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1.
Adv Mater ; 32(40): e2004210, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32864794

RESUMO

For rapid response against the prevailing COVID-19 (coronavirus disease 19), it is a global imperative to exploit the immunogenicity of existing formulations for safe and efficient vaccines. As the most accessible adjuvant, aluminum hydroxide (alum) is still the sole employed adjuvant in most countries. However, alum tends to attach on the membrane rather than entering the dendritic cells (DCs), leading to the absence of intracellular transfer and process of the antigens, and thus limits T-cell-mediated immunity. To address this, alum is packed on the squalene/water interphase is packed, forming an alum-stabilized Pickering emulsion (PAPE). "Inheriting" from alum and squalene, PAPE demonstrates a good biosafety profile. Intriguingly, with the dense array of alum on the oil/water interphase, PAPE not only adsorbs large quantities of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) antigens, but also harbors a higher affinity for DC uptake, which provokes the uptake and cross-presentation of the delivered antigens. Compared with alum-treated groups, more than six times higher antigen-specific antibody titer and three-fold more IFN-γ-secreting T cells are induced, indicating the potent humoral and cellular immune activations. Collectively, the data suggest that PAPE may provide potential insights toward a safe and efficient adjuvant platform for the enhanced COVID-19 vaccinations.


Assuntos
Adjuvantes Imunológicos/química , Vacinas Virais/química , Compostos de Alúmen/química , Animais , Antígenos Virais/química , Antígenos Virais/imunologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/prevenção & controle , Emulsões , Células HEK293 , Humanos , Interferon gama/metabolismo , Camundongos Endogâmicos BALB C , Pandemias , Pneumonia Viral/imunologia , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/imunologia , Linfócitos T/imunologia
2.
Int J Nanomedicine ; 15: 5083-5095, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32764938

RESUMO

Background: ß-glucans are chiral polysaccharides with well-defined immunological properties and supramolecular wrapping ability of its chiral feature. However, the exploitation of chiral properties of these nanoparticles in drug delivery systems was seldom conducted. Methods: ß-glucan molecules with different chain lengths were extracted from yeast Saccharomyces cerevisiae and thereafter modified. In a conformation transition process, these ß-glucan molecules were then self-assembled with anti-cancer drug doxorubicin into nanoparticles to construct drug delivery systems. The chiral interactions between the drug and carriers were revealed by circular dichroism spectra, ultraviolet and visible spectrum, fourier transform infrared spectroscopy, dynamic light scattering and transmission electron microscope. The immune-potentiation properties of modified ß-glucan nanoparticles were evaluated by analysis of the mRNA expression in RAW264.7 cell model. Further, the antitumor efficacy of the nanoparticles against the human breast cancer were studied in MCF-7 cell model by cellular uptake and cytotoxicity experiments. Results: ß-glucan nanoparticles can activate macrophages to produce immune enhancing cytokines (IL-1ß, IL-6, TNF-α, IFN-γ). A special chirality of the carriers in diameter of 50~160 nm can also associate with higher drug loading ability of 13.9% ~38.2% and pH-sensitive release with a change of pH from 7.4 to 5.0. Cellular uptake and cytotoxicity experiments also prove that the chiral-active ß-glucan nanoparticles can be used in anti-cancer nanomedicine. Conclusion: This work demonstrates that ß-glucans nanoparticles with special chiral feature which leading to strong immunopotentiation ability and high drug loading efficiency can be developed as a novel type of nanomedicine for anti-cancer treatment.


Assuntos
Adjuvantes Imunológicos/administração & dosagem , Antineoplásicos/administração & dosagem , Doxorrubicina/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Nanopartículas/administração & dosagem , beta-Glucanas/imunologia , Adjuvantes Imunológicos/química , Animais , Antineoplásicos/imunologia , Dicroísmo Circular , Portadores de Fármacos/química , Humanos , Células MCF-7 , Camundongos , Nanopartículas/química , Células RAW 264.7 , Saccharomyces cerevisiae/química , Espectrofotometria Ultravioleta , Espectroscopia de Infravermelho com Transformada de Fourier , Estereoisomerismo , beta-Glucanas/química
3.
Carbohydr Polym ; 240: 116346, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: covidwho-102080

RESUMO

The new coronavirus pneumonia, named COVID-19 by the World Health Organization, has become a pandemic. It is highly pathogenic and reproduces quickly. There are currently no specific drugs to prevent the reproduction and spread of COVID-19. Some traditional Chinese medicines, especially the Lung Cleansing and Detoxifying Decoction (Qing Fei Pai Du Tang), have shown therapeutic effects on mild and ordinary COVID-19 patients. Polysaccharides are important ingredients in this decoction. This review summarizes the potential pharmacological activities of polysaccharides isolated by hot water extraction from Lung Cleansing and Detoxifying Decoction, which is consistent with its production method, to provide the theoretical basis for ongoing research on its application.


