Nature Communications
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2025
·Vol. 16
·期 1
·1-17
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IF 15.7
He Hua,Ma Chong,Wei Wei,Wang Haonan,Lai Yutian,Liu Ming,Sun Shenfei,Ma Qing,Lai Jiashuang,Liu Hanxiang,Liu Hanmin,Sun Fei,Lin Xinhua
Postnatal respiration requires bulk formation of alveoli that produces extensive surface area for gas diffusion from epithelium to the circulatory system. Alveolar morphogenesis initiates at late gestation or postnatal stage during mammalian development and is mediated by coordination among multiple cell types. Here we show that fibroblast-derived Heparan Sulfate Glycosaminoglycan (HS-GAG) is essential for maintaining a niche that supports alveolar formation by modulating both biophysical and biochemical cues. Gli1-CreER mediated deletion of HS synthase gene Ext1 in lung fibroblasts results in enlarged and simplified alveolar structures. Ablation of HS results in loss of a subset of PDGFRα hi αSMA + alveolar myofibroblasts residing in the distal alveolar region, which exhibit contractile properties and maintain WNT signaling activity to support normal proliferation and differentiation of alveolar epithelial cells. HS is essential for proliferation while preventing precocious apoptosis of alveolar myofibroblasts. We show that these processes are dependent upon FGF/MAPK signaling and forced activation of MAPK/ERK signaling partially corrected alveolar simplification and restored alveolar myofibroblast number and AT2 cell proliferation in HS deficient mice. These data reveal HS-dependent myofibroblast heterogeneity and function as an essential orchestrator for developing alveolar niche critical for the generation of gas exchange units.
研究领域:
发育生物学
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细胞生物学
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呼吸系统医学
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Cell Reports
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2022
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IF 9.995
Xinyu Li,Jiasheng Li,Di Zhu,Ning Zhang,Xusheng Hao,Wenfeng Zhang,Qian Zhang,Yangli Liu,Xueying Wu,Ye Tian
Summary Coordination of inter-tissue stress signaling is essential for organismal fitness. Neuronal mitochondrial perturbations activate the mitochondrial unfolded-protein response (UPR mt ) in the intestine via the mitokine Wnt signaling in Caenorhabditis elegans . Here, we found that the protein disulfide isomerase PDI-6 coordinates inter-tissue UPR mt signaling via regulating the Wnt ligand EGL-20. PDI-6 is expressed in the endoplasmic reticulum (ER) and interacts with EGL-20 through disulfide bonds that are essential for EGL-20 stability and secretion. pdi-6 deficiency results in misfolded EGL-20, which leads to its degradation via ER-associated protein degradation (ERAD) machinery. Expression of PDI-6 declines drastically with aging, and animals with pdi-6 deficiency have decreased lifespan. Overexpression of PDI-6 is sufficient to maintain Wnt/EGL-20 protein levels during aging, activating the UPR mt , and significantly extending lifespan in a Wnt- and UPR mt -dependent manner. Our study reveals that protein disulfide isomerase facilitates Wnt secretion to coordinate the inter-tissue UPR mt signaling and organismal aging.
研究领域:
分子生物学
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衰老研究
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细胞信号传导
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发育生物学
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Frontiers in Oncology
·
2020
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IF 4.848
Jiang Tao,Gao Wenyu,Lin Shengjie,Chen Hao,Du Bin,Liu Qing,Lin Xiaoyan,Chen Qiang
Background: Gastric cancer (GC) has a high morbidity and mortality rate, with peritoneal metastasis (PM) identified as the main site of metastasis. Our previous study found that FNDC1 has a higher frequency of mutations in patients with PM by high-throughput sequencing assay, suggesting that it may be associated with GC invasion and PM, however the specific mechanism remains unclear.Methods: First, the correlation between FNDC1 and PM and prognosis of GC was clarified by bioinformatics and clinicopathological analysis. Next, the effect of FNDC1 expression on the invasion and metastasis ability of GC was investigated in vivo and in vitro. Finally, the signaling pathways involved in the regulation of FNDC1 were explored.Results: FNDC1 was highly expressed in GC and was associated with PM and poor prognosis. FNDC1 was also associated with epithelial-mesenchymal transition (EMT) in GC cells. Through in vivo and in vitro experiments, it was clarified that knockdown of FNDC1 could inhibit the proliferation, invasion, and migration of GC cells. In addition, it was elucidated that FNDC1 promotes EMT through the Wnt/β-catenin signaling pathway.Conclusion: FNDC1 may be associated with the invasion of GC and PM after surgery. FNDC1 was highly expressed in GC tissues and cell lines, while significantly associated with poor DFS and OS in GC patients. Both univariate and multivariate analyses suggested that the expression of FNDC1 was an independent factor for GC. Knockdown of FNDC1 also significantly inhibited the proliferation, migration, and activity of GC cells. FNDC1 may promote EMT in GC cells through the regulation of Wnt/β-catenin signaling pathway. FNDC1 has the potential to be used as a predictor of PM and may also be studied in depth as a therapeutic target for GC, which has potential clinical utility and is worthy of further validation.
