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MicroRNAs (miRNAs) are implicated in the development of cancers and may serve as potential targets for therapy. However, the functions and underlying mechanisms of miRNAs in cancers are not well understood. This work aims to study the role of miR-373-3p in colon cancer cells. We find that the expression of miR-373-3p mimics promotes and the miR-373-3p inhibitor suppresses aerobic glycolysis and proliferation of colon cancer cells. Mechanistically, miR-373-3p inhibits the expression of MFN2, a gene that is known to suppress glycolysis, which leads to the activation of glycolysis and eventually the proliferation of cells. In a nude mouse tumor model, the expression of miR-373-3p in colon cancer cells promotes tumor growth by enhancing lactate formation, which is inhibited by the co-expression of MFN2 in the cells. Administration of the miR-373-3p antagomir blunts in vivo tumor growth by decreasing lactate production. In addition, in human colon cancers, the expression levels of miR-373-3p are increased, while those of MFN2 mRNA are decreased, and the increase of miR-373-3p is associated with the decrease of MFN2 mRNA. Our results reveal a previously unknown function and underlying mechanism of miR-373-3p in the regulation of glycolysis and proliferation in cancer cells and underscore the potential of targeting miR-373-3p for colon cancer treatment.
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Upon ER stress, IRE1α is activated to splice XBP1 mRNA to generate XBP1s, a transcription factor that induces the expression of genes to cope with the stress. Expression of IRE1α is elevated in cancers and the IRE1α-XBP1s axis plays an important role in proliferation of cancer cells. However, the underlying mechanism is not well known. We found that ER stressors induced the expression of IRE1α, which was inhibited by depletion of XBP1s. XBP1s bound IRE1α promoter and initiated the transcription of IRE1α. These data indicate that XBP1s acts as a transcription factor of IRE1α. Overexpression of XBP1s increased the phosphorylation of JNK, a substrate of IRE1α kinase, which was inhibited by IRE1α kinase inhibitor Kira8. Overexpression of XBP1s also activated the regulated IRE1-dependent decay of mRNAs, which was suppressed by IRE1α RNase inhibitor STF083010. Moreover, we found that expression of XBP1s promoted proliferation of colon cancer cells, which was abrogated by Kira8 and STF083010. The results suggest that XBP1s functions to induce IRE1α expression and promote cancer cell proliferation. Our findings reveal a previously unknown mechanism of IRE1α expression by XBP1s and highlight the role of this regulation in proliferation of colon cancer cells, suggesting that IRE1α-targeting is a potential therapeutic strategy for colon cancer.
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Neoplasias do Colo , Proteínas Serina-Treonina Quinases , Humanos , Proteínas Serina-Treonina Quinases/metabolismo , Fatores de Transcrição/metabolismo , Endorribonucleases , Proliferação de Células , Estresse do Retículo Endoplasmático , Proteína 1 de Ligação a X-Box/metabolismoRESUMO
The SH2 domain-containing phosphatase 2 (SHP2) is a widely expressed protein tyrosine phosphatase, and it is proposed to act as an oncogenic protein. SHP2 is also engaged in drug resistance of a variety of cancers. However, the role of SHP2 in the proliferation and drug resistance of colon cancer cells remains elusive. In this work we determined the effect of SHP2 expression on colon cancer cell proliferation and resistance to oxaliplatin (L-OHP), a commonly used drug in the clinic. Our results show that knockdown of SHP2 decreased and overexpression of SHP2 increased the proliferation of SW480 cells, respectively. Knockdown of SHP2 increased, and overexpression of SHP2 decreased apoptosis of the cells. We selected oxaliplatin-resistant SW480(SW480/L-OHP) and HCT116(HCT116/L-OHP) cells and found that the SHP2 protein level was raised in these drug-resistant cells. The upregulated SHP2 contributed to oxaliplatin resistance of the cells, as knockdown of SHP2 decreased the IC50 of oxaliplatin and abated proliferation and survival of SW480/L-OHP and HCT116/L-OHP cells in the presence of oxaliplatin. Also, SW480/L-OHP and HCT116/L-OHP cells had increased phosphorylation of AKT and ERK. Inhibition of AKT, ERK, or SHP2 sensitized SW480/L-OHP and HCT116/L-OHP cells to oxaliplatin. Our results indicate that SHP2 contributes oxaliplatin resistance through AKT and ERK. These results also suggest that SHP2-targeting is a potential strategy for overcoming oxaliplatin resistance of colon cancer cells.
