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Hepatocellular carcinoma (HCC), a major form of liver cancer, is characterized by high lethality and a multifactorial etiology that includes hepatitis virus infections, lifestyle factors, and genetic predispositions. This study aimed to explore the impact of ZNF208 gene polymorphisms on the clinicopathological features of Taiwanese HCC patients, focusing on three specific single nucleotide polymorphisms (SNPs): rs2188971, rs2188972, and rs8105767. Our cohort consisted of 438 HCC patients and 1193 control individuals. Clinical staging was determined using the tumor/node/metastasis (TNM) system, and various clinical indicators were collected. Our analysis revealed a statistically significant increase in ZNF208 expression in HCC patients compared to controls, indicating a potential role in HCC progression. Although no substantial association was observed between ZNF208 SNPs and increased HCC risk, specific clinical features such as distant metastasis and vascular invasion showed significant associations with these SNPs, suggesting their influence on disease aggressiveness. Demographic analyses highlighted the importance of factors like alcohol consumption and viral hepatitis markers in HCC. Our study underscores the complexity of genetic influences on HCC, with ZNF208 polymorphisms potentially affecting tumor progression and patient outcomes.

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Background: Microwave ablation (MWA) is an important method for the treatment of lung cancer, but there is still a lack of standard guidelines for the selection of power. This study aimed to explore the effectiveness and safety of MWA at different power levels. Methods: The study gathered individuals underwent MWA for lung cancer between January 2012 and December 2020. All patients were divided into low power group and high power group based on the power of MWA. By intergroup comparisons, we clarified the differences between the two groups. Results: In this study, 265 participants were involved, with 192 in the low power group and 73 in the high power group. Compared to the low power group, the high power group had a significantly higher incidence of postoperative complications (63.0% vs. 24.0%). In the Kaplan-Meier analysis, overall survival (OS) and disease-free survival (DFS) of the high power group were both better than the low power group. We found through Cox regression analysis that smoking, tumor volume, tumor differentiation, gene mutation, neutrophil count, and lymphocyte count were independent factors affecting the OS of patients. Based on the above factors, we constructed a nomogram, with areas under the curve (AUCs) of 0.941, 0.903, and 0.905 for predicting 1-, 2-, and 3-year OS after MWA, respectively. Conclusions: While high-power MWA brings better long-term prognosis to patients, it also leads to an increase in postoperative complications. The application of a nomogram for stratifying the prognosis of patients may be a more feasible approach to further develop individualized treatment plans.

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Antimony selenosulfide (Sb2(S,Se)3) has obtained widespread concern for photovoltaic applications as a light absorber due to superior photoelectric features. Accordingly, various deposition technologies have been developed in recent years, especially hydrothermal deposition method, which has achieved a great success. However, device performances are limited with severe carrier recombination, relating to the quality of absorber and interfaces. Herein, bulk and interface defects are simultaneously suppressed by regulating heterogeneous nucleation kinetics with barium dibromide (BaBr2) introduction. In details, the Br adsorbs and dopes on the polar planes of cadmium sulfide (CdS) buffer layer, promoting the exposure of nonpolar planes of CdS, which facilitates the favorable growth of [hk1]-Sb2(S,Se)3 films possessing superior crystallinity and small interface defects. Additionally, the Se/S ratio is increased due to the replacement of S/Se by Br, causing a downshift of the Fermi levels with a benign band alignment and a shallow-level defect. Moreover, Ba2+ is located at grain boundaries by coordination with S and Se ions, passivating grain boundary defects. Consequently, the efficiency is increased from 7.70% to 10.12%. This work opens an avenue towards regulating the heterogeneous nucleation kinetics of Sb2(S,Se)3 film deposited via hydrothermal deposition approach to optimize its crystalline orientation and defect features.

