Targeting p53 for neuroinflammation: New therapeutic strategies in ischemic stroke.

Ischemic stroke (IS) is characterized by high incidence, high recurrence, and high mortality and places a heavy burden on society and families. The pathological mechanisms of IS are complex, among which secondary neurological impairment mediated by neuroinflammation is considered to be the main factor in cerebral ischemic injury. At present, there is still a lack of specific therapies to treat neuroinflammation. The tumor suppressor protein p53 has long been regarded as a key substance in the regulation of the cell cycle and apoptosis in the past. Recently, studies have found that p53 also plays an important role in neuroinflammatory diseases, such as IS. Therefore, p53 may be a crucial target for the regulation of the neuroinflammatory response. Here, we provide a comprehensive review of the potential of targeting p53 in the treatment of neuroinflammation after IS. We describe the function of p53, the major immune cells involved in neuroinflammation, and the role of p53 in inflammatory responses mediated by these cells. Finally, we summarize the therapeutic strategies of targeting p53 in regulating the neuroinflammatory response after IS to provide new directions and ideas for the treatment of ischemic brain injury.

Mechanism of ligusticum cycloprolactam against neuroinflammation based on network pharmacology and experimental verification.

Ligustilide, a natural phthalide mainly derived from chuanxiong rhizomes and Angelica Sinensis roots, possesses anti-inflammatory activity, particularly in the context of the nervous system. However, its application is limited because of its unstable chemical properties. To overcome this limitation, ligusticum cycloprolactam (LIGc) was synthesized through structural modification of ligustilide. In this study, we combined network pharmacological methods with experimental verification to investigate the anti-neuroinflammatory effects and mechanisms of ligustilide and LIGc. Based on our network pharmacology analysis, we identified four key targets of ligustilide involved in exerting an anti-inflammatory effect, with the nuclear factor (NF)-κB signal pathway suggested as the main signalling pathway. To verify these results, we examined the expression of inflammatory cytokines and inflammation-related proteins, analysed the phosphorylation level of NF-κB, inhibitor of κBα (IκBα) and inhibitor of κB kinase α and ß (IKKα+ß), and evaluated the effect of BV2 cell-conditioned medium on HT22 cells in vitro. Our results, demonstrate for the first time that LIGc can downregulate the activation of the NF-κB signal pathway in BV2 cells induced by lipopolysaccharide, suppress the production of inflammatory cytokines and reduce nerve injury in HT22 cells mediated by BV2 cells. These findings suggest that LIGc inhibits the neuroinflammatory response mediated by BV2 cells, providing strong scientific support for the development of anti-inflammatory drugs based on natural ligustilide or its derivatives. However, there are some limitations to our current study. In the future, further experiments using in vivo models may provide additional evidence to support our findings.

Molecular Mechanism of the Protective Effects of M2 Microglia on Neurons: A Review Focused on Exosomes and Secretory Proteins.

Microglia, as innate immune cells in the brain, closely monitor changes in the internal environment and participate in the maintenance of homeostasis in the central nervous system (CNS). Microglia can be polarized to the M1 or M2 phenotype in response to various stimuli in vivo or in vitro, affecting the functions of peripheral neurons. M2 microglia have attracted increasing attention in recent years owing to their beneficial effects on various diseases and injuries of the CNS, such as traumatic brain injury, stroke, Alzheimer's disease and multiple sclerosis. They exert neuroprotective effects by various mechanisms, e.g., suppressing inflammation, promoting the degradation of misfolded and aggregated proteins, promoting neurite growth, enhancing neurogenesis, inhibiting autophagy and apoptosis, promoting myelination, maintaining blood-brain barrier integrity, and enhancing phagocytic activity.This review summarizes the molecular mechanisms by which M2 microglia exert protective effects on neurons and provides a reference for the selection of therapeutic targets for CNS diseases.

Occurrence and health implications of heavy metals in preschool children's clothing manufactured in four Asian regions.

