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RATIONALE AND OBJECTIVES: To evaluate the image quality and PI-RADS scoring performance of prostate T2-weighted imaging (T2WI) based on AI-assisted compressed sensing (ACS). MATERIALS AND METHODS: In this prospective study, adult male urological outpatients or inpatients underwent prostate MRI, including T2WI, diffusion-weighted imaging and apparent diffusion coefficient maps. Three accelerated scanning protocols using parallel imaging (PI) and ACS: T2WIPI, T2WIACS1 and T2WIACS2 were evaluated through comparative analysis. Quantitative analysis included signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), slope profile, and edge rise distance (ERD). Image quality was qualitatively assessed using a five-point Likert scale (ranging from 1 = non-diagnostic to 5 = excellent). PI-RADS scores were determined for the largest or most suspicious lesions in each patient. The Friedman test and one-way ANOVA with post hoc tests were utilized for group comparisons, with statistical significance set at P < 0.05. RESULTS: This study included 40 participants. Compared to PI, ACS reduced acquisition time by over 50%, significantly enhancing the CNR of sagittal and axial T2WI (P < 0.05), significantly improving the image quality of sagittal and axial T2WI (P < 0.05). No significant differences were observed in slope profile, ERD, and PI-RADS scores between groups (P > 0.05). CONCLUSION: ACS reduced prostate T2WI acquisition time by half while improving image quality without affecting PI-RADS scores.
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The potential anti-cancer effect of traditional Chinese medicine (TCM) monomers has been widely studied due to their advantages of well-defined structure, clear therapeutic effects, and easy quality control during the manufacturing process. However, clinical trial information on these monomers is scarce, resulting in a lack of knowledge regarding the research progress, efficacy, and adverse reactions at the clinical stage. Therefore, this study systematically reviewed the clinical trials on the anti-cancer effect of TCM monomers registered in the Clinicaltrials.gov website before 2023.4.30, paying special attention to the trials on tumors, aiming to explore the research results and development prospects in this field. A total of 1982 trials were started using 69 of the 131 TCM monomers. The number of clinical trials performed each year showed an overall upward trend. However, only 26 monomers entered into 519 interventional anti-tumor trials, with vinblastine (194, 37.38%) and camptothecin (146, 28.13%) being the most used. A total of 45 tumors were studied in these 519 trials, with lymphoma (112, 21.58%) being the most frequently studied. Clinical trials are also unevenly distributed across locations and sponsors/collaborators. The location and the sponsor/collaborator with the highest number of performed trials were the United States (651,32.85%) and NIH (77). Therefore, China and its institutions still have large room for progress in promoting TCM monomers in anti-tumor clinical trials. In the next step, priority should be given to the improvement of the research and development ability of domestic enterprises, universities and other institutions, using modern scientific and technological means to solve the problems of poor water solubility and strong toxic and side effects of monomers, so as to promote the clinical research of TCM monomers.
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Ensaios Clínicos como Assunto , Medicamentos de Ervas Chinesas , Medicina Tradicional Chinesa , Neoplasias , Humanos , Neoplasias/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos/farmacologia , Antineoplásicos/químicaRESUMO
Sophora flavescens has been widely used in traditional Chinese medicine for over 1700 years. This plant is known for its heat-clearing, damp-drying, insecticidal, and diuretic properties. Phytochemical research has identified prenylated flavonoids as a unique class of bioactive compounds in S. flavescens. Recent pharmacological studies reveal that the prenylated flavonoids from S. flavescens (PFS) exhibit potent antitumor, anti-inflammatory, and glycolipid metabolism-regulating activities, offering significant therapeutic benefits for various diseases. However, the pharmacokinetics and toxicological profiles of PFS have not been systematically studied. Despite the diverse biological effects of prenylated flavonoid compounds against similar diseases, their structure-activity relationship is not yet fully understood. This review aims to summarize the latest findings regarding the chemical composition, drug metabolism, pharmacological properties, toxicity, and structure-activity relationship of prenylated flavonoids from S. flavescens. It seeks to highlight their potential for clinical use and suggest directions for future related studies.
