SUMF1 overexpression promotes tumorous cell growth and migration and is correlated with the immune status of patients with glioma.

BACKGROUND: Glioma is a prevalent type of malignant tumor. To date, there is a lack of literature reports that have examined the association between sulfatase modifying factor 1 (SUMF1) and glioma. METHODS: The levels of SUMF1 were examined, and their relationships with the diagnosis, prognosis, and immune microenvironment of patients with glioma were investigated. Cox and Lasso regression analysis were employed to construct nomograms and risk models associated with SUMF1. The functions and mechanisms of SUMF1 were explored and verified using gene ontology, cell counting kit-8, wound healing, western blotting, and transwell experiments. RESULTS: SUMF1 expression tended to increase in glioma tissues. SUMF1 overexpression was linked to the diagnosis of cancer, survival events, isocitrate dehydrogenase status, age, and histological subtype and was positively correlated with poor prognosis in patients with glioma. SUMF1 overexpression was an independent risk factor for poor prognosis. SUMF1-related nomograms and high-risk scores could predict the outcome of patients with glioma. SUMF1 co-expressed genes were involved in cytokine, T-cell activation, and lymphocyte proliferation. Inhibiting the expression of SUMF1 could deter the proliferation, migration, and invasion of glioma cells through epithelial mesenchymal transition. SUMF1 overexpression was significantly associated with the stromal score, immune cells (such as macrophages, neutrophils, activated dendritic cells), estimate score, immune score, and the expression of the programmed cell death 1, cytotoxic T-lymphocyte associated protein 4, CD79A and other immune cell marker. CONCLUSION: SUMF1 overexpression was found to be correlated with adverse prognosis, cancer detection, and immune status in patients with glioma. Inhibiting the expression of SUMF1 was observed to deter the proliferation, migration, and invasion of cancer cells. The nomograms and risk models associated with SUMF1 could predict the prognosis of patients with glioma.

Robust, Ultrafast and Reversible Photoswitching in Bulk Polymers Enabled by Octupolar Molecule Design.

Improving the photoswitching rate and robustness of photochromic molecules in bulk solids is paramount for practical applications but remains an on-going challenge. Here, we introduce an octupolar design paradigm to develop a new family of visible light organic photoswitches, namely multi-branched octupolar Stenhouse Adducts (MOPSAs) featuring a C3-symmetrical A3-(D-core) architecture with a dipolar donor-acceptor (D-A) photochrome in each branch. Our design couples multi-dimensional geometric and electronic effects of MOPSAs to enable robust ultrafast reversible photoswitching in bulk polymers. Specifically, the optimal MOPSA (4 wt %) in commercial polyurethane films accomplishes nearly 100 % discoloration in 6 s under visible light with ∼ 100 % thermal-recovery in 17.4 s at 60 °C, while the acquired kinetics constants are 3∼7 times that of dipolar DASA counterpart and 1∼2 orders of magnitude higher than those of reported DASAs in polymers. Importantly, the MOPSA-doped polymer films sustain 500 discoloration/recovery cycles with slow degradation, superior to the existing DASAs in polymers (≤30 cycles). We discover that multi-dipolar coupling in MOPSA enables enhanced polarization and electron delocalization, promoting the rate-determining thermal cyclization, while the branched and non-planar geometry of MOPSA induces large free volume to facilitate the isomerization. This design can be extended to develop spiropyran or azobenzene-based ultrafast photochromic films. The superior photoswitching performance of MOPSAs together with their high-yield and scalable synthesis and facile film processing inspires us to explore their versatile uses as smart inks or labels for time-temperature indicators, optical logic encryption and multi-levelled data encryption.

Overexpression of PPM1B inhibited chemoresistance to temozolomide and proliferation in glioma cells.

