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1.
Gene ; 786: 145625, 2021 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-33798683

RESUMO

BACKGROUND: Mounting evidences suggested that anlotinib exhibits effective anti-tumor activity in various cancer types, such as lung cancer, glioblastoma and medullary thyroid cancer. However, its function in colon cancer remains to be further revealed. METHODS: Colon cancer cells (HCT-116) were treated with or without anlotinib. Transcript and metabolite data were generated through RNA sequencing and liquid chromatography-tandem mass spectrometry, respectively. The integrated analysis transcriptomics and metabolomics was conducted using R programs and online tools, including ClusterProfiler R program, GSEA, Prognoscan and Cytoscape. RESULTS: We found that differentially expressed genes (DEGs) were mainly involved in metabolic pathways and ribosome pathway. Structural maintenance of chromosome 3 (SMC3), Topoisomerase II alpha (TOP2A) and Glycogen phosphorylase B (PYGB) are the most significant DEGs which bring poor clinical prognosis in colon cancer. The analysis of metabolomics presented that most of the differentially accumulated metabolites (DAMs) were amino acids, such as L-glutamine, DL-serine and aspartic acid. The joint analysis of DEGs and DAMs showed that they were mainly involved in protein digestion and absorption, ABC transporters, central carbon metabolism, choline metabolism and Gap junction. Anlotinib affected protein synthesis and energy supporting of colon cancer cells by regulating amino acid metabolism. CONCLUSIONS: Anlotinib has a significant effect on colon cancer in both transcriptome and metabolome. Our research will provide possible targets for colon cancer treatment using anlotinib.


Assuntos
Neoplasias do Colo/genética , Perfilação da Expressão Gênica/métodos , Indóis/farmacologia , Metabolômica/métodos , Quinolinas/farmacologia , Ácido Aspártico/metabolismo , Proteínas de Ciclo Celular/genética , Proteoglicanas de Sulfatos de Condroitina/genética , Cromatografia Líquida , Proteínas Cromossômicas não Histona/genética , Neoplasias do Colo/química , Neoplasias do Colo/tratamento farmacológico , DNA Topoisomerases Tipo II/genética , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Redes Reguladoras de Genes , Glutamina/metabolismo , Glicogênio Fosforilase/genética , Células HCT116 , Humanos , Proteínas de Ligação a Poli-ADP-Ribose/genética , Análise de Sequência de RNA , Espectrometria de Massas em Tandem
2.
Ann Palliat Med ; 10(3): 3307-3312, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33849115

RESUMO

BACKGROUND: The novel coronavirus disease 2019 (COVID-19) was broken out in December 2019 and soon became a global health emergency. Effective treatment for COVID-19 is urgently needed. In the present study, we aimed to evaluate the antiviral effect of Arbidol vs. Chloroquine in treating COVID-19. METHODS: We retrospectively analyzed 62 patients with COVID-19 diagnosed according to the guidelines for diagnosis and treatment of COVID-19 in China. They were divided into two groups depending on the antiviral drugs that they received. Participants in the Arbidol group (n=42) received 0.2 g Arbidol, tid for 10 days,and those in Chloroquine group (n=20) received 500 mg Chloroquine, bid for 10 days. The coronavirus negative conversion time and the length of hospital stay were analyzed and compared between the two groups. RESULTS: There was no significant difference in demographic and clinical characteristics between the two groups. After antiviral treatment, the nasopharyngeal specimen negative conversion time of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the length of hospital stay in the Arbidol group were significantly shorter than those in the Chloroquine group (18.50 vs. 25.05 days, P=0.001; 23.52 vs. 28.75 days, P=0.001). Adverse events observed during the antiviral treatment period were comparable between the two groups. Overall, 3 (7.14%) participants in the Arbidol group and 4 (20.0%) in the Chloroquine group experienced adverse events during antiviral treatment. CONCLUSIONS: These results suggest that Arbidol is advantageous over Chloroquine in terms of the SARS-CoV-2 negative conversion and the length of hospital stay in treating COVID-19 patients.


