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1.
Artigo em Inglês | MEDLINE | ID: mdl-36231760

RESUMO

The endocannabinoid (eCB) system is critically involved in the modulation of synaptic transmission in the central nervous system, playing an important role in the control of emotional responses, neurodevelopment and synaptic plasticity among other functions. The eCB system is also present in the retina, with studies indicating changes in function after application of cannabinoid receptor agonists, antagonists and in knockout models. Whether eCBs are tonically released in the retina and their physiological functions is, however, still unknown. We investigated the role of the eCB system in the modulation of response strength of retinal ganglion cells (RGCs) to light stimulation, their receptive field organization, contrast sensitivity and excitability properties by performing whole-cell patch-clamp recordings in mouse RGCs before and after bath application of URB597, an inhibitor of the enzyme that degrades the eCB anandamide. Our results show that URB597 application leads to a reduction in the strength of synaptic inputs onto RGCs but paradoxically increases RGC excitability. In addition, URB597 was shown to modulate receptive field organization and contrast sensitivity of RGCs. We conclude that tonically released eCBs modulate retinal signaling by acting on traditional cannabinoid receptors (CB1R/CB2R) as well as on non-cannabinoid receptor targets. Thus, a thorough understanding of the effects of drugs that alter the endogenous cannabinoid levels and of exogenous cannabinoids is necessary to fully comprehend the impact of their medical as well as recreational use on vision.


Assuntos
Agonistas de Receptores de Canabinoides , Endocanabinoides , Animais , Benzamidas , Carbamatos/farmacologia , Endocanabinoides/metabolismo , Endocanabinoides/farmacologia , Camundongos , Retina
2.
Am J Trop Med Hyg ; 107(4_Suppl): 21-32, 2022 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-36228916

RESUMO

The Program for Resistance, Immunology, Surveillance, and Modeling of Malaria (PRISM) has been conducting malaria research in Uganda since 2010 to improve the understanding of the disease and measure the impact of population-level control interventions in the country. Here, we will summarize key research findings from a series of studies addressing routine health facility-based surveillance, comprehensive cohort studies, studies of the molecular epidemiology, and transmission of malaria, evaluation of antimalarial drug efficacy, and resistance across the country, and assessments of insecticide resistance. Among our key findings are the following. First, we found that in historically high transmission areas of Uganda, a combination of universal distribution of long-lasting insecticidal-treated nets (LLINs) and sustained indoor residual spraying (IRS) of insecticides lowered the malaria burden greatly, but marked resurgences occurred if IRS was discontinued. Second, submicroscopic infections are common and key drivers of malaria transmission, especially in school-age children (5-15 years). Third, markers of drug resistance have changed over time, with new concerning emergence of markers predicting resistance to artemisinin antimalarials. Fourth, insecticide resistance monitoring has demonstrated high levels of resistance to pyrethroids, appreciable impact of the synergist piperonyl butoxide to pyrethroid susceptibility, emerging resistance to carbamates, and complete susceptibility of malaria vectors to organophosphates, which could have important implications for vector control interventions. Overall, PRISM has yielded a wealth of information informing researchers and policy-makers on the malaria burden and opportunities for improved malaria control and eventual elimination in Uganda. Continued studies concerning all the types of surveillance discussed above are ongoing.


Assuntos
Antimaláricos , Artemisininas , Mosquiteiros Tratados com Inseticida , Inseticidas , Malária , Piretrinas , Adolescente , Animais , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Artemisininas/farmacologia , Carbamatos/farmacologia , Criança , Pré-Escolar , Humanos , Resistência a Inseticidas , Inseticidas/farmacologia , Inseticidas/uso terapêutico , Malária/tratamento farmacológico , Malária/epidemiologia , Malária/prevenção & controle , Controle de Mosquitos , Mosquitos Vetores , Organofosfatos/farmacologia , Butóxido de Piperonila/farmacologia , Piretrinas/farmacologia , Uganda/epidemiologia
3.
J Med Chem ; 65(18): 12334-12345, 2022 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-36074125

RESUMO

Venglustat is a known allosteric inhibitor for ceramide glycosyltransferase, investigated in diseases caused by lysosomal dysfunction. Here, we identified venglustat as a potent inhibitor (IC50 = 0.42 µM) of protein N-terminal methyltransferase 1 (NTMT1) by screening 58,130 compounds. Furthermore, venglustat exhibited selectivity for NTMT1 over 36 other methyltransferases. The crystal structure of NTMT1-venglustat and inhibition mechanism revealed that venglustat competitively binds at the peptide substrate site. Meanwhile, venglustat potently inhibited protein N-terminal methylation levels in cells (IC50 = 0.5 µM). Preliminary structure-activity relationships indicated that the quinuclidine and fluorophenyl parts of venglustat are important for NTMT1 inhibition. In summary, we confirmed that venglustat is a bona fide NTMT1 inhibitor, which would advance the study on the biological roles of NTMT1. Additionally, this is the first disclosure of NTMT1 as a new molecular target of venglustat, which would cast light on its mechanism of action to guide the clinical investigations.


