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1.
Nano Lett ; 2024 Sep 03.
Artículo en Inglés | MEDLINE | ID: mdl-39225486

RESUMEN

Energetic carriers generated by localized surface plasmon resonance (LSPR) provide an efficient way to drive chemical reactions. However, their dynamics and impact on surface reactions remain unknown due to the challenge in observing hot holes. This makes it difficult to correlate the reduction and oxidation half-reactions involving hot electrons and holes, respectively. Here we detect hot holes in their chemical form, Ag(I), on a Ag surface using surface-enhanced Raman scattering (SERS) of SO32- as a hole-specific label. It allows us to determine the dynamic correlations of hot electrons and holes. We find that the equilibrium of holes is the key factor of the surface chemistry, and the wavelength-dependent plasmonic chemical anode refilling (PCAR) effect plays an important role, in addition to the LSPR, in promoting the electron transfer. This method paves the way for visualizing hot holes with nanoscale spatial resolution toward the rational design of a plasmonic catalytic platform.

2.
J Am Chem Soc ; 2024 Aug 31.
Artículo en Inglés | MEDLINE | ID: mdl-39215718

RESUMEN

Photodynamic therapy (PDT) has recently come to the forefront as an exceptionally powerful and promising method for the treatment of cancer. Existing photosensitizers are predominantly engineered to target diverse biomolecules, including proteins, DNA, lipids, and carbohydrates, and have proven to greatly enhance the efficacy or specificity of PDT. However, it is noteworthy that there exists a conspicuous scarcity of photosensitizers specifically designed to target RNAs. Recognizing the crucial and multifaceted roles played by RNAs in various cellular processes and disease states, we have ventured into the development of a novel RNA-targeting photosensitizer, named Se-718, designed specifically for PDT-based cancer therapy. Se-718 has been engineered to exhibit a high molar absorption coefficient in the NIR region, which is crucial for effective PDT. More importantly, Se-718 has demonstrated a distinct RNA-targeting capability, as evidenced through rigorous testing in both circular dichroism and fluorescence experiments. Furthermore, Se-718 has been shown to display both type I and type II photodynamic properties. This unique characteristic enables the efficient killing of cancer cells under a wide range of oxygen conditions, both normoxic (21% O2) and hypoxic (2% O2). The IC50 of Se-718 can be as low as 100 nM, and its light-to-dark toxicity ratio is an impressive 215 times higher, outperforming most photosensitizers currently available. Moreover, in vivo studies conducted with tumor-bearing mice have demonstrated the excellent antitumor effects and high safety profile of Se-718. Considering the outstanding PDT efficacy of Se-718, we are optimistic that the development of RNA-targeting photosensitizers may provide an innovative and highly effective option for cancer therapeutics in the near future.

3.
J Hepatol ; 81(3): 379-388, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38582304

RESUMEN

BACKGROUND & AIMS: Steatotic liver disease (SLD), characterized by elevated liver fat content (LFC), is influenced by genetics and diet. However, whether diet has a differential effect based on genetic risk is not well-characterized. We aimed to determine how genetic factors interact with diet to affect SLD in a large national biobank. METHODS: We included UK Biobank participants with dietary intake measured by 24-hour recall and genotyping. The primary predictors were dietary pattern, PNPLA3-rs738409-G, TM6SF2-rs58542926-T, a 16-variant hepatic steatosis polygenic risk score (PRS), and gene-environment interactions. The primary outcome was LFC, and secondary outcomes were iron-controlled T1 time (cT1, a measure of liver inflammation and fibrosis) and liver-related events/mortality. RESULTS: A total of 21,619 participants met inclusion criteria. In non-interaction models, Mediterranean diet and intake of fruit/vegetables/legumes and fish associated with lower LFC, while higher red/processed meat intake and all genetic predictors associated with higher LFC. In interaction models, all genetic predictors interacted with Mediterranean diet and fruit/vegetable/legume intake, while the steatosis PRS interacted with fish intake and the TM6SF2 genotype interacted with red/processed meat intake, to affect LFC. Dietary effects on LFC were up to 3.8-fold higher in PNPLA3-rs738409-GG vs. -CC individuals, and 1.4-3.0-fold higher in the top vs. bottom quartile of the steatosis PRS. Gene-diet interactions were stronger in participants with vs. without overweight. The steatosis PRS interacted with Mediterranean diet and fruit/vegetable/legume intake to affect cT1 and most dietary and genetic predictors associated with risk of liver-related events or mortality by age 70. CONCLUSIONS: Effects of diet on LFC and cT1 were markedly accentuated in patients at increased genetic risk for SLD, implying dietary interventions may be more impactful in these populations. IMPACT AND IMPLICATIONS: Genetic variants and diet both influence risk of hepatic steatosis, inflammation/fibrosis, and hepatic decompensation; however, how gene-diet interactions influence these outcomes has previously not been comprehensively characterized. We investigated this topic in the community-based UK Biobank and found that genetic risk and dietary quality interacted to influence hepatic steatosis and inflammation/fibrosis on liver MRI, so that the effects of diet were greater in people at elevated genetic risk. These results are relevant for patients and medical providers because they show that genetic risk is not fixed (i.e. modifiable factors can mitigate or exacerbate this risk) and realistic dietary changes may result in meaningful improvement in liver steatosis and inflammation/fibrosis. As genotyping becomes more routinely used in clinical practice, patients identified to be at high baseline genetic risk may benefit even more from intensive dietary counseling than those at lower risk, though future prospective studies are required.


