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1.
J Hazard Mater ; 401: 123430, 2021 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-32659591

RESUMO

Microplastics (MPs) have become hazardous materials, which have aroused widespread concern about their potential toxicity. However, the effects of MPs on reproductive systems in mammals are still ambiguous. In this study, the toxic effects of polystyrene MPs (PS-MPs) in male reproduction of mice were investigated. The results indicated that after exposure for 24 h, 4 µm and 10 µm PS-MPs accumulated in the testis of mice. Meanwhile, 0.5 µm, 4 µm, and 10 µm PS-MPs could enter into three kinds of testicular cells in vitro. In addition, sperm quality and testosterone level of mice were declined after exposure to 0.5 µm, 4 µm, and 10 µm PS-MPs for 28 days. H&E staining showed that spermatogenic cells abscissed and arranged disorderly, and multinucleated gonocytes occurred in the seminiferous tubule. Moreover, PS-MPs induced testicular inflammation and the disruption of blood-testis barrier. In summary, this study demonstrated that PS-MPs induced male reproductive dysfunctions in mice, which provided new insights into the toxicity of MPs in mammals.

2.
J Cell Physiol ; 236(2): 1418-1431, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32677057

RESUMO

Esophageal squamous cell carcinoma (ESCC) is one of the deadliest cancers, and long noncoding RNAs (lncRNAs) regulate gene expression or activities. This study investigated the role of lncRNA LINC00551 in ESCC development and progression. Three paired ESCC and normal tissues were subjected to next-generation sequencing and we identified 82 upregulated and 60 downregulated lncRNAs, including LINC00551, which was confirmed to markedly downregulated in 78 ESCC tissues and in the Gene Expression Profiling Interactive Analysis data set. Downregulated LINC00551 expression was associated with lymph node metastasis, advanced TNM stage, and tumor size. Moreover, downregulated LINC00551 expression was also associated with poor progression-free survival and overall survival of ESCC patients. In vitro and in vivo, LINC00551 overexpression inhibited ESCC cell proliferation and invasion, whereas knockdown of LINC00551 expression promoted ESCC cell proliferation and invasion. RNA pull-down and mass spectrometry assays identified the potential LINC00551 binding proteins, and HSP27 was a promising LINC00551 targeting proteins after RNA immunoprecipitation assay. At the protein level, LINC00551 bound to and decreased HSP27 phosphorylation, and in turn, downregulated ESCC cell proliferation and invasion. The current study demonstrated the functional significance of LINC00551 in ESCC development, progression, and prognosis. Further study will assess LINC00551 as a novel prognostic marker or therapeutic target for ESCC.

3.
J Ethnopharmacol ; 264: 113021, 2021 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-32479885

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Liver fibrosis is an outcome of many chronic liver diseases and often results in cirrhosis, liver failure, and even hepatocarcinoma. Xiaoyaosan decoction (XYS) as a classical Traditional Chinese Medicine (TCM) formula is used to liver fibrosis in clinical practice while its mechanism is unclear. AIM OF THE STUDY: The aim of this study was to investigate the anti-fibrosis effect of XYS and to explore the molecular mechanisms by combining network pharmacology and transcriptomic technologies. MATERIALS AND METHODS: The carbon tetrachloride (CCl4)-induced liver fibrosis rat were treated with three doses of XYS. The liver fibrosis and function were evaluated by histopathological examination and serum biochemical detection. The fibrosis related protein a-SMA and collagen I were assessed by Western blot. Different expressed genes (DEGs) between XYS-treated group and model group were analyzed. The herb-component-target network was constructed combined the network pharmacology. The predict targets and pathways were validated by in vitro and in vivo experiments. RESULTS: With XYS treatment, the liver function was significantly improved, and fibrotic changes were alleviated. The a-SMA and collagen I expression levels in the liver were also decreased in XYS-treated rats compared with CCl4 model rats. 108 active components and 42 targets from 8 herbs constituted herb-compound-target network by transcriptomics and network pharmacology analysis. The KEGG pathway and GO enrichment analyses showed that the FoxO, TGFß, AMPK, MAPK, PPAR, and hepatitis B and C pathways were involved in the anti-fibrosis effects of XYS. In the liver tissues, p-FoxO3a and p-Akt expression levels were significantly increased in the CCl4 model group but decreased in the XYS-treated group. The TGFß1/Smad pathway and Akt/FoxO3 pathway were verified in LX2 cells by inhibiting phosphorylation of Smad3 and Akt activity, respectively. CONCLUSIONS: Our findings suggested that XYS markedly alleviated CCl4-induced liver fibrosis in histopathological and serum liver function analyses, and this effect may occur via the TGFß1/Smad and Akt/FoxO signaling pathways.

