Category: 8. Health

In Western Finland, the longest-lived region thrives without following classic Blue Zone habits, while another community shows promising lifestyle patterns, challenging the idea that there’s only one path to a long and healthy life.

Study: Searching for a Potential Blue Zone in the Nordics: A Study on Differences in Lifestyle and Health in Regions Varying in Longevity in Western Finland. Image Credit: Trygve Finkelsen / Shutterstock

Since their description in 1999 by Poulain and colleagues, “Blue Zones”, geographical regions characterized by the unusual longevity of their inhabitants, have been identified worldwide. However, the Blue Zone framework has never explicitly investigated the Nordic areas. In a recent study published in the Journal of Aging Research, researchers evaluated four regions within Western Finland to see if any have the lifestyle principles typically associated with Blue Zones.

Study findings revealed an unexpected paradox – the most long-lived region, the Åland Islands, demonstrated the best health outcomes but did not adhere closely to the Blue Zone lifestyle. Conversely, areas demonstrating stronger adherence to these principles did not have uniformly high longevity. Finnish-speaking Ostrobothnia deviated most significantly from Blue Zone principles. The findings suggest that in a Nordic welfare state context, factors beyond the classic Blue Zone lifestyle,  like environmental agreeableness, genetics, and socioeconomic resources, may be critical drivers of healthy aging, guiding public health policy in these regions that are gradually aging.

Background

“Blue Zones” are geographical areas where people live significantly longer (measured through rigorous demographic validation like extreme longevity indexes) and healthier lives. First identified in Ogliastra, Italy (1999), these longevity hotspots, which now also include Nicoya, Costa Rica, and Okinawa, Japan, famously share common lifestyle traits, popularly distilled into principles like “move naturally,” “eat wisely,” and “avoid stress and get plenty of sleep” (combined as one principle).

The Blue Zone framework’s social and public health benefits cannot be understated, as the concept has inspired several global public health initiatives to leverage its principles to promote healthy aging. Critics, however, question whether the Blue Zone framework, derived from specific cultural contexts, can be universally applied, especially in regions such as Nordic welfare states with unique social and environmental landscapes that radically differ from those of validated Blue Zones.

About the Study

The present study addresses this knowledge gap by searching for a potential Blue Zone in Western Finland, a region known for its linguistic diversity with previously reported notable differences in health and longevity between its Swedish-speaking and Finnish-speaking populations. This research additionally aims to validate whether the region with the highest longevity also shows the best health and the strongest adherence to established Blue Zone lifestyle principles.

The study leveraged data from four distinct populations in Western Finland that differ in language (ethnolinguistically) and longevity: 1. The Åland Islands (Swedish), 2. Ostrobothnia (bilingual), split into Swedish- and Finnish-speaking subgroups for analysis, and 3. South Ostrobothnia (Finnish). Official (government) statistics comprised the study’s longevity data and were used to rank the regions on the longevity of their inhabitants. However, these statistics could not differentiate between language groups within Ostrobothnia.

Regions’ health and lifestyle data were obtained from surveys collected from older adults (aged 66-91) in these regions as part of the Gerontological Regional Database (GERDA) in 2021-2022. However, the GERDA survey’s self-response format may overrepresent healthier individuals, especially in Finnish-speaking regions with lower response rates.

Adherence to Blue Zone principles was assessed across seven core metrics plus an environmental supplement: 1. Move naturally, 2. Eat wisely, 3. Avoid stress and get plenty of sleep, 4. Strong family ties and community support, 5. Respect the planet, 6. A purpose in life, and 7. Environmental features (added as a supplementary principle). Health variables with known longevity associations (e.g., medical conditions and instrumental activities of daily living [IADL]) were used to measure healthy aging. Scoring was composite, with each principle awarded fractional points based on multiple sub-variables. Participants’ sociodemographic data (age, sex, education status, etc.) were accounted for in statistical models (Analysis of Variance [ANOVAs]).

Åland Islands. Image Credit: Heikki Wichmann / Shutterstock

Study Findings

Longevity data confirmed that the Åland Islands were the most long-lived region, with a life expectancy at birth of 83.47 years (2020-2022), closely followed by Ostrobothnia (83.10 years), while South Ostrobothnia had the lowest (81.83 years). Åland also showed the highest rates of nonagenarians and centenarians.

Unexpectedly, however, health and lifestyle data analysis revealed that while Åland demonstrated the best overall health scores (e.g., lowest medication use, best dental health, and least pain), its inhabitants did not follow the core Blue Zone lifestyle closely, scoring only 1.23 out of a possible 7+ principles. Its main strength was “environmental agreeableness” (0.8/1), a measure of living in a pleasant, activity-promoting natural environment linked to its archipelago setting. Researchers attribute Åland’s longevity to potential genetic advantages and higher socioeconomic status (education/income) alongside environmental factors.

