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1.
Exp Hematol ; 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32007477

RESUMO

Histone lysine demethylase KDM5 family is implicated in normal development and stem cell maintenance by epigenetic modulation of histone methylation status. Deregulation of KDM5 family was reported in various types of cancers, including hematological malignancies. However, their transcriptional regulatory roles in the context of leukemia remain unclear. Here, we find that KDM5B expression is strongly expressed in normal CD34+ hematopoietic stem/progenitor cells and chronic myeloid leukemia (CML) cells. Knockdown of KDM5B in K562 CML cells reduced leukemia colony-forming potential. Transcriptome profiling of KDM5B knockdown K562 cells demonstrated the deregulation of genes involved in myeloid differentiation and Toll-like receptor signaling. Through the integration of transcriptome and ChIP-seq profiling data, we show that KDM5B is enriched at the binding sites of GATA and AP-1 transcription factor families, suggesting their collaborations in the regulation of transcription. Even though the binding of KDM5B substantially overlapped with H3K4me1 or H3K4me3 mark at gene promoters, only a small subset of the KDM5B targets showed differential expression in association with the histone demethylation activity. By characterizing the interacting proteins in K562 cells, we discover that KDM5B recruits protein complexes involved in the mRNA processing machinery, implying an alternative epigenetic action mediated by KDM5B in gene regulation. Our study highlights the oncogenic functions of KDM5B in CML cells and suggests that KDM5B is vital to the transcriptional regulation via multiple epigenetic mechanisms.

2.
Neurotox Res ; 2020 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-32034697

RESUMO

The effect of plasma endostatin on cognitive impairment after ischemic stroke remains unclear. We conducted this study to explore the association between plasma endostatin in the acute phase of ischemic stroke and post-stroke cognitive impairment (PSCI). Baseline plasma endostatin levels were measured, and cognitive function status was assessed by Montreal cognitive assessment at 3 months among 613 ischemic stroke patients. PSCI was defined as Montreal cognitive assessment score less than 26. The association of endostatin with PSCI was analyzed by logistic regression model. The receiver operating characteristic curve was applied to explore the optimal cutoff value of plasma endostatin levels in predicting PSCI. In a multivariable-adjusted model, the odds ratio for the highest vs lowest quartile of endostatin was 2.01 (95% CI, 1.15-3.53) for PSCI. Restricted cubic spline regression model showed a linear dose-response association between endostatin and PSCI (p for linearity = 0.01). The optimal cut point of endostatin was 84.22 ng/mL; higher endostatin levels (≥ 84.22 ng/mL) were associated with increased risk of 2.17-fold for PSCI (adjusted odds ratio, 2.17; 95% CI, 1.44-3.26; p = 0.0002). Furthermore, adding endostatin to a model containing conventional factors led to significant reclassification for PSCI (net reclassification improvement, 0.20; p = 0.025; integrated discrimination improvement, 0.016; p = 0.002). Our findings showed that elevated plasma endostatin levels were associated with cognitive impairment at 3 months after acute ischemic stroke, independently of established conventional risk factors, suggesting that endostatin may be an important biomarker of cognitive impairment after ischemic stroke.

3.
Eur J Immunol ; 50(2): 160-169, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31953958

RESUMO

Regulatory T (Treg) cells are a specialized subpopulation of T cells that plays critical roles in the maintenance of immune homeostasis. Although efforts have been done, their role in human pregnancy is not fully understood. Numerous studies reported the presence of Treg cells throughout gestation by promoting maternal-fetal tolerance and fetal development. Furthermore, Treg population is heterogeneous as it is expressing different immune checkpoint molecules favoring immune suppressive function. Therefore, better understanding of the heterogeneity and function of Treg cells during pregnancy is critical for an effective immune intervention. Latest evidence has shown that several immune checkpoint molecules are closely associated with pregnancy outcome via multiple inhibitory mechanisms. Majority of these studies demonstrated the modulatory effects of immune checkpoint molecules on effector T-cell immunity, but their effects on Treg activation and function are still an enigma. In this review, we emphasize the potential influence of multiple immune checkpoint molecules, including CTLA-4, PD-1, Tim-3, LAG-3, and TIGIT, either in membrane or soluble form, on the function of decidual and peripheral Treg cells during pregnancy. Additionally, we discuss the promising future of targeting Treg cells via immune checkpoint molecules for pregnancy maintenance and prevention of complicated pregnancies.

