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1.
J Magn Reson Imaging ; 2021 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-34854521

RESUMO

BACKGROUND: Patients receiving cranial radiation face the risk of delayed brain dysfunction. However, an early medical imaging marker is not available until irreversible morphological changes emerge. PURPOSE: To explore the micromorphological white matter changes during the radiotherapy session by utilizing an along-tract analysis framework. STUDY TYPE: Prospective. POPULATION: Eighteen nasopharyngeal carcinoma (two female) patients receiving cranial radiation. FIELD STRENGTH/SEQUENCE: 3.0 T; Diffusion tensor imaging (DTI) and T1- and T2-weighted images (T1W, T2W); computed tomography (CT). ASSESSMENT: Patients received three DTI imaging scans during the radiotherapy (RT), namely the baseline scan (1-2 days before RT began), the middle scan (the middle of the RT session), and the end scan (1-2 days after RT ended). Twelve fibers were segmented after whole-brain tractography. Then, the fractional anisotropy (FA) values and the cumulative radiation dose received for each fiber streamline were resampled and projected into their center fiber. STATISTICAL TESTS: The contrast among the three scans (P1: middle scan-baseline scan; P2: end scan-middle scan; P3: end scan-baseline scan) were compared using the linear mixed model for each of the 12 center fibers. Then, a dose-responsiveness relationship was performed using Pearson correlation. P < 0.05 was considered statistically significant. RESULTS: Six of the 12 center fibers showed significant changes of FA values during the RT but with heterogeneous patterns. The significant changes along a specific center fiber were associated with their cumulative dose received (Genu: P1 r = -0.6182, P2 r = -0.5907; Splenium: P1 r = 0.4055, P = 0.1063, P2 r = 0.6742; right uncinate fasciculus: P1 r = -0.3865, P2 r = -0.4912, P = 0.0533; right corticospinal tract: P1 r = 0.4273, P = 0.1122, P2 r = -0.6885). DATA CONCLUSION: The along-tract analysis might provide sensitive measures on the early-onset micromorphological changes. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 3.

3.
J Hypertens ; 2021 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-34862331

RESUMO

OBJECTIVES: Hypertension is one of the major adverse effects of tyrosine kinase inhibitors (TKIs) targeting vascular endothelial growth factors. However, the mechanism underlying TKIs-induced hypertension remains unclear. Here, we explored the role of the RhoA/Rho kinase (ROCK) signaling pathway in elevation of blood pressure (BP) induced by apatinib, a selective TKI approved in China for treatment of advanced or metastatic gastric cancer. A nonspecific ROCK inhibitor, Y27632, was then combined with apatinib and its efficacy in alleviating apatinib-induced hypertension was evaluated. METHODS: Normotensive female Wistar-Kyoto rats were exposed to two different doses of apatinib, or apatinib combined with Y27632, or vehicle for 2 weeks. BP was monitored by a tail-cuff plethysmography system. The mRNA levels and protein expression in the RhoA/ROCK pathway were determined, and vascular remodeling assessed. RESULTS: Administration of either a high or low dose of apatinib was associated with a rapid rise in BP, reaching a plateau after 12 days. Apatinib treatment mediated upregulation of RhoA and ROCK II in the mid-aorta, more significant in the high-dose group. However, ROCK I expression showed no statistically significant differences. Furthermore, the mRNA level of GRAF3 decreased dose-dependently. Apatinib administration was also associated with decreased levels of MLCP, and elevated endothelin-1 (ET-1) and collagen I, which were accompanied with increased mid-aortic media. However, treatment with Y27632 attenuated the above changes. CONCLUSION: These findings suggest that activation of the RhoA/ROCK signaling pathway could be the underlying mechanism of apatinib-induced hypertension, while ROCK inhibitor have potential therapeutic value.

