Day: August 7, 2024

Categories : Diet and Nutrition GastrointestinalTags : Leave a comment

Ketogenic Diet Reduces Friendly Gut Bacteria and Raises Cholesterol Levels

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Photo by Jose Ignacio Pompe on Unsplash

A study from the University of Bath reveals that ketogenic low-carbohydrate diets can increase cholesterol levels and reduce beneficial gut bacteria, specifically Bifidobacterium.

Published in Cell Reports Medicine, the research from the Centre for Nutrition, Exercise, and Metabolism involved 53 healthy adults for up to 12 weeks. Participants followed either a moderate sugar diet (control), a low-sugar diet (less than 5% of calories from sugar), or a ketogenic (keto) low-carbohydrate diet (less than 8% of calories from carbohydrates).

Key findings include:

•Increased Cholesterol: The keto diet raised cholesterol levels, particularly in small and medium sized LDL particles. The diet increased apolipoprotein B (apoB), which causes plaque buildup in arteries. In contrast, the low-sugar diet significantly reduced cholesterol in LDL particles.

•Reduced Favourable Gut Bacteria: The keto diet altered gut microbiome composition, notably decreasing Bifidobacteria, beneficial bacteria often found in probiotics. This bacteria has wide ranging benefits: producing b vitamins, inhibiting pathogens and harmful bacteria and lowering cholesterol. Sugar restriction did not significantly impact the gut microbiome composition.

•Glucose Tolerance: The keto diet reduced glucose tolerance, meaning the adults’ bodies became less efficient at handling carbohydrates.

•Both Diets Resulted In Fat Loss: Keto Diet resulted in an average of 2.9kg fat mass loss per person, whilst the sugar restricted diet followed with an average 2.1kg fat mass loss per person at 12 weeks.

•Metabolism: Researchers also noticed that the keto diet caused significant changes in lipid metabolism and muscle energy use, shifting the body’s fuel preference from glucose to fats.

•Physical Activity Levels: Both sugar restriction and keto diets achieved fat loss without changing physical activity levels. Previous studies from the Centre for Nutrition, Exercise and Metabolism have shown that skipping breakfast or intermittent fasting cause reductions in physical activity.

Lead researcher Dr. Aaron Hengist highlighted the concerning cholesterol findings:

“Despite reducing fat mass, the ketogenic diet increased the levels of unfavourable fats in the blood of our participants, which, if sustained over years, could have long-term health implications such as increased risk of heart disease and stroke.”

Dr. Russell Davies, who led the microbiome research, explained the impact on gut health:

“Dietary fibre is essential for the survival of beneficial gut bacteria like Bifidobacteria. The ketogenic diet reduced fibre intake to around 15 grams per day, half the NHS recommended intake. This reduction in Bifidobacteria might contribute to significant long-term health consequences such as an increased risk of digestive disorders like irritable bowel disease, increased risk of intestinal infection and a weakened immune function.”

Professor Javier Gonzalez, who oversaw the research, commented on the glucose findings:

“The ketogenic diet reduced fasting glucose levels but also reduced the body’s ability to handle carbs from a meal. By measuring proteins in muscle samples taken from participants’ legs, we think this is probably an adaptive response to eating less carbohydrates day-to-day and reflects insulin resistance to storing carbs in muscle. This insulin resistance is not necessarily a bad thing if people are following a ketogenic diet, but if these changes persist when people switch back to a higher carbohydrate diet it could increase the risk of developing type 2 diabetes in the long-term”

In light of this new research, the academics conclude that if you’re considering a diet, a low sugar one will be better for most people. More work is needed to understand how individuals may benefit from each type of diet. The government recommends that free sugars (those added to food or drink or found naturally in honey, syrups, fruit juices and smoothies) should be restricted to less than 5% of total energy intake. Professor Dylan Thompson, who also oversaw the work, said:

“The ketogenic diet is effective for fat loss, but it comes with varied metabolic and microbiome effects that may not suit everyone. In contrast, sugar restriction supports government guidelines for reducing free sugar intake, promoting fat loss without apparent negative health impacts.”

Source: University of Bath

Categories : CancerTags : Leave a comment

Advanced Lung Cancer Mortality Plunged Since Standardisation of Immunotherapy

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The largest population-based study to date supports the survival benefits of immunotherapy for people with metastatic non–small cell lung cancer.

Squamous cancer cell being attacked by cytotoxic T cells. Image by National Cancer Institute on Unsplash

Since the first immunotherapy drug to boost the body’s immune response against advanced lung cancer was introduced in the United States in 2015, survival rates of patients with the disease have improved significantly. That’s the conclusion of a recent real-world study published by Wiley online in CANCER, a peer-reviewed journal of the American Cancer Society.

