Cells最新文献

{"title":"The p.R66W Variant in <i>RAC3</i> Causes Severe Fetopathy Through Variant-Specific Mechanisms.","authors":"Ryota Sugawara, Hidenori Ito, Hidenori Tabata, Hiroshi Ueda, Marcello Scala, Koh-Ichi Nagata","doi":"10.3390/cells13232032","DOIUrl":"https://doi.org/10.3390/cells13232032","url":null,"abstract":"<p><p><i>RAC3</i> encodes a small GTPase of the Rho family that plays a critical role in actin cytoskeleton remodeling and intracellular signaling regulation. Pathogenic variants in <i>RAC3</i>, all of which reported thus far affect conserved residues within its functional domains, have been linked to neurodevelopmental disorders characterized by diverse phenotypic features, including structural brain anomalies and facial dysmorphism (NEDBAF). Recently, a novel de novo <i>RAC3</i> variant (NM_005052.3): c.196C>T, p.R66W was identified in a prenatal case with fetal akinesia deformation sequence (a spectrum of conditions that interfere with the fetus's ability to move), and complex brain malformations featuring corpus callosum agenesis, diencephalosynapsis, kinked brainstem, and vermian hypoplasia. To investigate the mechanisms underlying the association between RAC3 deficiency and this unique, distinct clinical phenotype, we explored the pathophysiological significance of the p.R66W variant in brain development. Biochemical assays revealed a modest enhancement in intrinsic GDP/GTP exchange activity and an inhibitory effect on GTP hydrolysis. Transient expression studies in COS7 cells demonstrated that RAC3-R66W interacts with the downstream effectors PAK1, MLK2, and N-WASP but fails to activate SRF-, AP1-, and NFkB-mediated transcription. Additionally, overexpression of RAC3-R66W significantly impaired differentiation in primary cultured hippocampal neurons. Acute expression of RAC3-R66W in vivo by in utero electroporation resulted in impairments in cortical neuron migration and axonal elongation during corticogenesis. Collectively, these findings suggest that the p.R66W variant may function as an activated version in specific signaling pathways, leading to a distinctive and severe prenatal phenotype through variant-specific mechanisms.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"13 23","pages":""},"PeriodicalIF":5.1,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142834183","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Circular RNAs in Viral Infection and Antiviral Treatment.","authors":"Xiaocai Yin, Hongjun Li, Yan Zhou","doi":"10.3390/cells13232033","DOIUrl":"https://doi.org/10.3390/cells13232033","url":null,"abstract":"<p><p>Circular RNAs (circRNAs) are a class of noncoding RNAs that lack the 5'-cap structure and the 3' poly(A) tail. Their distinguishing feature is that the 3' and 5' ends are covalently linked to form a closed circular structure. CircRNAs have a longer half-life and stronger ribonuclease resistance compared with linear RNA. Viral infections lead to the production of circRNA molecules through the transcription and splicing mechanisms of host cells. circRNAs are produced from the transcription and splicing of the viral genome or from the splicing reactions of the host cell gene. They participate in regulating the replication of many viruses, including coronaviruses, human herpesviruses, human immunodeficiency virus, and cytomegalovirus. CircRNAs regulate the infection process by modulating circRNA expression in host cells and affect cellular biological processes. Some circRNAs have been proposed as diagnostic markers for viral infections. In this review, we discussed the properties of virus-derived circRNAs, the biological functions of diverse viruses-derived and host circRNAs during viral infections, and the critical role of circRNAs in the host's antiviral immune defense. Extensive research on the applications of circRNAs can help us better understand gene regulatory networks and disease mechanisms.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"13 23","pages":""},"PeriodicalIF":5.1,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142834196","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gene-Silencing Therapeutic Approaches Targeting PI3K/Akt/mTOR Signaling in Degenerative Intervertebral Disk Cells: An In Vitro Comparative Study Between RNA Interference and CRISPR-Cas9.","authors":"Masao Ryu, Takashi Yurube, Yoshiki Takeoka, Yutaro Kanda, Takeru Tsujimoto, Kunihiko Miyazaki, Hiroki Ohnishi, Tomoya Matsuo, Naotoshi Kumagai, Kohei Kuroshima, Yoshiaki Hiranaka, Ryosuke Kuroda, Kenichiro Kakutani","doi":"10.3390/cells13232030","DOIUrl":"https://doi.org/10.3390/cells13232030","url":null,"abstract":"<p><p>The mammalian target of rapamycin (mTOR), a serine/threonine kinase, promotes cell growth and inhibits autophagy. The following two complexes contain mTOR: mTORC1 with the regulatory associated protein of mTOR (RAPTOR) and mTORC2 with the rapamycin-insensitive companion