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1.
Cell Metab ; 2021 Oct 04.
Artigo em Inglês | MEDLINE | ID: mdl-34619075

RESUMO

Over the last few decades, China has witnessed a great leap in economic growth and social welfare. Unfortunately, Chinese people have also been affected by a pandemic of over-nutrition, lack of physical activity, and increasing prevalence of metabolic disorders including obesity, diabetes, non-alcohol fatty liver disease, and cardiovascular disease. For instance, China currently has the largest number of diabetic patients (∼116 million) in the world. The fire of metabolic disorders is further fanned by the increased aging population, according to the survey results from the National Bureau of Statistics. On the other hand, progress in metabolic research has also made big strides. Here, we offer a glimpse at metabolic research in China, including not only its status quo but also its prospects, which aims to make significant contributions to our understanding of metabolism from bench to bedside.

2.
Dev Cell ; 56(18): 2592-2606.e7, 2021 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-34508658

RESUMO

Membrane contact between intracellular organelles is important in mediating organelle communication. However, the assembly of molecular machinery at membrane contact site and its internal organization correlating with its functional activity remain unclear. Here, we demonstrate that a gel-like condensation of Cidec, a crucial protein for obesity development by facilitating lipid droplet (LD) fusion, occurs at the LD-LD contact site (LDCS) through phase separation. The homomeric interaction between the multivalent N terminus of Cidec is sufficient to promote its phase separation both in vivo and in vitro. Interestingly, Cidec condensation at LDCSs generates highly plastic and lipid-permeable fusion plates that are geometrically constrained by donor LDs. In addition, Cidec condensates are distributed unevenly in the fusion plate generating stochastic sub-compartments that may represent unique lipid passageways during LD fusion. We have thus uncovered the organization and functional significance of geometry-constrained Cidec phase separation in mediating LD fusion and lipid homeostasis.

3.
Food Chem ; 370: 131030, 2021 Sep 02.
Artigo em Inglês | MEDLINE | ID: mdl-34507209

RESUMO

Phytosterols are commonly found in vegetable oils and possess health benefits for humans. While investigating the chemical conversion of stigmasterol at deodorisation temperatures, gas chromatography-mass spectrometry (GC-MS) and ultra-high performance liquid chromatography coupled to high-resolution mass spectrometry (UHPLC-HRMS) experiments led to the identification of 5-ethyl-6-methyl-3-heptene-2-one, 3-hydoxy-steroid, 3-ketostigmasterol, and 3,7-diketostigmasterol as by-products. The identification of these compounds assisted in the interpretation of the stigmasterol oligomers characterised by high-pressure size exclusion chromatography (HPSEC). A similar analysis was conducted in stripped corn oil at the deodorisation temperatures. As such, 5-ethyl-6-methyl-3-heptene-2-one, 3-hydoxy-steroid, 3-ketostigmasterol and 3,7-diketostigmasterol were also detected in stripped corn oil, while the contents of 3-hydoxy-steroid and 5-ethyl-6-methyl-3-heptene-2-one were higher than those of 3-ketostigmasterol, as revealed by quantum chemical simulations. In addition, stripped corn oil exhibited the characteristic of preventing stigmasterol degradation below 200 °C, whereas it enhanced the chemical conversion (such as esterification and degradation) of stigmasterol at higher temperatures.

