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1.
Nanoscale ; 13(39): 16487-16498, 2021 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-34607337

RESUMO

The incorporation of catalytic components is a promising strategy to promote redox reaction kinetics and suppress polysulfide shuttling for high-performance lithium-sulfur batteries (LSBs). In this work, metastable marcasite NiSe2 nanodendrites grown on carbon fiber clothes (m-NiSe2/CFC) were synthesized to improve chemical adsorption and electrocatalytic activity towards lithium polysulfides. The multifunctional m-NiSe2/CFC film was utilized as both the interlayer and the three-dimensional (3D) current collector in LSBs. In comparison with the stable pyrite NiSe2 nanodendrite-covered CFC (p-NiSe2/CFC) counterpart, the m-NiSe2/CFC film exhibits even stronger chemisorption, higher catalytic activity and faster reaction kinetics, thereby resulting in significantly improved lithium storage performance. The Al@S/rGO@m-NiSe2/CFC cell has a high reversible capacity of 1646 mA h g-1 at 0.2C, a high QL/QH ratio of 3.00 at 0.2C, a high rate capability of 900 mA h g-1 at 4C, and an outstanding cyclic stability exhibiting a low capacity decay of 0.028% per cycle for 600 cycles at 4C. Moreover, a symmetrically sandwiched cathode of m-NiSe2/CFC@S/rGO@m-NiSe2/CFC was designed for high sulfur loading LSBs (4.5 mg cm-2) with superior electrochemical performance of 3.73 mA h cm-2 after 100 cycles at 1C rate. Our work opens up a new opportunity to enhance the electrochemical performance of LSBs by phase engineering of NiSe2 catalysts in sandwiched structural cathodes.

2.
J Med Chem ; 64(18): 13719-13735, 2021 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-34515481

RESUMO

Mitogen-activated protein kinase-interacting kinases (MNKs) and provirus integration in maloney murine leukemia virus kinases (PIMs) are downstream enzymes of cell proliferation signaling pathways associated with the resistance of tyrosine kinase inhibitors. MNKs and PIMs have complementary effects to regulate cap-dependent translation of oncoproteins. Dual inhibitors of MNKs and PIMs have not been developed. We developed a novel 4,6-disubstituted pyrido[3,2-d]pyrimidine compound 21o with selective inhibition of MNKs and PIMs. The IC50's of 21o to inhibit MNK1 and MNK2 are 1 and 7 nM and those to inhibit PIM1, PIM2, and PIM3 are 43, 232, and 774 nM, respectively. 21o inhibits the growth of myeloid leukemia K562 and MOLM-13 cells with GI50's of 2.1 and 1.2 µM, respectively. 21o decreases the levels of p-eIF4E and p-4EBP1, the downstream products of MNKs and PIMs, as well as cap-dependent proteins c-myc, cyclin D1, and Mcl-1. 21o inhibits the growth of MOLM-13 cell xenografts without causing evident toxicity. 21o represents an innovative dual MNK/PIM inhibitor with a good pharmacokinetic profile.

3.
Nat Commun ; 12(1): 5351, 2021 09 09.
Artigo em Inglês | MEDLINE | ID: mdl-34504063

RESUMO

Climate change has the potential to change the distribution of pests globally and their resistance to pesticides, thereby threatening global food security in the 21st century. However, predicting where these changes occur and how they will influence current pest control efforts is a challenge. Using experimentally parameterised and field-tested models, we show that climate change over the past 50 years increased the overwintering range of a global agricultural insect pest, the diamondback moth (Plutella xylostella), by ~2.4 million km2 worldwide. Our analysis of global data sets revealed that pesticide resistance levels are linked to the species' overwintering range: mean pesticide resistance was 158 times higher in overwintering sites compared to sites with only seasonal occurrence. By facilitating local persistence all year round, climate change can promote and expand pesticide resistance of this destructive species globally. These ecological and evolutionary changes would severely impede effectiveness of current pest control efforts and potentially cause large economic losses.

