The angiotensin-converting enzyme gene is one of the most studied candidate genes related to atrial fibrillation. Among the polymorphisms of the angiotensin-converting enzyme gene, the 2350 G/A polymorphism (rs4343) is known to have the most significant effects on the plasma angiotensin-converting enzyme concentration. The aim of the present study was to investigate the association of the angiotensin-converting enzyme 2350 G/A polymorphism with atrial fibrillation in Han Chinese patients with essential hypertension.
A total of 169 hypertensive patients were eligible for this study. Patients with atrial fibrillation (n = 75) were allocated to the atrial fibrillation group, and 94 subjects without atrial fibrillation were allocated to the control group. The PCR-based restriction fragment length polymorphism technique was used to assess the genotype frequencies.
The distributions of the angiotensin-converting enzyme 2350 G/A genotypes (GG, GA, and AA, respectively) were 40.43%, 41.49%, and 18.08% in the controls and 18.67%, 46.67%, and 34.66% in the atrial fibrillation subjects (p = 0.037). The frequency of the A allele in the atrial fibrillation group was significantly greater than in the control group (58.00% vs. 38.83%, p = 0.0007). Compared with the wild-type GG genotype, the GA and AA genotypes had an increased risk for atrial fibrillation. Additionally, atrial fibrillation patients with the AA genotype had greater left atrial dimensions than the patients with the GG or GA genotypes (p<0.01 and p<0.05, respectively).
The results obtained in this study indicate that the angiotensin-converting enzyme 2350 G/A polymorphism is associated with atrial fibrillation and that the A allele shows an increased risk for atrial fibrillation in Han Chinese patients with essential hypertension.
Angiotensin-converting enzyme; Genetic polymorphism; Atrial fibrillation; Essential hypertension; China
Cancer-associated protein tyrosine kinase (PTK) mutations usually are gain-of-function (GOF) mutations that drive tumor growth and metastasis. We have found 50 JAK1 truncating mutations in 36 of 635 gynecologic tumors in the Total Cancer Care® (TCC®) tumor bank. Among cancer cell lines containing JAK1 truncating mutations in the Cancer Cell Line Encyclopedia databank, 68% are gynecologic cancer cells. Within JAK1 the K142, P430, and K860 frame-shift mutations were identified as hot spot mutation sites. Sanger sequencing of cancer cell lines, primary tumors, and matched normal tissues confirmed the JAK1 mutations and showed that these mutations are somatic. JAK1 mediates interferon (IFN)-γ-regulated tumor immune surveillance. Functional assays show that JAK1 deficient cancer cells are defective in IFN-γ-induced LMP2 and TAP1 expression, loss of which inhibits presentation of tumor antigens. These findings identify recurrent JAK1 truncating mutations that could contribute to tumor immune evasion in gynecologic cancers, especially in endometrial cancer.
Telomeres are specialized chromatin structures essential for maintenance of chromosomal integrity and stability. Abnormal alteration of telomere length has been linked to several cancers; however, epidemiologic evidence regarding the association of telomere length with colorectal cancer risk has been conflicting.
We conducted a nested case-control study to evaluate the association between telomere length and colorectal cancer risk using peripheral blood samples collected prior to cancer diagnosis. The study included 441 women with incident colorectal cancer and 549 matched controls. Monochrome multiplex quantitative PCR was applied to measure relative telomere length. Multiple logistic regressions were used to derive adjusted odds ratios (OR) with 95% confidence intervals (CI) as the measure of association between telomere length and subsequent colorectal cancer risk.
A U-shaped association was observed between telomere length and colorectal cancer risk (test for nonlinearity P = 0.0112). Women with telomere length in the third quintile (40th to 60th percentiles) had the lowest risk of colorectal cancer, and the risks were elevated with a shorter or longer telomere length. This U-shaped association did not statistically differ for colon cancer and rectum cancer.
Conclusions and Impact
Our prospective study revealed a U-shaped association between telomere length in peripheral blood cells and colorectal cancer risk. Our findings provide strong evidence that both very short and very long telomeres are associated with increased risk of colorectal cancer.
We report on imaging of cell-substrate adhesion of a single cell with sub-cellular spatial resolution. Osmotic pressure was introduced to provide a controllable mechanical stimulation to the cell attached to a substrate, and high-resolution surface plasmon resonance microscopy was used to map the response of the cell, from which local cell-substrate adhesion was determined. In addition to high spatial resolution, the approach is non-invasive and fast, and allows for continuously mapping of cell-substrate interactions and single cell movements.