Asunto(s)
Hígado Graso , Humanos , Masculino , Femenino , Persona de Mediana Edad , Hígado Graso/etiología , Hígado Graso/genética , Cirrosis Hepática/etiología , Cirrosis Hepática/genética , Cirrosis Hepática/epidemiología , Anciano , Predisposición Genética a la Enfermedad , Lipasa/genética , Interacción Gen-Ambiente , Proteínas de la Membrana/genética , Reino Unido/epidemiología , Estudios de Cohortes , Dieta Mediterránea , Dieta/efectos adversos , Dieta/métodos , Inflamación/genética , Inflamación/etiología , Adulto , Factores de Riesgo , Polimorfismo de Nucleótido Simple , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/epidemiología , Aciltransferasas , Fosfolipasas A2 Calcio-Independiente
4.
Gastroenterology ; 164(6): 966-977.e17, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-36758837

RESUMEN

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) can progress to cirrhosis and hepatic decompensation, but whether genetic variants influence the rate of progression to cirrhosis or are useful in risk stratification among patients with NAFLD is uncertain. METHODS: We included participants from 2 independent cohorts, they Michigan Genomics Initiative (MGI) and UK Biobank (UKBB), who had NAFLD defined by elevated alanine aminotransferase (ALT) levels in the absence of alternative chronic liver disease. The primary predictors were genetic variants and metabolic comorbidities associated with cirrhosis. We conducted time-to-event analyses using Fine-Gray competing risk models. RESULTS: We included 7893 and 46,880 participants from MGI and UKBB, respectively. In univariable analysis, PNPLA3-rs738409-GG genotype, diabetes, obesity, and ALT of ≥2× upper limit of normal were associated with higher incidence rate of cirrhosis in both MGI and UKBB. PNPLA3-rs738409-GG had additive effects with clinical risk factors including diabetes, obesity, and ALT elevations. Among patients with indeterminate fibrosis-4 (FIB4) scores (1.3-2.67), those with diabetes and PNPLA3-rs738409-GG genotype had an incidence rate of cirrhosis comparable to that of patients with high-risk FIB4 scores (>2.67) and 2.9-4.8 times that of patients with diabetes but CC/CG genotypes. In contrast, FIB4 <1.3 was associated with an incidence rate of cirrhosis significantly lower than that of FIB4 of >2.67, even in the presence of clinical risk factors and high-risk PNPLA3 genotype. CONCLUSIONS: PNPLA3-rs738409 genotype and diabetes identified patients with NAFLD currently considered indeterminate risk (FIB4 1.3-2.67) who had a similar risk of cirrhosis as those considered high-risk (FIB4 >2.67). PNPLA3 genotyping may improve prognostication and allow for prioritization of intensive intervention.


Asunto(s)
Diabetes Mellitus , Enfermedad del Hígado Graso no Alcohólico , Humanos , Diabetes Mellitus/diagnóstico , Diabetes Mellitus/epidemiología , Diabetes Mellitus/genética , Predisposición Genética a la Enfermedad , Genotipo , Cirrosis Hepática/diagnóstico , Cirrosis Hepática/epidemiología , Cirrosis Hepática/genética , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Enfermedad del Hígado Graso no Alcohólico/epidemiología , Enfermedad del Hígado Graso no Alcohólico/genética , Obesidad/complicaciones , Polimorfismo de Nucleótido Simple
5.
J Stroke Cerebrovasc Dis ; 33(4): 107616, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38316284