4.
Chemosphere ; : 133109, 2021 Nov 29.
Artigo em Inglês | MEDLINE | ID: mdl-34856235

RESUMO

Dyes are intensively used in textile and dyeing industries, and substantial volumes of organic wastewater with residual dye require treatment before discharges to public waterways. Flotation separation is an efficient and widely used method for the treatment of massive organic dye wastewaters. The key scientific problems for dye flotation separation lie in the mineralization transformation of dissolved dye to tangible flocs. In this work, a high-efficiency removal of hazardous azo dye Congo red (CR) from simulated wastewaters via metal ions chelation flocculation followed by flotation separation was proposed. It's demonstrated that CR can be chelated by the trivalent metal ions, including Al(III), Fe(III), and its mixture to form hydrophobic flocs, and then the flocs were efficiently removed via flotation in a microbubble column. The effects of chelation flocculation and flotation separation conditions on the removal efficiencies of CR, COD, and chromaticity from CR simulated wastewaters were optimized. Chelation effect of CR by trivalent metal ions was in this order: Al(III)+Fe(III)>Fe(III)>Al(III). The chelation mechanism suggested that CR molecules gradually changed from hydrazones to electronegative azo with the increase of pH to 6-7, and electrostatic attraction between the Al3(OH)45+ or Fe(OH)2+ with the CR was favorable for the chelation reaction, in which the metal ions chelated with N atoms on naphthalene ring and amino groups of CR. Over 99% CR was removed under the optimal chelation and flotation conditions: chelation by composite Al(III)/Fe(III) with a concentration of 25 mg/L at pH of 7 for 25min; followed by flotation with SDS concentration of 20 mg/L and air flow rate of 50 mL/min for 20min. Under this condition, the COD and chromaticity removal efficiency were over 96% and 98%, respectively, and the turbidity was lower than 0.1 NTU, meeting the water discharge requirement. Eventually, resourceful utilization of flotation sludge via calcination was conducted to prepare Al-Fe spinel refractory material.

5.
FEBS J ; 2021 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-34741776

RESUMO

Retinal pigment epithelium (RPE) cell damage is implicated in the pathogenesis of age-related macular degeneration (AMD). An increase of interferon-γ (IFN-γ) levels was observed in patients with AMD, but whether inflammatory factors are causally related to AMD progression is unclear. Here, we demonstrate a direct causal relationship between IFN-γ and RPE cell death. IFN-γ induced human retinal pigment epithelial cell (ARPE-19) death accompanied by increases in Fe2+ , reactive oxygen species, lipid peroxidation, and glutathione (GSH) depletion, which are main characteristics of ferroptosis. Mechanistically, IFN-γ upregulates the level of intracellular Fe2+ through inhibiting Fe2+ efflux protein SLC40A1 and induces GSH depletion by blocking cystine/glutamate antiporter, System xc-. At the same time, treatment with IFN-γ decreases the level of glutathione peroxidase 4 (GPx4), rendering the cells more sensitive to ferroptosis. JAK1/2 and STAT1 inhibitors could reverse the reduction of SLC7A11, GPx4 and GSH expression induced by IFN-γ, indicating IFN-γ induces ARPE-19 cell ferroptosis via activation of the JAK1-2/STAT1/SLC7A11 signaling pathway. The above results were largely confirmed in IFN-γ-treated mice in vivo. Finally, we used sodium iodate (NaIO3 )-induced retinal degeneration to further explore the role of ferroptosis in AMD in vivo. Consistent with the role of IFN-γ, treatment with NaIO3 decreased SLC7A11, GPx4 and SLC40A1 expressions. NaIO3 -induced RPE damage was accompanied by increased iron, lipid peroxidation products (4-hydroxynonenal, malondialdehyde), and GSH depletion, and ferroptosis inhibitors could reverse the above phenomenon. Taken together, our findings suggest that inhibiting ferroptosis or reducing IFN-γ may serve as a promising target for AMD.

