Experimental and Molecular Medicine最新文献

{"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":"https://doi.org/10.1038/s12276-024-01338-4","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":9.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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":"<p><p>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.</p>","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":9.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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":"https://doi.org/10.1038/s12276-024-01334-8","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":9.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","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":"https://doi.org/10.1038/s12276-024-01326-8","url":null,"abstract":"<p><p>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.</p>","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":9.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","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":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"VISTA-mediated immune evasion in cancer.","authors":"Raymond J Zhang, Tae Kon Kim","doi":"10.1038/s12276-024-01336-6","DOIUrl":"https://doi.org/10.1038/s12276-024-01336-6","url":null,"abstract":"<p><p>Over the past decade, V-domain immunoglobulin suppressor of T-cell activation (VISTA) has been established as a negative immune checkpoint molecule. Since the role of VISTA in inhibiting T-cell activation was described, studies have demonstrated other diverse regulatory functions in multiple immune cell populations. Furthermore, its relevance has been identified in human cancers. The role of VISTA in cancer immune evasion has been determined, but its mechanisms in the tumor microenvironment remain to be further elucidated. Understanding its contributions to cancer initiation, progression, and resistance to current treatments will be critical to its utility as a target for novel immunotherapies. Here, we summarize the current understanding of VISTA biology in cancer.</p>","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":9.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142559291","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The MCP-3/Ccr3 axis contributes to increased bone mass by affecting osteoblast and osteoclast differentiation.","authors":"Jung Ha Kim, Kabsun Kim, Inyoung Kim, Semun Seong, Xiangguo Che, Je-Yong Choi, Jeong-Tae Koh, Nacksung Kim","doi":"10.1038/s12276-024-01344-6","DOIUrl":"https://doi.org/10.1038/s12276-024-01344-6","url":null,"abstract":"<p><p>Several CC subfamily chemokines have been reported to regulate bone metabolism by affecting osteoblast or osteoclast differentiation. However, the role of monocyte chemotactic protein 3 (MCP-3), a CC chemokine, in bone remodeling is not well understood. Here, we show that MCP-3 regulates bone remodeling by promoting osteoblast differentiation and inhibiting osteoclast differentiation. In a Ccr3-dependent manner, MCP-3 promoted osteoblast differentiation by stimulating p38 phosphorylation and suppressed osteoclast differentiation by upregulating interferon beta. MCP-3 increased bone morphogenetic protein 2-induced ectopic bone formation, and mice with MCP-3-overexpressing osteoblast precursor cells presented increased bone mass. Moreover, MCP-3 exhibited therapeutic effects by abrogating receptor activator of nuclear factor kappa-B ligand-induced bone loss. Therefore, MCP-3 has therapeutic potential for diseases involving bone loss due to its positive role in osteoblast differentiation and negative role in osteoclast differentiation.</p>","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":9.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142559289","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The transcription factor BBX regulates phosphate homeostasis through the modulation of FGF23.","authors":"Su Jeong Lee, Ju Ang Kim, Hye Jung Ihn, Je-Yong Choi, Tae-Yub Kwon, Hong-In Shin, Eui-Sic Cho, Yong Chul Bae, Rulang Jiang, Jung-Eun Kim, Eui Kyun Park","doi":"10.1038/s12276-024-01341-9","DOIUrl":"https://doi.org/10.1038/s12276-024-01341-9","url":null,"abstract":"<p><p>Fibroblast growth factor 23 (FGF23) plays an important role in phosphate homeostasis, and increased FGF23 levels result in hypophosphatemia; however, the molecular mechanism underlying increased FGF23 expression has not been fully elucidated. In this study, we found that mice lacking the bobby sox homolog (Bbx^-/-) presented increased FGF23 expression and low phosphate levels in the serum and skeletal abnormalities such as a low bone mineral density (BMD) and bone volume (BV), as well as short and weak bones associated with low bone formation. Osteocyte-specific deletion of Bbx using Dmp-1-Cre resulted in similar skeletal abnormalities, elevated serum FGF23 levels, and reduced serum phosphate levels. In Bbx^-/- mice, the expression of sodium phosphate cotransporter 2a (Npt2a) and Npt2c in the kidney and Npt2b in the small intestine, which are negatively regulated by FGF23, was downregulated, leading to phosphate excretion/wasting and malabsorption. An in vitro Fgf23 promoter analysis revealed that 1,25-dihydroxyvitamin D₃ (1,25(OH)₂D₃)-induced transactivation of the Fgf23 promoter was significantly inhibited by BBX overexpression, whereas it was increased following Bbx knockdown. Interestingly, 1,25(OH)₂D₃ induced an interaction of the 1,25(OH)₂D₃ receptor (VDR) with BBX and downregulated BBX protein levels. Cycloheximide (CHX) only partially downregulated BBX protein levels, indicating that 1,25(OH)₂D₃ regulates BBX protein stability. Furthermore, the ubiquitination of BBX followed by proteasomal degradation was required for the increase in Fgf23 expression induced by 1,25(OH)₂D₃. Collectively, our data demonstrate that BBX negatively regulates Fgf23 expression, and consequently, the ubiquitin-dependent proteasomal degradation of BBX is required for FGF23 expression, thereby regulating phosphate homeostasis and bone development in mice.