RESUMEN

OBJECTIVE: The clinical characteristics and mechanisms of stroke caused by anterior circulation atherosclerotic plaques (ACAPs) and posterior circulation atherosclerotic plaques (PCAPs) are distinct. We aimed to compare the differences in vulnerability, morphology, and distribution between ACAPs and PCAPs based on hign-resolution magnetic resonance imaging (HR-MRI). MATERIALS AND METHODS: The PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), and Wanfang database were retrieved from inception through May 2023. Meta-analysis was performed by R 4.2.1 software. The quality of the literature was assessed by the Agency for Healthcare Research and Quality (AHRQ). Subgroup analysis was conducted to explore the heterogeneity of the pooled results. RESULTS: There were a total of 13 articles, including 1194 ACAPs and 1037 PCAPs. The pooled estimates demonstrated that the incidence of intraplaque hemorrhage in the PCAPs was higher (OR 1.72, 95%CI 1.35-2.18). The plaque length (SMD 0.23, 95%CI 0.06-0.39) and remodeling index (SMD 0.29, 95%CI 0.14-0.44) of PCAPs were larger than those in ACAPs. However, there were no evident differences in significant enhancement or stenosis degree between the two groups. CONCLUSION: There were more unstable features in PCAPs, highlighting an elevated risk of recurrent ischemic stroke in the posterior circulation. Furthermore, PCAPs were prone to developing penetrating artery disease due to their wider distribution. Nevertheless, posterior circulation arteries exhibited a greater propensity for outward remodeling, which may lead treatment team to miss the optimal intervention stage by being overlooked on angiographic detection.


Asunto(s)
Circulación Cerebrovascular , Arteriosclerosis Intracraneal , Imagen por Resonancia Magnética , Placa Aterosclerótica , Valor Predictivo de las Pruebas , Humanos , Arteriosclerosis Intracraneal/diagnóstico por imagen , Factores de Riesgo , Masculino , Femenino , Anciano , Persona de Mediana Edad , Medición de Riesgo , Rotura Espontánea , Pronóstico , Arteria Cerebral Posterior/diagnóstico por imagen , Arteria Cerebral Posterior/fisiopatología , Arteria Cerebral Anterior/diagnóstico por imagen , Arteria Cerebral Anterior/fisiopatología , Anciano de 80 o más Años
6.
Angew Chem Int Ed Engl ; 63(10): e202318817, 2024 Mar 04.
Artículo en Inglés | MEDLINE | ID: mdl-38224169

RESUMEN

Plasmonic catalysis has emerged as a promising approach to solar-chemical energy conversion. Notably, hot carriers play a decisive role in plasmonic catalysis since only when their energy matches with the LUMO or HOMO energy of the reactant molecule, can the reaction be activated. However, the hot carrier energy depends on the intrinsic physicochemical properties of the plasmonic metal substrate and the interaction with incident light. Tuning the hot carrier energy is of great significance for plasmonic catalysis but remains challenging. Here, we demonstrate that the energy of hot electrons can be significantly elevated to an unprecedented level through the coordination of amines on Ag surface. The bonding of amines and Ag reduces the work function of nanoparticles, leading to the increase of hot electron energy by 0.4 eV. This enhancement of energy promotes the cleavage of C-X (X=Cl, F) bonds upon excitation by visible light. This study provides new insights for promoting plasmonic charge transfer and enhancing the photocatalytic performance of plasmon-mediated systems.

7.
Angew Chem Int Ed Engl ; 63(35): e202409656, 2024 Aug 26.
Artículo en Inglés | MEDLINE | ID: mdl-38837290

RESUMEN

Perovskite quantum dots (QDs) have shown attractive prospects in the field of visible photocatalysis, especially in the synthesis of high value-added chemicals. However, under aerobic conditions, the stable operation of QD catalysts has been limited by the reactive oxygen species (ROS) generated by photoexcitation, especially superoxide species O2⋅-. Here, we propose a strategy of Ce3+ doping in perovskite QDs to guide superoxide species for photocatalytic oxidation reactions. In C(sp3)-H bond oxidation of hydrocarbons, superoxide species were rapidly generated and efficiently utilized on the surface of perovskite QDs, which achieves the stable operation of the catalytic system and obtains a high product conversion rate (15.3 mmol/g/h for benzaldehydes). The mechanism studies show that the strong Ce-oxygen affinity accelerates the relaxation process of photoinduced exciton transfer to superoxide species and inhibits the radiative recombination pathway. This work provides a new idea of utilizing oxygen species on perovskite surface and broadens the design strategy of high-performance QD photocatalysts.

