INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2024
·
IF 7.7
Yadan Zhang,Xiaoyu Zhang,Tianhan Kai,Lin Zhang,Anping Li
Plant-derived exosome-like nanovesicles (ELNs) are nano-sized vesicles extracted from edible plants. Lycium ruthenicum Murray (LRM) has been gaining increasing attention due to its nutritional and medicinal value, but the ELNs in LRM has not been reported. In this study, LRM-ELNs were obtained, and the proteins, lipids, microRNAs (miRNAs) and active components in LRM tissues and LRM-ELNs was analyzed by LC-MS/MS, LC-MS, high-throughput sequencing techniques, and physical and chemical analysis. LRM-ELNs can be uptaken by PC12 cells through macropinocytosis and caveolin-mediated endocytosis primarily. Transcriptomic and western blot experiments indicate that LRM-ELNs can inhibit Aβ-induced apoptosis in PC12 cells through the MAPK and PI3K/AKT signaling pathways, with miRNAs playing a crucial role. These results indicate that LRM-ELNs have the protection effect on PC12 cells and can be considered as dietary supplements for alleviating neurodegenerative diseases.
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Biomaterials Advances
·
2024
·
IF 5.5
Longbiao Wan,Feng Liu,Ao Wang,Yan He,Jiali Pan,Liu Ye,Xu Jie,Chun Xu,Wu Fei,Qingsong Ye
Tissue engineering (TE) is commonly suggested as a promising remedy for the worldwide shortage of organ donors required for transplantation. Scholars are investigating organic and biocompatible materials as the principal options for regeneration to replicate the natural extracellular matrix. Hydrogels exhibit swift gel formation and outstanding biocompatibility, thus presenting considerable promise in tissue regeneration. The objective of this study was to investigate the role of a novel biomaterial complex, comprising gelatin (Gel), hyaluronic acid (HA) and exosomes (Exo), in promoting bone regeneration and elucidate its underlying molecular mechanism. The experimental results demonstrated that the Gel/HA/Exo complex could significantly enhance the proliferation and differentiation of osteoblasts, as well as the deposition and mineralization of bone matrix. Further mechanistic studies demonstrated that TGF-β in exosomes enhanced the biological activity of osteoblasts by activating the PI3K/Akt pathway, thus promoting the fracture healing process. The results of in vivo experiments indicated that the application of Gel/HA/Exo complexes significantly accelerated the fracture healing rate and improved the quality of healing, exhibiting good biocompatibility and controlled degradation properties. Consequently, the present study concluded that the Gel/HA/Exo complex not only has potential clinical applications, but also provides an important theoretical and experimental basis for the development of novel bone regeneration therapeutic strategies.
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Frontiers in Microbiology
·
2025
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IF 4.5
Lin Lin,Siyuan Li,Que Liu,Xingxing Zhang,Ying Xiong,Shaoyun Zhao,Liyue Cao,Jiaxuan Gong,Yaping Liu,Rong Wu
Objective: This study aimed to investigate the potential relation between the retarded growth of skeletal muscle (SM) and dysbiosis of gut microbiota (GM) in children with asthma, and to explore the potential action mechanisms of traditional pediatric massage (TPM) from the perspective of regulating GM and short-chain fatty acids (SCFAs) production by using an adolescent rat model of asthma.Methods: Male Sprague-Dawley rats aged 3weeks were divided randomly into the 5 groups (n=6~7) of control, ovalbumin (OVA), OVA + TPM, OVA + methylprednisolone sodium succinate (MP) and OVA + SCFAs. Pulmonary function (PF) was detected by whole body plethysmograph, including enhanced pause and minute ventilation. Airway allergic inflammation (AAI) status was assessed by concentrations of OVA-specific immunoglobulin E in plasma, interleukin (IL)-4 and IL-1β in bronchoalveolar lavage fluid via ELISA assay. SM mass was assessed by using cross-sectional areas of diaphragm muscle and gastrocnemius via hematoxylin and eosin staining. GM and SCFAs production were detected by 16S rDNA sequencing and GC-MS, respectively. The protein and gene expressions of free fatty acid receptor 2 in SM were detected by using immunohistochemical staining and qRT-PCR, respectively. qRT-PCR was used to detect other relative gene expressions that were closely related with SM mass. The activity of insulin-like growth factor-1 (IGF-1)/protein kinase B (PKB/AKT) pathway in SM was detected by western blotting test.Results: OVA exposure caused obvious AAI and poor PF in adolescent rats. OVA-exposed adolescent rats had a retarded growth of SM mass and inhibited activity of IGF-1/AKT pathway, which was related with GM dysbiosis, reduced SCFAs production and FFAR2 expressions in SM. TPM efficiently enhanced the SM mass, along with alleviating AAI and improving PF. TPM activated IGF-1/AKT pathway in SM, which was closely related with correcting GM dysbiosis, enhanced SCFAs production and FFAR2 expressions.Conclusion: The retarded growth of SM mass and inhibition of IGF-1/AKT pathway existed in OVA-exposed adolescent rats, which was related with GM dysbiosis, reduced SCFAs production and FFAR2 expressions in SM. TPM efficiently enhanced the SM mass, at least, partially via regulating GM, enhancing SCFAs production and activating FFAR2-IGF-1/AKT pathway.
