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Geminiviruses infect numerous crops and cause extensive agricultural losses worldwide. During viral infection, geminiviral C4/AC4 proteins relocate from the plasma membrane to chloroplasts, where they inhibit the production of host defense signaling molecules. However, mechanisms whereby C4/AC4 proteins are transported to chloroplasts are unknown. We report here that tomato (Solanum lycopersicum) COAT PROTEIN COMPLEX I (COPI) components play a critical role in redistributing Tomato yellow leaf curl virus C4 protein to chloroplasts via an interaction between the C4 and ß subunits of COPI. Coexpression of both proteins promotes the enrichment of C4 in chloroplasts that is blocked by a COPI inhibitor. Overexpressing or downregulating gene expression of COPI components promotes or inhibits the viral infection, respectively, suggesting a proviral role of COPI components. COPI components play similar roles in C4/AC4 transport and infections of two other geminiviruses: Beet curly top virus and East African cassava mosaic virus. Our results reveal an unconventional role of COPI components in protein trafficking to chloroplasts during geminivirus infection and suggest a broad-spectrum antiviral strategy in controlling geminivirus infections in plants.
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Geminiviruses cause serious symptoms and devastating losses in crop plants. With a circular, single-stranded DNA genome, geminiviruses multiply their genomic DNA in the nucleus, requiring the nuclear shuttling of viral proteins and viral genomic DNAs. Many host factors, acting as proviral or antiviral factors, play key roles in geminivirus infections. Here, we report the roles of a tomato glutaredoxin (GRX), SlGRXC6, in the infection of Tomato yellow leaf curl virus (TYLCV), a single-component geminivirus. The V2 protein of TYLCV specifically and preferentially interacts with SlGRXC6 among the 55-member tomato GRX family that are broadly involved in oxidative stress responses, plant development, and pathogen responses. We show that overexpressed SlGRXC6 increases the nuclear accumulation of V2 by inhibiting its nuclear export and, in turn, inhibits trafficking of the V1 protein and viral genomic DNA. Conversely, the silenced expression of SlGRXC6 leads to an enhanced susceptibility to TYLCV. SlGRXC6 is also involved in symptom development as we observed a positive correlation where overexpression of SlGRXC6 promotes while knockdown of SlGRXC6 expression inhibits plant growth. We further showed that SlGRXC6 works with SlNTRC80, a tomato NADPH-dependent thioredoxin reductase, to regulate plant growth. V2 didn't interact with SlNTRC80 but competed with SlNTR80 for binding to SlGRXC6, suggesting that the V2-disrupted SlGRXC6-SlNTRC80 interaction is partially responsible for the virus-caused symptoms. These results suggest that SlGRXC6 functions as a host restriction factor that inhibits the nuclear trafficking of viral components and point out a new way to control TYLCV infection by targeting the V2-SlGRXC6 interaction.
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Begomovirus/fisiologia , Núcleo Celular/metabolismo , Doenças das Plantas/imunologia , Proteínas de Plantas/metabolismo , Solanum lycopersicum/imunologia , Proteínas Virais/metabolismo , Replicação Viral , Transporte Ativo do Núcleo Celular , Glutarredoxinas/genética , Glutarredoxinas/metabolismo , Solanum lycopersicum/virologia , Doenças das Plantas/virologia , Proteínas de Plantas/genética , Proteínas Virais/genéticaRESUMO
Wheat (Triticum aestivum L.) is an important cereal crop widely cultivated worldwide. Viral disease is a major threat to wheat yield. In April 2022, fifteen winter wheat plants with yellowing and stunting symptoms were collected from wheat fields in Jingjiang, Jiangsu Province. Total RNA of each sample was extracted, and RT-PCR was performed using two pairs of degenerate luteovirus primers Lu-F (5'-CCAGTGGTTRTGGTC-3') and Lu-R (5'-GTCTACCTATTTGG-3'), Leu-F (5'-GCTCTAGAATTGTTAATGARTACGGTCG-3') and Leu-R (5'-CACGCGTCN ACCTATTTNGGRTTNTG-3'). Amplicons with the expected size were obtained from 10 of the 15 samples (using primers Lu-F/Lu-R) and 3 of the 15 samples (using primers Leu-F/Leu-R), respectively. These amplicons were cloned into the pDM18-T vector (TaKaRa) for sequencing. Blastn alignment showed that 10 amplicons (531 bp) from Lu-F/Lu-R primers were essentially identical to one another, which shared 99.62% nucleotide sequence identity to barley yellow dwarf virus-PAV (BYDV-PAV) isolate GJ1 from Avena sativa in South Korea (LC550014). Three amplicons (635 bp) from Leu-F/Leu-R primers had 99.68% nucleotide identity to the corresponding part of an isolate of beet western yellows virus (BWYV) from saffron (Crocus sativus) in China (MG002646). Among the 13 virus-positive samples, none were co-infected by BYDV-PAV and BWYV. Then, amplification using BWYV-specific primers (BWYV-F: 5'-TGCTCCGGTTTTGACTGGAGTGT-3', BWYV-R: 5'-CGTCTACCT ATTTTGGGTTGTGG-3') generated a 1409 bp product, corresponding to the partial sequence of the viral RNA-dependent RNA