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Cardiotoxicity associated with chemotherapy has gradually become the major cause of death in cancer patients. The development of bifunctional drugs with both cardioprotective and antitumor effects has become the future direction. HDAC6 plays important roles in the progression, treatment, and prognosis of cancer and cardiovascular diseases, but bifunctional inhibitors have not been reported. Herein, structure-activity relationship studies driven by pharmacophore-based remodification and fragment-based design were performed to yield highly potent HDAC6 inhibitor I-c4 containing imidazo[1,2-a]pyridine. Importantly, I-c4 effectively suppressed the growth of MGC-803 xenografts in vitro and in vivo by inhibiting the deacetylation pathway without causing myocardial damage after long-term administration. Meanwhile, I-c4 could mitigate severe myocardial damage against H2O2 or myocardial ischemia/reperfusion in vitro and in vivo. Further studies revealed that the cardioprotective effect of I-c4 was associated with reduction of inflammatory cytokines. Taken together, I-c4 may represent a novel lead compound for further development of an anticarcinogen with a cardioprotective effect.
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To recover methane from waste activated sludge through anaerobic digestion (AD) is one promising alternative to achieve carbon neutrality for wastewater treatment plants. However, humic acids (HAs) are one of the major compositions in waste activated sludge, and their accumulation performs inhibition effects on AD. This study investigated the potentials of biochar (BC) in alleviating inhibition effects of HAs on AD. Results showed that although the accumulated HAs reduced methane yield by 9.37% compared to control, the highest methane yield, 132.6 mL CH4/g VSS, was obtained after adding BC, which was 45.9% higher than that in HA group. Mechanism analysis showed that BC promoted the activities of hydrolase such as protease and α-glucosidase, which were 69.7% and 29.7% higher than those in HA group, respectively. The conversion of short-chain fatty acids was accelerated. In addition, the evolutions of electroactive microorganisms like Clostridium_sensu_stricto_13 and Methanosaeta were consistent with the activitiies of electron transfer and the contents of cytochrome c. Furthermore, parts of HAs rather than all of them were adsorbed by BC, and the remaining free HAs and BC formed synergistic effects on methanogenesis, then both CO2 reduction and acetoclastic methanogenesis pathways were improved. The findings may provide some solutions to alleviate inhibition effects of HAs on AD.
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Biochar has been used to enhance methane generation from anaerobic digestion through establishing direct interspecific electron transfer between microorganisms. However, the microbial communication is still inadequate, thereby limiting further methane production improvement contributed by biochar. This study investigated the roles of quorum-sensing molecules, acylated homoserine lactone (AHL), in anaerobic digestion of waste activated sludge aided by biochar. Results showed that the co-addition of separated biochar and AHL achieved best methane production performance, with the maximal methane yield of 154.7 mL/g volatile suspended solids, which increased by 51.9%, 47.2%, 17.9%, and 39.4% respectively compared to that of control, AHL-loaded biochar, sole AHL, and sole biochar groups. The reason was that the co-addition of separated biochar and AHL promoted the stages of hydrolysis and acidification, promoting the conversion of organic matters and short-chain fatty acids, and optimizing the accumulation of acetate acid. Moreover, the methanogenesis stage also performed best among experimental groups. Correspondingly, the highest activities of electron transfer and coenzyme F420 were obtained, with increase ratios of 33.2% and 27.2% respectively compared to that of control. Furthermore, biochar did more significant effects on the evolution of microbial communities than AHL, and the direct interspecific electron transfer between fermentative bacteria and methanogens were possibly promoted.
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Carvão Vegetal , Metano , Percepção de Quorum , Metano/metabolismo , Anaerobiose , Esgotos , Ácidos Graxos Voláteis/metabolismo , Acil-Butirolactonas/metabolismoRESUMO
In 2023, the U.S. Food and Drug Administration has approved 55 novel medications, consisting of 17 biologics license applications and 38 new molecular entities. Although the biologics license applications including antibody and enzyme replacement therapy set a historical record, the new molecular entities comprising small molecule drugs, diagnostic agent, RNA interference therapy and biomacromolecular peptide still account for over 50 % of the newly approved medications. The novel and privileged scaffolds derived from drugs, active molecules and natural products are consistently associated with the discovery of new mechanisms, the expansion of clinical indications and the reduction of side effects. Moreover, the structural modifications based on the promising scaffolds can provide the clinical candidates with the improved biological activities, bypass the patent protection and greatly shorten the period of new drug discovery. Therefore, conducting an appraisal of drug approval experience and related information will expedite the identification of more potent drug molecules. In this review, we comprehensively summarized the pertinent information encompassing the clinical application, mechanism, elegant design and development processes of 28 small molecule drugs, and expected to provide the promising structural basis and design inspiration for pharmaceutical chemists.
