Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 197
Filtrar
1.
Front Oncol ; 11: 688794, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34722240

RESUMO

Nerve growth factor (NGF) is increasingly implicated in cervical cancer progression, but its mechanism in cervical cancer is unclear. Here, studies demonstrate that NGF inhibits the Hippo signaling pathway and activates Yes-associated protein (YAP) to induce cervical cancer cell proliferation and migration. Our results suggested that stimulation of NGF promoted cell growth and migration and activated YAP in HeLa and C-33A cell lines. The expression of YAP target genes (CTGF and ANKRD1) was upregulated after NGF treatment. The NGF inhibitor Ro 08-2750 and siRNA-mediated NGF receptor gene silencing suppressed HeLa and C-33A cells proliferation and migration, activated large suppressor kinase 1 (LATS1) kinase activity, and suppressed YAP function. In addition, the expression of YAP target genes (CTGF and ANKRD1) was suppressed by Ro 08-2750 treatment in HeLa and C-33A cells. Interestingly, proliferation was significantly higher in NGF-treated cells than in control cells, and this effect was completely reversed by the YAP small molecule inhibitor-verteporfin. Furthermore, the mouse xenograft model shows that NGF regulates YAP oncogenic activity in vivo. Mechanistically, NGF stimulation inactivates LATS1 and activates YAP, and NGF inhibition was found to induce large suppressor kinase 1 (LATS1) phosphorylation. Taken together, these data provide the first direct evidence of crosstalk between the NGF signaling and Hippo cancer pathways, an interaction that affects cervical cancer progression. Our study indicates that combined targeting of the NGF signaling and the Hippo pathway represents a novel therapeutic strategy for treatment of cervical cancer.

2.
Sci Total Environ ; : 151775, 2021 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-34808172

RESUMO

This study explores the effects of prenatal exposure to air pollution on the risk of macrosomia and its window of susceptibility. We conducted a retrospective cohort study utilizing records of birth certificates for all full-term live newborns born in Xi'an city, China from January 1, 2015, to December 31, 2018.Weekly- and trimester-specific exposures of PM2.5, PM10, NO2, and O3 during pregnancy were calculated by inverse distance weighting (IDW) based on their residences. Cox proportional hazard model and distributed lag models (DLMs) were performed to estimate the effects of air pollution exposure during pregnancy on macrosomia risk and its window of susceptibility. In total, 318,323 full-term newborns were identified, including 24,996 (7.8%) cases of macrosomia. An IQR increase in PM2.5 exposure (45.46 µg/m3) from the 33rd until the 37th weeks of gestation was positively associated with an elevated risk of macrosomia, with the strongest effect in the 37th weeks (HR = 1.007, 95%CI: 1.002-1.013). The window of susceptibility for NO2 exposure on macrosomia risk was in the 29th-35th gestational weeks, with the strongest effect in the 34th weeks (IQR = 21.96 µg/m3, HR = 1.006, 95%CI:1.000-1.013). For prenatal exposure to O3, 5th-24th weeks of gestation was identified as susceptible windows for elevated risk of macrosomia, with the strongest associations observed in the 15th weeks (IQR = 80.53 µg/m3, HR = 1.022, 95%CI: 1.011-1.033). However, we did not observe any associations between weekly exposure of PM10 and macrosomia. Our findings imply that the windows of susceptibility to PM2.5 and NO2 exposure on macrosomia are mainly in late pregnancy, whereas the windows of susceptibility to O3 exposure are in early and middle pregnancy.

