Deregulated expression of zinc transporters was linked to several cancers. However, the detailed expression profile of all human zinc transporters in normal human organs and in human cancer, especially in pancreatic cancer is not available. The objectives of this study are to investigate the complete expression patterns of 14 ZIP and 10 ZnT transporters in a large number of normal human organs and in human pancreatic cancer tissues and cell lines. We examined the expression patterns of ZIP and ZnT transporters in 22 different human organs and tissues, 11 pairs of clinical human pancreatic cancer specimens and surrounding normal/benign tissues, as well as 10 established human pancreatic cancer cell lines plus normal human pancreatic ductal epithelium (HPDE) cells, using real time RT-PCR and immunohistochemistry. The results indicate that human zinc transporters have tissue specific expression patterns, and may play different roles in different organs or tissues. Almost all the ZIPs except for ZIP4, and most ZnTs were down-regulated in human pancreatic cancer tissues compared to the surrounding benign tissues. The expression patterns of individual ZIPs and ZnTs are similar among different pancreatic cancer lines. Those results and our previous studies suggest that ZIP4 is the only zinc transporter that is significantly up-regulated in human pancreatic cancer and might be the major zinc transporter that plays an important role in pancreatic cancer growth. ZIP4 might serve as a novel molecular target for pancreatic cancer diagnosis and therapy.
Pancreatic cancer; profile; zinc transporter; ZIP4
Many natural compounds derived from plants or microbes show promising potential for anticancer treatment, but few have been found to target energy-relevant regulators. In this study, we report that neoalbaconol (NA), a novel small-molecular compound isolated from the fungus, Albatrellus confluens, could target 3-phosphoinositide-dependent protein kinase 1 (PDK1) and inhibit its downstream phosphoinositide-3 kinase (PI3-K)/Akt-hexokinase 2 (HK2) pathway, which eventually resulted in energy depletion. By targeting PDK1, NA reduced the consumption of glucose and ATP generation, activated autophagy and caused apoptotic and necroptotic death of cancer cells through independent pathway. Necroptosis was remarkably induced, which was confirmed by several necroptosis-specific markers: the activation of autophagy, presence of necrotic morphology, increase of receptor-interacting protein 1 (RIP1)/RIP3 colocalization and interaction and rescued by necroptosis inhibitor necrostatin-1. The possibility that Akt overexpression reversed the NA-induced energy crisis confirmed the importance of the PDK1-Akt-energy pathway in NA-mediated cell death. Moreover, NA shows the capability to inhibit PI3-K/Akt signaling and suppress tumor growth in the nasopharyngeal carcinoma (NPC) nude mouse model. These results supported the feasibility of NA in anticancer treatments.
neoalbaconol; PDK1; PI3-K/Akt; energy depletion; cancer cell death
Topological superconductivity is one of most fascinating properties of topological quantum matters that was theoretically proposed and can support Majorana Fermions at the edge state. Superconductivity was previously realized in a Cu-intercalated Bi2Se3 topological compound or a Bi2Te3 topological compound at high pressure. Here we report the discovery of superconductivity in the topological compound Sb2Te3 when pressure was applied. The crystal structure analysis results reveal that superconductivity at a low-pressure range occurs at the ambient phase. The Hall coefficient measurements indicate the change of p-type carriers at a low-pressure range within the ambient phase, into n-type at higher pressures, showing intimate relation to superconducting transition temperature. The first principle calculations based on experimental measurements of the crystal lattice show that Sb2Te3 retains its Dirac surface states within the low-pressure ambient phase where superconductivity was observed, which indicates a strong relationship between superconductivity and topology nature.
