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1.
Anticancer Res ; 40(9): 5049-5057, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32878793

RESUMO

BACKGROUND/AIM: Studies with acridine compounds have reported anticancer effects. Herein, we evaluated the toxicity and antitumor effect of the (E)-1'-((4-chlorobenzylidene)amino)-5'-oxo-1',5'-dihydro-10H-spiro[acridine-9,2'-pyrrole]-4'-carbonitrile (AMTAC-06), a promising anticancer spiro-acridine compound. MATERIALS AND METHODS: The toxicity of AMTAC-06 was evaluated on zebrafish and mice. Antitumor activity was assessed in Ehrlich ascites carcinoma model. Effects on angiogenesis, cytokine levels and cell cycle were also investigated. RESULTS: AMTAC-06 did not induce toxicity on zebrafish and mice (LD50 approximately 5000 mg/kg, intraperitoneally). No genotoxicity was observed on micronucleus assay. AMTAC-06 significantly reduced the total viable Ehrlich tumor cells and increased sub-G1 peak, suggesting apoptosis was triggered. Moreover, the compound significantly decreased the density of peritumoral microvessels, indicating an anti-angiogenic action, possibly dependent on the cytokine modulation (TNF-α, IL-1ß and IFN-γ). No significant toxicological effects were recorded for AMTAC-06 on tumor transplanted animals. CONCLUSION: AMTAC-06 has low toxicity and a significant antitumor activity.


Assuntos
Acridinas/farmacologia , Inibidores da Angiogênese/farmacologia , Antineoplásicos/farmacologia , Fatores Imunológicos/farmacologia , Compostos de Espiro/farmacologia , Acridinas/química , Inibidores da Angiogênese/química , Animais , Antineoplásicos/química , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Fatores Imunológicos/química , Imunomodulação/efeitos dos fármacos , Camundongos , Estrutura Molecular , Compostos de Espiro/química , Ensaios Antitumorais Modelo de Xenoenxerto , Peixe-Zebra
2.
Nat Commun ; 11(1): 4578, 2020 09 14.
Artigo em Inglês | MEDLINE | ID: mdl-32929090

RESUMO

Thalidomide and its derivatives exert not only therapeutic effects as immunomodulatory drugs (IMiDs) but also adverse effects such as teratogenicity, which are due in part to different C2H2 zinc-finger (ZF) transcription factors, IKZF1 (or IKZF3) and SALL4, respectively. Here, we report the structural bases for the SALL4-specific proteasomal degradation induced by 5-hydroxythalidomide, a primary thalidomide metabolite generated by the enzymatic activity of cytochrome P450 isozymes, through the interaction with cereblon (CRBN). The crystal structure of the metabolite-mediated human SALL4-CRBN complex and mutagenesis studies elucidate the complex formation enhanced by the interaction between CRBN and an additional hydroxy group of (S)-5-hydroxythalidomide and the variation in the second residue of ß-hairpin structure that underlies the C2H2 ZF-type neo-morphic substrate (neosubstrate) selectivity of 5-hydroxythalidomide. These findings deepen our understanding of the pharmaceutical action of IMiDs and provide structural evidence that the glue-type E3 ligase modulators cause altered neosubstrate specificities through their metabolism.


Assuntos
Fatores Imunológicos/química , Fatores Imunológicos/farmacologia , Talidomida/análogos & derivados , Proteínas Adaptadoras de Transdução de Sinal/química , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Sequência de Aminoácidos , Células HEK293 , Humanos , Ligação Proteica/efeitos dos fármacos , Domínios Proteicos , Estereoisomerismo , Homologia Estrutural de Proteína , Especificidade por Substrato , Talidomida/química , Talidomida/farmacologia , Fatores de Transcrição/química , Fatores de Transcrição/metabolismo
3.
Sci Adv ; 6(23): eaaz5466, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32548259

RESUMO

Uncontrolled inflammatory processes are at the root of numerous pathologies. Most recently, studies on confirmed COVID-19 cases have suggested that mortality might be due to virally induced hyperinflammation. Uncontrolled pro-inflammatory states are often driven by continuous positive feedback loops between pro-inflammatory signaling and oxidative stress, which cannot be resolved in a targeted manner. Here, we report on the development of multidrug nanoparticles for the mitigation of uncontrolled inflammation. The nanoparticles are made by conjugating squalene, a natural lipid, to adenosine, an endogenous immunomodulator, and then encapsulating α-tocopherol, as antioxidant. This resulted in high drug loading, biocompatible, multidrug nanoparticles. By exploiting the endothelial dysfunction at sites of acute inflammation, these multidrug nanoparticles delivered the therapeutic agents in a targeted manner, conferring survival advantage to treated animals in models of endotoxemia. Selectively delivering adenosine and antioxidants together could serve as a novel therapeutic approach for safe treatment of acute paradoxal inflammation.


