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1.
Cell Stem Cell ; 30(1): 52-68.e13, 2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36608679

RESUMO

N6-methyladenosine (m6A), the most prevalent internal modification in mammalian mRNAs, is involved in many pathological processes. METTL16 is a recently identified m6A methyltransferase. However, its role in leukemia has yet to be investigated. Here, we show that METTL16 is a highly essential gene for the survival of acute myeloid leukemia (AML) cells via CRISPR-Cas9 screening and experimental validation. METTL16 is aberrantly overexpressed in human AML cells, especially in leukemia stem cells (LSCs) and leukemia-initiating cells (LICs). Genetic depletion of METTL16 dramatically suppresses AML initiation/development and maintenance and significantly attenuates LSC/LIC self-renewal, while moderately influencing normal hematopoiesis in mice. Mechanistically, METTL16 exerts its oncogenic role by promoting expression of branched-chain amino acid (BCAA) transaminase 1 (BCAT1) and BCAT2 in an m6A-dependent manner and reprogramming BCAA metabolism in AML. Collectively, our results characterize the METTL16/m6A/BCAT1-2/BCAA axis in leukemogenesis and highlight the essential role of METTL16-mediated m6A epitranscriptome and BCAA metabolism reprograming in leukemogenesis and LSC/LIC maintenance.


Assuntos
Autorrenovação Celular , Leucemia Mieloide Aguda , Camundongos , Humanos , Animais , Leucemia Mieloide Aguda/patologia , Carcinogênese/patologia , RNA Mensageiro/metabolismo , Aminoácidos de Cadeia Ramificada/genética , Aminoácidos de Cadeia Ramificada/metabolismo , Células-Tronco Neoplásicas/patologia , Mamíferos/metabolismo , Transaminases/genética , Transaminases/metabolismo , Metiltransferases/genética , Metiltransferases/metabolismo
2.
Food Chem Toxicol ; 172: 113602, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36610474

RESUMO

The endoplasmic reticulum (ER) controls many biological functions besides maintaining the function of liver cells. Various studies reported the role of the ER stress and UPR signaling pathway in various liver diseases via triggering hepatocytes apoptosis. This study aims to investigate the suppressive effect of ß-sitosterol (ßS) on apoptosis associated with liver injury and ER stress. METHODS: Liver damage in rats was induced by TAA (150 mg/kg I.P twice a week/3 weeks) and γ-irradiation (single dose 3.5 Gy) and treated with ßS (20 mg/kg daily for 30 days). Serum aminotransferase activity, lipid profile and lipid metabolic factors were measured beside liver oxidative stress and inflammatory markers. Moreover, the hepatic expression of ER stress markers (inositol-requiring enzyme 1 alpha (IRE1α), X-box-binding protein 1 (XBP1) and CCAAT/enhancer binding protein homologous protein (CHOP) and apoptotic markers were detected together with histopathological examination. RESULTS: ßS diminished the aminotransferase activity, the oxidative stress markers as well as the inflammatory mediators. Furthermore, ßS lowered the circulating TG and TC and the hepatic lipotoxicity via the suppression of lipogenesis (Srebp-1c) and improved the ß-oxidation (Pparα and Cpt1a) together with the mitochondrial biogenesis (Pgc-1 α). Moreover, the upregulated levels of ER stress markers were reduced upon treatment with ßS, which consequently attenuated hepatic apoptosis. CONCLUSION: ßS relieves hepatic injury, ameliorates mitochondrial biogenesis, and reduces lipotoxicity and apoptosis via inhibition of CHOP and ER stress response.


Assuntos
Endorribonucleases , Tioacetamida , Ratos , Animais , Endorribonucleases/metabolismo , Tioacetamida/metabolismo , Tioacetamida/farmacologia , Proteínas Serina-Treonina Quinases/metabolismo , Fígado , Hepatócitos , Apoptose , Sitosteroides/farmacologia , Estresse do Retículo Endoplasmático , Transaminases/metabolismo
3.
Medicine (Baltimore) ; 102(1): e32621, 2023 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-36607856