For the research, a team led by Dipesh Uprety, MD, FACP, of the Barbara Ann Karmanos Cancer Institute and the Wayne State University School of Medicine, analysed data from the National Cancer Institute Surveillance, Epidemiology, and End Results database, which compiles cancer-related data covering approximately 48% of the US population. The investigators’ analysis focused on non–small cell lung cancer (NSCLC), which accounts for up to 90% of all cases of lung cancer and is the leading cause of cancer-related death among both men and women in the United States.

In a comparison of 100 995 patients with metastatic NSCLC treated in 2015–2020 (after immunotherapy was deemed the standard of care) and 90 807 patients with metastatic NSCLC in the pre-immunotherapy era of 2010–2014, patients in the immunotherapy era were less likely to die from any cause. The overall survival rates at one, three, and five years were 40.1% versus 33.5%, 17.8% versus 11.7%, and 10.7% versus 6.8%. The median overall survival was eight months in patients in the immunotherapy era and seven months in those in the pre-immunotherapy era.

Similarly, patients treated after immunotherapy was available were less likely to die specifically from cancer than those treated before immunotherapy. The one-, three-, and five-year cancer-specific survival rates were 44.0% versus 36.8%, 21.7% versus 14.4%, and 14.3% versus 9.0%, with a median survival of 10 months versus eight months.

Survival rates remained significantly better in the immunotherapy era even after accounting for factors including age, sex, race, income, and geographical area.

“By utilizing a large national database, our study provided real-world evidence of the positive impact of immunotherapy in patients with lung cancer,” said Dr Uprety. The investigators stressed that additional studies are needed, however. “Immunotherapy provides long-term benefits. Since the durable benefits of immunotherapy are limited to a small subset of patients, future research should aim to optimize immunotherapy with new agents that can benefit a broader population,” said lead author Yating Wang, MD, of Ascension Providence Hospital.

Source: Wiley

Categories : Obstetrics & GynaecologyTags : Leave a comment

Fatty Acids in Umbilical Cord Blood Might Cause Autism Spectrum Disorder

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Scientists unveil the link between cord blood fatty acid metabolites and autism spectrum disorder symptoms in children

Source: Pixabay CC0

Autism spectrum disorder (ASD) is quite prevalent, but its underlying mechanism is not well understood. In a recent study, researchers from Japan have found a significant link between the levels of specific dihydroxy fatty acids in umbilical cord blood and ASD symptoms. Their findings, published in Psychiatry and Clinical Neurosciences, highlight the role of these metabolites in the developmental trajectory of ASD and could pave the way for early diagnostic techniques and a better understanding of ASD pathophysiology.

Although the exact causes of ASD are unclear, currently available evidence points to neuroinflammation as a major factor. Several studies in mouse models of ASD have hinted at the importance of polyunsaturated fatty acids (PUFA) and their metabolites during pregnancy in playing a key role in ASD development. PUFA metabolites regulated by the cytochrome P450 (CYP) affect foetal development in mice causing impairments closely linked to ASD symptoms. However, it is still unclear if the same is true for humans and needs further investigation.

To address this knowledge gap, a research team led by Professor Hideo Matsuzaki from the Research Center for Child Mental Development, analysed the CYP-PUFA levels in neonatal umbilical cord blood samples. Their study,  sheds light on the possible causes of ASD.

Sharing the motivation behind their study, Prof. Matsuzaki explains, “CYP metabolism forms both epoxy fatty acids (EpFAs), which have anti-inflammatory effects, and dihydroxy fatty acids, or ‘diols,’ which have inflammatory properties. We hypothesized that the dynamics of CYP-PUFA metabolites during the fetal period, that is, lower EpFA levels, higher diol levels, and/or increased EpFA metabolic enzymes would influence ASD symptoms and difficulties with daily functioning in children after birth.”

To test this hypothesis, the researchers investigated the link between PUFA metabolites in umbilical cord blood and ASD scores in 200 children. The cord blood samples had been collected immediately after birth and preserved appropriately, whereas ASD symptoms and adaptive functioning were assessed when the same children were six years old, with the help of their mothers.

After careful statistical analyses of the results, the researchers identified one compound in cord blood that may have strong implications for ASD severity, namely 11,12- dihydroxyeicosatrienoic acids (diHETrE), a dihydroxy fatty acid derived from arachidonic acid. This fatty acid is found in poultry, animal organs and meat, fish, seafood, and eggs.

“The levels of diHETrE, an arachidonic acid-derived diol, in cord blood at birth significantly impacted subsequent ASD symptoms in children and were also associated with impaired adaptive functioning. These findings suggest that the dynamics of diHETrE during the foetal period is important in the developmental trajectory of children after birth,” highlights Prof Matsuzaki.

