Previous studies have indicated that inflammatory stimulation represses protein phosphatase 2A (PP2A), a well-known tumor suppressor. However, whether PP2A repression participates in pancreatic cancer progression has not been verified. We used lipopolysaccharide (LPS) and macrophage-conditioned medium (MCM) to establish in vitro inflammation models, and investigated whether inflammatory stimuli affect pancreatic cancer cell growth and invasion PP2A catalytic subunit (PP2Ac)-dependently. Via nude mouse models of orthotopic tumor xenografts and dibutyltin dichloride (DBTC)-induced chronic pancreatitis, we evaluated the effect of an inflammatory microenvironment on PP2Ac expression in vivo. We cloned the PP2Acα and PP2Acβ isoform promoters to investigate the PP2Ac transcriptional regulation mechanisms. MCM accelerated pancreatic cancer cell growth; MCM and LPS promoted cell invasion. DBTC promoted xenograft growth and metastasis, induced tumor-associated macrophage infiltration, promoted angiogenesis, activated the nuclear factor-κB (NF-κB) pathway, and repressed PP2Ac expression. In vitro, LPS and MCM downregulated PP2Ac mRNA and protein. PP2Acα overexpression attenuated JNK, ERK, PKC, and IKK phosphorylation, and impaired LPS/MCM-stimulated cell invasion and MCM-promoted cell growth. LPS and MCM activated the NF-κB pathway in vitro. LPS and MCM induced IKK and IκB phosphorylation, leading to p65/RelA nuclear translocation and transcriptional activation. Overexpression of the dominant negative forms of IKKα attenuated LPS and MCM downregulation of PP2Ac, suggesting inflammatory stimuli repress PP2Ac expression NF-κB pathway–dependently. Luciferase reporter gene assay verified that LPS and MCM downregulated PP2Ac transcription through an NF-κB–dependent pathway. Our study presents a new mechanism in inflammation-driven cancer progression through NF-κB pathway–dependent PP2Ac repression.
inflammation; LPS; NF-κB; PP2A; pancreatic cancer; TAM
Premise of the study:
Ficus virens (Moraceae) is distributed widely in South and Southeast Asia, Melanesia, and northern Australia, and it is also cultivated outside its original northern range limit in southwestern China. Therefore, the species is well suited to explore the mechanism of range limits of Ficus species. However, little is known about its genetic background.
Methods and Results:
Fifteen polymorphic microsatellite markers were developed using the biotin-streptavidin capture method. Polymorphism was tested in 85 F. virens individuals sampled from three populations. The number of alleles ranged from three to 17. The observed and expected heterozygosity of each population varied from 0.0667 to 0.9286 and 0.0650 to 0.8890, respectively. Cross-species amplification was also carried out in eight other Ficus species.
These 15 markers will be valuable for studying the genetic variation and population structure of F. virens and related Ficus species.
cross-amplification; Ficus virens; genetic diversity; microsatellite; Moraceae; southwest China
Our previous studies have demonstrated that the levels of 5-hydroxytryptamine (5-HT) and 5-HT 2A receptor (5-HT2AR) in serum and platelet were associated with depression and myocardial infarction (MI), and pretreatment with ginseng fruit saponins (GFS) before MI and depression had an effect on the 5-HT system. In this study, the effects of GFS on the 5-HT system in the Sprague-Dawley (SD) rats with MI, depression, and MI + depression were evaluated.
A total of eighty SD rats were allocated to four groups: MI, depression, MI + depression, and control groups (n = 20 in each group). Each group included two subgroups (n = 10 in each subgroup): Saline treatment subgroup and GFS treatment subgroup. The levels of 5-HT, 5-HT2AR, and serotonin transporter (SERT) were quantified in serum, platelet lysate, and brain tissue through the enzyme-linked immunosorbent assay method, respectively.
Compared with those in the saline treatment subgroups, the levels of 5-HT in serum and platelet lysate statistically significantly increased in the GFS treatment subgroups of MI, depression, and MI + depression groups (serum: all P = 0.000; platelet lysate: P = 0.002, 0.000, 0.000, respectively). However, the 5-HT levels in brain homogenate significantly decreased in the GFS treatment subgroups compared with those in the saline treatment subgroups in MI and depression groups (P = 0.025 and 0.044 respectively), and no significant difference was observed between saline and GFS treatment subgroups in MI + depression group (P = 0.663). Compared with that in GFS treatment subgroup of control group, the 5-HT2AR levels in the platelet lysate significantly decreased in GFS treatment subgroups of MI, depression, and MI + depression groups (all P = 0.000). Compared to those in the saline treatment subgroups, the serum SERT levels significantly decreased in the GFS treatment subgroups in MI, depression, and MI + depression groups (P = 0.009, 0.038, and P = 0.001, respectively), while the SERT levels of platelet lysate significantly decreased in GFS treatment subgroup of MI group (P = 0.000), significantly increased in GFS treatment subgroup of depression group (P = 0.019), and slightly changed in GFS treatment subgroup of MI + depression group (P = 0.219). No significant changes for SERT levels in brain homogenate could be found between the saline and GFS treatment subgroups in MI, depression, and MI + depression groups (P = 0.421, 0.076 and P = 0.642).
