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1.
Acta Pharmacol Sin ; 2021 Sep 14.
Artigo em Inglês | MEDLINE | ID: mdl-34522005

RESUMO

Behavioral sensitization is a progressive increase in locomotor or stereotypic behaviours in response to drugs. It is believed to contribute to the reinforcing properties of drugs and to play an important role in relapse after cessation of drug abuse. However, the mechanism underlying this behaviour remains poorly understood. In this study, we showed that mTOR signaling was activated during the expression of behavioral sensitization to cocaine and that intraperitoneal or intra-nucleus accumbens (NAc) treatment with rapamycin, a specific mTOR inhibitor, attenuated cocaine-induced behavioural sensitization. Cocaine significantly modified brain lipid profiles in the NAc of cocaine-sensitized mice and markedly elevated the levels of phosphatidylinositol-4-monophosphates (PIPs), including PIP, PIP2, and PIP3. The behavioural effect of cocaine was attenuated by intra-NAc administration of LY294002, an AKT-specific inhibitor, suggesting that PIPs may contribute to mTOR activation in response to cocaine. An RNA-sequencing analysis of the downstream effectors of mTOR signalling revealed that cocaine significantly decreased the expression of SynDIG1, a known substrate of mTOR signalling, and decreased the surface expression of GluA2. In contrast, AAV-mediated SynDIG1 overexpression in NAc attenuated intracellular GluA2 internalization by promoting the SynDIG1-GluA2 interaction, thus maintaining GluA2 surface expression and repressing cocaine-induced behaviours. In conclusion, NAc SynDIG1 may play a negative regulatory role in cocaine-induced behavioural sensitization by regulating synaptic surface expression of GluA2.

2.
BMJ Open ; 11(9): e049581, 2021 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-34489283

RESUMO

OBJECTIVES: To evaluate the cost-effectiveness of four different primary screening strategies: high-risk factor questionnaire (HRFQ) alone, single immunochemical faecal occult blood test (iFOBT), double iFOBT and HRFQ+double iFOBT for colorectal cancer (CRC) screening compared with no screening using the Markov model. METHODS: Treeage Pro V.2011 software was used to simulate the Markov model. The incremental cost-effectiveness ratio, which was compared with the willingness-to-pay (WTP) threshold, was used to reflect the cost-effectiveness of the CRC screening method. One-way sensitivity analysis and probabilistic sensitivity analysis were used for parameter uncertainty. RESULTS: All strategies had greater effectiveness because they had more quality-adjusted life years (QALYs) than no screening. When the WTP was ¥435 762/QALY, all screening strategies were cost-effective compared with no screening. The double iFOBT strategy was the best-buy option compared with all other strategies because it had the most QALYs and the least cost. One-way sensitivity analysis showed that the sensitivity of low-risk adenoma, compliance with colonoscopy and primary screening cost were the main influencing factors comparing single iFOBT, double iFOBT and HRFQ+double iFOBT with no screening. However, within the scope of this study, there was no fundamental impact on cost-effectiveness. Probabilistic sensitivity analysis showed that when the WTP was ¥435 762/QALY, the probabilities of the cost-effectiveness acceptability curve with HRFQ alone, single iFOBT, double iFOBT and HRFQ+double iFOBT were 0.0%, 5.3%, 69.3% and 25.4%, respectively. CONCLUSIONS: All screening strategies for CRC were cost-effective compared with no screening strategy. Double iFOBT was the best-buy option compared with all other strategies. The significant influencing factors were the sensitivity of low-risk polyps, compliance with colonoscopy and cost of primary screening.


Assuntos
Neoplasias Colorretais , Detecção Precoce de Câncer , China , Colonoscopia , Neoplasias Colorretais/diagnóstico , Análise Custo-Benefício , Humanos , Cadeias de Markov , Programas de Rastreamento , Sangue Oculto , Anos de Vida Ajustados por Qualidade de Vida
3.
Curr Opin Hematol ; 28(5): 323-330, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34267080

RESUMO

PURPOSE OF REVIEW: Preeclampsia is a common complication of pregnancy and contributes significantly to maternal and fetal morbidity and mortality. A protective hypercoagulable state is often developed during late pregnancy and can evolve into a prothrombotic state in patients with preeclampsia. The underlying mechanism of this prothrombotic transition remains poorly understood. We discuss recent progress in understanding the pathophysiology of preeclampsia and associated prothrombotic state. RECENT FINDINGS: The hypercoagulable state developed during pregnancy is initiated by placental factors and progresses into the prothrombotic state in preeclampsia when the placenta is subjected ischemic and oxidative injuries. The cause of the preeclampsia-induced prothrombotic state is multifactorial, involving not only placental factors but also maternal conditions, which include genetic predisposition, preexisting medical conditions, and conditions acquired during pregnancy. Endotheliopathy is the primary pathology of preeclampsia and contributes to the prothrombotic state by inducing the dysregulation of coagulation, platelets, and adhesive ligands. SUMMARY: Patients with preeclampsia often develop a severe prothrombotic state that predisposes them to life-threatening thrombosis and thromboembolism during and after pregnancy. Early recognition and treatment of this prothrombotic state can improve maternal and infant outcomes of preeclampsia patients.


