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1.
Eur J Pharmacol ; 940: 175457, 2023 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-36529278

RESUMO

Accumulating evidence suggests that de novo lipogenesis is a typical characteristic facilitating nonalcoholic fatty liver disease (NAFLD) progression. Gallic acid (GA) is a naturally occurring phenolic acid with metabolic disease-related clinical significance and preclinical benefits. This study aimed to evaluate the anti-steatotic potentials of GA in a fructose-induced NAFLD mouse model featuring a hepatic lipogenic phenotype. The results revealed that GA alleviated hepatic steatosis, oxidative stress, and inflammatory response in fructose-fed mice. Mechanistically, GA treatment restored AMP-activated protein kinase α (AMPKα) phosphorylation, resulting in downregulations of pro-lipogenic factors, including sterol regulatory element binding protein-1 (SREBP-1), fatty acid synthetase (FASN), and acetyl-CoA carboxylase (ACC), in hepatocytes of mice and in vitro. Furthermore, computational docking analysis indicated that GA could directly interact with AMPKα/ß subunits to stabilize its activation. These results suggest that GA ameliorates fructose-induced hepatosteatosis by restraining hepatic lipogenesis via AMPK-dependent suppression of the SREBP-1/ACC/FASN cascade. Altogether, this study demonstrates that GA supplement may be a promising therapeutic strategy in NAFLD, especially in the subset with enhanced hepatic lipogenesis.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Humanos , Hepatopatia Gordurosa não Alcoólica/metabolismo , Lipogênese/genética , Acetil-CoA Carboxilase/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Ácidos Graxos/metabolismo , Ligases/metabolismo , Ácido Gálico/farmacologia , Ácido Gálico/uso terapêutico , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Frutose/efeitos adversos , Fígado/metabolismo , Ácido Graxo Sintase Tipo I/metabolismo
2.
Int J Mol Sci ; 23(23)2022 Nov 27.
Artigo em Inglês | MEDLINE | ID: mdl-36499166

RESUMO

Cilostazol is an antiplatelet agent with vasodilating effects that functions by increasing the intracellular concentration of cyclic adenosine monophosphate. We have previously shown that cilostazol has favorable effects on angiogenesis. However, there is no study to evaluate the effects of cilostazol on adiponectin. We investigated the effects of cilostazol on angiogenesis in diabetes in vitro and in vivo through adiponectin/adiponectin receptors (adipoRs) and the sirtuin 1 (SIRT1)/AMP-activated protein kinase (AMPK) signaling pathway. Human umbilical vein endothelial cells (HUVECs) and human aortic smooth muscle cells (HASMCs) were cocultured under high glucose (HG) conditions. Adiponectin concentrations in the supernatants were significantly increased when HASMCs were treated with cilostazol but not significantly changed when only HUVECs were treated with cilostazol. Cilostazol treatment enhanced the expression of SIRT1 and upregulated the phosphorylation of AMPK in HG-treated HUVECs. By sequential knockdown of adipoRs, SIRT1, and AMPK, our data demonstrated that cilostazol prevented apoptosis and stimulated proliferation, chemotactic motility, and capillary-like tube formation in HG-treated HUVECs through the adipoRs/SIRT1/AMPK signaling pathway. The phosphorylation of downstream signaling molecules, including acetyl-CoA carboxylase (ACC) and endothelial nitric oxide synthase (eNOS), was downregulated when HUVECs were treated with a SIRT1 inhibitor. In streptozotocin-induced diabetic mice, cilostazol treatment could improve blood flow recovery 21-28 days after inducing hindlimb ischemia as well as increase the circulating of CD34+CD45dim cells 14-21 days after operation; moreover, these effects were significantly attenuated by the knockdown of adipoR1 but not adipoR2. The expression of SIRT1 and phosphorylation of AMPK/ACC and Akt/eNOS in ischemic muscles were significantly attenuated by the gene knockdown of adipoRs. Cilostazol improves HG-induced endothelial dysfunction in vascular endothelial cells and enhances angiogenesis in diabetic mice by upregulating the expression of adiponectin/adipoRs and its SIRT1/AMPK downstream signaling pathway.


Assuntos
Diabetes Mellitus Experimental , Sirtuína 1 , Animais , Humanos , Camundongos , Acetil-CoA Carboxilase/metabolismo , Adiponectina/metabolismo , Proteínas Quinases Ativadas por AMP/metabolismo , Cilostazol/farmacologia , Diabetes Mellitus Experimental/metabolismo , Células Endoteliais da Veia Umbilical Humana/metabolismo , Isquemia/metabolismo , Fosforilação , Receptores de Adiponectina/genética , Receptores de Adiponectina/metabolismo , Transdução de Sinais , Sirtuína 1/genética , Sirtuína 1/metabolismo , Neovascularização Patológica
3.
Medicine (Baltimore) ; 101(50): e32357, 2022 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-36550852

