High level of C3 is associated with Th2 immune response and liver fibrosis in patients with schistosomiasis.

Long-term infection of schistosomiasis will seriously affect the liver health of patients. The serum of 334 chronic Schistosoma japonicum patients and 149 healthy volunteers was collected. Compared with heathy people, the level of C4 (complement 4) was increased, and the level of C3 (complement 3) was in an obvious skewed distribution. ELISA was performed to detect the serum cytokines, the results showed that the levels of IFN-γ (interferon-γ), IL (interleukin)-2 and TNF-α (tumour necrosis factor-α) were reduced, while the levels of Th2 cytokines (IL-4, IL-6 and IL-10) were increased. In the serum of patients with high C3, the secretion of HA (hyaluronic acid), LN (laminin), IV-C (type IV collagen) and PCIII (type III procollagen) were increased, the activation of hepatic stellate cells was promoted. Exogenous human recombinant C3 made mice liver structure of the mice damaged and collagen deposition. IFN-γ and IFN-γ/IL-4 were decreased, while HA, LN, PCIII and IV-C were increased, and the expressions of α-SMA and TGF-ß1 in liver tissues were up-regulated. However, the addition of IFN-γ partially reversed the effect of C3 on promoting fibrosis. High level of C3 is associated with Th2 immune response and liver fibrosis in patients with schistosomiasis.

The regulation of TRPA1 expression and function by Th1 and Th2-type inflammation in human A549 lung epithelial cells.

BACKGROUND: Transient Receptor Potential Ankyrin 1 (TRPA1) is a cation channel that mediates pain, itch, cough, and neurogenic inflammation in response to pungent compounds such as acrolein in cigarette smoke. TRPA1 is also activated by endogenous factors and promotes inflammation in asthma models. We have recently shown that TRPA1 is upregulated by inflammatory cytokines in A549 human lung epithelial cells. Here, we explored the effects of Th1 and Th2-type inflammation on TRPA1. METHODS AND RESULTS: TRPA1 expression and function was studied in A549 human lung epithelial cells. To induce inflammation, the cells were exposed to a combination of cytokines TNF-α and IL-1ß; and to model Th1 or Th2-type responses, IFN-γ or IL-4/IL-13 was added, respectively. TRPA1 expression (measured by RT-PCR and Western blot) and function (assessed by Fluo-3AM intracellular calcium measurement) was enhanced under the influence of TNF-α + IL-1ß. IFN-γ further enhanced TRPA1 expression and function, whereas IL-4 and IL-13 suppressed them. The effects of IFN-γ and IL-4 on TRPA1 expression were reversed by the Janus kinase (JAK) inhibitors baricitinib and tofacitinib, and those of IL-4 also by the STAT6 inhibitor AS1517499. The glucocorticoid dexamethasone downregulated TRPA1 expression, whereas the PDE4 inhibitor rolipram had no effect. Under all conditions, TRPA1 blockade was found to reduce the production of LCN2 and CXCL6. CONCLUSIONS: TRPA1 expression and function in lung epithelial cells was upregulated under inflammatory conditions. IFN-γ further increased TRPA1 expression while IL-4 and IL-13 suppressed that in a JAK-STAT6 dependent manner which is novel. TRPA1 also modulated the expression of genes relevant to innate immunity and lung disease. We propose that the paradigm of Th1 and Th2 inflammation is a major determinant of TRPA1 expression and function, which should be considered when targeting TRPA1 for pharmacotherapy in inflammatory (lung) disease.

Identification of the prognostic value of Th1/Th2 ratio and a novel prognostic signature in basal-like breast cancer.

