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1.
Environ Sci Technol ; 2021 Nov 17.
Artigo em Inglês | MEDLINE | ID: mdl-34787396

RESUMO

Sulfidated zero-valent iron (S-ZVI) enhances the degradation of chlorinated hydrocarbon (CHC) in contaminated groundwater. Despite numerous studies of S-ZVI, a versatile strategy to improve its dechlorination kinetics, electron efficiency (εe), and dechlorination capacity is still needed. Here, we used heteroatom incorporation of N(C) and S by ball-milling of microscale ZVI with melamine and sulfur via nitridation and sulfidation to synthesize S-N(C)-mZVIbm particles that contain reactive Fe-NX(C) and FeS species. Sulfidation and nitridation synergistically increased the trichloroethene (TCE) dechlorination rate, with reaction constants kSA of 2.98 × 10-2 L·h-1·m-2 by S-N(C)-mZVIbm, compared to 1.77 × 10-3 and 8.15 × 10-5 L·h-1·m-2 by S-mZVIbm and N(C)-mZVIbm, respectively. Data show that sulfidation suppressed the reductive dissociation of N(C) from S-N(C)-mZVIbm, which stabilized the reactive Fe-NX(C) and reserved electrons for TCE dechlorination. In addition to lowering H2 production, S-N(C)-mZVIbm dechlorinated TCE to less reduced products (e.g., acetylene), contributing to the material's higher εe and dechlorination capacity. This synergistic effect on TCE degradation can be extended to other recalcitrant CHCs (e.g., chloroform) in both deionized and groundwater. This multiheteroatom incorporation approach to optimize ZVI for groundwater remediation provides a basis for further advances in reactive material synthesis.

2.
Opt Lett ; 46(19): 4855-4858, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34598217

RESUMO

Electrically pumped semiconductor mode-locked lasers (SMLs) are promising in a wide range of applications due to compact size, high energy efficiency, and low cost. However, the long gain interaction length increases the spontaneous emission noise. In this Letter, an external cavity structure is adopted to improve the SML noise performance, as well as the flexibility to adjust the repetition rate. Two external cavity SMLs with repetition rates of 255 MHz and 10 GHz are demonstrated. For the 10 GHz SML, the signal-noise-ratio and radio frequency linewidth of the fundamental frequency reach 81.1 dB and 40 Hz, respectively. The high performance makes the laser a promising light source for microwave and communication applications.

3.
Clin Appl Thromb Hemost ; 27: 10760296211040109, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34617462

RESUMO

Objective: We tried to find the relationship between statin and diabetes retinopathy (DR) in patients with type 2 diabetes mellitus (T2DM). Methods: We searched the databases of PubMed, EMBASE, and the Cochrane Library for eligible studies reporting on the relationships between statin use and DR, from inception to September 25, 2020. The terms searched including Diabetes Mellitus, Type 2, Hydroxymethylglutaryl-CoA Reductase Inhibitors, and Diabetic Retinopathy. We expressed the results as the odds ratios (ORs) with 95% confidence intervals (CIs) which were calculated using a random-effects model. Results: A total of 6 eligible studies, including 43 826 patients, were included in the meta-analysis. The meta-analysis showed that statin was not associated with elevated risk of DR [OR = 0.96 (95% CI: 0.80-1.16), P = .68]. Similarly, no differences were found between statin and placebo in participants ≥500 [OR = 0.98 (95% CI: 0.80-1.21)] or participants <500 [OR = 0.90 (95% CI: 0.49-1.66)]. Further, we conducted a meta-analysis to study the effect of statin therapy on DR in people with type 2 diabetes according to age and found that statin use was associated with a decreased risk of DR in patients with type 2 diabetes 40 years of age or older [OR = 0.87 (95% CI: 0.82-0.92)]. Conclusion: Our meta-analysis revealed that statin was not associated with elevated risk of DR in patients with T2DM. Moreover, statin use was associated with a lower incidence of DR in patients with type 2 diabetes 40 years of age or older.

