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1.
Medicine (Baltimore) ; 99(20): e20161, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-32443332

RESUMO

INTRODUCTION: Psoriasis vulgaris (PV) is a chronic, painful, disfiguring, and disabling dermatological disease, which affects the physical and mental health of patients and impacts their quality of life. Current conventional systemic therapies can be costly, present risks of side effects, have limited efficacy and commonly recur following treatment cessation. Some Chinese herbal medicine therapies have shown therapeutic benefits for psoriasis vulgaris, including relieving symptoms and improving quality of life, and a potential of reducing relapse rate. However, explicit evidence has not yet been obtained. METHODS AND ANALYSIS: This is a pilot randomized controlled trial with the objective of investigating the effect of Jia Wei Liang Xue Xiao Feng San granules on relapse rate of recurrent PV and the correlation between Psoriasis area severity index (PASI) and key psoriasis-related cytokine changes and the number of cells. A total of 102 participants were recruited for this study, including 72 patients with recurrent PV, 15 healthy volunteers and 15 patients with psoriasis vulgaris who have recovered for more than 1 year. A total of 72 patients, with recurrent PV, will be randomized (1:1) to receive the oral Chinese herbal medicine Jia Wei Liang Xue Xiao Feng San or the oral Acitretin Capsule treatments for a period of 8 weeks. After this period, participants whose PASI scores improvement reached more than 75%, will undergo a 52-week follow-up phase.The primary outcome measures are as follows:The secondary study outcomes will include:This trial may provide a novel regimen for recurrent PV patients if the granules decrease recurrence rate without further adverse effects. ETHICS AND DISSEMINATION: The ethics approval was provided by the Sichuan Traditional Chinese medicine regional ethics review committee. The ethics approval number is 2018KL-055. The design and the results of the study will be disseminated through peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: Chinese Clinical Trial Registry (ChiCTR1900022766).


Assuntos
Exaustão por Calor/imunologia , Temperatura Alta/efeitos adversos , Imunidade Celular/efeitos dos fármacos , Psoríase/tratamento farmacológico , Linfócitos T Auxiliares-Indutores/imunologia , Acitretina/administração & dosagem , Acitretina/uso terapêutico , Administração Oral , Adolescente , Adulto , Idoso , Estudos de Casos e Controles , Citocinas/efeitos dos fármacos , Citocinas/metabolismo , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/uso terapêutico , Feminino , Humanos , Imunidade Celular/fisiologia , Ceratolíticos/administração & dosagem , Ceratolíticos/uso terapêutico , Masculino , Pessoa de Meia-Idade , Avaliação de Resultados em Cuidados de Saúde , Psoríase/psicologia , Qualidade de Vida , Recidiva , Índice de Gravidade de Doença , Adulto Jovem
2.
Nat Rev Rheumatol ; 16(3): 145-154, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32066940

RESUMO

Despite the introduction of numerous biologic agents for the treatment of rheumatoid arthritis (RA) and other forms of inflammatory arthritis, low-dose methotrexate therapy remains the gold standard in RA therapy. Methotrexate is generally the first-line drug for the treatment of RA, psoriatic arthritis and other forms of inflammatory arthritis, and it enhances the effect of most biologic agents in RA. Understanding the mechanism of action of methotrexate could be instructive in the appropriate use of the drug and in the design of new regimens for the treatment of RA. Although methotrexate is one of the first examples of intelligent drug design, multiple mechanisms potentially contribute to the anti-inflammatory actions of methotrexate, including the inhibition of purine and pyrimidine synthesis, transmethylation reactions, translocation of nuclear factor-κB (NF-κB) to the nucleus, signalling via the Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway and nitric oxide production, as well as the promotion of adenosine release and expression of certain long non-coding RNAs.


Assuntos
Aminoimidazol Carboxamida/análogos & derivados , Artrite/tratamento farmacológico , Imunidade Celular/efeitos dos fármacos , Metotrexato/uso terapêutico , Ribonucleotídeos/antagonistas & inibidores , Linfócitos T/imunologia , Tetra-Hidrofolato Desidrogenase/efeitos dos fármacos , Aminoimidazol Carboxamida/antagonistas & inibidores , Antirreumáticos/uso terapêutico , Artrite/imunologia , Artrite/metabolismo , Humanos , Linfócitos T/efeitos dos fármacos , Tetra-Hidrofolato Desidrogenase/metabolismo
3.
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
4.
Food Chem Toxicol ; 136: 110954, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31707033

