Bioinformatical and Biochemical Analyses on the Protective Role of Traditional Chinese Medicine against Age-Related Macular Degeneration.

PURPOSE: Age-related macular degeneration (AMD) is the commonest cause of permanent vision loss in the elderly. Traditional Chinese medicine (TCM) has long been used to treat AMD, although the underlying functional mechanisms are not understood. This study aims to predict the active ingredients through screening the chemical ingredients of anti-AMD decoction and to elucidate the underlying mechanisms. METHODS: We collected the prescriptions for effective AMD treatment with traditional Chinese medicine and screened several Chinese medicines that were used most frequently in order to compose "anti-AMD decoction." The pharmacologically active ingredients and corresponding targets in this anti-AMD decoction were mined using the Traditional Chinese Medicine Systems Pharmacology (TCMSP) database. Subsequently, the AMD-related targets were identified through the GeneCards database. Network pharmacology was performed to construct the visual network of anti-AMD decoction-AMD protein-protein interaction (PPI). Further, the Autodock software was adopted for molecular docking on the core active ingredients and core targets. The function of core ingredients against oxidative stress and inflammation in retinal pigment epithelial cells was assessed using biochemical assays. RESULTS: We screened out 268 active ingredients in anti-AMD decoction corresponding to 258 ingredient targets, combined with 2160 disease targets in AMD, and obtained 129 drug-disease common targets. The key core proteins were predominantly involved in inflammation. Furthermore, molecular docking showed that four potential active ingredients (Quercetin, luteolin, naringenin and hederagenin) had good affinity with the core proteins, IL-6, TNF, VEGFA and MAPK3. Quercetin, luteolin and naringenin demonstrated capacities against oxidative stress and inflammation in human retinal pigment epithelial cells. CONCLUSIONS: The data suggests that anti-AMD decoction has multiple functional components and targets in treating AMD, possibly mediated by suppression of oxidative stress and inflammation.

Association of Nutrients, Specific Dietary Patterns, and Probiotics with Age-related Macular Degeneration.

Age-related macular degeneration (AMD) is a complex disease that mainly affects people over 50 years of age. Even though management of the vascularisation associated with the "wet" form of AMD is effective using anti-VEGF drugs, there is currently no treatment for the "dry" form of AMD. Given this, it is imperative to develop methods for disease prevention and treatment. For this review, we searched scientific articles via PubMed and Google Scholar, and considered the impact of nutrients, specific dietary patterns, and probiotics on the incidence and progression of AMD. Many studies revealed that regular consumption of foods that contain ω-3 fatty acids is associated with a lower risk for late AMD. Particular dietary patterns, such as the Mediterranean diet that contains ω-3 FAs-rich foods (nuts, olive oil, and fish), seem to be protective against AMD progression compared to Western diets that are rich in fats and carbohydrates. Furthermore, randomized controlled trials that investigated the role of nutrient supplementation in AMD have shown that treatment with antioxidants, such as lutein/zeaxanthin, zinc, and carotenoids, may be effective against AMD progression. More recent studies have investigated the association of the antioxidant properties of gut bacteria, such as Bacteroides and Eysipelotrichi, with lower AMD risk in individuals whose microbiota is enriched with them. These are promising fields of research that may yield the capacity to improve the quality of life for millions of people, allowing them to live with a clear vision for longer and avoiding the high cost of vision-saving surgery.

The sound of silence: Predictive error responses to unexpected sound omission in adults.

The human auditory system excels at detecting patterns needed for processing speech and music. According to predictive coding, the brain predicts incoming sounds, compares predictions to sensory input and generates a prediction error whenever a mismatch between the prediction and sensory input occurs. Predictive coding can be indexed in electroencephalography (EEG) with the mismatch negativity (MMN) and P3a, two components of event-related potentials (ERP) that are elicited by infrequent deviant sounds (e.g., differing in pitch, duration and loudness) in a stream of frequent sounds. If these components reflect prediction error, they should also be elicited by omitting an expected sound, but few studies have examined this. We compared ERPs elicited by infrequent randomly occurring omissions (unexpected silences) in tone sequences presented at two tones per second to ERPs elicited by frequent, regularly occurring omissions (expected silences) within a sequence of tones presented at one tone per second. We found that unexpected silences elicited significant MMN and P3a, although the magnitude of these components was quite small and variable. These results provide evidence for hierarchical predictive coding, indicating that the brain predicts silences and sounds.