4.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 29(3): 944-950, 2021 Jun.
Artigo em Chinês | MEDLINE | ID: mdl-34105498

RESUMO

OBJECTIVE: To investigate the clinical characteristics and risk factors of cytomegalovirus (CMV) infection after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with severe aplastic anemia (SAA). METHODS: Clinical data from 270 SAA patients with allo-HSCT were retrospectively analyzed, including 108 sib congruence patients and 162 substitute donors (68 unrelated donor congruence patients and 94 related haploid patients). Different pretreatment schemes were selected for different transplantation modes. The HLA-identical sibling and haploid grafts were all bone marrow and peripheral blood stem cells, and the grafts from unrelated donors were peripheral blood stem cells. After granulocyte implantation, blood CMV-DNA was regularly monitored. Flow cytometry was also used to determine the absolute number of CD3+, CD4+T lymphocytes and CD19+B lymphocytes at 1, 2, 3, 6 and 12 months after transplantation. RESULTS: CMV infection occurred in 229 of 270 patients with an incidence of 84.8%. Among them, 18 patients developed giant cell disease. Univariate analysis showed that alternative donors (unrelated total and haploid donors), mycophenolate mofetil and acute graft-versus-host disease were statistically significantly associated with CMV infection (P<0.05). Multivariate analysis showed that alternative donors were associated with CMV infection. The recovery of CD3+ and CD4+ in 6 months in the substitute donors was delayed in comparison with that in the full sib group. CONCLUSION: After allo-HSCT, substitute donors are more easily to develop CMV infection than full-sibling donors, and the reconstruction of immune function is delayed after transplantation.


Assuntos
Anemia Aplástica , Infecções por Citomegalovirus , Doença Enxerto-Hospedeiro , Transplante de Células-Tronco Hematopoéticas , Humanos , Estudos Retrospectivos
5.
Cell Metab ; 33(8): 1655-1670.e8, 2021 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-34015269

RESUMO

How amphipathic phospholipids are shuttled between the membrane bilayer remains an essential but elusive process, particularly at the endoplasmic reticulum (ER). One prominent phospholipid shuttling process concerns the biogenesis of APOB-containing lipoproteins within the ER lumen, which may require bulk trans-bilayer movement of phospholipids from the cytoplasmic leaflet of the ER bilayer. Here, we show that TMEM41B, present in the lipoprotein export machinery, encodes a previously conceptualized ER lipid scramblase mediating trans-bilayer shuttling of bulk phospholipids. Loss of hepatic TMEM41B eliminates plasma lipids, due to complete absence of mature lipoproteins within the ER, but paradoxically also activates lipid production. Mechanistically, scramblase deficiency triggers unique ER morphological changes and unsuppressed activation of SREBPs, which potently promotes lipid synthesis despite stalled secretion. Together, this response induces full-blown nonalcoholic hepatosteatosis in the TMEM41B-deficient mice within weeks. Collectively, our data uncovered a fundamental mechanism safe-guarding ER function and integrity, dysfunction of which disrupts lipid homeostasis.

6.
PLoS Genet ; 17(3): e1009488, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33780446

RESUMO

Mitochondria are essential for maintaining skeletal muscle metabolic homeostasis during adaptive response to a myriad of physiologic or pathophysiological stresses. The mechanisms by which mitochondrial function and contractile fiber type are concordantly regulated to ensure muscle function remain poorly understood. Evidence is emerging that the Folliculin interacting protein 1 (Fnip1) is involved in skeletal muscle fiber type specification, function, and disease. In this study, Fnip1 was specifically expressed in skeletal muscle in Fnip1-transgenic (Fnip1Tg) mice. Fnip1Tg mice were crossed with Fnip1-knockout (Fnip1KO) mice to generate Fnip1TgKO mice expressing Fnip1 only in skeletal muscle but not in other tissues. Our results indicate that, in addition to the known role in type I fiber program, FNIP1 exerts control upon muscle mitochondrial oxidative program through AMPK signaling. Indeed, basal levels of FNIP1 are sufficient to inhibit AMPK but not mTORC1 activity in skeletal muscle cells. Gain-of-function and loss-of-function strategies in mice, together with assessment of primary muscle cells, demonstrated that skeletal muscle mitochondrial program is suppressed via the inhibitory actions of FNIP1 on AMPK. Surprisingly, the FNIP1 actions on type I fiber program is independent of AMPK and its downstream PGC-1α. These studies provide a vital framework for understanding the intrinsic role of FNIP1 as a crucial factor in the concerted regulation of mitochondrial function and muscle fiber type that determine muscle fitness.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Mitocôndrias Musculares/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Animais , Feminino , Perfilação da Expressão Gênica , Masculino , Camundongos , Camundongos Transgênicos , Mitocôndrias Musculares/ultraestrutura , Fibras Musculares Esqueléticas/ultraestrutura , Especificidade de Órgãos , Oxirredução , Estresse Oxidativo
7.
J Oleo Sci ; 70(2): 155-164, 2021 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-33456002

