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All metazoan guts are subjected to immunologically unique conditions in which an efficient antimicrobial system operates to eliminate pathogens while tolerating symbiotic commensal microbiota. However, the molecular mechanisms controlling this process are only partially understood. Here, we show that bacterial-derived uracil acts as a ligand for dual oxidase (DUOX)-dependent reactive oxygen species generation in Drosophila gut and that the uracil production in bacteria causes inflammation in the gut. The acute and controlled uracil-induced immune response is required for efficient elimination of bacteria, intestinal cell repair, and host survival during infection of nonresident species. Among resident gut microbiota, uracil production is absent in symbionts, allowing harmonious colonization without DUOX activation, whereas uracil release from opportunistic pathobionts provokes chronic inflammation. These results reveal that bacteria with distinct abilities to activate uracil-induced gut inflammation, in terms of intensity and duration, act as critical factors that determine homeostasis or pathogenesis in gut-microbe interactions.
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Drosophila/inmunología , Drosophila/microbiología , Inmunidad Mucosa , Pectobacterium carotovorum/fisiología , Simbiosis , Uracilo/metabolismo , Animales , Tracto Gastrointestinal/inmunología , Tracto Gastrointestinal/microbiología , Tracto Gastrointestinal/fisiología , Homeostasis , Humanos , Inflamación/inmunología , Inflamación/microbiología , Enfermedades Inflamatorias del Intestino/inmunología , Enfermedades Inflamatorias del Intestino/microbiología , NADPH Oxidasas/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Células Madre/metabolismoRESUMEN
Aziridines-three-membered nitrogen-containing cyclic molecules-are important synthetic targets. Their substantial ring strain and resultant proclivity towards ring-opening reactions makes them versatile precursors of diverse amine products1-3, and, in some cases, the aziridine functional group itself imbues important biological (for example, anti-tumour) activity4-6. Transformation of ubiquitous alkenes into aziridines is an attractive synthetic strategy, but is typically accomplished using electrophilic nitrogen sources rather than widely available amine nucleophiles. Here we show that unactivated alkenes can be electrochemically transformed into a metastable, dicationic intermediate that undergoes aziridination with primary amines under basic conditions. This new approach expands the scope of readily accessible N-alkyl aziridine products relative to those obtained through existing state-of-the-art methods. A key strategic advantage of this approach is that oxidative alkene activation is decoupled from the aziridination step, enabling a wide range of commercially available but oxidatively sensitive7 amines to act as coupling partners for this strain-inducing transformation. More broadly, our work lays the foundations for a diverse array of difunctionalization reactions using this dication pool approach.
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Alquenos/química , Aminas/química , Aziridinas/síntesis química , Técnicas de Química Sintética/métodos , Electroquímica/métodos , Alquenos/síntesis química , Aminas/síntesis química , Aziridinas/química , Oxidación-Reducción , TermodinámicaRESUMEN
Adherence to medication plays a crucial role in the effective management of chronic diseases. However, patients often miss their scheduled drug administrations, resulting in suboptimal disease control. Therefore, we propose an implantable device enabled with automated and precisely timed drug administration. Our device incorporates a built-in mechanical clock movement to utilize a clockwork mechanism, i.e., a periodic turn of the hour axis, enabling automatic drug infusion at precise 12-h intervals. The actuation principle relies on the sophisticated design of the device, where the rotational movement of the hour axis is converted into potential mechanical energy and is abruptly released at the exact moment for drug administration. The clock movement can be charged either automatically by mechanical agitations or manually by winding the crown, while the device remains implanted, thereby enabling the device to be used permanently without the need for batteries. When tested using metoprolol, an antihypertensive drug, in a spontaneously hypertensive animal model, the implanted device can deliver drug automatically at precise 12-h intervals without the need for further attention, leading to similarly effective blood pressure control and ultimately, prevention of ventricular hypertrophy as compared with scheduled drug administrations. These findings suggest that our device is a promising alternative to conventional methods for complex drug administration.
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Suministros de Energía Eléctrica , Animales , Humanos , Preparaciones FarmacéuticasRESUMEN
Mitochondrial activity is becoming an inherent aspect of cellular protein homeostasis (proteostasis). In this issue, Schlagowski et al (2021) report on the attractive notion that modulating mitochondrial protein import activity stimulates protein aggregate clearance in the cytosol, thereby affecting cytosolic proteostasis and its collapse observed in neurodegenerative diseases.
