RESUMO
Selenium is capable of forming a dynamic covalent bond with itself and other elements and can undergo metathesis and regeneration reactions under optimum conditions. Its dynamic nature endows selenium-containing polymers with striking sensitivity towards some environmental alterations. In the past decade, several selenium-containing polymers were synthesized and used for the preparation of oxidation-, reduction-, and radiation-responsive nanocarriers. Recently, thioredoxin reductase, sonication, and osmotic pressure triggered the cleavage of Se-Se bonds and swelling or disassembly of nanostructures. Moreover, some selenium-containing nanocarriers form oxidation products such as seleninic acids and acrylates with inherent anticancer activities. Thus, selenium-containing polymers hold promise for the fabrication of ultrasensitive and multifunctional nanocarriers of radiotherapeutic, chemotherapeutic, and immunotherapeutic significance. Herein, we discuss the most recent developments in selenium-containing polymeric micelles in light of their architecture, multiple stimuli-responsive properties, emerging immunomodulatory activities, and future perspectives in the delivery and controlled release of anticancer agents.
Assuntos
Antineoplásicos/farmacologia , Materiais Biocompatíveis/farmacologia , Desenvolvimento de Medicamentos , Fatores Imunológicos/farmacologia , Neoplasias/tratamento farmacológico , Polímeros/farmacologia , Selênio/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Materiais Biocompatíveis/síntese química , Materiais Biocompatíveis/química , Portadores de Fármacos/química , Portadores de Fármacos/farmacologia , Liberação Controlada de Fármacos , Humanos , Fatores Imunológicos/síntese química , Fatores Imunológicos/química , Teste de Materiais , Micelas , Tamanho da Partícula , Polímeros/síntese química , Polímeros/química , Selênio/químicaRESUMO
To explore the disease resistance mechanism of chitosan conjugates, chitosan-gentamicin conjugate (CS-GT) was synthesized and systematically characterized, the immune mechanism of CS-GT on Litopenaeus vannamei infected with Vibrio parahaemolyticus was further explored. The results showed that imine groups in CS-GT were effectively reduced. Dietary supplementation of CS-GT can significantly increase the survival rate, total hemocyte counts, the antioxidant and immune related enzyme activity levels of shrimps (P < 0.05), which are all dose-dependent under the experimental conditions. In addition, CS-GT can protect the hepatopancreas from invading bacteria and alleviate inflammation. Particularly, CS-GT promotes the expressions of legumain (LGMN), lysosomal acid lipase (LIPA) and Niemann-Pick type C2 (NPC2) up-regulated. It is speculated that CS-GT may stimulate the lysosome to phagocytose pathogens more effectively. In conclusions, shrimps fed with CS-GT can produce immune response via lysosome and greatly improve the disease resistance to Vibrio parahaemolyticus.
Assuntos
Quitosana/análogos & derivados , Quitosana/uso terapêutico , Gentamicinas/uso terapêutico , Imunidade Inata/efeitos dos fármacos , Fatores Imunológicos/uso terapêutico , Penaeidae/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Quitosana/síntese química , Cisteína Endopeptidases/metabolismo , Suplementos Nutricionais , Gentamicinas/síntese química , Hemócitos/metabolismo , Hepatopâncreas/efeitos dos fármacos , Hepatopâncreas/microbiologia , Hepatopâncreas/patologia , Fatores Imunológicos/síntese química , Penaeidae/imunologia , Penaeidae/metabolismo , Penaeidae/microbiologia , Fagócitos/metabolismo , Esterol Esterase/metabolismo , Proteínas de Transporte Vesicular/metabolismo , Vibrio parahaemolyticus/patogenicidadeRESUMO
The structures of melatonin and ferulic acid were merged into tertiary amide-based histone deacetylase 6 (HDAC6) inhibitors to develop multi-target-directed inhibitors for neurodegenerative diseases to incorporate antioxidant effects without losing affinity and selectivity at HDAC6. Structure-activity relationships led to compound 10b as a hybrid molecule showing pronounced and selective inhibition of HDAC6 (IC50 = 30.7 nM, > 25-fold selectivity over other subtypes). This compound shows comparable DPPH radical scavenging ability to ferulic acid, comparable ORAC value to melatonin and comparable Cu2+ chelating ability to EDTA. It also lacks neurotoxicity on HT-22 cells, exhibits a pronounced immunomodulatory effect, and is active in vivo showing significantly higher efficacy in an AD mouse model to prevent both Aß25-35-induced spatial working and long-term memory dysfunction at lower dose (0.3 mg/kg) compared to positive control HDAC6 inhibitor ACY1215 and an equimolar mixture of the three entities ACY1215, melatonin and ferulic acid, suggesting potentially disease-modifying properties.
