Exosomal miR-486 derived from bone marrow mesenchymal stem cells promotes angiogenesis following cerebral ischemic injury by regulating the PTEN/Akt pathway.

Bone marrow mesenchymal stem cell-derived exosomes (BMSC-Exos) have been shown to promote angiogenesis after ischemic stroke, in which microRNAs (miRs) are believed to play an important role in exosome-mediated therapeutic effects, though the mechanism is still not clear. In this study, a series of molecular biological and cellular assays, both in vitro and in vivo, were performed to elucidate the role of exosomal miR-486 in angiogenesis following cerebral ischemic and its molecular mechanisms. Our results revealed that BMSC-Exos significantly improved neurological function and increased microvessel density in ischemic stroke rats. In vitro assays showed that BMSC-Exos promoted the proliferation, migration, and tube formation ability of oxygen-glucose deprivation/reoxygenation (OGD/R) injured rat brain microvascular endothelial cells (RBMECs). Importantly, BMSC-Exos increased the expression of miR-486 and phosphorylated protein kinase B (p-Akt) and down-regulated the protein level of phosphatase and tensin homolog (PTEN) in vivo and in vitro. Mechanistic studies demonstrated that transfection with miR-486 mimic enhanced RBMECs angiogenesis and increased p-Akt expression, while inhibited PTEN expression. On the other hand, the miR-486 inhibitor induced an opposite effect, which could be blocked by PTEN siRNA. It was thus concluded that exosomal miR-486 from BMSCs may enhance the functional recovery by promoting angiogenesis following cerebral ischemic injury, which might be related to its regulation of the PTEN/Akt pathway.

Therapeutic Strategies for Ischemic Stroke: Modulating the Adult Neural Stem Cell Niche through the Wnt/ß-catenin Pathway.

Stroke is a prominent contributor to mortality and impairment on a global scale. Ischemic stroke accounts for approximately 80% of stroke cases and is caused by occlusion of cerebral blood vessels. Enhancing neurogenesis through the modulation of the neural stem cell niche in the adult brain is a promising therapeutic strategy for individuals afflicted with ischemic stroke. Neurogenesis results in the generation of newborn neurons that serve as replacements for deceased neural cells within the ischemic core, thereby playing a significant role in the process of neural restoration subsequent to cerebral ischemia. Research has shown that activation of the Wnt/ß-catenin pathway can augment neurogenesis following cerebral ischemia, suggesting that this pathway is a potentially beneficial therapeutic target for managing ischemic stroke. This review provides an extensive analysis of the current knowledge regarding the involvement of the Wnt/ß-catenin pathway in promoting neurogenesis, thereby offering a promising avenue for therapeutic intervention in the context of ischemic stroke or other neurological impairments.

STAT3-PTTG11 abrogation inhibits proliferation and induces apoptosis in malignant glioma cells.

Pituitary tumor transforming gene 1 (PTTG11) is abundantly expressed in glioma. Our previous study demonstrated that the downregulation of PTTG11 gene expression significantly inhibited the proliferation, migration and invasion ability, and increased the apoptosis of SHG44 glioma cells. However, the molecular mechanisms that regulate PTTG11 and its actions remain elusive. In the present study, CCK-8 and flow cytometry assays were used to assess the proliferation/viability and apoptosis, respectively, of the human glioma U251 cell line. STAT3-PTTG1 signals were further evaluated by western blotting. The findings of the present study revealed that STAT3 induced PTTG11 expression, which subsequently induced downstream c-Myc and Bcl-2 expression while inhibiting Bax expression, thereby promoting cell viability and inhibiting apoptosis. PTTG11 suppression via siRNA inhibited the viability and increased the apoptosis of glioma cells induced by the STAT3 activator S3I-201. c-Myc and Bcl-2 expression was suppressed by PTTG11 inhibition. The findings of the present study suggest that the STAT3-PTTG11 signaling pathway may play an important role in glioma progression by regulating cell proliferation and apoptosis.

