ACTA PHARMACOLOGICA SINICA
·
2026
·
IF 10.4
Yuan Man-man,Zheng Bing-feng,Wang Jing-lin,Xu Shuai-qi,Wang Sheng-lan,Tan Yang,Feng Yong,Dong Xian-chi,Zhu Qi-hua,Yan Jie,Xu Qiang,Wu Xing-xin
Hepatic stellate cells (HSCs) and macrophages are key regulators of liver fibrosis, yet their direct communication during fibrogenesis remains incompletely characterized. We showed that genetic deletion of folate receptor beta ( Folr2 ) significantly attenuated experimental liver fibrosis in mice. In both human and murine fibrotic livers, FOLR2 + macrophages are frequently juxtaposed with activated HSCs. Functionally, FOLR2 expressed by reparative, but not M1 or scar-associated, macrophages promotes HSC activation in a contact-dependent manner. Mechanistically, FOLR2 binds to transforming growth factor beta receptor II (TGFβRII) on HSCs, sustaining transforming growth factor beta 1 (TGF-β1) signaling and driving fibrogenesis. Finally, the natural compound fraxinellone targets FOLR2, disrupts its interaction with TGFβRII, and attenuates HSC activation and liver fibrosis. These findings identify the FOLR2-TGFβRII intercellular interaction as a critical mediator of macrophage-HSC crosstalk and highlight its disruption as a promising therapeutic strategy against liver fibrosis.
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Theranostics
·
2023
·
IF 12.4
Mingrui Xiong,Hong Chen,Yu Fan,Muchuan Jin,Dong Yang,Yuchen Chen,Yu Zhang,Robert B. Petersen,Hua Su,Anlin Peng,Congyi Wang,Ling Zheng,Kun Huang
Rationale: Ischemia-reperfusion injury (I/R) is a common cause of acute kidney injury (AKI). Post-ischemic recovery of renal blood supply plays an important role in attenuating injury. Exogenous application of elabela (ELA) peptides has been demonstrated by us and others to alleviate AKI, partly through its receptor APJ. However, the endogenous role of ELA in renal I/R remains unclear. Methods: Renal tubule specific ELA knockout ( Apela Ksp KO) mice challenged with bilateral or unilateral I/R were used to investigate the role of endogenous ELA in renal I/R. RNA-sequencing analysis was performed to unbiasedly investigate altered genes in kidneys of Apela Ksp KO mice. Injured mice were treated with ELA32 peptide, Nω-hydroxy-nor-L-arginine (nor-NOHA), prostaglandin E2 (PGE2), Paricalcitol, ML221 or respective vehicles, individually or in combination. Results: ELA is mostly expressed in renal tubules. Aggravated pathological injury and further reduction of renal microvascular blood flow were observed in Apela Ksp KO mice during AKI and the following transition to chronic kidney disease (AKI-CKD). RNA-seq analysis suggested that two blood flow regulators, arginine metabolizing enzyme arginase 2 (ARG2) and PGE2 metabolizing enzyme carbonyl reductases 1 and 3 (CBR1/3), were altered in injured Apela Ksp KO mice. Notably, combination application of an ARG2 inhibitor nor-NOHA, and Paricalcitol, a clinically used activator for PGE2 synthesis, alleviated injury-induced AKI/AKI-CKD stages and eliminated the worst outcomes observed in Apela Ksp KO mice. Moreover, while the APJ inhibitor ML221 blocked the beneficial effects of ELA32 peptide on AKI, it showed no effect on combination treatment of nor-NOHA and Paricalcitol. Conclusions: An endogenous tubular ELA-APJ axis regulates renal microvascular blood flow that plays a pivotal role in I/R-induced AKI. Furthermore, improving renal blood flow by inhibiting ARG2 and activating PGE2 is an effective treatment for AKI and prevents the subsequent AKI-CKD transition.