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Neoplasias do Colo/metabolismo , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Neoplasias do Colo/tratamento farmacológico , Neoplasias do Colo/patologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , MAP Quinases Reguladas por Sinal Extracelular/antagonistas & inibidores , Humanos , Oxaliplatina/farmacologia , Proteína Tirosina Fosfatase não Receptora Tipo 11/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidoresRESUMO
Cancer cells are often exposed to cell intrinsic stresses and environmental perturbations that may lead to accumulation of unfolded and/or misfolded proteins in the lumen of endoplasmic reticulum (ER), a cellular condition known as ER stress. In response to ER stress, the cells elicit an adaptive process called unfolded protein response (UPR) to cope with the stress, supporting cellular homeostasis and survival. The ER stress sensors inositol requiring protein 1α (IRE1α), eukaryotic translation initiation factor 2 alpha kinase 3 (EIF2AK3, also called PERK), and activating transcription factor 6 (ATF6) constitute the three branches of UPR to resolve ER stress. IRE1α, PERK, and ATF6 play an important role in tumor cell growth and survival. They are also involved in chemotherapy resistance of cancers. These have generated widespread interest in targeting these UPR branches for cancer treatment. In this review, we provide an overview of the role of IRE1α, PERK, and ATF6 in cancer progression and drug resistance and we summarize the research advances in targeting these UPR branches to enhance the efficacy of chemotherapy of cancers.
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Fator 6 Ativador da Transcrição/genética , Antineoplásicos/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Endorribonucleases/genética , Neoplasias/tratamento farmacológico , Proteínas Serina-Treonina Quinases/genética , Resposta a Proteínas não Dobradas/efeitos dos fármacos , eIF-2 Quinase/genética , Fator 6 Ativador da Transcrição/metabolismo , Animais , Apoptose/efeitos dos fármacos , Apoptose/genética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos/genética , Retículo Endoplasmático/efeitos dos fármacos , Retículo Endoplasmático/genética , Retículo Endoplasmático/metabolismo , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Endorribonucleases/metabolismo , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , Neoplasias/genética , Neoplasias/metabolismo , Neoplasias/patologia , Proteínas Serina-Treonina Quinases/metabolismo , Transdução de Sinais , Ensaios Antitumorais Modelo de Xenoenxerto , eIF-2 Quinase/metabolismoRESUMO
Colorectal cancer (CRC) is a type of malignant cancer that has become particularly prevalent worldwide. It is of crucial importance to CRC treatment that the underlying molecular mechanism of CRC progression is determined. The NRAS gene is an important small G protein that is involved in various biological processes, including cancers. NRAS is an oncogene in many neoplasms but its function and regulation in CRC have seldom been investigated. In this study, it was uncovered that the NRAS protein was significantly upregulated in CRC tissues. According to a bioinformatics prediction, we identified that miR-144 may target NRAS to suppress its expression. In vitro experiments indicated that miR-144 decreased NRAS expression in different CRC cell lines (SW480, LoVo, and Caco2). By inhibiting NRAS, miR-144 repress SW480 cell proliferation and migration. Moreover, miR-144 decelerated the growth of SW480 xenograft tumors in vivo by targeting NRAS. In summary, our results identified a novel miR-144-NRAS axis in CRC that could promote the research and treatment of CRC.
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Microparts with precise sizes, custom shapes, and a wide selection of materials have various applications, including biomedical microelectromechanical systems (MEMS), drug delivery, single-cell studies, and tissue engineering. Janus microparts containing multiple components are also demonstrated for biomolecule analysis, cell-cell interaction studies, and self-assembly. Small-footprint, affordable, and rapid technologies to fabricate microparts with customized morphologies and a wide selection of materials are highly desired. This paper reports on a SlipChip-based microfluidic molding method to control the interface for the synthesis of microparts-on-demand (mPods) with fast and easy loading-slipping-solidification operations that do not require pumps, masks, or other auxiliary fluidic control instruments. This method is based on the relative movement of two microfluidic plates that are in close contact, and the size and shape of the microparts can be accurately controlled by the geometry of the microcavities imprinted on the contacting surfaces of these microfluidic plates. To demonstrate the capability of this method, mPods of different sizes and various shapes are presented with photosensitive resin via a photopolymerization reaction. The synthesis of two-layer Janus microparts is also demonstrated by a slip overmolding method. This SlipChip-based molding method can offer new opportunities for producing customized microparts with great flexibility for a broad spectrum of applications.