This study indicated that GFS might inhibit the reuptake of 5-HT from serum to platelet according to decreased 5-HT2AR in platelet and SERT in serum and platelet. The change of 5-HT in serum after GFS treatment was inconsistent with that in the brain. It seemed that GFS could not pass through the blood-brain barrier to affect the central serotonergic system.
5-hydroxytryptamine 2A Receptor; Depression; Ginseng Fruit Saponins; 5-hydroxytryptamine; Myocardial Infarction; Serotonin Transporter
We compared the effectiveness of abatacept (ABA) vs tocilizumab (TCA) in tumor necrosis factor inhibitor (TNFi) experienced patients.
We identified rheumatoid arthritis (RA) patients from a large observational US cohort (1 January 2010–31 May 2014) who had discontinued at least one TNFi and initiated ABA or TCZ in moderate or high disease activity based on the Clinical Disease Activity Index (CDAI) and had no prior exposure to the comparator drug. Using propensity score matching (1:1) stratified by prior TNF use (1 TNFi vs ≥2 TNFis), effectiveness at 6 months after initiation was evaluated. Mean change in CDAI over 6 months following initiation was the primary outcome, with secondary outcomes of achievement of low disease activity/remission (CDAI ≤ 10) and mean change in modified Health Assessment Questionnaire (mHAQ) score.
The 264 pairs of propensity score-matched ABA and TCZ initiators were well matched with no substantial differences in the baseline characteristics, defined as standardized differences >0.1 in the stratification. Both treatment groups had similar mean change in CDAI at 6 months (–11.3 in ABA vs –9.9 in TCZ; mean difference –1.27, 95% CI –3.65, 1.11). Similar proportions of both treatment groups achieved low disease activity/remission (adjusted odds ratio for ABA vs TCZ 0.99, 95% CI 0.69, 1.43). Mean change in mHAQ was –0.12 in ABA initiators vs –0.11 in TCZ initiations (mean difference –0.01, 95% CI –0.09, 0.06).
Patients receiving either ABA or TCZ had substantial improvement in clinical disease activity. In this propensity score-matched sample, similar outcomes were observed for both treatment cohorts.
Electronic supplementary material
The online version of this article (doi:10.1186/s13075-016-1179-7) contains supplementary material, which is available to authorized users.
Rheumatoid arthritis; Disease-modifying anti-rheumatic drugs (biologic); Tocilizumab; Abatacept; Treatment
We previously demonstrated that serotonin (5-HT) and 5-HT2A receptor (5-HT2AR) levels in platelets were up- or down-regulated after myocardial infarction (MI) associated with depression. In this study, we further evaluated the effects of pretreatment with ginseng fruit saponins (GFS) on the expression of 5-HT and 5-HT2AR in MI with or without depression. Eighty Sprague-Dawley (SD) rats were treated with saline and GFS (n=40 per group). The animals were then randomly divided into four subgroups: sham, MI, depression, and MI + depression (n=10 per subgroup). Protein levels of 5-HT and 5-HT2AR in the serum, platelets and brain tissues were determined with ELISA. The results demonstrated that serum 5-HT levels was significantly increased by GFS pretreatment in all subgroups (except the sham subgroup) when compared with saline-treated counterparts (p<0.01). In platelets, GFS pretreatment significantly increased 5-HT levels in all subgroups when compared with their respective saline-treated counterparts (p<0.01). Brain 5-HT levels also declined with GFS pretreatment in the MI-only and depression-only subgroups (p<0.05 vs. saline pretreatment). With respect to 5-HT2AR levels, platelet 5-HT2AR was decreased in GFS pretreated MI, depression and MI + depression subgroups (p<0.01 vs. saline pretreatment). Similarly, brain 5-HT2AR levels decreased in all four subgroups pretreated with GFS (p<0.01 vs. saline pretreatment). We conclude that GFS plays a clear role in modulating 5-HT and 5-HT2AR expressions after MI and depression. Although the effects of GFS on brain 5-HT remain to be elucidated, its therapeutic potential for comorbidities of acute cardiovascular events and depression appears to hold much promise.