4.
J Insect Sci ; 20(6)2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-33159528

RESUMO

Quercetin is a flavonoid produced as a defense by plants. The effects of 1% quercetin on the growth and development of Bombyx mori were studied. The activities of the enzymes superoxide dismutase (SOD), catalase (CAT), peroxidase (POD), carboxy-lesterase (CarEs), and glutathione S-transferase (GST) were all measured at 24, 48, 72, and 96 h after quercetin exposure. The results show that quercetin induces the activities of antioxidant and detoxification enzymes. With longer exposure times, enzyme activity first increased and then decreased. The relative expressions of AMP (defensin, CecA), the Toll pathway (cactus, Spatzle, and Rel), the IMD pathway (Imd, Fadd, and Dorsal), the JAK-STAT pathway (STAT, HOP, and Pi3k60), and the Melanization gene (DDC and PAH) were analyzed using quantitative polymerase chain reaction (qPCR). The results indicated that long-term exposure to quercetin could inhibit the expression of immune-related pathway genes in silkworms. This suggests that it can inhibit the activities of antioxidant and detoxifying enzymes, thus inhibiting the immune system and affecting the growth and development, resulting in an increase in the death rate in silkworm. This study provides the novel conclusion that quercetin accumulation inhibits the immune system of silkworm and increases its death rate, a result that may promote the development and utilization of better biopesticides that avoid environmental pollution.

5.
Sci Total Environ ; : 142927, 2020 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-33143918

RESUMO

In this research, the impact of municipal green industry policies in 15 cities on the economic and environmental performance of local companies was evaluated, and the policy coordination mechanism was studied. As a dual-goal policy mix, the green industrial policy has been used by Chinese municipal governments to solve the dilemma between the economic growth and environmental mitigation. However, the quantitative evaluation of these green industrial policy trials remains limited. To address this issue, the policy evaluation in this research applied sewage discharge data and operation data of 22,670 Chinese textile firms from 1998 to 2013 from Chinese Environmental Statistics Database. Fixed-effect regression analysis and dynamic difference-in-differences (DID) approach were used to assess the dual-faceted impacts of green industrial policies and their subtypes, as well as the continuity of these impacts. The findings suggest that adopting a dual-objective green industrial policy is an effective approach to encourage heavy-polluting firms to develop in a more balanced and sustainable way. From dynamic DID analysis, these green industrial policies have continuity effects on both chemical oxygen demand discharge intensity and annual revenue of firms after implementation and the general impacts can last for at least 4 years. The study also reveals the heterogeneity in the impacts of three different subtypes of green industrial policy. The technology-push policy subtype can quickly reduce environmental discharge without compromising economic development, while demand-pull policy subtype has a slow effect on the improvement of environmental performance. The balanced policy subtype can promote enterprises to achieve both optimal performance of economy and environment, although the efficiency of balanced policy subtype is between two subtypes. Generally, this research provides reliable basis for the implementation of green industrial policies in developing countries and provides certain inspiration for the enriching of green industry policy theory.