BACKGROUND: Breast cancer is a heterogeneous group of diseases. The polarization of CD4+ T helper (Th) lymphocytes (mainly Th1 and Th2) may differ in breast cancers with different outcomes, but this has not been fully validated. METHODS: This study is a bioinformatic analysis, in which differentially expressed genes (DEGs) were identified in patients with low and high Th1/Th2 ratios. And then, DEG functions, hub genes and independent predictors were determined. RESULTS: Low Th1/Th2 ratio was associated with poor outcome in Luminal A and basal-like breast cancer (p < 0.05). GSEA and KEGG analysis of DEGs obtained from comparing low and high Th1/Th2 ratios illuminated downregulation of immune-related gene sets and pathways affecting Th1/Th2 balance toward Th2 polarization (p < 0.05). Survival and Cox analyses of all the DEGs confirmed CCL1 and MYH6 were independent protective factors and IFNK and SOAT2 were independent risk factors for basal-like breast cancer (95%CI: 1.06-2.5, p = 0.026). Then a four-gene signature was constructed and achieved a promising prognostic value (C-index = 0.82; AUC = 0.826). CONCLUSIONS: Low Th1/Th2 ratio predicts poor outcome in Luminal A and Basal-like breast cancer, and downregulation of immune-related gene sets and pathways contribute to Th1/Th2 balance toward Th2 polarization. CCL1, MYH6, IFNK, and SOAT2 have an independent prognostic value of survival outcome and might be novel markers in basal-like breast cancer.

Morphea after initiation of dupilumab in two pediatric atopic dermatitis patients.

Morphea is a rare multifactorial autoimmune disorder characterized by a complex and dynamic interplay between Th1 and Th2 signaling. Active clinical trials are currently investigating the safety and efficacy of dupilumab for the treatment of primary morphea. Here, we present two cases of morphea that developed in pediatric atopic dermatitis patients treated with dupilumab. These findings may support a causal relationship between IL-4 receptor blockade and the development of the early inflammatory phase of morphea.

Differential Roles of Cystathionine Gamma-Lyase and Mercaptopyruvate Sulfurtransferase in Hapten-Induced Colitis and Contact Dermatitis in Mice.

Hydrogen sulfide (H2S) has been shown to act as both anti-inflammatory and pro-inflammatory mediators. Application of H2S donors generally protects against inflammation; however, experimental results using mice lacking endogenous H2S-producing enzymes, such as cystathionine γ-lyase (CTH) and mercaptopyruvate sulfurtransferase (MPST), are often contradictory. We herein examined two types of model hapten-induced inflammation models, colitis (an inflammatory bowel disease model of mucosal immunity) and contact dermatitis (a type IV allergic model of systemic immunity), in CTH-deficient (Cth-/-) and MPST-deficient (Mpst-/-) mice. Both mice exhibited no significant alteration from wild-type mice in trinitrobenzene sulfonic acid (Th1-type hapten)-induced colitis (a Crohn's disease model) and oxazolone (Th1/Th2 mix-type; Th2 dominant)-induced colitis (an ulcerative colitis model). However, Cth-/- (not Mpst-/-) mice displayed more exacerbated phenotypes in trinitrochlorobenzene (TNCB; Th1-type)-induced contact dermatitis, but not oxazolone, at the delayed phase (24 h post-administration) of inflammation. CTH mRNA expression was upregulated in the TNCB-treated ears of both wild-type and Mpst-/- mice. Although mRNA expression of pro-inflammatory cytokines (IL-1ß and IL-6) was upregulated in both early (2 h) and delayed phases of TNCB-triggered dermatitis in all genotypes, that of Th2 (IL-4) and Treg cytokines (IL-10) was upregulated only in Cth-/- mice, when that of Th1 cytokines (IFNγ and IL-2) was upregulated in wild-type and Mpst-/- mice at the delayed phase. These results suggest that (upregulated) CTH or H2S produced by it helps maintain Th1/Th2 balance to protect against contact dermatitis.

Oral administration of Lactiplantibacillus plantarum NR16 isolated from Kimchi ameliorates murine allergic rhinitis.

