Luteolin and triptolide: Potential therapeutic compounds for post-stroke depression via protein STAT.

Post stroke depression (PSD) is a common neuropsychiatric complication following stroke closely associated with the immune system. The development of medications for PSD remains to be a considerable challenge due to the unclear mechanism of PSD. Multiple researches agree that the functions of gene ontology (GO) are efficient for the investigation of disease mechanisms, and DeepPurpose (DP) is extremely valuable for the mining of new drugs. However, GO terms and DP have not yet been applied to explore the pathogenesis and drug treatment of PSD. This study aimed to interpret the mechanism of PSD and discover important drug candidates targeting risk proteins, based on immune-related risk GO functions and informatics algorithms. According to the risk genes of PSD, we identified 335 immune-related risk GO functions and 37 compounds. Based on the construction of the GO function network, we found that STAT protein may be a pivot protein in underlying the mechanism of PSD. Additionally, we also established networks of Protein-Protein Interaction as well as Gene-GO function to facilitate the evaluation of key genes. Based on DP, a total of 37 candidate compounds targeting 7 key proteins were identified with a potential for the therapy of PSD. Furthermore, we noted that the mechanisms by which luteolin and triptolide acting on STAT-related GO function might involve three crucial pathways, including specifically hsa04010 (MAPK signaling pathway), hsa04151 (PI3K-Akt signaling pathway) and hsa04060 (Cytokine-cytokine receptor interaction). Thus, this study provided fresh and powerful information for the mechanism and therapeutic strategies of PSD.

NCBP1 Improves Cognitive Function in Mice by Reducing Oxidative Stress, Neuronal Loss, and Glial Activation After Status Epilepticus.

Status epilepticus (SE) is a severe manifestation of epilepsy which can cause neurologic injury and death. This study aimed to identify key proteins involved in the pathogenesis of epilepsy and find a potential drug target for SE treatment. Tandem mass tag (TMT)-based quantitative proteomic analysis was applied to screen differentially expressed proteins (DEPs) in epilepsy. The adeno-associated virus was employed to overexpress candidate DEP in mice, and kainic acid (KA) was used to generate a mouse model of epilepsy. Then histopathological examination of the hippocampal tissue was performed, and the inflammatory factors levels in serum and hippocampus were measured. The IP-MS analysis was carried out to identify the interacting protein of nuclear cap-binding protein 1 (NCBP1). The results were that NCBP1 was downregulated in the epileptic hippocampus. NCBP1 overexpression alleviated KA-induced cognitive impairment in mice and reduced the apoptosis and damage of hippocampal neurons. Additionally, overexpressed NCBP1 increased the expression of NeuN and reduced the expression of GFAP and IBA-1 in the hippocampus of the mice. Further study indicated that NCBP1 overexpression inhibited the expression of IL-6, IL-1ß, and IFN-γ in serum and hippocampus as well as MDA and LDH in the hippocampus, whereas it increased the SOD levels, suggesting that overexpression of NCBP1 could diminish KA-induced inflammatory responses and oxidative stress. The IP-MS analysis identified that ELAVL4 was the NCBP1-interacting protein. In conclusion, this finding suggests that NCBP1 may potentially serve as a drug target for the treatment of epilepsy.

Knowledge mapping of research on the mitochondrial unfolded protein response: a bibliometric and visual analysis.

Background: The mitochondrial unfolded protein response (UPRmt) is a mitochondria stress response, which exerts a crucial role in maintaining mitochondrial proteostasis during stress. However, there is no bibliometric analyses systematically studied this field which could comprehensively review research trends, evaluate publication performances and provide future perspectives. Methods: Articles investigating UPRmt published between 1994 and 2021 were downloaded from the Core Collection of the Web of Science (WOS). CiteSpace and VOSviewer bibliometric software were applied for bibliometric and visual analyses. Results: A total of 2,073 papers researching UPRmt were retrieved. According to the published number of papers, the field of UPRmt research has gone through its infancy (after 2000) and rapid growth (after 2021) phases. The United States and China contributed the most to UPRmt research. Regarding the distribution of institutions, Harvard University was the most influential institution. The most prolific authors are Johan Auwerx and CM Haynes. PLoS One is the most extensive journal in the field of UPRmt research, while the Cell Death and Differentiation journal had the greatest impact among the most-authored journals. Moreover, biochemistry/molecular biology, and cell biology are the largest subject areas. UPRmt research is mainly categorized as UPRmt, transcription, endoplasmic reticulum (ER) stress, lipotoxicity, mitophagy, inflammation, skeletal muscle, hypoxia, apoptosis, mitochondrial dysfunction, neurodegeneration, mitochondrial permeability transition, and integrated stress response. Conclusions: At present, research on UPRmt is booming. Further strengthening the cooperation and exchanges between countries, institutions, and authors in the future will surely promote the development of this field.