RESUMO

BACKGROUND: Galectins are a family of endogenous mammalian lectins involved in pathogen recognition, killing, and facilitating the entry of microbial pathogens and parasites into the host. They are the intermediators that decipher glycan-containing information about the host immune cells and microbial structures to modulate signaling events that cause cellular proliferation, chemotaxis, cytokine secretion, and cell-to-cell communication. They have subgroups that take place in different roles in the immune system. The effect of galectin-8 on multiple sclerosis disease (MS) has been studied in the literature, but the results seemed unclear. In this study, we aimed to determine anti-galectin-8 (anti-Gal-8) levels in MS and their potential use as biomarkers. METHODS: In this experimental study, 45 MS patients diagnosed according to McDonald criteria were included in the patient group. The healthy control group contained 45 people without MS diagnosis and any risk factors. Demographic data, height, weight, body mass index, blood glucose, thyroid-stimulating hormone, alanine transaminase, aspartate transaminase, creatinine, low-density lipoprotein, anti-Gal-8 levels, the prevalence of hypertension, diabetes mellitus and coronary artery disease were recorded. In addition, the expanded disability status scale and disease duration were evaluated in the patient group. Data were presented as mean ±â€…standard deviations. RESULTS: The mean blood anti-galectin-8 value of the patient group was 4.84 ±â€…4.53 ng/mL, while it was 4.67 ±â€…3.40 ng/mL in the control group, and the difference in these values was found statistically insignificant (P > .05). Moreover, body mass index, glucose, alanine transaminase, aspartate transaminase, thyroid-stimulating hormone, and low-density lipoprotein levels were also statistically insignificant (P > .05). CONCLUSION: This study examined anti-Gal-8 levels in MS patients. The relationship between MS and galectin-8 and anti-Gal-8 levels in patients needs further clarification. As a result, the study's results could help elucidate the pathogenesis of MS and give more evidence for diagnosis.


Assuntos
Galectina 3 , Esclerose Múltipla , Humanos , Alanina , Biomarcadores , Galectina 3/química , Mamíferos , Transaminases
4.
Biochim Biophys Acta Proteins Proteom ; 1871(2): 140886, 2023 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-36496204

RESUMO

Pyridoxal-5'-phosphate-(PLP-) dependent D-amino acid transaminases (DAATs) catalyze stereoselective reversible transfer of the amino group between D-amino acids and keto acids. In vivo DAATs are commonly known to synthesize D-glutamate for cell wall peptidoglycans. Today DAATs meet increasing attention for application in the synthesis of D-amino acids, whereas little is known about the mechanism of substrate recognition and catalytic steps of the D-amino acids conversion by DAATs. In this work, the pre-steady-state kinetics of the half-reactions of DAAT from Haliscomenobacter hydrossis with D-glutamate, D-alanine, D-leucine, and D-phenylalanine was examined at two wavelengths, 416 and 330 nm, using a stopped-flow technique. Monophasic kinetics was observed with specific substrates D-glutamate and D-alanine, whereas half-reactions with D-leucine and D-phenylalanine exhibited biphasic kinetics. All half-reactions proceeded until the complete conversion of PLP due to the release of the pyridoxamine-5'-phosphate form of cofactor from the holoenzyme . Comparison of kinetic parameters of half-reactions and the overall transamination reactions for D-leucine, D-phenylalanine revealed the increase in the rates of deamination of these substrates in the overall reaction with α-ketoglutarate. In the overall transamination reaction, the catalytic turnover rates for D-leucine and D-phenylalanine increased by 260 and 60 times, correspondingly, comparing with the slowest step rate constants in the half-reactions. We suggested the activating effect by a specific substrate α-ketoglutarate in the overall transamination reaction. The study of half-reactions helped to quantify the specificity of DAAT from H. hydrossis for D-amino acids with different properties. The results obtained are the first detailed analysis of half-reactions catalyzed by DAAT.


Assuntos
Aminoácidos , Transaminases , Transaminases/química , Ácido Glutâmico , Leucina , Ácidos Cetoglutáricos , Alanina , Fosfato de Piridoxal/química , Fenilalanina , Catálise , Fosfatos
5.
Nat Commun ; 13(1): 7458, 2022 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-36460668

RESUMO

Fast screening of enzyme variants is crucial for tailoring biocatalysts for the asymmetric synthesis of non-natural chiral chemicals, such as amines. However, most existing screening methods either are limited by the throughput or require specialized equipment. Herein, we report a simple, high-throughput, low-equipment dependent, and generally applicable growth selection system for engineering amine-forming or converting enzymes and apply it to improve biocatalysts belonging to three different enzyme classes. This results in (i) an amine transaminase variant with 110-fold increased specific activity for the asymmetric synthesis of the chiral amine intermediate of Linagliptin; (ii) a 270-fold improved monoamine oxidase to prepare the chiral amine intermediate of Cinacalcet by deracemization; and (iii) an ammonia lyase variant with a 26-fold increased activity in the asymmetric synthesis of a non-natural amino acid. Our growth selection system is adaptable to different enzyme classes, varying levels of enzyme activities, and thus a flexible tool for various stages of an engineering campaign.


