Experimental and Molecular Medicine最新文献

{"title":"Modulating neuroplasticity for chronic pain relief: noninvasive neuromodulation as a promising approach","authors":"Nishani Jayanika Jayathilake, Tien Thuy Phan, Jeongsook Kim, Kyu Pil Lee, Joo Min Park","doi":"10.1038/s12276-025-01409-0","DOIUrl":"10.1038/s12276-025-01409-0","url":null,"abstract":"Chronic neuropathic pain is a debilitating neuroplastic disorder that notably impacts the quality of life of millions of people worldwide. This complex condition, encompassing various manifestations, such as sciatica, diabetic neuropathy and postherpetic neuralgia, arises from nerve damage or malfunctions in pain processing pathways and involves various biological, physiological and psychological processes. Maladaptive neuroplasticity, known as central sensitization, plays a critical role in the persistence of chronic neuropathic pain. Current treatments for neuropathic pain include pharmacological interventions (for example, antidepressants and anticonvulsants), invasive procedures (for example, deep brain stimulation) and physical therapies. However, these approaches often have limitations and potential side effects. In light of these challenges, interest in noninvasive neuromodulation techniques as alternatives or complementary treatments for neuropathic pain is increasing. These methods aim to induce analgesia while reversing maladaptive plastic changes, offering potential advantages over conventional pharmacological practices and invasive methods. Recent technological advancements have spurred the exploration of noninvasive neuromodulation therapies, such as repetitive transcranial magnetic stimulation, transcranial direct current stimulation and transcranial ultrasound stimulation, as well as innovative transformations of invasive techniques into noninvasive methods at both the preclinical and clinical levels. Here this review aims to critically examine the mechanisms of maladaptive neuroplasticity in chronic neuropathic pain and evaluate the efficacy of noninvasive neuromodulation techniques in pain relief. By focusing on optimizing these techniques, we can better assess their short-term and long-term effects, refine treatment variables and ultimately improve the quality of neuropathic pain management. Chronic neuropathic pain is a serious health issue affecting many people worldwide. It results from nerve damage and involves complex changes in the nervous system, making it difficult to treat. Researchers are exploring new ways to manage this pain by focusing on neuroplasticity. This study reviews noninvasive techniques that aim to modulate neuroplasticity to alleviate chronic pain. The authors examined various noninvasive methods, such as transcranial magnetic stimulation, transcranial direct current stimulation and ultrasound, which target specific brain areas involved in pain processing. These techniques can alter neural activity without surgery, offering a safer alternative to traditional treatments. The findings suggest that these methods can reduce pain by influencing neural circuits and promoting beneficial changes in the brain. However, the effects are often temporary, highlighting the need for further research to develop long-lasting solutions. This summary was initially drafted using artificial intelligence, then revised and fact","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"57 3","pages":"501-514"},"PeriodicalIF":9.5,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-025-01409-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537953","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":"DNA repair and disease: insights from the human DNA glycosylase NEIL family","authors":"Yuna Hwang, Su-Jin Kang, Jieun Kang, Jeongwoo Choi, Seung-Jin Kim, Sunbok Jang","doi":"10.1038/s12276-025-01417-0","DOIUrl":"10.1038/s12276-025-01417-0","url":null,"abstract":"The base excision repair pathway protects DNA from base damage via oxidation, deamination, alkylation and methylation. DNA glycosylases are key enzymes that recognize damaged bases in a lesion-specific manner and initiate the base excision repair process. Among these, the endonuclease VIII-like 1–3 (NEIL1–3) family, which is found in mammalian genomes, is a homolog of bacterial DNA glycosylases known as Fpg/Nei. NEIL enzymes have similar structures and substrates but with slight differences. When repair