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1.
J Colloid Interface Sci ; 607(Pt 1): 848-856, 2022 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-34536939

RESUMO

HYPOTHESIS: Cubosomes made from the inverse micellar cubic mesophase (I2) with Fd3m symmetry possess a unique structure of closely packed inverse micelles. These have prospective functionality in sustained drug release. In this study, we hypothesised that similar to fatty acids, various fatty acetate compounds can induce the formation of micellar Fd3m cubosomes in monoolein (MO) nanoparticles. They are different to micellar cubosomes made of MO and a fatty acid, which are pH responsive and can transition from an Fd3m phase to an inverse hexagonal phase (H2) as pH increases. We hypothesised that by co-doping a fatty acetate and fatty acid into MO, precise control of the Fd3m-H2 phase transition pH in nanoparticles can be achieved. EXPERIMENTS: Five unsaturated fatty acetates with hydrocarbon chain lengths between 18 and 24 were added to MO at a weight ratio of 0.45 - 0.60 to form nanoparticles. The nanoparticles were prepared using high-throughput formulation and characterised with synchrotron small angle X-ray scattering (SAXS). MO nanoparticles doped with vaccenyl acetate and vaccenic acid were used to demonstrate the fine control over Fd3m-H2 phase transition pH. FINDINGS: Micellar cubosomes (Fd3m phase) were found in MO nanoparticles doped with fatty acetates. The Fd3m structure was stable in a wide pH range of 2.6 - 8 and at temperatures up to 45 °C. In MO nanoparticles doped with the acetate/acid mixture, the Fd3m-H2 phase transition pH was tuned between pH 5 and pH 7 by adjusting the ratio of vaccenyl acetate and vaccenic acid. As a H2 phase generally offers faster drug release than an Fd3m phase, the pH responsive lipid nanoparticles developed here may find application in orally administrated formulation, where the vehicles must pass a low pH environment in the stomach before reaching neutral pH in the blood.


Assuntos
Cristais Líquidos , Nanopartículas , Acetatos , Ácidos Graxos , Glicerídeos , Concentração de Íons de Hidrogênio , Micelas , Estudos Prospectivos , Espalhamento a Baixo Ângulo , Difração de Raios X
2.
Sci Total Environ ; 804: 150147, 2022 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-34509840

RESUMO

Microbial conversion of methane to electricity, fuels, and liquid chemicals has attracted much attention. However, due to the low solubility of methane, it is not considered a suitable substrate for microbial fuel cells (MFCs). In this study, a conductive fiber membrane (CFM) module was constructed as the bioanode of methane-driven MFCs, directly delivering methane. After biofilm formation on the CFM surface, a steady voltage output of 0.6 to 0.7 V was recorded, and the CFM-MFCs obtained a maximum power density of 64 ± 2 mW/m2. Moreover, methane oxidation produced a high concentration of intermediate acetate (up to 7.1 mM). High-throughput 16S rRNA gene sequencing suggests that the microbial community was significantly changed after electricity generation. Methane-related archaea formed a symbiotic consortium with characterized electroactive bacteria and fermentative bacteria, suggesting a combination of three types of microorganisms for methane conversion into acetate and electricity.


Assuntos
Fontes de Energia Bioelétrica , Acetatos , Eletricidade , Eletrodos , Metano , RNA Ribossômico 16S/genética
3.
Sci Total Environ ; 802: 149885, 2022 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-34474295

RESUMO

Chain elongation is an anaerobic biotechnological process that converts short chain carboxylates and an electron donor (e.g. ethanol, lactate) into more valuable medium chain carboxylates. Caproate production in lactate-based chain elongation is gaining popularity, however, the relation between lactate (electron donor) and acetate (electron acceptor) has not yet been fully elucidated. Herein, for the first time, the effect of an external acetate on the lactate-based chain elongation in a continuously-fed bioreactor was tested to verify how the external acetate would affect the product spectrum, gas production, as well as stability and efficiency of carboxylates production. Periodic fluctuations in caproate production were observed in bioreactor continuously fed with lactate as a sole carbon source due to the lack of an electron acceptor (acetate) and low chain elongation performance. The recovery of stable caproate production (68.9 ± 2.2 mmol C/L/d), total lactate consumption, and high hydrogen co-production (748 ± 76 mLH2/d) was observed as an effect of the addition of an external acetate. The lactate conversion with the external acetate in the second bioreactor ensured stable and dominant caproate production from the beginning of the process. Moreover, despite the continuous lactate overloading in the process with external acetate, stable caproate production was achieved (71.7 ± 2.4 mmol C/L/d) and previously unobserved hydrogen production occurred (213 ± 30 mLH2/d). Thus, external electron acceptor addition (i.e. acetate) was proposed as an effective method for stable lactate-based caproate production. Microbiological analysis showed the dominance of microbes closely related to Ruminococcaceae bacterium CPB6 and Acinetobacter throughout the process. Co-occurrence networks based on taxon abundances and process parameters revealed microbial sub-networks responding to lactate concentrations.