3.
Oxid Med Cell Longev ; 2021: 8043299, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34737846

RESUMO

Ghrelin has anti-inflammatory, antioxidant, and antiapoptotic effects, and it may be beneficial for the treatment of many ophthalmic diseases, such as cataract, uveitis, and glaucoma. Our previous work proved that ghrelin pretreatment reduced the apoptosis of lens epithelial cells induced by hydrogen peroxide, reduced the accumulation of reactive oxygen species (ROS), and effectively maintained the transparency of lens tissue. However, no study has yet investigated the effect of ghrelin on retina. In this study, we conducted in vitro and in vivo experiments to explore the effect of ghrelin on high-glucose- (HG-) induced ARPE-19 cell damage and diabetic retinopathy in streptozotocin-induced diabetic rats. ARPE-19 cells were incubated in a normal or an HG (30 mM glucose) medium with or without ghrelin. Cell viability was measured by 3-(4, 5-dimethylthiazol-3-yl)-2,5-diphenyl tetrazolium bromide assay, and apoptosis was detected by the Hoechst-PI staining assay. Intracellular reactive oxygen species (ROS) production levels within cells were measured using 2',7'-dichlorofluorescein diacetate staining, and the contents of superoxide dismutase and malondialdehyde were measured using relevant detection kits. The expression levels of IL-1ß and IL-18 were measured using an enzyme-linked immunosorbent assay, and those of NLRP3, IL-1ß, and IL-18 were measured using Western blotting. The rat diabetes models were induced using a single intraperitoneal injection of streptozotocin (80 mg/kg). The morphological and histopathological changes in the retinal tissues were examined. The results indicated that ghrelin reduced ROS generation, inhibited cell apoptosis and the activation of NLRP3 inflammasome, inhibited the apoptosis of retinal cells in diabetic rats, and protected the retina against HG-induced dysfunction. In conclusion, ghrelin may play a role in the treatment of ocular diseases involving diabetic retinopathy.

4.
Medicine (Baltimore) ; 100(40): e27396, 2021 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-34622844

RESUMO

BACKGROUND: Western medicine has played an essential role in treating poststroke insomnia (PSI) in China, and traditional Chinese medicine therapy based on Chinese characteristics is also effective. Combined with China's national conditions, we plan to conduct this systematic review and meta-analysis to compare the efficacy of integrated traditional Chinese medicine and Western medicine (INTEGRATED TCM and WM) therapy and Western medicine alone for PSI. METHODS: We will search the following 5 electronic databases: PubMed, Wanfang, Chinese biomedical literature database, the Chongqing VIP Chinese Science and Technology Periodical, and China national knowledge infrastructure. Randomized controlled trials that compared the efficacy of INTEGRATED TCM and WM with Western medicine alone in the treatment of PSI will be considered. Primary outcomes have Treatment effectiveness rate, and Pittsburgh sleep quality index. Secondary outcomes include traditional Chinese medicine syndrome score, Athens insomnia scale, the incidence of adverse reactions, and outcome follow-up. Based on the eligibility criteria, we will conduct literature screening and data extraction. The quality of the included literature will be evaluated using the Cochrane risk of bias tools. We will use Review Manager software (Version 5.3) for data synthesis and statistical analyses. If sources of heterogeneity exist, we will perform a subgroup analysis or sensitivity analysis. A funnel plot will be used to analyze publication bias. RESULTS: This study will provide evidence-based medicine evidence for treatment of PSI with INTEGRATED TCM and WM in terms of its efficacy. CONCLUSION: This systematic review aims to provide new options for INTEGRATED TCM and WM treatment of PSI in terms of its efficacy.


Assuntos
Medicina Tradicional Chinesa/métodos , Distúrbios do Início e da Manutenção do Sono/terapia , Acidente Vascular Cerebral/complicações , Humanos , Metanálise como Assunto , Distúrbios do Início e da Manutenção do Sono/etiologia , Revisões Sistemáticas como Assunto
5.
Front Cardiovasc Med ; 8: 728976, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34651026

RESUMO

Diabetic vascular complications are one of the main causes of death and disability. Previous studies have reported that genetic variation is associated with diabetic vascular complications. In this study, we aimed to investigate the association between GRB10 polymorphisms and susceptibility to type 2 diabetes mellitus (T2DM) vascular complications. Eight single nucleotide polymorphisms (SNPs) in the GRB10 gene were genotyped by MassARRAY system and 934 patients with type 2 diabetes mellitus (T2DM) were included for investigation. We found that GRB10 rs1800504 CC+CT genotypes were significantly associated with increased risk of coronary heart disease (CHD) compared with TT genotype (OR = 2.24; 95%CI: 1.36-3.70, p = 0.002). Consistently, levels of cholesterol (CHOL) (CC+CT vs. TT, 4.44 ± 1.25 vs. 4.10 ± 1.00 mmol/L; p = 0.009) and low density lipoprotein cholesterin (LDL-CH) (CC+CT vs. TT, 2.81 ± 1.07 vs. 2.53 ± 0.82 mmol/L; p = 0.01) in T2DM patients with TT genotype were significant lower than those of CC+CT genotypes. We further validated in MIHA cell that the total cholesterol (TC) level in GRB10-Mut was significantly reduced compared with GRB10-WT; p = 0.0005. Likewise, the reversed palmitic acid (PA) induced lipid droplet formation in GRB10-Mut was more effective than in GRB10-WT. These results suggest that rs1800504 of GRB10 variant may be associated with the blood lipids and then may also related to the risk of CHD in patients with T2DM.

