Idebenone-Activating Autophagic Degradation of α-Synuclein via Inhibition of AKT-mTOR Pathway in a SH-SY5Y-A53T Model of Parkinson's Disease: A Network Pharmacological Approach.

BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disease worldwide, which currently lacks disease-modifying therapy to slow down its progression. Idebenone, a coenzyme Q10 (CQ10) analogue, is a well-known antioxidant and has been used to treat neurological disorders. However, the mechanism of Idebenone on PD has not been fully elucidated. This study aims to predict the potential targets of Idebenone and explore its therapeutic mechanism against PD. METHOD: We obtained potential therapeutic targets through database prediction, followed by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis. Next, we constructed and analyzed a protein-protein interaction network (PPI) and a drug-target-pathway-disease network. A molecular docking test was conducted to identify the interactions between Idebenone and potential targets. Lastly, a PD cell line of SH-SY5Y overexpressing mutant α-synuclein was used to validate the molecular mechanism. RESULT: A total of 87 targets were identified based on network pharmacology. The enrichment analysis highlighted manipulation of MAP kinase activity and the PI3K-AKT signaling pathway as potential pharmacological targets for Idebenone against PD. Additionally, molecular docking showed that AKT and MAPK could bind tightly with Idebenone. In the cell model of PD, Idebenone activated autophagy and promoted α-synuclein degradation by suppressing the AKT/mTOR pathway. Pretreating cells with chloroquine (CQ) to block autophagic flux could diminish the pharmacological effect of Idebenone to clear α-synuclein. CONCLUSION: This study demonstrated that Idebenone exerts its anti-PD effects by enhancing autophagy and clearance of α-synuclein, thus providing a theoretical and experimental basis for Idebenone therapy against PD.

Enhanced photoelectrocatalytic activity of direct Z-scheme porous amorphous carbon nitride/manganese dioxide nanorod arrays.

Carbon nitride (C3N4) is a promising photocatalyst that can be applied in environmental remediation and energy conversion. However, the absorption range and charge separation efficiency of C3N4 are still severely restricted for its large-scale practical applications. Herein, we demonstrate a simple thermal polymerization and electrodeposition method, followed by partial etching strategy to synthesize direct Z-scheme porous zinc oxide/amorphous carbon nitride/manganese dioxide hybrid core-shell nanorod array (denoted as P-ZnO/ACN/MnO2) by encapsulating amorphous carbon nitride layers (ACN) and manganese dioxide nanosheets (MnO2) on the zinc oxide nanorod arrays (denoted as ZnO). Interestingly, ZnO serves as the collector of charge carriers and MnO2 plays a significant role in protecting ACN from corrosion. The as-prepared Z-scheme P-ZnO/ACN/MnO2 heterojunction exhibits high photocurrent density of 5.2 mA cm-2 at 0.6 V vs. Ag/AgCl, high photoconversion efficiency 0.98%, and universal photoelectrocatalytic degradation activity for degradation of organic dyes under visible light irradiation. The band gap energy and conduction band position of ZnO, ACN and MnO2 are calculated by UV-visible diffuse reflection and Mott-Schottky measurement, which strongly support the direct Z-scheme charge carrier migration mechanism. This finding provides an efficient strategy to construct highly active and stable C3N4-based Z-scheme photocatalytic system.

Treatment of lidocaine on subacute thyroiditis via restraining inflammatory factor expression and inhibiting pyroptosis pathway.

BACKGROUND: To explore the role of lidocaine on subacute thyroiditis (SAT) and the molecular mechanism. METHODS: SAT models were constructed by infecting adenovirus to thyroid follicular epithelial cells. Cells were randomly divided into five groups: model group, low lidocaine, middle lidocaine, high lidocaine, and a control group. Thyroid secretion related factors TG and TPO, T3 and T4 were separately determined by reverse transcription-polymerase chain reaction (RT-PCR) and radioimmunoassay. Flow cytometry was used to determine thyroid follicular epithelial cell apoptosis situation. RT-PCR and Western blot analysis were used to determine the expression of inflammatory cytokines and pyroptosis related factors interleukin (IL)-1α, IL-6, THF-α, ELAVL1, NLR family pyrin domain containing 3 (NLRP3), caspase-1, and IL-1ß. RESULTS: Lidocaine decreased the relative level of TG, TPO, T3, and T4 in adenovirus-infected thyroid follicular epithelial cells. All levels of concentrations, including low, middle, and high, of lidocaine, significantly decreased the apoptosis rate of adenovirus-infected cells. Lidocaine dramatically reduced the protein expression of IL-1α, IL-6, THF-α, ELAVL1, NLRP3, caspase-1, and IL-1ß in adenovirus-infected thyroid follicular epithelial cells. CONCLUSION: Lidocaine can improve SAT through inhibiting expression of inflammatory factors and the pyroptosis pathway.

