ABSTRACT
Parkinson's disease (PD) is characterized by the selective loss of dopaminergic neurons in the substantia nigra and the accumulation of α-synuclein (α-Syn) aggregates. However, the molecular mechanisms regulating α-Syn aggregation and neuronal degeneration remain poorly understood. The peptidase M20 domain containing 1 (PM20D1) gene lies within the PARK16 locus genetically linked to PD. Single nucleotide polymorphisms regulating PM20D1 expression are associated with changed risk of PD. Dopamine (DA) metabolism and DA metabolites have been reported to regulate α-Syn pathology. Here we report that PM20D1 catalyzes the conversion of DA to N-arachidonoyl dopamine (NADA), which interacts with α-Syn and inhibits its aggregation. Simultaneously, NADA competes with α-Syn fibrils to regulate TRPV4-mediated calcium influx and downstream phosphatases, thus alleviating α-Syn phosphorylation. The expression of PM20D1 decreases during aging. Overexpression of PM20D1 or the administration of NADA in a mouse model of synucleinopathy alleviated α-Syn pathology, dopaminergic neurodegeneration, and motor impairments. These observations support the protective effect of the PM20D1-NADA pathway against the progression of α-Syn pathology in PD.
ABSTRACT
Sepsis patients are highly prone to sepsis-associated encephalopathy (SAE) complications, resulting in a high mortality rate. Recently, there has been no specific treatment for long-term improvement of cerebral function. Ginsenoside Rh2 is a form of steroidal saponins isolated from plant ginseng and has been shown to possess anti-inflammatory as well as neuroprotective characteristics; yet, the effect of ginsenoside Rh2 on SAE treatment is obscure. Accordingly, we proposed to investigate the effect of ginsenoside Rh2 in alleviating SAE damage. We established and utilized the SAE mouse model to determine the effect of Rh2 treatment on alleviating SAE. We determined the expression levels of Heme oxygenase-1(HO-1) and Nuclear factor erythroid 2-related factor 2 (Nrf2) as well as measured neural apoptosis by flow cytometry. Also, we quantified the levels of caspase-3, malondialdehyde (MDA), GSH-Px superoxide dismutase (SOD) and evaluated the animals' neural reflex function. First, used Rh2 to treat microglia BV2 and mouse neuron MN-c whether LPS exist or not, and then measured expression level of Iba-1, apoptotic rate, and ROS content applying flow cytometry. Also, we quantified the levels of tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), and interleukin-6 (IL-6). In comparison with the Sham group, the SAE model exhibited an elevated MDA content, caspase-3 activity, and cell apoptosis. On the other hand, the GSH-Px activity and SOD level were decreased along with a decreased neural reflex score. Our investigation concluded that Rh2 treatment significantly alleviated SAE damage and inhibited LPS-induced response via up-regulation of the Nrf2/HO-1 pathway to promote anti-oxidative stress capacity and inhibit neural cell apoptosis.
ABSTRACT
Selenium (Se) has a dual nature, with beneficial and harmful effects on plants, essential for both humans and animals, playing a crucial role in ecosystem regulation. Insufficient Se in specific terrestrial environments raises concerns due to its potential to cause diseases, while excess Se can lead to severe toxicity. Thus, maintaining an optimal Se level is essential for living organisms. This review focuses first on Se transformation, speciation, and geochemical properties in soil, and then provides a concise overview of Se distribution in Chinese soil and crops, with a focus on the relationship between soil Se levels and parent materials. Additionally, this paper explores Se bioavailability, considering parent materials and soil physicochemical properties, using partial least squares path modeling for analysis. This paper aimed to be a valuable resource for effectively managing Se-enriched soil resources, contributing to a better understanding of Se role in ecosystems.
