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The complex pathologies in Alzheimer's disease (AD) severely limit the effectiveness of single-target pharmic interventions, thus necessitating multi-pronged therapeutic strategies. While flexibility is essentially demanded in constructing such multi-target systems, for achieving optimal synergies and also accommodating the inherent heterogeneity within AD. Utilizing the dynamic reversibility of supramolecular strategy for conferring sufficient tunability in component substitution and proportion adjustment, amphiphilic calixarenes are poised to be a privileged molecular tool for facilely achieving function integration. Herein, taking ß-amyloid (Aß) fibrillation and oxidative stress as model combination pattern, a supramolecular multifunctional integration is proposed by co-assembling guanidinium-modified calixarene with ascorbyl palmitate and loading dipotassium phytate within calixarene cavity. Serial pivotal events can be simultaneously addressed by this versatile system, including 1) inhibition of Aß production and aggregation, 2) disintegration of Aß fibrils, 3) acceleration of Aß metabolic clearance, and 4) regulation of oxidative stress, which is verified to significantly ameliorate the cognitive impairment of 5×FAD mice, with reduced Aß plaque content, neuroinflammation, and neuronal apoptosis. Confronted with the extremely intricate clinical realities of AD, the strategy presented here exhibits ample adaptability for necessary alterations on combinations, thereby may immensely expedite the advancement of AD combinational therapy through providing an exceptionally convenient platform.
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Doença de Alzheimer , Peptídeos beta-Amiloides , Calixarenos , Nanopartículas , Estresse Oxidativo , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Animais , Peptídeos beta-Amiloides/metabolismo , Peptídeos beta-Amiloides/antagonistas & inibidores , Peptídeos beta-Amiloides/química , Nanopartículas/química , Camundongos , Calixarenos/química , Estresse Oxidativo/efeitos dos fármacos , HumanosRESUMO
Human activity and climate change affect biodiversity and cause species range shifts, contractions, and expansions. Globally, human activities and climate change have emerged as persistent threats to biodiversity, leading to approximately 68% of the ~522 primate species being threatened with extinction. Here, we used habitat suitability models and integrated data on human population density, gross domestic product (GDP), road construction, the normalized difference vegetation index (NDVI), the location of protected areas (PAs), and climate change to predict potential changes in the distributional range and richness of 26 China's primate species. Our results indicate that both PAs and NDVI have a positive impact on primate distributions. With increasing anthropogenic pressure, species' ranges were restricted to areas of high vegetation cover and in PAs surrounded by buffer zones of 2.7-4.5 km and a core area of PAs at least 0.1-0.5 km from the closest edge of the PA. Areas with a GDP below the Chinese national average of 100,000 yuan were found to be ecologically vulnerable, and this had a negative impact on primate distributions. Changes in temperature and precipitation were also significant contributors to a reduction in the range of primate species. Under the expected influence of climate change over the next 30-50 years, we found that highly suitable habitat for primates will continue to decrease and species will be restricted to smaller and more peripheral parts of their current range. Areas of high primate diversity are expected to lose from 3 to 7 species. We recommend that immediate action be taken, including expanding China's National Park Program, the Ecological Conservation Redline Program, and the Natural Forest Protection Program, along with a stronger national policy promoting alternative/sustainable livelihoods for people in the local communities adjacent to primate ranges, to offset the detrimental effects of anthropogenic activities and climate change on primate survivorship.
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Mudança Climática , Conservação dos Recursos Naturais , Animais , Humanos , Primatas , Biodiversidade , Ecossistema , Atividades Humanas , ChinaRESUMO
The pursuit of synthetic receptors with high binding affinities has long been a central focus in supramolecular chemistry, driven by their significant practical relevance in various fields. Despite the numerous synthetic receptors that have been developed, most exhibit binding affinities in the micromolar range or lower. Only a few exceptional receptors achieve binding affinities exceeding 109 â M-1 , and their substrate scopes remain rather limited. In this context, we introduce SC[5]A, a conjugated corral-shaped macrocycle functionalized with ten sulfate groups. Owing to its deep one-dimensional confined hydrophobic cavity and multiple sulfate groups, SC[5]A displays an extraordinarily high binding strength of up to 1011 â M-1 towards several size-matched, rod-shaped organic dications in water. Besides, its conformation exhibits good adaptability, allowing it to encapsulate a wide range of other guests with diverse molecular sizes, shapes, and functionalities, exhibiting relatively strong affinities (Ka =106 -108 â M-1 ). Additionally, we've explored the preliminary application of SC[5]A in alleviating blood coagulation induced by hexadimethrine bromide in vitro and in vivo. Therefore, the combination of ultrahigh binding affinities (towards complementary guests) and adaptive recognition capability (towards a wide range of functional guests) of SC[5]A positions it as exceptionally valuable for numerous practical applications.
