PCSK9 inhibitor protects against ischemic cerebral injury by attenuating inflammation via the GPNMB/CD44 pathway.

BACKGROUND: Ischemic stroke is the second leading cause of death worldwide, and neuroinflammation has been recognized as a critical player in its progression. Meanwhile, proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i) has been demonstrated to inhibit inflammatory response. However, the effects of PCSK9i on ischemic stroke remain unclear and require further investigation. METHODS: Temporary middle cerebral artery occlusion (tMCAO) was performed to establish animal models of ischemic stroke in C57BL/6 mice. The PCSK9i were administered subcutaneously after 2 h tMCAO. Neurological function and cerebral infarct volume were measured by mNSS and TTC staining, respectively. RNA-seq was performed to investigate the changes in mechanistic pathways. Western blotting and immunofluorescence were applied to detect expression of GPNMB, CD44, IL-6, and iNOS. RESULTS: Treatment with PCSK9i significantly improved neurological deficits and reduced the volume of cerebral infarction. PCSK9i suppressed neuroinflammation by activating the GPNMB/CD44 signaling pathway, further exerting their protective effects. CONCLUSION: Taken together, treatment with PCSK9i is an effective way to prevent ischemic stroke-induced brain injury.

Exosomal MicroRNA Profiling in Vitreous Humor Derived From Pathological Myopia Patients.

Purpose: Pathologic myopia (PM) is one of the primary causes of blindness. This study aims to explore the possible relations between the composition of microRNA in vitreous exosomes of patients with PM and the progression of myopic maculopathy. Methods: Vitreous humor (VH) samples were collected from patients undergoing retinal surgery. A total of 15 and 12 VH samples were obtained from patients with PM and control, respectively. The PM group was divided into PM-L (G2) and PM-H groups (G3 and G4) in order to explore differentially expressed microRNAs (DEMs) that account for the relatively poor prognosis in G3 and G4 myopic maculopathy. A Weighted Gene Co-Expression Network Analysis (WGCNA) was conducted to find the persistently altered key microRNAs in myopic maculopathy progression. The Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genome (KEGG) pathway enrichment analysis were used. Results: High purity exosomes were extracted from the vitreous fluid of patients with PM and control. The top five downregulated DEMs of PM-H versus PM-L can reflect the tendency of deterioration of PM-H myopic maculopathy. MiR-143-3p and miR-145-5p, which were found in WGCNA, may participate in the development of myopic maculopathy. These microRNAs all relate to the insulin resistance pathway. Conclusions: This is the first study to explore the relations between the progression of myopic maculopathy and vitreous exosomal microRNAs. Vitreous exosomal miR-143-3p and miR-145-5p can be considered biomarkers for patients with PM, and the vitreous exosomal DEM associated with PM-H may represent alarming signals of myopic maculopathy deterioration.

Dysphagia Risk in Patients Prescribed Rivastigmine: A Systematic Analysis of FDA Adverse Event Reporting System.

BACKGROUND: Dysphagia has been reported as an adverse event for patients receiving rivastigmine for Alzheimer's disease (AD) treatment. OBJECTIVE: The purpose of this study was to determine the association between dysphagia and the usage of rivastigmine by using the pharmacovigilance data from the FDA Adverse Event Reporting System (FAERS). METHODS: The risk of dysphagia in patients who took rivastigmine was compared with those of patients who took other medications. In addition, this study sought to determine if the dysphagia risk was influenced by sex, age, dosage, and medication routes of administration. RESULTS: When compared to patients prescribed donepezil, galantamine, or memantine, individuals prescribed rivastigmine were almost twice as likely to report dysphagia as an adverse event. The dysphagia risk in individuals prescribed rivastigmine is comparable to individuals prescribed penicillamine but significantly higher than clozapine, drugs of which have been previously shown to be associated with elevated dysphagia likelihood. Individuals older than 80 were 122% more likely to report having dysphagia after being prescribed rivastigmine than patients that were 50-70 years of age. Oral administration of rivastigmine was associated with approximately 2 times greater likelihood of reporting dysphagia relative to users of the transdermal patch. In addition, dysphagia showed higher association with pneumonia than other commonly reported adverse events. CONCLUSION: Patients prescribed rivastigmine were at greater risk of reporting dysphagia as an adverse event than patients prescribed many other medicines. This increase in dysphagia occurrence may be attributed to the dual inhibition of both acetylcholinesterase and butyrylcholinesterase.

