Activation of Sirtuin-1 by Pinocembrin Treatment Contributes to Reduced Early Brain Injury after Subarachnoid Hemorrhage.

Subarachnoid hemorrhage (SAH) as a devastating neurological disorder is closely related to heightened oxidative insults and neuroinflammatory injury. Pinocembrin, a bioflavonoid, exhibits different biological functions, such as immunomodulatory, anti-inflammatory, antioxidative, and cerebroprotective activities. Herein, we examined the protective effects and molecular mechanisms of pinocembrin in a murine model of SAH. Using an endovascular perforation model in rats, pinocembrin significantly mitigated SAH-induced neuronal tissue damage, including inflammatory injury and free-radical insults. Meanwhile, pinocembrin improved behavior function and reduced neuronal apoptosis. We also revealed that sirtuin-1 (SIRT1) activation was significantly enhanced by pinocembrin. In addition, pinocembrin treatment evidently enhanced peroxisome proliferator-activated receptor-γ coactivator expression and suppressed ac-nuclear factor-kappa B levels. In contrast, EX-527, a selective SIRT1 inhibitor, blunted the protective effects of pinocembrin against SAH by suppressing SIRT1-mediated signaling. These results suggested that the cerebroprotective actions of pinocembrin after SAH were through SIRT1-dependent pathway, suggesting the potential application of pinocembrin for the treatment of SAH.

Cycloastragenol Confers Cerebral Protection after Subarachnoid Hemorrhage by Suppressing Oxidative Insults and Neuroinflammation via the SIRT1 Signaling Pathway.

Subarachnoid hemorrhage (SAH) is an acute cerebral vascular disease featured by oxidative insults and neuroinflammation. Cycloastragenol (CAG), the major active component of Astragalus radix, has a wide range of biological functions. However, the potential beneficial effects and the underlying molecular mechanisms of CAG on SAH remain obscure. In the current study, the cerebroprotective effects and mechanism of CAG on SAH were evaluated both in vivo and in vitro. Our results indicated that CAG significantly suppressed SAH-triggered oxidative insults, inflammatory mediators production, microglia activation, and the neutrophil infiltration in the brain. In addition, CAG improved neurological function and ameliorated neuronal apoptosis and degeneration after SAH. In vitro results also revealed the therapeutic effects of CAG on neurons and microglia co-culture system. Mechanistically, CAG treatment upregulated sirtuin 1 (SIRT1) expression, inhibited the levels of FoxO1, nuclear factor-kappa B, and p53 acetylation, and suppressed the subsequent oxidative, inflammatory, and apoptotic pathways. In contrast, inhibiting SIRT1 by pretreatment with Ex527 abrogated the protective actions of CAG both in vivo and in vitro models of SAH. Collectively, our findings indicated that CAG could be a promising and effective drug candidate for SAH.

Analysis of the Impact of Medical Features and Risk Prediction of Acute Kidney Injury for Critical Patients Using Temporal Electronic Health Record Data With Attention-Based Neural Network.

Acute kidney injury (AKI) is one of the most severe consequences of kidney injury, and it will also cause or aggravate the complications by the fast decline of kidney excretory function. Accurate AKI prediction, including the AKI case, AKI stage, and AKI onset time interval, can provide adequate support for effective interventions. Besides, discovering how the medical features affect the AKI result may also provide supporting information for disease treatment. An attention-based temporal neural network approach was employed in this study for AKI prediction and for the analysis of the impact of medical features from temporal electronic health record (EHR) data of patients before AKI diagnosis. We used the publicly available dataset provided by the Medical Information Mart for Intensive Care (MIMIC) for model training, validation, and testing, and then the model was applied in clinical practice. The improvement of AKI case prediction is around 5% AUC (area under the receiver operating characteristic curve), and the AUC value of AKI stage prediction on AKI stage 3 is over 82%. We also analyzed the data by two steps: the associations between the medical features and the AKI case (positive or inverse) and the extent of the impact of medical features on AKI prediction result. It shows that features, such as lactate, glucose, creatinine, blood urea nitrogen (BUN), prothrombin time (PT), and partial thromboplastin time (PTT), are positively associated with the AKI case, while there are inverse associations between the AKI case and features such as platelet, hemoglobin, hematocrit, urine, and international normalized ratio (INR). The laboratory test features such as urine, glucose, creatinine, sodium, and blood urea nitrogen and the medication features such as nonsteroidal anti-inflammatory drugs, agents acting on the renin-angiotensin system, and lipid-lowering medication were detected to have higher weights than other features in the proposed model, which may imply that these features have a great impact on the AKI case.

Preliminary study of the consciousness-promotion mechanism of electroacupuncture in comatose patients with diffuse axonal injuries.

