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Background: Pepper veinal mottle virus (PVMV) belongs to the genus Potyvirus within the family Potyviridae and is a major threat to pepper production, causing reduction in yield and fruit quality; however, efficient pesticides and chemical treatments for plant protection against viral infections are lacking. Hence, there is a critical need to discover highly active and environment-friendly antiviral agents derived from natural sources. Bacillus spp. are widely utilized as biocontrol agents to manage fungal, bacterial, and viral plant diseases. Particularly, Bacillus velezensis HN-2 exhibits a strong antibiotic activity against plant pathogens and can also induce plant resistance. Methods: The experimental subjects employed in this study were Bacillus velezensis HN-2, benzothiadiazole, and dufulin, aiming to evaluate their impact on antioxidant activity, levels of reactive oxygen species, activity of defense enzymes, and expression of defense-related genes in Nicotiana benthamiana. Furthermore, the colonization ability of Bacillus velezensis HN-2 in Capsicum chinense was investigated. Results: The results of bioassays revealed the robust colonization capability of Bacillus velezensis HN-2, particularly in intercellular spaces, leading to delayed infection and enhanced protection against PVMV through multiple plant defense mechanisms, thereby promoting plant growth. Furthermore, Bacillus velezensis HN-2 increased the activities of antioxidant enzymes, thereby mitigating the PVMV-induced ROS production in Nicotiana benthamiana. Moreover, the application of Bacillus velezensis HN-2 at 5 dpi significantly increased the expression of JA-responsive genes, whereas the expression of salicylic acid-responsive genes remained unchanged, implying the activation of the JA signaling pathway as a crucial mechanism underlying Bacillus velezensis HN-2-induced anti-PVMV activity. Immunoblot analysis revealed that HN-2 treatment delayed PVMV infection at 15 dpi, further highlighting its role in inducing plant resistance and promoting growth and development. Conclusions: These findings underscore the potential of Bacillus velezensis HN-2 for field application in managing viral plant diseases effectively.
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Porous crystalline conjugated macrocyclic materials (CMMs) possess high porosity, tunable structure/function and efficient charge transport ability owing to their planar macrocyclic conjugated π-electron system, which make them promising candidates for applications in energy storage. In this review, we thoroughly summarize the timely development of porous crystalline CMMs in energy storage related fields. Specifically, we summarize and discuss their structures and properties. In addition, their energy storage applications, such as lithium ion batteries, lithium sulfur batteries, sodium ion batteries, potassium ion batteries, Li-CO2 batteries, Li-O2 batteries, Zn-air batteries, supercapacitors and triboelectric nanogenerators, are also discussed. Finally, we present the existing challenges and future prospects. We hope this review will inspire the development of advanced energy storage materials based on porous crystalline CMMs.
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Background: Gastric cancer (GC) continues to be one of the leading causes of cancer-related deaths globally. Diet significantly influences the incidence and progression of GC. However, the relationship between dietary intake and GC is inconsistent. Methods: A study was conducted with adults who participated in the National Health and Nutrition Examination Survey (NHANES) from 2003 to 2016 to investigate possible associations between 32 dietary factors and GC. To further detect potential causal relationships between these dietary factors and the risk of GC, a two-sample Mendelian randomization (MR) analysis was conducted. The primary method employed was the inverse variance weighted (IVW) analysis, and its results were further validated by four other methods. Results: Of the 35,098 participants surveyed, 20 had a history of GC. Based on the results of weighted logistic multivariate analysis, it was observed that there was a positive correlation between total fat intake [odds ratio (OR) = 1.09, 95% confidence interval (CI): (1.01-1.17), p = 0.03] and GC as well as negative association of dietary monounsaturated fatty acids (MUFAs) intake [OR = 0.83, 95% CI: (0.76-0.92), p < 0.001]. Further evaluations of the odds of GC across the quartiles of dietary MUFAs showed that the top quartile of total MUFA intake was associated with a lower likelihood of GC in three different models [model1: OR = 0.03, 95% CI: (0.00-0.25), p < 0.01; model2: OR = 0.04, 95% CI: (0.00-0.38), p = 0.01; model3: OR = 0.04, 95% CI: (0.00-0.40), p = 0.01]. For the MR analyses, genetic instruments were selected from the IEU Open GWAS project; IVW analysis showed that GC risk was not associated with MUFAs [OR = 0.82, 95% CI: (0.59-1.14), p = 0.23] or the ratio of MUFAs to total fatty acids [OR = 1.00, 95% CI: (0.75-1.35), p = 0.98]. Similar results were observed when using the other MR methods. Conclusion: The NHANES study revealed that consuming MUFAs was linked to a lower risk of GC, although the results of MR analyses do not provide evidence of a causal relationship. Additional research is therefore necessary to clarify these findings.