8.
Hum Mol Genet ; 30(15): 1443-1456, 2021 07 09.
Artículo en Inglés | MEDLINE | ID: mdl-33856023

RESUMEN

Nonalcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease and is highly correlated with metabolic disease. NAFLD results from environmental exposures acting on a susceptible polygenic background. This study performed the largest multiethnic investigation of exonic variation associated with NAFLD and correlated metabolic traits and diseases. An exome array meta-analysis was carried out among eight multiethnic population-based cohorts (n = 16 492) with computed tomography (CT) measured hepatic steatosis. A fixed effects meta-analysis identified five exome-wide significant loci (P < 5.30 × 10-7); including a novel signal near TOMM40/APOE. Joint analysis of TOMM40/APOE variants revealed the TOMM40 signal was attributed to APOE rs429358-T; APOE rs7412 was not associated with liver attenuation. Moreover, rs429358-T was associated with higher serum alanine aminotransferase, liver steatosis, cirrhosis, triglycerides and obesity; as well as, lower cholesterol and decreased risk of myocardial infarction and Alzheimer's disease (AD) in phenome-wide association analyses in the Michigan Genomics Initiative, United Kingdom Biobank and/or public datasets. These results implicate APOE in imaging-based identification of NAFLD. This association may or may not translate to nonalcoholic steatohepatitis; however, these results indicate a significant association with advanced liver disease and hepatic cirrhosis. These findings highlight allelic heterogeneity at the APOE locus and demonstrate an inverse link between NAFLD and AD at the exome level in the largest analysis to date.


Asunto(s)
Apolipoproteínas E/genética , Enfermedad del Hígado Graso no Alcohólico/genética , Obesidad/genética , Alanina Transaminasa , Alelos , Enfermedad de Alzheimer/genética , Apolipoproteínas E/metabolismo , Bases de Datos Genéticas , Exoma/genética , Frecuencia de los Genes/genética , Estudio de Asociación del Genoma Completo/métodos , Humanos , Hígado , Cirrosis Hepática/genética , Infarto del Miocardio/genética , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Obesidad/metabolismo , Fenotipo , Polimorfismo de Nucleótido Simple/genética , Pronóstico , Factores de Riesgo , Triglicéridos
9.
J Hepatol ; 79(5): 1226-1235, 2023 11.
Artículo en Inglés | MEDLINE | ID: mdl-37567366

RESUMEN

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD), and its progressive form steatohepatitis (NASH), represent a genetically and phenotypically diverse entity for which there is no approved therapy, making it imperative to define the spectrum of pathways contributing to its pathogenesis. Rare variants in genes encoding nuclear envelope proteins cause lipodystrophy with early-onset NAFLD/NASH; we hypothesized that common variants in nuclear envelope-related genes might also contribute to hepatic steatosis and NAFLD. METHODS: Using hepatic steatosis as the outcome of interest, we performed an association meta-analysis of nuclear envelope-related coding variants in three large discovery cohorts (N >120,000 participants), followed by phenotype association studies in large validation cohorts (N >600,000) and functional testing of the top steatosis-associated variant in cell culture. RESULTS: A common protein-coding variant, rs6461378 (SUN1 H118Y), was the top steatosis-associated variant in our association meta-analysis (p <0.001). In ancestrally distinct validation cohorts, rs6461378 associated with histologic NAFLD and with NAFLD-related metabolic traits including increased serum fatty acids, type 2 diabetes, hypertension, cardiovascular disease, and decreased HDL. SUN1 H118Y was subject to increased proteasomal degradation relative to wild-type SUN1 in cells, and SUN1 H118Y-expressing cells exhibited insulin resistance and increased lipid accumulation. CONCLUSIONS: Collectively, these data support a potential causal role for the common SUN1 variant rs6461378 in NAFLD and metabolic disease. IMPACT AND IMPLICATIONS: Non-alcoholic fatty liver disease (NAFLD), with an estimated global prevalence of nearly 30%, is a growing cause of morbidity and mortality for which there is no approved pharmacologic therapy. Our data provide a rationale for broadening current concepts of NAFLD genetics and pathophysiology to include the nuclear envelope, and particularly Sad1 and UNC84 domain containing 1 (SUN1), as novel contributors to this common liver disease. Furthermore, if future studies confirm causality of the common SUN1 H118Y variant, it has the potential to become a broadly relevant therapeutic target in NAFLD and metabolic disease.