Protein phosphatase magnesium-dependent 1B (PPM1B) functions as IKKß phosphatases to terminate nuclear factor kappa B (NF-κB) signaling. NF-κB signaling was constitutively activated in glioma cells. At present, little is known about the role of PPM1B in glioma. In the current study, we found that the expression of PPM1B was reduced in glioma tissues and cells, and decreased expression of PPM1B was related to poor overall survival of patients. Overexpression of PPM1B inhibited the proliferation and promoted apoptosis of glioma cells. Moreover, PPM1B overexpression reduced the phosphorylation of IKKß and inhibited the nuclear localization of NF-κBp65. PDTC, an inhibitor of NF-κB signaling, reversed PPM1B-knockdown-induced cell proliferation. Furthermore, overexpression of PPM1B enhanced the sensitivity of glioma cells to temozolomide. In vivo experiments showed that overexpression of PPM1B could inhibit tumor growth, improve the survival rate of nude mice, and enhance the sensitivity to temozolomide. In conclusion, PPM1B suppressed glioma cell proliferation and the IKKß-NF-κB signaling pathway, and enhanced temozolomide sensitivity of glioma cells.

Retraction notice to "Globularifolin exerts anticancer effects on glioma U87 cells through inhibition of Akt/mTOR and MEK/ERK signaling pathways in vitro and inhibits tumor growth in vivo" [Biochmie 142C (2017) 144-151].

This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been retracted at the request of the Editor-in-Chief. Reason for retraction: Figures 5 and 7B show shared images with Figures 4 and 7 of a publication in Mol Med Reports, Zeng et al. (2018) 10.3892/mmr.2018.8599. The two manuscripts were submitted from different laboratories at almost exactly the same time. The authors were contacted but did not respond to the allegation.

Tripartite motif containing protein 37 involves in thrombin stimulated BV-2 microglial cell apoptosis and interleukin 1ß release.

Intracerebral hemorrhage (ICH) is the most common of stroke with high mortality and severe morbidity. Peroxisome proliferator-activated receptor gamma (PPARγ) plays a neuronprotective role in ICH. In the current study, TRIM37 mRNA expression in peripheral blood mononuclear cells (PBMCs) was found to be increased in ICH patients compared to that in healthy controls (n = 15). TRIM37 bound to PPARγ and enhanced its ubiquitination in mouse microglial BV-2 cell line. According to previous studies, thrombin is produced in the brain instantaneously after ICH and triggers the activation of microglia. Here, thrombin induced TRIM37 expression, cell apoptosis and interleukin-1ß (IL-1ß) release in BV-2 cells, while TRIM37 knockdown partially reversed the effects of thrombin on BV-2 cells. TRIM37 overexpression showed similar effects as thrombin on BV-2 cells, and PPARγ agonist rosiglitazone abolished the effects of TRIM37. In summary, TRIM37 involved in apoptosis and IL-1ß release in BV-2 microglia by regulating PPARγ ubiquitination. The present data established a potential biological role of TRIM37 in ICH-induced brain damage and may provide insight into the development of therapy strategies for ICH.

Early or late cranioplasty following decompressive craniotomy for traumatic brain injury: A systematic review and meta-analysis.

Objective To evaluate the effectiveness of early (<3 months) cranioplasty (CP) and late CP (>3 months) on post-operative complications in patients receiving decompressive craniotomy (DC) for traumatic brain injury (TBI). Methods The Cochrane Library, PubMed and EMBASE databases were systematically searched for studies published prior to May 21, 2017. A meta-analysis examined post-operative overall complication rates, infection rates, subdural fluid collection and operating times according to early and late CP. Results Of the initial 1675 references, five studies, all cohort, involving a total of 413 patients, were selected for the review. There was no difference between early and late CP in post-operative overall complication rate (RR=0.68, 95%CI [0.36, 1.29]) and the post-operative infection rate (RR=0.50, 95%CI [0.20, 1.24]) in patients receiving DC for TBI. However, there was a significant difference in post-operative subdural effusion (RR=0.24, 95%CI [0.07, 0.78]) and mean operative time (mean difference = -33.02 min, 95%CI [-48.19, -17.84]) both in favour of early CP. Conclusions No differences were found between early and late CP in post-operative overall complications and procedural related infections in patients receiving DC for TBI, but early CP reduced the complication of subdural effusion and the mean operating time. These findings need to be confirmed by large, randomised controlled trials.