RESUMO

BACKGROUND: The pathological mechanism of nonalcoholic steatohepatitis (NASH) is closely related to abnormal lipid regulation in hepatocytes. Patients with NASH generally have a significant increase in de novo lipogenesis, which acetyl-CoA carboxylase (ACC) catalyzes the first committed step. However, the treatment with ACC inhibitors remains controversial. Thus, our study will systematically evaluate the efficacy and safety of ACC inhibitors for the treatment of NASH. METHODS: We plan to search PubMed, Cochrane Library, Web of Science, EMBASE, Google Scholar, ClinicalTrials.gov, China Science and Technology Journal Database, Chinese Biomedical Literature Database, Wan-fang Database and China National Knowledge Infrastructure to obtain literatures from January 2015 to January 2030 under the inclusion and exclusion criteria, and include randomized controlled trials containing intervention of ACC inhibitors for NASH. The proportion of patients with reduction in ballooning, inflammation and fibrosis will be accepted as the main outcome. RoB 2 will be used for the risk of bias, as well as Egger's test and funnel plot for reporting bias. We will adopt Review Manager 5.4.1 for data synthesis, subgroup analysis, meta-regression analysis and sensitivity analysis, and conduct trial sequential analysis and quality of evidence evaluation using trial sequential analysis 0.9.5.10 Beta software and GRADE Profiler 3.6.1 software respectively. RESULTS: This systematic review will assess the proportion of patients with reduction of ballooning, inflammation and fibrosis, changes in hepatic steatosis, levels of liver enzymes and liver injury markers, metabolic parameters, safety and tolerability to measure the clinical benefits of ACC inhibitors for NASH. CONCLUSION: The conclusion of this systematic review will achieve convincing evidence to evaluate the efficacy and safety of ACC inhibitors for NASH.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Humanos , Hepatopatia Gordurosa não Alcoólica/patologia , Acetil-CoA Carboxilase , Inflamação , Fibrose , Revisões Sistemáticas como Assunto
4.
Molecules ; 27(23)2022 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-36500675

RESUMO

Dengue fever is the most common mosquito-borne viral disease and is caused by the dengue virus (DENV). There is still a lack of efficient drugs against DENV infection, so it is urgent to develop new inhibitors for future clinical use. Our previous research indicated the role of VEGFR2/AMPK in regulating cellular metabolism during DENV infection, while acetyl-CoA carboxylase (ACC) is located downstream of AMPK and plays a crucial role in mediating cellular lipid synthesis; therefore, we speculated that an ACC inhibitor could serve as an antiviral agent against DENV. Luckily, we found that CP640186, a reported noncompetitive ACC inhibitor, significantly inhibited DENV proliferation, and CP640186 clearly reduced DENV2 proliferation at an early stage with an EC50 of 0.50 µM. A mechanism study indicated that CP640186 inhibited ACC activation and destroyed the cellular lipid environment for viral proliferation. In the DENV2 infection mice model, oral CP640186 administration (10 mg/kg/day) significantly improved the mice survival rate after DENV2 infection. In summary, our research suggests that lipid synthesis plays an important role during DENV2 proliferation and indicates that CP640186 is a promising drug candidate against DNEV2 in the future.


Assuntos
Vírus da Dengue , Dengue , Camundongos , Animais , Dengue/tratamento farmacológico , Acetil-CoA Carboxilase , Replicação Viral , Linhagem Celular , Antivirais/farmacologia , Antivirais/uso terapêutico , Lipídeos/farmacologia
5.
Biochem J ; 479(22): 2327-2343, 2022 Nov 30.
Artigo em Inglês | MEDLINE | ID: mdl-36383046

RESUMO

A casual decision made one evening in 1976, in a bar near the Biochemistry Department at the University of Dundee, led me to start my personal research journey by following up a paper that suggested that acetyl-CoA carboxylase (ACC) (believed to be a key regulatory enzyme of fatty acid synthesis) was inactivated by phosphorylation by what appeared to be a novel, cyclic AMP-independent protein kinase. This led me to define and name the AMP-activated protein kinase (AMPK) signalling pathway, on which I am still working 46 years later. ACC was the first known downstream target for AMPK, but at least 100 others have now been identified. This article contains some personal reminiscences of that research journey, focussing on: (i) the early days when we were defining the kinase and developing the key tools required to study it; (ii) the late 1990s and early 2000s, an exciting time when we and others were identifying the upstream kinases; (iii) recent times when we have been studying the complex role of AMPK in cancer. The article is published in conjunction with the Sir Philip Randle Lecture of the Biochemical Society, which I gave in September 2022 at the European Workshop on AMPK and AMPK-related kinases in Clydebank, Scotland. During the early years of my research career, Sir Philip acted as a role model, due to his pioneering work on insulin signalling and the regulation of pyruvate dehydrogenase.


Assuntos
Proteínas Quinases Ativadas por AMP , Proteínas Serina-Treonina Quinases , Proteínas Quinases Ativadas por AMP/genética , Proteínas Quinases Ativadas por AMP/metabolismo , Complexos Multienzimáticos/metabolismo , Acetil-CoA Carboxilase/metabolismo , Fosforilação
6.
Sci Adv ; 8(47): eabq1984, 2022 11 25.
Artigo em Inglês | MEDLINE | ID: mdl-36417534

RESUMO

Acetyl-CoA carboxylase (ACC) regulates lipid synthesis; however, its role in inflammatory regulation in macrophages remains unclear. We generated mice that are deficient in both ACC isoforms in myeloid cells. ACC deficiency altered the lipidomic, transcriptomic, and bioenergetic profile of bone marrow-derived macrophages, resulting in a blunted response to proinflammatory stimulation. In response to lipopolysaccharide (LPS), ACC is required for the early metabolic switch to glycolysis and remodeling of the macrophage lipidome. ACC deficiency also resulted in impaired macrophage innate immune functions, including bacterial clearance. Myeloid-specific deletion or pharmacological inhibition of ACC in mice attenuated LPS-induced expression of proinflammatory cytokines interleukin-6 (IL-6) and IL-1ß, while pharmacological inhibition of ACC increased susceptibility to bacterial peritonitis in wild-type mice. Together, we identify a critical role for ACC in metabolic regulation of the innate immune response in macrophages, and thus a clinically relevant, unexpected consequence of pharmacological ACC inhibition.


