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1.
Int J Nanomedicine ; 15: 7937-7949, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33116510

RESUMO

Background: Cyclosporine A (CsA) is an exceptional immunosuppressant used for the treatment of immune disorders. Niosomal vesicles are promising drug carriers that are formed by self-association of nonionic surfactants and cholesterol in an aqueous phase. The objective of the study was to formulate combined nonionic surfactant based vesicles and to evaluate their in vitro characterization, release studies and in vivo studies. Materials and Methods: Five niosomal formulations (F7 to F11) were prepared using the thin film hydration method. The molar ratio of cholesterol and non-ionic surfactant taken was 1:1. In formulation F10, the combination of surfactants Span 20 and Brij 35 was used. The niosomes were characterized by zeta sizer and SEM for particle size analysis, in vitro drug release and stability studies. The pharmacokinetic studies were conducted on healthy albino rabbits. Results: The size of niosome was found in the range of 427.1 nm to 972.3 nm. SEM image of optimized formulations F10 exhibit the spherical nature of niosomal vesicles. DSC thermograms of niosomal formulations exhibited a broadened endothermic peak. The stability study exhibited that all formulations are stable and negligible change of vesicle size and entrapment was observed with time. The percentage drug release was significantly higher as compared to CsA plain dispersion for all niosomal formulations at pH 1.2 and 7.4. The release kinetic behavior showed that all preparations were best described by zero order and can release active ingredient in a sustained manner. The pharmacokinetic data showed the test formulation (F10) possessed greater bioavailability as compared to the reference formulation (CsA aqueous dispersion). Conclusion: The formulation F10 demonstrated a comparatively more delayed rate of release with enhanced dissolution as compared to a single surfactant scheme. The F10 formulation can be a remarkable nanotechnology for prolonged delivery of CsA orally with improved dissolution profile and bioavailability.


Assuntos
Portadores de Fármacos/química , Imunossupressores/química , Imunossupressores/farmacologia , Tensoativos/química , Animais , Disponibilidade Biológica , Colesterol/química , Ciclosporina/administração & dosagem , Ciclosporina/química , Ciclosporina/farmacocinética , Ciclosporina/farmacologia , Liberação Controlada de Fármacos , Imunossupressores/administração & dosagem , Imunossupressores/farmacocinética , Lipossomos , Tamanho da Partícula , Coelhos
2.
Int J Nanomedicine ; 15: 5603-5612, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32848390

RESUMO

Introduction: Organ transplantation is a critically important procedure, which requires immune modulation by using immunosuppressants. Development of nanoparticles is an emerging and beneficial engineering process to increase the dissolution rate of poorly soluble immunosuppressants as well as to provide controlled release for better therapeutic outcomes. Method: Currently, the nanoprecipitation method was employed to fabricate ß-cyclodextrin (ßCD) facilitated mycophenolate mofetil (MMF)-loaded solid lipid nanoparticles (SLNPs). The prime objectives of the study included, improvement of the dissolution profile of poorly aqueous soluble drug and controlled release from the SLNs to provide steady state drug concentration. Drug release from the prepared SLNs was assessed in two different media, ie, acidic buffer at pH 1.2 and phosphate buffer at pH 7.2 using USP dissolution apparatus for 12 h, followed by the evaluation of drug release mechanism and pattern by applying kinetic models. Results: Justifiably, in acidic medium, the release was found to be 12% more (68%) in comparison to that in basic medium (56%). However, in both dissolution media, drug release was independent of initial concentration (R2>0.95) with non-Fickian type of diffusion mechanism. The outcomes of the study have exhibited that prepared formulations were in nanosized range (80-170 nm) with a net charge of ±23 charge on their surface. They possessed fairly uniform surface with acceptable polydispersity index (0.23±0.09). Scanning electron microscopy (SEM) analysis illustrated that the nanoparticles had uniform particle size and shape. Discussion: The findings show potential applications of the nanoparticles and the method for the development of SLNPs in controlled release of MMF for better therapeutic outcomes. Conclusively, the prepared SLNPs were well designed in nanosized ranges and justifying the once daily controlled release formulation dose of MMF to enhance patient compliance.