proteins are impaired, the accumulation of damaged bases can lead to increased genomic instability, which is implicated in various pathologies, including cancer and neurodegeneration. Notably, mutations in these proteins also influence a range of other diseases and inflammation. This review focuses on the influence of the NEIL family on human health across different organ systems. Investigating the relationship between NEIL mutations and diseases can improve our understanding of how these enzymes affect the human body. This information is crucial for understanding the basic mechanisms of DNA repair and enabling the development of novel inhibitors or gene therapies that target only these enzymes. Understanding the role of the NEIL family provides insights into novel therapies and improves our ability to combat genetic diseases. The base excision repair pathway is crucial for fixing DNA damage, including oxidative base lesions, and maintaining genetic stability. This article reviews the role of NEIL enzymes, which are part of the base excision repair pathway, in various diseases. NEIL enzymes help to repair damaged DNA by removing faulty bases caused by oxidative or alkylation damage. The study highlights the diverse roles of NEIL1, NEIL2 and NEIL3 enzymes in various organ systems and diseases. The researchers found that NEIL1 is broadly associated with the nervous and cardiovascular systems, and uniquely affects the integumentary system and liver, while the functions of NEIL2 are primarily concentrated in the immune and respiratory systems and are specifically associated with bacterial infections of the stomach and large intestine. NEIL3 is linked to the cardiovascular and immune systems, but unlike other NEILs, it shows no independent organ-specific effects. This review also shows that these enzymes play roles in brain health, immune response and skin protection. These findings suggest that understanding NEIL enzymes can lead to better treatments for diseases related to DNA damage by enabling targeted therapies, such as small-molecule modulators, and guiding research to enhance DNA repair in specific 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":"57 3","pages":"524-532"},"PeriodicalIF":9.5,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-025-01417-0.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143544369","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":"Engineered EVs from LncEEF1G - overexpressing MSCs promote fibrotic liver regeneration by upregulating HGF release from hepatic stellate cells","authors":"Jiebin Zhang, Xiaotong Qiu, Yunguo Lei, Haitian Chen, Dongwei Wu, Tingting Wang, Xin Sui, Jiaqi Xiao, Chenhao Jiang, Huayao Zhang, Yasong Liu, Xiaoquan Liu, Yingcai Zhang, Xu Che, Ye Lin, Jia Yao, Zihao Pan, Rong Li, Jun Zheng","doi":"10.1038/s12276-025-01413-4","DOIUrl":"10.1038/s12276-025-01413-4","url":null,"abstract":"Fibrosis is a disease that negatively affects liver regeneration, resulting in severe complications after liver surgery. However, there is still no clinically effective treatment for promoting fibrotic liver regeneration because the underlying hepatocellular mechanism remains poorly understood. Through microRNA microarrays combined with the application of AAV6, we found that high expression of miR-181a-5p in activated hepatic stellate cells (HSCs) suppressed the expression of hepatic growth factor (HGF) and partially contributed to impaired regeneration potential in mice with hepatic fibrosis that had undergone two-thirds partial hepatectomy. As nanotherapeutics, mesenchymal stem-cell-derived extracellular vesicles (MSC-EVs) have been verified as effective treatments for liver regeneration. Here we observe that MSC-EVs can also promote fibrotic liver regeneration via enriched lncEEF1G, which acts as a competing endogenous RNA to directly sponge miR-181a-5p, leading to the upregulated expression of HGF in HSCs. Finally, engineered MSC-EVs with high expression of lncEEF1G (lncEEF1GOE-EVs) were constructed, suggesting greater potential for this model. In summary, our findings indicate that lncEEF1GOE-EVs have a nanotherapeutic effect on promoting regeneration of fibrotic livers by modulating the miR-181a-5p/HGF pathway in HSCs, which highlights the potential of extracellular vesicle engineering technology for patients with hepatic fibrosis who have undergone hepatic surgery. Partial