Safety and effectiveness of everolimus in maintenance kidney transplant patients in the real-world setting: results from a 2-year post-marketing surveillance study in Japan.

BACKGROUND: Data on real-world use of everolimus (EVR) in Japanese maintenance kidney transplant (KTx) patients are limited. This post-marketing surveillance study was conducted to assess the safety and effectiveness of EVR, and identify factors affecting renal impairment. METHODS: Adult maintenance KTx patients were enrolled within 14 days of initiating EVR. Patient medical data were collected using electronic data capture case report forms at 6 months, 1, and 2 years after initiating EVR, or at discontinuation. RESULTS: All patients receiving EVR in Japan during the surveillance period were enrolled (N = 263). Mean time from transplantation to EVR initiation was 75.7 months. Decreased renal function (31.56%) was the primary reason for initiating EVR. In combination with EVR, the mean daily dose of tacrolimus and cyclosporine could be reduced to ~ 79 and ~ 64%, by 2 years, respectively. Incidences of serious adverse events and adverse drug reactions were 15.97 and 49.43%, respectively. Two-year graft survival rate was 95.82% and low in patients with baseline estimated glomerular filtration rate (eGFR; modification of diet in renal disease) < 30 mL/min/1.73 m2 (69.57%; P < 0.0001) and urinary protein/creatinine ratio (UPCR) ≥ 0.55 g/gCr (84.21%; P = 0.0206). Throughout the survey, mean eGFR values were stable (> 55 mL/min/1.73 m2). Renal impairment was influenced by patient and donor age, eGFR, and UPCR at baseline. CONCLUSIONS: No new safety concerns for the use of EVR in adult maintenance KTx patients were identified. Early EVR initiation may be considered in these patients before renal function deterioration occurs.

Evaluation of the Influence of Halogenation on the Binding of Bisphenol A to the Estrogen-Related Receptor γ.

Halogenation of organic compounds is one the most important transformations in chemical synthesis and is used for the production of various industrial products. A variety of halogenated bisphenol analogs have recently been developed and are used as alternatives to bisphenol A (BPA), which is a raw material of polycarbonate that has adverse effects in animals. However, limited information is available on the potential toxicity of the halogenated BPA analogs. In the present study, to assess the latent toxicity of halogenated BPA analogs, we evaluated the binding and transcriptional activities of halogenated BPA analogs to the estrogen-related receptor γ (ERRγ), a nuclear receptor that contributes to the growth of nerves and sexual glands. Fluorinated BPA analogs demonstrated strong ERRγ binding potency, and inverse antagonistic activity, similar to BPA. X-ray crystallography and fragment molecular orbital (FMO) calculation revealed that a fluorine-substituted BPA analog could interact with several amino acid residues of ERRγ-LBD, strengthening the binding affinity of the analogs. The ERRγ binding affinity and transcriptional activity of the halogenated BPAs decreased with the increase in the size and number of halogen atom(s). The IC50 values, determined by the competitive binding assay, correlated well with the binding energy obtained from the docking calculation, suggesting that the docking calculation could correctly estimate the ERRγ binding potency of the BPA analogs. These results confirmed that ERRγ has a ligand binding pocket that fits very well to BPA. Furthermore, this study showed that the binding affinity of the BPA analogs can be predicted by the docking calculation, indicating the importance of the calculation method in the risk assessment of halogenated compounds.

Efficacy and safety of secukinumab in Japanese patients with active ankylosing spondylitis: 24-week results from an open-label phase 3 study (MEASURE 2-J).

Objective: Secukinumab, a fully human monoclonal antibody that neutralizes interleukin-17A, improved the signs and symptoms of ankylosing spondylitis (AS) in three Phase 3 global studies (MEASURE 1, 2, and 3). Here, we describe the efficacy and safety results through Week 24 of a study of secukinumab in Japanese patients with active AS.Methods: In this multicenter, open-label, single arm, 52-week study, 30 AS patients self-administered secukinumab 150 mg subcutaneously at baseline, Weeks 1, 2, 3, and 4, and every 4 weeks thereafter. The primary efficacy endpoint was ASAS 20 response at Week 16. Overall safety and tolerability were assessed beyond Week 24 up to the data reporting cut-off date.Results: The ASAS 20 response rate was 70% (21/30) at Week 16, which was sustained to Week 24. Secukinumab was effective in various clinical outcomes including patient's global assessment of disease activity, spinal pain, nocturnal pain, physical function, spinal mobility, and CRP level. Comparable ASAS 20 and 40 responses were observed regardless of previous anti-TNF therapy. Secukinumab was well-tolerated with a safety profile consistent with previous reports.Conclusion: Secukinumab 150 mg provided sustained improvement in the signs and symptoms of Japanese AS patients through 24 weeks, with no new or unexpected safety signals.