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Flavonoides , Prenilação , Sophora , Sophora/química , Flavonoides/química , Flavonoides/farmacologia , Flavonoides/isolamento & purificação , Humanos , Relação Estrutura-Atividade , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/química , Compostos Fitoquímicos/isolamento & purificação , Animais , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/farmacologia , Fitoterapia , Sophora flavescensRESUMO
INTRODUCTION: Midgut volvulus in adults based on congenital malrotation, which required emergency surgery, may occur under the stimulation of adverse factors and is rare and easy to be misdiagnosed. PRESENTATION OF CASE: A young male was taken to the emergency room of a local hospital after six hours abdominal pain. Computed tomography (CT) shows intestinal volvulus and exploratory laparotomy was performed. Postoperative CT revealed remission of small intestinal torsion and congenital malrotation of the midgut. The patient vomited frequently within 48 h after the surgery, and was transferred to our hospital for conservative treatment. After 4 days of conservative treatment, the vomiting symptoms were relieved at first, but worsened again after a liquid diet. CT showed complete duodenal obstruction and exploratory laparotomy was performed again. Congenital malrotation was found, which resulted in midgut volvulus and duodenal obstruction due to anomalous fixation of the mesentery. The bowel was placed in normal anatomical position, and the mesentery was sutured to the posterior abdominal wall. The patient was followed up for 24 months with no complaints. DISCUSSION: Due to the rare incidence and atypical pain clinical manifestations, it is difficult for the congenital malrotation in adults to be diagnosed. Midgut volvulus in adults with malrotation is even rarer and requires emergency operation, and may be misdiagnosed. CONCLUSION: Midgut volvulus with midgut malrotation is very rare in adults. Exploratory laparotomy must be careful to reduce misdiagnosis and recurrence of volvulus.
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Despite progress in cancer immunotherapy, ovarian cancer (OC) prognosis continues to be disappointing. Recent studies have shed light on how not just tumour cells, but also the complex tumour microenvironment, contribute to this unfavourable outcome of OC immunotherapy. The complexities of the immune microenvironment categorize OC as a 'cold tumour'. Nonetheless, understanding the precise mechanisms through which the microenvironment influences the effectiveness of OC immunotherapy remains an ongoing scientific endeavour. This review primarily aims to dissect the inherent characteristics and behaviours of diverse cells within the immune microenvironment, along with an exploration into its reprogramming and metabolic changes. It is expected that these insights will elucidate the operational dynamics of the immune microenvironment in OC and lay a theoretical groundwork for improving the efficacy of immunotherapy in OC management.
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Imunoterapia , Neoplasias Ovarianas , Microambiente Tumoral , Humanos , Microambiente Tumoral/imunologia , Feminino , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/terapia , Imunoterapia/métodos , Animais , Resultado do TratamentoRESUMO
OBJECTIVE: We examined the effectiveness and feasibility of the Mask Region-based Convolutional Neural Network (Mask R-CNN) for automatic detection of cephalometric landmarks on lateral cephalometric radiographs (LCRs). STUDY DESIGN: In total, 400 LCRs, each with 19 manually identified landmarks, were collected. Of this total, 320 images were randomly selected as the training dataset for Mask R-CNN, and the remaining 80 images were used for testing the automatic detection of the 19 cephalometric landmarks, for a total of 1520 landmarks. Detection rate, average error, and detection accuracy rate were calculated to assess Mask R-CNN performance. RESULTS: Of the 1520 landmarks, 1494 were detected, for a detection rate of 98.29%. The average error, or linear deviation distance between the detected points and the originally marked points of each detected landmark, ranged from 0.56 to 9.51 mm, with an average of 2.19 mm. For detection accuracy rate, 649 landmarks (43.44%) had a linear deviation distance less than 1 mm, 1020 (68.27%) less than 2 mm, and 1281 (85.74%) less than 4 mm in deviation from the manually marked point. The average detection time was 1.48 seconds per image. CONCLUSIONS: Deep learning Mask R-CNN shows promise in enhancing cephalometric analysis by automating landmark detection on LCRs, addressing the limitations of manual analysis, and demonstrating effectiveness and feasibility.