6.
Development ; 2020 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-33144398

RESUMO

E proteins transcription factors are critical for many cell fate decisions. However, the roles of E proteins in the germ-layer specification of human embryonic stem cells (hESC) are poorly understood. We disrupted the TCF3 gene locus to delete the E protein E2A in hESCs. E2A KO hESCs retained key features of pluripotency, but displayed decreased neural ectoderm coupled with enhanced mesoendoderm outcomes. Genome-wide analyses showed that E2A directly regulates neural ectoderm and Nodal pathway genes. Accordingly, inhibition of Nodal or E2A overexpression partially rescued the neural ectoderm defect in E2A KO hESCs. Loss of E2A had little impact on the epigenetic landscape of hESCs, whereas E2A KO neural precursors displayed increased accessibility of the gene locus encoding the Nodal agonist CRIPTO. Double-deletion of both E2A and HEB (TCF12) resulted in a more severe neural ectoderm defect. Therefore, this study reveals critical context-dependent functions for E2A in human neural ectoderm fate-specification.

7.
Brief Bioinform ; 2020 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-33147622

RESUMO

With the development of high-throughput sequencing technology, the genomic sequences increased exponentially over the last decade. In order to decode these new genomic data, machine learning methods were introduced for genome annotation and analysis. Due to the requirement of most machines learning methods, the biological sequences must be represented as fixed-length digital vectors. In this representation procedure, the physicochemical properties of k-tuple nucleotides are important information. However, the values of the physicochemical properties of k-tuple nucleotides are scattered in different resources. To facilitate the studies on genomic sequences, we developed the first comprehensive database, namely KNIndex (https://knindex.pufengdu.org), for depositing and visualizing physicochemical properties of k-tuple nucleotides. Currently, the KNIndex database contains 182 properties including one for mononucleotide (DNA), 169 for dinucleotide (147 for DNA and 22 for RNA) and 12 for trinucleotide (DNA). KNIndex database also provides a user-friendly web-based interface for the users to browse, query, visualize and download the physicochemical properties of k-tuple nucleotides. With the built-in conversion and visualization functions, users are allowed to display DNA/RNA sequences as curves of multiple physicochemical properties. We wish that the KNIndex will facilitate the related studies in computational biology.

8.
Asian J Androl ; 2020 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-33154202

RESUMO

This study aimed to propose an operational definition of late-onset hypogonadism (LOH) that incorporates both clinical symptoms and serum testosterone measurements to evaluate the prevalence of LOH in aging males in China. A population-based sample of 6296 men aged 40 years-79 years old was enrolled from six representative provinces in China. Serum total testosterone (TT), sex hormone-binding globulin (SHBG), and luteinizing hormone (LH) were measured and free testosterone (cFT) was calculated. The Aging Males' Symptoms (AMS) scale was used to evaluate the LOH symptoms. Finally, 5078 men were included in this analysis. The TT levels did not decrease with age (P = 0.59), and had no relationship with AMS symptoms (P = 0.87 for AMS total score, P = 0.74 for ≥ 3 sexual symptoms). The cFT levels decreased significantly with age (P < 0.01) and showed a negative association with the presence of ≥ 3 sexual symptoms (P = 0.03). The overall estimated prevalence of LOH was 7.8% (395/5078) if a cFT level <210 pmol l-1 combined with the presence of ≥ 3 sexual symptoms was used as the criterion of LOH. Among them, 26.1% (103/395) and 73.9% (292/395) had primary and secondary hypogonadism, respectively. After adjustment for confounding factors, primary and secondary hypogonadism was positively related to age and comorbidities. Body mass index was an independent risk factor for secondary hypogonadism. The results suggest that the AMS total score is not an appropriate indicator for decreased testosterone, and that the cFT level is more reliable than TT for LOH diagnosis. Secondary hypogonadism is the most common form of LOH.

