Association between red blood cell distribution width-to-albumin ratio and the prognosis in patients with autoimmune encephalitis: a retrospective cohort study.

Aim: Red blood cell distribution width-to-albumin ratio (RAR) is a combined new indicator reflecting immunology and has been reported to predict the prognosis of inflammation-related diseases and brain diseases. However, the association and predictive value of RAR in the prognosis of patients with autoimmune encephalitis (AE) has not been reported. Methods: This was a retrospective cohort study, and data were collected from the Henan Provincial People's Hospital. RAR was categorized according to quartile. The prognosis was assessed using the modified Rankin Scale (mRS), and an mRS score of ≥3 was defined as a poor prognosis. The logistical regression model was used to explore the association between RAR and the prognosis, with results reported as odds ratio (OR) and 95% confidence interval (CI). The predictive value of RAR was evaluated by calculating the area under the receiving operating curve (AUC), sensitivity, specificity, and accuracy. Results: A total of 175 eligible patients were included for analysis, and 51 patients were identified as having poor prognosis. After adjusting age, cancer, other diseases, histological subtype, antiepileptic therapy, anti-tumor treatment, ICU treatment, and length of stay, RAR in the highest quartile (Q4) was found to be significantly associated with the high odds of poor prognosis (OR = 5.63, 95%CI: 1.98-16.02) compared to RAR in the lowest quartile (Q1). In addition, RAR was identified as a predictor for the prognosis of AE patients (AUC = 0.660, 95%CI: 0.574-0.746). Conclusion: This study found the close association and predictive value of RAR for the prognosis of AE patients, indicating that RAR might help clinicians identify high-risk populations.

Buyang Huanwu Decoction: A Traditional Chinese Medicine, Promotes Lactate-Induced Angiogenesis in Experimental Intracerebral Hemorrhage.

Identifying the underlying mechanisms and exploring effective therapies for intracerebral hemorrhage (ICH) are urgently needed. Here, we aim to elucidate the potential roles and underlying mechanisms of Buyang Huanwu decoction (BYHWD) in ICH. In the first set of experiments, rats were randomly divided into five groups: Sham, ICH, ICH + sodium oxamate (OXA), ICH + BYHWD, and ICH + BYHWD + OXA. The lactate level around the hematoma was evaluated. PCNA+/vWF+ nuclei were observed. Additionally, an online bioinformatics analysis tool was used to predict the BYHWD druggable targets related to angiogenesis. Then, we validated these predictions. In the second set, exogenous sodium L-lactate (Lac) was infused into the intact brains of rats. Rats were randomly divided into three groups: Sham, Lac, and Lac + YC-1. The numbers of PCNA+/vWF+ nuclei and the expression of HIF-1α and VEGF were evaluated. In the first set of experiments, compared with the ICH group, the BYHWD group exhibited significantly increased numbers of PCNA+/vWF+ nuclei, and neurological dysfunction was markedly improved. Bioinformatics analysis revealed that the improvements caused by BYHWD indicated a role for the HIF-1α pathway. The HIF-1α and VEGF protein levels were upregulated after BYHWD administration. Moreover, we verified that lactate was involved in the predicted mechanisms. In the second set, lactate facilitated angiogenesis and HIF-1α and VEGF expression. Co-infusion with a HIF-1α inhibitor, YC-1, significantly inhibited these effects. Our data suggest that the pharmacological effects of BYHWD involve lactate-induced angiogenesis, these data may provide new evidence for its use in ICH.

Temporal profile of angiogenesis and expression of extracellular matrix-related genes in rat brains following experimental intracerebral hemorrhage.

BACKGROUND: Angiogenesis is essential for the repair process after intracerebral hemorrhage (ICH). METHODS: Given the importance of the extracellular matrix (ECM) in angiogenesis, we analysed the temporal profile of angiogenesis in rat brains on days 4, 7, and 21 after ICH. To this end, we compared the expression of ECM-related genes between ICH-induced and sham-operated groups using a complementary DNA (cDNA) array. We further measured protein expression using western blot and immunohistochemistry assays. Fluorescein isothiocyanate (FITC)-dextran was injected into the tail vein to examine the angioarchitecture in the perihematomal region. RESULTS: Among the 88 ECM-related genes, we identified 42, 50, and 38 genes that were significantly upregulated on days 4, 7, and 21 after ICH, respectively (P < 0.05). Particularly, collagens, integrins, and matrix metalloproteinases (MMPs) were significantly increased on day 4 post-ICH and continued to increase at the other time points. Western blot and immunohistochemistry analyses showed a comparable trend in the upregulation of MMPs. Compared to the sham group, FITC-dextran labelling demonstrated decreased perfusion and increased vascular permeability in the perihematomal region in the ICH group. Doxycycline, an MMP inhibitor, significantly reduced angiogenesis (P < 0.05). CONCLUSIONS: The results of this study indicate that MMPs are involved in modulating angiogenesis following ICH.

