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Tag: Cell

  • Researchers unlock the potential of whey-derived proteins for cancer prevention

    Researchers unlock the potential of whey-derived proteins for cancer prevention

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    In a recent review article published in Food and Humanity, researchers summarized the current evidence regarding the significance of whey protein for cancer prevention and treatment.

    Their conclusions highlighted the emerging role of whey protein supplements as a cost-effective, practicable, and viable strategy for cancer treatment and prevention.

    Study: Emerging potential of whey proteins in prevention of cancer. Image Credit: Dan_photography/Shutterstock.comStudy: Emerging potential of whey proteins in prevention of cancer. Image Credit: Dan_photography/Shutterstock.com

    Background

    Cancer is a leading cause of mortality globally, and its prevalence has increased significantly, prompting research to guide the development of effective strategies for treatment and prevention.

    Whey protein, known for its nutritional value and popularity in fitness, has recently garnered attention for its potential anticancer properties.

    Studies suggest whey protein contains bioactive compounds, such as lactoferrin, which demonstrate anticancer effects by inhibiting cancer cell growth and boosting the immune system.

    Whey protein also appears to modulate signaling pathways involved in cancer development, potentially slowing its progression. Additionally, it may enhance the efficacy and reduce the side effects of conventional cancer treatments like chemotherapy and radiation therapy.

    While more research is needed to understand the mechanisms underlying the anticancer effects of whey protein, initial findings offer promising avenues for cancer prevention and treatment.

    Whey protein and its benefits

    Whey protein, formed during milk processing as a by-product, can be sweet or acid. Sweet whey is used widely in supplements, with about 50% of the nutrients found in milk constituting approximately 20% of the protein content of milk.

    Whey contains various nutrients, including bioactive peptides, minerals, B-complex vitamins, and growth factors. These bioactive components, such as lactoperoxidase, beta-lactoglobulin, and lactoferrin, demonstrate diverse bioactivities and functionalities.

    Whey protein is highly regarded for its role in providing essential amino acids and promoting quick absorption, making it ideal for people with cancer and individuals seeking protein-rich diets.

    Commercially, whey protein is available in different forms like whey protein isolates (WPI), whey protein hydrolysates (WPH), and whey protein concentrates (WPC), each with varying protein concentrations.

    Whey protein concentrates generally contain between 25% and 89% protein, while isolates contain between 90% and 95%.

    Whey protein offers numerous health benefits, including weight loss support, muscle preservation, digestive health promotion, hypertension regulation, and anti-carcinogenic effects.

    It has probiotic properties and is a precursor for bioactive compounds like lactulose and lactobionic acid, and exhibits a low glycemic index and cariogenicity compared to other protein sources.

    The therapeutic properties of whey protein are attributed to its antioxidant activity, glutathione enhancement, apoptosis induction, iron-binding capacity, cell proliferation regulation, and potential in treating cancer cachexia-anorexia syndrome.

    It stimulates glutathione synthesis, promotes apoptosis in cancer cells, and regulates cell growth and division through insulin-like growth factor 1 pathways.

    Further research into whey protein and its bioactive components holds promise for enhancing human health and well-being.

    In vivo and clinical cancer studies

    Animal studies demonstrate that whey protein shows promise against oxidative stress-induced tissue injuries and cancers. Its potential anticancer and antioxidant properties may be associated with its ability to increase glutathione levels.

    WPC exhibits advantages over soy, casein, and other proteins in reducing colorectal cancer incidence via glutathione elevation.

    Whey protein diets have also shown promise in managing mucositis for individuals undergoing chemotherapy while improving nutritional outcomes.

    Subfractions of whey protein, particularly bovine lactoferrin and alpha-lactalbumin, exhibit antitumor effects inhibiting tumor development. Researchers are exploring novel nanocarriers incorporating components of whey protein to prevent tumors without side effects.

    Some clinical trials with human participants have shown positive outcomes, which are consistent with the evidence from in vitro studies of whey protein’s antioxidant and anti-cancer.

    Regarding nutritional and performance parameters, interventions that combined supplementation with dietary assistance and exercise improved nutritional parameters and handgrip strength; WPI supplementation also showed promise for protein status strengthening, boosting immunity during chemotherapy, and raising glutathione levels.

    Studies also indicate both positive and complex effects of whey protein concentrate and lactoferrin supplementation on the health of cancer patients.

    While these results are promising, robust multicentric trials must be conducted across various forms of cancer to confirm the pervasive efficacy of whey protein supplementation as an adjuvant therapy.

    Conclusions

    The narrative review discussed the role of whey protein in cancer prevention and treatment based on both animal and clinical studies, highlighting the potential benefits of whey protein, including its antioxidant and anticancer properties, its ability to increase glutathione levels, and its effectiveness in managing mucositis during chemotherapy.

    Various subfractions of whey protein, such as alpha-lactalbumin and lactoferrin, show promising antitumor effects. Additionally, novel approaches like utilizing nanocarriers incorporating whey protein components are being explored for tumor prevention.

    Clinical trials suggest positive outcomes of whey protein supplementation, including improved nutritional and performance parameters, raised glutathione levels and strengthened immunity in cancer patients.

    However, robust multicentric trials across different cancer types are needed to confirm the widespread efficacy of whey protein supplementation as an adjuvant therapy.

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  • New study reveals increased risk of allergic diseases after COVID-19 infection

    New study reveals increased risk of allergic diseases after COVID-19 infection

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    A recent study published in Nature Communications explored the association of COVID-19 with long-term allergic conditions.

    Study: Incident allergic diseases in post-COVID-19 condition: multinational cohort studies from South Korea, Japan and the UK. Image Credit: wavebreakmedia/Shutterstock.comStudy: Incident allergic diseases in post-COVID-19 condition: multinational cohort studies from South Korea, Japan and the UK. Image Credit: wavebreakmedia/Shutterstock.com

    Background

    The severe respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in late 2019, and led to the declaration of a coronavirus disease 2019 (COVID-19) pandemic in March 2020. It caused over seven million deaths and many times that number of infections and hospitalizations.

