RESUMEN
Atypical L858R or other L858X mutations in the epidermal growth factor receptor (EGFR) gene, beyond the classical EGFRL858R mutation caused by c.2573 T > G, have been identified in non-small cell lung cancer (NSCLC), yet their genomic features and survival benefits with EGFR tyrosine kinase inhibitor (TKI) treatment have not been fully explored. We retrospectively enrolled 489 NSCLC patients with baseline tumor tissue/plasma samples carrying uncommon EGFRL858R (N = 124), EGFRL858Q/M (N = 17), or classical EGFRL858R mutations (N = 348). The comparison of molecular features was performed using treatment-naïve tumor tissues. Survival benefits and resistance mechanisms of first-line EGFR TKI treatment were studied in an advanced disease subcohort. NSCLCs harboring uncommon EGFRL858R had lower TP53 mutation prevalence (p = 0.04) and chromosome instability scores (p = 0.02) than those with classical EGFRL858R. Concomitant EGFRL861Q mutations were enriched in NSCLCs with EGFRL858Q/M (p < 0.01), with cooccurrence in those carrying EGFRL858M. Patients with uncommon EGFRL858R experienced improved progression-free survival (PFS) compared to those with classical EGFRL858R (median: 13.0 vs. 10.0 months, hazard ratio [HR]: 0.57, 95% confidence interval [CI]: 0.41-0.80). The association remained significant when adjusting for sex, age, histological subtype, TKI category, and anti-vascular therapy (HR: 0.55, 95% CI: 0.39-0.77). Furthermore, EGFRL858Q/M patients showed enhanced first-line PFS (vs. classical EGFRL858R, HR: 0.26, 95% CI: 0.10-0.67), potentially benefiting more from afatinib. Additionally, NSCLCs with uncommon EGFRL858R and classical EGFRL858R had similar resistance profiles to EGFR TKIs. In conclusion, NSCLCs carrying atypical EGFR L858 aberrations, which had fewer TP53 mutations and higher chromosome stability, exhibited improved PFS under first-line EGFR TKIs than those with the classical EGFRL858R.
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Carcinoma de Pulmón de Células no Pequeñas , Receptores ErbB , Neoplasias Pulmonares , Mutación , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Resistencia a Antineoplásicos/genética , Receptores ErbB/genética , Receptores ErbB/antagonistas & inhibidores , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Estudios Retrospectivos , Resultado del Tratamiento , /uso terapéuticoRESUMEN
KRAS mutation is the most frequent type of genetic mutation in non-small cell lung cancer (NSCLC), especially in lung adenocarcinoma. However, KRAS mutation can affect many biological processes and the mechanisms underlying KRAS mutation-mediate carcinogenesis in NSCLC have not been fully understood. In this research, we found that KRASG12C mutation was associated with the upregulation of T-LAK cell-originated protein kinase (TOPK), which is a well-known serine/threonine MAPK-like protein kinase implicated in tumorigenesis. The overexpression of TOPK significantly promoted the malignant phenotype of A549 cells, and TOPK silencing impaired the malignant phenotype with KRASG12C mutation. Moreover, we demonstrated that TOPK level was regulated by MAPK/ERK signalling and the transcription factor Elk1. TOPK was also found to promote the activation of NF-κB signalling in A549 cells with KRASG12C mutation via facilitating the phosphorylation of TAK1. In the in vivo tumorigenesis model, the administration of TOPK inhibitor OTS514 enhanced the anticancer effect of 5-FU, and the combinatory use of OTS514 and KRASG12C inhibitor AMG510 showed synergistic anti-tumour effect. These results suggest that KRAS-TOPK axis contributes to the progression of NSCLC and targeting this axis could synergize with anticancer effect of the existing chemotherapeutics.
