Objective. To investigate the role of CD4+CD25+ T cells (Tregs) in protecting fine particulate matter (PM-) induced inflammatory responses, and its potential mechanisms. Methods. Human umbilical vein endothelial cells (HUVECs) were treated with graded concentrations (2, 5, 10, 20, and 40 µg/cm2) of suspension of fine particles for 24h. For coculture experiment, HUVECs were incubated alone, with CD4+CD25− T cells (Teff), or with Tregs in the presence of anti-CD3 monoclonal antibodies for 48 hours, and then were stimulated with or without suspension of fine particles for 24 hours. The expression of adhesion molecules and inflammatory cytokines was examined. Results. Adhesion molecules, including vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1), and inflammatory cytokines, such as interleukin (IL-) 6 and IL-8, were increased in a concentration-dependent manner. Moreover, the adhesion of human acute monocytic leukemia cells (THP-1) to endothelial cells was increased and NF-κB activity was upregulated in HUVECs after treatment with fine particles. However, after Tregs treatment, fine particles-induced inflammatory responses and NF-κB activation were significantly alleviated. Transwell experiments showed that Treg-mediated suppression of HUVECs inflammatory responses impaired by fine particles required cell contact and soluble factors. Conclusions. Tregs could attenuate fine particles-induced inflammatory responses and NF-κB activation in HUVECs.
Parahupehsuchus longus is a new species of marine reptile from the Lower Triassic of Yuan’an County, Hubei Province, China. It is unique among vertebrates for having a body wall that is completely surrounded by a bony tube, about 50 cm long and 6.5 cm deep, comprising overlapping ribs and gastralia. This tube and bony ossicles on the back are best interpreted as anti-predatory features, suggesting that there was predation pressure upon marine tetrapods in the Early Triassic. There is at least one sauropterygian that is sufficiently large to feed on Parahupehsuchus in the Nanzhang-Yuan’an fauna, together with six more species of potential prey marine reptiles with various degrees of body protection. Modern predators of marine tetrapods belong to the highest trophic levels in the marine ecosystem but such predators did not always exist through geologic time. The indication of marine-tetrapod feeding in the Nanzhang-Yuan’an fauna suggests that such a trophic level emerged for the first time in the Early Triassic. The recovery from the end-Permian extinction probably proceeded faster than traditionally thought for marine predators. Parahupehsuchus has superficially turtle-like features, namely expanded ribs without intercostal space, very short transverse processes, and a dorsal outgrowth from the neural spine. However, these features are structurally different from their turtle counterparts. Phylogeny suggests that they are convergent with the condition in turtles, which has a fundamentally different body plan that involves the folding of the body wall. Expanded ribs without intercostal space evolved at least twice and probably even more among reptiles.
PICK1 (protein interacting with C-kinase 1) is a PKC (protein kinase C)-binding protein, which is essential for synaptic plasticity. The trafficking of PKCα-PICK1 complex to plasma membrane is critical for the internalization of GluR2 and induction of long-term depression. ICA69 (islet cell autoantigen 69 kDa) is identified as a major binding partner of PICK1. While heteromeric BAR domain complex is suggested to underlie the interaction between PICK1 and ICA69, the role of C-terminal domain of ICA69 (ICAC) in PICK1-ICA69 complex is unknown.
We found that ICAC interacted with PICK1 and regulated the trafficking of PICK1-PKCα complex. ICAC and ΔICAC (containing BAR domain) might function distinctly in the association of ICA69 with PICK1. While ΔICAC domain inclined to form clusters, the distribution of ICAC was diffuse. The trafficking of PICK1 to plasma membrane mediated by activated PKCα was inhibited by ICA69. This action might ascribe to ICAC, because overexpression of ICAC, but not ΔICAC, interrupted PKCα-mediated PICK1 trafficking. Notably, infusion of maltose binding protein (MBP) fusion protein, MBP-ICA69 or MBP-ICAC, in cerebellar Purkinje cells significantly inhibited the induction of long-term depression at parallel fiber- and climbing fiber-Purkinje cell synapses.
