Cells最新文献

{"title":"Selinexor's Immunomodulatory Impact in Advancing Multiple Myeloma Treatment.","authors":"Kereshmeh Tasbihi, Heiko Bruns","doi":"10.3390/cells14060430","DOIUrl":"10.3390/cells14060430","url":null,"abstract":"<p><p>Despite the major advancements in the repertoire for multiple myeloma (MM) treatment, this disease remains a chronically progressive plasma cell malignancy. Drug resistance and high relapse rates complicate the extended treatment strategies. However, the tumor microenvironment (TME) in MM is decisive for the success of a therapy or relapse. Aiming to improve the outcome of relapsed and refractory MM patients, Selinexor has entered the drug arsenal of myeloma therapy through the implementation of a novel therapeutic approach by selectively inhibiting the nuclear export receptor Exportin-1 (XPO1). Selinexor leads to the inactivation of cancer-related proteins and induces apoptosis by disrupting the nucleocytoplasmic flow in myeloma cells. While this drug is selectively cytotoxic to neoplastic cells, Selinexor's immunomodulatory impact on the TME is currently being investigated. The aim of this review was to elucidate Selinexor's capacity to influence the cell interaction network of the TME from an immunological perspective. Deciphering the complex interplay of highly plastic immune cells provides a contribution to the molecular-biological exploration of disease initiation and progression in MM. Unraveling the novel therapeutic targets of the immunological TME and evaluating the advanced immunotherapeutic regimens implementing Selinexor will shape the future directions of immune-oncotherapy in MM.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"14 6","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11940887/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143708840","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Stabilization of Transcription Factor, HIF-1α by Prolylhydroxylase 1 Knockout Reduces Cardiac Injury After Myocardial Infarction in Mice.","authors":"Mahesh Thirunavukkarasu, Seetur R Pradeep, Babatunde Oriowo, Sue Ting Lim, Monica Maloney, Shayan Ahmed, Nicole Taylor, David M Russell, Pavayee Socrates, Ethan Batko, Matan Berkovsky, John Alexander Palesty, Nilanjana Maulik","doi":"10.3390/cells14060423","DOIUrl":"10.3390/cells14060423","url":null,"abstract":"<p><p>Inhibition of HIF-prolyl hydroxylases (PHD1, PHD2, and PHD3) causes the stabilization of hypoxia-inducible factor-1α and -2α (HIF-1α and HIF-2α) to regulate various cell signaling pathways. Hypoxia-inducible factor (HIF) is crucial in regulating signal responses mediated by hypoxia. HIF regulates the transcription of many genes involved in the response to hypoxia and ischemic insult. Our current work investigates the protective effects of PHD1 knockout in mice against myocardial infarction. <b>Study Design:</b> Myocardial infarction (MI) was induced by left anterior descending coronary artery (LAD) ligation (8-12-week-old mice) in both wild-type (WT) and PHD1 knockout (PHD1^-/-) mice. WT sham (S) and PHD1^-/-S group mice underwent surgery without LAD ligation. Thirty days post-surgery, cardiac functions were measured by echocardiogram. Mice in all the groups were euthanized at various time points for tissue collection post-MI 8 h (gel shift and microarray analysis), 4 days (Western blot analysis), 7 days (blood vessel density), or 30 days (histological analysis). For microarray analysis, WTMI and PHD1^-/-MI group mices' heart tissue was used for RNA isolation, then hybridization to a GeneChip™ Mouse Gene 1.0 ST Array as per the manufacturer's instructions. Bioinformatic analysis was performed using the transcriptome analysis console (TAC) to generate a list of differentially regulated genes, followed by ingenuity pathway analysis. <b>Results:</b> The study findings revealed a significant increase in vessel density (capillary and arteriolar density) in the PHD1^-/-MI mice compared to those with WTMI. The echocardiographic examination demonstrated that the PHD1^-/-MI mice group had an increased ejection fraction and fractional shortening than the WT mice 30 days post-MI. HIF-1α DNA binding activity was higher in PHD1^-/-MI mice than in WTMI. The Western blot analysis showed a significant increase in the expression of HSPA12B in the PHD1^-/-MI compared to WTMI mice. Bioinformatic analysis using TAC software, Version 4.0.2.15 (1.5 fold, <i>p</i> < 0.05) showed 174 differentially regulated genes. <b>Conclusions:</b> In conclusion, our study showed PHD1 knockout activates several important molecules and signaling pathways, resulting in increased angiogenesis and cardioprotection against myocardial infarction.