Subject(s)
Biological Availability , Selenium , Soil , Selenium/metabolism , China , Soil/chemistry , Soil Pollutants/metabolism , Plants/metabolism , Crops, Agricultural/metabolism , Environmental Monitoring/methods , EcosystemABSTRACT
Current limitations in mechanical performance and foreign body reactions (FBR) often lead to implant failure, restricting the application of bioceramic scaffolds. This study presents a novel 3D-printed scaffold that combines the release of anti-inflammatory drugs with osteogenic stimulation. Initially, the inorganic and organic phases were integrated to ensure the scaffold's mechanical integrity through catechol chemistry and the electrostatic interactions between tannic acid and quaternary ammonium chitosan. Subsequently, layers of polydopamine-encapsulated puerarin-loaded zeolitic imidazolate framework-8 (ZIF-8) were self-assembled onto the stent's surface, creating the drug-loaded scaffold that improved drug release without altering the scaffold's structure. Compared with unloaded scaffolds, the puerarin-loaded scaffold demonstrated excellent osteogenic differentiation properties along with superior anti-inflammatory and osteogenic effects in a range of in vitro and in vivo studies. RNA sequencing clarified the role of the TNF and NF/κB signaling pathways in these effects, further supporting the scaffold's osteogenic potential. This study introduces a novel approach for creating drug-loaded scaffolds, providing a unique method for treating cancellous bone defects.
Subject(s)
Alginates , Calcium Phosphates , Chitosan , Isoflavones , Osteogenesis , Tannins , Tissue Engineering , Tissue Scaffolds , Chitosan/chemistry , Tissue Scaffolds/chemistry , Tissue Engineering/methods , Isoflavones/chemistry , Isoflavones/pharmacology , Osteogenesis/drug effects , Animals , Alginates/chemistry , Calcium Phosphates/chemistry , Calcium Phosphates/pharmacology , Tannins/chemistry , Tannins/pharmacology , Bone and Bones/drug effects , Mice , Bone Regeneration/drug effects , Cell Differentiation/drug effects , Humans , PolyphenolsABSTRACT
Detecting early-stage esophageal squamous cell carcinoma (ESCC) and precancerous lesions is critical for improving survival. Here, we conduct whole-genome bisulfite sequencing (WGBS) on 460 cfDNA samples from patients with non-metastatic ESCC or precancerous lesions and matched healthy controls. We develop an expanded multimodal analysis (EMMA) framework to simultaneously identify cfDNA methylation, copy number variants (CNVs), and fragmentation markers in cfDNA WGBS data. cfDNA methylation markers are the earliest and most sensitive, detectable in 70% of ESCCs and 50% of precancerous lesions, and associated with molecular subtypes and tumor microenvironments. CNVs and fragmentation features show high specificity but are linked to late-stage disease. EMMA significantly improves detection rates, increasing AUCs from 0.90 to 0.99, and detects 87% of ESCCs and 62% of precancerous lesions with >95% specificity in validation cohorts. Our findings demonstrate the potential of multimodal analysis of cfDNA methylome for early detection and monitoring of molecular characteristics in ESCC.
Subject(s)
Biomarkers, Tumor , DNA Copy Number Variations , DNA Methylation , Early Detection of Cancer , Esophageal Neoplasms , Esophageal Squamous Cell Carcinoma , Precancerous Conditions , Humans , Esophageal Squamous Cell Carcinoma/genetics , Esophageal Squamous Cell Carcinoma/diagnosis , Precancerous Conditions/genetics , Precancerous Conditions/diagnosis , Precancerous Conditions/pathology , Esophageal Neoplasms/genetics , Esophageal Neoplasms/diagnosis , Esophageal Neoplasms/pathology , Male , Early Detection of Cancer/methods , Female , Biomarkers, Tumor/genetics , Middle Aged , Aged , Epigenome , Cell-Free Nucleic Acids/genetics , Cell-Free Nucleic Acids/blood , Whole Genome Sequencing/methods , Tumor Microenvironment/geneticsABSTRACT
Objective: Keratoconus is a commonly progressive and blinding corneal disorder. Iron metabolism and oxidative stress play crucial roles in both keratoconus and ferroptosis. However, the association between keratoconus and ferroptosis is currently unclear. This study aimed to analyze and verify the role of ferroptosis-related genes (FRGs) in the pathogenesis of keratoconus through bioinformatics. Methods: We first obtained keratoconus-related datasets and FRGs. Then, the differentially expressed FRGs (DE-FRGs) associated with keratoconus were screened through analysis, followed by analysis of their biological functions. Subsequently, the LASSO and SVM-RFE algorithms were used to screen for diagnostic biomarkers. GSEA was performed to explore the potential functions of the marker genes. Finally, the associations between these biomarkers and immune cells were analyzed. qRTâPCR was used to detect the expression of these biomarkers in corneal tissues. Results: A total of 39 DE-FRGs were screened, and functional enrichment analysis revealed that the DE-FRGs were closely related to apoptosis, oxidative stress, and the immune response. Then, using multiple algorithms, 6 diagnostic biomarkers were selected, and the ROC curve was used to verify their risk prediction ability. In addition, based on CIBERSORT analysis, alterations in the immune microenvironment of keratoconus patients might be associated with H19, GCH1, CHAC1, and CDKN1A. Finally, qRTâPCR confirmed that the expression of H19 and CHAC1 was elevated in the keratoconus group. Conclusion: This study identified 6 DE-FRGs, 4 of which were associated with immune infiltrating cells, and established a diagnostic model with predictive value for keratoconus.
