RESUMO
Traditional medicinal plants have been used for centuries for their immunomodulatory properties and therapeutic potentials. The present study aims to investigate the immunomodulatory constituents from traditional medicinal plant, Tinospora cordifolia (willd.). Our study resulted in the isolation of new compound, 27-hydroxy octacosyl ferulate (1) along with eleven known compounds (2-12). The structures of the isolated compounds were characterized by combination of NMR (1D and 2D) and Mass spectroscopic methods. The hemisynthesis of compound 12 (ferulic acid) yielded (12a-12d and 12e-12 m) derivatives. Further, the isolated compounds and synthesized derivatives were assessed for their immunomodulatory potentials by evaluating their cytotoxicity and pro-inflammatory effects against macrophage cells (IL-6) and DC activation markers (CD 11c and 86). The biological results indicated that crude extract displayed potent immunomodulatory activity while isolated compounds and synthetic analogues showed moderate activity. Among the tested compounds, new compound (1), quercetin (10) and derivatives 12b, 12c found to be non-cytotoxic and displayed immunomodulatory potentials. Therefore, these compounds can be studied for autoimmunity and other immune suppressing conditions.
Assuntos
Agentes de Imunomodulação , Compostos Fitoquímicos , Tinospora , Tinospora/química , Estrutura Molecular , Compostos Fitoquímicos/farmacologia , Compostos Fitoquímicos/isolamento & purificação , Animais , Camundongos , Agentes de Imunomodulação/farmacologia , Agentes de Imunomodulação/isolamento & purificação , Ácidos Cumáricos/farmacologia , Ácidos Cumáricos/isolamento & purificação , Fatores Imunológicos/farmacologia , Fatores Imunológicos/isolamento & purificação , Células RAW 264.7 , Macrófagos/efeitos dos fármacos , Extratos Vegetais/farmacologia , Extratos Vegetais/química , Interleucina-6RESUMO
Frequently occurring inflammatory skin conditions such as psoriasis, dermatitis, acne, including skin cancer, wounds and other disorders arising out of premature skin aging, deteriorate skin health and adversely impact human life. Even though several synthetic compounds have evolved for treating these skin conditions, natural-product-based therapeutics are gaining popularity with growing evidence of their efficacy and safety for treating skin disorders. Many of these inflammatory skin diseases have underlying disturbances in our immune system and immunomodulatory natural products provide solutions for their effective treatment and aid in understanding the underlying mechanism of such inflammatory skin conditions. Based on this premise, the present review summarizes the possible application of plant-derived immunomodulatory compositions and single molecules for treating inflammatory skin conditions. In vitro, in vivo and mechanistic studies reported the application of selected plant-derived natural products for the treatment of inflammatory skin disorders including, cancer and infections. Several online databases including PubMed, Google Scholar, and Science Direct have been searched for gathering the information covered in this review. Empirical studies demonstrated that most of these natural compounds exhibited therapeutic properties through their immunomodulatory and anti-inflammatory potential supplemented often with anti-microbial, anti-neoplastic, and anti- oxidant activities. Overall, plant-based natural products discussed here are capable of modulating the immune system to minimize or completely suppress the pro-inflammatory markers, scavenge free radicals (ROS), prevent bacteria, fungal, and virus-derived skin infections and often regress skin cancer through the induction of apoptosis. The challenges and opportunities associated with the application of plant-based immunomodulators for skin applications and their safety considerations are also discussed here. The present study indicated that immunomodulatory plant natural products being biologically validated ligands against various biological targets manifested in inflammatory skin diseases, offer an effective, safe and affordable treatment for such disorders affecting skin health. However, further clinical evaluations are needed to substantiate these findings.
