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Nanozyme catalytic therapy triggered by the tumor microenvironment (TME)-responsive enzyme-like catalytic activities is an emerging approach for tumor treatment. However, the poor catalytic efficiency of nanozymes in tumors and the toxic side effects on normal tissues limit their further development, primarily due to the limited uptake and penetration depth of nanozyme in tumor tissues. Here, a tumor-targeting TME and electric field stimuli-responsive nanozyme (AgPt@CaCO3-FA) is developed, which is capable of catalyzing the generation of ROS to induce cell death and releasing carbon monoxide (CO) specifically in tumor tissues for on-demand CO therapy and immunotherapy. Benefiting from the endogenous H2S activated NIR-II fluorescence (FL) imaging guidance, AgPt@CaCO3-FA can be delivered into the deeper site of tumor tissues resulted from the TME regulation via generated CO during the electrolysis process to improve the catalytic efficiency of nanozymes in tumors. Moreover, CO effectively relieve immunosuppression TME via reeducating tumor-supportive M2-like macrophages to tumoricidal M1-like macrophages and induce mitochondrial dysfunction by reducing mitochondrial membrane potential, triggering tumor cells apoptosis. The enzyme-like activities combined with CO therapy arouse distinct immunogenic cell death (ICD) effect. Therefore, AgPt@CaCO3-FA permits synergistic CO gas, catalytic therapy and immunotherapy, effectively eradicating orthotopic breast tumors and preventing tumor metastasis and recurrence.
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OBJECTIVE: The study aimed to evaluate the impact of Botulinum toxin A (BoNT/A) on neuropsychiatric symptoms in Parkinson's disease (PD) patients. METHODS: A total of 125 PD patients and an equal number of age- and gender-matched healthy controls were involved. Mental health status was assessed using the Cornell Medical Index (CMI) self-assessment questionnaire. Sixty-four PD patients exhibiting neuropsychiatric symptoms were selected for the controlled study and randomly grouped into treatment and control groups. The treatment group received BoNT/A injections, while the control group received a placebo. The primary outcome measures included depression scores from the CMI and the proportion of patients displaying improvement in neuropsychiatric symptoms at 8 weeks post-treatment. The secondary outcome was other CMI scores at 4, 8, and 12 weeks post-treatment. RESULTS: The outcomes revealed that PD patients had significantly higher scores in various neuropsychiatric factors compared to healthy controls. At 4 weeks post-treatment, the treatment group displayed improvements in depression and tension. At 8 weeks post-treatment, they exhibited significant reductions in depression, anxiety, sensitivity, and tension compared to the control group. Moreover, a notably higher percentage of patients in the treatment group showed improvement in neuropsychiatric symptoms compared to the control group. At 12 weeks post-treatment, the treatment group exhibited significant improvements in somatization, depression, sensitivity, and tension. CONCLUSION: PD patients commonly experience multiple neuropsychiatric symptoms, and BoNT/A has demonstrated efficacy in alleviating these symptoms. Specifically, BoNT/A was found to effectively alleviate somatization, tension, anxiety, depression, and sensitivity in PD patients.
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Background: Nirmatrelvir/Ritonavir is an orally administered anti-SARS-Cov-2 drug used in mild-to-moderate COVID-19 patients. Our retrospective cohort study aims to evaluate the efficacy and safety of Nirmatrelvir/Ritonavir in severe hospitalized patients with Omicron infection, as well as in patients at high risk for progression to critical illness in real-world settings. Methods: A total of 350 patients received Nirmatrelvir/Ritonavir while 350 matched controls did not. Patients with confirmed COVID-19 were administered Nirmatrelvir 300â mg and Ritonavir 100â mg orally twice a day for 5 days, with the medication initiated on the first day after admission. The primary endpoint of the study was a composite outcome of hospitalization or death from any cause within 28 days. Secondary endpoints included the occurrence of adverse events and the evaluation of serum levels of IL-6 and viral load. Results: We documented the mortality risk from any cause within 28 days, viral load, serum IL-6 levels, and adverse events. Nirmatrelvir/Ritonavir reduced the 28-day risk of all-cause mortality by 86% (P = .011, hazard ratio (HR) = 0.14, 95% confidence interval (CI) = 0.03, 0.64). At baseline, the serum level of IL-6 was significantly higher in the antiviral treatment group compared to the control group (P < .001), but no significant difference (P = .990) was found between the two groups at discharge. In CKD patients undergoing hemodialysis, no significant worsening of renal function was observed in the Nirmatrelvir/Ritonavir treatment group compared to the control group. Conclusion: Nirmatrelvir/Ritonavir may reduce the 28-day risk of all-cause mortality in critically ill patients with COVID-19 and in patients at high risk for critical disease progression.
