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1.
Chin Med J (Engl) ; 2020 Mar 05.
Artigo em Inglês | MEDLINE | ID: mdl-32149773

RESUMO

BACKGROUND: At the end of 2019, a novel coronavirus outbreak emerged in Wuhan, China, and its causative organism has been subsequently designated the 2019 novel coronavirus (2019-nCoV). The virus has since rapidly spread to all provinces and autonomous regions of China, and to countries outside of China. Patients who become infected with 2019-nCoV may initially develop mild upper respiratory tract symptoms. However, a significant fraction of these patients goes on to subsequently develop serious lower respiratory disease. The effectiveness of adjunctive glucocorticoid therapy uses in the management of 2019-nCoV infected patients with severe lower respiratory tract infections is not clear, and warrants further investigation. METHODS: The present study will be conducted as an open-labelled, randomised controlled trial. We will enrol 48 subjects from Chongqing Public Health Medical Center. Each eligible subject will be assigned to an intervention group (methylprednisolone via intravenous injection at a dose of 1-2mg/kg/day for 3 days) or a control group (no glucocorticoid use) randomly, at a 1:1 ratio. Subjects in both groups will be invited for 28 days of follow-up which will be scheduled at 4 consecutive visit points. We will use the clinical improvement rate as our primary endpoint. Secondary endpoints include the timing of clinical improvement after intervention, duration of mechanical ventilation, duration of hospitalization, overall incidence of adverse events, as well as rate of adverse events at each visit, and mortality at 2 and 4 weeks. DISCUSSION: The present coronavirus outbreak is the third serious global coronavirus outbreak in the past two decades. Oral and parenteral glucocorticoids have been used in the management of severe respiratory symptoms in coronavirus-infected patients in the past. However, there remains no definitive evidence in the literature for or against the utilization of systemic glucocorticoids in seriously ill patients with coronavirus-related severe respiratory disease, or indeed in other types of severe respiratory disease. In this study, we hope to discover evidence either supporting or opposing the systemic therapeutic administration of glucocorticoids in severe coronavirus disease 2019 (COVID-19) patients. TRIAL REGISTRATION: ClinicalTrials.gov, ChiCTR2000029386, http://www.chictr.org.cn/showproj.aspx?proj=48777.

2.
Sci Adv ; 6(8): eaaw9960, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32128390

RESUMO

Triple-negative breast cancer (TNBC) is life-threatening because of limited therapies and lack of effective therapeutic targets. Here, we found that moesin (MSN) was significantly overexpressed in TNBC compared with other subtypes of breast cancer and was positively correlated with poor overall survival. However, little is known about the regulatory mechanisms of MSN in TNBC. We found that MSN significantly stimulated breast cancer cell proliferation and invasion in vitro and tumor growth in vivo, requiring the phosphorylation of MSN and a nucleoprotein NONO-assisted nuclear localization of phosphorylated MSN with protein kinase C (PKC) and then the phosphorylation activation of CREB signaling by PKC. Our study also demonstrated that targeting MSN, NONO, or CREB significantly inhibited breast tumor growth in vivo. These results introduce a new understanding of MSN function in breast cancer and provide favorable evidence that MSN or its downstream molecules might serve as new targets for TNBC treatment.

3.
Arterioscler Thromb Vasc Biol ; : ATVBAHA120314033, 2020 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-32188273

