Dendrobium nobile Polysaccharide Attenuates Blue Light-Induced Injury in Retinal Cells and In Vivo in Drosophila.

Blue light is the higher-energy region of the visible spectrum. Excessive exposure to blue light is known to induce oxidative stress and is harmful to the eyes. The stems of Dendrobium nobile Lindl. (Orchidaceae), named Jinchaishihu, have long been used in traditional Chinese medicine (TCM) for nourishing yin, clearing heat, and brightening the eyes. The polysaccharide is one of the major components in D. nobile. However, the effect on ocular cells remains unclear. This study aimed to investigate whether the polysaccharide from D. nobile can protect the eyes from blue light-induced injury. A crude (DN-P) and a partially purified polysaccharide (DN-PP) from D. nobile were evaluated for their protective effects on blue light-induced damage in ARPE-19 and 661W cells. The in vivo study investigated the electroretinographic response and the expression of phototransduction-related genes in the retinas of a Drosophila model. The results showed that DN-P and DN-PP could improve blue light-induced damage in ARPE-19 and 661W cells, including cell viability, antioxidant activity, reactive oxygen species (ROS)/superoxide production, and reverse opsin 3 protein expression in a concentration-dependent manner. The in vivo study indicated that DN-P could alleviate eye damage and reverse the expression of phototransduction-related genes, including ninaE, norpA, Gαq, Gß76C, Gγ30A, TRP, and TRPL, in a dose-dependent manner in blue light-exposed Drosophila. In conclusion, this is the first report demonstrating that D. nobile polysaccharide pretreatment can protect retinal cells and retinal photoreceptors from blue light-induced damage. These results provide supporting evidence for the beneficial potential of D. nobile in preventing blue light-induced eye damage and improving eyesight.

An efficient swarm intelligence approach to the optimization on high-dimensional solutions with cross-dimensional constraints, with applications in supply chain management.

Introduction: The Swarm Intelligence Based (SIB) method has widely been applied to efficient optimization in many fields with discrete solution domains. E-commerce raises the importance of designing suitable selling strategies, including channel- and direct sales, and the mix of them, but researchers in this field seldom employ advanced metaheuristic techniques in their optimization problem due to the complexities caused by the high-dimensional problems and cross-dimensional constraints. Method: In this work, we introduce an extension of the SIB method that can simultaneously tackle these two challenges. To pursue faster computing, CPU parallelization techniques are employed for algorithm acceleration. Results: The performance of the SIB method is examined on the problems of designing selling schemes in different scales. It outperforms the Genetic Algorithm (GA) in terms of both the speed of convergence and the optimized capacity as measured using improvement multipliers.

Tyrosine Metabolism Pathway Is Downregulated in Dopaminergic Neurons with LRRK2 Overexpression in Drosophila.

LRRK2 mutations are the leading cause of familial Parkinson's disease (PD) and are a significant risk factor for idiopathic PD cases. However, the molecular mechanisms underlying the degeneration of dopaminergic (DA) neurons in LRRK2 PD patients remain unclear. To determine the translatomic impact of LRRK2 expression in DA neurons, we employed gene set enrichment analysis (GSEA) to analyze a translating ribosome affinity purification (TRAP) RNA-seq dataset from a DA-neuron-specific-expressing Drosophila model. We found that the tyrosine metabolism pathway, including tyrosine hydroxylase (TH), is downregulated in DA neurons with LRRK2 overexpression; in contrast, the Hippo signaling pathway is downregulated in the G2019S mutant compared to wild-type LRRK2 in the DA neurons. These results imply that the downregulation of tyrosine metabolism occurs before pronounced DA neuron loss and that LRRK2 may downregulate the tyrosine metabolism in a DA-neuron-loss-independent way.

