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1.
Int J Mol Med ; 49(6)2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35514302

RESUMO

Interleukin (IL)­27 can inhibit the differentiation of Th2 cells and plays a role in the development of asthma. However, whether the therapeutic administration of IL­27 in a mouse model of asthma can inhibit allergic responses remains a matter of debate. Additionally, the mechanisms through which IL­27 ameliorates inflammatory responses in asthma are not yet fully understood. Thus, the aim of the present study was to examine the effects of IL­27 on asthma using a mouse model and to elucidate the underlying mechanisms. For this purpose, mice received an intranasal administration of IL­27 and the total and differential cell counts, levels of cytokines and type 1 regulatory T (Tr1) cells in the lungs were detected. The protein and mRNA levels of signal transducer and activator of transcription (STAT)1 and STAT3 were analyzed and airway remodeling was assessed. The results indicated that IL­27 did not ameliorate airway inflammation, airway hyperresponsiveness, and airway remolding when administrated therapeutically. Preventatively, the administration of IL­27 decreased the concentrations of Th2 cytokines and increased the number of Tr1 cells. The protein and mRNA levels of STAT1 and STAT3 were increased. Taken together, these findings demonstrate that the prophylactic administration of IL­27 ameliorates asthma by alleviating the lung Th2 inflammatory environment through the restoration of both the STAT1 and STAT3 pathways. IL­27 may thus prove to be useful as a novel agent for the prevention of asthma.


Assuntos
Asma , Interleucina-27 , Pneumonia , Animais , Asma/tratamento farmacológico , Asma/metabolismo , Citocinas/metabolismo , Modelos Animais de Doenças , Interleucina-27/metabolismo , Interleucinas/metabolismo , Pulmão/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina , Pneumonia/metabolismo , RNA Mensageiro/metabolismo , Células Th2/metabolismo
2.
Int J Biol Sci ; 18(7): 2807-2820, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35541907

RESUMO

The self-renewal of spermatogonial stem cells (SSCs) requires a special microenvironment and is strictly controlled. Previously, we identified BMI1 as a key regulator of spermatogenesis in a knock-out mouse model. However, the mechanisms by which BMI1 regulates SSC maintenance remain largely unknown. Herein, we show that BMI1 is essential for SSC maintenance. BMI1 directs the transcriptional repression of target genes by increasing H2AK119ub and reducing H3K4me3 in SSCs. Furthermore, BMI1 inhibition resulted in the transcriptional activation of Wnt10b and thereby promoted the nuclear translocation of ß-catenin in SSCs. Importantly, the suppression of Wnt/ß-catenin signaling restored both the cytoplasmic expression of ß-catenin and SSC maintenance in BMI1-deficient SSCs. Finally, we demonstrated that Wnt/ß-catenin signaling was also involved in BMI1-mediated SSC maintenance in vivo. Altogether, our study not only reveals a novel mechanism for BMI1 in the process of SSC maintenance, but also provides a potential new strategy for treating male infertility.


Assuntos
Infertilidade Masculina , Complexo Repressor Polycomb 1 , Proteínas Proto-Oncogênicas , Proteínas Wnt , beta Catenina , Animais , Proliferação de Células/genética , Infertilidade Masculina/genética , Infertilidade Masculina/metabolismo , Masculino , Camundongos , Complexo Repressor Polycomb 1/genética , Complexo Repressor Polycomb 1/metabolismo , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/metabolismo , Espermatogênese/genética , Células-Tronco/metabolismo , Proteínas Wnt/genética , Proteínas Wnt/metabolismo , Via de Sinalização Wnt , beta Catenina/genética , beta Catenina/metabolismo
3.
BMC Cancer ; 22(1): 525, 2022 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-35534807