4.
J Neuroinflammation ; 17(1): 12, 2020 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-31918729

RESUMO

BACKGROUND: Dickkopf-3 (Dkk-3) is implicated in the progression of atherosclerosis. This study aimed to investigate the association between serum Dkk-3 and the prognosis of ischemic stroke. METHODS: We measured serum Dkk-3 levels in 3344 ischemic stroke patients from CATIS (China Antihypertensive Trial in Acute Ischemic Stroke). The primary outcome was a combination of death and vascular events within 3 months after ischemic stroke. RESULTS: During 3 months of follow-up, the cumulative incidence rates of primary outcome among ischemic stroke patients in five quintiles of serum Dkk-3 (from low to high) were 4.49%, 3.74%, 2.54%, 5.23%, and 6.73%, respectively (log-rank p = 0.004). Multivariable Cox proportional hazards regression analyses showed that compared with the third quintile of serum Dkk-3, the adjusted hazard ratios (95% confidence intervals) associated with the first and fifth quintile were 3.49 (1.46-8.34) and 4.23 (1.86-9.64) for primary outcome, 3.47 (1.06-11.36) and 5.30 (1.81-15.51) for death, and 2.66 (1.01-7.01) and 3.35 (1.33-8.40) for vascular events, respectively. Multivariable-adjusted Cox proportional hazards regression model with restricted cubic splines showed a U-shaped association between serum Dkk-3 and the risk of primary outcome (p for nonlinearity = 0.030). Moreover, adding serum Dkk-3 to conventional risk factors could improve the predictive power for primary outcome (net reclassification improvement 28.44%, p < 0.001; integrated discrimination improvement 0.48%, p = 0.001). CONCLUSIONS: Both low and high serum Dkk-3 levels are associated with increased risks of death and vascular events within 3 months after ischemic stroke, indicating that serum Dkk-3 may have a special effect on the prognosis of ischemic stroke. We also found that serum Dkk-3 might be a prognostic biomarker for ischemic stroke. Further studies are needed to replicate our findings and to determine the optimal levels of serum Dkk-3.

5.
Biomol NMR Assign ; 2020 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-31902070

RESUMO

Translation initiation factor 3 (IF3) is one of the three protein factors that bind to the small ribosomal subunit and it is required for the initiation of protein biosynthesis in bacteria. IF3 contains two independent domains, N- and C-terminal domains, which are connected by a lysine-rich interdomain linker. IF3 undergoes large-scale movements and conformational changes upon binding to the 30S subunit and also during the functional regulation of initiation. However, the precise dynamic interplay of the two domains and the molecular mechanism of IF3 is not well understood. A high-resolution 3D structure of a complete IF3 in bacteria has not been solved. Pseudomonas aeruginosa, a gram-negative opportunistic pathogen, is a primary cause of nosocomial infections in humans. Here we report the NMR chemical shift assignments of IF3 from P. aeruginosa as the first step toward NMR structure determination and interaction studies. Secondary structure analyses deduced from the NMR chemical shift data identified nine ß-strands and four α-helices arranged in the sequential order ß1-ß2-α1-ß3-ß4-α2-ß5-α3-ß6-α4-ß7-ß8-ß9.

6.
Mol Cell Probes ; 49: 101493, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31816413

RESUMO

Autophagy plays a crucial role in eliminating protein aggregates, damaged organelles and invading pathogens. Genetically engineered cell line stably expressing green fluorescent protein (GFP)-tagged microtubule-associated protein light chain 3 (LC3) is extensively used to test autophagy through observing GFP puncta formation in the cells by fluorescence imaging. However, canine LC3 (cLC3) gene has not been cloned, therefore, GFP-tagged canine LC3 (GFP-cLC3) detection system has not been established. To generate GFP-cLC3 stably expressing canine-derived macrophages, the cLC3 cDNA was first amplified by RT-PCR and inserted into pEGFP-C1 plasmid to create GFP-cLC3 gene fusion. This genetic element was then transducted into canine macrophages mediated by lentivirus vector to generate the canine macrophages stably expressing fusion protein. Results showed that the sequence of cLC3 cloned in this study is highly homologous with other animals (80-95% homology). Phenotypic and functional analysis of these engineered cells revealed that GFP-cLC3 was indeed stably expressed and rapamycin or starvation can effectively induce GFP puncta formation in the cells, indicative of autophagosome formation. These GFP-cLC3-expressing cells may thus be useful to study autophagy in canine.