Assuntos
Sistemas de Liberação de Medicamentos/métodos , Endotoxemia/tratamento farmacológico , Nanopartículas/química , Esqualeno/química , Síndrome de Resposta Inflamatória Sistêmica/tratamento farmacológico , Adenosina/administração & dosagem , Adenosina/química , Animais , Antioxidantes/administração & dosagem , Antioxidantes/química , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Modelos Animais de Doenças , Endotoxemia/induzido quimicamente , Feminino , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/química , Lipopolissacarídeos/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Nanopartículas/administração & dosagem , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Esqualeno/administração & dosagem , Síndrome de Resposta Inflamatória Sistêmica/induzido quimicamente , Resultado do Tratamento , alfa-Tocoferol/administração & dosagem , alfa-Tocoferol/química
4.
Nat Struct Mol Biol ; 27(7): 605-614, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32541897

RESUMO

Controlled perturbation of protein activity is essential to study protein function in cells and living organisms. Small molecules that hijack the cellular protein ubiquitination machinery to selectively degrade proteins of interest, so-called degraders, have recently emerged as alternatives to selective chemical inhibitors, both as therapeutic modalities and as powerful research tools. These systems offer unprecedented temporal and spatial control over protein function. Here, we review recent developments in this field, with a particular focus on the use of degraders as research tools to interrogate complex biological problems.


Assuntos
Descoberta de Drogas/métodos , Fatores Imunológicos/farmacologia , Proteínas/metabolismo , Humanos , Fatores Imunológicos/química , Ácidos Indolacéticos/metabolismo , Lisossomos/efeitos dos fármacos , Lisossomos/metabolismo , Proteólise/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Sulfonamidas/química , Sulfonamidas/farmacologia , Ubiquitinação/efeitos dos fármacos
5.
Biochim Biophys Acta Proteins Proteom ; 1868(6): 140410, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32169581

RESUMO

Isomerization of aspartate (Asp) is a common non-enzymatic posttranslational modification. Isomerized residues accumulate in proteins associated with age-related human disorders such as cataract and are well known to affect protein structure and function. We previously detected d-Asp-containing peptides in human serum. In this study, we investigated whether isomerized Asp residues are present in human immunoglobulin G (IgG) kappa chain by a qualitative d-amino acid analysis based on diastereomer formation and liquid chromatography tandem mass spectrometry (LC-MS/MS). We also investigated the d/l ratio of Asp residues in the IgG kappa chain in serum from donors aged 25, 37, 41, 54 and 67 years. As a result, two isomerized Asp residues, Asp151 and Asp170, were detected in the IgG kappa chain, and the d/l ratio of these residues was found to increase with aging. To assess the effects of this isomerization, we synthesized four isomeric peptides of IgG kappa chain containing lα-, lß-, dα-, or dß-Asp at position 170, and compared their secondary structures by CD spectroscopy. Peptide containing normal lα-Asp170 showed type II ß-turn structure, while the other isomeric peptides showed random structure, clearly indicating that substitution of a single Asp isomer alters the secondary structure of the peptide. Because IgG is a main component of humoral immunity, Asp isomerization in IgG may reflect changes of structure and decrease in immune function. Proteome research on serum from the standpoint of racemization might enable us to develop new kinds of biomarker and new directions to study the aging process.


Assuntos
Envelhecimento/metabolismo , Ácido Aspártico/química , Imunoglobulina G/química , Fatores Imunológicos/química , Adulto , Idoso , Biomarcadores , Catarata/metabolismo , Cromatografia Líquida/métodos , Humanos , Imunoglobulina G/metabolismo , Cadeias kappa de Imunoglobulina , Isomerismo , Pessoa de Meia-Idade , Modelos Moleculares , Peptídeos/química , Processamento de Proteína Pós-Traducional , Proteoma , Soro , Estereoisomerismo , Espectrometria de Massas em Tandem/métodos
6.
J Med Chem ; 63(7): 3713-3722, 2020 04 09.
Artigo em Inglês | MEDLINE | ID: mdl-32196345

RESUMO

A growing class of immunotherapeutics work by redirecting components of the immune system to recognize markers on the surface of cancer cells. However, such modalities will remain confined to a relatively small subgroup of patients because of the lack of universal targetable tumor biomarkers among all patients. Here, we designed a unique class of agents that exploit the inherent acidity of solid tumors to selectively graft cancer cells with immuno-engager epitopes. Our targeting approach is based on pHLIP, a unique peptide that selectively targets tumors in vivo by anchoring to cancer cell surfaces in a pH-dependent manner. We established that pHLIP-antigen conjugates trigger the recruitment of antibodies to the surface of cancer cells and induce cytotoxicity by peripheral blood mononuclear and engineered NK cells. These results indicate that these agents have the potential to be applicable to treating a wide range of solid tumors and to circumvent problems associated with narrow windows of selectivity.