Assuntos
Antivirais/uso terapêutico , Cloroquina/uso terapêutico , Indóis/uso terapêutico , China , Cloroquina/efeitos adversos , Humanos , Tempo de Internação , Estudos Retrospectivos
3.
Int J Mol Sci ; 22(6)2021 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-33805714

RESUMO

Trifluoperazine (TFP), an antipsychotic drug approved by the Food and Drug Administration, has been show to exhibit anti-cancer effects. Pulmonary arterial hypertension (PAH) is a devastating disease characterized by a progressive obliteration of small pulmonary arteries (PAs) due to exaggerated proliferation and resistance to apoptosis of PA smooth muscle cells (PASMCs). However, the therapeutic potential of TFP for correcting the cancer-like phenotype of PAH-PASMCs and improving PAH in animal models remains unknown. PASMCs isolated from PAH patients were exposed to different concentrations of TFP before assessments of cell proliferation and apoptosis. The in vivo therapeutic potential of TFP was tested in two preclinical models with established PAH, namely the monocrotaline and sugen/hypoxia-induced rat models. Assessments of hemodynamics by right heart catheterization and histopathology were conducted. TFP showed strong anti-survival and anti-proliferative effects on cultured PAH-PASMCs. Exposure to TFP was associated with downregulation of AKT activity and nuclear translocation of forkhead box protein O3 (FOXO3). In both preclinical models, TFP significantly lowered the right ventricular systolic pressure and total pulmonary resistance and improved cardiac function. Consistently, TFP reduced the medial wall thickness of distal PAs. Overall, our data indicate that TFP could have beneficial effects in PAH and support the view that seeking new uses for old drugs may represent a fruitful approach.


Assuntos
Fármacos Cardiovasculares/farmacologia , Regulação da Expressão Gênica/efeitos dos fármacos , Hipertensão Pulmonar/tratamento farmacológico , Hipóxia/prevenção & controle , Miócitos de Músculo Liso/efeitos dos fármacos , Trifluoperazina/farmacologia , Animais , Antipsicóticos/farmacologia , Proliferação de Células/efeitos dos fármacos , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Reposicionamento de Medicamentos , Feminino , Proteína Forkhead Box O3/genética , Proteína Forkhead Box O3/metabolismo , Hemodinâmica/efeitos dos fármacos , Humanos , Hipertensão Pulmonar/induzido quimicamente , Hipertensão Pulmonar/genética , Hipertensão Pulmonar/fisiopatologia , Hipóxia/induzido quimicamente , Hipóxia/genética , Hipóxia/fisiopatologia , Indóis/administração & dosagem , Monocrotalina/administração & dosagem , Músculo Liso Vascular/citologia , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/metabolismo , Cultura Primária de Células , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Artéria Pulmonar/citologia , Artéria Pulmonar/efeitos dos fármacos , Artéria Pulmonar/metabolismo , Pirróis/administração & dosagem , Ratos , Ratos Sprague-Dawley , Survivina/genética , Survivina/metabolismo
4.
Int J Mol Sci ; 22(6)2021 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-33808898

RESUMO

Ferroptosis is gaining followers as mechanism of selective killing cancer cells in a non-apoptotic manner, and novel nanosystems capable of inducing this iron-dependent death are being increasingly developed. Among them, polydopamine nanoparticles (PDA NPs) are arousing interest, since they have great capability of chelating iron. In this work, PDA NPs were loaded with Fe3+ at different pH values to assess the importance that the pH may have in determining their therapeutic activity and selectivity. In addition, doxorubicin was also loaded to the nanoparticles to achieve a synergist effect. The in vitro assays that were performed with the BT474 and HS5 cell lines showed that, when Fe3+ was adsorbed in PDA NPs at pH values close to which Fe(OH)3 begins to be formed, these nanoparticles had greater antitumor activity and selectivity despite having chelated a smaller amount of Fe3+. Otherwise, it was demonstrated that Fe3+ could be released in the late endo/lysosomes thanks to their acidic pH and their Ca2+ content, and that when Fe3+ was co-transported with doxorubicin, the therapeutic activity of PDA NPs was enhanced. Thus, reported PDA NPs loaded with both Fe3+ and doxorubicin may constitute a good approach to target breast tumors.


