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1.
Eur J Med Chem ; 245(Pt 1): 114903, 2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36375336

RESUMO

Farnesoid X receptor (FXR) is an attractive target for drug discovery against non-alcoholic fatty liver disease (NAFLD). We previously reported an orally active, new-chemotype FXR agonist XJ034 by ensemble learning-driven drug discovery. However, its FXR agonistic activity and the efficacy in vivo remain to be improved. In this study, we designed and synthesized 52 derivatives, and preliminarily evaluated their FXR transactivation activity in HEK293T cells at the concentration of 10 µM. 12 FXR agonists were superior or comparable to compound XJ034, two of which showed over 9-fold activity of compound XJ034, and were as potent as OCA. The molecular docking and molecular dynamics simulations implied an additional hydrogen bond with TYR383 is involved in FXR transactivation for both compounds. According to EC50 determined by the confirmatory transactivation assay, we selected adamantan-1-yl(4-(2-amino-5-chlorophenyl)piperazin-1-yl)methanone (10a, EC50: 1.05 µM) as our lead compound. Interestingly, compound 10a had no agonistic effect on TGR5 or PPAR, and no cytotoxicity to HepG2 cells. In vivo bioassays with high-fat-diet induced C57BL/6J obese (DIO) mice have shown that compound 10a (100 mg/kg) is more effective than compound XJ034 (200 mg/kg) in improving hyperlipidemia, hepatic steatosis and insulin resistance. We also observed that compound 10a down-regulated the expression of genes involved in liver inflammation in vivo, implying its potential to treat hepatic inflammation. In summary, the present data have proved that our strategy for structural optimization is effective, and compound 10a is a promising lead compound with improved efficacy for NAFLD.


Assuntos
Hepatopatia Gordurosa não Alcoólica , Piperazinas , Receptores Citoplasmáticos e Nucleares , Animais , Humanos , Camundongos , Células HEK293 , Inflamação/metabolismo , Fígado/efeitos dos fármacos , Fígado/metabolismo , Camundongos Endogâmicos C57BL , Simulação de Acoplamento Molecular , Hepatopatia Gordurosa não Alcoólica/metabolismo , Receptores Citoplasmáticos e Nucleares/agonistas , Piperazinas/química , Piperazinas/farmacologia
2.
Eur J Med Chem ; 245(Pt 1): 114906, 2023 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-36395647

RESUMO

We have already reported the modification on the piperazine and phenyl rings of JNJ4796, a small-molecule fuse inhibitor targeting hemagglutinin (HA). In this study, we described the structure-activity relationship of the benzoxazole and tetrazole rings of JNJ4796. Many derivatives demonstrated good in vitro activity against IAV H1N1and Oseltamivir-resistant IAV H1N1 stains. Although compounds (R)-1e and (R)-1h exhibited excellent in vitro activity, high drug exposure level and low hERG inhibition, they displayed low oral efficacy. Excitedly, (R)-1a, a representative identified in our previous study, was found to show potent in vivo anti-IAV activity with the survival rates of 100%, 100% and 70% at 15, 5 and 1.67 mg/kg, respectively, comparable to JNJ4796. Currently, we are exploring different ways to ease its gastrointestinal response.


Assuntos
Antivirais , Benzoxazóis , Vírus da Influenza A Subtipo H1N1 , Piperazinas , Tetrazóis , Benzoxazóis/química , Benzoxazóis/farmacologia , Vírus da Influenza A Subtipo H1N1/efeitos dos fármacos , Piperazinas/química , Piperazinas/farmacologia , Tetrazóis/química , Tetrazóis/farmacologia , Relação Estrutura-Atividade , Antivirais/química , Antivirais/farmacologia , Humanos
3.
N Engl J Med ; 388(1): 44-54, 2023 01 05.
Artigo em Inglês | MEDLINE | ID: mdl-36546659

