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OBJECTIVE: Secretoneurin may play a brain-protective role. We aim to discover the relationship between serum secretoneurin levels and severity plus neurological outcome after intracerebral hemorrhage (ICH). METHODS: In this prospective cohort study, serum secretoneurin levels were measured in 110 ICH patients and 110 healthy controls. Glasgow Coma Scale (GCS) and hematoma volume were used to assess stroke severity. Poor prognosis was defined as Glasgow Outcome Scale (GOS) scores of 1-3 at 90 days after ICH. A multivariate logistic regression model was constructed to determine independent correlation of serum secretoneurin levels with severity and poor prognosis. Under receiver operating characteristic (ROC) curve, prognostic ability of serum secretoneurin levels was assessed. Restricted cubic spline (RCS) model and subgroups analysis were used for discovering association of serum secretoneurin levels with risk of poor prognosis. Calibration curve and decision curve were evaluated to confirm performance of nomogram. RESULTS: Serum secretoneurin levels of patients were significantly higher than those of healthy controls. Serum secretoneurin levels of patients were independently correlated with GCS scores and hematoma volume. There were 42 patients with poor prognosis at 90 days following ICH. Serum secretoneurin levels were significantly higher in patients with poor outcome than in those with good outcome. Under the ROC curve, serum secretoneurin levels significantly differentiated poor outcome. Serum secretoneurin levels ≥ 22.8 ng/mL distinguished patients at risk of poor prognosis at 90 days with a sensitivity of 66.2% and a specificity of 81.0%. Besides, serum secretoneurin levels independently predicted a 90-day poor prognosis. Subgroup analysis showed that serum secretoneurin levels had non-significant interactions with other variables. The nomogram, including independent prognostic predictors, showed reliable prognosis capability using calibration curve and decision curve. Area under the curve of the predictive model was significantly higher than those of GCS scores and hematoma volume. CONCLUSION: Serum secretoneurin levels are strongly related to ICH severity and poor prognosis at 90 days after ICH. Thus, serum secretoneurin may be a promising prognostic biomarker in ICH.
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Biomarcadores , Hemorragia Cerebral , Humanos , Masculino , Hemorragia Cerebral/sangre , Hemorragia Cerebral/diagnóstico , Femenino , Persona de Mediana Edad , Pronóstico , Anciano , Biomarcadores/sangre , Estudios Prospectivos , Neuropéptidos/sangre , Secretogranina II/sangre , Escala de Coma de Glasgow , Estudios de Cohortes , Adulto , Curva ROC , Escala de Consecuencias de GlasgowRESUMEN
Receptor-interacting protein kinase-3 (RIP-3) is a key component for inducing necroptosis following acute brain injury. Purpose of this study is to unveil whether serum RIP-3 levels are related to severity and clinical outcomes after human severe traumatic brain injury (sTBI). In this two-center prospective cohort study, serum RIP-3 levels were detected in 127 healthy controls coupled with 127 sTBI patients. The prognostic indicators encompassed posttraumatic 180-day mortality, overall survival and poor prognosis (defined as extended Glasgow outcome scale scores of 1-4). The prognosis associations were verified via multivariate analysis. There was a significant incremental serum RIP-3 levels in patients with sTBI, relative to the controls. RIP-3 levels of patients were independently correlated with Rotterdam Computed Tomography (CT) scores and Glasgow coma scale (GCS) scores, as well as were independently predictive of mortality, overall survival and poor prognosis. Mortality and poor prognosis were effectively predicted by serum RIP-3 levels under the receiver operating characteristic curve. Linear relationships between RIP-3 levels and their risks were verified. Mortality and poor prognosis models of serum RIP-3 levels combined with GCS and Rotterdam CT scores displayed efficient predictive abilities. The two models were graphically represented, which were of clinical stability and value by employing the calibration and decision curves. Increased serum RIP-3 levels after sTBI are closely linked to heightened trauma severity and poor prognosis, signifying that serum RIP-3 may be an encouraging biomarker for evaluating severity and predicting clinical outcome of sTBI.