of mTOR (RICTOR). The phosphatidylinositol 3-kinase (PI3K)/Akt/mTOR signaling pathway is important in the intervertebral disk, which is the largest avascular, hypoxic, low-nutrient organ in the body. To examine gene-silencing therapeutic approaches targeting PI3K/Akt/mTOR signaling in degenerative disk cells, an in vitro comparative study was designed between small interfering RNA (siRNA)-mediated RNA interference (RNAi) and clustered regularly interspaced short palindromic repeat (CRISPR)-CRISPR-associated protein 9 (Cas9) gene editing. Surgically obtained human disk nucleus pulposus cells were transfected with a siRNA or CRISPR-Cas9 plasmid targeting <i>mTOR</i>, <i>RAPTOR</i>, or <i>RICTOR</i>. Both of the approaches specifically suppressed target protein expression; however, the 24-h transfection efficiency differed by 53.8-60.3% for RNAi and 88.1-89.3% for CRISPR-Cas9 (<i>p</i> < 0.0001). Targeting <i>mTOR</i>, <i>RAPTOR</i>, and <i>RICTOR</i> all induced autophagy and inhibited apoptosis, senescence, pyroptosis, and matrix catabolism, with the most prominent effects observed with <i>RAPTOR</i> CRISPR-Cas9. In the time-course analysis, the 168-h suppression ratio of RAPTOR protein expression was 83.2% by CRISPR-Cas9 but only 8.8% by RNAi. While RNAi facilitates transient gene knockdown, CRISPR-Cas9 provides extensive gene knockout. Our findings suggest that RAPTOR/mTORC1 is a potential therapeutic target for degenerative disk disease.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"13 23","pages":""},"PeriodicalIF":5.1,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142834304","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CycloZ Suppresses TLR4-Driven Inflammation to Reduce Asthma-Like Responses in HDM-Exposed Mouse Models.","authors":"Dohyun Lee, Jongsu Jeon, Seoyeong Baek, Onyu Park, Ah-Ram Kim, Myoung-Sool Do, Hoe-Yune Jung","doi":"10.3390/cells13232034","DOIUrl":"https://doi.org/10.3390/cells13232034","url":null,"abstract":"<p><p>Asthma is a chronic lung disease characterized by airway inflammation, hyperresponsiveness, and narrowing, with a risk of life-threatening attacks. Most current treatments primarily consist of inhalable steroids, which are not without adverse effects. Recently, there has been growing interest in alternative approaches to asthma management. In this study, we investigated the anti-asthmatic effects of the non-steroidal compound CycloZ using acute and chronic mouse models of asthma. Allergic reactions were induced with house dust mite (HDM) extract, and CycloZ or fluticasone propionate (FP) was administered orally or intranasally, respectively. CycloZ significantly ameliorated the HDM-induced robust expression of Th2 cytokines in both models. CycloZ also decreased immune cell infiltration into the lungs and reduced IL-4 and IL-13 cytokine levels in bronchoalveolar lavage fluid (BALF). Moreover, CycloZ greatly attenuated the activation of the TLR-4 pathway, which is involved in HDM recognition and signaling. The beneficial effects of CycloZ were comparable to or even superior to the current steroid treatment, FP, suggesting that CycloZ could be a promising new option for asthma therapy.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"13 23","pages":""},"PeriodicalIF":5.1,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142834230","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Extracellular Vesicles and Their Applications in Tumor Diagnostics and Immunotherapy.","authors":"Scott Strum, Valentina Evdokimova, Laszlo Radvanyi, Anna Spreafico","doi":"10.3390/cells13232031","DOIUrl":"https://doi.org/10.3390/cells13232031","url":null,"abstract":"<p><p>Extracellular vesicles (EVs) are cell-derived nanoparticles that have attracted significant attention in the investigation of human health and disease, including cancer biology and its clinical management. Concerning cancer, EVs have been shown to influence numerous aspects of oncogenesis, including tumor proliferation and metastasis. EVs can augment the immune system and have been implicated in virtually all aspects of innate and adaptive immunity. With immunotherapy changing the landscape of cancer treatment across multiple disease sites, it is paramount to understand their mechanisms of action and to further improve upon their efficacy. Despite a rapidly growing body of evidence supporting of the utility of EVs in cancer diagnostics and therapeutics, their application in clinical trials involving solid tumors and immunotherapy remains limited. To date, relatively few trials are known to incorporate EVs in this context, mainly employing them as biomarkers. To help address this gap, this review summarizes known applications of EVs in clinical trials and provides a brief overview of the roles that EVs play in cancer biology, immunology, and their proposed implications in immunotherapy. The impetus to leverage EVs in future clinical trials and correlative studies is crucial, as they are ideally positioned to synergize with advancements in multi-omics research to further therapeutic discovery and our understanding of cancer biology.