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1.
Biomed Pharmacother ; 126: 110057, 2020 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-32145590

RESUMO

Platinum-based chemotherapy remains the cornerstone of treatment for many malignancies. However, although therapeutic efficiency varies greatly among individuals, there is a lack of pharmacogenomic biomarkers that can be used in clinical settings to identify chemosensitive patients and allow stratification. With the development of high-throughput screening techniques and systems biology approaches, a growing body of evidence has shown that platinum resistance is a multifactorial, multi-dimensional, dynamic process incorporating genetic background, tumor evolution and gut microbes. This review critically summarizes potential pharmacogenomic biomarkers for predicting the efficacy of platinum drugs and provides a comprehensive, time-varying perspective that integrates multiple markers.

2.
Zhen Ci Yan Jiu ; 45(3): 251-4, 2020 Mar 25.
Artigo em Chinês | MEDLINE | ID: mdl-32202719

RESUMO

Acupuncture has become an effective approach in clinic for treating obesity, but its mechanism has not been clarified yet. A large number of researches have been conducted on the obesity mechanism in the aspects of neurophysiological regulation, feeding center regulation and peripheral digestion and absorption regulation at home and abroad. But, regarding the main storage site of excess energy, i.e. the remodeling and functional regulation of white adipose tissue (WAT), is still a new field in research. In the paper, focusing on the new filed of weight loss, in view of the promotion of WAT browning through the re-gulation of UCP1 and PPARγ signal pathway with acupuncture, the potential peripheral mechanism of acupuncture was explored on weight loss.

3.
World J Pediatr ; 2020 Mar 20.
Artigo em Inglês | MEDLINE | ID: mdl-32198610

RESUMO

BACKGROUND: Perforin (PRF1) gene mutation can cause the onset of hemophagocytic lymphohistiocytosis (HLH). It has reported that PRF1 Ala91Val polymorphism was related with HLH risk. In the meta-analysis, we aim to evaluate the association between PRF1 Ala91Val polymorphism and HLH risk. METHODS: We accomplished a meta-analysis of six published case-control studies including 391 patients with HLH and 975 controls. We evaluated the quality of each study through Newcastle-Ottawa Scale (NOS). Data analysis was performed with Stata software. RESULTS: In general, all studies were of high quality (NOS score higher than 7). There were statistically significant between the PRF1 Ala91Val polymorphism and HLH risk though the pooled analysis [for Ala/Val vs. Ala/Ala: pooled odds ratio (OR) = 3.22, 95% confidence interval (CI) 1.08-9.56, P = 0.035, random model; for Ala/Val + Val/Val vs. Ala/Ala: pooled OR = 2.96, 95% CI 1.14-7.69, P = 0.025, random model]. Furthermore, sensitivity analysis also revealed a relationship between PRF1 Ala91Val polymorphism and HLH risk (for Ala/Val vs. Ala/Ala: pooled OR = 5.236, 95% CI 2.72-10.08, P < 0.000, I2 = 12.1%, Pheterogeneity = 0.332; for Ala/Val + Val/Val vs. Ala/Ala, pooled OR = 4.856, 95% CI 2.66-8.85, P < 0.000, I2 = 5.9%, Pheterogeneity = 0.373). Funnel plot and Egger's test did not indicate obvious published bias (P = 0.841 for Ala/Val vs. Ala/Ala; P = 0.284 for Ala/Val + Val/Val vs. Ala/Ala). CONCLUSION: This meta-analysis indicated that PRF1 Ala91Val polymorphism affects the factor for developing HLH and future studies of PRF1 Ala91Val on the onset of HLH will be guaranteed.

5.
Artigo em Inglês | MEDLINE | ID: mdl-32112424

RESUMO

Imatinib was the first BCR-ABL inhibitor used in clinical practice to treat chronic myeloid leukemia (CML) and significantly improve the life expectancy of CML patients in the chronic phase. However, a portion of CML patients are resistant to imatinib. This study aimed to determine whether menadione (Vitamin K3) can improve imatinib efficacy in CML and to thoroughly explore the combination regimen mechanism between imatinib and menadione. Menadione improved imatinib efficacy in K562 cells by downregulating ABCB1 expression and increased the intracellular concentration of imatinib, which confirmed that this combination regimen is more effective than imatinib monotherapy. The results demonstrate that menadione and imatinib combination therapy may be a promising approach to refractory CML.