Assuntos
Predisposição Genética para Doença , Pré-Eclâmpsia , Trombose , Plaquetas/metabolismo , Feminino , Humanos , Placenta/metabolismo , Adesividade Plaquetária , Pré-Eclâmpsia/sangue , Pré-Eclâmpsia/genética , Gravidez , Proteínas da Gravidez/sangue , Proteínas da Gravidez/genética , Trombose/sangue , Trombose/genética
4.
Acta Pharmacol Sin ; 2021 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-33990764

RESUMO

Renal fibrosis contributes to progressive damage to renal structure and function. It is a common pathological process as chronic kidney disease develops into kidney failure, irrespective of diverse etiologies, and eventually leads to death. However, there are no effective drugs for renal fibrosis treatment at present. Lipid aggregation in the kidney and consequent lipotoxicity always accompany chronic kidney disease and fibrosis. Numerous studies have revealed that restoring the defective fatty acid oxidation in the kidney cells can mitigate renal fibrosis. Thus, it is an important strategy to reverse the dysfunctional lipid metabolism in the kidney, by targeting critical regulators of lipid metabolism. In this review, we highlight the potential "druggability" of lipid metabolism to ameliorate renal fibrosis and provide current pre-clinical evidence, exemplified by some representative druggable targets and several other metabolic regulators with anti-renal fibrosis roles. Then, we introduce the preliminary progress of noncoding RNAs as promising anti-renal fibrosis drug targets from the perspective of lipid metabolism. Finally, we discuss the prospects and deficiencies of drug targeting lipid reprogramming in the kidney.

5.
Sichuan Da Xue Xue Bao Yi Xue Ban ; 52(2): 207-215, 2021 Mar.
Artigo em Chinês | MEDLINE | ID: mdl-33829693

RESUMO

Objective: To investigate whether long-term exposure to inhaled sevoflurane, a volatile anesthetic, causes abnormal activities and memory impairment related to attention-deficit/hyperactivity disorder (ADHD) in neonatal rats. Methods: On postnatal day 5 (P5), Sprague-Dawley rats were randomly assigned to two sevoflurane subgroups and two control subgroups and underwent experimental intervention. The two sevoflurane (SEVO) subgroups were exposed to 3% sevoflurane for 2 h and 4 h respectively, while the two control subgroups were given pure oxygen for the same amount and duration. Behavioral tests, including open-field test (OFT), five-choice serial reaction time task (5-CSRTT), fear-conditioning (FC) and Morris water maze (MWM), were applied to evaluate changes in cognition, memory, anxiety and ADHD-related behavioral changes in the rats in adolescence (-P25) and in adulthood (-P65). Results: In OFT, the SEVO 2 h and SEVO 4 h subgroups displayed activity level and exploratory behaviors similar to those of the control subgroups on P21 and P61, with no statistically significant difference identified in the data. 5-CSRTT results on P25 and P65 indicated no statistically significant difference between the SEVO subgroups and the control subgroups in regard to ADHD-related abnormal behaviors, including number of immature reaction, rate of correct response and omission rate. In the FC experiment, SEVO 4 h group had a shorter freezing period and longer period of freezing latency ( P=0.029) in comparison to the control groups. The results of the MWM test showed that the escape latency period of rats in the SEVO 4 h group was significantly prolonged on the second day and the third day, compared to the control groups ( P<0.05). The average swimming speed of SEVO groups did no exhibit any statistically significant difference on P69 or P76. The time the SEVO 4 h group spent in the target quadrant was significantly shorter than that of the control group ( P=0.039) and percentage of distance traveled in the target quadrant was significantly reduced compared to that the control group ( P=0.048). Conclusion: The findings suggest that four hours of inhaled sevoflurane exposure in neonate rats may cause memory impairment, but does no increase risks for ADHD-related abnormal activities.


