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🏛️ Key Research Academy23 Indexed Works

Tongji University

Verified scientific contributions, CAS laboratory outputs, clinical trial papers, and engineering breakthroughs produced by researchers and faculty affiliated with Tongji University.

Stem Cell Research & Therapy•2026

Inhalation of Mesenchymal Stromal Cell-Derived Extracellular Vesicles Activates Macrophage Polarization through the miR-22-3p/NLRP3/IL-1β Pathway, Ameliorating Lung Ischemia-Reperfusion Injury

Authors: Tao Wang, Guodong Wu, Peigen Gao, Fenghui Zhuang, Zeyu Wang, Ziheng Zhou, Chongwu Li, Junqi Wu, Deping Zhao

Background: Lung ischemia–reperfusion injury (IRI) is a major contributor to primary graft dysfunction (PGD) after lung transplantation. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have emerged as promising therapeutic agents in inflammatory diseases by ameliorating tissue damage and promoting repair. However, the anti-inflammatory efficacy of these approaches and the underlying mechanisms in lung ischemia–reperfusion injury remain incompletely understood. Methods: The protective effects of mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) against lung ischemia–reperfusion injury were evaluated using two delivery approaches, inhalation and intravenous injection. Both in vivo and in vitro models were employed to assess the biological activity of MSC-EVs and to elucidate the underlying molecular mechanisms. In addition, a rat orthotopic lung transplantation (OLT) model was established to further examine the translational relevance of MSC-EVs. Results: MSC–EVs treatment significantly ameliorated lung IRI, with inhalation showing superior efficacy over intravenous delivery. Mechanistically, miR-22-3p within MSC-EVs targeted macrophage NLRP3, suppressing activation of the NLRP3/Caspase-1/IL-1β pathway and promoting M2 polarization. The protective efficacy was confirmed in a clinically relevant rat OLT model, underscoring their translational potential. Conclusions: Our findings indicate that inhaled MSC-derived extracellular vesicles attenuate lung ischemia–reperfusion injury by promoting macrophage polarization via the miR-22-3p/NLRP3/IL-1β pathway, supporting their potential as a cell-free therapeutic approach to mitigate primary graft dysfunction after lung transplantation.

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Acta Biochimica et Biophysica Sinica•2026

Cardiac PTN-SIRT1 axis alleviates oxidative stress and promotes mitochondrial energy reprogramming to mitigate doxorubicin-induced cardiotoxicity through AMPK/PGC1α signaling

Authors: Yuxiao Sun, Tianwen Wei, Hongping Xu, Hongda Li, Chang Zhou, Xianliang Liu, Yafei Li, Shangwei Huang, Qi Zhang, Xia Duan

Doxorubicin (DOX) remains a cornerstone chemotherapeutic agent for malignancies, yet its clinical utility is severely limited by dose-dependent cardiotoxicity, which can lead to progressive left ventricular dysfunction and heart failure. Pleiotrophin (PTN), a heparin-binding growth factor with diverse physiological functions, regulates glucose and lipid metabolism and promotes oxidative energy pathways. However, whether PTN exerts protective effects against DOX-induced cardiotoxicity (DIC) remains unclear. In this study, we establish cellular and animal models of DIC. DOX administration induces pronounced myocardial injury in both models, characterized by impaired ventricular contractility, increased fibrotic remodeling, and reduced cell viability. Concurrently, PTN protein expression is significantly downregulated in cardiomyocytes under DOX treatment. Overexpression of PTN substantially alleviates these pathological changes. In vitro, PTN reduces mitochondrial oxidative stress and apoptosis while restoring energy production and cell viability. In vivo, PTN improves mitochondrial ultrastructure, decreases cardiomyocyte apoptosis, and enhances cardiac function. Mechanistically, PTN directly binds to SIRT1 and activates AMPK phosphorylation at Thr172, triggering a downstream cascade through the AMPK-PGC1α axis that reprograms mitochondrial energy metabolism and attenuates cardiotoxicity. In conclusion, the PTN-SIRT1 axis protects against DIC by reducing oxidative stress and promoting mitochondrial energy homeostasis via the AMPK/PGC1α pathway, highlighting its potential as a novel therapeutic target for preventing chemotherapy-related cardiac injury.

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Chinese Journal of Tissue Engineering Research•2026

Performance of unstable barbell bench press and changes in electromyographic activity after transcranial direct current stimulation

Authors: Wang Lejun, Chi Wenxin, Song Xiaoqian, Li Qian, Qiao Minjie, Tao Haifeng