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Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Carcinogénesis/genética , Carcinoma de Pulmón de Células no Pequeñas/patología , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Células Asesinas Activadas por Linfocinas/metabolismo , Células Asesinas Activadas por Linfocinas/patología , Neoplasias Pulmonares/patología , Mutación/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas p21(ras)/metabolismoRESUMEN
PURPOSE: The present meta-analysis aimed to evaluate quantitively the recent scientific evidence regarding the association between obstructive sleep apnea (OSA) and periodontitis. METHODS: Databases searched were PubMed, EMBASE, Scopus, and Web of Science. Publications were included according to the inclusion criteria. The following outcomes were evaluated: the prevalence of periodontitis, probing depth (PD), clinical attachment loss (CAL), the percentage of sites with bleeding on probing (BOP), plaque index (PI), and gingival index (GI). The statistical analysis was processed using the software STATA. RESULTS: Thirteen eligible studies comprising a total of 31,800 patients were included. The meta-analysis showed an increased prevalence of periodontitis in OSA populations compared to controls. Both PD and CAL were increased in OSA populations compared with controls. (Prevalence of periodontitis: OR 2.348; 95%CI 2.221-2.482; PD: SMD = 0.681, 95% CI: 0.062-1.301, Z = 2.61, P = 0.031; CAL: SMD = 0.694, 95% CI: 0.167-1.22, Z = 2.58, P = 0.01). The study also found significantly increased BOP in patients with OSA after heterogeneity was clarified. (SMD = 0.357, 95% CI: 0.079-0.635, Z = 2.52, P = 0.012). CONCLUSIONS: The findings suggest that OSA was associated with an increased prevalence of periodontitis.
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Periodontitis , Apnea Obstructiva del Sueño , Humanos , Periodontitis/diagnóstico , Periodontitis/epidemiología , Apnea Obstructiva del Sueño/diagnóstico , Apnea Obstructiva del Sueño/epidemiología , Índice Periodontal , PrevalenciaRESUMEN
OBJECTIVE: Periodontitis is a common inflammatory disease associated with systemic factors. Visfatin is a pleiotropic adipokine that exerts metabolic and immune functions. Studies have shown visfatin played roles in the development of periodontitis. The present study aims to compare the levels of visfatin in body fluids including serum, saliva, and gingival crevicular fluid (GCF) between periodontitis patients and healthy individuals, and to elucidate the alteration of visfatin levels after periodontal treatments. MATERIALS AND METHODS: The database searched included Pubmed, Embase, Web of Science, and Cochrane Library. According to the Eligibility criteria, the records were screened and the eligible studies were included. The methodological qualities of the included case-controlled studies were assessed according to the Newcastle-Ottawa scale (NOS). The Methodological Index for Nonrandomized Studies (MINORS) was applied for assessing the qualities of the included clinical trials. The statistical analyses were processed using STATA 15.0. RESULTS: Twenty-three studies were included in the statistical analyses. The meta-analysis showed significantly elevated visfatin levels of GCF, serum, and saliva in the periodontitis population compared with the controls (GCF: SMD = 5.201, 95% CI: 3.886-6.516, Z = 7.75, P < 0.05; Serum: SMD = 7.417, 95% CI: 3.068-11.767, Z = 3.34, P = P < 0.05; Saliva: SMD = 2.683, 95% CI: 1.202-4.163, Z = 3.34, P < 0.05). Visfatin levels of saliva serum and GCF were significantly decreased after periodontal treatment. (Saliva: SMD = -1.338, 95% CI: -2.289-0.487, Z = 39.77, P < 0.05; Serum: SMD = -2.890, 95% CI: -5.300-0.480, Z = 2.35, P < 0.05; GCF: SMD = -6.075, 95% CI: -11.032-1.117, Z = 2.40, P = 0.016; I 2 = 95.9%, P < 0.05). CONCLUSIONS: Periodontitis elevated the visfatin levels in GCF, serum, and saliva. Additionally, GCF, serum, and saliva visfatin levels could be reduced after periodontal treatment.
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Periodontitis Crónica , Periodontitis , Humanos , Nicotinamida Fosforribosiltransferasa/análisis , Nicotinamida Fosforribosiltransferasa/metabolismo , Periodontitis/terapia , Periodontitis/metabolismo , Saliva/química , Líquido del Surco Gingival/química , Estudios de Casos y Controles , Periodontitis Crónica/terapiaRESUMEN
Reported here is a new [Cu4I4] cluster-based coordination polymer, namely [Cu4I4(bib)2]n·n(DMF) (1, bib = 1,4-bis(imidazolyl)butane, DMF = N,N'-dimethylformamide), which was synthesized by the self-assemble reaction of CuI, bib and KI under solvothermal conditions. Remarkably, compound 1 shows promising photocatalytic performance toward to the degradation of MB solution under visible light irradiation. For the COPD treatment, the ELISA detection kit was conducted to determine the content of INF-γ released by the respiratory tract mucosal epithelial cells. In addition to this, the activation levels of the NF-κB signaling pathway were still need to be assessed by the real time RT-PCR after the compound treatment.