In contrast, Swedish-speaking Ostrobothnia and South Ostrobothnia showed the strongest adherence to the core Blue Zone lifestyle principles, both scoring 1.73. They demonstrated the highest adherence in principles related to “strong family ties,” “community support,” and “purpose in life.” Both regions are part of Finland’s religious “Bible Belt,” with high rates of religious activity potentially contributing to purpose-driven living. South Ostrobothnia additionally showed notable strength in “respect for the planet.” Despite this, Swedish-speaking Ostrobothnia had slightly lower longevity than Åland, and South Ostrobothnia had the poorest health and the lowest longevity of the studied regions. Critically, Finnish-speaking Ostrobothnia scored 0, showing the weakest alignment with Blue Zone principles, yet had better health than South Ostrobothnia.

Conclusions

The present study challenges the universality of the Blue Zone framework and highlights that the pathways to a long and healthy life are not one-size-fits-all. In Nordic welfare states, longevity may stem from context-specific factors like environmental assets (Åland) or social-religious cohesion (Swedish-speaking Ostrobothnia) rather than universal lifestyle principles. The researchers suggest Swedish-speaking Ostrobothnia warrants further investigation as a potential Blue Zone candidate due to its balance of longevity, health, and lifestyle adherence.

In recent years, there has been growing concern over the H5N1 influenza virus. It was first identified in birds three decades ago and has now gradually found its way to humans. H5N1 is a strain of the influenza virus harboring type 5 hemagglutinin (H5) and type 1 neuraminidase (N1) surface proteins, which help in viral entry and spread, respectively.

Researchers led by Kesavardhana Sannula, Assistant Professor in the Department of Biochemistry, Indian Institute of Science (IISc) have now discovered that the currently circulating 2.3.4.4b clade of H5N1 has specific mutations in its genome that increase its human adaptive potential. Clade represents a group of organisms having a common ancestor.

The 2.3.4.4b clade has infected many mammalian species and is adapting to [non-human] mammals, which is a concern for human adaptation. The clade is panzootic, causing unprecedented mortality in birds and mammals, along with several sporadic human infections.”

Kesavardhana Sannula, Assistant Professor, Department of Biochemistry, Indian Institute of Science 

When the influenza virus enters a new organism, it can develop genetic mutations. This helps the virus adapt to the new host. The researchers were trying to decode whether the 2.3.4.4b clade was evolving to produce crucial adaptations in its proteins that allow it to infect humans. They also wanted to decipher which host animals can potentially accelerate this adaptation, giving the virus a leg up in scaling the evolutionary ladder.

Kesavardhana’s team took a computational approach and analysed 7,000 protein sequences of 2.3.4.4b H5N1 found in birds, 820 sequences from non-human mammals, and 35,000 human H1N1 and H3N2 sequences, in order to identify which amino acids are under selection pressure – rapidly changing. They used multiple sequence alignment (a tool to identify similar regions in multiple proteins), constructed phylogenetic trees (which represent how species have diverged from their common ancestor over time) and annotated specific variations in all the proteins of H5N1 infecting non-human mammals and humans. 

The team found an increased number of mutations specifically in the viral polymerase complex (PA, PB2), nucleoproteins, and hemagglutinin (HA) proteins. Once they identified these mutations, the team classified them depending on whether the mutations can help the virus spread from non-human mammals to humans (adaptive) or simply survive in the non-human host (barrier). Finally, they developed a simple mathematical approach and estimated the human adaptive potential for the 2.3.4.4b clade.

The team was also able to pinpoint animals that would be likely to harbor virus strains with the highest human adaptive potential. Interestingly, viruses that can adapt to fox hosts seemed to have higher adaptive potential than cattle-adapted strains. “It is very surprising,” Kesavardhana says. 

Based on their findings, the researchers suggest that enhanced and proactive surveillance measures need to be implemented.

“This clade is acquiring the same key mutations that pandemic human influenza strains possess, which could be a growing risk,” says Ranjana Nataraj, Project Associate at the Department of Biochemistry and the study’s first author.

In a recently published study, researchers at Fox Chase Cancer Center revealed for the first time that cancer cells can evade anti-cancer drugs by entering and surviving within bone marrow fibroblasts, a phenomenon they describe as “cell-in-cell.”