More specifically, the researchers found that higher levels of the molecule 11,12-diHETrE had an impact on social interactions, whereas low levels of 8,9-diHETrE impacted repetitive and restrictive behaviours. Moreover, this correlation was more specific for girls than for boys. This newfound knowledge could be crucial in understanding, diagnosing, and potentially preventing ASD. By measuring diHETrE levels at birth, it may be possible to predict the likelihood of ASD development in children.

“The effectiveness of early intervention for children with ASD is well established and detecting it at birth could enhance intervention and support for children with ASD,” muses Prof Matsuzaki. He also adds that inhibiting diHETrE metabolism during pregnancy might be a promising avenue for preventing ASD traits in children, although more research will be needed in this regard.

In conclusion, these findings open a promising avenue for researchers unravelling the mysteries surrounding ASD. We hope that enhanced understanding and early diagnostics will be able to improve the lives of people with ASD and their families.

Source: University of Fukui

Categories : CancerTags : Leave a comment

Pancreatic Cancer Drug is Promising Against Most Aggressive Medulloblastoma Subtype

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Pancreatic cancer. Credit: Scientific Animations CC BY-SA 4.0

A drug that was developed to treat pancreatic cancer has now been shown to increase symptom-free survival in preclinical medulloblastoma models – all without showing signs of toxicity. Survival rates for medulloblastoma vary according to which one of the four subtypes a patient has, but the worst survival rates of about 40%, are for Group 3. The research, published in the Journal of Clinical Investigation, focused on this most aggressive subtype.

Jezabel Rodriguez Blanco, PhD, an assistant professor at Medical University of South Carolina, led the research. Her work focused on the drug triptolide, which is extracted from a vine used in traditional Chinese medicine, and its water-soluble prodrug version, Minnelide. A prodrug is an inactive medication that the body converts into an active drug through enzymatic or chemical reactions.

MYC is an oncogene, or gene that has the potential to cause cancer. MYC is dysregulated, or out of control, in about 70% of human cancers, and it shows up in much higher levels in Group 3 medulloblastoma than in the other medulloblastoma subgroups. Despite its well-known role in cancer, this oncogene historically has been considered impossible to target with drugs.

Despite its poor druggability, previous research in other cancers had shown that triptolide and its derivatives had the ability to target MYC. When Blanco was still a postdoctoral fellow at the University of Miami, her mentor, David Robbins, PhD, attended a presentation by the research team that showed that the more copies of MYC that a tumour has, the better that triptolide works.

“He came to me, and he told me, ‘You know, as Group 3 medulloblastoma has many MYC copies, you should get some research models and try the drug,” Blanco recalled. She started the project from scratch. “I started talking to people, getting cell lines and animal models, learning how to propagate them, getting the drug, using it.” 

Blanco received initially received grants to on the Group 3 research, and continued it as a side project. She knew how well triptolide was working in these hard-to-treat tumours, and she did not want her initial results to fall through the cracks.

Determining the mechanism of action has been the most challenging part of the project, she noted, due to the drug’s multiple effects, and there could still be additional mechanisms beyond those that Blanco identified.

“It was affecting MYC gene expression by affecting the RNA pol II activity, and then it was affecting how long the protein lasts. So, the fact that it’s working through two different mechanisms on this oncogene may explain why it’s so effective in tumours that have extra copies of MYC,” she said, explaining that RNA polymerase II is a protein that helps to make copies of DNA instructions, which are used to produce proteins in the cell.

Despite the challenges of narrowing down the mechanism of action specific to the cancer, it was quite clear that however it worked, it did work, she said.

The efficacy was 100 times higher in the Group 3 tumours with extra MYC copies than in the Sonic Hedgehog tumours with normal levels of MYC, she said. She found that Minnelide reduced tumour growth and the spread of cancer cells to the thin tissues that cover the brain and spinal cord, called leptomeninges. It also increased the efficacy of the chemotherapy drug cyclophosphamide, which is currently used in treatment.

Blanco decided to move forward with publication rather than waiting to write a manuscript that answered all possible questions. Knowing that most parents whose children receive a Group 3 medulloblastoma diagnosis will lose their child in less than two years was the incentive she needed to push this work out.

“There was a point at which I could not hold these data anymore because it was working so well that it needed to go out,” she said. “The preclinical models were showing such a nice efficacy that it was like, ‘OK, I cannot keep on holding this work, digging deeper into the mechanism of action because the kids that have Group 3 medulloblastoma are dying while we are doing those experiments.”

Minnelide has been tested or is currently in testing in phase I and phase II clinical trials of adults with different types of cancer, including pancreatic cancer, where it showed some efficacy.

