Introduction
Clearance of damaged cells and debris is beneficial for the functional recovery after ischemic brain injury. However, the specific phagocytic receptor that mediates microglial ...phagocytosis after ischemic stroke is unknown.
Aim
To investigate whether P2Y6 receptor‐mediated microglial phagocytosis is beneficial for the debris clearance and functional recovery after ischemic stroke.
Results
The expression of the P2Y6 receptor in microglia increased within 3 days after transient middle cerebral artery occlusion. Inhibition of microglial phagocytosis by the selective inhibitor MRS2578 enlarged the brain atrophy and edema volume after ischemic stroke, subsequently aggravated neurological function as measured by modified neurological severity scores and Grid walking test. MRS2578 treatment had no effect on the expression of IL‐1α, IL‐1β, IL‐6, IL‐10, TNF‐α, TGF‐β, and MPO after ischemic stroke. Finally, we found that the expression of myosin light chain kinase decreased after microglial phagocytosis inhibition in the ischemic mouse brain, which suggested that myosin light chain kinase was involved in P2Y6 receptor‐mediated phagocytosis.
Conclusion
Our results indicate that P2Y6 receptor‐mediated microglial phagocytosis plays a beneficial role during the acute stage of ischemic stroke, which can be a therapeutic target for ischemic stroke.
This work confirms the presence of a large facet‐dependent photocatalytic activity of Cu2O crystals through sparse deposition of gold particles on Cu2O cubes, octahedra, and rhombic dodecahedra. ...Au‐decorated Cu2O rhombic dodecahedra and octahedra showed greatly enhanced photodegradation rates of methyl orange resulting from a better separation of the photogenerated electrons and holes, with the rhombic dodecahedra giving the best efficiency. Au–Cu2O core–shell rhombic dodecahedra also displayed a better photocatalytic activity than pristine rhombic dodecahedra. However, Au‐deposited Cu2O cubes, pristine cubes, and Au‐deposited small nanocubes bound by entirely {100} facets are all photocatalytically inactive. X‐ray photoelectron spectra (XPS) showed identical copper peak positions for these Au‐decorated crystals. Remarkably, electron paramagnetic resonance (EPR) measurements indicated a higher production of hydroxyl radicals for the photoirradiated Cu2O rhombic dodecahedra than for the octahedra, but no radicals were produced from photoirradiated Cu2O cubes. The Cu2O {100} face may present a high energy barrier through its large band edge bending and/or electrostatic repulsion, preventing charge carriers from reaching to this surface. The conventional photocatalysis model fails in this case. The facet‐dependent photocatalytic differences should be observable in other semiconductor systems whenever a photoinduced charge‐transfer process occurs across an interface.
Structure is the key: Whereas Au‐decorated Cu2O octahedra and rhombic dodecahedra (RD) show enhanced photocatalytic activities compared to their pristine particles, small and large Au‐decorated Cu2O cubes remain inactive. EPR measurements indicate a higher production of hydroxyl radicals for Cu2O rhombic dodecahedra than for octahedra upon photoirradiation, but no radicals are produced from photoirradiated Cu2O cubes (see figure).
Glial scars present a major obstacle for neuronal regeneration after stroke. Thus, approaches to promote their degradation and inhibit their formation are beneficial for stroke recovery. The ...interaction of microglia and astrocytes is known to be involved in glial scar formation after stroke; however, how microglia affect glial scar formation remains unclear.
Mice were treated daily with M2 microglial small extracellular vesicles through tail intravenous injections from day 1 to day 7 after middle cerebral artery occlusion. Glial scar, infarct volume, neurological score were detected after ischemia. microRNA and related protein were examined in peri-infarct areas of the brain following ischemia.
M2 microglial small extracellular vesicles reduced glial scar formation and promoted recovery after stroke and were enriched in miR-124. Furthermore, M2 microglial small extracellular vesicle treatment decreased the expression of the astrocyte proliferation gene signal transducer and activator of transcription 3, one of the targets of miR-124, and glial fibrillary acidic protein and inhibited astrocyte proliferation both
and
. It also decreased Notch 1 expression and increased Sox2 expression in astrocytes, which suggested that astrocytes had transformed into neuronal progenitor cells. Finally, miR-124 knockdown in M2 microglial small extracellular vesicles blocked their effects on glial scars and stroke recovery.
