Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 185
Filtrar
1.
Artigo em Inglês | MEDLINE | ID: mdl-34804186

RESUMO

Purpose: Curcumin is a potential drug for the treatment of colorectal cancer (CRC). Its mechanism of action has not been elucidated. This study aims to investigate the mechanism of action of curcumin in the treatment of CRC via bioinformatics methods such as network pharmacology and molecular docking. Methods: The targets of curcumin and CRC were obtained from the public databases. The component-targets network of curcumin in the treatment of CRC was constructed by Cytoscape v3.7.2. Through protein-protein interaction (PPI), the Gene Ontology (GO), and the Kyoto Encyclopedia of Genes and Genomes (KEGG), important targets and signaling pathways related to CRC treatment were identified. Finally, the results were verified by molecular docking, and the correlation between the key targets and tumor-infiltrating immune cells (TICs) was analyzed. Results: A total of 30 potential targets of curcumin for CRC treatment were collected. The GO function enrichment analysis showed 140 items, and the KEGG pathway enrichment analysis showed 61 signaling pathways related to the regulation of protein kinase activity, negative regulation of apoptosis process, cancer signaling pathway, and PI3K-Akt signaling pathway. The molecular docking results showed that curcumin could be combined with AKT1, EGFR, and STAT3 more stably, and AKT1 has the strongest binding to curcumin. Bioinformatics analysis discovered that the expression of core targets AKT1, EGFR, and STAT3 in CRC was related to TICs. Conclusion: This study explored the targets and pathways of curcumin in the treatment of CRC. The core targets are AKT1, EGFR, and STAT3. The study indicated that curcumin has preventive and treatment effects on CRC through multitarget and multipathway, which laid the foundation for follow-up research.

2.
Artigo em Inglês | MEDLINE | ID: mdl-34789677

RESUMO

PURPOSE OF REVIEW: Chronic rhinosinusitis (CRS) is a heterogeneous disorder with diverse responses to conventional anti-inflammatory medical and surgical treatments. Even for the newly developed mAbs targeting type 2 (T2) reaction, a considerable number of patients with CRS with nasal polyps (CRSwNP) exhibited unsatisfying response. Identifying patients with a tendency to poor prognosis is critical for selecting targeted therapies to improve the treatment outcome. This review focuses on clinical and biological markers associated with prognosis of CRS patients under conventional medical and surgical treatments and provides an update summary of potential markers for T2 biologics. RECENT FINDINGS: Allergic rhinitis, asthma, prior sinus surgery, nasal polyps, tissue eosinophilia and neutrophilia, blood eosinophilia and high levels of Charcot-Leyden crystal, cystatin SN, chemokine (C-C motif) ligand 17, macrophage inflammatory protein-1ß and interleukin (IL)-5 in nasal secretions have been associated with poor prognosis in CRS patients under conventional medical and surgical treatments. Blood eosinophil level might be a biomarker for anti-IL-5 (mepolizumab) and anti-IL-5R (benralizumab) biologic in patients with refractory CRSwNP. SUMMARY: Several clinical and biological markers have been associated with poor response to conventional treatments in CRS patients; however, majority of them should be verified by large-scale multicentre studies. More efforts are needed to identify biomarkers for biologics.

3.
Huan Jing Ke Xue ; 42(11): 5519-5525, 2021 Nov 08.
Artigo em Chinês | MEDLINE | ID: mdl-34708991

RESUMO

The levels of six toxic metals and five essential metals in five groups of vegetables marketed in the eastern coastal region of China were analyzed using inductively coupled plasma mass spectrometry. The results showed that the concentrations of six toxic heavy metals in all the vegetables did not exceed the maximum residue limits. The health risk assessment indicated that consumption of vegetables may not pose a potential noncarcinogenic risk to consumers, while there is a carcinogenic risk level of 10-5 level from inorganic arsenic exposure through vegetable consumption. Additionally, a similar trend was observed for the accumulation of toxic and essential metals. Furthermore, compared with other vegetable groups, edible fungi have a high potential to accumulate toxic and essential metals, which indicates that pollution monitoring of edible fungi should be strengthened.