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PHYTOMEDICINE
·
2023
·
IF 7.9
Qi-Rui Hu,Qing-Xin Huang,Huan Hong,Yao Pan,Ting Luo,Jing Li,Ze-Yuan Deng,Fang Chen
s Background Liver cancer is a topical global health issue. The treatment of liver cancer meets significant challenges in the high recurrence rate and invasive incidence. Therefore, the treatment strategies that target epithelial-mesenchymal transition (EMT) induced by cyclooxygenase 2 (COX2)/ prostaglandin E2 (PGE2) pathway have become epidemic. Ginsenoside Rh2 has been proved to inhibit the EMT. However, the underlying mechanisms remain unclear. Moreover, the octyl ester derivative of Rh2 (Rh2-O) exhibited superior anti-proliferative and immunomodulatory effects than Rh2 in our previous researches, which indicated that Rh2-O might also exert inhibitory effects on invasion and metastasis . Purpose The aim of current study is to explore the inhibitory effects of Rh2 and Rh2-O on invasion and metastasis of hepatocellular carcinoma , and to investigate whether these effects are dependent on the c-Jun/COX2/PGE2 pathway. Study Design The Huh-7 liver cancer cells and the H22 tumor-bearing mice were treated with Rh2 and Rh2-O. Method In this paper, the inhibitory effects of Rh2 and Rh2-O on invasion and metastasis were tested by wound healing, trans-well assay and tumor-bearing mice, and the involvement of c-Jun/COX2/PGE2 pathway were verified by exogenous PGE2, activation of COX2 and overexpression of c-Jun. Results The results showed that Rh2 and Rh2-O could efficiently inhibit the invasion and metastasis in a dose-dependent manner ( p < 0.05). And the Rh2-O showed stronger effects than Rh2. Moreover, the exogenous PGE2, activation of COX2 by exogenous LPS and the overexpression of c-Jun by transfection all reversed the inhibitory effects of Rh2 and Rh2-O on metastasis or EMT ( p < 0.05). Conclusion Rh2 and Rh2-O could inhibit the invasion and metastasis of hepatocellular carcinoma via restraining the EMT, which was mediated by c-Jun/COX2/PGE2 pathway.
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Bioactive Materials
·
2021
·
IF 14.593
Yongzhi Cui,Yuanyuan Guo,Li Kong,Jingyu Shi,Ping Liu,Rui Li,Yongtao Geng,Weihang Gao,Zhiping Zhang,Dehao Fu
The complex pathogenesis of osteoporosis includes excessive bone resorption, insufficient bone formation and inadequate vascularization, a combination which is difficult to completely address with conventional therapies. Engineered exosomes carrying curative molecules show promise as alternative osteoporosis therapies, but depend on specifically-functionalized vesicles and appropriate engineering strategies. Here, we developed an exosome delivery system based on exosomes secreted by mesenchymal stem cells (MSCs) derived from human induced pluripotent stem cells (iPSCs). The engineered exosomes BT-Exo-si Shn3 , took advantage of the intrinsic anti-osteoporosis function of these special MSC-derived exosomes and collaborated with the loaded siRNA of the Shn3 gene to enhance the therapeutic effects. Modification of a bone-targeting peptide endowed the BT-Exo-si Shn3 an ability to deliver siRNA to osteoblasts specifically. Silencing of the osteoblastic Shn3 gene enhanced osteogenic differentiation, decreased autologous RANKL expression and thereby inhibited osteoclast formation. Furthermore, Shn3 gene silencing increased production of SLIT3 and consequently facilitated vascularization, especially formation of type H vessels. Our study demonstrated that BT-Exo-si Shn3 could serve as a promising therapy to kill three birds with one stone and implement comprehensive anti-osteoporosis effects.
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Cancer Communications
·
2024
·
IF 20.1
Jian Xiao,Shuqing Cao,Jiawei Wang,Pengyu Li,Quan Cheng,Xinyi Zhou,Jiacheng Dong,Yuan Li,Xinyu Zhao,Zekuan Xu,Li Yang
Background Lymph node metastasis (LNM) is the primary mode of metastasis in gastric cancer (GC). However, the precise mechanisms underlying this process remain elusive. Tumor cells necessitate lipid metabolic reprogramming to facilitate metastasis, yet the role of lipoprotein lipase (LPL), a pivotal enzyme involved in exogenous lipid uptake, remains uncertain in tumor metastasis. Therefore, the aim of this study was to investigate the presence of lipid metabolic reprogramming during LNM of GC as well as the role of LPL in this process. Methods Intracellular lipid levels were quantified using oil red O staining, BODIPY 493/503 staining, and flow cytometry. Lipidomics analysis was employed to identify alterations in intracellular lipid composition following LPL knockdown. Protein expression levels were assessed through immunohistochemistry, Western blotting, and enzyme-linked immunosorbent assays. The mouse popliteal LNM model was utilized to investigate differences in LNM. Immunoprecipitation and mass spectrometry were employed to examine protein associations. In vitro phosphorylation assays and Phos-tag sodium dodecyl-sulfate polyacrylamide gel electrophoresis assays were conducted to detect angiopoietin-like protein 4 (ANGPTL4) phosphorylation. Results We identified that an elevated intracellular lipid level represents a crucial characteristic of node-positive (N+) GC and further demonstrated that a high-fat diet can expedite LNM. LPL was found to be significantly overexpressed in N+ GC tissues and shown to facilitate LNM by mediating dietary lipid uptake within GC cells. Leptin, an obesity-related hormone, intercepted the effect exerted by ANGPTL4/Furin on LPL cleavage. Circulating leptin binding to the leptin receptor could induce the activation of inositol-requiring enzyme-1 (IRE1) kinase, leading to the phosphorylation of ANGPTL4 at the serine 30 residue and subsequently reducing its binding affinity with LPL. Moreover, our research revealed that LPL disrupted lipid homeostasis by elevating intracellular levels of arachidonic acid, which then triggered the cyclooxygenase-2/prostaglandin E2 (PGE2) pathway, thereby promoting tumor lymphangiogenesis. Conclusions Leptin-induced phosphorylation of ANGPTL4 facilitates LPL-mediated lipid uptake and consequently stimulates the production of PGE2, ultimately facilitating LNM in GC.