Single cell imaging; Surface Plasmon Resonance imaging; osmotic effect; cell adhesion
This study explored the clinical value of endoscopic ligation for the treatment of upper gastrointestinal (GI) protuberant lesions in children. According to the appearance and size of lesions, we used different ligation techniques for the treatment of the lesions. Endoscopic ultrasonography was used for preliminary characterization of the lesions. One case diagnosed with Peutz-Jeghers syndrome was successfully treated by a detachable snare. Two cases with semi-pedunculated or broad-base lesions originating from the submucosal layer of the upper GI were treated with endoscopic variceal ligation; endoscopic examination showed that one case had complete healing 11 wk after ligation, while an ulcer scar was observed at the ligation site after 6 wk in the other case. All lesions were successfully ligated at the first attempt. No significant complications occurred either during or after the procedure. Selective endoscopic ligation of upper GI lesions is an effective and safe treatment for upper GI protuberant lesions in children.
Endoscopy; Ligation; Endoscopic ultrasonography; Protuberant lesion; Children
The aim of this study was to assess the feasibility of evaluating the therapeutic effects of intravenous diltiazem in a newly established rat model of coronary thrombotic micro-embolism (CME). CME was induced by injecting 0.199 ml saline containing 5 mg of automicrothrombotic particulates (∼10 μm) into the aorta of Sprague Dawley rats. The injection was carried out over 10 sec using a tuberculin syringe with a 28-gauge needle. The CME model rats were randomly divided into untreated (CME, n=38) and diltiazem-treated (CME+DIL, n=38) groups. Diltiazem (1 mg/ml, 50 μg/min/kg) was intravenously injected using an infusion pump through the tail vein for 175 min, 5 min following the injection of the automicrothrombotic particulates. Hemodynamic measurements, echocardiography and pathohistological examinations were performed at various time-points (3 h, 24 h and 7 and 28 days) postoperatively. Arteriolar thrombosis, multifocal myocardial necrosis, inflammatory cell infiltration with markedly increased myocardial tumor necrosis factor α (TNF-α) and interleukin-6 (IL-6) expression, reduced left ventricular (LV) systolic function and increased plasma von Willebrand factor (vWF), endothelin-1 (ET-1) and serum c-troponin I (c-TnI) levels (indicating vascular endothelial injury and myocardial necrosis) were observed in the CME model rats. These pathological responses in CME rats were partly attenuated by intravenous diltiazem treatment. The present CME model is suitable for evaluating the therapeutic effects of intravenous diltiazem; intravenous diltiazem treatment significantly improved cardiac function through alleviating inflammatory responses and microvascular thrombotic injury in this rat model of CME.
coronary thrombosis; microembolism; no flow phenomenon; diltiazem
Glioma stem cells in the quiescent state are resistant to clinical radiation therapy. An almost inevitable glioma recurrence is due to the persistence of these cells. The high linear energy transfer associated with boron neutron capture therapy (BNCT) could kill quiescent and proliferative cells.
The present study aimed to evaluate the effects of BNCT on glioma stem/progenitor cells in vitro. The damage induced by BNCT was assessed using cell cycle progression, apoptotic cell ratio and apoptosis-associated proteins expression.
The surviving fraction and cell viability of glioma stem/progenitor cells were decreased compared with differentiated glioma cells using the same boronophenylalanine pretreatment and the same dose of neutron flux. BNCT induced cell cycle arrest in the G2/M phase and cell apoptosis via the mitochondrial pathway, with changes in the expression of associated proteins.
Glioma stem/progenitor cells, which are resistant to current clinical radiotherapy, could be effectively killed by BNCT in vitro via cell cycle arrest and apoptosis using a prolonged neutron irradiation, although radiosensitivity of glioma stem/progenitor cells was decreased compared with differentiated glioma cells when using the same dose of thermal neutron exposure and boronophenylalanine pretreatment. Thus, BNCT could offer an appreciable therapeutic advantage to prevent tumor recurrence, and may become a promising treatment in recurrent glioma.