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Journal of Taibah University for Science
·
2024
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IF 2.8
Lingyu Wang,Ruolan Li,Meiyan Li,Jiayi Sun,Jia Liu,Min Xie,Yunhui Chen,Songqi Tang
This study aimed to investigate the inhibitory effect of Zuojin Pill (ZJP) on KYSE 150 cells and xenograft tumours of the digestive tract cancer – esophageal cancer (EC) and its underlying mechanism. Initially, in vivo research demonstrated that oral administration of ZJP effectively inhibited the growth of EC tumours, and in vitro studies revealed that ZJP suppressed the proliferation, migration, and invasion of cells. Then, network pharmacology prediction identified the core target, active ingredient, and involvement of the PI3K-Akt signalling pathway in ZJP treatment of EC. Cell studies validated that ZJP affected the expression of core targets, and its active ingredients inhibited the proliferation of cells. Additionally, ZJP was shown to induce cell apoptosis, decrease mitochondrial membrane potential, and increase the level of intracellular oxidative stress. Further experimental verifications suggested that the inhibitory effects of ZJP on EC might be attributed to the modulation of PI3 K/Akt signalling pathways.
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FASEB JOURNAL
·
2025
·Vol. 39
·期 14
·e70765
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IF 4.2
Xianbin Zeng,Zhongxiao Cong,Meng Xu,Yujie Ju,Yong Huang,Mingkai Zuo,Bo Cheng,Guiyou Tian,Xiaoping Xiao,Danmei Zhao,Wei Yuan,Huiqiang Lu,Yiyue Zhang,Yan Zhao
The widespread use of veterinary antibiotics in animal husbandry, such as tilmicosin (TIL), poses potential threats to environment pollution and human health. In this study, we conducted acute TIL exposure experiment using zebrafish model to explore the toxicological effects. In the concentration range of 20–80 mg/L, TIL did not affect zebrafish body length development but induced idiopathic scoliosis (IS)-like symptoms accompanied by impaired mobility. IS predominantly occurs in adolescents, while the etiology remains unclear. Further studies showed that the combination of quercetin and luteolin effectively alleviated TIL-induced spinal curvature and motor suppression. To explore the underlying mechanism, we performed network pharmacology analysis and enriched the PI3K-Akt pathway. We validated that the expression of key target genes in the PI3K-Akt pathway were significantly activated after TIL exposure, while quercetin and luteolin treatment effectively inhibited the PI3K-Akt pathway activation. Further experiments revealed that TIL exposure decreased brain neural cell apoptosis, thereby causing an increase in neurocytes, interfering with motor ability, and promoting IS-like vertebral malformations, which were especially noticeable during movement. This study expands our understanding that TIL exposure may be a predisposing factor for IS occurrence and progression, while the combination of quercetin and luteolin combination could protect against IS-like symptom by regulating PI3K-Akt pathway. Graphical The experiments revealed that exposure to tilmicosin (TIL) induces the development of scoliosis-like deformities, which could be effectively alleviated by the quercetin and luteolin combination. Further mechanistic studies found that TIL exposure activates the PI3K-Akt pathway, resulting in reduced apoptosis of brain neurons and increased neural cells, which could be inhibited by quercetin and luteolin. As disturbed brain development is a predisposing factor for scoliosis, the TIL-induced abnormalities in brain neurodevelopment exacerbate the progression of scoliosis-like deformities and dyskinesia.