研究领域:
肿瘤学
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分子生物学
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癌症研究
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Anti-Cancer Agents in Medicinal Chemistry
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2022
·Vol. 22
·期 18
·3172-3181
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IF 2.527
Xie Xiaoliang,Li Yumei,Zhu Haixia,Chen Lin,Chen Deta,Lin Shengming,Fan Tianyou
Background and Purpose: Osteosarcoma is the most commonly seen type of primary malignant bone tumors in children and adolescents. Partial patients with osteosarcoma cannot tolerate the side effects of chemotherapy drugs. Hence, it is urgent to find anti-osteosarcoma drugs with low side
effects. Melittin is an anti-tumor Traditional Chinese Medicine with low side effects. The purpose of this study was to explore the anti-osteosarcoma effect of melittin and its possible molecular mechanisms. Methods: The effects of melittin on cell growth were detected by CCK-8, clonal
formation, and flow cytometry. The related molecules were also investigated by Real-time PCR and Western blot. A xenograft model in nude mice was established to observe the effects of melittin on tumor growth and the related molecular expression was detected by immunohistochemistry. Results:
Melittin can inhibit the proliferation of osteosarcoma 143B cells, reduce colony formation, and induce apoptosis while significantly up-regulating the expression of Bax and Caspase-3 and down-regulating the expression of Bcl-2 proteins. Moreover, treatment with melittin significantly reduced
the mRNA and protein levels of β-catenin and Wnt/β- catenin related genes (LRP5, c-Myc, and Survivin) in osteosarcoma 143B cells in vitro. The xenograft model found that melittin significantly inhibited tumor growth and decreased the protein expression levels of β-catenin and
Wnt/β- catenin related genes in vivo. Conclusion: These findings show that melittin could inhibit the growth of osteosarcoma 143B cells, which may be related to the inhibition of Wnt/β-catenin signaling pathway activity and induce apoptosis by up-regulating the ratio of Bax/Bcl-2
in osteosarcoma 143B cells. Therefore, melittin is a promising anti-tumor drug for the treatment of osteosarcoma.
研究领域:
肿瘤学
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药理学
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分子生物学
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Environmental Technology & Innovation
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2026
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IF 7.3
Wenjie Wang,Xulong Fan,Yaquan Cao,Ruolin Shi,Ping Wang,Gaofeng Liang
Benzophenone-3 (BP-3), a common ultraviolet (UV) filter widely used in sunscreens, has raised increasing concern because early-life exposure may interfere with normal neurodevelopment. In this study, we fabricated a 3D inverse-opal polyethylene glycol diacrylate (PEGDA) scaffold and established a scaffold-supported brain organoid model for in vitro evaluation of BP-3-induced neurotoxicity. The scaffold was characterized by scanning electron microscopy (SEM), which revealed a highly ordered porous morphology with uniform pore size. It also showed good biocompatibility for organoid culture. BP-3 exposure induced concentration- and time-dependent toxicity in brain organoids, with more pronounced effects observed at 50 and 100 μM after 72 h of exposure. Under these defined exposure conditions, BP-3 was associated with increased oxidative stress, calcium-related functional changes, impaired membrane integrity, increased cytotoxicity, reduced expression of synaptic structural markers, and altered Wnt/β-catenin-related protein expression. These findings suggest that BP-3 exposure may disrupt early neurodevelopment-related processes in this model and is associated with synaptic-related alterations and Wnt/β-catenin dysregulation. Overall, this study supports the applicability of scaffold-supported brain organoids as an in vitro platform for evaluating BP-3-induced neurotoxic responses under controlled experimental conditions.
