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1.
FASEB J ; 2020 Jan 16.
Artigo em Inglês | MEDLINE | ID: mdl-31950551

RESUMO

Telomerase plays a pivotal role in tumorigenesis by maintaining telomere homeostasis, a hallmark of cancer. However, the mechanisms by which telomerase is reactivated or upregulated during tumorigenesis remain incompletely understood. Here, we report that the Hippo pathway effector Yes-associated protein (YAP) regulates the expression of human telomerase reverse transcriptase (hTERT). Ectopic expression or physiological activation of YAP increases hTERT expression, whereas knockdown of YAP decreases the expression of hTERT. YAP binds to the hTERT promoter through interaction with the TEA domain family transcription factors and activates hTERT transcription. Furthermore, sustained YAP hyperactivation promotes telomerase activity and extends telomere length, with increased hTERT expression. In addition, we show that hTERT expression is positively correlated with YAP activation in human liver cancer tissues. Together, our results demonstrate that YAP promotes hTERT expression, which could contribute to tumor progression.

2.
Artigo em Inglês | MEDLINE | ID: mdl-31919567

RESUMO

PURPOSE: The impact of myeloid sarcoma (MS) on clinical outcome of pediatric acute myeloid leukemia (AML) patients remains controversial. Moreover, little is known about the role of stem cell transplantation (SCT) in such patients. METHODS: Clinical data of patients with AML under 18 years of age were retrieved from the TARGET dataset. We analyzed the prevalence, clinical profile, molecular characteristics, and prognosis of MS in these patients. RESULTS: Among 884 pediatric patients with AML, the frequency of MS was 12.3%. Pediatric AML with MS was associated with age under 1-year, abnormal cytogenetics, and KMT2A rearrangement. Moreover, MS was associated with a low complete remission rate, high induction death, poor 5-year EFS, and OS. KMT2A rearrangement had a negative impact on clinical outcome in AML patients with MS. In addition, SCT had no significant effect on the survival of AML patients with MS. Multivariate analysis revealed that MS was an unfavorable prognostic factor in pediatric AML in terms of EFS (Hazard ratio 1.670, P < 0.001) and OS (Hazard ratio 1.623, P = 0.004). CONCLUSIONS: The presence of MS at diagnosis of pediatric AML is associated with poor clinical outcomes, particularly when associated with KMT2A rearrangements. Moreover, pediatric patients with AML and MS may not benefit from SCT.

3.
Blood Cancer J ; 10(1): 1, 2020 Jan 09.
Artigo em Inglês | MEDLINE | ID: mdl-31915364

RESUMO

Studies on the clinical significance of Nucleophosmin (NPM1) mutations in pediatric AML in a large cohort are lacking. Moreover, the prognosis of patients with co-occurring NPM1 and FLT3/ITD mutations is controversial. Here, we analyzed the impact of NPM1 mutations on prognoses of 869 pediatric AML patients from the TAGET dataset. The frequency of NPM1 mutations was 7.6%. NPM1 mutations were significantly associated with older age (P < 0.001), normal cytogenetics (P < 0.001), FLT3/ITD mutations (P < 0.001), and high complete remission induction rates (P < 0.05). Overall, NPM1-mutated patients had a significantly better 5-year EFS (P = 0.001) and OS (P = 0.016) compared to NPM1 wild-type patients, and this favorable impact was maintained even in the presence of FLT3/ITD mutations. Stem cell transplantation had no significant effect on the survival of patients with both NPM1 and FLT3/ITD mutations. Multivariate analysis revealed that NPM1 mutations were independent predictors of better outcome in terms of EFS (P = 0.004) and OS (P = 0.012). Our findings showed that NPM1 mutations confer an independent favorable prognostic impact in pediatric AML despite of FLT3/ITD mutations. In addition, pediatric AML patients with both NPM1 and FLT3/ITD mutations appear to have favorable prognoses and may not need hematopoietic stem cell transplantations.