Low Variability of Blood Pressure Predicts Abnormal Electroencephalogram in Infants with Hypoxic Ischemic Encephalopathy.

OBJECTIVE: This study aimed to evaluate the role of an objective physiologic biomarker, arterial blood pressure variability, for the early identification of adverse short-term electroencephalogram (EEG) outcomes in infants with hypoxic-ischemic encephalopathy (HIE). STUDY DESIGN: In this multicenter observational study, we analyzed blood pressure of infants meeting these criteria: (1) neonatal encephalopathy determined by modified Sarnat exam, (2) continuous mean arterial blood pressure (MABP) data between 18 and 27 hours after birth, and (3) continuous EEG performed for at least 48 hours. Adverse outcome was defined as moderate-severe grade EEG at 48 hours. Standardized signal preprocessing was used; the power spectral density was computed without interpolation. Multivariate binary logistic regression was used to identify which MABP time and frequency domain metrics provided improved predictive power for adverse outcomes compared with standard clinical predictors (5-minute Apgar score and cord pH) using receiver operator characteristic analysis. RESULTS: Ninety-one infants met inclusion criteria. The mean gestational age was 38.4 ± 1.8 weeks, the mean birth weight was 3,260 ± 591 g, 52/91 (57%) of infants were males, the mean cord pH was 6.95 ± 0.21, and 10/91 (11%) of infants died. At 48 hours, 58% of infants had normal or mildly abnormal EEG background and 42% had moderate or severe EEG backgrounds. Clinical predictor variables (10-minute Apgar score, Sarnat stage, and cord pH) were modestly predictive of 48 hours EEG outcome with area under curve (AUC) of 0.66 to 0.68. A composite model of clinical and optimal time- and frequency-domain blood pressure variability had a substantially improved AUC of 0.86. CONCLUSION: Time- and frequency-domain blood pressure variability biomarkers offer a substantial improvement in prediction of later adverse EEG outcomes over perinatal clinical variables in a two-center cohort of infants with HIE. KEY POINTS: · Early outcome prediction in HIE is suboptimal.. · Patterns in blood pressure physiology may be predictive of short-term outcomes.. · Early time- and frequency-domain measures of blood pressure variability predict short-term EEG outcomes in HIE infants better than perinatal factors alone..

Plasma Interleukin-37 is Elevated in Acute Ischemic Stroke Patients and Probably Associated With 3-month Functional Prognosis.

BACKGROUND: Interleukin-37 is a novel cytokine emerging as a natural suppressor of inflammatory responses. Inflammation and the immune response play important roles in acute ischemic stroke. This study aimed at evaluating the plasma levels and the association with 3-month outcomes of interleukin-37 in acute ischemic stroke patients. PATIENTS AND METHODS: In total, 152 consecutive patients with acute ischemic stroke and 45 healthy controls were included. Plasma interleukin-37 levels were determined in the first morning after admission using an enzyme-linked immunesorbent assay. The primary outcome was the 3-month functional outcome (modified Rankin Scale score >2). Logistic regression was used to evaluate the risk and 3-month outcome of stroke according to plasma interleukin-37 level. RESULTS: Plasma interleukin-37 levels were significantly higher in the patients with acute ischaemic stroke than in the healthy controls (182.26 versus 97.89 pg/mL, p<0.001). Patients with large-artery atherosclerosis had significantly higher IL-37 levels than those with small-artery occlusion (202.12±35.82 versus 175.67±33.71pg/mL, p<0.001). Plasma interleukin-37 levels were positively correlated with National Institutes of Health Stroke Scale scores (r=0.521, p<0.0001) and lesion volume (r=0.442, p<0.0001). Ninety-four and 58 patients had favourable and unfavourable 3-month outcomes, respectively. Elevated plasma interleukin-37 levels were independently associated with unfavourable 3-month outcomes (adjusted odds ratio=1.033, p=0.001, 95% confidence interval: 1.015-1.056). CONCLUSION: Admission plasma interleukin-37 levels were significantly increased after acute ischemic stroke. Elevated interleukin-37 levels were independently associated with unfavourable 3-month prognoses in acute ischemic stroke patients. Further studies with other populations are needed.