9.
Cancer Med ; 2020 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-33135335

RESUMO

BACKGROUND: Although the latest Gleason grading system in 2014 has distinguished between Gleason 3 + 4 and 4 + 3, Gleason 8 and Gleason 9-10 are remained systemically classified. METHODS: A total of 261,125 patients diagnosed with prostate cancer (PCa) were selected between 2005 and 2015 from the Surveillance, Epidemiology, and End Results (SEER) database. We used propensity score matching to balance clinical variables and then compared overall survival (OS) and cancer-specific survival (CSS) between Gleason score subgroups. We further establish a new Gleason survival grading system based on the hazard ratio (HR) values of each Gleason subgroup. Cox proportional hazards models and Kaplan-Meier curves were used to compare patient survival. RESULTS: Among PCa patients with Gleason score 8 disease, patients with Gleason 5 + 3 had significantly worse OS and CSS than those with Gleason 3 + 5 (OS: HR = 1.26, p = 0.042; CSS: HR = 1.42, p = 0.005) and 4 + 4 (HR = 1.50 for OS and HR = 1.69 for CSS, p < 0.001 for all). PCa patients with Gleason 5 + 3 and Gleason 4 + 5 may have the similar OS and CSS (reference Gleason score <=6, 5 + 3: OS HR = 2.44, CSS HR = 7.63; 4 + 5: OS HR = 2.40, CSS HR = 8.92; p < 0.001 for all). The new Gleason survival grading system reclassified the grades 4 and 5 of the 2014 updated Gleason grading system into three hierarchical grades, which makes the classification of grades more detailed and accurate. CONCLUSION: PCa patients with Gleason 8-10 may have three different survival subgroups, Gleason 3 + 5 and 4 + 4, Gleason 5 + 3 and 4 + 5, and Gleason 5 + 4 and 5 + 5. Our results maximize risk stratification for PCa patients, provide guidance for clinicians to assess their survival and clinical management, and make a recommendation for the next Gleason grading system update.

10.
Neuroscience ; 2020 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-33197504

RESUMO

Alzheimer's disease (AD) is the most common neurodegenerative disease and is characterized by progressive memory loss and cognitive dysfunction. Long non-coding RNAs (lncRNAs) have been shown to be among the most promising biomarkers and therapeutic targets of AD. Here, we aimed to investigate whether lncRNA BACE1-AS plays a role in the potential mechanisms of AD. The expression of BACE1-AS, miR-214-3p and ATG5 mRNA was detected using qRT-PCR. The expression of the LC3, P62, ATG5, Bcl-2, p-Tau and cleaved-caspase 3 proteins was examined using western blot analysis. Cell apoptosis, cytotoxicity and ROS levels were estimated using flow cytometry, an LDH kit and a DCFH-DA assay, respectively. The interaction between BACE1-AS or ATG5 and miR-214-3p was validated using a dual-luciferase reporter assay. HE staining and a TUNEL assay were employed to evaluate hippocampal neuronal injury. The BACE1-AS level was found to be upregulated in serum samples of AD patients, brain tissues of AD transgenic (Tg) mice and Aß1-42-treated SH-SY5Y cells. Autophagy activity was increased in both Tg mice and Aß1-42-treated cells. BACE1-AS knockdown alleviated Aß1-42-induced cell injury. Rapamycin abolished the protective effects of sh BACE1-AS against Aß1-42 induced cell injury. BACE1-AS indirectly regulated ATG5 expression by binding miR-214-3p. The miR-214-3p inhibitor reversed the protective effects of sh BACE1-AS and sh ATG5 against Aß1-42-induced cell injury. Knockdown of BACE1-AS alleviated neuronal injury by repressing autophagy in vivo. Our findings demonstrate that silencing of BACE1-AS alleviated neuronal injury by regulating autophagy through the miR-214-3p/ATG5 signalling axis in AD.