Assuntos
Metais Pesados , Poluentes do Solo , China , Exposição Dietética , Monitoramento Ambiental , Metais Pesados/análise , Medição de Risco , Poluentes do Solo/análise , Verduras
4.
Int J Epidemiol ; 2021 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-34632511

RESUMO

BACKGROUND: Exercise may increase the inhalation and deposition of air pollutants, which may counteract its beneficial effects. We thus examined the combined effects of chronic exposure to fine particulate matter (PM2.5) and habitual exercise on the risk of death from cancer in Taiwan. PATIENTS AND METHODS: A total of 384 128 adults (≥18 years of age) were recruited for a medical screening programme between 2001 and 2016, yielding 842 384 medical-examination records. All participants were followed up until 31 May 2019. Vital data were obtained from the National Death Registry of Taiwan and the ambient PM2.5 exposure was estimated using a satellite-based spatiotemporal model. Information on habitual exercise was collected using a standard self-administered questionnaire. The time-dependent Cox-regression model was used to evaluate the combined effects. RESULTS: A greater amount of habitual exercise was associated with lower risk of death from cancer, whilst a higher level of PM2.5 exposure was associated with a higher risk of death from cancer. The inverse associations of habitual exercise with death from cancer were not modified by chronic exposure to PM2.5. The participants in the group with a high level of exercise and a low level of PM2.5 exposure exhibited a 35% lower risk of death from cancer than those in the group with a low level of exercise and a high level of PM2.5 exposure (95% confidence interval: 28%, 42%). CONCLUSIONS: Increased levels of exercise and reduced exposure levels of PM2.5 are associated with a lower risk of death from cancer. Habitual exercise reduces the risk of death from cancer regardless of the levels of chronic PM2.5 exposure. Our results indicate that habitual exercise is a suitable health-promotion strategy even for people who reside in moderately polluted regions.

5.
J Mater Sci Mater Med ; 32(11): 135, 2021 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-34704134

RESUMO

Poly-ether-ether-ketone (PEEK) has attracted increasing attention as a promising orthopaedic implant material owing to its excellent mechanical properties and biocompatibility. However, its antibacterial properties must be improved as an implant material. In this study, PEEK was sulfonated to obtain a porous surface, and graphene oxide (GO) was deposited to form a coating with antibacterial activity and biocompatibility. After PEEK was sulfonated for different durations, GO was deposited on the surface to prepare the coating (SPEEK-GO), which was then characterised using scanning electron microscopy (SEM), Raman spectroscopy, and contact angle measurements. The in vitro study included antimicrobial and cellular tests. The results showed that the PEEK sulfonated using a 10-min treatment exhibited a uniform porous structure and provided a better basal surface for the deposition of GO. The SPEEK-GO coating displayed strong antibacterial activity against two common dental pathogens. It exhibited good adhesion and proliferation of MC3T3-E1. Moreover, it showed osteogenic differentiation as bone implant material.

6.
Microbiol Spectr ; 9(2): e0046321, 2021 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-34643440

RESUMO

Alteromonas is a ubiquitous, abundant, copiotrophic and phytoplankton-associated marine member of the Gammaproteobacteria with a range extending from tropical waters to polar regions and including hadal zones. Here, we describe a novel Alteromonas phage, ZP6, that was isolated from surface coastal waters of Qingdao, China. ZP6 contains a linear, double-stranded, 38,080-bp DNA molecule with 50.1% G+C content and 47 putative open reading frames (ORFs). Three auxiliary metabolic genes were identified, encoding metal-dependent phosphohydrolase, diaminopurine synthetase, and nucleotide pyrophosphohydrolase. The first two ORFs facilitate the replacement of adenine (A) by diaminopurine (Z) in phage genomes and help phages to evade attack from host restriction enzymes. The nucleotide pyrophosphohydrolase enables the host cells to stop programmed cell death and improves the survival rate of the host in a nutrient-depleted environment. Phylogenetic analysis based on the amino acid sequences of whole genomes and comparative genomic analysis revealed that ZP6 is most closely related to Enhodamvirus but with low similarity (shared genes, <30%, and average nucleotide sequence identity, <65%); it is distinct from other bacteriophages. Together, these results suggest that ZP6 could represent a novel viral genus, here named Mareflavirus. Combining its ability to infect Alteromonas, its harboring of a diaminopurine genome-biosynthetic system, and its representativeness of an understudied viral group, ZP6 could be an important and novel model system for marine virus research. IMPORTANCE Alteromonas is an important symbiotic bacterium of phytoplankton, but research on its bacteriophages is still at an elementary level. Our isolation and genome characterization of a novel Alteromonas podovirus, ZP6, identified a new viral genus of podovirus, namely, Mareflavirus. The ZP6 genome, with a diaminopurine genome-biosynthetic system, is different from those of other isolated Alteromonas phages and will bring new impetus to the development of virus classification and provide important insights into novel viral sequences from metagenomic data sets.

