Rhein induces apoptosis and autophagy in human and rat glioma cells and mediates cell differentiation by ERK inhibition.

In this study, we investigated the anticancer potentials of Rhein, an anthraquinone derivative of most commonly used Chinese rhubarb on the rat F98 glioma cells. The experimental studies revealed that Rhein induced cell cycle arrest, caspase mediated apoptosis. It results in the formation of intracellular acidic vesicles in cytoplasm, leading to autophagy. Differentiation of viable cells towards elongation of matured astrocytes was proved by monitoring dramatic changes in morphological characteristics as well as identified from the elevation of glial fibrillary acidic protein (GFAP) expression. Rhein treatment did not alter the phosphorylated MAPKs activation including p-38, JNK and NF-κB, transcription unit whereas rhein significantly inhibited ERK1/2 activation in F98 glioma cells. PD98059, a specific inhibitor for ERK activation imitates rhein effects on morphology and expressions of GFAP but did not help to induce any apoptosis or autophagy. Collective data exhibited that potentials of rhein in anti-cancer property in ERK-independent apoptosis and autophagy in association with downregulated ERK-dependent differentiation process of glioma cell lines.

Flow diverter treatment of posterior circulation aneurysms. A meta-analysis.

INTRODUCTION: Treatment of complex anterior circulation aneurysms with flow diverters (FDs) has become common practice in neurovascular centers. However, this treatment method for posterior circulation aneurysms (PCAs) still remains controversial. METHODS: Through searches for reports on the treatment of PCAs with FDs, we conducted a systematic review of the literature on its clinical efficacy and safety using random-effect binomial meta-analysis. RESULTS: We included 14 studies, which reported on a total of 225 PCAs in 220 patients. Procedure-related good outcome rate was 79% (95% confidence interval (CI), 72-84), with significantly lower odds among patients with ruptured aneurysms and basilar artery aneurysms. Procedure-related mortality rate was 15% (95% CI 10-21), with significantly higher rates among patients with giant aneurysms and basilar artery aneurysms. The rate of complete aneurysm occlusion at 6-month digital subtraction angiography (DSA) was 84%. Ischemic stroke rate was 11%. Perforator infarction rate was 7%. Postoperative subarachnoid hemorrhage (SAH) rate was 3%. Intraparenchymal hemorrhage (IPH) rate was 4%. CONCLUSIONS: Flow diverter treatment of PCAs is an effective method, which provides a high rate of complete occlusion at 6-month DSA. However, compared with anterior circulation aneurysms, patients with PCAs are at significantly higher risk of mortality, ischemic stroke and perforator infarction. Our findings indicate that, in most clinical centers, flow diverter treatment of PCAs should be conducted in carefully selected patients with poor natural history and no optimal treatment strategy. For ruptured and giant basilar artery aneurysms, there is still no good treatment option.

Establishment of swine-penetrating craniocerebral gunshot wound model.

BACKGROUND: Bullet-induced brain wounds are common among military personnel in war zones and among civilians with gun accidents or crime-related gun injuries. The goal of this study was to develop a nonfatal porcine model of penetrating craniocerebral gunshot wound (PCGW) by firing a projectile in live swine to induce PCGW in such a realistic manner as to reconstruct their physical characteristics. MATERIALS AND METHODS: We established a nonfatal porcine model of PCGW based on a custom-designed experimental gun that emulates the shooting of a 5.56-mm NATO standard rifle at 800 m (317 m/s; 200.9 J). Commercial swine (n = 20) were subjected to a ballistic wound to the bilateral frontal lobe, and four swine were used as controls. Surviving swine were used in subsequent first-aid, management, and monitoring experiments for neurosurgeons. Various physiological variables were measured continuously. After computed tomography (CT) scanning and three-dimensional CT reconstructions, all pigs underwent primary lifesaving emergency interventions, including emergency decompressive craniotomies and hemorrhage control. RESULTS: In our nonfatal porcine model of PCGW, injuries were comparable in their morphology to real gunshot wounds, as evidenced by analysis of wound characteristics and CT scan images. The survival rates of the pigs were 100% within 2 h, 95% within 6 h, 85% within 12 h, and 85% within 24 h (P < 0.01). Hemodynamics, hematology, blood routine biochemistry, coagulation, and other physiological parameters also exhibited significant changes in the PCGW pigs. CONCLUSIONS: This model makes possible the laboratory reproduction of real ballistic wounds in a live large animal model that is close to humans.

Biphasic activation of nuclear factor-kappa B in experimental models of subarachnoid hemorrhage in vivo and in vitro.

