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1.
J Cell Biochem ; 121(1): 497-507, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31267572

RESUMO

Patients with malignant tumors receive radiotherapy, and radiation could harm the skeletal system, leading to radiation-induced osteoporosis. A major cause of this phenomenon is the activation of osteoclasts by radiotherapy. In this study, we studied whether amifostine (AMI) could affect the differentiation of osteoclast precursor cells (RAW264.7 cells) into osteoclasts under 2 gray (Gy) radiation. Four groups were used in the experiment: (a) 0 Gy (no radiation); (b) 0 Gy + AMI; (c) 2 Gy radiation; and (d) 2 Gy radiation + AMI. After radiation, a proliferation assay, a reactive oxygen species (ROS) assay, a comet assay, Trap staining, reverse transcription polymerase chain reaction, and an animal study to test the effect of AMI on osteoclast precursor cells under 2 Gy radiation were conducted. Cell proliferation was significantly inhibited by AMI (P < .05). In addition, 2 Gy radiation led to longer "comet tails", high level of ROS, and more Trap-positive cells in vivo and in vitro (P < .05). Radiation improved the expression of CSTK, NFAT, and Rankl/OPG gene (P < .05), as well as Trap-5b levels in the serum, and decreased bone mineral density. AMI inhibited the differentiation of RAW264.7 cells, shortened the tail moment length of comets, and decreased the level of ROS induced by radiation. The expression of NFAT, CTSK, and Rankl/OPG was decreased by AMI at the detection time point in radiation groups (P < .05). AMI inhibits the maturation and differentiation of osteoclasts under radiation conditions by reducing DNA damage and ROS induced by radiation, thereby reducing the adverse effects of radiation in the skeletal system, indicating that AMI might be used to treat osteoradionecrosis.

2.
Eur J Med Chem ; : 111867, 2019 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-31757525

RESUMO

Using the principle of bioisosteric replacement, we present a structure-based design approach to obtain new Axl kinase inhibitors with significant activity at the kinase and cellular levels. Through a stepwise structure-activity relationships exploration, a series of 6,7-disubstituted quinoline derivatives, which contain 1,3,4-oxadiazol acetamide moiety as novel Linker, were ultimately synthesized with Axl as the primary target. Most of them exhibited moderate to excellent activity, with IC50 values ranging from 0.032 to 1.54 µM against the tested cell lines. Among them, the most promising compound 47e, as an Axl kinase inhibitor (IC50 = 10 nM), shows remarkable cytotoxicity against A549, HT-29, PC-3, MCF-7, H1975 and MDA-MB-231 cell lines. More importantly, 47e also shows a significant inhibitory effect on EGFR-TKI resistant NSCLC cell lines H1975/gefitinib. Meanwhile, this study provides a novel type of linker for Axl kinase inhibitors, namely 1,3,4-oxadiazol acetamide moiety, which is out of the scope of the "5- atoms role ".