Assuntos
Antineoplásicos/farmacologia , Ferroptose/efeitos dos fármacos , Indóis/química , Indóis/farmacologia , Nanopartículas/química , Polímeros/química , Polímeros/farmacologia , Animais , Neoplasias da Mama , Cálcio/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Feminino , Humanos , Ferro/química , Ferro/metabolismo , Camundongos , Espécies Reativas de Oxigênio/metabolismo
5.
Molecules ; 26(6)2021 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-33802860

RESUMO

The COVID-19 outbreak continues to spread worldwide at a rapid rate. Currently, the absence of any effective antiviral treatment is the major concern for the global population. The reports of the occurrence of various point mutations within the important therapeutic target protein of SARS-CoV-2 has elevated the problem. The SARS-CoV-2 main protease (Mpro) is a major therapeutic target for new antiviral designs. In this study, the efficacy of PF-00835231 was investigated (a Mpro inhibitor under clinical trials) against the Mpro and their reported mutants. Various in silico approaches were used to investigate and compare the efficacy of PF-00835231 and five drugs previously documented to inhibit the Mpro. Our study shows that PF-00835231 is not only effective against the wild type but demonstrates a high affinity against the studied mutants as well.


Assuntos
Antivirais/química , Antivirais/farmacologia , Indóis/química , Indóis/farmacologia , Leucina/química , Leucina/farmacologia , Inibidores de Proteases/química , Inibidores de Proteases/farmacologia , Pirrolidinonas/química , Pirrolidinonas/farmacologia , Sítios de Ligação , Simulação por Computador , /genética , Bases de Dados de Proteínas , Diarilquinolinas/química , Diarilquinolinas/farmacologia , Di-Hidropiridinas/química , Di-Hidropiridinas/farmacologia , Humanos , Ligantes , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Nitrobenzenos/química , Nitrobenzenos/farmacologia , Nitrofenóis/química , Nitrofenóis/farmacologia , Compostos Organofosforados/química , Compostos Organofosforados/farmacologia , Piperazinas/química , Piperazinas/farmacologia , Prolina/análogos & derivados , Prolina/química , Prolina/farmacologia , /genética
7.
Int J Mol Sci ; 22(5)2021 Mar 06.
Artigo em Inglês | MEDLINE | ID: mdl-33800748

RESUMO

The plant hormone indole-3-acetic acid (IAA) is one of the main signals playing a role in the communication between host and endophytes. Endophytes can synthesize IAA de novo to influence the IAA homeostasis in plants. Although much is known about IAA biosynthesis in microorganisms, there is still less known about the pathway by which IAA is synthesized in fungal endophytes. The aim of this study is to examine a possible IAA biosynthesis pathway in Cyanodermella asteris. In vitro cultures of C. asteris were incubated with the IAA precursors tryptophan (Trp) and indole, as well as possible intermediates, and they were additionally treated with IAA biosynthesis inhibitors (2-mercaptobenzimidazole and yucasin DF) to elucidate possible IAA biosynthesis pathways. It was shown that (a) C. asteris synthesized IAA without adding precursors; (b) indole-3-acetonitrile (IAN), indole-3-acetamide (IAM), and indole-3-acetaldehyde (IAD) increased IAA biosynthesis; and (c) C. asteris synthesized IAA also by a Trp-independent pathway. Together with the genome information of C. asteris, the possible IAA biosynthesis pathways found can improve the understanding of IAA biosynthesis in fungal endophytes. The uptake of fungal IAA into Arabidopsis thaliana is necessary for the induction of lateral roots and other fungus-related growth phenotypes, since the application of the influx inhibitor 2-naphthoxyacetic acid (NOA) but not the efflux inhibitor N-1-naphtylphthalamic acid (NPA) were altering these parameters. In addition, the root phenotype of the mutation in an influx carrier, aux1, was partially rescued by C. asteris.


Assuntos
Arabidopsis/microbiologia , Ascomicetos/metabolismo , Endófitos/metabolismo , Ácidos Indolacéticos/metabolismo , Indóis/farmacologia , Raízes de Plantas/microbiologia , Triptofano/farmacologia , Arabidopsis/metabolismo , Proteínas de Arabidopsis/genética , Ascomicetos/efeitos dos fármacos , Ascomicetos/genética , Benzimidazóis/farmacologia , Meios de Cultivo Condicionados , Genoma Fúngico , Glicolatos/farmacologia , Especificidade de Hospedeiro , Ácidos Indolacéticos/farmacologia , Indóis/metabolismo , Redes e Vias Metabólicas/genética , Ftalimidas/farmacologia , Raízes de Plantas/efeitos dos fármacos , Raízes de Plantas/genética , Triazóis/farmacologia , Triptofano/metabolismo
10.
Zhongguo Yi Xue Ke Xue Yuan Xue Bao ; 43(1): 32-36, 2021 Feb 28.
Artigo em Chinês | MEDLINE | ID: mdl-33663659

