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1.
Mol Cell Endocrinol ; 499: 110603, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31574295

RESUMO

Activin/Smad3 signaling plays a pivotal role in follicle development and atresia. However, the precise mechanisms underlying this process are not yet fully understood. Herein, we identified miR-181a as a central component of activin/Smad3-mediated follicle atresia. miR-181a was strikingly upregulated in porcine atretic follicles, which induced the apoptosis of porcine granulosa cells (GCs) in vitro. Furthermore, the transforming growth factor-ß type 1 receptor (TGFBR1) was confirmed as a direct target of miR-181a by bioinformatics analysis and luciferase assays. Transfection with an miR-181a agomir repressed the TGFBR1 mRNA and protein levels. In addition, TGFBR1 overexpression repressed GC apoptosis, whereas TGFBR1 inhibition promoted GC apoptosis. miR-181a overexpression downregulated the phosphorylation of Smad3 and blocked the activation of TGF-ß signaling. Moreover, activin A downregulated miR-181a expression and upregulated the TGFBR1 and p-Smad3 protein levels. Collectively, these data suggest that miR-181a regulates porcine GC apoptosis by targeting TGFBR1 via the activin signaling pathway.

2.
Sensors (Basel) ; 19(22)2019 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-31717598

RESUMO

Enrichment of cadmium ion (Cd2+) from the environment may lead to kidney disease and weakened immunity in the body. Current techniques are not convenient enough to measure Cd2+ concentration in the environment due to low sensitivity and poor linear range. In this paper, a new measurement technique is proposed using a new sensing electrode made of nano-copper-enhanced carbon fiber. Nano-copper was deposited onto the surface of carbon fiber to enhance the current concentration and mass transfer rate of Cd2+ during measurement, which improved the electrochemical detection sensitivity significantly (by up to 3.7 × 108 nA/nM) and broadened the linear range to 10~105 nM. This device provides a low-cost solution for measuring Cd2+ concentration in the environment.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31721336

RESUMO

RATIONALE: Interactions of drug molecules and proteins play an important role in physiological and pathological processes in vivo. It is of significance to establish a reliable strategy for studying protein-drug ligand interactions and would be helpful for the design and screening of new drugs in pharmacological research. METHODS: The interactions between four indole alkaloids (IAs) extracted from Ophiorrhiza japonica and myoglobin (Mb) protein were investigated by using a multi-spectrometric and computational method of native electrospray ionization mass spectrometry (Native ESI-MS), hydrogen/deuterium exchange mass spectrometry (HDX-MS), circular dichroism (CD) and molecular docking (MD). RESULTS: The IA bound-Mb complexes were analyzed by native ESI-MS, with the obtained stoichiometry of protein-ligand at 1:1, 1:2, 1:3, respectively. Binding constants were measured according to the interpretation of MS spectra. MD complemented MS measurement, probed that the binding sites and modes of four IAs to Mb. Analyses of CD and HDX-MS demonstrated that the exposure to IAs could affect the conformation of Mb by decreasing the α-helix content and make Mb more susceptible to HDX at the backbone. CONCLUSIONS: A new mass spectrometry-based integrated analysis method has been developed to successfully study the interactions of Mb and IAs extracted from Ophiorrhiza japonica. The experimental and calculation results have good consistency, revealing all of the four IA molecules could bind to Mb to form 1:1, 1:2 and 1:3 Mb-IA complexes, respectively. The order of binding ability of these IAs to Mb was Ophiorrhine B > Compound C > Ophiorrhine A > Compound D. CD and HDX-MS results indicated that binding with IAs destabilizes resulted of Mb. HDX-MS analysis suggests that Mb becomes more accessible to HDX, indicating that IAs binding destabilizes the structure of Mb. In addition, interacting with IAs affected the overall structure of Mb, ascribed to the decrease of α-helix content and less folding of backbone.