polymerase gene and complete sequence of the coat protein (CP) gene. The sequences (GenBank accession no. ON924175) of amplicons from 3 BWYV samples were identical to one another, which shared 98.41% nucleotide identity to BWYV isolate Hs from Japanese hop (Humulus scandens) in China (KC210049). The predicted coat protein of the BWYV wheat isolate had 99.51% nucleotide and 100% amino acid identity to BWYV isolate Hs. BWYV infection on wheat samples was also verified by dot-nucleic acid hybridization using a digoxigenin-labeled cDNA probe against the CP gene, as described previously (Liu et al. 2007). Further, RNA-positive samples were tested by enzyme-linked immunosorbent assay (ELISA) using the ELISA reagent kit for BWYV (Catalog No. KS19341, Shanghai Keshun Biotech, Shanghai, China); test results were also BWYV-positive, confirming that both BWYV nucleic and coat protein are present in these wheat samples. BYDV-PAV is a common wheat virus (Chay et al. 1996), while BWYV has never been reported to infect wheat. BWYV, an aphid-transmitted virus belonging to the Polerovirus genus, has an extensive host range, including over 150 plant species from 23 dicotyledonous families, such as Beta vulgaris, Spinacia oleracea, Lactuca sativa, and Brassica oleracea var. italica (Duffus 1964, 1973; Russell 1965; Beuve et al. 2008). In addition, BWYV was reported to infect a monocotyledonous plant, Crocus sativus (Iridaceae) (Zheng et al. 2018). To our knowledge, this is the first report of BWYV in wheat or any other Gramineae crop. The result also implies that BWYV has a potential risk to cereal crops in the field.
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Tomato mottled mosaic virus (ToMMV) was first identified in tomato in Mexico (Li et al. 2013). It belongs to the genus Tobamovirus and family Virgaviridae, and is a positive-sense single-stranded RNA virus. The viral genome contains about 6400 nucleotides, encoding four proteins, including the 126 K protein, 183 K protein, movement protein (MP) and coat protein (CP) (Tu et al. 2021). ToMMV mainly poses a serious risk to solanaceous crops. The virus-infected plants appear stunted growth and top necrosis, and the disease leaves show mottled, shrinkage and necrosis symptoms, resulting in a significant decline in tomato fruit yield and quality (Li et al. 2017; Tu et al. 2021). Chinese snake gourd (Trichosanthes kirilowii Maxim) is a perennial climbing herb in the family Cucurbitaceae, and the fruit, seed, peel and root can all be used as traditional Chinese medicine. In May of 2021, twenty-seven symptomless seedlings (developed from tissue culture plantlets) were randomly collected from nursery in Fengyang, Anhui Province. Total RNA of each sample was extracted, and RT-PCR was performed using degenerate tobamovirus primers Tob-Uni1 (5'-ATTTAAGTGGASGGAAAAVCACT-3') and Tob-Uni2 (5'-GTYGTT GATGAGTTCRTGGA-3') (Letschert et al. 2002). Amplicons with expected size were obtained from 6 of 27 samples and sequenced. Alignment results showed that the nucleotide sequence identities ranged from 98.7 to 100% with all ToMMV isolates deposited in NCBI GenBank. Then, ToMMV coat protein (CP) gene was amplified using specific primers CP-F (5'-ATGTCTTACGCTATTACTT CTCCG-3') and CP-R (5'-TTAGGACGCTGGCGCAGAAG-3'). The CP fragment was obtained and sequenced. Sequence alignment indicated that CP sequence of isolate FY (GenBank accession no. ON924176) exhibited a 100% identity with ToMMV isolate LN (MN853592.1). The anti-ToMMV polyclonal antibody (PAb) was prepared by the author (S.L.) by immunizing rabbit with purified virus from Nicotiana benthamiana, and serological tests (dot-enzyme linked immunosorbent assay, Dot-ELISA) of RNA-positive T. kirilowii leaf samples using anti-ToMMV PAb were also positive. To fulfill a Koch's postulate, a pure culture of ToMMV was obtained from N. benthamiana using infectious cDNA clone of ToMMV (Tu et al. 2021), and then healthy T. kirilowii plants were mechanically inoculated with a prepared inoculum from ToMMV-infected N. benthamiana, as described previously (Sui et al. 2017). T. kirilowii seedlings showed chlorosis and leaf tip necrosis symptoms at 10 and 20 day post-inoculation respectively, and ToMMV infection on symptomatic plants was also verified by RT-PCR detection using primers CP-F and CP-R. These results demonstrated that T. kirilowii is a host of ToMMV under natural conditions, which might threaten the production of this medicinal plant. The seedlings from nursery appeared to be asymptomatic, but the plants showed chlorosis and necrosis symptoms after indoor inoculation. In qRT-PCR analysis, viral accumulation level in greenhouse-inoculated plants was a 25.6-fold of that in field-collected samples, which may be the reason of different symptom expression between field samples and inoculated samples. ToMMV has now been detected from the solanaceous (tomato, pepper and eggplant) and leguminous (pea) crops in the field (Li et al. 2014; Ambrós et al. 2017; Zhang et al. 2022). To our knowledge, this is the first report of natural infection of ToMMV in T. kirilowii as well as its natural infection on Cucurbitaceae plants.