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Pontos de Referência Anatômicos , Cefalometria , Aprendizado Profundo , Estudos de Viabilidade , Redes Neurais de Computação , Cefalometria/métodos , Humanos , Projetos Piloto , Feminino , MasculinoRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Banxia Xiexin decoction (BXD) is a classic traditional Chinese medicine prescription for treating ulcerative colitis (UC). However, its potential mechanism of action is still unclear. AIM OF THE STUDY: Reveal the correlation between the beneficial impacts of BXD on UC and the composition of the gut microbiota. MATERIALS AND METHODS: The major constituents of BXD were identified using the HPLC-DAD technique. An experimental model of UC was induced in male C57BL/6 mice by administering dextran sodium sulfate (DSS). A total of 48 mice were divided into different groups, including control, model, high-dose BXD treatment, medium-dose BXD treatment, low-dose BXD treatment, and a group treated with 5-amino acid salicylic acid (5-ASA). Body weight changes and disease activity index (DAI) scores were documented; colon length, colon index, spleen index, and thymus index scores were determined; myeloperoxidase (MPO) and tumor necrosis factor-α (TNF-α) activities were assessed; and histological staining with hematoxylin-eosin and alcian blue/phosphate Schiff was performed. The immunofluorescence technique was employed to examine the presence of ZO-1 and occludin in the colon tissue. 16S rRNA sequencing was employed to assess the gut microbiota's diversity and metabolomics was utilized to examine alterations in metabolites within the gut microbiota. The impact of BXD on the gut microbiota was confirmed through fecal microbiota transplantation (FMT). RESULTS: BXD exhibited a positive impact on UC mice, particularly in the high-dose BXD treatment group. The BXD group experienced weight recovery, decreased DAI scores, improved colon length, and restored of spleen and thymus index scores compared to the DSS group. Additionally, BXD alleviated colon damage and the inflammatory response while restoring intestinal barrier function. FMT in BXD-treated mice also showed therapeutic effects in UC mice. At the phylum level, the relative abundance of Desulfobacterota, Deferribacterota and Actinobacteriota increased; at the genus level, g__norank__f__Muribaculaceae, Dubosiella, Akkermansia, and Lactobacillus increased, whereas Faecalibaculum, Alloprevotella, Turicibacter, and g_Paraprevotella decreased. g__norank_f__Muribaculaceae was positively correlated with body weight and colon length and negatively with colon index scores, splenic index scores, and MPO levels; Alloprevotella was positively correlated with splenic index scores, histological scores, and TNF-α levels and negatively with thymus index scores and thymus index scores. Faecalibaculum was positively correlated with colon index scores and MPO levels. Metabolic investigations revealed 58 potential indicators, primarily associated with the metabolism of amino acids, purines, and lipids. Alloprevotella, g_Paraprevotella, and Bifidobacterium were strongly associated with metabolic pathways. CONCLUSION: BXD showed beneficial therapeutic effects in UC mice. The mechanism may be by promoting the balance and variety of gut microbiota, as well as regulating the metabolism of amino acids, purines, and lipids.