ABSTRACT
Parkinson's disease (PD) is a neurodegenerative disease characterized by the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNpc) and the formation of Lewy bodies (LBs). The main proteinaceous component of LBs is aggregated α-synuclein (α-syn). However, the mechanisms underlying α-syn aggregation are not yet fully understood. Converging lines of evidence indicate that, under certain pathological conditions, various proteins can interact with α-syn and regulate its aggregation. Understanding these protein-protein interactions is crucial for unraveling the molecular mechanisms contributing to PD pathogenesis. In this review we provide an overview of the current knowledge on protein-protein interactions that regulate α-syn aggregation. Additionally, we briefly summarize the methods used to investigate the influence of protein-protein interactions on α-syn aggregation and propagation.
Subject(s)
Neurodegenerative Diseases , Parkinson Disease , Humans , alpha-Synuclein/metabolism , Dopaminergic Neurons/metabolism , Neurodegenerative Diseases/metabolism , Parkinson Disease/metabolismABSTRACT
Mercury (Hg) contamination in aquatic environments presents a significant ecological and human health concern. This study explored the relationship between catchment land use and Hg concentrations within Qinghai Lake sediment, the largest lake in China, situated on the Qinghai-Tibet plateau. The study entailed detailed mapping of Hg sediment concentrations and a subsequent environmental risk assessment. Considering the complex nature of the plateau landform and surface vegetation, the study area was delineated at a 100 km radius centered on Qinghai Lake, which was divided into 30 sectors to quantify relationships between land use and the sediment Hg concentration. The results revealed a mean sediment Hg concentration of 29.91 µg/kg, which was elevated above the background level. Kendall's correlation analysis revealed significant but weak associations between sediment Hg concentrations and three land use types: grassland (rangeland and trees) (rs = 0.27, p < 0.05), crops (rs = -0.37, p < 0.05), and bare ground (rs = -0.25, p < 0.1), suggesting that growing areas of grassland correlated with higher Hg levels in the lake sediment, in contrast to bare ground or crops area, which correlated with lower Hg concentrations. Multiple linear regression models also observed weak negative relationships between bare ground and crops with sediment Hg concentration. This research methodology enhances our understanding of the impact of land use on Hg accumulation in lake sediments and underscores the need for integrated watershed management strategies to mitigate Hg pollution in Qinghai Lake.
ABSTRACT
The 2019 novel coronavirus disease (COVID-19) is an infectious disease that began to spread globally since 2019. Some COVID-19 patients have neurological complications, such as olfactory disorders and movement disorders, which coincide with the symptoms of Parkinson's disease (PD). Increasing imaging and autopsy evidence supports that the density of dopaminergic neurons in the nigrostriatal pathway is damaged in some COVID-19 patients. However, the underlying mechanism that causes PD-like symptoms remains unclear. PD is an age-related neurodegenerative disease with Lewy bodies (LBs) as its histopathologic feature. The main component of LBs is abnormally aggregated α-synuclein (α-syn). The prion-like propagation of α-syn aggregates plays a key role in the onset and progression of PD. The spike protein (S protein) of SARS-CoV-2 is a heparin-binding protein that mediates the entry of the virus into host cells. Here we found that the S1 domain interacts with α-syn and promotes α-syn aggregation. The S1 domain induces mitochondrial dysfunction, oxidative stress, and cytotoxicity. The S1-seeded α-syn fibrils show enhanced seeding activity and induce synaptic damage and cytotoxicity. Thus, the S1 domain of SARS-CoV-2 promotes the aggregation of α-syn in the cellular model of synucleinopathy and may contribute to the pathogenesis of PD.