Assuntos
Doença de Alzheimer/tratamento farmacológico , Ácidos Cumáricos/uso terapêutico , Desacetilase 6 de Histona/antagonistas & inibidores , Fatores Imunológicos/uso terapêutico , Fármacos Neuroprotetores/uso terapêutico , Triptaminas/uso terapêutico , Doença de Alzheimer/enzimologia , Doença de Alzheimer/metabolismo , Animais , Domínio Catalítico , Linhagem Celular Transformada , Ácidos Cumáricos/síntese química , Ácidos Cumáricos/metabolismo , Desacetilase 6 de Histona/química , Desacetilase 6 de Histona/metabolismo , Inibidores de Histona Desacetilases/síntese química , Inibidores de Histona Desacetilases/metabolismo , Inibidores de Histona Desacetilases/uso terapêutico , Fatores Imunológicos/síntese química , Fatores Imunológicos/metabolismo , Masculino , Melatonina/análogos & derivados , Melatonina/metabolismo , Melatonina/uso terapêutico , Camundongos , Simulação de Acoplamento Molecular , Fármacos Neuroprotetores/síntese química , Fármacos Neuroprotetores/metabolismo , Relação Estrutura-Atividade , Triptaminas/síntese química , Triptaminas/metabolismoRESUMO
In this paper, selenized Artemisia sphaerocephala polysaccharides (SePAS) were obtained through employing N-methyl-2-pyrrolidone hydrosulfate as catalyst, which showed a maximum Se content enhanced to 8744 µg/g. FT-IR, 1D/2D NMR, X-ray photoelectron spectroscopy (XPS) and size-exclusion chromatograph analysis exhibited that Se had been successfully introduced into PAS and existed in the form of selenate group (Se4+) with the substitution position at C-6. Furthermore, immunostimulating assays indicated that SePAS with high Se content exhibited stronger immunomodulatory activities by upregulated the phosphorylation level of ERK, JNK and p38, thus enhancing RAW264.7 cells proliferation, phagocytosis, levels of interleukin-6, nitric oxide, tumor necrosis factor and interleukin-1ß. The current outcome suggested that Se content might be a critical factor affecting the immunomodulatory effects of selenized PAS on macrophage RAW264.7.
Assuntos
Fatores Imunológicos/síntese química , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Polissacarídeos/química , Pirrolidinonas/química , Ácido Selenioso/química , Animais , Artemisia/química , Proliferação de Células , Fatores Imunológicos/farmacologia , Interleucina-6/metabolismo , MAP Quinase Quinase 4/metabolismo , Camundongos , Óxido Nítrico/metabolismo , Fagocitose , Células RAW 264.7 , Fator de Necrose Tumoral alfa/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Currently, selenium and polysaccharide combinations can be identified as three forms: natural selenium polysaccharides, synthetic selenium polysaccharides and selenium nanoparticles decorated with polysaccharides. Previous studies have indicated that these three combinations generally show better bioactivities, including immunomodulation, anti-tumour, antioxidation and glucose regulation, than those of either selenium or polysaccharides alone. Although they have not yet been developed as new drugs for clinical trials, results from previous studies have already shown their therapeutic potential for the future. In this article, we summarize our current state of understanding of the sources, preparation methods, physicochemical characteristics and bioactivities of these combinations for the discovery of novel therapeutic drugs and adjuvants.