Mass Spectrometry-Based Untargeted Metabolomics and α-Glucosidase Inhibitory Activity of Lingzhi (Ganoderma lingzhi) During the Developmental Stages.

Lingzhi is a Ganoderma mushroom species which has a wide range of bioactivities. Analysis of the changes in metabolites during the developmental stages of lingzhi is important to understand the underlying mechanism of its biosynthesis, as well as its bioactivity. It may also provide valuable information for the cultivation efficiency of lingzhi. In this study, mass spectrometry based untargeted metabolomics was carried out to analyze the alteration of metabolites during developmental stages of lingzhi. Eight developmental stages were categorized on the basis of morphological changes; starting from mycelium stage to post-mature stage. GC/MS and LC/MS analyses along with multivariate analysis of lingzhi developmental stages were performed. Amino acids, organic acids, sugars, polyols, fatty acids, fatty alcohols, and some small polar metabolites were extracted as marker metabolites from GC/MS analysis, while, lanostane-type triterpenoids were observed in LC/MS analysis of lingzhi. The marker metabolites from untargeted analysis of lingzhi developmental stages were correlated with the α-glucosidase inhibitory activity. Two metabolites, compounds 34 and 35, were identified as potential contributors of the α-glucosidase inhibitory activity. The current result shows that some metabolites are involved in the developmental process and α-glucosidase inhibitory activity of lingzhi.

Efficacy and safety of everolimus with reduced tacrolimus in living-donor liver transplant recipients: 12-month results of a randomized multicenter study.

In a multicenter, open-label, study, 284 living-donor liver transplant patients were randomized at 30 ± 5 days posttransplant to start everolimus+reduced tacrolimus (EVR+rTAC) or continue standard tacrolimus (TAC Control). EVR+rTAC was non-inferior to TAC Control for the primary efficacy endpoint of treated BPAR, graft loss or death at 12 months posttransplant: difference -0.7% (90% CI -5.2%, 3.7%); P < .001 for non-inferiority. Treated BPAR occurred in 2.2% and 3.6% of patients, respectively. The key secondary endpoint, change in estimated glomerular filtration rate (eGFR) from randomization to month 12, achieved non-inferiority (P < .001 for non-inferiority), but not superiority and was similar between groups overall (mean -8.0 vs. -12.1 mL/min/1.73 m2 , P = .108), and in patients continuing randomized treatment (-8.0 vs. -13.3 mL/min/1.73 m2 , P = .046). In the EVR+rTAC and TAC control groups, study drug was discontinued in 15.5% and 17.6% of patients, adverse events with suspected relation to study drug occurred in 57.0% and 40.4%, and proteinuria ≥1 g/24 h in 9.3% and 0%, respectively. Everolimus did not negatively affect liver regeneration. At 12 months, hepatocellular recurrence was only seen in the standard TAC-treated patients (5/62; 8.1%). In conclusion, early introduction of EVR+rTAC was non-inferior to standard tacrolimus in terms of efficacy and renal function at 12 months, with hepatocellular carcinoma recurrence only in TAC Control patients. ClinicalTrials.gov Identifier: NCT01888432.

Lipidomic Profiling of Flammulina velutipes (Curtis) Singer (Agaricomycetes) through Ultra-Performance Liquid Chromatography Coupled with Quadrupole Time-of-Flight Mass Spectrometry: Examining Lipid Dynamics Changes during Fruiting Body Formation and Development.

Flammulina velutipes (enokitake) is widely recognized for its nutritional and medicinal properties. Understanding the biochemical processes, such as lipid metabolism during fruiting body formation, is essential for enhancing mushroom cultivation and utilization. This study aimed at elucidating the dynamic lipidomic changes during seven growth stages of F. velutipes using ultra-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry. Our results revealed significant increases in ceramides along with the growth and a sharp decline in phosphatidylinositols from mycelial to primordial stages. Fatty acid esters of hydroxy fatty acids, recently discovered for their bioactivities, showed high intensities in the mycelial and primordial stages but decreased rapidly thereafter. These findings provide profound insights into the lipid profiles associated with mushroom morphology and development. This lipidomics study establishes a foundational understanding for future research in agricultural and food chemistry applications, potentially improving industrial production and quality control of F. velutipes.

