Context-Based e2e Autonomous Operation in B5G Networks.

The research and innovation related to fifth-generation (5G) networks that has been carried out in recent years has decided on the fundamentals of the smart slice in radio access networks (RANs), as well as the autonomous fixed network operation. One of the most challenging objectives of beyond 5G (B5G) and sixth-generation (6G) networks is the deployment of mechanisms that enable smart end-to-end (e2e) network operation, which is required for the achievement of the stringent service requirements of the envisioned use cases to be supported in the short term. Therefore, smart actions, such as dynamic capacity allocation, flexible functional split, and dynamic slice management need to be performed in tight coordination with the autonomous capacity management of the fixed transport network infrastructure. Otherwise, the benefits of smart slice operation (i.e., cost and energy savings while ensuring per-slice service requirements) might be cancelled due to uncoordinated autonomous fixed network operation. Notably, the transport network in charge of supporting slices from the user equipment (UE) to the core expands across access and metro fixed networks. The required coordination needs to be performed while keeping the privacy of the radio and fixed network domains, which is important in multi-tenant scenarios where both network segments are managed by different operators. In this paper, we propose a novel approach that explores the concept of context-aware network operation, where the slice control anticipates the aggregated and anonymized information of the expected slice operation that is sent to the fixed network orchestrator in an asynchronous way. The context is then used as the input for the artificial intelligence (AI)-based models used by the fixed network control for the predictive capacity management of optical connections in support of RAN slices. This context-aware network operation aims at enabling accurate and reliable autonomous fixed network operation under extremely dynamic traffic originated by smart RAN operation. The exhaustive numerical results show that slice context availability improves the benchmarking fixed network predictive methods (90% reduction in prediction maximum error) remarkably in the foreseen B5G scenarios, for both access and metro segments and in heterogeneous service demand scenarios. Moreover, context-aware network operation enables robust and efficient operation of optical networks in support of dense RAN cells (>32 base stations per cell), while the benchmarking methods fail to guarantee different operational objectives.

The Beneficial Effects of Natural Extracts and Bioactive Compounds on the Gut-Liver Axis: A Promising Intervention for Alcoholic Liver Disease.

Alcoholic liver disease (ALD) is a major cause of morbidity and mortality worldwide. It can cause fatty liver (steatosis), steatohepatitis, fibrosis, cirrhosis, and liver cancer. Alcohol consumption can also disturb the composition of gut microbiota, increasing the composition of harmful microbes and decreasing beneficial ones. Restoring eubiosis or preventing dysbiosis after alcohol consumption is an important strategy in treating ALD. Plant natural products and polyphenolic compounds exert beneficial effects on several metabolic disorders associated with ALD. Natural products and related phytochemicals act through multiple pathways, such as modulating gut microbiota, improving redox stress, and anti-inflammation. In the present review article, we gather information on natural extract and bioactive compounds on the gut-liver axis for the possible treatment of ALD. Supplementation with natural extracts and bioactive compounds promoted the intestinal tight junction, protected against the alcohol-induced gut leakiness and inflammation, and reduced endotoxemia in alcohol-exposed animals. Taken together, natural extracts and bioactive compounds have strong potential against ALD; however, further clinical studies are still needed.

Applications of Nondominated Sorting Genetic Algorithm II Combined with WKNN Online Matching Algorithm in Building Indoor Optimization Design.

