ATF2/BAP1 Axis Mediates Neuronal Apoptosis After Subarachnoid Hemorrhage via P53 Pathway.

BACKGROUND: Neuronal apoptosis plays an essential role in the pathogenesis of brain injury after subarachnoid hemorrhage (SAH). BAP1 (BRCA1-associated protein 1) is considered to exert pro-apoptotic effects in multiple diseases. However, evidence supporting the effect of BAP1 on the apoptotic response to SAH is lacking. Therefore, we aimed to confirm the role of BAP1 in SAH-induced apoptosis. METHODS: Enzyme-linked immunosorbent assay (ELISA) was used to detect BAP1 expression in the cerebrospinal fluid. Endovascular perforation was performed in mice to induce SAH. Lentiviral short hairpin RNA targeting BAP1 mRNA was transduced into the ipsilateral cortex of mice with SAH to investigate the role of BAP1 in neuronal damage. Luciferase and coimmunoprecipitation assays were performed to investigate the mechanism through which BAP1 participates in hemin-induced SAH. RESULTS: First, BAP1 expression was upregulated in the cerebrospinal fluid of patients with SAH and positively associated with unfavorable outcomes. ATF2 (activating transcription factor-2) then regulated BAP1 expression by binding to the BAP1 promoter. In addition, BAP1 overexpression enhanced P53 activity and stability by reducing P53 proteasome-mediated degradation. Subsequently, elevated P53 promoted neuronal apoptosis via the P53 pathway. Inhibition of the neuronal BAP1/P53 axis significantly reduced neurological deficits and neuronal apoptosis and improved neurological dysfunction in mice after SAH. CONCLUSIONS: Our results suggest that the neuronal ATF2/BAP1 axis exerts a brain-damaging effect by modulating P53 activity and stability and may be a novel therapeutic target for SAH.

Integration analysis of cell division cycle-associated family genes revealed potential mechanisms of gliomagenesis and constructed an artificial intelligence-driven prognostic signature.

Cell division cycle-associated (CDCA) gene family members are essential cell proliferation regulators and play critical roles in various cancers. However, the function of the CDCA family genes in gliomas remains unclear. This study aims to elucidate the role of CDCA family members in gliomas using in vitro and in vivo experiments and bioinformatic analyses. We included eight glioma cohorts in this study. An unsupervised clustering algorithm was used to identify novel CDCA gene family clusters. Then, we utilized multi-omics data to elucidate the prognostic disparities, biological functionalities, genomic alterations, and immune microenvironment among glioma patients. Subsequently, the scRNA-seq analysis and spatial transcriptomic sequencing analysis were carried out to explore the expression distribution of CDCA2 in glioma samples. In vivo and in vitro experiments were used to investigate the effects of CDCA2 on the viability, migration, and invasion of glioma cells. Finally, based on ten machine-learning algorithms, we constructed an artificial intelligence-driven CDCA gene family signature called the machine learning-based CDCA gene family score (MLCS). Our results suggested that patients with the higher expression levels of CDCA family genes had a worse prognosis, more activated RAS signaling pathways, and more activated immunosuppressive microenvironments. CDCA2 knockdown inhibited the proliferation, migration, and invasion of glioma cells. In addition, the MLCS had robust and favorable prognostic predictive ability and could predict the response to immunotherapy and chemotherapy drug sensitivity.

Eriocitrin Alleviates Inflammation and Oxidative Stress in Subarachnoid Hemorrhage by Regulating DUSP14.

