Mechanism of artesunate on bone destruction in experimental rheumatoid arthritis based on transcriptomics and network pharmacology / 中国中药杂志

The present study investigated the mechanism of artesunate in the treatment of bone destruction in experimental rheumatoid arthritis(RA) based on transcriptomics and network pharmacology. The transcriptome sequencing data of artesunate in the inhibition of osteoclast differentiation were analyzed to obtain differentially expressed genes(DEGs). GraphPad Prism 8 software was used to plot volcano maps and heat maps were plotted through the website of bioinformatics. GeneCards and OMIM were used to collect information on key targets of bone destruction in RA. The DEGs of artesunate in inhibiting osteoclast differentiation and key target genes of bone destruction in RA were intersected by the Venny 2.1.0 platform, and the intersection target genes were analyzed by Gene Ontology(GO)/Kyoto Encyclopedia of Genes and Genomes(KEGG) enrichment. Finally, the receptor activator of nuclear factor-κB(RANKL)-induced osteoclast differentiation model and collagen-induced arthritis(CIA) model were established. Quantitative real time polymerase chain reaction(q-PCR), immunofluorescence, and immunohistochemistry were used to verify the pharmacological effect and molecular mechanism of artesunate in the treatment of bone destruction in RA. In this study, the RANKL-induced osteoclast differentiation model in vitro was established and intervened with artesunate, and transcriptome sequencing data were analyzed to obtain 744 DEGs of artesunate in inhibiting osteoclast differentiation. A total of 1 291 major target genes of bone destruction in RA were obtained from GeneCards and OMIM. The target genes of artesunate in inhibiting osteoclast differentiation and the target genes of bone destruction in RA were intersected to obtain 61 target genes of artesunate against bone destruction in RA. The intersected target genes were analyzed by GO/KEGG enrichment. According to the results previously reported, the cytokine-cytokine receptor interaction signaling pathway was selected for experimental verification. Artesunate intervention in the RANKL-induced osteoclast differentiation model showed that artesunate inhibited CC chemokine receptor 3(CCR3), CC chemokine receptor 1(CCR1) and leukemia inhibitory factor(LIF) mRNA expression in osteoclasts in a dose-dependent manner compared with the RANKL-induced group. Meanwhile, the results of immunofluorescence and immunohistochemistry showed that artesunate could dose-dependently reduce the expression of CCR3 in osteoclasts and joint tissues of the CIA rat model in vitro. This study indicated that artesunate regulated the CCR3 in the cytokine-cytokine receptor interaction signaling pathway in the treatment of bone destruction in RA and provided a new target gene for the treatment of bone destruction in RA.

Cytokine receptor-like factor 1 (CRLF1) promotes cardiac fibrosis via ERK1/2 signaling pathway / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Cardiac fibrosis is a cause of morbidity and mortality in people with heart disease. Anti-fibrosis treatment is a significant therapy for heart disease, but there is still no thorough understanding of fibrotic mechanisms. This study was carried out to ascertain the functions of cytokine receptor-like factor 1 (CRLF1) in cardiac fibrosis and clarify its regulatory mechanisms. We found that CRLF1 was expressed predominantly in cardiac fibroblasts. Its expression was up-regulated not only in a mouse heart fibrotic model induced by myocardial infarction, but also in mouse and human cardiac fibroblasts provoked by transforming growth factor-‍β1 (TGF‍-‍β1). Gain- and loss-of-function experiments of CRLF1 were carried out in neonatal mice cardiac fibroblasts (NMCFs) with or without TGF-‍β1 stimulation. CRLF1 overexpression increased cell viability, collagen production, cell proliferation capacity, and myofibroblast transformation of NMCFs with or without TGF‍-‍β1 stimulation, while silencing of CRLF1 had the opposite effects. An inhibitor of the extracellular signal-regulated kinase 1/2 (ERK1/2) signaling pathway and different inhibitors of TGF-‍β1 signaling cascades, comprising mothers against decapentaplegic homolog (SMAD)‍-dependent and SMAD-independent pathways, were applied to investigate the mechanisms involved. CRLF1 exerted its functions by activating the ERK1/2 signaling pathway. Furthermore, the SMAD-dependent pathway, not the SMAD-independent pathway, was responsible for CRLF1 up-regulation in NMCFs treated with TGF-‍β1. In summary, activation of the TGF-‍β1/SMAD signaling pathway in cardiac fibrosis increased CRLF1 expression. CRLF1 then aggravated cardiac fibrosis by activating the ERK1/2 signaling pathway. CRLF1 could become a novel potential target for intervention and remedy of cardiac fibrosis.