RESUMO

BACKGROUND: Recently, increasing evidence has indicated that platelet-activating factor acetylhydrolase 1b catalytic subunit 3 (PAFAH1B3) plays an important role in several cancers. However, its role in lung adenocarcinoma (LUAD) has not been reported until now. METHODS: The expression of PAFAH1B3 in LUAD was determined by using the Gene Expression Profiling Interactive Analysis (GEPIA) database and real-time PCR (RT-PCR), western blot and immunohistochemical (IHC) analyses. A chi-square test was used to investigate the correlation between PAFAH1B3 expression and clinical parameters. Cox regression and Kaplan-Meier analysis were performed to analyze the prognostic value of PAFAH1B3. The CCK-8 assay, clone formation assay, transwell invasion assay and flow cytometry were conducted to detect cell proliferation, clone formation, invasion and the cell cycle. The xenograft tumor model was constructed to explore the function of PAFAH1B3 in vivo. Western blot and IHC analyses were performed to detect epithelial-to-mesenchymal transition (EMT)-related markers. Immune Cell Abundance Identifier (ImmuneCellAI) and IHC analyses were used to analyze the effect of PAFAH1B3 on immune cell infiltration. RESULTS: Our study showed that the expression of PAFAH1B3 was upregulated in LUAD tissues and cells compared with noncancerous tissues and cells. Additionally, the results indicated that the expression of PAFAH1B3 was positively correlated with distant metastasis, TNM stage and poor clinical outcome and it was an independent prognostic risk factor for LUAD. In addition, silencing PAFAH1B3 suppressed cell proliferation, colony formation, and invasion and increased the cell population in the G0-G1 phases in vitro. Furthermore, our results showed that knockdown of PAFAH1B3 increased the epithelial marker E-cadherin level and decreased the mesenchymal marker N-cadherin level in vitro and in vivo. We also proved that PAFAH1B3 downregulation inhibited tumorigenesis and neutrophil infiltration in the xenograft tumor model. CONCLUSION: Our studies indicate that PAFAH1B3, a prognostic risk factor, promotes proliferation, invasion and EMT and affects immune infiltrates in LUAD.


Assuntos
Adenocarcinoma de Pulmão , Neoplasias Pulmonares , Adenocarcinoma de Pulmão/patologia , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/patologia , Prognóstico
4.
Nat Cell Biol ; 24(5): 685-696, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35513710

RESUMO

Acute trauma stimulates local repair mechanisms but can also impact structures distant from the injury, for example through the activity of circulating factors. To study the responses of remote tissues during tissue regeneration, we profiled transcriptomes of zebrafish brains after experimental cardiac damage. We found that the transcription factor gene cebpd was upregulated remotely in brain ependymal cells as well as kidney tubular cells, in addition to its local induction in epicardial cells. cebpd mutations altered both local and distant cardiac injury responses, altering the cycling of epicardial cells as well as exchange between distant fluid compartments. Genome-wide profiling and transgenesis identified a hormone-responsive enhancer near cebpd that exists in a permissive state, enabling rapid gene expression in heart, brain and kidney after cardiac injury. Deletion of this sequence selectively abolished cebpd induction in remote tissues and disrupted fluid regulation after injury, without affecting its local cardiac expression response. Our findings suggest a model to broaden gene function during regeneration in which enhancer regulatory elements define short- and long-range expression responses to injury.