Asunto(s)
Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , Enfermedad del Hígado Graso no Alcohólico , Humanos , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Fenotipo , Proteínas de la Membrana/genética , Proteínas Asociadas a Microtúbulos , Proteínas Nucleares
10.
Ann Surg ; 277(6): e1262-e1268, 2023 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-35876359

RESUMEN

OBJECTIVE: To derive and validate a polygenic risk score (PRS) to predict the occurrence and severity of diverticulitis and to understand the potential for incorporation of a PRS in current decision-making. BACKGROUND: PRS quantifies genetic variation into a continuous measure of risk. There is a need for improved risk stratification to guide surgical decision-making that could be fulfilled by PRS. It is unknown how surgeons might integrate PRS in decision-making. METHODS: We derived a PRS with 44 single-nucleotide polymorphisms associated with diverticular disease in the UK Biobank and validated this score in the Michigan Genomics Initiative (MGI). We performed a discrete choice experiment of practicing colorectal surgeons. Surgeons rated the influence of clinical factors and a hypothetical polygenic risk prediction tool. RESULTS: Among 2812 MGI participants with diverticular disease, 1964 were asymptomatic, 574 had mild disease, and 274 had severe disease. PRS was associated with occurrence and severity. Patients in the highest PRS decile were more likely to have diverticulitis [odds ratio (OR)=1.84; 95% confidence interval (CI), 1.42-2.38)] and more likely to have severe diverticulitis (OR=1.61; 95% CI, 1.04-2.51) than the bottom 50%. Among 213 surveyed surgeons, extreme disease-specific factors had the largest utility (3 episodes in the last year, +74.4; percutaneous drain, + 69.4). Factors with strongest influence against surgery included 1 lifetime episode (-63.3), outpatient management (-54.9), and patient preference (-39.6). PRS was predicted to have high utility (+71). CONCLUSIONS: A PRS derived from a large national biobank was externally validated, and found to be associated with the incidence and severity of diverticulitis. Surgeons have clear guidance at clinical extremes, but demonstrate equipoise in intermediate scenarios. Surgeons are receptive to PRS, which may be most useful in marginal clinical situations. Given the current lack of accurate prognostication in recurrent diverticulitis, PRS may provide a novel approach for improving patient counseling and decision-making.


Asunto(s)
Diverticulitis , Humanos , Factores de Riesgo , Michigan/epidemiología , Estudio de Asociación del Genoma Completo , Predisposición Genética a la Enfermedad
11.
Genet Epidemiol ; 45(1): 4-15, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-32964493

RESUMEN

Carotid artery atherosclerotic disease (CAAD) is a risk factor for stroke. We used a genome-wide association (GWAS) approach to discover genetic variants associated with CAAD in participants in the electronic Medical Records and Genomics (eMERGE) Network. We identified adult CAAD cases with unilateral or bilateral carotid artery stenosis and controls without evidence of stenosis from electronic health records at eight eMERGE sites. We performed GWAS with a model adjusting for age, sex, study site, and genetic principal components of ancestry. In eMERGE we found 1793 CAAD cases and 17,958 controls. Two loci reached genome-wide significance, on chr6 in LPA (rs10455872, odds ratio [OR] (95% confidence interval [CI]) = 1.50 (1.30-1.73), p = 2.1 × 10-8 ) and on chr7, an intergenic single nucleotide variant (SNV; rs6952610, OR (95% CI) = 1.25 (1.16-1.36), p = 4.3 × 10-8 ). The chr7 association remained significant in the presence of the LPA SNV as a covariate. The LPA SNV was also associated with coronary heart disease (CHD; 4199 cases and 11,679 controls) in this study (OR (95% CI) = 1.27 (1.13-1.43), p = 5 × 10-5 ) but the chr7 SNV was not (OR (95% CI) = 1.03 (0.97-1.09), p = .37). Both variants replicated in UK Biobank. Elevated lipoprotein(a) concentrations ([Lp(a)]) and LPA variants associated with elevated [Lp(a)] have previously been associated with CAAD and CHD, including rs10455872. With electronic health record phenotypes in eMERGE and UKB, we replicated a previously known association and identified a novel locus associated with CAAD.


Asunto(s)
Estenosis Carotídea , Estudio de Asociación del Genoma Completo , Registros Electrónicos de Salud , Predisposición Genética a la Enfermedad , Genómica , Humanos , Lipoproteína(a)/genética , Modelos Genéticos , Polimorfismo de Nucleótido Simple
12.
Small ; 18(31): e2202834, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35808966

RESUMEN

Chemoradiotherapy (CRT) is the most accepted treatment for locally advanced pancreatic ductal adenocarcinoma (PDAC) and can significantly improve the R0 resection rate. However, there are few long-term survivors after CRT. Although some polymer nanoparticles have shown potential in alleviating the dose-limiting toxicity and assisting the chemotherapy of PDAC, there are few efficient nanosensitizers (NS) available for CRT of this malignancy, especially in the context of its hypoxic nature. Herein, based on the biological features of PDAC, a γ-glutamyl transpeptidase (GGT)/glutathione (GSH)/hypoxia triple-responsive prodrug NS to overcome the biological barrier and microenvironmental limitations confronted by CRT in PDAC is developed. Due to triple-responsiveness, deep tumor penetration, GSH/hypoxia-responsive drug release/activation, and hypoxia-induced chemoradio-sensitization can be simultaneously achieved with this NS. As a result, tumor shrinkage after CRT with this NS can be observed in both subcutaneous and orthotopic PDAC models, foreshadowing its potential in clinical neoadjuvant CRT.


