RESUMO
This article employs six organic acids to selectively dissolve Mo, Ni and V from spent catalysts, and the most effective acid is identified. Then, the effects of key leaching parameters, including acid concentration, temperature, and S/L ratio, on metal leaching are systematically explored to determine the leaching mechanism. The results demonstrate that the leaching ability of organic acids followed the order: oxalic acid > citric acid > tartaric acid > malonic acid > acetic acid > formic acid. The leaching process of metals was jointly influenced by acidolysis and complexolysis. Among them, more than 93.07 % of Mo, 86.64 % of V, and 74.21 % of Ni were selectively leached with oxalic acid at the optimum condition: S/l: 1/20, oxalic acid: 1.0 mol/L, temp: 60 °C. From the correlation coefficients, the resulting activation energies, and n values, it was demonstrated that Mo and V followed the Avrami dissolution reaction model, V leaching was controlled by the diffusion mode, and Mo leaching was controlled by a mixed mode of chemical reaction and diffusion. The dissolution behavior of both metals consistently adhered to the linear trend of the Avrami kinetic model under varying S/L ratios and oxalic acid concentrations.
Assuntos
Molibdênio , Níquel , Ácido Oxálico , Cinética , Níquel/química , Catálise , Ácido Oxálico/química , Molibdênio/química , Tartaratos/química , Ácido Cítrico/química , Formiatos/química , Ácido Acético/química , MalonatosRESUMO
The mitochondrial metabolite succinate is a key driver of ischemia/reperfusion injury (IRI). Targeting succinate metabolism by inhibiting succinate dehydrogenase (SDH) upon reperfusion using malonate is an effective therapeutic strategy to achieve cardioprotection in the short term (< 24 h reperfusion) in mouse and pig in vivo myocardial infarction (MI) models. We aimed to assess whether inhibiting IRI with malonate given upon reperfusion could prevent post-MI heart failure (HF) assessed after 28 days. Male C57BL/6 J mice were subjected to 30 min left anterior coronary artery (LAD) occlusion, before reperfusion for 28 days. Malonate or without-malonate control was infused as a single dose upon reperfusion. Cardiac function was assessed by echocardiography and fibrosis by Masson's trichrome staining. Reperfusion without malonate significantly reduced ejection fraction (~ 47%), fractional shortening (~ 23%) and elevated collagen deposition 28 days post-MI. Malonate, administered as a single infusion (16 mg/kg/min for 10 min) upon reperfusion, gave a significant cardioprotective effect, with ejection fraction (~ 60%) and fractional shortening (~ 30%) preserved and less collagen deposition. Using an acidified malonate formulation, to enhance its uptake into cardiomyocytes via the monocarboxylate transporter 1, both 1.6 and 16 mg/kg/min 10 min infusion led to robust long-term cardioprotection with preserved ejection fraction (> 60%) and fractional shortening (~ 30%), as well as significantly less collagen deposition than control hearts. Malonate administration upon reperfusion prevents post-MI HF. Acidification of malonate enables lower doses of malonate to also achieve long-term cardioprotection post-MI. Therefore, the administration of acidified malonate upon reperfusion is a promising therapeutic strategy to prevent IRI and post-MI HF.
