Correlation of visual area with tremor improvement after MRgFUS thalamotomy in Parkinson's disease.

OBJECTIVE: MRI-guided focused ultrasound (MRgFUS) thalamotomy is a novel and minimally invasive alternative for medication-refractory tremor in Parkinson's disease (PD). However, the impact of MRgFUS thalamotomy on spontaneous neuronal activity in PD remains unclear. The purpose of the current study was to evaluate the effects of MRgFUS thalamotomy on local fluctuations in neuronal activity as measured by the fractional amplitude of low-frequency fluctuations (fALFF) in patients with PD. METHODS: Participants with PD undergoing MRgFUS thalamotomy were recruited. Tremor scores were assessed before and 3 and 12 months after treatment using the Clinical Rating Scale for Tremor. MRI data were collected before and 1 day, 1 week, 1 month, 3 months, and 12 months after thalamotomy. The fALFF was calculated. A whole-brain voxel-wise paired t-test was used to identify significant changes in fALFF at 12 months after treatment compared to baseline. Then fALFF in the regions with significant differences were extracted from fALFF maps of patients for further one-way repeated-measures ANOVA to investigate its dynamic alterations. The association between fALFF changes induced by thalamotomy and tremor improvement were evaluated using the nonparametric Spearman rank test. RESULTS: Nine participants with PD (mean age ± SD 64.7 ± 6.1 years, 8 males) were evaluated. Voxel-based analysis showed that fALFF in the left occipital cortex (Brodmann area 17 [BA17]) significantly decreased at 12 months after thalamotomy compared to baseline (voxel p < 0.001, cluster p < 0.05 family-wise error [FWE] corrected). At baseline, fALFF in the left occipital BA17 in patients was elevated compared with that in 9 age- and gender-matched healthy subjects (p < 0.05). Longitudinal analysis displayed the dynamic changes of fALFF in this region (F (5,40) = 3.61, p = 0.009). There was a significant positive correlation between the falling trend in fALFF in the left occipital BA17 and hand tremor improvement after treatment over 3 time points (Spearman's rho = 0.44, p = 0.02). CONCLUSIONS: The present study investigated the impact of MRgFUS ventral intermediate nucleus thalamotomy on spontaneous neural activity in medication-refractory tremor-dominant PD. The visual area is, for the first time, reported as relevant to tremor improvement in PD after MRgFUS thalamotomy, suggesting a distant effect of MRgFUS thalamotomy and the involvement of specific visuomotor networks in tremor control in PD.

Structural and Functional Thalamic Changes in Parkinson's Disease With Mild Cognitive Impairment.

BACKGROUND: The thalamus is a key node of deep gray matter and previous studies have demonstrated that it is involved in the modulation of cognition. PURPOSE: To investigate the volume changes of the thalamus and its subregions and altered thalamus functional connectivity patterns in Parkinson's disease (PD) patients with and without mild cognitive impairment (MCI). STUDY TYPE: Prospective. POPULATION: Thirty-three patients with MCI (PD-MCI), 36 PD patients having no cognitive impairment (PD-NCI), 21 healthy controls (HCs). SEQUENCE: 3.0T MRI scanner; 3D T1 -weighted fast spoiled gradient recalled echo (3D T1 -FSPGR); resting-state fMRI ASSESSMENT: Voxel-based morphometry (VBM) was performed to calculate the volume of the thalamus and its subregions. The left and right total thalamus were considered seeds and seed-based functional connectivity (FC) was analyzed. Additionally, correlations between volumes and cognitive performance and between FC values and cognitive performance were examined separately. STATISTICAL TEST: Analysis of covariance (ANCOVA); two-sample t-tests; partial correlation analysis. RESULTS: The volumes of the total thalamus (PD-MCI vs. PD-NCI vs. HCs: 18.39 ± 1.67 vs. 19.63 ± 1.79 vs. 19.47 ± 1.35) and its subregions were significantly reduced in PD-MCI as compared to PD-NCI (total thalamus: P = 0.002) and HCs (total thalamus: P = 0.012). Compared with PD-NCI, PD-MCI showed increased FC between the thalamus and bilateral middle cingulate cortex and left posterior cingulate cortex, and decreased FC between thalamus and the left superior occipital gyrus, left cuneus, left precuneus, and left middle occipital gyrus. Volumes of thalamus and the subregions, as well as the FC of thalamus with the identified regions, were significantly correlated (P < 0.05, FDR-corrected) with neuropsychological scores in PD patients. DATA CONCLUSION: We noted volume loss and altered FC of thalamus in PD-MCI patients, and these changes were correlated with global cognitive performance. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICIENCY: Stage 2 J. Magn. Reson. Imaging 2020;52:1207-1215.