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Background: For gastric cancer (GC) patients with pylorus outlet obstruction (POO), whether laparoscopic surgery has advantages over open surgery remains unclear. This study aims to investigate the differences between patients with and without POO in open and laparoscopic groups and to determine the differences between laparoscopic distal gastrectomy (LDG) and open distal gastrectomy (ODG) in GC patients with POO. Methods: A total of 241 GC patients with POO who underwent distal gastrectomy at the Department of Gastric Surgery of the First Affiliated Hospital of Nanjing Medical University between 2016 and 2021 were included in this study. A total of 1,121 non-POO patients who underwent laparoscopic surgery and 948 non-POO patients who underwent open surgery from 2016 to 2021 were also enrolled in the study. We compared complication rates and hospital stays between open and laparoscopic groups. Results: There was no significant difference for LDG between GC patients with and without POO regarding the overall complication rates (P = 0.063), the Grade III-V complication rate (P = 0.673), and the anastomotic complication rate (P = 0.497) from 2016 to 2021. The patients with POO had longer preoperative hospital stay (P = 0.001) and postoperative hospital stay (P=0.007) compared to patients without POO. No significant difference was observed for open patients between POO and non-POO patients regarding the overall complication rate (P = 0.357), grade III-V complication rate (P = 1.000), and anastomosis-related complication rate (P = 0.766). Compared with open surgery in GC patients with POO (n = 111), the total complication rate of the LDG group was 16.2%, which was significantly lower than that of the open group (26.1%, P = 0.041). No significant differences in the Grade III-V complication rate (P = 0.574) and anastomotic complication rate (P = 0.587) were observed between laparoscopic and open groups. Patients receiving laparoscopic surgery had shorter postoperative hospital stay than open surgery (P = 0.001). More resected lymph nodes (LNs) were also observed in the laparoscopic group (P = 0.0145). Conclusion: The comorbidity of GC with POO does not increase the complication rate after laparoscopic or open distal gastrectomy. In GC patients with POO, laparoscopic surgery shows advantages over open surgery with a lower overall complication rate, shorter postoperative hospital stay, and more harvested lymph nodes. Laparoscopic surgery is a safe, feasible, and effective treatment for GC with POO.
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Drug discovery is a costly and time-consuming process with a very high failure rate. Recently, click chemistry and computer-aided drug design (CADD) represent popular areas for new drug development. Herein, we summarized the recent updates in click and computational chemistry for drug discovery and development including clicking to effectively synthesize druggable candidates, synthesis and modification of natural products, targeted delivery systems, and computer-aided drug discovery for target identification, seeking out and optimizing lead compounds, ADMET prediction as well as compounds synthesis, hopefully, inspires new ideas for novel drug development in the future.
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BACKGROUND: Previous studies have revealed the critical role of transglutaminase 2 (TGM2) as a potential therapeutic target in cancers, but the oncogenic roles and underlying mechanisms of TGM2 in gastric cancer (GC) are not fully understood. In this study, we examined the role and potential mechanism of TGM2 in GC. METHODS: Western blotting, immunohistochemistry, CCK8, colony formation and transwell assays were used to measure TGM2 expression in the GC cells and tissues and to examine the in vitro role of TGM2 in GC. Xenograft and in vivo metastasis experiments were performed to examine the in vivo role of TGM2 in GC. Gene set enrichment analysis, quantitative PCR and western blotting were conducted to screen for potential TGM2 targets involved in GC. Gain/loss-of-function and rescue experiments were conducted to detect the biological roles of STAT1 in GC cells in the context of TGM2. Co-immunoprecipitation, mass spectrometry, quantitative PCR and western blotting were conducted to identify STAT1-interacting proteins and elucidate their regulatory mechanisms. Mutations in TGM2 and two molecules (ZM39923 and A23187) were used to identify the enzymatic activity of TGM2 involved in the malignant progression of GC and elucidate the underlying mechanism. RESULTS: In this study, we demonstrated elevated TGM2 expression in the GC tissues, which closely related to pathological grade, and predicted poor survival in patients with GC. TGM2 overexpression or knockdown promoted (and inhibited) cell proliferation, migration, and invasion, which were reversed by STAT1 knockdown or overexpression. Further studies showed that TGM2 promoted GC progression by inhibiting STAT1 ubiquitination/degradation. Then, tripartite motif-containing protein 21 (TRIM21) was identified as a ubiquitin E3 ligase of STAT1 in GC. TGM2 maintained STAT1 stability by facilitating the dissociation of TRIM21 and STAT1 with GTP-binding enzymatic activity. A23187 abolished the role of TGM2 in STAT1 and reversed the pro-tumor role of TGM2 in vitro and in vivo. CONCLUSIONS: This study revealed a critical role and regulatory mechanism of TGM2 on STAT1 in GC and highlighted the potential of TGM2 as a therapeutic target, which elucidates the development of medicine or strategies by regulating the GTP-binding activity of TGM2 in GC.
