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1.
Artigo em Chinês | MEDLINE | ID: mdl-36725288

RESUMO

Objective: To explore the value of paraquat (PQ) intake, urine protein and myocardial enzyme indexes in judging the prognosis of patients with acute PQ poisoning. Methods: From September to December 2021, all 201 patients with acute PQ poisoning admitted to Guangzhou Twelfth People's Hospital from January 2010 to December 2019 were selected as the research objects. Based on follow-up results 60 days after poisoning, the research objects were divided into survival group (n=78) and death group (n=123) . The differences in information about poisoning, treatment plan, PQ intake, urine protein, creatine kinase, creatine kinase isoenzyme, lactate dehydrogenase, and α-hydroxybutyrate dehydrogenase between the two groups of patients were compared and analyzed. Logistic regression and Cox regression were used to analyze the correlation between poisoning outcome and PQ intake, urine protein and myocardial enzymes. ROC curve and principal component analysis were used to explore high-efficiency indicators for predicting the outcome of acute PQ poisoning. Results: The PQ intake[50 (20, 100) ml], urine protein (total rank 15570.50) , creatine kinase[ (336.36±261.96) U/L], creatine kinase isoenzyme[ (43.91±43.74) U/L], lactate dehydrogenase [ (346.01±196.50) U/L], α-hydroxybutyrate dehydrogenase content[ (271.23±11.92) U/L] of patients in the death group were all higher than the survival group[15 (10, 20) ml, 4730.50, (187.78±178.06) U/L, (18.88±15.50) U/L, (190.92±60.50) U/L, (152.60±48.34) U/L, respectively] (P<0.05) . The outcome of acute PQ poisoning was positively correlated with PQ intake, urine protein, creatine kinase, creatine kinase isoenzyme, lactate dehydrogenase, and α-hydroxybutyrate dehydrogenase (P<0.05) . Multivariate logistic regression and multivariate Cox regression analysis showed that creatine kinase, creatine kinase isoenzyme, lactate dehydrogenase and α-hydroxybutyrate dehydrogenase was positively correlated with the prognosis of patients with acute PQ poisoning (P<0.05) . ROC curve analysis and principal component analysis showed that the combined indexes of PQ intake, urine protein and myocardial enzymes had the highest efficacy and weight in judging the prognosis of patients (AUC=0.91, weight coefficient=0.19, sensitivity=0.76, specificity=0.89) . When the combined score was ≥4, the probability of accurately predicting the death of patients was as high as 91% (positive predictive value=0.91) . Conclusion: PQ intake, urine protein combined with creatine kinase, creatine kinase isoenzyme, lactate dehydrogenase, and α-hydroxybutyrate dehydrogenase has high value in predicting the prognosis of patients with acute PQ poisoning.


Assuntos
Paraquat , Intoxicação , Humanos , Isoenzimas , Creatina , Estudos Retrospectivos , Creatina Quinase , Prognóstico , Lactato Desidrogenases
2.
Microb Cell Fact ; 22(1): 1, 2023 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-36593499

RESUMO

Two laccase isoenzymes (LacA and LacB) were isolated from a novel Trichoderma harzianum S7113 isolate employing ammonium sulfate precipitation, Sephadex G100, and DEAE Sepharose ion exchange chromatography. The molecular weights of the purified LacA and LacB laccases were estimated to be 63 and 48 kDa, respectively. The two isoenzymes had their optimum activities at the same temperature (50 °C), but at slightly different pH values (pH 3.0 for LacA and pH 2.5 for LacB). LacA and LacB had the same thermal stability at 40 °C and pH stability at pH 9.0. The two isoenzymes also showed a high level of specific activity toward ABTS, where the Km values of LacA and LacB were 0.100 and 0.065 mM, whereas their Vmax values were 0.603 and 0.182 µmol min-1, respectively. LacA and LacB catalytic activity was stimulated by Mg2+, Zn2+, K+, and Ni2+, whereas it was inhibited by Hg2+ and Pb2+, ß-mercaptoethanol, EDTA, and SDS, and completely inhibited by sodium azide. Our findings indicate that purified laccase has a promising capacity for bisphenol A (BPA) bioremediation across a broad pH range. This finding opens up new opportunities for the commercialization of this technique in a variety of biotechnology-based applications, particularly for removing endocrine chemicals from the environment.


