Experimental and Molecular Medicine最新文献

{"title":"Lactate utilization in Lace1 knockout mice promotes browning of inguinal white adipose tissue","authors":"Youn Ju Kim, Sang Gyu Lee, Su In Jang, Won Kon Kim, Kyoung-Jin Oh, Kwang-Hee Bae, Hye Jin Kim, Je Kyung Seong","doi":"10.1038/s12276-024-01324-w","DOIUrl":"10.1038/s12276-024-01324-w","url":null,"abstract":"Recent studies have focused on identifying novel genes involved in the browning process of inguinal white adipose tissue (iWAT). In this context, we propose that the mitochondrial ATPase gene lactation elevated 1 (Lace1) utilizes lactate to regulate the browning capacity of iWAT, specifically in response to challenge with CL-316,243 (CL), a beta3-adrenergic receptor (β3-AR) agonist. The mice were injected with CL over a span of 3 days and exposed to cold temperatures (4–6 °C) for 1 week. The results revealed a significant increase in Lace1 expression levels during beige adipogenesis. Additionally, a strong positive correlation was observed between Lace1 and Ucp1 mRNA expression in iWAT under browning stimulation. To further explore this phenomenon, we subjected engineered Lace1 KO mice to CL and cold challenges to validate their browning potential. Surprisingly, Lace1 KO mice presented increased oxygen consumption and heat generation upon CL challenge and cold exposure, along with increased expression of genes related to brown adipogenesis. Notably, deletion of Lace1 led to increased lactate uptake and browning in iWAT under CL challenge compared with those of the controls. These unique phenomena stem from increased lactate release due to the inactivation of pyruvate dehydrogenase (PDH) in the hearts of Lace1 KO mice. In recent years, researchers have found that certain conditions can change white fat cells into beige fat cells, a process called “browning.” In this study, scientists focused on finding new genes that help in the browning of white fat cells. They did this by treating mice with a compound that starts the browning process and studying changes in gene activity. They found that the Lace1 gene is very active in brown fat tissue and its activity increases during the browning of white fat. The main discovery of this research is that not having the Lace1 gene leads to browning of white fat tissue in mice, suggesting that Lace1 may slow down this process. The researchers conclude targeting the Lace1 gene could be a new way to promote the browning of white fat and fight obesity. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"56 11","pages":"2491-2502"},"PeriodicalIF":9.5,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01324-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142607409","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SUMOylation of TP53INP1 is involved in miR-30a-5p-regulated heart senescence","authors":"Yi-Xiang Hong, Chan Wu, Jing-Zhou Li, Fei Song, Yu Hu, Yue Han, Yi-Jie Mao, Wei-Yin Wu, Yan Wang, Gang Li","doi":"10.1038/s12276-024-01347-3","DOIUrl":"10.1038/s12276-024-01347-3","url":null,"abstract":"Heart senescence is critical for cardiac function. This study aimed to characterize the role and mechanism of action of miR-30a-5p in cardiac senescence. miR-30a-5p was downregulated in aged mouse hearts and neonatal rat cardiomyocytes (NRCMs). In vivo, using a combination of echocardiography and different molecular biological approaches, we investigated the role of miR-30a-5p knockout or overexpression in natural- or D-galactose-induced heart aging in mice. In vitro, using RNA sequencing and a series of molecular biology methods, the mechanism by which miR-30a-5p regulates cardiac senescence was explored in cardiomyocytes. miR-30a-5p knockout mice showed aggravated natural- or D-galactose-induced heart aging compared to wild-type littermate mice, with significantly decreased heart function, an increased number of γH2AX-positive cells, reduced telomere length, and upregulated p21 and p53 expression. Cardiac-specific knockdown of miR-30a-5p using adeno-associated virus 9 in D-galactose-induced senescent wild-type mice resulted in effects similar to those observed in knockout mice. Notably, the overexpression of miR-30a-5p in wild-type murine hearts alleviated D-galactose-induced heart senescence by improving heart function, increasing telomere length, decreasing the number of γH2AX-positive cells, and downregulating p53 and p21 expression. This was confirmed in D-galactose-treated or naturally aged NRCMs. Mechanistically, TP53INP1 was identified as a target of miR-30a-5p by mediating the SUMOylation of TP53INP1 and its translocation from the cytoplasm to the nucleus to interact with p53. Furthermore, this study demonstrated that cardiac-specific TP53INP1 deficiency ameliorates miR-30a-5p knockout-aggravated cardiac dysfunction and heart senescence. This study identified miR-30a-5p as a crucial