The present work aims to improve the comfort of architectural interior design and reduce indoor energy consumption. The Weight K-Nearest Neighborhood (WKNN) algorithm and Nondominated Sorting Genetic algorithm are proposed to locate and analyze the spatial location of indoor personnel and optimize the indoor energy consumption in combination with residential behavior. Firstly, the indoor human behavior data and energy-saving problems are analyzed based on residential behavior theory and architectural physics. The indoor positioning algorithm is proposed to identify the personnel activities to realize the optimization of indoor energy distribution. Secondly, mean filtering and cluster analysis are adopted to optimize sampling points' data and fingerprint database to eliminate data noise. Besides, the WKNN algorithm is used for Wireless Fidelity (Wi-Fi) indoor location fingerprint location. Then, aiming at the multiobjective optimization problem of building indoor energy consumption, the Nondominated Sorting Genetic algorithm obtains the optimal solution of the model. Combined with the indoor location information of personnel, the indoor heating and cooling system is monitored and distributed to reduce the energy consumption in the building while ensuring the living comfort of personnel. The test and simulation results demonstrate that the mean filtering algorithm can solve the room's fluctuation problem of Wi-Fi signals. The cluster analysis algorithm can eliminate the data noise of the fingerprint database and improve the positioning accuracy of the positioning algorithm. Moreover, the location result is independent of the number of nodes; the number of sampling points does not affect the location result. The positioning accuracy of the WKNN algorithm is 2 m, and the positioning error rate within 2 m is about 60%. Compared with other algorithms, the WKNN algorithm has better positioning accuracy and positioning stability. Therefore, the location algorithm designed here can be applied to indoor location optimization. This study provides a reference for optimizing buildings' indoor positioning and energy consumption.

Implementation and Optimization of Reverse Suspension Structure Design Model Using Deep Learning.

The present work aims to improve the design efficiency and optimize the results in the increasingly complex and diversified material design projects to help architects realize the better performance of building structures. According to the characteristics of comprehensive perception and intelligent processing of the Internet of Things, a reverse suspension structure design model is constructed based on the finite element method and simulated annealing algorithm. Besides, deep learning is adopted to train complex functions for performance correction and to optimize the plane structure of shell structure. Moreover, the force is transformed into shape, and the form-finding process is completed to facilitate the operation of designers. Finally, the spatial anchoring ability of the geographic information system is used to match and calculate the relevant characteristics of spatial elements. On this basis, the index construction strategy based on weight distribution is employed to realize the data fusion diagnosis framework and enhance the intelligence of architectural design. The simulation results show that the maximum tensile stress of the physical suspension experiment is 3.71 MPa and the maximum compressive stress is 14.7 MPa. The compressive stress value is much larger than the tensile stress value. The maximum deformation value's difference between the compressive and tensile stress is 0.07 and 0.11, respectively. The error is within the acceptable range, which is similar to the compression state results obtained from the actual suspension physical experiment, indicating that the initial design model of the reverse suspension structure based on deep learning is reliable. In addition, the evolutionary optimization effect analysis results demonstrate that the load of the design structure is relatively uniform, which verifies the feasibility of the algorithm reported here. The research significance of the reverse suspension structure model constructed here is to provide an accurate and feasible design idea for the reverse design of some complex structures in the building suspension. It can also shorten the creation and improvement cycle of this kind of structure and optimize the performance and construction cycle of the building structure.

SARS-CoV-2 RNA elements share human sequence identity and upregulate hyaluronan via NamiRNA-enhancer network.

BACKGROUND: Since late 2019, SARS-CoV-2 infection has resulted in COVID-19 accompanied by diverse clinical manifestations. However, the underlying mechanism of how SARS-CoV-2 interacts with host and develops multiple symptoms is largely unexplored. METHODS: Bioinformatics analysis determined the sequence similarity between SARS-CoV-2 and human genomes. Diverse fragments of SARS-CoV-2 genome containing Human Identical Sequences (HIS) were cloned into the lentiviral vector. HEK293T, MRC5 and HUVEC were infected with laboratory-packaged lentivirus or transfected with plasmids or antagomirs for HIS. Quantitative RT-PCR and chromatin immunoprecipitation assay detected gene expression and H3K27ac enrichment, respectively. UV-Vis spectroscopy assessed the interaction between HIS and their target locus. Enzyme-linked immunosorbent assay evaluated the hyaluronan (HA) levels of culture supernatant and plasma of COVID-19 patients. FINDINGS: Five short sequences (24-27 nt length) sharing identity between SARS-CoV-2 and human genome were identified. These RNA elements were highly conserved in primates. The genomic fragments containing HIS were predicted to form hairpin structures in silico similar to miRNA precursors. HIS may function through direct genomic interaction leading to activation of host enhancers, and upregulation of adjacent and distant genes, including cytokine genes and hyaluronan synthase 2 (HAS2). HIS antagomirs and Cas13d-mediated HIS degradation reduced HAS2 expression. Severe COVID-19 patients displayed decreased lymphocytes and elevated D-dimer, and C-reactive proteins, as well as increased plasma hyaluronan. Hymecromone inhibited hyaluronan production in vitro, and thus could be further investigated as a therapeutic option for preventing severe outcome in COVID-19 patients. INTERPRETATION: HIS of SARS-CoV-2 could promote COVID-19 progression by upregulating hyaluronan, providing novel targets for treatment. FUNDING: The National Key R&D Program of China (2018YFC1005004), Major Special Projects of Basic Research of Shanghai Science and Technology Commission (18JC1411101), and the National Natural Science Foundation of China (31872814, 32000505).