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Serial dilution is a commonly used technique that generates a low-concentration working sample from a high-concentration stock solution and is used to set up screening conditions over a large dynamic range for biological study, optimization of reaction conditions, drug screening, etc. Creating an array of serial dilutions usually requires cumbersome manual pipetting steps or a robotic liquid handling system. Moreover, it is very challenging to set up an array of serial dilutions in nanoliter volumes in miniaturized assays. Here, a multistep SlipChip microfluidic device is presented for generating serial dilution nanoliter arrays in high throughput with a series of simple sliding motions. The dilution ratio can be precisely predetermined by the volumes of mother microwells and daughter microwells, and this paper demonstrates devices designed to have dilution ratios of 1:1, 1:2, and 1:4. Furthermore, an eight-step serial dilution SlipChip with a dilution ratio of 1:4 is applied for digital loop-mediated isothermal amplification (LAMP) across a large dynamic range and tested for hepatitis B viral load quantification with clinical samples. With 64 wells of each dilution and fewer than 600 wells in total, the serial dilution SlipChip can achieve a theoretical quantification dynamic range of 7 orders of magnitude.
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Vírus da Hepatite B/isolamento & purificação , Hepatite B/diagnóstico , Técnicas de Amplificação de Ácido Nucleico/instrumentação , Carga Viral/instrumentação , Hepatite B/sangue , Humanos , Dispositivos Lab-On-A-ChipRESUMO
MicroRNAs (miRNAs) play an important role in the regulation of human cancers, including breast cancer (BC). In the current study, we examined the expression pattern of the miRNA miR-125a-5p in human BC tissues, tumorigenesis of BC progression. We found that miR-125a-5p was significantly downregulated in human BC tissues. Overexpression of miR-125a-5p in a xenograft mouse model indicated that miR-125a-5p may function as a tumour suppressor during carcinogenesis. To explore the molecular mechanism by which miR-125a-5p contributes to BC progression, we predicted the target genes of miR-125a-5p and identified BC susceptibility gene 1-associated protein 1 (BAP1) as a direct target. Finally, we demonstrated that BAP1 had opposing effects to those of miR-125a-5p on BC cells, suggesting that miR-125a-5p may inhibit cell proliferation and promote cell apoptosis by negatively regulating BAP1. Taken together, our findings provide the first clues regarding the role of miR-125a-5p as a tumour suppressor in BC via the inhibition of BAP1 translation.
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Neoplasias da Mama/genética , Regulação para Baixo , Genes Supressores de Tumor , MicroRNAs/genética , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genética , Animais , Apoptose , Neoplasias da Mama/metabolismo , Carcinogênese/genética , Carcinogênese/metabolismo , Proliferação de Células , Sobrevivência Celular , Feminino , Inativação Gênica , Humanos , Células MCF-7 , Camundongos , Camundongos Nus , MicroRNAs/química , MicroRNAs/metabolismo , Mimetismo Molecular , Terapia de Alvo Molecular , Transfecção , Carga Tumoral , Proteínas Supressoras de Tumor/metabolismo , Ubiquitina Tiolesterase/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
BACKGROUND: Colorectal cancer (CRC) is a severe health problem worldwide. Clarifying the mechanisms for the deregulation of oncogenes and tumour suppressors in CRC is vital for its diagnosis, treatment, prognosis and prevention. Hu antigen R (HuR), which is highly upregulated in CRC, functions as a pivotal oncogene to promote CRC progression. However, the underlying cause of its dysregulation is poorly understood. METHODS: In CRC tissue sample pairs, HuR protein levels were measured by Western blot and immunohistochemical (IHC) staining, respectively. HuR mRNA levels were also monitored by qRT-PCR. Combining meta-analysis and microRNA (miRNA) target prediction software, we predicted miRNAs that targeted HuR. Pull-down assay, Western blot and luciferase assay were utilized to demonstrate the direct binding of miR-22 on HuR's 3'-UTR. The biological effects of HuR and miR-22 were investigated both in vitro by CCK-8, EdU and Transwell assays and in vivo by a xenograft mice model. JASPAR and SABiosciences were used to predict transcriptional factors that could affect miR-22. Luciferase assay was used to explore the validity of putative Jun binding sites for miR-22 regulation. ChIP assay was performed to test the Jun's occupancy on the C17orf91 promoter. RESULTS: We observed a significant upregulation of HuR in CRC tissue pairs and confirmed the oncogenic function of HuR both in vitro and in vivo. We found that an important tumour-suppressive miRNA, miR-22, was significantly downregulated in CRC tissues and inversely correlated with HuR in both CRC tissues and CRC cell lines. We demonstrated that miR-22 directly bound to the 3'-UTR of HuR and led to inhibition of HuR protein, which repressed CRC proliferation and migration in vitro and decelerated CRC xenografted tumour growth in vivo. Furthermore, we found that the onco-transcription factor Jun could inhibit the transcription of miR-22. CONCLUSIONS: Our findings highlight the critical roles of the Jun/miR-22/HuR regulatory axis in CRC progression and may provide attractive potential targets for CRC prevention and treatment.
