The FASEB Journal最新文献

Individuals with metabolic syndrome have a high risk of developing cardiovascular disorders that is closely tied to visceral adipose tissue dysfunction, as well as an altered interaction between adipose tissue and the cardiovascular system. In metabolic syndrome, adipose tissue dysfunction is associated with increased hypertrophy, reduced vascularization, and hypoxia of adipocytes, leading to a pro-oxidative and pro-inflammatory environment. Among the pathways regulating adipose tissue homeostasis is the wingless-type mammary tumor virus integration site family (Wnt) signaling pathway, with both its canonical and non-canonical arms. Various modulators of the Wnt signaling have been identified to contribute to the development of metabolic diseases and their cardiovascular complications, with a particularly significant role played by Glycogen Synthase Kinase-3β (GSK-3β). GSK-3β levels and activities have various and often contrasting roles in obesity and related metabolic disorders, as well as their cardiovascular sequelae. Here, we explore the possibility that altered Wnt signaling and GSK-3β activities could serve as a connection between adipose tissue dysfunction and the development of cardiovascular disease in individuals with metabolic syndrome. We attempt to define a context-specific approach for intervention, which could possibly serve as a novel disease modifying therapy for the mitigation of such complications.

Osteosarcoma is the most common primary bone cancer, occurring frequently in children and young adults. Patients are treated with surgery and multi-agent chemotherapy, and despite the introduction of mifamurtide in 2011, there has been little improvement in survival for decades. 3-dimensional models offer the potential to understand the complexity of the osteosarcoma tumor microenvironment and aid in developing new treatment approaches. An osteosarcoma 3D bone core model was developed using human trabecular bone and the chorioallantoic membrane (CAM), to form a functioning vasculature. A tri-culture of cells, stromal cells, macrophages, and the Saos-2 osteosarcoma cell line, were implanted into this model to simulate components of the tumor microenvironment, and mifamurtide was tested in this context. Immunohistochemistry and micro-CT were performed to assess phenotypic and structural effects of implantation. Successful integration and angiogenesis of the bone cores were observed after incubation on the CAM. The 3D bone model also showed similar characteristics to osteosarcoma patient samples including CD68 and CD105 expression. Incubating bone cores with mifamurtide induced a reduction of cellular markers and an increase in bone volume. This 3D bone core model has the potential to investigate osteosarcoma tumor microenvironment and provides a representative model for evaluation of novel therapies.

Zhang S, You Y, Li Y, et al. Foxk1 stimulates adipogenic differentiation via a peroxisome proliferator-activated receptor gamma 2-dependent mechanism. The FASEB Journal. 2023; 37:e23266. doi:10.1096/fj.202301153R

In Figure 6, the bar chart in panel 6I was incorrect. We apologize for this error.

The corrected Figure 6 is as follows:

Decidualization of endometrial stromal cells is a prerequisite for successful embryo implantation and early pregnancy. Decidualization dysregulation results in implantation failure. In our previous study, we reported that PAI-1 is abnormally downregulated in the endometrial tissue samples of patients with recurrent implantation failure. This study will explore the dynamic expression changes of PAI-1 in the endometrium during the menstrual cycle and its molecular mechanism affecting endometrial decidualization. Our findings indicated that the abundance of PAI-1 increased in the mid-secretory phase and attached a peak in the decidual phase in the endometrium of women with regular menstrual cycles. In human endometrial stromal cells (HESCs), PAI-1 knockdown attenuated endometrial decidualization by upregulating VEGFR2/PI3K/AKT signaling pathway and impaired the F-actin reorganization. Furthermore, axitinib (a VEGFR2 inhibitor) was used to inhibit the VEGFR2 protein activity and the results suggested that it eliminated the effects of PAI-1 on PI3K/AKT signaling pathways and F-actin remodeling. In addition, the interaction between PAI-1 and KNG1 was confirmed by coimmunoprecipitation assay in HESCs. Altogether, PAI-1-KNG1 may enhance the decidualization of endometrium by inhibiting VEGFR2/PI3K/AKT signaling pathway-mediated F-actin reorganization in healthy females.

