Two Onnamide Analogs from the Marine Sponge Theonella conica: Evaluation of Geometric Effects in the Polyene Systems on Biological Activity.

Two previously unreported onnamide analogs, 2Z- and 6Z-onnamides A (1 and 2), were isolated from the marine sponge Theonella conica collected at Amami-Oshima Is., Kagoshima Prefecture, Japan. Structures of compounds 1 and 2 were elucidated by spectral analysis. Structure-activity relationships (SARs) for effects on histone modifications and cytotoxicity against HeLa and P388 cells were characterized. The geometry in the polyene systems of onnamides affected the histone modification levels and cytotoxicity.

Marine pharmacology in 2018: Marine compounds with antibacterial, antidiabetic, antifungal, anti-inflammatory, antiprotozoal, antituberculosis and antiviral activities; affecting the immune and nervous systems, and other miscellaneous mechanisms of action.

The 2018 marine pharmacology literature review represents a continuation of the previous 11 reviews of a series initiated in 1998. Preclinical marine pharmacology research during 2018 was performed by investigators in 44 countries and contributed novel pharmacology for 195 marine compounds. The peer-reviewed marine natural products pharmacology literature reported antibacterial, antifungal, antiprotozoal, antituberculosis, and antiviral activities for 53 compounds, 73 compounds which presented antidiabetic and anti-inflammatory activities as well as affecting the immune and nervous system, while in contrast 69 compounds were reported to show miscellaneous mechanisms of action which may contribute upon further investigation to several pharmacological classes. Thus, in 2018, the preclinical marine natural product pharmacology pipeline continued to report novel pharmacology as well as new lead compounds for the clinical marine pharmaceutical pipeline, which currently contributes to therapeutic strategies for several disease categories.

Coronarin D, a Metabolite from the Wild Turmeric, Curcuma aromatica, Promotes the Differentiation of Neural Stem Cells into Astrocytes.

Plants in the genus Curcuma have been widely used as traditional medicines in Asian countries. These plants contain bioactive compounds with neuroprotective properties or activities that increase neural stem cells (NSCs) and neurons. However, bioactive components in Curcuma that promote the differentiation of NSCs into astrocytes have not yet been reported. Here, the effects of Curcuma extracts on the in vitro differentiation of embryonic stem-cell-derived NSCs were evaluated. The extract of the wild turmeric, Curcuma aromatica, strongly promoted the differentiation of NSCs into astrocytes. Bioassay-guided isolation yielded coronarins C (1) and D (2), as well as (E)-labda-8(17),12-diene-15,16-dial (3) as the bioactive compounds. Coronarin D (2) markedly promoted the differentiation of NSCs into astrocytes up to approximately 4 times (3.64 ± 0.48) and increased the expression level of GFAP at the mRNA and protein level, while compounds 1 and 3 exhibited only weak effects, suggesting that the 15-hydroxy-Δ12-γ-lactone moiety is important for bioactivity. Moreover, compound 2 increased the number of pSTAT3-positive cells, suggesting that compound 2 promoted astrocytic differentiation through JAK/STAT signaling pathway.

Marine Pharmacology in 2016-2017: Marine Compounds with Antibacterial, Antidiabetic, Antifungal, Anti-Inflammatory, Antiprotozoal, Antituberculosis and Antiviral Activities; Affecting the Immune and Nervous Systems, and Other Miscellaneous Mechanisms of Action.

The review of the 2016-2017 marine pharmacology literature was prepared in a manner similar as the 10 prior reviews of this series. Preclinical marine pharmacology research during 2016-2017 assessed 313 marine compounds with novel pharmacology reported by a growing number of investigators from 54 countries. The peer-reviewed literature reported antibacterial, antifungal, antiprotozoal, antituberculosis, and antiviral activities for 123 marine natural products, 111 marine compounds with antidiabetic and anti-inflammatory activities as well as affecting the immune and nervous system, while in contrast 79 marine compounds displayed miscellaneous mechanisms of action which upon further investigation may contribute to several pharmacological classes. Therefore, in 2016-2017, the preclinical marine natural product pharmacology pipeline generated both novel pharmacology as well as potentially new lead compounds for the growing clinical marine pharmaceutical pipeline, and thus sustained with its contributions the global research for novel and effective therapeutic strategies for multiple disease categories.