The results of this five-year study, led by Y. Lynn Wang, MD, PhD, FCAP, a Professor and physician-scientist in the Department of Pathology and the Cell Signaling and Microenvironment Research Program at Fox Chase, could mark a major change in the treatment of chronic lymphocytic leukemia (CLL) and related diseases. CLL is the most common hematological cancer in western countries.

Our discovery that tumor cells can actually get inside bone marrow fibroblast cells, which support the tumor cells in their microenvironment, has never been reported before as a live phenomenon.”

Y. Lynn Wang, MD, PhD, FCAP, Professor and physician-scientist, Department of Pathology and the Cell Signaling and Microenvironment Research Program at Fox Chase

“This finding helps to explain why, even when CLL patients initially respond to treatment, many of them carry residual disease and later relapse. We are hopeful that our discovery will lead to treatments that better eliminate residual disease and move toward a cure for cancer,” added Wang, who conducted the study with researchers at Fox Chase and other institutions.

BTK inhibitors, a class of anti-cancer drugs, are the current standard of care for CLL. Over 90% of patients who are treated with these drugs show an initial response – they feel better and their tumors shrink – but only 8% to 11% achieve complete remission in which clinically patients show no evidence of disease. This means that a high number of patients carry residual disease that leaves them vulnerable to relapse. Wang and her team wanted to understand how the disease manages to persist in spite of good initial response to the drugs.

Using confocal microscopy and other techniques, the researchers analyzed bone marrow samples from patients. They witnessed live CLL cells entering bone marrow fibroblasts in response to BTK exposure, and by recording continued independent movement of those subsumed cells, they were able to confirm that the cancer cells stayed alive inside the fibroblasts. Wang’s team then demonstrated that the cancer cells hiding inside the fibroblasts had higher survival rates compared to the cells that remained outside the fibroblasts exposed to the drug.

“It’s like the tumor cells are retreating off the street into a house where they’re safer from the street bullies, i.e., the drugs,” Wang said.

The way CLL cells do this, her team found, is by increasing the expression of CXCR4, a receptor protein on the surface of the tumor cells, in response to exposure to BTK inhibitors. The expression of this protein makes tumor cells sense a chemical gradient that draws the tumor cells closer to the fibroblasts that secrete the ligands for the receptor, allowing the former to enter the latter.

Once Wang and her team understood the mechanism by which tumor cells got inside their “safe houses,” they were able to demonstrate how clinicians might alter treatment to stop this from happening. By blocking CXCR4 with drugs approved for other clinical indications, the researchers prevented CLL cells from entering fibroblasts, potentially making the cancer more vulnerable to treatment.

“If we can block CXCR4, it’s like locking the door of the house where tumor cells wanted to retreat and hide,” said Wang. “This could potentially increase complete response rates through combination therapy using both BTK inhibitors and CXCR4 blockers.”

The discovery may also have applications beyond CLL. The researchers found similar “cell-in-cell” hiding behavior in follicular lymphoma and suspect the mechanism could apply to many different cancer types. Wang is encouraged about the potential of her team’s discovery.

“We want the larger scientific community to know about this mechanism so other researchers can build on these findings. If we can understand what makes cancer cells persist as residual disease, we can better treat cancer and move toward the ultimate goal of cancer elimination.”

University of Oklahoma researchers are conducting a first-of-its-kind study to determine whether cannabis use affects recovery from the wounds associated with head and neck cancer surgery. The outcomes may have implications for other types of surgery and conditions.

Lurdes Queimado, M.D., Ph.D., and Mark Mims, M.D., have been funded by the Presbyterian Health Foundation in Oklahoma City to lead the research, which will include 220 adult patients undergoing surgery for head and neck cancer and reconstruction after the tumor removal. Many such surgeries compromise both appearance and physiological functions such as swallowing and breathing.

The research is unique in that it is prospective – patients will be followed for six months from the time of their treatment – rather than retrospectively looking at patient data. In addition, patients’ self-reporting of cannabis use will be biochemically verified through blood tests, which adds strength to the study.

Research has shown that there is a high rate of cannabis use among cancer patients – more than 50% in some studies, and up to 80% among those who also use tobacco. But there is very little in the medical literature about how cannabis use affects the healing of wounds. Importantly, there are no prospective studies on this topic. We believe the data that we gather will advance our understanding of how the diverse modes of cannabis use affect wound healing and establish a framework for related studies.”

Lurdes Queimado, M.D., Ph.D., lead principal investigator and Professor of Otolaryngology

Queimado also directs the Tobacco Regulatory Science Lab at the TSET Health Promotion Research Center, a program of OU Health Stephenson Cancer Center.

