IL-6 Up-Regulates Expression of LIM-Domain Only Protein 4 in Psoriatic Keratinocytes through Activation of the MEK/ERK/NF-κB Pathway.

Psoriasis is a chronic inflammatory skin disease characterized by the activation of keratinocytes and the infiltration of immune cells. Overexpression of the transcription factor LIM-domain only protein 4 (LMO4) promoted by IL-23 has critical roles in regulating the proliferation and differentiation of psoriatic keratinocytes. IL-6, an autocrine cytokine in psoriatic epidermis, is a key mediator of IL-23/T helper 17-driven cutaneous inflammation. However, little is known about how IL-6 regulates the up-regulation of LMO4 expression in psoriatic lesions. In this study, human immortalized keratinocyte cells, clinical biopsy specimens, and an animal model of psoriasis induced by imiquimod cream were used to investigate the role of IL-6 in the regulation of keratinocyte proliferation and differentiation. Psoriatic epidermis showed abnormal expression of IL-6 and LMO4. IL-6 up-regulated the expression of LMO4 and promoted keratinocyte proliferation and differentiation. Furthermore, in vitro and in vivo studies showed that IL-6 up-regulates LMO4 expression by activating the mitogen-activated extracellular signal-regulated kinase (MEK)/extracellular signal-regulated kinase (ERK)/NF-κB signaling pathway. These results suggest that IL-6 can activate the NF-κB signaling pathway, up-regulate the expression of LMO4, lead to abnormal proliferation and differentiation of keratinocytes, and promote the occurrence and development of psoriasis.

Pro-inflammatory cytokine IL-6 regulates LMO4 expression in psoriatic keratinocytes via AKT/STAT3 pathway.

The transcription factor LIM-only protein 4 (LMO4) is overexpressed in the psoriatic epidermis and regulates keratinocyte proliferation and differentiation. High LMO4 expression levels are induced by interleukin-23 (IL-23) to activate the AKT/STAT3 signaling pathway. Interleukin-6 (IL-6) is mainly involved in regulating T cell functions and development in patients with psoriasis. However, whether LMO4 expression is regulated by IL-6 remains unclear. Therefore, the purpose of this study is to explore the role and molecular mechanisms of IL-6 in regulating LMO4 expression. The interleukin-6 (IL-6) levels in human plasma were determined using a chemiluminescence immunoassay system. A psoriasis-like mouse model was established using imiquimod induction. Epidermal keratinocytes (HaCaT) were cultured in defined keratinocyte-serum-free medium and stimulated by IL-6 alone or with inhibitors. The proteins of interest were detected using western blot analysis, immunofluorescence, and immunohistochemistry. The 5-ethynyl-2'-deoxyuridine assay was used to detect cell proliferation. The results revealed that IL-6 levels were markedly increased in the plasma of patients with psoriasis, compared to healthy control. The high expression of LMO4 was consistent with high levels of IL-6, p-AKT, and p-STAT3 in the lesions of both psoriasis patients and imiquimod-induced psoriasis-like mice. IL-6 activates the AKT/STAT3 signaling pathway, followed by LMO4 high-expression in HaCaT cells. IL-6 induces HaCaT proliferation and differentiation via AKT/STAT3 signaling pathway activation. We think that the high expression of LMO4 in psoriatic keratinocytes requires IL-6 to activate the AKT/STAT3 signaling pathway and leads to epidermal keratinocytes abnormal proliferation and differentiation.

Ultrasound-Guided Cannulation of the Great Saphenous Vein in Neonates: A Randomized Study.

OBJECTIVE: This prospective randomized controlled study aimed to compare the ultrasound-guided (USG) technique with the standard single-wall puncture technique for epicutaneo-caval catheter (ECC) placement in neonates. STUDY DESIGN: A total of 100 neonates were included in this study. All enrolled neonates were randomly divided into two groups (n = 50): the USG group and the control group. The control group underwent standard single-wall puncture for ECC placement procedures, and the USG group underwent USG ECC placement procedures. RESULTS: The first attempt success rates (62 vs. 38%; p = 0.016) and the total success rates (92 vs. 74%; p = 0.017) were higher in the USG group than in the control group. The procedure time was shorter in the USG group than in the control group: 351.43 (112.95) versus 739.78 seconds (369.13), p < 0.001. The incidence of adverse events was not significantly different between the two groups. CONCLUSION: Compared with the standard single-wall puncture method, USG cannulation is superior for neonatal ECC placement, with a higher success rate, and decreases the total procedural time. KEY POINTS: · Establishing ECCs in neonates is challenging and lead to multiple attempts and adverse events.. · Information on the efficiency of USG dynamic needle tip positioning for ECCs in neonates is lacking.. · Compared with the standard puncture method, USG cannulation is superior for neonatal ECC placement..