RESUMO

BACKGROUND: Adagrasib, an oral small-molecule inhibitor of mutant KRAS G12C protein, has shown clinical activity in pretreated patients with several tumor types, including colorectal cancer. Preclinical studies suggest that combining a KRAS G12C inhibitor with an epidermal growth factor receptor antibody could be an effective clinical strategy. METHODS: In this phase 1-2, open-label, nonrandomized clinical trial, we assigned heavily pretreated patients with metastatic colorectal cancer with mutant KRAS G12C to receive adagrasib monotherapy (600 mg orally twice daily) or adagrasib (at the same dose) in combination with intravenous cetuximab once a week (with an initial loading dose of 400 mg per square meter of body-surface area, followed by a dose of 250 mg per square meter) or every 2 weeks (with a dose of 500 mg per square meter). The primary end points were objective response (complete or partial response) and safety. RESULTS: As of June 16, 2022, a total of 44 patients had received adagrasib, and 32 had received combination therapy with adagrasib and cetuximab, with a median follow-up of 20.1 months and 17.5 months, respectively. In the monotherapy group (43 evaluable patients), a response was reported in 19% of the patients (95% confidence interval [CI], 8 to 33). The median response duration was 4.3 months (95% CI, 2.3 to 8.3), and the median progression-free survival was 5.6 months (95% CI, 4.1 to 8.3). In the combination-therapy group (28 evaluable patients), the response was 46% (95% CI, 28 to 66). The median response duration was 7.6 months (95% CI, 5.7 to not estimable), and the median progression-free survival was 6.9 months (95% CI, 5.4 to 8.1). The percentage of grade 3 or 4 treatment-related adverse events was 34% in the monotherapy group and 16% in the combination-therapy group. No grade 5 adverse events were observed. CONCLUSIONS: Adagrasib had antitumor activity in heavily pretreated patients with metastatic colorectal cancer with mutant KRAS G12C, both as oral monotherapy and in combination with cetuximab. The median response duration was more than 6 months in the combination-therapy group. Reversible adverse events were common in the two groups. (Funded by Mirati Therapeutics; KRYSTAL-1 ClinicalTrials.gov number, NCT03785249.).


Assuntos
Antineoplásicos , Cetuximab , Neoplasias Colorretais , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cetuximab/administração & dosagem , Cetuximab/efeitos adversos , Cetuximab/uso terapêutico , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/secundário , Piperazinas/uso terapêutico , Proteínas Proto-Oncogênicas p21(ras)/genética , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico
4.
Mol Cell Endocrinol ; 561: 111828, 2023 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-36526026

RESUMO

Second-generation antipsychotics (SGAs), used as the cornerstone treatment for schizophrenia and other mental disorders, can cause adverse metabolic effects (e.g. obesity and type 2 diabetes). We investigated the effects of SGAs on adipocyte differentiation and metabolism. The presence of therapeutic concentrations of aripiprazole (ARI) or its active metabolite dehydroaripiprazole (DARI) during human adipocyte differentiation impaired adipocyte glucose uptake while the expression of gene markers of fatty acid oxidation were increased. Additionally, the use of a supra-therapeutic concentration of ARI inhibited adipocyte differentiation. Furthermore, olanzapine (OLA), a highly obesogenic SGA, directly increased leptin gene expression but did not affect adipocyte differentiation and metabolism. These molecular insights are novel, and suggest that ARI, but not OLA, may directly act via alterations in adipocyte differentiation and potentially by causing a switch from glucose to lipid utilization in human adipocytes. Additionally, SGAs may effect crosstalk with other organs, such as the brain, to exert their adverse metabolic effects.