Assuntos
Anestésicos Inalatórios , Transtorno do Deficit de Atenção com Hiperatividade , Anestésicos Inalatórios/toxicidade , Animais , Animais Recém-Nascidos , Transtorno do Deficit de Atenção com Hiperatividade/induzido quimicamente , Aprendizagem em Labirinto , Ratos , Ratos Sprague-Dawley , Sevoflurano
6.
Hepatol Int ; 15(1): 114-126, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33495903

RESUMO

BACKGROUND: Portal vein tumor thrombus (PVTT) and microvascular invasion (MVI) are types of intrahepatic vascular metastasis of hepatocellular carcinoma (HCC) and are highly correlated with poor prognosis. However, the underlying biomarkers of PVTT and MVI are unclear. METHODS: We identified a PVTT/MVI-associated gene S100P by cDNA microarray analysis, and assess the potential value of serum S100P measurement in the differential diagnosis of HCC and prediction of MVI status with large retrospective and perspective cohort studies. RESULTS: The mRNA and protein of S100P was increased in HCCs with PVTT or MVI. High S100P immunostaining in tumors was correlated with inferior tumor-free survival. Serum S100P values discriminated patients with HCCs from those with benign liver tumors, and it showed predictive potential of MVI status in both retrospective and perspective cohorts. S100P may regulate HCC tumorigenicity and invasive ability; S100P also was associated with up-regulation of CD44, which may mediate HCC cell adhesion to form PVTT/MVI. CONCLUSIONS: Serum S100P may be a novel differential diagnostic marker for HCC and a potential predictor of MVI status pre-surgery for HCC patients. S100P overexpression in HCC is highly correlated with the formation of PVTT and MVI, which may make S100P as a potential therapeutic target for HCC metastasis.

7.
Chem Biol Interact ; 337: 109396, 2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33508306

RESUMO

Aging as one of intrinsic biological processes is a risk factor for many chronic diseases. Kidney disease is a global problem and health care burden worldwide. The diagnosis of kidney disease is currently based on serum creatinine and urea levels. Novel biomarkers may improve diagnostic accuracy, thereby allowing early prevention and treatment. Over the past few years, advances in genome analyses have identified an emerging class of noncoding RNAs that play critical roles in the regulation of gene expression and epigenetic reprogramming. Long noncoding RNAs (lncRNAs) are pervasively transcribed in the genome and could bind DNA, RNA and protein. Emerging evidence has demonstrated that lncRNAs played an important role in all stages of kidney disease. To date, only some lncRNAs were well identified and characterized, but the complexity of multilevel regulation of transcriptional programs involved in these processes remains undefined. In this review, we summarized the lncRNA expression profiling of large-scale identified lncRNAs on kidney diseases including acute kidney injury, chronic kidney disease, diabetic nephropathy and kidney transplantation. We further discussed a number of annotated lncRNAs linking with complex etiology of kidney diseases. Finally, several lncRNAs were highlighted as diagnostic biomarkers and therapeutic targets. Targeting lncRNAs may represent a precise therapeutic strategy for progressive renal fibrosis.


Assuntos
Nefropatias/patologia , Rim/metabolismo , RNA Longo não Codificante/metabolismo , Envelhecimento , Nefropatias Diabéticas/genética , Nefropatias Diabéticas/patologia , Proteína Forkhead Box O1/química , Proteína Forkhead Box O1/genética , Proteína Forkhead Box O1/metabolismo , Humanos , Nefropatias/genética , Nefropatias/terapia , Transplante de Rim , RNA Longo não Codificante/genética
8.
Clin Microbiol Infect ; 27(7): 1000-1006, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33421578

RESUMO

OBJECTIVES: Delay in diagnosis of tuberculosis (TB) is an important but under-appreciated problem. Our study aimed to analyse the patient pathway and possible risk factors of long diagnostic delay (LDD). METHODS: We enrolled 400 new bacteriologically diagnosed patients with pulmonary TB from 20 hospitals across China. LDD was defined as an interval between the initial care visit and the confirmation of diagnosis exceeding 14 days. Its potential risk factors were investigated by multivariate logistic regression and multilevel logistic regression. Hospitals in China were classified by increasing size, from level 0 to level 3. TB laboratory equipment in hospitals was also evaluated. RESULTS: The median diagnostic delay was 20 days (IQR: 7-72 days), and 229 of 400 patients (57.3%, 95%CI 52.4-62.1) had LDD; 15% of participants were diagnosed at the initial care visit. Compared to level 0 facilities, choosing level 2 (OR 0.27, 95%CI 0.12-0.62, p 0.002) and level 3 facilities (OR 0.34, 95%CI 0.14-0.84, p 0.019) for the initial care visit was independently associated with shorter LDD. Equipping with smear, culture, and Xpert at initial care visit simultaneously also helped to avoid LDD (OR 0.28, 95%CI 0.09-0.82, p 0.020). The multilevel logistic regression yielded similar results. Availability of smear, culture, and Xpert was lower in level 0-1 facilities than in level 2-3 facilities (p < 0.001, respectively). CONCLUSIONS: Most patients failed to be diagnosed at the initial care visit. Patients who went to low-level facilities initially had a higher risk of LDD. Improvement of TB laboratory equipment, especially at low-level facilities, is urgently needed.