Assuntos
Acetil-CoA Carboxilase , Glucose , Animais , Camundongos , Acetil-CoA Carboxilase/genética , Acetil-CoA Carboxilase/metabolismo , Glucose/metabolismo , Metabolismo dos Lipídeos , Lipopolissacarídeos/toxicidade , Lipopolissacarídeos/metabolismo , Camundongos Knockout , Macrófagos/metabolismo , Inflamação/metabolismo
7.
BMC Genomics ; 23(1): 707, 2022 Oct 17.
Artigo em Inglês | MEDLINE | ID: mdl-36253756

RESUMO

BACKGROUND: Biotin carboxyl carrier protein (BCCP) is a subunit of Acetyl CoA-carboxylase (ACCase) which catalyzes the conversion of acetyl-CoA to malonyl-CoA in a committed step during the de novo biosynthesis of fatty acids. Lipids, lipid metabolites, lipid-metabolizing and -modifying enzymes are known to play a role in biotic and abiotic stress tolerance in plants. In this regard, an understanding of the Brassica napus BCCP genes will aid in the improvement of biotic and abiotic stress tolerance in canola. RESULTS: In this study, we identified 43 BCCP genes in five Brassica species based on published genome data. Among them, Brassica rapa, Brassica oleracea, Brassica nigra, Brassica napus and Brassica juncea had six, seven, seven, 10 and 13 BCCP homologs, respectively. Phylogenetic analysis categorized them into five classes, each with unique conserved domains. The promoter regions of all BCCP genes contained stress-related cis-acting elements as determined by cis-element analysis. We identified four and three duplicated gene pairs (segmental) in B. napus and B. juncea respectively, indicating the role of segmental duplication in the expansion of this gene family. The Ka/Ks ratios of orthologous gene pairs between Arabidopsis thaliana and five Brassica species were mostly less than 1.0, implying that purifying selection, i.e., selective removal of deleterious alleles, played a role during the evolution of Brassica genomes. Analysis of 10 BnaBCCP genes using qRT-PCR showed a different pattern of expression because of exposure of the plants to biotic stresses, such as clubroot and sclerotinia diseases, and abiotic stresses such as drought, low temperature and salinity stresses. CONCLUSIONS: The identification and functional analysis of the Brassica BCCPs demonstrated that some of these genes might play important roles in biotic and abiotic stress responses. Results from this study could lay the foundation for a better understanding of these genes for the improvement of Brassica crops for stress tolerance.


Assuntos
Arabidopsis , Brassica napus , Brassica , Acetilcoenzima A/genética , Acetilcoenzima A/metabolismo , Acetil-CoA Carboxilase/genética , Arabidopsis/genética , Biotina/genética , Biotina/metabolismo , Brassica/genética , Brassica/metabolismo , Brassica napus/metabolismo , Ácidos Graxos/metabolismo , Regulação da Expressão Gênica de Plantas , Lipídeos , Filogenia , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo
8.
BMC Res Notes ; 15(1): 315, 2022 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-36192786

RESUMO

OBJECTIVE: Non-alcoholic steatohepatitis (NASH) has become a global medical problem. Currently, there is no approved pharmacologic treatment for this condition. Previous studies have suggested that in the pathogenesis of this disease, regulatory pathways associated with de novo lipogenesis and ß-oxidation pathways genes are misregulated. Capparis spinosa (CS) belongs to the family of Capparidaceae and is a traditional plant used to treat various diseases, particularly dyslipidemia. The compounds and extracts of this plant in In vivo and in vitro studies resulted in a reduction in lipid profiles and glucose. However, the mechanism of these effects remains unknown. This study aimed to evaluate the effects of (CS) fruit extract on NASH compared to fenofibrate and explored the related molecular mechanism. RESULTS: In the rats (n = 40) model of NASH, biochemical and histopathological examinations showed that liver steatosis, inflammation, and hepatic fibrosis were markedly attenuated in response to CS and fenofibrate interventions. At the molecular level, CS treatment down-regulated sterol regulatory element-binding protein-1c (SREBP-1c) (p < 0.001), acetyl-CoA carboxylase (ACC) (p < 0.001), and up-regulated Carnitine palmitoyltransferase I (CPT1) expression (p < 0.001). In conclusion, CS has favorable therapeutic effects for NASH, which was associated with ameliorating steatosis and fibrosis via regulation of the DNL and ß-oxidation pathway genes.