serotonin; ginseng; myocardial infarction; depression; brain
Chronic hepatitis B virus (HBV) infection is a major cause of chronic liver diseases, but its involvement in hepatic fibrogenesis remains unclear. Special AT-rich binding protein 1 (SATB1) has been implicated in reprogramming chromatin organization and transcription profiles in many cancers and non-cancer-related conditions. We found that hepatic SATB1 expression was significantly up-regulated in fibrotic tissues from chronic hepatitis B virus (HBV)-infected patients and HBV transgenic (HBV-Tg) mouse model. Knockdown of SATB1 in the liver significantly alleviated CCl4-induced fibrosis in HBV-Tg mouse model. Moreover, we suggested HBV encoded x protein (HBx) induced SATB1 expression through activation of JNK and ERK pathways. Enforced expression of SATB1 in hepatocytes promoted the activation and proliferation of hepatic stellate cells (HSCs) by secretion of connective tissue growth factor (CTGF), Interleukin-6 (IL-6) and platelet derived growth factor-A (PDGF-AA). Our findings demonstrated that HBx upregulated hepatic SATB1 which exerted pro-fibrotic effects by paracrine activation of stellate cells in HBV-related fibrosis.
Our study aimed to investigate the correlation between single nucleotide polymorphisms of ERCC1/XRCC1/XPA genes and postoperative chemotherapy efficacy and prognosis of endometrial carcinoma. Our study included 108 patients with endometrial carcinoma and 100 healthy participants. ERCC1 rs11615/XRCC1 rs25487/XPA rs1800975 gene polymorphisms were detected by polymerase chain reaction–restriction fragment length polymorphism. Then the chemotherapy efficacy and toxic effects of the patients were assessed. The genotype and allele frequency of ERCC1 rs11615/XRCC1 rs25487 in the case group were significantly different from that in the control group (all P<0.05). The patients with AA + GA in ERCC1 rs11615 had an increased risk of endometrial carcinoma than those with GG, and the risk of endometrial carcinoma for patients with AA + GA was also higher in comparison with patients with GG genotype in XRCC1 rs25487 (all P<0.05). GG on both ERCC1 rs11615/XRCC1 rs25487 had a higher effective rate of chemotherapy than GA + AA (all P<0.05). ERCC1 rs11615/XRCC1 rs25487 gene polymorphisms were linked with toxic effects in liver, kidney, and nervous system. ERCC1 rs11615/XRCC1 rs25487, muscular invasion, and tumor stage were independent risk factors for the prognosis of endometrial carcinoma (all P<0.05). However, no significant associations were observed between XPA rs1800975 polymorphism and chemotherapy efficacy and prognosis of endometrial carcinoma (all P>0.05). These results indicated that ERCC1 and XRCC1 but not XPA polymorphisms correlate with response to chemotherapy in endometrial carcinoma.
ERCC1; XRCC1; XPA; single nucleotide polymorphism; endometrial carcinoma; chemotherapy; efficacy; toxic effects
Fulminant hepatic failure (FHF) is defined as rapid acute liver injury, often complicated with spontaneous bacterial peritonitis (SBP). The precise onset of FHF with SBP is still unknown, but it is thought that SBP closely correlates with a weakened intestinal barrier. Dendritic cells (DCs) play a crucial role in forming the intestinal immune barrier, therefore the number, maturity and chemotactic ability of intestinal DCs were studied in FHF. Mouse intestinal and spleen DCs were isolated by magnetic-activated cell sorting (MACS) and surface markers of DCs, namely CD11c, CD74, CD83 and CD86, were identified using flow cytometry. Immunohistochemistry and Western blotting were performed to detect the distribution and expression of CC-chemokine receptor 7 (CCR7) and CC-chemokine receptor 9 (CCR9), as well as their ligands-CC-chemokine ligand 21 (CCL21) and CC-chemokine ligand 25 (CCL25). Real-time PCR was used to detect CCR7 and CCR9 mRNA, along with their ligands-CCL21 and CCL25 mRNA. Flow cytometry analysis showed that the markers CD74, CD83 and CD86 of CD11c+DCs were lower in the D-galactosamine (D-GalN) group and were significantly decreased in the FHF group, while there were no significant changes in the expression of these markers in the lipopolysaccharide (LPS) group. Immunohistochemistry results showed that staining for CCR7 and CCR9, as well as their ligands CCL21 and CCL25, was significantly weaker in the D-GalN and FHF groups compared with the normal saline (NS) group or the LPS group; the FHF group even showed completely unstained parts. Protein expression of CCR7 and CCR9, as well as their ligands- CCL21 and CCL25, was also lower in the D-GalN group and decreased even more significantly in the FHF group. At the gene level, CCR7 and CCR9, along with CCL21 and CCL25 mRNA expression, was lower in the D-GalN group and significantly decreased in the FHF group compared to the NS and LPS groups, consisting with the protein expression. Our study indicated that intestinal DCs were decreased in number, maturity and chemotactic ability in FHF and might contribute to a decreased function of the intestinal immune barrier in FHF.
