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1.
Artigo em Inglês | MEDLINE | ID: mdl-38810241

RESUMO

In the field of pulmonary hypertension (PH), a well-established protocol to induce severe angioproliferation in rats (SuHx) involves combining the VEGF-R inhibitor Sugen 5416 (SU5416) with three weeks of hypoxia (Hx). Additionally, injecting monocrotaline (MCT) into rats can induce inflammation and shear stress in the pulmonary vasculature, leading to neointima-like remodeling. However, the SuHx protocol in mice is still controversial, with some studies suggesting it yields higher and reversible PH than Hx alone, possibly due to species-dependent hypoxic responses. To establish an alternative rodent model of PH, we hypothesized mice would be more sensitive to hemodynamic changes secondary to shear stress compared to Hx. We attempted to induce severe and irreversible PH in mice by combining SU5416 or monocrotaline pyrrole (MCTP) injection with pneumonectomy (PNx). However, our experiments showed SU5416 administered to mice at various time points after PNx did not result in severe PH. Similarly, mice injected with MCTP after PNx (MPNx) showed no difference in right ventricular systolic pressure or exacerbated pulmonary vascular remodeling compared to PNx alone. These findings collectively demonstrate that C57/B6 mice do not develop severe and persistent PH when PNx is combined with either SU5416 or MCTP.

2.
Int J Mol Sci ; 25(3)2024 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-38338913

RESUMO

DNA methylation and chromatin accessibility play important roles in gene expression, but their function in subgenome expression dominance remains largely unknown. We conducted comprehensive analyses of the transcriptome, DNA methylation, and chromatin accessibility in liver and muscle tissues of allotetraploid common carp, aiming to reveal the function of epigenetic modifications in subgenome expression dominance. A noteworthy overlap in differential expressed genes (DEGs) as well as their functions was observed across the two subgenomes. In the promoter and gene body, the DNA methylation level of the B subgenome was significantly different than that of the A subgenome. Nevertheless, differences in DNA methylation did not align with changes in homoeologous biased expression across liver and muscle tissues. Moreover, the B subgenome exhibited a higher prevalence of open chromatin regions and greater chromatin accessibility, in comparison to the A subgenome. The expression levels of genes located proximally to open chromatin regions were significantly higher than others. Genes with higher chromatin accessibility in the B subgenome exhibited significantly elevated expression levels compared to the A subgenome. Contrastingly, genes without accessibility exhibited similar expression levels in both subgenomes. This study contributes to understanding the regulation of subgenome expression dominance in allotetraploid common carp.


Assuntos
Carpas , Metilação de DNA , Animais , Carpas/genética , Genoma de Planta , Cromatina/genética , Poliploidia , Regulação da Expressão Gênica de Plantas
3.
Foods ; 12(17)2023 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-37685087

RESUMO

Hyperspectral imaging (HSI) has been applied to assess the texture profile analysis (TPA) of processed meat. However, whether the texture profiles of live fish muscle could be assessed using HSI has not been determined. In this study, we evaluated the texture profile of four muscle regions of live common carp by scanning the corresponding skin regions using HSI. We collected skin hyperspectral information from four regions of 387 scaled and live common carp. Eight texture indicators of the muscle corresponding to each skin region were measured. With the skin HSI of live common carp, six machine learning (ML) models were used to predict the muscle texture indicators. Backpropagation artificial neural network (BP-ANN), partial least-square regression (PLSR), and least-square support vector machine (LS-SVM) were identified as the optimal models for predicting the texture parameters of the dorsal (coefficients of determination for prediction (rp) ranged from 0.9191 to 0.9847, and the root-mean-square error for prediction ranged from 0.1070 to 0.3165), pectoral (rp ranged from 0.9033 to 0.9574, and RMSEP ranged from 0.2285 to 0.3930), abdominal (rp ranged from 0.9070 to 0.9776, and RMSEP ranged from 0.1649 to 0.3601), and gluteal (rp ranged from 0.8726 to 0.9768, and RMSEP ranged from 0.1804 to 0.3938) regions. The optimal ML models and skin HSI data were employed to generate visual prediction maps of TPA values in common carp muscles. These results demonstrated that skin HSI and the optimal models can be used to rapidly and accurately determine the texture qualities of different muscle regions in common carp.

