Excitotoxic Ca2+ accumulation contributes to ischemic neurodegeneration, and Ca2+ can enter the mitochondria through the mitochondrial calcium uniporter (MCU) to promote mitochondrial dysfunction. ...Yet, Ca2+-targeted therapies have met limited success. A growing body of evidence has highlighted the underappreciated importance of Zn2+, which also accumulates in neurons after ischemia and can induce mitochondrial dysfunction and cell death. While studies have indicated that Zn2+ can also enter the mitochondria through the MCU, the specificity of the pore's role in Zn2+-triggered injury is still debated. Present studies use recently available MCU knockout mice to examine how the deletion of this channel impacts deleterious effects of cytosolic Zn2+ loading. In cultured cortical neurons from MCU knockout mice, we find significantly reduced mitochondrial Zn2+ accumulation. Correspondingly, these neurons were protected from both acute and delayed Zn2+-triggered mitochondrial dysfunction, including mitochondrial reactive oxygen species generation, depolarization, swelling and inhibition of respiration. Furthermore, when toxic extramitochondrial effects of Ca2+ entry were moderated, both cultured neurons (exposed to Zn2+) and CA1 neurons of hippocampal slices (subjected to prolonged oxygen glucose deprivation to model ischemia) from MCU knockout mice displayed decreased neurodegeneration. Finally, to examine the therapeutic applicability of these findings, we added an MCU blocker after toxic Zn2+ exposure in wildtype neurons (to induce post-insult MCU blockade). This significantly attenuated the delayed evolution of both mitochondrial dysfunction and neurotoxicity. These data—combining both genetic and pharmacologic tools—support the hypothesis that Zn2+ entry through the MCU is a critical contributor to ischemic neurodegeneration that could be targeted for neuroprotection.
•Zn2+ thought to enter the mitochondria via the mitochondrial Ca2+ uniporter (MCU)•Mitochondrial Zn2+ loading and its consequences are attenuated in MCU knockout mice.•Zn2+ contributions to neurodegeneration are attenuated in MCU knockout.•Delayed MCU blockade attenuates mitochondrial dysfunction and neurotoxicity.•Targeting mitochondrial Zn2+ through the MCU may offer significant neuroprotection.
Angiogenesis is a key step in tumor growth and metastasis. The mechanism by which osteopontin (OPN) induces the angiogenesis of endothelial cells remains unclear. Here, we show that OPN confers ...cytoprotection through the activation of the PI3K/Akt pathway with subsequent upregulation of Bcl-xL and activation of nuclear factor-kappaB. OPN enhances the expression of vascular endothelial growth factor (VEGF) through the phosphorylation of AKT and extracellular signal-regulated kinase (ERK). In turn, OPN-induced VEGF activates PI3K/AKT and the ERK1/2 pathway as a positive feedback signal. Blocking the feedback signal by anti-VEGF antibody, PI3-kinase inhibitor or ERK inhibitor can partially inhibit the OPN-induced human umbilical vein endothelial cell (HUVEC) motility, proliferation and tube formation, while blocking the signal by anti-OPN or anti-alphavbeta3 antibody completely abrogates the biological effects of OPN on HUVECs. In addition, blood vessel formation is also investigated in vivo. The antiangiogenesis efficacy of anti-OPN antibody in vivo is more effective than that of anti-VEGF antibody, which only blocks the feedback signals. These data show that OPN enhances angiogenesis directly through PI3K/AKT- and ERK-mediated pathways with VEGF acting as a positive feedback signal. The results suggest that OPN might be a valuable target for developing novel antiangiogenesis therapy for treatment of cancer.
Corticothalamic networks are considered core pathologic substrates for idiopathic generalized epilepsy; however, the predominant epileptogenic epicenters within these networks are still largely ...unknown. The current study aims to identify these epicenters by resting-state functional connectivity.
To identify epicenters within the corticothalamic networks in idiopathic generalized epilepsy, we retrospectively studied a large cohort of patients with this condition (n = 97) along with healthy controls (n = 123) by resting-state functional MR imaging. The thalamus was functionally divided into subregions corresponding to distinct cortical lobes for 5 parallel corticothalamic networks. The functional connectivity between each voxel in the cortical lobe and the corresponding thalamic subregion was calculated, and functional connectivity strength was used to evaluate the interconnectivity of voxels in the cortex and thalamus.
The projection of 5 cortical lobes to the thalamus is consistent with previous histologic findings in humans. Compared with controls, patients with idiopathic generalized epilepsy showed increased functional connectivity strength in 4 corticothalamic networks: 1) the supplementary motor area, pulvinar, and ventral anterior nucleus in the prefrontal-thalamic network; 2) the premotor cortex and ventrolateral nucleus in motor/premotor-thalamic networks; 3) the visual cortex, posterior default mode regions, and pulvinar in parietal/occipital-thalamic networks; and 4) the middle temporal gyrus in the temporal-thalamic network.
