Carbon Chemist

Tag: Molecule

  • Sapio Sciences launches new multimodal registration capabilities for its lab informatics platform

    Sapio Sciences launches new multimodal registration capabilities for its lab informatics platform

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    Sapio Sciences, the science-awareTM lab informatics platform, today announced the launch of its new multimodal registration capabilities. This new functionality unifies small-molecule, large-molecule, and multimodal discovery workflows, including entity registration, on a single platform.

    With these latest features, Sapio is helping R&D teams overcome the collaboration and efficiency challenges traditionally associated with the development of multimodal therapies and products.   

    New modalities, such as recombinant proteins, peptides, and engineered antibodies, are key drivers of biopharmaceutical industry growth. According to BCG, revenues from new-modality products increased by $60 billion over the past few years, while revenues from conventional products declined by $10 billion.

    Furthermore, BCG projects that the percentage value of new modalities in the five-year forward pipeline between 2019 and 2023 will increase from 41% to 56%, far outpacing conventional ones.

    “The days of viewing drug discovery through the separate lenses of small molecules and large molecules are outdated,” said Kevin Cramer, president and CEO of Sapio Sciences. “Today, drug discovery in biopharma is increasingly multimodal, and leading-edge laboratories require a single unified informatics platform that supports small-molecule, large-molecule, and new modality discovery workflows, including registration.”

    Today, companies typically use separate registration systems, one for small molecules and another for large molecules. For multimodal discovery, separate registration becomes problematic. A unified registration system solves this by enabling researchers from diverse departments, such as chemistry and molecular biology, to work together on new modalities seamlessly, manage all data in one place, have one system for regulatory compliance, and collaborate with a single source of truth.

    The foundation of the Sapio Platform is a single materials management system that does not distinguish between small-molecule, large-molecule, or multimodal entities — rather, they are all collected and managed as molecular materials with attributes that record the unique characteristics of each type of entity.

    Uniquely, Sapio also connects its sample management with registered entities for seamless data visualizations and traceability.  As a result, chemists and biologists can work together on a single, unified drug discovery platform that combines Sapio LIMS™, Sapio ELN™ and Sapio Jarvis™ to integrate and harmonize collective scientific data across the laboratory informatics enterprise.

    New biotech ventures will want to adopt the Sapio Platform now to address leading-edge new modality drug discovery opportunities and position themselves for accelerated discovery and insights from day one.

    Established biopharma enterprises will want to reassess the limitations and risks of currently deployed separate chemistry- and biology-centric informatics and evaluate the benefits and advantages of a single unified lab informatics platform from Sapio to optimize leading-edge multimodal drug discovery.

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  • Vaccines targeting chronic diseases show promise in combatting age-related conditions

    Vaccines targeting chronic diseases show promise in combatting age-related conditions

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    In a recent review published in Nature Aging, researchers explored vaccine-based therapeutics for age-related disorders.

    Study: Targeting aging and age-related diseases with vaccines. Image Credit: Ground Picture/Shutterstock.comStudy: Targeting aging and age-related diseases with vaccines. Image Credit: Ground Picture/Shutterstock.com

    Background

    Aging is a primary risk factor for chronic illnesses, marked by reduced physiological capabilities. Cell senescence, genomic instability, stem cell fatigue, and mitochondrial failure are characteristics.

    Aging also increases the risk of chronic illnesses such as Alzheimer’s disease, atherosclerosis, osteoarthritis, type 2 diabetes, chronic obstructive pulmonary disease (COPD), and cancer. Healthy habits like calorie control and regular physical exercise help prevent age-related disorders.

    However, small-molecule therapies have limits, and vaccines provide a potential technique to target specific antigens to generate immune responses.

    About the review

    In the present review, researchers present new developments in vaccines using senescent cells to target the etiological agents of aging and related diseases.

    Immunology of senolytic vaccines that target aging

    Vaccines stimulate the innate immunological system, making it rapidly respond to infection. This reaction activates adaptive immune cells, causing humoral antibodies to manufacture antibodies and cell-mediated immunity to attack infected cells. Vaccinations lead to pathogen-targeted memory cell development to accelerate response to reinfections.
    Vaccines targeting microbes, cell populations, or chemicals can prevent and treat disease development. Senolytic vaccines, which target senescent cells, have been demonstrated to reduce arterial plaque development.

    These vaccination techniques provide new pathways for managing age-associated disorders, with advantages such as fewer injections, increased patient adherence, cost-effectiveness, and improved targeting efficiency.

    Senolytic vaccinations target senescent cells by targeting chemicals on their surfaces, using peptide-based platforms to eradicate them through complement-dependent cytotoxicity (CDC) or natural killer (NK) cell-mediated and antibody-dependent cell-mediated cytotoxicity (ADCC).

    Membrane proteins overexpressed in senescent cells are used as vaccine antigens or immune cell targets to stimulate the development of specific antibodies.

    Tumor-associated antigens (TAAs) and tumor-specific antigens (TSAs) trigger a cluster of differentiation 4-expressing helper T cells, CD8+ cytotoxic T cells, and B cells to kill cancer cells.

    Cancer vaccines use cell-based, virus-based, peptide-based, and nucleic acid-based platforms to stimulate adaptive immunity.

    Research on vaccine-based strategies for age-related disorders

    Alzheimer’s disease (AD) vaccinations attempt to lower the brain’s amyloid-beta (Aβ) and tau protein levels by stimulating the adaptive immune system to produce antibodies. Peptides with neuroprotective properties are potentially possible therapies.