7.
Clin Chem ; 67(11): 1554-1566, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34626187

RESUMO

BACKGROUND: The amounts of circulating cell-free DNA (cfDNA) and circulating-tumor DNA (ctDNA) present in peripheral blood liquid biopsies can vary due to preanalytic/analytic variables. In this study, we examined the impact of patient age, sex, stage, and tumor type on cfDNA yield, ctDNA fraction, and estimated ctDNA quantity from a large cohort of clinical liquid biopsy samples. METHODS: We performed a retrospective analysis of 12 139 consecutive samples received for liquid biopsy (FoundationOne® Liquid) clinical testing. RESULTS: Significant differences in both cfDNA yield and estimated ctDNA quantity were observed based on the underlying tumor type that initiated the liquid biopsy analysis and the stage of the patient (P < 0.001). In addition, significant differences in ctDNA quantity were present based in both the patient age and sex (P < 0.001). Importantly, we saw a significantly higher success rate of issuing a clinically useful report in patients with higher levels of cfDNA yield and ctDNA quantity (P < 0.001). CONCLUSIONS: In this study, we show that ctDNA quantity varied significantly based on patient age, sex, stage, and tumor type, which could offer an explanation as to why certain liquid biopsy specimens are more likely to fail sequencing or provide clinically meaningful results. In addition, this could affect future clinical decisions on the blood sample volumes required to allow successful liquid biopsy testing.

8.
BMC Genomics ; 22(1): 675, 2021 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-34544379

RESUMO

BACKGROUND: Marine bacteriophages play key roles in the community structure of microorganisms, biogeochemical cycles, and the mediation of genetic diversity through horizontal gene transfer. Recently, traditional isolation methods, complemented by high-throughput sequencing metagenomics technology, have greatly increased our understanding of the diversity of bacteriophages. Oceanospirillum, within the order Oceanospirillales, are important symbiotic marine bacteria associated with hydrocarbon degradation and algal blooms, especially in polar regions. However, until now there has been no isolate of an Oceanospirillum bacteriophage, and so details of their metagenome has remained unknown. RESULTS: Here, we reported the first Oceanospirillum phage, vB_OliS_GJ44, which was assembled into a 33,786 bp linear dsDNA genome, which includes abundant tail-related and recombinant proteins. The recombinant module was highly adapted to the host, according to the tetranucleotides correlations. Genomic and morphological analyses identified vB_OliS_GJ44 as a siphovirus, however, due to the distant evolutionary relationship with any other known siphovirus, it is proposed that this virus could be classified as the type phage of a new Oceanospirivirus genus within the Siphoviridae family. vB_OliS_GJ44 showed synteny with six uncultured phages, which supports its representation in uncultured environmental viral contigs from metagenomics. Homologs of several vB_OliS_GJ44 genes have mostly been found in marine metagenomes, suggesting the prevalence of this phage genus in the oceans. CONCLUSIONS: These results describe the first Oceanospirillum phage, vB_OliS_GJ44, that represents a novel viral cluster and exhibits interesting genetic features related to phage-host interactions and evolution. Thus, we propose a new viral genus Oceanospirivirus within the Siphoviridae family to reconcile this cluster, with vB_OliS_GJ44 as a representative member.