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Proteínas Mitocondriales , Proteostasis , Citosol/metabolismo , Mitocondrias/metabolismo , Proteínas Mitocondriales/metabolismo , Transporte de ProteínasRESUMEN
Dynamic regulation of mitochondrial morphology provides cells with the flexibility required to adapt and respond to electron transport chain (ETC) toxins and mitochondrial DNA-linked disease mutations, yet the mechanisms underpinning the regulation of mitochondrial dynamics machinery by these stimuli is poorly understood. Here, we show that pyruvate dehydrogenase kinase 4 (PDK4) is genetically required for cells to undergo rapid mitochondrial fragmentation when challenged with ETC toxins. Moreover, PDK4 overexpression was sufficient to promote mitochondrial fission even in the absence of mitochondrial stress. Importantly, we observed that the PDK4-mediated regulation of mitochondrial fission was independent of its canonical function, i.e., inhibitory phosphorylation of the pyruvate dehydrogenase complex (PDC). Phosphoproteomic screen for PDK4 substrates, followed by nonphosphorylatable and phosphomimetic mutations of the PDK4 site revealed cytoplasmic GTPase, Septin 2 (SEPT2), as the key effector molecule that acts as a receptor for DRP1 in the outer mitochondrial membrane to promote mitochondrial fission. Conversely, inhibition of the PDK4-SEPT2 axis could restore the balance in mitochondrial dynamics and reinvigorates cellular respiration in mitochondrial fusion factor, mitofusin 2-deficient cells. Furthermore, PDK4-mediated mitochondrial reshaping limits mitochondrial bioenergetics and supports cancer cell growth. Our results identify the PDK4-SEPT2-DRP1 axis as a regulator of mitochondrial function at the interface between cellular bioenergetics and mitochondrial dynamics.
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Dinámicas Mitocondriales , Proteínas Quinasas , Respiración de la Célula/genética , GTP Fosfohidrolasas/genética , Expresión Génica , Mitocondrias/genética , Mitocondrias/metabolismo , Dinámicas Mitocondriales/genética , Proteínas Quinasas/metabolismoRESUMEN
A detailed mechanistic study of the Z-selective allylic functionalization via thianthrenium salts is presented. Kinetic analyses, deuterium labeling experiments, and computational methods are used to rationalize the observed reactivity and selectivity. We find that the reaction proceeds via a rate-determining and stereodetermining allylic deprotonation of an alkenylthianthrenium species. The Z-configuration of the resultant allylic ylide is translated into the Z-allylic amine product through a sequence of subsequent fast and irreversible steps: protonation to form a Z-allylic thianthrenium electrophile and then regioselective substitution by the nucleophile. In the stereodetermining deprotonation step, computational studies identified a series of stabilizing nonbonding interactions in the Z-alkene-forming transition state that contribute to the stereoselectivity.
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Epstein-Barr virus-associated gastric carcinoma (EBVaGC) is characterized by prominent tumor-infiltrating lymphocytes (TILs) and has a favorable prognosis. Tertiary lymphoid structures (TLS), characterized by ectopic aggregated lymphocytes with high-endothelial venules (HEV), are associated with favorable outcomes in various solid tumors. We hypothesized that EBVaGC, characterized by intense TILs, may be closely associated with TLS or HEV. To test this hypothesis, we digitally analyzed the TLS, HEV, and TILs in 73 surgically resected advanced EBVaGCs. For HEV, dual MECA-79 and CD31 dual immunohistochemistry were performed, and the ectopic expression of MECA-79 in tumor cells was measured. In 73 patients with EBVaGC, a high-TLS ratio was found in 29 (39.7%) cases, high-tumor-associated HEV density in 44 (60.3%) cases, and high-CD8+ TIL density in 38 (52.1%) cases. Ectopic tumor expression of MECA-79 was observed in 36 patients (49.3%) cases. A low-TLS ratio and tumor-associated HEV density were significantly associated with lymph node metastasis (P = .005 and .042, respectively). Ectopic MECA-79 expression was significantly associated with lymph node metastasis (P = .003). Patients with a low-TLS ratio (P = .038), low-HEV density (P = .042), and ectopic tumor MECA-79 expression (P = .032) had significantly worse prognoses. In conclusion, TLS ratio and HEV density affect the survival of patients with EBVaGC and may be related to the immune response that interrupts lymph node metastasis.
