Virulence
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2026
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IF 5.4
Kun Yan,Xiuling Wang,Zongyi Bo,Chengcheng Zhang,Mengjiao Guo,Xiaorong Zhang,Yantao Wu
Avian infectious bronchitis virus (IBV) belongs to the genus Gammacoronavirus (family Coronaviridae), causes severe multi-system disease in chickens, inflicting major global economic losses. The molecular interplay between IBV and host metabolic networks remains poorly understood. Through integrated transcriptomic, metabolomic, and lipidomic profiling of oviduct tissues from specific-pathogen-free (SPF) chickens infected with the IBV QXL strain, we demonstrate tripartite metabolic reprogramming: 1) redirected glucose flux through the pentose phosphate pathway (PPP) to fuel nucleotide synthesis, 2) rewired lipid metabolism to prioritize de novo membrane biogenesis over fatty acid β-oxidation, and 3) orchestrated glycerophospholipid remodeling. This integrated analysis revealed a coordinated upregulation of fatty-acid biosynthesis genes and accumulation of specific glycerophospholipids and eicosanoids. Mechanistically, IBV co-opts the Warburg effect and PPP activation while uniquely suppressing fatty acid β-oxidation to channel fatty acids toward lipid droplets (LDs) biogenesis. Phosphatidylserine (PS) overproduction (e.g. 2.55-fold increase in PS(22:0/22:6)) and phospholipase A2 (PLA2)-mediated lysophospholipids (Lyso-PLs) and eicosanoids generation (e.g. 7.09-fold increase in prostaglandin E2 (PGE2)) emerged as critical regulators of membrane dynamics and inflammatory signaling. This process was centrally coordinated by the significant activation of peroxisome proliferator-activated receptor (PPAR) (e.g. 1.74-fold increase in ACSL1) and transforming growth factor-beta (TGF-β) (e.g. significant increase in p-SMAD2) signaling pathways, directly linking lipid remodeling to immunomodulation. Functionally, targeting acetyl-CoA carboxylase (ACC) or glucose-6-phosphate dehydrogenase (G6PD), alongside TGF-β pathway modulation, synergistically curtailed viral replication in vitro. Our findings delineate a critical PPAR-TGF-β cross-talk that governs lipid remodeling during infection and identify host metabolic nodes that are potentially targetable for antiviral intervention.
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Journal of Inflammation Research
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2026
·
IF 4.6
Jianglong Chen,Yunfei Cui,Rujie Zhou,Yu Zhu,Meijia Chen,Jinhua Su,Jinhui Wang,Guang Li
Objective To explore the therapeutic effect and molecular mechanism of Arundina graminifolia (D.Don) Hochr (BYJ) on renal fibrosis in chronic kidney disease (CKD) mice.Methods Phytochemical profiles of the methanol extract BYJ were analyzed using ultra-performance liquid chromatography-quadrupole time-of-flight tandem mass spectrometry (UPLC-Q-TOF-MS), while network pharmacology and molecular docking were employed to predict the core active components and therapeutic targets. For experimental validation, a CKD mouse model was established via adenine induction. Mice were randomly assigned to normal control, model, and three BYJ treatment groups (low-dose: 2 g/kg·d, middle-dose: 4 g/kg·d, and high-dose: 8 g/kg·d, crude drug equivalent). Assessments included renal function parameters, histopathological changes, inflammatory markers, and oxidative stress indicators. The associated molecular mechanisms were analyzed using immunohistochemistry staining and Western blot.Results In silico analysis identified five core targets—PIK3R1, AKT1, SRC, MTOR, and EGFR—and suggested esculetin as a key active component with strong binding affinity to these targets. Experimentally, BYJ administration significantly reduced in serum creatinine (SCr), blood urea nitrogen (BUN), and the kidney index, and ameliorated glomerular atrophy and tubular dilation. Furthermore, BYJ treatment downregulated pro-inflammatory factors (eg, IL-1β), elevated superoxide dismutase (SOD) activity, and decreased malondialdehyde (MDA) content. The intervention suppressed the epithelial-mesenchymal transition (EMT) process, as evidenced by the upregulation of E-cadherin and downregulation of α-SMA expression. Mechanistic verification indicated that BYJ treatment was associated with attenuated the overactivated of TGF-β/PI3K-AKT/mTOR pathway in renal tissues.Conclusion The methanolic extract of BYJ effectively attenuates CKD progression in mice, which is associated with by modulated the overactivation of the TGF-β/PI3K-AKT/mTOR pathway, inhibited the EMT process, and ameliorated inflammatory response and oxidative stress. These findings provide a preliminary theoretical basis for the development of BYJ as a potential candidate agent for CKD treatment.
