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1.
Nat Commun ; 12(1): 5327, 2021 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-34493717

RESUMO

Implantation-caused foreign-body response (FBR) is a commonly encountered issue and can result in failure of implants. The high L-serine content in low immunogenic silk sericin, and the high D-serine content as a neurotransmitter together inspire us to prepare poly-DL-serine (PSer) materials in mitigating the FBR. Here we report highly water soluble, biocompatible and easily accessible PSer hydrogels that cause negligible inflammatory response after subcutaneous implantation in mice for 1 week and 2 weeks. No obvious collagen capsulation is found surrounding the PSer hydrogels after 4 weeks, 3 months and 7 months post implantation. Histological analysis on inflammatory cytokines and RNA-seq assay both indicate that PSer hydrogels show low FBR, comparable to the Mock group. The anti-FBR performance of PSer hydrogels at all time points surpass the poly(ethyleneglycol) hydrogels that is widely utilized as bio-inert materials, implying the potent and wide application of PSer materials in implantable biomaterials and biomedical devices.


Assuntos
Materiais Biocompatíveis/farmacologia , Reação a Corpo Estranho/prevenção & controle , Peptídeos/farmacologia , Próteses e Implantes , Animais , Materiais Biocompatíveis/síntese química , Citocinas/antagonistas & inibidores , Citocinas/biossíntese , Citocinas/imunologia , Reação a Corpo Estranho/imunologia , Hidrogéis , Infusões Subcutâneas , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Peptídeos/síntese química , Polietilenoglicóis/farmacologia , Solubilidade , Água/química
2.
Carbohydr Polym ; 273: 118567, 2021 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-34560978

RESUMO

Diffuse alveolar injury and pulmonary fibrosis (PF) are the main causes of death of Covid-19 cases. In this study a low molecular weight fucoidan (LMWF) with unique structural was obtained from Laminaria japonica, and its anti- PF and anti-epithelial-mesenchymal transition (EMT) bioactivity were investigated both in vivo and in vitro. After LWMF treatment the fibrosis and inflammatory factors stimulated by Bleomycin (BLM) were in lung tissue. Immunohistochemical and Western-blot results found the expression of COL2A1, ß-catenin, TGF-ß, TNF-α and IL-6 were declined in mice lung tissue. Besides, the phosphorylation of PI3K and Akt were inhibited by LMWF. In addition, the progression of EMT induced by TGF-ß1 was inhibited by LMWF through down-regulated both TGF-ß/Smad and PI3K/AKT signaling pathways. These data indicate that unique LMWF can protect the lung from fibrosis by weakening the process of inflammation and EMT, and it is a promising therapeutic option for the treatment of PF.


Assuntos
COVID-19/complicações , Transição Epitelial-Mesenquimal/efeitos dos fármacos , Polissacarídeos/administração & dosagem , Polissacarídeos/química , Fibrose Pulmonar/complicações , Fibrose Pulmonar/tratamento farmacológico , SARS-CoV-2 , Células A549 , Animais , Bleomicina/efeitos adversos , COVID-19/virologia , Sobrevivência Celular/efeitos dos fármacos , Citocinas/antagonistas & inibidores , Citocinas/metabolismo , Citocinas/farmacologia , Modelos Animais de Doenças , Humanos , Inflamação/tratamento farmacológico , Pulmão/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Peso Molecular , Fibrose Pulmonar/induzido quimicamente , Fibrose Pulmonar/mortalidade , Transdução de Sinais/efeitos dos fármacos
3.
Front Immunol ; 12: 613461, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34456900

RESUMO

Allergy is an IgE-dependent type-I hypersensitivity reaction that can lead to life-threatening systemic symptoms such as anaphylaxis. In the pathogenesis of the allergic response, the common upstream event is the binding of allergens to specific IgE, inducing cross-linking of the high-affinity FcεRI on mast cells, triggering cellular degranulation and the release of histamine, proteases, lipids mediators, cytokines and chemokines with inflammatory activity. A number of novel therapeutic options to curb mast cell activation are in the pipeline for the treatment of severe allergies. In addition to anti-IgE therapy and allergen-specific immunotherapy, monoclonal antibodies targeted against several key Th2/alarmin cytokines (i.e. IL-4Rα, IL-33, TSLP), active modification of allergen-specific IgE (i.e. inhibitory compounds, monoclonal antibodies, de-sialylation), engagement of inhibitory receptors on mast cells and allergen-specific adjuvant vaccines, are new promising options to inhibit the uncontrolled release of mast cell mediators upon allergen exposure. In this review, we critically discuss the novel approaches targeting mast cells limiting allergic responses and the immunological mechanisms involved, with special interest on food allergy treatment.


