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1.
Biol Reprod ; 2020 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-32167535

RESUMO

Formin-like 3 (FMNL3) is a member of the formin-likes (FMNLs), which belong to the formin family. As an F-actin nucleator, FMNL3 is essential for several cellular functions, such as polarity control, invasion, and migration. However, the roles of FMNL3 during oocytes meiosis remain unclear. In this study, we investigated the functions of FMNL3 during mouse oocyte maturation. Our results showed that FMNL3 mainly concentrated in the oocyte cortex and spindle periphery. Depleting FMNL3 led to the failure of polar body extrusion, and we also found large polar bodies in the FMNL3-deleted oocytes, indicating the occurrence of symmetric meiotic division. There was no effect of FMNL3 on spindle organization; however, we observed spindle migration defects at late metaphase I, which might be due to the decreased cytoplasmic actin. Microinjecting Fmnl3-EGFP mRNA into Fmnl3-depleted oocytes significantly rescued these defects. In addition, the results of co-immunoprecipitation and the perturbation of protein expression experiments suggested that FMNL3 interacted with the actin-binding protein FASCIN for the regulation of actin filaments in oocytes. Thus, our results provide the evidence that FMNL3 regulates FASCIN for actin-mediated spindle migration and cytokinesis during mouse oocyte meiosis.

2.
Inorg Chem ; 2020 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-32081001

RESUMO

A versatile organic-inorganic hybrid structure makes a metal-organic framework (MOF) an outstanding host for different kinds of guests; in addition, its easy pyrolysis nature has been proven to be useful as precursors in the construction of carbon-based materials with a special porous structure. Herein, a novel porous composite nanostructure of an aminated MIL-53(Al)@carbon nanotube (CNT) has been successfully constructed for the first time based on in situ synthesis combining the pyrolysis of ZIF-67. The resulting composite nanostructure was performed by the means of scanning electron microscopy, Brunauer-Emmett-Teller analysis, typical and high-resolution transmission electronic microscopy, X-ray photoelectron spectroscopy, etc. The results showed that a compact heterostructure has been formed between an aminated MIL-53(Al) and a CNT. The resulting composites, named N-MIL@CNT, represent distinct promoted activities in the removal of Bisphenol AF (BPAF) and Metribuzin from wastewater, and the maximum adsorption values were 274 mg/g (BPAF) and 213 mg/g (Metribuzin), which are larger than the results obtained by other MOF-based nanomaterials. The adsorption isotherm, kinetics, and thermodynamics were studied in detail, and the selective adsorption mechanism was also suggested. The excellent selectivity, reusability, and structure stability suggest the potential application of this composite nanostructure in the selective removal of BPAF or Metribuzin from the practical wastewater.

4.
Neurosci Lett ; 723: 134774, 2020 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-31981720

RESUMO

BACKGROUND: Brain function relies on the capacity of neurons to locally modulate each other at the level of synapses. Therefore, the exosomal pathway may constitute a well-designed mechanism for local and systemic interneuronal transfer of information within functional brain networks. Exosomes bind to and are endocytosed by neurons of different brain regions to play a definite role. The medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) brain regions are known to involve in pain modulation. Our study observes the roles of exosomal activity in these two dominant regions of the pain-related pathway, and there influence on the analgesic effects in CCI mice. METHODS: We induced pain exosomes in the mPFC and NAc in the mice of chronic constriction injury of the sciatic nerve model to produce neuropathic pain, and assessed changes that might affect analgesic behaviors. These changes were measured through a combination of behavioral, surgical, and other cellular testings. RESULTS: Our study found that pain expression was elevated in mice given exogenous exosomes isolated from CCI mice, especially at the 2 h and 4 h time interval, in mice given exosomes at the mPFC and NAc, respectively. We also found that inhibiting formation of pain exosomes through GW4869 within the mPFC and NAc can elevate the pain threshold. CONCLUSION: Results from our study supported the idea that the release of mPFC and NAc exosomes of CCI model has elevated the pain sensations in the subjected mice. This study will further help in designing new clinical trials, and will revolutionize the drug-induced anesthetic responses.