4.
J Neurol ; 2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31797084

RESUMO

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a global disease, which adversely affects the life quality of patients and significantly increases the burden of families and society. We aimed to assess the changing incidence, prevalence of ALS around the world. METHODS: We searched Medline, Embase, Web of Science, and Cochrane library to identify articles published until September 9, 2018. Each included study was independently reviewed for methodological quality by two reviewers. We used a random-effects model to summarize individual studies and assessed heterogeneity (I2) with the χ2 test on Cochrane's Q statistic. RESULTS: We identified 124 studies that were eligible for final inclusion, including 110 studies of incidence and 58 studies of prevalence. The overall crude worldwide ALS prevalence and incidence were 4.42 (95% CI 3.92-4.96) per 1,00,000 population and 1.59 (95% CI 1.39-1.81) per 1,00,000 person-years, respectively. ALS prevalence and incidence increased by age until the age of 70-79. Since 1957, incidence has been significantly rising year by year, and this upward trend was weakened after standardization. The longest survival time were in Asia (ranging from 3.74 years in South Asia to 9.23 years in West Asia). CONCLUSIONS: With the aggravation of population aging and the rapid growth of economy, developing regions following the development pattern of the developed regions may suffer rising ALS prevalence and incidence which may increase their disease burden as well. These data highlight the need for research into underlying mechanism and innovations in health-care systems.

5.
Med Sci Monit ; 25: 9409-9415, 2019 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-31820741

RESUMO

BACKGROUND We developed a model based on ultrasound (US) features of thyroid nodules and cervical lymph nodes to distinguish papillary thyroid carcinomas (PTC) from benign thyroid nodules. MATERIAL AND METHODS We retrospectively collected data on preoperative ultrasonographic characteristics and postoperative histological data from 1119 patients who underwent thyroidectomy in our center from January 2017 to January 2018. Variables of age, sex, and US features of thyroid nodule and lymph nodes features were analyzed. A logistic regression model was established for PTC prediction. RESULTS Logistic regression analysis confirmed that age under 45 years (OR=2.22, p=0.00), hypoechogenicity (OR=3.70, p=0.00), irregular shape (OR=2.13, p=0.004), ill-defined margin (OR=2.26, p=0.08), spiculate margin (OR=3.30, p=0.00), indefinite border (OR=2.45, p=0.00), capsular invasion (OR=7.76, p=0.006), taller-than-wide shape (OR=2.94, p=0.00), solid structure (OR=2.46, p=0.001), microcalcifications (OR=3.92, p=0.00), coexistence of microcalcifications and macrocalcifications (OR=5.84, p=0.006), and central vascularity (OR=2.10, p=0.001) were independently associated with increased risks for PTC, as well as lymph nodes metastasis features (absence of an echogenic hilum [OR=3.74, p=0.027] and increased vascularization [OR=3.55, p=0.086]). The area under the curve (AUC) for the risk score diagnosis system was 0.916. CONCLUSIONS This predictive model is a reliable, simple, and cost-effective diagnostic tool for PTC.

6.
Acta Biomater ; 2019 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-31812844

RESUMO

Despite many efforts in the rational design of nanoparticles (NPs) to overcome the biological barriers to small interfering RNA (siRNA) delivery for improving gene silencing efficiency, little is known about the correlations between siRNA release kinetics and RNA interference (RNAi) efficiency and inflammation therapy via oral delivery. On the basis of mannose-modified trimethyl chitosan-cysteine (MTC) polymers, seven types of MTC NPs containing tumor necrosis factor (TNF)-α siRNA were prepared through ionic gelation. The siRNA release kinetics from MTC NPs were finely tuned by adjusting the kinds and amounts of the crosslinkers involved. These MTC NPs exhibited no disparities in siRNA protection against enzymatic degradation in physiological fluids and cellular uptake in macrophages; however, they showed distinct in vitro siRNA release profiles and intracellular unpacking kinetics. MTC NPs with relatively rapid and sustained siRNA release were responsible for efficient, prompt, and prolonged RNAi, contributing to desired therapeutic efficacy in acute and chronic inflammatory murine models following oral delivery. However, MTC NPs insufficiently releasing siRNA could not elicit effective RNAi. Collectively, the present investigation might provide broad insights into the optimization of siRNA nanocarriers with respect to their release kinetics for improving RNAi efficacies aiming at different types of inflammatory diseases.

