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1.
J Mater Sci Mater Med ; 35(1): 11, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38300359

RESUMO

The study of a macromolecule derived from DPP and triphenylamine, (DPP-BisTPA) by computational chemistry, its synthesis by direct arylation, optical characterization (UV-Vis and fluorescence) and electrochemistry (cyclic voltammetry), as well as its evaluation as a generator of reactive oxygen species indirectly, through the degradation of uric acid. The results obtained by DFT using B3LYP/6-31G (d, p) and TD-DFT using CAM-B3LYP/6-31G (d, p) reveal values of energy levels of the first singlet and triplet excited state that indicate a possible intersystem crossover and the possible generation of reactive oxygen species by a type I mechanism. The compound presents an absorption region within the phototherapeutic window. The electrochemical bandgap is 1.64 eV which suggests a behavior as a semiconductor. DPP-BisTPa were processed as hemispherical nanoparticles with a size around 100 nm, and NPOs were evaluated as a photosensitizer with a ROS generation yield of 4% using a photodynamic therapy flashlight as the light source.


Assuntos
Fotoquimioterapia , Fármacos Fotossensibilizantes , Espécies Reativas de Oxigênio , Aminas , Eletroquímica
2.
Food Res Int ; 178: 114004, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38309927

RESUMO

Cabbages are rich in sulfur-containing metabolites like glucosinolates (GLSs) and S-methyl-l-cysteine sulfoxide (SMCSO). Tissue disruption initiates hydrolysis of these compounds and bioactive volatile hydrolysis products such as isothiocyanates (ITCs), sulfides, and thiosulfinates are formed. However, nitriles, epithionitriles, or amines can also result from GLSs. Here, the influence of hydrolysis time, extent of tissue disruption (chopping vs. homogenization), and addition of lemon juice or vinegar on the outcome of enzymatic hydrolysis of GLSs and SMCSO was investigated in red cabbage. Chopping led to partial hydrolysis of GLSs, whereas homogenization completely degraded GLSs but only had a small effect on SMCSO. Homogenization increased amine formation from alkenyl and methylthioalkyl ITCs, but not from methylsulfinylalkyl ITCs. Acidification inhibited formation of products from SMCSO. Further, it reduced nitrile and epithionitrile formation and stopped amine formation, thereby increasing ITC levels. Therefore, acidification is a valuable mean to enhance ITC levels in fresh Brassica foods.


Assuntos
Brassica , Isotiocianatos , Isotiocianatos/farmacologia , Cisteína/metabolismo , Hidrólise , Glucosinolatos/metabolismo , Aminas , Brassica/metabolismo , Sulfóxidos/metabolismo , Nitrilas , Concentração de Íons de Hidrogênio
3.
Amino Acids ; 56(1): 9, 2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38315214

RESUMO

Nanostructures formed by the self-assembly of modified/unmodified amino acids have the potential to be useful in several biological/nonbiological applications. In that regard, the greater conformational space provided by γ-amino acids, owing to their additional backbone torsional degrees of freedom and enhanced proteolytic stability, compared to their α-counterparts, should be explored. Though, modified single amino acid-based nanomaterials such as nanobelts or hydrogels are developed by utilizing the monosubstituted γ-amino acids derived from the backbone homologation of phenylalanine (Phe). Examples of a single γ-amino acid-based porous nanostructure capable of accommodating solvent molecules are not really known. The crystal structures of a modified γ4(R)Phe residue, Boc-γ4(R)Phe-OH, at different temperatures, showed that hydrogen-bonded water molecules are forming a wire inside hydrophilic nanochannels. The dynamics of intermolecular interactions between the water wire and the inner wall of the channel with relation to the temperature change was investigated by analyzing the natural bonding orbital (NBO) calculation results performed with the single crystal structures obtained at different temperature points. The NBO results showed that from 325 K onward, the strength of water-water interactions in the water wire are getting weaker, whereas, for the water-inner wall interactions, it getting stronger, suggesting a favorable change in the orientation of water molecules with temperatures, for the latter.


