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1.
Chem Biodivers ; 2020 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-32068326

RESUMO

A series of novel chalcone malonate derivatives were synthesized and their antibacterial and antiviral activities were evaluated. All target compounds were characterized by spectral data. The results of antimicrobial bioassay showed that compound 3 e  showed excellent antibacterial activity against Xanthomonas oryzae pv oryzae  (Xoo) , with an EC 50  value of 10.2 µg/mL, which is significantly superior to bismerthiazol (71.7 µg/mL) and thiodiazole-copper (97.8 µg/mL). At the same time, the mechanism of  3 e  and 3 k  was confirmed by SEM. In addition, compound 3 g  showed significant curative activity to TMV, with a value of 74.3%, which was superior to 53.3% of ningnanmycin. The results of MST also showed that the Kd value of the combination of 3b  and 3 g  with the coat protein of TMV was 0.211 and 0.166 µmol / L, which was better than 0.596 µmol / L of ningnanmycin. At the same time, the molecular docking of 3b  and 3 g  with TMV-CP shows that the compound is well embedded in the pocket between the two subunits of TMV-CP. These results show that chalcone derivatives containing malonate group can be considered as activators in the design of antibacterial and antiviral agents.

2.
Bioorg Chem ; 96: 103614, 2020 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-32007725

RESUMO

Phytochemical investigation into the calyx of Physalis alkekengi L. var franchetii (Mast) Makino resulted in the isolation of ten cytotoxic withanolides, including five new withanolides, 1-5. Compounds 2-4 were obtained as epimeric withaphysalins. The new structures were elucidated by extensive spectroscopic analyses and electronic circular dichroism (ECD) calculations. The withanolides were evaluated for their cytotoxic activities against the A549 and K562 cell lines. Compounds 1 and 8 exhibited potent cytotoxic activity against both cell lines with IC50 values of 1.9-4.3 µM and induced typical apoptosis as evaluated by flow cytometric analysis. Further studies indicated that 1 and 8 displayed antitumour effects by suppressing the PI3K-Akt-mTOR signalling pathway.

3.
Artigo em Chinês | MEDLINE | ID: mdl-32086916

RESUMO

Objective:The aim of this study is to evaluate the efficacy of endoscopic surgery and conventional surgery combined with radiotherapy in the treatment of Neuroblastoma. Method:Forty-three patients with olfactory neuroblastoma undergoing surgery combined with radiotherapy were retrospectively analyzed. The patients were divided into endoscopic surgery and conventional surgery. All patients received postoperative radiotherapy at a dose of 60-70 Gy, the 5-year survival rate and local recurrence time of the two groups were compared, and the therapeutic effects of endoscopic surgery and traditional surgery were compared. Result:Through survival analysis, the 5-year overall survival rates of the traditional surgery group and the endoscopic surgery group were 50% and 58% (P=0.560), the local recurrence rates were 44% and 48% (P=0.288), and the mean recurrence time was 5.6 months and 12.5 months (P=0.032). Conclusion:There was no difference between endoscopic surgery and conventional surgery combined with radiotherapy in the treatment of Neuroblastoma, and the time of local recurrence was significantly prolonged. In early Neuroblastoma, endoscopic sinus surgery may be superior to open surgery in terms of efficacy and patient survival.

4.
Nanotechnology ; 2020 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-31986504

RESUMO

A facile, low-cost and environmentally-friendly technique has been developed to prepare highly conductive copper-graphene nanosheet (Cu-GNS) composite coatings on ABS (Acrylonitrile-Butadiene-Styrene) substrate. The surface activation of ABS substrate was obtained by a chrome-free and palladium-free pretreatment consisting of molecular bonding. Before electroplating Cu, the homogeneous single Ag film on ABS surface was achieved by the electroless spray-plating process. In addition, the deposition of Cu and GNS increased in the coatings along with the current density increasing. Four-point-probe test confirmed that the resistivity of Cu coatings (0.08 mΩ·mm) and Cu-GNS composite coatings (0.05 mΩ·mm) was in the same order of magnitude as pure copper (0.0175 mΩ·mm) at high current density. Meanwhile, comparing with the Cu coatings, the resistivity of Cu-GNS composite coatings was reduced by nearly 40% at the same current density. The conductive property was significantly improved owing to the deposition of GNS. Therefore, this work was expected to expand the method of polymer materials surface metallization.