Assuntos
Portadores de Fármacos/química , Imunossupressores/farmacocinética , Ácido Micofenólico/farmacocinética , Nanopartículas/química , Disponibilidade Biológica , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Difusão , Portadores de Fármacos/farmacocinética , Sistemas de Liberação de Medicamentos , Liberação Controlada de Fármacos , Concentração de Íons de Hidrogênio , Imunossupressores/química , Lipídeos/química , Microscopia Eletrônica de Varredura , Ácido Micofenólico/química , Nanopartículas/administração & dosagem , Tamanho da Partícula , Solubilidade , beta-Ciclodextrinas/química
3.
Food Chem ; 330: 127257, 2020 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-32535321

RESUMO

Huangshui (HS), the by-product of Chinese Baijiu, has attracted considerable attention due to its nutrient and microbial composition; however, none of the studies has explored the polysaccharides in HS yet. Here, from HS, we isolated a novel polysaccharide, HSP-3, with an average molecular weight of 26.40 kDa. The structure was elucidated based on monosaccharide composition and methylation analysis, NMR, FT-IR, and AFM analysis. It is mainly composed of mannose (46.6%), galactose (17.3%), arabinose (11.2%), glucose (10.5%), xylose (8.2%), fucose (5.2%), and rhamnose (1.0%). The backbone of HSP-3 was made up of â†’ 2)-ß-d-Manp-(1 â†’ 2,6)-ß-d-Manp-(1 â†’ 6)-ß-d-Galp-(1 â†’ 3,6)-ß-d-Galp-(1 â†’ 4)-α-l-Rhap-(1 â†’ 3,4)-α-l-Rhap-(1 â†’ . Moreover, stimulation of the production of ROS, NO, TNF-α and IL-6, upregulation of the mRNA and protein expression levels of TNF-α and IL-6 in THP-1 cells, and enhanced the pinocytic and phagocytic capacities of THP-1 cells exhibited significant immunomodulatory properties of HSP-3. Altogether, this study suggests that HSP-3 could be used as an active component in functional foods.


Assuntos
Imunossupressores/farmacologia , Interleucina-6/metabolismo , Óxido Nítrico/biossíntese , Polissacarídeos/farmacologia , Rios/química , Fator de Necrose Tumoral alfa/metabolismo , Humanos , Imunossupressores/química , Peso Molecular , Polissacarídeos/química , Células THP-1
4.
Org Biomol Chem ; 18(13): 2410-2415, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32195526

RESUMO

Xylarilongipins A (1) and B (2), two diterpenes each with an unusual cage-like bicyclo[2.2.2]octane moiety, along with their biosynthetic precursor hymatoxin L (3), were isolated from the culture broth of the fungicolous fungus Xylaria longipes HFG1018 inhabiting in the medicinal fungus Fomitopsis betulinus. The structures and absolute configurations of the three compounds were established by extensive spectroscopic analysis and single-crystal X-ray diffraction analysis. Xylarilongipin A (1) displayed moderate inhibitory activity against the cell proliferation of concanavalin A-induced T lymphocytes and lipopolysaccharide-induced B lymphocytes with IC50 values of 13.6 and 22.4 µM, respectively. Additionally, the biosynthetic pathways for compounds 1-3 are discussed. This work not only corroborates the structure of the 9,16-cyclo-(18-nor-)isopimarane skeleton by single-crystal X-ray diffraction analysis for the first time, but also provides new insights into the biosynthetic origin of the unusual diterpene skeletons.


Assuntos
Compostos Bicíclicos com Pontes/farmacologia , Diterpenos/farmacologia , Imunossupressores/farmacologia , Compostos Bicíclicos com Pontes/química , Compostos Bicíclicos com Pontes/toxicidade , Linhagem Celular Tumoral , Diterpenos/química , Diterpenos/toxicidade , Humanos , Imunossupressores/química , Imunossupressores/toxicidade , Xylariales/química
5.
Molecules ; 25(3)2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-32019202