Allergic rhinitis (AR) is a type I hypersensitivity mediated by dominant T helper 2 (Th2) response over the Th1 response after re-exposure to a specific allergen. Currently, socio-economic cost evoked by AR is quickly increasing since the prevalence of AR is gradually increasing in all ages worldwide. Several probiotic Lactobacillus strains have been described with potential immunomodulatory effects against type I hypersensitivity such as AR. Thus, the aim of the present work was to characterize basic probiotic property and immunomodulatory role of newly isolated Lactobacillus strains from Kimchi, a traditional fermented Korean food, in AR. Among the identified strains, Lactiplantibacillus plantarum NR16 revealed to be a powerful Th1 inducer since immune cells co-cultured with NR16 produced the highest quantity of interferon-γ (IFN-γ) and interleukin-12 (IL-12) but secreted a low amount of IL-4 in vitro. Therefore, NR16 was selected for the following assays conducted with mice with birch pollen-induced AR. Oral administration of NR16 reduced airway hyperresponsiveness and leukocyte infiltration in lesions of mice. In conclusion, oral administration of NR16 may mitigate symptoms of AR by inducing Th1 immune response, which might rebalance Th2/Th1 ratio by decreasing Th2 cytokine production in specific lesions of mucosa.

Astilbin improves pregnancy outcome in rats with recurrent spontaneous abortion by regulating Th1/Th2 balance.

OBJECTIVE: The purpose of this study was to investigate the effect of astilbin on pregnancy outcome in rats with recurrent spontaneous abortion (RSA). METHODS: A total of 40 pregnant female Sprague-Dawley rats were randomly divided into four groups: the control, model, astilbin, and prednisone groups. An RSA rat model was established by gavage with hydroxyurea and mifepristone. The number of surviving and reabsorbed embryos was counted on day 9 of gestation in each group. The rat serum was collected to detect the levels of IFN-γ, IL-2, IL-4, and IL-10 by enzyme-linked immunosorbent assay. The expressions of T-bet and GATA-3 in the decidual and placental tissues of the rats were determined by immunohistochemistry. RESULTS: The absorptivity of embryos was significantly higher in the model group than in the control group. The levels of serum IFN-γ and IL-2 were significantly lower in the astilbin group than in the model group, while the levels of serum IL-4 and IL-10 were significantly higher. Astilbin treatment significantly increased GATA-3 expression, while it significantly reduced T-bet expression and the T-bet/GATA-3 ratio. CONCLUSIONS: Astilbin has a therapeutic effect on RSA in rats by regulating the balance of Th1/Th2 in maternal circulation and likely in decidual tissue.

Artemisia gmelinii Extract Alleviates Allergic Airway Inflammation via Balancing TH1/TH2 Homeostasis and Inhibiting Mast Cell Degranulation.

A new terminology "combined allergic rhinitis and asthma syndrome (CARAS)" was introduced to describe patients suffering from both allergic rhinitis (AR) and asthma. The pathogenesis of allergic airway inflammation has been well known, with the main contribution of TH1/TH2 imbalance and mast cell degranulation. Artemisia gmelinii has been used as an herbal medicine with its hepaprotective, anti-inflammatory, and antioxidant properties. In this study, the effect of A. gmelinii extracts (AGE) on the ovalbumin (OVA)-induced CARAS mouse model was investigated. AGE administration significantly alleviated the nasal rubbing and sneezing, markedly down-regulated both OVA-specific IgE, IgG1, and histamine levels, and up-regulated OVA-specific IgG2a in serum. The altered histology of nasal and lung tissues of CARAS mice was effectively ameliorated by AGE. The AGE treatment group showed markedly increased levels of the TH1 cytokine interleukin (IL)-12 and TH1 transcription factor T-bet. In contrast, the levels of the TH2 cytokines, including IL-4, IL-5, IL-13, and the TH2 transcription factor GATA-3, were notably suppressed by AGE. Moreover, AGE effectively prevented mast cell degranulation in vitro and mast cell infiltration in lung tissues in vivo. Based on these results, we suggest that AGE could be a potential therapeutic agent in OVA-induced CARAS by virtue of its role in balancing the TH1/TH2 homeostasis and inhibiting the mast cell degranulation.