Quantification of computational fluid dynamics simulation assists the evaluation of protection by Gypenosides in a zebrafish pain model.

In recent years, due to its rapid reproduction rate and the similarity of its genetic structure to that of human, the zebrafish has been widely used as a pain model to study chemical influences on behavior. Swimming behaviors are mediated by motoneurons in the spinal cord that drive muscle contractions, therefore a knowledge of internal muscle mechanics can assist the understanding of the effects of drugs on swimming activity. To demonstrate that the technique used in our study can supplement biological observations by quantifying the contribution of muscle effects to altered swimming behaviours, we have evaluated the pain/damage caused by 0.1% acetic acid to the muscle of 5 dpf zebrafish larvae and the effect of protection from this pain/damage with the saponin Gypenosides (GYP) extracted from Gynostemma pentaphyllum. We have quantified the parameters related to muscle such as muscle power and the resultant hydrodynamic force, proving that GYP could alleviate the detrimental effect of acetic acid on zebrafish larvae, in the form of alleviation from swimming debility, and that the muscle status could be quantified to represent the degree of muscle damage due to the acetic acid and the recovery due to GYP. We have also linked the behavioral changes to alteration of antioxidant and inflammation gene expression. The above results provide novel insights into the reasons for pain-related behavioral changes in fish larvae, especially from an internal muscle perspective, and have quantified these changes to help understand the protection of swimming behaviors and internal muscle by GYP from acetic acid-induced damage.

Gypenosides attenuate retinal degeneration in a zebrafish retinitis pigmentosa model.

Retinitis pigmentosa (RP) is a collection of heterogenous genetic retinal disorders resulting in cumulative retinal deterioration involving progressive loss of photoreceptors and eventually in total blindness. Oxidative stress plays a central role in this photoreceptor loss. Gypenosides (Gyp) are the main functional component isolated from the climbing vine Gynostemma pentaphyllum and have been shown to defend cells against the effects of oxidative stress and inflammation, providing protection in experimentally-induced optic neuritis. The zebrafish model has been used to investigate a range of human diseases. Previously we reported early retinal degeneration in a mutant zebrafish line carrying a point-nonsense mutation in the retinitis pigmentosa GTPase regulator interacting protein 1 (rpgrip1) gene that is mutated in RP patients. The current study investigated the potential protective effects of Gyp against photoreceptor degeneration in the Rpgrip1 deleted zebrafish. Rpgrip1 mutant zebrafish were treated with 5 µg/ml of Gyp in E3 medium from 6 h post fertilization (hpf) till 1 month post fertilization (mpf). Rpgrip1 mutant zebrafish treated with 5 µg/ml of Gyp showed a significant decrease by 68.41% (p = 0.0002) in photoreceptor cell death compared to that of untreated mutant zebrafish. Expression of antioxidant genes catalase, sod1, sod2, gpx1, gclm, nqo-1 and nrf-2 was significantly decreased in rpgrip1 mutant zebrafish eyes by 61.51%, 77.40%, 60.11%, 81.17%, 72.07%, 78.95% and 85.42% (all p < 0.0001), respectively, when compared to that of wildtype zebrafish; superoxide dismutase and catalase activities, and glutathione levels in rpgrip1 mutant zebrafish eyes were significantly decreased by 87.21%, 21.55% and 96.51% (all p < 0.0001), respectively. There were marked increases in the production of reactive oxygen species (ROS) and malondialdehyde (MDA) by 2738.73% and 510.69% (all p < 0.0001), respectively, in rpgrip1 mutant zebrafish eyes; expression of pro-inflammatory cytokines IL-1ß, IL-6 and TNF-α was also significantly increased by 150.11%, 267.79% and 190.72% (all p < 0.0001), respectively, in rpgrip1 mutant zebrafish eyes, compared to that of wildtype zebrafish. Treatment with Gyp significantly counteracted these effects. This study indicates that Gyp has a potential role in the treatment of RP.

