Identification of diagnose related therapeutic targets of Danggui buxue decoction in Parkinson's disease.

BACKGROUND: Parkinson's disease (PD) is the fastest growing neurological disease. Currently, there is no disease-modifying therapy to slow the progression of the disease. Danggui buxue decoction (DBD) is widely used in the clinic because of its therapeutic effect. However, little is known about the molecular mechanism of DBD against PD. This study intends to explore the possible molecular mechanisms involved in DBD treatment of PD based on network pharmacology, and provide potential research directions for future research. METHODS: Firstly, the active components and target genes of DBD were screened from the traditional Chinese medicine systems pharmacology (TCMSP), DrugBank and UniProt database. Secondly, target genes of PD were identified from the (GEO) dataset, followed by identification of common target genes of DBD and PD. Thirdly, analysis of protein-protein interaction (PPI), functional enrichment and diagnosis was performed on common target genes, followed by correlation analysis between core target genes, immune cell, miRNAs, and transcription factors (TFs). Finally, molecular docking between core target genes and active components, and real-time PCR were performed. RESULTS: A total of 72 common target genes were identified between target genes of DBD and target genes of PD. Among which, 11 target genes with potential diagnostic value were further identified, including TP53, AKT1, IL1B, MMP9, NOS3, RELA, MAPK14, HMOX1, TGFB1, NOS2, and ERBB2. The combinations with the best docking binding were identified, including kaempferol-AKT1/HMOX1/NOS2/NOS3, quercetin-AKT1/ERBB2/IL1B/HMOX1/MMP9/TP53/NOS3/TGFB1. Moreover, IL1B and NOS2 respectively positively and negatively correlated with neutrophil and Type 1 T helper cell. Some miRNA-core target gene regulatory pairs were identified, such as hsa-miR-185-5p-TP53/TGFB1/RELA/MAPK14/IL1B/ERBB2/AKT1 and hsa-miR-214-3p-NOS3. These core target genes were significantly enriched in focal adhesion, TNF, HIF-1, and ErbB signaling pathway. CONCLUSION: Diagnostic TP53, AKT1, IL1B, MMP9, NOS3, RELA, MAPK14, HMOX1, TGFB1, NOS2, and ERBB2 may be considered as potential therapeutic targets of DBD in the treatment of PD.

Sensorimotor network connectivity correlates with motor improvement after repetitive transcranial magnetic stimulation in patients with Parkinson's disease.

BACKGROUND: Emerging evidence suggests that repetitive transcranial magnetic stimulation (rTMS) generally improves Parkinson's disease (PD) motor symptoms. However, personal responses to rTMS might be different. In this study, we explore the connectivity changes in PD patients with different responses to rTMS. METHODS: Among PD patients, 25 were treated with 10Hz-rTMS and seven were with sham rTMS over the supplementary motor area for 10 days. Resting-state functional connectivity magnetic resonance imaging (rs-fMRI) was performed in PD patients before and after rTMS stimulation. Neuropsychological scales such as Unified Parkinson's Disease Rating Scale Part III (UPDRS-III) were collected synchronously with rs-fMRI. To explore the connectivity changes after rTMS, degree centrality was calculated. RESULTS: 13 out of 25 participants were responsive to 10Hz rTMS. Degree centrality patterns in the left sensorimotor regions are primarily responsible for the differences between responsive and non-responsive individuals. Improvement in motor symptoms was substantially related to the baseline degree centrality in the left PreCG and the left PoCG. The performance in distinguishing non-responders from responders was further validated by the ROC analysis utilizing DC characteristics. Lastly, we found that connectivity increased in left PreCG and PoCG in patients with a better response to the rTMS. CONCLUSION: Taken together, these results suggest that the sensorimotor network is involved in the motor improvement following rTMS treatment, with patients with lower sensorimotor connectivity showing a tendency for greater motor improvement to HF-rTMS.

The Cerebellum is Involved in Motor Improvements After Repetitive Transcranial Magnetic Stimulation in Parkinson's Disease Patients.