Selenium deficiency induced necroptosis, Th1/Th2 imbalance, and inflammatory responses in swine ileum.

Selenium (Se) deficiency has a significant impact on the swine breeding industry by inducing digestive system damage and diarrhea. However, the molecular mechanism remains unclear. Our objectives were to investigate if different amounts of necroptosis, inflammatory responses, and T helper cell 1/T helper cell 2 (Th1/Th2) imbalances were induced by Se deficiency in intestinal porcine jejunal epithelial cells (IPEC-J2) and swine ileum tissue. Therefore, Se-deficient models were successfully established both in vitro and in vivo. In the current study, the cell morphological observation results showed that Se deficiency seriously affected the growth and differentiation of IPEC-J2 cells. Moreover, the necroptosis staining and histomorphology observation results showed that the number of necroptotic cells increased significantly, and the ileal tissue exhibited abnormal structures, including necroptotic features and inflammatory cell infiltration, in the Se-deficient group. Furthermore, Se deficiency resulted in accelerated cell necroptosis by increasing (p < .05) the expression of genes related to the tumor necrosis factor-α pathway at both the protein and messenger RNA (mRNA) levels compared to the control group. Moreover, the relative mRNA and protein expression of the inflammatory genes and their responses to dietary Se deficiency were consistent with the resultant Th1/Th2 imbalances in vitro and in vivo. Taken together, the results suggested that Se deficiency caused necroptosis, inflammatory responses, and abnormal expression of cytokines in swine ileum tissue. These findings might help us to explain the damage induced by Se deficiency to the digestive system of swine.

Insights into adult atopic dermatitis heterogeneity derived from circulating biomarker profiling in patients with moderate-to-severe disease.

Atopic dermatitis (AD) is a heterogeneous systemic inflammatory skin disease associated with dysregulated immune responses, barrier dysfunction and activated sensory nerves. To characterize circulating inflammatory profiles and underlying systemic disease heterogeneity within AD patients, blood samples from adult patients (N = 123) with moderate-to-severe AD in a phase 2 study of baricitinib (JAHG) were analysed. Baseline levels of 131 markers were evaluated using high-throughput and ultrasensitive proteomic platforms, patient clusters were generated based on these peripheral markers. We implemented a novel cluster reproducibility method to validate cluster outcomes within our study and used publicly available AD biomarker data set (73 markers, N = 58 patients) to validate our findings. Cluster reproducibility analysis demonstrated best consistency for 2 clusters by k-means, reproducibility of this clustering outcome was validated in an independent patient cohort. These unique JAHG patient subgroups either possessed elevated pro-inflammatory mediators, notably TNFß, MCP-3 and IL-13, among a variety of immune responses (high inflammatory) or lower levels of inflammatory biomarkers (low inflammatory). The high inflammatory subgroup was associated with greater baseline disease severity, demonstrated by greater EASI, SCORAD Index, Itch NRS and DLQI scores, compared with low inflammatory subgroup. African-American patients were predominantly associated with the high inflammatory subgroup and increased baseline disease severity. In patients with moderate-to-severe AD, heterogeneity was identified by the detection of 2 disease subgroups, differential clustering amongst ethnic groups and elevated pro-inflammatory mediators extending beyond traditional polarized immune responses. Therapeutic strategies targeting multiple pro-inflammatory cytokines may be needed to address this heterogeneity.

Histopathologic and immunophenotypic features of cutaneous solid organ transplant-associated graft-vs-host disease: Comparison with acute hematopoietic cell transplant-associated graft-vs-host disease and cutaneous drug eruption.

