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1.
Genome Med ; 13(1): 140, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34470661

RESUMO

BACKGROUND: Epithelial ovarian cancer (OC) is a heterogenous disease consisting of five major histologically distinct subtypes: high-grade serous (HGSOC), low-grade serous (LGSOC), endometrioid (ENOC), clear cell (CCOC) and mucinous (MOC). Although HGSOC is the most prevalent subtype, representing 70-80% of cases, a 2013 landmark study by Domcke et al. found that the most frequently used OC cell lines are not molecularly representative of this subtype. This raises the question, if not HGSOC, from which subtype do these cell lines derive? Indeed, non-HGSOC subtypes often respond poorly to chemotherapy; therefore, representative models are imperative for developing new targeted therapeutics. METHODS: Non-negative matrix factorisation (NMF) was applied to transcriptomic data from 44 OC cell lines in the Cancer Cell Line Encyclopedia, assessing the quality of clustering into 2-10 groups. Epithelial OC subtypes were assigned to cell lines optimally clustered into five transcriptionally distinct classes, confirmed by integration with subtype-specific mutations. A transcriptional subtype classifier was then developed by trialling three machine learning algorithms using subtype-specific metagenes defined by NMF. The ability of classifiers to predict subtype was tested using RNA sequencing of a living biobank of patient-derived OC models. RESULTS: Application of NMF optimally clustered the 44 cell lines into five transcriptionally distinct groups. Close inspection of orthogonal datasets revealed this five-cluster delineation corresponds to the five major OC subtypes. This NMF-based classification validates the Domcke et al. analysis, in identifying lines most representative of HGSOC, and additionally identifies models representing the four other subtypes. However, NMF of the cell lines into two clusters did not align with the dualistic model of OC and suggests this classification is an oversimplification. Subtype designation of patient-derived models by a random forest transcriptional classifier aligned with prior diagnosis in 76% of unambiguous cases. In cases where there was disagreement, this often indicated potential alternative diagnosis, supported by a review of histological, molecular and clinical features. CONCLUSIONS: This robust classification informs the selection of the most appropriate models for all five histotypes. Following further refinement on larger training cohorts, the transcriptional classification may represent a useful tool to support the classification of new model systems of OC subtypes.

2.
Artigo em Inglês | MEDLINE | ID: mdl-34200176

RESUMO

Prenatal exposure to bisphenol A (BPA) may increase the risk of abnormal birth outcomes, and DNA methylation might mediate these adverse effects. This study aimed to investigate the effects of maternal BPA exposure on maternal and fetal DNA methylation levels and explore whether epigenetic changes are related to the associations between BPA and low birth weight. We collected urine and blood samples originating from 162 mother-infant pairs in a Taiwanese cohort study. We measured DNA methylation using the Illumina Infinium HumanMethylation 450 BeadChip in 34 maternal blood samples with high and low BPA levels based on the 75th percentile level (9.5 µg/g creatinine). Eighty-seven CpGs with the most differentially methylated probes possibly interacting with BPA exposure or birth weight were selected using two multiple regression models. Ingenuity pathway analysis (IPA) was utilized to narrow down 18 candidate CpGs related to disease categories, including developmental disorders, skeletal and muscular disorders, skeletal and muscular system development, metabolic diseases, and lipid metabolism. We then validated these genes by pyrosequencing, and 8 CpGs met the primer design score requirements in 82 cord blood samples. The associations among low birth weight, BPA exposure, and DNA methylation were analyzed. Exposure to BPA was associated with low birth weight. Analysis of the epigenome-wide findings did not show significant associations between BPA and DNA methylation in cord blood of the 8 CpGs. However, the adjusted odds ratio for the dehydrogenase/reductase member 9 (DHRS9) gene, at the 2nd CG site, in the hypermethylated group was significantly associated with low birth weight. These results support a role of BPA, and possibly DHRS9 methylation, in fetal growth. However, additional studies with larger sample sizes are warranted.


Assuntos
Metilação de DNA , Efeitos Tardios da Exposição Pré-Natal , Compostos Benzidrílicos/toxicidade , Peso ao Nascer , Estudos de Coortes , Feminino , Humanos , Recém-Nascido de Baixo Peso , Recém-Nascido , Exposição Materna/efeitos adversos , Fenóis , Projetos Piloto , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Taiwan/epidemiologia
3.
Int J Mol Sci ; 22(4)2021 Feb 20.
Artigo em Inglês | MEDLINE | ID: mdl-33672763