Based on her preliminary research, Queimado hypothesizes that cannabis smoking negatively affects wound healing. Her initial studies, though limited, show that non-cancer patients who smoke cannabis have more inflammation and a decrease in immune system function, both of which could reduce wound healing and increase complications.

However, there are many factors to take into consideration, such as the mode in which patients consume cannabis and how often they use it. Queimado’s trial is designed with four groups of patients – those who use cannabis, those who use cannabis and tobacco, those who use tobacco only, and those who use neither.

“We will monitor each group of patients for infections, bleeding, medical complications and scar healing,” she said, “and we will assess how they are using cannabis, whether it’s smoking, vaping or edibles, because they are very different in the effects they have. The ultimate goal is to have information to guide the patient.”

Facial plastic and reconstructive surgeon Mark Mims, M.D., an assistant professor of otolaryngology and surgery, said this study is both relevant and timely.

“Patients come to my office and ask if using cannabis will affect their reconstructive surgery outcome, and we just don’t have enough data to counsel them with confidence,” Mims said.

While the main purpose of the study is to understand the effects of cannabis on wound healing in head and neck cancer patients, Queimado and her team will also gather information about patients’ responses to any treatment in addition to surgery, such as chemotherapy and radiation.

“I think this study has the potential to have major implications for other types of cancer and surgeries, but also for chronic diseases because inflammation and immunity play a significant role in many conditions, such as autoimmune diseases,” Queimado said. “I think there will be many opportunities for growth into other areas once we have established the framework of this study.”

For many breast cancer survivors, fatigue may linger long after treatment ends, which can have a significant impact on cognitive function, ability to work, and overall quality of life. A new study from George Mason University’s College of Public Health suggests that this is not just a subjective feeling but a measurable reality. 

Ali Weinstein, professor of global and community health and senior scholar at the Center for the Advancement of Well-Being studied how breast cancer survivors respond to physically and mentally tiring tasks. Researchers measured changes in both inflammation and participants’ self-reported fatigue, two common symptoms among breast cancer survivors that are believed to be connected, impact quality of life, and may also play a role in cancer recurrence. 

The researchers found that women who reported higher levels of fatigue at the beginning of the study experienced more inflammation after the tasks, particularly in levels of TGF-β and eotaxin (indicators of inflammation that are linked to immune function, stress, and mood). 

Even women in the control group (who watched a nature video) with high baseline fatigue showed signs of increased inflammation and fatigue, suggesting reactivity even to this relatively innocuous stimulus. 

Surprisingly, most inflammation markers and fatigue levels did not change following mentally or physically fatiguing tasks, suggesting that these short tasks do not affect inflammation or fatigue among most breast cancer survivors. 

This study, published in BMC Women’s Health, explores three previously unstudied areas among breast cancer survivors: 1) how mental fatigue may be connected to inflammation, 2) responses in the short term to tasks that may induce fatigue, and 3) the effects of physically versus mentally fatiguing tasks. 

Studying inflammation in breast cancer survivors is important because past research has shown a link between inflammation and cancer progression or recurrence. Fatigue can also strongly influence survivors’ daily quality of life, and we suspect it may be connected to inflammation. We’re working to better understand that connection, particularly with short-term exposures that may accumulate-and increase inflammation-over time.” 

Ali Weinstein, professor of global and community health and senior scholar at the Center for the Advancement of Well-Being

The team worked with female breast cancer survivors, each randomly assigned to one of three short activities: a physically demanding walk/run, a mentally challenging computer test, or simply watching a nature video (used as a control). Blood samples and fatigue ratings were collected before the task, immediately after, and again after a 30-minute recovery period. 

The researchers highlight the need for more personalized approaches to fatigue management for breast cancer survivors, particularly strategies that consider existing levels of fatigue and the body’s inflammatory response to everyday physical and cognitive demands. 

This work was supported by a grant from the PNC Charitable Trust (Grant #112881). 

Irritable bowel syndrome with diarrhea (IBS-D) is an unpleasant condition to live with, affecting millions of people worldwide. Now a new study has identified what could be a key trigger for the condition – a trigger which could be targeted by future treatments.

An investigation on 108 people with and without IBS-D and related conditions has revealed a hormone called insulin-like peptide 5 (INSL5) is released when bile acids that aid digestion find themselves further along the digestive tract than usual, in the large intestine.

This shouldn’t happen, but when it does – due to certain conditions and gut malfunctions – more INSL5 gets produced, which causes diarrhea-like symptoms.

This is potentially responsible for around two out of every five cases of IBS-D, the researchers say, and may explain why a lot of existing drugs and strategies to combat IBS-D are ineffective.