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Cephalopod skins evolve multiple functions in response to environmental adaptation, encompassing nonlinear mechanoreponse, damage tolerance property, and resistance to seawater. Despite tremendous progress in skin-mimicking materials, the integration of these desirable properties into a single material system remains an ongoing challenge. Here, drawing inspiration from the structure of reflectin proteins in cephalopod skins, a long-term anti-salt elastomer with skin-like nonlinear mechanical properties and extraordinary damage resistance properties is presented. Cation-π interaction is incorporated to induce the geometrically confined nanophases of hydrogen bond domains, resulting in elastomers with exceptional true tensile strength (456.5 ± 68.9 MPa) and unprecedently high fracture energy (103.7 ± 45.7 kJ m-2). Furthermore, the cation-π interaction effectively protects the hydrogen bond domains from corrosion by high-concentration saline solution. The utilization of the resultant skin-like elastomer has been demonstrated by aquatic soft robotics capable of grasping sharp objects. The combined advantages render the present elastomer highly promising for salt enviroment applications, particularly in addressing the challenges posed by sweat, in vivo, and harsh oceanic environments.

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Recycling spent lithium-ion batteries (LIBs) in a green and economical way is vital for maintaining the sustainability of the LIB industry. However, given the low content of high-value components in olivine-type lithium iron phosphate (LFP), traditional metallurgical processes are economically unfeasible for recycling due to high chemical/energy consumption and labor-intensive procedures. This study proposes a facile electrochemistry strategy to directly regenerate the spent LFP material by an electrically driven lithiation process as a spent LFP slurry (200 g/L) rather than as electrodes. Minimal energy and chemical consumption are achieved by enabling the healing of spent LFP without destroying the original olivine-type crystal structure. The proposed method utilizes mild healing conditions (25 °C for 2 h) and LiCl solution as the only reagent in the regeneration process, significantly lowering the expenses associated with producing cathode electrodes. The electrochemical performance of the regenerated LFP have been dramatically recovered after regeneration, exhibiting a capacity of 151.5 mA h g-1 at 0.1 C and 96.6% capacity retention over 400 cycles at 1 C. This approach demonstrates a high processing capability and offers considerable economic and environmental benefits, making it an eco-friendly option and supporting the sustainable development of the LFP industry.

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Atomic Force Microscopy (AFM) is a widely employed tool for micro- and nanoscale topographic imaging. However, conventional AFM scanning struggles to reconstruct complex 3D micro- and nanostructures precisely due to limitations such as incomplete sample topography capturing and tip-sample convolution artifacts. Here, we propose a multi-view neural-network-based framework with AFM, named MVN-AFM, which accurately reconstructs surface models of intricate micro- and nanostructures. Unlike previous 3D-AFM approaches, MVN-AFM does not depend on any specially shaped probes or costly modifications to the AFM system. To achieve this, MVN-AFM employs an iterative method to align multi-view data and eliminate AFM artifacts simultaneously. Furthermore, we apply the neural implicit surface reconstruction technique in nanotechnology and achieve improved results. Additional extensive experiments show that MVN-AFM effectively eliminates artifacts present in raw AFM images and reconstructs various micro- and nanostructures, including complex geometrical microstructures printed via two-photon lithography and nanoparticles such as poly(methyl methacrylate) (PMMA) nanospheres and zeolitic imidazolate framework-67 (ZIF-67) nanocrystals. This work presents a cost-effective tool for micro- and nanoscale 3D analysis.