3.
Int J Biol Markers ; : 1724600819882940, 2019 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-31603383

RESUMO

BACKGROUND: Cytidine deaminase (CDA) polymorphisms may affect the response to gemcitabine/cisplatin chemotherapy in patients with non-small cell lung cancer (NSCLC). This study is designed to investigate the associations of CDA-79A>C and 208G>A polymorphisms and gemcitabine/cisplatin chemotherapy effectiveness in Xinjiang Uyghur and Han patients. METHODS: This prospective cohort study enrolled consecutive patients with stage IIIb/IV NSCLC administered gemcitabine/cisplatin chemotherapy at the First Affiliated Hospital, Medical College of Shihezi University and the First People's Hospital, Kashgar Region. CDA-A79C and CDA-G208A polymorphisms were detected by direct sequencing. Progression-free survival was analyzed by the Kaplan-Meier method. Associations of A79C and G208A polymorphisms with treatment effectiveness and progression-free survival were analyzed using logistic regression and multivariate Cox regression analyses. Subgroup analyses based on ethnicity were performed. RESULTS: The study enrolled 120 patients. A79C and G208A polymorphisms followed the Hardy-Weinberg equilibrium. The frequencies of the AA, AC, and CC genotypes and the A and C alleles of A79C were 52.2%, 29.9%, 17.9%, 67.2%, and 32.8%, respectively, in Han patients and 75.4%, 18.9%, 5.7%, 84.9%, and 5.1%, respectively, in Uyghur patients. Uyghur patients had lower frequencies of A79C-AC/CC genotypes, A79C-C allele, G208A-GA genotype, and G208A-A allele (P<0.05). Compared with A79C-AA, the odds of ineffective chemotherapy were increased for A79C-AC (odds ratio [OR] 2.818; 95% confidence interval [95% CI] 1.031, 7.705; P=0.043) and A79C-CC (OR 9.864; 95% CI 1.232, 78.966; P=0.031). G208A polymorphisms did not influence chemotherapy effectiveness. Chemotherapy was more effective in Han patients than in Uyghur patients for A79C-AC and G208A-GG. Progression-free survival was longer for A79C-AA versus A79C-AC/CC (10 vs. 7 months, P=0.004) and G208A-GA/AA vs. G208A-AA (12 vs. 8 months, P=0.010). Polymorphisms of A79C (hazard ratio [HR] 1.617; 95% CI 1.009, 2.592; P=0.046) and G208A (HR 2.193; 95% CI 1.055, 4.557; P=0.035) were associated with progression-free survival. CONCLUSION: For Uyghur and Han ethnic groups, A79C and G208A polymorphisms can be used as a promising biomarker for the chemotherapy efficacy and prognosis of NSCLC.

4.
Bioorg Med Chem Lett ; 29(23): 126666, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31629631

RESUMO

A series of novel 4-phenoxyquinoline derivatives containing 3-oxo-3,4-dihydro-quinoxaline moiety were synthesized and evaluated for their antiproliferative activity against five human cancer cell lines (A549, H460, HT-29, MKN-45 and U87MG) in vitro. Most of the tested compounds exhibited more potent inhibitory activities than the positive control foretinib. Compound 1b, 1s and 1t were further examined for their inhibitory activity against c-Met kinase. The most promising compound 1s (with c-Met IC50 value of 1.42 nM) showed remarkable cytotoxicity against A549, H460, HT-29, MKN45 and U87MG cell lines with IC50 values of 0.39 µM, 0.18 µM, 0.38 µM, 0.81 µM, respectively. Their preliminary structure-activity relationships (SARs) study indicated that the replacement of the aromatic ring with the cyclohexane improved their antiproliferative activity.

5.
J Physiol Sci ; 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31487015

RESUMO

In the diabetic brain, hyperglycemia damages the cerebrovasculature and impairs neurovascular crosstalk. Calcitonin gene-related peptide (CGRP) is an important neuropeptide that is active in the vascular system. In this study, we aimed to investigate whether CGRP is involved in the high-glucose-induced damage in mouse cerebral microvascular endothelial (b.END3) cells and the possible mechanism in vitro. The overexpression of CGRP by lentiviral transduction inhibited cell apoptosis but not proliferation. In contrast to the promoting of angiogenesis and migration under normal glucose, CGRP inhibited hyperglycemia-induced tube formation but had no effect on migration. Calcitonin gene-related peptide partly reduced the increased level of intracellular reactive oxygen species (ROS) and altered nitric oxide synthase mRNA expression. Furthermore, CGRP suppressed the increased HIF-1α/VEGF-A expression and the phosphorylation of ERK1/2 in hyperglycemia. The ERK inhibitor U0126 showed similar inhibition of cell apoptosis, tube formation and HIF-1α/VEGF expression as that exhibited by lenti-CGRP. These findings demonstrate the protective role of CGRP overexpression against high-glucose-induced cerebrovascular changes in b.END3 cells, possibly through the inhibition of ERK/HIF-1/VEGF signaling.

6.
Hua Xi Kou Qiang Yi Xue Za Zhi ; 37(4): 350-354, 2019 Aug 01.
Artigo em Chinês | MEDLINE | ID: mdl-31512824

RESUMO

OBJECTIVE: To investigate the effect of platelet-derived growth factor (PDGF) on nerve regeneration in peri-implant tissues. METHODS: SD rats with implants in their femurs were injected with PDGF solution. The effects of PDGF on nerve regeneration in peri-implant tissues were analyzed by immunohistochemical staining. RESULTS: PDGF increased the number of nerve fibers in peri-implant tissues at early stage. PDGF had no significant effect on the number of nerve fibers in peri-implant tissues at late stage. Moreover, these nerves had a typical structure of peripheral nerve fibers. CONCLUSIONS: PDGF can promote nerve regeneration in peri-implant tissues at early stage. This study provided a certain experimental basis for the clinical application of PDGF to promote nerve regeneration and further improve the sensory function of the implant.


