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1.
Methods Mol Biol ; 2589: 145-155, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36255623

RESUMO

Class I histone deacetylase (HDAC) enzymes are key regulators of cell proliferation and are frequently dysregulated in cancer cells. Here we describe the synthesis of a novel series of class-I selective HDAC inhibitors containing anilinobenzamide moieties as ZBG connected with a central (piperazin-1-yl)pyrazine moiety. Compounds were tested in vitro against class-I HDAC1, 2, and 3 isoforms. Some highly potent HDAC inhibitors were obtained and were tested in pancreatic cancer cells and showed promising activity. Moreover, we summarize how the growth-inhibitory effects of these compounds can be determined in murine pancreatic cancer cell lines.


Assuntos
Inibidores de Histona Desacetilases , Neoplasias Pancreáticas , Humanos , Camundongos , Animais , Inibidores de Histona Desacetilases/farmacologia , Pirazinas/farmacologia , Linhagem Celular Tumoral , Histona Desacetilases/metabolismo , Proliferação de Células , Isoformas de Proteínas/metabolismo , Neoplasias Pancreáticas/tratamento farmacológico , Relação Estrutura-Atividade , Histona Desacetilase 1/metabolismo
2.
Spectrochim Acta A Mol Biomol Spectrosc ; 285: 121874, 2023 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-36122466

RESUMO

We designed the TPA-based linear pyrazine derivatives of PP-1 and PP-2, synthesized using the conventional Suzuki cross-linking reaction. It was followed by photophysical studies such as aprotic solvent (Haxene to DMF). A red-shift was observed from the non-polar aprotic solvent to the polar aprotic solvent, and the emission intensity was gradually decreased. In addition, the Aggregation-induced emission (AIE) effect has been studied against the DMF/water addition of linear pyrazine compounds. It showed a classic aggregation-caused quenching effect (ACQ) and red-shifted at an increase of (fw) 0 to 40%. After this case, when the water fraction in these studies was increased by (fw) 50 to 90%, a blue shift and a mild AIE effect has occurred. And also, was investigated acidochromic effect of compounds PP-1 and PP-2 using TFA acid. Absorption and emission intensity were gradually reduced as the acid concentration increased for these studies, while the new peaks appeared red-shifted in the absorption spectrum. They were examined before and after exposure to UV light irradiation in the synthesized dye compounds.


Assuntos
Pirazinas , Água , Espectrometria de Fluorescência , Solventes , Fenômenos Químicos
3.
J Pharm Biomed Anal ; 223: 115131, 2023 Jan 20.
Artigo em Inglês | MEDLINE | ID: mdl-36395627

RESUMO

A fast procedure obtained by the combination of fabric phase extraction (FPSE) with high performance liquid chromatography (HPLC) has been developed and validated for the quantification of favipiravir (FVP) in human plasma and breast milk. A sol-gel polycaprolactone-block-polydimethylsiloxane-block-polycaprolactone (sol-gel PCAP-PDMS-PCAP) coated on 100% cellose cotton fabric was selected as the most efficient membrane for FPSE in human plasma and breast milk samples. HPLC-UV analysis were performed using a RP C18 column under isocratic conditions. Under these optimezed settings, the overall chromatographic analysis time was limited to only 5 min without encountering any observable matrix interferences. Following the method validation procedure, the herein assay shows a linear calibration curve over the range of 0.2-50 µg/mL and 0.5-25 µg/mL for plasma and breast milk, respectively. The method sensitivities in terms of limit of detection (LOD) and limit of quantification (LOQ), validated in both the matrices, have been found to be 0.06 and 0.2 µg/mL for plasma and 0.15 and 0.5 µg/mL for milk, respectively. Intraday and interday precision and trueness, accordingly to the International Guidelines, were validated and were below 3.61% for both the matrices. The herein method was further tested on real samples in order to highlight the applicability and the advantage for therapeutic drug monitoring (TDM) applications. To the best of our knowledge, this is the first validated FPSE-HPLC-UV method in human plasma and breast milk for TDM purposes applied on real samples. The validated method provides fast, simple, cost reduced, and sensitive assay for the direct quantification of favipiravir in real biological matrices, also appliyng a well-known rugged and cheap instrument configuration.


