Targeting FTO induces colorectal cancer ferroptotic cell death by decreasing SLC7A11/GPX4 expression.

Ferroptosis is a newly identified iron-dependent form of death that is becoming increasingly recognized as a promising avenue for cancer therapy. N6-methyladenosine (m6A) is the most abundant reversible methylation modification in mRNA contributing to tumorigenesis. However, the crucial role of m6A modification in regulating ferroptosis during colorectal cancer (CRC) tumorigenesis remains elusive. Herein, we find that m6A modification is increased during ferroptotic cell death and correlates with the decreased m6A demethylase fat mass and obesity-associated protein (FTO) expression. Functionally, we demonstrate that suppressing FTO significantly induces CRC ferroptotic cell death, as well as enhancing CRC cell sensitivity to ferroptosis inducer (Erastin and RSL3) treatment. Mechanistically, high FTO expression increased solute carrier family 7 member 11 (SLC7A11) or glutathione peroxidase 4 (GPX4) expressions in an m6A-YTHDF2 dependent manner, thereby counteracting ferroptotic cell death stress. In addition, we identify Mupirocin as a novel inhibitor of FTO, and Mupirocin induces CRC ferroptosis and inhibits tumor growth. Clinically, the levels of FTO, SLC7A11, and GPX4, are highly correlated expression in CRC tissues. Our findings reveal that FTO protects CRC from ferroptotic cell death in promoting CRC tumorigenesis through triggering SLC7A11/GPX4 expression.

Three-dimensional evaluation of upper pharyngeal airway, hyoid bone, and craniocervical changes following stabilization splint therapy in adult patients with temporomandibular joint disorders and mandibular deviation: A retrospective study.

OBJECTIVE: This study aimed primarily to analyze the three-dimensional (3D) changes in the pharyngeal airway (PA), and secondarily, the hyoid bone (HB) and the craniocervical (CC) following stabilization splint (SS) therapy in adult patients with temporomandibular joint disorders (TMD) and mandibular deviation (MD). METHODS: Thirty-five adult patients with TMD and MD, who were treated using SS with a mean age of 25.14 ± 6.11 years, were enrolled in this retrospective clinical study. Pre- and post-therapeutic cone-beam computed tomography (CBCT) scans were analyzed. PA dimension,nasopharyngeal, oropharyngeal, hypopharyngeal, sub-hypopharyngeal, and total pharyngeal airway spaces were measured in surface area, volume, minimum constricted area (MCA) and width, HB position, and CC posture were analyzed three-dimensionally using InVivo 6.0.3 and Dolphin 11.95 software. Wilcoxon rank-sum or Paired t-test was conducted, and P < 0.05 was considered significant. RESULTS: SS therapy was administered for a period of 9.49 ± 4.02 months. The oropharyngeal airway space showed a significant decrease in sagittal width. The hypopharyngeal surface area, volume, MCA, and sagittal width decreased significantly. In terms of HB, hyoid-mandibular plane (H-MP), retrognathia-third vertebra's most inferior-anterior (RGN-C3ia), and retrognathia-Sella (RGN-S) distances significantly decreased. The Nasion-Sella line and the line that passes through C2ip to the odontoid process posterior tangent (NSL-OPT) angle in CC posture also decreased significantly. CONCLUSION: SS therapy in TMD patients with MD mainly results in narrowing of the hypopharyngeal region, no change in HB position and improvement in head posture. These results undoubtedly assist in diagnosis and treatment of clinical conditions.

The Association Between Work Environment, Work Attitudes, and Turnover Intentions Among Geriatric Social Workers in China.

The psychological state of geriatric social workers affects the intention to leave and thus the quality of services provided to older adults. This study explored the relationship between the work environment, work attitudes, and turnover intentions of geriatric social workers. This study obtained an analytic sample comprising 999 geriatric social workers from the 2019 Longitudinal Study of Social Work in China. Multivariate regression techniques combined with a mediation analysis was performed to explore the relationships. The study results provided preliminary evidence on the complex associations between and among work environment, work attitudes, and turnover intentions of geriatric social workers in China. We demonstrated that perceived organizational support reduced the turnover intentions of geriatric social workers through increased collective psychological ownership and reduced burnout. Regular inter- and intra-agency communication between social workers and their supervisors and colleagues have important roles in reducing turnover by enhancing support and emotional commitment to organizations. Policy decision-makers are suggested to clearly define the roles and responsibilities of geriatric social works to release their administrative burdens, which may help to reduce their burnout level and improve the stability of the geriatric social work force.

Network Pharmacology and Molecular Docking Analysis Explores the Mechanisms of Cordyceps sinensis in the Treatment of Oral Lichen Planus.

