A scoping review of music-based interventions for swallowing difficulties: implications for treating older adults with presbyphagia.

Objectives: Presbyphagia refers to age-related changes in the swallowing mechanism (e.g., reduced skeletal muscle strength that decreases bolus control). If left untreated, these changes can lead to dysphagia, which refers to impaired swallowing (e.g., coughing or choking when eating). Given that swallowing difficulties are common among older adults that they make up the fastest growing age group globally, the need for interventions to address presbyphagia is gaining urgency. To begin to address this need, we conducted a scoping review to analyze music therapy research aimed at enhancing swallowing function. The objective was to identify key intervention characteristics and propose clinical implications for treating presbyphagia using music therapy. Methods: This review followed the methodological frameworks outlined by Arksey and O'Malley and Levac et al. and used the Preferred Reporting Items for Systematic Reviews and Meta-Analysis for Scoping Reviews for analysis and reporting. Four electronic databases (i.e., ProQuest, PubMed, RISS, Web of Science) were searched for quantitative and qualitative studies in English or Korean that used music-based interventions to address swallowing function in older adults. Content analysis was conducted to identify and compare the main features of music interventions for swallowing difficulties among older adults. Results: Ten articles were identified and analyzed. It was found that three core components-respiration, vocalization, and singing-were employed to enhance swallowing function in populations with neurological impairments, dementia, or head and neck cancer. Notably, actions closely linked to swallowing function, such as laryngeal elevation and oral movements, were utilized therapeutically to speak or sing. Based on these characteristics, clinical implications are proposed to address presbyphagia. Conclusion: Singing entails a systematic and focused incorporation of stepwise activities that can be used to address swallowing disorders. In this context, critical clinical implications that music therapists should consider when treating individuals with presbyphagia include warmup breathing, vocalizing targeting laryngeal control, and singing targeting oral motor control. This review can contribute to the expansion of music therapy with older adults and the advancement of music therapy techniques.

Paeonol, the active component of Cynanchum paniculatum, ameliorated schizophrenia-like behaviors by regulating the PI3K-Akt-GSK3ß-NF-κB signalling pathway in MK-801-treated mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Cynanchum paniculatum (Bunge) Kitag. ex H. Hara (Asclepiadaceae) have been traditionally used in East Asia as analgesic or antiviral agents. Interestingly, some Chinese and Korean traditional medicinal books reported that the use of C. paniculatum in the treatment of psychotic symptoms, such as hallucinations and delusions. AIM OF THE STUDY: In this study, we aimed to investigate whether C. paniculatum could improve sensorimotor gating disruption in mice with MK-801-induced schizophrenia-like behaviors. We also aimed to identify the active component of C. paniculatum that could potentially serve as a treatment for schizophrenia and found that paeonol, the major constituent compound of C. paniculatum, showed potential as a treatment for schizophrenia. MATERIALS AND METHODS: To assess the effect of paeonol on mice with MK-801-induced schizophrenia-like behaviors, we carried out a series of behavioral tests related with symptoms of schizophrenia. In addition, we utilized Western blotting and ELISA techniques to investigate the antipsychotic actions of paeonol. RESULT: C. paniculatum extract (100 or 300 mg/kg) and paenol (10 or 30 mg/kg) significantly reversed MK-801-induced prepulse deficits in acoustic startle response test. In addition, paeonol (10 or 30 mg/kg) attenuated social novelty preference and novel object recognition memory on MK-801-induced schizophrenia-like behaviour in mice. Furthermore, the phosphorylation levels of PI3K, Akt, GSK3ß and NF-κB, as well as related pro-inflammatory cytokine, such as IL-1ß and TNF-α, were significantly reversed by the administration of paeonol (10 or 30 mg/kg) in the prefrontal cortex of MK-801-treated mice. CONCLUSIONS: Collectively, these data show that paeonol can potentially be used as an agent for treating sensorimotor gating deficits, negative symptoms, and cognitive deficits, such as those observed in schizophrenia with few adverse effects.

Multi-shell structured upconversion nanocarriers that combine IDO inhibitor-induced immunotherapy with NIR-triggered photodynamic therapy for deep tumors.