Propofol Inhibits Ferroptotic Cell Death Through the Nrf2/Gpx4 Signaling Pathway in the Mouse Model of Cerebral Ischemia-Reperfusion Injury.

Ferroptosis is characterized by excessive accumulation of iron and lipid peroxides, which are involved in ischemia, reperfusion-induced organ injury, and stroke. Propofol, an anesthetic agent, has neuroprotective effects due to its potent antioxidant, anti-ischemic, and anti-inflammatory properties. However, the relationship between propofol and ferroptosis is still unclear. In the current study, we elucidated the role of ferroptosis in the neuroprotective effect of propofol in mouse brains subjected to cerebral ischemia reperfusion injury (CIRI). Ferroptosis was confirmed by Western blotting assays, transmission electron microscopy, and glutathione assays. Propofol regulated Nrf2/Gpx4 signaling, enhanced antioxidant potential, inhibited the accumulation of lipid peroxides in CIRI-affected neurons, and significantly reversed CIRI-induced ferroptosis. Additionally, Gpx4 inhibitor RSL3 and Nrf2 inhibitor ML385 attenuated the effects of propofol on antioxidant capacity, lipid peroxidation, and ferroptosis in CIRI-affected neurons. Our data support a protective role of propofol against ferroptosis as a cause of cell death in mice with CIRI. Propofol protected against CIRI-induced ferroptosis partly by regulating the Nrf2/Gpx4 signaling pathway. These findings may contribute to the development of future therapies targeting ferroptosis induced by CIRI.

Inhibition of the expression of rgs-3 alleviates propofol-induced decline in learning and memory in Caenorhabditis elegans.

BACKGROUND: Exposure to anesthesia leads to extensive neurodegeneration and long-term cognitive deficits in the developing brain. Caenorhabditis elegans also shows persistent behavioral changes during development after exposure to anesthetics. Clinical and rodent studies have confirmed that altered expression of the regulators of G protein signaling (RGS) in the nervous system is a factor contributing to neurodegenerative and psychological diseases. Evidence from preclinical studies has suggested that RGS controls drug-induced plasticity, including morphine tolerance and addiction. This study aimed to observe the effect of propofol exposure in the neurodevelopmental stage on learning and memory in the L4 stage and to study whether this effect is related to changes in rgs-3 expression. METHODS: Caenorhabditis elegans were exposed to propofol at the L1 stage, and learning and memory abilities were observed at the L4 stage. The expression of rgs-3 and the nuclear distribution of EGL-4 were determined to study the relevant mechanisms. Finally, RNA interference was performed on rgs-3-expressing cells after propofol exposure. Then, we observed their learning and memory abilities. RESULTS: Propofol time- and dose-dependently impaired the learning capacity. Propofol induced a decline in non-associative and associative long-term memory, rgs-3 upregulation, and a failure of nuclear accumulation of EGL-4/PKG in AWC neurons. Inhibition of rgs-3 could alleviate the propofol-induced changes. CONCLUSION: Inhibition of the expression of rgs-3 alleviated propofol-induced learning and memory deficits in Caenorhabditis elegans.

sVCAM1 in the Hippocampus Contributes to Postoperative Cognitive Dysfunction in Mice by Inducing Microglial Activation Through the VLA-4 Receptor.