Research Status of TPO/c-MPL Signaling Pathway in Acute Myeloid Leukemia--Review / 中国实验血液学杂志

Thrombopoietin (TPO) can activate hematopoietic cell proliferation by its receptor c-MPL mediated downstream pathways and induce the generation of megakaryocyte. In recent years, domestic and foreign researches have confirmed that TPO/ c-MPL pathway also plays an important role in the self-renewal and quiescence of leukemia stem cell, and its expression in acute myeloid leukemia (AML) also indicates the chemotherapy resistance and poor prognosis. In this article, the research progress of the roles of TPO/c-MPL pathway in chemotherapy resistance, prognosis of AML patients, and the application of TPO/ c-MPL receptor agonists in AML were summarized briefly.

Effect of rhTPO to the Proliferation and Apoptosis of Acute Myeloid Leukemia Cell Lines / 中国实验血液学杂志

OBJECTIVE@#To investigate the effects of recombinant human thrombopoietin (rhTPO) to proliferation and apoptosis of acute myeloid leukemia (AML) cell lines.@*METHODS@#After the treatment of different concentrations of rhTPO (0, 50, 100 ng/ml) for different time (24,48,72 h)，the cell proliferation rates of the AML cell lines (Kasumi-1, Skno-1, HEL, HL-60, THP-1) were determined by CCK-8 method. Apoptosis rate of each cell line cocultured with rhTPO was detected by Annexin V/PI method. The relative expression of TPO receptor c-MPL (myeloproliferative clonal antibody) mRNA in AML cell lines was detected by Q-PCR. The expression of c-MPL protein in each cell line was detected by Western blot. The expression of c-MPL antigen in HL-60 cells treated by different concentrations of rhTPO was detected by Flow cytometry.@*RESULTS@#RhTPO showed no promotion to the proliferation of Kasumi-1, Skno-1, HEL, HL-60, THP-1 cell lines，however，it showed inhibitory effect to cell proliferation (72 h 0 ng/ml vs 100 ng/ml, P= 0.029) and pro-apoptotic (48 h 0 ng/ml vs 50 ng/ml, P=0.0143) in HL-60 cells. In Kasumi-1, Skno-1, HEL and THP-1 cells, there showed no statistically significant differences in apoptosis rate among each groups treated by different concentrations of rhTPO. Each AML cell line showed different levels of c-MPL gene and c-MPL protein expression, but HEL cells showed the highest expression in both of them. After HL-60 cells were treated by different concentrations of rhTPO for 48 hours, there showed no statistical difference in c-MPL antigen expression among each groups.@*CONCLUSION@#RhTPO can not promote the proliferation of Kasumi-1, Skno-1, HEL, HL-60 and THP-1 leukemia cell lines. On the contrary, rhTPO can inhibit HL-60 cell proliferation and promote its apoptosis, and this effect is not related to c-MPL gene expression or protein expression.