Combination therapies for cancer have attracted substantial research interest as an emerging treatment strategy that can reduce the chance of cancer resistance to chemotherapy and deal effectively with cancer cell heterogeneity. In this study, we designed novel nanocarriers that combine immunotherapy, which attacks tumors by stimulating the immune system, with photodynamic therapy (PDT), a non-invasive phototherapy that can selectively destroy only cancer cells. Multi-shell structured upconversion nanoparticles (MSUCNs) with good photoluminescence (PL) strength were synthesized for a combination therapy of near-infrared (NIR) light-induced PDT and immunotherapy using a specific immune checkpoint inhibitor. By optimizing the doping content of ytterbium ions (Yb3+) and forming a multi-shell structure, MSUCNs able to emit light at multiple wavelengths with the PL efficiency improved by 260-380 times compared to core particles were synthesized. Then, the surfaces of the MSUCNs were modified with folic acid (FA) as a tumor-targeting ligand, Ce6 as a photosensitizer (PS), and 1-methyl-tryptophan (1MT) as an indoleamine 2,3-dioxygenase (IDO) inhibitor. The FA-, Ce6-, and 1MT-conjugated MSUCNs (F-MSUCN3-Ce6/1MT) exhibited targeted cellular uptake by active targeting against HeLa cells, which are FA receptor-positive cancer cells. Upon irradiation with NIR at 808 nm, the F-MSUCN3-Ce6/1MT nanocarriers produced reactive oxygen species, which caused apoptosis of the cancer cells, and activated CD8+ T cells, which enhanced the immune response by binding with immune checkpoint inhibitory proteins and blocking the IDO pathway. Therefore, these F-MSUCN3-Ce6/1MT nanocarriers could be potential candidate materials for synergistic anticancer therapy that combines IDO inhibitor-based immunotherapy with enhanced NIR-triggered PDT.

Singing Interventions in Pulmonary Rehabilitation: A Scoping Review.

(1) Background: Individuals with pulmonary disease need intensive and consistent rehabilitation due to their high risk for serious illness and long-term complications. The purpose of this scoping review was to provide a comprehensive analysis of relevant research regarding the use of singing in pulmonary rehabilitation. (2) Methods: A systematic literature search was performed using the PsycINFO, CINAHL, PubMed, and Web of Science databases. A search for studies that employed singing in pulmonary rehabilitation for patients with pulmonary disease was conducted. (3) Results: Studies that met the selection criteria were summarized and analyzed. Twenty-seven studies were included in the final analysis. Results showed that research using singing in pulmonary rehabilitation generally employed an intervention with structured tasks and additional home practice or socialization time. However, the singing procedure in each intervention was not always specifically described and the findings were inconsistent. (4) Conclusions: Programmed singing interventions can support lung health and be an effective component of pulmonary rehabilitation. The therapeutic singing method in relation to respiratory exercises should be integrated into the main activity in the intervention. Overall, singing has physical and psychosocial effects, leading to improvements in symptoms, but more research is necessary to ensure that the respiratory needs of people with pulmonary disease are adequately met.

Anti-Inflammatory Effects of the LK5 Herbal Complex on LPS- and IL-4/IL-13-Stimulated HaCaT Cells and a DNCB-Induced Animal Model of Atopic Dermatitis in BALB/c Mice.

Atopic dermatitis (AD) is a chronic inflammatory skin disease influenced by a complex interplay of genetic and environmental factors. The activation of the JAK-STAT pathway increases the expression of inflammatory cytokines such as IL-4 and IL-13, further deteriorating AD. Therefore, for the treatment of AD, the JAK-STAT pathway is emerging as a significant target, alongside inflammatory cytokines. This study investigates the potential therapeutic effects of a novel herbal complex, LK5, composed of Scutellaria baicalensis, Liriope platyphylla, Sophora flavescens, Dictammus dasycarpus, and Phellodendron schneider, known for their anti-inflammatory and immune-modulating properties. We examined the anti-inflammatory and anti-AD effects of the LK5 herbal complex in HaCaT cells stimulated by LPS and IL-4/IL-13, as well as in a mouse model of AD induced by DNCB. In HaCaT cells stimulated with LPS or IL-4/IL-13, the LK5 herbal complex demonstrated anti-inflammatory effects by inhibiting the expression of inflammatory cytokines including TNF-α, IL-6, and IL-1ß, and downregulating the phosphorylation of STAT proteins. In a murine AD-like model induced by DNCB, administration of the LK5 herbal complex significantly ameliorated clinical symptoms, including dermatitis, ear thickness, and TEWL. Histological analysis revealed a reduction in epidermal thickness and mast cell infiltration. The LK5 herbal complex also inhibited pruritus induced by compound 48/80. Furthermore, the LK5 herbal complex treatment significantly decreased the levels of inflammatory cytokines such as TSLP, IL-6, and IgE in plasma and ear tissue of AD-induced mice. These findings suggest that the LK5 herbal complex may modulate the immune response and alleviate AD symptoms by inhibiting STAT pathways.

