[Progress on relationship between IL-23/IL-17 axis and inflammatory bowel disease].

Chronic inflammatory damage of intestinal mucosa is an important characteristic of inflammatory bowel disease (IBD). Studies have shown that the interleukin 23 (IL-23)/IL-17 axis is involved in intestinal mucosal inflammatory injury and plays a crucial role in the development and prognosis of IBD. IL-23 is one of the upstream molecules of IL-17, which can promote Th17 cell activation, proliferation and the secretion of inflammatory cytokines. Moreover, IL-23 is involved in the inflammatory response process of various immune cells such as neutrophils, macrophages, regulatory T cells (Tregs), the group 3 innate lymphocytes (ILC3) during IBD. Previous studies demonstrated that IL-23 and IL-17 increased in IBD, which lead to an imbalance between Tregs and auto-reactive T cells to exacerbate the inflammatory pathological damage of the intestinal mucosa. Notably, although IL-23/IL-17 is potential therapeutic target for inflammation-related diseases and anti-IL-23 strategies has proven to be effective in treating IBD, the strategy of blocking IL-17 to treat IBD has failed. Therefore, a deep understanding of the relationship between IL-17/IL-23 axis and IBD is necessary for the study of IBD treatment.

CD226 Attenuates Treg Proliferation via Akt and Erk Signaling in an EAE Model.

Cluster of differentiation 226 (CD226) molecules play a crucial role in the activation of effector CD4+ T cells during the immune response process, but a cell-intrinsic function of CD226 in CD4+ T subsets is not clear. In this study, we showed that Cd226-/- mice were resistant to myelin oligodendrocyte glycoprotein peptide 35-55 (MOG35-55)-induced experimental autoimmune encephalomyelitis (EAE) with highly expressed IL-10+CD4+ T cells and downregulated IL-17A+CD4+ T cells when compared with wild-type (WT) mice. Th17 cell infiltration into the central nervous system (CNS) was largely decreased in the absence of CD226 during EAE. CD226 deficiency facilitated the proliferation of regulatory T cells (Tregs), with increased numbers of Tregs observed in EAE mice, and supported the elevated induced regulatory T cell (iTregs) proliferation in vitro. The Akt and Erk signaling pathways were shown to be involved in Cd226-/- Treg proliferation and function in vivo and in vitro. These findings collectively indicate that CD226 is a key molecule regulating the Treg-mediated suppression of autoimmune responses by inhibiting Treg proliferation. Thus, the results of this study identify additional mechanisms by which CD226 regulates Treg functions in EAE and supports the potential therapeutic effects of anti-CD226 molecules on autoimmune diseases.

Shikonin inhibits proliferation and induces apoptosis in glioma cells via downregulation of CD147.

Shikonin, a traditional Chinese medicine, has been identified as being capable of inducing apoptosis in various tumors, including glioma, and is thus considered to be a promising therapeutic agent for tumor therapy. However, little is known about the molecular mechanism of shikonin in glioma. The present study investigated the influence of shikonin on the proliferation and apoptosis of glioma cells U251 and U87MG and explored the potential molecular mechanisms. It was identified that shikonin was able to induce apoptosis in human glioma cells in a time­ and dose­dependent manner, and a decreased expression level of cluster of differentiation (CD)147 was observed in shikonin­treated U251 and U87MG cells. Knockdown of CD147 inhibited U251 and U87MG cell growth, whereas CD147 overexpression enhanced cell growth and decreased shikonin­induced apoptosis. Additionally, an increased expression level of CD147 suppressed the elevated production of reactive oxygen species and mitochondrial membrane potential levels induced by shikonin. The data indicated that shikonin­induced apoptosis in glioma cells was associated with the downregulation of CD147 and the upregulation of oxidative stress. CD147 may be an optional target of shikonin­induced cell apoptosis in glioma cells.

Apple polysaccharide reduces NF-Kb mediated colitis-associated colon carcinogenesis.