Clinical Features and Prognosis of Acute Lymphoblastic Leukemia Children with P2RY8-CRLF2 Gene Rearrangement / 中国实验血液学杂志

OBJECTIVE@#To investigate the clinical features and prognostic factors of acute lymphoblastic leukemia (ALL) children with P2RY8-CRLF2 gene rearrangement.@*METHODS@#A total of 108 children with B-cell ALL (B-ALL) were diagnosed and systematically treated according to Chinese Children's Leukemia Group (CCLG) -ALL 2008 in our hospital from January 2016 to December 2016. The 108 patients were divided into two groups according to the result of mutiplex polymerase chain reaction: group with P2RY8-CRLF2 gene rearrangement and group without P2RY8-CRLF2 gene rearrangement. The ALL children with P2RY8-CRLF2 gene rearrangement were all treated by CCLG-ALL 2008 high-risk group (HR) regimens, and the ALL children in group without P2RY8-CRLF2 gene rearrangement received different intensity chemotherapy according to clinical risk classification.@*RESULTS@#Five (4 male and 1 female) out of 108 patients with B-ALL had P2RY8-CRLF2 gene rearrangement. In the 5 B-ALL patients with P2RY8-CRLF2 gene rearrangement, the median age of the was 4 (2-6) years old and the median WBC count was 26.2 (2.46-525.1)×10@*CONCLUSION@#The early treatment response and prognosis of ALL children with P2RY8-CRLF2 gene rearrangement are worse, and more effective protocol is needed for this subtype patients.

Clinical Significance of CRLF2 High Expression in Bone Marrow Mononuclear Cells from Children with Acute Lymphoblastic Leukemia / 中国实验血液学杂志

OBJECTIVE@#To detect the expression of CRLF2 in bone marrow mononuclear cells from children with newly diagnosed acute lymphoblastic leukemia(ALL) and to explore its clinical significance in pediatric ALL.@*METHODS@#A total of 218 children with newly diagnosed ALL who achieveal the complete remission and had the complete follow-up information were selected, and the expression level of CRLF2 in bone marrow mononuclear cells of these children was detected by real-time fluorescent quantitative PCR, and the significance of CRLF2 expression level in clinical prognosis of ALL children was analyzed by using statistical method.@*RESULTS@#28 cases in 218 children with complete data showed high expression of CRLF2. The cumulative recurrence rate in the CRLF2 high expression group was significantly higher than that in the low expression group (53.6% vs 12.6%) (P＜0.01). The predicted 5-year recurrence-free survival rate (RFS) of ALL children with CRLF2 high expression was significantly higher than that of low expression group (P＜0.01). There was no significant difference in the predicted 5-year RFS between ALL children with CRLF2 low and high expression in the standard-risk(SR) group (P＞0.05). The predicted 5-year RFS of ALL children with CRLF2 low expression was higher than that of ALL children with CRLF2 high expression in the intermediate-risk (IR) and high-risk (HR) groups. (P＜0.05). Cox analysis showed that CRLF2 high expression is an independent risk factor for the relapse of children with ALL.@*CONCLUSION@#The recurrence rate of pediatric ALL with CRLF2 high expression is high, and CRLF2 high expression is an important prognostic factor for high risk of relapse in ALL children with IR and HR. It is necessary to use CRLF2 expression as an indicator of risk stratification in pediatric ALL.

Lactobacillus pentosus Modulates Immune Response by Inducing IL-10 Producing Tr1 Cells

Several gut commensals have been shown to modulate host immune response. Recently, many food derived microbes have also been reported to affect the immune system. However, a mechanism to identify immunostimulatory and immunoregulatory microbes is needed. Here, we successfully established an in vitro screening system and identified an immunoregulatory bacterium, Lactobacillus pentosus KF340 (LP340), present in various fermented foods. LP340 induced a regulatory phenotype in mice Ag presenting cells which, in turn, induced IL-10 and IFN-γ producing Type 1 regulatory T cells (Tr1 cells) from naïve CD4⁺ T cells. Naïve CD4⁺ T cells co-cultured with LP340 treated dendritic cells highly expressed cytokine receptor IL-27R and were CD49b and lymphocyte-activation gene 3 double positive. Oral administration of LP340 in mice with atopic dermatitis reduced cellular infiltration in affected ear lobes and serum IgE levels, thus, ameliorating the disease symptoms. This suggests a systemic immunoregulatory effect of LP340. These findings demonstrate that LP340, a bacterium derived from food, prevents systemic inflammation through the induction of IL-10 producing Tr1 cells.