Assuntos
Aminas , Aminoácidos , Monoaminoxidase , Transaminases/genética , Cinacalcete
6.
Front Immunol ; 13: 1083862, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36532005

RESUMO

A 72-year-old woman presented to our hospital with elevation of serum transaminases. Her blood tests showed the hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) negative. Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) were given for the diffuse large B-cell lymphoma. She didn't receive anti- hepatitis B virus (HBV) drug for the isolated HBcAb positive. HBV reactivation confirmed based on the serum HBV DNA detectable until 19 months after stopping R-CHOP regimen. HBV DNA became undetectable after 4 weeks therapy with Tenofovir alafenamide fumarate (TAF). Serum transaminases went down to normal 3 months later after receiving TAF. HBV reactivation is a substantial risk for patients with isolated HBcAb positive receiving rituximab-containing chemotherapy without anti- HBV drug. Regular monitoring with a frequency of 1-3 months is the basis for timely diagnosis and treatment of HBV reactivation. Serum transaminases abnormalities may be the initial manifestation of HBV reactivation.


Assuntos
DNA Viral , Vírus da Hepatite B , Humanos , Feminino , Idoso , Rituximab/efeitos adversos , Ativação Viral , Anticorpos Monoclonais Murinos , Transaminases
7.
Medicine (Baltimore) ; 101(48): e32127, 2022 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-36482520

RESUMO

INTRODUCTION: Globally, the number of patients with primary biliary cholangitis (PBC) is increasing. Growing evidence suggests that oxidative stress plays a significant role in the pathogenesis of chronic liver disease regardless of its etiology. Hesperidin, a natural antioxidative substance derived from citrus peel, has been shown to have an anti-inflammatory effect in a rat arthritis model and may be a potential substance to attenuate intrahepatic inflammation in patients with PBC. In this study, the potential of glucosyl hesperidin as a therapeutic agent for PBC will be investigated through antioxidative stress mechanisms. METHODS: Patients with PBC who are 20 years or older will be eligible to participate. Patients will be assigned to 1 of 2 groups and given either 500 or 1000 mg of glucosyl hesperidin per day. The primary endpoint is the ratio of changes in serum gamma-glutamyl transferase levels before and after 24 weeks of glucosyl hesperidin administration. The secondary endpoints are serum hepatobiliary enzyme levels (alkaline phosphatase, transaminase, and total bilirubin levels) and the protein expression levels of nuclear factor erythroid 2-related factor 2 and its target molecule 8, 16, and 24 weeks after administration compared to before administration. DISCUSSION: The prospective clinical interventional study was designed to assess the supportive effect of glucosyl hesperidin on hepatic function in patients with PBC receiving basic ursodeoxycholic acid treatment.


Assuntos
Hesperidina , Cirrose Hepática Biliar , Adulto , Humanos , Cirrose Hepática Biliar/tratamento farmacológico , Estudos Prospectivos , Transaminases , Ensaios Clínicos Controlados Aleatórios como Assunto , Estudos Multicêntricos como Assunto , Hesperidina/uso terapêutico
8.
Molecules ; 27(24)2022 Dec 10.
Artigo em Inglês | MEDLINE | ID: mdl-36557898

RESUMO

The mutations G170R and I244T are the most common disease cause in primary hyperoxaluria type I (PH1). These mutations cause the misfolding of the AGT protein in the minor allele AGT-LM that contains the P11L polymorphism, which may affect the folding of the N-terminal segment (NTT-AGT). The NTT-AGT is phosphorylated at T9, although the role of this event in PH1 is unknown. In this work, phosphorylation of T9 was mimicked by introducing the T9E mutation in the NTT-AGT peptide and the full-length protein. The NTT-AGT conformational landscape was studied by circular dichroism, NMR, and statistical mechanical methods. Functional and stability effects on the full-length AGT protein were characterized by spectroscopic methods. The T9E and P11L mutations together reshaped the conformational landscape of the isolated NTT-AGT peptide by stabilizing ordered conformations. In the context of the full-length AGT protein, the T9E mutation had no effect on the overall AGT function or conformation, but enhanced aggregation of the minor allele (LM) protein and synergized with the mutations G170R and I244T. Our findings indicate that phosphorylation of T9 may affect the conformation of the NTT-AGT and synergize with PH1-causing mutations to promote aggregation in a genotype-specific manner. Phosphorylation should be considered a novel regulatory mechanism in PH1 pathogenesis.