miRNA profiling as a complementary diagnostic tool for amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS), the most prevalent motor neuron disease characterized by its complex genetic structure, lacks a single diagnostic test capable of providing a conclusive diagnosis. In order to demonstrate the potential for genetic diagnosis and shed light on the pathogenic role of miRNAs in ALS, we developed an ALS diagnostic rule by training the model using 80% of a miRNA profiling dataset consisting of 253 ALS samples and 103 control samples. Subsequently, we validated the diagnostic rule using the remaining 20% of unseen samples. The diagnostic rule we developed includes miR-205-5p, miR-206, miR-376a-5p, miR-412-5p, miR-3927-3p, miR-4701-3p, miR-6763-5p, and miR-6801-3p. Remarkably, the rule achieved an 82% true positive rate and a 73% true negative rate when predicting the unseen samples. Furthermore, the identified miRNAs target 21 genes in the PI3K-Akt pathway and 27 genes in the ALS pathway, including notable genes such as BCL2, NEFH, and OPTN. We propose that miRNA profiling may serve as a complementary diagnostic tool to supplement the clinical presentation and aid in the early recognition of ALS.

Osthole Antagonizes Microglial Activation in an NRF2-Dependent Manner.

Microglia are neuroglia in the brain with an innate immune function and participate in the progress of neurodegenerative diseases. Osthole (OST) is a coumarin derivative extracted from Cnidium monnieri and bears a microglia-antagonizing ability. However, the underlying mechanism of the antagonism is not clear. The lipopolysaccharides-induced microglial BV2 cell line and amyloid-overexpressing fruit fly were used as models to study OST treatment. We found that OST treatment is sufficient to evoke NRF2 cascade under an LPS-induced inflammatory environment, and silencing NRF2 is sufficient to abolish the process. Moreover, we found that OST is sufficient to antagonize microglial activation in both LPS-induced BV2 cells and Aß-overexpressing fruit flies, and silencing NRF2 abolishes OST's antagonism. Furthermore, OST treatment rescued survival, climbing, and the learning ability of Aß-overexpressing fruit flies and relieved oxidative stress. In conclusion, we proved that OST antagonizes microglial activation induced by either LPS or Aß and that NRF2 is necessary for OST's antagonism.

Alterations of RNA-binding protein found in neurons in Drosophila neurons and glia influence synaptic transmission and lifespan.

The found in neurons (fne), a paralog of the RNA-binding protein ELAV gene family in Drosophila, is required for post-transcriptional regulation of neuronal development and differentiation. Previous explorations into the functions of the FNE protein have been limited to neurons. The function of fne in Drosophila glia remains unclear. We induced the knockdown or overexpression of fne in Drosophila neurons and glia to determine how fne affects different types of behaviors, neuronal transmission and the lifespan. Our data indicate that changes in fne expression impair associative learning, thermal nociception, and phototransduction. Examination of synaptic transmission at presynaptic and postsynaptic terminals of the larval neuromuscular junction (NMJ) revealed that loss of fne in motor neurons and glia significantly decreased excitatory junction currents (EJCs) and quantal content, while flies with glial fne knockdown facilitated short-term synaptic plasticity. In muscle cells, overexpression of fne reduced both EJC and quantal content and increased short-term synaptic facilitation. In both genders, the lifespan could be extended by the knockdown of fne in neurons and glia; the overexpression of fne shortened the lifespan. Our results demonstrate that disturbances of fne in neurons and glia influence the function of the Drosophila nervous system. Further explorations into the physiological and molecular mechanisms underlying neuronal and glial fne and elucidation of how fne affects neuronal activity may clarify certain brain functions.

Imidacloprid Impairs Glutamatergic Synaptic Plasticity and Desensitizes Mechanosensitive, Nociceptive, and Photogenic Response of Drosophila melanogaster by Mediating Oxidative Stress, Which Could Be Rescued by Osthole.