    Additionally, nearly half of COVID-19 cases have to deal with delayed or chronic morbidity, which may have set in during or after the acute phase of infection. These are called post-COVID-19 conditions or post-acute sequelae of COVID-19 (PASC), otherwise known as long COVID.

    Symptoms of PASC, in some cases, include immunologic phenomena that may cause allergic conditions of various kinds.

    About the study

    The study aimed to investigate how ethnicity affects allergic conditions following COVID-19. Researchers formed a synthetic group comprising over 22 million individuals from South Korea, Japan, and the UK, drawing participants from multinational studies to represent these ethnic backgrounds. S

    pecifically, the South Korean segment included more than 800,000 people with an average age of 48. From the UK and Japan, the cohorts included over 325,000 and 2.5 million participants, respectively.

    Within these groups, approximately 150,000 participants from South Korea, 77,000 from the UK, and 542,000 from Japan had been infected with SARS-CoV-2. This large-scale analysis aimed to shed light on the ethnic variations in post-COVID-19 allergic reactions.

    What were the findings?

    After adjusting for all known variables that could affect the outcome, the researchers discovered that individuals infected with SARS-CoV-2 showed a 20% higher occurrence of allergic diseases compared to those not infected.

    This increased risk was consistent for infections from both the original and Delta variants of the virus. Specifically, the likelihood of developing asthma in those infected was more than double, at 2.25 times that in non-infected individuals.

    The chance of getting allergic rhinitis was 25% higher in the infected group, though no significant increase was observed for food allergies or atopic dermatitis.

    Moreover, while the risk for allergic diseases decreased over time after the infection, it didn’t disappear entirely. This decrease in risk varied from country to country.

    Severity of infection and allergy risk

    Moderate-to-severe COVID-19 was linked to a 50% higher risk of overall allergy, compared to 14% among those with mild disease.

    COVID-19 vaccination and allergy risk

    Those who had received the vaccine had a 44% higher risk of allergy (with one dose). This was reduced by 20% after two doses of the vaccine. The two-dose cohort had comparable allergy risk as the controls, both overall and for the various allergy subgroups.

    Other factors like coexisting morbidity, drinking, body mass index, exercise, and the SARS-CoV-2 strain responsible for the infection, did not show significant correlation with allergy risk.

    Conclusions

    “This is the first study that provides comprehensive evidence for the association between SARS-CoV-2 infection and subsequent incident allergic outcomes.”

    It emphasizes the relationship between COVID-19, especially moderate to severe, and subsequent allergy onset. It also indicates that COVID-19 vaccination with at least two doses weakens the risk of new allergies.

    The findings broadly corroborate earlier research, but there is a need for more studies on the allergic sequelae of COVID-19 on a larger and more multinational scale.

    Multiple pathways have been proposed to account for the observed correlations, including T cell disruption, regulatory T cell (Treg) disturbances, and the cytokine storm in acute severe COVID-19.     

    Over time, the virus may be slowly cleared from the host, especially if adaptive immunity has been strengthened by vaccination against the virus.

    The study underlines “a need for persistent health policies to manage the severity of SARS-CoV-2 infection.” People with a history of COVID-19 should be aware that they are at higher risk for allergic manifestations in the short-term future, at least.

    Journal reference:

    • Oh, J., Lee, M., Kim, M., et al. Incident allergic diseases in post-COVID-19 condition: multinational cohort studies from South Korea, Japan and the UK. Nature Communications. doi: https://doi.org/10.1038/s41467-024-47176-w.

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  • Revolutionizing hepatocyte count for researchers

    Revolutionizing hepatocyte count for researchers

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    Could you start by giving us an overview of the new CellDrop app and its significance in the realm of hepatocyte analysis?

    The Hepatocyte app on the latest version of CellDrop software is the first automated cell counter algorithm designed specifically to count hepatocytes (liver cells). This is also the first cell-counting app from DeNovix that uses machine-learning algorithms to analyze and count cells.

    What are the primary challenges in counting hepatocytes automatically, and how does the CellDrop hepatocyte app address these issues? 

    Counting hepatocytes with automated cell counters presents significant challenges. These cells are not only large and irregularly shaped, but they may also exhibit auto-fluorescence and contain multiple nuclei. Furthermore, hepatocyte samples often include other cell types, such as lymphocytes and erythrocytes, complicating the counting process.

    These factors significantly complicate the algorithms used by even the most advanced image-based cell counters, making it difficult to differentiate single cells from clusters or to identify cells of interest amidst debris. With the CellDrop Hepatocyte app, we worked with experts in the field and trained a machine-learning algorithm to count hepatocytes the way they would on a microscope using trypan blue.

    Then, we added the CellDrop’s dual channel fluorescence capabilities to the algorithm to better distinguish live vs dead and debris vs cells.

    How does the CellDrop app’s performance compare with traditional methods of hepatocyte counting in terms of speed, accuracy, and reliability?

    The Hepatocyte app’s counting speed is much faster than a human, and the area being counted is about 3.5 times larger than what a manual hemocytometer would count, yielding a larger and, therefore, more representative sample, but I think the main advantage is consistency.

    The way I count cells might be slightly different than the way you count cells or even the way I count cells on Friday afternoon might be slightly different than how I would have counted them on Tuesday morning. The Hepatocyte app eliminates all that and standardizes counts between people and labs.

    Could you discuss the app’s potential applications in drug discovery, toxicology, and virology research and how it might change the landscape in these fields?

    Cell counts need to be very accurate and consistent in these workflows where you are using liver models to study the effect of a drug or pathogen. Since hepatocyte cells come directly from a model organism and then are plated and experimentally treated, small variations in the density or viability of the cells between runs can have a statistically significant effect on the result.

    This, of course, requires the researchers to collect more data to confirm these differences and slows the whole process down. I hope that the standardization the CellDrop Hepatocyte app provides will streamline the process for our customers.

    What features have been incorporated into the app to ensure ease of use for researchers, and how accessible is it for varying laboratory setups?