Discovery of Novel Inhibitors of Uridine Diphosphate-N-Acetylenolpyruvylglucosamine Reductase (MurB) from Pseudomonas aeruginosa, an Opportunistic Infectious Agent Causing Death in Cystic Fibrosis Patients.

Pseudomonas aeruginosa is of major concern for cystic fibrosis patients where this infection can be fatal. With the emergence of drug-resistant strains, there is an urgent need to develop novel antibiotics against P. aeruginosa. MurB is a promising target for novel antibiotic development as it is involved in the cell wall biosynthesis. MurB has been shown to be essential in P. aeruginosa, and importantly, no MurB homologue exists in eukaryotic cells. A fragment-based drug discovery approach was used to target Pa MurB. This led to the identification of a number of fragments, which were shown to bind to MurB. One fragment, a phenylpyrazole scaffold, was shown by ITC to bind with an affinity of Kd = 2.88 mM (LE 0.23). Using a structure guided approach, different substitutions were synthesized and the initial fragment was optimized to obtain a small molecule with Kd = 3.57 µM (LE 0.35).

Enhanced biotransformation of the minor ginsenosides in red ginseng extract by Penicillium decumbens ß-glucosidase.

Compound K (C-K) and Rh2, which are present at low levels in ginseng and ginseng extracts, have higher intestinal absorption rates than other ginsenosides. Here, we attempted to convert ginsenoside Rb1 to C-K using a ß-glucosidase from Penicillium decumbens. Ten commercially available enzymes were screened to identify enzymes that can convert ginsenoside Rb1 to C-K, resulting in the selection of a P. decumbens-derived ß-glucosidase. ß-Glucosidase showed maximum activity at pH 4.0 and 60 °C; its substrate specificity for ginsenoside Rb1 was investigated. The main glucoside-hydrolyzing pathways were as follows: ginsenoside Rb1 or Rd → gypenoside XVII → F2 → C-K and ginsenoside Rg3 → Rh2. The P. decumbens-derived ß-glucosidase was used to generate C-K and Rh2 using protopanaxadiol-type ginsenosides as substrates. Additionally, to apply this enzyme to the commercialized red ginseng extract products, the contents of C-K and Rh2 in the total ginsenosides significantly (p < 0.05) increased up to 36-fold and 8.9-fold, respectively, higher than prior to subjecting to biotransformation. To the best of our knowledge, this is the first report of the dual biotransformation of C-K and Rh2 by a food-grade commercial enzyme. This study demonstrates that the use of a specific ß-glucosidase may increase C-K and Rh2 contents in the ginseng extract through a simple biotransformation process and, thus, enhance its health benefits.

Dracocephalum moldavica Ethanol Extract Suppresses LPS-Induced Inflammatory Responses through Inhibition of the JNK/ERK/NF-κB Signaling Pathway and IL-6 Production in RAW 264.7 Macrophages and in Endotoxic-Treated Mice.

The excessive synthesis of interleukin-6 (IL-6) is related to cytokine storm in COVID-19 patients. Moreover, blocking IL-6 has been suggested as a treatment strategy for inflammatory diseases such as sepsis. Sepsis is a severe systemic inflammatory response syndrome with high mortality. In the present study, we investigated the anti-inflammatory and anti-septic effects and the underlying mechanisms of Dracocephalum moldavica ethanol extract (DMEE) on lipopolysaccharide (LPS)-induced inflammatory stimulation in RAW 264.7 macrophages along with septic mouse models. We found that DMEE suppressed the release of inflammatory mediators NO and PGE2 and inhibited both the mRNA and protein expression levels of iNOS and COX-2, respectively. In addition, DMEE reduced the release of proinflammatory cytokines, mainly IL-6 and IL-1ß, in RAW 264.7 cells by inhibiting the phosphorylation of JNK, ERK and p65. Furthermore, treatment with DMEE increased the survival rate and decreased the level of IL-6 in plasma in LPS-induced septic shock mice. Our findings suggest that DMEE elicits an anti-inflammatory effect in LPS-stimulated RAW 264.7 macrophages and an anti-septic effect on septic mouse model through the inhibition of the ERK/JNK/NF-κB signaling cascades and production of IL-6.