Clothing may be a potential contributor to body metal burden in children. However, available information on heavy metals in children's clothing is extremely limited and the associated health risks remain poorly understood. This study investigated the concentrations of Pb, Cd, Co, Zn, Cr, As, Cu and Ni in new preschool children's clothing manufactured in four Asian regions. The children's clothing had higher levels of Ni and Cr but lower levels of Pb and Cd in comparison to the concentrations reported in other textile products. The concentrations of Cd were higher in the black clothing than those in the white and color samples. The non-cotton samples contained higher Co concentrations. The Pb concentrations in the samples manufactured in China were significantly higher than those in the other three regions. We estimated the dermal exposure doses for these metals and calculated the associated risks. The results indicated that the health risks from exposure to these metals in the children's clothing were acceptable. However, more research is required to investigate heavy metals and the associated risks in child clothing due to the increasing complexity of their materials and manufacturing processes.

Occurrence and Distribution of Phthalates in Sanitary Napkins from Six Countries: Implications for Women's Health.

Chemicals in feminine hygiene products can exert adverse health effects as a result of strong absorptive capacity of the vagina and vulva. However, little information is available on phthalates in sanitary napkins. We measured the concentrations of 15 phthalates in sanitary napkins collected from six countries and found total concentrations in the range of 1733-11942 ng/g. Di(isobutyl)phthalate (DiBP), bis(2-ethylhexyl)phthalate (DEHP), and di-n-butyl phthalate (DnBP) were the dominant congeners, representing a median of 27.3, 26.7, and 20.4% of the total median phthalate concentrations across all countries, respectively. The phthalates likely originated mainly from the introduction in the manufacturing process, and some may have been from the use of plastic or paper materials. The estimated intake (at the 90th percentile) of DiBP, DnBP, and DEHP from sanitary napkins approximately represented 6.35-23.6, 3.35-9.90, and 1.06-9.57%, respectively, of the total exposure, indicating that sanitary napkins are a relevant source of exposure to these chemicals. The calculated health risks of phthalates in sanitary napkins were generally low, but the carcinogenic risks in some samples exceeded acceptable levels. More research is required to investigate the contaminations in sanitary napkins and those associated with risks to women.

Contamination and health risks of heavy metals in street dust from a coal-mining city in eastern China.

We collected street dust from Huainan, a typical coal-mining city in China, to investigate the contamination features and health risks of heavy metals. Concentrations of Co, Cr, Cu, Pb, As, and Sb were generally low to moderate, while pollution levels of Cd and Hg were moderate to high. Concentrations of Cd and Hg were associated with considerable health risks at 64.3% and 58.6% of sites, respectively. In particular, about a fifth of samples had associated high risks as a result of Hg contamination levels. Relative to other urban areas, the street dust from the mining area had no more severe metal pollution, which might be partly attributed to the deposition of coal dust onto street dusts. A source assessment indicated that metals in dust form Huainan were mainly derived from vehicular-related activities, industrial emissions, weathering of coal dust and natural soils, and coal combustion. Although the health risk levels from exposure to individual metals in dusts were low, the non-carcinogenic risks from multiple metals to local children exceeded the acceptable level (1.0), suggesting that the overall risk from exposure to multiple metals in dust is concerning.

Contamination and risk of heavy metals in soils and sediments from a typical plastic waste recycling area in North China.

Plastic wastes are increasingly being recycled in many countries. However, available information on the metals released into the environment during recycling processes is rare. In this study, the contamination features and risks of eight heavy metals in soils and sediments were investigated in Wen'an, a typical plastic recycling area in North China. The surface soils and sediments have suffered from moderate to high metal pollution and in particular, high Cd and Hg pollution. The mean concentrations of Cd and Hg were 0.355 and 0.408 mg kg(-1), respectively, in the soils and 1.53 and 2.10 mg kg(-1), respectively, in the sediments. The findings suggested that there is considerable to high potential ecological risks in more than half of the soils and high potential ecological risk in almost all sediments. Although the health risk levels from exposure to soil metals were acceptable for adults, the non-carcinogenic risks to local children exceeded the acceptable level. Source assessment indicated that heavy metals in soils and sediments were mainly derived from inputs from poorly controlled plastic waste recycling operations in this area. The results suggested that the risks associated with heavy metal pollution from plastic waste recycling should be of great concern.