RESUMO

Functional compositions, physicochemical properties and antioxidant activities of Amaranthus caudatus L. oils (ACO) obtained by different solvents were comparatively investigated. All the resulted ACO were enrich in 75% unsaturated fatty acid and in squalene of about 4 g/100 g. Different solvents showed varying in oil extraction, where acetone results a highest yield of 6.80 g/100 g. ACO extracted by ethanol showed a highest tocopherol (1351.26 mg/kg), polyphenols (211.28 mg/kg) and squalene (42519.13 mg/kg). However, phytosterols in ACO extracted by hexane (27571.20 mg/kg) was higher than that by acetone (19789.91 mg/kg), ethanol (22015.73 mg/kg) and petroleum ether (24763.30 mg/kg). Furthermore, antioxidant activity of ACO was also measured by DPPH, ABTS and FRAP assay. According to principal component and correlation analysis, squalene was correlated with the DPPH scavenging ability, but phytosterols and tocopherols was correlated with the ABTS and ferric reducing ability of the oils, respectively. This study provides a promising excellent source of functional oil for food industries.


Assuntos
Amaranthus/química , Antioxidantes , Fenômenos Químicos , Extração Líquido-Líquido/métodos , Óleos Vegetais/isolamento & purificação , Óleos Vegetais/farmacologia , Solventes , Acetona , Alcanos , Cromatografia Líquida de Alta Pressão , Etanol , Ácidos Graxos Insaturados/análise , Ácidos Graxos Insaturados/isolamento & purificação , Ácidos Graxos Insaturados/farmacologia , Cromatografia Gasosa-Espectrometria de Massas , Hexanos , Fitosteróis/análise , Fitosteróis/isolamento & purificação , Fitosteróis/farmacologia , Óleos Vegetais/análise , Óleos Vegetais/química , Polifenóis/análise , Polifenóis/isolamento & purificação , Polifenóis/farmacologia , Esqualeno/análise , Esqualeno/isolamento & purificação , Esqualeno/farmacologia , Tocoferóis/análise , Tocoferóis/isolamento & purificação , Tocoferóis/farmacologia
8.
Chem Commun (Camb) ; 57(16): 2069-2072, 2021 Feb 25.
Artigo em Inglês | MEDLINE | ID: mdl-33507188

RESUMO

Commercially available cinchona alkaloids that can catalyze the enantiodivergent fluorination of ß-ketodiarylphosphine oxides were developed to construct carbon-fluorine quaternary stereocenters. This protocol features a wide scope of substrates and excellent enantioselectivities, and it is scalable.

9.
J Sci Food Agric ; 101(7): 2736-2743, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33124037

RESUMO

BACKGROUND: Phytosterols are partly removed during oil refining, and the magnitude of phytosterols loss largely depends on the refining conditions applied and the molecular conformation. The aim of this research was to study the effect of deodorization conditions and molecular unsaturation on the esterification of phytosterols during deodorization of corn oil. RESULTS: In the chemical model, free fatty acids (FFAs) were the major provider of acyl groups during the formation of phytosteryl fatty acid esters (PEs) under deodorization conditions. Among the main parameters of the deodorization, temperature played a role in the formation of PEs with a time-dependent manner. In comparison, saturated palmitic acid had a higher capability of esterifying free phytosterols (FPs) to PEs than unsaturated oleic acid and linoleic acid. Moreover, the influence of FFA unsaturation on the degradation of FPs depended on temperature. Besides, the formation of stigmasteryl ester had a competitive advantage over that of sitosteryl ester by quantum chemistry simulation. CONCLUSION: For laboratory-scale deodorization of corn oil, saturated fatty acids and deodorization process with steam as stripping gas could obviously esterify FPs to PEs. FPs were abundantly enriched in distillate during the deodorization process with nitrogen as stripping gas, whereas FPs and PEs were distilled simultaneously during the deodorization process with steam. © 2020 Society of Chemical Industry.