7.
Front Pharmacol ; 10: 1316, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31787897

RESUMO

Dysregulation of retinoblastoma (Rb) signaling pathway have been established as a requirement for glioblastoma (GBM) initiation and progression, which suggests that blockade of CDK4/6-Rb signaling axis for GBM treatment. Palbociclib, a selective inhibitor of the cyclin-dependent kinases CDK4/6, has been applied for breast cancer treatment. However, its efficacy against glioblastoma has not been well clarified. Here, effects of CDK4/6 inhibitors on various kinds of GBM cell lines are investigated and the functional mechanisms are identified. Data showed that cells with diverse PTEN status respond to palbociclib differently. Gain-of-function and loss-of-function studies indicated that PTEN enhanced the sensitivity of GBM cells to palbociclib in vitro and in vivo, which was associated with suppressions of Akt and ERK signaling and independent of Rb signaling inhibition. Hence, our findings support that palbociclib selectively.

8.
Transl Androl Urol ; 8(5): 442-447, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31807421

RESUMO

Background: Although immunosuppressive agents used in recipients of organ transplants can suppress T cell immune responses, type I allergy to ingested or inhaled allergens after organ transplantation have frequently been reported in pediatric patients. This study aims to investigate the relationship between the use of immunosuppressive agents and the transplant-acquired allergy (TAA) in adult renal transplant recipients (RTRs). Methods: Seventy-nine RTRs treated in our hospital from February 2015 to February 2016 were interviewed for allergic diseases by using a standard questionnaire. UniCAP allergen screening tests were performed to detect total IgE and specific IgE levels before and after renal transplantation after the use of calcineurin inhibitor tacrolimus (FK506) or cyclosporin A (CsA). The follow-up visits were scheduled for 6 months, 1 year, 2 years, and 3 years after transplantation. Results: Allergen sensitization occurred in 9 of 79 patients. Among them, the sensitization occurred in 2 cases within 6 months after renal transplantation, in 1 case from 6 months to 1 year, in 3 cases from 1 to 2 years, and in 3 cases from 2 to 3 years. The majority of sensitization was induced by inhaled allergens (n=7), among whom 3 patients (3/79, 3.8%) had a history of type I allergy, which occurred within 6 months after transplantation in 2 cases (allergic dermatitis) and from 2 to 3 years in 1 case (diarrhea after peanut allergy). The total IgE levels of RTRs using immunosuppressive agents at different time points including 6 months, 1 year, 2 years, and 3 years after renal transplantation were significantly lower than that before surgery (all P<0.05). Sensitization occurred in 8 RTRs using FK506 and in 1 patient treated with CsA (P=0.432), and allergies occurred in 3 RTRs using FK506 and were not found among CsA users (P=0.561). Conclusions: Administration of immunosuppressive agents in adult RTRs cannot wholly prevent allergy or sensitization. Studies with larger sample sizes and more extended follow-up periods are still required to further explore the potential association between the use of FK506 and CSA and the allergies or sensitization.

9.
Ann Transl Med ; 7(20): 538, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31807520

RESUMO

Background: The high incidence of post-transplant diabetes mellitus (PTDM) necessitates the identification of new factors to explain its pathogenesis. This study aimed to clarify the association between the C-peptide index (CPI) and PTDM. Methods: A total of 290 non-diabetic kidney transplant patients were analyzed. All subjects underwent a 75 g oral glucose tolerance test (OGTT). Plasma glucose concentrations, serum C-peptide levels, hemoglobin A1c (HbA1c), and other biochemical indicators were measured. CPI was calculated as the ratio of serum C-peptide to plasma glucose. Results: Among the 290 patients, 36 (12.4%) developed PTDM at the end of 1 year. Patients with PTDM had older age (P<0.001), higher levels of body mass index (BMI) (P=0.004) and HbA1c (P=0.001), a higher proportion of deceased donors (P=0.045), and lower levels of 2 h-CPI (P=0.02) than those without PTDM. The OGTT 2 h-CPI was positively correlated with BMI, HbA1c, type of calcineurin inhibitor, albumin, and triglyceride. Multivariate logistic regression and Cox hazard model analysis showed that pre-transplant OGTT 2 h-CPI was an independent predictor for the development of PTDM, together with age, BMI, and HbA1c. Conclusions: Of the pre-transplant factors studied, OGTT 2 h-CPI proved to be an independent predictor of PTDM.

