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1.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 29(2): 322-327, 2021 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-33812394

RESUMO

OBJECTIVE: To construct an acute myeloid leukemia cell line stably expressing CD123-CLL1 so as to provide an "in vitro" model for studying the role of CD123 and CLL-1 in leukemia and the treatment targeting CD123 and CLL-1. METHODS: The recombinant plasmid of lentivirus was constructed by synthesizing CD123 and CLL-1 sequences and PCR homologous recombination. The lentivirus vector was packaged by three-plasmid packaging system. After collecting the supernatant of lentivirus, the virus titer was determined by quantitative PCR. K562 leukemia cells were collected and transtected with virus supernatant. Leukemia cell line stably expressing the target gene were screened by purinomycin. The expression levels of CD123 and CLL-1 were detected by RT-PCR and flow cytometry. RESULTS: The lentiviral vector was successfully constructed, and identified by agarose gel electrophoresis and gene sequencing, then the virus titer of the supernatant was up to 5.81×108 after quantitative PCR assay. The K562 leukemia cell line obtained positive expression cells after being infected by puromycin. The high expression of CD123 and CLL-1 was confirmed by RT-PCR, while the significantly high expression of CD123 and CLL-1 was confirmed by flow cytometry. CONCLUSION: Lentiviral vector expressing CD123-CLL1 has been successfully constructed, and K562 leukemia cell line stably expressing CD123 and CLL-1 has been successfully obtained.


Assuntos
Subunidade alfa de Receptor de Interleucina-3 , Leucemia Linfocítica Crônica de Células B , Linhagem Celular Tumoral , Vetores Genéticos , Humanos , Células K562 , Lentivirus/genética , Leucemia Linfocítica Crônica de Células B/genética , Plasmídeos , Transfecção
2.
BMC Anesthesiol ; 21(1): 103, 2021 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-33823815

RESUMO

BACKROUND: At present, low-concentration carbohydrate is rarely used in minor trauma surgery, and its clinical efficacy is unknown. The aim of the study was to evaluate the effect of preoperative oral low-concentration carbohydrate on patient-centered quality of recovery in patients undergoing thyroidectomy using Quality of Recovery - 15 (QoR-15) questionnaire. METHODS: One hundred twenty patients were randomized to oral intake of 300 ml carbohydrate solution (CH group) or 300 ml pure water (PW group) 2 h before surgery or fasting for 8 h before surgery (F group). The QoR-15 questionnaire was administered to compare the quality of recovery at 1d before surgery (T0), 24 h, 48 h, 72 h after surgery (T1, T2, T3), and perioperative blood glucose was recorded. RESULTS: Compared to the F group, the QoR-15 scores were statistically higher in the CH and PW group at T1 (P < 0.05), and the enhancement of recovery quality reached the clinical significance at T1 in the CH group compared with the F group. Among the five dimensions of the QoR-15 questionnaire, physical comfort, physiological support and emotional dimension in the CH group were significantly better than the F group (P < 0.05) at T1. Besides, blood glucose of CH group was significantly lower than the PW group and F group at each time point after surgery. CONCLUSIONS: Low-concentration carbohydrate could decrease the incidence of postoperative hyperglycemia and improve the patient-centered quality of recovery on patients undergoing open thyroidectomy at the early stage postoperatively. TRIAL REGISTRATION: ChiCTR1900024731 . Date of registration: 25/07/2019.

3.
Chaos ; 31(3): 033123, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33810733

RESUMO

The structure of a social network plays a crucial role for dynamic analysis, which is invisible in most scenes. In this paper, we present a model for reconstructing the social network by taking into account the public opinion diffusion dynamic model for specific agenda. First, the initial polarity attitude of users i for the agenda, oi, is set in the range [-1,1], where negative and positive attitudes are set as -1 and 1, respectively, while 0 means that user i's attitude is uncertain. Second, we present an optimization model for detecting the relationship among each pair of users based on the generated public observable information. The experimental results for four synthetic networks and three real-world social networks show that the reconstruction accuracy depends on the uncertainty of the initial attitudes greatly. This work is helpful for revealing the structure of social networks in terms of public information.