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BACKGROUND: The relationship between metabolically healthy obesity (MHO) and cardiovascular disease (CVD) risk remains debated. The critical point may be the lack of consensus on MHO's definition and diagnostic criteria. OBJECTIVE: This study aimed to investigate the association of MHO status with arteriosclerosis-CVD (ASCVD) risk in Chinese under new diagnostic criteria. METHODS: Participants aged 35-79 in the 2009 China Health and Nutrition Survey cohort were included. The 10-year ASCVD risk was predicted by the prediction for ASCVD risk in China, and participants with a predicted risk of ⩾ 10% were classified into the high-risk group. The Bayesian network (BN) models were constructed to characterize the multivariable probabilistic connections between metabolically obesity phenotypes and ASCVD risk. RESULTS: The 10-year ASCVD risk score and the proportion of individuals at ASCVD high risk were significantly different between metabolically obesity phenotypes (P< 0.001). BN reasoning results showed that MHO individuals were not significantly associated with a 10-year ASCVD risk. Among metabolically unhealthy individuals, the conditional probability of high ASCVD risk increased with the Body Mass Index (BMI), with the conditional probability of high ASCVD risk was 24.63% (95% CI: 22.81-26.55%), 32.97% (95% CI: 30.75-35.27%) and 40.2% (95% CI: 36.64-43.86%) for metabolically unhealthy normal weight (MUNW), metabolically healthy overweight weight (MHOW), and metabolically unhealthy obesity (MUO) group, respectively. Subgroup analysis showed that MHO individuals were at increased risk of CVD compared with metabolically healthy normal weight (MHNW) individuals only in females. CONCLUSION: These results showed that there was no significant increase in ASCVD risk of MHO phenotype based on the new diagnostic criteria, suggesting that MHO is in a relatively healthy state.

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Peripheral nervous system (PNS) injuries often lead to significant sensory and motor impairments. Traditional artificial nerve conduits, lacking anisotropic structures, have been associated with prolonged repair time and failures in nerve regeneration. This study aimed to address these challenges by developing a novel approach for rapid repair of peripheral nerve injuries (PNI). A 3D oriented fibers scaffold featuring distinct radial (RFs) and longitudinal (LFs) fibers orientations was engineered using coaxial electrospinning and gas directional foaming techniques. This scaffold was then integrated with a shape memory conduit to form a directional multi-channel nerve conduit with micro/nanostructures. The results revealed that the grooved surface of the fibers significantly improved cellular directional guidance, effectively facilitating the migration of SCs from the periphery towards the center and from the base to the apex of the scaffold. In a rat model with a 10 mm nerve defect, the ND-PLATMC/LF ND-PCL scaffold significantly enhanced nerve regeneration and motor function recovery within 4 weeks. These results suggest the potential of this innovative scaffold for efficient repair of the nerve injuries.

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Demolding is a crucial step in nanoimprint lithography (NIL) for successfully transferring template structures onto resist materials. The process, however, is often hindered by the adhesion and friction between the template and resist, leading to inevitable defects on the replicas and posing challenges in replicating templates with high-aspect-ratio (HAR) structures. Here, we introduce a novel approach using the dissolvable template method to achieve the nondestructive demolding of structure-designable HAR nanoimprint templates. The templates were fabricated by the 3D lithography technology, employing a positive photoresist that can be easily dissolved in alkaline solutions after exposure to ultraviolet (UV) radiation. By implementing this method, we successfully transferred dense arrays of pillars with a minimal diameter of 1.2 µm and a significant aspect ratio of 18, as well as a microlens array diffuser with randomly distributed structural parameters. The dissolvable template method paves the way for stress-free demolding, broadening NIL's application range.

RESUMEN

Recent years have witnessed a rise in the popularity of information integration without sharing of raw data. By leveraging and incorporating summary information from external sources, internal studies can achieve enhanced estimation efficiency and prediction accuracy. However, a noteworthy challenge in utilizing summary-level information is accommodating the inherent heterogeneity across diverse data sources. In this study, we delve into the issue of prior probability shift between two cohorts, wherein the difference of two data distributions depends on the outcome. We introduce a novel semi-parametric constrained optimization-based approach to integrate information within this framework, which has not been extensively explored in existing literature. Our proposed method tackles the prior probability shift by introducing the outcome-dependent selection function and effectively addresses the estimation uncertainty associated with summary information from the external source. Our approach facilitates valid inference even in the absence of a known variance-covariance estimate from the external source. Through extensive simulation studies, we observe the superiority of our method over existing ones, showcasing minimal estimation bias and reduced variance for both binary and continuous outcomes. We further demonstrate the utility of our method through its application in investigating risk factors related to essential hypertension, where the reduced estimation variability is observed after integrating summary information from an external data.