6.
Pharmacogenomics J ; 2020 Feb 11.
Artigo em Inglês | MEDLINE | ID: mdl-32042095

RESUMO

Diffuse Large B-cell Lymphoma (DLBCL), a heterogeneous disease, is influenced by complex network of gene interactions. Most previous studies focused on individual genes, but ignored the importance of intergenic correlations. In current study, we aimed to explore the association between gene networks and overall survival (OS) of DLBCL patients treated with CHOP-based chemotherapy (cyclophosphamide combination with doxorubicin, vincristine and prednisone). Weighted gene co-expression network analysis was conducted to obtain insights into the molecular characteristics of DLBCL. Ten co-expression gene networks (modules) were identified in training dataset (n = 470), and their associations with patients' OS after chemotherapy were tested. The results were validated in four independent datasets (n = 802). Gene ontology (GO) biological function enrichment analysis was conducted with Metascape. Three modules (purple, brown and red), which were enriched in T-cell immune, cell-cell adhesion and extracellular matrix (ECM), respectively, were found to be related to longer OS. Higher expression of several hub genes within these three co-expression modules, for example, LCP2 (HR = 0.77, p = 5.40 × 10-2), CD2 (HR = 0.87, p = 6.31 × 10-2), CD3D (HR = 0.83, p = 6.94 × 10-3), FYB (HR = 0.82, p = 1.40 × 10-2), GZMK (HR = 0.92, p = 1.19 × 10-1), FN1 (HR = 0.88, p = 7.06 × 10-2), SPARC (HR = 0.82, p = 2.06 × 10-2), were found to be associated with favourable survival. Moreover, the associations of the modules and hub genes with OS in different molecular subtypes and different chemotherapy groups were also revealed. In general, our research revealed the key gene modules and several hub genes were upregulated correlated with good survival of DLBCL patients, which might provide potential therapeutic targets for future clinical research.

7.
Biomed Pharmacother ; 125: 109875, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32036211

RESUMO

Efficient DNA repair is critical for cell survival following exposure to DNA topoisomerase I (Top1) inhibitors camptothecin, a nature product from which the common chemotherapeutic drugs irinotecan and topotecan are derived. The camptothecin-derived agents exert their antitumor activities by specifically stabilizing the Top1-DNA covalent complexes (Top1cc) and blocking the DNA religation step. When exposed to these DNA damage agents, tumor cells quickly activate DNA damage response. This allows sufficient time to remove the Top1ccs and prevent tumor cells from apoptosis. Several repair pathways have been implicated in this process. One of the most relevant repair modes is DNA single strand break repair (SSBR) pathway. The expression level or mutagenesis of specific repair factors involved in SSBR pathway may play an indispensable role in individual's capacity of repairing camptothecin induced DNA damage. Therefore, understanding of the tolerance pathways counteracted to camptothecin cytotoxicity is crucial in alleviating chemotherapy resistance. This review focus on the SSBR pathway in repair camptothecin induced DNA damage, aiming to provide insights into the potential molecular determinants of camptothecin chemosensitivity.

