Iron overload facilitates neonatal hypoxic-ischemic brain damage via SLC7A11-mediated ferroptosis.

Oxidative damage and cell death are involved in the pathogenesis of hypoxic-ischemic brain damage (HIBD). Ferroptosis is a newly identified mode of cell death that results from the oxidative damage induced by excessive iron. In HIBD, iron accumulates in brain tissues due to the massive destruction of red blood cells and increased permeability of the blood brain barrier vasculature, which can trigger ferroptosis. Ferroptosis is implicated in various diseases involving neuronal injury; however, the roles of iron and ferroptosis in HIBD have not been identified. In the present study, we investigated the role of iron overload in neuronal ferroptosis both in HIBD rat models and in oxygen- and glucose-deprived (OGD) SH-SY5Y cells. We observed that iron deposition in the cerebral cortex was significantly increased in HIBD rats. Features of ferroptosis such as shrunken mitochondria, increased MDA (malondialdehyde) levels, and reduced solute carrier family 7 member 11 (SLC7A11) and glutathione peroxidase 4 (GPX4) expression were observed in the cerebral cortex of HIBD rats. Administration of an iron chelator in HIBD rats upregulated SLC7A11 expression and alleviated neuronal ferroptosis in cerebral cortex tissue. Additionally, overexpression of SLC7A11 in SH-SY5Y cells increased cell viability and attenuated OGD-induced ferroptosis. Our results demonstrate that iron overload induces neuronal ferroptosis by inhibiting SLC7A11 expression in HIBD. Inhibition of neuronal ferroptosis may be a promising strategy to alleviate brain damage in HIBD.

NR1 Splicing Variant NR1a in Cerebellar Granule Neurons Constitutes a Better Motor Learning in the Mouse.

As an excitatory neuron in the cerebellum, the granule cells play a crucial role in motor learning. The assembly of NMDAR in these neurons varies in developmental stages, while the significance of this variety is still not clear. In this study, we found that motor training could specially upregulate the expression level of NR1a, a splicing form of NR1 subunit. Interestingly, overexpression of this splicing variant in a cerebellar granule cell-specific manner dramatically elevated the NMDAR binding activity. Furthermore, the NR1a transgenic mice did not only show an enhanced motor learning, but also exhibit a higher efficacy for motor training in motor learning. Our results suggested that as a "junior" receptor, NR1a facilitates NMDAR activity as well as motor skill learning.

[Analysis of a case of Multiple pterygium syndrome due to a novel variant of CHRNG gene].

OBJECTIVE: To explore the clinical characteristics and genetic etiology of a child with multiple pterygium syndrome (MPS). METHODS: A child with MPS who was treated at the Orthopedics Department of Guangzhou Women and Children's Medical Center Affiliated to Guangzhou Medical University on August 19, 2020 was selected as the study subject. Clinical data of the child was collected. Peripheral blood samples of the child and her parents were also collected. Whole exome sequencing (WES) was carried out for the child. Candidate variant was validated by Sanger sequencing of her parents and bioinformatic analysis. RESULTS: The child, an 11-year-old female, had a complain of "scoliosis found 8 years before and aggravated with unequal shoulder height for 1 year". WES results revealed that she has carried a homozygous c.55+1G>C splice variant of the CHRNG gene, for which both of her parents were heterozygous carriers. By bioinformatic analysis, the c.55+1G>C variant has not been recorded by the CNKI, Wanfang data knowledge service platform and HGMG databases. Analysis with Multain online software suggested that the amino acid encoded by this site is highly conserved among various species. As predicted with the CRYP-SKIP online software, the probability of activation and skipping of the potential splice site in exon 1 caused by this variant is 0.30 and 0.70, respectively. The child was diagnosed with MPS. CONCLUSION: The CHRNG gene c.55+1G>C variant probably underlay the MPS in this patient.

The role of H3K9me2-regulated base excision repair genes in the repair of DNA damage induced by arsenic in HaCaT cells and the effects of Ginkgo biloba extract intervention.