RESUMO

The importance of the gut microbiota in drug metabolism, especially in that of nonabsorbable drugs, has become known. The aim of this study was to explore the metabolites of triptolide by the gut microbiota. With high-performance liquid chromatography coupled with tandem mass spectrometry and ion trap time-of-flight multistage mass spectrometry (LC-MS/MS and LC/MSn-IT-TOF), four metabolites of triptolide (M1, M2, M3, and M4) were found in the intestinal contents of rats. M1 and M2, were isomeric monocarbonyl-hydroxyl-substituted metabolites with molecular weights of 390. M3 and M4 were isomeric dehydrogenated metabolites with molecular weights of 356. Among the four metabolites, the dehydrogenated metabolites (M3 and M4) were reported in the gut microbiota for the first time. The metabolic behaviors of triptolide in the gut microbiota and liver microsomes of rats were further compared. The monocarbonyl-hydroxyl-substituted metabolites (M1 and M2) were generated in both systems, and another monohydroxylated metabolite (M5) was found only in the liver microsomes. The combined results suggested that the metabolism of triptolide in the gut microbiota was specific, with two characteristic, dehydrogenated metabolites. This investigation might provide a theoretical basis for the elucidation of the metabolism mechanism of triptolide and guide its proper application in clinical administration.


Assuntos
Diterpenos/metabolismo , Microbioma Gastrointestinal , Imunossupressores/metabolismo , Microssomos Hepáticos/metabolismo , Fenantrenos/metabolismo , Animais , Cromatografia Líquida de Alta Pressão , Diterpenos/química , Compostos de Epóxi/química , Compostos de Epóxi/metabolismo , Imunossupressores/química , Masculino , Fenantrenos/química , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem
6.
Eur J Med Chem ; 189: 112091, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-32007665

RESUMO

Mycophenolic acid (MPA) was coupled with amino acids and biologically active peptides including derivatives of tuftsin to modify its immunosuppressive properties. Both amino acid unit in the case of simple MPA amides and modifications within peptide moiety of MPA - tuftsin conjugates influenced the observed activity. Antiproliferative potential of the obtained conjugates was investigated in vitro and MPA amides with threonine methyl ester and conjugate of MPA with retro-tuftisin occurred to be more selective against PBMC in comparison to parent MPA. Both amino acid and peptide derivatives of MPA acted as inosine-5'-monophosphate dehydrogenaze (IMPDH) inhibitors.


Assuntos
Aminoácidos/química , Proliferação de Células , Inibidores Enzimáticos/farmacologia , Imunossupressores/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Ácido Micofenólico/química , Fragmentos de Peptídeos/química , Inibidores Enzimáticos/química , Humanos , IMP Desidrogenase/antagonistas & inibidores , Imunossupressores/química , Células Jurkat , Estrutura Molecular , Relação Estrutura-Atividade
7.
J Nanobiotechnology ; 18(1): 31, 2020 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-32066449

RESUMO

BACKGROUND: Myeloid derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) are two of the major players involved in the inhibition of anti-tumor immune response in cancer patients, leading to poor prognosis. Selective targeting of myeloid cells has therefore become an attractive therapeutic strategy to relieve immunosuppression and, in this frame, we previously demonstrated that lipid nanocapsules (LNCs) loaded with lauroyl-modified gemcitabine efficiently target monocytic MDSCs in melanoma patients. In this study, we investigated the impact of the physico-chemical characteristics of LNCs, namely size and surface potential, towards immunosuppressive cell targeting. We exploited myeloid cells isolated from glioblastoma patients, which play a relevant role in the immunosuppression, to demonstrate that tailored nanosystems can target not only tumor cells but also tumor-promoting cells, thus constituting an efficient system that could be used to inhibit their function. RESULTS: The incorporation of different LNC formulations with a size of 100 nm, carrying overall positive, neutral or negative charge, was evaluated on leukocytes and tumor-infiltrating cells freshly isolated from glioblastoma patients. We observed that the maximum LNC uptake was obtained in monocytes with neutral 100 nm LNCs, while positively charged 100 nm LNCs were more effective on macrophages and tumor cells, maintaining at low level the incorporation by T cells. The mechanism of uptake was elucidated, demonstrating that LNCs are incorporated mainly by caveolae-mediated endocytosis. CONCLUSIONS: We demonstrated that LNCs can be directed towards immunosuppressive cells by simply modulating their size and charge thus providing a novel approach to exploit nanosystems for anticancer treatment in the frame of immunotherapy.