4.
Biotechnol Lett ; 43(12): 2199-2208, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34626279

RESUMO

Nicotinamide mononucleotide (NMN) or Nicotinamide-1-ium-1-ß-D-ribofuranoside 5'-phosphate is a nucleotide that can be converted into nicotinamide adenine dinucleotide (NAD) in human cells. NMN has recently attracted great attention because of its potential as an anti-aging drug, leading to great efforts for its effective manufacture. The chemical synthesis of NMN is a challenging task since it is an isomeric compound with a complicated structure. The majority of biological synthetic routes for NMN is through the intermediate phosphoribosyl diphosphate (PRPP), which is further converted to NMN by nicotinamide phosphoribosyltransferase (Nampt). There are various routes for the synthesis of PRPP from simple starting materials such as ribose, adenosine, and xylose, but all of these require the expensive phosphate donor adenosine triphosphate (ATP). Thus, an ATP regeneration system can be included, leading to diminished ATP consumption during the catalytic process. The regulations of enzymes that are not directly involved in the synthesis of NMN are also critical for the production of NMN. The aim of this review is to present an overview of the biological production of NMN with respect to the critical enzymes, reaction conditions, and productivity.

5.
Front Oncol ; 11: 742149, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34660304

RESUMO

Ovarian cancer, a common malignant tumor, is one of the primary causes of cancer-related deaths in women. Systemic chemotherapy with platinum-based compounds or taxanes is the first-line treatment for ovarian cancer. However, resistance to these chemotherapeutic drugs worsens the prognosis. The underlying mechanism of chemotherapeutic resistance in ovarian cancer remains unclear. Non-coding RNAs, including long non-coding RNAs, microRNAs, and circular RNAs, have been implicated in the development of drug resistance. Abnormally expressed non-coding RNAs can promote ovarian cancer resistance by inducing apoptosis inhibition, protective autophagy, abnormal tumor cell proliferation, epithelial-mesenchymal transition, abnormal glycolysis, drug efflux, and cancer cell stemness. This review summarizes the role of non-coding RNAs in the development of chemotherapeutic resistance in ovarian cancer, including their mechanisms, targets, and potential signaling pathways. This will facilitate the development of novel chemotherapeutic agents that can target these non-coding RNAs and improve ovarian cancer treatment.

6.
J Med Chem ; 64(19): 14773-14792, 2021 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-34613725

RESUMO

MGAT2 inhibition is a potential therapeutic approach for the treatment of metabolic disorders. High-throughput screening of the BMS internal compound collection identified the aryl dihydropyridinone compound 1 (hMGAT2 IC50 = 175 nM) as a hit. Compound 1 had moderate potency against human MGAT2, was inactive vs mouse MGAT2 and had poor microsomal metabolic stability. A novel chemistry route was developed to synthesize aryl dihydropyridinone analogs to explore structure-activity relationship around this hit, leading to the discovery of potent and selective MGAT2 inhibitors 21f, 21s, and 28e that are stable to liver microsomal metabolism. After triaging out 21f due to its inferior in vivo potency, pharmacokinetics, and structure-based liabilities and tetrazole 28e due to its inferior channel liability profile, 21s (BMS-963272) was selected as the clinical candidate following demonstration of on-target weight loss efficacy in the diet-induced obese mouse model and an acceptable safety and tolerability profile in multiple preclinical species.

7.
Yi Chuan ; 43(9): 849-857, 2021 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-34702698

RESUMO

MicroRNAs (miRNAs), a family of endogenous non-coding RNAs with a length of about 22 nucleotides, are widely found in eukaryotes. miRNAs can affect gene expression through specific bindings with mRNAs of target genes and participate in the regulation of a variety of biological processes. Giant panda is not only a unique rare animal in China, but also the focus of attention on wildlife preservation worldwide. In recent years, with the popularization of next-generation sequencing (NGS) technology, miRNAs in giant panda have been discovered and identified one after another. In this review, we focus on the research progress on miRNAs in giant panda, involved in immune response, mammary gland development, sperm freezing tolerance and other biological processes, and then discuss future research directions of miRNAs in giant panda, and thus providing the scientific references and new ideas for studying the regulatory mechanisms of miRNAs and promoting the breeding and protection of giant panda.