Assuntos
Leite Humano , Pirazinas , Feminino , Humanos , Cromatografia Líquida de Alta Pressão/métodos , Limite de Detecção
4.
Cell Death Differ ; 29(1): 230-245, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-34453119

RESUMO

Mounting evidence indicates that immunogenic therapies engaging the unfolded protein response (UPR) following endoplasmic reticulum (ER) stress favor proficient cancer cell-immune interactions, by stimulating the release of immunomodulatory/proinflammatory factors by stressed or dying cancer cells. UPR-driven transcription of proinflammatory cytokines/chemokines exert beneficial or detrimental effects on tumor growth and antitumor immunity, but the cell-autonomous machinery governing the cancer cell inflammatory output in response to immunogenic therapies remains poorly defined. Here, we profiled the transcriptome of cancer cells responding to immunogenic or weakly immunogenic treatments. Bioinformatics-driven pathway analysis indicated that immunogenic treatments instigated a NF-κB/AP-1-inflammatory stress response, which dissociated from both cell death and UPR. This stress-induced inflammation was specifically abolished by the IRE1α-kinase inhibitor KIRA6. Supernatants from immunogenic chemotherapy and KIRA6 co-treated cancer cells were deprived of proinflammatory/chemoattractant factors and failed to mobilize neutrophils and induce dendritic cell maturation. Furthermore, KIRA6 significantly reduced the in vivo vaccination potential of dying cancer cells responding to immunogenic chemotherapy. Mechanistically, we found that the anti-inflammatory effect of KIRA6 was still effective in IRE1α-deficient cells, indicating a hitherto unknown off-target effector of this IRE1α-kinase inhibitor. Generation of a KIRA6-clickable photoaffinity probe, mass spectrometry, and co-immunoprecipitation analysis identified cytosolic HSP60 as a KIRA6 off-target in the IKK-driven NF-κB pathway. In sum, our study unravels that HSP60 is a KIRA6-inhibitable upstream regulator of the NF-κB/AP-1-inflammatory stress responses evoked by immunogenic treatments. It also urges caution when interpreting the anti-inflammatory action of IRE1α chemical inhibitors.


Assuntos
Endorribonucleases , Retículo Endoplasmático/metabolismo , Endorribonucleases/metabolismo , Humanos , Imidazóis , Morte Celular Imunogênica , Inflamação/metabolismo , Naftalenos , Pirazinas
5.
J Agric Food Chem ; 70(45): 14457-14467, 2022 Nov 16.
Artigo em Inglês | MEDLINE | ID: mdl-36342227

RESUMO

Methionine (Met) oxidation was observed during thermal degradation of methionine/glucose-derived Amadori rearrangement product (MG-ARP). The effects of oxidized methionine products, methionine sulfoxide (MetSO) and methionine sulfone (MetSO2), on pyrazine yields of the MG-ARP model were investigated. The pyrazine contents in the MG-ARP/Met and MG-ARP/MetSO models were found lower compared to those in the MG-ARP/MetSO2 model, and the inefficiency of pyrazine formation in the MG-ARP/Met model was proposed due to the fact that Met oxidation competitively inhibited the oxidation of dihydropyrazines for pyrazine formation in spite of relatively high methylglyoxal (MGO) content. The models of MGO mixed with Met, MetSO, or MetSO2 were established for further investigation of the mechanism for the involvement of Met oxidation in pyrazine formation. It was observed that the aldolization or carbonyl-amine reaction of MetSO with MGO was another important reason for the inhibition of pyrazine formation, except for the competitive inhibition of oxidative formation of MetSO on dihydropyrazine oxidation, and the adduct of MGO-MetSO was identified by MS/MS. These results also accounted for the phenomenon of low pyrazine yields but high yields of long-chain substituted pyrazines, which were converted from dihydropyrazines with the aldehyde involvement.