Assuntos
Modelos Animais de Doenças , Insuficiência Cardíaca , Malonatos , Camundongos Endogâmicos C57BL , Infarto do Miocárdio , Traumatismo por Reperfusão Miocárdica , Animais , Malonatos/farmacologia , Masculino , Infarto do Miocárdio/metabolismo , Infarto do Miocárdio/patologia , Infarto do Miocárdio/prevenção & controle , Infarto do Miocárdio/fisiopatologia , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Traumatismo por Reperfusão Miocárdica/metabolismo , Traumatismo por Reperfusão Miocárdica/patologia , Traumatismo por Reperfusão Miocárdica/fisiopatologia , Insuficiência Cardíaca/prevenção & controle , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/etiologia , Camundongos , Miocárdio/metabolismo , Miocárdio/patologia , Função Ventricular Esquerda/efeitos dos fármacos , Fibrose , Miócitos Cardíacos/metabolismo , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/patologia , Fatores de TempoRESUMO
The emergence of sustainable polymers and technologies has led to the development of innovative materials with minimal carbon emissions which find extensive applications in wearable electronics, biomedical sensors, and Internet of Things (IoT)-based monitoring systems. Nanocellulose which can be generated from abundant biomass materials has been widely recognized as a sustainable alternative for a diverse range of applications due to its remarkable properties and eco-friendly nature. By making use of the unique and easily accessible coordination transformation property of Co(II) ions and associated visible light absorption changes, we report a novel Co(II) cation-incorporated nanocellulose/malonic acid hybrid aerogel material that exhibits reversible thermochromism induced by thermal stimulus in the presence of atmospheric moisture. This effect is accentuated by the highly porous nature of the nanocellulose aerogel material we have developed. Besides the reversible thermochromic property which Co(II) ions exhibit, the metal ions act as very efficient reinforcing units contributing significantly to the structural stability and rigidity of the hierarchical aerogels by coordinative cross-linking through carboxylate moieties present in the TEMPO-oxidized cellulose nanofibers (TCNF) and additionally adding malonic acid to provide sufficient COO- for cross-linking. Thorough characterization and detailed investigation of as-prepared hybrid aerogels was conducted to evaluate their overall properties including reversible thermochromism and moisture sensor behaviour. Further, an Android mobile-based application was developed to demonstrate the real-world application of the aerogels for atmospheric humidity sensing.
Assuntos
Celulose , Cobalto , Géis , Malonatos , Cobalto/química , Celulose/química , Géis/química , Malonatos/química , Temperatura , Nanofibras/químicaRESUMO
Recent studies have demonstrated that one can control the packing density, and in turn the filterability, of protein precipitates by changing the pH and buffer composition of the precipitating solution to increase the structure/order within the precipitate. The objective of this study was to examine the effect of sodium malonate, which is known to enhance protein crystallizability, on the morphology of immunoglobulin precipitates formed using a combination of ZnCl2 and polyethylene glycol. The addition of sodium malonate significantly stabilized the precipitate particles as shown by an increase in melting temperature, as determined by differential scanning calorimetry, and an increase in the enthalpy of interaction, as determined by isothermal titration calorimetry. The sodium malonate also increased the selectivity of the precipitation, significantly reducing the coprecipitation of DNA from a clarified cell culture fluid. The resulting precipitate had a greater packing density and improved filterability, enabling continuous tangential flow filtration with minimal membrane fouling relative to precipitates formed under otherwise identical conditions but in the absence of sodium malonate. These results provide important insights into strategies for controlling precipitate morphology to enhance the performance of precipitation-filtration processes for the purification of therapeutic proteins.
Assuntos
Malonatos , Malonatos/química , Filtração , Precipitação Química , Imunoglobulinas/química , Polietilenoglicóis/química , Cloretos/química , Varredura Diferencial de Calorimetria , Malatos/química , Compostos de ZincoRESUMO
Lysine malonylation is a protein posttranslational modification. We present a protocol to generate stable gene-knockdown K562 cell lines through lentiviral infection of a CRISPR interference (CRISPRi) system followed by lysine malonylation measurement using mass spectrometry (MS). We detail guide RNA (gRNA) vector cloning, lentiviral infection, cell line purification, protein digestion, malonyl-lysine enrichment, desalting, and MS acquisition and analysis. For complete details on the use and execution of this protocol, please refer to Zhang et al.1 and Bons et al.2.
Assuntos
Lisina Acetiltransferases , Lisina , Espectrometria de Massas , Humanos , Células K562 , Lisina/metabolismo , Espectrometria de Massas/métodos , Lisina Acetiltransferases/metabolismo , Lisina Acetiltransferases/genética , Sistemas CRISPR-Cas , Processamento de Proteína Pós-Traducional , Malonatos/metabolismo , RNA Guia de Sistemas CRISPR-Cas/metabolismoRESUMO
High extracellular concentrations of adenosine triphosphate (ATP) in the tumor microenvironment generate adenosine by sequential dephosphorylation of CD39 and CD73, resulting in potent immunosuppression to inhibit T cell and natural killer (NK) cell function. CD73, as the determining enzyme for adenosine production, has been shown to correlate with poor clinical tumor prognosis. Conventional inhibitors as analogues of adenosine 5'-monophosphate (AMP) may have a risk of further metabolism to adenosine analogues. Here, we report a new series of malonic acid non-nucleoside inhibitors coordinating with zinc ions of CD73. Compound 12f was found to be a superior CD73 inhibitor (IC50 = 60 nM) by structural optimization, and its pharmacokinetic properties were investigated. In mouse tumor models, compound 12f showed excellent efficacy and reversal of immunosuppression in combination with chemotherapeutic agents or checkpoint inhibitors, suggesting that it deserves further development as a novel CD73 inhibitor.