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Importance: Programmed cell death ligand 1 inhibitors combined with chemotherapy has changed the approach to first-line treatment in patients with extensive-stage small cell lung cancer (SCLC). It remained unknown whether adding a programmed cell death 1 (PD-1) inhibitor to chemotherapy provided similar or better benefits in patients with extensive-stage SCLC, which would add evidence on the efficacy of checkpoint inhibitors in the treatment of extensive-stage SCLC. Objective: To evaluate the efficacy and adverse event profile of the PD-1 inhibitor serplulimab plus chemotherapy compared with placebo plus chemotherapy as first-line treatment in patients with extensive-stage SCLC. Design, Setting, and Participants: This international, double-blind, phase 3 randomized clinical trial (ASTRUM-005) enrolled patients at 114 hospital sites in 6 countries between September 12, 2019, and April 27, 2021. Of 894 patients who were screened, 585 with extensive-stage SCLC who had not previously received systemic therapy were randomized. Patients were followed up through October 22, 2021. Interventions: Patients were randomized 2:1 to receive either 4.5 mg/kg of serplulimab (n = 389) or placebo (n = 196) intravenously every 3 weeks. All patients received intravenous carboplatin and etoposide every 3 weeks for up to 12 weeks. Main Outcomes and Measures: The primary outcome was overall survival (prespecified significance threshold at the interim analysis, 2-sided P < .012). There were 13 secondary outcomes, including progression-free survival and adverse events. Results: Among the 585 patients who were randomized (mean age, 61.1 [SD, 8.67] years; 104 [17.8%] women), 246 (42.1%) completed the trial and 465 (79.5%) discontinued study treatment. All patients received study treatment and were included in the primary analyses. As of the data cutoff (October 22, 2021) for this interim analysis, the median duration of follow-up was 12.3 months (range, 0.2-24.8 months). The median overall survival was significantly longer in the serplulimab group (15.4 months [95% CI, 13.3 months-not evaluable]) than in the placebo group (10.9 months [95% CI, 10.0-14.3 months]) (hazard ratio, 0.63 [95% CI, 0.49-0.82]; P < .001). The median progression-free survival (assessed by an independent radiology review committee) also was longer in the serplulimab group (5.7 months [95% CI, 5.5-6.9 months]) than in the placebo group (4.3 months [95% CI, 4.2-4.5 months]) (hazard ratio, 0.48 [95% CI, 0.38-0.59]). Treatment-related adverse events that were grade 3 or higher occurred in 129 patients (33.2%) in the serplulimab group and in 54 patients (27.6%) in the placebo group. Conclusions and Relevance: Among patients with previously untreated extensive-stage SCLC, serplulimab plus chemotherapy significantly improved overall survival compared with chemotherapy alone, supporting the use of serplulimab plus chemotherapy as the first-line treatment for this patient population. Trial Registration: ClinicalTrials.gov Identifier: NCT04063163.
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Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Anticorpos Monoclonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carboplatina/efeitos adversos , Método Duplo-Cego , Etoposídeo/efeitos adversos , Feminino , Humanos , Inibidores de Checkpoint Imunológico , Ligantes , Neoplasias Pulmonares/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1 , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/etiologiaRESUMO
Plant and animal intracellular nucleotide-binding and leucine-rich repeat (NLR) receptors play important roles in sensing pathogens and activating defense signaling. However, the molecular mechanisms underlying the activation of host defense signaling by NLR proteins remain largely unknown. Many studies have determined that the coil-coil (CC) or Toll and interleukin-1 receptor/resistance protein (TIR) domain of NLR proteins and their dimerization/oligomerization are critical for activating downstream defense signaling. In this study, we demonstrated that, in tomato, the nucleotide-binding (NB) domain Sw-5b NLR alone can activate downstream defense signaling, leading to elicitor-independent cell death. Sw-5b NB domains can self-associate, and this self-association is crucial for activating cell death signaling. The self-association was strongly compromised after the introduction of a K568R mutation into the P-loop of the NB domain. Consequently, the NBK568R mutant induced cell death very weakly. The NBCΔ20 mutant lacking the C-terminal 20 amino acids can self-associate but cannot activate cell death signaling. The NBCΔ20 mutant also interfered with wild-type NB domain self-association, leading to compromised cell death induction. By contrast, the NBK568R mutant did not interfere with wild-type NB domain self-association and its ability to induce cell death. Structural modeling of Sw-5b suggests that NB domains associate with one another and likely participate in oligomerization. As Sw-5b-triggered cell death is dependent on helper NLR proteins, we propose that the Sw-5b NB domain acts as a nucleation point for the assembly of an oligomeric resistosome, probably by recruiting downstream helper partners, to trigger defense signaling.