Assuntos
Aminoácidos , Água , Aminoácidos/química , Fenilalanina/química , Aminas/química , Conformação Molecular , Ligação de Hidrogênio
4.
Bioinformatics ; 40(2)2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38310333

RESUMO

MOTIVATION: Protein language models (PLMs), which borrowed ideas for modelling and inference from natural language processing, have demonstrated the ability to extract meaningful representations in an unsupervised way. This led to significant performance improvement in several downstream tasks. Clustering amino acids based on their physical-chemical properties to achieve reduced alphabets has been of interest in past research, but their application to PLMs or folding models is unexplored. RESULTS: Here, we investigate the efficacy of PLMs trained on reduced amino acid alphabets in capturing evolutionary information, and we explore how the loss of protein sequence information impacts learned representations and downstream task performance. Our empirical work shows that PLMs trained on the full alphabet and a large number of sequences capture fine details that are lost in alphabet reduction methods. We further show the ability of a structure prediction model(ESMFold) to fold CASP14 protein sequences translated using a reduced alphabet. For 10 proteins out of the 50 targets, reduced alphabets improve structural predictions with LDDT-Cα differences of up to 19%. AVAILABILITY AND IMPLEMENTATION: Trained models and code are available at github.com/Ieremie/reduced-alph-PLM.


Assuntos
Dobramento de Proteína , Proteínas , Proteínas/química , Aminoácidos/química , Sequência de Aminoácidos , Aminas
5.
ACS Chem Biol ; 19(2): 249-253, 2024 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-38314716

RESUMO

Chemical modifications of RNA are important tools for the development of RNA therapeutics. The present study reports a novel RNA backbone modification that replaces the negatively charged phosphate with a positively charged amine linkage. Despite being thermally destabilizing in RNA duplexes, the amine linkage caused a relatively modest decrease of activity of a modified short interfering RNA (siRNA). At position 2 of the guide strand, the amine modification strongly enhanced the specificity of siRNA while causing an ∼5-fold drop of on-target activity. These results support the future development of amines as cationic RNA modifications and novel tools to modulate protein-RNA interactions.


Assuntos
Aminas , RNA de Cadeia Dupla , RNA Interferente Pequeno/química , Interferência de RNA
6.
Nature ; 626(8000): 859-863, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38326609

RESUMO

Bacteria in the gastrointestinal tract produce amino acid bile acid amidates that can affect host-mediated metabolic processes1-6; however, the bacterial gene(s) responsible for their production remain unknown. Herein, we report that bile salt hydrolase (BSH) possesses dual functions in bile acid metabolism. Specifically, we identified a previously unknown role for BSH as an amine N-acyltransferase that conjugates amines to bile acids, thus forming bacterial bile acid amidates (BBAAs). To characterize this amine N-acyltransferase BSH activity, we used pharmacological inhibition of BSH, heterologous expression of bsh and mutants in Escherichia coli and bsh knockout and complementation in Bacteroides fragilis to demonstrate that BSH generates BBAAs. We further show in a human infant cohort that BBAA production is positively correlated with the colonization of bsh-expressing bacteria. Lastly, we report that in cell culture models, BBAAs activate host ligand-activated transcription factors including the pregnane X receptor and the aryl hydrocarbon receptor. These findings enhance our understanding of how gut bacteria, through the promiscuous actions of BSH, have a significant role in regulating the bile acid metabolic network.


Assuntos
Amidoidrolases , Aminas , Humanos , Amidoidrolases/metabolismo , Bactérias/metabolismo , Ácidos e Sais Biliares , Catálise , Aciltransferases
7.
Compr Rev Food Sci Food Saf ; 23(2): e13306, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38369928

RESUMO

Biobased natural polymers, including polymers of natural origin such as casein, are growing rapidly in the light of the environmental pollution caused by many mass-produced commercial synthetic polymers. Although casein has interesting intrinsic properties, especially for the food industry, numerous chemical reactions have been carried out to broaden the range of its properties, most of them preserving casein's nontoxicity and biodegradability. New conjugates and graft copolymers have been developed especially by Maillard reaction of the amine functions of the casein backbone with the aldehyde functions of sugars, polysaccharides, or other molecules. Carried out with dialdehydes, these reactions lead to the cross-linking of casein giving three-dimensional polymers. Acylation and polymerization of various monomers initiated by amine functions are also described. Other reactions, far less numerous, involve alcohol and carboxylic acid functions in casein. This review provides an overview of casein-based conjugates and graft copolymers, their properties, and potential applications.