BYHWD Alleviates Inflammatory Response by NIK-Mediated Repression of the Noncanonical NF-κB Pathway During ICH Recovery.

Intracerebral hemorrhage (ICH) is a life-threatening type of stroke that lacks effective treatments. The inflammatory response following ICH is a vital response that affects brain repair and organism recovery. The nuclear factor κB (NF-κB) signaling pathway is considered one of the most important inflammatory response pathways and one of its response pathways, the noncanonical NF-κB signaling pathway, is known to be associated with persistent effect and chronic inflammation. NF-κB-inducing kinase (NIK) via the noncanonical NF-κB signaling plays a key role in controlling inflammation. Here, we investigated potential effects of the traditional Chinese medicine formula Buyang Huanwu Decoction (BYHWD) on inflammatory response in a rat model of ICH recovery by inhibiting the NIK-mediated the noncanonical NF-κB signaling pathway. In the first part, rats were randomly divided into three groups: the sham group, the ICH group, and the BYHWD group. ICH was induced in rats by injecting collagenase (type VII) into the right globus pallidus of rats' brain. For the BYHWD group, rats were administered BYHWD (4.36 g/kg) once a day by intragastric administration until they were sacrificed. Neurological function was evaluated in rats by a modified neurological severity score (mNSS), the corner turn test, and the foot-fault test. The cerebral edema showed the degree of inflammatory response by sacrificed brain water content. Western blot and real-time quantitative reverse transcription PCR tested the activity of inflammatory response and noncanonical NF-κB signaling. In the second part, siRNA treatment and assessment of inflammation level as well as alterations in the noncanonical NF-κB signaling were performed to determine whether the effect of BYHWD on inflammatory response was mediated by suppression of NIK via the noncanonical NF-κB signaling pathway. We show that BYHWD treated rats exhibited: (i) better health conditions and better neural functional recovery; (ii) decreased inflammatory cytokine and the edema; (iii) reduced expression of NIK, a key protein in unregulated the noncanonical NF-κB signaling pathways; (iv) when compared with pretreated rats with NIK targeting (NIK siRNAs), showed the same effect of inhibiting the pathway and decreased inflammatory cytokine. BYHWD can attenuate the inflammatory response during ICH recovery in rats by inhibiting the NIK-mediated noncanonical NF-κB signaling pathway.

Integrative analysis of transcriptomes highlights potential functions of transfer-RNA-derived small RNAs in experimental intracerebral hemorrhage.

Transfer-RNA-derived small RNAs (tsRNAs) are a novel class of short non-coding RNAs, that possess regulatory functions. However, their biological roles in hemorrhagic stroke are not understood. In this study, by RNA sequencing, we investigated the tsRNA expression profiles of intracerebral hemorrhagic rat brains in the chronic phase. A total of 331 tsRNAs were identified (308 in sham and 309 in intracerebral hemorrhage). Among them, the validation revealed that 7 tsRNAs (1 up-regulated and 6 down-regulated) were significantly changed. Subsequently, we predicted the target mRNAs of the 7 tsRNAs. Through integrative analysis, the predicted targets were validated by mRNA microarray data. Moreover, we confirmed the functions of tsRNAs targeting mRNAs in vitro. Furthermore, using bioinformatics tools and databases, we developed a tsRNA-mRNA-pathway interaction network to visualize their potential functions. Bioinformatics analyses and confirmatory experiments indicated that the altered genes were mainly enriched in several signaling pathways. These pathways were interrelated with intracerebral hemorrhage, such as response to oxidative stress, endocytosis, and regulation of G protein-coupled receptor signaling pathway. In summary, this study systematically revealed the profiles of tsRNAs after an experimental intracerebral hemorrhage. These results may provide novel therapeutic targets following a hemorrhagic stroke in the chronic phase.

Mechanism of delayed encephalopathy after acute carbon monoxide poisoning.