Boron neutron capture therapy; Glioma stem/progenitor cells; Radiosensitivity
The role of substance P and the neurokinin-1 receptor (NK-1R) in the transition from inflammation to dysplasia in inflammatory bowel disease is not clear.
Colitis-associated dysplasia was induced in Sprague-Dawley rats by intracolonic, then systemic, administration of trinitrobenzene sulfonic acid. One group of animals received the NK-1R antagonist SR140333; the rest received vehicle. Colons were removed and analyzed for damage and expression of NK-1R downstream components.
The NK-1R antagonist-treated animals had significantly reduced macroscopic and microscopic damage and decreased incidence of inflammatory bowel disease. Twice as many of these animals had a normal diagnosis in any region of the colon. A decrease in proliferation index, Cox-2 expression, and active Erk1/2 was found compared with the vehicle-treated group. In Caco-2 cells, Erk1/2 was activated by substance P and prostaglandin E2.
A selective NK-1R antagonist may delay the development of further colonic damage, offering a potential treatment for patients with long-standing colitis.
Animal model; antagonist; colitis; dysplasia; neurokinin
Generation of induced pluripotent stem cells (iPSCs) from somatic cells by defined factors is a mechanism-unknown, yet extremely time-consuming process. Inefficient reprogramming leads to prolonged periods of in vitro iPSC selection, resulting in subtle genetic and epigenetic abnormalities. To facilitate pluripotent reprogramming, we have identified the thyroid hormone triiodothyronine (T3) as an endogenous factor that can enhance reprogramming of human dermal fibroblasts (HDF) and umbilical cord mesenchymal stem cells (UCMSC). This potentiation of iPSC induction is associated with metabolic remodeling activity, including up-regulation of key glycolytic genes, an increase in cell proliferation, and the induction of mesenchymal-epithelial transition (MET). We further identify the activation of the PI3K/AKT signal pathway by T3 as an underlying mechanism for the enhanced conversion to cell pluripotency in this model. These studies demonstrate that T3 enhances metabolic remodeling of donor cells in potentiating cell reprogramming.
T3; thyroid hormone; PI3K/AKT signal pathway; Induced pluripotent stem cell; iPSC; reprogramming; metabolic remodeling
Hyperuricemia (HUA) is a potential risk factor for developing insulin resistance, hypertension, dyslipidemia and cardiovascular disease. Therefore, we studied the prevalence of HUA and associated risk factors in the population of two provinces in northern China.
Based on the research of Chinese Physiological Constant and Health Conditions conducted in 2008–2010, we enrolled 29,639 subjects in a randomized, stratified study in four sampling areas in Heilongjiang Province and the Inner Mongolia Autonomous Region. We collected 13,140 serum samples to determine biochemical indicators including uric acid(UA), glucose, blood lipids, liver function, and renal function, and finally a representative sample of 8439 aged 18 years and older was determined. We also defined and stratified HUA, hypertension, diabetes, obesity and lipid abnormalities according to international guidelines.
There were significant differences in the UA levels between different genders and regions. The total prevalence of HUA is 13.7%. Men had a higher prevalence of HUA than women (21% vs. 7.9%; P < 0.0001). As age increased, HUA prevalence decreased in men but rose in women. The suburbs of big cities had the highest HUA prevalence (18.7%), and in high-prevalence areas the proportion of women with HUA also increased. A stepwise logistic regression model was used to filter out twelve HUA risk factors, including age, gender, residence, hypercholesterolemia, hypertriglyceridemia, impaired fasting glucose, hypertension, obesity, abdominal obesity, CKD, drinking and sleeping. After adjusting for these factors, the odds ratio of HUA was 1.92 times higher in men than in women. Compared with agricultural and pastoral areas, the odds ratio of having HUA was 2.14 for participants in the suburbs of big cities and 1.57 in the center of big cities.
The prevalence of HUA is high in northern China. The differences in HUA prevalence by geographic region suggested that unbalanced economic development and health education, therefore HUA prevention measures should be strengthened to improve quality of life and reduce health care costs.