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Biomarcadores , Lesiones Traumáticas del Encéfalo , Proteína Serina-Treonina Quinasas de Interacción con Receptores , Humanos , Masculino , Femenino , Persona de Mediana Edad , Pronóstico , Adulto , Lesiones Traumáticas del Encéfalo/sangre , Lesiones Traumáticas del Encéfalo/mortalidad , Lesiones Traumáticas del Encéfalo/diagnóstico , Biomarcadores/sangre , Estudios Prospectivos , Proteína Serina-Treonina Quinasas de Interacción con Receptores/sangre , Anciano , Escala de Coma de Glasgow , Estudios de Cohortes , Adulto JovenRESUMEN
Xanthine oxidase (XO) may be involved in the induction of oxidative stress and inflammation. We measured serum XO levels at multiple days to determine whether it is associated with the severity and prognosis of severe traumatic brain injury (sTBI). In this prospective cohort study, we quantified serum XO levels in 112 sTBI patients and 112 controls. Serum XO levels of patients were measured at admission and at days 1, 3, 5, 7, and 10 after sTBI. Extended Glasgow outcome scale scores of 1-4 at post-trauma 180 days were defined as a poor prognosis. Multivariate analysis was employed to determine the relationship between poor prognosis and serum XO levels at multiple days. Serum XO levels were significantly increased at admission among patients, afterwards elevated gradually, peaked at day 3, and then diminished gradually until day 10, and were substantially higher during 10 days in patients than in controls. Serum XO levels at 6 different days were all correlated with admission Rotterdam computed tomography (CT) scores and Glasgow coma scale (GCS) scores. Serum XO levels at 6 different days were all substantially higher in patients with poor prognosis than in those with good prognosis. Serum XO levels at days 7 and 10, but not at days 1, 3, and 5, had significantly lower area under receiver operating characteristic (AUC) than those at admission. Serum XO levels at admission and at days 1 and 3, but not at day 5, were independently associated with 180-day poor prognosis. Prognostic prediction model containing GCS scores, Rotterdam CT scores, and serum XO levels at admission (or at days 1 and 3) showed substantially higher AUC than GCS scores and Rotterdam CT scores alone. The models were visually described using nomograms, which were comparatively stable under calibration curve and were relatively of clinical benefit under decision curve. Elevated serum XO levels during early period of sTBI are more closely associated with trauma severity and clinical adverse outcomes, assuming that serum XO may serve as a potential prognostic biomarker in sTBI.
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Lesiones Traumáticas del Encéfalo , Lesiones Encefálicas , Humanos , Xantina Oxidasa , Estudios Prospectivos , Pronóstico , Escala de Coma de GlasgowRESUMEN
The primary aim of the current study was to probe the longitudinal relationships between family dysfunction (FD) and adolescent Internet addiction (IA), as well as the group difference between only child and non-only child. Data were from a three-wave longitudinal data of 1301 Chinese adolescents, collected when adolescents were at Grade 7, Grade 8, and Grade 9. FD and IA were assessed via adolescent self-reported questionaries of Chinese Family Assessment Instrument and Internet Addiction Test. Cross-lagged panel model was constructed to estimate possible associations between FD and adolescent IA after controlling for demographic variables. Our results suggest that adolescents might get stuck in a vicious cycle of dysfunctional family and addictive Internet use: adolescents who lived in a dysfunctional family showed increased risk in IA in the subsequent year; in turn, adolescent IA further increased the possibility of FD. Moreover, multigroup comparison analysis revealed that the vicious cycle between FD and adolescent IA could be applied to both the only child and the non-only child. The findings may enrich the application of the Developmental Contextualism Theory and contribute to the identification of the starting points for intervention strategies of adolescent IA.