9.
Dent Mater J ; 40(1): 143-149, 2021 Jan 31.
Artigo em Inglês | MEDLINE | ID: mdl-33115999

RESUMO

The dimensional stability of core buildup materials plays an important role in clinical application. In this study, hygroscopic dimensional changes of four commercial core buildup materials were investigated in deionized water and artificial saliva for up to 150 days. Specimens were made within a customized cylindrical mold. The initial mass and the apparent mass in liquids were measured. All the tested materials showed hygroscopic expansion after a 150-days immersion time. Hygroscopic expansion of these four materials can partly compensate for the polymerization shrinkage. SDR showed the lowest hygroscopic expansion of the four tested materials when immersed in deionized water and artificial saliva. PC showed the highest hygroscopic expansion in deionized water, while LC showed the highest hygroscopic expansion in artificial saliva. In the case of different immersion solvents, osmotic pressure should be considered. For hygroscopic dimensional changes, the hydrophilicity of monomers and changes of intermolecular forces may be crucial factors.


Assuntos
Resinas Compostas , Água , Teste de Materiais , Saliva Artificial , Molhabilidade
10.
Chin Med J (Engl) ; 133(24): 2919-2927, 2020 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-33252379

RESUMO

BACKGROUND: Albuvirtide is a once-weekly injectable human immunodeficiency virus (HIV)-1 fusion inhibitor. We present interim data for a phase 3 trial assessing the safety and efficacy of albuvirtide plus lopinavir-ritonavir in HIV-1-infected adults already treated with antiretroviral drugs. METHODS: We carried out a 48-week, randomized, controlled, open-label non-inferiority trial at 12 sites in China. Adults on the World Health Organization (WHO)-recommended first-line treatment for >6 months with a plasma viral load >1000 copies/mL were enrolled and randomly assigned (1:1) to receive albuvirtide (once weekly) plus ritonavir-boosted lopinavir (ABT group) or the WHO-recommended second-line treatment (NRTI group). The primary endpoint was the proportion of patients with a plasma viral load below 50 copies/mL at 48 weeks. Non-inferiority was prespecified with a margin of 12%. RESULTS: At the time of analysis, week 24 data were available for 83 and 92 patients, and week 48 data were available for 46 and 50 patients in the albuvirtide and NRTI groups, respectively. At 48 weeks, 80.4% of patients in the ABT group and 66.0% of those in the NRTI group had HIV-1 RNA levels below 50 copies/mL, meeting the criteria for non-inferiority. For the per-protocol population, the superiority of albuvirtide over NRTI was demonstrated. The frequency of grade 3 to 4 adverse events was similar in the two groups; the most common adverse events were diarrhea, upper respiratory tract infections, and grade 3 to 4 increases in triglyceride concentration. Renal function was significantly more impaired at 12 weeks in the patients of the NRTI group who received tenofovir disoproxil fumarate than in those of the ABT group. CONCLUSIONS: The TALENT study is the first phase 3 trial of an injectable long-acting HIV drug. This interim analysis indicates that once-weekly albuvirtide in combination with ritonavir-boosted lopinavir is well tolerated and non-inferior to the WHO-recommended second-line regimen in patients with first-line treatment failure. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02369965; https://www.clinicaltrials.gov.Chinese Clinical Trial Registry No. ChiCTR-TRC-14004276; http://www.chictr.org.cn/enindex.aspx.


Assuntos
Fármacos Anti-HIV , Infecções por HIV , HIV-1 , Adulto , Fármacos Anti-HIV/efeitos adversos , Terapia Antirretroviral de Alta Atividade , China , Quimioterapia Combinada , Infecções por HIV/tratamento farmacológico , Humanos , Maleimidas , Peptídeos , Ritonavir/uso terapêutico , Resultado do Tratamento , Carga Viral
11.
Front Oncol ; 10: 596822, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33224892