Asunto(s)

Simulación por Computador , Hipertensión Esencial , Probabilidad , Humanos , Modelos Estadísticos , Factores de Riesgo , Hipertensión , Interpretación Estadística de Datos , Biometría/métodos

RESUMEN

BACKGROUND: Keratoconus (KC) is a corneal ectasia disease in which the vision of some patients cannot achieve satisfaction by spectacle corrections. However, not everyone can embrace contact lenses to achieve better vision. Perceptual learning (PL) is a potential treatment for vision improvement in such patients. PURPOSE: To investigate the effectiveness and maintenance of PL on vision improvement in KC patients corrected with spectacles. DESIGN: Randomized, double-blind clinical trial. PARTICIPANTS: Thirty-five non-progressive KC patients aged 9 years or older with unsatisfied spectacle-corrected vision were enrolled. METHODS: Non-progressive KC patients with best spectacle-corrected distance visual acuity (CDVA) of 0 to 1.0 logMAR (Snellen equivalent range 20/20 to 20/200) and contact lenses intolerant were enrolled. Eligible subjects were randomized into PL and control groups to receive PL and placebo training for 3 months, respectively. Spectacle-corrected visual acuity, contrast sensitivity function (CSF), stereoacuity, and visual functioning and quality of life questionnaires were measured at baseline, 3 months, and 6 months of follow-up. Statistics were analyzed following the intention-to-treat (ITT) principle. RESULTS: After 3 months of training, the CDVA of patients in the PL group improved as compared to the placebo group (0.17 ± 0.15 logMAR vs. 0.02 ± 0.06 logMAR; P = 0.0006). Eight out of seventeen (47.06 %) patients in the PL group reached CDVA improvement ≥ 2 lines (P=0.0010). This improvement persisted for at least 6 months (from baseline) as compared to the placebo group (0.17 ± 0.17 logMAR vs. 0.01 ± 0.07 logMAR; P = 0.0011). The increase of CSF in the PL group mainly was found for moderate spatial frequency (0.11 ± 0.17 log units at 3 cpd; 0.12 ± 0.19 log units at 6 cpd). Linear regression indicated that patients with worse initial CDVA achieved better gains in CDVA after PL (P = 0.009). No side effects were observed and no subjects quit because of training difficulties. CONCLUSION: Three-month perceptual learning improved vision in KC patients and the improvement maintained after 3 months of treatment cessation. The results indicate that perceptual learning may be a promising therapy for KC patients with unsatisfied spectacle-corrected visual acuity.

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Apolipoprotein E ε4 (APOE4) is a strong genetic risk factor of Alzheimer's disease and metabolic dysfunction. However, whether APOE4 and markers of metabolic dysfunction synergistically impact the deterioration of white matter (WM) integrity in older adults remains unknown. In the UK Biobank data, we conducted a multivariate analysis to investigate the interactions between APOE4 and 249 plasma metabolites (measured using nuclear magnetic resonance spectroscopy) with whole-brain WM integrity (measured by diffusion-weighted magnetic resonance imaging) in a cohort of 1917 older adults (aged 65.0-81.0 years; 52.4 % female). Although no main association was observed between either APOE4 or metabolites with WM integrity (adjusted P > 0.05), significant interactions between APOE4 and metabolites with WM integrity were identified. Among the examined metabolites, higher concentrations of low-density lipoprotein and very low-density lipoprotein were associated with a lower level of WM integrity (b=-0.12, CI=-0.14,-0.10) among APOE4 carriers. Conversely, among non-carriers, they were associated with a higher level of WM integrity (b=0.05, CI=0.04,0.07), demonstrating a significant moderation role of APOE4 (b =-0.18, CI=-0.20,-0.15, P<0.00001).