Assuntos
Capparis , Fenofibrato , Hepatopatia Gordurosa não Alcoólica , Acetil-CoA Carboxilase/metabolismo , Acetil-CoA Carboxilase/farmacologia , Animais , Capparis/metabolismo , Carnitina O-Palmitoiltransferase/genética , Carnitina O-Palmitoiltransferase/metabolismo , Carnitina O-Palmitoiltransferase/farmacologia , Dieta Hiperlipídica/efeitos adversos , Fenofibrato/metabolismo , Fenofibrato/farmacologia , Fenofibrato/uso terapêutico , Glucose/metabolismo , Lipídeos/farmacologia , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , PPAR alfa/genética , PPAR alfa/metabolismo , PPAR alfa/farmacologia , Ratos , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/farmacologia , Esteróis/metabolismo , Esteróis/farmacologia , Esteróis/uso terapêutico
9.
Mol Cell ; 82(21): 4116-4130.e6, 2022 Nov 03.
Artigo em Inglês | MEDLINE | ID: mdl-36283412

RESUMO

Pyruvate carboxylase (PC) catalyzes the two-step carboxylation of pyruvate to produce oxaloacetate, playing a key role in the maintenance of metabolic homeostasis in cells. Given its involvement in multiple diseases, PC has been regarded as a potential therapeutic target for obesity, diabetes, and cancer. Albeit acetyl-CoA has been recognized as the allosteric regulator of PC for over 60 years, the underlying mechanism of how acetyl-CoA induces PC activation remains enigmatic. Herein, by using time-resolved cryo-electron microscopy, we have captured the snapshots of PC transitional states during its catalytic cycle. These structures and the biochemical studies reveal that acetyl-CoA stabilizes PC in a catalytically competent conformation, which triggers a cascade of events, including ATP hydrolysis and the long-distance communication between the two reactive centers. These findings provide an integrated picture for PC catalysis and unveil the unique allosteric mechanism of acetyl-CoA in an essential biochemical reaction in all kingdoms of life.


Assuntos
Acetil-CoA Carboxilase , Piruvato Carboxilase , Humanos , Piruvato Carboxilase/genética , Piruvato Carboxilase/metabolismo , Acetilcoenzima A/metabolismo , Regulação Alostérica , Microscopia Crioeletrônica , Conformação Molecular , Acetil-CoA Carboxilase/metabolismo
10.
Med Oncol ; 39(12): 247, 2022 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-36209296

RESUMO

Cancer cells rewire the metabolic processes beneficial for cancer cell proliferation, survival, and their progression. In this study, metabolic processes related to glucose, glutamine, and fatty acid metabolism signatures were collected from the molecular signatures database and investigated in the context of energy metabolic pathways through available genome-wide expression profiles of liver cancer cohorts by gene sets-based pathway activation scoring analysis. The outcomes of this study portray that the fatty acid metabolism, transport, and its storage related signatures are highly expressed across early stages of liver tumors and on the contrary, the gene sets related to glucose transport and glucose metabolism are prominently activated in the hepatocellular carcinoma (HCC) stage. Based on the results, these metabolic pathways are clearly dysregulated across specific stages of carcinogenesis. The identified dimorphic metabolic pathway dysregulation patterns are further reconfirmed by examining corresponding metabolic pathway genes expression patterns across various stages encompassing profiles. Recurrence is the primary concern in the carcinogenesis of liver tumors due to liver tissues regeneration. Hence, to further explore these dysregulation effects on recurrent cirrhosis and recurrent HCC sample containing profile GSE20140 was examined and interestingly, this result also reiterated these differential metabolic pathways dysregulation. In addition, a recently established metabolome profile for the massive panel of cancer cell-lines, including liver cancer cell-lines, was used for further exploration. These findings also reassured those differential metabolites abundance of the fatty acid and glucose metabolic pathways enlighten those dimorphic metabolic pathways dysregulation. Moreover, ROC curves of fatty acid metabolic pathway genes such as acetyl-CoA carboxylase (ACACB), acyl-CoA dehydrogenase long chain (ACADL), and acyl-CoA dehydrogenase medium chain (ACADM) as well as glucose metabolic pathway genes such as phosphoglycerate kinase (PGK1), pyruvate dehydrogenase (PDHA1), pyruvate dehydrogenase kinase (PDK1) demonstrated greater sensitivity and specificity in the corresponding stage-specific tumors with significant p-values (p < 0.05). Furthermore, overall survival (OS) and recurrence-free survival (RFS) studies also reconfirmed that the rate-limiting genes expression of fatty acid and glucose metabolic pathways reveal better and poor survival in HCC patient cohorts, respectively. In conclusion, all these results clearly show that metabolic rewiring and the existence of two diverse metabolic pathways dysregulation involving fatty acid and glucose metabolism across the stages of liver tumors have been identified. These findings might be useful for developing therapeutic target treatments in stage-specific tumors.