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Cobre/química , Cobre/farmacología , Interferón gamma/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/metabolismo , Animales , Catálisis , Células Epiteliales/metabolismo , Humanos , Dosificación Letal Mediana , Ratones , FN-kappa B/metabolismo , Procesos Fotoquímicos , Polímeros , Reacción en Cadena en Tiempo Real de la Polimerasa , Mucosa Respiratoria/citología , Mucosa Respiratoria/metabolismo , Transducción de Señal , Difracción de Rayos XRESUMEN
Small heat shock proteins (sHSPs), a family of the ubiquitous stress proteins in plants acting as molecular chaperones to protect other proteins from stress-induced damage, have been implicated in plant growth and development as well as plant response to environmental stress, especially heat stress. In this study, a chloroplast-localized sHSP, AsHSP26.8, was overexpressed in creeping bentgrass (Agrostis stolonifera L.) to study its role in regulating plant growth and stress response. Transgenic (TG) creeping bentgrass plants displayed arrested root development, slow growth rate, twisted leaf blades and are more susceptible to heat and salt but less sensitive to drought stress compared to wild-type (WT) controls. RNA-seq analysis revealed that AsHSP26.8 modulated the expression of genes in auxin signalling and stress-related genes such as those encoding HSPs, heat shock factors and other transcription factors. Our results provide new evidence demonstrating that AsHSP26.8 negatively regulates plant growth and development and plays differential roles in plant response to a plethora of diverse abiotic stresses.
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Agrostis/fisiología , Proteínas de Cloroplastos/metabolismo , Proteínas de Choque Térmico Pequeñas/metabolismo , Estrés Fisiológico/fisiología , Agrostis/crecimiento & desarrollo , Membrana Celular/genética , Membrana Celular/patología , Clorofila/metabolismo , Proteínas de Cloroplastos/genética , Regulación de la Expresión Génica de las Plantas , Proteínas de Choque Térmico Pequeñas/genética , Hojas de la Planta/genética , Raíces de Plantas/genética , Raíces de Plantas/crecimiento & desarrollo , Plantas Modificadas Genéticamente , Potasio/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Sodio/metabolismo , Agua/metabolismoRESUMEN
NEW FINDINGS: What is the central question of this study? Does leptin have an effect on hypoxia-induced apoptosis in human periodontal ligament cells (hPDLCs), and what is the potential underlying mechanism? What is the main finding and its importance? Hypoxia induces cell apoptosis and leptin expression in hPDLCs through the induction of hypoxia-inducible factor-1α and accumulation of reactive oxygen species (ROS). Leptin shows feedback inhibition on hypoxia-induced ROS-mediated apoptosis in hPDLCs, suggesting a new application of leptin for hypoxic damage in periodontal diseases. ABSTRACT: Hypoxia-induced apoptosis of human periodontal ligament cells (hPDLCs) is an important contributor to the progression of various periodontal diseases. Although leptin has been shown to protect connective tissue cells against hypoxia-induced injury, whether it might do so by attenuating hypoxia-induced apoptosis in hPDLCs remains unclear. Here, using CoCl2 treatment, we simulated hypoxic conditions in hPDLCs and explored whether apoptosis and reactive oxygen species (ROS) levels were related to hypoxia. After small interfering RNA (siRNA) inhibition of leptin and hypoxia-inducible factor-1α (HIF-1α), the levels of apoptosis, ROS and leptin expression were measured. We showed that in CoCl2 -treated hPDLCs, significantly higher cell apoptosis rates and ROS accumulation were observed. Cobalt chloride also increased leptin and HIF-1α expression in hPDLCs. Further investigation of the pathway demonstrated that inhibition of ROS attenuated hypoxia-induced cell apoptosis and leptin expression, whereas siRNA inhibition of leptin aggravated hypoxia-induced cell apoptosis and ROS accumulation. Hypoxia induces cell apoptosis and leptin expression in hPDLCs through the induction of ROS and HIF-1α pathways, and leptin shows feedback inhibition on ROS-mediated apoptosis in hPDLCs. These findings suggest a new application of leptin for hypoxic damage in periodontal diseases.