RESUMO

Purpose: To explore risk factors for severe acute oral mucositis of nasopharyngeal carcinoma (NPC) patients receiving chemo-radiotherapy, build predictive models and determine preventive measures. Methods and Materials: Two hundred and seventy NPC patients receiving radical chemo-radiotherapy were included. Oral mucosa structure was contoured by oral cavity contour (OCC) and mucosa surface contour (MSC) methods. Oral mucositis during treatment was prospectively evaluated and divided into severe mucositis group (grade ≥ 3) and non-severe mucositis group (grade < 3) according to RTOG Acute Reaction Scoring System. Nineteen clinical features and nineteen dosimetric parameters were included in analysis, least absolute shrinkage and selection operator (LASSO) logistic regression model was used to construct a risk score (RS) system. Results: Two predictive models were built based on the two delineation methods. MSC based model is more simplified one, it includes body mass index (BMI) classification before radiation, retropharyngeal lymph node (RLN) area irradiation status and MSC V55%, RS = -1.480 + (0.021 × BMI classification before RT) + (0.126 × RLN irradiation) + (0.052 × MSC V55%). The cut-off of MSC based RS is -1.011, with an area under curve (AUC) of 0.737 (95%CI: 0.672-0.801), a specificity of 0.595 and a sensitivity of 0.786. OCC based model involved more variables, RS= -4.805+ (0.152 × BMI classification before RT) + (0.080 × RT Technique) + (0.097 × Concurrent Nimotuzumab) + (0.163 × RLN irradiation) + (0.028 × OCC V15%) + (0.120 × OCC V60%). The cut-off of OCC based RS is -0.950, with an AUC of 0.767 (95%CI: 0.702-0.831), a specificity of 0.602 and a sensitivity of 0.819. Analysis in testing set shown higher AUC of MSC based model than that of OCC based model (AUC: 0.782 vs 0.553). Analysis in entire set shown AUC in these two method-based models were close (AUC: 0.744 vs 0.717). Conclusion: We constructed two risk score predictive models for severe oral mucositis based on clinical features and dosimetric parameters of nasopharyngeal carcinoma patients receiving chemo-radiotherapy. These models might help to discriminate high risk population in clinical practice that susceptible to severe oral mucositis and individualize treatment plan to prevent it.

12.
Chin Med J (Engl) ; 133(24): 2953-2962, 2020 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-33093283

RESUMO

BACKGROUND: Myocardial infarction occurs due to insufficient (ischemia) blood supply to heart for long time; plasmacytoma variant translocation 1 (PVT1) is a long non-coding RNAs (lncRNAs) involved in the pathogenesis of various diseases, including heart disease; However, few studies have explored its role. The present study evaluated the effects of lncRNA PVT1 on hypoxic rat H9c2 cells. METHODS: Hypoxic injury was examined by measuring cell viability and apoptosis by using cell counting kit-8 activity and flow cytometry assays. Gene expressions after hypoxia were estimated by quantitative real time polymerase chain reaction and the signaling pathway were explored by Western blot analysis. RNA immunoprecipitation and luciferase reporter assays were applied to examine the interactions among genes. Data were analyzed using t-test with one-way or two-way analysis of variance. RESULTS: The lncRNA PVT1 is up-regulated in hypoxia-stressed H9c2 cells and knockdown of PVT1 mitigates hypoxia-induced injury in H9c2 cells. PVT1 acts as a sponge for miR-135a-5p and knockdown of PVT1 attenuated the increased hypoxia-induced injury by up-regulating miR-135a-5p. Forkhead box O1 (FOXO1) was identified as a target of miR-135a-5p, and the expression was negatively regulated by miR-135a-5p. The exploration of the underlying mechanism demonstrated that knockdown of FOXO1 reversed PVT1/miR-135a-5p mediated hypoxia-induced injury in H9c2 cells. CONCLUSIONS: PVT1 plays a crucial role in hypoxia-injured H9c2 cells through sponging miR-135a-5p and then positively regulating FOXO1.


Assuntos
MicroRNAs , Plasmocitoma , RNA Longo não Codificante , Animais , Hipóxia , MicroRNAs/genética , Miócitos Cardíacos , RNA Longo não Codificante/genética , Ratos
13.
Arch Biochem Biophys ; 695: 108623, 2020 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-33039388

RESUMO

Renal cell carcinoma (RCC) is a frequently diagnosed cancer with high prevalence, which is inversely associated with survival benefit. Although myriad studies have shed light on disease causality, unfortunately, thus far, RCC diagnosis is faced with numerous obstacles partly due to the insufficient knowledge of effective biomarkers, hinting deeper mechanistic understanding are urgently needed. Metabolites are recognized as final proxies for gene-environment interactions and physiological homeostasis as they reflect dynamic processes that are ongoing or have been taken place, and metabolomics may therefore offer a far more productive and cost-effective route to disease discovery, particularly within the arena for new biomarker identification. In this review, we primarily expatiate recent advances in metabolomics that may be amenable to novel biomarkers or therapeutic targets for RCC, which may expand our armaments to win more bettles against RCC.