Assuntos
Antipsicóticos , Diabetes Mellitus Tipo 2 , Humanos , Antipsicóticos/efeitos adversos , Olanzapina/farmacologia , Olanzapina/metabolismo , Aripiprazol/farmacologia , Aripiprazol/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Piperazinas/metabolismo , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Adipócitos/metabolismo
6.
Bioorg Med Chem ; 78: 117131, 2023 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-36571976

RESUMO

To follow up on our previous report on bivalent compounds exhibiting potent co-operative binding at dopamine D2 receptors, we modified the structure of the linker in our earlier bivalent molecules (S)-6-((9-(((R)-5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)nonyl)-(propyl)amino)-5,6,7,8-tetrahydronaphthalen-1-ol (Ia) and (S)-6-((10-(((R)-5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)decyl)(propyl)amino)-5,6,7,8-tetrahydronaphthalen-1-ol (Ib) (Fig. 1) connecting the two pharmaophoric moieties to observe any tolerance in maintaining similar affinities and potencies. Specifically, we introduced aromatic and piperazine moieties in the linker to explore their effect. Overall, similar activities at D2 receptors as observed in our earlier study was maintained in the new molecules e.g. (6S,6'S)-6,6'-((1,4-phenylenebis(ethane-2,1-diyl))bis(propylazanediyl))bis(5,6,7,8-tetrahydronaphthalen-1-ol) (D-382) (Ki, D2 = 3.88 nM). The aromatic moiety in D-382 was next functionalized by introducing hydroxyl groups to mimic polyhydroxy natural products which are known to interact with amyloidogenic proteins. Such a transformation resulted in development of compounds like 2,5-bis(2-(((S)-5-hydroxy-1,2,3,4-tetrahydronaphthalen-2-yl)(propyl)amino)ethyl)benzene-1,4-diol (D-666) (Ki, D2 = 7.62 nM) which retained similar affinity and potency at D2 receptors. Such dihydroxyl compounds turned out to be potent inhibitors against aggregation and toxicity of recombinant alpha synuclein protein. The work reported here is in line with our overall goal to develop multifunctional dopamine agonist for symptomatic and disease modifying treatment of Parkinson's disease.


Assuntos
Agonistas de Dopamina , Receptores de Dopamina D2 , Receptores de Dopamina D2/metabolismo , Agonistas de Dopamina/farmacologia , Agonistas de Dopamina/química , alfa-Sinucleína , Receptores de Dopamina D3/agonistas , Piperazinas/farmacologia , Receptores de Dopamina D1
7.
Artigo em Inglês | MEDLINE | ID: mdl-36563654

RESUMO

Tuberculosis, and especially multidrug-resistant tuberculosis (MDR-TB), is a major global health threat which emphasizes the need to develop new agents to improve and shorten treatment of this difficult-to-manage infectious disease. Among the new agents, macozinone (PBTZ169) is one of the most promising candidates, showing extraordinary potency in vitro and in murine models against drug-susceptible and drug-resistant Mycobacterium tuberculosis. A previous analytical method using liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) was developed by our group to support phase I clinical trials of PBTZ169. These plasma sample analyses revealed the presence of several additional metabolites among which the most prominent was H2PBTZ, a reduced species obtained by dearomatization of macozinone, one of the first examples of Meisenheimer Complex (MC) metabolites identified in mammals. Identification of these new metabolites required the optimization of our original method for enhancing the selectivity between isobaric metabolites as well as for ensuring optimal stability for H2PBTZ analyses. Sample preparation methods were also developed for plasma and urine, followed by extensive quantitative validation in accordance with international bioanalytical method recommendations, which include selectivity, linearity, qualitative and quantitative matrix effect, trueness, precision and the establishment of accuracy profiles using ß-expectation tolerance intervals for known and newer analytes. The newly optimized methods have been applied in a subsequent Phase Ib clinical trial conducted in our University Hospital with healthy subjects. H2PBTZ was found to be the most abundant species circulating in plasma, underscoring the importance of measuring accurately and precisely this unprecedented metabolite. Low concentrations were found in urine for all monitored analytes, suggesting extensive metabolism before renal excretion.