Asunto(s)

Apolipoproteína E4 , Heterocigoto , Lipoproteínas LDL , Sustancia Blanca , Humanos , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patología , Apolipoproteína E4/genética , Femenino , Masculino , Anciano , Lipoproteínas LDL/sangre , Anciano de 80 o más Años , Estudios de Cohortes , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/diagnóstico por imagen , Enfermedad de Alzheimer/sangre , Enfermedad de Alzheimer/patología , Imagen de Difusión por Resonancia Magnética , Espectroscopía de Resonancia Magnética , Factores de Riesgo

RESUMEN

Vancomycin is a clinically important glycopeptide antibiotic against Gram-positive pathogenic bacteria, especially methicillin-resistant Staphylococcus aureus. In the mutant strain of Amycolatopsis keratiniphila HCCB10007 Δeco-cds4-27, the production of ECO-0501 was disrupted, but enhanced vancomycin yield by 55% was observed compared with the original strain of A. keratiniphila HCCB10007. To gain insights into the mechanism of the enhanced production of vancomycin in the mutant strain, comparative metabolomics analyses were performed between the mutant strain and the original strain, A. keratiniphila HCCB10007 via GC-TOF-MS and UPLC-HRMS. The results of PCA and OPLS-DA revealed a significant distinction of the intracellular metabolites between the two strains during the fermentation process. 64 intracellular metabolites, which involved in amino acids, fatty acids and central carbon metabolism, were identified as differential metabolites. The high-yield mutant strain maintained high levels of glucose-1-phosphate and glucose-6-phosphate and they declined with the increases of vancomycin production. Particularly, a strong association of fatty acids accumulation as well as 3,5-dihydroxyphenylacetic acid and non-proteinogenic amino acid 3,5-dihydroxyphenylglycine (Dpg) with enhancement of vancomycin production was observed in the high-yield mutant strain, indicating that the consumption of fatty acid pools might be beneficial for giving rise to 3,5-dihydroxyphenylacetic acid and Dpg which further lead to improve vancomycin production. In addition, the lower levels of glyoxylic acid and lactic acid and the higher levels of sulfur amino acids might be beneficial for improving vancomycin production. These findings proposed more advanced elucidation of metabolomic characteristics in the high-yield strain for vancomycin production and could provide potential strategies to enhance the vancomycin production.

Asunto(s)

Amycolatopsis , Antibacterianos , Fermentación , Metabolómica , Vancomicina , Vancomicina/farmacología , Vancomicina/metabolismo , Metabolómica/métodos , Antibacterianos/metabolismo , Antibacterianos/farmacología , Amycolatopsis/metabolismo , Amycolatopsis/genética , Redes y Vías Metabólicas , Metaboloma , Mutación , Ácidos Grasos/metabolismo , Glioxilatos/metabolismo , Aminoácidos/metabolismo , Staphylococcus aureus Resistente a Meticilina/efectos de los fármacos , Staphylococcus aureus Resistente a Meticilina/metabolismo , Staphylococcus aureus Resistente a Meticilina/genética

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BACKGROUND: The relevant survey has shown a high incidence of psychiatric complications in patients with pancreatic cancer. While some studies have explored the factors influencing psychological complications in pancreatic cancer patients, some factors validated in other populations have not been confirmed in the pancreatic cancer population. This study aims to explore the predictors of psychiatric complications in patients with pancreatic cancer. METHODS: Patients with pancreatic cancer admitted to Yueqing People's Hospital Affiliated to Wenzhou Medical University, from January 2021 to January 2022 were retrospectively analyzed. The structured clinical interview (SCID-I) based on Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) was used by nurses to assess the incidence of psychiatric complications during hospitalization (baseline) and 3 months after the start of treatment. Binary logistic regression was used to identify predictors of psychiatric complications. RESULTS: 80 patients were enrolled in this study and 8 patients were diagnosed with psychiatric complications at base line. Among the rest 72 patients, 8 patients (11.11%) had new-onset psychiatric complications at 3-month follow-up. Gender (Odds Ratio (OR) = 1.674, p = 0.019), monthly income (OR = 1.735, p = 0.023) and sadness (M.D. Anderson Symptom Inventory (MDASI)) (OR = 1.804, p = 0.001) were all predictors for psychiatric complications in patients with pancreatic cancer. CONCLUSIONS: Gender, monthly income and MDASI score are predictors of psychiatric complications in patients with pancreatic cancer.