Assuntos
Carbamatos/farmacologia , Inibidores Enzimáticos , Metiltransferases , Quinuclidinas/farmacologia , Carbamatos/química , Ceramidas , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Glicosiltransferases/metabolismo , Metilação , Quinuclidinas/química
4.
Int J Mol Sci ; 23(15)2022 Jul 30.
Artigo em Inglês | MEDLINE | ID: mdl-35955600

RESUMO

Sesamol is a compound reported to have anti-melanogenesis and anti-melanoma actions. Sesamol, however, has low intracellular drug concentration and fast excretion, which can limit its benefits in the clinic. To overcome this drawback and increase intracellular delivery of sesamol into the target melanoma, research has focused on L-type amino acid transporter 1 (LAT1)-mediated prodrug delivery into melanoma cells. The sesamol prodrug was designed by conjugating sesamol with L-phenylalanine at the para position with a carbamate bond. LAT1 targeting was evaluated vis-à-vis a competitive [14C]-leucine uptake inhibition. The sesamol prodrug has a higher [14C]-leucine uptake inhibition than sesamol in human LAT1-transfected HEK293 cells. Moreover, the sesamol prodrug was taken up by LAT1-mediated transport into SK-MEL-2 cells more effectively than sesamol. The sesamol prodrug underwent complete hydrolysis, releasing the active sesamol at 72 h, which significantly exerted its cytotoxicity (IC50 of 29.3 µM) against SK-MEL-cells more than sesamol alone. Taken together, the strategy for LAT1-mediated prodrug delivery has utility for the selective uptake of sesamol, thereby increasing its intracellular concentration and antiproliferation activity, targeting melanoma SK-MEL-2 cells that overexpress the LAT1 protein. The sesamol prodrug thus warrants further evaluation in an in vivo model.


Assuntos
Melanoma , Pró-Fármacos , Aminoácidos/metabolismo , Benzodioxóis , Transporte Biológico , Carbamatos/farmacologia , Células HEK293 , Humanos , Transportador 1 de Aminoácidos Neutros Grandes/metabolismo , Leucina/metabolismo , Melanoma/tratamento farmacológico , Melanoma/metabolismo , Fenóis , Fenilalanina/metabolismo , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Síndrome
5.
Int J Mol Sci ; 23(15)2022 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-35955909

RESUMO

Colorectal cancer (CRC) is one of the most lethal cancers worldwide. If detected on time, surgery can expand life expectations of patients up to five more years. However, if metastasis has grown deliberately, the use of chemotherapy can play a crucial role in CRC control. Moreover, the lack of selectivity of current anticancer drugs, plus mutations that occur in cancerous cells, demands the development of new chemotherapeutic agents. Several steroids have shown their potentiality as anticancer agents, while some other compounds, such as Taxol and its derivatives bearing a carbamate functionality, have reached the market. In this article, the synthesis, characterization, and antiproliferative activity of four steroidal carbamates on mouse colon carcinoma CT26WT cells are described. Carbamate synthesis occurred via direct reaction between diosgenin, its B-ring modified derivative, and testosterone with phenyl isocyanate under a Brønsted acid catalysis. All obtained compounds were characterized by 1H and 13C Nuclear Magnetic Resonance (NMR), High Resolution Mass Spectroscopy (HRMS); their melting points are also reported. Results obtained from antiproliferative activity assays indicated that carbamates compounds have inhibitory effects on the growth of this colon cancer cell line. A molecular docking study carried out on Human Prostaglandin E Receptor (EP4) showed a high affinity between carbamates and protein, thus providing a valuable theoretical explanation of the in vitro results.