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"14 6","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11941588/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143708847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Localization and Single Molecule Dynamics of <i>Bacillus subtilis</i> Penicillin-Binding Proteins Depend on Substrate Availability and Are Affected by Stress Conditions.","authors":"Lisa Stuckenschneider, Peter L Graumann","doi":"10.3390/cells14060429","DOIUrl":"10.3390/cells14060429","url":null,"abstract":"<p><p>We have used single molecule tracking to investigate dynamics of four penicillin-binding proteins (PBPs) in <i>Bacillus subtilis</i> to shed light on their possible modes of action. We show that Pbp2a, Pbp3, Pbp4, and Pbp4a, when expressed at very low levels, show at least two distinct states of mobility: a state of slow motion, likely representing molecules involved in cell wall synthesis, and a mode of fast motion, likely representing freely diffusing molecules. Except for Pbp4, all other PBPs showed about 50% molecules in the slow mobility state, suggesting that roughly half of all molecules are engaged in a substrate-bound mode. We observed similar coefficients for the slow mobility state for Pbp4 and Pbp4a on the one hand, and for Pbp2a and Pbp3 on the other hand, indicating possible joint activities, respectively. Upon induction of osmotic stress, Pbp2a and Pbp4a changed from a pattern of localization mostly at the lateral cell membrane to also include localization at the septum, revealing that sites of preferred positioning for these two PBPs can be modified during stress conditions. While Pbp3 became more dynamic after induction of osmotic stress, Pbp4 became more static, showing that PBPs reacted markedly differently to envelope stress conditions. The data suggest that PBPs could take over functions in cell wall synthesis during different stress conditions, increasing the resilience of cell wall homeostasis in different environmental conditions. All PBPs lost their respective localization pattern after the addition of vancomycin or penicillin G, indicating that patterns largely depend on substrate availability. Our findings show that PBPs rapidly alter between non-targeted motion through the cell membrane and capture at sites of active cell wall synthesis, most likely guided by complex formation with other cell wall synthesis enzymes.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"14 6","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11940910/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143708809","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular Targets of 20-Hydroxyecdysone in Mammals, Mechanism of Action: Is It a Calorie Restriction Mimetic and Anti-Aging Compound?","authors":"Ernő Zádor","doi":"10.3390/cells14060431","DOIUrl":"10.3390/cells14060431","url":null,"abstract":"<p><p>The 20-hydroxyecdysone (20E) has been used in traditional medicine for a long time and acquired attention in the last decade as a food supplement and stimulant in physical activities. This polyhydroxylated cholesterol is found in the highest concentration in plants, and it is one of the secondary plant products that has a real hormonal influence in arthropods. Various beneficial effects have been reported in vivo and in vitro for 20E and its related compounds in mammals. Trials for the safety of clinical application showed a remarkably high tolerance in humans. This review aims to assess the latest development in the involvement of various pathways in tissues and organs and look if it is plausible to find a single primary target of this compound. The similarities with agents mimicking calorie restriction and anti-aging effects are also elucidated and discussed.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"14 6","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11941724/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143708763","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Salidroside Derivative SHPL-49 Exerts Anti-Neuroinflammatory Effects by Modulating Excessive Autophagy in Microglia.","authors":"Zhirui Zheng, Ruyi Wang, Yu Zhao, Pei Zhang, Dong Xie, Shoujiao Peng, Ruixiang Li, Jiange Zhang","doi":"10.3390/cells14060425","DOIUrl":"10.3390/cells14060425","url":null,"abstract":"<p><p>The neuroinflammation triggered by cellular demise plays a pivotal role in ameliorating the injury associated with ischemic stroke, which represents a significant global burden of mortality and disability. The compound SHPL-49, a derivative of rhodioloside, was discovered by our research team and has previously demonstrated neuroprotective effects in rats with ischemic stroke. This study aimed to elucidate the underlying mechanisms of SHPL-49's protective effects. Preliminary investigations revealed that SHPL-49 effectively alleviates PMCAO-induced neuroinflammation. Further studies indicated that SHPL-49 downregulates the expression of the lysosomal protein LAMP-2 and reduces lysosomal activity, impeding the fusion of lysosomes and autophagosomes, thus inhibiting excessive autophagy and increasing the expression levels of the autophagy proteins LC3-II and P62. Furthermore, SHPL-49 effectively reverses the NF-κB nuclear translocation induced by the autophagy inducer rapamycin, significantly lowering the expression levels of the inflammatory factors IL-6, IL-1β, and iNOS. In a co-culture system of BV2 and PC12 cells, SHPL-49 enhanced PC12 cell viability by inhibiting excessive autophagy in BV2 cells and reducing the ratio of apoptotic proteins Bax and BCL-2. The overall findings suggest that SHPL-49 exerts its neuroprotective effects through the inhibition of excessive autophagy and the suppression of the NF-κB signaling pathway in microglia, thereby attenuating neuroinflammation.