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1.
Medicine (Baltimore) ; 101(17): e29066, 2022 Apr 29.
Artigo em Inglês | MEDLINE | ID: mdl-35512066

RESUMO

ABSTRACT: The two non-nucleoside reverse transcriptase inhibitors (NNRTIs), efavirenz (EFV) and nevirapine (NVP), are currently the core antiretroviral drugs for treatment of HIV in sub-Saharan Africa including Botswana. The drugs are metabolized by Cytochrome P450 2B6 (CYP2B6) liver enzyme. The CYP2B6 gene that encodes for metabolism of these drugs is known to be highly polymorphic. One of the polymorphism in the CYP2B6 gene, 516G>T, particularly the 516T allele, is known to confer poor metabolism of EFV and NVP. This may lead to high levels of plasma drug concentrations and development of treatment toxicities, like central nervous system toxicities, and cutaneous and hepatic toxicities, for EFV and NVP, respectively. The CYP2B6 516G allele on the other hand is associated with an extensive metabolism of the two NNRTIs drugs. We sought to establish association between possible developments of NNRTIs toxicities with CYP2B6 516G>T variation in Botswana.A total of 316 peripheral blood mononuclear cells samples were used in a retrospective view. All the samples were from participants on EFV/NVP-containing regimen with known toxicity output. TaqMan Real-Time PCR approach was applied for assessing CYP2B6 516 allele variation in cases with treatment toxicity and those without. Analysis was performed by chi-square statistics and logistic regression analysis.The rate of poor metabolizers among participants with toxicity and those without toxicity was 18.4% and 15.1%, respectively. The CYP2B6 516 genotype distribution comparisons between the participants with toxicity and those without were not statistically different (chi-square = .326; P = .568).CYP2B6 516 variation was not associated with NNRTI toxicity. No other factors were associated with toxicity when considering age, baseline body mass index, baseline CD4, baseline HIV viral load and adherence. The results were discussed in the context of all the studies done in Botswana to date.


Assuntos
Fármacos Anti-HIV , Infecções por HIV , Alcinos , Fármacos Anti-HIV/efeitos adversos , Benzoxazinas/toxicidade , Botsuana , Ciclopropanos , Citocromo P-450 CYP2B6/genética , Genótipo , Infecções por HIV/tratamento farmacológico , Infecções por HIV/genética , Humanos , Leucócitos Mononucleares , Nevirapina/toxicidade , Polimorfismo de Nucleotídeo Único , Estudos Retrospectivos , Inibidores da Transcriptase Reversa/toxicidade
2.
AAPS PharmSciTech ; 23(5): 136, 2022 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-35534759

RESUMO

The present work was to construct a roflumilast (ROF) cream for the treatment of psoriasis and clarify the dual roles of propylene glycol monocaprylate (PGM) in both molecular mobility of the cream, and drug-skin miscibility via drug-PGM-ceramide and drug-PGM-collagen intermolecular interaction. The cream formulation was screened through the stability study and in vitro skin administration study, optimized by Plackett-Burman and Box-Behnken design, and finally verified by the in vivo tissue distribution study. PGM demonstrated a significant drug skin retention enhancement effect (Rmax in vivo = 19.5 µg/g). It increased the molecular mobility of the oil phase of the cream by decreasing the molecular interaction of oil molecules proven by the rheology study (Ec = 3.73 × 10-4 mJ·m-3). More importantly, because of the good stratum corneum (SC) compatibility (∆H = - 403.88 J/g), PGM promoted an orderly flow of SC lipids (X-ray scattering, ΔLPP = 1.18 nm) and entered the viable epidermis/dermis (VE/DE) in large quantities (RPGM = 1186 µg/g), acting as a bridge to connect the drug to collagen through two H-bonds (LengthH-bond = 2.846 Å and 3.313 Å), thus increasing the miscibility of drug and VE/DE significantly (∆H = - 310.10 J/g, Emix = 21.66 kcal/mol). In this study, a ROF cream was developed successfully and the effect of PGM on the skin retention was clarified at molecular level.