BACKGROUND: Imidacloprid (IMD) is a widely used neonicotinoid-targeting insect nicotine acetylcholine receptors (nAChRs). However, off-target effects raise environmental concerns, including the IMD's impairment of the memory of honeybees and rodents. Although the down-regulation of inotropic glutamate receptor (iGluR) was proposed as the cause, whether IMD directly manipulates the activation or inhibition of iGluR is unknown. Using electrophysiological recording on fruit fly neuromuscular junction (NMJ), we found that IMD of 0.125 and 12.5 mg/L did not activate glutamate receptors nor inhibit the glutamate-triggered depolarization of the glutamatergic synapse. However, chronic IMD treatment attenuated short-term facilitation (STF) of NMJ by more than 20%. Moreover, by behavioral assays, we found that IMD desensitized the fruit flies' response to mechanosensitive, nociceptive, and photogenic stimuli. Finally, the treatment of the antioxidant osthole rescued the chronic IMD-induced phenotypes. We clarified that IMD is neither agonist nor antagonist of glutamate receptors, but chronic treatment with environmental-relevant concentrations impairs glutamatergic plasticity of the NMJ of fruit flies and interferes with the sensory response by mediating oxidative stress.

Neuromuscular, retinal, and reproductive impact of low-dose polystyrene microplastics on Drosophila.

Facing the challenge of global microplastics (MPs) pollution, full characterization of MPs biohazards is urgent. Recent intensive studies revealed that the toxicity depends on the material, size, and exposure concentration of MP. To better elucidate MPs biohazards, we investigated the impact of polystyrene-MPs of size 0.1 µm at a low dose of 50 µg/L on the neuromuscular, retinal, and reproductive phenotypes of fruit fly model, by voltage-clamped electrophysiology, electroretinogram, and reproductive assay, respectively. We found that MPs decreased the frequency of spontaneous junction currents of synapse and altered the receptor potential amplitude of the retina. Furthermore, MPs lowered the rate of embryo-laying of fruit flies. The differential gene expression of ligand-receptor interaction, endocytosis, phototransduction, and Toll/Imd signaling pathways might underlie these MPs-induced phenotypes. These findings call for further investigation on the potential biohazards of low-dose MPs.

Pathway-targeting gene matrix for Drosophila gene set enrichment analysis.

Gene Set Enrichment Analysis (GSEA) is a powerful algorithm to determine biased pathways between groups based on expression profiling. However, for fruit fly, a popular animal model, gene matrixes for GSEA are unavailable. This study provides the pathway-targeting gene matrixes based on Reactome and KEGG database for fruit fly. An expression profiling containing neurons or glia of fruit fly was used to validate the feasibility of the generated gene matrixes. We validated the gene matrixes and identified characteristic neuronal and glial pathways, including mRNA splicing and endocytosis. In conclusion, we generated and validated the feasibility of Reactome and KEGG gene matrix files, which may benefit future profiling studies using Drosophila.

Ergosta-7,9(11),22-trien-3ß-ol Rescues AD Deficits by Modulating Microglia Activation but Not Oxidative Stress.

Ergosta-7,9(11),22-trien-3ß-ol (EK100) was isolated from the Taiwan-specific medicinal fungus Antrodia camphorata, which is known for its health-promotion and anti-aging effects in folk medicine. Alzheimer's disease (AD) is a major aging-associated disease. We investigated the efficacy and potential mechanism of ergosta-7,9(11),22-trien-3ß-ol for AD symptoms. Drosophila with the pan-neuronal overexpression of human amyloid-ß (Aß) was used as the AD model. We compared the life span, motor function, learning, memory, oxidative stress, and biomarkers of microglia activation and inflammation of the ergosta-7,9(11),22-trien-3ß-ol-treated group to those of the untreated control. Ergosta-7,9(11),22-trien-3ß-ol treatment effectively improved the life span, motor function, learning, and memory of the AD model compared to the untreated control. Biomarkers of microglia activation and inflammation were reduced, while the ubiquitous lipid peroxidation, catalase activity, and superoxide dismutase activity remained unchanged. In conclusion, ergosta-7,9(11),22-trien-3ß-ol rescues AD deficits by modulating microglia activation but not oxidative stress.