Assuntos
Hipersensibilidade Alimentar/terapia , Imunoglobulina E/imunologia , Mastócitos/fisiologia , Anticorpos Anti-Idiotípicos/uso terapêutico , Citocinas/antagonistas & inibidores , Citocinas/fisiologia , Dessensibilização Imunológica , Hipersensibilidade Alimentar/imunologia , Humanos , Mastócitos/efeitos dos fármacos
4.
Clin Immunol ; 231: 108828, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34425240

RESUMO

COVID-19 is characterized by a dysregulation of inflammatory cytokines ultimately resulting a cytokine storm that can result in significant morbidity and mortality. We developed an in-vitro assay using activated peripheral blood mononuclear cells (PBMCs) stimulated with lipopolysaccharide (LPS) or CD3 + CD28 to examine secretion of cytokines from antigen presenting cells (APCs) and T cells, respectively, in donor patients with a history of COVID-19 (convalescent) and uninfected negative controls. We hypothesized that a novel antioxidant called Tempol may decrease cytokines from activated peripheral blood cells from both COVID-19 patients and normal donors. Preincubation of immune cells with Tempol resulted in a significant (P < 0.05) decrease in multiple T cell and APC-derived cytokines from both cells of COVID-19 (n = 7) and uninfected donors (n = 7). These preliminary results suggest that Tempol has strong in-vitro anti-cytokine activity and supports additional studies examining the use of Tempol for the treatment of COVID-19.


Assuntos
Antioxidantes/farmacologia , COVID-19/imunologia , Óxidos N-Cíclicos/farmacologia , Ativação Linfocitária/efeitos dos fármacos , SARS-CoV-2 , Linfócitos T/efeitos dos fármacos , Adulto , Idoso , Células Apresentadoras de Antígenos/metabolismo , Antígenos Virais/metabolismo , Citocinas/antagonistas & inibidores , Citocinas/efeitos dos fármacos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Marcadores de Spin , Linfócitos T/fisiologia
5.
Molecules ; 26(15)2021 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-34361683

RESUMO

Six lignols (1-6), including two new compounds (+)-(7R,8R)-palmitoyl alatusol D (1) and (+)-(7R,8R)-linoleyl alatusol D (2), along with four phenolics (7-10), a neolignan (11), three alkyl aryl ether-type lignans (12-14), two furofuran-type lignans (15-16), three benzofuran-type lignans (17-19), a tetrahydrofuran-type lignan (20), and a dibenzylbutane-type lignan (21) were isolated from the ethyl acetate-soluble fraction of the methanol extract of Platycodon grandiflorum (Jacq.) A. DC. root. The chemical structures of the obtained compounds were elucidated via high-resolution mass spectrometry and nuclear magnetic resonance (NMR) spectroscopy analyses. The obtained spectroscopic data agreed well with literature. Among the isolated compounds, eighteen (1-7 and 11-21) were isolated from P. grandiflorum and the Campanulaceae family for the first time. This is the first report on lignol and lignan components of P. grandiflorum. The anti-inflammatory effects of the isolated compounds were examined in terms of their ability to inhibit the production of pro-inflammatory cytokines IL-6, IL-12 p40, and TNF-α in lipopolysaccharide-stimulated murine RAW264.7 macrophage cells. Nine compounds (4-6, 12, and 15-19) exhibited inhibitory effects on IL-12 p40 production, eleven compounds (1-6, 12, 15-17, and 19) exhibited inhibitory activity on IL-6 production, and eleven compounds (1-6 and 15-19) exhibited inhibitory effects against TNF-α. These results warrant further investigation into the potential anti-inflammatory activity and general benefits of the phenolic constituents of P. grandiflorum root.


