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Infectious bursal disease (IBD) is one of the most prevalent infectious diseases caused by IBD virus (IBDV), which results in bursal necrosis and immunosuppression that cause severe damage to the immune system in chickens. Cytokines are important mediators and regulators of both types of host responses. In the present study, layer chickens were artificially challenged with IBDV, and the differential expression of inflammatory genes was explored by using quantitative real-time PCR, which offered basic data for further study of IBDV pathogenesis. Data showed that after IBDV infection, the virus load in the bursa of Fabricius (BF) peaked at 96 h and then gradually decreased. Compared with those of the negative-infected group, the mRNA expression levels of pro-inflammatory cytokines (interleukin [IL]-1β, IL-6, IL-7, IL-8, tumor necrosis factor [TNF]-α, transforming growth factor [TGF]-β) and anti-inflammatory cytokine IL-10 in the infected group increased to varying degrees at 12 to 192 h, respectively. Furthermore, the IL-1β mRNA expression peaked at 48 h; the mRNA transcript levels of IL-6, IL-8, and IL-10 were the highest at 96 h; TNF-α mRNA expression peaked at 120 h; the IL-7 mRNA expression peaked at 144 h; and the TGF-β mRNA transcript level was the highest at 192 h. Taken together, these observations indicated that along with the change pattern of IBDV proliferation in BF, the mRNA expression of cytokines (IL-1β, IL-6, IL-7, IL-8, IL-10, TNF-α, TGF-β) obviously increased, and the kinetics of each of these cytokines was different. The kinetics of IL-6/IL-10 mRNA expression ratio was significantly positively correlated with that of the virus load. These results suggest that IBDV infection seriously interferes with the natural immune response mediated by inflammatory cytokines in chickens. [ABSTRACT FROM AUTHOR]

Dingxin Recipe Ⅲ (DXR Ⅲ) is a traditional Chinese medicine compound used for hyperlipidemia treatment in clinical practice. However, its curative effects and pharmacological mechanisms in hyperlipidemia have not been clarified to date. Studies have demonstrated that gut barrier was strongly implicated in lipid deposition. Based on gut barrier and lipid metabolism, this study examined the effects and molecular mechanisms of DXR Ⅲ in hyperlipidemia. The bioactive compounds of DXR Ⅲ were detected by ultra-high performance liquid chromatography-quadrupole time-of-flight mass spectrometry, and its effects were evaluated in high-fat diet-fed rats. Specifically, the serum levels of lipids and hepatic enzymes were measured using the appropriate kits; colon and liver sections were obtained for histological analyses; gut microbiota and metabolites were analyzed by 16S rDNA sequencing and liquid chromatography-MS/MS; and the expression of genes and proteins was determined by real-time quantitative polymerase chain reaction and western blotting and immunohistochemistry, respectively. The pharmacological mechanisms of DXR Ⅲ were further explored by fecal microbiota transplantation and short-chain fatty acid (SCFAs)-based interventions. DXR Ⅲ treatment significantly downregulated serum lipid levels, mitigated hepatocyte steatosis and improved lipid metabolism. Moreover, DXR Ⅲ improved the gut barrier, specifically by improving the physical barrier in the colon, causing part composition changes in the gut microbiota, and increasing the serum SCFAs level. DXR Ⅲ also upregulated the expression of colon GPR43/GPR109A. Fecal microbiota transplantation from rats treated with DXR Ⅲ downregulated part hyperlipidemia-related phenotypes, while the SCFAs intervention significantly improved most of the hyperlipidemia-related phenotypes and upregulated the expression of GPR43. Moreover, both DXR Ⅲ and SCFAs upregulated the expression of colon ABCA1. DXR Ⅲ protects against hyperlipidemia by improving the gut barrier, particularly the SCFAs/GPR43 pathway. [Display omitted] • This study examined the effects of Dingxin Recipe Ⅲ in hyperlipidemia based on gut barrier and lipid metabolism. • Mechanisms of Dingxin Recipe Ⅲ were explored by fecal microbiota transplantation and short chain fatty acid intervention. • Dingxin Recipe Ⅲ improved HFD-induced hyperlipidemia and gut barrier, including physical barrier, gut microbiota, and SCFAs. • Dingxin Recipe Ⅲ protects against hyperlipidemia by improving the gut barrier, particularly the SCFAs/GPR43 pathway. [ABSTRACT FROM AUTHOR]