[Recent advances and perspective in the study of the nano-reinforcing materials for molecular imprinting of proteins].

Molecular imprinting technique (MIT) involves the synthesis of polymer in the presence of a template to produce complementary binding sites in terms of its size, shape and functional group orientation. Such kind of polymer possesses specific recognition ability towards its template molecule. Despite the rapid development of MIT over the years, the majority of the template molecules that have been studied are small molecules, while molecular imprinting of proteins remains a significant yet challenging task due to their large size, structural flexibility and complex conformation. This review, we summarized the research findings over the past years, and discussed the nano-reinforcing materials used to prepare molecular imprinting of proteins and the perspective of these nano-reinforcing materials.

Effects of Bone Marrow Mesenchymal Stem Cell-Derived Exosomes in Central Nervous System Diseases.

Central nervous system (CNS) diseases are one of the diseases that threaten human health. The delivery of drugs targeting the CNS has always been a significant challenge; the blood-brain barrier (BBB) is the main obstacle that must be overcome. The rise of bone marrow mesenchymal stem cell (BMSC) therapy has brought hope for the treatment of CNS diseases. However, the problems of low homing rate, susceptibility differentiation into astrocytes, immune rejection, and formation of iatrogenic tumors of transplanted BMSCs limit their clinical application. Bone marrow mesenchymal stem cell-derived exosomes (BMSC-Exos) have become a hot research topic in the treatment of CNS diseases in recent years because of their excellent histocompatibility, low immunogenicity, ease of crossing the BBB, and their ability to serve as natural carriers for treatment. This article reviews the mechanisms of BMSC-Exos in CNS diseases and provides direction for further research.

Research progress on mechanisms of ischemic stroke: Regulatory pathways involving Microglia.

Microglia, as the intrinsic immune cells in the brain, are activated following ischemic stroke. Activated microglia participate in the pathological processes after stroke through polarization, autophagy, phagocytosis, pyroptosis, ferroptosis, apoptosis, and necrosis, thereby influencing the injury and repair following stroke. It has been established that polarized M1 and M2 microglia exhibit pro-inflammatory and anti-inflammatory effects, respectively. Autophagy and phagocytosis in microglia following ischemia are dynamic processes, where moderate levels promote cell survival, while excessive responses may exacerbate neurofunctional deficits following stroke. Additionally, pyroptosis and ferroptosis in microglia after ischemic stroke contribute to the release of harmful cytokines, further aggravating the damage to brain tissue due to ischemia. This article discusses the different functional states of microglia in ischemic stroke research, highlighting current research trends and gaps, and provides insights and guidance for further study of ischemic stroke.

Developing Two Rapid Protein Extraction Methods Using Focused-Ultrasonication and Zirconia-Silica Beads for Filamentous Fungi Identification by MALDI-TOF MS.