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Aprovação de Drogas , United States Food and Drug Administration , Humanos , Estados Unidos , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/farmacologia , Estrutura MolecularRESUMO
Soybean (Glycine max [L.] Merr.) is a valuable oil crop but is also highly susceptible to environmental stress. Thus, developing approaches to enhance soybean stress resistance is vital to soybean yield improvement. In previous studies, transcription factor Alfin has been shown to serve as an epigenetic regulator of plant growth and development. However, no studies on Alfin have yet been reported in soybean. In this study, the endoplasmic reticulum (ER) stress- and reactive oxygen species (ROS)-related GmAlfin09 was identified. Screening of genes co-expressed with GmAlfin09 unexpectedly led to the identification of soybean peroxidase 6 (GmPRDX6). Further analyses revealed that both GmAlfin09 and GmPRDX6 were responsive to ER stress, with GmPRDX6 localizing to the ER under stress. Promoter binding experiments confirmed the ability of GmAlfin09 to bind to the GmPRDX6 promoter directly. When GmAlfin09 and GmPRDX6 were overexpressed in soybean, enhanced ER stress resistance and decreased ROS levels were observed. Together, these findings suggest that GmAlfin09 promotes the upregulation of GmPRDX6, and GmPRDX6 subsequently localizes to the ER, reduces ROS levels, promotes ER homeostasis, and ensures the normal growth of soybean even under ER stress. This study highlights a vital target gene for future molecular breeding of stress-resistant soybean lines.
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Phosphorus is one of the important factors to successfully establish the microalgal-bacterial symbiosis (MABS) system. The migration and transformation of phosphorus can occur in various ways, and the effects of phosphate on the MABS system facing environmental impacts like heavy metal stress are often ignored. This study investigated the roles of phosphate on the response of the MABS system to zinc ion (Zn2+). The results showed that the pollutant removal effect in the MABS system was significantly reduced, and microbial growth and activity were inhibited with the presence of Zn2+. When phosphate and Zn2+ coexisted, the inhibition effects of pollutants removal and microbial growth rate were mitigated compared to that of only with the presence of Zn2+, with the increasing rates of 28.3% for total nitrogen removal, 48.9% for chemical oxygen demand removal, 78.3% for chlorophyll-a concentration, and 13.3% for volatile suspended solids concentration. When phosphate was subsequently supplemented in the MABS system after adding Zn2+, both pollutants removal efficiency and microbial growth and activity were not recovered. Thus, the inhibition effect of Zn2+ on the MABS system was irreversible. Further analysis showed that Zn2+ preferentially combined with phosphate could form chemical precipitate, which reduced the fixation of MABS system for Zn2+ through extracellular adsorption and intracellular uptake. Under Zn2+ stress, the succession of microbial communities occurred, and Parachlorella was more tolerant to Zn2+. This study revealed the comprehensive response mechanism of the co-effects of phosphate and Zn2+ on the MABS system, and provided some insights for the MABS system treating wastewater containing heavy metals, as well as migration and transformation of heavy metals in aquatic ecosystems.