    Vaccines like ACI-24, UB-311, AV-1959D, ABvac40, ACI-35, AADvac1, and GV1001 target Aβ and tau proteins in innate immune cells. ACI-24 targets Aβ1-15 liposomes, UB-311 targets Aβ protein, AV-1959D targets deoxyribonucleic acid (DNA), ABvac40 targets Aβ protein, ACI-35 targets tau protein accumulation, and AADvac1 and GV1001 demonstrate long-term safety, tolerance, and immunogenicity.

    Type 2 diabetes vaccinations target molecules like dipeptidyl-peptidase 4 (DPP4) and interleukin-1 beta (IL-1β) to restore levels and prevent problems.

    The vaccines use peptide sequences to produce anti-DPP4 antibodies, increase glucose tolerance, restore beta cell mass, and reduce IL-1β production. They also couple prorenin epitopes with keyhole limpet hemocyanin (KLH), improving retinal blood circulation, decreasing microglia activation, and reducing gliosis and vascular leakage in diabetic rats.

    Vaccines for age-related vascular diseases such as hypertension, abdominal aortic aneurysm (AAA), and atherosclerosis target molecules that regulate blood pressure, cholesterol, and blood vessel function. PMD-2850, PMD-3117, CYT006-AngQb, AT1R, ATRQβ-001, and ADR-004 inhibit angiopoietin 1 (Ang I) and age-related accumulation in hypertensive rats.

    Vaccines containing KLH and Ang II decreased macrophage aggregation in the AAA wall, suppressed tumor necrosis factor (TNF) expression, and protected against elastic fiber injury.

    The nerve growth factor (NGF) protein is an osteoarthritis target. Researchers covalently linked recombinant NGF proteins to virus-like particles (VLPs) derived from a cucumber mosaic virus with tetanus toxoid epitopes.

    Vaccinated mice developed measurable antibodies against NGF and showed reversed pain behavior. ADAM metallopeptidase domain 12 (ADAM12) and GLI family zinc finger 1 (GLI1) levels are associated with fibrosis. Lentiviral vectors that encode these proteins decrease fibrotic activity in mice.

    Proprotein convertase subtilisin/kexin type 9 (PCSK9) can treat fibrosis. PCSK9Qβ-003, an epitope peptide, enhanced kidney fibrosis, and increased fatty acid beta-oxidation-associated variables among Ldlr+/− murine animals. The vaccine can treat kidney fibrosis, hypercholesterolemia, and atherosclerosis.

    Conclusions

    Based on the review findings, senescent cells play a significant role in age-related chronic disorders and demonstrate immunogenicity, making them candidates for targeted vaccine elimination.

    However, vaccinations can cause adverse effects such as injection site redness, discomfort, fever, and headaches. Continuous evaluation of vaccination safety is required to comprehend long-term adverse effects.  

    Vaccines targeting key mediators in age-related disorders have seldom proven efficacy in slowing disease development. Researchers must select antigens from key disease drivers or investigate epitopes generating robust immune responses to boost vaccination effectiveness.

    Combinatorial therapy incorporating vaccinations and immunomodulatory medications may be more effective.

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  • Unveiling the key role of RNA modification in HIV-1 survival and replication

    Unveiling the key role of RNA modification in HIV-1 survival and replication

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    A chemical modification in the HIV-1 RNA genome whose function has been a matter of scientific debate is now confirmed to be key to the virus’s ability to survive and thrive after infecting host cells, a new study has found.

    This change to HIV-1 RNA, a tiny chemical modification on the adenosine building block of RNA known as m6A, is a common RNA editing process in all life forms that involves altering gene expression and protein production. The functional effect often represents a cellular solution but, in some cases, leads to disease.

    By developing technological advances to observe a full length of HIV-1 RNA, researchers at The Ohio State University discovered the m6A modification occurs nearly exclusively at three specific locations on the HIV-1 RNA genome – out of the total 242 potential sites that can harbor an m6A – and these three m6As are crucial in viral replication. The finding suggested that redundancy was built into the system, and further analyses suggested that is, indeed, the case with HIV-1.

    “These sites are very important for producing virus proteins and for producing viral genomic RNA,” said senior study author Sanggu Kim, associate professor of veterinary biosciences and an investigator in the Center for Retrovirus Research at The Ohio State University.

    “An intriguing question is, why does HIV maintain multiple m6As? Our conclusion is that m6A is so important that HIV wants to have multiples to have redundancy. If it loses one or two, it’s OK. If it loses all three, it’s a problem.”

    Though any drug development associated with this work is years away, Kim said the finding suggests targeting the site-specific m6A modifications could be the basis of designing an important new treatment for HIV infection.

    The study is published today (April 11, 2024) in the journal Nature Microbiology.

    HIV-1, the most common type of the human immunodeficiency virus, attacks immune cells and uses them to make copies of itself. An estimated 1.2 million people in the United States have HIV, according to the 2023 report from the Centers for Disease Control and Prevention.

    The virus is a good example of why research on RNA modification has been getting a lot of attention in recent years, Kim said. Once thought of as the “middle guy” between DNA’s genes and life-sustaining proteins, RNA is now known to contain not just genetic information, but also to possess functional significance – in part because of the chemical modifications that accompany its messenger task.

    Especially because HIV is an RNA virus with a very compact RNA genome, it has to encode all of the survival information within its RNA genome – it’s using not only nucleotide sequences, but all of the chemical and structural features of RNA as codes to execute its infection of host cells. We know every aspect of RNA function is very important, but we don’t really know how exactly these chemical and structural modifications of RNAs regulate virus infection.”


