Journal of Cellular Physiology最新文献

Front Cover Caption: The cover image is based on the article Quantitative assessment of morphological changes in lipid droplets and lipid-mito interactions with aging in brown adipose by Amber Crabtree et al., https://doi.org/10.1002/jcp.31340.

The nucleolar localization of proteins is regulated by specific signals directing their trafficking to nucleus and nucleolus. Here, we elucidate the mechanism underlying the nuclear and nucleolar localization of the nucleomethylin (NML) protein, focusing on its nuclear localization signals (NLSs) and nucleolar localization signal (NoLS). Using a combination of bioinformatic analysis and experimental validation, we identified two monopartite and one bipartite NLS motifs within NML. The combined presence of both monopartite NLSs significantly enhances nuclear localization of the protein, while specific basic amino acid clusters within the bipartite NLS are crucial for their functionality. We also reveal the functional role of the NLS-coupled NoLS motif in driving nucleolar localization of NML, which contains an arginine-rich motif essential for its function. The basic residues of the arginine-rich motif of NoLS of NML interacts with nucleophosmin 1 (NPM1), allowing the possible liquid-liquid phase separation and retention of NML in the nucleolus. Remarkably, the strong NoLS of NML can direct the nucleolar localization of a cytosolic protein, aldolase, emphasizing its potency. Overall, our findings provide insights into the combinatorial functioning of NLSs and NoLS in regulating the subcellular localization of NML, highlighting the intricate regulatory mechanisms governing its localization within the nucleus and nucleolus.

Neoplastic transformation reprograms tumor and surrounding host cell metabolism, increasing nutrient consumption and depletion in the tumor microenvironment. Tumors uptake nutrients from neighboring normal tissues or the bloodstream to meet energy and anabolic demands. Tumor-induced chronic inflammation, a high-energy process, also consumes nutrients to sustain its dysfunctional activities. These tumor-related metabolic and physiological changes, including chronic inflammation, negatively impact systemic metabolism and physiology. Furthermore, the adverse effects of antitumor therapy and tumor obstruction impair the endocrine, neural, and gastrointestinal systems, thereby confounding the systemic status of patients. These alterations result in decreased appetite, impaired nutrient absorption, inflammation, and shift from anabolic to catabolic metabolism. Consequently, cancer patients often suffer from malnutrition, which worsens prognosis and increases susceptibility to secondary adverse events. This review explores how neoplastic transformation affects tumor and microenvironment metabolism and inflammation, leading to poor prognosis, and discusses potential strategies and clinical interventions to improve patient outcomes.

Retraction: G. Di Bernardo, N. Alessio, C. Dell'Aversana, F. Casale, D. Teti, M. Cipollaro, L. Altucci, and U. Galderisi, "Impact of Histone Deacetylase Inhibitors SAHA and MS-275 on DNA Repair Pathways in Human Mesenchymal Stem Cells," Journal of Cellular Physiology 225, no. 2 (2010): 537-544, https://doi.org/10.1002/jcp.22236. The above article, published online on 17 March 2024 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Robert Heath; and Wiley Periodicals LLC. The retraction has been agreed upon following an investigation into concerns raised by a third party, which revealed unambiguous image manipulation in Figure 3, SAHA - H₂O₂ Treatment and SAHA - Untreated panels. The authors admitted to these image alterations, cooperated with the investigation, and were able to provide partial raw data of the article including some of the original, unmodified images. Nonetheless, the modification of the images to change the appearance is clearly against the ethical policy of the journal and Wiley's Best Practice Guidelines on Research Integrity and Publishing Ethics. In addition, based on the received partial raw data, regarding the positive cell counts for the 8oxodG assay, the journal team could not exclude that the visual modification of these images affects the number of counted 8oxodG-positive cells, and consequently the related conclusions of the article. Therefore, the editors have lost confidence in the data presented and have decided to retract the article. The authors were informed of the decision to retract but did not agree to the retraction.

Iron (Fe) storage in cereal seeds is the principal source of dietary Fe for humans. In maize (Zea mays), the accumulation of Fe in seeds is known to be negatively correlated with crop yield. Hence, it is essential to understand the underlying mechanism, which is crucial for developing and breeding maize cultivars with high yields and high Fe concentrations in the kernels. Here, through the successful application of in vitro kernel culture, we demonstrated that excess Fe supply in the medium caused the kernel to become collapsed and lighter in color, consistent with those found in yellow strip like 2 (ysl2, a small kernel mutant), implicated a crucial role of Fe concentration in kernel development. Indeed, over-accumulation of Fe in endosperm inhibited the abundance and activity of ADP-glucose pyrophosphorylase (AGPase) and the kernel development defect was alleviated by overexpression of Briittle 2 (Bt2, encoding a small subunit of AGPase) in ysl2 mutant. Imaging and quantitative analyses of reactive oxygen species (ROS) and cell death showed that Fe stress-induced ROS burst and severe DNA damage in endosperm cells. In addition, we have successfully identified candidate genes that are associated with iron homeostasis within the kernel, as well as upstream transcription factors that regulate ZmYSL2 by yeast one-hybrid screening. Collectively, our study will provide insights into the molecular mechanism of Fe accumulation-regulated seed development and promote the future efficient application of Fe element in corn improvement.