Combinatorial Effects of Soluble, Insoluble, and Organic Extracts from Jerusalem Artichokes on Gut Microbiota in Mice.

Jerusalem artichokes contain high amounts of inulin, which is a prebiotic that supports digestive health, as well as a variety of insoluble fibers and caffeoylquinic acid. The individual impact of these components on gut microbiota is well known; however, the combinatorial effects are less clear. In this investigation, we fractionated Jerusalem artichokes into three parts (water-soluble extract, insoluble extract, and organic extract) and powdered them. Mice were fed a high-fat diet that included one or more of these extracts for 10 days, and then their cecal pH, cecal short-chain fatty acids (SCFAs), and fecal microbiota were evaluated. The combination of the water-soluble and organic extract decreased cecal pH and increased the concentration of SCFAs and led to dynamic changes in the composition of the gut microbiota. These results demonstrate that both the water-soluble and organic extracts in Jerusalem artichokes are bioactive substances that are capable of changing SCFA production and the composition of gut microbiota. Powdered Jerusalem artichokes, rather than inulin supplements, may be superior for promoting a healthy gut.

Histone modification dynamics as revealed by multicolor immunofluorescence-based single-cell analysis.

Post-translational modifications on histones can be stable epigenetic marks or transient signals that can occur in response to internal and external stimuli. Levels of histone modifications fluctuate during the cell cycle and vary among different cell types. Here, we describe a simple system to monitor the levels of multiple histone modifications in single cells by multicolor immunofluorescence using directly labeled modification-specific antibodies. We analyzed histone H3 and H4 modifications during the cell cycle. Levels of active marks, such as acetylation and H3K4 methylation, were increased during the S phase, in association with chromatin duplication. By contrast, levels of some repressive modifications gradually increased during G2 and the next G1 phases. We applied this method to validate the target modifications of various histone demethylases in cells using a transient overexpression system. In extracts of marine organisms, we also screened chemical compounds that affect histone modifications and identified psammaplin A, which was previously reported to inhibit histone deacetylases. Thus, the method presented here is a powerful and convenient tool for analyzing the changes in histone modifications.

Marine Pharmacology in 2014-2015: Marine Compounds with Antibacterial, Antidiabetic, Antifungal, Anti-Inflammatory, Antiprotozoal, Antituberculosis, Antiviral, and Anthelmintic Activities; Affecting the Immune and Nervous Systems, and Other Miscellaneous Mechanisms of Action.

The systematic review of the marine pharmacology literature from 2014 to 2015 was completed in a manner consistent with the 1998-2013 reviews of this series. Research in marine pharmacology during 2014-2015, which was reported by investigators in 43 countries, described novel findings on the preclinical pharmacology of 301 marine compounds. These observations included antibacterial, antifungal, antiprotozoal, antituberculosis, antiviral, and anthelmintic pharmacological activities for 133 marine natural products, 85 marine compounds with antidiabetic, and anti-inflammatory activities, as well as those that affected the immune and nervous system, and 83 marine compounds that displayed miscellaneous mechanisms of action, and may probably contribute to novel pharmacological classes upon further research. Thus, in 2014-2015, the preclinical marine natural product pharmacology pipeline provided novel pharmacology as well as new lead compounds for the clinical marine pharmaceutical pipeline, and thus continued to contribute to ongoing global research for alternative therapeutic approaches to many disease categories.

Effect of mycalolides isolated from a marine sponge Mycale aff. nullarosette on actin in living cells.