Assuntos
Epitopos/farmacologia , Fatores Imunológicos/farmacologia , Proteínas de Membrana/farmacologia , 2,4-Dinitrofenol/química , 2,4-Dinitrofenol/imunologia , 2,4-Dinitrofenol/farmacologia , Sequência de Aminoácidos , Animais , Anticorpos Monoclonais/imunologia , Linhagem Celular Tumoral , Epitopos/química , Epitopos/imunologia , Fluoresceína-5-Isotiocianato/química , Fluoresceína-5-Isotiocianato/metabolismo , Fluoresceína-5-Isotiocianato/farmacologia , Humanos , Concentração de Íons de Hidrogênio , Fatores Imunológicos/química , Fatores Imunológicos/metabolismo , Imunoterapia/métodos , Células Matadoras Naturais/efeitos dos fármacos , Proteínas de Membrana/química , Proteínas de Membrana/metabolismo , Camundongos , Neoplasias/metabolismo , Neoplasias/terapia
7.
Science ; 368(6489): 387-394, 2020 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-32193360

RESUMO

The two tandem bromodomains of the BET (bromodomain and extraterminal domain) proteins enable chromatin binding to facilitate transcription. Drugs that inhibit both bromodomains equally have shown efficacy in certain malignant and inflammatory conditions. To explore the individual functional contributions of the first (BD1) and second (BD2) bromodomains in biology and therapy, we developed selective BD1 and BD2 inhibitors. We found that steady-state gene expression primarily requires BD1, whereas the rapid increase of gene expression induced by inflammatory stimuli requires both BD1 and BD2 of all BET proteins. BD1 inhibitors phenocopied the effects of pan-BET inhibitors in cancer models, whereas BD2 inhibitors were predominantly effective in models of inflammatory and autoimmune disease. These insights into the differential requirement of BD1 and BD2 for the maintenance and induction of gene expression may guide future BET-targeted therapies.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Antineoplásicos/farmacologia , Proteínas de Ciclo Celular/antagonistas & inibidores , Histona Acetiltransferases/antagonistas & inibidores , Fatores Imunológicos/farmacologia , Terapia de Alvo Molecular , Fatores de Transcrição/antagonistas & inibidores , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/uso terapêutico , Antineoplásicos/uso terapêutico , Proteínas de Ciclo Celular/química , Proteínas de Ciclo Celular/genética , Descoberta de Drogas , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Células HEK293 , Histona Acetiltransferases/química , Histona Acetiltransferases/genética , Humanos , Doenças do Sistema Imunitário/tratamento farmacológico , Fatores Imunológicos/química , Fatores Imunológicos/uso terapêutico , Inflamação/tratamento farmacológico , Neoplasias/tratamento farmacológico , Domínios Proteicos/efeitos dos fármacos , Fatores de Transcrição/química , Fatores de Transcrição/genética
8.
J Agric Food Chem ; 68(9): 2664-2672, 2020 Mar 04.
Artigo em Inglês | MEDLINE | ID: mdl-32033515

RESUMO

The immunomodulatory activity of a few Lactobacillus exopolysaccharides (EPS) has been reported. However, whether Lactobacillus EPS can promote the differentiation of CD4 T lymphocytes (CD4+T) cells into T-helper 17 cells (Th17 cells) in the Peyer's Patches (PPs) of mice has not been addressed. In this study, we found the molecular weight (Mw) of the purified EPS from L. casei ranged from 2.7 × 106 Da to 1.7 × 107 Da, and the average Mw was approximately 8.4 × 106 Da. In healthy BALB/c mice, EPS elevated the numbers of Th17 cells and levels of Th17-related cytokines. In vitro, EPS induced BMDCs to stimulate the differentiation of CD4+T cells of PPs into Th17 cells and the related cytokine secretions. Results suggest that L. casei EPS can effectively induce and promote the differentiation of CD4+T cells of PPs into Th17 cells in healthy mice and has the potential ability to improve intestinal mucosa immunity.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Fatores Imunológicos/farmacologia , Lactobacillus casei/química , Nódulos Linfáticos Agregados/efeitos dos fármacos , Polissacarídeos Bacterianos/farmacologia , Células Th17/imunologia , Animais , Citocinas/genética , Citocinas/imunologia , Feminino , Fatores Imunológicos/química , Fatores Imunológicos/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/imunologia , Lactobacillus casei/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Peso Molecular , Nódulos Linfáticos Agregados/citologia , Nódulos Linfáticos Agregados/imunologia , Polissacarídeos Bacterianos/química , Polissacarídeos Bacterianos/metabolismo , Células Th17/citologia , Células Th17/efeitos dos fármacos
9.
J Steroid Biochem Mol Biol ; 198: 105573, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32017993