Long-term icariin treatment ameliorates cognitive deficits via CD4+ T cell-mediated immuno-inflammatory responses in APP/PS1 mice.

Background: Alzheimer's disease (AD) is the most common neurodegenerative disorder that also involves neuroinflammation in addition to many other features. Icariin (ICA) as one of the active ingredients of Chinese herbal medicine has the immunomodulating function. This study aimed to investigate the immunotherapeutic potential of ICA on AD. Methods: APP/PS1 mice and wild type C57BL/6 mice were subjected to orally ICA administration (60 mg/kg/d) for 8 months. Then, the ethological and biochemical experiments, such as Morris water maze assay, Aß ELISA, blood T cell flow cytometry, and plasma and brain cytokines array, were conducted to evaluate the effects of ICA administration. Results: ICA significantly improved spatial learning and memory retention in APP/PS1 mice. Long-term application of ICA could also reduce hippocampus Aß deposition, modulate the differentiation of CD4+ T cells, and modulate the release of inflammatory cytokines in plasma and brain tissue. Conclusion: ICA shows the neuroprotective effects via modulating the CD4+ T lymphocyte-related immuno-inflammatory responses in APP/PS1 mice and may be a promising drug against AD progression.

Icariin Attenuates M1 Activation of Microglia and Aß Plaque Accumulation in the Hippocampus and Prefrontal Cortex by Up-Regulating PPARγ in Restraint/Isolation-Stressed APP/PS1 Mice.

BACKGROUND: Studies have shown that psychosocial stress is involved in Alzheimer's disease (AD) pathogenesis; it induces M1 microglia polarization and production of pro-inflammatory cytokines, leading to neurotoxic outcomes and decreased ß-amyloid (Aß) clearance. Icariin has been proven to be an effective anti-inflammatory agent and to activate peroxisome proliferator-activated receptors gamma (PPARγ) which induces the M2 phenotype in the microglia. However, whether restraint/isolation stress reduces the clearance ability of microglia by priming and polarizing microglia to the M1 phenotype, and the effects of icariin in attenuating the inflammatory response and relieving the pathological changes of AD are still unclear. METHODS: APP/PS1 mice (male, aged 3 months) were randomly divided into a control group, a restraint/isolation stress group, and a restraint/isolation stress + icariin group. The restraint/isolation stress group was subjected to a paradigm to build a depressive animal model. Sucrose preference, open field, elevated plus maze, and Y maze test were used to assess the stress paradigm. The Morris water maze test was performed to evaluate spatial reference learning and memory. Enzyme-linked immunosorbent assay and immunohistochemistry were used to identify the microglia phenotype and Aß accumulation. Western blotting was used to detect the expression of PPARγ in the hippocampus and prefrontal cortex (PFC). RESULTS: Restraint/isolation stress induced significant depressive-like behaviors in APP/PS1 mice at 4 months of age and memory impairment at 10 months of age, while 6 months of icariin administration relieved the memory damage. Restraint/isolation stressed mice had elevated pro-inflammatory cytokines, decreased anti-inflammatory cytokines, increased Aß plaque accumulation and more M1 phenotype microglia in the hippocampus and PFC at 10 months of age, while 6 months of icariin administration relieved these changes. Moreover, restraint/isolation stressed mice had down-regulated PPARγ expression in the hippocampus and PFC at 10 months of age, while 6 months of icariin administration reversed the alteration, especially in the hippocampus. CONCLUSION: Restraint/isolation stress induced depressive-like behaviors and spatial memory damage, over-expression of M1 microglia markers and more severe Aß accumulation by suppressing PPARγ in APP/PS1 mice. Icariin can be considered a new treatment option as it induces the switch of the microglia phenotype by activating PPARγ.