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Metais Pesados , Microalgas , Fosfatos , Simbiose , Águas Residuárias , Poluentes Químicos da Água , Metais Pesados/metabolismo , Águas Residuárias/química , Fosfatos/farmacologia , Fosfatos/metabolismo , Eliminação de Resíduos Líquidos/métodos , Bactérias/metabolismo , Bactérias/efeitos dos fármacos , ZincoRESUMO
Since Na3V2(PO4)3 (NVP) possesses modest volume deformation and three-dimensional ion diffusion channels, it is a potential sodium-ion battery cathode material that has been extensively researched. Nonetheless, NVP still endures the consequences of poor electronic conductivity and low voltage platforms, which need to be further improved. On this basis, a high voltage platform Na3V2(PO4)2F3 was introduced to form a composite with NVP to increase the energy density. In this study, the sol-gel technique was successfully used to synthesize a Na3V2(PO4)2.75F0.75/C (NVPF·3NVP/C) composite cathode material. The citric acid-derived carbon layer was utilized to construct three-dimensional conducting networks to effectively promote ion and electron diffusion. Furthermore, the composites' synergistic effect accelerates the quick ionic migration and improves the kinetic reaction. In particular, NVP as the dominant phase enhanced the structural stability and significantly increased the capacitive contribution. Therefore, at 0.1C, the discharge capacity of the modified NVPF·3NVP/C composite is 120.7 mA h g-1, which is greater than the theoretical discharge capacity of pure NVP (118 mA h g-1). It discharged 110.9 mA h g-1 of reversible capacity even at an elevated multiplicity of 10C, and after 200 cycles, it retained 64.1% of its capacity. Thus, the effort produced an optimized NVPF·3NVP/C composite cathode material that may be used in the sodium ion cathode.
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Alleviating the decomposition of the electrolyte is of great significance to improving the cycle stability of cathodes, especially for LiCoO2 (LCO), its volumetric energy density can be effectively promoted by increasing the charge cutoff voltage to 4.6 V, thereby supporting the large-scale application of clean energy. However, the rapid decomposition of the electrolyte under 4.6 V conditions not only loses the transport carrier for lithium ion, but also produces HF and insulators that destroy the interface of LCO and increase impedance. In this work, the decomposition of electrolyte is effectively suppressed by changing the adsorption force between LCO interface and EC. Density functional theory illustrates the LCO coated with lower electronegativity elements has a weaker adsorption force with the electrolyte, the adsorption energy between LCO@Mg and EC (0.49 eV) is weaker than that of LCO@Ti (0.73 eV). Meanwhile, based on the results of time of flight secondary ion mass spectrometry, conductivity-atomic force microscopy, in situ differential electrochemical mass spectrometry, soft X-ray absorption spectroscopy, and nuclear magnetic resonance, as the adsorption force increases, the electrolyte decomposes more seriously. This work provides a new perspective on the interaction between electrolyte and the interface of cathode and further improves the understanding of electrolyte decomposition.
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Biochar produced from bio-wastes has been widely used to promote the performance of anaerobic digestion. Waste activated sludge (WAS) is considered as a kind of popular precursor for biochar preparation, but the abundant resources in WAS were neglected previously. In this study, the roles of biochar prepared from raw, pretreated, and fermented sludge on anaerobic digestion were investigated. That is, parts of carbon sources and nutrients like polysaccharides, proteins, and phosphorus were firstly recovered after sludge pretreatment or fermentation, and then the sludge residuals were used as raw material to prepare biochar. The methane yield improved by 22.1% with adding the biochar (AK-BC) prepared by sludge residual obtained from alkaline pretreatment. Mechanism study suggested that the characteristics of AK-BC like specific surface area and defect levels were updated. Then, the conversion performance of intermediate metabolites and electro-activities of extracellular polymeric substances were up-regulated. As a result, the activity of electron transfer was increased with the presence of AK-BC, with increase ratio of 21.4%. In addition, the electroactive microorganisms like Anaerolineaceae and Methanosaeta were enriched with the presence of AK-BC, and the potential direct interspecies electron transfer was possibly established. Moreover, both aceticlastic and CO2-reducing methanogenesis pathways were improved by up-regulating related enzymes. Therefore, the proposed strategy can not only obtain preferred biochar but also recover abundant resources like carbon source, nutrients, and bioenergy.