Asunto(s)
Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Profármacos , Carcinoma Ductal Pancreático/tratamiento farmacológico , Quimioradioterapia , Humanos , Hipoxia/tratamiento farmacológico , Neoplasias Pancreáticas/tratamiento farmacológico , Profármacos/uso terapéutico , Neoplasias Pancreáticas
13.
Int J Mol Sci ; 22(18)2021 Sep 09.
Artículo en Inglés | MEDLINE | ID: mdl-34575933

RESUMEN

Non-alcoholic fatty liver disease (NAFLD) is caused by excess lipid accumulation in hepatocytes. Genome-wide association studies have identified a strong association of NAFLD with non-synonymous E167K amino acid mutation in the transmembrane 6 superfamily member 2 (TM6SF2) protein. The E167K mutation reduces TM6SF2 stability, and its carriers display increased hepatic lipids and lower serum triglycerides. However, the effects of TM6SF2 on hepatic lipid metabolism are not completely understood. We overexpressed wild-type or E167K variant of TM6SF2 or knocked down TM6SF2 expression in lipid-treated Huh-7 cells and used untargeted lipidomic analysis, RNAseq transcriptome analysis, and fluorescent imaging to determine changes in hepatic lipid metabolism. Both TM6SF2 knockdown and E167K overexpression increased hepatic lipid accumulation, while wild-type overexpression decreased acylglyceride levels. We also observed lipid chain remodeling for acylglycerides by TM6SF2 knockdown, leading to a relative increase in species with shorter, more saturated side chains. RNA-sequencing revealed differential expression of several lipid metabolizing genes, including genes belonging to AKR1 family and lipases, primarily in cells with TM6SF2 knockdown. Taken together, our data show that overexpression of TM6SF2 gene or its loss-of-function changes hepatic lipid species composition and expression of lipid metabolizing genes. Additionally, our data further confirms a loss-of-function effect for the E167K variant.


Asunto(s)
Regulación de la Expresión Génica , Hepatocitos/metabolismo , Metabolismo de los Lípidos/genética , Proteínas de la Membrana/genética , Línea Celular , Genotipo , Humanos , Metaboloma , Metabolómica/métodos
14.
Hepatology ; 69(4): 1504-1519, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30415504

RESUMEN

Nonalcoholic fatty liver disease (NAFLD) is a common cause of chronic liver disease. A single-nucleotide polymorphism (SNP), rs6834314, was associated with serum liver enzymes in the general population, presumably reflecting liver fat or injury. We studied rs6834314 and its nearest gene, 17-beta hydroxysteroid dehydrogenase 13 (HSD17B13), to identify associations with histological features of NAFLD and to characterize the functional role of HSD17B13 in NAFLD pathogenesis. The minor allele of rs6834314 was significantly associated with increased steatosis but decreased inflammation, ballooning, Mallory-Denk bodies, and liver enzyme levels in 768 adult Caucasians with biopsy-proven NAFLD and with cirrhosis in the general population. We found two plausible causative variants in the HSD17B13 gene. rs72613567, a splice-site SNP in high linkage with rs6834314 (r2 = 0.94) generates splice variants and shows a similar pattern of association with NAFLD histology. Its minor allele generates simultaneous expression of exon 6-skipping and G-nucleotide insertion variants. Another SNP, rs62305723 (encoding a P260S mutation), is significantly associated with decreased ballooning and inflammation. Hepatic expression of HSD17B13 is 5.9-fold higher (P = 0.003) in patients with NAFLD. HSD17B13 is targeted to lipid droplets, requiring the conserved amino acid 22-28 sequence and amino acid 71-106 region. The protein has retinol dehydrogenase (RDH) activity, with enzymatic activity dependent on lipid droplet targeting and cofactor binding site. The exon 6 deletion, G insertion, and naturally occurring P260S mutation all confer loss of enzymatic activity. Conclusion: We demonstrate the association of variants in HSD17B13 with specific features of NAFLD histology and identify the enzyme as a lipid droplet-associated RDH; our data suggest that HSD17B13 plays a role in NAFLD through its enzymatic activity.