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"14 6","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11941147/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143708837","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Microglia in ALS: Insights into Mechanisms and Therapeutic Potential.","authors":"Silvano Bond, Smita Saxena, Julieth A Sierra-Delgado","doi":"10.3390/cells14060421","DOIUrl":"10.3390/cells14060421","url":null,"abstract":"<p><p>Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the loss of motor neurons, leading to escalating muscle weakness, atrophy, and eventually paralysis. While neurons are the most visibly affected, emerging data highlight microglia-the brain's resident immune cells-as key contributors to disease onset and progression. Rather than existing in a simple beneficial or harmful duality, microglia can adopt multiple functional states shaped by internal and external factors, including those in ALS. Collectively, these disease-specific forms are called disease-associated microglia (DAM). Research using rodent models, patient-derived cells, and human postmortem tissue shows that microglia can transition into DAM phenotypes, driving inflammation and neuronal injury. However, these cells can also fulfill protective roles under certain conditions, revealing their adaptable nature. This review explores recent discoveries regarding the multifaceted behavior of microglia in ALS, highlights important findings that link these immune cells to motor neuron deterioration, and discusses emerging therapies-some already used in clinical trials-that aim to recalibrate microglial functions and potentially slow disease progression.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"14 6","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11941390/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143708604","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Endodontic Regeneration Therapy: Current Strategies and Tissue Engineering Solutions.","authors":"Moe Sandar Kyaw, Yuya Kamano, Yoshio Yahata, Toshinori Tanaka, Nobuya Sato, Fusami Toyama, Tomose Noguchi, Marina Saito, Masato Nakano, Futaba Harada, Masahiro Saito","doi":"10.3390/cells14060422","DOIUrl":"10.3390/cells14060422","url":null,"abstract":"<p><p>With increasing life expectancy and an aging population, the demand for dental treatments that preserve natural teeth has grown significantly. Among these treatments, endodontic therapies for pulpitis and apical periodontitis play a vital role, not only in keeping occlusal function, but also in preventing the exacerbation of systemic diseases. Both pulpitis and apical periodontitis are primarily caused by infections of the oral pathobiont within the root canal, leading to inflammation and destruction of the pulp, apical periodontal tissue, and bone. Standard root canal therapy aims to remove the infection source and facilitate natural tissue healing through the body's regenerative capacity. However, challenges remain, including limited tooth functionality after complete pulp removal in pulpitis and insufficient recovery of the large bone defect in apical periodontitis. To address these limitations, endodontic regenerative therapies have emerged as promising alternatives. Pulp regeneration therapy seeks to restore the functionality of dental pulp, while bone regeneration therapy aims to repair and regenerate large bone defects affected by apical periodontal tissue.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"14 6","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11941292/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143708771","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects of Space Flight on Inflammasome Activation in the Brain of Mice.","authors":"Upal Roy, Roey Hadad, Angel A Rodriguez, Alen Saju, Deepa Roy, Mario Gil, Robert W Keane, Ryan T Scott, Xiao W Mao, Juan Pablo de Rivero Vaccari","doi":"10.3390/cells14060417","DOIUrl":"10.3390/cells14060417","url":null,"abstract":"<p><p>Space flight exposes astronauts to stressors that alter the immune response, rendering them vulnerable to infections and diseases. In this study, we aimed to determine the levels of inflammasome activation in the brains of mice that were housed in the International Space Station (ISS) for 37 days. C57BL/6 mice were launched to the ISS as part of NASA's Rodent Research 1 Mission on SpaceX-4 CRS-4 Dragon cargo spacecraft from 21 September 2014 to 25 October 2014. Dissected mouse brains from that mission were analyzed by immunoblotting of inflammasome signaling proteins and Electrochemiluminescence Immunoassay (ECLIA) for inflammatory cytokine levels. Our data indicate decreased inflammasome activation in the brains of mice that were housed in the ISS for 37 days when compared to the brains of mice that were maintained on the ground, and in mice corresponding to the baseline group that were sacrificed at the time of launching of SpaceX-4. Moreover, we did not detect any significant changes in the expression levels of the pro-inflammatory cytokines TNF-α, IL-2, IFN-γ, IL-5, IL-6, IL-12p70 and IL-10 between the ground control and the flight groups. Together, these studies suggest that spaceflight results in a decrease in the levels of innate immune signaling molecules that govern inflammasome signaling in the brain of mice.