The FASEB Journal最新文献

With the global rise in advanced maternal age (AMA) pregnancies, the risk of gestational diabetes mellitus (GDM) increases. However, few GDM prediction models are tailored for AMA women. This study aims to develop a practical risk prediction model for GDM in AMA women. Data were obtained from a prospective observational cohort of AMA pregnant women from the Obstetrics and Gynecology Hospital in Shanghai, China. Singleton pregnancies with complete OGTT results at 24–28 weeks were selected and divided into training (70%) and validation (30%) sets. First-trimester predictors, including demographic, metabolic parameters, and clinical history, were evaluated for statistical significance. A multivariate logistic regression model was developed, with performance evaluated using receiver operating characteristic (ROC) curves and calibration plots. Predictors were primarily incorporated as categorical variables in a nomogram to enhance model convenience. A model using continuous predictors was also tested for comparison. A total of 1904 AMA women were included, with GDM incidence rates of 18.3% (243/1333) in the training set and 19.3% (110/571) in the validation set. Significant predictors for GDM diagnosis at 24–28 weeks included maternal age, GDM history, first-trimester fasting plasma glucose, mean arterial pressure, and triglyceride levels. The categorical model achieved an area under the ROC curve of 0.717 (95% CI: 0.682–0.753) in the training set and 0.702 (95% CI: 0.645–0.758) in the validation set. The Hosmer-Lemeshow test indicated good calibration (p = .97 in the training set; p = .66 in the validation set). The model with category and continuous predictors exhibited similar performance. This study developed and validated a practical early risk prediction nomogram for GDM in AMA women, using commonly available clinical data. The model shows good predictive performance and is resource-efficient, making it suitable for real-world clinical implementation.

Sepsis-induced acute lung injury (ALI) is a common acute and severe reason of death in the intensive care unit. Although the pathogenesis is complicated and multifactorial, elevated inflammation and oxidative stress are considered as fundamental mechanisms for the progression of ALI. Anemonin is a natural compound with diverse biological properties including anti-inflammatory and anti-oxidative effects. To identify whether anemonin has protective effects on sepsis-induced ALI, a mouse sepsis-induced ALI model and cellular models using the mouse alveolar macrophage MH-S cells and mouse lung epithelial MLE-12 cells were established. Our results showed that anemonin reduced lipopolysaccharide (LPS)-induced mortality, and improved sepsis-induced ALI in the mouse model, as shown by improved histopathological changes, decreased lung wet/dry weight ratio, and myeloperoxidase activity. Anemonin alleviated LPS-induced secretion of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and interleukin-6 (IL-6) in bronchoalveolar lavage fluid samples, as well as reversed the LPS-caused increase in malondialdehyde (MDA) content and decrease in activities of the antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT) in lung tissues. In the cellular model, anemonin inhibited the LPS-induced inflammatory responses and oxidative stress in MH-S and MLE-12 cells. In addition, anemonin inhibited LPS-induced nuclear factor-kappa B (NF-κB) pathway, while enhancing the activation of nuclear factor erythroid 2-related factor-2 (Nrf2) in lung tissues, MH-S, and MLE-12 cells. NF-κB inhibition enhanced the anti-inflammatory and anti-oxidative effects of anemonin, while Nrf2 knockdown attenuated these effects of anemonin, implying the critical roles of NF-κB and Nrf2. These results indicated that anemonin suppressed sepsis-induced acute lung injury by inhibition of NF-κB and activation of Nrf2/heme oxygenase-1 pathway, suggesting that anemonin might be developed as a new therapeutic agent for the treatment of sepsis-induced ALI.

Serum uric acid is an end-product of purine metabolism. Uric acid concentrations in excess of the physiological range may lead to diseases such as gout, cardiovascular disease, and kidney injury. The kidney includes a variety of cell types with specialized functions such as fluid and electrolyte homeostasis, detoxification, and endocrine functions. Two-thirds of uric acid is excreted through kidney, however, the exploration of markers and new therapeutic targets in renal tissue of hyperuricemia is still lacking. Single-cell and spatial omics techniques represent major milestones in life sciences. The combined measurement of the physical structure and molecular characteristics of tissues facilitates the exploration of the pathophysiological processes underlying disease development and the discovery of possible therapeutic targets. Here, the spatiotemporal atlas of hyperuricemic nephropathy was investigated using single-cell RNA sequencing, spatial transcriptomics, spatial proteomics, and spatial metabolomics in a urate oxidase knockout mouse model. Several emerging targets and pathways especially ribosome and metabolism related to uric acid excretion were discovered and will be investigated further in studies on lowering uric acid.