4.
J Cardiothorac Surg ; 14(1): 191, 2019 Nov 07.
Artigo em Inglês | MEDLINE | ID: mdl-31699143

RESUMO

BACKGROUND: Mild preoperative renal dysfunction (RD) is not rare in patients receiving isolated cardiopulmonary coronary artery bypass grafting (CCABG). However, there are not too many studies about the impact of mild preoperative RD on in-hospital and follow-up outcomes after isolated CCABG. This single-centre, retrospective propensity score matching study designed to study the impact of mild preoperative RD on in-hospital and long-term outcomes after first isolated CCABG. METHODS: After propensity score matching, 1144 patients with preoperative estimated glomerular filtration rate (eGFR) of more than 60 ml/min/1.73 m2 receiving first isolated CCABG surgery from January 2012 to December 2015 entered the study, who were divided into 2 groups: A group (eGFR ≥90 ml/min/1.73 m2, n = 572) and B group (eGFR of 60-89 ml/min/1.73 m2, n = 572). The in-hospital and long-term outcomes were recorded and analyzed. The mean follow-up time was 54.4 ± 10.7 months. Acute kidney injury (AKI) was defined and classified according to the Acute Kidney Injury Network (AKIN) criteria. RESULTS: The 2 propensity score-matched groups had similar baseline and procedure except the baseline eGFR. There were 8 patients died in A group (mortality is 1.4%) and 14 died in B group (mortality is 2.5%) during the in hospital and 30-day postoperatively(χ2 = 1.159, p = 0.282). There were totally 38 patients lost to follow-up, 18 in group A and 20 in group B. 21 patients died in group A and 37 died in group B during the follow-up, and long-term survival in group A was higher than in group B (96.2% vs 93.1%, χ2 = 4.336, p = 0.037). Comparing with group A, group B was associated with an increased rates and severity of AKI postoperatively (total AKI: 62 vs 144. AKIN stageI: 54 vs 113; AKIN stageII: 6 vs 22; AKIN stageIII: 2 vs 9, p<0.0001). During follow-up, group B also had a higher rate of new onset of dialysis (0 vs 6, χ2 = 4.432, p = 0.039). Multivariable logistic regression showed that comparing with A group, the HR for long-term mortality and new onset of dialysis in B group was 1.67 and 1.52 respectively (95%CI 1.09-2.90, p = 0.035; 95%CI 1.14-2.49, p = 0.027). CONCLUSIONS: Comparing with normal preoperative renal function, patients with mild preoperative RD had a similar in-hosptial mortality, but with an increased in-hosptial rates and severity of AKI, and with a decreased long-term survival and increased long-term new onset of dialysis.

5.
Asian J Androl ; 2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31670279

RESUMO

The aim of this study was to investigate the role of seminal plasma miR-210-3p in the impairment of semen quality caused by varicocele. This study included 102 patients whose semen quality was normal when they were diagnosed with varicocele. A 2-year follow-up for included patients was performed, and they were divided into Group A (semen quality became abnormal) and Group B (semen quality remained normal) according to the results of semen analysis during the follow-up. Semen parameters and seminal plasma miR-210-3p expression were investigated by semen analysis and quantitative real-time polymerase chain reaction, respectively. In vitro experiments with GC-2 cells were performed to explore the role of miR-210-3p in spermatogenic cells. The results of quantitative real-time polymerase chain reaction showed that the level of seminal plasma miR-210-3p in Group A was higher than that in Group B both after 2-year follow-up and when they were diagnosed with varicocele (both P < 0.01). Apoptosis and proliferation assays showed that miR-210-3p induces apoptosis of spermatogenic cells by promoting caspase-3 activation. In conclusion, our study indicated that seminal plasma miR-210-3p induces spermatogenic cell apoptosis by activating caspase-3 in patients with varicocele. Seminal plasma miR-210-3p may be a potential biomarker for predicting impaired semen quality caused by varicocele.

6.
Cell Metab ; 30(5): 937-951.e5, 2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31668872

RESUMO

Obesity-induced adipose dysfunction is a major contributor to atherosclerosis. Cold exposure has been reported to affect atherosclerosis through regulation of adipose function, but the mechanism has not been well clarified. Here, adipocyte hypoxia-inducible factor 2α (HIF-2α) was upregulated after mild cold exposure at 16°C and mediated cold-induced thermogenesis. Adipocyte HIF-2α deficiency exacerbated Western-diet-induced atherosclerosis by increasing adipose ceramide levels, which blunted hepatocyte cholesterol elimination and thermogenesis. Mechanistically, Acer2, the gene encoding alkaline ceramidase 2, was identified as a novel target gene of HIF-2α, triggering ceramide catabolism. Adipose overexpression of ACER2 rescued adipocyte HIF-2α-deficiency-induced exacerbation of atherosclerosis. Furthermore, activation of adipose HIF-2α by the HIF prolyl hydroxylase inhibitor FG-4592 had protective effects on atherosclerosis, accompanied by a reduction in adipose and plasma ceramide and plasma cholesterol levels. This study highlights adipocyte HIF-2α as a putative drug target against atherosclerosis.