Our experiments showed that ICAC is an important domain for the ICA69-PICK1 interaction and plays essential roles in PICK1-mediated neuronal plasticity.
The development cycle of an image-guided surgery navigation system is too long to meet current clinical needs. This paper presents an integrated system developed by the integration of two open-source software (IGSTK and MITK) to shorten the development cycle of the image-guided surgery navigation system and save human resources simultaneously. An image-guided surgery navigation system was established by connecting the two aforementioned open-source software libraries. It used the Medical Imaging Interaction Toolkit (MITK) as a framework providing image processing tools for the image-guided surgery navigation system of medical imaging software with a high degree of interaction and used the Image-Guided Surgery Toolkit (IGSTK) as a library that provided the basic components of the system for location, tracking, and registration. The electromagnetic tracking device was used to measure the real-time position of surgical tools and fiducials attached to the patient’s anatomy. IGSTK was integrated into MITK; at the same time, the compatibility and the stability of this system were emphasized. Experiments showed that an integrated system of the image-guided surgery navigation system could be developed in 2 months. The integration of IGSTK into MITK is feasible. Several techniques for 3D reconstruction, geometric analysis, mesh generation, and surface data analysis for medical image analysis of MITK can connect with the techniques for location, tracking, and registration of IGSTK. This integration of advanced modalities can decrease software development time and emphasize the precision, safety, and robustness of the image-guided surgery navigation system.
MITK; IGSTK; Image-guided surgery navigation; Development cycle; Open-source software; Integration
There are few studies on the neuropharmacological properties of asparagus, which was applied in Chinese traditional medicine as a tonic and heat-clearing agent. The present study was designed to investigate the anxiolytic-like activity of the aqueous extract of asparagus stem (AEAS) using elevated plus maze (EPM) and Vogel conflict tests (VCT) in mice. AEAS significantly increased the percentage of time spent in open arms in EPM, when compared with control group. In the Vogel conflict drinking test, the numbers of punished licks increased to 177% and 174% by the treatment of AEAS at the doses of 1.5 and 3.0 g/kg (250 and 500 mg sarsasapogenin per kilogram of body weight), compared with control group. The serum cortisol level decreased significantly, at the same time. In conclusion, these findings indicated that the aqueous extract of asparagus stem exhibited a strong anxiolytic-like effect at dose of 1.5 and 3.0 g/kg (250 and 500 mg sarsasapogenin per kilogram of body weight) in experimental models of anxiety and may be considered an alternative approach for the management of anxiety disorder.
Annular pancreas (AP) concurrent with pancreaticobiliary maljunction (PBMJ), an unusual coexisted congenital anomaly, often presented symptoms and subjected surgical treatment at the early age of life. We reported the first adult case of concurrent AP with PBMJ presented with symptoms until his twenties, and performed a literature review to analyze the clinicopathological features of such cases comparing with its pediatric counterpart.
The main clinical features of this case were abdominal pain and increased levels of plasma amylase as well as liver function test. A complete type of annular pancreas with duodenal stenosis was found, and dilated common bile duct with high confluence of pancreaticobiliary ducts was also observed. Meanwhile, extremely high levels of bile amylase were detected both in common bile duct and gallbladder. The patient received duodenojejunostomy (side-to-side anastomosis) as well as choledochojejunostomy (Roux-en-Y anastomosis), adnd was discharged in a good condition.
AP concurrent with PBMJ usually presents as duodenal obstruction in infancy, while manifests as pancreatitis in adulthood. Careful long-term follow-up is required for children with AP considering its association with PBMJ which would induce various intractable pathologic conditions in the biliary tract and pancreas.