Assuntos
Polimorfismo Genético , Agregados Proteicos , Humanos , Fosforilação , Mutação , Genótipo , Transaminases/metabolismo
9.
J Transl Med ; 20(1): 603, 2022 12 16.
Artigo em Inglês | MEDLINE | ID: mdl-36527113

RESUMO

BACKGROUND: Renal clear cell carcinoma (ccRCC) is the most prevalent tumors worldwide. Discovering effective biomarkers is essential to monitor the prognosis and provide alternative clinical options. SPTBN1 is implicated in various cancerous processes. However, its role in ccRCC remains unelucidated. This study intends to explore the biological function and mechanism of SPTBN1 in ccRCC. METHODS: Single-cell and bulk RNA-seq, tissue microarray, real-time quantitative PCR, and western blotting were applied to verify the expression and predictive value of SPTBN1 in ccRCC. Gain or loss of functional ccRCC cell line models were constructed, and in vitro and in vivo assays were performed to elucidate its tumorigenic phenotypes. Actinomycin D experiment, RNA immunoprecipitation (RIP), specific inhibitors, and rescue experiments were carried out to define the molecular mechanisms. RESULTS: SPTBN1 was down-regulated in ccRCC and knockdown of SPTBN1 displayed a remarkably oncogenic role both in vitro and in vivo; while overexpressing SPTBN1 reversed this effect. SPTBN1 mediated ccRCC progression via the pathway of glutamate pyruvate transaminase 2 (GPT2)-dependent glycolysis. The expression of GPT2 was significantly negatively correlated with that of SPTBN1. As an RNA binding protein SPTBN1, regulated the mRNA stability of GPT2. CONCLUSION: Our research demonstrated that SPTBN1 is significantly down-regulated in ccRCC. SPTBN1 knockdown promotes ccRCC progression via activating GPT2-dependent glycolysis. SPTBN1 may serve as a therapeutic target for the treatment of ccRCC.


Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Humanos , Carcinoma de Células Renais/patologia , Neoplasias Renais/patologia , Proliferação de Células/genética , Linhagem Celular Tumoral , Glicólise , Prognóstico , Regulação Neoplásica da Expressão Gênica , Espectrina/genética , Espectrina/metabolismo , Transaminases/genética
10.
Molecules ; 27(24)2022 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-36557783

RESUMO

Sophorae tonkinensis Radix et Rhizoma (STR) is a traditional Chinese herbal medicine. STR can reduce aminotransferase activity; however, the specific mechanism remains unclear. Here, we explored the potential therapeutic effects and hepatoprotective mechanism of STR on liver damage in mice. The chemical characteristics of the extract were characterized using ultra-high-performance liquid chromatography-tandem mass spectrometry fingerprinting, and its antioxidant capacity was verified using free radical scavenging tests. Forty-eight Kunming mice were randomly assigned into six groups. The model was made after the corresponding drug was given. The results showed that the STR water extract pretreatment significantly reduced serum aminotransferase and related liver function indicators compared with that in the model group. Furthermore, the STR water extract pretreatment significantly inhibited the apoptosis of liver cells, the level of liver high-mobility group box 1 (HMGB1), and inflammatory factors in hepatic tissue compared with that in the model group, and significantly downregulated the levels of toll-like receptor 4 (TLR4), Myeloid differentiation factor 88 (MyD88), and nuclear factor kappa B (NF-κB) compared with those in the model group. Overall, the STR water extract exerted a significant protective effect on CCL4-induced acute liver injury in this study, and the accurate active ingredients of the STR water extract will be explored in the near future.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Medicamentos de Ervas Chinesas , Sophora , Camundongos , Animais , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/química , Tetracloreto de Carbono/toxicidade , Sophora/química , Fígado , Transaminases , Doença Hepática Induzida por Substâncias e Drogas/tratamento farmacológico , Doença Hepática Induzida por Substâncias e Drogas/prevenção & controle
11.
Rev Gastroenterol Peru ; 42(2): 99-105, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36513355