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Recently, the asymmetric bifunctionalization of alkenes has received much attention. However, the development of enantioselective alkoxyalkenylation has posed a considerable challenge and has lagged largely behind. Herein, we report a new palladium-catalyzed enantioselective alkoxyalkenylation reaction, using a range of primary, secondary, and tertiary γ-hydroxy-alkenes with alkenyl halides. By employing newly identified Xu-Phos (Xu8 and Xu9) with a suitable side-arm adjacent to the PCy2 motif, a series of allyl-substituted tetrahydrofurans were obtained in good yields with up to 95% ee. Besides (E)-alkenyl halides, (Z)-alkenyl halide was also examined and provided the corresponding (Z)-product as a single diastereomer, supporting a stereospecific oxidative addition and reductive elimination step. Moreover, deuterium labeling and VCD experiments were employed to determine a cis-oxypalladation mechanism. DFT calculations helped us gain deeper insight into the side-arm effect on the chiral ligand. Finally, the practicability of this method is further demonstrated through a gram-scale synthesis and versatile transformations of the products.
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PURPOSE: Approximately 5% of differentiated thyroid cancers lose the ability to uptake iodine, leading to limited treatment options and poor prognosis due to invasion and distant metastasis. PSMA imaging probes have been proposed as a potential diagnostic and therapeutic tool for iodine-refractory thyroid cancer. However, there are limited reports and significant heterogeneity in patient selection, warranting further exploration of the application value of PSMA in thyroid cancer. METHODS: We performed Western Blot, PCR, and [68Ga]Ga-PSMA uptake experiments on cell lines and conducted in vivo small animal imaging. Clinical and radiological results of included differentiated thyroid cancer patients were collected. (Trial registration number: 2021-669, Trial registration date: December 30, 2021). RESULTS: PSMA expression levels were significantly higher in poorly differentiated thyroid cancer (7.86 ± 1.90 vs. 1.00 ± 0, P < 0.01; 7.86 ± 1.90 vs. 0.03 ± 0.02, P < 0.01), but [68Ga]Ga-PSMA imaging correlated with tumor burden, such as 18F-FDG (8.08 ± 7.74 and 5.67 ± 4.23, P = 0.01) and Tg levels (307.1 ± 183.4 vs. 118.0 ± 116.1, P = 0.002). CONCLUSION: Our results showed that PSMA expression increased with the decrease of thyroid cancer differentiation. However, the level of [68Ga]Ga-PSMA uptake in thyroid cancer patients was not significantly associated with the degree of thyroid cancer differentiation, but also with the metabolism and burden of tumors such as 2-[18F]FDG and Tg levels. These findings provide additional clinical significance and application value for PSMA in thyroid cancer.
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The spatial diffusion mechanism underlying cropland heavy metal contamination in a complex peri-urban environment provides a crucial basis for controlling soil contamination from the source and also for ensuring the quality of black soil croplands. However, previous studies have struggled to locate the contamination sources or trace their diffusion trajectories in space. In this regard, representative peri-urban croplands in the black soil region were selected as a case, and soil As, Pb, Hg, and Cd were deemed as the main research objects. Moreover, an affinity propagation algorithm and spatial autocorrelation regression were adopted to measure the contamination patterns and identify the major determinants, in an attempt to reveal how heavy metals are diffused in the peri-urban cultivated area. The results indicated that â the average concentrations of soil As and Cd were 39.35 mg·kg-1 and 0.183 mg·kg-1, respectively, which exhibited heavier accumulation in the study area. The Nemerow index indicated that there were 52.38% of croplands indicating slight contamination. â¡ The affinity propagation algorithm identified three potential sources with a similar impact extent for As, which were situated in the typical cultivated area. Both of the two identified potential sources for Pb were situated in close proximity to Fanjiatun Town. The diffusion patterns for Hg and Cd were complex, particularly for the latter, of which the potential sources were scattered in multiple places. ⢠The spatial lag model indicated that the distributions of As and Cd were mainly controlled by the intensive agriculture in peri-urban areas, among which As was related to the application of herbicide and Cd was related to the distribution of protected agriculture. Pb was mainly influenced by urbanization and industrialization, whereas Hg was found to be associated with the migration conditions of the soil. However, the regulating function provided by either croplands or their nearby environment did not play an important role in determining the diffusion patterns of heavy metals. The present study enriches the theory and methods for the spatial analysis of cropland heavy metal contamination and is significant for controlling contamination from the source in peri-urban croplands in the black soil region.