4.
Nat Protoc ; 16(10): 4722-4765, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34508260

RESUMO

CRISPR-based forward genetic screening represents a powerful approach for the systematic characterization of gene function. Recent efforts have been directed toward establishing CRISPR-based tools for the programmable delivery of combinatorial genetic perturbations, most of which are mediated by a single nuclease and the expression of structurally identical guide backbones from two promoters. In contrast, we have developed CHyMErA (Cas hybrid for multiplexed editing and screening applications), which is based on the co-expression of Cas9 and Cas12a nucleases in conjunction with a hybrid guide RNA (hgRNA) engineered by the fusion of Cas9 and Cas12a guides and expressed from a single U6 promoter. CHyMErA is suitable for the high-throughput deletion of genetic segments including the excision of individual exons. Furthermore, CHyMErA enables the concomitant targeting of two or more genes and can thus be used for the systematic mapping of genetic interactions in mammalian cells. CHyMErA can also be applied for the perturbation of paralogous gene pairs, thereby allowing the capturing of phenotypic roles that would otherwise be masked because of genetic redundancy. Here, we provide instructions for the cloning of hgRNA screening libraries and individual hgRNA constructs and offer guidelines for designing and performing combinatorial pooled genetic screens using CHyMErA. Starting with the generation of Cas9- and Cas12a-expressing cell lines, CHyMErA screening can be implemented within 15-20 weeks.

5.
J Immunol ; 207(9): 2265-2277, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34580107

RESUMO

Down syndrome cell adhesion molecule (Dscam) generates tens of thousands of isoforms by alternative splicing, thereby providing crucial functions during immune responses. In this study, a novel Dscam signaling pathway was investigated in crab, which remains poorly characterized in invertebrates. Bacterial infection induced the cytoplasmic cleavage of Dscam intracellular domains (ICDs) by γ-secretase, and then the released ICDs carrying specific alternatively spliced exons could directly interact with IPO5 to facilitate nuclear translocation. Nuclear imported ICDs thus promoted hemocyte proliferation and protect the host from bacterial infection. Protein-interaction studies revealed that the ectodomain of Dscam bound to a disintegrin and metalloprotease domain 10 (ADAM10) rather than ADAM17. Inhibition or overexpression of ADAM10 impaired or accelerated Dscam shedding activity post-bacterial stimulation, respectively. Moreover, the shedding signal then mediated Dscam with an intact cytoplasmic domain to promote the cleavage of ICDs by γ-secretase. Furthermore, the transcription of ADAM10 was regulated by Dscam-induced canonical signaling, but not nuclear imported ICDs, to serve as a feedback regulation between two different Dscam pathways. Thus, membrane-to-nuclear signaling of Dscam regulated hemocyte proliferation in response to bacterial infection.

6.
Signal Transduct Target Ther ; 6(1): 329, 2021 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-34471087

RESUMO

It's a challenge for detecting the therapeutic targets of a polypharmacological drug from variations in the responsed networks in the differentiated populations with complex diseases, as stable coronary heart disease. Here, in an adaptive, 31-center, randomized, double-blind trial involving 920 patients with moderate symptomatic stable angina treated by 14-day Danhong injection(DHI), a kind of polypharmacological drug with high quality control, or placebo (0.9% saline), with 76-day following-up, we firstly confirmed that DHI could increase the proportion of patients with clinically significant changes on angina-frequency assessed by Seattle Angina Questionnaire (ΔSAQ-AF ≥ 20) (12.78% at Day 30, 95% confidence interval [CI] 5.86-19.71%, P = 0.0003, 13.82% at Day 60, 95% CI 6.82-20.82%, P = 0.0001 and 8.95% at Day 90, 95% CI 2.06-15.85%, P = 0.01). We also found that there were no significant differences in new-onset major vascular events (P = 0.8502) and serious adverse events (P = 0.9105) between DHI and placebo. After performing the RNA sequencing in 62 selected patients, we developed a systemic modular approach to identify differentially expressed modules (DEMs) of DHI with the Zsummary value less than 0 compared with the control group, calculated by weighted gene co-expression network analysis (WGCNA), and sketched out the basic framework on a modular map with 25 functional modules targeted by DHI. Furthermore, the effective therapeutic module (ETM), defined as the highest correlation value with the phenotype alteration (ΔSAQ-AF, the change in SAQ-AF at Day 30 from baseline) calculated by WGCNA, was identified in the population with the best effect (ΔSAQ-AF ≥ 40), which is related to anticoagulation and regulation of cholesterol metabolism. We assessed the modular flexibility of this ETM using the global topological D value based on Euclidean distance, which is correlated with phenotype alteration (r2: 0.8204, P = 0.019) by linear regression. Our study identified the anti-angina therapeutic module in the effective population treated by the multi-target drug. Modular methods facilitate the discovery of network pharmacological mechanisms and the advancement of precision medicine. (ClinicalTrials.gov identifier: NCT01681316).