Assuntos
5'-Nucleotidase , 5'-Nucleotidase/antagonistas & inibidores , 5'-Nucleotidase/metabolismo , Animais , Humanos , Camundongos , Malonatos/farmacologia , Malonatos/química , Malonatos/síntese química , Zinco/química , Zinco/metabolismo , Relação Estrutura-Atividade , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Proteínas Ligadas por GPI/antagonistas & inibidores , Proteínas Ligadas por GPI/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacocinética , Descoberta de Drogas , Linhagem Celular TumoralRESUMO
Succinate dehydrogenase inhibition with malonate during initial reperfusion reduces myocardial infarct size in both isolated mouse hearts subjected to global ischemia and in in situ pig hearts subjected to transient coronary ligature. However, the long-term effects of acute malonate treatment are unknown. Here, we investigated whether the protective effects of succinate dehydrogenase inhibition extend to a reduction in scar size and adverse left ventricular remodeling 28 days after myocardial infarction. Initially, ten wild-type mice were subjected to 45 min of left anterior descending coronary artery (LAD) occlusion, followed by 24 h of reperfusion, and were infused during the first 15 min of reperfusion with saline with or without disodium malonate (10 mg/kg/min, 120 µL/kg/min). Malonate-treated mice depicted a significant reduction in infarct size (15.47 ± 3.40% of area at risk vs. 29.34 ± 4.44% in control animals, p < 0.05), assessed using triphenyltetrazolium chloride. Additional animals were then subjected to a 45 min LAD ligature, followed by 28 days of reperfusion. Treatment with a single dose of malonate during the first 15 min of reperfusion induced a significant reduction in scar area, measured using Picrosirius Red staining (11.94 ± 1.70% of left ventricular area (n = 5) vs. 23.25 ± 2.67% (n = 9), p < 0.05), an effect associated with improved ejection fraction 28 days after infarction, as determined using echocardiography, and an attenuated enhancement in expression of the pro-inflammatory and fibrotic markers NF-κB and Smad2/3 in remote myocardium. In conclusion, a reversible inhibition of succinate dehydrogenase with a single dose of malonate at the onset of reperfusion has long-term protective effects in mice subjected to transient coronary occlusion.
Assuntos
Malonatos , Infarto do Miocárdio , Traumatismo por Reperfusão Miocárdica , Succinato Desidrogenase , Remodelação Ventricular , Animais , Malonatos/farmacologia , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/patologia , Camundongos , Succinato Desidrogenase/metabolismo , Succinato Desidrogenase/antagonistas & inibidores , Masculino , Remodelação Ventricular/efeitos dos fármacos , Traumatismo por Reperfusão Miocárdica/tratamento farmacológico , Traumatismo por Reperfusão Miocárdica/patologia , Cicatriz/patologia , Cicatriz/tratamento farmacológico , Camundongos Endogâmicos C57BLRESUMO
Cysteine (Cys) and its oxidized form, cystine (Cys2), play crucial roles in biological systems and have considerable applications in cell culture. However, Cys in cell culture media is easily oxidized to Cys2, leading to solubility issues. Traditional analytical methods struggle to maintain the oxidation states of Cys and Cys2 during analysis, posing a significant challenge to accurately measuring and controlling these compounds. To effectively control the Cys and Cys2 levels, a rapid and accurate analytical method is required. Here, we screened derivatizing reagents that can react with Cys even under acidic conditions to realize a novel analytical method for simultaneously determining Cys and Cys2 levels. Diethyl 2-methylenemalonate (EMM) was found to possess the desired traits. EMM, characterized by its dual electron-withdrawing attributes, allowed for a rapid reaction with Cys under acidic conditions, preserving intact information for understanding the functions of target compounds. Combined with LC-MS/MS and an internal standard, this method provided high analytical accuracy in a short analytical time of 9 min. Using the developed method, the rapid oxidation of Cys in cell culture media was observed with the headspace of the storage container considerably influencing Cys oxidation and Cys2 precipitation rates. The developed method enabled the direct and simplified analysis of Cys behavior in practical media samples and could be used in formulating new media compositions, ensuring quality assurance, and real-time analysis of Cys and Cys2 in cell culture supernatants. This novel approach holds the potential to further enhance the media performance by enabling the timely optimal addition of Cys.