5.
PeerJ ; 10: e13319, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35529482

RESUMO

Background: Steroid-induced osteonecrosis of the femoral head (SONFH) is a disorder that causes severe disability in patients and has a high incidence worldwide. Although glucocorticoid (GC)-induced apoptosis of osteoblasts is an important cytological basis of SONFH, the detailed mechanism underlying SONFH pathogenesis remains elusive. PI3K/AKT signaling pathway was reported to involve in cell survival and apoptosis. Objective: We explored the role of PI3K/AKT/FOXO1 signaling pathway and its downstream targets during glucocorticoid -induced osteonecrosis of the femoral head. Methods: We obtained gene expression profile of osteoblasts subjected to dexamethasone (Dex) treatment from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were screened out and functional enrichment analysis were conducted by bioinformatics analysis. In vitro, we analyzed Dex-induced apoptosis in MC3T3-E1 cells and explored the role of PI3K/AKT/FOXO1 signaling pathway in this phenomenon by employing siRNA-FOXO1 and IGF-1(PI3K/AKT agonist). Finally, we verified our results in a rat model of SONFH. Results: In Dex-treated osteoblasts, DEGs were mainly enriched in the FOXO signaling pathway. Dex inhibited MC3T3-E1 cell viability in a dose-dependent effect and induced apoptosis by increasing the expression levels of FOXO1, Bax, cleaved-Caspase-3, and cleaved-Caspase-9, while reducing the expression of Bcl-2. Notably, these results were reversed by siRNA-FOXO1 treatment. Dex inhibited PI3K/AKT signaling pathway, upregulated FOXO1 expression and increased FOXO1 nuclear translocation, which were reversed by IGF-1. Compared to normal rats, the femoral head of SONFH showed increased expression of FOXO1, increased number of apoptotic cells, and empty osteocytic lacunas, as well as decreased bone tissue content and femoral head integrity. Significantly, the effects of GC-induced SONFH were alleviated following IGF-1 treatment. Conclusion: Dex induces osteoblast apoptosis via the PI3K/AKT/FOXO1 signaling pathway. Our research offers new insights into the underlying molecular mechanisms of glucocorticoid-induced osteonecrosis in SONFH and proposes FOXO1 as a therapeutic target for this disease.

6.
Ann Transl Med ; 10(7): 392, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35530943

RESUMO

Background: Because of focal spermatogenesis in some nonobstructive azoospermia (NOA) patients, testicular spermatozoa can be retrieved by microdissection testicular sperm extraction (micro-TESE) for intracytoplasmic sperm injection (ICSI) to achieve successful fertilization. Currently, testicular biopsy is widely performed for the prognosis of micro-TESE; however, it might miss foci with active spermatogenesis because of the 'blind manner' of puncture, highlighting the needs for biomarkers that could indicate actual spermatogenesis conditions in the testis. Thus, we screened microRNAs in the seminal plasma for potential biomarkers to provide a non-invasive and reliable preoperative assessment for micro-TESE. Methods: We screened the seminal plasma microRNAs from NOA patients with and without sperm retrieval (n=6 in each group) together with fertile men (n=6) by RNA sequencing, and the selected microRNAs were validated by quantitative polymerase chain reaction (qPCR). Next, a predictive model was established by performing ordered logistic regression using the qPCR data of 56 specimens, and the predictive accuracy of this model was evaluated using 40 more specimens in a blind manner. Results: Four microRNAs (hsa-miR-34b-3p, hsa-miR-34c-3p, hsa-miR-3065-3p, and hsa-miR-4446-3p) were identified as biomarkers, and the predictive model Logit = 2.0881+ 0.13448 mir-34b-3p + 0.58679 mir-34c-3p + 0.15636 mir-3065-3p + 0.09523 mir-4446-3p was established by machine learning. The model provided a high predictive accuracy (AUC =0.927). Conclusions: We developed a predictive model with high accuracy for micro-TESE, with which NOA patients might obtain accurate assessment of spermatogenesis conditions in testes before surgery.