    Sanggu Kim, associate professor of veterinary biosciences and investigator in the Center for Retrovirus Research at The Ohio State University

    Though the m6A (short for N6-methyladenosine) modification was known to exist in HIV-1, previous studies had produced conflicting results about whether it helped or harmed the virus, primarily because its location was unknown and efforts to understand its effect were based on knocking out host cell genes rather than mutating the virus genome itself.

    Kim and colleagues used – and refined – a technique called nanopore direct RNA sequencing to view a full length of HIV-1’s RNA genome, which is tricky to observe because RNA is a notoriously unstable and complex molecule.

    The team first discovered the three m6A modifications and their specific locations. From there, the researchers analyzed individual RNA molecules with distinct ensembles of m6A modifications, including those with multiple m6As and those with just one of the three m6As. They found that any ensemble of m6A modifications, regardless of the number or the position of m6As, produced similar functional changes. Removal of all three, however, caused devastating effects to viruses – a dead giveaway that these m6As are redundant.

    “Until now we didn’t know which exact nucleotides are modified and how they function, and how it’s important for viruses or how it’s important for cells. Our paper addresses the keys to these important questions,” Kim said.

    “Why would HIV need all three modifications if they’re functioning in the same way?” he said. “Our study is the first to show that HIV-1 utilizes this unique, important mechanism at the RNA level for its evolutionary benefit.”

    Almost all existing HIV drugs block virus replication, but no medications inhibit viral RNA and protein production. There is more to learn about the RNA modification in HIV-1, but Kim said the work hints at the potential to develop therapies that could target these later steps.

    This research was funded by the National Institutes of Health, U.S. Department of Defense, U.S. Department of Energy and the C. Glenn Barber Fund Trust.

    Co-authors include Alice Baek, Ga-Eun Lee, Sarah Golconda, Anastasios Manganaris, Shuliang Chen, Nagaraja Tirumuru, Hannah Yu, Shihyoung Kim, Christopher Kimmel, Olivier Zablocki and Matthew Sullivan of Ohio State, Asif Rayhan and Balasubrahmanyam Addepalli of the University of Cincinnati, and Li Wu of the University of Iowa.

    Source:

    The Ohio State University

    Journal reference:

    Baek, A., et al. (2024). Single-molecule epitranscriptomic analysis of full-length HIV-1 RNAs reveals functional roles of site-specific m6As. Nature Microbiology. doi.org/10.1038/s41564-024-01638-5.

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  • Study reveals how DNA gyrase resolves DNA entanglements

    Study reveals how DNA gyrase resolves DNA entanglements

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    Picture in your mind a traditional “landline” telephone with a coiled cord connecting the handset to the phone. The coiled telephone cord and the DNA double helix that stores the genetic material in every cell in the body have one thing in common; they both supercoil, or coil about themselves, and tangle in ways that can be difficult to undo. In the case of DNA, if this overwinding is not dealt with, essential processes such as copying DNA and cell division grind to a halt. Fortunately, cells have an ingenious solution to carefully regulate DNA supercoiling.

    In this study published in the journal Science, researchers at Baylor College of Medicine, Université de Strasbourg, Université Paris Cité and collaborating institutions reveal how DNA gyrase resolves DNA entanglements. The findings not only provide novel insights into this fundamental biological mechanism but also have potential practical applications. Gyrases are biomedical targets for the treatment of bacterial infections and the similar human versions of the enzymes are targets for many anti-cancer drugs. Better understanding of how gyrases work at the molecular level can potentially improve clinical treatments.

    Some DNA supercoiling is essential to make DNA accessible to allow the cell to read and make copies of the genetic information, but either too little or too much supercoiling is detrimental. For example, the act of copying and reading DNA overwinds it ahead of the enzymes that read and copy the genetic code, interrupting the process. It’s long been known that DNA gyrase plays a role in untangling the overwinding, but the details were not clear.

    DNA minicircles and advanced imaging techniques reveal first step to untangle DNA

    We typically picture DNA as the straight double helix structure, but inside cells, DNA exists in supercoiled loops. Understanding the molecular interactions between the supercoils and the enzymes that participate in DNA functions has been technically challenging, so we typically use linear DNA molecules instead of coiled DNA to study the interactions. One goal of our laboratory has been to study these interactions using a DNA structure that more closely mimics the actual supercoiled and looped DNA form present in living cells.”


    Dr. Lynn Zechiedrich, study author, Kyle and Josephine Morrow Chair in Molecular Virology and Microbiology and professor of the Verna and Marrs McLean Department of Biochemistry and Molecular Pharmacology at Baylor College of Medicine

    After years of work, the Zechiedrich lab has created small loops of supercoiled DNA. In essence, they took the familiar straight linear DNA double helix and twisted it in either direction once, twice, three times or more and connected the ends together to form a loop. Their previous study looking at the 3-D structures of the resulting supercoiled minicircles revealed that these loops form a variety of shapes that they hypothesized enzymes such as gyrase would recognize.

    In the current study, their hypothesis was proven correct. The team of researchers combined their expertise to study the interactions of DNA gyrase with DNA minicircles using recent technology advances in electron cryomicroscopy, an imaging technique that produces high-resolution 3-D views of large molecules, and other technologies.

    “My lab has long been interested in understanding how molecular nanomachines operate in the cell. We have been studying DNA gyrases, very large enzymes that regulate DNA supercoiling,” said co-corresponding author Dr. Valérie Lamour, associate professor at the Institut de Génétique et de Biologie Moléculaire et Cellulaire, Université de Strasbourg. “Among other functions, supercoiling is the cell’s way of confining about 2 meters (6.6 feet) of linear DNA into the microscopic nucleus of the cell.”

