Serum vitamin D and chronic musculoskeletal pain: a cross-sectional study of 349,221 adults in the UK.

Insufficient and deficient vitamin D may be associated with chronic musculoskeletal pain, but study findings are conflicting, and few account for important confounding factors. This cross-sectional study explored the association between serum vitamin D status and chronic musculoskeletal pain in various body sites, adjusting for a wide range and number of potential confounding factors. Data collected at the baseline assessments of 349,221 UK Biobank participants between 2006 and 2010 were analysed. Serum 25-hydroxyvitamin D (25-(OH) D) were measured and categorised as <25.0 nmol/L (severe deficiency), 25.0-49.9 nmol/L (deficiency), 50.0-74.9 nmol/L (insufficiency) and ≥75.0 nmol/L (sufficiency). The outcome was self-reported chronic musculoskeletal pain at any site, neck/shoulder, back, hip, knee, or widespread pain that interfered with usual activities. Potential confounders were identified using Directed Acyclic Graphs, and included sociodemographic, lifestyle, psychological factors, and medical comorbidities. Simple models adjusted for age and sex showed significant associations between suboptimal vitamin D status and chronic pain across all sites (odds ratios [ORs] ranged 1.07-2.85). These associations were weakened or became insignificant after accounting for all confounding factors (ORs ≤1.01) for chronic regional musculoskeletal pain. Severe vitamin D deficiency remained a significant and positive association with chronic widespread pain after adjusting for all confounding factors (OR [95% confidence interval]: 1.26 [1.07, 1.49]). This study suggests that while vitamin D status is not a key independent determinant of chronic regional musculoskeletal pain, severe vitamin D deficiency may be associated with chronic widespread pain. PERSPECTIVES: After counting for various confounders, severe vitamin D deficiency remained significantly associated with increased risk of experiencing chronic widespread pain. Considering the low risk and affordability of vitamin D supplements, their potential use in treating chronic widespread pain in severely vitamin D deficient individuals warrants further exploration.

Saponins from Allium macrostemon Bulbs Attenuate Endothelial Inflammation and Acute Lung Injury via the NF-κB/VCAM-1 Pathway.

Endothelial inflammation is a multifaceted physiological process that plays a pivotal role in the pathogenesis and progression of diverse diseases, encompassing but not limited to acute lung infections like COVID-19, coronary artery disease, stroke, sepsis, metabolic syndrome, certain malignancies, and even psychiatric disorders such as depression. This inflammatory response is characterized by augmented expression of adhesion molecules and secretion of pro-inflammatory cytokines. In this study, we discovered that saponins from Allium macrostemon bulbs (SAMB) effectively inhibited inflammation in human umbilical vein endothelial cells induced by the exogenous inflammatory mediator lipopolysaccharide or the endogenous inflammatory mediator tumor necrosis factor-α, as evidenced by a significant reduction in the expression of pro-inflammatory factors and vascular cell adhesion molecule-1 (VCAM-1) with decreased monocyte adhesion. By employing the NF-κB inhibitor BAY-117082, we demonstrated that the inhibitory effect of SAMB on VCAM-1 expression may be attributed to the NF-κB pathway's inactivation, as characterized by the suppressed IκBα degradation and NF-κB p65 phosphorylation. Subsequently, we employed a murine model of lipopolysaccharide-induced septic acute lung injury to substantiate the potential of SAMB in ameliorating endothelial inflammation and acute lung injury in vivo. These findings provide novel insight into potential preventive and therapeutic strategies for the clinical management of diseases associated with endothelial inflammation.

Edgeworthia gardneri (Wall.) Meisn. Ethanolic Extract Attenuates Endothelial Activation and Alleviates Cardiac Ischemia-Reperfusion Injury.