Assuntos
Caseínas , Polímeros , Caseínas/química , Polímeros/química , Polissacarídeos/química , Aminas
8.
J Chromatogr A ; 1717: 464656, 2024 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-38301332

RESUMO

Metabolomics has become an essential discipline in the study of microbiome, emerging gas chromatography coupled to mass spectrometry as the most mature, robust, and reproducible analytical technique. Silylation is the most widely used chemical derivatization strategy, although it has some limitations. In this regard, alkylation by alkyl chloroformate offers some advantages, such as a rapid reaction, milder conditions, better reproducibility, and the generation of more stable derivatives. However, commercial spectral libraries do not include many of the alkyl derivatives, mainly for polyfunctional metabolites, which can form multiple derivatives. That introduces a huge bias in untargeted metabolomics leading to common errors such as duplicates, unknowns, misidentifications, wrong assignations, and incomplete results from which non-reliable findings and conclusions will be retrieved. For this reason, the purpose of this study is to overcome these shortcomings and to expand the knowledge of metabolites in general and especially those closely related to the gut microbiota through the thorough study of the reactivity of the different functional groups in real matrix derivatized by methyl chloroformate, a common representative alkylation reagent. To this end, a systematic workflow has been developed based on exhaustive structural elucidation, along with computational simulation, and taking advantage of the high sensitivity and high-resolution gas chromatography-mass spectrometry. Several empirical rules have been established according to chemically different entities (free fatty acids, amino acids, polyols, sugars, amines, and polyfunctional groups, etc.) to predict the number of derivatives formed from a single metabolite, as well as their elution order and structure. In this work, some methyl chloroformate derivatives not previously reported as well as the mechanisms to explain them are given. Extremely important is the interconversion of E- and Z- geometric isomers of unsaturated dicarboxylic acids (case of fumaric-maleic and case of citraconic-mesaconic acids), or the formation of cycled derivatives for amino acids, as well as common metabolites, as in the case of serine and cysteine, and many others.


Assuntos
Aminoácidos , Formiatos , Microbioma Gastrointestinal , Cromatografia Gasosa-Espectrometria de Massas/métodos , Reprodutibilidade dos Testes , Aminoácidos/química , Aminas/análise
9.
Addict Biol ; 29(2): e13370, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38353028

RESUMO

N-Isopropylbenzylamine (N-ipb), a chain isomer of methamphetamine (METH) with similar physical properties, has been used as a substitute for METH in seized drug samples. However, the abuse potential of N-ipb remains unclear. Therefore, this study aimed to evaluate the abuse potential of N-ipb in comparison to METH, by using conditioned place preference (CPP), locomotor sensitization and intravenous self-administration tests. The results showed that N-ipb at a dose of 3 mg·kg-1 significantly induced CPP in mice, which was comparable to the effect of METH at 1 mg·kg-1 . Either acute or repeated N-ipb injections (1 or 3 mg·kg-1 ) failed to raise the locomotor activity. However, acute treatment with 10 mg·kg-1 N-ipb elevated the locomotor activity compared with saline, while chronic injection of 10 mg·kg-1 N-ipb induced a delayed and attenuated sensitization compared with 1 mg·kg-1 METH. Rats could acquire N-ipb self-administration at a dose of 1 mg·kg-1 ·infusion-1 , and a typical inverted U-shaped dose-response curve was obtained for N-ipb. The mean dose of N-ipb that maintained the maximum response was greater than that of METH, indicating that N-ipb is less potent for reinforcement than METH. In the economic behavioural analysis, comparison of essential values derived from the demand elasticity revealed that N-ipb is less efficacy as a reinforcer than METH. The present data demonstrate that N-ipb functions as a reinforcer and has a potential for abuse. However, the potency of psychomotor stimulation and the reinforcing effectiveness of N-ipb are lower than those of METH.