BACKGROUND: Transcranial direct current stimulation can enhance human motor performance by modulating cortical excitability, but its impact on the performance of unstable resistance exercise remains unclear. OBJECTIVE: To investigate the effects of transcranial direct current stimulation on unstable barbell bench press performance and electromyographic activity. METHODS: A randomized, self-controlled crossover design was employed. Twenty-two male college students were randomly assigned to receive either active anodal transcranial direct current stimulation or sham stimulation. After transcranial direct current stimulation interventions, subjects performed a fatigue test involving the unstable barbell bench press. Performance during the unstable barbell bench press task was assessed by recording both the number of completed repetitions and barbell acceleration, serving as indicators of load capacity and movement stability control. In addition, surface electromyographic signals were collected from the right biceps brachii, triceps brachii, anterior deltoid, posterior deltoid, and pectoralis major during the exercise. A paired t-test was used to examine differences in repetition counts between true and sham stimulation conditions. Repeated measures analysis of variance was applied to analyze differences in triaxial acceleration, agonist muscle activation levels, and antagonist co-activation levels. RESULTS AND CONCLUSION: (1) No significant difference in the number of barbell bench press repetitions was observed between the true and sham stimulation conditions. However, the mean amplitude of Y-axis acceleration was substantially lower in the true stimulation group than the sham stimulation group. (2) True transcranial direct current stimulation markedly increased the activation level of the anterior deltoid and the co-activation level of the posterior deltoid. (3) There was no significant interaction between transcranial direct current stimulation and exercise phase on any measured variable. (4) These findings suggest that transcranial direct current stimulation does not significantly affect muscle endurance performance during unstable barbell bench press, but it can improve movement stability, possibly by increasing anterior deltoid activation and posterior deltoid co-activation, thereby enhancing shoulder joint stiffness and stability. In competitive sports and clinical rehabilitation, transcranial direct current stimulation may be considered to modulate performance in unstable load-bearing tasks according to training objectives.

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Chinese Journal of Tissue Engineering Research•2026

Visual analysis of shear wave elastography in skeletal muscle research

Authors: Li Qian, Li Zhenxing, Qiao Pengyan, Wang Pingzhi

BACKGROUND: Shear-wave elastography is valuable for rehabilitation diagnosis and treatment, but it has not been sufficiently promoted in clinical practice. OBJECTIVE: To explore the trends and hotspots of ultrasound shear wave elastography in skeletal muscle research by visualizing and analyzing the international literature from the past 10 years, thereby providing a reference for clinical diagnosis and follow-up research. METHODS: Based on the Web of Science Core Collection database (2015-2024), the number of publications, countries/regions, institutions, authors, journals, cited literature, and key words from the 978 included articles were visualized and analyzed using CiteSpace software. RESULTS AND CONCLUSION: (1) With a 16.2% average annual growth in global publications, China has the highest number of publications worldwide (197), but its international collaborative network is relatively weak. The University of Nantes in France has the highest number of publications (50), and the University of Queensland has the most influential collaborative network. (2) Ultrasound in Medicine and Biology is the journal with the most publications (33). Noriaki Ichihashi is the most prolific author. (3) The gastrocnemius muscle is one of the most frequently examined sites. Shear wave elastography shows significant clinical potential in central nervous system diseases and sports injuries. (4) The research focus has shifted from basic biomechanics to dynamic clinical assessment and therapeutic interventions. (5) Future diagnostic techniques should be more standardized and refined, establishing normative data ranges for muscle tissue, while considering individual biological variability in elasticity values.

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Stem Cell Research & Therapy•2026

Inhalation of mesenchymal stromal cell-derived extracellular vesicles activates macrophage polarization through the miR-22-3p/NLRP3/IL-1β pathway, ameliorating lung ischemia-reperfusion injury

Authors: Tao Wang, Guodong Wu, Peigen Gao, Fenghui Zhuang, Zeyu Wang, Ziheng Zhou, Chongwu Li, Junqi Wu, Deping Zhao

Background Lung ischemia–reperfusion injury (IRI) is a major contributor to primary graft dysfunction (PGD) after lung transplantation. Mesenchymal stem cell-derived extracellular vesicles (MSC-EVs) have emerged as promising therapeutic agents in inflammatory diseases by ameliorating tissue damage and promoting repair. However, the anti-inflammatory efficacy of these approaches and the underlying mechanisms in lung ischemia–reperfusion injury remain incompletely understood. Methods The protective effects of mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) against lung ischemia–reperfusion injury were evaluated using two delivery approaches, inhalation and intravenous injection. Both in vivo and in vitro models were employed to assess the biological activity of MSC-EVs and to elucidate the underlying molecular mechanisms. In addition, a rat orthotopic lung transplantation (OLT) model was established to further examine the translational relevance of MSC-EVs. Results MSC–EVs treatment significantly ameliorated lung IRI, with inhalation showing superior efficacy over intravenous delivery. Mechanistically, miR-22-3p within MSC-EVs targeted macrophage NLRP3, suppressing activation of the NLRP3/Caspase-1/IL-1β pathway and promoting M2 polarization. The protective efficacy was confirmed in a clinically relevant rat OLT model, underscoring their translational potential

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Acta Biochimica et Biophysica Sinica•2026

Spatiotemporal Orchestration of Macrophage Heterogeneity by Cell Adhesion Molecules

