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1.
Gait Posture ; 75: 1-7, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31586751

RESUMO

BACKGROUND: Coordination is the ability to assemble and maintain appropriate relations between joints. Investigating limb coordination in curve-turning (CT) walking could provide insightful information about the coordinating strategies and neuro-musculoskeletal system (NMSS) control in human motion. RESEARCH QUESTION: Although preschoolers have already established an adult-like gait, how preschoolers perform their specific gait pattern when walking in CT and what coordination strategies they would choose during the turning process have not yet been systematically considered. Therefore, this study was aimed to investigate preschoolers' coordination mechanism during asymmetric motion, in order to understand the development of their NMSS control in locomotion. METHODS: Kinematics data in the lower and upper limbs of 45 healthy preschoolers walking with the curve-turning task was measured by the Coda Motion System. The Continuous Relative Phase (CRP) angle and the variability between the knee and ankle, hip and knee, as well as the thorax-humerus joint (THJ) and elbow were calculated. RESULTS: The outcome demonstrates that as the curve angles increased, the stride length and Froude number of preschoolers significantly decreased (p < 0.05 for all); meanwhile, a more out of phase coordination pattern in CRP and an increase in VCRP values were found. Group analysis showed that the significant differences in CRP and VCRP between preschoolers and adults increased with curve angles in all coupled joints - the highest in that of the Knee-Ankle coupling, followed by those of the Hip-Knee and THJ-Elbow. SIGNIFICANCE: Our results suggest that to achieve curve-turning, preschoolers first chose to modify their STP, then to adjust coordination for coupling-joints in the Knee-Ankle, Hip-Knee, and THJ-Elbow systems. Additionally, preschoolers are still in a gait fine-tuning period and their NMSS control of motion is not as precise as that of adults.

2.
Sci Rep ; 9(1): 18114, 2019 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-31792331

RESUMO

Thelytokous Wolbachia-infected Trichogramma spp. are widely used egg parasitoids against lepidopteran pests in biological control programs. Wolbachia may manipulate host wasps for superparasitism and is sensitive to temperature. To explore effects of temperature and superparasitism, we compared fitness parameters and Wolbachia-mediated phenotype of thelytokous Wolbachia-infected Trichogramma dendrolimi between those emerging from superparasitised or single-parasitised hosts at 17, 21, 25, or 29 °C. Infected mothers of T. dendrolimi showed reduced superparasitism and parasitism increased with temperature. Wolbachia titre decreased with temperature when females emerged from singly-parasitised hosts, but there was no correlation in superparasitised hosts. Females showed higher Wolbachia titres at 21, 25, or 29 °C when developing from superparasitised hosts. The daily male ratio of offspring increased with temperature, and the day-age threshold for 5%, 50%, or 95% daily male ratio decreased with temperature in both parasitism forms. Females that emerged from superparasitised hosts had a shorter life span and reduced fecundity. These results indicate that Wolbachia may affect host behaviour by increasing superparasitism to enhance its spread, but this has negative effects on thelytokous Wolbachia-infected T. dendrolimi.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31686248

RESUMO

PURPOSE: Early death (ED) is the main cause of acute promyelocytic leukemia (APL) treatment failure, and the ED rate is higher for elderly patients than that for young ones. To date, no studies have been found focusing on ED in elderly patients with APL. METHODS: This study retrospectively analyzed the clinical data of 409 consecutive patients with APL (139 patients ≥ 50 years old, 270 patients < 50 years old). All patients received arsenic trioxide alone as induction therapy. The baseline clinical characteristics and ED occurrence and predictors between elderly and young patients with APL were compared and analyzed. RESULTS: The clinical features of elderly patients at admission were not significantly different from those of young ones. The ED rate of elderly patients was significantly greater than that of young patients (23.74% vs 11.85%, P = 0.0018). Hemorrhage is the main cause of ED in elderly patients, followed by infection and differentiation syndrome. From the 15th to 30th days of treatment, elderly patients had a higher mortality rate than that of young patients (7.83% vs 2.06%, P = 0.009). Male, white blood cell (WBC) count > 10 × 109/L, fibrinogen < 1.0 g/L and low albumin levels were independent risk factors for ED in elderly patients, while ED was only correlated with WBC count, fibrinogen and creatinine levels in young patients. CONCLUSION: The results of this study may help design more rational treatment plans for elderly patients with APL based on early mortality risk to reduce the ED rate.