It has been proven that nuclear factor-kappa B (NF-κB) is activated as a well-known transcription factor after subarachnoid hemorrhage (SAH). However, the panoramic view of NF-κB activity after SAH remained obscure. Cultured neurons were signed into control group and six hemoglobin- (Hb-) incubated groups. One-hemorrhage rabbit SAH model was produced, and the rabbits were divided randomly into one control group and five SAH groups. NF-κB activity was detected by electrophoretic mobility shift assay (EMSA) and immunohistochemistry. Real-time polymerase chain reaction (PCR) was performed to assess the downstream genes of NF-κB. NeuN immunofluorescence and lactate dehydrogenase (LDH) quantification were used to estimate the neuron injury. Double drastically elevated NF-κB activity peaks were detected in rabbit brains and cultured neurons. The downstream gene expressions showed an accordant phase peaks. NeuN-positive cells decreased significantly in day 3 and day 10 groups. LDH leakage exhibited a significant increase in Hb-incubated groups, but no significant difference was found between the Hb incubated groups. These results suggested that biphasic increasing of NF-κB activity was induced after SAH, and the early NF-κB activity peak indicated the injury role on neurons; however, the late peak might not be involved in the deteriorated effect on neurons.

[Retracted] Retinoic acid­incorporated glycol chitosan nanoparticles inhibit the expression of Ezh2 in U118 and U138 human glioma cells.

We wish to retract our research article entitled "Retinoic acid-incorporated glycol chitosan nanoparticles inhibit Ezh2 expression in U118 and U138 human glioma cells" published in Molecular Medicine Reports 12: 6642-6648, 2015. An interested reader noted some anomalies in the presentation of Fig. 4 in our paper, calling into question the validity of the reported data. In examining our original article, we acknowledge that the data for RA (25 µm) did not show a higher density of cells compared with RA (10 µm), as shown in Fig. 4, and therefore Fig. 4 conveyed inaccurate information for the readers. Owing to the importance of these results, which bear significantly upon the conclusions that one may draw from this work, we have decided to withdraw our paper from Molecular Medicine Reports [the original article was published in Molecular Medicine Reports 12: 6642-6648, 2015; DOI: 10.3892/mmr.2015.4294.

Retinoic acid­incorporated glycol chitosan nanoparticles inhibit the expression of Ezh2 in U118 and U138 human glioma cells.

At present, one of the most life threatening types of adult brain tumor is glioblastoma multiforme (GBM). The molecular mechanism underlying the progression of GBM remains to be fully elucidated. The modern method of clinical treatment has only improved the average survival rates of a newly diagnosed patients with GBM by ~15 months. Therefore, the discovery of novel molecules, which are involved in glioma inhibition is required. In the present study, U118 and U138 human glioma cells were transfected with all­trans retinoic acid (RA)-incorporated glycol chitosan (GC) nanoparticles.An MTT assay was used for the analysis of cell proliferation and flow cytometric analysis and ssDNA detection assays were performed for the determination of induction of cell apoptosis. Cell cycle distribution was analyzed by flow cytometry. Exposure of the U118 and U138 human glioma cells to the RA­incorporated GC nanoparticles for 24 h resulted in a concentration­dependent inhibition of cell proliferation. Among the range of experimental RA concentrations, the minimum effective treatment concentration was 10 µM, with a half maximal inhibitory concentration of 25 µM. The results also demonstrated that RA transfection resulted in the inhibition of cell proliferation, inhibition of the expression of Ezh2, and apoptosis through the mitochondrial signaling pathway by a decrease in membrane potential, the release of cytochrome c, and cell cycle arrest in the G0/G1 phase.

Protective effect of quercetin on lipopolysaccharide-induced acute lung injury in mice by inhibiting inflammatory cell influx.

Sepsis may result in lung injury through a complex cascade of events including interstitium infiltration of inflammatory cells. Quercetin, the most abundant dietary flavonoid found in various plants and food products, possesses potent anti-inflammatory and antioxidative properties. The purpose of this study was to investigate whether preventive administration of quercetin could exert beneficial effects on experimental septic acute lung injury induced by lipopolysaccharide (LPS). C57/BL6 mice were challenged with LPS and survival time was monitored from 0-96 h after LPS treatment. Quercetin markedly rescued lethality, improved survival time, and inhibited serum necrosis factor α, interleukin 1ß, and interleukin 6, and nitric oxide (NO), and increased IL-10 secretion. Moreover, quercetin decreased lung pathological changes, myeloperoxidase activity, and malondialdehyde levels. Quercetin also reduced the lung permeability changes and neutrophil and macrophage recruitment to the bronchoalveolar lavage fluid compared to the vehicle. Additionally, quercetin significantly reduced COX-2, HMGB1, iNOS expression, and NF-κB p65 phosphorylation. These results suggest that treatment with quercetin in septic mice improved survival time and lung injury. Quercetin may be a promising potential therapeutic reagent for LPS-induced acute lung injury.

