BIOCHEMICAL PHARMACOLOGY
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2017
·
IF 4.581
Jinhua Hu,Zhao Mao,Shuangcheng He,Yuanran Zhan,Rui Ning,Wei Liu,Bingfang Yan,Jian Yang
Osteoporosis is a serious public health concern worldwide. Herba epimedii has been used for centuries and even thousands of years to treat osteoporotic conditions. Icariin , a flavonol glycoside , is one of the major active ingredients. In this study, we have shown that icariin protected against glucocorticoid-induced osteoporotic changes in SaoS-2 cells and mice. We have also shown that dexamethasone (a glucocorticoid) suppressed and icariin induced DEC1, a structurally distinct helix-loop-helix protein. DEC1 overexpression promoted whereas DEC1 knockdown decreased osteogenic activity. Likewise, DEC1 overexpression and knockdown inversely regulated the expression of β-catenin and PIK3CA, an essential player in the Wnt/β-catenin and PI3K/Akt signaling pathways, respectively. Interestingly, DKK1, an inhibitor of Wnt/β-catenin signaling inhibitor, and LY294002 , an inhibitor of PI3K/Akt signaling, abolished the induction of DEC1 by icariin. It is established that these two pathways are interconnected by the phosphorylation status of GSK3β. Dexamethasone decreased but icariin increased GSK3β phosphorylation. Finally, DEC1 deficient mice developed osteoporotic phenotypes. Taken together, it is concluded that DEC1 likely supports the action of icariin against glucocorticoid induced osteoporosis with an involvement of the PI3K/Akt/GSK3β/β-catenin integrated signaling pathway.
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BIOMATERIALS
·
2025
·
IF 12.9
Liyang Gong,Le Chang,Siyu Chen,Xuan Wei,Huiping Du,Jiamin Cheng,Xiaoxuan Chen,Zhang Yuan,Pan Zhao,Meijuan Geng,Hui Yang,Kaiyong Cai,Liangliang Dai
Hydrogen sulfide (H 2 S) gas therapy is beneficial for accelerating wound healing and alleviating the inflammatory process, but is seriously hindered by insufficient delivery and unsustainable release in vivo . This study presents a multifunctional injectable hydrogel, OC@ε-PL-SATO, composed of oxidized hyaluronic acid and N-acetylcysteine (NAC) as an initiator, carboxymethyl chitosan and S-aroylthiooxime modified ε-Poly-( l -lysine) (ε-PL-SATO). ε-PL-SATO is a NAC-responsive H 2 S donor. OC@ε-PL-SATO hydrogel is designed for the desired wound healing process, with rapid gelation (<30 s) and a sustained H 2 S release. After mixing and gelling, H 2 S could be long-term released from the hydrogel and effectively drives macrophages toward M2 polarization, thereby ameliorating the inflammatory response. Revealed by transcriptome analysis, the underlying mechanism is that OC@ε-PL-SATO hydrogel releasing H 2 S inhibits LPS-mediated inflammatory responses in RAW264.7 cells by interfering with phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) signaling and NF-κB activation. Furthermore, the OC@ε-PL-SATO hydrogel effectively eliminates the bacterial burden and alleviates the accompanying inflammation in a rat model of cutaneous wound infection. Importantly, the sustained generation of H 2 S gas significantly promotes angiogenesis and collagen deposition, ultimately accelerating the wound repair. In conclusion, this study provides a multifunctional injectable hydrogel with rapid gelatinization and continuous H 2 S release for accelerating the infected wound healing.