RESUMO

INTRODUCTION: Metabolic associated steatohepatitis (MASH) is one of the most frequent causes of chronic liver disease. Liver transaminases are important biomarkers to measure liver injury, however, a proportion of patients with MASH may present with normal levels of transaminases. The levels of serum transaminases may not correlate with the severity of histopathological changes. OBJECTIVE: We aimed to identify the frequency of normal transaminases in obese patients with MASH, as well as to describe the clinical, biochemical and histological characteristics in this specific group of patients. MATERIALS AND METHODS: A retrospective cross-sectional study was conducted in the bariatric surgery service of a private clinic. Obese patients older than 18 years with a body mass index (BMI) >30Kg/m2 and 2 co-morbidities undergoing a gastric sleeve surgery were included. Measurement of biochemical routine laboratory exams was performed. Insulin resistance was calculated using the homeostasis evaluation model (HOMA-IR). All patients underwent liver biopsies prior to surgery and the diagnosis of MASH was based on the Brunt criteria. RESULTS: 159 obese patients with MASH were included, of which 47.2% had normal transaminases and 52.8% elevated transaminases. Factors associated with alteration in transaminases were: being male OR=4.02 (95% CI: 2.03- 7.96; p<0.01), diagnosis of type 2 diabetes mellitus OR=4.86 (95% CI: 1.97- 11.95; p<0.01) and levels of GGT >50 IU/L OR=7.50 (95% CI: 3.40-16.56; p<0.01). The values of HOMA-IR and GGT were significantly higher in the group of high transaminases (p<0.01). Differences in the degree of fibrosis were not associated with transaminases levels. CONCLUSION: In conclusion we found that the frequency of normal transaminases was 47.2% in obese patients with MASH. Factors associated with elevation in liver enzymes were being male, diagnosis of diabetes mellitus and elevation in GGT levels. The degree of fibrosis was not associated with elevations in liver transaminases. These findings suggest that transaminases levels alone are not accurate markers to assess liver injury, as they do not necessarily correlate with histological liver damage.


Assuntos
Diabetes Mellitus Tipo 2 , Fígado Gorduroso , Hepatopatias , Hepatopatia Gordurosa não Alcoólica , Obesidade Mórbida , Humanos , Masculino , Feminino , Transaminases , Estudos Retrospectivos , Estudos Transversais , Diabetes Mellitus Tipo 2/complicações , Peru , Fígado Gorduroso/diagnóstico , Obesidade/complicações , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/diagnóstico , Obesidade Mórbida/complicações , Obesidade Mórbida/cirurgia
12.
Int J Mol Sci ; 23(23)2022 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-36499674

RESUMO

Amine transaminases (ATAs) are powerful biocatalysts for the stereoselective synthesis of chiral amines. However, wild-type ATAs usually show pH optima at slightly alkaline values and exhibit low catalytic activity under physiological conditions. For efficient asymmetric synthesis ATAs are commonly used in combination with lactate dehydrogenase (LDH, optimal pH: 7.5) and glucose dehydrogenase (GDH, optimal pH: 7.75) to shift the equilibrium towards the synthesis of the target chiral amine and hence their pH optima should fit to each other. Based on a protein structure alignment, variants of (R)-selective transaminases were rationally designed, produced in E. coli, purified and subjected to biochemical characterization. This resulted in the discovery of the variant E49Q of the ATA from Aspergillus fumigatus, for which the pH optimum was successfully shifted from pH 8.5 to 7.5 and this variant furthermore had a two times higher specific activity than the wild-type protein at pH 7.5. A possible mechanism for this shift of the optimal pH is proposed. Asymmetric synthesis of (R)-1-phenylethylamine from acetophenone in combination with LDH and GDH confirmed that the variant E49Q shows superior performance at pH 7.5 compared to the wild-type enzyme.