Gypenosides Protect Orbital Fibroblasts in Graves Ophthalmopathy via Anti-Inflammation and Anti-Fibrosis Effects.

Purpose: To investigate the effect of Gypenosides (Gyps) on the inflammation and fibrosis in orbital fibroblasts (OFs) in Graves ophthalmopathy (GO). Methods: Bioinformatics analyses were performed to identify the enriched genes and signaling pathways related to Gyps function. For ex vivo experiments, OFs were cultured from orbital connective tissues from patients with GO. OF proliferation was estimated by Cell Counting Kit-8 assay. Effects of Gyps treatment on interleukin (IL)-1ß-induced inflammation and transforming growth factor-ß1 (TGF-ß1)-induced fibrosis were evaluated by real-time quantitative PCR (RT-qPCR), enzyme-linked immunosorbent assay (ELISA), and Western blotting. OFs were treated with IL-1ß or TGF-ß1 in the absence or presence of Gyps pretreatment, and the levels of related mRNA or proteins were evaluated by RT-qPCR or ELISA. Results: Eight inflammation-related target genes and nine fibrosis-related target genes were screened out. These genes were mainly enriched in pathways corresponding to inflammation and fibrosis, respectively. IL-1ß-induced upregulation of inflammatory cytokines, and TGF-ß-induced upregulation of fibrotic mediators in OFs were downregulated by Gyps. Moreover, Gyps reduced the activation of Toll like receptors 4/nuclear factor-κ B signaling and TGF-ß1/SMAD2/SMAD4 signaling in GO OFs. Conclusions: Gyps could protect GO-derived OFs against IL-1ß-induced inflammation and TGF-ß1-induced fibrosis. Thus Gyps might have therapeutic potential on inflammation and fibrosis in GO.

Gypenosides Prevent H2O2-Induced Retinal Ganglion Cell Apoptosis by Concurrently Suppressing the Neuronal Oxidative Stress and Inflammatory Response.

Our previous study demonstrated that gypenosides (Gp) exert protective effects on retinal nerve fibers and axons in a mouse model of experimental autoimmune optic neuritis. However, the therapeutic mechanisms remain unclear. Thus, in this study, a model of oxidative damage in retinal ganglion cells (RGCs) was established to investigate the protective effect of Gp, and its possible influence on oxidative stress in RGCs. Treatment of cells with H2O2 induced RGC injury owing to the generation of intracellular reactive oxygen species (ROS). In addition, the activities of antioxidative enzymes decreased and the expression of inflammatory factors increased, resulting in an increase in cellular apoptosis. Gp helped RGCs to become resistant to oxidation damage by directly reducing the amount of ROS in cells and exerting protective effects against H2O2-induced apoptosis. Treatment with Gp also reduced the generation of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), and increased nuclear respiratory factor 2 (Nrf-2) levels so as to increase the levels of heme oxygenase-1 (HO-1) and glutathione peroxidase 1/2 (Gpx1/2), which can enhance antioxidation in RGCs. In conclusion, our data indicate that neuroprotection by Gp involves its antioxidation and anti-inflammation effects. Gp prevents apoptosis through a mitochondrial apoptotic pathway. This finding might provide novel insights into understanding the mechanism of the neuroprotective effects of gypenosides in the treatment of optic neuritis.

Medicinal Value and Potential Therapeutic Mechanisms of Gynostemma pentaphyllum (Thunb.) Makino and Its Derivatives: An Overview.

Gynostemma pentaphyllum (Thunb.) Makino (GpM) and its derivatives, especially gypenosides (Gyps), are widely used as safe and convenient natural herbal drugs for the treatment of many diseases for a long time, and Gyps have different oral bioavailability (OB) values and low ability to cross the blood-brain barrier (BBB). The effects of GpM and isolates on fibrosis, inflammation, oxidation, proliferation and migration are proved. GpM shows bidirectional regulation effect on proliferation, oxidation and apoptosis in tumor and non-tumor cells. GpM and its extractions can resist proliferation, activate oxidation and apoptosis in tumor cells and have opposite effects on non-tumor cells. We succinctly present some current views of medicinal value and potential therapeutic mechanisms of GpM and its derivatives.