RESUMO

Due to the growing number of applications of cadmium oxide nanoparticles (CdO NPs), there is a concern about their potential deleterious effects. The objective of our study was to investigate the effect of CdO NPs on the immune response, renal and intestine oxidative stress, blood antioxidant defence, renal fibrotic response, bone density and mineral content. Six-week-old female ICR mice were exposed to CdO NPs for 6 weeks by inhalation (particle size: 9.82 nm, mass concentration: 31.7 µg CdO/m3, total deposited dose: 0.195 µg CdO/g body weight). CdO NPs increased percentage of thymus CD3e+CD8a+ cells and moderately enhanced splenocyte proliferation and production of cytokines and chemokines. CdO NPs elevated pro-fibrotic factors (TGF-ß2, α-SMA and collagen I) in the kidney, and concentrations of AGEs in the intestine. The ratio of GSH and GSSG in blood was slightly reduced. Exposure to CdO NPs resulted in 10-fold higher Cd concentration in tibia bones. No differences were found in bone mass density, mineral content, bone area values, bone concentrations of Ca, P, Mg and Ca/P ratio. Our findings indicate stimulation of immune/inflammatory response, oxidative stress in the intestine, starting fibrotic response in kidneys and accumulation of CdO NPs in bones of mice.


Assuntos
Compostos de Cádmio/toxicidade , Fibrose/induzido quimicamente , Imunidade Celular/efeitos dos fármacos , Nanopartículas Metálicas/toxicidade , Estresse Oxidativo/efeitos dos fármacos , Óxidos/toxicidade , Tíbia/efeitos dos fármacos , Administração por Inalação , Animais , Compostos de Cádmio/administração & dosagem , Citocinas/metabolismo , Feminino , Intestinos/efeitos dos fármacos , Rim/efeitos dos fármacos , Rim/patologia , Linfonodos/efeitos dos fármacos , Nanopartículas Metálicas/administração & dosagem , Camundongos Endogâmicos ICR , Óxidos/administração & dosagem , Baço/efeitos dos fármacos , Timo/efeitos dos fármacos
5.
Cell Mol Life Sci ; 77(8): 1497-1509, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-31729564

RESUMO

Although tuberculosis (TB) is a curable disease, it remains the foremost cause of death from a single pathogen. Globally, approximately 1.6 million people died of TB in 2017. Many predisposing factors related to host immunity, genetics and the environment have been linked to TB. However, recent evidence suggests a relationship between dysbiosis in the gut microbiome and TB disease development. The underlying mechanism(s) whereby dysbiosis in the gut microbiota may impact the different stages in TB disease progression, are, however, not fully explained. In the wake of recently emerging literature, the gut microbiome could represent a potential modifiable host factor to improve TB immunity and treatment response. Herein, we summarize early data detailing (1) possible association between gut microbiome dysbiosis and TB (2) the potential for the use of microbiota biosignatures to discriminate active TB disease from healthy individuals (3) the adverse effect of protracted anti-TB antibiotics treatment on gut microbiota balance, and possible link to increased susceptibility to Mycobacterium tuberculosis re-infection or TB recrudescence following successful cure. We also discuss immune pathways whereby the gut microbiome could impact TB disease and serve as target for clinical manipulation.


Assuntos
Disbiose/complicações , Microbioma Gastrointestinal , Tuberculose/complicações , Animais , Antituberculosos/uso terapêutico , Progressão da Doença , Disbiose/imunologia , Disbiose/microbiologia , Disbiose/terapia , Microbioma Gastrointestinal/efeitos dos fármacos , Humanos , Imunidade Celular/efeitos dos fármacos , Mycobacterium tuberculosis/efeitos dos fármacos , Mycobacterium tuberculosis/imunologia , Probióticos/uso terapêutico , Receptores Toll-Like/imunologia , Tuberculose/imunologia , Tuberculose/microbiologia , Tuberculose/terapia
6.
Ecotoxicol Environ Saf ; 188: 109893, 2020 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-31735370

RESUMO

Cellular and humoral responses were evaluated in Litopenaeus vannamei juveniles when exposed to malathion, endosulfan, and their mixture. Each experiment was performed in the hemolymph collected at each exposure time (5 and 96 h) in duplicate; total hemocyte count, coagulation time, hemocyanin concentration, phenoloxidase (PO) and superoxide dismutase (SOD) activities were quantified. Survival was not affected by pesticides applied individually and mixed. Clotting time did not show significant differences concerning increase of concentration percentage of the pesticides tested. In organisms exposed to the pesticide mixture, hemocyanin decreased at 5 h of exposure as the concentration increased. Only in the malathion experiment did exposed shrimp to 10 and 50% of the LC50-96 h show significantly (p < 0.05) higher hemocyte contents. For malathion, significantly (p < 0.05) lower PO values in shrimp exposed to higher concentrations (10 and 50% of the LC50-96 h) were determined. While for the mixture treatment, high SOD value was determined at high exposure time and concentration. Malathion was the pesticide that showed an effect on some variables even at sublethal concentrations. The Continuous Concentration Criteria of the United States Environmental Protection Agency did not represent effects on the variables when they were compared with the averages of the control group.