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Infecciones por Virus de Epstein-Barr , Linfocitos Infiltrantes de Tumor , Neoplasias Gástricas , Estructuras Linfoides Terciarias , Humanos , Neoplasias Gástricas/patología , Neoplasias Gástricas/virología , Neoplasias Gástricas/inmunología , Masculino , Femenino , Persona de Mediana Edad , Estructuras Linfoides Terciarias/inmunología , Estructuras Linfoides Terciarias/patología , Estructuras Linfoides Terciarias/metabolismo , Pronóstico , Infecciones por Virus de Epstein-Barr/complicaciones , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Anciano , Adulto , Herpesvirus Humano 4 , Procesamiento de Imagen Asistido por Computador , Antígenos de Superficie , Proteínas de la MembranaRESUMEN
BACKGROUND: Sentinel lymph node biopsy (SLNB) is recommended for patients with ductal carcinoma in situ (DCIS) undergoing mastectomy, given the concerns regarding upstaging and technical difficulties of post-mastectomy SLNB. However, this may lead to potential overtreatment, considering favorable prognosis and de-escalation trends in DCIS. Data regarding upstaging and axillary lymph node metastasis among these patients remain limited. METHODS: We retrospectively reviewed patients with DCIS who underwent mastectomy with SLNB or axillary lymph node dissection at Gangnam Severance Hospital between January 2010 and December 2021. To explore the feasibility of omitting SLNB, we assessed the rates of DCIS upgraded to invasive carcinoma and axillary lymph node metastasis. Binary Cox regression analysis was performed to identify clinicopathologic factors associated with upstaging and axillary lymph node metastasis. RESULTS: Among 385 patients, 164 (42.6%) experienced an invasive carcinoma upgrade: microinvasion, pT1, and pT2 were confirmed in 53 (13.8%), 97 (25.2%), and 14 (3.6%) patients, respectively. Seventeen (4.4%) patients had axillary lymph node metastasis. Multivariable analysis identified age ≤ 50 years (adjusted odds ratio [OR], 12.73; 95% confidence interval [CI], 1.18-137.51; p = 0.036) and suspicious axillary lymph nodes on radiologic evaluation (adjusted OR, 9.31; 95% CI, 2.06-41.99; p = 0.004) as independent factors associated with axillary lymph node metastasis. Among patients aged > 50 years and/or no suspicious axillary lymph nodes, only 1.7-2.3%) experienced axillary lymph node metastasis. CONCLUSIONS: Although underestimation of the invasive component was relatively high among patients with DCIS undergoing mastectomy, axillary lymph node metastasis was rare. Our findings suggest that omitting SLNB may be feasible for patients over 50 and/or without suspicious axillary lymph nodes on radiologic evaluation.
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Neoplasias de la Mama , Carcinoma Intraductal no Infiltrante , Humanos , Femenino , Biopsia del Ganglio Linfático Centinela , Carcinoma Intraductal no Infiltrante/cirugía , Metástasis Linfática , Neoplasias de la Mama/cirugía , Estudios Retrospectivos , MastectomíaRESUMEN
Long intergenic non-coding RNA 346 (LINC00346) has been reported to be involved in the development of atherosclerosis and specific cancers by affecting signaling pathways. However, its function in inflammation has not been thoroughly studied. Therefore, its expression pattern and function were determined in the human macrophage-like cell line THP-1. Lipopolysaccharide (LPS) treatment induced the expression of LINC00346. LPS-induced NF-κB activation and proinflammatory cytokine expression were suppressed or enhanced by the overexpression or knockdown of LINC00346, respectively. Analyses using dual luciferase assay and decoy RNAs that could block RNA-RNA interactions indicated that LINC00346 improves phosphatase and tensin homolog (PTEN) expression by sponging miR-25-3p. Subsequently, PTEN suppresses phosphoinositide-3 kinase (PI3K)-mediated conversion of phosphatidylinositol-4,5-bisphosphate (PIP2) into phosphatidylinositol-3,4,5-trisphosphate (PIP3) as well as consequent activation of protein kinase B (AKT) and NF-κB. Interestingly, database analysis revealed that the expression levels of LINC00346 and PTEN were simultaneously decreased in breast cancer tissues. Further analyses conducted using a breast cancer cell line, MDA-MB-231, confirmed the functional relationship among LINC00346, miR-25-3p, and PTEN in LPS-induced activation of NF-κB. These results indicate that miR-25-3p-sponging activity of LINC00346 affects the balance between PTEN and PI3K as well as the downstream activation of AKT/NF-κB pathway in inflammatory conditions.
