Interferon Regulatory Factor 5 Regulates the Phagocytosis of Microglia and Alleviate Alzheimer's Pathology.

Microglia play a critical role in the pathophysiology of Alzheimer's disease. They are involved in Aß-induced neuroinflammatory responses, regulating the production of inflammatory mediators. Interferon regulatory factor 5 (IRF5) plays a central role in inflammatory diseases in the periphery, the role of which in central nervous system remains elusive. This study aimed to investigate the role of IRF5 in Aß-induced neuroinflammation and the progression of Aß pathology. We found that Aß1-42 oligomers significantly increased the level of IRF5 in BV2 microglia. The levels of proinflammatory cytokines TNF-α, IL-1ß, and IL-6 were significantly upregulated with Aß treatment. IRF5 knockdown with siRNA in microglia significantly reduced the expression of these proinflammatory factors induced by Aß and promoted Aß phagocytosis. Besides, LC3 upregulation and p62 downregulation were observed in IRF5 knockdown microglia. This was also validated in APP/PS1 mice with IRF5 knockdown, leading to reduced Aß levels in the brain. We conclude that IRF5 mediates Aß-induced microglial inflammatory responses. IRF5 knockdown attenuated Aß-induced inflammatory responses and promoted the phagocytosis and autophagy of Aß by microglia.

Case report: A longitudinal study of an unusual rapidly progressive dementia case.

It is daunting to determine the etiology of rapidly progressive dementia (RPD), which includes metabolic, neoplastic, infectious, autoimmune, neurodegenerative and other conditions. Herein, we illustrate an unusual case of a patient primarily exhibiting RPD, overlapping sleep dysfunction, psychosis and abnormal movement, which was finally defined as anti-IgLON5 disease, a novel and rare autoimmune encephalopathy. Furthermore, we longitudinally described his cognitive and psychological performance in detail, and determined that early initiation of immunotherapy in this patient did not result in a good outcome. These data highlight anti-IgLON5 disease as a possible differential diagnosis in patients with RPD.

Accelerating electrochemical CO2 reduction to multi-carbon products via asymmetric intermediate binding at confined nanointerfaces.

Electrochemical CO2 reduction (CO2R) to ethylene and ethanol enables the long-term storage of renewable electricity in valuable multi-carbon (C2+) chemicals. However, carbon-carbon (C-C) coupling, the rate-determining step in CO2R to C2+ conversion, has low efficiency and poor stability, especially in acid conditions. Here we find that, through alloying strategies, neighbouring binary sites enable asymmetric CO binding energies to promote CO2-to-C2+ electroreduction beyond the scaling-relation-determined activity limits on single-metal surfaces. We fabricate experimentally a series of Zn incorporated Cu catalysts that show increased asymmetric CO* binding and surface CO* coverage for fast C-C coupling and the consequent hydrogenation under electrochemical reduction conditions. Further optimization of the reaction environment at nanointerfaces suppresses hydrogen evolution and improves CO2 utilization under acidic conditions. We achieve, as a result, a high 31 ± 2% single-pass CO2-to-C2+ yield in a mild-acid pH 4 electrolyte with >80% single-pass CO2 utilization efficiency. In a single CO2R flow cell electrolyzer, we realize a combined performance of 91 ± 2% C2+ Faradaic efficiency with notable 73 ± 2% ethylene Faradaic efficiency, 31 ± 2% full-cell C2+ energy efficiency, and 24 ± 1% single-pass CO2 conversion at a commercially relevant current density of 150 mA cm-2 over 150 h.

Toxicity of Tetracycline and Metronidazole in Chlorella pyrenoidosa.