Assuntos
Reatores Biológicos , Ácido Láctico , Acetatos , Fermentação , Hidrogênio
4.
J Cosmet Dermatol ; 20(11): 3580-3585, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34648685

RESUMO

BACKGROUND: Acne is a chronic inflammatory skin disease which involves the pilosebaceous unit. Tissue inflammation isone of the crucial mechanisms, amongst others. Of the various cytokines, leukotriene B4 (LT-B4) is the most potentleucocyte chemotactic mediator. Montelukast is an antagonist of the LT-B4 receptor. Finasteride is an antiandrogen whichspecifically inhibits the 5α-reductase enzyme. AIMS: This study aimed at comparing the efficacy, tolerability and safety of montelukast versus finasteride in the treatmentof moderate acne in women. PATIENTS/METHOD: This randomized, single-blinded, prospective trial over 12 weeks recruited 65 female subjects with moderate acne vulgaris (Global Acne Grading System Scale) for evaluation. One group (n = 30) received oral montelukast (10 mg PO daily), while the second group (n = 25) received oral finasteride (2.5 mg PO daily) in combination with topical clindamycin 2% solution. Lesion count and acne severity were evaluated at time intervals of 0 (baseline), 4, 8, and 12 weeks. Adverse effects of the drugs were noted. RESULTS: Both lesion count and severity of acne decreased significantly after treatment in both the groups as compared to the baseline. The acne severity score reached from 33.93 in time zero to 20.6 in the 12th week and 35.71 at baseline to 16.43 at the end of treatment in the Montelukast and Finasteride groups, respectively. Side effects were noted in 3 patients and 2 patients in the monteleukast and finasteride group, respectively, which were transient and non-serious in nature proving the satisfactory tolerability and safety of these two drugs. CONCLUSION: The results of this study show that both montelukast and finasteride have good efficacy in the treatment of acne. Finasteride has more efficacy than montelukast for treating moderate acne in normo-androgenic women.


Assuntos
Acne Vulgar , Finasterida , Acetatos/efeitos adversos , Acne Vulgar/tratamento farmacológico , Ciclopropanos , Feminino , Finasterida/efeitos adversos , Humanos , Estudos Prospectivos , Quinolinas , Sulfetos
5.
Trials ; 22(1): 690, 2021 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-34629091

RESUMO

BACKGROUND: Young children with sickle cell anaemia (SCA) often have slowed processing speed associated with reduced brain white matter integrity, low oxygen saturation, and sleep-disordered breathing (SDB), related in part to enlarged adenoids and tonsils. Common treatments for SDB include adenotonsillectomy and nocturnal continuous positive airway pressure (CPAP), but adenotonsillectomy is an invasive surgical procedure, and CPAP is rarely well-tolerated. Further, there is no current consensus on the ability of these treatments to improve cognitive function. Several double-blind, randomised controlled trials (RCTs) have demonstrated the efficacy of montelukast, a safe, well-tolerated anti-inflammatory agent, as a treatment for airway obstruction and reducing adenoid size for children who do not have SCA. However, we do not yet know whether montelukast reduces adenoid size and improves cognition function in young children with SCA. METHODS: The Study of Montelukast In Children with Sickle Cell Disease (SMILES) is a 12-week multicentre, double-blind, RCT. SMILES aims to recruit 200 paediatric patients with SCA and SDB aged 3-7.99 years to assess the extent to which montelukast can improve cognitive function (i.e. processing speed) and sleep and reduce adenoidal size and white matter damage compared to placebo. Patients will be randomised to either montelukast or placebo for 12 weeks. The primary objective of the SMILES trial is to assess the effect of montelukast on processing speed in young children with SCA. At baseline and post-treatment, we will administer a cognitive evaluation; caregivers will complete questionnaires (e.g. sleep, pain) and measures of demographics. Laboratory values will be obtained from medical records collected as part of standard care. If a family agrees, patients will undergo brain MRIs for adenoid size and other structural and haemodynamic quantitative measures at baseline and post-treatment, and we will obtain overnight oximetry. DISCUSSION: Findings from this study will increase our understanding of whether montelukast is an effective treatment for young children with SCA. Using cognitive testing and MRI, the SMILES trial hopes to gain critical knowledge to help develop targeted interventions to improve the outcomes of young children with SCA. TRIAL REGISTRATION: ClinicalTrials.gov NCT04351698 . Registered on April 17, 2020. European Clinical Trials Database (EudraCT No. 2017-004539-36). Registered on May 19, 2020.