hepatectomy is a common treatment for liver diseases, but liver fibrosis can hinder recovery. This study explores how mesenchymal stem-cell-derived extracellular vesicles (MSC-EVs) might help fibrotic livers regenerate after partial hepatectomy. Researchers found that MSC-EVs can boost liver regeneration by increasing hepatocyte growth factor production in hepatic stellate cells. The study uses a mouse model with liver fibrosis induced by carbon tetrachloride and then performed a partial hepatectomy. Researchers isolated MSCs from umbilical cords and extracted EVs from these cells. They injected these MSC-EVs into the mice and observed their effects on liver regeneration. MSC-EVs were found to be taken up by hepatic stellate cells, leading to increased hepatocyte growth factor production, which is crucial for liver cell proliferation. The results suggest MSC-EVs could be a promising treatment to enhance liver regeneration in fibrotic conditions. 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":"57 3","pages":"584-600"},"PeriodicalIF":9.5,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-025-01413-4.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537946","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":"SARS-CoV-2 pseudovirus dysregulates hematopoiesis and induces inflammaging of hematopoietic stem and progenitor cells","authors":"Dong-Hoon Chae, Hyun Sung Park, Kyoung-Myeon Kim, Aaron Yu, Jae Han Park, Mi-Kyung Oh, Soon Won Choi, Jaechul Ryu, Cynthia E. Dunbar, Hee Min Yoo, Kyung-Rok Yu","doi":"10.1038/s12276-025-01416-1","DOIUrl":"10.1038/s12276-025-01416-1","url":null,"abstract":"Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection primarily affects the respiratory system but may induce hematological alterations such as anemia, lymphopenia and thrombocytopenia. Previous studies have reported that SARS-CoV-2 efficiently infects hematopoietic stem and progenitor cells (HSPCs); however, the subsequent effects on hematopoiesis and immune reconstitution have not yet been described. Here we evaluated the pathological effects of infection of umbilical-cord-blood-derived HSPCs with the SARS-CoV-2 Omicron variant pseudovirus (PsV). Transcriptomic analysis of Omicron PsV-infected HSPCs revealed the upregulation of genes involved in inflammation, aging and the NLRP3 inflammasome, suggesting a potential trigger of inflammaging. Omicron PsV-infected HSPCs presented decreased numbers of multipotential progenitors (granulocyte‒erythrocyte‒macrophage‒megakaryocyte colony-forming units) ex vivo and repopulated primitive hematopoietic stem cells (Ki-67−hCD34+ cells) in an HSPC transplantation NOD-scid IL2rγnull mouse model (Omicron mouse). Furthermore, Omicron PsV infection induced myeloid-biased differentiation of HSPCs. Treatment with nanographene oxide, an antiviral agent, partially mitigated the myeloid bias and inflammaging phenotype both in vitro and in vivo. These findings provide insights into the abnormal hematopoietic and immune effects of SARS-CoV-2 infection and highlight potential therapeutic interventions. The coronavirus disease 2019 (COVID-19) pandemic highlights systemic effects of SARS-CoV-2 beyond respiratory symptoms. Researchers investigated its impact on hematopoietic stem and progenitor cells (HSPCs), which produce blood cells, using a pseudovirus mimicking the Omicron variant. Infection caused inflammation and skewed blood production toward myeloid cells (e.g., macrophages), reducing lymphoid cells (e.g., T and B cells). This imbalance mirrors immune disruptions in COVID-19, such as lymphopenia and excessive inflammation. To address these effects, researchers tested nanographene oxide (NGO), a material with antiviral and anti-inflammatory properties. NGO reduced inflammation and partially restored normal blood production without harming HSPCs. Treated cells showed improved immune balance and reduced myeloid bias. These findings reveal how SARS-CoV-2 disrupts blood cell production and suggest NGO’s potential as a therapeutic tool to manage immune imbalances in COVID-19 and other viral infections. Further studies could explore its broader clinical applications. 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":"57 3","pages":"616-627"},"PeriodicalIF":9.5,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-025-01416-1.