Assuntos
Antineoplásicos , Carcinoma , Neoplasias do Colo , Animais , Antineoplásicos/química , Carbamatos/farmacologia , Linhagem Celular Tumoral , Proliferação de Células , Neoplasias do Colo/tratamento farmacológico , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Camundongos , Simulação de Acoplamento Molecular , Estrutura Molecular , Esteroides/química , Relação Estrutura-Atividade
6.
Braz J Infect Dis ; 26(4): 102388, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35905930

RESUMO

BACKGROUND AND AIMS: Treatment of hepatitis C with direct antiviral agents (DAA) is associated with almost 95% of sustained virological response. However, some patients need retreatment. In Brazil, it should be done according to the Ministry of Health guidelines, frequently updated to include newly available drugs. This study aimed to conduct a national survey about the characteristics and outcomes of retreatment of hepatitis C in previously non-responders to DAAs. PATIENTS AND METHODS: Institutions from all over the country were invited to participate in a national registry for retreatment, including information about clinical and epidemiological characteristics of the patients, type and outcomes of retreatment regimens. Only patients previously treated with interferon-free regimens were included. RESULTS: As previous treatments the distribution was: SOF/DCV (56%), SOF/SIM (22%), 3D (11%), SOF/LED (6%) and SOF/RBV (5%). For retreatment the most frequently used drugs were SOF/GP (46%), SOF/DCV (23%) and SOF/VEL (11%). From 159 patients retreated, 132/159 (83%) had complete information in the registry and among them only seven patients were non-responders (SVR of 94.6%). All retreatments were well tolerated, without any serious adverse events or interruptions. CONCLUSION: The retreatment of patients previously non-responders to DAAs was associated with high rate of SVR in this sample of Brazilian patients. This finding allows us to conclude that the retreatment options available in the public health system in Brazil are effective and safe and are an important component of the strategy of elimination of hepatitis C in our country.


Assuntos
Hepatite C Crônica , Hepatite C , Antivirais , Brasil , Carbamatos/farmacologia , Carbamatos/uso terapêutico , Quimioterapia Combinada , Genótipo , Hepacivirus/genética , Hepatite C/complicações , Hepatite C/tratamento farmacológico , Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Humanos , Retratamento , Ribavirina/farmacologia , Sofosbuvir/uso terapêutico , Resultado do Tratamento , Valina
7.
Eur J Med Chem ; 240: 114606, 2022 Oct 05.
Artigo em Inglês | MEDLINE | ID: mdl-35858523

RESUMO

Alzheimer's disease (AD), as the fourth leading cause of death among the elderly worldwide, has brought enormous challenge to the society. Due to its extremely complex pathogeneses, the development of multi-target directed ligands (MTDLs) becomes the major strategy for combating AD. Carbamate moiety, as an essential building block in the development of MTDLs, exhibits structural similarity to neurotransmitter acetylcholine (ACh) and has piqued extensive attention in discovering multifunctional cholinesterase inhibitors. To date, numerous preclinical studies demonstrate that carbamate-based cholinesterase inhibitors can prominently increase the level of ACh and improve cognition impairments and behavioral deficits, providing a privileged strategy for the treatment of AD. Based on the recent research focus on the novel cholinesterase inhibitors with multiple biofunctions, this review aims at summarizing and discussing the most recent studies excavating the potential carbamate-based MTDLs with cholinesterase inhibition efficacy, to accelerate the pace of pleiotropic cholinesterase inhibitors for coping AD.


Assuntos
Doença de Alzheimer , Inibidores da Colinesterase , Idoso , Doença de Alzheimer/tratamento farmacológico , Carbamatos/farmacologia , Carbamatos/uso terapêutico , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Humanos , Ligantes
8.
Bioorg Chem ; 127: 105993, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35834980

RESUMO

In this work, based on the potential anti-AD molecule previously studied by our group, we continue to introduce different substituents at different positions to improve both drug-like properties and on target activities. 33 N-salicyloyl tryptamine-carbamate hybrids were designed, synthesized and evaluated as cholinesterase inhibitors. H327 was the most potent BChE inhibitor (eqBChE IC50 = 0.057 ± 0.005 µM), and showed threefold improved inhibitory potency than the positive drug rivastigmine (eqBChE IC50 = 0.19 ± 0.001 µM). In addition, H327 as a pseudo-irreversible BChE inhibitor was endowed with neuroprotective, antioxidative and anti-neuroinflammatory properties. Cytotoxicity and acute toxicity tests confirmed the safety of compound H327. The pharmacokinetics study showed that compound H327 had a longer T1/2 time and higher bioavailability than the lead compound 1 g. Compound H327 was able to cross the blood-brain barrier (BBB) in vivo. Moreover, the behavioral tests showed that compound H327 could significantly improve scopolamine-induced cognitive impairment in vivo. Overall, these results demonstrated that compound H327 is a promising multi-target agent for the treatment of AD.