Colon cancer is on the rise in younger adults. Despite multimodal treatment strategies, clinical outcomes in advanced stage colon cancer patients remain poor. Neoadjuvant/adjuvant chemotherapy efficacy is limited due to chemoresistance, toxicity, and negative side effects. Overwhelming evidence supporting the small-molecule metabolites derived from breakdown of food or microbial sources confer an extensive array of host benefits, including chemo-preventive role in colon cancer. Our previous study indicated that the introduction of glyoxylate (Glx), an intermediate product of microbial or plant metabolism, exerts a cytotoxic effect in colon cancer cells. This study was designed to evaluate the effects of Glx on colon cancer with molecular insights. For this, we established an AOM/DSS-induced colitis associated colon cancer model in mice. Supplementation of Glx in vivo reduced colitis associated tumor growth and altered the metabolic characteristics of tumor tissue in mice without initiating any severe liver or renal toxicity. More specifically, intake of glyoxylate accumulated glycine in the colon tissue by elevation of alanine-glyoxylate transferase (AGXT) activity. Glycine accumulation increased intracellular Ca²⁺ concentration via glycine receptor activation and dysregulation of Ca²⁺ homeostasis lead to induction of apoptosis that resulted in arresting tumor growth. Interestingly, elevation of AGXT activity or Glx related specific metabolic pathway provides better survival in colon cancer patients. Collectively, our exclusive findings support the exploration of Glx either as a preventive molecule or its inclusion in the treatment regimens for colon cancer.

Abnormal mechanical loading is one of the major risk factors for articular cartilage degeneration. Engineered mesenchymal stromal cell (MSC)-derived cartilage holds great promise for cell-based cartilage repair. However, physiological loading protocols were shown to reduce matrix synthesis of MSC-derived neocartilage in vitro and the regulators of this undesired mechanoresponse remain poorly understood. Parathyroid hormone-related protein (PTHrP) is involved in cartilage development and can affect extracellular matrix (ECM) production during MSC chondrogenesis opposingly, depending on a continuous or transient exposure. PTHrP is induced by various mechanical cues in multiple tissues and species; but whether PTHrP is regulated in response to loading of human engineered neocartilage and may affect matrix synthesis in a positive or negative manner is unknown. The aim of this study was to investigate whether dynamic loading adjusts PTHrP-signaling in human MSC-derived neocartilage and whether it regulates matrix synthesis and other factors involved in the MSC mechanoresponse. Interestingly, MSC-derived chondrocytes significantly upregulated PTHrP mRNA (PTHLH) expression along with its second messenger cAMP in response to loading in our custom-built bioreactor. Exogenous PTHrP(1-34) induced the expression of known mechanoresponse genes (FOS, FOSB, BMP6) and significantly decreased glycosaminoglycan (GAG) and collagen synthesis similar to loading. The adenylate-cyclase inhibitor MDL-12,330A rescued the load-mediated decrease in GAG synthesis, indicating a direct involvement of cAMP-signaling in the reduction of ECM production. According to COL2A1-corrected hypertrophy-associated marker expression, load and PTHrP treatment shared the ability to reduce expression of MEF2C and PTH1R. In conclusion, the data demonstrate a significant mechanoinduction of PTHLH and a negative contribution of the PTHrP-cAMP signaling axis to GAG synthesis in MSC-derived chondrocytes after loading. To improve ECM synthesis and the mechanocompetence of load-exposed neocartilage, inhibition of PTHrP activity should be considered for MSC-based cartilage regeneration strategies.

The proopiomelanocortin (Pomc)-derived peptides, including adrenocorticotropic hormone and α-melanocyte stimulating hormone (α-Msh), play both a central and a peripheral role in modulating the stress response. The central role is predominantly associated with nutrient homeostasis, while peripherally they play an important role in the synthesis of glucocorticoids (GCs) in response to stress. Pomc mutations are a major risk factor in the development of early-onset childhood obesity in humans. This is attributed primarily to their central effects on melanocortin receptor dysfunction leading to hyperphagia and reduced energy expenditure, while the peripheral mechanism contributing to obesity has largely been unexplored. Here, we tested the hypothesis that Pomc mutation-mediated adrenal insufficiency and the associated changes in GC signaling contribute to postnatal adiposity using zebrafish as a model. We generated a ubiquitous Pomc knockout zebrafish that mimicked the mammalian mutant phenotype of adrenal insufficiency and enhanced adiposity. The loss of Pomc inhibited stress-induced cortisol production and reprogrammed GC signaling by reducing glucocorticoid receptor responsiveness, whereas the mineralocorticoid receptor (Mr) signaling was enhanced. Larval feeding led to enhanced growth and adipogenesis in the Pomc mutants, and this was inhibited by eplerenone, an Mr antagonist. Altogether, our results underscore a key role for Mr signaling in early developmental adipogenesis and a possible target for therapeutic intervention for early-onset childhood obesity due to Pomc dysfunction.