Risk Factors for Anticancer Drug-Induced Hyponatremia: An Analysis Using the Japanese Adverse Drug Report (JADER) Database.

Background and Objectives: Hyponatremia is among the most prevalent electrolyte abnormalities observed in patients with cancer during chemotherapy. Therefore, managing hyponatremia is crucial since it causes a severe electrolyte imbalance that can lead to significant mortality, and this study aimed to investigate the relationship between hyponatremia, anticancer drugs, and cancer types. Materials and Methods: Reported odds ratios were calculated and evaluated based on adverse event reports submitted to the Japanese Adverse Drug Event Report (JADER) database. Results: Overall, 2943 patients had hyponatremia. Notably, cisplatin, pemetrexed, and etoposide had marked hyponatremia signals. In addition, significant hyponatremia signals were detected for oesophageal, lung, and renal cancers. Conclusions: Hyponatremia has been reported in women and patients with lung cancer receiving cisplatin, with a growing trend in the number of elderly patients receiving cisplatin. Furthermore, since the onset of hyponatremia during cisplatin administration is frequently reported within 10 days, patient information should be thoroughly examined before and monitored throughout the administration, which can contribute to the early detection and prevention of hyponatremia.

Assisted Living and Medication Adherence in Super-aged Patients With Heart Failure in the Japanese Population.

ABSTRACT: Poor adherence to medication in patients with heart failure (HF) is associated with poor clinical outcomes. Although social support has been reported to improve medication adherence in patients with HF, the detailed underlying mechanism of this association is unclear. This study investigated appropriate social support types to ensure medication adherence, as well as patient characteristics that benefit from such social support in patients with HF. This was a retrospective observational study investigating the association of social support with medication adherence in 824 patients with HF who were registered in a prospective multicenter database. First, we analyzed the association between social support types and poor medication adherence leading to hospitalization. An interaction analysis was performed to detect patients' characteristics that benefited most from social support in terms of medical adherence. Fifty patients (6.1%) were hospitalized for poor adherence to medications. Multivariable analysis revealed that not receiving assisted living, which was defined as having supporting individuals at least once a week, was independently associated with poor medication adherence-related hospitalization. An interaction analysis revealed that patients with dementia benefited from assisted living significantly, whereas male patients or current smokers did not. Summarily, assisted living at least once a week was appropriate for improving medication adherence in patients with HF and was particularly effective in patients with dementia. Performed in a super-aging region in Japan, this study may also suggest the relevance of social support in preventing HF exacerbation in other developed countries that will experience an aging society in the near future.

Juzentaihoto Suppresses Muscle Atrophy in KKAy Mice.

In obese patients with type 2 diabetes, reduced insulin sensitivity, increased production of inflammatory cytokines, and increased oxidative stress were observed, which lead to decreased protein synthesis and increased proteolysis in the skeletal muscles. Juzentaihoto (JTT) is herbal medicine and we have previously reported that the administration of JTT hot water extract alleviates skeletal muscle atrophy in a mouse model with streptozotocin-induced type 1 diabetes. In this study, we evaluated the inhibitory effects of JTT on muscle atrophy in a mouse model with obesity and type 2 diabetes. JTT was administered to KKAy mice with type 2 diabetic obesity and its effects on the skeletal muscles were evaluated. After JTT administration in KKAy mice, the wet weight and muscle fibre cross-sectional area of gastrocnemius increased and the time duration of exercise in the rotarod test improved. In addition, the serum levels of tumour necrosis factor-α and interleukin-6 decreased, adiponectin levels increased, and homeostasis model assessment for insulin resistance improved. Furthermore, JTT administration decreased the mRNA levels of ubiquitin ligase (atrogin-1, muscle RING-finger protein-1), increased the mRNA levels of Sirtuin1 in gastrocnemius. Our results suggest that JTT improves insulin resistance, suppresses inflammation, and reduces oxidative stress in KKAy mice, thereby suppressing skeletal muscle atrophy. JTT administration in clinical practice is expected to improve muscle atrophy in patients with obesity and type 2 diabetes.