Fasting–refeeding perturbation has been extensively used to reveal specific genes and metabolic pathways that control energy metabolism in chickens. In this study, 200 chickens were randomly assigned to 2 groups after hatching: the control group (C, fed ad libitum) and the fasting–refeeding group (T, water ad libitum). The chicks in Group T were fasted for 72 h, and then fed for another 48 h. Liver, hypothalamus, and adipose samples were collected at 0 (F0), 24 (F24), 48 (F48), and 72 h (F72) after fasting and 4 (FR4), 12 (FR12), 24 (FR24), and 48 h (FR48) after refeeding, respectively. Results showed that Group T had a significantly higher number of liver vacuoles (P < 0.05 or P < 0.01) and a significantly lower gray value of Sudan IIIstained sections (P < 0.05 or P < 0.01) than Group C at F48–FR48. In addition, compared with the Group C, fasting and refeeding reduced the expression of stearoyl CoA desaturase (SCD) mRNA (P < 0.05 or P < 0.01) in the liver and adipose tissues, the expression of glucocorticoid receptor (GR) mRNA (P < 0.05 or P < 0.01) in the liver, adipose, and hypothalamus tissues, and the expression of fatty acid synthase (FAS) mRNA (P < 0.05 or P < 0.01) in the liver at F24–FR24. Moreover, relative to those in Group C, fasting and refeeding increased the mRNA expression levels of adenosine monophosphate-activated protein kinase (AMPK) α, AMPKβ, and AMPKγ in the hypothalamus (P < 0.05 or P < 0.01) at F24–FR24. In conclusion, fasting and refeeding increased the fat content of the liver, and the expression of lipolytic genes in the hypothalamus (e.g., AMPKα, AMPKβ, and AMPKγ) but decreased the expression of fat synthesis genes in the liver (e.g., SCD, GR, and FAS), adipose (SCD and GR), and hypothalamus (GR). [ABSTRACT FROM AUTHOR]

Abstract: As a member of the interleukin (IL)-1 family, IL-1β is a prototypical proinflammatory cytokine, which plays a crucial role in immune responses. Herein, we reported the full length cDNA of IL-1β in half-smooth tongue sole (Cynoglossus semilaevis). The csIL-1β cDNA contained a 130bp 5′ UTR, a 417bp 3′ UTR and a 741bp coding sequence (CDS) that translated into a polypeptide of 246 amino acids. The protein sequence included a typical IL-1 family signature and lacked an interleukin-converting enzyme (ICE) cut site. RT-PCR analysis indicated a broad expression of csIL-1β, especially in immune-related organs. After injection with inactive Vibrio anguillarum, the expression of csIL-1β was induced in the head kidney and spleen and reached the highest level at 8h post injection. Higher expression of csIL-1β was observed at gastrula stage, eye-bud stage and hatching stage and lower level of csIL-1β mRNA was detected at metamorphic stage. The expression of csIL-1β during development suggested IL-1β might be involved not only in immunity but also development. Taken together, the present study indicated that csIL-1β played an important role in immune responses and development like its mammalian counterparts, although species-specific features were present. [Copyright &y& Elsevier]

Abstract: In this study, the sheep CIB4 cDNA was cloned from the small tail Han sheep by RT-PCR and RACE (rapid amplification of cDNA ends), and CIB4 cDNA and amino acid sequence were analyzed. Our results showed that the sheep CIB4 gene expressed two alternatively spliced variants L-CIB4 (long CIB4) and S-CIB4 (short CIB4). Sequence analysis indicated that the sheep CIB4 cDNA cloned (L-CIB4) was 745-bp in length (GenBank accession number: FJ039532) with 185 amino acids residues. The sheep CIB4 cDNA showed more than 72% of sequence identity, at the nucleotide level, to its equivalents in cattle, horse, chimpanzee, humans, mice and rats, while at the deduced protein level, the value increased to 79.6%. Semi-quantitative RT-PCR using total RNA from different tissues showed that CIB4 has a strong tissue-specific expression pattern in sheep. L-CIB4 expression level was shown to be no different in small tail Han sheep and the Dorset ram, but both were significantly different from the Texel (P <0.05). Surprisingly, the short spliced form, S-CIB4, could only be detected in small tail Han sheep, suggesting that CIB4 may be linked in some way to the high fecundity of this breed. [Copyright &y& Elsevier]