Assuntos
Infecções por Coronavirus/terapia , Medicamentos de Ervas Chinesas/uso terapêutico , Pulmão/efeitos dos fármacos , Compostos Fitoquímicos/uso terapêutico , Pneumonia Viral/terapia , Polissacarídeos/uso terapêutico , Adjuvantes Imunológicos/química , Animais , Anti-Inflamatórios/uso terapêutico , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/prevenção & controle , Humanos , Medicina Tradicional Chinesa , Camundongos , Camundongos Endogâmicos C57BL , Pandemias , Vacinas Virais
4.
Carbohydr Polym ; 240: 116346, 2020 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-32475597

RESUMO

The new coronavirus pneumonia, named COVID-19 by the World Health Organization, has become a pandemic. It is highly pathogenic and reproduces quickly. There are currently no specific drugs to prevent the reproduction and spread of COVID-19. Some traditional Chinese medicines, especially the Lung Cleansing and Detoxifying Decoction (Qing Fei Pai Du Tang), have shown therapeutic effects on mild and ordinary COVID-19 patients. Polysaccharides are important ingredients in this decoction. This review summarizes the potential pharmacological activities of polysaccharides isolated by hot water extraction from Lung Cleansing and Detoxifying Decoction, which is consistent with its production method, to provide the theoretical basis for ongoing research on its application.


Assuntos
Infecções por Coronavirus/terapia , Medicamentos de Ervas Chinesas/uso terapêutico , Pulmão/efeitos dos fármacos , Compostos Fitoquímicos/uso terapêutico , Pneumonia Viral/terapia , Polissacarídeos/uso terapêutico , Adjuvantes Imunológicos/química , Animais , Anti-Inflamatórios/uso terapêutico , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/prevenção & controle , Humanos , Medicina Tradicional Chinesa , Camundongos , Camundongos Endogâmicos C57BL , Pandemias , Vacinas Virais
5.
Middle East Afr J Ophthalmol ; 27(1): 59-61, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32549727

RESUMO

We report a case of severe ocular injury and impaired vision after self-administration of alum. A 56-year-old female administered an alum substance in the left eye and experienced severe corneal thinning, a scar, and decreased vision. The active compounds in the alum substance were analyzed using scanning electron microscopy. When topically administered, alum may cause severe ocular injury. Public awareness, early recognition of the injuries, and timely intervention may prevent permanent ocular damage.


Assuntos
Adjuvantes Imunológicos/toxicidade , Compostos de Alúmen/toxicidade , Doenças da Córnea/induzido quimicamente , Transtornos da Visão/induzido quimicamente , Adjuvantes Imunológicos/química , Compostos de Alúmen/química , Doenças da Córnea/diagnóstico , Feminino , Medicina Herbária , Humanos , Microscopia Eletrônica de Varredura , Pessoa de Meia-Idade , Autoadministração , Microscopia com Lâmpada de Fenda , Espectrometria por Raios X , Transtornos da Visão/diagnóstico
6.
Phytomedicine ; 71: 153233, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32454348

RESUMO

BACKGROUND: Xanthohumol is known to exert anti-inflammatory properties but has poor oral bioavailability. Using advanced micellization technology, it has been possible to markedly enhance its bioavailability. PURPOSE: In the present study, we compared the chronic anti-inflammatory activities of native and micellar xanthohumol in the rat adjuvant arthritis model, using diclofenac as a reference drug. METHODS: Adjuvant arthritis was induced by injecting Freund's complete adjuvant into the right hind paw of rats and monitoring paw volume over 3 weeks. The drugs were given daily for 3 weeks, starting from the day of adjuvant inoculation. Serum was collected at the end of the experiment to measure inflammatory and oxidative stress parameters. Statistical comparisons between different groups were carried out by one-way analysis of variance followed by Tukey-Kramer multiple comparison test. RESULTS: Micellar solubilized xanthohumol showed a better anti-inflammatory activity than its native form. The reduction in paw volume was reflected in corresponding changes in relevant mediators of inflammation like tumor necrosis factor-α, interleukin-6 and C-reactive protein, myloperoxidase and lipid peroxidation markers. CONCLUSION: The findings confirm that micellar solubilization of xanthohumol enhances its anti-inflammatory activity, probably as a result of improving its bioavailabilty. The solubilized xanthohumol may prove to be a promising adjuvant tool for anti-inflammatory treatment and a potential anti-inflammatory alternative to synthetic drugs.


Assuntos
Anti-Inflamatórios/farmacologia , Flavonoides/química , Flavonoides/farmacologia , Propiofenonas/química , Propiofenonas/farmacologia , Adjuvantes Imunológicos/química , Adjuvantes Imunológicos/farmacologia , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacocinética , Artrite Experimental/tratamento farmacológico , Disponibilidade Biológica , Feminino , Flavonoides/farmacocinética , Adjuvante de Freund/efeitos adversos , Interleucina-6/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Micelas , Estresse Oxidativo/efeitos dos fármacos , Propiofenonas/farmacocinética , Ratos Wistar , Solubilidade , Fator de Necrose Tumoral alfa/metabolismo
7.
Chemistry ; 26(41): 8976-8982, 2020 Jul 22.
Artigo em Inglês | MEDLINE | ID: mdl-32428253