7.
Atherosclerosis ; 293: 42-48, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31835040

RESUMO

BACKGROUND AND AIMS: Endostatin is implicated in the atherosclerosis process and serves as a promising cardiovascular biomarker, while its clinical significance in ischemic stroke patients remains unclear. We aimed to examine the association between endostatin and mortality and disability after ischemic stroke. METHODS: A total of 3463 acute ischemic stroke patients with measured plasma endostatin from the China Antihypertensive Trial in Acute Ischemic Stroke were included in this study. The primary outcome was death or severe disability (modified Rankin scale score of 4-6), and secondary outcomes included death and vascular events. RESULTS: After 3-month follow-up, 402 (11.61%) participants experienced severe disability or died. Compared with the lowest quartile of endostatin, odds ratios or hazard ratios (95% confidence intervals) for the highest quartile were 1.47 (1.04-2.09) for the primary outcome, and 2.36 (1.23-4.54) for death after adjustment for multiple covariates, including age, sex, admission NIH Stroke Scale score and systolic blood pressure. Each 1-SD higher log-transformed endostatin was associated with a 20% (6%-36%) increased risk for primary outcome. Adding plasma endostatin to the basic model constructed with conventional factors significantly improved risk stratification of primary outcome, as observed by the category-free net reclassification index of 20.5% (95% CI 10.1%-30.8%; p < 0.001) and integrated discrimination improvement of 0.3% (95% CI 0.01%-0.6%; p = 0.04). CONCLUSIONS: Increased baseline plasma endostatin levels in acute ischemic stroke were associated with increased risk of mortality and severe disability at 3 months. Plasma endostatin may serve as an important prognostic marker for risk stratification in patients with ischemic stroke.

8.
Asian-Australas J Anim Sci ; 33(1): 79-90, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31480145

RESUMO

OBJECTIVE: In the present study, an liquid chromatography/mass spectrometry (LC/MS) metabolomics approach was performed to investigate potential biomarkers of milk production in high- and low-milk-yield dairy cows and to establish correlations among rumen fluid metabolites. METHODS: Sixteen lactating dairy cows with similar parity and days in milk were divided into high-yield (HY) and low-yield (LY) groups based on milk yield. On day 21, rumen fluid metabolites were quantified applying LC/MS. RESULTS: The principal component analysis and orthogonal correction partial least squares discriminant analysis showed significantly separated clusters of the ruminal metabolite profiles of HY and LY groups. Compared with HY group, a total of 24 ruminal metabolites were significantly greater in LY group, such as 3-hydroxyanthranilic acid, carboxylic acids, carboxylic acid derivatives (L-isoleucine, L-valine, L-tyrosine, etc.), diazines (uracil, thymine, cytosine), and palmitic acid, while the concentrations of 30 metabolites were dramatically decreased in LY group compared to HY group, included gentisic acid, caprylic acid, and myristic acid. The metabolite enrichment analysis indicated that protein digestion and absorption, ABC transporters and unsaturated fatty acid biosynthesis were significantly different between the two groups. Correlation analysis between the ruminal microbiome and metabolites revealed that certain typical metabolites were exceedingly associated with definite ruminal bacteria; Firmicutes, Actinobacteria, and Synergistetes phyla were highly correlated with most metabolites. CONCLUSION: These findings revealed that the ruminal metabolite profiles were significantly different between HY and LY groups, and these results may provide novel insights to evaluate biomarkers for a better feed digestion and may reveal the potential mechanism underlying the difference in milk yield in dairy cows.