Postoperative cognitive dysfunction (POCD) is a severe postsurgical complication, but its underlying mechanisms remain unclear. Neuroinflammation mediated by microglial activation plays a major role in POCD pathophysiology. Upregulation of vascular cell adhesion molecule 1 (VCAM1) on brain endothelial cells is closely correlated with microglial activation in the mouse hippocampus. However, the role of VCAM1 upregulation in microglial activation remains unknown. Soluble VCAM1 (sVCAM1) activates the very late antigen-4 (VLA-4) receptor under inflammatory conditions. Therefore, we hypothesized that sVCAM1 which is shed from VCAM1 contributes to POCD by triggering hippocampal microglial activation through the VLA-4 receptor. We found that VCAM1 and sVCAM1 expression in the mouse hippocampus was upregulated after surgery, and the upregulation was accompanied by hippocampal microglial activation. sVCAM1 levels in mouse and human serum were increased after surgery. Anti-VCAM1 treatment inhibited microglial activation, proinflammatory cytokine production, VLA-4 expression and P38 mitogen-associated protein kinase (MAPK) pathway activation and attenuated hippocampal-dependent cognitive dysfunction. In vitro, recombinant sVCAM1 promoted M1 polarization in BV2 cells, increased VLA-4 expression and activated the P38 MAPK pathway. These effects were reversed by VLA-4 receptor blockade. Anti-VLA-4 treatment ameliorated hippocampal-dependent cognitive dysfunction after surgery by inhibiting microglial activation, proinflammatory cytokine production and P38 pathway activation. In conclusion, increased sVCAM1 in the hippocampus is involved in microglial activation and cognitive dysfunction induced by surgery. Inhibiting the sVCAM1-VLA-4 interaction in microglia may be a therapeutic strategy for POCD.

Correlation between perioperative parecoxib use and postoperative acute kidney injury in patients undergoing radical mastectomy: a retrospective cohort analysis.

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely prescribed drugs worldwide. However, the effect of NSAIDS on postoperative renal function is still unclear. Few studies have assessed the effects of parecoxib on renal function. Our aim is to investigate a correlation between parecoxib and the presence or absence of AKI postoperatively after a breast cancer surgery operation. METHODS: This was a retrospective cohort study that we performed on our hospitalized database. From January 2012 to August 2021, 3542 female patients undergoing radical mastectomy were enrolled, all data including the patients' information and laboratory results were obtained from electronic medical system. The main outcome was the incidence of AKI postoperatively. AKI was defined in accordance with the KDIGO criteria. Study groups were treated with or without parecoxib. Univariable and multivariable logistic regression analyses were performed. RESULTS: In our study, about 5.76% experienced AKI. The incidence rate of postoperative AKI (3.49%) within 7 days in the parecoxib group was lower than that in the control group (6.00%, P = 0.05). Compared to the control group, the AKI's incidence was reduced by 49% (OR = 0.46; 95%CI 0.27-0.97) in parecoxib group in multivariable logistic regression analysis. There was a reduction in the incidence of postoperative AKI in other three subgroups: preoperative eGFR < 90 mL/min·1.73/m2 (OR = 0.52; 95%CI 0.27-0.97), blood loss < 1000 ml (OR = 0.48; 95%CI 0.24-0.96) and non-diabetes (OR = 0.51; 95%CI 0.26-0.98). CONCLUSIONS: Parecoxib was associated with incidence of postoperative acute kidney injury.

Propofol Suppresses Microglia Inflammation by Targeting TGM2/NF-κB Signaling.

BACKGROUND: Propofol is a known intravenous hypnotic drug used for induction and maintenance of sedation and general anesthesia. Emerging studies also reveal a neuroprotective effect of propofol in diverse diseases of neuronal injuries via modulating microglia activation. In this study, we aimed to uncover the downstream targets of propofol in this process. METHODS: RNA sequencing analysis to identify genes implicated in the propofol-mediated neuroprotective effect. Quantitative real-time PCR, enzyme-linked immunosorbent assay, and Western blotting analysis were performed to analyze inflammatory gene expression, cytokine levels, and TGM2. BV2 cells and primary microglia were used for functional verification and mechanism studies. RESULTS: The multifunctional enzyme transglutaminase 2 (TGM2) was identified as a putative functional mediator of propofol. TGM2 was significantly upregulated in lipopolysaccharide- (LPS-) primed BV2 cells. Genetic silencing of TGM2 abolished LPS-induced microglial activation. Notably, gain-of-function experiments showed that the proinflammatory effects of TGM2 were dependent on its GTP binding activity instead of transamidase activity. Then, TGM2 was revealed to activate the NF-κB signaling pathway to facilitate microglial activation. Propofol can inhibit TGM2 expression and NF-κB signaling in BV2 cells and primary microglia. Ectopic expression of TGM2 or constitutively active IKKß (CA-IKKß) can compromise propofol-induced anti-inflammatory effects. CONCLUSIONS: Our findings suggest that TGM2-mediated activation of NF-κB signaling is an important mechanism in the propofol-induced neuroprotective effect that prevents microglial activation.