Suppression of long non-coding RNA TNRC6C-AS1 protects against thyroid carcinoma through DNA demethylation of STK4 via the Hippo signalling pathway.

OBJECTIVES: Thyroid carcinoma (TC) represents a malignant neoplasm affecting the thyroid. Current treatment strategies include the removal of part of the thyroid; however, this approach is associated with a significant risk of developing hypothyroidism. In order to adequately understand the expression profiles of TNRC6C-AS1 and STK4 and their potential functions in TC, an investigation into their involvement with Hippo signalling pathway and the mechanism by which they influence TC apoptosis and autophagy were conducted. METHODS: A microarray analysis was performed to screen differentially expressed lncRNAs associated with TC. TC cells were employed to evaluate the role of TNRC6C-AS1 by over-expression or silencing means. The interaction of TNRC6C-AS1 with methylation of STK4 promoter was evaluated to elucidate its ability to elicit autophagy, proliferation and apoptosis. RESULTS: TNRC6C-AS1 was up-regulated while STK4 was down-regulated, where methylation level was elevated. STK4 was verified as a target gene of TNRC6C-AS1, which was enriched by methyltransferase. Methyltransferase's binding to STK4 increased expression of its promoter. Over-expressed TNRC6C-AS1 inhibited STK4 by promoting STK4 methylation and reducing the total protein levels of MST1 and LATS1/2. The phosphorylation of YAP1 phosphorylation was decreased, which resulted in the promotion of SW579 cell proliferation and tumorigenicity. CONCLUSION: Based on our observations, we subsequently confirmed the anti-proliferative, pro-apoptotic and pro-autophagy capabilities of TNRC6C-AS1 through STK4 methylation via the Hippo signalling pathway in TC.

Improvement of therapeutic effects of mesenchymal stem cells in myocardial infarction through genetic suppression of microRNA-142.

Transplanted mesenchymal stem cells (MSCs) have been shown to contribute to myocardial repair after myocardial infarction (MI), primarily through production and secretion some growth factors and cytokines related to cell survival and regeneration. Further improvement of the therapeutic potential of MSCs appears to be an attractive strategy for MI treatment. CXC chemokine receptor (CXCR) 7 is the receptor for stromal cell-derived factor-1 (SDF-1), an important chemokine that is essential for tissue repair and angiogenesis. SDF-1/CXCR7 axis plays a critical role in the mobilization, recruitment and function of MSCs during tissue regeneration. Here, we depleted miR-142 that targets CXCR7 in MSCs cells through expression of antisense of miR-142, resulting in enhanced expression of CXCR7 in these miR-142-depleted MSCs (md-MSCs). In vitro, presence of md-MSCs reduced hypoxia-induced cardiac muscle cell apoptosis in a more pronounced manner than MSCs. In vivo, compared to transplantation of MSCs, transplantation of md-MSCs further enhanced cardiac re-vascularization and further improved cardiac functions after MI in mice. Together, our data suggest that depletion of miR-142 in MSCs may improve their therapeutic effects on MI.

Compound Heterozygous Mutations in the DUOX2/DUOXA2 Genes Cause Congenital Hypothyroidism.

The mutations in the dual oxidase 2 (DUOX2) and dual oxidase maturation factor 2 (DUOXA2) genes can cause congenital hypothyroidism (CH). This study reports the pedigree with goitrous congenital hypothyroidism (GCH) due to the coexistence of heterozygous mutations in the DUOX2 and DUOXA2 genes. The two sisters with GCH were diagnosed with CH at neonatal screening and were enrolled in this study. The DUOX2, DUOXA2, and thyroid peroxidase (TPO) genes were considered for genetic defects screening. Family members of the patients and normal controls were also enrolled and evaluated. The two girls harbored compound heterozygous mutations, including a new mutation of c.2654G>T (p.R885L) in the maternal DUOX2 allele and c.738C>G (p.Y246X) in the paternal DUOXA2 allele, that has been previously reported. The germline mutations from the families were consistent with an autosomal recessive inheritance pattern. No mutations in the TPO gene and the controls were observed.