9.
Ann Vasc Surg ; 62: 442-451, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31394225

RESUMO

Diabetic foot ulcer and its complications are becoming more and more serious problems threatening people's health. In the last decade, multiple growth factors and their combined applications have shown potentials in promoting the healing process of diabetic foot ulcers. The purpose of this study is to perform a meta-analysis of the efficacy and safety of topical recombinant human epidermal growth factor (rhEGF) on the treatment of diabetic foot ulcers. As of November 30, 2018, we had conducted a comprehensive review of PubMed, EMBASE, Cochrane Library databases, and Web of Science. Seven randomized controlled trials (RCTs) that involved 610 participants were included in this review. The pooled results showed that topical rhEGF could significantly promote the healing of diabetic foot ulcers (risk ratio [RR] 1.54, 95% confidence interval [CI] 1.30 to 1.83; I2 = 18%). Topical application of rhEGF could promote ulceration healing of diabetic feet of Wagner grade 1 or 2 significantly (RR, 1.61; 95% CI, 1.32 to 1.97; I2 = 0%), and intralesional injection of rhEGF appeared to promote the healing of more severe ulcers (RR, 2.06, 95%, CI 0.35 to 12.22; I2 = 50%). However, patients developed more shivering (RR, 4.67; 95% CI, 1.39 to 15.71; I2 = 0%), nauseas/vomiting (RR, 2.18; 95% CI, 0.72 to 6.55; I2 = 0%) in the group of intralesional injection of rhEGF compared with the control group, although these symptoms were not found with the topical application of rhEGF. No serious complications were found associated with topical rhEGF. Topical rhEGF treatment of diabetic foot ulcers has showed a broad application prospect, yet more relevant well-designed RCTs are needed in the future.

10.
BMC Cardiovasc Disord ; 19(1): 276, 2019 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-31783793

RESUMO

BACKGROUND: Corrected QT (QTc) interval has been correlated with total and CVD mortality. Although much is known about the relation between prolonged QTc interval and clinical outcome, there is no information on the prevalence and specific risk factors of QTc prolongation in general Chinese population. We evaluated the prevalence of prolonged QTc interval and its risk factors in general Chinese population, aiming to fill in the gaps in the literature and provide evidence for potential CVD risk prediction and disease burden estimate in community. METHODS: A population-based survey was conducted on 11,209 participants over the age of 35 in rural areas of Liaoning Province from 2012 to 2013. Twelve-lead ECGs and automatic analysis were performed on all participants. Logistic regression adjustments were made by using the Bazett's formula to correlate specific risk factors with prolonged QTc intervals (> 440 ms) for potential confounders. RESULTS: The overall prevalence of prolonged QTc interval was 31.6%. The prevalence increased significantly with age (24.1% among those aged 35-44 years; 28.3%, 45-54 years; 35.2%, 55-64 years; 43.4%, ≥65 years, P < 0.001). Participants with a history of CVD had a higher prevalence of QTc prolongation (40.7% vs. 30.0%). In the fully adjusted logistic regress model, older age, abdominal obesity, hypertension, diabetes, hypokalemia and any medicine used in the past two weeks were associated independently with increased risk for prolonged QTc interval (All P < 0.05). We found no significant differences between general obesity, hypocalcemia and hypomagnesemia with prolongation of QTc interval. Female sex showed opposite results after applying clinical diagnostic criteria, and high physical activity could reduce the risk of prolonged QTc interval. CONCLUSIONS: The prevalence of prolonged QTc interval was relatively high in general Chinese population and listed relevant factors, which would help identify patients at risk in pre-clinical prevention and provide evidence for estimating potential CVD burden and making management strategies in community.

11.
Artigo em Inglês | MEDLINE | ID: mdl-31831364

RESUMO

BACKGROUND AND AIMS: High serum hepatocyte growth factor (HGF) levels increase the risk of ischemic stroke and are probably associated with outcomes after ischemic stroke. However, it remains unclear whether the association between HGF and ischemic stroke prognosis is modified by blood lipid status. METHODS AND RESULTS: Data were derived from the CATIS (China Antihypertensive Trial in Acute Ischemic Stroke), and we measured baseline serum HGF levels in 3027 ischemic stroke patients. The primary outcome was a combination of death and major disability (modified Rankin Scale score≥3) at 2 years after ischemic stroke. Blood lipid status could modify association between HGF and ischemic stroke prognosis (Pinteraction = 0.002). After multivariate adjustment, the odds ratios of primary outcome associated with the highest tertile of HGF were 2.13 (95% CI, 1.45-3.14; Ptrend<0.001) for patients with dyslipidemia and 0.81 (95% CI, 0.54-1.22; Ptrend = 0.310) for those with normal lipids. Adding HGF to conventional risk factors improved risk prediction for primary outcome in patients with dyslipidemia (net reclassification improvement: 24.28%, P < 0.001; integrated discrimination index: 0.43%, P = 0.022) but not in those with normal lipids. Secondary analyses further revealed that HDL-C was the main lipid component to modify the prognostic significance of serum HGF among ischemic stroke patients. CONCLUSIONS: There was a modified effect of blood lipid status on the association between serum HGF and ischemic stroke prognosis. Elevated serum HGF was associated with outcomes in ischemic stroke patients with dyslipidemia, especially low HDL-C. Further studies are warranted to replicate our findings and clarify the potential biological mechanisms.

