Comparison of the pharmacokinetic characteristics and bioequivalence between two nanosuspension formulations of megestrol acetate in healthy Korean male subjects.

Megestrol is commonly used to address appetite loss, cachexia, and significant weight loss in cancer or acquired immune deficiency syndrome patients. This study aimed to assess the pharmacokinetics and determine the bioequivalence of two orally administered megestrol acetate suspensions (625 mg/5 mL) in healthy Korean male subjects. A randomized, open-label, single-dose crossover study was conducted involving fifty-four healthy male subjects who were randomized into two sequence groups. Each subject received either a test or reference drug formulation of 625 mg/5 mL megestrol acetate with a two-week washout period between treatments. Plasma samples were collected before and up to 120 hours after administration, and their plasma drug concentrations were analyzed using validated liquid chromatography-mass spectrometry/mass spectrometry. The pharmacokinetic parameters were calculated, and bioequivalence was confirmed if the 90% confidence intervals of the geometric mean ratios were within the specified bounds of 80.00% to 125.00%. In total, fifty-two subjects completed the study, contributing to the pharmacokinetic analysis. The 90% confidence intervals for the geometric mean ratios of the test formulation compared to the reference formulation were 93.85% to 108.90% for maximum plasma concentration and 91.60% to 101.78% for area under the concentration-time curve from the point of administration to last time point of blood sampling. Throughout the study, no serious or unexpected adverse events were observed. The pharmacokinetic profiles of both formulations of megestrol acetate (625 mg) were comparable and well tolerated in healthy Korean male adult subjects. The test formulation met regulatory criteria for bioequivalence. Trial Registration: ClinicalTrials.gov Identifier: NCT06147908.

Carprofen alleviates Alzheimer-like phenotypes of 5XFAD transgenic mice by targeting the pathological hallmarks induced by amyloid-ß aggregation.

Alzheimer's disease (AD) is characterized by misfolding, oligomerization, and accumulation of amyloid-ß (Aß) peptides in the brain. Aß monomers transform into Aß oligomers, which are toxic species, inducing tau hyperphosphorylation and the downstream effects on microglia and astrocytes, triggering synaptic and cognitive dysfunctions. The oligomers then deposit into Aß plaques, primarily composed of ß-stranded fibrils, required for definitive AD diagnosis. As amyloid burden plays the pivotal role in AD pathogenesis, many efforts are devoted in preventing amyloidosis as a therapeutic approach to impede the disease progression. Here, we discovered carprofen, a non-steroidal anti-inflammatory drug, accelerates Aß aggregating into fibrils and increases Aß plaques when intraperitoneally injected to 5XFAD transgenic mouse model. However, the drug seems to alleviate the key Alzheimer-like phenotypes induced by Aß aggregation as we found attenuated neuroinflammation, improved post-synaptic density expression, associated with synaptic plasticity, and decreased phosphorylated tau levels. Carprofen also rescued impaired working memory as we discovered improved spontaneous alternation performance through Y-maze test assessed with Aß(1-42)-infused mouse model. Collectively, while carprofen accelerates the conversion of Aß monomers into fibrils in vitro, the drug ameliorates the major pathological hallmarks of AD in vivo.

Aryloxypropanolamine targets amyloid aggregates and reverses Alzheimer-like phenotypes in Alzheimer mouse models.