4.
Commun Biol ; 2: 410, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31754640

RESUMO

Bacterial ClpP is a highly conserved, cylindrical, self-compartmentalizing serine protease required for maintaining cellular proteostasis. Small molecule acyldepsipeptides (ADEPs) and activators of self-compartmentalized proteases 1 (ACP1s) cause dysregulation and activation of ClpP, leading to bacterial cell death, highlighting their potential use as novel antibiotics. Structural changes in Neisseria meningitidis and Escherichia coli ClpP upon binding to novel ACP1 and ADEP analogs were probed by X-ray crystallography, methyl-TROSY NMR, and small angle X-ray scattering. ACP1 and ADEP induce distinct conformational changes in the ClpP structure. However, reorganization of electrostatic interaction networks at the ClpP entrance pores is necessary and sufficient for activation. Further activation is achieved by formation of ordered N-terminal axial loops and reduction in the structural heterogeneity of the ClpP cylinder. Activating mutations recapitulate the structural effects of small molecule activator binding. Our data, together with previous findings, provide a structural basis for a unified mechanism of compound-based ClpP activation.

5.
Analyst ; 2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31746827

RESUMO

This study reports a surface-enhanced electrochemiluminescence (SEECL) sensor for the ultrasensitive detection of prostate-specific antigen (PSA) in human serum. First, we prepared the Au-SiO2 core-shell nanocomposites doped with Ru(bpy)32+ (Au@SiO2-Ru) as the ECL signal generation and amplification element of the SEECL sensor. Ru(bpy)32+ could emit ECL under the excitation of an electrochemical reaction, and generate the local surface plasmon resonance (LSPR) electromagnetic field from the gold nanoparticle (AuNP) core. The produced LSPR then effectively enhanced the ECL signals. This sensing strategy was utilized for the detection of PSA, which can be absorbed on the electrode surface by the reaction between PSA and monoclonal antibodies. When polyclonal antibody-modified Au@SiO2-Ru was added, the PSA-double-antibody sandwich structure was formed on the electrode surface and thus, the Au@SiO2-Ru were quantitatively immobilized on the electrode surface. The results show that this kind of SEECL sensor has good selectivity toward PSA. Notably, the minimum detection concentration reached 7 × 10-7 ng mL-1 under the optimum experimental conditions, which is much better than most of the previously reported approaches for the detection of PSA in serum.

6.
Artigo em Inglês | MEDLINE | ID: mdl-31759629

RESUMO

Renal CD133 + scattered tubular cells (STCs) have been regarded as progenitor-like cells in the kidney and participated in ischemic renal injury repair. However, the mechanism of this effect is not fully elucidated yet. The primary objective of this study was to investigate the hypothesis that the protective effect of CD133 + STCs depends on the transfer of mitochondria to injured tubular cells in vitro. In this study, renal ischemic reperfusion injury (IRI) rat model was established with one side kidney ischemic for 45 min and animals were sacrificed at 48 h after operation. Tubular cells were isolated and cultured in vitro, and then CD133 + STCs were selected from the cultured cells. Then, CD133 + STCs were co-cultured with CD133-tubular cells (TECs) to detect the tunneling nanotubes like structures, and the transfer of mitochondria from CD133 + STCs to injured tubular cells were detected by fluorescent imaging and flow cytometry. Further, cellular protective effects of CD133 + STCs were tested when cultured with TECs under hypoxic conditions. In results, renal CD133 + STCs were scattered throughout the normal kidney and increased upon ischemic injury. Nanotube formations were commonly found between CD133 + STCs and TECs, and the transfer of mitochondria was detected from CD133 + STCs to TECs. Further, CD133 + STCs exist significant anti-apoptosis and pro-proliferation effects for TECs under hypoxic culture conditions. Thus, this study was first described that renal CD133 + STCs could transfer mitochondria to injured TECs in vitro for its protective effects, which revealed an important novel mechanism for renal repair after ischemic injury.