7.
Environ Entomol ; 50(4): 888-897, 2021 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-33974683

RESUMO

Diurnal temperature fluctuations in nature can have a significant effect on many ectodermic traits. However, studies on the effects of diurnal temperature fluctuations on organisms, especially the effects on specific life stages, are still limited. We examined the immediate effects of the same average temperature (25°C) and different temperature amplitudes (±4, ±6, ±8, ±10, ±12°C) on the development and survival of Plutella xylostella (Lepidoptera: Plutellidae). We also assessed carry-over effects on adult longevity, reproduction, development, and survival of offspring across generations. The effect of moderate temperature amplitudes was similar to that of constant temperature. Wide temperature amplitudes inhibited the development of pupae, reduced total reproduction, lowered intrinsic rates of population growth, and slowed the development and survival of eggs on the first day, but the proportion of females ovipositing on the first three days increased. Insects coped with the adverse effects of wide temperature amplitudes by laying eggs as soon as possible. Our results confirmed that a logistic model based on daily average temperature cannot predict development rates under wide temperature amplitudes. These findings highlight the effect of environmental temperature fluctuations at the pupal stage on the development and oviposition patterns of P. xylostella and should be fully considered when predicting field occurrence.


Assuntos
Mariposas , Animais , Feminino , Larva , Óvulo , Pupa , Temperatura
8.
Pest Manag Sci ; 77(10): 4453-4461, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34002463

RESUMO

BACKGROUND: Experience of an earlier environment plays an important role in the induction of delayed and even intergenerational phenotypes of an organism. Evidence suggests that rapid adaptation to an environmental stressor can change the performance of organisms, and even enable them to deal with other stressors. The goal of this study was to determine the effects of adult imidacloprid exposure on life-history traits within and between generations of the cereal aphid, Sitobion avenae, under three developmental conditions: constant temperature, 22°C; a low-intensity thermal condition, 22 + 34°C for 2 h per day; and a high-intensity thermal condition, 22 + 38°C for 2 h per day. RESULTS: Early thermal experience not only changed the tolerance of S. avenae to the insecticide, imidacloprid, but also caused adults to incur fitness costs: the higher the heat intensity, the higher the costs. Negative transgenerational impacts of combined heat and insecticide stressors were limited to the developmental stage, whereas positive stimulation of heat intensity was observed during the adult stage. Overall, nymphal thermal experience exacerbated the detrimental effects of adult insecticidal exposure on the intrinsic rate of population increase in the maternal generation, but stimulated a net reproductive rate in the succeeding offspring generation. CONCLUSION: These findings underpin the importance of considering the experience of the early developmental environment, but also enhance our understanding of the transgenerational effects of combined thermal and insecticide stressors on the population fate of S. avenae. They also help to assess the efficacy of chemical control in a warming world. © 2021 Society of Chemical Industry.