Assuntos
Compostos Organosselênicos/uso terapêutico , Polissacarídeos/uso terapêutico , Animais , Antineoplásicos/síntese química , Antineoplásicos/isolamento & purificação , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Antioxidantes/síntese química , Antioxidantes/isolamento & purificação , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Bactérias/química , Linhagem Celular Tumoral , Fungos/química , Humanos , Hipoglicemiantes/síntese química , Hipoglicemiantes/isolamento & purificação , Hipoglicemiantes/farmacologia , Hipoglicemiantes/uso terapêutico , Fatores Imunológicos/síntese química , Fatores Imunológicos/isolamento & purificação , Fatores Imunológicos/farmacologia , Fatores Imunológicos/uso terapêutico , Nanopartículas/química , Neoplasias/tratamento farmacológico , Compostos Organosselênicos/síntese química , Compostos Organosselênicos/isolamento & purificação , Compostos Organosselênicos/farmacologia , Plantas/química , Polissacarídeos/síntese química , Polissacarídeos/isolamento & purificação , Polissacarídeos/farmacologia , Selênio/químicaRESUMO
Phytochemical investigation of the root extracts of Hypericum perforatum led to the isolation of two biphenyl derivatives named hyperbiphenyls A and B (1 and 2) and four known xanthones (3-6). These structures were elucidated by spectroscopic and spectrometric methods including UV, NMR, and HRMS. The absolute configuration of the biphenyl derivatives was defined by two different approaches: biomimetic total synthesis of racemic hyperbiphenyl A followed by 1H and 19F NMR Mosher's esters analysis and stereoselective total synthesis of hyperbiphenyl B, permitting assignment of the S absolute configuration for both compounds. The bioactivity of compounds 1-6 toward a set of biomolecules, including major histocompatibility complex (MHC) molecules expressed on vascular endothelial cells, was measured. The results showed that the major xanthone, i.e., 5- O-methyl-2-deprenylrheediaxanthone B (3), is a potent inhibitor of MHC that efficiently reduces HLA-E, MHC-II, and MICA biomolecules on cell surfaces.
Assuntos
Benzofuranos/química , Benzofuranos/farmacologia , Benzopiranos/química , Benzopiranos/farmacologia , Compostos de Bifenilo/química , Compostos de Bifenilo/farmacologia , Hypericum/química , Fatores Imunológicos/química , Fatores Imunológicos/farmacologia , Raízes de Plantas/química , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Humanos , Fatores Imunológicos/síntese química , Espectroscopia de Ressonância Magnética , Ressonância Magnética Nuclear Biomolecular , Espectrometria de Massas por Ionização por Electrospray , Espectrofotometria Ultravioleta , EstereoisomerismoRESUMO
Menaquinone (MK) biosynthesis pathway is a potential target for evaluating antimicrobials in gram-positive bacteria. Here, 1,4-dihydroxy-2-naphthoate prenyltransferase (MenA) was targeted to reduce methicillin-resistant Staphylococcus aureus (MRSA) growth. MenA inhibiting, long chain-based compounds were designed, synthesized and evaluated against MRSA and menaquinone utilizing bacteria in aerobic conditions. The results showed that these bacteria were susceptible to most of the compounds. Menaquinone (MK-4) supplementation rescued MRSA growth, suggesting these compounds inhibit MK biosynthesis. 3a and 7c exhibited promising inhibitory activities with MICs ranging 1-8 µg/mL against MRSA strains. The compounds did not facilitate small colony variant formation. These compounds also inhibited the biofilm growth by MRSA at high concentration. Compounds 3a, 6b and 7c displayed a promising extracellular bactericidal activity against MRSA at concentrations equal to and four-fold less than their respective MICs. We also observed cytokines released from THP-1 macrophages treated with compounds 3a, 6b and 7c and found decreases in TNF-α and IL-6 release and increase in IL-1ß. These data provide evidence that MenA inhibitors act as TNF-α and IL-6 inhibitors, raising the potential for development and application of these compounds as potential immunomodulatory agents.
