RESUMO
BACKGROUND: The purpose of this article is to identify and describe key components of research into the teaching methods of public health to postgraduate students. STUDY DESIGN: This is a systematic review of the published literature. METHODS: A detailed search of the literature based on keywords, Boolean operators, and free-text terms, identified from PubMed, Scopus and ERIC, published in the English language, between January 2000 and December 2017, was made. Teams of independent pairs agreed studies eligible for the review and performed data extraction. RESULTS: Of the 2,442 potential studies on education of public health professionals, 86 met all the inclusion criteria. Specific study designs, data collection, and techniques for data analysis varied widely across the individual studies, and there was a lack of consistency on the whole. The number of students in each study ranged from ten to 1,300. Forty-seven studies used quantitative methods to assess the effectiveness of teaching. Curriculum evaluation was the most common focus (n = 33), followed by course evaluation (n = 22). Few studies considered inequalities in terms of the types of students registered on the different courses/programs, with just three evaluating strategies to increase students from minority ethnic groups. Most studies evaluated short-term or medium-term outcomes rather than long-term impacts of education on students' careers or the relationship of education in meeting future public health workforce demands. CONCLUSIONS: This comprehensive systematic review identified a dearth of the literature on evaluations of approaches for teaching public health to health professions students. Those studies that had been published varied to such an extent in terms of their aims, methods, analysis, and results such that it was impossible to make any consistent comparisons of the observations reported in the studies. We conclude that evidence-based approaches for teaching public health to health professions students are either not sought by faculty and programs or, if conducted, not shared. As such, there are likely to be missed opportunities for ensuring that future graduates of health professions programs are as well prepared as possible to contribute to the health of the public.
Assuntos
Ocupações em Saúde/educação , Saúde Pública/educação , Currículo , Educação de Pós-Graduação/organização & administração , Humanos , Estudantes de Ciências da Saúde , EnsinoRESUMO
Scutellaria barbata is a recognized anti-cancer traditional Chinese medicine, with the effects of clearing heat and detoxi-fication, dispelling blood stasis and stopping bleeding, diuresis and detumescence. At present, terpenoids, flavonoids, polysaccharides and volatile oils have been isolated from S. barbata, which have many pharmacological effects, such as resisting tumor, virus, bacteria and oxidation, and immunomodulation. This paper reviews the studies on the chemical constituents, pharmacological action and quality control of S. barbata, in the expectation of providing ideas and references for the further development and studies of S. barbata.
Assuntos
Scutellaria , Flavonoides , Medicina Tradicional Chinesa , Extratos Vegetais/farmacologia , Controle de QualidadeRESUMO
Oryza longistaminata originates from African wild rice and contains valuable traits conferring tolerance to biotic and abiotic stress. However, interspecific crosses between O. longistaminata and Oryza sativa cultivars are hindered by reproductive barriers. To dissect the mechanism of interspecific hybrid sterility, we developed a near-isogenic line (NIL) using indica variety RD23 as the recipient parent and O. longistaminata as the donor parent. Both pollen and embryo sac semi-sterility were observed in F1 hybrids between RD23 and NIL. Cytological analysis demonstrated that pollen abortion in F1 hybrids occurred at the early bi-nucleate stage due to a failure of the first mitosis in microspores. Partial embryo sacs in the F1 hybrids were defective during the functional megaspore formation stage. Most notably, nearly half of the male or female gametes were aborted in heterozygotes S40iS40l, regardless of their genotypes. Thus, S40 was indicated as a one-locus sporophytic sterility gene controlling both male and female fertility in hybrids between RD23 and O. longistaminata. A population of 16 802 plants derived from the hybrid RD23/NIL-S40 was developed to fine-map S40. Finally, the S40 locus was delimited to an 80-kb region on the short arm of chromosome 1 in terms with reference sequences of cv. 93-11. Eight open reading frames (ORFs) were localized in this region. On the basis of gene expression and genomic sequence analysis, ORF5 and ORF8 were identified as candidate genes for the S40 locus. These results are helpful in cloning the S40 gene and marker-assisted transferring of the corresponding neutral allele in rice breeding programs.