Assuntos
Aminas , Estimulantes do Sistema Nervoso Central , Metanfetamina , Camundongos , Ratos , Animais , Estimulantes do Sistema Nervoso Central/farmacologia , Roedores , Atividade Motora , Metanfetamina/farmacologia
10.
ACS Appl Mater Interfaces ; 16(6): 7275-7287, 2024 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-38304929

RESUMO

The synthesis, characterization, and application of a new cyanostyrylcopillar[5]arene 1 is reported. Single-crystal X-ray diffraction and other spectroscopic techniques confirm the identity of the new copillar 1. The X-ray diffraction study reveals that the copillar 1 exhibits a 1D supramolecular chain in the solid state involving π···π interactions along the crystallographic c-axis and 1D chains are further connected by interchain C-H···π interactions to establish 2D supramolecular layers within the crystallographic bc-plane. 2D supramolecular chains on further packing introduce a 3D structure with void spaces filled with hexane molecules. Through minimal deviation in the dihedral angle, the cyano-substituted ethylenic group in 1 shows a conjugation with the phenolic -OH, favoring intramolecular bond conjugation (ITBC) and colorimetrically detects the aliphatic amines over aromatic amines in CH3CN. Among the aliphatic amines, tertiary amines are differentiated from primary and secondary amines by the naked eye through color change. Both in solution and solid states, 1 displays vapor phase detection of volatile aliphatic amines. Antibacterial activity analysis shows that while 1 exhibits the antibiofilm action against Gram-positive pathogenic bacteria, Staphylococcus aureus, it promotes biofilm formation by Gram-negative pathogenic bacteria, Pseudomonas aeruginosa.


Assuntos
Aminas , Biofilmes , Aminas/farmacologia , Aminas/química , Cristalografia por Raios X , Difração de Raios X , Antibacterianos/química
11.
J Pharm Biomed Anal ; 241: 116002, 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38309100

RESUMO

A novel synthetic approach to nemtabrutinib (MK-1026) was recently developed in our laboratories. The chemistry goes through a cyrene amine intermediate which does not contain any chromophore. As a result, analysis of this key chiral intermediate by HPLC-UV is not feasible. Initial attempts to develop a HPLC-CAD method were unfruitful; therefore, a gas chromatography method was developed and optimized to effectively monitor the cyrene amine free base and related impurities generated during the process. As the synthetic process continued to be optimized, the toluene sulfonic acid salt (p-TsOH) of the cyrene amine intermediate was later identified by our process chemistry group to be beneficial in terms of ease of isolation and purity upgrade. However, repeated injections of the cyrene amine p-TsOH intermediate resulted in rapid GC column deterioration. After identifying p-TsOH as the main cause of the issue, we developed a straightforward and practical procedure that involves using a resin to remove the p-TsOH counterion in-situ, which converts cyrene amine salt to its neutral form in sample solutions. This protocol was successfully demonstrated and proven to be an efficient solution. This methodology may find applications with other analytes containing counterions that need to be neutralized prior to analysis.


Assuntos
Cloreto de Sódio , Tolueno , Cromatografia Líquida de Alta Pressão/métodos , Aminas
12.
Cancer Immunol Immunother ; 73(3): 48, 2024 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-38349393

RESUMO

Monoamine oxidase A (MAOA) is a membrane-bound mitochondrial enzyme present in almost all vertebrate tissues that catalyzes the degradation of biogenic and dietary-derived monoamines. MAOA is known for regulating neurotransmitter metabolism and has been implicated in antitumor immune responses. In this review, we retrospect that MAOA inhibits the activities of various types of tumor-associated immune cells (such as CD8+ T cells and tumor-associated macrophages) by regulating their intracellular monoamines and metabolites. Developing novel MAOA inhibitor drugs and exploring multidrug combination strategies may enhance the efficacy of immune governance. Thus, MAOA may act as a novel immune checkpoint or immunomodulator by influencing the efficacy and effectiveness of immunotherapy. In conclusion, MAOA is a promising immune target that merits further in-depth exploration in preclinical and clinical settings.