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Subunidad alfa del Factor 1 Inducible por Hipoxia , Ligamento Periodontal , Apoptosis , Hipoxia de la Célula/fisiología , Humanos , Hipoxia/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Leptina/metabolismo , Ligamento Periodontal/metabolismo , Especies Reactivas de Oxígeno/metabolismoRESUMEN
BACKGROUND: Systemic sclerosis (SSc) is a multisystem rheumatic disease. Orofacial manifestations are commonly in SSc but maybe usually ignored and overshadowed by other systemic complications. Multiple comparative studies have been conducted to investigate the possible links between SSc and oral manifestations. The present study aimed to investigate the oral health status in patients with SSc. METHODS: Pubmed, Embase, Web of Science, and Scopus were searched up to July 2020. Following outcomes were evaluated: Probing depth (PD), Attachment loss (AL), Bleeding on probing (BOP), Number or percentage of Sites with PD ≥ 4 mm, Prevalence of periodontitis, Number of teeth, Decayed Teeth, Missing teeth, Filled teeth, DMFT index, and the interincisal distance. Newcastle-Ottawa Scale (NOS) were applied for quality assessment. The statistical analysis was processed using the software STATA. RESULTS: 11 eligible studies were included. The maximum interincisor distance was significantly restricted in SSc patients (SMD - 1.061; 95 %CI [- 1.546, - 0.576]; Z = 4.29, P = 0.000).The prevalence of Periodontitis (OR 7.007; 95 %CI [3.529, 13.915]; Z = 5.56, P = 0.000), PD (SMD 3.101; 95 %CI [1.374, 4.829]; Z = 3.52, P = 0.000), AL(SMD 2.584; 95 %CI [0.321, 4.846]; Z = 2.24, P = 0.025), sites with PD ≥ 4mm (SMD 2.071 ; 95 %CI [0.267, 3.875]; Z = 2.25, P = 0.024) and the number of decayed teeth (SMD, 0.186; 95 %CI [0.007, 0.365]; Z = 2.04, P = 0.041) were increased significantly in SSc population in comparison with the controls. CONCLUSIONS: SSc patients have limited mouth opening, higher periodontitis prevalence, and worse periodontal status, as well as an increased number of decayed teeth. Routinely oral hygiene instruction and initial periodontal treatment is recommended for SSc patients.
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Periodontitis , Esclerodermia Sistémica , Estudios de Casos y Controles , Humanos , Periodontitis/epidemiología , Prevalencia , Esclerodermia Sistémica/complicaciones , Esclerodermia Sistémica/epidemiologíaRESUMEN
BACKGROUND: Small heat shock proteins (sHSPs) are critical for plant response to biotic and abiotic stresses, especially heat stress. They have also been implicated in various aspects of plant development. However, the acting mechanisms of the sHSPs in plants, especially in perennial grass species, remain largely elusive. RESULTS: In this study, AsHSP26.8a, a novel chloroplast-localized sHSP gene from creeping bentgrass (Agrostis stolonifera L.) was cloned and its role in plant response to environmental stress was studied. AsHSP26.8a encodes a protein of 26.8 kDa. Its expression was strongly induced in both leaf and root tissues by heat stress. Transgenic Arabidopsis plants overexpressing AsHSP26.8a displayed reduced tolerance to heat stress. Furthermore, overexpression of AsHSP26.8a resulted in hypersensitivity to hormone ABA and salinity stress. Global gene expression analysis revealed AsHSP26.8a-modulated expression of heat-shock transcription factor gene, and the involvement of AsHSP26.8a in ABA-dependent and -independent as well as other stress signaling pathways. CONCLUSIONS: Our results suggest that AsHSP26.8a may negatively regulate plant response to various abiotic stresses through modulating ABA and other stress signaling pathways.