    The CellDrop has an autofocus capability that will ensure that focal planes are consistent, and the Hepatocyte app has a new auto-thresholding feature for determining live/dead fluorescent thresholds. These tools, along with the machine learning count algorithm, should ensure that hepatocyte counts are fast, easy, and consistent.

    Of course, microscope optics, fast processors and machine learning algorithms are not cheap. However, we have tried to make the CellDrop accessible to any lab’s budget by offering a pay-as-you-go option that allows users to buy the CellDrop hardware at a much lower cost and pay a small price as they use counts, eventually paying off the device. This allows labs to spread out the cost over time and based on use.

    What has been the initial feedback from early users of the app, and how has this influenced any further development?

    It was quite exciting and a little stressful the first time I took the Hepatocyte app out in the field for a real beta test. Luckily, we had help from a lot of good scientists refining the algorithm along the way, and the lab was thrilled with the results.

    Since then, we have received a lot of positive feedback, which has been incredibly rewarding after the many months spent in trial and error, fine-tuning the software to meet our expectations.

    Looking ahead, what enhancements or additional features can users expect to see in future versions of the CellDrop app?

    We would like to continue exploring the power of machine learning for cell counting. There are other fields where certain samples, or parts of samples, are difficult to count using traditional cell counting algorithms. We are also studying whether we can apply a similar model to those cell types.

    As the lead on this project, what has been the most rewarding aspect of developing this app, and what are your aspirations for its impact on the scientific community?

    My heart is still in the lab, so I have really enjoyed working closely with hepatocyte researchers and processing/analyzing the samples used in algorithm development.

    I also got to do a lot of the hands-on work training the model itself and see it start to deliver solid and consistent results. I see the tremendous potential machine learning algorithms have for scientific research. It has been a pleasure playing a small part in pushing this technology along.

    Before I started working at DeNovix, I spent a lot of time in graduate school in labs working as a researcher. Cell counting sounds simple, but everybody does it differently. As people work through complicated workflows, we can confirm that they got their cell count right. Helping people like this is really rewarding to me.

    What insights did you gain from developing a product aimed at solving a problem you previously faced as a researcher?

    The main takeaway for me was the critical importance of consistency. No matter the method—be it a machine learning algorithm, the initial approach to cell counting, or manual counting—there will invariably be challenges and ambiguities at the fringes. There are always going to be questions and uncertainties in those gray areas.

    As long as you are doing things consistently, which is what a cell counter does by definition, I think you can work out everything else about the cell count part of the process. This consistency means that, while I may not intervene in later stages of your experiment, such as when you’re performing a western blot or adding antibodies and encountering issues, I can guarantee that the cell counts you receive will be reliable and consistent.

    How has your cell counting technology been received by the scientific community?

    Our cell counter showed up on the Lab Rats Reddit recently. Someone had uploaded an image of cells they had counted using our device, recognizable by the software interface. They sought assistance with identifying a problem, and before I could offer my support, ten other individuals had already provided answers. Witnessing the community engagement and seeing our technology in action, functioning well and facilitating discussions, was truly rewarding.

    About DeNovix Inc.

    Welcome to DeNovix

    Award-Winning Products for Life Science

    Our multi-award winning products include the Reviewers’ Choice Life Science Product of the Year and Platinum Seal awarded- DS-11 Series Spectrophotometer / Fluorometer and CellDrop™ Automated Cell Counter. CellDrop is the first instrument of its kind to Count Cells Without Slides. These powerful instruments integrate patented DeNovix technology with easy-to-use software designed by life scientists for life scientists.

    Researchers tell us they love the industry leading performance, smart-phone-like operation, and the flexible connectivity of the instruments. When support is needed, the DeNovix team is here to help. DeNovix received the prestigious Life Sciences Customer Service of the Year based on independent reviews posted by scientists worldwide!

    CellDrop: Sustainable Laboratory Product of the Year

    The CellDrop Automated Cell Counter has been awarded Sustainable Laboratory Product of the Year in the SelectScience® Scientists’ Choice Awards®!

    CellDrop’s patented DirectPipette™ technology distinguishes it as the only cell counter to eliminate the need for cell counting slides. This innovation saves millions of single-use plastic slides from use and disposal each year.

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  • Atomic-level structural models of enzymes provide disease insights

    Atomic-level structural models of enzymes provide disease insights

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    When nucleic acids like DNA or RNA build up in a cell’s cytoplasm, it sets off an alarm call for the immune system. Enzymes usually clear these nucleic acids before they cause an issue, but when these enzymes don’t work and the immune system gets called in, it can lead to autoimmune and inflammatory diseases.

    In a new study published on March 26, 2024 in the journal Structure, Scripps Research scientists present the previously undescribed structure of two of these nucleic acid-degrading enzymes-;PLD3 and PLD4. Understanding these enzymes’ structures and molecular details is an important step toward designing therapies for the various diseases that arise when they malfunction, which include lupus erythematosus, rheumatoid arthritis and Alzheimer’s disease.

    These enzymes are important for cleaning up the cellular environment, and they also set the threshold for what is considered an infection or not. I’m hoping someday we may be able to help patients based on this information.”


    David Nemazee, PhD, senior author, professor in the Department of Immunology and Microbiology at Scripps Research

    Enzymes are proteins that speed up chemical reactions by binding and reacting to specific molecules called substrates. In the case of PLD3 and PLD4, the substrate is a strand of RNA or DNA, which the enzymes break down nucleotide by nucleotide.

    The team used X-ray crystallography to build atomic-scale models of the PLD3 and PLD4 in multiple states or situations, allowing them to examine how their shapes changed over the course of the catalytic reaction. This included when the enzymes were resting, or when they were actively bound to a substrate.

    “These models allow us to visualize PLD3 and PLD4 very clearly and with high resolution, so we know exactly how every atom interacts, meaning we can deduce how the enzymes work,” says first author Meng Yuan, a staff scientist in the Department of Integrative Structural and Computational Biology at Scripps Research.

    The structural analyses revealed that PLD3 and PLD4 are structurally similar and that they degrade DNA and RNA in a very similar fashion, even though PLD4 is a larger protein. Both enzymes degrade nucleic acids via a two-step process.