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Carvão Vegetal , Metano , Esgotos , Carvão Vegetal/química , Esgotos/química , Esgotos/microbiologia , Anaerobiose , Metano/metabolismo , Eliminação de Resíduos Líquidos/métodos , Álcalis/química , Reatores BiológicosRESUMO
Four new drimane-type sesquiterpenoids and two new nucleoside derivatives (1-6), were isolated from the fungus Helicoma septoconstrictum. Their structures were determined based on the combination of the analysis of their HR-ESI-MS, NMR, ECD calculations data and acid hydrolysis. All the isolated compounds were detected for their bio-activities against MDA-MB-231, A549/DDP, A2780 and HepG2 cell lines. Helicoside C (4) exhibited superior cytotoxicity against the A2780 cell line with IC50 7.5 ± 1.5 µM. The analysis of reactive oxygen species (ROS) revealed that Helicoside C induced an increase in intracellular ROS. Furthermore, the flow cytometry and mitochondrial membrane potential (MMP) analyses unveiled that Helicoside C mediated mitochondrial-dependent apoptosis in A2780 cells. The western blotting test showed that Helicoside C could suppress the STAT3's phosphorylation. These findings offered crucial support for development of H. septoconstrictum and highlighted the potential application of drimane-type sesquiterpenoids in pharmaceuticals.
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Ascomicetos , Neoplasias Ovarianas , Sesquiterpenos Policíclicos , Sesquiterpenos , Humanos , Feminino , Linhagem Celular Tumoral , Nucleosídeos , Neoplasias Ovarianas/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Sesquiterpenos/química , Ascomicetos/metabolismo , ApoptoseRESUMO
V5S8 has received extensive attention in the field of sodium-ion batteries (SIBs) due to its two-dimensional (2D) layered structure, and weak van der Waals forces between V-S accelerate the transport of sodium ions. However, the long-term cycling of V5S8 still suffers from volume expansion and low conductivity. Herein, a hollow nanotube V5S8@C (H-V5S8@C) with improved conductivity was synthesized by a solvothermal method to alleviate cracking caused by volume expansion. Benefiting from the large specific surface area of the hollow nanotube structure and uniform carbon coating, H-V5S8@C exhibits a more active site and enhanced conductivity. Meanwhile, the heterojunction formed by a few residual MoS2 and the outer layer of V5S8 stabilizes the structure and reduces the ion migration barrier with fast Na+ transport. Specifically, the H-V5S8@C anode provides an enhanced rate performance of 270.1 mAh g-1 at 15 A g-1 and high cycling stability of 291.7 mAh g-1 with a retention rate of 90.98% after 300 cycles at 5 A g-1. This work provides a feasible approach for the structural design of 2D layered materials, which can promote the practical application of fast-charging sodium-ion batteries.
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BACKGROUND: Endovascular treatment for patients with symptomatic nonacute middle cerebral artery occlusion remains clinically challenging, and proof of a beneficial effect on functional outcome is lacking. We aim to evaluate the effectiveness and safety of endovascular recanalization for patients with symptomatic nonacute middle cerebral artery occlusion. METHODS: Ninety-eight patients with symptomatic atherosclerotic nonacute middle cerebral artery occlusion were divided into drug treatment groups (42) and endovascular treatment groups (56). The rate of recanalization, peri-procedural complications, and follow-up results were evaluated. RESULTS: Among the 56 patients who received endovascular treatment, 53 (94.6%) achieved successful recanalization. The rate of peri-procedural complications was 7.1% (4/56), and the death rate was 1.8% (1/56). Any stroke within 90 days was 7.1% (4/56). Among the 42 patients in drug treatment group, any stroke within 90 days was 19.0% (8/42), death rate was 0. CONCLUSION: Among patients with symptomatic nonacute middle cerebral artery occlusion with a short length of occlusion and a moderate-to-good collateral circulation, endovascular treatment seems to be safe. And endovascular treatment could reduce the recurrence rate of stroke.
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Procedimentos Endovasculares , Acidente Vascular Cerebral , Humanos , Infarto da Artéria Cerebral Média/diagnóstico por imagem , Infarto da Artéria Cerebral Média/cirurgia , Resultado do Tratamento , Acidente Vascular Cerebral/terapia , Procedimentos Endovasculares/métodos , Estudos RetrospectivosRESUMO
Endophytic fungi are an important source of novel antitumor substances. Previously, we isolated an endophytic fungus, Alternaria alstroemeria, from the medicinal plant Artemisia artemisia, whose crude extracts strongly inhibited A549 tumor cells. We obtained a transformant, namely AaLaeAOE26 , which completely loses its antitumor activity due to overexpression of the global regulator AaLaeA. Re-sequencing analysis of the genome revealed that the insertion site was in the noncoding region and did not destroy any other genes. Metabolomics analysis revealed that the level of secondary antitumor metabolic substances was significantly lower in AaLaeAOE26 compared with the wild strain, in particular flavonoids were more downregulated according to the metabolomics analysis. A further comparative transcriptome analysis revealed that a gene encoding FAD-binding domain protein (Fla1) was significantly downregulated. On the other hand, overexpression of AaFla1 led to significant enhancement of antitumor activity against A549 with a sevenfold higher inhibition ratio than the wild strain. At the same time, we also found a significant increase in the accumulation of antitumor metabolites including quercetin, gitogenin, rhodioloside, liensinine, ginsenoside Rg2 and cinobufagin. Our data suggest that the global regulator AaLaeA negatively affects the production of antitumor compounds via controlling the transcription of AaFla1 in endophytic A. alstroemeria.