Connective tissue growth factor (CTGF) has different roles in different types of cancer. However, the involvement and molecular basis of CTGF in tumor progression and prognosis of human nasopharyngeal carcinoma (NPC) have almost never been reported. In this study, we observed that downregulated CTGF expression was significantly associated with NPC progression and poor prognosis. Knockdown of CTGF markedly elevated the ability of cell proliferation in vivo and in vitro. Subsequently, we discovered that the reduction of CTGF increased the expression of miR-18b, an oncomir-promoting cell proliferation. Further, we discovered that attenuated CTGF-mediated upregulation of miR-18b was dependent on the increased binding of transcription factors Jun proto-oncogene (C-Jun) and v-Myc myelocytomatosis viral oncogene homolog (C-Myc) to miR-18b promoter region via phosphoinositide 3-kinase (PI3K)/AKT pathway. Finally, we further found that miR-18b directly suppressed the expression of CTGF in NPC. In clinical fresh specimens, miR-18b was widely overexpressed and inversely correlated with CTGF expression in NPC. Our studies are the first to demonstrate that reduced CTGF as an unfavorable prognosis factor mediates the activation of miR-18b, an oncomir directly suppresses CTGF expression, by PI3K/AKT/C-Jun and C-Myc and promotes cell growth of NPC.
CTGF; NPC; miR-18b; PI3K/AKT
Suboptimal health status (SHS) has become a new public health challenge in urban China. Despite indications that SHS may be associated with progression or development of chronic diseases such as cardiovascular and metabolic diseases, there are few reports on SHS investigations. To explore the relationship between SHS and traditional cardiovascular risk factors, a cross-sectional study was conducted in a sample of 4,881 workers employed in 21 companies in urban Beijing. Blood pressure, glucose, lipid levels (total cholesterol, high-density lipoprotein [HDL] cholesterol, low-density lipoprotein [LDL] cholesterol and triglycerides), cortisol, and body mass index were measured. SHS score was derived from data collection in the SHS questionnaire (SHSQ-25). Univariate analysis and linear two-level model were used to analyze the association of SHS with the cardiovascular risk factors. Serum cortisol level was much higher among the SHS high-score group than that among the low SHS score group (204.31 versus 161.33 ng/ml, P < 0.001). In a linear two-level model, we found correlation between SHS and systolic blood pressure, diastolic blood pressure, plasma glucose, total cholesterol, and HDL cholesterol among men, and correlation between SHS and systolic blood pressure, diastolic blood pressure, total cholesterol, triglyceride, and HDL cholesterol among women after controlling for age, education background, occupation, smoking, and physical activity. SHS is associated with cardiovascular risk factors and contributes to the development of cardiovascular disease. SHS should be recognized in the health care system, especially in primary care.
Suboptimal health status; Cardiovascular disease; Risk factors
Bipolar and major depressive disorders are essentially relapsing and remitting disorders of affect with nearly full recovery between episodes. Although the underlying molecular mechanisms remain unclear, myelin-related abnormalities have long been suspected. Here, using novel statistical analysis, we show that subtle but significant abnormalities exist in the composition of fatty acids (FAs), including docosapentaenoic acid (22:5n-3), one of the omega-3 polyunsaturated FAs, found in the post-mortem frontopolar cortex (FPC) of subjects with bipolar or major depressive disorders, although not in those with schizophrenia. These abnormalities were all aggravated in a myelin level-dependent manner, suggesting their close relationship with myelination. Animal studies have further revealed that chronic antidepressant treatment induces robust changes in brain FA metabolism, but contributes only part of the abnormalities found in the affective disorder brains. These findings indicate that the pathophysiology of affective disorders involves an unknown type of perturbed myelination in the FPC that may serve as a novel diagnostic and therapeutic target.
bipolar disorder; fatty acid; frontopolar cortex; major depressive disorder; myelination; schizophrenia
We aimed to investigate the mechanism of shaking as a prenatal stressor impacting the development of the offspring and Chinese medicines correcting the alterations. Pregnant rats were randomized into earthquake simulation group (ESG), herbal group (HG) which received herbal supplements in feed after shaking, and control group (CG). Findings revealed body weight and open field test (OFT) score of ESG offspring were statistically inferior to the CG and HG offspring. The corticosterone levels of ESG were higher than those of CG but not than HG. The dopamine level of ESG was slightly lower than that of the CG and of HG was higher than that of ESG. The 5-HT of ESG was higher than CG and HG. The growth hormone level of the ESG was significantly lower than ESG but not than CG. Gene expression profile showed 81 genes upregulated and 39 genes downregulated in ESG versus CG, and 60 genes upregulated and 28 genes downregulated in ESG versus HG. Eighty-four genes were found differentially expressed in ESG versus CG comparison and were normalized in ESG versus HG. We conclude that maternal shaking negatively affected physical and nervous system development, with specific alterations in neurohormones and gene expression. Chinese herbal medicine reduced these negative outcomes.