Assuntos
Óleo de Milho/química , Ácidos Graxos não Esterificados/química , Fitosteróis/química , Esterificação , Ésteres/química , Odorantes/análise , Temperatura
10.
Cell Metab ; 33(2): 350-366.e7, 2021 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-33186557

RESUMO

Efficient delivery of specific cargos in vivo poses a major challenge to the secretory pathway, which shuttles products encoded by ∼30% of the genome. Newly synthesized protein and lipid cargos embark on the secretory pathway via COPII-coated vesicles, assembled by the GTPase SAR1 on the endoplasmic reticulum (ER), but how lipid-carrying lipoproteins are distinguished from the general protein cargos in the ER and selectively secreted has not been clear. Here, we show that this process is quantitatively governed by the GTPase SAR1B and SURF4, a high-efficiency cargo receptor. While both genes are implicated in lipid regulation in humans, hepatic inactivation of either mouse Sar1b or Surf4 selectively depletes plasma lipids to near-zero and protects the mice from atherosclerosis. These findings show that the pairing between SURF4 and SAR1B synergistically operates a specialized, dosage-sensitive transport program for circulating lipids, while further suggesting a potential translation to treat atherosclerosis and related cardio-metabolic diseases.

11.
J Agric Food Chem ; 68(47): 13854-13862, 2020 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-33166459

RESUMO

Assembly of amphiphiles at the interface of two immiscible fluids is of great scientific and technological interest in offering efficient routes to smart vehicles for functional deliveries. Natural Quillaja saponin (QS) has gathered widespread interest within the scientific community as a result of its unique interfacial properties. Herein, spontaneously interface-driven self-assembly (SIDSA) of QS at the oil-water interface was systematically studied by morphology and spectroscopy. It was found to self-assemble into a micrometer-scale network in helical fibers by combined intermolecular π-π stacking and hydrogen bonding among saponins at the liquid-liquid interface. From SIDSA, multilayer films on the surfaces of dispersed droplets were formed and enhanced emulsion stability. Interfacial QS-based films on droplet surfaces were also shown to confine interfacial diffusion processes by serving as transport barriers. Furthermore, they can be exploited to control the release of volatiles from the dispersed liquid phase by regulating the interface film, which is shown by molecular dynamics to occur through a hydrogen-bonded mechanism. These results provide new insight into the interfacial assembly structure that can enable unique controllable release in a broad range of applications in food, beverages, pharmaceuticals, and cosmetics.


Assuntos
Saponinas , Emulsões , Permeabilidade , Quillaja , Saponinas de Quilaia , Água
12.
World J Clin Cases ; 8(14): 2930-2941, 2020 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-32775375