4.
Int J Mol Sci ; 24(13)2023 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-37445816

RESUMO

Highly unsaturated fatty acids (HUFAs) are essential for mammalian health, development and growth. However, most mammals, including humans, are incapable of synthesizing n-6 and n-3 HUFAs. Fish can convert C18 unsaturated fatty acids into n-6 and n-3 HUFAs via fatty acid desaturase (Fads), in which Fads2 is a key enzyme in HUFA biosynthesis. The allo-tetraploid common carp theoretically encode two duplicated fads2 genes. The expression patterns and desaturase functions of these two homologous genes are still unknown. In this study, the full length of the fads2a and fads2b were identified in common carp (Cyprinus carpio). Expression analyses indicate that both genes were mainly expressed in the liver and the expression of fads2b is higher than fads2a at different developmental stages in carp embryos. Heterogenous expression and 3D docking analyses suggested that Fads2b demonstrated stronger ∆6 and ∆5 desaturase activities than Fads2a. The core promotor regions of fads2a and fads2b were characterized and found to have different potential transcriptional binding sites. These results revealed the same desaturase functions, but different activities of two homologues of fasd2 genes in common carp. The data showed that fads2b played a more important role in HUFA synthesis through both expression and functional analyses.


Assuntos
Carpas , Ácidos Graxos Ômega-3 , Animais , Humanos , Carpas/genética , Carpas/metabolismo , Linoleoil-CoA Desaturase , Ácidos Graxos Dessaturases/metabolismo , Ácidos Graxos Insaturados/metabolismo , Mamíferos/metabolismo
5.
Biology (Basel) ; 12(4)2023 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-37106724

RESUMO

The allo-tetraploid common carp encodes two duplicated fads2 genes (fads2a and fads2b) and two duplicated elovl5 genes (elovl5a and elovl5b). The coding SNPs (cSNPs) of these genes were reported to be significantly associated with the PUFA contents. Whether the promoter SNPs (pSNPs) were associated with the PUFA contents has not been reported yet. In this study, after sequencing the promoters of these four genes, we identified six pSNPs associated with the contents of PUFAs in common carp, including one elovl5a pSNP, one elovl5b pSNP, and four fads2b pSNPs. The pSNPs were predicted in the locations of transcriptional factor binding sites. Together with previously identified cSNPs in fads2b and elovl5b, the pSNPs and cSNPs of these two genes had the joint effects on the PUFA contents with higher explained percentage of phenotypic variation of the PUFA contents than single gene. The expression levels of both fads2a and fads2b were significantly positively correlated with the contents of six PUFAs. The fads2b pSNPs corresponding to higher fads2b expression levels were associated with higher PUFA contents. The pSNPs and cSNPs will be useful for the future selection breeding of common carp with higher PUFA contents.

6.
Chemistry ; 29(36): e202300793, 2023 Jun 27.
Artigo em Inglês | MEDLINE | ID: mdl-36989413

RESUMO

1,5,9-Tribromo-2,3,6,7,10,11-hexamethoxy-4b1 -methyltribenzotriquinacene, a C3 -symmetric TBTQ derivative, can be prepared conveniently and with high regioselectivity from readily available starting materials. It is a versatile key compound for the synthesis of other chiral 1,5,9-trifunctionalized TBTQ derivatives and π-extended congeners in which the bays of the TBTQ skeleton are bridged by vinylene and 1,2-arylene units. X-ray crystal structure analysis and UV-vis spectroscopy show that vinylene bay-bridging enables better π-conjugation with the arene rings of the TBTQ core than 1,2-arylene bay-bridging does.