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INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2024
·
IF 7.7
Chunyan Wang,Xu Huang,Kailing Sun,Xiang Li,Dingding Feng,Yoshimasa Nakamura,Hang Qi
Fucoxanthin (FX), a non-provitamin-A carotenoid, is a well-known major xanthophyll contained in edible brown algae. The nanoencapsulation of FX was motivated due to its multiple activities. Here, nano-encapsulated-FX (nano-FX) was prepared according to our early method by using whey protein and flaxseed gum as the biomacromolecule carrier material, then in vivo antitumor effect and mechanism of nano-FX on xenograft mice were investigated. Thirty 4-week-old male BALB/c nude mice were fed adaptively for 7 days to establish xenograft tumor model with Huh-7 cells. The tumor-bearing mice consumed nano-FX (50, 25, and 12.5 mg kg −1 ) and doxorubicin hydrochloride (DOX, 1 mg kg −1 ) or did not consume (Control) for 21 days, n = 6. The tumor inhibition rates of nano-FX were as high as 54.67 ± 1.04 %. Nano-FX intervention promoted apoptosis and induced hyperchromatic pyknosis and focal necrosis in tumor tissue by down-regulating the expression of p-JNK, p-ERK, PI3Kp85α, p-AKT, p-p38MAPK, Bcl-2, CyclinD1 and Ki-67, while up-regulating the expression of cleaved caspase-3 and Bax. Nano-FX inhibited tumor growth and protected liver function of tumor bearing mice in a dose-dependent manner, up-regulate the level of apoptosis-related proteins, inhibit the MAPK-PI3K/Akt pathways, and promote tumor cell apoptosis.
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高影响因子
ONCOLOGY REPORTS
·
2023
·Vol. 51
·期 1
·1-13
·
IF 4.2
Gongjie Ye,Linglan Tu,Zhuduo Li,Xiangyu Li,Xiaoliang Zheng,Yongfei Song
Synaptopodin 2 (SYNPO2) plays a pivotal role in regulating tumor growth, development and progression in bladder urothelial Carcinoma (BLCA). However, the precise biological functions and mechanisms of SYNPO2 in BLCA remain unclear. Based on TCGA database‑derived BLCA RNA sequencing data, survival analysis and prognosis analysis indicate that elevated SYNPO2 expression was associated with poor survival outcomes. Notably, exogenous SYNPO2 expression significantly promoted tumor invasion and migration by upregulating vimentin expression in BLCA cell lines. Enrichment analysis revealed the involvement of SYNPO2 in humoral immune responses and the PI3K/AKT signaling pathway. Moreover, increased SYNPO2 levels increased the sensitivity of BLCA to PI3K/AKT pathway‑targeted drugs while being resistant to conventional chemotherapy. In in vivo BLCA mouse models, SYNPO2 overexpression increased pulmonary metastasis of 5637 cells. High SYNPO2 expression led to increased infiltration of innate immune cells, particularly mast cells, in both nude mouse model and clinical BLCA samples. Furthermore, tumor immune dysfunction and exclusion score showed that patients with BLCA patients and high SYNPO2 expression exhibited worse clinical outcomes when treated with immune checkpoint inhibitors. Notably, in the IMvigor 210 cohort, SYNPO2 expression was significantly associated with the population of resting mast cells in BLCA tissue following PD1/PDL1 targeted therapy. In conclusion, SYNPO2 may be a promising prognostic factor in BLCA by modulating mast cell infiltration and exacerbating resistance to immune therapy and conventional chemotherapy.