6.
Front Microbiol ; 12: 698468, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34646242

RESUMO

Folates are required for the de novo biosynthesis of purines, thymine, methionine, glycine, and pantothenic acid, key metabolites that bacterial cells cannot survive without. Sulfonamides, which inhibit bacterial folate biosynthesis and are generally considered as bacteriostats, have been extensively used as broad-spectrum antimicrobials for decades. Here we show that, deleting relA in Escherichia coli and other bacterial species converted sulfamethoxazole from a bacteriostat into a bactericide. Not as previously assumed, the bactericidal effect of SMX was not caused by thymine deficiency. When E. coli ∆relA was treated with SMX, reactive oxygen species and ferrous ion accumulated inside the bacterial cells, which caused extensive DNA double-strand breaks without the involvement of incomplete base excision repair. In addition, sulfamethoxazole showed bactericidal effect against E. coli O157 ∆relA in mice, suggesting the possibility of designing new potentiators for sulfonamides targeting RelA. Thus, our study uncovered the previously unknown bactericidal effects of sulfonamides, which advances our understanding of their mechanisms of action, and will facilitate the designing of new potentiators for them.

7.
Neurotoxicology ; 87: 231-242, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34688786

RESUMO

BACKGROUND: Haloperidol is a commonly used antipsychotic drug and may increase neuronal oxidative stress associated with the side effects, including tardive dyskinesia and neurite withdraw. Autophagy plays a protective role in response to the accumulated reactive oxygen species (ROS) induced mitochondria damage. Resveratrol is an antioxidant compound having neuroprotective effects; however, it is unknown if resveratrol may stimulate autophagy and decrease mitochondria damage induced by haloperidol. HYPOTHESIS: We hypothesis that resveratrol stimulates the autophagic process and protects mitochondria lesion induced by haloperidol. METHODS: MitoSOX™ Red Mitochondrial Superoxide Indicator and MitoTracker™ Green FM staining were used to measure the amount of the mitochondria ROS production and mitochondria mass in human SH-SY5Y cells treated with haloperidol and/or resveratrol. Autophagic related dyes and Western blot were applied to study the autophagic process and related protein expression. Besides, tandem monomeric mRFP-GFP-LC3 was used to investigate the fusion of autophagosome and lysosome. Transmission electron microscopy was used to investigate the mitochondrial and autophagic ultrastructures with or without haloperidol and resveratrol treatment. RESULTS: Haloperidol administration significantly increased mitochondria ROS and mitochondrial mass, indicating the increase of mitochondria dysfunction. Although haloperidol increased the autophagosomes and lysosome formation, the autophagosome-lysosome fusion and degradation were impaired. This was because we found an increased p62 after haloperidol treatment, an indication of autophagy incompletion. Importantly, resveratrol promoted the degradation of p62, upregulated the formation of autophagolysosome, and reversed haloperidol-induced mitochondria damage. CONCLUSION: These results collectively suggest that resveratrol may be introduced as a protective compound against haloperidol-induced mitochondria impairment and aberrant autophagy.

8.
Molecules ; 26(20)2021 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-34684794

RESUMO

Luohuazizhu suppository is a Traditional Chinese Medicine used in clinic to treat cervicitis, which is prepared from Callicarpa nudiflora Hook. et Arn (C. nudiflora), an herbal Chinese medicine named Luohuazizhu. This study aimed to figure out the active constituents of C. nudiflora and the potential mechanism for its anti-cervicitis effect. The ethanol extract in C. nudiflora (CNE) and the different fractions of CNE extracted by petroleum ether (CNE-p), dichloromethane (CNE-d), and n-butanol (CNE-b) were tested in vivo for their anti-cervicitis effects. Then the isolated compounds from the CNE-p were tested in vitro for their anti-inflammatory activities. The results displayed that CNE-p, CNE-d, and CNE-b exhibited adequate anti-cervicitis effects, with CNE-p showing the highest efficacy. Further experiment demonstrated that CNE-p could significantly inhibit the expression of NLRP3 in vitro. Six diterpenoids obtained from the CNE-p showed the ability to regulate inflammatory factor levels in vitro. Among these compounds, compounds 1 (callicarpic acid A) and 2 (syn-3,4-seco-12S-hydroxy-15,16-epoxy-4(18),8(17),3(16),14(15)-labdatetraen-3-oic acid) were the most effective agents, and they also inhibited the expression level of NLRP3 in vitro. The results confirmed that C. nudiflora has significant anti-cervicitis effects and the diterpenoids were most likely to be its active components. These data provide scientific support for the clinic usage of Luohuazizhu suppository and the development of new agents in treating cervicitis.