Assuntos
Anti-Inflamatórios/farmacologia , Citocinas/metabolismo , Lignanas/farmacologia , Macrófagos/imunologia , Fenóis/farmacologia , Extratos Vegetais/farmacologia , Raízes de Plantas/química , Platycodon/química , Transdução de Sinais/efeitos dos fármacos , Animais , Anti-Inflamatórios/química , Citocinas/antagonistas & inibidores , Lignanas/química , Lipopolissacarídeos/farmacologia , Macrófagos/efeitos dos fármacos , Camundongos , Estrutura Molecular , Fenóis/química , Extratos Vegetais/química , Células RAW 264.7
6.
Molecules ; 26(16)2021 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-34443392

RESUMO

Thymic stromal lymphopoietin (TSLP) plays an important role in the pathophysiology of various allergic diseases that are mediated by T helper cell type-2 (Th2) responses, including asthma and atopic dermatitis. The primary focus of this study was the identification of potent inhibitors of the TSLP signaling pathway for potential therapeutic use. The 80% methanol extract of Machilus thunbergii bark significantly inhibited the signal transducer and activator of transcription 5 (STAT5) phosphorylation in human mast cell (HMC)-1 cells. Through activity-guided isolation, three lignans (1-3) were obtained and identified as (+)-galbelgin (1), meso-dihydroguaiaretic acid (2), and machilin A (3). Among them, two lignans (1 and 2) significantly inhibited STAT5 phosphorylation and TSLP/TSLPR interaction, as determined by ELISA. Our results indicated that lignans isolated from M. thunbergii are a promising resource for the treatment of allergic diseases.


Assuntos
Citocinas/antagonistas & inibidores , Lauraceae/química , Lignanas/farmacologia , Linhagem Celular , Fosforilação/efeitos dos fármacos , Casca de Planta/química , Fator de Transcrição STAT5/metabolismo , Células Th2/efeitos dos fármacos
7.
Aliment Pharmacol Ther ; 54(8): 1052-1060, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34323301

RESUMO

BACKGROUND: Several studies have reported a positive correlation between serum drug concentrations and endoscopic remission in patients with Crohn's disease. AIM: To examine the association between the concentrations of cytokine blockers (infliximab, adalimumab and ustekinumab) and endoscopic remission of small bowel lesions. METHOD: This was a cross-sectional study conducted at a single tertiary referral centre. Patients with Crohn's disease who received maintenance cytokine blocker therapy were recruited from April 2018 to May 2020. We performed balloon-assisted enteroscopy and collected serum samples to measure drug concentrations. The primary endpoint was the relationship between the concentrations of cytokine blockers and endoscopic remission in the small bowel. RESULTS: We enrolled 143 patients, 66, 44 and 33 of whom were receiving infliximab, adalimumab and ustekinumab, respectively. Enteroscopic findings showed that the rate of endoscopic remission of small bowel lesions was significantly lower than that of colonic lesions (P < 0.01). For each agent, the mean drug concentration in patients exhibiting endoscopic remission in the small bowel was higher than that observed in patients with endoscopic remission in the colon (but not in the small bowel) or with any active disease (either in the small bowel, colon or both). Patients with infliximab, adalimumab and ustekinumab concentrations >5, 14 and 4 µg/mL were nearly 5.3-, 9.4- and 14.7-times more likely to exhibit endoscopic remission of the small bowel, respectively. CONCLUSIONS: Cytokine blocker treatment was less efficacious for small bowel inflammation than colonic inflammation. Higher serum concentrations were needed to achieve endoscopic remission of small bowel lesions.


Assuntos
Doença de Crohn , Citocinas/antagonistas & inibidores , Adalimumab/uso terapêutico , Doença de Crohn/tratamento farmacológico , Estudos Transversais , Humanos , Infliximab/uso terapêutico , Indução de Remissão , Resultado do Tratamento
9.
Int J Mol Sci ; 22(14)2021 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-34299012