Alterations in intrinsic fronto-thalamo-parietal connectivity are associated with cognitive control deficits in psychotic disorders.

Despite a growing number of reports about alterations in intrinsic/resting brain activity observed in patients with psychotic disorders, their relevance to well-established cognitive control deficits in this patient group is not well understood. Totally 88 clinically stabilized patients with a psychotic disorder and 50 healthy controls participated in a resting-state magnetic resonance imaging study (rs-MRI) and performed an antisaccade task in the laboratory to assess voluntary inhibitory control ability. Deficits on this task are a well-established biomarker across psychotic disorders as we found in the present patient sample. First, regional cerebral function was evaluated by measuring the amplitude of low frequency fluctuations (ALFF) in rs-MRI BOLD signals. We found reduced ALFF in patients in regions known to be relevant to antisaccade task performance including bilateral frontal eye fields (FEF), supplementary eye fields (SEF) and thalamus. Second, areas with ALFF alterations were used as seed areas in whole-brain functional connectivity (FC) analysis. Altered FC was observed in a fronto-thalamo-parietal network that was associated with inhibition error rate in patients but not in controls. In contrast, faster time to generate a correct antisaccade was associated with FC in FEF and SEF in controls but this effect was not seen in patients. These findings establish a behavioral relevance of resting-state fMRI findings in psychotic disorders, and extend previous reports of alterations in fronto-thalamo-parietal network activation during antisaccade performance seen in task-based fMRI studies.

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.

Therapeutic Potential of Co-enzyme Q10 in Retinal Diseases.

BACKGROUND: Coenzyme Q10 (CoQ10) plays a critical role in mitochondrial oxidative phosphorylation by serving as an electron carrier in the respiratory electron transport chain. CoQ10 also functions as a lipid-soluble antioxidant by protecting lipids, proteins and DNA damaged by oxidative stress. CoQ10 deficiency has been associated with a number of human diseases in which CoQ10 supplementation therapy has been effective in slowing or reversing pathological changes. Oxidative stress is a major contributory factor in the process of retinal degeneration. METHOD: The related literature was reviewed through searching PubMed using keywords: CoQ10, CoQ10 and oxidative stress, CoQ10 and retinal degeneration. The functions of CoQ10 were summarized and its use in the treatment of age-related macular degeneration and glaucoma highlighted. The therapeutic potential of CoQ10 for other retinal diseases was also discussed. RESULTS: CoQ10 has been applied in different types of neurodegeneration. CoQ10 is detectable in retina and declines with ageing. Early studies showed treatment of CoQ10 improved visual function in patients with age-related macular degeneration. In glaucomatous models, CoQ10 exposure protected ganglion cell death from environmental stress; in glaucoma patients, CoQ10 treatment demonstrated beneficial effects on function of inner retina and enhancement of visual cortical response. Since oxidative stress also plays a critical role in the pathogenesis of diabetic retinopathy and retinitis pigmentosa, CoQ10 is a therapeutic target for both conditions. CONCLUSION: A wide range of evidence supports a role of CoQ10 in retinal diseases through inhibiting production of reactive oxygen species and protecting neuroretinal cells from oxidative damage.

Functionalized Triblock Copolymer Vectors for the Treatment of Acute Lymphoblastic Leukemia.

The chemotherapeutic Parthenolide is an exciting new candidate for the treatment of acute lymphoblastic leukemia, but like many other small-molecule drugs, it has low aqueous solubility. As a consequence, Parthenolide can only be administered clinically in the presence of harmful cosolvents. Accordingly, we describe the synthesis, characterization, and testing of a range of biocompatible triblock copolymer micelles as particle-based delivery vectors for the hydrophobic drug Parthenolide. The drug-loaded particles are produced via an emulsion-to-micelle transition method, and the effects of introducing anionic and cationic surface charges on stability, drug sequestration, biocompatibility, and efficacy are investigated. Significantly, we demonstrate high levels of efficacy in the organic solvent-free systems against human mesenchymal stem cells and primary T-acute lymphoblastic leukemia patient cells, highlighting the effectiveness of the delivery vectors for the treatment of acute lymphoblastic leukemia.