Discovery of novel bioactive compounds is important not only for therapeutic purposes but also for understanding the mechanisms of biological processes. To screen bioactive compounds that affect nuclear morphology in marine organism extracts, we employed a microscopy-based assay using DNA staining of human cancer cells. A crude extract from a marine sponge Mycale aff. nullarosette, collected from the east coast of Japan, induced cellular binucleation. Fractionation of the extract led to the isolation of mycalolides A and B, and 38-hydroxymycalolide B as the active components. Mycalolides have been identified as marine toxins that induce depolymerization of the actin filament. Live cell imaging revealed that low concentrations of mycalolide A produce binucleated cells by inhibiting the completion of cytokinesis. At higher concentrations, however, mycalolide A causes immediate disruption of actin filaments and changes in cell morphology, yielding rounded cells. These results suggest that the completion of cytokinesis is a process requiring high actin polymerization activity. Furthermore, luciferase reporter assays with mycalolide A treatments support the view that the level of globular actin can affect transcription of a serum response gene.

The number of CD34+CD133+ hematopoietic stem cells residing in umbilical cord blood (UCB) units is not correlated with the numbers of total nucleated cells and CD34+ cells: a possible new indicator for quality evaluation of UCB units.

Umbilical cord blood transplantation (UCBT) is often associated with delayed neutrophil and platelet recovery. Engraftment failure is another major obstacle. Several factors influence these serious complications, including the numbers of total nucleated cells (TNCs) and CD34+ cells which have been used as reliable factors for selecting UCB units for transplantation. However, whether both factors are reliable indices of the hematopoietic stem cell (HSC) activity of UCB units remains unknown. To evaluate the quality of UCB units, we quantified the actual number of transplantable CD34+CD133+ HSCs (tHSCs) residing in UCB units. The number of tHSCs was not correlated with the numbers of TNCs or CD34+ cells. These results strongly suggest that neither factor reflects the numbers of tHSCs residing in UCB units. To validate the significance of the number of tHSCs, further analysis is required to determine whether the number of tHSCs residing in UCB units is useful as a new indicator for the quality assessment of UCB units.

Impact of Intima-Media Thickness Progression in the Common Carotid Arteries on the Risk of Incident Cardiovascular Disease in the Suita Study.

BACKGROUND: No prospective study of the relationship between intima-media thickness (IMT) progression and incident cardiovascular disease (CVD) has been performed. METHODS AND RESULTS: We studied 4724 participants (mean age: 59.7±11.9 years; without CVD at the baseline) who had carotid ultrasonographic measurement of IMT on both sides of the entire carotid artery area (ie, the entire scanned common carotid artery [CCA], carotid artery bulb, internal carotid artery, and external carotid artery areas for both sides) between April 1994 and August 2001. Carotid ultrasonographic follow-up was performed every 2 years between April 1994 and March 2005 in 2722 of these participants, newly revealing 193 CCA plaques (maximum IMT in the CCA >1.1 mm). We followed up for incident CVD until December 2013. Statistical analyses were performed using a Cox proportional hazards regression model, evaluated using C statistics, and net reclassification improvement. During the 59 909 person-years of follow-up, we observed 221 strokes and 154 coronary heart disease events. CCA plaque and maximum IMT in the whole carotid artery area >1.7 mm were risk factors for CVD. CCA plaque presented an increased risk of CVD based on C statistics and the reclassification improvement of the current risk prediction model. After adding the new incident CCA plaques, during the 23 702 person-years of follow-up, 69 strokes and 43 coronary heart disease events occurred. The adjusted hazard ratios for incident CCA plaque were 1.95 (95% confidence interval, 1.14-3.30) in CVD and 2.01 (95% confidence interval, 1.01-3.99) in stroke. CONCLUSIONS: Maximum IMT in the CCA contributed significantly but modestly to the predictive power of incident CVD used in calculating traditional risk factors. This study provides the first demonstration that new progression of incident CCA plaque is a CVD risk.

Impact of a direct-to-consumer information campaign on prescription patterns for overactive bladder.