Assuntos
Monoaminoxidase , Neoplasias , Humanos , Adjuvantes Imunológicos , Aminas , Linfócitos T CD8-Positivos , Inibidores de Checkpoint Imunológico , Fatores Imunológicos , Neoplasias/tratamento farmacológico
13.
J Environ Sci (China) ; 140: 146-156, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38331496

RESUMO

Non-aqueous absorbents (NAAs) have attracted increasing attention for CO2 capture because of their great energy-saving potential. Primary diamines which can provide high CO2 absorption loading are promising candidates for formulating NAAs but suffer disadvantages in regenerability. In this study, a promising strategy that using tertiary amines (TAs) as proton-transfer mediators was proposed to enhance the regenerability of an aminoethylethanolamine (AEEA, diamine)/dimethyl sulfoxide (DMSO) (A/D) NAA. Surprisingly, some employed TAs such as N,N-diethylaminoethanol (DEEA), N,N,N',N'',N''-pentamethyldiethylenetriamine (PMDETA), 3-dimethylamino-1-propanol (3DMA1P), and N,N-dimethylethanolamine (DMEA) enhanced not only the regenerability of the A/D NAA but also the CO2 absorption performance. Specifically, the CO2 absorption loading and cyclic loading were increased by about 12.7% and 15.5%-22.7%, respectively. The TA-enhanced CO2 capture mechanism was comprehensively explored via nuclear magnetic resonance technique and quantum chemical calculations. During CO2 absorption, the TA acted as an ultimate proton acceptor for AEEA-zwitterion and enabled more AEEA to form carbamate species (AEEACOO-) to store CO2, thus enhancing CO2 absorption. For CO2 desorption, the TA first provided protons directly to AEEACOO- as a proton donor; moreover, it functioned as a proton carrier and facilitated the low-energy step-wise proton transfer from protonated AEEA to AEEACOO-. Consequently, the presence of TA made it easier for AEEACOO- to obtain protons to decompose, resulting in enhanced CO2 desorption. In a word, introducing the TA as a proton-transfer mediator into the A/D NAA enhanced both the CO2 absorption performance and the regenerability, which was an efficient way to "kill two birds with one stone".


Assuntos
Dióxido de Carbono , Etanolaminas , Prótons , Aminas , Diaminas
14.
Sci Total Environ ; 918: 170675, 2024 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-38316312

RESUMO

The early stage of heart development is highly susceptible to various environmental factors. While the use of animal models has aided in identifying numerous environmental risk factors, the variability between species and the low throughput limit their translational potential. Recently, a type of self-assembling cardiac structures, known as human heart organoids (hHOs), exhibits a remarkable biological consistency with human heart. However, the feasibility of hHOs for assessing cardiac developmental risk factors remains unexplored. Here, we focused on the cardiac developmental effects of core components of Glyphosate-based herbicides (GBHs), the most widely used herbicides, to evaluate the reliability of hHOs for the prediction of possible cardiogenesis toxicity. GBHs have been proven toxic to cardiac development based on multiple animal models, with the mechanism remaining unknown. We found that polyoxyethylene tallow amine (POEA), the most common surfactant in GBHs formulations, played a dominant role in GBHs' heart developmental toxicity. Though there were a few differences in transcriptive features, hHOs exposed to sole POEA and combined POEA and Glyphosate would suffer from both disruption of heart contraction and disturbance of commitment in cardiomyocyte isoforms. By contrast, Glyphosate only caused mild epicardial hyperplasia. This study not only sheds light on the toxic mechanism of GBHs, but also serves as a methodological demonstration, showcasing its effectiveness in recognizing and evaluating environmental risk factors, and deciphering toxic mechanisms.