Propofol Ameliorates Microglia Activation by Targeting MicroRNA-221/222-IRF2 Axis.

BACKGROUND: Propofol is a widely used intravenous anesthetic drug with potential neuroprotective effect in diverse diseases of neuronal injuries such as traumatic brain injury and ischemic stroke. However, the underlying molecular mechanism remains largely unknown. METHODS: Real-time qPCR, enzyme-linked immunosorbent assay, and Western blotting were used to identify the expression pattern of miR-221/222, inflammatory genes, cytokines, and IRF2. The biological roles and mechanisms of propofol in microglia activation were determined in BV2 cells and primary microglia. Bioinformatic analysis and luciferase reporter assay were used to confirm the regulatory role of miR-221/222 in Irf2 expression. RESULTS: We found that miR-221 and miR-222 were downstream targets of propofol and were consistently upregulated in lipopolysaccharide- (LPS-) primed BV2 cells. Gain- and loss-of-function studies revealed that miR-221 and miR-222 were profoundly implicated in microglia activation. Then, interferon regulatory factor 2 (Irf2) was identified as a direct target gene of miR-221/222. IRF2 protein levels were reduced by miR-221/222 and increased by propofol treatment. Ectopic expression of IRF2 attenuated the proinflammatory roles induced by LPS in BV2 cells. More importantly, the suppressive effects of propofol on LPS-primed activation of BV2 cells or primary mouse microglia involved the inhibition of miR-221/222-IRF2 axis. CONCLUSIONS: Our study highlights the critical function of miR-221/222, which inhibited Irf2 translation, in the anti-inflammatory effects of propofol, and provides a new perspective for the molecular mechanism of propofol-mediated neuroprotective effect.

Propofol Attenuates Hypoxia-Induced Inflammation in BV2 Microglia by Inhibiting Oxidative Stress and NF-κB/Hif-1α Signaling.

Hypoxia-induced neuroinflammation typically causes neurological damage and can occur during stroke, neonatal hypoxic-ischemic encephalopathy, and other diseases. Propofol is widely used as an intravenous anesthetic. Studies have shown that propofol has antineuroinflammatory effect. However, the underlying mechanism remains to be fully elucidated. Thus, we aimed to investigate the beneficial effects of propofol against hypoxia-induced neuroinflammation and elucidated its potential cellular and biochemical mechanisms of action. In this study, we chose cobalt chloride (CoCl2) to establish a hypoxic model. We found that propofol decreased hypoxia-induced proinflammatory cytokines (TNFα, IL-1ß, and IL-6) in BV2 microglia, significantly suppressed the excessive production of reactive oxygen species, and increased the total antioxidant capacity and superoxide dismutase activity. Furthermore, propofol attenuated the hypoxia-induced decrease in mitochondrial membrane potential andy 2 strongly inhibited protein expression of nuclear factor-kappa B (NF-κB) subunit p65 and hypoxia inducible factor-1α (Hif-1α) in hypoxic BV2 cells. To investigate the role of NF-κB p65, specific small interfering RNA (siRNA) against NF-κB p65 were transfected into BV2 cells, followed by exposure to hypoxia for 24 h. Hypoxia-induced Hif-1α production was downregulated after NF-κB p65 silencing. Further, propofol suppressed Hif-1α expression by inhibiting the upregulation of NF-κB p65 after exposure to hypoxia in BV2 microglia. In summary, propofol attenuates hypoxia-induced neuroinflammation, at least in part by inhibiting oxidative stress and NF-κB/Hif-1α signaling.

Intestinal Flora Dysbiosis Aggravates Cognitive Dysfunction Associated With Neuroinflammation in Heart Failure.

