Abstract Gallbladder polyps are most commonly treated with cholecystectomy, which is associated with various complications. For benign disease, preserving the gallbladder is preferable. Since 1994, we have been exploring percutaneous polypectomy and have recently developed an improved new technique. This study reports a new endoscopic-laparoscopic (Endolap) technique for the removal of polyps and the preservation of the gallbladder. Nine Chinese mini-pigs were used to observe mucosal regeneration. Microwaves of 50-70 mA for 9 seconds were safe, and the gallbladder mucosa of pigs recovered to nearly normal 2 weeks later. In the clinical cases, 60 patients with gallbladder polyps were studied. With the patient under general anesthesia, each polyp stem was coagulated, and then the polyp was removed. All procedures were successful at between 60 and 135 minutes. The success rate was 93.33% (56/60). A retrospective analysis was conducted to assess the recovery of gallbladder function. All patients were followed up and symptom-free, without recurrence of the polyps; 3 months after the operation, the volume and contraction of the gallbladder recovered to preoperative levels. Thus the Endolap technique is reliable for removing benign gallbladder polyps and is applicable to a wider range of clinical situations than percutaneous polypectomy.
In this report, we reasoned that non-covalent modification of amyloid beta (A?) by crown ethers could inhibit its aggregation. We demonstrated that PiB-C, a conjugate PiB and crown ether, could significantly reduce the aggregation in vitro. Additionally, two-photon imaging showed that PiB-C could efficiently label A? plaques and CAAs in AD mice.
In this paper we demonstrate a novel complex array structure comprising well-aligned Au nanorods (10 nm in diameter) encapsulated inside 15 nm radius multiwalled carbon nanotubes (MWCNTs). A pre-aligned and open-ended nanoporous MWCNT membrane is used as the starting material. Au nanorods are precisely deposited and aligned inside the hollow channels of CNTs by inter-diffusing the HAuCl4 precursor and the reductant solution. Ultra-long Au nanowires and spherical Au nanoparticles are also observed in the CNT cavity with the same diameter in special cases. Using high-resolution TEM (HRTEM), scanning transmission electron microscopy (STEM), 3-dimensional TEM (3D-TEM) and energy dispersive X-ray spectroscopy (EDX), the precise location and composition of the encapsulated Au components with various structures are confirmed. This aligned Au@CNT endohedral material has important potential applications in nanocatalysis, waveguides, as well as in novel plasmonic devices.
High-grade serous ovarian carcinoma (HGSOC), the most common and aggressive subtype of epithelial ovarian cancer, is characterized by TP53 mutations and genetic instability. Using miRNA profiling analysis, we found that miR-145, a p53 regulated miRNA, was frequently down-regulated in HGSOC. miR-145 down-regulation was further validated in a large cohort of HGSOCs by qPCR. Overexpression of miR-145 in ovarian cancer cells significantly suppressed proliferation, migration and invasion in vitro and inhibited tumor growth and metastasis in vivo. Metadherin (MTDH) was subsequently identified as a direct target of miR-145, and was found to be significantly up-regulated in HGSOC. Furthermore, overexpression of MTDH rescued the inhibitory effects of miR-145 in ovarian cancer cells. Finally, we found that high level of MTDH expression correlated with poor prognosis of HGSOC. Therefore, lack of suppression of MTDH by miR-145 when p53 is dysfunctional leads to increased tumor growth and metastasis of HGSOC. Our study established a new link between p53, miR-145 and MTDH in the regulation of tumor growth and metastasis in HGSOC.
In this paper, we numerically demonstrate the advantage of utilizing continuous amplitude and phase modulation in super-oscillation focusing lens design. Numerical results show that compared with simple binary amplitude modulation, continuous amplitude and phase modulation can greatly improve the super-oscillation focusing performance by increasing the central lobe intensity and the ratio of its energy to the total energy, reducing the sidelobe intensity, and substantially extending the field of view. Our study also reveals the role of phase distribution in reducing the spatial frequency bandwidth of the super-oscillation optical field on the focal plane. Based on continuous amplitude and binary phase modulation, a lens was designed with double layer metal slit array for wavelength of 4.6 µm. COMSOL is used to carry out the 2D simulation. The lens focal length is 40.18? and the focal spot FWHM is 0.308?. Two largest sidelobes are located right next to the central lobe with intensity about 40% of the central lobe intensity. Except for the two sidelobes, other sidelobes have intensity less than 25% of the central lobe intensity, which leads to a clear field of view on the whole focal plane.
Hypertension control rate in the US is low with the current clinical practice (JNC 7) and cardiovascular disease (CVD) remain is the leading cause of morbidity and mortality. A 6-month clinical trial simulation case study testing different virtual clinical practice strategies was performed in an attempt to increase the control rate. The CVD risk was calculated using the Framingham CVD risk model at baseline and 6 months post-treatment. The estimated CVD events for the baseline patient sample without any treatment was 998 (95 % CI: 967-1,026) over 6 months in 100,000 patients. Treating these patients for 6 months with current clinical practice, high dose strategy, high dose with low target BP strategy resulted in a reduction in CVD events of 191(95 % CI: 169-205), 284 (95 % CI: 261-305), and 353 (95 % CI: 331-375), respectively. Hence the two alternative strategies resulted in an increase in treatment effect by 49 % (95 %CI: 44-59 %) and 85 % (95 %CI: 79-99 %), respectively. The increased safety with the current low dose strategy may potentially be offset by increased CVD risk in the time necessary to control hypertension.
The meminductor was proposed to be a fundamental circuit memdevice parallel with the memristor, linking magnetic flux and current. However, a clear material model or experimental realization of a meminductor has been challenging. Here we demonstrate pinched hysteretic magnetic flux-current signals at room temperature based on the spin Hall magnetoresistance effect in several-nanometer-thick thin films, exhibiting the nonvolatile memorizing property and magnetic energy storage ability of the meminductor. Similar to the parameters of the capacitor, resistor, and inductor, meminductance, LM, is introduced to characterize the capability of the prepared meminductor. Our findings present an indispensable element of memdevices and open an avenue for nanoscale meminductor design and manufacture, which might contribute to low-power electronic circuits, information storage, and artificial intelligence.
To explore the expression status of carbonic anhydrase III (CAIII) from quadriceps femoris muscle in two kinds of muscle clinical phenotype (skeletal muscle atrophy group and skeletal muscles non-atrophy group) of chronic obstructive pulmonary disease (COPD).
Little cigars and cigarillos may resemble cigarettes, but may be less expensive and can be purchased singly and in flavored varieties. We used two major U.S. surveys to investigate use of cigarillos and cigarettes.
Biliary hyperplasia and liver fibrosis are common features in cholestatic liver disease. Melatonin is synthesized by the pineal gland as well as the liver. Melatonin inhibits biliary hyperplasia of bile duct-ligated (BDL) rats. Since melatonin synthesis (by the enzyme serotonin N-acetyltransferase, AANAT) from the pineal gland increases after dark exposure, we hypothesized that biliary hyperplasia and liver fibrosis are diminished by continuous darkness via increased melatonin synthesis from the pineal gland. Normal or BDL rats (immediately after surgery) were housed with light-dark cycles or complete dark for 1 wk before evaluation of 1) the expression of AANAT in the pineal gland and melatonin levels in pineal gland tissue supernatants and serum; 2) biliary proliferation and intrahepatic bile duct mass, liver histology, and serum chemistry; 3) secretin-stimulated ductal secretion (functional index of biliary growth); 4) collagen deposition, liver fibrosis markers in liver sections, total liver, and cholangiocytes; and 5) expression of clock genes in cholangiocytes. In BDL rats exposed to dark there was 1) enhanced AANAT expression/melatonin secretion in pineal gland and melatonin serum levels; 2) improved liver morphology, serum chemistry and decreased biliary proliferation and secretin-stimulated choleresis; and 4) decreased fibrosis and expression of fibrosis markers in liver sections, total liver and cholangiocytes and reduced biliary expression of the clock genes PER1, BMAL1, CLOCK, and Cry1. Thus prolonged dark exposure may be a beneficial noninvasive therapeutic approach for the management of biliary disorders.