Assuntos
Isoenzimas , Lacase , Lacase/metabolismo , Isoenzimas/metabolismo , Fenóis , Concentração de Íons de Hidrogênio , Estabilidade Enzimática , Temperatura
3.
In Vivo ; 37(1): 173-181, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36593010

RESUMO

BACKGROUND/AIM: The habitual consumption of excessive fructose is associated with the onset and progression of lifestyle-related diseases, such as nonalcoholic fatty liver disease (NAFLD). In this study, we investigated the physiological changes observed when consuming a diet containing excessive fructose on the viewpoints of hepatotoxicity biological markers using a rat model and explored the biomarker candidates that could detect the effects of excessive fructose intake at an early stage. MATERIALS AND METHODS: Male rats were fed 63% high fructose diet (HFrD) ad libitum and their blood samples were collected before and at 1, 2, 3, and 4 weeks after allocation. The plasma biochemical parameters, hepatotoxic enzyme activities including alkaline phosphatase (ALP) isozymes were analyzed. RESULTS: HFrD consumption for 4-weeks created NAFLD-like symptoms, including elevated plasma lipid parameters and hepatotoxicity markers, as well as fat accumulation in the liver compared with rats consuming a control diet. Alanine aminotransferase (ALT) and glutamate dehydrogenase (GLDH) were increased from the 3rd and 2nd weeks, respectively, but no changes were observed on ALP activity. However, the daily consumption of the HFrD increased the plasma activities of liver-type ALP isozyme, and decreased plasma small intestinal-type ALP isozyme soon after the start of feeding. CONCLUSION: ALP isozyme analysis in combination with GLDH and ALT activities in the plasma samples could be a useful tool to detect the physiological changes induced by excessive fructose intake at an early stage of the development of NAFLD.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Hepatopatia Gordurosa não Alcoólica , Ratos , Masculino , Animais , Hepatopatia Gordurosa não Alcoólica/etiologia , Frutose/efeitos adversos , Isoenzimas/farmacologia , Fígado , Biomarcadores
4.
Int J Mol Sci ; 24(2)2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36674864

RESUMO

The phospholipase A2 (PLA2) superfamily of phospholipase enzymes hydrolyzes the ester bond at the sn-2 position of the phospholipids, generating a free fatty acid and a lysophospholipid. The PLA2s are amphiphilic in nature and work only at the water/lipid interface, acting on phospholipid assemblies rather than on isolated single phospholipids. The superfamily of PLA2 comprises at least six big families of isoenzymes, based on their structure, location, substrate specificity and physiologic roles. We are reviewing the secreted PLA2 (sPLA2), cytosolic PLA2 (cPLA2), Ca2+-independent PLA2 (iPLA2), lipoprotein-associated PLA2 (LpPLA2), lysosomal PLA2 (LPLA2) and adipose-tissue-specific PLA2 (AdPLA2), focusing on the differences in their structure, mechanism of action, substrate specificity, interfacial kinetics and tissue distribution. The PLA2s play important roles both physiologically and pathologically, with their expression increasing significantly in diseases such as sepsis, inflammation, different cancers, glaucoma, obesity and Alzheimer's disease, which are also detailed in this review.


Assuntos
Neoplasias , Fosfolipases A2 Secretórias , Humanos , Isoenzimas/metabolismo , Fosfolipases A2 Secretórias/metabolismo , Catálise
5.
Int J Mol Sci ; 24(2)2023 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-36674970

RESUMO

Gypensapogenin C (GPC) is one of the important aglycones of Gynostemma pentaphyllum (GP), which is structurally glucuronidated and is highly likely to bind to UGT enzymes in vivo. Due to the important role of glucuronidation in the metabolism of GPC, the UDP-glucuronosyltransferase metabolic pathway of GPC in human and other species' liver microsomes is investigated in this study. In the present study, metabolites were detected using high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS). The results show that GPC could generate a metabolite through glucuronidation in the human liver microsomes (HLMs). Additionally, chemical inhibitors combined with recombinant human UGT enzymes clarified that UGT1A4 is the primary metabolic enzyme for GPC glucuronidation in HLMs according to the kinetic analysis of the enzyme. Metabolic differential analysis in seven other species indicated that rats exhibited the most similar metabolic rate to that of humans. In conclusion, UGT1A4 is a major enzyme responsible for the glucuronidation of GPC in HLMs, and rats may be an appropriate animal model to evaluate the GPC metabolism.