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PHYTOMEDICINE
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2024
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IF 6.7
Yu-Qing Li,Xin-Ming Yu,Xue-Mei Shang,Jing-Yi Lin,Rui-Zhi Tan,Jian-Chun Li,Hong-Wei Su,Hong-Ping Shen,Hong-Lian Wang,Li Wang
Background Renal fibrosis is a hallmark of chronic kidney disease (CKD). Smad3 serves as the principal transcription factor mediating the pro-fibrosis effects of TGF-β signaling in renal fibrosis. Biochanin A (BCA), a natural isoflavone, has been shown to attenuate renal fibrosis by inhibiting TGF-β signaling but the detailed mechanisms remain unresolved. This study aimed to elucidate the specific mechanisms by which BCA modulates TGF-β signaling. Methods Renal fibrosis models were established both in vitro , using TGF-β1-stimulated mouse renal tubular TCMK1 cells, and in vivo , employing mice with unilateral ureter obstruction (UUO). RNA-seq was conducted to identify BCA-regulated genes. The AnimalTFDB4.0 database was utilized to predict transcription factors with potential binding to Smad3 promoter. The activities of TGF-β signaling and the cloned mouse Smad3 promoter were assessed using luciferase reporter assays. Plasmid transfection was performed using polyethylenimine in TCMK1 cells or ultrasound microbubbles in UUO kidneys. Gene expression was analyzed by RT-PCR, western blot, and immunohistochemistry assays. Results BCA significantly inhibited TGF-β signaling activity and suppressed TGF-β1-induced fibrotic gene expression in TCMK1 cells. RNA-seq and in silico analyses identified Smad3 as the key gene downregulated by BCA, while leaving Smad2 unaffected. This selective transcriptional suppression of Smad3 by BCA was validated by luciferase reporter assays using the cloned Smad3 promoter. Furthermore, transcription factor binding prediction identified that Klf6, a transcription factor downregulated by BCA, has binding potential to the Smad3 promoter and promotes Smad3 transcription. Klf6 expression was induced in TGF-β1-stimulated TCMK1 cells and UUO kidneys, but this induction was abolished upon BCA treatment. Importantly, Klf6 overexpression restored Smad3 expression and counteracted the anti-fibrosis effects of BCA in both TGF-β1-stimulated TCMK1 cells and UUO kidneys. Conclusion TGF-β-responsive Klf6 transcriptionally transactivates Smad3 expression. BCA exerts anti-renal fibrosis effects by inhibiting the Klf6-Smad3 signaling axis, underscoring its therapeutic potential in the treatment of CKD.
研究领域:
药理学
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分子生物学
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肾病学
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高影响因子
Cell Reports
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2026
·Vol. 45
·期 6
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IF 7.7
Yifang Chen,Qian Zhang,Na Li,Zhaoqi Zhang,Tong Lei,Han Guo,Hezhe Lu,Yong Zhao
Dendritic cells (DCs) are professional antigen-presenting cells that exhibit significant heterogeneity in development and function. This study found that among 17 cytokines screened, only IL-33 could induce DCs to display a Th9-type cytokine profile, including IL-9, IL-4, and IL-13, in vitro . The response of DCs to IL-33 was synergistically enhanced by TGF-β and IL-4, defining a distinct subset termed DC9. Transcriptomic analysis revealed that DC9 possesses a unique gene expression signature, particularly in cytokine/chemokine clusters, compared to conventional DCs. Mechanistically, DC9 polarization depends on the JAK-STAT6-IRF4 signaling pathway. Functionally, DC9 preferentially drives naive CD4 + T cell differentiation toward Th9 cells in vitro . In an ovalbumin-induced allergic airway inflammatory mouse model, DC9 cells were detectable in lungs and adoptive transfer of DC9 exacerbated disease severity, and increased pulmonary Th9 cells. Collectively, we identify DC9 as a novel DC subset induced by IL-33/TGF-β/IL-4 through the JAK-STAT6-IRF4 axis, which promotes Th9 differentiation and aggravates allergic airway inflammation.