Annular pancreas; Pancreaticobiliary maljunction; Pancreatitis
Aims. To evaluate the efficacy of Chinese herbal medicines (CHMs) plus conventional treatment in patients with acute coronary syndrome (ACS) after percutaneous coronary intervention (PCI). Methods and Results. Participants (n = 808) with ACS who underwent PCI from thirteen hospitals of mainland China were randomized into two groups: CHMs plus conventional treatment group (treatment group) or conventional treatment alone group (control group). All participants received conventional treatment, and participants in treatment group additionally received CHMs for six months. The primary endpoint was the composite of cardiac death, nonfatal recurrent MI, and ischemia-driven revascularization. Secondary endpoint was the composite of readmission for ACS, stroke, or congestive heart failure. The safety endpoint involved occurrence of major bleeding events. The incidence of primary endpoint was 2.7% in treatment group versus 6.2% in control group (HR, 0.43; 95% CI, 0.21 to 0.87; P = 0.015). The incidence of secondary endpoint was 3.5% in treatment group versus 8.7% in control group (HR, 0.39; 95% CI, 0.21 to 0.72; P = 0.002). No major bleeding events were observed in any participant. Conclusion. Treatment with CHMs plus conventional treatment further reduced the occurrence of cardiovascular events in patients with ACS after PCI without increasing risk of major bleeding.
For polar/nonpolar heterostructures, Maxwell's theory dictates that the electric potential in the polar components will increase divergently with the film thickness. For LaAlO3/SrTiO3, a conceptually intriguing route, termed charge reconstruction, has been proposed to avert such “polar catastrophe”. The existence of a polar potential in LaAlO3 is a prerequisite for the validity of the charge reconstruction picture, yet to date, its direct measurement remains a major challenge. Here we establish unambiguously the existence of the residual polar potential in ultrathin LaAlO3 films on SrTiO3, using a novel photovoltaic device design as an effective probe. The measured lower bound of the residual polar potential is 1.0 V. Such a direct observation of the giant residual polar potential within the unit-cell-scale LaAlO3 films amounts to a definitive experimental evidence for the charge reconstruction picture, and also points to new technological significance of oxide heterostructures in photovoltaic and sensing devices with atomic-scale control.
Dickkopf-1 (DKK-1), a major regulator of the Wnt pathway, plays an important role in cardiovascular disease. However, no study has evaluated the association of DKK-1 and acute coronary syndrome (ACS). We investigated this association and whether the Global Registry of Acute Coronary Events (GRACE) hospital-discharge risk score predicting major adverse cardiac events (MACE) can be improved by adding the DKK-1 value.
We enrolled 291 patients (46 with ST-segment elevation myocardial infarction [STEMI] and 245 with non-ST elevated ACS [NSTE-ACS]) who were divided into groups by tertiles of baseline plasma DKK-1 level measured by ELISA. The GRACE risk score was calculated and predictive value alone and together with DKK-1 and/or high-sensitivity C-reactive protein (hs-CRP) level were assessed, respectively.
Compared with patients with NSTE-ACS, those with STEMI had higher plasma DKK-1 level at baseline (P = 0.006). Plasma DKK-1 level was correlated with hs-CRP level (r = 0.295, P<0.001) and was greater with high than intermediate or low GRACE scores (P = 0.002 and P<0.001, respectively). We found 44 (15.1%) MACEs during a median 2-year follow-up. DKK-1 levels were higher for patients with than without events (P<0.001). The rate of MACE increased with increasing DKK-1 level (P<0.001). The area under the receiver operating characteristic curve for GRACE score with MACE was 0.524 and improved to 0.791 with the addition of hs-CRP level, 0.775 with the addition of DKK-1 level and 0.847 with both values added.
DKK-1 is an independent predictor of long-term MACE of patients with ACS. The long-term predictive ability of post-discharge GRACE score may be enhanced by adding DKK-1 level.
Insomnia is a widespread human health problem, but there currently are the limitations of conventional therapies available. Suanzaoren decoction (SZRD) is a well known classic Chinese herbal prescription for insomnia and has been treating people’s insomnia for more than thousand years. The objective of this study was to evaluate the efficacy and safety of SZRD for insomnia.
A systematic literature search was performed for 6 databases up to July of 2012 to identify randomized control trials (RCTs) involving SZRD for insomniac patients. The methodological quality of RCTs was assessed independently using the Cochrane Handbook for Systematic Reviews of Interventions.