RESUMO

The addition of aluminum-based adjuvants in vaccines enhances the immune response to antigens. The strength of antigen adsorption on adjuvant gels is known to modulate vaccine efficacy. However, a detailed understanding of the mechanisms of interaction between aluminum gels and antigens is still missing. Herein, a new analytical approach based on dynamic nuclear polarization (DNP) enhanced NMR spectroscopy under magic angle spinning (MAS) is implemented to provide a molecular description of the antigen-adjuvant interface. This approach is demonstrated on hepatitis B surface antigen particles in combination with three aluminum gels obtained from different suppliers. Both noncovalent and covalent interactions between the phospholipids of the antigen particles and the surface of the aluminum gels are identified by using MAS DNP NMR 27 Al and 31 P correlation experiments. Although covalent interactions were detected for only one of the formulations, dipolar recoupling rotational echo adiabatic passage double resonance (REAPDOR) experiments reveal significant differences in the strength of weak interactions.


Assuntos
Adjuvantes Imunológicos/química , Alumínio/química , Antígenos/química , Vacinas/química , Adsorção , Antígenos/imunologia , Composição de Medicamentos , Espectroscopia de Ressonância Magnética/métodos , Vacinas/imunologia
8.
Parasit Vectors ; 13(1): 196, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32295617

RESUMO

BACKGROUND: Visceral leishmaniasis (VL) caused by dimorphic Leishmania species is a parasitic disease with high socioeconomic burden in endemic areas worldwide. Sustaining control of VL in terms of proper and prevailing immunity development is a global necessity amid unavailability of a prophylactic vaccine. Screening of experimental proteome of the human disease propagating form of Leishmania donovani (amastigote) can be more pragmatic for in silico mining of novel vaccine candidates. METHODS: By using an immunoinformatic approach, CD4+ and CD8+ T cell-specific epitopes from experimentally reported L. donovani proteins having secretory potential and increased abundance in amastigotes were screened. A chimera linked with a Toll-like receptor 4 (TLR4) peptide adjuvant was constructed and evaluated for physicochemical characteristics, binding interaction with TLR4 in simulated physiological condition and the trend of immune response following hypothetical immunization. RESULTS: Selected epitopes from physiologically important L. donovani proteins were found mostly conserved in L. infantum, covering theoretically more than 98% of the global population. The multi-epitope chimeric vaccine was predicted as stable, antigenic and non-allergenic. Structural analysis of vaccine-TLR4 receptor docked complex and its molecular dynamics simulation suggest sufficiently stable binding interface along with prospect of non-canonical receptor activation. Simulation dynamics of immune response following hypothetical immunization indicate active and memory B as well as CD4+ T cell generation potential, and likely chance of a more Th1 polarized response. CONCLUSIONS: The methodological approach and results from this study could facilitate more informed screening and selection of candidate antigenic proteins for entry into vaccine production pipeline in future to control human VL.


Assuntos
Antígenos de Protozoários/imunologia , Epitopos de Linfócito T/imunologia , Leishmania donovani/imunologia , Vacinas contra Leishmaniose/imunologia , Adjuvantes Imunológicos/química , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Biologia Computacional , Leishmania infantum/imunologia , Leishmaniose Visceral/parasitologia , Simulação de Acoplamento Molecular , Simulação de Dinâmica Molecular , Proteômica , Proteínas de Protozoários/imunologia , Vacinas de Subunidades/imunologia
9.
Int J Nanomedicine ; 15: 2071-2083, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32273703

RESUMO

Background and Purpose: Adjuvant can reduce vaccine dosage and acquire better immune protection to the body, which helps to deal with the frequent outbreaks of influenza. Nanoemulsion adjuvants have been proved efficient, but the relationship between their key properties and the controlled release which greatly affects immune response is still unclear. The present work explores the role of factors such as particle size, the polydispersity index (PDI), stability and the safety of nanoemulsions by optimizing the water concentration, oil phase and modes of carrying, to explain the impact of those key factors above on adjuvant effect. Methods: Isopropyl myristate (IPM), white oil, soybean oil, and grape-kernel oil were chosen as the oil phase to explore their roles in emulsion characteristics and the adjuvant effect. ICR mice were immunized with an emulsion-inactivated H3N2 split influenza vaccine mixture, to compare the nanoemulsion's adjuvant with traditional aluminium hydroxide or complete Freund's adjuvant. Results: Particle size of all the nanoemulsion formed in our experiment ranged from 20 nm to 200 nm and did not change much when diluted with water, while the PDI decreased obviously, indicating that the particles tended to become more dispersive. Formulas with 80% or 85.6% water concentration showed significant higher HAI titer than aluminium hydroxide or complete Freund's adjuvant, and adsorption rather than capsule mode showed higher antigen delivery efficiency. As mentioned about oil phase, G (IPM), F (white oil), H (soybean oil), and I (grape-kernel oil) showed a decreasing trend in their adjuvant efficiency, and nanoemulsion G was the best adjuvant with smaller and uniform particle size. Conclusion: Emulsions with a smaller, uniform particle size had a better adjuvant effect, and the adsorption mode was generally more efficient than the capsule mode. The potential adjuvant order of the different oils was as follows: IPM > white oil > soybean oil > grape-kernel oil.