RESUMO

Aging causes a decline in skeletal muscle function, resulting in a progressive loss of muscle mass, quality, and strength. A weak regenerative capacity is one of the critical causes of dysfunctional skeletal muscle in elderly individuals. The extracellular matrix (ECM) maintains the tissue framework structure in skeletal muscle. As shown by previous reports and our data, the gene expression of ECM components decreases with age, but the accumulation of collagen substantially increases in skeletal muscle. We examined the structural changes in ECM in aged skeletal muscle and found restricted ECM degradation. In aged skeletal muscles, several genes that maintain ECM structure, such as transforming growth factor ß (TGF-ß), tissue inhibitors of metalloproteinases (TIMPs), matrix metalloproteinases (MMPs), and cathepsins, were downregulated. Muscle injury can induce muscle repair and regeneration in young and adult skeletal muscles. Surprisingly, muscle injury could not only efficiently induce regeneration in aged skeletal muscle, but it could also activate ECM remodeling and the clearance of ECM deposition. These results will help elucidate the mechanisms of muscle fibrosis with age and develop innovative antifibrotic therapies to decrease excessive collagen deposition in aged muscle.


Assuntos
Envelhecimento/patologia , Colágeno/metabolismo , Músculo Esquelético/lesões , Animais , Colágeno/genética , Regulação para Baixo/genética , Masculino , Camundongos Endogâmicos C57BL , Músculo Esquelético/patologia , Transdução de Sinais , Transcriptoma/genética , Fator de Crescimento Transformador beta/metabolismo , Regulação para Cima/genética
4.
Theranostics ; 11(8): 3624-3641, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33664852

RESUMO

Arginine synthesis deficiency due to the suppressed expression of ASS1 (argininosuccinate synthetase 1) represents one of the most frequently occurring metabolic defects of tumor cells. Arginine-deprivation therapy has gained increasing attention in recent years. One challenge of ADI-PEG20 (pegylated ADI) therapy is the development of drug resistance caused by restoration of ASS1 expression and other factors. The goal of this work is to identify novel factors conferring therapy resistance. Methods: Multiple, independently derived ADI-resistant clones including derivatives of breast (MDA-MB-231 and BT-549) and prostate (PC3, CWR22Rv1, and DU145) cancer cells were developed. RNA-seq and RT-PCR were used to identify genes upregulated in the resistant clones. Unbiased genome-wide CRISPR/Cas9 knockout screening was used to identify genes whose absence confers sensitivity to these cells. shRNA and CRISPR/Cas9 knockout as well as overexpression approaches were used to validate the functions of the resistant genes both in vitro and in xenograft models. The signal pathways were verified by western blotting and cytokine release. Results: Based on unbiased CRISPR/Cas9 knockout screening and RNA-seq analyses of independently derived ADI-resistant (ADIR) clones, aberrant activation of the TREM1/CCL2 axis in addition to ASS1 expression was consistently identified as the resistant factors. Unlike ADIR, MDA-MB-231 overexpressing ASS1 cells achieved only moderate ADI resistance both in vitro and in vivo, and overexpression of ASS1 alone does not activate the TREM1/CCL2 axis. These data suggested that upregulation of TREM1 is an independent factor in the development of strong resistance, which is accompanied by activation of the AKT/mTOR/STAT3/CCL2 pathway and contributes to cell survival and overcoming the tumor suppressive effects of ASS1 overexpression. Importantly, knockdown of TREM1 or CCL2 significantly sensitized ADIR toward ADI. Similar results were obtained in BT-549 breast cancer cell line as well as castration-resistant prostate cancer cells. The present study sheds light on the detailed mechanisms of resistance to arginine-deprivation therapy and uncovers novel targets to overcome resistance. Conclusion: We uncovered TREM1/CCL2 activation, in addition to restored ASS1 expression, as a key pathway involved in full ADI-resistance in breast and prostate cancer models.


Assuntos
Arginina/deficiência , Hidrolases/farmacologia , Polietilenoglicóis/farmacologia , Animais , Argininossuccinato Sintase/deficiência , Argininossuccinato Sintase/genética , Argininossuccinato Sintase/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias da Mama/terapia , Sistemas CRISPR-Cas , Linhagem Celular Tumoral , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética , Feminino , Técnicas de Inativação de Genes , Humanos , Inflamação/genética , Inflamação/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Modelos Biológicos , Terapia de Alvo Molecular , Medicina de Precisão , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/terapia , Transdução de Sinais , Receptor Gatilho 1 Expresso em Células Mieloides/antagonistas & inibidores , Receptor Gatilho 1 Expresso em Células Mieloides/genética , Receptor Gatilho 1 Expresso em Células Mieloides/metabolismo , Regulação para Cima , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Proc Natl Acad Sci U S A ; 118(6)2021 02 09.
Artigo em Inglês | MEDLINE | ID: mdl-33542097

