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1.
Georgian Med News ; (348): 151-153, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38807409

RESUMO

Rebamipide contributes to the improvement of blood supply of the GI mucosa, activates its barrier function, activates alkaline secretion of the stomach, increases proliferation and metabolism of epithelial cells of the GI tract, cleanses the mucosa from hydroxyl radicals and suppresses superoxides, produced by polymorphonuclear leukocytes and neutrophils in the presence of Helicobacter pylori, protects the GI mucosa from bacterial invasion and the damaging effects of non-steroidal anti-inflammatory drugs (NSAIDs) on the mucosa. Rebamipide, originally developed as a treatment for gastric ulcers, has attracted the attention of researchers as a potential drug for the treatment of UC due to its ability to stimulate mucus production, reduce oxidative stress, and decrease inflammation. Due to the presence of these properties, it is hypothesized that rebamipide may have a protective effect on the intestinal mucosa during prolonged inflammation, making it a promising candidate for inclusion in therapeutic strategies for ulcerative colitis. The results of this study suggest that rebamipide holds potential therapeutic benefits for the treatment of ulcerative colitis.


Assuntos
Alanina , Colite Ulcerativa , Quinolonas , Quinolonas/uso terapêutico , Quinolonas/farmacologia , Alanina/análogos & derivados , Alanina/uso terapêutico , Alanina/farmacologia , Animais , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/patologia , Ratos , Antiulcerosos/uso terapêutico , Antiulcerosos/farmacologia , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Mucosa Intestinal/metabolismo , Masculino , Progressão da Doença , Modelos Animais de Doenças , Ratos Wistar
2.
Emerg Microbes Infect ; 13(1): 2353302, 2024 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-38753462

RESUMO

Animal models of COVID-19 facilitate the development of vaccines and antivirals against SARS-CoV-2. The efficacy of antivirals or vaccines may differ in different animal models with varied degrees of disease. Here, we introduce a mouse model expressing human angiotensin-converting enzyme 2 (ACE2). In this model, ACE2 with the human cytokeratin 18 promoter was knocked into the Hipp11 locus of C57BL/6J mouse by CRISPR - Cas9 (K18-hACE2 KI). Upon intranasal inoculation with high (3 × 105 PFU) or low (2.5 × 102 PFU) dose of SARS-CoV-2 wildtype (WT), Delta, Omicron BA.1, or Omicron BA.2 variants, all mice showed obvious infection symptoms, including weight loss, high viral loads in the lung, and interstitial pneumonia. 100% lethality was observed in K18-hACE2 KI mice infected by variants with a delay of endpoint for Delta and BA.1, and a significantly attenuated pathogenicity was observed for BA.2. The pneumonia of infected mice was accompanied by the infiltration of neutrophils and pulmonary fibrosis in the lung. Compared with K18-hACE2 Tg mice and HFH4-hACE2 Tg mice, K18-hACE2 KI mice are more susceptible to SARS-CoV-2. In the antivirals test, REGN10933 and Remdesivir had limited antiviral efficacies in K18-hACE2 KI mice upon the challenge of SARS-CoV-2 infections, while Nirmatrelvir, monoclonal antibody 4G4, and mRNA vaccines potently protected the mice from death. Our results suggest that the K18-hACE2 KI mouse model is lethal and stable for SARS-CoV-2 infection, and is practicable and stringent to antiviral development.


Assuntos
Enzima de Conversão de Angiotensina 2 , Antivirais , COVID-19 , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , SARS-CoV-2 , Animais , Enzima de Conversão de Angiotensina 2/genética , Enzima de Conversão de Angiotensina 2/metabolismo , COVID-19/virologia , Camundongos , SARS-CoV-2/genética , SARS-CoV-2/imunologia , SARS-CoV-2/efeitos dos fármacos , Antivirais/farmacologia , Humanos , Pulmão/virologia , Pulmão/patologia , Tratamento Farmacológico da COVID-19 , Queratina-18/genética , Carga Viral , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/farmacologia , Monofosfato de Adenosina/uso terapêutico , Alanina/análogos & derivados , Alanina/farmacologia , Técnicas de Introdução de Genes , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/sangue , Feminino
3.
Cells ; 13(10)2024 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-38786105

RESUMO

HIV infection is an ongoing global health issue, despite increased access to antiretroviral therapy (ART). People living with HIV (PLWH) who are virally suppressed through ART still experience negative health outcomes, including neurocognitive impairment. It is increasingly evident that ART may act independently or in combination with HIV infection to alter the immune state, though this is difficult to disentangle in the clinical population. Thus, these experiments used multiplexed chemokine/cytokine arrays to assess peripheral (plasma) and brain (nucleus accumbens; NAc) expression of immune targets in the presence and absence of ART treatment in the EcoHIV mouse model. The findings identify the effects of EcoHIV infection and of treatment with bictegravir (B), emtricitabine (F), and tenofovir alafenamide (TAF) on the expression of numerous immune targets. In the NAc, this included EcoHIV-induced increases in IL-1α and IL-13 expression and B/F/TAF-induced reductions in KC/CXCL1. In the periphery, EcoHIV suppressed IL-6 and LIF expression, while B/F/TAF reduced IL-12p40 expression. In the absence of ART, IBA-1 expression was negatively correlated with CX3CL1 expression in the NAc of EcoHIV-infected mice. These findings identify distinct effects of ART and EcoHIV infection on peripheral and central immune factors and emphasize the need to consider ART effects on neural and immune outcomes.