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BMC Pharmacology & Toxicology
·
2025
·Vol. 26
·期 1
·1-12
·
IF 2.7
Yang Lili,Liu Xiaotian
Section
Background
To evaluate the effects of tyrosine kinase inhibitors (TKIs) Dovitinib, Lapatinib, and Telatinib on angiogenesis in zebrafish, and to explore the regulatory mechanism of PI3K/AKT pathway activator SC79 on these inhibitory effects.
Section
Methods
Transgenic Fli-1:EGFP zebrafish embryos were used to observe the development and morphological changes of intersegmental vessels (ISVs) by fluorescence microscopy. Real-time fluorescence quantitative PCR was employed to detect the expression of angiogenesis-related genes including kdrl, flt1, vegfaa, akt2, and pik3r1. After determining the maximum tolerated concentration (MTC) of each compound, the effects of single-drug treatment and SC79 co-treatment on vascular development and gene expression were observed.
Section
Results
Dovitinib (0.488 µM) and Telatinib (0.031 µM) significantly reduced the number (by 16.9% and 33.8%, respectively, P < 0.001) and length (by 14.9% and 23.3%, respectively, P < 0.001) of complete ISVs, while Lapatinib (1.95 µM) showed no significant inhibitory effect. Gene expression analysis revealed that Dovitinib mainly downregulated flt1 expression ( P < 0.01), whereas Telatinib more broadly downregulated kdrl ( P < 0.05), flt1 ( P < 0.001), and akt2 ( P < 0.01) expression. SC79 (2.44 nM) promoted angiogenesis, increasing ISV number ( P < 0.01) and length ( P < 0.05), while upregulating kdrl (2.03-fold, P < 0.001), flt1 (1.31-fold, P < 0.05), vegfaa (1.45-fold, P < 0.01), akt2 (1.64-fold, P < 0.01), and pik3r1 (1.48-fold, P < 0.05) expression. Co-treatment experiments showed that all three TKIs could counteract SC79’s pro-angiogenic effects to varying degrees, with Telatinib showing the strongest effect. Under SC79 co-treatment conditions, all TKIs significantly downregulated kdrl expression ( P < 0.001), but had differential effects on other genes: Dovitinib mainly downregulated flt1 ( P < 0.05), Lapatinib specifically downregulated vegfaa ( P < 0.01), akt2 ( P < 0.05), and pik3r1 ( P < 0.05), while Telatinib simultaneously downregulated flt1 ( P < 0.01), akt2 ( P < 0.05), and pik3r1 ( P < 0.01).
Section
Conclusions
Dovitinib and Telatinib exhibit significant anti-angiogenic effects, while Lapatinib is less effective. Different TKIs inhibit angiogenesis by regulating different signaling molecules: Dovitinib primarily targets VEGF receptors, Telatinib targets both receptors and the downstream PI3K/AKT pathway, and Lapatinib shows inhibitory effects on VEGF ligand expression in the SC79 background. SC79 promotes angiogenesis by activating the PI3K/AKT pathway and partially reverses the inhibitory effects of TKIs. These findings provide new insights for targeted therapy of abnormal angiogenesis in ophthalmic diseases, suggesting that precise regulation of angiogenesis may be achieved by modulating the balance between TKIs and the PI3K/AKT signaling pathway.