GPR108 is required for gambogic acid inhibiting NF-κB signaling in cancer.

GPCRs are the most potential targets for drug discovery, however, their role in oncology is underappreciated and GPCR-based anti-cancer drug is not fully investigated. Herein, we identified GPR108, a GPCR protein described in innate immune system, is a potential therapeutic target of cancer. Depletion of GPR108 dramatically inhibited the survival of various cancers. Notably, TNFα activation of NF-κB was totally impaired after GPR108 knockout. We identified gambogic acid (GA), a natural prenylated xanthone, selectively targeting GPR108. Importantly, GA engaged with GPR108 and promoted its degradation, knockout of GPR108 remarkably blocked GA inhibition of NF-κB signaling. Furthermore, in vitro and in vivo assays demonstrated that GA was dependent on GPR108 to exert anti-cancer activity. Overall, our findings supported GPR108 as a promising therapeutic target of cancer, and provided a small molecule inhibitor GA directly and selectively targeting GPR108 for cancer therapy.

A novel four-gene signature predicts immunotherapy response of patients with different cancers.

BACKGROUND: Immune checkpoint blockade (ICB) therapy has demonstrated favorable clinical efficacy, particularly for advanced or difficult-to-treat cancer types. However, this therapy is ineffective for many patients displaying lack of immune response or resistance to ICB. This study aimed to establish a novel four-gene signature (CD8A, CD8B, TCF7, and LEF1) to provide a prognostic immunotherapy biomarker for different cancers. METHODS: Transcriptome profiles and clinical data were obtained from The Cancer Genome Atlas database. Multivariate Cox regression analysis was used to establish a four-gene signature. The R package estimate was used to obtain the immune score for every patient. RESULTS: Risk scores of the novel four-gene signature could effectively divided all patients into high- and low-risk groups, with distinct outcomes. The immune score calculated via the estimate package demonstrated that the four-gene signature was significantly associated with the immune infiltration level. Furthermore, the four-gene signature could predict the response to atezolizumab immunotherapy in patients with metastatic urothelial cancer. CONCLUSIONS: The novel four-gene signature developed in this study is a good prognostic biomarker, as it could identify many kinds of patients with cancer who are likely to respond to and benefit from immunotherapy.

Both high glucose and phosphate overload promote senescence-associated calcification of vascular muscle cells.

PURPOSE: The NAD+-dependent deacetylase, sirtuin 1 (SIRT1), plays an important role in vascular calcification induced by high glucose and/or high phosphate levels. However, the mechanism by which SIRT1 regulates this process is still not fully understood. Thus, this study aimed to determine the role of high glucose and phosphate in vascular calcification and the molecular mechanisms underlying SIRT1 regulation. METHODS: Vascular smooth muscle cells (VSMCs) were cultured under normal, high phosphate, and/or high-glucose conditions for 9 days. Alizarin red staining and calcification content analyses were used to determine calcium deposition. VSMC senescence was detected by ß-galactosidase (SA-ß-Gal) staining and p21 expression. RESULTS: Mouse VSMCs exposed to high phosphate and high glucose in vitro showed increased calcification, which was correlated with the induction of cell senescence, as confirmed by the increased SA-ß-galactosidase activity and p21 expression. SRT1720, an activator of SIRT1, inhibits p65 acetylation, the nuclear factor-κ-gene binding (NF-κB) pathway, and VSMC transdifferentiation, prevents senescence and reactive oxygen species (ROS) production, and reduces vascular calcification. In contrast, sirtinol, an inhibitor of SIRT1, increases p65 acetylation, activates the NF-κB pathway, induces vascular smooth muscle cell transdifferentiation and senescence, and promotes vascular calcification. CONCLUSIONS: High glucose and high phosphate levels induce senescence and vascular calcification in VSMCs, and the combined effect of high glucose and phosphate can inhibit SIRT1 expression. SIRT1 inhibits vascular smooth muscle cell senescence and osteogenic differentiation by inhibiting NF-κB activity, thereby inhibiting vascular calcification.