Assuntos
Glucuronídeos , Espectrometria de Massas em Tandem , Humanos , Ratos , Animais , Cromatografia Líquida , Cinética , Especificidade da Espécie , Glucuronídeos/metabolismo , Isoenzimas/metabolismo , Microssomos Hepáticos/metabolismo , Glucuronosiltransferase/metabolismo , UDP-Glucuronosiltransferase 1A , Difosfato de Uridina/metabolismo
6.
J Enzyme Inhib Med Chem ; 38(1): 2170370, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36718988

RESUMO

A series of 4-methyl-1,2,3-benzoxathiazine-2,2-dioxides with various substituents in 5, 6 or 7 positions was obtained from corresponding 2'-hydroxyacetophenones in their reaction with sulphamoyl chloride. 6- and 7-aryl substituted 4-methyl-1,2,3-benzoxathiazine-2,2-dioxides were obtained from aryl substituted 2'-hydroxyacetophenonesprepared from 4- or 5-bromo-2'-hydroxyacetophenones via two-step protocol. 4-Methyl-1,2,3-benzoxathiazine-2,2-dioxides were investigated as inhibitors of four human (h) carbonic anhydrase (hCA, EC 4.2.1.1) isoforms, off-target cytosolic hCA I and II, and target transmembrane, tumour-associated hCA IX and XII. Twenty derivatives of 4-methyl-1,2,3-benzoxathiazine 2,2-dioxide were obtained. With one exception (compound2a), they mostly act as nanomolar inhibitors of target hCA IX and XII. Basically, all screened compounds express none or low inhibitory properties towards off-target hCA I. hCA II is inhibited in micromolar range. Overwhelming majority of 4-methyl-1,2,3-benzoxathiazine 2,2-dioxides express excellent selectivity towards CA IX/XII over hCA I as well as very good selectivity towards CA IX/XII over hCA II.


Assuntos
Anidrases Carbônicas , Neoplasias , Humanos , Relação Estrutura-Atividade , Inibidores da Anidrase Carbônica/farmacologia , Anidrase Carbônica IX/metabolismo , Anidrases Carbônicas/metabolismo , Antígenos de Neoplasias , Isoenzimas/metabolismo , Estrutura Molecular
7.
Eur J Med Chem ; 247: 115019, 2023 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-36580731

RESUMO

Clk1 kinase is a key modulator of the pre-mRNA alternative splicing machinery which has been proposed as a promising target for treatment of various tumour types, Duchenne's muscular dystrophy and viral infections such as HIV-1 and influenza. Most reported Clk1 inhibitors showed significant co-inhibition of Clk2 and Clk4 in particular, which limits their usefulness for deciphering the individual roles of the Clk1 isoform in physiology and disease. Herein, we present a new 5-methoxybenzothiophene scaffold, enabling for the first time selective inhibition of Clk1 even among the isoenzymes. The 3,5-difluorophenyl and 3,5-dichlorophenyl derivatives 26a and 27a (Clk1 IC50 = 1.4 and 1.7 nM, respectively) showed unprecedented selectivity factors of 15 and 8 over Clk4, and selectivity factors of 535 and 84 over Clk2. Furthermore, 26a and 27a exhibited good growth inhibitory activity in T24 cancer cells and long metabolic half-lives of almost 1 and 6.4 h, respectively. The overall favorable profile of our new Clk1 inhibitors suggests that they may be used in in vivo disease models or as probes to unravel the physiological or pathogenic roles of the Clk1 isoenzyme.


Assuntos
Influenza Humana , Isoenzimas , Humanos , Inibidores de Proteínas Quinases/farmacologia
8.
J Agric Food Chem ; 71(1): 331-346, 2023 Jan 11.
Artigo em Inglês | MEDLINE | ID: mdl-36538288

RESUMO

Pterostilbene (PTE), a dietary derivative of resveratrol, displayed pleiotropic health-promoting activities. This study aimed to explore the metabolic profiles and species differences of the phase I metabolism of PTE and to investigate subsequent detoxification after PTE bioactivation. PTE was found to be biotransformed to two pharmacologically active metabolites, pinostilbene and 3'-hydroxypterostilbene, in vivo and in vitro with substantial species differences. Human CYP1A2 was proved to be mainly responsible for the demethylation and 3'-hydroxylation of PTE, with its contribution to a demethylation of 94.5% and to a 3'-hydroxylation of 97.9%. An in vitro glutathione trapping experiment revealed the presence of an ortho-quinone intermediate formed by further oxidation of 3'-hydroxypterostilbene. Human glutathione S-transferase isoforms A2, T1, and A1 inactivated the ortho-quinone intermediate by catalyzing glutathione conjugation, implicating a potential protective pathway against PTE bioactivation-derived toxicity. Overall, this study provided a comprehensive view of PTE phase I metabolism and facilitated its further development as a promising nutraceutical.