Assuntos
Aminopiridinas , Pele , Aminopiridinas/farmacologia , Benzamidas , Colágeno/farmacologia , Ciclopropanos , Preparações Farmacêuticas , Propilenoglicol/química , Propilenoglicóis , Creme para a Pele
3.
Curr Microbiol ; 79(6): 186, 2022 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-35524830

RESUMO

Although persistent sustained viral response rates are increased in hepatitis C infection following administration of direct-acting antiviral (DAA) agents, the pre-use predictive parameters of these antivirals and the clinical progression in patients post-treatment remain unknown. To obtain data pertaining to the predictive parameters prior to the use of ombitavir/paritaprevir/ritonavir + dasabuvir and the clinical progression in patients following antiviral treatment. The expression profiles of miR-223-3p, miR-17-5p, miR-24-3p, and TLR2 - 196 to - 174 del/ins polymorphisms from the blood/serum of 34 hepatitis C virus (HCV)-infected patients pre- and post-ombitavir/paritaprevir/ritonavir + dasabuvir treatment were determined by RT-qPCR. The expression levels of miR-17-5p (P < 0.001) and miR-24-3p (P = 0.011) were significantly downregulated post-treatment as compared with those pre-treatment; however, there was no significant difference between these two groups in terms of miR-223-3p expression. In addition, there was no significant difference in TLR2 genotype or allele distribution between pre-and post-treatment (P > 0.05); nevertheless, the TLR2 del allele was decreased post-treatment (16.2%) as compared with that pre-treatment (19.1%), although the difference was not statistically significant. Moreover, a significant difference was found between the mRNA levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and HCV RNA pre-and post-treatment (P < 0.05). Further, miR-17-5p expression correlated with both ALT and AST mRNA levels post-treatment (P.


Assuntos
Antivirais , Hepatite C , Compostos Macrocíclicos , MicroRNAs , 2-Naftilamina , Anilidas/uso terapêutico , Antivirais/uso terapêutico , Carbamatos/uso terapêutico , Ciclopropanos , Quimioterapia Combinada , Hepatite C/tratamento farmacológico , Humanos , Lactamas Macrocíclicas , Compostos Macrocíclicos/uso terapêutico , MicroRNAs/genética , Prolina/análogos & derivados , Prolina/uso terapêutico , RNA Mensageiro , Ribavirina/uso terapêutico , Ritonavir/uso terapêutico , Sulfonamidas , Receptor 2 Toll-Like , Resultado do Tratamento , Uracila/análogos & derivados , Valina
4.
PLoS One ; 17(5): e0267278, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35536780

RESUMO

BACKGROUND: With the recent occurrence of locally transmitted Aedes-borne viruses in the continental United States and Europe, and a lack of effective vaccines, new approaches to control Aedes aegypti and Aedes albopictus are needed. In sub-tropical urban settings in the US, Ae. albopictus is a dominant nuisance and arbovirus vector species. Unfortunately, the vector control toolbox against Ae. albopictus is not as well developed as for Ae. aegypti. Here, we evaluate the efficacy, longevity, and range of protectiveness of a novel passive metofluthrin emanator (10% active ingredient in a polyethylene mesh) against Ae. albopictus indoors and outdoors. METHODS: Four studies were conducted comparing the presence of the metofluthrin emanator to a control lacking emanator with interest in quantifying efficacy by human landing counts. Studies evaluated the effect of an emanator at varying distances from one or more human volunteers indoors and outdoors. Efficacy of emanators over time since activation was also evaluated. RESULTS: Mixed-effects models determined that sitting in close proximity to an emanator reduced landings by 89.5% outdoors and by 74.6% indoors. The emanator was determined protective when located immediately next to a human volunteer outdoors but not uniformly protective when located further away. The emanator was protective at all tested distances from the device indoors. Mortality of mosquitoes exposed to metofluthrin emanators was ~2x higher than those who were not exposed in indoor conditions. Finally, a Generalized Additive Model determined that emanators used continuously outdoors lost their effect after 2.5 weeks and stopped inducing paralysis in mosquitoes after 3.8 weeks of use. CONCLUSIONS: We show strong and lasting efficacy of 10% metofluthrin emanators against field Ae. albopictus both in indoor and outdoor conditions. Metofluthrin emanators can protect people from Ae. albopictus bites, representing a viable option for reducing human-mosquito contacts at home and beyond.