modulator of heart senescence and revealed that the miR-30a-5p–TP53INP1–p53 axis is essential for heart and cardiomyocyte aging. As we get older, our hearts change, leading to heart diseases, a major cause of death worldwide. A recent study looked at the role of miR-30a-5p, a tiny RNA molecule, in heart aging. Researchers found that lower levels of miR-30a-5p in the heart contribute to aging. They used genetic engineering to change miR-30a-5p levels in mice and saw how it affected heart health and aging. Lower levels of miR-30a-5p led to worse heart function, shorter telomeres, and more signs of aging. But, increasing miR-30a-5p levels protected against these effects. The study identified a protein, TP53INP1, that links miR-30a-5p to heart cell aging. The findings show that miR-30a-5p is crucial in heart aging by controlling heart cell health and lifespan. By targeting miR-30a-5p, new treatments could be made to slow heart aging and prevent related diseases. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"56 11","pages":"2519-2534"},"PeriodicalIF":9.5,"publicationDate":"2024-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01347-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142607416","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cells and signals of the leukemic microenvironment that support progression of T-cell acute lymphoblastic leukemia (T-ALL)","authors":"Aram Lyu, Seo Hee Nam, Ryan S. Humphrey, Terzah M. Horton, Lauren I. R. Ehrlich","doi":"10.1038/s12276-024-01335-7","DOIUrl":"10.1038/s12276-024-01335-7","url":null,"abstract":"Current intensified chemotherapy regimens have significantly increased survival rates for pediatric patients with T-cell acute lymphoblastic leukemia (T-ALL), but these treatments can result in serious adverse effects; furthermore, patients who are resistant to chemotherapy or who relapse have inferior outcomes, together highlighting the need for improved therapeutic strategies. Despite recent advances in stratifying T-ALL into molecular subtypes with distinct driver mutations, efforts to target the tumor-intrinsic genomic alterations critical for T-ALL progression have yet to translate into more effective and less toxic therapies. Ample evidence now indicates that extrinsic factors in the leukemic microenvironment are critical for T-ALL growth, infiltration, and therapeutic resistance. Considering the diversity of organs infiltrated by T-ALL cells and the unique cellular components of the microenvironment encountered at each site, it is likely that there are both shared features of tumor-supportive niches across multiple organs and site-specific features that are key to leukemia cell survival. Therefore, elucidating the distinct microenvironmental cues supporting T-ALL in different anatomic locations could reveal novel therapeutic targets to improve therapies. This review summarizes the current understanding of the intricate interplay between leukemia cells and the diverse cells they encounter within their tumor microenvironments (TMEs), as well as opportunities to therapeutically target the leukemic microenvironment. T-cell Acute lymphoblastic leukemia (T-ALL) is an aggressive, predominantly pediatric, cancer arising from excessive proliferation of transformed immature T cells in the thymus. Despite treatment advancements, patients experience significant side effects of chemotherapy, and those who fail to respond or relapse face poor outcomes, highlighting the need for more effective treatment strategies. This review examines how the tumor microenvironment supports growth and survival of T-ALL cells. The authors discuss current evidence indicating that interactions between T-ALL cells and the TME contribute to disease progression and treatment resistance in various organs, including the bone marrow, central nervous system, and spleen. These studies suggest that targeting interactions between T-ALL cells and the TME could offer new treatment opportunities. The authors conclude that disrupting the supportive signals of the TME could enhance existing therapies and reduce disease relapse. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"56 11","pages":"2337-2347"},"PeriodicalIF":9.