8.
Life Sci ; 248: 117467, 2020 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-32105706

RESUMO

BACKGROUND: NQO1 protein acts as a cellular protective system, on account of its role as a quinone reductase and redox regulator. Nonetheless, new NQO1 roles are emerging-including its regulation of the cellular proliferation of many tumor cells-and this enzyme has been found to relate to the incidence of various diseases, including chronic myeloid leukemia. However, the mechanisms through which NQO1 influences leukemia progression remain unclear. MARTIAL AND METHODS: The current study looks to name NQO1 as a novel molecular target that modulates DNA synthesis and chronic myeloid leukemia growth. RESULTS AND CONCLUSION: Our results indicate that the frequency of the T allele of NQO1 polymorphism in chronic myeloid leukemia patients is higher than that among healthy East Asian individuals (0.492 vs. 0.419) and much higher than the average level of the general population (0.492 vs. 0.289) (1000 Genomes). Functionally, NQO1 knockdown increases the protein expression of the TOP2A and MCM complex, and consequently promotes DNA synthesis and K562 cell growth. NQO1 knockdown also promotes tumorigenesis in a xenograft model. NQO1 overexpression, on the other hand, was found to have the opposite effects. SIGNIFICANCE: Our results show that NQO1 downregulation promotes K562 cellular proliferation via the elevation of DNA synthesis.

9.
PLoS Comput Biol ; 16(2): e1007287, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32084131

RESUMO

Hi-C is commonly used to study three-dimensional genome organization. However, due to the high sequencing cost and technical constraints, the resolution of most Hi-C datasets is coarse, resulting in a loss of information and biological interpretability. Here we develop DeepHiC, a generative adversarial network, to predict high-resolution Hi-C contact maps from low-coverage sequencing data. We demonstrated that DeepHiC is capable of reproducing high-resolution Hi-C data from as few as 1% downsampled reads. Empowered by adversarial training, our method can restore fine-grained details similar to those in high-resolution Hi-C matrices, boosting accuracy in chromatin loops identification and TADs detection, and outperforms the state-of-the-art methods in accuracy of prediction. Finally, application of DeepHiC to Hi-C data on mouse embryonic development can facilitate chromatin loop detection. We develop a web-based tool (DeepHiC, http://sysomics.com/deephic) that allows researchers to enhance their own Hi-C data with just a few clicks.

10.
Future Oncol ; 16(8): 367-382, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32065545

RESUMO

Background: The DNA damage repair (DDR) pathways play important roles for regulating cancer progression and therapeutic response. IDH mutations, well-known prognosis biomarkers for glioma, lead to hypermethylation of tumor cells and affect genes' expression. Whether IDH mutations affect glioma prognosis through influencing the expression of DDR genes remains unclear. Methods: A total of 272 DDR genes were selected for differential expression and survival analysis. The identified genes were then utilized to construct the prognosis predicting model. Results: PARPBP, PLK3, POLL and WEE1 were found differential expressed between IDH mutations carriers and wild-type carriers, and were associated with survival of low grade glioma (LGG) patients. The predicting algorithm can predicts the prognosis of LGG patients. Conclusion: IDH mutations may affect LGG prognosis through regulation of DDR pathways.

12.
Mass Spectrom Rev ; 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31904155

RESUMO

Personalized drug therapy aims to provide tailored treatment for individual patient. Mass spectrometry (MS) is revolutionarily involved in this area because MS is a rapid, customizable, cost-effective, and easy to be used high-throughput method with high sensitivity, specificity, and accuracy. It is driving the formation of a new field, MS-based personalized drug therapy, which currently mainly includes five subfields: therapeutic drug monitoring (TDM), pharmacogenomics (PGx), pharmacomicrobiomics, pharmacoepigenomics, and immunopeptidomics. Gas chromatography-MS (GC-MS) and liquid chromatography-MS (LC-MS) are considered as the gold standard for TDM, which can be used to optimize drug dosage. Matrix-assisted laser desorption ionization-time of flight-MS (MALDI-TOF-MS) significantly improves the capability of detecting biomacromolecule, and largely promotes the application of MS in PGx. It is becoming an indispensable tool for genotyping, which is used to discover and validate genetic biomarkers. In addition, MALDI-TOF-MS also plays important roles in identity of human microbiome whose diversity can explain interindividual differences of drug response. Pharmacoepigenetics is to study the role of epigenetic factors in individualized drug treatment. MS can be used to discover and validate pharmacoepigenetic markers (DNA methylation, histone modification, and noncoding RNA). For the emerging cancer immunotherapy, personalized cancer vaccine has effective immunotherapeutic activity in the clinic. MS-based immunopeptidomics can effectively discover and screen neoantigens. This article systematically reviewed MS-based personalized drug therapy in the above mentioned five subfields. © 2020 Wiley Periodicals, Inc. Mass Spec Rev.