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Agrostis/metabolismo , Proteínas de Choque Térmico Pequeñas/metabolismo , Proteínas de Plantas/metabolismo , Estrés Fisiológico , Ácido Abscísico/metabolismo , Arabidopsis , Plantas Modificadas Genéticamente , Tolerancia a la Sal , Transducción de SeñalRESUMEN
PURPOSE: The objective of the present systematic review was to compare the postoperative outcomes between envelope and triangular flaps after mandibular third molar surgery. MATERIALS AND METHODS: The PubMed, Embase, Web of Science, and Cochrane Library databases were systematically searched from the inception date to November 2018. Randomized and nonrandomized controlled trials were included if they had met certain inclusion and exclusion criteria. The predictor variable was the flap design, envelope or triangular. The outcome variables were operation time, pain, trismus, alveolar osteitis (AO) incidence, wound dehiscence, and swelling. The methodologic quality assessment was performed in accordance with the Cochrane Collaboration guidelines. The meta-analysis was performed using Review Manager, version 5.2. RESULTS: A total of 21 studies were included for qualitative synthesis, 18 of which were included in the meta-analysis. The use of envelope flaps required less operation time than triangular flaps (P < .00001; I2 = 9%). In the Pell and Gregory A and B subgroups, envelope flaps were associated with a significantly lower visual analog scale score at 3 (P = .05, I2 = 0%) and 7 (P = .02; I2 = 0%) postoperative days and with a greater postoperative interincisal distance at 7 postoperative days (P = .04; I2 = 0%). In contrast, envelope flaps were associated with a greater AO incidence in the subgroup of split-mouth randomized controlled trials (P = .001; I2 = 0%). CONCLUSIONS: Envelope flaps required a shorter operation time than triangular flaps and were associated with less postoperative pain and trismus when applied to impacted mandibular third molars of Pell and Gregory Class A or B. In contrast, triangular flaps were associated with a decreased incidence of AO compared with envelope flaps.
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Alveolo Seco , Extracción Dental , Diente Impactado , Humanos , Mandíbula , Tercer Molar , Dolor Postoperatorio , Complicaciones Posoperatorias , Colgajos Quirúrgicos , TrismoRESUMEN
Thermosensitive and imaging-traceable materials with fine-tunable lower critical solution temperature (LCST) around body temperature are highly valuable in biomedicine. However, such materials are rare because it is challenging to fine-tune the LCST and incorporate suitable imaging modalities. Herein, peptidic monodisperse polyethylene glycol (M-PEG) "combs" with fine-tunable LCST, "hot spot" fluorine-19 magnetic resonance imaging (19F MRI), thermoresponsive fluorescent imaging, and drug loading ability were developed through accurately programming their structures during solid phase peptide synthesis (SPPS). The easy availability, structural accuracy, biocompatibility, and versatility provide the M-PEG "combs" with promising prospects as thermoresponsive and imaging-traceable biomaterials for controlled drug delivery.
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Péptidos/química , Polietilenglicoles/química , Temperatura , Animales , Antibióticos Antineoplásicos/farmacología , Materiales Biocompatibles , Doxorrubicina/farmacología , Células Hep G2 , Humanos , Imagen por Resonancia Magnética , Ratones , Prueba de Estudio Conceptual , Técnicas de Síntesis en Fase SólidaRESUMEN
Oxygen deficiency is associated with various oral diseases, including chronic periodontitis, age-related alveolar bone loss, and mechanical stress-linked cell injury from orthodontic appliances. Nevertheless, our understanding of the impact of hypoxia on periodontal tissues and its biochemical mechanism is still rudimentary. The purpose of this research was to elucidate the effects of hypoxia on the apoptosis of human periodontal ligament stem cells (PDLSCs) in vitro and the underlying mechanism. Herein, we showed that cobalt chloride (CoCl2) triggered cell dysfunction in human PDLSCs in a concentration-dependent manner and resulted in cell apoptosis and oxidative stress overproduction and accumulation in PDLSCs. In addition, CoCl2 promoted mitochondrial fission in PDLSCs. Importantly, CoCl2 increased the expression of dynamin-related protein 1 (Drp1), the major regulator in mitochondrial fission, in PDLSCs. Mitochondrial division inhibitor-1, pharmacological inhibition of Drp1, not only inhibited mitochondrial fission but also protected against CoCl2-induced PDLSC dysfunction, as shown by increased mitochondrial membrane potential, increased ATP level, reduced reactive oxygen species (ROS) level, and decreased apoptosis. Furthermore, N-acety-l-cysteine, a pharmacological inhibitor of ROS, also abolished CoCl2-induced expression of Drp1 and protected against CoCl2-induced PDLSC dysfunction, as shown by restored mitochondrial membrane potential, ATP level, inhibited mitochondrial fission, and decreased apoptosis. Collectively, our data provide new insights into the role of the ROS-Drp1-dependent mitochondrial pathway in CoCl2-induced apoptosis in PDLSCs, indicating that ROS and Drp1 are promising therapeutic targets for the treatment of CoCl2-induced PDLSC dysfunction.