10.
J Phys Chem A ; 2019 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-31825639

RESUMO

The concept of hybrid orbitals is one of the key theoretical concepts used by chemists to explain the structures and other properties of molecules. Recent work by Shaik et al. and Xu et al. found that the hybrid orbitals from modern ab initio valence bond wave functions differ significantly from traditional hybrid orbitals. We report a detailed analysis of the orbitals of methane, ethylene and acetylene from Spin-Coupled Generalized Valence Bond (SCGVB) wave functions, a variationally optimized valence bond wave function that places no constraints on the orbitals and spin function. The carbon-centered orbitals in the SCGVB wave functions are found to be 2s-2p hybrid orbitals largely localized on the carbon atom and pointed directly at the hydrogen atoms to which they are bonded. However, the SCGVB orbitals for methane, ethylene and acetylene differ markedly from the sp3, sp2 and sp hybrid orbitals traditionally associated with these molecules. It is now clear that the orbitals in modern valence bond wave functions do not follow the hybridization rules of traditional valence bond theory. These findings imply that, in modern valence bond theories, other factors are responsible for the structures and properties of molecules that are traditionally attributed to orbital hybridization.

11.
Zhongguo Zhong Yao Za Zhi ; 44(21): 4704-4712, 2019 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-31872668

RESUMO

Rosmarinic acid,a hydrosoluble polyphenolic hydroxyl compound,is the active ingredient in such traditional Chinese medicines as Menthae Haplocalycis Herba,Salviae Miltiorrhizae Radix et Rhizoma,Rosemary,Perillae Folium. Because of its good anti-inflammatory,anti-oxidant and anti-tumor effects,it is widely used in food,medicine and other fields. However,the metabolic process and metabolites of rosmarinic acid in vivo have not been completely defined. In this study,an efficient method of ultra-high performance liquid chromatography combined with linear ion trap-Orbitrap(UHPLC-LTQ-Orbitrap) mass spectrometer was used to analyze the metabolites in vivo of rosmarinic acid in rats. Plasma,urine and feces samples were collected after oral administration of rosmarinic acid. After biological samples were processed by solid phase extraction,Acquity UPLC  BEH C18 column(2. 1 mm × 100 mm,1. 7 µm) was used with 0. 1% formic acid(A)-acetonitrile(B) solution as the mobile phase at the speed of 0. 30 m L·min-1 and temperature of 35 ℃ under gradient conditions. The plasma,urine,feces and the blank samples were then analyzed by ESI-LTQ-Orbitrap under both negative and positive ion modes. Based on the accurate mass measurement(<5),MS/MS fragmentation patterns,standards and literatures,a total of 36 metabolites were screened out and identified in the biological samples collected from rats after intragastric administration. Three were identified 3 from rat plasma,31 from urine,and 7 from feces. The main metabolic pathways of rosmarinic acid in rats can be divided into five parts. Rosmarinic acid were first decomposed into small molecules,such as trans-caffeic acid,coumaric acid,m-hydroxybenzoic acid and Danshensu,which were followed by sulfation,methylation,glucuronic acid conjugation and glucose conjugation. The results showed that UHPLC-LTQ-Orbitrap mass spectrometer could be used to analyze the metabolism of rosmarinic acid in rats,and provide reference for further studies on toxicology,pharmacodynamics and secondary development of Chinese medicine.


Assuntos
Cinamatos/metabolismo , Depsídeos/metabolismo , Medicamentos de Ervas Chinesas/metabolismo , Espectrometria de Massas em Tandem , Animais , Cromatografia Líquida de Alta Pressão , Ratos
12.
Fitoterapia ; 141: 104464, 2019 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-31870946

RESUMO

Coptis chinensis is a widely used traditional Chinese herbal medicine. In this work, 6 new alkaloids (coptisine A-F, 1-6) and 26 known alkaloids (7-32) were isolated from the chloroform extract of the rhizomes of C. chinensis. Compounds 1-3 are α-carbonylated benzylisoquinolines, and 4-6 are berberidic acid type alkaloids. Their structures were elucidated on the basis of extensive NMR and MS analyses. Seven compounds (7, 20, 22, 23, 25, 26, 29) exhibited significant AChE inhibitory activities at 10 µM (inhibition rates >80%).