7.
Hematol Oncol ; 41(2): 248-256, 2023 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34472655

RESUMO

This retrospective cohort study aimed to evaluate primary treatment and recent survival trends in patients with primary diffuse large B-cell lymphoma of central nervous system (CNS) from 1995 to 2016. Using the SEER data, patients diagnosed with non-HIV-associated primary central nervous system lymphoma (PCNSL)-diffuse large B-cell lymphoma (DLBCL) aged ⩾18 years between 1995 and 2016 were identified. The year of diagnosis was divided into the time period-1 (1995-2002), the time period-2 (2003-2012), and the time period-3 (2013-2016). Chi-square tests, the Kaplan-Meier method, log-rank test, and Cox regression model were used in the analysis. Overall, 3760 patients were included. Both the use of radiotherapy alone and the application of combined chemoradiotherapy decreased significantly, following the wider use of chemotherapy alone during 1995-2016. There was a significant improvement in PCNSL cause-specific survival (CSS) (period-1: 13 months vs. period-2: 19 months vs. period-3: 41 months, p < 0.001). Survival of patients aged above 70 years did not change from the time period-1 to the time period-2 (p = 0.101). However, there was an increase in CSS from the time period-2 to the time period-3 in the elderly patients (period-2: 5 months vs. period-3: 9 months, p < 0.001). On multivariable analyses, diagnosed in the time period-3 was significantly and independently associated with better CSS (hazard ratio 0.577, 95% confidence interval 0.506-0.659, p < 0.001). Our analysis shows the use of radiotherapy in the treatment of PCNSL has waned over the study span. There was a significant improvement in CSS during 1995-2016, which reflected developments in treatment over time. The elderly patient population also gained a significant CSS benefit in the most recent period.


Assuntos
Neoplasias do Sistema Nervoso Central , Linfoma Difuso de Grandes Células B , Linfoma não Hodgkin , Idoso , Humanos , Estudos Retrospectivos , Linfoma Difuso de Grandes Células B/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Sistema Nervoso Central/patologia
8.
Int J Mol Sci ; 23(23)2022 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-36498993

RESUMO

Most diploid freshwater and marine fish encode one elovl5 elongase, having substrate specificity and activities towards C18, C20 and C22 polyunsaturated fatty acids (PUFAs). The allo-tetraploid common carp is hypothesized to encode two duplicated elovl5 genes. How these two elovl5 genes adapt to coordinate the PUFA biosynthesis through elongase function and expression divergence requires elucidation. In this study, we obtained the full-length cDNA sequences of two elovl5 genes in common carp, named as elovl5a and elovl5b. Functional characterization showed that both enzymes had elongase activity towards C18, C20 and C22 PUFAs. Especially, the activities of these two enzymes towards C22 PUFAs ranged from 3.87% to 8.24%, higher than those in most freshwater and marine fish. The Elovl5a had higher elongase activities than Elovl5b towards seven substrates. The spatial-temporal expression showed that both genes co-transcribed in all tissues and development stages. However, the expression levels of elovl5b were significantly higher than those of elovl5a in all examined conditions, suggesting that elovl5b would be the dominantly expressed gene. These two genes had different potential transcriptional binding sites. These results revealed the complicated roles of elovl5 on PUFA synthesis in common carp. The data also increased the knowledge of co-ordination between two homoeologs of the polyploid fish through function and expression divergence.