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Antifibrinolíticos , Colite Ulcerativa , Colite , Medicamentos de Ervas Chinesas , Microbioma Gastrointestinal , Masculino , Animais , Camundongos , Camundongos Endogâmicos C57BL , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/tratamento farmacológico , RNA Ribossômico 16S , Fator de Necrose Tumoral alfa , Aminoácidos , Purinas , Peso Corporal , Lipídeos , Sulfato de Dextrana/toxicidade , Modelos Animais de Doenças , ColoRESUMO
Purpose: The study comprehensively evaluated the prognostic roles of the platelet-to-lymphocyte ratio (PLR), neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), basophil-to-lymphocyte ratio (BLR), and eosinophil-to-lymphocyte ratio (ELR) in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). Patients and Methods: Six hundred and nineteen patients with AECOPD and 300 healthy volunteers were retrospectively included into the study. The clinical characteristics of the patients with AECOPD and the complete blood counts (CBCs) of the healthy volunteers were collected. The associations of PLR, NLR, MLR, BLR, and ELR with airflow limitation, hospital length of stay (LOS), C-reactive protein (CRP), and in-hospital mortality in patients with AECOPD were analyzed. Results: Compared with the healthy volunteers, PLR, NLR, MLR, BLR, and ELR were all elevated in COPD patients under stable condition. PLR, NLR, MLR, and BLR were further elevated while ELR was lowered during exacerbation. In the patients with AECOPD, PLR, NLR, and MLR were positively correlated with hospital LOS as well as CRP. In contrast, ELR was negatively correlated with hospital LOS as well as CRP. Elevated PLR, NLR, and MLR were all associated with more severe airflow limitation in AECOPD. Elevated PLR, NLR, and MLR were all associated with increased in-hospital mortality while elevated ELR was associated with decreased in-hospital mortality. Binary logistic regression analysis showed that smoking history, FEV1% predicted, pneumonia, pulmonary heart disease (PHD), uric acid (UA), albumin, and MLR were significant independent predictors ofin-hospital mortality. These predictors along with ELR were used to construct a nomogram for predicting in-hospital mortality in AECOPD. The nomogram had a C-index of 0.850 (95% CI: 0.799-0.901), and the calibration curve, decision curve analysis (DCA), and clinical impact curve (CIC) further demonstrated its good predictive value and clinical applicability. Conclusion: In summary, PLR, NLR, MLR, and ELR served as useful biomarkers in patients with AECOPD.
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Neutrófilos , Doença Pulmonar Obstrutiva Crônica , Humanos , Monócitos , Eosinófilos , Estudos Retrospectivos , Linfócitos , Biomarcadores , Prognóstico , Proteína C-Reativa/análiseRESUMO
BACKGROUND: To assess the impact of coronavirus disease-2019 (COVID-19) in its outbreak stage (Spring Festival in 2020) on oral emergency services. METHODS: Oral emergency cases in Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, during the Spring Festival after the outbreak of the COVID-19 epidemic in 2020 were collected and compared with those in 2018 and 2019. Electronic medical records including the visited department, age, sex, time, date, region, and diagnosis were collected and analyzed. The results were statistically analyzed using Pearson's Chi-square test and one-way analysis of variance (ANOVA). RESULTS: Compared with that in 2018 and 2019, the total number of patients decreased during the Spring Festival in 2020 (p < 0.001), but the proportions of patients visiting Oral Surgery and Oral, Head, and Neck Oncology Emergency departments increased. The average age of patients increased, and the number of night visits decreased. Toothache diseases involving endodontic and periodontal diseases increased, while the proportion of maxillofacial trauma decreased. The wasn't a linear association between diagnosis or genders (P > 0.001) across years. However, a linear-by-linear association between age groups and years, visited departments and years were observed (P < 0.001). CONCLUSIONS: The study revealed that the transmission of COVID-19 affected the patient population and structure of disease types and oral services in 2020 during the Spring Festival, compared with those in the previous two years. The visits to oral emergency departments and the proportions of patients who were children and adolescents reduced; meanwhile, the percentage of the elderly people increased during the outbreak of COVID-19. The clear trend of age groups and visiting divisions could be used as a marker to reflect the severity of the COVID-19 pandemic. These results may serve as a reference for dental practitioners involved in oral emergency services and to allocate the limited emergency health resources.