Assuntos
Adjuvantes Imunológicos/química , Sistemas de Liberação de Medicamentos/métodos , Emulsões/química , Vacinas contra Influenza/administração & dosagem , Nanoestruturas/química , Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/farmacologia , Animais , Emulsões/administração & dosagem , Emulsões/farmacologia , Feminino , Vírus da Influenza A Subtipo H3N2 , Vacinas contra Influenza/imunologia , Camundongos Endogâmicos ICR , Óleos/química , Infecções por Orthomyxoviridae/prevenção & controle , Tamanho da Partícula , Óleo de Soja/química , Vacinas de Produtos Inativados , Água/química
10.
Int J Nanomedicine ; 15: 239-252, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32021177

RESUMO

Introduction: Aluminum salts, although they have been used as adjuvants in many vaccine formulations since 1926, exclusively induce a Th2-biased immune response, thereby limiting their use against intracellular pathogens like Mycobacterium tuberculosis. Methods and Results: Herein, we synthesized amorphous and crystalline forms of aluminum hydroxide nanoparticles (AH nps) of 150-200 nm size range. Using Bacillus anthracis protective antigen domain 4 (D4) as a model antigen, we demonstrated that both amorphous and crystalline forms of AH nps displayed enhanced antigen D4 uptake by THP1 cells as compared to commercial adjuvant aluminum hydroxide gel (AH gel). In a mouse model, both amorphous and crystalline AH nps triggered an enhanced D4-specific Th2- and Th1-type immune response and conferred superior protection against anthrax spore challenge as compared to AH gel. Physicochemical characterization of crystalline and amorphous AH nps revealed stronger antigen D4 binding and release than AH gel. Conclusion: These results demonstrate that size and crystallinity of AH nps play important roles in mediating enhanced antigen presenting cells (APCs) activation and potentiating a strong antigen-specific immune response, and are critical parameters for the rational design of alum-based Th1-type adjuvant to induce a more balanced antigen-specific immune response.


Assuntos
Adjuvantes Imunológicos/farmacologia , Hidróxido de Alumínio/química , Antraz/prevenção & controle , Antígenos de Bactérias/imunologia , Toxinas Bacterianas/imunologia , Nanopartículas Metálicas/química , Adjuvantes Imunológicos/química , Adjuvantes Imunológicos/farmacocinética , Hidróxido de Alumínio/imunologia , Hidróxido de Alumínio/farmacologia , Animais , Antraz/imunologia , Vacinas contra Antraz/química , Vacinas contra Antraz/imunologia , Vacinas contra Antraz/farmacologia , Linhagem Celular , Modelos Animais de Doenças , Difusão Dinâmica da Luz , Feminino , Humanos , Camundongos , Células RAW 264.7 , Espectroscopia de Infravermelho com Transformada de Fourier , Células Th1/imunologia
11.
Lancet HIV ; 7(6): e410-e421, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32078815

