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SARS-CoV-2, the causative agent of the COVID-19 pandemic, undergoes continuous evolution, highlighting an urgent need for development of novel antiviral therapies. Here we show a quantitative mass spectrometry-based succinylproteomics analysis of SARS-CoV-2 infection in Caco-2 cells, revealing dramatic reshape of succinylation on host and viral proteins. SARS-CoV-2 infection promotes succinylation of several key enzymes in the TCA, leading to inhibition of cellular metabolic pathways. We demonstrated that host protein succinylation is regulated by viral nonstructural protein (NSP14) through interaction with sirtuin 5 (SIRT5); overexpressed SIRT5 can effectively inhibit virus replication. We found succinylation inhibitors possess significant antiviral effects. We also found that SARS-CoV-2 nucleocapsid and membrane proteins underwent succinylation modification, which was conserved in SARS-CoV-2 and its variants. Collectively, our results uncover a regulatory mechanism of host protein posttranslational modification and cellular pathways mediated by SARS-CoV-2, which may become antiviral drug targets against COVID-19.
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Antivirales , Tratamiento Farmacológico de COVID-19 , COVID-19 , Interacciones Huésped-Patógeno , Terapia Molecular Dirigida , Procesamiento Proteico-Postraduccional , SARS-CoV-2 , Antivirales/farmacología , Antivirales/uso terapéutico , COVID-19/metabolismo , COVID-19/virología , Células CACO-2 , Exorribonucleasas/metabolismo , Interacciones Huésped-Patógeno/efectos de los fármacos , Humanos , Procesamiento Proteico-Postraduccional/efectos de los fármacos , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/fisiología , Sirtuinas/metabolismo , Succinatos/metabolismo , Proteínas no Estructurales Virales/metabolismo , Replicación Viral/efectos de los fármacosRESUMEN
BACKGROUND: Circular RNAs (circRNAs) have been proved to play crucial roles in the development of various cancers. However, the molecular mechanism of circGLIS3 involved in gastric cancer (GC) tumorigenesis has not been elucidated. METHODS: The higher expression level of circGLIS3 was identified in GC through RNA sequencing and subsequent tissue verification using Quantitative real-time PCR (qRT-PCR). A series of functional experiments in vitro and in vivo were performed to evaluated the effects of circGLIS3 on tumor growth and metastasis in GC. The interaction and regulation of circGLIS3/miR-1343-3p/PGK1 axis was confirmed by RNA pulldown, western blot, and rescue experiments. RIP and western blot were performed to demonstrate the role of circGLIS3 in regulating phosphorylation of VIMENTIN. We then used qRT-PCR and co culture system to trace circGLIS3 transmission via exosomal communication and identify the effect of exosomal circGLIS3 on gastric cancer and macrophages. Finally, RIP experiments were used to determine that EIF4A3 regulates circGLIS3 expression. RESULTS: CircGLIS3(hsa_circ_0002874) was significantly upregulated in GC tissues and high circGLIS3 expression was associated with advanced TNM stage and lymph node metastasis in GC patients. We discovered that overexpression of circGLIS3 promoted GC cell proliferation, migration, invasion in vitro and in vivo, while suppression of circGLIS3 exhibited the opposite effect. Mechanistically, circGLIS3 could sponge miR-1343-3p and up-regulate the expression of PGK1 to promote GC tumorigenesis. We also found that circGLIS3 reduced the phosphorylation of VIMENTIN at ser 83 site by binding with VIMENTIN. Moreover, it was proven that exosomal circGLIS3 could promote gastric cancer metastasis and the M2 type polarization of macrophages. In the final step, the mechanism of EIF4A3 regulating the generation of circGLIS3 was determined. CONCLUSION: Our findings demonstrate that circGLIS3 promotes GC progression through sponging miR-1343-3p and regulating VIMENTIN phosphorylation. CircGLIS3 is a potential therapeutic target for GC patients.