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Morte Celular , Proteínas NLR , Proteínas de Plantas , Solanum lycopersicum , Proteínas NLR/genética , Nucleotídeos , Proteínas de Plantas/genéticaRESUMO
Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancers. Chemotherapy is the most important therapeutic option for TNBC, and chemotherapy-induced nausea and vomiting (CINV) is inevitable. Metoclopramide is a good and cost-effective therapeutic option for chemotherapy-induced nausea and vomiting. However, it is not commonly used in breast cancer because it can increase serum prolactin levels by blocking dopamine D2 receptor. This study aimed at elucidating the effect of metoclopramide on triple-negative breast cancer, MDA-MB-231 cells were treated with various concentrations of metoclopramide, the cell proliferation was detected by MTT method, the apoptosis rate was detected by Annexin V/PI double staining method, the expression change of death-related protein was detected by Western Blot. We found that metoclopramide inhibits cell proliferation and induces cell apoptosis of MDA-MB-231 in a concentration-dependent manner, and the Bcl family was involved in this process.
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Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Metoclopramida/farmacologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Antineoplásicos/administração & dosagem , Linhagem Celular Tumoral , Antagonistas dos Receptores de Dopamina D2/administração & dosagem , Antagonistas dos Receptores de Dopamina D2/farmacologia , Relação Dose-Resposta a Droga , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Metoclopramida/administração & dosagem , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
OBJECTIVE: To investigate the effect of overexpression of miR-382-5p overexpression on malignant biological behavior of human glioma U251 cells. METHODS: U251 cells were transfected with miR-382-5pmimic. Then miR-382-5p and PTEN mRNA levels were detected by reverse transcription-polymerase chain reaction (RT-PCR) after transfection. Used bioinformatics to predicted the presence of base binding sites between miR-382-5p and PTEN, and constructed PTEN pcDNA vector overexpression plasmid was constructed. Luciluciase reporting experiment was used to detect the targeting relationship between miR-382-5p and PTEN. Cells were randomly divided into four groups: control group, mimics group, pc-PTEN group and mimics+pc-PTEN group for follow-up experiments. RT-PCR was carried out to detect the level of PTEN mRNA in each group. Cell proliferation was detected by clone formation method. The mRNA levels of Ki67, Survivin and c-Myc were detected by RT-PCR. Transwell experiment was used to assayed cell invasion ability. The expression levels of E-cadherin, N-cadherin and Vimentin were determined by Western blot. RESULTS: Results showed that miR-382-5p directly targeted PTEN. Compared with the control group, miR-382-5p and c-Myc mRNA levels and E-cadherin protein level were increased (P<0.05),PTEN, Ki67 and Survivin mRNA levels were decreased (P<0.05), cell clonal formation rate and cell invasion number were decreased (P<0.05), N-cadherin and Vimentin protein levels were decreased (P<0.05) in the mimics group; In pc-PTEN group, miR-382-5p mRNA and c-Myc mRNA levels and E-cadherin protein level were decreased (P<0.05),PTEN, Ki67 and Survivin mRNA levels were increased (P<0.05), cell clonal formation rate and cell invasion number were increased (P<0.05), N-cadherin and Vimentin protein levels were increased (P<0.05). Compared with pc-PTEN group, PTEN, Ki67 and Survivin mRNA levels, the cell clone formation rate, the number of invasion cells and the N-cadherin and Vimentin levels of mimics+PC-PTEN group decreased significantly (P<0.05), while the c-Myc mRNA level and E-cadherin protein level increased significantly (P<0.05). CONCLUSION: Overexpression of miR-382-5p mediates the downregulation of PTEN expression, causing the inhibition of the proliferation, invasion, growth and EMT of U251 glioma cells.
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Produtos Biológicos , Glioma , MicroRNAs , PTEN Fosfo-Hidrolase , Linhagem Celular Tumoral , Movimento Celular , Proliferação de Células , Regulação para Baixo , Glioma/metabolismo , Humanos , MicroRNAs/metabolismo , Invasividade Neoplásica , PTEN Fosfo-Hidrolase/metabolismoRESUMO
BACKGROUND: Long Noncoding-RNAs (LncRNAs) are known to be involved in some biological processes, but their roles in plant-virus interactions remain largely unexplored. While circular RNAs (circRNAs) have been studied in animals, there has yet to be extensive research on them in a plant system, especially in tomato-tomato yellow leaf curl virus (TYLCV) interaction. RESULTS: In this study, RNA transcripts from the susceptible tomato line JS-CT-9210 either infected with TYLCV or untreated, were sequenced in a pair-end strand-specific manner using ribo-zero rRNA removal library method. A total of 2056 lncRNAs including 1767 long intergenic non-coding RNA (lincRNAs) and 289 long non-coding natural antisense transcripts (lncNATs) were obtained. The expression patterns in lncRNAs were similar in susceptible tomato plants between control check (CK) and TYLCV infected samples. Our analysis suggested that lncRNAs likely played a role in a variety of functions, including plant hormone signaling, protein processing in the endoplasmic reticulum, RNA transport, ribosome function, photosynthesis, glulathione metabolism, and plant-pathogen interactions. Using virus-induced gene silencing (VIGS) analysis, we found that reduced expression of the lncRNA S-slylnc0957 resulted in enhanced resistance to TYLCV in susceptible tomato plants. Moreover, we identified 184 circRNAs candidates using the CircRNA Identifier (CIRI) software, of which 32 circRNAs were specifically expressed in untreated samples and 83 circRNAs in TYLCV samples. Approximately 62% of these circRNAs were derived from exons. We validated the circRNAs by both PCR and Sanger sequencing using divergent primers, and found that most of circRNAs were derived from the exons of protein coding genes. The silencing of these circRNAs parent genes resulted in decreased TYLCV virus accumulation. CONCLUSION: In this study, we identified novel lncRNAs and circRNAs using bioinformatic approaches and showed that these RNAs function as negative regulators of TYLCV infection. Moreover, the expression patterns of lncRNAs in susceptible tomato plants were different from that of resistant tomato plants, while exonic circRNAs expression positively associated with their respective protein coding genes. This work provides a foundation for elaborating the novel roles of lncRNAs and circRNAs in susceptible tomatoes following TYLCV infection.