12.
BMC Genet ; 20(1): 99, 2019 12 19.
Artigo em Inglês | MEDLINE | ID: mdl-31856714

RESUMO

BACKGROUND: Corin is an important convertase involved in the natriuretic peptide system and may indirectly regulate blood pressure. Genetic factors relate to corin remain unclear. The purpose of the current study was to comprehensively examine the associations among CORIN SNPs, methylations, serum corin levels and hypertension. RESULTS: We genotyped 9 tag-SNPs in the CORIN gene and measured serum corin levels in 731 new-onset hypertensive cases and 731 age- and sex-matched controls. DNA methylations were tested in 43 individuals. Mendelian randomization was used to investigate the causal associations. Under additive models, we observed associations of rs2289433 (p.Cys13Tyr), rs6823184, rs10517195, rs2271037 and rs12509275 with serum corin levels after adjustment for covariates (P = 0.0399, 0.0238, 0.0016, 0.0148 and 0.0038, respectively). The tag-SNP rs6823184 and SNPs that are in strong linkage disequilibrium with it, i.e., rs10049713, rs6823698 and rs1866689, were associated with CORIN gene expression (P = 2.38 × 10- 24, 5.94 × 10- 27, 6.31 × 10- 27 and 6.30 × 10- 27, respectively). Neither SNPs nor corin levels was found to be associated with hypertension. SNP rs6823184, which is located in a DNase hypersensitivity cluster, a CpG island and transcription factor binding sites, was significantly associated with cg02955940 methylation levels (P = 1.54 × 10- 7). A putative causal association between cg02955940 methylation and corin levels was detected (P = 0.0011). CONCLUSION: This study identified potentially functional CORIN SNPs that were associated with serum corin level in the Chinese Han population. The effect of CORIN SNPs on corin level may be mediated by DNA methylation.

14.
Front Microbiol ; 10: 2547, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31781063

RESUMO

The microbial ecosystem in the udders of dairy cows directly influences the flavor and quality of milk. However, to our knowledge, no published research has analyzed the complex relationship between the udder microbiome and its associated metabolism in animals with subclinical mastitis. We identified the bacterial species and measured relative population numbers in the milk of cows with subclinical Streptococcus agalactiae mastitis (GBS) and compared this information to that from the milk of healthy cows. Metabolite profiles were determined to investigate correlations between the milk microbiota and metabolic factors in healthy vs. GBS dairy cows. Six milk samples from GBS cows and six from healthy cows were subjected to 16S rRNA gene sequencing to identify the microbial species using a MiSeq high-throughput sequencing apparatus. The metabolites present in the milk were identified by gas chromatography time-of-flight mass spectrometry. Both principal component analysis and orthogonal partial least squares discriminant analysis indicated that the metabolites were well-separated from each other in the milk samples from the two groups. GBS dramatically altered microbial diversity, and the GBS group had significantly fewer Proteobacteria, Actinobacteria, and Acidobacteria than the CON group, with greater relative abundance of Firmicutes (p < 0.01). Several bacterial genera, such as Streptococcus, were significantly more abundant in milk from the GBS group than in milk from the CON group, and there was a tendency for greater abundance of Turicibacter (p = 0.07) and Enterococcus spp. (p = 0.07) in the GBS group. The levels of five milk metabolites were significantly higher in the GBS group than in the CON group: phenylpyruvic acid, the homogentisic acid: 4-hydroxyphenylpyruvic acid ratio, the xanthine: guanine ratio, uridine and glycerol. Metabolic pathway analysis of the different metabolites revealed that the following were enriched in both groups: galactose metabolism; pentose and glucuronate interconversion; starch and sucrose metabolism; alanine, aspartate and glutamate metabolism; arginine biosynthesis; citrate cycle (TCA cycle); D-glutamine and D-glutamate metabolism; and the neomycin, kanamycin, and gentamicin biosynthesis pathways. Several typical metabolites were highly correlated with specific ruminal bacteria, such as Streptococcaceae, Lachnospiraceae, Lactobacillaceae and Corynebacteriaceae, demonstrating the functional correlations between the milk microbiome and associated metabolites. These findings revealed that the milk microbiota and metabolite profiles were significantly different between the two groups of cows, raising the question of whether the microbiota associated with the bovine mammary gland could be related to mammary gland health. There was also a relationship between milk quality and the presence of spoilage bacteria. Other bacterial taxa should be investigated, as related information may provide insights into how perturbations in milk metabolomics profiles relate to differences in milk synthesis between healthy cows and those with subclinical mastitis.