Analysis of Drug-Induced Liver Injury from Bofutsushosan Administration Using Japanese Adverse Drug Event Report (JADER) Database.

Bofutsushosan is a traditional Japanese Kampo medicine. In recent years, it has been reported to be effective in the treatment of lifestyle-related diseases, and its use is increasing. However, side effects from bofutsushosan administration are common, with drug-induced liver injury being the most frequently reported complication. In this study, we analyzed the Japanese Adverse Drug Event Report (JADER) database regarding the occurrence of liver injury after bofutsushosan administration. The results showed that bofutsushosan presented a significant reporting odds ratio (ROR) signal [crude ROR 14, 95% confidence interval (CI) 12-17; p < 0.001], indicating liver injury. Furthermore, the incidents of adverse events following bofutsushosan administration, as recorded in the JADER database, were higher in women aged between 30 and 59 years. The results of logistic regression analysis in patients taking this agent showed that females in the aforementioned age range had higher odds of developing drug-induced liver injury (adjusted ROR 5.5, 95% CI 2.8-11; p < 0.001). Therefore, although bofutsushosan is a useful drug for lifestyle-related diseases, it may be necessary to refrain from its overuse, and caution should be taken during its occasional use to avoid severe adverse events.

Association of Aggression and Antiepileptic Drugs: Analysis Using the Japanese Adverse Drug Event Report (JADER) Database.

Aggression is the most common adverse effect of antiepileptic drugs (AEDs). This study aimed to investigate the association of aggression with AED use. The reporting odds ratio (ROR) from adverse event reports, submitted to the Japanese Adverse Drug Event Report database between 2004 and 2020, was used to calculate and investigate the association between AEDs and aggression. We also analyzed the association of aggression with the combined use of AEDs and the relationship between AED-associated aggression and patient characteristics. A total of 433 patients developed aggression. Significant aggression signals were detected for perampanel (crude ROR: 325.04, 95% confidence interval (CI): 118.48-752.58, p < 0.01), levetiracetam (crude ROR: 17.14, 95% CI: 10.33-26.90, p < 0.01), lacosamide (crude ROR: 16.90, 95% CI: 2.02-62.51, p < 0.01), lamotrigine (crude ROR: 15.98, 95% CI: 9.99-24.39, p < 0.01), valproate (crude ROR: 6.68, 95% CI: 4.27-10.02, p < 0.01), and carbamazepine (crude ROR: 2.47, 95% CI: 1.17-4.59, p < 0.01). The combined therapy with perampanel and levetiracetam had a significant aggression signal (adjusted ROR: 25.90, 95% CI: 1.14-59.10, p < 0.01). In addition, we found that aggression frequently occurred in patients <60 year (adjusted ROR: 2.88, 95% CI: 1.49-5.56, p < 0.01) treated with levetiracetam. These results may be useful for minimizing the risk of aggression during the treatment of AEDs.

Central Nervous System Ischemia Associated with Bevacizumab: An Analysis of the Japanese Adverse Drug Event Report Database.

Bevacizumab is an inhibitor of vascular endothelial growth factor (VEGF) that prevents tumor growth. While bevacizumab is therapeutically effective, it induces several adverse events. Among these, central nervous system (CNS) ischemia can lead to death or permanent disability. In this study, we reviewed the Japanese Adverse Drug Event Report database to analyze the occurrence of CNS ischemia after bevacizumab administration. Significant associations between the occurrence of CNS ischemia and bevacizumab use were detected (adjusted reporting odds ratios (ROR): 2.68, 95% confidence interval (CI): 2.00-3.59, p < 0.001). Furthermore, an association between diagnosis of glioma and bevacizumab use was also detected (p < 0.001). These events occurred early after the start of treatment and then gradually decreased; however, more than half of CNS ischemia events were reported beyond 30 d after the first administration. In addition, a logistic regression suggested that CNS ischemia caused by bevacizumab was associated with glioma, underlying hypertension and aging. A poor prognosis was reported for several cases occurring in elderly patients (over 60 years of age). Although bevacizumab is a useful pharmacological treatment for cancer, caution should be taken to avoid severe adverse events. Accordingly, the patient's general and medical condition should be carefully examined before initiating treatment, and blood pressure should be continuously assessed throughout treatment with bevacizumab to prevent CNS ischemia.