RESUMO

OBJECTIVE: TMEM55B (transmembrane protein 55B) is a phosphatidylinositol-(4,5)-bisphosphate (PI[4,5]P2) phosphatase that regulates cellular cholesterol, modulates LDLR (low-density lipoprotein receptor) decay, and lysosome function. We tested the effects of Tmem55b knockdown on plasma lipids in mice and assessed the roles of LDLR lysosomal degradation and change in (PI[4,5]P2) in mediating these effects. Approach and Results: Western diet-fed C57BL/6J mice were treated with antisense oligonucleotides against Tmem55b or a nontargeting control for 3 to 4 weeks. Hepatic Tmem55b transcript and protein levels were reduced by ≈70%, and plasma non-HDL (high-density lipoprotein) cholesterol was increased ≈1.8-fold (P<0.0001). Immunoblot analysis of fast protein liquid chromatography (FPLC) fractions revealed enrichment of apoE-containing particles in the LDL size range. In contrast, Tmem55b knockdown had no effect on plasma cholesterol in Ldlr-/- mice. In primary hepatocytes and liver tissues from Tmem55b knockdown mice, there was decreased LDLR protein. In the hepatocytes, there was increased lysosome staining and increased LDLR-lysosome colocalization. Impairment of lysosome function (incubation with NH4Cl or knockdown of the lysosomal proteins LAMP1 or RAB7) abolished the effect of TMEM55B knockdown on LDLR in HepG2 cells. Colocalization of the recycling endosome marker RAB11 (Ras-related protein 11) with LDLR in HepG2 cells was reduced by 50% upon TMEM55B knockdown. Finally, knockdown increased hepatic PI(4,5)P2 levels in vivo and in HepG2 cells, while TMEM55B overexpression in vitro decreased PI(4,5)P2. TMEM55B knockdown decreased, whereas overexpression increased, LDL uptake in HepG2 cells. Notably, TMEM55B overexpression effect was reversed by incubation with PI(4,5)P2. Conclusions: These findings indicate a role for TMEM55B in regulating plasma cholesterol levels by affecting PI(4,5)P2-mediated LDLR lysosomal degradation.

4.
Theranostics ; 10(5): 2405-2421, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32104513

RESUMO

Rationale: NOTCH4 receptor has been implicated in triple-negative breast cancer (TNBC) development and breast cancer stem cell (BCSC) regulation. However, the potential of NOTCH4 as a BCSC marker and the underlying mechanisms remain unclear. Methods: In this study, we determined the expression and activation of NOTCH4 in breast cancer cell lines and tumor samples by qRT-PCR, western blotting and immunohistochemistry. Subsequently, in vitro and in vivo serial dilution experiments were performed to demonstrate the application of NOTCH4 as an efficient mesenchymal-like (ML)-BCSC marker in TNBC. Stable overexpression of activated NOTCH4 and knockdown cell lines were established using lentivirus. RNA-seq and qRT-PCR were employed to reveal the downstream effectors of NOTCH4, followed by dual-luciferase reporter and chromatin immunoprecipitation assays to identify the genuine binding sites of NOTCH4 on SLUG and GAS1 promoters. Transwell assay, mammosphere formation and chemoresistance experiments were performed to determine the effects of SLUG, GAS1 and NOTCH4 on the mesenchymal-like characteristics of TNBC cells. Survival analysis was used to study the relation of NOTCH4, SLUG and GAS1 with prognosis of breast cancer. Results: NOTCH4 is aberrantly highly expressed and activated in TNBC, which contributes to the maintenance of ML-BCSCs. Furthermore, NOTCH4 shows significantly higher efficiency in labeling ML-BCSCs than the currently commonly used CD24-CD44+ marker. Mechanistically, NOTCH4 transcriptionally upregulates SLUG and GAS1 to promote EMT and quiescence in TNBC, respectively. The effects of NOTCH4 can be mimicked by simultaneous overexpression of SLUG and GAS1. Moreover, SLUG is also involved in harnessing GAS1, a known tumor suppressor gene, via its anti-apoptotic function. Conclusions: Our findings reveal that the NOTCH4-SLUG-GAS1 circuit serves as a potential target for tumor intervention by overcoming stemness of ML-BCSCs and by conquering the lethal chemoresistance and metastasis of TNBC.

5.
Adv Exp Med Biol ; 1231: 53-65, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32060846

RESUMO

CCL20, as a chemokine, plays an important role in rheumatoid arthritis, psoriasis, and other diseases by binding to its receptor CCR6. Recent 10 years' research has demonstrated that CCL20 also contributes to the progression of many cancers, such as liver cancer, colon cancer, breast cancer, pancreatic cancer, and gastric cancer. This article reviews and discusses the previous studies on CCL20 roles in cancers from the aspects of its specific effects on various cancers, its remodeling on tumor microenvironment (TME), its synergistic effects with other cytokines in tumor microenvironment, and the specific mechanisms of CCL20 signal activation, illustrating CCL20 signaling in TME from multiple directions.