Assuntos
Infecções por HIV , Animais , Camundongos , Infecções por HIV/imunologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , Emtricitabina/uso terapêutico , Emtricitabina/farmacologia , Antirretrovirais/uso terapêutico , Antirretrovirais/farmacologia , Modelos Animais de Doenças , Masculino , Tenofovir/uso terapêutico , Tenofovir/farmacologia , Tenofovir/análogos & derivados , Citocinas/metabolismo , Compostos Heterocíclicos com 3 Anéis/farmacologia , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Camundongos Endogâmicos C57BL , Imunidade/efeitos dos fármacos , Alanina/análogos & derivados , Alanina/uso terapêutico , Alanina/farmacologia , Piperazinas/farmacologia , Piperazinas/uso terapêutico , Amidas , Piridonas
4.
Bioorg Med Chem Lett ; 107: 129794, 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-38735344

RESUMO

Chem-KVL is a tandem repeating peptide, with 14 amino acids that was modified based on a short peptide from a fragment of the human host defense protein chemerin. Chem-KVL increases cationicity and hydrophobicity and shows broad-spectrum antibacterial activity. To determine the molecular determinants of Chem-KVL and whether staple-modified Chem-KVL would improve antibacterial activity and protease stability or decrease cytotoxicity, we combined alanine and stapling scanning, and designed a series of alanine and staple-derived Chem-KVL peptides, termed Chem-A1 to Chem-A14 and SCL-1 to SCL-7. We next examined their antibacterial activity against several gram-positive and gram-negative bacteria, their proteolytic stability, and their cytotoxicity. Ala scanning of Chem-KVL suggested that both the positively charged residues (Lys and Arg) and the hydrophobic residues (Lue and Val) were critical for the antibacterial activities of Chem-KVL peptide. Of note, Chem-A4 was able to remarkably inhibit the growth of gram-positive and gram-negative bacteria when compared to the original peptide. And the antibacterial activities of stapled SCL-4 and SCL-7 were several times higher than those of the linear peptide against gram-positive and gram-negative bacteria. Stapling modification of peptides resulted in increased helicity and protein stability when compared with the linear peptide. These stapled peptides, especially SCL-4 and SCL-7, may serve as the leading compounds for further optimization and antimicrobial therapy.


Assuntos
Alanina , Antibacterianos , Bactérias Gram-Negativas , Bactérias Gram-Positivas , Testes de Sensibilidade Microbiana , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/síntese química , Bactérias Gram-Positivas/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Alanina/química , Alanina/farmacologia , Humanos , Peptídeos Antimicrobianos/farmacologia , Peptídeos Antimicrobianos/química , Peptídeos Antimicrobianos/síntese química , Relação Estrutura-Atividade , Mutação , Sequência de Aminoácidos
5.
Microbiol Res ; 285: 127742, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38723390

RESUMO

In recent years, numerous oomycete mycoviruses have been discovered; however, very few studies have focused on their effects on the host oomycete phenotype. In this study, we investigated the impact of toti-like Pythium ultimum RNA virus 2 (PuRV2) infection on the phytopathogenic soil-borne oomycete Globisporangium ultimum, which serves as a model species for Globisporangium and Pythium, specifically the UOP226 isolate in Japan. We generated a PuRV2-free isogenic line through hyphal tip isolation using high-temperature culture and subsequently compared the phenotypic characteristics and gene expression profiles of UOP226 and the PuRV2-free isogenic line. Our findings revealed that the metalaxyl sensitivity of UOP226 was greater than that of the PuRV2-free isogenic line, whereas the mycelial growth rate and colony morphology remained unchanged in the absence of the fungicide. Furthermore, transcriptome analyses using RNA-seq revealed significant downregulation of ABC-type transporter genes, which are involved in fungicide sensitivity, in UOP226. Our results suggest that PuRV2 infection influences the ecology of G. ultimum in agricultural ecosystems where metalaxyl is applied.


Assuntos
Alanina , Micovírus , Fungicidas Industriais , Doenças das Plantas , Vírus de RNA , Fungicidas Industriais/farmacologia , Micovírus/genética , Micovírus/fisiologia , Micovírus/isolamento & purificação , Micovírus/efeitos dos fármacos , Alanina/análogos & derivados , Alanina/farmacologia , Doenças das Plantas/microbiologia , Doenças das Plantas/virologia , Vírus de RNA/efeitos dos fármacos , Vírus de RNA/genética , Pythium/efeitos dos fármacos , Pythium/crescimento & desenvolvimento , Hifas/crescimento & desenvolvimento , Hifas/efeitos dos fármacos , Perfilação da Expressão Gênica , Micélio/crescimento & desenvolvimento , Micélio/efeitos dos fármacos , Micélio/virologia , Japão , Transcriptoma
6.
Microbiol Res ; 285: 127750, 2024 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-38761489