RESUMO

A series of novel diosgenin (DSG) and tigogenin (TGG) derivatives with diosgenin or tigogenin steroid aglycons linked to levulinic and 3,4-dihydroxycinnamic acids, dipeptides and various amino acids by an ester bond at the C3-oxygen atom of the steroid skeleton has been synthesized. Diosgenyl esters have been prepared by an esterification reaction (DCC/DMAP) of diosgenin with the corresponding acids. All analogues have been evaluated in vitro for their antiproliferative profile against cancer cell lines (MCF-7, MDA-MB-231, PC-3) and human umbilical vein endothelial cells (HUVEC). Analogue2c (l-serine derivative of TGG), the best representative of the series showed IC50 of 1.5 µM (MCF-7), and induced apoptosis in MCF-7 by activating caspase-3/7. The immunomodulatory properties of six synthesized analogues have been determined by examining their effects on the expression of cytokine genes essential for the functioning of the human immune system (IL-1, IL-4, IL-10, IL-12 and TNF-α). Biological evaluation has revealed that new compounds 4c and 16a do not induce the expression of pro-inflammatory cytokines in THP-1 cells after the lipopolysaccharide (LPS) stimulation. They also stimulate the expression of anti-inflammatory IL-10 that acts stronger than diosgenin itself. An in silico ADME properties(absorption, distribution, metabolism, excretion) study was also performed to predict the pharmacokinetic profile of the synthesized compounds. To shed light on the molecular interactions between the synthesized compounds and the glucocorticoid receptor and the estrogen receptor, 2c, 4c and 16a compounds were docked into the active binding sites of these receptors. The in silico and in vitro data suggested that this new group of compounds might be considered as a promising scaffold for further modification of more potent and selective anticancer and immunomodulatory agents.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Diosgenina/análogos & derivados , Diosgenina/farmacologia , Espirostanos/química , Espirostanos/farmacologia , Anti-Inflamatórios/síntese química , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Antineoplásicos/síntese química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Diosgenina/síntese química , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Células Endoteliais da Veia Umbilical Humana , Humanos , Fatores Imunológicos/síntese química , Fatores Imunológicos/química , Fatores Imunológicos/farmacologia , Células MCF-7 , Simulação de Acoplamento Molecular , Células PC-3 , Espirostanos/síntese química
10.
EBioMedicine ; 52: 102645, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32014819

RESUMO

BACKGROUND: TLRs are some of the actively pursued drug-targets in immune disorders. Owing to a recent surge in the cognizance of TLR structural biology and signalling pathways, numerous therapeutic modulators, ranging from low-molecular-weight organic compounds to polypeptides and nucleic acid agents have been developed. METHODS: A penetratin-conjugated small peptide (TIP3), derived from the core ß-sheet of TIRAP, was evaluated in vitro by monitoring the TLR-mediated cytokine induction and quantifying the protein expression using western blot. The therapeutic potential of TIP3 was further evaluated in TLR-dependent in vivo disease models. FINDINGS: TIP3 blocks the TLR4-mediated cytokine production through both the MyD88- and TRIF-dependent pathways. A similar inhibitory-effect was exhibited for TLR3 but not on other TLRs. A profound therapeutic effect was observed in vivo, where TIP3 successfully alleviated the inflammatory response in mice model of collagen-induced arthritis and ameliorated the disease symptoms in psoriasis and SLE models. INTERPRETATION: Our data suggest that TIP3 may be a potential lead candidate for the development of effective therapeutics against TLR-mediated autoimmune disorders. FUNDING: This work was supported by the National Research Foundation of Korea (NRF-2019M3A9A8065098, 2019M3D1A1078940 and 2019R1A6A1A11051471). The funders did not have any role in the design of the present study, data collection, data analysis, interpretation, or the writing of the manuscript.