Assuntos
Afídeos , Inseticidas , Traços de História de Vida , Animais , Temperatura Alta , Ninfa
9.
Mol Med Rep ; 23(6)2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33899122

RESUMO

As a common factor of both type 2 diabetes mellitus (T2DM) and acute coronary syndrome (ACS), circulating microparticles (MPs) may provide a link between these two diseases. The present study compared the content and function of MPs from patients with ACS with or without T2DM. MPs from healthy subjects (n=20), patients with ACS (n=24), patients with T2DM (n=20) and patients with combined ACS and T2DM (n=24) were obtained. After incubating rat thoracic tissue with MPs, the effect of MPs on endothelial­dependent vasodilatation, expression of caveolin­1 and endothelial nitric oxide synthase (eNOS), phosphorylation of eNOS at the S1177 and T495 sites and its association with heat shock protein 90 (Hsp90), and the generation of NO and superoxide anion (O2˙­) were determined. MP concentrations were higher in patients with T2DM and patients with ACS with or without T2DM than in healthy subjects. Moreover, MPs from patients with T2DM or ACS led to impairment in endothelial­dependent vasodilatation, decreased expression of NO, as well as eNOS and its phosphorylation at Ser1177 and association with Hsp90, but increased eNOS phosphorylation at T495, caveolin­1 expression and O2˙­ generation. These effects were strengthened by MPs from patients with ACS combined with T2DM. T2DM not only increased MP content but also resulted in greater vascular impairment effects in ACS. These results may provide novel insight into the treatment of patients with ACS and T2DM.


Assuntos
Síndrome Coronariana Aguda/sangue , Micropartículas Derivadas de Células/metabolismo , Diabetes Mellitus Tipo 2/sangue , Angiopatias Diabéticas/sangue , Síndrome Coronariana Aguda/complicações , Síndrome Coronariana Aguda/patologia , Adulto , Animais , Caveolina 1/metabolismo , Células Cultivadas , Diabetes Mellitus Tipo 2/patologia , Angiopatias Diabéticas/patologia , Endotélio Vascular/metabolismo , Endotélio Vascular/patologia , Endotélio Vascular/fisiopatologia , Feminino , Proteínas de Choque Térmico HSP90/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Ratos , Vasodilatação
10.
J Insect Sci ; 21(2)2021 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-33693804

RESUMO

Diurnal temperature amplitude is known to have a large influence on insect life history. Population density affects intraspecific competition and many other aspects of insect life history. However, there is limited information on the interactive effects of these factors on insects. Here, we tested the interactive effects of three diurnal temperature amplitudes (22 ± 0°C, 22 ± 6°C, and 22 ± 12°C) and three population densities on the development, survival, longevity, and fecundity of the English grain aphid Sitobion avenae (Fabricius) (Homoptera: Aphididae). At a constant temperature, increasing population density reduced the growth and survival of early-instar nymphs, increased longevity, and reduced fecundity. At a low population density, increasing temperature amplitude inhibited nymph development. However, even at a high temperature amplitude, nymph survival rate was higher than expected, and reproduction was possible because the recovery of the lower night-temperatures eliminated thermal stress. Increasing the population density reduced, and even reversed, the negative effects of the wide temperature amplitude. This may reflect synergistic interactions between population density and wide temperature amplitude as these stressors each incur energetic costs. These findings emphasize the importance of temperature amplitude and population density for improving prediction accuracy and damage assessment during pest control modeling.


Assuntos
Afídeos , Densidade Demográfica , Temperatura , Animais , Afídeos/crescimento & desenvolvimento , Afídeos/fisiologia , Fertilidade , Estágios do Ciclo de Vida , Ninfa/crescimento & desenvolvimento , Reprodução
11.
J Anim Sci ; 99(6)2021 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-33744922

