Evidence for chromium crosses blood brain barrier from the hypothalamus in chromium mice model.

It has been shown that exposure to hexavalent Chromium, Cr (Ⅵ), via nasal cavity can have neurotoxicological effects and induces behavioral impairment due to the fact that blood brain barrier (BBB) does not cover olfactory bulb. But whether Cr (Ⅵ) can cross the BBB and have a toxicological effects in central nervous system (CNS) remains unclear. Therefore, we investigated the effects of Cr (Ⅵ) on mice treated with different concentrations and exposure time (14 days and 28 days) of Cr (Ⅵ) via intraperitoneal injection. Results revealed that Cr accumulated in hypothalamus (HY) in a timely dependent manner. Much more severer neuropathologies was observed in the group of mice exposed to Cr (Ⅵ) for 28 days than that for 14 days. Gliosis, neuronal morphological abnormalities, synaptic degeneration, BBB disruption and neuronal number loss were observed in HY. In terms of mechanism, the Nrf2 related antioxidant stress signaling dysfunction and activated NF-κB related inflammatory pathway were observed in HY of Cr (Ⅵ) intoxication mice. And these neuropathologies and signaling defects appeared in a timely dependent manner. Taking together, we proved that Cr (Ⅵ) can enter HY due to weaker BBB in HY and HY is the most vulnerable CNS region to Cr (Ⅵ) exposure. The concentration of Cr in HY increased along with time. The accumulated Cr in HY can cause BBB disruption, neuronal morphological abnormalities, synaptic degeneration and gliosis through Nrf2 and NF-κB signaling pathway. This finding improves our understanding of the neurological dysfunctions observed in individuals who have occupational exposure to Cr (Ⅵ), and provided potential therapeutic targets to treat neurotoxicological pathologies induced by Cr (Ⅵ).

α-synuclein-lack expression rescues methamphetamine-induced mossy fiber degeneration in dorsal hippocampal CA3.

Methamphetamine (METH) - induced cognitive impairments may be related to synaptic degeneration at mossy fiber terminals, critical for spatial memory formation in hippocampal circuits. We have previously found METH-induced neurodegeneration in the striatum by increasing the α-synuclein (α-SYN) level. However, whether and how the METH-induced mossy fiber degeneration is also blamed for the abnormal accumulation of α-SYN remains to be elucidated. Chronic METH exposure decreased mossy fiber density but upregulatedα-SYN and phosphorylated TAU (TAU-pSer396) in hippocampal CA3, associated with glial cell overactivation, axonal neuropathies, and memory impairment. Notably, the knockout of the α-SYN gene significantly alleviated the METH-induced mossy fiber degeneration and memory impairment. Meanwhile, the TAU-pSer396 accumulation and glial activation were ameliorated by α-SYN knockout. Our findings suggest an essential role of α-SYN in mediating METH-induced mossy fiber degeneration, providing promising therapeutic and prophylactic targets for METH-related neurodegenerative diseases.

Association of GAL-8 promoter methylation levels with coronary plaque inflammation.

BACKGROUND AND AIMS: Coronary heart disease (CHD) is a condition that carries a high risk of mortality and is associated with aging. CHD is characterized by the chronic inflammatory response of the coronary intima. Recent studies have shown that the methylation level of blood mononuclear cell DNA is closely associated with adverse events in CHD, but the roles and mechanisms of DNA methylation in CHD remain elusive. METHODS AND RESULTS: In this study, the DNA methylation status within the epigenome of human coronary tissue in the sudden coronary death (SCD) group and control (CON) group of coronary heart disease was analyzed using the Illumina® Infinium Methylation EPIC BeadChip (850 K chip), resulting in the identification of a total of 2553 differentially methylated genes (DMGs). The differentially methylated genes were then subjected to Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis, and significant differential DNA methylation was found. Among the differentially hypomethylated genes were GAL-8, LTF, and RFPL3, while the highly methylated genes were TMEM9B, ANK3, and C6orF48. These genes were mainly enriched in 10 significantly enriched pathways, such as cell adhesion junctions, among which the differentially methylated gene GAL-8 was involved in inflammatory pathway signaling. For functional analysis of GAL-8, we first examined the differences in GAL-8 promoter methylation levels among different subgroups of human coronary tissue in the CON, CHD, and SCD groups using pyrophosphate sequencing. The results revealed reduced GAL-8 promoter methylation levels in the SCD group, while the difference between the CHD and CON groups was not statistically significant (P > 0.05). The reduced GAL-8 promoter methylation level was associated with upregulated GAL-8 expression, which led to increased expression of the inflammatory markers TNF-α, IL-1ß, MCP-1, MIP-2, MMP-2, and MMP-9. This enhanced inflammatory response contributed to the accumulation of foam cells, thickening of the intima of human coronary arteries, and increased luminal stenosis, which promoted the occurrence of sudden coronary death. Next, we found that GAL-8 promoter methylation levels in PBMC were consistent with human coronary tissue. The unstable angina group (UAP) had significantly lower GAL-8 promoter methylation levels than stable angina (SAP) and healthy controls (CON) (P < 0.05), and there was a significant correlation between reduced GAL-8 promoter methylation levels and risk factors for coronary heart disease. These findings highlight the association between decreased GAL-8 promoter methylation and the presence of coronary heart disease risk factors. ROC curve analysis suggests that methylation of the GAL 8 promoter region is an independent risk factor for CHD. In conclusion, our study confirmed differential expression of GAL-8, LTF, MUC4D, TMEM9B, MYOM2, and ANK3 genes due to DNA methylation in the SCD group. We also established the consistency of GAL-8 promoter methylation alterations between human coronary tissue and patient peripheral blood monocytes. The decreased methylation level of the GAL-8 promoter may be related to the increased expression of GAL-8 and the coronary risk factors. CONCLUSIONS: Accordingly, we hypothesized that reduced levels of GAL-8 promoter methylation may be an independent risk factor for adverse events in coronary heart disease.