7.
J Clin Lab Anal ; : e24464, 2022 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-35527669

RESUMO

BACKGROUND: Few studies have investigated the generation of induced pluripotent stem cells (iPSCs) derived from human primary chorionic villi (CV) cells. The present study aimed to explore an optimal electroporation (EP) condition for generating non-integrated iPSCs from CV cells (CV-iPSCs). METHODS: The EGFP plasmid was transfected into CV cells under different EP conditions to evaluate cell adherence and the rate of EGFP positive cells. Subsequently, CV cells were transfected with the pEP4-E02S-ET2K and pCEP4-miR-302-367 plasmids under optimal EP conditions. Finally, CV-iPSC pluripotency, karyotype analysis, and differentiation ability were investigated. RESULTS: Following EP for 48 h under different conditions, different confluency, and transfection efficiency were observed in CV cells. Higher cell density was observed in CV cells exposed to 200 V for 100 s, while higher transfection efficiency was obtained in cells electroporated at a pulse of 300 V for 300 s. To generate typical primitive iPSCs, CV cells were transfected with pEP4-E02S-ET2K and pCEP4-miR-302-367 plasmids using EP and were then cultured in induction medium for 20 days under selected conditions. Subsequently, monoclonal iPSCs were isolated and were evaluated pluripotency with AP positive staining, the expression of OCT4, SOX2, and NANOG in vitro and the formation of three germ layer teratomas in vivo. CONCLUSION: CV-iPSCs were successfully established under the conditions of 100 µl shock cup and EP pulse of 200 V for 300 s for two times. This may provide a novel strategy for investigating the pathogenesis of several diseases and gene therapy.

8.
Plant Commun ; : 100326, 2022 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-35605203

RESUMO

Chia (Salvia hispanica) is a functional food crop for humans. Although its seeds contain high omega-3 fatty acids, the seed yield of chia is still low. Genomic resources available for this plant are limited. We report the first high-quality chromosome-level genome sequence of chia. The assembled genome size was 347.6 Mb and covered 98.1% of the estimated genome size. A total of 31 069 protein-coding genes were predicted. The absence of recent whole-genome duplication and the relatively low intensity of transposable element expansion in chia compared to its sister species contribute to its small genome size. Transcriptome sequencing and gene duplication analysis reveal that the expansion of the fab2 gene family is likely to be related to the high content of omega-3 in seeds. The white seed coat color is determined by a single locus on chromosome 4. This study provides novel insights into the evolution of Salvia species and high omega-3 content, as well as valuable genomic resources for genetic improvement of important commercial traits of chia and its related species.

9.
Mol Cell Endocrinol ; 551: 111664, 2022 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-35551947

RESUMO

Smtnl2 is an epithelial Smoothelin that binds to actin filaments and is crucial for epithelial morphogenesis. We examined the role of Smtnl2 in Sertoli cells, which undergo dynamic cytoskeleton reorganization to phagocytose apoptotic germ cells, a process known as efferocytosis. We observed Smtnl2 expression in primary mouse Sertoli cells and the 15P1 Sertoli cell line. Smtnl2 expression increased in 15P1 cells committing efferocytosis. Smtnl2-deficient Sertoli cells exhibited defective ability to engulf apoptotic germ cells and importantly, the phenomenon occurred in the setting of an unaffected maturation of phagosome. We demonstrated that Smtnl2 regulates the engulfment process through the function of branched actin nucleation protein ARP3, an actin assembly dictator. Intriguingly, a shift in glucose metabolism that restricts lactate production in Sertoli cells was induced upon Smtnl2 depletion, leading to the activation of downstream AMPK and AKT signaling. Using an in vivo RNAi approach, we found that silencing of Smtnl2 in testis triggers an obvious disruption in cytoskeleton architecture and blood-testis barrier integrity across seminiferous epithelium, causing the detachment of massive germ cells from their nest, as evidenced by their exfoliation into the lumen. Overall, our study identifies Smtnl2 as a determinant for Sertoli cells' functioning in supporting spermatogenesis.

10.
FASEB J ; 36 Suppl 12022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35553078

RESUMO

Acute trauma stimulates local repair but can also affect structures distant from the injury, for instance through the activity of circulating factors. To study the responses of remote tissues to injury and regeneration, we generated genome-wide profiles from zebrafish brains following experimental cardiac damage. Our findings indicate regulatory mechanisms that distinguish short- and long-range gene expression responses to injury.

