Neutrophil Extracellular Traps Regulate Surgical Brain Injury by Activating the cGAS-STING Pathway.

Surgical brain injury (SBI), induced by neurosurgical procedures or instruments, has not attracted adequate attention. The pathophysiological process of SBI remains sparse compared to that of other central nervous system diseases thus far. Therefore, novel and effective therapies for SBI are urgently needed. In this study, we found that neutrophil extracellular traps (NETs) were present in the circulation and brain tissues of rats after SBI, which promoted neuroinflammation, cerebral edema, neuronal cell death, and aggravated neurological dysfunction. Inhibition of NETs formation by peptidylarginine deiminase (PAD) inhibitor or disruption of NETs with deoxyribonuclease I (DNase I) attenuated SBI-induced damages and improved the recovery of neurological function. We show that SBI triggered the activation of cyclic guanosine monophosphate-adenosine monophosphate synthase stimulator of interferon genes (cGAS-STING), and that inhibition of the cGAS-STING pathway could be beneficial. It is worth noting that DNase I markedly suppressed the activation of cGAS-STING, which was reversed by the cGAS product cyclic guanosine monophosphate-adenosine monophosphate (cGMP-AMP, cGAMP). Furthermore, the neuroprotective effect of DNase I in SBI was also abolished by cGAMP. NETs may participate in the pathophysiological regulation of SBI by acting through the cGAS-STING pathway. We also found that high-dose vitamin C administration could effectively inhibit the formation of NETs post-SBI. Thus, targeting NETs may provide a novel therapeutic strategy for SBI treatment, and high-dose vitamin C intervention may be a promising translational therapy with an excellent safety profile and low cost.

Whole genome sequencing analysis of Limosilactobacillus reuteri from the intestinal tract of mice recovering from ulcerative colitis and preliminary study on anti-inflammatory effects of its derived peptides.

Limosilactobacillus reuteri is an indigenous inhabitant of the animal gut known for its probiotic effects on the host. In our previous study, a large number of L. reuteri strains were isolated from the gastrointestinal tract of mice recovering from ulcerative colitis, from which we randomly selected L. reuteri RE225 for whole genome sequencing to explore its probiotic properties. The results of next-generation sequencing and third-generation single molecule sequencing showed that L. reuteri RE225 contained many genes encoding functional proteins associated with adhesion, anti-inflammatory and pathogen inhibition. And compared to other L. reuteri strains in NCBI, L. reuteri RE225 has unique gene families with probiotic functions. In order to further explore the probiotic effect of the L. reuteri RE225, the derived peptides were identified by LC-MS/MS, and the peptides with tumor necrosis factor-α binding ability were screened by reverse molecular docking and microscale thermophoresis. Finally, cell experiments demonstrated the anti-inflammatory ability of the peptides. Western blotting and qPCR analyses confirmed that the selected peptides might alleviate LPS-induced inflammation in NCM460 cells by inhibiting JAK2/STAT3 pathway activation.

Long non-coding RNA KB-1460A1.5 promotes ferroptosis by inhibiting mTOR/SREBP-1/SCD1-mediated polyunsaturated fatty acid desaturation in glioma.

Ferroptosis is a new form of regulated cell death caused by the iron-dependent peroxidation of phospholipids and is related to cell metabolism, redox homeostasis and various signalling pathways related to cancer. The long noncoding RNA (lncRNA) KB-1460A1.5 acts as a tumour suppressor gene to regulate tumour growth in gliomas, but its molecular network regulatory mechanism is still unclear. In this study, we found that KB-1460A1.5 can induce ferroptosis in glioma and enhance sensitivity to RSL3, a ferroptosis inducer. TMT proteomics and nontargeted metabolomics suggest that KB-1460A1.5 affects polyunsaturated fatty acid metabolic processes. GC‒MS-based medium- and long-chain fatty acid-targeted metabolomics confirmed that upregulation of KB-1460A1.5 decreased the levels of monounsaturated fatty acids (MUFAs), oleic acid (OA) and palmitoleic acid (PO) in glioma cells. The addition of OA and PO restored KB-1460A1.5-induced cellular ferroptosis. Molecularly, KB-1460A1.5 inhibited the mTOR signalling pathway to suppress the expression of downstream sterol regulatory element binding protein 1 (SREBP-1), thereby attenuating the stearoyl-CoA desaturase-1 (SCD1)-mediated desaturation of polyunsaturated fatty acids. Finally, an animal model of subcutaneous glioma confirmed that KB-1460A1.5 could inhibit tumour progression, SREBP1/SCD1 expression, and ferroptosis. In conclusion, increasing the expression level of KB-1460A1.5 in glioma can promote the induction of oxidative stress and ferroptosis in cancer cells through SREBP1/SCD1-mediated adipogenesis, demonstrating therapeutic potential in preclinical models.