Assuntos
Meios de Cultura , Cisteína , Cistina , Compostos de Sulfidrila , Espectrometria de Massas em Tandem , Cromatografia Líquida/métodos , Química Click , Meios de Cultura/química , Cisteína/química , Cisteína/análise , Cistina/química , Cistina/análogos & derivados , Cistina/análise , Espectrometria de Massa com Cromatografia Líquida , Malonatos/química , Oxirredução , Compostos de Sulfidrila/química , Compostos de Sulfidrila/análise , Espectrometria de Massas em Tandem/métodosRESUMO
Field observations of daytime HONO source strengths have not been well explained by laboratory measurements and model predictions up until now. More efforts are urgently needed to fill the knowledge gaps concerning how environmental factors, especially relative humidity (RH), affect particulate nitrate photolysis. In this work, two critical attributes for atmospheric particles, i.e., phase state and bulk-phase acidity, both influenced by ambient RH, were focused to illuminate the key regulators for reactive nitrogen production from typical internally mixed systems, i.e., NaNO3 and dicarboxylic acid (DCA) mixtures. The dissolution of only few oxalic acid (OA) crystals resulted in a remarkable 50-fold increase in HONO production compared to pure nitrate photolysis at 85% RH. Furthermore, the HONO production rates (PHONO) increased by about 1 order of magnitude as RH rose from <5% to 95%, initially exhibiting an almost linear dependence on the amount of surface absorbed water and subsequently showing a substantial increase in PHONO once nitrate deliquescence occurred at approximately 75% RH. NaNO3/malonic acid (MA) and NaNO3/succinic acid (SA) mixtures exhibited similar phase state effects on the photochemical HONO production. These results offer a new perspective on how aerosol physicochemical properties influence particulate nitrate photolysis in the atmosphere.
Assuntos
Nitratos , Fotólise , Nitratos/química , Ácidos Dicarboxílicos/química , Ácido Nitroso/química , Umidade , Malonatos/química , Poluentes Atmosféricos/químicaRESUMO
Ischaemia-reperfusion (IR) injury is the paradoxical consequence of the rapid restoration of blood flow to an ischaemic organ. Although reperfusion is essential for tissue survival in conditions such as myocardial infarction and stroke, the excessive production of mitochondrial reactive oxygen species (ROS) upon reperfusion initiates the oxidative damage that underlies IR injury, by causing cell death and inflammation. This ROS production is caused by an accumulation of the mitochondrial metabolite succinate during ischaemia, followed by its rapid oxidation upon reperfusion by succinate dehydrogenase (SDH), driving superoxide production at complex I by reverse electron transport. Inhibitors of SDH, such as malonate, show therapeutic potential by decreasing succinate oxidation and superoxide production upon reperfusion. To better understand the mechanism of mitochondrial ROS production upon reperfusion and to assess potential therapies, we set up an in vitro model of IR injury. For this, isolated mitochondria were incubated anoxically with succinate to mimic ischaemia and then rapidly reoxygenated to replicate reperfusion, driving a burst of ROS formation. Using this system, we assess the factors that contribute to the magnitude of mitochondrial ROS production in heart, brain, and kidney mitochondria, as well as screening for inhibitors of succinate oxidation with therapeutic potential.
Assuntos
Mitocôndrias , Traumatismo por Reperfusão , Superóxidos , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/tratamento farmacológico , Animais , Superóxidos/metabolismo , Mitocôndrias/metabolismo , Ácido Succínico/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Succinato Desidrogenase/metabolismo , Succinato Desidrogenase/antagonistas & inibidores , Oxirredução , Malonatos/farmacologia , Malonatos/metabolismo , Masculino , Ratos , CamundongosRESUMO
Receptor-interacting serine/threonine-protein kinase 1 (RIPK1) plays a key role in cell death and inflammation. RIPK1 is a well-established therapeutic target, due to the presence of a unique kinase-regulating allosteric pocket, which enables selective inhibition. Herein we used GSK2982772 as our starting point in our discovery campaign. Applying isosteric replacement, we successfully identified the malonamide scaffold, instead of the well-established serine template. Further structural optimization led to the design and synthesis of a series of analog inhibitors. The enantiomers of the most promising compound were tested on 97 different kinases. The active enantiomer proved to be kinase selective.