In silico analysis of novel dipeptidyl peptidase-IV inhibitory peptides released from Macadamia integrifolia antimicrobial protein 2 (MiAMP2) and the possible pathways involved in diabetes protection.

The aim of the present study was to screen novel dipeptidyl peptidase IV (DPP-IV) inhibitory peptides from Macadamia integrifolia antimicrobial protein 2 (MiAMP2) and evaluate the potential antidiabetic targets and involved signaling pathways using in silico approaches. In silico digestion of MiAMP2 with pepsin, trypsin and chymotrypsin was performed with ExPASy PeptideCutter and the generated peptides were subjected to BIOPEP-UWM, iDrug, INNOVAGEN and Autodock Vina for further analyses. Six novel peptides EQVR, EQVK, AESE, EEDNK, EECK, and EVEE were predicted to possess good DPP-IV inhibitory potentials, water solubility, and absorption, distribution, metabolism, excretion, and toxicity properties. Molecular dynamic simulation and molecular docking displayed that AESE was the most potent DPP-IV inhibitory peptide and can bind with the active sites of DPP-IV through hydrogen bonding and van der Waals forces. The potential antidiabetic targets of AESE were retrieved from SwissTargetPrediction and GeneCards databases. Protein-protein interaction analysis identified BIRC2, CASP3, MMP7 and BIRC3 to be the hub targets. Moreover, the KEGG pathway enrichment analysis showed that AESE prevented diabetes through the apoptosis and TNF signaling pathways. These results will provide new insights into utilization of MiAMP2 as functional food ingredients for the prevention and treatment of diabetes.

ICOS+ follicular regulatory T cells are implicated in the pathogenesis of ulcerative colitis.

Ulcerative colitis (UC) is an inflammatory bowel disease (IBD) with a rising incidence worldwide. The precise aetiology is unclear, but aberrant regulatory T cell (Treg) responses have been documented in active UC patients. Follicular regulatory T cell (Tfr) is a recently identified subset of Treg cells. In this study, the role of ICOS in Tfr cells, which is a costimulatory molecule shown to stabilize and promote Treg differentiation, was investigated in UC patients. We found that with increasing UC severity, the frequency of ICOS+ CD4 T cells was increased, but the level of ICOS expression by ICOS+ CD4 T cells was decreased. ICOS+ cells were highly enriched in follicular regulatory T cells (Tfr), which is a subset of Treg cells characterized by CD25+ CD127- CXCR5+ Foxp3+ phenotype. Anti-CD3, anti-CD3/CD28, or anti-CD3/ICOS had all significantly increased the expression of Foxp3 and IL-10, and among the three stimulation methods, anti-CD3/ICOS was most effective at enhancing Foxp3 and IL-10 expression. Moreover, anti-CD3/ICOS-stimulated Tfr cells could suppress conventional T cell proliferation in an IL-10-dependent manner. Interestingly, anti-CD3/ICOS stimulation was less effective in UC-Mild and UC-Active patients compared to that in healthy and UC-Remission patients. In addition, UC patients presented impairment in ICOS upregulation following anti-CD3 stimulation. Overall, these data indicated that ICOS+ Tfr cells were dysregulated in UC patients and the level of dysregulation was associated with the severity of UC, suggesting that ICOS+ Tfr cells could serve as a biomarker of the progression of UC.

Reactivation of tumour suppressor in breast cancer by enhancer switching through NamiRNA network.