Twelve RCTs with total of 1376 adult participants were identified. The methodological quality of all included trials are no more than 3/8 score. Majority of the RCTs concluded that SZRD was more significantly effective than benzodiazepines for treating insomnia. Despite these positive outcomes, there were many methodological shortcomings in the studies reviewed, including insufficient information about randomization generation and absence of allocation concealment, lack of blinding and no placebo control, absence of intention-to-treat analysis and lack of follow-ups, selective publishing and reporting, and small number of sample sizes. A number of clinical heterogeneity such as diagnosis, intervention, control, and outcome measures were also reviewed. Only 3 trials reported adverse events, whereas the other 9 trials did not provide the safety information.
Despite the apparent reported positive findings, there is insufficient evidence to support efficacy of SZRD for insomnia due to the poor methodological quality and the small number of trials of the included studies. SZRD seems generally safe, but is insufficient evidence to make conclusions on the safety because fewer studies reported the adverse events. Further large sample-size and well-designed RCTs are needed.
Insomnia; Suanzaoren decoction; Systematic review
MicroRNAs (miRNAs) have been shown to be dysregulated in virus-related cancers; however, miRNA regulation of virus-related cancer development and progression remains poorly understood. Here, we report that miR-148a is repressed by hepatitis B virus (HBV) X protein (HBx) to promote cancer growth and metastasis in a mouse model of hepatocellular carcinoma (HCC). Hematopoietic pre–B cell leukemia transcription factor–interacting protein (HPIP) is an important regulator of cancer cell growth. We used miRNA target prediction programs to identify miR-148a as a regulator of HPIP. Expression of miR-148a in hepatoma cells reduced HPIP expression, leading to repression of AKT and ERK and subsequent inhibition of mTOR through the AKT/ERK/FOXO4/ATF5 pathway. HBx has been shown to play a critical role in the molecular pathogenesis of HBV-related HCC. We found that HBx suppressed p53-mediated activation of miR-148a. Moreover, expression of miR-148a was downregulated in patients with HBV-related liver cancer and negatively correlated with HPIP, which was upregulated in patients with liver cancer. In cultured cells and a mouse xenograft model, miR-148a reduced the growth, epithelial-to-mesenchymal transition, invasion, and metastasis of HBx-expressing hepatocarcinoma cells through inhibition of HPIP-mediated mTOR signaling. Thus, miR-148a activation or HPIP inhibition may be a useful strategy for cancer treatment.
Scalp acupuncture (SA) is a commonly used therapeutic approach for stroke throughout China and elsewhere in the world. The objective of this study was to assess clinical efficacy and safety of SA for acute ischemic stroke. A systematical literature search of 6 databases was conducted to identify randomized controlled trials (RCTs) of SA for acute ischemic stroke compared with western conventional medicines (WCMs). All statistical analyses were performed by the Rev Man Version 5.0. Eight studies with 538 participants were included in the studies. The studies were deemed to have an unclear risk of bias based on the Cochrane Back Review Group. Compared with the WCM, 6 RCTs showed significant effects of SA for improving neurological deficit scores (P < 0.01); 4 RCTs showed significant effects of SA for favoring the clinical effective rate (P < 0.01) However, the adverse events have not been documented. In conclusion, SA appears to be able to improve neurological deficit score and the clinical effective rate when compared with WCM, though the beneficial effect from SA is possibly overvalued because of generally low methodology of the included trials. No evidence is available for adverse effects. Rigorous well-designed clinical trials are needed.
Chinese fir (Cunninghamia lanceolata) is an important timber species that accounts for 20–30% of the total commercial timber production in China. However, the available genomic information of Chinese fir is limited, and this severely encumbers functional genomic analysis and molecular breeding in Chinese fir. Recently, major advances in transcriptome sequencing have provided fast and cost-effective approaches to generate large expression datasets that have proven to be powerful tools to profile the transcriptomes of non-model organisms with undetermined genomes.