Assuntos
Glucose , Pirazinas , Espectrometria de Massas em Tandem , Óxido de Magnésio , Metionina/metabolismo , Oxirredução , Racemetionina/metabolismo
6.
Int J Mol Sci ; 23(21)2022 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-36361837

RESUMO

The present study introduces a unique BL signature imaging system with novel CTZ analogues named "C-series." Nine kinds of C-series CTZ analogues were first synthesized, and BL intensity patterns and spectra were then examined according to the marine luciferases. The results show that the four CTZ analogues named C3, C4, C6, and C7, individually or collectively luminesce with completely distinctive BL spectral signatures and intensity patterns according to the luciferases: Renilla luciferase (RLuc), NanoLuc, and artificial luciferase (ALuc). The signatural reporters were multiplexed into a multi-reporter system comprising RLuc8.6-535SG and ALuc16. The usefulness of the signatural reporters was further determined with a multi-probe system that consists of two single-chain probes embedding RLuc8 and ALuc23. This study is a great addition to the study of conventional bioassays with a unique methodology, and for the specification of each signal in a single- or multi-reporter system using unique BL signatures and patterns of reporter luciferases.


Assuntos
Medições Luminescentes , Pirazinas , Medições Luminescentes/métodos , Luciferases/genética , Indicadores e Reagentes
7.
Sci Rep ; 12(1): 19888, 2022 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-36434117

RESUMO

The uncontrolled oxidative decomposition of electrolyte while operating at high potential (> 4.2 V vs Li/Li+) severely affects the performance of high-energy density transition metal oxide-based materials as cathodes in Li-ion batteries. To restrict this degradative response of electrolyte species, the need for functional molecules as electrolyte additives that can restrict the electrolytic decomposition is imminent. In this regard, bio-derived molecules are cost-effective, environment friendly, and non-toxic alternatives to their synthetic counter parts. Here, we report the application of microbially synthesized 2,5-dimethyl-3,6-bis(4-aminobenzyl)pyrazine (DMBAP) as an electrolyte additive that stabilizes high-voltage (4.5 V vs Li/Li+) LiNi1/3Mn1/3Co1/3O2 cathodes. The high-lying highest occupied molecular orbital of bio-additive (DMBAP) inspires its sacrificial in situ oxidative decomposition to form an organic passivation layer on the cathode surface. This restricts the excessive electrolyte decomposition to form a tailored cathode electrolyte interface to administer cyclic stability and enhance the capacity retention of the cathode.


Assuntos
Diaminas , Pirazinas , Eletrodos , Lítio , Íons , Óxidos
9.
Molecules ; 27(20)2022 Oct 20.
Artigo em Inglês | MEDLINE | ID: mdl-36296687

RESUMO

Jinhua ham is a traditional cured meat food in China. For a long time, its grade has mainly been evaluated by the human nose through the three-sticks method, which is highly subjective and is not conducive to establishing evaluation standards through odor markers. In this paper, we analyzed the well-graded Grade I-III hams provided by Jinzi Ham Co., Ltd. (Jinhua, China). Firstly, we used different extraction fibers, extraction temperatures, and extraction time to determine the optimal conditions for headspace solid-phase microextraction (HS-SPME). Then, the aroma components of Jinhua ham were analyzed by headspace solid-phase microextraction combined with gas chromatography-mass spectrometry (GC-MS), and OAV was calculated to screen the key aroma volatiles of three kinds of Jinhua ham. It was found that a total of 56 components were detected in the three types of ham. Among them, there are 21 kinds of key aroma volatiles. Aldehydes, alcohols, and acids are the three main components of Jinhua ham, and the content of aldehydes gradually decreases from Grade I to Grade III ham. The content of acids gradually increased, and we speculated that the increase in acid content was caused by the proliferation of microorganisms in Grade III ham. The key flavor volatiles in Grade I hams was hexanal and 2-methylbutanal. Grade I hams had a strong meat aroma, pleasant fatty, and roasted aroma without any off-flavors. In Grade II ham, the characteristic volatiles (E,E)-2,4-decadienal and ethyl isovalerate were detected. These two volatiles contribute greatly to the flavor of Grade II ham, which makes the flavor of Grade II ham have a special fruity aroma. They also may be prone to sourness and affect the flavor of the ham. Volatiles with low threshold values, such as pyrazines, furans, and sulfur-containing compounds, were relatively high in Grade III hams. This may also contribute to the poorer flavor quality of Grade III hams. This experiment provided a reliable test method and evaluation basis for the rating of Jinhua ham. These results have positive implications for the establishment of odor markers-based grading criteria.