Arsenic is an established human carcinogen that can induce DNA damage; however, the precise mechanism remains unknown. Histone modification is of great significance in chemical toxicity and carcinogenesis. To investigate the role of histone H3K9me2 in arsenic-induced DNA damage, HaCaT cells were exposed to sodium arsenite in this study, and the results showed that the enrichment level of H3K9me2 at the N-methylated purine-DNA-glycosylase (MPG), X-ray repair cross-complementary gene 1 (XRCC1), and polyadenylate diphosphate ribose polymerase-1 (PARP1) promoter regions of base-excision repair (BER) genes was increased, which inhibited the expression of these BER genes, thereby inhibiting the repair of DNA damage and aggravating the DNA damage. Furthermore, the molecular mechanism by which H3K9me2 participates in the BER repair of arsenic-induced DNA damage was verified based on functional loss and gain experiments. In addition, Ginkgo biloba extract can upregulate the expression of MPG, XRCC1, and PARP1 and ameliorate cell DNA damage by reducing the enrichment of H3K9me2 at repair gene promoter regions.

Histone demethylase JHDM2A regulates H3K9 dimethylation in response to arsenic-induced DNA damage and repair in normal human liver cells.

Long-term arsenic exposure is a worldwide public health problem that causes serious harm to human health. The liver is the main target organ of arsenic toxicity; arsenic induces disruption of the DNA damage repair pathway, but its mechanisms remain unclear. In recent years, studies have found that epigenetic mechanisms play an important role in arsenic-induced lesions. In this study, we conducted experiments in vitro using normal human liver cells (L-02) to explore the mechanism by which the histone demethylase JHDM2A regulates H3K9 dimethylation (me2) in response to arsenic-induced DNA damage. Our results indicated that arsenic exposure upregulated the expression of JHDM2A, downregulated global H3K9me2 modification levels, increased the H3K9me2 levels at the promoters of base excision repair (BER) genes (N-methylpurine-DNA glycosylase [MPG], XRCC1 and poly(ADP-ribose)polymerase 1) and inhibited their expression levels, causing DNA damage in cells. In addition, we studied the effects of overexpression and inhibition of JHDM2A and found that JHDM2A can participate in the molecular mechanism of arsenic-induced DNA damage via the BER pathway, which may not be involved in the BER process because H3K9me2 levels at the promoter region of the BER genes were unchanged following JHDM2A interference. These results suggest a potential mechanism by which JHDM2A can regulate the MPG and XRCC1 genes in the process of responding to DNA damage induced by arsenic exposure and can participate in the process of DNA damage repair, which provides a scientific basis for understanding the epigenetic mechanisms and treatments for endemic arsenic poisoning.

Misdiagnosed as a perianal abscess: case report of perianal endometriosis.

Perianal endometriosis represents a rare form of endometriosis occurring outside the pelvic cavity. Owing to its infrequency in clinical practice, this condition is highly susceptible to misdiagnosis and inappropriate treatment. This case report details a young female patient who was erroneously diagnosed with a perianal abscess. We conducted a para-anal mass resection under spinal anesthesia, and subsequent histopathological examination definitively confirmed the diagnosis of perianal endometriosis.

A case misdiagnosed as hyperthyroid heart disease: Surgical repair of unroofed coronary sinus syndrome with severe tricuspid regurgitation.

Unroofed coronary sinus syndrome (URCS), also known as coronary sinus septal defect, is a rare congenital heart disease. Because of its special anatomy and the lack of typical clinical symptoms, the disease is easily missed and misdiagnosed. This case report particularly describes a middle-aged male patient with URCS misdiagnosed for more than 19 years, covered by hyperthyroid heart disease, who subsequently developed uncontrollable symptoms such as chest tightness and shortness of breath and came to our hospital. After a clear diagnosis in our hospital, the patient was successfully cured after treatment with coronary sinus repair and tricuspid valvuloplasty under extracorporeal circulation.

Oxygen vacancies-rich Cu-W18O49 nanorods supported on reduced graphene oxide for electrochemical reduction ofN2to NH3.