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Transformação Celular Neoplásica/genética , Neoplasias Colorretais/genética , Proteína Semelhante a ELAV 1/genética , Regulação Neoplásica da Expressão Gênica , Genes jun , MicroRNAs/genética , Regiões 3' não Traduzidas , Animais , Linhagem Celular Tumoral , Proliferação de Células , Bases de Dados Genéticas , Modelos Animais de Doenças , Genes Reporter , Xenoenxertos , Humanos , Camundongos , Modelos Biológicos , Oncogenes , Interferência de RNA , Transcrição GênicaRESUMO
BACKGROUND: The inhibitor of growth (ING) gene family of tumor suppressors is involved in multiple cellular functions such as cell cycle regulation, apoptosis, and chromatin remodeling. ING5 is a new member of the ING family whose function and regulation remain largely unknown. METHODS: Quantitative real-time PCR and western blot were used to examine the expression levels of ING5 in breast cancer tissues. The miRNAs that potentially targeted ING5 were determined by bioinformatics analysis and luciferase reporter assay. Cell viability assay, transwell invasion and apoptosis assay were used to characterize the changes induced by overexpressing or knocking down miR-24 or ING5. Hematoxylin and eosin (H&E) staining and immunohistochemical staining for ING5 and Ki-67 were used for xenograft assays in BALB/c nude mice. RESULTS: We showed that the ING5 protein rather than the mRNA, was significantly downregulated in breast cancer tissues. We also investigated the potential function of ING5 in breast tumorigenesis and found that ING5 suppressed the proliferation and invasion of breast cancer cells and promoted their apoptosis. Furthermore, we explored the molecular mechanisms accounting for the dysregulation of ING5 in breast cancer cells and identified an oncomiR, miR-24, as a direct upstream regulator of ING5. We revealed that miR-24 had the opposite effects to those of ING5 on breast cancer cells and could accelerate xenografted tumor growth in vivo. CONCLUSION: Our findings uncover the tumor-suppressive role of ING5 and the regulatory pathway of ING5 in breast cancer and may provide insights into the molecular mechanisms of breast carcinogenesis.
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Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , MicroRNAs/genética , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genética , Animais , Apoptose/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Camundongos , RNA Mensageiro/genética , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Citrobacter braakii (C. braakii) is an anaerobic, gram-negative bacterium that has been isolated from the environment, food, and humans. Infection by C. braakii has been associated with acute mucosal inflammation in the intestine, respiratory tract, and urinary tract. However, the pathogenesis of C. braakii in the gastric mucosa has not yet been clarified. In this study, the bacterium was detected in 35.5% (61/172) of patients with chronic gastritis (CG) and was closely associated with the severity of mucosal inflammation. Citrobacter braakii P1 isolated from a patient with CG exhibited urease activity and acid resistance. It contained multiple secretion systems, including a complete type I secretion system (T1SS), T5aSS and T6SS. We then predicted the potential pilus-related adhesins. Citrobacter braakii P1 diffusely adhered to AGS cells and significantly increased lactate dehydrogenase (LDH) release; the adhesion rate and LDH release were much lower in HEp-2 cells. Strain P1 also induced markedly increased mRNA and protein expression of IL-8 and TNF-α in AGS cells, and the fold increase was much higher than that in HEp-2 cells. Our results demonstrate proinflammatory and cytotoxic role of C. braakii in gastric epithelial cells, indicating the bacterium is potentially involved in inducing gastric mucosa inflammation.