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537957","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":"Blockade of the vaspin–AP-1 axis inhibits arthritis development","authors":"Jimin Jeon, Chanmi Cho, Seoyeong Kim, Hyeran Kim, Hyemi Lee, Seok Jung Kim, Hwangseo Park, Ji Hoon Yu, Sangho Lee, Kyu-Sun Lee, Juyeon Jung, Siyoung Yang","doi":"10.1038/s12276-025-01418-z","DOIUrl":"10.1038/s12276-025-01418-z","url":null,"abstract":"The trapping of pathogenic ligands can potentially be used to prevent signal transduction mediated by catabolic factor expression in osteoarthritis (OA). Although vaspin is known to function as a pathogenic ligand and represents a novel adipokine, little is known about its function and the impact of its nebulization-based administration in OA. Here we provide a report on the function of vaspin in articular chondrocytes and OA model mice. RNA sequencing analysis and ingenuity pathway analysis demonstrated that vaspin upregulation in chondrocytes triggers OA development-related signaling. Vaspin is upregulated in the injured cartilage of patients with OA and DMM (Destabilization of the Medial Meniscus) mice, and its overexpression induces catabolic factor expression in vitro under OA-mimicked conditions. Col2a1–vaspin Tg (Transgenic) animals showed extensive cartilage degradation, whereas vaspin−/− (knockout) mice exhibited decreased OA development. Furthermore, in silico and biochemical analyses showed that vaspin activates the p38 and JNK signaling pathways to regulate AP-1-driven catabolic factor production and cartilage breakdown. Finally, we identified and characterized a vaspin-targeting nanobody, vas nanobody, and showed that intraarticularly injected vas nanobody could effectively block the vaspin–AP-1 axis to treat OA in DMM mice. Together, our results suggest that blockade of the vaspin–AP-1 axis could be an effective therapeutic approach for preventing OA development. Osteoarthritis (OA) is a common joint disease that causes pain and stiffness. This study explores the role of a protein called vaspin in OA. Researchers collected cartilage samples from humans and mice to study vaspin’s effects. They found that vaspin levels were higher in damaged cartilage, suggesting it may worsen OA. To test this, they used mice genetically modified to produce more or less vaspin. Mice with more vaspin had worse OA symptoms, while those with less had milder symptoms. The team also developed a small antibody called a nanobody to block vaspin. When injected into mice with OA, this nanobody reduced cartilage damage and pain without causing side effects. The study concludes that targeting vaspin could be a promising new approach for treating OA. Future research may focus on developing nanobody treatments for human use. 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":"57 3","pages":"628-636"},"PeriodicalIF":9.5,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-025-01418-z.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537881","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":"The brown fat-specific overexpression of RBP4 improves thermoregulation and systemic metabolism by activating the canonical adrenergic signaling pathway","authors":"Jong Yoen Park, Eun Sun Ha, Jimin Lee, Pierre-Jacques Brun, Yeri Kim, Sung Soo Chung, Daehee Hwang, Seung-Ah Lee, Kyong Soo Park","doi":"10.1038/s12276-025-01411-6","DOIUrl":"10.1038/s12276-025-01411-6","url":null,"abstract":"Retinol-binding protein 4 (RBP4), the sole specific carrier for retinol (vitamin A) in circulation, is highly expressed in liver and adipose tissues. Previous studies have demonstrated that RBP4 plays a role in cold-mediated adipose tissue browning and thermogenesis. However, the role of RBP4 in brown adipose tissue and its metabolic significance remain unclear. Here we generated and studied transgenic mice that express human RBP4 (hRBP4), specifically in brown adipocytes (UCP1-RBP4 mice), to better understand these uncertainties. When fed a chow diet, these mice presented significantly lower body weights and fat mass than their littermate controls. The UCP1-RBP4 mice also showed significant improvements in glucose clearance, enhanced energy expenditure and increased thermogenesis in response to a cold challenge. This was associated with increased lipolysis and fatty acid oxidation in brown adipose tissue, which was attributed to the activation of canonical adrenergic signaling