4.
Theranostics ; 11(9): 4381-4402, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33754067

RESUMO

Rationale: Nicotinamide adenine dinucleotide+ (NAD+)-boosting therapy has emerged as a promising strategy to treat various health disorders, while the underlying molecular mechanisms are not fully understood. Here, we investigated the involvement of fibronectin type III domain containing 5 (Fndc5) or irisin, which is a novel exercise-linked hormone, in the development and progression of nonalcoholic fatty liver disease (NAFLD). Methods: NAD+-boosting therapy was achieved by administrating of nicotinamide riboside (NR) in human and mice. The Fndc5/irisin levels in tissues and blood were measured in NR-treated mice or human volunteers. The therapeutic action of NR against NAFLD pathologies induced by high-fat diet (HFD) or methionine/choline-deficient diet (MCD) were compared between wild-type (WT) and Fndc5-/- mice. Recombinant Fndc5/irisin was infused to NALFD mice via osmotic minipump to test the therapeutic action of Fndc5/irisin. Various biomedical experiments were conducted in vivo and in vitro to know the molecular mechanisms underlying the stimulation of Fndc5/irisin by NR treatment. Results: NR treatment elevated plasma level of Fndc5/irisin in mice and human volunteers. NR treatment also increased Fndc5 expression in skeletal muscle, adipose and liver tissues in mice. In HFD-induced NAFLD mice model, NR displayed remarkable therapeutic effects on body weight gain, hepatic steatosis, steatohepatitis, insulin resistance, mitochondrial dysfunction, apoptosis and fibrosis; however, these actions of NR were compromised in Fndc5-/- mice. Chronic infusion of recombinant Fndc5/irisin alleviated the NAFLD pathological phenotypes in MCD-induced NAFLD mice model. Mechanistically, NR reduced the lipid stress-triggered ubiquitination of Fndc5, which increased Fndc5 protein stability and thus enhanced Fndc5 protein level. Using shRNA-mediated knockdown screening, we found that NAD+-dependent deacetylase SIRT2, rather than other sirtuins, interacts with Fndc5 to decrease Fndc5 acetylation, which reduces Fndc5 ubiquitination and stabilize it. Treatment of AGK2, a selective inhibitor of SIRT2, blocked the therapeutic action of NR against NAFLD pathologies and NR-induced Fndc5 deubiquitination/deacetylation. At last, we identified that the lysine sites K127/131 and K185/187/189 of Fndc5 may contribute to the SIRT2-dependent deacetylation and deubiquitination of Fndc5. Conclusions: The findings from this research for the first time demonstrate that NAD+-boosting therapy reverses NAFLD by regulating SIRT2-deppendent Fndc5 deacetylation and deubiquitination, which results in a stimulation of Fndc5/irisin, a novel exerkine. These results suggest that Fndc5/irisin may be a potential nexus between physical exercise and NAD+-boosting therapy in metabolic pathophysiology.

5.
Int Heart J ; 62(2): 458-462, 2021 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-33731530

RESUMO

In this study, we present the case of a 34-year-old man who was diagnosed with primary cardiac angiosarcoma 1 month after hospital admission. Cardiac angiosarcoma is a relatively rare disease that can be easily misdiagnosed as pneumonia or other diseases. Although surgery is the preferred treatment to prolong survival time, highly malignant tumors with local infiltration and systemic metastasis can lead to poor prognosis.


Assuntos
Neoplasias Cardíacas/diagnóstico , Hemangiossarcoma/diagnóstico , Adulto , Diagnóstico Diferencial , Ecocardiografia , Átrios do Coração , Humanos , Masculino , Tomografia Computadorizada por Raios X
6.
J Biomed Inform ; : 103744, 2021 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-33775815

RESUMO

Fast temporal query on large EHR-derived data sources presents an emerging big data challenge, as this query modality is intractable using conventional strategies that have not focused on addressing Covid-19-related research needs at scale. We introduce a novel approach called Event-level Inverted Index (ELII) to optimize time trade-offs between one-time batch preprocessing and subsequent open-ended, user-specified temporal queries. An experimental temporal query engine has been implemented in a NoSQL database using our new ELII strategy. Near-real-time performance was achieved on a large Covid-19 EHR dataset, with 1.3 million unique patients and 3.76 billion records. We evaluated the performance of ELII on several types of queries: classical (non-temporal), absolute temporal, and relative temporal. Our experimental results indicate that ELII accomplished these queries in seconds, achieving average speed accelerations of 26.8 times on relative temporal query, 88.6 times on absolute temporal query, and 1037.6 times on classical query compared to a baseline approach without using ELII. Our study suggests that ELII is a promising approach supporting fast temporal query, an important mode of cohort development for Covid-19 studies.