Our results showed, for the first time, that microglia regulate glial scar formation
small extracellular vesicles, indicating that M2 microglial small extracellular vesicles could represent a new therapeutic approach for stroke.
Triple-negative breast cancer (TNBC) remains a clinical challenge because of the absence of effective therapeutic targets. In TNBC, overexpression of YAP and TAZ correlates with bioactivities of ...cancer stem cells (CSCs), high histological grade, resistance to chemotherapy, and metastasis. Thus, YAP/TAZ may serve as potential therapeutic targets in TNBC. To identify YAP/TAZ inhibitors, in previous experiments, we screened a library of natural compounds by using YAP/TAZ luciferase reporter assay and identified apigenin as a potential inhibitor. In this study, we demonstrated that apigenin significantly suppressed the proliferation and migration of TNBC cells. Furthermore, we demonstrated that apigenin inhibited stemness features of TNBC cells in both in vitro and in vivo assays. Our mechanism study demonstrated that apigenin decreased YAP/TAZ activity and the expression of target genes, such as CTGF and CYR61, in TNBC cells. We also showed that apigenin disrupted the YAP/TAZ-TEADs protein-protein interaction and decreased expression of TAZ sensitized TNBC cells to apigenin treatment. Collectively, our studies suggest that apigenin is a promising therapeutic agent for the treatment of TNBC patients with high YAP/TAZ activity.
Triple-negative breast cancer (TNBC) is a highly lethal subtype of breast cancer associated with early relapse and metastasis. Epithelial to mesenchymal transition (EMT) plays pivotal roles in the ...progression of TNBC, including inducing cancer stem cell (CSC) properties, chemoresistance, tumor metastasis, and recurrence. Abnormally activated YAP/TAZ induces EMT in TNBC, making it a promising target for drug development. Our goal is to identify potential YAP/TAZ inhibitors from naturally derivative molecules and further study its effects on inhibiting EMT and metastasis of TNBC. In the current study, we demonstrate that luteolin significantly inhibits YAP/TAZ activity by promoting YAP/TAZ degradation in TNBC cells. Luteolin treatment leads to a decrease of mesenchymal markers and an increase of epithelial markers in both TNBC cells and TAZ-induced mesenchymal cells. Consistently, luteolin treatment inhibits cell migration in TNBC cells. Additionally, luteolin inhibits tumor growth in mice xenografted with TNBC cells. Collectively, our results support luteolin as a novel YAP/TAZ inhibitor for development as a new agent for the treatment of TNBC.
Cerebral ischemia upregulates aquaporin-4 expression, increases blood-brain barrier (BBB) permeability, and induces brain edema. Mesenchymal stem cells (MSCs) can repress inflammatory cytokines and ...show great potential for ischemic stroke therapy. However, the effect of MSCs regarding the protection of ischemia-induced BBB break down is unknown.
We test whether MSCs therapy protects BBB integrity and explore the molecular mechanisms of aquaporin-4 on BBB integrity.
Two hundred and twenty-eight adult CD1 male mice underwent 90 minutes transient middle cerebral artery occlusion and received 2 × 10(5) MSCs intracranial transplantation. The neurological severity score was improved and both ischemia-induced brain edema and BBB leakage were reduced in MSC-treated mice. MSCs therapy reduced astrocyte apoptosis and inhibited ischemia-induced aquaporin-4 upregulation. In addition, small-interfering RNA knockdown of aquaporin-4 after cerebral ischemia effectively reduced aquaporin-4 expression, brain edema, BBB leakage, and astrocyte apoptosis. Conditional medium from lipopolysaccharide (LPS)-activated microglia enhanced aquaporin-4 expression, p38 and JNK phosphorylation, and apoptosis of cultured astrocytes. MSC treatment reduced the expression of inflammatory cytokines in LPS-activated microglia, and subsequently reduced aquaporin-4 expression and apoptosis of astrocytes. Knockdown of aquaporin-4 in cultured astrocytes also reduced apoptosis. Treatment with p38 and JNK inhibitors showed that p38, but not the JNK signaling pathway, was responsible for the aquaporin-4 upregulation.