BACKGROUND: Direct-to-consumer information (DTCI) campaign is a new medium to inform and empower patients in their decision-making without directly promoting specific drugs. However, little is known about the impact of DTCI campaigns, expanding rapidly in developed countries, on changes in prescription patterns. We sought to determine whether a DTCI campaign on overactive bladder increases the prescription rate for overactive bladder treatment drugs. METHODS: We performed a 3-year retrospective cohort study of 1332 participants who were diagnosed overactive bladder but not prescribed treatment drugs prior to the examined DTCI campaign (exposure), using the health insurance claims dataset of the Japan Medical Data Center (November 19, 2010 to November 18, 2013). The DTCI campaign for overactive bladder included television, Internet, and print advertising (November 19, 2011 to December 22, 2011). We divided the study period into Pre-Campaign Year (2010-2011), Year 1 (2011-2012), and Year 2 (2012-2013). Each year began on November 19 and included Period 1 (weeks 1-5) through Period 10 (weeks 46-50). The main outcome was first-time prescription of the treatment drug for each patient, measured by 5-week periods. Using Period 10 in the Pre-Campaign Year as the referent period, we applied the Cox proportional hazard model for each period. Additionally, we performed the interrupted time series analysis (ITSA) for the first-time prescription rate per 5-week period. RESULTS: Following the DTCI campaign, patients were about seven times more likely to receive a first prescription of a treatment drug during Period 4 in Year 1 (hazard ratio 7.09; 95% CI, 2.11-23.8; p-value<.01) compared with the reference period. Similar increases were also observed for subsequent Periods 5 and 6 in Year 1. The ITSA confirmed the DTCI campaign impact on the level of prescription rate (one-time increase in the regression-intercept) that increased by 1128.1 [per standardized 100,000 persons] (p < .05) during Period 4 in Year 1. CONCLUSIONS: The examined DTCI campaign appeared to increase the prescription rate among patients with overactive bladder for 15 weeks with a 15-week delay. Clinical outcomes of the patients with targeted diseases need to be monitored after DTCI campaigns by a future study.

Kakeromamide A, a new cyclic pentapeptide inducing astrocyte differentiation isolated from the marine cyanobacterium Moorea bouillonii.

Kakeromamide A (1), a new cyclic pentapeptide encompassing a thiazole ring moiety and a ß-amino acid, was isolated from the marine cyanobacterium Moorea bouillonii. Its structure was elucidated by the spectral analysis and the modified Marfey's method. Compound 1 induced differentiation of neural stem cells into astrocytes at the concentration of 10 µM.

Comparing intracerebral hemorrhages associated with direct oral anticoagulants or warfarin.

OBJECTIVES: This cross-sectional survey explored the characteristics and outcomes of direct oral anticoagulant (DOAC)-associated nontraumatic intracerebral hemorrhages (ICHs) by analyzing a large nationwide Japanese discharge database. METHODS: We analyzed data from 2,245 patients who experienced ICHs while taking anticoagulants (DOAC: 227; warfarin: 2,018) and were urgently hospitalized at 621 institutions in Japan between April 2010 and March 2015. We compared the DOAC- and warfarin-treated patients based on their backgrounds, ICH severities, antiplatelet therapies at admission, hematoma removal surgeries, reversal agents, mortality rates, and modified Rankin Scale scores at discharge. RESULTS: DOAC-associated ICHs were less likely to cause moderately or severely impaired consciousness (DOAC-associated ICHs: 31.3%; warfarin-associated ICHs: 39.4%; p = 0.002) or require surgical removal (DOAC-associated ICHs: 5.3%; warfarin-associated ICHs: 9.9%; p = 0.024) in the univariate analysis. Propensity score analysis revealed that patients with DOAC-associated ICHs also exhibited lower mortality rates within 1 day (odds ratio [OR] 4.96, p = 0.005), within 7 days (OR 2.29, p = 0.037), and during hospitalization (OR 1.96, p = 0.039). CONCLUSIONS: This nationwide study revealed that DOAC-treated patients had less severe ICHs and lower mortality rates than did warfarin-treated patients, probably due to milder hemorrhages at admission and lower hematoma expansion frequencies.

Correction to: Halistanol sulfates I and J, new SIRT1-3 inhibitory steroid sulfates from a marine sponge of the genus Halichondria.

The original article can be found online at https://doi.org/10.1038/ja.2017.145 .

Halistanol sulfates I and J, new SIRT1-3 inhibitory steroid sulfates from a marine sponge of the genus Halichondria.