RESUMO

The progress of viral infection involves numerous transcriptional regulatory events. The identification of the newly synthesized transcripts helps us to understand the replication mechanisms and pathogenesis of the virus. Here, we utilized a time-resolved technique called metabolic RNA labeling approach called thiol(SH)-linked alkylation for the metabolic sequencing of RNA (SLAM-seq) to differentially elucidate the levels of steady-state and newly synthesized RNAs of BHK21 cell line in response to human coronavirus OC43 (HCoV-OC43) infection. Our results showed that the Wnt/ß-catenin signaling pathway was significantly enriched with the newly synthesized transcripts of BHK21 cell line in response to HCoV-OC43 infection. Moreover, inhibition of the Wnt pathway promoted viral replication in the early stage of infection, but inhibited it in the later stage of infection. Furthermore, remdesivir inhibits the upregulation of the Wnt/ß-catenin signaling pathway induced by early infection with HCoV-OC43. Collectively, our study showed the diverse roles of Wnt/ß-catenin pathway at different stages of HCoV-OC43 infection, suggesting a potential target for the antiviral treatment. In addition, although infection with HCoV-OC43 induces cytopathic effects in BHK21 cells, inhibiting apoptosis does not affect the intracellular replication of the virus. Monitoring newly synthesized RNA based on such time-resolved approach is a highly promising method for studying the mechanism of viral infections.


Assuntos
Monofosfato de Adenosina , Alanina , Antivirais , Coronavirus Humano OC43 , Transcriptoma , Replicação Viral , Via de Sinalização Wnt , Coronavirus Humano OC43/genética , Coronavirus Humano OC43/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos , Linhagem Celular , Humanos , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/farmacologia , Monofosfato de Adenosina/metabolismo , Antivirais/farmacologia , Alanina/análogos & derivados , Alanina/farmacologia , Alanina/metabolismo , Animais , Infecções por Coronavirus/virologia , Infecções por Coronavirus/tratamento farmacológico
7.
J Med Chem ; 67(9): 7470-7486, 2024 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-38690769

RESUMO

We assessed factors that determine the tissue-specific bioactivation of ProTide prodrugs by comparing the disposition and activation of remdesivir (RDV), its methylpropyl and isopropyl ester analogues (MeRDV and IsoRDV, respectively), the oral prodrug GS-621763, and the parent nucleotide GS-441524 (Nuc). RDV and MeRDV yielded more active metabolite remdesivir-triphosphate (RDV-TP) than IsoRDV, GS-621763, and Nuc in human lung cell models due to superior cell permeability and higher susceptivity to cathepsin A. Intravenous administration to mice showed that RDV and MeRDV delivered significantly more RDV-TP to the lung than other compounds. Nevertheless, all four ester prodrugs exhibited very low oral bioavailability (<2%), with Nuc being the predominant metabolite in blood. In conclusion, ProTides prodrugs, such as RDV and MeRDV, are more efficient in delivering active metabolites to the lung than Nuc, driven by high cell permeability and susceptivity to cathepsin A. Optimizing ProTides' ester structures is an effective strategy for enhancing prodrug activation in the lung.


Assuntos
Adenosina/análogos & derivados , Antivirais , Catepsina A , Pulmão , Pró-Fármacos , Pró-Fármacos/química , Pró-Fármacos/metabolismo , Pró-Fármacos/farmacocinética , Pró-Fármacos/farmacologia , Animais , Camundongos , Antivirais/farmacocinética , Antivirais/farmacologia , Antivirais/química , Antivirais/metabolismo , Humanos , Catepsina A/metabolismo , Pulmão/metabolismo , Permeabilidade da Membrana Celular/efeitos dos fármacos , Monofosfato de Adenosina/análogos & derivados , Monofosfato de Adenosina/farmacocinética , Monofosfato de Adenosina/metabolismo , Monofosfato de Adenosina/química , Monofosfato de Adenosina/farmacologia , Alanina/análogos & derivados , Alanina/química , Alanina/farmacocinética , Alanina/metabolismo , Alanina/farmacologia , Permeabilidade , Ariloxifosforamidatos
8.
Org Lett ; 26(19): 4127-4131, 2024 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-38718303

RESUMO

Hybrid genome-mining/15N-NMR was used to target compounds containing piperazate (Piz) residues, leading to the discovery of caveamides A (1) and B (2) from Streptomyces sp. strain BE230, isolated from New Rankin Cave (Missouri). Caveamides are highly dynamic molecules containing an unprecedented ß-ketoamide polyketide fragment, two Piz residues, and a new N-methyl-cyclohexenylalanine residue. Caveamide B (2) exhibited nanomolar cytotoxicity against several cancer cell lines and nanomolar antimicrobial activity against MRSA and E. coli.


Assuntos
Escherichia coli , Staphylococcus aureus Resistente à Meticilina , Streptomyces , Humanos , Estrutura Molecular , Streptomyces/química , Escherichia coli/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Antibacterianos/farmacologia , Antibacterianos/química , Antibacterianos/isolamento & purificação , Testes de Sensibilidade Microbiana , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/isolamento & purificação , Alanina/química , Alanina/farmacologia , Alanina/análogos & derivados , Ensaios de Seleção de Medicamentos Antitumorais , Peptídeos/química , Peptídeos/farmacologia , Peptídeos/isolamento & purificação , Linhagem Celular Tumoral , Piridazinas
9.
Viruses ; 16(4)2024 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-38675889