High-performance nitrogen fixation is severely limited by the efficiency and selectivity of a catalyst of electrochemical nitrogen reduction reaction (NRR) under ambient conditions. Here, the RGO/WOCu (reduced graphene oxide and Cu-doping W18O49) composite catalysts with abundant oxygen vacancies are prepared by the hydrothermal method. The obtained RGO/WOCu achieves an enhanced NRR performance (NH3 yield rate:11.4 µg h-1 mgcat-1, Faradaic efficiency: 4.4%) at -0.6 V (vs. RHE) in 0.1 mol L-1 Na2SO4 solution. Furthermore, the NRR performance of the RGO/WOCu still keeps at 95% after four cycles, demonstrating its excellent stability. The Cu+-doping increases the concentration of oxygen vacancies, which is conducive to the adsorption and activation of N2. Meanwhile, the introduction of RGO further improves the electrical conductivity and reaction kinetics of the RGO/WOCu due to the high specific surface area and conductivity. This work provides a simple and effective method for efficient electrochemical reduction ofN2.

Fucoxanthin induces apoptosis and reverses epithelial-mesenchymal transition via inhibiting Wnt/ß-catenin pathway in lung adenocarcinoma.

BACKGROUND: Invasion and metastasis are hallmark characteristics of cancer and the main causes of death in cancer patients. Studies have shown that epithelial-mesenchymal transition (EMT) plays significant role in tumor invasion and metastasis. Fucoxanthin, a carotenoid found in seaweeds, has been proved to have anti-tumor effects. Our study aimed to research the role of fucoxanthin on proliferation, apoptosis, migration and EMT of two types of LUAD cells. METHODS: Cell migration and invasion were examined by Wound-healing and Transwell assays. Western blot assay was used to detect the expression levels of apoptosis-related proteins, EMT-related proteins and ß-catenin. Immunohistochemistry was used to detect the expression of ß-catenin in human lung adenocarcinoma tissues and corresponding para-cancerous tissues. RESULTS: Our results revealed that fucoxanthin depressed the proliferation and induced apoptosis in A549 and NCI-H1299 cells. Moreover, fucoxanthin reversed TGF-ß1-induced EMT and cell motility. Meanwhile, we disclosed that fucoxanthin and XAV939 had similar effect on ß-catenin, EMT protein and cell motility. What is more, immunohistochemical results revealed that the high expression rate and abnormal expression rate of ß-catenin in cancer tissues was significantly higher than that in para-cancerous tissues. CONCLUSION: Taken together, the findings of our research highlight a novel role for fucoxanthin in NSCLC cells, which might be a potentially effective anti-tumor agent for the treatment of LUAD patients.

Detection of netrin-1 as a novel biomarker for diagnosis and chemotherapeutic monitoring of lung cancer.

OBJECTIVE: Lung cancer has high morbidity and mortality. We aimed to determine the value of netrin-1 for the diagnosis and chemotherapeutic monitoring of lung cancer. METHODS: Thirty pairs of lung cancer tissues and serum were collected. Netrin-1 expression was detected by immunohistochemistry and enzyme-linked immunosorbent assay. Netrin-1 expression was downregulated in A549 cells using small interfering RNA, and the effect of netrin-1 on cisplatin-induced lung cancer cell apoptosis was determined by flow cytometry. RESULTS: Netrin-1-positivity was significantly higher in lung cancer tissues than in paracarcinoma tissues and high expression of netrin-1 was closely related to a poor prognosis. Serum netrin-1 levels were also significantly higher in lung cancer patients than in healthy donors, and were higher in patients with lung cancer before the beginning of chemotherapy compared with after the completion of four cycles of chemotherapy. Netrin-1 knockdown increased the rate of cisplatin-induced apoptosis in A549 cells. CONCLUSIONS: Netrin-1 expression was increased in tissues and serum from lung cancer patients and decreased after chemotherapy, suggesting that it may be a potential diagnostic marker and indicator of chemosensitivity. Netrin-1 may participate in cisplatin resistance by reducing apoptosis, thus providing a new strategy for addressing chemoresistance in patients with lung cancer.

Identification of a novel TBX5 mutation in a Chinese family with rare symptoms of Holt-Oram syndrome.

Holt-Oram syndrome (HOS) is a rare autosomal dominant disorder characterized by skeletal abnormalities of the upper limbs and often cardiac malformations. We investigated a Chinese family with clinical features suggestive of HOS. Clinical examinations revealed that both the proband and his father had anomalies in the upper limbs and heart. The proband had a rare common atrium. Whole exome sequencing detected a novel small-insertion mutation (c.680_681insCTGAGAATAAT; p.Ile227fs∗) in TBX5 gene, the known disease gene for HOS. The mutation cosegregated with HOS phenotypes in the family and was predicted to cause frameshift, resulting in a truncated protein. In this study, we described a rare HOS case with common atrium. A novel small-insertion in TBX5 coding sequence was identified and speculated to be the disease-causing genetic variant in the family. Our finding expands the clinical feature spectrum and genetic aetiology spectrum of HOS.