Coexistence of resistance to thyroid hormone and ectopic thyroid: ten-year follow-up

SUMMARY Resistance to thyroid hormone (RTH) coexisting with ectopic thyroid is rare. Here we report a case of RTH with ectopic thyroid. A ten-year-old girl had been misdiagnosed as congenital hypothyroidism and treated with levothyroxine since she was born. Ten-year follow-up showed that the elevated thyrotropin was never suppressed by levothyroxine and no signs indicating hyperthyroidism or hypothyroidism despite elevated FT3 and FT4 levels. Therefore the girl developed no defects in physical and cognitive development. Pituitary adenoma was excluded by magnetic resonance imaging. Ultrasonography did not find the thyroid gland in the normal place, while the thyroid scan found a large lingual thyroid gland. The octreotide inhibition test showed a reduction in thyrotropin by 41.98%. No mutation was detected in the thyroid hormone receptor (THR) β, THRα, thyrotropin receptor (TSHR), and GNAS1 genes. To our knowledge, it is an interesting RTH case coexisting with lingual thyroid.

Coexistence of resistance to thyroid hormone and ectopic thyroid: ten-year follow-up.

Resistance to thyroid hormone (RTH) coexisting with ectopic thyroid is rare. Here we report a case of RTH with ectopic thyroid. A ten-year-old girl had been misdiagnosed as congenital hypothyroidism and treated with levothyroxine since she was born. Ten-year follow-up showed that the elevated thyrotropin was never suppressed by levothyroxine and no signs indicating hyperthyroidism or hypothyroidism despite elevated FT3 and FT4 levels. Therefore the girl developed no defects in physical and cognitive development. Pituitary adenoma was excluded by magnetic resonance imaging. Ultrasonography did not find the thyroid gland in the normal place, while the thyroid scan found a large lingual thyroid gland. The octreotide inhibition test showed a reduction in thyrotropin by 41.98%. No mutation was detected in the thyroid hormone receptor (THR) ß, THRα, thyrotropin receptor (TSHR), and GNAS1 genes. To our knowledge, it is an interesting RTH case coexisting with lingual thyroid.

Compound heterozygous mutations (p.T561M and c.2422delT) in the TPO gene associated with congenital hypothyroidism.

BACKGROUND: The objective of the study was to determine the genetic basis of goitrous congenital hypothyroidism (GCH) in Chinese siblings. METHODS: The proband and her younger brother with GCH were enrolled for molecular analysis of the dual oxidase 2 (DUOX2), dual oxidase maturation factor 2 (DUOXA2), and thyroid peroxidase (TPO) genes. Mutation screening was performed by Sanger sequencing the fragments amplified from genomic DNA. The detected mutations were verified among the close relatives of the patients and 105 controls. All participants underwent clinical examination and laboratory tests. RESULTS: Analysis of the TPO gene revealed two heterozygous mutations, the frameshift mutation c.2422delT in the exon14 of the TPO gene, that has been reported previously, and a novel missense mutation c.1682C>T (p.T561M) in the exon10 of the TPO gene. Nine family members of the patients were enrolled for mutation screening. The patients' parents and grandfathers harbored a single heterozygous mutation. The germline mutations from this family were consistent with an autosomal recessive inheritance pattern. No mutations in the DUOXA2 and DUOX2 genes were observed. CONCLUSIONS: The inactivating mutations (c.2422delT and p.T561M) in the TPO gene were identified in the Chinese siblings with GCH. The compound heterozygous mutations can cause GCH.

A Novel c.554+5C>T Mutation in the DUOXA2 Gene Combined with p.R885Q Mutation in the DUOX2 Gene Causing Congenital Hypothyroidism.

The coexistence of mutations in the dual oxidase maturation factor 2 (DUOXA2) and dual oxidase 2 (DUOX2) genes is rarely identified in congenital hypothyroidism (CH). This study reports a boy with CH due to a novel splice-site mutation in the DUOXA2 gene and a missense mutation in the DUOX2 gene. A four-year-old boy was diagnosed with CH at neonatal screening and was enrolled in this study. The DUOXA2, DUOX2, thyroid peroxidase (TPO), and thyrotropin receptor (TSHR) genes were considered for genetic defects screening. Genomic DNA was extracted from peripheral blood leukocytes, and Sanger sequencing was used to screen the mutations in the exon fragments. Family members of the patient and the controls were also enrolled and evaluated. The boy harbored compound heterozygous mutations including a novel splice-site mutation c.554+5C>T in the maternal DUOXA2 allele and c.2654G>A (p.R885Q) in the paternal DUOX2 allele. The germline mutations from his parents were consistent with an autosomal recessive inheritance pattern. No mutations in the TPO and TSHR genes were detected. A novel splice-site mutation c.554+5C>T in the DUOXA2 gene and a mutation p.R885Q in the DUOX2 gene were identified in a 4-year-old patient with goitrous CH.