Antibiotics have become a new kind of organic pollutant as they are widely used in the water environment of China. Tetracycline (TC) is a class of broad-spectrum antibiotics produced or semi-synthesized by actinomycetes. Metronidazole (MTZ) is the first generation of typical nitroimidazoles. The content of nitroimidazoles is relatively high in medical wastewater, and their ecotoxicity is worthy of attention because they are difficult to completely eliminate. In this paper, the effects of TC and MTZ on the growth, cell morphology, extracellular polymer and oxidative stress of Chlorella pyrenoidosa (C. pyrenoidosa) were studied, and the toxic interactions between TC and MTZ mixture components were analyzed. The results showed that the 96h-EC50 of TC and MTZ was 8.72 mg/L and 45.125 mg/L, respectively. The toxicity of TC to C. pyrenoidosa was higher than that of MTZ, and the combined toxicity effect of TC and MTZ was synergistic after the combined action of a 1:1 toxicity ratio. In addition, the algal cells of C. pyrenoidosa died to varying degrees, the membrane permeability of algal cells was increased, the membrane was damaged, the surface of algal cells exposed to higher concentration of pollutants was wrinkled, and their morphology was changed. The extracellular polymer of C. pyrenoidosa was affected by a change in concentration. The effect of pollutants on the reactive oxygen species (ROS) level and malondialdehyde (MDA) content of C. pyrenoidosa also had an obvious dose-effect relationship. This study contributes to the assessment of the possible ecological risks to green algae due to the presence of TC and MTZ in aquatic environments.

Salivary Aß1-42 may be a quick-tested biomarker for clinical use in Alzheimer's disease: a meta-analysis.

OBJECTIVE: Alzheimer's disease (AD) is the most prevalent form of dementia among the aging population. Cumulative studies aim to find non-invasive biomarkers in the early stages of AD. Saliva can be obtained easily, and salivary biomarkers have been proven effective in detecting neurodegenerative diseases. To find effective biomarkers in saliva and to help the diagnosis of AD, we performed a meta-analysis focusing on the salivary biomarkers (ß-amyloid 1-42 (Aß1-42), total tau (t-tau), phosphorylated tau (p-tau) and acetylcholinesterase (AChE)) in AD. METHODS: We conducted a systematic online search for eligible studies reporting data on salivary biomarkers reflecting Aß1-42, t-tau, p-tau, and AChE in AD cohorts versus controls. Biomarkers' performance was assessed in a random-effects meta-analysis with the ratio of mean (RoM). RESULTS: A total of thirteen studies were included in the meta-analysis, of them seven involved salivary Aß1-42 (271 AD and 489 controls), five involved salivary t-tau (324 AD and 252 controls), four involved salivary p-tau (130 AD and 161 controls), and three involved salivary AChE (81 AD and 54 controls). AD showed significantly higher salivary Aß1-42 levels than control (ROM = 1.90 (95% CI 1.28-2.81, P = 0.001), while AD and control did not differ significantly on salivary t-tau, p-tau and AChE (ROM = 0.94, 95% CI 0.67-1.31, P = 0.72; ROM = 0.91, 95% CI 0.56-1.45, P = 0.68; ROM = 0.83, 95% CI 0.24-2.88, P = 0.77; respectively). CONCLUSION: The pooled results provide evidence that salivary Aß1-42 may serve as a sensitive biomarker for AD; nevertheless, larger AD cohorts are required to further confirm the sensitivity and specificity of salivary Aß1-42 for AD diagnosis.

Metformin Attenuates Tau Pathology in Tau-Seeded PS19 Mice.

Accumulation of neurofibrillary tangles (NFTs) composed of hyperphosphorylated tau is a histopathological hallmark of Alzheimer's disease (AD) and related tauopathies. Growing evidence demonstrated that tau pathology in AD spreads in a prion-like manner. Previous studies showed that metformin might have a positive effect on cognition. However, the underlying mechanisms are still unknown. Therefore, the present study aimed to investigate the effects of metformin on tau propagation. Brain extracts containing tau aggregates were unilaterally injected into the hippocampus and the overlying cerebral cortex of PS19 mice. Metformin was administrated through drinking water for four months, and we observed tau spreading in the brain of tau-seeded PS19 mice. Metformin inhibited the spreading of tau pathology in the ipsilateral hemisphere, attenuated tau pathology in the contralateral hemisphere, and reduced the hyperphosphorylation of tau at Ser202/Thr205, Thr231, and Ser422 sites in the soluble fraction and Ser202/Thr205, Ser262, Thr396, Thr231, and Ser422 sites in the insoluble fraction of tau-seeded PS19 mice brains. Metformin did not affect tau kinases or phosphatase 2A protein levels but reduced mTORC1 protein levels. Additionally, metformin reduced learning and memory deficits of the tau-seeded PS19 mice. These findings indicate that metformin reduced tau hyperphosphorylation, attenuated tau pathology in tau-seeded PS19 mice, and improved learning and memory deficits. These findings highlight the potential mechanisms underlying the beneficial effects of metformin on cognition, implying that metformin could be a promising drug for the prevention and early treatment of AD.