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PHYTOMEDICINE
·
2025
·
IF 8.3
Chenying Zeng,Linjian Chen,Jiajie Lin,Zipeng Xiao,Qingqiang Tu,Wenhui Yu,Weihao Zhang,Qibo Li,Yanfeng Wu,Zhongyu Xie,Ziji Zhang
Background The shift in BMSC differentiation potential toward adipogenesis at the expense of osteogenesis is a critical mechanism underlying reduced bone formation in osteoporosis. Necroptosis has been implicated as a key driver of bone-fat imbalance in osteoporosis, though its mechanisms remain unclear. Taraxasterol (TAX), a bioactive triterpenoid derived from Taraxacum officinale , exhibits antitumor, antioxidant, and immunomodulatory properties. However, its potential role in osteoporosis has not yet been explored. Objective This study aimed to investigate whether TAX alleviates osteoporosis by regulating necroptosis and osteogenic–adipogenic differentiation in BMSCs, and to elucidate the underlying molecular mechanisms. Methods An ovariectomized (OVX) mouse model of osteoporosis was established for in vivo evaluation. Treatment groups received daily oral administration of TAX (5 or 20 mg/kg), with estradiol (E₂, 10 μg/kg) serving as a positive control. Bone microarchitecture and therapeutic response were assessed via micro-CT and immunohistochemistry, while femoral necroptosis and differentiation markers were evaluated by immunostaining. For in vitro studies, BMSCs isolated from osteoporosis patients were treated with the necroptosis inducer TSZ (TNF-α, SM-164, Z-VAD-FMK), with or without TAX. Flow cytometry was used to analyze the phenotype of MSCs. To identify molecular targets and mechanisms, an integrated approach combining network pharmacology, RNA sequencing, SPR assays, and molecular docking was employed. Subsequent analyses included western blotting, PI staining, and RNA interference to assess TAX-regulated necroptosis and PI3K/AKT/PPARγ pathway activity. ARS and ORO staining were employed to analyze osteogenic and adipogenic differentiation, respectively, and mitochondrial function was evaluated with TMRE and MitoSOX Red probes. Results TAX (20 mg/kg) significantly ameliorated bone loss in OVX mice, suppressed femoral necroptotic signaling, and reversed osteogenic–adipogenic imbalance in OVX-derived BMSCs. In vitro , TAX pretreatment attenuated TSZ-induced differentiation imbalance and necroptosis in patient-derived BMSCs and mitigated mitochondrial damage. Integrated network pharmacology and RNA sequencing revealed that TAX targets the PI3K/AKT/PPARγ axis. Immunohistochemical analysis demonstrated upregulation of the PI3K/AKT/PPARγ axis in the femurs of OVX mice following TAX administration. Molecular docking and SPR assays confirmed effective binding between TAX and PI3K. The protective effects of TAX were abolished by the PI3K inhibitor LY294002. Furthermore, TAX enhanced the rebalancing of osteogenic–adipogenic differentiation in PPARγ-silenced BMSCs. Conclusion Our study reveals for the first time that TAX restores osteogenic-adipogenic equilibrium in OP-BMSCs and promotes bone regeneration through PI3K/AKT/PPARγ activation and mitochondrial protection-mediated suppression of necroptosis. These results position TAX as a promising therapeutic candidate for osteoporosis.
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FEBS Open Bio
·
2025
·
IF 2.3
Wenheng Gao,Yunlong Li,Lihua Chen,Wenshuo Yang,Yong He,Ye Yang,Dengke Yin,Song Tan
Hyperlipidemia is a common chronic disease characterized by elevated levels of lipids in the blood. There is some evidence that suggests that berberine (BBR) might be beneficial for the treatment of hyperlipidemia. However, its low intestinal bioavailability limits its potential therapeutic action. In the present study, we explored the effect and the underlying mechanism of berberine–cinnamic acid co-crystal (BBR-CA), which is self-assembled from CA and BBR and displays a high intestinal bioavailability. In mice, BBR-CA showed the ability to decrease body weight gain and hepatic lipid accumulation in animals fed a high-fat diet. To further characterize the molecular basis of this effect, we established a hyperlipidemia cell model by treating human hepatocellular carcinoma cells (HepG2) with free fatty acids. Similarly to our in vivo experiments, lipid accumulation in free fatty acids-induced HepG2 cells was also reduced by BBR-CA. We hypothesized that BBR-CA might act through the regulation of sterol regulatory element-binding proteins-1 (SREBP-1), a key factor regulating lipid synthesis, and, indeed, SREBP-1 protein expression was inhibited by BBR-CA treatment, resulting in the decreased expression of its downstream proteins stearoyl-CoA desaturase 1 and acetyl-CoA carboxylase. Furthermore, the phosphorylation of phosphatidylinositol 3-kinase (PI3K), AKT and mammalian target of rapamycin (mTOR) was inhibited by BBR-CA, contributing to decreased active SREBP-1 in the nucleus, and was reversed and enhanced by the PI3K agonist recilisib and inhibitor LY294002, respectively. Taken together, our results suggest that BBR-CA could function by modulating the PI3K/AKT/mTOR signaling pathway, resulting in decreased nuclear expression of SREBP-1, as well as reduced expression of stearoyl-CoA desaturase 1 and acetyl-CoA carboxylase, thus alleviating hyperlipidemia. Further experimental validation is required to confirm these results.