Filamentous fungi identification by Matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) has been challenging due to the lack of simple and rapid protein extraction methods and insufficient species coverage in the database. In this study, we created two rapid protein extraction methods for filamentous fungi: a one-step zirconia-silica beads method (ZSB) and a focused-ultrasonication method (FUS). The identification accuracy of two methods were evaluated with the VITEK MS, as well as number of spectra peaks and signal-to-noise ratio (S/N) with M-Discover 100 MALDI-TOF MS compared to the routine method. The better method was applied to build a filamentous fungi in-house spectra library for the M-Discover 100 MS, and then another one and routine method were performed in parallel to verify the accuracy and commonality of the in-house library. Using the two optimized methods, the dedicated operating time before MALDI-TOF MS analysis was reduced from 30 min to 7 (ZSB) or 5 (FUS) min per sample, with only a few seconds added for each additional strain. And both two methods identified isolates from most mold types equal to or better than the routine method, and the total correct identification rate using VITEK MS was 79.67, 76.42, and 76.42%, respectively. On the other hand, the two rapid methods generally achieved higher maximum and minimum S/N ratios with these isolates tested as compared to the routine method. Besides, the ZSB method produced overall mean of maximum and minimum S/N ratio higher than that by FUS. An in-house library of M-Discover MS was successfully built from 135 isolates from 42 species belonging to 18 genera using the ZSB method. Analysis of 467 isolates resulted in 97.22% correctly identified isolates to the species level by the ZSB method versus 95.50% by the routine method. The two novel methods are time- and cost-effective and allow efficient identification of filamentous fungi while providing a simplified procedure to build an in-house library. Thus, more clinical laboratories may consider adopting MALDI-TOF MS for filamentous fungi identification in the future.

Phthalates in preschool children's clothing manufactured in seven Asian countries: Occurrence, profiles and potential health risks.

Phthalates could be introduced into clothing as chemical additives or impurities, becoming a potential source of human exposure. We measured the concentrations of 15 phthalates in new preschool children's clothing manufactured in seven Asian countries. Phthalates were prevalent in all samples, and total concentrations were 2.92-223 µg/g, indicating a moderate contamination level. Bis(2-ethylhexyl) phthalate, di(isobutyl) phthalate and di-n-butyl phthalate were the most abundant phthalates measured, representing a median of 48.5 %, 13.6 % and 13.4 % of the total concentrations, respectively. Total concentrations did not differ significantly by country of manufacture, while the concentrations of individual phthalates and their composition profiles varied widely. We also found differing phthalate levels by item type, fabric composition, and color. Under the assumed two exposure scenarios, the median of summed dermal exposure doses of six phthalate were 539 and 950 ng/kg of body weight per day, respectively. When children wore trousers, long-sleeved shirts, briefs and socks at the same time, the reproductive risks exceeded acceptable level, although the carcinogenic risk of DEHP was low. Our results suggested that new clothing is an important route of phthalate exposure to preschool children. More research is required to investigate the contaminations and associated with risks in child clothing.

Identification of a thymus microRNA­mRNA regulatory network in Down syndrome.

The present bioinformatics analysis was performed using a multi­step approach to identify a microRNA (miR)­mRNA regulatory network in Down syndrome. miR (GSE69210) and mRNA (GSE70573) data was downloaded and collected from the thymic tissues of both Down syndrome and karyotypically normal subjects and placed in a public repository. Then, weighted gene co­expression network analysis (WGCNA) was performed to screen for miRs and mRNAs associated with Down syndrome. Subsequently, differentially expressed miRs (DEmiRs) and mRNAs/differentially expressed genes (DEGs) were identified following screening and mapping to RNA data. Bidirectional hierarchical clustering analysis was then performed to distinguish DEmiRs and DEGs between Down syndrome samples and normal control samples. DEmiR targets were retrieved using the miRanda database and mapped to the mRNA module screen by WGCNA. A gene co­expression network was constructed and subjected to functional enrichment analysis. During WGCNA, a total of 6 miR modules and 20 mRNA modules associated with Down syndrome were identified. Following mapping of these miRs and mRNAs to the miR and mRNA modules screened using WGNCA, a total of 12 DEmiRs and 237 DEGs were collected. Following comparison with DEmiR targets retrieved from the miRanda database, a total of 255 DEmiR­DEG pairs, including 6 DEmiRs and 106 DEGs were obtained. At expression correlation coefficient >0.9, a total of 231 gene pairs were selected. These gene pairs were enriched in response to stress and response to stimuli following functional annotation and module division. An integrated analysis of miR and mRNA expression in the thymus in Down syndrome is reported in the present study. miR­30c, miR­145, miR­183 and their targets may serve important roles in the pathogenesis and development of complications in Down syndrome. However, further experimental studies are required to verify these results.