研究领域:
肿瘤学
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免疫学
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分子生物学
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癌症生物学
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PHYTOMEDICINE
·
2024
·
IF 6.7
Lin Chen,Xin Kong,Ruina Zhou,Jinhang Hu,Rui Zhou,Zhongxing Song,Zhishu Tang,Mei Wang
ABSTRACT Background Total flavonoids from Astragali Complanati Semen (TFACS), the main active ingredients in Astragali Complanati Semen (ACS), have been shown to have a protective effect on chronic liver injury (CLI), but the hepatoprotective targets and signalling pathways involved are unclear. Purpose The aim of our study was to identify the anti-CLI targets and signalling pathways of TFACS and to comprehensively elucidate its mechanism of action via proteomics analysis combined with in vivo and in vitro experiments. Methods A CLI mouse model was generated via intraperitoneal injection of carbon tetrachloride (CCl 4 ) (CCl 4 : olive oil = 1:4, 2 mL/kg, twice a week for 6 weeks). The hepatoprotective effect of TFACS was assessed by observing the pathological structure of the liver and analysing indicators of liver function. The key pathways and targets related to the hepatoprotective effect of TFACS were identified via 4D-label-free quantitative proteomics technology and further verified via in vivo indicator validation and in vitro cell experiments. Results TFACS administration significantly normalized the histopathological structure and function of the liver, decreased the levels of inflammatory factors and oxidative stress indicators, and reduced the iron staining area and the levels of hepcidin and iron in the liver compared with those in the CLI model. A total of 424 differentially expressed proteins (DEPs) were identified between the TFACS and model groups, and these DEPs were enriched in the focal adhesion, PI3K-Akt, and ferroptosis pathways. Akt1, Pik3ca, NF-κB p65, Itga5, Itgb5, Itga6, Prkca, Fn1, Tfrc, and Vdac3 were identified as key targets of TFACS. TFACS administration significantly reversed the changes in the gene and protein expression of the key targets compared with those in the model group. In addition, TFACS treatment significantly reduced the levels of inflammatory cytokines and inhibited Akt1, NF-κB p65 and FAK activation in lipopolysaccharide (LPS)-induced RAW 264.7 macrophages. In an erastin-induced L-O2 ferroptosis cell model, treatment with TFACS normalized the mitochondrial structure, reduced the protein levels of Tfrc and Vdac3, inhibited lipid peroxidation, and reduced the amount of Fe 2+ in the mitochondria. Conclusion TFACS protected against CLI, and its mechanism of action may be related to inhibition of the focal adhesion, PI3K/Akt and ferroptosis signalling pathways.
研究领域:
药理学
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蛋白质组学
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肝病学
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Frontiers in Pharmacology
·
2024
·
IF 4.4
Li Yan,Ge Jingping,Yin Yuanyuan,He Juan,Shang Longcheng
Background: This study aimed to explore the regulatory effect of anserine on HUVEC cell injury and thrombosis in deep venous thrombosis (DVT) rats, and to elucidate the underlying molecular mechanisms.Methods: Non-targeted metabolomics data analyses were conducted using an ultra-performance liquid chromatography system Vanquish UHPLC and mass spectrometer to detect plasma metabolism profiles. The transcriptome sequencing and gene intervention experiments were performed to verify the regulatory effect. Further in vivo and in vitro experiments were performed. Enzyme-linked immunosorbent assay was used to detect the levels of P-selectin, E-selectin, and vWF, hematoxylin-eosin (HE) staining was performed to observe thrombotic and inflammatory cell infiltration, flow cytometry and TUNEL assays were performed to detect apoptosis, and qPCR and WB assays were conducted to determine the gene and protein expression.Results: Anserine alleviated HUVECs injury, reduced adhesion molecule expression, and inflammation. It decreased P-selectin, E-selectin, vWF, THBD, TFPI levels, and apoptosis while promoting NOS3, ET-1, and NO release in HUVECs. In DVT rats, anserine reduced P-selectin, E-selectin, vWF, thrombosis, cell infiltration, apoptosis, and promoted NO release. Transcriptome sequencing and gene intervention confirmed anserine’s regulation of the PI3K-Akt pathway and coagulation via MYB. CARNMT1, a regulatory enzyme for anserine metabolism, increased anserine content, inhibiting coagulation, thrombosis, cell infiltration, and promoting NO release in rats.Conclusion: This study confirmed anserine could alleviate DVT by improving the inflammatory response, inhibiting blood agglutination, and promoting vasodilation, providing new potential therapeutic targets, important scientific evidence for the development of DVT management, and new clues for an in-depth understanding of its molecular mechanisms.