Assuntos
Escherichia coli , Transaminases , Transaminases/metabolismo , Escherichia coli/genética , Escherichia coli/metabolismo , Engenharia de Proteínas , Aminas/química , Concentração de Íons de Hidrogênio
13.
Molecules ; 27(21)2022 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-36364166

RESUMO

(R)-1-[3,5-bis(trifluoromethyl)phenyl]ethanamine, a key chiral intermediate of selective tetrodotoxin-sensitive blockers, was efficiently synthesized by a bienzyme cascade system formed by with R-ω-transaminase (ATA117) and an alcohol dehydrogenase (ADH) co-expression system. Herein, we report that the use of ATA117 as the biocatalyst for the amination of 3,5-bistrifluoromethylacetophenone led to the highest efficiency in product performance (enantiomeric excess > 99.9%). Moreover, to further improve the product yield, ADH was introduced into the reaction system to promote an equilibrium shift. Additionally, bienzyme cascade system was constructed by five different expression systems, including two tandem expression recombinant plasmids (pETDuet-ATA117-ADH and pACYCDuet-ATA117-ADH) and three co-expressed dual-plasmids (pETDuet-ATA117/pET28a-ADH, pACYCDuet-ATA117/pET28a-ADH, and pACYCDuet-ATA117/pETDuet-ADH), utilizing recombinant engineered bacteria. Subsequent studies revealed that as compared with ATA117 single enzyme, the substrate handling capacity of BL21(DE3)/pETDuet-ATA117-ADH (0.25 g wet weight) developed for bienzyme cascade system was increased by 1.50 folds under the condition of 40 °C, 180 rpm, 0.1 M pH9 Tris-HCl for 24 h. To the best of our knowledge, ours is the first report demonstrating the production of (R)-1-[3,5-bis(trifluoromethyl)phenyl]ethanamine using a bienzyme cascade system, thus providing valuable insights into the biosynthesis of chiral amines.


Assuntos
Álcool Desidrogenase , Transaminases , Álcool Desidrogenase/genética , Transaminases/genética , Transaminases/metabolismo , Plasmídeos/genética , Aminação , Estereoisomerismo
14.
Pathol Res Pract ; 240: 154192, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36399929

RESUMO

Long intergenic non-protein coding RNA 324 (LINC00324) is an example of lncRNAs whose roles in the carcinogenesis is being elucidated. This lncRNA is encoded by a gene located on 17p13.1. It has been shown to be over-expressed in a variety of cancer cell lines and tumoral tissues. However, there are few reports showing down-regulation of LINC00324 in cancer cell lines and tissues. miR-615-5p/AKT1, miR-139-5p/IGF1R, miR-769-5p/STAT3, miR-3200-5p/BCAT1 and miR-214-5p/CDK6/CCND1/MDM2/MDM4 are examples of miRNA/mRNA axes being influenced by LINC00324. LINC00324 can be regarded as a promising candidate for development of diagnostic and prognostic panels. Moreover, it can be used a therapeutic target for a wide range of cancers. The current review summarizes the evidence regarding the impact of lINC00324 in the carcinogenic processes.


Assuntos
MicroRNAs , Neoplasias , RNA Longo não Codificante , Humanos , Neoplasias/genética , Carcinogênese , RNA Longo não Codificante/genética , Carcinógenos , Proteínas Proto-Oncogênicas , Proteínas de Ciclo Celular , Transaminases
15.
Int J Med Mushrooms ; 24(11): 35-47, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36374947

RESUMO

Non-alcoholic fatty liver disease (NAFLD) is one of the most frequent, chronic liver diseases worldwide and currently has no specific therapy. Our previous study indicated the anti-NAFLD effect of Macrocybe gigantea (Massee) Pegler & Lodge in high-fat diet-fed animals. This study aimed to isolate and identify the active hepatoprotective constituents from M. gigantea using fatty acid induced steatotic HepG2 cells as in vitro model. The effect of the test materials on the viability of HepG2 cells was analyzed using MTT assay. The HepG2 cells were treated with a mixture of palmitate-oleate to induce steatosis; after 24 h of treatment with the test materials, the intracellular lipid content was estimated using Oil Red O staining. The levels of transaminases were also estimated in the spent media. Bioassay-guided isolation of hepatoprotective constituents from M. gigantea yielded two compounds viz., ergosterol and linoleic acid; their structures were confirmed using spectroscopic data. Among these two compounds, ergosterol significantly lowered the levels of intracellular triglyceride content of fatty acid induced HepG2 cells; it also lowered the leakage of transaminases. The reductions caused by linoleic acid were not statistically significant at the tested concentrations. Detailed investigations on efficacy and safety of these compounds and M. gigantea might yield some useful leads for the management of NAFLD.


