Glioma exosomal microRNA-148a-3p promotes tumor angiogenesis through activating the EGFR/MAPK signaling pathway via inhibiting ERRFI1.

BACKGROUND: Glioma is the most frequent and lethal primary brain malignancy. Amounting evidence has highlighted the importance of exosomal microRNAs (miRNAs or miRs) in this malignancy. This study aimed to investigate the regulatory role of exosomal miR-148a-3p in glioma. METHODS: Bioinformatics analysis was firstly used to predict the target genes of miR-148a-3p. Exosomes were then extracted from normal human astrocytes and glioma cells. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was applied to determine the expression patterns of miR-148a-3p and ERBB receptor feedback inhibitor 1 (ERRFI1). Dual-luciferase reporter gene assay was applied to verify the direct binding between miR-148a-3p and ERRFI1. Cell counting kit-8 and tube formation assays were further conducted to assess the proliferation and angiogenic properties of human umbilical vein endothelial cells (HUVECs) in the co-culture system with exosomes. Lastly, glioma tumor models were established in BALB/c nude mice to study the role of exosomal miR-148a-3p in vivo. RESULTS: miR-148a-3p was highly expressed, while ERRFI1 was poorly expressed in glioma. miR-148a-3p was found to be enriched in glioma cells-derived exosomes and could be transferred to HUVECs via exosomes to promote their proliferation and angiogenesis. ERRFI1 was identified as a target gene of miR-148a-3p. In addition, miR-148a-3p activated the epidermal growth factor receptor (EGFR)/mitogen-activated protein kinase (MAPK) signaling pathway by inhibiting ERRFI1. In the co-culture system, our data demonstrated that glioma cells-derived exosomal miR-148a-3p down-regulated ERRFI1 and activated the EGFR/MAPK signaling pathway, so as to promote cell proliferation and angiogenesis. In vivo experimentation further demonstrated that this mechanism was responsible for the promotive role of exosomal miR-148a-3p in tumorigenesis and angiogenesis. CONCLUSION: Taken together, glioma-derived exosomal miR-148a-3p promoted tumor angiogenesis through activation of the EGFR/MAPK signaling pathway by ERRFI1 inhibition.

Non-crosslinked systems modulate the gel behavior and structural properties of chitosan/silica composite aerogels.

The aim of this study was to achieve rapid gelation of chitosan (CS) and silica (SA) without crosslinking agent, the relationship between process parameters and the composite aerogels properties were also explored. By varying the composition ratio of the system (from SA:CS = 1:1 to 5:1), the system gelation time was reduced by >12 times, and the drying shrinkage of the composite aerogel reached a minimum of 7.6 %. During the two recombination processes, chitosan rapidly formed aqueous colloid secondary structure under the influence of ethanol. This phenomenon reduced the stability of the system and allowed silica to form a two-phase composite hydrogel. Because the network gap between the fibers was used as a limiting medium for gel growth. In addition, the chitosan/silica composite aerogels exhibited a mesoporous structure with low density (0.1144 g/cm3), and the thermal conductivity was 0.028 W/(m·K) at 30 °C. The trimethylchlorosilane made the composite aerogel have good hydrophobicity with water contact angle as 134.7°, and the adsorption capacity of carbon tetrachloride could reach >10 times of its own weight. This study provides an eco-friendly and high-efficiency method for preparing aerogels, which has potential applications in the fields of thermal insulation, oil-water separation, etc.

Effective glioblastoma immune sonodynamic treatment mediated by macrophage cell membrane cloaked biomimetic nanomedicines.

Glioblastoma (GBM) as one of the most lethal brain tumours, remains poor therapeutic index due to its typical characters including heterogeneous, severe immune suppression as well as the existence of blood brain barrier (BBB). Immune sonodynamic (ISD) therapy combines noninvasive sonodynamic therapy with immunotherapy, which has great prospects for the combinational treatment of GBM. Herein, we develop macrophage cell membrane cloaked reactive oxygen species (ROS) responsive biomimetic nanoparticles, co-delivering of sonosensitizer Ce6 and JQ1 (a bromo-domain protein 4 (BRD4) inhibitor which can down-regulate PD-L1) and realizing potent GBM ISD therapy. The ApoE peptide decorated macrophage membrane coating endows these biomimetic nanoparticles with low immunogenicity, efficient BBB permeability, prolonged blood circulation half-live and good biocompatibility. The ROS responsive polymeric inner core could be readily degraded as triggered by excessive ROS under the ultrasound once they accumulated in tumour cells, fast release encapsulated drugs. The generation of ROS not only killed tumour cells via sonodynamic therapy, but also induced immunogenic cell death (ICD) and further activated the anti-tumour immune response. The released JQ1 inhibited tumour cell proliferation and augmented the immune activities by inhibiting the PD-L1 expression on the surface of tumour cells. The cascade sonodynamic and immune therapy resulted in significantly improved median survival time in both orthotopic GL261 and PTEN deficient immunosuppressive CT2A GBM mice models. Therefore, our developed biomimetic nanoparticle platform provides a promising combinational therapy strategy to treat immune suppressive GBM.

Ketogenic therapy towards precision medicine for brain diseases.

Precision nutrition and nutrigenomics are emerging in the development of therapies for multiple diseases. The ketogenic diet (KD) is the most widely used clinical diet, providing high fat, low carbohydrate, and adequate protein. KD produces ketones and alters the metabolism of patients. Growing evidence suggests that KD has therapeutic effects in a wide range of neuronal diseases including epilepsy, neurodegeneration, cancer, and metabolic disorders. Although KD is considered to be a low-side-effect diet treatment, its therapeutic mechanism has not yet been fully elucidated. Also, its induced keto-response among different populations has not been elucidated. Understanding the ketone metabolism in health and disease is critical for the development of KD-associated therapeutics and synergistic therapy under any physiological background. Here, we review the current advances and known heterogeneity of the KD response and discuss the prospects for KD therapy from a precision nutrition perspective.