Summary Report of a Public Workshop: Case Studies of Multi-Regional Clinical Trial Incorporating Concept of the ICH E17 Guideline.

To further our understanding of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) E17 guideline and promote effective implementation, a public workshop was held in Japan by regulatory agency and industry representatives. In this workshop, important concepts explained in the ICH E17 guideline, such as intrinsic/extrinsic ethnic factors that influence treatment effects ("effect modifiers") and the holistic evaluation of consistency of treatment effect were actively discussed through case studies. The importance of holistic evaluation of consistency was recognized, and it was concluded that the evaluation and relevant discussion should be shared with regulatory authorities, sponsors, and broader stakeholders.

[The Relationship between the Autistic Traits and Everyday Memory Processing in Adults with Autism Spectrum Disorder and Healthy Adults].

We investigated the association between everyday memory and autistic traits in adults with autism spectrum disorder (ASD, n=22) and healthy adults (n=20) by using the Rivermead Behavioral Memory Test (RBMT). A generalized linear model (GLM) was used to explore the relationships between the subjects' performance on the RBMT as the objective variable and the composite score of the Autism Spectrum Quotient (AQ) as the explanatory variable. Multiple models were created with the AQ subscales ('Social skills,' 'Attention-shifting,' 'Attention to details,' 'Communication,' 'Imagination'), age, gender, the full-scale intelligence quotient (FSIQ), the Patient Health Questionnaire-9 (PHQ-9), and the General Anxiety Disorder-7 (GAD-7) scale added as the moderator variables. The GLM revealed that the AQ subscale 'Social skills' significantly predicted the RBMT-total scores with age, gender, and psychological measures scores as the moderator variables (Model 4: B=0.752, 95%CI: 0.191 to 1.313, p<0.01). Also, The GLM revealed that the AQ subscale 'Communication', in addition to 'Social skills', significantly predicted the RBMT- 'Prospective memory' (Model 4: B=0.298, 95%CI: 0.19 to 0.578, p<0.05). These results indicate an influence of social skills on everyday memory functioning, highlighting the weakness of memory processing in everyday life situations among individuals with ASD.

Long-Term Effects of Everolimus-Facilitated Tacrolimus Reduction in Living-Donor Liver Transplant Recipients with Hepatocellular Carcinoma.

BACKGROUND The study objective was to evaluate the effect of everolimus (EVR) in combination with reduced tacrolimus (rTAC) compared with a standard TAC (sTAC) regimen on hepatocellular carcinoma (HCC) recurrence in de novo living-donor liver transplantation recipients (LDLTRs) with primary HCC at liver transplantation through 5 years after transplantation. MATERIAL AND METHODS In this multicenter, non-interventional study, LDLTRs with primary HCC, who were previously randomized to either everolimus plus reduced tacrolimus (EVR+rTAC) or standard tacrolimus (sTAC), and who completed the 2-year core H2307 study, were followed up. Data were collected retrospectively (end of core to the start of follow-up study), and prospectively (during the 3-year follow-up study). RESULTS Of 117 LDLTRs with HCC at LT in the core H2307 study (EVR+rTAC, N=56; sTAC, N=61), 86 patients (EVR+rTAC, N=41; sTAC, N=45) entered the follow-up study. Overall HCC recurrence was lower but statistically non-significant in the EVR+rTAC group (3.6% vs 11.5% in sTAC; P=0.136) at 5 years after LT. There was no graft loss or chronic rejection. Acute rejection and death were comparable between treatment groups. Higher mean estimated glomerular filtration rate in the EVR+rTAC group (76.8 vs 65.8 mL/min/1.73 m² in sTAC) was maintained up to 5 years. Reported adverse events were numerically lower in the EVR+rTAC group (41.0% vs 53.5% sTAC) but not statistically significant. CONCLUSIONS Although statistically not significant, early EVR initiation reduced HCC recurrence, with comparable efficacy and safety, and better long-term renal function, than that of sTAC treatment.

Efficacy and Safety of Everolimus With Reduced Tacrolimus in Liver Transplant Recipients: 24-month Results From the Pooled Analysis of 2 Randomized Controlled Trials.