Assuntos
Implantes Dentários , Fator de Crescimento Derivado de Plaquetas , Animais , Fibras Nervosas , Regeneração Nervosa , Ratos , Ratos Sprague-Dawley
7.
Ultrasound Med Biol ; 45(12): 3128-3136, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31530420

RESUMO

Tumor angiogenesis plays an important role during breast tumor growth. However, conventional Doppler has limited sensitivity to detect small blood vessels, resulting in a large overlap of Doppler features between benign and malignant tumors. An ultrasensitive ultrasound microvessel imaging (UMI) technique was recently developed. To evaluate the performance of UMI, we studied 44 patients with 51 breast masses. Tumor pathology served as the gold standard: 28 malignancies and 23 benignities. UMI provided a significant improvement in depicting smaller vessels compared with conventional Doppler. The microvessel morphologies observed on UMI were associated with tumor benign/malignant classification. The diagnostic accuracy of correct Breast Imaging Reporting and Data System (BI-RADS) classification rate (BI-RADS ≥4a: test positive; BI-RADS ≤3: test negative) as a fraction of total mass population was improved by 16% after combining conventional ultrasound with UMI compared with using conventional ultrasound alone. This improvement indicates the potential of UMI in reducing unnecessary benign biopsies and avoiding missed malignant biopsies.

8.
Bioorg Med Chem Lett ; 29(19): 126630, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31466809

RESUMO

FMS-like tyrosine kinase 3 (FLT3) was an important therapeutic target in acute myeloid leukemia (AML). We synthesized two series of 4-((6,7-dimethoxyquinoline-4-yl)oxy)aniline derivatives possessing the semicarbazide moiety and 2,2,2-trifluoro-N,N'-dimethylacetamide moiety as the linker. The cell proliferation assay in vitro against HL-60 and MV4-11 cell lines demonstrated that most series I compounds containing semicarbazide moiety had more potent than Cabozantinib. Furthermore, the enzyme assay showed that compound 12c and 12g were potent FLT3 inhibitors with IC50 values of 312 nM and 384 nM, respectively. Following that, molecular docking analysis was also performed to determine possible binding mode between FLT3 and the target compound.

9.
Artigo em Inglês | MEDLINE | ID: mdl-31406983

RESUMO

BACKGROUND: Multimorbidity has become a prominent problem worldwide; however, few population-based studies have been conducted among older Chinese with multimorbidity. This study aimed to examine the prevalence of multimorbidity and explore its common patterns among a nationally representative sample of older Chinese. METHODS: This study utilized data from the China Health and Retirement Longitudinal Study (CHARLS) and included 19,841 participants aged ≥50 years. The prevalence of individual chronic diseases and multimorbidity during 2011-2015 were evaluated among the entire cohort and according to residential regions and gender. The relationships between participants' demographic characteristics and multimorbidity were examined using logistic regression model. Patterns of multimorbidity were explored using hierarchical cluster analysis (HCA) and association rule mining (ARM). RESULTS: Multimorbidity occurred in 42.4% of the participants. The prevalence of multimorbidity was higher among women (OR=1.31, 95%CI: 1.13-1.51) and urban residents (OR=1.14, 95% CI: 1.02-1.27) than their respective counterparts after accounting for potential confounders of age, education, smoking and alcohol consumption. HCA revealed four common multimorbidity patterns: the vascular-metabolic cluster; the stomach-arthritis cluster; the cognitive-emotional cluster; and the hepatorenal cluster. Regional differences were found in the distributions of stroke and memory-related disease. Most combinations of conditions and urban-rural difference in multimorbidity patterns from HCA were also observed in ARM. CONCLUSION: The prevalence and patterns of multimorbidity vary by gender and residential regions among older Chinese. Women and urban residents are more vulnerable to multimorbidity. Future studies are needed to understand the mechanisms underlying the identified multimorbidity patterns and their policy and interventional implications.