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Antivirales , Tratamiento Farmacológico de COVID-19 , COVID-19 , Enfermedad Crítica , Progresión de la Enfermedad , Ritonavir , SARS-CoV-2 , Humanos , Ritonavir/uso terapéutico , Ritonavir/efectos adversos , Masculino , Femenino , Estudios Retrospectivos , Persona de Mediana Edad , Anciano , Antivirales/uso terapéutico , Antivirales/efectos adversos , COVID-19/mortalidad , COVID-19/complicaciones , Hospitalización/estadística & datos numéricos , Resultado del Tratamiento , Carga Viral , Combinación de MedicamentosRESUMEN
OBJECTIVE: To explore the expression of the ten eleven translocation (TET) 2 protein in early esophageal squamous cell carcinoma (EESCC), precancerous lesions, and cell lines and to evaluate the effect of TET2 on the functional behavior of EC109 esophageal cancer cells. METHODS: Thirty-one samples of EESCC and precancerous lesions collected via endoscopic submucosal dissection at Taihe Hospital, Shiyan, from February 1, 2017, to February 1, 2019, were analyzed. The study involved evaluating TET2 expression levels in lesion tissue and adjacent normal epithelium, correlating these with clinical pathological features. Techniques including 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide, cell scratch assays, flow cytometry for propidium iodide (PI) staining, Hoechst 333258/PI double staining, and nude mouse tumorigenesis experiments were employed to assess the effect of TET2 on the proliferation, migration, cell cycle, apoptosis, and tumorigenic ability of esophageal cancer cells. RESULTS: TET2 expression was notably reduced in early esophageal cancer tissue and correlated with tumor invasion depth (P < 0.05). Overexpression of TET2 enhanced the proliferation and migration of esophageal cancer cells, increased the cell population in the G0 phase, decreased it in the S phase, and intensified cell necrosis (P < 0.05). There was a partial increase in tumorigenic ability (P = 0.087). CONCLUSION: TET2 downregulation in ESCC potentially influences the necrosis, cell cycle, and tumorigenic ability of esophageal cancer cells, suggesting a role in the onset and progression of esophageal cancer.
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Proteínas de Unión al ADN , Dioxigenasas , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Proteínas Proto-Oncogénicas , Animales , Femenino , Humanos , Masculino , Ratones , Persona de Mediana Edad , Apoptosis , Línea Celular Tumoral , Movimiento Celular , Proliferación Celular , Dioxigenasas/genética , Dioxigenasas/metabolismo , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética , Regulación hacia Abajo , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/metabolismo , Neoplasias Esofágicas/genética , Carcinoma de Células Escamosas de Esófago/metabolismo , Carcinoma de Células Escamosas de Esófago/patología , Carcinoma de Células Escamosas de Esófago/genética , Regulación Neoplásica de la Expresión Génica , Ratones Desnudos , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Proto-Oncogénicas/genéticaRESUMEN
Single-atom nanozymes (SAzymes) with atomically dispersed active sites are potential substitutes for natural enzymes. A systematic study of its multiple functions can in-depth understand SAzymes's nature, which remains elusive. Here, we develop a novel ultrafast synthesis of sputtered SAzymes by in situ bombarding-embedding technique. Using this method, sputtered copper (Cu) SAzymes (CuSA) is developed with unreported unique planar Cu-C3 coordinated configuration. To enhance the tumor-specific targeting, we employ a bioorthogonal approach to engineer CuSA, denoted as CuSACO. CuSACO not only exhibits minimal off-target toxicity but also possesses exceptional ultrahigh catalase-, oxidase-, peroxidase-like multienzyme activities, resulting in reactive oxygen species (ROS) storm generation for effective tumor destruction. Surprisingly, CuSACO can release Cu ions in the presence of glutathione (GSH) to induce cuproptosis, enhancing the tumor treatment efficacy. Notably, CuSACO's remarkable photothermal properties enables precise photothermal therapy (PTT) on tumors. This, combined with nanozyme catalytic activities, cuproptosis and immunotherapy, efficiently inhibiting the growth of orthotopic breast tumors and gliomas, and lung metastasis. Our research highlights the potential of CuSACO as an innovative strategy to utilize multiple mechanism to enhance tumor therapeutic efficacy, broadening the exploration and development of enzyme-like behavior and physiological mechanism of action of SAzymes.