Machine learning compensates fold-change method and highlights oxidative phosphorylation in the brain transcriptome of Alzheimer's disease.

Alzheimer's disease (AD) is a neurodegenerative disorder causing 70% of dementia cases. However, the mechanism of disease development is still elusive. Despite the availability of a wide range of biological data, a comprehensive understanding of AD's mechanism from machine learning (ML) is so far unrealized, majorly due to the lack of needed data density. To harness the AD mechanism's knowledge from the expression profiles of postmortem prefrontal cortex samples of 310 AD and 157 controls, we used seven predictive operators or combinations of RapidMiner Studio operators to establish predictive models from the input matrix and to assign a weight to each attribute. Besides, conventional fold-change methods were also applied as controls. The identified genes were further submitted to enrichment analysis for KEGG pathways. The average accuracy of ML models ranges from 86.30% to 91.22%. The overlap ratio of the identified genes between ML and conventional methods ranges from 19.7% to 21.3%. ML exclusively identified oxidative phosphorylation genes in the AD pathway. Our results highlighted the deficiency of oxidative phosphorylation in AD and suggest that ML should be considered as complementary to the conventional fold-change methods in transcriptome studies.

Identification of contributing genes of Huntington's disease by machine learning.

BACKGROUND: Huntington's disease (HD) is an inherited disorder caused by the polyglutamine (poly-Q) mutations of the HTT gene results in neurodegeneration characterized by chorea, loss of coordination, cognitive decline. However, HD pathogenesis is still elusive. Despite the availability of a wide range of biological data, a comprehensive understanding of HD's mechanism from machine learning is so far unrealized, majorly due to the lack of needed data density. METHODS: To harness the knowledge of the HD pathogenesis from the expression profiles of postmortem prefrontal cortex samples of 157 HD and 157 controls, we used gene profiling ranking as the criteria to reduce the dimension to the order of magnitude of the sample size, followed by machine learning using the decision tree, rule induction, random forest, and generalized linear model. RESULTS: These four Machine learning models identified 66 potential HD-contributing genes, with the cross-validated accuracy of 90.79 ± 4.57%, 89.49 ± 5.20%, 90.45 ± 4.24%, and 97.46 ± 3.26%, respectively. The identified genes enriched the gene ontology of transcriptional regulation, inflammatory response, neuron projection, and the cytoskeleton. Moreover, three genes in the cognitive, sensory, and perceptual systems were also identified. CONCLUSIONS: The mutant HTT may interfere with both the expression and transport of these identified genes to promote the HD pathogenesis.

The Effectiveness of Acupuncture in the Treatment of Frozen Shoulder: A Systematic Review and Meta-Analysis.

BACKGROUND: Frozen shoulder (FS) is associated with pain, reduced range of motion (ROM), and shoulder function. The condition occurs in 2-5% of the population, and it is especially common around the age of 50 years. FS symptoms will recover after 1-4 years. Many patients turn to acupuncture in order to alleviate the FS symptoms. OBJECTIVE: In this review, we will investigate the efficiency of acupuncture as a FS treatment. METHODS: A literature search of acupuncture and FS-related keywords was performed in the following databases: PubMed, Cochrane Library, Embase, and Web of Science. Thirteen publications were included for a systematic review, and a meta-analysis was done using the following measurements: visual analogue scale (VAS) for pain, Constant-Murley Shoulder Outcome Score (CMS) for shoulder function, and active shoulder ROM including flexion, abduction, and external rotation. The Cochrane Collaboration's risk of bias tool and quality of evidence GRADE recommendations and STRICTA 2010 were used to grade the included publications. RESULTS: A meta-analysis on VAS pain score showed significant pain reduction, restoring CMS shoulder function, and flexion ROM in favor of acupuncture versus the control. In external rotation and abduction ROM, a meta-analysis was not significant. The most used acupoints are Jian Yu (LI15) and Jian Liao (TB14). CONCLUSIONS: The results indicate that acupuncture could be safe and effective for pain reduction, restoring shoulder function, and restoring flexion ROM for FS patients in the short term and midterm. However, the level of evidence was very low. More high-quality and longer studies are needed in order to robust the evidence.