BACKGROUND AND METHODS: Data from 2 randomized liver transplant trials (N = 772; H2304 [deceased donor, n = 488], H2307 [living donor, n = 284]) were pooled to further evaluate the efficacy and safety of everolimus with reduced tacrolimus (EVR + rTAC) versus standard tacrolimus (sTAC) regimen at month 24. RESULTS: EVR + rTAC was comparable to sTAC for composite efficacy failure of treated biopsy-proven acute rejection, graft loss, or death (9.8% versus 10.8%; difference, -1.0%; 95% confidence interval, -5.4 to 3.4; P = 0.641) at month 24. EVR + rTAC was superior to sTAC for the mean change in estimated glomerular filtration rate (eGFR) from randomization to month 24 (-8.37 versus -13.40 mL/min/1.73 m2; P = 0.001). A subanalysis of renal function by chronic kidney disease (CKD) stage at randomization showed significantly lower decline in eGFR from randomization to month 24 for patients with CKD stage 1/2 (eGFR ≥ 60 mL/min/1.73 m2) in EVR + rTAC group versus sTAC (-12.82 versus -17.67 mL/min/1.73 m2, P = 0.009). In patients transplanted for hepatocellular carcinoma (HCC) beyond Milan criteria, HCC recurrence was numerically lower although not statistically significant with EVR + rTAC versus sTAC group (5.9% [1 of 17] versus 23.1% [6 of 26], P = 0.215), while comparable in patients within Milan criteria (2.9% [3 of 102] versus 2.1% [2 of 96], P = 1.000), irrespective of pretransplant alpha-fetoprotein levels. CONCLUSIONS: EVR + rTAC versus sTAC showed comparable efficacy and safety with significantly better renal function, particularly in patients with normal/mildly decreased renal function (CKD stage 1/2) at randomization and a trend toward lower HCC recurrence in patients transplanted with HCC beyond Milan at month 24. Further long-term data would be required to confirm these results.

Survey of Japanese Welfare Facility Staff and Special School Teachers Facing Difficulties at Work with Persons with Challenging Behaviors.

BACKGROUND: Effective training programs for managing people with challenging behaviors should be established in both welfare and education settings, as it is important that the support system for challenging behaviors covers the entire life span. For consistent support, it is necessary to understand the difficulties and needs of support staff in caring for people with challenging behaviors from infancy through adulthood. The purpose of this study was to gather data from welfare facility staff and special school teachers regarding their difficulties and needs for managing challenging behaviors, and to determine the differences between teachers and staff members. METHODS: We investigated Japanese special school teachers (n = 317) and the staff of welfare facilities for intellectual disabilities (n = 202) regarding their difficulties and needs. The questionnaire comprised 23 items related to the needs and difficulties in responding to challenging behaviors. RESULTS: Three factors were extracted from the analysis of the survey items: "Difficulty in coordination and information sharing with other organizations," "Difficulty in the workplace," and "Difficulty in support and response." The overall trend was that welfare staff have more difficulties and needs than special school teachers. CONCLUSION: It is necessary to emphasize not only how to respond to challenging behavior but also the importance of establishing a collaborative system within the workplace and with other organizations for staff training in light of their perceptions of working conditions.

Differences in cancer patients' work-cessation risk, based on gender and type of job: Examination of middle-aged and older adults in super-aged Japan.

OBJECTIVES: In this paper, we aim to estimate the effect cancer diagnosis has on labour-force participation among middle-aged and older populations in Japan. We investigate the impact of cancer diagnosis on job cessation and the gap between gender or job types. METHODS: We sourced data from a nationwide, annual survey targeted population aged 51-70 featuring the same cohort throughout, and examined respondents' cancer diagnoses and whether they continued to work, while also considering differences between gender (observations: 53 373 for men and 44 027 for women) and occupation type (observations: 64 501 for cognitive worker and 20 921 for manual worker) in this regard. We also examined one-year lag effects, using propensity score matching to control for confounding characteristics. We also implement Logistic regression and derive the odds ratio to evaluate the relative risk of cancer diagnosis, which supplements the main result by propensity score matching. RESULTS: Overall, the diagnosis of cancer has a huge effect on labour-force participation among the population, but this effect varies across subpopulations. Male workers are more likely to quit their job in the year they are diagnosed with cancer (10.1 percentage points), and also in the following year (5.0 percentage points). Contrastingly, female workers are more likely to quit their job immediately after being diagnosed with cancer (18.6 percentage points); however, this effect totally disappears when considering likelihoods for the following year. Cognitive workers are more prone to quit their job in the year of diagnosis by 11.6 percentage points, and this effect remains significant, 3.8 percentage points, in the following year. On the other hand, for manual workers the effect during the year of diagnosis is huge. It amounts to 18.7 percentage points; however, the effect almost disappears in the following year. CONCLUSION: Our results indicate the huge effect of cancer on job cessation, and that there might be a degree of discrimination in workplaces between gender and job types.

