Cell Communication and Signaling
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2024
·Vol. 22
·期 1
·1-21
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IF 8.2
Wu Chengyan,Hu Li,Liu Bing,Zeng Xingyue,Ma Haixiang,Cao Yongkai,Li Huijun,Zhang Xiaohan
Background Desensitization of G protein–coupled receptors (GPCRs) refers to the attenuation of receptor responsiveness by prolonged or intermittent exposure to agonists. The binding of β-arrestin to the cytoplasmic cavity of the phosphorylated receptor, which competes with the G protein, has been widely accepted as an extensive model for explaining GPCRs desensitization. However, studies on various GPCRs, including dopamine D 2 -like receptors (D 2 R, D 3 R, D 4 R), have suggested the existence of other desensitization mechanisms. The present study employed D 2 R/D 3 R variants with different desensitization properties and utilized loss-of-function approaches to uncover the mechanisms underlying GPCRs homologous desensitization, focusing on the signaling cascade that regulates the ubiquitination of AKT. Results AKT undergoes K8/14 ubiquitination by TRAF6, which occurs in the nucleus and promotes its membrane recruitment, phosphorylation and activation under receptor desensitization conditions. The nuclear entry of TRAF6 relies on the presence of the importin complex. Src regulates the nuclear entry of TRAF6 by mediating the interaction between TRAF6 and importin β1. Ubiquitinated AKT translocates to the plasma membrane where it associates with Mdm2 to phosphorylate it at the S166 and S186 residues. Thereafter, phosphorylated Mdm2 is recruited to the nucleus, resulting in the deubiquitination of β-Arr2. The deubiquitinated β-Arr2 then forms a complex with Gβγ, which serves as a biomarker for GPCRs desensitization. Like in D 3 R, ubiquitination of AKT is also involved in the desensitization of β 2 adrenoceptors. Conclusion Our study proposed that the property of a receptor that causes a change in the subcellular localization of TRAF6 from the cytoplasm to the nucleus to mediate AKT ubiquitination could initiate the desensitization of GPCRs.
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JOURNAL OF NANOBIOTECHNOLOGY
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2025
·
IF 12.6
Zhuoting Lu,Tong Wang,Xiangchi Xu,Qinglian Hu,Lei Wang,Yuanxiang Jin
A key challenge in clinical anticancer treatments is metastasis and recurrence, to address this challenge, it is crucial to develop combination treatment strategies that target different molecular pathways, considering the high complexity of tumors, as well as to create efficient drug delivery systems that enhance therapeutic efficacy and minimize systemic toxicity. Herein, two clinical small molecular drugs indocyanine green (ICG) and paclitaxel (PTX) were self-assembled into relatively stable, carrier-free nanoparticles (IP NPs) through a simple one-step nanoprecipitation method. The spherical IP NPs demonstrate excellent aqueous stability, tumor-targeted accumulation, and potent apoptosis induction. Combined with AKT inhibitor MK-2206, they effectively modulate survival pathways, suppress metastasis, and prevent tumor recurrence in rechallenge models. This synergistic approach achieves equivalent therapeutic efficacy at reduced doses, enhancing treatment safety. Encouraged by its effective therapy and sensitivity-enhancing properties, this study might show significant potential for malignant tumor synergistic therapy. Carrier-free nano-integrated strategy for combination therapy
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Regenerative Biomaterials
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2025
·
IF 8.1
Wen Zhuohao,Li Shuyi,Qiu Huiguo,Liu Xueyan,You Zhiying,Yan Yuhan,Che Yuejuan,Zhou Miao
Periosteum plays an indispensable role in bone regeneration by providing osteogenic and angiogenic cues essential for tissue repair. In cases of severe bone defects or nonunion, autologous vascularized periosteum transplantation remains a highly effective clinical solution. However, its application is restricted by donor site morbidity and limited tissue availability, thereby underscoring the urgent need for artificial periosteum that mimics both the composition and structure of the native counterpart. Among these properties, the topological morphology of the periosteum is believed to be critical, yet its influence on bone regeneration remains insufficiently understood. In this study, biomimetic periosteum membranes composed of coaxially electrospun poly(ε-caprolactone) (PCL) and periosteal extracellular matrix (pECM) were fabricated with either random or aligned nanofiber architectures. Their osteogenic potential was systematically evaluated in vitro and in vivo. Compared to the randomly arranged structure, aligned pECM (aPEC) significantly enhanced the adhesion, alignment, and osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs) by activating the ITGB1/PI3K/AKT signaling pathway, whereas these effects were not observed in pure PCL membranes. These findings demonstrate that aligned topological morphology in biomimetic periosteum plays a pivotal role in directing stem cell behavior and promoting bone regeneration. This work provides mechanistic insight and technical guidance for the future design of functionally enhanced artificial periosteum for bone tissue engineering applications.