RESUMO

Two experiments were conducted to investigate the effects of a combined α-galactosidase and xylanase preparation on nutrients digestibility and growth performance in broiler chickens. Experiment 1 had 240 broilers allocated to 3 treatments with the dietary supplementation of 0, 300, and 500 g/t of the enzyme combination. Diet and amino acid (AA) digestibility were assessed. Experiment 2 was a 2 × 3 (enzyme × diet) factorial arrangement with 10 replicates of 12 male broilers per replicate. Diets were based on corn-soybean meal (SBM) diet and had 3 nutritional levels (normal, 2% apparent metabolizable energy (AME) and crude protein (CP) reduction, and 4% AME and CP reduction). Each of these diets was fed with or without enzyme supplementation. Growth performance, chyme viscosity, nutrients digestibility, and endogenous enzymes activity were assessed. In experiment 1, enzyme supplementation improved the digestibility of Ca (P = 0.025) and ileal digestibility of total AA, Pro, Alu, Ile, Lys, His, Thr, Glu, Val, Leu, Tyr, and Phe (P < 0.05), and also tended to increase the AME of diets (P < 0.10). In experiment 2, broilers fed the corn-SBM diet with 4% nutrient reduction had better growth performance (P < 0.05), jejunal digesta viscosity at 42 d (P < 0.01), and lower digestibility of gross energy (GE; P < 0.05) when compared with those fed the normal nutrient diet. Enzyme inclusion increased digestibility of CP (P = 0.044), GE (P = 0.009), raffinose (P < 0.001) and stachyose (P < 0.001), improved average daily gain (P = 0.031), and reduced jejunal digesta viscosity at 42 d (P = 0.011). Besides, similar improvements trend in amylase, trypsin, sucrase, and maltase activity with enzyme inclusion were observed as with energy. These data support that the enzyme supplementation increased nutrients and ileal AA digestibility, improved performance and endogenous enzymes activity.


Assuntos
Ração Animal , Galinhas , Endo-1,4-beta-Xilanases , alfa-Galactosidase , Ração Animal/análise , Fenômenos Fisiológicos da Nutrição Animal , Animais , Dieta/veterinária , Suplementos Nutricionais , Digestão , Masculino , Nutrientes , Soja , Viscosidade , Zea mays
12.
Eur J Med Chem ; 209: 112885, 2021 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-33227576

RESUMO

In recent years, interest in sulfoximine chemistry has been greatly increased. For example, at least three sulfoximine containing drugs BAY 1143572, BAY 1251152 and AZD6738 have entered the clinic. Despite the increasing interest in sulfoximines and their chemistry, the routine application of this structure in drug discovery is still hampered due to limited experience in physicochemical and in vitro parameters of sulfoximines. Therefore, we reviewed all relevant articles from 2013 to the present in terms of potency and pharmacokinetic properties in order to support the addition of the sulfoximine component to the toolbox of medicinal chemists.


Assuntos
Desenvolvimento de Medicamentos , Descoberta de Drogas , Compostos de Enxofre/química , Animais , Química Farmacêutica , Humanos , Pirimidinas/química , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Sulfonamidas/química , Sulfonamidas/farmacocinética , Sulfonamidas/farmacologia , Sulfóxidos/química , Sulfóxidos/farmacocinética , Sulfóxidos/farmacologia , Compostos de Enxofre/farmacocinética , Compostos de Enxofre/farmacologia , Triazinas/química , Triazinas/farmacocinética , Triazinas/farmacologia
13.
Molecules ; 25(18)2020 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-32967084

RESUMO

Both HDACs and Mnks play important role in translating multiple oncogenic signaling pathways during oncogenesis. As HDAC and Mnk are highly expressed in a variety of tumors; thus simultaneous inhibit HDAC and Mnk can increase the inhibition of tumor cell proliferation and provide a new way of inhibiting tumor growth. Based on the previous work and the merge pharmacophore method; we designed and synthesized a series of 4,6-disubstituted pyrido[3,2-d]pyrimidine derivatives as HDAC and Mnk dual inhibitors. Among them; compound A12 displayed good HDAC and Mnk inhibitory activity. In vitro antiproliferative assay; compound A12 exhibited the best antiproliferative activity against human prostate cancer PC-3 cells. Docking study revealed that the pyrido[3,2-d]pyrimidine framework and hydroxamic acid motif of compound A12 were essential for maintaining the activity of HDAC and Mnk. These result indicated that A12 was a potent Mnk /HDAC inhibitor and will be further researched.


