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1.
Behav Brain Res ; : 112319, 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31669346

RESUMO

Chronic cerebral hypoperfusion is an important risk factor for vascular dementia (VaD) and other brain dysfunctions, for which there are currently no effective medications available. In the present study, we investigated the potential therapeutic effects of cornel iridoid glycoside (CIG) on VaD in rats modeled by permanent bilateral common carotid artery ligation (2-vessel occlusion, 2VO). The object recognition test (ORT) and Morris water maze (MWM) test were conducted to evaluate the learning and memory function. Western blot analysis and immunohistochemical staining were used to detect the expression of related proteins. Results showed that intragastric administration of CIG (30, 60, and 120 mg/kg) for 3 months significantly increased the discrimination index in ORT and decreased the escape latency in MWM test, ameliorating the learning and memory deficit in 2VO rats. Further data indicated that CIG increased the expression of neurotrophic factors (NGF and BDNF) and their receptors (TrkA and TrkB), glutamate receptor subunits (NMDAR1 and GluR2) in the cerebral cortex and hippocampus of 2VO rats. In addition, CIG elevated the expression of PI3K subunits p110α and p85, further upregulated the phosphorylation of Akt, GSK3ß-ser9 and CREB in the cerebral cortex and hippocampus at 3 months after 2VO surgery. Collectively, CIG treatment improved learning and memory deficit induced by chronic cerebral hypoperfusion via increasing neurotrophic factors thus protecting glutamate receptors and activating PI3K/Akt/GSK3ß/CREB signaling pathway in rats. These results suggest that CIG may be beneficial to VaD therapy.

2.
Fitoterapia ; : 104389, 2019 Oct 26.
Artigo em Inglês | MEDLINE | ID: mdl-31669963

RESUMO

A new heterodimer, rynchopeterine F (1), a new natural product, rynchopeterine G (2), and eleven known phenolics were isolated from Blap rynchopetera Fairmaire, a kind of medicinal insect utilized by the Yi and Bai Nationality in Yunnan Province of China. Their structures were established on the basis of extensive spectroscopic analyses (1D and 2D NMR, HR-MS) along with calculated electronic circular dichroism method. Rynchopeterine F was a unusual heterodimer of a 3,4-dihudroxy phenylethanol unit fused to a 3,4-dihudroxy phenylacetyl group through two ester bonds with lactic acid, and rynchopeterine G was a 3,4-dihudroxy phenylethanyl monoester succinate. Attributed to the adjacent dihydroxyl grops, compounds 1 and 2 exhibited significant anti-radical activity with an IC50 value of 3.52 and 7.83 µg/mL for DPPH radical-scavenging, similar with that of the positive controls, vitamin C, 6.92 µg/mL and rutin, 8.28 µg/mL.

3.
Transgenic Res ; 2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31673914

RESUMO

The vitamin E family includes tocopherols and tocotrienols, which are essential lipid-soluble antioxidants necessary for human and livestock health. The seeds of many plant species, including maize, have high gamma (γ)-tocopherol but low alpha (α)-tocopherol contents; however, α-tocopherol is the most effective antioxidant. Therefore, it is necessary to optimize the tocopherol composition in plants. α-Tocopherol is synthesized from γ-tocopherol by γ-tocopherol methyltransferase (γ-TMT, VTE4) in the final step of the tocopherol biosynthetic pathway. In the present study, the full-length coding sequence (CDS) of γ-TMT was isolated from Zea mays, named ZmTMT. The ZmTMT CDS was 1059 bp in size, encoding 352 amino acids. Recombinant ZmTMT was expressed in Escherichia coli and the purified protein effectively converted γ-tocopherol into α-tocopherol in vitro. A comparison of enzyme activities showed that the activity of ZmTMT was higher than that of GmTMT2a (Glycine max) and AtTMT (Arabidopsis thaliana). Overexpression of ZmTMT increased the α-tocopherol content 4-5-fold in transgenic Arabidopsis and around 6.5-fold in transgenic maize kernels, and increased the α-/γ-tocopherol ratio to approximately 15 and 17, respectively. These results show that it is feasible to overexpress ZmTMT to optimize the tocopherol composition in maize; such a corn product might be useful in the feed industry in the near future.