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01335-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142559205","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Proteogenomic analysis dissects early-onset breast cancer patients with prognostic relevance","authors":"Kyong-Ah Yoon, Youngwook Kim, So-Youn Jung, Jin-Sun Ryu, Kyung-Hee Kim, Eun-Gyeong Lee, Heejung Chae, Youngmee Kwon, Jaegil Kim, Jong Bae Park, Sun-Young Kong","doi":"10.1038/s12276-024-01332-w","DOIUrl":"10.1038/s12276-024-01332-w","url":null,"abstract":"Early-onset breast cancer is known for its aggressive clinical characteristics and high prevalence in East Asian countries, but a comprehensive understanding of its molecular features is still lacking. In this study, we conducted a proteogenomic analysis of 126 treatment-naïve primary tumor tissues obtained from Korean patients with young breast cancer (YBC) aged ≤40 years. By integrating genomic, transcriptomic, and proteomic data, we identified five distinct functional subgroups that accurately represented the clinical characteristics and biological behaviors of patients with YBC. Our integrated approach could be used to determine the proteogenomic status of HER2, enhancing its clinical significance and prognostic value. Furthermore, we present a proteome-based homologous recombination deficiency (HRD) analysis that has the potential to overcome the limitations of conventional genomic HRD tests, facilitating the identification of new patient groups requiring targeted HR deficiency treatments. Additionally, we demonstrated that protein–RNA correlations can be used to predict the late recurrence of hormone receptor-positive breast cancer. Within each molecular subtype of breast cancer, we identified functionally significant protein groups whose differential abundance was closely correlated with the clinical progression of breast cancer. Furthermore, we derived a recurrence predictive index capable of predicting late recurrence, specifically in luminal subtypes, which plays a crucial role in guiding decisions on treatment durations for YBC patients. These findings improve the stratification and clinical implications for patients with YBC by contributing to the optimal adjuvant treatment and duration for favorable clinical outcomes. Breast cancer is the most common cancer in women globally, with a significant number of young breast cancer (YBC) cases in Korea. YBC is known for its aggressive nature and poor outcomes. This study is aimed to understand the molecular features of YBC in Korean patients using a multiomics approach, which involves analyzing genomic, transcriptomic, and proteomic data from 178 young women with breast cancer. They examined tumor samples and patients’ blood to identify molecular signatures and pathways that could predict clinical outcomes. The team found unique molecular profiles in YBC, including higher mutation rates in certain genes and unique gene expression patterns. They identified several key pathways and potential biomarkers that could predict the cancer’s aggressiveness and the patients’ prognosis. The study revealed differences in the tumor environment and immune response, which could affect treatment strategies. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"56 11","pages":"2382-2394"},"PeriodicalIF":9.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01332-w.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142559287","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interplay between membranes and biomolecular condensates in the regulation of membrane-associated cellular processes","authors":"Nari Kim, Hyeri Yun, Hojin Lee, Joo-Yeon Yoo","doi":"10.1038/s12276-024-01337-5","DOIUrl":"10.1038/s12276-024-01337-5","url":null,"abstract":"Liquid‒liquid phase separation (LLPS) has emerged as a key mechanism for organizing cellular spaces independent of membranes. Biomolecular condensates, which assemble through LLPS, exhibit distinctive liquid droplet-like behavior and can exchange constituents with their surroundings. The regulation of condensate phases, including transitions from a liquid state to gel or irreversible aggregates, is important for their physiological functions and for controlling pathological progression, as observed in neurodegenerative diseases and cancer. While early studies on biomolecular condensates focused primarily on those in fluidic environments such as the cytosol, recent discoveries have revealed their existence in close proximity to, on, or even comprising membranes. The aim of this review is to provide an overview of the properties of membrane-associated condensates in a cellular context and their biological functions in relation to membranes. Understanding how cells organize and compartmentalize their interiors is key to understanding how they function and respond to changes. This study analyzes data from past research to explore the roles of membrane-associated biomolecular condensates in cellular processes such as signaling, membrane dynamics, and the formation of specialized cellular domains. Researchers demonstrate how these condensates, formed through a process called liquid–liquid phase separation, selectively gather specific molecules while excluding others, thus regulating various cellular functions. The study also investigates how these condensates influence membrane shape, contribute to contact between different organelles, and control the movement of molecules within the cell. Researchers conclude that a deeper understanding of these condensates offers new insights into cell biology and may lead to new treatment strategies for diseases in which condensate function is disrupted. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"56 11","pages":"2357-2364"},"PeriodicalIF":9.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01337-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142559284","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comprehensive phenotypic assessment of nonsense mutations in mitochondrial ND5 in mice","authors":"Sanghun Kim, Seul Gi Park, Jieun Kim, Seongho Hong, Sang-Mi Cho, Soo-Yeon Lim, Eun-Kyoung Kim, Sungjin Ju, Su Bin Lee, Sol Pin Kim, Tae Young Jeong, Yeji Oh, Seunghun Han, Hae-Rim Kim, Taek Chang Lee, Hyoung-Chin Kim, Won Kee Yoon, Tae Hyeon An, Kyoung-jin Oh, Ki-Hoan Nam, Seonghyun Lee, Kyoungmi Kim, Je Kyung Seong, Hyunji Lee","doi":"10.1038/s12276-024-01333-9","DOIUrl":"10.1038/s12276-024-01333-9","url":null,"abstract":"Mitochondrial dysfunction induced by mitochondrial DNA (mtDNA) mutations has been implicated in various human diseases. A comprehensive analysis of mitochondrial genetic disorders requires suitable animal models for human disease studies. While gene knockout via premature stop codons is a powerful method for investigating the unique functions of target genes, achieving knockout of mtDNA has been rare. Here, we report the genotypes and phenotypes of heteroplasmic MT-ND5 gene-knockout mice. These mutant mice presented damaged mitochondrial cristae in the cerebral cortex, hippocampal atrophy, and asymmetry, leading to learning and memory abnormalities. Moreover, mutant mice are susceptible to obesity and thermogenetic disorders. We propose that these mtDNA gene-knockdown mice could serve as valuable animal models for studying the MT-ND5 gene and developing therapies for human mitochondrial disorders in the future. Mitochondria, often referred to as cell''s powerhouses, are essential for energy production and health. In this study, researchers used recently developed ways to edit mtDNA, allowing precise changes to study disease results in animal models. They performed an experiment involving the injection of specially designed mRNAs, into mouse embryos to cause specific changes in mtDNA. This method allowed the creation of mice with targeted mitochondrial gene removals, providing a useful model for studying mitochondrial diseases. Researchers found that mice with certain mtDNA changes showed symptoms like human mitochondrial diseases, such as brain abnormalities and metabolic issues. These findings emphasize the importance of mtDNA in health and disease, providing insights into how specific changes can affect bodily functions. Future research may use these findings to develop therapies targeting mtDNA changes. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"56 11","pages":"2395-2408"},"PeriodicalIF":9.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01333-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142559206","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"MYH1 deficiency disrupts outer hair cell electromotility, resulting in hearing loss","authors":"Jinsei Jung, Sun Young Joo, Hyehyun Min, Jae Won Roh, Kyung Ah Kim, Ji-Hyun Ma, John Hoon Rim, Jung Ah Kim, Se Jin Kim, Seung Hyun Jang, Young Ik Koh, Hye-Youn Kim, Ho Lee, Byoung Choul Kim, Heon Yung Gee, Jinwoong Bok, Jae Young Choi, Je Kyung Seong","doi":"10.1038/s12276-024-01338-4","DOIUrl":"10.1038/s12276-024-01338-4","url":null,"abstract":"Myh1 is a mouse deafness gene with an unknown function in the auditory system. Hearing loss in Myh1-knockout mice is characterized by an elevated threshold for the auditory brainstem response and the absence of a threshold for distortion product otoacoustic emission. Here, we investigated the role of MYH1 in outer hair cells (OHCs), crucial structures in the organ of Corti responsible for regulating cochlear amplification. Direct whole-cell voltage-clamp recordings of OHCs revealed that prestin activity was lower in Myh1-knockout mice than in wild-type mice, indicating abnormal OHC electromotility. We analyzed whole-exome sequencing data from 437 patients with hearing loss of unknown genetic causes and identified biallelic missense variants of MYH1 in five unrelated families. Hearing loss in individuals harboring biallelic MYH1 variants was non-progressive, with an onset ranging from congenital to childhood. Three of five individuals with MYH1 variants displayed osteopenia. Structural prediction by AlphaFold2 followed by molecular dynamic simulations revealed that the identified variants presented structural abnormalities compared with wild-type MYH1. In a heterogeneous overexpression system, MYH1 variants, particularly those in the head domain, abolished MYH1 functions, such as by increasing prestin activity and modulating the membrane