Asunto(s)
17-Hidroxiesteroide Deshidrogenasas/genética , Enfermedad del Hígado Graso no Alcohólico/genética , 17-Hidroxiesteroide Deshidrogenasas/metabolismo , Adulto , Secuencia de Aminoácidos , Estudios de Cohortes , Femenino , Células HEK293 , Células Hep G2 , Humanos , Hígado/metabolismo , Masculino , Persona de Mediana Edad , Terapia Molecular Dirigida , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Polimorfismo de Nucleótido Simple , Retinoides/metabolismo
15.
Liver Int ; 40(2): 405-415, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31815349

RESUMEN

BACKGROUND AND AIMS: Cirrhosis is characterized by extensive fibrosis of the liver and is a major cause of liver-related mortality. Cirrhosis is partially heritable but genetic contributions to cirrhosis have not been systemically explored. Here, we carry out association analyses with cirrhosis in two large biobanks and determine the effects of cirrhosis associated variants on multiple human disease/traits. METHODS: We carried out a genome-wide association analysis of cirrhosis as a diagnosis in UK BioBank (UKBB; 1088 cases vs. 407 873 controls) and then tested top-associating loci for replication with cirrhosis in a hospital-based cohort from the Michigan Genomics Initiative (MGI; 875 cases of cirrhosis vs. 30 346 controls). For replicating variants or variants previously associated with cirrhosis that also affected cirrhosis in UKBB or MGI, we determined single nucleotide polymorphism effects on all other diagnoses in UKBB (PheWAS), common metabolic traits/diseases and serum/plasma metabolites. RESULTS: Unbiased genome-wide association study identified variants in/near PNPLA3 and HFE, and candidate variant analysis identified variants in/near TM6SF2, MBOAT7, SERPINA1, HSD17B13, STAT4 and IFNL4 that reproducibly affected cirrhosis. Most affected liver enzyme concentrations and/or aspartate transaminase-to-platelet ratio index. PheWAS, metabolic trait and serum/plasma metabolite association analyses revealed effects of these variants on lipid, inflammatory and other processes including new effects on many human diseases and traits. CONCLUSIONS: We identified eight loci that reproducibly associate with population-based cirrhosis and define their diverse effects on human diseases and traits.


Asunto(s)
Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Cirrosis Hepática , Pleiotropía Genética , Humanos , Cirrosis Hepática/genética , Fenotipo , Polimorfismo de Nucleótido Simple
16.
Analyst ; 144(6): 1916-1922, 2019 Mar 11.
Artículo en Inglés | MEDLINE | ID: mdl-30681671

RESUMEN

Antibiotics have been noted as an important class of emerging contaminants in the environment. Metal-organic frameworks (MOFs), which have been intensely investigated as a novel kind of sensing material, have been tentatively applied to the detection of antibiotics in recent years. In this work, a nanoscale MOF (In-sbdc) with a strong (quantum yield = 13%) and stable emission in water was synthesized. With its effective spectral overlap with tetracyclines, adsorption preconcentration and the usage of a masking agent, In-sbdc gave sensitive responses to a series of tetracycline antibiotics (tetracycline, chlorotetracycline and oxytetracycline) with detection limits of 0.28-0.30 µM, but another eight tested kinds of antibiotics did not cause a remarkable change in its emission (<10% of the response caused by an equal amount of tetracyclines). This MOF-based sensing system was successfully applied to tetracyclines detection in a series of actual water and food samples.


Asunto(s)
Antibacterianos/análisis , Técnicas Biosensibles , Monitoreo del Ambiente/métodos , Análisis de los Alimentos/métodos , Estructuras Metalorgánicas/química , Tetraciclinas/análisis , Contaminantes Químicos del Agua/análisis , Fluorescencia , Límite de Detección
17.
RSC Adv ; 14(21): 14470-14479, 2024 May 02.
Artículo en Inglés | MEDLINE | ID: mdl-38708116

RESUMEN

Promoting angiogenesis following biomaterial implantation is essential to bone tissue regeneration. Herein, the composite scaffolds composed of zein, whitlockite (WH), and levofloxacin (LEVO) were fabricated to augment bone repair by facilitating osteogenesis and angiogenesis. First, three-dimensional composite scaffolds containing zein and WH were prepared using the salt-leaching method. Then, as a model antibiotic drug, the LEVO was loaded into zein/WH scaffolds. Moreover, the addition of WH enhanced the adhesion, differentiation, and mineralization of osteoblasts. The zein/WH/LEVO composite scaffolds not only had significant osteoinductivity but also showed excellent antibacterial properties. The prepared composite scaffolds were then implanted into a calvarial defect model to evaluate their osteogenic induction effects in vivo. Micro-CT observation and histological analysis indicate that the scaffolds can accelerate bone regeneration with the contribution of endogenous cytokines. Based on amounts of data in vitro and in vivo, the scaffolds present profound effects on improving bone regeneration, especially for the favorable osteogenic, intensive angiogenic, and alleviated inflammation abilities. The results showed that the synthesized scaffolds could be a potential material for bone tissue engineering.