In this study, the transcriptomes of nine tissues from Chinese fir were analyzed using the Illumina HiSeq™ 2000 sequencing platform. Approximately 40 million paired-end reads were obtained, generating 3.62 gigabase pairs of sequencing data. These reads were assembled into 83,248 unique sequences (i.e. Unigenes) with an average length of 449 bp, amounting to 37.40 Mb. A total of 73,779 Unigenes were supported by more than 5 reads, 42,663 (57.83%) had homologs in the NCBI non-redundant and Swiss-Prot protein databases, corresponding to 27,224 unique protein entries. Of these Unigenes, 16,750 were assigned to Gene Ontology classes, and 14,877 were clustered into orthologous groups. A total of 21,689 (29.40%) were mapped to 119 pathways by BLAST comparison against the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. The majority of the genes encoding the enzymes in the biosynthetic pathways of cellulose and lignin were identified in the Unigene dataset by targeted searches of their annotations. And a number of candidate Chinese fir genes in the two metabolic pathways were discovered firstly. Eighteen genes related to cellulose and lignin biosynthesis were cloned for experimental validating of transcriptome data. Overall 49 Unigenes, covering different regions of these selected genes, were found by alignment. Their expression patterns in different tissues were analyzed by qRT-PCR to explore their putative functions.
A substantial fraction of transcript sequences was obtained from the deep sequencing of Chinese fir. The assembled Unigene dataset was used to discover candidate genes of cellulose and lignin biosynthesis. This transcriptome dataset will provide a comprehensive sequence resource for molecular genetics research of C. lanceolata.
Chinese fir; De novo assembly; RNA-Seq; Transcriptome; Cellulose and lignin biosynthesis; Gene expression
As it is often difficult for a transplant pathologist to make a definite diagnosis of acute cellular rejection (ACR) by routine morphological analysis of liver allograft biopsy, supplementary methods and objective markers are needed to facilitate this determination.
To evaluate the diagnostic value of cytotoxic molecules in ACR episodes, immunohistochemical staining for perforin, granzyme B and T-cell intracellular antigen-1 (TIA-1) were performed in liver allograft biopsies. The positive cells in the portal tract area and lobules were counted separately to investigate the distribution of the cytotoxic molecules.
The immunohistochemical study showed that the overall positive rates for the three markers were not significantly different between the ACR and non-ACR groups. However, in the portal tract area, perforin-, granzyme B- and TIA-1-positive cells in the ACR group were significantly more than those in the non-ACR groups. In the lobules, perforin- and granzyme B-positive cells in the ACR group were significantly more than those in the biliary complication and opportunistic infection groups, while TIA-1-positive cells was significantly fewer than those in non-ACR groups. The numbers of positive cells in the portal tract area correlated with the rejection activity index of ACR.
These results indicate that, though the overall positive rates have nonsense in ACR diagnosis, the quantification and local distribution analysis of cytotoxic molecule positive cells in liver tissue is helpful for differential diagnosis and severity evaluation of ACR following liver transplantation.
The virtual slide(s) for this article can be found here:
Liver transplantation; Acute cellular rejection (ACR); Rejection activity index (RAI); Perforin; Granzyme B; T-cell intracellular antigen-1
Stretch affects vascular smooth muscle cell proliferation and apoptosis, and several responsible genes have been proposed. We tested whether the expression of microRNA 21 (miR-21) is modulated by stretch and is involved in stretch-induced proliferation and apoptosis of human aortic smooth muscle cells (HASMCs).
Methods and Results
RT-PCR revealed that elevated stretch (16% elongation, 1 Hz) increased miR-21 expression in cultured HASMCs, and moderate stretch (10% elongation, 1 Hz) decreased the expression. BrdU incorporation assay and cell counting showed miR-21 involved in the proliferation of HASMCs mediated by stretch, likely by regulating the expression of p27 and phosphorylated retinoblastoma protein (p-Rb). FACS analysis revealed that the complex of miR-21 and programmed cell death protein 4 (PDCD4) participated in regulating apoptosis with stretch. Stretch increased the expression of primary miR-21 and pre-miR-21 in HASMCs. Electrophoretic mobility shift assay (EMSA) demonstrated that stretch increased NF-κB and AP-1 activities in HASMCs, and blockade of AP-1 activity by c-jun siRNA significantly suppressed stretch-induced miR-21 expression.