Assuntos
Glicoproteínas de Membrana/química , Peptídeos/química , Peptídeos/farmacologia , Conformação Proteica em Folha beta , Receptores de Interleucina-1/química , Receptor 4 Toll-Like/química , Sequência de Aminoácidos , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Autoimunidade , Linhagem Celular , Citocinas/metabolismo , Modelos Animais de Doenças , Fatores Imunológicos/química , Fatores Imunológicos/farmacologia , Inflamação/tratamento farmacológico , Inflamação/etiologia , Inflamação/metabolismo , Inflamação/patologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/metabolismo , Glicoproteínas de Membrana/metabolismo , Camundongos , Modelos Moleculares , Óxido Nítrico/metabolismo , Peptídeos/metabolismo , Psoríase/tratamento farmacológico , Psoríase/imunologia , Psoríase/metabolismo , Psoríase/patologia , Espécies Reativas de Oxigênio/metabolismo , Receptores de Interleucina-1/metabolismo , Transdução de Sinais , Relação Estrutura-Atividade , Receptor 4 Toll-Like/metabolismo , Receptores Toll-Like/metabolismo
11.
Phytochemistry ; 171: 112231, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31901473

RESUMO

Daphne giraldii Nitsche., a member of the genus Daphne (Thymelaeaceae), is a deciduous shrub with mild toxicity. Its rhizome bark, generally called 'Zushima' in Chinese, has many medicinal folkloric uses and good therapeutic effects. Previous studies investigating the chemical constituents and pharmacological activities of D. giraldii have focused on several major classes of compounds, such as coumarins, lignans and flavonoids, especially the interesting enantiomeric flavans. Extracts and pure compounds of D. giraldii were found to possess anti-inflammatory, anti-nociceptive, cytotoxicity, antimalarial, immunomodulating, sedative and hypnotic effects. They have also been reported to influence the cardiovascular functions and blood activities. This comprehensive review will describe the advances in the phytochemistry, pharmacology, medicinal uses and clinical applications of D. giraldii and its formulations covering the literature published from 1970 to 2018. Almost half of the reviewed studies were originally published in non-English languages (mainly in Chinese). Collectively, the aim of this article is to open new avenues for further in-depth pharmacological studies on D. giraldii.


Assuntos
Compostos Fitoquímicos/farmacologia , Thymelaeaceae/química , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/isolamento & purificação , Anti-Inflamatórios não Esteroides/farmacologia , Fármacos Antiobesidade/química , Fármacos Antiobesidade/isolamento & purificação , Fármacos Antiobesidade/farmacologia , Antimaláricos/química , Antimaláricos/isolamento & purificação , Antimaláricos/farmacologia , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Antineoplásicos Fitogênicos/farmacologia , Humanos , Hipnóticos e Sedativos/química , Hipnóticos e Sedativos/isolamento & purificação , Hipnóticos e Sedativos/farmacologia , Fatores Imunológicos/química , Fatores Imunológicos/isolamento & purificação , Fatores Imunológicos/farmacologia , Compostos Fitoquímicos/química , Compostos Fitoquímicos/isolamento & purificação
12.
Biochim Biophys Acta Gen Subj ; 1864(4): 129532, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31953126

RESUMO

BACKGROUND: Hybridization is a useful strategy to bond the advantages of different peptides into novel constructions. We designed a series of AMPs based on the structures of a synthetic AMP KFA3 and a naturally-occurred host defense peptide substance P (SP) to obtain peptides retaining the high antibacterial activity of KFA3 and the immunomodulatory activity and low cytotoxicity of SP. METHODS: Two repeats of KFA and different C terminal fragments of SP were hybridized, generating a series of novel AMPs (KFSP1-8). The antibacterial activities, host cell toxicity and immunomodulation were measured. The antibacterial mechanisms were investigated. RESULTS: Hybrid peptides KFSP1-4 exerted substantial antibacterial activities against Gram-negative bacteria of standard strains and clinical drug-resistant isolates including E.coli, A.baumannii and P.aeruginosa, while showing little toxicity towards host cells. Compared with KFA3, moderate reduction in α-helix content and the interruption in α-helix continuality were indicated in CD spectra analysis and secondary-structure simulation in these peptides. Membrane permeabilization combined with time-kill studies and FITC-labeled imaging, indicated a selective membrane interaction of KFSP1 with bacteria cell membranes. By specially activating NK1 receptor, the hybrid peptides kept the ability of SP to induce intracellular calcium release and ERK1/2 phosphorylation, but unable to stimulate NF-κB phosphorylation. KFSP1 facilitated the survival of mouse macrophage RAW264.7, directly interacting with LPS and inhibiting the LPS-induced NF-κB phosphorylation and TNF-α expression. CONCLUSION: Hybridization is a useful strategy to bond the advantages of different peptides. KFSP1 and its analogs are worth of advanced efforts to explore their potential applications as novel antimicrobial agents.