Assuntos
Hibridização Genética , Oryza/genética , Infertilidade das Plantas/genética , Pólen/genética , Mapeamento Cromossômico , Cruzamentos Genéticos , DNA de Plantas/genética , Genes de Plantas , Marcadores Genéticos , Genótipo , Oryza/classificaçãoRESUMO
We studied the differentiation-inducing effect of beta-methasone on human glioma cell line U251 cultured in vitro, and the underlying mechanism. U251 cells were divided into two groups: control group cells, cultured in Dulbecco's Modified Eagle's medium containing 10% fetal bovine serum; and medication group cells, treated with 15 µM betamethasone. Morphological cell changes were observed by inverted microscope, cell cycle changes were ascertained by flow cytometry, and vimentin expression was checked by immunocytochemistry. The expression levels of extracellular signal-regulated protein ki-nase (ERK), phosphorylated ERK (pERK), and glial fibrillary acidic protein (GFAP) were assessed by western blot. Compared with the control group, U251 cell processes increased significantly, but declined 96 h after betamethasone took effect. After 48 h, the percentage of S-phase cells decreased significantly (28.77 to 20.42%; P = 0.014); the percent-age of strongly positive vimentin cells decreased significantly (91 to 51%; P = 0.0092); and the ratio of expression of GFAP protein to the internal control ß-actin increased significantly (0.24 to 0.53; P = 0.1). The level of ERK protein did not change significantly 48 and 96 h after the action of betamethasone, and the pERK/ERK ratios were 0.37 and 0.23, respectively, which were significantly reduced compared with the control group (P = 0.028 and 0.006). Betamethasone has a significant effect on the induction and differentiation of U251 cells, and its mechanism may be related to the inhibition of the abnormal activation of the ERK signal pathway.
Assuntos
Betametasona/farmacologia , Neoplasias Encefálicas/patologia , Diferenciação Celular/efeitos dos fármacos , Glioma/patologia , Neoplasias Encefálicas/metabolismo , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Forma Celular/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Proteína Glial Fibrilar Ácida/metabolismo , Glioma/metabolismo , Humanos , Imuno-Histoquímica , Fosforilação/efeitos dos fármacos , Vimentina/metabolismoRESUMO
The aim of this study was to investigate the efficiency of uterine artery embolisation (UAE) for postpartum haemorrhage (PPH) related to placenta praevia. A total of 45 women with placenta praevia or placenta praevia state underwent UAE before inducing labour. The locations of uterine artery and placenta were determined through selective and super-selective catheterisation into the internal iliac artery and uterine artery digital subtraction angiography (DSA). The target arteries were then super-selectively catheterised and embolised using small pieces of gelatin sponge. The above processes were repeated until the darkly stained areas of placenta were no longer developing. The success rate of UAE was 100%. There was no longer haemorrhage after embolisation for all the cases of labour induction and the average volume of blood loss was 56 ml. UAE is an effective, reliable and minimally traumatic treatment method for preventing postpartum haemorrhage after induction of labour in patients with placenta praevia state.
Assuntos
Placenta Prévia/terapia , Embolização da Artéria Uterina , Adulto , Feminino , Humanos , Trabalho de Parto Induzido , Gravidez , Adulto JovemRESUMO
Multiple genes are restrictively expressed in mammalian testicular tissues, and they play important roles in the complex process of spermatogenesis. Investigation of these genes and their expression regulation mechanisms is valuable to elucidate the molecular process of spermatogenesis. In this study, we identified a novel human gene, ring finger protein 148 (RNF148) that is abundantly expressed in testes and slightly expressed in pancreas. In situ hybridization analysis showed that RNF148 messenger RNA was mainly present in the interstitial cells of human testicular tissues, and immunohistochemical analysis confirmed protein levels in that location. Treatment with histone deacetylase inhibitor trichostatin A activated the expression of RNF148 messenger RNA in a time- and concentration-dependent manner in HEK293T and HeLa cells, neither of which normally express RNF148. Chromatin immunoprecipitation analysis showed that trichostatin A treatment increased the binding of acetylated histone H3 to the RNF148 gene promoter. We identified a novel human testicular interstitial gene and observed that histone deacetylases regulate RNF148 expression.