Ultrasound guidance for internal jugular vein cannulation in neonates: Modified dynamic needle tip positioning short-axis out-of-plane technique versus long-axis in-plane technique, a randomized controlled trial.

BACKGROUND: Ultrasound-guided central venous catheter placement has significantly improved the success rate of punctures and reduced the risk of complications. However, catheterizing the internal jugular vein under ultrasound guidance in neonates remains challenging. METHODS: Ninety-six patients were screened for eligibility in this randomized controlled trial between November 2018 and October 2019. After meeting the inclusion criteria, 90 term neonates undergoing cardiothoracic, general, or neurosurgery procedures were randomly assigned to the modified dynamic needle tip positioning short-axis (n = 45) or long-axis groups (n = 45) using a computer-generated random numbers table. The primary outcome was the first-attempt success rate. The secondary outcomes included the total success rate, cannulation time, and incidence of cannulation-related complications, including hematoma, accidental arterial puncture, or pneumothorax. Data were compared between the two groups. RESULTS: The success rate for the first attempt was higher (88.9% vs 64.4%; p = 0.001; relative risk, 1.4; 95% confidence interval, 1.1-1.8), while the cannulation time was shorter (171.0 ± 47.8 s vs 304.4 ± 113.5 s; p = 0.001; estimated difference, -133.4; 95% confidence interval, -170.1 to -96.7), in the modified dynamic needle tip positioning short-axis group compared with the long-axis group. Six hematomas and two common carotid artery punctures were identified in the long-axis group, while none were identified in the modified dynamic needle tip positioning short-axis group. CONCLUSIONS: The modified dynamic needle tip positioning short-axis out-of-plane technique enhanced the procedural efficacy and safety of internal jugular vein catheterization in neonates.

A negative feedback loop involving NF-κB/TIR8 regulates IL-1ß-induced epithelial- myofibroblast transdifferentiation in human tubular cells.

Renal tubular epithelial-myofibroblast transdifferentiation (EMT) plays a central role in the development of renal interstitial fibrosis (RIF). The profibrotic cytokine interleukin (IL)-1 and the IL-1 receptor (IL-1R) also participate in RIF development, and Toll/IL-1R 8 (TIR8), a member of the Toll-like receptor superfamily, has been identified as a negative regulator of IL-1R signaling. However, the functions of TIR8 in IL-1-induced RIF remain unknown. Here, human embryonic kidney epithelial cells (HKC) and unilateral ureteric obstruction (UUO)-induced RIF models on SD rats were used to investigate the functions of TIR8 involving IL-1ß-induced EMT. We showed that IL-1ß primarily triggers TIR8 expression by activating nuclear factor-κB (NF-κB) in HKC cells. Conversely, high levels of TIR8 in HKC cells repress IL-1ß-induced NF-κB activation and inhibit IL-1ß-induced EMT. Moreover, in vitro and in vivo findings revealed that TIR8 downregulation facilitated IL-1ß-induced NF-κB activation and contributed to TGF-ß1-mediated EMT in renal tubular epithelial cells. These results suggested that TIR8 exerts a protective role in IL-1ß-mediated EMT and potentially represents a new target for RIF treatment.

Distal superficial femoral vein versus axillary vein central catheter placement under ultrasound guidance for neonates with difficult access: A randomized clinical trial.