Dysfunction of Tumour Suppressor Genes (TSGs) is a common feature in carcinogenesis. Epigenetic abnormalities including DNA hypermethylation or aberrant histone modifications in promoter regions have been described for interpreting TSG inactivation. However, in many instances, how TSGs are silenced in tumours are largely unknown. Given that miRNA with low expression in tumours is another recognized signature, we hypothesize that low expression of miRNA may reduce the activity of TSG related enhancers and further lead to inactivation of TSG during cancer development. Here, we reported that low expression of miRNA in cancer as a recognized signature leads to loss of function of TSGs in breast cancer. In 157 paired breast cancer and adjacent normal samples, tumour suppressor gene GPER1 and miR-339 are both downregulated in Luminal A/B and Triple Negative Breast Cancer subtypes. Mechanistic investigations revealed that miR-339 upregulates GPER1 expression in breast cancer cells by switching on the GPER1 enhancer, which can be blocked by enhancer deletion through the CRISPR/Cas9 system. Collectively, our findings reveal novel mechanistic insights into TSG dysfunction in cancer development, and provide evidence that reactivation of TSG by enhancer switching may be a promising alternative strategy for clinical breast cancer treatment.

IL-10 enhances T cell survival and is associated with faster relapse in patients with inactive ulcerative colitis.

Ulcerative colitis (UC) is characterized by a relapsing and remitting pattern. The remission phase may last weeks to years. It remains unclear what specific factors can cause the disease to exist the remission phase and enter an activated state. IL-10 is a cytokine best known for its anti-inflammatory roles. We hypothesized that IL-10 might have a role in suppressing disease flares in UC remission patients. Unexpectedly, we found that UC remission patients with higher serum IL-10 levels presented faster progression to disease flares. Subsequently, we found that exogenous IL-10 could significantly reduce the level of CD4 and CD8 T cell proliferation. On the other hand, IL-10 significantly elevated the viability of activated CD4 and CD8 T cells. Interestingly, it appeared that the IL-10-mediated pro-survival effects were more pronounced in CD8 T cells than in CD4 T cells and were able to promote the survival of activated T cells when administered prior to cell activation. To examine whether IL-10 in the serum of UC patients was able to enhance T cell survival, we separated UC remission patients into Low, Intermediate, and High groups based on the serum IL-10 level. The native serum from High IL-10 patients, but not the native serum from Low IL-10 patients, could significantly increase the viability of activated T cells. In conclusion, we demonstrated that high IL-10 level at the remission phase was associated with shorter duration of remission, possibly due to IL-10-mediated effects on T cell survival.

Circulating follicular regulatory T cells could inhibit Ig production in a CTLA-4-dependent manner but are dysregulated in ulcerative colitis.

Ulcerative colitis (UC) is a chronic relapsing inflammatory disease that occurs in the gastrointestinal tract, characterized by an upregulation in autoantibody production and antimicrobial antibody production. The interaction between follicular helper T cells (Tfh) and follicular regulatory T cells (Tfr) is critical to the induction and regulation of antibody production. In this study, we investigated the characteristics of Tfr cells in UC patients. We gated circulating Tfr cells as CD4+CXCR5+CD25+CD127- T cells, of which approximately 73% on average were Foxp3+. The circulating Tfh (CD4+CXCR5+CD25-) cells from control subjects and UC patients presented a comparable capacity to induce IgM production from naive B cells and to mediate class switching to IgG. Tfr cells significantly reduced Tfh-mediated B cell help in both healthy controls and UC patients in a concentration-dependent manner. However, the suppression capacity of Tfr cells was significantly lower in UC patients than in healthy controls. Subsequently, we found that the frequency of CTLA-4-expressing cells was only slightly lower in UC patients, but the MFI of CTLA-4, however, was markedly lower in UC patients. CTLA-4 blockade nearly abrogated Tfr-mediated suppression of IgM, and significantly reduced Tfr-mediated suppression of IgG. Moreover, CTLA-4 blockade removed the relative advantage of Tfr suppression capacity in healthy controls compared to UC patients. Overall, this study demonstrated that CTLA-4 was required for Tfr-mediated suppression of B cell help, but was expressed at lower levels in UC patients.