Prevalence; Hyperuricemia; Risk factors
Interferon-α2b (IFN-α2b) is used to treat melanoma but there is a need to improve its efficacy. IFN-α2b signaling requires STAT1/STAT2 tyrosine phosphorylation and is subject to negative regulation by phosphatases. In this study, we determined whether inhibition of the protein tyrosine phosphatase Shp2 could enhance IFN-α2b responses in human melanoma cells. Shp2 knockdown increased IFN-α2b-stimulated STAT1 Tyr-701 phosphorylation and ISRE-luciferase activity even though it did not affect STAT2 Tyr-690 phosphorylation in A375 cells. In A375 tumor xenografts, Shp2 knockdown enhanced the anti-melanoma effect of IFN-α2b. Furthermore, the Shp2 inhibitor SPI-112Me increased the IFN-α2b-induced STAT1 activation and anti-proliferative response in A375 and SK-MEL-2 cells. These results demonstrate that inhibition of Shp2 can enhance the anti-melanoma activity of IFN-α2b.
Shp2; STAT1; Melanoma; Interferon
Membrane proteins (MPs) mediate a variety of cellular responses to extracellular signals. While MPs are intensely studied for their values as disease biomarkers and therapeutic targets, in situ investigation of binding kinetics of MPs with their ligands has been a challenge. Traditional approaches isolate MPs and then study them ex situ, which does not accurately reflect their native structures and functions. We present here a label-free plasmonic microscopy method to map the local binding kinetics of MPs in their native environment. This new analytical method can perform simultaneous plasmonic and fluorescence imaging, thus making it possible to combine the strengths of both label-based and label-free techniques in one system. Using this method, we have determined the distribution of MPs on the surface of single cells, and the local binding kinetic constants of different MPs. Furthermore, we have studied the polarization of the MPs on the cell surface during chemotaxis.
Renal injuries in patients with diabetes include diabetic nephropathy (DN) and non-diabetic renal diseases (NDRD). The value of a clinical diagnosis of DN and NDRD remains inconclusive. We conducted a meta-analysis of the literature to identify predictive factors of NDRD and to compare the clinical characteristics of DN and NDRD for differential diagnosis.
We searched PubMed (1990 to January 2012), Embase (1990 to February 2009), and CNKI (1990 to January 2012) to identify studies that enrolled patients with DN and NDRD. Then, the quality of the studies was assessed, and data were extracted. The results were summarized as odds ratios (ORs) for dichotomous outcomes and weighted mean differences (WMDs) for continuous outcomes.
Twenty-six relevant studies with 2,322 patients were included. The meta-analysis showed that the absence of diabetic retinopathy (DR) predicts NDRD (OR, 0.15; 95% confidence interval [CI], 0.09–0.26, p<0.00001). A shorter duration of diabetes mellitus (DM) also predicted NDRD (weighted mean difference, −34.67; 95% CI, −45.23–−24.11, p<0.00001). The levels of glycosylated hemoglobin (HbA1C%), blood pressure (BP), and total cholesterol were lower in patients with NDRD, whereas triglycerides and body mass index were higher. Other clinical parameters, including age, 24-h urinary protein excretion, serum creatinine, creatinine clearance, blood urea nitrogen, and glomerular filtration rate were not different between patients with NDRD and DN.
We identified that the absence of DR, shorter duration of DM, lower HbA1C, and lower BP may help to distinguish NDRD from DN in patients with diabetes. This could assist clinicians in making a safe and sound diagnosis and lead to more effective treatments.
AIM: To examine fibrinogen-like protein 2 (fgl2) expression during taurocholate-induced acute pancreatitis progression in rats and its correlation with pancreatic injury severity.
METHODS: Forty-eight male Sprague-Dawley rats were randomly divided into the severe acute pancreatitis (SAP) group (n = 24) and the sham operation (SO) group (n = 24). Sodium taurocholate (4% at doses of 1 mL/kg body weight) was retrogradely injected into the biliopancreatic ducts of the rats to induce SAP. Pancreatic tissues were prepared immediately after sacrifice. At the time of sacrifice, blood was obtained for determination of serum amylase activity and isolation of peripheral blood mononuclear cells (PBMCs). Pancreatic tissue specimens were obtained for routine light microscopy including hematoxylin and eosin staining, and the severity of pancreatic injury was evaluated 1, 4 and 8 h after induction. Expression of fgl2 mRNA was measured in the pancreas and PBMCs using reverse transcription polymerase chain reaction. Expression of fgl2 protein was evaluated in pancreatic tissues using Western blotting and immunohistochemical staining. Masson staining was also performed to observe microthrombosis.