BACKGROUND: Although it is relatively common after hematopoietic cell transplant (HCT), graft-vs-host disease (GVHD) is a rare complication following solid organ transplantation (SOT). METHODS: This study evaluated skin biopsy specimens from five cases of SOT GVHD, 15 cases of HCT GVHD, and 15 cases of cutaneous drug eruption. Immunohistochemical staining for CD3, CD4, CD8, T-bet, and GATA-3 was performed to examine the density and immune phenotype of skin-infiltrating lymphocytes. RESULTS: Similar to HCT GVHD, the predominant histopathologic findings in skin biopsy specimens of SOT GVHD were widespread vacuolar interface dermatitis with scattered necrotic keratinocytes. However, the density of dermal inflammation was considerably higher in SOT GVHD. Features that were more predictive of a cutaneous drug eruption over GVHD included spongiosis, confluent parakeratosis, and many eosinophils. Involvement of the hair follicle epithelium was seen in all three disorders. Both forms of cutaneous GVHD showed a predominance of Th1 (CD3+/T-bet+) lymphocytes within the inflammatory infiltrates. This shift was more pronounced in SOT GVHD, particularly among intraepidermal T-cells. CONCLUSIONS: SOT GVHD shares many histopathologic features with HCT GVHD. However, SOT GVHD has a greater tendency to develop brisk lichenoid inflammation.

CD4+CD25+ Tregs as dependent factor in the course of bleomycin-induced pulmonary fibrosis in mice.

The immune system is felt to play an essential role in pulmonary fibrosis (PF). CD4+CD25+ regulatory T cells (Tregs) are crucial in maintaining immune tolerance and immune homeostasis, but their role in the pathogenesis of PF is controversial and still unclear. We here explored the relationship between peripheral blood CD4+CD25+ Tregs and the course of bleomycin-induced PF in mice. Mouse PF models were established by intratracheal instillation of bleomycin. Lung histology, hydroxyproline, Th1/Th2 balanc, CD4+CD25+ Tregse were analyzed at the 3rd，7th，14th，21st and 28th days after instillation. CD4+CD25+ Tregs were also transferred into mice with or without PF by tail vein injection. The trend of CD4+CD25+ Tregs changes was increased firstly, decreased, increased again from 7th to 28th days after bleomycin instillation, which had great relevance with alveolitis and fibrosis scores. There also were high Th1 polarization index from 3rd to 14th days and high Th2 polarization index at 21st and 28th days after bleomycin treatment. CD4+CD25+ Tregs could promote the secretion of Th2 cytokines and inhibit the secretion of Th1 cytokines, allow the Th1/Th2 balance to Th2 direction in PF. Moreover, preventive adoptive transfer of CD4+CD25+ Tregs may ameliorate the process of PF, while acute adoptive transfer of CD4+CD25+ Tregs may aggravate the process of PF. These findings suggested that the dynamic changes of CD4+CD25+ Tregs as dependent factor might designate a different course of PF induced by bleomycin in mice, and might be a selected drug use indicator for therapy of PF.

Effect of ligustrazine nanoparticles on Th1/Th2 balance by TLR4/MyD88/NF-κB pathway in rats with postoperative peritoneal adhesion.

BACKGROUND: Postoperative peritoneal adhesion (PPA) is regarded as fibrous bands connecting both injured abdominal wall and organs or adjacent tissues. It is associated with T helper (Th)1 and Th2 differentiation. However, the critical role of the immunopathogenesis of adhesion formation was precisely unknown. The aim of this study was to investigate the effect of a new agent polylactic acid (PLA) nanoparticles loaded with ligustrazine, that is, ligustrazine nanoparticles (LN) on PPA and identify the potential mechanism. METHODS: Twenty-four Sprague-Dawley rats were randomly divided into the sham, model, LN, and sodium hyaluronate (SH) groups. The structure of LN, including entrapment efficiency (EE) and loading capacity (LC), and in vitro drug release were calculated. Adhesions were scored and the Masson's trichrome staining was used to determine the collagen deposition. The expressions of TLR4, MyD88, and NF-κB were measured by qRT-PCR, immunohistochemistry, and western blot assay. Moreover, Th1-related cytokines (IFN-γ, IL-12), Th2-related cytokines (IL-4, IL-6) in the cecum tissue and serum were conducted by ELISA. RESULTS: LN had good EE, LC, and control-release delivery characters with fairly uniform diameter and spherical morphology. It could effectively prevent adhesion formation after surgery. Besides, it could reduce collagen fibers accumulation, downregulate the expression levels of TLR4, MyD88, and NF-κB, and maintain Th1/Th2 balance. CONCLUSIONS: Ligustrazine nanoparticles had effective effects on Th1/Th2 balance by regulating TLR4/MyD88/NF-κB pathway in PPA rats. It may be served as a promising therapy on postoperative adhesion formation.