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Citrobacter , Estômago , Humanos , InflamaçãoRESUMO
Circular RNAs (circRNAs) have been implicated in cancer development. However, their regulation, function, and underlying mechanisms of action remain unclear. We found that circHIPK2 was downregulated in colon cancer, and low expression levels of circHIPK2 were associated with high tumor grade and poor patient survival. The expression of circHIPK2 was observed to be regulated by the transcription factor HOXD10, which was downregulated in colon cancer. Consequently, low circHIPK2 expression promoted colon cancer cell proliferation, migration, and invasion in vitro and tumor growth and metastasis in vivo. Mechanistically, circHIPK2 sponges miR-373-3p to upregulate the expression of the tumor suppressor RGMA, leading to the activation of BMP/Smad signaling and, ultimately, the inhibition of colon cancer cells, indicating that circHIPK2 inhibits colon cancer cells through the miR-373-3p/RGMA/BMP pathway. These findings revealed a previously unknown regulation, function, and underlying mechanism of circHIPK2 in cancer cells. Hence, circHIPK2 may have a prognostic value and serve as a potential target for colon cancer treatment.
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Proliferação de Células , Neoplasias do Colo , Regulação Neoplásica da Expressão Gênica , MicroRNAs , RNA Circular , Animais , Feminino , Humanos , Masculino , Camundongos , Proteínas de Transporte , Linhagem Celular Tumoral , Movimento Celular , Neoplasias do Colo/genética , Neoplasias do Colo/patologia , Neoplasias do Colo/metabolismo , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/genética , MicroRNAs/metabolismo , Proteínas do Tecido Nervoso/genética , Proteínas do Tecido Nervoso/metabolismo , Prognóstico , Proteínas Serina-Treonina Quinases/genética , Proteínas Serina-Treonina Quinases/metabolismo , RNA Circular/genética , RNA Circular/metabolismo , Transdução de Sinais , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
Inflammatory bowel disease (IBD) is a chronic disease that is characterized by intestinal inflammation. Epithelial damage and loss of intestinal barrier function are believed to be the hallmark pathologies of the disease. In IBD, the resident and infiltrating immune cells consume much oxygen, rendering the inflamed intestinal mucosa hypoxic. In hypoxia, the hypoxia-inducible factor (HIF) is induced to cope with the lack of oxygen and protect intestinal barrier. Protein stability of HIF is tightly controlled by prolyl hydroxylases (PHDs). Stabilization of HIF through inhibition of PHDs is appearing as a new strategy of IBD treatment. Studies have shown that PHD-targeting is beneficial to the treatment of IBD. In this Review, we summarize the current understanding of the role of HIF and PHDs in IBD and discuss the therapeutic potential of targeting PHD-HIF pathway for IBD treatment.
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Inflammatory bowel disease (IBD) is a term encompassing a few chronic inflammatory disorders that leads to damage of the intestinal tract. Although much progress has been made in understanding the pathology of IBD, the precise pathogenesis is not completely understood. Circular RNAs (circRNAs) are single-stranded, covalently closed, endogenous molecules in eukaryotes with a variety of biological functions. CircRNAs have been shown to have regulatory effects in many diseases, such as cancer, cardiovascular disease, and neurological disorders. CircRNAs have also been found to play important roles in IBD, and although they are not sufficiently investigated in the context of IBD, a few circRNAs have been identified as potential biomarkers for the diagnosis and prognosis of IBD and as potential therapeutic targets for IBD. Herein, we survey recent progress in understanding the functions and roles of circRNAs in IBD and discuss their potential clinical applications.