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Apoptosis/efectos de los fármacos , Cobalto/farmacología , GTP Fosfohidrolasas/metabolismo , Proteínas Asociadas a Microtúbulos/metabolismo , Dinámicas Mitocondriales/efectos de los fármacos , Proteínas Mitocondriales/metabolismo , Ligamento Periodontal/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Células Madre/efectos de los fármacos , Adolescente , Adulto , Células Cultivadas , Niño , Dinaminas , Femenino , Humanos , Masculino , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias/efectos de los fármacos , Mitocondrias/metabolismo , Estrés Oxidativo/efectos de los fármacos , Ligamento Periodontal/metabolismo , Transducción de Señal/efectos de los fármacos , Células Madre/metabolismo , Adulto JovenRESUMEN
BACKGROUND: This study aimed to assess the difference in serum levels of leptin and adiponectin in patients with periodontitis and in periodontally healthy individuals and evaluate the changes in circulating leptin and adiponectin after periodontal therapy. Leptin and adiponectin are the most generally studied adipokines that function as inflammatory cytokines. Although the association between periodontitis and serum levels of leptin and adiponectin has been studied extensively, the results were not consistent. METHODS: A systematic search of the Pubmed, Embase, Web of Science, and Cochrane Library up to September 2016 was conducted. The studies were screened and selected by two writers according to the specific eligibility criteria. The quality of included cross-sectional studies was assessed using the quality assessment form recommended by the Agency for Healthcare Research and Quality and Methodological Index for Nonrandomized Studies. The meta-analyses were conducted using the STATA 12.0 software. RESULTS: A total of 399 manuscripts were yielded and 25 studies were included in the present meta-analysis. Significantly elevated serum levels of leptin and decreased serum levels of adiponectin in patients with periodontitis were observed in the subgroup analysis of body mass index (BMI) <30. The overall and subgroup analyses showed no significant change in the serum levels of leptin in patients with periodontitis after periodontal treatment. The subgroup analysis of systemically healthy patients showed no significant change in serum levels of adiponectin in patients with periodontitis after periodontal treatment. CONCLUSIONS: The present meta-analysis supported elevated serum levels of leptin and decreased serum levels of adiponectin in patients with periodontitis compared with controls in the BMI <30 population. In systemically healthy patients with periodontitis, serum levels of leptin and adiponectin do not significantly change after periodontal treatment.
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Adiponectina/sangre , Leptina/sangre , Periodontitis/sangre , HumanosRESUMEN
In the catalytic core of 10-23 DNAzyme, its five adenine residues are moderate conservative, but with highly conserved functional groups like 6-amino group and 7-nitrogen atom. It is this critical conservation that these two groups could be modified for better contribution. With 2'-deoxyadenosine analogues, several functional groups were introduced at the 6-amino group of the five adenine residues. 3-Aminopropyl substituent at 6-amino group of A15 resulted in a five-fold increase of kobs. More efficient DNAzymes are expected by delicate design of the linkage and the external functional groups for this 6-amino group of A15. With this modification approach, other functional groups or residues could be optimized for 10-23 DNAzyme.