Assuntos
Aedes , Inseticidas , Aedes/fisiologia , Animais , Ciclopropanos , Fluorbenzenos , Humanos , Inseticidas/farmacologia , Controle de Mosquitos , Mosquitos Vetores
5.
Biomed Pharmacother ; 149: 112881, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-35367758

RESUMO

Mibefradil and NNC-55-0396, tetralol derivatives with a proven -ability to block T-type calcium channels in excitable cells, reduce cancer cell viability in vitro, causing cell death. Furthermore, they reduce tumor growth in preclinical models of Glioblastoma multiforme (GBM), a brain tumor of poor prognosis. Here we found that GBM cells treated with cytotoxic concentrations of NNC-55-0396 paradoxically increased cytosolic calcium levels through the activation of inositol triphosphate receptors (IP3R) and ER stress. We used pharmacological inhibitors and gene silencing to dissect the cell death pathway stimulated by NNC-55-0396 in GBM cell lines and biopsy-derived cultures. Calcium chelation or IP3R inhibition prevented NNC-55-0396-mediated cytotoxicity, indicating that ER calcium efflux is the cause of cell death. Upstream of calcium mobilization, NNC-55-0396 activated the IRE1α arm of the Unfolded Protein Response (UPR) resulting in the nuclear translocation of pro-apoptotic CHOP. Consistent with these findings, silencing IRE1α or JNK1 rescued the cell death elicited by NNC-55-0396. Therefore, we demonstrate that activation of IRE1α and calcium signaling accounts for the cytotoxicity of NNC-55-0396 in GBM cells. The delineation of the signaling pathway that mediates the abrupt cell death triggered by this compound can help the development of new therapies for GBM.


Assuntos
Glioblastoma , Apoptose , Benzimidazóis , Cálcio/metabolismo , Sinalização do Cálcio , Morte Celular , Ciclopropanos , Estresse do Retículo Endoplasmático/genética , Endorribonucleases/genética , Endorribonucleases/metabolismo , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Humanos , Naftalenos , Tetralonas , Resposta a Proteínas não Dobradas
6.
In Vivo ; 36(3): 1438-1443, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35478152

RESUMO

BACKGROUND/AIM: Patients with hepatitis C virus (HCV)-associated cirrhosis are more prone to developing type 2 diabetes mellitus than patients with any other etiology of cirrhosis. The main objective of this study was to evaluate the impact of all oral antiviral treatment with ritonavir-boosted paritaprevir/ombitasvir and dasabuvir (OBV/PTV/r + DSV) in patients with chronic genotype 1b HCV infection. PATIENTS AND METHODS: We retrospectively evaluated 806 patients who underwent antiviral therapy between December 2015 and July 2019. The laboratory data analyzed were liver function tests, kidney function tests, HCV viremia, fasting glucose levels, and glycosylated hemoglobin. RESULTS: Patients with impaired glucose metabolism were predominantly male and of older age compared to patients with normal glucose tolerance, and also had higher levels of transaminases. Proteinuria and higher creatinine levels were found in patients with impaired glucose metabolism. Overall, we found a 98.01% rate of sustained virologic response (SVR), with a non-significant difference between patients with normal and abnormal glucose metabolism. A statistically significant difference in SVR rates in patients with low degrees of fibrosis (F0-F2) versus those with advanced degrees of fibrosis (F3-F4) was found in both groups. Antiviral treatment resulted in significant decreases in fasting glucose levels and glycosylated hemoglobin levels in all patients with impaired glucose metabolism at SVR. CONCLUSION: Patients with pre-diabetes, as well as diabetic patients, achieved a better glycemic control after SVR obtained by ritonavir-boosted paritaprevir/ombitasvir and dasabuvir.


Assuntos
Diabetes Mellitus Tipo 2 , Hepatite C Crônica , Compostos Macrocíclicos , 2-Naftilamina , Anilidas/efeitos adversos , Anilidas/uso terapêutico , Antivirais , Carbamatos/efeitos adversos , Ciclopropanos , Diabetes Mellitus Tipo 2/complicações , Diabetes Mellitus Tipo 2/tratamento farmacológico , Quimioterapia Combinada , Feminino , Glucose , Hemoglobina A Glicada/uso terapêutico , Controle Glicêmico , Hepacivirus , Hepatite C Crônica/complicações , Hepatite C Crônica/tratamento farmacológico , Humanos , Lactamas Macrocíclicas , Cirrose Hepática/complicações , Cirrose Hepática/etiologia , Compostos Macrocíclicos/efeitos adversos , Compostos Macrocíclicos/uso terapêutico , Masculino , Prolina/análogos & derivados , Estudos Retrospectivos , Ritonavir/uso terapêutico , Sulfonamidas , Uracila/análogos & derivados , Valina
7.
Molecules ; 27(8)2022 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-35458668