Assuntos
Regulação da Expressão Gênica , Histona Desacetilases/metabolismo , Células Intersticiais do Testículo/citologia , Células Intersticiais do Testículo/metabolismo , Ubiquitina-Proteína Ligases/genética , Acetilação , Sequência de Aminoácidos , China , Imunoprecipitação da Cromatina , Clonagem Molecular , Células HEK293 , Células HeLa , Inibidores de Histona Desacetilases/farmacologia , Histonas/genética , Histonas/metabolismo , Humanos , Ácidos Hidroxâmicos/farmacologia , Masculino , Dados de Sequência Molecular , Regiões Promotoras Genéticas , Domínios RING Finger , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Alinhamento de SequênciaRESUMO
This prospective study of 39 women living with human immunodeficiency virus (HIV) on antiretroviral therapy in Western Kenya aimed to quantify genital tract HIV-1 RNA (GT-HIV RNA) shedding before and after cryotherapy for cervical intraepithelial neoplasia. Most GT-HIV RNA shedding was detected precryotherapy, suggesting that cryotherapy was not the primary cause of shedding.
RESUMO
Prevention of bacterial infection and reduction of hemorrhage, the primary challenges posed by trauma before hospitalization, are essential steps in prolonging the patient's life until they have been transported to a trauma center. Extracellular matrix (ECM) hydrogel is a promising biocompatible material for accelerating wound closure. However, due to the lack of antibacterial properties, this hydrogel is difficult to be applied to acute contaminated wounds. This study formulates an injectable dermal extracellular matrix hydrogel (porcine acellular dermal matrix (ADM)) as a scaffold for skin defect repair. The hydrogel combines vancomycin, an antimicrobial agent for inducing hemostasis, expediting antimicrobial activity, and promoting tissue repair. The hydrogel possesses a porous structure beneficial for the adsorption of vancomycin. The antimicrobial agent can be timely released from the hydrogel within an hour, which is less than the time taken by bacteria to infest an injury, with a cumulative release rate of approximately 80%, and thus enables a relatively fast bactericidal effect. The cytotoxicity investigation demonstrates the biocompatibility of the ADM hydrogel. Dynamic coagulation experiments reveal accelerated blood coagulation by the hydrogel. In vivo antibacterial and hemostatic experiments on a rat model indicate the healing of infected tissue and effective control of hemorrhaging by the hydrogel. Therefore, the vancomycin-loaded ADM hydrogel will be a viable biomaterial for controlling hemorrhage and preventing bacterial infections in trauma patients.
RESUMO
As a common variation in the azoospermia factor c (AZFc) region of Y chromosome, the gr/gr deletion is regarded as a significant risk factor for spermatogenic impairment, whereas the association of the deletion's phenotypic expression with Y-chromosomal background is still a subject of debate. To further investigate the contribution of the deletion to spermatogenic impairment in different Y-chromosomal haplogroups, the partial AZFc deletion was detected with AZFc-specific sequence tagged sites, gene dosage and gene copy analyses of deleted in azoospermia (DAZ), chromodomain Y1 (CDY1) and basic protein Y2 (BPY2) in 1426 azoo/oligozoospermic and 672 normozoospermic men from a Chinese population. The haplogrouping was performed in 231 deletion carriers with 12 polymorphic loci of Y chromosome. As a result, five gr/gr rearrangement types in eight Y haplogroups were observed, in which the simple gr/gr deletion was the most common type, and its frequency was significantly higher in men with azoo/oligozoospermia relative to normozoospermia. Also the distribution of gr/gr-rearranged Y haplogroups was significantly different between the two groups, in which gr/gr-deleted haplogroups C and DE were more common in men with azoo/oligozoospermia. In the 6 gr/gr copy deletion haplotypes, the frequencies of DAZ1/DAZ2+CDY1a or CDY1b deletion were significantly higher in men with azoo/oligozoospermia, while all DAZ3/DAZ4+CDY1b+BPY2.2 or 2.3 deletions were found only in haplogroup Q1 without any distribution difference between the azoo/oligozoospermic and normozoospermic groups. This study provided further evidence for the existence of multiple subtypes of gr/gr deletion and indicates that gr/gr-DAZ1/DAZ2 deletion is a significant risk factor. However, the association of the phenotypic variation of gr/gr deletion with Y-chromosomal haplogroups is not definite yet, because of the limited amounts of the deletions observed in each of the haplogroups and the lack of the quantitative trait analyses such as sperm density analysis. The fact that a common gr/gr copy deletion haplotype was found exclusively in the Y hgr Q1, without pathogenic consequences, implies the importance of haplogrouping and of copy deletion typing prior to genetic counselling of deletion carriers of Chinese descent.