7.
Aesthetic Plast Surg ; 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31696242

RESUMO

OBJECTIVE: To study the anatomical location of retro-orbicularis oculi fat (ROOF) in the upper eyelid and to investigate how ROOF affects the appearance of the upper eyelid. METHODS: Twenty-eight Chinese hemifacial cadaver specimens were used (14 male cadavers; age range 52-82 years). In 28 hemifaces, the eyelids were dissected from the superficial to deep layers, and the appearance, location, extent, and surrounding tissue of ROOF were observed. Additionally, we observed the relationship between the upper eyelid morphology and ROOF of the upper eyelid in surgical patients who were treated in the plastic surgery department of Tongji Hospital affiliated with Huazhong University of Science and Technology in 2018. RESULTS: ROOF is a type of fascia adipose tissue that is located in a fat compartment between the muscles (the orbicularis oculi and frontalis muscles) and the orbital septum/frontalis fascia. In patients with hypertrophic ROOF, the upper eyelid appears as a heavy eyelid and as a drooping eyelid. And in patients with atrophic ROOF, the upper eyelid appears as a sunken eyelid. CONCLUSION: ROOF is located in the fat compartment between the orbicularis muscle and the orbital septum/frontalis fascia. ROOF covers the entire upper eyelid and appears thinner medially and thicker laterally. It is continuous with the fat under the frontalis muscle and affects the appearance of the upper eyelid. It represents an important factor in upper eyelid surgery. NO LEVEL ASSIGNED: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

8.
Cardiovasc Res ; 2019 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-31782769

RESUMO

AIMS: Overactivated B cells secrete pathological antibodies, which in turn accelerate the formation of abdominal aortic aneurysms (AAAs). Hyperhomocysteinemia (HHcy) aggravates AAA in mice; however, the underlying mechanisms remain largely elusive. In this study, we further investigated whether homocysteine (Hcy)-activated B cells produce antigen-specific antibodies that ultimately contribute to AAA formation. METHODS AND RESULTS: ELISA assays showed that HHcy induced the secretion of anti-beta 2 glycoprotein I (anti-ß2GPI) antibody from B cells both in vitro and in vivo. Mechanistically, Hcy increased the accumulation of various lipid metabolites in B cells tested by LC-MS/MS, which contributed to elevated anti-ß2GPI IgG secretion. By using the Toll-like receptor 4 (TLR4)-specific inhibitor TAK-242 or TLR4-deficient macrophages, we found that culture supernatants from Hcy-activated B cells and HHcy plasma IgG polarized inflammatory macrophages in a TLR4-dependent manner. In addition, HHcy markedly increased the incidence of elastase- and CaPO4-induced AAA in male BALB/c mice, which was prevented in µMT mice. To further determine the importance of IgG in HHcy-aggravated AAA formation, we purified plasma IgG from HHcy or control mice and then transferred the IgG into µMT mice, which were subsequently subjected to elastase- or CaPO4-induced AAA. Compared with µMT mice that received plasma IgG from control mice, µMT mice that received HHcy plasma IgG developed significantly exacerbated elastase- or CaPO4-induced AAA accompanied by increased elastin degradation, MMP2/9 expression, and anti-ß2GPI IgG deposition in vascular lesions, as shown by immunofluorescence histochemical staining. CONCLUSION: Our findings reveal a novel mechanism by which Hcy-induced B cell-derived pathogenic anti-ß2GPI IgG might, at least in part, contribute to HHcy-aggravated chronic vascular inflammation and AAA formation. TRANSLATIONAL PERSPECTIVE: HHcy is an independent risk factor for cardiovascular diseases in which B cell secretion of IgG antibodies play a key role. However, whether the antigen specific antibody production is changed during HHcy-accelerated AAA remains unclear. Our results provided the first evidence supporting the important role of activated B cell-derived anti-ß2GPI IgG in HHcy-aggravated chronic vascular inflammation and AAA formation. It sheds new light on understanding pathogenesis of HHcy-accelerated AAA. In addition, anti-ß2GPI IgG may be a potential diagnostic marker and therapeutic target for HHcy-related vascular injury.