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Proteína 2 Glutamina gama-Glutamiltransferase , Fator de Transcrição STAT1 , Neoplasias Gástricas , Humanos , Calcimicina , Linhagem Celular Tumoral , Guanosina Trifosfato/metabolismo , Proteína 2 Glutamina gama-Glutamiltransferase/metabolismo , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT1/metabolismo , Neoplasias Gástricas/patologia , UbiquitinaçãoRESUMO
BACKGROUND: Liver metastasis (LM) is a major obstacle to the prognosis of gastric cancer (GC) patients, but the molecular mechanism underlying gastric cancer liver metastasis (GC-LM) remains unknown. Exosomes have been identified as an important mediator of communication between tumor cells and the microenvironment. Therefore, we sought to investigate the effects of primary GC cells on the liver microenvironment and the role of exosomal microRNAs (exo-miRNA) in GC-LM. METHODS: Sequential differential centrifugation, transmission electron microscopy and NanoSight analysis were used to extract and characterize exosomes. MicroRNA sequencing in GC-derived exosomes and mRNA sequencing in PMA-treated THP-1 cells were used to identify differentially expressed miRNAs in exosomes and the functional targets of exosomal miR-519a-3p (exo-miR-519a-3p) in macrophages, respectively. Tracing and internalization of exosomes and transfer of exo-miR-519a-3p were observed by immunofluorescence. Tubule formation assays, aortic ring assays, and exosome-educated GC-LM model were used to investigate the roles of GC-derived exosomes and exo-miR-519a-3p in angiogenesis and GC-LM. Luciferase reporter assay, qRT-PCR, Western blot, ELISA, flow cytometry and immunofluorescence were used to investigate the regulatory mechanism of exo-miR-519a-3p at GC-LM. RESULTS: The expression level of miR-519a-3p in serum exosomes was significantly higher in GC-LM patients than in patients without LM, and high expression of exo-miR-519a-3p indicates a worse prognosis. GC-derived exosomes are mainly accumulated in the liver and internalized by intrahepatic macrophages. Mechanistically, exo-miR-519a-3p activates the MAPK/ERK pathway by targeting DUSP2, thereby causing M2-like polarization of macrophages. M2-like polarized macrophages accelerate GC-LM by inducing angiogenesis and promoting intrahepatic premetastatic niche formation. CONCLUSIONS: Our results indicate that exo-miR-519a-3p plays a critical role in mediating crosstalk between primary GC cells and intrahepatic macrophages and is a potential therapeutic target for GC-LM.
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Exossomos , Neoplasias Hepáticas , MicroRNAs , Neoplasias Gástricas , Linhagem Celular Tumoral , Proliferação de Células , Exossomos/genética , Exossomos/metabolismo , Humanos , Neoplasias Hepáticas/metabolismo , Macrófagos/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , Neovascularização Patológica/metabolismo , RNA Mensageiro/metabolismo , Neoplasias Gástricas/patologia , Microambiente Tumoral/genéticaRESUMO
The formation of polymeric micro-patterns on various substrates via a photolithography procedure has been widely used in semiconductor fabrication. Standard polymer patterns are usually fabricated via photosensitive polymer varnishes, in which large amounts of potentially harmful solvents with weight ratios over 50 wt% have to be removed. In the current work, a novel pattern-formation methodology via solvent-free electrospun photosensitive polymeric fibrous membranes (NFMs) instead of the conventional photosensitive solutions as the starting photoresists was proposed and practiced. For this purpose, a series of preimidized negative auto-photosensitive polyimide (PSPI) resins were first prepared via the two-step chemical imidization procedure from the copolymerization reactions of 3,3',4,4'-benzophenonetetracarboxylic- dianhydride (BTDA) and two ortho-methyl-substituted aromatic diamines, including 3,3',5,5'-tetramethyl-4,4'-diaminodiphenylmethane (TMMDA) and 3,7-diamino-2,8-dimethyl- dibenzothiophene sulfone (TSN). The derived homopolymer PI-1 (BTDA-TMMDA) and the copolymers, including SPI-2~SPI-6, with the molar ratio of 5~25% for TSN in the diamine units, showed good solubility in polar solvents. Then, a series of PSPI NFMs were fabricated via standard electrospinning procedure with the developed PSPI solutions in N,N-dimethylacetamide (DMAc) with a solid content of 25 wt% as the starting materials. The derived PSPI NFMs showed good thermal stability with 5% weight loss temperatures higher than 500 °C in nitrogen. Meanwhile, the derived PSPIs showed good photosensitivity to the ultraviolet (UV) emitting wavelengths of i-line (365 nm), g-line (405 nm) and h-line (436 nm) of the high-pressure mercury lamps in both forms of transparent films and opaque NFMs. Fine micro-patterns with a line width of around 100 µm were directly obtained from the representative SPI-4 NFM via standard photolithography procedure.