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JOURNAL OF THERMAL BIOLOGY
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2026
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IF 3.2
Yukun Cao,Xin Li,Wangang Gong,Jia Tan,Jing Shen,Xinli Zhou
Cryoablation remodels desmoplastic TME in pancreatic cancer. • Sub-lethal freezing inhibits TGF-β/Smad signaling pathway. • Cryoablation preceding chemotherapy yields superior efficacy. • Disruption of fibrotic barriers sensitizes PDAC to chemotherapy. Cryoablation is effective for solid tumors but is often constrained by limited thermal efficiency and incomplete ablation. Conventional strategies prioritize expanding lethal isotherms to minimize the sub-lethal zone, a practice that increases the risk of collateral injury to adjacent critical structures. This study proposes a novel strategy utilizing the sub-lethal zone to remodel the tumor microenvironment for enhanced therapeutic efficacy. Using pancreatic cancer and stellate cell co-cultured spheroids and subcutaneous tumor models, we investigated fibrotic tumor microenvironment changes induced by the cryoablation sub-lethal zone combined with gemcitabine plus nab-paclitaxel. Results demonstrated that cryoablation significantly disrupted collagen structures and downregulated TGF-β1, p-Smad3, α-SMA, and Collagen I expression. This modulation is associated with the mitigation of fibrotic barriers, thereby potentially improving the accessibility of chemotherapy drugs within the sub-lethal zone. In vivo, cryoablation followed by chemotherapy yielded optimal efficacy compared to reverse sequencing or monotherapy, significantly inhibiting angiogenesis and promoting mitochondrial apoptosis via upregulated Bax and Caspase-3 levels. In conclusion, cryoablation functions as a potent tumor microenvironment remodeler. By downregulating TGF-β/Smad signaling, it sensitizes pancreatic ductal adenocarcinoma to subsequent chemotherapy, offering a superior sequential strategy to effectively inhibit the growth of residual tumor cells, offering an approach to improve local tumor control in PDAC.
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INTERNATIONAL JOURNAL OF PHARMACEUTICS
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2024
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IF 5.3
Lili Niu,Yao Liu,Nannan Li,Yang Wang,Lin Kang,Xiaomin Su,Ce Xu,Zanya Sun,Weicong Sang,Jingyuan Xu,Huishu Guo,Shun Shen
Transforming growth factor β (TGF-β), a versatile immunosuppressive cytokine, has gained increasing attention as a potential target for cancer immunotherapy. However, current strategies are constrained by tumor heterogeneity and drug resistance. Therapeutic probiotics, such as Escherichia coli Nissle1917 ( EcN ), not only regulate the gut microbiota to increase beneficial bacteria with anti-tumor effects, but also modulate immune factors within the body, thereby enhancing immunity. In this study, we developed an oral microgel delivery system of EcN @(CS-SA) 2 by electrostatic interaction between chitosan (CS) and sodium alginate (SA), aiming to enhance its bioavailability in the gastrointestinal tract (GIT). Notably, EcN @(CS-SA) 2 microgel showed a synergistic enhancement of the anti-tumor efficacy of Galunisertib (Gal, a TGF-β inhibitor) by inducing apoptosis and immunogenic cell death (ICD) in tumor cells, as well as promoting increased infiltration of CD8 + T cells into the tumor microenvironment (TME).
