Defect in apoptotic signaling and up-regulation of drug transporters in cancer cells significantly limits the effectiveness of cancer chemotherapy. We propose that an agent inducing non-apoptotic cell death may overcome cancer drug resistance and showed that shikonin, a naturally occurring naphthoquinone, induced a cell death in MCF-7 and HEK293 distinct from apoptosis and characterized with (a) a morphology of necrotic cell death; (b ) loss of plasma membrane integrity; (c ) loss of mitochondrial membrane potentials; (d) activation of autophagy as a downstream consequence of cell death, but not a contributing factor; (e) elevation of reactive oxygen species with no critical roles contributing to cell death; and (f) that the cell death was prevented by a small molecule, necrostatin-1, that specifically prevents cells from necroptosis. The characteristics fully comply with those of necroptosis, a basic cell-death pathway recently identified by Degterev et al. with potential relevance to human pathology. Furthermore, we proved that shikonin showed a similar potency toward drug-sensitive cancer cell lines (MCF-7 and HEK293) and their drug-resistant lines overexpressing P-glycoprotein, Bcl-2, or Bcl-x L , which account for most of the clinical cancer drug resistance. To our best knowledge, this is the first report to document the induction of necroptosis by a small molecular compound to circumvent cancer drug resistance. [Mol Cancer Ther 2007;6(5):1641 -9]
BackgroundMetabolic syndrome (MS) comprises a set of conditions that are risk factors for cardiovascular diseases and diabetes. Numerous epidemiological studies on MS have been conducted, but there has not been a systematic analysis of the prevalence of MS in the Chinese population. Therefore, the aim of this study was to estimate the pooled prevalence of MS among subjects in Mainland China.MethodsWe performed a systematic review by searching both English and Chinese literature databases. Random or fixed effects models were used to summarize the prevalence of MS according to statistical tests for heterogeneity. Subgroup, sensitivity, and meta-regression analyses were performed to address heterogeneity. Publication bias was evaluated using Egger’s test.ResultsThirty-five papers were included in the meta-analysis, with a total population of 226,653 Chinese subjects. Among subjects aged 15 years and older, the pooled prevalence was 24.5 % (95 % CI: 22.0–26.9 %). By sex, the prevalences were 19.2 % (95 % CI: 16.9–21.6 %) in males and 27.0 % (95 % CI: 23.5–30.5 %) in females. The pooled prevalence of MS increased with age (15–39 years: 13.9 %; 40–59 years: 26.4 %; and ≥60 years: 32.4 %). Individuals living in urban areas (24.9 %, 95 % CI: 18.5–31.3 %) were more likely to suffer from MS than those living in rural areas (19.2 %, 95 % CI: 14.8–23.7 %). Hypertension was the most prevalent component of MS in males (52.8 %), while the most prevalent component of MS for females was central obesity (46.1 %).ConclusionsOur systematic review suggested a high prevalence of MS among subjects in Mainland China, indicating that MS is a serious public health problem. Therefore, more attention should be paid to the prevention and control of MS.Electronic supplementary materialThe online version of this article (doi:10.1186/s12889-016-2870-y) contains supplementary material, which is available to authorized users.
Neurons in the insular cortex are activated by acute and chronic pain, and inhibition of neuronal activity in the insular cortex has analgesic effects. We found that in a mouse model in which peripheral nerve injury leads to the development of neuropathic pain, the insular cortex showed changes in synaptic plasticity, which were associated with a long-term increase in the amount of synaptic N-methyl-d-aspartate receptors (NMDARs), but not that of extrasynaptic NMDARs. Activation of cyclic adenosine monophosphate (cAMP)-dependent signaling enhanced the amount of synaptic NMDARs in acutely isolated insular cortical slices and increased the surface localization of NMDARs in cultured cortical neurons. We found that the increase in the amount of NMDARs required phosphorylation of the NMDAR subunit GluN2B at Tyr(1472) by a pathway involving adenylyl cyclase subtype 1 (AC1), protein kinase A (PKA), and Src family kinases. Finally, injecting NMDAR or GluN2B-specific antagonists into the insular cortex reduced behavioral responses to normally nonnoxious stimuli in the mouse model of neuropathic pain. Our results suggest that activity-dependent plasticity takes place in the insular cortex after nerve injury and that inhibiting the increase in NMDAR function may help to prevent or treat neuropathic pain.
Objective-The present study is aimed at investigating the interaction of TRPV4 with TRPC1 and the functional role of such an interaction in flow-induced Ca 2ϩ influx. Hemodynamic blood flow is an important physiological factor that modulates vascular tone. One critical early event in this process is a cytosolic Ca 2ϩ ([Ca 2ϩ ] i ) rise in endothelial cells in response to flow. Methods and Results-With the use of fluorescence resonance energy transfer, coimmunoprecipitation, and subcellular colocalization methods, it was found that TRPC1 interacts physically with TRPV4 to form a complex. In functional studies, flow elicited a transient [Ca 2ϩ ] i increase in TRPV4-expressing human embryonic kidney (HEK) 293 cells. Coexpression of TRPC1 with TRPV4 markedly prolonged this [Ca 2ϩ ] i transient; it also enabled this [Ca 2ϩ ] i transient to be negatively modulated by protein kinase G. Furthermore, this flow-induced [Ca 2ϩ ] i increase was markedly inhibited by anti-TRPC1-blocking antibody T1E3 and a dominant-negative construct TRPC1⌬567-793 in TRPV4-C1-coexpressing HEK cells and human umbilical vein endothelial cells. T1E3 also inhibited flow-induced vascular dilation in isolated rat small mesenteric artery segments. H emodynamic blood flow is one of most important physiological factors that control vascular tone. 1 Flow shear stress acts on the endothelium to stimulate the release of vasodilators, such as NO and endothelium-derived hyperpolarizing factors, causing endothelium-dependent vascular relaxation. 1 In many cases, a key early signal in this flowinduced vascular dilation is Ca 2ϩ influx in endothelial cells in response to flow. [2][3][4] There is intense interest in searching for the molecular identity of the channels that mediate flowinduced Ca 2ϩ influx. Several candidate channels have been proposed. In renal epithelial cells, polycystins 1 and 2 form a channel complex to allow Ca 2ϩ influx in response to flow. 5 In vascular endothelial cells, flow may activate P2X 4 purinoceptors, which are Ca 2ϩ -permeable channels, resulting in vascular dilation. 6 Interestingly, several recent studies 2,3 demonstrate that TRPV4 channels play a key role in flow-induced endothelial Ca 2ϩ influx and subsequent vascular dilation. TRP channels are a superfamily of cation channels that can be divided into 7 subfamilies, which include TRPC, TRPV, and 5 others. TRPV4 is a Ca 2ϩ -permeable channel in the influx involves TRPV4. For store-operated Ca 2ϩ influx, several possible candidates could be involved, which include stromal interaction molecule (STIM1), Orai, and TRPC1. 10,11 In the present studies, we explored the possible interaction between the flow-sensing TRPV4 and store-operated Ca The human TRPC1 gene (NM_003304) and the mouse TRPV4 gene (NM_022017) were cloned into pcDNA6 and pCAGGS vectors, respectively. HEK cells were transfected using a reagent (Lipofectamine 2000). HUVECs were transfected by electroporation using Nucleofector II. All genes except PKG1␣ were transiently transfected in...
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