Assuntos
Anemia Falciforme , Quinolinas , Acetatos/efeitos adversos , Anemia Falciforme/diagnóstico , Anemia Falciforme/tratamento farmacológico , Anti-Inflamatórios , Criança , Pré-Escolar , Ciclopropanos , Humanos , Quinolinas/efeitos adversos , Ensaios Clínicos Controlados Aleatórios como Assunto , Sulfetos
6.
Int J Mol Sci ; 22(19)2021 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-34638573

RESUMO

13-lipoxygenases (13-LOX) catalyze the dioxygenation of various polyunsaturated fatty acids (PUFAs), of which α-linolenic acid (LeA) is converted to 13-S-hydroperoxyoctadeca-9, 11, 15-trienoic acid (13-HPOT), the precursor for the prostaglandin-like plant hormones cis-(+)-12-oxophytodienoic acid (12-OPDA) and methyl jasmonate (MJ). This study aimed for characterizing the four annotated A. thaliana 13-LOX enzymes (LOX2, LOX3, LOX4, and LOX6) focusing on synthesis of 12-OPDA and 4Z,7Z,10Z)-12-[[-(1S,5S)-4-oxo-5-(2Z)-pent-2-en-1yl] cyclopent-2-en-1yl] dodeca-4,7,10-trienoic acid (OCPD). In addition, we performed interaction studies of 13-LOXs with ions and molecules to advance our understanding of 13-LOX. Cell imaging indicated plastid targeting of fluorescent proteins fused to 13-LOXs-N-terminal extensions, supporting the prediction of 13-LOX localization to plastids. The apparent maximal velocity (Vmax app) values for LOX-catalyzed LeA oxidation were highest for LOX4 (128 nmol·s-1·mg protein-1), with a Km value of 5.8 µM. A. thaliana 13-LOXs, in cascade with 12-OPDA pathway enzymes, synthesized 12-OPDA and OCPD from LeA and docosahexaenoic acid, previously shown only for LOX6. The activities of the four isoforms were differently affected by physiologically relevant chemicals, such as Mg2+, Ca2+, Cu2+ and Cd2+, and by 12-OPDA and MJ. As demonstrated for LOX4, 12-OPDA inhibited enzymatic LeA hydroperoxidation, with half-maximal enzyme inhibition at 48 µM. Biochemical interactions, such as the sensitivity of LOX toward thiol-reactive agents belonging to cyclopentenone prostaglandins, are suggested to occur in human LOX homologs. Furthermore, we conclude that 13-LOXs are isoforms with rather specific functional and regulatory enzymatic features.


Assuntos
Proteínas de Arabidopsis/metabolismo , Arabidopsis/metabolismo , Lipoxigenase/metabolismo , Acetatos/metabolismo , Sequência de Aminoácidos , Ciclopentanos/metabolismo , Ácidos Graxos Insaturados/metabolismo , Regulação da Expressão Gênica de Plantas/fisiologia , Ácidos Linoleicos/metabolismo , Oxilipinas/metabolismo
7.
BMC Plant Biol ; 21(1): 450, 2021 Oct 06.
Artigo em Inglês | MEDLINE | ID: mdl-34615468

RESUMO

BACKGROUND: Methyl jasmonate (MeJA), which has been identified as a lipid-derived stress hormone, mediates plant resistance to biotic/abiotic stress. Understanding MeJA-induced plant defense provides insight into how they responding to environmental stimuli. RESULT: In this work, the dynamic network analysis method was used to quantitatively identify the tipping point of growth-to-defense transition and detect the associated genes. As a result, 146 genes were detected as dynamic network biomarker (DNB) members and the critical defense transition was identified based on dense time-series RNA-seq data of MeJA-treated Arabidopsis thaliana. The GO functional analysis showed that these DNB genes were significantly enriched in defense terms. The network analysis between DNB genes and differentially expressed genes showed that the hub genes including SYP121, SYP122, WRKY33 and MPK11 play a vital role in plant growth-to-defense transition. CONCLUSIONS: Based on the dynamic network analysis of MeJA-induced plant resistance, we provide an important guideline for understanding the growth-to-defense transition of plants' response to environment stimuli. This study also provides a database with the key genes of plant defense induced by MeJA.


Assuntos
Acetatos/metabolismo , Arabidopsis/crescimento & desenvolvimento , Arabidopsis/genética , Ciclopentanos/metabolismo , Oxilipinas/metabolismo , Reguladores de Crescimento de Plantas/metabolismo , Estresse Fisiológico/genética , Estresse Fisiológico/fisiologia , Regulação da Expressão Gênica de Plantas , Genes de Plantas , Estudo de Associação Genômica Ampla
8.
Drugs R D ; 21(4): 419-429, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34655050