BACKGROUND: Inflammation and oxidative stress (OS) are major causes of aneurysmal subarachnoid hemorrhage (aSAH)-induced early brain injury (EBI). Eriocitrin (EC), a flavonoid compound, has anti-inflammatory and antioxidant actions. However, there is still no relevant studies on the role of EC in SAH. Accordingly, this research aims to clarify the anti-OS and anti-inflammatory efficacy of EC in SAH. METHOD: Rat SAH model was established in vivo and administered with Eriocitrin (25 mg/kg). In vitro, BV2 cells were exposed to oxyhemoglobin (OxyHb) for 24 hours and pretreated with Eriocitrin (1 uM/mL, 2 uM/mL, 4 uM/mL) for 30 minutes. Water maze experiments and neurological function scores were conducted to assess cognitive and motor function. TdT-mediated dUTP Nick-End Labeling (TUNEL) staining was used to detect cortical cell apoptosis. Enzyme-linked immunosorbent assay (ELISA) and polymerase chain reaction (PCR) were used to detect the inflammatory factors and malondialdehyde (MDA), as well as the expression of superoxide dismutase (SOD) and glutathione peroxidase (GSH-px). Western blots were used to semi quantify nuclear factor erythroid-2-related factor 2 (Nrf2), nuclear factor-κB (NF-κB), dual specificity phosphatase 14 (DUSP14) expression. RESULTS: The findings suggest that EC (25 mg/kg) reduced SAH-induced central nervous system (CNS) damage, neuronal apoptosis, inflammatory reactions and OS. Regarding a mechanistic study, EC enhanced Nrf2 and NF-κB by increasing DUSP14 activation, thereby reducing the inflammatory cytokines interleukin (IL)-1ß, tumor necrosis factor (TNF)-α, and IL-6. In addition, EC decreased MDA while markedly elevating SOD and enhancing GSH-px. Furthermore, specifically inhibiting DUSP14 expression via using protein-tyrosine-phosphatase (PTP) inhibitor IV, neutralized the protective action of EC and aggravated inflammation and OS. In vitro experiments of OxyHb-induced BV2 cells revealed that EC promoted Nrf2 while markedly suppressing NF-κB by increasing DUSP14 activation, thereby reducing the concentrations of the above inflammatory cytokines. Moreover, EC decreased MDA while evidently increasing SOD and GSH-px. CONCLUSION: In summary, this paper lays a theoretical grounding for EC treatment of SAH-induced inflammatory reactions and OS by regulating DUSP14.

Advantages of computed tomography-based navigation in clipping distal anterior cerebral artery aneurysms: a retrospective cohort study.

Background: The occurrence rate of distal anterior cerebral artery (DACA) aneurysms is relatively low, primarily due to their deep-seated location, which makes surgical clamping challenging. The objective of this study was to investigate the efficacy and safety of computed tomography (CT) navigation-assisted clipping of DACA aneurysms compared to traditional clipping without navigation. Methods: A retrospective cohort study involving retrospective data collection was performed. The retrospective analysis was conducted on 139 patients with ruptured DACA aneurysms who underwent clipping. From January 2013 to November 2021, 164 patients were retrieved at the Department of Neurosurgery, Renmin Hospital of Wuhan University. The inclusion criteria were patients diagnosed with DACA aneurysms via CT angiography (CTA) or digital subtraction angiography (DSA), those with complete clinical data, and those who underwent craniotomy for aneurysm clipping. Meanwhile, the exclusion criteria were as follows: aneurysm recurrence, traumatic brain injury or surgery history, blood disorders or recent anticoagulant use, and severe organ dysfunction. Data on gender, age, Hunt-Hess grade, Fisher grade, modified Rankin Scale (mRS) score, aneurysm location, hospitalization time, aneurysm found time (the duration from incision to aneurysm discovery), and intraoperative bleeding volume were collected from medical records and neurosurgical databases. Patients were followed up in the clinic or by telephone in May 2022. All patients were divided into a navigation group or a traditional group for statistical analysis. Results: No statistically significant differences were observed in age, sex, Fisher grade, Hunt-Hess grade, hospitalization time, or aneurysm site between the navigation group and traditional group (P>0.05). Intraoperative blood loss was lower in the navigation group than in the traditional group {370 [280-460] vs. 430 [310-610] mL, P=0.045}. Patients in the traditional group had a shorter aneurysm found time than did those in the navigation group {49 [42-53] vs. 79 [63-84] min, P<0.001}. There was no significant difference in the mRS score at hospital discharge (P=0.336) or follow-up (P=0.157) between the two groups. Conclusions: CT neuronavigation-assisted microsurgery for clipping DACA aneurysms may improve surgical accuracy, shorten the time to locate aneurysms, and reduce intraoperative blood loss. Although no significant difference in prognosis was observed, this technique shows promise as a safe and effective alternative to traditional clipping without navigation.