Regulatory effects of miR-138 and RUNX3 on Th1/Th2 balance in peripheral blood of children with cough variant asthma. / 咳嗽变异性哮喘患儿外周血miR-138及RUNX3对Th1/Th2平衡的调节作用.

OBJECTIVES: To study the expression levels of microRNA-138 (miR-138) and Runt-related transcription factor 3 (RUNX3) in peripheral blood of children with cough variant asthma (CVA) and their regulatory effects on Th1/Th2 balance. METHODS: Sixty-five children with CVA (CVA group) and 30 healthy children (control group) were enrolled. Peripheral venous blood samples were collected for both groups, and CD4+ T cells were isolated and cultured. Enzyme-linked immunosorbent assay was used to measure the levels of interferon (IFN)-γ, interleukin (IL)-2, IL-4, IL-5, and IL-13 that were secreted by CD4+ T cells. Flow cytometry was used to determine the percentages of Th1 and Th2 cells. Quantitative real-time PCR was used to measure the level of RUNX3 mRNA in CD4+ T cells and the level of miR-138 in peripheral blood. Western blot was used to determine the protein expression of RUNX3 in CD4+ T cells. The dual-luciferase reporter assay was used to determine the targeting effects of miR-138 and RUNX3. The RUNX3-mimic plasmid was transfected into CD4+ T cells, and the effects on the levels of IFN-γ, IL-2, IL-4, IL-5, and IL-13 and the percentages of Th1 and Th2 cells were measured. RESULTS: Compared with the control group, the CVA group showed significantly decreased levels of IFN-γ and IL-2 from CD4+ T cells, significantly increased levels of IL-4, IL-5, and IL-13 from CD4+ T cells, significantly decreased Th1 cell percentage and Th1/Th2 ratio, and a significantly increased Th2 cell percentage (P<0.05). The CVA group showed significantly lower relative expression levels of RUNX3 mRNA and protein in CD4+ T cells in peripheral blood than the control group (P<0.001). The relative expression level of miR-138 was significantly higher in the CVA group than in the control group (P<0.001). MiR-138 could target the expression of RUNX3. Upregulating the expression of RUNX3 in CD4+ T cells induced significantly increased levels of IFN-γ and IL-2, significantly decreased levels of IL-4, IL-5, and IL-13, significantly increased Th1 cell percentage and Th1/Th2 ratio, and a significantly decreased Th2 cell percentage (P<0.05). CONCLUSIONS: MiR-138 regulates Th1/Th2 balance by targeting RUNX3 in children with CVA, providing a new direction for the treatment of CVA.

Invariant natural killer T cells stimulated with cholesteryl glycosides modulate immune responses in allergy and delayed-type hypersensitivity.

Invariant NKT cells were stimulated with cholesteryl O-acyl α-glycosides in the context of CD1d. The activated NKT cells have potential to sustain the homeostasis in the body exposed to excess in either Th1- or Th2-immunity.

Rosuvastatin suppresses cytokine production and lung inflammation in asthmatic, hyperlipidemic and asthmatic-hyperlipidemic rat models.