The SPI-2 type III secretion system (T3SS) of intracellular Salmonella enterica translocates effector proteins into mammalian cells. Infection of antigen-presenting cells results in SPI-2 T3SS-dependent ubiquitination and reduction of surface-localized mature MHC class II (mMHCII). We identify the effector SteD as required and sufficient for this process. In Mel Juso cells, SteD localized to the Golgi network and vesicles containing the E3 ubiquitin ligase MARCH8 and mMHCII. SteD caused MARCH8-dependent ubiquitination and depletion of surface mMHCII. One of two transmembrane domains and the C-terminal cytoplasmic region of SteD mediated binding to MARCH8 and mMHCII, respectively. Infection of dendritic cells resulted in SteD-dependent depletion of surface MHCII, the co-stimulatory molecule B7.2, and suppression of T cell activation. SteD also accounted for suppression of T cell activation during Salmonella infection of mice. We propose that SteD is an adaptor, forcing inappropriate ubiquitination of mMHCII by MARCH8 and thereby suppressing T cell activation.
•Salmonella effector SteD promotes ubiquitination and surface depletion of mature MHCII•SteD binds both MHCII and the host E3 ubiquitin ligase MARCH8•SteD uses MARCH8 to ubiquitinate and surface deplete MHCII•SteD suppresses T cell activation during Salmonella infection in vitro and in mice
Dendritic cell infection by Salmonella depletes mature MHC class II (mMHCII) from the cell surface. Bayer-Santos et al. reveal that the Salmonella effector SteD binds the E3 ligase MARCH8 and mMHCII to promote mMHCII ubiquitination and surface depletion. SteD suppressed dendritic cell-mediated T cell activation in vitro and in mice.
major histocompatibility complex; dendritic cells; Salmonella; effector; ubiquitin; ligase
Many previous studies have reported that regional cerebral blood flow (rCBF) aberrations may be one of the pathological characteristics of depression and rCBF has demonstrated a certain degree of asymmetry. However, studies investigating the cerebral blood perfusion asymmetry changes of drug-naïve patients experiencing their first episode of major depression using pseudo-continuous arterial spin labeling (pCASL) are rare. Ten drug-naïve patients experiencing their first major depression episode and 15 healthy volunteers were enrolled in the current study. A novel pCASL method was applied to whole brain MRI scans of all of the samples. The Statistics Parameter Mapping and Relative Expression Software Tool software packages were used for the pre-processing and statistical analysis of the two sets of images, and the differences in the cerebral blood perfusion at the whole brain level were compared between the two groups. Compared with the healthy control group, the cerebral perfusion of the depression patients showed an asymmetric pattern. Decreased cerebral blood perfusion regions were primarily located in the left hemisphere, specifically in the left temporal lobe, frontal lobe and cingulate cortex [P<0.05 and cluster size ≥30 with false discovery rate (FDR) correction]. Simultaneously, increased perfusion regions were predominantly located in the right hemisphere, specifically in the right cerebellum, thalamus, frontal lobe and anterior cingulate cortex (P<0.05 and cluster size ≥30, with FDR correction). Thus, pCASL may characterize the alterations in cerebral blood perfusion of patients with depression.
major depression; first-episode; drug naïve; magnetic resonance imaging; functional magnetic resonance imaging; pseudo continuous arterial spin labeling; pseudo-continuous arterial spin labeling; regional cerebral flow; regional cerebral blood flow; asymmetry
Chemokines are a group of low molecular weight peptides. Their major function is the recruitment of leukocytes to inflammation sites, but they also play a key role in tumor growth, angiogenesis, and metastasis. In the last few years, accumulated experimental evidence supports that monokine induced by interferon (IFN)‐gamma (CXCL9), a member of CXC chemokine family and known to attract CXCR3‐ (CXCR3‐A and CXCR3‐B) T lymphocytes, is involved in the pathogenesis of a variety of physiologic diseases during their initiation and their maintenance. This review for the first time presents the most comprehensive summary for the role of CXCL9 in different types of tumors, and demonstrates its contradictory role of CXCL9 in tumor progression. Altogether, this is a useful resource for researchers investigating therapeutic opportunities for cancer.
Cancer; CXCL9; therapy; tumor promoter; tumor suppressor
Vascular smooth muscle cell (VSMC) proliferation is a key event in the development of in-stent restenosis. Evodiamine is an indole alkaloid extracted from the Chinese medicine, evodia, and has been shown to inhibit tumor cell proliferation and protect the cardiovascular system. However, whether evodiamine affects VSMC proliferation remains to be elucidated. Therefore, the present study examined the effects and the mechanisms of action of evodiamine on the proliferation of rat VSMCs. The cells were treated with evodiamine alone or in combination with platelet-derived growth factor-BB (PDGF-BB) stimulation. It was found that evodiamine inhibited PDGF-BB-induced VSMC proliferation in a dose-dependent manner, without inducing cell death. Evodiamine also retarded cell cycle progression, evidenced by the suppression of the expression of cell cycle-promoting cyclin proteins and cyclin-dependent kinases. In addition, evodiamine attenuated the PDGF-BB-induced phosphorylation of mitogen-activated protein kinases p38 and extracellular signal-regulated kinases 1/2, however, it had no effect on the phosphorylation of Akt. Evodiamine also inhibited the increase of reactive oxygen species generation and upregulated the mRNA expression levels of genes encoding antioxidant enzymes. These findings provide important insights into the mechanisms underlying the vasoprotective actions of evodiamine and suggest that it may be a useful therapeutic agent for the treatment of vascular occlusive disease.