The distinctive epidemiologic profile of suicide in China, with notably high rates among rural young adult females, invites examination of possible underlying risk factors. Although there are accumulating data regarding the epidemiology of suicide among youth and young adults in China, there are meager data on suicidal ideation and attempts despite its importance.
Our study in 2005-06 sought to identify all potentially suitable rural participants, aged 16–34 years, from 10 representative villages in rural Sichuan Province. We conducted structured interviews regarding a range of socio-demographic characteristics and suicidal morbidity.
1654 of a potential 3008 participants participated; lifetime and one-year prevalence were: suicidal ideation (18.8%, 5.2%), serious ideation (8.6%, 2.3%), planning (5.8%, 1.5%), and attempt (2.7%, 0.5%). Comparisons among strata of socio-demographic characteristics showed more prevalent suicidal ideation associated with: female gender, lower education, poorer financial perception, greater rurality of residence, and marital status of “never married” or “others”. Suicidal attempt was associated with: female gender and a marital status of “others”.
The study was carried out in one province and caution is required when considering other rural regions of China. There were a substantial number of unapproachable subjects because of their migrant work at distant sites.
Our results revealed an apparently higher prevalence for suicide ideation and planning compared with residents of other countries, but a lower prevalence for attempts. These data suggests that the relatively high rate of suicide in rural China reflects an elevated case fatality ratio due to chosen methods. The results also revealed unique patterns for correlates with the occurrence of ideation and attempts.
Suicide Morbidity; Prevalence; Socio-demographic Correlates; Rural Community; China
Pressure-induced amorphous-to-amorphous configuration changes in Ca-Al metallic glasses (MGs) were studied by performing in-situ room-temperature high-pressure x-ray diffraction up to about 40 GPa. Changes in compressibility at about 18 GPa, 15.5 GPa and 7.5 GPa during compression are detected in Ca80Al20, Ca72.7Al27.3, and Ca66.4Al33.6 MGs, respectively, whereas no clear change has been detected in the Ca50Al50 MG. The transfer of s electrons into d orbitals under pressure, reported for the pressure-induced phase transformations in pure polycrystalline Ca, is suggested to explain the observation of an amorphous-to-amorphous configuration change in this Ca-Al MG system. Results presented here show that the pressure induced amorphous-to-amorphous configuration is not limited to f electron-containing MGs.
The aim of this study was to explore the effects of the bisphosphonate zoledronate on calcification induced by inorganic phosphate (Pi) and/or bone morphogenetic protein 2 (BMP-2) and the underlying mechanisms. Primary vascular smooth muscle cells (VSMCs) from rats were treated with 3 mM Pi or 3 mM Pi/BMP-2, with and without addition of zoledronate; 1.4 mM Pi served as a control. Calcium deposits, expression of core binding factor α-1 (Cbfa-1), osteopontin (OPN), parathyroid pituitary-specific transcription factor (Pit)-1 and Pit-2, and Pi uptake of VSMCs was determined. The calcification of VSMCs induced by elevated Pi or Pi/BMP-2 was significantly inhibited by zoledronate. The expression of Cbfa-1, OPN and Pit-1 was increased significantly after treatment with an elevated level of Pi or Pi/BMP-2, and this expression was significantly suppressed by addition of zoledronate. Pi uptake of VSMCs increased following treatment with elevated Pi and significantly decreased by addition of zoledronate. These results indicated that zoledronate effectively inhibited calcification induced by Pi/BMP-2, and this may have been achieved by means of the downregulation of expression of calcification-related proteins and uptake of Pi.
vascular calcification; zoledronate; bone morphogenetic protein 2; osteopontin; core binding factor α-1; phosphate uptake
Aberrant mitogen/extracellular signal-regulated kinase 5 (MEK5)–extracellular signal-regulated protein kinase 5 (ERK5)-mediated signalling has been implicated in a number of tumour types including prostate cancer (PCa). The molecular basis of ERK5-driven carcinogenesis and its clinical relevance remain to be fully characterised.