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Alstroemeria , Alternaria , Alternaria/genética , Metabolismo Secundário , Flavonoides/metabolismo , EndófitosRESUMO
Terminal drought is one of the major constraints to crop production in chickpea (Cicer arietinum L.). In order to map drought tolerance related traits at high resolution, we sequenced multi-parent advanced generation intercross (MAGIC) population using whole genome resequencing approach and phenotyped it under drought stress environments for two consecutive years (2013-14 and 2014-15). A total of 52.02 billion clean reads containing 4.67 TB clean data were generated on the 1136 MAGIC lines and eight parental lines. Alignment of clean data on to the reference genome enabled identification of a total, 932,172 of SNPs, 35,973 insertions, and 35,726 deletions among the parental lines. A high-density genetic map was constructed using 57,180 SNPs spanning a map distance of 1606.69 cM. Using compressed mixed linear model, genome-wide association study (GWAS) enabled us to identify 737 markers significantly associated with days to 50% flowering, days to maturity, plant height, 100 seed weight, biomass, and harvest index. In addition to the GWAS approach, an identity-by-descent (IBD)-based mixed model approach was used to map quantitative trait loci (QTLs). The IBD-based mixed model approach detected major QTLs that were comparable to those from the GWAS analysis as well as some exclusive QTLs with smaller effects. The candidate genes like FRIGIDA and CaTIFY4b can be used for enhancing drought tolerance in chickpea. The genomic resources, genetic map, marker-trait associations, and QTLs identified in the study are valuable resources for the chickpea community for developing climate resilient chickpeas.
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Cicer , Mapeamento Cromossômico , Cicer/genética , Genoma de Planta , Estudo de Associação Genômica Ampla , Resistência à SecaRESUMO
Objective To prepare flumazenil sublingual tablets and study its bioavailability. Methods Flumazenil sublingual tablets were prepared by compressing flumazenil inclusion compound with hydroxypropyl-β-cyclodextrin as the inclusion material. In a double-cycle crossover trial, twelve beagle dogs were randomly divided into two groups, one group receiving flumazenil sublingual tablets and the other receiving flumazenil injections. LC-MS method was developed and validated to determine flumazenil plasma concentration. The pharmacokinetic parameters and bioavailability were calculated using WinNonlin pharmacokinetic software. Results In the pharmacokinetic study, AUClast of flumazenil injection and sublingual tablet was (8.41±2.15) and (8.86±2.83) h·ng·ml−1, respectively; Cmax was (10.96±2.62) and (6.36±2.14) ng/ml, respectively; tmax was (0.18±0.05) and (0.58±0.24) h, respectively. The bioavailability of flumazenil sublingual tablet was 52.68%. Conclusion Clathrates were used to prepare flumazenil sublingual tablets to achieve safe and efficient delivery. LC-MS method was established for the determination of flumazenil plasma concentration, and the advantages were simple, accurate and sensitive.
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Objective To establish a method for the simultaneous determination of DOX·HCl and LND. Methods HPLC was performed on Agilent 5 HC-C18(2) (4.6 mm × 250 mm, 5 µm) column. The mobile phase was methanol-0.1% TFA aqueous solution, and the gradient elution procedure were: 0 to 3 min, 65% methanol; 3 to 7 min, 65%→90% methanol; 7 to 13 min, 90% methanol; 13 to 15 min, 90%→65% methanol; 15 to 20 min, 65% methanol. The collection time was 20 min, the balance time was 3 min, the UV detection wavelengths were 205 nm and 253 nm. The flow rate was 1.0 ml/min and the column temperature was 35℃. The amount of inlet was 10 µl. Results The method was highly specific, and both DOX·HCl and LND exhibited good linearity in the concentration range of 1-40 µg/ml and 6-240 µg/ml, respectively. The two compounds’ precision, stability, and recovery satisfied the requirements of the method. Conclusion This study established a HPLC method that was suitable for the simultaneous detection of DOX·HCl and LND. This method’s high level of specificity, accuracy, and reliability .