10.
Peptides ; 121: 170121, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31386894

RESUMO

Endothelial dysfunction is considered to be an initial indicator in diabetes-induced macrovascular complications. Evidence has shown that CGRP is an important neuropeptide active in vascular system, especially in vasorelaxation. This study aimed to investigate the role of CGRP in high-glucose-induced endothelial dysfunction in rat aorta endothelial cells (RAECs). Quantitative-real time PCR and western blots were used to determine the efficiency of overexpression and interference of CGRP. After incubation with normal glucose (5.5 mM) or high glucose (33 mM), the cell viability and cell apoptosis were tested. Afterwards, the Nitric Oxide (NO) production, the mRNA expression of inducible nitric oxide synthase (iNOS), endothelial nitric oxide synthase (eNOS) and angiotensin II (Ang II) and the level of reactive oxygen species (ROS) were determined. The involvement of ERK1/2-NOX4 was determined through western blots and the translocation of p47phox was also observed via cell immunofluorescence. CGRP alleviated the high-glucose-induced cell apoptosis while CGRP did not have an obvious impact on cell viability. Meanwhile, CGRP increased the NO production as well as the eNOS mRNA expression and reversely decreased the stimulated expression of iNOS and Ang II by high glucose. In addition, CGRP attenuated the high-glucose-stimulated intracellular ROS production by ERK1/2-NOX4 and the translocation of p47phox. These results indicated the protective role of CGRP in high-glucose-induced oxidative injury in RAECs possibly through inhibiting ERK1/2-NOX4. Our findings might help to further understand the potential role and possible mechanism of CGRP in endothelial dysfunction caused by high glucose.

11.
Cell Transplant ; 28(11): 1420-1431, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31426665

RESUMO

Alpha-calcitonin gene-related peptide (αCGRP) plays a significant pathophysiological role in the regulation of bone metabolism. Our previous research indicated that αCGRP might have a potential application in enhancing osseointegration in vivo. To further uncover the intrinsic mechanism of its networks in bone regeneration, here we investigate the impact of αCGRP on osteogenic differentiation in bone marrow-derived mesenchymal stem cells (BMSCs) from both wild-type and αCGRP-/- mice. Considering the half-life of αCGRP in plasma is only 10 min, we applied αCGRP lentivirus and stably transfected it into BMSCs, followed by transfection identification and cell cycle assay. We further conducted a series of in vitro tests, and the results revealed that biological functions including migratory ability and osteogenicity exhibited positive correlation with BMSCs' αCGRP expression. Meanwhile, this phenomenon was associated with an enhanced expression of YAP (Yes-associated protein), the key downstream effector of the Hippo pathway. To sum up, our data together with previous in vivo observations is likely to elucidate the intrinsic mechanism of αCGRP in bone remodeling, and αCGRP would appear to be a novel treatment to promote bone wound healing.

12.
Bioorg Med Chem ; 27(18): 4089-4100, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31378597

RESUMO

Aiming to develop potent JAK inhibitors, two series of 4-(1H-pyrazol-4-yl)-7H-pyrrolo[2,3-d]pyrimidine derivatives (8a-8p and 11a-11i) were designed and synthesized by coalescing various N-acylpiperidine motifs with baricitinib. The pharmacological results based on enzymatic and cellular assays identified the optimized compound 11e, which exerted over 90% inhibition rates against JAK1 and JAK2, and displayed the most compelling anti-inflammatory efficacy superior to baricitinib by inhibiting NO generation from LPS-induced RAW264.7 macrophages. Importantly, low cytotoxity of 11e was revealed by the IC50 value of 88.2 µM against normal RAW264.7 cells. The binding mode of 11e with JAK1 and JAK2 identified the essential structural bases in accord with SARs analysis. Furthermore, cellular morphology observation and western blot analysis disclosed the ability of 11e to relieve cells inflammatory damage by significantly down-regulating LPS-induced high expression of JAK1, JAK2, as well as pro cytokine IL-1ß. Together, 11e was verified as a promising lead for JAK inhibitors for the treatment of inflammatory diseases.