BACKGROUND: Aggregated amyloid-ß (Aß) is considered a pathogenic initiator of Alzheimer's disease (AD), in strong association with tau hyperphosphorylation, neuroinflammation, synaptic dysfunction, and cognitive decline. As the removal of amyloid burden from AD patient brains by antibodies has shown therapeutic potential, the development of small molecule drugs inducing chemical dissociation and clearance of Aß is compelling as a therapeutic strategy. In this study, we synthesized and screened aryloxypropanolamine derivatives and identified 1-(3-(2,4-di-tert-pentylphenoxy)-2-hydroxypropyl)pyrrolidin-1-ium chloride, YIAD002, as a strong dissociator of Aß aggregates. METHODS: The dissociative activity of aryloxypropanolamine derivatives against Aß aggregates were evaluated through in vitro assays. Immunohistochemical staining, immunoblot assays, and the Morris water maze were used to assess the anti-Alzheimer potential in YIAD002-treated 5XFAD and transgenic APP/PS1 mice. Target-ligand interaction mechanism was characterized via a combination of peptide mapping, fluorescence dissociation assays, and constrained docking simulations. RESULTS: Among 11 aryloxypropanolamine derivatives, YIAD002 exerted strongest dissociative activity against ß-sheet-rich Aß aggregates. Upon oral administration, YIAD002 substantially reduced amyloid burden and accordingly, improved cognitive performance in the Morris water maze and attenuated major pathological hallmarks of AD including tauopathy, neuroinflammation, and synaptic protein loss. Mechanism studies suggest that YIAD002 interferes with intermolecular ß-sheet fibrillation by directly interacting with KLVFFA and IGLMVG domains of Aß. In addition, YIAD002 was found to possess dissociative activity against aggregates of pyroglutamate-modified Aß and tau. CONCLUSIONS: Collectively, our results evince the potential of chemical-driven dissociation of Aß aggregates by aryloxypropanolamines as a therapeutic modality of the amyloid clearance approach.

Chemical-Driven Outflow of Dissociated Amyloid Burden from Brain to Blood.

Amyloid-ß (Aß) deposition in the brain is a primary biomarker of Alzheimer's disease (AD) and Aß measurement for AD diagnosis mostly depends on brain imaging and cerebrospinal fluid analyses. Blood Aß can become a reliable surrogate biomarker if issues of low concentration for conventional laboratory instruments and uncertain correlation with brain Aß are solved. Here, brain-to-blood efflux of Aß is stimulated in AD transgenic mice by orally administrating a chemical that dissociates amyloid plaques and observing the subsequent increase of blood Aß concentration. 5XFAD transgenic and wild-type mice of varying ages and genders are prepared, and blood samples of each mouse are collected six times for 12 weeks; three weeks of no treatment and additional nine weeks of daily oral administration, ad libitum, of Aß plaque-dissociating chemical agent. By the dissociation of Aß aggregates, the altered levels of plasma Aß distinguish between transgenic and wild-type mice, displaying potential as an amyloid burden marker of AD brains.

Long-term efficacy and feasibility of levonorgestrel-releasing intrauterine device use in patients with adenomyosis.

To evaluate the efficacy and feasibility of levonorgestrel-releasing intrauterine device (LNG-IUD) use longer than 5 years in women with adenomyosis.Data were retrospectively collected from patients who were treated with LNG-IUD longer than 5 years at the Chungnam National University hospital for adenomyosis diagnosed with ultrasonography from January 2006 to November 2013.A total of 131 patients who were diagnosed with adenomyosis had treated with LNG-IUD longer than 5 years. The mean duration of keeping 1 device without replacement was 58.35 ±â€Š15.98 months, and total duration of LNG-IUD treatment was 83.86 ±â€Š23.88 months. A total of 51 patients stopped using LNG-IUD after 5 years and the mean age at the time of LNG-IUD removal was 52.46 ±â€Š6.9. LNG-IUD treatment had a significant effect on both menorrhagia and dysmenorrhea starting from the first month of insertion (P < .01), which persisted until 6 years when the effect started to plateau. The decrease in uterine volume was not consistent during the treatment period. The uterine volume decreased significantly only in the first and second year of LNG-IUD treatment and then from eighth to tenth year of LNG-IUD treatment (P < .05). Adverse events after insertion of LNG-IUD decreased significantly after 5 years.LNG-IUD treatment longer than 5 years is an effective and feasible method for patients diagnosed with adenomyosis.

Factors associated with poor sleep quality in the Korean general population: Providing information from the Korean version of the Pittsburgh Sleep Quality Index.