RESUMO

The chimeric transcription factor E2A-PBX1, containing the N-terminal activation domains of E2A fused to the C-terminal DNA-binding domain of PBX1, results in 5% of pediatric acute lymphoblastic leukemias (ALL). We recently have reported a mechanism for RUNX1-dependent recruitment of E2A-PBX1 to chromatin in pre-B leukemic cells; but the subsequent E2A-PBX1 functions through various coactivators and the general transcriptional machinery remain unclear. The Mediator complex plays a critical role in cell-specific gene activation by serving as a key coactivator for gene-specific transcription factors that facilitates their function through the RNA polymerase II transcriptional machinery, but whether Mediator contributes to aberrant expression of E2A-PBX1 target genes remains largely unexplored. Here we show that Mediator interacts directly with E2A-PBX1 through an interaction of the MED1 subunit with an E2A activation domain. Results of MED1 depletion by CRISPR/Cas9 further indicate that MED1 is specifically required for E2A-PBX1-dependent gene activation and leukemic cell growth. Integrated transcriptome and cistrome analyses identify pre-B cell receptor and cell cycle regulatory genes as direct cotargets of MED1 and E2A-PBX1. Notably, complementary biochemical analyses also demonstrate that recruitment of E2A-PBX1 to a target DNA template involves a direct interaction with DNA-bound RUNX1 that can be further stabilized by EBF1. These findings suggest that E2A-PBX1 interactions with RUNX1 and MED1/Mediator are of functional importance for both gene-specific transcriptional activation and maintenance of E2A-PBX1-driven leukemia. The MED1 dependency for E2A-PBX1-mediated gene activation and leukemogenesis may provide a potential therapeutic opportunity by targeting MED1 in E2A-PBX1+ pre-B leukemia.


Assuntos
Carcinogênese/genética , Proteínas de Homeodomínio/metabolismo , Leucemia/genética , Leucemia/patologia , Subunidade 1 do Complexo Mediador/metabolismo , Proteínas de Fusão Oncogênica/metabolismo , Transcrição Genética , Linfócitos B/patologia , Carcinogênese/patologia , Pontos de Checagem do Ciclo Celular , Proliferação de Células/genética , Sobrevivência Celular , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , DNA de Neoplasias/metabolismo , Regulação para Baixo/genética , Regulação Leucêmica da Expressão Gênica , Genes Neoplásicos , Humanos , Ligação Proteica , Estabilidade Proteica
6.
J Chin Med Assoc ; 84(3): 290-298, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33496514

RESUMO

BACKGROUND: Supplemental oxygen is often required to treat preterm infants with respiratory disorders. Experimental studies have demonstrated that hyperoxia results in the disruption of intestinal and neuronal plasticity and myelination of the brain. The association between the neonatal hyperoxia and changes of phenotypes in gut microbiota and in behaviors is not clear to date. METHODS: We designed an animal experiment that C57BL/6 mice pups were reared in either room air (RA) or hyperoxia (85% O2) from postnatal days 1 to 7. From postnatal days 8 to 42, the mice were reared in RA. Intestinal microbiota was sampled from the lower gastrointestinal tract on postnatal days 7 and 42, and behavioral tests were performed and brain tissues were collected on postnatal day 42. RESULTS: Neonatal hyperoxia decreased intestinal tight junction protein expression and altered intestinal bacterial composition and diversity on postnatal day 7. Among the concrete discriminative features, Proteobacteria and Epsilonbacteraeota were significantly elevated in hyperoxia-reared mice on postnatal days 7 and 42, respectively. Hyperoxia-reared mice exhibited significantly reduced sociability and interest in social novelty and impaired motor coordination compared with RA-reared mice on postnatal day 42. Hyperoxia-reared mice also exhibited significantly reduced myelination and a significantly higher number of apoptotic cells in the brain compared with RA-reared mice on postnatal day 42. CONCLUSION: Neonatal hyperoxia during the first week of life altered gut microbiota and reduced brain myelination that might associate with the deficits of social interaction and motor coordination in adolescent mice.