Endothelial pro-inflammatory activation is pivotal in cardiac ischemia-reperfusion (I/R) injury pathophysiology. The dried flower bud of Edgeworthia gardneri (Wall.) Meisn. (EG) is a commonly utilized traditional Tibetan medicine. However, its role in regulating endothelium activation and cardiac I/R injury has not been investigated. Herein, we showed that the administration of EG ethanolic extract exhibited a potent therapeutic efficacy in ameliorating cardiac endothelial inflammation (p < 0.05) and thereby protecting against myocardial I/R injury in rats (p < 0.001). In line with the in vivo findings, the EG extract suppressed endothelial pro-inflammatory activation in vitro by downregulating the expression of pro-inflammatory mediators (p < 0.05) and diminishing monocytes' firm adhesion to endothelial cells (ECs) (p < 0.01). Mechanistically, we showed that EG extract inhibited the nuclear factor kappa-B (NF-κB), c-Jun N-terminal kinase (JNK), extracellular regulated protein kinase (ERK), and p38 mitogen-activated protein kinase (MAPK) signaling pathways to attenuate EC-mediated inflammation (p < 0.05). Collectively, for the first time, this study demonstrated the therapeutic potential of EG ethanolic extract in alleviating I/R-induced inflammation and the resulting cardiac injury through its inhibitory role in regulating endothelium activation.

Integrating network pharmacology and experimental models to identify notoginsenoside R1 ameliorates atherosclerosis by inhibiting macrophage NLRP3 inflammasome activation.

Atherosclerosis is a cardiovascular disease, accounting for the most common mortality cause worldwide. Notoginsenoside R1 (NGR1) is a characteristic saponin of Radix notoginseng that exhibits anti-inflammatory and antioxidant effects while modulating lipid metabolism. Evidence suggests that NGR1 exerts cardioprotective, neuroprotective, and anti-atherosclerosis effects. However, underlying NGR1 mechanisms alleviating atherosclerosis (AS) have not been examined. This study used a network pharmacology approach to construct the drug-target-disease correlation and protein-protein interaction (PPI) network of NGR1 and AS. Moreover, functional annotation and pathway enrichment analyses deciphered the critical biological processes and signaling pathways potentially regulated by NGR1. The protective effect of NGR1 against AS and the underlying mechanism(s) was assessed in an atherogenic apolipoprotein E-deficient (ApoE-/-) mice in vivo and an oxidized low-density lipoprotein (ox-LDL)-induced macrophage model in vitro. The network pharmacology and molecular docking analyses revealed that NGR1 protects against AS by targeting the NLRP3/caspase-1/IL-1ß pathway. NGR1 reduced foam cell formation in ox-LDL-induced macrophages and decreased atherosclerotic lesion formation, serum lipid metabolism, and inflammatory cytokines in AS mice in vivo. Therefore, NGR1 downregulates the NLRP3 inflammasome complex gene expression of NLRP3, caspase-1, ASC, IL-1ß, and IL-18, in vivo and in vitro.

Degradation of levofloxacin from antibiotic wastewater by pulse electrochemical oxidation with BDD electrode.

Antibiotic-containing wastewater is a typical biochemical refractory organic wastewater and general treatment methods cannot effectively and quickly degrade the antibiotic molecules. In this study, a novel boron-doped diamond (BDD) pulse electrochemical oxidation (PEO) technology was proposed for the efficient removal of levofloxacin (LFXN) from wastewater. The effects of current density (j), initial pH (pH0), frequency (f), electrolyte types and initial concentration (c0(LFXN)) on the degradation of LFXN were systematically investigated. The degradation kinetics under four different processes have also been studied. The possible degradation mechanism of LFXN was proposed by Density functional theory calculation and analysis of degradation intermediates. The results showed that under the optimal parameters, the COD removal efficiency (η(COD)) was 94.4% and the energy consumption (EEC) was 81.43 kWh·m-3 at t = 120 min. The degradation of LFXN at pH = 2.8/c(H2O2) followed pseudo-first-order kinetics. The apparent rate constant was 1.33 × 10-2 min-1, which was much higher than other processes. The degradation rate of LFXN was as follows: pH = 2.8/c(H2O2) > pH = 2.8 > pH = 7/c(H2O2) > pH = 7. Ten aromatic intermediates were formed during the degradation of LFXN, which were further degraded to F-, NH4+, NO3-, CO2 and H2O. This study provides a promising approach for efficiently treating LFXN antibiotic wastewater by pulsed electrochemical oxidation with a BDD electrode without adding H2O2.