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Cobre , Inmunoterapia , Terapia Fototérmica , Cobre/química , Cobre/farmacología , Humanos , Animales , Catálisis , Ratones , Especies Reactivas de Oxígeno/metabolismo , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular TumoralRESUMEN
Multidrug resistance is a primary factor in the poor response to chemotherapy and subsequent death in gastric cancer patients. However, the molecular mechanisms involved remain unclear. In this study, the high expression of special AT-rich sequence binding protein 1 (SATB1) in gastric cancer was found to be associated with reduced sensitivity to various chemotherapy drugs. Our results demonstrate that SATB1 can promote chemotherapy resistance in gastric cancer in vitro and in vivo. SATB1 exerts its effect by enhancing the activity of multiple ATP-binding cassette (ABC) transporters (P-glycoprotein, multidrug resistance-associated protein, and breast cancer resistance protein) in gastric cancer cell lines. We also found that SATB1 affects ABC transporters by altering the subcellular localization of the ABC transporter rather than its expression. Subsequently, we confirmed that Ezrin binds to various ABC transporters and affects their subcellular localization. In addition, we found that SATB1 can also bind to the Ezrin promoter and regulate its expression. In the present study, we elucidate the mechanism of SATB1-mediated multidrug resistance in gastric cancer, providing a basis for SATB1 as a potential target for reversal of resistance.
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Proteínas de Unión a la Región de Fijación a la Matriz , Neoplasias Gástricas , Humanos , Transportadoras de Casetes de Unión a ATP/metabolismo , Transportador de Casetes de Unión a ATP, Subfamilia G, Miembro 2 , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/genética , Proteínas de Unión a la Región de Fijación a la Matriz/genética , Proteínas de Unión a la Región de Fijación a la Matriz/metabolismo , Resistencia a Antineoplásicos/genética , Proteínas de Neoplasias/metabolismo , Resistencia a Múltiples Medicamentos/genética , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/metabolismo , Proteínas Asociadas a Resistencia a Múltiples Medicamentos/farmacologíaRESUMEN
Adipose tissue remodelling is considered a critical pathophysiological hallmark of obesity and related metabolic diseases. Berberine (BBR), a natural isoquinoline alkaloid, has potent anti-hyperlipidaemic and anti-hyperglycaemic effects. This study aimed to explore the role of BBR in modulating adipose tissue remodelling and the underlying mechanisms. BBR protected high fat diet (HFD)-fed mice against adiposity, insulin resistance and hyperlipidemia. BBR alleviated adipose tissue inflammation and fibrosis by inhibiting macrophage infiltration, pro-inflammatory macrophage polarization and the abnormal deposition of extracellular matrix, and the effect was mediated by BBR directly binding and activating the deacetylase Sirtuin 3 (SIRT3) and suppressing the activation of the mitogen-activated protein kinases and nuclear factor-κB signalling pathways. Furthermore, BBR decreased microRNA-155-5p secretion by macrophages, which in turn ameliorated liver injury. Moreover, BBR mitigated inflammatory responses in both LPS-stimulated macrophages and TNF-α-treated adipocytes and suppressed macrophage migration towards adipocytes by activating SIRT3. Collectively, this study revealed that BBR improved adipose tissue remodelling, and subsequently inhibited the secretion of microRNA-155-5p by macrophages, which alleviated adiposity, insulin resistance and liver injury in obese mice. The modulation of adipose tissue remodelling by activating SIRT3 could contribute to the anti-hyperlipidemic and anti-hyperglycemic effects of BBR.