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MicroARNs , Neoplasias Gástricas , Humanos , Carcinogénesis , Línea Celular Tumoral , Proliferación Celular/genética , Transformación Celular Neoplásica , ARN Helicasas DEAD-box , Factor 4A Eucariótico de Iniciación , Regulación Neoplásica de la Expresión Génica , MicroARNs/genética , Fosfoglicerato Quinasa , Fosforilación , Neoplasias Gástricas/genética , Vimentina/genéticaRESUMEN
BACKGROUND: Right hemicolectomy is the standard treatment for right-sided colon cancer. There is variation in the technical aspects of performing right hemicolectomy as well as in short-term outcomes. It is therefore necessary to explore best clinical practice following right hemicolectomy in expert centres. METHODS: This snapshot study of right hemicolectomy for colon cancer in China was a prospective, multicentre cohort study in which 52 tertiary hospitals participated. Eligible patients with stage I-III right-sided colon cancer who underwent elective right hemicolectomy were consecutively enrolled in all centres over 10 months. The primary endpoint was the incidence of postoperative 30-day anastomotic leak. RESULTS: Of the 1854 patients, 89.9 per cent underwent laparoscopic surgery and 52.3 per cent underwent D3 lymph node dissection. The overall 30-day morbidity and mortality were 11.7 and 0.2 per cent, respectively. The 30-day anastomotic leak rate was 1.4 per cent. In multivariate analysis, ASA grade > II (P < 0.001), intraoperative blood loss > 50â ml (P = 0.044) and D3 lymph node dissection (P = 0.008) were identified as independent risk factors for postoperative morbidity. Extracorporeal side-to-side anastomosis (P = 0.031), intraoperative blood loss > 50â ml (P = 0.004) and neoadjuvant chemotherapy (P = 0.004) were identified as independent risk factors for anastomotic leak. CONCLUSION: In high-volume expert centres in China, laparoscopic resection with D3 lymph node dissection was performed in most patients with right-sided colon cancer, and overall postoperative morbidity and mortality was low. Further studies are needed to explore the optimal technique for right hemicolectomy in order to improve outcomes further.
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Neoplasias del Colon , Laparoscopía , Humanos , Fuga Anastomótica/epidemiología , Fuga Anastomótica/etiología , Fuga Anastomótica/cirugía , Estudios de Cohortes , Estudios Prospectivos , Pérdida de Sangre Quirúrgica , Neoplasias del Colon/patología , Colectomía/efectos adversos , Colectomía/métodos , Morbilidad , Factores de Riesgo , Laparoscopía/efectos adversos , Laparoscopía/métodos , Estudios RetrospectivosRESUMEN
Multi-resistant Staphylococcus aureus (S. aureus) infection is a significant global health concern owing to its high mortality and morbidity rates. Coagulase (Coa), a key enzyme that activates prothrombin to initiate host coagulation, has emerged as a promising target for anti-infective therapeutic approaches. This study identified sinigrin as a potent Coa inhibitor that significantly inhibited S. aureus-induced coagulation at concentration as low as 32 mg/L. Additionally, at a higher concentration of 128 mg/L, sinigrin disrupted the self-protection mechanism of S. aureus. Thermal shift and fluorescence-quenching assays confirmed the direct binding of sinigrin to the Coa protein. Molecular docking analysis predicted specific binding sites for sinigrin in the Coa molecule, and point mutation experiments highlighted the importance of Arg-187 and Asp-222 as critical binding sites for both Coa and sinigrin. In vivo studies demonstrated that the combination of sinigrin with oxacillin exhibited greater antibacterial efficacy than oxacillin alone in the treatment of S. aureus-induced pneumonia in mice. Furthermore, sinigrin was shown to reduce bacterial counts and inflammatory cytokine levels in the lung tissues of S. aureus-infected mice. In summary, sinigrin was shown to directly target Coa, resulting in the attenuation of S. aureus virulence, which suggests the potential of sinigrin as an adjuvant for future antimicrobial therapies.