7.
Front Neurol ; 11: 549624, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33117257

RESUMO

Studies have indicated that concussive and sub-concussive brain injuries that are frequent during collision sports may lead to long-term neurological abnormalities, however there is a knowledge gap on how biological sex modifies outcomes. Blood-based biomarkers can help to identify the molecular pathology induced by brain injuries and to better understand how biological sex affects the molecular changes. We therefore analyzed serum protein biomarkers in male (n = 50) and female (n = 33) amateur Australian rules footballers (i.e., Australia's most participated collision sport), both with a history of concussion (HoC) and without a history of concussion (NoHoC). These profiles were compared to those of age-matched control male (n = 24) and female (n = 20) athletes with no history of neurotrauma or participation in collision sports. Serum levels of protein markers indicative of neuronal, axonal and glial injury (UCH-L1, NfL, tau, p-tau, GFAP, BLBP, PEA15), metabolic (4-HNE) and vascular changes (VEGF-A, vWF, CLDN5), and inflammation (HMGB1) were assessed using reverse phase protein microarrays. Male, but not female, footballers had increased serum levels of VEGF-A compared to controls regardless of concussion history. In addition, only male footballers who had HoC had increased serum levels of 4-HNE. These findings being restricted to males may be related to shorter collision sport career lengths for females compared to males. In summary, these findings show that male Australian rules footballers have elevated levels of serum biomarkers indicative of vascular abnormalities (VEGF-A) and oxidative stress (4-HNE) in comparison to non-collision control athletes. While future studies are required to determine how these findings relate to neurological function, serum levels of VEGF-A and 4-HNE may be useful to monitor subclinical neurological injury in males participating in collision sports.

8.
Artigo em Inglês | MEDLINE | ID: mdl-33085618

RESUMO

Hypnotic line art is a modern form in which white narrow curved ribbons, with the width and direction varying along each path over a black background, provide a keen sense of 3D objects regarding surface shapes and topological contours. However, the procedure of manually creating such line art work can be quite tedious and time-consuming. In this paper, we present an interactive system that offers a What-You-See-Is-What-You-Get (WYSIWYG) scheme for producing hypnotic line art images by integrating and placing evenly-spaced streamlines in tensor fields. With an input picture segmented, the user just needs to sketch a few illustrative strokes to guide the construction of a tensor field for each part of the objects therein. Specifically, we propose a new method which controls, with great precision, the aesthetic layout and artistic drawing of an array of streamlines in each tensor field to emulate the style of hypnotic line art. Given several parameters for streamlines such as density, thickness, and sharpness, our system is capable of generating professional-level hypnotic line art work. With great ease of use, it allows art designers to explore a wide variety of possibilities to obtain hypnotic line art results of their own preferences.

9.
Sci Rep ; 10(1): 17621, 2020 10 19.
Artigo em Inglês | MEDLINE | ID: mdl-33077830

RESUMO

Muscle wasting and atrophy are regulated by multiple molecular processes, including mRNA processing. Reduced levels of the polyadenylation binding protein nucleus 1 (PABPN1), a multifactorial regulator of mRNA processing, cause muscle atrophy. A proteomic study in muscles with reduced PABPN1 levels suggested dysregulation of sarcomeric and cytoskeletal proteins. Here we investigated the hypothesis that reduced PABPN1 levels lead to an aberrant organization of the cytoskeleton. MURC, a plasma membrane-associated protein, was found to be more abundant in muscles with reduced PABPN1 levels, and it was found to be expressed at regions showing regeneration. A polarized cytoskeletal organization is typical for muscle cells, but muscle cells with reduced PABPN1 levels (named as shPAB) were characterized by a disorganized cytoskeleton that lacked polarization. Moreover, cell mechanical features and myogenic differentiation were significantly reduced in shPAB cells. Importantly, restoring cytoskeletal stability, by actin overexpression, was beneficial for myogenesis, expression of sarcomeric proteins and proper localization of MURC in shPAB cell cultures and in shPAB muscle bundle. We suggest that poor cytoskeletal mechanical features are caused by altered expression levels of cytoskeletal proteins and contribute to muscle wasting and atrophy.


Assuntos
Citoesqueleto/metabolismo , Atrofia Muscular/metabolismo , Proteína I de Ligação a Poli(A)/metabolismo , Actinas/metabolismo , Linhagem Celular , Humanos , Desenvolvimento Muscular/fisiologia , Músculo Esquelético/metabolismo
10.
Int J Biol Macromol ; 165(Pt A): 1519-1528, 2020 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-33058973

RESUMO

This study investigated the gastroprotective effect of Lycium barbarum polysaccharides (LBP) and C-phycocyanin (C-PC) in rats with ethanol-induced gastric ulcer. Rats were divided into 5 groups: normal, ulcer, ulcer treated with 100 mg/kg bw LBP, ulcer treated with 50 mg/kg bw C-PC, and ulcer treated with 50 mg/kg bw LBP and 25 mg/kg bw C-PC. Pretreatment with LBP and/or C-PC was given a week before ulcer induction. Ulcer induction was produced by 50% ethanol administration orally every other day for 4 weeks. After 5-week treatment, the histopathological observation showed that LBP or C-PC attenuated the severity of gastric mucosal damage. LBP decreased serum malondialdehyde (MDA) levels and gastric interleukin-6 (IL-6), intercellular adhesion molecule-1 (ICAM-1) levels, and myeloperoxidase (MPO) activity. C-PC decreased serum MDA levels and gastric tumor necrosis factor-α (TNF-α), IL-1ß, IL-6, ICAM-1 levels, and MPO activity. Combined LBP and C-PC decreased serum MDA levels and gastric TNF-α, IL-1ß, IL-6, and ICAM-1 levels. LBP and/or C-PC increased gastric heat shock protein 70 and non-protein sulfhydryl compounds. Rats with ulcer and treatment had enriched with the family Bacillaceae. Therefore, pretreatment with LBP and/or C-PC attenuated ethanol-induced gastric ulcer in rats via suppressing oxidation and inflammation and increasing gastroprotection.