Assuntos
Carpas , Animais , Elongases de Ácidos Graxos/genética , Elongases de Ácidos Graxos/metabolismo , Carpas/genética , Carpas/metabolismo , Acetiltransferases/metabolismo , Ácidos Graxos Insaturados/metabolismo , Especificidade por Substrato
9.
Front Immunol ; 13: 766200, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35237257

RESUMO

Asparaginase/pegaspargase containing regimens combined with radiotherapy are highly effective and considered the cornerstone of localized Natural killer/T-cell lymphoma (NKTL) treatment. However, these chemotherapy regimens inevitably cause relatively high incidence of treatment-related adverse events (TRAEs). Herein we retrospectively evaluated the efficacy and safety of the combined regimen of anti-PD-1 antibody, anlotinib and pegaspargase "sandwich" with radiotherapy in localized NKTL. Anti-PD-1 antibody and pegaspargase at 2500 U/m2 were administered on day 1, while anlotinib (12 mg once a day) was orally administered on days 1-14. The treatment was repeated every 3 weeks. All the eight patients included received 3 cycles of the regimen followed by radiotherapy and an additional 3 cycles. The overall response rate was 100%, and the complete response rate was 87.5%. With a median follow-up time of 35.5 months (range, 34.03-40.90 months), median PFS and OS times were not reached. The 3-year PFS and OS rates were 100% and 100%, respectively. All patients were alive at the last follow-up. No treatment-related death and no grade 4 TRAE was reported. No grade 3/4 hematological toxicity was detected, and half of the patients didn't report any hematological toxicity. This study indicates that anti-PD-1 antibody combined with anlotinib and pegaspargase is a promising chemoradiotherapy regimen for localized NTKL, with mild toxicity and good tolerance.


Assuntos
Asparaginase , Linfoma Extranodal de Células T-NK , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Asparaginase/uso terapêutico , Desoxicitidina/uso terapêutico , Humanos , Indóis , Células Matadoras Naturais/patologia , Linfoma Extranodal de Células T-NK/tratamento farmacológico , Linfoma Extranodal de Células T-NK/radioterapia , Polietilenoglicóis , Quinolinas , Estudos Retrospectivos
10.
Biology (Basel) ; 11(3)2022 Mar 18.
Artigo em Inglês | MEDLINE | ID: mdl-35336839

RESUMO

The allo-tetraploid common carp, one widely cultured food fish, is able to produce poly-unsaturated fatty acids (PUFAs). The genetic markers on the PUFA contents for breeding was limited. The polymorphisms in elovl5a and elovl5b, the rate-limiting enzymes in the PUFA biosynthesis, have not been investigated yet. Herein, we identified one coding SNP (cSNP) in elovl5a associated with the content of one PUFA and two cSNPs in elovl5b with the contents of eight PUFAs. The heterozygous genotypes in these three loci were associated with higher contents than the homozygotes. Together with previously identified two associated cSNPs in fads2b, we found the joint effect of these four cSNPs in fads2b and elovl5b on the PUFA contents with the increased explained percentages of PUFA contents. The genotype combinations of more heterozygotes were associated with higher PUFA contents than the other combinations. Using ten genomic selection programs with all cSNPs in fads2b and elovl5b, we obtained the high and positive correlations between the phenotypes and the estimated breeding values of eight PUFAs. These results suggested that elovl5b might be the major gene corresponding to common carp PUFA contents compared with elovl5a. The cSNP combinations in fads2b and elovl5b and the optimal genomic selection program will be used in the future selection breeding to improve the PUFA contents of common carp.

11.
Biology (Basel) ; 11(3)2022 Mar 21.
Artigo em Inglês | MEDLINE | ID: mdl-35336850

RESUMO

The allotetraploid common carp is one of the most important freshwater food fish. However, the IBs found in allotetraploid common carp increase the difficulty in fish meat processing and consumption. Although candidate genes associated with the total IB number have been identified, the SNPs associated with the numbers of the total IBs and different forms of IBs have not yet been identified, hindering the breeding of IB-reduced common carp. Herein, the numbers of different types of IBs in three common carp strains were measured. Using whole-genome resequencing and bulked segregant analysis in three pairs of IB-more and IB-less groups, we identified the consensus nonsynonymous SNPs in three strains of common carp. Screening the flanking regions of these SNPs led to the detection of other SNPs. Association study detected 21 SNPs significantly associated with the number of total IBs, epineural-IBs, and ten detailed types of IBs. We observed the joint effects of multiple SNPs on each associated IB number with an improved explained percentage of phenotypic variation. The resulting dataset provides a resource to understand the molecular mechanisms of IB development in different common carp strains. These SNPs are potential markers for future selection to generate IB-reduced common carp.