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The increasing prevalence of infections related to methicillin-resistant Staphylococcus aureus (MRSA) necessitates the exploration of innovative therapeutic strategies that diverge from conventional antibiotic treatments. This is imperative to effectively combat resistance and manage these infections. The adoption of antivirulence strategies has emerged as a particularly promising avenue. This approach applies a heightened selective pressure on pathogens, thereby diminishing the likelihood of bacteria evolving resistance to antibiotics. In our pursuit of novel therapeutics for treating MRSA infections, we have focused on agents that inhibit the virulence of S. aureus without impeding its growth, aiming to minimize the development of drug resistance. α-Hemolysin, a critical virulence factor encoded by the hla gene, is a cytotoxin that forms pores in host cell membranes and plays a pivotal role in the progression of disease during bacterial infections. Herein, we identified that norwogonin could effectively inhibit Hla production via targeting agrAC, a crucial protein in quorum sensing, resulting in dose-dependent inhibition of hemolytic activity without suppressing S. aureus growth. In vitro assays illustrated that norwogonin decreased the thermal stability of agrAC, providing evidence of interaction between norwogonin and agrAC. Meanwhile, norwogonin alleviated Hla-mediated A549 cell damage and reduced lactate dehydrogenase release. In vivo studies suggested that norwogonin treatment blocked the establishment of a mouse model of pneumonia caused by S. aureus USA300. Notably, norwogonin enhanced the antibacterial potency of oxacillin. In conclusion, norwogonin is a promising candidate for treating S. aureus infections, offering a novel alternative to traditional antibiotics by targeting virulence factors and enhancing the efficacy of existing treatments.
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Antibacterianos , Proteínas Bacterianas , Proteínas Hemolisinas , Staphylococcus aureus Resistente a Meticilina , Factores de Virulencia , Animales , Femenino , Humanos , Ratones , Células A549 , Antibacterianos/farmacología , Proteínas Bacterianas/metabolismo , Proteínas Bacterianas/genética , Toxinas Bacterianas/metabolismo , Modelos Animales de Enfermedad , Proteínas Hemolisinas/metabolismo , Hemólisis/efectos de los fármacos , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Ratones Endogámicos BALB C , Percepción de Quorum/efectos de los fármacos , Infecciones Estafilocócicas/tratamiento farmacológico , Infecciones Estafilocócicas/microbiología , Virulencia/efectos de los fármacos , Factores de Virulencia/metabolismoRESUMEN
Background: Obstructive sleep apnea (OSA) is common in patients with chronic thromboembolic pulmonary hypertension (CTEPH), but the pathological determinants of adverse outcomes remain unknown. This study aimed to investigate the prognostic significance of various sleep parameters in patients with CTEPH undergoing pulmonary endarterectomy. Methods: Consecutive patients diagnosed with CTEPH who underwent overnight cardiorespiratory polygraphy for the assessment of OSA were enrolled. Time-to-event analysis was performed investigating cardiorespiratory indices (e.g., apnea-hypopnea index [AHI], time percentage with oxygen saturation below < 90% [T90]) and clinical worsening using the log-rank test, and multivariable Cox proportional hazard models adjusted for multiple confounders. Results: Of the 71 patients with operable CTEPH who underwent overnight cardiorespiratory polygraphy, 36 (50.7%) had OSA (AHI of ≥ 5) and 32 (45.1%) had nocturnal hypoxemia (T90 of ≥ 30%). A 10% increase in T90 was associated with a 27% greater risk of worse hemodynamics, as quantified by mean pulmonary artery pressure of ≥ 46 mmHg (odds ratio: 1.27, 95% confidence interval [CI]: 1.07-1.50, p = 0.006). Clinical worsening (CW) was experienced by 19 (26.8%) patients over a median follow-up of 26.8 months. AHI did not predict a higher risk of CW (hazard ratio [HR]: 1.00, 95% CI: 0.93-1.06, p = 0.906). A higher cumulative incidence of CW was seen in patients with nocturnal hypoxemia than in those with normoxemia (43.8% vs. 12.8%, log-rank p = 0.017). Cox regression analysis revealed the association between nocturnal hypoxemia and an increased risk of CW (HR: 3.27, 95% CI: 1.17-9.13, p = 0.024), and these associations persisted after covariate adjustment. Conclusions: Nocturnal hypoxemia quantified by T90 was a risk predictor of short- and long-term CW events among patients with operable CTEPH.
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Methicillin-resistant Staphylococcus aureus (MRSA) is a pathogenic bacterium responsible for a range of severe infections, such as skin infections, bacteremia, and pneumonia. Due to its antibiotic-resistant nature, current research focuses on targeting its virulence factors. Sortase A (SrtA) is a transpeptidase that anchors surface proteins to the bacterial cell wall and is involved in adhesion and invasion to host cells. Through fluorescence resonance energy transfer (FRET), we identified echinacoside (ECH), a natural polyphenol, as a potential SrtA inhibitor with an IC50 of 38.42 µM in vitro. It was demonstrated that ECH inhibited SrtA-mediated S. aureus fibrinogen binding, surface protein A anchoring, and biofilm formation. The fluorescence quenching assay determined the binding mode of ECH to SrtA and calculated the KA-binding constant of 3.09 × 105 L/mol, demonstrating the direct interaction between the two molecules. Molecular dynamics simulations revealed that ECH-SrtA interactions occurred primarily at the binding sites of A92G, A104G, V168A, G192A, and R197A. Importantly, the combination of ECH and vancomycin offered protection against murine models of MRSA-induced pneumonia. Therefore, ECH may serve as a potential antivirulence agent against S. aureus infections, either alone or in combination with vancomycin.