evodiamine; vascular smooth muscle cells; proliferation; cell cycle; oxidative stress
TAZ could promote cell proliferation and inhibit Celastrol-induced cell apoptosis. Up-regulation of B-cell lymphoma-2 (Bcl-2), down-regulation of Bcl-2 associated X protein (Bax) and activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway may be the mechanism underlying anti-apoptosis of TAZ.
Hippo pathway is a highly conservative signalling pathway related to the development of organisms, which has been demonstrated to be strongly linked to the tumorigenesis and tumour progression. As the major downstream effector of Hippo pathway, yes-associated protein (YAP), is a transcriptional activator of target genes that are involved in cell proliferation and survival. As an oncogene, YAP can promote cell growth and inhibit cell apoptosis. Another major downstream effector of Hippo pathway, transcriptional co-activators with PDZ-binding motif (TAZ), is nearly 60% homologous with YAP. In the present study, we assume that TAZ probably has the similar function to YAP. To test this issue, we established an inducible and a stable expression system of TAZ in T-Rex-293 and HEK293 cells respectively. The results of cell growth curves, colony formation assay and tumour xenograft growth showed that overexpression of TAZ could promote cell growth in vitro and in vivo. Meanwhile, we found that up-regulated expression of TAZ could partially restore Celastrol-induced cell apoptosis. Induced overexpression of TAZ could up-regulate its target genes including ankyrin repeat domain-containing protein (ANKRD), cysteine-rich 61 (CYR61) and connective tissue growth factor (CTGF), increase the expression of B-cell lymphoma-2 (Bcl-2), decrease the expression of Bcl-2 associated X protein (Bax) and activate the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway, which may be the mechanism underlying anti-apoptosis of TAZ. All these findings indicated that TAZ acts as an oncogene that could be a key regulator of cell proliferation and apoptosis.
anti-apoptosis; Celastrol; proliferation; transcriptional co-activators with PDZ-binding motif (TAZ)
Ménétrier disease (MD) is rare that is involved in both the small bowel and entire colon.
The main symptoms and the important clinical findings:
We describe a case of a 76-year-old male patient whose clinical presentations include intermittent diarrhea, epigastric pain, nausea, vomiting, asitia, and weight loss. An endoscopy was performed showing a large number of irregular forms and different sizes of polypoid lesions in the gastrointestinal tract, which is rare for MD.
The main diagnoses, therapeutics interventions, and outcomes:
Herein, this case was diagnosed as MD, mainly dependent on endoscopic evaluation, typical clinical symptoms, and histopathological examination of biopsy. As this patient was also infected with Helicobacter pylori, the eradication of H pylori was administered. Meanwhile, a high-protein diet was enjoined, the aforementioned patient's symptoms were alleviated evidently after 1 month.
Although the etiology of MD remained undetermined, we showed that eradication of H pylori in this case might contribute to the disease remission. This study enlarged the present understanding of MD.
entire colon; Ménétrier disease; small bowel
To evaluate the clinical therapeutic effects of mifepristone combined with gestrinone on patients with endometriosis.
A total of 150 endometriotic patients treated in our hospital between January 2014 and December 2015 were randomly divided into a control group and a treatment group (n=75). The control group began to orally take gestrinone capsules on the second day after menstruation started (2.5 mg/time, twice/week). The treatment group orally took mifepristone tablets (12.5 mg/time, once/day), and the dosage and administration of gestrinone capsules were the same as those of the control group. After 24 weeks of consecutive treatment, the clinical therapeutic effects of the two groups were assessed, and the pelvic symptom score, clinical sign score, serum sex hormone levels and pregnancy outcomes were compared.
The total effective rates of control and treatment groups were 77.3% and 90.7% respectively, between which the difference was statistically significant (P<0.05). After treatment, the scores of pelvic symptoms (dysmenorrhea, dyspareunia, pelvic pain) and clinical signs (pelvic tenderness, induration) significantly reduced (P<0.05). Each score of the treatment group decreased more significantly than that of the control group did (P<0.05). The serum follicle hormone, luteinizing hormone, estrogen and progesterone levels were significantly lower than those before treatment (P<0.05). Each level of the treatment group dropped more significantly than that of the control group did (P<0.05). The pregnancy rates in the 6th and 12th months of follow-up were 28.0% and 13.3% in the control group respectively, and 42.7% and 29.3% in the treatment group respectively. Such rates of the two groups were significantly different at each follow-up time point (P<0.05).