BACKGROUND: Given the role that T lymphocytes play on the pathogenesis of allergic asthma, drugs targeting Th2 and Th17 cells may be a hopeful therapeutic strategy. This study aimed to evaluate the effect of rosuvastatin treatment on cytokine production and lung inflammation in allergic asthma. METHODS: The animals were assigned into control (C), asthmatic (A), hyperlipidemic (H), asthmatic-hyperlipidemic (AH), rosuvastatin (40 mg/kg/day intraperitoneally, for 3 weeks)-treated asthmatic (AR), rosuvastatin-treated hyperlipidemic (HR) and rosuvastatin-treated asthmatic-hyperlipidemic (AHR) groups (n = 6 in each group). The levels of IL-4, IFN-γ and IL-17, total and differential WBC counts in bronchoalveolar lavage fluid (BALF), Th1/Th2 balance, and pathological changes were evaluated. RESULTS: The BALF level of IL-4 in A, H and AH groups, and IL-17A in A and AH groups were significantly higher than that in C group (p < 0.05 to p < 0.001). IFN-γ level and Th1/Th2 balance (IFN­Î³/IL-4 ratio) in A and AH groups were significantly decreased (p < 0.05 to p < 0.01). Inflammatory cells infiltration, muscle hypertrophy and emphysema were also observed in A and AH groups. The BALF levels of IL-4 in AR, HR and AHR groups, IFN-γ level in HR group, and IL-17A level in AR and AHR groups showed a significant improvement compared to that of A, H and AH groups (p < 0.05 to p < 0.001). Rosuvastatin treatment increased Th1/Th2 balance in all treated groups (p < 0.05 to p < 0.01), decreased total WBC counts, neutrophilia, eosinophilia and lung inflammation in AR and AHR groups, and improved muscle hypertrophy and emphysema in AHR group. CONCLUSIONS: Rosuvastatin treatment improved lung pathological changes by suppression of Th2 and Th17-mediated cytokines which was unrelated to its lipid-lowering activity. Therefore, rosuvastatin might be a candidate immunomodulatory drug for treatment of patients with allergic asthma.

The neuroprotective effect of Riparin IV on oxidative stress and neuroinflammation related to chronic stress-induced cognitive impairment.

BACKGROUND: Cognitive impairment is identified as one of the diagnostic criteria for major depressive disorder and can extensively affect the quality of life of patients. Based on these findings, this study aimed to investigate the possible effects of Riparin IV (Rip IV) on cognitive impairment induced by chronic administration of corticosterone in mice. METHODS: Female Swiss mice were divided into four groups: control (Control), corticosterone (Cort), Riparin IV (Cort + Rip IV), and Fluvoxamine (Cort + Flu). Three groups were administered corticosterone (20 mg/kg) subcutaneously during the 22-day study, while the control group received only vehicle. After the 14th day, the groups were administered medications: Riparin IV (Rip IV), fluvoxamine (Flu), or distilled water, by gavage, 1 h after the subcutaneous injections. After treatment, mice underwent behavioral testing, and brain areas were removed for oxidative stress and cytokine content assays. RESULTS: The results revealed that Cort-treated mice developed a cognitive impairment and exhibited a neuroinflammatory profile with an oxidative load and Th1/Th2 cytokine imbalance. Rip IV treatment significantly ameliorated the cognitive deficit induced by Cort and displayed a neuroprotective effect. CONCLUSION: The antidepressant-like ability of Rip IV treatment against chronic Cort-induced stress may be due to its potential to mitigate inflammatory damage and oxidative stress. The antioxidant and anti-inflammatory effect observed indicates Rip IV as a possible drug for antidepressant treatment of non-responsive patients with severe and cognitive symptoms.

Dicrocoelium ova can block the induction phase of experimental autoimmune encephalomyelitis.