Podocytes are essential to maintain the normal filtration function of glomerular basement membrane, which could be injured by ischemia–reperfusion. As complicated function of autophagy in terminal differentiated podocytes, autophagy dysfunction might contribute to I/R induced renal dysfunction following glomerular filtration membrane (GFM) injuries. Meanwhile, apelin-13, an endogenous polypeptide, has been proved to be effective in regulating autophagy and apoptosis in podocytes. Therefore, it is hypothesized that apelin-13 may protect podocytes from IRI by inhibiting podocyte apoptosis through regulation of podocyte autophagy. Our study demonstrates for that podocytes are also involved in renal ischemia–reperfusion (I/R) injury and shows in detail the morphological and functional changes in podocytes during renal I/R. Because podocytes are terminally differentiated cells whose homeostasis require high levels of autophagy, we investigate the cellular mechanisms underlying the effects of apelin-13 on I/R-mediated podocyte injury in terms of autophagy. In addition, our study demonstrates that apelin-13 ameliorates renal I/R injury in podocyte injury, by increasing podocyte autophagy through inhibition of m-TOR phosphorylation, which in turn inhibits apoptosis.

Changes in protein levels of the mammalian cleavage factor, CFIm25, play a role in regulating pathological processes including neural dysfunction, fibrosis, and tumorigenesis. However, despite these effects, little is known about how CFIm25 (NUDT21) expression is regulated at the RNA level. A potential regulator of NUDT21 mRNA are small non-coding microRNAs (miRNAs). In general, miRNAs bind to the 3′untranslated regions (3′UTRs) and can target the bound mRNA for degradation or inhibit translation thus affecting the levels of protein in cells. Interestingly, a mechanism known as alternative polyadenylation (APA) enables mRNAs to escape miRNA regulation by generating mRNAs with 3′UTRs of different sizes. As many miRNA target sites are located within the 3′UTR, shortening the 3′UTR allows mRNAs to evade miRNAs targeting this region. The differences in the lengths and the sequence composition of the 3′UTRs may also impact the mRNA's translatability and subcellular localization. APA has been reported to regulate over 70% of protein coding genes, thus increasing the transcript repertoire. Several proteins, including mammalian cleavage factor, CFIm25 (NUDT21), have been shown to regulate APA. In this study we wanted to determine whether CFIm25 (NUDT21), itself a regulator of APA, undergoes APA to evade miRNA regulation. We used the blood cancer mantle cell lymphoma (MCL) cells as a model and showed that in these cells, NUDT21 is relatively stable with a long half-life. In addition, the NUDT21 pre-mRNA undergoes alternative APA within the same terminal exon. The three different sized NUDT21 mRNAs have different 3′UTR lengths and they each use a different canonical polyadenylation signal, AAUAAA, for 3′end cleavage and polyadenylation. Use of miRNA mimics and inhibitors showed that miR-23a, miR-222, and miR-323a play a significant role in regulating NUDT21 expression. Hence, these results suggest that NUDT21 mRNA is stable and the different 3′UTRs generated through APA of NUDT21 play an important role in evading miRNA regulation and offers insights into how levels of CFIm25 (NUDT21) may be fine-tuned as needed under different physiological and pathological conditions.

Metabolic dysfunction-associated steatohepatitis (MASH) is characterized by severe liver inflammation and fibrosis due to an imbalanced immune response caused by enhanced bacterial components. The progression of MASH is closely linked to increased permeability of intestinal mucosal barrier facilitating enter of bacterial components into hepatic portal venous system. B cells are important immune cells for adaptive responses and enhance hepatic inflammation through cytokine production and T cell activation. B cells are influenced by gut microbiota, but the specific B cell populations in MASH and their pathologic mechanism remain obscure. Here, we found that the numbers of B cells highly expressing CXCR5, the receptor of CXCL13 chemokine, were increased in the livers of MASH. CXCR5 high B cells are non-proliferating naive B cells with inflammatory features mainly residing in hepatic parenchyma to affect liver pathology. Importantly, we revealed that CXCR5 high B cells were induced by bacterial components stimulating TLRs. These bacterial stimulator-induced CXCR5^hi B cells highly express TNFα, CD80, and MHC class II, leading to T cell activation. Consistently, we confirmed that intravenous injection of CXCR5 high B cells enhanced hepatic inflammation in MASH model. Ultimately, this study elucidates the role and mechanisms of CXCR5 high B cells in advancing MASH progression.

G-Protein Coupled Receptor, Class C, Group 5, Member A (GPRC5A) has been extensively studied in lung and various epithelial cancers. Nevertheless, its role in the skin remains to be elucidated. In this study, we sought to investigate the function of this receptor in skin biology. Our research demonstrated that its expression responds to mechanical substrate changes in human primary keratinocytes. Furthermore, we observed the reinduction of GPRC5A during wound healing at the leading edges in an ex vivo burn model, coinciding with the translocation of its C-terminal region into the nucleus. We identified the cleavage site of GPRC5A by N-TAILS analysis, and cathepsin G was characterized as the protease responsible for proteolysis in cultured cells. In order to gain a deeper understanding of the role of GPRC5A in keratinocytes, we performed a GPRC5A knockdown in N/TERT-1 cells using short-hairpin RNA. Our findings indicate a strong association between GPRC5A and adhesion regulation pathways. Additionally, our results demonstrate that GPRC5A^KD enhances cell adhesion while reducing cell migration and differentiation. It is noteworthy that these effects were reversed by the addition of a recombinant polypeptide that mimics the C-terminal region of GPRC5A. In conclusion, our study reveals that GPRC5A plays an unexpected role in regulating keratinocyte behavior, with implications for its C-terminal region translocation into the nucleus. These results offer promising avenues for future research in the field of wound healing.