BACKGROUND: Recently, studies have been conducted to address the research gap in the understanding of poor-quality sleep and its relationship to health outcomes, through the evaluation of sleep quality. The aim of this study was to provide information regarding poor sleep quality based on a nationwide general population sample in Korea. METHODS: We conducted a cross-sectional study using data from a nationwide sample of 165,193 individuals (males: 44%) aged 19 years or older from the 2018 Korea Community Health Survey. The age range of the participants was 19-107 years (mean: 55.3 ± 17.5). The Korean version of the Pittsburgh Sleep Quality Index (PSQI) was used for assessing sleep quality. Poor sleep quality was defined as a total PSQI score of >5. RESULTS: The overall prevalence of poor sleepers was 41.0% (males: 35.6%; females: 46.2%). Poor sociodemographic status (illiteracy, low income, and unemployment), poor health behaviors (smoking, high-risk drinking, diabetes, hypertension, non-participation in walking, and obesity), and poor mental health (perceived poor health status, stress, depressive symptoms, and subjective cognitive decline) were all associated with poor sleep quality in both males and females. LIMITATIONS: As this study relies on self-reported and cross-sectional data, causal inferences cannot be made. CONCLUSIONS: Poor sleep quality is highly prevalent in females. In addition, poor socio-demographic status, poor health behaviors, and poor mental health were associated with poor sleep quality. The mechanisms underlying sex differences in sleep quality remain to be elucidated, and further studies are required to address this.

Glucosylceramide synthase regulates adipo-osteogenic differentiation through synergistic activation of PPARγ with GlcCer.

Dysregulation of the adipo-osteogenic differentiation balance of mesenchymal stem cells (MSCs), which are common progenitor cells of adipocytes and osteoblasts, has been associated with many pathophysiologic diseases, such as obesity, osteopenia, and osteoporosis. Growing evidence suggests that lipid metabolism is crucial for maintaining stem cell homeostasis and cell differentiation; however, the detailed underlying mechanisms are largely unknown. Here, we demonstrate that glucosylceramide (GlcCer) and its synthase, glucosylceramide synthase (GCS), are key determinants of MSC differentiation into adipocytes or osteoblasts. GCS expression was increased during adipogenesis and decreased during osteogenesis. Targeting GCS using RNA interference or a chemical inhibitor enhanced osteogenesis and inhibited adipogenesis by controlling the transcriptional activity of peroxisome proliferator-activated receptor γ (PPARγ). Treatment with GlcCer sufficiently rescued adipogenesis and inhibited osteogenesis in GCS knockdown MSCs. Mechanistically, GlcCer interacted directly with PPARγ through A/B domain and synergistically enhanced rosiglitazone-induced PPARγ activation without changing PPARγ expression, thereby treatment with exogenous GlcCer increased adipogenesis and inhibited osteogenesis. Animal studies demonstrated that inhibiting GCS reduced adipocyte formation in white adipose tissues under normal chow diet and high-fat diet feeding and accelerated bone repair in a calvarial defect model. Taken together, our findings identify a novel lipid metabolic regulator for the control of MSC differentiation and may have important therapeutic implications.

Phospholipase C-ß1 potentiates glucose-stimulated insulin secretion.

PLC-ß exerts biologic influences through GPCR. GPCRs are involved in regulating glucose-stimulated insulin secretion (GSIS). Previous studies have suggested that PLC-ßs might play an important role in pancreatic ß cells. However, because of a lack of the specific inhibitors of PLC-ß isozymes and appropriate genetic models, the in vivo function of specific PLC-ß isozymes in pancreatic ß cells and their physiologic relevance in the regulation of insulin secretion have not been studied so far. The present study showed that PLC-ß1 was crucial for ß-cell function by generation of each PLC-ß conditional knockout mouse. Mice lacking PLC-ß1 in ß cells exhibited a marked defect in GSIS, leading to glucose intolerance. In ex vivo studies, the secreted insulin level and Ca2+ response in Plcb1f/f; pancreas/duodenum homeobox protein 1 (Pdx1)-Cre recombinase-estrogen receptor T2 (CreERt2) islets was lower than those in the Plcb1f/f islets under the high-glucose condition. PLC-ß1 led to potentiate insulin secretion via stimulation of particular Gq-protein-coupled receptors. Plcb1f/f; Pdx1-CreERt2 mice fed a high-fat diet developed more severe glucose intolerance because of a defect in insulin secretion. The present study identified PLC-ß1 as an important molecule that regulates ß cell insulin secretion and can be considered a candidate for therapeutic intervention in diabetes mellitus.-Hwang, H.-J., Yang, Y. R., Kim, H. Y., Choi, Y., Park, K.-S., Lee, H., Ma, J. S., Yamamoto, M., Kim, J., Chae, Y. C., Choi, J. H., Cocco, L., Berggren, P.-O., Jang, H.-J., Suh, P.-G. Phospholipase Cß1 potentiates glucose-stimulated insulin secretion.