7.
Biomater Sci ; 2019 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-31761913

RESUMO

Three SAP (self-assembling peptide)-tagged fluorinases (FLAs), namely, FLA-ELK16, FLA-L6KD and FLA-18A (named after the SAP used for tagging FLA) were successfully engineered. All three SAP-tagged FLAs could be highly over-expressed using engineered E. coli host cells despite being in the form of aggregates (inclusion bodies). It was noted that all three SAP-tagged FLAs exhibited enzymatic activity. It was also observed that all three SAP-tagged FLAs were capable of self-assembly to form nano-sized particles with different dimensions in aqueous solutions. Strikingly, one of the SAP-tagged FLA (FLA-L6KD) displayed improved enzyme activity, thermostability and reusability, which is potentially ideal for bio-transformation. FLA is an exotic enzyme that is capable of catalysing the formation of C-F bonds using inorganic fluorine ions as substrates. This significant feature enables it to incorporate [18F]-fluoride into different small molecules to generate radiopharmaceuticals in PET (positron emission tomography) labeling. In addition, fluorinase is greatly valuable in synthetic biology for incorporating the fluorine element into building blocks to produce non-natural organofluorines or as a biocatalyst for transforming non-native substrates. Our method would be a further step in making FLA-based biocatalysis even 'greener' by enhancing the enzymatic activity, thermostability and reusability of FLA through the introduction of nano-sized aggregates. Enzymes are such nontrivial biomaterials, which can be manifested in different scenarios. Our research expands their reach and tunes their properties by tagging SAP partners. Thus, this methodology can be put into the 'toolbox' of enzymologists, which can be further explored and generalised for others.

8.
Harmful Algae ; 89: 101666, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31672231

RESUMO

Harmful algal blooms caused by Chattonella marina recently have caused severe negative effect on coastal economy worldwide, with increased occurrence frequency and scale. It is therefore vital to establish new methods for rapid detection of this alga. In this study, the internal transcribed spacer (ITS) sequence was used as the target gene for molecular detection of C. marina. First, four loop-mediated isothermal amplification (LAMP) primers were designed based on the six regions of ITS, and the LAMP reaction system was established using these primers. Next, a probe was designed to detect the LAMP products by lateral-flow dipstick (LFD). Finally, a new method for rapid and sensitive detection of C. marina that is referred to as LAMP-LFD was established. The LAMP reaction system, amplification time, and amplification temperature were particularly optimized. The optimal parameters are as follows: Mg2+ concentration, 10 mM;dNTP concentration, 1.2 mM;ratio of internal primer concentration to outer primer concentration, 8:1;reaction time, 60 min;and reaction temperature, 60 °C. Both specificity and sensitivity were tested using the optimized LAMP reaction system in combination with LFD (LAMP-LFD). The established LAMP-LFD displayed good specificity and no cross reaction was detected with non-target algal species. The detection limit of LAMP-LFD was 3.4 × 10-4 ng µL-1 (3.4 × 10-4 ng per reaction) for the genomic DNA of target algae, and 1.3 copies µL-1 (1.3 copies per reaction) for the plasmid DNA containing the target ITS. Sensitivity tests using genomic DNA and plasmid DNA as templates consistently revealed that LAMP-LFD is 100 times more sensitive than regular PCR. The established LAMP-LFD was applied to analyze the simulated samples and the results showed that the detection limit of LAMP-LFD could reach 1 cell mL-1. LAMP-LFD also demonstrated good specificity and sensitivity in the analysis of natural samples. The whole procedure of LAMP-LFD could be completed within 1.5 h. Taken together, the LAMP-LFD assay developed here is characterized by simplicity, high specificity and sensitivity, and rapidity and therefore is promising for rapid detection of C. marina.

9.
Artigo em Inglês | MEDLINE | ID: mdl-31677818

RESUMO

It has been demonstrated that the incorporation of Ni into metal oxide-based gas sensors often enhances the sensing performance by increasing the catalytic and heterojunction effects. However, it remains unclear how these two effects work either individually or synergistically in gas sensing. Herein, a series of Ni-doped In2O3 nanotubes (NIO NTs) with different doping concentrations were synthesized through a traditional electrospinning technique. The as-prepared NIO NTs were uniform, with length of micron scale, an average diameter of approximately 70 nm, and a tube wall thickness of approximately 10 nm. Following their incorporation into gas sensors, the NIO NTs often showed improved sensing properties (including excellent response and selectivity) for ethanol vapor compared to the pristine In2O3 NTs. Specifically, at 100 ppm ethanol and 220 °C, the response of NIO-7 NTs (7 mol% Ni) was approximately four-fold higher than that of pristine In2O3 NTs (49.74 vs. 13.39). The gas sensing test results indicated that the improved sensing performance was due to the formation of a heterojunction between In2O3 and NiO, as well as to the catalysis effects of Ni3+ ions. Additionally, simulation results indicated that the improved gas selectivity could be due to the Ni doping-induced change in surface adsorption energies of the tested gases.