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高影响因子
Cells
·
2021
·Vol. 10
·期 2
·237
·
IF 6.6
Guobin Li,Lan Zhang,Kaiting Ning,Baoqiang Yang,Francisca M. Acosta,Peng Shang,Jean X. Jiang,Huiyun Xu
Bone–muscle crosstalk plays an important role in skeletal biomechanical function, the progression of numerous pathological conditions, and the modulation of local and distant cellular environments. Previous work has revealed that the deletion of connexin (Cx) 43 in osteoblasts, and consequently, osteocytes, indirectly compromises skeletal muscle formation and function. However, the respective roles of Cx43-formed gap junction channels (GJs) and hemichannels (HCs) in the bone–muscle crosstalk are poorly understood. To this end, we used two Cx43 osteocyte-specific transgenic mouse models expressing dominant negative mutants, Δ130–136 (GJs and HCs functions are inhibited), and R76W (only GJs function is blocked), to determine the effect of these two types of Cx43 channels on neighboring skeletal muscle. Blockage of osteocyte Cx43 GJs and HCs in Δ130–136 mice decreased fast-twitch muscle mass with reduced muscle protein synthesis and increased muscle protein degradation. Both R76W and Δ130–136 mice exhibited decreased muscle contractile force accompanied by a fast-to-slow fiber transition in typically fast-twitch muscles. In vitro results further showed that myotube formation of C2C12 myoblasts was inhibited after treatment with the primary osteocyte conditioned media (PO CM) from R76W and Δ130–136 mice. Additionally, prostaglandin E2 (PGE2) level was significantly reduced in both the circulation and PO CM of the transgenic mice. Interestingly, the injection of PGE2 to the transgenic mice rescued fast-twitch muscle mass and function; however, this had little effect on protein synthesis and degradation. These findings indicate a channel-specific response: inhibition of osteocytic Cx43 HCs decreases fast-twitch skeletal muscle mass alongside reduced protein synthesis and increased protein degradation. In contrast, blockage of Cx43 GJs results in decreased fast-twitch skeletal muscle contractile force and myogenesis, with PGE2 partially accounting for the measured differences.Keywords:osteocytes;Cx43;gap junctions;hemichannels;bone–muscle crosstalk
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JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH
·
2025
·Vol. 44
·期 1
·321
·
IF 12.8
Lei Yu,Bai Yaowei,Bai Xiatong,Sun Bo,Zhu Licheng,Wu Wenlong,Su Yang,Zhang Hongsen,Wang Yingliang,Zheng Chuansheng
Background and aims Radiofrequency ablation (RFA) is an effective treatment for hepatocellular carcinoma (HCC), but incomplete ablation and recurrence of residual tumors remain significant challenges, partly due to local inflammation and elevated COX-2 levels in the tumor microenvironment. This study aims to investigate the potential of combining celecoxib, a COX-2 inhibitor, with anti-PD-1 monoclonal antibody (αPD-1) to enhance anti-tumor efficacy and activate immune responses. Methods In vitro, ELISA was used to assess the effects of radiofrequency heat treatment and celecoxib on PGE 2 secretion by Hepa1-6 cells. Scanning electron microscopy, flow cytometry, and CCK-8 assays were employed to evaluate the function and cytotoxic activity of NK92 cells against Hepa1-6 cells. In vivo, orthotopic HCC mice were divided into five groups to evaluate tumor volume, pathology, and survival. The role of celecoxib in the COX-2/PGE 2 /NK cell axis and its impact on NK cell immune function were investigated. Results In vitro experiments showed that celecoxib reversed PGE 2 -mediated suppression of NK cell function and cytotoxic activity against HCC cells by inhibiting PGE 2 secretion. In vivo, orthotopic HCC mice treated with celecoxib and αPD-1 exhibited significantly reduced tumor volumes, attenuated the infiltration and activation of NK cells, and prolonged survival compared to control groups. The combination therapy also demonstrated a notable abscopal-like effect, inhibiting metastatic tumor growth and activating systemic immunity. Conclusions Taken together, these findings suggest that celecoxib combined with αPD-1 represents a promising strategy for treating residual HCC after RFA, with enhanced anti-tumor effects and good safety. Graphical abstract
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