4.
Ann Vasc Surg ; 2019 Oct 23.
Artigo em Inglês | MEDLINE | ID: mdl-31655109

RESUMO

BACKGROUND: Neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) are two markers of inflammation, which are associated with worse cardiovascular disease outcomes. Here we aimed to determine the association between these ratios and disease severity, and evaulate predictive validity of NLR and PLR in lower limb arteriosclerosis obliterans (ASO). METHODS: We evaluated 211 patients with a diagnosis of ASO from January 2016 to December 2018 at Shanghai Jiaotong University Renji hospital. NLR and PLR were accessed from routinely drawn peripheral venous blood at the ward of vascular surgery during hospitalization. the association between NLR and PLR with baseline characteristics, disease severity, one-year outcomes were determined, respectively. RESULTS: Both NLR and PLR showed significant values on predicting disease severity. Higher NLR(p=0.001) and PLR(p<0.001) were associated with lower ABI index and worse clinical presentation. Both NLR and PLR are positively correlated with one-year readmission rate (p<0.001, p=0.001, respectively). Both NLR and PLR also positively correlated with tissue loss rate and one-year mortality (p=0.007, p=0.034, respectively). CONCLUSION: NLR and PLR show a positive association with the severity of lower extremity PAD, both higher ratios correlate with poor prognosis, especially, the risk of one-year readmission. A higher NLR also correlates with one-year mortality.

5.
PLoS One ; 14(10): e0223185, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31581205

RESUMO

BACKGROUND: Physical therapy can prevent functional impairments and improve the quality of life of patients after hospital discharge. However, the effect of early mobilization on patients with a critical illness remains unclear. This study was performed to assess the evidence available regarding the effect of early mobilization on critically ill patients in the intensive care unit (ICU). METHODS: Electronic databases were searched from their inception to March 21, 2019. Randomized controlled trials (RCTs) comprising critically ill patients who received early mobilization were included. The methodological quality and risk of bias of each eligible trial were assessed using the Cochrane Collaboration tool. Data were extracted using a standard collection form each included study, and processed using the Mantel-Haenszel (M-H) or inverse-variance (I-V) test in the STATA v12.0 statistical software. RESULTS: A total of 1,898 records were screened. Twenty-three RCTs comprising 2,308 critically ill patients were ultimately included. Early mobilization decreased the incidence of ICU-acquired weakness (ICU-AW) at hospital discharge (three studies, 190 patients, relative risk (RR): 0.60, 95% confidence interval (CI) [0.40, 0.90]; p = 0.013, I2 = 0.0%), increased the number of patients who were able to stand (one study, 50 patients, 90% vs. 62%, p = 0.02), increased the number of ventilator-free days (six studies, 745 patients, standardized mean difference (SMD): 0.17, 95% CI [0.02, 0.31]; p = 0.023, I2 = 35.5%) during hospitalization, increased the distance the patient was able to walk unassisted (one study, 104 patients, 33.4 (0-91.4) meters vs. 0 (0-30.4) meters, p = 0.004) at hospital discharge, and increased the discharged-to-home rate (seven studies, 793 patients, RR: 1.16, 95% CI [1.00, 1.34]; p = 0.046). The mortality (28-day, ICU and hospital) and adverse event rates were moderately increased by early mobilization, but the differences were statistically non-significant. However, due to the substantial heterogeneity among the included studies, and the low quality of the evidence, the results of this study should be interpreted with caution. Publication bias was not identified. CONCLUSIONS: Early mobilization appears to decrease the incidence of ICU-AW, improve the functional capacity, and increase the number of ventilator-free days and the discharged-to-home rate for patients with a critical illness in the ICU setting.