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A phosphorous-based bi-functional compound HPDAl was used as a reactive-type flame retardant (FR) in an epoxy thermoset (EP) aiming to improve the flame retardant efficiency of phosphorus-based compounds. HPDAl, consisting of two different P-groups of aluminum phosphinate (AHP) and phosphophenanthrene (DOPO) with different phosphorous chemical environments and thus exerting different FR actions, exhibited an intramolecular P-P groups synergy and possessed superior flame-retardant efficiency compared with DOPO or AHP alone or the physical combination of DOPO/AHP in EP. Adding 2 wt.% HPDAl made EP composites acquire a LOI value of 32.3%, pass a UL94 V-0 rating with a blowing-out effect, and exhibit a decrease in the heat/smoke release. The flame retardant modes of action of HPDAl were confirmed by the experiments of the scanning electron microscope (SEM), X-ray photoelectron spectroscopy (XPS), and thermogravimetry-Fourier transform infrared spectroscopy-gas chromatograph/mass spectrometer (TG-FTIR-GC/MS). The results indicate that the phosphorous-based FRs show different influences on the flame retardancy of composites, mainly depending on their chemical structures. HPDAl had a flame inhibition effect in the gas phase and a charring effect in the condensed phase, with a well-balanced distribution of P content in the gas/condensed phase. Furthermore, the addition of HPDAl hardly impaired the mechanical properties of the matrix due to the link by chemical bonds between them.
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Retardadores de Llama , Aluminio/química , Resinas Epoxi/química , Fósforo , HumoRESUMEN
Non-alcoholic fatty liver disease (NAFLD) is the fastest-growing liver disease in the world. Despite targeted agents which are needed to provide permanent benefits for patients with NAFLD, no drugs have been approved to treat NASH. Thyroid hormone is an important signaling molecule to maintain normal metabolism, and in vivo and vitro studies have shown that regulation of the 3,5,3'-triiodothyronine (T3)/ thyroid hormone receptor (TR) axis is beneficial not only for metabolic symptoms but also for the improvement of NAFLD and even for the repair of liver injury. However, the non-selective regulation of T3 to TR subtypes (TRα/TRß) could cause unacceptable side effects represented by cardiotoxicity. To avoid deleterious effects, TRß-selective thyromimetics were developed for NASH studies in recent decades. Herein, we will review the development of thyroid hormones and synthetic thyromimetics based on TR selectivity for NAFLD, and analyze the role of TR-targeted drugs for the treatment of NAFLD in the future.
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Biomimética/métodos , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Receptores de Hormona Tiroidea/agonistas , Hormonas Tiroideas/farmacología , Animales , Humanos , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/patologíaRESUMEN
Single atom catalyst and ultrathin two-dimensional (2D) nanostructures exhibit improved properties because of the improved exposure of more active atomic sites and optimized electronic structures. However, the oxygen reduction reaction (ORR) in fuel cells via a fast four-electron path usually uses at least two Pt atoms, which cannot be realized in highly isolated single Pt atoms. The synthesis of a densely dispersed single atom catalyst with adjacent atoms accessible at the same time on a matrix with a high surface area provides a feasible way and, however, is challenging. Here, we synthesize ultrathin FePt nanosheets (NSs) with 6.7 wt % neighboring dispersed Pt atoms. Different from the reported isolated Pt single atom catalysts, these ultrathin wrinkled FePt NSs with neighboring Pt sites adopt a four-electron reduction pathway, a high electrochemical active surface area (ECSA) of 545.54 m2 gPt-1, and an improved mass activity 7 times as high as Pt/C in the ORR. The improved performance results from the optimal use of neighboring Pt atoms dispersed in a more packed spacing and exposed on the surface of ultrathin sheets. The Pt atoms can interact synergistically to catalyze a fast ORR process. Furthermore, both the experiment and density functional theory (DFT) calculation indicated an outstanding CO-tolerance performance of this catalyst in the ORR.
