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1.
Artigo em Inglês | MEDLINE | ID: mdl-32024317

RESUMO

Karst water is rich in calcium ions (Ca2+) and exhibits poor metal availability and low biodegradation efficiency. This study sought to analyze the effects and mechanisms of Ca2+ on lead (Pb) removal and absorption by Eichhornia crassipes (a floating plant common in karst areas). Moreover, the morphology and functional groups of E. crassipes in water were characterized via SEM, and FTIR. The results demonstrated that the removal rate of Pb in karst water (85.31%) was higher than that in non-karst water (77.04%); however, the Pb bioconcentration amount (BCA) in E. crassipes roots in karst water (1763 mg/kg) was lower than that in non-karst water (2143 mg/kg). With increased Ca2+ concentrations (60, 80, and 100 mg/L) in karst water, the Pb removal rate increased (85.31%, 88.87%, and 92.44%), the Pb BCA decreased (1763, 1317, and 1095 mg/kg), and the Ca BCA increased (6801, 6955, and 9368 mg/kg), which was attributed to PbCO3 and PbSO4 precipitation and competitive Ca and Pb absorption. High Ca2+ concentrations increased the strength of cation exchange, alleviated the fracture degree of fibrous roots, reduced the atrophy of vascular bundles, protected the cell wall, promoted C-O combined with Pb, enhanced the strength of O‒H, SO42-, C=O, and reduced the oxidization of alkynyl acetylene bonds.

2.
Cell Immunol ; : 104046, 2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-32057354

RESUMO

Uncontrolled activation of NLRP3 inflammasome initiates a series of human inflammatory diseases. Targeting NLRP3 inflammasome has attracted considerable attention in developing potential therapeutic interventions. Here, we reported that dehydrocostus lactone (DCL), a main component of Saussurea lappa from the traditional Chinese medicine, inhibited NLRP3 inflammasome-mediated caspase-1 activation and subsequent interleukin (IL)-1ß production in primary mouse macrophages and human peripheral blood mononuclear cells and exerted an inhibitory effect on NLRP3-driven inflammation. Mechanistically, DCL significantly blocked the ASC oligomerization, which is essential for the assembly of activated inflammasome. Importantly, in vivo experiments showed that DCL reduced IL-1ß secretion and peritoneal neutrophils recruitment in LPS-mediated inflammation mouse model, which is demonstrated to be NLRP3 dependent. These results suggest that DCL is a potent pharmacological inhibitor of NLRP3 inflammasome and may be developed as a therapeutic drug for treating NLRP3-associated diseases.

3.
Sensors (Basel) ; 20(3)2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31979160

RESUMO

This research demonstrated the development of a simple, cost-effective, and label-free immunosensor for the detection of α-synuclein (α-Syn) based on a cystamine (CYS) self-assembled monolayer (SAM) decorated fluorine-doped tin oxide (FTO) electrode. CYS-SAM was formed onto the FTO electrode by the adsorption of CYS molecules through the head sulfur groups. The free amine (-NH2) groups at the tail of the CYS-SAM enabled the immobilization of anti-α-Syn-antibody, which concurrently allowed the formation of immunocomplex by covalent bonding with α-Syn-antigen. The variation of the concentrations of the attached α-Syn at the immunosensor probe induced the alternation of the current and the charge transfer resistance (Rct) for the redox response of [Fe(CN)6]3-/4-, which displayed a linear dynamic range from 10 to 1000 ng/mL with a low detection limit (S/N = 3) of ca. 3.62 and 1.13 ng/mL in differential pulse voltammetry (DPV) and electrochemical impedance spectra (EIS) measurements, respectively. The immunosensor displayed good reproducibility, anti-interference ability, and good recoveries of α-Syn detection in diluted human serum samples. The proposed immunosensor is a promising platform to detect α-Syn for the early diagnose of Parkinson's disease, which can be extended for the determination of other biologically important biomarkers.