6.
Gastric Cancer ; 2019 Oct 24.
Artigo em Inglês | MEDLINE | ID: mdl-31650323

RESUMO

BACKGROUND: The aberrant expression of long noncoding RNAs (lncRNAs) is found in various types of cancers and also showed its association with the occurrence and development of gastric cancer (GC). We found lncRNA COL1A1-014 was frequently upregulated in GC. METHODS: This study investigated COL1A1-014 for its biological function at both cellular and animal levels, using MTT, flow cytometry, colony formation and transwell assays. The expression levels of COL1A1-014 and other genes were detected by RT-PCR and western blot. Luciferase reporter assay was used to detect the potential binding of miR-1273h-5p to COL1A1-014 and CXCL12. RESULTS: We found that COL1A1-014 was frequently upregulated in GC tissues as well as cells. COL1A1-014 increased cell proliferation, colony forming efficiency, migration ability, invasion ability, and weight and volume of grafted tumors, while reduced cell apoptosis. Overexpression of COL1A1-014 increased the mRNA expression of chemokine (CXCmotif) ligand (CXCL12) and high levels of CXCL12 and CXCR4 proteins in GC cells. The levels of miR-1273h-5p showed an inverse correlation with COL1A1-014 and CXCL12 in GC cells transfected with miR-1273h-5p. The mRNAs of wild-type COL1A1-014 and CXCL12 showed reduction in HEK293 cells transfected with miR-1273h-5p. This suggested that COL1A1-014 functions as an efficient miR-1273h-5p sponge and as a competing endogenous RNA (ceRNA) to regulate CXCL12. The proliferative activity of COL1A1-014 on GC cells was blocked by CXCL12-CXCR4 axis inhibitor AMD-3100. CONCLUSIONS: These findings demonstrated that COL1A1-014 play an important regulatory role in GC development by functioning as a ceRNA in regulating the CXCL12/CXCR4 axis via sponging miR-1273h-5p.

7.
DNA Cell Biol ; 2019 Oct 16.
Artigo em Inglês | MEDLINE | ID: mdl-31618054

RESUMO

DNA hydroxymethylation is one of the major epigenetic mechanisms mediating the development of several human cancers. This study aimed to identify key hydroxymethylated genes and transcription factors (TFs) associated with alpha-fetoprotein (AFP)-negative hepatocellular carcinoma (HCC) using whole-genome DNA hydroxymethylation profiling. A total of 615 differentially hydroxymethylated regions (DHMRs) were identified from AFP-negative HCC tissues compared to adjacent normal tissues. DHMR-associated genes were significantly enriched in gene ontology functions associated with actin binding, cell leading edge, and blood vessel morphogenesis and pathways such as MAPK signaling pathway, neuroactive ligand-receptor interaction, and axon guidance. Moreover, protein-protein interaction (PPI) network analysis showed that PH domain and leucine-rich repeat protein phosphatase 1 (PHLPP1) and SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily A, member 2 (SMARCA2) had higher degrees and were hub nodes. Furthermore, TF prediction analysis showed that TFs, such as nuclear factor I C (NFIC) and GATA binding protein 3 (GATA3), regulated many DHMR-associated genes. Our findings reveal that key hydroxymethylated genes such as PHLPP1 and SMARCA2, as well as TFs such as NFIC and GATA, may be involved in the development of AFP-negative HCC. These molecules may be potential biomarkers for AFP-negative HCC.

8.
J Am Chem Soc ; 2019 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-31656073

RESUMO

Covalent organic frameworks (COFs) represent a new class of porous crystalline polymers with a diversi-ty of applications. However, synthesis of uniform spherical COFs poses a great challenge. Here we presented size-controllable synthesis of uniform spherical COFs from nanometer to micrometer scale by a facile approach at room temperature. The as-prepared spherical COFs with different sizes exhibited ultrahigh surface area, good crystallinity and chemical/thermal stability. Multifarious microscopic and spectroscopic techniques were performed to understand the formation mechanism and influencing factors of the spherical COFs. Moreover, the general applicability for room-temperature synthesis of the spherical COFs was demonstrated by varying different building blocks. Taking the ad-vantages of the spherical COFs in term of surface area, hydrophobicity, and mesoporous microenvironment, the spheri-cal COFs can serve as an attractive restricted-access adsorption material for highly selective and efficient enrichment of hydrophobic peptides and size-exclusion of macromolecular proteins simultaneously. On this basis, the spherical COFs were successfully applied to the specific capture of ultratrace C-peptide from human serum and urine samples. This re-search provides a new strategy for room-temperature controllable synthesis of uniform spherical COFs with different sizes and extends the application of COFs as an attractive sample enrichment probe for clinical analysis.