Modulation of ERK5 expression or function in human PCa PC3 and PC3–ERK5 (stably transfected with ERK5) cells was performed using siRNA-mediated knockdown or the MEK inhibitor PD18435 respectively. In vitro significance of ERK5 signalling was assessed by assays for proliferation, motility, invasion and invadopodia. Expression of matrix metalloproteinases/tissue inhibitors of metalloproteases was determined by Q-RT–PCR. Extracellular signal-regulated protein kinase 5 expression in primary and metastatic PCa was examined using immunohistochemistry.
Reduction of ERK5 expression or signalling significantly inhibited the motility and invasive capability of PC3 cells. Extracellular signal-regulated protein kinase 5-mediated signalling significantly promoted formation of in vivo metastasis in an orthotopic PCa model (P<0.05). Invadopodia formation was also enhanced by forced ERK5 expression in PC3 cells. Furthermore, in metastatic PCa, nuclear ERK5 immunoreactivity was significantly upregulated when compared with benign prostatic hyperplasia and primary PCa (P=0.013 and P<0.0001, respectively).
Our in vitro, in vivo and clinical data support an important role for the MEK5–ERK5 signalling pathway in invasive PCa, which represents a potential target for therapy in primary and metastatic PCa.
prostate cancer; signalling; invasive phenotype
Mutations in the Leucine Rich Repeat Kinase 2 (LRRK2) gene, first described in 2004 have now emerged as the most important genetic finding in both autosomal dominant and sporadic Parkinson’s Disease (PD). While a formidable research effort has ensued since the initial gene discovery, little is known of either the normal or the pathological role of LRRK2. We have created lines of mice that express human mutant wild-type (hWT) or G2019S Lrrk2 via bacterial artificial chromosome (BAC) transgenesis. In vivo analysis of the dopaminergic system revealed abnormal dopamine neurotransmission in both hWT and G2019S transgenic mice evidenced by a decrease in extra-cellular dopamine levels, which was detected without pharmacological manipulation. Immunopathological analysis revealed changes in localization and increased phosphorylation of microtubule binding protein tau in G2019S mice. Quantitative biochemical analysis confirmed the presence of differential phospho-tau species in G2019S mice but surprisingly, upon dephosphorylation the tau isoform banding pattern in G2019S mice remained altered. This suggests that other post-translational modifications of tau occur in G2019S mice. We hypothesize that Lrrk2 may impact on tau processing which subsequently leads to increased phosphorylation. Our models will be useful for further understanding of the mechanistic actions of LRRK2 and future therapeutic screening.
Parkinson’s Disease; Transgenic; Dopamine; Microdialysis; Neuropathology; Anxiety
Caspase-dependent apoptotic cell death has been extensively studied in cultured cells and during embryonic development, but the existence of analogous molecular pathways in single-cell species is uncertain. This has reduced enthusiasm for applying the advanced genetic tools available for yeast to study cell death regulation. However, partial characterization in mammals of additional genetically encoded cell death mechanisms, which lead to a range of dying cell morphologies and necrosis, suggests potential applications for yeast genetics. In this light, we revisited the topic of gene-dependent cell death in yeast to determine the prevalence of yeast genes with the capacity to contribute to cell-autonomous death. We developed a rigorous strategy by allowing sufficient time for gene-dependent events to occur, but insufficient time to evolve new populations, and applied this strategy to the Saccharomyces cerevisiae gene knockout collection. Unlike sudden heat shock, a ramped heat stimulus delivered over several minutes with a thermocycler, coupled with assessment of viability by automated counting of microscopic colonies revealed highly reproducible gene-specific survival phenotypes, which typically persist under alternative conditions. Unexpectedly, we identified over 800 yeast knockout strains that exhibit significantly increased survival following insult, implying that these genes can contribute to cell death. Although these death mechanisms are yet uncharacterized, this study facilitates further exploration.