Inhibition of CCR1 attenuates neuroinflammation via the JAK2/STAT3 signaling pathway after subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: Neuroinflammation is an important mechanism underlying brain injury caused by subarachnoid hemorrhage (SAH). C-C chemokine receptor type 1 (CCR1)-mediated inflammation is involved in the pathology of many central nervous system diseases. Herein, we investigated whether inhibition of CCR1 alleviated neuroinflammation after experimental SAH and aimed to elucidate the mechanisms of its potential protective effects. METHODS: To analyze SAH transcriptome data R studio was used, and a mouse model of SAH was established using endovascular perforations. In this model, the selective CCR1 antagonist Met-RANTES (Met-R) and the CCR1 agonist recombinant CCL5 (rCCL5) were administered 1 h after SAH induction. To investigate the possible downstream mechanisms of CCR1, the JAK2 inhibitor AG490 and the JAK2 activator coumermycin A1 (C-A1) were administered 1 h after SAH induction. Furthermore, post-SAH evaluation, including SAH grading, neurological function tests, Western blot, the terminal deoxynucleotidyl transferase dUTP nick end labeling assay, and Fluoro-Jade B and fluorescent immunohistochemical staining were performed. Cerebrospinal fluid (CSF) samples were detected by ELISA. RESULTS: CCL5 and CCR1 expression levels increased significantly following SAH. Met-R significantly improved neurological deficits in mice, decreased apoptosis and degeneration of ipsilateral cerebral cortex neurons, reduced infiltrating neutrophils, and promoted microglial activation after SAH induction. Furthermore, Met-R inhibited the expression of p-JAK2, p-STAT3, interleukin-1ß, and tumor necrosis factor-α. However, the protective effects of Met-R were abolished by C-A1 treatment. Furthermore, rCCL5 injection aggravated neurological dysfunction and increased the expression of p-JAK2, p-STAT3, interleukin-1ß, and tumor necrosis factor-α in SAH mice, all of which were reversed by the administration of AG490. Finally, the levels of CCL5 and CCR1 were elevate in the CSF of SAH patient and high level of CCL5 and CCR1 levels were associated with poor outcome. CONCLUSION: The present results suggested that inhibition of CCR1 attenuates neuroinflammation after SAH via the JAK2/STAT3 signaling pathway, which may provide a new target for the treatment of SAH.

Inhibition of S100A9 alleviates neurogenic pulmonary edema after subarachnoid hemorrhage.

BACKGROUND AND PURPOSE: Neurogenic pulmonary edema (NPE) frequently arises as a complication subsequent to subarachnoid hemorrhage (SAH). Heterodimers of S100A8 and S100A9 are commonly formed, thereby initiating an inflammatory reaction through receptor binding on the cell surface. Paquinimod serves as a specific inhibitor of S100A9. The objective of this investigation is to assess the impact of Paquinimod administration and S100A9 knockout on NPE following SAH. METHODS: In this study, SAH models of C57BL/6J wild-type (WT) and S100A9 knockout mice were established through intravascular perforation. These models were then divided into several groups, including the WT-sham group, S100A9-KO-sham group, WT-SAH group, WT-SAH + Paquinimod group, and S100A9-KO-SAH group. After 24 h of SAH induction, pulmonary edema was assessed using the lung wet-dry weight method and Hematoxylin and eosin (HE) staining. Additionally, the expression levels of various proteins, such as interleukin-1ß (IL-1ß), tumor necrosis factor α (TNF-α), occludin, claudin-3, Bax, Bcl-2, TLR4, MYD88, and pNF-κB, in lung tissue were analyzed using western blot and immunofluorescence staining. Lung tissue apoptosis was detected by TUNEL staining. RESULTS: Firstly, our findings indicate that the knockout of S100A9 has a protective effect on early brain injury following subarachnoid hemorrhage (SAH). Additionally, the reduction of brain injury after SAH can also alleviate neurogenic pulmonary edema (NPE). Immunofluorescence staining and western blot analysis revealed that compared to SAH mice with wild-type S100A9 expression (WT-SAH), the lungs of S100A9 knockout SAH mice (S100A9-KO-SAH) and mice treated with Paquinimod exhibited decreased levels of inflammatory molecules (IL-1ß and TNF-α) and increased levels of tight junction proteins. Furthermore, the knockout of S100A9 resulted in upregulated expression of the apoptotic-associated protein Bax and down-regulated expression of Bcl-2. Furthermore, a decrease in TLR4, MYD88, and phosphorylated pNF-κB was noted in S100A9-KO-SAH and Paquinimod treated mice, indicating the potential involvement of the TLR4/MYD88/NF-κB signaling pathway in the inhibition of the protective effect of S100A9 on NPE following SAH. CONCLUSION: The knockout of S100A9 not only ameliorated initial cerebral injury following subarachnoid hemorrhage (SAH), but also mitigated SAH-associated neurogenic pulmonary edema (NPE). Additionally, Paquinimod was found to diminish NPE. These findings imply a correlation between the central nervous system and peripheral organs, highlighting the potential of safeguarding the brain to mitigate harm to peripheral organs.

Diabetes or calcium channel blocker contribute to cerebral hemodynamics after bypass surgery in adult patients with moyamoya disease.