Subject(s)
COVID-19 , Neurodegenerative Diseases , Parkinson Disease , Synucleinopathies , Humans , alpha-Synuclein/metabolism , Spike Glycoprotein, Coronavirus/metabolism , Phosphorylation , SARS-CoV-2 , Parkinson Disease/pathologyABSTRACT
Objective@#To understand sleep quarity among primary and middle school students in Shenzhen City, so as to provide data support for sleeping quality improvement.@*Methods@#A survey was conducted among 8 742 children selected from two 12 year schools in Longhua District of Shenzhen City, by purposive sampling method from December 22, 2020 to January 15, 2021. The general information was investigated with the self designed questionnaire, and sleep disturbance was investigated and evaluated with the Sleep Disturbance Scale for Children (SDSC). And Chi square test was applied for data analysis.@*Results@#About 47.61 % of primary and middle school students in Shenzhen City reported sleep disturbance, 10.84% of students had moderate to severe sleep disturbance. The overall rate of sleep disturbance and moderate and to severe sleep disturbance among primary school students (48.03%, 10.04%), junior middle schools (45.89%, 11.30%), senior middle schools (52.61%, 16.83%) were found of statistically significant differences ( χ 2=8.89, 27.05, P <0.05). The time to fall asleep for primary school students, junior school students and senior school students at night during the study period were 22:00-23:00 (90.35%), 22:00-23:00 (62.37%), and 23:00-01:00 (61.44%), respectively, and the time to fall asleep of the different stages students were found of statistically significant differences ( χ 2=1 470.17, P <0.01). About 41.04% of students could fall asleep within 15 minutes and 50.57% could fall asleep within 15 to 30 minutes, and the differences in the latency for different stages students to fall asleep at night were of statistical significance ( χ 2=82.92, P <0.01); 8.03% of primary and middle school students had a night sleep time of over 9 hours, and 45.97 % had a night sleep time of 8-9 hours, and the differences in the night sleep time among different stages students were of statistical significance ( χ 2=1 292.86, P <0.01).@*Conclusions@#The main sleep problems among primary and secondary school students in Shenzhen City are insufficient sleep and poor sleep quality. The relevant departments should emphasize the sleep health education among children and their parents, so as to improve their sleep quality.
ABSTRACT
Active colloids in a bath of inert particles of smaller size cause anisotropic depletion. The active hydrodynamics of this nonequilibrium phenomenon, which is fundamentally different from its equilibrium counterpart and passive particles in an active bath, remains scarcely understood. Here we combine mesoscale hydrodynamic simulation as well as theoretical analysis to examine the physical origin for the active depletion around a self-propelled noninteractive colloid. Our results elucidate that the variable hydrodynamic effect critically governs the microstructure of the depletion zone. Three characteristic states of anisotropic depletion are identified, depending on the strength and stress of activity. This yields a state diagram of depletion in the two-parameter space, captured by developing a theoretical model with the continuum kinetic theory and leading to a mechanistic interpretation of the hydrodynamic anisotropy of depletion. Furthermore, we demonstrate that such depletion in nonequilibrium results in various clusters with ordered organization of squirmers, which follows a distinct principle contrary to that of the entropy scenario of depletion in equilibrium. The findings might be of immediate interest to tune the hydrodynamics-mediated anisotropic interactions and active nonequilibrium organizations in the self-propulsion systems.