BACKGROUND: Cognitive dysfunction after heart failure (HF) is characterized by neuroinflammation, which plays an important role in the occurrence and development of cognitive dysfunction. Recent studies have shown that an intestinal flora imbalance may also trigger neuroinflammation in Alzheimer's disease. The present study was designed to reveal that intestinal flora dysbiosis caused by HF aggravates neuroinflammation-associated cognitive impairment. METHODS AND RESULTS: Adult male Sprague-Dawley rats were fed daily for 2 weeks with probiotics or placebo until the day of surgery. HF was then triggered by 8 weeks of sustained coronary artery occlusion. 16S rDNA sequencing was used to confirm intestinal flora dysbiosis after HF and demonstrate that the changes paralleled intestinal pathology scores. The permeability of the blood-brain barrier was increased after HF, and such an increase in permeability may increase the levels of inflammatory cytokines caused by intestinal flora disorders. The changes in the intestinal flora caused by probiotics significantly reduced the level of neuroinflammation. In addition, probiotic administration considerably improved the impaired spatial memory in HF rats. CONCLUSIONS: We conclude that intestinal flora dysbiosis plays a potential role in aggravating the impaired cognition associated with neuroinflammation and that these effects may be attenuated by probiotics.

Network and Pathway-Based Integrated Analysis Identified a Novel "rs28457673-miR-15/16/195/424/497 Family-IGF1R-MAPK Signaling Pathway" Axis Associated With Post-stroke Depression.

Single-nucleotide polymorphisms (SNPs) of microRNA (miRNA) (miRSNP) are SNPs located on miRNA genes or miRNA target sites, which have been supposed to be involved in the development of central nervous system diseases by interfering with miRNA-mediated regulatory functions. However, the association of miRSNP with post-stroke depression (PSD) has not been well-investigated. In this study, we collected 54 PSD risk genes via manual literature-mining and integrated PSD-related risk pathways based on multiple public databases. Furthermore, we systematically screened candidate functional miRSNPs for PSD and integrated a miRSNP-based PSD-associated pathway network, which included 99 miRNAs that target 12 PSD risk pathways. We also reviewed the association between three risk pathways and PSD pathogenetic mechanism thoroughly. Combining literature mining and network analysis, our results proposed an underlying mechanism of "miRSNP → miRNA → risk gene → pathway" axis effects on PSD pathogenesis, especially for rs28457673 (miR-15/16/195/424/497 family) → IGF1R → hsa04010 (MAPK signaling pathway). Our studies revealed a functional role in genetic modifier at the system level in the pathogenesis of PSD, which might provide further information for the miRSNP studies in PSD.

Impact of echocardiographic wall motion abnormality and cardiac biomarker elevation on outcome after subarachnoid hemorrhage: a meta-analysis.

Cardiac abnormalities (echocardiographic wall motion abnormality (WMA), biomarker elevation of cardiac troponin (cTn), B-type natriuretic peptide (BNP), or N-terminal prohormone of B-type natriuretic peptide (NT-proBNP)) frequently occur after subarachnoid hemorrhage (SAH). The clinical significance of cardiac abnormalities after SAH remains controversial. This meta-analysis was performed to assess the association between cardiac abnormalities and patient outcomes, including delayed cerebral ischemia (DCI), poor outcome, and death in SAH patients. PubMed and Embase were searched for observational studies reporting an association between cardiac abnormalities and outcome after SAH that were published before 31 December 2017. We extracted data regarding patient characteristics, cardiac abnormalities, and outcome measurements (DCI, poor outcome, or death). Risk ratios (RRs) and 95% confidence intervals (CIs) were calculated using a random-effects model. Twenty-six studies involving 3917 patients were included in our data analysis. WMA showed significant associations with higher rates of DCI (RR, 2.03; 95% CI, 0.99-4.15), poor outcome (RR, 1.45; 95% CI, 1.08-1.93), and death (RR, 2.54; 95% CI, 1.59-4.05). cTn elevation was associated with an increased risk of DCI (RR, 1.48; 95% CI, 1.23-1.79), poor outcome (RR, 1.85; 95% CI, 1.49-2.30), and death (RR, 2.68; 95% CI, 2.19-3.27). Elevation of BNP or NT-proBNT was significantly associated with higher rates of DCI (RR, 1.87; 95% CI, 1.16-3.02). WMA and elevation of cTn, BNP, and NT-proBNP in SAH patients are associated with an increased risk of DCI, poor outcome, and death after SAH.