10.
Mar Genomics ; : 100719, 2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31680055

RESUMO

The Acinetobacter baumanni J1 isolated from surface water of the Eastern Pacific Ocean, demonstrated significant algicidal activity on the algae Alexandrium tamarense. Interestingly, this strain showed the ability to produce an acyl-homoserine lactone (AHL) quorum sensing molecule. To better understand its AHL producing mechanism and its ecological functions, the genome of A. baumanni strain J1 was completely sequenced. The genome contained a circular chromosome of 3,948,465 bp with an average GC content of 39.9 mol%. A total of 3707 protein coding genes, 41 tRNA genes and 16 rRNA genes were obtained. In silico genome annotation identified a LuxI putative gene located on contig 4. Subsequent thin-layer chromatography analysis indicated that C8-AHL could be produced by A. baumanni J1, which confirmed the authenticity of the LuxI gene. Taken together, this work describes an algicidal bacterium that is capable of producing an AHL molecule, which may represent a valuable tool for developing microbial methods to control harmful algae.

11.
Cancer Discov ; 2019 Nov 26.
Artigo em Inglês | MEDLINE | ID: mdl-31771969

RESUMO

Diffuse gastric cancer (DGC) is a lethal malignancy lacking effective systemic therapy. Among the most provocative recent results in DGC has been that of highly recurrent missense mutations in the GTPase RHOA. The function of these mutations has remained unresolved. We demonstrate that RHOAY42C, the most common RHOA mutation in DGC, is a gain-of-function oncogenic mutant and that expression of RHOAY42C with inactivation of canonical tumor suppressor Cdh1 induces metastatic DGC in a mouse model. Biochemically, RHOAY42C exhibits impaired GTP hydrolysis and enhances interaction with its effector ROCK. RHOAY42C mutation and Cdh1 loss induce actin/cytoskeletal rearrangements and activity of focal adhesion kinase (FAK), which activates YAP/TAZ, phosphoinositide 3-kinase (PI3K)/AKT and ß-catenin. RHOAY42C murine models were sensitive to FAK inhibition and to combined YAP and PI3K pathway blockade. These results, coupled to sensitivity to FAK inhibition in patient-derived DGC cell lines, nominate FAK as a novel target for these cancers.

12.
Sci Rep ; 9(1): 17480, 2019 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-31767914

RESUMO

Trichogramma dendrolimi is one of the most successful biocontrol agents in China. However, an inundative condition is necessary to obtain acceptable parasitism effect. A good solution to this is the application of its thelytokous counterparts which unfortunately are scarce in field. We here report the first case of a natural T. dendrolimi population in China comprising both bisexual wasps and an extremely low proportion of thelytokous wasps. These two forms of T. dendrolimi are phylogenetically related based on the reconstructions of ITS-2 and COI genes. Also, the phylogenetic results suggested a potentially Wolbachia-drived ITS-2 variation. The expression of thelytoky was hardly affected by temperature, which might help control Asian corn borer and Dendrolimus punctatus. Wolbachia are responsible for current thelytoky according to phylogenetic analyses, antibiotic treatment and introgression experiment. We also present the third case of paternal sex ratio chromosome that restrains the expansion of Wolbachia. Moreover, the low frequency of thelytoky may be common in natural populations. Consequently if for biological control it is determined that a thelytokous strain is to be preferred, then large number of field collected females should be set up as isofemale lines, to detect the rare thelytoky.