7.
Phytochem Anal ; 2021 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-33779008

RESUMO

INTRODUCTION: Pyranosides as one kind of natural glycosides contain a pyran ring linked to an aglycone in the structure. They occur widely in plants and possess diverse biological activities. The discovery of new pyranosides not only contributes to research on natural products but also may promote pharmaceutical development. OBJECTIVES: A non-targeted liquid chromatography-quadrupole time-of-flight mass spectrometry method coupled with an all ion fragmentation-exact neutral loss (AIF-ENL) strategy was developed for the screening of pyranosides in plants. METHODS: Pyranosides in various types were collected as a model. The AIF-ENL strategy comprised three steps: AIF spectrum acquisition and generation, ENL-based searching and identification, and confirmation of structural type using target second-stage mass spectrometry (MS/MS). The strategy was systematically evaluated based on the matrix effects, fragmentation stability, scan rate and screening efficiency and finally applied to Rhodiola crenulata (Hook. f. et Thoms) H. Ohba. RESULTS: The method was proved to be an efficient tool for the screening of pyranosides. When it was applied to R. crenulata, a total of 24 pyranoside candidates were detected. Among them, six were tentatively identified on the basis of the agreement of their elemental composition with the reported. The other 18 were detected in R. crenulata for the first time. CONCLUSION: The method offers a new platform for discovering pyranosides. In addition, the developed non-targeted strategy can also be used for other natural products, such as flavonoids and coumarins, as long as there is a common fragmentation behaviour in their MS/MS to generate characteristic neutral losses or fragments.

8.
JMIR Res Protoc ; 10(3): e25576, 2021 Mar 26.
Artigo em Inglês | MEDLINE | ID: mdl-33769305

RESUMO

BACKGROUND: Genomic medicine is poised to improve care for common complex diseases such as epilepsy, but additional clinical informatics and implementation science research is needed for it to become a part of the standard of care. Epilepsy is an exemplary complex neurological disorder for which DNA diagnostics have shown to be advantageous for patient care. OBJECTIVE: We designed the Implementation Science for Genomic Health Translation (INSIGHT) study to leverage the fact that both the clinic and testing laboratory control the development and customization of their respective electronic health records and clinical reporting platforms. Through INSIGHT, we can rapidly prototype and benchmark novel approaches to incorporating clinical genomics into patient care. Of particular interest are clinical decision support tools that take advantage of domain knowledge from clinical genomics and can be rapidly adjusted based on feedback from clinicians. METHODS: Building on previously developed evidence and infrastructure components, our model includes the following: establishment of an intervention-ready genomic knowledge base for patient care, creation of a health informatics platform and linking it to a clinical genomics reporting system, and scaling and evaluation of INSIGHT following established implementation science principles. RESULTS: INSIGHT was approved by the Institutional Review Board at the University of Texas Health Science Center at Houston on May 15, 2020, and is designed as a 2-year proof-of-concept study beginning in December 2021. By design, 120 patients from the Texas Comprehensive Epilepsy Program are to be enrolled to test the INSIGHT workflow. Initial results are expected in the first half of 2023. CONCLUSIONS: INSIGHT's domain-specific, practical but generalizable approach may help catalyze a pathway to accelerate translation of genomic knowledge into impactful interventions in patient care. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/25576.

9.
Nat Commun ; 12(1): 1411, 2021 03 03.
Artigo em Inglês | MEDLINE | ID: mdl-33658500

RESUMO

Genetically programmed circuits allowing bifunctional dynamic regulation of enzyme expression have far-reaching significances for various bio-manufactural purposes. However, building a bio-switch with a post log-phase response and reversibility during scale-up bioprocesses is still a challenge in metabolic engineering due to the lack of robustness. Here, we report a robust thermosensitive bio-switch that enables stringent bidirectional control of gene expression over time and levels in living cells. Based on the bio-switch, we obtain tree ring-like colonies with spatially distributed patterns and transformer cells shifting among spherical-, rod- and fiber-shapes of the engineered Escherichia coli. Moreover, fed-batch fermentations of recombinant E. coli are conducted to obtain ordered assembly of tailor-made biopolymers polyhydroxyalkanoates including diblock- and random-copolymer, composed of 3-hydroxybutyrate and 4-hydroxybutyrate with controllable monomer molar fraction. This study demonstrates the possibility of well-organized, chemosynthesis-like block polymerization on a molecular scale by reprogrammed microbes, exemplifying the versatility of thermo-response control for various practical uses.


