IRGD-modified erythrocyte membrane biomimetic temozolomide nanodots for the treatment of glioblastoma.

The crossing of the blood-brain barrier (BBB) for conventional anticancer drugs is still a big challenge in treating glioma. The biomimetic nanoparticle delivery system has attracted increasing attention and has a promising future for crossing the BBB. Herein, we construct a multifunctional biomimetic nanoplatform using the erythrocyte membrane (EM) with the tumor-penetrating peptide iRGD (CRGDK/RGPD/EC) as a delivery, and the inner core loaded with the chemotherapeutic drug temozolomide (TMZ). The resulting biomimetic nanoparticle has perfect biocompatibility and stealth ability, which will provide more chances to escape the reticuloendothelial system (RES) entrapment, and increase the opportunity to enter the tumor site. Moreover, the decorated iRGD has been extensively used to actively targeting and deliver therapeutic agents across the BBB into glioma tissue. We show that this biomimetic delivery of TMZ with a diameter of 22 nm efficiently slowed the growth of glioblastoma multiforme (GBM) and increased the survival rate of the 30 d from 0% to 100%.

Role of O-GlcNAcylation in Central Nervous System Development and Injuries: A Systematic Review.

The development of central nervous system (CNS) can form perceptual, memory, and cognitive functions, while injuries to CNS often lead to severe neurological dysfunction and even death. As one of the prevalent post-translational modifications (PTMs), O-GlcNAcylation has recently attracted great attentions due to its functions in regulating the activity, subcellular localization, and stability of target proteins. It has been indicated that O-GlcNAcylation could interact with phosphorylation, ubiquitination, and methylation to jointly regulate the function and activity of proteins. Furthermore, a growing number of studies have suggested that O-GlcNAcylation played an important role in the CNS. During development, O-GlcNAcylation participated in the neurogenesis, neuronal development, and neuronal function. In addition, O-GlcNAcylation was involved in the progress of CNS injuries including ischemic stroke, subarachnoid hemorrhage (SAH), and intracerebral hemorrhage (ICH) and played a crucial role in the improvement of brain damage such as attenuating cognitive impairment, inhibiting neuroinflammation, suppressing endoplasmic reticulum (ER) stress, and maintaining blood-brain barrier (BBB) integrity. Therefore, O-GlcNAcylation showed great promise as a potential target in CNS development and injuries. In this article, we presented a review highlighting the role of O-GlcNAcylation in CNS development and injuries. Hence, on the basis of these properties and effects, intervention with O-GlcNAcylation may be developed as therapeutic agents for CNS diseases.

Human umbilical cord mesenchymal stem cell-derived exosomes provide neuroprotection in traumatic brain injury through the lncRNA TUBB6/Nrf2 pathway.

Recently, human umbilical cord mesenchymal stem cell (HucMSC) is a new focus of research in neurological diseases, and the beneficial effect of HucMSC is mediated by paracrine factors which are transported by exosome. Our previous study has shown that HucMSC-derived exosome could provide neuroprotection after traumatic brain injury (TBI). However, the underlying mechanisms were not fully understood. In the present study, we found that administration of exosome suppressed TBI-induced inflammation and ferroptosis. In addition, exosome activated the long non-coding ribonucleic acid (lncRNA) TUBB6/nuclear factor erythroid 2-related factor 2 (Nrf2) pathway after TBI. However, exosome partly failed to provide neuroprotection following TBI when TUBB6 was knockdown. Importantly, exosome treatment also decreased neuron cell death, suppressed inflammation, inhibited ferroptosis and activated the lncRNA TUBB6/Nrf2 pathway after TBI in vitro. Taken together, our results provided the first evidence that HucMSC-derived exosome played a key role in neuroprotection after TBI through the lncRNA TUBB6/Nrf2 pathway.

Fucoxanthin ameliorates traumatic brain injury by suppressing the blood-brain barrier disruption.