Assuntos
Dermatite , Humanos , Fatores Imunológicos/química , Fatores Imunológicos/metabolismo , Fatores Imunológicos/uso terapêutico , Produtos Biológicos/química , Produtos Biológicos/metabolismo , Produtos Biológicos/uso terapêutico , Dermatite/tratamento farmacológico , Dermatite/metabolismo , Plantas/química , Plantas/metabolismo , Bases de Dados Factuais , Radicais Livres/metabolismoRESUMO
A focused library of six new 2, 5-disubstituted tetrazole (2, 5-DST) analogues of N-acetylmuramyl-l-alanyl-d-isoglutamine (MDP) as potential immunomodulators were synthesized by the bioisosteric replacement of α-amide of d-isoglutamine with 5-substituted tetrazole (5-ST). Another parameter 'lipophilicity' was also considered to improve the pharmacological properties of MDP through the alkylation of 5-substituted tetrazole during synthesis. In total, six 2, 5-DST analogues of MDP were synthesized and bio-evaluated for the study of human NOD2 stimulation activity in the innate immune response. Interestingly, among the varied lengths of the alkyl chain in 2, 5-disubstituted tetrazole derivatives, the tetrazole analogues 12b bearing the -Butyl (C4) and 12c having -Octyl (C8) chain showed the best NOD2 stimulation potency equivalent with reference compound MDP. These analogues were evaluated for their adjuvanticity against dengue antigen and analogues 12b and 12c have elicited a potent humoral and cell mediated response.
Assuntos
Acetilmuramil-Alanil-Isoglutamina , Adjuvantes Imunológicos , Humanos , Acetilmuramil-Alanil-Isoglutamina/farmacologia , Adjuvantes Imunológicos/farmacologia , Imunidade Inata , Antígenos , Proteína Adaptadora de Sinalização NOD2/metabolismoRESUMO
Toll-like receptors-7 and -8 are expressed abundantly on antigen-presenting cells, and their agonists make potential adjuvant candidates for the development of new efficacious vaccines. In view of the importance of new efficacious imidazoquinoline based adjuvants, herein we have synthesized a focused library of a new class of imidazoquinolines retaining the N-isobutyl substitution of an imidazole moiety as in imiquimod and introduced a 1,2,3-triazolyl moiety upon alkyl substitution at the imidazolemethyne carbon employing triazolyl click chemistry. All the novel analogues were characterized using various spectroscopic techniques and the target specificity of these molecules was determined using HEK TLR7/8 transfected cell lines. TLR7/8 activity and also the molecular docking results correlated primarily to the position of the substituent for aromatic groups and also to the chain length in alkyl substitutions. The immunomodulatory properties of these analogues were evaluated using murine DC activation and also with hPBMC activation markers, cytokines which revealed that these analogues after modification were able to target the TLR7 receptors and also had a pro-inflammatory immune response.
RESUMO
CD1d-arbitrated activation of i-NKT cells by α-galactosylceramide results in the effective secretion of Th1 and Th2 cytokines, with adjuvanticity skewed toward Th2 immunity. However, the polarization of immune response could be achieved by suitable modification of the glycolipid structure. In the current study, novel glycolipids with an amphiphilic oligo ethylene glycol lipid moiety bearing the benzyloxy group at the terminus on the acyl arm of sphingosine, exhibited CD1d ligand binding as quantified by IL-2 cytokine production. When immunized with quadrivalent split influenza virus in BALB/c mice, the novel ceramide analogues with a longer oligo (ethylene glycol) chain length induced significant levels of antibody (IgG) with Th1-polarized immune response.
RESUMO
A focused library of water soluble 1,2,3-triazole tethered glycopeptide conjugates derived from variety of azido-monosaccharides and aliphatic azido-alcohols were synthesized through manipulation at the C-terminus of Pam3CAG and screened for their potential as TLR2 agonistic adjuvants against HBsAg antigen. In vitro ligand induced TLR2 signal activation was observed with all the analogues upon treatment with HEK blue TLR2 cell lines. Conjugate derived from ribose (6e), which exhibited pronounced HBsAg specific antibody (IgG) titer also shown enhanced CD8+ population indicating superior cell mediated immunity compared to standard adjuvant Pam3CSK4. Further, docking studies revealed ligand induced heterodimerization between TLR1 and 2. Overall, the result indicates the usefulness of novel conjugates as potential vaccine adjuvant.