Assuntos
Lycium/química , Ficocianina/química , Polissacarídeos/química , Substâncias Protetoras/química , Animais , Antiulcerosos/química , Antiulcerosos/farmacologia , Etanol/toxicidade , Mucosa Gástrica/efeitos dos fármacos , Mucosa Gástrica/patologia , Humanos , Estresse Oxidativo/efeitos dos fármacos , Ficocianina/farmacologia , Extratos Vegetais , Polissacarídeos/farmacologia , Substâncias Protetoras/farmacologia , Ratos , Estômago/efeitos dos fármacos , Estômago/patologia , Úlcera Gástrica/induzido quimicamente
11.
Artigo em Inglês | MEDLINE | ID: mdl-32197386

RESUMO

This study examined the factors related to the preference about laws to legalize same-sex relationships in participants of the first wave of a survey (Wave 1, 23 months before the same-sex marriage referendum) and the second wave of a survey (Wave 2, 1 week after the same-sex marriage referendum) in Taiwan. The data of 3286 participants in Wave 1 and 1370 participants in Wave 2 recruited through a Facebook advertisement were analyzed. Each participant completed an online questionnaire assessing their attitude toward the legal recognition of same-sex relationships, preference about laws to legalize same-sex relationships (establishing same-sex couple laws outside the Civil Code vs. changing the Civil Code to include same-sex marriage laws), belief in the importance of legalizing same-sex relationships, and perceived social attitudes toward the legal recognition of same-sex relationships. The results revealed that those who did not support legalizing same-sex relationships were more likely to prefer establishing same-sex couple laws outside the Civil Code than those who supported the legalization. The form of law preferred to legalize same-sex relationships significantly changed between Wave 1 and Wave 2. Multiple factors, including gender, age, sexual orientation, belief in the importance of legalizing same-sex relationships to human rights and the social status of sexual minorities, and perceived peers' and families' attitudes toward the legal recognition of same-sex relationships, were significantly associated with the preference of laws, although these associations varied among heterosexual and non-heterosexual participants and at various stages of the survey.


Assuntos
Homossexualidade , Casamento , Mídias Sociais , Feminino , Humanos , Masculino , Inquéritos e Questionários , Taiwan
12.
Artigo em Inglês | MEDLINE | ID: mdl-32045994

RESUMO

This study examined the associations of perceived socially unfavorable attitudes toward homosexuality and same-sex marriage with suicidal ideation in non-heterosexual and heterosexual participants from first (Wave 1, 23 months prior to same-sex marriage referendums) and second (Wave 2, one week after the referendums) wave surveys in Taiwan. Data provided by 3239 participants in Wave 1 and 1337 participants in Wave 2 who were recruited through a Facebook advertisement were analyzed. Participants completed an online questionnaire assessing suicidal ideation and perceived unfavorable attitudes toward homosexuality and same-sex marriage from Taiwanese society, heterosexual friends, and family members. The results indicate that perceived unfavorable attitudes toward homosexuality from Taiwanese society, heterosexual friends, and family members were positively associated with suicidal ideation among non-heterosexual individuals in the first but not the second survey. In addition, among non-heterosexual individuals, such attitudes toward same-sex marriage in family members and in heterosexual friends were positively associated with suicidal ideation in the Wave 1 and Wave 2 surveys, respectively. Perceived unfavorable attitudes toward homosexuality and same-sex marriage in heterosexual friends were associated with suicidal ideation in heterosexual participants with a favorable attitude but not in those individuals with an unfavorable attitude toward homosexuality, in both surveys. Perceived socially unfavorable attitudes toward homosexuality and same-sex marriage were significantly associated with suicidal ideation before and after same-sex marriage referendums; however, the associations varied between non-heterosexual and heterosexual individuals.