The expression of CRLF2 in adult Ph negative acute B lymphocytic leukemia and its prognostic significance / 中华血液学杂志

Objective: To detect the expression of CRLF2 in adult Ph negative acute B lymphocytic leukemia (B-ALL) in newly diagnosed cases, and to investigate the relationship between CRLF2 and the general clinical characteristics, efficacy and prognosis. Methods: 103 cases of newly diagnosed adult B-ALL patients were investigated from Apr 2016 to Dec 2017 in the Department of Hematology, Henan Cancer Hospital. Bone marrow samples was used to detect the expression of CRLF2 in leukemic cells. The expression of CRLF2 ≥20% was defined as CRLF2-high group and <20% was defined as CRLF2-low group. The clinical characteristics and prognosis of the two groups were compared. Results: The Median overall survival (OS) and disease free survial (DFS) in CRLF2-high group were 9.0 months and 4.25 months, respectively. CRLF2-low group were 15.5 months and 10.25 months, respectively. There was a statistically significant difference in median OS and DFS between the two groups (P=0.007, P=0.000) . The 18-month OS and DFS in CRLF2-high group were 38.6% and 25.1%, respectively. CRLF2-low group were 57.8% and 42.3%, respectively. Multivariate analysis showed high expression of CRLF2 was an independent risk factor for OS (HR=2.991, 95% CI 1.429-6.261, P=0.004) and DFS (HR=2.374, 95%CI 1.146-4.960, P=0.041) in patients. Conclusion: Patients with high expression of CRLF2 had poor prognosis.

Out-sourcing for Trans-presentation: Assessing T Cell Intrinsic and Extrinsic IL-15 Expression with Il15 Gene Reporter Mice

IL-15 is a cytokine of the common γ-chain family that is critical for natural killer (NK), invariant natural killer T (iNKT), and CD8 memory T cell development and homeostasis. The role of IL-15 in regulating effector T cell subsets, however, remains incompletely understood. IL-15 is mostly expressed by stromal cells, myeloid cells, and dendritic cells (DCs). Whether T cells themselves can express IL-15, and if so, whether such T cell-derived IL-15 could play an autocrine role in T cells are interesting questions that were previously addressed but answered with mixed results. Recently, three independent studies described the generation of IL-15 reporter mice which facilitated the identification of IL-15-producing cells and helped to clarify the role of IL-15 both in vitro and in vivo. Here, we review the findings of these studies and place them in context of recent reports that examined T cell-intrinsic IL-15 expression during CD4 effector T cell differentiation.

Effects of interleukin 27 and its receptor on TGFβinduced murine pulmonary fibroblast proliferation and transformation / 南方医科大学学报

<p><b>OBJECTIVE</b>To investigate the effects of interleukin-27 (IL-27) and its receptor (WSX-1) on the proliferation, transformation and collagen synthesis of the mouse lung fibroblasts.</p><p><b>METHODS</b>Cultured mouse lung fibroblasts were treated with TGF-β1, recombinant murine IL-27, a IL-27 receptor (IL-27R) overexpression vector IL-27R/pCDNA3.1, IL-27 and IL-27R, or all the 3 combined. MTT assay was used to assess the proliferation of the cells, and RT-PCR and Western blotting were employed to examine the mRNA and protein expressions of a-smooth muscle actin (α-SMA) and types I and III collagen; immunofluorescence assay was used to test the expression and location of α-SMA.</p><p><b>RESULTS</b>TGF-β1 promoted the cell proliferation and obviously enhanced α-SMA expression and types I and III collagen synthesis in the fibroblasts. Both IL-27 and IL-27R significantly inhibited the proliferation of the pulmonary fibroblasts and obviously decreased their α-SMA expression and types I and III collagen synthesis, but when combined,they produced no obvious inhibitory effect on TGF-1-induced proliferation and transformation of pulmonary fibroblasts.</p><p><b>CONCLUSION</b>Both IL-27 and IL-27R alone can suppress the proliferation, transformation, and collagen synthesis of mouse pulmonary fibroblasts, but their combined treatment produces no such inhibitory effect because of the neutralization of exogenous IL-27 by IL-27R to result in the failure of activating the cell signaling pathways.</p>