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CHEMICAL ENGINEERING JOURNAL
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2025
·
IF 13.2
Siyu Zhao,Yue Li,Lin Dai,Bo Cheng
The development of artificial biomaterials that simulate the extracellular matrix of bone tissue is a promising strategy for bone regeneration. Hydrogel has become a feasible alternative, yet its lack of biological activity still needs to be improved. Herein, a piezoelectric composite hydrogel (TBP) based on tripolyglycerol monostearate (TM) and loaded with barium titanate (BTO) nanoparticles through hydrogen bonding provided by polydopamine has been developed to promote osteogenesis. In vitro , TBP exhibits excellent injectability, shape adaptability and biodegradability, ensuring the feasibility of its biological applications. Moreover, by virtue of the piezoelectric conversion capability of BTO, TBP has the response ability to low-intensity pulsed ultrasound (LIPUS) and can generate local electrical signals. Meanwhile, TBP performs outstandingly in promoting the proliferation, migration, adhesion and osteogenic differentiation of MC-3 T3-E1 cells. More importantly, TBP combined with LIPUS stimulation can regulate mitochondrial oxidative phosphorylation (OXPHOS) through the AKT/GSK3β/β-catenin signaling cascade, thereby accelerating osteogenesis. In vivo , the application of TBP hydrogel to the bone defect site of rats, combined with LIPUS stimulation, shows satisfactory effects in promoting bone regeneration. To sum up, this piezoelectric composite hydrogel is expected to become a promising candidate for bone tissue engineering.
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JOURNAL OF BIOLOGICAL CHEMISTRY
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2025
·
IF 3.9
Yijun Yang,Nengyi Wang,Yuankun Chen,Tianpeng Ma,Minhua Weng,Haifeng Wu,Qiuping Wu,Yiqiang Xie,Chuanwu Zhu,Wenting Li
Nonalcoholic fatty liver disease (NAFLD) has posed a huge threat to public health globally, but there are currently no approved drugs available. Growing evidence has proved the close association between increased Th17 cells and NAFLD progression. Interleukin-4 induced protein 1 (IL4I1), an amino acid oxidase secreted by immune cells, was reported to regulate the Th17 cells, but its exact role in NAFLD progression has not been fully explained yet. We found that IL4I1 was highly expressed in the liver of C57BL/6J mice with NAFLD induced by an 8-weeks western diet. To explore the IL4I1’s effect, mice were injected with AAV8 encoding IL4I1 1 week before western diet administration. The results showed that IL4I1 overexpression inhibited the NAFLD progression, demonstrated by relieved liver damage and lipid accumulation. The underlying mechanism in which IL4I1 acts on NAFLD might be attributed to the inactivated AKT/forkhead box protein O1 (FOXO1) signaling pathway–mediated decrease of Th17 cells in liver tissues. Subsequently, by culturing naive CD4 + T cells isolated from the spleen of mice in Th17 cell-polarizing conditions, we determined that IL4I1 overexpression inhibited Th17 cell differentiation by inactivating the AKT/FOXO1 pathway, whereas its knockdown exhibited opposite effects. Further, the AKT activator SC79 reversed the effect of IL4I1 overexpression on Th17 cell differentiation. Collectively, our study supports that compensatory upregulation of IL4I1 protects against liver damage and lipid accumulation in NAFLD progression, partially by inhibiting the activated AKT/FOXO1 signaling pathway-induced Th17 cell differentiation.