Impact of Gut Microbiota on the Pharmacokinetics of Glycyrrhizic Acid in Yokukansan, a Kampo Medicine.

Individual differences in gut microbiota can affect the pharmacokinetics of drugs. Yokukansan is a traditional Japanese kampo medicine used to treat peripheral symptoms of dementia and delirium. A study examining the pharmacokinetics of the components of yokukansan reported large individual differences in the pharmacokinetics of glycyrrhizic acid (GL). It is known that GL is metabolized by intestinal bacteria to glycyrrhetinic acid (GA), which is absorbed in the gastrointestinal tract. Thus, the gut microbiota may affect GL pharmacokinetics. We aimed to clarify the relationship between the gut microbiota composition and pharmacokinetics of GL in yokukansan. Mice were orally administered yokukansan, following the administration of various antibiotics, and the plasma concentration of GA and composition of gut microbiota were measured. The GA plasma concentration was low in mice treated with amoxicillin and vancomycin. The composition of gut microbiota revealed a different pattern from that of the control group. Mice with low plasma levels of GA had lower levels of the phylum Bacteroides and Firmicutes. Additionally, bacteria, such as those belonging to the genera Parabaceroides, Bacteroides, Ruminococcus and an unknown genus in families Lachnospiraceae and Ruminococcaceae, exerted positive correlations between the gene copies and plasma GA levels. These bacteria may contribute to the absorption of GA in the gastrointestinal tract, and multiple bacteria may be involved in GL pharmacokinetics. The pharmacokinetics of GL may be predicted by evaluating the composition of gut bacteria, rather than by evaluating the amount of a single bacterium.

Adverse Reaction Profiles Related to Gastrointestinal Bleeding Events Associated with BCR-ABL Tyrosine Kinase Inhibitors.

Background and Objectives: The aim of this study is to investigate the characteristics of gastrointestinal bleeding events associated with BCR-ABL tyrosine kinase inhibitor (TKI) treatment, using the reporting odds ratio (ROR) of the adverse event reports submitted to the Japanese Adverse Drug Event Report database between 2004 and 2020, and to examine the number of reported TKI-related gastrointestinal bleeding cases according to sex and age, as well as the actual number of TKI prescriptions issued in Japan. Materials and Methods: The RORs and 95% confidence intervals (CIs) of gastrointestinal bleeding events related to TKIs were calculated using the data of the 595,121 included cases. Results: Significant gastrointestinal bleeding events were detected for dasatinib (crude ROR: 4.47, 95% CI: 3.77-5.28) and imatinib (crude ROR: 1.22, 95% CI: 1.01-1.46). In multiple logistic regression analyses, significant gastrointestinal bleeding events were detected for dasatinib (adjusted ROR: 8.02, 95% CI: 5.75-10.2), imatinib (adjusted ROR: 1.81, 95% CI: 1.2-2.72), age (≥60 years, adjusted ROR: 2.22, 95% CI: 2.1-2.36), reporting year (adjusted ROR: 1.04, 95% CI: 1.04-1.05), and male sex (adjusted ROR: 1.47, 95% CI: 1.37-1.57). Interaction analysis revealed that the association of gastrointestinal bleeding with dasatinib was affected by age (≥60 years) and sex (female), with the number and proportion of dasatinib-related gastrointestinal bleeding cases increasing among those aged ≥60 years. Conclusions: Specific TKIs and patient characteristics were associated with gastrointestinal bleeding. Our results aid the prompt identification and treatment of TKI-related gastrointestinal bleeding.

Juzentaihoto Suppresses Muscle Atrophy and Decreased Motor Function in SAMP8 Mice.