Assuntos
Bacteriófagos , Siphoviridae , Bacteriófagos/genética , DNA Viral/genética , Genoma Viral , Genômica , Filogenia , Siphoviridae/genética
9.
Acta Pharm Sin B ; 11(9): 2945-2956, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34589407

RESUMO

Mushroom-derived cyathane-type diterpenes possess unusual chemical skeleton and diverse bioactivities. To efficiently supply bioactive cyathanes for deep studies and explore their structural diversity, de novo synthesis of cyathane diterpenes in a geranylgeranyl pyrophosphate engineered Saccharomyces cerevisiae is investigated. Aided by homologous analyses, one new unclustered FAD-dependent oxidase EriM accounting for the formation of allyl aldehyde and three new NADP(H)-dependent reductases in the biosynthesis of cyathanes are identified and elucidated. By combinatorial biosynthetic strategy, S. cerevisiae strains generating twenty-two cyathane-type diterpenes, including seven "unnatural" cyathane xylosides (12, 13, 14a, 14b, 19, 20, and 22) are established. Compounds 12-14, 19, and 20 show significant neurotrophic effects on PC12 cells in the dose of 6.3-25.0 µmol/L. These studies provide new insights into the divergent biosynthesis of mushroom-originated cyathanes and a straightforward approach to produce bioactive cyathane-type diterpenes.

10.
Front Oncol ; 11: 736225, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34513713

RESUMO

Objective: To screen and identify molecular targets and bacteria genus leading to adenomatous polyps in mouse induced by high-fat diet (HFD) +AOM/DSS using omics technology. Methods: The molecular targets of colorectal adenoma disease were obtained from the GeneCards and OMIM database. The SPF C57BL mice were randomly divided into blank (Control) and AOM/DSS+HFD colorectal adenoma model (ADH) groups. The ADH model group was intraperitoneally injected with AOM reagent. Then, mice were given with 2.5% DSS (in free drinking water) and high-fat diet to establish the mouse model. During this period, the changes of physical signs of mice in each group were observed. After the end of modeling, HE staining was used to evaluate the histopathological change of mice. The differentially expressed genes and proteins in the Control group and ADH group were detected by RNA-seq transcriptome sequencing and Tandem Mass Tags (TMT) quantitative proteomics. The histological results were analyzed by intersection with the intestinal adenoma molecular targets obtained from the database. Moreover, the changes of intestinal flora in the two groups were examined. The correlation between targets and differential bacteria was analyzed and verified by Parallel Reaction Monitoring (PRM) to comprehensively evaluate the mouse model of adenomatous polyp induced by AOM/DSS+HFD. Results: The general condition and histopathological results of mice confirmed that the ADH mouse model was successfully established and tubular adenoma was formed. A total of 604 genes and 42 proteins related to intestinal adenoma were obtained by histological analysis and database intersection analysis. The intestinal microflora of ADH mice was different from that of normal mice, and the constituents and abundance of intestinal flora were similar to those of human intestinal adenoma. GATA4 and LHPP were selected as potential pathological markers of the model mice by correlation analysis of targets and intestinal flora. The results of PRM verification were highly consistent with the results of RNA-Seq transcriptome sequencing and TMT analysis. Conclusion: The pathological results, molecular pathological markers and the changes of intestinal flora suggest that the mouse ADH model is ideal for studying the transformation of inflammatory cancer. The ADH model will be helpful for understanding the occurrence and development of human colorectal cancer at the transcriptomic and proteomic level.