Histidine is converted to histamine by histidine decarboxylase (HDC). We have shown that cholangiocytes 1) express HDC, 2) secrete histamine, and 3) proliferate after histamine treatment via ERK1/2 signaling. In bile duct-ligated (BDL) rodents, there is enhanced biliary hyperplasia, HDC expression, and histamine secretion. This studied aimed to demonstrate that knockdown of HDC inhibits biliary proliferation via downregulation of PKA/ERK1/2 signaling. HDC(-/-) mice and matching wild-type (WT) were subjected to sham or BDL. After 1 wk, serum, liver blocks, and cholangiocytes were collected. Immunohistochemistry was performed for 1) hematoxylin and eosin, 2) intrahepatic bile duct mass (IBDM) by cytokeratin-19, and 3) HDC biliary expression. We measured serum and cholangiocyte histamine levels by enzyme immunoassay. In total liver or cholangiocytes, we studied: 1) HDC and VEGF/HIF-1? expression and 2) PCNA and PKA/ERK1/2 protein expression. In vitro, cholangiocytes were stably transfected with shRNA-HDC plasmids (or control). After transfection we evaluated pPKA, pERK1/2, and cholangiocyte proliferation by immunoblots and MTT assay. In BDL HDC(-/-) mice, there was decreased IBDM, PCNA, VEGF, and HDC expression compared with BDL WT mice. Histamine levels were decreased in BDL HDC(-/-). BDL HDC(-/-) livers were void of necrosis and inflammation compared with BDL WT. PKA/ERK1/2 protein expression (increased in WT BDL) was lower in BDL HDC(-/-) cholangiocytes. In vitro, knockdown of HDC decreased proliferation and protein expression of PKA/ERK1/2 compared with control. In conclusion, loss of HDC decreases BDL-induced biliary mass and VEGF/HIF-1? expression via PKA/ERK1/2 signaling. Our data suggest that HDC is a key regulator of biliary proliferation.
Based on the k-mer model for genetic sequence, a k-mer sparse matrix representation is proposed to denote the types and sites of k-mers appearing in a genetic sequence, and there exists a one-to-one relationship between a genetic sequence and its associated k-mer sparse matrix. With the singular value decomposition of the k-mer sparse matrix, the k-mer singular value vector is constructed and utilized to numerically quantify the characteristics of a genetic sequence. We investigate and evaluate the optimum value k(?) chosen for our k-mer sparse matrix model for genetic sequence. To show the usefulness of our k-mer sparse matrix model method, it is applied to the comparison of genetic sequences, and the results obtained fully demonstrate that our proposed method is very powerful in analyzing and determining the relationships of genetic sequences.
Boosting cold hardiness in parasitoids is a goal that is particularly attractive for increasing shelf life and shipment of biological control agents. In the experiments reported here we use the parasitoid Nasonia vitripennis as a model to evaluate manipulations that may be capable of enhancing the wasp's cold tolerance. We altered the parasitoid's cold tolerance by manipulating the wasp's diapause status, the diapause status of the host fly (Sarcophaga crassipalpis), and the diet of the host. Larval diapause in N. vitripennis dramatically increased cold tolerance and the diapause status of the host also exerted a positive, although less dramatic, effect. Augmenting the host fly's diet with supplements of putative cryoprotectants (alanine, proline and glycerol) enhanced cold tolerance in parasitoids that fed on the flies, thus indicating a tri-trophic effect on parasitoid cold tolerance. The most pronounced improvement in cold tolerance was noted in parasitoids fed on fly hosts that had received a diet augmented with proline. These results suggest mechanisms that could be exploited for enhancement of cold tolerance in parasitoids of commercial interest.
In this report, we designed a highly bright bifunctional curcumin analogue CRANAD-28. In vivo two-photon imaging suggested that CRANAD-28 could penetrate the blood brain barrier (BBB) and label plaques and cerebral amyloid angiopathies (CAAs). We also demonstrated that this imaging probe could inhibit the crosslinking of amyloid beta induced either by copper or by natural conditions.
IL-6/Stat3 is associated with the regulation of transcription of key cellular regulatory genes (microRNAs) during different types of liver injury. This study evaluated the role of IL-6/Stat3 in regulating miRNA and miR-21 in alcoholic liver disease. By microarray, we identified that ethanol feeding significantly up-regulated 0.8% of known microRNAs in mouse liver compared with controls, including miR-21. Similarly, the treatment of normal human hepatocytes (N-Heps) and hepatic stellate cells (HSCs) with ethanol and IL-6 significantly increased miR-21 expression. Overexpression of miR-21 decreased ethanol-induced apoptosis in both N-Heps and HSCs. The expression level of miR-21 was significantly increased after Stat3 activation in N-Heps and HSCs, in support of the concept that the 5'-promoter region of miR-21 is regulated by Stat3. Using real time PCR, we confirmed that miR-21 activation is associated with ethanol-linked Stat3 binding of the miR-21 promoter. A combination of bioinformatics, PCR array, dual-luciferase reporter assay, and Western blot analysis revealed that Fas ligand (TNF superfamily, member 6) (FASLG) and death receptor 5 (DR5) are the direct targets of miR-21. Furthermore, inhibition of miR-21 by specific Vivo-Morpholino and knock-out of IL-6 in ethanol-treated mice also increased the expression of DR5 and FASLG in vivo during alcoholic liver injury. The identification of miR-21 as an important regulator of hepatic cell survival, transformation, and remodeling in vitro, as well as its upstream modulators and downstream targets, will provide insight into the involvement of altered miRNA expression in contributing to alcoholic liver disease progression and testing novel therapeutic approaches for human alcoholic liver diseases.
Poly(lactic co-glycolic acid) (PLGA) is widely used in diverse fields, especially in delivering biologically active proteins and drugs. For these applications, the knowledge of morphology and microstructure of PLGA micro-porous microspheres is of great importance since they strongly influence the drug delivering efficiency. In this study, micro-porous PLGA microspheres loaded by bovine serum albumin are investigated by using a full-field Zernike phase contrast transmission hard X-ray microscope. From three-dimensional reconstructions and segmentations, fundamental microstructural parameters such as size, shape, distribution and volume ratio among pores and proteins inside PLGA microspheres were obtained. These parameters are useful to understand the relationship between the internal microstructure and drug encapsulation, as well as the drug release efficiency of PLGA microspheres. The presented results demonstrate the capability of hard X-ray nano-tomography to characterize porous microspheres loaded with proteins and drugs, and also open a way to analyse, optimize and design new PLGA microspheres for specific applications.
High-dimensional large sample data sets, between feature variables and between samples, may cause some correlative or repetitive factors, occupy lots of storage space, and consume much computing time. Using the Elman neural network to deal with them, too many inputs will influence the operating efficiency and recognition accuracy; too many simultaneous training samples, as well as being not able to get precise neural network model, also restrict the recognition accuracy. Aiming at these series of problems, we introduce the partial least squares (PLS) and cluster analysis (CA) into Elman neural network algorithm, by the PLS for dimension reduction which can eliminate the correlative and repetitive factors of the features. Using CA eliminates the correlative and repetitive factors of the sample. If some subclass becomes small sample, with high-dimensional feature and fewer numbers, PLS shows a unique advantage. Each subclass is regarded as one training sample to train the different precise neural network models. Then simulation samples are discriminated and classified into different subclasses, using the corresponding neural network to recognize it. An optimized Elman neural network classification algorithm based on PLS and CA (PLS-CA-Elman algorithm) is established. The new algorithm aims at improving the operating efficiency and recognition accuracy. By the case analysis, the new algorithm has unique superiority, worthy of further promotion.