Nuclear factor-kappa B (NF-κB) is an important molecule in mediating inflammatory colitis, which can lead to colorectal cancer (CRC). The aim of this study was to evaluate the chemopreventive efficacy of apple polysaccharide extract (AP) in inhibiting NF-κB-mediated inflammation pathways in CRC. We evaluated AP in vitro in HT-29 and SW620 human CRC cells. We also used the azoxymethane and dextran sodium sulphate (AOM/DSS) model to induce colon carcinogenesis in vivo. The chemoprotective effects of AP were assessed using Western blot, immunofluorescence assay, real-time PCR, electrophoretic mobility shift assay, and flow cytometry. AP reduced AOM/DSS-associated toxicities, prevented carcinogenesis, and decreased the expression of TLR4, MD2, MyD88, TRAM, TRIF-related adapter molecule, interferon-ß, tumor necrosis factor-α, and interleukin-6. The protective effects of AP may be related to the inhibition of TLR4/MD2-mediated signaling, including MyD88 and TRIF, as well as the inhibition of NF-κB-mediated inflammatory signaling pathways. Therefore, AP could be used in combination therapy for the prevention of colitis-associated colon cancer.

The PHLDB1 rs498872 (11q23.3) polymorphism and glioma risk: A meta-analysis.

The association between the rs498872 single nucleotide polymorphism (SNP) and glioma risk has been studied, but these studies have yielded conflicting results. In order to explore this association, we performed a meta-analysis. A comprehensive literature search was performed using PubMed and EMBASE database, with the last search up to August 23, 2013. Six articles including 10 case-control studies in English with 18 002 controls and 8434 cases were eligible for the meta-analysis. Subgroup analyses were conducted by source of controls and ethnicity. The combined results showed that rs498872 polymorphism was significantly associated with glioma risks (TT vs CC: OR = 1.337, 95% CI = 1.222-1.462; TC vs CC: OR = 1.173, 95% CI = 1.081-1.272; dominant model: OR = 1.199, 95% CI = 1.101-1.306; recessive model: OR = 1.237, 95% CI = 1.135-1.347; additive model: OR = 1.156, 95% CI = 1.085-1.232). Moreover, there was increased cancer risk in all genetic models after stratification of the SNP data by the source of controls and ethnicity, and no evidence of publication bias was produced. Our meta-analysis suggested that rs498872 polymorphism was associated with increased risk of glioma. However, additional studies exploring the combined effects of rs498872 polymorphisms in Asian population should be investigated.

PirB is a novel potential therapeutic target for enhancing axonal regeneration and synaptic plasticity following CNS injury in mammals.

A major barrier to axonal regeneration in mammals is the unfavorable extracellular environment that develops following injury to the central nervous system (CNS). In particular, three myelin-associated inhibitory proteins (MAIs) - Nogo, myelin-associated glycoprotein (MAG) and oligodendrocyte myelin glycoprotein (OMgp) - are known to inhibit axonal regeneration and functional recovery. These MAIs share a common receptor, glycosylphosphatidylinositol-anchored Nogo receptor (NgR). However, paired immunoglobulin-like receptor B (PirB) - which was originally identified as a receptor for class I major histocompatibility complex (MHCI) in the immune system - is also expressed in neurones and plays a similarly inhibitory role in axonal regeneration and synaptic plasticity following CNS injury through its association with MAIs. Importantly, suppression of PirB activity through antibody antagonism or genetic means can partially relieve the inhibition of neurite outgrowth in vitro and in vivo. In this review, we present the molecular features, expression patterns and known signaling pathways of PirB, and we specifically focus on putative roles for PirB in the CNS and its potential as a target of molecular therapies for enhancing axonal regeneration and synaptic plasticity following CNS injury.

Modified apple polysaccharides suppress the migration and invasion of colorectal cancer cells induced by lipopolysaccharide.