5.
Cell Death Differ ; 2020 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-31959915

RESUMO

The identification of viability-associated long noncoding RNAs (lncRNAs) is a means of uncovering therapeutic approaches for hepatocellular carcinoma (HCC). In addition, aberrant genome-wide hypomethylation has been implicated in HCC initiation and progression. However, the relationship between lncRNA dysregulation and genome-wide hypomethylation in hepatocarcinogenesis has not been fully elucidated. A novel lncRNA named LINC00662 was previously demonstrated to play a role in gastrointestinal cancer. In this study, we demonstrated that this lncRNA was correlated with survival and exhibited oncogenic properties, both in vitro and in vivo. Moreover, we determined that LINC00662 could lead to genome-wide hypomethylation and alter the genomic methylation profile by synchronously reducing the S-adenosylmethionine (SAM) level and enhancing the S-adenosylhomocysteine (SAH) level. Mechanistically, LINC00662 was determined to regulate the key enzymes influencing SAM and SAH levels, namely, methionine adenosyltransferase 1A (MAT1A) and S-adenosylhomocysteine hydrolase (AHCY), by RNA-RNA and RNA-protein interactions. In addition, we demonstrated that some SAM-dependent HCC-promoting genes could be regulated by LINC00662 by altering the methylation status of their promoters via the LINC00662-coupled axes of MAT1A/SAM and AHCY/SAH. Taken together, the results of this this study indicate that LINC00662 could be a potential biomarker for HCC therapy. More importantly, we proposed a new role of lncRNA in regulating genomic methylation to promote oncogene activation.

6.
Org Lett ; 22(2): 694-699, 2020 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-31913642

RESUMO

A general intermolecular reductive Heck reaction of organohalides with both terminal and internal unactivated aliphatic alkenes has been first realized in high yield with complete anti-Markovnikov selectivity. The challenging vinyl bromides, aryl chlorides, and polysubstituted internal alkenes were first applied. More than 100 remote carbofunctionalized alkyl carboxylic acid derivatives were rapidly synthesized from easily accessible starting materials. The synthesis of drug molecules has further demonstrated the wide synthetic utility of this scalable strategy. Preliminary mechanistic studies are consistent with the proposed catalytic cycle.

7.
Psychiatry Res Neuroimaging ; 296: 111029, 2020 Feb 29.
Artigo em Inglês | MEDLINE | ID: mdl-31918166

RESUMO

Parkinson's disease (PD) pathology may damage emotion circuit and cause depression. We investigated whether the neural basis of depressive symptoms varies at different PD stages. Seventy-six healthy controls (HC) and 98 PD patients (divided into early and middle stage groups) underwent brain magnetic resonance imaging (MRI) and general neuropsychological tests. Voxel-based morphometry and tract-based analysis were used to study the association between brain structural alterations and the Hamilton Depression Scale 17 Item (HAMD-17) scores in different groups. Comparing with HC group, PD patients showed widespread brain alterations in both gray and white matter. The HAMD-17 scores were positively correlated with GM volume in the right pre-central gyrus of early PD patients. In the middle stage group, HAMD-17 scores were positively correlated with GM volume in midbrain and right superior temporal gyrus, and negatively associated with GM volume in left anterior cingulate and superior frontal gyrus. In white matter analysis, The HAMD-17 scores were positively correlated with fractional anisotropy value of the bilateral inferior fronto-occipital fasciculus in the early stage group, but not the middle stage group. We concluded that the neural basis of depressive symptoms might be distinct in different stages of PD, implying the need for differential treatments.