RESUMO

The synthesis of new insecticidal gem-dimethyspiro-cyclopropanes derived from pyrrolidine-2,3-dione have been described, and their biological effect against different insect species has been evaluated. The presented results demonstrate the excellent insecticidal activity of cyclopropane 5c against Aedes aegypti and Musca domestica. Cyclopropane 5c showed the quickest knockdown and the best killing against Aedes aegypti and Musca domestica compared to trans-chrysanthemic acid and pyrethrin. The biological results of the high insecticidal activity were confirmed by the results of docking. This is evident in the binding affinity obtained for cyclopropane 5c, indicating good binding with an important active amino acid residue of the 5FT3 protein.


Assuntos
Aedes , Moscas Domésticas , Inseticidas , Animais , Ciclopropanos/farmacologia , Inseticidas/química
8.
J Am Chem Soc ; 144(16): 7465-7478, 2022 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-35420801

RESUMO

A heteroleptic dirhodium paddlewheel complex comprising three chiral carboxylate ligands and one achiral acetamidate ligand has recently been found to be uniquely effective in catalyzing the asymmetric cyclopropanation of olefins with α-stannylated (silylated and germylated) α-diazoacetate derivatives. A number of control experiments in combination with detailed computational studies provide compelling evidence that an interligand hydrogen bond between the -NH group of the amidate and the ester carbonyl group of the reactive rhodium carbene intermediate plays a quintessential role in the stereodetermining transition state. The penalty for distorting this array outweighs steric arguments and renders two of the four conceivable transitions states unviable. Based on this mechanistic insight, the design of the parent catalyst is revisited herein: placement of appropriate peripheral substituents allows high levels of diastereocontrol to be imposed upon cyclopropanation, which the original catalyst lacks. Because the new complexes allow either trans- or cis-configured stannylated cyclopropanes to be made selectively and in excellent optical purity, this transformation also marks a rare case of diastereodivergent asymmetric catalysis. The products are amenable to stereospecific cross coupling with aryl halides or alkenyl triflates; these transformations appear to be the first examples of the formation of stereogenic quaternary carbon centers by the Stille reaction; carbonylative coupling is also achieved. Moreover, tin/lithium exchange affords chiral lithium enolates, which can be intercepted with a variety of electrophilic partners. The virtues and inherent flexibility of this new methodology are illustrated by an efficient synthesis of two salinilactones, extremely scarce bacterial metabolites with signaling function involved in the self-regulatory growth inhibition of the producing strain.


Assuntos
Lítio , Ródio , Alcenos/química , Catálise , Ciclopropanos/química , Humanos , Ligantes , Ródio/química
9.
Nat Commun ; 13(1): 2268, 2022 Apr 27.
Artigo em Inglês | MEDLINE | ID: mdl-35477935

RESUMO

Emerging SARS-CoV-2 variants continue to threaten the effectiveness of COVID-19 vaccines, and small-molecule antivirals can provide an important therapeutic treatment option. The viral main protease (Mpro) is critical for virus replication and thus is considered an attractive drug target. We performed the design and characterization of three covalent hybrid inhibitors BBH-1, BBH-2 and NBH-2 created by splicing components of hepatitis C protease inhibitors boceprevir and narlaprevir, and known SARS-CoV-1 protease inhibitors. A joint X-ray/neutron structure of the Mpro/BBH-1 complex demonstrates that a Cys145 thiolate reaction with the inhibitor's keto-warhead creates a negatively charged oxyanion. Protonation states of the ionizable residues in the Mpro active site adapt to the inhibitor, which appears to be an intrinsic property of Mpro. Structural comparisons of the hybrid inhibitors with PF-07321332 reveal unconventional F···O interactions of PF-07321332 with Mpro which may explain its more favorable enthalpy of binding. BBH-1, BBH-2 and NBH-2 exhibit comparable antiviral properties in vitro relative to PF-07321332, making them good candidates for further design of improved antivirals.