We report a facile and scalable synthesis of ultra-long (>100 ?m) nanoribbons based on self-assembly of positively charged carbon dots (C-dots) and anionic oligomers of styrene and 4-styrenesulfonate (PS-PSS) in a mixture of ethanol and water (4/1, v/v). The obtained hybrid (PS-PSS)/C-dot nanoribbons show a multi-colored fluorescence and an electrical conductivity of 3.368 S m(-1).
Background: Primary thyroid lymphoma (PTL) is uncommon, accounting for 2%-5% of all thyroid malignancies. Papillary thyroid carcinoma (PTC) is the most frequent thyroid cancer. The coexistence of PTL and PTC is very rare, and the pre-operative diagnosis is rather difficult. Methods: A 41 year-old male patient complaining of fast painless thyroid enlargement for 2 months and a cervical mass for half a month was presented. Imaging demonstrated an enlarged thyroid and a mass in the thyroid. Results: A surgery was conducted, and the final diagnosis of coexistence of PTL and PTC was confirmed by histopathological and immunohistochemical examination. The patient was then treated with CHOP chemotherapy and radiotherapy. With 2 months of follow-up, no recurrence or metastasis was noted. Conclusions: This rare case highlights the importance for physicians to keep PTL in mind for differential diagnosis in patients with sudden thyroid enlargement and who have clinical history of Hashimoto's thyroiditis. Head Neck, 2014.
Understanding the exotic quantum phenomena in bulk bismuth beyond its ultraquantum limit remains controversial and gives rise to renewed interest. The focus of the issues is whether these quantum properties have a conventional bulk nature or just the surface effect due to the significant spin-orbital interaction and in relation to the Bi-based topological insulators. Here, we present angular-dependent magnetoresistance (AMR) measurements on single-crystal bismuth nanoribbons of different thicknesses with magnetic fields up to 31 T. In thin nanoribbons with thickness of ?40 nm, a two-fold rational symmetry of the low field AMR spectra and two sets of 1/2-shifted (i.e., ? = 1/2) Shubnikov-de Haas (SdH) quantum oscillations with exact two- dimensional (2D) character were obtained. However, when the thickness of the ribbon increases, a 3D bulk-like SdH oscillations with ? = 0 and a four-fold rotational symmetry of the AMR spectra appear. These results provided unambiguous transport evidence of the topological 2D metallic surface states in thinner nanoribbons with an insulating bulk. Our observations provide a promising pathway to understand the quantum phenomena in Bi arising from the surface states.
While a two-dimensional (2D) metallic surface state in bismuth has been proposed, experimental 2D evidence of quantum transport, e.g., angular dependent Shubnikov-de Haas (SdH) oscillations is still lacking. Here, we report the angular-dependent magnetoresistance measurements in single-crystal Bi nanoribbons, and found that both the low-field weak antilocalization behavior and the high-field angle-dependent SdH oscillations follow exactly the 2D character, indicative of the 2D metallic surface states which dominate the transport properties of thin Bi nanoribbons. Moreover, by controllable exposing the ribbons to ambient environment (1 atm and room temperature), the metallic surface states were found to be robust to the oxidation although the carrier density in the surface states are modified after the exposures. These results suggest that the metallic surface states in Bi nanoribbons should be topologically protected which can provide key information in understanding the surface properties of Bi in nanometer scale.
A high performance liquid chromatography method with pre-column derivatization was developed for the simultaneous determination of formaldehyde, acetaldehyde, propionaldehyde, benzaldehyde, n-valeraldehyde and p-tolualdehyde in water-based coatings. After ultrasonic extraction with water, the samples were derivatized with 2,4-dinitrophenylhydrazine (2,4-DNPH) in acetonitrile under acidic condition, then filtrated by 0.45 microm organic syringe filters for the determination. Systematic investigation was carried out on the dependence of the derivatization conditions such as the acidity regulator, pH value, reaction temperature, reaction time and other factors. The optimized conditions were as follows: the dilute hydrochloric acid solution as acidity regulator, the pH of the buffer solution of 3, the reaction temperature of 60 degrees C, and the reaction time of 30 min. Under the conditions, a linear relation was achieved in the range of 0.08-2.0 mg/L for the peak area to concentration of the six aldehydes. The detection limits were 0.05-2.50 mg/kg. The recoveries of standard addition at the spiked levels of 2.0, 4.0, 6.0 mg/kg were 87.0%-112.8% with the relative standard deviations (RSDs, n = 6) of 1.12%-9.54%. The results showed that this method has a wide linear range, good precision and accuracy, and it is suitable for the simultaneous determination of the six aldehydes in water-based coatings.
When confronting the complex problems, radial basis function (RBF) neural network has the advantages of adaptive and self-learning ability, but it is difficult to determine the number of hidden layer neurons, and the weights learning ability from hidden layer to the output layer is low; these deficiencies easily lead to decreasing learning ability and recognition precision. Aiming at this problem, we propose a new optimized RBF neural network algorithm based on genetic algorithm (GA-RBF algorithm), which uses genetic algorithm to optimize the weights and structure of RBF neural network; it chooses new ways of hybrid encoding and optimizing simultaneously. Using the binary encoding encodes the number of the hidden layer's neurons and using real encoding encodes the connection weights. Hidden layer neurons number and connection weights are optimized simultaneously in the new algorithm. However, the connection weights optimization is not complete; we need to use least mean square (LMS) algorithm for further leaning, and finally get a new algorithm model. Using two UCI standard data sets to test the new algorithm, the results show that the new algorithm improves the operating efficiency in dealing with complex problems and also improves the recognition precision, which proves that the new algorithm is valid.
Cloves (Syzygium aromaticum) have been used as a traditional Chinese medicinal herb for thousands of years. Cloves possess antiseptic, antibacterial, antifungal, and antiviral properties, but their potential anticancer activity remains unknown. In this study, we investigated the in vitro and in vivo antitumor effects and biological mechanisms of ethyl acetate extract of cloves (EAEC) and the potential bioactive components responsible for its antitumor activity. The effects of EAEC on cell growth, cell cycle distribution, and apoptosis were investigated using human cancer cell lines. The molecular changes associated with the effects of EAEC were analyzed by Western blot and (qRT)-PCR analysis. The in vivo effect of EAEC and its bioactive component was investigated using the HT-29 tumor xenograft model. We identified oleanolic acid (OA) as one of the components of EAEC responsible for its antitumor activity. Both EAEC and OA display cytotoxicity against several human cancer cell lines. Interestingly, EAEC was superior to OA and the chemotherapeutic agent 5-fluorouracil at suppressing growth of colon tumor xenografts. EAEC promoted G0/G1 cell cycle arrest and induced apoptosis in a dose-dependent manner. Treatment with EAEC and OA selectively increased protein expression of p21(WAF1/Cip1) and ?-H2AX and downregulated expression of cell cycle-regulated proteins. Moreover, many of these changes were at the mRNA level, suggesting transcriptional regulation by EAEC treatment. Our results demonstrate that clove extract may represent a novel therapeutic herb for the treatment of colorectal cancer, and OA appears to be one of the bioactive components.
Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease (ESRD). Renal tubular injury by overproduction of ROS in mitochondria plays a critical role in the pathogenesis of DKD. Evidences have shown that p66Shc was involved in renal tubular injury via mitochondrial-dependent ROS production pathway, but little is known about the upstream signaling of p66Shc that leads to tubular oxidative damage under high glucose conditions. In this study, an increased PKC? and p66Shc activation and ROS production in renal tissues of patients with diabetic nephropathy were seen and further analysis revealed a positive correlation between the tubulointerstitial damage and p-PKC?, p-p66Shc, and ROS production. In vitro, we investigated the phosphorylation and activation of p66Shc and PKC? during treatment of HK-2 cells with high glucose (HG). Results showed that the activation of p66Shc and PKC? was increased in a dose- and time-dependent manner, and this effect was suppressed by Rottlerin, a pharmacologic inhibitor of PKC?. Moreover, PKC? siRNA partially blocked HG-induced p66Shc phosphorylation, translocation, and ROS production in HK-2 cells. Taken together, these data suggest that activation of PKC? promotes tubular cell injury through regulating p66Shc phosphorylation and mitochondrial translocation in HG ambient.
Polymer micro/nano-actuators are attracting tremendous interest due to their potential applications in micro/nano-mechanical systems and lab-on-a-chip systems. To achieve this, thin films of stimuli-responsive polymers are required to be patterned at the micro/nanometer scale, and also to possess highly ordered orientation in the responsive component. We demonstrate here that nanoscale patterning and uniaxial alignment of liquid crystalline mesogens can be simultaneously achieved by nanoimprint lithography performed in the liquid crystalline mesophase. Photoactive azobenzene mesogens were aligned parallel to the nanogratings imprinted in the films. The degree of alignment depended on the extent of nanoconfinement. The nanogratings expanded in the direction perpendicular to the film upon exposure to uniform UV irradiation, because of trans-to-cis isomerization. In addition, the reversible deformation amplitude strongly depended on the degree of alignment of the photoactive azobenzene mesogens.
Silk fibroin is an ideal blood vessel substitute due to its advantageous qualities including variable size, good suture retention, low thrombogenicity, non-toxicity, non-immunogenicity, biocompatibility, and controllable biodegradation. In this study, silk fibroin films with a variety of surface patterns (e.g. square wells, round wells plus square pillars, square pillars, and gratings) were prepared for in vitro characterization of human umbilical vein endothelial cell's (HUVEC) response. The affects of biomimetic length-scale topographic cues on the cell orientation/elongation, proliferation, and cell-substrate interactions have been investigated. The density of cells is significantly decreased in response to the grating patterns (70±3nm depth, 600±8nm pitch) and the square pillars (333±42nm gap). Most notably, we observed the contact guidance response of filopodia of cells cultured on the surface of round wells plus square pillars. Overall, our data demonstrates that the patterned silk fibroin films have an impact on the behaviors of human umbilical vein endothelial cells.
Orexin-A is a regulatory peptide involved in the regulation of food intake, sleep-wakefulness, and it has various endocrine and metabolic functions. It orchestrates diverse central and peripheral processes through the stimulation of two G-protein coupled receptors, orexin receptor type 1 (OX1 receptor) and orexin receptor type 2 (OX2 receptor). In this study, human adrenocortical cells (NCI-H295R cells) were incubated with various concentrations of orexin-A (10-10 to 10-6 M) in vitro, and the mRNA and protein expression of OX1 receptor was determined in the cells. In addition, NCI-H295R cells treated with 10-6 M orexin-A were then treated with or without OX1 receptor specific antagonist (SB334867), AKT antagonist (PF-04691502), or a combination of both. Subsequently, cell proliferation, the cortisol content in the medium and the mRNA and protein expression expression of 3?-hydroxysteroid dehydrogenase (3?-HSD) were analyzed. The activity of the AKT signaling pathway was also determined in the NCI-H295R cells. We observed that the increase in the mRNA and protein expression of OX1 receptor was orexin-A concentration-dependent, with 10-6 M orexin-A exerting the most potent effect. Orexin-A enhanced cell proliferation and cortisol production, and increased the mRNA and protein expression of 3?-HSD in the NCI-H295R cells; however, these effects were partly blocked by the OX1 receptor antagonist, the AKT antagonist and the combination of both. Furthermore, orexin-A significantly increased the phosphorylation of AKT, with the levels of total AKT protein remaining unaltered. This effect was blocked in the presence of PF-04691502 (10-6 M), SB334867 (10-6 M) and the combination of both. On the whole, our data demonstrate that the effects of orexin-A on the survival and function of human adrenocortical cells are mediated through the AKT signaling pathway.
The intrahepatic biliary epithelium is a three-dimensional tubular system lined by cholangiocytes, epithelial cells that in addition to modify ductal bile are also the targets of vanishing bile duct syndromes (i.e., cholangiopathies) such as primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) that are characterized by the damage/proliferation of cholangiocytes. Cholangiocyte proliferation is critical for the maintenance of the biliary mass and secretory function during the pathogenesis of cholangiopathies. Proliferating cholangiocytes serve as a neuroendocrine compartment during the progression of cholangiopathies, and as such secrete and respond to hormones, neurotransmitters and neuropeptides contributing to the autocrine and paracrine pathways that regulate biliary homeostasis. The focus of this review is to summarize the recent findings related to the role of melatonin in the modulation of biliary functions and liver damage in response to a number of insults. We first provide a general background on the general function of cholangiocytes including their anatomic characteristics, their innervation and vascularization as well the role of these cells on secretory and proliferation events. After a background on the synthesis and regulation of melatonin and its role on the maintenance of circadian rhythm, we will describe the specific effects of melatonin on biliary functions and liver damage. After a summary of the topics discussed, we provide a paragraph on the future perspectives related to melatonin and liver functions.
To elucidate and compare the seroprevalence of human herpesvirus 8 (HHV8) and hepatitis C virus (HCV) among Chinese drug users, a cross-sectional study of 441 participants, was conducted in Shanghai, China, from 2012 through 2013. Seventy-seven (17.5%) participants were found to be positive for HHV8 antibodies, while 271 (61.5%) participants were positive for HCV. No significant association between HHV8 seropositivity and drug use characteristics, sexual behaviors, HCV, or syphilis was observed. In contrast, a statistically significant association between HCV seropositivity and injected drug history (OR, 2.18, 95% CI 1.41-3.37) was detected, whereas no statistically significant association between HCV seropositivity and syphilis infection (OR, 7.56, 95% CI 0.94-60.57) were observed. Pairwise comparisons showed no significant differences between latent and lytic antibodies regarding HCV and HHV8 serostatus. The study demonstrated a moderate but elevated prevalence of HHV8 infection among drug users. The discordance between HHV8 and HCV infections suggests that blood borne transmission of HHV8 might not be the predominant mode of transmission in this population, which is in contrast to HCV.
Acid fibroblast growth factor (aFGF) has been shown to prevent epithelial damage under various conditions, suggesting its potential to inhibit GVHD. However, because aFGF receptors are expressed on tumor cells, it may possibly offset the graft-vs.-tumor (GVT) effects of allogeneic bone marrow transplantation (allo-BMT). Here, we addressed these questions in a B6?B6D2F1 allo-BMT model. Although aFGF administration attenuated GVHD in non-leukemic recipients, aFGF treatment markedly accelerated death in mice that received recipient-type tumor (P815) cells along with allo- or syngeneic-BMT. Similar protection against GVHD was achieved by administration of a non-mitogenic form of aFGF (naFGF). Importantly, GVT effects were fully preserved in naFGF-treated recipients. Furthermore, aFGF, but not naFGF, significantly enhanced P815 cell proliferation both in vitro and in vivo. Our data indicate that the tumor-promoting, but not GVHD-protecting, effect of aFGF largely depends on its mitogenic activity, and suggest that naFGF may provide a safer approach to inhibiting GVHD in patients with malignancies.