Background: Moyamoya disease (MMD) is a teratogenic and lethal disease. However, existing studies do not sufficiently indicate the impact factors. Therefore, we investigated the different impact factors on cerebral hemodynamics after revascularization in patients with MMD. Methods: We retrospectively collected the clinical data of 233 adult patients with MMD who underwent revascularization surgery in the Department of Neurosurgery, Renmin Hospital of Wuhan University, from January 2015 to June 2021 for this retrospective cohort study. We analyzed the effects on hemodynamic improvement of age, sex, stroke type, early symptoms, Suzuki stage, history of hypertension, history of diabetes, and history of hyperlipidemia in patients with MMD. We also evaluated the efficacy of different revascularization strategies and we verified the effect of computed tomography perfusion (CTP) in evaluating cerebral hemodynamics. Results: The CTP values demonstrated that δ cerebral blood volume (CBV) values were significantly higher in the combined group [1.01 (0.87-1.75)] relative to those in the indirect group [1.34 (1.01-1.63); P=0.027]. There was no statistical significance in the improvement of clinical symptoms and clinical prognosis between the indirect and combined groups. Patients with MMD with diabetes [δ mean transit time (MTT), 0.49 (0.35-0.70) vs. 0.72 (0.52-0.87); P<0.001] or calcium channel blocker (CCB) [δCBV, 1.46 (1.10-1.83) vs. 1.12 (0.93-1.54); P=0.001] had better cerebral hemodynamics than patients in non-diabetic group or non-CCB group after revascularization. Conclusions: We didn't find differences in clinical outcome between indirect and combined revascularization in patients with MMD. we demonstrated that CTP values can be used as a way to detect postoperative cerebral hemodynamic changes in MMD patients. Interestingly, we found that MMD patients with diabetes or CCB showed better cerebral perfusion after revascularization.

Blocking P2RX7 Attenuates Ferroptosis in Endothelium and Reduces HG-induced Hemorrhagic Transformation After MCAO by Inhibiting ERK1/2 and P53 Signaling Pathways.

Hyperglycemia is a risk factor for poor prognosis after acute ischemic stroke and promote the occurrence of hemorrhagic transformation (HT). The activation of P2RX7 play an important role in endotheliocyte damage and BBB disruption. Ferroptosis is a novel pattern of programmed cell death caused by the accumulation of intracellular iron and lipid peroxidation, resulting in ROS production and cell death. This study is to explore the mechanism of P2RX7 in reducing HT pathogenesis after acute ischemic stroke through regulating endotheliocyte ferroptosis. Male SD rats were performed to establish middle cerebral artery occlusion (MCAO) model injected with 50% high glucose (HG) and HUVECs were subjected to OGD/R treated with high glucose (30 mM) for establishing HT model in vivo and in vitro. P2RX7 inhibitor (BBG), and P2RX7 small interfering RNAs (siRNA) were used to investigate the role of P2RX7 in BBB after MCAO in vivo and OGD/R in vitro, respectively. The neurological deficits, infarct volume, degree of intracranial hemorrhage, integrity of the BBB, immunoblotting, and immunofluorescence were evaluated at 24 h after MCAO. Our study found that the level of P2RX7 was gradually increased after MCAO and/or treated with HG. Our results showed that treatment with HG after MCAO can aggravate neurological deficits, infarct volume, oxidative stress, iron accumulation, and BBB injury in HT model, and HG-induced HUVECs damage. The inhibition of P2RX7 reversed the damage effect of HG, significantly downregulated the expression level of P53, HO-1, and p-ERK1/2 and upregulated the level of SLC7A11 and GPX4, which implicated that P2RX7 inhibition could attenuate oxidative stress and ferroptosis of endothelium in vivo and in vitro. Our data provided evidence that the P2RX7 play an important role in HG-associated oxidative stress, endothelial damage, and BBB disruption, which regulates HG-induced HT by ERK1/2 and P53 signaling pathways after MCAO.

Inhibition of CCR2 attenuates neuroinflammation and neuronal apoptosis after subarachnoid hemorrhage through the PI3K/Akt pathway.

BACKGROUND: Neuroinflammation and neuronal apoptosis are closely associated with a poor prognosis in patients with subarachnoid hemorrhage (SAH). We investigated the role of C-C motif chemokine receptor 2 (CCR2) in SAH. METHODS: Pre-processed RNA-seq transcriptome datasets GSE167110 and GSE79416 from the Gene Expression Omnibus (GEO) database were screened for genes differentially expressed between mice with SAH and control mice, using bioinformatics analysis. The endovascular perforation model was performed to establish SAH. RS504393 (a CCR2 antagonist) and LY294002 (PI3K inhibitor) were administered to explore the mechanism of neuroinflammation after SAH. SAH grading, neurological scoring, brain water content and blood-brain barrier (BBB) permeability determination, enzyme-linked immunosorbent assay (ELISA), western blotting, and immunofluorescence were performed. An in vitro model of SAH was induced in H22 cells by hemin treatment. The protective mechanism of CCR2 inhibition was studied by adding RS504393 and LY294002. Clinical cerebrospinal fluid (CST) samples were detected by ELISA. RESULTS: Expression of CCR2 was upregulated in both datasets and was identified as a hub gene. CCR2 expression was significantly upregulated in the cytoplasm of neurons after SAH, both in vitro and in vivo. RS significantly reduced the brain water content and blood-brain barrier permeability, alleviated neuroinflammation, and reduced neuronal apoptosis after SAH. Additionally, the protective effects of CCR2 inhibition were abolished by LY treatment. Finally, the levels of CCR2, inflammatory factors, and apoptotic factors were elevated in the CSF of patients with SAH. CCR2 levels were associated with patient outcomes at the 6-month follow-up. CONCLUSION: CCR2 expression was upregulated in both in vitro and in vivo SAH models. Additionally, inhibition of CCR2, at least partly through the PI3K/AKT pathway, alleviated neuroinflammation and neuronal apoptosis in vivo and in vitro. CCR2 levels in the CSF have a moderate diagnostic value for 6-month outcome prediction in patients with SAH.