Assuntos
Alquil e Aril Transferases/antagonistas & inibidores , Antibacterianos/farmacologia , Biofilmes/crescimento & desenvolvimento , Citocinas/metabolismo , Inibidores Enzimáticos/farmacologia , Fatores Imunológicos/farmacologia , Staphylococcus aureus Resistente à Meticilina/crescimento & desenvolvimento , Antibacterianos/síntese química , Bactérias Aeróbias/efeitos dos fármacos , Bactérias Aeróbias/crescimento & desenvolvimento , Biofilmes/efeitos dos fármacos , Inibidores Enzimáticos/síntese química , Humanos , Fatores Imunológicos/síntese química , Macrófagos/efeitos dos fármacos , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Testes de Sensibilidade Microbiana , Viabilidade Microbiana/efeitos dos fármacos , Células THP-1 , Vitamina K 2/metabolismoRESUMO
BACKGROUND: Psoriasis is a chronic inflammatory skin disorder involving marked immunological changes. IL-17-targeting biologics have been successful in reducing the disease burden of psoriasis patients with moderate-to-severe disease. Unfortunately, the stratum corneum prevents penetration of large molecule weight proteins, including monoclonal antibodies. Thus, for the majority of psoriasis patients ineligible for systemic treatments, a small molecule targeting RORγt, the master regulator of IL-17 family cytokines, may represent an alternative topical medicine with biologic-like efficacy. METHODS AND FINDINGS: The preclinical studies described in this manuscript bridge the gap from bench to bedside to provide the scientific foundation for a compound entering clinical trials for patients with mild to moderate psoriasis. In addition to several ex vivo reporter assays, primary T cell cultures, and the imiquimod mouse model, we demonstrate efficacy in a newly developed human ex vivo skin assay, where Th17-skewed cytokine expression is induced from skin-resident immune cells. Importantly, the skin barrier remains intact allowing for the demonstration of topical drug delivery. With the development of this novel assay, we demonstrate potent compound activity in the target tissue: human skin. Finally, target engagement by this small molecule was confirmed in ex vivo lesional psoriatic skin. CONCLUSIONS: Our work describes a progressive series of assays to demonstrate the potential clinical value of a novel RORγ inverse agonist small molecule with high potency and selectivity, which will enter clinical trials in late 2015 for psoriasis patients.
Assuntos
Fatores Imunológicos/farmacologia , Interleucina-17/antagonistas & inibidores , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/antagonistas & inibidores , Psoríase/tratamento farmacológico , Pele/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Administração Cutânea , Aminoquinolinas , Animais , Avaliação Pré-Clínica de Medicamentos , Feminino , Expressão Gênica , Genes Reporter , Humanos , Imiquimode , Fatores Imunológicos/síntese química , Interleucina-17/genética , Interleucina-17/imunologia , Células Jurkat , Luciferases/genética , Luciferases/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/imunologia , Permeabilidade , Cultura Primária de Células , Psoríase/induzido quimicamente , Psoríase/imunologia , Psoríase/patologia , Pele/imunologia , Pele/patologia , Bibliotecas de Moléculas Pequenas/síntese química , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Células Th17/patologia , Pesquisa Translacional BiomédicaRESUMO
The recent observation that certain cationic peptides possess potent antibiofilm activity demonstrated that small peptides could be used to treat biofilm-associated infections. Other so-called innate defense regulator peptides possess potent immunomodulatory properties such as leukocyte recruitment and suppression of harmful inflammation. A peptide that directly targets biofilm cells while favorably modulating the immune response would be particularly advantageous for treating serious skin infections caused by Staphylococcus aureus. In the present work, using SPOT-synthesized peptide arrays on cellulose membranes, we outline a strategy for systematically assessing the antibiofilm activity of hundreds of IDR-1002 (VQRWLIVWRIRK-NH2) and IDR-HH2 (VQLRIRVAVIRA-NH2) peptide variants against MRSA biofilms. In addition, the ability of these peptides to stimulate production of a monocyte chemoattractant protein (MCP-1) and suppress LPS-induced interleukin (IL)-1ß production in human peripheral blood mononuclear cells (PBMCs) was evaluated. These results informed the synthesis of second-generation peptides resulting in a new peptide, IDR-2009 (KWRLLIRWRIQK-NH2), with enhanced MCP-1 stimulatory activity, favorable IL-1ß suppression characteristics and strong antibiofilm activity against MRSA and Pseudomonas aeruginosa biofilms. This work provides a proof-of-concept that multiple peptide activities can be optimized simultaneously to generate novel sequences that possess a variety of biological properties.