Mifepristone combined with gestrinone had satisfactory clinical therapeutic effects on endometriosis by reducing hormone levels and improving pregnancy outcomes. Therefore, this regimen is worthy of promotion and application in clinical practice.
Endometriosis; Gestrinone; Mifepristone
Widespread white matter (WM) abnormalities have been found in patients with schizophrenia. Corpus callosum (CC) is the key area that connects the left and right brain hemispheres. However, the results of studies considering different subregions of the CC as regions of interest in patients with schizophrenia have been inconsistent. To obtain a more consistent evaluation of the diffusion characteristics change of the corpus callosum (CC) related to schizophrenia. A meta-analysis involving fractional anisotropy (FA) values in the CC of 729 schizophrenic subjects and 682 healthy controls from 22 studies was conducted. Overall FA values in the CC of the schizophrenic group were less than that of the healthy control group [weighted mean difference (WMD) = -0.021,P< 0.001]. So were the FA values in the genus region (WMD = -0.019, P< 0.001) and the splenium region (WMD = -0.020, P< 0.001) of the CC respectively. The FA reduction was also significant in subjects with chronic schizophrenia (WMD = -0.032, P< 0.001) and first-episode schizophrenia (WMD = -0.014, P = 0.001). In present study, we demonstrated an overall FA decrease in the CC of schizophrenic patients. In the two subgroup analyses of the genu vs splenium region and chronic vs first-episode schizophrenia, the decrease of all groups was significant. Further studies with more homogenous populations and standardized DTI protocols are needed to confirm and extend these findings.
Following infection of mammalian cells, Salmonella enterica serovar Typhimurium (S. Typhimurium) replicates within membrane-bound compartments known as Salmonella-containing vacuoles (SCVs). The Salmonella pathogenicity island 2 type III secretion system (SPI-2 T3SS) translocates approximately 30 different effectors across the vacuolar membrane. SseF and SseG are two such effectors that are required for SCVs to localize close to the Golgi network in infected epithelial cells. In a yeast two-hybrid assay, SseG and an N-terminal variant of SseF interacted directly with mammalian ACBD3, a multifunctional cytosolic Golgi network-associated protein. Knockdown of ACBD3 by small interfering RNA (siRNA) reduced epithelial cell Golgi network association of wild-type bacteria, phenocopying the effect of null mutations of sseG or sseF. Binding of SseF to ACBD3 in infected cells required the presence of SseG. A single-amino-acid mutant of SseG and a double-amino-acid mutant of SseF were obtained that did not interact with ACBD3 in Saccharomyces cerevisiae. When either of these was produced together with the corresponding wild-type effector by Salmonella in infected cells, they enabled SCV-Golgi network association and interacted with ACBD3. However, these properties were lost and bacteria displayed an intracellular replication defect when cells were infected with Salmonella carrying both mutant genes. Knockdown of ACBD3 resulted in a replication defect of wild-type bacteria but did not further attenuate the growth defect of a ΔsseFG mutant strain. We propose a model in which interaction between SseF and SseG enables both proteins to bind ACBD3, thereby anchoring SCVs at the Golgi network and facilitating bacterial replication.
Upon invasion of epithelial cells, the majority of vacuoles containing Salmonella enterica migrate to the perinuclear region-located Golgi network and remain in this region of the cell during the first few rounds of bacterial replication, forming a clustered microcolony of vacuoles. This process requires the action of SseF and SseG, two effector proteins that are translocated by the Salmonella SPI-2 type III secretion system. However, little is known about how they function. Here, we show that both proteins interact with the mammalian Golgi network-associated protein ACBD3. To our knowledge, the SseF-SseG-ACBD3 interaction is the first example of a tethering complex between a pathogen-containing vacuole and a host cell organelle.
Transendothelial migration is a pivotal step before the dissemination of tumor cells into the blood circulation. Related researches about the crosstalk between tumor cells and endothelial cells could contribute to understanding the mechanism of transendothelial migration. Cumulative studies showed that CD133 was an important marker for cancer stem cells. In our research, a co-culture system was developed to study the interaction between CD133+ liver cancer cells and human umbilical vein endothelial cells. The results showed that the direct co-cultured supernatants promoted the migration and invasion of CD133+ liver cancer cells. It was further investigated that the expression level of chemokine CXCL9 was significantly elevated in the culture supernatants of direct co-culture system by activating the NF-kB, rather than in the indirect co-culture system or mono-culture system. High expression of CXCL9 in the direct co-cultured supernatants played a significant role in enhancing the migration and invasion of CD133+ liver cancer cells. Collectively, these findings suggest that chemokine CXCL9 may function as a potential target during the process of transendothelial migration.