Variation in rhizosphere microbial communities and its association with the symbiotic efficiency of rhizobia in soybean.

Rhizobia-legume symbiosis is an important type of plant-microbe mutualism; however, the establishment of this association is complicated and can be affected by many factors. The soybean rhizosphere has a specific microbial community, yet whether these organisms affect rhizobial nodulation has not been well investigated. Here, we analyzed the compositions and relationships of soybean rhizocompartment microbiota in three types of soil. First, we found that the rhizosphere community composition of soybean varied significantly in different soils, and the association network between rhizobia and other rhizosphere bacteria was examined. Second, we found that some rhizosphere microbes were correlated with the composition of bradyrhizobia and sinorhizobia in nodules. We cultivated 278 candidate Bacillus isolates from alkaline soil. Finally, interaction and nodulation assays showed that the Bacillus cereus group specifically promotes and suppresses the growth of sinorhizobia and bradyrhizobia, respectively, and alleviates the effects of saline-alkali conditions on the nodulation of sinorhizobia as well as affecting its colonization in nodules. Our findings demonstrate a crucial role of the bacterial microbiota in shaping rhizobia-host interactions in soybean, and provide a framework for improving the symbiotic efficiency of this system of mutualism through the use of synthetic bacterial communities.

Propane-2-sulfonic acid octadec-9-enyl-amide, a novel peroxisome proliferator-activated receptors α and γ dual agonist, enhances hippocampal neurogenesis and neuroplasticity in rats with cerebral ischaemia.

Our previous studies showed that propane-2-sulfonic acid octadec-9-enyl-amide (N15), a novel peroxisome proliferator-activated receptors α and γ (PPARα/γ) dual agonist, protected against ischaemia-induced acute brain damage in mice and improved cognitive ability in the chronic phase of ischaemic stroke. It is well known that hippocampal neurogenesis is closely related to cognitive function. In the present study, we investigated the effect of N15 on hippocampal neurogenesis and neuroplasticity in a middle cerebral artery occlusion (MCAO) rat model. The middle cerebral artery of rats was blocked for 2 hours. Oral administration of 100 mg/kg N15 or vehicle was given once daily for days 2-13 after MCAO. The newly mature neurons were detected by staining. The expressions of synapse-related proteins were observed by qRT-PCR or western blotting. We found that N15-treated rats showed improved survival post-MCAO. In addition, N15 treatment markedly increased the newly mature neurons and enhanced the expression levels of growth-associated protein-43, synaptophysin, brain-derived neurotrophic factor and neurotrophin-3 in the hippocampus. Moreover, N15 promoted the activation of PPARα and PPARγ on day 7 and 14 after cerebral ischaemia. These results reveal that N15 may promote neurogenesis and neuroplasticity in MCAO rats through the activation of the PPARα/γ dual signal pathway.

Moringa oleifera seed extract protects against brain damage in both the acute and delayed stages of ischemic stroke.

The extract of Moringa oleifera (M. oleifera) seeds exerts various pharmacological effects. Our previous study demonstrated that M. oleifera seed extract (MSE) alleviates scopolamine-induced learning and memory impairment in mice. In the present study, we investigate the neuropharmacological properties of 70% ethanolic MSE in the acute and delayed stages of ischemic stroke. MSE may be effective for the prevention and/or treatment of acute ischemic stroke. The most effective dose was 500 mg/kg, and the therapeutic window seemed to be within 4 h after reperfusion. Additionally, we found that MSE treatment improved animal survival, reversed spatial cognitive impairment and promoted hippocampal neurogenesis and neuroplasticity as well as the cholinergic neurotransmission system during the recovery stages of ischemic stroke. Our findings verified that MSE has neuroprotective effects in both the acute and chronic stages of ischemic stroke. The relevant mechanism of protection may occur by promoting hippocampal neurogenesis and synaptic plasticity as well as improving cholinergic function. These findings suggest that M. oleifera seed extract may be a promising neuroprotective agent for the treatment of ischemic stroke.