Assuntos
Gorduras , Herbicidas , Animais , Humanos , Aminas , Glicina/toxicidade , Glicina/química , Reprodutibilidade dos Testes , Polietilenoglicóis/química , Herbicidas/toxicidade , Herbicidas/química
15.
J Med Chem ; 67(4): 2732-2744, 2024 Feb 22.
Artigo em Inglês | MEDLINE | ID: mdl-38331433

RESUMO

The need for anticancer therapies that overcome metallodrug resistance while minimizing adverse toxicities is targeted, herein, using titanium coordination complexes. Octahedral titanium(IV) trans,mer-[Ti{R1N(CH2-2-MeO-4-R1-C6H2)2}2] [R1 = Et, allyl, n-Pr, CHO, F, CH2(morpholino), the latter from the formyl derivative; R2 = Me, Et; not all combinations] are attained from Mannich reactions of commercial 2-methoxyphenols (27-74% overall yield, 2 steps). These crystalline (four X-ray structures) Ti(IV)-complexes are active against MCF-7, HCT-116, HT-29, PANC-1, and MDA-MB-468 cancer cell lines (GI50 = 0.5-38 µM). Their activity and cancer selectivity (vs nontumor MRC-5 cells) typically exceeds that of cisplatin (up to 16-fold). Proteomic analysis (in MCF-7) supported by other studies (G2/M cell cycle arrest, ROS generation, γH2AX production, caspase activation, annexin positivity, western blot, and kinase screens in MCF-7 and HCT-116) suggest apoptosis elicited by more than one mechanism of action. Comparison of these data to the modes of action proposed for salan Ti(IV) complexes is made.


Assuntos
Antineoplásicos , Titânio , Humanos , Titânio/farmacologia , Titânio/química , Aminas/farmacologia , Proteômica , Linhagem Celular Tumoral , Antineoplásicos/farmacologia , Antineoplásicos/química , Apoptose
16.
Appl Microbiol Biotechnol ; 108(1): 101, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38229296

RESUMO

Enzymatic processes play an increasing role in synthetic organic chemistry which requires the access to a broad and diverse set of enzymes. Metagenome mining is a valuable and efficient way to discover novel enzymes with unique properties for biotechnological applications. Here, we report the discovery and biocatalytic characterization of six novel metagenomic opine dehydrogenases from a hot spring environment (mODHs) (EC 1.5.1.X). These enzymes catalyze the asymmetric reductive amination between an amino acid and a keto acid resulting in opines which have defined biochemical roles and represent promising building blocks for pharmaceutical applications. The newly identified enzymes exhibit unique substrate specificity and higher thermostability compared to known examples. The feature that they preferably utilize negatively charged polar amino acids is so far unprecedented for opine dehydrogenases. We have identified two spatially correlated positions in their active sites that govern this substrate specificity and demonstrated a switch of substrate preference by site-directed mutagenesis. While they still suffer from a relatively narrow substrate scope, their enhanced thermostability and the orthogonality of their substrate preference make them a valuable addition to the toolbox of enzymes for reductive aminations. Importantly, enzymatic reductive aminations with highly polar amines are very rare in the literature. Thus, the preparative-scale enzymatic production, purification, and characterization of three highly functionalized chiral secondary amines lend a special significance to our work in filling this gap. KEY POINTS: • Six new opine dehydrogenases have been discovered from a hot spring metagenome • The newly identified enzymes display a unique substrate scope • Substrate specificity is governed by two correlated active-site residues.