Albizia julibrissin Ameliorates Memory Loss Induced by Insomnia in Drosophila.

In clinical practice in Taiwan, Albizia julibrissin is the most prescribed Chinese herbal medicine for insomnia. Short-term insomnia and hypnotic use both attenuate cognitive functions, especially learning memory. In previous studies, A. julibrissin exhibits sedative activity, antidepressant-like effects, and protection of learning and memory against amnesia. However, whether A. julibrissin ameliorates memory loss caused by short-term sleep deprivation is not clear. We utilized the sleep-deprived Drosophila model and olfactory associative learning-memory assay to test the effects of A. julibrissin on sleep-deprivation induced memory loss. We found that A. julibrissin ameliorated 3-hour memory but not 1-hour memory or instant learning. The findings might be applied to an anticipated short-term sleep disturbance.

Dystonin/BPAG1 modulates diabetes and Alzheimer's disease cross-talk: a meta-analysis.

Dementia is one of the diabetic complications under intensive study. Alteration of synaptic adhesion protein (SAP) associates with neurological diseases, including Alzheimer's disease. However, the regulation of SAPs in the brain of diabetes mellitus remains elusive. To pinpoint the candidate SAPs underlining the mechanism of diabetic dementia, we investigated expression profiling of SAPs in both streptozotocin (STZ)-induced diabetic mice, AppNL-G-F/NL-G-F mice, and amyloid precursor protein intracellular domain (AICD)-induced human neural cell line from public databases. DST (Dystonin/BPAG1) was identified upregulated in both models. Our finding suggests that DST alteration may involve in the mechanism of diabetic dementia.

Transgenerational impact of DEHP on body weight of Drosophila.

Bis(2-ethylhexyl) phthalate (DEHP) is the most typical plasticizer and an environmental endocrine disruptor (EDC). DEHP is known to influence offspring fertility, growth, and obesity. However, the role of the DEHP as a transgenerational obesogen is still controversial. In this study, we used fruit flies (Drosophila melanogaster) to investigate where the exposure period, doses, and exposed parental sex are critical to change the body weight of the offspring. We found long-term but not short-term, and high-dose but low-dose exposure resulted in significant change. Moreover, we found DEHP treatment on the father or mother Drosophila resulted in increased or decreased body weight of the offspring respectively. Our results demonstrated the heterogeneity of transgenerational impact of DEHP and highlighted the involvement of parental endocrine system in its role as an obesogen.

The Effectiveness of Preoperative Preparation for Improving Perioperative Outcomes in Children and Caregivers.

Most children experience significant anxiety during the preoperative period. Greater preoperative anxiety may be related to a higher incidence of negative behaviors. This study aimed to develop a family-centered preoperative preparation program and to evaluate the effects of this program on children's preoperative emotional behaviors, postoperative behavior, and posthospital behavior, and on caregiver anxiety. A prospective, randomized controlled study was conducted. The population consisted of children who underwent minor surgery and their caregivers. The control group received standard care, and the experimental group received standard care plus preoperative preparation, which included a tour, a cartoon video depicting a boy's surgical journey, and familiarization with medical equipment. Children's emotional behaviors and caregiver anxiety were measured at the preoperative visit, in the preoperative holding area, and at induction of anesthesia. Postoperative behavior was measured when children were in the recovery room, and the researcher also contacted caregivers 2 weeks after the surgery to assess the children's behavior at home. A linear mixed-effects model results showed that as the surgery approached, the experimental group had fewer and more stable preoperative emotional behaviors (least squares means of preoperative emotional behaviors from preoperative visit to induction of anesthesia = 10.01-10.95). However, the control group exhibited significantly increased preoperative emotional behaviors as the surgery approached (least squares means of preoperative emotional behaviors from the preoperative visit to induction of anesthesia = 7.87-12.23). Family-centered preoperative preparation can effectively improve children's negative emotional behaviors from their time in the preoperative holding area to the induction of anesthesia.