Sarcopenia is a disease whose symptoms include decreased muscle mass and weakened muscle strength with age. In sarcopenia, decreased production of insulin-like growth factor-1 (IGF-1) increases ubiquitin ligases, such as Atrogin1 and Muscle RING-Finger Protein-1 (MuRF1), by activating forkhead box O (FOXO), and inflammatory cytokines and oxidative stress increase the expression of ubiquitin ligases by activating the transcription factor nuclear factor-kappa B (NF-κB). In addition, increased levels of ubiquitin ligases cause skeletal muscle atrophy. Conversely, sirtuin 1 (Sirt1) is known to regulate the expression of ubiquitin ligases by suppressing the activities of NF-κB and FOXO. In this study, we evaluated the effect that juzentaihoto hot water extract (JTT) has on skeletal muscle atrophy and motor function by administering it to senescence-accelerated mouse prone-8 (SAMP8). The group treated with JTT displayed larger gastrocnemius muscle (GA) and extensor digitorum longus (EDL) weights, larger GA muscle fiber cross-sectional areas, and motor function decline during rota-rod tests. JTT also increased IGF-1 serum levels, as well as mRNA Sirt1 levels in GA. Serum levels of tumor necrosis factor-α, interleukin-6, and mRNA levels of Atrogin1 and MuRF1 in GA were reduced by JTT. The muscle fiber cross-sectional area of GA was correlated with the mRNA levels of Sirt1 in GA. The results of this study suggested that JTT administration suppresses skeletal muscle atrophy and motor function decline in SAMP8 mice. This effect may be associated with the increased expression levels of Sirt1 and IGF-1 by JTT.

Risk Factors for Pseudoaldosteronism with Yokukansan Use: Analysis Using the Japanese Adverse Drug Report (JADER) Database.

Yokukansan is a Kampo formula that is commonly used by the elderly because it is expected to improve peripheral symptoms of dementia and delirium. However, side effects from its use are frequently reported in the elderly. In particular, pseudoaldosteronism caused by the licorice contained in yokukansan leads to hypertension, hypokalemia, and muscle weakness, which may result in death. This study aimed to identify the risk factors of pseudoaldosteronism with yokukansan use. Using cases reported in the Japanese Adverse Drug Report (JADER) database, the reporting odds ratio (ROR) was calculated and compared to assess the risk of pseudoaldosteronism for each licorice-containing Kampo formula. We also analyzed the risk factors for pseudoaldosteronism in patients taking yokukansan. Yokukansan (ROR 2.4, 95% confidence interval (CI) 1.9-2.8; p < 0.001) had a higher risk of pseudoaldosteronism than that of other licorice-containing Kampo formulas. Furthermore, the results of a logistic regression analysis in patients taking yokukansan showed that the licorice dose (OR 1.5, 95% CI 1.2-2.0; p < 0.01), older age (<70 years, OR 5.9, 95% CI 1.8-20; p < 0.01), dementia (OR 2.8, 95% CI 1.6-4.9; p < 0.001), low body weight (<50 kg, OR 2.2, 95% CI 1.1-3.5; p = 0.034) were risk factors for pseudoaldosteronism, Although not significant, treatment with loop diuretics (OR 1.8, 95% CI 0.98-3.5; p = 0.059) tended to increase the risk of pseudoaldosteronism. In summary, patients must understand the risk factors when considering taking yokukansan and reduce the licorice dose they consume.

Juzentaihoto Suppresses Muscle Atrophy in Streptozotocin-Induced Diabetic Mice.

In diabetic patients, skeletal muscle atrophy occurs due to increased oxidative stress and inflammation. Skeletal muscle atrophy reduces the QOL of patients and worsens life prognosis. Therefore, development of preventive therapy for muscle atrophy in hyperglycemic state is eagerly awaited. Juzentaihoto is a medicinal herb that has a function to supplement physical strength, and it is expected to prevent muscle atrophy. To determine the preventive effect of juzentaihoto on muscle atrophy in hyperglycemic state, streptozotocin (STZ) was administered to induce diabetes in mice and the preventive effect of juzentaihoto was evaluated. Mice that received juzentaihoto extract (JTT) showed that the decrease in muscle fiber cross-sectional area in the gastrocnemius muscle was reversed. Additionally, the expression level of tumor necrosis factor α (TNF-α), an inflammatory cytokine, in serum decreased, and that of ubiquitin ligase (atrogin-1, muscle RING-finger protein-1) mRNA in skeletal muscle decreased. An anti-inflammatory cytokine interleukin-10 showed increased levels in the serum and increased levels in spleen cell culture supernatant collected from mice that received JTT. JTT had no effect on the blood glucose level. These results suggest that prophylactic administration of JTT to STZ-induced diabetic mice affects immune cells such as in spleen, causing an anti-inflammatory effect and inhibiting excessive activation of the ubiquitin-proteasome system, to reverse muscle atrophy.