Related: Surprising ‘Nocebo Effect’ Shows Gluten May Not Be The Problem in IBS

“When you go to the doctor with chronic diarrhea, they’ll likely test for food intolerances, rule out an infection or look for signs of inflammation,” says Chris Bannon, an endocrinologist at the University of Cambridge in the UK. “There has been significant research interest in the microbiome, but gut hormones have been neglected.”

“It’s becoming increasingly clear that gut hormones play an important role in things like gut health and weight management.”

The study included participants with bile acid diarrhea (BAD) as well as IBS-D, helping the researchers identify a link between these conditions, the differences between them, and the triggers responsible for them.

At the moment, BAD is difficult to diagnose and is often classed as IBS, and the researchers hope that being better able to spot it will lead to treatments that can more effectively target the underlying causes.

It’s also important to note that INSL5 is naturally produced by the body. Although it brings on diarrhea, it’s actually a sign of the body trying to protect itself: it detects that bile acids shouldn’t be in the colon, and flushes them out.

“It makes sense that you would have something that detects toxins and helps the body rid itself of them,” says Bannon. “But a problem develops if it’s always being triggered by bile acid, causing very dramatic symptoms.”

Studies using mouse models had found that INSL5 could cause diarrhea, but this is the first time researchers have been able to show the same processes in people, and in ways that are connected to two recognized conditions.

The next steps are to look at potential treatments targeting INSL5. Some IBS-D patients in previous studies showed improved symptoms when given the anti-sickness medicine ondansetron – a known INSL5 blocker – which may indicate one route forward, although it’s not yet clear why ondansetron works so well.

“This was a very exciting finding because it showed us that this hormone could be playing a big part in symptoms of this misunderstood condition,” says Bannon.

“It also meant it might allow us to develop a blood test to help diagnose bile acid diarrhea if INSL5 levels are only high in these individuals.”

The research has been published in Gut.

During Australia’s National Science Week in August, Hort Innovation has announced a new research project developing “plant vaccines” to protect Australia’s vegetables from viral diseases.  

The project, which is funded by the organisation and led by The University of Queensland (UQ), is a five-year initiative exploring how peptides – which are tiny biological molecules – can be used to prime plants to defend themselves against viruses, much like vaccines do in humans.  

The research team will use advanced plant molecular biology tools to identify promising peptide candidates and assess their ability to trigger broad immune responses in vegetable crops. In parallel, the project will also investigate beneficial bacteria from vegetable root systems that may act as natural defence primers.  

Brett Fifield, Hort Innovation CEO said the cutting-edge initiative is set to solve “real-world problems”. 

“The project is using advanced plant molecular biology to develop eco-friendly, scalable solutions for growers across the country,” he said. “We’re combining cutting-edge science with practical farming needs to create virus-resistant crops that don’t rely on chemicals. This is science in action, using biology to solve real-world problems, which is exactly the kind of innovation we celebrate during National Science Week.”  

UQ’s Mark Jackson added: “Just like people might get a flu shot to prepare their immune systems, we’re helping plants get ready for viral attacks using peptides. These molecules can prime the plant’s natural defences, so when a real virus shows up, the plant knows how to fight back”.  

However, unlike traditional vaccines that use weakened or dead viruses, this project is investigating peptide elicitors – molecules that simulate the presence of a virus without introducing any actual pathogen. These peptides trigger a “teaching effect,” helping plants build immunity before infection occurs.  

“Peptides are like keys that fit into the plant’s immune system locks,” Jackson said. “But finding the right key is complex, as there are many peptides and receptors, and only a perfect match will trigger the defence response. Our goal is to find generalist peptides that can protect against a wide range of viruses, offering a more holistic and scalable solution for growers.”  

The project will be focused on Queensland growing regions, where viruses like papaya ringspot virus and zucchini yellow mosaic virus are spread rapidly by insect carriers.   

“Importantly, this research will support reduced reliance on chemical treatments by offering growers practical, eco-friendly virus control options,” added Fifield. It will also enhance crop resilience and productivity, helping to future-proof farming systems against emerging viral threats.” 

Chinese researchers have developed an ingestible optoelectronic capsule that enables two-way communication between humans and engineered gut bacteria, which is a global first. The breakthrough, jointly achieved by teams from Tianjin University and Northwest A&F University, was published on July 28 in the journal Nature Microbiology.

The technology marks a major step forward in biomedical engineering, offering a new tool for real time monitoring of gut health and potential interventions for gastrointestinal diseases, the research team said.

With this system, humans cannot only remotely receive health signals from engineered bacteria but also send precise commands to them, enabling active regulation of gut microbiota.