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Neoplasias de la Mama , MicroARNs , Femenino , Humanos , Lipopolisacáridos/farmacología , MicroARNs/genética , MicroARNs/metabolismo , FN-kappa B/metabolismo , Fosfatidilinositol 3-Quinasa , Fosfatidilinositol 3-Quinasas/metabolismo , Fosfatidilinositoles , Proteínas Proto-Oncogénicas c-akt/metabolismo , Fosfohidrolasa PTEN/genética , Fosfohidrolasa PTEN/metabolismoRESUMEN
The incorporation of cationic groups onto electron-poor compounds is a viable strategy for achieving potent electron acceptors, as evidenced by reports of air-stable radical forms of large aromatic diimides such as naphthalene and perylene diimides. These ions have also been observed to exhibit anion-π interaction tendencies of interest in molecular recognition applications. The benefits of phosphonium incorporation, however, have not yet been extended to the smallest benzene diimides. Here, we report that dibrominated pyromellitic diimide and mellophanic diimide both readily undergo substitution reactions with phosphine sources to yield bisphosphonium compounds. In the single crystalline form, these dications display anion-π interactions and, in the case of mellophanic diimide, the stabilization of a bromide-water H-bonding ring pattern. The reaction of these dications with chemical reductants readily provides the singly and doubly reduced redox states, which were characterized by UV-vis spectroscopy and found to exhibit intense absorptions extending into the near-IR region. Taken together, this work demonstrates that phosphonium incorporation onto congested aromatic diimide scaffolds is synthetically viable and produces unusual electron-poor compounds.
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A new target that stimulates bone formation is needed to overcome limitations of current anti-osteoporotic drugs. Myokines, factors secreted from muscles, may modulate it. In this study, we investigated the role of aortic carboxypeptidase-like protein (ACLP), which is highly expressed in skeletal muscles, on bone formation. MC3T3-E1 cells and/or calvaria osteoblasts were treated with recombinant N-terminal mouse ACLP containing a signal peptide [rmACLP (N)]. The expression and secretion of ACLP were higher in skeletal muscle and differentiated myotube than in other tissues and undifferentiated myoblasts, respectively. rmACLP (N) increased bone formation, ALP activity, and phosphorylated p38 mitogen-activated protein (MAP) kinase in osteoblasts; reversal was achieved by pre-treatment with a TGF-ß receptor inhibitor. Under H2 O2 treatment, rmACLP (N) increased osteoblast survival, phosphorylated p38 MAP kinase, and the nuclear translocation of FoxO3a in osteoblasts. H2 O2 treatment caused rmACLP (N) to suppress its apoptotic, oxidative, and caspase-9 activities. rmACLP (N)-stimulated osteoblast survival was reversed by pre-treatment with a p38 inhibitor, a TGF-ß-receptor II blocking antibody, and a FoxO3a shRNA. Conditioned media (CM) from muscle cells stimulated osteoblast survival under H2 O2 treatment, in contrast to CM from ACLP knockdown muscle cells. rmACLP (N) increased the expressions of FoxO3a target anti-oxidant genes such as Sod2, Trx2, and Prx5. In conclusion, ACLP stimulated the differentiation and survival of osteoblasts. This led to the stimulation of bone formation by the activation of p38 MAP kinase and/or FoxO3a via TGF-ß receptors. These findings suggest a novel role for ACLP in bone metabolism as a putative myokine.