Assuntos
Desenho de Fármacos , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Pirimidinas/síntese química , Pirimidinas/farmacologia , Proliferação de Células/efeitos dos fármacos , Técnicas de Química Sintética , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/química , Inibidores de Histona Desacetilases/metabolismo , Inibidores de Histona Desacetilases/farmacologia , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/química , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Simulação de Acoplamento Molecular , Células PC-3 , Conformação Proteica , Inibidores de Proteínas Quinases/síntese química , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/química , Proteínas Serina-Treonina Quinases/metabolismo , Pirimidinas/química , Pirimidinas/metabolismo
14.
Cancer Res ; 80(21): 4791-4804, 2020 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-32855208

RESUMO

The majority of clinical deaths in patients with triple-negative breast cancer (TNBC) are due to chemoresistance and aggressive metastases, with high prevalence in younger women of African ethnicity. Although tumorigenic drivers are numerous and varied, the drivers of metastatic transition remain largely unknown. Here, we uncovered a molecular dependence of TNBC tumors on the TRIM37 network, which enables tumor cells to resist chemotherapeutic as well as metastatic stress. TRIM37-directed histone H2A monoubiquitination enforces changes in DNA repair that rendered TP53-mutant TNBC cells resistant to chemotherapy. Chemotherapeutic drugs triggered a positive feedback loop via ATM/E2F1/STAT signaling, amplifying the TRIM37 network in chemoresistant cancer cells. High expression of TRIM37 induced transcriptomic changes characteristic of a metastatic phenotype, and inhibition of TRIM37 substantially reduced the in vivo propensity of TNBC cells. Selective delivery of TRIM37-specific antisense oligonucleotides using antifolate receptor 1-conjugated nanoparticles in combination with chemotherapy suppressed lung metastasis in spontaneous metastatic murine models. Collectively, these findings establish TRIM37 as a clinically relevant target with opportunities for therapeutic intervention. SIGNIFICANCE: TRIM37 drives aggressive TNBC biology by promoting resistance to chemotherapy and inducing a prometastatic transcriptional program; inhibition of TRIM37 increases chemotherapy efficacy and reduces metastasis risk in patients with TNBC.


Assuntos
Resistencia a Medicamentos Antineoplásicos/fisiologia , Proteínas com Motivo Tripartido/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Ubiquitina-Proteína Ligases/metabolismo , Animais , Feminino , Regulação Neoplásica da Expressão Gênica/fisiologia , Humanos , Camundongos , Ensaios Antitumorais Modelo de Xenoenxerto
15.
Appl Microbiol Biotechnol ; 104(11): 4863-4875, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32285173

RESUMO

Although microbial exopolysaccharides (EPSs) are applied in different fields, no EPS has been used to protect human skin cells against UV-induced oxidative stress. The EPS produced by the Arctic bacterium Polaribacter sp. SM1127 has high moisture-retention ability and antioxidant activity, suggesting its good industrial potentials. In this study, we improved the EPS production of SM1127 and evaluated its protective effect on human dermal fibroblasts (HDFs) against UV-induced oxidative stress. With glucose as carbon source, the EPS yield was increased from 2.11 to 6.12 g/L by optimizing the fermentation conditions using response surface methodology. To lower the fermentation cost and decrease corrosive speed in stainless steel tanks, whole sugar, whose price is only 8% of that of glucose, was used to replace glucose and NaCl concentration was reduced to 4 g/L in the medium. With the optimized conditions, fed-batch fermentation in a 5-L bioreactor was conducted, and the EPS production reached 19.25 g/L, which represents the highest one reported for a polar microorganism. Moreover, SM1127 EPS could maintain the cell viability and integrity of HDFs under UV-B radiation, probably via decreasing intracellular reactive oxygen species level and increasing intracellular glutathione content and superoxide dismutase activity. Therefore, SM1127 EPS has significant protective effect on HDFs against UV-induced oxidative stress, suggesting its potential to be used in preventing photoaging and photocarcinogenesis. Altogether, this study lays a good foundation for the industrialization of SM1127 EPS, which has promising potential to be used in cosmetics and medical fields.