Assuntos
Acil-CoA Desidrogenases , Carcinoma Hepatocelular , Neoplasias Hepáticas , Acetil-CoA Carboxilase/genética , Acetil-CoA Carboxilase/metabolismo , Acil-CoA Desidrogenases/metabolismo , Carcinogênese , Carcinoma Hepatocelular/patologia , Ácidos Graxos/metabolismo , Glucose/metabolismo , Glutamina/metabolismo , Humanos , Neoplasias Hepáticas/patologia , Redes e Vias Metabólicas , Oxirredutases , Fosfoglicerato Quinase/metabolismo , Piruvato Desidrogenase Quinase de Transferência de Acetil , Piruvatos
11.
Microbiol Spectr ; 10(5): e0039422, 2022 10 26.
Artigo em Inglês | MEDLINE | ID: mdl-36200894

RESUMO

Microalgae can adapt to extreme environments with specialized metabolic mechanisms. Here, we report comparative physiological and genetic regulation analyses of Chlorella sorokiniana from different environmental regions of an arctic glacier, desert, and temperate native lake in response to N deprivation, for screening the optimal strain with high lipid accumulation. Strains from the three regions showed different growth and biochemical compositions under N deprivation. The arctic glacier and desert strains produced higher soluble sugar content than strains from the native lake. The arctic glacier strains produced the highest levels of lipid content and neutral lipids under N deprivation compared with strains from desert and native lake. At a molecular level, the arctic strain produced more differentially expressed genes related to fatty acid biosynthesis, glycolysis gluconeogenesis, and glycerolipid metabolism. The important functional genes acetyl coenzyme A (acetyl-CoA) carboxylase (ACCase), fatty acid synthase complex, pyruvate dehydrogenase component, and fatty acyl-acyl carrier protein (acyl-ACP) thioesterase were highly expressed in arctic strains. More acetyl-CoA was produced from glycolysis gluconeogenesis and glycerolipid metabolism, which then produced more fatty acid with the catalytic function of ACCase and acyl-ACP thioesterase in fatty acid biosynthesis. Our results indicated that the C. sorokiniana strains from the arctic region had the fullest potential for biodiesel production due to special genetic regulation related to fatty acid synthesis, glycolysis gluconeogenesis, and glycerolipid metabolism. IMPORTANCE It is important to reveal the physiological and genetic regulation mechanisms of microalgae for screening potential strains with high lipid production. Our results showed that Chlorella sorokiniana strains from arctic glacier, desert, and temperate native lake had different growth, biochemical composition, and genetic expression under N deprivation. The strains from an arctic glacier produced the highest lipid content (including neutral lipid), which was related to the genetic regulation of fatty acid biosynthesis, glycolysis gluconeogenesis, and glycerolipid metabolism. The functional genes for acetyl-CoA carboxylase, fatty acid synthase complex, pyruvate dehydrogenase component, and fatty acyl-ACP thioesterase in the three pathways were highly expressed in arctic strains. The revelation of physiological and genetic regulation of strains from different environmental regions will contribute to the microalgae selection for high lipid accumulation.


Assuntos
Chlorella , Chlorella/genética , Chlorella/metabolismo , Regiões Árticas , Biocombustíveis , Acetilcoenzima A/metabolismo , Acetil-CoA Carboxilase/genética , Acetil-CoA Carboxilase/metabolismo , Camada de Gelo , Lagos , Proteína de Transporte de Acila/metabolismo , Ácidos Graxos/metabolismo , Nitrogênio/metabolismo , Açúcares/metabolismo , Complexo Piruvato Desidrogenase/metabolismo , Ácido Graxo Sintases/metabolismo
12.
Appl Microbiol Biotechnol ; 106(21): 6963-6976, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36197457

RESUMO

Papiliotrema laurentii, previously classified as Cryptococcus laurentii, is an oleaginous yeast that has been isolated from soil, plants, and agricultural and industrial residues. This variety of habitats reflects the diversity of carbon sources that it can metabolize, including monosaccharides, oligosaccharides, glycerol, organic acids, and oils. Compared to other oleaginous yeasts, such as Yarrowia lipolytica and Rhodotorula toruloides, there is little information regarding its genetic and physiological characteristics. From a biotechnological point of view, P. laurentii can produce surfactants, enzymes, and high concentrations of lipids, which can be used as feedstock for fatty acid-derived products. Moreover, it can be applied for the biocontrol of phytopathogenic fungi, contributing to quality maintenance in post- and pre-harvest fruits. It can also improve mycorrhizal colonization, nitrogen nutrition, and plant growth. P. laurentii is also capable of degrading polyester and diesel derivatives and acting in the bioremediation of heavy metals. In this review, we present the current knowledge about the basic and applied aspects of P. laurentii, underscoring its biotechnological potential and future perspectives. KEY POINTS: • The physiological characteristics of P. laurentii confer a wide range of biotechnological applications. • The regulation of the acetyl-CoA carboxylase in P. laurentii is different from most other oleaginous yeasts. • The GEM is a valuable tool to guide the construction of engineered P. laurentii strains with improved features for bio-based products.


Assuntos
Acetil-CoA Carboxilase , Yarrowia , Glicerol , Yarrowia/metabolismo , Ácidos Graxos/metabolismo , Nitrogênio , Carbono , Óleos , Solo , Monossacarídeos , Tensoativos , Poliésteres
13.
Artigo em Inglês | MEDLINE | ID: mdl-36231391