Assuntos
MicroRNAs , Ursidae , Animais , China , Masculino , MicroRNAs/genética , RNA Mensageiro , Espermatozoides , Ursidae/genética
8.
Nanomaterials (Basel) ; 11(9)2021 Aug 30.
Artigo em Inglês | MEDLINE | ID: mdl-34578552

RESUMO

After the discovery of graphene, a lot of research has been conducted on two-dimensional (2D) materials. In order to increase the performance of 2D materials and expand their applications, two different layered materials are usually combined by van der Waals (vdW) interactions to form a heterostructure. In this work, based on first-principles calculation, some charming properties of the heterostructure constructed by Hf2CO2, AlN and GaN are addressed. The results show that Hf2CO2/AlN and Hf2CO2/GaN vdW heterostructures can keep their original band structure shape and have strong thermal stability at 300 K. In addition, the Hf2CO2/MN heterostructure has I-type band alignment structure, which can be used as a promising light-emitting device material. The charge transfer between the Hf2CO2 and AlN (or GaN) monolayers is 0.1513 (or 0.0414) |e|. The potential of Hf2CO2/AlN and Hf2CO2/GaN vdW heterostructures decreases by 6.445 eV and 3.752 eV, respectively, across the interface. Furthermore, both Hf2CO2/AlN and Hf2CO2/GaN heterostructures have remarkable optical absorption capacity, which further shows the application prospect of the Hf2CO2/MN heterostructure. The study of this work provides theoretical guidance for the design of heterostructures for use as photocatalytic and photovoltaic devices.

9.
Hum Mol Genet ; 2021 Sep 30.
Artigo em Inglês | MEDLINE | ID: mdl-34590683

RESUMO

BACKGROUND: Activated neutrophil-derived exosomes reportedly contribute to the proliferation of airway smooth muscle cells (ASMCs), thereby aggravating the airway wall remodeling during asthma; however, the specific mechanism remains unclear. METHODS: Lipopolysaccharide (LPS)-EXO and si-CRNDE-EXO were extracted from the media of human neutrophils treated with LPS and LPS + si-CRNDE (a siRNA targets long non-coding RNA CRNDE), respectively. Human ASMCs were co-cultured with LPS-EXO or si-CRNDE-EXO, and cell viability, proliferation, and migration were measured. The interplay of CRNDE, inhibitor of nuclear factor kappa B kinase subunit beta (IKKß), and nuclear receptor subfamily 2 group C member 2 (TAK1) was explored using RNA immunoprecipitation (RIP) and Co-IP assays. A mouse model of asthma was induced using ovalbumin. RESULTS: CRNDE was upregulated in LPS-EXO and successfully transferred from LPS-treated neutrophils to ASMCs through exosome. Mechanically, CRNDE loaded in LPS-EXO reinforced TAK1-mediated IKKß phosphorylation, thereby activating the nuclear factor kappa B (NF-κB) pathway. Functionally, silencing CRNDE in LPS-EXO, an IKKß inhibitor, and an NF-κB inhibitor all removed the upregulation of cell viability, proliferation, and migration induced by LPS-EXO in ASMCs. In the end, the in vivo experiment demonstrated that CRNDE knockdown in neutrophils effectively reduced the thickness of bronchial smooth muscle in a mouse model for asthma. CONCLUSION: Activated neutrophils-derived CRNDE was transferred to ASMCs through exosomes and activated the NF-κB pathway by enhancing IKKß phosphorylation. The latter promoted the proliferation and migration of ASMCs and then contributed to airway remodeling in asthma.

10.
J Asian Nat Prod Res ; : 1-7, 2021 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-34581213

RESUMO

Two new flavonol glycosides 3,5,7-trimethoxyflavone-4'-O-[5'''-O-p-coumaroyl-ß-D-apiofuranoyl-(1'''→2'')-ß-D-glucopyranoside] (1) and 3,5,7-trimethoxyflavone -4'-O-ß-D-glucopyranoside (2) were isolated from Selaginella tamariscina. The structures of 1 and 2 were elucidated on the basis of chemical and spectral analysis, including 1D, 2D NMR analyses and HRESIMS spectrometry. Two compounds were evaluated for cytotoxic activities against A-375, MCF-7, MDA-MB-231 and MDA-MB-468 cell lines by MTT assay. Unfortunately, two compounds displayed no cytotoxic activities.