Assuntos
Biomarcadores Tumorais/metabolismo , Carcinoma de Células Renais/metabolismo , Neoplasias Renais/metabolismo , Metabolômica , Animais , Carcinoma de Células Renais/patologia , Carcinoma de Células Renais/terapia , Humanos , Neoplasias Renais/patologia , Neoplasias Renais/terapia
14.
Biomark Res ; 8: 42, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32944245

RESUMO

Abstract: Aging and average life expectancy have been increasing at a rapid rate, while there is an exponential risk to suffer from brain-related frailties and neurodegenerative diseases as the population ages. Alzheimer's disease (AD) is the most common neurodegenerative disease worldwide with a projected expectation to blossom into the major challenge in elders and the cases are forecasted to increase about 3-fold in the next 40 years. Considering the etiological factors of AD are too complex to be completely understood, there is almost no effective cure to date, suggesting deeper pathomechanism insights are urgently needed. Metabolites are able to reflect the dynamic processes that are in progress or have happened, and metabolomic may therefore provide a more cost-effective and productive route to disease intervention, especially in the arena for pathomechanism exploration and new biomarker identification. In this review, we primarily focused on how redox signaling was involved in AD-related pathologies and the association between redox signaling and altered metabolic pathways. Moreover, we also expatiated the main redox signaling-associated mechanisms and their cross-talk that may be amenable to mechanism-based therapies. Five natural products with promising efficacy on AD inhibition and the benefit of AD intervention on its complications were highlighted as well.

15.
Phytomedicine ; 79: 153323, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32920287

RESUMO

BACKGROUND: Renal fibrosis is the final manifestation of chronic kidney disease (CKD). Renal fibrosis is largely driven by oxidative stress and inflammation. PURPOSE: The aim of the current study was to identify novel poricoic acids from Poria cocos and investigated their antifibrotic effects and the underlying mechanism. METHODS: In this study, we identified six novel poricoic acids from Poria cocos and examined their antifibrotic effect using transforming growth factor-ß1- (TGF-ß1-) induced cultured human kidney proximal tubular epithelial cells (HK-2) and mice with unilateral ureteral obstruction (UUO). RESULTS: Treatment with six poricoic acids significantly inhibited TGF-ß1-induced α-smooth muscle actin expression at both mRNA and protein levels in HK-2 cells. Three compounds with an intact carboxyl group at C-3 position showed a stronger inhibitory effect than that of other three compounds with esterified carboxyl group at the C-3 position. Mechanistically, poricoic acid ZM (PZM) and poricoic acid ZP (PZP) attenuate renal fibrosis through the modulation of redox signalling including the inhibition of proinflammatory nuclear factor kappa B (NF-κB) signalling and its target genes as well as the activation of antioxidative nuclear factor-erythroid-2-related factor 2 (Nrf2) signalling and its downstream target gene in both TGF-ß1-induced HK-2 cells and UUO mice. PZM treatment and PZP treatment inhibit the upregulated aryl hydrocarbon receptor and they target the gene expression in UUO mice. Intriguingly, PZM treatment exhibits a stronger inhibitory effect than that of the PZP treatment. Structure-function relationship reveals that the carboxyl group at C-3 position is the most important bioactive function group in secolanostane tetracyclic triterpenoids against renal fibrosis. CONCLUSIONS: PZM and PZP attenuated renal fibrosis through the modulation of redox signalling and the aryl hydrocarbon receptor signalling pathway. Our findings will provide several promising leading compounds against renal fibrosis.


Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Nefropatias/tratamento farmacológico , Rim/efeitos dos fármacos , Rim/patologia , Receptores de Hidrocarboneto Arílico/metabolismo , Animais , Linhagem Celular , Fibrose , Humanos , Nefropatias/metabolismo , Nefropatias/patologia , Túbulos Renais Proximais/citologia , Masculino , Camundongos Endogâmicos BALB C , Estrutura Molecular , Fator 2 Relacionado a NF-E2/metabolismo , NF-kappa B/metabolismo , Oxirredução/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Obstrução Ureteral/tratamento farmacológico , Obstrução Ureteral/genética , Wolfiporia/química
16.
Cancer Manag Res ; 12: 5909-5918, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32765092