CD133+; liver cancer cells; HUVEC; co-culture system; CXCL9
Monitoring the quality of frying oil is important for the health of consumers. This paper reports a microfluidic technique for rapidly quantifying the degradation of frying oil. The microfluidic device generates monodispersed water-in-oil droplets and exploits viscosity and interfacial tension changes of frying oil samples over their frying/degradation process. The measured parameters were correlated to the total polar material percentage that is widely used in the food industry. The results reveal that the steady-state length of droplets can be used for unambiguously assessing frying oil quality degradation.
Supplemental Digital Content is available in the text
The aim of the present study was to explore the relationship between plasma sphingolipids and hepatitis C virus (HCV) replication in chronic hepatitis C (CHC) patients.
A cohort of 120 treatment-naïve CHC patients was included. Liver biopsies and the Scheuer scoring system were used to assess hepatic inflammatory activity. Blood biochemical indicators, HCV-RNA load, and immunological markers were also measured. Forty-four plasma sphingolipids were identified and quantified using high-performance liquid chromatography–tandem mass spectrometry.
The hexosylceramide (HexCer) (d18:1/18:1) level was significantly different between patients with a low HCV load (<106 IU/mL) and a high HCV load (≥106 IU/mL), and it was positively correlated with the HCV-RNA load (r = 0.337, P = 0.001) in CHC patients. Additionally, the plasma HexCer (d18:1/18:1) level (odds ratio 1.302, 95% confidence interval 1.129–1.502) was an independent factor for a high HCV-RNA load. For patients with hepatic inflammation grade ≤2 or HCV genotype 2, HexCer (d18:1/18:1) was independently related to a high HCV-RNA load.
Plasma HexCer (d18:1/18:1) might be involved in the high viral replication level in chronic HCV infection, especially for CHC patients with genotype 2.
Hepatocellular carcinoma (HCC) cells rapidly switch their energy source from oxidative phosphorylation to glycolytic metabolism in order to efficiently proliferate. However, the molecular mechanisms responsible for this switch remain unclear. In this study, we found that miR-592 was frequently downregulated in human HCC tissues and cell lines, and its downregulation was closely correlated with aggressive clinicopathological features and poor prognosis of HCC patients. Overexpression of miR-592 inhibited aerobic glycolysis and proliferation in HCC cells in vitro. Conversely, knockdown of miR-592 promoted HCC growth in both subcutaneous injection and orthotopic liver tumor implantation models in vivo. Mechanistically, miR-592 downregulation in human HCCs was correlated with an upregulation of WD repeat and SOCS box containing 1 (WSB1). We further showed that miR-592 directly binds to the 3′-UTR of the WSB1 gene, thus disrupting hypoxia inducible factor-1α (HIF-1α) protein stabilization. In turn, overexpression of WSB1 in HCC cells rescued decreased HIF-1α expression, glucose uptake, and HCC growth induced by miR-592. Collectively, our clinical data and functional studies suggest that miR-592 is a new robust inhibitor of the Warburg effect and a promising therapeutic target for HCC treatment.
hepatocellular carcinoma; miR-592; hypoxia inducible factor-1α; glycolysis; WSB1
Salmonella enterica replicates in macrophages through the action of effector proteins translocated across the vacuolar membrane by a type III secretion system (T3SS). Here we show that the SPI-2 T3SS effector SpvD suppresses proinflammatory immune responses. SpvD prevented activation of an NF-ĸB-dependent promoter and caused nuclear accumulation of importin-α, which is required for nuclear import of p65. SpvD interacted specifically with the exportin Xpo2, which mediates nuclear-cytoplasmic recycling of importins. We propose that interaction between SpvD and Xpo2 disrupts the normal recycling of importin-α from the nucleus, leading to a defect in nuclear translocation of p65 and inhibition of activation of NF-ĸB regulated promoters. SpvD down-regulated pro-inflammatory responses and contributed to systemic growth of bacteria in mice. This work shows that a bacterial pathogen can manipulate host cell immune responses by interfering with the nuclear transport machinery.
Salmonella Typhimurium replicates in macrophages through the action of effector proteins translocated into host cells by a type III secretion system (T3SS). We show that the T3SS effector SpvD targets the NF-ĸB pathway by interfering with nuclear translocation of p65. SpvD interacts with the exportin Xpo2. Perturbation of Xpo2 disrupts recycling of importin-α from the nucleus, leading to abrogation of p65 nuclear translocation. These data show that a bacterial pathogen manipulates host cell immune responses by interfering with nuclear transport machinery.