RESUMO

OBJECTIVE: The aim of this study was to identify factors affecting blood concentrations of voriconazole following letermovir coadministration using population pharmacokinetic (PPK) analysis in allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients. METHODS: The following data were retrospectively collected: voriconazole trough levels, patient characteristics, concomitant drugs, and laboratory information. PPK analysis was performed with NONMEM® version 7.4.3, using the first-order conditional estimation method with interaction. We collected data on plasma voriconazole steady-state trough concentrations at 216 timepoints for 47 patients. A nonlinear pharmacokinetic model with the Michaelis-Menten equation was applied to describe the relationship between steady-state trough concentration and daily maintenance dose of voriconazole. After stepwise covariate modeling, the final model was evaluated using a goodness-of-fit plot, case deletion diagnostics, and bootstrap methods. RESULTS: The maximum elimination rate (Vmax) of voriconazole in patients coadministered letermovir and methylprednisolone was 1.72 and 1.30 times larger than that in patients not coadministered these drugs, respectively, resulting in decreased voriconazole trough concentrations. The developed PPK model adequately described the voriconazole trough concentration profiles in allo-HSCT recipients. Simulations clearly showed that increased daily doses of voriconazole were required to achieve an optimal trough voriconazole concentration (1-5 mg/L) when patients received voriconazole with letermovir and/or methylprednisolone. CONCLUSIONS: The development of individualized dose adjustment is critical to achieve optimal voriconazole concentration, especially among allo-HSCT recipients receiving concomitant letermovir and/or methylprednisolone.


Assuntos
Transplante de Células-Tronco Hematopoéticas , Metilprednisolona , Acetatos , Antifúngicos , Humanos , Quinazolinas , Estudos Retrospectivos , Voriconazol
9.
Phytomedicine ; 93: 153798, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34673348

RESUMO

BACKGROUND: NLRP3 inflammasome activation and pyroptosis play an important role in myocardial ischemia/reperfusion injury (MI/RI). Cinnamomi ramulus (CR), is an important folk medicinal plant in China, which derived from the dried twig of Cinnamomum cassia (L.) Presl, has function of "warming and tonifying heart yang", and traditionally utilized to treat the cold, blood-cold amenorrhea, phlegm, edema, arthralgia, and palpitations as well as improve blood circulation. The aqueous extract of C. ramulus was reported to show significant therapeutic potential for treating MI/RI. Whereas, there are no previous investigations in China or abroad has reported the cardioprotective effects and underlying mechanism of the ethyl acetate extract of C. ramulus (CREAE) and its bioactive substance cinnamic acid (CA) in triggering NLRP3 inflammasome activation and subsequent pyroptosis. PURPOSE: The present study aimed to assess the cardioprotective function of CREAE and CA against the MI/RI in rats and involved the underlying mechanisms. METHODS: The MI/RI model was established in male SD rats by occlusion of the left anterior descending coronary artery for 30 min followed by reperfusion for 120 min, respectively. The rats were intragastrically administered with CREAE (74 and 37 mg/kg) and CA (45 mg/kg) for 7 successive days before vascular ligation. The cardioprotective effects of CREAE and CA against myocardial injury of rats were detected by HE staining, TTC staining, echocardiograms, and myocardial enzymes detections. Serum levels of inflammatory factors, such as IL-6, IL-1ß, and TNF-α, were analyzed by ELISA kits to evaluate the effects of CREAE and CA. The protein and gene expression levels of NLRP3 and the pyroptosis-related factors in heart tissue were conducted by western blot and RT-qPCR. RESULTS: Our results showed that CREAE and CA decrease myocardial infarct size and improve cardiac function, mitigate myocardial damage, and repress inflammatory response in rats after I/R. Mechanistically, our results revealed that CREAE and CA can dramatically suppress the activation of NLRP3 inflammasome and subsequent cardiomyocyte pyroptosis in myocardial tissues that as evidenced by downregulating the protein and gene expressions of NLRP3, ASC, IL-1ß, caspase-1, gasdermin D, and N-terminal GSDMD. CONCLUSIONS: Our data indicated that CREAE and CA may attenuate MI/RI through suppression of NLRP3 inflammasome and subsequent pyroptosis-related signaling pathways.


Assuntos
Traumatismo por Reperfusão Miocárdica , Piroptose , Acetatos , Animais , Inflamassomos , Masculino , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Proteína 3 que Contém Domínio de Pirina da Família NLR , Ratos , Ratos Sprague-Dawley
10.
Molecules ; 26(20)2021 Oct 14.
Artigo em Inglês | MEDLINE | ID: mdl-34684788

RESUMO

It is known that Senna obtusifolia has been used in medicine since ancient times due to the content of many valuable compounds with a pro-health effect. One of them is betulinic acid, which is a pentacyclic triterpene with antimalarial, antiviral, anti-inflammatory and anticancer properties. In this work, a continuation of our previous research, an attempt was made to increase the level of betulinic acid accumulation by the cultivation of transgenic hairy roots that overexpress the squalene synthase gene in a 10 L sprinkle bioreactor with methyl jasmonate elicitation. We present that the applied strategy allowed us to increase the content of betulinic acid in hairy root cultures to the level of 48 mg/g dry weight. The obtained plant extracts showed a stronger cytotoxic effect on the U87MG glioblastoma cell line than the roots grown without elicitors. Additionally, the induction of apoptosis, reduction of mitochondrial membrane potential, chromosomal DNA fragmentation and activation of caspase cascades are demonstrated. Moreover, the tested extract showed inhibition of topoisomerase I activity.