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Adenina/química , ADN Catalítico/química , Dominio CatalíticoRESUMEN
10-23 DNAzyme is a small catalytic DNA molecule. Studies on its conformation in solution are critical for understanding its catalytic mechanism and functional optimization. Based on our previous research, two fluorescent nucleoside analogues 1 and 2 were designed for the introduction of a pyrenyl group at one of the five dA residues in the catalytic core and the unpaired adenosine residue in its full-DNA substrate, respectively. Ten pyrenyl-pyrenyl pairs are formed in the DNAzyme-substrate complexes in solution for sensing the spacial positions of the five dA residues relative to the cleavage site using fluorescence spectra. The position-dependent quenching effect of pyrene emission fluorescence by nucleobases, especially the pyrenyl-pyrenyl interaction, was observed for some positions. The adenine residues in the 3'-part of the catalytic loop seem to be closer to the cleavage site than the adenine residues in the 5'-part, which is consistent with the molecular dynamics simulation result. The catalytic activities and Tm changes also confirmed the effect of the pyrenyl-nucleobase and pyrenyl-pyrenyl pair interactions. Together with functional group mutations, catalytically relevant nucleobases will be identified for understanding the catalytic mechanism of 10-23 DNAzyme.
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ADN Catalítico/química , ADN Catalítico/metabolismo , ADN de Cadena Simple/química , ADN de Cadena Simple/metabolismo , Desoxiadenosinas/química , Desoxiadenosinas/metabolismo , Conformación de Ácido Nucleico , Pirenos/química , Biocatálisis , SolucionesRESUMEN
2'-Positioned isonucleotides and enantiomers were used to evaluate the conservation of the spatial location of five adenines and two thymines in the catalytic core of 10-23 DNAzyme. The positive effect of isonucleotides at A15 and T8 along with inherent enzymatic resistance could be a tangible solution for the practical applications of 10-23 DNAzyme.
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Adenina/química , ADN Catalítico/química , ADN de Cadena Simple/química , Timina/química , Adenina/metabolismo , Biocatálisis , Dominio Catalítico , ADN Catalítico/metabolismo , ADN de Cadena Simple/metabolismo , Activación Enzimática , Simulación de Dinámica Molecular , Estereoisomerismo , Timina/metabolismoRESUMEN
10-23 DNAzyme is capable of catalytically cleaving RNA substrates with the preferred cleavage sites rAU and rGU, in which the common base pair U-dA0 forms between the substrate and the DNAzyme in the cleavage reaction. Here its conservation was studied with base modifications on dA and extra functional groups introduced. The nitrogen atom at 7- or 8-position of adenine was demonstrated to be equally important for the cleavage reaction, although it is not related to the thermal stability of the base pair. Deletion of 6-amino group led to decreased stability of the base pair and a slight slower reaction rate. Extra functional groups through 6-amino group were not favorably accommodated in the cleavage site. From these modifications at the level of functional groups, it demonstrated that the base pair U-dA0 not only contributes to the recognition and binding stability, but also it is involved in the active catalytic center by its functional groups and base stacking. This kind of chemical modifications with 7-substituted 8-aza-7-deaza-2'-deoxyadenosine at dA0 is favorable for the introduction of signal molecules for mechanistic studies and biological applications, without significant loss of the catalytic function and structural destruction.
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Adenina/química , ADN Catalítico/química , ADN Catalítico/metabolismo , ADN de Cadena Simple/química , ADN de Cadena Simple/metabolismo , Emparejamiento Base , Dominio Catalítico , Técnicas de Química Sintética , Dicroismo Circular , ADN Catalítico/síntesis química , ADN de Cadena Simple/síntesis química , Desoxiadenosinas/química , Manganeso/química , Uracilo/químicaRESUMEN
Nucleoside analogues with imidazolyl and histidinyl groups were synthesized for site-specific modification on the catalytic core of 10-23 DNAzyme. The distinct position-dependent effect of imidazolyl group was observed. Positive effect at A9 position was always observed. The pH- and Mg(2+)-dependence of the imidazolyl-modified DNAzymes suggested that imidazolyl group in 10-23 DNAzyme probably plays a dual role, its hydrogen bonding ability and spacial occupation play the favorable influence on the catalytic conformation of the modified DNAzymes. This research demonstrated that the catalytic performance of DNAzymes could be enhanced by incorporation of additional functional groups. Chemical modification is a feasible approach toward more efficient DNAzymes for therapeutic and biotechnological applications.