RESUMO

Objective To evaluate the effect of methylprednisolone sodium succinate combined with tropisetron on postoperative nausea and vomiting(PONV)under microvascular decompression of hemifacial spasm.Methods From January to June 2019,485 patients undergoing microvascular decompression for facial spasm at Department of Neurosurgery,Peking University People's Hospital were randomly assigned into two groups with random number table method.For group A(n=242),2 ml saline was administrated by intravenous drip before induction and 5 mg tropisetron after operation.For group B(n=243),40 mg methylprednisolone sodium succinate was administrated by intravenous drip before induction and 5 mg tropisetron after operation.The anesthesia time,operation time,and incidence of PONV in 0-24 h and 24-48 h were recorded for the comparison of the remedial treatment rate of nausea and vomiting between the two groups.Results There was no significant difference in age,gender,smoking history,body mass index value,American Society of Anesthesiologists score,medical history,surgical side,PONV history,operation time or anesthesia time between the two groups(all P > 0.05).The incidence of PONV in group A was 35.5% and 18.2% during 0-24 h and 24-48 h,respectively,which was significantly higher than that(18.5%,χ 2=7.331,P=0.007;8.2%,χ 2=4.364,P=0.037)in group B.The application rate of antiemetic drugs in group A was 15.2% and 8.7% during 0-24 h and 24-48 h,respectively,which was significantly higher than that(5.3%,χ 2=5.327,P=0.021;2.0%,χ 2=4.432,P=0.035)in group B.Conclusion The combination of methylprednisolone sodium succinate and tropisetron can effectively prevent PONV under microvascular decompression of hemifacial spasm,with the performance superior to single drug treatment.


Assuntos
Antieméticos , Espasmo Hemifacial , Cirurgia de Descompressão Microvascular , Método Duplo-Cego , Espasmo Hemifacial/tratamento farmacológico , Espasmo Hemifacial/cirurgia , Humanos , Indóis , Hemissuccinato de Metilprednisolona/uso terapêutico , Tropizetrona
11.
Nat Commun ; 12(1): 1689, 2021 03 16.
Artigo em Inglês | MEDLINE | ID: mdl-33727548

RESUMO

Administration of drugs via the buccal route has attracted much attention in recent years. However, developing systems with satisfactory adhesion under wet conditions and adequate drug bioavailability still remains a challenge. Here, we propose a mussel-inspired mucoadhesive film. Ex vivo models show that this film can achieve strong adhesion to wet buccal tissues (up to 38.72 ± 10.94 kPa). We also demonstrate that the adhesion mechanism of this film relies on both physical association and covalent bonding between the film and mucus. Additionally, the film with incorporated polydopamine nanoparticles shows superior advantages for transport across the mucosal barrier, with improved drug bioavailability (~3.5-fold greater than observed with oral delivery) and therapeutic efficacy in oral mucositis models (~6.0-fold improvement in wound closure at day 5 compared with that observed with no treatment). We anticipate that this platform might aid the development of tissue adhesives and inspire the design of nanoparticle-based buccal delivery systems.


Assuntos
Biomimética , Bivalves/química , Sistemas de Liberação de Medicamentos , Mucosa Bucal/fisiologia , Adesividade , Administração Bucal , Animais , Linhagem Celular , Dexametasona/farmacologia , Di-Hidroxifenilalanina/química , Liberação Controlada de Fármacos , Humanos , Indóis/toxicidade , Masculino , Mucinas/química , Muco/química , Nanopartículas/química , Nanopartículas/ultraestrutura , Tamanho da Partícula , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/toxicidade , Polímeros/toxicidade , Álcool de Polivinil/química , Álcool de Polivinil/toxicidade , Ratos Sprague-Dawley , Espectrofotometria Ultravioleta , Suínos , Distribuição Tecidual
12.
Carbohydr Polym ; 260: 117760, 2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-33712122