12.
Cells ; 11(6)2022 03 12.
Artigo em Inglês | MEDLINE | ID: mdl-35326434

RESUMO

Over the past decades, a better understanding of the genetic and molecular alterations underlying several respiratory diseases has encouraged the development of new therapeutic strategies. Gene therapy offers new therapeutic alternatives for inherited and acquired diseases by delivering exogenous genetic materials into cells or tissues to restore physiological protein expression and/or activity. In this review, we review (1) different types of viral and non-viral vectors as well as gene-editing techniques; and (2) the application of gene therapy for the treatment of respiratory diseases and disorders, including pulmonary arterial hypertension, idiopathic pulmonary fibrosis, cystic fibrosis, asthma, alpha-1 antitrypsin deficiency, chronic obstructive pulmonary disease, non-small-cell lung cancer, and COVID-19. Further, we also provide specific examples of lung-targeted therapies and discuss the major limitations of gene therapy.


Assuntos
COVID-19 , Carcinoma Pulmonar de Células não Pequenas , Fibrose Cística , Neoplasias Pulmonares , COVID-19/genética , COVID-19/terapia , Fibrose Cística/metabolismo , Humanos , Pulmão/metabolismo
14.
Nat Genet ; 53(10): 1493-1503, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34594040

RESUMO

How two subgenomes in allo-tetraploids adapt to coexistence and coordinate through structure and expression evolution requires extensive studies. In the present study, we report an improved genome assembly of allo-tetraploid common carp, an updated genome annotation of allo-tetraploid goldfish and the chromosome-scale assemblies of a progenitor-like diploid Puntius tetrazona and an outgroup diploid Paracanthobrama guichenoti. Parallel subgenome structure evolution in the allo-tetraploids was featured with equivalent chromosome components, higher protein identities, similar transposon divergence and contents, homoeologous exchanges, better synteny level, strong sequence compensation and symmetric purifying selection. Furthermore, we observed subgenome expression divergence processes in the allo-tetraploids, including inter-/intrasubgenome trans-splicing events, expression dominance, decreased expression levels, dosage compensation, stronger expression correlation, dynamic functionalization and balancing of differential expression. The potential disorders introduced by different progenitors in the allo-tetraploids were hypothesized to be alleviated by increasing structural homogeneity and performing versatile expression processes. Resequencing three common carp strains revealed two major ecotypes and uncovered candidate genes relevant to growth and survival rate.


Assuntos
Carpas/genética , Evolução Molecular , Regulação da Expressão Gênica , Genoma , Carpa Dourada/genética , Tetraploidia , Processamento Alternativo/genética , Animais , Sequência de Bases , Variação Genética , Cariótipo , Funções Verossimilhança , Anotação de Sequência Molecular , Filogenia , Seleção Genética , Especificidade da Espécie , Sintenia/genética
15.
Animals (Basel) ; 11(6)2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34203588