13.
Microbiol Immunol ; 63(10): 427-437, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31313848

RESUMO

Bovine mastitis is the most common disease in dairy cattle. Bacterial infections are the main cause of mastitis. Lipopolysaccharide (LPS), a major structural component of the cell wall of Escherichia coli, is a good inducer used to replicate inflammation models. 8-Methoxypsoralen (8-MOP), a formerly considered photosensitizing agent, has been used in immunotherapy. This study investigated the protective effects of 8-MOP on LPS-induced inflammatory injury in bovine mammary epithelial cells (BMECs). LPS treatment (50 µg/mL for 12 hr) caused a decrease in cell viability, morphological damage, and cell apoptosis. Pretreatment with 8-MOP at concentrations of 25 and 50 µg/ml significantly attenuated LPS-induced inflammation in BMECs. qRT-PCR analysis revealed that the messenger RNA expression of inflammatory cytokines and chemokine (interleukin-1ß [IL-1ß], IL-6, tumor necrosis factor-α, and IL-8) was suppressed by 8-MOP in LPS-stimulated BMECs. Western blot analysis showed that 8-MOP could also reduce the protein levels of cyclooxygenase-2 and promote the translocation of high-mobility group box 1 from the nucleus to cytoplasm. Furthermore, the anti-inflammatory property of 8-MOP was mediated by inhibiting nuclear factor kappa-light-chain-enhancer of activated B cells activation and STAT1 phosphorylation. Taken together, 8-MOP could protect cells from inflammatory injury induced by LPS, and may be a potential agent against bovine mastitis.

14.
J Affect Disord ; 257: 108-115, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31301610

RESUMO

BACKGROUND: Limited published research has examined the relationships of coping styles and sleep quality with anxiety symptoms in Chinese school adolescents. We aimed to explore the effect of coping styles and sleep quality on anxiety symptoms. Furthermore, we investigated the interactions of coping styles and sleep quality with anxiety symptoms. METHODS: The survey was conducted in Jiangxi Province, China. The Simplified Coping Style Questionnaire, Pittsburgh Sleep Quality Index and Chinese Secondary School Students Anxiety Scale were utilized to assess sleep quality, coping styles and anxiety symptoms, respectively. Multiple logistic regression analysis was applied to explore the relationships of coping styles and sleep quality with anxiety symptoms. RESULTS: A total of 3081 students participated in this study, 50.8% of whom were boys; the number of participants in grades 1, 2 and 3 were 979, 1085 and 1017, respectively. The prevalence of anxiety symptoms was 27.3%. Individuals with poor sleep quality were 3.558 (95% CI = 2.716-4.660) times as likely to have anxiety symptoms than those with good sleep quality. Higher negative coping style scores increased the prevalence of anxiety symptoms (OR = 2.101, 95% CI = 1.894-2.332), whereas higher positive coping style scores were related to reduced odds of anxiety symptoms (OR = 0.892, 95% CI = 0.800-0.995). Interactions of coping styles and sleep quality with anxiety symptoms were not found (all p > 0.05). The association between negative coping style and anxiety symptoms was mediated by sleep quality. LIMITATIONS: This study was cross-sectional and limited to Ganzhou City. CONCLUSIONS: The results of our study showed a higher prevalence of anxiety symptoms compared with the result of a previous study in Chinese school adolescents. Negative coping style and poor sleep quality were associated with an increased prevalence of anxiety symptoms, whereas positive coping style was related to a decreased prevalence of anxiety symptoms. Sleep quality was a mediating factor between negative coping style and anxiety symptoms.

15.
Bioorg Chem ; 90: 103086, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31280016

RESUMO

Four series of novel thieno[3,2-d]pyrimidine and quinazoline derivatives containing N-acylhydrazone or semicarbazone were designed, synthesized, and evaluated for their biological activity. Of which compound 14 showed the most potent antitumor activities with IC50 values of 1.78 µM, 1.02 µM, 1.98 µM, 0.41 µM and 0.22 µM against HT-29, MDA-MB-231, U87MG, PC-3 and HCT-116 cell lines respectively. Inhibition of enzymatic assays showed that PI3Kα was very likely to be one of the drug targets of 14 with the IC50 value of 0.20 µM. According to the results of antitumor activity, the SARs were summarized, which indicated that thieno[3,2-d]pyrimidine and semicarbazone are optimal fragments. In addition, compounds with hydroxyl group at the 4-position on the terminal phenyl ring were more active. Annexin-V and propidium iodide (PI) double staining confirmed that the most active cytotoxic compound 14 can induce cell apoptosis in HCT-116 cells. Moreover, the influence of 14 on the cell cycle distribution was assessed on the HCT-116 cell line, exhibiting a cell cycle arrest at the G2/M phase. Furthermore, molecular docking analysis was also performed to determine possible binding modes between PI3Kα and the target compound. These results will guide us to further refine the structure of the thieno[3,2-d]pyrimidine and quinazoline derivatives to achieve optimal antitumor activity.