    As the DNA supercoils inside the nucleus, it twists and folds in different forms. Imagine twisting that telephone cord mentioned at the beginning, several times on itself. It will overwind and form a loop by crossing over DNA chains, tightening the structure.

    “We found, just as we had hypothesized, that gyrase is attracted to the supercoiled minicircle and places itself in the inside of this supercoiled loop,” said co-author, Dr. Jonathan Fogg, senior staff scientist of molecular virology and microbiology, and biochemistry and molecular pharmacology in the Zechiedrich lab.

    “This is the first step of the mechanism that prompts the enzyme for resolving DNA entanglements,” Lamour said.

    “DNA gyrase, now surrounded by a tightly supercoiled loop, will cut one DNA helix in the loop, pass the other DNA helix through the cut in the other, and reseal the break, which relaxes the overwinding and eases the tangles, regulating DNA supercoiling to control DNA activity,” Zechiedrich said. “Imagine watching the rodeo. Like roping cattle with a lasso, supercoiled looped DNA captures gyrase in the first step. Gyrase then cuts one double-helix of the DNA lasso and passes the other helix through the break to get free.”

    Co-corresponding author, Dr. Marc Nadal, professor at the École Normale in Paris confirmed the observation of the path of the DNA wrapped in the loop around gyrase using magnetic tweezers, a biophysical technique that allows to measure the deformation and fluctuations in the length of a single molecule of DNA. Observing a single molecule provides information that is often obscured when looking at thousands of molecules in traditional so-called “ensemble” experiments in a test tube.

    Interestingly, the “DNA strand inversion model” for gyrase activity was proposed in 1979 by Drs. Patrick O. Brown and the late Nicholas R. Cozzarelli, also in a Science paper, well before researchers had access to supercoiled minicircles or the 3-D molecular structure of the enzyme. “It’s especially meaningful to me that 45 years later, we finally provide experimental evidence supporting their hypothesis because Nick was my postdoctoral mentor,” Zechiedrich said.

    “This work opens a myriad of perspectives to study the mechanism of this conserved class of enzymes, which are of great clinical value,” Lamour said.

    “This work supports new ideas on how DNA activities are regulated. We propose that DNA is not a passive biomolecule acted upon by enzymes, but an active one that uses supercoiling, looping and 3-D shapes to direct accessibility of enzymes such as gyrase to specific DNA sequences in a variety of situations, which will likely impact cellular responses to antibiotics or other treatments,” Fogg said.

    Contributors to this work also include Marlène Vayssières (lead author), Nils Marechal, Long Yun, Brian Lopez Duran and Naveen Kumar Murugasamy. The authors are affiliated with one or more of the following institutions: Baylor College of Medicine, Université de Strasbourg, Institut de Génétique et de Biologie Moléculaire et Cellulaire, INSERM, Université Paris and Hôpitaux Universitaires de Strasbourg.

    Source:

    Baylor College of Medicine

    Journal reference:

    Vayssières, M., et al. (2024) Structural basis of DNA crossover capture by Escherichia coli DNA gyrase. Science. doi.org/10.1126/science.adl5899.

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  • Research identifies how leukemia develops resistance to first line treatments

    Research identifies how leukemia develops resistance to first line treatments

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    Relapses in a common form of leukemia may be preventable following new research which has identified how the cancer develops resistance to first line treatments.

    New research published in iScience by researchers from the University of Birmingham, the Institute of Cancer Research (ICR), Newcastle University, the Princess Maxima Centre of Pediatric oncology and the University of Virginia identified changes in a mutated form of acute myeloid leukemia (AML) samples from patients who relapsed after receiving FLT3 inhibitor treatment.

    The team found that the resistant cancer had up-regulated multiple other signalling pathways to overcome the drug’s action, and that the genetic change was able to be replicated in lab tests.

    These experiments revealed that by targeting RAS family proteins, using a small molecule inhibitor developed from a chemical library screen using the paratope of an inhibitory intracellular antibody by Terry Rabbitts’ team at the Weatherall Institute of Molecular Medicine University of Oxford and the ICR, increased signalling no longer rescued the cells from cell death.

    The team identified that the transcription factors AP-1 and RUNX1 were at the heart of mediating drug resistance. The two factors cooperate and bind to their target genes together, but only in the presence of growth factor signalling. The drugs targeting FLT3 rewire the cell, resulting in the upregulation of other signalling pathway associated genes, which then restored AP-1 and RUNX1 binding. Drugging RAS, which is a key component in multiple signalling pathways, prevented this restoration of RUNX1 binding, and therefore signalling from growth factors no longer rescued the cancer cells from death.

    Professor Constanze Bonifer from the Institute of Cancer and Genomic Sciences at the University of Birmingham, who has just taken up a position at the University of Melbourne, and is one of the senior authors of the paper said:

    “The pharmaceutical industry had high hopes that drugs targeting aberrant growth factor receptors such as the FLT3-ITD would prevent people from relapse. However, cancer cells are smart, and rewire their growth control machinery to use other growth factors present in the body. Targeting RAS family members prevents the cancer from rewiring and using different signalling pathways to escape cell death.”

    Targeting RAS blocks rewiring

    The small molecule inhibitors used to target RAS in this study were developed using intracellular antibody technology. This technology involves screening a large number of antibody fragments to identify those which bind to the target protein in cells and prevent their protein-protein interactions. Small molecule inhibitors are can be screened from chemical libraries that interact with the parts of the target protein where these antibody fragments bind (the paratope). Due to the unparalleled natural specificity of these antibody fragments, this technology (called Antibody derived or Abd technology) can be used to target difficult to drug proteins and identify new parts of the protein which can be targeted to prevent protein-protein interactions.