Cardiac stem cells or precursor cells regenerate cardiomyocytes; however, the mechanism underlying this effect remains unclear. We generated CreLacZ mice in which more than 99.9% of the cardiomyocytes in the left ventricular field were positive for 5-bromo-4-chloro-3-indolyl-β-d-galactoside (X-gal) staining immediately after tamoxifen injection. Three months after myocardial infarction (MI), the MI mice had more X-gal-negative (newly generated) cells than the control mice (3.04 ± 0.38/mm2, MI; 0.47 ± 0.16/mm2, sham; p < 0.05). The cardiac side population (CSP) cell fraction contained label-retaining cells, which differentiated into X-gal-negative cardiomyocytes after MI. We injected a leukemia inhibitory factor (LIF)-expression construct at the time of MI and identified a significant functional improvement in the LIF-treated group. At 1 month after MI, in the MI border and scar area, the LIF-injected mice had 31.41 ± 5.83 X-gal-negative cardiomyocytes/mm2, whereas the control mice had 12.34 ± 2.56 X-gal-negative cardiomyocytes/mm2 (p < 0.05). Using 5-ethynyl-2'-deoxyurinide (EdU) administration after MI, the percentages of EdU-positive CSP cells in the LIF-treated and control mice were 29.4 ± 2.7% and 10.6 ± 3.7%, respectively, which suggests that LIF influenced CSP proliferation. Moreover, LIF activated the Janus kinase (JAK)signal transducer and activator of transcription (STAT), mitogen-activated protein kinase/extracellular signal-regulated (MEK)extracellular signal-regulated kinase (ERK), and phosphatidylinositol 3-kinase (PI3K)–AKT pathways in CSPs in vivo and in vitro. The enhanced green fluorescent protein (EGFP)-bone marrow-chimeric CreLacZ mouse results indicated that LIF did not stimulate cardiogenesis via circulating bone marrow-derived cells during the 4 weeks following MI. Thus, LIF stimulates, in part, stem cell-derived cardiomyocyte regeneration by activating cardiac stem or precursor cells. This approach may represent a novel therapeutic strategy for cardiogenesis.
In this study, we hypothesized that an increase in integrin αvβ3 and its co-activator vascular endothelial growth factor play important neuroprotective roles in ischemic injury. We performed ischemic preconditioning with bilateral common carotid artery occlusion for 5 minutes in C57BL/6J mice. This was followed by ischemic injury with bilateral common carotid artery occlusion for 30 minutes. The time interval between ischemic preconditioning and lethal ischemia was 48 hours. Histopathological analysis showed that ischemic preconditioning substantially diminished damage to neurons in the hippocampus 7 days after ischemia. Evans Blue dye assay showed that ischemic preconditioning reduced damage to the blood-brain barrier 24 hours after ischemia. This demonstrates the neuroprotective effect of ischemic preconditioning. Western blot assay revealed a significant reduction in protein levels of integrin αvβ3, vascular endothelial growth factor and its receptor in mice given ischemic preconditioning compared with mice not given ischemic preconditioning 24 hours after ischemia. These findings suggest that the neuroprotective effect of ischemic preconditioning is associated with lower integrin αvβ3 and vascular endothelial growth factor levels in the brain following ischemia.
nerve regeneration; brain injury; integrin αvβ3; vascular endothelial growth factor; vascular endothelial growth factor receptor; vascular endothelial growth factor receptor-2; fetal liver kinase 1; ischemic preconditioning; ischemic tolerance; global cerebral ischemia; cerebral ischemia; cerebral infarction; NSFC grant; neural regeneration
The high recurrence rate remains a major problem that strongly influenced the prognosis of hepatocellular carcinoma (HCC) patients who received hepatectomy. The presence of microvascular invasion (MVI) is regarded as the most important risk factor that contributes to the postoperative recurrence. Our previous study has hinted that serum microRNA-125b (miR-125b) was associated with MVI. The aim of the present study was to identify whether serum miR-125b can serve as a biomarker to reliably predict microvascular invasion (MVI) preoperatively. MiR-125b was quantified in 108 HCC patients’ serum before they received surgery by quantitative real-time PCR (qRT-PCR). Our results revealed that MVI was associated with relapse free survival (RFS) of postoperative HCC patients; surgical margin width was associated with postoperative RFS in MVI present patients, but not in the patients without MVI. Multivariate analysis revealed that miR-125b, tumor size and AFP were the independent predictive factors associated with MVI in this cohort (P = .001, .001, .003, respectively). The probability of the predictive accuracy of miR-125b was 76.95% (51.32% specificity and 87.50% sensitivity), which was almost equal to the classifier established by combination of AFP and tumor size (78.82% probability, 65.63% specificity and 84.21% sensitivity). Furthermore, the combination of tumor size, AFP and miR-125b yielded a ROC curve area of 86.68% (72.37% specificity and 84.38% sensitivity). Our study indicated that serum miR-125b can be used to predict MVI of HCC patients before they received hepatic resection. Therefore, miR-125b can potentially guide individualized treatment, which helps HCC patients, with or without MVI, to benefit from different surgical approach.