excited two-photon fluorophore, TP-MOF probes serve to sense and image their respective targets in live cells and tissue slices with a penetration of 130 µm. The molecular design presented here bodes well for the extension to other MOFs displaying sensing components for other analytes of interest.

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