6.
ACS Appl Mater Interfaces ; 13(47): 55879-55889, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34786930

RESUMO

ß-Amyloid (Aß) fibrillogenesis is closely associated with the pathogenesis of Alzheimer's disease (AD), so detection and inhibition of Aß aggregation are of significance for the theranostics of AD. In this work, the coassembled nanoparticles of chitosan and hyaluronic acid cross-linked with glutaraldehyde (CHG NPs) were found to work as a theranostic agent for imaging/probing and inhibition of Aß fibrillization both in vitro and in vivo. The biomass-based CHG NPs of high stability exhibited a wide range of excitation/emission wavelengths and showed binding affinity toward Aß aggregates, especially for soluble Aß oligomers. CHG NPs displayed weak emission in the monodispersed state, while they remarkably emitted increased red fluorescence upon interacting with Aß oligomers and fibrils, showing high sensitivity with a detection limit of 0.1 nM. By comparing the different fluorescence responses of CHG NPs and Thioflavin T to Aß aggregation, the Aß oligomerization rate during nucleation can be determined. Moreover, the fluorescence recognition behavior of CHG NPs was selective. CHG NPs specifically bind to negatively charged amyloid aggregates but not to positively charged amyloids and negatively charged soluble proteins. Such enhancement in fluorescence emission is attributed to the clustering-triggered emission effect of CHG NPs after interaction with Aß aggregates via various electronic conjugations and hydrogen bonding, electrostatic, and hydrophobic interactions. Besides fluorescent imaging/probing, CHG NPs over 360 µg/mL could almost completely inhibit the formation of Aß fibrils, exhibiting the capability of regulating Aß aggregation. In-vivo assays with Caenorhabditis elegans CL2006 demonstrated the potency of CHG NPs as an effective theranostic nanoagent for imaging Aß plaques and inhibiting Aß deposition. The findings proved the potential of CHG NPs for development as a potent agent for the diagnosis and treatment of AD.

7.
Artigo em Inglês | MEDLINE | ID: mdl-34820731

RESUMO

The distribution patterns and health risk assessment of nitrated polycyclic aromatic hydrocarbons (NPAHs), hydroxy polycyclic aromatic hydrocarbons (OH-PAHs), and regular 16 priority polycyclic aromatic hydrocarbons (PAHs) in sediment from the Songhua River in northeastern China were investigated in this research. During dry seasons, concentrations of 16 USEPA priority PAHs, OH-PAHs, and NPAHs were extremely high, with average values of 1220 ± 288, 317 ± 641, 2.54 ± 3.98, and 12.2 ± 22.1 ng/g (dry weight, dw). The dry period level was confirmed to be 4 times greater than the wet period concentration. Modeling with positive matrix factorization (PMF) and estimation of diagnostic isomeric ratios were applied for identifying sources, according to the positive matrix factorization model: vehicle emissions (38.1%), biomass burning (25%), petroleum source (23.4%), and diesel engines source (13.5%) in wet season as well as wood combustion (44.1%), vehicle source (40.2%), coke oven (10.8%), and biomass burning (4.9%) in the dry season. The greatest seasonal variability was attributed to high molecular weight compounds (HMW PAHs). BaP was confirmed to be 81% carcinogenic in this study, which offers convincing proof of the escalating health issues.

8.
Gene ; : 146066, 2021 Nov 24.
Artigo em Inglês | MEDLINE | ID: mdl-34838638

RESUMO

Bone morphogenetic protein-6 (BMP-6) and dihydrotestosterone (DHT) affect steroid synthesis in follicles and regulate cell proliferation in the ovaries of female animals. However, little is known about granular cells (GCs) in sheep. We identified the key BMP-6 receptors, activin receptor-like kinase(ALK-6), and bone morphogenetic protein receptor type 2 (BMPRII) in sheep follicles using immunohistochemistry (IHC) and immunofluorescence (IF). Both ALK-6 and BMPRII were expressed in the GC layer, GC membranes, and cytoplasm. We evaluated ALK-6 and BMPRII expression at the follicular development stage using quantitative real-time PCR and western blotting to detect sheep GCs from large, medium, and small follicles (diameters of ≥5, 2-5, and ≤2 mm, respectively). The mRNA abundance and protein expression of ALK-6 and BMPRII were significantly higher in GCs from large follicles compared to those in GCs from small follicles (P < 0.05) and were the lowest in GCs from medium follicles. To assess whether DHT affects ALK-6 and BMPRII expression in sheep GCs, we cultured GCs from large follicles in vitro then incubated them with DHT (10-11, 10-9, 10-7 M). We found that 10-7-M DHT significantly inhibited ALK-6 and BMPRII mRNA and protein (P < 0.05). We further explored whether DHT regulates ALK-6 and BMPRII through the nuclear androgen receptor (AR) pathway and found that 10-6-M flutamide, a non-selective androgen inhibitor, partially relieved the inhibitory effect of 10-7-M DHT on ALK-6 and BMPRII expression. Thus, GCs in sheep antral follicles differentially expressed ALK-6 and BMPRII at various stages, indicating that BMP-6 plays different roles to some extent during the development of antral follicles, and that high concentrations of DHT can inhibit the expression of ALK-6 and BMPRII via the androgen receptor pathway in sheep GCs. The present study aimed to determine the expression of the main BMP-6-related main receptors, namely, ALK-6 and BMPRII, during the development of GCs in sheep antral follicles and a potential mechanism of DHT regulation in sheep GCs. Our findings lay a foundation for the further exploration of the effects of ovarian BMP-6 expression on follicular development.