Assuntos
Escherichia coli/genética , Regulação Bacteriana da Expressão Gênica , Engenharia Metabólica/métodos , Poli-Hidroxialcanoatos/metabolismo , Ácido 3-Hidroxibutírico/metabolismo , Escherichia coli/crescimento & desenvolvimento , Escherichia coli/metabolismo , Fermentação , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Hidroxibutiratos/metabolismo , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Microrganismos Geneticamente Modificados , Poliésteres/metabolismo , Temperatura , Imagem com Lapso de Tempo
10.
Org Lett ; 2021 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-33764787

RESUMO

A palladium-catalyzed alkyl C-H borylation with bromide as a traceless directing group is described, providing a convenient approach to access alkyl boronates bearing a ß-all-carbon quaternary stereocenter. The protocol features a broad substrate scope, excellent site selectivity, and good functional group tolerance.

11.
Org Lett ; 2021 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-33764790

RESUMO

Here we describe an unprecedented metal-free C(sp3)-H aroylation of amines via visible-light photoredox catalysis, which provides a straightforward route for the construction of a useful α-amino aryl ketone skeleton. Additionally, a number of selected products exhibit good biological activity for protecting PC12 cell damage, which shows that this skeleton has the potential to become a new neuroprotective agent. Finally, a series of mechanism experiments indicate that this transformation undergoes a photoredox catalytic radical-radical cross-coupling pathway.

12.
World J Pediatr ; 2021 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-33740237

RESUMO

BACKGROUND: We collected neonatal neurological, clinical, and imaging data to study the neurological manifestations and imaging characteristics of neonates with coronavirus disease 2019 (COVID-19). METHODS: This case-control study included newborns diagnosed with COVID-19 in Wuhan, China from January 2020 to July 2020. All included newborns had complete neurological evaluations and head magnetic resonance imaging. We normalized the extracted T2-weighted imaging data to a standard neonate template space, and segmented them into gray matter, white matter, and cerebrospinal fluid. The comparison of gray matter volume was conducted between the two groups. RESULTS: A total of five neonates with COVID-19 were included in this study. The median reflex scores were 2 points lower in the infected group than in the control group (P = 0.0094), and the median orientation and behavior scores were 2.5 points lower in the infected group than in the control group (P = 0.0008). There were also significant differences between the two groups in the total scale score (P = 0.0426). The caudate nucleus, parahippocampal gyrus, and thalamus had the strongest correlations with the Hammersmith neonatal neurologic examination (HNNE) score, and the absolute correlation coefficients between the gray matter volumes and each part of the HNNE score were all almost greater than 0.5. CONCLUSIONS: We first compared the neurological performance of neonates with and without COVID-19 by quantitative neuroimaging and neurological examination methods. Considering the limited numbers of patients, more studies focusing on the structural or functional aspects of the virus in the central nervous system in different age groups will be carried out in the future.

13.
Clin Transl Med ; 11(3): e341, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33784003

RESUMO

PARP inhibitors induce DNA lesions, the repair of which are highly dependent on homologous recombination (HR), and preferentially kill HR- deficient cancers. However, cancer cells have developed several mechanisms to transform HR and confer drug resistance to PARP inhibition. Therefore, there is a great clinical interest in exploring new therapies that induce HR deficiency (HRD), thereby sensitizing cancer cells to PARP inhibitors. Here, we found that GSK2578215A, a high-selective and effective leucine-rich repeat kinase 2 (LRRK2) inhibitor, or LRRK2 depletion suppresses HR preventing the recruitment of RAD51 to DNA damage sites through disruption of the interaction of RAD51 and BRCA2. Moreover, LRRK2 inhibition or depletion increases the susceptibility of ovarian cancer cells to Olaparib in vitro and in vivo. In clinical specimens, LRRK2 high expression is high related with advanced clinical characteristics and poor survival of ovarian cancer patients. All these findings indicate ovarian cancers expressing high levels of LRRK2 are more resistant to treatment potentially through promoting HR. Furthermore, combination treatment with an LRRK2 and PARP inhibitor may be a novel strategy to improve the effectiveness of LRRK2 expression ovarian cancers.