Assuntos
Doença de Alzheimer , Fármacos Neuroprotetores , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides , Carbamatos/farmacologia , Carbamatos/uso terapêutico , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Humanos , Estrutura Molecular , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Relação Estrutura-Atividade , Triptaminas/farmacologia , Triptaminas/uso terapêutico
9.
Molecules ; 27(11)2022 Jun 04.
Artigo em Inglês | MEDLINE | ID: mdl-35684552

RESUMO

Natural cytokinines are a promising group of cytoprotective and anti-tumor agents. In this research, we synthesized a set of aryl carbamate, pyridyl urea, and aryl urea cytokinine analogs with alkyl and chlorine substitutions and tested their antiproliferative activity in MDA-MB-231, A-375, and U-87 MG cell lines, and cytoprotective properties in H2O2 and CoCl2 models. Aryl carbamates with the oxamate moiety were selectively anti-proliferative for the cancer cell lines tested, while the aryl ureas were inactive. In the cytoprotection studies, the same aryl carbamates were able to counteract the CoCl2 cytotoxicity by 3-8%. The possible molecular targets of the aryl carbamates during the anti-proliferative action were the adenosine A2 receptor and CDK2. The obtained results are promising for the development of novel anti-cancer therapeutics.


Assuntos
Carbamatos , Ureia , Carbamatos/farmacologia , Linhagem Celular , Cloro/química , Halogênios/química , Peróxido de Hidrogênio/química , Relação Estrutura-Atividade , Ureia/farmacologia
10.
Exp Neurol ; 355: 114141, 2022 09.
Artigo em Inglês | MEDLINE | ID: mdl-35691372

RESUMO

Anti-seizure drug (ASD) targets are widely expressed in both excitatory and inhibitory neurons. It remains unknown if the action of an ASD upon inhibitory neurons could counteract its beneficial effects on excitatory neurons (or vice versa), thereby reducing the efficacy of the ASD. Here, we examine whether the efficacy of the ASD retigabine (RTG) is altered after removal of the Kv7 potassium channel subunit KCNQ2, one of its drug targets, from parvalbumin-expressing interneurons (PV-INs). Parvalbumin-Cre (PV-Cre) mice were crossed with Kcnq2-floxed (Kcnq2fl/fl) mice to conditionally delete Kcnq2 from PV-INs. In these conditional knockout mice (cKO, PV-Kcnq2fl/fl), RTG (10 mg/kg, i.p.) significantly delayed the onset of either picrotoxin (PTX, 10 mg/kg, i.p)- or kainic acid (KA, 30 mg/kg, i.p.)-induced convulsive seizures compared to vehicle, while RTG was not effective in wild-type littermates (WT). Immunostaining for KCNQ2 and KCNQ3 revealed that both subunits were enriched at axon initial segments (AISs) of hippocampal CA1 PV-INs, and their specific expression was selectively abolished in cKO mice. Accordingly, the M-currents recorded from CA1 PV-INs and their sensitivity to RTG were significantly reduced in cKO mice. While the ability of RTG to suppress CA1 excitatory neurons in hippocampal slices was unchanged in cKO mice, its suppressive effect on the spike activity of CA1 PV-INs was significantly reduced compared with WT mice. In addition, the RTG-induced suppression on intrinsic membrane excitability of PV-INs in WT mice was significantly reduced in cKO mice. These findings suggest that preventing RTG from suppressing PV-INs improves its anticonvulsant effect.


Assuntos
Parvalbuminas , Fenilenodiaminas , Animais , Carbamatos/farmacologia , Carbamatos/uso terapêutico , Interneurônios/metabolismo , Canal de Potássio KCNQ2/genética , Canal de Potássio KCNQ2/metabolismo , Camundongos , Proteínas do Tecido Nervoso/metabolismo , Parvalbuminas/metabolismo , Fenilenodiaminas/farmacologia , Fenilenodiaminas/uso terapêutico
11.
ChemMedChem ; 17(16): e202200262, 2022 08 17.
Artigo em Inglês | MEDLINE | ID: mdl-35687532

RESUMO

The KV 7 potassium channel openers flupirtine and retigabine have been valuable options in the therapy of pain and epilepsy. However, as a result of adverse reactions, both drugs are currently no longer in therapeutic use. The flupirtine-induced liver injury and the retigabine linked tissue discolouration do not appear related at first glance; nevertheless, both events can be attributed to the triaminoaryl scaffold, which is affected by oxidation leading to elusive reactive quinone diimine or azaquinone diimine metabolites. Since the mechanism of action, i. e. KV 7 channel opening, seems not to be involved in toxicity, this study aimed to further develop safer replacements for flupirtine and retigabine. In a ligand-based design strategy, replacing amino substituents of the triaminoaryl core with alkyl substituents led to carba analogues with improved oxidation resistance and negligible risk of quinoid metabolite formation. In addition to these improved safety features, some of the novel analogues exhibited significantly improved KV 7.2/3 channel opening activity, indicated by an up to 13-fold increase in potency and an efficacy of up to 176 % compared to flupirtine, thus being attractive candidates for further development.