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COVID-19 , Criança , Adolescente , Humanos , Masculino , Feminino , Idoso , Estudos Retrospectivos , Pandemias , Odontólogos , China/epidemiologia , Papel ProfissionalRESUMO
Metal-hydride hydrogen atom transfer (MHAT) has been recognized as a powerful method for alkene functionalization; however, photochemical MAT-mediated chemoselective functionalization of dienes remains undeveloped. In this study, we report a radical strategy (1e-) through MHAT using photoredox cobalt and titanium dual catalysis for aldehyde crotylation with butadiene, achieving excellent regio- and diastereoselectivity.
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Ovarian cancer stands as the prevailing gynecologic malignancy, afflicting over 313,959 individuals annually worldwide, accompanied by more than 207,252 fatalities. Perturbations in calcium signaling contribute significantly to the pathogenesis of numerous cancers, including ovarian cancer, wherein alterations in calcium transporter expression have been reported. Overexpression of TRPM7, a prominent calcium transporter, has been linked to adverse prognostic outcomes in various cancer types. The focus of this comprehensive review centers around delineating the oncogenic role of TRPM7 in cancer development and exploring its therapeutic potential as a target in combating this disease. Notably, TRPM7 fosters cancer invasion, metastasis, and uncontrolled cell proliferation, thereby perpetuating the expansion and reinforcement of these malignant entities. Furthermore, this review takes ovarian cancer as an example and summarizes the "dual-mode" regulatory role of TRPM7 in cancer. Within the domain of ovarian cancer, TRPM7 assumes the role of a harsh tyrant, firmly controlling the calcium ion signaling pathway and metabolic reprogramming pathways.
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Neoplasias Ovarianas , Canais de Cátion TRPM , Humanos , Feminino , Canais de Cátion TRPM/genética , Canais de Cátion TRPM/metabolismo , Cálcio/metabolismo , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/patologia , Proliferação de Células , Proteínas Serina-Treonina Quinases/metabolismoRESUMO
Focal segmental glomerulosclerosis (FSGS), a podocyte disease, is the leading cause of end-stage renal disease (ESRD). Nevertheless, the current effective treatment for FSGS is deficient. Curcumin (CUR) is a principal curcuminoid of turmeric, which is a member of the ginger family. Previous studies have shown that CUR has renoprotective effects. However, the mechanism of CUR in anti-FSGS is not clear. This study aimed to explore the mechanism of CUR against FSGS through a combination of network pharmacological methods and verification of experiments. The analysis identified 98 shared targets of CUR against FSGS, and these 98 targets formed a network of protein-protein interactions (PPI). Of these 98 targets, AKT1, TNF, IL-6, VEGFA, STAT3, MAPK3, HIF1A, CASP3, IL1B, and JUN were identified as the hub targets. Molecular docking suggested that the best binding to CUR is MAPK3 and AKT1. Apoptotic process and cell proliferation were identified as the main biological processes of CUR against FSGS by gene ontology (GO) analysis. The most enriched signaling pathway in the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was the PI3K-AKT signaling pathway. Western blots and flow cytometry showed that CUR could inhibit adriamycin (ADR) induced apoptosis, oxidative stress damage, and attenuate podocyte epithelial-mesenchymal transition (EMT) by repressing the AKT signaling pathway. Collectively, our study demonstrates that CUR can attenuate apoptosis, oxidative stress damage, and EMT in FSGS in vitro. These results supply a compelling basis for future studies of CUR for the clinical treatment of FSGS.
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Curcumina , Glomerulosclerose Segmentar e Focal , Podócitos , Humanos , Curcumina/farmacologia , Curcumina/uso terapêutico , Glomerulosclerose Segmentar e Focal/tratamento farmacológico , Simulação de Acoplamento Molecular , Fosfatidilinositol 3-Quinases , Proteínas Proto-Oncogênicas c-akt , ApoptoseRESUMO
SLIT ligand and its receptor ROBO were initially recognized for their role in axon guidance in central nervous system development. In recent years, as research has advanced, the role of the SLIT-ROBO signaling pathway has gradually expanded from axonal repulsion to cell migration, tumor development, angiogenesis, and bone metabolism. As a secreted protein, SLIT regulates various pathophysiological processes in the kidney, such as proinflammatory responses and fibrosis progression. Many studies have shown that SLIT-ROBO is extensively involved in various aspects of kidney development and maintenance of structure and function. The SLIT-ROBO signaling pathway also plays an important role in different types of kidney disease. This article reviews the advances in the study of the SLIT-ROBO pathway in various renal pathophysiological and kidney disorders and proposes new directions for further research in this field.
