FASEB Journal最新文献

Recently, amyloid-β oligomers (AβOs) have been studied as the primary pathogenic substances in Alzheimer's disease (AD). Our previous study revealed that the Aβ expression level is closely related to ARC progression. Here, we demonstrated that the accumulation of AβOs in the lens epithelium of age-related cataract (ARC) patients increased during ARC progression and that this alteration was consistent with the changes in mitochondrial function, oxidative stress, and cellular apoptosis. In vitro, human lens epithelial cells (HLECs) treated with AβOs exhibited Ca²⁺ dyshomeostasis, impaired mitochondrial function, elevated oxidative stress levels, and increased apoptosis. Moreover, the proapoptotic effect of AβOs was alleviated after the uptake of mitochondrial Ca²⁺ was inhibited. These results establish that AβOs may promote HLEC apoptosis by inducing mitochondrial Ca²⁺ overload, thus preliminarily revealing the possible association between the accumulation of AβOs and other pathological processes in ARC.

Metabolic dysfunction-associated diseases often refer to various diseases caused by metabolic problems such as glucose and lipid metabolism disorders. With the improvement of living standards, the increasing prevalence of metabolic diseases has become a severe public health problem, including metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-related liver disease (ALD), diabetes and obesity. These diseases are both independent and interdependent, with complex and diverse molecular mechanisms. Therefore, it is urgent to explore the molecular mechanisms and find effective therapeutic targets of these diseases. MicroRNAs (miRNAs) have emerged as key regulators of metabolic homoeostasis due to their multitargets and network regulatory properties within the past few decades. In this review, we discussed the latest progress in the roles of miRNA-mediated regulatory networks in the development and progression of MASLD, ALD, diabetes and obesity.

Pre-implantation embryonic development occurs in the oviduct during the first few days of pregnancy. The presence of oviductal extracellular vesicles (oEVs, also called oviductosomes) is crucial for pre-implantation embryonic development in vivo as oEVs often contain molecular transmitters such as proteins. Therefore, evaluating oEV cargo during early pregnancy could provide insights into factors required for proper early embryonic development that are missing in the current in vitro embryo culture setting. In this study, we isolated oEVs from the oviductal fluid at estrus and different stages of early embryonic development. The 2306–3066 proteins in oEVs identified at the different time points revealed 58–60 common EV markers identified in exosome databases. Oviductal extracellular vesicle proteins from pregnant samples significantly differed from those in non-pregnant samples. In addition, superovulation changes the protein contents in oEVs compared to natural ovulation at estrus. Importantly, we have identified that embryo-protectant proteins such as high-mobility protein group B1 and serine (or cysteine) peptidase inhibitor were only enriched in the presence of embryos. We also visualized the physical interaction of EVs and the zona pellucida of 4- to 8-cell stage embryos using transmission electron microscopy as well as in vivo live imaging of epithelial cell-derived GFP-tagged CD9 mouse model. All protein data in this study are readily available to the scientific community in a searchable format at https://genes.winuthayanon.com/winuthayanon/oviduct_ev_proteins/. In conclusion, we identified oEVs proteins that could be tested to determine whether they can improve embryonic developmental outcomes in vivo and in vitro setting.

Sun SY, Zhai W, Zhang RX, Cai N. Deletion of Dux ameliorates muscular dystrophy in mdx mice by attenuating oxidative stress via Nrf2. The FASEB Journal. 2024;38:e23771. doi:10.1096/fj.202400195R

In paragraph 1 of the “Materials and Methods” section, the text “C57BL/10ScSnJ mice (WT), C57BL/10ScSn-Dmdmdx/J mice (mdx) and Dux^−/− mice were provided by The Jackson Laboratory (Bar Harbor, ME, USA).” was incorrect. This should have read: “C57BL/10ScSnJ mice (WT) and C57BL/10ScSn-Dmdmdx/J mice (mdx) were provided by The Jackson Laboratory (Bar Harbor, ME, USA), Dux^−/− mice were provided by Shanghai Model Organisms Center, Inc. (Shanghai, China).”

In paragraph 8 of the “Materials and Methods” section, the text “Dux, 5′-ATGGCCCTCCCGACACCCT-3′ (forward), 5′-ATGCCCGGGTACGGGTTCCGCTCAAAG-3′ (reverse); Nrf2, 5′-TAGAGTCAGCAACGTGGAAG-3′ (forward), 5′-TATCGAGGCTGTGTCGACTG-3′ (reverse)” was incorrect. This should have read: “Dux, 5′-AACCCACGACCAGGCTTTG-3′ (forward), 5′-CCGAGCTCTTCGGTTTTGAA-3′ (reverse); Nrf2, 5′-CTTTAGTCAGCGACAGAAGGAC-3′ (forward), 5′-AGGCATCTTGTTTGGGAATGTG-3′ (reverse)”.