Assuntos
Carne de Porco , Compostos Orgânicos Voláteis , Humanos , Odorantes/análise , Microextração em Fase Sólida/métodos , Aldeídos/química , Pirazinas/análise , Enxofre , Biomarcadores , Furanos/análise , Compostos Orgânicos Voláteis/análise
10.
Org Lett ; 24(43): 7918-7923, 2022 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-36278884

RESUMO

An efficient difunctionalization at C5/C8 of imidazo[1,2-a]pyrazines has been developed using disulfides and Grignard reagents under cheap cobalt catalysis. This one-pot, two-step, three-component transformation is performed under mild conditions; various Grignard reagents (aryl and alkyl) and disulfides are tolerated. Mechanistic studies and control experiments demonstrate this reaction proceeded via an anionic intermediate.


Assuntos
Dissulfetos , Pirazinas , Indicadores e Reagentes , Pirazinas/química , Estrutura Molecular , Catálise
11.
World J Microbiol Biotechnol ; 38(12): 234, 2022 Oct 12.
Artigo em Inglês | MEDLINE | ID: mdl-36222911

RESUMO

The maturation period of high-temperature Daqu (HTD) is usually 3-6 months, and the characteristics of HTD at different maturation stages were different. In this study, the microbial characteristics and metabolite profiles of HTD at different maturation stages were revealed with the combination of physicochemical detection, the third generation Pacific Biosciences (PacBio) single-molecule, real-time (SMRT) sequencing technology, gas chromatography-mass spectrometry (GC-MS), and gas chromatography-ion mobility spectrometry (GC-IMS). Results showed that HTD matured for 6 months (Mix_m6) had higher saccharification power but less culturable thermotolerant bacteria and fungi than HTD matured for 3 months (Mix_m3). The average relative abundances of Thermoactinomyces, Paenibacillus, and Rasamsonia in Mix_m3 were higher than that in Mix_m6, while the average relative abundances of Bacillus, Pseudomonas, Thermoascus increased obviously with the prolongation of the maturation period. Streptomyces and Thermoactinomyces were biomarkers in Mix_m3, while Burkholderia and Pseudomonas were regarded as biomarkers in Mix_m6. Differences in microbiota structure led to different enrichment of metabolic pathways in HTD at different maturation stages, resulting in different flavor profiles, especially in ethyl acetate, 1-octen-3-one, (E)-3-Hexen-1, 2,3,5-trimethy-6-ethylpyrazine, pyrazine, tetramethyl content. The microbiota and metabolite characteristics of HTD comprehensively reflected the HTD quality in different maturation stages, which provided a reference for determining the optimal maturation time.


Assuntos
Bebidas Alcoólicas , Pirazinas , Bebidas Alcoólicas/microbiologia , Fermentação , Cromatografia Gasosa-Espectrometria de Massas , Pirazinas/análise , Temperatura
14.
Theranostics ; 12(16): 6883-6897, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36276646