Genetic Analysis of Orf Virus (ORFV) Strains Isolated from Goats in China: Insights into Epidemiological Characteristics and Evolutionary Patterns.

Contagious ecthyma (CE) is an acute infectious zoonosis caused by orf virus (ORFV) that mainly infects sheep and goats and causes obvious lesions and low market value of livestock, resulting in huge economic losses for farmers. In this study, two strains of ORFV were isolated from Shaanxi Province and Yunnan Province in China, named FX and LX. The two ORFVs were located in the major clades of domestic strains respectively, and exhibited distinct sequence homology. We analyzed the genetic data of core genes (B2L, F1L, VIR, ORF109) and variable genes (GIF, ORF125 and vIL-10) of ORFV to investigate its epidemiological and evolutionary characteristics. The sequences from 2007 to 2018 constituted the majority of the viral population, predominantly concentrated in India and China. Most genes were clustered into SA00-like type and IA82-like type, and the hotspots in East and South Asia were identified in the ORFV transmission trajectories. For these genes, VIR had the highest substitution rate of 4.85 × 10-4, both VIR and vIL-10 suffered the positive selection pressure during ORFV evolution. Many motifs associated with viral survival were distributed among ORFVs. In addition, some possible viral epitopes have been predicted, which still require validation in vivo and in vitro. This work gives more insight into the prevalence and phylogenetic relationships of existing orf viruses and facilitate better vaccine design.

ORFV entry into host cells via clathrin-mediated endocytosis and macropinocytosis.

Orf virus (ORFV), also known as infectious pustular virus, leads to an acute contagious zoonotic infectious disease. ORFV can directly contact and infect epithelial cells of skin and mucosa, causing damage to tissue cells. So far, the pathway of ORFV entry into cells is unclear. Therefore, finding the internalization pathway of ORFV will help to elucidate the cellular and molecular mechanisms of ORFV infection and invasion, which in turn will provide a certain reference for the prevention and treatment of ORFV. In the present study, chemical inhibitors were used to analyze the mechanism of ORFV entry into target cells. The results showed that the inhibitor of clathrin-mediated endocytosis could inhibit ORFV entry into cells. However, the inhibitor of caveolae-mediated endocytosis cannot inhibit ORFV entry into cells. In addition, inhibition of macropinocytosis pathway also significantly reduced ORFV internalization. Furthermore, the inhibitors of acidification and dynamin also prevented ORFV entry. However, results demonstrated that inhibitors inhibited ORFV entry but did not inhibit ORFV binding. Notably, extracellular trypsin promoted ORFV entry into cells directly, even when the endocytic pathway was inhibited. In conclusion, ORFV enters into its target cells by clathrin-mediated endocytosis and macropinocytosis, while caveolae-dependent endocytosis has little effects on this process. In addition, the entry into target cells by ORFV required an acid environment and the effect of dynamin. Meanwhile, we emphasize that broad-spectrum antiviral inhibitors and extracellular enzyme inhibitors are likely to be effective strategies for the prevention and treatment of ORFV infection.

Stigma following acquired brain injury and spinal cord injury: relationship to psychological distress and community integration in the first-year post-discharge.

PURPOSE: This study aimed to compare stigma levels after acquired brain injury (ABI) and spinal cord injury (SCI) during the first 12-months post-discharge and investigate relationships between stigma, psychological distress and community integration. METHODS: 110 adults with ABI (55%) or SCI (45%) were recruited from brain and spinal cord injury inpatient rehabilitation units of a tertiary healthcare facility. They were administered Neuro-QOL Stigma subscale and Depression Anxiety and Stress Scales (DASS-21) at discharge, 3-months and 12-months post-discharge, and Community Integration Measure at 12-months post-discharge. RESULTS: Stigma levels did not significantly differ between individuals with ABI and SCI. However, stigma significantly decreased between discharge and 12-months post-discharge for the total sample. Stigma was positively associated with psychological distress at discharge and 3-months post-discharge, but not at 12-months post-discharge. Lower functional status and power wheelchair use were associated with higher stigma at 12-months post-discharge. Stigma at 3-months post-discharge predicted community integration at 12-months post-discharge, controlling for psychological distress and functional status. CONCLUSION: Experience of stigma in the first few months post-discharge may negatively impact individuals' community reintegration. The early post-discharge period may be a pivotal time for supporting individuals to explore disability and injury-related appraisals and enhance connection to their community.