11.
Dis Markers ; 2022: 2056837, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35578691

RESUMO

Identifying an epidermal growth factor receptor (EGFR) mutation is important because EGFR tyrosine kinase inhibitors are the first-line treatment of choice for patients with EGFR mutation-positive lung adenocarcinomas (LUAC). This study is aimed at developing and validating a radiomics-based machine learning (ML) approach to identify EGFR mutations in patients with LUAC. We retrospectively collected data from 201 patients with positive EGFR mutation LUAC (140 in the training cohort and 61 in the validation cohort). We extracted 1316 radiomics features from preprocessed CT images and selected 14 radiomics features and 1 clinical feature which were most relevant to mutations through filter method. Subsequently, we built models using 7 ML approaches and established the receiver operating characteristic (ROC) curve to assess the discriminating performance of these models. In terms of predicting EGFR mutation, the model derived from radiomics features and combined models (radiomics features and relevant clinical factors) had an AUC of 0.79 (95% confidence interval (CI): 0.77-0.82), 0.86 (0.87-0.88), respectively. Our study offers a radiomics-based ML model using filter methods to detect the EGFR mutation in patients with LUAC. This convenient and low-cost method may be of help to noninvasively identify patients before obtaining tumor sample for molecule testing.

12.
PLoS One ; 17(4): e0266952, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35427370

RESUMO

The clinicopathological features of early gastric cancer (EGC) with mixed-type histology (differentiated and undifferentiated) are incompletely understood, and the capacity of endoscopic submucosal dissection (ESD) to treat mixed-type cancer remains controversial. This systematic review analyzed the rate of lymph node metastasis (LNM) in mixed-type EGC. We gathered articles published up to February 21, 2021, that analyzed the relationship between LNM and mixed-type EGC from Embase, PubMed, and Web of Science. The primary outcome was the LNM rate associated with different histological types of EGC, and the secondary outcomes were the odds ratios (ORs) for LNM risk factors among EGC patients. From the 24 studies included in this meta-analysis, the overall rate of LNM in predominantly differentiated mixed-type (MD) EGC was 12%, whereas the LNM rate in predominantly undifferentiated mixed-type (MU) EGC was 22%. We further divided these studies into 2 groups according to the depth of invasion. In mixed-type mucosal EGC, the pooled LNM rate was 15%; in submucosal EGC, the rate was 33% for MU, which was higher than the rates for pure types (pure differentiated type, 13%; pure undifferentiated type, 21%; p<0.05). The LNM rate of MD was 20%, it was higher than those of the pure differentiated type and nearly the same as pure undifferentiated type. Other pooled statistics showed that submucosal invasion, pure undifferentiated EGC, and mixed-type EGC were independent risk factors for LNM. This meta-analysis showed that MD submucosal EGC has a high rate of LNM and is highly correlated with LNM; thus, the management of MD EGC as purely differentiated EGC according to the indications for ESD is inappropriate, and the mixed type should be added as a parameter in these indications.


Assuntos
Ressecção Endoscópica de Mucosa , Neoplasias Gástricas , Gastrectomia , Mucosa Gástrica/patologia , Mucosa Gástrica/cirurgia , Humanos , Excisão de Linfonodo , Metástase Linfática/patologia , Estudos Retrospectivos , Fatores de Risco , Neoplasias Gástricas/patologia , Neoplasias Gástricas/cirurgia
13.
Dementia (London) ; : 14713012221089416, 2022 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-35470700