Blockade of CXCR4 promotes macrophage autophagy through the PI3K/AKT/mTOR pathway to alleviate coronary heart disease.

OBJECTIVE: Autophagy is important in regulating inflammation and cholesterol efflux, suggesting that targeting autophagy may slow down atherosclerosis (AS). Since the pathological basis of coronary artery disease (CAD) is atherosclerosis, it is crucial to investigate the role of autophagy in atherosclerosis. This study aimed to investigate the role of the chemokine CXC chemokine receptor 4 (CXCR4) in promoting macrophage autophagy through the phosphoinositide-3 kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway to alleviate coronary artery disease. METHODS: The human left coronary artery and myocardium were collected to detect CXCR4, MAP1LC3(LC3) and SQSTM1(p62) expression. ApoE-/- mice were used to establish an atherosclerosis mice model, while human monocytes (THP-1) were used to establish a foam cell model and co-cultured with foam cells using siRNACXCR4. Western blotting was conducted to quantify CXCR4, PI3K/AKT/mTOR pathway protein, LC3, Beclin1 and p62 protein levels. The left coronary artery from humans and mouse aorta and myocardium were stained with Hematoxylin and Eosin (H&E), macrophages with Oil Red O staining and foam cells were assessed by Movat's staining. CXCR4 levels, PI3K/AKT/mTOR pathway protein, LC3 and p62 were detected by immunohistochemistry (IHC) and immunofluorescence assays. Detection of autophagosomes in macrophages using transmission electron microscopy. We further assessed whether the effect of CXCR4-mediated macrophage autophagy on the formation of atherosclerosis and structural changes in the myocardium was mediated via the PI3K/AKT/mTOR signaling pathway. RESULTS: CXCR4 and p62 proteins were upregulated in human coronary lesions, mouse aorta, myocardial tissue, and foam cells, while LC3II/LC3I was downregulated. p85 (P-PI3K), Ser473 (P-AKT), and Ser2448 (P-mTOR) phosphorylated proteins associated with the PI3K/AKT/mTOR pathway were detected in AS and foam cell models. Upregulated CXCR4 inhibited autophagy of macrophages and increased the severity of atherosclerotic lesions. After specific knockdown of CXCR4 by adeno-associated virus (AAV9-CXCR4-RNAi) and siRNACXCR4, the above indicators were reversed, macrophage autophagy was promoted, the severity of atherosclerotic lesions was reduced, and the disorganized arrangement of myocardial architecture was improved. CONCLUSION: Knockdown of CXCR4 reduces the extent of coronary artery disease by promoting macrophage autophagy through the PI3K/AKT/mTOR pathway to attenuate atherosclerosis.

Cdc42GAP deficiency contributes to the Alzheimer's disease phenotype.