Fucoxanthin is the most abundant marine carotenoid extracted from seaweed. Our previous study has shown that fucoxanthin inhibited oxidative stress after traumatic brain injury (TBI). However, the effects of fucoxanthin on TBI-induced blood-brain barrier (BBB) destruction have not been well understood. In the present study, we found that fucoxanthin improved neurological dysfunction, reduced brain edema, attenuated cortical lesion volume, and decreased dendrites loss after TBI in vivo. Moreover, fucoxanthin suppressed BBB leakage, preserved tight junction (TJ) and adherens junction (AJ) proteins, and inhibited MMP-9 expression. Furthermore, fucoxanthin alleviated apoptosis and ferroptosis, and activated mitophagy in endothelial cells (ECs) after TBI. However, the protection of fucoxanthin on BBB was attenuated when mitophagy was inhibited. Importantly, fucoxanthin also provided protective effects in bEnd.3 cells after TBI. Taken together, our results suggested that fucoxanthin played a key role in the protection of BBB after TBI through mitophagy.

Exploration and functionalization of M1-macrophage extracellular vesicles for effective accumulation in glioblastoma and strong synergistic therapeutic effects.

Glioblastoma multiforme (GBM) is a highly aggressive brain tumor with an extremely low survival rate. New and effective approaches for treatment are therefore urgently needed. Here, we successfully developed M1-like macrophage-derived extracellular vesicles (M1EVs) that overcome multiple challenges via guidance from two macrophage-related observations in clinical specimens from GBM patients: enrichment of M2 macrophages in GBM; and origination of a majority of infiltrating macrophage from peripheral blood. To maximize the synergistic effect, we further functionalized the membranes of M1EVs with two hydrophobic agents (the chemical excitation source CPPO (C) and the photosensitizer Ce6 (C)) and loaded the hydrophilic hypoxia-activated prodrug AQ4N (A) into the inner core of the M1EVs. After intravenous injection, the inherent nature of M1-derived extracellular vesicles CCA-M1EVs allowed for blood-brain barrier penetration, and modulated the immunosuppressive tumor microenvironment via M2-to-M1 polarization, which increased hydrogen peroxide (H2O2) levels. Furthermore, the reaction between H2O2 and CPPO produced chemical energy, which could be used for Ce6 activation to generate large amounts of reactive oxygen species to achieve chemiexcited photodynamic therapy (CDT). As this reaction consumed oxygen, the aggravation of tumor hypoxia also led to the conversion of non-toxic AQ4N into toxic AQ4 for chemotherapy. Therefore, CCA-M1EVs achieved synergistic immunomodulation, CDT, and hypoxia-activated chemotherapy in GBM to exert a potent therapeutic effect. Finally, we demonstrated the excellent effect of CCA-M1EVs against GBM in cell-derived xenograft and patient-derived xenograft models, underscoring the strong potential of our highly flexible M1EVs system to support multi-modal therapies for difficult-to-treat GBM.

Identifying critical genes associated with aneurysmal subarachnoid hemorrhage by weighted gene co-expression network analysis.

Aneurysmal subarachnoid hemorrhage (aSAH) is a life-threatening medical condition with a high mortality and disability rate. aSAH has an unclear pathogenesis, and limited treatment options are available. Here, we aimed to identify critical genes involved in aSAH pathogenesis using peripheral blood gene expression data of 43 patients with aSAH due to ruptured intracranial aneurysms and 18 controls with headache, downloaded from Gene Expression Omnibus. These data were used to construct a co-expression network using weighted gene co-expression network analysis (WGCNA). The biological functions of the hub genes were explored, and critical genes were selected by combining with differentially expressed genes analysis. Fourteen modules were identified by WGCNA. Among those modules, red, blue, brown and cyan modules were closely associated with aSAH. Moreover, 364 hub genes in the significant modules were found to play important roles in aSAH. Biological function analysis suggested that protein biosynthesis-related processes and inflammatory responses-related processes were involved in the pathology of aSAH pathology. Combined with differentially expressed genes analysis and validation in 35 clinical samples, seven gene (CD27, ANXA3, ACSL1, PGLYRP1, ALPL, ARG1, and TPST1) were identified as potential biomarkers for aSAH, and three genes (ANXA3, ALPL, and ARG1) were changed with disease development, that may provide new insights into potential molecular mechanisms for aSAH.