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This study aimed to examine the effectiveness of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) in treating patients with nonsmall cell lung cancer (NSCLC), and the association between clinical characteristics and effectiveness. This retrospective study included 140 patients with NSCLC admitted to our hospital between July 2020 and July 2022. The patients were categorized into 2 groups according to the treatment that they received: a comparison group (67 patients) and a research group (73 patients). The comparison group received conventional chemotherapy, and the research group received conventional chemotherapy and EGFR-TKI-targeted therapy. The immune and tumor marker levels, clinical response, and relationship between clinical characteristics and response to therapy were compared between the 2 groups before and after treatment. After treatment, the levels of neuron-specific enolase and carcinoembryonic antigen (CEA) and CD8+ count were significantly lower, and forced vital capacity, forced expiratory volume in 1 second, and CD4+ count were significantly higher in the research group than in the comparison group. After treatment, the clinical effectiveness in the 2 groups significantly improved, and the disease control rate in the research group was significantly higher than that in the comparison group (89% vs 69%, P = .014). The bivariate analysis revealed that smoking history, ECOG Performance Status score, and CEA level were significantly associated with clinical effectiveness. Conventional chemotherapy combined with EGFR-TKI-targeted therapy is effective in patients with NSCLC and has a clinically significant effect on improving patients' immune function and lung function.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Antígeno Carcinoembrionário , Estudos Retrospectivos , Neoplasias Pulmonares/tratamento farmacológico , Receptores ErbBRESUMO
This study aims to address the lack of relevant researches in the field of waste recycling using the Theory of Planned Behavior (TPB). A village-scale social survey was conducted to investigate the degree of farmers' participation in a waste plastic film program, i.e. Old for New in northwest China. The program required farmers to recycle plastic film residues in exchange for new films. Survey results showed that 67.5% of farmers accepted the program, yet only 14.5% of them actually participated. Logistic regression analysis was used to analyze questionnaire data and identify the factors that significantly affected farmers' recycling behavior. Principal component and weight analysis further showed that farmers' participation was mainly influenced by their attitudes (p < 0.01), with a relative weight (RW) of 46.3%. Yet, subjective norms (p < 0.1) and perceived behavior control (p < 0.1) had less effect on the degree of participation, and their RWs were 4.2% and 4.1% only, respectively. Moreover, the RW of plastic film usage characteristics and household characteristics reached up to 13.2% and 6.4%, respectively. Interestingly, environmental awareness (ß = 0.083) and compulsory environmental education (ß = 0.130) as surface factors strongly affected the farmers' adoption and response, with the RW of 25.7%. As such, the extended TPB model was established to analyze the participation behavior of farmers for stronger explanatory power. This study highlighted a promising strategy based on TPB for waste plastic film recycling and similar environmental management practices.
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Fazendeiros , Teoria do Comportamento Planejado , Humanos , Agricultura , China , PlásticosRESUMO
The rhizome is an economically important part of ginger (Zingiber officinale Rosc.). However, the mechanism of ginger rhizome enlargement remains unclear. In this study, we performed an integrated analysis of the hormone content and transcriptome of ginger at three rhizome enlargement stages: initial enlargement (S1), middle enlargement (S2), and peak enlargement (S3). With rhizome enlargement, the levels of the hormones zeatin (ZT), gibberellic acid (GA), indole acetic acid (IAA), and jasmonic acid (JA) were significantly increased, and this increase was positively correlated with rhizome diameter. Transcriptomic analysis identified a large number of differentially expressed genes (DEGs); the number of DEGs were 2,206 in the transition from S1 to S2, and 1,151 in the transition from S2 to S3. The expression of several genes related to hormone biosynthesis and signalling and cell division or expansion, and transcription factors was significantly altered, which suggests that these genes play essential roles in rhizome enlargement. The results of correlation analysis suggested that the process of ginger rhizome enlargement may be primarily related to the regulation of endogenous cytokinin, GA3, auxin, and JA biosynthesis pathways and signal transduction; GRAS, HB, MYB, MYB122, bZIP60, ARF1, ARF2, E2FB1, and E2FB2, which may regulate the expression of rhizome formation-related genes; and CYC2, CDKB1, CDKB2, EXPA1, and XTH7, which may mediate cell division and expansion. These results provide gene resources and information that will be useful for the molecular breeding in ginger.