ATP-adenosine axis regulation combined with microneedle assisted photoimmunotherapy to boost the immunotherapy efficiency.

Immunogenic cell death (ICD) is associated with the release of damage-associated molecular patterns, including ATP, to promote an effective immune cycle against tumors. However, tumors have evolved an effective strategy for degrading extracellular immunostimulatory ATP via the ATP-adenosine axis, allowing the sequential action of the ectonucleotidases CD39 to degrade accumulated immunostimulatory ATP into pleiotropic immunosuppressive adenosine. Here, an ingenious dissolving microneedle patch (DMNs) is designed for the intralesional delivery of CD39 inhibitor (sodium polyoxotungstate, POM-1) and ICD inducer (IR780) co-encapsulated solid lipid nanoparticles (P/I SLNs) for antitumor therapy. Upon insertion into the tumor site, IR780 induces ICD modalities with the release of damage-associated molecular patterns from endogenous tissues, which activates the antitumor immune cycle. Simultaneously, POM-1 promotes the liberation of immunostimulatory ATP and lowers the level of immunosuppressive extracellular adenosine, which supported immune control of tumors via recruiting CD39-expressing immune cells. In vivo antitumor studies prove that this platform can effectively eliminate mice melanoma (tumor growth inhibitory rate of 96.5%) and colorectal adenocarcinoma (tumor growth inhibitory rate of 93.5%). Our results shed light on the immunological aspects of combinatorial phototherapy and ATP-adenosine regulation, which will broaden the scope of synergistic antitumor immunotherapy.

Temozolomide-based sonodynamic therapy induces immunogenic cell death in glioma.

BACKGROUND: In our previous study, we found for the first time that temozolomide (TMZ), the first-line chemotherapeutic agent for glioblastoma (GBM), can generate a large amount of reactive oxygen species (ROS) under ultrasound irradiation. Sonodynamic therapy (SDT) using TMZ as the sonosensitizer produced more potent antitumor effects than TMZ alone. Here, we further evaluate the effects of TMZ-based SDT on subcellular structures and investigate the immunogenic cell death (ICD)-inducing capability of TMZ-based SDT. METHODS: The sonotoxic effects of TMZ were explored in LN229 and GL261 glioma cells. The morphology of endoplasmic reticulum and mitochondria was observed by transmission electron microscopy. The nuclear DNA damage was represented by γ-H2AX staining. Bone marrow-derived dendritic cells (BMDCs) were employed to assess ICD-inducing capability of TMZ-based SDT. A cyclic arginine-glycine-aspartic (c(RGDyC))-modified nanoliposome drug delivery platform was used to improve the tumor targeting of SDT. RESULTS: TMZ-based SDT had a greater inhibitory effect on glioma cells than TMZ alone. Transmission electron microscopy revealed that TMZ-based SDT caused endoplasmic reticulum dilation and mitochondrial swelling. In addition, endoplasmic reticulum stress response (ERSR), nuclear DNA damage and mitochondrial permeability transition pore (mPTP) opening were promoted in TMZ-based SDT group. Most importantly, we found that TMZ-based SDT could promote the "danger signals" produced by glioma cells and induce the maturation and activation of BMDCs, which was associated with the mitochondrial DNA released into the cytoplasm in glioma cells. In vivo experiments showed that TMZ-based SDT could remodel glioma immune microenvironment and provoke durable and powerful anti-tumor immune responses. What's more, the engineered nanoliposome vector of TMZ conferred SDT tumor targeting, providing an option for safer clinical application of TMZ in combination with SDT in the future. CONCLUSIONS: TMZ-based SDT was capable of triggering ICD in glioma. The discovery of TMZ as a sonosensitizer have shown great promise in the treatment of GBM.