13.
J Sep Sci ; 2019 Dec 26.
Artigo em Inglês | MEDLINE | ID: mdl-31876986

RESUMO

Menthae Haplocalycis Herba has been utilized for food and medicinal purposes in China for thousands of years. It has various efficacies, including dispelling wind and heat and relieving sore throat. M. Haplocalycis Herba has been also widely used in food, cosmetics, spices, and other fields. Exploring the constituents and detecting the metabolites of M. Haplocalycis are of great significance to clarify the effective substances. However, the in vivo metabolites of M. Haplocalycis Herba water extract are still unclear. Herein, a sensitive and specific method, ultra-high performance liquid chromatography with linear ion trap-Orbitrap mass spectrometry, established in this assay was used to study the metabolism of M. Haplocalycis Herba water extract in rat plasma, urine, and feces. We characterized and identified 9, 50, and 34 metabolites in plasma, urine, and feces, respectively. Seven metabolic pathways, including phase Ⅰ (isomerization, demethylation, hydroxylation, and dehydration) and phase Ⅱ (sulfation and glucuronidation) were mainly involved in the metabolism. It is the first systematic study on the metabolism of M. Haplocalycis Herba water extract in vivo, which enrich current understanding of the metabolic behavior of M. Haplocalycis Herba water extract and provide a metabolic rationale for further in-depth in vivo biotransformation and pharmacokinetic analysis.

14.
Gastroenterol Res Pract ; 2019: 9123521, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31772572

RESUMO

Background and Objective: The aim of the current study was to compare the efficacy and safety of polypectomy by using rotary snare vs. traditional snare during colonoscopy. Methods: A single-center randomized controlled trial, which included consecutive participants who were ≥18 years old and detected with polyp(s) during routine colonoscopy between July and September 2018, was conducted. Participants with colorectal polyps were randomized to receive polypectomy using rotary snares or traditional snares. The primary outcome measure was the comparison of the average time of removing a polyp between those two groups. The secondary outcome measure was to compare the polyp resection time by using SMSA (size, morphology, site, and access) scores. Results: A total of two hundred participants were included in this study. Of them, 100 participants were randomly assigned to the rotary snare group (214 polyps) and the other 100 participants were randomly assigned to the traditional group (232 polyps). The mean resection time was significantly shorter in the rotary snare group than in the traditional snare group (24.41 ± 18.14 seconds vs. 29.53 ± 25.74 seconds, P = 0.021). In the subgroup analysis, the resection time was also shorter in the rotary snare group than in the traditional snare group in SMSA level 1 (18.51 ± 8.26 seconds vs.23.84 ± 15.07 seconds, P = 0.013) and in SMSA level 2 (25.03 ± 15.32 seconds vs.29.15 ± 24.82 seconds, P = 0.009), respectively. Conclusion: Colorectal polyps could be removed more efficient by using rotary snares than by using traditional snares in SMSA level 1 and SMSA level 2.

15.
Br J Pharmacol ; 2019 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-31758699

RESUMO

BACKGROUND AND PURPOSE: Our previous study demonstrate that Naringenin (NGN), a flavonoid compound with strong anti-inflammatory activity, could attenuate nonalcoholic fatty liver disease (NAFLD) induced by a methionine-choline deficient (MCD) diet in mice. However, its underlying mechanisms in regulation of inflammation and NAFLD remain unknown. EXPERIMENTAL APPROACH: WT and NLRP3-/- mice were fed with MCD diet for seven days to induce NAFLD, and administrated by gavage with different doses of NGN at the same time. In vitro experiments were implemented on HepG2 cells, primary hepatocytes and Kupffer cells (KCs) stimulated by lipopolysaccharide (LPS) or LPS plus oleic acid (OA). KEY RESULTS: Treating the WT mice with NGN (100 mg/kg/d) significantly attenuated hepatic lipid accumulation and inflammation activation in the mice livers induced by MCD diet. NLRP3-/- mice showed less hepatic lipid accumulation than WT mice, but NGN treatment could not ameliorate hepatic lipid accumulation further in NLRP3-/- mice. Treating the HepG2 cells with NGN or NLRP3 inhibitor MCC950 reduced lipid accumulation, and NGN inhibited activation of NLRP3/NF-κB pathway stimulated by OA together with LPS. In KCs isolated from WT mice, NGN could inhibit NLRP3 expression. Besides, NGN also inhibited lipid deposition, NLRP3 and IL-1ß expression in WT hepatocytes, but lost efficacy in NLRP3-/- hepatocytes. After re-expressing NLRP3 in NLRP3-/- hepatocytes by adenovirus, the anti-lipid deposition effect of NGN was restored. CONCLUSION AND IMPLICATIONS: Our results elucidated that NGN prevented NAFLD via downregulating NLRP3/NF-κB signaling pathway both in KCs and hepatocytes, thus attenuating inflammation in the mice livers.