9.
Gels ; 7(4)2021 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-34842652

RESUMO

Metal nanoclusters (NCs) with excellent photoluminescence properties are an emerging functional material that have rich physical and chemical properties and broad application prospects. However, it is a challenging problem to construct such materials into complex ordered aggregates and cause aggregation-induced emission (AIE). In this article, we use the supramolecular self-assembly strategy to regulate a water-soluble, atomically precise Ag NCs (NH4)9[Ag9(C7H4SO2)9] (Ag9-NCs, [Ag9(mba)9], H2mba = 2-mercaptobenzoic acid) and L-malic acid (L-MA) to form a phosphorescent hydrogel with stable and bright luminescence, which is ascribed to AIE phenomenon. In this process, the AIE of Ag9-NCs could be attributed to the non-covalent interactions between L-MA and Ag9-NCs, which restrict the intramolecular vibration and rotation of ligands on the periphery of Ag9-NCs, thus inhibiting the ligand-related, non-radiative excited state relaxation and promoting radiation energy transfer. In addition, the fluorescent Ag9-NCs/L-MA xerogel was introduced into polymethylmethacrylate (PMMA) to form an excellently fluorescent film for sensing of Fe3+. Ag9-NCs/L-MA/PMMA film exhibits an excellent ability to recognize Fe3+ ion with high selectivity and a low detection limit of 0.3 µM. This research enriches self-assembly system for enhancing the AIE of metal NCs, and the prepared hybrid films will become good candidates for optical materials.

10.
Artigo em Inglês | MEDLINE | ID: mdl-34743308

RESUMO

Lead (Pb) is one of the most toxic and harmful pollutants to the environment and human health. Centipedegrass (Eremochloa ophiuroides (Munro) Hack.), an excellent ground cover plant for urban plant communities, exhibits the outstanding lead tolerance and accumulation. Nitrilotriacetic acid (NTA) is an environmentally friendly chelating agent that strengthens phytoremediation. This study explored the effects of different NTA concentrations on the absorption and transportation of mineral elements and Pb in centipedegrass. Following exposure to Pb (500 µM) for 7 days in hydroponic nutrient solution, NTA increased root Mg, K, and Ca concentrations and shoot Fe, Cu, and Mg concentrations and significantly enhanced the translocation factors of mineral elements to the shoot. Although NTA notably decreased root Pb absorption and accumulation, it significantly enhanced Pb translocation factors, and the Pb TF value was the highest in the 2.0 mM NTA treatment. Furthermore, the shoot translocation of Pb and mineral elements was synergistic. NTA can support mineral element homeostasis and improve Pb translocation efficiency in centipedegrass. Regarding root radial transport, NTA (2.0 mM) significantly promoted Pb transport by the symplastic pathway under the treatments with low-temperature and metabolic inhibitors. Meanwhile, NTA increased apoplastic Pb transport at medium and high Pb concentrations (200-800 µM). NTA also enhanced the Pb radial transport efficiency in roots and thus assisted Pb translocation. The results of this study elucidate the effects of NTA on the absorption and transportation of mineral elements and Pb in plants and provide a theoretical basis for the practical application of the biodegradable chelating agent NTA in soil Pb remediation.