11.
Aging (Albany NY) ; 13(18): 22556-22570, 2021 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-34587120

RESUMO

OBJECTIVE: To verify if AngII/NOX/ROS/MAPK signaling pathway is involved in Doxorubicin (DOX)-induced myocardial injury and if mesenchymal stem cells (MSCs) could enhance the protective effects of valsartan (Val) on attenuating DOX-induced injury in vitro. METHODS: Reactive oxygen species (ROS) formation and the protein expression of AT1R, NOX2, NOX4, caspase-3, caspase-9 and MAPK signaling were assessed in H9c2 cardiomyocytes exposed to DOX for 24 h in the absence or presence of Val, NADPH oxidase inhibitor DPI or knockdown and overexpression of NADPH oxidase subunit: NOX2 and NOX4, co-culture with MSCs, respectively. Finally, MTT assay was used to determine the cell viability of H9c2 cells, MDA-MB-231 breast cancer cells and A549 pulmonary cancer cells under Val, DOX and Val+ DOX treatments. RESULTS: DOX increased ROS formation and upregulated proteins expression of AT1R, NOX2, NOX4, caspase-3, caspase-9 and MAPK signaling including p-p38, p-JNK, p-ERK in H9c2 cells. These effects could be attenuated by Val, DPI, NOX2 siRNA and NOX4 siRNA. Meanwhile, overexpression of NOX2 and NOX4 could significantly increase DOX-induced ROS formation and further upregulate apoptotic protein expressions and protein expressions of MAPK signaling. MSCs on top of Val further enhanced the protective effects of Val on reducing the DOX-induced ROS formation and downregulating the expression of apoptotic proteins and MAPK signaling as compared with Val alone in DOX-treated H9c2 cells. Simultaneous Val and DOX treatment did not affect cell viability of DOX-treated MDA-MB-231 breast cancer cells or A549 pulmonary cancer cells but significantly improved cell viability of DOX-treated H9c2 cardiomyocytes. CONCLUSIONS: AT1R/NOX/ROS/MAPK signaling pathway is involved in DOX-induced cardiotoxicity. Val treatment significantly attenuated DOX-induced cardiotoxicity, without affecting the anti-tumor effect of DOX. MSCs enhance the protective effects of Val on reducing the DOX-induced toxicity in H9c2 cells.

12.
Comput Methods Programs Biomed ; 211: 106297, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34536633

RESUMO

PURPOSE: We used convolutional neural network (CNN) technology to improve the accuracy of diagnosis of knee meniscus injury and shorten the diagnosis time. METHOD: We propose a meniscus detection method based on Fusion of CNN1 and CNN2 (CNNf), which uses Magnetic Resonance Imaging (MRI) and Computer tomography (CT) to compare the diagnosis results, verifies the proposed method through 2460 images collected from 205 patients in the hospital. We used accuracy, sensitivity, specificity, receiver operating characteristics (ROC), and damage total rate to evaluate performance. RESULTS: The accuracy of our model was 93.86%, the sensitivity was 91.35%, the specificity was 94.65%, and the area under the receiver operating characteristic curve was 96.78%. The total damage rate of MRI is 91.57%, which is far greater than the total damage rate of CT diagnosis of 80.13%. CONCLUSION: CNNf-based MRI technology of knee meniscus injury has high practical value in clinical practice. It can effectively improve the accuracy of diagnosis and reduce the rate of misdiagnosis.


Assuntos
Menisco , Humanos , Articulação do Joelho/diagnóstico por imagem , Imageamento por Ressonância Magnética , Redes Neurais de Computação , Sensibilidade e Especificidade , Tomografia Computadorizada por Raios X
13.
Biosensors (Basel) ; 11(8)2021 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-34436060

RESUMO

Point-of-care monitoring of hydrogen peroxide is important due to its wide usage in biomedicine, the household and industry. Herein, a paper sensor is developed for sensitive, visual and selective detection of H2O2 using a mesoporous metal oxide hollow sphere as a nanozyme. The mesoporous CuO hollow sphere is synthesized by direct decomposition of copper-polyphenol colloidal spheres. The obtained mesoporous CuO hollow sphere shows a large specific surface area (58.77 m2/g), pore volume (0.56 cm3/g), accessible mesopores (5.8 nm), a hollow structure and a uniform diameter (~100 nm). Furthermore, they are proven to show excellent peroxidase-like activities with Km and Vmax values of 120 mM and 1.396 × 10-5 M·s-1, respectively. Such mesoporous CuO hollow spheres are then loaded on the low-cost and disposable filter paper test strip. The obtained paper sensor can be effectively used for detection of H2O2 in the range of 2.4-150 µM. This work provides a new kind of paper sensor fabricated from a mesoporous metal oxide hollow sphere nanozyme. These sensors could be potentially used in bioanalysis, food security and environmental protection.