Effects of renin-angiotensin system inhibitor and beta-blocker use on mortality in older patients with heart failure with reduced ejection fraction in Japan.

Introduction: Guideline-directed medical therapy with renin-angiotensin system (RAS) inhibitors and beta-blockers has improved the survival of patients with heart failure (HF) and reduced left ventricular ejection fraction (HFrEF). However, it is unclear whether RAS inhibitors and beta-blockers can be administered to older patients with HF. Therefore, this study aimed to investigate the effects of beta-blockers and RAS inhibitors on the prognosis of older patients with HFrEF. Methods: Demographic, clinical, and pharmacological data from 1,061 patients with acute decompensated HF, enrolled in the Kochi Registry of Subjects with Acute Decompensated Heart Failure (Kochi YOSACOI study), were analyzed to assess their impact on mortality. Additionally, a machine learning approach was applied to complement the conventional statistical model for analysis. Patients with HFrEF (n = 314) were divided into the all-cause mortality within 2 years group (n = 80) and the survivor group (n = 234). Results: Overall, 41.1% (129/314) of the patients were aged ≥80, and 25.5% (80/314) experienced all-cause mortality within 2 years. Furthermore, 57.6% (181/314) and 79.0% (248/314) were prescribed RAS inhibitors and beta-blockers, respectively. Our analysis showed that RAS inhibitor use was associated with reduced all-cause mortality and cardiac death in patients with HFrEF of all ages (P < 0.001), and beta-blocker use had an interaction with age. Machine learning revealed that the use of beta-blockers altered the risk of mortality, with a threshold of approximately 80 years of age. Beta-blocker use was associated with lower all-cause mortality and cardiac death in patients with HFrEF aged <80 years (P < 0.001) but not in those aged ≥80 years (P = 0.319 and P = 0.246, respectively). These results suggest that beta blockers may differ in their all-cause mortality benefits according to age. Conclusions: RAS inhibitors prevented all-cause mortality and cardiac death at all ages, whereas beta-blockers had different effects depending on the patient's age. This study suggested that the choice of beta-blockers and RAS inhibitors is more important in older patients with HFrEF than in younger patients with the same condition.

Atractylodes lancea (Thunb.) DC. [Asteraceae] rhizome-derived exosome-like nanoparticles suppress lipopolysaccharide-induced inflammation in murine microglial cells.

Background: Exosome-like nanoparticles (ELNs) mediate interspecies intercellular communications and modulate gene expression. Hypothesis/Purpose: In this study, we isolated and purified ELNs from the dried rhizome of Atractylodes lancea (Thunb.) DC. [Asteraceae] (ALR-ELNs), a traditional natural medicine, and investigated their potential as neuroinflammatory therapeutic agents. Methods: ALR-ELN samples were isolated and purified using differential centrifugation, and their physical features and microRNA contents were analyzed through transmission electron microscopy and RNA sequencing, respectively. BV-2 microglial murine cells and primary mouse microglial cells were cultured in vitro, and their ability to uptake ALR-ELNs was explored using fluorescence microscopy. The capacity of ALR-ELNs to modulate the anti-inflammatory responses of these cells to lipopolysaccharide (LPS) exposure was assessed through mRNA and protein expression analyses. Results: Overall, BV-2 cells were found to internalize ALR-ELNs, which comprised three microRNAs (ath-miR166f, ath-miR162a-5p, and ath-miR162b-5p) that could have anti-inflammatory activity. Pretreatment of BV-2 cells with ALR-ELN prevented the pro-inflammatory effects of LPS stimulation by significantly reducing the levels of nitric oxide, interleukin-1ß, interleukin-6, and tumor necrosis factor-α. Notably, the mRNA levels of Il1b, Il6, iNos, ccl2, and cxcl10 in BV-2 cells, which increased upon LPS exposure, were significantly reduced following ALR-ELN treatment. Moreover, the mRNA levels of heme oxygenase 1, Irf7, ccl12, and Irg1 also increased significantly following ALR-ELN treatment. In addition, pretreatment of primary mouse microglial cells with ALR-ELN prevented the pro-inflammatory effects of LPS stimulation by significantly reducing the levels of nitric oxide. Conclusion: Our findings indicate that ALR-ELNs exhibit anti-inflammatory effects on murine microglial cells. Further validation may prove ALR-ELNs as a promising neuroinflammatory therapeutic agent.

