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1.
Front Endocrinol (Lausanne) ; 12: 604100, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33763027

RESUMO

Background and Aim: Circulating levels of interleukin (IL)-6, a well-known inflammatory cytokine, are often elevated in coronavirus disease-2019 (COVID-19). Elevated IL-6 levels are also observed in patients with metabolic dysfunction-associated fatty liver disease (MAFLD). Our study aimed to describe the association between circulating IL-6 levels and MAFLD at hospital admission with risk of severe COVID-19. Methods: A total of 167 patients with laboratory-confirmed COVID-19 from three Chinese hospitals were enrolled. Circulating levels of IL-2, IL-4, IL-6, IL-10, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ were measured at admission. All patients were screened for fatty liver by computed tomography. Forty-six patients were diagnosed as MAFLD. Results: Patients with MAFLD (n = 46) had higher serum IL-6 levels (median 7.1 [interquartile range, 4.3-20.0] vs. 4.8 [2.6-11.6] pg/mL, p = 0.030) compared to their counterparts without MAFLD (n = 121). After adjustment for age and sex, patients with MAFLD had a ~2.6-fold higher risk of having severe COVID-19 than those without MAFLD. After adjustment for age, sex and metabolic co-morbidities, increased serum IL-6 levels remained associated with higher risk of severe COVID-19, especially among infected patients with MAFLD (adjusted-odds ratio 1.14, 95% CI 1.05-1.23; p = 0.002). There was a significant interaction effect between serum IL-6 levels and MAFLD for risk of severe COVID-19 (p for interaction = 0.008). Conclusions: Patients with MAFLD and elevated serum IL-6 levels at admission are at higher risk for severe illness from COVID-19.


Assuntos
/complicações , Fígado Gorduroso/epidemiologia , Interleucina-6/sangue , Doenças Metabólicas/fisiopatologia , Índice de Gravidade de Doença , Adolescente , Adulto , Idoso , /virologia , China/epidemiologia , Fígado Gorduroso/sangue , Fígado Gorduroso/patologia , Fígado Gorduroso/virologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Adulto Jovem
2.
Life Sci Alliance ; 4(3)2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33376133

RESUMO

p53 is the most frequently mutated gene in human cancers. Li-Fraumeni syndrome patients inheriting heterozygous p53 mutations often have a much-increased risk to develop cancer(s) at early ages. Recent studies suggest that some individuals inherited p53 mutations do not have the early onset or high frequency of cancers. These observations suggest that other genetic, environmental, immunological, epigenetic, or stochastic factors modify the penetrance of the cancerous mutant Tp53 phenotype. To test this possibility, this study explored dominant genetic modifiers of Tp53 mutations in heterozygous mice with different genetic backgrounds. Both genetic and stochastic effects upon tumor formation were observed in these mice. The genetic background of mice carrying Tp53 mutations has a strong influence upon the tissue type of the tumor produced and the number of tumors formed in a single mouse. The onset age of a tumor is correlated with the tissue type of that tumor, although identical tumor tissue types can occur at very different ages. These observations help to explain the great diversity of cancers in different Li-Fraumeni patients over lifetimes.

3.
Drug Des Devel Ther ; 14: 4765-4774, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33192052

RESUMO

Objective: We aimed to investigate the effects of snake-derived phospholipase A2 inhibitor (PLA2) from Sinonatrix percarinata and Bungarus multicinctus on acute pancreatitis in vivo and in vitro and assess the mechanisms. Methods: The levels of platelet-activating factor (PAF) and tumor necrosis factor (TNF)-α were detected by ELISA, and the characteristics of autophagy were detected by transmission electron microscopy and Western blotting (LC3, p62, and ATG5). Results: In vitro experiments showed that PLA2 treatment caused obvious formation of autophagic bodies. By contrast, Sinonatrix and Bungarus peptides reduced the number of autophagic bodies. The concentrations of PAF and TNF-α, and the expressions of p62, autophagy-related 5 (ATG5), and microtubule-associated protein 1A/1B-light chain 3 (LC3)II/LC3I in the PLA2-treated group were significantly higher than in the control group (P<0.05). The concentrations of PAF and TNF-α, and the expressions of p62, ATG5, and LC3II/LC3I in the Sinonatrix or Bungarus peptide treatment groups were significantly lower than in the PLA2-treated cells (P<0.05). In the pancreatic tissue, autophagic bodies were observed in the model group; autophagic bodies were remarkably reduced in Sinonatrix or Bungarus peptide-treated groups compared with the model group. In vivo experiments also showed that the levels of PAF and TNF-α, and the expressions of p62, ATG5, and LC3II/LC3I were significantly higher in the model group than in the control group (P<0.05). The levels of PAF and TNF-α in the model group, and the expressions of p62, ATG5, and LC3II/LC3I in Sinonatrix or Bungarus peptide-treated groups were significantly lower than in the model group (P<0.05). Conclusion: Sinonatrix or Bungarus peptide could ameliorate the features of acute pancreatitis, likely through regulating autophagy.