The role of soluble common gamma chain in autoimmune disease / 대한해부학회지

The common gamma chain (gammac) is the central signaling unit for a number of cytokine receptors collectively known as the gammac cytokine receptor family. gammac is critical for ligand binding and signaling by gammac cytokines. gammac cytokine signaling had been thought to be mainly regulated by cytokine-specific receptor alpha chain expression levels with little or no effect by gammac surface levels because gammac expression was presumed to remain unchanged during T-cell activation and development. The extent of gammac cytokine responses is thought to be regulated by cytokine specific receptor subunits and not by the gammac receptor. In contrast to this prevailing view, we have recently reported that gammac itself actively regulates gammac cytokine responses. Interestingly, gammac exerted its regulatory effects not only as a conventional membrane receptor protein but also as a secreted protein whose expression was upregulated upon T-cell stimulation. Here we will review how a soluble form of gammac, which is generated by alternative splicing, regulates gammac cytokine signaling and plays a role in controlling immune activation related to autoimmune disease.

Effects of curcumin on pain threshold and on the expression of nuclear factor κ B and CX3C receptor 1 after sciatic nerve chronic constrictive injury in rats / 中国结合医学杂志

<p><b>OBJECTIVE</b>To investigate the effects of curcumin on pain threshold and the expressions of nuclear factor κ B (NF-κ B) and CX3C chemokine receptor 1 (CX3CR1) in spinal cord and dorsal root ganglion (DRG) of the rats with sciatic nerve chronic constrictive injury.</p><p><b>METHODS</b>One hundred and twenty male Sprague Dawley rats, weighing 220-250 g, were randomly divided into 4 groups. Sham surgery (sham) group: the sciatic nerves of rats were only made apart but not ligated; chronic constrictive injury (CCI) group: the sciatic nerves of rats were only ligated without any drug treatment; curcumin treated injury (Cur) model group: the rats were administrated with curcumin 100 mg/(kg·d) by intraperitoneal injection for 14 days after CCI; solvent control (SC) group: the rats were administrated with the solvent at the same dose for 14 days after CCI. Thermal withdrawal latency (TWL) and mechanical withdrawal threshold (MWT) of rats were respectively measured on pre-operative day 2 and postoperative day 1, 3, 5, 7, 10 and 14. The lumbar segment L4-5 of the spinal cord and the L4, L5 DRG was removed at post-operative day 3, 7 and 14. The change of nuclear factor κ B (NF-κ B) p65 expression was detected by Western blotting while the expression of CX3CR1 was determined by immunohistochemical staining.</p><p><b>RESULTS</b>Compared with the sham group, the TWL and MWT of rats in the CCI group were significantly decreased on each post-operative day (P<0.01), which reached a nadir on the 3rd day after CCI, and the expressions of NF-κ B p65 and CX3CR1 were markedly increased in spinal cord dorsal horn and DRG. In the Cur group, the TWL of rats were significantly increased than those in the CCI group on post-operative day 7, 10 and 14 (P<0.05) and MWT increased than those in the CCI group on post-operative day 10 and 14 (P<0.05). In addition, the administration of curcumin significantly decreased the positive expressions of NF-κ B p65 and CX3CR1 in spinal cord and DRG (P<0.05).</p><p><b>CONCLUSION</b>Our study suggests that curcumin could ameliorate the CCI-induced neuropathic pain, probably through inhibiting CX3CR1 expression by the activation of NF-κ B p65 in spinal cord and DRG.</p>

Thymic stromal lmphopoietin pomotes macrophage-derived foam cell formation / 华中科技大学学报（医学）（英德文版）