研究领域:
肿瘤学
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免疫治疗
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药学
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微生物学
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分子生物学
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Frontiers in Immunology
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2022
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IF 8.786
Liu Siqi,Guo Junfu,Cheng Xianda,Li Wenna,Lyu Shuangyu,Chen Xuanyi,Li Qingwei,Wang Hao
The transforming growth factor-βs (TGF-βs) are multifunctional cytokines capable of regulating a wide range of cellular behaviors and play a key role in maintaining the homeostasis of the immune system. The TGF-β subfamily, which is only present in deuterostomes, expands from a single gene in invertebrates to multiple members in jawed vertebrates. However, the evolutionary processes of the TGF-β subfamily in vertebrates still lack sufficient elucidation. In this study, the TGF-β homologs are identified at the genome-wide level in the reissner lamprey (Lethenteron reissneri), the sea lamprey (Petromyzon marinus), and the Japanese lamprey (Lampetra japonica), which are the extant representatives of jawless vertebrates with a history of more than 350 million years. The molecular evolutionary analyses reveal that the lamprey TGF-β subfamily contains two members representing ancestors of TGF-β2 and 3 in vertebrates, respectively, but TGF-β1 is absent. The transcriptional expression patterns show that the lamprey TGF-β2 may play a central regulatory role in the innate immune response of the lamprey since it exhibits a more rapid and significant upregulation of expression than TGF-β3 during lipopolysaccharide stimuli. The incorporation of BrdU assay reveals that the lamprey TGF-β2 recombinant protein exerts the bipolar regulation on the proliferation of the supraneural myeloid body cells (SMB cells) in the quiescent and LPS-activated state, while plays an inhibitory role in the proliferation of quiescent and activated leukocytes in lampreys. Furthermore, caspase-3/7 activity analysis indicates that the lamprey TGF-β2 protects SMB cells from apoptosis after serum deprivation, in contrast to promoting apoptosis of leukocytes. Our composite results offer valuable clues to the origin and evolution of the TGF-β subfamily and imply that TGF-βs are among the most ancestral immune regulators in vertebrates.
研究领域:
进化生物学
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免疫学
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分子生物学
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基因组学
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Stem Cell Research & Therapy
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2026
·Vol. 17
·期 1
·200
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IF 7.8
Chen Qi,Chen Xiaolong,Yang Qu,Miao Xinxin,Yuan Jinghong,Ding Shuihua,Ding Rui,Cai Shenghao,Li Bin,Cheng Xigao
Background Intervertebral disc degeneration (IVDD) is characterized by progressive nucleus pulposus cell loss and extracellular matrix degradation, in which persistent oxidative stress plays a critical pathogenic role. Transplantation of nucleus pulposus–derived stem cells (NPSCs) is a promising therapeutic strategy, yet the hostile oxidative microenvironment severely compromises cell survival. Although cellular quiescence has been suggested to enhance stress tolerance, its regulatory mechanisms and relevance in NPSCs remain largely unexplored. Methods Oxidative stress was evaluated in human degenerated disc tissues, a rat needle-puncture degeneration model, and tert-butyl hydroperoxide–treated NPSCs in vitro. Proliferating and quiescent NPSCs were compared for reactive oxygen species (ROS) levels, apoptosis, viability, and transcriptomic profiles. Pathway enrichment analyses were performed to identify critical signaling mechanisms. Recombinant transforming growth factor-beta 3 (rhTGF-β3) was used to activate the pathway, while small interfering RNA targeting the transforming growth factor-beta receptor type 2 ( Tgfbr2 ) and the pharmacological inhibitor SB431542 were applied for pathway suppression. Functional assays, organ culture, and in vivo transplantation were conducted to assess cell survival and regenerative effects. Results Elevated oxidative stress was consistently observed across clinical, animal, and cellular models of disc degeneration. Quiescent NPSCs demonstrated enhanced resistance to oxidative injury, with reduced ROS accumulation, decreased apoptosis, and improved survival. Transcriptomic analyses revealed suppression of metabolic and P53-mediated apoptotic pathways, alongside marked activation of TGF-β/SMAD signaling. Activation of this pathway induced quiescence, reduced ROS levels, inhibited mitochondrial apoptotic signaling, and protected NPSCs from oxidative injury, whereas pathway inhibition abolished these protective effects. In both organ culture and in vivo transplantation models, quiescent and TGF-β–activated NPSCs exhibited superior survival and significantly improved disc structural preservation compared with proliferating or pathway-blocked cells. Conclusion Activation of the TGF-β/SMAD pathway induces NPSC quiescence and enhances oxidative stress tolerance by suppressing P53-dependent mitochondrial apoptosis. Pharmacological induction of quiescence represents a potential strategy to improve stem cell–based therapies for intervertebral disc degeneration.