4.
Chem Commun (Camb) ; 56(92): 14353-14356, 2020 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-33169746

RESUMO

In the present work, we have introduced a series of stable radical-doped coordination compounds composed of donor-acceptor structures and shown to produce organic radicals in situ as a result of unconventional lone pair-π interactions in ambient conditions. Inconspicuous lone pair-π and C-Hπ interactions were shown to play a key role in self-assembly as well as the charge transfer process, resulting in a long-lived charge-separated state able to generate organic radicals. The resultant species displayed broad-spectrum antimicrobial activity, including against multi-drug-resistant bacteria. This study unveiled the promise of reactive organic radical-doped materials as a new platform for developing antimicrobial agents that can overcome antibiotic resistance.

5.
Artigo em Inglês | MEDLINE | ID: mdl-33089632

RESUMO

Buried salt bridges widely exist in protein structures but are rarely used in synthetic systems for molecular recognition in water. By mimicking the binding pocket of bioreceptors, we designed and synthesized a pair of endo-functionalized macrocyclic hosts with secondary ammonium groups in a hydrophobic cavity. We found that these macrocycles are able to selectively recognize carboxylic acids in water through salt bridges and the hydrophobic effect. Moreover, it was demonstrated that these macrocyclic receptors can be used in circular-dichroism-based optical chirality sensing of chiral carboxylic acids and fluorescent sensing of phenylpyruvic acid-a biomarker for phenylketonuria. This research showcases that buried salt bridges can be effectively used by endo-functionalized macrocyclic hosts for molecular recognition in water, where solvent screening on polar noncovalent interactions is high.

6.
Org Lett ; 22(19): 7699-7703, 2020 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-32959657

RESUMO

A selenium-catalyzed trifluoromethylthiolation/[2,3]-sigmatropic rearrangement of tertiary allylic and propargylic alcohols which could provide straightforward and facile access to trifluoromethyl sulfoxides was developed. Various allylic and allenic trifluoromethyl sulfoxides were obtained with moderate to excellent yields. Meanwhile, a Lewis acid mediated trifluoromethylthiolation/1,2-rearrangement to synthesize ß-SCF3 carbonyl compounds was also accomplished. These two tandem reactions feature with mild reaction conditions and metal-free. During these two reactions, the chemoselectivity of electrophilic trifluoromethylthiolation was revealed.

7.
MedComm (Beijing) ; 2020 Aug 13.
Artigo em Inglês | MEDLINE | ID: mdl-32838396

RESUMO

Clinicians have been faced with the challenge of differentiating between severe acute respiratory syndrome associated coronavirus 2 (SARS-CoV-2) infected pneumonia (NCP) and influenza A infected pneumonia (IAP), a seasonal disease that coincided with the outbreak. We aim to develop a machine-learning algorithm based on radiomics to distinguish NCP from IAP by texture analysis based on computed tomography (CT) imaging. Forty-one NCP and 37 IAP patients admitted from January to February 6, 2019 admitted to two hospitals in Wenzhou, China. All patients had undergone chest CT examination and blood routine tests prior to receiving medical treatment. NCP was diagnosed by real-time RT-PCR assays. Eight of 56 radiomic features extracted by LIFEx were selected by least absolute shrinkage and selection operator regression to develop a radiomics score and subsequently constructed into a nomogram to predict NCP with area under the operating characteristics curve of 0.87 (95% confidence interval: 0.77-0.93). The nomogram also showed excellent calibration with Hosmer-Lemeshow test yielding a nonsignificant statistic (P = .904). The novel nomogram may efficiently distinguish between NCP and IAP patients. The nomogram may be incorporated to existing diagnostic algorithm to effectively stratify suspected patients for SARS-CoV-2 pneumonia.

8.
Liver Int ; 40(9): 2160-2163, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32573883

RESUMO

The Corona Virus Disease 2019 (COVID-19) pandemic has attracted increasing worldwide attention. While metabolic-associated fatty liver disease (MAFLD) affects a quarter of world population, its impact on COVID-19 severity has not been characterized. We identified 55 MAFLD patients with COVID-19, who were 1:1 matched by age, sex and obesity status to non-aged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected patients without MAFLD. Our results demonstrate that in patients aged less than 60 years with COVID-19, MAFLD is associated with an approximately fourfold increase (adjusted odds ratio 4.07, 95% confidence interval 1.20-13.79, P = .02) in the probability for severe disease, after adjusting for confounders. Healthcare professionals caring for patients with COVID-19 need to be aware that there is a positive association between MAFLD and severe illness with COVID-19.