Objective: Oral lichen planus (OLP) is the most common potentially malignant disorder of the oral cavity. This study aimed to investigate the mechanism of action of Cordyceps sinensis in the treatment of OLP and provides a theoretical support for improving current treatment regimens for OLP. Methods: The active components and therapeutic targets of Cordyceps sinensis were predicted and screened using the TCMSP, SymMap, PubMed, HIT 2.0, and PharmMapper databases, while the relevant OLP targets were predicted and screened using the DisGeNET and GeneCards databases. Protein-protein interactions (PPI) were examined using the String database, and Cytoscape was used to combine and illustrate the findings. GO and KEGG pathway enrichment analyses were carried out using RStudio, and AutoDock Vina and Pymol were used for molecular docking and visualization, respectively. Results: A total of 404 potential target genes were discovered after evaluating 21 active compounds from Cordyceps sinensis. Potential therapeutic targets included 67 targets that matched and overlapped with OLP, including TNF, IL-6, CD4, EGFR, and IL1B. Key targets were predominantly engaged in the PI3K-Akt signaling pathway and the MAPK signaling pathway, according to the GO and KEGG analyses. These targets have a connection to biological processes including apoptosis signaling pathway regulation, T cell activation, and oxidative stress response. The molecular docking results showed that TNF, IL-6, CD4, EGFR, and IL1B could bind to their corresponding active components. Conclusions: Cordyceps sinensis contains multiple components and acts on multiple targets and multiple pathways. Particularly, Cordyceps sinensis targets TNF, IL-6, CD4, EGFR, and IL1B, regulates PI3K-Akt and MAPK signaling pathways, as well as takes part in biological processes including apoptosis, T cell activation, and oxidative stress. Cordyceps sinensis could be a crucial choice in the therapy of OLP.

Identification of Biomarkers Associated with Cancerous Change in Oral Leukoplakia Based on Integrated Transcriptome Analysis.

OBJECTIVE: Oral leukoplakia (OLK) is the most common precancerous lesion in the oral cavity. This study aimed to explore key biomarkers for monitoring OLK for early diagnosis of oral squamous cell carcinoma (OSCC) and screen small-molecule drugs for the prevention of OSCC. METHOD: The Gene Expression Omnibus (GEO) database was explored to extract two microarray datasets, namely, GSE85195 and GSE25099. The data of the normal group, OLK group, and OSCC group were analyzed by weighted gene coexpression network analysis (WGCNA) to identify the most significant gene module and differentially expressed genes (DEGs). The intersection genes were extracted as the key genes of OLK carcinogenesis. Subsequently, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were analyzed in the module. Connectivity Map and molecular docking were used to screen small-molecule drugs. The diagnostic values of four key genes were identified and verified in the GSE26549 dataset. RESULTS: WGCNA obtained the red module (r = -0.91, p < 0.05) with the strongest correlation with cancerous phenotype. GO enrichment analysis showed 60 pathways, including 28 biological processes, 11 cell components, and 21 molecular functions, and KEGG enrichment analysis showed 4 pathways (p < 0.05). In the differential expression analysis, there was no intersection between the upregulated genes and the red module genes. However, the intersection of the downregulated genes and the red module genes yielded 4 key genes: dopachrome tautomerase (DCT), keratin 3 (KRT3), keratin 76 (KRT76), and FAM3 metabolic regulation signal molecule B (FAM3B). The area under the curve of the diagnostic model constructed by these four genes was 0.963 (CI = 0.913-1.000). The sensitivity was 0.933, and the specificity was 0.923. The diagnostic model was successfully verified in GSE26549 (AUC = 0.745, CI = 0.638-0.851). Compared with the diagnostic models of the previous studies, the diagnostic efficiency of this model was the highest. The small-molecule drugs, selumetinib and benidipine, were selected according to the gene expression profile and showed binding activity when docking with the above molecules. CONCLUSIONS: This study provides new targets and drugs for OLK. These targets could be used as the key diagnostic molecules for long-term follow-up of OLK. The small-molecule drugs selumetinib and benidipine could be used for the prevention and treatment of OSCC.

Metabolomics and Transcriptomics Analysis on Metabolic Characteristics of Oral Lichen Planus.

OBJECTIVE: To explore metabolic biomarkers related to erosive and reticulated oral lichen planus (OLP) by non-targeted metabolomics methods and correlate metabolites with gene expression, and to investigate the pathological network pathways of OLP from the perspective of metabolism. METHODS: A total of 153 individuals were enrolled in this study, including 50 patients with erosive oral lichen planus (EOLP), 51 patients with reticulated oral lichen planus (ROLP), and 52 healthy controls (HC). The ultra-high-performance liquid chromatography quadrupole-Orbitrap high-resolution accurate mass spectrometry (UHPLC/Q-Orbitrap HRMS) was used to analyze the metabolites of 40 EOLP, 40 ROLP, and 40 HC samples, and the differential metabolic biomarkers were screened and identified. The regulatory genes were further screened through the shared metabolites between EOLP and ROLP, and cross-correlated with the OLP-related differential genes in the network database. A "gene-metabolite" network was constructed after finding the key differential genes. Finally, the diagnostic efficiency of the biomarkers was verified in the validation set and a diagnostic model was constructed. RESULT: Compared with HC group, a total of 19 and 25 differential metabolites were identified in the EOLP group and the ROLP group, respectively. A total of 14 different metabolites were identified between EOLP and ROLP. Two diagnostic models were constructed based on these differential metabolites. There are 14 differential metabolites shared by EOLP and ROLP. The transcriptomics data showed 756 differentially expressed genes, and the final crossover network showed that 19 differential genes were associated with 12 metabolites. Enrichment analysis showed that alanine, aspartate and glutamate metabolism were closely associated with the pathogenesis of OLP. CONCLUSION: The metabolic change of different types of OLP were clarified. The potential gene perturbation of OLP was provided. This study provided a strong support for further exploration of the pathogenic mechanism of OLP.

