Okayama University

Norcembranolide diterpenes, isolated from the soft corals of the genus Sinularia, are important compounds for the development of new drugs, owing to their diverse biological activities. However, total synthesis methods for these compounds are scarce. Now, a team of researchers has achieved the total synthesis of scabrolide F, a norcembranolide diterpene. They also revealed its non-toxic antifouling properties. This novel method can lead to the development of new drugs and antifouling agents. Marine organisms produce many organic compounds with diverse chemical structures and biological activities. These natural marine products are regarded as potential starting points for the discovery and development of new drugs. Among these are norcembranolide diterpenes isolated from the soft corals of the genus Sinularia. These compounds exhibit diverse biological activities, and many of them have anti-cancer and anti-inflammatory properties. Consequently, many studies have investigated the properties of norcembranolide diterpenes and their synthesis methods. Given their potential in drug discovery, developing a synthetic method to produce these compounds is essential. However, reports on the total synthesis of norcembranolide diterpenes are limited. In a recent study, a team of researchers from Japan led by Associate Professor Hiroyoshi Takamura and including Yuki Sugitani, Ryohei Morishita, and Isao Kadota, all from the Department of Chemistry, Graduate School of Natural Science and Technology at Okayama University, achieved the total synthesis of a norcembranolide diterpene. "In this research, we succeeded in the chemical synthesis of scabrolide F, a natural product that was isolated from a soft coral Sinularia scabra. Moreover, we found that synthetic scabrolide F and its related compounds exhibited antifouling activity without toxicity, which can potentially prevent the damage caused by biofouling, namely, the accumulation of microorganisms, plants, and algae," explains Dr. Takamura. The study, published in the journal Organic & Biomolecular Chemistry on May 23, 2024, included contributions from Takefumi Yorisue from the Institute of Natural and Environmental Sciences, University of Hyogo, as well as the Division of Nature and Environmental Management, Museum of Nature and Human Activities. To synthesize scabrolide F, the researchers designed a hydrocarboxylic acid compound as the key intermediate. They initially attempted to synthesize the intermediate through the coupling of the tetrahydrofuran and the dithiane fragments. The coupling product could then be transformed into the intermediate through an allylation reaction. However, their model study for testing the allylation reaction failed to yield the desired product, prompting the team to pursue an alternative method. In the second approach, they successfully fabricated the intermediate through a reaction called fragment coupling between an alkyl iodide and an aldehyde. The intermediate was then transformed to the desired scabrolide F, through two key transformations, namely, macrolactonization, which refers to the intramolecular reaction between the hydroxyl group and carboxylic group of the intermediate, and transannular ring-closing metathesis, which forms a ring within an existing macrocyclic ring. This innovative method represents the total synthesis of scabrolide F. Furthermore, the researchers evaluated the antifouling activity and toxicity of this compound and its five key synthetic intermediates against the cypris larvae of the barnacle Amphibalanus amphitrite. All six compounds were found to have antifouling activity with 50% effective concentration or EC50 values ranging from 2.65-9.46 μg/mL and were non-toxic with 50% lethal concentration or LC50 toxicity level greater than 50 μg/mL. Additionally, one of the intermediates was identified as suitable for the preparation of non-toxic antifouling agents. The synthesis method present in the study will also be useful for the synthesis of other norcembranolide diterpenes. Highlighting the practical applications of the study, Dr. Takamura says "Preventing damage caused by biofouling is a key global issue. It is expected that organic compounds synthesized in this research can be used to create new antifouling agents and paints." Overall, the strategy for the total synthesis of norcembranolide diterpenes proposed in this study can aid in the development of antifouling agents and the discovery of new drugs.