Assuntos
Quimiocina CCL20/metabolismo , Neoplasias/metabolismo , Transdução de Sinais , Microambiente Tumoral , Animais , Humanos , Receptores CCR6/metabolismo
6.
J Exp Bot ; 71(6): 2072-2084, 2020 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-31925954

RESUMO

The effect of shading during seed development on subsequent germination remains largely unknown. In this study, two soybean (Glycine max) seed production systems, monocropping (MC) and maize-soybean intercropping (IC), were employed to examine the effects of shading of the mother plant on subsequent seed germination. Compared to the MC soybean seeds, which received light, the developing IC seeds were exposed to shade resulting from the taller neighboring maize plants. The IC seeds germinated faster than the MC seeds, although there was no significant difference in the thickness of the seed coat. The concentration of soluble pro-anthocyanidin in the IC seed coat was significantly lower than that in the MC seed coat. Changes in the concentrations of several types of fatty acids in IC seeds were also observed, the nature of which were consistent with the effect on germination. The expression levels of genes involved in abscisic acid (ABA) biosynthesis were down-regulated in IC seeds, while the transcription levels of the genes related to gibberellin (GA) biosynthesis were up-regulated. This was consistently reflected in decreased ABA concentrations and increased active GA4 concentrations in IC seeds, resulting in an increased GA4/ABA ratio. Our results thus indicated that shading of the mother plant during seed development in soybean promoted subsequent germination by mediating the biosynthesis of pro-anthocyanidins, fatty acids, and phytohormones.

7.
Acta Pharmacol Sin ; 41(2): 181-191, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31142800

RESUMO

Breast cancer resistance protein (BCRP) is one of ATP-binding cassette (ABC) transporters in brain microvessel endothelial cells that transport their substrates from brain to blood, thus limiting substrates to crossing into brain through blood-brain barrier. Our previous works show that bile duct ligation (BDL) impairs expression and function of brain BCRP in rats. Since zidovudine (AZT) is BCRP substrate, we investigated whether impaired expression and function of BCRP increased brain distribution and toxicity of AZT in BDL-D7 rats. After administration of AZT (10 mg/kg, i.v.), BDL markedly increased brain AZT concentrations, compared with sham-operated (SO) rats. The ratio of AZT brain-to-plasma area under concentration curve (AUC) in BDL rats was increased to 1.6-folds of SO rats. After treatment with AZT (100 mg/kg every day, i.v.) for 7 days, BDL significantly impaired cognitive functions compared with SO rats, evidenced by the significantly decreased percentage of alternation in Y-maze test and prolonged escaped latency in two-way passive avoidance trial. Furthermore, AZT treatment caused significant decrease in copies of mitochondrial DNA and mitochondrial membrane potential in hippocampus of BDL rats. Moreover, AZT treatment caused a significant decrease of cortex microtubule-associated protein 2 and hippocampus synaptophysin levels in BDL rats. AZT-induced CNS adverse alterations in BDL rats were not observed in SO rats treated with AZT. In conclusion, BDL decreases the function and expression of brain BCRP in rats, leading to increased brain distribution of AZT, which in turn enhances AZT CNS toxicity, leading to mitochondrial dysfunction, neuronal damage, and ultimately cognitive dysfunction.

8.
Eur J Radiol ; 123: 108777, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31855655

RESUMO

PURPOSE: To characterize brown adipose tissue (BAT) in polycystic ovary syndrome (PCOS) patients in comparison to healthy subjects using Z-spectral imaging (ZSI). METHOD: ZSI data were collected on 19 normal control females (NCF), 17 males (NCM), and 13 PCOS patients. By fitting to multiple Lorentzian functions, ZSI provides fat-water fraction (FWF) of tissue in the supraclavicular area that can be used to differentiate between white adipose tissue (WAT), BAT, and muscle. The fraction of BAT over the total fat depot (BATf) and the average FWF in BAT or FWF(BAT) were then computed, reflecting relative BAT mass and BAT metabolism respectively. The parameters were compared among the three groups, and the correlations to Body Mass Index (BMI) were also quantified. RESULTS: There was an inverse correlation between BATf and BMI in normal subjects. The BATf of the PCOS group was significantly smaller than the NCF (P < 0.001). On the other hand, FWF(BAT) correlated linearly with BMI in healthy subjects. The PCOS group had higher FWF(BAT) than the NCF group (P < 0.001). CONCLUSIONS: Normal subjects with higher BMI show less BATf and have increased FWF(BAT), indicating relatively higher level of metabolic passive WAT depot and relatively reduced metabolism in their BAT depots. PCOS patients have the least BATf and the highest FWF(BAT), suggesting decreased BAT mass and function in PCOS. Novel imaging technique with ZSI for the characterization of BAT mass and function in PCOS may help to monitor treatment responses of PCOS therapies.