15.
Artigo em Inglês | MEDLINE | ID: mdl-31749435

RESUMO

BACKGROUND: Ganoderma lucidum (Leyss. ex Fr.) Karst. (G. lucidum, GL) belongs to the family of Ganodermataceae (Basidiomycetes), and possesses activities including antitumor, antimicrobial, antiviral, and antiaging activities. Triterpenoids are typical chemical constituents in G. lucidum, and play an important role in the anti-cancer effects. According to the substituent group at carbon 26 position, GL total triterpenes fraction can be divided into two types, a Neutral Triterpene Fraction (NTF) and an Acidic Triterpene Fraction (ATF). The anti-cancer effects of total triterpenes fraction and total acidic triterpene fraction extracted from G. lucidum have been widely known in vivo and in vitro, whereas few have focused on total neutral triterpene fraction. OBJECTIVE: The aim of this study was to evaluate the anti-cancer effects of NTF extracted from G. lucidum in vitro and in vivo and explore its anti-cancer active constituents on SW620 human colorectal cancer cells. METHODS: NTF and ATF were extracted from the dry fruiting body of G. lucidum by impregnation method with 90% ethanol, and further isolated by using alkaline extraction and acid precipitation method. The total triterpenoids content of NTF and ATF were determined by using ultraviolet-visible spectrophotometry. The cytotoxic effects on human colon cancer cells SW480, SW620, SW1116, and mouse embryonic fibroblast cell line NIH3T3 were evaluated by using MTT method. Anti-cancer activity of NTF in vivo was evaluated in Athymic nude mice against SW620 cells. An activity-guided separation and purification process was used to identify the anti-cancer active constituents of NTF by column and preparative high performance liquid chromatography. Structures of the constituents were confirmed by 1H-NMR, 13C-NMR and MS. Protein expression was performed by Western blotting. RESULTS: The percentage of total triterpenoids was 46.7% and 57.6% in ATF and NTF, respectively. Both fractions could reduce the viability of SW480, SW620, and SW1116 cells in vitro, whereby NTF exhibited a stronger effect than ATF. NTF markedly inhibited the growth of SW620 cell xenografts in mice at doses (250, 500mg/kg) during the treatment. Furthermore, a new garnoderic alcohol, named as ethyl ganoderate A and eight known ganoderic alcohols were isolated and identified from NTF by a bioassay-guided separation process. All of these compounds possessed anti-cancer activities against SW620 cells in vitro. As a representative ganoderma alcohol, ganodermanondiol significantly reduced the viability of SW620 cells through the induction of apoptosis, which was associated with the upregulated the levels of cleaved-poly (ADP-ribose) polymerase (PARP), cleaved-caspase-3, and -9. In addition, ganodermanondiol showed low cytotoxic activity against normal NIH3T3 cells. CONCLUSION: NTF are potential anti-cancer agents against colon cancer and the active constituents may be ganoderic alcohols whose inhibitory mechanism of anti-cancer action may be related to the activation of a mitochondrial-dependent pathway.