Assuntos
Isoenzimas , Quinonas , Humanos , Resveratrol , Especificidade da Espécie , Glutationa/metabolismo
9.
Calcif Tissue Int ; 112(2): 233-242, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36571614

RESUMO

Alkaline phosphatases (ALPs) are a group of isoenzymes, situated on the external layer of the cell membrane; they catalyze the hydrolysis of organic phosphate esters present in the extracellular space. Zinc and magnesium are significant co-factors for the biological activity of these enzymes. Although ALPs are available in various body tissues and have distinct physiochemical properties, they are true isoenzymes since they catalyze a similar reaction. In the liver, ALP is cytosolic and present in the canalicular membrane of the hepatocytes. ALPs are available in placenta, ileal mucosa, kidney, bone, and liver. However, most of the ALPs in serum (over 80%) are delivered from liver and bone and in more modest quantities from the intestines. Despite the fact that alkaline phosphatases are found in numerous tissues all through the body, their exact physiological function remains largely unknown.


Assuntos
Fosfatase Alcalina , Isoenzimas , Gravidez , Feminino , Humanos , Isoenzimas/metabolismo , Placenta/metabolismo , Osso e Ossos/metabolismo , Intestinos , Fígado/metabolismo
10.
Placenta ; 131: 82-89, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36527743

RESUMO

INTRODUCTION: Drug metabolism during pregnancy is a complex process that involves maternal, placental and fetal sites of metabolism. Indeed, there is a lack of clarity provided from drug metabolism in human pregnancy due to ethical limitations. Large animal models of human pregnancy provide an opportunity to quantify activity of phase 1 drug metabolism mediated by cytochrome P450 (CYP) enzymes in the maternal, placental, and fetal compartments. Herein, we have validated a comprehensive assay to quantify maternal, placental, and fetal CYP activity. METHODS: Isolated microsomes from sheep maternal liver, placenta, and fetal liver (140d gestation, term = 150d) were incubated with CYP-specific probe drugs to quantify the activity of CYP1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A. Inhibition studies were performed to validate specificity of probe drugs. The validated assay was developed using liquid chromatography-tandem mass spectrometry (LC-MS/MS). RESULTS: CYP1A2, CYP2B6, CYP2C8, CYP2C19, CYP2D6, CYP2E1 and CYP3A were active in maternal liver. In contrast, only CYP1A2, CYP2C8 and CYP2D6 were active in the placenta, whereas CYP2B6, CYP2C8 and CYP2D6 were active in the fetal liver. Of the placental-specific CYPs validated, CYP1A2 increased in type A compared with type D placentomes, whereas CYP2C8 activity increased in type B compared with type A and C. DISCUSSION: This study has established conditions for compartment-specific CYP activity in the sheep maternal-placental-fetal unit using a validated and standardised experimental workflow. Compartment- and placentome type-specific CYP activity are important considerations when examining drug metabolism in the maternal-placental-fetal unit and in determining the impact of pregnancy complications.


Assuntos
Citocromo P-450 CYP1A2 , Citocromo P-450 CYP2E1 , Animais , Feminino , Gravidez , Cromatografia Líquida , Citocromo P-450 CYP1A2/metabolismo , Citocromo P-450 CYP2B6/metabolismo , Citocromo P-450 CYP2C19/metabolismo , Citocromo P-450 CYP2C8/metabolismo , Citocromo P-450 CYP2D6/metabolismo , Citocromo P-450 CYP2E1/metabolismo , Citocromo P-450 CYP3A/metabolismo , Sistema Enzimático do Citocromo P-450/metabolismo , Isoenzimas/metabolismo , Fígado , Microssomos Hepáticos/metabolismo , Placenta/metabolismo , Ovinos , Espectrometria de Massas em Tandem
11.
Arch Immunol Ther Exp (Warsz) ; 71(1): 2, 2022 Dec 28.
Artigo em Inglês | MEDLINE | ID: mdl-36575342