RESUMO

PURPOSES: Dementia-friendly initiatives (DFI) are community-based movements aimed to address stigma, exclusion, and discrimination associated with dementia. This study examined the challenges faced and strategies used by DFI prior to and during the COVID-19 pandemic from the perspectives of stakeholders in the USA and China. METHODS: Qualitative interviews with 17 stakeholders involved in DFI from the United States and mainland China were conducted via the Zoom platform. Semi-structured interview questions focused on DFI challenges and strategies prior to and during the pandemic. Thematic analysis was used to analyze the data. RESULTS: Three major challenges prior to the COVID-19 pandemic included low participation of persons with dementia, difficulties in building community collaborations, and limited funding and resources needed to sustain DFI. During the COVID-19 pandemic, challenges included exacerbated difficulties of involving persons with dementia and reduced policy support for DFI. Strategies implemented prior to COVID-19 included partnerships with community organizations to outreach and engage persons with dementia, and coordination of resources and diversification of funding sources to sustain DFI. Strategies during the COVID-19 pandemic centered on the implementation of person-centered technology to support persons with dementia and family caregivers, and the development of new programs that integrated efforts to address the impact of COVID-19. IMPLICATIONS: DFI in the USA and mainland China shared similar challenges for DFI prior to and during COVID-19. During the COVID-19 pandemic, DFI in both countries showed resourcefulness through reliance on technology, community collaboration, and COVID-19-related resources to provide support and services. While it remains critical to advocate to the central government to fund DFI, DFI in both societies need to be open to other funding sources, hire persons with dementia as key staff members of DFI, and demonstrate its effectiveness through rigorous evaluation.

14.
Food Chem Toxicol ; 164: 113051, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35460824

RESUMO

Individuals of all ages, including children and teenagers, consume 4-methylimidazole (4-MI) in their food. 4-MI is a caramel-colored waste product that has previously been linked to human carcinogenesis and has shown possible signs of reproductive toxicity. This study aimed to determine whether 4-MI is harmful to oocytes during meiosis and fertilization. Female mice were intragastrically administered 0, 50, or 100 mg/kg body weight of 4-MI daily for 10 days. We found that 4-MI affects the quality of oocytes by affecting their meiotic ability and fertility potential. Specifically, 4-MI rendered the meiotic spindles and chromosomes less stable, which halted oocyte maturation and resulted in aneuploidy. 4-MI also slowed the decrease in the levels of cortical granules and their component ovastacin; consequently, sperms could not be bound and fertilization could not occur. We also found that mitochondrial dysfunction was associated with oocytes deterioration. This led to reactive oxygen species accumulation and cell death. Altogether, our findings reveal that the poor condition of oocytes subjected to 4-MI is primarily attributable to mitochondrial malfunction and redox alterations.


Assuntos
Meiose , Oócitos , Animais , Feminino , Fertilização , Imidazóis/metabolismo , Camundongos
15.
Ecotoxicol Environ Saf ; 236: 113467, 2022 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-35390687

RESUMO

The epidemiological studies regarding perfluorooctanoic acid (PFOA) suggests that its exposure causes reproductive health issues, the underlying mechanisms of which are still in its infancy. Here, we report that PFOA deteriorates female reproduction at multiple development stages. Oocyte meiosis and preimplantation development are severely impaired by PFOA with oxidative stress being a contributor. Supplementing with antioxidant melatonin partially rescues oocyte meiotic maturation and non-apoptotic demise. The attenuation in ovarian follicle development however can be improved by metformin but not melatonin. Importantly, metformin blunts PFOA-induced fetal growth retardation (FGR) and such protective effect could be recapitulated by transplantation of fecal material and pharmacological activation of AMPK. Mechanistically, PFOA causes gut microbiota dysbiosis, which might thereby rewire host metabolism of L-phenylalanine, histamine and L-palmitoylcarnitine that triggers hyperphenylalaninaemia, inflammation and ferroptosis to initiate FGR. Deregulated serine metabolism by the gut microbe constitutes an alternative mechanism underlying PFOA-induced FGR in that modulation of serine in dam's diet phenocopied the FGR. Our study expands the understanding of risk factors that impair human reproductive health, and proposes restoration of gut microbiota diversity and intervention of metabolism as therapeutics mitigating health risks predisposed by environmental perturbation.