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INTERNATIONAL IMMUNOPHARMACOLOGY
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2025
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IF 4.7
Xue-Li Jiang,Chuang Liu,Zi-Ying Zhan,Xiao-Qi Lan,Yan-Ling Wu,Ji-Xing Nan,Cheng-Hua Jin,Li-Hua Lian
Liver fibrosis is a critical precursor to the progression of cirrhosis and liver cancer. However, the development of precision therapies for this condition has been impeded by incompletely elucidated molecular mechanisms. Activin receptor like kinase 5 (ALK5), termed TGF-β type I receptor (TGF-βRI), has been identified as a promising therapeutic target for antifibrotic drug development. In this study, we designed and synthesized two novel thiazole derivatives (J-1155 and J-1156) featuring enantiomeric amino acid moieties to selectively target ALK5 for hepatic fibrosis treatment. Our data demonstrated that both compounds effectively attenuate hepatic fibrosis and associated inflammation through dual inhibition of the TGF-β/Smad signaling pathway and blockade of the P2X7R-NLRP3 inflammasome axis. In comparison, J-1156 demonstrated superior overall therapeutic efficacy to J-1155 in terms of anti-fibrotic efficacy, while J-1155 exhibited superior modulation of Smurf2. Collectively, our observations demonstrate the potential of J-1155 and J-1156 as dual novel therapeutic agents targeting hepatic fibrosis.
研究领域:
药理学
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分子生物学
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肝脏疾病研究
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Translational Research
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2025
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IF 5.9
Junjuan Lu,Caihong Liu,Ting Yuan,Honghui Yang,Li Zhang
Background Chronic obstructive pulmonary disease (COPD) is a chronic respiratory condition primarily caused by inhalation of harmful particles such as tobacco smoke. Cellular senescence serves as a key driver in its pathogenesis. Although endothelial progenitor cells (EPCs) have been shown to alleviate COPD by reducing inflammatory cell infiltration, the role and mechanisms underlying EPC senescence in this disease remain unclear. Methods A cigarette smoke (CS)-exposed COPD mouse model was established. Lung injury was assessed histologically, with concurrent quantification of neutrophil infiltration and cellular senescence levels in lung tissues. Pearson analysis evaluated the correlation between senescence severity and neutrophil numbers. In vivo neutrophil depletion was achieved using anti-Ly6G antibody, while GW4869 was used to inhibit exosome secretion from COPD-derived neutrophils. Neutrophils were then co-cultured with EPCs to assess their impact on EPC senescence and DNA damage. Proteomic analyses were employed to identify mechanisms of neutrophil-derived exosomes in COPD. Results COPD mice exhibited significant lung tissue damage, accelerated cellular senescence, and increased neutrophil infiltration. Senescence severity positively correlated with neutrophil proportion. Mechanistically, thrombospondin-1 (TSP-1) was highly expressed in COPD-derived neutrophils. Knockdown of neutrophil-derived exosomal TSP-1 alleviated EPC senescence. Furthermore, TSP-1 expression was regulated by transcription factor FOS, whereas TGF-β inhibition attenuated the promoting effects of TSP-1 overexpression on cellular senescence and lung injury in COPD mice. Conclusion This study demonstrates that neutrophil-derived exosomal TSP-1 aggravates EPC senescence and lung injury in COPD, revealing the pathogenic role of TSP-1 in disease progression and highlighting its potential as a therapeutic target.