RESULTS: At each time point, levels of fgl2 mRNAs in pancreatic tissues and PBMCs were higher (P < 0.05) in the SAP group than in the SO group. For pancreatic tissue in SAP vs SO, the levels were: after 1 h, 3.911 ± 1.277 vs 1.000 ± 0.673; after 4 h, 9.850 ± 3.095 vs 1.136 ± 0.609; and after 8 h, 12.870 ± 3.046 vs 1.177 ± 0.458. For PBMCs in SAP vs SO, the levels were: after 1 h, 2.678 ± 1.509 vs 1.000 ± 0.965; after 4 h, 6.922 ± 1.984 vs 1.051 ± 0.781; and after 8 h, 13.533 ± 6.575 vs 1.306 ± 1.179. Levels of fgl2 protein expression as determined by Western blotting and immunohistochemical staining were markedly up-regulated (P < 0.001) in the SAP group compared with those in the SO group. For Western blotting in SAP vs SO, the results were: after 1 h, 2.183 ± 0.115 vs 1.110 ± 0.158; after 4 h, 2.697 ± 0.090 vs 0.947 ± 0.361; and after 8 h, 3.258 ± 0.094 vs 1.208 ± 0.082. For immunohistochemical staining in SAP vs SO, the results were: after 1 h, 1.793 ± 0.463 vs 0.808 ± 0.252; after 4 h, 4.535 ± 0.550 vs 0.871 ± 0.318; and after 8 h, 6.071 ± 0.941 vs 1.020 ± 0.406. Moreover, we observed a positive correlation in the pancreas (r = 0.852, P < 0.001) and PBMCs (r = 0.735, P < 0.001) between fgl2 expression and the severity of pancreatic injury. Masson staining showed that microthrombosis (%) in rats with SAP was increased (P < 0.001) compared with that in the SO group and it was closely correlated with fgl2 expression in the pancreas (r = 0.842, P < 0.001). For Masson staining in SAP vs SO, the results were: after 1 h, 26.880 ± 9.031 vs 8.630 ± 3.739; after 4 h, 53.750 ± 19.039 vs 8.500 ± 4.472; and after 8 h, 80.250 ± 12.915 vs 10.630 ± 7.003.
CONCLUSION: Microthrombosis due to fgl2 overexpression contributes to pancreatic impairment in rats with SAP, and fgl2 level may serve as a biomarker during early stages of disease.
Fibrinogen-like protein 2; Microthrombosis; Fibrin; Severe acute pancreatitis; Peripheral blood mononuclear cell
Heterozygous loss-of-function SMAD3 (Mothers against decapentaplegic homolog 3) mutations lead to aneurysm-osteoarthritis syndrome (AOS). In the present study, we found that mice lacking Smad3 had a vascular phenotype similar to AOS, marked by the progressive development of aneurysms. These aneurysms were associated with various pathological changes in transmural inflammatory cell infiltration. Bone marrow transplants from Smad3–/– mice induced aortitis and aortic root dilation in irradiated WT recipient mice. Transplantation of CD4+ T cells from Smad3–/– mice also induced aortitis in Smad3+/+ recipient mice, while depletion of CD4+ T cells in Smad3–/– mice reduced the infiltration of inflammatory cells in the aortic root. Furthermore, IFN-γ deficiency increased, while IL-17 deficiency decreased, disease severity in Smad3+/– mice. Cytokine secretion was measured using a cytokine quantibody array, and Smad3–/– CD4+ T cells secreted more GM-CSF than Smad3+/+ CD4+ T cells. GM-CSF induced CD11b+Gr-1+Ly-6Chi inflammatory monocyte accumulation in the aortic root, but administration of anti–GM-CSF mAb to Smad3–/– mice resulted in significantly less inflammation and dilation in the aortic root. We also identified a missense mutation (c.985A>G) in a family of thoracic aortic aneurysms. Intense inflammatory infiltration and GM-CSF expression was observed in aortas specimens of these patients, suggesting that GM-CSF is potentially involved in the development of AOS.