4.
Zhongguo Zhen Jiu ; 40(1): 103-5, 2020 Jan 12.
Artigo em Chinês | MEDLINE | ID: mdl-31930908

RESUMO

In this paper, the micro-video teaching mode was explored in the course construction of Characteristic Clinical Technology of Acupuncture and Moxibustion. The micro-video teaching contents include the academic thought, experience in diagnosis and treatment, characteristic technology and clinical manipulation of famous acupuncture experts in the Henan University of CM. Each micro-video film is designed within 15-18 min, including three sections of knowledge, i.e. basic theory, technological application and clinical manipulation. Each section is designed within 5-6 min. The construction of the teaching course of Characteristic Clinical Technology of Acupuncture and Moxibustion is the innovation of practice mode of TCM and the new approach to the inheritance of the experience of experts. The construction of micro-video teaching course propels the reform of teaching mode, improves the learning initiative of students and clinical manipulative ability so as to improve the teaching effect and quality.


Assuntos
Terapia por Acupuntura , Moxibustão , Humanos , Aprendizagem , Estudantes , Ensino
5.
J Med Microbiol ; 69(1): 120-131, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31916929

RESUMO

Introduction. Staphylococcus aureus biofilms are difficult to treat and the effect of telithromycin treatment is still unclear.Aim. This study aimed to explore the effect of telithromycin against Staphylococcus aureus biofilms compared with azithromycin, clindamycin, vancomycin and daptomycin.Methodology. Eight methicillin-susceptible and eight methicillin-resistant S. aureus isolates (MSSA and MRSA, respectively) were used for this study. Biofilm biomasses were detected by crystal violet staining and the adherent cells in the established biofilms were quantified by determination of colony-forming units (c.f.u.). The RNA levels of biofilm formation-related genes were determined by RT-qPCR.Results. Telithromycin [8× minimum inhibitory concentration (MIC)] eradicated more established biofilms than azithromycin or clindamycin in the four MSSA isolates, and eliminated the established biofilms of six MRSA isolates more effectively than vancomycin or daptomycin. Telithromycin (8× MIC) killed more adherent cells in the established biofilms than azithromycin or clindamycin in the six MSSA isolates, and killed more adherent cells than vancomycin in all eight MRSA isolates. Daptomycin also showed an excellent effect on the adherent cells of MRSA isolates, with similarresults to telithromycin. The effect of a subinhibitory concentration of telithromycin (1/4× MIC) was significantly superior to that of azithromycin or clindamycin, inhibiting the biofilm formation of six MSSA isolates and seven MRSA isolates more effectively than vancomycin or daptomycin. The RNA levels of agrA, agrC, clfA, icaA and sigB decreased when treated with telithromycin (1/4× MIC).Conclusions. Telithromycin is more effective than azithromycin, clindamycin, vancomycin, or daptomycin against S. aureus biofilms.


Assuntos
Antibacterianos/farmacologia , Biofilmes/efeitos dos fármacos , Cetolídeos/farmacologia , Staphylococcus aureus/efeitos dos fármacos , Contagem de Colônia Microbiana , Testes de Sensibilidade Microbiana , Viabilidade Microbiana/efeitos dos fármacos , RNA Bacteriano/análise , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa
6.
Thorac Cancer ; 2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31967724

RESUMO

BACKGROUND: The aim of this study was to evaluate the effect of uniportal and three-portal VATS in lung cancer patients on the postoperative short-term quality of life (QOL). METHODS: A single-center, prospective, nonrandomized study was performed on patients who underwent uniportal or three-portal video-assisted thoracoscopic surgery (VATS) lobectomy and systemic mediastinal lymph node dissection. QOL was measured before surgery at baseline and at one, two, four, and eight weeks after the operation. The measured data of normal distribution were indicated by the mean ± standard deviation, the independent sample t-test was used among the groups, and the χ2 test was used to compare the counting. Non-normal distribution of the measurement data was carried out using the Mann-Whitney test. RESULTS: Preoperative functional areas, symptom areas and overall health scores were similar in the two groups. The physical, role, emotional and social functions and overall health status of the uniportal group were significantly higher than those of the three-portal group in postoperative time. The score of symptom field was higher in one week after operation, the score of two, four and eight weeks decreased gradually, but it was still above the preoperative level, and the fatigue and pain of the uniportal group were significantly lower than that of the three-portal group. CONCLUSION: The advantages of uniportal VATS include a shorter hospital stay, more rapid recovery and superior cosmetic results compared to three-portal VATS. Additionally, uniportal VATS is superior to three-portal thoracoscopic surgery in terms of the immediate postoperative short-term QOL.