Assuntos
Acetatos/farmacologia , Antineoplásicos Fitogênicos/metabolismo , Ciclopentanos/farmacologia , Oxilipinas/farmacologia , Triterpenos Pentacíclicos/metabolismo , Senna (Planta)/efeitos dos fármacos , Senna (Planta)/metabolismo , Células A549 , Antineoplásicos Fitogênicos/biossíntese , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Reatores Biológicos , Biotecnologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Dano ao DNA , Fragmentação do DNA/efeitos dos fármacos , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Triterpenos Pentacíclicos/farmacologia , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Reguladores de Crescimento de Plantas/farmacologia , Raízes de Plantas/efeitos dos fármacos , Raízes de Plantas/crescimento & desenvolvimento , Raízes de Plantas/metabolismo , Plantas Geneticamente Modificadas , Plantas Medicinais/efeitos dos fármacos , Plantas Medicinais/crescimento & desenvolvimento , Plantas Medicinais/metabolismo , Senna (Planta)/crescimento & desenvolvimento
11.
Molecules ; 26(17)2021 Aug 27.
Artigo em Inglês | MEDLINE | ID: mdl-34500623

RESUMO

Lignans are the main secondary metabolites synthetized by Linum species as plant defense molecules. They are also valuable for human health, in particular, for their potent antiviral and antineoplastic properties. In this study, the adventitious root cultures of three Linum species (L. flavum, L. mucronatum and L. dolomiticum) were developed to produce aryltetralin lignans. The effect of two elicitors, methyl jasmonate and coronatine, on aryltetralin lignans production was also evaluated. The adventitious root cultures from L. dolomiticum were obtained and analyzed for the first time and resulted as the best producer for all the aryltetralins highlighted in this system: Podophyllotoxin, 6-methoxypodophyllotoxin and 6-methoxypodophyllotoxin-7-O-ß-glucoside, the last showing a productivity of 92.6 mg/g DW. The two elicitors differently affected the production of the 6-methoxypodophyllotoxin and 6-methoxypodophyllotoxin-7-O-ß-glucoside.


Assuntos
Linho/metabolismo , Lignanas/biossíntese , Raízes de Plantas/metabolismo , Acetatos/metabolismo , Aminoácidos/biossíntese , Ciclopentanos/metabolismo , Indenos , Oxilipinas/metabolismo , Podofilotoxina/análogos & derivados , Podofilotoxina/biossíntese
12.
Artigo em Inglês | MEDLINE | ID: mdl-34559623

RESUMO

A Gram-positive, aerobic, heterotrophic, non-endospore-forming, rod-shaped and indole-acetic acid-producing strain, designated NEAU-184T, was isolated from marine sand collected in Sanya, PR China, and its taxonomic position was investigated using a polyphasic approach. Phylogenetic analysis based on 16S rRNA gene sequence data indicated that strain NEAU-184T should be assigned to the genus Agromyces and formed a distinct branch with its closest neighbour, Agromyces iriomotensis NBRC 106452T (99.1 %). 2,4-Diaminobutyric acid, d-alanine, d-glutamic acid and glycine were detected in cell-wall hydrolysate and glucose, rhamnose and xylose were detected in whole-cell hydrolysate. The polar lipids were found to contain diphosphatidylglycerol, glycolipid, phosphatidylglycerol and two unidentified lipids. The major menaquinone was MK-12 and the minor menaquinones were MK-13 and MK-11. The predominant fatty acids were anteiso-C17 : 0, anteiso-C15 : 0 and iso-C16 : 0. The DNA G+C content was 71.5 mol%. Furthermore, the strain could be clearly distinguished from its closely related type strains by the combination of DNA-DNA hybridization results and some phenotypic characteristics. Meanwhile, the strain has the ability to produce indole-acetic acid (0.334mg ml-1). Therefore, strain NEAU-184T represents a novel species of the genus Agromyces, for which the name Agromyces mariniharenae sp. nov. is proposed, with strain NEAU-184T (=CGMCC 4.7505T=JCM 32546T) as the type strain.