Authors: Jing Yu, Chen Li, Hanlin Qiao, Jinrong Suo, Danting Yang, Changdong Lin

Monocyte-derived macrophages (mo-macs) are central regulators of innate immunity and are essential for maintaining physiological homeostasis and host defense. Their functional efficacy relies on precisely coordinated transendothelial migration (TEM) and phenotypic polarization into classically activated (M1) or alternatively activated (M2) macrophages. This review delineates how cell adhesion molecules (CAMs), including integrins, selectins, the immunoglobulin superfamily (IgSF), and cadherins, act as pivotal sensors that orchestrate these spatiotemporal dynamics. CAMs facilitate the multi-step TEM of mo-macs and trigger intracellular signaling pathways, such as nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and signal transducer and activator of transcription (STAT), to dictate macrophage plasticity in response to inflammation and the tumor microenvironment (TME). We highlight the dual role of CAMs in driving the pathogenesis of atherosclerosis and cancer while also exploring their potential in bioengineering for regenerative medicine. Elucidating these CAM-dependent regulatory networks not only helps to explain the intrinsic mechanisms underlying immune regulation but also provides a theoretical framework for designing next-generation targeted immunotherapies and personalized clinical interventions for inflammatory diseases and malignancies.

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Acta Biochimica et Biophysica Sinica•2026

Cardiac PTN-SIRT1 axis alleviates oxidative stress and promotes mitochondrial energy reprogramming to mitigate doxorubicin-induced cardiotoxicity through AMPK/PGC1α signaling

Authors: Yuxiao Sun, Tianwen Wei, Hongping Xu, Hongda Li, Chang Zhou, Xianliang Liu, Yafei Li, Shangwei Huang, Qi Zhang, Xia Duan

Doxorubicin (DOX) remains a cornerstone chemotherapeutic agent for malignancies, yet its clinical utility is severely limited by dose-dependent cardiotoxicity, which can lead to progressive left ventricular dysfunction and heart failure. Pleiotrophin (PTN), a heparin-binding growth factor with diverse physiological functions, regulates glucose and lipid metabolism and promotes oxidative energy pathways. However, whether PTN exerts protective effects against DOX-induced cardiotoxicity (DIC) remains unclear. In this study, we establish cellular and animal models of DIC. DOX administration induces pronounced myocardial injury in both models, characterized by impaired ventricular contractility, increased fibrotic remodeling, and reduced cell viability. Concurrently, PTN protein expression is significantly downregulated in cardiomyocytes under DOX treatment. Overexpression of PTN substantially alleviates these pathological changes. In vitro, PTN reduces mitochondrial oxidative stress and apoptosis while restoring energy production and cell viability. In vivo, PTN improves mitochondrial ultrastructure, decreases cardiomyocyte apoptosis, and enhances cardiac function. Mechanistically, PTN directly binds to SIRT1 and activates AMPK phosphorylation at Thr172, triggering a downstream cascade through the AMPK-PGC1α axis that reprograms mitochondrial energy metabolism and attenuates cardiotoxicity. In conclusion, the PTN-SIRT1 axis protects against DIC by reducing oxidative stress and promoting mitochondrial energy homeostasis via the AMPK/PGC1α pathway, highlighting its potential as a novel therapeutic target for preventing chemotherapy-related cardiac injury.

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Acta Biochimica et Biophysica Sinica•2026

PIPKI-PIP2 promotes cell migration by recruiting Smurf1 to the membrane and increasing its activity

Authors: Yuxin Chen, Xiao Tan, Meiling Lu, Yunfei Chen, Weijuan Pan, Rong Wei, Yingcong Wang

Smurf1 is a member of the Nedd4 family of E3 ubiquitin ligases. Numerous lines of evidence indicate that the membrane localization of Smurf1 is essential for its activity. However, the underlying mechanisms that regulate the membrane localization of Smurf1 remain unclear. Type I phosphatidylinositol phosphate kinase (PIPKI) is a phosphatidylinositol kinase that generates phosphatidylinositol 4,5-bisphosphate (PIP2), which is located in the plasma membrane and regulates cellular processes, including ion channel activity and cell migration. In this study, we show that PIP2 and PIPKI regulate the membrane translocation of Smurf1. Importantly, the recruitment of Smurf1 to the cell membrane through the association of its C2 domain with PIPKI-produced PIP2 is essential for Smurf1-mediated E3 ligase activity and cell migration. Therefore, we identify a PIPKI-PIP2-Smurf1 signaling axis that regulates cell migration.

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Acta Biochimica et Biophysica Sinica•2026

Genetic characterization and functional analysis of novel PITX2 variants identified in Chinese families with Axenfeld-Rieger syndrome

Authors: Junqin Xu, Xinyao Wang, Zilin Zhong, Jianjun Chen, Peng Yang

Axenfeld-Rieger syndrome (ARS) is a rare genetic disorder characterized by anterior segment dysgenesis and systemic features. PITX2 variants are a major cause. In this study, we recruited four unrelated Chinese families with ARS and performed Sanger sequencing of PITX2. We identified four heterozygous variants: c.118delA (p.Arg40Glyfs*115), c.211G>T (p.Glu71X), c.253-1G>T, and c.663_670dupGACTCCTC (p.Pro224Argfs*18). These variants co-segregated with the phenotype in an autosomal dominant pattern, with two arising de novo. All variants were absent from ExAC and gnomAD, indicating rarity. Our findings expand the mutation spectrum of PITX2 and provide insights into the molecular mechanisms of ARS.