5.
Artigo em Inglês | MEDLINE | ID: mdl-31999069

RESUMO

BACKGROUND: Sarcopenia is commonly observed in patients with advanced-stage epithelial ovarian cancer (EOC). However, the effect of body composition changes-during primary debulking surgery (PDS) and adjuvant platinum-based chemotherapy-on outcomes of patients with advanced-stage EOC is unknown. This study aimed to evaluate the association between body composition changes and outcomes of patients with stage III EOC treated with PDS and adjuvant platinum-based chemotherapy. METHODS: Pre-treatment and post-treatment computed tomography (CT) images of 139 patients with stage III EOC were analysed. All CT images were contrast-enhanced scans and were acquired according to a standardized protocol. The skeletal muscle index (SMI), skeletal muscle radiodensity (SMD), and total adipose tissue index were measured using CT images obtained at the L3 vertebral level. Predictors of overall survival were identified using Cox regression models. RESULTS: The median follow-up was 37.9 months. The median duration between pre-treatment and post-treatment CT was 182 days (interquartile range: 161-225 days). Patients experienced an average SMI loss of 1.8%/180 days (95% confidence interval: -3.1 to -0.4; P = 0.01) and SMD loss of 1.7%/180 days (95% confidence interval: -3.3 to -0.03; P = 0.046). SMI and SMD changes were weakly correlated with body mass index changes (Spearman ρ for SMI, 0.15, P = 0.07; ρ for SMD, 0.02, P = 0.82). The modified Glasgow prognostic score was associated with SMI loss (odds ratio: 2.42, 95% confidence interval: 1.03-5.69; P = 0.04). The median time to disease recurrence was significantly shorter in patients with SMI loss ≥5% after treatment than in those with SMI loss <5% or gain (5.4 vs. 11.2 months, P = 0.01). Pre-treatment SMI (1 cm2 /m2 decrease; hazard ratio: 1.08, 95% confidence interval: 1.03-1.11; P = 0.002) and SMI change (1%/180 days decrease; hazard ratio: 1.04, 95% confidence interval: 1.01-1.08; P = 0.002) were independently associated with poorer overall survival. SMD, body mass index, and total adipose tissue index at baseline and changes were not associated with overall survival. CONCLUSIONS: Skeletal muscle index decreased significantly during treatment and was independently associated with poor overall survival in patients with stage III EOC treated with PDS and adjuvant platinum-based chemotherapy. The modified Glasgow prognostic score might be a predictor of SMI loss during treatment.

6.
J Ind Microbiol Biotechnol ; 47(1): 83-96, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31768773

RESUMO

A method called Cas-3P allowing for immediate, multiplexed and sequential genome engineering was developed using one plasmid expressing Cas9 and three marked plasmid backbones (P1, P2 and P3) for guide RNA (gRNA) expression. The three marked gRNA plasmid backbones were recurred in a P1-P2-P3 order for sequential gene targeting, without construction of any additional plasmid and elimination of gRNA plasmid by induction in each round. The efficiency of direct gRNA plasmid curing mediated by Cas-3P was more than 40% in sequential gene targeting. Besides, Cas-3P allowed single-, double- and triple-loci gene targeting with an efficiency of 75%, 36.8% and 8.2% within 3-4 days, respectively. Through three sequential rounds of gene targeting within 10 days, S. cerevisiae was optimized for the production of patchoulol by replacing one promoter, overexpressing three genes and disrupting four genes. The work is important for practical application in the cell factory engineering of S. cerevisiae.

7.
Environ Pollut ; 256: 113374, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31672358

RESUMO

Melatonin is a hormone which is generated from pineal gland, and it is responsible for the regulation of wake-sleep cycle. Melatonin is a well-known antioxidant and free radical scavenger to protect against multiple type of tissue damage. While ochratoxin A (OTA) is a mycotoxin found widely in contaminated food and foodstuffs, which causes nephrotoxicity, hepatotoxicity, immunotoxicity, and reproductive damage in humans and animals. In present study we report the toxicity of OTA on porcine oocyte quality and the protective effects of melatonin on OTA-exposed oocytes. Using transcriptome analysis our results show that OTA exposure alters the expression of multiple genes in oocytes, indicating its effect on oocyte maturation. The cellular changes following OTA treatment are examined, and the results show that OTA adversely affects oocyte polar body extrusion, which is confirmed by the delay of Cdc2-mediated cell cycle progression. OTA exposure also disrupts meiotic spindle formation, which is confirmed by altered phosphorylated MAPK expression. RNA-seq screening and further fluorescence staining results show that OTA induces aberrant mitochondria distribution and oxidative phosphorylation defects, which then causes oxidative stress, followed by early apoptosis and autophagy. Treatment with melatonin significantly ameliorates oxidative stress and apoptosis, which further protects cell cycle and spindle formation in OTA-exposed oocytes. Collectively, these results show the protective effects of melatonin against defects induced by OTA during porcine meiotic oocyte maturation.