8.
Clin Sci (Lond) ; 134(3): 349-358, 2020 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-31971563

RESUMO

BACKGROUND/AIMS: Congenital heart disease (CHD) is one of the most common and severe congenital defects. The incidence of fetal cardiac malformation is increased in the context of maternal gestational diabetes mellitus (GDM). Therefore, we wanted to determine whether abnormalities in the insulin signaling pathway are associated with the occurrence of nonsyndromic CHD (ns-CHD). METHODS: We used digital gene expression profiling (DGE) of right atrial myocardial tissue samples from eight ns-CHD patients and four controls. The genes potentially associated with CHD were validated by real-time fluorescence quantitative PCR analysis of right atrial myocardial tissues from 37 patients and 10 controls and the H9C2 cell line. RESULTS: The results showed that the insulin signaling pathway, which is mediated by the SHC gene family, was inhibited in the ns-CHD patients. The expression levels of five genes (PTPRF, SHC4, MAP2K2, MKNK2, and ELK1) in the pathway were significantly down-regulated in the patients' atrial tissues (P<0.05 for all). In vitro, the H9C2 cells cultured in high glucose (33 mmol/l) expressed less SHC4, MAP2K2, and Elk-1 than those cultured in low glucose (25 mmol/l). Furthermore, the high glucose concentration down-regulated the 25 genes associated with blood vessel development based on Gene Ontology (GO) term enrichment analyses of RNA-seq data. CONCLUSION: We considered that changes in the insulin signaling pathway mediated by SHC might be involved in the heart development process. This mechanism might account for the increase in the incidence of fetal cardiac malformations in the context of GDM.

9.
J Cell Mol Med ; 2020 Jan 22.
Artigo em Inglês | MEDLINE | ID: mdl-31970902

RESUMO

Macrophage activation participates in the pathogenesis of pulmonary inflammation. As a coenzyme, vitamin B6 (VitB6) is mainly involved in the metabolism of amino acids, nucleic acids, glycogen and lipids. We have previously reported that activation of AMP-activated protein kinase (AMPK) produces anti-inflammatory effects both in vitro and in vivo. Whether VitB6 via AMPK activation prevents pulmonary inflammation remains unknown. The model of acute pneumonia was induced by injecting mice with lipopolysaccharide (LPS). The inflammation was determined by measuring the levels of interleukin-1 beta (IL-1ß), IL-6 and tumour necrosis factor alpha (TNF-α) using real time PCR, ELISA and immunohistochemistry. Exposure of cultured primary macrophages to VitB6 increased AMP-activated protein kinase (AMPK) Thr172 phosphorylation in a time/dose-dependent manner, which was inhibited by compound C. VitB6 downregulated the inflammatory gene expressions including IL-1ß, IL-6 and TNF-α in macrophages challenged with LPS. These effects of VitB6 were mirrored by AMPK activator 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR). However, VitB6 was unable to inhibit LPS-induced macrophage activation if AMPK was in deficient through siRNA-mediated approaches. Further, the anti-inflammatory effects produced by VitB6 or AICAR in LPS-treated macrophages were abolished in DOK3 gene knockout (DOK3-/- ) macrophages, but were enhanced in macrophages if DOK3 was overexpressed. In vivo studies indicated that administration of VitB6 remarkably inhibited LPS-induced both systemic inflammation and acute pneumonia in wild-type mice, but not in DOK3-/- mice. VitB6 prevents LPS-induced acute pulmonary inflammation in mice via the inhibition of macrophage activation.