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Rizoma , Zingiber officinale , Rizoma/genética , Rizoma/metabolismo , Zingiber officinale/genética , Perfilação da Expressão Gênica , Transcriptoma , Hormônios/metabolismoRESUMO
AIM: To observe ocular surface changes after phacovitrectomy in patients with mild to moderate meibomian gland dysfunction (MGD)-type dry eye and track clinical treatment response using a Keratograph 5M and a LipiView interferometer. METHODS: Forty cases were randomized into control group A and treatment group B; the latter received meibomian gland treatment 3d before phacovitrectomy and sodium hyaluronate before and after surgery. The average non-invasive tear film break-up time (NITBUTav), first non-invasive tear film break-up time (NITBUTf), non-invasive measured tear meniscus height (NTMH), meibomian gland loss (MGL), lipid layer thickness (LLT) and partial blink rate (PBR) were measured preoperatively and 1wk, 1 and 3mo postoperatively. RESULTS: The NITBUTav values of group A at 1wk (4.38±0.47), 1mo (6.76±0.70), and 3mo (7.25±0.68) were significantly lower than those of group B (7.45±0.78, 10.46±0.97, and 11.31±0.89; P=0.002, 0.004, and 0.001, respectively). The NTMH values of group B at 1wk (0.20±0.01) and 1mo (0.22±0.01) were markedly higher than those of group A (0.15±0.01 and 0.15±0.01; P=0.008 and P<0.001, respectively); however, there was no difference at 3mo. The LLT of group B at 3mo [91.5 (76.25-100.00)] significantly exceeded that of group A [65.00 (54.50-91.25), P=0.017]. No obvious intergroup difference was found in MGL or PBR (P>0.05). CONCLUSION: Mild to moderate MGD dry eye worsens in the short term after phacovitrectomy. Preoperative cleaning, hot compresses, and meibomian gland massage as well as preoperative and postoperative sodium hyaluronate promote the rapid recovery of tear film stability.
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Predicting the spatial distribution of species and suitable areas under global climate change could provide a reference for species conservation and long-term management strategies. Macaca thibetana and Macaca arctoides are two endangered species of Chinese macaques. However, limited information is available on their distribution, and their habitat needs lack proper assessment due to complicated taxonomy and less research attention. In recent years, scholars widely used the maximum entropy (MaxEnt) model to predict the impact of global climate and certain environmental factors on species distribution. Therefore, we used the MaxEnt model to predict the spatiotemporal distribution of both macaque species under six climate change scenarios using occurrence and high-resolution ecological data. We identified climatic factors, elevation, and land cover that shape their distribution range and determined shifts in their habitat range. The results demonstrated that temperature range, annual precipitation, forest land cover, and temperature seasonality, including the precipitation of the driest month are the main factors affecting their distribution. Currently, M. thibetana is mainly concentrated in central, eastern, southern, and southwestern China, and M. arctoides is mainly concentrated in three provinces (Yunnan, Guangxi, and Guangdong) in southern China. The MaxEnt model predicted that the suitable habitat for both species will increase with increased greenhouse emission scenarios. We also found that with the further increase in greenhouse emissions M. thibetana is expected to migrate to western China, and M. arctoides is expected to migrate to western or eastern China. This reinterpretation of the distribution of M. thibetana and M. arctoides in China, and predicted potential suitable habitat and possible migration direction, may provide new insights into the future conservation and management of these two species.