In paragraph 9 of the “Materials and Methods” section, the Invitrogen antibody (item number PA5-114311) was used to detect Dux in this study. PVDF membranes were incubated with this antibody (dilution ratio 1:1000) at 4°C overnight.

For muscle histology, we claim that: Muscle tissues were isolated from mice and stained according to HE and Masson kit instructions. Consistent with a previously published report (1), the gastrocnemius muscle of mdx mice had a significant inflammatory infiltrate and collagen deposition. More importantly, all images in this article are unedited and original.

We apologize for this error.

Oxygen (O₂) metabolism plays a critical role in cornea wound healing, regeneration, and homeostasis; however, the underlying spatiotemporal mechanisms are poorly understood. Here we used an optical sensor to profile O₂ flux in intact and wounded corneas of mouse eyes. Intact corneas have unique centrifugal O₂ influx profiles, smallest flux at the cornea center, and highest at the limbus. Following cornea injury, the O₂ influx profile presents three distinct consecutive phases: a “decreasing” phase from 0 to 6 h, a “recovering” phase from 12 to 48 h, and a ‘peak’ phase from 48 to 72 h, congruent to previously described healing phases. Immediately after wounding, the O₂ influx drops at wound center and wound edge but does not change significantly at the wound side or limbus. Inhibition of reactive oxygen species (ROS) in the decreasing phase significantly reduces O₂ influx, decreases epithelial migration and consequently delays healing. The dynamics of O₂ influx show a positive correlation with cell proliferation at the wound side, with significantly increased proliferation at the peak phase of O₂ influx. This study elucidates the spatiotemporal O₂ dynamics in both intact and wounded rodent cornea and shows the crucial role of O₂ dynamics in regulating cell migration and proliferation through ROS metabolism, ultimately contributing to wound healing. These results demonstrate the usefulness of the micro-optrode in the characterization of spatiotemporal O₂ dynamics. Injury-induced changes in O₂ metabolism and ROS production modulate O₂ dynamics at wound and control cell migration and proliferation, both essential for proper wound healing.

Pancreatic cancer is a highly aggressive and lethal carcinoma. Circular RNAs (circRNAs) serve key regulatory functions in pancreatic cancer. Ferroptosis was induced by erastin treatment and analyzed by examining malondialdehyde (MDA), iron, Fe²⁺ and glutathione (GSH). C11-BODIPY 581/591 was used to stain cells for analyzing lipid peroxidation. RNA immunoprecipitation, pull-down and chromatin immunoprecipitation assays were applied to evaluate intermolecular interaction. Mice received subcutaneous injection of pancreatic cancer cells as a model of subcutaneous tumor for in vivo tests. Circ_0005397 was abundantly expressed in pancreatic cancer, and its upregulation was associated with low survival of patients with pancreatic cancer. Circ_0005397 expression was induced by EIF4A3. PCBP2 was highly expressed in pancreatic cancer, and circ_0005397 and PCBP2 were positively correlated in patients with pancreatic cancer. Circ_0005397 knockdown sensitized pancreatic carcinoma cells to ferroptosis via downregulating PCBP2. Circ_0005397 promoted PCBP2 transcription via facilitating the binding of KAT6A and H3K9ac to PCBP2 promoter. Silencing of circ_0005397 reduced tumor growth by enhancing erastin-induced ferroptosis in vivo. EIF4A3-induced circ_0005397 inhibited erastin-induced ferroptosis in pancreatic cancer by promoting PCBP2 expression through KAT6A and H3K9ac.

Polycystic kidney disease (PKD) is a common hereditary kidney disease. Although PKD occurrence is associated with certain gene mutations, its onset regulatory mechanisms are still not well understood. Here, we first report that the key enzyme geranylgeranyl diphosphate synthase (GGPPS) is specifically expressed in renal tubular epithelial cells of mouse kidneys. We aimed to explore the role of GGPPS in PKD. In this study, we established a Ggpps^fl/fl:Cdh16^cre mouse model and compared its phenotype with that of wild-type mice. A Ggpps-downregulation HK2 cell model was also used to further determine the role of GGPPS. We found that GGPPS was specifically expressed in renal tubular epithelial cells of mouse kidneys. Its expression also increased with age. Low GGPPS expression was observed in human ADPKD tissues. In the Ggpps^fl/fl:Cdh16^cre mouse model, Ggpps deletion in renal tubular epithelial cells induced the occurrence and development of renal tubule cystic dilation and caused the death of mice after birth due to abnormal renal function. Enhanced proliferation of cyst-lining epithelial cells was also observed after the knockout of Ggpps. These processes were related to the increased rate of Rheb on membrane/cytoplasm and hyperactivation of mTORC1 signaling. In conclusion, the deficiency of GGPPS in kidney tubules induced the formation of renal cysts. It may play a critical role in PKD pathophysiology. A novel therapeutic strategy could be designed according to this work.