Assuntos
Infecções por Coronavirus/complicações , Fígado Gorduroso/complicações , Pneumonia Viral/complicações , Adulto , Betacoronavirus , China/epidemiologia , Estudos de Coortes , Infecções por Coronavirus/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/epidemiologia
10.
Artigo em Inglês | MEDLINE | ID: mdl-32436622

RESUMO

BACKGROUND AND AIM: Coronavirus disease 2019 (COVID-19) has attracted increasing worldwide attention. While diabetes is known to aggravate COVID-19 severity, it is not known whether nondiabetic patients with metabolic dysfunction are also more prone to more severe disease. The association of metabolic associated fatty liver disease (MAFLD) with COVID-19 severity in nondiabetic patients was investigated here. METHODS: The study cohort comprised 65 patients with (i.e. cases) and 65 patients without MAFLD (i.e. controls). Each case was randomly matched with one control by sex (1:1) and age (±5 years). The association between the presence of MAFLD (as exposure) and COVID-19 severity (as the outcome) was assessed by binary logistic regression analysis. RESULTS: In nondiabetic patients with COVID-19, the presence of MAFLD was associated with a four-fold increased risk of severe COVID-19; the risk increased with increasing numbers of metabolic risk factors. The association with COVID-19 severity persisted after adjusting for age, sex, and coexisting morbid conditions. CONCLUSION: Health-care professionals caring for nondiabetic patients with COVID-19 should be cognizant of the increased likelihood of severe COVID-19 in patients with MAFLD.

16.
J Cell Physiol ; 235(7-8): 5679-5688, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31975377

RESUMO

Deletion of TGFß inducible early gene-1 (TIEG) in mice results in an osteopenic phenotype that exists only in female animals. Molecular analyses on female TIEG knockout (KO) mouse bones identified increased expression of sclerostin, an effect that was confirmed at the protein level in serum. Sclerostin antibody (Scl-Ab) therapy has been shown to elicit bone beneficial effects in multiple animal model systems and human clinical trials. For these reasons, we hypothesized that Scl-Ab therapy would reverse the low bone mass phenotype of female TIEG KO mice. In this study, wildtype (WT) and TIEG KO female mice were randomized to either vehicle control (Veh, n = 12/group) or Scl-Ab therapy (10 mg/kg, 1×/wk, s.c.; n = 12/group) and treated for 6 weeks. Following treatment, bone imaging analyses revealed that Scl-Ab therapy significantly increased cancellous and cortical bone in the femur of both WT and TIEG KO mice. Similar effects also occurred in the vertebra of both WT and TIEG KO animals. Additionally, histomorphometric analyses revealed that Scl-Ab therapy resulted in increased osteoblast perimeter/bone perimeter in both WT and TIEG KO animals, with a concomitant increase in P1NP, a serum marker of bone formation. In contrast, osteoclast perimeter/bone perimeter and CTX-1 serum levels were unaffected by Scl-Ab therapy, irrespective of mouse genotype. Overall, our findings demonstrate that Scl-Ab therapy elicits potent bone-forming effects in both WT and TIEG KO mice and effectively increases bone mass in female TIEG KO mice.

17.
Genome ; 63(3): 133-143, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31794256

RESUMO

Bone size is an important trait for chickens because of its association with osteoporosis in layers and meat production in broilers. Here, we employed high density genotyping platforms to detect candidate genes for bone traits. Estimates of the narrow heritabilities ranged from 0.37 ± 0.04 for shank length to 0.59 ± 0.04 for tibia length. The dominance heritability was 0.12 ± 0.04 for shank length. Using a linear mixed model approach, we identified a promising locus within NCAPG on chromosome 4, which was associated with tibia length and mass, femur length and area, and shank length. In addition, three other loci were associated with bone size or mass at a Bonferroni-corrected genome-wide significance threshold of 1%. One region on chicken chromosome 1 between 168.38 and 171.82 Mb harbored HTR2A, LPAR6, CAB39L, and TRPC4. A second region that accounted for 2.2% of the phenotypic variance was located around WNT9A on chromosome 2, where allele substitution was predicted to be associated with tibia length. Four candidate genes identified on chromosome 27 comprising SPOP, NGFR, GIP, and HOXB3 were associated with tibia length and mass, femur length and area, and shank length. Genome partitioning analysis indicated that the variance explained by each chromosome was proportional to its length.