Many hypotheses exist regarding the mechanism underlying delayed encephalopathy after acute carbon monoxide poisoning (DEACMP), including the inflammation and immune-mediated damage hypothesis and the cellular apoptosis and direct neuronal toxicity hypothesis; however, no existing hypothesis provides a satisfactory explanation for the complex clinical processes observed in DEACMP. Leucine-rich repeat and immunoglobulin-like domain-containing protein-1 (LINGO-1) activates the Ras homolog gene family member A (RhoA)/Rho-associated coiled-coil containing protein kinase 2 (ROCK2) signaling pathway, which negatively regulates oligodendrocyte myelination, axonal growth, and neuronal survival, causing myelin damage and participating in the pathophysiological processes associated with many central nervous system diseases. However, whether LINGO-1 is involved in DEACMP remains unclear. A DEACMP model was established in rats by allowing them to inhale 1000 ppm carbon monoxide gas for 40 minutes, followed by 3000 ppm carbon monoxide gas for an additional 20 minutes. The results showed that compared with control rats, DEACMP rats showed significantly increased water maze latency and increased protein and mRNA expression levels of LINGO-1, RhoA, and ROCK2 in the brain. Compared with normal rats, significant increases in injured neurons in the hippocampus and myelin sheath damage in the lateral geniculate body were observed in DEACMP rats. From days 1 to 21 after DEACMP, the intraperitoneal injection of retinoic acid (10 mg/kg), which can inhibit LINGO-1 expression, was able to improve the above changes observed in the DEACMP model. Therefore, the overexpression of LINGO-1 appeared to increase following carbon monoxide poisoning, activating the RhoA/ROCK2 signaling pathway, which may be an important pathophysiological mechanism underlying DEACMP. This study was reviewed and approved by the Medical Ethics Committee of Xiangya Hospital of Central South Hospital (approval No. 201612684) on December 26, 2016.

Thrombin-induced miRNA-24-1-5p upregulation promotes angiogenesis by targeting prolyl hydroxylase domain 1 in intracerebral hemorrhagic rats.

OBJECTIVE: Thrombin is a unique factor that triggers post-intracerebral hemorrhage (ICH) angiogenesis by increasing hypoxia-inducible factor-1α (HIF-1α) at the protein level. However, HIF-1α mRNA remains unchanged. MicroRNAs (miRNAs) mediate posttranscriptional regulation by suppressing protein translation from mRNAs. This study aimed to determine if miRNAs might be involved in thrombin-induced angiogenesis after ICH by targeting HIF-1α or its upstream prolyl hydroxylase domains (PHDs). METHODS: The study was divided into two parts. In part 1, rats received an injection of thrombin into the right globus pallidus. An miRNA array combined with miRNA target prediction, luciferase activity assay, and miRNA mimic/inhibitor transfection were used to identify candidate miRNAs and target genes. Part 2 included experiments 1 and 2. In experiment 1, rats were randomly divided into the sham group, ICH group, and ICH+hirudin-treated (thrombin inhibitor) group. In experiment 2, the rats were randomly divided into the sham group, ICH group, ICH+antagomir group, ICH+antagomir-control group, and ICH+vehicle group. Western blotting and quantitative real-time polymerase chain reaction were used to determine the expression of protein and miRNA, respectively. The coexpression of miR-24-1-5p (abbreviated to miR-24) and von Willebrand factor was detected by in situ hybridization and immunohistochemical analysis. The angiogenesis was evaluated by double-labeling immunofluorescence. Neurological function was evaluated by body weight, modified Neurological Severity Scores, and corner turn and foot-fault tests. RESULTS: In part 1, it was shown that miR-24, which is predicted to target PHD1, was upregulated (fold-change of 1.83) after thrombin infusion, and that the miR-24 mimic transfection decreased luciferase activity and downregulated PHD1 expression (p < 0.05). miR-24 inhibitor transfection increased PHD1 expression (p < 0.05). In part 2, it was shown that miR-24 was expressed in endothelial cells. The HIF-1α protein level and proliferating cell nuclear antigen-positive (PCNA+) nuclei in vessels were increased, while the PHD1 protein level was decreased after ICH, and these effects were reversed by hirudin (p < 0.05). The antagomiR-24-treated rats exhibited a markedly lower body weight and significantly poorer recovery from neurological deficit compared with those in ICH groups (p < 0.05). AntagomiR-24 intervention also led to lower miR-24 expression, a higher PHD1 protein level, and fewer PCNA+ nuclei in vessels compared with those in ICH groups (p < 0.05). CONCLUSIONS: The present study suggests that thrombin reduces HIF-1α degradation and initiates angiogenesis by increasing miR-24, which targets PHD1 after ICH.