Taurine-Upregulated Gene 1 Attenuates Cerebral Angiogenesis following Ischemic Stroke in Rats.

Objective: Angiogenesis is one of the therapeutic targets of cerebral infarction. Long noncoding RNAs (lncRNAs) can regulate the pathological process of angiogenesis following ischemic stroke. Taurine-upregulated gene 1 (TUG1), an lncRNA, is correlated to ischemic stroke. We intended to determine the effect of TUG1 on angiogenesis following an ischemic stroke. Materials and Methods: Middle cerebral artery occlusion (MCAO) was adopted to build a focal ischemic model of the rat brain, and pcDNA-TUG1 and miR-26a mimics were injected into rats. Neurological function was estimated through modified neurological severity scores. The volume of focal brain infarction was calculated through 2,3,5-triphenyltetrazolium chloride staining. The level of TUG1 and miR-26a was measured by PCR. The expression of vascular endothelial growth factor (VEGF) and CD31 was checked using immunohistochemistry and western blot. The correlation between miR-26a and TUG1 was verified through a luciferase reporter assay. Results: TUG1 increased noticeably while miR-26a was markedly reduced in MCAO rats. Overexpression of miR-26a improved neurological function recovery and enhanced cerebral angiogenesis in MCAO rats. TUG1 overexpression aggravated neurological deficits and suppressed cerebral angiogenesis in MCAO rats. Bioinformatics analysis revealed that miR-26a was one of the predicted targets of TUG1. Furthermore, TUG1 combined with miR-26a to regulate angiogenesis. TUG1 overexpression antagonized the role of miR-26a in neurological recovery and angiogenesis in MCAO rats. Conclusions: TUG1/miR-26a, which may act as a regulatory axis in angiogenesis following ischemic stroke, can be considered a potential target for cerebral infarction therapy.

Taurine attenuates neuronal ferroptosis by regulating GABAB/AKT/GSK3ß/ß-catenin pathway after subarachnoid hemorrhage.

Ferroptosis, characterized by lipid peroxidation and intracellular iron accumulation, has been reported to be involving in the pathophysiological of early brain injury (EBI) after subarachnoid hemorrhage (SAH). Although taurine reportedly yields neuroprotective effects in multiple central neurological diseases and can attenuated neuron damage after stroke, its role in EBI after SAH remains unclear. The present study indicated that taurine levels in cerebrospinal fluid were significantly reduced in SAH patients, which suggested that taurine treatment after SAH could improve neurological impairment, oxidative stress, iron accumulation, BBB integrity and neuronal ferroptosis in the SAH model in vivo. Taurine could attenuate MDA levels and ROS accumulation and regulate the expression of SLC7A11 and GPX4 and the AKT/GSK3ß pathway in vitro. GABAB receptor inhibition and Ly294002 could reverse the therapeutic effects of taurine and significantly downregulate the levels of p-AKT, p-GSK3ß, ß-catenin, SLC7A11 and GPX4. The protective effects of taurine on SLC7A11 and GPX4 expression were reversed by ICG001 treatment in vitro. Taken together, our findings revealed that taurine could improve neurological function and alleviate cerebral edema, oxidative stress and BBB disruption after SAH, which reduced neuronal ferroptosis by regulating the GABAB/AKT/GSK3ß/ß-catenin signaling pathway.

Stress-responses of microbes in oil reservoir under high tetracycline exposure and their environmental risks.