Mesenchymal stromal stem cells (MSCs) or skeletal stem cells (SSCs) play a major role in tissue repair due to their robust ability to differentiate into osteoblasts, chondrocytes, and adipocytes. Complex cell signaling cascades tightly regulate this differentiation. In osteogenic differentiation, Runt-related transcription factor 2 (RUNX2) and ALP activity are essential. Furthermore, during the latter stages of osteogenic differentiation, mineral formation mediated by the osteoblast occurs with the secretion of a collagenous extracellular matrix and calcium deposition. Activation of nuclear factor erythroid 2-related factor 2 (NRF2), an important transcription factor against oxidative stress, inhibits osteogenic differentiation and mineralization via modulation of RUNX2 function; however, the exact role of NRF2 in osteoblastogenesis remains unclear. Here, we demonstrate that NRF2 activation in human bone marrow-derived stromal cells (HBMSCs) suppressed osteogenic differentiation. NRF2 activation increased the expression of STRO-1 and KITLG (stem cell markers), indicating NRF2 protects HBMSCs stemness against osteogenic differentiation. In contrast, NRF2 activation enhanced mineralization, which is typically linked to osteogenic differentiation. We determined that these divergent results were due in part to the modulation of cellular calcium flux genes by NRF2 activation. The current findings demonstrate a dual role for NRF2 as a HBMSC maintenance factor as well as a central factor in mineralization, with implications therein for elucidation of bone formation and cellular Ca²⁺ kinetics, dystrophic calcification and, potentially, application in the modulation of bone formation.

Traditional Chinese medical literature contains numerous records of many traditional Chinese herbal medicines that exhibit efficacy in enhancing resistance to cold, yet there is a lack of scientific explanation. Lycium barbarum is among the herbal medicines that are explicitly documented to enhance resistance to cold in the “Ben Cao Gang Mu (Compendium of Materia Medica)”. Herein, we investigated L. barbarum polysaccharide (LBP)-induced browning of inguinal white adipose tissue (iWAT), energy expenditure and thermogenic function in a long-term (4 months) treatment mouse model. LBP supplementation resulted in a significant reduction in weight and adipocyte size in iWAT, along with increased gut microbiota diversity. Specifically, the levels of Lachnospiraceae, Ruminococcaceae and Bacteroidaceae (short-chain fatty acid-producing bacteria) were elevated, leading to a higher level of short-chain fatty acids (SCFAs) in the caecal content. These effects subsequently triggered the release of glucagon-like peptide-1 (GLP-1) and activated the CREB/PGC1α signaling pathway in iWAT, thereby increasing energy expenditure and enhancing thermogenic function. The antibiotic treatment experiments confirmed that the LBP-mediated gut microbiota participated in the process of iWAT browning. In summary, our findings provide the first scientific explanation and mechanistic insights into the cold resistance of L. barbarum and identify potentially safe natural product supplements for individuals in alpine areas.

Articular cartilage phenotypic homeostasis is crucial for life-long joint function, but the underlying cellular and molecular mechanisms governing chondrocyte stability remain poorly understood. Here, we show that the protein tyrosine phosphatase SHP2 is differentially expressed in articular cartilage (AC) and growth plate cartilage (GPC) and that it negatively regulates cell proliferation and cartilage phenotypic program. Postnatal SHP2 deletion in Prg4⁺ AC chondrocytes increased articular cellularity and thickness, whereas SHP2 deletion in Acan⁺ pan-chondrocytes caused excessive GPC chondrocyte proliferation and led to joint malformation post-puberty. These observations were verified in mice and in cultured chondrocytes following treatment with the SHP2 PROTAC inhibitor SHP2D26. Further mechanistic studies indicated that SHP2 negatively regulates SOX9 stability and transcriptional activity by influencing SOX9 phosphorylation and promoting its proteasome degradation. In contrast to published work, SHP2 ablation in chondrocytes did not impact IL-1-evoked inflammation responses, and SHP2's negative regulation of SOX9 could be curtailed by genetic or chemical SHP2 inhibition, suggesting that manipulating SHP2 signaling has translational potential for diseases of cartilage dyshomeostasis.