Assuntos
Carbamatos , Fenilenodiaminas , Aminopiridinas/farmacologia , Aminopiridinas/uso terapêutico , Carbamatos/farmacologia , Canais de Potássio KCNQ/metabolismo , Fenilenodiaminas/farmacologia
12.
Int J Mol Sci ; 23(9)2022 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-35563056

RESUMO

Endocannabinoids act as analgesic agents in a number of headache models. However, their effectiveness varies with the route of administration and the type of pain. In this study, we assessed the role of the fatty acid amide hydrolase inhibitor URB597 in an animal model of orofacial pain based on tooth pulp stimulation. More specifically, we assessed the effects of intracerbroventricular (i.c.v.) and intraperitoneal (i.p.) administration of URB597 on the amplitude of evoked tongue jerks (ETJ) in rats. The levels of the investigated mediators anandamide (AEA), 2-arachidonyl glycerol (2-AG), Substance P (SP), calcitonin-gene-related peptide (CGRP), endomorphin-2 (EM-2) and fatty acid amide hydrolase (FAAH) inhibitor by URB597 and receptors cannabinoid type-1 receptors (CB1R), cannabinoid type-2 receptors (CB2R) and µ-opioid receptors (MOR) were determined in the mesencephalon, thalamus and hypothalamus tissues. We have shown that increasing endocannabinoid AEA levels by both central and peripheral inhibition of FAAH inhibitor by URB597 has an antinociceptive effect on the trigemino-hypoglossal reflex mediated by CB1R and influences the activation of the brain areas studied. On the other hand, URB597 had no effect on the concentration of 2-AG in the examined brain structures and caused a significant decrease in CB2R mRNA expression in the hypothalamus only. Tooth pulp stimulation caused in a significant increase in SP, CGRP and EM-2 gene expression in the midbrain, thalamus and hypothalamus. In contrast, URB597 administered peripherally one hour before stimulation decreased the mRNA level of these endogenous neuropeptides in comparison with the control and stimulation in all examined brain structures. Our results show that centrally and peripherally administered URB597 is effective at preventing orofacial pain by inhibiting AEA catabolism and reducing the level of CGRP, SP and EM-2 gene expression and that AEA and 2-AG have different species and model-specific regulatory mechanisms. The data presented in this study may represent a new promising therapeutic target in the treatment of orofacial pain.


Assuntos
Benzamidas , Peptídeo Relacionado com Gene de Calcitonina , Carbamatos , Percepção da Dor , Amidoidrolases/genética , Animais , Benzamidas/farmacologia , Benzamidas/uso terapêutico , Carbamatos/farmacologia , Carbamatos/uso terapêutico , Endocanabinoides/metabolismo , Dor Facial/tratamento farmacológico , Percepção da Dor/efeitos dos fármacos , Alcamidas Poli-Insaturadas/metabolismo , RNA Mensageiro , Ratos , Receptor CB1 de Canabinoide/efeitos dos fármacos , Receptores de Canabinoides/efeitos dos fármacos
13.
Bioorg Chem ; 125: 105844, 2022 08.
Artigo em Inglês | MEDLINE | ID: mdl-35594720

RESUMO

A novel series of carbamate-based N-substituted tryptamine derivatives were designed and synthesized based on functional group combination strategy, and possessed both cholinesterase inhibition and neuroprotective effects. After systematically evaluating the cholinesterase inhibitory activity of 24 synthesized compounds, compound 6H6, bearing n-heptyl residue as carbamate moiety, was highlighted due to its great BChE-selective inhibition (eeAChE IC50 > 100 µM; eqBChE IC50 = 7 nM), neuronal protection, antioxidation and anti-neuroinflammation efficacy. Cytotoxicity and acute toxicity assays confirmed the safety-efficacy profiles of compound 6H6. Besides, pharmacokinetic properties and blood-brain barrier (BBB) permeability of compound 6H6 were favorable and suitable for further study in vivo. The behavioral tests revealed that compound 6H6 could remarkably improve the scop-induced ethological changes and memory impairment, suggesting compound 6H6, as an attractive pleiotropic molecule, had great promise in treating Alzheimer's disease.