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Autophagy is an evolutionarily conserved 'self-eating' process that maintains cellular, tissue, and organismal homeostasis. New studies on autophagy, mediated by subsets of autophagy proteins, are emerging in many physiological and pathological processes. Astragalus membranaceus (AM), also named Huangqi, is one of the fundamental herbs in traditional Chinese medicine and its extracts have been proved to possess many biological activities related to autophagy, including anti-oxidation, anti-inflammation, anticancer, anti-photoaging, and improvement of cardiomyocyte function. Evidence suggests that AM extracts can have therapeutic potential in autophagy dysregulation-associated diseases because of their biological positive effects. Here we will review the literature concerning the effects of AM extracts on autophagy dysregulation-associated diseases.
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Astragalus propinquus , Autofagia/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Extractos Vegetales/farmacología , Animales , Antiinflamatorios/química , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Antineoplásicos/química , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Antioxidantes/química , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Astragalus propinquus/química , Cardiotónicos/química , Cardiotónicos/farmacología , Cardiotónicos/uso terapéutico , Enfermedades Cardiovasculares/tratamiento farmacológico , Medicamentos Herbarios Chinos/química , Medicamentos Herbarios Chinos/uso terapéutico , Humanos , Neoplasias/tratamiento farmacológico , Enfermedades Neurodegenerativas/tratamiento farmacológico , Extractos Vegetales/química , Extractos Vegetales/uso terapéutico , Envejecimiento de la Piel/efectos de los fármacosRESUMEN
Isoquinoline alkaloids possess a wide range of structural features and pharmaceutical activities and are promising drug candidates. Ten water-soluble catecholic isoquinolines were isolated from the medicinal plant Portulaca oleracea, including three new (1-3) and seven known compounds (4-10), along with the known catecholamines 11 and 12 and four other known compounds (13-16). A method of polyamide column chromatography using EtOAc-MeOH as the mobile phase was developed for the isolation of catecholic isoquinolines. Alkaloids 1-12 exhibited anti-inflammatory activities (EC50 = 18.0-497.7 µM) through inhibition of NO production in lipopolysaccharide-induced murine macrophage RAW 264.7 cells. Among these compounds, 11, 2, 5, 4, and 8 were more potent than was the positive control, 3,4-dihydroxybenzohydroxamic acid (EC50 = 82.4 µM), with EC50 values of 18.0, 18.1, 35.4, 36.3, and 58.7 µM, respectively. Additionally, at 100 µM, compounds 1-12 showed different degrees of ß2-adrenergic receptor (ß2-AR) agonist activity in the CHO-K1/GA15 cell line which stably expressed ß2-AR as detected by a calcium assay. The EC50 values of 2 and 10 were 5.1 µM and 87.9 nM, respectively.
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Agonistas Adrenérgicos/farmacología , Agonistas de Receptores Adrenérgicos beta 2/metabolismo , Antiinflamatorios/farmacología , Isoquinolinas/farmacología , Portulaca/química , Agonistas Adrenérgicos/química , Animales , Antiinflamatorios/química , Células CHO , Línea Celular , Cricetulus , Isoquinolinas/química , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ratones , Extractos Vegetales/química , Extractos Vegetales/farmacología , Plantas Medicinales/química , Células RAW 264.7RESUMEN
Icosahedral, octahedral, and cubic Pd@Pt core-shell nanocrystals with two atomic Pt layers are epitaxially generated under thermodynamic control. Such icosahedra exhibit remarkably enhanced catalytic properties for oxygen reduction reaction compared to the octahedra and cubes as well as commercial Pt/C, which can be attributed to ligand and geometry effects, especially twin-induced strain effect that is revealed by geometrical phase analysis.
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Pt-based multimetallic core-shell nanoplates have received great attention as advanced catalysts, but the synthesis is still challenging. Here we report the synthesis of multimetallic Pd@PtM (M = Ni, Rh, Ru) nanoplates including Pd@Pt nanoplates, in which Pt or Pt alloy shells with controlled thickness epitaxially grow on plate-like Pd seeds. The key to achieve high-quality Pt-based multimetallic nanoplates is in situ generation of CO through interfacial catalytic reactions associated with Pd nanoplates and benzyl alcohol. In addition, the accurate control in a trace amount of CO is also of great importance for conformal growth of multimetallic core-shell nanoplates. The Pd@PtNi nanoplates exhibit substantially improved activity and stability for methanol oxidation reaction (MOR) compared to the Pd@Pt nanoplates and commercial Pt catalysts due to the advantages arising from plate-like, core-shell, and alloy structures.