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With the acceleration of globalization, the number of foreigners in China is rising year by year, and their demand for medical treatment is also increasing. It is imperative to strengthen the supply of international professional medical services in China and improve the cross-cultural competence of medical staff. As the origin of cross-cultural medical competence research, the United States has accumulated rich theoretical and practical experience. By defining the concept and connotation of cross-cultural competence in the medical context and explaining its constituent elements, based on the experience of the United States and combined with the actual situation of China, this paper put forward that the cultivation path of cross-cultural competence of medical staff should be explored from the aspects of enhancing cross-cultural awareness of medical staff, strengthening cross-cultural medical competence training, and utilizing a variety of measures and tools.
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This paper collected and sorted out the cross-cultural medical practice in the top 20 US hospitals in 2019-2020 through web surveys, and summarized the concepts, featured projects and models of cross-cultural medical services in American hospitals. Generally, hospitals in the US advocate the service concept of "patient-centered", provide full-process services before, during and after the treatment, involving appointments, accommodation, transportation, language translation, medical process management, etc., and attach great importance to the role of culture factors in medical treatment and cross-cultural medical education and training for employees. On this basis, it is proposed that Chinese medical institutions should focus on the following aspects in the development of foreign-related medical services: conform to international medical service concepts and standards, improve the cross-cultural medical competence of medical staff and other groups, explore cross-cultural medical service models with localized characteristics, and build the international image of the hospital with the construction of international environment.
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OBJECTIVE To evaluate the palatability and chewability of chewable tablets, and provide reference for the quality evaluation of various types of chewable tablets. METHODS Using self-made Glucosamine hydrochloride chewable tablets as the model drug, the quality test was conducted. The in vitro simulation system for chewable tablets was established by using a texture analyzer and rheometer, and an oral simulation experiment was conducted on chewable tablets. The texture analyzer was used to measure the force required for chewing and simulate the static disintegration process of chewable tablets; the rheometer was adopted to measure the viscoelasticity, thixotropy, and deformability of chewable tablets during the chewing process. RESULTS The disintegration time limit, principal component content, and dissolution of self-made Glucosamine hydrochloride chewable tablets all met the limit requirements. The in vitro simulation results of the texture analyzer showed that self-made chewable tablets were easy to chew in both axial and radial directions, and the force required for chewing was within the range of the chewing force of the teeth; chewable tablets could disintegrate at an appropriate time without being chewed and only taken in the oral cavity. The in vitro simulation results of the rheometer showed that the chewable tablets in the oral cavity exhibited a behavior of elasticity as the main factor and viscosity as the secondary factor through the continuous stirring of the tongue, and the viscosity of the chewable tablets gradually decreased with tongue stirring or tooth chewing; when chewing with teeth, the internal force of the chewing tablets decreased, causing plastic deformation and crushing. After being crushed, the shape couldn’t be restored, making it easy to chew and swallow. CONCLUSIONS The combination of texture analyzer and rheometer can be used to simulate the oral chewing process and evaluate the palatability and chewability of self-made Glucosamine hydrochloride chewable tablets. This model can provide reference for the evaluation of various chewable tablets.
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Needle-free injection technology (NFIT) refers to the drug delivery systems in which drugs are propelled as high-speed jet streams using any of the pressure source to penetrate the skin to the required depth. NFIT is a promising drug delivery system as it enables the injection of liquids, powders, and depot/projectiles, and has the advantages of preventing needle stick accidents, improving drug bioavailability, eliminating needle-phobia, increasing vaccine immunity, simplifying operations and is convenient for patients to use. NFIT and its research background, the structure and classification of needle-free jet injectors (NFJI), drugs that can be delivered using NFJI and the factors affecting the injection effect are comprehensively reviewed in this paper. The limitations and potential development directions are summarized to provide a theoretical basis for the application and development of NFIT.