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Acta Biochimica et Biophysica Sinica•2026

A modified system to promote stemness of mouse intestinal stem cells by activating Nrf2 and α2-adrenergic receptor signaling pathway

Authors: Xingyu Zhou, Li Yang, Sentao Song, Xiaolei Yin

Intestinal stem cells (ISCs) maintain epithelial homeostasis through continuous self-renewal and differentiation, but their regulatory mechanisms remain incompletely understood. Using a simplified culture system, we identify two novel pathways that synergistically enhance stem cell characteristics: antioxidant signaling through 2-phospho-L-ascorbic acid (pVc) and α2-adrenergic receptor (α2-AR) activation by dexmedetomidine (Dex). Mechanistic studies reveal that pVc promotes stem cell maintenance through Nrf2-mediated antioxidant responses, while α2-AR activation functions through suppression of cAMP signaling. In vivo administration of these compounds enhances intestinal epithelial renewal while maintaining proper stem cell positioning and identity. Notably, α2-AR activation promotes regeneration after radiation injury by enhancing proliferation of stem cells produced by Bmi1+ cells in the post-injury process, demonstrating therapeutic potential. These findings advance our understanding of ISC regulation and suggest new strategies for protecting intestinal integrity during injury or disease.

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Acta Biochimica et Biophysica Sinica•2025

miR-199a-3p suppresses Vldlr expression to promote cardiomyocyte proliferation

Authors: Rui Jiang, Lijuan Pei, Hongjie Zhang, Fenglian He, Yuhan Min, Xinhang Li, Ke Wei

The proliferative capacity of cardiomyocytes is limited in adult mammals, and replacing lost tissue following acute ischemic injury is challenging. Previous studies have demonstrated that miR-199a-3p can promote cardiomyocyte proliferation, but the exact mechanism by which this occurs remains unclear, although multiple targets of miR-199a-3p have been identified. We recently showed that very-low-density-lipoprotein receptor (Vldlr) inhibits cardiomyocyte proliferation, and in this study we aim to test whether Vldlr is a functional target gene of miR-199a-3p. 3′UTR reporter assays demonstrate that miR-199a-3p directly binds to the 3′UTR of Vldlr and inhibits its translation. Overexpressing Vldlr blunts the pro-proliferative effect of miR-199a-3p on cardiomyocytes, suggesting that Vldlr is indeed a functional target of miR-199a-3p. Mechanistically, Vldlr reduces S807/811 phosphorylation of RB1, and inhibiting CDK4/6 to prevent RB1 phosphorylation can block the pro-proliferative effect of both Vldlr knockdown and miR-199a-3p, suggesting that RB1 phosphorylation is required for the cardiomyocyte proliferation induced by miR-199a-3p and Vldlr knockdown. The findings of this study reveal Vldlr as a novel functional target of miR-199a-3p in cardiomyocytes and identify RB1 as a downstream effector of cardiomyocyte proliferation. The identification of the role of the miR-199a-3p-Vldlr-RB1 axis in cardiomyocyte proliferation may provide potential therapeutic targets for cardiac regenerative medicine.

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Stem Cell Research & Therapy•2025

Mesenchymal stem cell therapy for end-stage liver disease: adversity and opportunity

Authors: Shiqi Li, Yichen Wang, Su-meng Li, Yaxin Zhu, Yan-qin Du, Xin Zheng, Jun Wu

End-stage liver disease (ESLD) is one of the predominant diseases contributing to high morbidity and mortality worldwide, with etiologies including alcoholic liver disease, viral hepatitis, non-alcoholic fatty liver disease, and metabolic-associated liver disease. Currently, liver transplantation remains the only effective treatment, however, its clinical application is significantly limited by donor shortages, immune rejection, and high medical costs. Among the five types of stem cells that have been experimentally applied to liver diseases, mesenchymal stem cells (MSCs) have emerged as the most extensively studied, with the largest number of experimental and clinical research platforms worldwide. This review compiles findings from 25 preclinical and clinical studies on MSCs in the treatment of ESLD, aiming to elucidate the core mechanisms of action and then outline both the challenges in MSC clinical translation and the novel opportunities arising from cutting-edge research.