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Begomovirus/fisiologia , Doenças das Plantas/imunologia , RNA Longo não Codificante/genética , RNA/genética , Solanum lycopersicum/genética , Suscetibilidade a Doenças , Inativação Gênica , Solanum lycopersicum/imunologia , Solanum lycopersicum/virologia , Fenótipo , Doenças das Plantas/virologia , Folhas de Planta/genética , Folhas de Planta/imunologia , Folhas de Planta/virologia , RNA Circular , RNA de Plantas/genéticaRESUMO
In this paper, the tuning characteristics of locally bent microfiber taper covered with a nanosized high-refractive-index liquid crystal (LC) layer under different temperatures and electric field intensities have been theoretically analyzed and experimentally investigated. A locally bent microfiber taper interferometer with a waist diameter of â¼3.72 µm is fabricated by using the flame brushing technique, followed by bending the transition region of the taper to form a modal interferometer and later by placing a â¼200 nm LC layer over the uniform taper waist region. Experimental results indicate that a high-efficiency thermal or electric tuning of an LC-coated locally bent microfiber taper interferometer could be achieved. This suggests a potential application of this device as tunable all-fiber photonic devices, such as filters, modulators, and sensing elements.
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MicroRNAs (miRNAs) are small non-coding RNAs which regulate gene expressions post-transcriptionally. Nowadays, various miRNAs have been found to be sensitive and specific biomarkers for the early diagnosis of colorectal cancer (CRC); however, there are different, even conflicting results in different publications concerning the diagnostic accuracy of miRNA. Therefore, we aim to conduct a meta-analysis of the relevant publications to comprehensively evaluate the diagnostic value of miRNAs in CRC detection. Several public databases such as PubMed, Embase, and Google Scholar were retrieved up to July 13, 2014. Sensitivity was applied to plot the summary receiver operator characteristic (SROC) curve against specificity. The area under the SROC curve (AUC) was calculated to assess the classified effects. STATA 12.0 software was used to perform all statistic analyses. A total of 29 articles, including 80 studies, were involved in our meta-analysis, 55 of which focus on single-miRNA assays and the other 25 on multiple-miRNA assays. Our results suggested that multiple-miRNA assays show a better diagnostic accuracy compared with single-miRNA assays. In addition, blood-based miRNA assays were more accurate than feces-based miRNA assays in CRC diagnosis. Our results also showed that miRNA diagnosis appear to be more accurate in Asians than in Caucasians. However, further researches are needed to validate our results and the feasibility of miRNAs as biomarkers in routine clinical diagnosis of CRC.
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Biomarcadores Tumorais/genética , Neoplasias Colorretais/genética , MicroRNAs/genética , Povo Asiático , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , HumanosRESUMO
BACKGROUND: The phosphoinositide 3 kinase (PI3K)/AKT/mammalian target of the rapamycin (mTOR) pathway is a complicated intracellular pathway which leads to cell growth and tumor proliferation and plays a significant role in breast cancer. Multiple compounds targeting this pathway are being evaluated in clinical trials. NVP-BEZ235, a novel and orally available dual PI3K/mTOR inhibitor, showed great antitumor effect and provided a therapy strategy in breast cancer. METHODS: In this study, we detect the effect of NVP-BEZ235 on cell viability, apoptosis, and autophagy in a breast cancer cell line. We also test the effect of NVP-BEZ235 on the expression of PI3K/AKT/mTOR pathway proteins p-AKT, p-mTOR, and p-70S6K. RESULTS: The results showed that the PI3K/AKT/mTOR proteins p-AKT, p-mTOR, and p-70S6K were obviously suppressed by NVP-BEZ235. NVP-BEZ235 inhibited cell proliferation and induced apoptosis and autophagy in breast cancer cells. In combination with autophagy inhibitors or autophagy gene knockdown, enhanced growth inhibition and apoptosis was induced by NVP-BEZ235 in MCF-7 cells. CONCLUSIONS: This study provides a novel treatment strategy that PI3K/AKT/mTOR pathway inhibitors in combination with autophagy inhibitors lead to further apoptosis in breast cancer cells.