Cough Suppression during Flexible Bronchoscopy Using Transcutaneous Electric Acupoint Stimulation: A Randomized Controlled Study.

Background and Objective. Transcutaneous electric acupoint stimulation (TEAS) is recommended for its sedative and analgesic effects. We sought to evaluate the effect of TEAS on cough suppression during flexible bronchoscopy (FB) and explore the underlying mechanism. Methods. In this single-center, randomized, single-blind, parallel-controlled study, we randomized 100 patients scheduled for FB into two equal groups treated with or without TEAS (TEAS group and control group). Patients in the TEAS group received 30 min of stimulation at the Hegu (LI4), Neiguan (PC6), and Lieque (LU7) points before FB. The control group underwent the same procedure, but without stimulation. The primary outcome was the intraoperative cough score determined by the bronchoscopist. The secondary outcomes were patient-reported discomfort scores and other procedural parameters. Results. Compared with the controls, patients who received TEAS preconditioning had lower cough scores (P=0.0027) and requirement of lidocaine and fentanyl (P < 0.05) and significantly higher postprocedural plasma ß-endorphin levels (P=0.0367). There were no intergroup differences in discomfort scores, midazolam dosage, rate of premature termination, oxygen requirement, sedation level, airway assistance, oxygen saturation, lowest oxygen saturation level, heart rate, plasma substance-P levels, and rate of complications after 24 h. The total procedure duration, time for passage of the bronchoscope through the vocal cords, and systolic and diastolic blood pressure levels were less in the TEAS group than in the control group (P=0.033, 0.039 and <0.05, respectively). Conclusion. The combination of midazolam and TEAS was superior to midazolam alone for cough suppression during FB, probably due to increased plasma ß-endorphin levels. This trial is registered with ChiCTR1800016612 at chictr.org.cn/index.aspx.

Combination of propofol and dezocine to improve safety and efficacy of anesthesia for gastroscopy and colonoscopy in adults: A randomized, double-blind, controlled trial.

BACKGROUND: Gastroscopy and colonoscopy are important and common endoscopic methods for the diagnosis and treatment of gastrointestinal and colorectal diseases. However, endoscopy is usually associated with adverse reactions such as nervousness, nausea, vomiting, choking cough, and pain. Severe discomfort, such as vomiting, coughing, or body movement, may lead to aggravation of a pre-existing condition or even interruption of examination or treatment, especially in some critically ill patients with physiological dysfunction (e.g., cardiovascular or respiratory disease). The optimal methods for inducing analgesia and sedation in endoscopy are areas of ongoing debate; nevertheless, determining an appropriate regimen of sedation and analgesia is important. AIM: To evaluate the effects of propofol combined with dezocine, sufentanil, or fentanyl in painless gastroscopy and colonoscopy. METHODS: Four hundred patients were randomly assigned to one of four groups for anesthesia: intravenous dezocine, sufentanil, fentanyl, or saline. Propofol was administered intravenously for induction and maintenance of anesthesia. RESULTS: The dosage of propofol in the dezocine group was significantly lower than those in other groups (P < 0.01). Bispectral index and Steward score (0-6 points, an unresponsive, immobile patient whose airway requires maintenance to a fully recovered patient) after eye opening in the dezocine group were significantly higher than those in other groups (P < 0.01). Awakening time and postoperative pain score (0-10 points, no pain to unbearable pain) in the dezocine group were significantly lower than those in other groups (P < 0.01). Mean arterial pressure and pulse oxygen saturation in the dezocine group were significantly more stable at various time points (before dosing, disappearance of eyelash reflex, and wakeup) than those in other groups (P < 0.01). The rates of hypopnea, jaw thrust, body movements, and usage of vasoactive drugs in the dezocine group were significantly lower than those in other groups (P < 0.01). Additionally, the rates of reflex coughing, nausea, and vomiting were not statistically different between the four groups (P > 0.05). CONCLUSION: The combination of propofol and dezocine can decrease propofol dosage, reduce the risk for the development of inhibitory effects on the respiratory and cardiovascular systems, increase analgesic effect, decrease body movement, shorten awakening time, and improve awakening quality.