RESUMO

Fatty acid desaturase 2 (fads2) is one of the rate-limiting enzymes in PUFAs biosynthesis. Compared with the diploid fish encoding one fads2, the allo-tetraploid common carp, one most important food fish, encodes two fads2 genes (fads2a and fads2b). The associations between the contents of different PUFAs and the polymorphisms of fads2a and fads2b have not been studied. The contents of 12 PUFAs in common carp individuals were measured, and the polymorphisms in the coding sequences of fads2a and fads2b were screened. We identified five coding single nucleotide polymorphisms (cSNPs) in fads2a and eleven cSNPs in fads2b. Using the mixed linear model and analysis of variance, a synonymous fads2a cSNP was significantly associated with the content of C20:3n-6. One non-synonymous fads2b cSNP (fads2b.751) and one synonymous fads2b cSNP (fads2b.1197) were associated with the contents of seven PUFAs and the contents of six PUFAs, respectively. The heterozygous genotypes in both loci were associated with higher contents than the homozygous genotypes. The fads2b.751 genotype explained more phenotype variation than the fads2b.1197 genotype. These two SNPs were distributed in one haplotype block and associated with the contents of five common PUFAs. These results suggested that fads2b might be the major gene responding to common carp PUFA contents and that fads.751 might be the main effect SNP. These cSNPs would be potential markers for future selection to improve the PUFA contents in common carp.

16.
Ann Transl Med ; 9(7): 532, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33987230

RESUMO

BACKGROUND: Nutritional status is a key factor influencing the prognosis of patients with cancer. The Geriatric Nutritional Risk Index (GNRI) has been used to predict mortality risk and long-term outcomes. In this study, we aimed to evaluate the predictive value of pretreatment GNRI in patients with nasopharyngeal carcinoma (NPC). METHODS: A total of 1,065 patients with biopsy-proven non-disseminated nasopharyngeal carcinoma were included. Based on a cutoff value of pretreatment GNRI, patients were divided into two groups (low ≤107.7 and high >107.7). Combining GNRI and baseline Epstein-Barr virus (EBV) DNA, all patients were further stratified into three risk groups, namely, high-risk (high EBV DNA and low GNRI), low-risk (low EBV DNA and high GNRI), and medium-risk (except the above) groups. Multivariate analyses were performed using the Cox proportional hazards model to assess the predictive value of the GNRI. RESULTS: Among the 1,065 patients, 527 (49.5%) and 538 (50.5%) were divided into low and high GNRI groups, respectively. Within a median follow-up of 83 months, patients with a high GNRI score exhibited significantly higher overall survival (OS), progression-free survival (PFS), and distant metastasis-free survival (DMFS) compared to those with low GNRI scores (P<0.05). Multivariate analyses revealed that high GNRI is an independent prognostic factor for OS and PFS (hazard ratio, HR, 0.471, 95% CI, 0.270-0.822, P=0.008; HR 0.638, 95% CI, 0.433-0.941, P=0.023, respectively). Using a combination of baseline GNRI and EBV DNA, a satisfying separation of survival curves between different risk groups for OS, PFS, DMFS was observed. The survival rates of patients in the high-risk group were significantly lower than those in the low- and medium-risk groups (all P<0.001). The combined classification was demonstrated to be an independent prognostic factor for OS and PFS after adjustment using multivariate analysis. CONCLUSIONS: Pretreatment GNRI is an independent prognostic factor for NPC patients. The combination of baseline GNRI score and EBV DNA level improved the prognostic stratification of NPC patients.

17.
J Cancer ; 12(7): 2059-2064, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33754004

RESUMO

Purpose: Diffuse large B cell lymphoma (DLBCL) with MYC rearrangement or double expression of MYC and BCL-2 (DE DLBCL) has a relatively poor prognosis and does not respond well to standard R-CHOP. In the current study, we aimed to investigate the efficacy and safety of R-split-EPOCH plus high dose methotrexate (HD-MTX) in the particular patient population. Methods: A total of 28 patients diagnosed with DE DLBCL or DLBCL with MYC rearrangement between January 2015 and December 2018 were included and retrospectively analyzed. All the participants underwent R-split-EPOCH plus HD-MTX as introduction therapy, with split infusion of etoposide, doxorubicin, and vincristine for 48 hours on D1-2 and D10-11, respectively. Results: The overall objective response (ORR) rate was 100%, with 24 (85.7%) complete response (CR) and 4 (14.3%) partial response (PR). The CR rate was 76.9% and 93.3% for DLBCL patients with MYC rearrangement and DE DLBCL patients, respectively. The 1- and 3-year PFS rate was 100% and 74.9%, respectively. The 1- and 3-year OS rate was 100% and 92.9%, respectively. Grade 3/4 non-hematological toxicity and grade 3/4 hematological toxicity occurred in 50% and 85.7% of patients, respectively. No treatment-related death was reported. Conclusions: R-split-EPOCH plus HD-MTX regimen is an effective and feasible treatment option for DE DLBCL and DLBCL with MYC rearrangement.