Assuntos
Antimetabólitos Antineoplásicos/química , Desoxicitidina/análogos & derivados , Glioblastoma/tratamento farmacológico , Imunossupressores/química , Lipídeos/química , Macrófagos/metabolismo , Células Supressoras Mieloides/metabolismo , Nanocápsulas/química , Antimetabólitos Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Permeabilidade da Membrana Celular , Desoxicitidina/química , Desoxicitidina/farmacologia , Composição de Medicamentos , Endocitose , Humanos , Imunossupressores/farmacologia , Imunoterapia/métodos , Leucócitos/metabolismo , Tamanho da Partícula , Transdução de Sinais , Propriedades de Superfície
8.
Nanoscale ; 12(4): 2626-2637, 2020 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-31939969

RESUMO

Immunosuppression with glucocorticoids is a common treatment for autoimmune liver diseases and after liver transplant, which is however associated with severe side-effects. Targeted delivery of glucocorticoids to inflammatory cells, e.g. liver macrophages and Kupffer cells, is a promising approach for minimizing side effects. Herein, we prepare core-shell silica nanocapsules (SiO2 NCs) via a sol-gel process confined in nanodroplets for targeted delivery of dexamethasone (DXM) for liver immunosuppressive therapy. DXM with concentrations up to 100 mg mL-1 in olive oil are encapsulated while encapsulation efficiency remains over 95% after 15 days. Internalization of NCs by non-parenchymal murine liver cells significantly reduces the release of inflammatory cytokines, indicating an effective suppression of inflammatory response of liver macrophages. Fluorescent and magnetic labeling of the NCs allows for monitoring their intracellular trafficking and biodegradation. Controlled interaction with blood proteins and good colloidal stability in blood plasma are achieved via PEGylation of the NCs. Specific proteins responsible for stealth effect, such as apolipoprotein A-I, apolipoprotein A-IV, and clusterin, are present in large amounts on the PEGylated NCs. In vivo biodistribution investigations prove an efficient accumulation of NCs in the liver, underlining the suitability of the SiO2 NCs as a dexamethasone carrier for treating inflammatory liver diseases.


Assuntos
Imunossupressão/métodos , Fígado/efeitos dos fármacos , Nanocápsulas/administração & dosagem , Dióxido de Silício/administração & dosagem , Animais , Sobrevivência Celular , Coloides , Citocinas/metabolismo , Dexametasona/administração & dosagem , Dexametasona/química , Sistemas de Liberação de Medicamentos , Estabilidade de Medicamentos , Células HeLa , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/química , Fígado/citologia , Fígado/imunologia , Fígado/metabolismo , Camundongos , Nanocápsulas/química , Dióxido de Silício/química , Distribuição Tecidual
9.
Carbohydr Polym ; 230: 115698, 2020 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-31887892

RESUMO

Two fucosylated chondroitin sulfates FCShp and FCSht were isolated from the sea cucumber Holothuria polii and Holothuria tubulosa, respectively. The NMR spectroscopy and HILIC-FTMS methods were applied for their detailed structural characterization. Chemical analysis indicated that the two FCSs all contained a chondroitin sulfate backbone chondroitin sulfate-like core and fucosyl branches of α-L-Fuc2,4S, α-L-Fuc4S or α-L-Fuc3,4S linked to O-3 of glucuronic acid residues. The main branches of FCShp and FCSht were monofucose, and the small amounts of di-, tri- and tetrafucose with α-1,3-linkage type were also detected. Finally, we investigated the immunomodulatory function of FCShp and FCSht in cyclophosphamide (CTX)-induced immunosuppressed mouse models. The results showed that FCShp and FCSht had beneficial effects on hematopoietic function recovery in CTX-induced bone marrow suppression mice. Notably, the α-L-Fuc2,4S was more important to the activity than α-L-Fuc3,4S. These results provided basis for developing the drugs to reduce side effects of chemotherapy.


Assuntos
Sulfatos de Condroitina , Hematopoese/efeitos dos fármacos , Holothuria/metabolismo , Imunossupressores/farmacologia , Animais , Sulfatos de Condroitina/química , Sulfatos de Condroitina/farmacologia , Imunossupressores/química , Camundongos , Camundongos Endogâmicos BALB C
10.
Biomater Sci ; 8(1): 266-277, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31690897