“This is like creating an optical language between humans and gut microbes,” said Wang Hanjie, a professor at Tianjin University, who co-led the project with Professor Liu Duo. “It opens a path for precise diagnosis and dynamic treatment of diseases from within the body.”

The human gut hosts billions of microorganisms that influence everything from immunity to emotional well-being. However, due to the gut”s complex structure, observing and regulating these microbes in real time has always been challenging.

“Tackling this issue is like trying to detect and control fish in the deep ocean,” said Wang. Traditional methods, such as stool analysis, offer only indirect clues.

“It’s like picking up shells on a beach. Although it can provide some information about the deep sea, it cannot directly interact with the microorganisms within the gut,” added Liu.

The researchers turned to capsule technology, a field under exploration for over two decades, and combined it with genetic engineering. Their solution involved modifying gut bacteria to act as sensors and responders, while an ingestible capsule, equipped with light-based communication tools, serves as a mobile command unit inside the digestive tract.

The capsule uses light signals to communicate, a deliberate choice. “There are no natural light signals in the human gut,” explained Zhang Xinyu, a core member of the team. “That makes light a secure, coded language between the device and the bacteria.”

He further elaborated, “The electronic capsule acts as an ‘interpreter’, translating the bacteria’s optical language into readable signals for humans.”

Engineered bacteria are programmed to emit light upon detecting disease markers such as nitrate, an indicator of inflammation. The capsule’s photoelectric sensors convert this light into electrical signals, which are wirelessly transmitted to a mobile phone app via Bluetooth, Zhang said.

Conversely, the capsule also sends out preset light commands using built-in LEDs. The bacteria detect these through light-sensitive proteins and respond by performing specific functions, such as producing anti-inflammatory nanobodies.

To verify the system’s stability, researchers ran tests both in vitro and in live pigs.

“Higher bacterial luminescence led to stronger photocurrent signals from the capsule,” said the team, confirming the reliability of the signal conversion process.

In tests using a pig model of enteritis, the system proved its practical value. “The engineered bacteria could send early warnings one to two days before traditional stool testing methods,” said Liu. The team was also able to issue real time intervention commands remotely through the app, successfully alleviating inflammation.

“The capsule functions like a flexible ‘command boat’ deep inside the gut,” said Liu. “Our next goal is to tailor bacterial sensing to specific clinical needs.”

Professor Wang Hanjie added, “In the future, electronic capsules could serve as a digital smart platform, incorporating artificial intelligence and cloud data technologies to intelligently regulate microbial functions, offering new strategies for precise and dynamic disease diagnosis and treatment.”

Experts say the study represents a fundamental shift from passive observation of gut flora to active and remote control, offering a foundation for future digital diagnostics and treatment solutions.

Zang Yifan contributed to this story.

yandongjie@chinadaily.com.cn

Brightly colored sea slugs could hold the key to tomorrow’s cancer treatments, with their diet-derived and self-made chemicals showing potent tumor-killing abilities.

​​​​​​​Review: Nudibranchs as Sources of Marine Natural Products with Antitumor Activity: A Comprehensive Review. ​​​​​​​Image Credit: Sakis Lazarides / Shutterstock

In a recent study published in the journal Marine Drugs, researchers in Spain reviewed the bioactive potential of nudibranch-derived compounds, with emphasis on their antitumor properties.

Background

Cancer is among the leading causes of mortality and morbidity. In 2022, 20 million cancer diagnoses and 9.7 million cancer-related deaths were recorded. Moreover, 30% of premature deaths in people aged 30–69 were due to cancer. Thus, it is paramount to augment existing treatments or develop novel therapies. The search for new drugs has focused on natural resources, extending to oceans.

Marine organisms have adapted to extreme conditions, resulting in the production of secondary metabolites with high bioactivity. Besides, marine metabolites have more halogen atoms, longer carbon chains, and larger ring systems with fewer oxygen and more nitrogen atoms than terrestrial metabolites.

To date, more than twenty marine-derived drugs have been approved by the U.S. Food and Drug Administration, many for cancer treatment. However, these often face limitations such as drug resistance and a lack of selectivity, underscoring the need for continued bioprospecting. Nudibranchs are a group of marine gastropod mollusks with about 4,700 species.

Due to the lack of an external shell and other physical defenses, nudibranchs have unique chemical defense strategies, involving de novo synthesis of bioactive metabolites or accumulation and modification of toxins and secondary dietary compounds, which are often concentrated in accessible tissues like the mantle or dorsal extensions called cerata.

In the present study, researchers reviewed the potential of nudibranchs as a source of marine natural products with antitumor properties.