14.
Exp Neurol ; 341: 113692, 2021 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-33727099

RESUMO

Triggering receptor expressed on myeloid cells-1 (TREM-1) was found to be induced in the context of subarachnoid hemorrhage (SAH) before. This study further investigates its role in the development of SAH-induced early brain injury (EBI). Firstly, rats were randomly divided into Sham and SAH groups for analysis of temporal patterns and cellular localization of TREM-1. Secondly, TREM-1 intervention was administrated to produce Sham, vehicle, antagonist and agonist groups, for analyzing TREM-1, Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88) and NF-κB expressions at 24 h post-modeling, and EBI assessment at 24 h and 72 h. Thirdly, TLR4 inhibitor (TAK-242) was exploited to produce Sham, Sham+TAK-242, SAH, and SAH + TAK-242 groups to analyze the effects of TLR4 inhibition on TREM-1 induction and EBI evaluation at 72 h. Fourthly, the relationship of soluble TREM-1 (sTREM-1) levels in cerebrospinal fluid of SAH patients with Hunt-Hess grades were explored. The results showed that TREM-1 increased in the brain after experimental SAH (eSAH) early at 6 h and peaked at 48 h, which was found to be located in microglia and endothelial cells. TREM-1 inhibition attenuated EBI associated with TLR4/MyD88/NF-κB suppression, while enhancement had the opposite effects. Contrarily, TLR4 inhibition prevented TREM-1 induction and ameliorated EBI. In addition, sTREM-1 levels in SAH patients positively correlated with Hunt-Hess grades. Overall, the present study provides new evidence that TREM-1 increases dynamically in the brain after eSAH and it is located in microglia and endothelial cells, which may aggravate EBI by interacting with TLR4 pathway. And sTREM-1 in patients might act as a monitoring biomarker of EBI, providing new insights for future studies.

16.
Cell Mol Neurobiol ; 2021 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-33712886

RESUMO

Neurons in the penumbra (the area surrounding ischemic tissue that consists of still viable tissue but with reduced blood flow and oxygen transport) may be rescued following stroke if adequate perfusion is restored in time. It has been speculated that post-stroke angiogenesis in the penumbra can reduce damage caused by ischemia. However, the mechanism for neovasculature formation in the brain remains unclear and vascular-targeted therapies for brain ischemia remain suboptimal. Here, we show that VEGFR1 was highly upregulated in pericytes after stroke. Knockdown of VEGFR1 in pericytes led to increased infarct area and compromised post-ischemia vessel formation. Furthermore, in vitro studies confirmed a critical role for pericyte-derived VEGFR1 in both endothelial tube formation and pericyte migration. Interestingly, our results show that pericyte-derived VEGFR1 has opposite effects on Akt activity in endothelial cells and pericytes. Collectively, these results indicate that pericyte-specific expression of VEGFR1 modulates ischemia-induced vessel formation and vascular integrity in the brain.

17.
Epilepsia ; 2021 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-33713438

RESUMO

OBJECTIVE: To develop and validate a model to predict seizure freedom in children undergoing cerebral hemispheric surgery for the treatment of drug-resistant epilepsy. METHODS: We analyzed 1267 hemispheric surgeries performed in pediatric participants across 32 centers and 12 countries to identify predictors of seizure freedom at 3 months after surgery. A multivariate logistic regression model was developed based on 70% of the dataset (training set) and validated on 30% of the dataset (validation set). Missing data were handled using multiple imputation techniques. RESULTS: Overall, 817 of 1237 (66%) hemispheric surgeries led to seizure freedom (median follow-up = 24 months), and 1050 of 1237 (85%) were seizure-free at 12 months after surgery. A simple regression model containing age at seizure onset, presence of generalized seizure semiology, presence of contralateral 18-fluoro-2-deoxyglucose-positron emission tomography hypometabolism, etiologic substrate, and previous nonhemispheric resective surgery is predictive of seizure freedom (area under the curve = .72). A Hemispheric Surgery Outcome Prediction Scale (HOPS) score was devised that can be used to predict seizure freedom. SIGNIFICANCE: Children most likely to benefit from hemispheric surgery can be selected and counseled through the implementation of a scale derived from a multiple regression model. Importantly, children who are unlikely to experience seizure control can be spared from the complications and deficits associated with this surgery. The HOPS score is likely to help physicians in clinical decision-making.