Early intervention with Didang decoction delays macrovascular lesions in diabetic rats through regulating AMP-activated protein kinase signaling pathway.

The study aimed to investigate the intervening role of Didang decoction (DDD) at different times in macrovascular endothelial defense function, focusing on its effects on the AMP-activated protein kinase (AMPK) signaling pathway. The effects of DDD on mitochondrial energy metabolism were also investigated in rat aortic endothelial cells (RAECs). Type 2 diabetes were induced in rats by streptozotocin (STZ) combined with high fat diet. Rats were randomly divided into non-intervention group, metformin group, simvastatin group, and early-, middle-, late-stage DDD groups. Normal rats were used as control. All the rats received 12 weeks of intervention or control treatment. Western blots were used to detect the expression of AMP-activated protein kinase α1 (AMPKα1) and peroxisome proliferator-activated receptor 1α (PGC-1α). Changes in the intracellular AMP and ATP levels were detected with ELISA. Real-time-PCR was used to detect the mRNA level of caspase-3, endothelial nitric oxide synthase (eNOS), and Bcl-2. Compared to the diabetic non-intervention group, a significant increase in the expression of AMPKα1 and PGC-1α were observed in the early-stage, middle-stage DDD groups and simvastatin group (P < 0.05). The levels of Bcl-2, eNOS, and ATP were significantly increased (P < 0.05), while the level of AMP and caspase-3 were decreased (P < 0.05) in the early-stage DDD group and simvastatin group. Early intervention with DDD enhances mitochondrial energy metabolism by regulating the AMPK signaling pathway and therefore may play a role in strengthening the defense function of large vascular endothelial cells and postpone the development of macrovascular diseases in diabetes.

Early Intervention of Didang Decoction on MLCK Signaling Pathways in Vascular Endothelial Cells of Type 2 Diabetic Rats.

In the study, type 2 diabetic rat model was established using streptozotocin (STZ) combined with a high-fat diet, and the rats were divided into control and diabetic groups. Diabetic groups were further divided into nonintervening, simvastatin, Didang Decoction (DDD) early-phase intervening, DDD mid-phase intervening, and DDD late-phase intervening groups. The expression level of MLCK was detected using Western Blot analysis, and the levels of cyclic adenosine monophosphate (cAMP), protein kinase C (PKC), and protein kinase A (PKA) were examined using Real Time PCR. Under the electron microscope, the cells in the early-DDD-intervention group and the simvastatin group were significantly more continuous and compact than those in the diabetic group. Compared with the control group, the expression of cAMP-1 and PKA was decreased in all diabetic groups, whereas the expression of MLCK and PKC was increased in early- and mid-phase DDD-intervening groups (P < 0.05); compared with the late-phase DDD-intervening group, the expression of cAMP-1 and PKA was higher, but the level of MLCK and PKC was lower in early-phase DDD-intervening group (P < 0.05). In conclusion, the early use of DDD improves the permeability of vascular endothelial cells by regulating the MLCK signaling pathway.

Neutroprotective efficacy of sodium tanshinone B on hippocampus neuron in a rat model of focal cerebral ischemia.

OBJECTIVE: To investigate the protective effects of sodium tanshinone B (STB) on brain damage following focal ischemia-reperfusion (I/R) injury through interfering with N-methyl-D-aspartic acid receptor (NMDAR) and excitatory and inhibitory amino acids, and evaluate the potential mechanisms of the neuroprotective activity of STB. METHODS: Transient forebrain ischemia was induced by middle cerebral artery occlusion (MCAO). The rats were randomized into a sham operated group, a model group (I/R) and three STB different dose groups. Rats were pretreated with STB at the doses of 4, 8, 16 mg/kg (STB(1), STB(2), STB(3)) for 3 days before MCAO. The expression of NMDAR1 was detected by immunohistochemistry and Western blotting. The concentrations of glutamate and γ-aminobutyric acid (GABA) were analyzed using high performance liquid chromatography. RESULTS: STB treatment reduced neurological defect scores, cerebral infarction volume and brain water content. The levels of NMDAR1 were significantly higher in the l/R and STB(1) groups than that of the sham and the STB(3) groups (P<0.01). Optical density of NMDAR1 was significantly increased in cornu ammonis (CA)1 region of the l/R group (P<0.05). STB treatment reduced NMDAR1 optical density in the CA1 region (P<0.01). The levels of glutamate were significantly lower in the hippocampus in the STB(3) group than that of the l/R, STB(1) and STB(2) groups (P<0.01). CONCLUSION: Preconditioning with STB appears to be a simple and promising strategy to reduce or even prevent cerebral l/R injury and has potential for future clinical application.