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Circular RNAs (circRNAs) play vital regulatory roles in the progression of multiple cancers. In our study, transcriptome analysis and self-organizing maps (SOM) were applied to screen backbone circRNAs in gastric cancer (GC). Upon validation of the expression patterns of screened circRNAs, gain- and loss-of-function assays were performed in vitro and in vivo. Underlying mechanisms were investigated using RNA pull-down, luciferase reporter assay and RNA immunoprecipitation. The expression of circTHBS1 was significantly increased in GC and associated with poor prognosis. CircTHBS1 facilitated the malignant behavior and epithelial-to-mesenchymal transition of GC cells. Mechanistically, circTHBS1 sponged miR-204-5p to promote the expression of Inhibin Subunit Beta A (INHBA). Moreover, circTHBS1 could enhance the HuR-mediated mRNA stability of INHBA, which subsequently activated the TGF-ß pathway. Our research identified circTHBS1 as an oncogenic circRNA that enhances GC malignancy by elevating INHBA expression, providing new insight and a feasible target for the diagnosis and treatment of GC.
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MicroRNAs , Neoplasias Gástricas , Linhagem Celular Tumoral , Proliferação de Células/genética , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Subunidades beta de Inibinas , MicroRNAs/genética , MicroRNAs/metabolismo , RNA Circular/genética , RNA Mensageiro/genética , Neoplasias Gástricas/patologia , Trombospondina 1RESUMO
BACKGROUND: Chemotherapy can significantly improve the disease-free survival and overall survival of patients with advanced gastric cancer (GC). 5-fluorouracil (5-FU) is frequently applied in the clinic, acting as a first-line chemotherapy drug of advanced GC, which could be used alone or combining platinum drugs. However, its efficacy is significantly attenuated by chemoresistance, which is associated with patients' poor survival. Recently, there is evidence suggesting that dysregulation of autophagy may contribute to drug resistance in cancer, and circular RNAs (circRNAs) also take part in chemoresistance. However, whether circRNAs participate in 5-FU chemoresistance through autophagy remains largely unknown. METHODS: RNA sequencing technologies and bioinformatics analysis were performed in GC. Sanger sequencing, Actinomycin D assay and RNase R assay confirmed the circular structure of circular CPM (circCPM). Various cell line models and animal models were used to explore related functions in vitro and in vivo. Quantitative Real-time PCR (qRT-PCR), fluorescence in situ hybridization, ribonucleic acid; (RNA) pulldown assays, RNA binding protein immunoprecipitation assays and Luciferase reporter assays were applied to explore involved pathways. RESULTS: circCPM was up-regulated in 5-FU resistant GC cell lines and tissue. Moreover, high circCPM expression is positively associated with poor survival. Silencing circCPM greatly improved chemosensitivity in vitro and in vivo. Mechanistically, it directly binds to miR-21-3p in the cytoplasm and therefore increases the expression of PRKAA2, contributing to the activation of autophagy and chemoresistance. CONCLUSION: Our results reveal that circCPM has a crucial role in regulating GC autophagy and 5-FU resistance by targeting PRKAA2. It may function as a new theory basis for assessing the curative effect of GC and reversing 5-FU chemoresistance.