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Advanced Science
·
2024
·
IF 14.3
Qun Cui,Xiaona Zheng,Yunyang Bai,Yaru Guo,Shuo Liu,Yanhui Lu,Lulu Liu,Jia Song,Yang Liu,Boon Chin Heng,Fuping You,Mingming Xu,Xuliang Deng,Xuehui Zhang
Regulation of the immune response is key to promoting bone regeneration by electroactive biomaterials. However, how electrical signals at the micro- and nanoscale regulate the immune response and subsequent angiogenesis during bone regeneration remains to be elucidated. Here, the distinctly different surface potential distributions on charged poly(vinylidene fluoridetrifluoroethylene) (P(VDF-TrFE)) matrix surfaces are established by altering the dimensions of ferroelectric nanofillers from 0D BaTiO 3 nanoparticles (homogeneous surface potential distribution, HOPD) to 1D BaTiO 3 nanofibers (heterogeneous surface potential distribution, HEPD). Compared to HOPD, HEPD is significantly better at inducing the M2 polarization of macrophages and promoting neovascularization, which results in accelerated bone regeneration in vivo. The transcriptomic analysis reveals that macrophages modulated by HEPD display high expression levels of pro-angiogenic genes, which is corroborated by tube-formation assays, RT-qPCR, and western blot analyses in vitro. Mechanistic explorations elucidate activation of the PI3K-Akt signaling pathway, which in turn induces the polarization of macrophages toward a pro-angiogenic phenotype. This study elucidates the cascade of biological processes by which heterogeneous electrical signals at the micro- and nanoscale modulate macrophage functions to promote vascularization and bone regeneration. Hence, this study provides new insights into how the micro- and nanoscale distribution characteristics of electrical signals facilitate bone regeneration.
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BIOORGANIC CHEMISTRY
·
2021
·
IF 5.275
Yingying Ma,Xiaorong Yang,Hongwei Han,Zhongling Wen,Minkai Yang,Yahan Zhang,Jiangyan Fu,Xuan Wang,Tongming Yin,Guihua Lu,Jinliang Qi,Hongyan Lin,Xiaoming Wang,Yonghua Yang
Triple-negative breast cancer (TNBC) has an unfavorable prognosis attribute to its low differentiation, rapid proliferation and high distant metastasis rate. PI3K/Akt/mTOR as an intracellular signaling pathway plays a key role in the cell proliferation, migration, invasion, metabolism and regeneration. In this work, we designed and synthesized a series of anilide (dicarboxylic acid) shikonin esters targeting PI3K/Akt/mTOR signaling pathway, and assessed their antitumor effects. Through three rounds of screening by computer-aided drug design method (CADD), we preliminarily obtained sixteen novel anilide (dicarboxylic acid) shikonin esters and identified them as excellent compounds. CCK-8 assay results demonstrated that compound M9 exhibited better antiproliferative activities against MDA-MB-231, A549 and HeLa cell lines than shikonin (SK), especially for MDA-MB-231 (M9: IC 50 = 4.52 ± 0.28 μM; SK: IC 50 = 7.62 ± 0.26 μM). Moreover, the antiproliferative activity of M9 was better than that of paclitaxel. Further pharmacological studies showed that M9 could induce apoptosis of MDA-MB-231 cells and arrest the cell cycle in G2/M phase. M9 also inhibited the migration of MDA-MB-231 cells by inhibiting Wnt/β-catenin signaling pathway. In addition, western blot results showed that M9 could inhibit cell proliferation and migration by down-regulating PI3K/Akt/mTOR signaling pathway. Finally, a three-dimensional quantitative structure–activity relationship (3D-QSAR) model was also constructed to provide a basis for further development of shikonin derivatives as potential antitumor drugs through structure–activity relationship analysis. To sum up, M9 could be a potential candidate for TNBC therapy.