RESUMO

Atopic dermatitis (AD) represents a severe global burden on physical, physiological and mental health. Innate immune cell basophils are essential for provoking allergic inflammation in AD. However, the roles of novel immunoregulatory cytokine IL-37 in basophils remain elusive. We employed in vitro co-culture of human basophils and human keratinocyte HaCaT cells and an in vivo MC903-induced AD murine model to investigate the anti-inflammatory mechanism of IL-37. In the in vitro model, IL-37b significantly decreased Der p1-induced thymic stromal lymphopoietin (TSLP) overexpression in HaCaT cells and decreased the expression of TSLP receptor as well as basophil activation marker CD203c on basophils. IL-37 could also reduce Th2 cytokine IL-4 release from TSLP-primed basophils ex vivo. In the in vivo model, alternative depletion of basophils ameliorated AD symptoms and significantly lowered the Th2 cell and eosinophil populations in the ear and spleen of the mice. Blocking TSLP alleviated the AD-like symptoms and reduced the infiltration of basophils in the spleen. In CRISPR/Cas9 human IL-37b knock-in mice or mice with direct treatment by human IL-37b antibody, AD symptoms including ear swelling and itching were significantly alleviated upon MC903 challenge. Notably, IL-37b presence significantly reduced the basophil infiltration in ear lesions. In summary, IL-37b could regulate the TSLP-mediated activation of basophils and reduce the release of IL-4. The results, therefore, suggest that IL-37 may target TSLP-primed basophils to alleviate AD.


Assuntos
Basófilos/imunologia , Citocinas/metabolismo , Dermatite Atópica/metabolismo , Interleucina-1/metabolismo , Animais , Anti-Inflamatórios/uso terapêutico , Basófilos/efeitos dos fármacos , Linhagem Celular , Técnicas de Cocultura , Citocinas/antagonistas & inibidores , Citocinas/farmacologia , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/genética , Dermatite Atópica/imunologia , Regulação para Baixo , Orelha/patologia , Eosinófilos/metabolismo , Técnicas de Introdução de Genes , Humanos , Interleucina-1/genética , Interleucina-1/farmacologia , Interleucina-1/uso terapêutico , Interleucina-4/metabolismo , Queratinócitos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Diester Fosfórico Hidrolases/metabolismo , Pirofosfatases/metabolismo , Baço/imunologia , Baço/metabolismo , Células Th2/imunologia , Regulação para Cima
10.
Mol Cells ; 44(6): 408-421, 2021 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-34059561

RESUMO

The outbreak of coronavirus disease 2019 (COVID-19) has not only affected human health but also diverted the focus of research and derailed the world economy over the past year. Recently, vaccination against COVID-19 has begun, but further studies on effective therapeutic agents are still needed. The severity of COVID-19 is attributable to several factors such as the dysfunctional host immune response manifested by uncontrolled viral replication, type I interferon suppression, and release of impaired cytokines by the infected resident and recruited cells. Due to the evolving pathophysiology and direct involvement of the host immune system in COVID-19, the use of immune-modulating drugs is still challenging. For the use of immune-modulating drugs in severe COVID-19, it is important to balance the fight between the aggravated immune system and suppression of immune defense against the virus that causes secondary infection. In addition, the interplaying events that occur during virus-host interactions, such as activation of the host immune system, immune evasion mechanism of the virus, and manifestation of different stages of COVID-19, are disjunctive and require thorough streamlining. This review provides an update on the immunotherapeutic interventions implemented to combat COVID-19 along with the understanding of molecular aspects of the immune evasion of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which may provide opportunities to develop more effective and promising therapeutics.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antivirais/uso terapêutico , COVID-19/terapia , Evasão da Resposta Imune/efeitos dos fármacos , Fatores Imunológicos/uso terapêutico , Replicação Viral/efeitos dos fármacos , COVID-19/imunologia , COVID-19/patologia , COVID-19/prevenção & controle , Vacinas contra COVID-19/administração & dosagem , Ensaios Clínicos como Assunto , Citocinas/antagonistas & inibidores , Citocinas/biossíntese , Dexametasona/uso terapêutico , Combinação de Medicamentos , Humanos , Imunidade Inata/efeitos dos fármacos , Imunização Passiva/métodos , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Peptídeos/uso terapêutico , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/imunologia , SARS-CoV-2/patogenicidade , Replicação Viral/imunologia
11.
Int J Mol Sci ; 22(11)2021 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-34070254