11.
J Mater Chem B ; 9(34): 6902-6914, 2021 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-34612337

RESUMO

Misfolding and the subsequent self-assembly of amyloid-ß protein (Aß) is very important in the occurrence of Alzheimer's disease (AD). Thus, inhibition of Aß aggregation is currently an effective method to alleviate and treat AD. Herein, a carboxylated single-walled carbon nanotube (SWCNT-COOH) was rationally designed based on the hydrophobic binding-electrostatic repulsion (HyBER) mechanism. The inhibitory effect of SWCNT-COOH on Aß fibrillogenesis was first studied. Based on the results of thioflavin T fluorescence and atomic force microscopy imaging assays, it was shown that SWCNT-COOH can not only effectively inhibit Aß aggregation, but also depolymerize the mature fibrils of Aß. In addition, its inhibitory action will be affected by the content of carboxyl groups. Moreover, the influence of SWCNT-COOH on cytotoxicity induced by Aß was investigated by the MTT method. It was found that SWCNT-COOH can produce an anti-Aß neuroprotective effect in vitro. Molecular dynamics simulations showed that SWCNT-COOH significantly destroyed the overall and internal structural stability of an Aß40 trimer. Moreover, SWCNT-COOH interacted strongly with the N-terminal region, turn region and C-terminal region of the Aß40 trimer via hydrogen bonds, salt bridges and π-π interactions, which triggered a large structural disturbance of the Aß40 trimer, reduced the ß-sheet content of the Aß40 trimer and led to more disorder in these regions. All the above data not only reveal the suppressive effect of SWCNT-COOH on Aß aggregation, but also reveal its inhibitory mechanism, which provides a useful clue to exploit anti-Aß drugs in the future.

12.
Chem Phys Lipids ; 242: 105150, 2021 Oct 19.
Artigo em Inglês | MEDLINE | ID: mdl-34673008

RESUMO

Phloretin is a powerful antioxidant with many effects, such as anti-cancer, anti-inflammatory, promoting cell renewal, delaying aging and so on. However, the application of phloretin was limited by its low water solubility, low absorption in vivo and unstable properties. A phloretin-loaded nanostructured lipid carrier was designed with a high-pressure homogenization technique. The mean particle size of phloretin NLC was 137.40 ± 3.27 nm, and the Polydispersity index (PdI) value was 0.237 ± 0.005. The encapsulation efficiency was 96.68% ± 0.06%. Transmission electron microscopy images showed that the phloretin-loaded nanostructured lipid carriers were spherical. Phloretin in NLC showed a sustained release pattern in vitro. The results showed that phloretin NLC is more suitable for absorption than phloretin ethanol solution, and NLC can be a promising carrier for phloretin in the food industry.

13.
J Cell Mol Med ; 25(22): 10575-10590, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34655278

RESUMO

Metastasis is the main cause of colon cancer-related deaths. RBP-Jκ is involved in colon cancer development, but its function in colon cancer metastasis is still unclear. Tumour-associated macrophages are the main cell components in tumour microenvironments. Here, we aimed to determine the function of RBP-Jκ in colon cancer metastasis and its underlying mechanisms for modulating interactions between colon cancer cell and tumour-associated macrophages. Through bioinformation analysis, we found that RBP-Jκ was overexpressed in colon cancer tissues and associated with advanced colon cancer phenotypes, macrophage infiltration and shorter survival overall as confirmed by our patients' data. And our patients' data show that RBP-Jκ expression and tumour-associated macrophages infiltration are associated with colon cancer metastasis and are independent prognostic factors for colon cancer patients. Tumour-associated macrophages induced colon cancer cell migration, invasion and epithelial-mesenchymal transition through secreting TGF-ß1. Colon cancer cells with high RBP-Jκ expression induced the expression of TGF-ß1 in tumour-associated macrophages by secreting CXCL11. Our research revealed that colon cancer cells secreted CXCL11 via overexpression of RBP-Jκ to enhance the expression of TGF-ß1 in tumour-associated macrophages to further promote metastasis of colon cancer cells.

14.
Front Endocrinol (Lausanne) ; 12: 740902, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34621244

RESUMO

Fatty acid binding protein 4 (FABP4) has been associated with insulin resistance. Gestational diabetes mellitus (GDM) impairs fetal insulin sensitivity. Female newborns are more insulin resistant than male newborns. We sought to evaluate the association between GDM and cord blood FABP4, and explore potential sex dimorphic associations and the roles of sex hormones. This was a nested case-control study in the Shanghai Birth Cohort, including 153 pairs of newborns in GDM vs. euglycemic pregnancies matched by infant sex and gestational age at delivery. Cord plasma FABP4, leptin, total and high-molecular-weight adiponectin, testosterone and estradiol concentrations were measured. Adjusting for maternal and neonatal characteristics, cord plasma FABP4 (Mean ± SD: 27.0 ± 19.6 vs. 18.8 ± 9.6 ng/mL, P=0.045) and estradiol (52.0 ± 28.6 vs. 44.2 ± 26.6, ng/mL, P=0.005) concentrations were higher comparing GDM vs. euglycemic pregnancies in males, but similar in females (all P>0.5). Mediation analyses showed that the positive association between GDM and cord plasma FABP4 in males could be partly mediated by estradiol (P=0.03), but not by testosterone (P=0.72). Cord plasma FABP4 was positively correlated with total adiponectin in females (r=0.17, P=0.053), but the correlation was in the opposite direction in males (r=-0.11, P=0.16) (test for difference in r, P=0.02). Cord plasma FABP4 was not correlated with leptin in both sexes. The study is the first to demonstrate sex-dimorphic associations between GDM and cord plasma FABP4 or estradiol, and between FABP4 and adiponectin in newborns. GDM may affect fetal circulating FABP4 and estradiol levels in males only.