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Berberina , Resistencia a la Insulina , MicroARNs , Sirtuina 3 , Tejido Adiposo , Animales , Berberina/farmacología , Berberina/uso terapéutico , Dieta Alta en Grasa , Inflamación , Ratones , MicroARNs/farmacología , Obesidad/tratamiento farmacológico , Obesidad/metabolismoRESUMEN
AIM: This study aimed to determine whether periodontitis in early pregnancy and periodontal therapy during gestation affect the incidence of gestational diabetes mellitus (GDM) through a population-based clinical study. MATERIALS AND METHODS: Subjects without periodontitis at 1-4 weeks of gestation who met our inclusion criteria were enrolled in the non-periodontitis group. Periodontitis patients who agreed or refused to receive periodontal therapy during pregnancy were separately enrolled in the periodontitis treated or untreated group. At 12-16 weeks of gestation, gingival crevicular fluid (GCF) and venous blood were collected for analyses of bacterial species and serum inflammatory mediators, respectively. At 24-28 weeks of gestation, GDM patients were identified by oral glucose tolerance tests. The association tests were performed using Chi-squared statistics and regression analyses. RESULTS: The complete data of 3523 pregnant women were recorded during the study period. GDM incidence among the untreated periodontitis participants (84/749, 11.21%) was significantly higher than that among the non-periodontitis participants (108/2255, 4.79%) (p < .05), and periodontal treatment during gestation reduced the incidence from 11.21% (untreated group) to 7.32% (38/519, treated group) (p < .05). Based on multiple logistic regression analyses, it was found that periodontitis in early pregnancy was associated with GDM, and three-step regression analyses showed that Porphyromonas gingivalis (P. gingivalis) and the serum TNF-α and IL-8 levels played a role in the association between untreated periodontitis and GDM. Furthermore, Pearson's correlation test indicated that the existence of P. gingivalis in GCF was positively correlated with high serum levels of these two inflammatory mediators. CONCLUSIONS: This study establishes a connection between periodontitis in early pregnancy and GDM and demonstrates that the presence of P. gingivalis is associated with high levels of inflammatory mediators in serum, and thereby may contribute to the development of GDM. In-depth mechanistic studies are needed to further support these findings.
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Diabetes Gestacional , Periodontitis , Diabetes Gestacional/epidemiología , Femenino , Líquido del Surco Gingival , Prueba de Tolerancia a la Glucosa , Humanos , Periodontitis/complicaciones , Periodontitis/epidemiología , Embarazo , Factor de Necrosis Tumoral alfaRESUMEN
Intestinal epithelial cells are an essential barrier in human gastrointestinal tract, and healing of epithelial wound is a key process in many intestinal diseases. α-Lipoic acid (ALA) was shown to have antioxidative and anti-inflammatory effects, which could be helpful in intestinal epithelial injury repair. The effects of ALA in human colonic epithelial cells NCM460 and human colorectal adenocarcinoma cells Caco-2 were studied. ALA significantly promoted NCM460 and Caco-2 migration, increased mucosal tight junction factors ZO-1 and OCLN expression, and ALA accelerated cell injury repair of both cells in wound healing assay. Western blot analysis indicated that ALA inhibited a variety of mitogen-activated protein kinase (MAPK) signaling pathways in the epithelial cells. In conclusion, ALA was beneficial to repair of intestinal epithelial injury by regulating MAPK signaling pathways.