Assuntos
Peptídeos Catiônicos Antimicrobianos , Biofilmes/efeitos dos fármacos , Fatores Imunológicos , Leucócitos Mononucleares/imunologia , Staphylococcus aureus Resistente à Meticilina/fisiologia , Pseudomonas aeruginosa/fisiologia , Peptídeos Catiônicos Antimicrobianos/síntese química , Peptídeos Catiônicos Antimicrobianos/química , Peptídeos Catiônicos Antimicrobianos/farmacologia , Quimiocina CCL2/imunologia , Avaliação Pré-Clínica de Medicamentos , Humanos , Fatores Imunológicos/síntese química , Fatores Imunológicos/química , Fatores Imunológicos/farmacologia , Interleucina-1beta/imunologia , Lipopolissacarídeos/farmacologiaRESUMO
Antimicrobial peptides (AMPs) are garnering attention as possible alternatives to antibiotics. Here, we describe the antimicrobial properties of epinecidin-1 against a multidrug-resistant clinical isolate of P. aeruginosa (P. aeruginosa R) and a P. aeruginosa strain from ATCC (P. aeruginosa ATCC 19660) in vivo. The MICs of epinecidin-1 against P. aeruginosa R and P. aeruginosa ATCC 19660 were determined and compared with those of imipenem. Epinecidin-1 was found to be highly effective at combating peritonitis infection caused by P. aeruginosa R or P. aeruginosa ATCC 19660 in mouse models, without inducing adverse behavioral effects or liver or kidney toxicity. Taken together, our results indicate that epinecidin-1 enhances the rate of survival of mice infected with the bacterial pathogen P. aeruginosa through both antimicrobial and immunomodulatory effects.
Assuntos
Peptídeos Catiônicos Antimicrobianos/farmacologia , Proteínas de Peixes/farmacologia , Fatores Imunológicos/farmacologia , Infecções por Pseudomonas/tratamento farmacológico , Pseudomonas aeruginosa/patogenicidade , Sepse/tratamento farmacológico , Sequência de Aminoácidos , Animais , Antibacterianos/farmacologia , Peptídeos Catiônicos Antimicrobianos/síntese química , Comportamento Animal/efeitos dos fármacos , Modelos Animais de Doenças , Farmacorresistência Bacteriana Múltipla , Proteínas de Peixes/síntese química , Humanos , Imipenem/farmacologia , Fatores Imunológicos/síntese química , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Testes de Sensibilidade Microbiana , Dados de Sequência Molecular , Infecções por Pseudomonas/imunologia , Infecções por Pseudomonas/microbiologia , Infecções por Pseudomonas/mortalidade , Pseudomonas aeruginosa/efeitos dos fármacos , Pseudomonas aeruginosa/crescimento & desenvolvimento , Sepse/imunologia , Sepse/microbiologia , Sepse/mortalidade , Análise de Sobrevida , Testes de Toxicidade AgudaRESUMO
N-Acetyl-d-glucosamine branches were incorporated at the C-6 position of curdlan, a linear ß-1,3-d-glucan, and the resulting nonnatural branched polysaccharides were evaluated in terms of the immunomodulation activities in comparison with lentinan, a ß-1,3-d-glucan having d-glucose branches at C-6. To incorporate the amino sugar branches, we conducted a series of regioselective protection-deprotections of curdlan involving triphenylmethylation at C-6, phenylcarbamoylation at C-2 and C-4, and detriphenylmethylation. Subsequent glycosylation with a d-glucosamine-derived oxazoline, followed by deprotection gave rise to the branched curdlans with various substitution degrees. The products exhibited remarkable solubility in both organic solvents and water. Their immunomodulation activities were determined using mouse macrophagelike cells, and the secretions of both the tumor necrosis factor and nitric oxide proved to be significantly higher than those with lentinan. These results conclude that the amino sugar/curdlan hybrid materials are promising as a new type of polysaccharide immunoadjuvants useful for cancer chemotherapy.