Cyclic stretch modulates miR-21 expression in cultured HASMCs, and miR-21 plays important roles in regulating proliferation and apoptosis mediated by stretch. Stretch upregulates miR-21 expression at least in part at the transcription level and AP-1 is essential for stretch-induced miR-21 expression.
Parkinson's disease (PD) is a common and debilitating neurodegenerative disorder that needs long-term levodopa administration and can result in progressive deterioration of body functions, daily activities and participation. The objective of this meta-analysis evaluates the clinical efficacy and safety of Chinese herbal medicine (CHM) as an adjunct therapy for PD patients. Methodological issues include a systematic literature search between 1950 and April 2011 to identify randomized trials involving CHM adjuvant therapy versus western conventional treatment. The outcome measures assessed were the reduction in scores of Unified Parkinson's Disease Rating Scale (UPDRS) and adverse effects. 19 trials involving 1371 participants were included in the meta-analysis. As compared to western conventional treatment, CHM adjuvant therapy resulted in greater improvement in UPDRS I, II, III, IV scores, and UPDRS I–IV total scores (P < 0.001). Adverse effects were reported in 9 studies. The side effects in CHM adjuvant therapy group were generally less than or lighter than the conventional treatment group. In conclusion, CHM adjuvant therapy may potentially alleviate symptoms of PD and generally appeared to be safe and well tolerated by PD patients. However, well-designed, randomized, placebo-controlled clinical trials are still needed due to the generally low methodological quality of the included studies.
In the title compound, C15H11N5, the benzimidazole ring system is nearly planar [maximum deviation = 0.039 (2) Å], and is oriented at a dihedral angle of 28.85 (10)° with respect to the benzene ring; the dihedral angle between the triazole and benzene rings is 17.30 (15)°. In the crystal N—H⋯N hydrogen bonds link the molecules into chains. Weak C—H⋯N interactions are also present.
A 65-year-old female patient with no clinical manifestations was hospitalized for examination and treatment of an anterior mediastinal tumor found at the time of a regular health checkup. Enhanced computed tomography (CT) and magnetic resonance imaging revealed a cystic lesion containing a solid tumor. Positron emission tomography-CT demonstrated increased uptake in the solid lesion. Tumor resection with total thymectomy was performed. A pathological diagnosis of thymic neuroblastoma within a thymic cyst was made. Micorscopic examination revealed that tumor cells of the solid component were lined with thymic epithelial cells of the inner cyst wall. Furthermore, some tumor cells of the solid component had melanin granules. These findings suggest that this tumor arose from progenitors of the thymic epithelial cells with the potential to differentiate along neural lines.
Neuroblastoma commonly occurs in children. However, the diagnosis of neuroblastoma in adults has been reported in several case reports. We report an adult case of histogenetically informative thymic neuroblastoma within a thymic cyst. There are no standard treatment strategies and chemotherapy protocols. Complete surgical resection might be important for a better outcome.
Thymic neuroblastoma; Thymic cyst; Adult
Depolarization-induced suppression of excitation (DSE) at parallel fiber-Purkinje cell synapse is an endocannabinoid-mediated short-term retrograde plasticity. Intracellular Ca2+ elevation is critical for the endocannabinoid production and DSE. Nevertheless, how elevated Ca2+ leads to DSE is unclear.
We utilized cytosolic phospholipase A2 alpha (cPLA2α) knock-out mice and whole-cell patch clamp in cerebellar slices to observed the action of cPLA2α/arachidonic acid signaling on DSE at parallel fiber-Purkinje cell synapse. Our data showed that DSE was significantly inhibited in cPLA2α knock-out mice, which was rescued by arachidonic acid. The degradation enzyme of 2-arachidonoylglycerol (2-AG), monoacylglycerol lipase (MAGL), blocked DSE, while another catabolism enzyme for N-arachidonoylethanolamine (AEA), fatty acid amide hydrolase (FAAH), did not affect DSE. These results suggested that 2-AG is responsible for DSE in Purkinje cells. Co-application of paxilline reversed the blockade of DSE by internal K+, indicating that large conductance Ca2+-activated potassium channel (BK) is sufficient to inhibit cPLA2α/arachidonic acid-mediated DSE. In addition, we showed that the release of 2-AG was independent of soluble NSF attachment protein receptor (SNARE), protein kinase C and protein kinase A.