11.
Stem Cell Res Ther ; 11(1): 10, 2020 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-31900223

RESUMO

BACKGROUND: To explore the effect of aerobic training (AT), resistance training (RT) or a combination of AT and RT (AT+RT) on the function of endothelial progenitor cells (EPCs) in mice with type 2 diabetes and the potential effective mechanisms METHODS: Eight-week-old db/db male mice were used as type 2 diabetic animal models in this study. Mice were randomly assigned to the control group (n = 5), AT group (n = 5), RT group (n = 5) and AT+RT group (n = 5). Mice in the control group remained sedentary with no specific training requirement. Mice were motivated to perform AT, RT or AT+RT by a gentle pat on their body for 3 or 4 days/week for 14 days. AT was performed by treadmill running, RT was performed by ladder climbing and AT+RT involved both AT and RT. Bone-derived EPCs were isolated after 14 days of the intervention. EPC expression of CD31, CD34, CD133, CD144 and VEGFR2 was detected by immunofluorescence staining. Fluorescence detection was performed on attached mononuclear cells to detect double-positive EPCs. We then explored the effect of caveolin-1 knockdown (lentiviral vector with caveolin-1-siRNA) on the proliferation and adherence of EPCs and the concentration of caveolin-1 and PI3K/AKT via western blot analyses. RESULTS: Compared to the mice in the control group, the mice in the AT, RT and AT+RT groups presented significant increases in proliferation and adherence after 14 days of intervention. AT+RT induced an increase in EPC adherence, which was greater than that of the control, RT and AT groups. Caveolin-1 knockdown inhibited the EPC proliferative and adherent abilities. The AT+RT group showed higher levels of caveolin-1 and p-AKT than the control group, but these changes were decreased by caveolin-1-siRNA transfection. CONCLUSION: Combined AT and RT is an effective way to improve EPC function through upregulation of caveolin-1 in mice with type 2 diabetes.

12.
Biochim Biophys Acta Gen Subj ; 1864(4): 129520, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31931020

RESUMO

In the peripheral nervous system (PNS), Schwann cells (SCs) are required for the myelination of axons. Periaxin (PRX), one of the myelination proteins expressed in SCs, is critical for the normal development and maintenance of PNS. As a member of the ERM (ezrin-radxin-moesin) protein family, ezrin holds our attention since their link to the formation of the nodes of Ranvier. Furthermore, PRX and ezrin are co-expressed in cytoskeletal complexes with periplakin and desmoyokin in lens fiber cells. In the present study, we observed that L-periaxin and ezrin interacted in a "head to head and tail to tail" mode in SC RSC96 through NLS3 region of L-periaxin with F3 subdomain of ezrin interaction, and the region of L-periaxin (residues 1368-1461) with ezrin (residues 475-557) interaction. A phosphorylation-mimicking mutation of ezrin resulted in L-periaxin accumulation on SC RSC96 membrane. Ezrin could inhibit the self-association of L-periaxin, and ezrin overexpression in sciatic nerve injury rats could facilitate the repair of impaired myelin sheath. Therefore, the interaction between L-periaxin and ezrin may adopt a close form to complete protein accumulation and to participate in myelin sheath maintenance.

13.
Curr Pharm Biotechnol ; 21(1): 79-88, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31580250

RESUMO

BACKGROUND: Large-scale population studies showed that the SNP rs1764391 of Connexin37 gene also known as Cx37 gene may play a pivotal role in the occurrence and development of acute myocardial infarction (AMI). Published results, however, are highly controversial. OBJECTIVE: This study aimed to examine the association between SNP rs1764391 of Cx37 and diseasesusceptibility, several risk factors, and gene-environment interactions of AMI in Guangxi Han Chinese population. METHODS: In this study, 344 healthy controls and 344 AMI patients of Han Chinese population were enrolled. The TaqMan assay was implemented to identify genotypes of Cx37 and allele frequencies of SNP rs1764391 in both the AMI and control groups. RESULTS: Significant differences were detected in TT genotype frequencies of SNP rs1764391 between the AMI and control groups (P < 0.05). In the context of gender stratification, the result was also statistically different in women (P < 0.05). Each variable such as age, BMI, diabetes, high blood pressure, smoking and TC was a risk factor and correlated significantly (P < 0.05) with the development of AMI. HDL-C correlated negatively with the risk of AMI (P < 0.001). BMI, smoking or alcohol consumed interacts significantly (P < 0.017) with the presence of the SNP rs1764391 CC genotype. CONCLUSION: Evidences were presented that Cx37 rs1764391 variation may contribute to the risk for AMI, especially in women and this genetic variant may prove to be a potential biomarker for AMI risk stratification and may prove to be a useful target for therapeutic intervention to further improve prognosis in high-risk patients.