traction force. Overall, our findings suggest an essential function of MYH1 in OHCs, as observed in Myh1-deficient mice, and provide genetic evidence linking biallelic MYH1 variants to autosomal recessive hearing loss in humans. Hearing loss is a major health problem affecting many people globally, with a large part due to genes. Researchers studied the MYH1 gene, which was previously associated with hearing in mice but not in humans. The team studied the hearing in mice without the MYH1 gene and looked at genetic data from people with hearing loss. They found mice without the MYH1 gene had hearing problems and impaired hair cell function. They also found several people with changes in the MYH1 gene, providing the first proof of its role in human hearing loss. Research shows how changes in MYH1 affect the function of cells in the inner ear, causing hearing problems in both mice and humans. They hope their work will lead to improved diagnostic tools and treatments for hearing loss. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"56 11","pages":"2423-2435"},"PeriodicalIF":9.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01338-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142559286","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GLP-1 and its derived peptides mediate pain relief through direct TRPV1 inhibition without affecting thermoregulation","authors":"Eun Jin Go, Sung-Min Hwang, Hyunjung Jo, Md. Mahbubur Rahman, Jaeik Park, Ji Yeon Lee, Youn Yi Jo, Byung-Gil Lee, YunJae Jung, Temugin Berta, Yong Ho Kim, Chul-Kyu Park","doi":"10.1038/s12276-024-01342-8","DOIUrl":"10.1038/s12276-024-01342-8","url":null,"abstract":"Hormonal regulation during food ingestion and its association with pain prompted the investigation of the impact of glucagon-like peptide-1 (GLP-1) on transient receptor potential vanilloid 1 (TRPV1). Both endogenous and synthetic GLP-1, as well as a GLP-1R antagonist, exendin 9–39, reduced heat sensitivity in naïve mice. GLP-1-derived peptides (liraglutide, exendin-4, and exendin 9–39) effectively inhibited capsaicin (CAP)-induced currents and calcium responses in cultured sensory neurons and TRPV1-expressing cell lines. Notably, exendin 9–39 alleviated CAP-induced acute pain, as well as chronic pain induced by complete Freund’s adjuvant (CFA) and spared nerve injury (SNI), in mice without causing hyperthermia associated with other TRPV1 inhibitors. Electrophysiological analyses revealed that exendin 9–39 binds to the extracellular side of TRPV1, functioning as a noncompetitive inhibitor of CAP. Exendin 9–39 did not affect proton-induced TRPV1 activation, suggesting its selective antagonism. Among the exendin 9–39 fragments, exendin 20–29 specifically binds to TRPV1, alleviating pain in both acute and chronic pain models without interfering with GLP-1R function. Our study revealed a novel role for GLP-1 and its derivatives in pain relief, suggesting exendin 20–29 as a promising therapeutic candidate. People often consume more sweet and fatty foods when they’re hurting, a pattern observed in both humans and animals. This research investigates how eating can lessen pain, focusing on a hormone named glucagon-like peptide-1 (GLP-1), which is created in the stomach after eating. Researchers carried out tests on mice, using different techniques to see how GLP-1 and its byproducts influence pain perception through their impact on a specific pain receptor located in sensory nerves. The main discovery is that GLP-1 and its byproducts provide a potential new technique for pain relief by directly inhibiting the TRPV1 receptor, which could result in new pain management strategies without the negative effects linked with current treatments. The scientists conclude that targeting the GLP-1 pathway could be a promising approach to developing safer pain medications. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"56 11","pages":"2449-2464"},"PeriodicalIF":9.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01342-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142559283","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Longitudinal analysis of genetic and epigenetic changes in human pluripotent stem cells in the landscape of culture-induced abnormality","authors":"Yun-Jeong Kim, Byunghee Kang, Solbi Kweon, Sejin Oh, Dayeon Kim, Dayeon Gil, Hyeonji Lee, Jung-Hyun Kim, Ji Hyeon Ju, Tae-Young Roh, Chang Pyo Hong, Hyuk-Jin Cha","doi":"10.1038/s12276-024-01334-8","DOIUrl":"10.1038/s12276-024-01334-8","url":null,"abstract":"Human embryonic stem cells (hESCs) are naturally equipped to maintain genome integrity to minimize genetic mutations during early embryo development. However, genetic aberration risks and subsequent cellular changes in hESCs during in vitro culture pose a significant threat to stem cell therapy. While a few studies have reported specific