Fecal bacteria from ulcerative colitis patients downregulate Tim-3-mediated inhibitory effects on monocytes in vitro.

Tim-3 is highly expressed on monocytes and macrophages. Blocking Tim-3 was shown to promote macrophage activation. We previously showed that fecal bacteria from patients with active ulcerative colitis (UC) presented significantly higher capacity to stimulate monocyte activation, resulting in higher expression of MHC molecules, costimulatory molecules, and proinflammatory cytokines, but the underlying mechanism remained unclear. Here, we found that fecal bacteria could significantly downregulate the expression of Tim-3 on CD14+ classical monocytes in vitro. Compared to the monocytes from healthy individuals, the monocytes from UC patients not only presented lower Tim-3 expression directly ex vivo, but also presented lower Tim-3 expression after stimulation. Moreover, the extent of Tim-3 downregulation was higher in UC monocytes than in control monocytes. This effect was, at least in part, attributable to differences in fecal bacterium composition between UC patients and healthy controls, since when tested in unrelated volunteers, the fecal bacteria from UC patients presented higher capacity at mediating Tim-3 downregulation. Fecal bacteria also induced TNF-α and IL-6 secretion from monocytes, which was repressible by the Tim-3 ligand Galectin 9 (Gal-9). Interestingly, we found that monocytes from UC patients presented significantly reduced response to exogenous Gal-9, and the extent of Gal-9-mediated inhibition was directly correlated with the level of Tim-3 expression. Overall, our data suggested that the monocytes from UC patients presented lower Tim-3 expression and reduced response to exogenous Gal-9, and the fecal bacteria from UC patients could potently downregulate Tim-3 expression on monocytes in vitro.

FABP7 promotes cell proliferation and survival in colon cancer through MEK/ERK signaling pathway.

Colon cancer (CC), one of the most frequently diagnosed malignancies deriving from the digestive system, has greatly threatened human health and life. Fatty acid binding protein 7 (FABP7), an intracellular protein with the tissue-specific expression pattern, has been reported to be implicated in diverse types of human tumors. However, the biological role of FABP7 in CC is still poorly understood. The current study aimed to investigate the role of FABP7 in CC and illuminate the potential molecular mechanisms. In this present study, we found that FABP7 was highly expressed in CC tissues and cell lines, suggesting the possible involvement of FABP7 in CC tumorigenesis. Moreover, functional investigations showed that FABP7-overexpression promoted CC cell proliferation, colony formation, cell cycle progression and inhibited cell apoptosis; on the contrary, FABP7 knockdown produced an inhibitory effects on CC cell proliferation and survival. Notably, FABP7 knockdown inhibited colon tumor growth in vivo. In addition, mechanistic investigations demonstrated that FABP7 exerted its promoting effects on CC cell proliferation and survival through activation of the MEK/ERK signaling pathway. Collectively, our data indicate that FABP7 may be used as a novel diagnostic bio-marker and a potential therapeutic target for CC.

Calycosin alleviates cerulein-induced acute pancreatitis by inhibiting the inflammatory response and oxidative stress via the p38 MAPK and NF-κB signal pathways in mice.

Acute pancreatitis (AP) is a common acute abdominal disease accompanied by systemic inflammatory response syndrome, and could even be complicated by multiple-organ damage. This study aimed to examine whether calycosin, an isoflavone isolated from Radix astragali with antioxidant and anti-inflammatory activity, could protect against AP induced by cerulein. To this end, Balb/C mice were injected with cerulein (50 µg/kg) to establish the animal model of AP. Calycosin (25 and 50 mg/kg, p.o.) was administered 1 h prior to the first cerulein injection. After the last injection of cerulein, the mice were sacrificed and blood was obtained for cytokine analysis. The pancreas was removed for morphological examination, myeloperoxidase (MPO) and malondialdehyde (MDA) analyses, immunohistochemistry, and western blot analysis. Calycosin treatment reversed the increased serum levels of amylase and lipase, alleviated the pathological damage in the pancreas, and decreased the levels of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1ß in mice with AP. Additionally, calycosin significantly reduced cerulein-induced pancreatic edema, inhibited MPO activity and increased superoxide dismutase (SOD) activity, and inhibited the expression of NF-κB/p65 and phosphorylation of the inhibitor of NF-κB (IκBα) and p38 MAPK. These results suggested that calycosin protects against AP by exerting anti-inflammatory and anti-oxidative stress effects via the p38 MAPK and NF-κB signal pathways. Calycosin's benefits for AP patients need to be explored further.