MSCs protected BBB integrity by reducing the apoptosis of astrocytes after ischemic attack, which was due to the attenuation of inflammatory response and downregulation of aquaporin-4 expression via p38 signaling pathway.
Tumor-repopulating cells (TRCs) are cancer stem cell (CSC)-like cells with highly tumorigenic and self-renewing abilities, which were selected from tumor cells in soft three-dimensional (3D) fibrin ...gels with unidentified mechanisms. Here we evaluated the transcriptome alteration during TRCs generation in 3D culture and revealed that a variety of molecules related with integrin/membrane and stemness were continuously altered by mechanical environment. Some key regulators such as MYC/STAT3/hsa-miR-199a-5p, were changed in the TRCs generation. They regulated membrane genes and the downstream mechanotransduction pathways such as Hippo/WNT/TGF-β/PI3K-AKT pathways, thus further affecting the expression of downstream cancer-related genes. By integrating networks for membrane proteins, the WNT pathway and cancer-related genes, we identified key molecules in the selection of TRCs, such as ATF4, SLC3A2, CCT3, and hsa-miR-199a-5p. Silencing ATF4 or CCT3 inhibited the selection and growth of TRCs whereas reduction of SLC3A2 or hsa-miR-199a-5p promoted TRCs growth. Further studies showed that CCT3 promoted cell proliferation and stemness in vitro, while its suppression inhibited TRCs-induced tumor formation. We also contemplated CCT3 as a stemness-related gene. Our findings provide insights in the mechanism of TRCs selection through transcriptome analysis.
Super-enhancers are clusters of enhancer elements that play critical roles in the maintenance of cell identity. Current investigations on super-enhancers are centered on the established ones in ...static cell types. How super-enhancers are established during cell differentiation remains obscure.
Here, by developing an unbiased approach to systematically analyze the evolving landscape of super-enhancers during cell differentiation in multiple lineages, we discover a general trend where super-enhancers emerge through three distinct temporal patterns: conserved, temporally hierarchical, and de novo. The three types of super-enhancers differ further in association patterns in target gene expression, functional enrichment, and 3D chromatin organization, suggesting they may represent distinct structural and functional subtypes. Furthermore, we dissect the enhancer repertoire within temporally hierarchical super-enhancers, and find enhancers that emerge at early and late stages are enriched with distinct transcription factors, suggesting that the temporal order of establishment of elements within super-enhancers may be directed by underlying DNA sequence. CRISPR-mediated deletion of individual enhancers in differentiated cells shows that both the early- and late-emerged enhancers are indispensable for target gene expression, while in undifferentiated cells early enhancers are involved in the regulation of target genes.
In summary, our analysis highlights the heterogeneity of the super-enhancer population and provides new insights to enhancer functions within super-enhancers.
The CCCTC-binding factor (CTCF), which anchors DNA loops that organize the genome into structural domains, has a central role in gene control by facilitating or constraining interactions between ...genes and their regulatory elements
. In cancer cells, the disruption of CTCF binding at specific loci by somatic mutation
or DNA hypermethylation
results in the loss of loop anchors and consequent activation of oncogenes. By contrast, the germ-cell-specific paralogue of CTCF, BORIS (brother of the regulator of imprinted sites, also known as CTCFL)
, is overexpressed in several cancers
, but its contributions to the malignant phenotype remain unclear. Here we show that aberrant upregulation of BORIS promotes chromatin interactions in ALK-mutated, MYCN-amplified neuroblastoma
cells that develop resistance to ALK inhibition. These cells are reprogrammed to a distinct phenotypic state during the acquisition of resistance, a process defined by the initial loss of MYCN expression followed by subsequent overexpression of BORIS and a concomitant switch in cellular dependence from MYCN to BORIS. The resultant BORIS-regulated alterations in chromatin looping lead to the formation of super-enhancers that drive the ectopic expression of a subset of proneural transcription factors that ultimately define the resistance phenotype. These results identify a previously unrecognized role of BORIS-to promote regulatory chromatin interactions that support specific cancer phenotypes.
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