ATP1A3 mutation in rapid-onset dystonia parkinsonism: New data and genotype-phenotype correlation analysis.

Background: Rapid-onset dystonia parkinsonism (RDP) is a rare disease caused by ATP1A3 mutation with considerable clinical heterogeneity. Increased knowledge of RDP could be beneficial in its early diagnosis and treatment. Objective: This study aimed to summarize the gene mutation spectrum of ATP1A3 associated with RDP, and to explore the correlation of ATP1A3 variants with RDP clinical phenotypes. Methods: In this study, we reported two RDP patients from a family with a novel inherited ATP1A3 variant. Then, we reviewed and analyzed the available literature in English focused on ATP1A3-causative RDP. A total of 35 articles covering 15 families (59 patients) and 36 sporadic RDP cases were included in our analysis. Results: The variant A813V (2438C>T) in ATP1A3 found in our cases was a novel mutant. Delays in diagnosis were common, with a mean delay time of 14 years. ATP1A3 had distinct RDP-related mutation hotspots, which consisted of exon8, 14, 17, and 18, and the most frequently occurring variants were T613M and I578S. Approximately 74.5% of patients have specific triggers before disease onset, and 82.1% of RDPs have stable symptoms within 1 month. The incidence rates of dystonia and bradykinesia are 100 and 88.1%, respectively. The onset site varied and exhibited a rostrocaudal gradient distribution pattern in 45% of patients with RDP. Approximately 63.6% of patients had mild improvement after receiving comprehensive interventions, especially in gait disturbance amelioration. Conclusion: In patients with acute and unexplained dystonia or bradykinesia, gene screening on ATP1A3 should be timely performed. When a diagnosis has been made, treatments that may be effective are to be attempted. Our study would be helpful for the early diagnosis and treatment of ATP1T3-related RDP.

Algal Inhibiting Effects of Salicylic Acid Sustained-Release Microspheres on Algae in Different Growth Cycles.

Microcystis blooms and microcystins caused by eutrophication are harmful to the environment. At present, algicide based on allelochemicals is widely used in algae control. Environment-friendly sustained-release salicylate chitosan microspheres (SA-CS) were prepared by acylation of chitosan and glutaraldehyde. SA-CS was characterized by scanning electron microscopy, Fourier transform infrared spectral analysis, and laser particle sizer. The inhibitory effects of SA-CS on Microcystis aeruginosa at different stages, and the environmental impact of the inorganic index, were studied. The results showed that the mean size of SA-CS was 53.3 µm, the encapsulation rate was 40.66%, and SA-CS had a good sustained-release effect (stable release within 25 days). On the seventh day, a 90% inhibition rate in the lag phase required 105 mg/L of SA-CS, whereas a 90% inhibition rate in the log phase required 675 mg/L of SA-CS. The sensitivity of Microcystis aeruginosa at the lag phase to salicylic acid was about 1.4 times that of the log phase, thus, it is recommended to control the algae in the lag phase. The long-term inhibition effect of SA-CS on algae was detected after adding sufficient SA-CS. In terms of salicylic acid, pH, and dissolved oxygen, no lousy effect was observed for the addition of SA-CS. SA-CS could effectively reduce the concentration of microcystin-LR by 50%. SA-CS is an environment-friendly sustained-release microsphere with good algal inhibition performance for Microcystis aeruginosa.

Optimization, Characterization and in vivo Evaluation of Paclitaxel-Loaded Folate-Conjugated Superparamagnetic Iron Oxide Nanoparticles.