RESUMO

Bioactive compounds provide new insights into the prevention and treatment of obesity. Lycium barbarum polysaccharide (LBP), a biological macromolecule extracted from Goji berry, has displayed potential for regulating lipid metabolism. However, the relationship between gut microbiota regulation and lipid metabolism is not entirely clear. In the present study, 50, 100, and 150 mg/kg LBP were intragastrically administered to C57BL/6J male mice fed with a high-fat diet simultaneously lasting for twelve weeks. The results showed that 150 mg/kg LBP showed significant results and all doses of LBP feeding (50, 100, 150 mg/kg) remarkably decreased both serum and liver total cholesterol (TC) and triglyceride (TG) levels. Treatment of 150 mg/kg LBP seems to be more effective in weight loss, lowering free fatty acid (FFA) levels in serum and liver tissues of mice. LBP feeding increased the gene expression of adiponectin and decreased the gene expression of peroxisome proliferator-activated receptor γ, Cluster of Differentiation 36, acetyl-coA carboxylase, and fatty acid synthase in a dose-dependent manner. In addition, the 16s rDNA Sequencing analysis showed that 150 mg/kg LBP feeding may significantly increase the richness of gut microbiota by up-regulation of the ACE and Chao1 index and altered ß-diversity among groups. Treatment of 150 mg/kg LBP feeding significantly regulated the microbial distribution by decreasing the relative abundance of Firmicutes and increasing the relative abundance of Bacteroidetes at the phylum level. Furthermore, the relative abundance of Faecalibaculum, Pantoea, and uncultured_bacterium_f_Muribaculaceae at the genus level was significantly affected by LBP feeding. A significant correlation was observed between body weight, TC, TG, FFA and bile acid and phyla at the genus level. The above results indicate that LBP plays a vital role in preventing obesity by co-regulating lipid metabolism and gut microbiota, but its effects vary with the dose.


Assuntos
Microbioma Gastrointestinal , Lycium , Acetil-CoA Carboxilase/metabolismo , Acetil-CoA Carboxilase/farmacologia , Adiponectina/metabolismo , Animais , Ácidos e Sais Biliares , Colesterol , DNA Ribossômico , Dieta Hiperlipídica , Medicamentos de Ervas Chinesas , Ácido Graxo Sintases/metabolismo , Ácido Graxo Sintases/farmacologia , Ácidos Graxos não Esterificados/farmacologia , Metabolismo dos Lipídeos , Lycium/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Obesidade/metabolismo , PPAR gama/metabolismo , Triglicerídeos
14.
Ecotoxicology ; 31(8): 1276-1286, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36125661

RESUMO

Radiation can cause the differential expression of biological miRNA molecules. This research was based on the development of the laboratory red crucian carp (LRCC) to explore the feasibility of its application in the detection of low-dose ionizing radiation-induced biological damage in aquatic environments and the development of related molecular markers. Adult LRCC were irradiated with caesium-137 at 0.3 Gy, while RNA-seq and bioinformatics techniques were used to identify miRNAs that were differentially expressed relative to their levels in the nonirradiation group. Analysis of liver sections showed that liver cells in the radiation group showed nuclear pyknosis. In this study, 34 miRNAs differentially expressed in the liver of LRCC after irradiation were identified, among which seven were new crucian carp miRNAs; a total of 632 target genes were predicted in the prediction analysis. The results of comprehensive GO enrichment and KEGG pathway analyses showed that these target genes were mainly involved in energy transfer and material catabolism, especially malonyl-CoA biosynthesis, acetyl-CoA carboxylase activity, fatty acid biosynthesis and metabolism, and pyruvate metabolism; in addition, the AMPK signalling pathway was the most active pathway. This study shows that the LRCC is sensitive to radiation, or can be used as a candidate experimental animal to study the biological effects of radiation, and the screened miRNA can be used as a pre-selected biomarker for radiation damage detection and radiation biological environmental monitoring. CLINICAL TRIALS REGISTRATION: None.


Assuntos
Carpas , MicroRNAs , Proteínas Quinases Ativadas por AMP , Acetil-CoA Carboxilase , Animais , Biomarcadores , Carpas/genética , Radioisótopos de Césio , Coenzima A , Ácidos Graxos , MicroRNAs/genética , Piruvatos
15.
Hum Exp Toxicol ; 41: 9603271221129852, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36137816

RESUMO

Lipid metabolism is an important biochemical process in the body. Recent studies have found that environmental endocrine disruptors play an important role in the regulation of lipid metabolism. Bisphenol A (BPA), a common environmental endocrine disruptor, has adverse effects on lipid metabolism, but the mechanism is still unclear. This study aimed to investigate the effects of gestational BPA exposure on hepatic lipid metabolism and its possible mechanism in male offspring. The pregnant Sprague-Dawley rats were exposed to BPA (0, 0.05, 0.5, 5 mg/kg/day) from day 5 to day 19 of gestation to investigate the levels of triglyceride (TG) and total cholesterol (TC), and the expression of liver lipid metabolism-related genes in male offspring rats. The results showed that compared with the control group, the TG and TC levels in serum and liver in BPA-exposed groups was increased. And the expressions of liver fatty acid oxidation related genes, such as peroxisome proliferators-activated receptor α (PPARα) and carnitine palmitoyl transferase 1α (CPT1α), were down-regulated. However, the expressions of fatty acid synthesis related genes, such as sterol regulatory element binding proteins 1 (SREBP-1), acetyl-CoA carboxylase 1 (ACC1), fatty acid synthase (FAS) and stearoyl-CoA desaturase 1 (SCD-1), were up-regulated. The increased protein levels of mTOR and p-CRTC2 suggested that CREB-regulated transcription coactivator 2 (CRTC2) might be an important mediator in the mTOR/SREBP-1 pathway. In conclusion, these results demonstrated that mTOR/CRTC2/SREBP-1 could be affected by gestational BPA exposure, which may involve in the lipid metabolic disorders in later life.