The ubiquitin-proteasome pathway plays a pivotal role in the regulation of cellular protein processing and degradation. Proteasome inhibitors (PIs) have enormous potential to treat multiple myeloma, solid tumors, parasites, inflammation, and immune diseases, which is spurring the development of new types of PIs with enhanced efficacy, fewer side effects, and reduced drug resistance. Nevertheless, virtual screening for covalent PIs has rarely been reported because calculating the covalent binding energy is a challenging task. The aim of this study was to discover new covalent inhibitors of the 20S proteasome. The structures of PIs were manually divided into two parts: a noncovalent binding part resulting from virtual screening, and an epoxyketone group that was pre-selected as a covalent binding part. The SPECS database was screened by noncovalent docking and a pharmacophore model built with the 20S proteasome. After validating the covalent conjugation, 88 hits with epoxyketone were covalently docked into the 20S proteasome to analyze the intermolecular interactions. Four compounds were selected after multiple filtration and validations. Molecular dynamics simulations were performed to check the stability of the noncovalent and covalent docked ligand-enzyme complexes and investigate the interaction patterns of the screened inhibitors. Finally, two compounds with novel aromatic backbones, reasonable interactions, and stable covalent binding modes were retained. These compounds can serve as potential hits for further biological evaluation.
Substance P (SP) promotes cholangiocyte growth during cholestasis by activating its receptor, NK1R. SP is a proteolytic product of tachykinin (Tac1) and is deactivated by membrane metalloendopeptidase (MME). This study aimed to evaluate the functional role of SP in the regulation of cholangiocarcinoma (CCA) growth. NK1R, Tac1, and MME expression and SP secretion were assessed in human CCA cells and nonmalignant cholangiocytes. The proliferative effects of SP (in the absence/presence of the NK1R inhibitor, L-733,060) and of L-733,060 were evaluated. In vivo, the effect of L-733,060 treatment or MME overexpression on tumor growth was evaluated by using a xenograft model of CCA in nu/nu nude mice. The expression of Tac1, MME, NK1R, PCNA, CK-19, and VEGF-A was analyzed in the resulting tumors. Human CCA cell lines had increased expression of Tac1 and NK1R, along with reduced levels of MME compared with nonmalignant cholangiocytes, resulting in a subsequent increase in SP secretion. SP treatment increased CCA cell proliferation in vitro, which was blocked by L-733,060. Treatment with L-733,060 alone inhibited CCA proliferation in vitro and in vivo. Xenograft tumors derived from MME-overexpressed human Mz-ChA-1 CCA cells had a slower growth rate than those derived from control cells. Expression of PCNA, CK-19, and VEGF-A decreased, whereas MME expression increased in the xenograft tumors treated with L-733,060 or MME-overexpressed xenograft tumors compared with controls. The study suggests that SP secreted by CCA promotes CCA growth via autocrine pathway. Blockade of SP secretion and NK1R signaling may be important for the management of CCA.
Our previous study has shown that cerebral ischemic preconditioning (CIP) can up-regulate the expression of glial glutamate transporter-1 (GLT-1) during the induction of brain ischemic tolerance in rats. The present study was undertaken to further explore the uptake activity of GLT-1 in the process by observing the changes in the concentration of extracellular glutamate with cerebral microdialysis and high-performance liquid chromatography. The results showed that a significant pulse of glutamate concentration reached the peak value of sevenfold of the basal level after lethal ischemic insult, which was associated with delayed neuronal death in the CA1 hippocampus. When the rats were pretreated 2 days before the lethal ischemic insult with CIP which protected the pyramidal neurons against delayed neuronal death, the peak value of glutamate concentration decreased to 3.9 fold of the basal level. Furthermore, pre-administration of dihydrokainate, an inhibitor of GLT-1, prevented the protective effect of CIP on ischemia-induced CA1 cell death. At the same time, compared with the CIP + Ischemia group, the peak value of glutamate concentration significantly increased and reached sixfold of the basal level. These results indicate that CIP induced brain ischemic tolerance via up-regulating GLT-1 uptake activity for glutamate and then decreasing the excitotoxicity of glutamate.
Dopamine-containing monomers, N-3,4-dihydroxybenzenethyl methacrylamide (DMA) and dimethylaminoethyl methacrylate (DMAEMA), are successfully copolymerized in a well-controlled manner via ambient temperature single-electron transfer initiation and propagation through the radical addition fragmentation chain transfer (SET-RAFT) method. The controlled behaviors of the copolymerization are confirmed by the first-order kinetic plots, the linear relationships between molecular weights, and the monomer conversions while keeping relatively narrow molecular weight distribution (Mw/Mn ? 1.45). Moreover, biomimetic self-assembly of poly(N-3,4-dihydroxybenzenethyl methacrylamide-co-dimethylaminoethyl methacrylate) PDMA-co-PDMAEMA and inorganic particles are employed to prepare tunable honeycomb-like porous hybrid particles (HPHPs) by regulating the predesigned chemical composition. In addition, the inorganic sacrificial templates are successfully selective etched for the formation of porous organic materials.
Both biological and social sciences have identified contributing factors to human health. However, health outcomes are unlikely to equal a simple sum of these identified factors. This article makes an attempt to put together the information, methods, and technologies that relate to health outcomes from biological, behavioral, and social disciplines. Much of this information was obtained by controlling for the variations of the factors in 'other' disciplines. For example, genetic factors were controlled for in identifying the behavioral determinants of health. Looking forward, better understandings of health outcomes may require exploiting the interactions of health determinants that were identified from different disciplines. We propose the concept of 'systems health' studies, which take health outcomes as the outputs of a system, where the inputs and their interactions from multiple disciplines are considered.
This study is to investigate the possibility of zinc (Zn) biofortification in the grains of rice (Oryza sativa L.) by inoculation of endophytic strains isolated from a Zn hyperaccumulator, Sedum alfredii Hance. Five endophytic strains, Burkholderia sp. SaZR4, Burkholderia sp. SaMR10, Sphingomonas sp. SaMR12, Variovorax sp. SaNR1, and Enterobacter sp. SaCS20, isolated from S. alfredii, were inoculated in the roots of Japonica rice Nipponbare under hydroponic condition. Fluorescence images showed that endophytic strains successfully colonized rice roots after 72 h. Improved root morphology and plant growth of rice was observed after inoculation with endophytic strains especially SaMR12 and SaCS20. Under hydroponic conditions, endophytic inoculation with SaMR12 and SaCS20 increased Zn concentration by 44.4% and 51.1% in shoots, and by 73.6% and 83.4% in roots, respectively. Under soil conditions, endophytic inoculation with SaMR12 and SaCS20 resulted in an increase of grain yields and elevated Zn concentrations by 20.3% and 21.9% in brown rice and by 13.7% and 11.2% in polished rice, respectively. After inoculation of SaMR12 and SaCS20, rhizosphere soils of rice plants contained higher concentration of DTPA-Zn by 10.4% and 20.6%, respectively. In situ micro-X-ray fluorescence mapping of Zn confirmed the elevated Zn content in the rhizosphere zone of rice treated with SaMR12 as compared with the control. The above results suggested that endophytic microbes isolated from S. alfredii could successfully colonize rice roots, resulting in improved root morphology and plant growth, increased Zn bioavailability in rhizosphere soils, and elevated grain yields and Zn densities in grains.
UNC5 receptors are putative tumor suppressors whose expressions are lost in some cancers, but the role of UNC5A during DNA damage in bladder cancer remains undefined. To investigate into the potential function of UNC5A in bladder cancer, we examined UNC5A expression with real-time RT-PCR and Western blotting in bladder cancer specimens and analyzed the effects of chemotherapeutic drug on the expression level of UNC5A and knocking down of UNC5A on chemotherapeutic drug-mediated cell death. In this current study, we found low expression of UNC5A in bladder cancer, an effective induction of UNC5A by cisplatin in bladder cancer cell lines with wt p53, and a significant reduction of cisplatin-mediated cell death following silencing the endogenous UNC5A. Moreover, colony formation assay indicated that reexpression of UNC5A inhibited the survival of 5637 cells. Together, these data suggest an important role for UNC5A, a candidate tumor suppressor, in predicting response to DNA damage induced by chemotherapeutic drug and regulating cell death in bladder cancer.