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In the context of antitumor immune responses, the activation of the stimulator of interferon genes (STING) assumes a critical role and imparts enhanced immunogenicity. An effective strategy for exogenously activating the immune system involves the utilization of STING agonists, and prior investigations primarily concentrated on modifying endogenous cyclic dinucleotides (CDNs) to achieve this. Nevertheless, the practical utility of CDNs was restricted due to limitations associated with their physicochemical attributes and administration protocols. In this article, we present the discovery of a novel small-molecule agonist denoted as M335, identified through high-throughput screening using surface plasmon resonance (SPR). M335 demonstrates the ability to activate the TBK1-IRF3-IFN axis in a STING-dependent manner in vitro. Through experimentation on mouse models bearing tumors, we observed that the administration of M335 resulted in the activation of immune cells. Notably, significant antitumor effects were achieved with both intratumoral and intraperitoneal administration of M335. These findings suggest the potential of M335 as a promising agent for cancer immunotherapy, which will promote the development of STING agonists in anti-tumor applications.
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Neoplasias , Animales , Ratones , Neoplasias/tratamiento farmacológico , Inmunidad Innata , Ensayos Analíticos de Alto Rendimiento , Modelos Animales de Enfermedad , Inmunoterapia/métodosRESUMEN
Absent in melanoma 2 (AIM2) is implicated in neuroinflammation. Here, we explored the prognostic significance of serum AIM2 in human aneurysmal subarachnoid hemorrhage (aSAH). We conducted a consecutive enrollment of 127 patients, 56 of whom agreed with blood-drawings not only at admission but also at days 1, 2, 3, 5, 7 and 10 days after aSAH. Serum AIM2 levels of patients and 56 healthy controls were measured. Disease severity was assessed using the modified Fisher scale (mFisher) and World Federation of Neurological Surgeons Scale (WFNS). Neurological outcome at poststroke 90 days was evaluated via the modified Rankin Scale (mRS). Univariate analysis and multivariate analysis were sequentially done to ascertain relationship between serum AIM2 levels, severity, delayed cerebral ischemia (DCI) and 90-day poor prognosis (mRS scores of 3-6). Patients, in comparison to controls, had a significant elevation of serum AIM2 levels at admission and at days 1, 2, 3, 5, 7 and 10 days after aSAH, with the highest levels at days 1, 2, 3 and 5. AIM2 levels were independently correlated with WFNS scores and mFisher scores. Significantly higher serum AIM2 levels were detected in patients with a poor prognosis than in those with a good prognosis, as well as in patients with DCI than in those without DCI. Moreover, serum AIM2 levels independently predicted a poor prognosis and DCI, and were linearly correlated with their risks. Using subgroup analysis, there were no significant interactions between serum AIM2 levels and age, gender, hypertension and so on. There were substantially high predictive abilities of serum AIM2 for poor prognosis and DCI under the receiver operating characteristic curve. The combination models of DCI and poor prognosis, in which serum AIM2, WFNS scores and mFisher scores were incorporated, showed higher discriminatory efficiencies than anyone of the preceding three variables. Moreover, the models are delineated using the nomogram, and performed well under the calibration curve and decision curve. Serum AIM2 levels, with a substantial enhancement during early phase after aSAH, are closely related to bleeding severity, poor 90-day prognosis and DCI of patients, substantializing serum AIM2 as a potential prognostic biomarker of aSAH.