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Mucosa Intestinal , Sistema de Señalización de MAP Quinasas , Ácido Tióctico , Células CACO-2 , Células Epiteliales/metabolismo , Humanos , Mucosa Intestinal/lesiones , Mucosa Intestinal/metabolismo , Intestinos/patología , Ácido Tióctico/farmacologíaRESUMEN
Dynamin-Related-Protein 1 (DRP1) critically regulates mitochondrial and peroxisomal fission in multicellular organisms. However, the impact of DRP1 on other organelles, especially its direct influence on ER functions remains largely unclear. Here, we report that DRP1 translocates to endoplasmic reticulum (ER) in response to ß-adrenergic stimulation. To further investigate the function of DRP1 on ER-lipid droplet (LD) dynamics and the metabolic subsequences, we generated an adipose tissue-specific DRP1 knockout model (Adipo-Drp1flx/flx ). We found that the LDs in adipose tissues of Adipo-Drp1flx/flx mice exhibited more unilocular morphology with larger sizes, and formed less multilocular structures upon cold exposure. Mechanistically, we discovered that abnormal LD morphology occurs because newly generated micro-LDs fail to dissociate from the ER due to DRP1 ablation. Conversely, the ER retention of LDs can be rescued by the overexpressed DRP1 in the adipocytes. The alteration of LD dynamics, combined with abnormal mitochondrial and autophagy functions in adipose tissue, ultimately lead to abnormalities in lipid metabolism in Adipo-Drp1flx/flx mice.
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Tejido Adiposo/metabolismo , Dinaminas/metabolismo , Retículo Endoplásmico/metabolismo , Gotas Lipídicas/metabolismo , Células 3T3 , Adipocitos/metabolismo , Animales , Autofagia/fisiología , Línea Celular , Células HEK293 , Humanos , Metabolismo de los Lípidos/fisiología , Masculino , Ratones , Mitocondrias/metabolismo , Dinámicas Mitocondriales/fisiología , Proteínas Mitocondriales/metabolismoRESUMEN
Long noncoding RNAs are important regulators of gene expression in innate immune responses. Antisense IL-7 (IL-7-AS) is a newly discovered long noncoding RNA in human and mouse that has been reported to regulate the expression of IL-6. However, the potential function of IL-7-AS in innate immune system is not fully understood. In this study, we found that the expression of IL-7-AS is primarily dependent on the NF-κB and MAPK signaling pathways in macrophages and intestinal epithelial cells. Functionally, IL-7-AS promotes the expression of several inflammatory genes, including CCL2, CCL5, CCL7, and IL-6, in cells in response to LPS. Specifically, IL-7-AS physically interacts with p300 to regulate histone acetylation levels around the promoter regions of these gene loci. Moreover, IL-7-AS and p300 complex modulate the assembly of SWI/SNF complex to the promoters. IL-7-AS regulates chemotaxis activity of monocytes to intestine epithelial cells with involvement of CCL2. Therefore, our data indicate a new promoting role for NF-κB/MAPK-responsive IL-7-AS in the transcriptional regulation of inflammatory genes in the innate immune system although modulation of histone acetylation around the promoters of related genes.
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Ensamble y Desensamble de Cromatina/genética , Histonas/genética , Inflamación/genética , Interleucina-7/genética , ARN Largo no Codificante/genética , Transcripción Genética/genética , Acetilación , Animales , Línea Celular , Línea Celular Tumoral , Femenino , Células HEK293 , Humanos , Inmunidad Innata/genética , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Regiones Promotoras Genéticas/genética , Células RAW 264.7 , Transducción de Señal/genética , Células U937RESUMEN
BACKGROUND: Early diagnosis of anastomotic leakage (AL) after rectal surgery can reduce the adverse effects of AL, thereby reducing morbidity and mortality. Currently, there are no accepted indicators or effective scoring systems that can clearly identify patients at risk of anastomotic leakage. METHODS: A prospective study with assessment of the diagnostic accuracy of oxidative stress level (CAT, SOD, MDA) in serum and drain fluid compared to white blood cell count (WBC), C-reactive protein (CRP), and neutrophil percentage (NEUT) in prediction of AL in patients undergoing elective rectal surgery with anastomosis. RESULTS: Most of the oxidative stress indicators we detected are of considerable significance in the diagnosis of anastomotic leakage. The level of MDA on postoperative day (POD)3 (areas under the curve (AUC): 0.831) and POD5 (AUC: 0.837) in the serum and on POD3 (AUC: 0.845) in the drain fluid showed the same excellent diagnostic accuracy as the level of CRP on the POD3 (AUC: 0.847) and POD5 (AUC: 0.896). CONCLUSIONS: The overall level of oxidative stress in serum and drain fluid is a reliable indicator for the early diagnosis of anastomotic leakage after rectal surgery. More specifically, among the redox indicators analyzed, MDA has almost the same predictive value as CRP, which provides another useful biomarker for the early diagnosis of anastomotic leakage.