Integration of phospholipid-complex nanocarrier assembly with endogenous N-oleoylethanolamine for efficient stroke therapy.

BACKGROUND: Leading to more and more deaths and disabilities, stroke has become a serious threat to human health. What's more, few effective drugs are available in clinic till now. RESULTS: In this research, we prepared a novel neuroprotective nanoformation (OEA-SPC NPs) via the combination of the nanoparticle drug delivery system with the endogenous N-oleoylethanolamine (OEA). By forming hydrogen bond between OEA and the carrier-soybean phosphatidylcholine (SPC), the form of OEA was turned into amorphus state when loading to the nanoparticles, which greatly improved its bioavailability. Then the following systematic experiments revealed the efficient neuroprotective effect of OEA-SPC NPs in vivo. Compared with the MCAO group, the cerebral infarct volume was reduced by 81.1%, and the edema degree by 78.4% via the oral administration of OEA-SPC NPs. And the neurological deficit scores illustrated that the MCAO rats treated with OEA-SPC NPs exhibited significantly less neurological dysfunction. The Morris water maze test indicated that the spatial learning and memory of cerebral ischemia model rats were almost recovered to the normal level. Besides, the OEA-SPC NPs could inhibit the inflammation of reperfusion to a very slight level. CONCLUSIONS: These results suggest that the OEA-SPC NPs have a great chance to be a potential anti-stroke formation for clinic application and actually bring hope to thousands of stroke patients.

A study for multiscale information transfer measures based on conditional mutual information.

As the big data science develops, efficient methods are demanded for various data analysis. Granger causality provides the prime model for quantifying causal interactions. However, this theoretic model does not meet the requirement for real-world data analysis, because real-world time series are diverse whose models are usually unknown. Therefore, model-free measures such as information transfer measures are strongly desired. Here, we propose the multi-scale extension of conditional mutual information measures using MORLET wavelet, which are named the WM and WPM. The proposed measures are computational efficient and interpret information transfer by multi-scales. We use both synthetic data and real-world examples to demonstrate the efficiency of the new methods. The results of the new methods are robust and reliable. Via the simulation studies, we found the new methods outperform the wavelet extension of transfer entropy (WTE) in both computational efficiency and accuracy. The features and properties of the proposed measures are also discussed.

Moringa oleifera Seed Extract Alleviates Scopolamine-Induced Learning and Memory Impairment in Mice.

The extract of Moringa oleifera seeds has been shown to possess various pharmacological properties. In the present study, we assessed the neuropharmacological effects of 70% ethanolic M. oleifera seed extract (MSE) on cognitive impairment caused by scopolamine injection in mice using the passive avoidance and Morris water maze (MWM) tests. MSE (250 or 500 mg/kg) was administered to mice by oral gavage for 7 or 14 days, and cognitive impairment was induced by intraperitoneal injection of scopolamine (4 mg/kg) for 1 or 6 days. Mice that received scopolamine alone showed impaired learning and memory retention and considerably decreased cholinergic system reactivity and neurogenesis in the hippocampus. MSE pretreatment significantly ameliorated scopolamine-induced cognitive impairment and enhanced cholinergic system reactivity and neurogenesis in the hippocampus. Additionally, the protein expressions of phosphorylated Akt, ERK1/2, and CREB in the hippocampus were significantly decreased by scopolamine, but these decreases were reversed by MSE treatment. These results suggest that MSE-induced ameliorative cognitive effects are mediated by enhancement of the cholinergic neurotransmission system and neurogenesis via activation of the Akt, ERK1/2, and CREB signaling pathways. These findings suggest that MSE could be a potent neuropharmacological drug against amnesia, and its mechanism might be modulation of cholinergic activity via the Akt, ERK1/2, and CREB signaling pathways.