The effect of thymic stromal lymphopoietin (TSLP) on macrophage-derived foam cell formation and the underlying mechanism were studied. Macrophages isolated from C57BL/6 mice were co-cultured in vitro with different concentrations of TSLP or TSLPR-antibody in the presence of oxidized low density lipoprotein (ox-LDL). The effects of TSLP on macrophage-derived foam cell formation were observed by using oil red O staining and intracellular lipid determination. The expression levels of foam cell scavenger receptors (CD36 and SRA) as well as ABCA1 and TSLPR were detected by using RT-PCR and Western blotting. As compared with the control group, TSLP treatment significantly promoted lipid accumulation in macrophages, significantly increased protein expression of CD36 and TSLPR in a dose-dependent manner, and significantly reduced the expression of ABCA1 protein in a dose-dependent manner. No significant differences were noted between the TSLPR-antibody group and the control group. TSLP may down-regulate the expression of cholesterol efflux receptor ABCA1 and up-regulate scavenger receptor expression via the TSLPR signaling pathway, thereby promoting macrophage-derived foam cell formation.

The Potential Role of Monocyte Chemoattractant Protein-1 for Major Depressive Disorder

The immune hypothesis of major depressive disorder (MDD) fits well with the supposed interaction between genetic and environmental factors in disorders with a complicated etiopathogenesis. It has been suggested that infectious diseases are associated with MDD in that cytokines may play a critical role as a key modulator in the transition between infection and the development of MDD. It has been also suggested that antidepressants have immunomodulatory effects on some cytokines and cytokine receptors, although the exact mechanism has not yet been fully elucidated. Among cytokines, monocyte chemoattractant protein-1 (MCP-1) is especially well known and has attracted considerable interest owing to its immunomodulatory functions. MCP-1 is expressed in highly regionalized neuronal areas in the brain, leading to kind of modulation of neuronal activity and neuroendocrine functions commonly seen in patients with MDD. Additionally, it is involved in the control of other cytokines that have been consistently proposed as associated with the development of MDD. It also has a possible role in the neurodegenerative process of a number of central nervous system (CNS) diseases. Hence, this paper draws from the perspective of immunology to offer several suggestions about the role of MPC-1 in the development of MDD.

The Potential Role of Monocyte Chemoattractant Protein-1 for Major Depressive Disorder

The immune hypothesis of major depressive disorder (MDD) fits well with the supposed interaction between genetic and environmental factors in disorders with a complicated etiopathogenesis. It has been suggested that infectious diseases are associated with MDD in that cytokines may play a critical role as a key modulator in the transition between infection and the development of MDD. It has been also suggested that antidepressants have immunomodulatory effects on some cytokines and cytokine receptors, although the exact mechanism has not yet been fully elucidated. Among cytokines, monocyte chemoattractant protein-1 (MCP-1) is especially well known and has attracted considerable interest owing to its immunomodulatory functions. MCP-1 is expressed in highly regionalized neuronal areas in the brain, leading to kind of modulation of neuronal activity and neuroendocrine functions commonly seen in patients with MDD. Additionally, it is involved in the control of other cytokines that have been consistently proposed as associated with the development of MDD. It also has a possible role in the neurodegenerative process of a number of central nervous system (CNS) diseases. Hence, this paper draws from the perspective of immunology to offer several suggestions about the role of MPC-1 in the development of MDD.

Immune Response and the Tumor Microenvironment: How They Communicate to Regulate Gastric Cancer

Gastric cancer is the second most common cause of cancer-related death in the world. A growing body of evidence indicates that inflammation is closely associated with the initiation, progression, and metastasis of many tumors, including those of gastric cancer. In addition, approximately 60% of the world's population is colonized by Helicobacter pylori, which accounts for more than 50% of gastric cancers. While the role of inflammation in intestinal and colonic cancers is relatively well defined, its role in stomach neoplasia is still unclear because of the limited access of pathogens to the acidic environment and the technical difficulties isolating and characterizing immune cells in the stomach, especially in animal models. In this review, we will provide recent updates addressing how inflammation is involved in gastric malignancies, and what immune characteristics regulate the pathogenesis of stomach cancer. Also, we will discuss potential therapeutics that target the immune system for the efficient treatment of gastric cancer.