Assuntos
Povo Asiático/genética , Azoospermia/genética , Deleção de Genes , Espermatogênese/genética , China , Proteína 1 Suprimida em Azoospermia , Rearranjo Gênico/genética , Haplótipos , Humanos , Masculino , Proteínas Nucleares/genética , Proteínas/genética , Proteínas de Ligação a RNA/genéticaRESUMO
BACKGROUND: Chloroplast development is coordinately regulated by plastid- and nuclear-encoding genes. Although many regulators have been reported to be involved in chloroplast development, new factors remain to be identified, given the complexity of this process. RESULTS: In this study, we characterized a rice mutant lethal albinic seedling 1(las1)form of a 4-hydroxy-3-methylbut-2-enyl diphosphate reductase (OsHMBPP) that was targeted to the chloroplasts. The LAS1 mutation caused the albino lethal phenotype in seedlings. Transmission electron microscopy indicated that las1 were defective in early chloroplast development. LAS1 is preferentially expressed in leaves, implying its role in controlling chloroplast development. The expression levels of many chloroplast-encoded genes were altered significantly in las1. The expression levels of nuclear-encoded gene involved in Chl biosynthesis were also decreased in las1. We further investigated plastidic RNA editing in las1 and found that the edit efficiency of four chloroplast genes were markly altered. Compared with WT, las1 exhibited defective in biogenesis of chloroplast ribosomes. CONCLUSIONS: Our results show that LAS1/OsHMBPP plays an essential role in the early chloroplast development in rice.
RESUMO
Objective: To observe the status of the sinus membrane using fiber optic endoscope during the lateral window approach sinus floor elevation to provide a reference for clinicians when evelvating the sinus mucoperiosteum. Methods: Sixty-six patients (72 sides) who underwent maxillary sinus floor elevation in Beijing Ruicheng Stomatology Hospital from September 2016 to December 2019 were selected, including 40 males and 26 females, aged 26-80 years old [(56.2±11.5) years]. And fiber optic endoscopy was used to observe the maxillary mucoperiosteum during the operation. Results: The status of maxillary sinus mucoperiosteal during lateral window approach sinus floor elevation can be divided into four categories: â Class â , complete periosteal, no damage to mucoperiosteum; â¡Class â ¡, periosteal injury, unexposed laminae propria; â¢Class â ¢, periosteal Rupture, exposed lamina propria; ⣠Class â £, mucoperiosteum perforation, rupture of periosteum, lamina propria and epithelial layer. A total of 72 operations were performed, including 18 cases of class I, 28 cases of class â ¡, 4 cases of class â ¢, and 22 cases of class â £. Conclusions: The status of maxillary sinus mucoperiosteal during lateral window approach sinus floor elevation can be divided into four categories. Fiberoptic endoscopy as a clinical auxiliary examination method can improve the operator's control of the status of the maxillary sinus membrane and assist the peeling of the mucosa.