Assuntos
Atitude , Homossexualidade , Casamento , Ideação Suicida , Adulto , Feminino , Homossexualidade Masculina , Humanos , Masculino , Casamento/legislação & jurisprudência , Política Pública , Taiwan , Adulto Jovem
13.
Sci Rep ; 10(1): 866, 2020 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-31964941

RESUMO

Proton pump inhibitors (PPIs) are used for the long-term treatment of gastroesophageal disorders and the non-prescription medicines for acid reflux. However, there is growing concerns about PPI misuse, overuse and abuse. This study aimed to develop an animal model to examine the effects of long-term use of PPI in vivo. Twenty one Wistar rats were given omeprazole orally or intravenously for 30 days, and caerulein as a positive control. After euthanization, the serum and stool were collected to perform MS-based quantitative analysis of metabolites. We carried out 16S-based profiling of fecal microbiota, assessed the expression of bile acid metabolism regulators and examined the immunopathological characteristics of bile ducts. After long-term PPI exposure, the fecal microbial profile was altered and showed similarity to those observed in high-fat diet studies. The concentrations of several metabolites were also changed in various specimens. Surprisingly, morphological changes were observed in the bile duct, including ductal epithelial proliferation, micropapillary growth of biliary epithelium, focal bile duct stricture formation and bile duct obstruction. These are characteristics of precancerous lesions of bile duct. FXR and RXRα expressions were significantly reduced, which were similar to that observed in cholangiocarcinoma in TCGA and Oncomine databases. We established a novel animal model to examine the effects of long-term use of omeprazole. The gut microbes and metabolic change are consequences of long-term PPI exposure. And the results showed the environment in vivo tends to a high-fat diet. More importantly, we observed biliary epithelial hyperplasia, which is an indicator of a high-fat diet.


Assuntos
Ductos Biliares/efeitos dos fármacos , Microbioma Gastrointestinal/efeitos dos fármacos , Omeprazol/efeitos adversos , Inibidores da Bomba de Prótons/efeitos adversos , Administração Oral , Animais , Neoplasias dos Ductos Biliares/genética , Ductos Biliares/patologia , Transformação Celular Neoplásica/efeitos dos fármacos , Colangiocarcinoma/genética , Colestase/induzido quimicamente , Colestase/patologia , Fezes/microbiologia , Microbioma Gastrointestinal/fisiologia , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Omeprazol/administração & dosagem , Omeprazol/farmacologia , Inibidores da Bomba de Prótons/administração & dosagem , Inibidores da Bomba de Prótons/farmacologia , RNA Ribossômico 16S , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Ratos Wistar , Receptor X Retinoide alfa/genética , Receptor X Retinoide alfa/metabolismo , Tirosina/sangue , alfa-Tocoferol/sangue
14.
Int J Food Sci Nutr ; 71(4): 440-452, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31645150

RESUMO

This study explored the effects of the degree of lipid saturation on depressive behaviour and gut microbiota in mice. Thirty-two mice were divided into normal (N), Prozac (NP), lard (L) and fish oil (F) groups. After a 12-week dietary intervention, the open field test (OFT) and the forced swim test (FST) were conducted before sacrifice. The mice in the L group exhibited anxiety-like behaviours in the OFT and depressive-like behaviours in the FST. A significant difference was observed in ß-diversity indices between the L group and the F group. The abundance of Allobaculum and Bifidobacterium was significantly higher in the F group than in the L and N groups. The prefrontal cortex fatty acid composition was altered in various lipid-treated groups and was highly correlated with depressive-like behaviours. In conclusion, the degree of lipid saturation affects depressive-like behaviour, gut microbiota composition, and the prefrontal cortex fatty acid profile in mice.


Assuntos
Comportamento Animal , Gorduras na Dieta/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Lipídeos , Animais , Ansiedade , Encéfalo/metabolismo , Ácidos Graxos , Camundongos , Camundongos Endogâmicos BALB C , Teste de Campo Aberto
15.
J Pathol ; 250(3): 299-311, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31837018

RESUMO

CDGSH iron-sulfur domain-containing protein 2 (Cisd2), a protein that declines in an age-dependent manner, mediates lifespan in mammals. Cisd2 deficiency causes accelerated aging and shortened lifespan, whereas persistent expression of Cisd2 promotes longevity in mice. Alzheimer's disease (AD) is the most prevalent form of senile dementia and is without an effective therapeutic strategy. We investigated whether Cisd2 upregulation is able to ameliorate amyloid ß (Aß) toxicity and prevent neuronal loss using an AD mouse model. Our study makes three major discoveries. First, using the AD mouse model (APP/PS1 double transgenic mice), the dosage of Cisd2 appears to modulate the severity of AD phenotypes. Cisd2 overexpression (∼two-fold) significantly promoted survival and alleviated the pathological defects associated with AD. Conversely, Cisd2 deficiency accelerated AD pathogenesis. Secondly, Cisd2 overexpression protected against Aß-mediated mitochondrial damage and attenuated loss of neurons and neuronal progenitor cells. Finally, an increase in Cisd2 shifted the expression profiles of a panel of genes that are dysregulated by AD toward the patterns observed in wild-type mice. These findings highlight Cisd2-based therapies as a potential disease-modifying strategy for AD. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.