9.
BMC Cancer ; 19(1): 1049, 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31694577

RESUMO

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is characterized by its clinical and biological heterogeneity. The clinical prognostic implications of tumor-associated macrophages (TAMs) in DLBCL remain controversial and the correlation between TAMs and peripheral absolute monocyte count (AMC) has not yet been elucidated. METHODS: In 221 untreated, newly diagnosed patients with DLBCL, we evaluated the prognostic value of TAMs using immunohistochemical analysis, as well as the association of TAMs and AMC. RESULTS: We found that high CD68 or high CD163 expression was correlated with clinicopathological characteristics, high CD163 expression was an adverse predictor for both overall survival (OS) [hazard ratio (HR) = 2.265, P = 0.005] and progression- free survival (PFS) (HR = 1.925, P = 0.017) in patients with DLBCL. Patients with high CD68 or high CD163 expression had significantly poorer OS and PFS than those with low CD68 or low CD163 expression, respectively (CD68: OS: P<0.001, PFS: P<0.001; CD163: OS: P<0.001, PFS: P<0.001), even in the rituximab era. Moreover, high-risk patients could be further identified by the expression of CD68 or CD163, especially in those classified as low/intermediate risk by International Prognostic Index (IPI). Furthermore, the significant positive correlation was also detected between CD68 expression or CD163 expression and AMC (r = 0.256, P<0.001; r = 0.303, P<0.001). CONCLUSIONS: Patients with high expression of TAMs tend to have poorer OS and PFS, even in the rituximab era, and have positive correlation with AMC. Therefore, the peripheral AMC is a useful prognostic marker reflecting the status of the tumor microenvironment (TME) in DLBCL.

10.
Arch Gynecol Obstet ; 300(6): 1551-1557, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31667606

RESUMO

PURPOSE: To evaluate whether programmed intermittent epidural bolus (PIEB) reduces the incidence of maternal intra-partum fever compared with continuous epidural infusion (CEI) during labor. METHODS: Parturients were randomized to receive CEI (CEI group) or PIEB (PIEB group) with 10 ml per hour for epidural labor analgesia with 1500 subjects in each group. The maintaining dose of two groups is 0.08% ropivacaine with 0.4 µg/ml sufentanil, with patient-controlled epidural analgesia (PCEA) dose of 5 ml and lockout interval of 30 min. The incidence of maternal fever, pain score, epidural sensory levels, the number and proportion of PCEA demand, anesthetics consumption, satisfaction score, neonatal Apgar scale, and maternal and neonatal side effects were recorded. RESULTS: It was significantly lower of the incidence of maternal fever beginning at 4 h post-analgesia and continuing until delivery in the PIEB group than the CEI group (4 h: 2.6% vs. 4.2%; 5 h: 7.3% vs. 10.2%; delivery: 5.6% vs. 7.9%; 1 h post-delivery: 3.9% vs. 6.2%; 2 h post-delivery: 2.1 vs. 3.5%; total: 5.8% vs. 8.4% in PIEB and CEI, respectively). Compared with CEI group, pain scores at 3, 4, 5 h post-analgesia and delivery (3 h: 2 [1, 2] vs. 2 [1-3]; 4 h: 2 [2, 3] vs. 3 [2-4]; 5 h: 2 [2, 3] vs. 3 [2-4]; delivery: 3 [2-4] vs. 4 [3, 4] in PIEB and CEI, respectively), the number and proportion of PCEA demand (number: 0.7 ± 0.9 vs. 2.2 ± 1.9; proportion: 42.0% vs. 80.3% in PIEB and CEI, respectively), and anesthetics consumption significantly decreased in the PIEB group (Ropivacaine: 60 ± 13 mg vs. 76 ± 17 mg; Sufentanil: 26 ± 4 mg vs. 32 ± 6 mg in PIEB and CEI, respectively), without severe maternal and neonatal side effects and any difference in neonatal Apgar scale. The epidural sensory levels 2 h post-analgesia (2 h: 8[8, 9] vs. 9[8, 9] in PIEB and CEI) and satisfaction score (9 [9, 10] vs. 7 [6, 7] in PIEB and CEI) were significantly higher in the PIEB group compared with those in the CEI group. CONCLUSIONS: PIEB with 10 ml of 0.08% ropivacaine and 0.4 µg/ml sufentanil hourly provided a lower incidence of intra-partum fever with a better analgesic effect compared with CEI, without any severe maternal and neonatal adverse reactions.