Assuntos
Antibacterianos/farmacologia , Bactérias Gram-Negativas/efeitos dos fármacos , Fatores Imunológicos/farmacologia , Oligopeptídeos/farmacologia , Substância P/farmacologia , Animais , Antibacterianos/síntese química , Antibacterianos/química , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Bactérias Gram-Negativas/química , Células Hep G2 , Humanos , Fatores Imunológicos/síntese química , Fatores Imunológicos/química , Lipopolissacarídeos/antagonistas & inibidores , Camundongos , Oligopeptídeos/síntese química , Oligopeptídeos/química , Células RAW 264.7 , Relação Estrutura-Atividade , Substância P/síntese química , Substância P/química
13.
Ann Neurol ; 87(3): 442-455, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31925846

RESUMO

OBJECTIVE: There are currently no definitive disease-modifying therapies for traumatic brain injury (TBI). In this study, we present a strong therapeutic candidate for TBI, immunomodulatory nanoparticles (IMPs), which ablate a specific subset of hematogenous monocytes (hMos). We hypothesized that prevention of infiltration of these cells into brain acutely after TBI would attenuate secondary damage and preserve anatomic and neurologic function. METHODS: IMPs, composed of US Food and Drug Administration-approved 500nm carboxylated-poly(lactic-co-glycolic) acid, were infused intravenously into wild-type C57BL/6 mice following 2 different models of experimental TBI, controlled cortical impact (CCI), and closed head injury (CHI). RESULTS: IMP administration resulted in remarkable preservation of both tissue and neurological function in both CCI and CHI TBI models in mice. After acute treatment, there was a reduction in the number of immune cells infiltrating into the brain, mitigation of the inflammatory status of the infiltrating cells, improved electrophysiologic visual function, improved long-term motor behavior, reduced edema formation as assessed by magnetic resonance imaging, and reduced lesion volumes on anatomic examination. INTERPRETATION: Our findings suggest that IMPs are a clinically translatable acute intervention for TBI with a well-defined mechanism of action and beneficial anatomic and physiologic preservation and recovery. Ann Neurol 2020;87:442-455.


Assuntos
Lesões Encefálicas Traumáticas/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Administração Intravenosa , Animais , Encéfalo/imunologia , Encéfalo/patologia , Lesões Encefálicas Traumáticas/imunologia , Lesões Encefálicas Traumáticas/patologia , Movimento Celular/efeitos dos fármacos , Edema/complicações , Edema/tratamento farmacológico , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/química , Imagem por Ressonância Magnética , Masculino , Camundongos , Nanopartículas/administração & dosagem , Nanopartículas/química , Neuroimagem , Recuperação de Função Fisiológica/efeitos dos fármacos
14.
Carbohydr Polym ; 232: 115804, 2020 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-31952602

RESUMO

In this present study, the structure and immunomodulatory activity of a novel polysaccharide (WSRP-1b) from Kushui rose (Rosa setate x Rosa rugosa) waste were investigated. Structure characterization demonstrated that WSRP-1b had a weight-average molecular weight of 1.11 × 104 Da and consisted of glucose (42.6 %), mannose (21.4 %), arabinose (9.9 %), xylose (2.2 %), and galactose (23.9 %). Its backbone was composed of 1, 4-linked α-Glcp, 1, 4-linked ß-Glcp, and 1, 4-linked ß-Manp, with branches of 1, 4-linked α-Glcp and 1, 4-linked ß-Manp substituted at C-6 by 1, 6-linked ß-Galp. The branches mainly contained 1, 5-linked Araf, terminal arabinose and terminal glucose. Bioactivity assays showed that WSRP-1b had immunomodulatory activity by enhancing phagocytosis of macrophages, increasing production of ROS, NO, cytokines (IL-6, TNF-α), and activating NF-κB signaling pathway. These results suggested that it could be developed as a potential and safe immunomodulatory agent in fields of pharmacological or functional foods.


Assuntos
Fatores Imunológicos/farmacologia , Macrófagos/efeitos dos fármacos , Polissacarídeos/farmacologia , Rosa/química , Configuração de Carboidratos , Citocinas/biossíntese , Humanos , Fatores Imunológicos/química , Macrófagos/metabolismo , NF-kappa B/imunologia , Óxido Nítrico/biossíntese , Polissacarídeos/química , Espécies Reativas de Oxigênio/metabolismo
15.
Eur J Med Chem ; 188: 111977, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31927313