9.
Zhongguo Zhong Yao Za Zhi ; 44(15): 3233-3238, 2019 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-31602877

RESUMO

In order to study the correlation between the traits of Andrographis paniculata. The main agronomic traits and the content of four kinds of diterpene lactons were measured by the seedlings and the unmutagenized seeds carried by the spacecraft,and multiple comparisons,correlations and principal component analysis were carried out. The results showed that the agronomic traits of A. paniculata have different degrees of difference after being carried by space. The contents of diterpene lactones were quite different. The variation coefficients of deoxyandrographolide content,fresh weight,leaf dry weight,dehydrated andrographolide content,dry weight,neoandrographolide content and andrographolide content were all over 35%. There was a significant correlation between multiple traits,and the leaf weight ratio was significantly positively correlated with the number of primary tillers,leaf dry weight and dry weight,and was significantly negatively correlated with the content of deoxyandrographolide. Andrographolide content was a significantly negatively correlated with the number of leaves and the number of primary tillers,and positively correlated with the other three lactones. Five principal components were extracted from principal component analysis,and the cumulative contribution rate was 83. 127%,which were yield factor,plant type factor,leaf type factor,component factor and seed weight factor. Among the traits affecting the quality of A. paniculata,the yield factor for reliability of the selection of A. paniculata is higher than other factors. There are abundant variations among the traits of A. paniculata,carried in space which increase the genetic diversity. The principal component analysis method can be used to select the principal component factors according to the breeding requirements,which provides a theoretical basis for the breeding of high-yield and high-quality A. paniculata and the high-yield and stable cultivation of A. paniculata.


Assuntos
Andrographis/química , Diterpenos/análise , Lactonas/análise , Compostos Fitoquímicos/análise , Folhas de Planta , Reprodutibilidade dos Testes
10.
Mikrochim Acta ; 186(11): 713, 2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31650278

RESUMO

Inspired by the increasing use of plasmonic gold and silver nanoplates as probes for diverse analytes, the research community often questions which metal nanoplates should be chosen for a given application. A comparative study was performed on the performance and physicochemical properties of three types of metal nanoplates for use in plasmonic detection of Hg(II) ion. Specifically, gold, silver and Ag@Au nanoplates were studied. The established amalgamation method integrated into a detection scheme using nanoplates affords a unique yet straightforward signaling and extraction route for selective recognition of Hg(II) ion. Upon transformation of Hg(II) ion to metallic mercury, nanoplate amalgamation takes place instantly. This reshapes both the morphology and the optical characteristics of nanoplates. It is found that gold and Ag@Au nanoplates enable highly selective quantitation of Hg(II) ion by using a DNA oligomer consisting of poly-deoxycytidine (poly(C)) as a masking agent against Ag(I) ion. The silver nanoplates, in turn, display the best sensitivity owing to the chemical instability. The induced surface plasmonic shifts (of up to 250 nm and color changes from red to green) allows for determination of Hg(II) over a wide range and with a limit of detection of ~10 nM. It is recommended that the gold and Ag@Au nanoplates are used in relatively complex systems, while silver nanoplates are suited for simple matrices. Graphic abstract The amalgamation process integrated with metal (e.g., Au, Ag and Ag@Au) nanoplates affords plasmonic detection of Hg(II) ion with the aid of a poly(c) DNA sequence as the masking agent for Ag(I) ion.