Depression-like Behavior Induced by Nesfatin-1 in Rats: Involvement of Increased Immune Activation and Imbalance of Synaptic Vesicle Proteins.

Depression is a multicausal disorder and has been associated with metabolism regulation and immuno-inflammatory reaction. The anorectic molecule nesfatin-1 has recently been characterized as a potential mood regulator, but its precise effect on depression and the possible mechanisms remain unknown, especially when given peripherally. In the present study, nesfatin-1 was intraperitoneally injected to the rats and the depression-like behavior and activity of the hypothalamic-pituitary-adrenal (HPA) axis were evaluated. The plasma concentrations of nesfatin-1, interleukin 6 (IL-6), and C-reactive protein (CRP); and the hypothalamic expression levels of nesfatin-1, synapsin I, and synaptotagmin I mRNA were evaluated in nesfatin-1 chronically treated rats. The results showed that both acute and chronic administration of nesfatin-1 increased immobility in the forced swimming test (FST), and resulted in the hyperactivity of HPA axis, as indicated by the increase of plasma corticosterone concentration and hypothalamic expression of corticotropin-releasing hormone (CRH) mRNA. Moreover, after chronic nesfatin-1 administration, the rats exhibited decreased activity and exploratory behavior in the open field test (OFT) and increased mRNA expression of synapsin I and synaptotagmin I in the hypothalamus. Furthermore, chronic administration of nesfatin-1 elevated plasma concentrations of IL-6 and CRP, which were positively correlated with despair behavior, plasma corticosterone level, and the hypothalamic mRNA expression of synapsin I and synaptotagmin I. These results indicated that exogenous nesfatin-1 could induce the immune-inflammatory activation, which might be a central hug linking the depression-like behavior and the imbalanced mRNA expression of synaptic vesicle proteins in the hypothalamus.

Acute, but not chronic, stress increased the plasma concentration and hypothalamic mRNA expression of NUCB2/nesfatin-1 in rats.

Nesfatin-1, a newly discovered satiety peptide, has recently been reported to be involved in the stress response. Stress-induced expression of nesfatin-1 has been reported and few studies focus on its expression in the hypothalamus, which is the center of the stress response. To test our hypothesis that peripheral and hypothalamic nesfatin-1 overexpression should play an important role in the stress response and the associated hyperactivity of hypothalamic-pituitary-adrenal (HPA) axis, acute stress (AS) was induced using water avoidance stress (WAS), and chronic unpredictable mild stress (CUMS) was also induced using 3 consecutive weeks of 7 different stressors. The behavior of CUMS rats was evaluated by an open field test (OFT), sucrose preference test (SPT), and forced swimming test (FST). The activity of the HPA axis was detected by measurement of the plasma corticosterone concentration and hypothalamic mRNA expression of corticotropin-releasing-hormone (CRH). The plasma concentration and hypothalamic mRNA expression of nesfatin-1 were measured with an enzyme-linked immunosorbent assay (ELISA) and real-time fluorescent quantitative PCR, respectively. The results showed that both AS and CUMS increased the plasma corticosterone concentration and hypothalamic CRH mRNA expression. Depression-like behavior was induced in CUMS rats, as indicated by a decreased movement distance, frequency of rearing and grooming in the OFT, and sucrose preference index and increased immobility in the FST. Moreover, the AS rats showed increased plasma concentration and hypothalamic mRNA expression of nesfatin-1, which were positively correlated with the plasma corticosterone concentration and hypothalamic CRH expression, respectively. These results indicated that acute stress, but not chronic stress, increased the plasma concentration and hypothalamic mRNA expression of NUCB2/nesfatin-1 in rats.