Assuntos
Adjuvantes Imunológicos/farmacologia , Receptor 2 Toll-Like/agonistas , Triazóis/farmacologia , Vacinas/farmacologia , Adjuvantes Imunológicos/química , Linhagem Celular , Relação Dose-Resposta a Droga , Humanos , Imunidade Celular/efeitos dos fármacos , Estrutura Molecular , Relação Estrutura-Atividade , Triazóis/química , Vacinas/químicaRESUMO
Prolonged exposure to Ultra Violet Radiation (UVR) adversely alters the functions of many skin cell types causing skin cancer and photoaging, which had led to increase in demand for more safe and natural sunscreens against UVR. The present study focuses on production, structural characterization and evaluation of photoprotective nature of melanin pigment derived from lime dwelling Pseudomonas sp. Melanin was characterized by solubility, UV-Vis, FT-IR, 13C-CPMAS, ESI-MS spectroscopy, including particle size, melting point and elemental analyses. In vitro cytotoxicity and photo-protective effect of Pseudomonas derived melanin (Mel-P) against UV-B (Broad Band-BB) radiations were assessed on mouse fibroblasts NIH 3 T3 cell lines. Reactive Oxygen Species (ROS) generated in NIH 3 T3 cells upon UV-B (BB) exposure was determined and quantified by Fluorescent microscopic and Flow cytometric analyses. A natural melanin obtained from Pseudomonas sp. contains 5,6- dihydroxy indole 2-carboxyic acid (DHICA) as its basic constituent and possess typical properties of eumelanin as revealed by the characterization studies. Mel-P has shown cell viability of 61.33 ± 6.58% at the concentration of 500 µg/mL proving its non-cytotoxic effect. Owing to its anti-oxidant property, melanin efficiently protected the mouse fibroblast cells from UV-B (BB) irradiation in a dose dependant manner demonstrating its potential as an active photoprotective agent.
Assuntos
Compostos de Cálcio/química , Melaninas/química , Óxidos/química , Substâncias Protetoras/química , Pseudomonas/efeitos da radiação , Neoplasias Cutâneas/prevenção & controle , Protetores Solares/química , Células 3T3 , Animais , Antioxidantes/química , Antioxidantes/metabolismo , Compostos de Cálcio/metabolismo , Fibroblastos/citologia , Fibroblastos/efeitos da radiação , Humanos , Melaninas/metabolismo , Melaninas/farmacologia , Camundongos , Óxidos/metabolismo , Substâncias Protetoras/farmacologia , Pseudomonas/metabolismo , Espécies Reativas de Oxigênio/química , Espécies Reativas de Oxigênio/metabolismo , Pele , Solubilidade , Protetores Solares/metabolismo , Raios UltravioletaRESUMO
Two new secophragmalin-type limonoids, secotrichagmalins B (1) and C (2) along with two known compounds, were isolated from the fruits of Trichilia connaroides. The structures of the new compounds were elucidated by analysis of spectroscopic (IR, MS, and 2D NMR) data and single crystal X-ray diffraction studies. In addition, semisynthetic derivatives (2a-2l) were efficiently synthesized and evaluated for their in vitro cytotoxicity along with the isolated limonoids against a panel of human cancer cell lines. The results indicated that new analogues 2a, 2d, and 2e showed cytotoxicity on the DU145 cell line with IC50 values of 3.6, 4.2, and 5.2 µM, respectively. Flow cytometric analysis revealed that these analogues arrested the cell cycle in the G0/G1 phase and markedly induced apoptosis.
Assuntos
Antineoplásicos Fitogênicos/isolamento & purificação , Limoninas/isolamento & purificação , Meliaceae/química , Antineoplásicos Fitogênicos/síntese química , Antineoplásicos Fitogênicos/farmacologia , Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Limoninas/síntese química , Limoninas/química , Limoninas/farmacologiaRESUMO
Emulsions play an important role in present-day subunit vaccine delivery. Squalane-based emulsion was formulated using surfactants viz., Pluronic F68, Span 85 along with Murabutide (MB) as immunepotentiator. Particle size and zetapotential of the final optimized emulsion was found to be 134 nm and -13 mV, respectively. The in vitro cellular uptake studies performed using fluorescein isothiocyanate (FITC)-labeled ovalbumin (OVA) clearly revealed the rapid uptake of antigen in the presence of emulsion. The in vivo subcutaneous studies involving measurement of OVA-specific IgG antibody titers, Th1/Th2 cytokines were performed and a marked up regulation in IL-2, IL-12 and IFN-γ cytokines indicate Th1 immune response. Results supported that the squalane-based delivery system enhanced the uptake of the antigen by immune cells and elicited humoral as well as cell-mediated immune response in mice. These results indicate the promising application of the new squalane based oil-in-water (O/W) emulsion as capable vaccine delivery system useful for vaccine development.