EEG and fMRI agree: Mental arithmetic is the easiest form of imagery to detect.

fMRI and EEG during mental imagery provide alternative methods of detecting awareness in patients with disorders of consciousness (DOC) without reliance on behaviour. Because using fMRI in patients with DOC is difficult, studies increasingly employ EEG. However, there has been no verification that these modalities provide converging information at the individual subject level. The present study examined simultaneous EEG and fMRI in healthy volunteers during six mental imagery tasks to determine whether one mental imagery task generates more robust activation across subjects; whether activation can be predicted from familiarity with the imagined activity; and whether EEG and fMRI converge upon the same conclusions about individual imagery performance. Mental arithmetic generated the most robust activation in the majority of subjects for both EEG and fMRI, and level of activation could not be predicted from familiarity, with either modality. We conclude that overall, EEG and fMRI agree regarding individual mental imagery performance.

Automatic and continuous assessment of ERPs for mismatch negativity detection.

Accurate and fast detection of event related potential (ERP) components is an unresolved issue in neuroscience and critical health care. Mismatch negativity (MMN) is a component of the ERP to an odd stimulus in a sequence of identical stimuli which has good correlation with coma awakening. All of the previous studies for MMN detection are based on visual inspection of the averaged ERPs (over a long recording time) by a skilled neurophysiologist. However, in practical situations, such an expert may not be available or familiar with all aspects of evoked potential methods. Further, we may miss important clinically essential events due to the implicit averaging process used to acquire the ERPs. In this paper we propose a practical machine learning approach for automatic and continuous assessment of the ERPs for detecting the presence of the MMN component. The proposed method is realized in a classification framework. Performance of the proposed method is demonstrated on 22 healthy subjects through a leave-one subject-out strategy where the MMN components are identified with about 93% accuracy.

Microstructural abnormalities of white matter differentiate pediatric and adult-onset bipolar disorder.

OBJECTIVES: White-matter microstructure, known to undergo significant developmental transformation, is abnormal in bipolar disorder (BD). Available evidence suggests that white-matter deviation may be more pronounced in pediatric than adult-onset BD. The present study aimed to examine how white-matter microstructure deviates from a typical maturational trajectory in BD. METHODS: Fractional anisotropy (FA) was measured in 35 individuals presenting with first episode BD (type I) and 46 healthy controls (HC) (aged 9-42) using diffusion tensor imaging (DTI). Patients were medication free and close to illness onset at the time of the DTI scans. Tract-based spatial statistics were used to examine the center of white-matter tracts, and FA was extracted from nine tracts of interest. Axial, radial, and mean diffusivity were examined in post-hoc analyses. RESULTS: The left anterior limb of the internal capsule (ALIC) showed significantly lower FA in pediatric than adult-onset BD. The lower FA in BD was due primarily to greater radial, rather than decreased axial, diffusivity. CONCLUSIONS: The ALIC connects the frontal lobes with archistriatum, thalamus, and medial temporal regions, and alteration in these pathways may contribute to mood dysregulation in BD. Abnormalities in this pathway appear to be associated with an earlier onset of illness and thus may reflect a greater susceptibility to illness.

MicroRNA-155 as a proinflammatory regulator in clinical and experimental arthritis.