    Professor Terry Rabbitts from the Institute of Cancer Research who developed these drugs said:

    “The strength of the Antibody-derived technology approach is that intracellular antibodies can selected to essentially any protein. In turn, their specific binding sites can be employed to select chemical compounds for drug discovery against hard to drug proteins. Mutant RAS was considered undruggable, but the Abd technology facilitated the development of the RAS-binding compounds used in the current study of cancer cell re-wiring. Abd technology will allow development of a new generation of drugs to hard-to-drug and intrinsically disordered proteins.“

    AML with a FLT3-ITD mutation occurs in nearly 30% of all patients and is a highly aggressive disease with a poor prognosis. This genetic change causes the expression of a mutant growth factor receptor which is always active and therefore cancer cells expressing it grow uncontrollably. While inhibitors which specifically target the FLT3 protein are now in use in the clinic, patients treated with these inhibitors frequently relapse.

    This work was funded by Leukaemia Research UK, the Medical Research Council, Blood Cancer Research UK, the Royal Society, the Wellcome and Cancer Research UK. The first author, Daniel Coleman is a John Goldman Fellow of Leukaemia UK.

    Source:

    Journal reference:

    Daniel J.L., et al. (2024). Pharmacological inhibition of RAS overcomes FLT3 inhibitor resistance in FLT3-ITD+ AML through AP-1 and RUNX1. iScience. doi.org/10.1016/j.isci.2024.109576.

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  • Women’s skin study shows distinct chemical changes in response to psychological stress

    Women’s skin study shows distinct chemical changes in response to psychological stress

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    In a recent study published in Scientific Reports, researchers investigated the volatile organic compounds (VOCs) generated by the skin in response to psychological stress.

    Study: Effects of psychological stress on the emission of volatile organic compounds from the skin. Image Credit: Geinz Angelina/Shutterstock.comStudy: Effects of psychological stress on the emission of volatile organic compounds from the skin. Image Credit: Geinz Angelina/Shutterstock.com

    Background

    The volatilome is a collection of volatile organic compounds (VOCs) generated by plants, microbes, or animals that contribute to the skin’s olfactory profile and constitute part of the odor print.

    The human volatilome contains thousands of VOCs released by various sources, including exhaled breath, saliva, blood, urine, milk, feces, and skin emissions.

    These VOCs are not only associated with clinical conditions; they can also be exogenous, resulting from environmental exposure or product usage. Eccrine, sebaceous, and apocrine glands generate most endogenous skin volatiles in conjunction with naturally present microorganisms.

    Psychological stress can disrupt the skin barrier and modify inflammatory responses of the skin, although its effect on VOC emission from human skin is unclear.

    About the study

    In the present study, researchers examined the effects of stress on VOC emissions from the skin.

    The primary goal was to investigate volatile organic compounds secreted by forehead skin following stress induction among middle-aged women by performing cognitive tasks such as problem-solving and word scrambling to identify VOC stress markers.

    The secondary purpose was to examine the impact of skin sebum concentration, pH, and transepidermal water loss (TEWL) on VOC release.

    The research was comprised of 35 nonsmoking women aged 24 to 40 (mean age 35). The researchers sampled VOCs from the forehead prior to and post-stress induction with a silicon polymer. They evaluated the sample device linearity using four VOCs: heptanal, 2-phenylethanol, isoamyl acetate, and 2,3-dimethylpyrazine.

    Three measurements were taken concurrently inside the calibration curve’s linearity domain, using a reference solution of 15 ng/µL to evaluate technique repeatability.

    The team induced cognitive stress through timed exercises utilizing customized software, including a clock for semantic and arithmetic tasks, and confirmed using physiological and clinical data.

    They assessed stress levels using a State-Trait Anxiety Inventory (STAI) questionnaire, verbal expression analysis, and clinical assessments.

    The researchers identified and quantified VOCs using gas chromatography-mass spectrometry (GC-MS). Stress induction was substantiated by a substantial rise in state anxiety as measured by the questionnaire, changes in electrodermal activity (EDA) measures, and verbatim stress expressions.

    The researchers also assessed sebum production and skin pH. They analyzed the data qualitatively and quantitatively to determine VOC expression before and after the psychological stress tests.

    The RSD was determined for every volatile chemical using the average relative abundance values for two to three predominant ions.

    To examine the durability of adsorbed VOCs on the silicon polymer, the researchers performed assessments on day 3.0 and day 12 following the sample phase, simulating the delay between invoicing and GC-MS assessment.

    They derived three parameters from the EDA signals collected throughout the adaptation and stress induction phases. The first parameter was the average SCL (µS). The second parameter was the frequency (peaks/min), while the third was the average amplitude (µS) of the NS-SCRs.

    Results

    The study found 198 VOCs with a higher concentration of straight-chain alkanes, alcohols, esters, cyclic alkanes, nitrogen compounds, and ketones. Among the chemicals, 69 originated from cosmetic components, 49 from food, 37 from human or microbial metabolisms, and 33 from the environment.

    Three VOCs (2-hydroxyethyl acetate, 3-methylpentadecane, and 2-hydroxyethyl propanoate) were associated with stress induction, and 14 compounds were statistically significant.

    The VOCs were primarily from the alkane family, with fatty acyls produced from lipids and ethylbenzenes being the most common. In addition, the researchers characterized a nitrogen molecule (N, N-dibutylformamide).

    The least represented molecule was detected at 3.6 ng/µL (2-hydroxyethyl propanoate), while the most prevalent were geranyl acetone and butylated hydroxytoluene at concentrations of 121 ng/µL and 177 ng/µL, respectively.