The inhibitory effect on aldose reductase by an extract of Ganoderma lucidum.

The human aldose reductase inhibitory effects of the methanol extracts of 17 medicinal and edible mushrooms were examined. Ganoderma lucidum showed the highest aldose reductase inhibitory activity compared with the other mushrooms. The effect of an ethanol extract of G. lucidum on the galactitol level in the eye lens was studied in a galactosemic rat model in vivo. This mushroom significantly decreased the galactitol accumulation.

Pragmatic dose-escalation methods incorporating relative dose intensity assessment for molecularly targeted agents in phase I trials.

The recommended phase 2 doses of molecularly targeted agents, determined by using an ordinal dose-finding method that only uses toxicity data at first cycle, may not be optimal. Some researchers have proposed the use of relative dose intensity that can account for late-onset, cumulative, and low-grade toxicities to determine the recommended phase 2 dose (RP2D). In this study, we proposed two dose escalation methods based on the observed relative dose intensities (RDIs) between the pre-specified intervals (cycles) for toxicity evaluation used in combination with DLT evaluation in the first cycle. First, we propose the modified 3 + 3 design that incorporates longitudinal RDI assessment. Second, we propose the sequential assessment method for longitudinal RDI (SARDI) to achieve faster dose escalation compared to that of the modified 3 + 3 design. Simulation studies demonstrated that the SARDI was, in many cases, superior to the ordinal and modified 3 + 3 designs in respect to the selection rate of true RP2D and study period. The two proposed methods could also in some cases decrease the average number of patients enrolled in the trial compared to that of the ordinary 3 + 3 design. Incorporation of the RDI assessment into the 3 + 3 design is not difficult and does not require the use of complex statistical techniques. Therefore, we believe that investigators who routinely use the 3 + 3 design in practice can easily use our proposed methods.

How do cardiovascular diseases harm labor force participation? Evidence of nationally representative survey data from Japan, a super-aged society.

OBJECTIVE: To evaluate how cardiovascular diseases harm labor force participation (LFP) among the Japanese population and verify the validity of plasma biomarkers as instrumental variables of cardiovascular diseases after adjusting for a broad set of confounders including dietary intake. DESIGN: Using nationally representative repeated cross-sectional surveys in Japan, the Comprehensive Survey of Living Conditions and National Health and Nutrition Survey, with plasma biomarkers as instrumental variables for quasi-randomization. SETTING: Onset of cardiovascular diseases in those receiving regular treatment for hypertension, intracerebral hemorrhage, intracerebral infarction, angina pectoris, myocardial infarction, or other types of cardiovascular diseases. PARTICIPANTS: A total of 65,615 persons aged ≥ 20 years (35,037 women and 30,578 men) who completed a survey conducted every three years from 1995 through 2013. MAIN OUTCOME MEASURES: Respondent employment and weekly working hours during each survey year. RESULTS: Cardiovascular diseases significantly and remarkably reduced the probability of working by 15.4% (95% CI: -30.6% to -0.2%). The reduction in working probability was detected for women only. Respondents aged ≥ 40 years were less likely to work once diagnosed and the reduction was enlarged for those aged ≥ 65 years, while those aged < 40 years appeared to be unaffected. Probability of engaging in manual labor significantly decreased once diagnosed; however, no impact was found for cognitive occupations. Among employed respondents, the adverse effects of cardiovascular diseases decreased working hours by five hours per week. Validity of the biomarker instrumental variables was generally verified. CONCLUSIONS: A vicious circle is suggested between LFP and unfavorable health. However, the effects vary across age, sex, and occupation type, even after adjusting for causal effects, which could cause a downward bias in LFP impact. ATTRIBUTES: cardiovascular disease, labor force participation, instrumental variable method as quasi-randomization, plasma biomarker, Comprehensive Survey of Living Conditions, National Health and Nutrition Survey.

Changes in content of triterpenoids and polysaccharides in Ganoderma lingzhi at different growth stages.