BACKGROUND: Paclitaxel (PTX) has interesting anticancer activity. However, it is insoluble in water, which seriously hinders its use in clinical. Superparamagnetic iron oxide nanoparticles (SPIONs) are used as an ideal drug delivery system. Therefore, we proposed a folic acid (FA) targeting drug-loaded SPIONs to reduce its adverse reaction. METHODS: To improve the hydrophilicity of PTX, the structure of PTX was modified by succinic anhydride to obtain 2'-succinate paclitaxel (SPTX). FA conjugated Polyethylene glycol (PEG)/polyethyleneimine (PEI)-SPIONs SPTX-loaded nanoparticles (SPTX@FA@PEG/PEI-SPIONs) were prepared by solvent volatilization and hydrogen bond adsorption, and the nano-formulation was optimized by response surface methodology (RSM). The characteristics, antitumor effect in vitro, pharmacokinetics, and biodistribution of SPTX@FA@PEG/PEI-SPIONs were evaluated. RESULTS: SPTX was successfully loaded on the surface of FA@PEG/PEI-SPIONs. The formation of SPTX@FA@PEG/PEI-SPIONs was exhibited water-dispersive monodispersity with high stability by RSM, and dynamic light scattering (DLS) was 178.1±3.12 nm, particle size observed in the transmission electron microscope (TEM) was 13.01±1.10 nm, and the encapsulation efficiency (EE) and loading efficiency (LE) were 81.1±1.66% and 14.8±1.46%, respectively. It enhanced the stability in normal physiological condition, accelerated drug release at tumorous pH, and preferentially prolonged the circulation time. In vitro, the SPTX@FA@PEG/PEI-SPIONs significantly targeted to folate receptor (FR) positive cancers cell (HNE-1) via the receptor-ligand mediated pathway, resulting in effective cytotoxic activity. Pharmacokinetic results demonstrated that SPTX@FA@PEG/PEI-SPIONs (t1/2=3.41 h) had longer than free SPTX or PTX (t1/2=1.67 h) in rats in vivo. Tissue distribution studies showed that SPTX@FA@PEG/PEI-SPIONs were present at high levels in the liver and help in targeting the folate receptors present on the kidneys. CONCLUSION: These results suggest that SPTX@FA@PEG/PEI-SPIONs offer a highly promising approach to control drug release, improve drug pharmacokinetics and actively target the nasopharyngeal carcinoma.

Metformin attenuates plaque-associated tau pathology and reduces amyloid-ß burden in APP/PS1 mice.

BACKGROUND: The neuropathological hallmarks of Alzheimer's disease (AD) are amyloid-ß (Aß) plaques and neurofibrillary tangles (NFTs). The amyloid cascade theory is the leading hypothesis of AD pathology. Aß deposition precedes the aggregation of tau pathology and Aß pathology precipitates tau pathology. Evidence also indicates the reciprocal interactions between amyloid and tau pathology. However, the detailed relationship between amyloid and tau pathology in AD remains elusive. Metformin might have a positive effect on cognitive impairments. However, whether metformin can reduce AD-related pathologies is still unconclusive. METHODS: Brain extracts containing tau aggregates were unilaterally injected into the hippocampus and the overlying cerebral cortex of 9-month-old APPswe/PS1DE9 (APP/PS1) mice and age-matched wild-type (WT) mice. Metformin was administrated in the drinking water for 2 months. Aß pathology, tau pathology, plaque-associated microgliosis, and autophagy marker were analyzed by immunohistochemical staining and immunofluorescence analysis 2 months after injection of proteopathic tau seeds. The effects of metformin on both pathologies were explored. RESULTS: We observed tau aggregates in dystrophic neurites surrounding Aß plaques (NP tau) in the bilateral hippocampi and cortices of tau-injected APP/PS1 mice but not WT mice. Aß plaques promoted the aggregation of NP tau pathology. Injection of proteopathic tau seeds exacerbated Aß deposits and decreased the number of microglia around Aß plaques in the hippocampus and cortex of APP/PS1 mice. Metformin ameliorated the microglial autophagy impairment, increased the number of microglia around Aß plaques, promoted the phagocytosis of NP tau, and reduced Aß load and NP tau pathology in APP/PS1 mice. CONCLUSION: These findings indicate the existence of the crosstalk between amyloid and NP tau pathology. Metformin promoted the phagocytosis of pathological Aß and tau proteins by enhancing microglial autophagy capability. It reduced Aß deposits and limited the spreading of NP tau pathology in APP/PS1 mice, which exerts a beneficial effect on both pathologies.