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Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Apoptose/efeitos dos fármacos , Autofagia/efeitos dos fármacos , Neoplasias da Mama/enzimologia , Proliferação de Células/efeitos dos fármacos , Inibidores de Fosfoinositídeo-3 Quinase , Serina-Treonina Quinases TOR/antagonistas & inibidores , Adenina/análogos & derivados , Adenina/farmacologia , Proteína 7 Relacionada à Autofagia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Sobrevivência Celular/efeitos dos fármacos , Cloroquina/farmacologia , Relação Dose-Resposta a Droga , Feminino , Humanos , Imidazóis/farmacologia , Células MCF-7 , Fosfatidilinositol 3-Quinase/metabolismo , Fosforilação , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Quinolinas/farmacologia , Interferência de RNA , Proteínas Quinases S6 Ribossômicas 70-kDa/metabolismo , Transdução de Sinais/efeitos dos fármacos , Serina-Treonina Quinases TOR/metabolismo , Fatores de Tempo , Transfecção , Enzimas Ativadoras de Ubiquitina/genética , Enzimas Ativadoras de Ubiquitina/metabolismoRESUMO
BACKGROUND: This meta-analysis investigates the associations of adiponectin (ADIPOQ) genetic polymorphisms with the susceptibility to colorectal cancer (CRC). MATERIAL AND METHODS: 2 reviewers independently searched 6 databases - PubMed, Cochrane Library, Ovid, Embase, China National Knowledge Infrastructure (CNKI) and Wanfang databases - to identify published studies relevant to adiponectin gene polymorphisms and CRC. Studies retrieved from database searches were screened using our stringent inclusion and exclusion criteria. Full texts of the selected studies were accessed and related data was extracted using a standardized data extraction form. Comprehensive Meta-analysis 2.0 software was used for statistical analyses. RESULTS: A total of 188 studies were initially retrieved from database search, and 6 studies were eventually selected, through a rigorous screening process, for inclusion in this meta-analysis. The 6 studies contained a total of 1897 patients (Asians: 1190; white: 707) with CRC in case group and 2475 healthy controls (Asians: 1325; white: 1150) in the control group. Results of the current meta-analysis revealed that the rs2241766 T>G single-nucleotide polymorphisms (SNP) increase the risk of CRC; rs1501299 G>T under dominant model was associated with increased risk of CRC; and rs266729 C>G SNP under allele model conferred an increased risk of CRC. CONCLUSIONS: Our meta-analysis strongly suggests that the ADIPOQ rs2241766 T>G, rs1501299 G>T, and rs266729 C>G SNPs correlate with an increased risk of CRC.
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Adiponectina/genética , Neoplasias Colorretais/genética , Polimorfismo de Nucleotídeo Único , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Humanos , Modelos GenéticosRESUMO
BACKGROUND: MicroRNAs (miRNAs) are non-coding RNAs that play a pivotal role in antiviral infection. The miR184-3p has been identified to promote rice black streaked dwarf virus (RBSDV) infection in vector Laodelphax striatellus, whether it targets other genes of L. striatellus to modulate RBSDV propagation remains unknown. RESULTS: We first analyzed the expression profiles of miR184-3p and its role in regulating RBSDV infection in L. striatellus. Then the candidate genes expression of miR184-3p were systemically analyzed with gain and loss function of miR184-3p, and the interaction of candidate gene, ecdysone inducible protein 78 (Eip78) with miR184-3p was verified by dual luciferase reporter assay. We found Eip78 is evolutionary conserved among agricultural pests and predominantly expressed in the central nervous system (CNS) of L. striatellus. Knockdown of Eip78 effectively increased RBSDV propagation and transmission. Blockade with Eip78 antibody or injection with Eip78 protein could significantly regulate RBSDV infection. Further analysis revealed that knockdown of Eip78 specifically suppresses RBSDV infection in the head part but not in the body part of L. striatellus. Besides, knockdown of ecdysone receptor (EcR) notably restricted Eip78 expression and increased RBSDV accumulation in L. striatellus. CONCLUSIONS: Taken together, we identified a novel target gene of miR184-3p, Eip78, a member of the ecdysone signaling pathway, and revealed the anti-RBSDV role of Eip78 in the CNS of L. striatellus. These results shed light on the interaction mechanisms of miRNAs, virus and ecdysone signaling pathway in insect vector. © 2024 Society of Chemical Industry.