Assuntos
Acetilmuramil-Alanil-Isoglutamina/análogos & derivados , Adjuvantes Imunológicos/administração & dosagem , Esqualeno/análogos & derivados , Vacinas/administração & dosagem , Acetilmuramil-Alanil-Isoglutamina/administração & dosagem , Acetilmuramil-Alanil-Isoglutamina/imunologia , Animais , Antígenos/imunologia , Citocinas/imunologia , Sistemas de Liberação de Medicamentos , Emulsões , Fluoresceína-5-Isotiocianato/química , Hexoses/química , Camundongos , Camundongos Endogâmicos BALB C , Ovalbumina/administração & dosagem , Ovalbumina/imunologia , Tamanho da Partícula , Poloxâmero/química , Células RAW 264.7 , Esqualeno/química , Tensoativos/química , Células Th1/imunologia , Células Th2/imunologiaRESUMO
Research on amalgamation of an antigen with a delivery system for developing a potent mucosal vaccine that elicits both cellular and humoral response has captured immense attention these days. Cationic delivery systems being the first choice for mucosal antigen delivery, despite being effective, are associated with inherent problems like cytotoxicity. Therefore, the quest for developing a precise system that can effectively deliver antigen to immune cells without adverse toxic effect has led to the use of partial cationic systems which are mostly humoral immune mediators. The art of fine-tuning cationic nature, avoiding side effects, and being immune responsive are the needs of the hour. Herein, we try to optimize the cationic nature of polycaprolactone (USFDA approved) by conjugating it with hydrazine. The polymer was modified using two stoichiometry ratios (5 and 10 equiv) of hydrazine monohydrate and characterized using FTIR and XRD. Free amine quantification of the modified polymers concluded that both the modified polymers had 232 and 457 µM/mg amine groups, respectively. A cytotoxicity assay performed using RAW 264.7 macrophages proved the safety of cationic polymers. In vitro assays for antigen colocalization and cross-presentation have revealed that the modified polymers could effectively execute the anticipated function. In vivo evaluation in BALB/c mice using recombinant dengue antigen for intranasal immunization affirmed that the modified polymer having 457 µM/mg of free amine groups effectively stimulated humoral and potent cellular immune response. The overall data suggests that the modified polymeric nanoparticles-with their cationic, pH-responsive, and adjuvanting characteristics-proved to be a versatile system for effective mucosal antigen delivery.
RESUMO
Nasal vaccine delivery systems are emerging alternatives to the conventional sub unit vaccine delivery systems owing to their ability to stimulate potent antigen specific humoral and cellular immune responses. Additional virtue of nasal delivery is its close proximity of immune cells to external epithelial layer which is the route of entry to pathogens. Toxicity of emulsion based vaccine delivery systems may be attributed to the presence of high quantities of surfactants used for stabilizing the emulsions. A safer approach would be to reduce physiologically unwanted surfactant burden in the emulsion to the bare limit to necessity. Oleic acid was used as oil phase due to its ability to enhance penetration of system in nasal mucosa. This emulsion was designed with the purpose that it activates the innate (TLR 4) and adaptive immune systems apart from performing its antigen delivery function. Proving the hypothesis, emulsion when immunized along with recombinant tetravalent dengue antigen has elicited a profound antigen specific humoral and cellular response. Antigen cross presenting and sustained release of antigen by emulsion is the key factor in shaping this immune response. Moreover, the dose sparing effect of emulsion has also been proven which has a crucial role in modern day vaccine delivery. This significant humoral and cellular response elicited proves the suitability of this emulsion system for enhancing the protective effect of vaccines against various intracellular pathogens.