pathways. In addition, high-performance liquid chromatography analysis revealed that plasma RBP4 and retinol levels were elevated in the UCP1-RBP4 mice, whereas their hepatic retinol levels decreased in parallel with a chow diet. Steady-state brown fat levels of total retinol were significantly elevated in the UCP1-RBP4 mice, suggesting that their retinol uptake was increased in RBP4-expressing brown adipocytes when fed a chow diet. These findings reveal a critical role for RBP4 in canonical adrenergic signaling that promotes lipid mobilization and oxidation in brown adipocytes, where the harnessed energy is dissipated as heat by adaptive thermogenesis. Brown adipose tissue, or brown fat, helps generate heat in our bodies. This study explores how retinol-binding protein 4 affects the ability of brown fat to burn energy. The researchers used mice genetically modified to produce more RBP4 in their brown fat. They found that these mice had lower body weight and better glucose control compared with normal mice. The study involved analyzing the mice’s fat tissues and measuring their energy use and fat breakdown. The researchers discovered that increased RBP4 in brown fat led to higher energy expenditure and improved fat metabolism. This suggests that RBP4 plays a role in activating brown fat and could help in managing obesity and related metabolic disorders. The findings indicate that targeting RBP4 in brown fat might be a potential strategy for treating 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":"57 3","pages":"554-566"},"PeriodicalIF":9.5,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-025-01411-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537962","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":"Metabolic reprogramming in hepatocellular carcinoma: mechanisms and therapeutic implications","authors":"Sujin Park, Michael N. Hall","doi":"10.1038/s12276-025-01415-2","DOIUrl":"10.1038/s12276-025-01415-2","url":null,"abstract":"Hepatocellular carcinoma features extensive metabolic reprogramming. This includes alterations in major biochemical pathways such as glycolysis, the pentose phosphate pathway, amino acid metabolism and fatty acid metabolism. Moreover, there is a complex interplay among these altered pathways, particularly involving acetyl-CoA (coenzyme-A) metabolism and redox homeostasis, which in turn influences reprogramming of other metabolic pathways. Understanding these metabolic changes and their interactions with cellular signaling pathways offers potential strategies for the targeted treatment of hepatocellular carcinoma and improved patient outcomes. This review explores the specific metabolic alterations observed in hepatocellular carcinoma and highlights their roles in the progression of the disease. Cancer cells often change their metabolism to support rapid growth. This study examines how liver cancer, specifically hepatocellular carcinoma (HCC), alters its metabolism and explores potential treatments. The authors focus on how HCC cells use glucose, amino acids and fatty acids differently from normal cells. HCC cells rely heavily on glycolysis even when oxygen is present, a phenomenon known as the Warburg effect. They also activate the pentose phosphate pathway to produce molecules needed for growth and survival. Additionally, HCC cells depend on certain amino acids such as glutamine and serine for building blocks and energy. This study highlights that targeting these altered metabolic pathways could be a promising strategy for treating HCC. In conclusion, understanding these metabolic changes in HCC can lead to new treatment approaches. 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":"57 3","pages":"515-523"},"PeriodicalIF":9.5,"publicationDate":"2025-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-025-01415-2.