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Aging-US
·
2020
·
IF 4.831
Yan Sun,Shiting Dai,Jin Tao,Yunlong Li,Ziqi He,Quan Liu,Jiawen Zhao,Yaoliang Deng,Juening Kang,Xuepei Zhang,Sixing Yang,Yunlong Liu
Oxidative stress and autophagy are the key promoters of calcium oxalate (CaOx) nephrolithiasis. Taurine is an antioxidant that plays a protective role in the pathogenesis of kidney disease. Previous studies found that taurine suppressed cellular oxidative stress, and inhibited autophagy activation. However, the effect of taurine on CaOx kidney stone formation remains unknown. In the present work, we explored the regulatory effects of taurine on CaOx crystals-induced HK-2 cell injury. Results showed that pretreatment with taurine significantly enhanced the viability of HK-2 cells and ameliorated kidney tissue injury induced by CaOx crystals. Taurine also markedly reduced the levels of inflammatory cytokines, apoptosis, and CaOx crystals deposition. Furthermore, we observed that taurine supplementation alleviated CaOx crystals-induced autophagy. Mechanism studies showed that taurine reduced oxidative stress via increasing SOD activity, reducing MDA concentration, alleviating mitochondrial oxidative injury, and decreasing the production of intracellular ROS. Taurine treatment also effectively activated Akt/mTOR signaling pathway in CaOx crystals-induced HK-2 cells both in vitro and in vivo . In summary, the current study shows that taurine inhibits ROS-dependent autophagy via activating Akt/mTOR signaling pathway in CaOx crystals-induced HK-2 cell and kidney injury, suggesting that taurine may serve as an effective therapeutic agent for the treatment of CaOx nephrolithiasis.
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EXPERIMENTAL CELL RESEARCH
·
2021
·
IF 3.905
Yiming Li,Yi He,Guanhui Chen,Ziqing Huang,Chen Yi,Xiliu Zhang,Feilong Deng,Dongsheng Yu
abstract Dental implant surgery is currently a routine therapy for the repair of missing dentition or dentition defects. Both clinical and basic research have elucidated that oxidative stress caused by the accumulation of reactive oxygen species (ROS) for various reasons impairs the process of osteointegration after dental implantation. Therefore, the osteogenic micro-environment must be ameliorated to decrease the damage caused by oxidative stress. Selenomethionine (SEMET) has been reported to play an important role in alleviating oxidative stress and accelerating cell viability and growth. However, it remains unclear whether it exerts protective effects on bone-marrow-derived mesenchymal stem cells (BMSCs) under oxidative stress. In this study, we explored the influence of selenomethionine on the viability and osteogenic differentiation of BMSCs under oxidative stress and the underlying mechanisms. Results showed that 1 μM selenomethionine was the optimum concentration for BMSCs under H 2 O 2 stimulation. H 2 O 2 -induced oxidative stress suppressed the viability and osteogenic differentiation of BMSCs, manifested by the increases in ROS production and cell apoptosis rates , and by the decrease of osteogenic differentiation-related markers. Notably, the aforementioned oxidative damage and osteogenic dysfunction induced by H 2 O 2 were rescued by selenomethionine. Furthermore, we found that the PTEN expression level was suppressed and its downstream PI3K/AKT pathway was activated by selenomethionine. However, when PTEN was stimulated, the PI3K/AKT pathway was down-regulated, and the protective effects of selenomethionine on BMSC osteogenic differentiation diminished, while the inhibition of PTEN up-regulated the protective effects of selenomethionine. Together, these results revealed that selenomethionine could attenuate H 2 O 2 -induced BMSC dysfunction through an antioxidant effect, modulated via the PTEN/PI3K/AKT pathway, suggesting that selenomethionine is a promising antioxidant candidate for reducing oxidative stress during the process of dental implant osteointegration.
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