Alzheimer's disease, the most common cause of dementia, is a chronic degenerative disease with typical pathological features of extracellular senile plaques and intracellular neurofibrillary tangles and a significant decrease in the density of neuronal dendritic spines. Cdc42 is a member of the small G protein family that plays an important role in regulating synaptic plasticity and is regulated by Cdc42GAP, which switches Cdc42 from active GTP-bound to inactive GDP-bound states regulating downstream pathways via effector proteins. However, few studies have focused on Cdc42 in the progression of Alzheimer's disease. In a heterozygous Cdc42GAP mouse model that exhibited elevated Cdc42-GTPase activity accompanied by increased Cdc42-PAK1-cofilin signalling, we found impairments in cognitive behaviours, neuron senescence, synaptic loss with depolymerization of F-actin and the pathological phenotypes of Alzheimer's disease, including phosphorylated tau (p-T231, AT8), along with increased soluble and insoluble Aß1-42 and Aß1-40, which are consistent with typical Alzheimer's disease mice. Interestingly, these impairments increased significantly with age. Furthermore, the results of quantitative phosphoproteomic analysis of the hippocampus of 11-month-old GAP mice suggested that Cdc42GAP deficiency induces and accelerates Alzheimer's disease-like phenotypes through activation of GSK-3ß by dephosphorylation at Ser9, Ser389 and/or phosphorylation at Tyr216. In addition, overexpression of dominant-negative Cdc42 in the primary hippocampal and cortical neurons of heterozygous Cdc42GAP mice reversed synaptic loss and tau hyperphosphorylation. Importantly, the Cdc42 signalling pathway, Aß1-42, Aß1-40 and GSK-3ß activity were increased in the cortical sections of Alzheimer's disease patients compared with those in healthy controls. Together, these data indicated that Cdc42GAP is involved in regulating Alzheimer's disease-like phenotypes such as cognitive deficits, dendritic spine loss, phosphorylated tau (p-T231, AT8) and increased soluble and insoluble Aß1-42 and Aß1-40, possibly through the activation of GSK-3ß, and these impairments increased significantly with age. Thus, we provide the first evidence that Cdc42 is involved in the progression of Alzheimer's disease-like phenotypes, which may provide new targets for Alzheimer's disease treatment.

DEL-1 suppression attenuates atherosclerosis by modulating macrophagic GSK-3ß/CEBP-ß signaling pathway.

OBJECTIVE: The study aims to investigate the effect of developmental endothelial locus-1(DEL-1) expression in atherosclerotic plaque formation and its mechanism. METHODS: Human left coronary arteries were collected to detect the DEL-1 expression. The ApoE-/- mice were used to establish the atherosclerosis mice model. The left coronary artery and mouse aorta were stained with HE, Oil Red O, and Movat staining. The DEL-1 levels, chemokines CXC chemokine receptor 4 (CXCR4) and its ligand stromal cell-derived factor-1alpha (SDF-1α), pathway protein glycogen synthase kinase-3ß (GSK-3ß), CCAAT enhanced binding protein ß (C/EBPß), and downstream inflammatory factors (C-X-C motif chemokine 2 (MIP-2or CXCL2), macrophage inflammatory protein-1alpha (MIP-1α or CCL3),Tumor Necrosis Factor alpha (TNF-α) were detected by immunoblotting and immunohistochemistry. Pearson correlation coefficient was used to analyze the correlation between DEL-1 gene expression and inflammatory factors in the lesion group and the correlation between DEL-1 gene expression and structure-related indexes. RESULTS: Compared with Control group(CON), the intravascular plaque area was widened, accompanied by narrowed lumens. The number of plaque foam cells was significantly increased in the high fat and high cholesterol (AS group) or AAV9-eGFP group (P < 0.05). Compared to CON, the enhanced fluorescence intensity of DEL-1 with CD68 in the AS or AAV9-eGFP groups. Diminished fluorescence of DEL-1 with CD68 expression in AAV9-CXCR4 group compared to AS group or AAV9-eGFP group. The DEL-1 and its downstream proteins in AS group or AAV9-eGFP group were mainly accumulated in the macrophage cytoplasm. The DEL-1 expression level was significantly and positively correlated with plaque area, lumen stenosis, plaque foam cell count, TNFα, CXCL2, and CCL3 levels. CONCLUSION: DEL-1 inhibition decreases macrophagic inflammatory factors involved in atherosclerotic plaque formation.

Low and high dose methamphetamine differentially regulate synaptic structural plasticity in cortex and hippocampus.