18.
J Imaging Inform Med ; 2024 Aug 15.
Artículo en Inglés | MEDLINE | ID: mdl-39147885

RESUMEN

This study aimed to establish and validate the efficacy of a nomogram model, synthesized through the integration of multi-parametric magnetic resonance radiomics and clinical risk factors, for forecasting perineural invasion in rectal cancer. We retrospectively collected data from 108 patients with pathologically confirmed rectal adenocarcinoma who underwent preoperative multiparametric MRI at the First Affiliated Hospital of Bengbu Medical College between April 2019 and August 2023. This dataset was subsequently divided into training and validation sets following a ratio of 7:3. Both univariate and multivariate logistic regression analyses were implemented to identify independent clinical risk factors associated with perineural invasion (PNI) in rectal cancer. We manually delineated the region of interest (ROI) layer-by-layer on T2-weighted imaging (T2WI) and diffusion-weighted imaging (DWI) sequences and extracted the image features. Five machine learning algorithms were used to construct radiomics model with the features selected by least absolute shrinkage and selection operator (LASSO) method. The optimal radiomics model was then selected and combined with clinical features to formulate a nomogram model. The model performance was evaluated using receiver operating characteristic (ROC) curve analysis, and its clinical value was assessed via decision curve analysis (DCA). Our final selection comprised 10 optimal radiological features and the SVM model showcased superior predictive efficiency and robustness among the five classifiers. The area under the curve (AUC) values of the nomogram model were 0.945 (0.899, 0.991) and 0.846 (0.703, 0.99) for the training and validation sets, respectively. The nomogram model developed in this study exhibited excellent predictive performance in foretelling PNI of rectal cancer, thereby offering valuable guidance for clinical decision-making. The nomogram could predict the perineural invasion status of rectal cancer in early stage.

19.
Nat Genet ; 56(2): 212-221, 2024 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38200128

RESUMEN

Insulin resistance (IR) is a well-established risk factor for metabolic disease. The ratio of triglycerides to high-density lipoprotein cholesterol (TG:HDL-C) is a surrogate marker of IR. We conducted a genome-wide association study of the TG:HDL-C ratio in 402,398 Europeans within the UK Biobank. We identified 369 independent SNPs, of which 114 had a false discovery rate-adjusted P value < 0.05 in other genome-wide studies of IR making them high-confidence IR-associated loci. Seventy-two of these 114 loci have not been previously associated with IR. These 114 loci cluster into five groups upon phenome-wide analysis and are enriched for candidate genes important in insulin signaling, adipocyte physiology and protein metabolism. We created a polygenic-risk score from the high-confidence IR-associated loci using 51,550 European individuals in the Michigan Genomics Initiative. We identified associations with diabetes, hyperglyceridemia, hypertension, nonalcoholic fatty liver disease and ischemic heart disease. Collectively, this study provides insight into the genes, pathways, tissues and subtypes critical in IR.


Asunto(s)
Resistencia a la Insulina , Humanos , Resistencia a la Insulina/genética , Biobanco del Reino Unido , Estudio de Asociación del Genoma Completo , Bancos de Muestras Biológicas , Insulina , Biomarcadores , HDL-Colesterol/genética , Triglicéridos/genética
20.
Sci Adv ; 10(14): eadm9322, 2024 Apr 05.
Artículo en Inglés | MEDLINE | ID: mdl-38578997

RESUMEN

Flexible and stretchable thin-film transistors (TFTs) are crucial in skin-like electronics for wearable and implantable applications. Such electronics are usually constrained in performance owing to a lack of high-mobility and stretchable semiconducting channels. Tellurium, a rising semiconductor with superior charge carrier mobilities, has been limited by its intrinsic brittleness and anisotropy. Here, we achieve highly oriented arrays of tellurium nanowires (TeNWs) on various substrates with wafer-scale scalability by a facile lock-and-shear strategy. Such an assembly approach mimics the alignment process of the trailing tentacles of a swimming jellyfish. We further apply these TeNW arrays in high-mobility TFTs and logic gates with improved flexibility and stretchability. More specifically, mobilities over 100 square centimeters per volt per second and on/off ratios of ~104 are achieved in TeNW-TFTs. The TeNW-TFTs on polyethylene terephthalate can sustain an omnidirectional bending strain of 1.3% for more than 1000 cycles. Furthermore, TeNW-TFTs on an elastomeric substrate can withstand a unidirectional strain of 40% with no performance degradation.

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