13.
Chem Res Toxicol ; 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31714069

RESUMO

The current study aimed to examine the anticancer activity of HTF-1, a cardiac glycoside (CG) isolated from Helleborus thibetanus Franch, using a cell-based model and to discover the underlying mechanisms with specific focus on autophagy. We found that HTF-1 was able to potently decrease the viability of several cancer cell lines especially for HeLa cervical carcinoma cells. It was discovered that HTF-1 dose dependently induced overproduction of ROS in HeLa cells, and the cell viability can be rescued when adding ROS scavenger N-acetyl-l-cysteine (NAC). More, we found that HTF-1 induced ROS-independent autophagy in concentration- and time-dependent manners in HeLa cells. This can be collectively verified by LC3-II and p62 abundance and also eGFP-LC3 puncta assay, bafilomycin clamp experiment, and acidotropic dye fluorescent labeling experiment. Additionally, TEM examination showed more autophagic vacuoles for HTF-1-treated HeLa cells. In HeLa cells, pretreatment with wortmannin (an inhibitor of the initial stages of autophagy to block autophagosome formation, thus, it should weaken the autophagy induction effect of HTF-1) decreased the autophagic flux and partially antagonized cell death induced by HTF-1, indicating that autophagy induced by HTF-1 played a cancer-suppressing role. Furthermore, coadministration of BAF (as a distal inhibitor of autophagy) with HTF-1 demonstrated a synergistic anticancer effect against HeLa cells. We believe that our work will enrich the understanding of CGs and especially anticarcinoma activity, also, pave the way for natural-product-based anticancer drug development.

14.
Angew Chem Int Ed Engl ; 58(50): 18146-18149, 2019 Dec 09.
Artigo em Inglês | MEDLINE | ID: mdl-31591785

RESUMO

The key issue holding back the application of solid polymeric electrolytes in high-energy density lithium metal batteries is the contradictory requirements of high ion conductivity and mechanical stability. In this work, self-healable solid polymeric electrolytes (SHSPEs) with rigid-flexible backbones and high ion conductivity are synthesized by a facile condensation polymerization approach. The all-solid Li metal full batteries based on the SHSPEs possess freely bending flexibility and stable cycling performance as a result of the more disciplined metal Li plating/stripping, which have great implications as long-lifespan energy sources compatible with other wearable devices.

15.
Biomater Sci ; 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31664285

RESUMO

Fe3O4 magnetic nanoparticles (MNPs), as one of the most intensively researched NPs, have a range of applications in cancer treatments. In current research, we have focused on the influences of MNPs on cancer cells. We chose polyethyleneimine (PEI) coated MNPs (PEI-MNPs) as a model and they are colloidally stable in biological media. It can be proved that PEI-MNPs result in autophagy induction via mTOR-Akt-p70S6 K and ATG7 signaling pathways. For the first time, we have reported that PEI-MNPs activate both NF-κB and TGF-ß signaling, two key pro-inflammatory pathways, in cancer cells. More significantly, we have found that autophagy induction and NF-κB and TGF-ß activation can be efficiently suppressed through the inhibition of PEI-MNP dependent reactive oxygen species (ROS) over-production. ROS are deemed as a 'double edge sword' for cancer cells, owing to the cancer-suppressing and cancer-promoting actions. Our findings would be useful for designing MNPs induced ROS anti-cancer strategies or diminishing long-term toxic effects.