Assuntos
Seio Maxilar , Levantamento do Assoalho do Seio Maxilar , Adulto , Idoso , Idoso de 80 Anos ou mais , Endoscópios , Feminino , Humanos , Masculino , Maxila , Seio Maxilar/cirurgia , Pessoa de Meia-Idade , Mucosa NasalRESUMO
OBJECTIVE: To analyze the sequences of mitochondrial cytochrome C oxidase subunit I gene (COI) and 18S ribosomal RNA gene (18S rRNA), so as to identify the feasible DNA barcodes for 4 species of cheyletid mites and improve the DNA barcoding database for cheyletid mites. METHODS: Cheyletid mite samples were collected from small-scale flour mills in Fuyang, Wuhu and Tongling cities of Anhui Province from May 2018 to July 2019, extracted and morphologically identified. Then, genomic DNA was extracted from a single cheyletid mite, and the COI and 18S rRNA gene sequences were obtained by PCR amplification, cloning and sequencing. The obtained sequences were aligned using the BLAST software. Multiple sequence alignment was done using the software ClustalX version 1.83 using the known gene sequences from cheyletid mites. The genetic distance was calculated using the software MEGA X, and the phylogenetic tree was created using the maximum likelihood method. RESULTS: The DNA barcoding results of Cheyletus malaccensis, C. carnifex and Cheletomorpha lepidopterorum were consistent with the morphological identification, while no sequences pertaining to Eucheyletia reticulate were retrieved in the GenBank database. The proportions of A + T were 69.6% and 55.1% in the COI and 18S rRNA sequences of 4 cheyletid mites species, respectively, and the numbers of base substitutions were 137 and 46, respectively. There were 154 to 321 and 58 to 99 inter-species variation loci in the COI and 18S rRNA gene sequences of 4 cheyletid mites species, respectively, and the intra-species genetic distance was all 0.020 or less in the COI and 18S rRNA gene sequences of 4 cheyletid mites species, with inter-species genetic distance of 0.235 to 0.583 and 0.078 to 0.114, respectively. Phylogenetic analysis based on COI and 18S rRNA genes showed that all four species of cheyletid mites were clustered into a branch with a 100% supportive rate, which was consistent with the morphological identification. CONCLUSIONS: Mitochondrial COI gene is superior to 18S rRNA gene as DNA barcodes for 4 species of cheyletid mites, which is more suitable to be used to investigate the phylogenetic relationship of at genus and species levels.
Assuntos
Código de Barras de DNA Taxonômico , Ácaros , Animais , DNA , Genes de RNAr , Ácaros/genética , Filogenia , RNA Ribossômico 18S/genéticaRESUMO
INTRODUCTION: Y chromosomes are genetically highly variable due to frequent structural rearrangements. The variations may create a genetic background for the susceptibility to Y-related spermatogenic impairment, although few data have been accumulated about the possible correlation between the Y-chromosome haplotype and the predisposition of men to spermatogenic failure. OBJECTIVE: To investigate the possible association of Y-chromosome background with spermatogenic failure. METHODS: The distribution of 18 Y-chromosome haplogroups was compared between 414 infertile men with azoospermia or oligozoospermia and 262 normozoospermic men with or without AZFc deletions in a Han population of Southwest China. RESULTS: A significant population difference in Y-haplogroup distribution was found between the groups of normozoospermia and azoospemia or oligozoospermia, and between the patient groups with oligozoospermia and azoospermia without AZFc deletions. Interpopulation comparison of Y haplogroup frequencies showed that the distribution of the haplogroups C, K* and O3* were significantly different between the groups. CONCLUSION: This study provides evidence for the association of Y-chromosome background with impaired spermatogenesis, suggesting that Y variations play a role in the occurrence and even the severity of spermatogenic failure. Furthermore, both AZFc deletions and other Y-chromosome structural variations may be important for determining the susceptibility to spermatogenic failure. Our findings emphasise the necessity of more extensive study on Y-chromosome variations for better understanding of spermatogenesis and its pathology.
Assuntos
Cromossomos Humanos Y/genética , Infertilidade Masculina/genética , Espermatogênese/genética , Povo Asiático/genética , Azoospermia/genética , Estudos de Casos e Controles , China , Deleção de Genes , Loci Gênicos , Haplótipos , Humanos , Masculino , Oligospermia/genética , Fenótipo , Filogenia , Polimorfismo de Nucleotídeo Único , Proteínas de Plasma Seminal/genética , Sitios de Sequências RotuladasRESUMO
Using the method of isolation of specific nucleic acids associated with proteins (SNAAP), we have identified 10 candidate target mRNA substrates bound by mT-STAR (mouse T-STAR protein) from testis extract. Among them, our study focused on Fabp9, a gene that is essential for male gametogenesis, and showed that mT-STAR could directly bind to Fabp9 mRNAs. The binding sites are in a short sequence of the coding region and 3' untranslated region of Fabp9 mRNA. These suggest that mT-STAR can regulate the metabolism and expression of Fabp9. In conclusion, identification of mT-STAR-bound mRNA substrates might help to illustrate the potential spectrum of the process and provide valuable insight into the biological function of this RNA-binding protein in spermatogenesis.