BACKGROUND: Epicutaneo-caval catheters (ECCs) are extensively used in premature and ill neonates. This prospective, randomized, observational study aimed to compare the outcomes of ECC placement in the distal superficial femoral and axillary veins in neonates with difficult ECC access. METHODS: In a neonatal intensive care unit at a tertiary referral center, 60 neonates with difficult ECC access were randomized into two groups with catheters placed using the ultrasound-guided modified dynamic needle tip positioning (MDNTP) technique: distal superficial femoral vein (DSFV) and axillary vein (AV) groups. RESULTS: The first attempt success rate was significantly higher in the DSFV group than in the AV group [23/30 (76.7%) vs 11/30 (36.7%), p = 0.001; odds ratio (OR), 0.176; 95% confidence interval (CI) 0.057-0.543]. The mean procedural duration was significantly shorter in the DSFV group than in the AV group [mean: 308.5 (standard deviation: 81.1) s vs 522.74 (134.8) s, t = -7.17, p < 0.001]. The incidence of complications was significantly lower in the DSFV group than in the AV group [4/30 (13.3%) vs 12/30 (40.0%), p = 0.019; OR, 4.333; 95% CI 1.203-15.604]. The number of attempts was significantly fewer in the DSFV group than in the AV group (p = 0.012). CONCLUSIONS: The distal superficial femoral and axillary veins are two alternative and safe access points for ECC placement in premature neonates (weight < 2.5 kg) with difficult access. However, access through the distal superficial femoral vein was quicker, easier, and had fewer complications than through the axillary vein.

Combined short- and long-axis method for internal jugular vein catheterization in premature newborns: A randomized controlled trial.

BACKGROUND: Rapid central venous catheterization is critical for the rescue and perioperative management of premature infants requiring surgery. Ultrasound-guided dynamic needle tip positioning (DNTP) has been widely used as a very effective technique, especially in paediatric vascular puncture and catheterization. However, for low-weight premature newborns, central vein catheterization still poses greater difficulties for paediatricians and paediatric anaesthesiologists. This prospective randomized control study aimed to evaluate the efficacy of combined short- and long-axis (CSLA) internal jugular vein catheterization for premature newborns in comparison with the DNTP technique. METHODS: A total of 90 premature newborns (gestational age < 37 weeks and < 28 days after birth) who were scheduled for surgery were included in this study. All enrolled premature newborns were randomly divided into two groups (n = 45): the CSLA group and the DNTP group. We compared the first-puncture success rate, total success rate, procedure time, number of needle passes, occurrence of complications and other outcome measures between the two groups. RESULTS: The two groups (n = 45 per group) were similar in sex, gestational age, weight, mean arterial blood pressure, and vein-related measurements of the internal jugular vein. Total success was achieved in 43 (95.6%) and 36 (80.0%) patients in the CSLA and DNTP groups respectively. Compared with the DNTP group, the CSLA group showed a significantly higher first-attempt success rate (71.1% vs 46.7%, χ2  = 5.5533, P = .0184) and significantly fewer needle passes (1.0[1.0-2.0] vs 2.0[1.0-3.0], χ2  = -2.6094, P = .0091). There was no significant difference between the groups in the procedure time (368[304-573] vs 478[324-79]s, Z = -1.7690, P = .0769). Complications occurred in both groups, but the incidence was significantly lower in the CSLA group than in the DNTP group (6.7% vs 22.2%, χ2  = 4.4056, P = .0358). CONCLUSIONS: Ultrasound-guided internal jugular vein catheterization by the CSLA method is effective and safe. The CSLA method may be superior to the DNTP technique in premature newborns.

TRPV1 Contributes to the Neuroprotective Effect of Dexmedetomidine in Pilocarpine-Induced Status Epilepticus Juvenile Rats.

To investigate the antiepileptic and neuroprotective effects of dexmedetomidine (Dex) in pilocarpine- (Pilo-) induced status epilepticus (SE) juvenile rats, rats were randomly assigned to the following six groups (n = 20): normal, normal+Dex, SE, SE+Cap, SE+Dex, and SE+Dex+Cap. The rats were treated with either diazepam (i.p., an antiepileptic drug) or Dex after the onset of SE. The Morris water maze was used to assess rat cognitive behavior. Flow cytometry was used to detect the concentrations of Ca2+, mitochondrial membrane potential, and reactive oxygen species. Transmission electron microscopy was performed to evaluate specimens of brain tissue. The levels of caspase 3 and TRPV1 were examined by western blot and immunohistochemistry (IHC). Treatment with Dex significantly decreased the escape latency of the SE rats (P < 0.05). Capsaicin, a TRPV1 agonist, delivery aggravated the performance of SE rats. Pathological changes in SE rat were attenuated by Dex and deteriorated by capsaicin. Swollen mitochondria and abnormal endoplasmic reticulum were found in SE rats and were then aggravated by capsaicin and reversed by Dex. Moreover, our data showed that Dex significantly restrained calcium overload, ROS production, and mitochondrial membrane potential loss, all of which were induced by Pilo and capsaicin (P < 0.05). Dex decreased the apoptotic rate in the Model SE group (P < 0.05) and TRPV1 and caspase 3 expression in the Dex treatment group (P < 0.05). Interestingly, all these effects of Dex were partially counteracted by the TRPV1 agonist, capsaicin (P < 0.05). Our study showed that Dex exerted a neuroprotective effect in Pilo-induced SE rats by inhibiting TRPV1 expression and provided information for therapy to SE patients.

