Search

Abstract Sea slugs of the family Chromodorididae (Nudibranchia, Gastropoda, Mollusca) have garnered attention by researchers and hobbyists alike for their bright and variable color patterns. However, the chromodorid life cycle has yet to be fully elucidated as there exist no reports of their rearing in the laboratory. Here, we report the rearing of Hypselodoris festiva from eggs to adults, where we categorized their post-settlement growth patterns from juvenile to adult stages. Body coloration appeared around 36 days, and organogenesis of vital adult organs began within 42 days after hatching. The anus of H. festiva was observed to change from a ventral to dorsal position during juvenile growth. Individuals reached sexual maturity after six months post-hatching, with successful mating and spawning observed ex situ. This study outlines comprehensive rearing methods and life cycle staging that could be applied to other chromodorid species. We propose H. festiva as a model organism for chromodorid research, with this research contributing to the progress of developmental and evolutionary research on sea slugs.

Summary: The interplay between metabolism and chromatin signaling is implicated in cancer progression. However, whether and how metabolic reprogramming in tumors generates chromatin vulnerabilities remain unclear. Lung adenocarcinoma (LUAD) tumors frequently harbor aberrant activation of the NRF2 antioxidant pathway, which drives aggressive and chemo-resistant disease. Using a chromatin-focused CRISPR screen, we report that NRF2 activation sensitizes LUAD cells to genetic and chemical inhibition of class I histone deacetylases (HDACs). This association is observed across cultured cells, mouse models, and patient-derived xenografts. Integrative epigenomic, transcriptomic, and metabolomic analysis demonstrates that HDAC inhibition causes widespread redistribution of H4ac and its reader protein, which transcriptionally downregulates metabolic enzymes. This results in reduced flux into amino acid metabolism and de novo nucleotide synthesis pathways that are preferentially required for the survival of NRF2-active cancer cells. Together, our findings suggest NRF2 activation as a potential biomarker for effective repurposing of HDAC inhibitors to treat solid tumors.

Summary: Lung cancer treatment has benefited greatly through advancements in immunotherapies. However, immunotherapy often fails in patients with specific mutations like KEAP1, which are frequently found in lung adenocarcinoma. We established an antigenic lung cancer model and used it to explore how Keap1 mutations remodel the tumor immune microenvironment. Using single-cell technology and depletion studies, we demonstrate that Keap1-mutant tumors diminish dendritic cell and T cell responses driving immunotherapy resistance. This observation was corroborated in patient samples. CRISPR-Cas9-mediated gene targeting revealed that hyperactivation of the NRF2 antioxidant pathway is responsible for diminished immune responses in Keap1-mutant tumors. Importantly, we demonstrate that combining glutaminase inhibition with immune checkpoint blockade can reverse immunosuppression, making Keap1-mutant tumors susceptible to immunotherapy. Our study provides new insight into the role of KEAP1 mutations in immune evasion, paving the way for novel immune-based therapeutic strategies for KEAP1-mutant cancers.

Summary: Aortic dissection (AD) is the acute destruction of aortic wall and is reportedly induced by inflammatory response. Here we investigated the role of smooth muscle Socs3 (a negative regulator of Janus kinases/signal transducer and activator of transcription signaling) in AD pathogenesis using a mouse model generated via β-aminopropionitrile and angiotensin II infusion. Socs3 deletion specifically in smooth muscle cells yielded a chronic inflammatory response of the aortic wall, which was associated with increased fibroblasts, reinforced aortic tensile strength, and less-severe tissue destruction. Although an acute inflammatory response is detrimental in AD, smooth muscle-regulated inflammatory response seemed protective against AD. Key Words: aortic dissection, inflammation, Jak/Stat, smooth muscle cells