Abstract: Bone morphogenetic proteins (BMPs) are potent bone inducers used clinically to enhance fracture repair. BMPs have been shown to be produced in the fracture callus; however, the comparative expression of BMPs and BMP signaling components has only been partially examined at the cellular level. The aim of the present study was to establish a detailed spatiotemporal localization of BMPs and BMP signaling components in mouse models of stabilized and nonstabilized fractures. During healing of nonstabilized fractures, which occurs via endochondral ossification, BMP2, 3, 4, 5, and 8, noggin, BMPRIA, BMPRII, and pSmad 1/5/8 were immunolocalized in the activated periosteum as early as 3 days after fracture. BMP2, 4, 5, 6, 7, and 8 and noggin were also found in isolated inflammatory cells within granulation tissue during the early stages of repair, but not BMP receptors and effectors. During the soft callus phase of repair, all BMPs and BMP signaling components were detected in chondrocytes with various intensities of staining depending on the stage of chondrocyte differentiation and their location in the callus. The strongest staining was observed in hypertrophic chondrocytes with decreased intensity during the hard callus phase of repair. All BMPs and components of the BMP pathway were detected in osteoblasts and osteocytes within new bone, with strongest intensity of immunoreaction reported during the early soft callus phase followed by decreasing intensity during the hard callus phase of repair. Most components of the BMP pathway were also detected in endothelial cells associated with new bone. In stabilized fractures that heal strictly via intramembranous ossification, BMPs and BMP antagonists were detected in isolated inflammatory cells and BMP signaling components were not detectable in osteoblasts or osteocytes within new bone. In conclusion, the BMP signaling pathway is primarily activated during fracture healing via endochondral ossification, suggesting that this pathway may influence the mode of healing during the recruitment of skeletal progenitors. [Copyright &y& Elsevier]

The effects of indoleacetic acid (IAA) treatment on chilling injury and endogenous phytohormones in peach fruit were studied. The results showed that IAA treatment decreased chilling injury index of cold-stored peaches, effectively maintaining fruit firmness and reducing the electrical conductivity level. IAA treatment upregulated the expression of IAA biosynthetic gene PpMES and signaling pathway gene PpSAUR , but reduced the transcript abundance of IAA degradative genes PpDAO , PpGH3 , and PpIAMT , leading to endogenous IAA accumulation in treated peaches. Meanwhile, after IAA treatment, contents of melatonin and γ-aminobutyric acid (GABA) were also increased which was associated with the upregulation of their anabolic genes and downregulation in GABA catabolic genes. In addition, the levels of abscisic acid (ABA) and gibberellin (GA) were reduced in treated peaches due to its modification in the transcript levels of ABA and GA metabolic genes. Collectively, IAA could alleviate the symptoms of chilling injury in peach fruit via regulating contents of endogenous phytohomones such as IAA, melatonin, GABA and GA. • IAA treatment reduced chilling injury and maintain fruit quality in peaches. • IAA induced endogenous IAA content in harvested peaches. • IAA increased melatonin and GABA contents in harvested peaches. • IAA inhibited ABA and GA contents in harvested peaches. [ABSTRACT FROM AUTHOR]

In biological control programs, knowledge about diapause regulation in natural enemy insects provides important insight for improving long-term storage, transportation, and field adoption of these biological control agents. As a natural predator of agricultural pests, the lady beetle Coccinella septempunctata has been commercially mass-cultured and widely employed in pest management. In some insects, insulin signaling, in conjunction with the downstream transcription factor Forkhead box O (FoxO), are master regulators of multiple physiological processes involved in diapause, but it is unclear whether insulin signaling and FoxO affect the diapause of C. septempunctata. In this study, we use a combination of approaches to demonstrate that insulin signaling and FoxO mediate the diapause response in C. septempunctata. In diapausing beetles, application of exogenous insulin and knocking down expression of CsFoxo with RNA interference (RNAi) both rescued beetles from developmental arrest. In non-diapausing beetles, knocking down expression of the insulin receptor (CsInR) with RNA interference (RNAi) arrested ovarian development and decreased juvenile hormone (JH) content to levels comparable to the diapause state. Taken together, these results suggest that a shutdown of insulin signaling prompts the activation of the downstream FoxO gene, leading to the diapause phenotype. • The shutdown of insulin signaling prompts the activation of the downstream FoxO gene, leading to the diapause phenotype. • Under a long day photoperiod, insulin signaling leads to the suppression of FoxO gene and production of the JH. • In response to short day lengths, the insulin signaling pathway is shut down, thereby releasing the suppression of FoxO gene. [ABSTRACT FROM AUTHOR]