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Acta Biochimica et Biophysica Sinica•2025

Increased neutrophil senescence is associated with impaired immunosuppressive activity in systemic lupus erythematosus

Authors: Lei Han, Fengling Huang, Qingchen Zhu, Huan Wang, Tianlin Lu, Chunyuan Xiao, Jing Xu, Xiaoyan Zhang, Yichuan Xiao, Xinfang Huang

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by a complex pathogenesis that was previously thought to involve primarily adaptive immunity. Emerging evidence underscores the role of neutrophils in shaping immune dysregulation and inducing organ damage in lupus. This study aims to investigate the dynamics of neutrophil senescence and its relationship with lupus, an area that remains poorly understood. Here, we identify a significantly elevated proportion of CXCR4hiCD62Llo senescence-like neutrophils in the peripheral blood of SLE patients compare to that in the healthy donors. Increased numbers of senescence-like neutrophils are positively correlated with SLE disease activity and autoantibody production in SLE patients. In addition, senescence-like neutrophils derived from SLE patients exhibit an impaired ability to suppress the proinflammatory activity of natural killer (NK) cells and CD4+ T cells. Further mechanistic exploration suggests that these senescence-like neutrophils might exert their immunosuppressive effects via reactive oxygen species (ROS) production under physiological conditions. Our results demonstrate that senescence-like neutrophils could serve as biomarkers for assessing the disease activity of SLE. The compromised immunosuppressive function of senescence-like neutrophils provides a new perspective on SLE pathophysiology and may pave the way for the development of novel therapies.

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Acta Biochimica et Biophysica Sinica•2025

D-mannose suppresses the angiogenesis and progression of colorectal cancer

Authors: Yu Du, Xinchao Zhang, Yixin Xu, Yuefan Zhou, Yanping Xu

Angiogenesis is an important factor influencing the development of solid tumors, and vascular endothelial growth factor receptor-2 (VEGFR2) is a central regulator of angiogenesis. Antibodies and inhibitors against VEGFR2 have been widely used in various malignancies. However, the regulatory mechanism of VEGFR2 has not been fully clarified. Here, we show that D-mannose can significantly inhibit angiogenesis and tumor growth by degrading VEGFR2. Specifically, D-mannose inactivates GSK3β by promoting the phosphorylation of GSK3β at Ser9, enhances the nuclear translocation of TFE3, and promotes lysosomal biogenesis, thereby increasing the lysosome-mediated degradation of VEGFR2. Thus, D-mannose significantly inhibits the proliferation, migration, and capillary formation of human umbilical vein endothelial cells (HUVECs) in vitro. Oral administration of D-mannose dramatically inhibits angiogenesis and tumor growth in mice. Our findings reveal a previously unrecognized anti-tumor mechanism of D-mannose by destabilizing VEGFR2 and provide a new strategy for the clinical treatment of colorectal cancer (CRC).

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Acta Biochimica et Biophysica Sinica•2025

CDC5L facilitates cardiomyocyte proliferation and ameliorates myocardial ischemia-reperfusion injury via modulation of the FGF10-YAP axis

Authors: Tianwen Wei, Tangjiang Wan, Yuxiao Sun, Yucheng Liang, Zhihao Lin, Shitong Shen, Qi Zhang, Mengli Chen, Yafei Li

Myocardial infarction (MI) causes irreversible cardiomyocyte loss, creating a need for cardiac repair therapies. The role of cell division cycle 5-like (CDC5L), a cell cycle regulator, in cardiac repair is unknown. This study aims to define the role of CDC5L in mitigating ischemia-reperfusion (I/R) injury by assessing its impact on cardiomyocyte proliferation and apoptosis and to determine the mechanism involving the FGF10-YAP axis. We model cardiac injury using in vitro oxygen-glucose deprivation/reoxygenation (OGD/R) in neonatal mouse cardiomyocytes and in vivo I/R in adult mice. To investigate CDC5L function, we modulate its expression via adenoviral or AAV9-mediated overexpression or knockdown. Proliferation markers (EdU+, Ki67+, pH3+), apoptosis (TUNEL staining, Bax/Bcl-2 ratio), and cardiac function (echocardiography) are assessed. Through transcriptomic screening, we identify CDC5L downstream targets and validate their functional roles using FGF10 knockdown rescue assays. We find that CDC5L is upregulated in the post-I/R murine myocardium. Its overexpression enhances cardiomyocyte proliferation, preserves cardiac function, reduces apoptosis, and diminishes infarct size. Transcriptomic analysis identifies FGF10 as a key downstream effector, and we confirm that CDC5L upregulates FGF10 expression. Notably, FGF10 knockdown reverses the proliferative and anti-apoptotic effects of CDC5L. Moreover, the CDC5L-mediated reduction in YAP phosphorylation is also dependent on FGF10, as this effect is abolished upon FGF10 knockdown. In conclusion, CDC5L attenuates cardiac I/R injury by promoting cardiomyocyte proliferation and inhibiting apoptosis through the FGF10-YAP pathway. This CDC5L-FGF10-YAP axis represents a promising therapeutic target to improve myocardial regeneration and recovery after myocardial infarction.