Assuntos
Endossulfano/toxicidade , Imunidade Celular/efeitos dos fármacos , Imunidade Humoral/efeitos dos fármacos , Malation/toxicidade , Penaeidae/efeitos dos fármacos , Animais , Sinergismo Farmacológico , Hemocianinas/sangue , Hemócitos/efeitos dos fármacos , Hemócitos/imunologia , Hemolinfa/efeitos dos fármacos , Hemolinfa/imunologia , Monofenol Mono-Oxigenase/metabolismo , Penaeidae/imunologia
7.
Life Sci ; 242: 117191, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31863775

RESUMO

Melatonin is an indole neuroendocrine hormone that is mainly secreted by the pineal gland to regulate circadian rhythm, antioxidation, and immune regulation. Melatonin plays an important role in T cell-mediated immune responses against cancer, infections, and the development of many autoimmune diseases. The aim of this study was to investigate the immunomodulatory effects of melatonin on T/B cell activation in pinealectomy mice. The improved pinealectomy procedure for mice presented in this study is a good animal model to be used in follow-up studies on melatonin. After pinealectomy, the tissue removed was identified as the pineal body using HE staining. The effects of melatonin supplementation on T cell activation and activation-related changes to the MAPK/NF-κ B pathways were analyzed by flow cytometry and real-time PCR. We found that expression levels of Th1, Th2 and Th17-related cytokines in peripheral blood were lower in mice that had undergone pinealectomy, compared with normal mice. After melatonin supplementation, cytokine levels rapidly increased within a short period of time, which resulted in the gradual recovery of cytokine expression levels. Moreover, activation of T/B cells in mice was weakened and decreased after pineal gland removal. Melatonin was found to inhibit the expression of TLR3, p38, JNK, and MAPK/NF-κ B within a short period (2 weeks) of melatonin replenishment. This inhibition gradually weakened with time, since the degree of inhibition is negatively related with the dosage of melatonin. In conclusion, melatonin may regulate the activation of T/B cells, playing a critical role in the regulation of immune balance.


Assuntos
Linfócitos B/efeitos dos fármacos , Imunidade Celular/efeitos dos fármacos , Fatores Imunológicos/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Melatonina/farmacologia , Pinealectomia , Linfócitos T/efeitos dos fármacos , Animais , Citocinas/metabolismo , Citometria de Fluxo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Glândula Pineal/anatomia & histologia , Reação em Cadeia da Polimerase em Tempo Real
8.
Carbohydr Polym ; 229: 115436, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31826393

RESUMO

With the rising trend of incidence of cancers, effective therapies are urgently needed to control human malignancies. However, the chemotherapy drugs currently on the market cause serious side effects. Polysaccharides belong to a class of biomacromolecules, which have drawn considerable research interest over the years as it possess anti-cancer activities or can increase the efficacy of conventional chemotherapy drugs with fewer side effects. The antitumor activity of many polysaccharides was significantly increased after modification. Based on these encouraging observations, a great deal of effort has been focused on discovering anti-cancer polysaccharides and modified derivatives for the development of effective therapeutics for various human cancers. This review highlights recent advances on the major chemical modification methods of polysaccharides, and discusses the effect of molecular modification on the physicochemical properties and anti-tumor activities of polysaccharides. Meanwhile, the underlying anti-tumor mechanisms of polysaccharide and its modified derivatives were also discussed.


Assuntos
Inibidores da Angiogênese/uso terapêutico , Neoplasias/tratamento farmacológico , Polissacarídeos/uso terapêutico , Acetilação , Inibidores da Angiogênese/química , Inibidores da Angiogênese/farmacologia , Animais , Linhagem Celular Tumoral , Humanos , Imunidade Celular/efeitos dos fármacos , Polissacarídeos/química , Polissacarídeos/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Carbohydr Polym ; 229: 115457, 2020 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-31826423

RESUMO

We previously demonstrated that porphyran, a sulfated polysaccharide extracted from Pyropia yezoensis, shows protective effects on LPS-induced septic shock in the mouse. However, the immune cell-mediated inhibitory effect of porphyran in LPS-induced activation of immune cells has not been well investigated. In this study, we found that treatment of porphyran suppressed LPS-induced upregulation of costimulatory molecule and C-C chemokine receptor type 7 (CCR7) expression in bone marrow-derived dendritic cells (BMDCs) in vitro and spleen DCs in vivo. Moreover, the LPS-induced expression of IL-6, IL-12, and TNF-α in the culture medium of BMDCs and serum dose-dependently decreased by porphyran treatment, which contributed to the inhibition of the intracellular cytokine production in spleen DCs. In addition, LPS-induced differentiation of helper T1 (Th1) and cytotoxic T1 (Tc1) cells was effectively suppressed by porphyran treatment in mice. The inhibitory effect of porphyran in LPS-induced immune activation was mediated by competitive binding of porphyran with LPS in spleen DCs. Thus, these results suggest that porphyran is a promising potential therapeutic agent in endotoxin-mediated inflammatory disease and septic shock.