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Mudança Climática , Macaca arctoides , Macaca , Animais , China , Ecossistema , Distribuição AnimalRESUMO
The active structural change of actin cytoskeleton is a general host response upon pathogen attack. This study characterized the function of the cotton (Gossypium hirsutum) actin-binding protein VILLIN2 (GhVLN2) in host defense against the soilborne fungus Verticillium dahliae. Biochemical analysis demonstrated that GhVLN2 possessed actin-binding, -bundling, and -severing activities. A low concentration of GhVLN2 could shift its activity from actin bundling to actin severing in the presence of Ca2+. Knockdown of GhVLN2 expression by virus-induced gene silencing reduced the extent of actin filament bundling and interfered with the growth of cotton plants, resulting in the formation of twisted organs and brittle stems with a decreased cellulose content of the cell wall. Upon V. dahliae infection, the expression of GhVLN2 was downregulated in root cells, and silencing of GhVLN2 enhanced the disease tolerance of cotton plants. The actin bundles were less abundant in root cells of GhVLN2-silenced plants than in control plants. However, upon infection by V. dahliae, the number of actin filaments and bundles in the cells of GhVLN2-silenced plants was raised to a comparable level as those in control plants, with the dynamic remodeling of the actin cytoskeleton appearing several hours in advance. GhVLN2-silenced plants exhibited a higher incidence of actin filament cleavage in the presence of Ca2+, suggesting that pathogen-responsive downregulation of GhVLN2 could activate its actin-severing activity. These data indicate that the regulated expression and functional shift of GhVLN2 contribute to modulating the dynamic remodeling of the actin cytoskeleton in host immune responses against V. dahliae.
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Ascomicetos , Verticillium , Gossypium/metabolismo , Resistência à Doença/genética , Actinas/metabolismo , Cálcio/metabolismo , Verticillium/fisiologia , Ascomicetos/metabolismo , Citoesqueleto de Actina/metabolismo , Doenças das Plantas/microbiologia , Regulação da Expressão Gênica de Plantas , Proteínas de Plantas/metabolismoRESUMO
Covalent organic frameworks (COFs) are a type of crystalline porous polymers that possess ordered structures and eternal pores. Because of their unique structural characteristics and diverse functional groups, COFs have been used in various application fields, such as adsorption, catalysis, separation, ion conduction, and energy storage. Among COFs, the fluorine-containing COFs (fCOFs) have been developed for special applications by virtue of special physical and chemical properties resulting from fluorine element, which is a nonmetallic halogen element and possesses strong electronegativity. In the organic chemistry field, introducing fluorine into chemicals enables those chemicals to exhibit many interesting properties, and fluorine chemistry increasingly plays an important role in the history of chemical development. The introduction of fluorine in COFs can enhance the crystallinity, porosity, and stability of COFs, making COFs having superior performances and some new applications. In this review, the synthesis and application of fCOFs are systematically summarized. The application involves photocatalytic production of hydrogen peroxide, photocatalytic water splitting, electrocatalytic CO2 reduction, adsorption for different substances (H2 , pesticides, per-/polyfluoroalkyl substances, polybrominated diphenyl ethers, bisphenols, and positively charged organic dye molecules), oil-water separation, energy storage (e.g., zinc-ion batteries, lithium-sulfur batteries), and proton conduction. Perspectives of remaining challenges and possible directions for fCOFs are also discussed.
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Flúor , Estruturas Metalorgânicas , Halogênios , PolímerosRESUMO
At present, receptor tyrosine kinase signaling-related pathways have been successfully mediated to inhibit tumor proliferation and promote anti-angiogenesis effects for cancer therapy. Tyrosine kinase inhibitors (TKIs), a group of novel chemotherapeutic agents, have been applied to treat diverse malignant tumors effectively. However, the latent toxic and side effects of TKIs, such as hepatotoxicity and cardiotoxicity, limit their use in clinical practice. Metabolic activation has the potential to lead to toxic effects. Numerous TKIs have been demonstrated to be transformed into chemically reactive/potentially toxic metabolites following cytochrome P450-catalyzed activation, which causes severe adverse reactions, including hepatotoxicity, cardiotoxicity, skin toxicity, immune injury, mitochondria injury, and cytochrome P450 inactivation. However, the precise mechanisms of how these chemically reactive/potentially toxic species induce toxicity remain poorly understood. In addition, we present our viewpoints that regulating the production of reactive metabolites may decrease the toxicity of TKIs. Exploring this topic will improve understanding of metabolic activation and its underlying mechanisms, promoting the rational use of TKIs. This review summarizes the updated evidence concerning the reactive metabolites of TKIs and the associated toxicities. This paper provides novel insight into the safe use of TKIs and the prevention and treatment of multiple TKIs adverse effects in clinical practice.