    The average abundance of primary ions in volatile standards increased dramatically during storage, with RSD values ranging from 1.3 to 3.1% on day 0 and 9.9% on day 3.

    The trait-anxiety scores and state-anxiety levels rose significantly by 7.90% and 34%, respectively, between the no-stress and stress periods.

    During the stress phase, all three EDA measures rose. SCL increased from 0.5 to 1.9 µS, and NS-SCRs increased to 4.0 from 0.04 peaks per minute. 71% of participants’ verbatims included deception/failure, stress/pressure, and difficulty/complicated.

    After stress induction, the sebum level on the foreheads increased by 37%, while the skin pH dropped by 14%.

    Conclusion

    Overall, the study findings highlighted the impact of psychological stress on the modulation of cutaneous VOC emission. The relative measurement of these chemicals demonstrated a production range throughout the stress period.

    They are components of lipid metabolism, oxidative stress, air pollution, and cosmetic applications. Some were previously known as disease biomarkers, but only one is stress-related. Future studies could examine the possible impact of modulating these VOC expressions on skin physiology.

    Another approach to this research may be to investigate their influence on human communication by understanding chemosignaling.

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  • Newly discovered molecule may be a potential therapeutic target for triple-negative breast cancer

    Newly discovered molecule may be a potential therapeutic target for triple-negative breast cancer

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    A team of researchers from Hiroshima University has discovered a molecule that promotes the production of cancer cells. This molecule may prove to be a potential therapeutic target in the treatment of triple-negative breast cancer, an aggressive form of breast cancer.

    Their work was published in the journal Molecular Cancer Research on January 18, 2024.

    Breast cancer is the most common type of cancer, ranking fifth among all cancers in cancer-related deaths. In 2020, there were 2.3 million new cases of breast cancers reported around the globe. In that year, breast cancer caused 685,000 deaths.

    Several studies have reported that a molecule called AIbZIP (androgen-induced basic leucine zipper) promotes malignant behavior in different cancer types. So the research team examined the potential role of AIbZIP in malignant tumors. Their computer simulation analysis revealed that AIbZIP was highly expressed in the luminal androgen receptor subtype of triple negative breast cancer, playing a significant role in cell cycle regulation. They identified a novel mechanism by which AIbZIP regulates cancer cell proliferation in this type of breast cancer.

    “We found that AIbZIP is highly upregulated in triple negative breast cancer. AIbZIP plays a crucial role for hyper proliferation of triple negative breast cancer cells by promoting the degradation of p27, a negative regulator for cell proliferation. Our study indicates that AIbZIP may be potential therapeutic target of triple negative breast cancer” said Atsushi Saito, an associate professor and Kazunori Imaizumi, a professor in the Department of Biochemistry, Graduate School of Biomedical and Health Sciences, Hiroshima University.

    Breast cancer is divided into three types. These types, defined mainly by receptor and protein expression, are luminal breast cancer, HER2-positive breast cancer, and triple-negative breast cancer. Triple-negative breast cancer does not have the estrogen receptor, progesterone receptor, or HER2 (human epidermal growth factor receptor 2) found in the other two types of breast cancer. Without these receptors, or targets, this cancer is challenging to treat. “Among breast cancer, triple negative breast cancer has no known therapeutic targets and a poor prognosis. Therefore, new therapeutic targets and strategies against TNBC are required,” said Taichi Ito, a student in the Department of Biochemistry, Graduate School of Biomedical and Health Sciences, Hiroshima University.

    Triple negative breast cancer has been further divided into subtypes, based on gene expression. The luminal androgen receptor is a subtype of triple negative breast cancer. This subtype represents 15 to 20 percent of all triple negative breast cancer cases.

    Recent treatments for triple-negative breast cancer include chemotherapy, immunotherapy, and targeted therapies. These treatments hold promise, but they are not ideal solutions. Researchers continue to explore new therapeutic targets and strategies against triple-negative breast cancer.

    The luminal androgen receptor subtype of triple negative breast cancer has a high expression of the androgen receptor and genes associated with androgenic hormonally-regulated pathways. As a result, researchers have made many attempts to develop new strategies to treat the luminal androgen receptor subtype of triple negative breast cancer with drugs that inhibit the androgen receptor activity. However, their therapeutic value is limited, and effective treatment for luminal androgen receptor subtype of triple negative breast cancer has not yet been achieved. So scientists have worked to identify new targets that can inhibit proliferation, invasion, and metastasis of the luminal androgen receptor subtype of triple negative breast cancer.

    Further studies are required to verify whether this regulation of cell cycle progression occurs in other cell types. The team knows that AIbZIP is highly upregulated in many cancers, including luminal and HER2-positive breast cancer. The novel pathway they have discovered may contribute to cancer treatments in other cancer types besides triple negative breast cancer.

    Looking ahead, the team sees more work to be done. They want to check the expression level of AIbZIP in tumors derived from triple negative breast cancer patients to confirm the robust link between AIbZIP and the development of triple negative breast cancer. “If we can downregulate the AIbZIP activity, it may lead to develop the novel therapeutic strategy against triple negative breast cancer,” said Imaizumi.

    The research team includes Taichi Ito, Atsushi Saito, Yasunao Kamikawa, Nayuta Nakazawa, and Kazunori Imaizumi from the Department of Biochemistry, Graduate School of Biomedical and Health Sciences, Hiroshima University, Japan.

    The research is funded by JSPS KAKENHI; Takeda Science Foundation; MSD Life Science Foundation; The UBE Foundation; the Program of the Network-type Joint Usage/Research Center for Radiation Disaster Medical Science, Analysis Center of Life Science, the Natural Science Center for Basic Research and Development, Hiroshima University.