Assuntos
Anti-Inflamatórios/farmacologia , Células Dendríticas/efeitos dos fármacos , Polissacarídeos Bacterianos/farmacologia , Sefarose/análogos & derivados , Animais , Células da Medula Óssea/efeitos dos fármacos , Diferenciação Celular/efeitos dos fármacos , Citocinas/metabolismo , Imunidade Celular/efeitos dos fármacos , Lipopolissacarídeos/farmacologia , Camundongos Endogâmicos C57BL , Rodófitas/química , Sefarose/farmacologia , Baço/citologia , Linfócitos T Citotóxicos/metabolismo , Células Th1/metabolismo
10.
J Neuroinflammation ; 16(1): 250, 2019 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-31796095

RESUMO

Parkinson's disease (PD) is characterized by the accumulation of alpha-synuclein (α-syn) inclusions, the major component of Lewy bodies. Extracellular α-syn aggregates act as a damage-associated molecular pattern (DAMP) and the presence of autoantibodies against α-syn species in the cerebrospinal fluid and the serum of PD patients implicate the involvement of innate and adaptive immune responses. In non-transgenic (Tg) mice, intrastriatal injection of preformed fibril (PFF) α-syn results in widespread pathologic α-syn inclusions in the CNS. While the PFF model has been broadly utilized to study the mechanistic relationship between α-syn transmission and other neuropathological phenotypes, the immune phenotypes in this model are not clearly demonstrated. This study aimed to characterize the immune phenotypes during pathologic α-syn propagation by utilizing PFF α-syn-injected non-tg mice. Here, we showed that pathologic α-syn inclusions are prevalent in various brain regions and the gut at 5 months post injection (p.i.), preceding the degeneration of dopaminergic neurons in substantia nigra (SN). We discovered a distinct inflammatory response involving both activation of microglia and astrocytes and infiltration of B, CD4+ T, CD8+ T, and natural killer cells in the brain at 5 months p.i. Moreover, PFF α-syn-injected mice display significant alterations in the frequency and number of leukocyte subsets in the spleen and lymph nodes with minimum alterations in the blood. Our data provide primary evidence that intracerebral-initiated synucleinopathies in non-tg mice alter immune cell profiles both in the CNS and peripheral lymphoid organs. Furthermore, our data provides support for utilizing this mouse model to assess the mechanistic connection between immune responses and synuclein pathology.


Assuntos
Imunidade Celular/imunologia , Substância Negra/imunologia , Linfócitos T/imunologia , alfa-Sinucleína/administração & dosagem , Animais , Animais Recém-Nascidos , Células Cultivadas , Feminino , Humanos , Imunidade Celular/efeitos dos fármacos , Injeções Intraventriculares , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Substância Negra/efeitos dos fármacos , Substância Negra/metabolismo , Linfócitos T/efeitos dos fármacos , Linfócitos T/metabolismo
11.
PLoS One ; 14(12): e0226869, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31877168

RESUMO

Immune checkpoint inhibitors, such as pembrolizumab, are transforming clinical oncology. Yet, insufficient overall response rate, and accelerated tumor growth rate in some patients, highlight the need for identifying potential responders. To construct a computational model, identifying response predictors, and enabling immunotherapy personalization. The combined dynamics of cellular immunity, pembrolizumab, and the melanoma cancer were modeled by a set of ordinary differential equations. The model relies on a scheme of T memory stem cells, progressively differentiating into effector CD8+ T cells, and additionally includes T cell exhaustion, reinvigoration and senescence. Clinical data of a pembrolizumab-treated patient with advanced melanoma (Patient O') were used for model calibration and simulations. Virtual patient populations, varying in one parameter or more, were generated for retrieving clinical studies. Simulations captured the major features of Patient O's disease, displaying a good fit to her clinical data. A temporary increase in tumor burden, as implied by the clinical data, was obtained only when assuming aberrant self-renewal rates. Variation in effector T cell cytotoxicity was sufficient for simulating dynamics that vary from rapid progression to complete cure, while variation in tumor immunogenicity has a delayed and limited effect on response. Simulations of a-specific clinical trial were in good agreement with the clinical results, demonstrating positive correlations between response to pembrolizumab and the ratio of reinvigoration to baseline tumor load. These results were obtained by assuming inter-patient variation in the toxicity of effector CD8+ T cells, and in their intrinsic division rate, as well as by assuming that the intrinsic division rate of cancer cells is correlated with the baseline tumor burden. In conclusion, hyperprogression can result from lower patient-specific effector cytotoxicity, a temporary increase in tumor load is unlikely to result from real tumor growth, and the ratio of reinvigoration to tumor load can predict personal response to pembrolizumab. Upon further validation, the model can serve for immunotherapy personalization.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Imunidade Celular/efeitos dos fármacos , Melanoma/tratamento farmacológico , Adulto , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Simulação por Computador , Feminino , Humanos , Melanoma/imunologia , Melanoma/patologia , Modelos Biológicos
12.
BMC Cancer ; 19(1): 1243, 2019 Dec 23.
Artigo em Inglês | MEDLINE | ID: mdl-31870331