16.
EBioMedicine ; 48: 386-404, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31594754

RESUMO

BACKGROUND: Nasopharyngeal carcinoma (NPC) is an Epstein-Barr virus (EBV)-related tumor. The role of EBV-encoding miR-BART22 is still unclear in NPC. This study aimed to identify the detailed mechanisms by which EBV-miR-BART22 functions as a tumor-promoting factor and evaluate the action of cinobufotalin in treating EBV-miR-BART22-overexpressing NPC cells. METHODS: Using real-time PCR, western blotting, immunohistochemistry, and In situ hybridization, we detected the expression of miR-BART22 and MAP2K4 in tissues and cells, as well as evaluated their clinical relevance in NPC patients. The effects of miR-BART22 on cell metastasis, stemness and DDP chemoresistance were examined by sphere formation assay, side population analysis, transwell, boyden, in vivo xenograft tumor mouse model et al. Western blotting, immunofluorescence staining, luciferase reporter assay, ChIP, EMSA and Co-IP assay et al. were performed to explore the detailed molecular mechanism of EBV-miR-BART22 in NPC. Finally, we estimated the effects and molecular basis of Cinobufotalin on EBV-miR-BART22-overexpressing NPC cells in vitro and in vivo assays. FINDINGS: We observed that EBV-miR-BART22 not only promoted tumor stemness and metastasis, but also enhanced the resistance to Cisplatin (DDP) in vitro and in vivo. Mechanistic analysis indicated that EBV-miR-BART22 directly targeted the MAP2K4 and upregulated non-muscle myosin heavy chain IIA (MYH9) expression by PI3K/AKT/c-Jun-induced transcription. Further, MYH9 interacted with glycogen synthase 3ß(GSK3ß) protein and induced its ubiquitin degradation by activating PI3K/AKT/c-Jun-induced ubiquitin transcription and the latter combined with increased TRAF6 E3 ligase, which further bound to GSK3ß protein. Reductions in the GSK3ß protein thus promoted ß-catenin expression and nuclear translocation, which induced tumor stemness and the epithelial-to-mesenchymal transition (EMT) signals. Furthermore, we observed that cinobufotalin, a new chemically synthesized compound, significantly suppressed EBV-miR-BART22-induced DDP chemoresistance by upregulating MAP2K4 to suppress MYH9/GSK3ß/ß-catenin and its downstream tumor stemness and EMT signals in NPC. Finally, clinical data revealed that increased miR-BART22 and reduced MAP2K4 expression caused the poor prognoses of NPC patients. INTERPRETATION: Our study provides a novel mechanism that cinobufotalin reversed the DDP chemoresistance and EMT induced by EBV-miR-BART22 in NPC.

17.
Curr Mol Med ; 2019 Oct 09.
Artigo em Inglês | MEDLINE | ID: mdl-31595851

RESUMO

BACKGROUND: This study took the untreated OSAHS patients as the control group, exploring the influence of minimally invasive surgery treatment and CPAP therapy on OSAHS patients, subjective and objective performance, discussing their relationship, finding out the effect factor and providing a simple and practical evaluation of clinical efficacy. METHODS: Choose 90 OSAHS patients diagnosed in the Sleep Disorders Diagnosis and Treatment Center of Sichuan Province from May 2014 to May 2016,divide into surgery group, CPAP group and untreated group,then follow up in six month、1year、2year respectively. Compare three groups, physiological indicators, clinical symptoms, the degree of daytime sleepiness and quality of life, evaluate the daytime sleepiness and quality of life changes before and after minimally invasive surgery and CPAP treatment, explore the subjective and objective efficacy of surgery and CPAP treatment. RESULTS: In the 90 patients,11(12.2%) had the hypertension, 2(2.2%) had the diabetes. The average AHI was 50.53±23.39 per hour,and the mean minimum oxygen saturation and mean oxygen saturation was 71.25±14.16%,90.13±5.90% respectively; There were statistical significant in mouth breathing、morning throat、daytime sleepiness in surgery group at 0.5 year and 1year; In CPAP group,there were statistical significant in mouth breathing、morning throat、daytime sleepiness at 0.5 year、1year and 2year, there was statistical significant in memory loss at 1year and 2year, there was statistical significant in frequent nocturia at 1year; The ESS value in surgery group decreased at 0.5y and 1y,but increased at 2year.The situation was the same in total points and each dimension of SF-36; The delta values of ESS among three groups had statistical significant at 0.5year、1year and 2year, and CPAP group changed the most, followed by surgery group and healthy education group. CONCLUSIONS: All the minimally invasive surgery、CPAP therapy and healthy education can improve the daytime sleepiness and quality of life, CPAP therapy changed the most, followed by minimally invasive surgery and healthy education. But the treatment of OSAHS should be comprehensive.