13.
EBioMedicine ; 51: 102602, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31911269

RESUMO

BACKGROUND: Increasing evidence supports that the immune infiltration of tumours is associated with prognosis. Here, we sought to assess the relevance of the cellular composition of the immune infiltrate to survival after platinum-based chemotherapy amongst patients with high-grade serous ovarian cancer and evaluate these effects by molecular subtype. METHODS: We searched publicly available databases and identified 13 studies with more than 2000 patients. We estimated the proportions of 22 immune cell subsets by using a computational approach (CIBERSORT). Then, we investigated the associations between each immune cell subset and progression-free survival (PFS) and overall survival (OS), with cellular proportions modelled as quartiles. FINDINGS: A high fraction of M1 [hazard ratio (HR) = 0.92, 95% confidence interval (CI) = 0.86-0.99] and M0 (HR = 0.93, 95% CI = 0.87-0.99) macrophages emerged as the most closely associated with favourable OS. Neutrophils were associated with poor OS (HR = 1.06, 95% CI = 1.00-1.13) and PFS (HR = 1.10, 95% CI = 1.02-1.13). Amongst the immunoreactive tumours, the M0 macrophages and the CD8+ T cells were associated with improved OS, whereas the M2 macrophages conferred worse OS. Interestingly, PD-1 was associated with good OS (HR=0.89, 95% CI = 0.80-1.00) and PFS (HR=0.89, 95% CI = 0.79-1.01) in this subtype. Four subgroups of tumours with distinct survival patterns were identified using immune cell proportions with unsupervised clustering. INTERPRETATION: Further investigations of the quantitative cellular immune infiltrations in tumours may contribute to therapeutic advances.

14.
Int Immunopharmacol ; 78: 105947, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31796384

RESUMO

Our previous study has found that zileuton, a selective 5-lipoxygenase (5LO) inhibitor, abrogated lipopolysaccharide-induced depressive-like behaviors and hippocampal neuroinflammation. Herein, we further extended our curiosity to investigate effects of zileuton on stress-induced depressive-like behaviors. Our data indicated that zileuton significantly ameliorated depressive-like behaviors in mice subjected to chronic mild stress (CMS), as shown in the tail suspension test, forced swimming test and novelty-suppressed feeding test. The further studies indicated that zileuton suppressed hippocampal neuroinflammation, evidenced by lower levels of TNF-α, IL-1ß and nuclear NF-κB p65 as well as decreased number of Iba1-positive cells. It also significantly ameliorated hippocampal apoptosis, indicated by deceased number of TUNEL-positive cells, deceased ratio of cleaved caspase-3/procaspase-3 and increased ratio of Bcl-2/Bax. More importantly, zileuton increased the level of synaptic proteins PSD-95 and SYN and the number of NeuN+/BrdU+ cells in the hippocampus. Over all, zileuton alleviated CMS-induced depressive-like behaviors, neuroinflammatory and apoptotic responses, abnormalities of synapse and neurogenesis in the hippocampus, suggesting that it might has beneficial effects on depression.

15.
CNS Neurosci Ther ; 26(1): 66-75, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31102349

RESUMO

AIMS: Altered activities of long noncoding RNAs (lncRNAs) have been associated with cancer development, and lncRNA FOXD1-AS1 (FOXD1-AS1) is the antisense transcript of the gene encoding for FOXD1, known for its role as an oncogene in several tumor types including glioma. However, the role of FOXD1-AS1 in the differentiation and progression of glioma is not well known. METHODS: Expression profile chip and qPCR were used to screen and identify FOXD1-AS1. Glioma cells were transfected with siRNA or eukaryotic expression vector to observe FOXD1-AS1 function in vitro and in vivo. Dual luciferase reporter gene analysis, Western blot, and ChIRP-MS were used to detect microRNAs and protein that combine with FOXD1-AS1. RESULTS: FOXD1-AS1 was upregulated and directly correlated with the glioma grade, and it was localized in both the nucleus and the cytoplasm of the glioma cell. FOXD1-AS1 silencing caused tumor suppressive effects via inhibiting cell proliferation, migration, and apoptosis, while FOXD1-AS1 overexpression resulted in opposite effects. Additionally, in vivo experiments showed that FOXD1-AS1 knockdown reduced tumor volume and weight. More importantly, mechanical studies revealed that FOXD1-AS1 targeted both miR339-5p and miR342-3p (miR339/342). Furthermore, protein eukaryotic translation initiation factor 5 subunit A (eIF5a) resulted a direct target of FOXD1-AS1. CONCLUSIONS: These data indicated that FOXD1-AS1, a miR339/342 target, affected biological processes via protein eIF5a; thus, it might be considered as a new therapeutic target for glioblastoma.