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Hemípteros , Proteínas de Insetos , Insetos Vetores , MicroRNAs , Animais , MicroRNAs/genética , MicroRNAs/metabolismo , Hemípteros/virologia , Hemípteros/genética , Hemípteros/metabolismo , Proteínas de Insetos/genética , Proteínas de Insetos/metabolismo , Insetos Vetores/virologia , Insetos Vetores/genética , Vírus de Plantas/fisiologia , Vírus de Plantas/genética , Doenças das Plantas/virologia , Ecdisona/metabolismoRESUMO
MicroRNAs (miRNAs) are non-coding RNAs, which, as members of the RNA interference pathway, play a pivotal role in antiviral infection. Almost 80% of plant viruses are transmitted by insect vectors; however, little is known about the interaction of the miRNAs of insect vectors with plant viruses. Here, we took rice black-streaked dwarf virus (RBSDV), a devastating virus to rice production in eastern Asia, and the small brown planthopper, (SBPH, Laodelphax striatellus) as a model to investigate the role of microRNA750-3p (miR750-3p) in regulating viral transmission. Our results showed that Ls-miR750-3p was downregulated in RBSDV-infected SBPH and predominately expressed in the midgut of SBPH. Injection with miR750-3p agomir significantly reduced viral accumulation, and the injection with the miR750-3p inhibitor, antagomir-750-3p, dramatically promoted the viral accumulation in SBPH, as detected using RT-qPCR and Western blotting. The processing of precursor 7 (POP7), a subunit of RNase P and RNase MRP, was screened, identified, and verified using a dual luciferase reporter assay as one target of miR750-3p. Knockdown of POP7 notably increased RBSDV viral propagation in SBPH and then increased the viral transmission rate by SBPH. Taken together, our data indicate that miR750-3p targets POP7 to suppress RBSDV infection in its insect vector. These results enriched the role of POP7 in modulating virus infection in host insects and shared new insight into the function of miRNAs in plant virus and insect vector interaction.
Assuntos
Hemípteros , MicroRNAs , Vírus de Plantas , Animais , Vírus de Plantas/genética , Antagomirs , MicroRNAs/genéticaRESUMO
Background: Bleomycin is a glycopeptide antibiotic with outstanding anti-tumor effects. A major adverse effect of bleomycin is lung fibrosis. However, the development of cataracts as a severe adverse effect has not been reported. Case summary: Herein, we describe the first case of cataract induced by bleomycin therapy in a 22-year-old male with testicular cancer. After surgical intervention and following five successive chemotherapy cycles of the BEP regimen, including bleomycin, etoposide and cisplatin, the patient reported a gradual painless loss of vision, with substantial decline in visual ability, especially in the right eye. Following comprehensive eye examinations, a cataract was diagnosed. Eventually, the patient underwent phacoemulsification and received replacement of the intraocular lenses. Conclusion: Bleomycin can cause cataracts, which induces a significant loss of vision. Therefore, clinicians should observe early symptoms and properly adjust treatment to prevent aggravation of symptoms.
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This was a single-arm, multicenter phase 2 clinical trial (ChiCTR1900021726) involving advanced squamous non-small cell lung cancer (sq-NSCLC) patients undergoing 2 cycles of nab-paclitaxel/carboplatin and sintilimab (anti-PD-1), followed by sintilimab maintenance therapy. The median progression-free survival (PFS) was 11.4 months (95% CI: 6.7-18.1), which met the pre-specified primary endpoint. Secondary endpoints included objective response rate reaching 70.5% and a disease control rate of 93.2%, with a median duration of response of 13.6 months [95% CI: 7.0-not evaluable (NE)]. The median overall survival was 27.2 months (95% CI: 20.2-NE) with treatment-related adverse events grades ≥3 occurring in 10.9% of patients. Predefined exploratory endpoints comprised relationships between biomarkers and treatment efficacy, and the association between circulating tumor DNA (ctDNA) dynamics and PFS. Biomarker analysis revealed that the breast cancer gene 2, BMP/Retinoic Acid Inducible Neural Specific 3, F-box/WD repeat-containing protein 7, tyrosine-protein kinase KIT and retinoblastoma 1 abnormalities led to shorter PFS, while ctDNA negative at baseline or clearance at 2 cycles of treatment was associated with longer PFS (18.1 vs. 4.3 months). Taken together, sintilimab in combination with 2 cycles of nab-paclitaxel/carboplatin treatment produced encouraging PFS and better tolerability as first-line treatment for advanced sq-NSCLC.
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Anticorpos Monoclonais Humanizados , Carcinoma Pulmonar de Células não Pequenas , Carcinoma de Células Escamosas , Neoplasias Pulmonares , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carboplatina/uso terapêutico , Carboplatina/efeitos adversos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/genética , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/genéticaRESUMO
Defence against pathogens relies on intracellular nucleotide-binding, leucine-rich repeat immune receptors (NLRs) in plants. Hormone signaling including abscisic acid (ABA) pathways are activated by NLRs and play pivotal roles in defence against different pathogens. However, little is known about how hormone signaling pathways are activated by plant immune receptors. Here, we report that a plant NLR Sw-5b mimics the behavior of the ABA receptor and directly employs the ABA central regulator PP2C-SnRK2 complex to activate an ABA-dependent defence against viral pathogens. PP2C4 interacts with and constitutively inhibits SnRK2.3/2.4. Behaving in a similar manner as the ABA receptor, pathogen effector ligand recognition triggers the conformational change of Sw-5b NLR that enables binding to PP2C4 via the NB domain. This receptor-PP2C4 binding interferes with the interaction between PP2C4 and SnRK2.3/2.4, thereby releasing SnRK2.3/2.4 from PP2C4 inhibition to activate an ABA-specific antiviral immunity. These findings provide important insights into the activation of hormone signaling pathways by plant immune receptors.