RESUMO

BACKGROUND: Budd-Chiari syndrome is defined as hepatic venous outflow tract obstruction. For Asian Budd-Chiari syndrome patients, the major treatment modality is recanalization (percutaneous transluminal angioplasty with or without stent implantation). The cumulative 1-, 5-, and 10-year primary patency rates and survival rates are reported to be excellent or satisfactory, but the long-term outcome of patients with restenosis (the most common complication after recanalization) is unknown. AIM: To explore the treatment strategy for restenosis in patients with Budd-Chiari syndrome after interventional therapy and to evaluate the long-term follow-up results. METHODS: The clinical data and follow-up results of 60 patients with restenosis after interventional therapy from November 1983 to December 2013 were retrospectively analyzed. RESULTS: Sixty patients with restenosis were retrospectively divided into a percutaneous transluminal angioplasty (PTA) group (40 patients) and a PTA + stent group (20 patients) according to the primary recanalization method. For the patients with restenosis in the PTA group, 13 refused treatment, and 27 received further treatment; among these patients, five had a second restenosis, two had a third restenosis, and one had a fourth restenosis. For the patients with restenosis in the PTA + stent group, nine refused treatment, ten received PTA alone, and the other received PTA + stent implantation. Among the patients who received further treatment, five had a second restenosis, three had a third restenosis, and one had a fourth restenosis. The 1-, 5-, 10-, 20-, and 25-year cumulative survival rates of the 38 patients who received further treatment after restenosis were 100%, 78.3%, 78.3%, 70.5%, and 70.5%, respectively; however, for the 22 patients who refused treatment, the survival rates were 72.7%, 45.9%, 30.6%, 10.2%, and unavailable, respectively (P < 0.001). CONCLUSION: Long-term follow-up after interventional therapy is very important. Active treatment for patients with restenosis can improve prognosis, and minimally invasive treatment strategies for restenosis allows to obtain satisfactory results.

13.
Hear Res ; 396: 108055, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32814237

RESUMO

Inner ear hair cells are mechanosensitive cells responsible for sensing and transmitting signals to the brain to be interpreted as sound or head position/movement. The zinc-finger protein, gfi1, is expressed in differentiating neurons and inner ear hair cells. Gfi1 deficiency leads to a massive loss of cochlear hair cells in mice. However, the mechanism remains unclear. To develop an effective molecular therapy for hearing loss, it is critical to first understand the relationship between gfi1 and hair cell development. We demonstrated in the zebrafish model that gfi1.2 was initially expressed in the inner ear at 14 h post-fertilization (hpf), preceding the expression of gfi1.1 at 19 hpf. In the morpholino-mediated gfi1.2 knockdown mutants, hair cells reduced in number without altering the expression of pax2a, dlx3b, atho1a and pou4f3, the markers for otic patterning and specification. There was a down-regulation of the pro-neuronal genes, ngn1 and atoh1b in the context of gfi1.2 knockdown, which was rescued by the exogenous gfi1.2. We also found that gfi1.2 may regulate ngn1 expression by suppressing id2a. Our results suggested that knockdown of gfi1.2 may lead to deafness through promoting cells proliferation in the pro-sensory region and interrupting cell differentiation.

14.
Mol Psychiatry ; 2020 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-32681097

RESUMO

It is traditionally believed that cerebral amyloid-beta (Aß) deposits are derived from the brain itself in Alzheimer's disease (AD). Peripheral cells such as blood cells also produce Aß. The role of peripherally produced Aß in the pathogenesis of AD remains unknown. In this study, we established a bone marrow transplantation model to investigate the contribution of blood cell-produced Aß to AD pathogenesis. We found that bone marrow cells (BMCs) transplanted from APPswe/PS1dE9 transgenic mice into wild-type (Wt) mice at 3 months of age continuously expressed human Aß in the blood, and caused AD phenotypes including Aß plaques, cerebral amyloid angiopathy (CAA), tau hyperphosphorylation, neuronal degeneration, neuroinflammation, and behavioral deficits in the Wt recipient mice at 12 months after transplantation. Bone marrow reconstitution in APPswe/PS1dE9 mice with Wt-BMCs at 3 months of age reduced blood Aß levels, and alleviated brain Aß burden, neuronal degeneration, neuroinflammation, and behavioral deficits in the AD model mice at 12 months after transplantation. Our study demonstrated that blood cell-produced Aß plays a significant role in AD pathogenesis, and the elimination of peripheral production of Aß can decrease brain Aß deposition and represents a novel therapeutic approach for AD.