RESUMO

BACKGROUND: The gut microbiota is an important modulator of immune, metabolic, psychological and cognitive mechanisms. Chemotherapy adversely affects the gut microbiota, inducing acute dysbiosis, and alters physiological and psychological function. Cancer among young adults has risen 38% in recent decades. Understanding chemotherapy's long-term effects on gut microbiota and psycho-physiological function is critical to improve survivors' physical and mental health, but remains unexamined. Restoration of the gut microbiota via targeted therapies (e.g. probiotics) could potentially prevent or reverse the psycho-physiological deficits often found in young survivors following chemotherapy, ultimately leading to reduced symptom burden and improved health. METHODS: This longitudinal study investigates chemotherapy induced long-term gut dysbiosis, and associations between gut microbiota, and immune, metabolic, cognitive and psychological parameters using data collected at < 2 month (T1), 3-4 months (T2), and 5-6 months (T3) post-chemotherapy. Participants will be 18-39 year old blood or solid tumor cancer survivors (n = 50), and a healthy sibling, partner or friend as a control (n = 50). Gut microbiota composition will be measured from fecal samples using 16 s RNA sequencing. Psychological and cognitive patient reported outcome measures will include depression, anxiety, post-traumatic stress disorder symptoms, pain, fatigue, and social and cognitive function. Dual-energy X-ray Absorptiometry (DXA) will be used to measure fat and lean mass, and bone mineral concentration. Pro-inflammatory cytokines, C-reactive protein (CRP), lipopolysaccharide (LPS), serotonin, and brain derived neurotrophic factor (BDNF) will be measured in serum, and long-term cortisol will be assayed from hair. Regression and linear mixed model (LMM) analyses will examine associations across time points (T1 - T3), between groups, and covariates with gut microbiota, cognitive, psychological, and physiological parameters. CONCLUSION: Knowing what bacterial species are depleted after chemotherapy, how long these effects last, and the physiological mechanisms that may drive psychological and cognitive issues among survivors will allow for targeted, integrative interventions to be developed, helping to prevent or reverse some of the late-effects of treatment that many young cancer survivors face. This protocol has been approved by the Health Research Ethics Board of Alberta Cancer Committee (ID: HREBA.CC-19-0018).


Assuntos
Antineoplásicos/efeitos adversos , Composição Corporal/efeitos dos fármacos , Sobreviventes de Câncer/psicologia , Transtornos Cognitivos/induzido quimicamente , Microbioma Gastrointestinal/efeitos dos fármacos , Imunidade Celular/efeitos dos fármacos , Neoplasias/tratamento farmacológico , Neoplasias/microbiologia , Adolescente , Adulto , Antineoplásicos/administração & dosagem , Estudos de Casos e Controles , Protocolos Clínicos , Transtornos Cognitivos/patologia , Citocinas/metabolismo , Feminino , Microbioma Gastrointestinal/imunologia , Humanos , Estudos Longitudinais , Masculino , Neoplasias/imunologia , Neoplasias/psicologia , Qualidade de Vida , Adulto Jovem
13.
EBioMedicine ; 49: 247-257, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31680000

RESUMO

BACKGROUND: Chronic Hepatitis B (CHB) remains a major problem for global public health. Viral persistence and immune defects are the two major reasons for CHB, and it was hypothesized that based on a transient clearance of serum viral DNA and HBsAg "window stage", active immunization against hepatitis B virus (HBV) might initiate effective host immune responses versus HBV to achieve functional cure of CHB. METHODS: Two experimental mouse models that mice hydrodynamic injected HBV DNA or infected with recombinant AAV/HBV were used. The "sandwich" therapeutic effect by using a potent human anti-HBsAg neutralizing monoclonal antibody (G12) in combination with antiviral drug tenofovir disoproxil fumarate (TDF), followed by active immunization with HBsAg-HBsAb (mYIC) was evaluated. FINDINGS: A single G12 injection rapidly cleared serum HBsAg in HDI-HBV carrier mice, with a synergistic effect in decreasing viral DNA load when TDF was given orally. When both serum viral DNA and HBsAg load became low or undetectable, mYIC was administered. A more effective clearance of viral DNA and HBsAg was observed and serum HBsAb was developed only in these "sandwich"-treated mice. Efficient intrahepatic anti-HBV immune responses were also observed in these mice, including the formation of aggregates of myeloid cells with CD8+T cells and increased TNF-α, granzyme B production. INTERPRETATION: The "sandwich" combination therapy not only efficiently decreased HBsAg and HBV DNA levels but also induced effective cellular and humoral immunity, which may result in functional cure of CHB.