Ultrasound-excited temozolomide sonosensitization induces necroptosis in glioblastoma.

Temozolomide (TMZ) has been determined to be the chemotherapeutic drug with efficacy for glioblastoma (GBM). Thus, potentiating the therapeutic effect of TMZ can undoubtedly yield twice the result with half the effort. In this study, we found for the first time that TMZ can produce reactive oxygen species (ROS) under the influence of ultrasound (US). This property allows TMZ-US therapy to have better efficacy in the treatment of GBM. Given that the increasing use of US in central nervous system (CNS) diseases and the importance of TMZ for GBM therapy, our results will facilitate the development of TMZ-associated glioblastoma therapies. Moreover, we found that chemotherapeutic drugs might have the ability to generate ROS under the excitation of US. On a larger scale, our findings may be applicable to a wide range of known drugs.

Mesenchymal stem cell-derived extracellular vesicles attenuate tPA-induced blood-brain barrier disruption in murine ischemic stroke models.

Intracerebral hemorrhage following blood-brain barrier (BBB) disruption resulting from thrombolysis of ischemic stroke with tissue plasminogen activator (tPA) remains a critical clinical problem. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) are promising nanotherapeutic agents that have the potential to repair the BBB after ischemic stroke; however, whether they can attenuate BBB disruption and hemorrhagic transformation after tPA thrombolysis is largely unknown. Here, we observed that MSC-EVs efficiently passed through the BBB and selectively accumulated in injured brain regions in ischemic stroke model mice in real time using aggregation-induced emission luminogens (AIEgens), which exhibit better tracking ability than the commercially available tracer DiR. Moreover, tPA administration promoted the homing of MSC-EVs to the ischemic brain and increased the uptake of MSC-EVs by astrocytes. Furthermore, the accumulated MSC-EVs attenuated the tPA-induced disruption of BBB integrity and alleviated hemorrhage by inhibiting astrocyte activation and inflammation. Mechanistically, miR-125b-5p delivered by MSC-EVs played an indispensable role in maintaining BBB integrity by targeting Toll-like receptor 4 (TLR4) and inhibiting nuclear transcription factor-kappaB (NF-κB) signaling in astrocytes. This study provides a noninvasive method for real-time tracking of MSC-EVs in the ischemic brain after tPA treatment and highlights the potential of MSC-EVs as thrombolytic adjuvants for ischemic stroke. STATEMENT OF SIGNIFICANCE: Although tPA thrombolysis is the most effective pharmaceutical strategy for acute ischemic stroke, its clinical application and therapeutic efficacy are challenged by tPA-induced BBB disruption and hemorrhagic transformation. Our study demonstrated that MSC-EVs can act as an attractive thrombolytic adjuvant to repair the BBB and improve thrombolysis in a mouse ischemic stroke model. Notably, by labeling MSC-EVs with AIEgens, we achieved accurate real-time imaging of MSC-EVs in the ischemic brain and therapeutic visualization. MSC-EVs inhibit astrocyte activation and associated inflammation through miR-125b-5p/TLR4/NF-κB pathway. Consequently, we revealed that MSC-EVs combined with tPA thrombolysis may be a promising approach for the treatment of ischemic stroke in clinical setting.

Integrated Analysis of Transcriptome Data Revealed AURKA and KIF20A as Critical Genes in Medulloblastoma Progression.