Research on the Potential Mechanism of Gypenosides on Treating Thyroid-Associated Ophthalmopathy Based on Network Pharmacology.

Thyroid-associated ophthalmopathy is the commonest orbital disease in adults. However, shortcomings still exist in treatments. The aim of this study was to identify the efficacy and potential mechanism of gypenosides in the treatment of thyroid-associated ophthalmopathy. The Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform was screened for active compounds of gypenosides, and targets were predicted using Swiss Target Prediction. The targets of thyroid-associated ophthalmopathy were obtained from Online Mendelian Inheritance in Man, Comparative Toxicogenomic Database and GeneCards Human gene database. Gene Ontology (GO), the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Reactome Pathways were determined based on the common targets. Protein-protein interaction (PPI) network was constructed to further understand of relationship among target genes, compounds and proteins. Molecular docking was performed to investigate the binding ability between gypenosides and hub genes. A total of 70 targets for gypenosides and 804 targets for thyroid-associated ophthalmopathy were obtained with 8 common targets identified. GO analysis and KEGG pathway analysis revealed that the hub genes were enriched in JAK-STAT, while Reactome pathways analysis indicated genes enriched in interleukin pathways. PPI network showed STAT1, STAT3, and STAT4 were at the center. Additionally, molecular docking indicated that STAT1 and STAT3 display good binding forces with gypenosides. This study indicates that target genes mainly enriched in JAK-STAT signaling pathway, particularly in STATs, which can be combined with gypenosides. This may suggest that gypenosides have curative effect on thyroid-associated ophthalmopathy via the JAK-STAT pathway.

Yangxin Tongmai Formula ameliorates impaired glucose tolerance in children with Graves' disease through upregulation of the insulin receptor levels.

Graves' disease (GD) is the leading cause of hyperthyroidism, and the majority of GD patients eventually develop disorders of glucose handling, which further affects their quality of life. Yangxin Tongmai formula (YTF) is modified from a famous formula of traditional Chinese medicine for the treatment of cardiovascular diseases. In this study we investigated the potential effects of YTF in the treatment of pediatric GD patients with impaired glucose tolerance. Forty pediatric GD patients and 20 healthy children were recruited for this clinical study. Based on the glucose tolerance, the GD patients were divided into two groups: 20 patients displayed impaired glucose tolerance, while the other 20 patients displayed normal glucose tolerance. YTF was orally administered for 60 days. YTF administration significantly ameliorated the abnormal glucose tolerance and insulin sensitivity in the GD patients with impaired glucose tolerance. To determine the molecular mechanisms of this observation, the number of plasma insulin receptors was determined by ELISA. Before treatment, the fasting and postprandial levels of the insulin receptor were significantly lower in patients with impaired glucose tolerance compared with those in patients with normal glucose tolerance and healthy children. After YTF treatment, both the fasting and the postprandial circulating insulin receptor levels were upregulated, and close to those in healthy children. Therefore, YTF is a potential effective treatment to enhance glucose handling in GD children with impaired glucose tolerance.

Gypenosides protect retinal pigment epithelium cells from oxidative stress.

Oxidative stress plays a critical role in the pathogenesis of retinal degeneration. Gypenosides are the major functional components isolated from Gynostemma pentaphyllum. They have been shown to protect against oxidative stress and inflammation and have also demonstrated a protective effect on experimental optic neuritis. In order to determine the protective properties of gypenosides against oxidative stress in human retinal pigment epithelium (RPE) cells, ARPE-19 cells were treated with H2O2 or H2O2 plus gypenosides for 24 h. ARPE-19 cells co-treated with gypenosides had significantly increased cell viability and decreased cell death rate when compared to cells treated with H2O2 alone. The level of GSH, the activities of SOD and catalase, and the expression of NRF2 and antioxidant genes were notably decreased, while there were marked increases in ROS, MDA and pro-inflammatory cytokines in ARPE-19 cells exposed to H2O2; co-treatment with gypenosides significantly counteract these changes. Our study suggests that gypenosides protect RPE cells from oxidative damage and offer therapeutic potential for the treatment of retinal degeneration.