Identification of genes and signaling pathways associated with arthrogryposis­renal dysfunction­cholestasis syndrome using weighted correlation network analysis.

The present study aimed to identify the molecular basis of the arthrogryposis­renal dysfunction­cholestasis (ARC) syndrome, which is caused by mutations in the vacuolar protein sorting 33 homolog B (VPS33B) gene. The microarray dataset GSE83192, which contained six liver tissue samples from VPS33B knockout mice and four liver tissue samples from control mice, was downloaded from the Gene Expression Omnibus database. The differentially expressed genes (DEGs) were screened by the Limma package in R software. The DEGs most relevant to ARC were selected via weighted gene co­expression network analysis to construct a protein­protein interaction (PPI) network. In addition, module analysis was performed for the PPI network using the Molecular Complex Detection function. Functional and pathway enrichment analyses were also performed for DEGs in the PPI network. Potential drugs for ARC treatment were predicted using the Connectivity Map database. In total, 768 upregulated and 379 downregulated DEGs were detected in the VPS33B knockout mice, while three modules were identified from the PPI network constructed. The DEGs in module 1 (CD83, IL1B and TLR2) were mainly involved in the positive regulation of cytokine production and the Toll­like receptor (TLR) signaling pathway. The DEGs in module 2 (COL1A1 and COL1A2) were significantly enriched with respect to cellular component organization, extracellular matrix­receptor interactions and focal adhesion. The DEGs in module 3 (ABCG8 and ABCG3) were clearly associated with sterol absorption and transport. Furthermore, mercaptopurine was identified to be a potential drug (connectivity score=­0.939) for ARC treatment. In conclusion, the results of the current study may help to further understand the pathology of ARC, and the DEGs identified in these modules may serve as therapeutic targets.

Polybrominated diphenyl ethers (PBDEs) and heavy metals in road dusts from a plastic waste recycling area in north China: implications for human health.

Road dusts were collected from an area where intense mechanical recycling of plastic wastes occurs in Wen'an, north China. These dusts were investigated for polybrominated diphenyl ethers (PBDEs) and heavy metals contamination to assess the health risk related to these components. Decabromodiphenyl ether (BDE-209) and Σ21PBDE concentrations in these dusts ranged from 2.67 to 10,424 ng g(-1) and from 3.23 to 10,640 ng g(-1), respectively. These PBDE concentrations were comparable to those observed in road dust from e-waste recycling areas but were 1-2 orders of magnitude higher than concentrations in outdoor or road dusts from other areas. This indicates that road dusts in the study area have high levels of PBDE pollution. BDE-209 was the predominant congener, accounting for 86.3% of the total PBDE content in dusts. Thus, commercial deca-BDE products were the dominant source. The average concentrations of As, Cd, Cr, Cu, Hg, Pb, Sb, and Zn in these same dust samples were 10.1, 0.495, 112, 54.7, 0.150, 71.8, 10.6, and 186 mg kg(-1), respectively. The geoaccumulation index suggests that road dusts in this area are moderately to heavily polluted with Cd, Hg, and Sb. This study shows that plastic waste processing is a major source of toxic pollutants in road dusts in this area. Although the health risk from exposure to dust PBDEs was low, levels of some heavy metals in this dust exceeded acceptable risk levels for children and are of great concern.

[Optimization of method of titration rabies virus with fluorescence focus units assay].

OBJECTIVE: A new Fluorescence Focus Units (FFU) developed for Rabies Virus titration replace current reference method (LD50) so as to reduce the cost. METHODS: The BSR cell was infected by triple serial dilution of the Rabies Virus CTN strain, then detect the fluorescent focus by FITC labeling anti-Rabies Virus monoclonal antibodies. All the samples were assayed in both FFU and LD50. RESULTS: Data generated indicateed that a significant correlation between the two methods (r=99). CONCLUSION: This method is simple and rapid. It will be considered as a useful alternative method to the LD50.