RESUMO

Allotransplantation offers the potential to restore the anatomy and function of injured tissues and organs, but typically requires life-long, systemic administration of immunosuppressive drugs to prevent rejection, which can result in serious complications. Targeting the immunosuppressive drug to the graft favors local tissue concentration versus systemic drug exposure and end-organ toxicity. This could reduce the overall dose and dosing frequency of immunosuppressive drugs, and improve the safety and efficacy of treatment. Here, we developed dibenzocyclooctyne (DBCO)-modified prodrugs of the immunosuppressive drugs tacrolimus, rapamycin and mycophenolic acid, and demonstrated their targeted conjugation both in vitro and in vivo to azido-modified hydrogels via Click chemistry. Such azido-modified hydrogels placed in transplanted tissues enable sustained local release of drugs, and could be repeatedly refilled with systemically administered acid-labile prodrugs after drug exhaustion. Thus, clickable prodrugs with degradable linkers provide new possibilities for graft targeted immunosuppression in the context of allotransplantation.


Assuntos
Química Click , Imunossupressores/química , Pró-Fármacos/química , Alginatos/química , Animais , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Meia-Vida , Hidrocarbonetos Cíclicos/química , Hidrogéis/química , Concentração de Íons de Hidrogênio , Imunossupressores/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Ácido Micofenólico/química , Pró-Fármacos/metabolismo , Sirolimo/química , Tacrolimo/química
11.
Fitoterapia ; 141: 104468, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31887326

RESUMO

Thirteen new withanolide aglycones, baimantuoluolines L-X (1-13) and one new withanolide glycoside, baimantuoluoside J (14) were isolated from Datura metel L. flowers. The structures of the new compounds were elucidated by the detailed analysis of 1D and 2D NMR techniques and mass spectrometry, together with the closely related literatures. Meanwhile, all isolated compounds were evaluated for their immunosuppressive activities against mice splenocyte proliferation and antiproliferative activities against human gastric adenocarcinoma cells (SGC-7901), human hepatoma (HepG2), and human breast cancer (MCF-7) in vitro. It was found that compounds 1-14 showed obvious immunosupressive effects and some of them have moderated antiproliferative activities.


Assuntos
Datura metel/química , Folhas de Planta/química , Vitanolídeos/química , Animais , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Flores/química , Humanos , Imunossupressores/química , Imunossupressores/farmacologia , Camundongos , Estrutura Molecular , Baço/citologia
12.
J Pharm Biomed Anal ; 177: 112853, 2020 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-31499431

RESUMO

Tacrolimus (TAC) is an immunosuppressant for preventing solid-organ transplant rejection. Because of its narrow therapeutic window, analytical methods which can detect TAC in serum samples with high accuracy and reliability are required. In this study, specific aptamers (Apt122 and Apt125) for TAC were isolated via systematic evolution of ligands by exponential enrichment method using magnetic beads to immobilize the target. After determination of binding constants of aptamers by flow cytometry analysis, Apt122 was selected and labeled with ATTO 647 N as a fluorophore to develop a fluorescent sensing platform for detection of TAC using graphene oxide (GO) as a fluorescence quencher. The designed aptasensor could detect TAC in phosphate buffer saline (10 mM PBS) and serum samples with detection limits as low as 1.4 and 2.5 nM, respectively.


Assuntos
Aptâmeros de Nucleotídeos/química , Monitoramento de Medicamentos/métodos , Imunossupressores/sangue , Técnica de Seleção de Aptâmeros/métodos , Tacrolimo/sangue , Técnicas Biossensoriais/instrumentação , Técnicas Biossensoriais/métodos , Monitoramento de Medicamentos/instrumentação , Estudos de Viabilidade , Corantes Fluorescentes/química , Grafite/química , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/química , Ligantes , Limite de Detecção , Reprodutibilidade dos Testes , Tacrolimo/administração & dosagem , Tacrolimo/química
13.
Molecules ; 24(24)2019 Dec 13.
Artigo em Inglês | MEDLINE | ID: mdl-31847258

RESUMO

Three new 11-hydroxyburnamine (1) and rauvoyunnanines A-B (2-3), and fourteen known (4-17) monoterpenoid indole alkaloids were isolated from the total alkaloids extract of Rauvolfia yunnanensis, which exhibited promising immunosuppressive activity on T cell proliferation in preliminary screening. Their structures were determined by analysis of high-resolution electrospray ionization mass (HRESIMS), ultraviolet (UV) and nuclear magnetic resonance (NMR) data, and by comparison with the literature. All the alkaloids were evaluated for inhibitory activity on T cell proliferation. Among them, one new compound (1) and reserpine (6) exhibited moderate immunosuppressive activity, with IC50 values of 5.9 µM and 5.0 µM, respectively.