Systematic Analysis of tRNA-Derived Small RNAs Reveals Novel Potential Therapeutic Targets of Traditional Chinese Medicine (Buyang-Huanwu-Decoction) on Intracerebral Hemorrhage.

Although Buyang-Huanwu-Decoction (BYHWD), a famous traditional Chinese medicine, has been utilized to promote the recovery of neurological function in intracerebral hemorrhage (ICH) for centuries, its therapeutic mechanisms remain unclear. tRNA-derived small RNA (tsRNA) is a novel class of short non-coding RNA, possessing potential regulating functions. In the current study, we explored the novel therapeutic targets of BYHWD by tsRNA-sequencing. Rats were randomly divided into three groups: sham, ICH, and BYHWD-treated groups. The modified neurological severity score, corner turn test, foot-fault test, and weight change were used to assess neurological injury. After BYHWD treatment, these behavioral tests were obviously meliorated compared with ICH group in the recovery phase. In the rat brain tissues surrounding the hemorrhagic region, a total of 350 tsRNAs for exact match were identified. 12 of tRNAs (fold change >1.3 and P-value <0.05) were significantly changed in ICH group compared to sham group. Among them, 3 of tRNAs (rno-tRFi-Ser-25a, rno-tRF5-Ala-16a and rno-tRF5-Glu-29a) were markedly regulated by BYHWD treatment and validated with quantitative real-time PCR. Additionally, target prediction and bioinformatics analyses revealed that these tsRNAs could play therapeutic roles through FoxO signaling pathway, positive regulation of long term synaptic depression, autophagy - animal, IL-17 signaling pathway and regulation of cytoskeleton and transforming growth factor beta. In conclusion, tsRNAs are the potential therapeutic targets of BYHWD on ICH treatment. The present study provides novel insights for future investigations to explore the mechanisms, by which BYHWD promotes neurological function recovery after ICH.

Thrombin promotes pericyte coverage by Tie2 activation in a rat model of intracerebral hemorrhage.

Pericyte coverage on the endothelial tubes leads to the formation of a mature and stable microvessel system, which is critical for brain repair after intracerebral hemorrhage (ICH). We report herein that thrombin promotes pericyte coverage by activating Tie2 and the downstream signaling pathway PI3K/Akt in a rat model of ICH. ICH was induced by injection of autologous blood with or without thrombin inhibitor hirudin. Rats were treated with thrombin alone or in combination with a Tie2 inhibitor. The expression of total- and phospho-Tie2, PI3K and phospho-Akt, blood perfusion, pericyte coverage, IgG extravasation, neuron survival and neurological deficits were evaluated by western blot, fluorescein-5-isothiocyanate-dextran staining, immunohistochemistry, Nissl staining and modified neurological severity scores respectively. Induction of ICH resulted in increased phosphorylation of Tie2 on endothelial cells and pericyte coverage, better formation of integral and functional microvessels, more surviving neurons and accelerated motor function recovery, all of which were significantly attenuated by hirudin at 7 and 14 days after ICH induction. Furthermore, thrombin increased phosphorylation of Tie2 and Akt, expression of PI3K, and pericyte coverage, which were however reversed by pharmacological inhibition of Tie2. Our results demonstrated that thrombin promotes pericyte coverage on microvessels following ICH by enhancing activation of Tie2, in which the downstream PI3K/Akt signaling pathway might be involved.

Lactate potentiates angiogenesis and neurogenesis in experimental intracerebral hemorrhage.

Lactate accumulation has been observed in the brain with intracerebral hemorrhage (ICH). However, the outcome of lactate accumulation has not been well characterized. Here, we report that lactate accumulation contributes to angiogenesis and neurogenesis in ICH. In the first set of the experiment,  a rat model of ICH was induced by injecting collagenase into the brain. The effects of lactate accumulation on the neurological function, apoptosis, and numbers of newborn endothelial cells and neurons, as well as the proliferation-associated signaling pathway, were evaluated in the rat brain.  In the second set, exogenous L-lactate was infused into intact rat brains so that its effects could be further assessed. Following ICH, lactate accumulated around the hematoma; the numbers of PCNA+/vWF+ nuclei and PCNA+/DCX+ cells were significantly increased compared with the numbers in the Sham group. Moreover, ICH induced translocation of nuclear factor-kappa B (NF-κB) p65 into the nucleus, resulting in a notable upregulation of VEGF and bFGF mRNAs and proteins compared with the levels in the Sham controls. Administration of a lactate dehydrogenase inhibitor dramatically inhibited these effects, decreased the vascular density, and aggravated neurological severity scores and apoptosis after ICH. After exogenous L-lactate infusion, the numbers of PCNA+/vWF+ nuclei and PCNA+/DCX+ cells were strikingly increased compared with the numbers in the Sham controls. In addition, lactate facilitated NF-κB translocation to induce increased transcription of VEGF and bFGF. Co-infusion with an NF-κB inhibitor significantly inhibited these effects. These data suggest that lactate potentiates angiogenesis and neurogenesis by activating the NF-κB signaling pathway following ICH.