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NEUROBIOLOGY OF DISEASE
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2025
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IF 5.6
Shiyuan Xiao,Yue Li,Jun Wang,Mengran Wang,Bing Bu,Wenmin Jiang
Elevated intraocular pressure (IOP) imposes a substantial glycolytic demand on retinal tissue, driving excessive lactate production to sustain neuronal energy homeostasis. In the present study, we demonstrate that this metabolic stress markedly increases histone H4 lysine 8 lactylation (H4K8la) throughout the glaucomatous retina. Genome-wide profiling using Cleavage Under Targets and Tagmentation (CUT&Tag) revealed pronounced and selective H4K8la enrichment within the promoter region of mitofusin-2 (MFN2), a key mitochondrial fusion GTPase. Functionally, suppression of MFN2 mediated by H4K8la reciprocally enhances β-catenin expression, particularly under oxidative stress, indicating the existence of a lactate-responsive epigenetic circuit that couples mitochondrial dynamics to activation of the Wnt/β-catenin signaling pathway. In vivo experiments demonstrated that activated Müller glia orchestrate synchronous mitochondrial remodeling in retinal ganglion cells (RGCs) and photoreceptors. We propose that MFN2 functions as a molecular conduit, enabling intercellular mitochondrial transfer between Müller glia and neurons to sustain elevated glycolytic flux. This metabolic reprogramming increases lactate release, stimulates Wnt/β-catenin pathway activation, and ultimately leads to RGC apoptosis. Single-cell RNA sequencing (scRNA-seq) further revealed intensified Müller–amacrine/bipolar cell communication under ocular hypertension, accompanied by a marked reduction in neurexin- and VEGF-mediated interactions. Collectively, these findings identify a lactylation-governed epigenetic checkpoint that links mitochondrial dysfunction to glial–neuronal metabolic coupling in glaucoma, nominating MFN2 as a potential neuroprotective therapeutic target.
研究领域:
眼科学
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表观遗传学
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代谢学
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神经科学
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细胞生物学
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分子生物学
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ACTA BIOCHIMICA POLONICA
·
2021
·Vol. 68
·期 4
·725-732
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IF 2.149
Ziyan Wu,Zhong Zhou,Weiguo Zhang,Yi Yu
MicroRNA (miR)-21 has been found to be overexpressed in osteosarcoma (OS). The aim of the present study was to investigate the effect of miR-21-5p on the Warburg effect and stemness maintenance in OS cells and its potential molecular mechanism. Herein, miR-21-5p was overexpressed or inhibited in MG-63 cells via transfection with mimics or inhibitors. The effect of miR-21-5p on cell viability, apoptosis, Warburg effect and stemness maintenance were explored in OS cells. The results demonstrated that miR-21-5p inhibition suppressed MG-63 cell viability and enhanced their apoptosis. Additionally, miR-21-5p inhibition attenuated the stemness maintenance of MG-63 cells, as demonstrated by the reduced proportion of CD133-positive MG-63 cells, the decrease in tumorsphere formation capacity, and the downregulation of Sox2, Oct4, and Nanog proteins. Moreover, miR-21-5p inhibition suppressed the Warburg effect in MG-63 cells, as indicated by the decrease in glucose uptake, lactic acid production, and ATP level and the downregulation of proteins involved in the Warburg effect (GLUT1, LDHA, HK2, and PKM2). Furthermore, the results suggested that the effect of miR-21-5p suppression on stemness and the Warburg effect may be associated with the decreased activity of the Wnt/β-catenin pathway in OS cells. Our findings suggest a novel potential biomarker for OS therapy.