    Source:

    Journal reference:

    Ito, T., et al. (2024). AIbZIP/CREB3L4 Promotes Cell Proliferation via the SKP2-p27 Axis in Luminal Androgen Receptor Subtype Triple Negative Breast Cancer. Molecular Cancer Research. doi.org/10.1158/1541-7786.mcr-23-0629.

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  • New insights into the exacerbation of psoriasis through specific genetic defects

    New insights into the exacerbation of psoriasis through specific genetic defects

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    In a recent study featured in Nature Communications, researchers created mice that carry a gain-of-function (GoF) mutation in the gene encoding the inhibitor of nuclear factor kappa-b kinase subunit beta (IKBKB), known as the IKK2-encoding IKBKB gene. This was done to explore how this mutation works.

    Study: IKK2 controls the inflammatory potential of tissue-resident regulatory T cells in a murine gain of function model. Image Credit: Gorodenkoff/Shutterstock.comStudy: IKK2 controls the inflammatory potential of tissue-resident regulatory T cells in a murine gain of function model. Image Credit: Gorodenkoff/Shutterstock.com

    Background

    Loss-of-function mutations demonstrate the importance of forkhead box P3-positive (Foxp3+) regulatory T cells (Tregs) in immunological control. Tregs mediate dominant tolerance and protect against autoimmune disorders.

    They undergo positive selection in the thymus, and interleukin-2 (IL-2) protects them from apoptosis. Treg formation needs effective signaling downstream of the T-cell receptor (TCR), particularly the CARD11-BCL10-MALT1 (CBM) complex.

    Mice lacking particular genes have a Treg deficit that causes a selective loss of cluster of differentiation 4-positive (CD4+) Helios+ thymic T cells.

    Tregs move between lymphoid organs according to adhesion molecule expression. The presence of an activated or effector phenotype (eTreg) in recirculating Tregs increases disease risk.

    About the study

    The present study examined mice with an Ikbkb GoF mutation homologous to a problematic human IKBKB GoF variation.

    The researchers tracked a cohort of mice with various Ikbkb genotypes and recorded the age at which skin disease appeared. Animal house technicians were unaware of the mouse genotype and identified abnormal Ikbkbmut/+ and Ikbkbmut/mut animals. The researchers examined the transcriptomes of tails and ears from Ikbkbmut/mut and Ikbkb+/+ mice.

    The team investigated the inflammatory infiltrate in skin lesions and the nature of Treg growth inside pathological lesions. They created mixed bone marrow chimeras with allotype-marked donor cells from WT and mutant mice.

    They isolated naïve CD4+ T cells from mouse splenocyte suspensions and activated them with Th17-inducing conditions. The researchers then counted IL-17+ Tregs ex vivo and labeled them for cytokine production after gating on Foxp3.

    The researchers extracted them from WT mice and cocultured them with pure WT conventional T cells labeled with CTV to explore Tregs’ traditional immunosuppressive activity. They followed up with an in vivo test of mutant Treg suppression.

    They analyzed mice for signs of systemic immunological dysregulation and created reciprocal bone marrow (BM) chimeras to study Ikbkbmut’s cell-intrinsic effects on the Treg phenotype.

    The team obtained serum from recipient mice to analyze a panel of cytokines. They isolated green fluorescent protein (GFP)-labeled Foxp3+ Tregs from Ikbkbmut donors and implanted them into Ikbkbmut x Rag1−/− or IkbkbWT x Rag1−/− animals to establish disease cause as pro-inflammatory Treg activity.

    The researchers used mice aged six weeks to 12 months for analysis. They performed flow cytometry, flow cytometric cell sorting, ex vivo PMA/ionomycin stimulation for cytokine production, T-cell polarization, an in vitro Treg suppression experiment, cell trace violet (CTV) labeling, and single-cell and bulk ribonucleic acid (RNA) sequencing studies.

    Results

    Canonical NF-κB overactivity led to the growth of pathogenic, NF-κB-dependent, and modified non-lymphoid tissue skin Tregs. Mice with Ikbkb GoF mutation heterozygosity developed psoriasis, and Ikbkb-mut mice included IL-17-producing Tregs.

    These animals maintained suppressive function, indicating that normal CD4+ T cells are not the source of IL-17 in Ikbkb mutant mice. Foxp3+ CD4+ T cells from Ikbkb mutant mice maintained suppressive function.

    The study additionally examined the effects of doubling the IkbkbGoF/GoF gene dosage on psoriatic arthritis, characterized by spondylitis, dactylitis, and distinctive nail abnormalities.

    IkbkbGoF mice showed selective CD25+ and Foxp3+ Treg expansion, with a fraction expressing IL-17. These transformed Tregs were present in inflamed tissues, spleen, and blood, and their transfer was sufficient to cause illness without ordinary T lymphocytes.

    Single-cell phenotyping and transcriptional investigations of isolated regulatory T cells indicated the non-lymphocytic tissue proliferation of Treg expressing Th17-associated genes, Helios, tissue-related markers such as CD69 and CD103, and a significant nuclear factor kappa B (NF-κB) transcriptome.

    Overactive IKK2 caused dermal Treg accumulation and psoriasis. Heterozygous (Ikbkbmut/+) and homozygous (Ikbkbmut/mut) mutant mice developed skin illnesses with histopathological similarities to psoriasis.

    Humans heterozygous for IKBKBV203I have combined immune insufficiency, but their Treg count increased. Ikbkbmut has a similar phenotype, with gene-dose-dependent lymphopenia caused by a decrease in αβ and γδ T cells in homozygous mice.