The therapeutic effect of controlled reoxygenation on chronic hypoxia-associated brain injury.

Cardiopulmonary bypass (CPB) is the most general technique applied in congenital heart disease (CHD). However, standard CPB poses a specific pathologic condition for patients during surgery: exposure to reoxygenation. When surgery is performed on cyanotic infants, standard CPB is usually initiated at a high concentration of oxygen without consideration of cytotoxic effects. Controlled reoxygenation is defined as using normoxic CPB with a pump primed to the PO2 (oxygen tension in the blood), which is matched to the patient's preoperative saturation. The aim of this study was to determine whether controlled reoxygenation could avoid standard reoxygenation injury and also to clarify the molecular signaling pathways during hypoxia. We successfully reproduced the abnormal brain observed in mice with chronic hypoxia during early postnatal development - equivalent to the third trimester in human. Mice were treated with standard reoxygenation and controlled reoxygenation after hypoxia for 24 h. We then assessed the brain tissue of these mice. In standard reoxygenation-treated hypoxia mice, the caspase-3-dependent neuronal apoptosis was enhanced by increasing concentration of oxygen. Interestingly, controlled reoxygenation inhibited neuron and glial cell apoptosis through suppressing cleavage of caspase-3 and PARP. We also found that controlled reoxygenation suppressed LCN2 expression and inflammatory cytokine (including TNF-α, IL-6, and CXCL10) production, in which the JAK2/STAT3 signaling pathway might participate. In conclusion, our findings propose the novel therapeutic potential of controlled reoxygenation on CPB during CHD.

Anticonvulsant and Neuroprotective Effects of Dexmedetomidine on Pilocarpine-Induced Status Epilepticus in Rats Using a Metabolomics Approach.

BACKGROUND Status epilepticus (SE) is the most extreme form of seizure. It is a medical and neurological emergency that requires prompt and appropriate treatment and early neuroprotection. Dexmedetomidine (DEX) is mainly used for its sedative, analgesic, anxiolytic, and neuroprotective effects with light respiratory depression. The purpose of this study was to comprehensively analyze the metabolic events associated with anticonvulsion and neuroprotection of DEX on pilocarpine-induced status epilepticus rats by LC-MS/MS-based on metabolomics methods combined with histopathology. MATERIAL AND METHODS In this research, rats were divided into 3 groups: a normal group, an SE group, and an SE+DEX group. Hippocampus of rats from each group were collected for further LC-MS/MS-based metabolomic analysis. We collected brains for HE staining and Nissl staining. Multivariate analysis and KEGG enrichment analysis were performed. RESULTS Results of metabolic profiles of the hippocampus tissues of rats proved that dexmedetomidine relieved rats suffering from the status epilepticus by restoring the damaged neuromodulatory metabolism and neurotransmitters, reducing the disturbance in energy, improving oxidative stress, and alleviating nucleic acid metabolism and amino acid in pilocarpine-induced status epilepticus rats. CONCLUSIONS This integral metabolomics research provides an extremely effective method to access the therapeutic effects of DEX. This research will further development of new treats for status epilepticus and provide new insights into the anticonvulsive and neuroprotective effects of DEX on status epilepticus.

The Efficacy and Safety of Dexmedetomidine Combined with Bupivacaine on Caudal Epidural Block in Children: A Meta-Analysis.