Co-expression of LAG3 and TIM3 identifies a potent Treg population that suppresses macrophage functions in colorectal cancer patients.

Regulatory T (Treg) cells are critical suppressors of inflammation and are thought to exert mainly deleterious effects in cancers. In colorectal cancer (CRC), Foxp3+ Treg accumulation in tumors was associated with poor prognosis. Hence, we examined the circulating Treg cells in CRC patients. Compared to controls, CRC patients presented mild upregulations in CD4+ CD25+/hi T cells and in the more canonical CD4+ CD25+/hi Foxp3+ Treg cells in peripheral blood mononuclear cells. Both of these Treg populations could be roughly divided into lymphocyte activation gene 3 negative T cell immunoglobulin and mucin-domain containing-3 negative (LAG3- TIM3- ) and LAG3+ TIM3+ subsets. In CRC patients, the LAG3+ TIM3+ subset represented approximately half of CD4+ CD25+/hi T cells and greater than 60% of CD4+ CD25+/hi Foxp3+ Treg cells, which was significantly more frequent than in healthy controls. Compared to the LAG3- TIM3- CD4+ CD25+/hi T cells, the LAG3+ TIM3+ CD4+ CD25+/hi T cells presented considerably higher transforming growth factor-ß and slightly higher interleukin (IL)-10 secretion, together with higher cytotoxic T-lymphocyte associated protein 4 and Foxp3 expression levels. Notably, macrophages following incubation with LAG3- TIM3- CD4+ CD25+/hi T cells and LAG3+ TIM3+ CD4+ CD25+/hi T cells displayed different characteristics. Macrophages incubated with LAG3+ TIM3+ CD4+ CD25+/hi T cells presented lower expression of major histocompatibility complex class II, CD80, CD86, and tumor necrosis factor-α but higher expression of IL-10, than macrophages incubated with LAG3- TIM3- CD4+ CD25+/hi T cells. Together, our investigations demonstrated that CRC patients presented an enrichment of circulating Treg cells, in which the LAG3+ TIM3+ subset exhibited more potent expression of inhibitory molecules, and furthermore, the LAG3+ TIM3+ Treg cells could suppress the proinflammatory activation of macrophages more potently than the LAG3- TIM3- Treg cells.

Fecal microbiome from patients with ulcerative colitis is potent to induce inflammatory responses.

Ulcerative colitis (UC) is a chronic idiopathic disease affecting the colon. Patients with UC display a number of alterations in immune-related molecules and cells, as well as dysbiosis in the intestinal microbiota. It remains unclear whether the alterations in the patients' immune systems are initiating factors of UC or a result from external insults. Also, precisely how these intestinal microorganisms affect UC development is not completely understood. To answer these questions, fecal bacteria were collected from UC patients during the active phase (UC-active), UC patients during the remission phase (UC-remission), and healthy controls. The fecal bacteria were then used to stimulate monocytes from three additional healthy subjects. We found that fecal bacteria from both UC-active and UC-remission patients presented higher capacity than fecal bacteria from healthy controls, resulting higher expression of MHC class I and MHC class II molecules, as well as higher expression of costimulatory molecules CD80 and CD86. The production of multiple cytokines, including IL-6, TNF-α, IL-10, and IL-12, were higher following stimulation with fecal bacteria from UC-active and UC-remission patients. Notably, when fecal bacteria were diluted to lower concentration, the bacteria from UC-active patients was clearly more effective at activating monocytes than those from UC-remission patients and controls. Collectively, our results revealed that the fecal bacteria from UC patients could cause stronger inflammatory responses than fecal bacteria from healthy controls.