Our data first showed that cPLA2α/arachidonic acid/2-AG signaling pathway mediates DSE at parallel fiber-Purkinje cell synapse.
The initiation of breast cancer is associated with increased expression of tumor-promoting estrogen receptor α (ERα) protein and decreased expression of tumor-suppressive ERβ protein. However, the mechanism underlying this process is unknown. Here we show that PES1 (also known as Pescadillo), an estrogen-inducible protein that is overexpressed in breast cancer, can regulate the balance between ERα and ERβ. We found that PES1 modulated many estrogen-responsive genes by enhancing the transcriptional activity of ERα while inhibiting transcriptional activity of ERβ. Consistent with this regulation of ERα and ERβ transcriptional activity, PES1 increased the stability of the ERα protein and decreased that of ERβ through the ubiquitin-proteasome pathway, mediated by the carboxyl terminus of Hsc70-interacting protein (CHIP). Moreover, PES1 transformed normal human mammary epithelial cells and was required for estrogen-induced breast tumor growth in nude mice. Further analysis of clinical samples showed that expression of PES1 correlated positively with ERα expression and negatively with ERβ expression and predicted good clinical outcome in breast cancer. Our data demonstrate that PES1 contributes to breast tumor growth through regulating the balance between ERα and ERβ and may be a better target for the development of drugs that selectively regulate ERα and ERβ activities.
Selective blockade of Kv1.3 channels in effector memory T (TEM) cells was validated to ameliorate autoimmune or autoimmune-associated diseases. We generated the antibody directed against one peptide of human Kv1.3 (hKv1.3) extracellular loop as a novel and possible Kv1.3 blocker. One peptide of hKv1.3 extracellular loop E3 containing 14 amino acids (E314) was chosen as an antigenic determinant to generate the E314 antibody. The E314 antibody specifically recognized 63.8KD protein stably expressed in hKv1.3-HEK 293 cell lines, whereas it did not recognize or cross-react to human Kv1.1(hKv1.1), Kv1.2(hKv1.2), Kv1.4(hKv1.4), Kv1.5(hKv1.5), KCa3.1(hKCa3.1), HERG, hKCNQ1/hKCNE1, Nav1.5 and Cav1.2 proteins stably expressed in HEK 293 cell lines or in human atrial or ventricular myocytes by Western blotting analysis and immunostaining detection. By the technique of whole-cell patch clamp, the E314 antibody was shown to have a directly inhibitory effect on hKv1.3 currents expressed in HEK 293 or Jurkat T cells and the inhibition showed a concentration-dependence. However, it exerted no significant difference on hKv1.1, hKv1.2, hKv1.4, hKv1.5, hKCa3.1, HERG, hKCNQ1/hKCNE1, L-type Ca2+ or voltage-gated Na+ currents. The present study demonstrates that the antibody targeting the E314 peptide of hKv1.3 pore region could be a novel, potent and specific hKv1.3 blocker without affecting a variety of closely related Kv1 channels, KCa3.1 channels and functional cardiac ion channels underlying central nervous systerm (CNS) disorders or drug-acquired arrhythmias, which is required as a safe clinic-promising channel blocker.