Assuntos
Apoptose/efeitos dos fármacos , Melatonina/farmacologia , Ocratoxinas/toxicidade , Oócitos/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Suínos , Animais , Antioxidantes/metabolismo , Autofagia/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Ciclo Celular/genética , Feminino , Humanos , Oócitos/metabolismo , Oócitos/patologia
8.
Accid Anal Prev ; 134: 105350, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31715549

RESUMO

Previous studies have acknowledged the impact of risk perception on safety behavior, but were largely controversial. This study aims to clarify this conflict and the mechanism through which risk perception can have an impact on safety behavior. From the perspective of the dual attribute of the job demand concept in job demands-resources theory, we posit that risk perception can be considered as a job hindrance or a job challenge depending on the context, thereby resulting in a negative or positive impact on safety behavior, respectively. The current research context is the construction industry and the hypotheses were tested using hierarchically nested data collected from 311 workers in 35 workgroups. Risk perception was demonstrated to be a job hindrance exerting a negative impact on safety behavior and safety motivation mediated this effect. In addition, two dimensions of group-level safety climate--supervisor's and coworkers'--were expected to alleviate or even reverse the detrimental effects of hindrance risk perception on safety motivation and on safety behavior via motivation. A moderation model and a first-stage moderated mediation model were established, respectively, for testing the moderating roles of safety climate in the relationship between risk perception and safety motivation, and in the indirect relationship of risk perception with safety behavior via motivation. Surprisingly, contrary to the hypotheses, when supervisor's safety climate changed from a low level to a high level, the impact of risk perception on safety motivation changed from positive to negative, and the negative effect of risk perception on safety behavior via safety motivation was not alleviated but worsened. As expected, for workers in a positive coworkers' safety climate, the negative effect of risk perception on motivation and the indirect negative effect of risk perception on behavior were both reversed to the positive. This indicates that coworkers' safety climate helped to change perceived risk from a job hindrance to a challenge. This research contributes to workplace risk perception and safety behavior research by theoretically viewing risk perception as a dual job hindrance-challenge concept and proposing two competing hypotheses concerning the impact of risk perception on safety behavior. The empirical investigation confirmed the hindrance attribute of risk perception in the construction context. It provides a theoretical framework and empirical evidence for future research to synthesize the conflict risk perception-safety behavior relationship. We also contribute to the literature by pointing out the potential negative role of certain supervisor safety activities such as paternalistic leadership in influencing employee safety.


Assuntos
Cultura Organizacional , Gestão da Segurança/organização & administração , Prevenção de Acidentes/métodos , Adulto , Indústria da Construção/organização & administração , Feminino , Humanos , Masculino , Motivação , Saúde do Trabalhador
9.
Biochem Genet ; 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31696339

RESUMO

Mitochondrial DNA (mtDNA) has been widely employed as one tool for the studies of human migration and phylogenetic evolution owing to the characteristics of its lack of recombination and matrilineal inheritance. In this study, we analyze genetic distributions of 60 mtDNA markers in 126 unrelated individuals of Southern Shaanxi Han population and classify their haplogroups. Genetic distribution comparisons between Southern Shaanxi Han and other populations from different continents are conducted based on the same mtDNA markers. The majority of 60 mtDNA markers are polymorphic in Southern Shaanxi Han population. The most common haplogroups observed in Southern Shaanxi Han population are B5, followed by D5, A, D4e, and N9a1'3. Obtained matching probability for these 60 mtDNA markers indicates that the panel could be used as a valuable tool in forensic caseworks. Results of genetic distances (Fst) and multidimensional scaling analysis show that Southern Shaanxi Han population has relatively close genetic relationships with other Han populations in different regions. In conclusion, the panel comprising 60 mtDNA markers could be utilized for forensic applications in Southern Shaanxi Han population.