RESUMO

BACKGROUND: Current efficacy studies of a mosaic HIV-1 prophylactic vaccine require four vaccination visits over one year, which is a complex regimen that could prove challenging for vaccine delivery at the community level, both for recipients and clinics. In this study, we evaluated the safety, tolerability, and immunogenicity of shorter, simpler regimens of trivalent Ad26.Mos.HIV expressing mosaic HIV-1 Env/Gag/Pol antigens combined with aluminium phosphate-adjuvanted clade C gp140 protein. METHODS: We did this randomised, double-blind, placebo-controlled phase 1 trial (IPCAVD010/HPX1002) at Beth Israel Deaconess Medical Center in Boston, MA, USA. We included healthy, HIV-uninfected participants (aged 18-50 years) who were considered at low risk for HIV infection and had not received any vaccines in the 14 days before study commencement. We randomly assigned participants via a computer-generated randomisation schedule and interactive web response system to one of three study groups (1:1:1) testing different regimens of trivalent Ad26.Mos.HIV (5 × 1010 viral particles per 0·5 mL) combined with 250 µg adjuvanted clade C gp140 protein. They were then assigned to treatment or placebo subgroups (5:1) within each of the three main groups. Participants and investigators were masked to treatment allocation until the end of the follow-up period. Group 1 received Ad26.Mos.HIV alone at weeks 0 and 12 and Ad26.Mos.HIV plus adjuvanted gp140 at weeks 24 and 48. Group 2 received Ad26.Mos.HIV plus adjuvanted gp140 at weeks 0, 12, and 24. Group 3 received Ad26.Mos.HIV alone at week 0 and Ad26.Mos.HIV plus adjuvanted gp140 at weeks 8 and 24. Participants in the control group received 0·5 mL of 0·9% saline. All study interventions were administered intramuscularly. The primary endpoints were Env-specific binding antibody responses at weeks 28, 52, and 72 and safety and tolerability of the vaccine regimens for 28 days after the injection. All participants who received at least one vaccine dose or placebo were included in the safety analysis; immunogenicity was analysed using the per-protocol population. The IPCAVD010/HPX1002 trial is registered with ClinicalTrials.gov, NCT02685020. We also did a parallel preclinical study in rhesus monkeys to test the protective efficacy of the shortened group 3 regimen. FINDINGS: Between March 7, 2016, and Aug 19, 2016, we randomly assigned 36 participants to receive at least one dose of study vaccine or placebo, ten to each vaccine group and two to the corresponding placebo group. 30 (83%) participants completed the full study, and six (17%) discontinued it prematurely because of loss to follow-up, withdrawal of consent, investigator decision, and an unrelated death from a motor vehicle accident. The two shortened regimens elicited comparable antibody titres against autologous clade C Env at peak immunity to the longer, 12-month regimen: geometric mean titre (GMT) 41 007 (95% CI 17 959-93 636) for group 2 and 49 243 (29 346-82 630) for group 3 at week 28 compared with 44 590 (19 345-102 781) for group 1 at week 52). Antibody responses remained increased (GMT >5000) in groups 2 and 3 at week 52 but were highest in group 1 at week 72. Antibody-dependent cellular phagocytosis, Env-specific IgG3, tier 1A neutralising activity, and broad cellular immune responses were detected in all groups. All vaccine regimens were well tolerated. Mild-to-moderate pain or tenderness at the injection site was the most commonly reported solicited local adverse event, reported by 28 vaccine recipients (93%) and two placebo recipients (33%). Grade 3 solicited systemic adverse events were reported by eight (27%) vaccine recipients and no placebo recipients; the most commonly reported grade 3 systemic symptoms were fatigue, myalgia, and chills. The shortened group 3 regimen induced comparable peak immune responses in 30 rhesus monkeys as in humans and resulted in an 83% (95% CI 38·7-95, p=0·004 log-rank test) reduction in per-exposure acquisition risk after six intrarectal challenges with SHIV-SF162P3 at week 54, more than 6 months after final vaccination. INTERPRETATION: Short, 6-month regimens of a mosaic HIV-1 prophylactic vaccine elicited robust HIV-specific immune responses that were similar to responses elicited by a longer, 12-month schedule. Preclinical data showed partial protective efficacy of one of the short vaccine regimens in rhesus monkeys. Further clinical studies are required to test the suitability of the shortened vaccine regimens in humans. Such shortened regimens would be valuable to increase vaccine delivery at the community level, particularly in resource-limited settings. FUNDING: Ragon Institute (Massachusetts General Hospital, Massachusetts Institute of Technology, and Harvard University; Cambridge, MA, USA) and Janssen Vaccines & Prevention (Leiden, Netherlands).


Assuntos
Vacinas contra a AIDS/administração & dosagem , Adjuvantes Imunológicos/administração & dosagem , Infecções por HIV/prevenção & controle , Macaca mulatta/imunologia , Produtos do Gene env do Vírus da Imunodeficiência Humana/administração & dosagem , Vacinas contra a AIDS/efeitos adversos , Vacinas contra a AIDS/imunologia , Adjuvantes Imunológicos/efeitos adversos , Adjuvantes Imunológicos/química , Adulto , Animais , Método Duplo-Cego , Feminino , Anticorpos Anti-HIV/metabolismo , Infecções por HIV/imunologia , HIV-1/imunologia , Humanos , Esquemas de Imunização , Injeções Intramusculares , Masculino , Pessoa de Meia-Idade , Fatores de Tempo , Adulto Jovem , Produtos do Gene env do Vírus da Imunodeficiência Humana/efeitos adversos , Produtos do Gene env do Vírus da Imunodeficiência Humana/imunologia
12.
Life Sci ; 247: 117435, 2020 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-32081661

RESUMO

Toll-like receptors (TLRs) are critical sensors related to inflammation and tumorigenesis. Among all subtypes, the TLR4 is a highly described transmembrane protein involved in the inflammatory process. The TLR4/myeloid differentiation factor 88 (MyD88) signaling pathway has been implicated in oncogenic events in several tissues and is associated with survival of patients. Through activation, TLR4 recruits adaptor proteins, i.e., MyD88 or TRIF, to triggers canonical and non-canonical signaling pathways that result in distinct immune responses. In most cancer cells, uncontrolled TLR4 signaling modifies the tumor microenvironment to proliferate and evade immune surveillance. By contrast, TLR4 activation can produce antitumor activities, thereby inhibiting tumor growth and enhancing the proper immune response. We review herein recent approaches on the role of the TLR4 signaling pathway and discuss potential candidates for gynecological cancer therapies; among these agents, natural and synthetic compounds have been tested both in vitro and in vivo. Since TLR4 ligands have been investigated as effective immune-adjuvants in the context of these aggressive malignancies, we described how TLR4 signaling controls part of the tumor-related inflammatory process and which are the new targeting molecules implicated in the regulation of tumorigenicity in ovarian, cervical, and endometrial cancers.