Assuntos
Aminas , Metagenoma , Aminas/metabolismo , Aminação , Biocatálise , Aminoácidos/metabolismo , Especificidade por Substrato , Oxirredutases/metabolismo
17.
Int J Mol Sci ; 25(1)2024 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-38203832

RESUMO

Chemotherapy currently available for leishmaniasis treatment has many adverse side effects and drug resistance. Therefore, the identification of new targets and the development of new drugs are urgently needed. Previously, we reported the synthesis of a N-(2-methoxyphenyl)-1-methyl-1H-benzimidazol-2-amine, named compound 8, with an IC50 value in the micromolar range against L. mexicana, it also inhibited 68.27% the activity of recombinant L. mexicana arginase. Herein, we report studies carried out to characterize the mechanism of action of compound 8, as well as its in vivo leishmanicidal activity. It was shown in our ultrastructural studies that compound 8 induces several changes, such as membrane blebbing, the presence of autophagosomes, membrane detachment and mitochondrial and kinetoplast disorganization, among others. Compound 8 triggers the production of ROS and parasite apoptosis. It reduced 71% of the parasite load of L. mexicana in an experimental model of cutaneous leishmaniasis in comparison with a control. Altogether, the data obtained suggest the potential use of compound 8 in the treatment of cutaneous leishmaniasis.


Assuntos
Leishmania mexicana , Leishmaniose Cutânea , Humanos , Leishmaniose Cutânea/tratamento farmacológico , Apoptose , Arginase , Benzimidazóis/farmacologia , Aminas
18.
Eur J Med Chem ; 265: 116106, 2024 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-38169271

RESUMO

Clinical researches have shown that epidermal growth factor receptor (EGFR) is a key target for treatment of non-small cell lung cancer (NSCLC). Many EGFR inhibitors were successfully developed as ani-tumor drugs to treat NSCLC patients. Unfortunately, drug resistances were found in clinic. To overcome C797S mutation in EGFR, a novel series of 4-arylamine substituted pyrimidine derivatives were designed and synthesized under the principle of structure-based drug design. Interestingly, compounds 6e and 9i demonstrated the best anti-proliferative activity against A549, NCI-H1975, and HCC827 cells. In particular, the IC50 values against HCC827 cells reached to 24.6 nM and 31.6 nM, which were much lower than human normal cells 2BS and LO2. Furthermore, compounds 6e and 9i showed extraordinary activity against EGFR19del/T790M/C797S (IC50 = 16.06 nM and 37.95 nM) and EGFRL858R/T790M/C797S (IC50 = 11.81 nM and 26.68 nM), which were potent than Osimertinib (IC50 = 52.28 nM and 157.60 nM). Further studies have shown that compounds 6e and 9i could pertain inhibition of HCC827 colony formation, and arrest HCC827 cells at G2/M phase. Moreover, the most promising compound 6e could inhibit the migration of HCC827 cells, induce HCC827 cells apoptosis, and significantly inhibit the phosphorylation of EGFR, AKT and Erk1/2. In vivo xenograft mouse model with HCC827 cells, compound 6e resulted in remarkable tumor regression without obvious toxicity. In addition, molecular docking studies suggested that compound 6e could firmly combine with T790M-mutant, T790 M/C797S-mutant, and L858R/T790 M/C797S-mutant EGFR kinases as ATP-competitive inhibitor.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Animais , Humanos , Camundongos , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Linhagem Celular Tumoral , Proliferação de Células , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB , Neoplasias Pulmonares/patologia , Simulação de Acoplamento Molecular , Mutação , Inibidores de Proteínas Quinases , Pirimidinas/farmacologia , Pirimidinas/uso terapêutico , Aminas/química
19.
Zhonghua Kou Qiang Yi Xue Za Zhi ; 59(1): 45-53, 2024 Jan 09.
Artigo em Chinês | MEDLINE | ID: mdl-38172061