RESUMO

Primary biliary cholangitis (PBC; previously known as primary biliary cirrhosis) is a chronic inflammation-induced cholestatic process in the liver. Antimitochondrial antibodies (AMAs) are observed in around 90% of patients, which suggests that PBC is an autoimmune disease. Alcohol dehydrogenase (ADH), ADH isoenzymes and aldehyde dehydrogenase (ALDH) are localized in the liver, and they are useful markers of liver dysfunction. In this study, the activity of total ADH, ADH isoenzymes and ALDH was evaluated in the blood serum of patients with PBC. The experimental group comprised 50 PBC patients, both male and female, aged 28-67. The control group consisted of 50 healthy subjects, both male and female, aged 25-65. The serum activity of class I ADH, class II ADH and ALDH was measured by spectrofluorophotometry, whereas total ADH and class III ADH activity was determined by photometry methods. The activity of class I ADH and total ADH was significantly higher in the experimental group than in the control group (p < 0.001). An increase in class I ADH and total ADH activity indicates that the isoenzyme class I ADH is released by compromised liver cells and can be useful diagnostic markers of PBC.


Assuntos
Aldeído Desidrogenase , Cirrose Hepática Biliar , Feminino , Humanos , Masculino , Aldeído Desidrogenase/sangue , Inflamação , Isoenzimas , Cirrose Hepática Biliar/diagnóstico , Álcool Desidrogenase/sangue , Adulto , Pessoa de Meia-Idade , Idoso
12.
World J Microbiol Biotechnol ; 39(2): 42, 2022 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-36513951

RESUMO

Driven by the massive demand in recent years, the production of ß-alanine has significantly progressed in chemical and biological ways. Although the chemical method is relatively mature compared to biological synthesis, its high cost of waste disposal and environmental pollution does not meet the environmental protection standard. Hence, the biological method has become more prevalent as a potential alternative to the chemical synthesis of ß-alanine in recent years. As a result, the aspartate pathway from L-aspartate to ß-alanine (the most significant rate-limiting step in the ß-alanine synthesis) catalyzed by L-aspartate-α-decarboxylase (ADC) has become a research hotspot in recent years. Therefore, it is vital to comprehensively understand the different enzymes that possess a similar catalytic ability to ADC. This review will investigate the exploratory process of unique synthesis features and catalytic properties of ADC/ADC-like enzymes in particular creatures with similar catalytic capacity or high sequence homology. At the same time, we will discuss the different ß-alanine production methods which can apply to future industrialization.


Assuntos
Glutamato Descarboxilase , Isoenzimas , Glutamato Descarboxilase/metabolismo , Ácido Aspártico/metabolismo , beta-Alanina
13.
Nat Metab ; 4(12): 1830-1846, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36536137

RESUMO

The glycolytic enzyme lactate dehydrogenase A (LDHA) is frequently overexpressed in cancer, which promotes glycolysis and cancer. The oncogenic effect of LDHA has been attributed to its glycolytic enzyme activity. Here we report an unexpected noncanonical oncogenic mechanism of LDHA; LDHA activates small GTPase Rac1 to promote cancer independently of its glycolytic enzyme activity. Mechanistically, LDHA interacts with the active form of Rac1, Rac1-GTP, to inhibit Rac1-GTP interaction with its negative regulator, GTPase-activating proteins, leading to Rac1 activation in cancer cells and mouse tissues. In clinical breast cancer specimens, LDHA overexpression is associated with higher Rac1 activity. Rac1 inhibition suppresses the oncogenic effect of LDHA. Combination inhibition of LDHA enzyme activity and Rac1 activity by small-molecule inhibitors displays a synergistic inhibitory effect on breast cancers with LDHA overexpression. These results reveal a critical oncogenic mechanism of LDHA and suggest a promising therapeutic strategy for breast cancers with LDHA overexpression.