RESUMO

Remdesivir (RDV) is a broad-spectrum nucleotide analog prodrug approved for the treatment of COVID-19 in hospitalized and non-hospitalized patients with clinical benefit demonstrated in multiple Phase 3 trials. Here we present SARS-CoV-2 resistance analyses from the Phase 3 SIMPLE clinical studies evaluating RDV in hospitalized participants with severe or moderate COVID-19 disease. The severe and moderate studies enrolled participants with radiologic evidence of pneumonia and a room-air oxygen saturation of ≤94% or >94%, respectively. Virology sample collection was optional in the study protocols. Sequencing and related viral load data were obtained retrospectively from participants at a subset of study sites with local sequencing capabilities (10 of 183 sites) at timepoints with detectable viral load. Among participants with both baseline and post-baseline sequencing data treated with RDV, emergent Nsp12 substitutions were observed in 4 of 19 (21%) participants in the severe study and none of the 2 participants in the moderate study. The following 5 substitutions emerged: T76I, A526V, A554V, E665K, and C697F. The substitutions T76I, A526V, A554V, and C697F had an EC50 fold change of ≤1.5 relative to the wildtype reference using a SARS-CoV-2 subgenomic replicon system, indicating no significant change in the susceptibility to RDV. The phenotyping of E665K could not be determined due to a lack of replication. These data reveal no evidence of relevant resistance emergence and further confirm the established efficacy profile of RDV with a high resistance barrier in COVID-19 patients.


Assuntos
Monofosfato de Adenosina , Monofosfato de Adenosina/análogos & derivados , Alanina , Alanina/análogos & derivados , Antivirais , Tratamento Farmacológico da COVID-19 , COVID-19 , Farmacorresistência Viral , SARS-CoV-2 , Carga Viral , Humanos , Alanina/uso terapêutico , Alanina/farmacologia , Monofosfato de Adenosina/farmacologia , Monofosfato de Adenosina/uso terapêutico , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/genética , Antivirais/farmacologia , Antivirais/uso terapêutico , Carga Viral/efeitos dos fármacos , COVID-19/virologia , Masculino , Feminino , Estudos Retrospectivos , Pessoa de Meia-Idade , Índice de Gravidade de Doença
10.
Drug Alcohol Depend ; 259: 111276, 2024 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-38676968

RESUMO

BACKGROUND: As nicotine dependence represents a longstanding major public health issue, new nicotine cessation pharmacotherapies are needed. Administration of N-oleoyl glycine (OlGly), an endogenous lipid signaling molecule, prevents nicotine-induced conditioned place preference (CPP) through a peroxisome proliferator-activated receptor-alpha (PPARα) dependent mechanism, and also ameliorated withdrawal signs in nicotine-dependent mice. Pharmacological evidence suggests that the methylated analog of OlGly, N-oleoyl alanine (OlAla), has an increased duration of action and may offer translational benefit. Accordingly, OlAla was assessed in nicotine CPP and dependence assays as well as its pharmacokinetics compared to OlGly. METHODS: ICR female and male mice were tested in nicotine-induced CPP with and without the PPARα antagonist GW6471. OlAla was also assessed in nicotine-dependent mice following removal of nicotine minipumps: somatic withdrawal signs, thermal hyper-nociception and altered affective behavior (i.e., light/dark box). Finally, plasma and brain were collected after administration of OlGly or OlAla and analyzed by high-performance liquid chromatography tandem mass spectrometry. RESULTS: OlAla prevented nicotine-induced CPP, but this effect was not blocked by GW6471. OlAla attenuated somatic and affective nicotine withdrawal signs, but not thermal hyper-nociception in nicotine-dependent mice undergoing withdrawal. OlAla and OlGly showed similar time-courses in plasma and brain. CONCLUSIONS: The observation that both molecules showed similar pharmacokinetics argues against the notion that OlAla offers increased metabolic stability. Moreover, while these structurally similar lipids show efficacy in mouse models of reward and dependence, they reduce nicotine reward through distinct mechanisms.


Assuntos
Camundongos Endogâmicos ICR , Nicotina , Recompensa , Síndrome de Abstinência a Substâncias , Tabagismo , Animais , Síndrome de Abstinência a Substâncias/metabolismo , Síndrome de Abstinência a Substâncias/tratamento farmacológico , Camundongos , Masculino , Nicotina/farmacologia , Feminino , Tabagismo/metabolismo , PPAR alfa/metabolismo , Alanina/farmacologia , Alanina/análogos & derivados , Ácidos Oleicos/farmacologia , Glicina/farmacologia , Glicina/análogos & derivados , Aminopiridinas/farmacologia , Encéfalo/metabolismo , Encéfalo/efeitos dos fármacos , Oxazóis , Tirosina/análogos & derivados
11.
Molecules ; 29(8)2024 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-38675600

RESUMO

The natural pesticide phenazine-1-carboxylic acid (PCA) is known to lack phloem mobility, whereas Metalaxyl is a representative phloem systemic fungicide. In order to endow PCA with phloem mobility and also enhance its antifungal activity, thirty-two phenazine-1-carboxylic acid-N-phenylalanine esters conjugates were designed and synthesized by conjugating PCA with the active structure N-acylalanine methyl ester of Metalaxyl. All target compounds were characterized by 1H NMR, 13C NMR and HRMS. The antifungal evaluation results revealed that several target compounds exhibited moderate to potent antifungal activities against Sclerotinia sclerotiorum, Bipolaris sorokiniana, Phytophthora parasitica, Phytophthora citrophthora. In particular, compound F7 displayed excellent antifungal activity against S. sclerotiorum with an EC50 value of 6.57 µg/mL, which was superior to that of Metalaxyl. Phloem mobility study in castor bean system indicated good phloem mobility for the target compounds F1-F16. Particularly, compound F2 exhibited excellent phloem mobility; the content of compound F2 in the phloem sap of castor bean was 19.12 µmol/L, which was six times higher than Metalaxyl (3.56 µmol/L). The phloem mobility tests under different pH culture solutions verified the phloem translocation of compounds related to the "ion trap" effect. The distribution of the compound F2 in tobacco plants further suggested its ambimobility in the phloem, exhibiting directional accumulation towards the apical growth point and the root. These results provide valuable insights for developing phloem mobility fungicides mediated by exogenous compounds.