9.
Diabetes Metab Syndr Obes ; 12: 2583-2587, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31824185

RESUMO

Purpose: This study aims to report the clinical features of an infant with CGL in a Chinese Zhuang ethnic family, whose family members were discovered to carry new pathogenic mutations in the BSCL2. Patients and methods: In this study, we report clinical and molecular investigations of CGL disease in a family of 4 members (parents and two sons). We used whole exome sequencing (WES) in the family to examine the genetic cause of the disease. Results: The proband presented with skin pigmentation, hypertriglyceridemia and diabetes. WES identified a previously unreported compound heterozygous mutation in the BSCL2 (c.545_546insCCG heterozygous mutation and exon 3 heterozygous deletion) in the proband. His mother is a heterozygous carrier of the c.545_546insCCG mutation and his father and brother are carriers of the exon 3 heterozygous deletion. Conclusion: Compound heterozygous mutation of the BSCL2 (new c.545_546insCCG heterozygous mutation and new exon 3 heterozygous deletion) was detected in the proband with characteristic clinical manifestations of CGL2.

10.
Medicine (Baltimore) ; 98(40): e17127, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31577703

RESUMO

To investigate the functional connectome alterations in cerebral small-vessel disease (CSVD) patients with thalamus lacunes and its relation to cognitive impairment.This case-control study was approved by the local research ethics committee, and all participants provided informed consent. There were 14 CSVD patients with thalamus lacunes (CSVDw.), 27 without (CSVDwo.), and 34 healthy controls (HC) recruited matched for age, sex, and education to undergo a 3T resting-state functional MR examination. The whole-brain functional connectome was constructed by thresholding the Pearson correlation matrices of 90 brain regions, and the topologic properties were analyzed by using graph theory approaches. Networks were compared between CSVD patients and HC, and associations between network measures and cognitive function were tested.Compared with HC, the functional connectome in CSVDw. patients showed abnormalities at the global level and at the nodal level (P < .05, false discovery rate corrected). The network-based statistics method identified a significantly altered network consisting 6 nodes and 13 connections. Among all the 13 connections, only two connections had significant correlation with episodic memory (EM) and processing speed (PS) respectively (P < .05). The CSVDwo. patients showed no significant network alterations relative to controls (P > .05).The configurations of brain functional connectome in CSVDw. patients were perturbed but not obvious for those without, and correlated with the mild cognitive impairment, especially for EM and PS. This study suggested that lacunes on thalamus played a vital role in mediating the neural functional changes of CSVD patients.


Assuntos
Doenças de Pequenos Vasos Cerebrais/patologia , Disfunção Cognitiva/patologia , Conectoma , Leucoencefalopatias/patologia , Tálamo/patologia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Doenças de Pequenos Vasos Cerebrais/complicações , Doenças de Pequenos Vasos Cerebrais/diagnóstico por imagem , Disfunção Cognitiva/diagnóstico por imagem , Disfunção Cognitiva/etiologia , Estudos Transversais , Escolaridade , Feminino , Humanos , Processamento de Imagem Assistida por Computador , Leucoencefalopatias/complicações , Masculino , Pessoa de Meia-Idade , Avaliação Nutricional , Índice de Gravidade de Doença , Fatores Sexuais , Tálamo/diagnóstico por imagem
11.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 27(5): 1482-1489, 2019 Oct.
Artigo em Chinês | MEDLINE | ID: mdl-31607302

RESUMO

OBJECTIVE: To investigate the effects and its potential mechanism of asparaginase on proliferation, cell cycle and apoptosis of diffuse large B-cell lymphoma (DLBCL) cell lines. METHODS: CCK-8 assay was used to detect the effect of asparaginase on proliferation of DLBCL cell lines. Flow cytometry was used to analyze cell cycle and apoptosis. Western blot was used to analyze apoptosis and its potential mechanism. RESULTS: Asparaginase obviously inhibited the proliferation of multiple DLBCL cell lines and caused G0/G1 cell arrest. Furtherly, asparaginase inhibited the expression of HIF-1α which related to poor prognosis of patients with DLBCL, up-regulated the expression of DR4 and caspase 8, reduce the expression of c-FLIP. Meanwhile, asparaginase induced the expression of pro-apoptotic protein BAX and inhibited the expression of anti-apoptotic protein MCL-1. CONCLUSION: Asparaginase can inhibit the proliferation of DLBCL cell lines, cause the arrest of cells in G0/G1 and induce apoptosis via the endogenous and exogenous apoptotic pathways.