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The deubiquitinating enzyme OTUB1 possesses canonical deubiquitinase (DUB) activity and noncanonical, catalytic-independent activity, which has been identified as an essential regulator of diverse physiological processes. Posttranslational modifications of OTUB1 affect both its DUB activity and its noncanonical activity of binding to the E2 ubiquitin-conjugation enzyme UBC13, but further investigation is needed to characterize the full inventory of modifications to OTUB1. Here, we demonstrate that SET7, a lysine monomethylase, directly interacts with OTUB1 to catalyze OTUB1 methylation at lysine 122. This modification does not affect DUB activity of OTUB1 but impairs its noncanonical activity, binding to UBC13. Moreover, we found using cell viability analysis and intracellular reactive oxygen species assay that SET7-mediated methylation of OTUB1 relieves its suppressive role on ferroptosis. Notably, the methylation-mimic mutant of OTUB1 not only loses the ability to bind to UBC13 but also relieves its suppressive role on Tert-Butyl hydroperoxide-induced cell death and Cystine starvation/Erastin-induced cellular reactive oxygen species. Collectively, our data identify a novel modification of OTUB1 that is critical for inhibiting its noncanonical activity.
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Enzimas Desubiquitinantes , Ferroptose , Histona-Lisina N-Metiltransferase , Enzimas de Conjugação de Ubiquitina , Enzimas Desubiquitinantes/metabolismo , Lisina/metabolismo , Ligação Proteica , Espécies Reativas de Oxigênio/metabolismo , Ubiquitinação , Humanos , Histona-Lisina N-Metiltransferase/metabolismoRESUMO
BACKGROUND: Increasing evidence shows that liver-specific long non-coding RNAs (lncRNAs) play important roles in the development of hepatocellular carcinoma (HCC). We identified a novel liver-specific lncRNA, FAM99A, and examined its clinical significance and biological functions in HCC. METHODS: The expression level and clinical value of FAM99A in HCC were examined using The Cancer Genome Atlas (TCGA), International Cancer Genome Consortium (ICGC), and Gene Expression Omnibus (GEO) databases, and were further verified using quantitative real-time polymerase chain reaction (qRT-PCR) in our HCC cohort. Univariate and multivariate Cox proportional hazards regression models were also applied to identify independent prognostic indicators for HCC patients. Cell counting kit-8, colony formation, and Transwell assays were performed to evaluate the effects of FAM99A on the proliferation, migration, and invasion abilities of HCC cells in vitro. A subcutaneous xenograft tumor model was implemented to determine the effect of FAM99A on the tumor growth of HCC cells in vivo. RNA pull-down and mass spectrometry assays were performed to reveal the potential molecular mechanisms of FAM99A in HCC. RESULTS: The three public online databases and qRT-PCR data showed that FAM99A was frequently downregulated in HCC tissues and inversely correlated with microvascular invasion and advanced histological grade of HCC patients. Kaplan-Meier survival analysis indicated that decreased FAM99A was significantly associated with poor overall survival of HCC patients based on TCGA database (P = 0.040), ICGC data portal (P < 0.001), and our HCC cohort (P = 0.010). A multivariate Cox proportional hazards regression model based on our HCC cohort suggested that FAM99A was an independent prognostic factor of overall survival for HCC patients (hazard ratio: 0.425, P = 0.039). Upregulation of FAM99A suppressed the proliferation, colony formation, migration, and invasion capacities of HCC cells in vitro, and knockdown of FAM99A had the opposite effects. A subcutaneous xenograft tumor model demonstrated that overexpression of FAM99A significantly inhibited the tumor growth of HCC cells in vivo. Seven tumor-related proteins (PCBP1, SRSF5, SRSF6, YBX1, IGF2BP2, HNRNPK, and HNRNPL) were recognized as possible FAM99A-binding proteins by the RNA pull-down and mass spectrometry assays. CONCLUSION: Our results suggest that FAM99A exerts cancer-inhibiting effects on HCC progression, and it may be a promising prognostic indicator for HCC patients.