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"13 23","pages":""},"PeriodicalIF":5.1,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142834302","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical Potential of Novel Microbial Therapeutic LP51 Based on Xerosis-Microbiome Index.","authors":"Sukyung Kim, Md Abdur Rahim, Hanieh Tajdozian, Indrajeet Barman, Hyun-A Park, Youjin Yoon, Sujin Jo, Soyeon Lee, Md Sarower Hossen Shuvo, Sung Hae Bae, Hyunji Lee, Sehee Ju, Chae-Eun Park, Ho-Kyoung Kim, Jeung Hi Han, Ji-Woong Kim, Sung Geon Yoon, Jae Hong Kim, Yang Gyu Choi, Saebim Lee, Hoonhee Seo, Ho-Yeon Song","doi":"10.3390/cells13232029","DOIUrl":"https://doi.org/10.3390/cells13232029","url":null,"abstract":"<p><p>Xerosis, characterized by dry, rough skin, causes discomfort and aesthetic concerns, necessitating effective treatment. Traditional treatments often show limited efficacy, prompting the need for innovative therapies. This study highlights the efficacy of microbiome therapeutic LP51, derived from a healthy vaginal microbiome, in improving xerosis. A double-blind clinical trial involving 43 subjects with dry inner arm skin compared the effects of a 2.9% LP51 extract formulation to a placebo over 4 weeks. The LP51 group exhibited a significant increase in stratum corneum hydration (10.0 A.U.) compared to the placebo group (4.8 A.U.) and a 21.4% decrease in transepidermal water loss (TEWL), whereas the placebo group showed no significant change. LP51 also demonstrated benefits in enhancing skin hydration, improving the skin barrier, and exhibited anti-atopic, anti-inflammatory, and antioxidant properties. Safety was confirmed through in vitro cytotoxicity tests. These effects are attributed to the microbiome-safe component in LP51 and its role in improving xerosis, reflected by an increase in the xerosis-microbiome index, defined by the Firmicutes/Actinobacteria ratio. These findings position microbiome therapeutic LP51 as a promising novel treatment for xerosis.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"13 23","pages":""},"PeriodicalIF":5.1,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142834205","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"LINC01270 Regulates the NF-κB-Mediated Pro-Inflammatory Response via the miR-326/LDOC1 Axis in THP-1 Cells.","authors":"Imene Arab, Su-Geun Lim, Kyoungho Suk, Won-Ha Lee","doi":"10.3390/cells13232027","DOIUrl":"https://doi.org/10.3390/cells13232027","url":null,"abstract":"<p><p>Long intergenic noncoding (LINC)01270 is a 2278 bp transcript belonging to the intergenic subset of long noncoding (lnc)RNAs. Despite increased reports of LINC01270's involvement in different diseases, evident research on its effects on inflammation is yet to be achieved. In the present study, we investigated the potential role of LINC01270 in modulating the inflammatory response in the human monocytic leukemia cell line THP-1. Lipopolysaccharide treatment upregulated LINC01270 expression, and siRNA-mediated suppression of LINC01270 enhanced NF-κB activity and the subsequent production of cytokines IL-6, IL-8, and MCP-1. Interestingly, the knockdown of LINC01270 downregulated expression of leucine zipper downregulated in cancer 1 (LDOC1), a novel NF-κB suppressor. An analysis of the LINC01270/micro-RNA (miRNA)/protein interactome profile identified miR-326 as a possible mediator. Synthetic RNA agents that perturb the interaction among LINC01270, miR-326, and LDOC1 mRNA mitigated the changes caused by LINC01270 knockdown in THP-1 cells. Additionally, a luciferase reporter assay in HEK293 cells further confirmed that LINC01270 knockdown enhances NF-κB activation, while its overexpression has the opposite effect. This study provides insight into LINC01270's role in modulating inflammatory responses to lipopolysaccharide stimulation in THP-1 cells via the miR-326/LDOC1 axis, which negatively regulates NF-κB activation.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"13 23","pages":""},"PeriodicalIF":5.1,"publicationDate":"2024-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142834188","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Extract of <i>Curculigo capitulata</i> Ameliorates Postmenopausal Osteoporosis by Promoting Osteoblast Proliferation and Differentiation.","authors":"Ying Wang, Xueru Wang, Kaijin Wang, Weiwei Qin, Ning Li","doi":"10.3390/cells13232028","DOIUrl":"https://doi.org/10.3390/cells13232028","url":null,"abstract":"<p><p>Postmenopausal osteoporosis (PMOP) is a bone disease characterized by bone thinning and an increased risk of fractures due to estrogen deficiency. Current PMOP therapies often result in adverse side effects. The traditional medicinal plant <i>Curculigo capitulata</i> is commonly used to strengthen bones and support kidney function, but its role in treating PMOP is not well understood. This study aims to investigate the therapeutic effects of the total extract of <i>Curculigo capitulata</i> (Eocc) on PMOP and to explore the underlying mechanisms. The major components of the extract were identified using HPLC. Transcriptomics was employed to predict potential targets. An osteogenic differentiation model of MC3T3-E1 cells was used in vitro. The osteogenic potential of the Eocc was assessed through CCK-8 cell viability assays, alkaline phosphatase (ALP) staining, Alizarin Red staining, Western blotting, and qPCR. MCF-7 and HEK-293 cells were utilized to evaluate the estrogen-like activity of Eocc. Apoptosis rates were detected by flow cytometry. In vivo, a bilateral ovariectomized mouse model of PMOP was used to further validate the in vitro findings through histopathological analysis and WB results. The results demonstrated that the Eocc promoted the proliferation of MC3T3-E1 cells, increased ALP activity, and stimulated the formation of osteogenic mineralized nodules. It also upregulated the expression of osteogenic markers (Runx2, OCN, OPN, and BSP) at both the protein and mRNA levels. The Eocc induced the activation of ERα both in vitro and in vivo, initiating the Src/PI3K/AKT signaling pathway, leading to the phosphorylation of GSK3β and subsequent osteogenesis. The activation of this pathway also stimulated the phosphorylation of mTOR and p70S6K while downregulating cleaved caspase-3 and caspase-9. Additionally, the Eocc reduced apoptosis during osteogenic differentiation and promoted cell proliferation. These findings suggest that the Eocc facilitates osteoblast proliferation and differentiation, improving bone integrity in PMOP mice, and may represent a promising therapeutic candidate for managing PMOP.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"13 23","pages":""},"PeriodicalIF":5.1,"publicationDate":"2024-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142834303","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interplay Between Metabolic Pathways and Increased Oxidative Stress in Human Red Blood Cells.","authors":"Sara Spinelli, Angela Marino, Rossana Morabito, Alessia Remigante","doi":"10.3390/cells13232026","DOIUrl":"https://doi.org/10.3390/cells13232026","url":null,"abstract":"<p><p>Red blood cells (RBCs) are highly specialized cells with a limited metabolic repertoire. However, it has been demonstrated that metabolic processes are affected by the production of reactive oxygen species (ROS), and critical enzymes allied to metabolic pathways can be impaired by redox reactions. Thus, oxidative stress-induced alternations in the metabolic pathways can contribute to cell dysfunction of human RBCs. Herein, we aim to provide an overview on the metabolic pathways of human RBCs, focusing on their pathophysiological relevance and their regulation in oxidative stress-related conditions.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"13 23","pages":""},"PeriodicalIF":5.1,"publicationDate":"2024-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142834162","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Painful Diabetic Neuropathy: Sex-Specific Mechanisms and Differences from Animal Models to Clinical Outcomes.","authors":"Emma Merlin, Chiara Salio, Francesco Ferrini","doi":"10.3390/cells13232024","DOIUrl":"10.3390/cells13232024","url":null,"abstract":"<p><p>Diabetes is a chronic and progressive disease associated with high blood glucose levels. Several co-morbidities arise from diabetes, the most common and severe one is diabetic neuropathy whose symptoms also include pain hypersensitivity. Currently, there are no effective therapies to counteract painful diabetic neuropathy or slow down the progression of the disease, and the underlying mechanisms are yet to be fully understood. Emerging data in recent decades have provided compelling evidence that the molecular and cellular mechanisms underlying chronic pain are different across the sexes. Interestingly, relevant differences have also been observed in the course and clinical presentation of painful diabetic neuropathy in humans. Here, we reviewed the current state of the art on sex differences in diabetic neuropathy, from animal models to clinical data. Comparing the output of both preclinical and clinical studies is necessary for properly orienting future choices in pain research, refining animal models, and interpreting clinical data. The identification of sex-specific mechanisms may help to develop more targeted therapies to counteract pain symptoms in diabetes.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"13 23","pages":""},"PeriodicalIF":5.1,"publicationDate":"2024-12-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142834259","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}