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Ativação Metabólica , Humanos , Cardiotoxicidade , Doença Hepática Induzida por Substâncias e Drogas , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Inibidores de Proteínas Quinases/efeitos adversos , /metabolismoRESUMO
BACKGROUND: Kazal-type serine protease inhibitors play a role in physiological processes such as blood coagulation and fibrinolysis. The amino acid residues at the P1 site are different, and they inhibit different types of proteases. The inhibitory mechanism of the protease in the salivary glands of Poecilobdella manillensis is still unclear. METHODS AND RESULTS: Based on cloning, prokaryotic expression and bioinformatics analysis, we studied the role of Kazal-type serine protease inhibitors in P. manillensis and analyzed their expression by quantitative real-time PCR. The results suggested that the recombinant protein was successfully expressed in the supernatant when a prokaryotic expression vector was constructed and induced with 0.2 mmol/L IPTG at 37 °C for 4 h, and the enzymatic activity was determined. The mature protein encodes 91 amino acids and has a relative molecular weight of 9929.32 Da, and after removing the signal peptide, the theoretical isoelectric point was 8.79. It is an unstable protein without a transmembrane domain. The mature protein contains two Kazal-type domains, in which all P1 residues are Lys, consisting of an α helix and three antiparallel ß sheets. The upregulated expression of the mRNA was induced after a meal was provided, and the results showed an increasing and then decreasing trend. CONCLUSIONS: Taken together, the results indicate that mature proteins from P. manillensis inhibit thrombin activity, laying the foundation for the subsequent in-depth study of the function of genes encoding Kazal-type serine protease inhibitors.
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Inibidores de Serina Proteinase , DNA Complementar/genética , Proteínas Recombinantes/genética , Domínios Proteicos , Inibidores de Serina Proteinase/genética , Clonagem MolecularRESUMO
PI3Ks and HDACs play essential roles in the occurrence and progression of leukemia. Herein, a series of novel pyrazin-2(1H)-one derivatives were rationally designed and synthesized as novel dual PI3K and HDAC inhibitors based on scaffold replacement and heterozygous strategies. Most of the target compounds showed potent inhibitory potency to PI3Kα and HDAC6. Especially, compound 9q displayed PI3Kα and HDAC6 inhibitory with IC50 values of 372 nM and 4.5 nM, and anti-proliferative activity against MV4-11 cells with IC50 value of 0.093 ± 0.012 µM. Further mechanistic studies revealed that 9q induced apoptosis, arrested the cell cycle in the G2/M phase, promoted the acetylation of α-tubulin, and blocked the PI3K/AKT/mTOR signal way in MV4-11 cells. All the results demonstrated that 9q was a promising lead candidate for further development of novel PI3K/HDAC dual inhibitors for leukemia treatment.
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Antineoplásicos , Leucemia , Humanos , Inibidores de Histona Desacetilases/farmacologia , Fosfatidilinositol 3-Quinases/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Leucemia/tratamento farmacológico , Desenho de Fármacos , Relação Estrutura-Atividade , Ensaios de Seleção de Medicamentos Antitumorais , Simulação de Acoplamento MolecularRESUMO
Activity rhythms and time budgets are important to understand behavioral variability and adaptation in primates because animals normally use a behavioral adjustment as a preferential choice in response to environmental changes. Therefore, we observed a group of un-provisioned Tibetan macaques (Macaca thibetana) in Tianhu Mountain County Nature Reserve, Mount Huangshan, Southern Anhui, China. We used the instantaneous scan sampling method to collect behavioral data on their activity rhythms and time budget. The results showed that Tibetan macaques have two foraging peaks (9:00-10:00 and 14:00-15:00) and a resting peak at 12:00-13:00. They spent 31.96% resting, 28.59% foraging, 26.96% moving, 6.90% grooming, and 5.59% other. The total time of foraging and moving per month significantly and positively correlated with fruits and buds and negatively correlated with leaves. Different sexes and age groups demonstrated different activity time budgets, with adult males, adult females, and young macaques spending most of their time resting, grooming, and playing, respectively. We elucidated the effects of different environmental conditions on Tibetan macaques and their behavioral adaptation strategies.