Lower functional status and use of a power wheelchair after acquired neurological injury may increase the experience of stigma.Individuals with acquired brain injury or spinal cord injury who perceive high levels of stigma in the first few months post-discharge are more likely to experience poorer long-term community integration.The first few months post-discharge represent an important phase for health professionals to support individuals to explore their beliefs regarding disability and injury-related self-appraisals and enhance connection to their community.

Exploring the Mechanism of Buyang Huanwu Decoction Alleviating Restenosis by Regulating VSMC Phenotype Switching and Proliferation by Network Pharmacology and Molecular Docking.

BACKGROUND: Buyang Huanwu Decoction (BHD) is used to regulate blood circulation and clear collaterals and is widely used in coronary heart disease. However, the active compounds and the mechanism of BHD used to treat restenosis are less understood. OBJECTIVE: The study aimed to explore the potential mechanism of Buyang Huanwu decoction BHD for the treatment of restenosis using network pharmacology and molecular docking experiments. METHODS: The bioactive components of BHD and their corresponding targets were retrieved from the Traditional Chinese Medicine Systems Pharmacology (TCMSP) and Encyclopaedia of Traditional Chinese Medicine (ETCM) databases as well as literature. Restenosisassociated therapeutic genes were identified from the OMIM, Drugbank, GEO, and Dis- GeNET databases. Genes related to the vascular smooth muscle cell (VSMC) phenotype were obtained from the gene ontology (GO) database and literature. The core target genes for the drug-disease-VSMC phenotype were identified using the Venn tool and Cytoscape software. Moreover, the "drug-component-target-pathway" network was constructed and analyzed, and pathway enrichment analysis was performed. The connection between the main active components and core targets was analyzed using the AutoDock tool, and PyMOL was used to visualize the results. RESULTS: The "compound-target-disease" network included 80 active ingredients and 599 overlapping targets. Among the bioactive components, quercetin, ligustrazine, ligustilide, hydroxysafflor yellow A, and dihydrocapsaicin had high degree values, and the core targets included TP53, MYC, APP, UBC, JUN, EP300, TGFB1, UBB, SP1, MAPK1, SMAD2, CTNNB1, FOXO3, PIN1, EGR1, TCF4, FOS, SMAD3, and CREBBP. A total of 365 items were obtained from the GO functional enrichment analysis (p < 0.05), whereas the enrichment analysis of the KEGG pathway identified 30 signaling pathways (p < 0.05), which involved the TGF-ß signaling pathway, Wnt signaling pathway, TRAF6-mediated induction of NF-κB and MAPK pathway, TLR7/8 cascade, and others. The molecular docking results revealed quercetin, luteolin, and ligustilide to have good affinity with the core targets MYC and TP53. CONCLUSION: The active ingredients in BHD might act on TP53, MYC, APP, UBC, JUN, and other targets through its active components (such as quercetin, ligustrazine, ligustilide, hydroxysafflor yellow A, and dihydrocapsaicin). This action of BHD may be transmitted via the involvement of multiple signaling pathways, including the TGF-ß signaling pathway, Wnt signaling pathway, TRAF6-mediated induction of NF-κB and MAPK pathway, and TLR7/8 cascade, to treat restenosis by inhibiting the phenotype switching and proliferation of VSMC.

Cervical and axioscapular muscle stiffness measured with shear wave elastography: A comparison between different levels of work-related neck disability.