Several key nodes were distinguished in 4 corticothalamic networks. The identification of these epicenters refines the corticothalamic network theory and provides insight into the pathophysiology of idiopathic generalized epilepsy.
In components built by selective laser melting (SLM), possible anisotropy in microstructure significantly affects mechanical properties (i.e. service performance) and there is a constant effort to ...solve this problem. This work carried out a comparative study using fully dense AlSi10Mg alloy and in-situ nano-TiB2 decorated AlSi10Mg composite samples processed by SLM. The aim was at clarifying the effect of integrated nanoparticles on the anisotropy of the as-built component. Microstructure and texture evolution were investigated by scanning and transmission electron microscopy, electron backscatter diffraction, X-ray and neutron diffraction. The SLMed AlSi10Mg sample shows a coarse columnar grain structure with and fiber orientation texture and obvious anisotropy in mechanical properties. However, the nano-TiB2 modified AlSi10Mg sample exhibits fine equiaxed grains, no preferred crystallographic texture and remarkably reduced anisotropy. Besides, both tensile strength and ductility have been improved in the SLMed TiB2 decorated AlSi10Mg sample. The preliminary mechanism upon grain refinement effect due to nano-TiB2 particles on columnar-to-equiaxed transition and reduction of anisotropy was discussed.
Display omitted
•A competition growth of and fiber texture is found in SLMed Al alloy.•The introduction of TiB2 eliminates texture and anisotropic mechanical behavior.•Random orientation of TiB2 nucleation agents determines random orientation of Al.•Both strength and ductility have been improved in SLMed TiB2/AlSi10Mg alloy.
Obesity-related brain structural abnormalities have been reported extensively, and bariatric surgery (BS) is currently the most effective intervention to produce sustained weight reduction in overtly ...obese (OB) people. It is unknown whether BS can repair the brain circuitry abnormalities concomitantly with long-term weight loss.
In order to investigate whether BS promotes neuroplastic structural recovery in morbidly OB patients, we quantified fractional anisotropy (FA), mean diffusivity (MD) and gray (GM) and white (WM) matter densities in 15 morbidly OB patients and in 18 normal weight (NW) individuals. OB patients were studied at baseline and also 1 month after laparoscopic sleeve gastrectomy surgery.
Two-sample t-test between OB (baseline) and NW groups showed decreased FA values, GM/WM densities and increased MD value in brain regions associated with food intake control (that is, caudate, orbitofrontal cortex, body and genu of corpus callosum) and cognitive-emotion regulation (that is, inferior frontal gyrus, hippocampus, insula, external capsule) (P<0.05, family-wise error correction). Paired t-test in the OB group between before and after surgery showed that BS generated partial neuroplastic structural recovery in the OB group, but the differences had relative less strength and smaller volume (P<0.001).
This study provides the first anatomical evidence for BS-induced acute neuroplastic recovery that might in part mediate the long-term benefit of BS in weight reduction. It also highlights the importance of this line of gut-brain axis research employing the combined BS and neuroimaging model for identifying longitudinal changes in brain structure that correlated with obesity status.
The cognitive effects of stress are profound, yet it is unknown if the consequences of concurrent multiple stresses on learning and memory differ from those of a single stress of equal intensity and ...duration. We compared the effects on hippocampus-dependent memory of concurrent, hours-long light, loud noise, jostling and restraint (multimodal stress) with those of restraint or of loud noise alone. We then examined if differences in memory impairment following these two stress types might derive from their differential impact on hippocampal synapses, distinguishing dorsal and ventral hippocampus. Mice exposed to hours-long restraint or loud noise were modestly or minimally impaired in novel object recognition, whereas similar-duration multimodal stress provoked severe deficits. Differences in memory were not explained by differences in plasma corticosterone levels or numbers of Fos-labeled neurons in stress-sensitive hypothalamic neurons. However, although synapses in hippocampal CA3 were impacted by both restraint and multimodal stress, multimodal stress alone reduced synapse numbers severely in dorsal CA1, a region crucial for hippocampus-dependent memory. Ventral CA1 synapses were not significantly affected by either stress modality. Probing the basis of the preferential loss of dorsal synapses after multimodal stress, we found differential patterns of neuronal activation by the two stress types. Cross-correlation matrices, reflecting functional connectivity among activated regions, demonstrated that multimodal stress reduced hippocampal correlations with septum and thalamus and increased correlations with amygdala and BST. Thus, despite similar effects on plasma corticosterone and on hypothalamic stress-sensitive cells, multimodal and restraint stress differ in their activation of brain networks and in their impact on hippocampal synapses. Both of these processes might contribute to amplified memory impairments following short, multimodal stress.