Assuntos
Doença de Alzheimer , Fármacos Neuroprotetores , Acetilcolinesterase/metabolismo , Doença de Alzheimer/tratamento farmacológico , Carbamatos/química , Carbamatos/farmacologia , Carbamatos/uso terapêutico , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Inibidores da Colinesterase/uso terapêutico , Humanos , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Relação Estrutura-Atividade , Triptaminas/farmacologia , Triptaminas/uso terapêutico
14.
Mol Metab ; 61: 101510, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35504532

RESUMO

OBJECTIVES: Lysosomal acid lipase (LAL) is the key enzyme, which degrades neutral lipids at an acidic pH in lysosomes. The role of LAL in various cellular processes has mostly been studied in LAL-knockout mice, which share phenotypical characteristics with humans suffering from LAL deficiency. In vitro, the cell-specific functions of LAL have been commonly investigated by using the LAL inhibitors Lalistat-1 and Lalistat-2. METHODS: We performed lipid hydrolase activity assays and serine hydrolase-specific activity-based labeling combined with quantitative proteomics to investigate potential off-target effects of Lalistat-1 and -2. RESULTS: Pharmacological LAL inhibition but not genetic loss of LAL impairs isoproterenol-stimulated lipolysis as well as neutral triglyceride and cholesteryl ester hydrolase activities. Apart from LAL, Lalistat-1 and -2 also inhibit major cytosolic lipid hydrolases responsible for lipid degradation in primary cells at neutral pH through off-target effects. Their binding to the active center of the enzymes leads to a decrease in neutral lipid hydrolase activities in cells overexpressing the respective enzymes. CONCLUSIONS: Our findings are critically important since they demonstrate that commonly used concentrations of these inhibitors are not suitable to investigate the role of LAL-specific lipolysis in lysosomal function, signaling pathways, and autophagy. The interpretation of their effects on lipid metabolism should be taken with caution and the applied inhibitor concentrations in cell culture studies should not exceed 1 µM.


Assuntos
Carbamatos/farmacologia , Esterol Esterase , Tiadiazóis/farmacologia , Doença de Wolman , Animais , Hidrolases/metabolismo , Metabolismo dos Lipídeos , Camundongos , Esterol Esterase/metabolismo , Triglicerídeos , Doença de Wolman/genética , Doença de Wolman/metabolismo
15.
Int J Mol Sci ; 23(8)2022 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-35457225

RESUMO

Migraine is a disabling neurovascular disorder characterized by severe pain with still limited efficient treatments. Endocannabinoids, the endogenous painkillers, emerged, alternative to plant cannabis, as promising analgesics against migraine pain. In this thematic review, we discuss how inhibition of the main endocannabinoid-degrading enzymes, monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH), could raise the level of endocannabinoids (endoCBs) such as 2-AG and anandamide in order to alleviate migraine pain. We describe here: (i) migraine pain signaling pathways, which could serve as specific targets for antinociception; (ii) a divergent distribution of MAGL and FAAH activities in the key regions of the PNS and CNS implicated in migraine pain signaling; (iii) a complexity of anti-nociceptive effects of endoCBs mediated by cannabinoid receptors and through a direct modulation of ion channels in nociceptive neurons; and (iv) the spectrum of emerging potent MAGL and FAAH inhibitors which efficiently increase endoCBs levels. The specific distribution and homeostasis of endoCBs in the main regions of the nociceptive system and their generation 'on demand', along with recent availability of MAGL and FAAH inhibitors suggest new perspectives for endoCBs-mediated analgesia in migraine pain.


Assuntos
Endocanabinoides , Transtornos de Enxaqueca , Amidoidrolases/metabolismo , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Carbamatos/farmacologia , Endocanabinoides/metabolismo , Inibidores Enzimáticos/farmacologia , Humanos , Hidrólise , Canais Iônicos , Transtornos de Enxaqueca/tratamento farmacológico , Monoacilglicerol Lipases/metabolismo , Dor
16.
J Enzyme Inhib Med Chem ; 37(1): 1241-1256, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-35484855