Asunto(s)
ADN Catalítico/metabolismo , ADN de Cadena Simple/metabolismo , Imidazoles/química , Catálisis , Dicroismo Circular , ADN Catalítico/química , ADN de Cadena Simple/química , Enlace de Hidrógeno , Concentración de Iones de Hidrógeno , Cinética , Magnesio/química , Temperatura de TransiciónRESUMEN
OBJECTIVE: To investigate the correlations between the expressions of proto-oncogenes C-myc and B-cell-specific Moloney leukemia virus integration site-1 (BMI-1), vaginal microecology, and human papillomavirus-DNA (HPV-DNA) load in patients with different cervical lesions. METHODS: A total of 51 patients with cervix squamous cell carcinoma (CSCC), 72 patients with cervical intraepithelial neoplasia (CIN) and 50 patients with normal cervix (NC) who were diagnosed or admitted between Jan. 1st 2020 and Dec. 31st 2022 at the Suzhou Hospital of Integrated Traditional Chinese and Western Medicine were selected and divided into three groups, i.e., the CSCC group, the CIN group and the NC group, for a retrospective analysis. Hybrid capture 2 (hc2) was used to detect the HPV-DNA load in each group. Immunohistochemistry was performed to detect C-myc and BMI-1 expressions in each group. The indicators of vaginal microecology in patients were compared among groups to analyze the correlations between C-myc, BMI-1 expressions, vaginal microecology and HPV-DNA load. RESULTS: The HPV-DNA load and expression levels of positive C-myc and BMI-1 in the CSCC group were all higher than those of the CIN and NC groups (P<0.05). The detection rate of lactobacillus in the CSCC group was lower than that of the CIN and NC groups. The percentages of leukocyte esterase (LE) positivity and pH ≥4.6 were higher in the CSCC group than those in the CIN and NC groups (P<0.05). The difference in the detection rate of spores among the three groups was not significant (P>0.05). Both C-myc and BMI-1 scores were positively correlated with HPV-DNA load in the 173 samples. CONCLUSION: The proto-oncogenes C-myc and BMI-1 were highly expressed in the cervical tissues of CIN and CSCC patients, whose vaginal microecology was also altered. Both may play an important role in the progression of cervical lesions.
RESUMEN
Background: In China, most of the citizens experienced SARS-CoV-2 infection since the end of 2022. The Coronavirus disease 2019 (COVID-19) pandemic affected people's physical health and also had a significant impact on mental well-being. The present study aims to discover if the experience of SARS-CoV-2 infection influences patients' anxiety toward third molar surgery in the Chinese population. Materials and methods: The present study took the form of a questionnaire survey. From January 1, 2023, to June 30, 2023, patients who went to the Stomatology Center of China-Japan Friendship Hospital (Beijing, China) for the third molar extraction were included according to the inclusion criteria. The information on COVID-19 infection and the Modified Dental Anxiety Scale (MDAS) was collected. The software SPSS 22.0 was used for the statistical analyses. Results: A total of 574 survey results were harvested in the present study. The infection rate of COVID-19 was 86.6% (p > 0.05). The Average MDAS scores between patients who had been infected with COVID-19 and patients who were never infected were not significantly different (11.65 ± 4.41 vs. 11.42 ± 4.41, p > 0.05). The subgroup analysis was conducted according to the length of time after the recovery of COVID-19 (Model 1), and the highest temperature during the infection (Model 2). In Model 1 and Model 2, the one-way ANOVA test did not find statistical significance between the groups (Model 1 p = 0.114; Model 2 p = 0.481). The MDAS scores in female patients were significantly higher than in male patients (12.29 ± 4.53 vs. 9.91 ± 3.80, p < 0.001). Patients who extracted double teeth got significantly higher MDAS scores than those who extracted single teeth before the surgery (12.03 ± 4.74 vs. 11.24 ± 4.18, p = 0.037). Conclusion: The present study did not establish a significant impact of SARS-CoV-2 infection on the anxiety levels associated with third molar surgery among Chinese patients. The potential long-term biopsychological effects of the virus warrant further investigation.