Proliferating cholangiocytes secrete and respond to neuroendocrine hormones, including secretin. We investigated whether secretin secreted by S cells and cholangiocytes stimulates biliary proliferation in mice.
Danhong injection (DHI), a Chinese medical product extracted from Radix et Rhizoma Salviae Miltiorrhizae (Salvia miltiorrhiza Bge., Labiatae, Danshen in Chinese) and Flos Carthami (Carthamus tinctorius L., Compositae, Honghua in Chinese), has been reported to have anti-inflammatory, anti-oxidative and anti-fibrinolytic properties and is used extensively for the clinical treatment of cardiovascular disease in clinic. This study aimed to investigate the preventive and therapeutic effects of DHI on hyperlipidemia.
Implicated in autoimmune encephalitis, neuromyotonia and genetic forms of autism, here we report that contactin-associated protein-like 2 (CNTNAP2) contains a potential autoepitope within the extracellular region.
Porous structure and surface modification have been widely studied in applying metal oxide nanomaterials as Li-ion battery anodes for overcoming problems such as poor conductivity and large volume variation. Here, we demonstrate a direct triple-decomposition process for the in situ synthesis of C/Cu/ZnO porous hybrids. In a typical porous structure, 5-10 nm sized ZnO and Cu nanoparticles aggregate randomly and are modified with carbon layers in thickness of 1 nm. Moreover, the resulted hybrid nanostructures show a high and stable specific capacity of 818 mAh g(-1) at a current rate of 50 mA g(-1) with almost 100% capacity retention for up to 100 cycles when used an anode material for lithium ion batteries. By combination of the structural analyses and electrochemical behaviors, it could be speculated that the porous structure and the modifications of copper nanoparticles and carbon layers are mainly responsible for the dramatically improved electrochemical performance of ZnO anodes.
Caspase recruitment domain and membrane-associated guanylate kinase-like domain protein 3 (CARMA3) was reported as an oncoprotein overexpressed in several cancers. The expression pattern of CARMA3 and its clinical significance in human bladder cancer have not been well characterized. In the present study, CARMA3 expression was analyzed in 90 archived bladder cancer specimens using immunohistochemistry, and the correlation between CARMA3 expression and clinicopathological parameters was evaluated. We found that CARMA3 was overexpressed in 35 of 90 (38.8%) bladder cancer specimens. Significant association was observed between CARMA3 overexpression with tumor status (p?=?0.081) and tumor grade (p?=?0.027). To further explore the biological functions of CARMA3 in bladder cancer, we depleted CARMA3 in T24 and 5637 cell lines using small interfering RNA (siRNA). Using cell counting kit-8 (CCK8) assay and colony formation assay, we were able to show that CARMA3 depletion inhibited cell proliferation and colony number. Further study demonstrated that CARMA3 depletion decreased an expression of nuclear factor kappa B (NF-?B) targets cyclin D1 and Bcl-2 expression, as well as I?B phosphorylation. Luciferase reporter assay showed that CARMA3 depletion could downregulate NF-?B reporter activity. In conclusion, CARMA3 is overexpressed in bladder cancer and regulates malignant cell growth and NF-?B signaling, which makes CARMA3 a candidate therapeutic target for bladder cancer.
Progesterone is a steroid hormone and plays an important role during pregnancy. But the regulation mechanisms of progesterone-progesterone receptor (P4-PR) signaling during pregnancy remain largely unknown. In this study, we used medroxyprogesterone 17-acetate (MPA) which is a synthetic variant of progesterone and has 20-30 times the activity of progesterone to find that at the same physiological concentration as progesterone during early pregnancy MPA had no significant influence on ES cells self-renewal. But with the increasing of dosage, MPA can inhibit the self-renewal capacity of mouse embryonic stem cells (ES cells) and promote differentiation untimely. We further determined that MPA can influence the miR-200a/zeb2 pathway by down regulating the level of miR-200a. miR-200a significantly higher expressed in ES cells to down-regulate the expression of zeb2 to inhibit the self-renewal and promote differentiation of ES cells. Then we found that the function of MPA can be rescued by over-expression of miR-200a or down-regulation of zeb2. Our findings revealed the progesterone signaling/miR-200a/zeb2 axis regulating the progesterone signaling to insure the balance of self-renewal and differentiation of ES cells. Our study also provided new insight into the dosage of progesterone and it's derivant in the hormone replacement therapy for pregnant woman.
Reduced graphene oxide (rGO) nanosheets decorated with tunable magnetic nanoparticles (MNPs) were synthesized by a simple co-precipitation method and employed for recyclable removal of bisphenol A (BPA) from aqueous solution. The morphological characterization shows that Fe3O4 nanoparticles are uniformly deposited on rGO sheets. The magnetic characterization demonstrates that composites with various amounts of Fe3O4 nanoparticles are superparamagnetic. Due to the superparamagnetism, rGO-MNPs were used as recyclable adsorbents for BPA removal in aqueous solution. The kinetics of the adsorption process and the adsorption isotherm were investigated. The results indicate that the adsorption process is fitted to Langmuir model and the composites with lower density of MNPs represent better adsorption ability. In addition, its kinetics follows pseudo-second-order rate equation. Moreover, the adsorbents could be recovered conveniently by magnetic separation and recyclable used because of the easy desorption of BPA.
This study aimed to investigate neuroprotection of Danhong injection (DHI) in a rat model of cerebral ischemia using (18)F-fluorodeoxyglucose positron emission tomography ((18)F-FDG-PET). Method. Rats were divided into 5 groups: sham group, ischemia-reperfusion untreated (IRU) group, DHI-1 group (DHI 1?mL/kg/d), DHI-2 group (DHI 2?mL/kg/d), and DHI-4 group (DHI 4?mL/kg/d). AII the treated groups were intraperitoneally injected with DHI daily for 14 days. The therapeutic effects in terms of cerebral infarct volume, neurological function, and cerebral glucose metabolism were evaluated. Expression of TNF-? and IL-1? was detected with enzyme-linked immunosorbent assay (ELISA). Levels of mature neuronal marker (NeuN), glial marker (GFAP), vascular density factor (vWF), and glucose transporter 1 (GLUT1) were assessed by immunohistochemistry. Results. Compared with the IRU group, rats treated with DHI showed dose dependent reductions in cerebral infarct volume and levels of proinflammatory cytokines, improvement of neurological function, and recovery of cerebral glucose metabolism. Meanwhile, the significantly increased numbers of neurons, gliocytes, and vessels and the recovery of glucose utilization were found in the peri-infarct region after DHI treatment using immunohistochemical analysis. Conclusion. This study demonstrated the metabolic recovery after DHI treatment by micro-PET imaging with (18)F-FDG and the neuroprotective effects of DHI in a rat model of cerebral ischemic-reperfusion injury.
Identifying potential targets would improve therapeutic planning and disease management. Therefore, we investigated whether the novel identified dependence receptor UNC5D acts as a tumor suppressor in bladder malignancies.
The effectiveness of cryotherapy on joint arthroplasty recovery remains controversial. This systematic review was conducted to assess the effectiveness of cryotherapy in patients after joint arthroplasty.