11.
Front Microbiol ; 12: 726074, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34512604

RESUMO

Marinobacter is the abundant and important algal-associated and hydrocarbon biodegradation bacteria in the ocean. However, little knowledge about their phages has been reported. Here, a novel siphovirus, vB_MalS-PS3, infecting Marinobacter algicola DG893(T), was isolated from the surface waters of the western Pacific Ocean. Transmission electron microscopy (TEM) indicated that vB_MalS-PS3 has the morphology of siphoviruses. VB_MalS-PS3 was stable from -20 to 55°C, and with the latent and rise periods of about 80 and 10 min, respectively. The genome sequence of VB_MalS-PS3 contains a linear, double-strand 42,168-bp DNA molecule with a G + C content of 56.23% and 54 putative open reading frames (ORFs). Nineteen conserved domains were predicted by BLASTp in NCBI. We found that vB_MalS-PS3 represent an understudied viral group with only one known isolate. The phylogenetic tree based on the amino acid sequences of whole genomes revealed that vB_MalS-PS3 has a distant evolutionary relationship with other siphoviruses, and can be grouped into a novel viral genus cluster with six uncultured assembled viral genomes from metagenomics, named here as Marinovirus. This study of the Marinobacter phage vB_MalS-PS3 genome enriched the genetic database of marine bacteriophages, in addition, will provide useful information for further research on the interaction between Marinobacter phages and their hosts, and their relationship with algal blooms and hydrocarbon biodegradation in the ocean.

12.
Phys Rev Lett ; 127(11): 116801, 2021 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-34558927

RESUMO

Systems with non-Hermitian skin effects are very sensitive to the imposed boundary conditions and lattice size, and thus an important question is whether non-Hermitian skin effects can survive when deviating from the open boundary condition. To unveil the origin of boundary sensitivity, we present exact solutions for one-dimensional non-Hermitian models with generalized boundary conditions and study rigorously the interplay effect of lattice size and boundary terms. Besides the open boundary condition, we identify the existence of non-Hermitian skin effect when one of the boundary hopping terms vanishes. Apart from this critical line on the boundary parameter space, we find that the skin effect is fragile under any tiny boundary perturbation in the thermodynamic limit, although it can survive in a finite size system. Moreover, we demonstrate that the non-Hermitian Su-Schreieffer-Heeger model exhibits a new phase diagram in the boundary critical line, which is different from either open or periodical boundary case.

13.
Z Rheumatol ; 2021 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-34545431

RESUMO

BACKGROUND: Sclerostin, a regulator of bone metabolism and vascular calcification involved in regulating the Wnt/ß-catenin signaling pathway, has been shown to be involved in the pathogenesis of rheumatoid arthritis (RA). However, current results regarding the circulating sclerostin level of RA patients are debatable. This study aimed to evaluate the circulating level of sclerostin in RA patients and briefly summarize its role. METHOD: PubMed, EMBASE, and the Cochrane Library databases were systematically searched till May 27, 2021, for eligible articles. Useful data from all qualified papers were systematically extracted and analyzed using Stata 12.0 software (Stata Corp LP, College Station, TX, USA). RESULTS: Overall, 13 qualifying studies including 1030 cases and 561 normal controls were analyzed in this updated meta-analysis. Forest plot of this meta-analysis showed that RA patients had higher circulating sclerostin levels (P < 0.001, standardized mean difference [SMD] = 0.916, 95% CI: 0.235-1.597) compared to normal controls. Subgroup analyses implied that age, region, and assay method were associated with sclerostin level in RA patients. CONCLUSION: RA patients have higher circulating sclerostin levels, and these was influenced by age, region, and assay method.

14.
Lupus ; 30(12): 1923-1930, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34482739

RESUMO

Background: Abnormal expression and function of long non-coding RNAs (lncRNAs) are closely related to the pathogenesis of systemic lupus erythematosus (SLE). In this study, we aimed to investigate the association of lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT-1) gene single-nucleotide polymorphisms (SNPs) with susceptibility and clinical characteristics of SLE patients. Methods: A case-control study including 489 SLE patients and 492 healthy controls was conducted. Four MALAT-1 SNPs (rs4102217, rs591291, rs11227209, and rs619586) were genotyped in all subjects, their correlation with SLE susceptibility and clinical characteristics were also analyzed. Results: Results showed that the rs4102217 locus was associated with the risk of SLE. In recessive models, the GG+CG genotype of rs4102217 was associated with the decreased risk of SLE compared to CC (p = 0.036, OR = 0.348, 95% CI: 0.124-0.975). In additive models, the GG genotype of rs4102217 was associated with the decreased risk of SLE compared to CC (p = 0.040, OR = 0.355, 95% CI: 0.127-0.996). However, no association was found between MALAT-1 gene polymorphism and clinical manifestations of SLE (all p > 0.05). Conclusion: In summary, MALAT-1 rs4102217 is associated with susceptibility to SLE, suggesting that MALAT-1 may play a role in SLE.