RESUMO

We evaluated the utility of optical redox imaging (ORI) to identify the therapeutic response of triple-negative breast cancers (TNBC) under various drug treatments. Cultured HCC1806 and MDA-MB-231 cells treated with FK866 (nicotinamide phosphoribosyltransferase (Nampt) inhibitor), FX11 (lactate dehydrogenase A inhibitor), paclitaxel, and their combinations were subjected to ORI, followed by imaging fluorescently labeled reactive oxygen species (ROS). Cell growth inhibition was measured by a cell viability assay. We found that both cell lines experienced significant NADH decrease and redox ratio (Fp/(NADH+Fp)) increase due to FK866 treatment; however, HCC1806 was much more responsive than MDA-MB-231. We further studied HCC1806 with the main findings: (i) nicotinamide riboside (NR) partially restored NADH in FK866-treated cells; (ii) FX11 induced an over 3-fold NADH increase in FK866 or FK866+NR pretreated cells; (iii) FK866 combined with paclitaxel caused synergistic increases in both Fp and the redox ratio; (iv) FK866 sensitized cells to paclitaxel treatments, which agrees with the redox changes detected by ORI; (v) Fp and the redox ratio positively correlated with cell growth inhibition; and (vi) Fp and NADH positively correlated with ROS level. Our study supports the utility of ORI for detecting the treatment responses of TNBC to Nampt inhibition and the sensitization effects on standard chemotherapeutics.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Citocinas , Nicotinamida Fosforribosiltransferase , Neoplasias de Mama Triplo Negativas , Acrilamidas/farmacologia , Citocinas/antagonistas & inibidores , Citocinas/metabolismo , Feminino , Humanos , Microscopia de Fluorescência , Naftalenos/farmacologia , Nicotinamida Fosforribosiltransferase/antagonistas & inibidores , Nicotinamida Fosforribosiltransferase/metabolismo , Oxirredução/efeitos dos fármacos , Piperidinas/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/enzimologia , Neoplasias de Mama Triplo Negativas/patologia
12.
J Med Chem ; 64(13): 9365-9380, 2021 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-34161728

RESUMO

Cyclic peptide diversity has been broadened by elaborating the A3-macrocyclization to include various di-amino carboxylate components with different Nε-amine substituents. Triple-bond reduction provided new cyclic peptide macrocycles with Z-olefin and completely saturated structures. Moreover, cyclic azasulfurylpeptides were prepared by exchanging the propargylglycine (Pra) component for an amino sulfamide surrogate. Examination of such diversity-oriented methods on potent cyclic azapeptide modulators of the cluster of differentiation 36 receptor (CD36) identified the importance of the triple bond as well as the Nε-allyl lysine and azaPra residues for high CD36 binding affinity. Cyclic azapeptides which engaged CD36 effectively reduced pro-inflammatory nitric oxide and downstream cytokine and chemokine production in macrophages stimulated with a Toll-like receptor-2 agonist. Studying the triple bond and amine components in the multiple-component A3-macrocyclization has given a diverse array of macrocycles and pertinent information to guide the development of ideal CD36 modulators with biomedical potential for curbing macrophage-driven inflammation.


Assuntos
Antígenos CD36/metabolismo , Compostos Macrocíclicos/farmacologia , Peptídeos Cíclicos/farmacologia , Citocinas/antagonistas & inibidores , Citocinas/biossíntese , Relação Dose-Resposta a Droga , Humanos , Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/química , Estrutura Molecular , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Peptídeos Cíclicos/síntese química , Peptídeos Cíclicos/química , Relação Estrutura-Atividade
13.
Front Immunol ; 12: 601842, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34084159

RESUMO

Asthma is a heterogeneous inflammatory disease characterized by airflow obstruction, wheezing, eosinophilia and neutrophilia of the airways. Identification of distinct inflammatory patterns characterizing asthma endotypes led to the development of novel therapeutic approaches. Cytokine or cytokine receptor targeting by therapeutic antibodies, such as anti-IL-4 and anti-IL-5, is now approved for severe asthma treatment. However, the complexity of cytokine networks in asthma should not be underestimated. Inhibition of one pro-inflammatory cytokine may lead to perturbed expression of another pro-inflammatory cytokine. Without understanding of the underlying mechanisms and defining the molecular predictors it may be difficult to control cytokine release that accompanies certain disease manifestations. Accumulating evidence suggests that in some cases a combined pharmacological inhibition of pathogenic cytokines, such as simultaneous blockade of IL-4 and IL-13 signaling, or blockade of upstream cytokines, such as TSLP, are more effective than single cytokine targeting. IL-6 and TNF are the important inflammatory mediators in the pathogenesis of asthma. Preliminary data suggests that combined pharmacological inhibition of TNF and IL-6 during asthma may be more efficient as compared to individual neutralization of these cytokines. Here we summarize recent findings in the field of anti-cytokine therapy of asthma and discuss immunological mechanisms by which simultaneous targeting of multiple cytokines as opposed to targeting of a single cytokine may improve disease outcomes.