RESUMO

An efficient method for synthesising NMDAR co-agonist Sunifiram (DM235), in addition to Sunifram-carbamate and anthranilamide hybrids, has been developed in high yields via protecting group-free stepwise unsymmetric diacylation of piperazine using N-acylbenzotiazole. Compounds 3f, 3d, and 3i exhibited promising nootropic activity by enhancing acetylecholine (ACh) release in A549 cell line. Moreover, the carbamate hybrid 3f was found to exhibit higher in vitro potency than donepezil with IC50 = 18 ± 0.2 nM, 29.9 ± 0.15 nM for 3f and donepezil, respectively. 3f was also found to effectively inhibit AChE activity in rat brain (AChE = 1.266 ng/mL) compared to tacrine (AChE = 1.137 ng/ml). An assessment of the ADMET properties revealed that compounds 3f, 3d, and 3i are drug-like and can penetrate blood-brain barrier. Findings presented here showcase highly potential cholinergic agents, with expected partial agonist activity towards glycine binding pocket of NMDAR which could lead to development and optimisation of novel nootropic drugs.


Assuntos
Inibidores da Colinesterase , Nootrópicos , Acetilcolinesterase/metabolismo , Animais , Carbamatos/farmacologia , Inibidores da Colinesterase/química , Inibidores da Colinesterase/farmacologia , Donepezila , Piperazinas , Ratos , Receptores de N-Metil-D-Aspartato
17.
Dis Markers ; 2022: 6309188, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35371345

RESUMO

Objective: Diabetes, a common endocrine and metabolic disease in clinical practice, generally manifests a certain defect in insulin secretion due to several factors, thereafter leading to a metabolic disorder such as hyperglycemia. This study was conducted to explore the clinical effects of repaglinide combined with exercise rehabilitation on improving the blood glucose of patients with diabetes. Methods: In this retrospective study, 100 patients with diabetes treated in our hospital from January 2018 to January 2020 were assessed for eligibility and recruited. They were assigned at a ratio of 1 : 1 to receive either repaglinide (control group) or repaglinide plus exercise rehabilitation (experimental group). Outcome measures include fasting blood glucose, 2 h postprandial blood glucose, glycosylated hemoglobin, time to normal blood glucose, blood glucose fluctuation, insulin dosage, adverse reactions, and blood glucose adequate rate. Results: All eligible patients showed similar pretreatment fasting blood glucose, glycosylated hemoglobin, and 2 h postprandial blood glucose (P > 0.05). After treatment, repaglinide plus exercise rehabilitation resulted in lower levels of fasting blood glucose, glycosylated hemoglobin, and 2 h postprandial blood glucose versus repaglinide alone (P < 0.05). Repaglinide plus exercise rehabilitation was associated with a significantly shorter time to normal blood glucose and a milder fluctuation versus repaglinide (P < 0.05). The incidence of adverse reactions and blood glucose adequate rate was 6% and 94% in the experimental group and 50% and 52% in the control group, respectively (P < 0.05). Conclusion: Repaglinide plus exercise rehabilitation results in effective blood glucose control and reduced incidence of adverse reactions and yields a promising efficacy, so it is worthy of clinical promotion and application.


Assuntos
Diabetes Mellitus Tipo 2 , Hipoglicemiantes , Carbamatos/farmacologia , Carbamatos/uso terapêutico , Humanos , Hipoglicemiantes/uso terapêutico , Piperidinas , Estudos Retrospectivos
18.
Braz J Biol ; 84: e253469, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35293530

RESUMO

Agriculture sector of Saudi Arabia is growing swiftly and tomato is an important crop cultivated mostly under green houses. Unfortunately, it is facing severe infestation due to divers mite species. Present study, relates to evaluation of toxicity of oxamyl against two phytophagous mites; Aculops lycopersici and Tetranychus urticae, isolated from tomato plants suffering from infestation. Simultaneous effect of oxamyl on two predatory mites; Neosiulus cucumeris and Euseius scutalis, was also evaluated. Three concentrations of oxamyl; half of the recommended dose (HRD), recommended dose (RD) and double recommended dose (DRD), were used against each mite specie to observe mortality within seven days as compared to the control. Significant mortality of 97.91% and 93.92% was observed in A. lycopersici and T. urticae, respectively at RD. In case of predatory mites; N. cucumeris and E. scutalis, mortality was 60.61% and 64.48%, respectively, under same conditions. Mortality of mites observed at HRD was insignificant and there was negligible increase in mortality at DRD. Oxamyl being less toxic to predatory mites and significantly mortal to phytophagous mites is recommended as a tool to as a tool to achieve biological control parallel to pesticidal effect.