15.
Appl Environ Microbiol ; 87(22): e0116021, 2021 10 28.
Artigo em Inglês | MEDLINE | ID: mdl-34469192

RESUMO

Nordic Seas are the subarctic seas connecting the Arctic Ocean and North Atlantic Ocean with complex water masses, experiencing an abrupt climate change. Though knowledge of the marine virosphere has expanded rapidly, the diversity of viruses and their relationships with host cells and water masses in the Nordic Seas remain to be fully revealed. Here, we establish the Nordic Sea DNA virome (NSV) data set of 55,315 viral contigs including 1,478 unique viral populations from seven stations influenced by both the warm Atlantic and cold Arctic water masses. Caudovirales dominated in the seven NSVs, especially in the warm Atlantic waters. The major giant nucleocytoplasmic large DNA viruses (NCLDVs) contributed a significant proportion of the classified viral contigs in the NSVs (32.2%), especially in the cold Arctic waters (44.9%). The distribution patterns of Caudovirales and NCLDVs were a reflection of the community structure of their hosts in the corresponding water masses and currents. Latitude, pH, and flow speed were found to be key factors influencing the microbial communities and coinfluencing the variation of viral communities. Network analysis illustrated the tight coupling between the variation of viral communities and microbial communities in the Nordic Seas. This study suggests a probable linkage between viromes, host cells, and surface water masses from both the cool Arctic and warm Atlantic Oceans. IMPORTANCE This is a systematic study of Nordic Sea viromes using metagenomic analysis. The viral diversity, community structure, and their relationships with host cells and the complex water masses from both the cool Arctic and the warm Atlantic oceans were illustrated. The NCLDVs and Caudovirales are proposed as the viral characteristics of the cold Arctic and warm Atlantic waters, respectively. This study provides an important background for the viromes in the subarctic seas connecting the Arctic Ocean and North Atlantic Ocean and sheds light on their responses to abrupt climate change in the future.

16.
CMAJ ; 193(32): E1240-E1249, 2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34400482

RESUMO

BACKGROUND: Exercise may exacerbate the adverse health effects of air pollution by increasing the inhalation of air pollutants. We investigated the combined effects of long-term exposure to fine particle matter (PM2.5) and habitual exercise on deaths from natural causes in Taiwan. METHODS: We recruited 384 130 adults (aged ≥ 18 yr) with 842 394 medical examination records between 2001 and 2016, and followed all participants until May 31, 2019. We obtained vital data from the National Death Registry of Taiwan. We estimated PM2.5 exposure using a satellite-based spatiotemporal model, and collected information on exercise habits using a standard self-administered questionnaire. We analyzed the data using a Cox regression model with time-dependent covariates. RESULTS: A higher level of habitual exercise was associated with a lower risk of death from natural causes, compared with inactivity (hazard ratio [HR] 0.84, 95% confidence interval [CI] 0.80-0.88 for the moderate exercise group; HR 0.65, 95% CI 0.62-0.68 for the high exercise groups), whereas a higher PM2.5 exposure was associated with a higher risk of death from natural causes compared with lower exposure (HR 1.02, 95% CI 0.98-1.07, and HR 1.15, 95% CI 1.10-1.20, for the moderate and high PM2.5 exposure groups, respectively). Compared with inactive adults with high PM2.5 exposure, adults with high levels of habitual exercise and low PM2.5 exposure had a substantially lower risk of death from natural causes. We found a minor, but statistically significant, interaction effect between exercise and PM2.5 exposure on risk of death (HR 1.03 95% CI 1.01-1.06). Subgroup analyses, stratified by PM2.5 categories, suggested that moderate and high levels of exercise were associated with a lower risk of death in each PM2.5 stratum, compared with inactivity. INTERPRETATION: Increased levels of exercise and reduced PM2.5 exposure are associated with a lower risk of death from natural causes. Habitual exercise can reduce risk regardless of the levels of PM2.5 exposure. Our results suggest that exercise is a safe health improvement strategy, even for people residing in relatively polluted regions.