16.
PLoS One ; 14(7): e0219939, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31318951

RESUMO

OBJECTIVES: The main objective of this study was to explore the associations of family relationships and negative life events with depressive symptoms among Chinese adolescents. METHODS: A cross-sectional study of 3081 middle school students was conducted in Ganzhou City, Jiangxi Province, China. Students were asked to complete questionnaires regarding family relationships, negative life events, and depressive symptoms. A mediation analysis was carried out using a multiple regression analysis and the PROCESS macro method. RESULTS: Of all participants, 19.9% reported experiencing depressive symptoms. The prevalence of depressive symptoms was 13.0% and 29.2% in participants with good and poor parental relationships, and the prevalence of depressive symptoms was 11.4% and 30.9% in participants with closed and alienated parental-child relationships, respectively. Parental relationships, parental-child relationships, and negative life events were positively correlated with depressive symptoms. The effect of parental relationships on depressive symptoms was fully mediated by negative life events (Effect = 0.052, 95% CI = [0.023, 0.082]), while the effect of parent-child relationships on adolescent depressive symptoms was partially mediated by negative life events (Effect = 0.075, 95% CI = [0.048, 0.104]). CONCLUSIONS: Our results showed a high prevalence of depressive symptoms in Chinese adolescents. Poor family relationships may have the potential to increase the risk of depressive symptoms, and they could affect depressive symptoms through negative life events.

17.
Curr Med Sci ; 39(3): 385-390, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31209807

RESUMO

Esophageal cancer (EC) is one of the most deadly malignant diseases. Several studies revealed that variations of the phospholipase C epsilon 1 (PLCE1) gene were associated with EC susceptibility. PLCE1 is located downstream of the epidermal growth factor receptor (EGFR) pathway. Presently, the single nucleotide polymorphisms (SNPs) of EGFR/PLCE1 genes and their associations with EC survival remain unclear. In this study, the associations between genetic variants in the EGFR/PLCE1 pathway and prognosis in 124 esophageal squamous cell carcinoma (ESCC) patients with radical resection were explored. The results showed that CC genotype of both PLCE1 rs17109671 and EGFR rs2072454 was associated with ESCC prognosis. Multivariate analysis revealed that patients with the two unfavorable genotypes had the worst overall survival (OS) or disease-free survival (DFS) (HR=6.099, 95%CI=1.903-19.552; HR=3.994, 95%CI=1.49-10.702, respectively). Additionally, combination of SNPs and tumor stage could better predict OS (for AUC, 0.774 vs. 0.709) and PFS (for AUC, 0.773 vs. 0.704) than tumor stage alone. In conclusion, genetic variants of the EGFR/PLCE1 may be predictors of the prognosis of ESCC after surgery. The individuals with the CC genotype of PLCE1 rs17109671 and EGFR rs2072454 should receive more aggressive treatments.