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Staphylococcus aureus Resistente a Meticilina , Neumonía , Animales , Ratones , Humanos , Staphylococcus aureus Resistente a Meticilina/metabolismo , Vancomicina/farmacología , Vancomicina/uso terapéutico , Staphylococcus aureus/metabolismo , Modelos Animales de Enfermedad , Proteínas Bacterianas/metabolismoRESUMEN
AIMS: Disabling bacterial virulence with small molecules has been proposed as a potential strategy to prevent bacterial pathogenicity. The von Willebrand factor-binding protein of Staphylococcus aureus was identified previously as a key virulence determinant. Our objective was to discover a von Willebrand-factor binding protein (vWbp) inhibitor distinct from the antibiotics used to prevent infections resulting from S. aureus. METHODS AND RESULTS: Using coagulation assays, we found that the sesquiterpene trilactone bilobalide blocks coagulation mediated by vWbp, but has no impact on the growth of S. aureus at a concentration of 128 µg ml-1. Moreover, a mouse model of pneumonia caused by S. aureus indicated that bilobalide could attenuate S. aureus virulence in vivo. This effect is achieved not by interfering with the expression of vWbp but by binding to vWbp, as demonstrated by western blotting, thermal shift assays, and fluorescence quenching assays. Using molecular dynamic simulations and point mutagenesis analysis, we identified that the Q17A and R453A residues are key residues for the binding of bilobalide to vWbp. CONCLUSIONS: Overall, we tested the ability of bilobalide to inhibit S. aureus infections by targeting vWbp and explored the potential mechanism of this activity.
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Bilobálidos , Neumonía , Infecciones Estafilocócicas , Ratones , Animales , Proteínas Portadoras/metabolismo , Factor de von Willebrand/genética , Factor de von Willebrand/metabolismo , Staphylococcus aureus/metabolismo , Infecciones Estafilocócicas/tratamiento farmacológicoRESUMEN
AIMS: The main purpose of this study was to study the therapeutical effect of oroxylin A glucuronide (OAG) on methicillin-resistant Staphylococcus aureus (MRSA). METHODS AND RESULTS: By substrate peptide reaction-based fluorescence resonance energy transfer (FRET) screening, we identified that OAG was an efficient inhibitor of Sortase A (SrtA) with an IC50 of 45.61 µg mL-1, and achieved efficacy in the treatment of Staphylococcus aureus (S. aureus) infections. We further demonstrated that OAG inhibited the adhesion of the S. aureus to fibrinogen, the surface protein A anchoring and diminished biofilm formation. Results obtained from fluorescence quenching assay elucidated a direct interaction between OAG and SrtA. Employing molecular dynamics simulations, we proved that OAG binds to the binding sites of R197, G192, E105, and V168 in the SrtA. Notably, OAG exhibited a robust therapeutic effect in a MRSA-induced pneumonia model. CONCLUSIONS: We identified that OAG as a novel class of reversible inhibitors of SrtA, combats MRSA-induced Infections.