18.
Acta Pharmacol Sin ; 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31645659

RESUMO

The global prevalence of nonalcoholic steatohepatitis (NASH) increases incredibly. NASH ends up to advanced liver disease, which is highly threatening to human health. Currently, treatment of NASH is very limited. Acetyl-CoA carboxylases (ACC1/ACC2) are proved as effective drug targets for NASH. We aimed to develop novel ACC inhibitors and evaluate their therapeutic value for NASH prevention. ACC inhibitors were obtained through structure-based drug design, synthesized, screened from ACC enzymatic measurement platform and elucidated in cell culture-based assays and animal models. The lipidome and microbiome analysis were integrated to assess the effects of WZ66 on lipids profiles in liver and plasma as well as gut microbiota in the intestine. WZ66 was identified as a novel ACC1/2 inhibitor. It entered systemic circulation rapidly and could accumulate in liver. WZ66 alleviated NASH-related liver features including steatosis, Kupffer cells and hepatic stellate cells activation in diet-induced obese mice. The triglycerides (TGs) and other lipids including diglycerides (DGs), phosphatidylcholine (PC) and sphingomyelin (SM) were decreased in WZ66-treated mice as evidenced by lipidome analysis in livers. The lipids profiles in plasma were also altered with WZ66 treatment. Plasma TG were moderately increased, while the activation of SREBP1c was not detected. WZ66 also downregulated the abundance of Allobaculum, Mucispirillum and Prevotella genera as well as Mucispirillum schaedleri species in gut microbiota. WZ66 is an ideal lead compound and a potential drug candidate deserving further investigation in the therapeutics of NASH.

19.
Int J Oncol ; 55(4): 845-859, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31485592

RESUMO

Reports have highlighted an association between connexins (CXs) or gap junction proteins and non­small cell lung cancer (NSCLC). In the present study, it was aimed to elucidate the regulatory mechanism of CX26 and CX43 under hypoxic conditions in NSCLC. Clinical samples were collected for analysis of CX26 and CX43 expression and clinical cancerization followed by quantification of CX26 and CX43 expression. Following the establishment of an in vitro hypoxia model, P53/murine double minute­2 (MDM2) signaling pathway­, proliferation­ and epithelial­mesenchymal transition (EMT)­related genes were quantified to evaluate the influence of CX26 and CX43 on the biological functions of pulmonary epithelial cells in NSCLC. In addition, the proliferation and tumorigenicity of cancer cells were assessed by EdU staining and xenograft tumors, respectively. Decreased expression of CX26 and CX43 was found in cancer tissues compared with surrounding normal tissue. Hypoxia was shown to activate the P53/MDM2 axis and stimulate the downregulation, ubiquitination and degradation of CX26 and CX43, which were translocated from the membrane to the cytoplasm. Low levels of CX26 and CX43 were demonstrated to further promote EMT and the induction of the proliferation and tumorigenicity of cancer cells. These results were reflected by decreased E­cadherin expression and increased N­cadherin expression, along with increased cell migration, promoted cell proliferation ability and elevated relative protein expression of Oct4 and Nanog, and accelerated tumor growth, accompanied by a higher number of metastatic nodes. Taken together, the key observations of the present study demonstrate that the internalization of CX26 and CX43 promoted proliferation, EMT and migration and thus induced NSCLC via aberrant activation of the P53/MDM2 signaling pathway under hypoxic conditions.

20.
Nutrients ; 11(9)2019 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-31480423

RESUMO

Although the major risk factors for liver cancer have been established, preventive factors for liver cancer have not been fully explored. We evaluated the association between raw garlic consumption and liver cancer in a large population-based case-control study in Eastern China. The study was conducted in Jiangsu, China, from 2003 to 2010. A total of 2011 incident liver cancer cases and 7933 randomly selected population-controls were interviewed. Epidemiological data including raw garlic intake and other exposures were collected, and serum markers of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection were assayed. Overall, eating raw garlic twice or more per week was inversely associated with liver cancer, with an adjusted odds ratio (aOR) of 0.77 (95% confidence interval (CI): 0.62-0.96) compared to those ingesting no raw garlic or less than twice per week. In stratified analyses, high intake of raw garlic was inversely associated with liver cancer among Hepatitis B surface antigen (HBsAg) negative individuals, frequent alcohol drinkers, those having history of eating mold-contaminated food or drinking raw water, and those without family history of liver cancer. Marginal interactions on an additive scale were observed between low raw garlic intake and HBsAg positivity (attributable proportion due to interaction (AP) = 0.31, 95% CI: -0.01-0.62) and heavy alcohol drinking (AP = 0.28, 95% CI: 0.00-0.57). Raw garlic consumption is inversely associated with liver cancer. Such an association shed some light on the potential etiologic role of garlic intake on liver cancer, which in turn might provide a possible dietary intervention to reduce liver cancer in Chinese population.

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