Assuntos
Ácidos Graxos , Areia , Acetatos , Actinobacteria , Técnicas de Tipagem Bacteriana , Composição de Bases , DNA Bacteriano/genética , Ácidos Graxos/química , Indóis , Fosfolipídeos , Filogenia , RNA Ribossômico 16S/genética , Análise de Sequência de DNA , Vitamina K 2
13.
J Enzyme Inhib Med Chem ; 36(1): 1996-2009, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34525898

RESUMO

Microtubule dynamics are crucial for multiple cell functions, and cancer cells are particularly sensitive to microtubule-modulating agents. Here, we describe the design and synthesis of a series of (Z)-2-(5-benzylidene-4-oxo-2-thioxothiazolidin-3-yl)-N-phenylacetamide derivatives and evaluation of their microtubule-modulating and anticancer activities in vitro. Proliferation assays identified I20 as the most potent of the antiproliferative compounds, with 50% inhibitory concentrations ranging from 7.0 to 20.3 µM with A549, PC-3, and HepG2 human cancer cell lines. Compound I20 also disrupted cancer A549 cell migration in a concentration-dependent manner. Immunofluorescence microscopy, transmission electron microscopy, and tubulin polymerisation assays suggested that compound I20 promoted protofilament assembly. In support of this possibility, computational docking studies revealed a strong interaction between compound I20 and tubulin Arg ß369, which is also the binding site for the anticancer drug Taxol. Our results suggest that (Z)-2-(5-benzylidene-4-oxo-2-thioxothiazolidin-3-yl)-N-phenylacetamide derivatives could have utility for the development of microtubule-stabilising therapeutic agents.


Assuntos
Acetatos/farmacologia , Amidas/farmacologia , Antineoplásicos/farmacologia , Descoberta de Drogas , Microtúbulos/efeitos dos fármacos , Rodanina/farmacologia , Moduladores de Tubulina/farmacologia , Células A549 , Acetatos/síntese química , Acetatos/química , Amidas/química , Antineoplásicos/síntese química , Antineoplásicos/química , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Microtúbulos/metabolismo , Estrutura Molecular , Polimerização/efeitos dos fármacos , Rodanina/análogos & derivados , Rodanina/química , Relação Estrutura-Atividade , Tubulina (Proteína)/metabolismo , Moduladores de Tubulina/síntese química , Moduladores de Tubulina/química
14.
J Proteomics ; 249: 104381, 2021 10 30.
Artigo em Inglês | MEDLINE | ID: mdl-34536592

RESUMO

The diatom Stauroneis sp. was previously identified as a promising source of fucoxanthin and omega-3 oils. Methyl jasmonate (MJ) supplementation is known to enhance metabolite yields in this species without impacting on growth or photosynthesis. Therefore, a label-free proteomics approach was undertaken to further evaluate the functional role of MJ on the diatom's physiology. Of the twenty cultivation regimes were screened, Uf/2 medium with green+white LED's induced the greatest metabolic response when exposed to 10 µM MJ treatment. These conditions significantly enhanced the pigment and total cellular lipids contents. The increase in fucoxanthin correlating with a 20% increase in Trolox reducing equivalent in the total antioxidant assay, indicating a non-enzymatic antioxidant role of fucoxanthin to mitigate the detrimental effects of a redox imbalance within chloroplasts. The proteomics identified 197 proteins up-regulated 48 h after MJ exposure including cell signalling cascades, photosynthetic processes, carbohydrate metabolism, lipid biosynthesis and chloroplast biogenesis. MJ strengthened the dark reactions of photosynthesis to support growth and metabolite fluxes. The MJ-induced ER stress protein triggered lipid body production, facilitating metabolite turnover and trafficking between cellular organelles. Plastid terminal oxidase and glutamate 1-semialdehyde 2,1-aminomutase may act as MJ-induced ROS responsive regulatory switch to support chloroplast biosynthesis. SIGNIFICANCE STATEMENT: Phytohormones represents a promising tool to enhance the high-value metabolite yields in plants and algae, however little is known of the role of methyl jasmonate in diatoms at a molecular level. A shotgun proteomics approach was undertaken to determine the influence of MJ on the diatom's cellular physiology in the marine diatom Stauroneis sp., revealing a signal transduction cascade leading to increased lipid and pigment content and identified promising targets for genetic engineering.


Assuntos
Diatomáceas , Acetatos , Biomassa , Ciclopentanos , Oxilipinas/farmacologia , Proteoma
15.
Planta ; 254(5): 89, 2021 Sep 29.
Artigo em Inglês | MEDLINE | ID: mdl-34586513