RESUMO

Purpose: Radiotherapy is a powerful strategy to prevent chest wall recurrence (CWR) of postmastectomy breast cancer (BC). This retrospective study aims at analyzing patterns of CWR to explore the delineation of clinical target volume. Patients and Methods: Detailed clinicopathological information of postmastectomy BC patients with CWR was collected from our single cancer center based on clear criteria. To describe recurrent positions more accurately, the chest wall was divided into three layers: skin layer (skin and subcutaneous tissues), pectoralis layer (pectoralis major and minor), and rib layer (rib and intercostal muscle). The frequency distribution of recurrence location and its association with clinical pathological factors were analyzed. Results: A total of 121 postmastectomy BC with CWR were included in this study. The percentages of breast tumor located in the upper outer quadrant, upper inner quadrant, lower inner quadrant, lower outer quadrant, overlapping quadrant, and areola area were 31.0% (35/113), 26.5% (30/113), 12.4% (14/113), 5.3% (6/113), 21.1% (25/113), and 2.7% (3/113), respectively. HER2-positive BC (51/113, 45.1%) is the most common BC subtype. Analysis on the patterns of CWR showed that recurrences locating in the skin layer, pectoralis layer, rib layer, mixed layers, and incision periphery accounted for 58.6% (68/116), 9.5% (11/116), 1.7% (2/116), 30.2% (35/116), and 60.5% (46/76), respectively. Rates of recurrences located in the skin and/or pectoralis layers for all BC patients, patients with concomitant distance metastasis, and patients without concomitant distance metastasis were 82.8% (96/116), 85.9% (49/57), and 81.0% (47/58), respectively. Conclusion: For BC patients receiving mastectomy, skin, subcutaneous tissues, pectoralis, and area around incision have a high risk of recurrence, which should be paid more attention in chest wall radiotherapy.

17.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(4): 1221-1227, 2020 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-32798402

RESUMO

OBJECTIVE: To investigate the clinical efficacy and prognosis of double-hit multiple myeloma patients with deletion P53 treated with regimen based on bortezomib. METHODS: The ethnical data from 186 newly diagnosed MM patients hospitalized in the Department of Hematology of Harrison International Peace hospital from January 2012 to January 2019 were analyzed retrospectively. The fluorescent in situ hybridization (FISH) and G-binding staining were used to detect cytogenetic abnormalities (P53 deletion, lq21 amplification and IgH rearranagement) for analyses of complete remission (CR), overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) of patients treated with bortezomib for 4 circles. RESULTS: In 186 patients, simple P53 deletion was 14 cases, 1q21 amplification and P53 deletion were found in 11 cases (A group), t (14;16) and P53 deletion in 7 cases (B group), t (4;14) and P53 deletion in 9 cases (C group). The complete remission rate (CR%) of above-mentioned three groups was 27.27%, 28.57% and 33.33% respectively, and the ORR of the three groups was 54.54%, 57.14% and 55.56%, respectively, there was no statistically significant difference between the three groups (P>0.05). The patients with 1q21 amplification and P53 deletion had shorter OS and PFS time (P=0.041, P=0.046). The double-hit patients with 1q21 amplification showed shorter OS time, compared with the patients with P53 deletion (P=0.027). The double-hit patients with t(14;16) and t(4;14) showed shorter OS time (P=0.871, P=0.276) and PFS time (P=0.955, P=0.379) than those of the patients with P53 deletion. CONCLUSION: P53 deletion and 1q21 amplification are an adverse prognostic factor of early recurrence and short lifetime in patients with newly diagnosed double-hit MM.


Assuntos
Mieloma Múltiplo , Bortezomib , Aberrações Cromossômicas , Humanos , Hibridização in Situ Fluorescente , Prognóstico , Estudos Retrospectivos , Resultado do Tratamento , Proteína Supressora de Tumor p53
18.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 28(4): 1292-1297, 2020 Aug.
Artigo em Chinês | MEDLINE | ID: mdl-32798414

RESUMO

OBJECTIVE: To study therapeutic efficacy and side effects of single decitabine for DNMT3A+ myelodysplastic syndrome (MDS) patients. METHODS: The clinical characteristics, efficacy and side effects of 59 myelodysplastic syndrome patients received the decitabine therapy in our center from January 2015 to December 2018 were retrospectively analyzed. Based on gene mutations, these patients were divided into 2 groups: DNMT3A+ MDS patients (n=27) and DNMT3A- MDS patients (n=32). All patients in two groups were treated with decitabine for 4 circles. The efficacy and side effects in the two groups were compared. RESULTS: The median age of patients in DNMT3A+ MDS group was 56.2 (37-81) which was no statistic difference from DNMT3A- MDS group. And there was no statistical difference including age, white blood cells, hemoglobin and platelet count between the two groups (P>0.05). The ORR and complete response (CR) rate of DNMT3A+ group were 70.37% and 40.74%, the ORR and CR rate of DNMT3A- group were 40.63% and 21.88% respectively. Significant differences were observed in ORR rate (P=0.035) between two groups. However, significant differences did not found in CR rate (P=0.159) between two groups, The similar adverse reaction was observed in DNMT3A+ and DNMT3A- MDS patients. Among the 59 patients, 21 patients showed TP53+ mutation. DNMT3A+/TP53+ MDS patients (n=13) had similar ORR and CR compared with the DNMT3A-/TP53+ MDS patients (n=8) (P>0.05). The overall survival (OS) in DNMT3A+ MDS group and DNMT3A- MDS group were 29.1±13.4 months and 27.8±14.4 months, respectively, no significant differences between two groups were observed (P=0.475). CONCLUSION: Decitabine treatment is an effective and safe for DNMT3A+ MDS patients, but not shows better survival advantage.