Following injury, skeletal muscle undergoes repair via satellite cell (SC)-mediated myogenic progression. In SCs, the circadian molecular clock gene, Bmal1, is necessary for appropriate myogenic progression and repair with evidence that muscle molecular clocks can also affect force production. Utilizing a mouse model allowing for inducible depletion of Bmal1 within SCs, we determined contractile function, SC myogenic progression and muscle damage and repair following eccentric contractile-induced injury. At baseline, SC-Bmal1^iKO animals exhibited a ~20–25% reduction in normalized force production (ex vivo and in vivo) versus control SC-Bmal1^Cntrl and SC-Bmal1^iKO untreated littermates (p < .05). Following contractile injury, SC-Bmal1^iKO animals displayed reduced muscle damage and subsequent repair post-injury (Dystrophin^negative fibers 24 h: SC-Bmal1^Cntrl 199 ± 41; SC-Bmal1^iKO 36 ± 13, p < .05) (eMHC⁺ fibers 7 day: SC-Bmal1^Cntrl 217.8 ± 115.5; SC-Bmal1^iKO 27.8 ± 17.3; Centralized nuclei 7 day: SC-Bmal1^Cntrl 160.7 ± 70.5; SC-Bmal1^iKO 46.2 ± 15.7). SC-Bmal1^iKO animals also showed reduced neutrophil infiltration, consistent with less injury (Neutrophil content 24 h: SC-Bmal1^Cntrl 2.4 ± 0.4; SC-Bmal1^iKO 0.4 ± 0.2, % area fraction, p < .05). SC-Bmal1^iKO animals had greater SC activation/proliferation at an earlier timepoint (p < .05) and an unexplained increase in activation 7 days post injury. Collectively, these data suggest SC-Bmal1 plays a regulatory role in force production, influencing the magnitude of muscle damage/repair, with an altered SC myogenic progression following contractile-induced muscle injury.

The correct synthesis and degradation of proteins are vital for numerous biological processes in the human body, with protein degradation primarily facilitated by the ubiquitin-proteasome system. The SKP1-CUL1-F-box (SCF) E3 ubiquitin ligase, a member of the Cullin-RING E3 ubiquitin ligase (CRL) family, plays a crucial role in mediating protein ubiquitination and subsequent 26S proteasome degradation during normal cellular metabolism. Notably, SCF is intricately linked to the pathogenesis of various diseases, including malignant tumors. This paper provides a comprehensive overview of the functional characteristics of SCF complexes, encompassing their assembly, disassembly, and regulatory factors. Furthermore, we discuss the diverse effects of SCF on crucial cellular processes such as cell cycle progression, DNA replication, oxidative stress response, cell proliferation, apoptosis, cell differentiation, maintenance of stem cell characteristics, tissue development, circadian rhythm regulation, and immune response modulation. Additionally, we summarize the associations between SCF and the onset, progression, and prognosis of malignant tumors. By synthesizing current knowledge, this review aims to offer a novel perspective for a holistic and systematic understanding of SCF complexes and their multifaceted functions in cellular physiology and disease pathogenesis.

EXPRESSION OF CONCERN: C. Blázquez, A. Carracedo, L. Barrado, P. J. Real, J. L. Fernández-Luna, G. Velasco, M. Malumbres, and M. Guzmán, “Cannabinoid Receptors as Novel Targets for the Treatment of Melanoma,” The FASEB Journal. 20, no. 14 (2006): 2633-2635, https://doi.org/10.1096/fj.06-6638fje

This Expression of Concern is for the above article, published online on 25 October 2006 in Wiley Online Library (wileyonlinelibrary.com), and has been published by agreement between the journal Editor-in-Chief, Loren E. Wold; the Federation of American Societies for Experimental Biology; and Wiley Periodicals LLC. This Expression of Concern has been published due to concerns raised by a third party regarding duplicated image sections and undeclared splicing within the subpanels of Figure 1A. The authors acknowledged the image compilation error, but due to the time elapsed since publication, the raw data was not available. The authors stated that their findings regarding melanoma cells expressing functional CB1 and CB2 receptors are supported by other experimental approaches shown in this article, and have been confirmed and published by other independent investigators. Therefore, the authors believe that the irregularities found in Figure 1A do not affect the results and the conclusions of this publication.

Nevertheless, without an explanation of the anomaly in the figure and in the absence of the original raw data, the journal team could not verify the authenticity of this figure. Therefore, the journal has decided to issue an Expression of Concern to inform and alert the readers.