Transected axons fail to regrow in the mature central nervous system. Astrocytic scars are widely regarded as causal in this failure. Here, using three genetically targeted loss-of-function ...manipulations in adult mice, we show that preventing astrocyte scar formation, attenuating scar-forming astrocytes, or ablating chronic astrocytic scars all failed to result in spontaneous regrowth of transected corticospinal, sensory or serotonergic axons through severe spinal cord injury (SCI) lesions. By contrast, sustained local delivery via hydrogel depots of required axon-specific growth factors not present in SCI lesions, plus growth-activating priming injuries, stimulated robust, laminin-dependent sensory axon regrowth past scar-forming astrocytes and inhibitory molecules in SCI lesions. Preventing astrocytic scar formation significantly reduced this stimulated axon regrowth. RNA sequencing revealed that astrocytes and non-astrocyte cells in SCI lesions express multiple axon-growth-supporting molecules. Our findings show that contrary to the prevailing dogma, astrocyte scar formation aids rather than prevents central nervous system axon regeneration.
Changes in gene expression that occur across the central nervous system (CNS) during neurological diseases do not address the heterogeneity of cell types from one CNS region to another and are ...complicated by alterations in cellular composition during disease. Multiple sclerosis (MS) is multifocal by definition. Here, a cell-specific and region-specific transcriptomics approach was used to determine gene expression changes in astrocytes in the most widely used MS model, experimental autoimmune encephalomyelitis (EAE). Astrocyte-specific RNAs from various neuroanatomic regions were attained using RiboTag technology. Sequencing and bioinformatics analyses showed that EAE-induced gene expression changes differed between neuroanatomic regions when comparing astrocytes from spinal cord, cerebellum, cerebral cortex, and hippocampus. The top gene pathways that were changed in astrocytes from spinal cord during chronic EAE involved decreases in expression of cholesterol synthesis genes while immune pathway gene expression in astrocytes was increased. Optic nerve from EAE and optic chiasm from MS also showed decreased cholesterol synthesis gene expression. The potential role of cholesterol synthesized by astrocytes during EAE and MS is discussed. Together, this provides proof-of-concept that a cell-specific and region-specific gene expression approach can provide potential treatment targets in distinct neuroanatomic regions during multifocal neurological diseases.
Excessive exposure to manganese in the environment or workplace is strongly linked to neurodegeneration and cognitive impairment, but the precise pathogenic mechanism and preventive measures are ...still not fully understood. The study aimed to investigate manganese -induced oxidative damage in the nervous system from an epigenetic perspective, focusing on the H3K36ac-dependent antioxidant pathway. Additionally, it sought to examine the potential of curcumin in preventing manganese-induced oxidative damage. Histopathology and transmission electron microscopy revealed that apoptosis and necrosis of neurons and mitochondrial ultrastructure damage were observed in the striatum of manganese-exposed rats. manganese suppressed the expression of mitochondrial antioxidant genes, leading to oxidative damage in the rats' striatum and SH-SY5Y cells. With higher doses of manganese, levels of histone acetyltransferase lysine acetyltransferase 2 A (KAT2A) expression and H3K36ac level decreased. ChIP-qPCR confirmed that H3K36ac enrichment in the promoter regions of antioxidant genes SOD2, PRDX3, and TXN2 was reduced in SH-SY5Y cells after manganese exposure, leading to decreased expression of these genes. Overexpression of KAT2A confirms that it attenuates manganese-induced mitochondrial oxidative damage by regulating H3K36ac levels, which in turn controls the expression of antioxidant genes SOD2, PRDX3, and TXN2 in the manganese-exposed cell model. Furthermore, curcumin might control H3K36ac levels by influencing KAT2A expression, boosting antioxidant genes expression, and reducing manganese-induced mitochondrial oxidative damage. In conclusion, the regulation of mitochondrial oxidative stress by histone acetylation may be an important mechanism of manganese-induced neurotoxicity. This regulation could be achieved by reducing the level of H3K36ac near the promoter region of mitochondrial-associated antioxidant genes via KAT2A. Curcumin mitigates manganese-induced oxidative damage in mitochondria and plays a crucial protective role in manganese-induced oxidative injury in the nervous system.