Orexin A and B are multifunctional neuropeptides that are involved in the regulation of food intake, energy metabolism, glucose regulation and wakefulness. They signal through two G-protein?coupled receptors (GPCR): orexin receptor 1 (OX1R) and orexin receptor 2 (OX2R). Previous studies have shown that orexins interact with PI3K/AKT signaling pathways through OX1R-coupling in other cell types, but are seldom involved in hepatocytes. In the present study, reverse transcription (RT)-PCR and western blot analysis revealed that OX1R mRNA expression and activation in rat hepatocytes in vitro were upregulated by exogenous orexin A (10(-10) to 10(-6) M) in a dose-dependent manner. The result showed that orexin A affects increasing cell proliferation and protects cells from apoptosis. Additionally, inhibition studies showed that orexin A induced forkhead box O1 (FoxO1) and mammalian target of rapamycin 1 (mTORC1) phosphorylation, while OX1R antagonist (SB334867, 10(-6) M), AKT antagonist (PF-04691502, 10(-6) M), Foxo1 inhibitor (AS1842856, 10(-6) M) or mTORC1 inhibitor (everolimus, 10(-5) M) blocked these effects of orexin A. The results of the present study showed a possible effect of orexin A on cell apoptosis in regulating Foxo1 and mTORC1 through the OX1R/PI3K/AKT signaling pathway in rat hepatocytes.
CS5931 is a novel polypeptide from Ciona savignyi with anticancer activities. Previous study in our laboratory has shown that CS5931 can induce cell death via mitochondrial apoptotic pathway. In the present study, we found that the polypeptide could inhibit angiogenesis both in vitro and in vivo. CS5931 inhibited the proliferation, migration and formation of capillary-like structures of HUVECs (Human Umbilical Vein Endothelial Cell) in a dose-dependent manner. Additionally, CS5931 repressed spontaneous angiogenesis of the zebrafish vessels. Further studies showed that CS5931 also blocked vascular endothelial growth factor (VEGF) production but without any effect on its mRNA expression. Moreover, CS5931 reduced the expression of matrix metalloproteinases (MMP-2 and MMP-9) both on protein and mRNA levels in HUVEC cells. We demonstrated that CS5931 possessed strong anti-angiogenic activity both in vitro and in vivo, possible via VEGF and MMPs. This study indicates that CS5931 has the potential to be developed as a novel therapeutic agent as an inhibitor of angiogenesis for the treatment of cancer.
The function of microRNAs (miRNAs) during alcoholic liver disease (ALD) has recently become of great interest in biological research. Studies have shown that ALD associated miRNAs play a crucial role in the regulation of liver-inflammatory agents such as tumour necrosis factor-alpha (TNF-?), one of the key inflammatory agents responsible for liver fibrosis (liver scarring) and the critical contributor of alcoholic liver disease. Lipopolysaccharide (LPS), a component of the cell wall of gram-negative bacteria, is responsible for TNF-? release by Kupffer cells. miRNAs are the critical mediators of LPS signalling in Kupffer cells, hepatocytes and hepatic stellate cells. Certain miRNAs, in particular miR-155 and miR-21, show a positive correlation in up-regulation of LPS signalling when they are exposed to ethanol. ALD is related to enhanced gut permeability that allows the levels of LPS to increase, leads to increased secretion of TNF-? by the Kupffer cells and subsequently promotes alcoholic liver injury through specific miRNAs. Meanwhile, two of the most frequently dysregulated miRNAs in steatohepatitis, miR-122 and miR-34a are the critical mediators in ethanol/LPS activated survival signalling during ALD. In this review, we summarize recent findings regarding the experimental and clinical aspects of functions of specific microRNAs, focusing mainly on inflammation and cell survival after ethanol/LPS treatment, and advances on the role of circulating miRNAs in human alcoholic disorders.
Among advanced non-small cell lung cancer (NSCLC) patients with an acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKI), about 50% carry the T790M mutation, but this frequency in EGFR-TKI-naïve patients and dynamic change during therapy remains unclear. This study investigated the quantification and dynamic change of T790M mutation in plasma cell-free DNA (cf-DNA) of advanced NSCLC patients to assess the clinical outcomes of EGFR-TKI therapy.
Hemiballism-hemichorea (HB-HC) is commonly used to describe the basal ganglion dysfunction in non-ketotic hyperglycemic elderly patients. Here we report two elderly female patients with acute onset of involuntary movements induced by hyperglycemia with positive urine ketones. We described the computed tomography and magnetic resonance imaging findings in these two patients, which is similar to that of non-ketotic hyperglycemic HB-HC patients. FDG-PET was performed and the glucose metabolism in the corresponding lesion in these two patients was contradictory with each other. We tried to clarify the underlying mechanisms of HB-HC and explain the contradictory neuroradiological findings in FDG-PET as being performed at different clinical stages.
Previous studies have suggested that fat mass-and obesity-associated (FTO) gene is associated with body mass index (BMI) and the risk of obesity. This study aims to assess the association of five FTO polymorphisms (rs9939609, rs8050136, rs1558902, rs3751812 and rs6499640) with obesity and relative parameters in Han Chinese adolescents.
Vitamin D, which influences cellular proliferation and breast tissue characteristics, has been inversely correlated with breast cancer risk. Dietary vitamin D intake has been associated with lower mammographic density (MD), a strong intermediate marker of breast cancer risk.
Warburg effect, one of the hallmarks for cancer cells, is characterized by metabolic switch from mitochondrial oxidative phosphorylation to aerobic glycolysis. In recent years, increased expression level of pyruvate kinase M2 (PKM2) has been found to be the culprit of enhanced aerobic glycolysis in cancer cells. However, there is no agent inhibiting aerobic glycolysis by targeting PKM2. In this study, we found that Oleanolic acid (OA) induced a switch from PKM2 to PKM1, and consistently, abrogated Warburg effect in cancer cells. Suppression of aerobic glycolysis by OA is mediated by PKM2/PKM1 switch. Furthermore, mTOR signaling was found to be inactivated in OA-treated cancer cells, and mTOR inhibition is required for the effect of OA on PKM2/PKM1 switch. Decreased expression of c-Myc-dependent hnRNPA1 and hnRNPA1 was responsible for OA-induced switch between PKM isoforms. Collectively, we identified that OA is an antitumor compound that suppresses aerobic glycolysis in cancer cells and there is potential that PKM2 may be developed as an important target in aerobic glycolysis pathway for developing novel anticancer agents.
Interleukin-6 (IL-6) is one of the most important cytokines which has been shown to play a critical role in the pathogenesis of cholesteatoma. In this study, we aimed to investigate the expression of interleukin-6 (IL-6) and phosphorylated signal transducer and activator of transcription 3 (p-STAT3) in middle ear cholesteatoma epithelium in an effort to determine the role of IL-6/JAK/STAT3 signaling pathway in the pathogenesis of cholesteatoma. Immunohistochemistry was used to examine the expression of IL-6 and p-STAT3 in 25 human middle ear cholesteatoma samples and 15 normal external auditory canal (EAC) epithelium specimens. We also analyzed the relation of IL-6 and p-STAT3 expression levels to the degree of bone destruction in cholesteatoma. We found that the expression of IL-6 and p-STAT3 were significantly higher in cholesteatoma epithelium than in normal EAC epithelium (p<0.05). In cholesteatoma epithelium, a significant positive association was observed between IL-6 and p-STAT3 expression (p<0.05). However, no significant relationships were observed between the degree of bone destruction and the levels of IL-6 and p-STAT3 expression (p>0.05). To conclude, our results support the concept that IL-6/JAK/STAT3 signaling pathway is active and may play an important role in the mechanisms of epithelial hyper-proliferation responsible for cholesteatoma.