16.
Artigo em Inglês | MEDLINE | ID: mdl-31747243

RESUMO

Cell membrane-coated nanocarriers have been developed for drug delivery due to their enhanced blood circulation and tissue targeting capacities; however, previous works have generally focused on spherical nanoparticles and extracellular barriers. Many living organisms with different shapes, such as rod-shaped bacilli and rhabdovirus, display different functionalities regarding tissue penetration, cellular uptake, and intracellular distribution. Herein, we developed cancer cell membrane (CCM)-coated nanoparticles with spherical and rod shapes. CCM-coated nanorods (CRs) showed superior endocytosis efficiency compared with their spherical counterparts (CCM-coated nanospheres, CSs) due to the caveolin-mediated pathway. Moreover, CRs can effectively accumulate in the endoplasmic reticulum (ER) region and ship the loaded DOX to the nucleus at a considerable concentration, resulting in ER stress and subsequent apoptosis. After intravenous injection into human pancreatic adenocarcinoma cell (BxPC-3) and pancreatic stellate cell (HPSC) hybrid tumor-bearing nude mice, CRs exhibited improved immune escape ability, rapid extracellular matrix (ECM) penetration (8.2-fold higher than CSs), and enhanced tumor accumulation, further contributing to the enhanced antitumor efficacy. These findings may actually suggest the significance of shape design in improving current cell membrane-based drug delivery systems for effective subcellular targets and tumor therapy.

17.
Artigo em Inglês | MEDLINE | ID: mdl-31678992

RESUMO

CONTEXT: The effects of dietary intake of different fatty acids and pharmacological use of fatty acids, specifically long-chain n-3 polyunsaturated fatty acids (LC n-3 PUFAs), on cardiovascular health and atherosclerotic cardiovascular disease (ASCVD) prevention have been examined in a large number of observational studies and clinical trials. This review summarizes recent data and discusses potential mechanisms. EVIDENCE ACQUISITION: The review is based on the authors' knowledge of the field supplemented by a PubMed search using the terms "seafood," "fish oil," "saturated fatty acids," "omega-3 fatty acids," "eicosapentaenoic acid," "docosahexaenoic acid," "polyunsaturated fatty acids," "monounsaturated fatty acids," and "ASCVD." EVIDENCE SYNTHESIS: We mainly discuss the recent clinical trials that examine the effects of different types of dietary fatty acids and pharmacological use of n-3 PUFA products on ASCVD prevention and the potential mechanisms. CONCLUSIONS: While replacement of dietary saturated fat with unsaturated fat, polyunsaturated fat in particular, or intake of LC n-3 PUFA-rich seafood has generally shown benefit for ASCVD prevention and is recommended for cardiovascular benefits, data on effects of n-3 PUFA products on ASCVD health are inconsistent. However, recent clinical trials support benefits of prescription EPA in ASCVD prevention. n-3 PUFAs may contribute to ASCVD prevention through multiple mechanisms, including lowering plasma triglyceride levels, anti-inflammatory effects, and other effects.