Assuntos
Adjuvantes Imunológicos/síntese química , Materiais Biomiméticos/síntese química , Fatores Imunológicos/síntese química , Lentinano/química , Macrófagos/imunologia , beta-Glucanas/química , Acetilglucosamina/química , Adjuvantes Imunológicos/farmacologia , Animais , Materiais Biomiméticos/farmacologia , Sequência de Carboidratos , Linhagem Celular , Glucose/química , Glicosilação , Fatores Imunológicos/farmacologia , Lentinano/imunologia , Lentinano/farmacologia , Ativação de Macrófagos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Espectroscopia de Ressonância Magnética , Metilação , Camundongos , Mimetismo Molecular/imunologia , Dados de Sequência Molecular , Óxido Nítrico/biossíntese , Solubilidade , Fator de Necrose Tumoral alfa/biossíntese , beta-Glucanas/imunologia , beta-Glucanas/farmacologiaRESUMO
Several caged Garcinia xanthone natural products have potent bioactivity and a documented value in traditional Eastern medicine. Previous synthesis and structure activity relationship studies of these natural products resulted in the identification of the pharmacophore represented by the structure of cluvenone. In the current study, we examined the anticancer activity of cluvenone and conducted gene expression profiling and pathway analyses. Cluvenone was found to induce apoptosis in T-cell acute lymphoblastic leukemia cells (EC50 = 0.25 µmol/L) and had potent growth-inhibitory activity against the NCI60 cell panel, including those that are multidrug-resistant, with a GI50 range of 0.1 to 2.7 µmol/L. Importantly, cluvenone was approximately 5-fold more potent against a primary B-cell acute lymphoblastic leukemia compared with peripheral blood mononuclear cells from normal donors, suggesting that it has significant tumor selectivity. Comparison of cluvenone's growth-inhibitory profile to those in the National Cancer Institute database revealed that compounds with a similar profile to cluvenone were mechanistically unlike known agents, but were associated with cell stress and survival signaling. Gene expression profiling studies determined that cluvenone induced the activation of mitogen-activated protein kinase and NrF2 stress response pathways. Furthermore, cluvenone was found to induce intracellular reactive oxygen species formation. Lastly, the modulation in the expression of several genes associated with T cell and natural killer cell activation and function by cluvenone suggests a role as an immune-modulator. The current work highlights the potential of cluvenone as a chemotherapeutic agent and provides support for further investigation of these intriguing molecules with regard to mechanism and targets.
Assuntos
Apoptose/efeitos dos fármacos , Células/efeitos dos fármacos , Imunomodulação/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Xantonas/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Células/imunologia , Células/metabolismo , Avaliação Pré-Clínica de Medicamentos , Garcinia/química , Perfilação da Expressão Gênica , Ensaios de Triagem em Larga Escala , Humanos , Fatores Imunológicos/síntese química , Fatores Imunológicos/química , Fatores Imunológicos/farmacologia , Análise em Microsséries , Modelos Biológicos , Células Tumorais Cultivadas , Xantonas/síntese química , Xantonas/químicaRESUMO
A study of biological activity of the derivatives of the chitin-chitosan oligomer with salicylic acid and its fragments showed that chitosan salicylate actively protected potato tubers against Phytophthora infestans but sharply inhibited reparation of potato tissues. N-(2-Hydroxybenzyl)chitosan exhibited good protective properties but did not influence wound reparation. N-(2-Hydroxy-3-methoxybenzyl)-N-pyridox-chitosan, which contained the pyridoxal and 2-hydroxy-3-methoxy fragments, was the most efficient, stimulating both defense against late blight and wound reparation in potato tissues.
Assuntos
Quitosana/farmacologia , Phytophthora infestans/crescimento & desenvolvimento , Doenças das Plantas/microbiologia , Tubérculos/microbiologia , Salicilatos/farmacologia , Solanum tuberosum/microbiologia , Quitosana/análogos & derivados , Quitosana/síntese química , Quitosana/química , Fatores Imunológicos/síntese química , Fatores Imunológicos/química , Fatores Imunológicos/farmacologia , Phytophthora infestans/imunologia , Doenças das Plantas/imunologia , Tubérculos/imunologia , Salicilatos/síntese química , Salicilatos/química , Solanum tuberosum/imunologiaRESUMO
To enhance the potential therapeutic efficacy of an antimicrobial peptide human beta-defensin 3, two fusion peptides, a bactericidal-immunomodulatory fusion peptide human beta-defensin 3-mannose-binding lectin and a bactericidal-bactericidal fusion peptide human beta-defensin 3-lysozyme were synthesized and the bactericidal activities in vitro and in vivo against methicillin-resistant Staphylococcus aureus N315 were demonstrated in this study. Peptide human beta-defensin 3-lysozyme showed the best bactericidal activity in vitro, but human beta-defensin 3-mannose-binding lectin showed a significant improvement in angiogenesis and tissue reconstruction. Our results illustrated that outstanding bactericidal activity in vitro is not essential in the development of antimicrobial peptides. Fusion strategy and immunomodulatory factors should be utilized in novel antimicrobial peptide development.