Assuntos
COVID-19 , SARS-CoV-2 , Antivirais/química , Antivirais/farmacologia , COVID-19/tratamento farmacológico , Vacinas contra COVID-19 , Proteases 3C de Coronavírus , Ciclopropanos , Humanos , Lactamas , Leucina/análogos & derivados , Nitrilas , Prolina/análogos & derivados , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Inibidores de Proteases/uso terapêutico , Sulfonas , Ureia
10.
J Am Chem Soc ; 144(17): 7871-7880, 2022 May 04.
Artigo em Inglês | MEDLINE | ID: mdl-35442034

RESUMO

Fluorogenic bioorthogonal reactions enable biomolecule visualization in real time. These reactions comprise reporters that "light up" upon reaction with complementary partners. While the spectrum of fluorogenic chemistries is expanding, few transformations are compatible with live cells due to cross-reactivities or insufficient signal turn-on. To address the need for more suitable chemistries for cellular imaging, we developed a fluorogenic reaction featuring cyclopropenone reporters and phosphines. The transformation involves regioselective activation and cyclization of cyclopropenones to form coumarin products. With optimal probes, the reaction provides >1600-fold signal turn-on, one of the highest fluorescence enhancements reported to date. The bioorthogonal motifs were evaluated in vitro and in cells. The reaction was also found to be compatible with other common fluorogenic transformations, enabling multicomponent, real-time imaging. Collectively, these data suggest that the cyclopropenone-phosphine reaction will bolster efforts to track biomolecule targets in their native settings.


Assuntos
Ciclopropanos , Corantes Fluorescentes
11.
Dalton Trans ; 51(17): 6936-6943, 2022 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-35448899

RESUMO

A new class of CO-releasing molecules, M-CPOnes, was prepared combining cyclopropenone-based ligands for CO release with the modular scaffold of transition metal complexes. In proof-of-concept studies, M-CPOnes based on ZnII, FeII and CoII are stable in the dark but undergo light-triggered CO release with the cyclopropenone substituents and metal ions enabling tuning of the photophysical properties. Furthermore, the choice of metal allows the use of different spectroscopic methods to monitor photodecarbonylation from fluorescence spectroscopy to UV/vis spectroscopy and paramagnetic NMR spectroscopy. The modularity of M-CPOnes from the metal ion to the cyclopropenone substitution and potential for further functionalisation of the ligand make M-CPOnes appealing for tailored functionality in applications.


Assuntos
Complexos de Coordenação , Elementos de Transição , Monóxido de Carbono , Complexos de Coordenação/química , Ciclopropanos , Íons , Ligantes , Metais/química , Elementos de Transição/química
12.
J Smooth Muscle Res ; 58(0): 22-33, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35418530

RESUMO

CPI-17 regulates the myosin phosphatase and mediates the agonist-induced contraction of smooth muscle. PKC and ROCK phosphorylate CPI-17 at Thr38 leading to a conformational change of the central inhibitory domain (PHIN domain). The N- and C-terminal tails of CPI-17 are predicted as unstructured loops and their sequences are conserved among mammals. Here we characterized CPI-17 N- and C-terminal unstructured tails using recombinant proteins that lack the potions. Recombinant CPI-17 proteins at a physiologic level (10 µM) were doped into beta-escin-permeabilized smooth muscle strips for Ca2+ sensitization force measurement. The ectopic full-length CPI-17 augmented the PDBu-induced Ca2+ sensitization force at pCa6.3, indicating myosin phosphatase inhibition. Deletion of N- and C-terminal tails of CPI-17 attenuated the extent of PDBu-induced Ca2+-sensitization force. The N-terminal deletion dampened phosphorylation at Thr38 by protein kinase C (PKC), and the C-terminal truncation lowered the affinity to the myosin phosphatase. Under the physiologic conditions, PKC and myosin phosphatase may recognize CPI-17 N-/C-terminal unstructured tails inducing Ca2+ sensitization force in smooth muscle cells.


Assuntos
Contração Muscular , Proteínas Musculares , Animais , Cálcio/metabolismo , Ciclopropanos , Indóis , Mamíferos/metabolismo , Contração Muscular/fisiologia , Proteínas Musculares/metabolismo , Músculo Liso/metabolismo , Fosfatase de Miosina-de-Cadeia-Leve/metabolismo , Fosfoproteínas Fosfatases/metabolismo , Fosfoproteínas/metabolismo , Fosforilação , Proteína Quinase C/metabolismo
13.
Eur J Pharmacol ; 923: 174892, 2022 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-35358494