Assuntos
Disruptores Endócrinos , Metabolismo dos Lipídeos , Acetil-CoA Carboxilase/metabolismo , Acetil-CoA Carboxilase/farmacologia , Animais , Compostos Benzidrílicos , Carnitina/farmacologia , Colesterol , Disruptores Endócrinos/toxicidade , Ácido Graxo Sintases/metabolismo , Ácido Graxo Sintases/farmacologia , Ácidos Graxos/farmacologia , Feminino , Fígado , Masculino , PPAR alfa/metabolismo , Proliferadores de Peroxissomos/metabolismo , Proliferadores de Peroxissomos/farmacologia , Fenóis , Gravidez , Ratos , Ratos Sprague-Dawley , Estearoil-CoA Dessaturase/metabolismo , Estearoil-CoA Dessaturase/farmacologia , Proteína de Ligação a Elemento Regulador de Esterol 1/genética , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 1/farmacologia , Serina-Treonina Quinases TOR/metabolismo , Transferases/metabolismo , Transferases/farmacologia , Triglicerídeos
16.
J Environ Sci Health B ; 57(9): 765-773, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36093783

RESUMO

Research work featured in this article describes the impurity profile of spirotetramat, a widely used broad-spectrum pesticide targeting acetyl-CoA carboxylase. Technical grade spirotetramat from four different sources were analyzed and compared with commercial Movento using UPLC-MS. Seven potential impurities were detected and six of them except for the trans-isomer of spirotetramat were subsequently isolated using preparative HPLC. All impurities were characterized mainly by MS and NMR spectroscopy and their structures were further confirmed by chemical synthesis. The formation of the impurities was described in this report as well.


Assuntos
Praguicidas , Espectrometria de Massas em Tandem , Acetil-CoA Carboxilase , Compostos Aza , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia Líquida/métodos , Contaminação de Medicamentos , Compostos de Espiro , Espectrometria de Massas em Tandem/métodos
17.
Fitoterapia ; 162: 105288, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36058473

RESUMO

A new pentacyclic triterpenoid, 2-hydroxy-1-ene-hydroxyhopanone (19), and a new benzoxepin-5-one, 3-(4-methyl-3-penten-1-yl)-6-hydroxy-9-methoxy-2H-1-benzoxepin-5-one (25), along with 26 known compounds (1-18, 20-24, 26-28), were isolated from the roots of Arnebia euchroma (Royle) Johnst. The structures of the new compounds were elucidated by extensive spectroscopic analyses. The absolute configurations of shikonofurans 9-13 were determined by quantum chemical ECD calculations and CD spectra comparison for the first time. Pharmacological study revealed that naphthoquinones 1-5, 7, and 8 had obvious cytotoxicity toward human lung adenocarcinoma A549 cell line. Meanwhile, the hypoglycemic and lipid-lowering effects of isolated compounds were assessed by checking their inhibitory effects on key enzymes regulating glucose and lipid metabolism. Results showed that compounds 1, 3, 5, 6, 8, 18, and 19 could inhibit the activity of ATP-citrate lyase (ACL); compound 7 could inhibit the activity of acetyl-CoA carboxylase (ACC1); while compounds 8 and 19 showed inhibitory effects on protein tyrosine phosphatase 1B (PTP1B). Among them, the naphthoquinone 6, steroid 18, and triterpenoid 19 showed moderate inhibitory effects on ACL and PTP1B, but didn't exhibit obvious cytotoxicity. This study demonstrated that compounds 6, 18, and 19 show great promising for the development of new agents for the treatment of metabolic diseases.


Assuntos
Benzoxepinas , Boraginaceae , Naftoquinonas , Triterpenos , Acetil-CoA Carboxilase/metabolismo , Trifosfato de Adenosina/metabolismo , Benzoxepinas/metabolismo , Boraginaceae/química , Glucose/metabolismo , Humanos , Hipoglicemiantes/farmacologia , Lipídeos , Estrutura Molecular , Naftoquinonas/química , Proteína Tirosina Fosfatase não Receptora Tipo 1 , Triterpenos/metabolismo
18.
J Clin Lab Anal ; 36(10): e24607, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36059084

RESUMO

BACKGROUND: Acetyl-coenzyme A carboxylase 1 (ACC1) regulates lipid homeostasis, T helper (Th) cell differentiation, oxidative stress, inflammation response, and neurological process, engaging in acute ischemic stroke (AIS) pathogenesis, while its clinical utility in AIS is unclear. Hence, this study intended to explore the correlation among blood ACC1, Th17, and Th1 cells, and ACC1's potency as a prognostic biomarker for AIS management. METHODS: ACC1 in peripheral blood mononuclear cells (PBMCs) of 160 AIS patients and 30 controls were determined using RT-qPCR; blood Th17 and Th1 cells in AIS patients were quantified by flow cytometry. RESULTS: ACC1 was increased in AIS patients compared with controls (median (interquartile range): 2.540 (1.753-3.548) vs. 0.980 (0.655-1.743), p < 0.001), which exhibited a good value to reflect AIS risk with the area under the curve of 0.872 (95% CI: 0.805-0.939). Moreover, ACC1 was positively linked with Th17 (r = 0.374, p < 0.001) and Th1 (r = 0.178, p = 0.024) cells in AIS patients. Additionally, ACC1 (r = 0.328, p < 0.001), Th17 (r = 0.272, p = 0.001), and Th1 cells (r = 0.195, p = 0.014) were positively associated with the National Institutes of Health Stroke Scale score in AIS patients. ACC1 high vs. low (p = 0.038) and Th17 high vs. low (p = 0.026) were related to shortened recurrence-free survival (RFS) in AIS patients, while Th1 cells (p = 0.179) were not correlated with RFS. Whereas ACC1 (p = 0.248), Th17 (p = 0.079), and Th1 cells (p = 0.130) were not linked with overall survival (OS) in AIS patients. CONCLUSION: Circulating ACC1 overexpression correlates with increased Th17, Th1 cells, NIHSS score, and shortened RFS in AIS patients.