RESUMO

A transparent versatile cellulose platform film was prepared from Eucalyptus pulp in this work. Based on such cellulose platform, multifunctional cellulose films with ultraviolet-shielding, photochromism, and strong mechanical strength were fabricated via nucleophilic postmodification strategy by introducing a versatile spiropyran moiety into cellulose molecules. The fabricated cellulose films exhibited super-high transmittance up to 96% and performed notable ultraviolet-shielding capacity at 200-400 nm. Moreover, the photochromic performance of cellulose films with color changes could be clearly observed by the naked eyes, and the fluorescent blue could be excited. Besides, the tensile stress of multi-functional cellulose film was about 80 MPa, which was almost 8 times stronger than that of the commercial polyethylene film at the same thickness. It is noteworthy that these superior performances promote such a cellulose platform to be a versatile precursor for fabricating various multi-functional cellulose used in the fields of out-door coating, transparent packaging, optical screen,etc.


Assuntos
Celulose/química , Benzopiranos/química , Eucalyptus/metabolismo , Indóis/química , Nanocompostos/química , Nitrocompostos/química , Espectroscopia de Infravermelho com Transformada de Fourier , Protetores Solares/química , Propriedades de Superfície , Resistência à Tração , Raios Ultravioleta
13.
Nat Commun ; 12(1): 1883, 2021 03 25.
Artigo em Inglês | MEDLINE | ID: mdl-33767198

RESUMO

Natural product structure and fragment-based compound development inspire pseudo-natural product design through different combinations of a given natural product fragment set to compound classes expected to be chemically and biologically diverse. We describe the synthetic combination of the fragment-sized natural products quinine, quinidine, sinomenine, and griseofulvin with chromanone or indole-containing fragments to provide a 244-member pseudo-natural product collection. Cheminformatic analyses reveal that the resulting eight pseudo-natural product classes are chemically diverse and share both drug- and natural product-like properties. Unbiased biological evaluation by cell painting demonstrates that bioactivity of pseudo-natural products, guiding natural products, and fragments differ and that combination of different fragments dominates establishment of unique bioactivity. Identification of phenotypic fragment dominance enables design of compound classes with correctly predicted bioactivity. The results demonstrate that fusion of natural product fragments in different combinations and arrangements can provide chemically and biologically diverse pseudo-natural product classes for wider exploration of biologically relevant chemical space.


Assuntos
Produtos Biológicos/química , Produtos Biológicos/síntese química , Descoberta de Drogas/métodos , Quimioinformática , Cromonas/química , Griseofulvina/química , Indóis/química , Morfinanos/química , Quinidina/química , Quinina/química , Bibliotecas de Moléculas Pequenas/química
14.
Cell Death Dis ; 12(4): 310, 2021 03 24.
Artigo em Inglês | MEDLINE | ID: mdl-33762578

RESUMO

SARS-CoV-2 is responsible for the ongoing world-wide pandemic which has already taken more than two million lives. Effective treatments are urgently needed. The enzymatic activity of the HECT-E3 ligase family members has been implicated in the cell egression phase of deadly RNA viruses such as Ebola through direct interaction of its VP40 Protein. Here we report that HECT-E3 ligase family members such as NEDD4 and WWP1 interact with and ubiquitylate the SARS-CoV-2 Spike protein. Furthermore, we find that HECT family members are overexpressed in primary samples derived from COVID-19 infected patients and COVID-19 mouse models. Importantly, rare germline activating variants in the NEDD4 and WWP1 genes are associated with severe COVID-19 cases. Critically, I3C, a natural NEDD4 and WWP1 inhibitor from Brassicaceae, displays potent antiviral effects and inhibits viral egression. In conclusion, we identify the HECT family members of E3 ligases as likely novel biomarkers for COVID-19, as well as new potential targets of therapeutic strategy easily testable in clinical trials in view of the established well-tolerated nature of the Brassicaceae natural compounds.


Assuntos
/tratamento farmacológico , Ubiquitina-Proteína Ligases/antagonistas & inibidores , Ubiquitina-Proteína Ligases/metabolismo , Adulto , Idoso , Animais , Antivirais/farmacologia , /metabolismo , Chlorocebus aethiops , Complexos Endossomais de Distribuição Requeridos para Transporte/metabolismo , Feminino , Humanos , Indóis/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Pessoa de Meia-Idade , Ubiquitina-Proteína Ligases Nedd4/genética , Ubiquitina-Proteína Ligases Nedd4/metabolismo , /metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Ubiquitina-Proteína Ligases/genética , Ubiquitinação , Células Vero
15.
Life Sci ; 273: 119304, 2021 May 15.
Artigo em Inglês | MEDLINE | ID: mdl-33662432