10.
J Endocrinol ; 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31770098

RESUMO

High-fat diet (HFD) not only induces insulin resistance in liver, but also causes autophagic imbalance, metabolic disorders, increases chronic inflammatory response and induces mitochondrial dysfunction. Calcium/calmodulin-dependent protein kinase IV (CaMKIV) has recently emerged as an important regulator of glucose metabolism and skeletal muscle insulin action. Its activation has been involved in the improvement of hepatic and adipose insulin action. But the underlying mechanism are not fully understood. In the present study, we aimed to address the direct effects of CaMKIV in vivo and to evaluate the potential interaction of impaired insulin sensitivity and autophagic disorders in hepatic insulin resistance. Our results indicated obese mice receiving CaMKIV showed a decreased blood glucose and serum insulin, and improved insulin sensitivity as well as increased glucose tolerance compared with vehicle injection. Meanwhile, defective hepatic autophagy activity, impaired insulin signaling, increased inflammatory response and mitochondrial dysfunction in liver tissues which induced by high-fat diet were also effectively alleviated by injection of CaMKIV. Consistent with these results, the additional of CaMKIV to the culture medium of BNL cl.2 hepatocytes markedly restored palmitate induced hepatic insulin resistance and autophagic imbalance. These effects were nullified by blockade of cyclic AMP response element binding protein (CREB), indicating the causative role of CREB in action of CaMKIV. Our findings suggested that CaMKIV restores hepatic autophagic imbalance and improves impaired insulin sensitivity via phosphorylated CREB signaling pathway. Which may offer novel opportunities for treatment of obesity and diabetes.

11.
Front Aging Neurosci ; 11: 313, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31780922

RESUMO

Neurodegenerative diseases are disorders that are characterized by a progressive decline of motor and/or cognitive functions caused by the selective degeneration and loss of neurons within the central nervous system. The most common neurodegenerative diseases are Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington's disease (HD). Neurons have high energy demands, and dysregulation of mitochondrial quality and function is an important cause of neuronal degeneration. Mitochondrial quality control plays an important role in maintaining mitochondrial integrity and ensuring normal mitochondrial function; thus, defects in mitochondrial quality control are also significant causes of neurodegenerative diseases. The mitochondrial deacetylase SIRT3 has been found to have a large effect on mitochondrial function. Recent studies have also shown that SIRT3 has a role in mitochondrial quality control, including in the refolding or degradation of misfolded/unfolded proteins, mitochondrial dynamics, mitophagy, and mitochondrial biogenesis, all of which are affected in neurodegenerative diseases.

12.
Diabetes Metab Syndr Obes ; 12: 1705-1716, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31564938

RESUMO

Objective: To investigate the effect of gross saponins of Tribulus terrestris (GSTT) on erectile function in rats resulting from type 2 diabetes mellitus (T2DMED). Methods: The T2DMED model was constructed by high-fat and high-sugar feeding and streptozotocin injection. After 4 weeks of GSTT intervention. Intracavernous pressure (ICP) and mean arterial pressure (MAP) were measured in each group. The level of nitric oxide (NO) in the cavernous tissue was detected using the nitrate reductase method. The production of reactive oxygen species (ROS) was detected using DHE fluorescent probe detection. Cyclic adenosine monophosphate (cGMP) level was detected by enzyme-linked immunosorbent assay, and endothelial nitric oxide synthase (eNOS) was detected using immunohistochemistry. Masson staining was used to detect the cavernosal smooth muscle/collagen ratio. Apoptosis in endothelial cells was measured using TUNEL. Western blotting method to detect the protein expression level of eNOS, TIMP-1, cleaved caspase 3, and cleaved caspase 9. Results: After treatment, the ICP and ICP/MAP values of the GSTT were significantly higher than those of the T2DMED group (P<0.05). Unlike the T2DMED group, the GSTT group showed significantly increased NO levels (P<0.05) and decreased ROS levels (P<0.05). There was no significant difference between the GSTT group and the sildenafil group in increasing cGMP levels (P>0.05), and the mixed group had higher levels than these two groups (P<0.05). Immunohistochemistry and Western blotting showed that the expression of eNOS in the GSTT was significantly higher than that in the T2DMED groups (P<0.05). Masson staining showed that the smooth muscle/collagen ratio of the GSTT group was significantly higher than that of the T2DMED groups (P<0.05), the expression of TIMP-1 was lower than that of T2DMED group (P<0.05). TUNEL assay showed that the apoptotic index and cleaved caspase 3 and cleaved caspase 9 expression level of GSTT group were lower than that of the T2DMED group (P<0.05). Conclusion: GSTT can protect T2DMED rats' erectile function by improving penile endothelial function and inhibiting cavernosum fibrosis, inhibiting apoptosis, and is synergistic with sildenafil.