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Anastomosis Quirúrgica/efectos adversos , Fuga Anastomótica/metabolismo , Estrés Oxidativo , Neoplasias del Recto/metabolismo , Anciano , Área Bajo la Curva , Biomarcadores/metabolismo , Procedimientos Quirúrgicos del Sistema Digestivo/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Oxidación-Reducción , Periodo Posoperatorio , Estudios Prospectivos , Curva ROC , Neoplasias del Recto/cirugía , Recto/cirugía , Reproducibilidad de los Resultados , Riesgo , Factores de TiempoRESUMEN
OBJECTIVE: To explore the value of the heart rate, body temperature, and respiratory rate in the early prediction of anastomotic leakage after rectal cancer surgery. METHODS: Clinical data from patients with rectal cancer who underwent anterior rectal resection in the Department of Gastroenterology, Renmin Hospital of Wuhan University, from January 2017 to December 2019 were collected and analyzed retrospectively. Based on the occurrence of anastomotic leakage after surgery, the patients were divided into two groups: those with and without anastomotic leakage. The quantitative values of the heart rate, body temperature, and respiration rate at day 7 postsurgery were compared between the two groups. The ROC curve was used to analyze their role in the early prediction of anastomotic leakage. RESULTS: Among 441 patients with rectal cancer, 30 (6.81%) had clinical anastomotic leakage and were diagnosed at 7 ± 3 days postsurgery. Within 7 days postsurgery, the heart rate, body temperature, and respiratory rate in the anastomotic leakage group were higher than those in the nonanastomotic leakage group. The differences in heart rate (1-5 d), body temperature (2-7 d), and respiratory rate (1-7 d) were statistically significant (P < 0.05). The three ROC curves were drawn, respectively. The predictive value of the heart rate is greatest at days 2-3 postsurgery. The predictive value of the body temperature is greatest at days 4-6 postsurgery. The predictive value of the respiratory rate is best at days 1-4 postsurgery. CONCLUSION: The changes of vital signs (heart rate, body temperature, and respiratory rate) have a certain value in the early prediction of anastomotic leakage after rectal cancer surgery. Observation of postoperative vital signs at 7 days postsurgery is helpful for the early diagnosis of anastomotic leakage.
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Neoplasias del Recto , Frecuencia Respiratoria , Fuga Anastomótica/diagnóstico , Temperatura Corporal , Detección Precoz del Cáncer , Frecuencia Cardíaca , Humanos , Neoplasias del Recto/cirugía , Estudios Retrospectivos , Factores de RiesgoRESUMEN
The establishment of the epigenetic mark H4K20me1 (monomethylation of H4K20) by PR-Set7 during G2/M directly impacts S-phase progression and genome stability. However, the mechanisms involved in the regulation of this event are not well understood. Here we show that SirT2 regulates H4K20me1 deposition through the deacetylation of H4K16Ac (acetylation of H4K16) and determines the levels of H4K20me2/3 throughout the cell cycle. SirT2 binds and deacetylates PR-Set7 at K90, modulating its chromatin localization. Consistently, SirT2 depletion significantly reduces PR-Set7 chromatin levels, alters the size and number of PR-Set7 foci, and decreases the overall mitotic deposition of H4K20me1. Upon stress, the interaction between SirT2 and PR-Set7 increases along with the H4K20me1 levels, suggesting a novel mitotic checkpoint mechanism. SirT2 loss in mice induces significant defects associated with defective H4K20me1-3 levels. Accordingly, SirT2-deficient animals exhibit genomic instability and chromosomal aberrations and are prone to tumorigenesis. Our studies suggest that the dynamic cross-talk between the environment and the genome during mitosis determines the fate of the subsequent cell cycle.