Multi-target strategy can serve as a valid treatment for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but existing drugs most focus on a single target. Thus, multi-target drugs that bind multiple sites simultaneously need to be urgently studied. Apigenin has antiviral and anti-inflammatory properties. Here, we comprehensively explored the potential effect and mechanism of apigenin in SARS-CoV-2 treatment by a network algorithm, deep learning, molecular docking, molecular dynamics (MD) simulation, and normal mode analysis (NMA). KATZ-based VDA prediction method (VDA-KATZ) indicated that apigenin may provide a latent drug therapy for SARS-CoV-2. Prediction of DTA using convolution model with self-attention (CSatDTA) showed potential binding affinity of apigenin with multiple targets of virus entry, assembly, and cytokine storms including cathepsin L (CTSL), membrane (M), envelope (E), Toll-like receptor 4 (TLR4), nuclear factor-kappa B (NF-κB), NOD-like receptor pyrin domain-containing protein 3 (NLRP3), apoptosis-associated speck-like protein (ASC), and cysteinyl aspartate-specific proteinase-1 (Caspase-1). Molecular docking indicated that apigenin could effectively bind these targets, and its stability was confirmed using MD simulation and NMA. Overall, apigenin is a multi-target inhibitor for the entry, assembly, and cytokine storms of SARS-CoV-2.

Flavan-3-ols (FL) are poorly bioavailable astringent polyphenols that induce hyperactivation of the sympathetic nervous system. The aim of this study was to investigate the effects of repeated oral administration of FL on mice hindlimb skeletal muscle using immunohistochemical techniques. C57BL/6J male mice were orally administered 50 mg/kg of FL for a period of 2 weeks, and bromideoxyuridine (BrdU) was administered intraperitoneally 3 days prior to the dissection. The soleus and extensor digitorum longus (EDL) were excised and prepared for frozen sections. Myosin heavy chain (MHC) antibodies were used to classify muscle types, in addition, muscle cross-sectional areas (CSA) were measured. We observed a shift in the peak of CSA in the soleus muscle and to a larger extent in the EDL. In addition, a distinct shift toward fast muscle was detected, documented by a reduction in type I and an increase in type IIb in the soleus muscle, whereas in the EDL, we observed a decline in type IIa and an expansion in type IIb. Incorporation of BrdU into cells was significantly increased in all skeletal muscles, with a significant increase in cells co-expressing pair box 7 (Pax7), a marker of differentiation, as observed in the EDL. Given the evidence that β2-adrenergic receptors in skeletal muscles regulate differentiation and size, we measured plasma catecholamine (CA) concentrations following a single differentiation of FL. A single oral dose of FL was observed to significantly increase plasma CA. These findings indicate that catecholamines secreted into the bloodstream from the adrenal gland following oral administration of FL may influence skeletal muscle size and type via β2-receptors.

Intervertebral disc degeneration (IVDD), is one of the leading causes of low back pain. Inflammation is considered to be the main pathophysiological process of IVDD. The nucleotide-binding domain and leucine-rich pyrin domain containing 3 (NLRP3) inflammasome-mediated inflammatory responses are critically involved in the progression of IVDD. Melatonin is known for its anti-inflammatory and antioxidant effects. However, little is known about the potential effects of melatonin in the pathological process of IVDD. We found that the expression of EGR1, DDX3X, and NLRP3 inflammasome increased and extracellular matrix (ECM) degraded in IVDD. With the application of EGR1 siRNA, the expression of DDX3X and the activation of NLRP3 inflammasome were inhibited in stress-induced NP cells. DDX3X/NLRP3 was regulated on dependence of EGR1. Besides, the utility of melatonin mitigated the EGR1-induced overproduction of DDX3X and activation of NLRP3 inflammasome, thus protecting cells from pyroptosis and ECM degradation. In vivo, in a rat IVDD model, melatonin was found to be able to delay the development of IVDD by imageological and histological evaluation. In conclusion, our study demonstrated that melatonin prevented IVDD progression by regulating EGR1/DDX3X/NLRP3 axis. Our study provides insight into melatonin as a new target for therapeutic approaches for IVDD.