Dracocephalum moldavica attenuates scopolamine-induced cognitive impairment through activation of hippocampal ERK-CREB signaling in mice.

ETHNOPHARMACOLOGICAL RELEVANCE: Dracocephalum moldavica (Moldavian balm) has been traditionally used for the treatment of intellectual disabilities, migraines and cardiovascular problems in East Asia. Recent scientific studies have demonstrated the usefulness of this plant to treat neurodegenerative disorders, including Alzheimer's disease. AIM OF THE STUDY: This study aimed to investigate the effects of the ethanolic extract of D. moldavica leaves (EEDM) on scopolamine-induced cognitive impairment in mice and the underlying mechanisms of action. MATERIALS AND METHODS: The behavioral effects of EEDM were examined using the step-through passive avoidance and Morris water maze tasks. To elucidate the underlying mechanism, we tested whether EEDM affects acetylcholinesterase activity and the expression of memory-related signaling molecules including extracellular signal-regulated kinase (ERK) and cAMP response element-binding protein (CREB) in the hippocampus. RESULTS: EEDM (25, 50 or 100 mg/kg) significantly ameliorated the scopolamine-induced step-through latency reduction in the passive avoidance task in mice. In the Morris water maze task, EEDM (50 mg/kg) significantly attenuated scopolamine-induced memory impairment. Furthermore, the administration of EEDM increased the phosphorylation levels of ERK and CREB in the hippocampus but did not alter acetylcholinesterase activity. CONCLUSIONS: These findings suggest that EEDM significantly attenuates scopolamine-induced memory impairment in mice and may be a promising therapeutic agent for improving memory impairment.

New Chemical Constituents from the Bark of Dendropanax morbifera Leveille and their Evaluation of Antioxidant Activities.

Four new constituents, as cis-6-oxogeran-4-enyl-10-oxy-O-ß-arabinopyranosyl-4'-O-ß-arabinopyranosyl-2''-octadec-9''',12''',15'''-trienoate (1), geran-3(10)-enyl-1-oxy-O-ß-arabinopyranosyl-4'-O-ß-arabinopyranosyl-2''-octadec-9''',12''',15'''-trienoate (2), geranilan-8-oxy-O-α-d-xylopyranosyl-2'-n-octadec-9'',12'',15''-trienoate (3), 1-cyclohex-2', 5'-dienyl 1-cyclohexylethanol-O-ß-d-xylopyranoside (4), along with six known constituents, guaiacol-O-ß-d-arabinopyaranoside (5), n-tetradecanyl oleate (6), oleyl-O-ß-d-xyloside (7), n-octadec-9,12-dienoyl-O-ß-d-arabinopyranoside (8), linolenyl-O-ß-d-arabinofuranoside (9) andglyceryl-1,3-dipalmito-2-olein (10), were isolated and identified from the Dendropanax morbifera bark. The new structures were established by one-and two-dimensional NMR (and in combination with IR, FAB-MSand HR-ESI-FTMS. The comparative evaluation of antioxidant potential by phosphomolybdenum, DPPH, FRAP and the NO assay of four different compounds (1-4), we have found that the compounds 1 and 2 have power as a natural antioxidant, whereas the compound 3 and 4 exhibited mild activity in comparison to compounds 1 and 2.

Danshensu attenuates scopolamine and amyloid-ß-induced cognitive impairments through the activation of PKA-CREB signaling in mice.