Two phenolic antioxidants in Suoyang enhance viability of •OH-damaged mesenchymal stem cells: comparison and mechanistic chemistry.

BACKGROUND: Suoyang originates from a psammophyte named Cynomorium songaricum Rupr and has been known as a phenolic-antioxidant-enriched traditional Chinese herbal medicine. The present study attempted to investigate the protective effect of phenolic antioxidants in Suoyang towards •OH-mediated MSCs and then further discusses the chemical mechanisms. METHODS: The lyophilized aqueous extract of Suoyang (LAS) was prepared and characterized using HPLC. Then, two phenolic antioxidant references, epicatechin and luteolin-7-O-ß-D-glucoside, along with LAS, were investigated for their effects on the viability of •OH-treated MSCs using the 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyl (MTT) assay. The comparison and mechanistic chemistry of epicatechin and luteolin-7-O-ß-D-glucoside were further explored using various antioxidant assays, including PTIO•-scavenging, FRAP (ferric ion reducing antioxidant power), ABTS+•-scavenging, and DPPH•-scavenging. Their Fe2+-binding capacities were also compared using ultraviolet (UV) spectra. RESULTS: The HPLC analysis indicated that there are 8 phenolic antioxidants in LAS, including epicatechin, luteolin-7-O-ß-D-glucoside, gallic acid, protocatechuic acid, catechin, isoquercitrin, phlorizin, and naringenin. The MTT assay revealed that epicatechin could more effectively increase the survival of •OH-treated MSCs than luteolin-7-O-ß-D-glucoside. Similarly, epicatechin exhibited higher antioxidant abilities than luteolin-7-O-ß-D-glucoside in the DPPH•-scavenging, ABTS+•-scavenging, FRAP, and PTIO•-scavenging assays. In the Fe2+-binding assay, luteolin-7-O-ß-D-glucoside gave a stronger UV peak at 600 nm, with ε = 2.62 × 106 M-1 cm-1, while epicatechin produced two peaks at 450 nm (ε = 8.47 × 105 M-1 cm-1) and 750 nm (ε = 9.68 × 105 M-1 cm-1). CONCLUSION: As two reference antioxidants in Suoyang, epicatechin and luteolin-7-O-ß-D-glucoside can enhance the viability of •OH-damaged MSCs. Such a beneficial effect may be from their antioxidant effects, including direct-antioxidant and indirect-antioxidant (i.e., Fe2+-binding) processes. In the direct-antioxidant process, proton (H+), one electron (e), or even hydrogen-atom (•H) transfer may occur to fulfill radical-scavenging (especially •OH-scavenging); in this aspect, epicatechin is superior to luteolin-7-O-ß-D-glucoside due to the presence of more phenolic -OHs. The additional -OHs can also be responsible for the better cytoprotective effect. In terms of indirect-antioxidant potential, however, epicatechin is inferior to luteolin-7-O-ß-D-glucoside due to the absence of a hydroxyl-keto moiety. These findings will provide new information about medicinal psammophytes for MSC transplantation.

Gypenosides might have neuroprotective and immunomodulatory effects on optic neuritis.

Optic neuritis is a common disease in young adults, inducing apoptosis of retinal ganglion cells, which leads to varying degree of visual function damages, even blindness. As the standard treatment, methylprednisolone pulse therapy can only promote the recovery of visual acuity but not prevent retinal ganglion cell degeneration. It cannot help improve the ultimate visual outcome. Both inflammatory response and endogenous oxidative stress play crucial roles in the progression of optic neuritis. The combination of immunomodulatory and antioxidant is expected to improve the prognosis of the disease by preventing the apoptosis of retinal ganglion cells. Triterpenoids (oleanolic acid derived) were reported to have the dual capacity of simultaneously repressing production of pro-inflammatory mediators and exerting neuroprotective effects through induction of anti-oxidant genes in experimental optic neuritis. Gypenosides with an aglycone mainly of dammarane-type tetracyclic triterpenoids, also has the dual capacity of immune regulation and antioxidation. Both gypenosides and oleanolic acid were reported to have similar roles in hepatoprotection. Beside, gypenosides were reported to have the capacity of modulating the activation of immune cells and the expression of cytokines. In addition, gypenosides showed neuroprotective effect against oxidative injury in dopaminergic neurons and mouse model of Parkinson's disease. Accordingly, we propose that gypenosides have potential neuroprotective and immunomodulatory effects on optic neuritis through antioxidation and immune regulation. The application of gypenosides might prevent the apoptosis of retinal ganglion cells and improve the ultimate visual outcome in patients with optic neuritis.