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"14 6","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11941215/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143708764","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Autophagy and Respiratory Viruses: Mechanisms, Viral Exploitation, and Therapeutic Insights.","authors":"Farnaz Aligolighasemabadi, Estera Bakinowska, Kajetan Kiełbowski, Mohammadamin Sadeghdoust, Kevin M Coombs, Parvaneh Mehrbod, Saeid Ghavami","doi":"10.3390/cells14060418","DOIUrl":"10.3390/cells14060418","url":null,"abstract":"<p><p>Respiratory viruses, such as influenza virus, rhinovirus, coronavirus, and respiratory syncytial virus (RSV), continue to impose a heavy global health burden. Despite existing vaccination programs, these infections remain leading causes of morbidity and mortality, especially among vulnerable populations like children, older adults, and immunocompromised individuals. However, the current therapeutic options for respiratory viral infections are often limited to supportive care, underscoring the need for novel treatment strategies. Autophagy, particularly macroautophagy, has emerged as a fundamental cellular process in the host response to respiratory viral infections. This process not only supports cellular homeostasis by degrading damaged organelles and pathogens but also enables xenophagy, which selectively targets viral particles for degradation and enhances cellular defense. However, viruses have evolved mechanisms to manipulate the autophagy pathways, using them to evade immune detection and promote viral replication. This review examines the dual role of autophagy in viral manipulation and host defense, focusing on the complex interplay between respiratory viruses and autophagy-related pathways. By elucidating these mechanisms, we aim to highlight the therapeutic potential of targeting autophagy to enhance antiviral responses, offering promising directions for the development of effective treatments against respiratory viral infections.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"14 6","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11941543/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143708646","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differential Regulation of PKM2, AMPK, and mTOR in Response to Insulin and Dietary Management.","authors":"Emily Broberg, Jillise English, Derek M Clarke, Marley J Shin, Benjamin T Bikman, Paul R Reynolds, Juan A Arroyo","doi":"10.3390/cells14060416","DOIUrl":"10.3390/cells14060416","url":null,"abstract":"<p><p>Gestational diabetes mellitus (GDM) affects placental metabolism, influencing both maternal and fetal outcomes. This study investigated the expression of metabolic regulators-Pyruvate Kinase M2 (PKM2), AMP-activated protein kinase (AMPK), and mTOR pathway components-in placental tissues from GDM pregnancies managed with either insulin (GDM-I) or dietary interventions (GDM-D). We hypothesize that metabolic adaptation in GDM is differentially regulated by treatment modality. This study analyzed 30 cases, including 10 control pregnancies,10 GDM-D cases, and 10 GDM-I cases. Analytical methods included immunofluorescence and immunoblotting. We observed an upregulation of PKM2 in both GDM-I and GDM-D placentas, suggesting enhanced glycolytic adaptation under GDM-induced metabolic stress. AMPK expression was significantly elevated in GDM-I and moderately increased in GDM-D placentas, potentially compensating for insulin resistance by promoting glucose uptake and energy homeostasis. Furthermore, mTOR pathway activation differed by treatment type, suggesting a treatment-specific mTOR response. The metabolic changes observed suggest that treatment modality in GDM may have direct implications for maternal and fetal health. Our findings indicate that while insulin and dietary management support metabolic adaptation in GDM, they do so through distinct mechanisms. These findings support a personalized approach in GDM treatment, where patient-specific metabolic responses should guide therapeutic decisions.</p>","PeriodicalId":9743,"journal":{"name":"Cells","volume":"14 6","pages":""},"PeriodicalIF":5.1,"publicationDate":"2025-03-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11940920/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143708761","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}