Assuntos
Fluorcarbonetos , Melatonina , Metformina , Animais , Caprilatos/toxicidade , Feminino , Retardo do Crescimento Fetal , Fluorcarbonetos/toxicidade , Células Germinativas , Humanos , Roedores , Serina
16.
Mar Biotechnol (NY) ; 2022 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-35416601

RESUMO

Understanding of the relationships between genotypes and phenotypes is a central problem in biology. Although teleosts have colorful phenotypes, not much is known about their underlying mechanisms. Our previous study showed that golden skin color in Mozambique tilapia was mapped in the major locus containing the Pmel gene, and an insertion in 3' UTR of Pmel17 was fully correlated with the golden color. However, the molecular mechanism of how Pmel17 determines the golden skin color is unknown. In this study, knockout of Pmel17 with CRISPR/Cas9 in blackish tilapias resulted in golden coloration, and rescue of Pmel17 in golden tilapias recovered the wild-type blackish color, indicating that Pmel17 is the gene determining the golden and blackish color. Functional analysis in vitro showed that the insertion in the 3' UTR of Pmel17 reduced the transcripts of Pmel17. Our data supplies more evidence to support that Pmel17 is the gene for blackish and golden colors, and highlights that the insertion in the 3' UTR of Pmel17 is the causative mutation for the golden coloration.

17.
BJU Int ; 2022 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-35417622

RESUMO

OBJECTIVE: To assess and compare the clinical efficacy and safety of prostatic urethral lift (PUL) and prostatic artery embolization (PAE) for the treatment of lower urinary tract symptoms (LUTS) in patients with benign prostatic hyperplasia (BPH) by means of a systematic review and network meta-analysis. METHODS: A systematic literature search was performed using PubMed and Web of Science from inception to March 2021 to identify randomized controlled trials (RCTs) that compared PUL or PAE with either transurethral resection of the prostate (TURP) or sham procedures as control interventions. Qualitative and quantitative analyses were performed to pool the data on direct and indirect comparisons between interventions using STATA 14. RESULTS: Eight RCTs with 675 participants were included in our network meta-analysis. Quantitative synthesis revealed that TURP was the most efficacious intervention for clinical (International Prostate Symptoms Score and quality of life) and functional outcomes (maximum urinary flow rate and post-void residual urine volume), and was associated with a lower reintervention rate compared with PAE (risk ratio [RR] 2.08 with 95% confidence interval [CI] 0.96 to 4.51) and PUL (RR 2.33 with 95% CI 0.50 to 10.86), although the difference were not statistically significant. Indirect comparison indicated that PUL and PAE resulted in similar outcomes. PAE was associated with fewer minor adverse events (AEs; RR 0.75 with 95% CI 0.48 to 1.18) and PUL with fewer major AEs (RR 0.72 with 95% CI 0.17 to 3.13) when compared with TURP. Whilst PAE had a better ranking with regard to improvement of most clinical and functional outcomes, PUL was the best ranked procedure regarding erectile function, as measured by the International Index of Erectile Function 5, but no significant difference was observed. CONCLUSION: Current evidence suggests that PUL and PAE have similar clinical efficacy and safety profiles in the management of LUTS associated with BPH. However, the quality of evidence is relatively low because of the paucity of RCTs available, and results should be interpreted with caution.