Assuntos
Fatores Imunológicos/uso terapêutico , Lectina de Ligação a Manose/uso terapêutico , Peptídeos/uso terapêutico , Proteínas Recombinantes de Fusão/uso terapêutico , Infecções Cutâneas Estafilocócicas/tratamento farmacológico , beta-Defensinas/uso terapêutico , Sequência de Aminoácidos , Animais , Humanos , Fatores Imunológicos/síntese química , Fatores Imunológicos/química , Fatores Imunológicos/farmacologia , Masculino , Lectina de Ligação a Manose/síntese química , Lectina de Ligação a Manose/química , Lectina de Ligação a Manose/farmacologia , Staphylococcus aureus Resistente à Meticilina/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos BALB C , Testes de Sensibilidade Microbiana , Dados de Sequência Molecular , Peptídeos/síntese química , Peptídeos/química , Peptídeos/farmacologia , Proteínas Recombinantes de Fusão/farmacologia , Infecções Cutâneas Estafilocócicas/imunologia , Infecções Cutâneas Estafilocócicas/microbiologia , Resultado do Tratamento , Infecção dos Ferimentos/tratamento farmacológico , Infecção dos Ferimentos/microbiologia , beta-Defensinas/síntese química , beta-Defensinas/química , beta-Defensinas/farmacologiaRESUMO
An ideal antimicrobial should be not toxic and possess board spectrum antiviral, antibacterial, antifungal activity, excluding resistance and should affect pathogen-mediated damage of host physiology including immune, nervous and endocrine systems. With the purpose of a combination of nonspecific antimicrobial action of molecular and ionized iodine with systemic immune-modulating property of the negatively charged polysaccharides a complex drug of iodine and lithium on a template of a alpha-dextrin liquid crystal was designed. The physicochemical model of iodine-lithium-alpha-dextrin (ILalphaD) is based on the human blood and the stereochemistry of moving equilibred systems of dynamically balanced organic polymers conformation complexed with the iodine and lithium molecules. Here we reviewed the antibacterial, antiviral, immune-modulating and anti-inflammatory mechanisms in vivo and in vitro as well as pharmacokinetics, metabolism, chronic toxicity, cumulative properties, embryo toxicity and carcinogenicity of ILalphaD. Clinical efficacy, tolerability and safety of ILalphaD monotherapy have been evaluated in HIV-infected patients, administered intravenously for a total of 12 infusions in 4 cycles. ILalphaD therapy contributes to anti-HIV and anti-inflammatory effects, resolution of dermatological and neurological pathology and dramatically improves the quality of life reflecting on enhanced treatment adherence. ILalphaD appears to be safe and perspective for an adjuvant therapy of bacterial and viral infections, including HIV/AIDS, hypothyroid, autoimmune and inflammatory diseases for controlling pathogen production from infected cells, immune response, inflammation and metabolism.
Assuntos
Anti-Infecciosos/síntese química , Anti-Infecciosos/farmacologia , Anti-Inflamatórios não Esteroides/síntese química , Anti-Inflamatórios não Esteroides/farmacologia , Dextrinas/síntese química , Dextrinas/farmacologia , Compostos de Iodo/química , Compostos de Iodo/farmacologia , Cristais Líquidos/química , Compostos de Lítio/química , Animais , Antibacterianos/síntese química , Antibacterianos/farmacologia , Fármacos Anti-HIV/síntese química , Fármacos Anti-HIV/farmacologia , Anti-Infecciosos/farmacocinética , Antivirais/síntese química , Antivirais/farmacologia , Dextrinas/farmacocinética , Infecções por HIV/tratamento farmacológico , Humanos , Fatores Imunológicos/síntese química , Fatores Imunológicos/farmacologia , Compostos de Lítio/farmacologia , Testes de Sensibilidade MicrobianaRESUMO
In a previous work our group showed that some synthetic stigmastanes may play a role in immune-mediated inflammation. In this paper we report the syntheses of a series of new steroidal compounds derived from dehydroepiandrosterone and stigmasterol, and the evaluation of their in vitro inhibitory activity of the TNF-alpha production by macrophages. A preliminary qualitative structure-activity relationship was established.