Medulloblastoma is the neuroepithelial tumor with the highest degree of malignancy in the central nervous system, accounting for about 8% to 10% of children's brain tumors. It has a high degree of malignancy and is easily transmitted through cerebrospinal fluid, with a relatively poor prognosis. Although medulloblastoma has been widely studied and treated, its molecular mechanism remains unclear. To determine which gene plays a crucial role in medulloblastoma development and progression, we analyzed three microarray datasets from Gene Expression Omnibus. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes were used to detect and evaluate differentially expressed genes. Protein interaction network was established, and the hub genes were determined in cytoHubba through various assessment methods, while the target genes were screened out using survival analysis. Ultimately, human medulloblastoma samples were utilized to confirm target gene expression. In conclusion, This study found that aurora kinase A (AURKA) and kinesin family member 20A (KIF20A) may be involved in the initiation and development of medulloblastoma, have a close association with prognosis, and may become a potential therapeutic target and prognostic marker of MED.

Long noncoding RNA KB-1460A1.5 inhibits glioma tumorigenesis via miR-130a-3p/TSC1/mTOR/YY1 feedback loop.

Long noncoding RNAs (lncRNAs) have been shown to be closely related to cancer progression and therapy. However, the clinical significance of lncRNAs and the mechanisms by which they function in glioma are largely unknown. In this study, using online data sets combined with collected clinical glioma tissues, we determined that the lncRNA KB-1460A1.5 is downregulated and positively correlated with prognosis in glioma. Functional experiments showed that overexpression of KB-1460A1.5 inhibits glioma cell proliferation, migration and invasion in vitro and in vivo, while downregulation of KB-1460A1.5 has the opposite effects. Mechanistically, tandem mass tag (TMT)-based quantitative proteomic analysis revealed that KB-1460A1.5 preferentially affects the Akt/TSC1/mTOR pathway. KB-1460A1.5 was found to function as a competing endogenous RNA (ceRNA) to regulate the expression of TSC1, a key regulatory component of the mTOR pathway, by sponging miR-130a-3p in glioma cells. Furthermore, our data demonstrate that the mTOR pathway regulates the expression of the transcription factor Yin Yang 1 (YY1), which in turn binds directly to the KB-1460A1.5 promoter and affects the expression of KB-1460A1.5. Untargeted metabolomics and quantitative real-time PCR (qRT-PCR) analysis further confirmed the effects of KB-1460A1.5 on amino acid metabolism. In conclusion, this study revealed that lncRNA KB-1460A1.5 inhibits glioma tumorigenesis via miR-130a-3p/TSC1/mTOR/YY1 feedback loop.

RPN2 is targeted by miR-181c and mediates glioma progression and temozolomide sensitivity via the wnt/ß-catenin signaling pathway.

Accumulating evidence indicates that the dysregulation of the miRNAs/mRNA-mediated carcinogenic signaling pathway network is intimately involved in glioma initiation and progression. In the present study, by performing experiments and bioinformatics analysis, we found that RPN2 was markedly elevated in glioma specimens compared with normal controls, and its upregulation was significantly linked to WHO grade and poor prognosis. Knockdown of RPN2 inhibited tumor proliferation and invasion, promoted apoptosis, and enhanced temozolomide (TMZ) sensitivity in vitro and in vivo. Mechanistic investigation revealed that RPN2 deletion repressed ß-catenin/Tcf-4 transcription activity partly through functional activation of glycogen synthase kinase-3ß (GSK-3ß). Furthermore, we showed that RPN2 is a direct functional target of miR-181c. Ectopic miR-181c expression suppressed ß-catenin/Tcf-4 activity, while restoration of RPN2 partly reversed this inhibitory effect mediated by miR-181c, implying a molecular mechanism in which TMZ sensitivity is mediated by miR-181c. Taken together, our data revealed a new miR-181c/RPN2/wnt/ß-catenin signaling axis that plays significant roles in glioma tumorigenesis and TMZ resistance, and it represents a potential therapeutic target, especially in GBM.

Mechanisms of BCG in the treatment of bladder cancer-current understanding and the prospect.