Psychostimulants, such as methamphetamine (METH) can induce structural remodeling of synapses by remodeling presynaptic and postsynaptic morphology. Escalating or long-lasting high dose METH accounts for neurodegeneration by targeting multiple neurotransmitters. However, the effects of low dose METH on synaptic structure and the modulation mechanism remain elusive. This study aims to assess the effects of low dose (2 mg/kg) and high dose (10 mg/kg) of METH on synaptic structure alternation in hippocampus and prefrontal cortex (PFC) and to reveal the underlying mechanism involved in the process. Low dose METH promoted spine formation, synaptic number increase, post-synaptic density length elongation, and memory function. High dose of METH induced synaptic degeneration, neuronal number loss and memory impairment. Moreover, high dose, but not low dose, of METH caused gliosis in PFC and hippocampus. Mechanism-wise, low dose METH inactivated ras-related C3 botulinum toxin substrate 1 (Rac1) and activated cell division control protein 42 homolog (Cdc42); whereas high dose METH inactivated Cdc42 and activated Rac1. We provided evidence that low and high doses of METH differentially regulate synaptic plasticity in cortex and hippocampus.

A Transvenous Endovascular Approach in Straight Sinus has Minor Impacts on Chordae Willisii.

Background: The transvenous endovascular approach has become an optimal method for the treatment of cerebrovascular diseases. This procedure might cause iatrogenic damage to the chordae willisii (CW) in the straight sinus. However, little literature has been found to support this hypothesis. Objective: To investigate the possible damage of CW in the straight sinus during a transvenous endovascular procedure. Materials and Methods: The features of the CW from 38 cadaveric heads were observed via an endoscope mimicking a mechanical thrombectomy procedure in the straight sinus. Endoscopic observation and light microscopy examination were used to assess the damage of the CW throughout the procedure. Results: Valve-like lamellae and longitudinal lamellae were found predominantly in the posterior portion of the straight sinus. Trabeculae were present in both the anterior and posterior portions of the straight sinus. Samples treated with a stent had a significantly higher rate of Grade 1 damage during the eight procedures compared with samples treated with a balloon (P = 0.02). The incidence of damage to the CW surface was higher in the stent group than in the balloon group (P = 0.00). The use of stent or balloon did not increase the rate of CW damage during repeated experiments. Conclusions: The stent or balloon navigation through the straight sinus can cause minor damage to the CW. Frequent uses of retrograde navigation through the straight sinus do not seem to increase the possibility of damage to CW.

Transfer of neuron-derived α-synuclein to astrocytes induces neuroinflammation and blood-brain barrier damage after methamphetamine exposure: Involving the regulation of nuclear receptor-associated protein 1.

The α-synuclein (α-syn) is involved in methamphetamine (METH)-induced neurotoxicity. Neurons can transfer excessive α-syn to neighboring neurons and glial cells. The effects of α-syn aggregation in astrocytes after METH exposure on the blood-brain barrier (BBB) remains unclear. Our previous study demonstrated that nuclear receptor-related protein 1 (Nurr1), a member of the nuclear receptor family widely expressed in the brain, was involved in the process of METH-induced α-syn accumulated in astrocytes to activate neuroinflammation. The role Nurr1 plays in astrocyte-mediated neuroinflammation, which results in BBB injury induced by METH, remains uncertain. This study found that METH up-regulated α-syn expression in neurons extended to astrocytes, thereby eliciting astrocyte activation, increasing and decreasing IL-1ß, IL-6, TNF-α, and GDNF levels by down-regulating Nurr1 expression, and ultimately damaging the BBB. Specifically, the permeability of BBB to Evans blue and sodium fluorescein (NaF) increased; IgG deposits in the brain parenchyma increased; the Claudin5, Occludin, and PDGFRß levels decreased. Several ultrastructural pathological changes occurred in the BBB, such as abnormal cerebral microvascular diameter, astrocyte end-foot swelling, decreased pericyte coverage, and loss of tight junctions. However, knockout or inhibition of α-syn or astrocyte-specific overexpression of Nurr1 partially alleviated these symptoms and BBB injury. Moreover, the in vitro experiments confirmed that METH increased α-syn level in the primary cultured neurons, which could be further transferred to primary cultured astrocytes, resulting in decreased Nurr1 levels. The decreased Nurr1 levels mediated the increase of IL-1ß, IL-6, and TNF-α, and the decrease of GDNF, thereby changing the permeability to NaF, transendothelial electrical resistance, and Claudin5 and Occludin levels of primary cultured brain microvascular endothelial cells. Based on our findings, we proposed a new mechanism to elucidate METH-induced BBB injury and presented α-syn and Nurr1 as promising drug intervention targets to reduce BBB injury and resulting neurotoxicity in METH abusers.

Genetic polymorphisms and phylogenetic analyses of the Ü-Tsang Tibetan from Lhasa based on 30 slowly and moderately mutated Y-STR loci.