Assuntos
Tuberculose Resistente a Múltiplos Medicamentos , Tuberculose , Animais , Humanos , Camundongos , Cromatografia Líquida/métodos , Mamíferos , Piperazinas , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/métodos , Tuberculose/tratamento farmacológico , Tuberculose Resistente a Múltiplos Medicamentos/tratamento farmacológico , Ensaios Clínicos Fase I como Assunto
8.
Behav Brain Res ; 417: 113588, 2022 01 24.
Artigo em Inglês | MEDLINE | ID: mdl-34547341

RESUMO

The monoamine neurotransmitter serotonin (5-HT) modulates anxiety by its activity on 5-HT2C receptors (5-HT2CR) expressed in the dorsal periaqueductal gray (dPAG). Here, we investigated the presence of 5-HT3A receptors (5-HT3AR) in the dPAG, and the interplay between 5-HT2CR and 5-HT3AR in the dPAG in mediating anxiety-like behavior in mice. We found that 5-HT3AR is expressed in the dPAG and the blockade of these receptors using intra-dPAG infusion of ondansetron (5-HT3AR antagonist; 3.0 nmol) induced an anxiogenic-like effect. The activation of 5-HT3ABR by the infusion of mCPBG [1-(m-Chlorophenyl)-biguanide; 5-HT3R agonist] did not alter anxiety-like behaviors. In addition, blockade of 5-HT3AR (1.0 nmol) prevented the anxiolytic-like effect induced by the infusion of the 5-HT2CR agonist mCPP (1-(3-chlorophenyl) piperazine; 0.03 nmol). None of the treatment effects on anxiety-like behaviors altered the locomotor activity levels. The present results suggest that the anxiolytic-like effect exerted by serotonin activity on 5-HT2CR in the dPAG is modulated by 5-HT3AR expressed in same region.


Assuntos
Ansiedade/fisiopatologia , Biguanidas/metabolismo , Ondansetron/farmacologia , Substância Cinzenta Periaquedutal/metabolismo , Receptor 5-HT2C de Serotonina/metabolismo , Receptores 5-HT3 de Serotonina/metabolismo , Serotonina/metabolismo , Animais , Comportamento Animal/efeitos dos fármacos , Masculino , Camundongos , Ondansetron/antagonistas & inibidores , Piperazinas
9.
Cancer Discov ; 12(2): 356-371, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34544752

RESUMO

Cyclin-dependent kinases 4 and 6 (CDK4/6) represent a major therapeutic vulnerability for breast cancer. The kinases are clinically targeted via ATP competitive inhibitors (CDK4/6i); however, drug resistance commonly emerges over time. To understand CDK4/6i resistance, we surveyed over 1,300 breast cancers and identified several genetic alterations (e.g., FAT1, PTEN, or ARID1A loss) converging on upregulation of CDK6. Mechanistically, we demonstrate CDK6 causes resistance by inducing and binding CDK inhibitor INK4 proteins (e.g., p18INK4C). In vitro binding and kinase assays together with physical modeling reveal that the p18INK4C-cyclin D-CDK6 complex occludes CDK4/6i binding while only weakly suppressing ATP binding. Suppression of INK4 expression or its binding to CDK6 restores CDK4/6i sensitivity. To overcome this constraint, we developed bifunctional degraders conjugating palbociclib with E3 ligands. Two resulting lead compounds potently degraded CDK4/6, leading to substantial antitumor effects in vivo, demonstrating the promising therapeutic potential for retargeting CDK4/6 despite CDK4/6i resistance. SIGNIFICANCE: CDK4/6 kinase activation represents a common mechanism by which oncogenic signaling induces proliferation and is potentially targetable by ATP competitive inhibitors. We identify a CDK6-INK4 complex that is resilient to current-generation inhibitors and develop a new strategy for more effective inhibition of CDK4/6 kinases.This article is highlighted in the In This Issue feature, p. 275.