Assuntos
Linfoma Difuso de Grandes Células B , Apoptose , Asparaginase , Linhagem Celular Tumoral , Proliferação de Células , Humanos
12.
Angew Chem Int Ed Engl ; 58(48): 17277-17281, 2019 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-31553514

RESUMO

Alkynyl isocyanates have been postulated as highly reactive intermediates in synthetic chemistry. Herein, the parent molecule HC≡CNCO is isolated for the first time. In sharp contrast to the previously reported short lifetime (ca. 15 s) at room temperature, we found that HC≡CNCO has a lifetime of 55 h in the gas phase (2 mbar, 300 K) with a melting point of -79.5 °C and vaporization enthalpy (ΔHvap ) of 23.1(1) kJ mol-1 . Apart from the IR (gas, solid, and matrix), 1 H and 13 C NMR, and UV/Vis spectroscopic characterization, its photoisomerization with a acylnitrene HC≡CC(O)N and cyanoketene NCC(H)CO has been observed.

13.
Zhonghua Yi Xue Yi Chuan Xue Za Zhi ; 36(8): 844-847, 2019 Aug 10.
Artigo em Chinês | MEDLINE | ID: mdl-31400143

RESUMO

Congenital lipodystrophic diabetes (CLD) is a rare genetic disease characterized by generalized or topical subcutaneous fat loss combined with various metabolic disorders such as insulin resistance, dyslipidemia, and impaired glucose tolerance. Recent studies have discovered genes underlying the disease. Mutations of such genes are associated with adipogenic anomaly, especially regulational function of peroxisome proliferators-activated receptor γ (γPPAR) for lipid. This paper has provided a review for the main clinical symptoms, classification, pathogenic genes, molecular mechanism and the relationship between PPARγ and fat loss.


Assuntos
Diabetes Mellitus/genética , Lipodistrofia Generalizada Congênita/genética , PPAR gama/genética , Diferenciação Celular , Humanos , Resistência à Insulina , Fatores de Transcrição
14.
J Magn Reson Imaging ; 2019 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-31448477

RESUMO

BACKGROUND: Previous studies have found widespread impairment of white matter (WM) integrity and disruption of structural network connectivity in cerebral small-vessel disease, but have not evaluated these changes jointly in nondemented patients. PURPOSE: To jointly investigate the microstructural impairment of WM and the related alterations of structural network topology in nondemented cerebral small-vessel disease (CSVD-ND). STUDY TYPE: Prospective. POPULATION: Thirty-seven CSVD-ND patients and 34 elderly controls, who were age-, sex-, and education-matched. FIELD STRENGTH/SEQUENCE: 3.0T/diffusion tensor imaging (DTI). ASSESSMENT: Clinical characteristics, lacunar infarct, and white matter hyperintensity (WMH) was assessed. A multiatlas likelihood fusion (MALF) algorithm was used for DTI-based brain segmentation and network node defining. Then the alterations of WM integrity and structural network topology were investigated jointly. STATISTICAL TESTS: Student's t-test, chi-square test, Mann-Whitney U-test, linear regression, Pearson correlation, and multiple comparison correction. RESULTS: Decreased fractional anisotropy and increased trace values were observed in predefined structures (P < 0.05, familywise error rate-corrected), including major commissural fibers, projection fibers, and some association fibers. Topologically, both groups showed small-worldness. CSVD-ND patients showed reduced global and local efficiency (P < 0.001). Despite widespread impairment of WM integrity, CSVD-ND patients only showed reduced nodal efficiency in the right superior occipital gyrus and the right lingual gyrus (P < 0.05, familywise error rate-corrected). The nodal local efficiency of the right precuneus was associated with the processing speed after adjusting the effect of lacunar infarct and WMH (r = -0.499, P = 0.038). DATA CONCLUSION: WM integrity was widely impaired in nondemented CSVD patients but structural network connectivity was relatively preserved. DTI may potentially provide information for the pathophysiology of CSVD in the nondemented phase. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2019.