Assuntos
AVC Isquêmico , Acidente Vascular Cerebral , Acetil-CoA Carboxilase , Biomarcadores , Coenzima A , Humanos , Leucócitos Mononucleares , Lipídeos , Prognóstico , Células Th1 , Células Th17
19.
Chemosphere ; 308(Pt 3): 136558, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36150488

RESUMO

Synthetic phytohormone (SP) is regarded as an attractive candidate for microalgae cultivation due to its potential for high-value microalgae biomass production. Herein, α-naphthylacetic acid (NAA), indomethacin (IN) and 2,4-dichlorophenoxyacetic acid (2,4-D) were used for the mixotrophic cultivation of Chlorella pyrenoidosa with mariculture wastewater (MW) acidogenic fermentation effluent. The growth and lipid accumulation of Chlorella pyrenoidosa added with SP were enhanced, given their high bioavailability of the nutrients. Among these three SPs, IN was optimal for Chlorella pyrenoidosa growth, with the maximum optical density of 1.81. NAA exhibited the best performance for lipid production and the proportion of lipid reached 50.24%. Furthermore, the energy of Chlorella pyrenoidosa cultured with SP preferentially allocated to lipogenesis. To understand the mechanism of lipid accumulation in Chlorella pyrenoidosa in response to SP, the enzyme activities involved in carbon metabolism were determined. The malic enzyme (ME) and acetyl-CoA carboxylase (ACCase) were positively correlated with lipid accumulation. Phosphoenolpyruvate carboxylase (PEPC) was the negative feedback enzyme for lipid synthesis. The findings could provide valuable information for regulation mechanism of lipid accumulation and value-added products recovery by microalgae.


Assuntos
Chlorella , Microalgas , Ácido 2,4-Diclorofenoxiacético/metabolismo , Acetil-CoA Carboxilase/metabolismo , Biomassa , Carbono/metabolismo , Chlorella/metabolismo , Indometacina , Lipídeos , Microalgas/metabolismo , Fosfoenolpiruvato Carboxilase/metabolismo , Reguladores de Crescimento de Plantas/metabolismo , Reguladores de Crescimento de Plantas/farmacologia
20.
Pest Manag Sci ; 78(11): 4994-5001, 2022 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-36054028

RESUMO

BACKGROUND: Insecticide resistance has developed in several populations of the whitefly Bemisia tabaci worldwide and threatens to compromise the efficacy of chemical control. The molecular mechanisms underpinning resistance have been characterized and markers associated with the trait have been identified, allowing the development of diagnostics for individual insects. RESULTS: TaqMan and Droplet Digital PCR (ddPCR) assays were developed and validated, in individual and pooled whitefly samples, respectively, for the following target-site mutations: the acetylcholinesterase (ace1) F331W mutation conferring organophosphate-resistance; the voltage-gated sodium channel (vgsc) mutations L925I and T929V conferring pyrethroid-resistance; and the acetyl-CoA carboxylase (acc) A2083V mutation conferring ketoenol-resistance. The ddPCR's limit of detection (LoD) was <0.2% (i.e. detection of one heterozygote whitefly in a pool of 249 wild-type individuals). The assays were applied in 11 B. tabaci field populations from four locations in Crete, Greece. The F331W mutation was detected to be fixed or close to fixation in eight of 11 B. tabaci populations, and at lower frequency in the remaining ones. The pyrethroid-resistance mutations were detected at very high frequencies. The A2083V spiromesifen resistance mutation was detected in eight of 11 populations (frequencies = 6.16-89.56%). Spiromesifen phenotypic resistance monitoring showed that the populations tested had variable levels of resistance, ranging from full susceptibility to high resistance. A strong spiromesifen-resistance phenotype-genotype (A2083V) correlation (rs  = -0.839, P = 0.002) was observed confirming the ddPCR diagnostic value. CONCLUSION: The ddPCR diagnostics developed in this study are a valuable tool to support evidence-based rational use of insecticides and resistance management strategies. © 2022 Society of Chemical Industry.


Assuntos
Hemípteros , Inseticidas , Piretrinas , Canais de Sódio Disparados por Voltagem , Acetil-CoA Carboxilase , Acetilcolinesterase/genética , Animais , Hemípteros/genética , Resistência a Inseticidas/genética , Inseticidas/farmacologia , Organofosfatos , Patologia Molecular , Reação em Cadeia da Polimerase , Piretrinas/farmacologia , Compostos de Espiro , Canais de Sódio Disparados por Voltagem/genética
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