Astragaloside IV Improves Vasodilatation Function by Regulating the PI3K/Akt/eNOS Signaling Pathway in Rat Aorta Endothelial Cells.

Coronary heart disease (CHD) remains a major public health burden. Endothelial-dependent coronary artery vasoreactivity is a significant indicator of vascular function. Endothelial dysfunction is characterized by decreased nitric oxide (NO) bioavailability and predicts late cardiovascular events. Astragaloside IV (AGIV) is the main active component of the herb Astragalus membranaceus. Although it shows a significant protective effect against vascular endothelial dysfunction, the mechanisms of AGIV promoting the vascular dilation have not been elucidated. This study investigated the vasodilator effect of AGIV on rat aortic rings and the underlying effect of AGIV via the PI3K/Akt/eNOS signaling pathway. We measured the relaxation of isolated RARs after different concentrations of AGIV treatment. Rat aorta endothelial cells were cultured with different doses of AGIV, dimethylsulfoxide, and NG-nitro L-arginine methyl ester. The expression of phosphorylated (p)-Akt and -endothelial nitric oxide synthase (p-eNOS) were tested by Western blot analysis. The messenger (m)RNA expression of eNOS was quantified by real-time polymerase chain reaction. AGIV exerted a vasodilator effect on the aortic rings and increased the NO content in a concentration-dependent manner. The vasorelaxation was suppressed by an eNOS inhibitor. AGIV regulated the PI3K/Akt/eNOS signaling pathway via phosphorylation of Akt at Ser473 and dephosphorylation of eNOS at Thr495. The mRNA expression of eNOS was remarkably upregulated by AGIV. AGIV significantly induced the dilation of the aortic rings, leading to the vasodilator response by enhancing the eNOS release via the PI3K/Akt/eNOS signaling pathway.

An Intersectional Study of LncRNAs and mRNAs Reveals the Potential Therapeutic Targets of Buyang Huanwu Decoction in Experimental Intracerebral Hemorrhage.

BACKGROUND/AIMS: Both experimental and clinical studies have revealed satisfactory effects of the traditional Chinese formula Buyang Huanwu decoction (BYHWD) in improving post-intracerebral hemorrhage (ICH) neurological deficiencies. However, the multifaceted mechanisms of BYHWD in ICH treatment are not comprehensively understood. The present study explored various therapeutic targets of BYHWD by using lncRNA and mRNA transcriptomics. METHODS: LncRNA and mRNA microarrays were used to identify differentially expressed genes. ICH-induced upregulated genes (ICH vs sham) and BYHWD-induced downregulated genes (BYHWD vs ICH) were first identified. The intersection between these 2 sets was determined to identify ICH-induced highly expressed genes that were reversed by BYHWD. Then, the genes downregulated after ICH and the genes upregulated after BYHWD treatment were used to generate another set of intersections. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses were subsequently performed to determine relative biological functions and signaling transduction pathways according to genes within the intersections. Quantitative real-time PCR was used to validate changes in gene expression observed using the microarray. Finally, a lncRNA-mRNA co-expression network was established to identify links among the genes within the intersections. RESULTS: A total of 18 differentially expressed lncRNAs and 33 differentially expressed mRNAs were identified using 2 lncRNA arrays (ICH vs sham and BYHWD vs ICH). The altered genes were enriched in the hemoglobin complex, oxygen transport and oxygen transporter and were closely associated with pyruvate metabolism. The co-expression network consisted of 53 nodes and 595 connections (308 positive interactions and 287 negative interactions). CONCLUSION: The hemoglobin complex, oxygen transport, oxygen transporter activity and pyruvate metabolism are possible therapeutic targets of BYHWD in ICH treatment. The present study provides the basis and direction for future investigations to explore the mechanisms by which BYHWD protects against long-term neurological deficiencies after ICH.