RESUMO

MAIN CONCLUSION: Transcriptome and biochemical analyses suggested that, while suppression of multiple flavonoids and anthocyanins occurs at least partially at the transcriptional level, increased biosynthesis of non-jasmonate phyto-oxylipins is likely controlled non-transcriptionally. Methyl jasmonate (MeJA) produced in plants can mediate their response to environmental stresses. Exogenous application of MeJA has also shown to activate signaling pathways and induce phytoalexin accumulation in many plant species. To understand how pomegranate plants respond biochemically to environmental stresses, metabolite analysis was conducted in pomegranate leaves subjected to MeJA application and revealed unique changes in hydrolyzable tannins, flavonoids, and phyto-oxylipins. Additionally, transcriptome and real-time qPCR analyses of mock- and MeJA-treated pomegranate leaves identified differentially expressed metabolic genes and transcription factors that are potentially involved in the control of hydrolyzable tannin, flavonoid, and phyto-oxylipin pathways. Molecular, biochemical, and bioinformatic characterization of the only lipoxygenase with sustained, MeJA-induced expression showed that it is capable of oxidizing polyunsaturated fatty acids, though not located in the subcellular compartment where non-jasmonate (non-JA) phyto-oxylipins were produced. These results collectively suggested that while the broad suppression of flavonoids and anthocyanins is at least partially controlled at the transcriptional level, the induced biosynthesis of non-JA phyto-oxylipins is likely not regulated transcriptionally. Overall, a better understanding of how pomegranate leaves respond to environmental stresses will not only promote plant health and productivity, but also have an impact on human health as fruits produced by pomegranate plants are a rich source of nutritional compounds.


Assuntos
Oxilipinas , Romã (Fruta) , Acetatos/farmacologia , Antocianinas , Ciclopentanos/farmacologia , Flavonoides , Frutas , Regulação da Expressão Gênica de Plantas , Taninos Hidrolisáveis , Oxilipinas/farmacologia , Folhas de Planta
16.
Microbiome ; 9(1): 188, 2021 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-34530928

RESUMO

BACKGROUND: Non-alcoholic liver disease (NAFLD) is the hepatic manifestation of metabolic syndrome, and it can progress to non-alcoholic steatohepatitis (NASH). Alterations in the gut microbiome have been implicated in the development of NAFLD/NASH, although the underlying mechanisms remain unclear. RESULTS: We found that the consumption of the prebiotic inulin markedly ameliorated the phenotype of NAFLD/NASH, including hepatic steatosis and fibrosis, in mice. Inulin consumption resulted in global changes in the gut microbiome, including concomitant enrichment of the genera Bacteroides and Blautia, and increased concentrations of short-chain fatty acids, particularly acetate, in the gut lumen and portal blood. The consumption of acetate-releasing resistant starch protected against NAFLD development. Colonisation by Bacteroides acidifaciens and Blautia producta in germ-free mice resulted in synergetic effects on acetate production from inulin. Furthermore, the absence of free fatty acid receptor 2 (FFAR2), an acetate receptor, abolished the protective effect of inulin, as indicated by the more severe liver hypertrophy, hypercholesterolaemia and inflammation. These effects can be attributed to an exacerbation of insulin resistance in the liver, but not in muscle or adipose tissue. CONCLUSION: These findings demonstrated that the commensal microbiome-acetate-FFAR2 molecular circuit improves insulin sensitivity in the liver and prevents the development of NAFLD/NASH. Video abstract.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Acetatos , Animais , Bacteroides , Clostridiales , Camundongos , Receptores Acoplados a Proteínas G/genética
17.
J Phys Chem B ; 125(36): 10273-10281, 2021 09 16.
Artigo em Inglês | MEDLINE | ID: mdl-34472354

RESUMO

The excited state proton transfer (ESPT) reaction from the photoacid 8-hydroxypyrene-1,3,6-trisulfonic acid (HPTS or pyranine) to an acetate molecule has been investigated in explicit aqueous solution via excited state ab initio molecular dynamics simulations based on hybrid quantum/molecular mechanics (QM/MM) potentials. In all the trajectories, the direct proton transfer has been observed in the excited state within 1 ps. We find that the initial structural configuration extracted from the ground state distribution strongly affects the ESPT kinetics. Indeed, the relative orientation of the proton donor-acceptor pair and the presence of a water molecule hydrogen bonded to the phenolic acid group of the pyranine are the key factors to facilitate the ESPT. Furthermore, we analyze the vibrational fingerprints of the ESPT reaction, reproducing the blue shift of the acetate CO stretching (COac), from 1666 to 1763 cm-1 testifying the transformation of acetate to acetic acid. Finally, our findings suggest that the acetate CC stretching (CCac) is also sensitive to the progress of the ESPT reaction. The CCac stretching is indeed ruled by the two vibrational modes (928 and 1426 cm-1), that in the excited state are alternately activated when the proton is shared or bound to the donor/acceptor, respectively.