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Ciclo Celular/fisiología , Inestabilidad Genómica , Sirtuina 2/metabolismo , Acetilación , Secuencia de Aminoácidos , Animales , Transformación Celular Neoplásica/genética , Cromatina/metabolismo , Daño del ADN/genética , Técnicas de Inactivación de Genes , Células HeLa , N-Metiltransferasa de Histona-Lisina/metabolismo , Histonas/metabolismo , Humanos , Puntos de Control de la Fase M del Ciclo Celular/fisiología , Metilación , Ratones , Ratones Noqueados , Mitosis , Unión Proteica , Sirtuina 2/genéticaRESUMEN
A novel coronavirus disease (COVID-19), caused by infection with SARS-CoV-2, has swept across 31 provinces in China and over 40 countries worldwide. The transition from first symptoms to acute respiratory distress syndrome (ARDS) is highly likely to be due to uncontrolled cytokine release. There is an urgent need to identify safe and effective drugs for treatment. Chloroquine (CQ) exhibits a promising inhibitory effect. However, the clinical use of CQ can cause severe side effects. We propose that hydroxychloroquine (HCQ), which exhibits an antiviral effect highly similar to that of CQ, could serve as a better therapeutic approach. HCQ is likely to attenuate the severe progression of COVID-19, inhibiting the cytokine storm by suppressing T cell activation. It has a safer clinical profile and is suitable for those who are pregnant. It is cheaper and more readily available in China. We herein strongly urge that clinical trials are performed to assess the preventive effects of HCQ in both disease infection and progression.
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Infecciones por Coronavirus/tratamiento farmacológico , Hidroxicloroquina/uso terapéutico , Neumonía Viral/tratamiento farmacológico , Betacoronavirus , COVID-19 , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Síndrome de Liberación de Citoquinas/prevención & control , Progresión de la Enfermedad , Humanos , Hidroxicloroquina/efectos adversos , Activación de Linfocitos/efectos de los fármacos , Pandemias , Síndrome de Dificultad Respiratoria/tratamiento farmacológico , Síndrome de Dificultad Respiratoria/prevención & control , Síndrome de Dificultad Respiratoria/virología , SARS-CoV-2 , Linfocitos T/efectos de los fármacos , Tratamiento Farmacológico de COVID-19RESUMEN
[This corrects the article DOI: 10.1371/journal.pbio.2000374.].
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Sirtuin genes have been associated with aging and are known to affect multiple cellular pathways. Sirtuin 2 was previously shown to modulate proteotoxicity associated with age-associated neurodegenerative disorders such as Alzheimer and Parkinson disease (PD). However, the precise molecular mechanisms involved remain unclear. Here, we provide mechanistic insight into the interplay between sirtuin 2 and α-synuclein, the major component of the pathognomonic protein inclusions in PD and other synucleinopathies. We found that α-synuclein is acetylated on lysines 6 and 10 and that these residues are deacetylated by sirtuin 2. Genetic manipulation of sirtuin 2 levels in vitro and in vivo modulates the levels of α-synuclein acetylation, its aggregation, and autophagy. Strikingly, mutants blocking acetylation exacerbate α-synuclein toxicity in vivo, in the substantia nigra of rats. Our study identifies α-synuclein acetylation as a key regulatory mechanism governing α-synuclein aggregation and toxicity, demonstrating the potential therapeutic value of sirtuin 2 inhibition in synucleinopathies.
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Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/patología , Sirtuina 2/metabolismo , alfa-Sinucleína/toxicidad , 1-Metil-4-fenil-1,2,3,6-Tetrahidropiridina , Acetilación/efectos de los fármacos , Animales , Autofagia/efectos de los fármacos , Membrana Celular/efectos de los fármacos , Membrana Celular/metabolismo , Células Cultivadas , Corteza Cerebral/patología , Modelos Animales de Enfermedad , Neuronas Dopaminérgicas/efectos de los fármacos , Neuronas Dopaminérgicas/metabolismo , Eliminación de Gen , Técnicas de Silenciamiento del Gen , Células HEK293 , Humanos , Lisina/metabolismo , Ratones Endogámicos C57BL , Ratones Noqueados , Mutación/genética , Neuroprotección/efectos de los fármacos , Agregado de Proteínas/efectos de los fármacos , Unión ProteicaRESUMEN
A less invasive endoscopic therapy has been used as a routine treatment for superficial esophageal squamous cell carcinoma (SESCC). However, lymph node metastasis (LNM) in SESCC limits the effectiveness of this medical procedure. This meta-analysis aimed to screen the risk factors for LNM in SESCC in Asia to provide evidence for clinicians in selecting treatment. We searched the main reference databases for research involving patients who received esophagectomy (open or minimally invasive) with lymph node dissection for SESCC. Meta-analysis was performed using RevMan 5.3 software. Twenty studies including 3983 patients were obtained in this analysis. The meta-analysis showed that tumor size, macroscopic type of tumor, degree of differentiation, depth of tumor invasion, and lymphovascular involvement are risk factors of LNM in SESCC, whereas age, sex, and tumor location showed no association with LNM. Five variables were screened as predictive factors for LNM in SESCC. The incidence of LNM in SESCC is not rare, and the physicians must be careful when making clinical decisions.