Assuntos
Antivirais/uso terapêutico , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/imunologia , Imunização Passiva , Vacinação , Animais , Anticorpos Monoclonais/farmacocinética , Anticorpos Monoclonais/uso terapêutico , Antivirais/farmacologia , Modelos Animais de Doenças , Quimioterapia Combinada , Antígenos de Superfície da Hepatite B/imunologia , Humanos , Hidrodinâmica , Imunidade Celular/efeitos dos fármacos , Imunidade Humoral/efeitos dos fármacos , Injeções , Fígado/efeitos dos fármacos , Fígado/imunologia , Fígado/patologia , Camundongos Endogâmicos C57BL
14.
Int J Mol Sci ; 20(21)2019 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-31694167

RESUMO

Classical Hodgkin Lymphoma (cHL) is a B-cell malignancy that, typically, responds well to standard therapies. However, patients who relapse after standard regimens or are refractory to induction therapy have a dismal outcome. The implementation of novel therapies such as the anti-CD30 monoclonal antibody Brentuximab Vedotin and immune checkpoint inhibitors has provided curative options for many of these patients. Nonetheless, responses are rarely durable, emphasizing the need for new agents. cHL is characterized by a unique microenvironment in which cellular and humoral components interact to promote tumor survival and dissemination. Knowledge of the complex composition of cHL microenvironment is constantly evolving; in particular, there is growing interest in certain cell subsets such as tumor-associated macrophages, myeloid-derived suppressor cells and neutrophils, all of which have a relevant role in the pathogenesis of the disease. The unique biology of the cHL microenvironment has provided opportunities to develop new drugs, many of which are currently being tested in preclinical and clinical settings. In this review, we will summarize novel insights in the crosstalk between tumor cells and non-malignant inflammatory cells. In addition, we will discuss the relevance of tumor-microenvironment interactions as potential therapeutic targets.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Doença de Hodgkin/tratamento farmacológico , Doença de Hodgkin/imunologia , Microambiente Tumoral/efeitos dos fármacos , Animais , Antineoplásicos Imunológicos/farmacologia , Doença de Hodgkin/patologia , Humanos , Imunidade Celular/efeitos dos fármacos , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/patologia , Terapia de Alvo Molecular , Evasão Tumoral/efeitos dos fármacos
15.
ACS Appl Mater Interfaces ; 11(49): 45404-45415, 2019 Dec 11.
Artigo em Inglês | MEDLINE | ID: mdl-31736295

RESUMO

Developing versatile nanomaterials has offered a myriad of opportunities to surmount cancer. In particular, the combination of therapy and immunomodulatory effect to further enhance immune response provides a new idea for effective tumor treatment. Herein, for the first time, an in situ growth strategy is developed to construct highly dispersed noncrystalline selenium nanoparticles (Se NPs) with thiolated cyclo(Arg-Gly-Asp-Phe-Lys-(mpa)) (RGD) peptide modification (R-Se@DMSND) for targeted cancer treatment. Se NPs could be homogeneously grown into the pore channels of dendritic mesoporous silica nanoparticles (DMSNs) since the DMSNs could stabilize Se NPs to prevent their aggregations. Moreover, Se NPs could not only act as a therapeutic agent, inducing ROS overproduction, to effectively suppress primary tumor but also as an immunomodulatory agent to simultaneously inhibit the growth of secondary tumors by enhancement of the immune response, as confirmed by the in vivo results. Such the therapeutic-immunomodulatory strategy for tumorous therapy combining with immunomodulation using one simple nanoplatform may pave a new avenue in the biomedical field.


Assuntos
Imunomodulação , Nanopartículas Metálicas/química , Neoplasias/tratamento farmacológico , Selênio/química , Animais , Linhagem Celular Tumoral , Humanos , Imunidade Celular/efeitos dos fármacos , Imunidade Celular/imunologia , Camundongos , Neoplasias/imunologia , Oligopeptídeos/química , Oligopeptídeos/farmacologia , Selênio/farmacologia , Dióxido de Silício/química
16.
Immunol Res ; 67(4-5): 398-407, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31773490

RESUMO

Limited protective effects of commercially available vaccines necessitate the development of novel pneumococcal vaccines. We recently reported a pneumococcal systemic vaccine containing two proteins, Pneumococcal surface protein A (PspA of family 1 and 2) and a bacterium-like particle-based pneumococcal mucosal vaccine containing PspA2 and PspA4 fragments, both eliciting broad protective immune responses. We had previously reported that subcutaneous (s.c.+s.c.+s.c.) immunization with the systemic vaccine induced more pronounced humoral serum IgG responses, while intranasal (i.n.+i.n.+i.n.) immunization with the mucosal vaccine elicited a more pronounced mucosal secretory IgA (sIgA) response. We hypothesized that a combinatorial administration of the two vaccines might elicit more pronounced and broader protective immune responses. Therefore, this study aimed to determine the efficacy of combinatorial prime-boost immunization using both systemic and mucosal vaccines for a pneumococcal infection. Combinatorial prime-boost immunization (s.c.+i.n. and i.n.+s.c.) induced not only IgG, but also mucosal sIgA production at high levels. Systemic priming and mucosal boosting immunization (s.c.+i.n.) provided markedly better protection than homologous prime-boost immunization (s.c.+s.c.+s.c. and i.n.+i.n.+i.n.). Moreover, it induced more robust Th1 and Th17 cell-mediated immune responses than mucosal priming and systemic boosting immunization (i.n.+s.c.). These results indicate that combinatorial prime-boost immunization potentially induces a robust systemic and mucosal immune response, making it an optimal alternative for maximum protection against lethal pneumococcal infections.