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Staphylococcus aureus Resistente a Meticilina , Staphylococcus aureus Resistente a Meticilina/metabolismo , Staphylococcus aureus , Glucurónidos/farmacología , Proteínas Bacterianas/metabolismoRESUMEN
Staphylococcus aureus (S. aureus) induces a variety of infectious diseases in humans and animals and is responsible for hospital- and community-acquired infections. The aim of this study was to investigate how bilobetin, a natural compound, attenuates S. aureus virulence by inhibiting two key virulence factors, von Willebrand factor-binding protein (vWbp) and staphylocoagulase (Coa). The results showed that bilobetin inhibited Coa- or vWbp-induced coagulation without affecting S. aureus proliferation. The Western blotting and fluorescence quenching assays indicated that bilobetin did not affect the expression of vWbp and Coa but directly bound to the proteins with KA values of 1.66 × 104 L/mol and 1.04 × 104 L/mol, respectively. To gain further insight into the mechanism of interaction of bilobetin with these virulence factors, we performed molecular docking and point mutation assays, which indicated that the TYR-6 and TYR-18 residues on vWbp and the ALA-190 and ASP-189 residues on Coa were essential for the binding of bilobetin. In addition, the in vivo studies showed that bilobetin ameliorated lung tissue damage and inflammation caused by S. aureus, thereby improving the survival of mice. Furthermore, the use of bilobetin as an adjuvant in combination with vancomycin was more effective in the treatment of a mouse model of pneumonia. Taken together, bilobetin had a dual inhibitory effect on vWbp and Coa by reducing the virulence of S. aureus, suggesting that it is a viable lead compound against S. aureus infections.
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Coagulasa , Infecciones Estafilocócicas , Humanos , Ratones , Animales , Coagulasa/genética , Coagulasa/metabolismo , Coagulasa/farmacología , Proteínas Portadoras/metabolismo , Staphylococcus aureus , Virulencia , Factor de von Willebrand/metabolismo , Factor de von Willebrand/farmacología , Simulación del Acoplamiento Molecular , Infecciones Estafilocócicas/tratamiento farmacológico , Factores de Virulencia/genética , Factores de Virulencia/metabolismoRESUMEN
Antimicrobial resistance (AMR) poses a major threat to human health globally. Staphylococcus aureus is recognized as a cause of disease worldwide, especially methicillin-resistant S. aureus (MRSA) and vancomycin-resistant S. aureus (VRSA). The enzyme sortase A (SrtA), present on the cell surface of S. aureus, plays a key role in bacterial virulence without affecting the bacterial viability, and SrtA-deficient S. aureus strains do not affect the growth of bacteria. Here, we found that punicalagin, a natural compound, was able to inhibit SrtA activity with a very low half maximal inhibitory concentration (IC50) value of 4.23 µg/mL, and punicalagin is a reversible inhibitor of SrtA. Moreover, punicalagin has no distinct cytotoxicity toward A549, HEK293T, or HepG2 cells at a much higher concentration than the IC50 detected by MTT [3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2H-tetrazolium bromide] assays. In addition, punicalagin visibly attenuated the virulence-related phenotype of SrtA in vitro by decreasing adhesion of S. aureus to fibrinogen, reducing the ability of protein A (SpA) displayed on the surface of the bacteria and biofilm formation. Fluorescence quenching elucidated the interaction between punicalagin and SrtA. Molecular docking further implied that the inhibitory activity lay in the bond between punicalagin and SrtA residues LYS190, TYR187, ALA104, and GLU106. In In vivo studies, we surprisingly found that punicalagin had a more effective curative effect combined with cefotaxime when mice were infected with pneumonia caused by MRSA. Essentially, punicalagin, a therapeutic compound targeting SrtA, demonstrates great potential for combating MRSA infections.
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Staphylococcus aureus Resistente a Meticilina , Infecciones Estafilocócicas , Aminoaciltransferasas , Animales , Antibacterianos/farmacología , Antibacterianos/uso terapéutico , Proteínas Bacterianas/genética , Cisteína Endopeptidasas , Células HEK293 , Humanos , Taninos Hidrolizables , Ratones , Simulación del Acoplamiento Molecular , Infecciones Estafilocócicas/tratamiento farmacológico , Infecciones Estafilocócicas/microbiología , Staphylococcus aureusRESUMEN
Drug-resistant bacteria was the third leading cause of death worldwide in 2019, which sounds like a cautionary note for global public health. Therefore, developing novel strategies to combat Methicillin-resistant Staphylococcus aureus (MRSA) infections is the need of the hour. Caseinolytic protease P (ClpP) represents pivotal microbial degradation machinery in MRSA involved in bacterial homeostasis and pathogenicity, considered an ideal target for combating S. aureus infections. Herein, we identified a natural compound, hinokiflavone, that inhibited the activity of ClpP of MRSA strain USA300 with an IC50 of 34.36 µg/mL. Further assays showed that hinokiflavone reduced the virulence of S. aureus by inhibiting multiple virulence factors expression. Results obtained from cellular thermal transfer assay (CETSA), thermal shift assay (TSA), local surface plasmon resonance (LSPR) and molecular docking (MD) assay enunciated that hinokiflavone directly bonded to ClpP with confirmed docking sites, including SER-22, LYS-26 and ARG-28. In vivo, the evaluation of anti-infective activity showed that hinokiflavone in combination with vancomycin effectively protected mice from MRSA-induced fatal pneumonia, which was more potent than vancomycin alone. As mentioned above, hinokiflavone, as an inhibitor of ClpP, could be further developed into a promising adjuvant against S. aureus infections.