As a result of the expansion of old Tibet on the Qinghai-Tibet Plateau, Tibetans diverged into three main branches, Ü-Tsang, Amdo, and Kham Tibetan. Ü-Tsang Tibetans are geographically distributed across the wide central and western portions of the Qinghai-Tibet Plateau while Lhasa is the central gathering place for Tibetan culture. The AGCU Y30, a 6-dye fluorescence kit including 30 slowly and moderately mutated Y-STR loci, has been validated for its stability and sensitivity in different biomaterials and diverse Chinese populations (Han and other minorities), and widely used in the practical work of forensic science. However, the 30 Y-STR profiling of Tibetan, especially for Ü-Tsang Tibetan, were insufficient. We utilized the AGCU Y30 to genotype 577 Ü-Tsang Tibetan unrelated males from Lhasa in the Tibet Autonomous Region of China to fill up the full and accurate Y-STR profiles. A total of 552 haplotypes were observed, 536 (97.10%) of which were unique. One hundred and ninety-four alleles were observed at 26 single copy loci and the allelic frequencies ranged from 0.0017 to 0.8180. For the two multi-copy loci DYS385a/b and DYS527a/b, 64 and 36 allelic combinations were observed, respectively. The gene diversity (GD) values ranged from 0.3079 at DYS391 to 0.9142 at DYS385a/b and the overall haplotype diversity (HD) was 0.9998, and its discrimination capacity (DC) was 0.9567. The population genetic analyses demonstrated that Lhasa Ü-Tsang Tibetan had close relationships with other Tibetan populations from Tibet and Qinghai, especially with Ü-Tsang Tibetan. From the perspective of Y haplogroups, the admixture of the southward Qiang people with dominant haplogroup O-M122 and the northward migrations of the initial settlers of East Asia with haplogroup D-M175 hinted the Sino-Tibetan homologous, thus, we could not ignore the gene flows with other Sino-Tibetan populations, especially for Han Chinese, to characterize the forensic genetic landscape of Tibetan.

High-Throughput Sequencing to Investigate lncRNA-circRNA-miRNA-mRNA Networks Underlying the Effects of Beta-Amyloid Peptide and Senescence on Astrocytes.

Astrocytes are widely distributed in the central nervous system and play an essential role in the function of neuronal cells. Associations between astrocytes and Alzheimer's disease (AD) have been noted, and recent work has implicated circular RNA (circRNA) and long non-coding RNA (lncRNA) in the development of AD. However, few reports have investigated which lncRNA and circRNA are involved in the influence of amyloid beta (Aß) and senescence on astrocytes. This study therefore examines changes at the transcriptome level to explore the effects of Aß and senescence on astrocytes. Primary cultured astrocytes were treated with Aß and cultured for 90 days in vitro, and high-throughput sequencing was performed to identify differentially expressed RNAs. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses revealed that differentially expressed genes were associated with the focal adhesion signaling pathway, extracellular matrix receptor signaling pathway, and the extracellular matrix. The protein-protein interaction network was then constructed, and 103 hub genes were screened out; most of these were strongly associated with the expression of the extracellular matrix, extracellular matrix receptor signaling pathway, and focal adhesion. Two competing endogenous RNA networks were constructed based on the selected hub gene and differential RNAs, and we identified multiple competing endogenous RNA regulatory axes that were involved in the effects of Aß and senescence on astrocytes. This is the first study to explore the molecular regulation mechanism of Aß and senescence on primary astrocytes from the perspective of the whole transcriptome. In uncovering the signaling pathways and biological processes involved in the effects of Aß and senescence on astrocytes, this work provides novel insights into the pathogenesis of AD at the level of competing endogenous RNA network regulation.

Microhaplotype and Y-SNP/STR (MY): A novel MPS-based system for genotype pattern recognition in two-person DNA mixtures.