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Carboxipeptidasas , Proteínas Quinasas p38 Activadas por Mitógenos , Animales , Ratones , Diferenciación Celular/fisiología , Carboxipeptidasas/metabolismo , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismo , Osteogénesis , Osteoblastos/metabolismo , FosforilaciónRESUMEN
Defects in mitochondrial function activate compensatory responses in the cell. Mitochondrial stress that is caused by unfolded proteins inside the organelle induces a transcriptional response (termed the "mitochondrial unfolded protein response" [UPRmt]) that is mediated by activating transcription factor associated with stress 1 (ATFS-1). The UPRmt increases mitochondrial protein quality control. Mitochondrial dysfunction frequently causes defects in the import of proteins, resulting in the accumulation of mitochondrial proteins outside the organelle. In yeast, cells respond to mistargeted mitochondrial proteins by increasing activity of the proteasome in the cytosol (termed the "unfolded protein response activated by mistargeting of proteins" [UPRam]). The presence and relevance of this response in higher eukaryotes is unclear. Here, we demonstrate that defects in mitochondrial protein import in Caenorhabditis elegans lead to proteasome activation and life span extension. Both proteasome activation and life span prolongation partially depend on ATFS-1, despite its lack of influence on proteasomal gene transcription. Importantly, life span prolongation depends on the fully assembled proteasome. Our data provide a link between mitochondrial dysfunction and proteasomal activity and demonstrate its direct relevance to mechanisms that promote longevity.
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Caenorhabditis elegans/fisiología , Mitocondrias/metabolismo , Proteínas Mitocondriales/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Estrés Fisiológico , Animales , Caenorhabditis elegans/enzimología , Proteínas de Caenorhabditis elegans/genética , Activación Enzimática , Técnicas de Silenciamiento del Gen , Respuesta de Proteína DesplegadaRESUMEN
OBJECTIVES: To investigate the feasibility of using preoperative imaging indices to predict 2-year native liver survival after the Kasai procedure in patients with biliary atresia (BA). MATERIALS AND METHODS: The retrospective review included 190 BA patients who underwent the Kasai procedure between 2000 and 2020, with preoperative US and/or MRI, excluding cases with less than 2-year follow-up period. Multivariable logistic regression analysis was performed to identify imaging indices to predict 2-year native liver survival. Kasai failure was defined as the need for liver transplantation or death within 2 years of the Kasai procedure. RESULTS: Of the 90 patients included, all had preoperative US, and 61 also had MRI. Kasai failure occurred in 52% (47/90). Preoperative US identified gallbladder length (OR 0.40, 95% CI 0.17-0.95, p = 0.039; cutoff 1.6 cm, AUC 67.66) and biliary cysts (OR 24.64, 95% CI 1.97-308.08, p = 0.013) as significant Kasai failure predictors, with a combined accuracy of 73% (60/82). For patients having both preoperative US and MRI, significant predictors were hepatic artery diameter (OR 6.75, 95% CI 1.31-34.88, p = 0.023; cutoff 2 mm, AUC 73.83) and biliary cysts (OR 23.89, 95% CI 1.43-398.82, p = 0.027) on US, and gallbladder length (OR 0.25, 95% CI 0.08-0.76, p = 0.014; cutoff 1.2 cm, AUC 74.72) and spleen size (OR 2.53, 95% CI 1.02-6.29, p = 0.045; cutoff 6.9 cm, AUC 73.72) on MRI, with a combined accuracy of 85% (52/61). CONCLUSION: Preoperative US and/or MRI enhance the 2-year native liver survival prediction in BA patients after the Kasai procedure. CLINICAL RELEVANCE STATEMENT: BA patients with hepatic artery diameter > 2 mm (US), gallbladder length < 1.6 cm (US) or < 1.2 cm (MRI), spleen size > 6.9 cm (MRI), and absence of biliary cysts (US/MRI) have a decreased likelihood of 2-year native liver survival. KEY POINTS: ⢠Preoperative US and/or MRI can predict the probability of achieving 2-year native liver survival following the Kasai procedure. ⢠Combining US and MRI improved the accuracy to 85% for predicting 2-year native liver survival in BA patients. ⢠The hepatic artery diameter > 2 mm (US), gallbladder length < 1.6 cm (US) or < 1.2 cm (MRI), spleen size > 6.9 cm (MRI), and no biliary cysts (US/MRI) are significant predictors of Kasai failure in patients with biliary atresia.