Zhou G, Zhu F, Zhang H, et al. PTK2B regulates immune responses of neutrophils and protects mucosal inflammation in ulcerative colitis. The FASEB Journal. 2023; 37:e22967. doi:10.1096/fj.202201995RR

The authors report a mistake in Figure 9E that occurred during image naming and selection. The images in panels Ctrl TAE and DSS PBS are similar to the images in Figure 6 representing PTK2B KO Ctrl and DSS, respectively. This error does not change the results or conclusions of the study. The authors apologize for the error.

The corrected Figure 9 is as follows:

Mammalian spermatogenesis is a tightly controlled cellular process including spermatogonial development and differentiation, meiosis of spermatocyte, and the morphological specification of haploid spermatozoa, during which the post-transcriptional gene regulations are vital but poorly understood. Nonsense-mediated mRNA decay (NMD), a highly conserved post-transcriptional regulatory mechanism of gene expression in eukaryotes, recently emerges as a licensing mechanism in cell fate transition, including stem cell differentiation and organogenesis. The function of NMD in spermatogonial development remains elusive. Here we found knockout of SMG5, an important component of the NMD machinery, in embryonic germ cells led to the failure of spermatogenesis and male infertility. SMG5 null resulted in defective differentiation and maintenance of spermatogonia, which affected initiation of meiosis, ultimately caused a “Sertoli cell-only” phenotype. Transcriptome analysis revealed that SMG5 loss led to serious defects in NMD with targets features including PTC, long 3′ UTR, and 5′ uORFs. Furthermore, SMG5 loss downregulates gene transcripts involved in spermatogonia expansion and differentiation. During the spermatogonial differentiation, the deletion of SMG5 led to hyperactivation of the p38 MAPK signaling pathway, which triggered widespread cell death. These results suggest that SMG5 mediated NMD plays an important role in spermatogenesis by regulating the p38 MAPK signaling pathway.

Numerous studies have reported altered cytokine levels in type 1 diabetes (T1D) patients, yet findings remain inconsistent. In this pilot study, we tested the hypothesis that circulating immune markers exhibit sex-based differences in T1D, both prior to and after disease onset. We analyzed 47–48 cytokine, chemokine, and growth factor levels in two cohorts. To assess post-disease differences, we analyzed serum samples from 25 controls and 25 T1D patients. To examine pre-disease progression, we utilized samples from 21 control children and 16 T1D progressors, collected at age 5 years before disease onset. Across all T1D patients and controls, only macrophage colony-stimulating factor and interleukin (IL)-6 showed significant differences. However, we identified notable alterations when comparing sex-age-matched controls and T1D samples. Female T1D patients exhibited lower levels of inflammatory cytokines (tumor necrosis factor-α, IL-6, IL-1a), Th2 cytokines (IL-4, IL-13), and chemokines (macrophage inflammatory protein (MIP)-1α, regulated upon activation, normal T cell expressed and secreted, MIP-3) compared to female controls, differences that were not observed in males. Notably, IL-22 was lower in female T1D patients compared to female controls, whereas it was higher in male T1D patients compared to male controls. Male T1D patients showed elevated levels of growth factors (epidermal growth factor, platelet-derived growth factor-AB/BB) compared to male controls. In T1D progressors, growth-regulated alpha was lower compared to controls in both sexes. Multiple regression analysis further revealed associations between cytokine levels and factors such as age, BMI, and breastfeeding duration. Overall, our findings serve as a proof of concept, highlighting the importance of sex-specific differences in T1D pathogenesis. However, follow-up studies with larger sample sizes are needed to validate and generalize these results.