Analysis of Clinical Characteristic and Risk Factors for Short-Term Prognosis of Moyamoya Disease with Intraventricular Hemorrhage in Adults.

BACKGROUND: Intraventricular hemorrhage (IVH) is the most common type of hemorrhage in moyamoya disease (MMD) with intracerebral hemorrhage (ICH), but the risk factors affecting the short-term prognosis of MMD with IVH in adults are still unclear. METHODS: We retrospectively analyzed patients of MMD with IVH between January 1, 2018 and January 31, 2020 in the First Affiliated Hospital of Zhengzhou University. According to the modified Rankin Scale (mRS) score at 3 months after discharge, the patients were divided into mRS score ≤2 (good prognosis) group and mRS score >2 (poor prognosis) groups. Univariate and multivariate logistics regression analysis was used to analyze the risk factors affecting the short-term prognosis of adult MMD with IVH. RESULTS: Univariable analyses showed that patients in the poor prognosis group had a significantly older age of onset (48.48 ± 8.34 vs. 43.74 ± 5.44 years; P = 0.002), a higher percentage of hypertension (57.97% vs. 33.33%; P = 0.014), a higher percentage of tracheotomy (23.19% vs. 2.56%; P = 0.005), a lower Glasgow Coma Scale (GCS) score (7.90 ± 3.58 vs. 11.19 ± 2.56; P = 0.000), a higher Graeb score (7.46 ± 4.04 vs. 5.23 ± 1.93; P = 0.002), and treatment methods (P = 0.000). Multiple logistic regression analysis showed that the lower GCS score (odds ratio [OR], 1.761; P = 0.001) and higher Graeb score (OR, 1.767; P = 0.002) were independently associated with the poor prognosis of MMD with IVH, and surgery treatment (OR, 0.032; P = 0.000) was independently related to the good prognosis of MMD with IVH. CONCLUSIONS: Among patients with MMD with IVH, the lower GCS score and higher Graeb score are independent risk factors for poor prognosis, whereas in patients with MMD with IVH, surgery treatment acts as a protective factor.

Neuroprotection of Chikusetsu saponin V on transient focal cerebral ischemia/reperfusion and the underlying mechanism.

BACKGROUND: Oxidative stress and frequently unwanted alterations in mitochondrial structure and function are key aspects of the pathological cascade in transient focal cerebral ischemia. Chikusetsu saponin V (CHS V), a major component of saponins from Panax japonicas, can attenuate H2O2-induced oxidative stress in SH-SY5Y cells. PURPOSE: The aim of the present study was to investigate the neuroprotective effects and the possible underlying mechanism of CHS V on transient focal cerebral ischemia/reperfusion. METHODS: Mice with middle cerebral artery occlusion (MCAO) and cultured cortical neurons exposed to oxygen glucose deprivation (OGD) were used as in vivo and in vitro models of cerebral ischemia, respectively. The neurobehavioral scores, infarction volumes, H&E staining and some antioxidant levels in the brain were evaluated. The occurrence of neuronal death was estimated. Total and mitochondrial reactive oxygen species (ROS) levels, as well as mitochondrial potential were measured using flow cytometry analysis. Mitochondrial structure and respiratory activity were also examined. Protein levels were investigated by western blotting and immunohistochemistry. RESULTS: CHS V effectively attenuated cerebral ischemia/reperfusion (CI/R) injury, including improving neurological deficits, shrinking infarct volume and reducing the number of apoptotic cells. Furthermore, CHS V treatment remarkably increased antioxidant levels and reduced ROS levels and mitochondrial damage by enhancing the expression and deacetylation of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) by activating AMPK and SIRT-1, respectively. CONCLUSION: Our data demonstrated that CHS V prevented CI/R injury by suppressing oxidative stress and mitochondrial damage through the modulation of PGC-1α with AMPK and SIRT-1.

Effectiveness and feasibility of cilostazol in patients with aneurysmal subarachnoid hemorrhage: a systematic review and meta-analysis.

BACKGROUND: Delayed cerebral ischemia seriously affects the prognosis of patients surviving the initial aneurysmal subarachnoid hemorrhage. Application of cilostazol was reported to ameliorate vasospasm and improve outcomes in series and clinical trials. But the effectiveness and feasibility of cilostazol on aneurysmal subarachnoid hemorrhage remained controversial. We performed a systematic review to clarify this issue. METHODS: PubMed, Ovid and Cochrane library database were systematically searched up to May 2018 for eligible publications in English. Quality assessment was conducted for included studies. Meta-analysis was conducted to evaluate the overall effect on events of interest. Subgroup analyses and sensitivity analyses were used to check whether the results were robust. Publication bias was evaluated with the funnel plot. RESULTS: Pooled analyses found cilostazol significantly reduced incidences of severe angiographic vasospasm (p = 0.0001), symptomatic vasospasm (p < 0.00001), new cerebral infarction (p < 0.00001) and the poor outcome (p < 0.0001). Subgroup and sensitivity analyses achieved consistent results. There was no statistical difference between cilostazol and the control group in reducing mortality (p = 0.07). But sensitivity analysis changed the result after excluding one study. Under the prescribed dosage, complication was few and non-lethal. CONCLUSIONS: Cilostazol was effective and safe to reduce incidences of severe angiographic vasospasm, symptomatic vasospasm, new cerebral infarction and poor outcome in patients after aneurysmal subarachnoid hemorrhage. However, its effect on mortality and the interactive effect with nimodipine warranted further research.