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Proteínas de Unión al ADN , Hemorragia Subaracnoidea , Humanos , Masculino , Femenino , Persona de Mediana Edad , Hemorragia Subaracnoidea/sangre , Hemorragia Subaracnoidea/diagnóstico , Hemorragia Subaracnoidea/mortalidad , Pronóstico , Estudios Prospectivos , Proteínas de Unión al ADN/sangre , Anciano , Adulto , Biomarcadores/sangre , Estudios de Casos y Controles , Estudios Longitudinales , Índice de Severidad de la Enfermedad , Isquemia Encefálica/sangreRESUMEN
OBJECTIVE: Extramedullary relapse (EMR) is rare in acute promyelocytic leukemia (APL) and, there is a lack of information on its management. Current practices for EMR in APL are always to adopt strategies from other subtypes of Acute lymphoblastic leukemia (ALL) and Acute myeloid leukemia (AML). Gilteritinib, a highly selective FLT3 inhibitor, has demonstrated a remarkable effect on EMR in FLT3-mutant AML. Therefore, it is worthwhile exploring if FLT3 mutation can be a therapeutic target and assessing the efficacy of Gilteritinib on FLT3-mutant EMR in APL. METHODS: We described three cases of FLT3-mutant EMR in APL, comprising two isolated EMR cases and one systemic relapse. The patients underwent treatment with Gilteritinib-based regimens based on FLT3 mutation. RESULTS: All three patients achieved complete regression of EMR, and no signs of tumor lysis syndrome during Gilteritinib-based therapy, only patient 1 showed mild granulocytopenia. They all maintained molecular complete remission (mCR) during the follow-up period. CONCLUSIONS: The Gilteritinib-based regimen shows a high and sustained therapeutic effect with minimal adverse effects, and provides a valuable experience for further evaluation in EMR APL patients.
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Leucemia Mieloide Aguda , Leucemia Promielocítica Aguda , Humanos , Leucemia Promielocítica Aguda/tratamiento farmacológico , Leucemia Promielocítica Aguda/genética , Mutación , Leucemia Mieloide Aguda/genética , Recurrencia , Tirosina Quinasa 3 Similar a fms/genéticaRESUMEN
This work investigated the effect of different valence states of phosphorus-containing compounds on thermal decomposition and flame retardancy of polyethylene terephthalate (PET). Three polyphosphates-PBPP with +3-valence P, PBDP with +5-valence P and PBPDP with both +3/+5-valence P-were synthesized. The combustion behaviors of flame-retardant PET were studied and the structure-property relationships between the phosphorus-based structures with different valence states and flame-retardant properties were further explored. It was found that phosphorus valence states significantly affected the flame-retardant modes of action of polyphosphate in PET. For the phosphorus structures with +3-valence, more phosphorus-containing fragments were released in the gas phase, inhibiting polymer chain decomposition reactions; by contrast, those with +5-valence phosphorus retained more P in the condensed phase, promoting the formation of more P-rich char layers. It is worth noting that the polyphosphate containing both +3/+5-valence phosphorous tended to combine the advantage of phosphorus structures with two valence states and balance the flame-retardant effect in the gas phase and condensed phase. These results contribute to guiding the design of specified phosphorus-based structures of flame-retardant compounds in polymer materials.