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Acta Biochimica et Biophysica Sinica•2025

CDDO-imidazolide ameliorates sepsis-induced ARDS by enhancing mitophagy via the Nrf2 pathway to prohibit alveolar macrophage pyroptosis and HMGB1 release

Authors: Yajing Liu, Pengcheng Ye, Cijun Tang, Meiru Jiang, Yiru Shen, Xiangrui Wang, Lei Hou, Yupeng Zhao

Accumulating evidence suggests that NLRP3-mediated alveolar macrophage (AM) pyroptosis and subsequent high mobility group box protein 1 (HMGB1) secretion play significant roles in the pathogenesis of acute respiratory distress syndrome (ARDS). Nrf2 has been shown to be individually involved in regulating pyroptosis. In this study, we investigate the ability of CDDO-imidazolide, a potent Nrf2 activator, to regulate AM pyroptosis and HMGB1 secretion in sepsis-associated ARDS, along with its underlying mechanism. The in vitro alveolar macrophage (AM) pyroptosis model, established by stimulating J774A.1 cells with LPS and ATP, was treated with CDDO-imidazolide or utilized Nrf2-knockout cells. The mice are intraperitoneally administered with CDDO-imidazolide before the in vivo sepsis-associated ARDS model is constructed via caecal ligation perforation and the Nrf2 inhibitor, ML385. In vitro studies reveal that the use of 3-MA to prohibit PINK1/Parkin-dependent mitophagy aggravates NLRP3-mediated pyroptosis and HMGB1 release in J774A.1 cells via LPS and ATP exposure. CDDO-imidazolide also significantly prevents NLRP3-mediated pyroptosis and HMGB1 release to increase PINK1/Parkin-dependent mitophagy, but these effects are not detected in Nrf2-knockout macrophages. Most importantly, CDDO-imidazolide significantly alleviates NLRP3 inflammasome protein expression in the lung tissues of septic mice and HMGB1 protein levels in the serum and bronchoalveolar lavage fluid (BALF), which can be reversed by ML385. Taken together, our results demonstrate that CDDO-imidazolide prominently protects the lungs by promoting Nrf2 activation and enhancing PINK1/Parkin mitophagy to inhibit AM pyroptosis and HMGB1 release. These findings provide novel insights for therapeutic strategies for sepsis-associated ARDS.

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Acta Biochimica et Biophysica Sinica•2025

Small molecules enhance the high-efficiency generation of pancreatic ductal organoids

Authors: Yuwei Liao, Zhifan Lin, Siyu Li, Xiaolei Yin

Advancements in three-dimensional (3D) organoid cultures have created more physiologically relevant models for pancreatic disease research, but efficiently generating mature pancreatic ductal cells remains challenging. In this study, we develop a novel protocol to generate pancreatic ductal organoids (PDOs) with high initiation efficiency and an enrichment of pancreatic ductal cells. By utilizing a cocktail of small molecules, we optimize the culture conditions to improve organoid formation. Our findings demonstrate that this protocol facilitates the formation and expansion of PDOs derived from Sox9-positive ductal cells, including heterogeneous ductal cells and acinar cells. These organoid cultures exhibit remarkable stability, supporting long-term expansion. This system provides an efficient model with potential applications in high-throughput drug screening. Moreover, these organoids recapitulate the exocrine cell composition and may reflect the cellular plasticity between ductal and acinar cells, providing a valuable platform for investigating pancreatic diseases such as pancreatic ductal adenocarcinoma (PDAC). The model presents a promising tool for future research aimed at understanding disease mechanisms and potentially helping drug development for pancreatic disorders.

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Stem Cell Research & Therapy•2024

N-CADHERIN+/CD168− subpopulation determines therapeutic variations of UC-MSCs for cardiac repair after myocardial infarction

Authors: Yukang Wu, Jianguo Li, Ke Feng, Ailing Tan, Yingying Gao, Wen Chen, Wenwen Jia, Xudong Guo, Jiuhong Kang

Background The efficiency of mesenchymal stem cells (MSCs) in treating myocardial infarction (MI) remains inconsistent, which limits their therapeutic applications. Therefore, exploring the mechanism for the inconsistent efficacy of MSCs and identification the criteria for screening MSCs are important for improving the efficiency of MSCs. Methods Mouse model after MI was utilized to test the role of MSCs from different donors and the functional subpopulation in improving cardiac function. Heterogeneity of MSCs was identified using single-cell RNA sequencing (scRNA-seq) of MSC-GY. GSEA and Scissor analyses were used to find the functional subpopulations of MSCs that promote angiogenesis. The role of functional subpopulations in promoting angiogenesis was verified by detecting the secretory proteins, the ratio of N-CADHERIN+/CD168− subpopulations in MSCs, and the tube formation, migration, and proliferation of HUVECs after treatment with conditional medium (CM) derived from different MSCs. Results We found that umbilical cord-derived MSCs (UC-MSCs) from different donors have varied therapeutic efficacy in MI mice and UC-MSCs with higher therapeutic effectiveness exhibited the most potent pro-angiogenic effects by secreting elevated levels of angiogenesis-related proteins, such as MYDGF, VEGFA, and FGF2. ScRNA-seq of 10,463 UC-MSCs revealed that the N-CADHERIN+/CD168− subpopulation was closely associated with pro-angiogenic effects, and the ratio of this cell subpopulation was positively correlated with the angiogenic potential of MSCs. We also found that the N-CADHERIN+/CD168− subpopulation was the functional subpopulation of MSCs in improving cardiac function of MI mice. Conclusions Our study identified that the N-CADHERIN+/CD168− subpopulation was the functional subpopulation of MSCs in treating MI, which was essential for the development and utilization of MSCs in MI treatment.