Assuntos
Proteínas de Bactérias/farmacologia , Imunidade Celular/efeitos dos fármacos , Imunidade nas Mucosas/efeitos dos fármacos , Imunização Secundária , Infecções Pneumocócicas/prevenção & controle , Vacinas Pneumocócicas/farmacologia , Streptococcus pneumoniae/imunologia , Animais , Anticorpos Antibacterianos/imunologia , Proteínas de Bactérias/imunologia , Feminino , Imunoglobulina A/imunologia , Imunoglobulina G/imunologia , Camundongos , Camundongos Endogâmicos BALB C , Infecções Pneumocócicas/imunologia , Infecções Pneumocócicas/patologia , Vacinas Pneumocócicas/imunologia , Células Th1/imunologia , Células Th17/imunologia
17.
Nanoscale ; 11(42): 20206-20220, 2019 Nov 14.
Artigo em Inglês | MEDLINE | ID: mdl-31621735

RESUMO

Immunosuppression and immune tolerance lead tumor cells to evade immune system surveillance and weaken drug efficacy. The presence of various immunosuppressive cells in the tumor microenvironment, especially tumor-associated macrophages (TAMs), has been shown to be a driving force in tumor initiation and development. Reversion of the TAM phenotype is an effective way to induce a subsequent antitumor immune response. In this study, we developed baicalin-loaded poly(d,l-lactide-co-glycolide) (PLGA) nanoparticles containing an antigenic peptide (Hgp 10025-33, Hgp) and a toll-like receptor 9 agonist (CpG). The nanoparticles were further coated with a galactose-inserted erythrocyte membrane, which actively targeted the TAMs. The TAM polarization and tumor treatment effectiveness of the nanoparticles were evaluated. The biomimetic nanoparticles showed enhanced cell uptake in vitro and targeted effects in vivo. In addition, compared with baicalin-loaded PLGA-NPs (B@NPs), the biomimetic nanoparticles, such as Hgp/B@NPs-CpG and NPs@RBC-Gala, significantly polarized the TAMs such that they changed from the M2 type to the M1 type both in vitro and in vivo. Subsequently, the infiltration of CD4+ T and CD8+ T cells into tumor sites after being induced by the biomimetic nanoparticles was greatly increased, which suggested a significant enhancement of the immune activation effect and T cell response. In addition, the activation of the T cells and induction of the CTL responses effectively suppressed melanoma tumor growth in vivo. In conclusion, the biomimetic nanoparticles effectively reversed the TAM phenotype from M2 to M1, which further improved the tumor immune microenvironment and promoted tumor immunotherapy. These results suggested that the TAM-targeted biomimetic drug delivery system had the potential to reverse the phenotypes of TAMs contributing to reverse the immunosuppressive tumor microenvironment and promote tumor treatment.


Assuntos
Materiais Biomiméticos , Flavonoides , Imunidade Celular/efeitos dos fármacos , Macrófagos , Melanoma Experimental , Nanopartículas/química , Animais , Materiais Biomiméticos/química , Materiais Biomiméticos/farmacologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Feminino , Flavonoides/química , Flavonoides/farmacologia , Macrófagos/imunologia , Macrófagos/patologia , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Melanoma Experimental/terapia , Antígenos Específicos de Melanoma/química , Antígenos Específicos de Melanoma/farmacologia , Camundongos , Oligodesoxirribonucleotídeos/química , Oligodesoxirribonucleotídeos/farmacologia , Peptídeos/química , Peptídeos/farmacologia , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/imunologia
18.
Vet Res ; 50(1): 82, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31615555

RESUMO

Effective vaccines against tuberculosis (TB) are needed in order to prevent TB transmission in human and animal populations. Evaluation of TB vaccines may be facilitated by using reliable animal models that mimic host pathophysiology and natural transmission of the disease as closely as possible. In this study, we evaluated the immunogenicity and efficacy of two attenuated vaccines, BCG and MTBVAC, after each was given to 17 goats (2 months old) and then exposed for 9 months to goats infected with M. caprae. In general, MTBVAC-vaccinated goats showed higher interferon-gamma release than BCG vaccinated goats in response to bovine protein purified derivative and ESAT-6/CFP-10 antigens and the response was significantly higher than that observed in the control group until challenge. All animals showed lesions consistent with TB at the end of the study. Goats that received either vaccine showed significantly lower scores for pulmonary lymph nodes and total lesions than unvaccinated controls. Both MTBVAC and BCG vaccines proved to be immunogenic and effective in reducing severity of TB pathology caused by M. caprae. Our model system of natural TB transmission may be useful for evaluating and optimizing vaccines.