Assuntos
Alanina , Alanina/análogos & derivados , Fenazinas , Fenazinas/química , Fenazinas/farmacologia , Fenazinas/síntese química , Alanina/química , Alanina/farmacologia , Phytophthora/efeitos dos fármacos , Antifúngicos/farmacologia , Antifúngicos/síntese química , Antifúngicos/química , Floema/metabolismo , Floema/efeitos dos fármacos , Ascomicetos/efeitos dos fármacos , Ascomicetos/metabolismo , Fungicidas Industriais/farmacologia , Fungicidas Industriais/síntese química , Fungicidas Industriais/química , Desenho de Fármacos , Ésteres/química , Ésteres/farmacologia , Ésteres/síntese química
12.
Science ; 383(6688): eadk6176, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38484056

RESUMO

Obeldesivir (ODV, GS-5245) is an orally administered prodrug of the parent nucleoside of remdesivir (RDV) and is presently in phase 3 trials for COVID-19 treatment. In this work, we show that ODV and its circulating parent nucleoside metabolite, GS-441524, have similar in vitro antiviral activity against filoviruses, including Marburg virus, Ebola virus, and Sudan virus (SUDV). We also report that once-daily oral ODV treatment of cynomolgus monkeys for 10 days beginning 24 hours after SUDV exposure confers 100% protection against lethal infection. Transcriptomics data show that ODV treatment delayed the onset of inflammation and correlated with antigen presentation and lymphocyte activation. Our results offer promise for the further development of ODV to control outbreaks of filovirus disease more rapidly.


Assuntos
Alanina , Antivirais , Ebolavirus , Doença pelo Vírus Ebola , Nucleosídeos , Pró-Fármacos , Animais , Administração Oral , Ebolavirus/efeitos dos fármacos , Doença pelo Vírus Ebola/tratamento farmacológico , Doença pelo Vírus Ebola/prevenção & controle , Macaca fascicularis , Nucleosídeos/administração & dosagem , Nucleosídeos/farmacologia , Monofosfato de Adenosina/administração & dosagem , Monofosfato de Adenosina/farmacologia , Alanina/administração & dosagem , Alanina/análogos & derivados , Alanina/farmacologia , Pró-Fármacos/administração & dosagem , Pró-Fármacos/farmacologia , Antivirais/administração & dosagem , Antivirais/farmacologia
13.
J Crohns Colitis ; 18(6): 908-919, 2024 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-38165390

RESUMO

BACKGROUND AND AIMS: Free D-amino acids, which have different functions from L-amino acids, have recently been discovered in various tissues. However, studies on the potential interactions between intestinal inflammation and D-amino acids are limited. We examined the inhibitory effects of D-alanine on the pathogenesis of intestinal inflammation. METHODS: We investigated serum D-amino acid levels in 40 patients with ulcerative colitis and 34 healthy volunteers. For 7 days [d], acute colitis was induced using dextran sulphate sodium in C57BL/6J mice. Plasma D-amino acid levels were quantified in mice with dextran sulphate sodium-induced colitis, and these animals were administered D-alanine via intraperitoneal injection. IFN-γ, IL-12p35, IL-17A, and IL-23p19 mRNA expression in the colonic mucosa was measured using real-time polymerase chain reaction [PCR]. In vitro proliferation assays were performed to assess naïve CD4+ T cell activation under Th-skewing conditions. Bone marrow cells were stimulated with mouse macrophage-colony stimulating factor to generate mouse bone marrow-derived macrophages. RESULTS: Serum D-alanine levels were significantly lower in patients with ulcerative colitis than in healthy volunteers. Dextran sulphate sodium-treated mice had significantly lower plasma D-alanine levels than control mice. D-alanine-treated mice had significantly lower disease activity index than control mice. IFN-γ, IL-12p35, IL-17A, and IL-23p19 mRNA expression levels were significantly lower in D-alanine-administered mice than in control mice. D-alanine suppressed naïve T cell differentiation into Th1 cells in vitro, and inhibited the production of IL-12p35 and IL-23p19 in bone marrow-derived macrophages. CONCLUSIONS: Our results suggest that D-alanine prevents dextran sulphate sodium-induced colitis in mice and suppresses IL-12p35 and IL-23p19 production in macrophages.