Esquistossomose mansônica humana: avaliação do receptor antagonista de IL-13 (IL-13Ra2) e da resposta imune celular / Human schistosomiasis: evaluation of receptor antagonist IL-13 (IL-13ra2) and cellular immune responses

Estudos indicam que citocinas Th1 (IL-2, TNF-alfa e IFN-gama) reduzem a fibrose na esquistossomose mansônica, enquanto que as Th2 (IL-4, IL-5, IL-6, IL-10 e IL-13) tem papel crítico na patogênese da doença. O desenvolvimento da resposta Th2 é dependente de IL-4, mas estudos revelaram a IL-13 como a mediadora da fibrose. Os mecanismos de controle da IL-13 estão ligados aos receptores desta citocina. O receptor IL-13Ra2, conhecida como receptor antagonista se liga com alta afinidade a IL-13, e estudos identificaram a sua participação na diminuição da fibrose e tamanho do granuloma. O principal objetivo desse projeto é avaliar o papel do IL-13Ra2 e da resposta imune celular nos diferentes graus de fibrose hepática e nas formas clínicas da esquistossomose mansônica humana. Os pacientes com diversas formas clínicas foram selecionados no Ambulatório de Gastroenterologia do HC- UFPE e avaliados através da ultrassonografia. As citocinas Th1 e Th2 foram dosadas através de citometria de fluxo e ELISA (IL-13 e IFN-gama), para a análise estatística foram utilizados testes de Mann-Whitney e Kruskal-Wallis e o teste de correlação de Spearman considerando um p 0,05 como significativo. Foi encontrado uma correlação negativa (p 0,05) entre o IL-13Ra2 e a IL-13, sugerindo um aumento da citocina no início da fibrose. Foi encontrada correlação inicialmente negativa nos pacientes sem fibrose e posteriormente positiva, nos pacientes com fibrose grave, entre IFN-gama e IL-13, salientando um novo mecanismo de regulação no processo de fibrose periportal na doença. Houve correlação positiva entre as citocinas do perfil Th1 e entre as citocinas do perfil Th2, sugerindo falta de supressão imunológica e presença de ambas às respostas, regulando a doença, com diferentes graus de fibrose periportal. Os resultados contribuirão para um melhor entendimento sobre os mecanismos imunes que controlam o processo de fibrogênese hepática em humanos e poderão ainda permitir um melhor entendimento da relação entre resposta imune celular e esquistossomose mansônica.

Consideraciones sobre la evolución de la respuesta inmunitaria Th2 y sus posibles relaciones con parasitosis y alergia / The evolution of the Th2 immune responses and its relationships with parasitic diseases and allergy

Hay diversos vínculos entre las parasitosis, especialmente las helmintiasis, y las enfermedades alérgicas, ambas condiciones de importancia epidemiológica en las regiones tropicales. Mientras que se ha especulado con frecuencia los efectos de las enfermedades parasitarias sobre la evolución del sistema inmunitario, no se conocen las fuerzas selectivas que han moldeado la respuesta alérgica y pensamos que incluyen mecanismos evolutivos distintos a los tradicionalmente divulgados. Los helmintos, fuente infecciosa y antigénica inductora de una respuesta parecida a la alérgica, se establecieron como parásitos en huéspedes que ya tenían grupos celulares de inmunidad de tipo 2. Hoy sabemos que un componente esencial en la relación de parasitismo entre los helmintos y sus huéspedes es la inmunosupresión que los primeros inducen, al crear una especie de equilibrio que permite la supervivencia de ambos. El desarrollo de este equilibrio debió incluir adaptaciones de ambos organismos y la supervivencia del parásito podría ser el resultado de la adquisición de mecanismos supresores de la respuesta defensiva, la selección de los huéspedes con menor intensidad de la respuesta de tipo 2, o ambas. Esto, a su vez, sugiere que aunque las infecciones helmínticas hayan influido en la conformación de la inmunidad de tipo 2, no han sido una fuerza selectiva importante en el caso particular de la respuesta alérgica que, a su vez, está más ligada a una exagerada respuesta Th2/IgE.