RESUMO

AIMS: Necroptosis, an inflammatory form of regulated necrosis mediated by receptor-interacting kinase 1 (RIP1), RIP3, and pseudokinase mixed lineage kinase domain-like protein (MLKL) is extensively implicated in liver inflammatory disease. Thus identification small-molecule inhibitor of necroptosis has emerged as a potential therapeutic strategy to prevent liver damage. In this study, we identified 5-((7-chloro-6-fluoro-1 h-indol-3-yl) methyl)-3-methylimidazolidine-2,4-dione (F-nec) as a novel potent necroptosis inhibitor. MAIN METHODS: To find out the potent chemical inhibitors of necroptosis, human monocytic U937 cells were treated with a combination of tumor necrosis factor alpha (TNFα) and a pan-caspase inhibitor z-VAD-fmk. LPS and D-galactosamine (LPS/GalN) were further employed to simulate acute liver failure to explore therapeutic potency of F-nec in vivo. In addition, a specific inhibitor of c-Jun NH (2)-terminal kinases (JNK) SP600125 and its activator anisomycin are used to elucidate its mechanisms in acute liver failure therapy. Necroptosis pathway related proteins were tested by western blot. KEY FINDINGS: In this study, we identified F-nec as a novel potent RIP1 inhibitor which efficiently blocked TNFα-induced necroptosis in human and mice cells. Furthermore, pre-treatment of F-nec could prevent hepatic necrosis by reducing RIP1-mediated necroptosis also effectively ameliorated LPS/GalN induced acute liver failure by attenuating cell death signaling-stimulated JNK pathway activation and then suppressing JNK-triggered inflammation. SIGNIFICANCE: Altogether, this study demonstrates that F-nec is a potent inhibitor of RIP1 and highlights its great potential for use in the treatment of RIP1-driven inflammatory liver diseases.


Assuntos
Proteínas Ativadoras de GTPase/antagonistas & inibidores , Galactosamina/toxicidade , Indóis/química , Lipopolissacarídeos/toxicidade , Falência Hepática Aguda/tratamento farmacológico , Necroptose , Substâncias Protetoras/farmacologia , Animais , Humanos , Falência Hepática Aguda/induzido quimicamente , Falência Hepática Aguda/metabolismo , Falência Hepática Aguda/patologia , Camundongos , Camundongos Endogâmicos C57BL , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais , Células U937
16.
Nat Commun ; 12(1): 1517, 2021 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-33750821

RESUMO

Up to date, effective antivirals have not been widely available for treating COVID-19. In this study, we identify a dual-functional cross-linking peptide 8P9R which can inhibit the two entry pathways (endocytic pathway and TMPRSS2-mediated surface pathway) of SARS-CoV-2 in cells. The endosomal acidification inhibitors (8P9R and chloroquine) can synergistically enhance the activity of arbidol, a spike-ACE2 fusion inhibitor, against SARS-CoV-2 and SARS-CoV in cells. In vivo studies indicate that 8P9R or the combination of repurposed drugs (umifenovir also known as arbidol, chloroquine and camostat which is a TMPRSS2 inhibitor), simultaneously interfering with the two entry pathways of coronaviruses, can significantly suppress SARS-CoV-2 replication in hamsters and SARS-CoV in mice. Here, we use drug combination (arbidol, chloroquine, and camostat) and a dual-functional 8P9R to demonstrate that blocking the two entry pathways of coronavirus can be a promising and achievable approach for inhibiting SARS-CoV-2 replication in vivo. Cocktail therapy of these drug combinations should be considered in treatment trials for COVID-19.


Assuntos
Antivirais/farmacologia , Reposicionamento de Medicamentos , Peptídeos/farmacologia , Internalização do Vírus/efeitos dos fármacos , Animais , Chlorocebus aethiops , Cloroquina/farmacologia , Descoberta de Drogas , Feminino , Células HEK293 , Humanos , Indóis/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Serina Endopeptidases/metabolismo , Células Vero
17.
BMC Cancer ; 21(1): 270, 2021 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-33711962