16.
Front Plant Sci ; 10: 1274, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31681373

RESUMO

Polygonum cuspidatum (Japanese knotweed, also known as Huzhang in Chinese), a plant that produces bioactive components such as stilbenes and quinones, has long been recognized as important in traditional Chinese herbal medicine. To better understand the biological features of this plant and to gain genetic insight into the biosynthesis of its natural products, we assembled a draft genome of P. cuspidatum using Illumina sequencing technology. The draft genome is ca. 2.56 Gb long, with 71.54% of the genome annotated as transposable elements. Integrated gene prediction suggested that the P. cuspidatum genome encodes 55,075 functional genes, including 6,776 gene families that are conserved in the five eudicot species examined and 2,386 that are unique to P. cuspidatum. Among the functional genes identified, 4,753 are predicted to encode transcription factors. We traced the gene duplication history of P. cuspidatum and determined that it has undergone two whole-genome duplication events about 65 and 6.6 million years ago. Roots are considered the primary medicinal tissue, and transcriptome analysis identified 2,173 genes that were expressed at higher levels in roots compared to aboveground tissues. Detailed phylogenetic analysis demonstrated expansion of the gene family encoding stilbene synthase and chalcone synthase enzymes in the phenylpropanoid metabolic pathway, which is associated with the biosynthesis of resveratrol, a pharmacologically important stilbene. Analysis of the draft genome identified 7 abscisic acid and water deficit stress-induced protein-coding genes and 14 cysteine-rich transmembrane module genes predicted to be involved in stress responses. The draft de novo genome assembly produced in this study represents a valuable resource for the molecular characterization of medicinal compounds in P. cuspidatum, the improvement of this important medicinal plant, and the exploration of its abiotic stress resistance.

17.
Front Oncol ; 9: 1069, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31681602

RESUMO

Background: Hepatocellular carcinoma (HCC) is very common globally prevalent cancer. Due to its poor clinical prognosis, increasing the diagnostic rate of HCC is urgently needed. Herein, we validate discovered metabolomic biomarkers to distinguish Hepatitis B virus (HBV)-related HCC, including alpha-fetoprotein (AFP) negative (AFP-) and positive (AFP+) individuals. Methods: We recruited 130 HCC subjects (independent case-control, randomized clinical cohorts) to our study. We separated the subjects randomly into two panels: (1) 58 individuals for the discovery panel; and (2) 72 individuals for the validation panel. For each panel, gender and age-matched hepatitis B group (HBG) and healthy group were included as controls. Plasma samples were collected for metabolic profiling by liquid chromatography-mass spectrometry-based metabolomics assays. We applied both non-targeted metabolomics analyses and targeted metabolomics analyses. Significantly changed metabolites (SCMs) were identified. The power of SCMs to discriminate HCC and HBG or healthy group was determined by receiver operating characteristic curve (ROC) analysis. Results: Ten SCMs were selected form the discovery panel, and further verified in the validation panel. ROC analyses indicated that 1 SCMs (LysoPC (24:0)) could discriminate HCC from HBG (AUC = 0.765). Further, 8 SCMs including (LysoPC (17:0), LysoPC (20:4(8Z,11Z,14Z,17Z)), LysoPC (22:0), LysoPC (24:0), PE (P-16:0/22:4(7Z,10Z,13Z,16Z)), SM (d18:1/22:1(13Z)), Creatinine, and L-Isoleucine) displayed a heightened ability to discriminate between HCC and healthy controls (AUC were more than 0.800). Most of these SCMs were important in lipid metabolism. Conclusions: LysoPC (24:0) could distinguished HCC from HBG, and 8 SCMs distinguished HCC from healthy controls. LysoPC and other metabolites have the potential to serve as non-invasive biomarkers for HBV related AFP- and AFP+ HCC.

18.
Immunology ; 2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31670388

RESUMO

Genome-wide association studies (GWAS) have identified many loci for systemic lupus erythematosus (SLE). However, identification of functionally relevant genes remains a challenge. The aim of this study was to highlight potential causal genes for SLE in the GWAS loci. By applying Mendelian randomization (MR) methods, such as summary data-based MR (SMR), generalized SMR and MR pleiotropy residual sum and outlier, we identified DNA methylations in 15 loci and mRNA expression of 21 genes that were causally associated with SLE. The identified genes enriched in 14 specific KEGG pathways (e.g. SLE, viral carcinogenesis) and two GO terms (interferon-γ-mediated signaling pathway and innate immune response). Among the identified genes, UBE2L3 and BLK variants were significantly associated with UBE2L3 and BLK methylations and gene expressions, respectively. UBE2L3 was up-regulated in SLE patients in several types of immune cells. Methylations (e.g. cg06850285) and mRNA expression of UBE2L3 were causally associated with SLE. Methylation site cg09528494 and mRNA expression of BLK were causally associated with SLE. BLK single nucleotide polymorphisms that were significantly associated with SLE were strongly associated with plasma cathepsin B level. Deep analysis identified that plasma cathepsin B level was causally associated with SLE. In summary, this study identified hundreds of DNA methylations and genes as potential risk factors for SLE. Genetic variants in UBE2L3 gene might affect SLE by influencing gene expression. Genetic variants in BLK gene might affect SLE by influencing BLK gene expression and plasma cathepsin B protein level.