BACKGROUNDS: Y-chromosomal haplotypes based on Y-short tandem repeats (STRs) and Y-single nucleotide polymorphisms/insertion and deletion polymorphisms (SNPs/InDels) are used to characterize paternal lineages of unknown male trace donors. However, Y-chromosomal genetic markers are not currently sufficient for precise individual identification. Microhaplotype (MH), generally < 200 bp on autosomes and consisting of two or more SNPs, was recently introduced in forensic genetics with the development of massive parallel sequencing technology and may facilitate identification and DNA mixture deconvolution. Therefore, combining the two kinds of genetic markers may be beneficial in many forensic scenarios, especially crime scenes with male suspects, such as sexual assault cases. METHODS: In the present study, we developed a novel MPS-based panel, Microhaplotype and Y-SNP/STR (MY), by multiplex PCR and 150-bp paired-end sequencing, including 114 Y-SNPs (twelve dominant Y-DNA haplogroups), 45 Y-STRs (N-1 stutter < 0.09; estimated mutation rate < 5 × 10-3), and 22 MHs (allele coverage ratio > 0.91; pairwise distance > 10 Mb). Additionally, MY system-based genotype pattern recognition (GPR), a regression-based method to identify the genotype pattern for each MH locus, is proposed for two-person DNA mixture deconvolution. We integrated 26 two-person genotype combinations into nine genotype patterns and validated the application range of GPR based on DNA profiles of ten sets of simulated male-male DNA mixtures (1:10-1:2). RESULTS: The effective number of alleles (Ae) ranged from 3.62 to 14.72, with an average of 7.17, in 100 Chinese Guangdong Han individuals. The cumulative discrimination power was 1-5.00 × 10-31, and the cumulative power of exclusion was 1-5.00 × 10-8 and 1-4.85 × 10-12 for duo and trio paternity testing, respectively. Furthermore, the actual mixing ratio-depth of coverage (DoC) ratio (RDoC) regression relationships were established for different genetic markers and genotype patterns. In five overlapping areas, genotype differentiation of the major and minor contributors required likelihood ratio methods. In nonoverlapping areas, the genotype pattern could be recognized by comparing the observed RDoC and RDoC ranges. CONCLUSION: The GPR can be used to deconvolute two-person DNA mixtures (application range: 1:10-1:2) for individual identification.

Anatomical Study of Arachnoid Granulation in Superior Sagittal Sinus Correlated to Growth Patterns of Meningiomas.

Meningiomas in the parasagittal region were formed by arachnoidal cells disseminated among arachnoid granulations. The purpose of this study was to characterize the morphology of chordae willisii, and AGs found in the superior sagittal sinus. This study used 20 anatomical specimens. Rigid endoscopes were introduced via torcula herophili into the sinus lumen. The morphological features of arachnoid granulation and chordae willisii were analyzed, and then arachnoid granulations and chordae willisii were assessed by elastic fiber stains, Masson's stains, and imaging analysis. Three types of arachnoid granulations were present in the examined sinuses. There were 365 counts of arachnoid granulations in examined sinuses by imaging analysis, averaging 1.36 ± 2.58 per sinus. Types I, II, and III made up 20.27, 45.20, and 34.52% of 268 patients, respectively. Microscopy of chordae willisii transverse sections indicated the existence of a single layer and a multiple-layered dura sinus wall. The dural sinus wall was the thickest one in the superior sagittal sinus. The thickness of longitudinal lamellae was significantly greater than trabeculae. This study reveals the anatomical differences between arachnoid granulations in the superior sagittal sinus. The arachnoid granulations classification enables surgeons to predict preoperatively growth patterns, followed by safely achieving the optimal range of parasagittal meningioma resection.

Inflammasome Inhibition Prevents Motor Deficit and Cerebellar Degeneration Induced by Chronic Methamphetamine Administration.

Methamphetamine (METH), a psychostimulant, has the potential to cause neurodegeneration by targeting the cerebrum and cerebellum. It has been suggested that the NLRP3 inflammasome may be responsible for the neurotoxicity caused by METH. However, the role of NLRP3 in METH-induced cerebellar Purkinje cell (PC) degeneration and the underlying mechanism remain elusive. This study aims to determine the consequences of NLRP3 modulation and the underlying mechanism of chronic METH-induced cerebellar PC degeneration. In METH mice models, increased NLRP3 expression, PC degeneration, myelin sheath destruction, axon degeneration, glial cell activation, and motor coordination impairment were observed. Using the NLRP3 inhibitor MCC950, we found that inhibiting NLRP3 alleviated the above-mentioned motor deficits and cerebellar pathologies. Furthermore, decreased mature IL-1ß expression mediated by Caspase 1 in the cerebellum may be associated with the neuroprotective effects of NLRP3 inflammasome inhibition. Collectively, these findings suggest that mature IL-1ß secretion mediated by NLRP3-ASC-Caspase 1 may be a critical step in METH-induced cerebellar degeneration and highlight the neuroprotective properties of inflammasome inhibition in cerebellar degeneration.

Luteolin Ameliorates Methamphetamine-Induced Podocyte Pathology by Inhibiting Tau Phosphorylation in Mice.