研究领域:
药理学
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分子生物学
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心血管疾病
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血栓
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BIOMEDICAL CHROMATOGRAPHY
·
2026
·Vol. 40
·期 9
·e70570
·
IF 1.7
Yi Han,Renbin Li,Baobao Yao,Xuefeng Hou,Shixia Xu,Lizhen Yu,Jun Han,Huidan Huang,Di Cao
Inflammation is a defensive immune response to tissue damage or infection. Polygonatum cyrtonema Hua ( P . cyrtonema Hua, PCH) is bioactive on immune homeostasis due to its rich components and reportedly plays a therapeutic role in the treatment and prevention of diabetes. Flavonoids of PCH possess anti‐inflammatory properties, but their molecular mechanisms remain elusive. Here, chemical profiling of key flavonoids was conducted using UPLC‐QTOF‐MS/MS and the Global Natural Products Social Molecular Networking (GNPS) platform. Network pharmacology predicted potential targets and pathways, validated by molecular docking, surface plasmon resonance (SPR), and western blotting. Totally, 67 compounds were identified, with methylophiopogonanone B (MOB) as the key bioactive flavonoid. Although MOB's anti‐inflammatory activity has been previously noted, the present study provides the first evidence that this effect may be mediated through targeting SRC and modulating the PI3K/AKT signaling axis. Core therapeutic targets were identified as SRC, TNF, and AKT1 by topological analysis of network pharmacology. Molecular docking and SPR confirmed strong MOB‐SRC binding affinity. Western blotting revealed MOB dose‐dependently inhibited LPS‐induced phosphorylation of SRC, PI3K, and AKT1, without altering total protein levels. Furthermore, MOB significantly suppressed the phosphorylation of NF‐κB pathway proteins IκB and p65, confirming the involvement of NF‐κB as a downstream effector. In conclusion, this study integrates chemical profiling and network pharmacology with experimental validation to define the flavonoid composition of PCH, and is the first to implicate the SRC‐PI3K‐Akt pathway in MOB's anti‐inflammatory action and providing novel evidence supporting the mechanism and use of PCH in contemporary diabetes treatment.
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Translational Cancer Research
·
2026
·Vol. 15
·期 5
·378
·
IF 2.1
Zhongshun He,Aiping Huang,Jing Lv,Jing Zhou,Wenrong Lou,Biao Xu,Xuesong Wu
Background Malignant melanoma is among the most aggressive and life-threatening forms of skin cancer, and effective therapeutic treatment options remain limited. Thus, there is an urgent need to develop efficient and broadly applicable anti-melanoma drugs. Growing evidence suggests that baicalin (BAI) possesses anti-cancer potential; however, its anti-tumor mechanisms in melanoma cells remain to be fully elucidated. Therefore, this study aimed to investigate whether BAI exerts anti-melanoma effects. Methods A375 melanoma cells were treated with varying concentrations of BAI to assess its effects on cell proliferation, migration, invasion, and apoptosis. Network pharmacology analysis was then employed to predict potential molecular targets of BAI in melanoma treatment. Molecular docking was used to evaluate the binding interactions between BAI and the predicted targets. Finally, in vitro experiments were performed to investigate the regulatory effects of the potential targets on A375 cell functions. Results BAI significantly inhibited A375 cell proliferation, invasion, and migration, as well as inducing apoptosis of A375 cells in a dose-dependent manner (all P<0.05). Subsequent network pharmacology analysis identified three potential therapeutic targets of BAI, among which epidermal growth factor receptor (EGFR) exhibited strong binding affinity with BAI. Further in vitro experiments demonstrated that BAI suppressed EGFR-mediated PI3K/AKT pathway activation in a dose-dependent manner. Consistent with previous findings, EGFR overexpression exerted oncogenic effects in melanoma cells by inhibiting apoptosis. Mechanistically, BAI induced apoptosis in melanoma cells by targeting the EGFR-mediated PI3K/AKT signaling pathway. Conclusions This study demonstrates that BAI exerted cytotoxic effects on melanoma cells by targeting EGFR and inhibiting the PI3K/AKT pathway, thereby inducing apoptosis. These findings suggest that BAI may serve as a promising therapeutic candidate for the treatment of malignant melanoma.