Assuntos
Alanina , Colite Ulcerativa , Sulfato de Dextrana , Interleucina-23 , Macrófagos , Camundongos Endogâmicos C57BL , Animais , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/metabolismo , Colite Ulcerativa/imunologia , Colite Ulcerativa/patologia , Colite Ulcerativa/tratamento farmacológico , Humanos , Camundongos , Macrófagos/metabolismo , Macrófagos/efeitos dos fármacos , Masculino , Adulto , Feminino , Alanina/farmacologia , Interleucina-23/metabolismo , Interleucina-12/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/patologia , Interferon gama/metabolismo , Interleucina-17/metabolismo , Pessoa de Meia-Idade , Modelos Animais de Doenças , Estudos de Casos e Controles , RNA Mensageiro/metabolismo , Subunidade p35 da Interleucina-12/metabolismo , Subunidade p19 da Interleucina-23/metabolismo , Adulto Jovem
14.
Environ Toxicol ; 39(5): 2732-2740, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38251951

RESUMO

BACKGROUND: Cervical cancer, a life-threatening disease, is the seventh most commonly detected cancer among women throughout the world. The present study investigated the effect of tretinoin on cervical cancer growth and metastasis in vitro and in vivo in the mice model. MATERIALS AND METHODS: Cell Counting Kit-8, clonogenic survival, and transwell chamber assays were used for determination cells proliferation, colony formation, and invasiveness. Western blotting assay was used for assessment of protein expression whereas AutoDock Vina and Discovery studio software for in silico studies. RESULTS: Tretinoin treatment significantly (p < .05) reduced the proliferation of HT-3 and Caski cells in concentration-based manner. Incubation with tretinoin caused a significant decrease in clonogenic survival of HT-3 and Caski cells compared with the control cultures. The invasive potential of HT-3 cells was decreased to 18%, whereas that of Caski cells to 21% on treatment with 8 µM concentration of tretinoin. In HT-3 cells, tretinoin treatment led to a prominent reduction in p-focal adhesion kinase (FAK), matrix metalloproteinases (MMP)-2, and MMP-9 expression in HT-3 cells. Treatment of the cervical cancer mice model with tretinoin led to a prominent decrease in tumor growth. The metastasis of tumor in model cervical cancer mice group was effectively inhibited in spleen, intestines, and peritoneal cavity. In silico studies showed that tretinoin interacts with alanine, proline, isoleucine, and glycine amino acid residues of FAK protein to block its activation. The 2-dimensional diagram of interaction of tretinoin with FAK protein revealed that tretinoin binds to alanine and glycine amino acids through conventional hydrogen bonding. CONCLUSION: In summary, tretinoin suppressed the proliferation, colony formation, and invasiveness of cervical cancer cells in vitro. It decreased the expression of activated focal adhesion kinase, MMP-2, and MMP-9 in HT-3 cells in dose-dependent manner. In silico studies showed that tretinoin interacts with alanine and glycine amino acids through conventional hydrogen bonding. In vivo data demonstrated that treatment of the cervical cancer mice model with tretinoin led to a prominent decrease in tumor growth. Therefore, tretinoin can be developed as an effective therapeutic agent for cervical cancer treatment.


Assuntos
Neoplasias do Colo do Útero , Humanos , Feminino , Animais , Camundongos , Neoplasias do Colo do Útero/metabolismo , Tretinoína/farmacologia , Tretinoína/uso terapêutico , Linhagem Celular Tumoral , Regulação para Baixo , Metaloproteinase 9 da Matriz/metabolismo , Proliferação de Células , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Alanina/metabolismo , Alanina/farmacologia , Alanina/uso terapêutico , Glicina/metabolismo , Glicina/farmacologia , Glicina/uso terapêutico , Aminoácidos/metabolismo , Aminoácidos/farmacologia , Aminoácidos/uso terapêutico , Invasividade Neoplásica , Movimento Celular
15.
Animal ; 18(2): 101049, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38215677

RESUMO

Our understanding of metabolic alterations triggered by heat stress is incomplete, which limits the designing of nutritional strategies to mitigate negative productive and health effects. Thus, this study aimed to explore the metabolic responses of heat-stressed dairy cows to dietary supplementation with vitamin D3/Ca and vitamin E/Se. Twelve multiparous Holstein cows were enrolled in a split-plot Latin square design with two distinct vitamin E/Se supplementation levels, either at a low (ESe-, n = 6, 11.1 IU/kg vitamin E and 0.55 mg/kg Se) or a high dose (ESe+, n = 6 223 IU/kg vitamin E and 1.8 mg/kg Se) as the main plot. Treatment subplots, arranged in a replicated 3 × 3 Latin square design, comprised heat challenge (Temperature Humidity Index, THI: 72.0-82.0) supplemented with different levels of vitamin D3/Ca: either low (HS/DCa-, 1 012 IU/kg and 0.73%, respectively) or high (HS/DCa+, 3 764 IU/kg and 0.97%, respectively), and a pair-fed control group in thermoneutrality (THI = 61.0-64.0) receiving the low dose of vitamin D3/Ca (TN). The liquid chromatography-mass spectrometry-based metabolome profile was determined in blood plasma and milk sampled at the beginning (day 0) and end (day 14) of each experimental period. The results were analyzed for the effect of (1) TN vs. HS/ESe-/DCa-, and (2) the vitamin E/Se and vitamin D3/Ca supplementation. No group or group × day effects were detected in the plasma metabolome (false discovery rate, FDR > 0.05), except for triglyceride 52:2 being higher (FDR = 0.03) on day 0 than 14. Taurine, creatinine and butyryl-carnitine showed group × day interactions in the milk metabolome (FDR ≤ 0.05) as creatinine (+22%) and butyryl-carnitine (+190%) were increased (P < 0.01) on day 14, and taurine was decreased (-65%, P < 0.01) on day 14 in the heat stress (HS) cows, compared with day 0. Most compounds were unaffected by vitamin E/Se or vitamin D3/Ca supplementation level or their interaction (FDR > 0.05) in plasma and milk, except for milk alanine which was lower (-69%, FDR = 0.03) in the E/Se+ groups, compared with E/Se-. Our results indicated that HS triggered more prominent changes in the milk than in the plasma metabolome, with consistent results in milk suggesting increased muscle catabolism, as reflected by increased creatinine, alanine and citrulline levels. Supplementing with high levels of vitamin E/Se or vitamin D3/Ca or their combination did not appear to affect the metabolic remodeling triggered by HS.