Assuntos
Callicarpa/química , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Compostos Fitoquímicos/farmacologia , Cervicite Uterina/tratamento farmacológico , Animais , Anti-Inflamatórios/isolamento & purificação , Anti-Inflamatórios/farmacologia , Citocinas/metabolismo , Modelos Animais de Doenças , Diterpenos/isolamento & purificação , Diterpenos/farmacologia , Feminino , Humanos , Medicina Tradicional Chinesa , Camundongos , Simulação de Acoplamento Molecular , Proteína 3 que Contém Domínio de Pirina da Família NLR/química , Compostos Fitoquímicos/isolamento & purificação , Extratos Vegetais/farmacologia , Plantas Medicinais/química , Células RAW 264.7 , Ratos , Ratos Sprague-Dawley , Cervicite Uterina/metabolismo , Cervicite Uterina/patologia
9.
Biomark Med ; 15(14): 1277-1288, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34486883

RESUMO

Aim: The potential of long noncoding RNA in hepatocellular carcinoma (HCC) has led to promising insights into therapeutic intervention. The clinical significance of LINC02518 in HCC is unclear. This study aimed to evaluate the predictive value of a novel long noncoding RNA, LINC02518, for the prognosis of patients with HCC. Methods: Between December 2005 and November 2011, 125 and 75 HCC patients in the training and validation groups, respectively, who underwent liver surgery were included in our study. The LINC02518 expression of HCC and corresponding nontumor liver tissues was detected using microarray and reverse transcription quantitative polymerase chain reaction (RT-qPCR). These HCC patients were assigned into high and low LINC02518 expression groups based on the threshold of the receiver operating characteristic curve. Kaplan-Meier analysis was performed to determine the prognosis of HCC patients. Results: LINC02518 expression was upregulated in paired tumor samples compared with corresponding nontumor samples in the two groups. The area under the receiver operating characteristic curve for the levels of LINC02518 in the diagnosis of HCC was 0.66, 95% CI: 0.59-0.73. HCC patients with high LINC02518 expression had significantly worse tumor recurrence-free, metastasis-free, disease-free and overall survival than those with low LINC02518 expression. Conclusion: LINC02518 is negatively correlated with the prognosis of HCC and provides a promising strategy for the treatment and prognosis of HCC.

10.
Iran J Public Health ; 50(7): 1324-1333, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34568170

RESUMO

Background: This study investigated the impact of socio-economic factors on the spread and outbreak of COVID-19 based on Chinese data. Methods: Cumulative confirmed cases were collected and divided into the First-stage cases cluster dominated by imported cases, and the Second-stage cases cluster dominated by secondary cases, according to the time of emergency state and Wuhan city lockdown. The linear regression was used for data analysis. Results: A total of 12,877 cases in 30 provinces were analyzed in the study. The First-stage cases cluster included 675 cases and Second-stage cases cluster included 12,202 cases. The socio-economic factors were significantly associated with the cases (P<0.05). The GDP and proportion of population moving out of Wuhan were associate with the First-stage dominated by imported cases (ß>0, P<0.05). The First-stage cases cluster, proportion of population moving out of Wuhan and urban population were associate with the Second-stage dominated by secondary cases (ß>0, P<0.05). Conclusion: Socio-economic factors had impacts on the spread and outbreak of COVID-19. The combination of different socio-economic indicators at different stages of the epidemic may help control the epidemic.