BACKGROUND This meta-analysis was conducted to evaluate the analgesics effect and safety of dexmedetomidine (DEX) combined with bupivacaine (BU) on caudal epidural block. MATERIAL AND METHODS Published studies were identified using the PubMed, EMBASE, Web of Science, and the Cochrane Library from inception until October 2017. Relative risk (RR), the standardized mean difference (SMD), and the corresponding 95% confidence interval (CI) were calculated using the STATA 12.0. RESULTS Ten randomized controlled trials (RCTs) were selected for this meta-analysis, involving a total of 691 patients. There was a longer duration of postoperative analgesia in children receiving DEX (SMD=3.19, 95% CI: 2.16-4.22, P<0.001). Furthermore, there was a lower number of patients requiring rescue analgesics in the (BU) + (DEX) group (6 hours: RR=0.09, 95% CI: 0.05-0.17, P<0.001; 12 hours: RR=0.50, 95% CI: 0.32-0.79, P=0.003; 24 hours: RR=0.66, 95% CI: 0.51-0.85, P=0.002). Finally, the occurrence of adverse events, between BU and DEX + BU group, was not statistically significant (RR=0.96, 95% CI: 0.58-1.58, P>0.05). CONCLUSIONS DEX seems to be a promising adjuvant to BU increase duration of caudal analgesia without an increase in side effects in children. However, the result may be influenced by clinical heterogeneity. More large-scale, multicenter, approaching, double-blinded RCTs are required to confirm our results.

A Fluorophores Probe for Selectively Detecting Cu(II) and Zn(II) Based on Photochromic Diarylethenes.

A novel photochromic fluorophores based on diarylethene (BMBT) was synthesized with simple process, which displays high selectivity for metal ion Cu2+ and Zn2+. BMBT displays an excellent photochromism characteristic with reversibly spectral change upon alternating irradiation with ultraviolet and visible light. BMBT can detect Cu2+ by color change from pale yellow to dark green in THF solution and exhibits an easily detectable change in fluorescence intensity when the concentration of metal ion Cu2+ and Zn2+ were increased, respectively. More importantly, BMBT exhibits good hydrophilic, low toxicity and good biocompatibility, which indicated that it can serve as a detector for the metal ion Cu2+ and Zn2+ in environmental pollutants and biological systems.

Photoswitchable probe with distinctive characteristics for selective fluorescence imaging and long-term tracing.

A photo-switchable and high-contrast bio-imaging indicator 4,4'-(1E,1'E)-(4,4'-(cyclopentene-1,2-diyl)bis(5-methylthiophene-4,2-diyl))bis(methan-1-yl-1-ylidene)bis(azan-1-yl-1-ylidene)bis(2-(benzo[d]thiazol-2-yl)phenol) (BMBT) has been demonstrated, by integrating photochromophore with excited-state intramolecular proton transfer (ESIPT) moiety. The ability of reversible emission switching enables arbitrarily selective labeling or concealing of cells simply by controlling light irradiation. Besides, when the emission was switched on, BMBT is demonstrated to exhibit unique characteristics of aggregation induced emission (AIE), providing a high on-off ratio for favorable bio-imaging. Thus, the non-labeling and easily-controlled selective imaging, as well as good biocompatibility indicates BMBT to be a favorable cell probe with great potentials for functional bio-imaging fluorophore.

LMO4 Is a Disease-Provocative Transcription Coregulator Activated by IL-23 in Psoriatic Keratinocytes.

Psoriasis is an autoimmune disease characterized by abnormal differentiation and hyperproliferation of epidermal keratinocytes. LIM-domain only protein 4 (LMO4) is a transcription factor coregulator that promotes the assembly of multiprotein complexes to regulate mammary epithelium and keratinocyte differentiation and proliferation during embryogenesis. In this study, LMO4 has been found to be abundantly expressed in psoriatic epidermis. LMO4 expression is increased in human keratinocytes induced to differentiate by calcium ex vivo, and LMO4 overexpression induces spontaneous differentiation and growth acceleration of human keratinocytes in the absence of calcium. IL-23, a cytokine highly expressed in psoriatic skin lesions, induces differentiation and promotes proliferation of human keratinocytes. The IL-23-mediated effects are accompanied by an increase in LMO4 expression mediated by signal transducer and activator of transcription 3 through an IL-23/acutely transforming retrovirus AKT8 in rodent T-cell lymphoma/signal transducer and activator of transcription 3 pathway in keratinocytes. Knockdown of LMO4 effectively inhibits differentiation and growth of keratinocytes both ex vivo and in IL-23-injected ears of mice. LMO4 appears to mediate IL-23-related responses in psoriatic keratinocytes and is a potential therapeutic target in psoriasis.