14.
CNS Neurosci Ther ; 26(1): 117-125, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31278861

RESUMO

AIMS: Cognitive impairment is a common symptom in the trajectory of Parkinson's disease (PD). However, the pathological underpinning is not fully known. We aimed to explore the critical structural alterations in the process of cognitive decline and its relationships with the dopaminergic deficit and the level of related cerebrospinal fluid (CSF) proteins. METHODS: Ninety-four patients with PD and 32 controls were included in this study. Neuropsychological tests were performed at baseline and after 28 months to identify which patients had normal cognition and which ones developed PD-MCI after follow-up ("converters"). Gray matter atrophy was assessed in cross-sectional and longitudinal analyses, respectively. The associations between altered GMV with dopamine transporter (DAT) results and the level of CSF proteins were assessed. RESULTS: Among the 94 patients with normal cognition at baseline, 24 (mean age, 63.1 years) developed PD-MCI after 28 months of follow-up, and 70 (mean age, 62.3 years) remained nonconverters. The converters showed significant right temporal atrophy at baseline and extensive atrophy in temporal lobe at follow-up. Progressive bilateral frontal lobe atrophy was found in the converters. Baseline right temporal atrophy was correlated with the striatal dopaminergic degeneration in the converters. No correlation was found between the right temporal atrophy and the alterations of CSF proteins. CONCLUSION: Early atrophy in temporal lobes and progressive atrophy in frontal lobes might be a biomarker for developing multidomain impairment of cognition and converting to PD-MCI. Furthermore, cognition-related temporal atrophy might be associated with dopaminergic deficit reflected by DAT scan but independent of CSF proteins in patients with PD who convert to PD-MCI.

15.
Acta Paediatr ; 109(2): 321-326, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31393023

RESUMO

AIM: The aim of this study was to determine reference values for oxygen saturation (SpO2 ) in neonates at mild and moderate altitudes. METHODS: Our study included 41 097 consecutively born, asymptomatic neonates from 35 hospitals, located in Yunnan, China, with altitudes ranging from 267 to 2202 m. Pre-and post-ductal SpO2 of each neonate was measured at 24 hours of age and before hospital discharge. All study participants, according to the altitude of birth, were categorised into three groups: low (0-500 m), mild (500-1500 m) and moderate altitude (1500-2500 m). RESULTS: Every 1000-m increase in altitude was associated with a 1.54 per cent decrease in mean SpO2 . The means of pre-ductal SpO2 at low, mild and moderate groups were 97.9%, 96.4% and 95.5%, respectively. We used the 2.5th percentile of SpO2 distribution as the cut-off for neonatal SpO2 screening and defined new cut-off values of ≤93% for mild altitudes, ≤92% for moderate altitudes and no adjustment for low altitudes. CONCLUSION: We recommend revised cut-off values for neonatal SpO2 at mild and moderate altitudes and provide new values for paediatricians to refer to when screening neonates for severe congenital heart or lung diseases.