Alzheimer's disease (AD) is an important chronic neurodegenerative disorder and is mainly associated with cognitive dysfunction. At present, bioactive compounds from traditional medicinal plants have received much attention for the enhancement of cognitive function. Danshensu, a phenolic acid isolated from herbal medicines, has various pharmacological activities in the central nervous system, including anxiolytic-like and neuroprotective properties. The present study aimed to investigate the ameliorating effects of danshensu on scopolamine- and amyloid-ß (Aß) protein-induced cognitive impairments in mice. Danshensu (3 and 10 mg/kg, p.o.) effectively ameliorated scopolamine-induced cognitive dysfunction in mice, as measured in passive avoidance and Y-maze tasks. In a mechanistic study, danshensu inhibited monoamine oxidase A (MAO-A) activity but not MAO-B. Additionally, danshensu treatment increased the dopamine level and the phosphorylation levels of protein kinase A (PKA) and cAMP response element binding protein (CREB), in the cortex of the brain. Furthermore, the ameliorating effect of danshensu against scopolamine-induced cognitive impairment was fully blocked by H89, a PKA inhibitor. Finally, danshensu also ameliorated Aß-induced cognitive impairments in an animal model of AD. The results revealed that danshensu treatment significantly improved scopolamine and Aß-induced cognitive impairments in mice by facilitation of dopamine signaling cascade such as PKA and CREB due to MAO-A inhibition. Thus, danshensu could be used as a promising therapeutic agent for preventing and treating AD.

The Immediate and Sustained Positive Effects of Meditation on Resilience Are Mediated by Changes in the Resting Brain.

While recent studies have explored the maintenance of the effect of meditation on stress resilience, the underlying neural mechanisms have not yet been investigated. The present study conducted a highly controlled residential study of a 4-day meditation intervention to investigate the brain functional changes and long-term effects of meditation on mindfulness and resilience. Thirty participants in meditation practice and 17 participants in a relaxation retreat (control group) underwent magnetic resonance imaging scans at baseline and post-intervention and completed the Cognitive and Affective Mindfulness Scale (CAMS) and Resilience Quotient Test (RQT) at baseline, post-intervention, and the 3-month follow-up. All participants showed increased CAMS and RQT scores post-intervention, but only the meditation group sustained the enhancement after 3 months. Resting-state functional connectivity (rsFC) between the left rostral anterior cingulate cortex (rACC) and the dorsomedial prefrontal cortex (dmPFC), precuneus, and angular gyrus was significantly increased post-intervention in the meditation group compared with the relaxation group. The changes in rACC-dmPFC rsFC mediated the relationship between the changes in the CAMS and RQT scores and correlated with the changes in the RQT score both immediately and at 3 months post-intervention. Our findings suggest that increased rACC-dmPFC rsFC via meditation causes an immediate enhancement in resilience that is sustained. Since resilience is known to be associated with the preventative effect of various psychiatric disorders, the improvement in stress-related neural mechanisms may be beneficial to individuals at high clinical risk.

The Effect of Polydeoxyribonucleotide Extracted from Salmon Sperm on the Restoration of Bisphosphonate-Related Osteonecrosis of the Jaw.

Bisphosphonates (BPs) used for treating skeletal diseases can induce bisphosphonate-related osteonecrosis of the jaw (BRONJ). Despite much effort, effective remedies are yet to be established. In the present study, we investigated the feasibility of polydeoxyribonucleotide (PDRN) extracted from salmon sperm for the treatment of BRONJ, in a BRONJ-induced rat model. Compared with BRONJ-induced samples, PDRN-treated samples exhibited lower necrotic bone percentages and increased numbers of blood vessels and attached osteoclast production. Moreover, local administration of PDRN at a high concentration (8 mg/kg) remarkably resolved the osteonecrosis. Findings from this study suggest that local administration of PDRN at a specific concentration may be considered clinically for the management of BRONJ.

Enhanced Attentional Network by Short-Term Intensive Meditation.