14.
Clin Transl Med ; 11(8): e482, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34459123

RESUMO

BACKGROUND: Atrial fibrillation (AF), a supraventricular arrhythmia that impairs cardiac function, is a main source of morbidity and mortality. Serum-derived extracellular vesicles (EVs) have been identified to carry potential biomarker or target for the diagnosis and treatment of AF. We intended to dissect out the role of lncRNA MIAT enriched in serum-derived EVs in AF. METHODS: MIAT expression was quantified in EVs isolated from serum samples of AF patients. Mouse and cell models of AF were developed after angiotensin II (Ang II) induction. Relationship between MIAT, miR-485-5p, and CXCL10 was identified. Ectopic expression and depletion assays were implemented in Ang II-treated mice or HL-1 cells, or those co-cultured with serum-derived EVs to explore the roles of EV-carried MIAT. RESULTS: MIAT was upregulated in EVs from serum samples of AF patients. Further analysis indicated that MIAT enriched in serum-derived EVs promoted atrial fibrosis, inflammation and oxidative stress, and aggravated the atrial remodeling and resultant AF. Mechanistically, MIAT bound to miR-485-5p and weakened its inhibitory role on the target CXCL10, which was responsible for the role of serum-derived EV containing MIAT in cellular fibrosis, oxidative stress and inflammation, and atrial remodeling in vivo. CONCLUSIONS: In conclusion, serum-derived EV containing MIAT facilitates atrial remodeling and exacerbates the AF by abolishing the miR-485-5p-mediated CXCL10 inhibition. This finding aids in the deeper understanding about the pathophysiology of AF.

15.
ACS Appl Mater Interfaces ; 13(34): 40302-40314, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34412471

RESUMO

Nanozyme has been regarded as one of the antibacterial agents to kill bacteria via a Fenton-like reaction in the presence of H2O2. However, it still suffers drawbacks such as insufficient catalytic activity in near-neutral conditions and the requirement of high H2O2 levels, which would minimize the side effects to healthy tissues. Herein, a mesoporous ceria hollow sphere/enzyme nanoreactor is constructed by loading glucose oxidase in the mesoporous ceria hollow sphere nanozyme. Due to the mesoporous framework, large internal voids, and high specific surface area, the obtained nanoreactor can effectively convert the nontoxic glucose into highly toxic hydroxyl radicals via a cascade catalytic reaction. Moreover, the generated glucose acid can decrease the localized pH value, further boosting the peroxidase-like catalytic performance of mesoporous ceria. The generated hydroxyl radicals could damage severely the cell structure of the bacteria and prevent biofilm formation. Moreover, the in vivo experiments demonstrate that the nanoreactor can efficiently eliminate 99.9% of bacteria in the wound tissues and prevent persistent inflammation without damage to normal tissues in mice. This work provides a rational design of a nanoreactor with enhanced catalytic activity, which can covert glucose to hydroxyl radicals and exhibits potential applications in antibacterial therapy.

16.
Glycobiology ; 31(10): 1390-1400, 2021 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-34228782

RESUMO

Galectin-3 (Gal-3), a ß-galactoside-binding lectin, has been implicated in a plethora of pathological disorders including fibrosis, inflammation, cancer and metabolic diseases. TD139-a thio-digalactoside inhibitor developed by Galecto Biotech as a potential therapeutic for idiopathic pulmonary fibrosis-is the most advanced small-molecule Gal-3 inhibitor in clinical studies. It binds to human Gal-3 with high affinity but has lower affinity towards mouse and rat homologs, which is also manifested in the differential inhibition of Gal-3 function. Using biophysical methods and high-resolution X-ray co-crystal structures of TD139 and Gal-3 proteins, we demonstrate that a single amino acid change corresponding to A146 in human Gal-3 is sufficient for the observed reduction in the binding affinity of TD139 in rodents. Site-directed mutagenesis of A146V (in human Gal-3) and V160A (in mouse Gal-3) was sufficient to interchange the affinities, mainly by affecting the off rates of the inhibitor binding. In addition, molecular dynamics simulations of both wild-type and mutant structures revealed the sustained favorable noncovalent interactions between the fluorophenyl ring and the active site A146 (human Gal-3 and mouse V160A) that corroborate the finding from biophysical studies. Current findings have ramifications in the context of optimization of drug candidates against Gal-3.