Scientists developed a human pancreatic cancer fibrotic barrier 3D cell-culture model to assess treatments for pancreatic ductal adenocarcinoma. By targeting the ROCK2 pathway, they achieved a notable decrease in fibrosis and enhanced tissue permeability to drugs, offering promising avenues for overcoming treatment obstacles in pancreatic cancer. In a pioneering study, scientists at Okayama University developed a human pancreatic cancer fibrotic barrier 3D cell-culture model to assess treatments for pancreatic ductal adenocarcinoma. By targeting the ROCK2 pathway, they achieved a notable decrease in fibrosis and enhanced tissue permeability to drugs, offering promising avenues for overcoming treatment obstacles in pancreatic cancer. This innovative strategy has the potential to transform therapeutic interventions, representing a pivotal advancement in tackling this formidable disease. Pancreatic cancer, recognized as one of the deadliest cancers, poses a persistent challenge for medical professionals globally due to its aggressive behavior and resistance to conventional therapies. The dense fibrotic tissue surrounding pancreatic tumors acts as a significant barrier, hindering the delivery of macromolecular drugs such as antibodies and nanomedicines. Therefore, addressing fibrosis is crucial in enhancing therapeutic outcomes for patients with pancreatic cancer, whose prognosis remains bleak. Understanding the underlying mechanisms driving fibrosis is essential in advancing treatment strategies for this devastating illness. The conventional models used for studying pancreatic ductal adenocarcinoma (PDAC) fibrotic environment often fail to accurately mimic the complexity of the disease. Seeking a more clinically relevant approach, a team of researchers led by Professor Mitsunobu R. Kano from Okayama University, Japan in collaboration with The University of Tokyo and Tohoku University developed a realistic human pancreatic cancer fibrotic barrier model using patient-derived pancreatic stellate cells (PSCs). Their research, co-authored by Prof. Hiroyoshi Y. Tanaka from Okayama University, Prof. Horacio Cabral from The University of Tokyo, and Prof. Atsushi Masamune from Tohoku University, was made available online on 29 March 2024 and was formally published in the May 2024 issue of the Journal of Controlled Release. This innovative model offers a convenient, rapid, and highly reproducible experimental platform to assess pathogenetic mechanisms driving fibrosis as well as to test the efficacy of potential therapeutic interventions. Understanding the molecular mechanisms driving extracellular matrix (ECM) remodeling in PDAC fibrosis is crucial for overcoming treatment barriers. By dissecting these signaling pathways, researchers aimed to determine points of intervention that could be manipulated to enhance tissue permeability and develop more effective treatments for pancreatic cancer. "We used advanced cell culture techniques along with molecular and pharmacological interventions to examine the signaling pathways involved in PDAC fibrosis," explained Professor Kano. "Initially, we assessed the impact of blocking the transforming growth factor-β (TGFβ) and Rho-associated kinase (ROCK) pathways on ECM remodeling and tissue permeability within our 3D fibrotic tissue model. Additionally, we also investigated the involvement of YAP (Yes-associated protein), a key regulator of cell differentiation, in mediating the effects of ROCK inhibition on ECM remodeling and tissue permeability." The results shed light on promising avenues for enhancing drug delivery in PDAC by targeting specific signaling pathways involved in fibrosis. "Inhibition of the TGFβ pathway led to a reduction in ECM remodeling and improved tissue permeability of drugs in 3D-PDAC fibrotic model. Similarly, blocking the ROCK pathway, particularly through ROCK2 inhibition, resulted in decreased ECM remodeling and enhanced drug permeability. Knockdown experiments revealed the predominant role of ROCK2 in regulating these processes," shares Prof. Kano. "Additionally, targeting the YAP protein, a downstream effector of ROCK signaling, produced similar improvements in ECM remodeling and drug permeability." These findings highlight the potential of targeting the TGFβ/ROCK2/YAP signaling axis to mitigate fibrotic barriers and enhance drug delivery in pancreatic cancer, offering promising prospects for improving treatment outcomes in this challenging disease. Looking ahead, the implications of the study extend beyond pancreatic cancer alone. "Fibrosis is prevalent not only in pancreatic cancer but also in other cancers that are difficult to treat, such as those affecting the stomach, breast, and lung, as well as in some non-cancerous diseases. With effective medical treatments lacking for fibrotic conditions, our findings offer a glimmer of hope for enhancing treatment strategies and outcomes in a broader spectrum of fibrotic cancers as well as non-cancerous fibrotic conditions," concludes Prof. Kano.

Dendritic cells are immune cells that capture and present antigens to T cells, activating an immune response. Researchers have discovered that short-chain fatty acids produced by intestinal bacteria regulate a crucial step in this process, the extension of dendritic 'arms.' This breakthrough finding could potentially lead to the development of disease prevention strategies involving beneficial bacteria and new drugs targeting the regulation of dendritic cell function. Dendritic cells are immune cells that capture and present antigens to T cells, activating an immune response. Researchers from Okayama University have discovered that short-chain fatty acids produced by intestinal bacteria regulate a crucial step in this process, the extension of dendritic "arms." This breakthrough finding could potentially lead to the development of disease prevention strategies involving beneficial bacteria and new drugs targeting the regulation of dendritic cell function. Dendritic cells play a key role in the mammalian immune system. These cells are present throughout the human body and are known to capture foreign bodies, i.e., antigens, using extendable "arms" called dendrites. Once captured, dendritic cells present these substances to immune T cells, thereby initiating an immune response. Dendritic cells are responsive to their environment and capable of changing their morphology and other attributes dynamically. For instance, dendritic cells in the intestine's mucosa (inner layer) capture harmful bacteria by extending their dendrites through the epithelium (outermost layer) and into the intestinal lumen (inner space). However, the exact mechanism through which they do is not clear. In a study that was published in The FEBS Journal on August 30, 2023, a team of researchers led by Associate Professor Kazuyuki Furuta, Mr. Takuho Inamoto, Dr. Kazuya Ishikawa, and Dr. Chikara Kaito from the Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences at Okayama University, Japan found that short-chain fatty acids (SCFAs) produced by intestinal bacteria are responsible for initiating the extension of dendrites into the intestinal lumen by dendritic cells. SCFAs are a group of fatty acids with six or fewer carbon atoms, found in high concentrations in the intestine. The research team found that SCFAs such as acetic, propionic, butyric and valeric acids induce dendrite elongation by inhibiting an enzyme called histone deacetylase. Inhibition of histone deacetylase leads to the reorganization of the actin cytoskeleton of dendritic cells, inducing morphological changes. To arrive at these findings, the team examined the effects of SCFAs on a dendritic cell line (DC2.4 cells) and mouse bone marrow-derived dendritic cells (BMDCs) in a laboratory setting. "Ours is the first study to demonstrate that SCFAs induce dendrite elongation by inhibiting histone deacetylase. Moreover, dendritic cells activated by SCFAs exhibited more stronger immune responses, due to increased pathogen uptake," explains Dr. Furuta. Upon conducting further analyses, the team found that treating dendritic cells with valeric acid led to an increase in the uptake of soluble proteins, insoluble beads, and Staphylococcus aureus bacteria. In contrast, the treatment of BMDCs with valeric acid enhanced their antigen presentation ability. It was also observed that SCAFs activated dendrite elongation by stimulating a signaling pathway involved in reorganization of the actin cytoskeleton -- forces responsible for cell movement and cell morphology. So, what are the implications of these findings? "Our findings may be leveraged to identify beneficial intestinal bacteria producing SCFAs to activate immune responses and aid in the prevention of diseases. In addition, the dendritic elongation mechanism we discovered can be used as a target to develop drugs regulate immune responses artificially," remarks Dr. Furuta. By revealing the exact mechanism through which SCFAs trigger dendritic elongation, this study has paved the way for new drugs that directly target dendritic cells. We cannot wait to see these new treatments unfold!