RESUMO

Montelukast, cysteinyl leukotriene receptor 1 (CysLT1R) antagonist, is used clinically for patients with asthma, chronic obstructive pulmonary diseases (COPD), and allergic rhinitis. It has been reported that CysLT1R antagonists could reduce the risks of cardiovascular diseases in animal studies. Cardiac fibrosis is one of the major causes of heart failure. But little is known about the role of Montelukast in cardiac fibrosis and its underlying mechanism. In transverse aortic constriction (TAC) mice, Montelukast improved cardiac pumping function and inhibited cardiac fibrosis by down-regulation of the proteins related to the fibrosis, such as connective tissue growth factor (CTGF), Transforming Growth Factor ß (TGF-ß), and Alpha-smooth muscle actin (α-SMA). Montelukast reduced cell proliferation and collagen production in neonatal cardiac fibroblasts (CFs) with the pretreatment of 20% serum, while down-regulating the expression of TGF-ß, CTGF and α-SMA. Molecules docking methods estimated a high affinity of Montelukast to Apelin receptor (APJ) and an effective chemical structure for Montelukast binding APJ. In Chinese hamster ovary (CHO) cells with stable overexpressing APJ, Montelukast inhibited forskolin (1 µM)-mediated cyclic adenosine monophosphate (cAMP) production and extracellular signal-regulated kinase1/2 (ERK1/2) phosphorylation, while these effects were reversed by pertussis toxin (PTX) pretreatment. APJ silence disrupted the effects of Montelukast in CFs pretreatment by serum 20%. So we concluded that Montelukast inhibited cardiac fibrosis due presumably to the coupling to the APJ-mediated Gi signaling pathway, which may be a promising therapeutic target for cardiac fibrosis.


Assuntos
Síndrome de Fadiga Crônica , Acetatos , Animais , Células CHO , Cricetinae , Cricetulus , Ciclopropanos , Fibrose , Humanos , Camundongos , Quinolinas , Receptores de Leucotrienos , Sulfetos , Fator de Crescimento Transformador beta
14.
Org Biomol Chem ; 20(15): 3145-3153, 2022 04 13.
Artigo em Inglês | MEDLINE | ID: mdl-35343561

RESUMO

The chemistry of donor-acceptor (D-A) cyclopropanes containing alkyl donors has been scantily investigated. In the present work, we have synthesized new D-A cyclopropanes containing arylethyl donors and explored their reactivity in the presence of Lewis acids. Upon treatment with SnCl4, these cyclopropanes underwent the Cloke-Wilson rearrangement to yield 3,4,5-trisubstituted γ-butyrolactones in good yields with high diastereoselectivity.


Assuntos
Ciclopropanos , Ácidos de Lewis , 4-Butirolactona , Estrutura Molecular , Estereoisomerismo
15.
Bioengineered ; 13(3): 7894-7903, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-35291928

RESUMO

Pemetrexed (PEM) is an effective chemotherapeutic drug used for the treatment of clinical non-small-cell lung cancer (NSCLC) and is reported to induce severe hepatotoxicity. Exploring potential drugs which could counteract the side effects of PEM is of great clinical interest. Here, we aim to examine the beneficial effects of Montelukast, a novel anti-asthma drug, against PEM-induced cytotoxicity in hepatocytes, and to explore the underlying mechanism. We found that Montelukast reduces cytotoxicity of PEM in hepatocytes, confirmed by its increasing cell viability and reducing lactate dehydrogenase (LDH) release. In addition, Montelukast attenuated PEM-induced oxidative stress by reducing mitochondrial reactive oxygen species (ROS), increasing reduced glutathione (GSH), and downregulating NADPH oxidase 4 (NOX-4) expression. Importantly, Montelukast suppressed PEM-induced activation of the nucleotide oligomerization domain-like receptor protein 3 (NLRP3) inflammasome and mitigated endoplasmic reticulum (ER) stress by reducing NLRP3, growth arrest, and DNA damage-inducible protein 34 (GADD34), CEBP-homologous protein (CHOP), and also blocking the eukaryotic initiation factor 2 (eIF-2α)/activating transcription factor 4 (ATF4) signaling pathway. Lastly, we found that Montelukast inhibited the transcriptional activity of nuclear factor kappa-B (NF-κB). Montelukast exerted a protective action against PEM-induced cytotoxicity in hepatocytes by mitigating ER stress and NLRP3 activation.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Acetatos , Apoptose , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Ciclopropanos , Retículo Endoplasmático/metabolismo , Hepatócitos/metabolismo , Humanos , Neoplasias Pulmonares/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Nucleotídeos/metabolismo , Estresse Oxidativo/fisiologia , Pemetrexede/metabolismo , Pemetrexede/farmacologia , Quinolinas , Espécies Reativas de Oxigênio/metabolismo , Sulfetos
16.
Biochem Biophys Res Commun ; 606: 87-93, 2022 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-35339757