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Experimental and Therapeutic Medicine
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2023
·Vol. 26
·期 1
·1-10
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IF 2.7
Shixiong Lei,Xilin Du,Kai Tan,Xiaojun He,Yejing Zhu,Shoujie Zhao,Zhenyu Yang,Gang Dou
Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. It has been reported that cysteine rich protein 1 (CRP‑1) is dysregulated in several types of human cancer; however, its role in HCC is poorly understood. Therefore, the current study aimed to investigate the role of CRP‑1 in HCC. Western blotting and reverse transcription‑quantitative PCR results showed that CRP‑1 was upregulated in HCC cell lines. Furthermore, for in vitro experiments, CRP‑1 was knocked down and overexpressed in the HCC cell lines Hep 3B2.1‑7 and BEL‑7405, respectively. c‑Myc and proliferating cell nuclear antigen upregulation, and cleaved caspase 3 and poly(ADP‑ribose) polymerase downregulation suggested that CRP‑1 silencing could inhibit the proliferation and colony‑forming ability of HCC cells, and induce apoptosis. In addition, CRP‑1 overexpression promoted the malignant behavior of HCC cells and induced epithelial‑mesenchymal transition (EMT), as verified by E‑cadherin downregulation, and N‑cadherin and vimentin upregulation. Additionally, CRP‑1 overexpression promoted the nuclear translocation of β‑catenin, and activated the expression of cyclin D1 and matrix metalloproteinase‑7. Furthermore, inhibition of Wnt/β‑catenin signaling, following cell treatment with XAV‑939, an inhibitor of the Wnt/β‑catenin signaling pathway, abrogated the effects of CRP‑1 on enhancing the proliferation and migration of HCC cells. These findings indicated that the regulatory effect of CRP‑1 on HCC cells could be mediated by the Wnt/β‑catenin signaling pathway. Overall, CRP‑1 could promote the proliferation and migration of HCC cell lines, partially via promoting EMT and activating the Wnt/β‑catenin signaling pathway.
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PHYTOMEDICINE
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2022
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IF 6.656
Chuan Li,Liru Tian,Yihai Wang,Huan Luo,Jia Zeng,Peiqiang Su,Shulin Chen,Zhiheng Liao,Weimin Guo,Xiangjiu He,Shuqing Chen,Caixia Xu
Background Morinda officinalis (MO) is a herb used in Traditional Chinese Medicine (TCM) for the treatment of osteoporosis. M13, a MO-based anthraquinone compound is known to suppress osteoclast activity. However, whether M13 promotes MSCs osteogenic differentiation and its potential mechanism remains unknown. Purpose To examine the influence of M13 on MSCs proliferation and osteogenic differentiation and elucidate the underlying mechanism. Methods/Study designs The effect of M13 exposure on MSCs proliferation was assessed via CCK8 assay, clone formation assay, immunofluorescence, RT-qPCR, and Western blot. The M13-mediated osteogenesis in vitro and ex vivo were evaluated via ALP and Alizarin red S staining, osteogenesis-associated gene (Runx2, Col1a1 and Opn) expression, and fetal limb explants culture. Molecular docking was employed for target signal pathway screening. The potential signaling mechanisms of M13-promoted MSCs osteogenic differentiation were analyzed by introducing XAV939 (Wnt/β-catenin signaling inhibitor). Results M13 induced certain obvious positive effects on MSCs proliferation and osteogenic differentiation. Treatment with M13 enhanced MSCs viability and clone numbers. Meanwhile, M13 promoted osteogenic gene expression, enhanced ALP intensity and Alizarin red S staining in MSCs. In terms of mechanism, M13 strongly interacted with the docking site of the WNT signaling complex, thereby activating the Wnt/β-catenin pathway. Furthermore, the M13-mediated osteogenic effect was partially inhibited by XAV939 both in vitro and ex vivo , which confirmed that the Wnt/β-catenin axis is a critical regulator of M13-induced osteogenic differentiation of MSCs. Conclusion Our study elucidated for the first time that M13 significantly promoted osteogenic differentiation of MSCs via stimulation of the Wnt/β-catenin pathway in vitro and ex vivo .Our findings offered new additional evidence to support the MO or M13-based therapy of osteoporosis.