IL-6 increases SDCBP expression, cell proliferation, and cell invasion by activating JAK2/STAT3 in human glioma cells.

Syndecan-binding protein (SDCBP), which is induced by tumor necrosis factor-α and interferon-γ, controls the proliferation and invasion of several different types of cancer cells. Interleukin-6 (IL-6) is known to play an important role in the glioma cell growth and invasion. The present study aimed to investigate the relationship between IL-6 and SDCBP in glioma cells. SDCBP expression was knocked down in two glioma cell lines (T98G and U87) by small interfering RNA (siRNA) transfection. Cell proliferation and invasion were significantly repressed following SDCBP knockdown, and there was a positive correlation between SDCBP and IL-6 expression levels in glioma tissues. IL-6 stimulation dose- and time-dependently induced SDCBP expression at both mRNA and protein levels. Furthermore, pre-treatment with the Janus kinase 2 (JAK2) inhibitor AG490 abolished the IL-6-induced SDCBP expression, suggesting that the effect of IL-6 on SDCBP transcription is dependent on JAK2/signal transducer and activator of transcription 3 (STAT3) signaling. Finally, IL-6 did not stimulate glioma cell growth or invasion when SDCBP expression was suppressed. In summary, our results suggest that IL-6 promotes glioma cell proliferation and invasion by inducing SDCBP expression, which is mediated by JAK2/STAT3 signaling.

Should preventive antibiotics be used in patients with acute stroke? A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Infection is a common complication in acute stroke. Whether or not preventive antibiotics reduce the risk of infection or even lead to a favorable outcome and reduction of mortality after a stroke still remains equivocal. This review was performed to update the current knowledge on the effect and possible benefits of prophylactic antibiotic therapy in patients with stroke. METHODS: A systematic review and meta-analysis of preventive antibiotics`effect on the incidence of infection, favorable outcome (mRS≤2) and mortality in patients with acute stroke is performed with relevant randomized controlled trials. RESULTS: Six studies were identified, involving 4125 participants. Compared with the control group, the treated groups were significantly less prone to suffer from early overall infections [RR = 0.52, 95%CI (0.39, 0.70), p<0.0001], early pneumonia [RR = 0.64, 95%CI (0.42, 0.96), p = 0.03] and early urinary tract infections [RR = 0.35, 95%CI (0.25, 0.48), p<0.00001]. However, there was no significant difference in overall mortality [RR = 1.07, 95%CI (0.90, 1.27), p = 0.44], early mortality [RR = 0.99, 95%CI (0.78, 1.26), p = 0.92], late mortality [RR = 1.12, 95%CI (0.94, 1.35), p = 0.21] or favorable outcome [RR = 1.00, 95%CI (0.92, 1.08), p = 0.98]. CONCLUSION: Although preventive antibiotic treatment did reduce the occurrence of early overall infections, early pneumonia and early urinary tract infection in patients with acute stroke, this advantage was not eventually translated to a favorable outcome and reduction in mortality. Future studies are warranted to identify any subgroup of stroke patients who might benefit from preventive antibiotic treatment.

miR-6743-5p, as a direct upstream regulator of GRIM-19, enhances proliferation and suppresses apoptosis in glioma cells.

Gene associated with retinoid-interferon-induced mortality-19 (GRIM-19) has been recognized as a tumor suppressor protein, which regulates cell growth, apoptosis, and migration by signal transducer and activator of transcription 3 (STAT3) signaling pathway and non-STAT3 pathway in glioma cells. Here, we investigated the molecular mechanisms that regulated GRIM-19 expression in glioma cells. By the TargetScan algorithm, four miRNAs, hsa-miR-17-3p, hsa-miR-423-5p, hsa-miR-3184-5p, and hsa-miR-6743-5p, were identified with the potential to bind with 3'-UTR of GRIM-19. Further miRNA inhibitor transfection and luciferase assays revealed that miR-6743-5p was able to directly target the 3'-UTR of GRIM-19. Additionally, miR-6743-5p expression was inversely related with GRIM-19 expression in glioma specimens and cell lines. Moreover, the inhibition of miR-6743-5p caused a significant inhibition of cell proliferation and a marked promotion of cell apoptosis in glioma cells, and this phenotype was rescued by GRIM-19 knockdown. Finally, the inhibition of miR-6743-5p expression suppressed the phosphorylation of STAT3, and the mRNA expression of CyclinD1 and Bcl-2, two target genes of STAT3, while miR-6743-5p mimic had the inversed effects. Treatment with STAT3 inhibitor AG490 partially rescued the proliferation-promoting and anti-apoptosis effects of miR-6743-5p overexpression or GRIM-19 knockdown. Collectively, miR-6743-5p may act as an oncomiRNA in glioma by targetting GRIM-19 and STAT3.