17.
Ann Transl Med ; 9(13): 1063, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34422975

RESUMO

Background: High-density lipoprotein (HDL) plays an antiatherogenic role by mediating reverse cholesterol transport (RCT), antioxidation, anti-inflammation, and endothelial cell protection. Recently, series of evidence have shown that HDL can also convert to proatherogenic HDL under certain circumstances. Plasma paraoxonase 1 (PON1) as an HDL-bound esterase, is responsible for most of the antioxidant properties of HDL. However, whether PON1 can serve as a therapeutic target of dysfunctional HDL-related atherosclerosis remains unclear. Methods: In this study, scavenger receptor class B type I deficient (Scarb1-/- ) mice were used as the animal model with dysfunctional HDL and increased atherosclerotic susceptibility. Hepatic PON1 overexpression and secretion into circulation were achieved by lentivirus injection through the tail vein. We monitored plasma lipids levels and lipoprotein profiles in Scarb1-/- mice, and measured the levels and activities of proteins associated with HDL function. Meanwhile, lipid deposition in the liver and atherosclerotic lesions was quantified. Hepatic genes relevant to HDL metabolism and inflammation were analyzed. Results: The results showed the relative levels of PON1 in liver and plasma were increased by 1.1-fold and 1.6-fold, respectively, and mean plasma PON1 activity was increased by 63%. High-level PON1 increased the antioxidative and anti-inflammatory properties, promoted HDL maturation and macrophage cholesterol efflux through increasing HDL functional proteins components apolipoprotein A1 (APOA1), apolipoprotein E (APOE), and lecithin-cholesterol acyltransferase (LCAT), while decreased inflammatory protein markers, such as serum amyloid A (SAA), apolipoprotein A4 (APOA4) and alpha 1 antitrypsin (A1AT). Furthermore, hepatic PON1 overexpression linked the effects of antioxidation and anti-inflammation with HDL metabolism regulation mainly through up-regulating liver X receptor alpha (LXRα) and its downstream genes. The pleiotropic effects involved promoting HDL biogenesis by raising the level of APOA1, increasing cholesterol uptake by the liver through the APOE-low density lipoprotein receptor (LDLR) pathway, and increasing cholesterol excretion into the bile, thereby reducing hepatic steatosis and aorta atherosclerosis in Western diet-fed mice. Conclusions: Our study reveals that high-level PON1 improved dysfunctional HDL and alleviated the development of atherosclerosis in Scarb1-/- mice. It is suggested that PON1 represents a promising target of HDL-based therapeutic strategy for HDL-related atherosclerotic cardiovascular disease.

18.
J Org Chem ; 86(18): 12988-13000, 2021 09 17.
Artigo em Inglês | MEDLINE | ID: mdl-34459187

RESUMO

Pd-catalyzed hydroaminocarbonylation (HAC) of alkenes with CO and NH4Cl enables atom-economic and regiodivergent synthesis of primary amides, but the origin of regioselectivity was incorrectly interpreted in previous computational studies. A density functional theory study was performed herein to investigate the mechanism. Different from the previous proposals, both alkene insertion and aminolysis were found to be potential regioselectivity-determining stages. In the alkene insertion stage, 2,1-insertion is generally faster than 1,2-insertion irrespective of neutral or cationic pathways for both P(tBu)3 and xantphos. Such selectivity results from the unconventional proton-like hydrogen of the Pd-H bond in alkene insertion transition states. For less bulky alkenes, aminolysis with P(tBu)3 shows low selectivity, while linear selectivity dominates in this stage with xantphos due to a stronger repulsion between xantphos and branched acyl ligands. It was further revealed that the less-mentioned CO concentration and solvents also influence the regioselectivity by adjusting the relative feasibilities of CO-involved steps and NH3 release from ammonium chloride, respectively. The presented double-regiodetermining-stages mechanistic model associated with the effects of ligands, CO concentration, and solvents well reproduced the experimental selectivity to prove its validity and illuminated new perspectives for the regioselectivity control of HAC reactions.