Circulating tumor cells (CTCs) enter peripheral blood from primary tumors and seed metastases. The genome sequencing of CTCs could offer noninvasive prognosis or even diagnosis, but has been hampered by low single-cell genome coverage of scarce CTCs. Here, we report the use of the recently developed multiple annealing and looping-based amplification cycles for whole-genome amplification of single CTCs from lung cancer patients. We observed characteristic cancer-associated single-nucleotide variations and insertions/deletions in exomes of CTCs. These mutations provided information needed for individualized therapy, such as drug resistance and phenotypic transition, but were heterogeneous from cell to cell. In contrast, every CTC from an individual patient, regardless of the cancer subtypes, exhibited reproducible copy number variation (CNV) patterns, similar to those of the metastatic tumor of the same patient. Interestingly, different patients with the same lung cancer adenocarcinoma (ADC) shared similar CNV patterns in their CTCs. Even more interestingly, patients of small-cell lung cancer have CNV patterns distinctly different from those of ADC patients. Our finding suggests that CNVs at certain genomic loci are selected for the metastasis of cancer. The reproducibility of cancer-specific CNVs offers potential for CTC-based cancer diagnostics.
Researchers have long been interested in the emergence of transitive reasoning abilities (e.g., if A>B and B>C, then A>C). Preschool-aged children are found to make transitive inferences. Additionally, nonhuman animals demonstrate parallel abilities, pointing to evolutionary roots of transitive reasoning. The present research examines whether 16-month-old infants can make transitive inferences about other peoples preferences. If an agent prefers object-A over B (A>B) and B over C (B>C), infants seem to reason that she also prefers A over C (A>C) (Experiment 1). Experiment 2 provides indirect evidence that a one-directional linear ordering of the three items (A>B>C) may have helped infants to succeed in the task. These and control results present the first piece of evidence that precursors of transitive reasoning cognitive abilities exist in infancy.
Breast cancer clusters within families but identified genetic factors only explain a portion of this clustering. Lower global DNA methylation in white blood cells (WBC) has been associated with increased breast cancer risk. We examined whether WBC DNA methylation varies by extent of breast cancer family history in unaffected women from high-risk breast cancer families. We evaluated DNA methylation levels in LINE-1, Alu and Sat2 in 333 cancer-free female family members of the New York site of the Breast Cancer Family Registry, the minority of which were known BRCA1 or BRCA2 mutation carriers. We used generalized estimated equation models to test for differences in DNA methylation levels by extent of their breast cancer family history after adjusting for age. All unaffected women had at least one sister affected with breast cancer. LINE-1 and Sat2 DNA methylation levels were lower in individuals with 3 or more (3+) first-degree relatives with breast cancer relative to women with only one first-degree relative. For LINE-1, Alu, and Sat2, having 3+ affected first-degree relatives was associated with a decrease of 23.4% (95%CI = -46.8%, 0.1%), 17.9 (95%CI = -39.5, 3.7) and 11.4% (95% CI = -20.3%, -2.5%), respectively, relative to individuals with only one affected first-degree relative, but the results were only statistically significant for Sat2. Individuals having an affected mother had a 17.9% lower LINE-1 DNA methylation (95% CI = -28.8%, -7.1%) when compared with those not having an affected mother. No associations were observed for Alu or Sat2 by maternal breast cancer status. If replicated, these results indicate that lower global WBC DNA methylation levels in families with extensive cancer histories may be one explanation for the clustering of cancers in these families. Family clustering of disease may reflect epigenetic as well as genetic and shared-environment factors.
Aluminum-induced neuronal injury has been implicated in various neurodegenerative disorders. However, the underlying mechanism involved in this pathogenesis still remains unknown. Our present findings demonstrated that chronic aluminum exposure resulted in spatial learning impairment and significantly increased intracellular calcium level in the hippocampus of rats. Examination of the associated protein molecules essential for induction and maintenance of long-term potentiation revealed that aluminum exposure could increase the expression level of calmodulin (CaM), but the expression levels of CaM-dependent protein kinase II (CaMKII), and phosphorylated cAMP-responsive element binding protein (CREB) were significantly reduced, whereas the total protein levels of CaMKII and CREB did not change in the aluminum-treated hippocampus. Thus, we provide a previously unrecognized mechanism whereby chronic aluminum exposure impairs hippocampal learning and memory, at least in part, through disruption of intracellular calcium homeostasis and CaM/CaMKII/CREB signaling pathway.
Our aim is to investigate the role of the AKT/PKB (protein kinase B) signaling pathway acting via orexin receptor 1 (OX1R) and the effects of orexin A (OXA) on cell proliferation in the insulin-secreting beta-cell line (INS-1 cells). Rat INS-1 cells were exposed to different concentrations of OXA in vitro and treated with OX1R antagonist (SB334867), PI3K antagonist (wortmannin), AKT antagonist (PF-04691502), or negative control. INS-1 amount of cell proliferation, viability and apoptosis, insulin secretion, OX1R protein expression, caspase-3 activity, and AKT protein levels were determined. We report that OXA (10(-10) to 10(-6)?M) stimulates INS-1 cell proliferation and viability, reduces the proapoptotic activity of caspase-3 to protect against apoptotic cell death, and increases insulin secretion. Additionally, AKT phosphorylation was stimulated by OXA (10(-10) to 10(-6)?M). However, the OX1R antagonist SB334867 (10(-6)?M), the PI3K antagonist wortmannin (10(-8)?M), the AKT antagonist PF-04691502 (10(-6)?M), or the combination of both abolished the effects of OXA to a certain extent. These results suggest that the upregulation of OXA-OX1R mediated by AKT activation may inhibit cell apoptosis and promote cell proliferation in INS-1 cells. This finding provides functional evidence of the biological actions of OXA in rat insulinoma cells.
Environmentally responsive materials are attractive for advance biomedicine applications such as controlled drug delivery and gene therapies. Recently, we have introduced the fabrication of a novel type of stimuli-sensitive lipogel composite consisting of poly(N-isopropylacrylamide) (pNIPAM) microgel particles and lipids. In this study, we demonstrated the temperature-triggered drug release behavior and the tunable drug loading and release capacities of the lipogel. At room temperature (22 °C), no calcein was released from the lipogel over time. At body temperature (37 °C), the release process was significantly promoted; lipids in the lipogel acted as drug holders on the pNIPAM scaffold carrier and prolonged the calcein release process from 10 min to 2 h. Furthermore, the loading and release of calcein could be effectively controlled by modulating the relative amount of lipids incorporated in the lipogel, which can be realized by the salt-induced lipid release of the lipogel.
This review focuses on the recent advances related to the heterogeneity of different-sized bile ducts with regard to the morphological and phenotypical characteristics, and the differential secretory, apoptotic and proliferative responses of small and large cholangiocytes to gastrointestinal hormones/peptides, neuropeptides and toxins. We describe several in vivo and in vitro models used for evaluating biliary heterogeneity. Subsequently, we discuss the heterogeneous proliferative and apoptotic responses of small and large cholangiocytes to liver injury and the mechanisms regulating the differentiation of small into large (more differentiated) cholangiocytes. Following a discussion on the heterogeneity of stem/progenitor cells in the biliary epithelium, we outline the heterogeneity of bile ducts in human cholangiopathies. After a summary section, we discuss the future perspectives that will further advance the field of the functional heterogeneity of the biliary epithelium.
Cellular uptake of materials plays a key role in their biomedical applications. In this work, based on the cell-mimic giant unilamellar vesicles (GUVs) and a novel type of microscale materials consisting of stimuli-responsive poly(N-isopropylacrylamide) microgel particles and the incorporated lipids, the influence of particle surface chemistry, including hydrophobic/hydrophilic property and lipid decorations, on the adsorption and consequent internalization of particles into GUVs was investigated. It is found that the decoration of particle surface with lipids facilitates the adsorption of particles on GUV membrane. After that, the hydrophobic property of particle surface further triggers the internalization of particles into GUVs. These results demonstrate the importance of surface properties of particles on their interactions with lipid membranes and are helpful to the understanding of cellular uptake mechanism.
To determine the association of high birth weight (HBW) with the risk of obesity in childhood and adolescence. We also aimed to explore the interactions of HBW with physical activity and dietary habits.
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