Assuntos
Antineoplásicos/química , Neoplasias da Mama/tratamento farmacológico , Proteínas Inibidoras de Quinase Dependente de Ciclina/química , Resistencia a Medicamentos Antineoplásicos , Piperazinas/química , Inibidores de Proteínas Quinases/química , Piridinas/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Neoplasias da Mama/patologia , Linhagem Celular Tumoral/efeitos dos fármacos , Proteínas Inibidoras de Quinase Dependente de Ciclina/administração & dosagem , Proteínas Inibidoras de Quinase Dependente de Ciclina/uso terapêutico , Feminino , Humanos , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Piridinas/farmacologia , Piridinas/uso terapêutico , Proteínas Supressoras de Tumor/metabolismo
11.
Forensic Toxicol ; 40(1): 132-143, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36454490

RESUMO

PURPOSE: New psychoactive substances (NPSs) still appear on the market, mainly due to their legal status. This situation indicates and alarms that permanent recognition of the designer drug scene should be conducted. In this paper, we describe the detection of three psychoactive substances in samples collected from drug users. METHODS: Qualitative characterization was performed using liquid chromatography-high-resolution tandem mass spectrometry with a quadrupole time-of-flight analyzer, gas chromatography with mass spectrometry and nuclear magnetic resonance spectroscopy. RESULTS: In this study, we reported the detection and structural elucidation of three psychoactive substances: 1-(4-bromophenyl)piperazine (pBPP), 1-(3-chloro-4-fluorophenyl)piperazine (3,4-CFPP) and methyl 8-methyl-3-phenyl-8-azabicyclo[3.2.1]octane-4-carboxylate (troparil). CONCLUSIONS: To the best of our knowledge, this is the first report that presents an identification methodology for these substances found in illegal products. Comprehensive characterization of the NPSs presented in this paper facilitates their detection and identification by forensic and clinical laboratories.


Assuntos
Fármacos do Sistema Nervoso Central , Cocaína , Cromatografia Gasosa-Espectrometria de Massas , Piperazinas
12.
PLoS One ; 17(12): e0278842, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36520950

RESUMO

Inverse odds of participation weighting (IOPW) has been proposed to transport clinical trial findings to target populations of interest when the distribution of treatment effect modifiers differs between trial and target populations. We set out to apply IOPW to transport results from an observational study to a target population of interest. We demonstrated the feasibility of this idea with a real-world example using a nationwide electronic health record derived de-identified database from Flatiron Health. First, we conducted an observational study that carefully adjusted for confounding to estimate the treatment effect of fulvestrant plus palbociclib relative to letrozole plus palbociclib as a second-line therapy among estrogen receptor (ER)-positive, human epidermal growth factor receptor (HER2)-negative metastatic breast cancer patients. Second, we transported these findings to the broader cohort of patients who were eligible for a first-line therapy. The interpretation of the findings and validity of such studies, however, rely on the extent that causal inference assumptions are met.


Assuntos
Neoplasias da Mama , Receptor ErbB-2 , Humanos , Feminino , Receptor ErbB-2/metabolismo , Letrozol/uso terapêutico , Receptores de Estrogênio/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Piperazinas/uso terapêutico , Piridinas/uso terapêutico , Neoplasias da Mama/patologia
13.
J Med Chem ; 65(24): 16902-16917, 2022 12 22.
Artigo em Inglês | MEDLINE | ID: mdl-36475694

RESUMO

The spread of SARS-CoV-2 keeps threatening human life and health, and small-molecule antivirals are in demand. The main protease (Mpro) is an effective and highly conserved target for anti-SARS-CoV-2 drug design. Herein, we report the discovery of potent covalent non-peptide-derived Mpro inhibitors. A series of covalent compounds with a piperazine scaffold containing different warheads were designed and synthesized. Among them, GD-9 was identified as the most potent compound with a significant enzymatic inhibition of Mpro (IC50 = 0.18 µM) and good antiviral potency against SARS-CoV-2 (EC50 = 2.64 µM), similar to that of remdesivir (EC50 = 2.27 µM). Additionally, GD-9 presented favorable target selectivity for SARS-CoV-2 Mpro versus human cysteine proteases. The X-ray co-crystal structure confirmed our original design concept showing that GD-9 covalently binds to the active site of Mpro. Our nonpeptidic covalent inhibitors provide a basis for the future development of more efficient COVID-19 therapeutics.