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Stem Cell Research & Therapy•2024

Transplantation of the LRP1high subpopulation of human umbilical cord-derived mesenchymal stem cells improves ovarian function in mice with premature ovarian failure and aged mice

Authors: Jiacheng Shen, Li Wu, Xiaoying Shi, Gang Chen, Tingwei Liu, Fangfang Xu, Xiaocui Xu, Xiaochen Kou, Yanhong Zhao, Hong Wang, Chenfei Wang, Shaorong Gao, Shaohua Xu

Background Premature ovarian failure (POF) has a profound impact on female reproductive and psychological health. In recent years, the transplantation of umbilical cord-derived mesenchymal stem cells (UC-MSCs) has demonstrated unprecedented potential in the treatment of POF. However, the heterogeneity of human UC-MSCs remains a challenge for their large-scale clinical application. Therefore, it is imperative to identify specific subpopulations within UC-MSCs that possess the capability to improve ovarian function, with the aim of reducing the uncertainty arising from the heterogeneity while achieving more effective treatment of POF. Methods 10× Genomics was performed to investigate the heterogeneity of human UC-MSCs. We used LRP1 as a marker and distinguished the potential therapeutic subpopulation by flow cytometry, and determined its secretory functions. Unsorted UC-MSCs, LRP1high and LRP1low subpopulation was transplanted under the ovarian capsules of aged mice and CTX-induced POF mice, and therapeutic effects was evaluated by assessing hormone levels, estrous cycles, follicle counts, and embryo numbers. RNA sequencing on mouse oocytes and granulosa cells after transplantation was performed to explore the mechanism of LRP1high subpopulation on mouse oocytes and granulosa cells. Results We identified three distinct functional subtypes, including mesenchymal stem cells, multilymphoid progenitor cells and trophoblasts. Additionally, we identified the LRP1high subpopulation, which improved ovarian function in aged and POF mice. We elucidated the unique secretory functions of the LRP1high subpopulation, capable of secreting various chemokines, cytokines, and growth factors. Furthermore, LRP1 plays a crucial role in regulating the ovarian microenvironment, including tissue repair and extracellular matrix remodeling. Consistent with its functions, the transcriptomes of oocytes and granulosa cells after transplantation revealed that the LRP1high subpopulation improves ovarian function by modulating the extracellular matrix of oocytes, NAD metabolism, and mitochondrial function in granulosa cells. Conclusion Through exploration of the heterogeneity of UC-MSCs, we identified the LRP1high subpopulation capable of improving ovarian function in aged and POF mice by secreting various factors and remodeling the extracellular matrix. This study provides new insights into the targeted exploration of human UC-MSCs in the precise treatment of POF.

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Acta Biochimica et Biophysica Sinica•2024

A PCR-independent, annealing-free cloning method for the insertion of short DNA fragments

Authors: Linbo Li, Jin Yan, Yuan Qi, Zhenglong Xiang, Na Jiang, Tongkang Yuan, Zhenyi Wang, Yuan Wang, Huaizhe Zhan, Shiyi Liu, Li Zhao, Jing Xu, Xiaowei Lei, Yuxuan Liu, Gui Wang, Jiayang Xie, Zhenming Guo, Chunhai Cai, Shan Bian

Cloning short DNA fragments, such as shRNA and sgRNA, is a routine but time-consuming task in molecular biology. Traditional methods require annealing of complementary oligos or PCR amplification, which are labor-intensive and time-consuming. Here, we report a novel PCR-independent, annealing-free cloning method that enables the insertion of short DNA fragments using a single oligo. The method relies on T4 DNA ligase for ligation and host cell DNA polymerase for complementary strand synthesis. We demonstrate that adding T4 DNA polymerase and dNTPs to the ligation mixture significantly improves cloning efficiency. This approach simplifies the cloning process, reduces time to less than 1 hour, and is compatible with standard laboratory reagents. Our method provides a rapid and efficient alternative for cloning short DNA fragments, with broad applications in gene knockdown and genome editing.

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Acta Biochimica et Biophysica Sinica•2024

EZH2 inhibition induces senescence via ERK1/2 signaling pathway in multiple myeloma

Authors: Shushan Guo, Qiongwei Tang, Xuejie Gao, Liangning Hu, Ke Hu, Hui Zhang, Qikai Zhang, Yue Lai, Yujie Liu, Zhuning Wang, Shuaikang Chang, Yifei Zhang, Huifang Hu, Dong An, Yu Peng, Haiyan Cai, Jumei Shi