In vitro inhibitory effect on pancreatic lipase activity of subfractions from ethanol extracts of fermented Oats (Avena sativa L.) and synergistic effect of three phenolic acids.

The purpose of the present work is to study the pancreatic lipase inhibitory effects of different subfractions (n-hexane, ethyl acetate (EA), n-butanol, and water) from ethanol extracts of nonfermented and fungi-fermented oats and to delineate the interactions of three primary phenolic acids in the EA subfractions. The EA subfraction showed the highest inhibitory effect on pancreatic lipase activity at 1.5 mg/mL compared to the other subfractions, regardless of whether the oats were fermented. Meanwhile, both of the EA subfractions of two fungi-fermented oats demonstrated more effective inhibitory activity than that of nonfermented oats. A positive correlation between the total phenolics content and inhibitory activity was found. The inhibitory ability of the EA subfraction from nonfermented or fermented oats also displayed a dose-dependent effect. The standards of caffeic, ferulic, and p-coumaric acids, mainly included in EA subfractions of fermented oats, also displayed a dose-dependent inhibitory effect. A synergistic effect of each binary combination of p-coumaric, ferulic, and caffeic acids was observed, especially at 150.0 µg/mL. Those results indicate that fungi-fermented oats have a more effective inhibitory ability on pancreatic lipase and polyphenols may be the most effective component and could be potentially used for dietary therapy of obesity.

Polymeric human Fc-fusion proteins with modified effector functions.

The success of Fc-fusion bio-therapeutics has spurred the development of other Fc-fusion products for treating and/or vaccinating against a range of diseases. We describe a method to modulate their function by converting them into well-defined stable polymers. This strategy resulted in cylindrical hexameric structures revealed by tapping mode atomic force microscopy (AFM). Polymeric Fc-fusions were significantly less immunogenic than their dimeric or monomeric counterparts, a result partly owing to their reduced ability to interact with critical Fc-receptors. However, in the absence of the fusion partner, polymeric IgG1-Fc molecules were capable of binding selectively to FcγRs, with significantly increased affinity owing to their increased valency, suggesting that these reagents may prove of immediate utility in the development of well-defined replacements for intravenous immunoglobulin (IVIG) therapy. Overall, these findings establish an effective IgG Fc-fusion based polymeric platform with which the therapeutic and vaccination applications of Fc-fusion immune-complexes can now be explored.

Predicting protein subcellular locations with feature selection and analysis.

In this paper, we propose a strategy to predict the subcellular locations of proteins by combining various feature selection methods. Firstly, proteins are coded by amino-acid composition and physicochemical properties, then these features are arranged by Minimum Redundancy Maximum Relevance method and further filtered by feature selection procedure. Nearest Neighbor Algorithm is used as a prediction model to predict the protein subcellular locations, and gains a correct prediction rate of 70.63%, evaluated by Jackknife cross-validation. Results of feature selection also enable us to identify the most important protein properties. The prediction software is available for public access on the website http://chemdata.shu.edu.cn/sub22/, which may play a important complementary role to a series of web-server predictors summarized recently in a review by Chou and Shen (Chou, K.C., Shen, H.B. Natural Science, 2009, 2, 63-92, http://www.scirp.org/journal/NS/).

[Monomers optimization and properties evaluation of quercetin-imprinted polymer and its application to thin layer chromatography stationary phase].

The quercetin-molecularly imprinted polymers with specific affinity and selectivity were prepared by using methacrylic acid (MAA), acrylamide (AM), N,N-(diethylamino) ethyl methacrylate and 2-vinylpyridine as functional monomers, respectively. The adsorption properties for template were studied by equilibrium binding experiments. The results showed 2-VP and DEAEM based on ionic interaction with quercetin possessed better imprinting effects. Using the quercetin-imprinted polymers as thin layer chromatographic stationary could successfully separate the template from the other structurally related compounds. In addition, the influence on adsorption effect about the particle size and repeating times of MIP were investigated.