Assuntos
Ácido Abscísico , Transdução de Sinais , Inibição Psicológica , Domínios Proteicos , HormôniosRESUMO
BACKGROUND: The initial randomized, double-blinded, actively controlled, phase III ANEAS study (NCT03849768) demonstrated that aumolertinib showed superior efficacy relative to gefitinib as first-line therapy in epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung cancer (NSCLC). Metastatic disease in the central nervous system (CNS) remains a challenge in the management of NSCLC. This study aimed to compare the efficacy of aumolertinib versus gefitinib among patients with baseline CNS metastases in the ANEAS study. METHODS: Eligible patients were enrolled and randomly assigned in a 1:1 ratio to orally receive either aumolertinib or gefitinib in a double-blinded fashion. Patients with asymptomatic, stable CNS metastases were included. Follow-up imaging of the same modality as the initial CNS imaging was performed every 6 weeks for 15 months, then every 12 weeks. CNS response was assessed by a neuroradiological blinded, independent central review (neuroradiological-BICR). The primary endpoint for this subgroup analysis was CNS progression-free survival (PFS). RESULTS: Of the 429 patients enrolled and randomized in the ANEAS study, 106 patients were found to have CNS metastases (CNS Full Analysis Set, cFAS) at baseline by neuroradiological-BICR, and 60 of them had CNS target lesions (CNS Evaluable for Response, cEFR). Treatment with aumolertinib significantly prolonged median CNS PFS compared with gefitinib in both cFAS (29.0 vs. 8.3 months; hazard ratio [HR] = 0.31; 95% confidence interval [CI], 0.17-0.56; P < 0.001) and cEFR (29.0 vs. 8.3 months; HR = 0.26; 95% CI, 0.11-0.57; P < 0.001). The confirmed CNS overall response rate in cEFR was 85.7% and 75.0% in patients treated with aumolertinib and gefitinib, respectively. Competing risk analysis showed that the estimated probability of CNS progression without prior non-CNS progression or death was consistently lower with aumolertinib than with gefitinib in patients with and without CNS metastases at baseline. No new safety findings were observed. CONCLUSIONS: These results indicate a potential advantage of aumolertinib over gefitinib in terms of CNS PFS and the risk of CNS progression in patients with EGFR-mutated advanced NSCLC with baseline CNS metastases. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT03849768.
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Background: In ORIENT-15 study, sintilimab plus chemotherapy demonstrated significant improvement on overall survival (OS) versus placebo plus chemotherapy in first-line treatment of advanced esophageal squamous cell carcinoma (ESCC). Here, we report effect of sintilimab plus chemotherapy on health-related quality of life (HRQoL) in patients with advanced ESCC. Methods: From December 14, 2018 to August 28, 2022, HRQoL was evaluated in all randomized patients using European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 items (QLQ-C30), EORTC Quality of Life Questionnaire Oesophageal Cancer Module 18 items (QLQ-OES18), and visual analogue scale (VAS) of the EuroQol five-dimensional five-level questionnaire (EQ-5D-5L). Mean scores of each scale were described by treatment group through week 60. Least-squares mean (LSM) score change from baseline through week 24 were analyzed using the mixed-model repeated-measures method. Time to the first onset of deterioration (TTD) and OS for each scale were estimated. Clinical Trials Registration: NCT03748134. Findings: As of August 28, 2022, 689 of 690 enrolled patients were assessed for HRQoL analysis (sintilimab group: 340, placebo group: 349). Median follow-up was 32.2 months. Differences in LSM favored sintilimab over placebo for QLQ-C30 social functioning (LSM difference: 3.06, 95% CI: 0.55 to 5.57; P = 0.0170), pain (-2.24, 95% CI: -4.30 to -0.17; P = 0.0337), fatigue (-2.24, 95% CI: -4.46 to -0.02; P = 0.0479), constipation (-3.27, 95% CI -5.49 to -1.05; P = 0.0039), QLQ-OES18 pain (-1.77, 95% CI -3.11 to -0.43; P = 0.0097), trouble swallowing saliva (-2.09, 95% CI: -3.77 to -0.42; P = 0.0146), and choked when swallowing (-3.23, 95% CI: -5.60 to -0.86; P = 0.0076). TTD favored sintilimab over placebo for QLQ-OES18 dysphagia (Hazard ratio [HR]: 0.76, 95% CI: 0.61-0.94, P = 0.0104), and trouble swallowing saliva (HR: 0.48, 95% CI: 0.35-0.67, P < 0.0001). Improved OS were observed in patients with better performance in several functioning and symptom scales of QLQ-C30 and QLQ-QES18. Interpretation: The statistically significant differences of several HRQoL scales and improvements in delayed deterioration observed in our study further support the use of sintilimab plus chemotherapy as first-line treatment for advanced ESCC. Funding: This study was funded by Innovent Biologics and was co-funded by Eli Lilly.