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , RNA Longo não Codificante , Humanos , Carcinoma Hepatocelular/patologia , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Neoplasias Hepáticas/patologia , Prognóstico , Regulação Neoplásica da Expressão Gênica , Biomarcadores , Proliferação de Células/genética , Proteínas de Ligação a RNA/genética , Fatores de Processamento de Serina-Arginina/genética , Fosfoproteínas/genéticaRESUMO
Hypoxia-inducible factor (HIF)1α, a main transcriptional regulator of the cellular response to hypoxia, also plays important roles in oxygen homeostasis of aerobic organisms, which is regulated by multiple mechanisms. However, the full cellular response to hypoxia has not been elucidated. In this study, we found that expression of SMYD3, a methyltransferase, augments hypoxia signaling independent of its enzymatic activity. We demonstrated SMYD3 binds to and stabilizes HIF1α via co-immunoprecipitation and Western blot assays, leading to the enhancement of HIF1α transcriptional activity under hypoxia conditions. In addition, the stabilization of HIF1α by SMYD3 is independent of HIF1α hydroxylation by prolyl hydroxylases and the intactness of the von Hippel-Lindau ubiquitin ligase complex. Furthermore, we showed SMYD3 induces reactive oxygen species accumulation and promotes hypoxia-induced cell apoptosis. Consistent with these results, we found smyd3-null zebrafish exhibit higher hypoxia tolerance compared to their wildtype siblings. Together, these findings define a novel role of SMYD3 in affecting hypoxia signaling and demonstrate that SMYD3-mediated HIF1α stabilization augments hypoxia signaling, leading to the impairment of hypoxia tolerance.
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Histona-Lisina N-Metiltransferase , Hipóxia , Metiltransferases , Proteínas de Peixe-Zebra , Animais , Hipóxia/metabolismo , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Metiltransferases/metabolismo , Transdução de Sinais , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Proteína Supressora de Tumor Von Hippel-Lindau/metabolismo , Peixe-Zebra/metabolismo , Histona-Lisina N-Metiltransferase/genética , Histona-Lisina N-Metiltransferase/metabolismo , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismoRESUMO
A large number of viral delivery systems have been developed for characterizing functional genes and producing heterologous recombinant proteins in plants, and but most of them are unable to co-express two fusion-free foreign proteins in the whole plant for extended periods of time. In this study, we modified tobacco rattle virus (TRV) as a TRVe dual delivery vector, using the strategy of gene substitution. The reconstructed TRVe had the capability to simultaneously produce two fusion-free foreign proteins at the whole level of Nicotiana benthamiana, and maintained the genetic stability for the insert of double foreign genes. Moreover, TRVe allowed systemic expression of two foreign proteins with the total lengths up to â¼900 aa residues. In addition, Cas12a protein and crRNA were delivered by the TRVe expression system for site-directed editing of genomic DNA in N. benthamiana 16c line constitutively expressing green fluorescent protein (GFP). Taker together, the TRV-based delivery system will be a simple and powerful means to rapidly co-express two non-fused foreign proteins at the whole level and facilitate functional genomics studies in plants.