15.
Int J Endocrinol ; 2019: 7514802, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31467529

RESUMO

Nonalcoholic fatty liver disease (NAFLD) is one of the common diseases in the world, and it can progress from simple lipid accumulation to sustained inflammation. The present study was designed to investigate the effects and underlying mechanisms of ginsenoside Rg1 (G-Rg1) treatment on NAFLD in vitro. HepG2 cells were treated with palmitic acid (PA) to induce steatosis and inflammation and then successively incubated with G-Rg1. Lipids accumulation was analyzed by Oil Red O staining and intracellular triglyceride (TG) quantification. Inflammatory conditions were examined by quantifying the levels of cell supernatant alanine transaminase/aspartate aminotransferase (ALT/AST) and secretory proinflammatory cytokines, including IL-1ß, IL-6, and TNF-α in the cell supernatants. Quantitative RT-PCR and western blotting were used to measure the expressions of genes and proteins associated with lipogenic synthesis and inflammation, including AMP-activated protein kinase (AMPK) and nuclear factor-kappa B (NF-κB) pathways. HepG2 cells were pretreated with an AMPK inhibitor; then, Oil Red O staining and TG quantification were performed to study the lipid deposition. Phospho-AMPK (Thr172) (p-AMPK) and phospho-acetyl-CoA carboxylase (Ser79) (p-ACCα) were quantified by immunoblotting. Immunofluorescence was performed to demonstrate the nuclear translocation of NF-κB P65. The present study showed that PA markedly increased the intracellular lipid droplets accumulation and TG levels, but decreased AMPK phosphorylation and the expressions of its downstream lipogenic genes. However, G-Rg1 alleviated hepatic steatosis and reduced the intracellular TG content; these changes were accompanied by the activation of the AMPK pathway. In addition, blocking AMPK by using the AMPK inhibitor markedly abolished the G-Rg1-mediated protection against PA-induced lipid deposition in HepG2 cells. Furthermore, G-Rg1 reduced the ALT/AST levels and proinflammatory cytokines release, which were all enhanced by PA. These effects were correlated with the inactivation of the NF-κB pathway and translocation of P65 from the cytoplasm to the nucleus. Overall, these results suggest that G-Rg1 effectively ameliorates hepatic steatosis and inflammation, which might be associated with the AMPK/NF-κB pathway.

16.
J Neural Transm (Vienna) ; 126(8): 1081-1094, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31292734

RESUMO

Various studies report discordant results regarding the efficacy, parameters, and underlying mechanisms of repetitive transcranial magnetic stimulation (rTMS) combined with cognitive training (CT) on Alzheimer's disease (AD). The objective of the study was to assess the effect of rTMS-CT on cognition, the activities of daily life, neuropsychiatric behavioral symptoms, and metabolite levels beneath the stimulated areas of the brain in patients with AD and to investigate the correlation of metabolic changes (measured with proton magnetic resonance spectroscopy [1H-MRS]) with clinical outcomes after treatment. Thirty consecutive patients with mild or moderate AD were enrolled and randomly divided into one of the two intervention groups: (1) real rTMS with CT (i.e., real group) and (2) sham rTMS with CT (i.e., sham group). 10 Hz rTMS was used to stimulate the left dorsolateral prefrontal cortex (DLPFC) and then to stimulate the left lateral temporal lobe (LTL) for 20 min each day for 4 weeks. Each patient underwent neuropsychological assessment at baseline (T0), immediately after treatment (T1), and 4 weeks after treatment (T2). The ratios of N-acetylaspartate/creatine (NAA/Cr), myoinositol/creatine (mI/Cr), and choline/creatine (Cho/Cr) in the stimulated cortex were measured using 1H-MRS at T0 and T1. Twenty-eight patients were treated with rTMS-CT for 4 weeks. Two patients in the sham group withdrew after being treated several times. Compared with the sham group, the cognitive function and behavior in the real rTMS group improved significantly at T1 and T2. In the real group, compared with the sham group, the NAA/Cr ratio in the left DLPFC was significantly elevated (p = 0.045); however, in the left LTL, it only showed a tendency toward increase (p = 0.162). The change in the NAA/Cr ratio in the left DLPFC was negatively correlated with the change in the cognitive scales of the Alzheimer's Disease Assessment Scale (ADAS-cog). This study indicated a possible modest effect of rTMS-CT on preventing clinical and neuronal functional deterioration in the left DLPFC of patients with AD. The left DLPFC is a better candidate area than the left LTL.