15.
Transl Psychiatry ; 10(1): 230, 2020 07 13.
Artigo em Inglês | MEDLINE | ID: mdl-32661266

RESUMO

Alzheimer's disease (AD) is the most common cause of age-related dementia and is currently incurable. The failures of current clinical trials and the establishment of modifiable risk factors have shifted the AD intervention from treatment to prevention in the at-risk population. Previous studies suggest that there is a geographic overlap between AD incidence and spicy food consumption. We previously reported that capsaicin-rich diet consumption was associated with better cognition and lower serum Amyloid-beta (Aß) levels in people aged 40 years and over. In the present study, we found that intake of capsaicin, the pungent ingredient in chili peppers, reduced brain Aß burden and rescued cognitive decline in APP/PS1 mice. Our in vivo and in vitro studies revealed that capsaicin shifted Amyloid precursor protein (APP) processing towards α-cleavage and precluded Aß generation by promoting the maturation of a disintegrin and metalloproteinase 10 (ADAM10). We also found that capsaicin alleviated other AD-type pathologies, such as tau hyperphosphorylation, neuroinflammation and neurodegeneration. The present study suggests that capsaicin is a potential therapeutic candidate for AD and warrants clinical trials on chili peppers or capsaicin as dietary supplementation for the prevention and treatment of AD.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/prevenção & controle , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Encéfalo/metabolismo , Capsaicina/farmacologia , Cognição , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/prevenção & controle , Modelos Animais de Doenças , Camundongos , Camundongos Transgênicos , Presenilina-1/metabolismo
16.
Ying Yong Sheng Tai Xue Bao ; 31(4): 1063-1072, 2020 Apr.
Artigo em Chinês | MEDLINE | ID: mdl-32530179

RESUMO

We investigated the fire resistance conferred by different forest age groups (young, middle-age and mature forest) and organs (leaf, branch, and bark) of six typical tree species (Myrica rubra, Schima superba, Symplocos sumuntia, Machilus pingii, Castanopsis eyrei, and Quercus glauca) in Qingshigang national forest farm, Yanling County, Hunan Province, subtropical China. We measured morphological, physical, and chemical properties that could be used as proxies for fire resistance and examined the variances of fire resistance among different organs and age groups in the same tree species. Further, we comprehensively ranked all the tree species by their capacity in fire resistance. We found considerable variation in fire resistance among organs and age groups. Compared with branches and barks, leaves had relatively higher water content (53.7%), higher crude ash content (4.5%), and lower crude fiber content (23.9%). Fire resistance of trees decreased first and then increased with increasing stand age. Trees in middle-aged stage showed the lowest contents of water, crude ash, and crude fiber. The comprehensive scores of fire resistance for diffe-rent organs were significantly different among species. Fire resistance of leaves generally decreased in the order of M. pingii > C. eyrei > S. sumuntia > M. rubra > S. superba > Q. glauca. For branches, M. pingii and C. eyrei showed the strongest fire resistance, followed by M. rubra and S. superba. For barks, S. superba and C. eyrei were relatively stronger in fire resistance than other species, while M. pingii and Q. glauca were the weakest. The comprehensive scores of fire resistance performance of species were different. S. superba (1.033) and M. rubra (0.526) were the most fire-resistant species, while M. pingii (-0.405) and Q. glauca (-1.151) were the least fire-resistant. Therefore, S. superba and M. rubra were the preferred tree species for fire prevention forest belt in forests of subtropical southern China.