While recent studies have suggested behavioral effects of short-term meditation on the executive attentional functions, functional changes in the neural correlates of attentional networks after short-term meditation have been unspecified. Here, we conducted a randomized control trial to investigate the effects of a 4-day intensive meditation on the neural correlates of three attentional functions: alerting, orienting, and executive attention. Twenty-three participants in meditation practice and 14 participants in a relaxation retreat group performed attention network test (ANT) during functional magnetic resonance imaging both before and immediately after intervention. The meditation group showed significantly improved behavioral performance in the executive control network in ANT after the intervention. Moreover, neural activities in the executive control network, namely, the anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex (DLPFC), were also significantly increased during the ANT after meditation. Interestingly, neural activity in the right ACC was significantly predicted by behavioral conflict levels in each individual in the meditation group, indicating significant effects of the program on the executive control network. Moreover, brain regions associated with the alerting and orienting networks also showed enhanced activity during the ANT after the meditation. Our study provides novel evidence on the enhancement of the attentional networks at the neural level via short-term meditation. We also suggest that short-term meditation may be beneficial to individuals at high risk of cognitive deficits by improving neural mechanisms of attention.

Saccharina japonica Extract Suppresses Stemness of Glioma Stem Cells by Degrading Epidermal Growth Factor Receptor/Epidermal Growth Factor Receptor Variant III.

Cancer stem cells, a small subpopulation of cells with stem cell-like characteristics found within most solid tumors, are widely reported to be responsible for the malignancy of aggressive cancer cells, and targeting these cells presents a sound therapeutic strategy for reducing the risk of tumor relapse. In the present study, we examined the effects of an extract of Saccharina japonica (ESJ) on glioblastoma stem cells (GSCs). Saccharina japonica is a member of the Phaeophyceae (brown algae) family, which displays biological activities, including antitumor effects. ESJ inhibited the sphere-forming ability of GSCs in vitro as evidenced by neurosphere formation and limiting dilution assays. Treatment with ESJ partially induced apoptosis, reduced cell invasiveness, and sensitized GSCs to ionizing radiation. In addition, ESJ inhibited the maintenance of stemness in GSCs by suppressing the expression of epidermal growth factor receptor (EGFR)/EGFR variant III (EGFRvIII) and Notch intracellular domain. Intriguingly, the observed ESJ-induced suppression also appeared to induce the proteasomal degradation of EGFR/EGFRvIII. Our results indicate that ESJ could be considered a potent therapeutic adjuvant that targets GSCs.

The complete chloroplast genome of Codonopsis lanceolata (Campanulaceae).

The complete chloroplast genome sequence of Codonopsis lanceolata was determined by next generation sequencing. The total length of chloroplast genome of C. lanceolata was 169,447 bp long, including a large single-copy (LSC) region of 85,253 bp, a small single-copy (SSC) region of 8060 bp, and a pair of identical inverted repeat regions (IRs) of 38,067 bp. A total of 110 genes was annotated, resulting in 79 protein-coding genes, 27 tRNA genes, and 4 rRNA genes. The phylogenetic analysis of C. lanceolata with related chloroplast genome sequences in this study provided the taxonomical relationship of C. lanceolata in the genus Campanula.

Gold nanorod-photosensitizer conjugates with glutathione-sensitive linkages for synergistic cancer photodynamic/photothermal therapy.

Recently, photodynamic therapy (PDT) has been intensively investigated as a useful modality for the treatment of various cancers. In addition, near infrared (NIR) photothermal therapy (PTT) using gold nanocarriers has attracted particular interest as a hyperthermia strategy. In this study, gold nanorod (AuNR)-photosensitizer conjugates with glutathione-sensitive linkages were designed for PDT and PTT. Several kinds of AuNRs with different aspect ratios were synthesized and modified with FA-conjugated block copolymers (FA-PEG-P(Asp)-DHLA) and Chlorin e6 (Ce6) as a photosensitizer. The surface-modified AuNRs showed excellent stability and solubility in aqueous solution. In particular, FA-PEG-P(Asp)-DHLA-AuNR100-SS-Ce6 with a 3.84 aspect ratio exhibited strong photothermal effects, enhanced singlet oxygen generation, and marked phototoxicity. Based on these results, we suggest that AuNR-photosensitizer conjugates with glutathione-sensitive linkages have potential application in PDT/PTT for effective clinical treatment of various cancers.

Number of daily antihypertensive drugs and the risk of osteoporotic fractures in older hypertensive adults: National health insurance service - Senior cohort.