Activation of the Notch-1 signaling pathway may be involved in intracerebral hemorrhage-induced reactive astrogliosis in rats.

OBJECTIVE Reactive astrogliosis, a key feature that is characterized by glial proliferation, has been observed in rat brains after intracerebral hemorrhage (ICH). However, the mechanisms that control reactive astrogliosis formation remain unknown. Notch-1 signaling plays a critical role in modulating reactive astrogliosis. The purpose of this paper was to establish whether Notch-1 signaling is involved in reactive astrogliosis after ICH. METHODS ICH was induced in adult male Sprague-Dawley rats via stereotactic injection of autologous blood into the right globus pallidus. N-[ N-(3,5-difluorophenacetyl)-l-alanyl]- S-phenylglycine t-butyl ester (DAPT) was injected into the lateral ventricle to block Notch-1 signaling. The rats' brains were perfused to identify proliferating cell nuclear antigen (PCNA)-positive/GFAP-positive nuclei. The expression of GFAP, Notch-1, and the activated form of Notch-1 (Notch intracellular domain [NICD]) and its ligand Jagged-1 was assessed using immunohistochemical and Western blot analyses, respectively. RESULTS Notch-1 signaling was upregulated and activated after ICH as confirmed by an increase in the expression of Notch-1 and NICD and its ligand Jagged-1. Remarkably, blockade of Notch-1 signaling with the specific inhibitor DAPT suppressed astrocytic proliferation and GFAP levels caused by ICH. In addition, DAPT improved neurological outcome after ICH. CONCLUSIONS Notch-1 signaling is a critical regulator of ICH-induced reactive astrogliosis, and its blockage may be a potential therapeutic strategy for hemorrhagic injury.

Xuefu zhuyu decoction improves cognitive impairment in experimental traumatic brain injury via synaptic regulation.

An overarching consequence of traumatic brain injury (TBI) is the cognitive impairment. It may hinder individual performance of daily tasks and determine people's subjective well-being. The damage to synaptic plasticity, one of the key mechanisms of cognitive dysfunction, becomes the potential therapeutic strategy of TBI. In this study, we aimed to investigate whether Xuefu Zhuyu Decoction (XFZYD), a traditional Chinese medicine, provided a synaptic regulation to improve cognitive disorder following TBI. Morris water maze and modified neurological severity scores were performed to assess the neurological and cognitive abilities. The PubChem Compound IDs of the major compounds of XFZYD were submitted into BATMAN-TCM, an online bioinformatics analysis tool, to predict the druggable targets related to synaptic function. Furthermore, we validated the prediction through immunohistochemical, RT-PCR and western blot analyses. We found that XFZYD enhanced neuroprotection, simultaneously improved learning and memory performances in controlled cortical impact rats. Bioinformatics analysis revealed that the improvements of XFZYD implied the Long-term potentiation relative proteins including NMDAR1, CaMKII and GAP-43. The further confirmation of molecular biological studies confirmed that XFZYD upregulated the mRNA and protein levels of NMDAR1, CaMKII and GAP-43. Pharmacological synaptic regulation of XFZYD could provide a novel therapeutic strategy for cognitive impairment following TBI.

Hyperbaric oxygen for experimental intracerebral haemorrhage: Systematic review and stratified meta-analysis.

OBJECTIVE: Hyperbaric oxygen (HBO) is widely used in treating various neurological diseases. However, HBO for treatment of intracerebral haemorrhage (ICH) remains controversial, in either animal or clinical studies. Therefore, we conducted this systematic review and meta-analysis on studies describing the efficacy of HBO in animal models of ICH. METHODS: Studies were identified by searching mainstream databases through November 2015. The efficacy of HBO in animal models of ICH was assessed by changes in the brain water content (BWC), neurobehavioural outcome (NO) or both. Subgroup analyses were performed according to different design characteristics. RESULTS: In total 15 studies met our inclusion criteria. HBO can reduce the BWC (-0.982, 95% CI, -1.148 to -0.817; P < 0.01; 57 comparisons), and improve NO (-0.767, 95% CI, -1.376 to -0.159; P < 0.01; eight comparisons). HBO was most effective in reducing BWC when given 72 h after ICH for a 4- to 5-day consecutive treatment at the chamber pressure of 3.0 atmosphere absolute. Efficacy was higher with phenobarbital anaesthesia, the blood infusion model and in rabbits. CONCLUSION: Although HBO was found to be effective in experimental ICH, additional confirmation is needed due to possible publication bias, poor study quality and the limited number of studies conducting clinical trials.