Assuntos
L-Lactato Desidrogenase , Neoplasias , Animais , Camundongos , Lactato Desidrogenase 5 , L-Lactato Desidrogenase/metabolismo , GTP Fosfo-Hidrolases , Isoenzimas/genética , Isoenzimas/metabolismo , Guanosina Trifosfato
14.
Molecules ; 27(21)2022 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-36364255

RESUMO

In this work, nine new bromophenol derivatives were designed and synthesized. The alkylation reactions of (2-bromo-4,5-dimethoxyphenyl)methanol (7) with substituted benzenes 8-12 produced new diaryl methanes 13-17. Targeted bromophenol derivatives 18-21 were synthesized via the O-Me demethylation of diaryl methanes with BBr3. Moreover, the synthesized bromophenol compounds were tested with some metabolic enzymes such as acetylcholinesterase (AChE), carbonic anhydrase I (CA I), and II (CA II) isoenzymes. The novel synthesized bromophenol compounds showed Ki values that ranged from 2.53 ± 0.25 to 25.67 ± 4.58 nM against hCA I, from 1.63 ± 0.11 to 15.05 ± 1.07 nM against hCA II, and from 6.54 ± 1.03 to 24.86 ± 5.30 nM against AChE. The studied compounds in this work exhibited effective hCA isoenzyme and AChE enzyme inhibition effects. The results show that they can be used for the treatment of glaucoma, epilepsy, Parkinson's as well as Alzheimer's disease (AD) after some imperative pharmacological studies that would reveal their drug potential.


Assuntos
Acetilcolinesterase , Anidrases Carbônicas , Acetilcolinesterase/metabolismo , Anidrases Carbônicas/metabolismo , Anidrase Carbônica II , Inibidores da Anidrase Carbônica/farmacologia , Metano , Inibidores da Colinesterase/farmacologia , Isoenzimas/metabolismo , Relação Estrutura-Atividade , Estrutura Molecular
15.
Medicine (Baltimore) ; 101(45): e31028, 2022 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-36397395

RESUMO

To investigate the changes to the myocardial enzyme profile and its clinical value in patients with different degrees of spleen injury. Of all patients who underwent total splenectomy due to trauma-induced spleen injury from January 2019 to January 2022 were selected, 70 patients with grade III and IV spleen injuries were selected as the experimental group. In addition, 70 patients with grade I and II were selected as control group 1, and another 70 patients as control group 2. The levels of creatine kinase (CK), creatine kinase isoenzyme (CK-MB), lactate dehydrogenase (LDH) in the 3 groups were detected before (T0) and on the 1st day (T1) after surgery, on the 3rd day (T2) and on the 7th day (T3) after surgery, and on the 14th day (T4) after surgery, respectively, to analyze the relationship with the severity of spleen injury. The spleen injury experimental group, control group 1, and control group 2 were all cured and discharged after corresponding treatment, and there was no myocardial infarction within 3 months of hospitalization and discharge follow-up. The experimental group had higher CK, CK-MB, and LDH than control group 1 and control group 2 at the same time point from T0 to T4 (P<.05); the CK and CK-MB of control group 1 were higher than those of control group 2 at the same time points from T0 to T4 (P < .05), the LDH at points T0 to T2 was higher than that of control group 2 (P < .05), and the LDH was lower at points T3 and T4. Compared with T0 in the same group, CK, CK-MB, and LDH at T1 to T4 in the 3 groups were all lower than those at T0 (P < .05). The early peripheral blood myocardial enzyme spectrum of patients with different degrees of spleen injury is increased, and the increase of myocardial enzyme spectrum is positively correlated with the severity of spleen injury, suggesting that patients with traumatic spleen injury may have myocardial damage in the early stage, and should be treated as soon as possible.


Assuntos
Isoenzimas , Baço , Humanos , Baço/cirurgia , Miocárdio , Creatina Quinase Forma MB , Creatina Quinase , L-Lactato Desidrogenase
16.
Semin Cancer Biol ; 87: 184-195, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36371026