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Proteínas Quinases Ativadas por AMP/metabolismo , Neoplasias Gástricas/genética , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/farmacologia , Autofagia/genética , Proteínas Ligadas por GPI/agonistas , Proteínas Ligadas por GPI/metabolismo , Humanos , Estimativa de Kaplan-Meier , Metaloendopeptidases/metabolismo , MicroRNAs/genética , MicroRNAs/metabolismo , MicroRNAs/uso terapêuticoRESUMO
Gastric cancer (GC) ranks third in mortality among all cancers worldwide. Circular RNAs (circRNAs) play an important role in the occurrence and development of gastric cancer. Forkhead box P2 (FOXP2), as a transcription factor, is closely associated with the development of many types of tumours. However, the regulatory network between FOXP2 and circRNAs remains to be explored. In our study, circST3GAL6 was significantly downregulated in GC and was associated with poor prognosis in GC patients. Overexpression of circST3GAL6 inhibited the malignant behaviours of GC cells, which was mediated by inducing apoptosis and autophagy. In addition, we demonstrated that circST3GAL6 regulated FOXP2 through the mir-300 sponge. We further found that FOXP2 inhibited MET Proto-Oncogene (MET), which was the initiating factor that regulated the classic AKT/mTOR pathway of autophagy. In conclusion, our results suggested that circST3GAL6 played a tumour suppressive role in gastric cancer through miR-300/FOXP2 axis and regulated apoptosis and autophagy through FOXP2-mediated transcriptional inhibition of the MET axis, which may become a potential target for GC therapy.
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Autofagia/efeitos dos fármacos , Sialiltransferases/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Animais , Movimento Celular/efeitos dos fármacos , Movimento Celular/genética , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/genética , Modelos Animais de Doenças , Fatores de Transcrição Forkhead/efeitos dos fármacos , Camundongos , Neoplasias/tratamento farmacológico , Neoplasias/prevenção & controle , Proteínas Proto-Oncogênicas c-met/efeitos dos fármacos , Sialiltransferases/farmacologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Neoplasias Gástricas/prevenção & controle , Serina-Treonina Quinases TOR/efeitos dos fármacos , beta-Galactosídeo alfa-2,3-SialiltransferaseRESUMO
Gastric cancer (GC) ranks the third among global cancer-related mortality, especially in East Asia. Angiogenesis plays an important role in promoting tumor progression, and clinical trials have demonstrated that anti-angiogenesis therapy is effective in GC management. Natriuretic peptide receptor A (NPRA) functions significantly in promoting GC development and progression. Whether NPRA can promote angiogenesis of GC remains unclear. Tumor samples collection and immunohistochemical experiment showed that the expression of NPRA was positively correlated with the expression of CD31 and vessel density. In vivo and in vitro analysis showed that NPRA could promote GC-associated angiogenesis and tumor metastasis. Results of Co-IP/MS showed that NPRA could prevent HIF-1α from being degraded by binding to HIF-1α. Protection of HIF-1α improved VEGF levels and thus promoted angiogenesis. In summary, NPRA protected HIF-1α from proteolysis by binding to HIF-1α, increased the expression of HIF-1α, and promoted GC angiogenesis. This study has discovered a new mechanism for NPRA to promote gastric cancer development and a new regulatory mechanism for HIF-1α.
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Neovascularização Patológica/metabolismo , Receptores do Fator Natriurético Atrial/metabolismo , Neoplasias Gástricas/irrigação sanguínea , Neoplasias Gástricas/metabolismo , Animais , Linhagem Celular Tumoral , Proliferação de Células/genética , Modelos Animais de Doenças , Feminino , Regulação Neoplásica da Expressão Gênica , Inativação Gênica , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Camundongos Nus , Modelos Biológicos , Estadiamento de Neoplasias , Neovascularização Patológica/genética , Neovascularização Patológica/patologia , Prognóstico , Proteólise , Transdução de Sinais , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Regulação para Cima/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Liver metastasis (LM) severely affects gastric cancer (GC) patients' prognosis. Small extracellular vesicles (sEVs) play key roles in intercellular communication. Specific sEV-miRNAs from several types of cancer were found to induce a premetastatic niche in target organs before tumor cell arrive. However, whether the primary GC affects hepatic microenvironment or the role of sEV-miRNAs in GC-LM is yet unclear. We report that GC-derived sEVs are primarily absorbed by Kupffer cells (KCs). sEV-miR-151a-3p is highly expressed in GC-LM patients' plasma and presents poor prognosis. Treating mice with sEVs-enriched in miR-151a-3p promotes GC-LM, whereas has no influence on the proliferation of GC cells in situ. Mechanistically, sEV-miR-151a-3p inhibits SP3 in KCs. Simultaneously, sEV-miR-151a-3p targets YTHDF3 to decrease the transcriptional inhibitory activity of SP3 by reducing SUMO1 translation in a N6-methyladenosine-dependent manner. These factors contribute to TGF-ß1 transactivation in KCs, subsequently activating the SMAD2/3 pathway and enhancing the stem cell-like properties of incoming GC cells. Furthermore, sEV-miR-151a-3p induces miR-151a-3p transcription in KCs to form a positive feedback loop. In summary, our results reveal a previously unidentified regulatory axis initiated by sEV-miR-151a-3p that establishes a hepatic stemness-permissive niche to support GC-LM. sEV-miR-151a-3p could be a promising diagnostic biomarker and preventive treatment candidate for GC-LM.