Silencing MicroRNA-134 Alleviates Hippocampal Damage and Occurrence of Spontaneous Seizures After Intraventricular Kainic Acid-Induced Status Epilepticus in Rats.

Epilepsy is a disorder of abnormal brain activity typified by spontaneous and recurrent seizures. MicroRNAs (miRNAs) are short non-coding RNAs, critical for the post-transcriptional regulation of gene expression. MiRNA dysregulation has previously been implicated in the induction of epilepsy. In this study, we examined the effect of silencing miR-134 against status epilepticus (SE). Our results showed that level of miR-134 was significantly up-regulated in rat brain after Kainic acid (KA)-induced SE. TUNEL staining showed that silencing miR-134 alleviated seizure-induced neuronal apoptosis in the CA3 subfield of the hippocampus. Western blot showed that a miR-134 antagonist suppressed lesion-induced endoplasmic reticulum (ER) stress and apoptosis related expression of CHOP, Bim and Cytochrome C, while facilitated the expression of CREB at 24 h post KA-induced lesion in the hippocampus. Consistently, silencing miR-134 significantly diminished loss of CA3 pyramidal neurons using Nissl staining as well as reducing aberrant mossy fiber sprouting (MFS) in a rat epileptic model. In addition, the results of EEG and behavior analyses showed seizures were alleviated by miR-134 antagonist in our experimental models. These results suggest that silencing miR-134 modulates the epileptic phenotype by upregulating its target gene, CREB. This in turn attenuates oxidative and ER stress, inhibits apoptosis, and decreases MFS long term. This indicates that silencing miR-134 might be a promising intervention for the treatment of epilepsy.

Exogenous ghrelin ameliorates acute lung injury by modulating the nuclear factor κB inhibitor kinase/nuclear factor κB inhibitor/nuclear factor κB pathway after hemorrhagic shock.

Previous studies have shown that ghrelin, a peptide produced in the stomach, attenuates acute lung injury (ALI) in various animal models, and that some of these effects are associated with inhibition of the nuclear factor κB signaling pathway. This study investigated whether ghrelin exerts beneficial effects on hemorrhagic shock (HS)-induced ALI by modulating nuclear factor κB inhibitor kinase/nuclear factor κB inhibitor/nuclear factor κB (IKK/IκBα/NF-κB) pathway activity. HS was induced in male SD rats by withdrawing blood to a mean arterial pressure (MAP) of 40 mm Hg for 1 h; rats then received ghrelin (10 nmol/kg) or vehicle intravenously and were resuscitated with the shed blood and an equal volume of Ringer lactate solution followed by observation for 2 h. After resuscitation, samples were collected and analyzed for lung histopathology, wet to dry weight ratio (W/D), bronchoalveolar lavage fluid (BALF) protein, neutrophil infiltration, plasma inflammatory cytokines (TNF-α and IL-6), and cytoplasmic phosphorylated IKKß, IκBα, phosphorylated IκBα and nuclear NF-κB expression. Compared to those in the two sham groups, lung injury, W/D, BALF protein, neutrophil infiltration, plasma TNF-α and IL-6 levels, and IKK/IκBα/NF-κB pathway activation were significantly increased in HS rats. After ghrelin administration, all parameters analyzed were decreased compared to those without ghrelin in HS rats. Moreover, ghrelin alleviated the decreased MAP after resuscitation compared to that in HS rats. Exogenous ghrelin attenuates the inflammatory response and acute lung injury after HS. These beneficial effects appear to be mediated through inhibition of IKK/IκBα/NF-κB signaling.

Probiotics alleviate cognitive dysfunction associated with neuroinflammation in cardiac surgery.

Neuroinflammation plays a key role in the progression and pathogenesis of postoperative cognitive dysfunction, but it does not always occur in the local response to primary injury. In this study, we revealed that probiotics alleviate cognitive dysfunction associated with neuroinflammation in cardiac surgery. Rats were administered a probiotic or placebo once a day by gavage for 2 weeks until the day of surgery. Cardiac surgery was induced by ischemia/reperfusion of the left coronary artery. Key factors, such as the gut microbiome, the gut barrier and the blood-brain barrier (BBB), were systematically investigated to determine whether changes in the gut microbiome lead to neuroinflammation. We used 16S rDNA sequencing to confirm that cardiac surgery induced intestinal flora dysbiosis by altering the number of organisms rather than the structure in the cecum microbiome, which occurs at the same time as damage to the gut barrier. Cardiac surgery also increased BBB permeability, suggesting that disruption of the microbiome may increase the likelihood of neuroinflammation. Probiotics-induced alterations in the intestinal flora significantly reduced the level of inflammatory cytokines (IL-6 and IL-1ß). Importantly, we found that the administration of probiotics significantly improved spatial memory impairment in rats after cardiac surgery, as measured by the Morris water maze. Overall, dysbiosis of the gut flora may aggravate cognitive impairment associated with neuroinflammation after cardiac surgery, and probiotics may attenuate this effect.