ABSTRACT
The long-term and large-scale mining of rare earth minerals may lead to an accumulation of rare earth elements (REEs) in the environment, posing potential health risks to residents. We collected scalp hair (n = 254) from residents of a smelting area, a mining area, and a reference area to clarify human exposure to REEs. The contents of 15 REEs investigated in human hair samples were notably higher in the mining and smelting areas than in the reference area. Significant differences between some REEs were observed between the mining and smelting areas, for instance, cerium (Ce), dysprosium, and praseodymium. In the study areas, exposure to different sources of REEs may be one of the factors that contributed to the variations of REE correlations and clusters in human hair. Furthermore, in the smelting area, Ce contents in hair decreased with increasing age of children. However, Ce contents in the hair of adults increased with age. In contrast, Ce accumulation continuously increased in the reference area residents' hair with age. Regression results indicated that age and location were more important than sex when considering the influence on REE accumulation in residents' hair. The results of this study may help policymakers to implement guidelines to alleviate residents' exposure to REE in mining and smelting areas.
Subject(s)
Cerium , Metals, Rare Earth , Adult , Child , Humans , Biological Monitoring , Hair , ChinaABSTRACT
The presence of trace metals (TMs) in agricultural soil has garnered considerable attention due to their potential migration into crops, posing a significant risk to human health. In this study, we examined the concentrations of eight trace metals (Cd, Cr, Cu, Hg, Mn, Ni, Pb, and Zn) in the soil and investigated various soil physicochemical characteristics in the Three Rivers Plain region, China. The assessment of the geoaccumulation index (Igeo) for the mean concentration of all trace metals indicated that the soils were generally free from significant TM pollution. However, a noteworthy finding emerged in relation to Hg, where the maximum Igeo value suggested moderate pollution levels. Kriging prediction results further indicated that approximately 1.55% of the study area might be impacted by Hg pollution. Moreover, it is prudent to direct attention towards Cd, Cr, Cu, Mn, and Ni, as their Igeo values revealed that the region with the highest concentrations of these metals ranged from unpolluted to moderately polluted. This study employed a comprehensive approach, utilizing the Self-Organizing Map (SOM), Kriging spatial distribution, and the Positive Matrix Factorization (PMF) model to identify the sources of TMs in agricultural soil. The results unveiled that the primary contributors to TM presence were the natural parental materials, alongside industrial activities such as coal mining and coal plant operations, as well as agricultural practices. These findings provide foundational insights for future management strategies in the Three Rivers Plain, aiming to enhance agricultural productivity and promote sustainability.
Subject(s)
Mercury , Metals, Heavy , Soil Pollutants , Trace Elements , Humans , Soil , Farms , Metals, Heavy/analysis , Cadmium , Environmental Monitoring/methods , Soil Pollutants/analysis , Risk Assessment , ChinaABSTRACT
BACKGROUND: The accumulation and aggregation of α-synuclein (α-Syn) are characteristic of Parkinson's disease (PD). Epidemiological evidence indicates that hyperlipidemia is associated with an increased risk of PD. The levels of 27-hydroxycholesterol (27-OHC), a cholesterol oxidation derivative, are increased in the brain and cerebrospinal fluid of patients with PD. However, whether 27-OHC plays a role in α-Syn aggregation and propagation remains elusive. OBJECTIVE: The aim of this study was to determine whether 27-OHC regulates α-Syn aggregation and propagation. METHODS: Purified recombinant α-Syn, neuronal cultures, and α-Syn fibril-injected mouse model of PD were treated with 27-OHC. In addition, CYP27A1 knockout mice were used to investigate the effect of lowering 27-OHC on α-Syn pathology in vivo. RESULTS: 27-OHC accelerates the aggregation of α-Syn and enhances the seeding activity of α-Syn fibrils. Furthermore, the 27-OHC-modified α-Syn fibrils localize to the mitochondria and induce mitochondrial dysfunction and neurotoxicity. Injection of 27-OHC-modified α-Syn fibrils induces enhanced spread of α-Syn pathology and dopaminergic neurodegeneration compared with pure α-Syn fibrils. Similarly, subcutaneous administration of 27-OHC facilitates the seeding of α-Syn pathology. Genetic deletion of cytochrome P450 27A1 (CYP27A1), the enzyme that converts cholesterol to 27-OHC, ameliorates the spread of pathologic α-Syn, degeneration of the nigrostriatal dopaminergic pathway, and motor impairments. These results indicate that the cholesterol metabolite 27-OHC plays an important role in the pathogenesis of PD. CONCLUSIONS: 27-OHC promotes the aggregation and spread of α-Syn. Strategies aimed at inhibiting the CYP27A1-27-OHC axis may hold promise as a disease-modifying therapy to halt the progression of α-Syn pathology in PD. © 2023 International Parkinson and Movement Disorder Society.