Polygonum multiflorum Thunb. is a traditional Chinese medicine with extensive distribution and robust adaptability, but comprehensive research on its acid and alkali resistance is presently lacking. This study aimed to analyze the effects of 5 months of continuous pH stress on the physiological and photosynthetic parameters of P. multiflorum , and the content of effective components. Results revealed that pH stress significantly influenced the normal growth, physiological functions, and photosynthetic indicators of P. multiflorum. At soil pH 4.5, the tubers of P. multiflorum exhibited the highest levels of 2,3,5,4′-tetrahydroxy stilbene-2-O-β- d -glucoside (THSG) and total anthraquinones at 5.41% and 0.38%, respectively. However, increased soil pH significantly reduced the content of THSG and total anthraquinones. Reference-free transcriptome analysis was further conducted on P. multiflorum treated at pH 4.5 and 9.5, generating a total of 47,305 unigenes with an N50 of 2118 bp, of which 31,058 (65.65%) were annotated. Additionally, 2472 differentially expressed genes (DEGs) were identified. Among them, 17 DEGs associated with the biosynthesis of THSG and anthraquinones were screened. A comprehensive analysis of differential gene expression and effective component content demonstrated a significant positive correlation between the content of effective components and the 14 DEGs' expression but a negative correlation with soil pH. This study highlighted the influence of varying soil pH values on the effective component content of P. multiflorum. Specific acidic conditions proved beneficial for the synthesis and accumulation of THSG and total anthraquinones in P. multiflorum , thereby enhancing the quality of the medicinal material. [Display omitted] • PH effects on the P. multiflorum physiology and effective components were analyzed. • The effective component content of P. multiflorum is the highest in the pH 4.5. • RNA-seq revealed the molecular mechanisms of P. multiflorum under pH stress. • The contents of THSG and anthraquinones were positively correlated with 14 DEGs. [ABSTRACT FROM AUTHOR]

Hepatic fibrosis is a pathological process in which extracellular matrix excessively aggregates in an injured liver. Research on hepatic fibrosis is expanding, however, much information in this process is still unclear. Here, we examined the gene expression changes within the process of liver fibrosis, providing the first evidence that secreted S100A6 is a critical contributor. We discovered that expression of the S100 family is highly correlated with CCl 4 -induced liver fibrosis and post self-recovery in mice. Recombinant human S100A6 (rhS100A6) introduced to CCl 4 -induced mice was found to enhance liver fibrosis through the promotion of activated hepatic stellate cell (HSC) proliferation. More importantly, we showed that rhS100A6 can induce cell cycle transition from S to G2 stage and significantly elevate the level of ERK phosphorylation in the MARK pathway. In contrast to rhS100A6, recombinant human and soluble receptor for advanced glycation end products (sRAGE), a natural antagonist of the S100/RAGE pathway, was found to have a preventative effect on liver fibrosis in CCl 4 -induced mice. In conclusion, our study supports that S100A6 could be a novel therapeutic in liver fibrosis and its receptor antagonist, sRAGE, proofed to be effective for the treatment of liver fibrosis. [ABSTRACT FROM AUTHOR]