Assuntos
COVID-19 , Humanos , SARS-CoV-2/metabolismo , Proteínas não Estruturais Virais/metabolismo , Antivirais/farmacologia , Antivirais/química , Piperazinas/farmacologia , Inibidores de Proteases/farmacologia , Inibidores de Proteases/química , Simulação de Acoplamento Molecular
14.
Artigo em Russo | MEDLINE | ID: mdl-36537633

RESUMO

The review is devoted to the actual problem of anti-relapse therapy for schizophrenia. The features of the use, efficiency, tolerability and safety of typical and atypical antipsychotics are discussed. The possibilities of using atypical antipsychotics of the third generation - partial dopamine receptor agonists - on the aripiprazole model are considered. According to numerous studies, aripiprazole, due to its unique pharmacological profile and combination of clinical factors, is the drug of first choice for anti-relapse supportive therapy of schizophrenia.


Assuntos
Antipsicóticos , Quinolonas , Esquizofrenia , Humanos , Aripiprazol/uso terapêutico , Esquizofrenia/tratamento farmacológico , Piperazinas/uso terapêutico , Quinolonas/uso terapêutico , Antipsicóticos/uso terapêutico , Recidiva
15.
Drug Des Devel Ther ; 16: 4301-4310, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36573067

RESUMO

Purpose: Evogliptin (DA-1229) is a novel, potent, and selective dipeptidyl peptidase 4 (DPP-4) inhibitor for treating type 2 diabetes mellitus. This study investigates the effect of rifampicin on evogliptin pharmacokinetics. Patients and Methods: An open-label, crossover, one-sequence study was conducted on 12 healthy subjects. Reference baseline pharmacokinetic samples were collected on day 1 after the subjects were administered a single dose of 5 mg evogliptin. After a washout period, the subjects were administered 600 mg rifampicin once daily for 10 days, from days 8 to 17, for full induction of hepatic enzyme activity. On day 17, single doses of evogliptin (5 mg) were administered along with rifampicin (600 mg). The test pharmacokinetic samples were collected with a sampling schedule identical to that used for the reference. Results: Maximum concentration (Cmax) and area under the plasma drug concentration-time curve (AUC0-96h) of evogliptin with and without co-administration of rifampicin were compared. Reference and test Cmax and AUC0-96h values of evogliptin were 4.70 ng/mL vs 4.86 ng/mL and 153.97 ng∙h/mL vs 58.83 ng∙h/mL, respectively. All adverse events were mild in intensity and considered unrelated to evogliptin administration. Conclusion: Rifampicin decreased the AUC0-96h of evogliptin by 61.8% without significantly affecting Cmax. The mechanism underlying the decrease in AUC0-96h is thought to be the induction of cytochrome P450 (CYP), especially 3A, by rifampicin. The adverse events, none of which were serious, were not significantly altered by the concomitant administration of evogliptin and rifampicin. Nevertheless, it would be prudent that evogliptin dosing should be carefully considered when co-administered with CYP3A inducers.