Two new analogs of halistanol sulfate (1) were isolated from a marine sponge Halichondria sp. collected at Hachijo-jima Island. Structures of these new halistanol sulfates I (2) and J (3) were elucidated by spectral analyses. Compounds 1-3 showed inhibitory activity against SIRT 1-3 with IC50 ranges of 45.9-67.9, 18.9-21.1 and 21.8-37.5 µM, respectively. X-ray crystallography of the halistanol sulfate (1) and SIRT3 complex clearly indicates that 1 binds to the exosite of SIRT3 that we have discovered in this study.

Effect of treatment modality on in-hospital outcome in patients with subarachnoid hemorrhage: a nationwide study in Japan (J-ASPECT Study).

OBJECTIVE Although heterogeneity in patient outcomes following subarachnoid hemorrhage (SAH) has been observed across different centers, the relative merits of clipping and coiling for SAH remain unknown. The authors sought to compare the patient outcomes between these therapeutic modalities using a large nationwide discharge database encompassing hospitals with different comprehensive stroke center (CSC) capabilities. METHODS They analyzed data from 5214 patients with SAH (clipping 3624, coiling 1590) who had been urgently hospitalized at 393 institutions in Japan in the period from April 2012 to March 2013. In-hospital mortality, modified Rankin Scale (mRS) score, cerebral infarction, complications, hospital length of stay, and medical costs were compared between the clipping and coiling groups after adjustment for patient-level and hospital-level characteristics by using mixed-model analysis. RESULTS Patients who had undergone coiling had significantly higher in-hospital mortality (12.4% vs 8.7%, OR 1.3) and a shorter median hospital stay (32.0 vs 37.0 days, p < 0.001) than those who had undergone clipping. The respective proportions of patients discharged with mRS scores of 3-6 (46.4% and 42.9%) and median medical costs (thousands US$, 35.7 and 36.7) were not significantly different between the groups. These results remained robust after further adjustment for CSC capabilities as a hospital-related covariate. CONCLUSIONS Despite the increasing use of coiling, clipping remains the mainstay treatment for SAH. Regardless of CSC capabilities, clipping was associated with reduced in-hospital mortality, similar unfavorable functional outcomes and medical costs, and a longer hospital stay as compared with coiling in 2012 in Japan. Further study is required to determine the influence of unmeasured confounders.

Cancer in adolescents and young adults: National incidence and characteristics in Japan.

OBJECTIVE: Adolescents and young adults (AYA) with cancer are confronted with unique challenges in areas of paramount concern within their age group, such as fertility, education, career, and delayed and long-term effects of treatment. However, the extent and depth of the problem has never been examined in the Japanese population. The aim of this study was to describe the status of cancer patients in the AYA population, using data from the hospital-based cancer registry (HBCR). STUDY DESIGN: Patients included in the HBCR from January 2011 to December 2014 were included in this study to evaluate the incidence and cancer distribution trends among AYA. The total number and the proportion of AYA (15-39 years of age) stratified by sex, age, and cancer type were obtained. The incidence of age-specific cancer among AYA was also calculated. RESULTS: We identified 30,394 male (35.1%) and 56,100 female (64.9%) cancer patients in the population, which collectively constituted about 3% of all invasive cancer cases. The incidence of cancer in AYA was estimated as 86.2 per 100,000 per year, and increased with age. The most affected population was women between 35 and 39 years of age (35%). Breast cancer was the most common type of cancer, followed by cervical, uterine, and thyroid cancers. CONCLUSION: A substantial number of AYA are diagnosed with cancer every year. The distribution of cancer types in AYA was dependent on age and sex. These diversities in cancer types can inform researchers and policy makers to fine-tune their studies and policies.

Development and validation of a score for evaluating comprehensive stroke care capabilities: J-ASPECT Study.