Assuntos
Alcenos , Monóxido de Carbono , Cloreto de Amônio , Catálise , Paládio
19.
Artigo em Inglês | MEDLINE | ID: mdl-34224786

RESUMO

BACKGROUND: Local immunoglobulin hyperproduction is observed in nasal polyps (NPs) with and without ectopic lymphoid tissues (eLTs). OBJECTIVE: Our aim was to identify the T-cell subsets involved in local immunoglobulin production independent of eLTs in NPs. METHODS: The localization, abundance, and phenotype of CD4+ T-cell subsets were studied by immunofluorescence, flow cytometry, and single-cell RNA sequencing. Purified nasal T-cell subsets were cultured with autologous peripheral naive B cells to explore their function. Programmed death ligand 1 and programmed death ligand 2 expression in NPs was investigated by immunofluorescence staining and flow cytometry. RESULTS: Accumulation of PD-1highCXCR5-CD4+ T cells outside lymphoid aggregates was found in NPs. Nasal PD-1highCXCR5-CD4+ T cells were characterized by a unique phenotype that was related to B-cell help and tissue residency and distinct from PD-1-/intCXCR5- and CXCR5+ CD4+ T cells in NPs as well as PD-1highCXCR5highCD4+ follicular helper T cells in tonsils. Compared with the frequencies of PD-1highCXCR5-CD4+ T cells and their IFN-γ+, IL-17A+, and IL-21+ subsets in the control inferior turbinate tissues, the frequencies of these cells and their subsets were increased in both eosinophilic and noneosinophilic NPs, whereas the frequencies of the IL-4+ and IL-4+IL-21+ subsets were increased only in eosinophilic NPs. Nasal PD-1highCXCR5-CD4+ T cells induced immunoglobulin production from B cells in a potency comparable to that induced by tonsillar follicular helper T cells. PD-1highCXCR5-CD4+ T-cell frequencies were correlated with IgE levels in eosinophilic NPs. PD-L1 and PD-L2 suppressed the function of PD-1highCXCR5-CD4+ T cells, and their levels were reduced in NPs. PD-1highCXCR5-CD4+ T-cell abundance was associated with the postsurgical relapse of NPs. CONCLUSION: PD-1highCXCR5-CD4+ T cells participate in local immunoglobulin production independent of eLTs in NPs.

20.
Autoimmun Rev ; 20(8): 102866, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34118460

RESUMO

Circadian rhythm is a natural, endogenous process whose physiological functions are controlled by a set of clock genes. Disturbance of the clock genes have detrimental effects on both innate and adaptive immunity, which significantly enhance pro-inflammatory responses and susceptibility to autoimmune diseases via strictly controlling the individual cellular components of the immune system that initiate and perpetuate the inflammation pathways. Autoimmune diseases, especially rheumatoid arthritis (RA), often exhibit substantial circadian oscillations, and circadian rhythm is involved in the onset and progression of autoimmune diseases. Mounting evidence indicate that the synthetic ligands of circadian clock genes have the property of reducing the susceptibility and clinical severity of subjects. This review supplies an overview of the roles of circadian clock genes in the pathology of autoimmune diseases, including BMAL1, CLOCK, PER, CRY, REV-ERBα, and ROR. Furthermore, summarized some circadian clock genes as candidate genes for autoimmune diseases and current advancement on therapy of autoimmune diseases with synthetic ligands of circadian clock genes. The existing body of knowledge demonstrates that circadian clock genes are inextricably linked to autoimmune diseases. Future research should pay attention to improve the quality of life of patients with autoimmune diseases and reduce the effects of drug preparation on the normal circadian rhythms.


Assuntos
Artrite Reumatoide , Relógios Circadianos , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/genética , Relógios Circadianos/genética , Ritmo Circadiano/genética , Humanos , Qualidade de Vida
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...