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Vesículas Extracelulares/genética , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/secundário , MicroRNAs/genética , Neoplasias Gástricas/patologia , Regulação para Cima , Animais , Linhagem Celular Tumoral , Transição Epitelial-Mesenquimal , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Hepáticas/genética , Camundongos , Transplante de Neoplasias , Prognóstico , Proteínas de Ligação a RNA/genética , Proteína SUMO-1/genética , Transdução de Sinais , Fator de Transcrição Sp3/genética , Neoplasias Gástricas/genética , Análise de Sobrevida , Células THP-1 , Fator de Crescimento Transformador beta1/genéticaRESUMO
BACKGROUND: A novel type of noncoding RNA, circRNA has been reported to participate in the occurrence and development of diseases through many mechanisms. The MAPK pathway is a common signal transduction pathway involved in cell proliferation, inflammation and apoptosis and plays a particularly important role in cancers. However, the role of circRNAs related to the MAPK pathway in gastric cancer has not been explored. METHODS: A bioinformatics analysis was performed to profile and identify the circRNAs involved in the MAPK pathway in gastric cancer. The tumor-suppressive role of circMAPK1 was confirmed both in vitro and in vivo. Mass spectrometry, Western blot and immunofluorescence staining assays were used to validate the existence and expression of MAPK1-109aa. The molecular mechanism of circMAPK1 was investigated by mass spectrometry and immunoprecipitation analyses. RESULTS: In this study, we identified that circMAPK1 (hsa_circ_0004872) was downregulated in gastric cancer tissues compared with adjacent normal tissues. Importantly, lower circMAPK1 expression predicted poor survival in GC patients. CircMAPK1 inhibited the proliferation and invasion of gastric cancer cells in vitro and in vivo. Next, we found that circMAPK1 encoded a novel protein with 109 amino acids in length. Through a series of functional experiments, we confirmed that circMAPK1 exerted a tumor-suppressing effect via the encoded protein MAPK1-109aa. Mechanistically, the tumor suppressor MAPK1-109aa inhibited the phosphorylation of MAPK1 by competitively binding to MEK1, thereby suppressing the activation of MAPK1 and its downstream factors in MAPK pathway. CONCLUSIONS: Our study revealed that circMAPK1 inhibits the malignant biological behavior of gastric cancer cells through its encoded protein MAPK1-109aa. More importantly, circMAPK1 is a favorable predictor for gastric cancer patients and may provide a new therapeutic target in the treatment of gastric cancer.
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Biomarcadores Tumorais , Sistema de Sinalização das MAP Quinases , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , RNA Circular/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/metabolismo , Adulto , Idoso , Sequência de Aminoácidos , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Suscetibilidade a Doenças , Feminino , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Proteína Quinase 1 Ativada por Mitógeno/química , Metástase Neoplásica , Estadiamento de Neoplasias , Fosforilação , Neoplasias Gástricas/patologia , Carga TumoralRESUMO
BACKGROUND: Circular RNAs (circRNAs) have emerged as a new subclass of regulatory RNAs that play critical roles in various cancers. Cancer stem cells (CSCs), a small subset of cancer cells, are believed to possess the capacities to initiate tumorigenesis and promote progression. Although accumulating evidence has suggested that cells with CSC-like properties are crucial for the malignancy of gastric cancer (GC), it remains unclear whether circRNAs are related to the acquisition of CSC-like properties in GC. METHODS: CircFAM73A expression was analyzed by GEO datasets and verified in GC samples. The roles of circFAM73A in GC cell proliferation, migration, cisplatin resistance, and CSC-like properties were determined by a series of functional experiments both in vitro and in vivo. RNA pulldown was used to explore the miRNAs and proteins binding to circFAM73A. Bioinformatic analysis and experimental verification confirmed the downstream targets of circFAM73A. The regulation of circFAM73A by HMGA2 was verified by ChIP and RIP assays. RESULTS: Elevated circFAM73A expression was confirmed in GC tissues, and higher circFAM73A predicted poor prognosis in GC patients. The upregulation of circFAM73A enhanced CSC-like properties in GC, thus facilitating cell proliferation, migration, and cisplatin resistance. Mechanistically, circFAM73A promoted GC malignancy by regulating miR-490-3p/HMGA2 in a positive feedback loop and recruiting HNRNPK to facilitate ß-catenin stabilization. Moreover, HMGA2 further enhanced E2F1 and HNRNPL activity, which in turn promoted circFAM73A expression. CONCLUSIONS: Our work demonstrates the crucial role of circFAM73A in the CSC-like properties of GC and uncovers a positive feedback loop in circFAM73A regulation that leads to the progression of gastric cancer, which may provide new insights into circRNA-based diagnostic and therapeutic strategies.