Assuntos
RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/metabolismo , Testículo/química , Animais , Proteínas de Ligação a Ácido Graxo/química , Proteínas de Ligação a Ácido Graxo/genética , Proteínas de Ligação a Ácido Graxo/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Dados de Sequência Molecular , Ligação Proteica , RNA Mensageiro/química , RNA Mensageiro/genética , RNA Mensageiro/isolamento & purificação , Proteínas de Ligação a RNA/química , Proteínas de Ligação a RNA/genética , Testículo/metabolismoAssuntos
Carcinoma Adenoide Cístico , Neoplasias da Traqueia , Humanos , Carcinoma Adenoide Cístico/radioterapia , Carcinoma Adenoide Cístico/patologia , Carcinoma Adenoide Cístico/diagnóstico por imagem , Neoplasias da Traqueia/diagnóstico por imagem , Neoplasias da Traqueia/patologia , Masculino , Pessoa de Meia-Idade , Feminino , Tomografia Computadorizada por Raios XRESUMO
OBJECTIVE: To elucidate the effect of cyclooxygenase 2 (COX-2) on cisplatin resistance of NSCLC and its molecular mechanisms, with special attention to its pro-EMT (epithelial-mesenchymal transition) properties. MATERIALS AND METHODS: COX-2 levels were compared in two NSCLC cell lines, A549 and H460, by qPCR (quantitative Polymerase Chain Reaction) and Western blot. Cytotoxicity of cisplatin was also determined in the two cell lines using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay. The expression of EMT-related proteins and activation of AKT (protein kinase B) signaling were detected in H460 cells with ectopic COX-2 expression. RESULTS: Cisplatin-induced apoptosis was assessed in COX-2 overexpressing H460 cells by FACS. NS398, a COX-2 inhibitor, was also applied to determine EMT status and effect on cisplatin sensitivity in H460 cells. COX-2 levels were positively correlated with cisplatin resistance in both NSCLC cell lines tested. In response to COX-2 overexpression, EMT-related proteins, such as E-cadherin, were inhibited, while vimentin and N-cadherin were upregulated. The AKT signaling pathway was also activated in H460 cells. Ectopic expression of COX-2 potentiated cisplatin resistance of H460 cells, which was accompanied by decreased levels of apoptosis. Notably, NS398 effectively increased the cytotoxicity of cisplatin in A549 cells by inhibiting EMT and the AKT pathway. CONCLUSIONS: COX-2 might promote cisplatin resistance in NSCLC by promoting EMT through the AKT signaling pathway activation.
Assuntos
Antineoplásicos/farmacologia , Cisplatino/farmacologia , Ciclo-Oxigenase 2/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Transição Epitelial-Mesenquimal , Proteínas Proto-Oncogênicas c-akt/metabolismo , Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Caderinas/metabolismo , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Cisplatino/uso terapêutico , Ciclo-Oxigenase 2/genética , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Nitrobenzenos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/farmacologia , Vimentina/metabolismoRESUMO
An amendment to this paper has been published and can be accessed via a link at the top of the paper.
RESUMO
Cancer stem cells (CSCs) are inherently resistant to chemotherapy, and CSCs in chemotherapy-failed recurrent tumors are enriched; however, the cellular origin of chemotherapy-induced CSC enrichment remains unclear. Communication with stromal fibroblasts may induce cancer cell dedifferentiation into CSCs through secreted factors. We recently demonstrated that fibroblast-derived exosomes promote chemoresistance in colorectal cancer (CRC). Here, we report that fibroblasts confer CRC chemoresistance via exosome-induced reprogramming (dedifferentiation) of bulk CRC cells to phenotypic and functional CSCs. At the molecular level, we provided evidence that the major reprogramming regulators in fibroblast-exosomes are Wnts. Exosomal Wnts were found to increase Wnt activity and drug resistance in differentiated CRC cells, and inhibiting Wnt release diminished this effect in vitro and in vivo. Together, our results indicate that exosomal Wnts derived from fibroblasts could induce the dedifferentiation of cancer cells to promote chemoresistance in CRC, and suggest that interfering with exosomal Wnt signaling may help to improve chemosensitivity and the therapeutic window.