18.
Nat Commun ; 12(1): 1513, 2021 03 08.
Artigo em Inglês | MEDLINE | ID: mdl-33686068

RESUMO

3-Hydroxypropionic acid (3HP), an important three carbon (C3) chemical, is designated as one of the top platform chemicals with an urgent need for improved industrial production. Halomonas bluephagenesis shows the potential as a chassis for competitive bioproduction of various chemicals due to its ability to grow under an open, unsterile and continuous process. Here, we report the strategy for producing 3HP and its copolymer poly(3-hydroxybutyrate-co-3-hydroxypropionate) (P3HB3HP) by the development of H. bluephagenesis. The transcriptome analysis reveals its 3HP degradation and synthesis pathways involving endogenous synthetic enzymes from 1,3-propanediol. Combing the optimized expression of aldehyde dehydrogenase (AldDHb), an engineered H. bluephagenesis strain of whose 3HP degradation pathway is deleted and that overexpresses alcohol dehydrogenases (AdhP) on its genome under a balanced redox state, is constructed with an enhanced 1.3-propanediol-dependent 3HP biosynthetic pathway to produce 154 g L-1 of 3HP with a yield and productivity of 0.93 g g-1 1,3-propanediol and 2.4 g L-1 h-1, respectively. Moreover, the strain could also accumulate 60% poly(3-hydroxybutyrate-co-32-45% 3-hydroxypropionate) in the dry cell mass, demonstrating to be a suitable chassis for hyperproduction of 3HP and P3HB3HP.


Assuntos
Vias Biossintéticas , Halomonas/genética , Halomonas/metabolismo , Ácido Láctico/análogos & derivados , Ácido Láctico/biossíntese , Engenharia Metabólica , Proteínas de Bactérias/metabolismo , Biopolímeros/metabolismo , Vias Biossintéticas/genética , Edição de Genes , Regulação Bacteriana da Expressão Gênica , Halomonas/enzimologia , Hidroxibutiratos/metabolismo , Poliésteres/metabolismo , Propilenoglicóis/metabolismo
19.
Int J Pediatr Otorhinolaryngol ; 143: 110659, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33667834

RESUMO

OBJECTIVE: The research on the etiology of nonsyndromic cleft lip with or without cleft palate(NSCL/P) is challenging, and DNA methylation has an impact on the formation of cleft lip and palate. SUBJECTS: In this study, one of a pair of monozygotic twins (T1) had nonsyndromic cleft lip (NSCL), and one of a pair of monozygotic twins (T2) had nonsyndromic cleft lip and palate (NSCLP). We determined the methylation profiles of more than 850,000 CpGs in the DNA of the blood samples from the two pairs of monozygotic twins. RESULT: Methylation data indicated that 1184 differentially methylated CpG sites were found in the T1 group (651 hypermethylated and 533 hypomethylated) and 8099 differentially methylated CpG sites in the T2 group (1713 hypermethylated and 6386 hypomethylated) compared with the healthy twin.The common difference was 107 methylation sites.GO enrichment analysis showed that regulation of smooth muscle cell migration and actin cytoskeleton reorganization were the most prominent classes.KEGG pathway enrichment analysis showed that the TGF-ß signaling pathway, Notch signaling pathway and Wnt signaling pathway are relevant to the formation of NSCL/P.Two selected genes (NTN1 and PLEKHA7) are involved in the formation of NSCL/P. CONCLUSION: These findings provide some support for the hypothesis that abnormal DNA methylation may influence the formation of clefts.

20.
Eur J Med Chem ; 217: 113379, 2021 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-33756126

RESUMO

Emerging evidence suggests that cancer metabolism is closely associated to the serine biosynthesis pathway (SSP), in which glycolytic intermediate 3-phosphoglycerate is converted to serine through a three-step enzymatic transformation. As the rate-limiting enzyme in the first step of SSP, phosphoglycerate dehydrogenase (PHGDH) is overexpressed in various diseases, especially in cancer. Genetic knockdown or silencing of PHGDH exhibits obvious anti-tumor response both in vitro and in vivo, demonstrating that PHGDH is a promising drug target for cancer therapy. So far, several types of PHGDH inhibitors have been identified as a significant and newly emerging option for anticancer treatment. Herein, this comprehensive review summarizes the recent achievements of PHGDH, especially its critical role in cancer and the development of PHGDH inhibitors in drug discovery.

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