Assuntos
Lycopersicon esculentum , Ácaros , Tetranychidae , Animais , Carbamatos/farmacologia
19.
Biochem J ; 479(3): 401-424, 2022 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-35147166

RESUMO

The extracellular signal-regulated kinase 1/2 (ERK1/2) cascade promotes cardiomyocyte hypertrophy and is cardioprotective, with the three RAF kinases forming a node for signal integration. Our aims were to determine if BRAF is relevant for human heart failure, whether BRAF promotes cardiomyocyte hypertrophy, and if Type 1 RAF inhibitors developed for cancer (that paradoxically activate ERK1/2 at low concentrations: the 'RAF paradox') may have the same effect. BRAF was up-regulated in heart samples from patients with heart failure compared with normal controls. We assessed the effects of activated BRAF in the heart using mice with tamoxifen-activated Cre for cardiomyocyte-specific knock-in of the activating V600E mutation into the endogenous gene. We used echocardiography to measure cardiac dimensions/function. Cardiomyocyte BRAFV600E induced cardiac hypertrophy within 10 d, resulting in increased ejection fraction and fractional shortening over 6 weeks. This was associated with increased cardiomyocyte size without significant fibrosis, consistent with compensated hypertrophy. The experimental Type 1 RAF inhibitor, SB590885, and/or encorafenib (a RAF inhibitor used clinically) increased ERK1/2 phosphorylation in cardiomyocytes, and promoted hypertrophy, consistent with a 'RAF paradox' effect. Both promoted cardiac hypertrophy in mouse hearts in vivo, with increased cardiomyocyte size and no overt fibrosis. In conclusion, BRAF potentially plays an important role in human failing hearts, activation of BRAF is sufficient to induce hypertrophy, and Type 1 RAF inhibitors promote hypertrophy via the 'RAF paradox'. Cardiac hypertrophy resulting from these interventions was not associated with pathological features, suggesting that Type 1 RAF inhibitors may be useful to boost cardiomyocyte function.


Assuntos
Cardiomegalia/patologia , Sistema de Sinalização das MAP Quinases/fisiologia , Miócitos Cardíacos/patologia , Proteínas Proto-Oncogênicas B-raf/fisiologia , Animais , Carbamatos/farmacologia , Carbamatos/toxicidade , Cardiomegalia/metabolismo , Tamanho Celular/efeitos dos fármacos , Células Cultivadas , Dimerização , Técnicas de Introdução de Genes , Insuficiência Cardíaca/patologia , Humanos , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mutação de Sentido Incorreto , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Mutação Puntual , Conformação Proteica/efeitos dos fármacos , Mapeamento de Interação de Proteínas , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-raf/biossíntese , Ratos , Ratos Sprague-Dawley , Sulfonamidas/farmacologia , Sulfonamidas/toxicidade
20.
Biosensors (Basel) ; 12(2)2022 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-35200343

RESUMO

In this study, a fluorometric and colorimetric dual-readout lateral flow immunoassay (LFIA) using antibody functionalized polydopamine-coated gold nanoparticles (Au@PDAs) as a probe was developed for the detection of carbendazim (CBD). Colloidal gold nanoparticles (AuNPs) were coated with polydopamines (PDA) by the oxidation of dopamine to synthesize Au@PDA nanoparticles. The Au@PDA nanoparticles mediated ZnCdSe/ZnS quantum dots (QDs) fluorescence quenching and recovery, resulting in a reverse fluorescence enhancement detection format of CBD. The CBD detection was obtained by the competition between the CBD and the immobilized antigen for Au@PDAs labelled antibody binding, resulting in a significant fluorescence increase and colorimetry decrease corresponded to the concentration of CBD. Dual readout modes were incorporated into the LFIA using the colorimetry signal under natural light and the fluorescence signal under UV light. The cut-off value in the mode of the colorimetric signal and fluorometric signal for CBD detection was 0.5 µg/mL and 0.0156 µg/mL, respectively. The sensitivity of LFIA of the fluorescence mode was 32 times higher than that of the colorimetry mode. There was negligible cross reactivity obtained by using LFIA for the determination of thiabendazole, benomyl, thiophanate-methyl, and thiophanate-ethyl. Consistent and satisfactory results have been achieved by comparing the results of Au@PDAs-QDs-LFIA and liquid chromatography-tandem mass spectrometry (LC-MS/MS) testing spiked cucumber and strawberry samples, indicating good reliability of the Au@PDAs-QDs-LFIA.


Assuntos
Nanopartículas Metálicas , Pontos Quânticos , Benzimidazóis/farmacologia , Carbamatos/farmacologia , Cromatografia Líquida , Ouro/química , Imunoensaio/métodos , Indóis/química , Nanopartículas Metálicas/química , Polímeros/química , Pontos Quânticos/química , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem
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