RESUMO

Rationale: Immunogenic cell death (ICD)-associated immunogenicity evoked through reactive oxygen species (ROS) is an efficient way to fight against the immune-dysfunctional microenvironment, so as to provoke potent anti-tumor immunity. However, the unknown ROS dose during cancer therapies may induce adverse immune responses (e.g., insufficient ICD, toxicity toward normal tissues or immune system). Methods: Herein, we developed a pyrido pyrazine - thiophene based semiconducting polymer as novel near-infrared (NIR) organic afterglow nanoparticles for the real-time visualization of self-generated ROS, during photodynamic-mediated immunogenic cell death. Specifically, we introduced the strong "acceptor" (pyrido pyrazine) into thiophene based semiconducting polymer to redshift emission wavelength, and further modulate the "donor" to afford more afterglow reaction sites and reducing ΔEst, so as to enhance luminescence intensity. Results: The semiconducting polymer-based afterglow nanoparticles exhibit strong afterglow emission with longer-wavelength emission (> 800 nm), compared with the reported organic afterglow nanoparticles (e.g., MEHPPV, PFODBT or Chlorin, < 690 nm), which endows this afterglow nanoparticles with a greatly improvement of signal to noise ratio. Moreover, the photodynamic effect of this afterglow nanoparticles can induce immunogenic cell death of cancer cells and further cause immune responses in mice. Conclusions: The NIR afterglow signal presents a good relationship with ROS generation, immunogenic cell death and outcome of treatment. Therefore, it was able to provide a non-invasive tool for predicting the degree of ICD that occurs during ROS-mediated cancer therapy and may contribute to precise immunotherapy.


Assuntos
Nanopartículas , Neoplasias , Camundongos , Animais , Espécies Reativas de Oxigênio/metabolismo , Nanopartículas/uso terapêutico , Polímeros/uso terapêutico , Tiofenos/uso terapêutico , Pirazinas , Linhagem Celular Tumoral , Neoplasias/tratamento farmacológico
15.
Food Funct ; 13(21): 10956-10969, 2022 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-36239358

RESUMO

The present study focused on the role of roasting pretreatment in improving the flavor of WOs. In total, 71 volatile compounds were detected, 35 odorants were perceived, and 17 aroma-active compounds were identified in WOs by using headspace-solid phase microextraction-gas chromatography-mass spectrometry (HS-SPME-GC-MS) and aroma extract dilution analysis of gas chromatography-olfactometry (AEDA/GC-O). The results indicate that extended roasting pretreatment is effective in generating aldehydes and pyrazine aroma-active compounds in WOs. The correlation between the aroma-active compounds and chemical composition was identified by Pearson correlation analysis. The branched-chain aldehyde, 3-methylbutanal, is a Maillard reaction product with ribose as a precursor. Pyrazine aroma-active compounds were also related to ribose, with absolute correlation coefficients of 0.85 to 0.96; among pyrazine compounds, 2-ethyl-5-methylpyrazine showed strong correlation with isoleucine and arginine, while 2-methylpyrazine and 2,3,5-trimethylpyrazine showed strong correlation with glycine, lysine, and histidine. The determination of the effect of roasting on aroma-active compound alteration and the study of aroma precursors will be helpful for walnut oils' flavor quality control, which directly enable their industrial application.


Assuntos
Juglans , Compostos Orgânicos Voláteis , Cromatografia Gasosa-Espectrometria de Massas/métodos , Compostos Orgânicos Voláteis/análise , Ribose , Odorantes/análise , Microextração em Fase Sólida/métodos , Óleos , Pirazinas
16.
Cells ; 11(19)2022 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-36231019

RESUMO

Glioblastoma multiforme (GBM), the most aggressive primary brain tumor, displays a highly infiltrative growth pattern and remains refractory to chemotherapy. Phytochemicals carrying specificity and low cytotoxicity may serve as potent and safer alternatives to conventional chemotherapy for treating GBM. We have evaluated the anticancer effects of Oltipraz (Olt), a synthetic dithiolethione found in many vegetables, including crucifers. While Olt exposure was non-toxic to the HEK-293 cell line, it impaired the cell growth in three GBM cell lines (LN18, LN229, and U-87 MG), arresting those at the G2/M phase. Olt-exposed GBM cells induced the generation of reactive oxygen species (ROS), mitochondrial depolarization, caspase 3/7-mediated apoptosis, nuclear condensation, and DNA fragmentation, and decreased glutathione, a natural ROS scavenger, as well as vimentin and ß-catenin, the EMT-associated markers. Its effect on a subpopulation of GBM cells exhibiting glioblastoma stem cell (GSCs)-like characteristics revealed a reduced expression of Oct4, Sox2, CD133, CD44, and a decrease in ALDH+, Nestin+ and CD44+ cells. In contrast, there was an increase in the expression of GFAP and GFAP+ cells. The Olt also significantly suppressed the oncosphere-forming ability of cells. Its efficacy was further validated in vivo, wherein oral administration of Olt could suppress the ectopically established GBM tumor growth in SCID mice. However, there was no alteration in body weight, organ ratio, and biochemical parameters, reflecting the absence of any toxicity otherwise. Together, our findings could demonstrate the promising chemotherapeutic efficacy of Olt with potential implications in treating GBM.