Nudibranchs and Their Antitumor Potential

Nudibranchs have emerged as promising candidates for novel pharmacological agents for cancer therapy. Studies have identified numerous secondary metabolites in nudibranchs that exhibit cytotoxic properties, with many showing antitumor potential. Alkaloids and terpenes, primarily diterpenoids and sesquiterpenes, are the major types of bioactive molecules in nudibranchs.

The review notes that many of these compounds are not made by the nudibranchs themselves but are sequestered from their diet, such as sponges, and sometimes chemically modified for their own defense.

A study demonstrated potent cytotoxic effects of methanol-dichloromethane extracts derived from Dolabella auricularia and Phyllidia varicosa against colorectal cancer (CRC) cell lines. Another study reported lower cytotoxic effect of acetone extracts derived from Armina maculata, Armina tricolorata, and Armina tigrina against lung and stomach cancer cell lines.

Acetone extracts from Phyllidia coelestis have been purified to obtain bisabolane-type sesquiterpenoids such as 7-isocyano-7,8-dihydro-α-bisabolene, theonellin isothiocyanate, and 3-isocyanotheonellin. Notably, the paper highlights that structural analogs of these compounds were also found in the nudibranch’s sponge prey, Axinissa variabilis, strongly suggesting a dietary origin for these metabolites.

Studies have reported cytotoxicity of 3-isocyanotheonellin against lung, liver, CRC, and pancreatic cancer cell lines, and 7-isocyano-7,8-dihydro-α-bisabolene and theonellin isothiocyanate against one liver cancer cell line only.

Potent isoquinolinequinone alkaloids derived from Jorunna funebris have shown antitumor activity against various cancer cell lines. Examples include fennebricin A against leukemia and lung cancer cell lines, renieramycin M against CRC and lung cancer cell lines, and jorumycin against melanoma, lymphocytic leukemia, and lung cancer cell lines. These compounds belong to a class of aromatic alkaloids characterized by fused quinone and isoquinoline ring systems, often associated with DNA-interactive and pro-apoptotic activity.

In another example of compounds showing activity against hard-to-treat cancers, the paper mentions phorbazole alkaloids from Aldisa andersoni, which demonstrated cytotoxicity against several cell lines known to be resistant to pro-apoptotic stimuli.

Furthermore, tambjamines are the primary metabolites from Tambja brasiliensis and Tambja stegosauriformis. Tambjamine K has demonstrated antitumor activity in glioma and cervical cancer cell lines, though the review notes that some tambjamines also exhibit toxicity against non-tumor cells, highlighting the critical challenge of achieving selectivity.

Nudibranch morphological groups: cladobranch nudibranchs, including Nemesignis banyulensis (a) and Facelina vicina (b), and dorid nudibranchs, including Felimare picta (c,d).

A Reservoir of Defense: The Role of Egg Masses

The review also highlights that the brightly colored and exposed egg masses of some nudibranchs, such as Hexabranchus sanguineus, serve as concentrated reservoirs for defensive compounds. Molecules like ulapualides, isolated from these egg masses, have shown potent antitumor activity and may be easier to isolate in larger quantities compared to extracting them from the adult animals, offering another strategic avenue for drug discovery.

Mechanisms of Action of Nudibranch Derivatives

Research has unveiled several mechanisms of action contributing to the antitumor activity of nudibranch compounds. These include DNA damage induction, oxidative and endoplasmic reticulum (ER) stress, reactive oxygen species (ROS) generation, cell cycle arrest, and apoptosis. A study reported that dendrodoristerol isolated from Dendrodoris fumata exhibits antitumor activity by inducing apoptosis in leukemia cells.

Further, another study showed that palmadorin M isolated from Austrodoris kerguelenensis inhibits the activation of extracellular signal-regulated kinase 1 and 2 (Erk1/2), Janus kinase 2 (Jak2), and signal transducer and activator of transcription 5 (STAT5), inducing apoptosis in leukemia cells. The methanol-dichloromethane extracts from P. varicosa and D. auricularia exhibit antitumor and anti-proliferative effects by inducing DNA damage, oxidative stress, and apoptosis in CRC cell lines.

A subsequent study reported that the D. auricularia extract had selective cytotoxicity against CRC cells and minimal impact on normal colon fibroblasts; the antitumor activity was mediated through the generation of ROS, inducing ER stress and activating unfolded protein response. The ROS-mediated ER stress resulted in G2/M phase cell cycle arrest, DNA damage, and apoptosis.

​​​​​​​Main mechanisms of action of nudibranch-derived molecules and extracts.