Assuntos
Decitabina , Síndromes Mielodisplásicas , Azacitidina , Humanos , Estudos Retrospectivos , Resultado do Tratamento
19.
Huan Jing Ke Xue ; 41(2): 702-712, 2020 Feb 08.
Artigo em Chinês | MEDLINE | ID: mdl-32608729

RESUMO

The Wenyu River is an important ecological corridor of Beijing. In this study, the spatio-temporal dynamics of water quality and phytoplankton community in the Wenyu River in 2006, 2011, and 2018, as well as their relationship were thoroughly analyzed by historical data analysis and field surveys. Results show that the water quality in the Wenyu River improved significantly from serious pollution owing to pollution containment. The major water pollutant has shifted from ammonia nitrogen (NH4+-N) to total nitrogen (TN). Compared with 2011, the average multiple of NH4+-N and total nitrogen TN exceeding the national standard were reduced by factors of 0.29-0.33 and 2.77-2.39, respectively, in 2018. The average concentration of NH4+-N and TN decreased from 15.52-19.16 mg·L-1 and 20.21-19.58 mg·L-1 in 2011 to 1.93-2.66 mg·L-1 and 5.66-6.79 mg·L-1 in 2018. Moreover, dissolved oxygen (DO) and NH4+-N concentrations in the Wenyu River and its tributaries, the Qinghe River, almost met requirements of their water function zoning target. Corresponding with the water quality improvement, the phytoplankton and community species increased dramatically. Phytoplankton species increased from 6 to 8 phyla, as well as community species. The dominant species changed from Chlorophyta in 2006 to the Cyanophyta in 2011, then to Bacillariophyta in 2018. The Shannon-Wiener diversity index (H') and evenness Pielou index (J) had improved. However, the major dominant species such as Cyclotella and Melosira persisted, and the Wenyu River was still in the eutrophication state in 2018. Statistical analysis results indicated that Cyanophyta, Bacillariophyta, and other algae abundance were significantly correlated with DO, pH, NH4+-N, TN, and TP.


Assuntos
Fitoplâncton/classificação , Rios , Poluição da Água/análise , Qualidade da Água , Pequim , China , Estações do Ano , Análise Espaço-Temporal
20.
Ther Adv Chronic Dis ; 11: 2040622320920025, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32547719

RESUMO

Background: Increasing evidence suggests a link between the gut microbiome and various diseases including hypertension and chronic kidney disease (CKD). However, studies examining the efficacy of controlling blood pressure and inhibiting the renin-angiotensin system (RAS) in preventing CKD progression are limited. Methods: In the present study, we used 5/6 nephrectomised (NX) and unilateral ureteral obstructed (UUO) rat models and cultured renal tubular epithelial cells and fibroblasts to test whether alisol B 23-acetate (ABA) can attenuate renal fibrogenesis by regulating blood pressure and inhibiting RAS. Results: ABA treatment re-established dysbiosis of the gut microbiome, lowered blood pressure, reduced serum creatinine and proteinuria, suppressed expression of RAS constituents and inhibited the epithelial-to-mesenchymal transition in NX rats. Similarly, ABA treatment inhibited expression of collagen I, fibronectin, vimentin, α-smooth muscle actin and fibroblast-specific protein 1 at both mRNA and protein levels in UUO rats. ABA was also effective in suppressing activation of the transforming growth factor-ß (TGF-ß)/Smad3 and preserving Smad7 expression in both NX and UUO rats. In vitro experiments demonstrated that ABA treatment inhibited the Wnt/ß-catenin and mitochondrial-associated caspase pathways. Conclusion: These data suggest that ABA attenuated renal fibrosis through a mechanism associated with re-establishing dysbiosis of the gut microbiome and regulating blood pressure, and Smad7-mediated inhibition of Smad3 phosphorylation. Thus, we demonstrate ABA as a promising candidate for treatment of CKD by improving the gut microbiome and regulating blood pressure.

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