Assuntos
Glioblastoma , Animais , Carcinogênese/patologia , Caspase 3/metabolismo , Linhagem Celular Tumoral , Glioblastoma/metabolismo , Glutationa/metabolismo , Células HEK293 , Humanos , Camundongos , Camundongos SCID , Células-Tronco Neoplásicas/patologia , Nestina/metabolismo , Pirazinas , Espécies Reativas de Oxigênio/metabolismo , Tionas , Tiofenos , Vimentina/metabolismo , beta Catenina/metabolismo
17.
Cells ; 11(19)2022 10 04.
Artigo em Inglês | MEDLINE | ID: mdl-36231088

RESUMO

Human dermal fibroblasts (HDFs) have the potential to differentiate into endothelial cells (VECs). In our previous research, we reported that a hypochlorous acid (HOCl) probe CPP efficiently induced the differentiation of HDFs into VECs, however, the mechanism of differentiation was not clear. As an HOCI probe, CPP binds HOCI to modulate its effects. In this study, through Western blotting, qPCR, and PHD2 enzyme activity assay, we found that CPP inhibited the enzyme activity of prolyl-4-hydroxylase 2 (PHD2), thereby stabilizing HIF-1α. To further clarify the mechanism by which CPP inhibits PHD2 enzyme activity, we constructed plasmids, and found that CPP inhibited PHD2 activity to increase the HIF-1α level through the modulation of PHD2 at Cys302 by HOCl in HDFs. Furthermore, RNA-seq experiments showed that CPP could induce the expression of HEY1, which is not only a target gene regulated by HIF1α, but also a key transcription factor for VECs. We used siRNA transfection and in vivo experiments to confirm that CPP could induce HDFs to differentiate into VECs by HEY1. In summary, we identified a new inhibitor of PHD2, demonstrated the new role of HOCl in cell differentiation, and elucidated the mechanism by which HOCl probe CPP induced the differentiation of HDFs into VECs.


Assuntos
Células Endoteliais , Prolina Dioxigenases do Fator Induzível por Hipóxia , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Proteínas de Ciclo Celular/metabolismo , Células Endoteliais/metabolismo , Fibroblastos/metabolismo , Humanos , Ácido Hipocloroso/farmacologia , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Pró-Colágeno-Prolina Dioxigenase/genética , Pró-Colágeno-Prolina Dioxigenase/metabolismo , Prolil Hidroxilases/metabolismo , Pirazinas , RNA Interferente Pequeno/genética , Transdução de Sinais
18.
PLoS One ; 17(10): e0274881, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36194604

RESUMO

To study the difference between the fungal community compositional and fragrance components in medium- and high-Temperature Taorong-type Baijiu Daqu. The microbial communities and fragrance components of Taorong-type Baijiu Daqu were analyzed using high-throughput sequencing (HTS) and headspace-solid-phase microextraction-gas chromatography-mass spectrometry (HS-SPME-GC-MS). With an abundance at the phylum and genus levels ≥0.01% as the threshold, 3 phyla, Mucoromycota, Ascomycota, and Basidiomycota, were found in both medium- and high-temperature Daqu, but their abundances differed. At the genus level, 15 and 13 genera were recognized. Rhizopus (72.40%) and Thermomyces (53.32%) accounted for the most significant proportions in medium-temperature and high-temperature Daqu, respectively. Medium-temperature Daqu and high-temperature Daqu were found to have 40 and 29 fragrance components, respectively and contained the highest proportions of pyrazines (53.12%) and acids (32.68%). Correlation analyses between microbes and fragrance components showed that Aspergillus, Hyphopichia, Trichosporon, Alternaria were all highly and positively correlated with pyrazines, but the dominant fungal communities were highly correlated with only a few individual acid compounds but not with acid compounds overall. The unique Daqu -making process and environment lead to these differences.