Over 30 years' successful application of Bacillus Calmette Guerin (BCG) to the clinical treatment of bladder cancer has proved it one of the most promising immunotherapies for cancer. However, the applications and achievements have failed to uncover the mechanism of BCG works on bladder cancer fully. Clinically, the administration of BCG on patients results in no effect, or apparent resistance, and even severe adverse reactions, which are inexplicable. At present, the widely confirmed and accepted immunity mechanism of BCG fall in the processes of the absorption after the instillation of BCG, the internalization of BCG, cytokine release induced by a series of signal transduction pathways, and the effect stage of innate and acquired immune responses. Nonetheless, the limited ascertainments of the mechanism of BCG action cannot fully explain the clinical phenomenon caused by BCG. Therefore, the other mechanisms of BCG action have remained the research hotspot aiming to explore more targeted treatments or to initiate new therapeutic methods avoiding harm. By summarizing the recent research achievements of the mechanism of BCG works on bladder cancer, this review aims to provide clues for researchers to quest more valuable ideas.

Tissue plasminogen activator disrupts the blood-brain barrier through increasing the inflammatory response mediated by pericytes after cerebral ischemia.

Pericytes, important elements of the blood-brain barrier (BBB), play critical roles in maintaining BBB integrity and modulating hemostasis, angiogenesis, inflammation and phagocytic function. We investigated whether pericytes are involved in the recombinant tissue plasminogen activator (rt-PA)-induced inflammatory response, which disrupts the BBB, and investigated the potential mechanisms. Middle cerebral artery occlusion (MCAO) and oxygen-glucose deprivation (OGD) were employed to mimic hypoxic-ischemic conditions. Rt-PA was intravenously injected into mice 1 h after 1 h MCAO, and Rt-PA was added to the culture medium after 4 h OGD. Rt-PA treatment aggravated the disruption of the BBB compared with hypoxia treatment, and etanercept (TNF-α inhibitor) combined with rt-PA alleviated the rt-PA-induced BBB disruption in vivo and in vitro. Rt-PA treatment increased the TNF-α and MCP-1 levels and decreased the TGF-ß, p-Smad2/3 and PDGFR-ß levels compared with hypoxia treatment in vivo and vitro. TGF-ß combined with rt-PA decreased TNF-α and MCP-1 secretion and alleviated BBB disruption compared with rt-PA; these changes were abrogated by TPO427736 HCL (a TGF-ß/p-Smad2/3 pathway inhibitor) cotreatment in vitro. Rt-PA did not decrease TGF-ß and p-Smad2/3 expression in PDGFR-ß-overexpressing pericytes after OGD. These findings identify PDGFR-ß/TGF-ß/p-Smad2/3 signaling in pericytes as a new therapeutic target for the treatment of rt-PA-induced BBB damage.

Novel Inhalable Ciprofloxacin Dry Powders for Bronchiectasis Therapy: Mannitol-Silk Fibroin Binary Microparticles with High-Payload and Improved Aerosolized Properties.

Non-cystic fibrosis bronchiectasis (NCFB) is a chronic respiratory disease associated with the high morbidity and mortality. Long-term intermittent therapy by inhalable antibiotics has recently emerged as an effective approach for NCFB treatment. However, the effective delivery of antibiotics to the lung requires administering a high dose to the site of infection. Herein, we investigated the novel inhalable silk-based microparticles as a promising approach to deliver high-payload ciprofloxacin (CIP) for NCFB therapy. Silk fibroin (SF) was applied to improve drug-payload and deposit efficiency of the dry powder particles. Mannitol was added as a mucokinetic agent. The dry powder inhaler (DPI) formulations of CIP microparticles were evaluated in vitro in terms of the aerodynamic performance, particle size distribution, drug loading, morphology, and their solid state. The optimal formulation (highest drug loading, 80%) exhibited superior aerosolization performance in terms of fine particle fraction (45.04 ± 0.84%), emitted dose (98.10 ± 1.27%), mass median aerodynamic diameter (3.75 ± 0.03 µm), and geometric standard deviation (1.66 ± 0.10). The improved drug loading was due to the electrostatic interactions between the SF and CIP by adsorption, and the superior aerosolization efficiency would be largely attributed to the fluffy and porous cotton-like property and low-density structure of SF. The presented results indicated the novel inhalable silk-based DPI microparticles of CIP could provide a promising strategy for the treatment of NCFB.