15.
Biomacromolecules ; 22(11): 4823-4832, 2021 11 08.
Artigo em Inglês | MEDLINE | ID: mdl-34669395

RESUMO

With regard to polyesters based on biobased 2,5-furandicarboxylic acid (FDCA), our work presents a new strategy, heteroatom substitution, to adjust the thermal and gas barrier properties. The effects of nonhydroxyl oxygen heteroatoms in the diols on the properties of FDCA-based polyesters were first investigated by a combination of an experiment and molecular simulation. The results demonstrated that the introduction of oxygen heteroatoms significantly influenced the thermal and gas barrier properties. As for the two model polymers with a very similar skeleton structure, poly(pentylene 2,5-furandicarboxylate) (PPeF) and poly(diethylene glycol 2,5-furandicarboxylate) (PDEF), their Tg exhibited an obviously increasing order. Moreover, they showed similar thermal stability and thermal oxidative stability. Dynamic mechanical analysis, positron annihilation lifetime spectroscopy, and molecular dynamics simulation indicated that the gas barrier properties followed the sequence of PDEF > PPeF mainly due to the decreased chain mobility and smaller fractional free volume. In-depth analysis of the effects of heteroatom substitution has an important directive significance for the design and preparation of new high glass transition temperature or novel excellent gas barrier materials. Through the manipulation of different heteroatoms in the diols, the polyesters with varied properties can be expected.


Assuntos
Oxigênio , Poliésteres , Ácidos Dicarboxílicos , Etilenoglicóis , Furanos
16.
J Integr Neurosci ; 20(3): 585-594, 2021 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-34645091

RESUMO

Demyelination is one of the pathological outcomes that occur immediately following spinal cord injury. Protection of oligodendrocytes against death/apoptosis proves to be beneficial for the preservation of neurological functions. Suppressors of cytokine signaling 1 protein inhibit the harmful effects of several inflammatory cytokines on oligodendrocytes, but its roles in spinal cord injury (SCI) induced apoptosis of oligodendrocytes remain unclear. We cloned suppressors of cytokine signaling 1 cDNA from Gekko japonicus (Japanese gecko) and analyzed the protein structure revealing the conserved domains contained in other vertebrate suppressors of cytokine signaling 1 proteins. The gecko suppressors of cytokine signaling 1 protein expression were increased in the injured spinal cord following gecko tail amputation and displayed colocalization with oligodendrocytes. The enforced expression of gecko suppressors of cytokine signaling 1 by adenovirus in the Gsn3 gecko oligodendrocyte cell line demonstrated that gecko suppressors of cytokine signaling 1 significantly suppressed cell apoptosis-induced by glucose deprivation. Determination of apoptosis-related proteins revealed that gecko suppressors of cytokine signaling 1 was able to activate extracellular regulated protein kinases (ERK) and serine/threonine protein kinases (Akt). The results presented a distinct protective role of gecko suppressors of cytokine signaling 1 in the regenerative model of the spinal cord, which may provide new cues for central nervous system repair in mammals.