Abstract: Both the occurrence and recurrence of acute leukemia (AL) might suggest the presence of leukemia stem cells. Side population (SP) cells, exhibiting stem cell-like properties, express ABCG2 (breast cancer resistance protein [BCRP]). This study revealed that over-expression of ABCG2 in Jurkat and HL60 cells led to an increased SP fraction, up-regulated levels of phosphorylated-PI3K and phosphorylated-Akt, and enhanced drug resistance, all of which could be attenuated by treatment with either the PI3K inhibitor LY294002 or the mTOR inhibitor rapamycin. ABCG2 expression and SP cell counts were further characterized in 222 adult AL patients at three disease stages: upon diagnosis, at remission and at refractory/relapse (R/R), while 10 healthy donors served as the normal controls. Only a small fraction of the ABCG2+population (0.05–12.3%) and SP cells (0.02–1.60%) were observed in acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) patients. In the normal control population, the SP cell fraction represented a statistically higher percentage of total cells compared to the fraction of SP cells upon diagnosis or relapse in both AML and ALL. In addition, we demonstrated that ABCG2 expression and SP cell ratios can be upregulated by the inactivation of phosphatase and tensin homolog (PTEN) protein, achieved in this study by removing inhibition of the PI3K/Akt pathway. Collectively, this study suggests that the PTEN/PI3K/Akt pathway up-regulates ABCG2 expression and the SP cell population and is a potential AL-specific treatment target worth investigating further. [Copyright &y& Elsevier]

Abstract: Angiotensin-(1-7) [Ang-(1-7)] is a new bioactive heptapeptide in the renin–angiotensin–aldosterone system (RAAS) with potent protective effects in cardiovascular diseases, opposing many actions of angiotensin II (Ang II) mediated by Ang II type 1 (AT1) receptor. It is produced mainly by the activity of angiotensin-converting enzyme 2 (ACE2) and acts through the Mas receptor. However, the role of Ang-(1-7) in vascular calcification (VC) is still unclear. In this study, we investigated the protective effects of Ang-(1-7) on VC in an in vivo rat VC model induced by vitamin D3 plus nicotine. The levels of ACE2 and the Mas receptor, as well as ACE, AT1 receptor, Ang II type 2 receptor and angiotensinogen, were significantly increased in calcified aortas, and Ang-(1-7) reversed the increased levels. Ang-(1-7) restored the reduced expression of lineage markers, including smooth muscle (SM) α-actin, SM22α, calponin and smoothelin, in vascular smooth muscle cells (VSMCs) and retarded the osteogenic transition of VSMCs by decreasing the expression of bone-associated proteins. It reduced alkaline phosphatase activity and calcium deposition in VC and alleviated the hemodynamic disorders of rats with VC. We provide the first in vivo evidence that Ang-(1-7) can inhibit the development of VC by inhibiting the osteogenic transition of VSMCs, at least in part by decreasing levels of the ACE/Ang II/AT1 axis. The increased expression of ACE2 and the Mas receptor in calcified aortas suggests the involvement of the ACE2/Ang-(1-7)/Mas axis during VC. Ang-(1-7) might be an efficient endogenous vasoprotective factor for VC. [Copyright &y& Elsevier]

Expression of glutathione peroxidase 3 (GPx3) is down-regulated in a variety of human malignancies. Both methylation and deletion of GPx3 gene underlie the alterations of GPx3 expression in prostate cancer. A strong correlation between the down-regulation of GPx3 expression and progression of prostate cancer and the suppression of prostate cancer xenografts in SCID mice by forced expression of GPx3 suggests a tumor suppression role of GPx3 in prostate cancer. However, the mechanism of GPx3-mediated tumor suppression remains unclear. In this report, GPx3 was found to interact directly with p53-induced gene 3 (PIG3). Forced overexpression of GPx3 in prostate cancer cell lines DU145 and PC3 as well as immortalized prostate epithelial cells RWPE-1 increased apoptotic cell death. Expression of GPx3x73c, a peroxidase-negative OPAL codon mutant, in DU145 and PC3 cells also increased cell death. The induced expression of GPx3 in DU145 and PC3 cells resulted in an increase in reactive oxygen species and caspase-3 activity. These activities were abrogated by either knocking down PIG3 or mutating the PIG3 binding motif in GPx3 or binding interference from a peptide corresponding to PIG3 binding motif in GPx3. In addition, UV-treated RWPE-1 cells underwent apoptotic death, which was partially prevented by knocking down GPx3 or PIG3, suggesting that GPx3-PIG3 signaling is critical for UV-induced apoptosis. Taken together, these results reveal a novel signaling pathway of GPx3-PIG3 in the regulation of cell death in prostate cancer. [ABSTRACT FROM AUTHOR]