Knockdown of BCL6 Inhibited Malignant Phenotype and Enhanced Sensitivity of Glioblastoma Cells to TMZ through AKT Pathway.

BACKGROUND: BCL6 was a critical prooncogene of human B-cell lymphomas which promoted tumor progress and contributed to malignant behavior in several kinds of cancers. This study was to detect the expression of BCL6 and its biological effect on glioma. METHODS: RT-PCR and Western blot were used to detect the expression of BCL6 mRNA and protein in tissues and glioblastoma cell lines. The expression of BCL6 was knockdown in two glioblastoma cell lines (U87 and U251) using BCL6 shRNA. The CCK8, colony-formation, flow cytometry, Transwell, and wound-healing assays were used to evaluate the malignant phenotypic change of glioblastoma cells. RESULTS: The expression of BCL6 was higher in glioma tissues and glioblastoma cell lines than normal tissues. Knockdown of BCL6 expression reduced the proliferation, migration, and invasion of glioblastoma cells. Moreover, knockdown of BCL6 changed expression of proteins related to malignant behaviors of glioblastoma cells. The suppression of BCL6 could increase chemosensitivity of U87 and U251 to temozolomide. Downregulation of BCL6 levels suppressed the expression of BCL2, cyclin D1, MMP2, and MMP9 proteins as well as two classic signaling pathway proteins p-AKT and p-ERK. Simultaneously, BAX and p21 protein levels were upregulated along with knockdown of BCL6. CONCLUSIONS: Our results indicated that BCL6 may be a tumor oncogene involved in the progression of glioma via affecting AKT and MAPK signaling pathways.

Overexpression of Epsin 3 enhances migration and invasion of glioma cells by inducing epithelial­mesenchymal transition.

Epsin 3 (EPN3) expression is limited to gastric parietal cells and wounded or pathological tissue rather than normal brain tissue, and although it has been identified as an oncogene in estrogen receptor­positive breast cancer and non­small cell lung cancer, its function in cancer is poorly understood. The present study aimed to investigate the association of EPN3 expression with the clinicopathological features of patients with glioma, as well as the effects of EPN3 on glioblastoma cells and the potential molecular mechanisms for its effects on glioblastoma cell behavior. EPN3 expression was assessed by immunohistochemistry in tissue samples from 167 patients with glioma, as well as by western blotting in 5 glioblastoma cell lines. The U87 and U251 glioblastoma cell lines were used to investigate the effects of EPN3 on glioblastoma cell invasion and migration through gain and loss of EPN3 expression experiments; expression levels were further investigated by reverse transcription­quantitative polymerase chain reaction (RT­qPCR) and western blot analyses. The results demonstrated that EPN3 expression levels were upregulated in high­grade glioma tissues compared with low­grade tissues, and there were varying expression levels of EPN3 in the five glioblastoma cell lines. No significant differences were observed in EPN3 expression in relation to patient age, sex or tumor size. Overexpression of EPN3 promoted glioblastoma cell migration and invasion, which we hypothesized was through affecting epithelial­mesenchymal transition (EMT). RT­qPCR and western blotting revealed that EPN3 upregulation increased the expression of Notch1 intracellular domain, ß­catenin, Slug, Twist and zinc­finger E­box­binding homeobox (ZEB)­1. These results suggested that EPN3 enhances the migration and invasion of glioblastoma cells by activating the transcription factors Slug, Twist and ZEB1, but not Snail 1 or ZEB2, to induce EMT in glioma cells; EPN3 involvement in the Notch and WNT/ß­catenin signaling pathways may contribute to this process.

MicroRNA-124-3p represses cell growth and cell motility by targeting EphA2 in glioma.