Interleukin 35 Rescues Regulatory B Cell Function, but the Effect Is Dysregulated in Ulcerative Colitis.

Ulcerative colitis (UC) is a long-time inflammatory condition arising from aberrant immune activation in the colon and the rectum. Interleukin (IL)-35 plays critical roles in autoimmune disorders. In this study, we explored the pathways of IL-35 in affecting UC. First, peripheral blood mononuclear cells (PBMCs) from UC patients were obtained. Pretreating PBMCs with IL-35 resulted in significantly elevated IL-10 production from whole PBMCs as well as B cells, whereas pretreating PBMCs with IL-12 or IL-27 did not demonstrate a similar effect. IL-35 suppressed the proliferation of CD4+CD25- conventional T cells, CD4+CD25+ regulatory T (Treg) cells, and CD8+ T cells, but did not inhibit the proliferation of B cells. IL-35-mediated IL-10 secretion in B cells did not require the presence of Treg cells. After treatment with IL-35, B cells from UC patients presented significantly enhanced regulatory function, characterized by inhibiting cell proliferation and interferon (IFN)-γ, IL-17, and tumor necrosis factor (TNF)-α secretion from autologous CD4+CD25- T cells and CD8+ T cells, which was dependent on IL-10 signaling. However, IL-35-treatment did not demonstrate an effect on regulating IL-5 and IL-13 responses. These discoveries identified a Th1, Th17, and CD8+ T cell-targeting role of IL-35 in UC patients. Next, we examined the IL-35 expression in the intestinal mucosal in UC patients. Data showed that both noninflamed and inflamed tissues from UC patients presented significantly lower IL-35 secretion compared to healthy control tissues, which was associated with suppressed p35 transcription. UC patients with higher IL-35 also presented higher IL-10 secretion in gut mucosa. Together, our study identified that IL-35 could mediate anti-inflammatory function through promoting regulatory B cell functions, but this effect was suppressed in UC patients.

CXCR5+CD8+ T cells infiltrate the colorectal tumors and nearby lymph nodes, and are associated with enhanced IgG response in B cells.

Colorectal cancer is the third most prevalent cancer type worldwide and contributes to a significant percentage of cancer-related mortality. Recent studies have shown that the CXCR5+CD8+ T cells present more potent proinflammatory function than CXCR5-CD8+ T cells in chronic virus infections and in follicular lymphoma, but the role of CXCR5+CD8+ T cells in colorectal cancer is yet unclear. In this study, we demonstrated that CXCR5+CD8+ T cells were very rare in peripheral blood mononuclear cells from healthy and colorectal cancer individuals, but were significantly enriched in resected tumors and tumor-associated lymph nodes. Compared to CXCR5-CD8+ T cells, the CXCR5+CD8+ T cells demonstrated significantly higher Bcl-6 expression and lower Blimp1 expression, suggesting that CXCR5+CD8+ T cells might represent a memory CD8+ T cell subset. CXCR5+CD8+ T cells also enhanced the IgG expression by autologous B cells. Under ex vivo condition, the CXCR5+CD8+ T cells demonstrated lower degranulation, TNFα expression and IFNγ expression than CXCR5-CD8+ T cells. However, after PMA + ionomycin stimulation, the degranulation and TNFα expression by CXCR5+CD8+ T cells were significantly elevated to a level comparable with CXCR5-CD8+ T cells, whereas the IFNγ expression by PMA + ionomycin-stimulated CXCR5+CD8+ T cells were significantly higher than that by CXCR5-CD8+ T cells. Following long-term TCR-stimulation, CXCR5+CD8+ T cells demonstrated significantly more potent proliferation capacity and higher IFNγ expression than CXCR5-CD8+ T cells. TCR-stimulated CXCR5+CD8+ T cells also showed a gradual downregulation in CXCR5 expression. We further found that TCR-stimulated CXCR5+CD8+ T cells demonstrated higher granzyme B production and induced more specific lysis of autologous tumor cells than CXCR5-CD8+ T cells. Together, these data demonstrate that CXCR5+CD8+ T cells represent a significant CD8+ T cell subset in colorectal tumors and have the potential to contribute to antitumor immunity, but their specific roles require further studies in vivo.