Subject(s)
Parkinson Disease , Humans , Mice , Animals , Parkinson Disease/genetics , alpha-Synuclein/genetics , alpha-Synuclein/metabolism , Hydroxycholesterols/pharmacology , CholesterolABSTRACT
Increased poll gland secretion is a major characteristic and indicator of estrus in male Bactrian camels; however, research on these poll glands and their secretion is extremely rare. In this study, we determine the chemical composition of poll gland secretions and identify the key functional substances that regulate seasonal estrus in male camels. A GC/LC-MS dual platform was used to analyze ventral hair (control) and neck mane samples containing poll gland secretions from male Bactrian camels during estrus. Multidimensional and single-dimensional analyses were used to screen differentially expressed metabolites (DEMs) between groups. Functional prediction of enriched metabolites was performed using a Human Metabolome Database comparison and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis, which were then compared with a behavioral analysis of male Bactrian camels in estrus. A total of 1172 DEMs and 34 differential metabolic pathways were identified. One metabolite group was found to relate to steroid synthesis and metabolism, and another metabolite group was associated with neural metabolism. Therefore, we speculate that steroids and neurochemicals jointly regulate estrous behavior in male Bactrian camels, thus providing theoretical insights into the development and function of poll glands in Bactrian camels.
ABSTRACT
BACKGROUND: IDH1/2 hotspot mutations are well known to drive oncogenic mutations in gliomas and are well-defined in the WHO 2021 classification of central nervous system tumors. Specifically, IDH mutations lead to aberrant hypermethylation of under-methylated regions (UMRs) in normal tissues through the disruption of TET enzymes. However, the chromatin reprogramming and transcriptional changes induced by IDH-related hypermethylation in gliomas remain unclear. RESULTS: Here, we have developed a precise computational framework based on Hidden Markov Model to identify altered methylation states of UMRs at single-base resolution. By applying this framework to whole-genome bisulfite sequencing data from 75 normal brain tissues and 15 IDH mutant glioma tissues, we identified two distinct types of hypermethylated UMRs in IDH mutant gliomas. We named them partially hypermethylated UMRs (phUMRs) and fully hypermethylated UMRs (fhUMRs), respectively. We found that the phUMRs and fhUMRs exhibit distinct genomic features and chromatin states. Genes related to fhUMRs were more likely to be repressed in IDH mutant gliomas. In contrast, genes related to phUMRs were prone to be up-regulated in IDH mutant gliomas. Such activation of phUMR genes is associated with the accumulation of active H3K4me3 and the loss of H3K27me3, as well as H3K36me3 accumulation in gene bodies to maintain gene expression stability. In summary, partial erosion on UMRs was accompanied by locus-specific changes in key chromatin marks, which may contribute to oncogene activation. CONCLUSIONS: Our study provides a computational strategy for precise decoding of methylation encroachment patterns in IDH mutant gliomas, revealing potential mechanistic insights into chromatin reprogramming that contribute to oncogenesis.
Subject(s)
Brain Neoplasms , Glioma , Humans , Brain Neoplasms/genetics , Chromatin/genetics , Glioma/genetics , Glioma/metabolism , Glioma/pathology , DNA Methylation , Mutation , Oncogenes , Isocitrate Dehydrogenase/genetics , Isocitrate Dehydrogenase/metabolismABSTRACT
The molecular mechanisms mediating the aggregation and transmission of tau in AD remain unclear. Here, we show that the actin-binding protein cofilin is cleaved by a cysteine protease asparagine endopeptidase (AEP) at N138 in the brains of patients with AD. The AEP-generated cofilin 1-138 fragment interacts with tau and promotes its aggregation. The mixed fibrils consisting of cofilin 1-138 and tau are more pathogenic to cells than pure tau fibrils. Furthermore, overexpression of cofilin 1-138 in the brain facilitates the propagation of pathological tau aggregates and promotes AD-like cognitive impairments in tau P301S mice. However, mice infected with adeno-associated viruses (AAVs) encoding an AEP-uncleavable cofilin mutant show attenuated tau pathology and cognitive impairments compared with mice injected with AAVs encoding wild-type cofilin. Together, these observations support the role of the cofilin 1-138 fragment in the aggregation and transmission of tau pathology during the onset and progression of AD.