17.
Huan Jing Ke Xue ; 42(7): 3565-3576, 2021 Jul 08.
Artigo em Chinês | MEDLINE | ID: mdl-34212683

RESUMO

This study explored the responses of soil dissolved organic matter (DOM) to the application of different types of compost using a soil sample without compost as a control. Ultraviolet and fluorescence spectrum technology and EEM-PARAFAC was used to analyze DOM structure and driving factors in soil added with different proportion of cow dung compost (SCC), food and kitchen waste compost (SFC), and sludge compost (SCC). Compared with the control group, contents of AN, NH4+-N, DOC, and SOM in soil added with compost were significantly increased, and contents of SOM and DOC increased with the increasing of compost amount. When added compost in the same proportion, contents of AN, NO3--N, and DOC in SCC and SFC were significantly higher than those in SSC, while contents of NH4+-N and SOM were higher in SSC. The results of spectral analysis showed that the structure of conjugated benzene ring, hydrophobic component, quinone group, and chromogenic component in DOM of soil added with compost were significantly increased, the transition of unsaturated organic molecule (π→π*) was more active, the molecular weight of DOM increased, and the degree of humification was enhanced. When the amount of compost added is 5%, the influence of food and kitchen waste compost on DOM structure was greatest among three types of compost. At 10% and 20%, sludge compost had the greatest impact on DOM structure. The results of EEM-PARAFAC analysis showed that the relative content of fulvic acid-like substances with low molecular in DOM of soil added with compost was increased, while the relative content of proteoid-like substances decreased. 2D-COS analysis showed that compost affected the change order of fluorescence components in DOM. SCC and SFC were as follows:proteoid-like > fulvic acid-like > humus-like; in SSC, it was fulvic acid-like > proteoid-like > humus-like. The enhance of humification and the decrease of relative content of protein-like substances in DOM were related to increased DOC and AN, the relative content of humus-like in low molecular weight was positively correlated with the content of NO3--N, and the relative content of macromolecule fulvic acid-like was increased due to the input of SOM from compost.


Assuntos
Compostagem , Solo , Substâncias Húmicas/análise , Espectrometria de Fluorescência
18.
J Med Chem ; 64(10): 6634-6655, 2021 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-33988358

RESUMO

Galectin-3 is a member of a family of ß-galactoside-binding proteins. A substantial body of literature reports that galectin-3 plays important roles in cancer, inflammation, and fibrosis. Small-molecule galectin-3 inhibitors, which are generally lactose or galactose-based derivatives, have the potential to be valuable disease-modifying agents. In our efforts to identify novel galectin-3 disaccharide mimics to improve drug-like properties, we found that one of the monosaccharide subunits can be replaced with a suitably functionalized tetrahydropyran ring. Optimization of the structure-activity relationships around the tetrahydropyran-based scaffold led to the discovery of potent galectin-3 inhibitors. Compounds 36, 40, and 45 were selected for further in vivo evaluation. The synthesis, structure-activity relationships, and in vivo evaluation of novel tetrahydropyran-based galectin-3 inhibitors are described.


Assuntos
Dissacarídeos/química , Galectina 3/antagonistas & inibidores , Piranos/química , Animais , Sítios de Ligação , Quimiotaxia/efeitos dos fármacos , Cristalografia por Raios X , Dissacarídeos/síntese química , Dissacarídeos/metabolismo , Dissacarídeos/farmacologia , Galectina 3/metabolismo , Meia-Vida , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Conformação Molecular , Simulação de Dinâmica Molecular , Permeabilidade/efeitos dos fármacos , Ligação Proteica , Relação Estrutura-Atividade , Triazóis/química
19.
BMC Musculoskelet Disord ; 22(1): 427, 2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-33962613