18.
Neurochem Res ; 44(12): 2809-2820, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31680194

RESUMO

Apolipoprotein E (APOE) is implicated not only in chronic degenerative neurological diseases, such as Alzheimer's disease, but also in acute brain disorders, including traumatic brain injury. Bexarotene, a selective agonist of the retinoid X receptor, has been reported to enhance markedly the expression of APOE. Previous studies have indicated that bexarotene exerts neuroprotective effects in animal models of ischemic stroke by modulating the peripheral immune response and autophagy. However, the role of this drug in neuronal apoptosis and the potential mechanisms involved have yet to be elucidated. The present study employed transient middle cerebral artery occlusion (t-MCAO) as a model of acute cerebral ischemia/reperfusion injury. The experiments were performed in wild-type C57BL/6 mice and APOE gene knockout (APOE-KO) mice. After t-MCAO, mice received intraperitoneal injection of bexarotene (5 mg/kg) or an equal volume of the vehicle. The outcome measurements included neurological deficits, learning ability, spatial memory, infarct volume, histopathology, magnitude of apoptosis, and the level of expression of proteins of the JNK/caspase-3 signaling pathway. The obtained results demonstrated that bexarotene administration significantly improved neurological function, learning ability, and spatial memory in C57BL/6 mice, but not in APOE-KO mice. Infarct volume, tissue damage, neuronal apoptosis rate, and the expression of proteins involved in the JNK/caspase-3 signaling pathway were markedly increased after t-MCAO in both C57BL/6 and APOE-KO mice. Importantly, bexarotene treatment significantly ameliorated all these changes in C57BL/6, but not in APOE-KO mice. In conclusion, bexarotene markedly alleviates the neurological deficits, improves the histological outcome, and inhibits cell apoptosis in mice after t-MCAO. This effect is mediated, at least in part, by up-regulation of APOE. Thus, bexarotene may be a candidate drug for the treatment of cerebral ischemia patients.

19.
Int J Biochem Cell Biol ; 117: 105640, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31689531

RESUMO

The tyrosine kinase receptor ErbB2 is frequently found to be overexpressed in multiple cancer types. Targeted therapeutic approaches against ErbB2 have shown promising results and received FDA approvals in the treatment of breast cancer. However, this approach has not been granted in ovarian cancers till now. In order to assess the validity of ErbB2-targeted therapy in ovarian cancer, we investigated the effectiveness of two FDA-approved tyrosine kinase inhibitors of ErbB2, lapatinib and neratinib, on the growth of ovarian cancers. We observed that both lapatinib and neratinib displayed inhibitory effects towards the proliferation and migration of ErbB2-positive ovarian cancer cells in vitro, with neratinib showing stronger suppression in general. Neratinib treatment led to the reduction of ErbB2 protein levels, with concomitant attenuation of the phosphorylation of AKT, MEK, and ERK1/2. Immunofluorescence assays revealed that neratinib induced the internalization and lysosomal degradation of ErbB2, which was accompanied by its hyperubiquitylation. Lapatinib and neratinib also repressed the in vivo growth of SKOV3 cells, and neratinib downregulated ErbB2 levels in xenograft tumors to cause potent inhibition. Therefore, the ubiquitylation-mediated endocytic degradation of ErbB2 incurred by neratinib treatment conferred potent inhibition of ovarian cancer growth. Clinical investigations of neratinib in ErbB2-positive ovarian cancer are warranted.

20.
Stem Cells ; 2019 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-31721342

RESUMO

The tunica adventitia ensheathes arteries and veins and contains presumptive mesenchymal stem cells (MSCs) involved in vascular remodeling. We show here that a subset of human adventitial cells express the CD10/CALLA cell surface metalloprotease. Both CD10+ and CD10- adventitial cells displayed phenotypic features of MSCs when expanded in culture. However, CD10+ adventitial cells exhibited higher proliferation, clonogenic and osteogenic potentials in comparison to their CD10- counterparts. CD10+ adventitial cells increased expression of the cell cycle protein CCND2 via ERK1/2 signaling and osteoblastogenic gene expression via NF-κB signaling. CD10 expression was upregulated in adventitial cells through Sonic hedgehog-mediated GLI1 signaling. These results suggest that CD10, which marks rapidly dividing cells in other normal and malignant cell lineages, plays a role in perivascular MSC function and cell fate specification. These findings also point to a role for CD10+ perivascular cells in vascular remodeling and calcification.

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