    “We call this process a two-step catalysis: bite down and release,” says Yuan. “In the first step, the enzyme bites down on the DNA strand and separates a single ‘brick’ or nucleotide from the rest of the strand, and in the second step, it opens its ‘mouth’ and releases the brick to be recycled.”

    Because the enzymatic reaction happens so quickly-;within milliseconds-;researchers needed to use an alternative substrate to visualize the enzymes’ structure during catalysis. To do this, they incubated the enzymes together with a molecule that looks very similar to the DNA that the enzyme usually degrades, but that the enzymes degrade much more slowly.

    This method uncovered a previously unknown function for one of the enzymes: In addition to biting off nucleotides from single-stranded RNA and DNA, PLD4 also showed phosphatase activity, which means it might also be involved in breaking down DNA’s phosphate backbone.

    “I think it’s amazing that the crystal structure told us about this phosphatase activity,” says Nemazee. “To discover new enzymatic activity is unheard of in structural biology. It’s only because Meng was able to solve such an amazingly accurate and detailed structure that he could inform us about this extra enzymatic activity that we had no idea about.”

    After they had elucidated PLD3 and PLD4’s usual structure, the researchers examined the structure of variants that are associated with diseases, including Alzheimer’s and spinocerebellar ataxia. These analyses revealed that some of these variants had decreased enzymatic capability, while others-;including a mutation associated with late-onset Alzheimer’s-;appeared to be more active.

    “Some of our data suggests that one of these Alzheimer’s-associated enzyme variants might function better, which was a surprise to me, but it also may be less stable and more easily aggregated,” says Nemazee.

    The researchers plan to continue investigating the structure and function of these enzymes. Their next steps include exploring possible ways of inhibiting the enzymes in scenarios where they are overactive, and they also plan to investigate the possibility of replacing the enzymes in people who carry non-functional (or non-working) versions.

    In addition to Nemazee and Yuan, authors of the study, “Structural and mechanistic insights into disease-associated endolysosomal exonucleases PLD3 and PLD4,” were Linghang Peng, Deli Huang, Amanda Gavin, Fangkun Luan, Jenny Tran, Ziqi Feng, Xueyong Zhu, Jeanne Matteson, and Ian Wilson, all of Scripps Research.

    This study was supported by the National Institutes of Health (grants R01AI142945 and RF1AG070775) and Skaggs Institute for Chemical Biology at Scripps Research.

    Source:

    Scripps Research Institute

    Journal reference:

    Yuan, M., et al. (2024). Structural and mechanistic insights into disease-associated endolysosomal exonucleases PLD3 and PLD4. Structure. doi.org/10.1016/j.str.2024.02.019.

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  • New method for detecting and treating breast cancer subtypes

    New method for detecting and treating breast cancer subtypes

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    The most prevalent disease in women, breast cancer, poses a major risk to the health of women. Patients’ clinical treatment and prognosis might differ significantly because of the high levels of intra- and intertumoral heterogeneity in breast cancer.

    New Method for Detecting and Treating Breast Cancer Subtypes
    The dual-mirna triggered DNA-Au nanomachine based on toehold-mediated strand displacement reactions for controlled release of dox. Image Credit: Li S. M., Bi X., Yang F., et al.

    Chemotherapy is now the primary systemic treatment for triple-negative breast cancer (TNBC), a prevalent type of breast cancer that lacks any of the typical breast cancer receptors. However, treatment with a homogeneous high-dose chemotherapy regimen without genetic subtyping usually results in inadequate effectiveness, adding additional stress to patients.

    In a study published in Biomedical Analysis, a group of Chinese researchers describe a novel discriminating and treatment strategy—a dual-miRNA-triggered DNA-programmed nanomachine capable of imaging endogenous miRNA expressions. This method enables subtype-based identification, hence controlling the release of drugs during chemotherapy.

    For the diagnosis and subtyping of breast cancer, histological examination of puncture biopsy sample is the ‘gold standard,’ but it is invasive and difficult to realize dynamic monitoring of tumor progression and prognosis for treatment guidance.”

    Yun Xiang, Study Corresponding Author and Professor, Southwest University

    Xiang added, “Fluorescence imaging techniques are capable of visualizing and monitoring minimal molecular changes occurring at an early stage of cancers with high resolution and sensitivity. However, single miRNA imaging is not suitable for discrimination of cancer cell types.”

    Notably, targeted treatments, like high-dose chemotherapy in TNBC and conventional-dose chemotherapy in other breast subtypes, have not been realized despite prior research showing that dual miRNA-triggered drug release can be applied for cancer therapy via the toehold-mediated strand displacement reactions (TSDR).

    We developed a DNA-programmed nanomachine for effective discrimination and tailored treatment of specific breast cancer cell types.”

    Shunmei Li, Study First Author, Southwest University

    “It is a responsive therapy strategy towards the various cell states. This intelligent nanomachine with controlled release of anti-cancer drug in specific cancer cell subtypes can reduce the side effect to normal cells and facilitate the targeted therapy, which is promising as a theranostics nanoplatform in precise medicine,” Li concluded.

    Source:

    Journal reference:

    Li, S., et. al. (2024) Dual-microRNA triggered and DNA-programmed nanomachine for subtype-based detection and tailored treatment of breast cancer cells. Biomedical Analysis. doi:10.1016/j.bioana.2024.01.001

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  • Stem cell therapy safe and potentially beneficial for spinal cord injury patients

    Stem cell therapy safe and potentially beneficial for spinal cord injury patients

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    A Mayo Clinic study shows stem cells derived from patients’ own fat are safe and may improve sensation and movement after traumatic spinal cord injuries. The findings from the phase 1 clinical trial appear in Nature Communications. The results of this early research offer insights on the potential of cell therapy for people living with spinal cord injuries and paralysis for whom options to improve function are extremely limited.