AIMS: This study aimed at investigating the impact of Dicrocoelium ova on experimental autoimmune encephalomyelitis (EAE) treatment in C57BL6 mice. METHODS AND RESULTS: Twenty-eight C57BL/6 mice were assigned into four groups as PBS, prophylaxis (P), treatment1 (T1) and treatment2 (T2). Prior to induction of EAE in prophylaxis group and on days 7 and 18 in T1 and T2 groups, respectively, Dicrocoelium eggs were injected intraperitoneally to each mouse. The clinical score, weight changes and incidence time of EAE were recorded. IFN-γ and IL-4 expression is quantified on spleen cells. Also, histopathological study by (H&E) and Toluidine-Blue (TB), and Luxol Fast Blue (LFB) were performed. The data were analysed using SPSS version 21. Mean disease scores were significantly lower in P and T1 groups than the PBS group (P = .01). IFN-γ was lower in P and T1 groups than the PBS group. The highest level of IL-4 was observed in T1 group. The total number of neuroglia cells of corpus callosum was similar in all groups, but the density increased in T1 group compared to the PBS group (P = .03). CONCLUSIONS: Dicrocoelium eggs have a great potential to stimulate immunomodulation towards treatment of EAE during the initial phase.

Dendritic Cells Therapy with Cytokine-Induced Killer Cells and Activated Cytotoxic T Cells Attenuated Th2 Bias Immune Response.

THE AIM OF THIS STUDY: The purpose of this study is to investigate whether the DC cells combined with CIK cells (DC/CIK) and DC activated cytotoxic T cells (DC-ACT) treatment can promote antitumor response and change the immune indicators by targeting the heterogeneous tumor cell populations at a system level. METHODS: In this study, 112 patients with cancer were assigned to the DC/CIK treatment and 116 patients received the DC-ACT therapy. We detected the lymphocyte subsets and other immune indicators pre- and post-treatment to evaluate the changes of patient's immunity and compare the differences in immune status between two adoptive cellular immunotherapies. RESULTS: DC/CIK therapy elevated the percentage of CD3+ HLA-DR+ T cells, NK cells and several serological cytokines such as IL-2, IL-6 after cell infusion (p < .05). DC-ACT therapy could increase the total CD3 + T cells, CD8 + T cells, CD3+ HLA-DR+ cells and IL-12 cytokines after cell infusion (p < .05). The levels of IL-4/IFN-γ, IL-4/IL-12 and IL-6/IL-12 were reduced significantly in the DC-ACT group compared with DC/CIK group. These observations suggested that DC-ACT therapy has more dominance to induce Th1 cytokine response instead of skewing toward the Th2 cytokine profile based on the immunomodulatory properties. CONCLUSIONS: These results indicated that DC, CIK, and DC-ACT cells exert anti-tumor activity through the different pathways. Thus, this work may provide valuable insights into the clinical curative effect evaluation of immunocyte therapy and the design of combined immunotherapeutic strategies for malignant tumors.

Interleukin-13 ameliorates postischemic hepatic gluconeogenesis and hyperglycemia in rat model of stroke.

Hyperglycemia is a well-known indicator of stroke prognosis, and one-third of nondiabetic patients develop postischemic hyperglycemia during the acute phase of stroke; this is related to relatively poor prognosis, high mortality, and impaired neurological recovery. Interleukin-13 (IL-13), a member of the Th2 cytokine family, is involved in both the regulation of immune response and glucose metabolism. Thus, we investigated the mechanism of postischemic hyperglycemia and the role of IL-13 by using a permanent middle cerebral artery occlusion (MCAO) rat model. Our results indicated that postischemic hyperglycemia was accompanied with hyperinsulinemia and increased HOMA-IR, elevated hepatic gluconeogenesis, and suppressed insulin signaling. A shift towards inflammatory response was evident with results of elevated proinflammatory cytokines and increased expression of negative regulatory proteins, suggesting an ongoing vicious cycle of inflammatory-induced insulin-resistant hyperglycemia. IL-13 treatment counteracted the proinflammatory states and abolished the vicious cycle through enhancing STAT6 and STAT3, which mediated the immune and metabolic pathways respectively; these effects resolved the formerly described pathological changes of postischemic hyperglycemia and reduced infarction size in the MCAO rats. Our findings demonstrated the importance of Th1-Th2 balance in the peripheral glucose metabolism affected by acute ischemic stroke, which provides a new perspective for the prevention and control of postischemic hyperglycemia.