A method for addressing right upper lobe obstruction with right-sided double-lumen endobronchial tubes during surgery: a randomized controlled trial.

BACKGROUND: A right-sided double-lumen tube (R-DLT) tends to obstruct the right upper lobe intraoperatively due to anatomical distortion during surgery. If the R-DLT is poorly matched with the patient's airway anatomy, it will not be possible to correctly replace the tube with a fiberoptic bronchoscope (FOB). In our study, we aimed to explore an efficient method for difficult repositioning caused by right upper lobe occlusion during surgery: repositioning the R-DLT from the right main bronchus into the left main bronchus. The current study was designed to assess the efficacy and safety of this method. METHODS: Sixty adult patients scheduled to undergo left-sided thoracic surgery were randomly assigned to two groups. With the patient in the right lateral position during surgery, the R-DLT was pulled back to the trachea while being rotated 90° clockwise; it was then either rotated 90° clockwise for placement into the left main bronchus (Group L) or rotated 90° anticlockwise and returned to the right main bronchus (Group R) using FOB guidance. The primary outcomes included clinical performance, which was measured by intubation time, and the quality of lung collapse. A secondary outcome was safety, which was determined according to bronchial injury and vocal cord injury. RESULTS: The median intubation time (IQR [range]) required for placement of a R-DLT into the left main bronchus was shorter than the time required for placement into the right main bronchus (15.0 s [IQR, 12.0 to 20.0 s]) vs 23.5 s [IQR, 14.5 to 65.8 s], P = 0.005). The groups showed comparable overall results for the quality of lung collapse during the total period of one-lung ventilation (P = 1.000). The numbers of patients with bronchial injuries or vocal cord injuries were also comparable between groups (Group R, 11/30 vs. Group L 8/30, P = 0.580 for bronchus injuries; Group R, 15/30 vs. Group L 13/30, P = 0.796 for vocal cord injuries). CONCLUSIONS: Repositioning a R-DLT from the right main bronchus into the left main bronchus had good clinical performance without causing additional injury. This may be an efficient method for the difficult repositioning of a R-DLT due to right upper lobe occlusion during surgery. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR-IPR-15006933 , registered on 15 August 2015.

Weaponized Health Communication: Twitter Bots and Russian Trolls Amplify the Vaccine Debate.

OBJECTIVES: To understand how Twitter bots and trolls ("bots") promote online health content. METHODS: We compared bots' to average users' rates of vaccine-relevant messages, which we collected online from July 2014 through September 2017. We estimated the likelihood that users were bots, comparing proportions of polarized and antivaccine tweets across user types. We conducted a content analysis of a Twitter hashtag associated with Russian troll activity. RESULTS: Compared with average users, Russian trolls (χ2(1) = 102.0; P < .001), sophisticated bots (χ2(1) = 28.6; P < .001), and "content polluters" (χ2(1) = 7.0; P < .001) tweeted about vaccination at higher rates. Whereas content polluters posted more antivaccine content (χ2(1) = 11.18; P < .001), Russian trolls amplified both sides. Unidentifiable accounts were more polarized (χ2(1) = 12.1; P < .001) and antivaccine (χ2(1) = 35.9; P < .001). Analysis of the Russian troll hashtag showed that its messages were more political and divisive. CONCLUSIONS: Whereas bots that spread malware and unsolicited content disseminated antivaccine messages, Russian trolls promoted discord. Accounts masquerading as legitimate users create false equivalency, eroding public consensus on vaccination. Public Health Implications. Directly confronting vaccine skeptics enables bots to legitimize the vaccine debate. More research is needed to determine how best to combat bot-driven content.