16.
Anal Chim Acta ; 1094: 122-129, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31761038

RESUMO

Hypochlorite (HClO) is involved in various physiological and pathological processes as well as regulation of lysosomal functions. Thus, it is appreciated to develop efficient molecule tools for precisely detecting HClO in lysosomes. Although several lysosomal-targetable fluorogenic probes for HClO have been developed to date, they still suffered from the discounted sensing performance under lysosomal acidic condition. Herein, on the basis of the "AND" logic gate strategy, a novel dual-activatable fluorogenic probe CS has been rationally designed by simultaneously incorporating HClO recognition site and pH-sensitive group with lysosomal-targetable characteristic into a coumarin fluorophore. Different from the single-activated ones previously reported, CS exhibited good sensitivity, high specificity and fast response towards HClO under the acidic conditions but was out of operation in the neutral or alkaline environment. Importantly, it had been successfully applied for spatial-resolution imaging of exogenous or endogenous HClO in lysosomes.

17.
Lipids Health Dis ; 18(1): 218, 2019 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-31829191

RESUMO

BACKGROUND: The cholesterol gallstones diseases (CGD) is highly correlated with metabolic syndrome and type 2 diabetes. The present study aimed to investigate preventive effects of pioglitazone (PIO), an antidiabetic drug, on the CGD in guinea pigs fed with a lithogenic diet (LD). METHODS: The guinea pigs were fed with the LD for 8 weeks. All guinea pigs were grouped as follows: low fat diet; LD; LD plus PIO (4 mg/kg); LD plus PIO (8 mg/kg); LD plus ezetimibe (EZE) (2 mg/kg). Gallbladder stones were observed using microscopy. The profile of biliary composition, and blood glucose, insulin and lipid were analyzed. The liver or ileum was harvested for determinations of hydroxyl-methyl-glutaryl-CoA reductase (HMGCR), sterol regulatory element-binding proteins 2 (SREBP2), 7α-hydroxylase (CYP7A1), adenosine triphosphate-binding cassette (ABC) sterol transporters G5 and G8 (ABCG5, ABCG8), bile salt export pump (BSEP), Niemann-Pick C1-Like 1 (NPC1L1) and acetyl-coenzyme A cholesterol acyltransferase (ACAT2) by Western blot. The gallbladders were used for histological examination. RESULTS: The LD successfully induced gallstone. Both pioglitazone and ezetimibe prevented gallstone formation, as well as hepatic and cholecystic damages. Pioglitazone significantly decreased HMGCR and SREBP2, but increased CYP7A1, ABCG5, ABCG8, and BSEP in the liver. Pioglitazone also remarkably decreased NPC1L1 and ACAT2, while increased ABCG5/8 in the intestine. The beneficial alterations of cholesterol and bile acids in the bile, as well as profile of glucose, insulin and lipid in the blood were found in the guinea pigs treated with pioglitazone. CONCLUSION: Pioglitazone has a noticeable benefit towards the CGD, which is involved in changes of synthesis, transformation, absorption, and transportation of cholesterol.