Assessing muscle mechanical properties in terms of stiffness may provide important insights into mechanisms underlying work-related neck pain. This study compared stiffness of cervical and axioscapular muscles between 92 participants (sonographers) with no (n = 31), mild (n = 43) or moderate/severe (n = 18) neck disability. It was hypothesized that participants with more severe neck pain and disability would present with altered distribution of stiffness in cervical and axioscapular muscles than those with no disability. Using shear wave elastography, the shear modulus (kPa) of five cervical and six axioscapular muscles or muscle segments were measured in a relaxed seated upright or side-lying position. Muscle activity was measured simultaneously using surface electromyography during the elastography measurements and scapular depression was measured using a measurement tape and inclinometer before the elastography measurements to evaluate their potential confounding influences on shear modulus. Increased shear modulus was found in deeper than superficial cervical muscles and more cranial than caudal axioscapular muscles. However, no differences in shear modulus of the cervical or axioscapular muscles were found between sonographers with varying levels of disability. This study suggests no alterations in stiffness of cervical and axioscapular muscles were associated with work-related neck pain and disability.

Transforming municipal cotton waste into a multilayer fibre biocomposite with high strength.

We analyzed the problematic textile fiber waste as potential precursor material to produce multilayer cotton fiber biocomposite. The properties of the products were better than the current dry bearing type particleboards and ordinary dry medium-density fiberboard in terms of the static bending strength (67.86 MPa), internal bonding strength (1.52 MPa) and water expansion rate (9.57%). The three-layer, four-layer and five-layer waste cotton fiber composite (WCFC) were tried in the experiment, the mechanical properties of the three-layer WCFC are insufficient, the five-layer WCFC is too thick and the four-layer WCFC had the best comprehensive performance. The cross-section morphology of the four-layer WCFC shows a dense structure with a high number of adhesives attached to the fiber. The hardness and stiffness of the four-layer cotton fiber composite enhanced by the high crystallinity of cellulose content, and several chemical bondings were presence in the composites. Minimum mass loss (30%) and thermal weight loss rate (0.70%/°C) was found for the four-layer WCFC. Overall, our findings suggested that the use of waste cotton fiber (WCF) to prepare biocomposite with desirable physical and chemical properties is feasible, and which can potentially be used as building material, furniture and automotive applications.

Rose Bengal inhibits ß-amyloid oligomers-induced tau hyperphosphorylation via acting on Akt and CDK5 kinases.

RATIONALE: Tau hyperphosphorylation and aggregation is considered as a main pathological mechanism underlying Alzheimer's disease (AD). Rose Bengal (RB) is a synthetic dye used for disease diagnosis, which was reported to inhibit tau toxicity via inhibiting tau aggregation in Drosophila. However, it was unknown if RB could produce anti-AD effects in rodents. OBJECTIVES: The research aimed to investigate if and how RB could prevent ß-amyloid (Aß) oligomers-induced tau hyperphosphorylation in rodents. METHODS AND RESULTS: RB was tested in vitro (0.3-1 µM) and prevented Aß oligomers-induced tau hyperphosphorylation in PC12 cells. Moreover, RB (10-30 mg/kg, i.p.) effectively attenuated cognitive impairments induced by Aß oligomers in mice. Western blotting analysis demonstrated that RB significantly increased the expression of pSer473-Akt, pSer9-glycogen synthase kinase-3ß (GSK3ß) and reduced the expression of cyclin-dependent kinase 5 (CDK5) both in vitro and in vivo. Molecular docking analysis suggested that RB might directly interact with GSK3ß and CDK5 by acting on ATP binding sites. Gene Ontology enrichment analysis indicated that RB might act on protein phosphorylation pathways to inhibit tau hyperphosphorylation. CONCLUSIONS: RB was shown to inhibit tau neurotoxicity at least partially via inhibiting the activity of GSK3ß and CDK5, which is a novel neuroprotective mechanism besides the inhibition of tau aggregation. As tau hyperphosphorylation is an important target for AD therapy, this study also provided support for investigating the drug repurposing of RB as an anti-AD drug candidate.