18.
BMC Cancer ; 22(1): 408, 2022 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-35421957

RESUMO

BACKGROUND: Although uveal melanoma (UM) at the early stage is controllable to some extent, it inevitably ultimately leads to death due to its metastasis. At present, the difficulty is that there is no way to effectively tackle the metastasis. It is hypothesized that these will be treated by target molecules, but the recognized target molecule has not yet been found. In this study, the target molecule was explored through proteomics. METHODS: Transgenic enhanced green fluorescent protein (EGFP) inbred nude mice, which spontaneously display a tumor microenvironment (TME), were used as model animal carriers. The UM cell line 92.1 was inoculated into the brain ventricle stimulating metastatic growth of UM, and a graft re-cultured Next, the UM cell line 92.1-A was obtained through monoclonal amplification, and a differential proteomics database, between 92.1 and ectopic 92.1-A, was established. Finally, bioinformatics methodologies were adopted to optimize key regulatory proteins, and in vivo and in vitro functional verification and targeted drug screening were performed. RESULTS: Cells and tissues displaying green fluorescence in animal models were determined as TME characteristics provided by hosts. The data of various biological phenotypes detected proved that 92.1-A were more malignant than 92.1. Besides this malignancy, the key protein p62 (SQSTM1), selected from 5267 quantifiable differential proteomics databases, was a multifunctional autophagy linker protein, and its expression could be suppressed by chloroquine and dacarbazine. Inhibition of p62 could reduce the malignancy degree of 92.1-A. CONCLUSIONS: As the carriers of human UM orthotopic and ectopic xenotransplantation, transgenic EGFP inbred nude mice clearly display the characteristics of TME. In addition, the p62 protein optimized by the proteomics is the key protein that increases the malignancy of 92.1 cells, which therefore provides a basis for further exploration of target molecule therapy for refractory metastatic UM.


Assuntos
Dacarbazina , Neoplasias Uveais , Animais , Linhagem Celular Tumoral , Cloroquina/uso terapêutico , Dacarbazina/farmacologia , Dacarbazina/uso terapêutico , Humanos , Melanoma , Camundongos , Camundongos Nus , Proteômica , Microambiente Tumoral , Neoplasias Uveais/tratamento farmacológico , Neoplasias Uveais/genética , Neoplasias Uveais/patologia
19.
Sci Adv ; 8(13): eabm5482, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35363531

RESUMO

Although the tools based on split proteins have found broad applications, ranging from controlled biological signaling to advanced molecular architectures, many of them suffer from drawbacks such as background reassembly, low thermodynamic stability, and static structural features. Here, we present a chemically inducible protein assembly method enabled by the dissection of the carboxyl-terminal domain of a B12-dependent photoreceptor, CarHC. The resulting segments reassemble efficiently upon addition of cobalamin (AdoB12, MeB12, or CNB12). Photolysis of the cofactors such as AdoB12 and MeB12 further leads to stable protein adducts harboring a bis-His-ligated B12. Split CarHC enables the creation of a series of protein hydrogels, of which the mechanics can be either photostrengthened or photoweakened, depending on the type of B12. These materials are also well suited for three dimensional cell culturing. Together, this new protein chemistry, featuring negligible background autoassembly, stable conjugation, and phototunability, has opened up opportunities for designing smart materials.

20.
J Oncol ; 2022: 4829697, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35359341

RESUMO

KIF26B has been identified as an oncogene in several tumors; however, its utility as a prognostic indicator for various cancers has not yet been comprehensively evaluated. Here, we first examined how KIF26B intervenes in thirty-three cancers within the TCGA database, including potential immunological functions, and how it affects the prognosis. Based on the open databases TCGA, TIMER2, GEPIA2, GTEx, CPTAC, and HPA, we found that, when compared with normal tissues, KIF26B is overexpressed in 22 tumor tissues. Following a survival analysis, a relationship between the expression of KIF26B and the prognosis of various cancers was observed. Among the genetic alterations assessed, mutations were the most frequent. On the contrary, high phosphorylation levels of S977 were detected in breast cancer, KIRC, LUAD, and UCEC. We also found positive or negative correlations between KIF26B and the immune infiltration of endothelial cells and cancer-associated fibroblast infiltration. This could imply that patients may benefit from immunotherapy. Finally, KEGG pathways and GO enrichment analyses were implemented to identify the molecular mechanisms of KIF26B. This study illustrates the function of KIF26B from a pan-cancer perspective and offers a new horizon for cancer prognostic and immunotherapeutic investigations.

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