MicroRNA (miRNA) species (miR) regulate mRNA translation and are implicated as mediators of disease pathology via coordinated regulation of molecular effector pathways. Unraveling miR disease-related activities will facilitate future therapeutic interventions. miR-155 recently has been identified with critical immune regulatory functions. Although detected in articular tissues, the functional role of miR-155 in inflammatory arthritis has not been defined. We report here that miR-155 is up-regulated in synovial membrane and synovial fluid (SF) macrophages from patients with rheumatoid arthritis (RA). The increased expression of miR-155 in SF CD14(+) cells was associated with lower expression of the miR-155 target, Src homology 2-containing inositol phosphatase-1 (SHIP-1), an inhibitor of inflammation. Similarly, SHIP-1 expression was decreased in CD68(+) cells in the synovial lining layer in RA patients as compared with osteoarthritis patients. Overexpression of miR-155 in PB CD14(+) cells led to down-regulation of SHIP-1 and an increase in the production of proinflammatory cytokines. Conversely, inhibition of miR-155 in RA synovial CD14(+) cells reduced TNF-α production. Finally, miR-155-deficient mice are resistant to collagen-induced arthritis, with profound suppression of antigen-specific Th17 cell and autoantibody responses and markedly reduced articular inflammation. Our data therefore identify a role of miR-155 in clinical and experimental arthritis and suggest that miR-155 may be an intriguing therapeutic target.

Using pre-treatment electroencephalography data to predict response to transcranial magnetic stimulation therapy for major depression.

We investigate the use of machine learning methods based on the pre-treatment electroencephalograph (EEG) to predict response to repetitive transcranial magnetic stimulation (rTMS), which is a non-pharmacological form of therapy for treating major depressive disorder (MDD). The learning procedure involves the extraction of a large number of candidate features from EEG data, from which a very small subset of most statistically relevant features is selected for further processing. A statistical prediction model based on mixture of factor analysis (MFA) model is constructed from a training set that classifies the respective subject into responder and non-responder classes. A leave-2-out (L2O) cross-validation procedure is used to evaluate the prediction performance. This pilot study involves 27 subjects who received either left high-frequency (HF) active rTMS therapy or simultaneous left HF and right low-frequency active rTMS therapy. Our results indicate that it is possible to predict rTMS treatment efficacy of either treatment modality with a specificity of 83% and a sensitivity of 78%, for a combined accuracy of 80%.

Off-label or out of bounds? Prescriber and marketer liability for unapproved uses of FDA-approved drugs.

Professor O'Reilly's study of recent drug review legislation applies a historical and holistic view of promotion practices for unapproved uses of prescription drugs. He faults Congress for moving public health protections away from a strictly protective mode and toward assistance to drug marketers. He argues that the adverse health consequences of "off-label" promotion of drugs are not well understood, and that the 1997 amendments deserved the public health interest while expanding pharmaceutical company profits.

The effect of pre-incisional infiltration of tonsils with bupivacaine on the pain following tonsillectomy under general anesthesia.

The aim of the present study was to test the hypothesis that blockade of nociceptive input with bupivacaine during tonsillectomy can decrease pain beyond the immediate postoperative period. Fourteen patients between the ages of 6 and 18 years scheduled for tonsillectomy (with or without adenoidectomy) were randomly divided into two groups. The patients of both groups received 0.006 mg/kg atropine and anesthesia was induced by inhalation of halothane. Atracurium 0.5 mg/kg was used for myorelaxation. After oral intubation anesthesia was maintained with isoflurane plus nitrous oxide 67% in oxygen. In the bupivacaine group, 5 min before incision the tonsillar fossae were infiltrated with 0.25% bupivacaine with epinephrine (1 : 200,000). In the control group, the tonsillar fossae were infiltrated with normal saline with epinephrine (1 : 200,000). All patients received morphine 0.07 mg/kg (in the recovery room) and oral elixir with codeine 0.05 mg/kg plus acetaminophen 5 mg/kg every 4 h. Pain assessments were made using the visual analog (100 mm scale) self-rating method. Two types of pain were assessed: constant incisional pain and pain caused by drinking 100 ml of water. In the bupivacaine group, the constant pain score on the second day after surgery was 19 +/- 6 compared to 74 +/- 8 in the saline group (P less than 0.0002). By the 4-5th day after surgery almost no constant pain occurred in the bupivacaine group, but the pain score remained at the 40-60 level in the saline group. The difference in pain intensity on swallowing between the bupivacaine and saline groups was present even on the 10th postoperative day (1 +/- 1 vs. 14 +/- 5, P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)