Assuntos
Imunossupressores/farmacologia , Rauwolfia/química , Reserpina/farmacologia , Alcaloides de Triptamina e Secologanina/química , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Humanos , Imunossupressores/química , Concentração Inibidora 50 , Estrutura Molecular , Reserpina/química , Alcaloides de Triptamina e Secologanina/farmacologia , Linfócitos T/citologia , Linfócitos T/efeitos dos fármacos
14.
Chin J Nat Med ; 17(12): 982-987, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31882054

RESUMO

Cangumycins A-F (1-6), six new angucyclinone analogues, together with two known ones (7 and 8), were isolated from the fermentation broth of a soil-derived Streptomyces sp. KIB-M10. Structures of these compounds were elucidated via a joint use of spectroscopic analyses and single-crystal X-ray diffractions. Among them, cangumycins E (5) and F (6) share a C-ring cleaved backbone, and cangumycins B (2) and E (5) exhibit potent immunosuppressive activity (IC50 8.1 and 2.7 µmol·L-1, respectively) against human T cell proliferation at a non-cytotoxic concentration.


Assuntos
Antraquinonas/química , Produtos Biológicos/química , Imunossupressores/química , Streptomyces/química , Antraquinonas/isolamento & purificação , Produtos Biológicos/isolamento & purificação , China , Cristalografia por Raios X , Fermentação , Imunossupressores/isolamento & purificação , Espectroscopia de Ressonância Magnética , Estrutura Molecular , Streptomyces/isolamento & purificação
15.
Molecules ; 24(21)2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31731388

RESUMO

Elaiophylins belong to a special family of 16-membered macrodiolides with C2-symmetry. They have exhibited remarkable biological activities, such as antimicrobial, anthelmintic, anticancer, immunosuppressive, anti-inflammatory, antiviral, and α-glucosidase inhibitory activities. A member of elaiophylins, efomycin M, is as a specific small molecule inhibitor of selectin in preclinical trial for the treatment of psoriasis, ischemia-reperfusion, and allergy. The biosynthetic investigation of elaiophylins has uncovered a unique thioesterase, which is responsible for the formation of C2-symmetric diolide. We herein summarize the natural occurrence, bioactivity, and biosynthesis of elaiophylins covering the literatures from 1959 to 2019. Hopefully, this review will inspire further research interests of these compounds and encourage the discovery of new analogues by metabolic engineering or genome mining.


Assuntos
Macrolídeos/uso terapêutico , Streptomyces/química , Antibacterianos/química , Antibacterianos/uso terapêutico , Anti-Infecciosos/química , Anti-Infecciosos/uso terapêutico , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Humanos , Hipersensibilidade/tratamento farmacológico , Imunossupressores/química , Imunossupressores/uso terapêutico , Macrolídeos/química , Engenharia Metabólica , Psoríase/tratamento farmacológico , Bibliotecas de Moléculas Pequenas/química , Bibliotecas de Moléculas Pequenas/uso terapêutico
17.
Colloids Surf B Biointerfaces ; 184: 110564, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31704647

RESUMO

One of the key challenges in dry eye syndrome therapy is to find a suitable carrier for immunosuppressant drug - cyclosporine A (CsA) - delivery to the eye. To investigate this issue, herein we present a methodology based on the combined analysis in macro- (Langmuir monolayers), micro- (Brewster angle microscopy) and nanoscale (atomic force microscopy and infrared nano-spectroscopy). The applied approach proves that CsA affects the phospholipid part of the tear film lipid layer by loosening molecular packing. This effect can be reversed by the addition of perfluorohexyloctane (F6H8). We have highlighted that F6H8 increases the availability of CsA and therefore is appropriate carrier for CsA topical delivery to the eye in the dry eye syndrome. In addition, the applied herein procedure provides a simple, low-cost laboratory tool for preliminary studies involving membrane active pharmaceuticals, preceding in vivo tests.