Assuntos
Androstanos/síntese química , Androstanos/farmacologia , Colestanos/síntese química , Colestanos/farmacologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Androstanos/química , Animais , Linhagem Celular , Colestanos/química , Desidroepiandrosterona/química , Avaliação Pré-Clínica de Medicamentos , Fatores Imunológicos/síntese química , Fatores Imunológicos/química , Fatores Imunológicos/farmacologia , Camundongos , Estrutura Molecular , Estigmasterol/química , Relação Estrutura-AtividadeRESUMO
Research on immunomodulation by natural products or synthetic derivatives is of key interest for anti-infective therapy for a number of reasons. Many plant remedies well-known in traditional medicine or refined natural products in clinical use exert their anti-infective effects not only (if at all) by directly affecting the pathogen. At least part of their effect is indirect, by stimulating natural and adaptive defense mechanisms of the host. These findings have now given many empirical therapies a rationale, scientific basis and thereby a means for 'intelligent' improvement. In discovering the molecular mechanisms by which known remedies exert their effects, chosen elements further down the 'chain of command' might be synthesized and applied directly for more rapid and selective cure, omitting unwanted side effects. The direct use of recombinant cytokines, often in combination with antibiotics, is one consequence of this rationale.
Assuntos
Produtos Biológicos/farmacologia , Fatores Imunológicos/farmacologia , Animais , Bactérias/química , Citocinas/farmacologia , Fungos/química , Humanos , Fatores Imunológicos/síntese química , Plantas/químicaRESUMO
The synthesis and chemical and physical properties of some N2-[omega-(pyrimidin-1-yl)carboxyalkyl]-L-arginines are here described. Experiments of immunopharmacological evaluations are also described.
Assuntos
Arginina/análogos & derivados , Fatores Imunológicos/síntese química , Adjuvantes Imunológicos/síntese química , Adjuvantes Imunológicos/química , Adjuvantes Imunológicos/farmacologia , Animais , Células Cultivadas , Feminino , Humanos , Fatores Imunológicos/química , Fatores Imunológicos/farmacologia , Interleucina-6/metabolismo , Camundongos , Placenta/efeitos dos fármacos , Relação Estrutura-Atividade , Uracila/análogos & derivadosRESUMO
A new compound with a peptide-like structure, (R)-3-[(S)-(5-oxo-2-pyrrolidinyl)carbonyl]-thiazolidine-4-carboxylic acid, its enantiomer, diastereomers and carboxamido derivatives were synthesized and tested for immunostimulant activity. Synthesis, preliminary, pharmacological data and structure-activity relationships are reported. (R)-3-[(S)-(5-Oxo-2-pyrrolidinyl)carbonyl]-thiazolidine-4-carboxylic acid (Ib, Pidotimod, PGT/1A, CAS 121808-62-6) was selected for further research.
Assuntos
Adjuvantes Imunológicos/farmacologia , Fatores Imunológicos/farmacologia , Ácido Pirrolidonocarboxílico/análogos & derivados , Tiazóis/farmacologia , Adjuvantes Imunológicos/síntese química , Adjuvantes Imunológicos/química , Animais , Infecções Bacterianas/imunologia , Fatores Imunológicos/síntese química , Fatores Imunológicos/química , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos , Prednisolona/farmacologia , Ácido Pirrolidonocarboxílico/síntese química , Ácido Pirrolidonocarboxílico/química , Ácido Pirrolidonocarboxílico/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade , Superóxidos/metabolismo , Tiazóis/síntese química , Tiazóis/química , TiazolidinasRESUMO
The synthesis and the main chemical and physical properties of some N2-(omega-(hypoxanthin-9-yl)alkoxycarbonyl)-L-arginines are described. The ability of the synthesized compounds to modulate the natural cytotoxic response (NK cells) in mice has also been analyzed and described.