Assuntos
Sulfonatos de Arila , Prótons , Acetatos , Água
18.
Toxicon ; 202: 40-45, 2021 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-34562493

RESUMO

Varespladib (LY315920) is a synthetic phospholipase A2 (PLA2) inhibitor that has been demonstrating antiophidic potential against snake venoms that present PLA2 neurotoxins. In this study, we evaluate the capacity of Varespladib to inhibit the neuromuscular effects of crotoxin (CTX), the main toxic component of Crotalus durissus terrificus snake venom, and its PLA2 subunit (CB). We performed a myographic study to compare the neuromuscular effects of CTX or CB and the mixture of these substances plus Varespladib in mice phrenic nerve-diaphragm muscle preparations. CTX (5 µg/mL), CB (20 µg/mL), or toxin-inhibitor mixtures pre-incubated with different concentration ratios of Varespladib (1:0.25; 1:0.5; 1:1; w/w) were added to the preparations and maintained throughout the experimentation period. Myotoxicity was assessed by light microscopic analysis of diaphragm muscle after myographic study. CTX and CB blocked the nerve-evoked twitches, and only CTX induced histological alterations in diaphragm muscle. Pre-incubation with Varespladib abolished the muscle-paralyzing activity of CTX and CB, and also the muscle-damaging activity of CTX. These findings emphasize the clinical potential of Varespladib in mitigating the toxic effects of C. d. terrificus snakebites and as a research tool to advance the knowledge of the mechanism of action of snake toxins.


Assuntos
Venenos de Crotalídeos , Crotoxina , Acetatos , Animais , Venenos de Crotalídeos/toxicidade , Crotoxina/toxicidade , Indóis , Cetoácidos , Camundongos , Miotoxicidade
19.
Water Res ; 204: 117586, 2021 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-34474248

RESUMO

Insights into microbiota adaptation to increased ammonia stress, and identification of indicator microorganisms can help to optimize the operation of anaerobic digesters. To identify microbial indicators and investigate their metabolic contribution to acetoclastic methanogenesis (AM), syntrophic acetate oxidation (SAO) or hydrogenotrophic methanogenesis (HM), 40 anaerobic batch reactors fed with acetate of 110 mmol/L were set up at NH4+-N concentrations of 0.14 g/L, 5.00 g/L or 7.00 g/L, inoculated with thermophilic or mesophilic microbiota with or without pre-exposure to ammonia stress. Four stable carbon isotope probing approaches were applied in parallel, with [1,2-13C]-CH3COOH, [2-13C]-CH3COOH, [13C]NaHCO3 or non-labeled CH3COOH used individually. The last three approaches were used to quantify the methanogenic pathways by tracking labeled 13C or natural 13C signatures in the resulting CH4 and CO2, and consistently detected the dynamic transition of dominant pathways from AM to SAO-HM under ammonia stress. Results of quantitative PCR and fluorescence in-situ hybridization illustrated the procedure, acetotrophic methanogens being outcompeted by acetate-oxidizing syntrophs. The first and last isotope-labeling approaches were designed to probe the active acetate-mineralizing microbes with DNA-SIP. Known acetate-oxidizing bacteria like Syntrophaceticus and Tepidanaerobacter, as well as novel members of Pseudomonas, Bacillus and Symbiobacteraceae were detected, with Methanoculleus as the predominant H2/CO2-utilizing partner. Using NanoSIMS, some bacterial cells were observed to be fixing CO2 from [13C]NaHCO3. In this study, Methanosaeta was only active with ammonia < 200 mg-N/L; the syntrophs catalyzing SAO-HM started to compete with AM-conducting Methanosarcina at intermediate concentrations of ammonia, i.e. 200-500 mg-N/L, and outcompeted the acetotrophic methanogens with ammonia > 500 mg-N/L. Under ammonia stress, diverse known and novel microbial taxa were involved in acetate mineralization, comparable with those identified in previous studies.


Assuntos
Amônia , Metano , Acetatos , Anaerobiose , Methanosarcina , Oxirredução
20.
Bioresour Technol ; 341: 125879, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34523550

RESUMO

Microbial conversion of carbon monoxide (CO) to acetate is a promising upcycling strategy for carbon sequestration. Herein, we demonstrate that CO conversion and acetate production rates of Eubacterium limosum KIST612 strain can be improved by in silico prediction and in vivo assessment. The mimicked CO metabolic model of KIST612 predicted that overexpressing the CO dehydrogenase (CODH) increases CO conversion and acetate production rates. To validate the prediction, we constructed mutant strains overexpressing CODH gene cluster and measured their CO conversion and acetate production rates. A mutant strain (ELM031) co-overexpressing CODH, coenzyme CooC2 and ACS showed a 3.1 × increased specific CO oxidation rate as well as 1.4 × increased specific acetate production rate, compared to the wild type strain. The transcriptional and translational data with redox balance analysis showed that ELM031 has enhanced reducing potential from up-regulation of ferredoxin and related metabolism directly linked to energy conservation.


Assuntos
Aldeído Oxirredutases , Monóxido de Carbono , Acetatos , Acetilcoenzima A , Aldeído Oxirredutases/genética , Eubacterium , Complexos Multienzimáticos
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