Atractylodes lancea rhizome derived exosome-like nanoparticles prevent alpha-melanocyte stimulating hormone-induced melanogenesis in B16-F10 melanoma cells.

Aberrant melanin overproduction can significantly impact an individual's appearance and cause mental and psychological distress. Current inhibitors of melanin production exert harmful side effects due to inadequate selectivity; thus a need to develop more selective melanin synthesis inhibitors is necessary. Extracellular vesicles are important agents of intercellular signalling in prokaryotes and eukaryotes. Recently, plant-derived nanoparticles, similar to mammalian exosomes, have attracted attention for their use in health research. In this study, to investigate the potential of plant-derived exosome-like nanoparticles (ELNs) as inhibitors of melanin production, we used hot water to extract ELNs from the rhizome of Atractylodes lancea (A-ELNs). The size of A-ENLs ranged from 34 to 401 nm and carried three microRNA: ath-miR166f, ath-miR162a-5p, and ath-miR162b-5p. These A-ENLs were applied to B16-F10 melanoma cells treated with α-melanocyte-stimulating hormone (α-MSH). After A-ELNs were taken up by B16-F10 cells, their melanin levels were significantly reduced. Furthermore, A-ELNs significantly reduced tyrosinase activity in B16-F10 cells and mRNA expression of microphthalmia-associated transcription factor (Mitf), tyrosinase, tyrosinase-related protein 1, and DOPA chrome tautomerase. These results suggest that A-ELN suppresses melanogenic enzymes expression by downregulating Mitf, thereby inhibiting melanin synthesis. Hence, A-ELN can be developed into a novel topical drug after additional studies and optimization.

c-Myc/microRNA-17-92 Axis Phase-Dependently Regulates PTEN and p21 Expression via ceRNA during Reprogramming to Mouse Pluripotent Stem Cells.

Induced pluripotent stem cells (iPSCs) are promising cell sources for regenerative medicine and disease modeling. iPSCs are commonly established by introducing the defined reprogramming factors Oct4, Sox2, Klf4, and c-Myc. However, iPSC reprogramming efficiency remains low. Although recent studies have identified microRNAs that contribute to efficient reprogramming, the underlying molecular mechanisms are not completely understood. miR-17-92 is highly expressed in embryonic stem cells and may play an important role in regulating stem cell properties. Therefore, we examined the role of miR-17-92 in the induction of mouse iPSC production. c-Myc-mediated miR-17-92 upregulation increased reprogramming efficiency, whereas CRISPR/Cas9-based deletion of the miR-17-92 cluster decreased reprogramming efficiency. A combination of in silico and microarray analyses revealed that Pten and cyclin-dependent kinase inhibitor 1 (known as p21) are common target genes of miR-17 and miR-20a, which are transcribed from the miR-17-92 cluster. Moreover, miR-17-92 downregulated p21 in the early phase and PTEN in the mid-to-late phase of reprogramming. These downregulations were perturbed by introducing the 3' UTR of PTEN and p21, respectively, suggesting that PTEN and p21 mRNAs are competing endogenous RNAs (ceRNA) against miR-17-92. Collectively, we propose that the c-Myc-mediated expression of miR-17-92 is involved in iPSC reprogramming through the phase-dependent inhibition of PTEN and p21 in a ceRNA manner, thus elucidating an underlying mechanism of iPSC reprogramming.