    In the study of 10 adults, the research team noted seven participants demonstrated improvements based on the American Spinal Injury Association (ASIA) Impairment Scale. Improvements included increased sensation when tested with pinprick and light touch, increased strength in muscle motor groups, and recovery of voluntary anal contraction, which aids in bowel function. The scale has five levels, ranging from complete loss of function to normal function. The seven participants who improved each moved up at least one level on the ASIA scale. Three patients in the study had no response, meaning they did not improve but did not get worse.

    This study documents the safety and potential benefit of stem cells and regenerative medicine. Spinal cord injury is a complex condition. Future research may show whether stem cells in combination with other therapies could be part of a new paradigm of treatment to improve outcomes for patients.”


    Mohamad Bydon, M.D., a Mayo Clinic neurosurgeon and first author of the study

    No serious adverse events were reported after stem cell treatment. The most commonly reported side effects were headache and musculoskeletal pain that resolved with over-the-counter treatment.

    In addition to evaluating safety, this phase 1 clinical trial had a secondary outcome of assessing changes in motor and sensory function. The authors note that motor and sensory results are to be interpreted with caution given limits of phase 1 trials. Additional research is underway among a larger group of participants to further assess risks and benefits.

    The full data on the 10 patients follows a 2019 case report that highlighted the experience of the first study participant who demonstrated significant improvement in motor and sensory function.

    Stem cells’ mechanism of action not fully understood

    In the multidisciplinary clinical trial, participants had spinal cord injuries from motor vehicle accidents, falls and other causes. Six had neck injuries; four had back injuries. Participants ranged in age from 18 to 65.

    Participants’ stem cells were collected by taking a small amount of fat from a 1- to 2-inch incision in the abdomen or thigh. Over four weeks, the cells were expanded in the laboratory to 100 million cells and then injected into the patients’ lumbar spine in the lower back. Over two years, each study participant was evaluated at Mayo Clinic 10 times.

    Although it is understood that stem cells move toward areas of inflammation -; in this case the location of the spinal cord injury -; the cells’ mechanism of interacting with the spinal cord is not fully understood, Dr. Bydon says. As part of the study, researchers analyzed changes in participants’ MRIs and cerebrospinal fluid as well as in responses to pain, pressure and other sensation. The investigators are looking for clues to identify injury processes at a cellular level and avenues for potential regeneration and healing.

    The spinal cord has limited ability to repair its cells or make new ones. Patients typically experience most of their recovery in the first six to 12 months after injuries occur. Improvement generally stops 12 to 24 months after injury. One unexpected outcome of the trial was that two patients with cervical spine injuries of the neck received stem cells 22 months after their injuries and improved one level on the ASIA scale after treatment.

    Two of three patients with complete injuries of the thoracic spine -; meaning they had no feeling or movement below their injury between the base of the neck and mid-back -; moved up two ASIA levels after treatment. Each regained some sensation and some control of movement below the level of injury. Based on researchers’ understanding of traumatic thoracic spinal cord injury, only 5% of people with a complete injury would be expected to regain any feeling or movement.

    “In spinal cord injury, even a mild improvement can make a significant difference in that patient’s quality of life,” Dr. Bydon says.

    Research continues into stem cells for spinal cord injuries

    Stem cells are used mainly in research in the U.S., and fat-derived stem cell treatment for spinal cord injury is considered experimental by the Food and Drug Administration.

    Between 250,000 and 500,000 people worldwide suffer a spinal cord injury each year, according to the World Health Organization.

    An important next step is assessing the effectiveness of stem cell therapies and subsets of patients who would most benefit, Dr. Bydon says. Research is continuing with a larger, controlled trial that randomly assigns patients to receive either the stem cell treatment or a placebo without stem cells.

    “For years, treatment of spinal cord injury has been limited to supportive care, more specifically stabilization surgery and physical therapy,” Dr. Bydon says. “Many historical textbooks state that this condition does not improve. In recent years, we have seen findings from the medical and scientific community that challenge prior assumptions. This research is a step forward toward the ultimate goal of improving treatments for patients.”

    Dr. Bydon is the Charles B. and Ann L. Johnson Professor of Neurosurgery. This research was made possible with support from Leonard A. Lauder, C and A Johnson Family Foundation, The Park Foundation, Sanger Family Foundation, Eileen R.B. and Steve D. Scheel, Schultz Family Foundation, and other generous Mayo Clinic benefactors. The research is funded in part by a Mayo Clinic Transform the Practice grant.

    Source:

    Journal reference:

    Bydon, M., et al. (2024). Intrathecal delivery of adipose-derived mesenchymal stem cells in traumatic spinal cord injury: Phase I trial. Nature Communications. doi.org/10.1038/s41467-024-46259-y.

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  • New treatment rejuvenates elderly defenses

    New treatment rejuvenates elderly defenses

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    In a recent study published in Nature, researchers developed a treatment to restore the immunological system to a younger condition, with fewer myeloid-biased output-hematopoietic stem cells (my-HSCs), more HSCs, and a balanced generation of myeloid and lymphoid lineage cells (bal-HSCs).

    Study: Depleting myeloid-biased haematopoietic stem cells rejuvenates aged immunity. Image Credit: Lightspring / Shutterstock.com Study: Depleting myeloid-biased haematopoietic stem cells rejuvenates aged immunity. Image Credit: Lightspring / Shutterstock.com

    The effects of aging on the immune system

    The aging immune system is associated with reduced lymphopoiesis, increased inflammation, and myeloid diseases due to alterations in self-renewing HSCs. During childhood, bal-HSCs predominate, thereby facilitating lymphopoiesis and adaptive immune responses.

    Age increases my-HSCs, which reduces lymphopoiesis and enhances myelopoiesis. Myeloid-HSC origin and possible interconversions are unclear; however, removing my-HSCs in aged mice may reverse the aging phenotype.

    About the study

    The researchers investigated whether antibody-regulated reduction of my-HSCs may cure age-related immunological reductions by restricting myeloid cell-induced inflammation and restoring lymphopoiesis. To this end, the impact of reduced my-HSCs on the hematopoietic system, immunological phenotypes, and functional responses to incident infections was assessed.