17.
Am J Sports Med ; 47(9): 2200-2215, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31194571

RESUMO

BACKGROUND: Platelet-rich plasma (PRP) has been considered a promising tool for cartilage regeneration. However, increasing evidence has demonstrated the controversial effects of PRP on tissue regeneration, partially due to the unsatisfactory cell source. Chondrogenic progenitor cells (CPCs) have gained increasing attention as a potential cell source due to their self-renewal and multipotency, especially toward the chondrogenic lineage, and, thus, may be an appropriate alternative for cartilage engineering. PURPOSE: To compare the effects of PRP on CPC, mesenchymal stem cell (MSC), and chondrocyte proliferation, chondrogenesis, and cartilage regeneration. STUDY DESIGN: Controlled laboratory study. METHODS: Whole blood samples were obtained from 5 human donors to create PRPs (0, 1000 × 109, and 2000 × 109 platelets per liter). The proliferation and chondrogenesis of CPCs, bone marrow-derived MSCs (BMSCs), and chondrocytes were evaluated via growth kinetic and CCK-8 assays. Immunofluorescence, cytochemical staining, and gene expression analyses were performed to assess chondrogenic differentiation and cartilaginous matrix formation. The in vivo effects of CPCs, BMSCs, and chondrocytes on cartilage regeneration after PRP treatment were measured by use of histopathological, biochemical, and biomechanical techniques in a cartilage defect model involving mature male New Zealand White rabbits (critical size, 5 mm). RESULTS: The CPCs possessed migration abilities and proliferative capacities superior to those of the chondrocytes, while exhibiting a chondrogenic predisposition stronger than that of the BMSCs. The growth kinetic, CCK-8, cytochemical staining, and biochemical analyses revealed that the CPCs simultaneously displayed a higher cell density than the chondrocytes and stronger chondrogenesis than the BMSCs after PRP stimulation. In addition, the in vivo study demonstrated that the PRP+CPC construct yielded better histological (International Cartilage Repair Society [ICRS] score, mean ± SEM, 1197.2 ± 163.2) and biomechanical (tensile modulus, 1.523 ± 0.194) results than the PRP+BMSC (701.1 ± 104.9, P < .05; 0.791 ± 0.151, P < .05) and PRP+chondrocyte (541.6 ± 98.3, P < .01; 0.587 ± 0.142, P < .01) constructs at 12 weeks after implantation. CONCLUSION: CPCs exhibit superiority over MSCs and chondrocytes in PRP scaffold-based cartilage regeneration, and PRP+CPC treatment may be a favorable strategy for cartilage repair. CLINICAL RELEVANCE: These findings provide evidence highlighting the preferable role of CPCs as a cell source in PRP-mediated cartilage regeneration and may help researchers address the problem of unsatisfactory cell sources in cartilage engineering.

18.
BMC Cancer ; 19(1): 314, 2019 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-30947696

RESUMO

BACKGROUND: Mean platelet volume (MPV) is a marker of platelet activation. MPV and platelet count (PC) are negatively correlated, and their ratio (MPV/PC) is informative for the diagnosis of malignant tumors. However, the relationship between MPV/PC and colorectal cancer is unclear. This retrospective clinical study aimed to evaluate the diagnostic value of MPV/PC in colorectal cancer. METHODS: Hematological examinations were performed at initial diagnosis in patients with colorectal cancer (n = 186) or adenomatous polyp (n = 132) and healthy controls (n = 108). Hematological parameters evaluated included white blood cells, red blood cells, hemoglobin, neutrophils, lymphocytes, monocytes, PC, and MPV. Statistical analyses included Student's t-test, one-way ANOVA or Kruskal-Wallis H test, chi-square tests, Spearman's correlation test and receiver operating characteristic (ROC). ROC curve was used to evaluate the diagnostic values of MPV and MPV/PC in colorectal cancer. RESULTS: Among these groups, MPV was significantly lower in colorectal cancer than in adenomatous polyp (p = 0.002) and healthy controls (p < 0.001) but did not significantly differ between adenomatous polyp and healthy controls (p = 0.210). MPV/PC was lower in colorectal cancer compared with adenomatous polyp and healthy controls (p < 0.001) and in adenomatous polyp compared with healthy controls (p = 0.010). MPV did not significantly differ among colorectal cancer subgroups, while MPV/PC significantly differed between TNM stages and the presence/absence of lymph node metastasis. MPV/PC was negatively correlated with the neutrophil to lymphocyte ratio(NLR) (p = 0.002) and platelet to lymphocyte ratio(PLR) concentration (p < 0.001). In the differential diagnosis between colorectal cancer and adenomatous polyp, MPV/PC produced a larger ROC curve than MPV, NLR or PLR alone. Using MPV/PC to distinguish between colorectal cancer and controls produced a larger AUC than using MPV or NLR alone. CONCLUSIONS: MPV/PC may be useful for the diagnosis of colorectal cancer. However, further studies are warranted to include additional regions and more data, to assess the utility of MPV/PC as a novel diagnostic screening tool for colorectal cancer.