Assuntos
Lactação , Leite , Feminino , Bovinos , Animais , Leite/metabolismo , Creatinina/análise , Creatinina/metabolismo , Creatinina/farmacologia , Dieta/veterinária , Temperatura Alta , Suplementos Nutricionais/análise , Resposta ao Choque Térmico , Vitamina E , Carnitina/metabolismo , Alanina/análise , Alanina/metabolismo , Alanina/farmacologia , Aminoácidos/metabolismo , Vitamina D/metabolismo
16.
BMC Gastroenterol ; 23(1): 384, 2023 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-37950196

RESUMO

BACKGROUND: Nucleoside analogues are currently applied as a first-line treatment for chronic hepatitis B (CHB) patients. However, the long-term effects of this type of treatment on kidney and bone tissue need to be further investigated. METHODS: We conducted a search of entecavir (ETV), tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide fumarate (TAF) for treatment of CHB patients through October 29, 2023. Side effects of the three drugs were compared. Standardized mean difference (SMD), 95% confidence interval (95%CI), and surface under the cumulative ranking curve (SUCRA) were reported for each outcome. Further subgroup analysis was conducted according to duration of administration. RESULTS: ETV and TAF exhibited less effect on estimated glomerular filtration rate (eGFR) than TDF (SMD = -3.60 (95%CI: -1.94 ~ -5.26) and SMD = -4.27 (95%CI: -2.62 ~ -5.93)). ETV also exhibited less effect on creatinine rise than TAF and TDF (SMD = -0.55 (95%CI: -0.09 ~ -1.01) and SMD = -0.61 (95%CI: -0.15 ~ -1.06)). Moreover, the effect of TAF on bone mineral density (BMD) was less than that of TDF (SMD = -0.02 (95%CI: -0.01 ~ -0.02)). The probabilities of the three drugs changing relevant indicators exhibited similar patterns: eGFR (TDF (100.0%) > ETV (41.2%) > TAF (8.8%)), creatinine (TDF (94.7%) > TAF (54.7%) > ETV (0.6%)), BMD (TDF (79.7%) > ETV (50.6%) > TAF (19.6%)), and blood phosphorus (TDF (90.6%) > TAF (49.8%) > ETV (9.7%)). After 6 and 24 months of treatment, no statistically significant difference in renal function or bone tissue was observed between ETV and TDF. However, greater adverse effects on renal function were observed for TDF than ETV at 60 months compared to 12 months. TDF also exhibited greater adverse effects on bone tissue than ETV at 36 months than at 12 months. CONCLUSIONS: Long-term administration of TDF has resulted in stronger adverse effects than TAF and ETV in regard to both renal function and bone tissue in CHB patients. The effect of TAF on creatinine increase was greater than ETV. The difference in side effects between ETV and TDF was independent of treatment duration.


Assuntos
Hepatite B Crônica , Hepatite B , Humanos , Tenofovir/efeitos adversos , Creatinina , Metanálise em Rede , Adenina , Rim/fisiologia , Osso e Ossos , Fumaratos/farmacologia , Fumaratos/uso terapêutico , Hepatite B Crônica/tratamento farmacológico , Antivirais/efeitos adversos , Resultado do Tratamento , Alanina/farmacologia , Alanina/uso terapêutico
17.
Mol Metab ; 77: 101808, 2023 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-37716594

RESUMO

OBJECTIVE: Mitochondrial pyruvate is a critical intermediary metabolite in gluconeogenesis, lipogenesis, and NADH production. As a result, the mitochondrial pyruvate carrier (MPC) complex has emerged as a promising therapeutic target in metabolic diseases. Clinical trials are currently underway. However, recent in vitro data indicate that MPC inhibition diverts glutamine/glutamate away from glutathione synthesis and toward glutaminolysis to compensate for loss of pyruvate oxidation, possibly sensitizing cells to oxidative insult. Here, we explored this in vivo using the clinically relevant acetaminophen (APAP) overdose model of acute liver injury, which is driven by oxidative stress. METHODS: We used pharmacological and genetic approaches to inhibit MPC2 and alanine aminotransferase 2 (ALT2), individually and concomitantly, in mice and cell culture models and determined the effects on APAP hepatotoxicity. RESULTS: We found that MPC inhibition sensitizes the liver to APAP-induced injury in vivo only with concomitant loss of alanine aminotransferase 2 (ALT2). Pharmacological and genetic manipulation of neither MPC2 nor ALT2 alone affected APAP toxicity, but liver-specific double knockout (DKO) significantly worsened APAP-induced liver damage. Further investigation indicated that DKO impaired glutathione synthesis and increased urea cycle flux, consistent with increased glutaminolysis, and these results were reproducible in vitro. Finally, induction of ALT2 and post-treatment with dichloroacetate both reduced APAP-induced liver injury, suggesting new therapeutic avenues. CONCLUSIONS: Increased susceptibility to APAP toxicity requires loss of both the MPC and ALT2 in vivo, indicating that MPC inhibition alone is insufficient to disrupt redox balance. Furthermore, the results from ALT2 induction and dichloroacetate in the APAP model suggest new metabolic approaches to the treatment of liver damage.