A crucial step in analyzing mRNA-Seq data is to accurately and efficiently map hundreds of millions of reads to the reference genome and exon junctions. Here we present OLego, an algorithm specifically designed for de novo mapping of spliced mRNA-Seq reads. OLego adopts a multiple-seed-and-extend scheme, and does not rely on a separate external aligner. It achieves high sensitivity of junction detection by strategic searches with small seeds (∼14 nt for mammalian genomes). To improve accuracy and resolve ambiguous mapping at junctions, OLego uses a built-in statistical model to score exon junctions by splice-site strength and intron size. Burrows–Wheeler transform is used in multiple steps of the algorithm to efficiently map seeds, locate junctions and identify small exons. OLego is implemented in C++ with fully multithreaded execution, and allows fast processing of large-scale data. We systematically evaluated the performance of OLego in comparison with published tools using both simulated and real data. OLego demonstrated better sensitivity, higher or comparable accuracy and substantially improved speed. OLego also identified hundreds of novel micro-exons (<30 nt) in the mouse transcriptome, many of which are phylogenetically conserved and can be validated experimentally in vivo. OLego is freely available at http://zhanglab.c2b2.columbia.edu/index.php/OLego.
Serum γ-glutamyltransferase (GGT) and uric acid (UA) levels are elevated in patients with diabetes or cardiovascular disease. Prediabetes, characterized by impaired glucose tolerance, is an important risk factor for overt diabetes as well as cardiovascular disease. Therefore, the aim of this study was to explore the relationship between GGT, UA and prediabetes in a Chinese population, and provide a scientific basis for the early prevention and treatment of diabetes.
We performed a cross-sectional population-based study in a cohort of 2694 subjects (1211 men and 1483 women, aged 35–86 years). Questionnaires and physical examinations were performed using standardized procedures. Fasting blood was collected to measure glucose and other biochemical parameters. The subjects were divided into two groups with either normal fasting glucose (NFG) or impaired fasting glucose (IFG), according to international diagnostic criteria. Logistic regression analysis was performed to estimate odds ratios (OR) and 95% confidence intervals.
Compared with the NFG group, the IFG group had significantly higher blood pressure but lower high-density lipoprotein–cholesterol in women. Body mass index, waist circumference, triglyceride, glucose, GGT, and UA levels were significantly higher in males and females in the IFG group than those in the NFG group. Logistic regression analysis revealed that the OR for prediabetes increased with increasing serum GGT quartiles and UA quartiles. GGT and UA were positively associated with prediabetes in men and women, independent of age, ethnicity, smoking, alcohol consumption, blood pressure, physical labor, and other confounders.
We found that serum GGT and UA levels were positively associated with prediabetes in men and women living in areas inhabited by Chinese ethnic minorities. As elevated GGT and UA levels were associated with significantly increased risk of prediabetes, they may be used as sensitive biological markers of prediabetes.
γ-Glutamyltransferase; Uric acid; Prediabetes; Impaired fasting glucose
To retrospectively investigate the role of contrast-enhanced ultrasonography (CEUS) in percutaneous radiofrequency ablation (RFA) in patients with liver metastases and evaluate the therapeutic efficacy of RFA assisted by CEUS.
From May 2004 to September 2010, 136 patients with 219 liver metastatic lesions received CEUS examination 1 h before RFA (CEUS group), and other 126 patients with 216 lesions without CEUS examination in the earlier period were served as a historical control group. The mean tumor size was 3.2 cm and the mean tumor number was 1.6 in the CEUS group, while 3.4 cm and 1.7 in the control group, respectively (P>0.05). The clinical characteristics, recurrence results and survival outcomes were compared between two groups.
In the CEUS group, two isoechoic tumors were not demonstrated on unenhanced ultrasonography (US), and 63 (47%) of 134 tumors examined with CEUS were 0.3 cm larger than with unenhanced US. Furthermore, in 18.4% of 136 patients, additional 1-3 tumors were detected on CEUS. The CEUS group showed higher early tumor necrosis and lower intrahepatic recurrence than the control group. The 3-year overall survival (OS) rate and the 3-year local recurrence-free survival (LRFS) rate in the CEUS group were 50.1% and 38.3%, in contrast to 25.3% and 19.3% in the control group, respectively (P=0.002 and P<0.001).
CEUS provides important information for RFA treatment in patients with liver metastases and better therapeutic effect could be attained.