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Frontiers in Microbiology
·
2025
·
IF 4.5
Wencheng Liu,Yanbin Cheng,Xue Han,Junlin Xia,Qingyu Wei,Bing Chang,Quansheng Li
Introduction: Hepatic sinusoidal obstruction syndrome (HSOS) is a vascular liver disease with a high mortality rate, and treatment methods are limited. Rivaroxaban is an oral anticoagulant. This study aimed to investigate the pharmacological effect and potential mechanism of rivaroxaban on HSOS.Methods: In this study, we induced an HSOS mouse model in male C57BL/6J mice by administering monocrotaline orally. The mice were randomly divided into four groups: the control group, the rivaroxaban (RIV) group, the monocrotaline (MCT) group, and the monocrotaline + rivaroxaban (MCT + RIV) group. Liver function and histopathology were evaluated. 16S rDNA sequencing of the small intestinal contents, transcriptomic sequencing of small intestine tissues, real-time qPCR, Western blot analysis of liver tissues, and correlation analysis were conducted. Antibiotic (ABX) treatment and fecal microbiota transplantation (FMT) experiments were also performed to explore the role of the gut microbiota.Results: Compared with the MCT group, rivaroxaban alleviated serum biochemical liver function analysis and liver histopathology in the MCT + RIV group. Additionally, 16S rDNA sequencing of the small intestinal contents revealed that, compared with the MCT group, the MCT + RIV group presented increased relative abundances of Allobaculum and Pediococcus but decreased relative abundances of Streptococcus, Staphylococcus, and Candidatus Arthromitus. Mechanistically, integrated analyses, including transcriptomic sequencing of small intestin e tissues, real-time qPCR, Western blot analysis of liver tissues, and correlation analysis, demonstrated that rivaroxaban protected against MCT-HSOS by inhibiting the PI3K/Akt signaling pathway. In addition, antimicrobial cocktail (ABX) treatment eliminated the beneficial effects of rivaroxaban on liver function and histopathological injury, whereas fecal microbiota transplantation (FMT) from rivaroxaban-treated donors significantly ameliorated liver dysfunction and histological damage in MCT-HSOS mice.Discussion: These findings suggest that rivaroxaban alleviates hepatic sinusoidal obstruction syndrome in mice by modulating the gut microbiota and inhibiting the PI3K/Akt signaling pathway. Rivaroxaban may be a promising therapeutic option for treating HSOS.
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Bioactive Materials
·
2025
·
IF 20.3
Jieying Liu,Fuze Liu,Cairong Li,Zhengyao Li,Tianle Li,Yuanhao Wu,Di Wu,Yue Huang,Hui Chen,Hai Wang,Yuxiao Lai,Zhihong Wu
Background Iron oxide nanoparticles (IONPs)-based bone scaffolds have attracted increasing attention because of their potential to enhance osteogenesis and angiogenesis. However, the underlying mechanisms remain incompletely understood. Methods We fabricated a biocompatible bone scaffold by incorporating γ-Fe 2 O 3 magnetic nanoparticles into a PLGA matrix using 3D printing technology. The biosafety and effectiveness of the scaffold was validated through in vitro cell assays and in vivo implantation studies. To evaluate osteogenesis and neovascularization, we employed micro-CT imaging with a vascular contrast agent. In-depth mechanistic investigations were conducted via label-free proteomic profiling and pathway enrichment analysis. Results The PLGA/Fe 2 O 3 scaffolds demonstrated excellent biocompatibility and promoted both bone formation and angiogenesis in vitro and in vivo . Micro-CT analysis revealed enhanced new bone and vessel formation in the presence of magnetic scaffolds. Proteomic analysis revealed that alpha-B crystallin (CRYAB) is a key regulatory protein upregulated under a static magnetic field, thereby activating the PI3K/AKT signaling cascade and promoting osteogenic differentiation. In endothelial cells, we observed the upregulation of nuclear NF-κB and HIF-1α, leading to VEGF expression and angiogenic activation. Conclusion Our findings provide direct evidence that 3D-printed PLGA/Fe 2 O 3 scaffolds promote osteogenesis and angiogenesis both in vitro and in vivo . Importantly, we report for the first time that CRYAB-mediated stabilization of β-catenin plays a central role in magnetic scaffold-induced bone regeneration, offering new insights into the design of functional bone substitutes.