MiR-124-3p and EphA2 are aberrantly expressed in glioma tissue specimens. In the present study, we firstly investigated that miR-124-3p inhibits EphA2 expression mediated by binding its 3'-UTR to regulate the progression of human glioma. The U87MG and LN229 cells were transfected with miR-124-3p mimics and/or siRNA-EphA2, and then the role of miR-124-3p and EphA2 in the colony-formation, cell-cycle, migration and invasion of glioma cells in vitro were examined. Proteins involved in the epithelial-mesenchymal transition were examined using western blot. The results showed that miR-124-3p was significantly downregulated in glioma tissues, whereas a marked upregulation of EphA2 expression was found. Colony-formation and flow cytometry assays demonstrated that EphA2 downregulation or miR-124-3p mimics caused growth and cell-cycle inhibition in glioma. Transwell migration and invasion assays demonstrated that EphA2 downregulation or miR-124-3p mimics suppressed the migration and invasion of glioma cells. EphA2 downregulation or miR-124-3p mimics reduced the level of vimentin in U87MG and LN229 cells. In conclusion, miR-124-3p was found to suppress the growth, migration and invasion of glioma cells in vitro via EphA2. Furthermore, we validated miR-124-3p enforced its biological modulation via targeting EphA2 through the rescue experiment. Conclusively, our study proclaimed that miR-124-3p can counteract the malignant phenotypes of glioma cells by the inhibitory effect of the EphA2.

Aß inhibits mesenchymal stem cell-pericyte transition through MAPK pathway.

Multiple independent reports have demonstrated pericyte loss in both the hippocampus and cortex in human Alzheimer's disease (AD). The differentiation and recruitment of pericytes are the essential steps in vasculature development. However, the role of amyloid beta (Aß) in pericyte differentiation has not yet been fully elucidated. In this study, we investigated the interaction between Aß and differentiation of mesenchymal stem cells (MSCs) toward pericytes in culture. Our results showed that mice overexpressing Aß-precursor protein (APP/PS1) exhibited the loss of pericytes compared with the control group mice, evidenced by the lack of desmin expression in the cortex of 12-month-old mice. Interestingly, we further found that both Aß40 and Aß42 inhibited the expressions of pericyte markers (α-SMA, desmin, and PDGFRß) in cultured MSCs which can be differentiated into mature pericytes. Mechanistically, the inhibitory effects of Aßs on MSC-pericyte transition is mediated by the activation of the ERK1/2 MAPK signal pathway. These new insights into the roles of Aß in pericyte differentiation may help to develop more effective strategies for the treatment of AD.

Mesoporous silica nanoparticles for drug and gene delivery.

Mesoporous silica nanoparticles (MSNs) are attracting increasing interest for potential biomedical applications. With tailored mesoporous structure, huge surface area and pore volume, selective surface functionality, as well as morphology control, MSNs exhibit high loading capacity for therapeutic agents and controlled release properties if modified with stimuli-responsive groups, polymers or proteins. In this review article, the applications of MSNs in pharmaceutics to improve drug bioavailability, reduce drug toxicity, and deliver with cellular targetability are summarized. Particularly, the exciting progress in the development of MSNs-based effective delivery systems for poorly soluble drugs, anticancer agents, and therapeutic genes are highlighted.

MiRNA-154-5p inhibits cell proliferation and metastasis by targeting PIWIL1 in glioblastoma.

MicroRNAs (miRNAs) play a critical role in glioblastoma initiation and progression. PIWIL1, a human homolog of the PIWI family, has a critical effect on glioblastoma progression. In present study, we found that the expression of miR-154-5p was significantly lower in glioblastoma. Our results suggested that the overexpression of miR-154-5p suppressed proliferation and metastasis, induced apoptosis, whereas inhibiting the expression of miR-154-5p significantly promoted proliferation and metastasis of glioblastoma. We further proved that miR-154-5p directly integrated with the 3'-UTR of PIWIL1 and reintroduction of PIWIL1 can rescue the phenotype changes induced by miR-154-5p. Taken together, our study reveals that miR-154-5p can counteract the malignant phenotypes of glioblastoma by targeting PIWIL1, which might be beneficial to reveal new therapeutic targets for glioblastoma.