Assuntos
Antioxidantes/farmacologia , Fibroblastos/efeitos dos fármacos , Estresse Oxidativo , Polissacarídeos Bacterianos/farmacologia , Pele/citologia , Raios Ultravioleta , Regiões Árticas , Reatores Biológicos , Fermentação , Fibroblastos/efeitos da radiação , Flavobacteriaceae/metabolismo , Humanos , Microbiologia Industrial , Polissacarídeos Bacterianos/biossíntese
16.
Sci Transl Med ; 12(532)2020 02 26.
Artigo em Inglês | MEDLINE | ID: mdl-32102932

RESUMO

Therapeutic resistance remains a persistent challenge for patients with malignant tumors. Here, we reveal that endothelial cells (ECs) acquire transformation into mesenchymal stem cell (MSC)-like cells in glioblastoma (GBM), driving tumor resistance to cytotoxic treatment. Transcriptome analysis by RNA sequencing (RNA-seq) revealed that ECs undergo mesenchymal transformation and stemness-like activation in GBM microenvironment. Furthermore, we identified a c-Met-mediated axis that induces ß-catenin phosphorylation at Ser675 and Wnt signaling activation, inducing multidrug resistance-associated protein-1(MRP-1) expression and leading to EC stemness-like activation and chemoresistance. Last, genetic ablation of ß-catenin in ECs overcome GBM tumor resistance to temozolomide (TMZ) chemotherapy in vivo. Combination of Wnt inhibition and TMZ chemotherapy eliminated tumor-associated ECs, inhibited GBM growth, and increased mouse survival. These findings identified a cell plasticity-based, microenvironment-dependent mechanism that controls tumor chemoresistance, and suggest that targeting Wnt/ß-catenin-mediated EC transformation and stemness activation may overcome therapeutic resistance in GBM.


Assuntos
Neoplasias Encefálicas , Glioblastoma , Células-Tronco Mesenquimais , Animais , Neoplasias Encefálicas/tratamento farmacológico , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos , Células Endoteliais , Glioblastoma/tratamento farmacológico , Humanos , Camundongos , Temozolomida/farmacologia , Microambiente Tumoral
17.
J Therm Biol ; 84: 8-15, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31466793

RESUMO

Although thermal variability is known to influence the performance of ectotherms, there is limited information on the influence of variation in diurnal temperature range (DTR) during early developmental stages. Here we test variation in DTR ( ±0 °C, ±4 °C, ±6 °C, ±8 °C, ±10 °C and±12 °C) with a constant mean temperature (25 °C) on the larval stage of diamondback moth (DBM), Plutella xylostella (L.), and assess immediate effects on larval development and survival, and delayed effects on pupal development and survival and adult longevity and reproductive performance. Wide amplitudes ( ±10 °C and±12 °C) inhibited larval development and adult performance, but increased the proportion of eggs laid early, while moderate amplitudes ( ±4 °C, ±6 °C and±8 °C) resulted in only minor effects. Larval development rate under wide amplitudes ( ±10 °C and±12 °C) was faster than predicted by a degree-hour model. Overall, the intrinsic rate of increase of the population was lowered with increasing DTR, despite mean temperatures being the same. These findings highlight marked cross-stage effects of DTR when temperatures fluctuate substantially, likely linked to maximum temperature, and they emphasize the importance of considering DTR when assessing effects of climate warming.


Assuntos
Ritmo Circadiano , Larva/fisiologia , Mariposas/fisiologia , Temperatura , Animais , Feminino , Larva/crescimento & desenvolvimento , Masculino , Mariposas/crescimento & desenvolvimento , Reprodução
18.
Eur J Pharmacol ; 859: 172516, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31265839

RESUMO

Angiotensin II (Ang II) is a vasoactive peptide that elevates arterial blood pressure and leads to hypertension. Ang II has been reported to induce endothelial dysfunction by induction of apoptosis and oxidative stress in vascular endothelial cells. Sirtuin6 (SIRT6) has emerged as a critical regulator for modulating Ang II-induced injury of the cardiovascular system. However, little is known about the role of SIRT6 in regulating Ang II-induced injury in vascular endothelial cells. Here, our results showed that SIRT6 expression was decreased in vascular endothelial cells exposed to Ang II. This was accompanied by decreased cell viabilities as well as increased apoptosis and the production of reactive oxygen species. Functional experiments showed that the overexpression of SIRT6 significantly prohibited Ang II-induced apoptosis and reactive oxygen species generation, while silencing SIRT6 resulted in the opposite effect. Notably, our results showed that overexpression of SIRT6 resulted in a significant increase in the nuclear expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and upregulated the expression of the Nrf2 target gene in vascular endothelial cells exposed to Ang II. Moreover, knockdown of Nrf2 significantly blocked the SIRT6-mediated protection effect against Ang II-induced apoptosis and reactive oxygen species generation. Taken together, these results demonstrate that SIRT6 overexpression alleviates Ang II-induced apoptosis and oxidative stress in vascular endothelial cells by promoting Nrf2 antioxidant signaling. Our study suggests that SIRT6 may serve as a potential therapeutic target for treating hypertension associated with endothelial dysfunction.