18.
Cells ; 10(1)2021 01 06.
Artigo em Inglês | MEDLINE | ID: mdl-33419137

RESUMO

Recent translational studies highlighted the inhibition of transforming growth factor (TGF)-ß signaling as a promising target to treat pulmonary arterial hypertension (PAH). However, it remains unclear whether alterations in TGF-ß signaling are consistent between PAH patients and animal models. Therefore, we compared TGF-ß signaling in the lungs of PAH patients and rats with experimental PAH induced by monocrotaline (MCT) or SU5416+hypoxia (SuHx). In hereditary PAH (hPAH) patients, there was a moderate increase in both TGFßR2 and pSMAD2/3 protein levels, while these were unaltered in idiopathic PAH (iPAH) patients. Protein levels of TGFßR2 and pSMAD2/3 were locally increased in the pulmonary vasculature of PAH rats under both experimental conditions. Conversely, the protein levels of TGFßR2 and pSMAD2/3 were reduced in SuHx while slightly increased in MCT. mRNA levels of plasminogen activator inhibitor (PAI)-1 were increased only in MCT animals and such an increase was not observed in SuHx rats or in iPAH and hPAH patients. In conclusion, our data demonstrate considerable discrepancies in TGFß-SMAD signaling between iPAH and hPAH patients, as well as between patients and rats with experimental PAH.


Assuntos
Hipertensão Pulmonar/metabolismo , Transdução de Sinais , Proteínas Smad/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Animais , Pressão Sanguínea , Modelos Animais de Doenças , Humanos , Hipertensão Pulmonar/genética , Hipertensão Pulmonar/fisiopatologia , Fosforilação , Inibidor 1 de Ativador de Plasminogênio/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Receptor do Fator de Crescimento Transformador beta Tipo I/genética , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo II/genética , Receptor do Fator de Crescimento Transformador beta Tipo II/metabolismo , Sístole
19.
Am J Respir Cell Mol Biol ; 64(3): 331-343, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33264068

RESUMO

Monoamine oxidases (MAOs), a class of enzymes bound to the outer mitochondrial membrane, are important sources of reactive oxygen species. Increased MAO-A activity in endothelial cells and cardiomyocytes contributes to vascular dysfunction and progression of left heart failure. We hypothesized that inhibition of MAO-A can be used to treat pulmonary arterial hypertension (PAH) and right ventricular (RV) failure. MAO-A levels in lung and RV samples from patients with PAH were compared with levels in samples from donors without PAH. Experimental PAH was induced in male Sprague-Dawley rats by using Sugen 5416 and hypoxia (SuHx), and RV failure was induced in male Wistar rats by using pulmonary trunk banding (PTB). Animals were randomized to receive either saline or the MAO-A inhibitor clorgyline at 10 mg/kg. Echocardiography and RV catheterization were performed, and heart and lung tissues were collected for further analysis. We found increased MAO-A expression in the pulmonary vasculature of patients with PAH and in experimental experimental PAH induced by SuHx. Cardiac MAO-A expression and activity was increased in SuHx- and PTB-induced RV failure. Clorgyline treatment reduced RV afterload and pulmonary vascular remodeling in SuHx rats through reduced pulmonary vascular proliferation and oxidative stress. Moreover, clorgyline improved RV stiffness and relaxation and reversed RV hypertrophy in SuHx rats. In PTB rats, clorgyline had no direct clorgyline had no direct effect on the right ventricle effect. Our study reveals the role of MAO-A in the progression of PAH. Collectively, these findings indicated that MAO-A may be involved in pulmonary vascular remodeling and consecutive RV failure.