Assuntos
Asma , Citocinas , Mediadores da Inflamação , Pulmão , Asma/imunologia , Asma/patologia , Asma/terapia , Citocinas/antagonistas & inibidores , Citocinas/imunologia , Humanos , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/imunologia , Pulmão/imunologia , Pulmão/patologia
14.
Bioorg Chem ; 112: 104944, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33962090

RESUMO

Twelve previously undescribed diterpenoids, euplarisans A-L (1-12), including one premyrsinane and eleven lathyranes, along with ten known analogues 13-22 were isolated from the seeds of Euphorbia lathyris. Their chemical structures were delineated by spectroscopic analysis and single-crystal X-ray diffraction. Interestingly, both 5 and 6 possessed an unusual trans-gem-dimethylcyclopropane as structural features and compound 8 was elucidated as premyrsinane-type diterpenoid. Meanwhile, a plausible biogenetic pathway for compounds 1-12 was proposed. In the anti-inflammatory bioassay, compounds 1, 2, 4, 13, 16, and 18 markedly inhibited the nitric oxide production in LPS-induced RAW264.7 macrophage cells. Compound 1 showed a more remarkable anti-inflammatory effect than others. It inhibited the generation of inflammatory cytokines (IL-1ß, IL-6, and TNF-α) and also obviously decreased the expression of iNOS, COX-2, and p-IκBα in a dose-dependent manner. The structure-activity relationships (SARs) of these diterpenoids were also discussed.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Diterpenos/farmacologia , Euphorbia/química , Animais , Anti-Inflamatórios não Esteroides/química , Anti-Inflamatórios não Esteroides/isolamento & purificação , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Citocinas/antagonistas & inibidores , Citocinas/biossíntese , Diterpenos/química , Diterpenos/isolamento & purificação , Relação Dose-Resposta a Droga , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Camundongos , Estrutura Molecular , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/biossíntese , Células RAW 264.7 , Sementes/química , Relação Estrutura-Atividade
15.
Front Immunol ; 12: 623725, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33995347

RESUMO

The profound impact that vision loss has on human activities and quality of life necessitates understanding the etiology of potentially blinding diseases and their clinical management. The unique anatomic features of the eye and its sequestration from peripheral immune system also provides a framework for studying other diseases in immune privileged sites and validating basic immunological principles. Thus, early studies of intraocular inflammatory diseases (uveitis) were at the forefront of research on organ transplantation. These studies laid the groundwork for foundational discoveries on how immune system distinguishes self from non-self and established current concepts of acquired immune tolerance and autoimmunity. Our charge in this review is to examine how advances in molecular cell biology and immunology over the past 3 decades have contributed to the understanding of mechanisms that underlie immunopathogenesis of uveitis. Particular emphasis is on how advances in biotechnology have been leveraged in developing biologics and cell-based immunotherapies for uveitis and other neuroinflammatory diseases.


Assuntos
Anti-Inflamatórios/uso terapêutico , Autoimunidade/efeitos dos fármacos , Produtos Biológicos/uso terapêutico , Tolerância Imunológica/efeitos dos fármacos , Imunoterapia , Úvea/efeitos dos fármacos , Uveíte/terapia , Animais , Citocinas/antagonistas & inibidores , Citocinas/metabolismo , Modelos Animais de Doenças , Humanos , Mediadores da Inflamação/antagonistas & inibidores , Mediadores da Inflamação/metabolismo , Terapia de Alvo Molecular , Transdução de Sinais , Úvea/imunologia , Úvea/metabolismo , Uveíte/imunologia , Uveíte/metabolismo
16.
Invest Ophthalmol Vis Sci ; 62(6): 26, 2021 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-34038512