Assuntos
Micobioma , Bebidas Alcoólicas/análise , Bactérias , Fermentação , Pirazinas , Temperatura
19.
Antiviral Res ; 208: 105425, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36181971

RESUMO

Foot-and-mouth disease (FMD) is a contagious disease affecting cloven-hoofed animals. Its transmissibility and antigenic variety make this disease difficult to control. Antiviral agents are expected to have an immediate effect that is independent of viral antigenicity; thus, they can serve as effective tools for inhibiting the spread of the causative agent, the FMD virus (FMDV), from infected animals. In this study, we investigated the antiviral activity of a pyrazinecarboxamide derivative, T-1105, against FMDV. Cytopathic effect inhibition assays revealed that T-1105 strongly inhibited the replication of 28 reference strains of all seven FMDV serotypes at non-cytotoxic concentrations. The antiviral effect of T-1105 against FMDV was also evaluated by experimental infection of domestic pigs. T-1105 was administered orally to pigs starting 1 h before or 6 h after the inoculation of a porcinophilic FMDV serotype O, topotype CATHAY. None of the pigs administered with T-1105 showed clinical signs of FMD. Moreover, no infectious FMDVs or FMDV-specific genes were detected in their sera, oral and nasal discharges, or tissues collected 48 h after virus inoculation. These findings strongly suggest that administration of T-1105 is effective in controlling the spread of FMDV in pigs.


Assuntos
Vírus da Febre Aftosa , Febre Aftosa , Suínos , Animais , Febre Aftosa/tratamento farmacológico , Febre Aftosa/prevenção & controle , Antivirais/uso terapêutico , Pirazinas/farmacologia
20.
Antiviral Res ; 208: 105444, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36243175

RESUMO

Infections by pathogenic New World mammarenaviruses (NWM)s, including Junín virus (JUNV), can result in a severe life-threatening viral hemorrhagic fever syndrome. In the absence of FDA-licensed vaccines or antivirals, these viruses are considered high priority pathogens. The mammarenavirus envelope glycoprotein complex (GPC) mediates pH-dependent fusion between viral and cellular membranes, which is essential to viral entry and may be vulnerable to small-molecule inhibitors that disrupt this process. ARN-75039 is a potent fusion inhibitor of a broad spectrum of pseudotyped and native mammarenaviruses in cell culture and Tacaribe virus infection in mice. In the present study, we evaluated ARN-75039 against pathogenic JUNV in the rigorous guinea pig infection model. The compound was well-tolerated and had favorable pharmacokinetics supporting once-per-day oral dosing in guinea pigs. Importantly, significant protection against JUNV challenge was observed even when ARN-75039 was withheld until 6 days after the viral challenge when clinical signs of disease are starting to develop. We also show that ARN-75039 combination treatment with favipiravir, a viral polymerase inhibitor, results in synergistic activity in vitro and improves survival outcomes in JUNV-challenged guinea pigs. Our findings support the continued development of ARN-75039 as an attractive therapeutic candidate for treating mammarenaviral hemorrhagic fevers, including those associated with NWM infection.


Assuntos
Arenaviridae , Febre Hemorrágica Americana , Febres Hemorrágicas Virais , Vírus Junin , Cobaias , Camundongos , Animais , Febre Hemorrágica Americana/tratamento farmacológico , Pirazinas/farmacologia , Pirazinas/uso terapêutico , Amidas/farmacologia , Amidas/uso terapêutico , Antirretrovirais/farmacologia
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