11.
Genome Med ; 12(1): 102, 2020 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-33225985

RESUMO

BACKGROUND: The gut-liver axis plays a pivotal role in the pathogenesis of hepatocellular carcinoma (HCC). However, the correlations between the gut microbiome and the liver tumor transcriptome in patients with HCC and the impact of the gut microbiota on clinical outcome are less well-understood. METHODS: Fecal samples collected from HBV-related HCC patients (n = 113) and healthy volunteers (n = 100) were subjected to 16S rRNA sequencing of the microbiome. After a rigorous selection process, 32 paired tumor and adjacent non-tumor liver tissues from the HCC group were subjected to next-generation sequencing (NGS) RNA-seq. The datasets were analyzed individually and integrated with clinical characteristics for combined analysis using bioinformatics approaches. We further verified the potential of the gut microbiota to predict clinical outcome by a random forest model and a support vector machine model. RESULTS: We found that Bacteroides, Lachnospiracea incertae sedis, and Clostridium XIVa were enriched in HCC patients with a high tumor burden. By integrating the microbiome and transcriptome, we identified 31 robust associations between the above three genera and well-characterized genes, indicating possible mechanistic relationships in tumor immune microenvironment. Clinical characteristics and database analysis suggested that serum bile acids may be important communication mediators between these three genera and the host transcriptome. Finally, among these three genera, six important microbial markers associated with tumor immune microenvironment or bile acid metabolism showed the potential to predict clinical outcome (AUC = 81%). CONCLUSIONS: This study revealed that changes in tumor immune microenvironment caused by the gut microbiota via serum bile acids may be important factors associated with tumor burden and adverse clinical outcome. Gut microbes can be used as biomarkers of clinical features and outcomes, and the microbe-associated transcripts of host tumors can partly explain how gut microbiota promotes HCC pathogenesis.

12.
Virol Sin ; 2020 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-33165771

RESUMO

Hepatitis B virus (HBV) belongs to Hepadnaviridae family and mainly infects hepatocytes, which can cause acute or chronic hepatitis. Currently, two types of antiviral drugs are approved for chronic infection clinically: interferons and nucleos(t)ide analogues. However, the clinical cure for chronic infection is still rare, and it is a huge challenge for all researchers to develop high-efficiency, safe, non-tolerant, and low-toxicity anti-HBV drugs. Antazoline hydrochloride is a first-generation antihistamine with anticholinergic properties, and it is commonly used to relieve nasal congestion and in eye drops. Recently, an in vitro high-throughput evaluation system was constructed to screen nearly 800 compounds from the Food and Drug Administration (FDA)-approved Drug Library. We found that arbidol hydrochloride and antazoline hydrochloride can effectively reduce HBV DNA in the extracellular supernatant in a dose-dependent manner, with EC50 of 4.321 µmol/L and 2.910 µmol/L in HepAD38 cells, respectively. Moreover, the antiviral effects and potential mechanism of action of antazoline hydrochloride were studied in different HBV replication systems. The results indicate that antazoline hydrochloride also has a significant inhibitory effect on HBV DNA in the extracellular supernatant of Huh7 cells, with an EC50 of 2.349 µmol/L. These findings provide new ideas for screening and research related to HBV agents.

13.
Free Radic Biol Med ; 2020 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-33157209

RESUMO

Iron overload triggers the ferroptosis in the heart following ischemia/reperfusion (I/R) and transferrin receptor 1 (TfR1) charges the cellular iron uptake. Bioinformatics analysis shows that the three molecules of ubiquitin-specific protease 7 (USP7), p53 and TfR1 form a unique pathway of USP7/p53/TfR1. This study aims to explore whether USP7/p53/TfR1 pathway promotes ferroptosis in rat hearts suffered I/R and the underlying mechanisms. The SD rat hearts were subjected to 1 h-ischemia plus 3 h-reperfusion, showing myocardial injury (increase in creatine kinase release, infarct size, myocardial fiber loss and disarray) and up-regulation of USP7, p53 and TfR1 concomitant with an increase of ferroptosis (reflecting by accumulation of iron and lipid peroxidation while decrease of glutathione peroxidase activity). Inhibition of USP7 activated p53 via suppressing deubiquitination, which led to down-regulation of TfR1, accompanied by the decreased ferroptosis and myocardial I/R injury. Next, H9c2 cells underwent hypoxia/reoxygenation (H/R) in vitro to mimic the myocardial I/R model in vivo. Consistent with the results in vivo, inhibition or knockdown of USP7 reduced the H/R injury (decrease of LDH release and necrosis) and enhanced the ubiquitination of p53 along with the decreased levels of p53 and TfR1 as well as the attenuated ferroptosis (manifesting as the decreased iron content and lipid peroxidation while the increased GPX activity). Knockdown of TfR1 inhibited H/R-induced ferroptosis without p53 deubiquitination. Based on these observations, we conclude that a novel pathway of USP7/p53/TfR1 has been identified in the I/R-treated rat hearts, where up-regulation of USP7promotes ferrptosis via activation of the p53/TfR1 pathway.