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Food Bioscience
·
2024
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IF 4.8
Jindan Xiao,Liuming Xie,Bing Zheng,Wenjie Ma,Yi Chen,Jianhua Xie,Xiaobo Hu,Qiang Yu
Autophagy is pivotal for the management of intestinal homeostasis, modulation of intestinal immunity response and anti-microbial protection. Previous studies have documented the protective function of Polygonatum cyrtonema Saponin (PCS) against intestinal injury, but whether PCS modulated autophagy and its associated responses remained unknown. A model of dextran sodium sulfate (DSS)- elicited intestinal injury was employed to confirm this hypothesis. The results showed that PCS effectively relieved the typical symptoms of DSS-induced weight reduction, shortened colon length, and augmented disease activity index score, down-regulated organ indices, reduced hepatic oxidative stress, and inhibited excessive inflammatory mediators. Meanwhile, PCS intervention ameliorated the intestinal barrier dysfunction via promoting the differentiation of goblet cells and augmenting the expression of tight junction proteins (TJs). It also suppressed apoptosis in intestinal cells by altering the Bcl-2/Bax ratios and diminishing the expressions of Caspase-9 and Caspase-3. Additionally, PCS remarkably enhanced autophagy by modulating the PI3K/AKT/mTOR signal pathway. More importantly, the classical autophagy inducer rapamycin augmented the beneficial effects of PCS. In contrast, the autophagy inhibitor 3-methyladenine essentially eliminated the above effects, revealing a role for autophagy in the response. Further studies have demonstrated that PCS intervention improved the diversities of the intestinal flora, increased occupancy of beneficial bacteria in Lachnospiraceaeae and Akkermansia , which was closely associated with autophagy. Taken together, these findings demonstrated that PCS is a potential supplier of prebiotics by modulating immunity, repairing intestinal mucosal injury, regulating autophagy and intestinal flora, and autophagy is a key target for PCS-mediated intestinal barrier protection.
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JOURNAL OF NUTRITIONAL BIOCHEMISTRY
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2024
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IF 4.8
Suizhi Cheng,Jin Chen,Qianhui Li,Yuhong Nie,Ting Ni,Caiting Peng,Xi Luo,Yasin Pazilat,Shumin Zhang,Jiancai Tang,Zhenzhong Liu
Recent research has revealed that N-methyl-N′-nitro-N-nitrosoguanidine (MNNG) constitutes a significant risk factor in the development of esophageal cancer. Several investigations have elucidated the beneficial impact of folic acid (FA) in safeguarding esophageal epithelial cells against MNNG-induced damage. Therefore, we hypothesized that FA might prevent MNNG-induced proliferation of esophageal epithelial cells by interfering with the PI3K/AKT/mTOR signaling pathway. In vivo experiments, we found that FA antagonized MNNG-induced proliferation of rat esophageal mucosal epithelial echinocytes and activation of the PI3K/AKT/mTOR signaling pathway. In our in vitro experiments, it was observed that acute exposure to MNNG for 24 h led to a decrease in proliferative capacity and inhibition of the PI3K/AKT/mTOR signaling pathway in an immortalized human normal esophageal epithelial cell line (Het-1A), which was also ameliorated by supplementation with FA. We successfully established a Het-1A-T-cell line by inducing malignant transformation in Het-1A cells through exposure to MNNG. Notably, the PI3K/AKT2/mTOR pathway showed early suppression followed by activation during this transition. Next, we observed that FA inhibited cell proliferation and activation of the PI3K/AKT2/mTOR signaling pathway in Het-1A-T malignantly transformed cells. We further investigated the impact of 740Y-P, a PI3K agonist, and LY294002, a PI3K inhibitor, on Het-1A-T-cell proliferation. Overall, our findings show that FA supplementation may be beneficial in safeguarding normal esophageal epithelial cell proliferation and avoiding the development of esophageal cancer by decreasing the activation of the MNNG-induced PI3K/AKT2/mTOR signaling pathway.