7.
Environ Technol ; 41(5): 556-565, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-30052142

RESUMO

Dust emission from the bauxite residue drying areas is of great concern for its serious environmental and health impacts. The application of polymer stabilizers is a promising approach to mitigate such issues. However, limited studies have been done on their application on red sand and the investigation of the effect of polymers on penetration resistance, which is a key mechanical property closely related to the dust control performance. Stabilizers reduce the dust emission potential by forming a crust on the surface of treated material. This paper investigates the relationship of crust properties and dust control performance by applying synthetic (polyacrylamide) and natural (xanthan gum and guar gum) polymers. Results illustrated that the water retention property of treated sand is greatly improved after the application of stabilizers. The thickness of the formed crust decreases with stabilizer concentration. Results from wind tunnel simulation illustrated that the polymer stabilizer offers nearly 8 times longer protective period than water when used as a stabilizing agent. Cationic PAM performed the best, and cationic guar gum outperformed anionic xanthan gum. The penetration resistance is proved in this study to be a primary index for predicting dust control performance of polymer stabilizers.


Assuntos
Óxido de Alumínio , Poeira , Poluição Ambiental , Polímeros , Água
8.
Thorac Cancer ; 11(1): 156-165, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31777195

RESUMO

BACKGROUND: To investigate the regulatory mechanism behind miR-34a-altered Axl levels in non-small-cell lung cancer (NSCLC) with gefitinib-acquired resistance. METHODS: The expression of miR-34a, Axl, Gas6 and related downstream signaling proteins in the EGFR mutant NSCLC cell lines were determined by qRT-PCR and Western blot; PC9-Gef-miR-34a and HCC827-Gef-miR-34a cells were established by transfecting the parent cells with a miR-34a overexpressing virus, then the expression of Axl, Gas6 and the downstream channel-related proteins were also compared in PC9-Gef-miR-34a and HCC827-Gef-miR-34a and drug-resistant strains. The survival rate of the cells were measured by CCK8 assay. A luciferase reporter detected whether Axl was the target of miR-34a. Finally, a tumor-bearing nude mouse model was established to verify the relationship between the expression of miR-34a, Axl and Gas6 mRNA in vivo. RESULTS: The expression levels of Axl mRNA and protein, Gas6 mRNA and protein, and related downstream proteins in PC9-Gef and HCC827-Gef cell lines were higher than those in PC9 and HCC827 parental cell lines, while the expression of miR-34a was lower than it was in the parental cell lines (P < 0.05). The expression of Axl mRNA and protein, Gas6 mRNA and protein, and related downstream signaling proteins in PC9-Gef and HCC827-Gef cell lines was higher than the expression in PC9-Gef-miR-34a and HCC827-Gef-miR-34a cells, which overexpressed miR-34a (P < 0.05). CONCLUSION: The miR-34a regulation of Axl plays an important role in NSCLC-acquired gefitinib resistance, and their expression is inversely correlated, which suggests that they can be used as prognostic markers or potential therapeutic targets for NSCLC.

9.
Biochem J ; 477(2): 445-458, 2020 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-31808794

RESUMO

The neuroblastoma breakpoint family (NBPF) consists of 24 members that play an important role in neuroblastoma and other cancers. NBPF is an evolutionarily recent gene family that encodes several repeats of Olduvai domain and an abundant N-terminal region. The function and biochemical properties of both Olduvai domain and the N-terminal region remain enigmatic. Human NBPF15 encodes a 670 AA protein consisting of six clades of Olduvai domains. In this study, we synthesized and expressed full-length NBPF15, and purified a range of NBPF15 truncations which were analyzed using dynamic light scattering (DLS), superdex200 (S200), small-angle X-ray scattering (SAXS), far-UV circular dichroism (CD) spectroscopy, transmission electron microscope (TEM), and crystallography. We found that proteins containing both the N-terminal region and Olduvai domain are heterogeneous with multiple types of aggregates, and some of them underwent a liquid-to-solid phase transition, probably because of the entanglement within the N-terminal coiled-coil. Proteins that contain only the Olduvai domain are homogeneous extended monomers, and those with the conserved clade 1 (CON1) have manifested a tendency to crystallize. We suggest that the entanglements between the mosaic disorder-ordered segments in NBPF15 N terminus have triggered the multiple types of aggregates and phase transition of NBPF15 proteins, which could be associated with Olduvai-related cognitive dysfunction diseases.