TNF-α increases the intrinsic excitability of cerebellar Purkinje cells through elevating glutamate release in Bergmann Glia.

For decades, the glial function has been highlighted not only as the 'structural glue', but also as an 'active participant' in neural circuits. Here, we suggest that tumor necrosis factor α (TNF-α), a key inflammatory cytokine, alters the neural activity of the cerebellar Purkinje cells (PCs) by facilitating gliotransmission in the juvenile male rat cerebellum. A bath application of TNF-α (100 ng/ml) in acute cerebellar slices elevates spiking activity of PCs with no alterations in the regularity of PC firings. Interestingly, the effect of TNF-α on the intrinsic excitability of PCs was abolished under a condition in which the type1 TNF receptor (TNFR1) in Bergmann glia (BG) was genetically suppressed by viral delivery of an adeno-associated virus (AAV) containing TNFR1-shRNA. In addition, we measured the concentration of glutamate derived from dissociated cerebellar cortical astrocyte cultures treated with TNF-α and observed a progressive increase of glutamate in a time-dependent manner. We hypothesised that TNF-α-induced elevation of glutamate from BGs enveloping the synaptic cleft may directly activate metabotropic glutamate receptor1 (mGluR1). Pharmacological inhibition of mGluR1, indeed, prevented the TNF-α-mediated elevation of the intrinsic excitability in PCs. Taken together, our study reveals that TNF-α triggers glutamate release in BG, thereby increasing the intrinsic excitability of cerebellar PCs in a mGluR1-dependent manner.

ERK-mediated phosphorylation of BIS regulates nuclear translocation of HSF1 under oxidative stress.

B-cell lymphoma (BCL)-2-interacting cell death suppressor (BIS) has diverse cellular functions depending on its binding partners. However, little is known about the effects of biochemical modification of BIS on its various activities under oxidative stress conditions. In this study, we showed that H2O2 reduced BIS mobility on SDS-polyacrylamide gels in a time-dependent manner via the activation of extracellular signaling-regulated kinase (ERK). The combined results of mass spectroscopy and computational prediction identified Thr285 and Ser289 in BIS as candidate residues for phosphorylation by ERK under oxidative stress conditions. Deletion of these sites resulted in a partial reduction in the H2O2-induced mobility shift relative to that of the wild-type BIS protein; overexpression of the deletion mutant sensitized A172 cells to H2O2-induced cell death without increasing the level of intracellular reactive oxygen species. Expression of the BIS deletion mutant decreased the level of heat shock protein (HSP) 70 mRNA following H2O2 treatment, which was accompanied by impaired nuclear translocation of heat shock transcription factor (HSF) 1. Co-immunoprecipitation assays revealed that the binding of wild-type BIS to HSF1 was decreased by oxidative stress, while the binding of the BIS deletion mutant to HSF1 was not affected. These results indicate that ERK-dependent phosphorylation of BIS has a role in the regulation of nuclear translocation of HSF1 likely through modulation of its interaction affinity with HSF1, which affects HSP70 expression and sensitivity to oxidative stress.

Bis Expression in Patients with Surgically Resected Lung Cancer and its Clinical Significance.