Assuntos
Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Humanos , Rifampina/farmacologia , Voluntários Saudáveis , Piperazinas/farmacocinética , Hipoglicemiantes , Inibidores da Dipeptidil Peptidase IV/farmacologia , Área Sob a Curva , Inibidores de Proteases , Citocromo P-450 CYP3A/metabolismo , Antivirais , Interações Medicamentosas , Estudos Cross-Over
18.
Biosensors (Basel) ; 12(12)2022 Dec 17.
Artigo em Inglês | MEDLINE | ID: mdl-36551145

RESUMO

Glutathione peroxidase 4 (GPX4) plays an important effect on ferroptosis. Down-regulating the expression of GPX4 mRNA can decrease the content of GPX4. In this work, a gold nanoflare (AuNF) probe loaded with anti-sense sequences targeting for GPX4 mRNA was designed to monitor and down-regulate intracellular GPX4 mRNA using fluorescence imaging in situ and using anti-sense technology. The results revealed that there was a marked difference for the expression of GPX4 mRNA in different cell lines, and the survival rate of cancer cells was not significantly effected when the relative mRNA and protein expression levels of GPX4 was down-regulated by AuNF probes. However, when co-treated with AuNF probes, the low expression of GPX4 strengthened erastin-induced ferroptosis, and this synergy showed a better effect on inhibiting the proliferation of cancer cells.


Assuntos
Ferroptose , Glutationa Peroxidase/genética , Glutationa Peroxidase/metabolismo , Glutationa Peroxidase/farmacologia , Ferroptose/genética , Linhagem Celular , Piperazinas/farmacologia
19.
Sensors (Basel) ; 22(24)2022 Dec 08.
Artigo em Inglês | MEDLINE | ID: mdl-36560000

RESUMO

Transformer-based object detection has recently attracted increasing interest and shown promising results. As one of the DETR-like models, DETR with improved denoising anchor boxes (DINO) produced superior performance on COCO val2017 and achieved a new state of the art. However, it often encounters challenges when applied to new scenarios where no annotated data is available, and the imaging conditions differ significantly. To alleviate this problem of domain shift, in this paper, unsupervised domain adaptive DINO via cascading alignment (CA-DINO) was proposed, which consists of attention-enhanced double discriminators (AEDD) and weak-restraints on category-level token (WROT). Specifically, AEDD is used to aggregate and align the local-global context from the feature representations of both domains while reducing the domain discrepancy before entering the transformer encoder and decoder. WROT extends Deep CORAL loss to adapt class tokens after embedding, minimizing the difference in second-order statistics between the source and target domain. Our approach is trained end to end, and experiments on two challenging benchmarks demonstrate the effectiveness of our method, which yields 41% relative improvement compared to baseline on the benchmark dataset Foggy Cityscapes, in particular.


Assuntos
Antozoários , Animais , Benchmarking , Fontes de Energia Elétrica , Piperazinas
20.
Indian J Pharmacol ; 54(5): 349-352, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36537404

RESUMO

BACKGROUND: Imatinib mesylate is the cornerstone therapy in the management of chronic myeloid leukemia (CML). Monitoring of adverse drug reactions (ADRs) of imatinib in our patients is very important to ensure their safety. Aims and Objectives: The current study aims to monitor ADRs encountered in CML patients in the chronic phase with imatinib (400 mg/day). MATERIALS AND METHODS: This prospective, observational study was conducted from November 2011 to May 2015 on 310 patients presented to the Departments of Clinical Hematology and Pharmacology of SCB MCH, Cuttack, diagnosed with CML at chronic phase. Collected ADRs were entered in the ADR reporting form (PvPI) and were analyzed for causality and severity. RESULTS: Anemia was the most common hematological ADR, whereas hyperpigmentation and nausea were the most common nonhematological ADRs reported. Maximum ADRs were mild to moderate and required no change in the treatment course. CONCLUSION: The study revealed that imatinib mesylate, a well tolerated drug, has very few cases of severe ADRs in Indian patients at the chronic stable phase of CML.


Assuntos
Antineoplásicos , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Leucemia Mielogênica Crônica BCR-ABL Positiva , Humanos , Mesilato de Imatinib/uso terapêutico , Antineoplásicos/efeitos adversos , Estudos Prospectivos , Pirimidinas/efeitos adversos , Piperazinas/efeitos adversos , Benzamidas/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/induzido quimicamente , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico
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