11.
Environ Sci Technol ; 2019 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-31763828

RESUMO

Highly toxic iodinated products would form in oxidation and disinfection of iodine containing water. Variation of iodinated aromatic products in ferrate [Fe(VI)] oxidation of phenolic compounds [phenol, bisphenol A (BPA), and p-hydroxybenzoic acid (p-HBA)] in iodine containing water was investigated. At pH 5.0, oxidation of phenolic compounds was inhibited by competitive reaction of ferrate with I-, and no formation of iodinated aromatic products was detected. Almost all I- was converted into non-toxic IO3-. At pH 7.0, 8.0 and 9.0, HOI formed in ferrate oxidation of I- and further reacted with phenols, with the formation of iodinated aromatic products. Mass spectrometry analysis showed that both kinds and content of iodinated aromatic products were raised with the increase of solution pH and content of I-, and these iodinated aromatic products were further oxidized by ferrate. Ferrate deprived iodine from iodinated aromatic products and transferred highly-toxic organic iodine into non-toxic IO3-. Electron-donating substituent (alkyl) increased reactivity of phenol with ferrate and HOI, and facilitated ferrate oxidation of iodinated phenols. Electron-drawing substituent (carboxyl) decreased reactivity of phenol with ferrate and HOI, and hindered the further oxidation of iodinated aromatic products. A kinetic model about the variation of phenol, BPA and p-HBA in reaction with ferrate in iodine containing water was developed, and the oxidation profile of phenolic compounds could be satisfactorily predicted at various iodide concentrations.

12.
J Am Chem Soc ; 2019 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-31763837

RESUMO

Emerging as a new frontier in heterogenous catalysis, single-atom site catalysts (SSCs) have sparked enormous attention and bring about new opportunities to the oxygen reduction electrocatalysis. Despite considerable progress achieved re-cently, most of the reported SSCs suffer from either insufficient activity or unsatisfactory stability, which severely retards their practical application. Here, we demonstrate a novel Ru-SSC with appropriate adsorption free energy of OH* (ΔGOH*) to confer excellent activity and low Fenton reactivity to maintain long-term stability. The as-developed Ru-SSC exhibits encouraging ORR turn-over frequency (TOF) of 4.99 e- s-1 sites-1, far exceeding the-state-of-the-art Fe-SSC counterpart (0.816 e- s-1 sites-1), as a result of Ru energy level regulation via spontaneously OH binding. Furthermore, Ru-SSC exhibits greatly suppressed Fenton reactivity, with restrained generation of reactive oxygen species (ROS) directly observed, thus endowing the Ru-SSC with much superior stability (only 17 mV negative shift after 20000 cycles) than the Fe-SSC coun-terpart (31 mV). The practical application of Ru-SSC is further validated by showing excellent activity and stability in a real fuel cell device.

13.
Opt Lett ; 44(22): 5545-5548, 2019 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-31730104

RESUMO

A novel low-loss selenium-based chalcohalide fiber, with a low zero-dispersion wavelength, was prepared by an innovative preparation process. The composition optimized fiber has a wide transmission range of up to 11.5 µm, a lowest fundamental mode zero-dispersion wavelength of 4.03 µm, and a minimum optical loss of 1.12 dB/m at 6.4 µm, which provides a possibility to replace As2S3 and As2Se3 in a cascade of ZrF4-BaF2-LaF3-AlF3-NaF(ZBLAN)-As2S3-As2Se3 fiber in the practical all-fiberized supercontinuum (SC) source. Meanwhile, the broadest SC spectrum, ∼1.2 to 15.2 µm, was achieved by pumping a 12-cm-long fiber with a femtosecond laser at a deep anomalous-dispersion region. Furthermore, simulations are adopted to interpret the results as well as to demonstrate spectral evolution along the fiber. To the best of our knowledge, this is the broadest SC spectrum reported in any selenium-based chalcogenide fiber.