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Staphylococcus aureus Resistente a Meticilina , Infecciones Estafilocócicas , Animales , Antibacterianos/farmacología , Biflavonoides , Ratones , Simulación del Acoplamiento Molecular , Péptido Hidrolasas/farmacología , Infecciones Estafilocócicas/tratamiento farmacológico , Infecciones Estafilocócicas/microbiología , Staphylococcus aureus , Vancomicina/farmacología , VirulenciaRESUMEN
Staphylococcus aureus (S. aureus) is a common pathogenic bacterium that induces a variety of diseases in humans and animals. The significant pathogenicity of S. aureus is due to its expression of several virulence factors. Alpha-hemolysin (Hla) has attracted attention as a virulence factor in staphylococcal pathogenesis and has been the predominant focus of intense research. In this study, we found that kaempferol, a flavonoid compound, inhibited hemolysis at a low concentration (32 µg/mL) and exerted no effect on bacterial growth. Western blot and RT-qPCR assays further demonstrated that kaempferol downregulated the expression of Hla in S. aureus. We observed that kaempferol alleviated the damage from S. aureus Hla in A549 cells. More importantly, kaempferol showed a potent protective effect on mice pneumonia induced by MRSA, as evidenced by a significant improvement in the survival of mice, a reduction in the number of colonized colonies in lung tissue and a decrease in the pathological damage to lung tissues. In summary, the results demonstrate the protective effect of kaempferol on MRSA-induced lethal pneumonia in mice and indicate that kaempferol could be developed as a potential anti-MRSA drug.
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Toxinas Bacterianas , Staphylococcus aureus Resistente a Meticilina , Neumonía Estafilocócica , Animales , Antibacterianos , Proteínas Hemolisinas , Quempferoles/farmacología , Ratones , Neumonía Estafilocócica/tratamiento farmacológico , Staphylococcus aureusRESUMEN
Objectives: To assess the outcomes of transcatheter mitral valve repair (TMVr) for failed previous surgical mitral valve repair (MVr). Methods: We searched Pubmed, Embase, and Cochrane Library databases for studies that reported the outcomes of TMVr for failed initial surgical MVr. Data were extracted by 2 independent investigators and subjected to meta-analysis. The 95% confidence interval (CI) was calculated for preoperative demographics, peri-operative outcomes, and follow-up outcomes using binary and continuous data from single-arm studies. Results: Eight single-arm studies were included, with a total of 212 patients, and mean follow-up ranged from 1.0 to 15.9 months. The pooled rate of residual procedural mitral regurgitation ≤ mild was 76% (95% CI: 67%~84%; I 2 = 0%; 7 studies, 199 patients). During follow-up, mitral regurgitation ≤ mild was found in 68% of patients (95% CI: 52%~82%; I 2 = 57%; 6 studies, 147 patients). Follow-up survival was 94% (95% CI: 88%~98%; I 2 = 0%; 7 studies, 196 patients). 83% patients (95% CI: 75%~89%; I 2 = 47%; 6 studies, 148 patients) were in NYHA class I or II. Conclusions: TMVr for failed surgical MVr was safe and effective, which should be recommended in selected patients if technically feasible.