    The study also found an increase in Th17 CD4+ T cells, strongly associated with psoriasis. Ikbkbmut/mut mice spleen Tregs produced more IL-17 than wild-type mice.

    Interferon-gamma (IFNγ) production by Tregs was similar between WT and mutant animals, indicating that Ikbkbmut imparts an expansion of the IL-17-producing Foxp3+ Treg population.

    Foxp3 deficiency and Treg functional abnormalities were associated with early-onset and severe widespread lymphadenopathy unrelated to the Ikbkbmut mutation.

    Conclusion

    The study linked psoriasis and psoriatic arthritis to NF-κB malfunction, which causes non-specific leukocytes to acquire an effector-like function, resulting in disease. The primary finding is a route that leads Foxp3+CD4+ tissue-resident Tregs to turn pro-inflammatory and pathogenic.

    In vivo, a modified Treg population emerges owing to enhanced activity of the canonical NF-κB pathway. This route controls Treg abundance, increases tissue-resident Tregs, and mediates end-organ pathologies.

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  • Natural molecule trigonelline can help to improve muscle health and function

    Natural molecule trigonelline can help to improve muscle health and function

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    A research consortium led by Nestlé Research in Switzerland and the Yong Loo Lin School of Medicine, National University of Singapore (NUS Medicine) made a recent discovery that the natural molecule trigonelline present in coffee, fenugreek, and also in the human body, can help to improve muscle health and function. In an international collaboration among the University of Southampton, University of Melbourne, University of Tehran, University of South Alabama, University of Toyama and University of Copenhagen, the work builds on a previous collaborative study that described novel mechanisms of human sarcopenia.

    Sarcopenia is a condition where cellular changes that happen during aging gradually weaken the muscles in the body and lead to accelerated loss of muscle mass, strength and reduced physical independence.

    One important problem during sarcopenia is that the cellular cofactor NAD+ declines during ageing, while mitochondria, the energy powerhouses in our cells, produce less energy. The study team discovered that levels of trigonelline were lower in older people with sarcopenia. Providing this molecule in pre-clinical models resulted in increased levels of NAD+, increased mitochondrial activity and contributed to the maintenance of muscle function during aging.

    NAD+ levels can be enhanced with different dietary precursors like the essential amino acid L-tryptophan (L-Trp), and vitamin B3 forms such as nicotinic acid (NA), nicotinamide (NAM), nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN).

    Assistant Professor Vincenzo Sorrentino from the Healthy Longevity Translational Research Programme at NUS Medicine added, “Our findings expand the current understanding of NAD+ metabolism with the discovery of trigonelline as a novel NAD+ precursor and increase the potential of establishing interventions with NAD+-producing vitamins for both healthy longevity and age-associated diseases applications”.

    Nutrition and physical activity are important lifestyle recommendations to maintain healthy muscles during aging.

    We were excited to discover through collaborative research that a natural molecule from food cross-talks with cellular hallmarks of aging. The benefits of trigonelline on cellular metabolism and muscle health during aging opens promising translational applications.”

    Jerome Feige, Head of the Physical Health department at Nestlé Research

    Source:

    National University of Singapore, Yong Loo Lin School of Medicine

    Journal reference:

    Membrez, M., et al. (2024). Trigonelline is an NAD+ precursor that improves muscle function during ageing and is reduced in human sarcopenia. Nature Metabolism. doi.org/10.1038/s42255-024-00997-x.

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  • BU study reveals key to combating high-risk neuroblastoma

    BU study reveals key to combating high-risk neuroblastoma

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    The MYCN oncoprotein (proteins related to the growth of cancer cells) plays a key role in starting, advancing and making it difficult to treat various human cancers. When MYCN is overactive, especially in high-risk neuroblastoma (childhood cancer often found in the adrenal glands), the tumors become less responsive to immunotherapy-;a treatment that uses the body’s immune system to fight cancer. Still, recognition of this problem has not led to any effective strategies to tackle this problem.

    In a new study from Boston University Chobanian & Avedisian School of Medicine, researchers found that MYCN selectively increases the levels of a signaling molecule, CKLF, in neuroblastoma cells to suppress anti-tumor immune responses and promote tumor aggressiveness.

    As scientists, we are looking for ways to make these less responsive tumors more receptive to immunotherapy to increase its effectiveness. Understanding how tumor cells utilize this molecule to communicate with immune cells will facilitate the development of effective immunotherapeutic strategies to provide more effective treatments with fewer toxicities for children with high-risk neuroblastoma.”


    Hui Feng, MD, PhD, corresponding author, associate professor of pharmacology, physiology & biophysics, Boston University School of Medicine

    The researchers studied an experimental model, clinical patient samples, and in-vitro cell culture. The experimental models of neuroblastoma with and without overexpression of the signaling molecule, CKLF, were compared for their ability to increase tumor aggression through the suppression of anti-tumor immune responses.

    According to Xiaodan Qin, PhD, the first author of the study and a research scientist in the Feng Lab, the research is critical to understanding the mechanisms by which tumor cells induce a tumor microenvironment that compromises the function of immune cells, and it uncovered additional therapeutic approaches to evoke anti-tumor immune responses. “The long-term goal of this research is to uncover effective drugs that are much less toxic than chemotherapy and radiotherapy for treating high-risk neuroblastoma and perhaps other types of MYCN-driven childhood cancers,” Feng says.

    The findings appear online in Science Advances.

    Source:

    Boston University School of Medicine

    Journal reference:

    Qin, X., et al. (2024). CKLF instigates a “cold” microenvironment to promote MYCN-mediated tumor aggressiveness. Science Advances. doi.org/10.1126/sciadv.adh9547.

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