    Several cell-surface antigen molecules were developed and validated to identify potential targets for therapeutic my-HSC reduction. The levels of my-HSCs and balanced-HSCs were determined using antibodies and flow cytometry.

    Several my-HSC antigens, including neogenin 1 (NEO1), cluster of differentiation 62p (CD62p), and CD150, were subsequently targeted to determine their role in reducing my-HSC levels. Separate antibody-conditioning treatments were then developed for my-HSC depletion for each target, with a focus on cell clearance regulators such as anti-phagocytic signals, isotype, and antibody density.

    To establish the role of CD150 targeting, the ability of CD150-targeted antibodies to reduce my-HSCs in vivo was assessed. To target CD62p or NEO1, goat anti-mouse NEO1 antisera was mixed with anti-CD47 and anti-KIT antibodies.

    Gene expression analysis of pure total HSCs extracted from 11-month-old mice was performed to confirm alterations in HSC composition following my-HSC elimination. Transplant tests using pure HSCs were also performed to compare the myeloid and lymphoid lineage potential in recipient mice.
    After antibody conditioning, myeloid and common lymphocyte progenitors (CLPs) were measured in murine bone marrow. These analyses were performed after one week to assess acute effects, as well as after eight and sixteen weeks to determine long-term effects. The impact of this treatment on non-self-renewing progenitors was also evaluated after eight weeks.

    T-cell subsets were analyzed using canonical markers or cluster-based analysis. The effects of my-HSC depletion in aged animals on pro-inflammatory mediators and functional immunity to infection were also examined by analyzing mouse immune responses to a live-attenuated virus and subsequent challenge with a pathogenic viral infection using the mouse Friend retrovirus (FV) model.

    Study findings

    Antibody-mediated reduction of my-HSCs in elderly mice restored young immune system characteristics, such as increased CLPs, naïve T-cells, and B-cells, while lowering immunological decline indicators associated with aging. Depletion of my-HSCs in old mice increased primary and secondary adaptive immune responses to viral infection.

    Twelve potential genes that encode cell-surface proteins significantly expressed in aged HSCs and my-HSCs were identified. Moreover, CD150, CD4, CD6, CD62p20, and NEO1 were identified as markers for my-HSCs.

    Antibodies to CD41 and NEO1 enhanced the frequency of my-HSC staining, thus indicating myeloid bias. CD62p targeting resulted in the highest my-HSC enrichment.

    The most abundant protein molecules on my-HSCs were NEO1, CD41, and CD62p. Flow cytometry analysis did not identify any surface protein strongly expressed by the subgroups, except CD41, which was highly expressed by megakaryocyte progenitor cells.

    Anti-CD150 antibodies significantly reduced my-HSCs in mice, thereby increasing naïve T-cell and mature B-cell levels. In aged mice, CD4+ T lymphocytes with an exhausted phenotype (PD1+ CD62L-) grew more than those with a non-exhausted phenotype (PD1- CD62L+).

    Antibody training reduced CD4+ PD1+ CD62L- cells as compared to CD4+ PD1- CD62L+. Aged mice also acquired age-associated B-cells associated with impaired humoral immunity.

    Antibody training reduced the levels of pro-inflammatory proteins including interleukin-1 alpha (IL-1α), and C‐X‐C motif chemokine ligand 5 (CXCL5), which were higher in elderly animals. Aged animals with my-HSC depletion exhibited higher virus-specific CD8+ T-cell responses in the spleen following vaccination, thus indicating a better initial response to live-attenuated viral infection.

    Conclusions

    Rising my-HSC levels during aging may result in inadequate adaptive immunological and inflammatory responses. Thus, depleting my-HSCs may improve immune responses by enhancing the synthesis of new T- and B-cells while decreasing the production of inflammatory myeloid cells. In the current study, my-HSC depletion in older animals allowed bal-HSCs to recover youthful immunological characteristics such as enhanced lymphocyte progenitors and naïve cells and decreased lymphocyte dysfunction or exhaustion indicators and inflammatory mediators.

    Further research could refine conditioning techniques and examine the impact on differentiated cells, such as regulatory T-cells.

    Journal reference:

    • Ross, J. B., Myers, L. M., Noh, J. J., et al. (2024). Depleting myeloid-biased haematopoietic stem cells rejuvenates aged immunity. Nature. doi:10.1038/s41586-024-07238-x

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  • Space travel alters human vascular cell function, study finds

    Space travel alters human vascular cell function, study finds

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    In a recent study published in NPJ Microgravity, scientists explore the impact of spaceflight on human vascular smooth muscle cells at the transcriptomic level.

    Study: Spaceflight effects on human vascular smooth muscle cell phenotype and function. Image Credit: Cinefootage Visuals / Shutterstock.com

    Study: Spaceflight effects on human vascular smooth muscle cell phenotype and function. Image Credit: Cinefootage Visuals / Shutterstock.com

    Background

    Astronauts traveling in spaceflight are exposed to a highly hostile environment characterized by microgravity, high-level radiation, and many other foreign factors. Taken together, these factors induce a wide range of physiological changes, especially at the cellular level.

    More specifically, human exposure to microgravity can cause muscular atrophy, bone resorption, flattening of the eye, and cardiovascular deconditioning. The latter is characterized by loss of vascular tone, reduced total blood volume, and diminished cardiac output, and it can lead to severe health complications in astronauts.

    In the current study, scientists explore cardiovascular deconditioning-associated behavioral changes at the cellular level. To this end, human vascular smooth muscle cells cultured in microgravity and aboard the International Space Station (ISS) were subjected to a transcriptomic analysis to determine the mechanisms involved in potential pathway regulation.

    Important findings

    Compared to control cells, which remained at the ground level, spaceflight vascular smooth muscle cells exhibited differential expression of over 4,422 genes, 43% of which were upregulated and 57% downregulated.

    The pathway analysis of transcriptomic data identified 28 pathways that were significantly inhibited. Comparatively, the phosphatase and tensin homolog (PTEN) signaling and peroxisome proliferator-activated receptor α (PPARα)/retinoid X receptor α (RXRα) pathways were significantly activated.