Is the Chinese medicinal formula Guipi Decoction () effective as an adjunctive treatment for depression? A meta-analysis of randomized controlled trials.

OBJECTIVES: To evaluate the effectiveness and safety of Guipi Decoction (, GPD) as an adjunctive in the treatment of depression. METHODS: A review of all relevant studies retrieved from a search of the following databases were conducted without any language restriction: Excerpt Medica Database (EMBASE), PubMed, Cochrane Central Register of Controlled Trials, China National Knowledge Infrastructure (CNKI), VIP Information, Wanfang Data, and the Chinese Biomedical Literature Database. Papers published until February 2013 were taken into consideration. The analysis was performed using the Cochrane software Revman 5.1. RESULTS: Nine randomized controlled trials involving 620 patients with depression were included in this review. The meta-analysis revealed that compared with antidepressant therapy alone, treatment with a combination of GPD and an antidepressant drug signifificantly improved the symptoms of depression [weighted mean difference (WMD):-3.09; 95% confifidence interval (CI):-4.11 to-2.07] and increased the rates of effectiveness (OR: 4.75; 95% CI: 2.66-8.51) as well as recovery (OR: 1.73; 95% CI: 1.17-2.56). The adverse effects of GPD were not found to be signifificant in these studies. CONCLUSIONS: The fifindings of this meta-analysis were in keeping with the notion that GPD formulations were effective in the treatment of depression without causing any serious adverse effects. However, currently available evidence was of low quality and therefore inadequate to justify a strong recommendation of using GPD formulations in the management of depression.

Leukemia Inhibitory Factor Contributes to Reactive Astrogliosis via Activation of Signal Transducer and Activator of Transcription 3 Signaling after Intracerebral Hemorrhage in Rats.

Reactive astrogliosis has occurred after intracerebral hemorrhage (ICH). Leukemia inhibitory factor (LIF) can act as a modulator for glial gene expression. Signal transducer and activator of transcription 3 (STAT3) is a critical regulator of reactive astrogliosis. The present study tested whether endogenous LIF acted on ICH-induced reactive astrogliosis via the STAT3 signaling pathway. Rats were divided into three experimental groups: 1) Rats received either an ICH or a needle insertion (sham), 2) Rats received 100 ng LIF or an equal volume of phosphate-buffered saline (PBS) by direct infusion into the lateral ventricle (LV) after ICH, and 3) AG490 (0.25 mg/kg) was injected into the LV to block STAT3 signaling. Brains were perfused to identify proliferating cell nuclear antigen (PCNA)+/glial fibrillary acidic protein (GFAP)+nuclei. The expression of GFAP, LIF, LIF receptor (LIFR), glycoprotein 130 (gp130), and phospho-STAT3 (p-STAT3) was evaluated by immunohistochemistry and Western blot, respectively. After ICH, the number of the PCNA+/GFAP+ nuclei and the expression of GFAP, LIF, LIFR, gp130, and p-STAT3 were increased. Moreover, LIF increased the number of PCNA+/GFAP+ nuclei and the expression of GFAP, LIFR, gp130, and p-STAT3. The number of PCNA+/ GFAP+ nuclei and GFAP protein levels were attenuated markedly after inhibition of p-STAT3. Together, these data suggest that LIF contributes to ICH-related reactive astrogliosis via activation of STAT3 signaling.

Efficacy of deferoxamine in animal models of intracerebral hemorrhage: a systematic review and stratified meta-analysis.

Intracerebral hemorrhage (ICH) is a subtype of stroke associated with high morbidity and mortality rates. No proven treatments are available for this condition. Iron-mediated free radical injury is associated with secondary damage following ICH. Deferoxamine (DFX), a ferric-iron chelator, is a candidate drug for the treatment of ICH. We performed a systematic review of studies involving the administration of DFX following ICH. In total, 20 studies were identified that described the efficacy of DFX in animal models of ICH and assessed changes in the brain water content, neurobehavioral score, or both. DFX reduced the brain water content by 85.7% in animal models of ICH (-0.86, 95% CI: -.48- -0.23; P < 0.01; 23 comparisons), and improved the neurobehavioral score by -1.08 (95% CI: -1.23- -0.92; P < 0.01; 62 comparisons). DFX was most efficacious when administered 2-4 h after ICH at a dose of 10-50 mg/kg depending on species, and this beneficial effect remained for up to 24 h postinjury. The efficacy was higher with phenobarbital anesthesia, intramuscular injection, and lysed erythrocyte infusion, and in Fischer 344 rats or aged animals. Overall, although DFX was found to be effective in experimental ICH, additional confirmation is needed due to possible publication bias, poor study quality, and the limited number of studies conducting clinical trials.