Globularifolin exerts anticancer effects on glioma U87 cells through inhibition of Akt/mTOR and MEK/ERK signaling pathways in vitro and inhibits tumor growth in vivo.

Gliomas are the most recurrently occurring primary malignancies in the central nervous system. Despite surgical interventions, chemo- and radiotherapy, the results are unfortunately poor. Therefore, there is pressing need to explore more effective and efficient treatment options for treatment of glioma. In the present study we determined the anticancer potential of globularifolin against human glioma U87 cell line and human astrocytes. The results showed that globularifolin exhibits an IC50 value of 7.5 µM against glioma U87 cells as against the IC50 of 65 µM against human astrocytes. The molecule exerted its anticancer activity through induction of apoptosis as evident from the Bid-, and Bax controlled cytochrome c and Omi/HtrA2 release, XIAP suppression, and caspase-9 and 3 signalling cascade. Additionally, it also caused cell cycle arrest of human glioma U87 cancer cells in the S phase of the cell cycle. Interestingly, globularifolin also caused significant inhibition of Akt/mTOR/p70S6K and MEK/ERK pathways. Globularifolin also inhibits cell migration and invasion by regulating the expression of matrix metalloproteinases (MMPs) in U87 glioma cells. We further investigated whether globularifolin exhibits the same effectiveness against glioma cell xenografts in nude mice in vivo and it was observed that globularifolin significantly reduced the tumor growth and volume in vivo indicating the potential of globularifolin as lead molecule for glioma chemotherapy.

Long non-coding RNA Gm4419 promotes trauma-induced astrocyte apoptosis by targeting tumor necrosis factor α.

Traumatic brain injury (TBI) remains a life-threatening disease. Accumulating evidences have showed that neuroinflammatory response is a critical biological event in the progression of TBI induced astrocyte damage. However, the exact mechanisms are not well understood. In this study, we demonstrated that long non-coding RNA (lncRNA) Gm4419 promoted trauma-induced astrocyte apoptosis by up-regulating the expression of inflammatory cytokine tumor necrosis factor α (TNF-α). We observed that Gm4419 was aberrantly induced after injury on astroglial cells in vitro. Overexpression of Gm4419 in injury-treated astrocytes increased protein expressions of TNF-α, Bax, cleaved caspase-3 and cleaved caspase-9, decreased levels of Bcl-2 and CyclinD1, and significantly led to cellular apoptosis. Mechanically, Gm4419 transcript could function as a sponge for miR-466l and miR-466l could target TNF-α 3' UTR for degradation and translation inhibition. Therefore, Gm4419 could up-regulate TNF-α expression by competitively binding miR-466l and then contribute to inflammatory damage as well as astrocyte apoptosis during TBI. Generally speaking, our findings provide better understandings of the mechanism underlying Gm4419 in trauma-induced neuroinflammation and neurological deficits. Thus, the present study would expand the insight into the novel approaches for TBI therapy.

[Retracted] Regulatory T cells exhibit neuroprotective effect in a mouse model of traumatic brain injury.

We would like to retract our article entitled 'Regulatory T cells exhibit neuroprotective effect in a mouse model of traumatic brain injury' published in Molecular Medicine Reports 14: 5556-5566, 2016. After careful consideration, we recognize that there was an undeclared conflict of interest on the part of certain of the authors. All the authors agree to this retraction. We sincerely apologize for any inconvenience that might result from the retraction of this article. [The original article was published in Molecular Medicine Reports 14: 5556-5566, 2016; DOI: 10.3892/mmr.2016.5954].