11.
Ann Transl Med ; 9(15): 1253, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34532390

RESUMO

Background: Tribble pseudokinase 3 (TRIB3) plays a key role in regulating the malignancy of many tumors. This study examined its function in cancer cells and explored the potential mechanisms of action. Methods: The expression of TRIB3 was examined in hepatocellular carcinomas (HCCs) using The Cancer Genome Atlas (TCGA) database. A TRIB3 lentivirus with a flag label was constructed and transfected into Huh7 and Hep3B human hepatoma cell lines to generate cells that stably overexpress TRIB3. A small interfering RNA (siRNA) was designed to knockdown TRIB3 mRNA in HepG2 and Huh7. Cell viability and cell colony formation assays were conducted. Flow cytometry was performed to assess the cell cycle in cells overexpressing TRIB3. Western blotting were performed to examine the expression of (Mitogen-activated protein kinase, MAPKK) (MEK), phosphorylated-MEK (p-MEK), extracellular signal-regulated kinase (ERK), and p-MEK in cells with TRIB3 knockdown. The correlation between TRIB3 and SMARCD3 was assessed using co-immunoprecipitation assays and immunofluorescence. Results: TRIB3 was significantly overexpressed in advanced grade HCC tissues and was closely correlated with poor prognosis. TRIB3 overexpression promoted the cell growth and cell cycle but had little effect on migration capabilities in Huh7 and Hep3B cells. Conversely, knockdown of TRIB3 had slow down the cell growth in Huh7 and HepG2 cells detected by CCK8 and colony formation assay. The expression of MEK and ERK at both the protein and mRNA levels were downregulated when TRIB3 was knocked down. The protein expression of p-ERK and p-MEK were also downregulated upon TRIB3 silencing. SMARCD3 is a transcript factor that is belongs to the SWI/SNF complex and has been shown to regulate many genes. Indeed, co-immunoprecipitation assays demonstrated that TRIB3 interacts with SMARCD3 in the nucleus, suggesting that it may regulate TRIB3 in HCCs. Conclusions: This study demonstrated that TRIB3 promotes the malignancy of HCC cells and its expression may be a potential diagnostic biomarker for HCC progression.

12.
ACS Nano ; 15(9): 14295-14304, 2021 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-34435493

RESUMO

High performance photodetectors based on van der Waals heterostructures (vdWHs) are crucial to developing micro-nano-optoelectronic devices. However, reports show that it is difficult to balance fast response and high sensitivity. In this work, we design a photovoltaic field-effect photodiode (PVFED) based on the WSe2/MoS2/WSe2 double vdWHs, where the photovoltage that originated from one vdWH modulates the optoelectronic characteristics of another vdWH. The proposed photodiode exhibits an excellent self-powered ability with a high responsivity of 715 mA·W-1 and fast response time of 45 µs. This work demonstrates an efficient method that optimizes the photoelectric performance of vdWH by introducing the photovoltaic field effect.

13.
Medicine (Baltimore) ; 100(29): e26699, 2021 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-34398042

RESUMO

BACKGROUND: Endometriosis (EMs) affects about 10% of women of childbearing age. It is defined as functional endometrial tissue appearing in other parts of the uterine cavity, manifested by varying degrees of pelvic pain and pelvic mass, etc. Therefore, to improve the therapeutic effect of endometriosis, we must constantly explore new ways to treat the disease. The purpose of this study is to evaluate the effectiveness and safety of the combined use of laparoscopy and traditional Chinese medicine in the treatment of patients with EMs. METHODS: A systematic literature search will be conducted at China National Knowledge Infrastructure, WanFang databases, VIP, SinoMed, PubMed, Embase, Web of Science, and the Cochrane library. The search period limit is from the time the date of database establishment to June 21, 2021. To ensure the comprehensiveness of the search, relevant references and conference literature are also included. The risk of bias in the final included studies will be evaluated based on the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions. The RevMan software will be employed to perform data synthesis and statistical analysis. RESULTS: The effectiveness and safety of laparoscopic surgery combined with traditional Chinese medicine decoction in the treatment of patients with EMs will be systematically evaluated. CONCLUSION: The results of this study will provide strong evidence for judging whether laparoscopy combined with traditional Chinese medicine decoction is an effective strategy for the treatment of patients with EMs.


Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Endometriose/tratamento farmacológico , Terapia Combinada , Medicamentos de Ervas Chinesas/administração & dosagem , Endometriose/cirurgia , Feminino , Humanos , Laparoscopia , Fitoterapia , Projetos de Pesquisa
14.
Int J Mol Sci ; 22(16)2021 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-34445508

RESUMO

This study investigated the effects of root-restriction cultivation on the root architecture, endogenous strigolactone (SL) content, and SL-related genes expression in grapevine (Vitis vinifera L.). In addition, we clarified the effects of synthetic SL analog GR24 application on grapevine roots to explore the role of SLs in their development. The results showed that the root architecture changed significantly under root-restriction cultivation. At 40 days after transplantation (DAT), the contents of two types of SLs in roots under root restriction were both significantly lower than that in roots of the control. SL content was significantly positively correlated with the expression levels of VvCCD8 and VvD27, indicating that they play vital roles in SLs synthesis. After GR24 treatment for 20 days, the root length was significantly shorter than in the control. A low concentration (0.1 µM) of GR24 significantly reduced the root diameter and increased the fine-root density, while a high concentration (10 µM) of GR24 significantly reduced the lateral root (LR) length and increased the LR density. Concomitantly, GR24 (0.1 µM) reduced endogenous SL content. After GR24 treatment for 5 days, the total content of two tested SLs was highly positively correlated with the expression levels of VvDAD2, whereas it was highly negatively correlated with VvSMAXL4 at 20 days after GR24 treatment. This study helps to clarify the internal mechanism of root-restriction cultivation affecting the changes in grapevine root architecture, as well as further explore the important role of SLs in the growth of grapevine roots in response to root-restriction treatment.


Assuntos
Compostos Heterocíclicos com 3 Anéis/farmacologia , Lactonas/farmacologia , Proteínas de Plantas/genética , Vitis/crescimento & desenvolvimento , Dioxigenases/genética , Relação Dose-Resposta a Droga , Perfilação da Expressão Gênica , Regulação da Expressão Gênica de Plantas/efeitos dos fármacos , Raízes de Plantas/efeitos dos fármacos , Raízes de Plantas/genética , Raízes de Plantas/crescimento & desenvolvimento , Vitis/efeitos dos fármacos , Vitis/genética
15.
J Am Heart Assoc ; 10(16): e020554, 2021 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-34350769

RESUMO

Background Adventitial remodeling is a pathological hallmark of hypertension that results in target organ damage. Activated adventitial fibroblasts have emerged as critical regulators in this process, but the precise mechanism remains unclear. Methods and Results Interleukin 11 (IL-11) knockout and wild-type mice were subjected to angiotensin II (Ang II) infusion to establish models of hypertension-associated vascular remodeling. IL-11 mRNA and protein were increased especially in the adventitia in response to Ang II. Compared with wild-type mice, Ang II-treated IL-11 knockout mice showed amelioration of vascular hypertrophy, adventitial fibrosis, macrophage infiltration, and inflammatory factor expression. Recombination mouse IL-11 exacerbated adventitial fibrosis in Ang II-infused wild-type mice. Interestingly, IL-11 neutralizing antibody attenuated adventitial fibrosis, macrophage infiltration, and inflammatory factor expression after Ang II infusion for 7 days. Mechanistically, in primary cultured adventitial fibroblasts, Krüppel-like factor 15 negatively regulated Ang II-induced IL-11 expression. Ang II increased extracellular signal-regulated kinases 1 and 2 activation, especially in adventitia, and caused biphasic extracellular signal-regulated kinases 1 and 2 activation in adventitial fibroblasts. A rapid and early activation increased IL-11 production through decreasing Krüppel-like factor 15 expression, which, in turn, induced the second extracellular signal-regulated kinases 1 and 2 activation, resulting in posttranscriptional profibrotic gene expression. Conclusions These results demonstrate that extracellular signal-regulated kinases 1 and 2 activation is important for Krüppel-like factor 15-mediated IL-11 expression in adventitial fibroblasts to promote adventitial remodeling in Ang II-induced hypertension. Therefore, targeting the Krüppel-like factor 15/IL-11 axis might serve as a new therapeutic strategy for vascular diseases.