RESUMO

Objective: To explore the application prospect of a new pH-responsive tertiary amine monomer dodecylmethylaminoethyl methacrylate (DMAEM) modified resin adhesive (DMAEM@RA) in the prevention and treatment of secondary caries. Methods: Five percents DMAEM was added to the resin adhesive to synthesize DMAEM@RA for modifying. Streptococcus mutans (Sm) and Lactobacillus casei (Lc) biofilms were cultured on resin adhesive and DMAEM@RA, respectively. The culture systems were set up at pH=7.4, 6.0, 5.5, and 5.0. The antimicrobial activity of DMAEM@RA was evaluated by quantitative PCR. The effects of DMAEM@RA on biofilm thickness, bacterial amount, and extracellular polysaccharides were studied by scanning electron microscope (SEM) and extracellular polysaccharide staining. Real-time fluorescence quantitative PCR was used to study the effect of DMAEM@RA on the expression levels of cariogenic genes in Sm. Results: DMAEM@RA could significantly reduce the amount of Sm and Lc under acidic conditions, especially Lc. At pH=5.0, the logarithm value of co-cultured Sm bacteria [lg (CFU/ml)] in DMAEM@RA group (7.58±0.01) was significantly lower than that in control group (7.87±0.03) (t=14.32, P<0.001), and the logarithm value of Lc bacteria [lg (CFU/ml)] (7.29±0.04) was also significantly lower than that in control group (7.93±0.15) (t=6.93, P=0.002). SEM observed that the bacteria decreased and the cell fragments appeared in DMAEM@RA group. In addition, DMAEM@RA significantly reduced the biomass of extracellular polysaccharides in the dual-species biofilm under acidic conditions. At pH=5.0, the biomass of extracellular polysaccharides in DMAEM@RA group [(25.13±3.14) mm3/mm2] was significantly lower than that in the control group [(42.66±7.46) mm3/mm2] (t=3.75, P=0.020). DMAEM@RA could significantly up-regulate the expressions of gtfB and gtfC genes in Sm under acidic conditions. At pH=5.0, gtfB and gtfC genes were significantly up-regulated by (14.64± 0.44) times and (2.99±0.20) times, respectively (t=-42.74, P<0.001; t=-13.55, P<0.001). Conclusions: The DMAEM@RA has a good antibacterial effect under acidic conditions, demonstrating that it has a good potential to prevent the occurrence and development of secondary caries.


Assuntos
Cárie Dentária , Lacticaseibacillus casei , Humanos , Streptococcus mutans , Metacrilatos/farmacologia , Metacrilatos/metabolismo , Cimentos Dentários , Cárie Dentária/prevenção & controle , Cárie Dentária/microbiologia , Polissacarídeos/metabolismo , Polissacarídeos/farmacologia , Aminas/metabolismo , Aminas/farmacologia , Biofilmes , Concentração de Íons de Hidrogênio
20.
ACS Appl Mater Interfaces ; 16(2): 2075-2085, 2024 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-38176018

RESUMO

Microbially induced calcium carbonate precipitation (MICP) has emerged as a novel technology with the potential to produce building materials through lower-temperature processes. The formation of calcium carbonate bridges in MICP allows the biocementation of aggregate particles to produce biobricks. Current approaches require several pulses of microbes and mineralization media to increase the quantity of calcium carbonate minerals and improve the strength of the material, thus leading to a reduction in sustainability. One potential technique to improve the efficiency of strength development involves trapping the bacteria on the aggregate surfaces using silane coupling agents such as positively charged 3-aminopropyl-methyl-diethoxysilane (APMDES). This treatment traps bacteria on sand through electrostatic interactions that attract negatively charged walls of bacteria to positively charged amine groups. The APMDES treatment promoted an abundant and immediate association of bacteria with sand, increasing the spatial density of ureolytic microbes on sand and promoting efficient initial calcium carbonate precipitation. Though microbial viability was compromised by treatment, urea hydrolysis was minimally affected. Strength was gained much more rapidly for the APMDES-treated sand than for the untreated sand. Three injections of bacteria and biomineralization media using APMDES-treated sand led to the same strength gain as seven injections using untreated sand. The higher strength with APMDES treatment was not explained by increased calcium carbonate accrual in the structure and may be influenced by additional factors such as differences in the microstructure of calcium carbonate bridges between sand particles. Overall, incorporating pretreatment methods, such as amine silane coupling agents, opens a new avenue in biomineralization research by producing materials with an improved efficiency and sustainability.


Assuntos
Areia , Sporosarcina , Silanos , Bactérias , Carbonatos , Carbonato de Cálcio/química , Aminas , Precipitação Química
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