RESUMO

Flavivirus, such as Dengue Virus (DENV) and Zika virus (ZIKV), infects millions of people and cause the death of thousands of people every year. Despite many efforts, there is no approved anti-flaviviral treatment available. In particular, some antiflavivirus compounds were investigated the cellular activities of DENV and ZIKV, but lacking the exploration of specific target enzyme, thereby resulting in the hindrance of structure-based drug design. One example is Montlukast, which was found to inhibit the replicon replication in DENV and ZIKV infected cells, with EC50 values as 1.03 µM (DENV) and 1.14 µM (ZIKV), while the underlying mechanism remains unclear. In our study, the inhibitory mechanisms of Montelukast against the replicon replication of DENV and ZIKV infected cells were studied by using in silico approaches including inverse virtual screening (IVS), molecular dynamics (MD) simulations and binding free energy calculation, and validated through in vitro protease assay, confirming Montelukast could bind to NS2B-NS3 proteases of DENV and ZIKV as a competitive inhibitor (IC50 for DENV: 25.65 µM, for ZIKV: 15.57 µM). Moreover, Montelukast has no potential off-target effect on NS2B-NS3 protease from thrombin and trypsin inhibitory assay. Overall, Montelukast may be used as a potential candidate to block NS2B-NS3 protease as well as lead for structural modification.


Assuntos
Flavivirus , Infecção por Zika virus , Zika virus , Acetatos , Antivirais/química , Ciclopropanos , Inibidores Enzimáticos/farmacologia , Humanos , Peptídeo Hidrolases , Inibidores de Proteases/farmacologia , Quinolinas , Sulfetos , Proteínas não Estruturais Virais/metabolismo
17.
Viruses ; 14(3)2022 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-35337021

RESUMO

Enhancing treatment uptake for hepatitis C to achieve the elimination goals set by the World Health Organization could be achieved by reducing the treatment duration. The aim of this study was to compare the sustained virological response at week 12 (SVR12) after four weeks of glecaprevir/pibrentasvir (GLE/PIB) + ribavirin compared to eight weeks of GLE/PIB and to estimate predictors for SVR12 with four weeks of treatment through a multicenter open label randomized controlled trial. Patients were randomized 2:1 (4 weeks:8 weeks) and stratified by genotype 3 and were treatment naïve of all genotypes and without significant liver fibrosis. A total of 27 patients were analyzed for predictors for SVR12, including 15 from the first pilot phase of the study. In the 'modified intention to treat' group, 100% (7/7) achieved cure after eight weeks and for patients treated for four weeks the SVR12 was 58.3% (7/12). However, patients with a baseline viral load <2 mill IU/mL had 93% SVR12. The study closed prematurely due to the low number of included patients due to the COVID-19 pandemic. Our results suggest that viral load should be taken into account when considering trials of short course treatment.


Assuntos
COVID-19 , Hepatite C Crônica , Ácidos Aminoisobutíricos , Antivirais/uso terapêutico , Benzimidazóis , Ciclopropanos , Hepatite C Crônica/tratamento farmacológico , Humanos , Lactamas Macrocíclicas , Leucina/análogos & derivados , Pandemias , Prolina/análogos & derivados , Pirrolidinas , Quinoxalinas , Ribavirina/uso terapêutico , Sulfonamidas
18.
Braz J Med Biol Res ; 55: e11877, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35239781