Assuntos
Angiotensina II/farmacologia , Elementos de Resposta Antioxidante/efeitos dos fármacos , Apoptose/efeitos dos fármacos , Células Endoteliais/citologia , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Sirtuínas/metabolismo , Linhagem Celular , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/metabolismo , Regulação Enzimológica da Expressão Gênica/efeitos dos fármacos , Humanos , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Sirtuínas/genética
19.
Bioorg Chem ; 89: 102971, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31200288

RESUMO

Usnic acid (UA) is the main secondary metabolite isolated from lichens, with moderate anticancer activity. A small group of (+)-UA derivatives characterized with flavanone moiety was designed and synthesized, and their anticancer activities were evaluated in leukemia cells. It was demonstrated that (+)-UA derivatives 6a-6g inhibited the proliferation of leukemia cells HL-60 and K562 with low micromolar IC50 values. Mechanisms of action were investigated to find that 6g induced apoptosis in HL-60 and K562 cell lines, and affected the expression of MNK/eIF4E axis-related proteins, such as Mcl-1, p-eIF4E, p-4E-BP1. Finally, kinase inhibition assay suggested 6g was a potential inhibitor of pan-Pim kinases. Meanwhile, the blocking of phosphorylation of BAD and 4E-BP1 by 6g, together with the proposed binding mode of 6g with Pim-1 further confirmed its Pim inhibition effects. Our finding provides the sight towards the potential mechanism of (+)-UA derivatives 6g as anti-leukemia agents.


Assuntos
Antineoplásicos/química , Benzofuranos/química , Inibidores de Proteínas Quinases/química , Proteínas Proto-Oncogênicas c-pim-1/antagonistas & inibidores , Proteínas Adaptadoras de Transdução de Sinal/genética , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Benzofuranos/farmacologia , Sítios de Ligação , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Leucemia/metabolismo , Leucemia/patologia , Simulação de Acoplamento Molecular , Fosforilação/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Estrutura Terciária de Proteína , Proteínas Proto-Oncogênicas c-pim-1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Estereoisomerismo
20.
Molecules ; 24(7)2019 Mar 27.
Artigo em Inglês | MEDLINE | ID: mdl-30934730

RESUMO

Peptidyl-prolyl cis/trans isomerase Pin1 plays a key role in amplifying and translating multiple oncogenic signaling pathways during oncogenesis. The blockade of Pin1 provided a unique way of disrupting multiple oncogenic pathways and inducing apoptosis. Aiming to develop potent Pin1 inhibitors, a series of benzimidazole derivatives were designed and synthesized. Among the derivatives, compounds 6h and 13g showed the most potent Pin1 inhibitory activity with IC50 values of 0.64 and 0.37 µM, respectively. In vitro antiproliferative assay demonstrated that compounds 6d, 6g, 6h, 6n, 6o and 7c exhibited moderate antiproliferative activity against human prostate cancer PC-3 cells. Taken together, these unique benzimidazole derivatives exhibited great potential to be further explored as potent Pin1 inhibitors with improved potency.


Assuntos
Benzimidazóis/química , Desenho de Fármacos , Inibidores Enzimáticos/química , Peptidilprolil Isomerase de Interação com NIMA/química , Apoptose/efeitos dos fármacos , Benzimidazóis/farmacologia , Linhagem Celular Tumoral , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Humanos , Estrutura Molecular , Peptidilprolil Isomerase de Interação com NIMA/antagonistas & inibidores , Relação Estrutura-Atividade
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