Neuroprotective Effects of an Edible Pigment Brilliant Blue FCF against Behavioral Abnormity in MCAO Rats.

Ischemic stroke leads to hypoxia-induced neuronal death and behavioral abnormity, and is a major cause of death in the modern society. However, the treatments of this disease are limited. Brilliant Blue FCF (BBF) is an edible pigment used in the food industry that with multiple aromatic rings and sulfonic acid groups in its structure. BBF and its derivatives were proved to cross the blood-brain barrier and have advantages on the therapy of neuropsychiatric diseases. In this study, BBF, but not its derivatives, significantly ameliorated chemical hypoxia-induced cell death in HT22 hippocampal neuronal cell line. Moreover, protective effects of BBF were attributed to the inhibition of the extracellular regulated protein kinase (ERK) and glycogen synthase kinase-3ß (GSK3ß) pathways as evidenced by Western blotting analysis and specific inhibitors. Furthermore, BBF significantly reduced neurological and behavioral abnormity, and decreased brain infarct volume and cerebral edema induced by middle cerebral artery occlusion/reperfusion (MCAO) in rats. MCAO-induced increase of p-ERK in ischemic penumbra was reduced by BBF in rats. These results suggested that BBF prevented chemical hypoxia-induced otoxicity and MCAO-induced behavioral abnormity via the inhibition of the ERK and GSK3ß pathways, indicating the potential use of BBF for treating ischemic stroke.

Phloroglucinol, a clinical-used antispasmodic, inhibits amyloid aggregation and degrades the pre-formed amyloid proteins.

Amyloid proteins, such as ß-amyloid (Aß) and α-synuclein (α-syn), could form neurotoxic aggregates during the progression of neurodegenerative disorders. Phloroglucinol, a clinical-used drug for treating spasmodic pain, was predicted to cross the blood brain-barrier and possesses neuroprotective potential. In this study, we have found, for the first time, that phloroglucinol inhibited the formation of amyloid aggregates, and degraded pre-formed amyloid aggregates with the similar efficacy as curcumin, a widely known amyloid aggregation inhibitor. Moreover, phloroglucinol decreased the seeding during aggregation process and inhibited the aggregation of Aß1-42 with homocysteine (Hcy) seeds. Molecular docking analysis further demonstrated hydrophobic interactions and hydrogen bonds between phloroglucinol and Aß1-42/α-syn. Furthermore, phloroglucinol inhibited amyloid aggregates-induced cytotoxicity in neuronal cells and prevented Aß1-42 + Hcy aggregates-induced cognitive impairments in mice. All these results suggested that phloroglucinol possesses the ability to degrade pre-formed amyloid aggregates, to inhibit the seeding during amyloid aggregation, and to reduce the neurotoxicity, indicating the reposition possibility of phloroglucinol as a novel drug for treating neurodegenerative disorders.

Time Course and Risk Profile of Work-Related Neck Disability: A Longitudinal Latent Class Growth Analysis.

OBJECTIVE: Given the economic burden of work-related neck pain and disability, it is important to understand its time course and associated risk factors to direct better management strategies. This study aimed to identify the 1-year trajectories of work-related neck disability in a high-risk occupation group such as sonography and to investigate which baseline biopsychosocial factors are associated with the identified trajectories. METHODS: A longitudinal study was conducted among 92 sonographers with neck disability assessed at 3 time points-baseline, 6 months, and 12 months-using the Neck Disability Index. Baseline biopsychosocial measures included individual characteristics (demographics and physical activity levels), work-related physical and psychosocial factors (eg, ergonomic risk, workplace social support, job satisfaction), general psychological features (depression, anxiety, pain catastrophizing, and fear-avoidance beliefs), and quantitative sensory testing of somatosensory function (cold and pressure pain thresholds at neck and tibialis anterior, and temporal summation). RESULTS: Two distinct trajectories of neck disability were identified, including a "low-resolving disability" trajectory showing slow improvement toward no disability (64.8%) and a "moderate-fluctuating disability" trajectory characterized by persistent moderate disability with a small fluctuation across time (35.2%). The trajectory of moderate-fluctuating disability was associated with more severe symptoms, lower vigorous physical activity, higher ergonomic risk, remote cold hyperalgesia, widespread mechanical hyperalgesia, heightened pain facilitation, and several psychosocial factors such as anxiety, depression, lower job satisfaction, and lower workplace social support at baseline. CONCLUSION: Over one-third of sonographers were at risk of developing a moderate-fluctuating disability trajectory. This unfavorable trajectory was associated with low physical activity level, poor ergonomics, psychosocial distress, and central sensitization at baseline. IMPACT: This study has important implications for the management of neck disability in workers. Addressing modifiable factors including low vigorous physical activity, poor ergonomics, anxiety, depression, and lack of workplace social support may improve the trajectory of work-related neck disability.