Malignant pleural mesothelioma (MPM) is an aggressive thoracic tumor with a poor prognosis. We performed a comprehensive clinical study on the intratumoral expression of Wnt1, Wnt2B and Wnt5A in MPM. One hundred and seven MPM patients were investigated. Immunohistochemistry was performed to evaluate the intratumoral expression of Wnt1, Wnt2B, Wnt5A, survivin and c-Myc, and the Ki-67 proliferation index. The apoptotic index was evaluated by the TUNEL method. Among the 107 MPMs, 23 MPMs (21.5%) were Wnt1-high tumors, 72 MPMs (67.3%) were Wnt2B-high tumors and 54 MPMs (50.5%) were Wnt5A-high tumors. There was no correlation among the levels of Wnt expression. The percentage of Wnt2B-positive tumors was significantly higher compared to that of the other Wnts (p<0.0001). Furthermore, intratumoral Wnt2B expression significantly correlated with the expression of survivin (p<0.001) and c-Myc (p<0.001). Regarding tumor biology, the Ki-67 proliferation index was significantly higher in the Wnt2B-high tumors than in the Wnt2B-low tumors (p=0.0438). In addition, the overall survival was significantly lower in patients with Wnt2B-high tumors than in those with Wnt2B-low tumors (p=0.0238). A Cox multivariate analysis also demonstrated the Wnt2B status to be a significant prognostic factor in MPM patients (p=0.0042). Intratumoral Wnt2B expression was associated with the expression of survivin and c-Myc, tumor proliferation and patient survival in MPM. Wnt2B is a potential molecular target for the treatment of Wnt2B-overexpressing MPMs.
Wnt2B; survivin; c-Myc; proliferation; prognosis; mesothelioma
Intracerebral hemorrhage (ICH) is an important public health problem with high rates of mortality, morbidity, and disability, but no clinically proven treatment strategy is available to date. Scalp acupuncture (SA) refers to a therapy for treating diseases by needling and stimulating the specific areas of the scalp. The evidence from clinical studies suggested that SA therapy may produce significant benefits for patients with acute ICH. However, the therapeutic mechanisms are yet not well addressed. Therefore, in this paper, we provide a comprehensive overview on the history and mechanisms of SA therapy on acute ICH. Although SA has been practiced for thousands of years in China and could date back to 5 BC, SA therapy for acute ICH develops only in the recent 30 years. The possible mechanisms associated with the therapeutic effects of SA on ICH include the influence on hematoma, brain edema, and blood brain barrier, the products released from haematoma, the immune and inflammatory reaction, focal perihemorrhagic hypoperfusion and hemorheology, neuroelectrophysiology, and so on. At last, the existence of instant effect of SA on acute ICH and its possible mechanisms are presented.
TC-2559 is a selective α4β2 subtype of nicotinic acetylcholine receptor (nAChR) partial agonist and α4β2 nAChR activation has been related to antinociception. The aim of this study is to investigate the analgesic effect of TC-2559 and its underlying spinal mechanisms.
1) In vivo bioavailability study: TC-2559 (3 mg/kg) had high absorption rate in rats with maximal total brain concentration reached over 4.6 μM within first 15 min after administration and eliminated rapidly with brain half life of about 20 min after injection. 2) In vivo behavioral experiments: TC-2559 exerts dose dependent antinociceptive effects in both formalin test in mice and chronic constriction injury (CCI) model in rats by activation of α4β2 nAChRs; 3) Whole-cell patch-clamp studies in the superficial dorsal horn neurons of the spinal cord slices: perfusion of TC-2559 (2 μM) significantly increased the frequency, but not amplitude of spontaneous inhibitory postsynaptic currents (sIPSCs). The enhancement of sIPSCs was blocked by pre-application of DHβE (2 μM), a selective α4β2 nicotinic receptor antagonist. Neither the frequency nor the amplitude of spontaneous excitatory postsynaptic currents (sEPSCs) of spinal dorsal horn neurons were affected by TC-2559.
Enhancement of inhibitory synaptic transmission in the spinal dorsal horn via activation of α4β2 nAChRs may be one of the mechanisms of the antinociceptive effects of TC-2559 on pathological pain models. It provides further evidence to support the notion that selective α4β2 subtype nAChR agonist may be developed as new analgesic drug for the treatment of neuropathic pain.
TC-2559; α4β2 nAChRs; Formalin test; CCI; sIPSCs; Pain; Spinal cord slice