Assuntos
Polipose Adenomatosa do Colo/diagnóstico , Neoplasias Colorretais/diagnóstico , Volume Plaquetário Médio , Polipose Adenomatosa do Colo/sangue , Adulto , Idoso , Estudos de Casos e Controles , Neoplasias Colorretais/sangue , Feminino , Voluntários Saudáveis , Humanos , Masculino , Pessoa de Meia-Idade , Contagem de Plaquetas , Curva ROC , Estudos Retrospectivos
19.
J Phys Chem A ; 123(17): 3793-3801, 2019 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-30978289

RESUMO

Recently, nicotinoyl nitrene (2) has been generated from the photodecomposition of nicotinoyl azide (1) and used as the key intermediate in probing nucleobase solvent accessibility inside cells. Following the 266 nm laser photolysis of nicotinoyl azide (1) and isonicotinoyl azide (5) in solid N2 matrices at 15 K, nicotinoyl nitrene (2) and isonicotinoyl nitrene (6) have now been identified by matrix-isolation infrared (IR) spectroscopy. Both aroyl nitrenes 2 and 6 adopt closed-shell singlet ground states stabilized by significant Nnitrene···O interactions, which is consistent with the spectroscopic analysis and calculations at the CBS-QB3 level of theory. Upon subsequent visible light irradiations, 2 (400 ± 20 nm) and 6 (532 nm) undergo rearrangement to pyridyl isocyanates 3 and 7. Further dissociation of 3 and 7 under 193 nm laser irradiation results in CO elimination and formation of ketenimines 12 and 13 via the ring opening of elusive pyridyl nitrenes 4 and 8, respectively. In addition to the IR spectroscopic identification of 8 in the triplet ground state, its reversible photointerconversion with ring expansion to diazacycloheptatetraene 9 has been observed directly. The spectroscopic identification of the nitrene intermediates was aided by calculations at the B3LYP/6-311++G(3df,3pd) level, and the mechanism for their generation in stepwise decompositions of the azides is discussed in the light of CBS-QB3 calculations.

20.
Free Radic Biol Med ; 137: 13-23, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30978385

RESUMO

Autophagy has been reported to play protective and pathogenetic roles in cerebral ischemia/reperfusion (I/R)-induced neuronal injury. Our previous studies have shown that TP53-induced glycolysis and apoptosis regulator (TIGAR) ameliorates I/R-induced brain injury and reduces anti-cancer drug-induced autophagy activation. However, if TIGAR plays a regulatory role on autophagy in cerebral I/R injury is still unclear. The purpose of the present study is to investigate the role of TIGAR on I/R-induced autophagy activation and ischemic neuronal injury in vivo and in vitro stroke models using TIGAR-transgenic (tg-TIGAR) mice and TIGAR-knockout (ko-TIGAR) mice. The present study confirmed that autophagy was activated after I/R. Overexpression of TIGAR in tg-TIGAR mice significantly reduced I/R-induced autophagy activation and alleviated brain damage, while knockout of TIGAR in ko-TIGAR mice enhanced I/R-induced autophagy activation and exacerbated brain injury in vivo and in vitro. The different activity of autophagy in tg-TIGAR and ko-TIGAR primary neurons after OGD/R were largely reversed by knockdown or re-expression of TIGAR in these neurons. The autophagy inhibitor 3-methyladenine (3-MA) partly prevented exacerbation of brain damage induced by ko-TIGAR, whereas the autophagy inducer rapamycin partially abolished the neuroprotective effect of tg-TIGAR. Knockout of TIGAR reduced the levels of phosphorylated mTOR and S6KP70, which were blocked by 3-MA and NADPH after I/R and OGD/R in vivo and in vitro, respectively. Overexpression of TIGAR increased the levels of phosphorylated mTOR and S6KP70 under OGD/R condition, this enhancement effect was suppressed by rapamycin. In conclusion, our current data suggest that TIGAR protected against neuronal injury partly through inhibiting autophagy by regulating the mTOR-S6KP70 signaling pathway.

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