RESUMO

Roflumilast, a highly selective oral phosphodiesterase IV inhibitor, exerts anti-inflammatory and anti-fibrotic effects. Oral roflumilast causes gastrointestinal side effects, especially vomiting, which could be reduced by administering roflumilast via off-label routes. Inhaled roflumilast reportedly improved inflammatory and histopathological changes in asthmatic mice. The current study investigated the effects of oral and rectal roflumilast on trinitrobenzenesulfonic acid (TNBS)-induced chronic colitis in rats, an experimental model resembling human Crohn's disease. Five groups of rats (n=8) were used: normal control, TNBS-induced colitis, and three TNBS-treated colitic groups, which received oral sulfasalazine (500 mg·kg-1·day-1), oral roflumilast (5 mg·kg-1·day-1), or rectal roflumilast (5 mg·kg-1·day-1) for 15 days after colitis induction. Then, the following were assessed: the colitis activity score, tumor necrosis factor (TNF)-α, interleukin (IL)-2, and IL-6 serum levels, colonic length, and myeloperoxidase, malonaldehyde, and glutathione levels. Histological examinations employed H&E, Masson trichrome, and PAS stains in addition to immunostaining for KI-67 and TNF-α. The TNBS-induced colitis rats showed significant increases in disease activity scores, serum TNF-α, IL-2, and IL-6 levels, and colonic myeloperoxidase and malonaldehyde content. They also showed significant decreases in colonic length and glutathione levels in addition to histopathological and immunohistochemical changes. All the treatments significantly improved all these changes. Sulfasalazine provided the greatest improvement, followed by oral roflumilast, and then rectal roflumilast. In conclusion, both oral and rectal roflumilast partially improved TNBS-induced chronic colitis, suggesting the potential of roflumilast as an additional treatment for Crohn's disease.


Assuntos
Colite , Aminopiridinas/uso terapêutico , Animais , Benzamidas/efeitos adversos , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/patologia , Ciclopropanos , Modelos Animais de Doenças , Camundongos , Peroxidase , Ratos , Ácido Trinitrobenzenossulfônico/efeitos adversos , Fator de Necrose Tumoral alfa
19.
Chemistry ; 28(23): e202104364, 2022 Apr 22.
Artigo em Inglês | MEDLINE | ID: mdl-35182090

RESUMO

A facile synthesis of cyclopropenes and fluorinated cyclopropanes from readily available alkyl triflones was developed. The reaction, regardless of electronic effect, gave products in good to excellent yields and moderate diastereoselectivity. The mechanism may involve tandem Michael addition of triflones/intramolecular nucleophilic cyclization (elimination of -SO2 CF3 )/elimination of fluoride.


Assuntos
Ciclopropanos , Halogenação , Ciclização , Estrutura Molecular , Estereoisomerismo
20.
Neurotox Res ; 40(2): 432-448, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35192144

RESUMO

Alzheimer's disease (AD) is a neurological disease that gradually causes memory loss and cognitive impairment. The intracellular secondary messenger cyclic nucleotide cAMP helps in memory acquisition and consolidation. In several models of AD, increasing their levels using phosphodiesterase (PDE) inhibitors improved cognitive performance and prevent memory loss. Thus, the current investigation was undertaken to investigate the therapeutic potential of the PDE-4 inhibitor roflumilast (RFM) against intracerebroventricular (ICV) streptozotocin (STZ)-induced sporadic AD in rats. STZ (3 mg/kg) was given to rats via the ICV route on the stereotaxic apparatus, followed by RFM (0.51 mg/kg/oral) treatment for 15 days, and donepezil (5 mg/kg/oral) was employed as a reference standard drug. Subsequently, we observed that RFM dramatically increased rats learning and memory capacities as measured by the Morris water maze and a novel object recognition task. RFM enhanced the levels of cAMP and brain-derived neurotrophic factors (BDNFs) while decreasing the expression of nuclear factor kappa B (NF-κB) and glial fibrillary acidic protein (GFAP) in the hippocampus of ICV-STZ-infused rats. RFM was found to significantly reduce ICV-STZ-induced neuroinflammation, amyloidogenesis, oxidative stress cholinergic impairments, GSK-3ß, and phosphorylated tau levels in the rat hippocampus. Supporting these, histopathological study using Cresyl violet and Congo red demonstrated that RFM reduced neuronal alterations and Aß deposition in the hippocampus of AD rats. These findings suggest that RFM could be a promising candidate for the management of AD by inhibiting NF-κB/BACE-1 mediated Aß production in the hippocampus and activating the cAMP/BDNF signalling pathway.


Assuntos
Doença de Alzheimer , Doença de Alzheimer/induzido quimicamente , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Aminopiridinas , Animais , Benzamidas , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Ciclopropanos , Modelos Animais de Doenças , Glicogênio Sintase Quinase 3 beta/metabolismo , Hipocampo/metabolismo , Aprendizagem em Labirinto , Transtornos da Memória/induzido quimicamente , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/metabolismo , NF-kappa B/metabolismo , Ratos , Estreptozocina/toxicidade
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