Abstract: Using mouse gene expression microarray analysis, we earlier obtained dynamic profiles of whole genome expression in the CCl4-induced liver injury mouse model. CXCL14 expression was increased in the liver injury phase and returned to normal after liver regeneration suggesting its involvement in the liver injury or regeneration regulation. The role of CXCL14 in liver injury was investigated. The dynamic of CXCL14 transcription was analyzed in CCl4-induced mouse liver damage by qRT-PCR. Plasmid mediated CXCL14 overexpression and antibody neutralization of endogenous CXCL14 were used to demonstrate its effects and mechanisms on CCl4-induced liver injury and acute liver failure. We showed that CXCL14 expression was immediately upregulated post CCl4 injection with a dose-dependent response. CXCL14 over-expression aggravated CCl4-induced liver injuries, evidenced by enhanced acidophilic change and necrosis of hepatocyte, increased fat deposition in hepatocytes (P <0.01), and inhibited hepatocyte proliferation (P <0.01). On the contrary, anti-CXCL14 antibody treatment reduced the severity of CCL4-induced liver injuries Significant reductions in hepatic necrosis area (P <0.05), the liver fat deposition (P <0.01), and the lipid peroxidation measured by serum MDA (P <0.05) were observed. Importantly, the antibody treatment reduced the mouse mortality caused by CCl4-induced liver failure (P <0.05). The data suggest that CXCL14 and its receptor present potential targets for the treatment of liver diseases. [Copyright &y& Elsevier]

Abstract: It is well known that neurons in the CA3 and dentate gyrus (DG) subfields of the hippocampus are resistant to short period of ischemia which is usually lethal to pyramidal neurons in hippocampal CA1 subfield. The present study was undertaken to clarify whether the inherent higher resistance of neurons in CA3 and DG to ischemia is associated with glial glutamate transporter-1 (GLT-1) in rats. Western blot analysis and immunohistochemistry assay showed that the basal expressions of GLT-1 in both CA3 and DG were much higher than that in CA1 subfield. Mild global brain ischemia for 8min induced delayed death of almost all CA1 pyramidal neurons and marked GLT-1 down-regulation in the CA1 subfield, but it was not lethal to the neurons in either CA3 or DG and induced GLT-1 up-regulation and astrocyte activation showed normal soma and aplenty slender processes in the both areas. When the global brain ischemia was prolonged to 25min, neuronal death was clearly observed in CA3 and DG accompanied with down-regulation of GLT-1 expression and abnormal astrocytes represented with hypertrophic somas, but shortened processes. After down-regulating of GLT-1 expression and function by its antisense oligodeoxynucleotides or inhibiting GLT-1 function by dihydrokainate, an inhibitor of GLT-1, the mild global brain ischemia for 8min, which usually was not lethal to CA3 and DG neurons, induced the neuronal death in CA3 and DG subfields. Taken together, the higher expression of GLT-1 in the CA3 and DG contributes to their inherent resistance to ischemia. [Copyright &y& Elsevier]

Abstract: Tumor necrosis factor-α induced protein 8 like-2 (TNFAIP8L2, TIPE2), a lately discovered negative regulator of innate immunity and cellular immunity, shares considerable sequence homology with members of the tumor necrosis factor-α induced protein 8 (TNFAIP8) family. It is preferentially expressed in lymphoid-derived and marrow-derived cells. However, it is unclear whether TIPE2 is expressed in the regulatory T cells (Tregs) to contribute to its negative regulatory property in immune response. The present study was designed to examine whether naturally occurring CD4+CD25+ Tregs isolated from murine spleens expressed TIPE2 by the use of Western blot and reverse transcription-polymerase chain reaction (RT-PCR). Based on the expression of cell surface molecules, including cytotoxic T-lymphocyte-associated antigen (CTLA)-4 and forkhead/winged helix transcription factor p3 (Foxp3) on CD4+CD25+ Tregs, and cytokines including interleukin (IL)-10 as well as transforming growth factor (TGF)-β were analyzed to investigate the functional role of TIPE2 in controlling suppressive activity of CD4+CD25+ Tregs. Meanwhile, IL-2, the ratio of interferon (IFN)-γ/IL-4 in CD4+CD25+Treg/CD4+CD25− T cell coculture supernatant and nuclear factor of activated T cells (NF-AT) activation in T lymphocytes were determined to examine the effects of TIPE2 on the T-cell proliferation and differentiation induced by CD4+CD25+ Tregs. It was found that TIPE2 was a cytoplasmic protein expressed in CD4+CD25+ Tregs, and cell surface molecules as well as cytokines (IL-10, TGF-β) expressions were significantly down-regulated when TIPE2 gene silenced by siRNA. On the other hand, CD4+CD25+ Tregs treated with TIPE2 knock-down promoted T-cell proliferation as well as differentiation, and markedly upregulated IL-2 expression and intranuclear NF-AT activation. The results suggested that TIPE2 appeared to be a critical immunoregulatory molecule involved in immunosuppressive function of CD4+CD25+ Tregs. [Copyright &y& Elsevier]