BACKGROUND: Diffuse axonal injury (DAI) accounts for 30-40% of total neurotrauma,majority among them manifest with consciousness disturbance.At present, the understanding of the treatment of coma and awakening in patients with DAIs is still limited.This study is characterized by the use of electroacupuncture along with conventional Western medicine to promote consciousness more effectively in comatose patients with DAIs, shorten their time spent in a coma, and gain time for more favorable treatments during follow-up rehabilitation in order to improve the cure rate, reduce the morbidity rate, and achieve better therapeutic effects. METHODS: In this randomized controlled study, 145 comatose patients with DAIs (type III) were divided into the treatment group (n = 71) and control group (n = 74). The patients in the control group were treated with conventional Western medicine, while those in the treatment group were treated with both electroacupuncture and conventional treatment. The Glasgow Coma Scale (GCS) scores and consciousness-promotion rates of both groups were observed before treatment as well as 10, 20, and 30 days after treatment. Meanwhile, serum acetylcholinesterase E (AchE) concentrations in both groups were measured with ELISA, while AchE activity was determined with the rate method. Correlations between GCS score, AchE concentration, and AchE activity in the treatment group were analyzed by using the stepwise multiple regression method. RESULTS: The GCS scores in the treatment group showed significant increases after the first, second, and third courses of treatment when compared to the pre-treatment scores (P <0.05). After 1 course of treatment, the GCS scores in the control group were not statistically significantly different compared to the pre-treatment scores(P >0.05), whereas after 2 and 3 courses of treatment, the differences were of greater statistical significance (P <0.05). Statistically significant differences between the 2 groups were found in GCS scores in the same course of treatment (P <0.05). The consciousness-promotion rates between the 2 groups after the same treatment course were statistically significantly different (P <0.05). Both the standardized regression coefficients and partial correlation coefficients showed that AchE concentration had a certain influence on GCS score (|Beta| = 0.3601; r Y2.1 = 0.726). CONCLUSIONS: Conventional Western medicine combined with electroacupuncture treatment may promote the consciousness of patients with DAIs and shorten the amount of time they spend comatose. Furthermore, the neurotransmitter AchE may play a role in the pathophysiological mechanism of consciousness promotion.

Blockage of miR-485-5p on Cortical Neuronal Apoptosis Induced by Oxygen and Glucose Deprivation/Reoxygenation Through Inactivating MAPK Pathway.

This study is designed to explore the role of miR-485-5p in hypoxia/reoxygenation-induced neuronal injury in primary rat cortical neurons. Hypoxia/reoxygenation model was established through oxygen and glucose deprivation/reoxygenation (OGD/R). RN-c cells were transfected with miR-485-5p mimics, miR-485-5p inhibitors, si-SOX6, pCNDA3.1-SOX6 or miR-485-5p + pCDNA3.1-SOX6, in which cell viability, apoptosis, lactate dehydrogenase (LDH) release rate were assessed. Western blot detected the protein expressions of apoptotic-related proteins (caspase3, Bcl-2, Bax) and the phosphorylated level of ERK1/2. The potential binding sites between miR-485-5p and SOX6 were predicted by STARBASE and identified using dual luciferase reporter gene assay. OGD/R-treated RN-c cell presented increases in apoptosis and LDH release rate as well as a decrease in cell viability. miR-485-5p was downregulated while SOX6 was upregulated in OGD/R-treated RN-c cells. Overexpression of miR-485-5p or SOX6 knockdown rescued cell viability and Bcl-2 expression, while attenuated apoptosis, LDH release rate, expression of SOX6 and the phosphorylated level of ERK1/2. Consistently, miR-485-5p inhibition led to the reverse pattern. Co-transfection of miR-485-5p and SOX6 reversed the protective effect of miR-485-5p on OGD/R-induced neuronal apoptosis. miR-485-5p can directly target SOX6. Together, miR-485-5p inhibited SOX6 to alleviate OGD/R-induced apoptosis. Collectively, miR-485-5p protects primary cortical neurons against hypoxia injury through downregulating SOX6 and inhibiting MAPK pathway.

Long non-coding RNA MALAT1 promotes neuronal apoptosis during spinal cord injury through miR-199a-5p/PRDM5 axis.

AIM: This study aimed to determine the regulation of long non-coding RNA (lncRNA) MALAT1 on neuronal apoptosis during spinal cord injury (SCI) and to explore its possible mechanisms. MATERIAL AND METHODS: The motor ability of SCI rat models and apoptosis in spinal cord tissue were evaluated. Primary spinal cord neurons (SCNs) were isolated and treated with H2O2 before cell transfection. The apoptosis of SCNs and expression of PRDM5 and MALAT1 were also measured. The interactions among MALAT1, miR-199a-5p, and PRDM5 were detected. RESULTS: The motor ability of SCI rats decreased significantly. The proportion of apoptotic neurons increased in damaged tissue and SCN, along with an increase in the expression of apoptosis-related proteins c-caspase-3/9, autophagy-related proteins (p62 and LC3 II/I ratio), and proinflammatory factors. Moreover, overexpression of MALAT1 and PRDM5 in damaged SCN resulted in an increased apoptosis rate of neurons, elevated expression of apoptosis-related proteins, and upregulated levels of inflammatory factors. However, miR-199a-5p overexpression/PRDM5 knockdown partially counteracted the effects of MALAT1 overexpression on H2O2-induced SCNs. In addition, MALAT1 negatively regulated miR-199a-5p, which targeted PRDM5. CONCLUSION: LncRNA MALAT1 promotes neuronal apoptosis during SCI by regulating the miR-199a-5p/PRDM5 axis.