BACKGROUND: Bis, also known as BAG3, has been identified as a Bcl-2-interacting protein that enhances cellular anti-apoptotic activity. It is involved in cellular differentiation, angiogenesis, migration, and invasion in various tumors. The purpose of this study was to investigate the Bis expression pattern, and the clinical significance thereof, in patients with resected lung cancer. METHODS: We studied 121 lung cancer patients who underwent curative surgical resection. Patient clinicopathological characteristics were reviewed retrospectively from medical records, including tumor recurrence and survival. The expression of Bis protein in lung cancer tissues was evaluated by immunohistochemical staining and was assessed using a four-tiered intensity score system (negative, weak, moderate, strong). Enhanced Bis expression at the periphery of a tumor facing the adjacent nontumor region was referred as "marginal activity." RESULTS: Although Bis expression was higher in squamous cell carcinoma than in adenocarcinoma, marginal activity was higher in adenocarcinoma than in squamous cell carcinoma. All of the small cell carcinomas and lung cancer with neuroendocrine differentiation examined were negative for Bis expression. Compared with stage I lung cancer, patients with stage II and IIIA lung cancer exhibited higher Bis protein levels in lung tissues. Recurrence and survival rates did not differ significantly according to Bis expression intensity score or marginal activity. CONCLUSIONS: Our study demonstrated that Bis expression differed according to the histological type and pathological stage of the lung cancer. Further studies are needed to assess its use as a biomarker and its role in the molecular pathogenesis of lung cancer.

Taurine in drinking water recovers learning and memory in the adult APP/PS1 mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is a lethal progressive neurological disorder affecting the memory. Recently, US Food and Drug Administration mitigated the standard for drug approval, allowing symptomatic drugs that only improve cognitive deficits to be allowed to accelerate on to clinical trials. Our study focuses on taurine, an endogenous amino acid found in high concentrations in humans. It has demonstrated neuroprotective properties against many forms of dementia. In this study, we assessed cognitively enhancing property of taurine in transgenic mouse model of AD. We orally administered taurine via drinking water to adult APP/PS1 transgenic mouse model for 6 weeks. Taurine treatment rescued cognitive deficits in APP/PS1 mice up to the age-matching wild-type mice in Y-maze and passive avoidance tests without modifying the behaviours of cognitively normal mice. In the cortex of APP/PS1 mice, taurine slightly decreased insoluble fraction of Aß. While the exact mechanism of taurine in AD has not yet been ascertained, our results suggest that taurine can aid cognitive impairment and may inhibit Aß-related damages.

Discovery of thienopyrimidine-based FLT3 inhibitors from the structural modification of known IKKß inhibitors.

Inactivation of the NF-κB signaling pathway by inhibition of IKKß is a well-known approach to treat inflammatory diseases such as rheumatoid arthritis and cancer. Thienopyrimidine-based analogues were designed through modification of the known IKKß inhibitor, SPC-839, and then biologically evaluated. The resulting analogues had good inhibitory activity against both nitric oxide and TNF-α, which are well-known inflammatory responses generated by activated NF-κB. However, no inhibitory activity against IKKß was observed with these compounds. The thienopyrimidine-based analogues were subsequently screened for a target kinase, and FLT3, which is a potential target for acute myeloid leukemia (AML), was identified. Thienopyrimidine-based FLT3 inhibitors showed good inhibition profiles against FLT3 under 1µM. Overall, these compounds represent a promising family of inhibitors for future development of a treatment for AML.

Down-modulation of Bis reduces the invasive ability of glioma cells induced by TPA, through NF-κB mediated activation of MMP-9.

Bcl-2 interacting cell death suppressor (Bis) has been shown to have anti-apoptotic and anti-stress functions. Recently, increased Bis expression was reported to correlate with glioma aggressiveness. Here, we investigated the effect of Bis knockdown on the acquisition of the invasive phenotype of A172 glioma cells, induced by 12-O-Tetradecanoylphorbol-3-acetate (TPA), using a Transwell assay. Bis knockdown resulted in a significant decrease in the migration and invasion of A172 cells. Furthermore, Bis knockdown notably decreased TPA-induced matrix metalloproteinase-9 (MMP-9) activity and mRNA expression, as measured by zymography and quantitative real time PCR, respectively. A luciferase reporter assay indicated that Bis suppression significantly down-regulated NF-κB-driven transcription. Finally, we demonstrated that the rapid phosphorylation and subsequent degradation of IκB-α induced by TPA was remarkably delayed by Bis knockdown. These results suggest that Bis regulates the invasive ability of glioma cells elicited by TPA, by modulating NF-κB activation, and subsequent induction of MMP-9 mRNA.

Therapeutic and pharmacokinetic characterizations of an anti-amyloidogenic bis-styrylbenzene derivative for Alzheimer's disease treatment.