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Non-small cell lung cancer (NSCLC) poses a serious threat to public health due to its significant morbidity and mortality rates. The processes of NSCLC formation and development are quite complex and involve numerous regulatory biomolecules. Long non-coding RNAs (lncRNAs) have attracted attention since they have been found to play critical roles in the tumorigenesis of various human malignancies. Recently, double homeobox A pseudogene 8 (DUXAP8) was identified as an oncogenic lncRNA that is overexpressed in different tumor types. In NSCLC, high expression of DUXAP8 is associated with poor prognosis in patients. The regulatory mechanism underlying the oncogenic effects of DUXAP8 can be divided into transcriptional level and post-transcriptional level. DUXAP8 promotes proliferation, epithelial-mesenchymal transition, and aerobic glycolysis in NSCLC cells. Moreover, DUXAP8 shows potential for the diagnosis and treatment of NSCLC. Herein, we review the molecular mechanisms underlying the DUXAP8-mediated phenotypes of NSCLC as well as its potential clinical applications.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , MicroARNs , ARN Largo no Codificante , Carcinoma de Pulmón de Células no Pequeñas/genética , Línea Celular Tumoral , Proliferación Celular/genética , Regulación Neoplásica de la Expresión Génica/genética , Genes Homeobox , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , MicroARNs/genética , Seudogenes , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismoRESUMEN
Staphylococcus aureus, especially drug-resistant S. aureus infections, is a worldwide healthcare challenge. There is a growing focus on antivirulence therapy against S. aureus. Caseinolytic protease p (ClpP) is a protein hydrolase essential for pathogenicity in S. aureus. A flavonoid compound, tamarixetin, which was screened in this work, was specifically able to inhibit the hydrolytic activity of ClpP on the fluorescent substrate Suc-LY-AMC with an IC50 of 49.73 µM, without affecting the growth of methicillin-resistant S. aureus strain USA300 and was without obvious cytotoxicity. Further assays found that tamarixetin inhibited the transcription of hla, agr, RNAIII, pvl, PSM-α, and spa genes as well as suppressed the protein expression levels of Hla and PVL. Moreover, tamarixetin was observed to dramatically inhibit the hemolytic activity of hla in S. aureus. Consistent with that of S. aureus USA300-ΔclpP, tamarixetin was shown to increase urease expression. The thermal shift and cellular thermal shift assays showed that tamarixetin markedly changed the thermal stability of ClpP. The dissociation constant (KD) value of tamarixetin with ClpP was 2.52 × 10-6 M measured by surface plasmon resonance. The molecular docking and ClpP point mutation results also demonstrated that tamarixetin had a strong interaction with ClpP. In vivo study showed that tamarixetin was effective in protecting mice from S. aureus pneumonia by increasing survival, reducing lung tissue load, and slowing down the infiltration of inflammatory factors. In addition, tamarixetin was able to enhance the antibacterial activity of cefotaxime in combination. In conclusion, tamarixetin was promising as a ClpP inhibitor for S. aureus infections.
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Staphylococcus aureus Resistente a Meticilina , Infecciones Estafilocócicas , Animales , Proteínas Bacterianas/genética , Disacáridos , Ratones , Simulación del Acoplamiento Molecular , Péptido Hidrolasas , Quercetina/análogos & derivados , Staphylococcus aureus , Virulencia , Factores de Virulencia/genéticaRESUMEN
The long-term prognosis of patients with chronic thromboembolic pulmonary hypertension (CTEPH) receiving different treatments is deserved to be analyzed in modern era of CTEPH treatment. From 2013 to 2019, a total of 364 patients diagnosed with CTEPH were retrospectively included, 14 patients were lost during follow-up. Among 350 patients included in the final analysis: 123 underwent pulmonary endarterectomy (PEA), 121 received balloon pulmonary angioplasty (BPA), and 106 treated with targeted drug alone. The median period of follow-up was 51.2 months, the estimated survival at 1-, 3-, 5- and 7-year was 97.1%, 93.3%, 86.9%, and 82.0% for the whole cohort; 100%, 99.20%, 96.5% and 92.5% in PEA group; 98.4%, 97.4%, 95.3% and 89.3% in BPA group;92.5%, 81.9%, 70.1% and 66.8% in patients who received targeted drug alone. In comparing with targeted treatment along, results of multivariate Cox analysis after adjusting the confounders showed that receiving PEA decreased the risk of death by 83% (HR [hazard ratio] 0.17, 95% CI [Confidence interval] 0.07-0.44) and receiving BPA decreased the risk of death by 89% (HR 0.11, 95% CI 0.04-0.29). In conclusion, the estimated survival of CTEPH patients at 1-, 3-, 5- and 7-year was 97.1%, 93.3%, 86.9%, and 82.0% respectively. The intervention of revascularization, including PEA and BPA, were preferred than treating with targeted drug alone in the view of long-term prognosis of CTEPH.