Blanco is hopeful that, with this new research on Group 3 medulloblastoma, a clinical trial for children with this disease can be launched.

Her paper is dedicated to the memory of Insley Horn, a 9-year-old Charleston girl who succumbed to one of these aggressive brain tumours. Research, Blanco said, is the only tool we have to prevent the loss of lives like Insley’s.

Source: Medical University of South Carolina

Categories : Allergies Immune SystemTags : Leave a comment

Scientists Discover that Mast Cells Gobble up Other Immune Cells

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This scanning electron microscopy image captures the moment where degranulating mast cells (pseudo-colored in sepia) attract and start to incorporate living neutrophils (pseudo-colored in cyan), forming cell-in-cell structures where mast cells trap living neutrophils inside them. © Marcus Frank & Karoline Schul11z, Universitätsmedizin Rostock, Germany

When it comes to allergies, mast cells are key immune system players, releasing pro-inflammatory substances in response to allergens. Now, scientists in Germany have discovered something weird: other immune cells nested inside them like Russian dolls. But how exactly did these cells wind up there?

As reported in the journal Cell, the researchers observed mast cells observed capturing and making use of neutrophils. This surprising discovery sheds new light on how our immune system works, particularly during allergic reactions.

Mast cells, residing in tissues and critical for initiating inflammation, are filled with granules containing pro-inflammatory substances. These granules are released upon encountering potential dangers, including allergens, causing allergic reactions – which for some includes innocuous materials like pollens. But despite how common allergies are, the interaction between mast cells and other immune cells at sites of allergic responses has been largely unexplored.

The research group at the Max Planck Institute of Immunobiology and Epigenetics in Freiburg and the University of Münster used specialised microscopy to visualise the real-time dynamics of activated mast cells and other cell types during allergic reactions in living mouse tissues. The team discovered a surprising interaction: neutrophils were found inside mast cells.

“We could hardly believe our eyes: living neutrophils were sitting inside living mast cells. This phenomenon was completely unexpected and probably would not have been discovered in experiments outside a living organism and highlights the power of intravital microscopy,” says Tim Lämmermann, research leader and Director at the Institute of Medical Biochemistry at the University of Münster.

Pulling a neutrophil trick to trap neutrophils

Neutrophils are frontline immune system defenders, responding quickly and broadly to potential threats. They circulate in the blood and quickly exit blood vessels at sites of inflammation. They are well-equipped to combat pathogens by engulfing the invaders, releasing antimicrobial substances, or forming web-like traps known as ‘neutrophil extracellular traps’. Additionally, neutrophils can communicate with each other and form cell swarms to combine their individual functions for the protection of healthy tissue. While much is known about neutrophils’ role in infections and sterile injuries, their role in inflammation caused by allergic reactions is less understood.

“It quickly became clear that the double-pack immune cells were no mere coincidence. We wanted to understand how mast cells trap their colleagues and why they do it,” explains Michael Mihlan, first and co-corresponding author of the study. Once the team was able to mimic the neutrophil trapping observed in living tissue in cell culture, they we were able to identify the molecular pathways involved in this process. The researchers found that mast cells release leukotriene B4, a substance commonly used by neutrophils to initiate their own swarming behaviour.

By secreting this substance, mast cells attract neutrophils. Once the neutrophils are close enough, mast cells engulf them into a vacuole, forming a cell-in-cell structure that the researchers refer to as ‘mast cell intracellular trap’ (MIT). “It is ironic that neutrophils, which create web-like traps made of DNA and histones to capture microbes during infections, are now trapped themselves by mast cells under allergic conditions,” says Tim Lämmermann.

Recycled neutrophils to boost mast cell function

With the help of an international team, the researchers confirmed the formation of MITs in human samples and investigated the fate of the two cell types involved after trapping. They found that trapped neutrophils eventually die, and their remains get stored inside mast cells. “This is where the story takes an unexpected turn. Mast cells can recycle the material from the neutrophils to boost their own function and metabolism. In addition, mast cells can release the newly acquired neutrophil components in a delayed manner, triggering additional immune responses and helping to sustain inflammation and immune defense”, says Michael Mihlan.

“This new understanding of how mast cells and neutrophils work together adds a whole new layer to our knowledge of allergic reactions and inflammation. It shows that mast cells can use neutrophils to boost their own capabilities – an aspect that could have implications for chronic allergic conditions where inflammation occurs repeatedly,” says Tim Lämmermann. The researchers have already begun investigating this interaction in mast cell-mediated inflammatory diseases in humans, exploring whether this discovery could lead to new approaches to treating allergies and inflammatory diseases.

Source: Max Planck Institute of Immunobiology and Epigenetics