DEHP toxicity on vision, neuromuscular junction, and courtship behaviors of Drosophila.

Bis(2-ethylhexyl) phthalate (DEHP) is the most common plasticizer. Previous studies have shown DEHP treatment accelerates neurological degeneration, suggesting that DEHP may impact retinal sensitivity to light, neurotransmission, and copulation behaviors. Although its neurotoxicity and antifertility properties have been studied, whether DEHP exposure disrupts vision and how DEHP influences neuromuscular junction (NMJ) have not been reported yet. Moreover, the impact of DEHP on insect courtship behavior is still elusive. Fruit flies (Drosophila melanogaster) were treated with series concentrations of DEHP and observed for lifespan, motor function, electroretinogram (ERG), electrophysiology of neuromuscular junction (NMJ), courtship behaviors, and relevant gene expression. Our results confirmed the DEHP toxicity on lifespan and capacity of motor function and updated its effect on copulation behaviors. Additionally, we report for the first time that DEHP exposure may harm vision by affecting the synaptic signaling between the photoreceptor and the laminar neurons. Further, DEHP treatment altered both spontaneous and evoked neurotransmission properties. Noteworthy, the effect of DEHP exposure on the copulation behavior is sex-dependent, and we proposed potential mechanisms for future investigation.

Matrix metalloproteinase 14 modulates diabetes and Alzheimer's disease cross-talk: a meta-analysis.

Diabetes mellitus is associated with dementia, but whether diabetes is associated with Alzheimer's disease remains controversial. Alzheimer's disease is characterized by amyloid beta aggregation. We hypothesized that genes, involved in amyloid beta degradation, may be altered due to diabetes and thus participate in progression of Alzheimer's disease. Expression profiling of amyloid beta-degrading enzymes in streptozotocin-induced diabetic mice and their correlation with expression of amyloid precursor protein in hippocampus of Alzheimer's disease patients were accessed. We found that matrix metalloproteinase 14 decreased in brain but not in other tissues of streptozotocin-induced diabetic mice, and was negatively correlated with expression of amyloid precursor protein in hippocampus of Alzheimer's disease patients. These findings suggested matrix metalloproteinase 14 may link insulin-deficient diabetes to Alzheimer's disease.

Molecular pathways related to the longevity promotion and cognitive improvement of Cistanche tubulosa in Drosophila.

BACKGROUND: The aging process, including physical dysfunction and age-related memory impairment (AMI), are considered to be correlated with cumulative oxidative damages and insulin/IGF-1 signaling pathway. PURPOSE: The present study was to elucidate the in vivo effects on delaying aging and ameliorating AMI and underlying molecular mechanisms of Cistanche tubulosa (CT), a herb used in traditional Chinese medicine to improve sexual function and treat kidney dysfunction. METHODS: The flies, treated and untreated with CT, were observed for lifespan, resistance to oxidative stress with H2O2 or paraquat, starvation assay, cognitive behaviors with T-maze, and transcript levels of target genes with quantitative RT-PCR. RESULTS: Administering CT extended the mean and maximum lifespan and increased resistance to oxidative stress in flies. CT supplementation also enhanced memory formation in young flies and suppressed AMI upon aging. Several genes and signaling pathways, including the mechanistic target of rapamycin (mTOR) and Notch networks, have been identified as causing these pharmacological effects and alterations in the gene expression of glutamate receptors. CONCLUSION: Our results indicate that CT supplementation may contribute to slowing aging phenotypes and alleviating cognitive behavioral decline in flies, indicating potential applicability for enhancing human health and reducing susceptibility to age-related disorders.