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STING1 (stimulator of interferon response cGAMP interactor 1) plays an essential role in immune responses for virus inhibition via inducing the production of type I interferon, inflammatory factors and macroautophagy/autophagy. In this study, we found that STING1 activation could induce not only canonical autophagy but also non-canonical autophagy (NCA) which is independent of the ULK1 or BECN1 complexes to form MAP1LC3/LC3-positive structures. Whether STING1-induced NCA has similar characters and physiological functions to canonical autophagy is totally unknown. Different from canonical autophagy, NCA could increase single-membrane structures and failed to degrade long-lived proteins, and could be strongly suppressed by interrupting vacuolar-type H+-translocating ATPase (V-ATPase) activity. Importantly, STING1-induced NCA could effectively inhibit DNA virus HSV-1 in cell model. Moreover, STING1 [1-340], a STING1 mutant lacking immunity and inflammatory response due to deletion of the tail end of STING1, could degrade virus through NCA alone, suggesting that the antiviral effect of activated STING1 could be separately mediated by inherent immunity, canonical autophagy, and NCA. In addition, the translocation and dimerization of STING1 do not rely on its immunity function and autophagy pathway. Similar to canonical autophagy, LC3-positive structures of NCA induced by STING1 could finally fuse with lysosomes, and the degradation of HSV-1 could be reverted by inhibition of lysosome function, suggesting that the elimination of DNA virus via NCA still requires the lysosome pathway. Collectively, we proved that besides its classical immunity function and canonical autophagy pathway, STING1-induced NCA is also an efficient antiviral pathway for the host cell.Abbreviations: ATG: autophagy related; Baf: bafilomycin A1; CASM: conjugation of LC3 to a single membrane; CGAS: cyclic GMP-AMP synthase; cGAMP: cyclic GMP-AMP; CQ: chloroquine; CTD: C-terminal domain; CTT: C-terminal tail; ER: endoplasmic reticulum; ERGIC: ER-Golgi intermediate compartment; HSV-1: herpes simplex virus 1; IRF3: interferon regulatory factor 3; IFNs: interferons; LAMP1: lysosomal associated membrane protein 1; LAP: LC3-associated phagocytosis; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MOI: multiplicity of infection; RB1CC1/FIP200: RB1 inducible coiled-coil 1; STING1: stimulator of interferon response cGAMP interactor 1; TBK1: TANK binding kinase 1; TGOLN2/TGN46: trans-golgi network protein 2; ULK1: unc-51 like autophagy activating kinase 1; V-ATPase: vacuolar-type H+-translocating ATPase; VSV: vesicular stomatitis virus.
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Autofagia , Herpesvirus Humano 1 , Autofagia/fisiología , Proteínas , Interferones , Antivirales/farmacología , Adenosina TrifosfatasasRESUMEN
Objectives: This study aimed to examine the associations between warm and harsh parenting and adolescent well-being, and the mediating effects of self-kindness and self-judgment, in relationships. Moreover, this study investigated developmental differences across three adolescence stages (early, middle, and late). Methods: In total, 14,776 Chinese adolescents (mean age = 13.53 ± 2.08, 52.3% males), including individuals in early (10-12 years old, N = 5055), middle (13-15 years old, N = 6714), and late adolescence (16-18 years old, N = 3007) participated in this study. All the adolescents rated their levels of warm and harsh parenting, self-kindness and self-judgment, and well-being. Structural equation modeling (SEM) was adopted to examine the mediation model. Multi-group analysis was conducted to investigate differences in the mediation model across the different developmental stages. Results: Both warm and harsh parenting were related to adolescent well-being through the mediating effects of self-kindness and self-judgment. However, warm parenting exerted a more substantial impact on adolescent well-being. Self-kindness had a more robust mediating effect than self-judgment in relationships. Moreover, harsh parenting had a weaker impact on adolescent well-being in late adolescence than in early and middle adolescence. Warm parenting had a more significant impact on adolescent well-being in early adolescence than in middle and late adolescence. Conclusions: Overall, warm parenting had a more substantial effect than harsh parenting on adolescent well-being. The findings also highlighted the crucial mediating effect of self-kindness in the relationships between parenting and well-being. Moreover, this study also indicated the importance of warm parenting in early adolescence. Intervention programs should focus on enhancing the level of warm parenting to promote self-kindness in adolescents, in order to improve their well-being.