Design and synthesis of novel tacrine-dipicolylamine dimers that are multiple-target-directed ligands with potential to treat Alzheimer's disease.

Alzheimer's disease (AD) is a prevalent neurodegenerative disorder that has multiple causes. Therefore, multiple-target-directed ligands (MTDLs), which act on multiple targets, have been developed as a novel strategy for AD therapy. In this study, novel drug candidates were designed and synthesized by the covalent linkings of tacrine, a previously used anti-AD acetylcholinesterase (AChE) inhibitor, and dipicolylamine, an ß-amyloid (Aß) aggregation inhibitor. Most tacrine-dipicolylamine dimers potently inhibited AChE and Aß1-42 aggregation in vitro, and 13a exhibited nanomolar level inhibition. Molecular docking analysis suggested that 13a could interact with the catalytic active sites and the peripheral anion site of AChE, and bind to Aß1-42 pentamers. Moreover, 13a effectively attenuated Aß1-42 oligomers-induced cognitive dysfunction in mice by activating the cAMP-response element binding protein/brain-derived neurotrophic factor signaling pathway, decreasing tau phosphorylation, preventing synaptic toxicity, and inhibiting neuroinflammation. The safety profile of 13a in mice was demonstrated by acute toxicity experiments. All these results suggested that novel tacrine-dipicolylamine dimers, especially 13a, have multi-target neuroprotective and cognitive-enhancing potentials, and therefore might be developed as MTDLs to combat AD.

PLGA-PEG Nanoparticles Facilitate In Vivo Anti-Alzheimer's Effects of Fucoxanthin, a Marine Carotenoid Derived from Edible Brown Algae.

The marine natural product fucoxanthin has been reported previously to produce anti-Alzheimer's disease (AD) neuroprotective effects in vitro and in vivo. Fucoxanthin was also demonstrated to be safe in preclinical and small population clinical studies, but the low bioavailability of fucoxanthin in the central nervous system (CNS) has limited its clinical applications. To overcome this, poly lactic-co-glycolic acid-block-polyethylene glycol loaded fucoxanthin (PLGA-PEG-Fuc) nanoparticles with diameter at around 200 nm and negative charge were synthesized and suggested to penetrate into the CNS. Loaded fucoxanthin could be liberated from PLGA-PEG nanoparticles by sustained released in the physiological environment. PLGA-PEG-Fuc nanoparticles were shown to significantly inhibit the formation of Aß fibrils and oligomers. Moreover, these nanoparticles were taken up by both neurons and microglia, leading to the reduction of Aß oligomers-induced neurotoxicity in vitro. Most importantly, intravenous injection of PLGA-PEG-Fuc nanoparticles prevented cognitive impairments in Aß oligomers-induced AD mice with greater efficacy than free fucoxanthin, possibly via acting on Nrf2 and NF-κB signaling pathways. These results altogether suggest that PLGA-PEG nanoparticles can enhance the bioavailability of fucoxanthin and potentiate its efficacy for the treatment of AD, thus potentially enabling its future use for AD therapy.