As the groundwater ecosystem is connected with surface, antibiotics and antibiotic resistance genes (ARGs) in aquatic environments will gradually infiltrate into the deep environment, posing a potential threat to groundwater ecosystem. However, knowledge on the environmental risk of antibiotics and ARGs in groundwater ecosystem and their ecological process still remains unexplored. In this study, lab-scale oil reservoirs under high tetracycline stress were performed to evaluate the dynamics of microbial communities, ARGs and potential functions by using 16S rRNA gene sequencing and metagenomics analysis. Although the presence of antibiotics remarkably reduced the microbial abundance and diversity in a short term, but remain stable or even increased after a long-term incubation. Antibiotic stress caused a greater diversity and abundance of ARGs, and higher numbers of ARGs-related species with the capacity to transfer ARGs to other microbes through horizontal gene transfer. Thus, a much more frequent associations of microbial community at both node- and network-level and a selective pressure on enrichment of antibiotic resistant bacteria related to "anaerobic n-alkane degradation" and "methylotrophic methanogenesis" were observed. It is important to emphasize that high antibiotic stress could also prevent some microbes related to "Sulfate reduction", "Fe(II) oxidation", "Nitrate reduction", and "Xylene and Toluene degradation". This study provides an insight into the long-term stress-responses of microbial communities and functions in oil reservoir under tetracycline exposure, which may help to elucidate the effect of antibiotic stress on biogeochemical cycling with microbial involvement in groundwater ecosystem.

The eIF4A Inhibitor Silvestrol Blocks the Growth of Human Glioblastoma Cells by Inhibiting AKT/mTOR and ERK1/2 Signaling Pathway.

The most frequently identified central nervous system tumor in adults is glioblastoma multiforme (GBM). GBM prognosis remains poor despite multimodal treatment, i.e., surgery and radiation therapy with concurrent temozolomide-based chemotherapy. Silvestrol, an eIF4A inhibitor, has been demonstrated to be able to kill tumor cells in previous studies. In this study, it was found that silvestrol considerably attenuated the proliferative potential of U251 and U87 glioma cells and reduced expression of cyclin D1. In addition, silvestrol reduced the level of ERK1/2 and decreased the levels of AKT phosphorylation. Unfortunately, the effect of silvestrol in inhibiting GBM cells was greatly reduced with hypoxia, and the downregulation in AKT/mTOR and ERK1/2 were also rescued with an upregulation of HIF1α, which warranted further research. Taken together, silvestrol exerted antitumor effects in GBM cells by inhibiting the AKT/mTOR and ERK1/2 signaling cascades.

Dental pulp stem cell transplantation facilitates neuronal neuroprotection following cerebral ischemic stroke.

OBJECTIVES: This study aimed to identify and evaluate the intracranial transplantation of dental pulp stem cells (DPSCs) as a possible ischemic stroke therapy that mitigates neuronal death/apoptosis. MATERIALS AND METHODS: DPSCs were isolated from the impacted third molars of healthy volunteers and then intracranially injected at 24 h post-ischemic stroke to Sprague Dawley rats that had been subjected to 2 h of middle cerebral artery occlusion. Neurological functional deficits were assessed using the modified neurological severity score (mNSS), and cerebral edema was quantified using brain water content. Neuronal death/apoptosis was indicated by TdT-mediated dUTP Nick-End Labeling (TUNEL) staining, NeuN immunofluorescence and immunohistochemistry, and Western blot analysis of the protein expression of anti-apoptotic indicator of Bcl-2 and apoptotic indicators of Bax and caspase 3. RESULTS: DPSC transplantation could ameliorate neurological dysfunction and brain edema, reduce infarct volume, decrease the percentage of TUNEL-positive nuclei, increase the number and percentage of NeuN-positive cells in ischemic penumbra, increase the ratio of Bcl-2 and Bax and down-regulate the production of caspase 3 in the cortical infarct zone. CONCLUSIONS: DPSC therapy via intracranial injection exerted remarkably neuroprotection mainly by inhibiting neuronal death/apoptosis.

Classification and Characteristics of Mesenchymal Stem Cells and Its Potential Therapeutic Mechanisms and Applications against Ischemic Stroke.

Ischemic stroke is a serious cerebral disease that often induces death and long-term disability. As a currently available therapy for recanalization after ischemic stroke, thrombolysis, including intravenous thrombolysis and endovascular therapy, still cannot be applicable to all patients due to the narrow time window. Mesenchymal stem cell (MSC) transplantation therapy, which can trigger neuronal regeneration and repair, has been considered as a significant advance in treatment of ischemic stroke. MSC transplantation therapy has exhibited its potential to improve the neurological function in ischemic stroke. Our review describes the current progress and future perspective of MSC transplantation therapy in ischemic stroke treatment, including cell types, transplantation approaches, therapeutic mechanisms, and preliminary clinical trials of MSC transplantation, for providing us an update role of MSC transplantation in ischemic stroke treatment.

The neuroprotective effects of Insulin-Like Growth Factor 1 via the Hippo/YAP signaling pathway are mediated by the PI3K/AKT cascade following cerebral ischemia/reperfusion injury.