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•Manganese causes mitochondrial oxidative damage in rat striatum and SH-SY5Y cells.•KAT2A inhibits the levels of mitochondrial antioxidant genes by reducing H3K36ac level.•Curcumin attenuates mitochondrial oxidative damage by raising H3K36ac level via KAT2A.
Transected axons fail to regrow across anatomically complete spinal cord injuries (SCI) in adults. Diverse molecules can partially facilitate or attenuate axon growth during development or after ...injury
, but efficient reversal of this regrowth failure remains elusive
. Here we show that three factors that are essential for axon growth during development but are attenuated or lacking in adults-(i) neuron intrinsic growth capacity
, (ii) growth-supportive substrate
and (iii) chemoattraction
-are all individually required and, in combination, are sufficient to stimulate robust axon regrowth across anatomically complete SCI lesions in adult rodents. We reactivated the growth capacity of mature descending propriospinal neurons with osteopontin, insulin-like growth factor 1 and ciliary-derived neurotrophic factor before SCI
; induced growth-supportive substrates with fibroblast growth factor 2 and epidermal growth factor; and chemoattracted propriospinal axons with glial-derived neurotrophic factor
delivered via spatially and temporally controlled release from biomaterial depots
, placed sequentially after SCI. We show in both mice and rats that providing these three mechanisms in combination, but not individually, stimulated robust propriospinal axon regrowth through astrocyte scar borders and across lesion cores of non-neural tissue that was over 100-fold greater than controls. Stimulated, supported and chemoattracted propriospinal axons regrew a full spinal segment beyond lesion centres, passed well into spared neural tissue, formed terminal-like contacts exhibiting synaptic markers and conveyed a significant return of electrophysiological conduction capacity across lesions. Thus, overcoming the failure of axon regrowth across anatomically complete SCI lesions after maturity required the combined sequential reinstatement of several developmentally essential mechanisms that facilitate axon growth. These findings identify a mechanism-based biological repair strategy for complete SCI lesions that could be suitable to use with rehabilitation models designed to augment the functional recovery of remodelling circuits.
Huntington's disease (HD) is characterized by striatal medium spiny neuron (MSN) dysfunction, but the underlying mechanisms remain unclear. We explored roles for astrocytes, in which mutant ...huntingtin is expressed in HD patients and mouse models. We found that symptom onset in R6/2 and Q175 HD mouse models was not associated with classical astrogliosis, but was associated with decreased Kir4.1 K(+) channel functional expression, leading to elevated in vivo striatal extracellular K(+), which increased MSN excitability in vitro. Viral delivery of Kir4.1 channels to striatal astrocytes restored Kir4.1 function, normalized extracellular K(+), ameliorated aspects of MSN dysfunction, prolonged survival and attenuated some motor phenotypes in R6/2 mice. These findings indicate that components of altered MSN excitability in HD may be caused by heretofore unknown disturbances of astrocyte-mediated K(+) homeostasis, revealing astrocytes and Kir4.1 channels as therapeutic targets.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Astrocytes respond to injury and disease in the central nervous system with reactive changes that influence the outcome of the disorder
. These changes include differentially expressed genes (DEGs) ...whose contextual diversity and regulation are poorly understood. Here we combined biological and informatic analyses, including RNA sequencing, protein detection, assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) and conditional gene deletion, to predict transcriptional regulators that differentially control more than 12,000 DEGs that are potentially associated with astrocyte reactivity across diverse central nervous system disorders in mice and humans. DEGs associated with astrocyte reactivity exhibited pronounced heterogeneity across disorders. Transcriptional regulators also exhibited disorder-specific differences, but a core group of 61 transcriptional regulators was identified as common across multiple disorders in both species. We show experimentally that DEG diversity is determined by combinatorial, context-specific interactions between transcriptional regulators. Notably, the same reactivity transcriptional regulators can regulate markedly different DEG cohorts in different disorders; changes in the access of transcriptional regulators to DNA-binding motifs differ markedly across disorders; and DEG changes can crucially require multiple reactivity transcriptional regulators. We show that, by modulating reactivity, transcriptional regulators can substantially alter disorder outcome, implicating them as therapeutic targets. We provide searchable resources of disorder-related reactive astrocyte DEGs and their predicted transcriptional regulators. Our findings show that transcriptional changes associated with astrocyte reactivity are highly heterogeneous and are customized from vast numbers of potential DEGs through context-specific combinatorial transcriptional-regulator interactions.