RESUMO

Lactate dehydrogenase (LDH) is one of the crucial enzymes in aerobic glycolysis, catalyzing the last step of glycolysis, i.e. the conversion of pyruvate to lactate. Most cancer cells are characterized by an enhanced rate of tumor glycolysis to ensure the energy demand of fast-growing cancer cells leading to increased lactate production. Excess lactate creates extracellular acidosis which facilitates invasion, angiogenesis, and metastasis and affects the immune response. Lactate shuttle and lactate symbiosis is established in cancer cells, which may further increase the poor prognosis. Several genetic and phenotypic studies established the potential role of lactate dehydrogenase A (LDHA) or LDH5, the one homo-tetramer of subunit A, in cancer development and metastasis. The LDHA is considered a viable target for drug design and discovery. Several small molecules have been discovered to date exhibiting significant LDHA inhibitory activities and anticancer activities, therefore the starvation of cancer cells by targeting tumor glycolysis through LDHA inhibition with improved selectivity can generate alternative anticancer therapeutics. This review provides an overview of the role of LDHA in metabolic reprogramming and its association with proto-oncogenes and oncogenes. This review also aims to deliver an update on significant LDHA inhibitors with anticancer properties and future direction in this area.


Assuntos
L-Lactato Desidrogenase , Neoplasias , Humanos , Lactato Desidrogenase 5 , L-Lactato Desidrogenase/genética , Linhagem Celular Tumoral , Isoenzimas/genética , Isoenzimas/metabolismo , Glicólise , Ácido Láctico/metabolismo , Proliferação de Células , Neoplasias/tratamento farmacológico
17.
Nat Commun ; 13(1): 7200, 2022 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-36418293

RESUMO

Exquisitely tuned activity of protein kinase C (PKC) isozymes is essential to maintaining cellular homeostasis. Whereas loss-of-function mutations are generally associated with cancer, gain-of-function variants in one isozyme, PKCα, are associated with Alzheimer's disease (AD). Here we show that the enhanced activity of one variant, PKCα M489V, is sufficient to rewire the brain phosphoproteome, drive synaptic degeneration, and impair cognition in a mouse model. This variant causes a modest 30% increase in catalytic activity without altering on/off activation dynamics or stability, underscoring that enhanced catalytic activity is sufficient to drive the biochemical, cellular, and ultimately cognitive effects observed. Analysis of hippocampal neurons from PKCα M489V mice reveals enhanced amyloid-ß-induced synaptic depression and reduced spine density compared to wild-type mice. Behavioral studies reveal that this mutation alone is sufficient to impair cognition, and, when coupled to a mouse model of AD, further accelerates cognitive decline. The druggability of protein kinases positions PKCα as a promising therapeutic target in AD.


Assuntos
Doença de Alzheimer , Disfunção Cognitiva , Camundongos , Animais , Doença de Alzheimer/metabolismo , Proteína Quinase C-alfa/genética , Proteína Quinase C-alfa/metabolismo , Disfunção Cognitiva/genética , Modelos Animais de Doenças , Peptídeos beta-Amiloides/metabolismo , Isoenzimas
18.
Molecules ; 27(22)2022 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-36431826

RESUMO

Human carbonic anhydrase (CA, EC 4.2.1.1) (hCA) isoforms I, II, IX, and XII were investigated for their inhibitory activity with a series of new Schiff's bases based on quinazoline scaffold 4-27. The hCA I isoform was efficiently inhibited by Schiff's bases 4-6, 10-19, 22-27 and had an inhibition constant (Ki) value of 52.8-991.7 nM compared with AAZ (Ki, 250 nM). Amongst the quinazoline derivatives, the compounds 2, 3, 4, 10, 11, 16, 18, 24, 26, and 27 were proven to be effective hCA II inhibitors, with Ki values of 10.8-52.6 nM, measuring up to AAZ (Ki, 12 nM). Compounds 2-27 revealed compelling hCA IX inhibitory interest with Ki values of 10.5-99.6 nM, rivaling AAZ (Ki, 25.0 nM). Quinazoline derivatives 3, 10, 11, 13, 15-19, and 24 possessed potent hCA XII inhibitory activities with KI values of 5.4-25.5 nM vs. 5.7 nM of AAZ. Schiff's bases 7, 8, 9, and 21 represented attractive antitumor hCA IX carbonic anhydrase inhibitors (CAIs) with KI rates (22.0, 34.8, 49.2, and 45.3 nM, respectively). Compounds 5, 7, 8, 9, 14, 18, 19, and 21 showed hCA I inhibitors on hCA IX with a selectivity index of 22.46-107, while derivatives 12, 14, and 18 showed selective hCA I inhibitors on hCA XII with a selectivity profile of 45.04-58.58, in contrast to AAZ (SI, 10.0 and 43.86). Compounds 2, 5, 7-14, 19-23, and 25 showed a selectivity profile for hCA II inhibitors over hCA IX with a selectivity index of 2.02-19.67, whereas derivatives 5, 7, 8, 13, 14, 15, 17, 20, 21, and 22 showed selective hCA II inhibitors on hCA XII with a selectivity profile of 4.84-26.60 balanced to AAZ (SI, 0.48 and 2.10).