Insulin-like growth factor 1 (IGF-1) has neuroprotective actions, including vasodilatory, anti-inflammatory, and antithrombotic effects, following ischemic stroke. However, the molecular mechanisms underlying the neuroprotective effects of IGF-1 following ischemic stroke remain unknown. Therefore, in the present study, we investigated whether IGF-1 exerted its neuroprotective effects by regulating the Hippo/YAP signaling pathway, potentially via activation of the PI3K/AKT cascade, following ischemic stroke. In the in vitro study, we exposed cultured PC12 and SH-5YSY cells, and cortical primary neurons, to oxygen-glucose deprivation. Cell viability was measured using CCK-8 assay. In the in vivo study, Sprague-Dawley rats were subjected to middle cerebral artery occlusion. Neurological function was assessed using a modified neurologic scoring system and the modified neurological severity score (mNSS) test, brain edema was detected by brain water content measurement, infarct volume was measured using triphenyltetrazolium chloride staining, and neuronal death and apoptosis were evaluated by TUNEL/NeuN double staining, HE and Nissl staining, and immunohistochemistry staining for NeuN. Finally, western blot analysis was used to measure the level of IGF-1 in vivo and levels of YAP/TAZ, PI3K and phosphorylated AKT (p-AKT) both in vitro and in vivo. IGF-1 induced activation of YAP/TAZ, which resulted in improved cell viability in vitro, and reduced neurological deficits, brain water content, neuronal death and apoptosis, and cerebral infarct volume in vivo. Notably, the neuroprotective effects of IGF-1 were blocked by an inhibitor of the PI3K/AKT cascade, LY294002. LY294002 treatment not only downregulated PI3K and p-AKT, but YAP/TAZ as well, leading to aggravation of neurological dysfunction and worsening of brain damage. Our findings indicate that the neuroprotective effects of IGF-1 are, at least in part mediated by upregulation of YAP/TAZ via activation of the PI3K/AKT cascade following cerebral ischemic stroke.

Chronic Obstructive Pulmonary Disease and Its Acute Exacerbation before Colon Adenocarcinoma Treatment Are Associated with Higher Mortality: A Propensity Score-Matched, Nationwide, Population-Based Cohort Study.

PURPOSE: To investigate whether chronic obstructive pulmonary disease (COPD) and COPD severity (acute exacerbation of COPD (AECOPD)) affect the survival outcomes of patients with colon adenocarcinoma receiving standard treatments. METHODS: From the Taiwan Cancer Registry Database, we recruited patients with clinical stage I-III colon adenocarcinoma who had received surgery. The Cox proportional hazards model was used to analyze all-cause mortality. We categorized the patients into COPD and non-COPD (Group 1 and 2) groups through propensity score matching. RESULTS: In total, 1512 patients were eligible for further comparative analysis between non-COPD (1008 patients) and COPD (504 patients) cohorts. In the multivariate Cox regression analysis, the adjusted hazard ratio (aHR; 95% confidence interval (CI)) for all-cause mortality for Group 1 compared with Group 2 was 1.17 (1.03, 1.29). In patients with colon adenocarcinoma undergoing curative resection, the aHRs (95% CIs) for all-cause mortality in patients with hospitalization frequencies of ≥1 and ≥2 times for AECOPD within 1 year before adenocarcinoma diagnosis were 1.08 (1.03, 1.51) and 1.55 (1.15, 2.09), respectively, compared with those without AECOPD. CONCLUSION: In patients with colon adenocarcinoma undergoing curative resection, COPD was associated with worse survival outcomes. Being hospitalized at least once for AECOPD within 1 year before colon adenocarcinoma diagnosis was an independent risk factor for poor overall survival in these patients, and a higher number of hospitalizations for AECOPD within 1 year before diagnosis was associated with poorer survival. Our study highlights the importance of COPD management, particularly the identification of frequent exacerbators and the prevention of AECOPD before standard colon adenocarcinoma treatments are applied.

lnc-NLC1-C inhibits migration, invasion and autophagy of glioma cells by targeting miR-383 and regulating PRDX-3 expression.