Glycyrrhizae Radix suppresses lipopolysaccharide- and diazepam-induced nerve inflammation in the hippocampus, and contracts the duration of pentobarbital- induced loss of righting reflex in a mouse model.

Nerve inflammation is linked to the development of various neurological disorders. This study aimed to examine whether Glycyrrhizae Radix effectively influences the duration of the pentobarbital-induced loss of righting reflex, which may increase in a mouse model of lipopolysaccharide (LPS)-induced nerve inflammation and diazepam-induced γ-aminobutyric acid receptor hypersensitivity. Furthermore, we examined the anti-inflammatory effects of Glycyrrhizae Radix extract on LPS-stimulated BV2 microglial cells, in vitro. Treatment with Glycyrrhizae Radix significantly decreased the duration of pentobarbital-induced loss of righting reflex in the mouse model. Furthermore, treatment with Glycyrrhizae Radix significantly attenuated the LPS-induced increases in interleukin-1ß, interleukin-6, and tumor necrosis factor-alpha at the mRNA level, and it significantly reduced the number of ionized calcium-binding adapter molecule-1-positive cells in the hippocampal dentate gyrus 24 h after LPS treatment. Treatment with Glycyrrhizae Radix also suppressed the release of nitric oxide, interleukin-1ß, interleukin-6, and tumor necrosis factor protein in culture supernatants of LPS-stimulated BV2 cells. In addition, glycyrrhizic acid and liquiritin, active ingredients of Glycyrrhizae Radix extract, reduced the duration of pentobarbital-induced loss of righting reflex. These findings suggest that Glycyrrhizae Radix, as well as its active ingredients, glycyrrhizic acid and liquiritin, may be effective therapeutic agents for the treatment of nerve inflammation-induced neurological disorders.

Exosome-like nanoparticles derived from Allium tuberosum prevent neuroinflammation in microglia-like cells.

OBJECTIVE: Exosome-like nanoparticles (ELNs), which are plant-derived extracellular membrane vesicles, can regulate mammalian gene expression. ELNs can cross the blood-brain barrier, making them potential therapeutic agents or drug-delivery carriers for neuroinflammation-related diseases. Here, we investigated the anti-neuroinflammatory potential of ELNs extracted from Allium tuberosum (A-ELNs). METHODS: A-ELNs were extracted, and their miRNA profile was characterized. A-ELNs were also applied to BV-2 microglial and MG-6 cells derived from C57/BL6 mice stimulated with lipopolysaccharide (LPS), followed by an examination of levels of inflammatory-related factors. To test their drug-carrying potential, A-ELNs were mixed with dexamethasone, an anti-inflammatory drug, to prepare dexamethasone-incorporated A-ELNs (Dex-A-ELNs). KEY FINDINGS: A-ELNs showed a particle size of 145 ± 2 nm and characteristic miRNAs. A-ELNs significantly decreased the LPS-induced nitric oxide (NO) and inflammatory cytokines levels in BV-2 and MG-6 cells. The mRNA expression of heme oxygenase-1 was significantly increased, and that of inducible NO synthase and inflammatory cytokines was significantly decreased by A-ELNs in BV-2 cells. Dex-A-ELNs inhibited NO production in BV-2 cells more potently than either A-ELNs or dexamethasone alone. CONCLUSION: A-ELNs can alleviate microglial inflammation. Their effects can be potentiated by incorporating anti-inflammatory drugs, such as dexamethasone, making them potential therapeutic agents or drug-delivery carriers for neuroinflammation.

Canonical Wnt signaling activation by chimeric antigen receptors for efficient cardiac differentiation from mouse embryonic stem cells.