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143537949","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":"Cannabidiol reshapes the gut microbiome to promote endurance exercise in mice","authors":"Si Chen, Yu-Bin Lee, Mi-Young Song, Changjin Lim, Hwangeui Cho, Hyun Joo Shim, Jong-Suk Kim, Byung-Hyun Park, Jeon-Kyung Kim, Eun Ju Bae","doi":"10.1038/s12276-025-01404-5","DOIUrl":"10.1038/s12276-025-01404-5","url":null,"abstract":"Cannabidiol (CBD), a nonpsychoactive compound from Cannabis, has various bioactive functions in humans and animals. Evidence suggests that CBD promotes muscle injury recovery in athletes, but whether and how CBD improves endurance performance remains unclear. Here we investigated the effects of CBD treatment on exercise performance in mice and assessed whether this effect involves the gut microbiome. CBD administration significantly increased treadmill running performance in mice, accompanied by an increase in oxidative myofiber composition. CBD also increased mitochondrial biogenesis and the expression of associated genes such as PGC-1α, phosphorylated CREB and AMPK in muscle tissue. Interestingly, CBD altered the composition of the gut microbiome, and antibiotic treatment reduced the muscle endurance-enhancing effects of CBD and mitochondrial biogenesis. We isolated Bifidobacterium animalis, a microbe increased by CBD administration, and named it KBP-1. Treatment with B. animalis KBP-1 in mice resulted in improved running performance. Whole-genome analysis revealed that B. animalis KBP-1 presented high expression of genes involved in branched-chain amino acid biosynthesis, expression of branched-chain amino acid release pumps and metabolism of lactic acid. In summary, our study identified CBD and B. animalis KBP-1 as potential endurance exercise-promoting agents. This study explores how cannabidiol (CBD), a compound from the Cannabis sativa plant, affects exercise performance and muscle function. The researchers wanted to see if CBD could improve endurance by changing gut bacteria. They found that CBD improved endurance and increased the presence of certain gut bacteria, including Bifidobacterium animalis, that may help muscles use energy more efficiently. The study involved treating mice with either CBD or B. animalis for 4 weeks and measuring their running ability on a treadmill. The researchers examined changes in muscle fibers and gut bacteria composition. They discovered that CBD and B. animalis increased oxidative muscle fibers, which benefit endurance performance. The results suggest that CBD enhances exercise performance by promoting beneficial gut bacteria and improving muscle energy use. The researchers conclude that both CBD and B. animalis could be used to boost endurance.","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"57 2","pages":"489-500"},"PeriodicalIF":9.5,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-025-01404-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143450895","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":"Activin E is a new guardian protecting against hepatic steatosis via inhibiting lipolysis in white adipose tissue","authors":"Shi-Young Park, Yoonil Cho, Sae-Mi Son, Jang Ho Hur, Yeongmin Kim, Hyunhee Oh, Hui-Young Lee, Sungwon Jung, Sanghee Park, Il-Young Kim, Se-Jin Lee, Cheol Soo Choi","doi":"10.1038/s12276-025-01403-6","DOIUrl":"10.1038/s12276-025-01403-6","url":null,"abstract":"Hepatic endoplasmic reticulum (ER) stress is implicated in the development of steatosis and its progression to nonalcoholic steatohepatitis (NASH). The ER in the liver can sustain metabolic function by activating defense mechanisms that delay or prevent the progression of nonalcoholic fatty liver disease (NAFLD). However, the precise mechanisms by which the ER stress response protects against NAFLD remain largely unknown. Recently, activin E has been linked to metabolic diseases such as insulin resistance and NAFLD. However, the physiological conditions and regulatory mechanisms driving hepatic Inhbe expression (which encodes activin E) as well as the metabolic role of activin E in NAFLD require further investigation. Here we found that hepatic Inhbe expression increased under prolonged fasting and ER stress conditions, which was mediated by ATF4, as determined by promoter analysis in a mouse model. Consistently, a positive correlation between INHBE and ATF4 expression levels in relation to NAFLD status was confirmed using public human NAFLD datasets. To investigate the role of activin E in hepatic steatosis, we assessed the fluxes of the lipid metabolism in an Inhbe-knockout mouse model. These mice displayed a lean phenotype but developed severe hepatic steatosis under a high-fat diet. The deficiency of Inhbe resulted in increased lipolysis in adipose tissue, leading to increased fatty acid influx into the liver. Conversely, hepatic overexpression of Inhbe ameliorated hepatic steatosis by suppressing