Assuntos
Doença Hepática Induzida por Substâncias e Drogas , Hepatopatias , Camundongos , Animais , Antioxidantes/metabolismo , Antioxidantes/farmacologia , Acetaminofen/efeitos adversos , Acetaminofen/metabolismo , Ácido Pirúvico/farmacologia , Alanina Transaminase , Estresse Oxidativo , Oxirredução , Glutationa/metabolismo , Alanina/farmacologia
18.
J Microorg Control ; 28(1): 3-13, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37277956

RESUMO

This study aimed to clarify how the phenolic monoterpene carvacrol and its structural isomer thymol both as essential oil components (EOCs) inhibit the germination of Bacillus subtilis spore. Germination was evaluated by the OD600 reduction rate in a growth medium and phosphate buffer containing either l-alanine (l-Ala) system or l-asparagine, d-glucose, d-fructose plus KCl (AGFK) system. The germination of the wild-type spores in the Trypticase Soy broth (TSB) was found to be greatly inhibited by thymol than by carvacrol. Such a difference in the germination inhibition was confirmed by the dipicolinic acid (DPA) release from germinating spores in the AGFK buffer system, but not in the l-Ala system. Similar to the wild-type spores, no difference in the inhibitory activity between the EOCs was also indicated with the gerB, gerK-deletion mutant spores in the l-Ala buffer system and the above substantial difference was also done with the gerA-deleted mutant spores in the AGFK. Fructose was found to release spores from the EOC inhibition and inversely even stimulated. Increased concentrations of glucose and fructose partially suppressed the germination inhibition by carvacrol. The results obtained should contribute to the elucidation of the control effects of these EOCs on bacterial spores in foods.


Assuntos
Bacillus subtilis , Timol , Bacillus subtilis/genética , Timol/farmacologia , Esporos Bacterianos , Alanina/farmacologia , Frutose/farmacologia
19.
Antiviral Res ; 216: 105658, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37356729

RESUMO

Remdesivir is a nucleotide prodrug with preclinical efficacy against lethal Nipah virus infection in African green monkeys when administered 1 day post inoculation (dpi) (Lo et al., 2019). Here, we determined whether remdesivir treatment was still effective when treatment administration initiation was delayed until 3 dpi. Three groups of six African green monkeys were inoculated with a lethal dose of Nipah virus, genotype Bangladesh. On 3 dpi, one group received a loading dose of 10 mg/kg remdesivir followed by daily dosing with 5 mg/kg for 11 days, one group received 10 mg/kg on 12 consecutive days, and the remaining group received an equivalent volume of vehicle solution. Remdesivir treatment initiation on 3 dpi provided partial protection from severe Nipah virus disease that was dose dependent, with 67% of animals in the high dose group surviving the challenge. However, remdesivir treatment did not prevent clinical disease, and surviving animals showed histologic lesions in the brain. Thus, early administration seems critical for effective remdesivir treatment during Nipah virus infection.


Assuntos
Infecções por Henipavirus , Vírus Nipah , Animais , Chlorocebus aethiops , Infecções por Henipavirus/tratamento farmacológico , Infecções por Henipavirus/prevenção & controle , Encéfalo , Monofosfato de Adenosina/farmacologia , Monofosfato de Adenosina/uso terapêutico , Alanina/farmacologia , Alanina/uso terapêutico
20.
Behav Brain Res ; 452: 114555, 2023 08 24.
Artigo em Inglês | MEDLINE | ID: mdl-37355233

RESUMO

Pain is one of the most frequent non-motor symptoms of Parkinson's disease (PD). Neuropathic pain is highly prevalent in PD and negatively affects the quality of life of patients with PD. However, there is currently no evidence-based treatment for its control. Safinamide, a monoamine oxidase (MAO)-B inhibitor with a sodium channel inhibitory effect, showed improvement in PD-related pain in several clinical trials. However, it is unclear for which of the various types of pain in PD safinamide is effective. The aim of the present study was to examine the effect of safinamide on neuropathic pain in a rat model of chronic constriction injury (CCI). Pain was evaluated on postoperative days 14 and 21 using von Frey or weight-bearing tests. Male CCI model rats showed a decreased paw withdrawal threshold and a weight-bearing deficit on postoperative days 14 and 21. Single oral administration of safinamide (15, 30, 45 or 70 mg/kg) dose-dependently improved neuropathic pain in both pain assessments on day 14. Subsequently, the 15 and 45 mg/kg dose groups were administered safinamide orally once daily until day 21. With repeated administration, the effect of safinamide on pain was enhanced. The present findings show that safinamide improves neuropathic pain in male CCI model rats. Further animal model research and pathological and molecular pharmacological investigations are warranted.


Assuntos
Neuralgia , Doença de Parkinson , Ratos , Masculino , Animais , Qualidade de Vida , Doença de Parkinson/tratamento farmacológico , Neuralgia/tratamento farmacológico , Benzilaminas/farmacologia , Benzilaminas/uso terapêutico , Alanina/farmacologia , Inibidores da Monoaminoxidase/farmacologia , Analgésicos/farmacologia , Analgésicos/uso terapêutico , Mesilatos/uso terapêutico , Antiparkinsonianos/farmacologia
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