Assuntos
Malonatos , Serina , Morte CelularRESUMO
Myocardial infarction (MI) is the leading cause of death worldwide. The most effective way to treat myocardial infarction is to rescue ischemic cardiomyocytes. After an ischemic event, the overproduction of reactive oxygen species (ROS) is a key driver of myocardial injury. The produced ROS affects mitochondrial function and induces apoptosis in cardiomyocytes. This was accomplished by constructing platelet-membrane-encapsulated ROS-responsive drug-releasing nanoparticles (PMN@NIC-MalNPs) to deliver malonate and niclosamide (NIC). The results revealed that PMN@NIC-MalNPs degraded and released malonate and niclosamide in a high-level ROS microenvironment, effectively reducing the oxidative stress and apoptosis rate. By enhancing basal mitochondrial oxygen consumption rate (OCR), adenosine triphosphate (ATP) production, and spare respiratory capacity (SRC) in vitro, reduced the oxidative stress levels and restored mitochondrial function. In vivo studies revealed that the PMN@NIC-MalNPs improved cardiac dysfunction, inhibited succinate dehydrogenase (SDH) activity, increased ATP production, and reduced the myocardial infarct size in myocardial infarction model mice. Further, transcriptome analysis and Western blot revealed that PMN@NIC-MalNPs prevented apoptosis by activating the expressions of the signal transducer and activator of transcription 3 (STAT3) and Bcl-2, and inhibiting the expression of Bax. Thus, this study provides a novel therapeutic solution for treating myocardial infarction and predicting the viability of an antioxidant and antiapoptotic therapeutic solution in the treatment of myocardial injury.
Assuntos
Infarto do Miocárdio , Fator de Transcrição STAT3 , Camundongos , Animais , Espécies Reativas de Oxigênio/metabolismo , Niclosamida/metabolismo , Niclosamida/farmacologia , Niclosamida/uso terapêutico , Infarto do Miocárdio/tratamento farmacológico , Infarto do Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Estresse Oxidativo , Trifosfato de Adenosina/metabolismo , Malonatos/metabolismo , Malonatos/farmacologia , Malonatos/uso terapêutico , ApoptoseRESUMO
The incorporation of malonic acid (MA) into compost as a regulator of the tricarboxylic acid (TCA) cycle has the potential to increase carbon sequestration. However, the influence of MA on the transformation of the microbial community during the composting process remains unclear. In this investigation, MA was introduced at different stages of chicken manure (CM) composting to characterize the bacterial community within the compost using high-throughput sequencing. We assess the extent of increased carbon sequestration by comparing the concentration of total organic carbon (TOC). At the same time, this study examines whether increased carbon sequestration contributes to humus formation, which was elucidated by evaluating the content and composition of humus. Our results show that the addition of MA significantly improved carbon sequestration within the compost, reducing the carbon loss rate (C loss (%)) from 64.70% to 52.94%, while increasing HS content and stability. High throughput sequencing and Random Forest (RF) analysis show that the introduction of MA leads to a reduction in the diversity of the bacterial communities, but enhanced the ability of bacterial communities to synthesize humus. Furthermore, the addition of MA favors the proliferation of Firmicutes. Also, the hub of operational taxonomic units (OTUs) within the community co-occurrence network shifts from Proteobacteria to Firmicutes. Remarkably, our study finds a significant decrease in negative correlations between bacteria, potentially mitigating substrate consumption due to negative interactions such as competition. This phenomenon contributes to the improved retention of TOC in the compost. This research provides new insights into the mechanisms by which MA regulates bacterial communities in compost, and provides a valuable theoretical basis for the adoption of this innovative composting strategy.