Methamphetamine (METH) can cause kidney dysfunction. Luteolin is a flavonoid compound that can alleviate kidney dysfunction. We aimed to observe the renal-protective effect of luteolin on METH-induced nephropathies and to clarify the potential mechanism of action. The mice were treated with METH (1.0-20.0 mg/kg/d bodyweight) for 14 consecutive days. Morphological studies, renal function, and podocyte specific proteins were analyzed in the chronic METH model in vivo. Cultured podocytes were used to support the protective effects of luteolin on METH-induced podocyte injury. We observed increased levels of p-Tau and p-GSK3ß and elevated glomerular pathology, renal dysfunction, renal fibrosis, foot process effacement, macrophage infiltration, and podocyte specific protein loss. Inhibition of GSK3ß activation protected METH-induced kidney injury. Furthermore, luteolin could obliterate glomerular pathologies, inhibit podocyte protein loss, and stop p-Tau level increase. Luteolin could also abolish the METH-induced podocyte injury by inactivating GSK3ß-p-Tau in cultured podocytes. These results indicate that luteolin might ameliorate methamphetamine-induced podocyte pathology through GSK3ß-p-Tau axis.

Icariside II Attenuates Methamphetamine-Induced Neurotoxicity and Behavioral Impairments via Activating the Keap1-Nrf2 Pathway.

Chronic and long-term methamphetamine (METH) abuse is bound to cause damages to multiple organs and systems, especially the central nervous system (CNS). Icariside II (ICS), a type of flavonoid and one of the main active ingredients of the traditional Chinese medicine Epimedium, exhibits a variety of biological and pharmacological properties such as anti-inflammatory, antioxidant, and anticancer activities. However, whether ICS could protect against METH-induced neurotoxicity remains unknown. Based on a chronic METH abuse mouse model, we detected the neurotoxicity after METH exposure and determined the intervention effect of ICS and the potential mechanism of action. Here, we found that METH could trigger neurotoxicity, which was characterized by loss of dopaminergic neurons, depletion of dopamine (DA), activation of glial cells, upregulation of α-synuclein (α-syn), abnormal dendritic spine plasticity, and dysfunction of motor coordination and balance. ICS treatment, however, alleviated the above-mentioned neurotoxicity elicited by METH. Our data also indicated that when ICS combated METH-induced neurotoxicity, it was accompanied by partial correction of the abnormal Kelch 2 like ECH2 associated protein 1 (Keap1)-nuclear factor erythroid-2-related factor 2 (Nrf2) pathway and oxidative stress response. In the presence of ML385, an inhibitor of Nrf2, ICS failed to activate the Nrf2-related protein expression and reduce the oxidative stress response. More importantly, ICS could not attenuate METH-induced dopaminergic neurotoxicity and behavioral damage when the Nrf2 was inhibited, suggesting that the neuroprotective effect of ICS on METH-induced neurotoxicity was dependent on activating the Keap1-Nrf2 pathway. Although further research is needed to dig deeper into the actual molecular targets of ICS, it is undeniable that the current results imply the potential value of ICS to reduce the neurotoxicity of METH abusers.

A Transvenous Endovascular Approach in Straight Sinus Has Minor Impacts on Chordae Willisii.

Cerebral dural sinuses contain different types of chordae willisii (CW). The transvenous endovascular approach, which has become an optimal method for the treatment of cerebrovascular diseases, such as malformation, fistula, and chronic intracranial hypertension, due to sinus thromboses, frequently uses retrograde navigation through dural sinuses. Whether or how much the endoscopic procedure damages the chordae willisii is often not well-assessed. In our study, an overall number of 38 cadaveric heads were analyzed for the distribution and features of the chordae willisii in the straight sinus. We used an endoscope on these samples mimicking a mechanical thrombectomy procedure performed in the straight sinus. Both endoscopic gross observation and light microscopic histological examination were used to assess the damages to the chordae willisii by the procedure. We found that the valve-like lamellae and longitudinal lamellae structures were mainly found in the posterior part of straight sinus whereas trabeculae were present in both anterior and posterior portions. We treated a group of samples with a stent and another with a balloon. The stent-treated group had a significantly higher rate of Grade 1 damage comparing with the balloon-treated group (p = 0.02). The incidence of damage to the surface of chordae willisii was also higher in the stent-treated group (p = 0.00). Neither the use of stent nor of balloon increased the rate of damage to chordae willisii during repeated experiments. These findings indicated that stent or balloon navigation through the straight sinus can cause minor damages to the chordae willisii and frequent uses of retrograde navigation through the straight sinus do not appear to increase the rates of damage to chordae willisii.