NLRP3 is Required for Complement-Mediated Caspase-1 and IL-1beta Activation in ICH.

Complement-mediated inflammation plays a vital role in intracerebral hemorrhage (ICH), implicating pro-inflammatory factor interleukin-1beta (IL-1ß) secretion. Brain samples and contralateral hemiencephalon were all collected and detected by Western blot. NLRP3 expression was located by dual immunofluorescence staining at 1, 3, and 5 days post-ICH. Brain water content was examined post-ICH. The neural deficit scores were evaluated by observers blindly. ILs were detected by ELISA. SiRNAs targeting NLRP3 (siNLRP3), siASC, and siControl were injected to inhibit NLRP3 function. To test the complement activation via Nod-like receptor (NLR) family pyrin domain-containing 3 (NLRP3), normal rabbit complement (NRC) was injected with lipopolysaccharide (LPS) to facilitate the complement function. As a result, complement 3a (C3a) and complement 5a (C5a) were upregulated during the ICH-induced neuroinflammation, and ablation of C3 attenuates ICH-induced IL-1ß release. Though the LPS rescues the neuroinflammation in the ICH model, C3 deficiency attenuates the LPS-induced inflammatory effect. The NLRP3 inflammasome was activated after ICH and was located in the microglial cell of the mouse brain, which exhibits a time-dependent manner. However, the number of NLRP3/Iba-1 dual-labeled cells in the C3-/- group is less than that in the WT group in each time course, respectively. IL-1ß and IL-18 released in perihematoma tissue, caspase-1-p20, brain water content, and behavioral outcomes were attenuated in the siNLRP3 and siASC groups than in the siControl and ICH groups. We also found that 5% of complement supplement enhances ICH-induced IL-1ß release, while NLRP3 and ASC inhibition attenuates it. In conclusion, complement-induced ICH neuroinflammation depended on NLRP3 activation, which facilities LPS- and ICH-induced neuroinflammation, and NLRP3 is required for ICH-induced inflammation.

Effects of syndecan-1 on the expression of syntenin and the migration of U251 glioma cells.

Glioma is the most frequently occuring primary brain tumor. Syndecan-1 (SDC1) expression is related to poor prognosis of numerous human malignancies including glioma. Syndecan binding protein (SDCBP) is an important partner for SDC1. The present study investigated whether SDC1 and SDCBP are expressed in glioma and their functions on glioma cell migration. An immunohistochemical assay revealed that SDC1 and SDCBP were expressed and were positively related to malignant level of glioma (SDC1, rs=0.576, P=0.001; SDCBP, rs=0.661, P<0.001). Moreover, the protein levels of SDC1 were positively correlated with those of SDCBP in glioma tissues (rs=0.628, P=0.001). In U251 glioma cells, protein levels of SDC1 and SDCBP were both upregulated in U251 cells with SDC1 overexpression, while downregulated with SDC1 knockdown. Transwell assay and scratch-wound healing assay showed that SDC1 overexpression significantly increased U251 cell migration, while SDC1 knockdown had the opposite effects. Rac1 activity, signal transducer and activator of transcription 3 (STAT3) phosphorylation, as well as expression of matrix metalloproteinase 2 (MMP2) and MMP9 was significantly increased by SDC1 overexpression, while was decreased by SDC1 knockdown. In conclusion, SDC1 overexpression upregulated SDCBP expression, and promoted glioma cell migration via Rac1 activation.

Regulatory T cells exhibit neuroprotective effect in a mouse model of traumatic brain injury.