14.
Mikrochim Acta ; 187(12): 649, 2020 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-33165704

RESUMO

The development of a novel signal amplification system is described for sensitive determination of α2,6-sialylated glycans (α2,6-sial-Gs), an important prognostic tumor biomarker. First, Fe-based metal-organic frameworks (Fe-MOFs) with silver nanoparticles (AgNPs) decorated onto the outer surface were designed and synthesized with controlled octahedron structures. The new Ag/Fe-MOFs nanocomposite possessed strong conductivity and a large surface area to carry more nanoprobes. To connect the Ag/Fe-MOFs nanocomposite with more groups, the nanocomposite was functionalized by -COOH with SH-PEG-COOH to bind with an α2,6-sial-Gs catcher, M-APBA, via -CONH- bonds. More importantly, the Ag/Fe-MOFs also exhibited an excellent endogenous redox mediator property to produce electrons, which is the fundamental mechanism underlying amplification of an electronic signal. A gold electrode was used to accelerate electron transfer and immobilize the α2,6-sial-Gs lectin (SNA). After the sandwich-type catcher recognition (SNA/α2,6-sial-Gs/M-APBA), the current peak response was provoked in the process of oxidizing AgNPs to Ag+ in the forward anodic potential sweep, while Cl- in a PBS solution was transferred into Ag+ to maintain charge neutrality. Optimized particles were employed for direct fabrication of the sandwich-type affinity biosensor, which was found to show a linear detection range from 1 fg mL-1 to 1 ng mL-1 with a detection limit of 0.09 fg mL-1. Furthermore, the biosensor exhibited excellent specificity and stability, indicating that such a novel nanobiotechnology platform can be used to initiate potential utility for monitoring biomarkers in serum. (A)Schematic presentation of synthesis and surface modification of Ag/Fe-MOFs. The new Ag/Fe-MOFs nanocomposite possessed commendable conductivity and large surface area to carry more nanoprobe; after functionalizing the Ag/MOFs with SH-PEG-COOH, the functionalized endogenous redox mediator (c-Ag/MOFs) realized the possibility that can connect with the biological catcher. (B) Schematic diagram of electrode construction for detecting α2,6-sialylated glycans (α2,6-sial-Gs). By using the c-Ag/Fe-MOFs functional endogenous redox mediator, we successfully implemented the electrochemical detection of α2,6-sial-Gs.

15.
Anal Chim Acta ; 1140: 89-98, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-33218493

RESUMO

Here, a novel electrochemiluminescence biosensor based on potential-resolved strategy was firstly prepared for the detection of dual targets α2,3-sialylated glycans and α2,6-sialylated glycans. This is the first time that Au@BSA microsphere was used to connect with luminol to enhance its ECL intensity, and it can generate ECL signals at positive potential. Zeolitic Imidazolate Framework-8 (ZIF-8) and Meso-tetra (4-carboxyphenyl) porphyrin (TCPP) were linked using a one-pot method to synthesize a novel luminescent ZIF (L-ZIF) named TZZ, which can emit ECL signals at negative potential. Moreover, magnetite microspheres were used to construct a sandwich-type biosensor to obtain higher sensitivity and reduce background signals. In addition, the biosensor manufactured directly in solution have a wider linear range than constructed on electrode because it has more available space than the electrode surface. Due to the above advantages, the prepared ECL biosensor exhibited high sensitivity, stability and broader linear range, even for practical analysis. Therefore, the prepared ECL biosensor will become a promising method for determination of α2,3-sialylated glycans and α2,6-sialylated glycans in clinical applications in the future. What is more, it provides a potential method for detection of other multi-targets.