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Proteína HMGA2/metabolismo , Ribonucleoproteínas Nucleares Heterogêneas Grupo K/metabolismo , MicroRNAs/metabolismo , Células-Tronco Neoplásicas/metabolismo , RNA Circular/metabolismo , Neoplasias Gástricas/metabolismo , beta Catenina/metabolismo , Animais , Linhagem Celular Tumoral , Cisplatino/farmacologia , Progressão da Doença , Resistencia a Medicamentos Antineoplásicos , Retroalimentação Fisiológica , Feminino , Proteína HMGA2/genética , Ribonucleoproteínas Nucleares Heterogêneas Grupo K/genética , Xenoenxertos , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , MicroRNAs/genética , Pessoa de Meia-Idade , Células-Tronco Neoplásicas/patologia , RNA Circular/genética , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Regulação para CimaRESUMO
BACKGROUND: Circular RNAs (circRNAs) act as vital regulators of gene expression in a variety of cancers. However, the role of circRNAs in gastric cancer (GC) remains largely unexplored. Herein, we identified that circTMEM87A sponges miR-142-5p to promote GC progression through up-regulating ULK1 expression. METHODS: The expression of circTMEM87A in GC was determined by RNA sequencing and quantitative real-time PCR (qRT-PCR). The effects of knockdown or exogenous expression of circTMEM87A on GC cell phenotypes were evaluated both in vitro and in vivo. The interacting miRNA of circTMEM87A was predicted by bioinformatics and confirmed by RNA pull-down, dual-luciferase reporter assay and fluorescence in situ hybridization (FISH). The mechanism by which circTMEM87A/miR-142-5p/ULK1 axis promotes GC was determined by western blot, GFP/mRFP-LC3 puncta analysis, transmission electron microscope (TEM). RESULTS: CircTMEM87A was dramatically elevated in GC tissues and cell lines, and high circTMEM87A expression was closely correlated with poor prognosis of GC patients. Knockdown of circTMEM87A suppressed cell growth, migration, invasion and induced apoptosis in vitro, as well as inhibited GC tumorigenicity and lung metastasis potential in vivo. Meanwhile, circTMEM87A overexpression had the opposite effects. Furthermore, we demonstrated that circTMEM87A could act as a sponge of miR-142-5p to regulate ULK1 expression and GC progression. CONCLUSIONS: Our findings suggest that circTMEM87A functions as an oncogene through the miR-142-5p/ULK1 axis in GC. CircTMEM87A might be a prognostic biomarker as well as a promising therapeutic target for GC.