This article provides the background to the special issue by reviewing the status of traffic problems in South East Asian countries, and in particular, the case of Cambodia. The “Make Roads Safe” report by the Commission for Global Road Safety (2011) confirms traffic accidents as the primary cause of youth mortality worldwide. Thus, the United Nations declared the decade from 2011 to 2020 as the “UN Decade of Action for Road Safety 2011-2020”, promoting road safety and to reduce the number of deaths in road accidents by 2020. Furthermore, the “Sustainable Development Goals” adopted in 2015 highlight the important role of sustainable transport in tackling the exclusion of vulnerable groups. On the other hand, the World Health Organization in 2015 indicate an increase in the death rate due to traffic accidents in low-income countries since 2000. Traffic accidents were already recognized as a social problem before the 2000s in countries such as Thailand and the Philippines. At the same time, other ASEAN member states such as Vietnam and Cambodia which have experienced rapid economic growth since the 2000s are now experiencing the seriousness of traffic problems. It is said that 70% of road accidents in Thailand, Cambodia and Laos involve motorcycles and three-wheelers, but despite this situation, the regulatory framework for motorcycles remains undeveloped. In the case of Cambodia, speeding by young people remains the major cause of road deaths and this can be explained by the fact that people can now travel at a higher speed because of road developments but remaining challenges related to underdeveloped traffic legislation, and limited public awareness and knowledge of road safety are overlooked. In 2010, the Cambodian National Road Safety Action Plan 2010–2020 was drafted, aiming to halve the number of deaths in traffic accidents in 2020. However, in reality, the number of road deaths did not decrease to the level anticipated in the action plan until 2016. In this article, the authors emphasize the importance of implementing the “three Es” namely Engineering, Enforcement and Education in developing countries such as Cambodia. In particular, the authors claim that the role of education to increase people's road safety awareness is neglected compared to the other two dimensions and thus, it is highly important to raise people's road safety awareness through education among the young people. Keywords: Traffic accidents, Motorcycle, Youth, Cambodia, Developing countries, Southeast Asia

Aortic dissection (AD) is a major cause of acute aortic syndrome with high mortality due to the destruction of aortic walls. Although recent studies indicate the critical role of inflammation in the disease mechanism of AD, it is unclear how inflammatory response is initiated. Here, we demonstrate that myocardin-related transcription factor A (MRTF-A), a signal transducer of humoral and mechanical stress, plays an important role in pathogenesis of AD in a mouse model. A mouse model of AD was created by continuous infusion of angiotensin II (AngII) that induced MRTF-A expression and caused AD in 4 days. Systemic deletion of Mrtfa gene resulted in a marked suppression of AD development. Transcriptome and gene annotation enrichment analyses revealed that AngII infusion for 1 day caused pro-inflammatory and pro-apoptotic responses before AD development, which were suppressed by Mrtfa deletion. AngII infusion for 1 day induced pro-inflammatory response, as demonstrated by expressions of Il6, Tnf, and Ccl2, and apoptosis of aortic wall cells, as detected by TUNEL staining, in an MRTF-A-dependent manner. Pharmacological inhibition of MRTF-A by CCG-203971 during AngII infusion partially suppressed AD phenotype, indicating that acute suppression of MRTF-A is effective in preventing the aortic wall destruction. These results indicate that MRTF-A transduces the stress of AngII challenge to the pro-inflammatory and pro-apoptotic responses, ultimately leading to AD development. Intervening this pathway may represent a potential therapeutic strategy.

Nrf2 is a transcriptional activator of oxidative stress response genes. Here the authors show that Nrf2 binds to promoters of proinflammatory genes and interferes with their transcriptional upregulation in LPS-stimulated macrophages independently of its role in regulation of reactive oxygen species.

Aortic dissection (AD) is a serious clinical condition that is unpredictable and frequently results in fatal outcome. Although rapamycin, an inhibitor of mechanistic target of rapamycin (mTOR), has been reported to be effective in preventing aortopathies in mouse models, its mode of action has yet to be clarified. A mouse AD model that was created by the simultaneous administration of β-aminopropionitrile (BAPN) and angiotensin II (AngII) for 14 days. Rapamycin treatment was started either at day 1 or at day 7 of BAPN+AngII challenge, and continued throughout the observational period. Rapamycin was effective both in preventing AD development and in suppressing AD progression. On the other hand, gefitinib, an inhibitor of growth factor signaling, did not show such a beneficial effect, even though both rapamycin and gefitinib suppressed cell cycle activation in AD. Rapamycin suppressed cell cycle-related genes and induced muscle development-related genes in an AD-related gene expression network without a major impact on inflammation-related genes. Rapamycin augmented the activation of Akt1, Akt2, and Stat3, and maintained the contractile phenotype of aortic smooth muscle cells. These findings indicate that rapamycin was effective both in preventing the development and in suppressing the progression of AD, indicating the importance of the mTOR pathway in AD pathogenesis.