Interferon Regulatory Factor 5 Mediates Lipopolysaccharide-Induced Neuroinflammation.

Background: Activated microglia play a vital role in neuroinflammation in the central nervous system (CNS), which is associated with the pathogenesis and the progression of neurological diseases. Interferon regulatory factor 5 (IRF5) has been well established participating in inflammatory responses and is highly expressed in M1 macrophage in the periphery, the role of which in the CNS remains elusive. Methods: Lipopolysaccharide (LPS) was employed to induce neuroinflammation. Down-regulation of IRF5 in C57/BL6 mice and BV2 microglial cells were achieved by IRF5 siRNA transfection. The levels of pro-inflammatory cytokines were evaluated by ELISA and quantitative real-time PCR. The expression levels of IRF5 were examined by immunofluorescence and Western blot. Results: LPS induced significantly elevated expression of IRF5 in mouse brain, which co-localized with CD11b-positive microglia. Down-regulation of IRF5 quenched the pro-inflammatory responses. The levels of pro-inflammatory cytokines TNF-α, IL-1ß, and IL-6 were up-regulated at 4 h after LPS treatment, which were significantly down-regulated with the knockdown of IRF5. LPS-induced pro-inflammatory responses were transient, which were comparable to control group at 24 h after LPS treatment. However, LPS did not up-regulate the expression of IRF5 in BV2 microglial cells, indicating that LPS-induced inflammation in BV2 cells does not involve IRF5 signaling. Conclusions: IRF5 mediates the inflammatory responses in the CNS, which might serve as a therapeutic target for CNS inflammatory diseases. LPS-induced inflammation does not involve IRF5 signaling in BV2 microglia.

The differential effects of isoflurane and sevoflurane on neonatal mice.

Previous research has shown that exposure to volatile anesthetics can induce acute neuroinflammation and neuroapoptopsis in neonatal rodents and that these events can lead to cognitive dysfunction at later stages. Isoflurane and sevoflurane are two of the most popular anesthetics used in the field of pediatrics. However, the relative impact of these two anesthetics on the developing brain at distinct time points after the induction of anesthesia has not been compared. In the present study, we exposed 7-day-old mice to clinically equivalent doses of isoflurane (1.5%) and sevoflurane (2.5%) for 4 h and then investigated consequential changes in the brains of these mice at six different time points. We analyzed the levels of proteins that are directly related to neuroapoptosis, neuroinflammation, synaptic function, and memory, in the brains of neonatal mice. Exposure of neonatal mice to isoflurane and sevoflurane resulted in acute neuronal apoptosis. Our analysis observed significant levels of neuroinflammation and changes in the expression levels of proteins associated with both synaptic transmission and memory in mice from the isoflurane group but not the sevoflurane group. Our results therefore indicate that isoflurane and sevoflurane induce differential effects in the brains of neonatal mice.

Evaluation of the Mini-Mental State Examination and the Montreal Cognitive Assessment for Predicting Post-stroke Cognitive Impairment During the Acute Phase in Chinese Minor Stroke Patients.

Objective: To assess the value of the Mini-Mental State Examination (MMSE) and the Montreal Cognitive Assessment (MoCA) during acute phase in predicting post-stroke cognitive impairment (PSCI) at 3-6 months. Methods: We prospectively recruited 229 patients who had suffered their first-ever ischemic stroke. PSCI was determined in 104 of these patients by a comprehensive neuropsychological battery performed at 3-6 months. Receiver operating characteristic (ROC) curve analysis was then performed to compare the discriminatory ability of the MMSE and MoCA. Also, we applied a decision tree generated by the classification and regression tree methodology. Results: In total, 66 patients had PSCI when evaluated 3-6 months after the onset of minor stroke. Logistic regression analysis revealed that education, body mass index (BMI), and baseline MoCA scores were independently associated with PSCI. ROC curve analysis showed that the ability to predict PSCI was similar when compared between baseline MoCA scores [area under curve (AUC), 0.821; 95% confidence interval (CI), 0.743-0.898] and baseline MMSE scores (AUC, 0.809; 95% CI, 0.725-0.892, P = 0.75). Both MMSE and MoCA exhibited similar predictive values at their optimal cut-off points (MMSE ≤27; sensitivity, 0.682; specificity, 0.816; MoCA ≤21; sensitivity, 0.636; specificity, 0.895). Classification and regression tree-derived analysis yielded an AUC of 0.823 (sensitivity, 0.803; specificity, 0.842). Conclusion: When applied within 2 weeks of stroke, the MMSE and MoCA are both useful and have similar predictive value for PSCI 3-6 months after the onset of minor stroke.