Assuntos
Antineoplásicos/química , Neoplasias do Endométrio/metabolismo , Neoplasias Ovarianas/metabolismo , Receptor 4 Toll-Like/metabolismo , Neoplasias do Colo do Útero/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Adjuvantes Imunológicos/química , Adjuvantes Imunológicos/uso terapêutico , Animais , Antineoplásicos/uso terapêutico , Citocinas/metabolismo , Feminino , Humanos , Inflamação/metabolismo , Terapia de Alvo Molecular/métodos , Fator 88 de Diferenciação Mieloide/metabolismo , Transdução de Sinais , Microambiente Tumoral/efeitos dos fármacos
13.
Nat Commun ; 11(1): 315, 2020 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-31949137

RESUMO

Standard inactivated influenza vaccines are poorly immunogenic in immunologically naive healthy young children, who are particularly vulnerable to complications from influenza. For them, there is an unmet need for better influenza vaccines. Oil-in-water emulsion-adjuvanted influenza vaccines are promising candidates, but clinical trials yielded inconsistent results. Here, we meta-analyze randomized controlled trials with efficacy data (3 trials, n = 15,310) and immunogenicity data (17 trials, n = 9062). Compared with non-adjuvanted counterparts, adjuvanted influenza vaccines provide a significantly better protection (weighted estimate for risk ratio of RT-PCR-confirmed influenza: 0.26) and are significantly more immunogenic (weighted estimates for seroprotection rate ratio: 4.6 to 7.9) in healthy immunologically naive young children. Nevertheless, in immunologically non-naive children, adjuvanted and non-adjuvanted vaccines provide similar protection and are similarly immunogenic. These results indicate that oil-in-water emulsion adjuvant improves the efficacy of inactivated influenza vaccines in healthy young children at the first-time seasonal influenza vaccination.


Assuntos
Adjuvantes Imunológicos/química , Vacinas contra Influenza/imunologia , Influenza Humana/prevenção & controle , Óleos/química , Água/química , Anticorpos Antivirais/sangue , Formação de Anticorpos , Criança , Bases de Dados Factuais , Emulsões , Humanos , Imunidade , Vacinas contra Influenza/sangue , Vacinas contra Influenza/química , Influenza Humana/imunologia , Orthomyxoviridae , Vacinação
14.
Food Chem ; 315: 126266, 2020 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-32000083

RESUMO

Flaxseeds are widely consumed for their desirable sensory attributes and health benefits. We focused on enhancing the sustainability and economic potential of flaxseeds by characterizing functional attributes of polysaccharides isolated from flaxseed hull residues. In particular, antioxidant and immune-stimulatory polysaccharides were isolated and purified from flaxseed hull. Infrared spectroscopy was used to identify the key functional groups. The polysaccharides were composed of mannose, rhamnose, galactose, glucose, galactose, xylose, arabinose, and fucose. In vitro studies showed certain flaxseed hull polysaccharide fractions exhibited strong antioxidant activities, increased nitric oxide levels, and enhanced the production of cytokines (TNF-α and IL-6). In the presence of 200 µg/mL of one of these fractions, the levels of p-ERK, p-JNK, and p-p38 increased significantly by 1.8-, 9.0-, and 6.7-fold. These polysaccharide fractions may exhibit their immune-regulatory properties partly by modulating the MAPK pathway. The flaxseed hull polysaccharides identified have potential application as natural antioxidants and immune-enhancing nutraceuticals.


Assuntos
Adjuvantes Imunológicos/farmacologia , Antioxidantes/farmacologia , Linho/química , Polissacarídeos/análise , Polissacarídeos/farmacologia , Adjuvantes Imunológicos/química , Animais , Antioxidantes/análise , Antioxidantes/química , Antioxidantes/isolamento & purificação , Citocinas/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Camundongos , Óxido Nítrico/biossíntese , Polissacarídeos/química , Polissacarídeos/isolamento & purificação , Células RAW 264.7 , Relação Estrutura-Atividade
15.
PLoS One ; 15(1): e0227891, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31978077

RESUMO

For the induction of antigen-specific T-cell responses by vaccination, an appropriate immune adjuvant is required. Vaccine adjuvants generally provide two functions, namely, immune potentiator and delivery, and many adjuvants that can efficiently induce T-cell responses are known to have the combination of these two functions. In this study, we explored a cationic lipid DOTAP-based adjuvant. We found that the microfluidic preparation of DOTAP nanoparticles induced stronger CD4+ and CD8+ T-cell responses than liposomal DOTAP. The further addition of Type-A CpG D35 in DOTAP nanoparticles increased the induction of T-cell responses, particularly in CD4+ T cells. Further investigations revealed that the size of DOTAP nanoparticles, prepared buffer conditions, and physicochemical interaction with vaccine antigen are important factors for the efficient induction of T-cell responses with a relatively small antigen dose. These results suggested that microfluidic-prepared DOTAP nanoparticles plus D35 are a promising adjuvant for a vaccine that induces therapeutic T-cell responses for treating cancer and infectious diseases.