Assuntos
Incêndios , Theaceae , China , Florestas , Árvores
17.
Spectrochim Acta A Mol Biomol Spectrosc ; 239: 118511, 2020 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-32480275

RESUMO

Phenol, o-cresol, p-cresol, catechol and resorcinol are five phenolic compounds with extremely similar structure. Their fluorescence spectra are hard to be analyzed because of the serious spectral overlaps between any two of the five phenolic components in the mixture system. In this experiment, multi-dimensional partial least-squares (N-PLS), unfolded partial least-squares (U-PLS) with residual bilinearization (RBL) and parallel factor analysis (PARAFAC) are employed to analyze the three-way fluorescence spectra aiming to achieve quantitative results. Meanwhile, a contrast of these three methods is given. The experiment results show that N-PLS/RBL and U-PLS/RBL algorithms are superior to PARARFAC in terms of analysis of highly overlapping three-way fluorescence spectra for concentration determination.

18.
Org Lett ; 22(14): 5314-5319, 2020 Jul 17.
Artigo em Inglês | MEDLINE | ID: mdl-32589432

RESUMO

A general γ-C(sp2)-H iodination method directed by an aliphatic keto group has been developed under transition-metal-free conditions for the first time, generating iodoarenes in good to excellent yields with excellent site selectivity. This protocol features a wide range of aryl-substituted ketones, short reaction times, mild reaction conditions, and scalable synthetic procedures. A possible reaction mechanism was also proposed based on several control experiments.

19.
Autophagy ; : 1-22, 2020 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-32432943

RESUMO

SCAP (SREBF chaperone) regulates SREBFs (sterol regulatory element binding transcription factors) processing and stability, and, thus, becomes an emerging drug target to treat dyslipidemia and fatty liver disease. However, the current known SCAP inhibitors, such as oxysterols, induce endoplasmic reticulum (ER) stress and NR1H3/LXRα (nuclear receptor subfamily 1 group H member 3)-SREBF1/SREBP-1 c-mediated hepatic steatosis, which severely limited the clinical application of this inhibitor. In this study, we identified a small molecule, lycorine, which binds to SCAP, which suppressed the SREBF pathway without inducing ER stress or activating NR1H3. Mechanistically, lycorine promotes SCAP lysosomal degradation in a macroautophagy/autophagy-independent pathway, a mechanism completely distinct from current SCAP inhibitors. Furthermore, we determined that SQSTM1 captured SCAP after its exit from the ER. The interaction of SCAP and SQSTM1 requires the WD40 domain of SCAP and the TB domain of SQSTM1. Interestingly, lycorine triggers the lysosome translocation of SCAP independent of autophagy. We termed this novel protein degradation pathway as the SQSTM1-mediated autophagy-independent lysosomal degradation (SMAILD) pathway. In vivo, lycorine ameliorates high-fat diet-induced hyperlipidemia, hepatic steatosis, and insulin resistance in mice. Our study demonstrated that the inhibition of SCAP through the SMAILD pathway could be employed as a useful therapeutic strategy for treating metabolic diseases. ABBREVIATION: 25-OHD: 25-hydroxyvitamin D; 3-MA: 3-methyladenine; ABCG5: ATP binding cassette subfamily G member 5; ABCG8: ATP binding cassette subfamily G member 8; ACACA: acetyl-CoA carboxylase alpha; AEBSF: 4-(2-aminoethyl) benzenesulfonyl fluoride hydrochloride; AHI: anhydroicaritin; AKT/protein kinase B: AKT serine/threonine kinase; APOE: apolipoprotein E; ATF6: activating transcription factor 6; ATG: autophagy-related; BAT: brown adipose tissue; CD274/PD-L1: CD274 molecule; CETSA: cellular thermal shift assay; CMA: chaperone-mediated autophagy; COPII: cytoplasmic coat protein complex-II; CQ: chloroquine; DDIT3/CHOP: DNA damage inducible transcript 3; DNL: de novo lipogenesis; EE: energy expenditure; EGFR: epithelial growth factor receptor; eMI: endosomal microautophagy; ERN1/IRE1α: endoplasmic reticulum to nucleus signaling 1; FADS2: fatty acid desaturase 2; FASN: fatty acid synthase; GOT1/AST: glutamic-oxaloacetic transaminase 1; GPT/ALT: glutamic-pyruvate transaminase; HMGCR: 3-hydroxy-3-methylglutaryl-CoA reductase; HMGCS1: 3-hydroxy-3-methylglutaryl-CoA synthase 1; HSP90B1/GRP94: heat shock protein 90 beta family member 1; HSPA5/GRP78: heat hock protein family A (Hsp70) member 5; HSPA8/HSC70: heat shock protein family A (Hsp70) member 8; INSIG1: insulin induced gene 1; LAMP2A: lysosomal associated membrane protein 2A; LDLR: low density lipoprotein receptor; LyTACs: lysosome targeting chimeras; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MBTPS1: membrane bound transcription factor peptidase, site 1; MEF: mouse embryonic fibroblast; MST: microscale thermophoresis; MTOR: mechanistic target of rapamycin kinase; MVK: mevalonate kinase; PROTAC: proteolysis targeting chimera; RQ: respiratory quotient; SCAP: SREBF chaperone; SCD1: stearoyl-coenzemy A desaturase 1; SMAILD: sequestosome 1 mediated autophagy-independent lysosomal degradation; SQSTM1: sequestosome 1; SREBF: sterol regulatory element binding transcription factor; TNFRSF10B/DR5: TNF receptor superfamily member 10b; TRAF6: TNF receptor associated factor 6; UPR: unfolded protein response; WAT: white adipose tissue; XBP1: X-box binding protein 1.