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Doenças Cardiovasculares , Doenças Inflamatórias Intestinais , Humanos , RNA Circular/genética , Doenças Inflamatórias Intestinais/diagnóstico , Doenças Inflamatórias Intestinais/genéticaRESUMO
Genetic variations are associated with individual susceptibility to gastric cancer. Recently, polygenic risk score (PRS) models have been established based on genetic variants to predict the risk of gastric cancer. To assess the accuracy of current PRS models in the risk prediction, a systematic review was conducted. A total of eight eligible studies consisted of 544842 participants were included for evaluation of the performance of PRS models. The overall accuracy was moderate with Area under the curve values ranging from 0.5600 to 0.7823. Incorporation of epidemiological factors or Helicobacter pylori (H. pylori) status increased the accuracy for risk prediction, while selection of single nucleotide polymorphism (SNP) and number of SNPs appeared to have little impact on the model performance. To further improve the accuracy of PRS models for risk prediction of gastric cancer, we summarized the association between gastric cancer risk and H. pylori genomic variations, cancer associated bacteria members in the gastric microbiome, discussed the potentials for performance improvement of PRS models with these microbial factors. Future studies on comprehensive PRS models established with human SNPs, epidemiological factors and microbial factors are indicated.
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The goal of this study was to determine the net energy (NE) value of wheat for growing ducks and establish a NE prediction equation based on the grain's chemical composition. Forty wheat samples were selected based on bulk weight from major wheat-producing regions in China. A total of 460 1-week-old ducks (initial body weight (BW): 134.86 ± 3.32 g) were randomly assigned to 46 diets, including a basal diet, 5 restricted feeding diets and 40 test diets. Each diet contained five replicates, each with two ducks. The basic diet was a corn-soybean meal, and 40 kinds of experimental diets were prepared by mixing the basic diet with 20% wheat. A prediction equation for the NE concentration was created using the chemical make-up of wheat samples. The results indicated that the NE and apparent metabolism energy (AME) content of 40 wheat samples ranged from 6.81 to 9.12 MJ/kg and from 11.03 to 14.34 MJ/kg, respectively. The ether extract (EE), neutral detergent fiber (NDF), acid detergent fiber (ADF) and AME were highly correlated with NE value (p < 0.01), with the AME and NE showing the strongest correlation (r = 0.884). Chemical features could be used to predict the NE values with accuracy, and the prediction equation was strengthened by the inclusion of the AME. The best-fit equation was as follows: NE = 0.380 AME - 0.147 NDF - 0.274 ADF + 5.262 (R2 = 0.874, RSD = 0.19, p < 0.001). In summary, the NE value of wheat is 8.49 ± 0.30 MJ/kg for growing ducks, and the chemical composition can be used to accurately predict NE in wheat.
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BACKGROUND: Genetic variants of Helicobacter pylori (H. pylori) are involved in gastric cancer occurrence. Single nucleotide polymorphisms (SNPs) of H. pylori that are associated with gastric cancer have been reported. The combined effect of H. pylori SNPs on the risk of gastric cancer remains unclear. AIM: To assess the performance of a polygenic risk score (PRS) based on H. pylori SNPs in predicting the risk of gastric cancer. METHODS: A total of 15 gastric cancer-associated H. pylori SNPs were selected. The associations between these SNPs and gastric cancer were further validated in 1022 global strains with publicly available genome sequences. The PRS model was established based on the validated SNPs. The performance of the PRS for predicting the risk of gastric cancer was assessed in global strains using quintiles and random forest (RF) methods. The variation in the performance of the PRS among different populations of H. pylori was further examined. RESULTS: Analyses of the association between selected SNPs and gastric cancer in the global dataset revealed that the risk allele frequencies of six SNPs were significantly higher in gastric cancer cases than non-gastric cancer cases. The PRS model constructed subsequently with these validated SNPs produced significantly higher scores in gastric cancer. The odds ratio (OR) value for gastric cancer gradually increased from the first to the fifth quintile of PRS, with the fifth quintile having an OR value as high as 9.76 (95% confidence interval: 5.84-16.29). The results of RF analyses indicated that the area under the curve (AUC) value for classifying gastric cancer and non-gastric cancer was 0.75, suggesting that the PRS based on H. pylori SNPs was capable of predicting the risk of gastric cancer. Assessing the performance of the PRS among different H. pylori populations demonstrated that it had good predictive power for cancer risk for hpEurope strains, with an AUC value of 0.78. CONCLUSION: The PRS model based on H. pylori SNPs had a good performance for assessment of gastric cancer risk. It would be useful in the prediction of final consequences of the H. pylori infection and beneficial for the management of the infection in clinical settings.