Assuntos
Progressão da Doença , Monoaminoxidase/metabolismo , Hipertensão Arterial Pulmonar/enzimologia , Animais , Clorgilina/farmacologia , Clorgilina/uso terapêutico , Modelos Animais de Doenças , Ventrículos do Coração/efeitos dos fármacos , Ventrículos do Coração/enzimologia , Ventrículos do Coração/patologia , Ventrículos do Coração/fisiopatologia , Humanos , Hipertrofia Ventricular Direita/complicações , Hipertrofia Ventricular Direita/fisiopatologia , Indóis , Estresse Oxidativo/efeitos dos fármacos , Hipertensão Arterial Pulmonar/induzido quimicamente , Hipertensão Arterial Pulmonar/tratamento farmacológico , Hipertensão Arterial Pulmonar/fisiopatologia , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/enzimologia , Artéria Pulmonar/patologia , Artéria Pulmonar/fisiopatologia , Pirróis , Ratos , Remodelação Vascular/efeitos dos fármacos , Rigidez Vascular/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos
20.
Zhonghua Nan Ke Xue ; 26(9): 788-792, 2020 Sep.
Artigo em Chinês | MEDLINE | ID: mdl-33377700

RESUMO

OBJECTIVE: To investigate the effect and safety of the 3-week paclitaxel liposome protocol in the treatment of castration-resistant prostate cancer (CRPC). METHODS: This retrospective study included 40 cases of CRPC treated by the 3-week paclitaxel liposome protocol from February 2014 to February 2019, which involved intravenous injection of 10 mg dexamethasone in 100 ml normal saline on the first day and that of metoclopramide and panxi tora azole on the second day, followed by about 3 hours of intravenous drip of paclitaxel liposome at 135 mg/m2 for a course of 3 weeks. During the follow-up period, the patients received detection of the serum PSA level before treatment and chest x-ray and whole-body bone scan every six months. After two courses of treatment, the patients were observed for the changes in the serum PSA level, relief of bone pain, quality of survival, overall survival rate, overall survival time and toxic reactions. The protocol was continued unless the patient underwent progression, refused for unacceptable toxicity, or died. RESULTS: The patients were aged 59 to 79 (mean 68.80±5.67) years old, with the serum PSA level of (28.05 ± 3.22) µg/L at the baseline and (4.12 ± 0.23) µg/L after treatment. Thirty-eight of the patients were followed up for 3 to 33 (mean 12.2) months. PSA-based evaluation showed therapeutic effectiveness in 14 cases (35%), stable condition in 21 (52.5 %) and progression in 5 (12.5 %). Of the 18 patients with bone metastasis and pain, 16 (88.9 %) experienced relief of the symptoms and reduced the use of painkillers, with the bone pain scores of 5.20 ± 1.22 vs 2.79 ± 0.57 before and after treatment. By the end of the follow-up, the overall survival rate was 55.0% (22/40) and the median survival time was 17 months (95% CI: 13.4-24.6). During the treatment, no obvious adverse reactions were observed except for anemia in 1 case and hair loss in another. CONCLUSIONS: For the treatment of CRPC in China, the 3-week paclitaxel liposome protocol has the advantages of desirable safety, low toxicity, acceptable drug tolerance and improved quality of survival, but its curative effect needs to be verified with more randomized clinical trials with larger samples and longer follow-ups.


Assuntos
Lipossomos/administração & dosagem , Paclitaxel/administração & dosagem , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Idoso , Neoplasias Ósseas/secundário , China , Humanos , Masculino , Pessoa de Meia-Idade , Antígeno Prostático Específico/sangue , Neoplasias de Próstata Resistentes à Castração/patologia , Estudos Retrospectivos , Taxa de Sobrevida , Resultado do Tratamento
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