20.
J Stroke Cerebrovasc Dis ; 29(7): 104866, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32404283

RESUMO

OBJECTIVE: Post-stroke paralysis is a common contributor to deep vein thrombosis (DVT) of the lower extremities, but little is known about its epidemiology and anatomy. This prospective study aimed to investigate the clinical incidence and anatomical distribution of lower-extremity DVT in acute stroke. PATIENTS AND METHODS: A total of 679 patients diagnosed with acute stroke (ischemic stroke, n = 507; hemorrhagic stroke, n = 172) were enrolled. Lower-extremity DVT was evaluated using vascular ultrasonography, and classified into three subtypes: central type, peripheral type and mixed type. Then, the incidence and anatomical distribution of DVT were analyzed. RESULTS: For patients with ischemic stroke, a total of 107 patients (21.1%) were affected by DVT, and 119 extremities were found with DVT, which included 114 extremities with peripheral-type DVT and five extremities with mixed-type DVT. For patients with hemorrhagic stroke, a total of 49 patients (28.5%) were affected by DVT, and 55 extremities were found with DVT, which included 51 extremities with peripheral-type DVT and four extremities with mixed-type DVT. The incidence of DVT was significantly higher in patients with hemorrhagic stroke than in patients with ischemic stroke (P < 0.05). Intermuscular veins were the most commonly affected (96.6%), followed by peroneal veins (15.5%), posterior tibial veins (9.2%), popliteal veins (4.0%), and femoral veins (4.0%). There was no significant difference in the anatomical distribution of DVT between ischemic and hemorrhagic stroke (P > 0.05). CONCLUSION: DVT is a common complication of acute stroke, and hemorrhagic stroke is associated with a higher incidence of DVT. The anatomical distribution of DVT revealed no heterogeneity between ischemic and hemorrhagic stroke, and isolated DVT in intermuscular veins were the most common.


Assuntos
Isquemia Encefálica/epidemiologia , Hemorragias Intracranianas/epidemiologia , Extremidade Inferior/irrigação sanguínea , Acidente Vascular Cerebral/epidemiologia , Ultrassonografia , Trombose Venosa/diagnóstico por imagem , Trombose Venosa/etiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Isquemia Encefálica/diagnóstico por imagem , China/epidemiologia , Feminino , Humanos , Incidência , Hemorragias Intracranianas/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Estudos Prospectivos , Fatores de Risco , Acidente Vascular Cerebral/diagnóstico por imagem
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