BACKGROUND: Canonical Wnt signaling is involved in a variety of biological processes including stem cell renewal and differentiation, embryonic development, and tissue regeneration. Previous studies reported the stage-specific roles of the Wnt signaling in heart development. Canonical Wnt signal activation by recombinant Wnt3a in the early phase of differentiation enhances the efficiency of myocardial cell production from pluripotent stem cells. However, the hydrophobicity of Wnt proteins results in high cost to produce the recombinant proteins and presents an obstacle to their preparation and application for therapeutics, cell therapy, or molecular analysis of Wnt signaling. METHODS: To solve this problem, we generated an inexpensive molecule-responsive differentiation-inducing chimeric antigen receptor (designated as diCAR) that can activate Wnt3a signaling. The extracellular domains of low-density-lipoprotein receptor-related protein 6 (LRP6) and frizzeled-8 (FZD8) were replaced with single-chain Fv of anti-fluorescein (FL) antibody, which can respond to FL-conjugated bovine serum albumin (BSA-FL) as a cognate ligand. We then analyzed the effect of this diCAR on Wnt signal activation and cardiomyocyte differentiation of mouse embryonic stem cells in response to BSA-FL treatment. RESULTS: Embryonic stem cell lines stably expressing this paired diCAR, named Wnt3a-diCAR, showed TCF/ß-catenin-dependent transactivation by BSA-FL in a dose-dependent manner. Treatment with either Wnt3a recombinant protein or BSA-FL in the early phase of differentiation revealed similar changes of global gene expressions and resulted in efficient myocardial cell differentiation. Furthermore, BSA-FL-mediated signal activation was not affected by a Wnt3a antagonist, Dkk1, suggesting that the signal transduction via Wnt3a-diCAR is independent of endogenous LRP6 or FZD8. CONCLUSION: We anticipate that Wnt3a-diCAR enables target-specific signal activation, and could be an economical and powerful tool for stem cell-based regeneration therapy.

[Development and Assessment of a New Oral Selenium Fast-disintegrating Tablets].

Selenium is an essential trace element and its deficiency causes myositis, myocardial damage, and other symptoms. Patients receiving long-term intravenous nutrition or tube-feeding in particular are deficient in essential trace elements, including selenium, and require regular supplementation. In Japan, injectable selenium-containing products are listed on the National Health Insurance drug price list, and oral solutions are prepared and used in hospitals. However, these formulations have problems related to preservation and require complicated administration procedures. In this study, we developed a new fast-disintegrating tablet formulation of selenium, using SmartEx® (D-mannitol·low substituted hydroxypropylcellulose (L-HPC)·fully hydrolyzed polyvinyl alcohol (PVA) mixture) as a coprocessing additive, that can be administered orally or by feeding tube. The tablet formulation had excellent disintegrable capability, sufficient hardness, and did not cause tube blockage when administered in the simple suspension method. In addition, the tablet formulation showed no changes in properties in an accelerated test without packaging for 42 d, indicating that it could be stored for a long period. Fast-disintegrating tablets prepared with SmartEx® are expected to improve the adherence and quality of life of patients who require selenium supplementation.

Saikokeishikankyoto extract alleviates muscle atrophy in KKAy mice.

Sarcopenic obesity is associated with increased visceral fat and decreased muscle mass, resulting in decreased insulin sensitivity, increased production of inflammatory cytokines, and oxidative stress. In this study, we first evaluated the effects of herbal medicines on the transcriptional activity of the Sirtuin 1 (sirt1) promoter in vitro as an indicator of their therapeutic effect. Our data suggested that hot water Saikokeishikankyoto (SKK) extracts increased sirt1 transcriptional activity in vitro, identifying it as a candidate therapeutic for evaluation in the KKAy type 2 diabetic obesity mouse model. These in vivo evaluations revealed that SKK treatment increased the wet weight and muscle fiber content in cross sections of the gastrocnemius muscle (GA) and restored motor function in these animals. In addition, SKK treatment reduced tumor necrosis factor-α (TNFα) expression in the sera and suppressed Atrogin1 and MuRF1 transcription in the GA samples. This treatment also increased sirt1 expression in these tissues. These results suggest that SKK inhibits skeletal muscle atrophy and improves motor function in KKAy mice by suppressing inflammation. In actual clinical practice, SKK is expected to inhibit muscle atrophy and improve motor dysfunction in sarcopenic obesity.