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Sistemas CRISPR-Cas , Vírus de Plantas , Indicadores e Reagentes/metabolismo , Vírus de Plantas/genética , Nicotiana/metabolismo , Proteínas Recombinantes/metabolismo , Expressão Gênica , Vetores Genéticos/genéticaRESUMO
PURPOSE: To investigate the clinical characteristics and associated factors of colonic polyps in patients with acromegaly. METHODS: Clinical characteristics and colonoscopy findings of 86 acromegaly patients who received treatment were retrospectively reviewed, and colonoscopy findings and the correlation with growth hormone (GH)-secreting pituitary adenoma (GHPA) volume and hormonal/metabolic levels were analyzed. RESULTS: The prevalence of colonic polyps in acromegaly patients was 40.7% and increased significantly with advanced age, especially in those ≥50 years. Multiple polyps (62.8%) and colonic polyps in the left colon (54.2%) were detected more frequently. Compared to acromegaly patients without polyps, those with polyps displayed higher insulin-like growth factor-1 × upper limit of normal (IGF-1×ULN) levels (P=0.03). IGF-1 levels and GHPA volumes in patients with polyps showed increasing trends, although the differences were not significant. GH levels were higher in patients with polyps of diameter ≤5 mm than those with polyps of diameter >5 mm (P=0.031). The univariate and multivariate logistic regression analysis revealed that GHPA volumes (OR: 1.09, 95% CI: 1.01-1.20; P=0.039) and IGF-1×ULN Q2 levels (OR: 6.51, 95% CI: 1.20-44.60; P=0.038) were independent factors for predicting the risk of colonic polyp occurrence in acromegaly patients. A nomogram was prepared to evaluate the risk of colonic polyps in acromegaly patients. CONCLUSION: The acromegalic patients are a population with a high prevalence of colonic polyps. GHPA volumes and IGF-1×ULN levels may be predictors of colonic polyp occurrence.
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Acromegalia , Adenoma , Pólipos do Colo , Adenoma Hipofisário Secretor de Hormônio do Crescimento , Humanos , Pessoa de Meia-Idade , Pólipos do Colo/epidemiologia , Acromegalia/complicações , Acromegalia/epidemiologia , Fator de Crescimento Insulin-Like I/análise , Estudos Retrospectivos , Adenoma/complicações , Adenoma/epidemiologiaRESUMO
The therapeutic limitations such as insufficient efficacy, drug resistance, metastasis, and undesirable side effects are frequently caused by the long duration monotherapy based on chemotherapeutic drugs. multiple combinational anticancer strategies such as nucleic acids combined with chemotherapeutic agents, chemotherapeutic combinations, chemotherapy and tumor immunotherapy combinations have been embraced, holding great promise to counter these limitations, while still taking including some potential risks. Nowadays, an increasing number of research has manifested the anticancer effects of phytochemicals mediated by modulating cancer cellular events directly as well as the tumor microenvironment. Specifically, these natural compounds exhibited suppression of cancer cell proliferation, apoptosis, migration and invasion of cancer cells, P-glycoprotein inhibition, decreasing vascularization and activation of tumor immunosuppression. Due to the low toxicity and multiple modulation pathways of these phytochemicals, the combination of chemotherapeutic agents with natural compounds acts as a novel approach to cancer therapy to increase the efficiency of cancer treatments as well as reduce the adverse consequences. In order to achieve the maximized combination advantages of small-molecule chemotherapeutic drugs and natural compounds, a variety of functional nano-scaled drug delivery systems, such as liposomes, host-guest supramolecules, supramolecules, dendrimers, micelles and inorganic systems have been developed for dual/multiple drug co-delivery. These co-delivery nanomedicines can improve pharmacokinetic behavior, tumor accumulation capacity, and achieve tumor site-targeting delivery. In that way, the improved antitumor effects through multiple-target therapy and reduced side effects by decreasing dose can be implemented. Here, we present the synergistic anticancer outcomes and the related mechanisms of the combination of phytochemicals with small-molecule anticancer drugs. We also focus on illustrating the design concept, and action mechanisms of nanosystems with co-delivery of drugs to synergistically improve anticancer efficacy. In addition, the challenges and prospects of how these insights can be translated into clinical benefits are discussed.