    Three networks associated with differentially expressed genes were identified and corresponded to cardiovascular disease, as well as cardiovascular system development and function.

    Spaceflight also strongly affected several components of the signal transducer and activator of transcription 3 (STAT3), nuclear factor κB (NF-κB), phosphoinositide 3 kinase (PI3K)/AKT, hypoxia-inducible factor 1 α (HIF1α), and endothelin-1 pathways.

    A total of 22 cardiovascular signaling pathways were also identified, three of which were significantly inhibited. These pathways were involved in cardiac hypertrophy signaling, the role of nuclear factor of activated T-cells (NFAT) in cardiac hypertrophy, and cardiac hypertrophy signaling.

    Gene ontology (GO) analysis of significantly affected differentially expressed genes was also performed. Moreover, GO annotations were divided into three parent terms of biological process, cellular component, and molecular function.

    Most of the differentially expressed genes were associated with extracellular processes and extracellular matrix interaction terms. Extracellular region and space were the most represented cellular component terms. Molecular function included several binding terms, such as heparin, extracellular matrix, and glycosaminoglycan binding, as well as extracellular matrix structural constituent.

    The analysis of cellular component and molecular function terms revealed significant changes in extracellular matrix genes related to both production and cellular adherence. The analysis of biological process terms showed enrichment of cell, cell-cell, and homophilic cell adhesion. 

    These findings collectively indicate significant changes in extracellular matrix function and binding, as well as cellular processes related to proliferation, migration, and angiogenesis in spaceflight-exposed vascular smooth muscle cells.

    Further analysis revealed that upregulated genes were associated with cell division-related processes and components. Comparatively, downregulated genes were associated with cellular adhesion, signal transduction, and various binding functions, including protein, calcium ion, heparin, and integrin binding.

    Significantly altered expression of genes related to vascular smooth muscle cell contraction, synthetic and osteogenic phenotypes were observed during spaceflight. Most of the components related to these phenotypes, including smooth muscle alpha-actin (αSMA), matrix metalloproteinases (MMPs), and bone morphogenic proteins (BMPs), were downregulated in vascular smooth muscle cells exposed to spaceflight.

    Study significance

    The current study reports a reduction in the contractile phenotype of vascular smooth muscle cells exposed to spaceflight. These cells also appear to undergo a phenotype switching towards a synthetic or osteogenic phenotype. Additionally, the downregulated expression of most of the identified genes indicates that spaceflight exposure causes broad transcriptional inhibition in vascular smooth muscle cells.

    Given the unaltered functioning of certain cellular processes during a 72-hour spaceflight, the scientists hypothesize that vascular smooth muscle cells may adapt to microgravity when exposed to the space environment for more than 72 hours. However, genetic changes may collectively lead to an alteration in vascular smooth muscle cell functions.

    Future studies are needed to determine the specific mechanisms by which cells alter their behavior in response to spaceflight.  

    Journal reference:

    • Scotti, M. M., Wilson, B. K., Bubenik, J. L., et al. (2024). Spaceflight effects on human vascular smooth muscle cell phenotype and function. NPJ Microgravity 10(41). doi:10.1038/s41526-024-00380-w/

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  • DNA repair process key to memory formation, study finds

    DNA repair process key to memory formation, study finds

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    In a recent study published in the journal Nature, researchers found that the recruitment of neurons to memory circuits is preceded by a cascade of molecular events induced during learning, which includes double-stranded deoxyribonucleic acid (DNA) damage in hippocampal neuronal clusters and repair mediated by toll-like receptor 9 (TLR9).

    Study: Formation of memory assemblies through the DNA-sensing TLR9 pathway. Image Credit: Billion Photos / ShutterstockStudy: Formation of memory assemblies through the DNA-sensing TLR9 pathway. Image Credit: Billion Photos / Shutterstock

    Background

    Memories are formed when neurons in the hippocampus undergo long-term molecular adaptations to form cortical microcircuits in response to stimuli. This process is energy-intensive and involves substantial morphological and biochemical changes. These molecular changes are believed to cause transient breaks in the double-stranded DNA.

    Studies have also explored the role of intrinsic neuronal and pre-existing developmental programs in memory formation and have found that transcriptional factors such as cyclic adenosine monophosphate (cAMP)-response element binding protein (CREB) are involved in the process. Recent research has also focused on understanding how interneuronal perineuronal nets control inhibitory inputs to neuronal assemblies to stabilize memory circuits.

    About the study

    In the present study, the researchers attempted to understand and identify any overarching processes that integrated pre-existing developmental mechanisms and stimulus-initiated pathways that influenced neurons to commit to assemblies or microcircuits specific to memory.

    Murine models were used to analyze transcriptional profiles of neurons in the dorso-hippocampal regions for more than 48 hours to understand immediate, early, and delayed gene expressions and protein signaling. For this analysis, mice were subjected to contextual fear conditioning, and hippocampus samples obtained either four or 21 days after the conditioning were used for bulk ribonucleic acid (RNA) sequencing.

    Given that transient breaks in double-stranded DNA are known to be induced during neuronal activity for the induction of immediate early gene expression, they hypothesized that the DNA damage induced by learning activity might be more extensive and sustained in discrete populations of neurons. Immunofluorescence labeling was conducted using antibodies specific for the phospho-histone γH2AX binding to double-stranded DNA breaks to understand the origin of the contextual fear conditioning-generated extranuclear double-stranded DNA fragments.

    Brain sections were also collected an hour after contextual fear conditioning to analyze the γH2AX signals associated with immediate early gene expression. Additionally, the baseline expression of CREB, which has already been identified to play a role in memory, was also analyzed using immunostaining. The researchers also examined the upregulation of the Fos protein during memory reactivation and the respective roles of immediate early gene expression and DNA damage repair.

    Based on their identification of inflammatory signaling in these neuronal populations, the researchers further investigated whether these inflammatory responses were a result of the double-stranded DNA breaks induced during learning or the inflammation had a specific role to play in memory formation. Given the role of TLR9 in these inflammatory responses, they conducted TLR9 knockout experiments in specific neurons to determine how it impacted memory formation.