Assuntos
Compostagem , Substâncias Húmicas , Malonatos , Sequestro de Carbono , Solo , Bactérias/genética , Carbono , Firmicutes , EstercoRESUMO
BACKGROUND: Succinate is a proinflammatory citric acid cycle metabolite that accumulates in tissues during pathophysiological states. Oxidation of succinate after ischemia-reperfusion leads to reversal of the electron transport chain and generation of reactive oxygen species. Dimethyl malonate (DMM) is a competitive inhibitor of succinate dehydrogenase, which has been shown to reduce succinate accumulation. We hypothesized that DMM would protect against inflammation in a murine model of ARDS. METHODS: C57BL/6 mice were given ARDS via 67.7 µg of intratracheally administered lipopolysaccharide. Dimethyl malonate (50 mg/kg) was administered via tail vein injection 30 minutes after injury, then daily for 3 days. The animals were sacrificed on day 4 after bronchoalveolar lavage (BAL). Bronchoalveolar lavage cell counts were performed to examine cellular influx. Supernatant protein was quantified via Bradford protein assay. Animals receiving DMM (n = 8) were compared with those receiving sham injection (n = 8). Cells were fixed and stained with FITC-labeled wheat germ agglutinin to quantify the endothelial glycocalyx (EGX). RESULTS: Total cell counts in BAL was less for animals receiving DMM (6.93 × 10 6 vs. 2.46 × 10 6 , p = 0.04). The DMM group had less BAL macrophages (168.6 vs. 85.1, p = 0.04) and lymphocytes (527.7 vs. 248.3; p = 0.04). Dimethyl malonate-treated animals had less protein leak in BAL than sham treated (1.48 vs. 1.15 µg/µl, p = 0.03). Treatment with DMM resulted in greater staining intensity of the EGX in the lung when compared with sham (12,016 vs. 15,186 arbitrary units, p = 0.03). Untreated animals had a greater degree of weight loss than treated animals (3.7% vs. 1.1%, p = 0.04). Dimethyl malonate prevented the upregulation of monocyte chemoattractant protein-1 (1.66 vs. 0.92 RE, p = 0.02) and ICAM-1 (1.40 vs. 1.01 RE, p = 0.05). CONCLUSION: Dimethyl malonate reduces lung inflammation and capillary leak in ARDS. This may be mediated by protection of the EGX and inhibition of monocyte chemoattractant protein-1 and ICAM-1. Dimethyl malonate may be a novel therapeutic for ARDS.
Assuntos
Quimiocina CCL2 , Malonatos , Síndrome do Desconforto Respiratório , Camundongos , Animais , Molécula 1 de Adesão Intercelular , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Pulmão/metabolismo , Síndrome do Desconforto Respiratório/tratamento farmacológico , Síndrome do Desconforto Respiratório/prevenção & controle , SuccinatosRESUMO
Metabolic network intertwines with cancerous signaling and drug responses. Malonate is a prevailing metabolite in cancer and a competitive inhibitor of succinate dehydrogenase (SDH). Recent studies showed that malonate induced reactive oxygen species (ROS)-dependent apoptosis in neuroblastoma cells, but protected cells from ischemia-reperfusion injury. We here revealed that malonate differentially regulated cell death and survival in cancer cells. While high-dose malonate triggered ROS-dependent apoptosis, the low-dose malonate induced autophagy and conferred resistance to multiple chemotherapeutic agents. Mechanistically, our results showed that malonate increased p53 stability and transcriptionally up-regulated autophagy modulator DRAM (damage-regulated autophagy modulator), thus promoting autophagy. We further proved that autophagy is required for malonate-associated chemoresistance. Collectively, our findings suggest that malonate plays a double-edge function in cancer response to stressors, and highlights a pro-cancer impact of p53-induced autophagy in response to malonate.