Assuntos
Túnica Adventícia/enzimologia , Aorta Torácica/enzimologia , Fibroblastos/enzimologia , Hipertensão/enzimologia , Interleucina-11/metabolismo , Fatores de Transcrição Kruppel-Like/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Remodelação Vascular , Túnica Adventícia/patologia , Angiotensina II , Animais , Aorta Torácica/patologia , Modelos Animais de Doenças , Fibroblastos/patologia , Fibrose , Células HEK293 , Humanos , Hipertensão/induzido quimicamente , Hipertensão/genética , Hipertensão/patologia , Mediadores da Inflamação/metabolismo , Interleucina-11/genética , Fatores de Transcrição Kruppel-Like/genética , Macrófagos/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ratos Sprague-Dawley , Transdução de Sinais
16.
Pharm Biol ; 59(1): 884-892, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34219593

RESUMO

CONTEXT: Laurolitsine is an aporphine alkaloid and exhibits potent antihyperglycemic and antihyperlipidemic effects in ob/ob mice. OBJECTIVE: To investigate the pharmacokinetics, tissue distribution and excretion of laurolitsine. MATERIALS AND METHODS: A LC-MS/MS method was established and validated to determine laurolitsine concentrations in the biological matrix of rats (plasma, tissue homogenate, urine and faeces). 10 Sprague-Dawley (SD) rats were used for plasma exposure study: 5 rats were injected with 2.0 mg/kg of laurolitsine via the tail vein, and the other 5 rats were administered laurolitsine (10.0 mg/kg) by gavage. 25 SD rats used for tissue distribution study and 5 SD rats for urine and faeces excretion study: rats administered laurolitsine (10.0 mg/kg) by gavage. After administered, serial blood, tissue, urine and faeces were collected. Analytical quantification was performed by a previous LC-MS/MS method. The pharmacokinetics, bioavailability, tissue distribution and excretion of laurolitsine were described. RESULTS: The pharmacokinetic parameters of oral and intravenous administration with Tmax were 0.47 and 0.083 h, t1/2 were 3.73 and 1.67 h, respectively. Oral bioavailability was as low as 18.17%. Laurolitsine was found at a high concentration in the gastrointestinal tract, liver, lungs and kidneys (26 015.33, 905.12, 442.32 and 214.99 ng/g at 0.5 h, respectively) and low excretion to parent laurolitsine in urine and faeces (0.03 and 1.20% in 36 h, respectively). CONCLUSIONS: This study established a simple, rapid and accurate LC-MS/MS method to determine laurolitsine in different rat samples and successful application in a pharmacokinetic study.

17.
Int J Biol Macromol ; 187: 24-34, 2021 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-34284054

RESUMO

Human serum albumin (HSA)-based therapeutics have attracted tremendous attention in the development of anticancer agents. The versatile properties of HSA make HSA-based therapeutics possess improved pharmacokinetics, extended circulation half-life, enhanced efficacy, reduced toxicity, etc. Generally, the HSA-based therapeutics systems can be divided into four categories, i.e. HSA-drug nanoparticles, HSA-drug conjugates, HSA-binding prodrugs, and HSA-based recombinant fusion proteins: the latter mainly include antibody (domain)- and cytokine- fusion proteins. Advances in this area revealed the advantages of HSA-based systems in the development of tumor site-oriented therapeutics, partly referring to the enhanced penetration and retention (EPR) effect and the intensive macropinocytosis. Accordingly, a variety of technical platforms for the design and preparation of HSA-based therapeutics have been reported. Major strategies and directions for the drug development were discussed; those include (1) Tumor-site oriented drug delivery and enhanced drug retention, (2) Tumor-site prodrug release and activation, (3) Cancer cell bound intensive drug internalization, and (4) Tumor microenvironment (TME) directed immunomodulation. Notably, the multimodal HSA-based approach is promising for the development of tumor-oriented therapeutics for cancer therapy.

18.
Leuk Res ; 110: 106645, 2021 11.
Artigo em Inglês | MEDLINE | ID: mdl-34217112

RESUMO

BACKGROUND: The value of pre-transplant cytoreductive therapy for patients with myelodysplastic syndromes (MDS) is controversial. Here, we conducted a meta-analysis to explore the effects of cytoreduction before transplantation. METHODS: PubMed, Embase, Cochrane, and Chinese databases were searched to identify studies comparing post-transplant outcomes in MDS patients receiving different pre-transplant therapy. Pooled hazard ratios (HRs) and 95 % confidence intervals (CI) were calculated. RESULTS: Eighteen reports were included. Post-transplant outcomes were similar for MDS patients receiving pre-transplant cytoreductive therapy and upfront transplantation in terms of overall survival (OS: HR, 0.92; 95 % CI, 0.79-1.07), relapse-free survival (RFS: HR, 1.18; 95 % CI, 0.94-1.47), cumulative incidence of relapse (CIR: HR, 1.08; 95 % CI, 0.88-1.33), and non-relapse mortality (NRM: HR, 0.93; 95 % CI, 0.74-1.18). Pre-transplant hypomethylating agents (HMAs) and chemotherapy were not different regarding post-transplant OS, RFS, CIR, and NRM. Achieving complete remission (CR) before transplantation was associated with increased RFS (HR, 0.80; 95 %CI, 0.63-1.00) and decreased NRM (HR, 0.53; 95 % CI, 0.32-0.90) when compared with upfront transplantation. CONCLUSIONS: Timely transplantation is of great value for MDS patients. Suitable pre-transplant cytoreduction could be used during the search for donors.