Trilobatin Alleviates Cognitive Deficits and Pathologies in an Alzheimer's Disease Mouse Model.

Alzheimer's disease (AD) is the most common neurodegenerative disease nowadays that causes memory impairments. It is characterized by extracellular aggregates of amyloid-beta (Aß), intracellular aggregates of hyperphosphorylated Tau (p-Tau), and other pathological features. Trilobatin (TLB), a natural flavonoid compound isolated from Lithocarpuspolystachyus Rehd., has emerged as a neuroprotective agent. However, the effects and mechanisms of TLB on Alzheimer's disease (AD) remain unclear. In this research, different doses of TLB were orally introduced to 3×FAD AD model mice. The pathology, memory performance, and Toll-like receptor 4- (TLR4-) dependent inflammatory pathway protein level were assessed. Here, we show that TLB oral treatment protected 3×FAD AD model mice against the Aß burden, neuroinflammation, Tau hyperphosphorylation, synaptic degeneration, hippocampal neuronal loss, and memory impairment. The TLR4, a pattern recognition immune receptor, has been implicated in neurodegenerative disease-related neuroinflammation. We found that TLB suppressed glial activation by inhibiting the TLR4-MYD88-NFκB pathway, which leads to the inflammatory factor TNF-α, IL-1ß, and IL-6 reduction. Our study shows that TLR4 might be a key target of TLB in AD treatment and suggests a multifaceted target of TLB in halting AD. Taken together, our findings suggest a potential therapeutic effect of TLB in AD treatment.

Transfer of α-synuclein from neurons to oligodendrocytes triggers myelin sheath destruction in methamphetamine administration mice.

Methamphetamine (METH), a widely abused nervous system stimulant, could induce neurotoxicity through α-synuclein (α-syn). Not much is known about the neuronal derived α-syn transmission that underlies oligodendrocyte pathology in METH mice model. In this study, we tested α-syn level, oligodendroglial pathology and autophagy lysosome pathway (ALP) function in corpus callosum in a chronic METH mice model. METH increased α-syn level in neurons and then accumulated in oligodendrocytes. METH increased phosphor-mTOR level, decreased transcription factor EB (TFEB) level and triggered autophagy lysosomal pathway (ALP) impairment, leading to myelin sheath destruction, oligodendroglial proteins loss, mature dendritic spine loss, neuron loss, and astrocyte activation. Deleting endogenous α-syn increased TFEB level, alleviated ALP deficit, and diminished neuropathology induced by METH. TFEB overexpression in oligodendrocytes exerted beneficial effects in METH mice model. These neuroprotective effects were associated with the rescued ALP machinery after oligodendroglial TFEB overexpression. Our study demonstrated, for the first time, that α-syn-TFEB axis might be involve in the METH induced myelin loss, oligodendroglial pathology, and neuropathology. In summary, targeting at the α-syn-TFEB axis might be a promising therapeutic strategy for treating METH induced oligodendroglial pathology, and to a broader view, neurodegenerative diseases.

Impacts on Thrombus and Chordae Willisii During Mechanical Thrombectomy in the Superior Sagittal Sinus.

The anatomical structures of the superior sagittal sinus (SSS) are usually damaged during mechanical thrombectomy (MT), and MT procedure could lead to new thrombosis in the sinuses. However, the mechanism remains unclear. We aimed to investigate the risks of embolism and assess the damage to chordae willisii (CW)-associated MT using a stent passing across the thrombus. A contrast-enhanced in vitro model was used to mimick MT in the SSS. The thrombus was removed with a stent. The emboli generated during the procedure were collected and measured. The residual thrombus area after the MT was measured by J Image software. The damage of CW was evaluated by an endoscope. Three procedural experiments were carried out on each cadaveric sample. The average numbers of visible emboli particles in experiments 1, 2, and 3 were 11.17 ± 2.17, 9.00 ± 2.07, and 5.00 ± 2.96, respectively. The number of large size particles produced by experiment 1 was significantly higher than that of the other experiments. The thrombus area measured after experiment 3 was larger than that of experiments 1 and 2. The number of minor damage cases to CW was 55 (90.16%), and there were six serious damage cases (9.84%). The use of stent resulted in no significant increase in damage to CW after the three experimental procedures. A large amount of thrombi particles was produced during MT, and multiple MT procedures on the same sample can increase residual thrombus area. Moreover, the stent caused minor damages to the CW in SSS.