Assuntos
Desdiferenciação Celular , Neoplasias Colorretais/patologia , Resistencia a Medicamentos Antineoplásicos , Exossomos/metabolismo , Células-Tronco Neoplásicas/fisiologia , Via de Sinalização Wnt/fisiologia , Animais , Antineoplásicos/farmacologia , Desdiferenciação Celular/efeitos dos fármacos , Desdiferenciação Celular/genética , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Exossomos/efeitos dos fármacos , Exossomos/patologia , Feminino , Fibroblastos/patologia , Fibroblastos/fisiologia , Fluoruracila/farmacologia , Células HT29 , Humanos , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Oxaliplatina/farmacologia , Comunicação Parácrina/efeitos dos fármacos , Pirazinas/farmacologia , Piridinas/farmacologia , Via de Sinalização Wnt/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
After 10-minute incubation of [3H]-tyrosine methionine-enkephalin (MET) with 100,000 x g supernatant from select brain regions of patients with chronic schizophrenia (n = 3), essentially all of the labeled tyrosine was recovered as the free amino acid. Initial velocity and half-life of MET degradation obtained from different brain areas (limbic system, thalamus, basal ganglia, cerebellum, and cortex) of individual brains or from equivalent sections from different brains were scattered and considerable spread out (brains A, B, and C: 21.7-60.2 and 2.1-14.3, 25.6-88.7 and 1.6-14.1, 24.5-56.1 and 2.6-14.3 pg MET/mg brain tissue/min and min, respectively; brains A-C range, 21.7-88.7 pg MET/mg brain tissue/min and 1.6-14.3 min, respectively). These results failed to identify consistent differences in peptide degradation kinetics between the various brains areas studied from the same individual or from equivalent section from different subjects. MET metabolic rate was pH and temperature-dependent (optimum 7.4 degrees C and 37 degrees C), reduced by the aminopeptidase inhibitors puromycin, bacitracin, and bestatin, and to a lesser extent by thioridazine. However, peptide metabolism was not significantly affected by differences in tissue storage time or repeated freezing and thawing; by preincubation with N-carboxymethyl phenyl leucine, captopril, or thiorphan (dipeptidyl peptidase[s] or peptidyl dipeptidase[s] inhibitors, respectively); or by the many different drugs used by the patients with chronic schizophrenia. Our findings, although of a preliminary nature and generally similar to those recently reported for comparable studies on nonneuropsychiatric patients, provide a much needed understanding of the mechanisms regulating brain MET metabolism. Whether these results may contribute to the rational design of pharmacologic strategies for the treatment of pathologies associated with alterations in the enkephalinergic system needs further research.
Assuntos
Encéfalo/metabolismo , Encefalina Metionina/metabolismo , Esquizofrenia/metabolismo , Idoso , Doença Crônica , Meia-Vida , Humanos , Concentração de Íons de Hidrogênio , Cinética , Masculino , TemperaturaRESUMO
OBJECTIVE: We investigated the correlation between the methylation of LIVIN gene and the pathogenesis of bone tumor at the molecular level, in order to improve the treatment method and enhance the cure rate of bone tumor. PATIENTS AND METHODS: The expression level of Livin protein was detected using Western blot analysis, and its expressions in control group and patients were detected by immunohistochemistry. The methylation frequency of LIVIN gene was calculated by direct sequencing. Finally, the prognosis of treatment was investigated by follow-up. RESULTS: The experiment found that Livin protein was not expressed in normal cells, while its expression rate was about 71.4% in 112 patients. The methylation frequency of LIVIN gene was gradually decreased with the increase of clinical stage, and had no significant relationship with age and sex. The prognosis experiment indicated that the lower the methylation frequency of LIVIN gene was, the shorter the survival time would be. CONCLUSIONS: The methylation of LIVIN gene was closely related to the pathogenesis of bone tumor, which may be one of the important factors to induce the formation of a bone tumor. In addition, the methylation frequency of LIVIN gene could be used as a biomarker for the prognosis of bone tumor treatment.