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Enfermedades de los Conductos Biliares , Atresia Biliar , Quistes , Trasplante de Hígado , Humanos , Lactante , Atresia Biliar/diagnóstico por imagen , Atresia Biliar/cirugía , Portoenterostomía Hepática/métodos , Hígado/diagnóstico por imagen , Hígado/cirugía , Trasplante de Hígado/métodos , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND AND AIMS: Unlike iron, evidence of the association between dietary copper and zinc intake and type 2 diabetes (T2D) risk is limited. This study aimed to examine the prospective associations of dietary intake of iron (total, plant-based, and animal-based), copper, and zinc with T2D risk among adults aged ≥40 years. METHODS AND RESULTS: For 16,666 participants, dietary intakes (baseline, cumulative average, and most recent) of iron, copper, and zinc were calculated from repeated food frequency questionnaires; a modified Poisson regression model with a robust error estimator was conducted. In men, positive associations between T2D and baseline dietary intake of Cu and Zn, cumulative average dietary intake of Fe (total and animal-based), Cu and Zn, and most recent dietary intake of Fe (total, plant-based, and animal-based), Cu, and Zn [most recent diet: for total Fe, IRR(95%CI) = 1.93 (1.41-2.64); for plant-based Fe, 1.56 (1.15-2.11); for animal-based Fe, 1.44 (1.09-1.90); for Cu, 3.17 (2.33-4.30); for Zn, 2.18 (1.64-2.89)] were observed, where as in women, there were positive associations of only cumulative average dietary Zn intake and most recent dietary intake of plant-based Fe, Cu, and Zn [most recent diet: for plant-based Fe, 1.30 (1.01-1.68); for Cu, 1.62 (1.27-2.08); for Zn, 2.07 (1.61-2.66)]. CONCLUSION: Dietary intakes of iron (total, plant-based, and animal-based), copper, and zinc may be positively associated with T2D risk. These positive associations are predominantly observed in most recent diet and appear to be stronger compared to baseline and cumulative average diet.
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Enfermedades Cardiovasculares , Diabetes Mellitus Tipo 2 , Adulto , Masculino , Animales , Femenino , Humanos , Cobre/efectos adversos , Zinc/efectos adversos , Hierro/efectos adversos , Diabetes Mellitus Tipo 2/diagnóstico , Diabetes Mellitus Tipo 2/epidemiología , Diabetes Mellitus Tipo 2/prevención & control , Dieta/efectos adversosRESUMEN
BACKGROUND: Nutritional status and sarcopenia affects the prognosis of head and neck cancers including hypopharyngeal cancer. Hypopharyngeal cancer patients tend to exhibit sarcopenia, which is associated with poor treatment outcomes. This study aims to determine the correlation between nutritional status and sarcopenia, and their prognostic role in surgically treated hypopharyngeal cancer. MATERIALS AND METHODS: Patients who had been diagnosed with squamous cell carcinoma originating from the hypopharynx and underwent surgery between January 2009 and December 2019 were enrolled in this study. The median neutrophil-to-lymphocyte ratio and prognostic nutritional index (PNI) of the cohort were considered the cut-off values. Sarcopenia was evaluated by measuring skeletal muscle index (SMI) at the third lumbar vertebra. Clinical and serological factors predictive of survival outcomes were evaluated. RESULTS: Patients with high PNI showed better 5-year Overall survival (OS) (52.8% vs. 27.2%, p = 0.001) and disease-free survival (DFS) (59.6% vs. 44.6%, p = 0.033) than those with low PNI. Likewise, patients with low SMI showed worse 5-year OS (25.0% vs. 60.9%, p = 0.002) and DFS (42.4% vs. 68.7%, p = 0.034) than patients with high SMI. Among the patients with high PNI, those with sarcopenia displayed significantly worse OS than those with high SMI (78.0% vs. 34.4%, p = 0.049). High PNI with high SMI presented better overall (p = 0.010) and DFS (p = 0.055) than any other group. CONCLUSIONS: Both sarcopenia and PNI were associated with the prognosis of hypopharyngeal cancer. Considering that PNI and sarcopenia indicate the nutritional status, nutritional status may be a significant risk factor. Therefore, nutritional support that ameliorates sarcopenia may improve survival outcomes in surgically treated patients with hypopharyngeal cancer.