RESUMO

Purpose: To investigate the antifungal and anti-inflammatory effects of baicalein on Aspergillus fumigatus (A. fumigatus) keratitis and the underlying mechanisms. Methods: The noncytotoxic antifungal concentration of baicalein was determined using CCK8, cell scratch assay, minimum inhibitory concentration, biofilm formation, scanning electron microscopy, propidium iodide uptake test and adherence assay in vitro and Draize test in vivo. In fungal keratitis (FK) mouse models, clinical score and plate count were used to evaluate FK severity, and myeloperoxidase assay and immunofluorescence staining were performed to examine neutrophil infiltration and activity. Real-time PCR, ELISA, and Western blot were performed to explore the anti-inflammatory activity of baicalein and the underlying mechanisms in vivo and in vitro. Results: Baicalein at 0.25 mM (noncytotoxic) significantly inhibited A. fumigatus growth, biofilm formation, and adhesion in vitro. In A. fumigatus keratitis mice, baicalein mitigated FK severity, reduced fungal load, and inhibited neutrophil infiltration and activity. Baicalein not only suppressed mRNA and protein levels of proinflammatory factors IL-1ß, IL-6, and TNF-α, but also inhibited the expression of thymic stromal lymphopoietin (TSLP) and TSLP receptor (TSLPR) in vivo and in vitro. In HCECs, mRNA and protein levels of IL-1ß, IL-6, and TNF-α were significantly lower in the TSLP siRNA-treated group, while higher in the rTSLP-treated group than in the corresponding control. Baicalein treatment significantly inhibited rTSLP induced the expression of IL-1ß, IL-6, and TNF-α. Conclusions: Baicalein plays a protective role in mouse A. fumigatus keratitis by inhibiting fungal growth, biofilm formation, and adhesion, and suppressing inflammatory response via downregulation of the TSLP/TSLPR pathway.


Assuntos
Antifúngicos/uso terapêutico , Aspergilose/tratamento farmacológico , Citocinas/antagonistas & inibidores , Infecções Oculares Fúngicas/tratamento farmacológico , Flavanonas/uso terapêutico , Inflamação/tratamento farmacológico , Ceratite/tratamento farmacológico , Animais , Aspergilose/metabolismo , Aspergilose/microbiologia , Aspergillus fumigatus/efeitos dos fármacos , Aspergillus fumigatus/isolamento & purificação , Aspergillus fumigatus/ultraestrutura , Western Blotting , Células Cultivadas , Citocinas/genética , Citocinas/metabolismo , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Epitélio Corneano/efeitos dos fármacos , Epitélio Corneano/metabolismo , Infecções Oculares Fúngicas/metabolismo , Infecções Oculares Fúngicas/microbiologia , Feminino , Ceratite/metabolismo , Ceratite/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Testes de Sensibilidade Microbiana , Microscopia Eletrônica de Varredura , Reação em Cadeia da Polimerase em Tempo Real
17.
Eur J Immunol ; 51(8): 2074-2085, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-33945643

RESUMO

The aberrant release of inflammatory mediators often referred to as a cytokine storm or cytokine release syndrome (CRS), is a common and sometimes fatal complication in acute infectious diseases including Ebola, dengue, COVID-19, and influenza. Fatal CRS occurrences have also plagued the development of highly promising cancer therapies based on T-cell engagers and chimeric antigen receptor (CAR) T cells. CRS is intimately linked with dysregulated and excessive cytokine release, including IFN-γ, TNF-α, IL 1, IL-6, and IL-10, resulting in a systemic inflammatory response leading to multiple organ failure. Here, we show that mice intravenously administered the agonistic hamster anti-mouse CD3ε monoclonal antibody 145-2C11 develop clinical and laboratory manifestations seen in patients afflicted with CRS, including body weight loss, hepatosplenomegaly, thrombocytopenia, increased vascular permeability, lung inflammation, and hypercytokinemia. Blood cytokine levels and gene expression analysis from lung, liver, and spleen demonstrated a hierarchy of inflammatory cytokine production and infiltrating immune cells with differentiating organ-dependent kinetics. IL-2, IFN-γ, TNF-α, and IL-6 up-regulation preceded clinical signs of CRS. The co-treatment of mice with a neutralizing anti-cytokine antibody cocktail transiently improved early clinical and laboratory features of CRS. We discuss the predictive use of this model in the context of new anti-cytokine strategies to treat human CRS.