Buyang huanwu decoction promotes angiogenesis via vascular endothelial growth factor receptor-2 activation through the PI3K/Akt pathway in a mouse model of intracerebral hemorrhage.

BACKGROUND: Intracerebral hemorrhage (ICH) is a fatal subtype of stroke that lacks effective treatments. Angiogenesis following ICH is an important response mediating brain recovery and repair. Phosphorylation of vascular endothelial growth factor receptor 2 (pVEGFR2) via PI3K/Akt signaling plays a key role in mediating cellular processes involved in repair, such as mitogenesis, angiogenesis, and vascular permeability. This study aimed to investigate the potential effects of Buyang Huanwu Decoction (BYHWD), a traditional Chinese medicine formula, on angiogenesis by VEGFR2 activation through the phosphatidylinositol 3 kinase (PI3K)/Akt signaling pathway in a mouse model of ICH. METHODS: Adult male Kunming mice (n = 50) were randomly assigned into sham and ICH-operated groups and treated with one of the followings SU5416 (VEGFR2 inhibitor), BYHWT and BYHWT + SU5416. ICH was induced in mice by injecting collagenase (type VII) into the right globus pallidus of the mouse brain. BYHWD (4.36 g/kg) was administrated in mice by intragastric infusion. Neurological function was evaluated in mice by a modified Neurological Severity Scores (mNSS) as well as corner turn and foot-fault tests. Angiogenesis was examined by intraperitoneal injection of 5-bromodeoxyuridine (BrdU) in mice to quantify new brain vessel growth. SU5416 treatment and assessment of VEGFR2 phosphorylation as well as alterations in PI3K/Akt signaling were performed to determine whether the effect of BYHWD on angiogenesis was partly mediated by phosphorylation of VEGFR2 via the PI3K/Akt signaling pathway. RESULTS: We show that BYHWD treated mice exhibited (i) significantly better recovery from neurological dysfunction, (ii) increased BrdU(+) nuclei in vWF(+) dilated brain vessels and (iii) higher VEGFR2 phosphorylation immunoreactivity in brain microvessels (P <0.05), (iv) higher expression of PI3K and pAkt at the protein level (P <0.05) when compared to untreated ICH mice. These beneficial effects were reversed by SU5416 (P <0.05). CONCLUSIONS: BYHWD promoted neurological recovery and angiogenesis after ICH in mice by enhancing VEGFR2 phosphorylation through the PI3K/Akt signaling pathway.

Movement-related cortical potentials during muscle fatigue induced by upper limb submaximal isometric contractions.

The aim of this study was to examine the central neurophysiological mechanisms during fatigue induced by submaximal isometric contractions. A total of 23 individuals participated in the study and were assigned to fatigue and nonfatigue groups. Handgrip force, root mean square (RMS) of surface electromyography (sEMG) signal and movement-related cortical potentials during self-paced submaximal handgrip isometric contractions were assessed for each participant. The experimental data showed significant decreases in both maximal voluntary contraction [-24.3%; F(3, 42)=19.62, P<0.001, ηp=0.48] and RMS [-30.1%; F(3, 42)=19.01, P<0.001, ηp=0.57] during maximal voluntary contractions and a significant increase [F(3, 42)=14.27, P<0.001, ηp=0.50] in the average RMS of sEMG over four blocks in the fatigue group. There was no significant difference in the readiness potential between the fatigue and the nonfatigue groups at early stages, and at late stages, significant differences were observed only at the Fp1 and FC1 sites. Motor potential amplitudes were significantly higher in the fatigue group than in the nonfatigue group irrespective of block or electrode positions. Positive waveforms were observed in the prefrontal cortex in states without muscle fatigue, whereas a negative waveform pattern was observed with muscle fatigue. Significant within-subject correlations were observed between motor potential at the C1 site and RMS of sEMG (r=-0.439, P=0.02, ηp=0.11). Neurophysiological evidence indicates that cortical activity increases in the prefrontal cortex, primary motor cortex and supplementary motor cortex with muscle fatigue. Muscle fatigue appears to have considerable effects on the components of movement-related cortical potentials during movement execution, whereas the readiness potential before movement is sensitive to cognitive demands during prolonged exercise. Our results provide additional evidence for a link between central motor command during movement execution and motor unit recruitment.