Long non-coding RNAs (lncRNAs) serve an important role in tumor progression, and their abnormal expression is associated with tumor development. The lncRNA narcolepsy candidate region 1 gene C (lnc-NLC1-C) is involved in numerous types of cancer, but its biological function in glioma remains unknown. In the present study, lnc-NLC1-C expression was detected using reverse transcription-quantitative (RT-q)PCR in U251, SHG44, U87MG and U118MG glioma cells. U87MG cells were transfected with lnc-NLC1-C overexpression or interference vectors. Cell proliferation was detected using a Cell Counting Kit-8 assay. Cell migration and invasion were examined using a Transwell assay, while apoptosis, cell cycle and reactive oxygen species production were evaluated using flow cytometry, and the expression levels of lnc-NLC1-C, microRNA (miR)-383 and peroxiredoxin 3 (PRDX-3) were measured using western blotting and RT-qPCR. Rescue experiments were performed to verify the function of the lnc-NLC1-C/miR-383/PRDX-3 axis. The highest expression levels of lnc-NLC1-C were identified in U87MG glioma cells. Overexpression of lnc-NLC1-C expression promoted cell proliferation, G1 phase blocking, migration and invasion, while inhibiting apoptosis and autophagy in U87MG cells. Mechanistically, miR-383 could bind to lnc-NLC1-C to regulate PRDX-3 expression and improve its oncogenic effect. Rescue experiments confirmed that the lnc-NLC1-C/miR-383/PRDX-3 axis was involved in the molecular mechanism of glioma progression. Therefore, lnc-NLC1-C may be a tumor promoter that affects multiple biological functions, such as migration, invasion and autophagy, in glioma cells.

Angelica dahurica and Rheum officinale Facilitated Diabetic Wound Healing by Elevating Vascular Endothelial Growth Factor.

Traditional Chinese medicine (TCM) provides alternative treatment choices for diabetic wounds. The aim of this study was to evaluate the effects of Angelica dahurica and Rheum officinale (ARE) on diabetic wounds and its underlying action mechanism. A total of 36 healthy male Sprague-Dawley rats were randomly divided into three groups: diabetes mellitus (DM) rats treated with ARE (DM-ARE), DM rats treated with 0.9% saline (DM-NS), and non-DM rats treated with 0.9% saline (NDM-NS). DM was induced by intraperitoneal administration of 40 mg/kg of streptozotocin after a 2-week high-fat diet feeding. After excisional skin wounds and treatments, the remaining wound area (RWA) in each group was measured. The RWA in the DM-NS group (69.60% ± 2.35%) was greater than that in the DM-ARE (55.70% ± 1.85%) and NDM-NS groups (52.50% ± 2.77%) on day 6. Besides, the DM-ARE group showed higher vascular endothelial growth factor (VEGF), higher inducible nitric oxide synthase (iNOs), higher [Formula: see text]-smooth muscle actin ([Formula: see text]-SMA), and lower nuclear factor kappa-light-chain-enhancer of activated B cell (NF-[Formula: see text]B) expression in the wound skin tissue. These results showed that treatment with ARE shifted the recovery pattern of diabetic rats to the pattern of nondiabetic rats, indicating that ARE may improve wound healing in diabetic conditions.

MicroRNA-383 promotes reactive oxygen species-induced autophagy via downregulating peroxiredoxin 3 in human glioma U87 cells.

Peroxiredoxin 3 (PRDX3) is an abundant and effective enzyme, which aids in the removal of H2O2 in the mitochondria, thereby inhibiting cell autophagy. PRDX3 is a target protein of microRNA (miRNA/miR)-383, the overexpression of which has been found to inhibit the growth of glioma cells. We hypothesized that miR-383 serves an antitumor role by inhibiting oxidative stress during tumor growth. In the current study, human glioma U87 cells were transfected with pre-/short hairpin (sh)-PRDX3 vectors and miR-383 mimics/inhibitors. Apoptosis and reactive oxygen species (ROS) production were detected using flow cytometry. Autophagy was examined using acridine orange staining, and the expression of cytoplasmic autophagy-related proteins [autophagy-related protein 9 (ATG9), Ras-related protein Rab-1A (Rab1) and p62] was determined using western blot analysis. The interaction between miR-383 and PRDX3 was assessed using a dual-luciferase assay. The results indicated that both sh-PRDX3 and miR-383 mimics promoted apoptosis and increased the level of mitochondrial ROS, whilst acridine orange staining revealed that sh-PRDX3 promoted autophagy in U87 cells compared with that in the control cells. The detection of autophagic proteins indicated that sh-PRDX3 and miR-383 mimics increased the protein expression level of ATG9 and RAB1, and inhibited that of p62. On the contrary, the effect of miR-383 mimics was opposite to that of pre-PRDX3 in U87 cells. Reverse transcription-quantitative PCR and western blot assays revealed that miR-383 was negatively associated with PRDX3 in U87 cells. miR-383 was indicated to interact with PRDX3, as demonstrated using a dual-luciferase assay. In conclusion, the present study demonstrated that miR-383 induced cell apoptosis and mitochondrial ROS production by downregulating PRDX3 in U87 cells, thereby promoting oxidative stress-induced autophagy.