RESUMO

BACKGROUND: Tributyltin, a well-known endocrine disruptor, is widely used in agriculture and industry. Previous studies have shown that tributyltin could cause deleterious effects on bone health by impairing the adipo-osteogenic balance in bone marrow. METHODS: To investigate further the effects of tributyltin on bone, weaned male SD rats were treated with tributyltin (0.5, 5 or 50 µg·kg- 1) or corn oil by gavage once every 3 days for 60 days in this study. Then, we analyzed the effects of tributyltin on geometry, the polar moment of inertia, mineral content, relative abundances of mRNA from representative genes related to adipogenesis and osteogenesis, serum calcium ion and inorganic phosphate levels. RESULTS: Micro-computed tomography analysis revealed that treatment with 50 µg·kg- 1 tributyltin caused an obvious decrease in femoral cortical cross sectional area, marrow area, periosteal circumference and derived polar moment of inertia in rats. However, other test results showed that exposure to tributyltin resulted in no significant changes in the expression of genes detected, femoral cancellous architecture, ash content, as well as serum calcium ion and inorganic phosphate levels. CONCLUSIONS: Exposure to a low dose of tributyltin from the prepubertal to adult stage produced adverse effects on skeletal architecture and strength.


Assuntos
Densidade Óssea , Fêmur , Animais , Fêmur/diagnóstico por imagem , Masculino , Ratos , Ratos Sprague-Dawley , Compostos de Trialquitina , Microtomografia por Raio-X
20.
Biochem J ; 478(9): 1689-1703, 2021 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-33876829

RESUMO

Hepatic stellate cells (HSCs) are thought to play key roles in the development of liver fibrosis. Extensive evidence has established the concept that αV integrins are involved in the activation of latent transforming growth factor ß (TGF-ß), a master regulator of the fibrotic signaling cascade. Based on mRNA and protein expression profiling data, we found that αVß1 integrin is the most abundant member of the αV integrin family in either quiescent or TGF-ß1-activated primary human HSCs. Unexpectedly, either a selective αVß1 inhibitor, Compound 8 (C8), or a pan-αV integrin inhibitor, GSK3008348, decreased TGF-ß1-activated procollagen I production in primary human HSCs, in which the role of ß1 integrin was confirmed by ITGB1 siRNA. In contrast with an Activin receptor-like kinase 5 (Alk5) inhibitor, C8 and GSK3008348 failed to inhibit TGF-ß1 induced SMAD3 and SMAD2 phosphorylation, but inhibited TGF-ß-induced phosphorylation of ERK1/2 and STAT3, suggesting that αVß1 integrin is involved in non-canonical TGF-ß signaling pathways. Consistently, ITGB1 siRNA significantly decreased phosphorylation of ERK1/2. Furthermore, a selective inhibitor of MEK1/2 blocked TGF-ß1 induced phosphorylation of ERK1/2 and decreased TGF-ß1 induced procollagen I production, while a specific inhibitor of STAT3 had no effect on TGF-ß1 induced procollagen I production. Taken together, current data indicate that αVß1 integrin can regulate TGF-ß signaling independent of its reported role in activating latent TGF-ß. Our data further support that αVß1 inhibition is a promising therapeutic target for the treatment of liver fibrosis.


Assuntos
Células Estreladas do Fígado/metabolismo , Integrina alfa5beta1/genética , Pró-Colágeno/genética , Receptor do Fator de Crescimento Transformador beta Tipo I/genética , Proteína Smad2/genética , Fator de Crescimento Transformador beta1/genética , Butiratos/farmacologia , Regulação da Expressão Gênica , Células Estreladas do Fígado/citologia , Células Estreladas do Fígado/efeitos dos fármacos , Humanos , Integrina alfa5beta1/antagonistas & inibidores , Integrina alfa5beta1/metabolismo , MAP Quinase Quinase 1/genética , MAP Quinase Quinase 1/metabolismo , MAP Quinase Quinase 2/genética , MAP Quinase Quinase 2/metabolismo , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Naftiridinas/farmacologia , Fosforilação/efeitos dos fármacos , Cultura Primária de Células , Pró-Colágeno/metabolismo , Pirazóis/farmacologia , Pirrolidinas/farmacologia , RNA Interferente Pequeno/genética , RNA Interferente Pequeno/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismo , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Proteína Smad2/metabolismo , Proteína Smad3/genética , Proteína Smad3/metabolismo , Fator de Crescimento Transformador beta1/metabolismo
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