KLF16 suppresses human glioma cell proliferation and tumourigenicity by targeting TFAM.

BACKGROUND: This study aims to via unveiling the novel mechanisms of KLF16 in regulating expression of genes involved in glioma. METHODS: KLF16 or KLF16-siRNA was transfected to U87MG cells by lentivirus. Colony formation assay was applied for detecting cell proliferation. MTT assay was adopted to assess cell viability. TUNEL assay was selected to evaluate cell apoptosis. Flow cytometry was used to determine cell cycle. Real-time PCR was performed to test mRNA expression. Western blot was used to detect protein level. Luciferase assay was applied to confirm the regulatory relationship between KLF16 and Mitochondrial transcription factor A (TFAM). Chromatin immunoprecipitation was adopted to test the protein binding site. The nude mouse transplantation tumour experiment was selected to test cancer cell proliferation in vivo. RESULTS: KLF16 was decreased in glioma cells and tissues. KLF16 obviously restrained U87MG cell proliferation both in vivo and in vitro. KLF16 transfection reduced mRNA and protein levels related to cell proliferation. KLF16 targeted a putative binding site near the transcription start sites (TSSs) of TFAM gene, thus suppressing glioma cell proliferation. KLF16-siRNA exhibited the opposite impact. KLF16 presented significant negative correlation with TFAM level in glioma patients. CONCLUSIONS: KLF16 is a key regulator of glioma cell proliferation by directly targeting TFAM.

Letter regarding Xiao WZ et al. entitled "Relationships between PTEN gene mutations and prognosis in glioma: a meta-analysis".

With great interest, we read the article "Relationships between PTEN gene mutations and prognosis in glioma: a meta-analysis" (by Xiao et al. Tumor Biol 35(7):6687-6693, 2014), which has reached important conclusions that the phosphatase and tensin homolog (PTEN) gene mutations were closely related to poor prognosis of glioma patients. Through quantitative analysis, the investigators (Xiao WZ et al.) showed that glioma patients with PTEN gene mutations exhibited a significantly shorter overall survival (OS) than those without PTEN gene mutations (HR = 3.66, 95 % CI = 2.02∼5.30, P < 0.001). Ethnicity-stratified subgroup analysis demonstrated that PTEN gene mutations were closely linked to poor prognosis in glioma among Americans (HR = 3.72, 95 % CI = 1.72∼5.73, P < 0.001), while similar correlations were not observed among populations in Sweden, Italy, and Malaysia (all P > 0.05). The meta-analysis results are encouraging. Nevertheless, some deficiencies still existed that we would like to raise.

Aripiprazole-associated tic in a schizophrenia patient.

Tic disorder, characterized by the presence of both motor and vocal tics is common in adolescents and adults. Antipsychotics including typical antipsychotics and atypical antipsychotics are generally recognized by experts as the most effective pharmacological treatment for tics. However, previous studies suggest that tic-like symptoms might manifest during treatment with atypical antipsychotics such as clozapine, quetiapine, but not aripiprazole. We present the first case, to our knowledge, of an adult schizophrenia patient who developed tics during treatment with aripiprazole.

Solitary skull metastasis as the first symptom of hepatocellular carcinoma: case report and literature review.

Skull metastasis from hepatocellular carcinoma (HCC) is reported rarely. In addition, solitary skull metastasis as the first symptom of HCC is reported even less. Here, we reported a case of solitary skull metastasis as the first symptom of HCC and reviewed the literature on skull metastasis. A 49-year-old male patient was admitted to Jinjiang Hospital of Quanzhou Medical College with a painless parietal-occipital scalp mass, and he denied any history of hepatic disease. A cranial computed tomography demonstrated a hypervascular enhancement with osteolytic change in the right parietal-occipital region, cranial magnetic resonance imaging indicated a highly enhanced and osteolytic skull tumor, and abdominal computed tomography showed a huge tumor in the liver. The other examinations showed no other metastases. Laboratory data showed no liver dysfunction while hepatitis B surface antigen was positive, and alpha fetal protein level was high. A craniectomy was performed and the mass was totally removed. The histological diagnosis was skull metastasis from HCC. The patient was subsequently treated by transcatheter arterial chemoembolization. In a review of published literature, the incidence of skull metastasis from HCC in the period between 1990 and 2011 has significantly increased. The misdiagnosis rate of skull metastases as the first symptom from HCC was high. Therefore, it is necessary to give each patient with a scalp mass that has invaded the skull a liver ultrasound or computed tomography scan. On the other hand, we found that metastases that occurred in the calvaria site were more frequent than those that occurred in the skull base and facial skeleton. This may be worthy of further investigation in the future.