Assuntos
Ciclosporina/uso terapêutico , Sistemas de Liberação de Medicamentos , Síndromes do Olho Seco/tratamento farmacológico , Fluorcarbonetos/química , Imunossupressores/uso terapêutico , Ciclosporina/química , Portadores de Fármacos/química , Imunossupressores/química , Microscopia de Força Atômica , Tamanho da Partícula , Espectrofotometria Infravermelho , Propriedades de Superfície
18.
Molecules ; 24(19)2019 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-31554326

RESUMO

With the increase in the number of medicines patients have to take, there has been a rapid rise of fixed-dose combinations (FDCs) in the last two decades. Prior to FDC development, pharmacokinetic properties of active pharmaceutical ingredients (APIs) have to be evaluated, as well as methods for their determination developed. So as to increase patient compliance in inflammatory bowel disease, three novel FDCs of thiopurine immunosuppressants and folic acid are proposed; physico-chemical and pharmacokinetic properties such as hydrophobicity, lipophilicity and plasma protein binding of all APIs are evaluated. Moreover, experimental results of different properties are compared to those computed by various on-line prediction platforms so as to evaluate the viability of the in silico approach. A simultaneous method for their determination is developed, optimized, validated and applied to commercial tablet formulations. The method has shown to be fast, selective, accurate and precise, showing potential for reliable determination of API content in proposed FDCs during its development.


Assuntos
Cromatografia , Ácido Fólico/farmacocinética , Imunossupressores/farmacocinética , Fenômenos Químicos , Cromatografia Líquida de Alta Pressão , Ácido Fólico/administração & dosagem , Ácido Fólico/química , Humanos , Imunossupressores/administração & dosagem , Imunossupressores/química , Estrutura Molecular
19.
Phytochemistry ; 168: 112127, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31550672

RESUMO

Five undescribed C21 pregnane glycosides, epigycosides D-H, together with four known analogues, two lignans, and a flavonoid have been isolated from the stems of Epigynum cochinchinensis. The structures of pregnane glycosides were elucidated using spectroscopic techniques and acid hydrolysis. The in vitro immunological activities were assessed against Con A-stimulated proliferation of mice splenocytes. The C21 pregnane glycosides showed immunosuppressive activity in a concentration-dependent manner. Moreover, epigycoside E exhibited a potent immunosuppressive effect, and the IC50 value on Con A-stimulated mice splenocytes was 22.1 ±â€¯6.4 µM. Epigycoside E also caused G0/G1 arrest, and inhibited TNF-α and IL-2 production.


Assuntos
Apocynaceae/química , Glicosídeos/isolamento & purificação , Glicosídeos/farmacologia , Imunossupressores/isolamento & purificação , Imunossupressores/farmacologia , Pregnanos/isolamento & purificação , Pregnanos/farmacologia , Baço/efeitos dos fármacos , Baço/imunologia , Animais , Ciclo Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Concanavalina A/antagonistas & inibidores , Concanavalina A/farmacologia , Cristalografia por Raios X , Relação Dose-Resposta a Droga , Glicosídeos/química , Imunossupressores/química , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Modelos Moleculares , Estrutura Molecular , Caules de Planta/química , Pregnanos/química , Relação Estrutura-Atividade , Linfócitos T/efeitos dos fármacos
20.
Biochemistry (Mosc) ; 84(7): 773-781, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31509728

RESUMO

Understanding of the functioning of MUC1 (human mucin) has advanced significantly over 40 years of its investigation. The anti-adhesive properties of the extracellular domain, which were the main focus of early studies initially explaining overexpression of MUC1 in progressing oncological diseases, were gradually put on the back burner. Researchers became more interested in its regulatory and signaling functions in cells rather in its anti-adhesive properties. The found the ability of MUC1 for signal transduction, and its ability to participate in cell metabolism opened new possibilities for improved control over cancer cells in addition to just attracting antigens of the immune system to a target. Nevertheless, there are issues in the functioning of MUC1 that raise doubts about its effectiveness in cancer immunotherapy.


Assuntos
Imunossupressores/metabolismo , Imunoterapia , Terapia de Alvo Molecular , Mucina-1/química , Mucina-1/metabolismo , Neoplasias/terapia , Biomarcadores Tumorais/química , Biomarcadores Tumorais/metabolismo , Linfócitos T CD4-Positivos/metabolismo , Glicosilação , Humanos , Imunossupressores/química , Ativação Linfocitária , Isoformas de Proteínas , Transdução de Sinais , Sequências de Repetição em Tandem
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