16.
J Cell Mol Med ; 24(3): 2319-2329, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31880857

RESUMO

Cardiac fibrosis is a key factor to determine the prognosis in patient with myocardial infarction (MI). The aim of this study is to investigate whether the transcriptional factor paired-related homeobox 2 (Prrx2) regulates Wnt5a gene expression and the role in myocardial fibrosis following MI. The MI surgery was performed by ligation of left anterior descending coronary artery. Cardiac remodelling was assessed by measuring interstitial fibrosis performed with Masson staining. Cell differentiation was examined by analysis the expression of alpha-smooth muscle actin (α-SMA). Both Prrx2 and Wnt5a gene expressions were up-regulated in mice following MI, accompanied with increased mRNA and protein levels of α-SMA, collagen I and collagen III, compared to mice with sham surgery. Adenovirus-mediated gene knock down of Prrx2 increased survival rate, alleviated cardiac fibrosis, decreased infarction sizes and improved cardiac functions in mice with MI. Importantly, inhibition of Prrx2 suppressed ischaemia-induced Wnt5a gene expression and Wnt5a signalling. In cultured cardiac fibroblasts, TGF-ß increased gene expressions of Prrx2 and Wnt5a, and induced cell differentiations, which were abolished by gene silence of either Prrx2 or Wnt5a. Further, overexpression of Prrx2 or Wnt5a mirrored the effects of TGF-ß on cell differentiations of cardiac fibroblasts. Gene silence of Wnt5a also ablated cell differentiations induced by Prrx2 overexpression in cardiac fibroblasts. Mechanically, Prrx2 was able to bind with Wnt5a gene promoter to up-regulate Wnt5a gene expression. In conclusions, targeting Prrx2-Wnt5a signalling should be considered to improve cardiac remodelling in patients with ischaemic heart diseases.

17.
Transl Neurodegener ; 8: 36, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31807287

RESUMO

Background: Different oscillations of brain networks could carry different dimensions of brain integration. We aimed to investigate oscillation-specific nodal alterations in patients with Parkinson's disease (PD) across early stage to middle stage by using graph theory-based analysis. Methods: Eighty-eight PD patients including 39 PD patients in the early stage (EPD) and 49 patients in the middle stage (MPD) and 36 controls were recruited in the present study. Graph theory-based network analyses from three oscillation frequencies (slow-5: 0.01-0.027 Hz; slow-4: 0.027-0.073 Hz; slow-3: 0.073-0.198 Hz) were analyzed. Nodal metrics (e.g. nodal degree centrality, betweenness centrality and nodal efficiency) were calculated. Results: Our results showed that (1) a divergent effect of oscillation frequencies on nodal metrics, especially on nodal degree centrality and nodal efficiency, that the anteroventral neocortex and subcortex had high nodal metrics within low oscillation frequencies while the posterolateral neocortex had high values within the relative high oscillation frequency was observed, which visually showed that network was perturbed in PD; (2) PD patients in early stage relatively preserved nodal properties while MPD patients showed widespread abnormalities, which was consistently detected within all three oscillation frequencies; (3) the involvement of basal ganglia could be specifically observed within slow-5 oscillation frequency in MPD patients; (4) logistic regression and receiver operating characteristic curve analyses demonstrated that some of those oscillation-specific nodal alterations had the ability to well discriminate PD patients from controls or MPD from EPD patients at the individual level; (5) occipital disruption within high frequency (slow-3) made a significant influence on motor impairment which was dominated by akinesia and rigidity. Conclusions: Coupling various oscillations could provide potentially useful information for large-scale network and progressive oscillation-specific nodal alterations were observed in PD patients across early to middle stages.

18.
Ann Transl Med ; 7(20): 551, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31807532

RESUMO

Background: Heat shock cognate protein 70 (HSC70) is a constitutively expressed molecular chaperone protein which can maintain the structure and function of the protein. HSC70 is engaged in a variety of physiological processes, yet its role during skeletal muscle differentiation is still unclear. Methods: C2C12 cells were obtained and cultured. During differentiation, the expression of HSC70 was evaluated by RT-PCR. To determine the function of HSC70 during C2C12 myoblast differentiation, myotube transfection of siR-HSC70 was performed with Lipofectamine 2000 Reagent. Western blot was used to measure the expression of Yin Yang 1 (YY1) after down-regulating HSC70. To further assess if YY1 mediates the pro-differentiation effect of HSC70, a plasmid of YY1 overexpression was used to increase the expression of YY1 in the presence of siR-HSC70-2. The formation of myotubes was visualized by immunofluorescent staining, while the expression levels of MyoD and MyoG were evaluated by RT-PCR. Results: In this study, we found that HSC70 was up-regulated during C2C12 myoblast differentiation. Knockdown of HSC70 not only inhibited the C2C12 myoblast differentiation but also reduced the expression of MyoD and MyoG. When YY1 protein was over-expressed, it could restore the differentiation in cells with HSC70 knockdown or inhibition. Conclusions: Collectively, this study demonstrates that HSC70 is involved in the regulation of C2C12 myoblast differentiation via YY1 and may serve as a potential target for a therapeutic strategy to prevent muscle atrophy.