</p>","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":9.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142559290","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The inflammasome-activating poxvirus peptide IAMP29 promotes antimicrobial and anticancer responses.","authors":"Taylor Roh, Wonhyoung Seo, Minho Won, Woo Seok Yang, Asmita Sapkota, Eun-Jin Park, Sung-Ho Yun, Sang Min Jeon, Kyung Tae Kim, Bomi Lee, Gyoungah Ryu, Sang-Hee Lee, Jung-Min Shin, Hyo Jung Shin, Young Jae Kim, Young Lee, Chaeuk Chung, Ik-Chan Song, Hyun Kyu Song, Eun-Kyeong Jo","doi":"10.1038/s12276-024-01339-3","DOIUrl":"https://doi.org/10.1038/s12276-024-01339-3","url":null,"abstract":"<p><p>Poxviruses are implicated in a variety of infectious diseases; however, little is known about the molecular mechanisms that underlie the immune response during poxvirus infection. We investigated the function and mechanisms of the monkeypox virus envelope protein (A30L) and its core peptide (IAMP29) during the activation of innate immune responses. The A30L protein and its core peptide, IAMP29 (a 29-amino-acid inflammasome-activating peptide encompassing His40 to Asp69 of A30L), strongly activated the nucleotide-binding oligomerization domain, leucine rich repeat and pyrin domain-containing 3 (NLRP3) inflammasome by inducing the production of mitochondrial reactive oxygen species in human monocytes. Specifically, IAMP29 triggered metabolic reprogramming toward glycolysis and interacted with pyruvate kinase M isoforms (PKM1 and PKM2), thus activating the NLRP3 inflammasome and interleukin (IL)-1β production in human monocytes and murine macrophages. In human primary monocyte-derived macrophages, IAMP29-induced inflammasome activation promoted an antimicrobial response to rapidly growing non-tuberculous mycobacteria. Furthermore, IAMP29 exhibited cytotoxic activity against leukemia cells, which was mediated by pyroptosis and apoptosis. These findings provide insights into the immunological function of the poxvirus envelope peptide and suggest its therapeutic potential.</p>","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":" ","pages":""},"PeriodicalIF":9.5,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142607419","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Single-cell transcriptomic analysis reveals dynamic activation of cellular signaling pathways regulating beige adipogenesis","authors":"Dong Soo Kyung,&nbsp;Eunmin Lee,&nbsp;Sehyun Chae,&nbsp;Yeonho Son,&nbsp;Ye-Jin Moon,&nbsp;Daehee Hwang,&nbsp;Jong Kyoung Kim,&nbsp;Yun-Hee Lee,&nbsp;Je Kyung Seong","doi":"10.1038/s12276-024-01252-9","DOIUrl":"10.1038/s12276-024-01252-9","url":null,"abstract":"PDGFRA+ cells have been identified as adipocyte stem cells (ASCs) that differentiate into beige adipocytes in white adipose tissue (WAT) following thermogenic stimuli. To elucidate the molecular heterogeneity of ASCs, we conducted single-cell transcriptomic profiling of PDGFRA+ cells isolated from the inguinal WAT (iWAT) of mice treated with the beta3 adrenergic receptor agonist CL316243. Single-cell RNA-seq revealed nine major clusters, which were categorized into four groups: resting, proliferating, differentiating, and adipogenic factor-expressing cells (AFECs). Trajectory analysis revealed sequential activation of molecular pathways, including the Hedgehog and Notch signaling pathways, during beige adipogenesis. AFECs expressed Dpp4 and did not differentiate into adipocytes in culture or after transplantation. Furthermore, genetic lineage tracing studies indicated that DPP4+ cells did not differentiate into adipocytes in iWAT during CL316243-induced beige adipogenesis. However, high-fat diet feeding led to the recruitment of adipocytes from DPP4+ cells in iWAT. Overall, this study improved our understanding of the dynamic molecular basis of beige adipogenesis and the potential contribution of DPP4+ adipocyte lineages to the pathological expansion of WAT during diet-induced obesity. This research examines beige adipogenesis, or the creation of ‘beige’ fat cells that burn energy and could help fight obesity. The scientists discovered a group of cells, identifed by specific markers PDGFRA and DPP4, which serve as a source for beige adipogenesis but don’t turn into beige fat cells themselves. They also found that these cells can change to become fat cells under certain situations, like a high-fat diet. The study also showed that the Hedgehog and Notch signaling pathways are vital in the transformation of PDGFRA+ cells into beige fat cells. These discoveries could be important for developing anti-obesity therapeutics. 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 10","pages":"2309-2322"},"PeriodicalIF":9.5,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01252-9.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142512268","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":"Author Correction: Ablation of the deubiquitinase USP15 ameliorates nonalcoholic fatty liver disease and nonalcoholic steatohepatitis","authors":"Jung-Hwan Baek,&nbsp;Myung Sup Kim,&nbsp;Hye Ryeon Jung,&nbsp;Min-Seon Hwang,&nbsp;Chan-ho Lee,&nbsp;Dai Hoon Han,&nbsp;Yong-ho Lee,&nbsp;Eugene C. Yi,&nbsp;Seung-Soon Im,&nbsp;Ilseon Hwang,&nbsp;Kyungeun Kim,&nbsp;Joon-Yong Chung,&nbsp;Kyung-Hee Chun","doi":"10.1038/s12276-024-01343-7","DOIUrl":"10.1038/s12276-024-01343-7","url":null,"abstract":"","PeriodicalId":50466,"journal":{"name":"Experimental and Molecular Medicine","volume":"56 10","pages":"2324-2324"},"PeriodicalIF":9.5,"publicationDate":"2024-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s12276-024-01343-7.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142523504","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}