Celastrol nanoparticles inhibit corneal neovascularization induced by suturing in rats

Zhanrong Li1, Lin Yao1, Jingguo Li2, Wenxin Zhang1, Xianghua Wu1, Yi Liu1, Miaoli Lin1, Wenru Su1, Yongping Li1, Dan Liang11State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, 2School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou, People's Republic of ChinaPurpose: Celastrol, a traditional Chinese medicine, is widely used in anti-inflammation and anti-angiogenesis research. However, the poor water solubility of celastrol restricts its further application. This paper aims to study the effect of celastrol nanoparticles (CNPs) on corneal neovascularization (CNV) and determine the possible mechanism.Methods: To improve the hydrophilicity of celastrol, celastrol-loaded poly(ethylene glycol)-block-poly(ε-caprolactone) nanopolymeric micelles were developed. The characterization of CNPs was measured by dynamic light scattering and transmission electron microscopy analysis. Celastrol loading content and release were assessed by ultraviolet-visible analysis and high performance liquid chromatography, respectively. In vitro, human umbilical vein endothelial cell proliferation and capillary-like tube formation were assayed. In vivo, suture-induced CNV was chosen to evaluate the effect of CNPs on CNV in rats. Immunohistochemistry for CD68 assessed the macrophage infiltration of the cornea on day 6 after surgery. Real-time quantitative reverse transcription-polymerase chain reaction and enzyme-linked immunosorbent assay were used to evaluate the messenger ribonucleic acid and protein levels, respectively, of vascular endothelial growth factor, matrix metalloproteinase 9, and monocyte chemoattractant protein 1 in the cornea.Results: The mean diameter of CNPs with spherical shape was 48 nm. The celastrol loading content was 7.36%. The release behavior of CNPs in buffered solution (pH 7.4) showed a typical two-phase release profile. CNPs inhibited the proliferation of human umbilical vein endothelial cells in a dose-independent manner and suppressed the capillary structure formation. After treatment with CNPs, the length and area of CNV reduced from 1.16 ± 0.18 mm to 0.49 ± 0.12 mm and from 7.71 ± 0.94 mm2 to 2.29 ± 0.61 mm2, respectively. Macrophage infiltration decreased significantly in the CNP-treated corneas. CNPs reduced the expression of vascular endothelial growth factor, matrix metalloproteinase 9, and monocyte chemoattractant protein 1 in the cornea on day 6 after suturing.Conclusion: CNPs significantly inhibited suture-induced CNV by suppressing macrophage infiltration and the expression of vascular endothelial growth factor and matrix metalloproteinase 9 in the rat cornea.Keywords: celastrol, PEG-b-PCL nanopolymeric micelles, corneal neovascularization, macrophages, VEGF, MMP-

Adoptive Transfer of Human Gingiva-derived Mesenchymal Stem Cells Ameliorates Collagen-induced Arthritis via Suppression of Th1 and Th17 Cells and Enhancement of Regulatory T Cell Differentiation

Objective Current approaches offer no cures for rheumatoid arthritis (RA). Accumulating evidence has revealed that manipulation of bone marrow-derived mesenchymal stem cells (BM-MSCs) may have the potential to control or even prevent RA, but BM-MSC-based therapy faces many challenges, such as limited cell availability and reduced clinical feasibility. This study in mice with established collagen-induced arthritis (CIA) was undertaken to determine whether substitution of human gingiva-derived mesenchymal stem cells (G-MSCs) would significantly improve the therapeutic effects. Methods CIA was induced in DBA/1J mice by immunization with type II collagen and Freund\u27s complete adjuvant. G-MSCs were injected intravenously into the mice on day 14 after immunization. In some experiments, intraperitoneal injection of PC61 (anti-CD25 antibody) was used to deplete Treg cells in arthritic mice. Results Infusion of G-MSCs in DBA/1J mice with CIA significantly reduced the severity of arthritis, decreased the histopathology scores, and down-regulated the production of inflammatory cytokines (interferon-γ and interleukin-17A). Infusion of G-MSCs also resulted in increased levels of CD4+CD39+FoxP3+ cells in arthritic mice. These increases were noted early after infusion in the spleens and lymph nodes, and later after infusion in the synovial fluid. The FoxP3+ Treg cells that were increased in frequency mainly consisted of Helios-negative cells. When Treg cells were depleted, infusion of G-MSCs partially interfered with the progression of CIA. Pretreatment of G-MSCs with a CD39 or CD73 inhibitor significantly reversed the protective effect of G-MSCs on CIA. Conclusion The role of G-MSCs in controlling the development and severity of CIA mostly depends on CD39/CD73 signals and partially depends on the induction of CD4+CD39+FoxP3+ Treg cells. G-MSCs provide a promising approach for the treatment of autoimmune diseases. Copyright © 2013 by the American College of Rheumatology