In addition, similar mechanisms of action were reported for KLM155, a toluhydroquinone (a hydroquinone derivative) derived from Leminda millecra, in an esophageal cancer cell line. Its antitumor activity was associated with cell cycle arrest in the G2 phase, ROS production, and apoptosis induction. In addition to antitumor activity, various nudibranch derivatives exhibit other biological activities. For instance, A. tigrina, A. tricolorata, and A. maculata extracts exhibit anti-inflammatory activity.

Echinoclerodane A, a diterpenoid from Hexabranchus sanguineus, has potent inhibitory effects on inflammatory responses in RAW264.7 macrophages. Besides, fennebricin A acts as an inhibitor of nuclear factor kappa B (NF-κB) signaling. Nudibranchs have also been recognized for antiparasitic and antimicrobial potential. For example, compounds with leishmanicidal and antibacterial activity have been isolated from Chromodoris willani and Doriprismatica stellata, respectively.

Concluding Remarks

Together, nudibranchs are a group of marine invertebrates with largely underexplored pharmacological and biological potential. The study has highlighted the remarkable antitumor activity of extracts and compounds derived from the limited number of nudibranchs studied to date.

Despite the promising findings, the review emphasizes that further research is needed to corroborate the clinical potential of nudibranch derivatives. More specifically, the paper suggests that future studies should focus not only on standardization of extraction methodologies and optimization of isolation and purification protocols, but also on several key areas. These include exploring the relatively unstudied cladobranch group of nudibranchs, which have different diets and may yield novel compounds; analyzing different anatomical parts of the organisms, such as the mantle versus the viscera; and investigating the microbiome associated with nudibranchs, as their symbiotic bacteria represent another significant source of bioactive molecules.

China has established a four-tier risk assessment system to enhance the nation”s early warning capabilities for infectious diseases, according to a guideline released by the National Disease Control and Prevention Administration recently.

The trial regulation, which takes effect immediately, aims to tackle public health risks caused by various infectious diseases, including the nation’s 41 notifiable diseases, novel infectious illnesses and those with unknown causes.

Under the guideline, local disease control agencies are required to collect infectious disease monitoring information from multiple sources and carry out risk evaluations. The risk levels are classified into four tiers from extremely low risk to high risk.

An extremely low risk assessment only requires continuous implementation of regular monitoring, while a low-risk evaluation should prompt the release of health risk advisories to the public.

“A health risk advisory is supposed to include pathogenic and epidemic characteristics of the disease, typical clinical symptoms, recent monitoring results, key control and preventive measures,” it said. “Such an advisory should be scientific, clear, easy to understand and capable of being disseminated through various channels.”

With a medium-risk assessment, medical institutions and other related departments should take professional precautionary measures. Disease control authorities will consider issuing a warning, which is meant to be circulated across related government departments and healthcare institutions.

A warning will include information about the hazards of the disease, the range of affected areas, development trends and suggestions on personnel technical training, supplies preparation, case identification and reporting procedures, ventilation and disinfection at key venues and other preventive measures, the guideline said.

With a high-risk evaluation, disease control agencies should make reports to disease control authorities within two hours, who in turn will gather experts to further analyze and evaluate the severity of epidemic risk and determine if an alert should be issued by the regional government.

The guideline also requests encouraging and supporting the use of digital technologies to define warning thresholds, as well as calls for the establishment of an epidemic database and related algorithm model libraries to build a multi-trigger and smart early warning system.

It stresses providing necessary personnel, funding, equipment, infrastructure and policy support, as well as strengthening cross-department cooperation to facilitate early warning operations.

“The early warning information should be clear, accurate, authoritative and professional, and pay attention to protecting personal privacy,” it added.

China aims to build a highly-efficient infectious early warning mechanism featuring multi-trigger points and swift dissemination by 2030, positioning itself among world-leading ranks in the field of early detection, scientific assessment and prompt early warning of epidemics.

According to Lei Zhenglong, an official at the administration, China has carried out surveillance for the novel coronavirus, influenza and other acute respiratory diseases at 1,041 sentinel hospitals, covering all municipal-level regions and key counties.

Meanwhile, various monitoring channels, including vector organisms, urban sewage, global trends and public opinions, have been used to improve the sensitivity and accuracy of monitoring.

The central finance also invested funds in 2023 and 2024 to support the establishment of provincial-level information platforms, with Beijing, Tianjin and the provinces of Hubei and Zhejiang having completed initial construction.

As of the end of last year, about 71 percent of secondary or tertiary public hospitals had been equipped with smart surveillance and early warning software as part of efforts to use novel technologies to improve analysis and assessments of epidemic data, Lei said.