研究领域:
呼吸病学
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细胞生物学
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分子生物学
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免疫学
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BIOCHEMICAL PHARMACOLOGY
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2025
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IF 5.6
Xiaoshen Zhang,Tao Jiang,Lingyun Ye,Jianguo Sun,Lei Wang,Juanjuan Li,Fengying Wu,Shengxiang Ren,Guanghui Gao
Non-small cell lung cancer (NSCLC) accounts for 85% of lung cancer cases, posing a major health burden. Our prior work indicated fibronectin promotes NSCLC angiogenesis and progression by upregulating Wnt-inducible signaling pathway protein 3 (WISP3) and activating Wnt signaling. This study aims to explore WISP3 ′ s role and mechanisms in NSCLC progression. Cells were transfected with a reconstructed plasmid to study gene overexpression/silenced effects. Functional assays were conducted, including tube formation, sphere formation, immunohistochemistry, western blotting, Transwell, and MTT. Mass spectrometry and bioinformatics analysis were used to identify differentially expressed proteins and their associated signaling pathways in NSCLC cells. Additionally, the xenograft tumor model of NSCLC was constructed. High expression of WISP3 in NSCLC is associated with poor prognosis, as it enhances angiogenic and tumorigenic potential in NSCLC cells, further verified in our constructed xenograft tumor experiment. In terms of mechanisms, the activation of the TGF-β signaling pathway, indicated by p-smad2/3 activation, is implicated in the progression of NSCLC promoted by WISP3. Additionally, overexpression of WISP3 leads to increased syntenin binding protein (SDCBP) expression in vitro and in vivo , and WISP3 binding to SDCBP enhances angiogenic and tumorigenic potential in NSCLC, which can be counteracted by silencing SDCBP, indicating their crucial role in NSCLC progression. We offer new insights into WISP3 ′ s role in promoting NSCLC progression, showing it upregulates SDCBP and is involved in TGF-β signaling. The findings contribute to a better understanding of NSCLC biology and suggest potential therapeutic targets for the disease.
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ACTA PHARMACOLOGICA SINICA
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2024
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IF 6.9
Zhao Tong,Zhou Zhi-ruo,Wan Hui-qi,Feng Tian,Hu Xu-hui,Li Xiao-qian,Zhao Shi-mei,Li Hong-lin,Hou Ji-wei,Li Wei,Lu Da-yun,Qian Min-yi,Shen Xu
Pulmonary fibrosis (PF) is a chronic, progressive and irreversible interstitial lung disease characterized by unremitting pulmonary myofibroblasts activation, extracellular matrix (ECM) deposition and inflammatory recruitment. PF has no curable medication yet. In this study we investigated the molecular pathogenesis and potential therapeutic targets of PF and discovered drug lead compounds for PF therapy. A murine PF model was established in mice by intratracheal instillation of bleomycin (BLM, 5 mg/kg). We showed that the protein level of pulmonary protein phosphatase magnesium-dependent 1A (PPM1A, also known as PP2Cα) was significantly downregulated in PF patients and BLM-induced PF mice. We demonstrated that TRIM47 promoted ubiquitination and decreased PPM1A protein in PF progression. By screening the lab in-house compound library, we discovered otilonium bromide (OB, clinically used for treating irritable bowel syndrome) as a PPM1A enzymatic activator with an EC 50 value of 4.23 μM. Treatment with OB (2.5, 5 mg·kg −1 ·d −1 , i.p., for 20 days) significantly ameliorated PF-like pathology in mice. We constructed PF mice with PPM1A-specific knockdown in the lung tissues, and determined that by targeting PPM1A, OB treatment suppressed ECM deposition through TGF-β/SMAD3 pathway in fibroblasts, repressed inflammatory responses through NF-κB/NLRP3 pathway in alveolar epithelial cells, and blunted the crosstalk between inflammation in alveolar epithelial cells and ECM deposition in fibroblasts. Together, our results demonstrate that pulmonary PPM1A activation is a promising therapeutic strategy for PF and highlighted the potential of OB in the treatment of the disease.
研究领域:
药理学
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肺病学
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分子生物学
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治疗学
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PubMed
高影响因子
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