Synergistic enhancement of the antitumor activity of 5-fluorouracil by bornyl acetate in SGC-7901 human gastric cancer cells and the determination of the underlying mechanism of action.

PURPOSE: To investigate the anticancer activity of bornyl acetate and its combination with low dose 5-fluorouracil (5-FU) in human gastric cancer (SGC-7901) cells and to evaluate their effects on cell cycle, apoptosis, cancer cell morphology and DNA fragmentation. METHODS: The anticancer activity of bornyl acetate, 5-FU and their combination against human gastric cancer (SGC-7901) cells was evaluated by MTT assay. Flow cytometry using propidium iodide (PI) as a staining agent was used to study the effect of the extract on cell cycle phase distribution. Apoptosis induced by bornyl acetate and 5-FU was evaluated by Annexin V binding assay using flow cytometer. Alterations in cell morphology following apoptosis was studied by fluorescence microscopy as well as transmission electron microscopy. RESULTS: Bornyl acetate induced dose-dependent growth inhibitory effects on human gastric cancer cells in vitro.The combination of bornyl acetate with 5-FU induced a much more growth inhibitory effect on these cells indicating a synergistic enhancement of anticancer activity of 5-FU. The combined effect of bornyl acetate and 5-FU also resulted in greater apoptosis induction as well as cell cycle arrest in comparison to the individual treatment by bornyl acetate or 5-FU. Fluorescence microscopy as well as transmission electron microscopy also revealed that the combination of bornyl acetate with 5-FU resulted in greater apoptosis induction as well as cell morphology alterations. The percentages of early as well as late apoptotic cells were much higher in the combination treatment in comparison to separate treatment by bornyl acetate or 5-FU. CONCLUSION: Bornyl acetate potentiates the anticancer activity of 5-FU in human gastric cancer (SGC-7901) cells by inducing apoptosis, DNA fragmentation as well as G2/M cell cycle arrest.

Effects of psychological stress on small intestinal motility and bacteria and mucosa in mice.

AIM: To investigate the effects of psychological stress on small intestinal motility and bacteria and mucosa in mice, and to explore the relationship between small intestinal dysfunction and small intestinal motility and bacteria and mucosa under psychological stress. METHODS: Sixty mice were randomly divided into psychological stress group and control group. Each group were subdivided into small intestinal motility group (n = 10), bacteria group (n = 10), and D-xylose administered to stomach group (n = 10). An animal model with psychological stress was established housing the mice with a hungry cat in separate layers of a two-layer cage. A semi-solid colored marker (carbon-ink) was used for monitoring small intestinal transit. The proximal small intestine was harvested under sterile condition and processed for quantitation for aerobes (Escherichia coli) and anaerobes (Lactobacilli). The quantitation of bacteria was expressed as log10(colony forming units/g). D-xylose levels in plasma were measured for estimating the damage of small intestinal mucosa. RESULTS: Small intestinal transit was inhibited (39.80+/-9.50% vs 58.79+/-11.47%, P<0.01) in mice after psychological stress, compared with the controls. Psychological stress resulted in quantitative alterations in the aerobes (E. coli). There was an increase in the number of E. coli in the proximal small intestinal flora (1.78+/-0.30 log10 (CFU/g) vs 1.37+/-0.21 log10 (CFU/g), P<0.01), and there was decrease in relative proportion of Lactobacilli and E. coli of stressed mice (0.53+/-0.63 vs 1.14+/-1.07, P<0.05), while there was no significant difference in the anaerobes (Lactobacilli) between the two groups (2.31+/-0.70 log10 (CFU/g) vs 2.44+/-0.37 log10 (CFU/g), P>0.05). D-xylose concentrations in plasma in psychological stress mice were significantly higher than those in the control group (2.90+/-0.89 mmol/L vs 0.97+/-0.33 mmol/L, P<0.01). CONCLUSION: Small intestinal dysfunction under psychological stress may be related to the small intestinal motility disorder and dysbacteriosis and the damage of mucosa probably caused by psychological stress.