11.
Chin J Integr Med ; 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31630361

RESUMO

OBJECTIVE: To analyze the effective components of Chinese medicine (CM) contained in Chaihu Shugan Powder (, CSP) in the treatment of depressive disorders and to predict its anti-depressant mechanism by network pharmacology. METHODS: Absorption, distribution, metabolism, excretion, and toxicity calculation method was used to screen the active components of CSP. Traditional Chinese Medicine System Pharmacological Database Analysis Platform and text mining tool (GoPuMed database) were used to predict and screen the active ingredients of CSP and anti-depressive targets. Through Genetic Association Database, Therapeutic Target Database, and PharmGkb database targets for depression were obtained. Cytoscape3.2.1 software was used to establish a network map of the active ingredients-targets of CSP, and to analyze gene function and metabolic pathways through Database for Annotation, Visualization and Integrated Discovery and the Omicshare database. RESULTS: The 121 active ingredients and 15 depression-related targets which were screened from the database can exert antidepressant effects by improving the neural plasticity, growth, transfer condition and gene expression of neuronal cell, and the raise of the expression of gap junction protein. The 15 targets passed 14 metabolic pathways, mainly involved in the regulation of neurotransmitters (5-hydroxytryptamine, dopamine and epinephrine), inflammatory mediator regulation of TRP channels, calcium signaling pathway, cyclic adenosine monophosphate signaling pathway and neuroactive ligand-receptor interaction and other signal channels to exert anti-depressant effects. CONCLUSION: This article reveals the possible mechanism of CSP in the treatment of depression through network pharmacology research, and lays a foundation for further target studies.

12.
J Agric Food Chem ; 2019 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-31630515

RESUMO

Biochanin A is a dietary isoflavone with multiple biological functions. Due to a lack of comprehensive studies of biochanin A metabolism, this study was designed to further clarify the processes involved in biochanin A metabolism. In this study, ultrahigh-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (UHPLC-Q-TOF-MS/MS) was utilized to characterize the metabolism of biochanin A in vivo and in vitro. As a result, 43 metabolites in rats, 22 metabolites in liver microsomes and 18 metabolites in intestinal flora were elucidated, and 5 metabolites were identified by comparison with standards. Oxidation, demethylation, hydrogenation, internal hydrolysis, conjugation (e.g., glucuronidation, sulfonation, glucose conjugation, methylation and acetylation) and their composite reactions were determined to be the major processes involved in biochanin A biotransformation. The results contribute to a better understanding of the pharmacological mechanism of biochanin A and provide a basis for comprehension of the safety and toxicity of biochanin A.

13.
Nat Prod Res ; : 1-6, 2019 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-31542946

RESUMO

Two new lanostane-type triterpenoids characterized with farnesyl hydroquinone moieties, ganocalidoins A (1) and B (2), were isolated from the fruiting body of Ganoderma calidophilum, together with two known tripterpenes (3-4). The structures of compounds 1 and 2 were determined by extensive spectroscopic data including HRESIMS, 1D and 2D NMR. Ganocalidoins A and B showed anti-oxidant capacity with IC50 values of 38.7 ± 2.8 and 34.2 ± 1.8 µM, respectively. The compounds did not show tyrosinase inhibition activity.

14.
Anal Chim Acta ; 1084: 43-52, 2019 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-31519233

RESUMO

In this work, oxygenated carbon nitride nanosheets (OCNNSs) were first introduced to the field of analytic chemistry for solid-phase microextraction (SPME). The rich hydroxyl and carboxyl contents of OCNNSs provided abundant adsorption sites. The coated stainless steel fibers, synthesized by the layer-by-layer chemical bonding method, had good chemical stability (in organic solvents), long life (durability ≥ 150 cycles), and good reproducibility (RSDs ≤ 9.2%). This novel OCNNSs-coated fiber was used for SPME with gas chromatography-mass spectrometry (GC-MS) for the analysis of phthalic acid esters (PAEs) in three types of food products (seafood, samshu, and instant noodles). Under optimal conditions, the limits of detection (LODs) for the PAEs ranged from 0.1 to 10.0 pg mL-1, and recovery was in the range of 80.0-118.1%. These novel coated SPME fibers displayed excellent separation and enrichment properties, which suggest a pretreatment application for analysis of PAEs.