Epithelial ovarian cancer (EOC) is one of the most common gynecological cancers, with diagnosis often at a late stage. Metastasis is a major cause of death in patients with EOC, but the underlying ...molecular mechanisms remain obscure. Here, we utilized an integrated approach to find potential key transcription factors involved in ovarian cancer metastasis and identified STAT4 as a critical player in ovarian cancer metastasis. We found that activated STAT4 was overexpressed in epithelial cells of ovarian cancer and STAT4 overexpression was associated with poor outcome of ovarian cancer patients, which promoted metastasis of ovarian cancer in both in vivo and in vitro. Although STAT4 mediated EOC metastasis via inducing epithelial-to-mesenchymal transition (EMT) of ovarian cancer cells in vivo, STAT4 failed to induce EMT directly in vitro, suggesting that STAT4 might mediate EMT process via cancer-stroma interactions. Further functional analysis revealed that STAT4 overexpression induced normal omental fibroblasts and adipose- and bone marrow-derived mesenchymal stem cells to obtain cancer-associated fibroblasts (CAF)-like features via induction of tumor-derived Wnt7a. Reciprocally, increased production of CAF-induced CXCL12, IL6 and VEGFA within tumor microenvironment could enable peritoneal metastasis of ovarian cancer via induction of EMT program. In summary, our study established a model that STAT4 promotes ovarian cancer metastasis via tumor-derived Wnt7a-induced activation of CAFs.
Activation of cyclin E1, a key regulator of the G1/S cell-cycle transition, has been implicated in many cancers including hepatocellular carcinoma (HCC). Although much is known about the regulation ...of cyclin E1 expression and stability, its post-transcriptional regulation mechanism remains incompletely understood. Here, we report that nuclear factor 90 (NF90), a double-stranded RNA (dsRNA) binding protein, regulates cyclin E1 in HCC. We demonstrate that NF90 is upregulated in HCC specimens and that suppression of NF90 decreases HCC cell growth and delays G1/S transition. We identified cyclin E1 as a new target of NF90 and found a significant correlation between NF90 and cyclin E1 expression in HCC. The mRNA and protein levels of cyclin E1 were downregulated upon NF90 knockdown. Suppression of NF90 caused a decrease in the half-life of cyclin E1 mRNA, which was rescued by ectopic expression of NF90. Furthermore, NF90 bound to the 3' untranslated regions (3'UTRs) of cyclin E1 mRNA in vitro and in vivo. Knockdown of NF90 also inhibited tumor growth of HCC cell lines in mouse xenograft model. Moreover, we showed that inhibition of NF90 sensitized HCC cells to the cyclin-dependent kinase 2 (CDK2) inhibitor, roscovitine. Taken together, downregulation of NF90 in HCC cell lines can delay cell-cycle progression, inhibit cell proliferation, and reduce tumorigenic capacity in vivo. These results suggest that NF90 has an important role in HCC pathogenesis and that it can serve as a novel therapeutic target for HCC.
The microstructural evolution of in-situ TiB2 nano-particle reinforced AlZnMgCu composites during hot extrusion was investigated from micro to macro scales by a combination of various techniques, ...including neutron and synchrotron X-ray diffraction, optical microscopy, scanning and transmission electron microscopy and electron backscatter diffraction (EBSD). The development of microstructure has shown a bimodal grain structure with distinctive spatial distributions of TiB2 particles: the elongated coarse grain structure with smaller dispersed particles and the fine grains mixed with clusters of relatively larger particles. The particle stimulated nucleation occurs at large particle clusters, resulting in recystallized (sub)micron sized fine grains. The dispersed smaller particles are observed to promote dislocation generation and to prohibit recovery. They are shown to reduce the misorientation of low angle grain boundaries due to the pinning effects on independent dislocations, which also lead to the suppression of dynamic recovery and increase of driving force for dynamic recrystallization. Quantitative texture analysis combined with neutron diffraction and EBSD has exhibited the development of a strong 〈111〉 and 〈001〉 dual fiber texture, and both texture volume fractions are changing with the particle content. In addition, the synchrotron diffraction experiments have shown that dislocation density increases with the particle content in both texture components. The microstructure evolution is the result from a complex process of particles/matrix interaction during the deformation and dynamic recrystallization. In comparison with its particle-free alloy counterpart, the thermomechanical response of the composites at high temperature is discussed in terms of aluminum deformation and recrystallization mechanisms combined with nanosized particle effects.
Display omitted
•The microstructures and textures of in-situ TiB2/Al composites are characterized quantitatively.•The effects of TiB2 particles on the (sub-)grain boundaries and dislocations are characterized and discussed.•The dynamic recovery and recrystallization mechanisms of in-situ TiB2/Al composites are studied.
PDF