Dimeric Tacrine(10)-hupyridone as a Multitarget-Directed Ligand To Treat Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disorder with multiple pathological features. Therefore, a multitarget-directed ligands (MTDLs) strategy has been developed to treat AD. We have previously designed and synthesized dimeric tacrine(10)-hupyridone (A10E), a novel tacrine derivative with acetylcholinesterase (AChE) inhibition and brain-derived neurotrophic factor (BDNF) activation activity, by linking tacrine and a fragment of huperzine A. However, it was largely unknown whether A10E could act on other AD targets and produce cognitive-enhancing ability in AD animal models. In this study, A10E could prevent cognitive impairments in APP/PS1 transgenic mice and ß-amyloid (Aß) oligomers-treated mice, with higher potency than tacrine and huperzine A. Moreover, A10E could effectively inhibit Aß production and deposition, alleviate neuroinflammation, enhance BDNF expression, and elevate cholinergic neurotransmission in vivo. At nanomolar concentrations, A10E could inhibit Aß oligomers-induced neurotoxicity via the activation of tyrosine kinase receptor B (TrkB)/Akt pathway in SH-SY5Y cells. Furthermore, Aß oligomerization and fibrillization could be directly disrupted by A10E. Importantly, A10E at high concentrations did not produce obvious hepatotoxicity. Our results indicated that A10E could produce anti-AD neuroprotective effects via the inhibition of Aß aggregation, the activation of the BDNF/TrkB pathway, the alleviation of neuroinflammation, and the decrease of AChE activity. As MTDLs could produce additional benefits, such as overcoming the deficits of drug combination and enhancing the compliance of AD patients, our results also suggested that A10E might be developed as a promising MTDL lead for the treatment of AD.

Interleukin-17 mediates inflammatory tissue injury during orf development in goats.

Orf is an epithelial zoonotic infectious disease caused by orf virus (ORFV). Mounting studies have shown that IL-17-driven neutrophil inflammation plays a central role in inflammatory skin diseases. However, whether IL-17 plays a similar role and how does it work in the pathogenesis of orf is unclear. In this study, we found that during orf development, numerous inflammatory cells, especially neutrophils, infiltrated in the damaged lip tissue. Meanwhile, the production of IL-17 was increased in the lesion site. Further evidence showed that IL-17 potently stimulated the production of several chemokines that are crucial for neutrophil migration. In addition, IL-17 was mostly produced by CD4+ T cells and gamma delta T (γδ T) cells of the skin. In conclusion, the present study highlighted a critical role of IL-17-driven inflammation in the pathogenesis of orf and suggested that this cytokine may be a potential therapeutic target of this disease in goats.

Interventions to Promote Work-Focused Care by Healthcare Providers for Individuals with Musculoskeletal Conditions a Scoping Review.

PURPOSE: Building on an emerging body of evidence, this scoping review aimed to provide an overview of current interventions to promote work-focused care by healthcare providers for individuals with musculoskeletal conditions and to identify current knowledge gaps for future research. METHODS: Literature searches were performed in Pubmed, CINAHL, EMBASE, and PsycInfo using Medical Subject Heading terms and text words relating to musculoskeletal conditions, interventions to promote work-focused care and work-related outcomes. Articles involving any interventions with elements of work-focused care delivered by healthcare providers to manage musculoskeletal conditions were reviewed for suitability and inclusion. RESULTS: A total of 22 articles (18 intervention trials) were identified. Most studies were multidisciplinary interventions incorporating one or more elements of work-focused care including: work-related assessment to identify barriers to working, vocational advice/coaching or education to address barriers to working, involvement of the workplace stakeholders, restoration of fitness for work and regular communication with multidisciplinary team members. Most studies (61 %) concluded that their interventions achieved the desired work-related outcomes although firm conclusions could not be made regarding the effectiveness of a particular component, content or strategy of work-focused care itself because of the variability in the type and number of elements and outcomes used. CONCLUSIONS: There is good evidence demonstrating the potential for healthcare providers to improve work outcomes for those with musculoskeletal conditions. Additional training is required to increase confidence in this area of practice. Accepting that work-focused care is important, however, does not diminish the challenge it presents.