16.
J Virol ; 2020 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-33208450

RESUMO

Tick-borne encephalitis virus (TBEV), a major tick-borne viral pathogen of humans, is known to cause neurological diseases such as meningitis, encephalitis and meningoencephalitis. However, the life cycle and pathogenesis of TBEV are not well understood. Here, we show that the knockdown or knockout of ADAM15 (a disintegrin and metalloproteinase 15), a host protein involved in neuroblastoma diseases, leads to TBEV replication and assembly defects. We characterized the disintegrin domain in ADAM15 and found that the ADAM15 subcellular localization was changed following TBEV infection. RNAi screen analysis confirmed the non-redundant ADAM's functions and identified a specific role for ADAM15 in TBEV infection. An RNA-sequencing analysis was also conducted to understand the causal link between TBEV infection and the cellular endomembrane network, namely, the generation of replication organelles promoting viral genome replication and virus production. Our data demonstrated that TBEV infection changes ADAM15 cellular localization, which contributes to membrane reorganization and viral replication.Importance Tick populations are increasing and their geographic ranges are expanding. Increases in tick-borne disease prevalence and transmission are important public health issues. Tick-borne encephalitis virus (TBEV) often results in meningitis, encephalitis and meningoencephalitis. TBEV causes clinical disease in more than 10,000 to 20,000 humans in Europe and Asia per year. An increased incidence of TBE has been noted in Europe and Asia, as a consequence of climate and socioeconomic changes. The need to investigate the mechanism(s) of the interaction between the virus and the host factors is apparent, which helps to understand the roles of host factors related to the life cycle of TBEV. The significance of our research is in identifying the ADAM15 for TBEV replication, which will greatly enhance our understanding of TBEV life cycle and highlight a target for pharmaceutical consideration.

17.
Cell Mol Biol (Noisy-le-grand) ; 66(5): 191-198, 2020 Jul 31.
Artigo em Inglês | MEDLINE | ID: mdl-33040835

RESUMO

Fibronectin 1 (FN1) is a glycoprotein molecule widely distributed in cell structures such as smooth muscle cell layer, vascular cell membrane and nerve cell layer. It participates in cell adhesion, migration and movement of various cells. In recent years, FN1 has been shown to play an important role in the regulation of various malignant tumors such as lung cancer, colorectal cancer, and ovarian cancer. However, its regulation and mechanism of action in gastric cancer have been rarely reported, and these are also associated with some controversy. The aim of this study was to investigate the clinical significance of FN1 in gastric cancer, to study the effects of FN1 on proliferation, apoptosis, migration and invasion of GC cells, and the mechanisms involved. The expression of FN1 in gastric cancer tissues was determined using immunohistochemistry staining. The comparative expression levels of FN1 were assayed with RT-PCR and Western blotting. The correlation amongst FN1 expression, clinicopathological parameters and prognosis of gastric cancer patients was determined. Cell transfection was used to silenceFN1 expression in gastric cancer cells. Plate cloning and CCK-8 assays were used to determine cell proliferation, while apoptosis was assayed with flow cytometry. Cell migration and invasion was measured with transwell assay. The expressions of EMT-related proteins were assayed using western blotting. The results showed that FN1 was upregulated in GC tissues and cell lines, and its expression level was closely related to tumor invasion, TNM stage, lymph node metastasis and survival. Inhibition of FN1 expression significantly reduced proliferation, migration, invasion and EMT processes of GC cells, and enhanced cell apoptosis. These results confirm that FN1 is up-regulated in GC, thereby functioning as an oncogenic gene. The high expression of FN1 might affect the clinicopathological parameters and prognosis of gastric cancer patients.