Transplantation of Lymphocytes Co-Cultured with Human Cord Blood-Derived Multipotent Stem Cells Attenuates Inflammasome Activity in Ischemic Stroke.

BACKGROUND: Manipulating the immune inflammatory response after cerebral ischemia has been a novel therapeutic strategy for ischemic stroke. This study attempted to investigate the effects of the transplantation of lymphocytes co-cultured with human cord blood-derived multipotent stem cells (HCB-SCs) on the inflammatory response in transient middle cerebral occlusion (tMCAO) rats. METHODS: The tMCAO rats were subjected to the transplantation of lymphocytes co-cultured with HCB-SCs through tail vein injection. Infarct size and neurological deficits were measured at 48 hrs after stroke. Neurological deficits were assessed using Bederson's scoring system and tape removal test. Blood T cell flow cytometry was performed to measure the differentiation of regulatory T cells (Tregs). Western blot was used to detect the protein levels of inflammation-related molecules, apoptosis-related molecule, and signaling molecules in ischemic brain. TUNEL staining was performed to analyze cell apoptosis in ischemic cerebral cortex. RESULTS: The transplantation of lymphocytes co-cultured with HCB-SCs significantly improved the neurological defects, reduced ischemic brain damage, and increased the proportion of peripheral CD4+CD25+Foxp3+ Tregs. Meanwhile, the transplantation of co-cultured cells decreased the expression of NLRP3 inflammasome and associated factors, such as caspase-1 and IL-1ß, and inhibited the activation of NF-κB, ERK and caspase-3 in ischemic brain. The co-cultured cells significantly decreased the number of tMCAO-induced cell apoptosis. CONCLUSION: Lymphocytes co-cultured with HCB-SCs exhibit a neuroprotective effect after ischemic stroke by promoting Tregs differentiation and suppressing NLRP3 inflammasome activation and neuron apoptosis, and might be a promising therapeutic strategy for ischemic stroke.

Immunotherapeutic effects of lymphocytes co-cultured with human cord blood-derived multipotent stem cells transplantation on APP/PS1 mice.

Alzheimer's disease (AD) is an inexorable neurodegenerative disease that involves neuroinflammation in the brain, in addition to abnormal accumulation of amyloid-ß (Aß) and hyperphosphorylated tau. Evidence shows that human cord blood-derived multipotent stem cells (CB-SCs) can modulate autoimmune responses by altering regulatory T cells (Tregs). Our previous study found that CB-SCs could regulate the peripheral immune system of AD patients in vitro, mainly increasing the proportion of Tregs and anti-inflammatory cytokines. To further investigate the effects of lymphocytes co-cultured with CB-SCs on AD, the APP/PS1 mice received monthly transplants of lymphocytes co-cultured with CB-SCs for 4 months. Then, the ethological and biochemical experiments were conducted. We found that APP/PS1 mice injected with lymphocytes co-cultured with CB-SCs showed improved spatial learning, which significantly correlated with fewer Aß plaques in brain. The present study also indicated that lymphocytes co-cultured with CB-SCs could promote the protective and reparative cytokines in the peripheral blood and brain to alleviate neuroinflammation in AD mice. These findings conclude that the systemic transplantation of lymphocytes co-cultured with CB-SCs can improve cognitive and pathological impairment of APP/PS1 mice via an immunomodulatory effect.