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OBJECTIVE: To observe the clinical significance of translocator proteins (TSPO) gene in the treatment of FLT3-ITD/DNMT3A R882 double-mutated acute myeloid leukemia (AML). METHODS: Seventy-six patients with AML hospitalized in the Department of Hematology of the Affiliated People's Hospital of Ningbo University from June 2018 to June 2020 were selected, including 34 patients with FLT3-ITD mutation, 27 patients with DNMT3A R882 mutation, 15 patients with FLT3-ITD/DNMT3A R882 double mutation, as well as 19 patients with immune thrombocytopenia (ITP) hospitalized during the same period as control group. RNA was routinely extracted from 3 ml bone marrow retained during bone puncture, and TSPO gene expression was detected by transcriptome sequencing (using 2-deltadeltaCt calculation). RESULTS: The expression of TSPO gene in FLT3-ITD group and DNMT3A R882 group at first diagnosis was 2.02±1.04 and 1.85±0.76, respectively, which were both higher than 1.00±0.06 in control group, but the differences were not statistically significant (P=0.671, P=0.821). The expression of TSPO gene in the FLT3-ITD/DNMT3A R882 group was 3.98±1.07, wich was significantly higher than that in the FLT3-ITD group and DNMT3A R882 group, the differences were statistically significant (P=0.032, P=0.021). The expression of TSPO gene in patients who achieved complete response after chemotherapy in the FLT3-ITD/DNMT3A R882 group was 1.19±0.87, which was significantly lower than that at first diagnosis, and the difference was statistically significant (P=0.011). CONCLUSION: TSPO gene may be used as an indicator of efficacy in FLT3-ITD /DNMT3A R882 double-mutated AML.
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ADN (Citosina-5-)-Metiltransferasas , Leucemia Mieloide Aguda , Humanos , ADN (Citosina-5-)-Metiltransferasas/genética , ADN Metiltransferasa 3A , Mutación , Leucemia Mieloide Aguda/tratamiento farmacológico , Nucleofosmina , Pronóstico , Tirosina Quinasa 3 Similar a fms/genética , Receptores de GABA/genética , Receptores de GABA/uso terapéuticoRESUMEN
Huntington's disease (HD) is a neurodegenerative disorder caused by aggregation of the mutant huntingtin (mHTT) protein encoded from extra tracts of CAG repeats in exon 1 of the HTT gene. mHTT proteins are neurotoxic to render the death of neurons and a series of disease-associated phenotypes. The mHTT is degraded through autophagy pathway and ubiquitin-proteasome system (UPS). This study identified a small molecule, J3, as an autophagy inducer by high-content screening. The results revealed that J3 could inhibit mTOR, thus promoting autophagic flux and long-lived protein degradation. Further, J3 selectively lowered the soluble and insoluble mHTT but not wild type HTT levels in cell models. The HdhQ140 mice showed reduced HD-associated activity and loss of motor functions. However, administration of J3 showed increased activity and a slight improvement in the motor function in the open-field test, balance beam test, and rotarod tests. Furthermore, in vivo studies revealed that J3 decreased T-HTT and misfolded protein levels in the striatum and increased the levels of the medium spiny neuron marker DARPP-32. In addition, J3 showed good permeability across the brain-blood barrier efficiently, suggesting that J3 was a promising candidate for the treatment of HD.
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Infectious diseases caused by nontuberculous mycobacteria (NTM) are increasingly common. This retrospective cohort study examined factors associated with outcomes in patients from Shanghai who had NTM pulmonary disease (NTMPD) from January 2014 to December 2018. The causative bacterial species, drug susceptibility test results, treatment outcomes, sputum culture conversion rate, and risk factors associated with treatment failure were determined. The most common species were Mycobacterium avium complex (MAC) (50%), M. abscessus (28%), and M. kansasii (15%). Over five years, the proportions of M. kansasii and M. abscessus increased, and that of MAC decreased. The treatment success rate was significantly greater for patients infected with M. kansasii (89.9%) than MAC (65.0%, p < 0.001) and M. abscessus (36.1%, p < 0.001). Multivariate analysis indicated the risk factors for treatment failure were pathogenic NTM species (M. abscessus: aOR = 9.355, p < 0.001; MAC: aOR = 2.970, p < 0.001), elevated ESR (>60 mm/h: aOR = 2.658, p < 0.001), receipt of retreatment (aOR = 2.074, p < 0.001), and being middle-aged or elderly (>60 years-old: aOR = 1.739, p = 0.021; 45-60 years-old: aOR = 1.661, p = 0.034). The main bacterial species responsible for NTMPD were MAC, M. abscessus, and M. kansasii. Patients who were infected by M. abscessus or MAC, with elevated ESR, received retreatment, and were middle-aged or elderly had an increased risk of treatment failure.