Assuntos
Doença de Alzheimer/metabolismo , Proteínas Relacionadas à Autofagia/metabolismo , Encéfalo/metabolismo , Morte Celular/fisiologia , Proteínas do Tecido Nervoso/metabolismo , Neurônios/metabolismo , Regulação para Cima , Doença de Alzheimer/genética , Doença de Alzheimer/patologia , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Proteínas Relacionadas à Autofagia/genética , Encéfalo/patologia , Modelos Animais de Doenças , Longevidade/genética , Camundongos , Camundongos Transgênicos , Mitocôndrias/genética , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Proteínas do Tecido Nervoso/genética , Neurônios/patologia , Presenilina-1/genética , Presenilina-1/metabolismo
16.
Sci Rep ; 9(1): 13238, 2019 09 13.
Artigo em Inglês | MEDLINE | ID: mdl-31519977

RESUMO

Renal diseases impose considerable health and economic burdens on health systems worldwide, and there is a lack of efficient methods for the prevention and treatment due to their complexity and heterogeneity. Kidneys are organs with a high demand for energy produced by mitochondria, in which Rrm2b has critical functions as reported. The Rrm2b kidney-specific knockout mice we generated exhibited age-dependent exacerbated features, including mitochondrial dysfunction and increased oxidative stress; additionally, resulted in severe disruption of mitochondria-related metabolism. Rrm2b is vital not only to supply dNTPs for DNA replication and repair, but also to maintain structural integrity and metabolic homeostasis in mitochondria. Thence, Rrm2b deletion might induce chronic kidney defects in mice. This model can facilitate exploration of novel mechanisms and targeted therapies in the kidney diseases and has important translational and clinical implications.


Assuntos
Proteínas de Ciclo Celular/fisiologia , Túbulos Renais/patologia , Mitocôndrias/patologia , Estresse Oxidativo , Ribonucleotídeo Redutases/fisiologia , Animais , Replicação do DNA , Feminino , Túbulos Renais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/metabolismo , Oxirredução
17.
Biomolecules ; 9(10)2019 09 21.
Artigo em Inglês | MEDLINE | ID: mdl-31546592

RESUMO

BACKGROUND: This study investigated the effects of fish oil and olive oil in improving dysbiosis and depressive-like symptoms. METHODS AND RESULTS: Male rats were fed normal, fish oil-rich or olive oil-rich diets for 14 weeks. Chronic mild stress (CMS) was administered from week 2. The sucrose preference test (SPT) and forced swimming test (FST) were used to determine depressive-like behavior. The SPT results revealed that the CMS, CMS with imipramine (CMS+P) treatment, and CMS with olive oil diet (CMS+O) groups exhibited significantly reduced sucrose intake from week 8, whereas the fish oil diet (CMS+F) group exhibited significantly reduced sucrose intake from week 10. The FST results showed that the immobile time of the CMS+F group was significantly less than that of the CMS-only group. Next generation sequencing (NGS) results showed CMS significantly reduced the abundance of Lactobacillus and increased that of Marvinbryantia and Ruminiclostridium_6. However, the CMS+F group showed an increase in the abundance of Eisenbergiella, Ruminococcaceae_UCG_009, and Holdemania, whereas the CMS+O group showed an increase in the abundance of Akkermansia. CONCLUSIONS: CMS stimuli altered the gut microbiome in depressed rats. Fish oil and olive oil exerted part of a prebiotic-like effect to ameliorate dysbiosis induced by CMS. However, only fish oil ameliorated depressive-like symptoms.


Assuntos
Depressão/tratamento farmacológico , Disbiose/tratamento farmacológico , Óleos de Peixe/administração & dosagem , Azeite de Oliva/administração & dosagem , Animais , Bactérias/classificação , Bactérias/efeitos dos fármacos , Bactérias/genética , Bactérias/isolamento & purificação , Comportamento Animal/efeitos dos fármacos , Depressão/metabolismo , Depressão/microbiologia , Modelos Animais de Doenças , Disbiose/metabolismo , Óleos de Peixe/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Sequenciamento de Nucleotídeos em Larga Escala , Imipramina/administração & dosagem , Imipramina/farmacologia , Masculino , Azeite de Oliva/farmacologia , Ratos , Sacarose/metabolismo
18.
Artigo em Inglês | MEDLINE | ID: mdl-31533353