As a common insecticide, nitenpyram (NTP) seriously threatens the human health and environmental safety. In this work, a visible-light-responsive photocatalyst two-dimensional (2D) Bi
2
WO
6
was ...synthesized and applied to degrade NTP. Compared with bulk Bi
2
WO
6
, the 2D Bi
2
WO
6
exhibits better photocatalytic performance for NTP degradation under visible-light irradiation. The enhanced activity can be ascribed to the unique 2D structure which would induce to higher efficiency of carrier separation. Moreover, hole (h
+
) plays a major role (and ·O
2
−
) in the degradation of NTP. Based on the intermediates detected by high-performance liquid chromatography–mass spectrometry (HPLC–MS), the degradation pathway of NTP was proposed. In addition, the influence of typical environmental factors (pH, water matrix, inorganic cations and common anions) on the degradation of NTP was also investigated. This work not only helps people to understand the degradation of pesticides in actual water bodies, but also provides reference for the subsequent treatment of agricultural wastewater.
Graphical abstract
Long-term manganese exposure causes a neurodegenerative disorder referred to as manganese poisoning, but the mechanism remains unclear and no specific treatment is available. Oxidative stress is ...widely recognised as one of the main causes of manganese-induced neurotoxicity. In recent years, the role of histone acetylation in neurodegenerative diseases has been widely concerned. curcumin is a natural polyphenol compound extracted from the rhizome of turmeric and exhibits both antioxidant and neuroprotective properties. Therefore, we aimed to investigate whether and how curcumin protects against manganese-induced neurotoxicity from the perspective of histone acetylation, based on the reversibility of histone acetylation modification. In this study, rats were treated with or without curcumin and subjected to long-term manganese exposure. Results that treatment of manganese decreased the protein expression of H3K18 acetylation and H3K27 acetylation at the promoters of oxidative stress-related genes and inhibited the expression of these genes. Nevertheless, curcumin increased the H3K27 acetylation level at the manganese superoxide dismutase (SOD2) gene promoter and promoted the expression of SOD2 gene. Oxidative damage in the rat striatum as well as learning and memory dysfunction were ameliorated after curcumin treatment. Taken together, our results suggest that the regulation of oxidative stress by histone acetylation may be a key mechanism of manganese-induced neurotoxicity. In addition, curcumin ameliorates Mn-induced neurotoxicity may be due to alleviation of oxidative damage mediated by increased activation of H3K27 acetylation at the SOD2 gene promoter.
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•Down-acetylation levels of H3K27 and H3K18 may inhibit the expression of OSR genes.•Curcumin ameliorates Mn-induced neurotoxicity in rat.•Curcumin increases the expression of SOD2 gene by the up-acetylation level of H3K27.
Dihydrouridine (D) is an abundant post-transcriptional modification present in transfer RNA from eukaryotes, bacteria, and archaea. D has contributed to treatments for cancerous diseases. Therefore, ...the precise detection of D modification sites can enable further understanding of its functional roles. Traditional experimental techniques to identify D are laborious and time-consuming. In addition, there are few computational tools for such analysis. In this study, we utilized eleven sequence-derived feature extraction methods and implemented five popular machine algorithms to identify an optimal model. During data preprocessing, data were partitioned for training and testing. Oversampling was also adopted to reduce the effect of the imbalance between positive and negative samples. The best-performing model was obtained through a combination of random forest and nucleotide chemical property modeling. The optimized model presented high sensitivity and specificity values of 0.9688 and 0.9706 in independent tests, respectively. Our proposed model surpassed published tools in independent tests. Furthermore, a series of validations across several aspects was conducted in order to demonstrate the robustness and reliability of our model.
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