15.
Surg Radiol Anat ; 2019 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-31563971

RESUMO

PURPOSE: The connective tissue between suboccipital muscles and the cervical spinal dura mater (SDM) is known as the myodural bridge (MDB). However, the adjacent relationship of the different connective tissue fibers that form the MDB remains unclear. This information will be highly useful in exploring the function of the MDB. METHODS: The adjacent relationship of different connective tissue fibers of MDB was demonstrated based upon three-dimensional visualization model, P45 plastinated slices and histological sections of human MDB. RESULTS: We found that the MDB originating from the rectus capitis posterior minor muscle (RCPmi), rectus capitis posterior major muscle (RCPma) and obliquus capitis inferior muscle (OCI) in the suboccipital region coexists. Part of the MDB fibers originate from the ventral aspect of the RCPmi and, together with that from the cranial segment of the RCPma, pass through the posterior atlanto-occipital interspace (PAOiS) and enter into the posterior aspect of the upper cervical SDM. Also, part of the MDB fibers originate from the dorsal aspect of the RCPmi, the ventral aspect of the caudal segment of the RCPma, and the ventral aspect of the medial segment of the OCI, enter the central part of the posterior atlanto-axial interspace (PAAiS) and fuse with the vertebral dura ligament (VDL), which connects with the cervical SDM. CONCLUSIONS: Our findings prove that the MDB exists as a complex structure which we termed the 'myodural bridge complex' (MDBC). In the process of head movement, tensile forces could be transferred possibly and effectively by means of the MDBC. The concept of MDBC will be beneficial in the overall exploration of the function of the MDB.

16.
J Med Primatol ; 2019 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-31478213

RESUMO

BACKGROUND: As the widely used biomarker of whole-blood stimulation assays for tuberculosis diagnosis, the release of IFN-γ might be affected by multiple factors, such as immunosuppression and some infectious agents. Here, we evaluated additional cytokines as diagnostic biomarkers. METHODS: Forty-three cytokines were measured by Luminex xMAP technologies in 30 healthy and 10 naturally Mycobacterium tuberculosis (MTB)-infected rhesus monkeys pre- and post-stimulation by purified protein derivative (PPD). RESULTS: After stimulation, production of 23 and 38 cytokines was markedly increased in healthy and MTB-infected macaques, respectively. A comparison of the stimulation index (SI) between MTB infections and healthy macaques showed that the SIs of 32 cytokines in MTB-infected macaques were significantly higher than those in healthy macaques. Pooling the results, eight cytokines were suggested as ideal biomarkers for a whole-blood stimulation assay for MTB diagnosis. CONCLUSION: PPD could induce multiple cytokine responses in either healthy or MTB-infected monkeys, and eight cytokines had reliable predictive capacity as diagnostic biomarkers of MTB infection.

17.
Nat Commun ; 10(1): 4153, 2019 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-31515478

RESUMO

Respiratory syncytial virus (RSV) infection is the leading cause of hospitalization and infant mortality under six months of age worldwide; therefore, the prevention of RSV infection in all infants represents a significant unmet medical need. Here we report the isolation of a potent and broadly neutralizing RSV monoclonal antibody derived from a human memory B-cell. This antibody, RB1, is equipotent on RSV A and B subtypes, potently neutralizes a diverse panel of clinical isolates in vitro and demonstrates in vivo protection. It binds to a highly conserved epitope in antigenic site IV of the RSV fusion glycoprotein. RB1 is the parental antibody to MK-1654 which is currently in clinical development for the prevention of RSV infection in infants.