13.
Phys Rev Lett ; 123(10): 105701, 2019 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-31573294

RESUMO

Relaxation processes significantly influence the properties of glass materials. However, understanding their specific origins is difficult; even more challenging is to forecast them theoretically. In this study, using microseconds molecular dynamics simulations together with an accurate many-body interaction potential, we predict that an Al_{90}Sm_{10} metallic glass would have complex relaxation behaviors: In addition to the main (α) relaxation, the glass (i) shows a pronounced secondary (ß) relaxation at cryogenic temperatures and (ii) exhibits an anomalous relaxation process (α_{2}) accompanying α relaxation. Both of the predictions are verified by experiments. Computational simulations reveal the microscopic origins of relaxation processes: while the pronounced ß relaxation is attributed to the abundance of stringlike cooperative atomic rearrangements, the anomalous α_{2} process is found to correlate with the decoupling of the faster motions of Al with slower Sm atoms. The combination of simulations and experiments represents a first glimpse of what may become a predictive routine and integral step for glass physics.

14.
Sensors (Basel) ; 19(20)2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31640136

RESUMO

This paper derives an improved multistage in-motion attitude determination alignment (IMADA) for strapdown inertial navigation system, which integrates the traditional IMADA and the designed dual velocity-modeling IMADA, as well as the multiple repeated alignment process, to address the principled model errors and the calculation errors of traditional V b -aided IMADA. With the proposed algorithm, not only the designed drawbacks of traditional V b -based IMADA can be solved, but also the degradation phenomenon of high-level alignment for multistage IMADA would be largely less. Moreover, the degradation of the alignment accuracy with the vehicle velocity is also removed. Finally, the 30 groups of car-mounted experiments and the Monte Carlo simulation experiments with the navigation-grade SINS are carried out to demonstrate the validity of the proposed algorithm. The results show that the number of the heading degradation of the second-level alignment is reduced to 10 as compared the traditional number 20. Moreover, the alignment accuracy of heading is improved by 23%. Even with the different speeds of 20 m/s, 60 m/s, 80 m/s, the heading alignment accuracies are 1.3063°, 1.3102°, 1.3564° and are still almost the same.

15.
Oncol Lett ; 18(4): 4016-4021, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31516603

RESUMO

The long noncoding (lnc) RNA MIR4435-2HG is known to promote lung cancer; however, its role in prostate carcinoma (PCa) remains unknown. The aim of the current study was therefore to investigate the role of MIR4435-2HG in PCa by detecting differential gene expression using quantitative PCR and ELISA kits. Furthermore, overexpression experiments were performed to analyze gene interactions and Transwell assays were used to analyze cell invasion and migration. The present study demonstrated that plasma levels of MIR4435-2HG and transforming growth factor-ß1 (TGF-ß1) were significantly higher in patients with PCa compared with healthy controls. Furthermore, MIR4435-2HG and TGF-ß1 plasma levels were positively correlated in patients with PCa, but not in healthy controls. The results from the follow-up study suggested that MIR4435-2HG was closely associated with patient survival. MIR4435-2HG overexpression and treatment with TGF-ß1 promoted cancer cell invasion and migration. In addition, TGF-ß inhibitor attenuated the enhancing effects of MIR4435-2HG overexpression on cell invasion and migration. MIR4435-2HG overexpression led to upregulation of TGF-ß1 expression, whereas TGF-ß1 treatment had no effect on MIR4435-2HG expression. These results suggested that MIR4435-2HG may promote PCa by upregulating TGF-ß1.

16.
Adv Mater ; 31(46): e1904742, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31560141

RESUMO

Chemotherapy is widely used in the clinic though its benefits are controversial owing to low cancer specificity. Nanovehicles capable of selectively transporting drugs to cancer cells have been energetically pursued to remodel cancer treatment. However, no active targeting nanomedicines have succeeded in clinical translation to date, partly due to either modest targetability or complex fabrication. CD44-specific A6 short peptide (KPSSPPEE) functionalized polymersomal epirubicin (A6-PS-EPI), which boosts targetability and anticancer efficacy toward human multiple myeloma (MM) in vivo, is described. A6-PS-EPI encapsulating 11 wt% EPI is small (≈55 nm), robust, reduction-responsive, and easy to fabricate. Of note, A6 decoration markedly augments the uptake and anticancer activity of PS-EPI in CD44-overexpressing LP-1 MM cells. A6-PS-EPI displays remarkable targeting ability to orthotopic LP-1 MM, causing depleted bone damage and striking survival benefits compared to nontargeted PS-EPI. Overall, A6-PS-EPI, as a simple and intelligent nanotherapeutic, demonstrates high potential for clinical translation.