Oleoylethanolamide inhibits α-melanocyte stimulating hormone-stimulated melanogenesis via ERK, Akt and CREB signaling pathways in B16 melanoma cells.

The present study aimed to examine the potential inhibitory activity of oleoylethanolamide (OEA) on α-melanocyte stimulating hormone (α-MSH)-stimulated melanogenesis and the molecular mechanism(s) involved in the process in B16 mouse melanoma cells. Our data demonstrated that OEA markedly inhibited melanin synthesis and tyrosinase activity in α-MSH-stimulated B16 cells. In addition, the expression of melanogenesis-related proteins, such as melanocortin-1 receptor (MC1R), microphthalmia-associated transcription factor (MITF), tyrosinase-related protein-1 (TRP-1) and tyrosinase, was suppressed in a concentration-dependent manner by OEA. In addition, OEA may suppress melanogenesis through a peroxisome proliferator-activated receptor α (PPARα)-independent pathway. Moreover, OEA activated ERK, Akt, p38 pathways and inhibits CREB pathway in α-MSH-stimulated B16 cells. The specific ERK inhibitor PD98059 partly blocked OEA-inhibited melanin synthesis and tyrosinase activity and partly abrogated the OEA-suppressed expression of melanogenic proteins. Furthermore, OEA presented remarkable inhibition on the body pigmentation in the zebrafish model system. Our findings demonstrated that OEA is an effective inhibitor of hyperpigmentation through activation of ERK, Akt and p38 pathways, inhibition of the CREB pathway, and subsequent down-regulation of MITF, TRP-1 and tyrosinase production.

Propane-2-sulfonic acid octadec-9-enyl-amide, a novel PPARα/γ dual agonist, protects against ischemia-induced brain damage in mice by inhibiting inflammatory responses.

Propane-2-sulfonic acid octadec-9-enyl-amide (N15), an analogue of oleoylethanolamide (OEA), is a novel PPARα/γ dual agonist. Our previous studies verified the positive effects of OEA on the acute and delayed stages of cerebral ischemia. However, it is not clear whether N15 is effective against ischemic cerebral injury. In the present study, male Kunming mice were subjected to middle cerebral artery occlusion (MCAO). To evaluate its preventive effects, N15 (50, 100 or 200mg/kg, ip) was administered for 3days before ischemia. To evaluate its therapeutic effects, N15 (200mg/kg, ip) was administered 1h before reperfusion or 0, 1, 2 or 4h after reperfusion. Neurological deficit scores, infarct volume and the degree of brain oedema were determined at 24h after reperfusion. Blood brain barrier (BBB) disruption was evaluated by Evans blue (EB) and FITC-dextran leakages at 6h after reperfusion. The activation/inflammatory responses of microglia/macrophages were detected using immunohistochemistry and western blot. N15 pretreatment improved neurological dysfunction, reduced infarct volume and alleviated brain oedema in a dose-dependent manner; the most effective dose was 200mg/kg. The therapeutic time window was within 2h after reperfusion. N15 treatment preserved the BBB integrity and suppressed the activation of microglia/macrophages. N15 inhibited inflammatory cytokine expression not only in MCAO mice but also in lipopolysaccharide (LPS)-stimulated BV-2 microglial cells. Additionally, N15 markedly decreased the phosphorylation levels of NF-κBp65, STAT3, and ERK1/2 both in vivo and in vitro. Furthermore, the PPARα antagonist MK886 or PPARγ antagonist T0070907 respectively partly abolished the anti-inflammatory effects of N15 in vitro. Our findings demonstrated that N15 can exert neuroprotective effects against cerebral ischemic insult. Moreover, the neuroprotective effects of N15 on cerebral ischemia may be attributed to its anti-inflammatory properties, at least in part, by enhancing PPARα/γ dual signaling and inhibiting the activation of the NF-κB, STAT3, and ERK1/2 signaling pathways. These findings suggest that N15 may be a potential therapeutic choice for the prevention and treatment of ischemic stroke.