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IN VITRO CELLULAR & DEVELOPMENTAL BIOLOGY-ANIMAL
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2025
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IF 1.7
Sun Jingchi,Zheng Zhousong
Activated microglia are considered to be closely related to brain senescence and the pathogenesis of neurodegenerative diseases. Ginkgo biloba extract (GBE) is widely used to treat cognitive impairment and Alzheimer's disease (AD). This study aims to investigate the active ingredients of GBE and the underlying molecular mechanisms. The active ingredients of GBE in AD treatment were first analyzed by network pharmacology, culminating in the identification of the key ingredient, quercetin, and its targeted protein, NQO1. GO function enriched the oxidative stress pathway, while KEGG enriched the PI3K/Akt/mTOR pathway. Quercetin binding to NQO1 was verified by molecular docking and DARTS analysis. Cytotoxicity assay revealed no significant toxicity of GBE (0–1 mg/mL) and quercetin (0–0.4 μM) over 48 h. Subsequently, we constructed the microglial injury model by H 2 O 2 -induced HMC3 and BV2 cell lines. GBE and quercetin suppressed the senescence characteristics in H 2 O 2 -induced microglia. Further investigation revealed that the expression of NQO1 was downregulated in the injury model, and treatment with GBE and quercetin facilitated the protein expression of NQO1. In addition, silencing NQO1 reduced the promoting effect of quercetin on microglia viability and phosphorylation levels of PI3K, Akt, and mTOR. At the same time, it significantly increased the levels of p53, p21, p16 and β-galactosidase (SA-β-gal). Collectively, GBE mitigated H 2 O 2 -induced microglial injury, which activated the PI3K/Akt/mTOR pathway through the quercetin/NQO1 axis. These findings highlight quercetin/NQO1 signaling as a possible therapeutic target for senescence-related neurodegeneration.
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JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY
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2025
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IF 6.2
Xinyuan Wu,Dan Su,Jiaxin Xu,Ge Ge,Yongzhen Zhang,Bingjian Wu,Kun Hu,Jie Ren,Hao Yang
Alzheimer’s disease (AD), the most prevalent neurodegenerative disorder among older adults, significantly impairs behavioral and cognitive functions, posing a severe threat to patients’ health and quality of life. The Tricetin (TRN), a natural flavonoid found in wheat, pomegranate, and eucalyptus honey, has demonstrated anti-inflammatory, antitumor, and neuroprotective properties. However, its role in the context of AD has not been previously explored. This study investigated the antineuroinflammatory and autophagic protective effects of TRN in lipopolysaccharide (LPS)-induced BV2 cells and D-galactose/sodium nitrite/aluminum chloride (D-gal/NaNO2/AlCl3)-induced AD mice. The RNA sequencing examined the underlying mechanisms by which TRN ameliorates AD-related pathologies. Our research findings revealed that TRN significantly improved memory and mobility in AD mice, reduced Aβ deposition, and inhibited Tau protein phosphorylation. Furthermore, TRN regulated enzyme activities and reduced pathological markers associated with AD. Moreover, it modulated inflammatory mediators, inhibited the nuclear translocation of NF-κB in LPS-induced BV2 cells, and exerted anti-inflammatory and autophagic protective effects via the PI3K/Akt/mTOR signaling pathway. In conclusion, TRN demonstrated robust neuroprotective effects in vitro and in vivo AD models by regulating the PI3K/Akt/mTOR signaling pathway. These findings highlight its potential as a promising therapeutic agent for treating AD.
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JOURNAL OF NEUROSCIENCE RESEARCH
·
2025
·Vol. 103
·期 7
·e70064
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IF 3.4
Sun Hong,Liu GuoYan,Wu JiaWen,Yu Xin,Zhan ShuQin,Reng HongWei,Chen MengYing,Cheng YuXuan
Chronic epilepsy is mainly characterized by spontaneous recurrent seizures (SRS). The peroxisome proliferator activated receptor gamma/phosphatase and tensin homolog/protein kinase B (PPARγ/PTEN/Akt) pathway is involved in the pathogenesis of SRS and neuronal loss. Curcumin is a natural compound, and previous studies have shown it provides neuroprotection via anti-inflammation and anti-oxidant effects in many central nervous system (CNS) diseases. In the present study, we show that curcumin regulates the abnormal expression of PTEN and Akt in the SRS phase, improves the neuronal loss in the hippocampus, and suppresses SRS development and seizure spike activity in epileptic rats. More importantly, these effects are reversed by the PPARγ antagonist, T0070907, suggesting that curcumin exerts neuroprotective and anti-epileptic effects through the PPARγ/PTEN/Akt signaling pathway. Other studies have shown that curcumin can cross the BBB and has a safety profiles and pleiotropic pharmacological effects. Thus, our data support the proposition that curcumin might be a potential neuroprotective and anti-epileptic agent for chronic epilepsy.
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