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Nutrients
·
2022
·Vol. 14
·期 15
·3042
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IF 6.706
Jun Chen,Zhiguang Duan,Yannan Liu,Rongzhan Fu,Chenhui Zhu
The metastasis of esophageal squamous cell carcinoma (ESCC) is a leading cause of death worldwide, however, it has a poor prognosis. Ginsenoside Rh4 is a rare saponin that has been shown to have potential antitumor effectiveness in ESCC. However, the utility of Rh4 in ESCC metastasis and its undiscovered mode of action has not yet been explored. In this study, we found that Rh4 could inhibit ESCC metastasis by regulating the Wnt/β-catenin signaling pathway and the level of c-Myc, which is an important transcription factor in cancer. In in vitro experiments, Rh4 could inhibit the migration and invasion of ESCC cells without affecting cell viability. In in vivo experiments, Rh4 restrained ESCC metastasis to the lymph nodes and lungs via the suppression of epithelial-mesenchymal transition (EMT). The Wnt agonist HLY78 promoted EMT and migration of ESCC cells, whereas treatment of Rh4 can attenuate the promotion effect of HLY78. The siRNA knocking out c-Myc can also significantly reduce the expression of EMT-related marker proteins. This study illustrates a new concept for further research on the mechanism of Rh4 in ESCC.Keywords:metastasis;ginsenoside Rh4;ESCC;Wnt/β-catenin;c-Myc
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NEUROSCIENCE
·
2026
·
IF 3.3
Xiaoyu Lin,Wanliang Du,Ruile Fang,Ying Ma,Yongjun Wang,Jialei Yang
Systemic inflammation worsens ischemic stroke by increasing brain injury, neurological deficits, and neuroinflammation. • Systemic inflammation enhances microglial NF-κB activity and promotes p65/β-catenin interaction. • Systemic inflammation downregulates microglial Wnt/β-catenin/CD36 axis and impairs microglial efferocytosis. • Lithium chloride restores Wnt/β-catenin signaling and microglial efferocytosis, improving stroke outcome under systemic inflammation. Systemic inflammation is associated with worse outcomes after ischemic stroke, but the underlying mechanisms remain poorly understood. Microglial efferocytosis limits post-stroke inflammation and promotes recovery, whereas Wnt/β-catenin signaling has been implicated in neuroprotection and in regulation of CD36, a key efferocytotic receptor. Here, we investigated whether systemic inflammation is associated with alterations in microglial Wnt/β-catenin/CD36 axis and efferocytosis during ischemic injury. Mice were pretreated with lipopolysaccharide (LPS) before transient middle cerebral artery occlusion/reperfusion (tMCAO/R), and BV2 microglia were exposed to LPS before oxygen-glucose deprivation/reoxygenation (OGD/R). LPS pretreatment markedly increased infarct volume, worsened neurological deficits, and amplified post-ischemic neuroinflammatory responses. These effects were accompanied by enhanced microglial NF-κB signaling, increased p65/β-catenin interaction, and reduced nuclear β-catenin, consistent with suppression of Wnt/β-catenin signaling. Reduced CD36 expression and impaired microglial efferocytosis were observed in parallel. Notably, pharmacological activation of Wnt/β-catenin signaling with lithium chloride (LiCl) restored CD36 expression and microglial efferocytosis under LPS-pretreated conditions, and was accompanied by smaller infarcts, improved neurological function, and attenuated neuroinflammation. Collectively, these findings show that LPS pretreatment exacerbates ischemic stroke and is associated with enhanced microglial NF-κB signaling, dysregulation of the Wnt/β-catenin/CD36 axis, and impaired microglial efferocytosis. These results support defective microglial efferocytosis as a potential biological link between systemic inflammation and aggravated ischemic injury and identify Wnt/β-catenin signaling as a candidate pathway for further therapeutic investigation Download: Download high-res image (128KB) Download: Download full-size image
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JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
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2023
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IF 5.3
Xiaojing Xing,Meichen Liu,Xuguang Wang,Qianxue Guo,Hongyue Wang,Wenxue Wang
Diffuse large B-cell lymphoma (DLBCL) is difficult to treat due to the high recurrence rate and therapy intolerance, so finding potential therapeutic targets for DLBCL is critical. FK506-binding protein 3 (FKBP3) contributes to the progression of various cancers and is highly expressed in DLBCL, but the role of FKBP3 in DLBCL and its mechanism are not clear. Our study demonstrated that FKBP3 aggravated the proliferation and stemness of DLBCL cells, and tumour growth in a xenograft mouse model. The interaction between FKBP3 and parkinsonism associated deglycase (PARK7) in DB cells was found using co-immunoprecipitation assay. Knockdown of FKBP3 enhanced the degradation of PARK7 through increasing its ubiquitination modification. Forkhead Box O3 (FOXO3) belongs to the forkhead family of transcription factors and inhibits DLBCL, but the underlying mechanism has not been reported. We found that FOXO3 bound the promoter of FKBP3 and then suppressed its transcription, eventually weakening DLBCL. Mechanically, FKBP3 activated Wnt/β-catenin signalling pathway mediated by PARK7. Together, FKBP3 increased PARK7 and then facilitated the malignant phenotype of DLBCL through activating Wnt/β-catenin pathway. These results indicated that FKBP3 might be a potential therapeutic target for the treatment of DLBCL.
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