RESUMO

a series of 2-oxospiro[indoline-3,4'-pyran]derivatives 4 and 7 were obtained in good yield under mild conditions from the one-pot reaction of indole-2,3-dione derivatives 1, appropriate methylene active nitriles 2 and ß-dicarbonyl compound 3 or 6. The newly synthesized compounds were characterized and evaluated for their in vitro antibacterial, antifungal as well as immunomodulatory activity. According to MIC values, the most potent compounds 4f, 4h, 7a, 7c, 7e, 7f, 7g, 8a, and 8c were evaluated for MBC and displayed high activity to killing pathogens with a good MBC value against norfloxacin as well as investigated against an extended panel of multidrug resistance bacteria (MDRB) and exhibited promising to moderate multidrug resistance activities, compounds 7f showed the much better than norfloxacin with higher potency results. Furthermore, the most potent compounds showed an increase in the intracellular killing activity of neutrophils which confirmed the immunostimulatory power. Eight of the nine active compounds exhibited inhibitory activities with IC50 ranged between (18.07 ± 0.18) to (27.03 ± 0.24) µM stronger than ciprofloxacin (26.43 ± 0.64 µM) for S. aureus DNA gyrase. Molecular docking was performed inside the active site of S. aureus DNA gyrase to predict the binding mode.


Assuntos
Antibacterianos/farmacologia , Antifúngicos/farmacologia , Sulfonatos de Arila/farmacologia , Fatores Imunológicos/farmacologia , Compostos de Espiro/farmacologia , Inibidores da Topoisomerase/farmacologia , Antibacterianos/síntese química , Antibacterianos/química , Antifúngicos/síntese química , Antifúngicos/química , Sulfonatos de Arila/síntese química , Sulfonatos de Arila/química , DNA Girase/metabolismo , Relação Dose-Resposta a Droga , Fungos/efeitos dos fármacos , Bactérias Gram-Negativas/efeitos dos fármacos , Bactérias Gram-Positivas/efeitos dos fármacos , Fatores Imunológicos/síntese química , Fatores Imunológicos/química , Testes de Sensibilidade Microbiana , Simulação de Acoplamento Molecular , Estrutura Molecular , Compostos de Espiro/síntese química , Compostos de Espiro/química , Relação Estrutura-Atividade , Inibidores da Topoisomerase/síntese química , Inibidores da Topoisomerase/química
16.
Planta Med ; 86(2): 96-103, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31777053

RESUMO

Novel immunomodulating agents are currently sought after for the treatment of autoimmune diseases and cancers. In this context, a screening campaign of a collection of 575 cyanobacteria extracts for immunomodulatory effects has been conducted. The screening resulted in several active extracts. Here we report the results of subsequent studies on an extract from the cyanobacterium Hapalosiphon sp. CBT1235. We identified 5 hapalindoles as the compounds responsible for the observed immunomodulatory effect. These indole alkaloids are produced by several strains of the cyanobacterial family Hapalosiphonaceae. They are known for their anti-infective, cytotoxic, and other bioactivities. Modulation of the activity of human immune cells has not yet been described. The immunomodulatory activity of the hapalindoles was characterized in vitro using flow cytometry-based measurements of T cell proliferation after carboxyfluorescein diacetate succinimidyl ester staining, and apoptosis and necrosis induction after annexin V/propidium iodide staining. The most potent compound, hapalindole A, reduced T cell proliferation with an IC50 of 1.56 µM, while relevant levels of apoptosis were measurable only at 10-fold higher concentrations. Hapalindole A-formamide and hapalindole J-formamide, isolated for the first time from a natural source, had much lower activity than the nonformylated derivatives while, at the same time, being less selective for antiproliferative over apoptotic effects.


Assuntos
Proliferação de Células/efeitos dos fármacos , Cianobactérias/química , Fatores Imunológicos/farmacologia , Alcaloides Indólicos/farmacologia , Linfócitos T/efeitos dos fármacos , Adulto , Humanos , Fatores Imunológicos/química , Fatores Imunológicos/isolamento & purificação , Alcaloides Indólicos/química , Alcaloides Indólicos/isolamento & purificação , Estrutura Molecular , Linfócitos T/citologia
17.
Eur J Med Chem ; 187: 111949, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31830637

RESUMO

A combination therapeutic regimen via introducing tryptophan 2,3-dioxygenase inhibitors into microtubule inhibitors was performed and evaluated for their antitumor activity. Thereinto, HT2, composed of combretastatin A-4 (CA-4) and tryptophan-2,3-dioxygenase (TDO) inhibitor by a linker, displayed the most potent activity with 10-fold higher than its parent CA-4 against HepG2, A549 and HCT-116 cancer cell lines. Mechanism studies suggested that HT2 inhibited tubulin polymerization and cell migration, caused G2 phase arrest, induced apoptosis by mitochondrial mediated apoptotic pathway, concurrent depolarized the mitochondria membrane potentials and caused reactive oxygen species (ROS) production in HepG2 cells. Moreover, HT2 could enhance T-cell immune responses in vitro by releasing a TDO inhibitor to suppress TDO expression and blockade kynurenine production. As expected, HT2 could remarkably promote the antitumor activity of CA-4 in either immunocompetent H22 or immunodeficient A549 tumor xenograft models without observable toxic effects. More importantly, HT2 increased the level of splenic and tumor-infiltrated T cells and in turn effectively boosted the inhibition effect in H22 xenografted tumor growth. Collectively, this immunochemotherapeutic strategy can be applied to promote chemotherapeutic effect.


Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , Fatores Imunológicos/farmacologia , Microtúbulos/efeitos dos fármacos , Triptofano Oxigenase/antagonistas & inibidores , Tubulina (Proteína)/metabolismo , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Fatores Imunológicos/síntese química , Fatores Imunológicos/química , Imunomodulação/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Estrutura Molecular , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Polimerização/efeitos dos fármacos , Relação Estrutura-Atividade , Triptofano Oxigenase/metabolismo
18.
Eur J Med Chem ; 185: 111853, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31732253

RESUMO

Immune suppression in the tumor microenvironment (TME) is an intractable issue in anti-cancer immunotherapy. The chemokine receptors CXCR1 and CXCR2 recruit immune suppressive cells such as the myeloid derived suppressor cells (MDSCs) to the TME. Therefore, CXCR1/2 antagonists have aroused pharmaceutical interest in recent years. In this review, the medicinal chemistry of CXCR1/2 antagonists and their relevance in cancer immunotherapy have been summarized. The development of the drug candidates, along with their design rationale, clinical status and current challenges have also been discussed.


Assuntos
Fatores Imunológicos/farmacologia , Imunoterapia , Neoplasias/terapia , Receptores de Interleucina-8A/agonistas , Receptores de Interleucina-8B/agonistas , Animais , Relação Dose-Resposta a Droga , Humanos , Fatores Imunológicos/química , Estrutura Molecular , Neoplasias/imunologia , Receptores de Interleucina-8A/imunologia , Receptores de Interleucina-8B/imunologia , Relação Estrutura-Atividade
19.
Carbohydr Polym ; 227: 115314, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31590844

RESUMO

The physicochemical properties, structural features and immunomodulatory effects of the white asparagus (Asparagus officinalis L.) skin polysaccharides (WASP) were systematically studied. WASP showed a pectic-like structure with a relatively low degree of esterification (DE, 18%); the weight-average molecular weight (Mw) and intrinsic viscosity were 76.1 kDa and 13 mL/g, respectively. Structurally, the dominated sugar residue of WASP was 4-α-D-GalpA (39.7 mol%), while other residues including α-L-Araf, 3-α-L-Rhap, 2,4-α-L-Rhap, and 4-ß-D-Galp were also detected with a comparable amount. A proposed structure of WASP was also presented. Physiologically, WASP could modulate the immune response of RAW 264.7 macrophages through increasing the release of immune factors (IL-6, TNF-α and IL-10) and improving the expression of mRNA. To conclude, the pectic-like polysaccharides from white asparagus (Asparagus officinalis L.) skin could be potentially used as an immunomodulatory agent in functional food.


Assuntos
Asparagus (Planta) , Fatores Imunológicos/química , Fatores Imunológicos/farmacologia , Polissacarídeos/química , Polissacarídeos/farmacologia , Animais , Sobrevivência Celular/efeitos dos fármacos , Citocinas/genética , Citocinas/metabolismo , Camundongos , Estrutura Molecular , Peso Molecular , Células RAW 264.7 , RNA Mensageiro/metabolismo
20.
Carbohydr Polym ; 227: 115354, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31590849

RESUMO

Certain polysaccharides can serve as bio-active natural polymers that provide health benefits, however their complex structures tend to induce dramatically different activities. In this work, the immunomodulatory activity of the two arabinogalactans from larch was investigated, based upon comparison of native arabinogalactans and those modified to have lesser quantities of side-chain paraphernalia. Various in vitro assays demonstrated that the native arabinogalactans increased the secretion of macrophage-derived biological factors including NO, TNF-α, IL-1ß and IL-6. Methylation analysis and nuclear magnetic resonance spectra results indicated that part side chains of arabinogalactan were successfully removed. Partial removal of the side-chains enhanced immunomodulatory activity, while excessive removal resulted in a sharp decrease in immunomodulatory activity. These results provide new evidence that alludes to the structure-function relationship of bio-active polysaccharides, furthering the case for development of a universal assessment of polysaccharide structure-function proclivities.


Assuntos
Galactanos/química , Galactanos/farmacologia , Fatores Imunológicos/química , Fatores Imunológicos/farmacologia , Larix , Animais , Sobrevivência Celular/efeitos dos fármacos , Citocinas/metabolismo , Camundongos , Óxido Nítrico/metabolismo , Células RAW 264.7 , Relação Estrutura-Atividade
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