yeast; programmed cell death; genetic screen; apoptosis; heat ramp; genomic
Autosomal recessive limb-girdle muscular dystrophy type 2G (LGMD2G) is an adult-onset myopathy characterized by distal lower limb weakness, calf hypertrophy and progressive decline in ambulation. The disease is caused by mutations in Tcap, a z-disc protein of skeletal muscle, although the precise mechanisms resulting in clinical symptoms are unknown. To provide a model for preclinical trials and for mechanistic studies, we generated knockout (KO) mice carrying a null mutation in the Tcap gene. Here we present the first report of a Tcap KO mouse model for LGMD2G and the results of an investigation into the effects of Tcap deficiency on skeletal muscle function in 4- and 12-month-old mice. Muscle histology of Tcap-null mice revealed abnormal myofiber size variation with central nucleation, similar to findings in the muscles of LGMD2G patients. An analysis of a Tcap binding protein, myostatin, showed that deletion of Tcap was accompanied by increased protein levels of myostatin. Our Tcap-null mice exhibited a decline in the ability to maintain balance on a rotating rod, relative to wild-type controls. No differences were detected in force or fatigue assays of isolated extensor digitorum longus (EDL) and soleus (SOL) muscles. Finally, a mechanical investigation of EDL and SOL indicated an increase in muscle stiffness in KO animals. We are the first to establish a viable KO mouse model of Tcap deficiency and our model mice demonstrate a dystrophic phenotype comparable to humans with LGMD2G.
A complete explanation of the mechanisms by which Pb2+ exerts toxic effects on developmental central nervous system remains unknown. Glutamate is critical to the developing brain through various subtypes of ionotropic or metabotropic glutamate receptors (mGluRs). Ionotropic N-methyl-D-aspartate receptors have been considered as a principal target in lead-induced neurotoxicity. The relationship between mGluR3/mGluR7 and synaptic plasticity had been verified by many recent studies. The present study aimed to examine the role of mGluR3/mGluR7 in lead-induced neurotoxicity.
Twenty-four adult and female rats were randomly selected and placed on control or 0.2% lead acetate during gestation and lactation. Blood lead and hippocampal lead levels of pups were analyzed at weaning to evaluate the actual lead content at the end of the exposure. Impairments of short -term memory and long-term memory of pups were assessed by tests using Morris water maze and by detection of hippocampal ultrastructural alterations on electron microscopy. The impact of lead exposure on mGluR3 and mGluR7 mRNA expression in hippocampal tissue of pups were investigated by quantitative real-time polymerase chain reaction and its potential role in lead neurotoxicity were discussed.
Lead levels of blood and hippocampi in the lead-exposed rats were significantly higher than those in the controls (P < 0.001). In tests using Morris Water Maze, the overall decrease in goal latency and swimming distance was taken to indicate that controls had shorter latencies and distance than lead-exposed rats (P = 0.001 and P < 0.001 by repeated-measures analysis of variance). On transmission electron microscopy neuronal ultrastructural alterations were observed and the results of real-time polymerase chain reaction showed that exposure to 0.2% lead acetate did not substantially change gene expression of mGluR3 and mGluR7 mRNA compared with controls.
Exposure to lead before and after birth can damage short-term and long-term memory ability of young rats and hippocampal ultrastructure. However, the current study does not provide evidence that the expression of rat hippocampal mGluR3 and mGluR7 can be altered by systemic administration of lead during gestation and lactation, which are informative for the field of lead-induced developmental neurotoxicity noting that it seems not to be worthwhile to include mGluR3 and mGluR7 in future studies.