BACKGROUND: Although the Brain Attack Coalition recommended establishing centers of comprehensive care for stroke and cerebrovascular disease patients, a scoring system for such centers was lacking. We created and validated a comprehensive stroke center (CSC) score, adapted to Japanese circumstances. METHODS: Of the selected 1369 certified training institutions in Japan, 749 completed an acute stroke care capabilities survey. Hospital performance was determined using a 25-item score, evaluating 5 subcategories: personnel, diagnostic techniques, specific expertise, infrastructure, and education. Consistency and validity were examined using correlation coefficients and factorial analysis. RESULTS: The CSC score (median, 14; interquartile range, 11-18) varied according to hospital volume. The five subcategories showed moderate consistency (Cronbach's α = 0.765). A strong correlation existed between types of available personnel and specific expertise. Using the 2011 Japanese Diagnosis Procedure Combination database for patients hospitalized with stroke, four constructs were identified by factorial analysis (neurovascular surgery and intervention, vascular neurology, diagnostic neuroradiology, and neurocritical care and rehabilitation) that affected in-hospital mortality from ischemic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage. The total CSC score was related to in-hospital mortality from ischemic stroke (odds ratio [OR], 0.973; 95% confidence interval [CI], 0.958-0.989), intracerebral hemorrhage (OR, 0.970; 95% CI, 0.950-0.990), and subarachnoid hemorrhage (OR, 0.951; 95% CI, 0.925-0.977), with varying contributions from the four constructs. CONCLUSIONS: The CSC score is a valid measure for assessing CSC capabilities, based on the availability of neurovascular surgery and intervention, vascular neurology, diagnostic neuroradiology, and critical care and rehabilitation services.

Prescription of Prophylactic Antiemetic Drugs for Patients Receiving Chemotherapy With Minimal and Low Emetic Risk.

IMPORTANCE: The use of antiemetic drugs for patients receiving chemotherapy with low or minimal emetic risk has been recognized as a growing concern for health care costs and patients' welfare. Relatively few studies have examined antiemetic prophylaxis or treatment of emesis associated with chemotherapy with lower emetic risk. OBJECTIVE: To describe the pattern in Japan of overprescribing prophylactic antiemetic drugs to patients who have received intravenous chemotherapy with minimal or low emetic risk. DESIGN, SETTING, AND PARTICIPANTS: This secondary analysis of a health insurance claims database linked with the hospital-based cancer registry of 122 designated cancer care hospitals covered the period from September 1, 2010, to December 31, 2012. Data were included from patients who (1) were diagnosed with breast, lung, colorectal, stomach, cervical, or prostate cancer; (2) were 20 years or older at the time of the diagnosis; and (3) received intravenous chemotherapy with minimal or low emetic risk. The data from patients with advanced stage cancer (stage IV) were excluded. Data were analyzed from March 20, 2014, to June 30, 2016. MAIN OUTCOMES AND MEASURES: The percentage of chemotherapy administration involving patients prescribed prophylactic antiemetic drugs, namely, a neurokinin 1 receptor antagonist, serotonin receptor antagonist, and/or dexamethasone, was calculated. The costs of potentially unnecessary antiemetic drugs were estimated using the National Health Insurance drug price list for 2011. RESULTS: A total of 8545 patients (5886 women [68.9%] and 2659 men [31.1%]; mean [SD] age, 61.9 [12.8] years) undergoing 73 577 administrations of chemotherapy with minimal emetic risk (2464 patients; 22 619 administrations) or low emetic risk (6081 patients; 50 958 administrations) were identified. Of these, patients who received 24 373 administrations of chemotherapy with a low emetic risk (47.8%) and 633 administrations of chemotherapy with a minimal emetic risk (2.8%) were prescribed serotonin receptor antagonists and dexamethasone. Outpatients in the low emetic risk group underwent more frequent administration of chemotherapy that included prescription of both drugs (53.1% of the chemotherapy; 95% CI, 51.6%-54.7%) compared with inpatients (33.7% of the chemotherapy; 95% CI, 31.7%-35.9%). Consequently, approximately ¥170 million (US $1.6 million) was unnecessarily spent on prophylactic antiemetic drugs for these patients. CONCLUSIONS AND RELEVANCE: A substantial number of patients receiving chemotherapy with minimal and low emetic risk were prescribed potentially unnecessary prophylactic antiemetic drugs. The judicious use of these drugs could spare the burden of extra costs and the potential risk for adverse effects for patients.