lipolysis in adipose tissue through ALK7–Smad signaling. In conclusion, activin E serves as a regulatory hepatokine that prevents fatty acid influx into the liver, thereby protecting against NAFLD. Hepatic endoplasmic reticulum (ER) stress is associated with nonalcoholic fatty liver disease (NAFLD). Although it is known that the liver’s ER can activate defense mechanisms to slow NAFLD progression, the specific protective processes remain unclear. Recent studies have identified activin E, encoded by the Inhbe gene, as being linked to metabolic conditions such as insulin resistance and NAFLD. This research demonstrates that hepatic Inhbe expression increases during ER stress, a process regulated by ATF4. Loss of Inhbe led to severe hepatic steatosis due to enhanced lipolysis in adipose tissue. By contrast, hepatic overexpression of Inhbe alleviated hepatic steatosis by suppressing adipose tissue lipolysis through ALK7–Smad signaling. These findings suggest that activin E functions as a regulatory hepatokine, protecting against NAFLD by preventing excessive fatty acid influx into the liver through the inhibition of adipose lipolysis. 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":"57 2","pages":"466-477"},"PeriodicalIF":9.5,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-025-01403-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143416141","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":"ACOT12, a novel factor in the pathogenesis of kidney fibrosis, modulates ACBD5","authors":"Ee Hyun Kim, Mi Kyung Kim, MiSun Choe, Ji Hyun Ryu, Eun Seon Pak, Hunjoo Ha, Eun-Jung Jin","doi":"10.1038/s12276-025-01406-3","DOIUrl":"10.1038/s12276-025-01406-3","url":null,"abstract":"Lipid metabolism, particularly fatty acid oxidation dysfunction, is a major driver of renal fibrosis. However, the detailed regulatory mechanisms underlying this process remain unclear. Here we demonstrated that acyl-CoA thioesterase 12 (Acot12), an enzyme involved in the hydrolysis of acyl-CoA thioesters into free fatty acids and CoA, is a key regulator of lipid metabolism in fibrotic kidneys. A significantly decreased level of ACOT12 was observed in kidney samples from human patients with chronic kidney disease as well as in samples from mice with kidney injuries. Acot12 deficiency induces lipid accumulation and fibrosis in mice subjected to unilateral ureteral obstruction (UUO). Fenofibrate administration does not reduce renal fibrosis in Acot12−/− mice with UUO. Moreover, the restoration of peroxisome proliferator-activated receptor α (PPARα) in Acot12−/−Pparα−/− kidneys with UUO exacerbated lipid accumulation and renal fibrosis, whereas the restoration of Acot12 in Acot12−/− Pparα−/− kidneys with UUO significantly reduced lipid accumulation and renal fibrosis, suggesting that, mechanistically, Acot12 deficiency exacerbates renal fibrosis independently of PPARα. In Acot12−/− kidneys with UUO, a reduction in the selective autophagic degradation of peroxisomes and pexophagy with a decreased level of ACBD5 was observed. In conclusion, our study demonstrates the functional role and mechanistic details of Acot12 in the progression of renal fibrosis, provides a preclinical rationale for regulating Acot12 expression and presents a novel means of preventing renal fibrosis. Chronic kidney disease (CKD) is a serious condition that affects kidney function over time. It can lead to other health problems, but current treatments are limited. Here the authors wanted to explore new ways to treat CKD by focusing on kidney fibrosis, a major factor in CKD progression. This study demonstrates that decreased level of ACOT12, a critical enzyme in lipid metabolism, correlates with increased fibrosis and lipid accumulation in the kidney tissues. Mice lacking ACOT12 had more kidney fibrosis and lipid accumulation, suggesting that ACOT12 plays a protective role, while restoring ACOT12 in these mice reduced fibrosis and lipid buildup. These findings suggest that targeting ACOT12 could be a novel therapeutic approach for preventing kidney fibrosis by regulating lipid metabolism in CKD. 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":"57 2","pages":"478-488"},"PeriodicalIF":9.5,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-025-01406-3.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143410770","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}