18.
Autophagy ; : 1-18, 2019 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-31223056

RESUMO

Macroautophagy/autophagy deficit induces intracellular MAPT/tau accumulation, the hallmark pathology in Alzheimer disease (AD) and other tauopathies; however, the reverse role of MAPT accumulation in autophagy and neurodegeneration is not clear. Here, we found that overexpression of human wild-type full-length MAPT, which models MAPT pathologies as seen in sporadic AD patients, induced autophagy deficits via repression of autophagosome-lysosome fusion leading to significantly increased LC3 (microtubule-associated protein 1 light chain 3)-II and SQSTM1/p62 (sequestosome 1) protein levels with autophagosome accumulation. At the molecular level, intracellular MAPT aggregation inhibited expression of IST1 (IST1 factor associated with ESCRT-III), a positive modulator for the formation of ESCRT (the Endosomal Sorting Complex Required for Transport) complex that is required for autophagosome-lysosome fusion. Upregulating IST1 in human MAPT transgenic mice attenuated autophagy deficit with reduced MAPT aggregation and ameliorated synaptic plasticity and cognitive functions, while downregulating IST1 per se induced autophagy deficit with impaired synapse and cognitive function in naïve mice. IST1 can facilitate association of CHMP2B (charged multivesicular body protein 2B) and CHMP4B/SNF7-2 to form ESCRT-III complex, while lack of IST1 impeded the complex formation. Finally, we demonstrate that MAPT accumulation suppresses IST1 transcription with the mechanisms involving the ANP32A-regulated mask of histone acetylation. Our findings suggest that the AD-like MAPT accumulation can repress autophagosome-lysosome fusion by deregulating ANP32A-INHAT-IST1-ESCRT-III pathway, which also reveals a vicious cycle of MAPT accumulation and autophagy deficit in the chronic course of AD neurodegeneration.Abbreviations: AAV: adeno-associated virus; Aß: ß-amyloid; aCSF: artificial cerebrospinal fluid; AD: Alzheimer disease; ANP32A: acidic nuclear phosphoprotein 32 family member A; ATG: autophagy related; AVs: autophagic vacuoles; CEBPB: CCAAT enhancer binding protein beta; CHMP: charged multivesicular body protein; DMEM: Dulbecco's modified eagle's medium; EBSS: Earle's balanced salt solution; EGFR: epidermal growth factor receptor; ESCRT: endosomal sorting complex required for transport; fEPSPs: field excitatory postsynaptic potentials; GAPDH: glyceraldehyde-3-phosphate dehydrogenase; GSK3B: glycogen synthase kinase 3 beta; HAT: histone acetyl transferase; HDAC: histone deacetylase; INHAT: inhibitor of histone acetyl transferase; IST1: IST1 factor associated with ESCRT-III; LAMP2: lysosomal associated membrane protein 2; LTP: long-term potentiation; MAP1LC3: microtubule associated protein 1 light chain 3; MAPT/tau: microtubule associated protein tau; MVB: multivesicular bodies; MWM: Morris water maze; PBS: phosphate-buffered saline solution; RAB7: member RAS oncogene family; SNAREs: soluble N-ethylmaleimide-sensitive factor attachment protein receptors; SQSTM1/p62: sequestosome 1.

19.
Bioorg Med Chem ; 27(14): 3135-3144, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31178268

RESUMO

Two series of novel aryl-acrylic derivatives were designed, synthesized, and screened in enzymatic and cellular inhibitory activities. All compounds showed moderate to significant potency. The SAR analyses indicated that the semicarbazone linker is better than the 1,2,3-triazole linker. Among semicarbazone compounds that R1 bearing di-chain amino groups exhibited superior activities to those with morpholino group. Furthermore, compounds with electron-withdrawing groups at the 2-position or 4-position on the terminal phenyl ring were more active. Among these, compounds 7g, 7i, 7m and 7n exhibited the inhibitory potency in the low micromolar range and displayed negligible level of cytotoxicity against normal HeLa cells. In addition, the study suggested that the aryl-acrylic is an interesting novel scaffold for IDO1 inhibition for further development.

20.
Technol Health Care ; 27(S1): 357-365, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31045553

RESUMO

Dexamethasone (DEX) is associated with many inflammation and metabolic diseases. We analyzed the effects of DEX on the expression of estrogen metabolism enzyme 17ß-HSD1 at the optic nerve. Rats were treated with different concentrations of intraperitoneal DEX. Western Blot analysis showed that 17ß-HSD protein was expressed in the optic nerve tissue. The enzyme was detected by immunohistochemistry on the terminal foot of Muller cells from the ganglion cell layer of rat retina. ELISA analysis showed that the 17ß-HSD1 protein expression of DEX-treated group is 2.4 fold comparing to the control group. The results indicated that DMXS sodium phosphate might modulate the expression of 17ß-HSD1 protein in optic tissue. This study sheds light on understanding of the relationship among DEX, 17ß-HSD presence and distribution of visual neural systems. At the same time, DEX treatment affects the athletic ability and memory of the animals. Compared with the control group, the experimental group showed slow response to stimulation, inertia, depression, cowardice and lack of appetite. The results of ethology experiments showed that all the parameters decreased by 15-30%.

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