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Angioplastia de Balón , Hipertensión Pulmonar , Embolia Pulmonar , Angioplastia de Balón/métodos , Enfermedad Crónica , Endarterectomía/métodos , Humanos , Hipertensión Pulmonar/diagnóstico , Hipertensión Pulmonar/cirugía , Arteria Pulmonar/cirugía , Embolia Pulmonar/complicaciones , Embolia Pulmonar/diagnóstico , Embolia Pulmonar/terapia , Estudios RetrospectivosRESUMEN
ABSTRACT: The zygomatico-orbital artery (ZOA) originating from the superficial temporal artery and supplying the lower temporal region superficially has been reported. Previous studies of this artery have used definitions that are too ambiguous for the results to be directly adapted to clinical practice, including since they have resulted in marked variations in the reported incidence ofthe artery. This study dissected 193 hemifaces of 123 fixed human cadavers aged 36 to 102âyears (119 males and 74 females). The authors investigated the ZOA based on the following definition: (1) it originates from the superficial temporal artery, (2) it runs mostly above the zygomatic arch, and (3) it terminates below the superior border of the orbicularis oculi muscle. The incidence of the ZOA was 22.8% (44 cases of 193 sides), and its mean diameter was 1.1âmm. The meanvertical distances from the superior borderofthe zygomatic arch to the artery were 29.6, 17.8, and 2.9âmm at the jugale, zygion, and the origin of the ZOA, respectively. An accurate definition of the ZOA and accurate knowledge of its incidence and course could be important for clinicians to avoid unintentional complications in clinical practice.
Asunto(s)
Cabeza , Cigoma , Arterias , Cadáver , Femenino , Humanos , Masculino , Arterias Temporales , Cigoma/anatomía & histologíaRESUMEN
ABSTRACT: The present study is to identify primarily the morphological characteristics in the growth proportion of the head and face for young Korean (8-24âyears) and compare the magnitude of growth changes to the sex-related differences. Total 1255 were divided into 3 age groups: childhood (8-10âyears), adolescence (14-16âyears), and young adult (20-24âyears). The anthropometric assessments were performed with 11 landmarks on the head and facial dimensions. The standardized frontal and lateral head and face photographs were analyzed the craniofacial growth proportions and morphological features for the comparison of both sexes. The noteworthy differences of anthropometric measurements between sexes with growing were noted on the lower head height (22.6%, 17.8%), midface height (22.0%, 19.6%), lower face height (23.5%, 14.7%), and face length (21.1%, 14.9%), face breadth (14.8%, 11.3%) of males and females, respectively. Whereas the upper head height (7.9%, 6.0%) and upper face height (4.2%, 0%, respectively) were less growing features. The most remarkable changes are the dimension of midface height and lower face height in both sexes. The present study could demonstrate a fundamental example to elucidate the sex-related dimensional differences for the analysis of the growth proportion of both sexes in Koreans.
Asunto(s)
Cara , Cabeza , Adolescente , Antropometría , Pueblo Asiatico , Cefalometría , Niño , Cara/anatomía & histología , Femenino , Cabeza/anatomía & histología , Humanos , Masculino , República de Corea , Adulto JovenRESUMEN
The purpose of this study is to identify the location of the orbital part of the lacrimal gland using external landmarks to facilitate effective botulinum toxin A (BTX-A) injections for epiphora treatment. Dissections were performed on 45 hemifaces from 27 cadavers. The length, anterior protrusion, and thickness of the orbital part of the lacrimal gland were measured directly. The midpoint of the line running horizontal through the medial and lateral canthus was used as the horizontal reference point. Vertical lines perpendicular to the midpoint of the horizontal reference line were the vertical reference lines. The angles from the horizontal reference line to the lacrimal gland center and to the frontal tubercle were also measured. The length and thickness of the lacrimal gland were 12.8 and 2.4 mm, respectively. The lacrimal gland had an anterior protrusion of 4.1 mm from the superolateral orbital margin. The superior and inferior margins of the lacrimal gland were located 35.7° and 15.8° from the two reference lines, respectively. The angle from the horizontal reference line to the lacrimal gland center was 35.1°, which was similar to that to the frontal tubercle (34.4°). The orbital part of the lacrimal gland was more inferior in elderly subjects and the angle between the horizontal reference line and its center was 35.1°, which was similar to the location of the frontal tubercle. The location of this tubercle can help clinicians to perform BTX-A injections into the lacrimal gland, thereby enhancing the effectiveness of epiphora treatment.