Assuntos
Agaricales , Hepatopatia Gordurosa não Alcoólica , Animais , Humanos , Dieta Hiperlipídica , Ergosterol/farmacologia , Ácidos Graxos/farmacologia , Células Hep G2 , Ácido Linoleico/farmacologia , Fígado , Transaminases/farmacologia , Agaricales/química
16.
J Infect Dev Ctries ; 16(10): 1660-1663, 2022 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-36332223

RESUMO

INTRODUCTION: Drug-induced liver injury (DILI) is one of the most common causes of liver damage. A large number of drugs, dietary supplements, and herbal medications can cause hepatotoxicity. In some situations, it is difficult to distinguish between DILI and autoimmune hepatitis, especially when the mechanism is immune-mediated. Albendazole is a drug that has been used for decades for the treatment of parasitic infections in humans. One of the side effects is liver enzyme elevation, but rarely requires the discontinuation of therapy. Previous experience has shown that hypersensitivity is the most common mechanism of albendazole hepatotoxicity. CASE REPORT: Here we presented a paediatric patient in whom albendazole induced severe liver injury. In laboratory analyses, in addition to markedly elevated transaminases and parameters of cholestasis, there was also a significant increase in IgG, so autoimmune hepatitis was considered. Even though the liver histology indicated toxic liver disease, prednisolone was started. Corticosteroid therapy resulted in the complete normalization of liver function, as well as IgG. With the cessation of corticosteroid therapy, transaminases, bilirubin and gamma-glutamyl transferase (GGT) remained within normal levels, but an increase in anti-smooth muscle antibodies (SMA) was noted in immunological analyses after one year of follow-up. CONCLUSIONS: Immune-mediated hepatotoxicity from albendazole is one possible mechanism of liver injury. The use of albendazole in the treatment of parasitic infections, especially in children, requires close monitoring. The question remains as to whether albendazole is a drug that can induce autoimmune hepatitis in the paediatric population.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Hepatite A , Hepatite Autoimune , Humanos , Criança , Hepatite Autoimune/tratamento farmacológico , Hepatite Autoimune/etiologia , Hepatite Autoimune/patologia , Albendazol/efeitos adversos , Doença Hepática Induzida por Substâncias e Drogas/diagnóstico , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Doença Aguda , Imunoglobulina G , Transaminases , Corticosteroides
17.
Reprod Biol ; 22(4): 100702, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36327671

RESUMO

Circular RNA (circRNA) have been shown to exert vital functions in the pathological progressions of ovarian cancer (OC). Herein, this study aimed to investigate the role and mechanisms of circ_0015756 in OC progression. Levels of circ_0015756, microRNA (miR)- 145-5p and phosphoserine aminotransferase 1 (PSAT1) were detected using quantitative real-time polymerase chain reaction, Western blot or immunohistochemistry assays. Cell proliferation, apoptosis, migration and invasion were determined using cell counting kit-8, 5-Ethynyl-2'-Deoxyuridine (Edu) incorporation, flow cytometry, transwell and Western blot assays. The binding interaction between miR-145-5p and circ_0015756 or PSAT1 was confirmed by bioinformatics prediction and dual-luciferase reporter assay. Tumor formation assay in nude mice was performed to determine the tumor growth in vivo. Circ_0015756 was highly expressed in OC tissues and cells. Knockdown of circ_0015756 suppressed cancer cell growth, migration and invasion in vitro, as well as impeded tumor growth in vivo. In a mechanical study, circ_0015756 directly bound to miR-145-5p, and inhibition of miR-145-5p reversed the effects of circ_0015756 knockdown on OC cells. Moreover, miR-145-5p directly targeted PSAT1, and miR-145-5p weakened OC cell growth, migration and invasion via targeting PSAT1. Importantly, further studies confirmed that circ_0015756 could indirectly regulate PSAT1 expression via sponging miR-145-5p. In all, circ_0015756 accelerated OC tumorigenesis through regulating miR-145-5p/PSAT1 axis, providing a new therapeutic target for OC.