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Given the complex nature of ulcerative colitis, combination therapy targeting multiple pathogenic genes and pathways of ulcerative colitis may be required. Unfortunately, current therapeutic strategies are usually based on independent chemical compounds or monoclonal antibodies, and the full potential of combination therapy has not yet been realized for the treatment of ulcerative colitis. Here, we develop a synthetic biology strategy that integrates the naturally existing circulating system of small extracellular vesicles with artificial genetic circuits to reprogram the liver of male mice to self-assemble multiple siRNAs into secretory small extracellular vesicles and facilitate in vivo delivery siRNAs through circulating small extracellular vesicles for the combination therapy of mouse models of ulcerative colitis. Particularly, repeated injection of the multi-targeted genetic circuit designed for simultaneous inhibition of TNF-α, B7-1 and integrin α4 rapidly relieves intestinal inflammation and exerts a synergistic therapeutic effect against ulcerative colitis through suppressing the pro-inflammatory cascade in colonic macrophages, inhibiting the costimulatory signal to T cells and blocking T cell homing to sites of inflammation. More importantly, we design an AAV-driven genetic circuit to induce substantial and lasting inhibition of TNF-α, B7-1 and integrin α4 through only a single injection. Overall, this study establishes a feasible combination therapeutic strategy for ulcerative colitis, which may offer an alternative to conventional biological therapies requiring two or more independent compounds or antibodies.
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Colite Ulcerativa , Animais , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/terapia , Inflamação/genética , Integrina alfa4 , Masculino , Camundongos , RNA Interferente Pequeno , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/uso terapêuticoRESUMO
The hypoxia-inducible factor (HIF) prolyl hydroxylases (PHDs) are dioxygenases using oxygen and 2-oxoglutarate as co-substrates. Under normoxia, PHDs hydroxylate the conserved prolyl residues of HIFα, leading to HIFα degradation. In hypoxia PHDs are inactivated, which results in HIFα accumulation. The accumulated HIFα enters nucleus and initiates gene transcription. Many studies have shown that PHDs have substrates other than HIFα, implying that they have HIF-independent non-canonical functions. Besides modulating protein stability, the PHDs-mediated prolyl hydroxylation affects protein-protein interaction and protein activity for alternative substrates. Increasing evidence indicates that PHDs also have hydroxylase-independent functions. They influence protein stability, enzyme activity, and protein-protein interaction in a hydroxylase-independent manner. These findings highlight the functional diversity and complexity of PHDs. Due to having inhibitory activity on HIFα, PHDs are proposed to act as tumor suppressors. However, research shows that PHDs exert either tumor-promoting or tumor-suppressing features. Here, we try to summarize the current understanding of PHDs hydroxylase-dependent and -independent functions and their roles in cancer.
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Prolina Dioxigenases do Fator Induzível por Hipóxia/metabolismo , Neoplasias/patologia , Oxigênio/metabolismo , Animais , Humanos , Hidroxilação , Neoplasias/metabolismoRESUMO
HER2 amplification greatly contributes to the tumorigenesis of multiple cancers. Intronic miR-4728-5p is transcribed along with its host gene HER2. However, little is known about the role of miR-4728-5p in cancer. This study aims to elucidate the potential role of miR-4728-5p and the underlying mechanism in breast cancer. Kaplan-Meier analysis showed that higher expression of HER2 led to worse survival outcomes in breast cancer patients. The TCGA dataset revealed that compared to normal breast tissues, HER2 and miR-4728-5p levels were significantly upregulated in breast cancer tissues with a positive correlation. In functional assays, miR-4728-5p was confirmed to promote the proliferation and migration in breast cancer cell BT474. EBP1 was identified as a direct target of miR-4728-5p via bioinformatics and luciferase reporter assays. miR-4728-5p was further demonstrated to increase HER2 expression and promote cell proliferation and migration by directly inhibiting EBP1 in breast cancer. Taken together, the HER2-intronic miR-4728-5p/EBP1/HER2 feedback loop plays an important role in promoting breast cancer cell proliferation and migration. Our study provides novel insights for targeted therapies of breast cancer.