Assuntos
Neoplasias , Proteína Supressora de Tumor p53 , Humanos , Espécies Reativas de Oxigênio/metabolismo , Proteína Supressora de Tumor p53/genética , Proteína Supressora de Tumor p53/metabolismo , Sobrevivência Celular , Resistencia a Medicamentos Antineoplásicos , Apoptose , Autofagia , Malonatos/farmacologia , Linhagem Celular TumoralRESUMO
Malonyl-Coenzyme A Reductase (MCR) in Chloroflexus aurantiacus, a characteristic enzyme of the 3-hydroxypropionate (3-HP) cycle, catalyses the reduction of malonyl-CoA to 3-HP. MCR is a bi-functional enzyme; in the first step, malonyl-CoA is reduced to the free intermediate malonate semialdehyde by the C-terminal region of MCR, and this is further reduced to 3-HP by the N-terminal region of MCR. Here we present the crystal structures of both N-terminal and C-terminal regions of the MCR from C. aurantiacus. A catalytic mechanism is suggested by ligand and substrate bound structures, and structural and kinetic studies of MCR variants. Both MCR structures reveal one catalytic, and one non-catalytic SDR (short chain dehydrogenase/reductase) domain. C-terminal MCR has a lid domain which undergoes a conformational change and controls the reaction. In the proposed mechanism of the C-terminal MCR, the conversion of malonyl-CoA to malonate semialdehyde is based on the reduction of malonyl-CoA by NADPH, followed by the decomposition of the hemithioacetal to produce malonate semialdehyde and coenzyme A. Conserved arginines, Arg734 and Arg773 are proposed to play key roles in the mechanism and conserved Ser719, and Tyr737 are other essential residues forming an oxyanion hole for the substrate intermediates.
Assuntos
Chloroflexus , Malonil Coenzima A , Oxirredutases , Cinética , Oxirredutases/metabolismo , Malonil Coenzima A/metabolismo , MalonatosRESUMO
BACKGROUND: Acute kidney injury (AKI), often experienced at the intensive care units, is associated with high morbidity/mortality where ischemia-reperfusion injury is a main causative factor. Succinate accumulation during ischemia contributes to the excessive generation of reactive oxygen species at reperfusion. Inhibition of succinate dehydrogenase has been associated with protective outcome in cardiac ischemia-reperfusion after 24h, but the effects on kidney and mitochondrial functions are less well studied. AIM: To investigate the therapeutic potential of succinate dehydrogenase inhibition, by using dimethyl malonate (DMM), on kidney and mitochondria functions in a mouse model of AKI. METHODS: Male C57BL/6J mice were pre-treated with DMM or placebo, i.p. 30min prior to bilateral renal ischemia (20min). After 3-days of reperfusion, glomerular filtration rate (GFR) was calculated from plasma clearance of FITC-inulin. Kidney mitochondria was isolated and mass specific and intrinsic mitochondrial function were evaluated by high resolution respirometry. Kidney sections were stained (i.e., hematoxylin-eosin and TUNEL) and analyzed for histopathological evaluation of injuries and apotosis, respectively. NADPH oxidase activity in kidney and human proximal tubular cell-line (HK2) were measured luminometrically. RESULTS: DMM treatment improved GFR (p < 0.05) and reduced levels of blood urea nitrogen (p < 0.01) compared to untreated animals, which was associated with lower degree of ischemia-reperfusion-induced tubular injuries (P < 0.001) and apoptosis (P < 0.01). These therapeutic renal effects were linked with improved mitochondrial function, both mass-specific and intrinsic. Finally, DMM treatment prevented ischemia-reperfusion-induced NADPH oxidase activity in the kidney (p < 0.001), which was showed also in HK2 cells exposed to hypoxia and reoxygenation (P < 0.01). CONCLUSION: Inhibition of succinate dehydrogenase with DMM, in conjunction with the ischemia-reperfusion phase, significantly improved both renal and mitochondrial functions. These findings may have clinical implications for future therapeutic strategies to prevent development of AKI and associated adverse complications, especially in high risk hospitalized patients.