Assuntos
Vacina BCG/imunologia , Doenças das Cabras/imunologia , Imunogenicidade da Vacina/imunologia , Mycoplasma/fisiologia , Vacinas contra a Tuberculose/imunologia , Tuberculose/veterinária , Animais , Doenças das Cabras/transmissão , Cabras , Imunidade Celular/efeitos dos fármacos , Imunidade Celular/imunologia , Imunidade Humoral/efeitos dos fármacos , Imunidade Humoral/imunologia , Tuberculose/imunologia , Tuberculose/transmissão , Vacinas Atenuadas/imunologia
19.
J Anim Sci ; 97(11): 4496-4502, 2019 Nov 04.
Artigo em Inglês | MEDLINE | ID: mdl-31504598

RESUMO

Hazel leaves (Corylus avellana) fed to sheep resulted in decreased methane emissions without negatively affecting feed intake and were found to have antioxidant properties in vitro. The objective of this study was to evaluate effects of hazel leaves, rich in tannins, on blood antioxidant activity, cellular immune response, and heart beat parameters in sheep. Four experimental pellets were produced by mixing alfalfa and hazel leaves in different proportions, including alfalfa alone as a control, 30% and 60% of hazel leaves, the latter also with 3.8% polyethylene glycol (PEG). Six adult, nonpregnant, nonlactating female sheep (71 ± 5.7 kg of body weight) were allocated to 4 treatments in a 6 × 4 crossover design with four 18-d periods. The diet consisted of experimental pellets and ryegrass-dominated hay (ratio 80% to 20% in dry matter), resulting in hazel leaf proportions of approximately 0%, 25%, and 50% in the total diet. Blood samples were collected at the end of each period to determine plasma total phenol concentration and markers of oxidative status as well as peripheral blood mononuclear cells (PBMC) activation and proliferation response in vitro. Heart rate (HR) and HR variability parameters were measured for 2 consecutive days in each period, during different activities (i.e., eating pellets or hay, or lying). Treatments were compared with multiple comparisons and contrast analysis was used to test for linear and quadratic relations. Compared with control, feeding a high dosage of hazel leaves enhanced (P = 0.006) the plasma total antioxidant capacity, which linearly (P = 0.016) increased with increasing level of hazel leaves in the diet. The total phenol concentration and activities of the antioxidant enzymes superoxide dismutase, catalase, and glutathione reductase in the plasma were not different (P ≥ 0.23) among the treatments; however, the latter slightly increased linearly (P = 0.047) with increasing hazel leaves proportion. No differences were observed in the activation and proliferation of PBMC among treatments. The HR decreased linearly (P ≤ 0.009) during pellet eating and lying and the root mean square of successive differences of interbeat intervals (RMSSD) increased linearly (P = 0.037) when lying with increasing level of hazel leaves in the diet. In conclusion, our findings indicate that hazel leaves are a promising supplement to improve oxidative status with no effect on cellular immune response and cardiac stress level of sheep.


Assuntos
Antioxidantes/metabolismo , Corylus/química , Suplementos Nutricionais/análise , Imunidade Celular/efeitos dos fármacos , Ovinos/fisiologia , Ração Animal/análise , Animais , Proliferação de Células , Dieta/veterinária , Feminino , Frequência Cardíaca/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Lolium , Medicago sativa , Metano/metabolismo , Folhas de Planta/química , Ovinos/sangue , Ovinos/imunologia , Taninos/metabolismo
20.
Mar Drugs ; 17(10)2019 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-31554251

RESUMO

Okinawa mozuku (Cladosiphon okamuranus Tokida) is an edible seaweed classified as brown algae and is a native species of the Ryukyu Islands in Japan. In recent years, the genomic decoding of Okinawa mozuku has been completed. Previous studies on the anti-inflammatory, antiviral, and antitumor properties of Okinawa mozuku have suggested that it affects the regulation of cellular and humoral immunity. The aim of the present study was to examine the immunoregulatory effect of fucoidan derived from Okinawa mozuku in mice. A product containing fucoidan (purity, 88.3%; molecular weight, 49.8 kDa) was developed from Okinawa mozuku and tested for its immunoregulatory effects in mice. The experimental animals were 8-week-old female BALB/c mice to which fucoidan (0, 102.5, 205.0, 410.0, and 1025.0 mg/kg) was administered orally continuously for six weeks. Immune cell proliferation, cytokine production, macrophage phagocytosis, and serum antibody concentration were measured. We found that immune cell proliferation, interleukin (IL)-2, macrophage phagocytes, and serum antibodies (IgM, -G, -A) increased significantly, but IL-4, -5, and IgE decreased significantly. These results indicated that fucoidan modulated cellular and humoral immunity.


Assuntos
Fatores Imunológicos/farmacologia , Feófitas/química , Polissacarídeos/farmacologia , Alga Marinha/química , Animais , Proliferação de Células/efeitos dos fármacos , Citocinas/metabolismo , Feminino , Imunidade Celular/efeitos dos fármacos , Imunidade Humoral/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Fagocitose/efeitos dos fármacos
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