`Folate-Conjugated Phosphorescent Silica Nanoparticles for Bioimaging and Cancer Cell Targeting.

Besides their superior photophysical properties, phosphorescent transition-metal complexes have some drawbacks for biological applications because of their poor solubility in aqueous solutions and toxicity. In order to avoid the biological environmental impacts on their optical function and solve the problems of water-solubility and toxicity in sensing and bioimaging, two biocompatible organic/inorganic hybrid phosphorescent nanoprobes (Ir-MSN) by using mesoporous silica nanoparticles (MSN) as carriers and an iridium(III) complex as signaling unit were prepared in the present study. In addition, folic acid (FA) was covalently attached to them to endow the particles with characteristic of tumor targeting. The photophysical properties, cell staining and tumor cell targeting functions of FA-ligated Ir-MSN were investigated. These results demonstrated that such a design strategy of phosphorescent nanoprobes is an effective way to develop excellent phosphorescent cellular probes for living cell applications.

Grhl3 induces human epithelial tumor cell migration and invasion via downregulation of E-cadherin.

Grainyhead genes are involved in wound healing and developmental neural tube closure. Metastasis is a multistep process during which cancer cells disseminate from the site of primary tumors and establish secondary tumors in distant organs. The adhesion protein E-cadherin plays an essential role in metastasis. In light of the high degree of similarity between the epithelial-mesenchymal transition (EMT) occurring in wound-healing processes and the EMT occurring during the acquisition of invasiveness in skin or breast cancer, we investigated the role of the Grainyhead genes in cancer invasion. Here, we show that there is an inverse relationship between Grainyhead-like 3 (Grhl3) and E-cadherin expression in some epithelial tumor cell lines. Overexpression of Grhl3 in the E-cadherin-positive epithelial tumor cell line, characterized by less invasiveness, generated a transcriptional blockage of the E-cadherin gene and promoted cell migration and cell invasion. Conversely, Grhl3 depletion inhibited cell migration and cell invasion and was associated with a gain of E-cadherin expression. To further explore the mechanism by which Grhl3 regulated E-cadherin expression, an E-cadherin promoter report analysis was performed and results showed that Grhl3 repressed E-cadherin gene expression by directly or indirectly binding to the E-boxes present in the proximal E-cadherin promoter. Taken together, our findings define a major role for Grhl3 in the induction of migration and invasion by the downregulation of E-cadherin in cancer cells.

NFκB up-regulation of glucose transporter 3 is essential for hyperactive mammalian target of rapamycin-induced aerobic glycolysis and tumor growth.

Accumulating evidence indicates that mammalian target of rapamycin (mTOR) exerts a crucial role in aerobic glycolysis and tumorigenesis, but the underlying mechanisms remain largely obscure. Results from Tsc1- or Tsc2-null mouse embryonic fibroblasts (MEFs) and human cancer cell lines consistently indicate that the expression of glucose transporter 3 (Glut3) is dramatically up-regulated by mTOR. The rapamycin-sensitive mTOR complex 1 (mTORC1), but not the rapamycin-insensitive mTOR complex 2 (mTORC2), was involved in the regulation of Glut3 expression. Moreover, mTORC1 enhances Glut3 expression through the activation of the IKK/NFκB pathway. Depletion of Glut3 led to the suppression of aerobic glycolysis, the inhibition of cell proliferation and colony formation, and the attenuation of the tumorigenic potential of the cells with aberrantly hyper-activated mTORC1 signaling in nude mice. We conclude that Glut3 is a downstream target of mTORC1, and it is critical for oncogenic mTORC1-mediated aerobic glycolysis and tumorigenesis. Hence Glut3 may be a potential target for therapy against cancers caused by the aberrantly activated mTORC1 signaling.