Abstract: Chemotherapy induced intestinal mucositis is still an unmet medical problem. 5-fluorouracil (5-Fu), a chemotherapy drug, was used to create the animal model of mucositis. Global gene expression array was applied to identify genetic signals involved in the pathogenesis of mucositis. Interleukin 1 receptor antagonist (IL-1Ra) was one of the candidates with the characteristic gene expression profile. Its temporal expression pattern correlated to the damage and regeneration phase of the small intestine after a single injection of 5-Fu to mice. Administration of recombinant IL-1Ra to the mouse model of intestinal mucositis induced by 5-Fu demonstrated its therapeutic effects to the symptoms and pathology of the disease. The IL-1Ra treatment reduced the acute lethality, accelerated their body weight recovery, and eliminated severe diarrhea. The symptomatic benefits were supported by the pathological benefits, in which the mice treated with IL-1Ra has less damage and faster recovery of the structure integrity of their small intestine than that of the mice treated with vehicle control. To deliver the therapeutics to the unmet medical condition, further mechanism and translational studies of IL-1Ra in the settings of chemotherapy induced intestinal mucositis are warranted. [Copyright &y& Elsevier]

Abstract: Chemotherapy-induced intestinal mucositis is still an unmet medical problem. 5-Fluorouracil (5-Fu), a chemotherapy drug, was used to create the animal model of mucositis. Global gene expression array was applied to identify genetic signals involved in the pathogenesis of mucositis. Interleukin 1 receptor antagonist (IL-1Ra) was one of the candidates with the characteristic gene expression profile. Its temporal expression pattern correlated to the damage and regeneration phase of the small intestine after a single injection of 5-Fu to mice. Administration of recombinant IL-1Ra to the mouse model of intestinal mucositis induced by 5-Fu demonstrated its therapeutic effects to the symptoms and pathology of the disease. The IL-1Ra treatment reduced the acute lethality, accelerated their body weight recovery, and eliminated severe diarrhea. The symptomatic benefits were supported by the pathological benefits, in which the mice treated with IL-1Ra had less damage and faster recovery of the structure integrity of their small intestine than that of the mice treated with vehicle control. To deliver the therapeutics to the unmet medical condition, further mechanism and translational studies of IL-1Ra in the settings of chemotherapy-induced intestinal mucositis are warranted. [ABSTRACT FROM AUTHOR]

SIRT1 (Sirtuin type 1), a mammalian orthologue of yeast SIR2 (silent information regulator 2), has been shown to mediate a variety of calorie restriction (CR)-induced physiological events, such as cell fate regulation via deacetylation of the substrate proteins. However, whether SIRT1 deacetylates activator protein-1 (AP-1) to influence its transcriptional activity and target gene expression is still unknown. Here we demonstrate that SIRT1 directly interacts with the basic leucine zipper domains of c-Fos and c-Jun, the major components of AP-1, by which SIRT1 suppressed the transcriptional activity of AP-1. This process requires the deacetylase activity of SIRT1. Notably, SIRT1 reduced the expression of COX-2, a typical AP-1 target gene, and decreased prostaglandin E2 (PGE2) production of peritoneal macrophages (pMΦs). pMΦs with SIRT1 overexpression displayed improved phagocytosis and tumoricidal functions, which are associated with depressed PGE2. Furthermore, SIRT1 protein level was up-regulated in CR mouse pMΦs, whereas elevated SIRT1 decreased COX-2 expression and improved PGE2-related macrophage functions that were reversed following inhibition of SIRT1 deacetylase activity. Thus, our results indicate that SIRT1 may be a mediator of CR-induced macrophage regulation, and its deacetylase activity contributes to the inhibition of AP-1 transcriptional activity and COX-2 expression leading to amelioration of macrophage function. [ABSTRACT FROM AUTHOR]