Assuntos
MicroRNAs , Neoplasias Ovarianas , RNA Circular , Transaminases , Animais , Feminino , Humanos , Camundongos , Carcinogênese , Proliferação de Células , Camundongos Nus , MicroRNAs/genética , Neoplasias Ovarianas/genética , RNA Circular/genética , Transaminases/genética
18.
Arq Bras Cir Dig ; 35: e1694, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36449864

RESUMO

BACKGROUND: The differential diagnosis of the causal factors of acute pancreatitis is fundamental for its clinical follow-up, becoming relevant to establishing laboratory criteria that elucidate the difference between biliary and nonbiliary causes. AIM: The aim of this study was to establish criteria based on laboratory tests for the differential diagnosis between acute pancreatitis of biliary and nonbiliary causes and to identify laboratory tests with sufficient sensitivity to propose the creation of an algorithm for differential diagnosis between the causes. METHODS: The research consisted of observational analysis, with a cross-sectional design of laboratory tests of two groups of patients with acute pancreatitis: group A: nonbiliary cause and group B: biliary cause. Hematocrit, white blood cell count, lactate dehydrogenase, glucose, lipase, amylase, total bilirubin, oxalacetic transaminase, pyruvic transaminase, gamma-glutamyltransferase, and alkaline phosphatase were investigated. Data were submitted to nonparametric tests and receiver operating characteristics. RESULTS: Hematocrit values, number of leukocytes, lactate dehydrogenase, and glucose showed no significant difference between the groups (p>0.1). Lipase, amylase, total bilirubin, oxalacetic transaminase, pyruvic transaminase, gamma-glutamyltransferase, and alkaline phosphatase values showed a significant difference between groups (p<0.05). The oxalacetic transaminase, pyruvic transaminase, and alkaline phosphatase tests were most sensitive in determining the biliary cause, allowing the establishment of a cutoff point by the receiver operating characteristic test: pyruvic transaminase: 123.0 U/L (sensitivity: 69.2%; specificity: 81.5%), oxalacetic transaminase: 123.5 U/L (sensitivity: 57.3%; specificity: 78.8%), and alkaline phosphatase: 126.5 U/L (sensitivity: 66.1%; specificity: 69.4%), from which the probability of a correct answer increases. CONCLUSION: It was possible to establish criteria based on laboratory tests for the differential diagnosis between acute pancreatitis of biliary and nonbiliary origin; however, the tests did not show enough sensitivity to propose the creation of an algorithm for differential diagnosis between the same causes.


Assuntos
Pancreatite , Humanos , Diagnóstico Diferencial , Pancreatite/diagnóstico , gama-Glutamiltransferase , Fosfatase Alcalina , Doença Aguda , Estudos Transversais , Amilases , Lipase , Transaminases , Bilirrubina
20.
Int J Mol Sci ; 23(20)2022 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-36293465

RESUMO

The scarcity of livers for transplantation is rising, and new strategies to extend the donor pool are being explored. One solution is to use marginal grafts from extended criteria donors, presenting, for example, liver steatosis. As current preservation solutions (UW, HTK, and IGL-1) were mainly designed for static cold storage (SCS) only, IGL-2, a modified version of IGL-1, was developed to be suitable for SCS and dynamic preservation, such as hypothermic oxygenated perfusion (HOPE). In this study, we investigated the combined effect of IGL-2, SCS, and HOPE and compared it to the most used preservation solution (UW and Belzer MPS). Four experimental groups with six rats each were designed using Zucker rats. All groups underwent 24 h of SCS (in IGL-2 or UW) + 2 h of normothermic machine perfusion (NMP) at 37 °C to mimic transplantation. HOPE (IGL-2 or Belzer MPS) was performed before NMP on half of the rats. The IGL-2 group demonstrated lower transaminases and a significantly low level of glycocalyx proteins, CASP3, and HMGB1 in the perfusates. These data suggest the protective role of IGL-2 for fatty livers in preserving the endothelial glycocalyx, apoptosis, and inflammation.


Assuntos
Fígado Gorduroso , Proteína HMGB1 , Soluções para Preservação de Órgãos , Ratos , Animais , Preservação de Órgãos , Soluções para Preservação de Órgãos/farmacologia , Soluções para Preservação de Órgãos/metabolismo , Proteína HMGB1/metabolismo , Caspase 3/metabolismo , Ratos Zucker , Fígado Gorduroso/metabolismo , Fígado/metabolismo , Transaminases/metabolismo , Perfusão
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