14.
Plant Physiol Biochem ; 146: 98-111, 2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31734522

RESUMO

Drought stress is the primary factor limiting the growth and fruit quality of grapevines worldwide. However, the biological function of the NAC [No apical meristem (NAM), Arabidopsis transcription activation factor (ATAF), Cup-shaped cotyledon (CUC)] transcription factor (TF) in grapevine is not clear. In this study, we reported that VvNAC17, a novel NAC transcription factor, was expressed in various tissues following drought, high temperature (45 °C), freezing (4 °C), salicylic acid (SA), and abscisic acid (ABA) treatments in grapevine. The VvNAC17 protein was localized in the nucleus of Arabidopsis thaliana protoplasts and demonstrated transcriptional activation activities at its C-terminus in yeast. The VvNAC17 gene was overexpressed in Arabidopsis thaliana. Under mannitol and salt stress, the germination rates of the VvNAC17-overexpression lines were higher than those of the wild-type plants, as were the root lengths. The VvNAC17-overexpression lines showed greater tolerance to freezing stress along with a higher survival rate. Following ABA treatment, the seed germination rate and the root length of the VvNAC17-overexpression lines were inhibited, and the stomatal opening and stomatal density were reduced. When subjected to drought and dehydration stress, the VvNAC17-overexpression lines showed improved survival and reduced water loss rates in comparison to the wild-type plants. Under drought conditions, the VvNAC17-overexpression lines had lower malondialdehyde and H2O2 contents, but higher peroxidase, superoxide dismutase, and catalase activities as well as higher proline content. Moreover, the expression of marker genes, including ABI5, AREB1, COR15A, COR47, P5CS, RD22, and RD29A, was up-regulated in the VvNAC17-overexpression lines when subjected to ABA and drought treatments. The results suggest that in transgenic Arabidopsis over-expression of VvNAC17 enhances resistance to drought while up-regulating the expression of ABA- and stress-related genes.

15.
Chem Res Toxicol ; 32(11): 2320-2328, 2019 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-31576746

RESUMO

Environmental exposure to triclocarban (TCC), a common antibacterial agent widely used in thousands of personal care products, poses a potential risk for human health. Previous in vitro studies about biological effects of TCC have yielded a variety of inconsistent results and apparently not been verified in vivo. In the current study, dose-dependent effects of TCC exposure on lipid homeostasis in rats were investigated using a combination of untargeted 1H NMR metabolomics, targeted metabolite profiling (LC/GC-MS), histopathological assessments, and biological assays. Our results revealed that TCC dose-dependently activated aryl hydrocarbon receptor (AHR) and its transcriptional targets such as Cyp1a1 and Cyp1b1 in the liver of rats, suggesting that TCC may be a potent AHR agonist. Although TCC exhibited dose-dependent toxicity, oral exposure with relatively low dose TCC caused more significant hepatic lipogenesis of rats than relatively high and moderate doses of TCC. It was mainly manifested by histopathological observations and promotion of de novo fatty acid, phospholipid, and ceramide biosynthesis and gut microbiota fermentation. Our findings provide new insights into health effects of TCC exposure with different dosages in vivo, especially on the induction and progression of nonalcoholic fatty liver disease, and further our understanding in the pathogenesis of metabolic diseases induced by environmental pollutants.

16.
EBioMedicine ; 49: 291-304, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31640947

RESUMO

BACKGROUND: Aortic dissection is a severe inflammatory vascular disease with high mortality and limited therapeutic options. The hallmarks of aortic dissection comprise aortic inflammatory cell infiltration and elastic fiber disruption, highlighting the involvement of macrophage. Here a role for macrophage hypoxia-inducible factor 1-alpha (HIF-1α) in aortic dissection was uncovered. METHODS: Immunochemistry, immunofluorescence, western blot and qPCR were performed to test the change of macrophage HIF-1α in two kinds of aortic dissection models and human tissues. Metabolomics and Seahorse extracellular flux analysis were used to detect the metabolic state of macrophages involved in the development of aortic dissection. Chromatin Immunoprecipitation (ChIP), enzyme-linked immunosorbent assay (ELISA) and cytometric bead array (CBA) were employed for mechanistic studies. FINDINGS: Macrophages involved underwent distinct metabolic reprogramming, especially fumarate accumulation, thus inducing HIF-1α activation in the development of aortic dissection in human and mouse models. Mechanistic studies revealed that macrophage HIF-1α activation triggered vascular inflammation, extracellular matrix degradation and elastic plate breakage through increased a disintegrin and metallopeptidase domain 17 (ADAM17), identified as a novel target gene of HIF-1α. A HIF-1α specific inhibitor acriflavine elicited protective effects on aortic dissection dependent on macrophage HIF-1α. INTERPRETATION: This study reveals that macrophage metabolic reprogramming activates HIF-1α and subsequently promotes aortic dissection progression, suggesting that macrophage HIF-1α inhibition might be a potential therapeutic target for treating aortic dissection.