Alzheimer's disease drug discovery regarding exploration into the molecules and processes has focused on the intrinsic causes of the brain disorder correlated with the accumulation of amyloid-ß. An anti-amyloidogenic bis-styrylbenzene derivative, KMS80013, showed excellent oral bioavailability (F=46.2%), facilitated brain penetration (26%, iv) in mouse and target specific in vivo efficacy in acute AD mouse model attenuating the cognitive deficiency in Y-maze test. Acute toxicity (LD50 >2000 mg/kg) and hERG channel inhibition (14% at 10 µM) results indicated safety of KMS80013.

Amelioration of Alzheimer's disease by neuroprotective effect of sulforaphane in animal model.

Pathophysiological evidences of AD have indicated that aggregation of Aß is one of the principal causes of neuronal dysfunction, largely by way of inducing oxidative stresses such as free radical formation. We hypothesized that the known antioxidative attribute of SFN could be harnessed in Alzheimer's treatment. SFN is an indirect, potent antioxidant derived from broccoli that has previously been found to stimulate the Nrf2-ARE pathway and facilitate several other cytoprotective mechanisms. In this study, administration of SFN ameliorated cognitive function of Aß-induced AD acute mouse models in Y-maze and passive avoidance behavior tests. Interestingly, we found that the therapeutic effect of SFN did not involve inhibition of Aß aggregation. While the exact mechanism of interaction of SFN in AD has not yet been ascertained, our results suggest that SFN can aid in cognitive impairment and may protect the brain from amyloidogenic damages.

Efficient access to highly pure ß-amyloid peptide by optimized solid-phase synthesis.

Feasible and reproducible synthesis of full-length Aß peptides has been one of the major challenges in Alzheimer's disease research. By using dimethyl sulfoxide as an anti-aggregation solvent and as an agent to promote double-coupling of two phenylalanine that frequently experience residual deletion, we developed a reliable manual Fmoc solid phase peptide synthesis procedure to produce biologically active Aß in large quantities at relatively high purity. The amyloidogenic activity of the synthesized Aß was confirmed via thioflavin T assay, transmission electron microscopic analysis and electrophoresis.

A case of rheumatoid meningitis: pathologic and magnetic resonance imaging findings.

Central nervous system (CNS) involvement is extremely rare in patients with rheumatoid arthritis (RA). Additionally, most patients with CNS involvement have chronic and severe RA. We present a report of a 66-year-old man who was diagnosed with rheumatoid meningitis and CNS vasculitis without a history of RA. His initial symptom was seizure. Brain magnetic resonance imaging showed leptomeningeal enhancement.CSF analysis revealed slight increase in the number of white blood cells. An examination of viral markers and culture studies for infectious etiology were unremarkable. However, the rheumatoid factor was positive and the levels of anti-cyclic citrullinated peptide antibody were very high. The patient was diagnosed with rheumatoid meningitis and received steroid therapy. However, he developed CNS vasculitis. We suggested that the possibility of rheumatoid meningitis should be considered during the differential diagnosis stage in patients with uncontrolled meningitis, even though RA does not typically show CNS involvement.

Magnetic resonance imaging of pachymeningeal enhancement in Vogt-Koyanagi-Harada disease.

Vogt-Koyanagi-Harada (VKH) disease is a systemic disease consisting of bilateral granulomatous panuveitis combined with cutaneous and neurologic manifestations. However, there have been few reports of brain magnetic resonance imaging (MRI) in VKH disease. A 54-year-old Korean woman presented with severe periorbital pain, blurred vision and meningismus. Ophthalmologic examination disclosed bilateral optic disc edema with peripapillary nerve fiber hemorrhages. Lumbar puncture revealed monocytic pleocytosis. After a diagnosis of VKH disease was made, the patient was treated with high-dose corticosteroid. Brain MRI showed diffusely thickened posterior ocular walls with retinal detachment and perineural infiltrative changes along the optic nerves and adjacent pachymeningeal enhancement of the anterior temporal lobes bilaterally. We report a case of VKH disease with panuveitis and meningeal involvement of the anterior temporal lobe detected by brain MRI.