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The primary purpose of the Man and the Biosphere Program is the sustainable development of both the economy and nature conservation activities. Although the effectiveness of eco-tourism to reach this goal has been proposed, due to the lack of long-term monitoring data and a model species, there has been no obvious mechanism to evaluate the effectiveness of this policy. This study explored the effectiveness of the sustainable development policy of HMBR based on 30 years data of monitoring the Tibetan macaque, local human population, visitors, and annual ecotourism income in Huangshan by estimating species habitat suitability and the impact of ecotourism. The results showed increases in the income for the local human population, the number of visitors, and annual eco-tourism. Simultaneously, the reserve's Tibetan macaque population size and suitable habitat areas increased. The macaques expanded their habitat to the low-altitude buffer zone (400-800 m), an area with lower eco-tourism disturbance. Scenic spots had a significant negative impact on habitat suitability (the substantially increased contributions of scenic spots from 0.71% to 32.88%). Our results and methods provide a suitable evaluation framework for monitoring the sustainable development and effectiveness of eco-tourism and wildlife conservation in Man and the Biosphere reserves.
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The bromodomain and extra-terminal (BET) bromodomains, particularly BRD4, have been identified as promising therapeutic targets in the treatment of many human disorders such as cancer. Coumarin is a highly privileged moiety for the development of novel anticancer drugs which has been identified in clinical trials for the treatment of various cancers. Herein, we modified BRD4i ABBV-075 with a coumarin ring and synthesized a novel series of coumarin derivatives as BRD4 inhibitors. Among them, the representative compound 27d showed excellent BRD4 inhibitory activities with an IC50 value of 99 nM in the TR-FRET assay. Compared with ABBV-075, compound 27d displayed a favorable cell proliferation inhibitory activity in solid tumors, such as MCF-7, HGC-27 and HepG-2. Further mechanism investigation illustrated that 27d-treatment resulted in G0/G1 phase arrest and promoted apoptosis of MCF-7 cells. Compound 27d also blocked colony formation in a concentration-dependent manner in McF-7 cell lines. As the downstream-protein of BRD4, the expression of c-Myc was decreased in a dose-dependent manner after the treatment of compound 27d. Moreover, compound 27d also exhibited good in vivo and in vitro metabolic stability. All the findings meaningfully make it as a promising lead compound for further drug development.
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Antineoplásicos , Proteínas Nucleares , Proteínas de Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Cumarínicos/farmacologia , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Relação Estrutura-Atividade , Fatores de TranscriçãoRESUMO
BACKGROUND: The tradeoff between negative and positive interactions of facilitated species and facilitators may depend on the degree of resource availability in agroecosystems. However, the rhizospheric mechanisms driving trade-offs that occur along phosphorus (P) and water availability gradients have not yet been systematically clarified. We established three types of root isolation conditions (no barrier, nylon barrier and solid barrier) at different P and water addition levels to address the above issue in a maize-grass pea intercropping system. RESULTS: The total yield and biomass net effect (NE) and the relative interaction index (RII) were significantly higher than 0 under all environmental conditions, demonstrating that plant-plant interactions generated positive effects in the intercropping system. The maize yield and biomass RII were 0.029-0.095 and 0.018-0.066, respectively, which indicated that maize growth was constantly facilitated. However, the RII for grass pea yield and biomass exhibited a different trend in comparison with maize. It was higher than 0 (as the facilitated species) under low soil P and moisture conditions and transitioned to values lower than 0 (facilitator species) under high P and moisture conditions, which showed that the type and intensity of plant-plant interactions steadily shifted with the applied stressors. Direct interactions decreased the maize rhizospheric soil pH by 1.5% and 1.9% under Low-P conditions. Notably, the rhizospheric soil acid and alkaline phosphatase secretions of maize and grass pea increased by 17.4-27.4% and 15.3-27.7%, respectively, in P-deficient soils. These results show that plant-plant interactions can effectively relieve P stress by mineralizing organophosphorus in P-deficient soils. Furthermore, the above tendency became more pronounced under drought-stressed conditions. The nylon barrier partially restricted the exchange and utilization of available nutrients and decreased the total yield and biomass by 1.8-7.8% and 1.1-7.8%, respectively. The presence of a solid barrier completely restricted interspecific rhizospheric interactions and decreased the total yield and biomass by 2.1-13.8% and 1.6-15.7%, respectively. Phytate and KH2PO4 addition intensified asymmetric interspecific competition, and grass pea was consistently subjected to competitive pressures. CONCLUSION: Briefly, the tradeoff between facilitation and competition was driven by rhizospheric interactions, and the transition in the intensity and type of interaction was highly dependent on resource availability in a biologically diverse system.