Contrast media; liver metastases; radiofrequency ablation; ultrasonography
Systemic administration of nicotine increases dopaminergic (DA) neuron firing in the ventral tegmental area (VTA), which is thought to underlie nicotine reward. Here, we report that the medial prefrontal cortex (mPFC) plays a critical role in nicotine-induced excitation of VTA DA neurons. In chloral hydrate-anesthetized rats, extracellular single-unit recordings showed that VTA DA neurons exhibited two types of firing responses to systemic nicotine. After nicotine injection, the neurons with type-I response showed a biphasic early inhibition and later excitation, whereas the neurons with type-II response showed a monophasic excitation. The neurons with type-I, but not type-II, response exhibited pronounced slow oscillations (SO) in firing. Pharmacological or structural mPFC inactivation abolished SO and prevented systemic nicotine-induced excitation in the neurons with type-I, but not type-II, response, suggesting that these VTA DA neurons are functionally coupled to the mPFC and nicotine increases firing rate in these neurons in part through the mPFC. Systemic nicotine also increased the firing rate and SO in mPFC pyramidal neurons. mPFC infusion of a non-α7 nAChR antagonist mecamylamine blocked the excitatory effect of systemic nicotine on the VTA DA neurons with type-I response, but mPFC infusion of nicotine failed to excite these neurons. These results suggest that nAChR activation in the mPFC is necessary, but not sufficient, for systemic nicotine-induced excitation of VTA neurons. Finally, systemic injection of bicuculline prevented nicotine-induced firing alterations in the neurons with type-I response. We propose that the mPFC plays a critical role in systemic nicotine-induced excitation of VTA DA neurons.
nicotine; prefrontal cortex; ventral tegmental area; dopamine neuron; in vivo recording; slow oscillation
Zuo Jin Wan (ZJW), a typical traditional Chinese medicine (TCM) formula, has been identified to have anticancer activity in recent studies. In this study, we determined the underlying mechanism of ZJW in the reversal effect of multidrug resistance on colorectal cancer in vitro and in vivo. Our results showed that ZJW significantly enhanced the sensitivity of chemotherapeutic drugs in HCT116/L-OHP, SGC7901/DDP, and Bel/Fu MDR cells. Moreover, combination of chemotherapy with ZJW could reverse the drug resistance of HCT116/L-OHP cells, increase the sensitivity of HCT116/L-OHP cells to L-OHP, DDP, 5-Fu, and MMC in vitro, and inhibit the tumor growth in the colorectal MDR cancer xenograft model. ICP-MS results showed that ZJW could increase the concentration of chemotherapeutic drugs in HCT116/L-OHP cells in a dose-dependent manner. Furthermore, we showed that ZJW could reverse drug resistance of colorectal cancer cells by decreasing P-gp level in vitro and in vivo, which has been represented as one of the major mechanisms that contribute to the MDR phenotype. Our study has provided the first direct evidence that ZJW plays an important role in reversing multidrug resistance of human colorectal cancer and may be considered as a useful target for cancer therapy.
Recent reports have demonstrated that somatic cells can be directly converted to other differentiated cell types through ectopic expression of sets of transcription factors, directly avoiding the transition through a pluripotent state. Our previous experiments generated induced neural progenitor-like cells (iNPCs) by a novel combination of five transcription factors (Sox2, Brn2, TLX, Bmi1 and c-Myc). Here we demonstrated that the iNPCs not only possess NPC-specific marker genes, but also have qualities of primary brain-derived NPCs (WT-NPCs), including tripotent differentiation potential, mature neuron differentiation capability and synapse formation. Importantly, the mature neurons derived from iNPCs exhibit significant physiological properties, such as potassium channel activity and generation of action potential-like spikes. These results suggest that directly reprogrammed iNPCs closely resemble WT-NPCs, which may suggest an alternative strategy to overcome the restricted proliferative and lineage potential of induced neurons (iNCs) and broaden applications of cell therapy in the treatment of neurodegenerative disorders.