17.
Acta Pharmacol Sin ; 2019 Oct 13.
Artigo em Inglês | MEDLINE | ID: mdl-31607752

RESUMO

T cell metabolic activation plays a crucial role in inflammation of atherosclerosis. Shikonin (SKN), a natural naphthoquinone with anti-inflammatory activity, has shown to exert cardioprotective effects, but the effect of SKN on atherosclerosis is unclear. In addition, SKN was found to inhibit glycolysis via targeting pyruvate kinase muscle isozyme 2 (PKM2). In the present study, we investigated the effects of SKN on hyperhomocysteinemia (HHcy)-accelerated atherosclerosis and T cell inflammatory activation in ApoE-/- mice and the metabolic mechanisms in this process. Drinking water supplemented with Hcy (1.8 g/L) was administered to ApoE-/- mice for 2 weeks and the mice were injected with SKN (1.2 mg/kg, i.p.) or vehicle every 3 days. We showed that SKN treatment markedly attenuated HHcy-accelerated atherosclerosis in ApoE-/- mice and significantly decreased inflammatory activated CD4+ T cells and proinflammatory macrophages in plaques. In splenic CD4+ T cells isolated from HHcy-ApoE-/- mice, SKN treatment significantly inhibited HHcy-stimulated PKM2 activity, interferon-γ secretion and the capacity of these T cells to promote macrophage proinflammatory polarization. SKN treatment significantly inhibited HHcy-stimulated CD4+ T cell glycolysis and oxidative phosphorylation. Metabolic profiling analysis of CD4+ T cells revealed that Hcy administration significantly increased various glucose metabolites as well as lipids and acetyl-CoA carboxylase 1, which were reversed by SKN treatment. In conclusion, our results suggest that SKN is effective to ameliorate atherosclerosis in HHcy-ApoE-/- mice and this is at least partly associated with the inhibition of SKN on CD4+ T cell inflammatory activation via PKM2-dependent metabolic suppression.

18.
ACS Appl Mater Interfaces ; 11(43): 39782-39788, 2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31589011

RESUMO

The catalytic activity of 2H-MoS2 is retarded by the deficiency in active sites, inferior intrinsic activity, and slow electron transfer kinetics. However, the strategies to concurrently resolve these issues have been challenging and rarely reported. Herein, we successfully endow MoS2 with exceptional acidic HER performance by concurrently doping nitrogen and metal atoms into the basal plane of MoS2. The experimental results reveal that the N dopant that induces the intervalence charge transfer between two ions (Mo4+/Mo3+) and the atoms rearrangement can enable the successful synthesis of 1T MoS2 on reduced graphene oxides, which can concurrently increase the active-site density and facilitate the charge transfer from the substrate to the catalyst active sites. The spontaneous doping of metal cation atoms further improves the intrinsic activity of MoS2 by creating more sulfur vacancy sites and tailoring the energy level matching. The optimized electrocatalyst exhibited unprecedented activity and stability for HER with a low overpotential of 143 mV at 150 mA cm-2 and a high exchange current density of 1 mA cm-2. Therefore, our work opens up possibility to manipulate the MoS2 catalytic performance to rival Pt, which is of significant importance to both fundamental study and industry applications.

20.
J Am Chem Soc ; 141(44): 17763-17770, 2019 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-31603677

RESUMO

Great enthusiasm in single-atom catalysts (SACs) for the oxygen reduction reaction (ORR) has been aroused by the discovery of M-NX as a promising ORR catalysis center. However, the performance of SACs lags far behind that of state-of-the-art Pt due to the unsatisfactory adsorption-desorption behaviors of the reported catalytic centers. To address this issue, rational manipulation of the active site configuration toward a well-managed energy level and geometric structure is urgently desired, yet still remains a challenge. Herein, we report a novel strategy to accomplish this task through the construction of an Fe-Co dual-atom centered site. A spontaneously absorbed electron-withdrawing OH ligand was proposed to act proactively as an energy level modifier to empower easy intermediate desorption, while the triangular Fe-Co-OH coordination facilitates O-O bond scission. Benefiting from these attributes, the as-constructed FeCoN5-OH site enables an ORR onset potential and half-wave potential of up to 1.02 and 0.86 V (vs RHE), respectively, with an intrinsic activity over 20 times higher than the single-atom FeN4 site. Our finding not only opens up a novel strategy to tailor the electronic structure of an atomic site toward boosted activity but also provides new insights into the fundamental understanding of diatomic sites for ORR electrocatalysis.

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