The Efficacy of Adalimumab as an Initial Treatment in Patients with Behçet’s Retinal Vasculitis

Background: No study has evaluated the effectiveness of Adalimumab (ADA) as first-line in treatment-naïve patients with retinal vasculitis due to Behçet’s Uveitis (BU).Objective: To compare the efficacy of ADA plus conventional therapy and conventional therapy alone as initial treatments in naïve BU patients characterized by retinal vasculitis.Methods: Medical records of BU patients characterized by retinal vasculitis treated with conventional therapy (CT, refers to glucocorticoid and immunosuppressive agents) alone or ADA plus conventional therapy with at least 6 months of follow-up between February 2015 and June 2020 were analyzed. Only patients who were first diagnosed with BU without previous systemic treatment were reviewed. The retinal vasculitis score based on fluorescein angiography (FA), best-corrected visual acuity, glucocorticoid-sparing effect, the number of relapses and ocular complications were evaluated.Results: A total of 45 patients (87 eyes) were included. Twenty-four patients (55.33%) in the CT group were treated with conventional therapy and 21 patients (46.67%) in the ADA group were treated with ADA plus conventional therapy. The inflammatory parameters improved in both groups. FA scores showed significantly greater improvement in ADA group than CT group (p < 0.001). The median number of relapses was significantly lower, and the duration of remission was longer in ADA group than CT group (p < 0.001). At the last visit, a significantly better BCVA improvement (p = 0.024), better inflammation control (anterior chamber inflammation p = 0.017 and vitritis p < 0.001) and lower daily glucocorticoid dosage (p = 0.005) were identified in patients received ADA therapy. In CT group, 1 patient suffered hepatitis B and tuberculosis, 1 had growth retardation, 1 patient had with osteoporosis, then followed by other mild AEs (mostly respiratory upper tract infections); while in ADA group, 1 patient experienced a mild pneumonia (n = 1) while milder AEs were represented mostly by respiratory upper tract infections followed by gastrointestinal discomfort.Conclusion: ADA plus conventional therapy achieved superiority over conventional therapy as initial treatment in naïve BU patients with retinal vasculitis

RETRATO SIN IDENTIFICAR [Material gráfico]

Copia digital. Madrid : Ministerio de Educación, Cultura y Deporte, 201

BAFF Promotes Th17 Cells and Aggravates Experimental Autoimmune Encephalomyelitis

BAFF, in addition to promoting B cell survival and differentiation, may affect T cells. The objective of this study was to determine the effect of BAFF on Th17 cell generation and its ramifications for the Th17 cell-driven disease, EAE.Th17 cells were increased in BAFF-Tg B6 (B6.BTg) mice and decreased in B6.Baff(-/-) mice. Th17 cells in B6.Baff(-/-) mice bearing a BAFF Tg (B6.Baff(-/-).BTg mice) were identical to those in B6.BTg mice, indicating that membrane BAFF is dispensable for Th17 cell generation as long as soluble BAFF is plentiful. In T + non-T cell criss-cross co-cultures, Th17 cell generation was greatest in cultures containing B6.BTg T cells and lowest in cultures containing B6.Baff(-/-) T cells, regardless of the source of non-T cells. In cultures containing only T cells, Th17 cell generation followed an identical pattern. CD4(+) cell expression of CD126 (IL-6R α chain) was increased in B6.BTg mice and decreased in B6.Baff(-/-) mice, and activation of STAT3 following stimulation with IL-6 + TGF-β was also greatest in B6.BTg cells and lowest in B6.Baff(-/-) cells. EAE was clinically and pathologically most severe in B6.BTg mice and least severe in B6.Baff(-/-) mice and correlated with MOG(35-55) peptide-induced Th17 cell responses.Collectively, these findings document a contribution of BAFF to pathogenic Th17 cell responses and suggest that BAFF antagonism may be efficacious in Th17 cell-driven diseases

LOS PACIENTES RECUPERADOS DEL COVID-19 PUEDEN SEGUIR CON UNA RESPUESTA HIPERINFLAMATORIA.

En un estudio reciente se caracterizó de manera integral los cambiostranscripcionales en las células mononucleares de sangre periférica durante la etapa de recuperación de COVID-19 mediante la técnica de secuenciación de ARN de células individuales. Los resultados obtenidos indican que las células T disminuyeron notablemente, mientras que los monocitos con alta expresión de genes proinflamatorios aumentaron en pacientes en la etapa de recuperación temprana (ERS) de COVID-19. Este estudio proporciona la primera evidencia de una firme respuesta inmune inflamatoria durante laERS, lo que sugiere que los pacientes con COVID-19 siguen siendo vulnerables después del alta hospitalaria