Assuntos
Adjuvantes Imunológicos/farmacologia , Ácidos Graxos Monoinsaturados/farmacologia , Imunidade Celular/efeitos dos fármacos , Compostos de Amônio Quaternário/farmacologia , Vacinas/farmacologia , Adjuvantes Imunológicos/química , Animais , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Humanos , Imunidade Celular/imunologia , Lipossomos/farmacologia , Camundongos , Microfluídica , Nanopartículas/química , Vacinas/química
16.
Nat Biotechnol ; 38(3): 320-332, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-31932728

RESUMO

Personalized cancer vaccines targeting patient-specific neoantigens are a promising cancer treatment modality; however, neoantigen physicochemical variability can present challenges to manufacturing personalized cancer vaccines in an optimal format for inducing anticancer T cells. Here, we developed a vaccine platform (SNP-7/8a) based on charge-modified peptide-TLR-7/8a conjugates that are chemically programmed to self-assemble into nanoparticles of uniform size (~20 nm) irrespective of the peptide antigen composition. This approach provided precise loading of diverse peptide neoantigens linked to TLR-7/8a (adjuvant) in nanoparticles, which increased uptake by and activation of antigen-presenting cells that promote T-cell immunity. Vaccination of mice with SNP-7/8a using predicted neoantigens (n = 179) from three tumor models induced CD8 T cells against ~50% of neoantigens with high predicted MHC-I binding affinity and led to enhanced tumor clearance. SNP-7/8a delivering in silico-designed mock neoantigens also induced CD8 T cells in nonhuman primates. Altogether, SNP-7/8a is a generalizable approach for codelivering peptide antigens and adjuvants in nanoparticles for inducing anticancer T-cell immunity.


Assuntos
Adjuvantes Imunológicos/química , Antígenos de Neoplasias/imunologia , Linfócitos T CD8-Positivos/metabolismo , Vacinas Anticâncer/administração & dosagem , Melanoma Experimental/tratamento farmacológico , Animais , Vacinas Anticâncer/imunologia , Linhagem Celular Tumoral , Melanoma Experimental/imunologia , Camundongos , Nanopartículas , Medicina de Precisão , Primatas , Receptor 7 Toll-Like/imunologia , Receptor 8 Toll-Like/imunologia , Vacinação , Vacinas Conjugadas
17.
Phytochemistry ; 170: 112215, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31812106

RESUMO

Acyclotides are plant-based, acyclic miniproteins with cystine knot motif formed by three conserved disulfide linkages and lack head to tail ligation. Acyclotides may not necessarily be less stable, even though they lack cyclic backbone, as the conserved cystine knot feature provides the required stability. Violacin A was the first acyclotide, isolated from Viola odorata in 2006. Until now, acyclotides have been reported from five dicot families (Violaceae, Rubiaceae, Cucurbitaceae, Solanaceae, Fabaceae) and one monocot family (Poaceae). In Poaceae, only acyclotides have been found whereas in dicot families both cyclotides and acyclotides have been isolated. In last 15 years, several acyclotides with antimicrobial, cytotoxic and hemolytic bioactivities have been discovered. Thus, although many naturally expressed acyclotides do exhibit bioactivities, the linearization of the cyclic peptides may result in loss of bioactivities. Although, bioactivities of acyclotides are comparable to their cyclic counterparts, the numbers of isolated acyclotides are still few. Further, those discovered, have the scope to be screened for agriculturally important activities (insecticidal, anti-helminthic, molluscicidal) and pharmaceutical properties (anticancer, anti-HIV, immuno-stimulant). The feasibility of application of acyclotides is because of their relatively less complex biological synthesis compared to cyclotides, as the cyclization step is not needed. This attribute facilitates the production of transgenic crops and/or its expression in heterologous organisms, lacking cyclization machinery. Keeping in view the bioactivities and the wide array of emerging potential applications of acyclotides, the present review discusses their distribution in plants, gene and protein structure, biosynthesis, bioactivities and mechanism of action. Further, their potential applications and future perspectives to exploit them in agriculture and pharmaceutical industries have been highlighted.


Assuntos
Adjuvantes Imunológicos/farmacologia , Fármacos Anti-HIV/farmacologia , Antineoplásicos Fitogênicos/farmacologia , Ciclotídeos/farmacologia , Inseticidas/farmacologia , Compostos Fitoquímicos/farmacologia , Adjuvantes Imunológicos/química , Adjuvantes Imunológicos/isolamento & purificação , Fármacos Anti-HIV/química , Fármacos Anti-HIV/isolamento & purificação , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/isolamento & purificação , Ciclotídeos/química , Ciclotídeos/isolamento & purificação , Humanos , Inseticidas/química , Inseticidas/isolamento & purificação , Compostos Fitoquímicos/química , Compostos Fitoquímicos/isolamento & purificação
18.
Vet Immunol Immunopathol ; 220: 109986, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31855742