Epigenetic modifications play an important role in cellular senescence, and enhancer of zeste homolog 2 (EZH2) is a key methyltransferase involved in epigenetic remodeling in multiple myeloma (MM) cells. We have previously demonstrated that GSK126, a specific EZH2 inhibitor, exhibits anti-MM therapeutic efficacy and safety in vivo and in vitro; however, its specific mechanism remains unclear. This study shows that GSK126 induces cellular senescence in MM, which is characterized by the accumulation of senescence-associated heterochromatin foci (SAHF) and p21, and increased senescence-associated β galactosidase activity. Furthermore, EZH2 is inhibited in ribonucleotide reductase regulatory subunit M2 (RRM2)-overexpressing OCI-MY5 and RPMI-8226 cells. RRM2 overexpression inhibits the methyltransferase function of EZH2 and promotes its degradation through the ubiquitin-proteasome pathway, thereby inducing cellular senescence. In this senescence model, Lamin B1, a key component of the nuclear envelope and a marker of senescence, does not decrease but instead undergoes aberrant accumulation. Meanwhile, phosphorylation of extracellular signal-regulated protein kinase (ERK1/2) is significantly increased. The inhibition of ERK1/2 phosphorylation in turn partially restores Lamin B1 level and alleviates senescence. These findings suggest that EZH2 inhibition increases Lamin B1 level and induces senescence by promoting ERK1/2 phosphorylation. These data indicate that EZH2 plays an important role in MM cellular senescence and provide insights into the relationships among Lamin B1, p-ERK1/2, and cellular senescence.

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Acta Biochimica et Biophysica Sinica•2024

Mass spectrometry-based structure-specific N-glycoproteomics and biomedical applications

Authors: Ming Bi, Zhixin Tian

N-linked glycosylation is a common posttranslational modification of proteins that results in macroheterogeneity of the modification site. However, unlike simpler modifications, N-glycosylation introduces an additional layer of complexity with tens of thousands of possible structures arising from various dimensions, including different monosaccharide compositions, sequence structures, linking structures, isomerism, and three-dimensional conformations. This results in additional microheterogeneity of the modification site of N-glycosylation, i.e., the same N-glycosylation site can be modified with different glycans with a certain stoichiometric ratio. N-glycosylation regulates the structure and function of N-glycoproteins in a site- and structure-specific manner, and differential expression of N-glycosylation under disease conditions needs to be characterized through site- and structure-specific quantitative analysis. Numerous advanced methods ranging from sample preparation to mass spectrum analysis have been developed to distinguish N-glycan structures. Chemical derivatization of monosaccharides, online liquid chromatography separation and ion mobility spectrometry enable the physical differentiation of samples. Tandem mass spectrometry further analyzes the macro/microheterogeneity of intact N-glycopeptides through the analysis of fragment ions. Moreover, the development of search engines and AI-based software has enhanced our understanding of the dissociation patterns of intact N-glycopeptides and the clinical significance of differentially expressed intact N-glycopeptides. With the help of these modern methods, structure-specific N-glycoproteomics has become an important tool with extensive applications in the biomedical field.

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Acta Biochimica et Biophysica Sinica•2024

PRR34-AS1 promotes mitochondrial division and glycolytic reprogramming in hepatocellular carcinoma cells through upregulation of MIEF2

Authors: Xuejing Yang, Huijing Feng, Jonghwa Kim, Gang Ti, Lin Wang, Kun Wang, Dong Song

LncRNA PRR34-AS1 overexpression promotes the proliferation and invasion of hepatocellular carcinoma (HCC) cells, but whether it affects HCC energy metabolism remains unclear. Mitochondrial division and glycolytic reprogramming play important roles in tumor development. In this study, the differential expression of PRR34-AS1 is explored via TCGA analysis, and higher levels of PRR34-AS1 are detected in patients with liver cancer than in healthy individuals. A series of experiments, such as CCK-8, PCR, and immunofluorescence staining, reveal that the proliferation, invasion, glycolysis, and mitochondrial division of PRR34-AS1-overexpressing hepatoma cells are significantly promoted. TCGA analysis and immunohistochemistry reveal high expression of the mitochondrial dynamin MIEF2 in liver cancer tissues. Dual-luciferase reporter assays confirm that miR-498 targets and binds to mitochondrial elongation factor 2 (MIEF2). In addition, we show that PRR34-AS1 can sponge miR-498. Therefore, we further investigate the effects of the lncRNA PRR34-AS1/miR-498/MIEF2 axis on the growth, glucose metabolism, and mitochondrial division in hepatocellular carcinoma cells. A series of experiments are performed on hepatocellular carcinoma cells after different treatments. The results show that the proliferative activity, invasive ability, and glycolytic level of hepatocellular carcinoma cells are decreased in HCC cells with low PRR34-AS1 expression, and the miR-498 expression level is increased in these cells. Inhibition of miR-498 or overexpression of MIEF2 restored the proliferative activity, invasive ability, glycolysis, and mitochondrial division in hepatocellular carcinoma cells. Thus, PRR34-AS1 regulates MIEF2 by sponging miR-498, thereby promoting mitochondrial division, mediating glycolytic reprogramming and ultimately driving the growth and invasion of HCC cells. Furthermore, in vivo mouse experiments yield results similar to those of the in vitro experiments, verifying the above results.

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