Microbiota-gut-brain axis and toll-like receptors in Alzheimer's disease.

Alzheimer's disease (AD) is a multifactorial disease which involves both the periphery and central nervous system (CNS). It has been recently recognized that gut microbiota interacts with the gut and brain (microbiota-gut-brain axis), contributing to the pathogenesis of neurodegenerative diseases, such as AD. Dysbiosis of gut microbiota can induce increased intestinal permeability and systemic inflammation, which may lead to the development of AD pathologies and cognitive impairment via the neural, immune, endocrine, and metabolic pathways. Toll-like receptors (TLRs) play an important role in the innate immune system via recognizing microbes-derived pathogens and initiating the inflammatory process. TLRs have also been found in the brain, especially in the microglia, and have been indicated in the development of AD. In this review, we summarized the relationship between microbiota-gut-brain axis and AD, as well as the complex role of TLRs in AD. Intervention of the gut microbiota or modulation of TLRs properly might emerge as promising preventive and therapeutic strategies for AD.

Efficacy of intermittent pneumatic compression for venous thromboembolism prophylaxis in patients undergoing gynecologic surgery: A systematic review and meta-analysis.

We sought to comprehensively assess the efficacy of Intermittent Pneumatic Compression (IPC) in patients undergoing gynecologic surgery. A computerized literature search was conducted in Pubmed, Embase and Cochrane Library databases. Seven randomized controlled trials involving 1001 participants were included. Compared with control, IPC significantly lowered the deep vein thrombosis (DVT) risk [risk ratio (RR) = 0.33, 95% confidence interval (CI): 0.16 - 0.66]. The incidence of DVT in IPC and drugs group was similar (4.5% versus. 3.99%, RR = 1.19, 95% CI: 0.42 - 3.44). With regards to pulmonary embolism risk, no significant difference was observed in IPC versus control or IPC versus drugs. IPC had a lower postoperative transfusion rate than heparin (RR = 0.53, 95% CI: 0.32 - 0.89), but had a similar transfusion rate in operating room to low molecular weight heparin (RR = 1.06, 95% CI: 0.69 - 1.63). Combined use of IPC and graduated compression stockings (GCS) had a marginally lower risk of DVT than GCS alone (RR = 0.38, 95% CI: 0.14 - 1.03). In summary, IPC is effective in reducing DVT complications in gynecologic surgery. IPC is neither superior nor inferior to pharmacological thromboprophylaxis. However, whether combination of IPC and chemoprophylaxis is more effective than IPC or chemoprophylaxis alone remains unknown in this patient population.

A facile synthesis, antibacterial activity of pulvinone and its derivatives.

Pulvinone and several 3-fluoro-4-morpholino substituted pulvinone derivatives were synthesized in five steps from a common precursor, phenyl acetic acid. Most of synthetic morpholine substituted pulvinones showed inhibitory activity against Esherichia coli. For the first time, the inhibition of pulvinone and its derivatives against Gram-negative bacteria was reported.

Genome sequence of Pseudomonas putida S12, a potential platform strain for industrial production of valuable chemicals.

Pseudomonas putida strain S12, a well-studied solvent-tolerant bacterium, is considered a platform strain for the production of many chemicals. Here, we present a 6.28-Mb assembly of its genome sequence. We have annotated 32 coding sequences (CDSs) encoding efflux systems of organic compounds and 195 CDSs responsible for the metabolism of aromatic compounds.