BackgroundAbdominal aortic aneurysm (AAA) is a potentially life‐threatening disease that is common in older individuals. Currently, therapeutic options are limited to surgical interventions. Although it has long been known that AAA tissue is enriched in B cells and immunoglobulins, their involvement in AAA pathogenesis remains controversial. Methods and ResultsWe investigated the role of B cells and immunoglobulins in a murine model of AAA, induced with a periaortic application of CaCl2, and in human AAA. Both human and mouse AAA tissue showed B‐cell infiltration. Mouse AAA tissue showed deposition of IgG and activation of Syk, a key molecule in B‐cell activation and immunoglobulin function, which were localized to infiltrating cells including B cells and macrophages. B‐cell–deficient muMT mice showed suppression of AAA development that was associated with reduced activation of Syk and less expression of matrix metalloproteinase‐9. Administration of exogenous immunoglobulins restored the blunted Syk activation and AAA development in muMT mice. Additionally, exogenous immunoglobulins induced interleukin‐6 and metalloproteinase‐9 secretions in human AAA tissue cultures. Furthermore, administration of R788, a specific Syk inhibitor, suppressed AAA expansion, reduced inflammatory response, and reduced immunoglobulin deposition in AAA tissue. ConclusionsFrom these results, we concluded that B cells and immunoglobulins participated in AAA pathogenesis by promoting inflammatory and tissue‐destructive activities. Finally, we identified Syk as a potential therapeutic target.

BackgroundAortic dissection (AD) is a life‐threatening medical emergency caused by the abrupt destruction of the intimomedial layer of the aortic walls. Given that previous studies have reported the involvement of proinflammatory cytokine interleukin‐6 in AD pathogenesis, we investigated the role of signal transduction and activator of transcription 3 signaling, a downstream pathway of interleukin‐6 in macrophages in pathogenesis of AD. Methods and ResultsWe characterized the pathological and molecular events triggered by aortic stress, which can lead to AD. Aortic stress on the suprarenal aorta because of infrarenal aorta stiffening and angiotensin II infusion for 1 week caused focal medial rupture at the branching point of the celiac trunk and superior mesenteric artery. This focal medial rupture healed in 6 weeks in wild‐type (WT) mice, but progressed to AD in mice with macrophage‐specific deletion of Socs3 gene (mSocs3‐KO). mSocs3‐KO mice showed premature activation of cell proliferation, an inflammatory response, and skewed differentiation of macrophages toward the tissue‐destructive phenotype. Concomitantly, they showed aberrant phenotypic modulation of smooth muscle cells and transforming growth factor beta signaling, which are likely to participate in tissue repair. Human AD samples revealed signal transduction and activator of transcription 3 activation in adventitial macrophages adjacent to the site of tissue destruction. ConclusionsThese findings suggest that AD development is preceded by focal medial rupture, in which macrophage Socs3 maintains proper inflammatory response and differentiation of SMCs, thus promoting fibrotic healing to prevent tissue destruction and AD development. Understanding the sequence of the pathological and molecular events preceding AD development will help predict and prevent AD development and progression.

Although the pathogenesis of abdominal aortic aneurysm (AAA) remains unclear, evidence is accumulating to support a central role for inflammation. Inflammatory responses are coordinated by various soluble cytokines of which IL-6 is one of the major proinflammatory cytokines. In this study we examined the role of IL-6 in the pathogenesis of experimental AAA induced by a periaortic exposure to CaCl2 in mice. We now report that the administration of MR16-1, a neutralizing monoclonal antibody specific for the mouse IL-6 receptor, mildly suppressed the development of AAA. The inhibition of IL-6 signaling provoked by MR16-1 also resulted in a suppression of Stat3 activity. Conversely, no significant changes in either NFκB activity, Jnk activity or the expression of matrix metalloproteinases (Mmp) -2 and -9 were identified. Transcriptome analyses revealed that MR16-1-sensitive genes encode chemokines and their receptors, as well as factors that regulate vascular permeability and cell migration. Imaging cytometric analyses then consistently demonstrated reduced cellular infiltration for MR16-1-treated AAA. These results suggest that IL-6 plays an important but limited role in AAA pathogenesis, and primarily regulates cell migration and infiltration. These data would also suggest that IL-6 activity may play an important role in scenarios of continuous cellular infiltration, possibly including human AAA.