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Neoplasias Hipofaríngeas , Estado Nutricional , Sarcopenia , Humanos , Sarcopenia/complicaciones , Neoplasias Hipofaríngeas/cirugía , Neoplasias Hipofaríngeas/mortalidad , Neoplasias Hipofaríngeas/complicaciones , Neoplasias Hipofaríngeas/patología , Masculino , Femenino , Pronóstico , Persona de Mediana Edad , Anciano , Estudios Retrospectivos , Evaluación Nutricional , Carcinoma de Células Escamosas/cirugía , Carcinoma de Células Escamosas/mortalidad , Carcinoma de Células Escamosas/complicaciones , Carcinoma de Células Escamosas/patología , Tasa de Supervivencia , AdultoRESUMEN
Homologous recombination (HR) is critical for error-free repair of DNA double-strand breaks. Chromatin loading of RAD51, a key protein that mediates the recombination, is a crucial step in the execution of the HR repair. Here, we present evidence that SUMOylation of RAD51 is crucial for the RAD51 recruitment to chromatin and HR repair. We found that topoisomerase 1-binding arginine/serine-rich protein (TOPORS) induces the SUMOylation of RAD51 at lysine residues 57 and 70 in response to DNA damaging agents. The SUMOylation was facilitated by an ATM-induced phosphorylation of TOPORS at threonine 515 upon DNA damage. Knockdown of TOPORS or expression of SUMOylation-deficient RAD51 mutants caused reduction in supporting normal RAD51 functions during the HR repair, suggesting the physiological importance of the modification. We found that the SUMOylation-deficient RAD51 reduces the association with its crucial binding partner BRCA2, explaining its deficiency in supporting the HR repair. These findings altogether demonstrate a crucial role for TOPORS-mediated RAD51 SUMOylation in promoting HR repair and genomic maintenance.
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Recombinasa Rad51 , Reparación del ADN por Recombinación , Cromatina , ADN/metabolismo , Daño del ADN , Reparación del ADN/genética , Recombinación Homóloga , Recombinasa Rad51/genética , Recombinasa Rad51/metabolismo , SumoilaciónRESUMEN
Human CtIP maintains genomic integrity primarily by promoting 5' DNA end resection, an initial step of the homologous recombination (HR). A few mechanisms have been suggested as to how CtIP recruitment to damage sites is controlled, but it is likely that we do not yet have full understanding of the process. Here, we provide evidence that CtIP recruitment and functioning are controlled by the SIAH2 E3 ubiquitin ligase. We found that SIAH2 interacts and ubiquitinates CtIP at its N-terminal lysine residues. Mutating the key CtIP lysine residues impaired CtIP recruitment to DSBs and stalled replication forks, DSB end resection, overall HR repair capacity of cells, and recovery of stalled replication forks, suggesting that the SIAH2-induced ubiquitination is important for relocating CtIP to sites of damage. Depleting SIAH2 consistently phenocopied these results. Overall, our work suggests that SIAH2 is a new regulator of CtIP and HR repair, and emphasizes that SIAH2-mediated recruitment of the CtIP is an important step for CtIP's function during HR repair.
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Reparación del ADN , Replicación del ADN , Endodesoxirribonucleasas/metabolismo , Proteínas Nucleares/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Roturas del ADN de Doble Cadena , Endodesoxirribonucleasas/genética , Humanos , Ubiquitina-Proteína Ligasas/genética , UbiquitinaciónRESUMEN
BACKGROUND: Despite a plethora of research on the topic, there is still no solid evidence that pharmacological treatment actually reduces the risk of suicide in patients with mental illness. In this study, we aimed to assess the effect of psychotropic medications on suicidal ideation in patients with major depressive disorder (MDD) and bipolar disorder (BPD) in two age groups: less than 25 years and 25 years and older. METHODS: We analyzed 312 patients with mood disorders with current suicidal thoughts or recent suicide attempts. We followed the participants from baseline for 6 months and assessed changes in suicidal ideation with Columbia-Suicide Severity Rating Scale (C-SSRS). The effect of psychotropic drug administration on suicidal ideation over time was analyzed using a linear mixed model. RESULTS: In patients aged 25 years and older with mood disorders, suicidal ideation was more severe when using psychotropic drugs than when not using them. However, suicidal ideation decreased rapidly over time. The time-dependent reduction in suicidal ideation was accelerated when using antidepressants and sedatives/hypnotics in adult MDD, and when using mood stabilizers in adult BPD. However, this effect was not observed in participants aged less than 25 years. CONCLUSION: Adequate psychotropic medication may reduce suicidal ideation in patients with mood disorders aged 25 years and older. Additional research on psychotropic drugs is needed to effectively reduce the risk of suicide among children and adolescents with mood disorders.