Ganoderma lingzhi is a traditional medicinal mushroom, and its extract contains many bioactive compounds. Triterpenoids and polysaccharides are the primary bioactive components that contribute to its medicinal properties. In this study, we quantified 18 triterpenoids, total triterpenoid content and total polysaccharide content in the ethanol and water extracts of G. lingzhi at different growth stages. Triterpenoids were quantified by liquid chromatograph-tandem mass spectrometry in the multiple-reaction-monitoring mode. Total triterpenoid and total polysaccharide content were determined by colorimetric analysis. The results indicated that the fruit bodies at an early growth stage had a higher content of ganoderic acid A, C2, I and LM2, as well as of ganoderenic acid C and D, than those at a later growth stage. In contrast, ganoderic acid K, TN and T-Q contents were higher in mature fruit bodies (maturation stage). The highest total triterpenoid and total polysaccharide contents were found in fruit bodies before maturity (stipe elongation stage or early stage of pileus formation). Our results provide information which will contribute to the establishment of an efficient cultivation system for G. lingzhi with a higher content of triterpenoids.

Anti-androgenic activities of Ganoderma lucidum.

The inhibitory effects of methanol extracts of 19 edible and medicinal mushrooms on 5alpha-reductase activity were examined. The extract of Ganoderma lucidum Fr. Krast (Ganodermataceae) showed the strongest 5alpha-reductase inhibitory activity. The treatment of the fruit body of Ganoderma lucidum or the extract prepared from it significantly inhibited the testosterone-induced growth of the ventral prostate in castrated rats. These results showed that Ganoderma lucidum might be a useful ingredient for the treatment of benign prostatic hyperplasia (BPH).

Enhancing the Lasso Approach for Developing a Survival Prediction Model Based on Gene Expression Data.

In the past decade, researchers in oncology have sought to develop survival prediction models using gene expression data. The least absolute shrinkage and selection operator (lasso) has been widely used to select genes that truly correlated with a patient's survival. The lasso selects genes for prediction by shrinking a large number of coefficients of the candidate genes towards zero based on a tuning parameter that is often determined by a cross-validation (CV). However, this method can pass over (or fail to identify) true positive genes (i.e., it identifies false negatives) in certain instances, because the lasso tends to favor the development of a simple prediction model. Here, we attempt to monitor the identification of false negatives by developing a method for estimating the number of true positive (TP) genes for a series of values of a tuning parameter that assumes a mixture distribution for the lasso estimates. Using our developed method, we performed a simulation study to examine its precision in estimating the number of TP genes. Additionally, we applied our method to a real gene expression dataset and found that it was able to identify genes correlated with survival that a CV method was unable to detect.

Gene Selection using a High-Dimensional Regression Model with Microarrays in Cancer Prognostic Studies.

Mining of gene expression data to identify genes associated with patient survival is an ongoing problem in cancer prognostic studies using microarrays in order to use such genes to achieve more accurate prognoses. The least absolute shrinkage and selection operator (lasso) is often used for gene selection and parameter estimation in high-dimensional microarray data. The lasso shrinks some of the coefficients to zero, and the amount of shrinkage is determined by the tuning parameter, often determined by cross validation. The model determined by this cross validation contains many false positives whose coefficients are actually zero. We propose a method for estimating the false positive rate (FPR) for lasso estimates in a high-dimensional Cox model. We performed a simulation study to examine the precision of the FPR estimate by the proposed method. We applied the proposed method to real data and illustrated the identification of false positive genes.

Suppression of AP-1 activity by cycloprodigiosin hydrochloride.

Cycloprodigiosin hydrochloride (cPrG.HCl), a compound isolated from a marine bacterium, acts as an immunosuppressant and an anti-cancer drug. We have previously reported that cPrG.HCl suppressed the transcriptional activation of nuclear factor (NF)-kappaB. Here we studied the effect of cPrG.HCl on activation of another transcription factor, activator protein 1 (AP-1). cPrG.HCl potently suppressed AP-1 activity induced by tumor necrosis factor (TNF) alpha and phorbol myristate acetate (PMA). cPrG.HCl did not inhibit any of the mitogen-activated protein kinase (MAPK) families, whereas it did suppress transcriptional activation of AP-1 induced by constitutively activated mutants of MEKK1 or Ras. cPrG.HCl inhibited neither TNFalpha- or PMA-induced DNA-binding of AP-1 nor co-activator p300-induced activation of AP-1. Taken together, cPrG.HCl suppresses AP-1-dependent gene expression downstream of MAPK group through the inhibition of the transcription activation step of the AP-1 promoter complex.