A variety of links occur between parasites, particularly helminths, and allergic diseases--both common conditions of epidemiological importance in tropical regions. Although speculations are often made about the effects of parasitic diseases on the evolution of the immune system, the selective forces that have shaped the allergic response are unknown and probably include evolutionary mechanisms different to those traditionally reported. Helminths, infectious and antigenic sources that induce allergic-like responses, established themselves as parasites in organisms that already had cell groups related to the type 2 immunity. An essential component in the relationship between helminths and their hosts is that the former induce immunosuppression, creating a kind of balance that allows the survival of both. The development of this equilibrium undoubtedly includes adaptations in both organisms, and the survival of the parasite is the result of (a) acquiring immune suppressor mechanisms and (b) finding hosts with lower intensity of the type 2 response. This in turn suggests that although helminth infections have influenced the formation of type 2 immunity, they have not been an important selective force in the particular case of allergic response. The latter is more related to an exaggerated Th2/IgE response.

Novel Drugs for Asthma Treatment: Immunomodulatory Therapy / 대한내과학회지

The management of asthma focuses on the reduction of airway inflammation accompany with symptomatic care after recognition. Glucocorticosteroid is the most important drug to reduce airway inflammation, and it has been used inhaled, orally and systemically. New knowledge about the pathogenesis of allergy and asthma has made the development and clinical trial of target or immunomodulator therapy. It includes cytokine, cytokine blockers, specific cytokine receptor blocker, and immunostimulatory oligodeoxynucleotides. These agents are thought to hold the promise for more beneficial outcomes in the future, although it showed limited therapeutic benefits only for patients, especially intractable or severe asthma, until now.

ANKRD7 and CYTL1 are novel risk genes for alcohol drinking behavior / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Alcohol dependence (AD) is a complex disorder characterized by impaired control over drinking. It is determined by both genetic and environmental factors. The recent approach of genome-wide association study (GWAS) is a powerful tool for identifying complex disease-associated susceptibility alleles, however, a few GWASs have been conducted for AD, and their results are largely inconsistent. The present study aimed to screen the loci associated with alcohol-related phenotypes using GWAS technology.</p><p><b>METHODS</b>A genome-wide association study with the behavior of regular alcohol drinking and alcohol consumption was performed to identify susceptibility genes associated with AD, using the Affymetrix 500K SNP array in an initial sample consisting of 904 unrelated Caucasian subjects. Then, the initial results in GWAS were replicated in three independent samples: 1972 Caucasians in 593 nuclear families, 761 unrelated Caucasian subjects, and 2955 unrelated Chinese Hans.</p><p><b>RESULTS</b>Several genes were associated with the alcohol-related phenotypes at the genome-wide significance level, with the ankyrin repeat domain 7 gene (ANKRD7) showing the strongest statistical evidence for regular alcohol drinking and suggestive statistical evidence for alcohol consumption. In addition, certain haplotypes within the ANKRD7 and cytokine-like1 (CYTL1) genes were significantly associated with regular drinking behavior, such as one ANKRD7 block composed of the SNPs rs6466686-rs4295599-rs12531086 (P = 6.51 × 10(-8)). The association of alcohol consumption was successfully replicated with rs4295599 in ANKRD7 gene in independent Caucasian nuclear families and independent unrelated Chinese Hans, and with rs16836497 in CYTL1 gene in independent unrelated Caucasians. Meta-analyses based on both the GWAS and replication samples further supported the observed significant associations between the ANKRD7 or CYTL1 gene and alcohol consumption.</p><p><b>CONCLUSION</b>The evidence suggests that ANKRD7 and CYTL1 genes may play an important role in the variance in AD risk.</p>