19.
Chemosphere ; 283: 131169, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34146867

RESUMO

BACKGROUND: More and more studies began to explore the hazardous health effects of PM2.5, but few reported its impacts on stillbirth. The sparse results were inconsistent and remained to be integrated. Therefore, we aimed to reveal the association between maternal exposure to PM2.5 and stillbirth. METHODS: In this meta-analysis, we searched PubMed, Web of Science, Embase, and Cochrane Central Register of Controlled Trials (CENTRAL) databases for related articles written in English and published before October 18, 2020. Study selection was conducted according to the predetermined criteria and data attraction was done with predesigned form. A new instrument was applied to conduct the risk of bias assessment. And random-effect models were used to pool the estimates. RESULTS: A total of 3655 records were identified from the databases, but only 7 studies were ultimately included in this study. Positive association was found between the maternal exposure to PM2.5 (per 10 µg/m3 increased) in the entire pregnancy (OR: 1.15, 95% CI: 1.07-1.25) and third trimester (OR: 1.09, 95% CI: 1.01-1.18) and stillbirth, but the association between the maternal exposure to PM2.5 (per 10 µg/m3 increased) in the first trimester (OR: 1.01, 95% CI: 0.90-1.13) and second trimester (OR: 1.06, 95% CI: 0.98-1.14) and stillbirth was not statistically significant. Besides, there was no publication bias. CONCLUSIONS: Maternal exposure to PM2.5 in the entire pregnancy and third trimester was associated with elevated risk of stillbirth. However, due to the high heterogeneity, further pathophysiological researches and high quality population studies were still warranted.


Assuntos
Poluentes Atmosféricos , Poluição do Ar , Poluentes Atmosféricos/análise , Poluição do Ar/análise , Feminino , Humanos , Exposição Materna/efeitos adversos , Material Particulado/análise , Gravidez , Natimorto/epidemiologia
20.
Clin Lymphoma Myeloma Leuk ; 21(9): 631-640, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34074612

RESUMO

BACKGROUND: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the only curative therapy for advanced myelodysplastic syndrome (MDS). However, the value of pretransplant cytoreduction remains debatable. PATIENTS AND METHODS: We retrospectively compared the outcomes of upfront transplantation and pretransplant cytoreduction. Of 69 patients, 39 received upfront allo-HSCT and 30 received pretransplant cytoreduction, including chemotherapy (n = 16), hypomethylating agents (HMAs, n = 6), and HMAs with chemotherapy (n = 8). RESULTS: The upfront group achieved similar overall survival (OS) and a trend of better progression-free survival (PFS) from diagnosis compared with the cytoreduction group (3-year PFS, 64.0% vs. 44.4%, P = .076). Posttransplant outcomes were comparable between the two groups in terms of OS, relapse-free survival (RFS), cumulative incidence of relapse (CIR), and non-relapse mortality (NRM). In patients with ≥2 mutations, the upfront group achieved better OS and PFS (3-year OS, 100.0% vs. 68.6%, P = .044; 3-year PFS: 92.3% vs. 43.9%, P = .016) than the cytoreduction group. Patients achieving remission in the cytoreduction group had outcomes similar to the upfront group, but those without remission before transplantation had a significantly worse posttransplant OS (3-year OS, 46.7% vs. 75.7%, P = .038). Patients with pretransplant HMAs had better PFS than those with chemotherapy or HMAs plus chemotherapy (P < 0.05). CONCLUSION: Compared with pretransplant cytoreduction, upfront allo-HSCT might provide more benefit to some patients with advanced MDS if there are suitable donors. HMAs would be a good alternative during the donor search.

SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...