    Additionally, single nuclear RNA sequencing was performed to characterize gene expression changes in neuronal and non-neuronal hippocampal cell populations due to the impact of contextual fear conditioning and neuron-specific knockout of TLR9. The researchers also examined the contributions of infiltrating immune cells and cell-free DNA from blood in memory formation and the upregulation of TLR9 signaling.

    Results

    The study found that learning and memory formation involved ruptures in the nuclear envelope, the release of histone into the perinuclear region, and persistent breaks in double-stranded DNA in clusters of neurons in the Cornu Ammonis 1 (CA1) region of the hippocampus. Furthermore, these damages to the double-stranded DNA and nuclear envelope were followed by TLR9 signaling activation, a resulting inflammatory response, and the accumulation of centrosomal complexes to repair the damaged double-stranded DNA.

    The role of TLR9-associated inflammatory responses in the establishment of learning-induced memory was confirmed when TLR9 knockout in specific neurons resulted in memory impairments and the blunting of gene expression changes linked to contextual fear conditioning. TLR9 was also found to play an important role in the formation of DNA damage, repairing centrosomal complexes, ciliogenesis, and the construction of perineuronal nets.

    The results suggested that learning-associated stimuli triggered a cascade of molecular events that included double-stranded DNA damage and DNA repair mediated by TLR9 in specific neuronal clusters in the hippocampus that recruited these neurons for memory formation. The researchers also speculated that when TLR9 function is compromised, errors in this fundamental mechanism could lead to cognitive impairments, psychiatric disorders, acceleration of senescence, and neurodegenerative disorders.

    Conclusions

    To summarize, the study found that learning-associated stimuli trigger a cascade of DNA damage and TLR9-mediated DNA repair that commit hippocampal neuronal clusters to memory formation. The inflammatory responses mediated by TLR9 have a vital role in memory formation, and impairments in TLR9 function could be implicated in cognitive, neurodegenerative, and psychiatric disorders.

    Journal reference:

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  • New insights into gas vesicle clustering in bacteria open doors for biomedical applications

    New insights into gas vesicle clustering in bacteria open doors for biomedical applications

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    Gas vesicles are hollow structures made of protein found in the cells of certain microorganisms, and researchers at Rice University believe they can be programmed for use in biomedical applications.

    Inside cells, gas vesicles are packed in a beautiful honeycomb pattern. How this pattern is formed has never been thoroughly understood. We are presenting the first identification of a protein that can regulate this patterning, and we believe this will be a milestone in molecular microbiology.”


    George Lu, assistant professor of bioengineering and a Cancer Prevention and Research Institute of Texas scholar

    Lu and colleagues have published their findings in a paper published in Nature Microbiology. The lead author is Zongru Li, a fourth-year bioengineering doctoral student in Lu’s Laboratory for Synthetic Macromolecular Assemblies.

    “Gas vesicles are cylindrical tubes closed by conical end caps,” Li said. “They provide buoyancy within the cells of their native hosts.”

    The vesicles are found naturally in five phyla of bacteria and two groups of the archaea (single-cell organisms). Most are restricted to planktonic microorganisms often found in fresh-water ponds. The recent engineering of vesicles has led to several applications, including reporter gene imaging, acoustic control and payload delivery.

    Co-author Yifan Dai, assistant professor of biomedical engineering at McKelvey School of Engineering at Washington University in Saint Louis, said they were drawn to the research with the question of why the vesicles can form in the honeycomb pattern.

    With help from his WashU colleague Alex Holehouse and colleagues from Duke University, Ashutosh Chilkoti and Lingchong You, the team of researchers found that this pattern is the most efficient use of space and the cluster form plays a part in how it functions. Most notably, these protein clusters formed in subsaturated solution, a previously identified new form of biological structure, and that drives the organization of these vesicles. Bottom line, they found the function behind this mysterious new form.

    “These teams led by Lu lab found that a unique form of protein clusters exclusively assembled in subsaturated solution drives the clustering behaviors,” said Dai. This adds to the line of evidence on how phase transition affects cellular organization and cellular functions, he added.

    Lu and his team, using genetic, biochemical and imaging approaches, are exploring the protein nanostructures. Gas vesicles stabilize the air bubbles inside the bacterial cytosol ⎯ the fluids inside the cells ⎯ and provide a liquid-gas interface which can be used for ultrasound or MRI contrast.

    “In our lab, we are leveraging the power of synthetic biology to expand the applications of these protein nanostructures,” Li said. “By engineering genes and cells, we aim to build gas vesicles that perform even more efficiently in biotechnological and biomedical applications.”

    Li earned his B.S. in chemical engineering from the University of Rochester in 2018 and his M.S. in biotechnology from Northwestern University in 2020.

    Co-authors of the paper are Andrew Anderson, Manuel Iburg, Qionghua Shen, postdoctoral researchers in BIOE at Rice; Richard Lin ’23 BIOE, sustainable solutions and innovation analyst, NRG; Brandon Zimmer ’23 BIOE; Matthew Meyer, Rice electron microscopy research scientist; Yifan Dai and Alex Holehouse, assistant professors of biomedical engineering at WashU; Lingchong You, James L. Meriam Distinguished Professor of Biomedical Engineering at Duke; Ashutosh Chilkoti, the Alan L. Kaganov Distinguished Professor of Biomedical Engineering at Duke; and Emery Usher, postdoctoral researcher in biochemistry and molecular biology at WashU.

    The research was supported by the Cancer Prevention and Research Institute of Texas, the National Institutes of Health (R00 EB024600, R21 EB033607), the Welch Foundation, G. Harold and Leila Y. Mathers Foundation, Hearing Health Foundation, John S. Dunn Foundation, German Research Foundation, W.M. Keck Foundation, the Institute of Biosciences and Bioengineering at Rice and the Air Force Office of Scientific Research (FA9550-20-1-0241).

    Source:

    Journal reference:

    Li, Z., et al. (2024). Phase transition of GvpU regulates gas vesicle clustering in bacteria. Nature Microbiology. doi.org/10.1038/s41564-024-01648-3.

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