Accumulating evidence indicates that repetitive transcranial magnetic stimulation (rTMS) ameliorates motor symptoms in patients with Parkinson's disease (PD); however, patients' responses to rTMS are different. Here, we aimed to explore neural activity changes in patients with PD exhibiting different responses to high-frequency rTMS treatments using functional magnetic resonance imaging (fMRI). We treated 24 patients with PD using 10-session rTMS (10 Hz) over the supplementary motor area (SMA) for 10 days. Resting-state functional magnetic resonance imaging (rs-fMRI), the Unified Parkinson's Disease Rating Scale Part III (UPDRS-III) and other neuropsychological scales were performed at the baseline and endpoint of rTMS treatment. The changes in the fractional amplitude of low-frequency fluctuation (fALFF) were calculated. Significant improvements were observed in motor symptoms, especially in the sub-symptoms of bradykinesia. All the participants were subsequently stratified into responders and non-responders according to the UPDRS-III reduction. We identified increased fALFF values in the left Crus II of the cerebellar hemisphere and bilateral thalamus as responsive signs to rTMS. Furthermore, the motor response to rTMS over the SMA, measured by the reduction in UPDRS-III and bradykinesia scores, was positively associated with increased fALFF values in the left Crus2 of cerebellar hemisphere, left lobule VIIB of cerebellar hemisphere, right lobule VI of the cerebellar hemisphere, and the right postcentral gyrus. These findings provide evidence for the involvement of cerebellar activity in the motor response to rTMS treatment.

Characterization of the Immune Cell Infiltration Landscape and a New Prognostic Score in Glioblastoma.

Glioblastoma (GBM) is the most aggressive, malignant primary brain tumor, which has abundant tumor-infiltrating immune cells and stroma in the tumor microenvironment (TME). So far, the TME landscape of GBM has not been elucidated. GBM samples were retrieved from TCGA and GEO databases. We used ESTIMATE and CIBERSORT algorithms to calculate risk score associated with TME, and immune cell infiltration (ICI) score of each patient is calculated by PCA. GSEA analysis is explored for each subgroup. Finally, the patient prognosis in different ICI score subgroup is determined. Two ICI clusters are determined in 208 GBM patients, and 207 differentially expressed genes (DGEs) are found between ICI clusters. And then, two gene clusters were determined. Finally, we obtained ICI score for each patient using principal component analysis (PCA). Patients were divided into high and low ICI score subgroups by setting the median as cutoff. Through GSEA, we found ECM-receptor interaction, mTOR signaling pathway, pathways in cancer, TGF-beta signaling pathway, and other immunosuppressive pathway related genes in the low ICI score group. Furthermore, patients with high ICI score group have more better prognosis. Targeting the stroma in GBM may be an effective new therapeutic approach, and the ICI score is an effective potential prognostic classifier of GBM.

Comprehensive characterization of differentially expressed genes in thyroid cancer.

AIM: To explore the patterns of gene expression and functionally characterize the differentially expressed genes (DEGs) in thyroid cancer. METHODS: DEGs were determined between 57 paired thyroid cancer and noncancerous tissues using DESeq2. Subsequently, the main functions of the DEGs were studied by a variety of analyses. RESULTS: We identified a cohort of 752 upregulated and 309 downregulated DEGs in thyroid cancer. Several hub DEGs were found in the protein-protein interaction networks. We also revealed a set of DEGs that were dysmethylated, involved in copy number variations and associated with clinical features in thyroid cancer. CONCLUSION: These results provide some novel findings on DEGs in thyroid cancer, which will be useful to guide further investigation and target therapy for this disease. [Formula: see text].

Intranasal delivery of calcitonin gene-related peptide reduces cerebral vasospasm in rats.

Cerebral vasospasm is the primary cause of sequelae and poor clinical conditions of subarachnoid hemorrhage (SAH); therefore, it is imperative to relieve vasospasm and improve cerebral blood supply. Calcitonin gene-related peptide (CGRP) is a potent vasodilator that is normally released by trigeminal sensory fibers but depleted following SAH. We propose that intranasal application may be an effective way to deliver CGRP to the brain and ameliorate vasospasm after SAH. In this study, we intranasally applied CGRP to rats and induced SAH by double-injection of autologous blood into the cisterna magna. Compared to intravenous injection, intranasal delivery led to a 10-fold higher level of CGRP in the brain. Intranasal CGRP significantly ameliorated vasospasm, improved cerebral blood flow, and reduced cortical and endothelial cell death. Moreover, CGRP increased the levels of vascular endothelial growth factor and stimulated angiogenesis. Altogether, our data demonstrate that intranasal CGRP delivery is a promising method for moderating vasospasm and reducing the associated ischemic brain injury after SAH in rats, and suggest that it may be a potential approach in clinic.