somatic mutations and copy number variations (CNVs), the molecular mechanisms underlying the acquisition of ‘culture-adapted phenotypes’ by hESCs are largely unknown. Therefore, we conducted comprehensive genomic, single-cell transcriptomic, and single-cell ATAC-seq analyses of an isogenic hESC model displaying definitive ‘culture-adapted phenotypes’. We found that hESCs lacking TP53, in which loss-of-function mutations were identified in human pluripotent stem cells (hPSCs), presented a surge in somatic mutations. Notably, hPSCs with a copy number gain of 20q11.21 during early passage did not present ‘culture-adapted phenotypes’ or BCL2L1 induction. Single-cell RNA-seq and ATAC-seq analyses revealed active transcriptional regulation at the 20q11.21 locus. Furthermore, the induction of BCL2L1 and TPX2 to trigger ‘culture-adapted phenotypes’ was associated with epigenetic changes facilitating TEA domain (TEAD) binding. These results suggest that 20q11.21 copy number gain and additional epigenetic changes are necessary for expressing ‘culture-adapted phenotypes’ by activating gene transcription at this specific locus. Human pluripotent stem cells (hPSCs) hold significant potential in regenerative medicine due to their ability to produce all types of cells. This study examines how genetic changes in hPSCs impact their stability and safety. Researchers used a set of identical human embryonic stem cells, grown for up to six years, and analyzed them using whole genome sequencing and single-cell sequencing techniques. The study found that certain genetic aberrations, especially mutations in the TP53 gene and a recurrent gain at 20q11.21, become more frequent as hPSCs are grown longer. These findings emphasize that TP53 mutations and 20q11.21 gains can alter the biological characteristics of hPSCs, affecting their safety more than the number of times the cells have been replicated. Understanding these changes is important for establishing guidelines to ensure the safety of stem cell therapy. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"56 11","pages":"2409-2422"},"PeriodicalIF":9.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01334-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142559285","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SMYD family in cancer: epigenetic regulation and molecular mechanisms of cancer proliferation, metastasis, and drug resistance","authors":"Tae-Su Han, Dae-Soo Kim, Mi-Young Son, Hyun-Soo Cho","doi":"10.1038/s12276-024-01326-8","DOIUrl":"10.1038/s12276-024-01326-8","url":null,"abstract":"Epigenetic modifiers (miRNAs, histone methyltransferases (HMTs)/demethylases, and DNA methyltransferases/demethylases) are associated with cancer proliferation, metastasis, angiogenesis, and drug resistance. Among these modifiers, HMTs are frequently overexpressed in various cancers, and recent studies have increasingly identified these proteins as potential therapeutic targets. In this review, we discuss members of the SET and MYND domain-containing protein (SMYD) family that are topics of extensive research on the histone methylation and nonhistone methylation of cancer-related genes. Various members of the SMYD family play significant roles in cancer proliferation, metastasis, and drug resistance by regulating cancer-specific histone methylation and nonhistone methylation. Thus, the development of specific inhibitors that target SMYD family members may lead to the development of cancer treatments, and combination therapy with various anticancer therapeutic agents may increase treatment efficacy. Understanding cancer growth and spread is vital for creating new treatments. Histone methyltransferases play a key role in cancer by controlling genes that can either encourage or inhibit tumor growth. This review focuses on the SMYD family of HMTs, which are associated with cancer progression, spread, and resistance to chemotherapy. The researchers studied the structure, function, and effects of different SMYD family members on cancer, using clinical data and biological experiments. The review also explores how these enzymes can be targeted by specific inhibitors, potentially offering new cancer treatments. The findings suggest that targeting SMYD family members, especially SMYD2 and SMYD3, could be an effective cancer treatment strategy. By developing drugs that specifically inhibit SMYD2 and SMYD3, researchers hope to provide new, more effective treatments for cancer patients. This summary was initially drafted using artificial intelligence, then revised and fact-checked by the author.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"56 11","pages":"2325-2336"},"PeriodicalIF":9.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01326-8.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142559288","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}