RESUMO

BACKGROUND: Epidermal growth factor receptor (EGFR) is a target for cancer therapy as it is overexpressed in a wide variety of cancers. Therapeutic antibodies that bind EGFR are being evaluated in clinical trials as imaging agents for positron emission tomography and image-guided surgery. However, some of these antibodies have safety concerns such as infusion reactions, limiting their use in imaging applications. Nimotuzumab is a therapeutic monoclonal antibody that is specific for EGFR and has been used as a therapy in a number of countries. METHODS: Formulation of IRDye800CW-nimotuzumab for a clinical trial application was prepared. The physical, chemical, and pharmaceutical properties were tested to develop the specifications to determine stability of the product. The acute and delayed toxicities were tested and IRDye800CW-nimotuzumab was determined to be non-toxic. Non-compartmental pharmacokinetics analysis was used to determine the half-life of IRDye800CW-nimotuzumab. RESULTS: IRDye800CW-nimotuzumab was determined to be non-toxic from the acute and delayed toxicity study. The half-life of IRDye800CW-nimotuzumab was determined to be 38 ± 1.5 h. A bi-exponential analysis was also used which gave a t1/2 alpha of 1.5 h and t1/2 beta of 40.8 h. CONCLUSIONS: Here, we show preclinical studies demonstrating that nimotuzumab conjugated to IRDye800CW is safe and does not exhibit toxicities commonly associated with EGFR targeting antibodies.


Assuntos
Drogas em Investigação/administração & dosagem , Imunoconjugados/administração & dosagem , Neoplasias/diagnóstico por imagem , Imagem Óptica/métodos , Animais , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/farmacocinética , Anticorpos Monoclonais Humanizados/toxicidade , Benzenossulfonatos/administração & dosagem , Benzenossulfonatos/farmacocinética , Benzenossulfonatos/toxicidade , Linhagem Celular Tumoral , Ensaios Clínicos como Assunto , Estabilidade de Medicamentos , Drogas em Investigação/farmacologia , Drogas em Investigação/toxicidade , Receptores ErbB/antagonistas & inibidores , Feminino , Meia-Vida , Humanos , Imunoconjugados/farmacocinética , Imunoconjugados/toxicidade , Indóis/administração & dosagem , Indóis/farmacocinética , Indóis/toxicidade , Aplicação de Novas Drogas em Teste , Masculino , Camundongos , Neoplasias/patologia , Neoplasias/cirurgia , Cirurgia Assistida por Computador/métodos , Testes de Toxicidade Aguda , Ensaios Antitumorais Modelo de Xenoenxerto
18.
Life Sci ; 275: 119361, 2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-33774022

RESUMO

AIMS: Indole-3-carbinol (I3C) is a natural compound derived from brassica vegetables, displaying antibacterial activity. The study aims to elucidate the antibacterial mode of action(s) induced by indole-3-carbionol in Escherichia coli and enhance the understandings on the respective contribution of each reactive oxygen species (ROS), superoxide anion (O2-), hydrogen peroxide (H2O2), hydroxyl radical (OH-) during the process. MAIN METHODS: The antibacterial activity of I3C was assessed through kinetic assay. The generation of ROS was measured by flow cytometer using H2DCFDA dye, while further analysis of respective contribution was done through application of each scavenger: tiron, thiourea and sodium pyruvate. DNA fragmentation and chromatin condensation were observed by TUNEL and DAPI staining agent. Finally, Annexin V/PI, FITC-VAD-FMK and DiBAC4(3) was applied for detection of apoptosis-like death. KEY FINDINGS: I3C exhibited antibacterial activity in E. coli through accumulation of ROS and DNA damage, eventually leading to apoptosis-like death. Contribution of each ROS displayed respective manner, OH- exerting the most potent influence whereas O2- showed least impact. SIGNIFICANCE: Our study is the first to link I3C to the bacterial apoptosis-like death and displays the potential of this agent as a candidate for potential drugs that could help regulating the E. coli, an opportunistic human pathogen. Moreover, the study focused on investigating the individual contribution of each ROS during the process, trying to enhance the understanding regarding ROS and cellular processes followed by oxidative stress in bacteria.