10.
Neurosci Lett ; 715: 134611, 2020 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-31698026

RESUMO

Continuous theta burst stimulation (cTBS) has been widely recognized as a therapeutic treatment for ischemic stroke, but the underlying mechanism is still elusive. Here, we investigated the protective effects of cTBS in the posterior parietal cortex during the chronic phase of stroke in the photothrombotic ischemic model. Infarction volume and neuron excitability in the peri-infarct area were assessed using immunohistochemistry and whole-cell patch-clamp. Spatial cognitive function was measured using the Morris water maze. Gamma-Amino butyric acid (GABA) interneurons were responsive to cTBS, and cTBS induced elevated phasic inhibition rather than tonic inhibition. Given that GABA-A-mediated phasic inhibition was elevated during the chronic phase of ischemic stroke for 30 days and was beneficial for stroke recovery, we investigated the therapeutic potential of cTBS in promoting functional recovery and found that the elevated phasic inhibition by cTBS improved spatial cognitive function in the photothrombotic stroke mouse model with induction in the posterior parietal cortex. Our study indicates the mechanism by which cTBS may modify the excitability of the brain cortex and provides novel insight into the potential of cTBS to protect against neuronal dysfunction in ischemic stroke.

11.
Neurosci Bull ; 36(2): 110-120, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31428926

RESUMO

Multiple sclerosis (MS) is a chronic and incurable autoimmune neurodegenerative disease of the central nervous system. Although the symptoms of MS can be managed by vitamin D3 treatment alone, this condition cannot be completely eradicated. Thus, there might be unknown factors capable of regulating the vitamin D receptor (VDR). Genome-wide analysis showed that miRNAs were associated with VDRs. We sought to determine the role and mechanism of action of miRNA-125a-5p and VDRs in a model of MS, mice with experimental autoimmune encephalomyelitis (EAE), which was induced by myelin oligodendrocyte glycoprotein 35-55 peptides. EAE mice showed decreased mean body weight but increased mean clinical scores compared with vehicle or control mice. And inflammatory infiltration was found in the lumbosacral spinal cord of EAE mice. In addition, VDR expression was significantly lower while the expression of miR-125a-5p was markedly higher in the spinal ventral horn of EAE mice than in vehicle or control mice. Importantly, activation of VDRs by paricalcitol or inhibition of miR-125a-5p by its antagomir markedly decreased the mean clinical scores in EAE mice. Interestingly, VDR and miR-125a-5p were co-localized in the same neurons of the ventral horn. More importantly, inhibition of miR-125a-5p remarkably blocked the decrease of VDRs in EAE mice. These results support a critical role for miR-125a-5p in modulating VDR activity in EAE and suggest potential novel therapeutic interventions.