17.
ACS Appl Mater Interfaces ; 11(38): 35458-35467, 2019 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-31483597

RESUMO

Interfacial properties play a vital role in spin current injection from the ferromagnetic (FM) layer into the nonmagnetic (NM) layer. So far, impedance matching and spin-orbit coupling are two important, well-known factors in spin current transport in FM/NM heterostructures. In this work, the spin current transport in Y3Fe5O12 (YIG)/NiO/Pt heterostructures was investigated by spin Hall magnetoresistance and inverse spin Hall effect measurements. By inserting a layer of antiferromagnetic insulator NiO, the magnetic proximity effect affecting the Pt atoms owing to YIG and the anomalous spin Hall voltage can be efficiently blocked. Ferromagnetic resonance and spin pumping measurements verified that the ferromagnetic/antiferromagnetic exchange coupling inhibits transmission of the spin current at the YIG/NiO interface when the NiO layer is thick. Atomic force microscopy and spherical aberration-corrected transmission electron microscopy proved that the strong interfacial roughness-enhanced spin scattering between NiO and Pt can greatly increase both the inverse spin Hall voltage and the spin Hall magnetoresistance when the NiO layer is thin or even discontinuous. This interface roughness-dominated spin scattering mechanism based on the YIG/NiO/Pt heterostructure is a new discovery, and there is significant potential for exploiting this mechanism in the construction of low-dissipation spintronic devices with an efficient spin current injection.

19.
Acta Pharm Sin B ; 9(4): 769-781, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31384537

RESUMO

Bicyclol is a synthetic drug for hepatoprotection in clinic since 2004. Preliminary clinical observations suggest that bicyclol might be active against hepatitis C virus (HCV) with unknown mechanism. Here, we showed that bicyclol significantly inhibited HCV replication in vitro and in hepatitis C patients. Using bicyclol as a probe, we identified glycolipid transfer protein (GLTP) to be a novel restrictive factor for HCV replication. The GLTP preferentially bound host vesicle-associated membrane protein-associated protein-A (VAP-A) in competition with the HCV NS5A, causing an interruption of the complex formation between VAP-A and HCV NS5A. As the formation of VAP-A/NS5A complex is essential for viral RNA replication, up-regulation of GLTP by bicyclol reduced the level of VAP-A/NS5A complex and thus inhibited HCV replication. Bicyclol also exhibited an inhibition on HCV variants resistant to direct-acting antiviral agents (DAAs) with an efficacy identical to that on wild type HCV. In combination with bicyclol, DAAs inhibited HCV replication in a synergistic fashion. GLTP appears to be a newly discovered host restrictive factor for HCV replication, Up-regulation of GLTP causes spontaneous restriction of HCV replication.

20.
Neurochem Res ; 44(9): 2031-2043, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31410709

RESUMO

As one of the major cell organelles responsible for ATP production, it is important that neurons maintain mitochondria with structural and functional integrity; this is especially true for neurons with high metabolic requirements. When mitochondrial damage occurs, mitochondria are able to maintain a steady state of functioning through molecular and organellar quality control, thus ensuring neuronal function. And when mitochondrial quality control (MQC) fails, mitochondria mediate apoptosis. An apparently key molecule in MQC is the transcriptional coactivator peroxisome proliferator activated receptor γ coactivator-1α (PGC-1α). Recent findings have demonstrated that upregulation of PGC-1α expression in neurons can modulate MQC to prevent mitochondrial dysfunction in certain in vivo and in vitro aging or neurodegenerative encephalopathy models, such as Huntington's disease, Alzheimer's disease, and Parkinson's disease. Because mitochondrial function and quality control disorders are the basis of pathogenesis in almost all neurodegenerative diseases (NDDs), the role of PGC-1α may make it a viable entry point for the treatment of such diseases. This review focuses on multi-level MQC in neurons, as well as the regulation of MQC by PGC-1α in these major NDDs.


Assuntos
Doença de Alzheimer/fisiopatologia , Doença de Huntington/fisiopatologia , Mitocôndrias/fisiologia , Doença de Parkinson/fisiopatologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/fisiologia , Animais , Humanos , Neurônios/fisiologia , Biogênese de Organelas
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