Assuntos
Osso e Ossos/anatomia & histologia , Galinhas/genética , Estudo de Associação Genômica Ampla/veterinária , Locos de Características Quantitativas , Animais , Galinhas/anatomia & histologia , Mapeamento Cromossômico , Cromossomos/genética , Fenótipo , Polimorfismo de Nucleotídeo Único
18.
Acta Crystallogr C Struct Chem ; 75(Pt 8): 1128-1133, 2019 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-31380795

RESUMO

Noncovalent interactions, such as π-π stacking interactions, C-H...π interactions and hydrogen bonding, are important driving forces for self-assembly in the construction of functional supermolecules and materials, especially in multicomponent supramolecular systems. Herein, a novel compound based on a π-acidic naphthalene diimide derivative and a double hydroxide-bridged dinuclear Al3+ aqua ion cluster, namely bis[N,N'-bis(2-sulfonatoethyl)-1,4,5,8-naphthalene diimide] di-µ-hydroxido-bis[tetraaquaaluminium(III)] tetrahydrate, (C18H12N2O10S2)2[Al2(OH)2(H2O)8]·4H2O, was obtained using the above-mentioned common noncovalent interactions, as well as uncommon lone-pair-π interactions. Functional molecular modules were connected by these noncovalent interactions to generate obvious photochromic properties. The compound was prepared by the self-assembly of N,N'-bis(2-sulfoethyl)-1,4,5,8-naphthalene diimide and Al(NO3)3·9H2O under mixed solvothermal conditions, and was characterized in detail by single-crystal X-ray diffraction, powder X-ray diffraction and FT-IR spectroscopy. The thermal stability and photochromic properties were also investigated; furthermore, in-situ solid-state UV-Vis absorption spectroscopy and electron spin resonance (ESR) were used to clarify the photochromic mechanism.

19.
Cancer Res ; 79(17): 4339-4347, 2019 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-31300474

RESUMO

Lung carcinoids (LC) are rare and slow growing primary lung neuroendocrine tumors. We performed targeted exome sequencing, mRNA sequencing, and DNA methylation array analysis on macro-dissected LCs. Recurrent mutations were enriched for genes involved in covalent histone modification/chromatin remodeling (34.5%; MEN1, ARID1A, KMT2C, and KMT2A) as well as DNA repair (17.2%) pathways. Unsupervised clustering and principle component analysis on gene expression and DNA methylation profiles showed three robust molecular subtypes (LC1, LC2, LC3) with distinct clinical features. MEN1 gene mutations were found to be exclusively enriched in the LC2 subtype. LC1 and LC3 subtypes were predominately found at peripheral and endobronchial lung, respectively. The LC3 subtype was diagnosed at a younger age than LC1 and LC2 subtypes. IHC staining of two biomarkers, ASCL1 and S100, sufficiently stratified the three subtypes. This molecular classification of LCs into three subtypes may facilitate understanding of their molecular mechanisms and improve diagnosis and clinical management. SIGNIFICANCE: Integrative genomic analysis of lung carcinoids identifies three novel molecular subtypes with distinct clinical features and provides insight into their distinctive molecular signatures of tumorigenesis, diagnosis, and prognosis.


Assuntos
Tumor Carcinoide/genética , Tumor Carcinoide/patologia , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Ciclo Celular/genética , Estudos de Coortes , Metilação de DNA , Epigênese Genética , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Mutação , Proteínas Proto-Oncogênicas/genética , RNA Mensageiro/genética , Reprodutibilidade dos Testes , Proteínas S100/metabolismo
20.
Nat Chem ; 11(5): 470-477, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30936522

RESUMO

Dissipative self-assembly is common in biological systems, where it serves to maintain a far-from-equilibrium functional state through fuel consumption. Synthetic dissipative systems have been prepared that can mimic some of the properties of biological systems, but they often show poor mechanical performance. Here, we report a shear-induced transient hydrogel that is highly stretchable. The system is constructed by adding Cu(II) into the aqueous solution of a pseudopolyrotaxane, which is itself formed by threading molecular tubes on polyethylene glycol chains. Vigorous shaking transforms the solution into a gel, which gradually relaxes back to the sol state over time. This cycle can be repeated at least five times. A mechanism is proposed that relies on a shear-induced transition from intrachain to interchain coordination and subsequent thermal relaxation. The far-from-equilibrium hydrogel is highly stretchable, which is probably due to 'frictional' sliding of the molecular tubes on the polyethylene glycol chains. On shaking, the hydrogel undergoes fast self-healing.

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