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Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Neoplasias de Cabeza y Cuello , Asia , Neoplasias Esofágicas/cirugía , Carcinoma de Células Escamosas de Esófago/cirugía , Esofagectomía , Humanos , Escisión del Ganglio Linfático , Ganglios Linfáticos/cirugía , Metástasis Linfática , Invasividad Neoplásica , Estudios Retrospectivos , Factores de RiesgoRESUMEN
Obesity is increasing at an alarming rate worldwide, which is characterized by the excessive accumulation of triglycerides in adipocytes. Emerging evidence has demonstrated that macroautophagy and chaperone-mediated autophagy (CMA) regulate lipid mobilization and play a key role in energy balance. Sirtuin 3 (SIRT3) is an NAD+-dependent deacetylase, which is important in regulating macroautophagy and lipid metabolism. It is still unknown whether SIRT3 modulates macroautophagy and CMA in adipocytes. The current study found that macroautophagy was dynamically regulated during 3T3-L1 adipocyte differentiation, which coincided with SIRT3 expression. In mature adipocytes, overexpression of SIRT3 activated macroautophagy, mainly on lipid droplets (LDs), through activating the AMP-activated protein kinase (AMPK)-unc-51-like kinase 1 (ULK1) pathway, which in turn resulting in smaller LD size and reduced lipid accumulation. Moreover, SIRT3 overexpression induced the formation of perilipin-1 (PLN1)-heat shock cognate 71 kDa protein (HSC70)-lysosome-associated membrane protein 2 (LAMP2) complex, to activate CMA and cause the instability of LDs in adipocytes. In summary, we found SIRT3 is a positive regulator of macroautophagy and CMA in adipocytes, which might be a promising therapeutic target for treatment of obesity and its related metabolic dysfunction.
Asunto(s)
Proteínas Quinasas Activadas por AMP/metabolismo , Adipocitos/metabolismo , Autofagia , Movilización Lipídica , Sirtuina 3/metabolismo , Células 3T3-L1 , Adipocitos/citología , Adipogénesis , Animales , Activación Enzimática , RatonesRESUMEN
The zinc finger transcription factor Crz1 is an important downstream regulator of calcium-dependent signal transduction pathways in many organisms. The function of Crz1 in the wheat-head blight pathogen Fusarium graminearum remains unclear. In this study, we identified and functionally characterised FgCrz1A, a potential ortholog of yeast Crz1. The deletion mutant ΔFgCrz1A exhibited slower hyphal growth on basic medium, and conidia formation and sexual reproduction were completely blocked. ΔFgCrz1A also displayed increased sensitivity to metal cations Ca2+, Mg2+, Mn2+ and Li+, but decreased sensitivity to Zn2+. Unexpectedly, the deletion mutant was more resistant to osmotic stress and cell wall-damaging agents than the wild-type fungus. Pathogenicity assays showed that virulence of the mutant was dramatically decreased on flowering wheat heads and corn silks, consistent with the observed reduction in deoxynivalenol production. Moreover, GFP-fused FgCrz1A was mainly localised in the nucleus, and was required for transcriptional induction of abaA and wetA that are involved in conidiogenesis, as well as genes of the MAT locus during sexual reproduction, and TRI genes responsible for deoxynivalenol biosynthesis. Taken together, the results indicate that FgCrz1A plays critical roles not only in regulating fungal development, secondary metabolism and virulence in F. graminearum, but also in multiple stress responses.