Corrigendum: Changes in Resting-State Functional Connectivity of Cerebellum in Amnestic Mild Cognitive Impairment and Alzheimer's Disease: A Case-Control Study.

[This corrects the article DOI: 10.3389/fnsys.2021.596221.].

Changes in Resting-State Functional Connectivity of Cerebellum in Amnestic Mild Cognitive Impairment and Alzheimer's Disease: A Case-Control Study.

This case-control study is aimed to investigate the correlation of altered functional connectivity (FC) in cerebellum with cognitive impairment in amnestic mild cognitive impairment (aMCI) and Alzheimer's disease (AD). The morphometric and resting-state FC MRI analysis including 46 participants with AD, 32 with aMCI and 42 age-matched normal controls (NCs) were conducted. We compared the cerebellar gray matter volume and cerebellar FC with cerebral cortical regions among three groups. To investigate the relationship of cerebellar FC with cognition, we measure the correlation of significant altered FC and individual cognitive domain. No significant morphometric differences of cerebellum was observed across three groups. The patients with AD had weaker cerebral cortical FCs in bilateral Crus I and left VIIb compared to NCs, and in bilateral Crus I compared to patients with aMCI. For patients with aMCI, the weaker FC were found between right Crus I, left VIIb and cerebral cortical regions compared to NCs. The strength of left cerebellar FC positively correlated with specific cognitive subdomains, including memory, executive function, visuospatial function, and global cognition in AD and aMCI. These findings demonstrated the alteration of cerebellar FC with cerebral cortical regions, and the correlation of cerebellar FC and cognitive impairment in AD and aMCI.

Transient Global Amnesia: An Electrophysiological Disorder Based on Cortical Spreading Depression-Transient Global Amnesia Model.

Transient global amnesia (TGA) is a benign memory disorder with etiologies that have been debated for a long time. The prevalence of stressful events before a TGA attack makes it hard to overlook these precipitating factors, given that stress has the potential to organically effect the brain. Cortical spreading depression (CSD) was proposed as a possible cause decades ago. Being a regional phenomenon, CSD seems to affect every aspect of the micro-mechanism in maintaining the homeostasis of the central nervous system (CNS). Corresponding evidence regarding hemodynamic and morphological changes from TGA and CSD have been accumulated separately, but the resemblance between the two has not been systematically explored so far, which is surprising especially considering that CSD had been confirmed to cause secondary damage in the human brain. Thus, by deeply delving into the anatomic and electrophysiological properties of the CNS, the CSD-TGA model may render insights into the basic pathophysiology behind the façade of the enigmatic clinical presentation.

Hyperspectral inversion of heavy metal content in reclaimed soil from a mining wasteland based on different spectral transformation and modeling methods.

Conventional methods for investigating heavy metal contamination in soil are time consuming and expensive. We explored reflectance spectroscopy as an alternative method for assessing heavy metals. Four spectral transformation methods, first-order differential (FDR), second-order differential (SDR), continuum removal (CR) and continuous wavelet transform (CWT), are used for the original spectral data. Spectral preprocessing effectively eliminated the noise and baseline drifting and also highlighted the locations of the spectral feature bands. Partial least squares regression (PLSR) and radial basis function neural network (RBF) were used to study the hyperspectral inversion of four heavy metals (Cr, As, Ni, Cd). The inversion models of four heavy metals were established in the bands with the highest correlation coefficient. The inversion effects were evaluated by the coefficient of determination (R2), root mean square error (RMSE) and residual predictive deviation (RPD) indexes. The R values of the correlation coefficient were significantly improved after smoothing and spectral transformation compared to the original waveband. The method combining continuous wavelet transform (CWT) with radial basis function neural network (RBF) had the best inversion effect on the four heavy metals. When compared to partial least squares regression (PLSR), the RMSE values were reduced by approximately 2. The CWT-RBF method can be used as a means of inversion of heavy metals in mining wasteland reclaimed land.