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Trastornos Mentales , Neoplasias Pancreáticas , Humanos , Neoplasias Pancreáticas/complicaciones , Neoplasias Pancreáticas/psicología , Masculino , Femenino , Estudios Retrospectivos , Persona de Mediana Edad , Trastornos Mentales/etiología , Trastornos Mentales/epidemiología , Anciano , Factores de Riesgo , Adulto

RESUMEN

Background: Breast cancer ranks as one of the most prevalent malignancies among women globally, with increasing incidence rates. Physical activity, particularly exercise, has emerged as a potentially significant modifier of cancer prognosis, influencing tumor biology and patient outcomes. Methods: Using a murine breast cancer model, we established a control and an exercise group, where the latter was subjected to 21 days of voluntary running. RNA Sequencing, bioinformatics analysis, pan-cancer analysis, and cell experiments were performed to validate the underlying mechanisms. Results: We observed that exercise significantly reduced tumor size and weight, without notable changes in body weight, suggesting that physical activity can modulate tumor dynamics. mRNA sequencing post-exercise revealed substantial downregulation of CD300E in the exercise group, accompanied by alterations in critical pathways such as MicroRNAs in cancers and the Calcium signaling pathway. Expanding our analysis to a broader cancer spectrum, CD300E demonstrated significant expression variability across multiple cancer types, with pronounced upregulation in myeloma, ovarian, lung, and colorectal cancers. This upregulation was correlated with poorer prognostic outcomes, emphasizing CD300E's potential role as a prognostic marker and therapeutic target. Moreover, CD300E expression was associated with cancer cell proliferation and apoptosis. Conclusion: The study highlights the dual role of exercise in modulating gene expression relevant to tumor growth and the potential of CD300E as a target in cancer therapeutics. Further research is encouraged to explore the mechanisms by which exercise and CD300E influence cancer progression and to develop targeted strategies that could enhance patient outcomes in clinical settings.

Asunto(s)

Regulación Neoplásica de la Expresión Génica , Animales , Femenino , Humanos , Ratones , Apoptosis/genética , Biomarcadores de Tumor/genética , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Neoplasias de la Mama/terapia , Línea Celular Tumoral , Proliferación Celular , Regulación hacia Abajo , Neoplasias/genética , Condicionamiento Físico Animal , Pronóstico , Receptores Inmunológicos/genética , Receptores Inmunológicos/metabolismo

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BACKGROUND: While short sleep duration is linked to higher risk of non-alcoholic fatty liver disease (NAFLD), the combined effects of sleep timing and sleep duration on NAFLD are less explored. METHODS: In this cross-sectional study of 39,471 participants from Beijing-Tianjin-Hebei region of China, self-reported sleep information and ultrasonography-diagnosed NAFLD were obtained from Jan 2018 to Jan 2020. Sleep timing was categorized based on sleep midpoint: early-type (before 2:00 AM), intermediate-type (2:00-2:30 AM), and late-type (after 2:30 AM). We used multivariable logistic regression to explore the relationship between sleep timing, duration, and NAFLD. We analyzed sleep midpoint and duration categorically and continuously, and conducted stratification analyses by age, sex, body mass index, hypertension, diabetes, and dyslipidemia. RESULTS: Intermediate-type (OR: 1.15, 95% confidence interval: 1.05-1.26) and late-type sleep timing (OR: 1.08, 1.00-1.16) were associated with higher NAFLD risk compared to early-type. Additionally, longer sleep duration was linked to lower risk (OR: 0.92, 0.90-0.95 per hour increase). Notably, intermediate to late-type sleepers with normal sleep duration (7 to <8 h) exhibited a 20% higher NAFLD risk compared to early-type sleepers with the same duration (OR: 1.20, 1.04-1.39). The increased NAFLD risk associated with intermediate to late sleep timing was particularly evident in men, hypertension, and prediabetes or diabetes participants. CONCLUSIONS: Intermediate to late sleep timing, even with normal sleep duration, is associated with increased NAFLD risk. These findings underscore the importance of considering both sleep timing and sleep duration for NAFLD prevention, especially in men and individuals with cardiometabolic conditions.