Subject(s)
Alzheimer Disease , Animals , Humans , Mice , Actin Depolymerizing Factors/metabolism , Alzheimer Disease/metabolism , Brain/metabolism , Cofilin 1/metabolism , Disease Models, Animal , Mice, Transgenic , tau Proteins/metabolismABSTRACT
Tumor necrosis factor-α (TNFα) inhibitors are widely used in treating autoimmune diseases like rheumatoid arthritis (RA). These inhibitors can presumably alleviate RA symptoms by blocking TNFα-TNF receptor 1 (TNFR1)-mediated pro-inflammatory signaling pathways. However, the strategy also interrupts the survival and reproduction functions conducted by TNFα-TNFR2 interaction and causes side effects. Thus, it is urgently needed to develop inhibitors that can selectively block TNFα-TNFR1 but not TNFα-TNFR2. Here, nucleic acid-based aptamers against TNFR1 are explored as potential anti-RA candidates. Through the systematic evolution of ligands by exponential enrichment (SELEX), two types of TNFR1-targeting aptamers were obtained, and their KD values are approximately 100-300 nM. In silico analysis shows that the binding interface of aptamer-TNFR1 highly overlapped with natural TNFα-TNFR1 binding. On the cellular level, the aptamers can exert TNFα inhibitory activity by binding to TNFR1. The anti-inflammatory efficiencies of aptamers were assessed and further enhanced using divalent aptamer constructs. These findings provide a new strategy to block TNFR1 for potential anti-RA treatment precisely.
Subject(s)
Arthritis, Rheumatoid , Receptors, Tumor Necrosis Factor, Type I , Humans , Receptors, Tumor Necrosis Factor, Type I/metabolism , Receptors, Tumor Necrosis Factor, Type II/metabolism , Arthritis, Rheumatoid/pathology , Signal Transduction , Anti-Inflammatory Agents/pharmacology , Oligonucleotides , Tumor Necrosis Factor-alpha/metabolismABSTRACT
There is a growing concern about human health of residents living in areas where mining and smelting occur. In order to understand the exposure to the potentially toxic elements (PTEs), we here identify and examine the cadmium (Cd), chromium (Cr), copper (Cu), manganese (Mn), nickel (Ni), lead (Pb) and zinc (Zn) in scalp hair of residents living in the mining area (Bayan Obo, n = 76), smelting area (Baotou, n = 57) and a reference area (Hohhot, n = 61). In total, 194 hair samples were collected from the volunteers (men = 87, women = 107) aged 5-77 years old in the three areas. Comparing median PTEs levels between the young and adults, Ni levels were significantly higher in adults living in the smelting area while Cr was highest in adults from the mining area, no significant difference was found for any of the elements in the reference area. From the linear regression model, no significant relationship between PTEs concentration, log10(PTEs), and age was found. The concentrations of Ni, Cd, and Pb in hair were significantly lower in the reference area when compared to both mining and smelting areas. In addition, Cu was significantly higher in the mining area when compared to the smelting area. Factor analysis (FA) indicated that men and women from the smelting area (Baotou) and mining area (Bayan Obo), respectively, had different underlying communality of log10(PTEs), suggesting different sources of these PTEs. Multiple factor analysis quantilized the importance of gender and location when combined with PTEs levels in human hair. The results of this study indicate that people living in mining and/or smelting areas have significantly higher PTEs (Cu, Ni, Cd, and Pb) hair levels compared to reference areas, which may cause adverse health effects. Remediation should therefore be implemented to improve the health of local residents in the mining and smelting areas.