Assuntos
Anidrases Carbônicas , Quinazolinas , Humanos , Quinazolinas/farmacologia , Relação Estrutura-Atividade , Estrutura Molecular , Isoenzimas/metabolismo , Anidrases Carbônicas/metabolismo , Inibidores da Anidrase Carbônica/farmacologia , Anidrase Carbônica I , Anidrase Carbônica II
19.
Molecules ; 27(22)2022 Nov 18.
Artigo em Inglês | MEDLINE | ID: mdl-36432129

RESUMO

A novel series of twenty-five rhodamine-linked benzenesulfonamide derivatives (7a-u and 9a-d) were synthesized and screened for their inhibitory action against four physiologically relevant human (h) carbonic anhydrase (CA) isoforms, namely hCA I, hCA II, hCA IX, and hCA XII. All the synthesized molecules showed good to excellent inhibition against all the tested isoforms in the nanomolar range due to the presence of the sulfonamide as a zinc binding group. The target compounds were developed from indol-3-ylchalcone-linked benzenesulfonamide where the indol-3-ylchalcone moiety was replaced with rhodanine-linked aldehydes or isatins to improve the inhibition. Interestingly, the molecules were slightly more selective towards hCA IX and XII compared to hCA I and II. The most potent and efficient ones against hCA I were 7h (KI 22.4 nM) and 9d (KI 35.8 nM) compared to the standard drug AAZ (KI 250.0 nM), whereas in case of hCA II inhibition, the derivatives containing the isatin nucleus as a tail were preferred. Collectively, all compounds were endowed with better inhibition against hCA IX compared to AAZ (KI 25.8 nM) as well as strong potency against hCA XII. Finally, these newly synthesized molecules could be taken as potential leads for the development of isoform selective hCA IX and XII inhibitors.


Assuntos
Inibidores da Anidrase Carbônica , Rodanina , Humanos , Inibidores da Anidrase Carbônica/química , Rodanina/farmacologia , Relação Estrutura-Atividade , Estrutura Molecular , Isoenzimas/metabolismo , Sulfonamidas/química
20.
Int J Mol Sci ; 23(21)2022 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-36361903

RESUMO

Over 10 million people worldwide live with Parkinson's disease (PD) and 4% of affected people are diagnosed before the age of 50. Research on early PD-related pathways is therefore of considerable importance. Peptidylarginine deiminases (PADs) are a family of calcium-activated enzymes that, through post-translational deimination of arginine to citrulline, contribute to changes in protein function, including in pathological processes. Recent studies have highlighted roles for PADs in a range of neurological disorders including PD, but overall, investigations on PADs in Lewy body disease (LBD), including PD, are still scarce. Hence, the current pilot study aimed at performing an immunohistochemistry screen of post-mortem human brain sections from Braak stages 4-6 from PD patients, as well as patients with incidental LBD (ILBD). We assessed differences in PAD isozyme detection (assessing all five PADs), in total protein deimination/citrullination and histone H3 deimination-which is an indicator of epigenetic changes and extracellular trap formation (ETosis), which can elicit immune responses and has involvement in pathogenic conditions. The findings of our pilot study indicate that PADs and deimination are increased in cingulate cortex and hippocampus, particularly in earlier stages of the disease. PAD2 and PAD3 were the most strongly upregulated PAD isozymes, with some elevation also observed for PAD1, while PAD4 and PAD6 increase was less marked in PD brains. Total protein deimination and histone H3 deimination were furthermore increased in PD brains, with a considerable increase at earlier Braak stages, compared with controls. Our findings point to a significant contribution of PADs, which may further aid early disease biomarker discovery, in PD and other LBDs.


Assuntos
Citrulinação , Doença por Corpos de Lewy , Humanos , Desiminases de Arginina em Proteínas/metabolismo , Projetos Piloto , Histonas/metabolismo , Doença por Corpos de Lewy/metabolismo , Corpos de Lewy/metabolismo , Isoenzimas/metabolismo , Hidrolases/metabolismo
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