12.
Biosci Rep ; 40(1)2020 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-31778149

RESUMO

BACKGROUND: Tuberculous meningitis (TBM) is one of the most serious types of extrapulmonary tuberculosis. However, low sensitivity of culture of cerebrospinal fluid (CSF) increases the difficulty in clinical diagnosis, leading to diagnostic delay, and misdiagnosis. Xpert MTB/RIF assay is a rapid and simple method to detect tuberculosis. However, the efficacy of this technique in diagnosing TBM remains unclear. Therefore, a meta-analysis was conducted to evaluate the diagnostic efficacy of Xpert MTB/RIF for TBM, which may enhance the development of early diagnosis of TBM. METHODS: Relevant studies in the PubMed, Embase, and Web of Science databases were retrieved using the keywords 'Xpert MTB/RIF', 'tuberculous meningitis (TBM)'. The pooled sensitivity, pooled specificity, positive likelihood ratio, negative likelihood ratio, diagnostic odds ratio, summary receiver operator characteristic curve, and area under the curve (AUC) of Xpert MTB/RIF were determined and analyzed. RESULTS: A total of 162 studies were enrolled and only 14 met the criteria for meta-analysis. The overall pooled sensitivity of Xpert MTB/RIF was 63% [95% confidence interval (CI), 59-66%], while the overall pooled specificity was 98.1% (95% CI, 97.5-98.5%). The pooled values of positive likelihood ratio, negative likelihood ratio, and diagnostic odds ratio were 20.91% (12.71-52.82%), 0.40% (0.32-0.50%), and 71.49% (32.64-156.56%), respectively. The AUC was 0.76. CONCLUSIONS: Xpert MTB/RIF exhibited high specificity in diagnosing TBM in CSF samples, but its sensitivity was relatively low. It is necessary to combine other high-sensitive detection methods for the early diagnosis of TBM. Moreover, the centrifugation of CSF samples was found to be beneficial in improving the sensitivity.

13.
J Cell Biol ; 219(1)2020 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-31816056

RESUMO

The development of cerebral cortex requires spatially and temporally orchestrated proliferation, migration, and differentiation of neural progenitor cells (NPCs). The molecular mechanisms underlying cortical development are, however, not fully understood. The neural cell adhesion molecule (NCAM) has been suggested to play a role in corticogenesis. Here we show that NCAM is dynamically expressed in the developing cortex. NCAM expression in NPCs is highest in the neurogenic period and declines during the gliogenic period. In mice bearing an NPC-specific NCAM deletion, proliferation of NPCs is reduced, and production of cortical neurons is delayed, while formation of cortical glia is advanced. Mechanistically, NCAM enhances actin polymerization in NPCs by interacting with actin-associated protein profilin2. NCAM-dependent regulation of NPCs is blocked by mutations in the profilin2 binding site. Thus, NCAM plays an essential role in NPC proliferation and fate decision during cortical development by regulating profilin2-dependent actin polymerization.

14.
Brain Res ; 1726: 146488, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31586625

RESUMO

Acute ischemic stroke is a leading cause of disability with limited therapeutic options. Continuous theta burst stimulation (cTBS) has recently been shown to be a promising noninvasive therapeutic strategy for neuroprotection in ischemic stroke patients. Here, we investigated the protective effects of cTBS following acute infarction using a photothrombotic stroke (PTS) model in the right posterior parietal cortex (PPC) of C57BL/6 mice. Treatment with cTBS resulted in a reduction in the volume of the infarct region and significantly increased vascular diameter and blood flow velocity in peri-infarct region, as well as decreased the numbers of calcium binding adapter molecule 1 (Iba-1)-positive microglia and glial fibrillary acidic protein (GFAP)-positive astrocytes. Moreover, the number of CD16/32 positive microglia was decreased, whereas the number of CD206 positive microglia was increased. In addition, performance in a water maze task was significantly improved. These results indicated that cTBS protected against PPC infarct region, leading to an improvement in spatial cognitive function, possibly as a result of changes to cerebral microvascular function and inflammatory responses.

15.
Phytother Res ; 2019 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-31823428

RESUMO

In this study, we investigated the effect of astragaloside IV on skeletal muscle energy metabolism disorder caused by statins and explored the possible mechanisms. High-fat diet-fed apolipoprotein E knockout (ApoE-/- ) mice performed aerobic exercise and were administered simvastatin, simvastatin + trimetazidine, or simvastatin + astragaloside IV by gavage. At the end of treatment, exercise performance was assessed by the hanging grid test, forelimb grip test, and running tolerance test. Moreover, plasma lipid and creatine kinase concentrations were measured. After sacrifice, the gastrocnemius muscle was used to assess muscle morphology, and energy metabolism was evaluated by determining the concentration of lactic acid and the storage capacity of adenosine triphosphate and glycogen. Mitochondrial function was assessed by measuring mitochondrial complex III and citrate synthase activity and membrane potential. In addition, oxidative stress was assessed by determining the level of hydrogen peroxide. Finally, using western blotting and reverse transcription polymerase chain reaction, we explored the mechanism of astragaloside IV in alleviating simvastatin-induced muscle injury. Our results demonstrated that astragaloside IV reversed simvastatin-induced muscle injury without affecting the lipid-lowering effect of simvastatin. Moreover, astragaloside IV promoted the phosphorylation of AMPK and activated PGC-1α, which upregulated the expression of NRF1 to enhance energy metabolism and inhibit skeletal muscle cell apoptosis.