Assuntos
Antibacterianos/farmacologia , Apoptose/efeitos dos fármacos , Escherichia coli/efeitos dos fármacos , Indóis/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Cromatina/efeitos dos fármacos , Dano ao DNA/efeitos dos fármacos , Escherichia coli/metabolismo , Peróxido de Hidrogênio/metabolismo , Radical Hidroxila/metabolismo , Oxigênio Singlete/metabolismo
19.
Int J Mol Sci ; 22(4)2021 Feb 18.
Artigo em Inglês | MEDLINE | ID: mdl-33670600

RESUMO

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of the synovial joints. Inflammation, new blood vessel formation (angiogenesis) and bone resorption (osteoclastogenesis) are three key processes involved in the joint damage and deformities of arthritis. Various gut microbiota-derived metabolites are implicated in RA pathogenesis. However, there is barely any information about the impact of two such metabolites, indole-3-aldehyde (IAld) and indole-3-acetic acid (I3AA), on arthritis-related processes. We conducted a comparative analysis of IAld and I3AA using established cell-based models to understand how they might influence RA pathogenesis. Although structurally similar, the bioactivities of these two metabolites were profoundly different. IAld but not I3AA, inhibited the expression of pro-inflammatory cytokines (IL-1ß and IL-6) in RAW 264.7 (RAW) cells stimulated with heat-killed M. tuberculosis sonicate (Mtb) and lipopolysaccharide (LPS). IAld also exhibited pro-angiogenic activity and pro-osteoclastogenic activity. In contrast, I3AA exhibited anti-angiogenic activity on endothelial cell tube formation but had no effect on osteoclastogenesis. Both IAld and I3AA have been proposed as aryl hydrocarbon receptor (AhR) agonists. Use of CH-223191, an inhibitor of the AhR, suppressed the anti-angiogenic activity of I3AA but failed to mitigate the effects of IAld. Further investigation of the anti-inflammatory activities of IAld and I3AA in LPS-treated RAW cells indicated that inhibition of MyD88-dependent activation of NF-κB and MAPK pathways was not likely involved. Our results suggest that the relative bioavailability of these indole derivatives may differentially impact RA progression and possibly other diseases that share similar cellular processes.


Assuntos
Artrite Reumatoide/imunologia , Doenças Autoimunes/imunologia , Citocinas/imunologia , Ácidos Indolacéticos/imunologia , Indóis/imunologia , Microbiota/imunologia , Animais , Artrite Reumatoide/metabolismo , Doenças Autoimunes/metabolismo , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/imunologia , Células Cultivadas , Citocinas/metabolismo , Temperatura Alta , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/imunologia , Células Endoteliais da Veia Umbilical Humana/fisiologia , Humanos , Ácidos Indolacéticos/metabolismo , Ácidos Indolacéticos/farmacologia , Indóis/metabolismo , Indóis/farmacologia , Lipopolissacarídeos/imunologia , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Mycobacterium tuberculosis/imunologia , Mycobacterium tuberculosis/metabolismo , Neovascularização Fisiológica/efeitos dos fármacos , Neovascularização Fisiológica/imunologia , Osteoclastos/citologia , Osteoclastos/efeitos dos fármacos , Osteoclastos/imunologia , Células RAW 264.7
20.
Molecules ; 26(5)2021 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-33670890

RESUMO

Prostate cancer is one of the most common cancers in men. Cell invasion is an important step in the process of cancer metastasis. Herein, gold nanorods (GNRs) and polyethylene glycol (PEG)-coated GNRs were conjugated with polydopamine (PDA). The PDA-nanoconjugates demonstrated excellent colloidal stability upon lyophilization and dispersion in cell culture media with or without the addition of fetal bovine albumin (FBS), compared to unconjugated GNRs. PDA-nanoconjugates exhibited a considerable cytotoxicity against DU-145 and PC3 prostate cancer cell lines over a concentration range of 48 µg/mL-12 µg/mL, while they were biocompatible over a concentration range of 3.0 µg/mL-0.185 µg/mL. Furthermore, PDA-nanoconjugates demonstrated possible anti-invasion activity towards prostate cancer cell lines, particularly DU-145 cell line, by reducing cell migration and cell adhesion properties. The PDA-nanoconjugates could be considered a promising nano-platform toward cancer treatment by reducing the invasion activity; it could also be considered a drug delivery system for chemotherapeutic agents.


Assuntos
Antineoplásicos/química , Ouro/química , Indóis/química , Nanoconjugados/química , Nanotubos/química , Polímeros/química , Neoplasias da Próstata/tratamento farmacológico , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Materiais Biocompatíveis/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Masculino , Polietilenoglicóis/química , Propriedades de Superfície
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