18.
J Cell Mol Med ; 2020 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-33048454

RESUMO

Protein phosphatase 1B (PPM1B), a member of metal-dependent protein serine/threonine phosphatase family, is involved in the regulation of several signalling pathways. However, our understanding of its substrate interaction and physiological functions is still largely limited. There is no reported PPM1B inhibitor to date. In this study, we identified HN252, a p-terphenyl derivative, as a potent PPM1B inhibitor (Ki  = 0.52 ± 0.06 µM). HN252 binding to PPM1B displayed remarkable and specific inhibition of PPM1B in both in vitro and ex vivo. With the aid of this small molecular inhibitor, we identified 30 proteins' serine/threonine phosphorylation as potential substrates of PPM1B, 5 of which were demonstrated by immunoprecipitation, including one known (CDK2) and 4 novel ones (AKT1, HSP90B, ß-catenin and BRCA1). Furthermore, GO and KEGG analysis of dramatically phosphorylated proteins by PPM1B inhibition indicated that PPM1B plays roles in the regulation of multiple cellular processes and signalling pathways, such as gene transcription, inflammatory regulation, ageing and tumorigenesis. Our work provides novel insights into further investigation of molecular mechanisms of PPM1B.

19.
Pain ; 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-33009246

RESUMO

Global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues unabated. Binding of SARS-CoV-2's Spike protein to host angiotensin converting enzyme 2 triggers viral entry, but other proteins may participate, including neuropilin-1 receptor (NRP-1). As both Spike protein and vascular endothelial growth factor-A (VEGF-A) - a pro-nociceptive and angiogenic factor, bind NRP-1, we tested if Spike could block VEGF-A/NRP-1 signaling. VEGF-A-triggered sensory neuronal firing was blocked by Spike protein and NRP-1 inhibitor EG00229. Pro-nociceptive behaviors of VEGF-A were similarly blocked via suppression of spontaneous spinal synaptic activity and reduction of electrogenic currents in sensory neurons. Remarkably, preventing VEGF-A/NRP-1 signaling was antiallodynic in a neuropathic pain model. A 'silencing' of pain via subversion of VEGF-A/NRP-1 signaling may underlie increased disease transmission in asymptomatic individuals.

20.
Genes (Basel) ; 11(11)2020 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-33114530

RESUMO

Hexokinase (HK) is a key enzyme in chitin biosynthesis in insects and plays an important role in development and energy regulation. It also performs a crucial role in the synthesis of Glucose-6-phosphate and its putative functions are studied via injection of dsRNA corresponding to the hexokinase gene from Cnaphalocrocis medinalis (CmHK). This study was designed to analyze the characteristics and expression patterns of HK-related genes in various tissues of C. medinalis at different developmental stages. The CmHK ORF is a 1359 bp in length, encoding a protein of 452 amino acids, with homology and cluster analysis showing that CmHK shares an 85.11% sequence similarity with hexokinase from Ostrinia furnacalis.CmHK was highly expressed in the ovary and in the fifth instar larvae. Injection of dsCmHK significantly suppressed mRNA expression (73.6%) 120 h post-dsRNA injection as compared to a control group. The results demonstrated an increased incidence of larval and pupal mortality of 80% and 78%, respectively, with significant variation in the sex ratio between males (68.33%) and females (35%), overt larval deformities, and a reduction in average weight gain observed 120 h post-dsRNA injection. In addition, dsCmHK-injected C. medinalis showed a significant reduction in ovulation per female and larval hatching rate, along with increased larval and pupal mortality and variation in male and female emergence over three generations (G1, G2, and G3). Taken together, the outcomes of the study provide a foundation to study gene function and a new dimension to control C. medinalis by transgenic RNAi technology.

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