17.
J Sep Sci ; 2021 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-34670011

RESUMO

The flavonoids from Euonymus alatus exhibit many biological activities including significant antioxidant, anti-inflammatory, anti-cancer. In this work, a high-speed countercurrent chromatography method for the isolation and purification of flavonoids from crude extracts of Euonymus alatus was established. The effects of several solvent systems on the separation efficiency of target compounds in the extract of Euonymus alatus were studied. The solvent system composed of n-hexane-ethyl acetate-methanol-water at a volume ratio of (3:5:3:5, v/v) was chosen, in which the lower phase was used as the mobile phase at the rotation speed of 800 rpm and flow rate of 2.0 mL/min. The three flavonoids were obtained and identified as patuletin-3-O-rutinoside, rhamnazin-3-O-rutinoside, and dehydrodicatechin A by mass spectroscopy and nuclear magnetic resonance, and the quantities of patuletin-3-O-rutinoside, rhamnazin-3-O-rutinoside, and dehydrodicatechin A were 2.2, 9.7, and 1.8 mg, respectively. The results indicated that high-speed countercurrent chromatography was a simple and efficient method for the isolation and purification of flavonoids from the crude extracts of Euonymus alatus. The cellular antioxidant activity experimental result indicated that rhamnazin-3-O-rutinoside could alleviate H2 O2 -induced oxidative stress.

18.
Chem Sci ; 12(38): 12776-12784, 2021 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-34703564

RESUMO

RNA-guided Streptococcus pyogenes Cas9 (SpCas9) is a sequence-specific DNA endonuclease that works as one of the most powerful genetic editing tools. However, how Cas9 locates its target among huge amounts of dsDNAs remains elusive. Here, combining biochemical and single-molecule fluorescence assays, we revealed that Cas9 uses both three-dimensional and one-dimensional diffusion to find its target with high efficiency. We further observed surprising apparent asymmetric target search regions flanking PAM sites on dsDNA under physiological salt conditions, which accelerates the target search efficiency of Cas9 by ∼10-fold. Illustrated by a cryo-EM structure of the Cas9/sgRNA/dsDNA dimer, non-specific interactions between DNA ∼8 bp downstream of the PAM site and lysines within residues 1151-1156 of Cas9, especially lys1153, are the key elements to mediate the one-dimensional diffusion of Cas9 and cause asymmetric target search regions flanking the PAM. Disrupting these non-specific interactions, such as mutating these lysines to alanines, diminishes the contribution of one-dimensional diffusion and reduces the target search rate by several times. In addition, low ionic concentrations or mutations on PAM recognition residues that modulate interactions between Cas9 and dsDNA alter apparent asymmetric target search behaviors. Together, our results reveal a unique searching mechanism of Cas9 under physiological salt conditions, and provide important guidance for both in vitro and in vivo applications of Cas9.

20.
Toxicol Appl Pharmacol ; 432: 115757, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34673086

RESUMO

An increasing number of studies have shown that arsenic exposure increases the risk of lung cancer as well as a variety of non-malignant respiratory diseases, including bronchitis and tracheobronchitis. HMGB1 is widely expressed in a variety of tissues and cells and is involved in the pathological processes of many lung diseases through binding to the corresponding receptors and activating the downstream signaling pathways. However, the exact role of HMGB1/RAGE in arsenic-induced lung injury remains unknown. The aim of this study was to investigate whether HMGB1/RAGE and its activated downstream pathways are involved in the process of arsenic exposure-induced lung injury in rats. In this study, an animal model of oral exposure to arsenic was induced using 2.5, 5 and 10 mg/kg NaAsO2. The results showed that capillary permeability (LDH, TP, ACP, and AKP) was increased in the arsenic exposure groups, resulting in cell damage; this was accompanied by acute inflammation marked by significant neutrophil infiltration. Meanwhile, obvious histopathological damage, including thickening of the lung epithelium, increased infiltration of inflammatory cells, rupture of the alveolar wall, swelling of the mitochondria, and chromatin agglutination was observed by H&E staining and transmission electron microscopy. Furthermore, the results confirmed that the expressions of HMGB1 and RAGE in lung tissue were enhanced, and protein expression of PI3K, p-AKT, IL-1ß, IL-18, and MMP-9 was increased in lung homogenates from the arsenic-exposed groups compared to the control group. Finally, Masson's staining results revealed arsenic-induced fibrosis and collagen deposition. Moreover, a significant increase in key fibrosis factors, including TGF-ß1, p-SMAD2, p-SMAD3, and SMAD4 was observed in the lung homogenates in arsenic-exposed groups. In conclusion, the current study demonstrates that sub-chronic arsenic exposure triggers the inflammatory response and collagen fiber deposition in rat lung tissue. The potential mechanism may be closely related to activation of the pro-inflammatory-related HMGB1/RAGE pathway and initiation of the PI3K/AKT and TGF-ß1/SMAD pathways.

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