Assuntos
Injúria Renal Aguda , Malonatos , Traumatismo por Reperfusão , Camundongos , Animais , Humanos , Masculino , Succinato Desidrogenase , Camundongos Endogâmicos C57BL , Rim/patologia , Isquemia/patologia , Mitocôndrias , Traumatismo por Reperfusão/tratamento farmacológico , Traumatismo por Reperfusão/patologia , Injúria Renal Aguda/tratamento farmacológico , Injúria Renal Aguda/etiologia , Injúria Renal Aguda/patologia , Reperfusão , NADPH OxidasesRESUMO
Sea-salt aerosols (SSA) are one of the key natural aerosols in our atmosphere, consisting predominantly of sodium chloride (NaCl). Throughout their atmospheric transport, these aerosols undergo complex internal mixing, giving rise to a rich variety of inorganic and organic species, including dicarboxylic acids. This study investigates firstly the composition and deliquescence properties of coarse particles containing pure malonic acid (MA2, CH2(COOH)2) and internally mixed NaCl and MA2, by means of an acoustic levitation system coupled with a Raman microspectrometer. Secondly, we report here the first experimental observation and characterization of the products arising from photochemical reactions under UV-Visible irradiation (338 ≤ λ ≤ 414 nm) in the absence of an oxidant under acoustic levitation conditions in MA2 and NaCl/MA2 aerosols. Furthermore, the impact of photodegradation on the hygroscopic properties of these particles is examined. We confirmed the irreversible formation of monosodium malonate (NaMA, HOOCCH2COONa), which coexists with NaCl or MA2 on non-irradiated particles. We also demonstrated the formation of oxalic acid (OA2, HOOC-COOH) within irradiated MA2 droplets and the appearance of glyoxylic acid (GlyA, HCOCOOH) in NaCl containing droplets. The photolysis process exerts a marked effect on the hygroscopic properties of the particles, resulting in a shift in deliquescence transitions toward higher relative humidity (RH) values. This study contributes to the understanding of the intricate physicochemical processes involved in SSA during their atmospheric transport. Likewise, this work sheds light on the impacts of these types of aerosols on cloud formation and climate change.
Assuntos
Malonatos , Cloreto de Sódio , Cloreto de Sódio/química , Fotólise , Aerossóis/químicaRESUMO
The objective of this research is to conduct a comprehensive characterization of chitosan while also improving its attributes by crosslinking with malonic acid, with a focus on its efficacy in removing hexavalent chromium, arsenite and fluoride ions. Crosslinking chitosan in 1:0.5 mass ratio forming a film led to substantial enhancement in confiscation of these target pollutants. The characterization of the adsorbent involved several techniques, including FT-IR, TGA-DSC, SEM-EDX, XRD, and BET surface area analysis. In batch adsorption experiments, Chitosan-malonic acid (CMA) was employed to remove CrVI, AsIII and F- from aqueous solutions. These experiments were conducted while varying conditions such as pH, dosage, concentration, temperature, and time. Through the implementation of response surface methodology (RSM), parameters were optimized, resulting in over 95% removal of CrVI, AsIII and F- ions. The isotherm and kinetics data demonstrated a good fit with the Langmuir isotherm model and pseudo second-order kinetics, respectively. According to the Langmuir isotherm, the maximum adsorption capacities on CMA for CrVI, AsIII and F- were determined to be 687.05 mg g-1, 26.72 mg g-1 and 51.38 mg g-1 respectively under optimum pH of 4.0, 7.0 and 5.0 respectively under ambient temperature of 303 K. Thermodynamic analysis indicated that the adsorption process was spontaneous and driven by enthalpy. The regenerability of the adsorbent was validated through five adsorption-desorption cycles, signifying its reusability. An assessment of the adsorbent's sustainability indicated an eco-friendly synthesis, as reflected by the low E-factor value of 0.0028.
Assuntos
Quitosana , Malonatos , Poluentes Químicos da Água , Purificação da Água , Quitosana/química , Espectroscopia de Infravermelho com Transformada de Fourier , Adsorção , Poluentes Químicos da Água/química , Purificação da Água/métodos , Termodinâmica , Cromo/química , Cinética , Íons , Concentração de Íons de HidrogênioRESUMO
Stereoselective protonation is a challenge in asymmetric catalysis. The small size and high rate of transfer of protons mean that face-selective delivery to planar intermediates is hard to control, but it can unlock previously obscure asymmetric transformations. Particularly, when coupled with a preceding decarboxylation, enantioselective protonation can convert the abundant acid feedstocks into structurally diverse chiral molecules. Here an anchoring group strategy is demonstrated as a potential alternative and supplement to the conventional structural modification of catalysts by creating additional catalyst-substrate interactions. We show that a tailored benzamide group in aminomalonic acids can help build a coordinated network of non-covalent interactions, including hydrogen bonds, π-π interactions and dispersion forces, with a chiral acid catalyst. This allows enantioselective decarboxylative protonation to give α-amino acids. The malonate-based synthesis introduces side chains via a facile substitution of aminomalonic esters and thus can access structurally and functionally diverse amino acids.