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Proteína Homóloga à Proteína-1 Relacionada à Autofagia/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Peptídeos e Proteínas de Sinalização Intracelular/efeitos dos fármacos , MicroRNAs/efeitos dos fármacos , RNA Circular/farmacologia , Neoplasias Gástricas/etiologia , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/análise , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/genética , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/sangue , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral/efeitos dos fármacos , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/análise , Peptídeos e Proteínas de Sinalização Intracelular/genética , MicroRNAs/análise , MicroRNAs/genética , RNA Circular/uso terapêutico , Neoplasias Gástricas/fisiopatologiaRESUMO
BACKGROUND: Cisplatin (CDDP) is the first-line chemotherapy for gastric cancer (GC). The poor prognosis of GC patients is partially due to the development of CDDP resistance. Circular RNAs (circRNAs) are a subclass of noncoding RNAs that function as microRNA (miRNA) sponges. The role of circRNAs in CDDP resistance in GC has not been evaluated. METHODS: RNA sequencing was used to identify the differentially expressed circRNAs between CDDP-resistant and CDDP-sensitive GC cells. qRT-PCR was used to detect the expression of circMCTP2 in GC tissues. The effects of circMCTP2 on CDDP resistance were investigated in vitro and in vivo. Pull-down assays and luciferase reporter assays were performed to confirm the interactions among circMCTP2, miR-99a-5p, and myotubularin-related protein 3 (MTMR3). The protein expression levels of MTMR3 were detected by western blotting. Autophagy was evaluated by confocal microscopy and transmission electron microscopy (TEM). RESULTS: CircMCTP2 was downregulated in CDDP-resistant GC cells and tissues compared to CDDP-sensitive GC cells and tissues. A high level of circMCTP2 was found to be a favorable factor for the prognosis of patients with GC. CircMCTP2 inhibited proliferation while promoting apoptosis of CDDP-resistant GC cells in response to CDDP treatment. CircMCTP2 was also found to reduce autophagy in CDDP-resistant GC cells. MiR-99a-5p was verified to be sponged by circMCTP2. Inhibition of miR-99a-5p could sensitize GC cells to CDDP. MTMR3 was confirmed to be a direct target of miR-99a-5p. Knockdown of MTMR3 reversed the effects of circMCTP2 on the proliferation, apoptosis and autophagy of CDDP-resistant GC cells. CircMCTP2 was also confirmed to inhibit CDDP resistance in vivo in a nude mouse xenograft model. CONCLUSIONS: CircMCTP2 sensitizes GC to CDDP through the upregulation of MTMR3 by sponging miR-99a-5p. Overexpression of CircMCTP2 could be a new therapeutic strategy for counteracting CDDP resistance in GC.
Assuntos
Cisplatino/farmacologia , Proteínas de Membrana/genética , MicroRNAs/metabolismo , Proteínas Tirosina Fosfatases não Receptoras/metabolismo , RNA Circular/metabolismo , Neoplasias Gástricas/tratamento farmacológico , Neoplasias Gástricas/genética , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Humanos , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Prognóstico , TransfecçãoRESUMO
Coherent optical communication provides optical links with a high spectral efficiency and sensitivity. An essential feature of a coherent optical receiver is to phase lock the optical local oscillator to the carrier of the incoming signal. In this work, we propose and demonstrate, for the first time, a novel coherent optical receiver, where the relative instantaneous phase between the incoming optical carrier and a semiconductor laser (SCL), serving as the optical local oscillator, is first detected using a balanced photodiode, filtered, and used in a feed-forward scheme to modify the phase of the optical local oscillator, effectively recovering the input carrier, which is then used for data recovery. The proposed architecture leverages high-performance on-chip photonic devices to realize a low-power coherent optical receiver without utilizing a phase-locked loop and eliminates the required high data-rate ADC, lowering the complexity of the backend DSP. The photonic part of the implemented prototype was integrated on a 180 nm silicon-on-insulator photonic process within a footprint of 1.0 mm × 0.8 mm. Clock and data recovery at 10 GBaud/s with bit-error-rates better than 10-6 and 10-3 for optical BPSK and QPSK have been demonstrated, respectively.
RESUMO
Anthracnose is a leaf spot, blossom blight, or fruit rot disease caused by Colletotrichum gloeosporioides (Penz.). It is the most prevalent disease in mango-growing countries worldwide. Lipopeptides, such as those in the iturin family, account for the majority of antifungal secondary metabolites in Bacillus subtilis, Bacillus amyloliquefaciens and Bacillus velezensis, and includes bacillomycin D. Thus far, the mechanism of bacillomycin D's activity has not been clear. In this study, bacillomycin D was isolated from B. velezensis HN-2, which strongly inhibits C. gloeosporioides (Penz.). The median inhibitory concentration of bacillomycin D was 2.162⯵g/mL, causing deformation and damage to C. gloeosporioides (Penz.). Bacillomycin D showed more potent activity against C. gloeosporioides (Penz.) than two common fungicides prochloraz and mancozeb. Scanning and transmission electron microscopy revealed that bacillomycin D could injure the cell wall and cell membrane of the hyphae and spores of C. gloeosporioides (Penz.), and the cytoplasm and organelles inside the cell were exuded and formed empty holes. This research clarifies the mechanism underlying bacillomycin D antifungal activity and reveals its high potential as a biopesticide to control phytopathogens.