18.
Artigo em Inglês | MEDLINE | ID: mdl-31824431

RESUMO

Adiponectin is an adipokine that has recently been under investigation for potential neuroprotective effects in various brain disorders including Alzheimer's disease, stroke, and depression. Adiponectin receptors (AdipoR1 and AdipoR2) are found throughout various brain regions, including the hippocampus. However, the role of these receptors in synaptic and cognitive function is not clear. Therefore, the goal of the current study was to evaluate synaptic and cognitive function in the absence of adiponectin. The current study utilized 12-month-old adiponectin knockout (APN-KO) mice and age-matched controls to study cognitive and hippocampal synaptic alterations. We determined that AdipoR1 and AdipoR2 are present in the synaptosome, with AdipoR2 displaying increased presynaptic vs. postsynaptic localization, whereas AdipoR1 was enriched in both the presynaptic and postsynaptic fractions. APN-KO mice displayed cognitive deficits in the novel object recognition (NOR) and Y-maze tests. This was mirrored by deficits in long-term potentiation (LTP) of the hippocampal Schaefer collateral pathway in APN-KO mice. APN-KO mice also displayed a reduction in basal synaptic transmission and an increase in presynaptic release probability. Deficits in LTP were rescued through hippocampal slice incubation with the adiponectin receptor agonist, AdipoRon, indicating that acute alterations in adiponectin receptor signaling influence synaptic function. Along with the deficits in LTP, altered levels of key presynaptic and postsynaptic proteins involved in glutamatergic neurotransmission were observed in APN-KO mice. Taken together, these results indicate that adiponectin is an important regulator of cognition and synaptic function in the hippocampus. Future studies should examine the role of specific adiponectin receptors in synaptic processes.

19.
Oxid Med Cell Longev ; 2019: 2749173, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31871543

RESUMO

5-Lipoxygenase (ALOX5) is an iron-containing and nonheme dioxygenase that catalyzes the peroxidation of polyunsaturated fatty acids such as arachidonic acid. ALOX5 is the rate-limiting enzyme for the biosynthesis of leukotrienes, a family of proinflammatory lipid mediators derived from arachidonic acid. ALOX5 also make great contributions to mediating lipid peroxidation. In recent years, it has been discovered that ALOX5 plays a central role in cell death including apoptosis, pyroptosis, and ferroptosis, a newly discovered type of cell death. According to the previous studies, ALOX5 can regulate cell death in two ways: one is inflammation and the other is lipid peroxidation. Meanwhile, it has been shown that ALOX5 activity is regulated by several factors including protein phosphorylation, ALOX5-interactng protein, redox state, and metal ions such as iron and calcium. In this review, we aim to summarize the knowledge on the emerging roles of ALOX5 protein phosphorylation in the regulation of cell death and inflammation in order to explore a potential target for human diseases.

20.
Br J Ophthalmol ; 2019 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-31704700

RESUMO

PURPOSE: Amblyopia is a leading cause of vision impairment among children and young adults. Individual studies showed significant variations in the prevalence of amblyopia in different regions and age groups. This study is to estimate the global prevalence of amblyopia by pooling its prevalence from the previous studies and to project the number of people affected through 2040. METHODS: We performed a systematic review and meta-analysis on the prevalence of amblyopia using data published before 20 October 2018. We estimated the prevalence rate of amblyopia and its 95% CI globally and by subgroups (eg, region and age). The prevalence data were applied to United Nations World Population Prospects to derive the projected number with amblyopia through 2040. RESULTS: A meta-analysis of 60 studies (1 859 327 subjects) showed that the pooled prevalence rate of amblyopia was 1.44% (95% CI 1.17% to 1.78%). Prevalences in Europe (2.90%) and North America (2.41%) were higher than in Asia (1.09%) and Africa (0.72%). The highest prevalence was found in subjects over 20 years old (3.29%). There was no difference in the prevalence between genders. We estimated 99.2 (95% CI 71.7 to 146.1) million people with amblyopia in 2019 worldwide, increasing to 175.2 (95% CI 81.3 to 307.8) million by 2030 and 221.9 (95% CI 83.7 to 429.2) million by 2040. CONCLUSIONS: The amblyopia is becoming a significant vision problem worldwide. It is of great importance to design and implement amblyopia screening, treatment and related public health strategies.

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