RESUMO

: Taiwan held voter-initiated referendums to determine same-sex marriage legalization on 24 November 2018. This study aims to compare suicidal ideation rates in heterosexual and nonheterosexual participants of a first-wave survey (Wave 1, 23 months before the same-sex marriage referendums) and a second-wave survey (Wave 2, one week after the same-sex marriage referendums) in Taiwan and to examine the influence of gender, age, and sexual orientation on the change in suicidal ideation rates in nonheterosexual participants. In total, 3286 participants in Wave 1 and 1370 participants in Wave 2 were recruited through a Facebook advertisement. Each participant completed an online questionnaire assessing suicidal ideation. The proportions of heterosexual and nonheterosexual participants with suicidal ideation were compared between the Wave 1 and Wave 2 surveys. Suicidal ideation rates between participants in the Wave 1 and Wave 2 surveys were further compared by stratifying nonheterosexual participants according to gender, age, and sexual orientation. Nonheterosexual participants in the Wave 2 survey had a higher suicidal ideation rate than those in the Wave 1 survey, whereas no difference was observed in suicidal ideation rates between heterosexual participants in Wave 2 and Wave 1. Nonheterosexual participants who were female, younger, gay, lesbian, and bisexual in Wave 2 had a higher suicidal ideation rate than those in Wave 1. The suicidal ideation rate significantly increased in nonheterosexual participants experiencing the same-sex marriage referendums in Taiwan. Whether civil rights of sexual minority individuals can be determined through referendums should be evaluated.


Assuntos
Homossexualidade/psicologia , Casamento/legislação & jurisprudência , Casamento/psicologia , Ideação Suicida , Adolescente , Adulto , Feminino , Humanos , Masculino , Inquéritos e Questionários , Taiwan , Adulto Jovem
19.
J Cell Biol ; 218(10): 3489-3505, 2019 10 07.
Artigo em Inglês | MEDLINE | ID: mdl-31455668

RESUMO

Primary cilia are microtubule-based organelles that play important roles in development and tissue homeostasis. Tau-tubulin kinase-2 (TTBK2) is genetically linked to spinocerebellar ataxia type 11, and its kinase activity is crucial for ciliogenesis. Although it has been shown that TTBK2 is recruited to the centriole by distal appendage protein CEP164, little is known about TTBK2 substrates associated with its role in ciliogenesis. Here, we perform superresolution microscopy and discover that serum starvation results in TTBK2 redistribution from the periphery toward the root of distal appendages. Our biochemical analyses uncover CEP83 as a bona fide TTBK2 substrate with four phosphorylation sites characterized. We also demonstrate that CEP164-dependent TTBK2 recruitment to distal appendages is required for subsequent CEP83 phosphorylation. Specifically, TTBK2-dependent CEP83 phosphorylation is important for early ciliogenesis steps, including ciliary vesicle docking and CP110 removal. In summary, our results reveal a molecular mechanism of kinase regulation in ciliogenesis and identify CEP83 as a key substrate of TTBK2 during cilia initiation.


Assuntos
Cílios/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Células Cultivadas , Células HEK293 , Humanos , Fosforilação
20.
Food Chem Toxicol ; 132: 110700, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31356917

RESUMO

Postnatal exposure to di-(2-ethylhexyl) phthalate (DEHP), a common plasticizer, is associated with allergy development in childhood, suggesting that DEHP exposure may dysregulate immune response in infants. We investigated whether DEHP exposure in newborns through medical treatment affected the gut microbiota pattern and vaccine response, which are both related to immune development. In this prospective cohort study from May 1, 2016 through July 31, 2017, newborns with respiratory distress who were given intravenous infusions (IVs) were enrolled as the DEHP group, and newborns who did not receive IVs were enrolled as the control group. We excluded patients with perinatal maternal probiotics, vaginal delivery, antibiotic treatment, and exclusive human milk or formula feeding. Of 118 infants, urinary phthalate metabolite analysis revealed that the calculated DEHP concentrations of the newborns treated with IVs (n = 15) were higher than those in the control group (n = 10) (p = 0.0001). DEHP exposure altered bacterial communities both in composition and diversity, particularly decreases in Rothia sp. and Bifidobacterium longum in the DEHP group. Furthermore, DEHP exposure significantly enhanced anti-HBsAg-IgM responses in the DEHP group (p = 0.013). Early-life DEHP exposure alter gut microbiota of newborns and may change their immune responses in later life.


Assuntos
Dietilexilftalato/farmacologia , Microbioma Gastrointestinal/efeitos dos fármacos , Vacinas contra Hepatite B/administração & dosagem , Imunoglobulina M/sangue , Plastificantes/farmacologia , Dietilexilftalato/urina , Feminino , Hidratação , Humanos , Imunoglobulina M/imunologia , Recém-Nascido , Infusões Intravenosas , Masculino , Plastificantes/análise
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