19.
Mol Cancer ; 18(1): 175, 2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31796058

RESUMO

OBJECTIVES: Carcinoma-associated fibroblasts (CAFs) have been known to promote cancer progression by modifying the primary tumor microenvironment. We aimed to elucidate the intercellular communication between CAFs and secondary organs in salivary adenoid cystic carcinoma (SACC) metastasis. METHODS: Pre-metastatic and metastatic animal models of SACC were established using extracellular vesicles (EVs) from CAFs and SACC cells. Lung fibroblasts (LFs) were treated with EVs and their transcriptomic alterations were identified by RNA sequencing. ITRAQ were performed to analyze EV cargos. TC I-15 was used to inhibit EV uptake by LFs and SACC lung metastasis in vivo. RESULTS: Here, we show that CAF EVs induced lung pre-metastatic niche formation in mice and consequently increased SACC lung metastasis. The pre-metastatic niche induced by CAF EVs was different from that induced by SACC EVs. CAF EVs presented a great ability for matrix remodeling and periostin is a potential biomarker characterizing the CAF EV-induced pre-metastatic niche. We found that lung fibroblast activation promoted by CAF EVs was a critical event at the pre-metastatic niche. Integrin α2ß1 mediated CAF EV uptake by lung fibroblasts, and its blockage by TC I-15 prevented lung pre-metastatic niche formation and subsequent metastasis. Plasma EV integrin ß1 was considerably upregulated in the mice bearing xenografts with high risk of lung metastasis. CONCLUSIONS: We demonstrated that CAF EVs participated in the pre-metastatic niche formation in the lung. Plasma EV integrin ß1 might be a promising biomarker to predict SACC metastasis at an early stage. An integrated strategy targeting both tumor and stromal cells is necessary to prevent SACC metastasis.

20.
Plant Physiol ; 2019 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-31882455

RESUMO

Phosphoinositides (PIs) as regulatory membrane lipids play essential roles in multiple cellular processes. Although the exact molecular targets of PI-dependent modulation remain largely elusive, the effects of disturbed PI metabolism could be employed to identify regulatory modules associated with particular downstream targets of PIs. Here, we identified the role of GRAIN NUMBER AND PLANT HEIGHT1 (GH1), which encodes a suppressor of actin (SAC) domain-containing phosphatase with unknown function in rice (Oryza sativa). Endoplasmic reticulum-localized GH1 specifically dephosphorylated and hydrolyzed phosphatidylinositol 4-phosphate (PI4P) and phosphatidylinositol 4,5-bisphosphate [PI(4,5)P2]. Inactivation of GH1 resulted in massive accumulation of both PI4P and PI(4,5)P2, while excessive GH1 caused their depletion. Notably, superabundant PI4P and PI(4,5)P2 could both disrupt actin cytoskeleton organization and suppress cell elongation. Interestingly, both PI4P and PI(4,5)P2 inhibited actin-related proteins 2 and 3 (Arp2/3) complex-nucleated actin branching networks in vitro, whereas PI(4,5)P2 showed more dramatic effects in a dose-dependent manner. Overall, the overaccumulation of PI(4,5)P2 resulting from dysfunction of SAC phosphatase possibly perturbs Arp2/3 complex-mediated actin polymerization, thereby disordering cell development. These findings imply that the Arp2/3 complex might be the potential molecular target of PI(4,5)P2-dependent modulation in eukaryotes, thereby providing insights into the relationship between PI homeostasis and plant growth and development.

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