Metastasis is the major cause of death in colorectal cancer (CRC). In colitis-associated carcinogenesis, the activation of nuclear factor-κB (NF-κB) occurs via lipopolysaccharide (LPS) binding to the toll-like receptor 4 (TLR4). The LPS/TLR4/NF-κB pathway contributes to the development and metastasis of colitis-associated colon cancer. In the present study, we hypothesized that an extracted modified Fuji apple polysaccharide (MAP) would alter the LPS/TLR4/NF-κB pathway. Thus, we evaluated the effect of MAP in vitro on the LPS/TLR4/NF-κB pathway in CRC cells (HT-29 and SW620 cells). The results suggest that (i) MAP competed with LPS for binding to TLR4 to reduce LPS-induced NF-κB expression and (ii) MAP suppressed the nuclear translocation of NF-κB p65. MAP significantly decreased LPS-induced expression of TLR4, cyclooxygenase-2, matrix metallopeptidase 9 (MMP9), matrix metallopeptidase 2, inducible nitric oxide synthase, and prostaglandin E2, and it increased the protein expression of the inhibitor of κBα and NF-κB p65 in cytoplasm when it was given in combination with LPS. These results indicate that MAP suppressed LPS-induced migration and invasiveness of CRC cells by targeting the LPS/TLR4/NF-κB pathway. Therefore, we propose that MAP has potential for the clinical prevention of CRC cell metastasis.

Targeted delivery of neurogenin-2 protein in the treatment for cerebral ischemia-reperfusion injury.

Neurogenin-2 (Ngn2), as a proneural gene that promotes the survival and differentiation of neural precursor cells, is an attractive candidate for therapy against cerebral ischemia-reperfusion injury. However, the delivery approach limits its clinical application. To deliver Ngn2 protein into the cerebral ischemic region and exert a therapeutic effect on injured neurons after ischemia, we here reported that the fusion protein TAT-LBD-Ngn2 was constructed by fusing a transactivator of transcription (TAT) domain and a laminin-binding domain (LBD) to Ngn2. TAT-LBD-Ngn2 promoted the outgrowth of neuronal neurite, increased the survival rate and alleviated apoptosis of hippocampal neurons exposed to oxygen glucose deprivation in vitro. Furthermore, a focal cerebral ischemia model in C57BL/6 mice showed that TAT-LBD-Ngn2 efficiently crossed the blood brain barrier, aggregated in the ischemic zone and was consistently incorporated into neurons. Moreover, TAT-LBD-Ngn2 transduced into brains attenuated neuronal degeneration and apoptosis in the ischemic zone. TAT-LBD-Ngn2 treatment resulted in a reduction of infarct volume that was associated with a parallel improvement in neurological functional outcomes after reperfusion. In conclusion, the targeted delivery of TAT-LBD-Ngn2 into the ischemic zone attenuated cerebral ischemia-reperfusion injury through the inhibition of neuronal degeneration and apoptosis, suggesting that TAT-LBD-Ngn2 is a promising target candidate for the treatment of ischemic stroke.

Apple polysaccharides induce apoptosis in colorectal cancer cells.

Certain components of apples have been shown to prevent cancer growth and impede cancer progression. We hypothesized that extracted apple polysaccharides (APs) might, therefore, have anticancer effects, through a mechanism involving the induction of apoptosis in cancer cells, partly via the NF-κB pathway. Two human colorectal cancer (CRC) cell lines, HT-29 and SW620, were exposed to different concentrations of APs (0.01, 0.1 or 1 mg/ml). Cell apoptosis was measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay by flow cytometry and incorporation of 5'-bromodeoxyuridine (BrdU) into DNA to identify the proliferating cell fraction, using fluorescence microscopy in vitro. The protein levels of NF-κB/p65, I-κBα, pI-κBα, Bax, Bcl-xl and Bcl-2 were evaluated by western blotting. The target sites of APs on CRC cells were assessed by flow cytometry. At concentrations of 0.1 and 1 mg/ml, APs showed apoptosis-inducing effects, increased expressions of Bax, nuclear p65 and cytoplasmic pI-κBα, and decreased expressions of Bcl-2, Bcl-xl and cytoplasmic I-κBα. APs induced apoptosis by slightly activating the NF-κB pathway; the AP target site could be the Toll-like receptor 4 on the cell membrane. These results demonstrate the potential of APs as agents for clinical prevention and treatment of CRC.