Cigarette smoking is associated with a decreased incidence of Parkinson disease (PD) through unknown mechanisms. Interestingly, a decrease in the numbers of α4β2 nicotinic acetylcholine receptors (α4β2-nAChRs) in PD patients suggests an α4β2-nAChR-mediated cholinergic deficit in PD. Although oligomeric forms of α-synuclein have been recognized to be toxic and involved in the pathogenesis of PD, their direct effects on nAChR-mediated cholinergic signaling remains undefined. Here, we report for the first time that oligomeric α-synuclein selectively inhibits human α4β2-nAChR-mediated currents in a dose-dependent, non-competitive and use-independent manner. We show that pre-loading cells with guanyl-5′-yl thiophosphate fails to prevent this inhibition, suggesting that the α-synuclein-induced inhibition of α4β2-nAChR function is not mediated by nAChR internalization. By using a pharmacological approach and cultures expressing transfected human nAChRs, we have shown a clear effect of oligomeric α-synuclein on α4β2-nAChRs, but not on α4β4- or α7-nAChRs, suggesting nAChR subunit selectivity of oligomeric α-synuclein-induced inhibition. In addition, by combining the size exclusion chromatography and atomic force microscopy (AFM) analyses, we find that only large (>4 nm) oligomeric α-synuclein aggregates (but not monomeric, small oligomeric or fibrillar α-synuclein aggregates) exhibit the inhibitory effect on human α4β2-nAChRs. Collectively, we have provided direct evidence that α4β2-nAChR is a sensitive target to mediate oligomeric α-synuclein-induced modulation of cholinergic signaling, and our data imply that therapeutic strategies targeted toward α4β2-nAChRs may have potential for developing new treatments for PD.
High-mobility group box 1 protein (HMGB1), which mainly exists in the nucleus, has recently been shown to function as a sentinel molecule for viral nucleic acid sensing and an autophagy regulator in the cytoplasm. In this study, we studied the chaperone-like activity of HMGB1 and found that HMGB1 inhibited the chemically induced aggregation of insulin and lysozyme, as well as the heat-induced aggregation of citrate synthase. HMGB1 also restored the heat-induced suppression of cytoplasmic luciferase activity as a reporter protein in hamster lung fibroblast O23 cells with expression of HMGB1. Next, we demonstrated that HMGB1 inhibited the formation of aggregates and toxicity caused by expanded polyglutamine (polyQ), one of the main causes of Huntington disease. HMGB1 directly interacted with polyQ on immunofluorescence and coimmunoprecipitation assay, whereas the overexpression of HMGB1 or exogenous administration of recombinant HMGB1 protein remarkably reduced polyQ aggregates in SHSY5Y cells and hmgb1−/− mouse embryonic fibroblasts upon filter trap and immunofluorescence assay. Finally, overexpressed HMGB1 proteins in mouse embryonic primary striatal neurons also bound to polyQ and decreased the formation of polyQ aggregates. To this end, we have demonstrated that HMGB1 exhibits chaperone-like activity and a possible therapeutic candidate in polyQ disease.
We present two cases of glioma (WHO grade III) in pregnant females presenting in the third trimester. Gliomas during pregnancy are rare. At present, the association between gliomas and pregnancy is poorly understood and little has been reported with regard to the management of patients with gliomas in pregnancy. Management of these cases presents a medical dilemma. Gliomas during pregnancy pose a risk to maternal and fetal life. The benefit-to-risk ratio should be carefully evaluated and discussed prior to surgery. In the present cases, caesarean section (CS) followed by craniotomy was performed under the same general anesthesia at 34 weeks’ gestation. The mothers received radiotherapy and chemotherapy following surgery. They have been followed up to the present date and remain in good health. These two cases indicate that early CS followed by craniotomy is an effective choice in pregnant patients with gliomas at ≥34 weeks’ gestation. In the present study, we describe these two cases and review the literature with regard to gliomas during pregnancy.
brain tumors; pregnancy; treatment; outcome research
Microsaccades during fixation have been suggested to counteract visual fading. Recent experiments have also observed microsaccade-related neural responses from cellular record, scalp electroencephalogram (EEG), and functional magnetic resonance imaging (fMRI). The underlying mechanism, however, is not yet understood and highly debated. It has been proposed that the neural activity of primary visual cortex (V1) is a crucial component for counteracting visual adaptation. In this paper, we use computational modeling to investigate how short-term depression (STD) in thalamocortical synapses might affect the neural responses of V1 in the presence of microsaccades. Our model not only gives a possible synaptic explanation for microsaccades in counteracting visual fading, but also reproduces several features in experimental findings. These modeling results suggest that STD in thalamocortical synapses plays an important role in microsaccade-related neural responses and the model may be useful for further investigation of behavioral properties and functional roles of microsaccades.
short-term depression; microsaccades; feedforward network; visual fading; fixation