BACKGROUND: Antihypertensive medication represents one of the most common prescriptions for senior individuals. Numerous studies have assessed the influence of antihypertensive treatment on the risk for osteoporotic fracture, yet much controversy remains. We analyzed the relationship between the incidence of osteoporotic fracture and the average number of daily antihypertensive drugs (NDAD) included in the prescription of elderly hypertensive patients. METHODS: The study population was derived from the National Health Insurance Service-Senior Cohort (2002-2013), and consisted of elderly patients (≥60 years) diagnosed with hypertension in 2009, who did not have osteoporotic fractures in 2008, and underwent at least one national health check-up between 2009 and 2013, and had complete records after 2010. The outcome measured was the incidence of osteoporotic fractures between 2010 and 2013. The study population was stratified into the three groups (low, moderate, and high), in terms of NDAD. RESULTS: A total of 137,304 hypertensive patients were included. A multivariate model corrected by age, gender, body mass index, systolic blood pressure, underlying disease, smoking status, and use of medicines showed that the groups with moderate and high NDAD exhibited, respectively, 12% and 16% lower risk of osteoporotic fracture compared to that in the group with low NDAD. In terms of the risk of osteoporotic fracture associated with the number of daily thiazide diuretics (NDTD), the adjusted odds ratios (aOR; 95%CI) were 0.89 (0.84-0.94) and 0.93 (0.84-1.02) in the groups with moderate and high NDTD, respectively compared to low NDTD as reference. As to NDADnotTD, the aOR (95%CI) were 0.90 (95%CI, 0.86-0.94) and 0.89 (95%CI, 0.84-0.95) in the groups with moderate and high NDADnotTD, respectively compared to low NDADnotTD as reference. CONCLUSION: In elderly hypertensive patients, the incidence of osteoporotic fracture decreased as the NDAD increased. The incidence rate of osteoporotic fracture also decreased with the increase in the number of daily non-thiazide antihypertensive drugs.

The Effect of GCSB-5 a New Herbal Medicine on Changes in Pain Behavior and Neuroglial Activation in a Rat Model of Lumbar Disc Herniation.

OBJECTIVE: Lumbar disc herniation can induce sciatica by mechanical compression and/or chemical irritation. The aim of this study was to compare the effects of GCSB-5 (Shinbaro®) and NSAIDs on pain-related behavior and on the expressions of microglia, astrocytes, CGRP, TRPV1, IL-6, and CX3CL1 in a rat model of lumbar disc herniation. METHODS: 112 male Sprague-Dawley rats underwent implantation of nucleus pulposus to a dorsal root ganglion (DRG). Rats were divided into five groups as follows; a saline group (the vehicle control group) (n=27), a 10 mg/kg aceclofenac group (the aceclofenac group) (n=22), and 100, 300 or 600 mg/kg GCSB-5 groups (the GCSB-5 100, 300, or 600 groups) (n=21 for each group). Rats were tested for mechanical allodynia at 3 days after surgery and at 1 day, 3 days, 7 days, 14 days, 21 days, 28 days, 35 days, 42 days, 49 days, and 56 days after treatment commencement. Immunohistochemical staining of microglia (Iba1), astrocytes (GFAP), CGRP, and TRPV1, and PCR for IL-6 and CX3CL1 were performed on spinal dorsal horns and DRGs at 56 days after medication commencement. RESULTS: After 56 days of GCSB-5 300 administration, mechanical withdrawal thresholds were significantly increased (p<0.05), and immunohisto-chemical expressions of Iba1, GFAP, CGRP, and TRPV1 were reduced than other groups, but this difference was not statistically significant. CONCLUSION: These results indicate GCSB-5 reduces mechanical allodynia and downregulates neuroglial activity and the expressions of CGRP and TRPV1 in the spinal segments of a rat model of lumbar disc herniation.

Pyrithione Zn selectively inhibits hypoxia-inducible factor prolyl hydroxylase PHD3.

Increasing evidence emphasizes the role of the hypoxia-inducible factor (HIF) prolyl hydroxylase (PHD) isoforms in regulating non-HIF substrates, but isoform selective PHD inhibitors under physiological conditions have not yet been reported. Here we have identified pyrithione Zn (PZ) as a potent, isoform-selective PHD3 inhibitor. The IC50 value of PZ was determined as 0.98 µM for PHD3, while it did not show any inhibitory activity toward full length and truncated PHD2 up to 1 mM. The selective efficacy of PZ was further demonstrated at the cellular level by observing inhibition of the PHD3-dependent DNA damage response pathway without stabilization of HIF-1α.