18.
J Periodontol ; 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31487049

RESUMO

BACKGROUND: Occlusal trauma is an important factor promoting bone loss caused by periodontal diseases. Although there are reports of traumatic force promoting bone resorption in periodontal diseases, no studies examining the inhibition of bone formation by traumatic force and the underlying mechanism have been reported. The aim of this study was to investigate the mechanism whereby traumatic force inhibits bone formation. METHODS: MC3T3-E1 cells were induced to undergo osteogenic differentiation and subjected to cyclic uniaxial compressive stress with or without stimulation with Pg. LPS. The expression of osteoblast markers and the activation of IKK-NF-κB signaling were evaluated in vitro. Then, MC3T3-E1 cells were induced to undergo osteogenic differentiation and subjected to cyclic uniaxial compressive stress with or without IKK-2 Inhibitor VI. The expression of osteoblast markers was determined. Then, the classic Wnt signaling pathway (ß-catenin, Gsk3ß, p-Gsk3ß, and Dkk1) was further evaluated in vitro. Finally, occlusal trauma was induced in Wistar rats with or without the injection of IKK-2 Inhibitor VI, to evaluate changes in bone mass and IKK-NF-κB and Wnt/ß-catenin signaling in vivo. RESULTS: After stimulation with Pg. LPS and traumatic force, IKK-NF-κB signaling was significantly activated in vitro. The expression of osteoblast markers and the activity of alkaline phosphatase in MC3T3-E1 cells declined after traumatic force loading and were rescued when IKK-NF-κB signaling was blocked. Wnt/ß-catenin signaling was accordingly inhibited upon force loading, but this inhibition was reversed when IKK-NF-κB was antagonized in vitro. X-ray and Micro-CT analysis of the mandibles of the rats as well as HE and TRAP staining showed that bone loss induced by occlusal trauma declined after IKK-NF-κB was inhibited. The expression of p65 and IκBα was increased when occlusal trauma was induced in Wistar rats, whereas ß-catenin, OCN, and Runx2 levels were decreased. After blocking IKK-NF-κB, significant upregulation of ß-catenin, OCN, and Runx2 was observed in rats suffering from occlusal trauma. CONCLUSIONS: IKK-NF-κB signaling could be activated by traumatic force or occlusal trauma. Its activation promoted the degradation of ß-catenin, ultimately inhibiting osteogenic differentiation in vitro and bone formation in vivo.

19.
MAbs ; 11(8): 1415-1427, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31402751

RESUMO

Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infection in young children and older adults. Currently, no licensed vaccine is available, and therapeutic options are limited. The primary target of neutralizing antibodies to RSV is the surface fusion (F) glycoprotein. Understanding the recognition of antibodies with high neutralization potencies to RSV F antigen will provide critical insights in developing efficacious RSV antibodies and vaccines. In this study, we isolated and characterized a panel of monoclonal antibodies (mAbs) with high binding affinity to RSV prefusion F trimer and neutralization potency to RSV viruses. The mAbs were mapped to previously defined antigenic sites, and some that mapped to the same antigenic sites showed remarkable diversity in specificity, binding, and neutralization potencies. We found that the isolated site III mAbs shared highly conserved germline V-gene usage, but had different cross-reactivities to human metapneumovirus (hMPV), possibly due to the distinct modes/angles of interaction with RSV and hMPV F proteins. Furthermore, we identified a subset of potent RSV/hMPV cross-neutralizing mAbs that target antigenic site IV and the recently defined antigenic site V, while the majority of the mAbs targeting these two sites only neutralize RSV. Additionally, the isolated mAbs targeting site Ø were mono-specific for RSV and showed a wide range of neutralizing potencies on different RSV subtypes. Our data exemplify the diversity of anti-RSV mAbs and provide new insights into the immune recognition of respiratory viruses in the Pneumoviridae family.

20.
Sci Rep ; 9(1): 11046, 2019 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-31363142

RESUMO

Arteriovenous fistulae (AVF) are the most common access created for hemodialysis, but up to 60% do not sustain dialysis within a year, suggesting a need to improve AVF maturation and patency. In a mouse AVF model, Akt1 regulates fistula wall thickness and diameter. We hypothesized that inhibition of the Akt1-mTORC1 axis alters venous remodeling to improve AVF patency. Daily intraperitoneal injections of rapamycin reduced AVF wall thickness with no change in diameter. Rapamycin decreased smooth muscle cell (SMC) and macrophage proliferation; rapamycin also reduced both M1 and M2 type macrophages. AVF in mice treated with rapamycin had reduced Akt1 and mTORC1 but not mTORC2 phosphorylation. Depletion of macrophages with clodronate-containing liposomes was also associated with reduced AVF wall thickness and both M1- and M2-type macrophages; however, AVF patency was reduced. Rapamycin was associated with improved long-term patency, enhanced early AVF remodeling and sustained reduction of SMC proliferation. These results suggest that rapamycin improves AVF patency by reducing early inflammation and wall thickening while attenuating the Akt1-mTORC1 signaling pathway in SMC and macrophages. Macrophages are associated with AVF wall thickening and M2-type macrophages may play a mechanistic role in AVF maturation. Rapamycin is a potential translational strategy to improve AVF patency.

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