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Enfermedad del Hígado Graso no Alcohólico , Sueño , Humanos , Enfermedad del Hígado Graso no Alcohólico/epidemiología , Masculino , Femenino , Estudios Transversales , Persona de Mediana Edad , Sueño/fisiología , China/epidemiología , Adulto , Factores de Riesgo , Factores de Tiempo , Autoinforme , Índice de Masa Corporal , Duración del Sueño

RESUMEN

BACKGROUND: Preliminary evidence suggests that people with schizophrenia have decreased relative abundance of butyrate-producing bacteria in the gut microbiota. Butyrate plays a critical role in maintaining the integrity of the gut-blood barrier and has a number of anti-inflammatory effects. This proof-of-concept study was designed to assess whether the addition of the oligofructose-enriched inulin (OEI) prebiotic: Prebiotin could increase the production of butyrate. METHODS: Twenty-seven people who met the criteria for either Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, schizophrenia or schizoaffective disorder were entered into a 10-day, double-blind, placebo-controlled, randomized clinical trial. The study was conducted on an inpatient unit to standardize the participant diet and environment. Participants were randomized to either OEI (4 g, 3 times a day) or a placebo (4 g of maltodextrin, 3 times a day). In order to assess the effect of OEI treatment on butyrate levels, participants underwent pretreatment and posttreatment OEI challenges. The primary outcome measure was relative change in postchallenge plasma butyrate levels after 10 days of OEI treatment. RESULTS: In both the intent-to-treat and completer analyses, OEI treatment was associated with a greater number of participants who met the OEI challenge responder criteria than those treated with placebo. OEI treatment was also associated with an increase in baseline butyrate levels (effect size for the group difference in the change of baseline butyrate levels was 0.58). CONCLUSIONS: We were able to demonstrate that treatment with the prebiotic OEI selectively increased the level of plasma butyrate in people with schizophrenia.Trial registration:ClinicalTrials.gov identifier NCT03617783.

Asunto(s)

Butiratos , Oligosacáridos , Prebióticos , Esquizofrenia , Humanos , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/sangre , Prebióticos/administración & dosificación , Método Doble Ciego , Masculino , Femenino , Adulto , Persona de Mediana Edad , Oligosacáridos/administración & dosificación , Oligosacáridos/farmacología , Inulina/administración & dosificación , Inulina/farmacología , Microbioma Gastrointestinal/efectos de los fármacos , Prueba de Estudio Conceptual , Trastornos Psicóticos/tratamiento farmacológico , Trastornos Psicóticos/dietoterapia , Trastornos Psicóticos/sangre , Adulto Joven