Quercetin reduces oxidative stress and inhibits activation of c­Jun N­terminal kinase/activator protein­1 signaling in an experimental mouse model of abdominal aortic aneurysm.

Oxidative stress is becoming increasingly linked to the pathogenesis of abdominal aortic aneurysms (AAAs). The antioxidant activity of flavonoids has attracted attention for their possible role in the prevention of cardiovascular diseases. The purpose of this study was to determine whether an antioxidant mechanism is involved in the aneurysm formation inhibitory effect afforded by quercetin. Male C57/BL6 mice received quercetin continuously from 2 weeks prior to and 6 weeks following the AAA induction with extraluminal CaCl2. Quercetin treatment decreased AAA incidence and inhibited the reactive oxygen species generation, nitrotyrosine formation and lipid peroxidation production in the aortic tissue during AAA development. In addition, quercetin­treated mice exhibited significantly lower expression of the p47phox subunit of nicotinamide adenine dinucleotide phosphate oxidase and inducible nitric oxide synthase, as well as coordinated downregulation of manganese­superoxide dismutase activities and glutathione peroxidase (GPx)­1 and GPx­3 expression. Quercetin also blunted the expression of c­Jun N­terminal kinase (JNK) and phospho­JNK and, in addition, diminished activation of the activator protein (AP)­1 transcription factor. Gelatin zymography showed that quercetin eliminated matrix metalloproteinase (MMP)­2 and MMP­9 activation during AAA formation. In conclusion, the inhibitory effects of quercetin on oxidative stress and MMP activation, through modulation of JNK/AP­1 signaling, may partly account for its benefit in CaCl2­induced AAA.

Regional hypothermia inhibits spinal cord somatosensory-evoked potentials without neural damage in uninjured rats.

Both the therapeutic effects of regional hypothermia (RH) and somatosensory-evoked potentials (SSEP) have been intensively studied; however, the in vivo relationship between the two remains unknown. The primary focus of the current study was to investigate the impact of RH on SSEP in uninjured rats, as well as the neural safety of RH on neuronal health. An epidural perfusion model was used to keep local temperature steady by adjusting perfusion speed at 30°C, 26°C, 22°C, and 18°C for 30 min, respectively. Total hypothermic duration lasted up to 3 h. Neural signals were recorded at the end of each hypothermic period, as well as before cooling and after spontaneous rewarming. In addition, the Basso, Beattie, and Bresnahan (BBB) Locomotor Rating Scale was used to evaluate the effects of RH pre- and post-operative, combined with hematoxylin and eosin (H&E) and Fluoro-Jade C (FJC) staining. The results showed a marked declining trend in SSEP amplitude, as well as a significant prolongation in latency only during profound hypothermia (18°C). The BBB scale remained consistent at 21 throughout the entire process, signifying that no motor function injury was caused by RH. In addition, H&E and FJC staining did not show obvious histological injury. These findings firmly support the conclusion that RH, specifically profound RH, inhibits spinal cord SSEP in both amplitude and latency without neural damage in uninjured rats.

Quercetin, a flavonoid with anti-inflammatory activity, suppresses the development of abdominal aortic aneurysms in mice.

Inflammation has been implicated as a contributing factor in the development of abdominal aortic aneurysms (AAA). Quercetin, a natural flavonoid with anti-inflammatory properties, is known for its beneficial effects on vascular disease. In this study, we examined the effects of quercetin to inflammatory cell infiltration, subsequent expression of cytokines and activation of proteases on the expansion of experimental AAA. Aneurysms were induced by abluminal application of calcium chloride in C57/BL6 mice. Quercetin (60 mg/kg) was administered once daily by gavage beginning 2 weeks before AAA induction and continuing for 8 weeks. Mice treated with quercetin exhibited a 32.7% reduction in aortic size compared with vehicle-treated controls. Prevention of AAA was associated with preservation of medial structure, as well as a relative reduction in macrophage and CD3(+) T cell infiltration in aortic tissue, inflammatory cytokines release and nuclear factor κB activation. Quercetin also reduced the expression of matrix metalloproteinase (MMP)-2, MMP-9, cathepsin B, and cathepsin K in aortic tissue. In addition, quercetin treatment increased tissue inhibitors of metalloproteinases (TIMP)-1 gene expression. These data indicate that quercetin may be useful for the prevention and treatment of AAA via blocking the inflammatory response and inhibiting the proteases involved in the pathogenesis of this disease.