16.
Environ Pollut ; 259: 113821, 2019 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-31884212

RESUMO

Human-induced temperature changes influence coastal regions, both via thermal pollution and ocean warming, which exerts profound effects on the chemistry of metals and the physiology of organisms. However, it remains unknown whether the increased temperature of discharged water or ocean warming, as a result of climate change, lead to an increase of human health risks associated with the consumption of sea foods. In this study, the influence of temperature on metal accumulation by oysters was studied in individuals collected from a coastal area affected by the thermal water discharge of the Houshi Power Plant, China. The bioaccumulation factor (BAF) and oral bioavailability (OBA) of metals in oysters was determined. Elevated temperatures led to an increase in BAF for Cu, Zn, Hg, and Cd (p < 0.05), but no change was observed for As and Pb (p > 0.05). The OBA for Cd, As, and Pb correlated positively to elevated temperatures (p < 0.05). However, for Cu and Zn, OBA was negatively correlated with increasing temperature (p < 0.05). As, Pb, and Cd in the trophically available metal (defined as a sum of heat-stable proteins, heat-denaturable proteins, and organelles) was significantly elevated at the highest temperature seawater site (site A) compared to the lowest seawater site (site B). Thus, the irregular variation of OBA for each metal may be the result of variations in the subcellular distribution of metals and the protein quality influenced by the increased temperature. Moreover, the increased temperature and increased the hazard quotient values of As and Cd (p < 0.05 for As, n = 6, p < 0.05 for Cd, n = 6), which provided an indication of the potential risks of the consumption of oysters or other seafood to future warming under climate change scenarios.

17.
Huan Jing Ke Xue ; 40(6): 2675-2685, 2019 Jun 08.
Artigo em Chinês | MEDLINE | ID: mdl-31854659

RESUMO

To investigate the environmental quality and human health risks of different types of groundwater at Xiangshui, Chongzuo, several regular water quality indexes and concentrations of metals in 60 groundwater samples were measured and analyzed. The environmental quality of groundwater was analyzed by means of the Nemerow index. The health risks were assessed by using a human health risk assessment model. The regular water quality indexes and concentrations of metals of the well water, spring water, and underground river water exceeded the standards to different degrees. The environmental quality of groundwater was at a poor grade. The comprehensive evaluation score of underground river water (F=4.26) was the lowest. The well water had the same score as spring water (F=7.10). The high hardness and salinity were conducive to enrichment of Cr, and the reducing environment was of great advantage for the enrichment of As. The environmental geochemistry of Zn, Pb, Cd, and Cu was similar. The sources of Fe, Al, and Mn were similar. The results of the health risk assessment indicated that the health risks of well water, spring water, and underground river water were relatively high. The health risks decreased in the order of well water > underground river water > spring water. The health risks mainly came from the carcinogenic metallic element Cr. Carcinogenic risks were 4-6 orders of magnitude higher than non-carcinogenic risks. Carcinogenic risks were higher than the maximum allowance levels (5.0×10-5 a-1). Non-carcinogenic risks were lower than the allowance levels (10-6 a-1). Children had greater health risks than adults. The health risks of metals through the drinking pathway were 2-3 orders of magnitude higher than the values caused by the dermal contact pathway. For the sake of drinking water safety, the well water, underground river water, and spring water should be properly treated and the concentration of Cr in groundwater should be controlled before drinking.