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Due to the emerging global epidemic of obesity, developing safe and effective agents for anti-obesity is urgently needed. Our previous study found that 2-pyrimidinylindole derivative Wd3d exhibited potential anti-obesity activity. Herein, to further optimize the potential moiety, structural modifications were proceeded for two rounds in this study. Firstly, we designed, synthesized, and evaluated 36 new derivatives of 2-pyrimidinylindole scaffold with different substituents on the indole ring and pyrimidine ring to investigate their structure-activity relationship (SAR). Then, analogs with potent activity had the aldehyde group replaced with the acylhydrazone group to reduce cytotoxicity and improve metabolic stability. Detailed SAR studies and animal evaluation experiments led to the discovery of the compound 9ga, which significantly reduced TG accumulation with an EC50 value of 0.07 µM and showed relatively low cytotoxicity with an IC50 value of around 24 µM. Oral administration of 9ga effectively prevented the excessive growth of body weight and lessened fat mass as well as liver mass, decreased lipid accumulation in the liver and blood, and improved the heart injury parameter in the diet-induced obesity mouse model significantly better than Wd3d. A mechanism study showed that 9ga regulated the lipid metabolism during early adipogenesis by inhibiting PPARγ pathway. In conclusion, our study further highlights the anti-obesity potential of 2-pyrimidinylindole derivatives in diet-induced obesity.

Asunto(s)

Fármacos Antiobesidad , Diseño de Fármacos , Indoles , Obesidad , Relación Estructura-Actividad , Animales , Fármacos Antiobesidad/farmacología , Fármacos Antiobesidad/síntesis química , Fármacos Antiobesidad/química , Ratones , Indoles/química , Indoles/farmacología , Indoles/síntesis química , Obesidad/tratamiento farmacológico , Administración Oral , Estructura Molecular , Masculino , Pirimidinas/química , Pirimidinas/farmacología , Pirimidinas/síntesis química , Relación Dosis-Respuesta a Droga , Ratones Endogámicos C57BL , Humanos , Células 3T3-L1

RESUMEN

Periodontitis is a chronic inflammatory disease that affects about 45 %-50 % of adults worldwide, but the efficacy of current clinical therapies is unsatisfactory due to the complicated periodontal immune microenvironment. Thus, developing drugs that can regulate innate immune cells (e.g., macrophages) is a potent strategy to treat periodontitis. Here, we report that phloretin, a food plant-derived natural compound, is sufficient to alleviate periodontitis through immune regulation. In vivo, phloretin treatment could significantly reduce alveolar bone resorption and periodontal inflammation in mouse periodontitis models. In vitro, phloretin could suppress proinflammatory (M1-like) polarization and cytokine release in macrophages induced by LPS. Mechanistically, the immune regulatory role of phloretin in macrophages may be due to its metabolic regulation effect. Phloretin might restore the balance of M1/M2 macrophage transition in periodontitis by inhibiting HIF-1α-mediated glycolysis and PI3k/Akt pathways, thereby reducing the proinflammatory effect and immune disorder caused by over-activated M1 macrophages. Together, this study highlights that natural compound, such as phloretin, can restore periodontal immune homeostasis by metabolic regulation of macrophages, which may provide novel insight into the treatment of periodontitis.

Asunto(s)

Glucólisis , Homeostasis , Subunidad alfa del Factor 1 Inducible por Hipoxia , Macrófagos , Ratones Endogámicos C57BL , Periodontitis , Floretina , Fosfatidilinositol 3-Quinasas , Proteínas Proto-Oncogénicas c-akt , Animales , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Floretina/farmacología , Floretina/uso terapéutico , Glucólisis/efectos de los fármacos , Ratones , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Macrófagos/metabolismo , Periodontitis/tratamiento farmacológico , Periodontitis/inmunología , Periodontitis/metabolismo , Homeostasis/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Masculino , Lipopolisacáridos/inmunología , Humanos , Células RAW 264.7 , Modelos Animales de Enfermedad , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Citocinas/metabolismo , Pérdida de Hueso Alveolar/tratamiento farmacológico

RESUMEN

Exercise has emerged as one of the important and effective non-drug therapies used for management of type 2 diabetes (T2D) in certain nations. The present report summarizes the latest findings from the research on the beneficial effect of exercise on T2D. The objectives were to provide references for the theoretical study and the clinical practice of exercise-based management of T2D, in addition to identify the limitations of the existing literature, thereby provide direction for future research in this field.