Assuntos
Anticorpos Monoclonais/farmacologia , Anticorpos/imunologia , Complexo CD3/antagonistas & inibidores , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/metabolismo , Citocinas/antagonistas & inibidores , Citocinas/metabolismo , Animais , Anticorpos/efeitos adversos , Anticorpos Monoclonais/uso terapêutico , Síndrome da Liberação de Citocina/diagnóstico , Síndrome da Liberação de Citocina/tratamento farmacológico , Citocinas/sangue , Modelos Animais de Doenças , Quimioterapia Combinada , Mediadores da Inflamação/sangue , Mediadores da Inflamação/metabolismo , Ativação Linfocitária/imunologia , Camundongos , Fenótipo , Índice de Gravidade de Doença , Linfócitos T/imunologia , Linfócitos T/metabolismo , Resultado do Tratamento
18.
Immunopharmacol Immunotoxicol ; 43(4): 395-409, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34057871

RESUMO

A global threat has emerged in 2019 due to the rapid spread of Coronavirus disease (COVID-19). As of January 2021, the number of cases worldwide reached 103 million cases and 2.22 million deaths which were confirmed as the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This global pandemic galvanized the scientific community to study the causative virus (SARS-CoV2) pathogenesis, transmission, and clinical symptoms. Remarkably, the most common complication associated with this disease is the cytokine storm which is responsible for COVID-19 mortality. Thus, targeting the cytokine storm with new medications is needed to hamper COVID-19 complications where the most prominent strategy for the treatment is drug repurposing. Through this strategy, several steps are skipped especially those required for testing drug safety and thus may help in reducing the dissemination of this pandemic. Accordingly, the aim of this review is to outline the pathogenesis, clinical features, and immune complications of SARS-CoV2 in addition to suggesting several repurposed drugs with their plausible mechanism of action for possible management of severe COVID-19 cases.


Assuntos
Anti-Inflamatórios/uso terapêutico , COVID-19/tratamento farmacológico , Síndrome da Liberação de Citocina/tratamento farmacológico , Citocinas/antagonistas & inibidores , Reposicionamento de Medicamentos , SARS-CoV-2/patogenicidade , Animais , Anti-Inflamatórios/efeitos adversos , COVID-19/imunologia , COVID-19/virologia , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/virologia , Citocinas/imunologia , Interações Hospedeiro-Patógeno , Humanos , SARS-CoV-2/imunologia
19.
Scand J Clin Lab Invest ; 81(4): 255-263, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34032527

RESUMO

Coronaviruses belonging to the Coronaviridae family are single-stranded RNA viruses. The entry of SARS-CoV-2 is accomplished via ACE-2 receptors. SARS-CoV-2 infection coactivates both innate and adaptive immune responses. Although SARS-CoV-2 stimulates antibody production with a typical pattern of IgM/IgG, cellular immunity is also impaired. In severe cases, low CD4 + and CD8 + T cell counts are associated with impaired immune functions, and high neutrophil/lymphocyte ratios accompanying low lymphocyte subsets have been demonstrated. Recently, high IFN -α/γ ratios with impaired T cell responses, and increased IL-1, IL-6, TNF-α, MCP-1, IP-10, IL-4, IL-10 have been reported in COVID-19 infection. Increased proinflammatory cytokines and chemokines in patients with severe COVID-19 may cause the suppression of CD4 + and CD8 + T cells and regulatory T cells, causing excessive inflammatory responses and fatal cytokine storm with tissue and organ damage. Consequently, novel therapeutics to be developed against host immune system, including blockade of cytokines (IL-6, IL-1, IFN) themselves, their receptors or signaling pathways- JAK inhibitors- could be effective as potential therapeutics.


Assuntos
Antivirais/farmacologia , COVID-19/tratamento farmacológico , COVID-19/imunologia , COVID-19/fisiopatologia , Corticosteroides/uso terapêutico , Animais , Antivirais/uso terapêutico , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/virologia , Citocinas/antagonistas & inibidores , Citocinas/metabolismo , Glucocorticoides/uso terapêutico , Humanos , Hidroxicloroquina/uso terapêutico , Imunoterapia/métodos , Macrófagos/imunologia , Macrófagos/patologia , Macrófagos/virologia
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