Traumatic brain injury (TBI) is a major health and socioeconomic problem as it is associated with high rates of mortality and morbidity worldwide. Regulatory T cells (Tregs) have been reported to reduce inflammatory response in several diseases, including myasthenia gravis, viral myocarditis and cerebral infarction. The present study investigated the role of Tregs in mediating neuro­protective effects in a mouse model of TBI. Initially, Treg levels were determined, and compared between the controlled cortical impact (CCI) model for moderate TBI and the sham group, by using flow cytometry and ELISA. Afterwards, the number of Tregs was upregulated (by injection) and downregulated (by depletion), respectively, to elucidate the effect of Tregs in the presence of an inflammatory reaction and a deficient neurological function and consequently, in the prognosis of TBI in the mouse. The expression of pro­inflammatory cytokines [tumor necrosis factor (TNF)­α, interleukin (IL)­1ß, IL­6)] and anti­inflammatory cytokines [IL­10, transforming growth factor (TGF)­ß] in blood and brain tissues was also measured in the five groups: Μice receiving a saline injection, mice experiencing Treg depletion, small­dose (SD Tregs, 1.25x105), and mice receiving different doses of Tregs: Moderate­dose (MD Tregs, 2.5x105) and large­dose (LD Tregs, 5x105), using ELISA and PCR. Co­cultures of Tregs and microglia were performed to evaluate the expression of pro­inflammatory cytokines and observe the interaction between the two types of cells. The regulation patterns in JNK­NF­κB pathway by Tregs were also evaluated by western blot analysis. Treg levels were significantly reduced in TBI mouse group on the 3rd day after TBI (P<0.05). In the mouse model of TBI, the expression of pro­inflammatory cytokines (TNF­α, IL­1ß, IL­6) was enhanced, while the expression of anti­inflammatory cytokines (IL­10, TGF­ß) was reduced (P<0.05). Tregs exhibited a suppressive effect on inflammatory reactions. In the MD group, the activation of microglia cells was markedly inhibited, compared to the activation in SD and LD groups. The expression of ERK1/2, JNK1/2/3 and NK­κB was significantly downregulated in the MD group. The results indicated that Tregs exhibited significant neuro­protective effects, suppressing pro­inflammatory responses and promoting tissue repair after TBI injury in the mouse, specifically by deactivating the JNK­NF­κB pathway. The results of the study show that Tregs potentially participates in neuro­therapeutic approaches for TBI.

Activation of the Notch signaling pathway promotes neurovascular repair after traumatic brain injury.

The Notch signaling pathway plays a key role in angiogenesis and endothelial cell formation, but it remains unclear whether it is involved in vascular repair by endothelial progenitor cells after traumatic brain injury. Therefore, in the present study, we controlled the Notch signaling pathway using overexpression and knockdown constructs. Activation of the Notch signaling pathway by Notch1 or Jagged1 overexpression enhanced the migration, invasiveness and angiogenic ability of endothelial progenitor cells. Suppression of the Notch signaling pathway with Notch1 or Jagged1 siRNAs reduced the migratory capacity, invasiveness and angiogenic ability of endothelial progenitor cells. Activation of the Notch signaling pathway in vivo in a rat model of mild traumatic brain injury promoted neurovascular repair. These findings suggest that the activation of the Notch signaling pathway promotes blood vessel formation and tissue repair after brain trauma.

Nuclear SMAD2 restrains proliferation of glioblastoma.

AIMS: Although TGFß receptor signaling has been shown to play a role in regulation of the growth and metastasis of glioblastoma multiforme (GBM), the downstream pathway through either SMAD2 or SMAD3 has not been elucidated. In this study, we investigate whether nuclear SMAD2 can restrain the proliferation of glioblastoma. METHODS: A total of 23 resected specimens from GBM patients were collected for SMAD2 detection. Human GBM cell line A172, U87mg, D341m and Hs683 were maintained in Dulbecco's modified Eagle's medium and transfected with SMAD2 and SMAD3 shRNA plasmids. Gene expression was detected by RT-qPCR and Western and cell growth were detected by MTT assay. RESULTS: Our results showed that the phosphorylated SMAD2 (pSMAD2, the nuclear and functional form of SMAD2) levels in GBM were significantly lower than the paired normal brain tissue in patients. Depletion of SMAD2, but not SMAD3, significantly abolished the inhibitory effects of TGFß1 on the growth of GBM cells, possibly through pSMAD2-mediated increases in cell-cycle inhibitor, p27. CONCLUSION: Our data suggest that TGFß/SMAD2 signaling cascades restrains growth of GBM.