Assuntos
Água Subterrânea/análise , Metais Pesados/análise , Medição de Risco , Poluentes Químicos da Água/análise , Qualidade da Água , Adulto , Criança , China , Água Potável/análise , Monitoramento Ambiental , Humanos
18.
Sci Adv ; 5(11): eaaw9807, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31763447

RESUMO

Cas9 is an RNA-guided endonuclease that targets complementary DNA for cleavage and has been repurposed for many biological usages. Cas9 activities are governed by its direct interactions with DNA. However, information about this interplay and the mechanism involved in its direction of Cas9 activity remain obscure. Using a single-molecule approach, we probed Cas9/sgRNA/DNA interactions along the DNA sequence and found two stable interactions flanking the protospacer adjacent motif (PAM). Unexpectedly, one of them is located approximately 14 base pairs downstream of the PAM (post-PAM interaction), which is beyond the apparent footprint of Cas9 on DNA. Loss or occupation of this interaction site on DNA impairs Cas9 binding and cleavage. Consistently, a downstream helicase could readily displace DNA-bound Cas9 by disrupting this relatively weak post-PAM interaction. Our work identifies a critical interaction of Cas9 with DNA that dictates its binding and dissociation, which may suggest distinct strategies to modulate Cas9 activity.

19.
Nat Commun ; 10(1): 5334, 2019 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-31767869

RESUMO

Protein products of the regenerating islet-derived (REG) gene family are important regulators of many cellular processes. Here we functionally characterise a non-protein coding product of the family, the long noncoding RNA (lncRNA) REG1CP that is transcribed from a DNA fragment at the family locus previously thought to be a pseudogene. REG1CP forms an RNA-DNA triplex with a homopurine stretch at the distal promoter of the REG3A gene, through which the DNA helicase FANCJ is tethered to the core promoter of REG3A where it unwinds double stranded DNA and facilitates a permissive state for glucocorticoid receptor α (GRα)-mediated REG3A transcription. As such, REG1CP promotes cancer cell proliferation and tumorigenicity and its upregulation is associated with poor outcome of patients. REG1CP is also transcriptionally inducible by GRα, indicative of feedforward regulation. These results reveal the function and regulation of REG1CP and suggest that REG1CP may constitute a target for cancer treatment.

20.
Arch Toxicol ; 93(12): 3585-3599, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31677073

RESUMO

The occurrence of idiosyncratic drug-induced liver injury (IDILI) is a leading cause of post-marketing safety warnings and withdrawals of drugs. Carbamazepine (CBZ), widely used as an antiepileptic agent, could cause rare but severe idiosyncratic liver injury in humans. Although recent studies have shown that inflammasome is implicated in CBZ-induced hepatocellular injury in vitro, the precise pathogenesis of hepatotoxicity remains largely unexplored. Here we report that CBZ causes idiosyncratic liver injury through promoting specific stimuli-induced NLRP3 inflammasome activation. CBZ (40 µM) enhances NLRP3 inflammasome activation triggered by adenosine triphosphate (ATP) or nigericin, rather than SiO2, monosodium urate crystal or intracellular lipopolysaccharide (LPS). In addition, CBZ has no effect on NLRC4 or AIM2 inflammasome activation. Mechanistically, synergistic induction of mitochondrial reactive oxygen species (mtROS) is a crucial event in the enhancement effect of CBZ on ATP- or nigericin-induced NLRP3 inflammasome activation. Moreover, the "C=C" on the seven-membered ring and "C=O" on the nitrogen of CBZ may be contribute to NLRP3 inflammasome hyperactivation and hepatotoxicity. Notably, in vivo data indicate that CBZ (50 mg/kg) causes liver injury in an LPS (2 mg/kg)-mediated susceptibility mouse model of IDILI, accompanied by an increase in caspase-1 activity and IL-1ß production, whereas the combination of CBZ and LPS does not exhibit the effect in NLRP3-knockout mice. In conclusion, CBZ specifically promotes ATP- or nigericin-induced NLRP3 inflammasome activation and causes idiosyncratic liver injury. Our findings also suggest that CBZ may be avoided in patients with NLRP3 inflammasome activation-related diseases that are triggered by ATP or nigericin, which may be risk factors for IDILI.

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