19.
Front Oncol ; 9: 1066, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31709176

RESUMO

Background: Cancer patients often display dysfunctional antitumor T-cell responses. Because noteworthy benefits of immune checkpoint pathway blockade, such as programmed cell death protein 1 (PD-1) inhibitors, have been achieved in multiple advanced cancers, the next critical question is which mono-blockade or combinatorial blockade regimens may reinvigorate antitumor T-cell immunity in those cancer patients while limiting immune-related adverse effects. Method: This study recruited, in total, 172 primary cancer patients (131 were blood-tumor-matched patients) who were treatment-naïve prior to the surgeries or biopsies covering the eight most prevalent types of cancer. With access to fresh surgical samples, this study simultaneously investigated the ex vivo expression level of eight known immune checkpoint receptors [PD-1, cytotoxic T-lymphocyte antigen-4 [CTLA-4], T-cell immunoglobulin and mucin-domain containing-3 [Tim-3], 2B4, killer cell lectin like receptor G1 [KLRG-1], TIGIT, B- and T-lymphocyte attenuator [BTLA], and CD160] on tumor-infiltrating T cells (TILs) and paired circulating T cells in blood from a 131-patient cohort. Results: We found increased an expression of PD-1 and Tim-3 but a decreased expression of BTLA on TILs when compared with peripheral blood from multiple types of cancer. Moreover, our co-expression analysis of key immune checkpoint receptors delineates "shared" subsets as PD-1+Tim-3+TIGIT+2B4+KLRG-1-CTLA-4- and PD-1+TIGIT+2B4+Tim-3-KLRG-1-CTLA-4- from bulk CD8 TILs. Furthermore, we found that a higher frequency of advanced differentiation stage T cells (CD27-CCR7-CD45RA-) among the "shared" subset (PD-1+Tim-3+TIGIT+2B4+KLRG-1-CTLA-4-) in bulk CD8 TILs was associated with poorly differentiated cancer type in cervical cancer patients. Conclusions: To our knowledge, our study is the first comprehensive analysis of key immune checkpoint receptors on T cells in treatment-naïve, primary cancer patients from the eight most prevalent types of cancer. These findings might provide useful information for future design of mono-blockade/combinatorial blockades and/or genetically modified T-cell immunotherapy.

20.
Metabolomics ; 15(12): 152, 2019 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-31754808

RESUMO

INTRODUCTION: Ischemic stroke (IS) is a major contributor to the global disease burden, and effective biomarkers for IS management in clinical practice are urgently needed. Metabolomics can detect metabolites that are small enough to cross the blood-brain barrier in a high-throughput manner, and thus represents a powerful tool for discovering biomarkers of IS. OBJECTIVES: In this study, we conducted a systematic review to identify potential metabolic biomarkers and pathways that might facilitate risk predictions, clinical diagnoses, the recognition of complications, predictions of recurrence and an understanding of the pathogenesis of IS. METHODS: The PubMed and Web of Science databases were searched for relevant studies published between January 2000 and July 2019. The study objectives, study designs and reported metabolic biomarkers were systematically examined and compared. Pathway analysis was performed using the MetaboAnalyst online software. RESULTS: Twenty-eight studies were included in this systematic review. Many consistent metabolites, including isoleucine, leucine, valine, glycine, lysine, glutamate, LysoPC(16:0), LysoPC(18:2), serine, uric acid, citrate and palmitic acid, possess potential as biomarkers of IS. Metabolic pathways and dysregulations that are implicated in excitotoxicity, inflammation, apoptosis, oxidative stress, neuroprotection, energy failure, and elevation of intracellular Ca2+ levels, were indicated as playing important roles in the development and progression of IS. CONCLUSIONS: This systematic review summarizes potential metabolic biomarkers and pathways related to IS, which may provide opportunities for the construction of diagnostic or predictive models for IS and the discovery of novel therapeutic targets.

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