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Trastorno Bipolar , Trastorno Depresivo Mayor , Psicotrópicos , Ideación Suicida , Humanos , Adulto , Masculino , Femenino , Estudios Prospectivos , Psicotrópicos/uso terapéutico , Trastorno Depresivo Mayor/tratamiento farmacológico , Trastorno Depresivo Mayor/psicología , Trastorno Bipolar/tratamiento farmacológico , Trastorno Bipolar/psicología , Adulto Joven , Antidepresivos/uso terapéutico , Trastornos del Humor/tratamiento farmacológico , Trastornos del Humor/psicología , Persona de Mediana Edad , Intento de Suicidio/psicología , Adolescente , Factores de TiempoRESUMEN
Using (S)-decursinol isolated from root of Angelica gigas Nakai (AGN), we semi-synthesized and evaluated a series of both enantiomerically pure decursin derivatives for their antiproliferative activities against A549 human lung cancer cells. All synthesized compounds showed a broad spectrum of inhibitory activities against the growth of A549 cells. Especially, compound (S)-2d with (E)-(furan-3-yl)acryloyl group showed the most potent activity (IC50: 14.03 µM) against A549 cancer cells as compared with the reference compound, decursin (IC50: 43.55 µM) and its enantiomer, (R)-2d (IC50: 151.59 µM). Western blotting assays indicated that (S)-2d more strongly inhibited Janus kinase 1 (JAK1) and signal transducer and activator of transcription activation 3 (STAT3) phosphorylation than decursin in a dose-dependent manner, while having no effect on CXCR7 overexpression and total STAT3 level. In addition, (S)-2d induced cell cycle arrest at G1 phase and subsequent apoptotic cell death in A549 cancer cells. Our combined analysis of molecular docking studies and biological data suggests that the inhibition of JAK1 with (S)-2d resulted in loss of STAT3 phosphorylation and inhibition of cell growth in A549 cancer cells. These overall results strongly suggest that (S)-2d (MRC-D-004) as a novel JAK1 inhibitor may have therapeutic potential in the treatment of A549 human lung cancers by targeting the JAK1/STAT3 signaling pathway.
Asunto(s)
Apoptosis , Benzopiranos , Butiratos , Proliferación Celular , Ensayos de Selección de Medicamentos Antitumorales , Simulación del Acoplamiento Molecular , Factor de Transcripción STAT3 , Humanos , Proliferación Celular/efectos de los fármacos , Factor de Transcripción STAT3/antagonistas & inhibidores , Factor de Transcripción STAT3/metabolismo , Benzopiranos/farmacología , Benzopiranos/química , Benzopiranos/síntesis química , Butiratos/farmacología , Butiratos/química , Butiratos/síntesis química , Apoptosis/efectos de los fármacos , Células A549 , Estereoisomerismo , Relación Dosis-Respuesta a Droga , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Relación Estructura-Actividad , Janus Quinasa 1/antagonistas & inhibidores , Janus Quinasa 1/metabolismo , Estructura Molecular , Angelica/química , Antineoplásicos Fitogénicos/farmacología , Antineoplásicos Fitogénicos/síntesis química , Antineoplásicos Fitogénicos/químicaRESUMEN
Root extracts of Ancistrocladus tectorius (AT), a shrub native to China, have been shown to have antiviral and antitumor activities, but the anti-obesity effects of AT aerial parts, mainly the leaves and stems, have not been investigated. This study is the first to investigate the anti-obesity effects and molecular mechanism of AT 70% ethanol extract in 3T3-L1 adipocytes and high-fat diet (HFD)-fed C57BL/6J mice. Treatment with AT extract inhibited lipid accumulation in 3T3-L1 cells and decreased the expression of adipogenesis-related genes. AT extract also upregulated the mRNA expression of genes related to mitochondrial dynamics in 3T3-L1 adipocytes. AT administration for 12 weeks reduced body weight and organ weights, including liver, pancreas, and white and brown adipose tissue, and improved plasma profiles such as glucose, insulin, homeostasis model assessment of insulin resistance, triglyceride (TG), and total cholesterol in HFD-fed mice. AT extract reduced HFD-induced hepatic steatosis with levels of liver TG and lipogenesis-related genes. AT extract upregulated thermogenesis-related genes such as Cidea, Pgc1α, Ucp1, Prdm16, Adrb1, and Adrb3 and mitochondrial dynamics-related genes such as Mff, Opa1, and Mfn2 in brown adipose tissue (BAT). Therefore, AT extract effectively reduced obesity by promoting thermogenesis and the mitochondrial dynamics of BAT in HFD-fed mice.