RESUMO

In a previous study, we proposed as an alternative to the use of animals in infectious challenge studies, a new approach describing the vaccine-induced immune response through the multivariate analysis of a defined set of immune parameters characterizing the B and T immune responses. This multivariate analysis, i.e. immune fingerprint, was evaluated first to assess the impact of minor changes in well characterized vaccines. The approach showed promising results in the assessment of the compatibility between two licensed vaccines. In the present study, the immune fingerprint was used to compare adjuvants with the various immunological parameters of the immune fingerprint as well as to assess the ability of this approach to discriminate different Rabies vaccine formulations in dogs. RABISIN® was the reference vaccine, adjuvanted with aluminum hydroxide. An exploratory factor analysis was used to analyse the covariance structure of the immunological data. Significant differences were observed between groups. RABISIN and a linear polyacrylate (SPA09) adjuvanted vaccine performed better than chitosan adjuvanted ones, both for humoral and cell immune responses. This study showed that the immune fingerprint approach can be used to screen vaccine formulations. It provides additional information compared to classical vaccination and infectious challenge efficacy study.


Assuntos
Adjuvantes Imunológicos/química , Anticorpos Antivirais/sangue , Vacinas Antirrábicas/imunologia , Raiva/prevenção & controle , Animais , Anticorpos Neutralizantes/sangue , Cães , Análise Multivariada , Raiva/imunologia , Vacinas Antirrábicas/classificação , Vacinação/veterinária
19.
BMC Mol Cell Biol ; 20(Suppl 2): 56, 2019 Dec 20.
Artigo em Inglês | MEDLINE | ID: mdl-31856726

RESUMO

BACKGROUND: Toll-like receptor 9 is a key innate immune receptor involved in detecting infectious diseases and cancer. TLR9 activates the innate immune system following the recognition of single-stranded DNA oligonucleotides (ODN) containing unmethylated cytosine-guanine (CpG) motifs. Due to the considerable number of rotatable bonds in ODNs, high-throughput in silico screening for potential TLR9 activity via traditional structure-based virtual screening approaches of CpG ODNs is challenging. In the current study, we present a machine learning based method for predicting novel mouse TLR9 (mTLR9) agonists based on features including count and position of motifs, the distance between the motifs and graphically derived features such as the radius of gyration and moment of Inertia. We employed an in-house experimentally validated dataset of 396 single-stranded synthetic ODNs, to compare the results of five machine learning algorithms. Since the dataset was highly imbalanced, we used an ensemble learning approach based on repeated random down-sampling. RESULTS: Using in-house experimental TLR9 activity data we found that random forest algorithm outperformed other algorithms for our dataset for TLR9 activity prediction. Therefore, we developed a cross-validated ensemble classifier of 20 random forest models. The average Matthews correlation coefficient and balanced accuracy of our ensemble classifier in test samples was 0.61 and 80.0%, respectively, with the maximum balanced accuracy and Matthews correlation coefficient of 87.0% and 0.75, respectively. We confirmed common sequence motifs including 'CC', 'GG','AG', 'CCCG' and 'CGGC' were overrepresented in mTLR9 agonists. Predictions on 6000 randomly generated ODNs were ranked and the top 100 ODNs were synthesized and experimentally tested for activity in a mTLR9 reporter cell assay, with 91 of the 100 selected ODNs showing high activity, confirming the accuracy of the model in predicting mTLR9 activity. CONCLUSION: We combined repeated random down-sampling with random forest to overcome the class imbalance problem and achieved promising results. Overall, we showed that the random forest algorithm outperformed other machine learning algorithms including support vector machines, shrinkage discriminant analysis, gradient boosting machine and neural networks. Due to its predictive performance and simplicity, the random forest technique is a useful method for prediction of mTLR9 ODN agonists.


Assuntos
Adjuvantes Imunológicos/química , Algoritmos , Descoberta de Drogas/métodos , Oligodesoxirribonucleotídeos/química , Receptor Toll-Like 9/agonistas , Adjuvantes Imunológicos/farmacologia , Motivos de Aminoácidos , Animais , Camundongos , Redes Neurais de Computação , Oligodesoxirribonucleotídeos/farmacologia , Reprodutibilidade dos Testes , Relação Estrutura-Atividade , Receptor Toll-Like 9/química , Receptor Toll-Like 9/metabolismo
20.
Biomolecules ; 9(12)2019 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-31842458

RESUMO

TFPR1 is a novel peptide vaccine adjuvant we recently discovered. To define the structural basis and optimize its application as an adjuvant, we designed three different truncated fragments that have removed dominant B epitopes on TFPR1, and evaluated their capacity to activate bone marrow-derived dendritic cells and their adjuvanticity. Results demonstrated that the integrity of an α-ß-α sandwich conformation is essential for TFPR1 to maintain its immunologic activity and adjuvanticity. We obtained a functional truncated fragment TFPR-ta ranging from 40-168 aa of triflin that has similar adjuvanticity as TFPR1 but with 2-log fold lower immunogenicity. These results demonstrated a novel approach to evaluate and improve the activity of protein-based vaccine adjuvant.


Assuntos
Adjuvantes Imunológicos/química , Fatores de Transcrição Hélice-Alça-Hélice Básicos/química , Antígenos HIV/química , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/imunologia , Feminino , Antígenos HIV/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Conformação Proteica
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