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FREE RADICAL BIOLOGY AND MEDICINE
·
2026
·
IF 8
Jiwang Liang,Boying Liu,Ming Sun,Xiao Yang,Yuejiao Zhao
Bisphenol A (BPA), a pervasive endocrine-disrupting chemical, has been increasingly implicated in thyroid carcinogenesis, yet the links between redox imbalance and metabolic alterations remain incompletely defined. Here, we combined LC-MS/MS quantification of BPA and its major conjugates with in vitro and in vivo thyroid cancer models to examine oxidative stress markers and lipid indices assessed by targeted biochemical assays and to evaluate a curcumin-modified, quercetin-loaded chitosan nanomicelle system (Que@CSNPs-Cur). We observed BPA enrichment in tumor-bearing mice, accompanied by increased lipid indices (free fatty acids, triglycerides, and total cholesterol) and elevated oxidative stress markers (ROS, TOS, and MDA), as assessed by targeted enzymatic and colorimetric assays. At the molecular level, BPA exposure was associated with reduced PTEN expression and increased PI3K/AKT phosphorylation, consistent with enhanced proliferative and invasive phenotypes in papillary thyroid carcinoma cells. Que@CSNPs-Cur restored PTEN levels, reduced PI3K/AKT activation, attenuated redox and lipid indices, and promoted caspase-3-dependent apoptosis. In xenograft mice, Que@CSNPs-Cur suppressed tumor growth, decreased oxidative stress markers and lipid indices, and reduced tumor BPA residue. Collectively, these results suggest that BPA exposure is linked to PTEN/PI3K/AKT dysregulation, oxidative stress and lipid disturbances. Que@CSNPs-Cur is a promising redox-oriented nanotherapeutic strategy for BPA-associated thyroid cancer phenotypes. Notably, the present study does not determine whether oxidative stress is upstream or downstream of PTEN suppression.
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Nanomedicine
·
2026
·
IF 4.6
Jing Zhang,Dongdong Gao
Background Hepatocellular carcinoma (HCC) remains a highly aggressive malignancy with poor therapeutic outcomes due to drug resistance, systemic toxicity, and limited tumor-targeted drug delivery. This study aimed to develop dual-drug-loaded exosome nanocarrier encapsulating rapamycin (RAP) and Astragaloside IV (AST-IV) (RAP@AST-IV/EXO NC) to inhibit PI3K/Akt/mTOR signaling and enhance mitochondrial apoptosis in HCC.Methods Bone marrow mesenchymal stem cell-derived exosomes (BM-MSC-Exos) were isolated and used for co-delivery of RAP and AST-IV via sonication-assisted loading. Physicochemical properties, drug loading, and release behavior were evaluated. In vitro efficacy was assessed through cell viability, apoptosis, ROS generation, mitochondrial membrane potential, migration, and Western blot assays. In vivo therapeutic efficacy and safety were evaluated in male BALB/c mice bearing HepG2 xenografts.Results RAP@AST-IV/EXO NC showed favorable physicochemical characteristics, sustained drug release, enhanced apoptosis, increased ROS generation, mitochondrial membrane disruption, and inhibition of cancer cell migration. The RAP@AST-IV/EXO NC significantly reduced cell viability and suppressed phosphorylated PI3K, Akt, and mTOR expression while activating mitochondrial apoptotic markers. In vivo, RAP@AST-IV/EXO NC markedly inhibited tumor growth without evident systemic toxicity.Conclusion RAP@AST-IV/EXO NC represent a promising biocompatible strategy for targeted HCC therapy through combined PI3K/Akt/mTOR inhibition and mitochondrial apoptosis induction.
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Chemical Biology & Drug Design
·
2022
·Vol. 99
·期 6
·828-838
·
IF 2.873
Yan Zhao,Danyao Li,Yun Han,Haohao Wang,Rui Du,Zhaowei Yan
Infantile hemangioma (IH) is a common benign endothelial cell tumor in infants and young children, sometimes accompanied by potential complications, and may develop into malignant tumors. Hemangioma endothelial cells (HemECs) are one of the main components of IH. Podophyllotoxin (PPT) has been reported to have many pharmacological activities, especially anti-tumor, but its high toxicity, poor water solubility, and serious gastrointestinal side effects limit its clinical application. In this study, we have designed and synthesized 20 ester derivatives by introducing Boc-amino acids or organic acids at the C-4 position of podophyllotoxin through esterification reactions. The cytotoxicity of these compounds was evaluated on HemECs. Changes in cell proliferation and apoptotic signaling pathways were studied by DAPI staining, colony formation assay, migration assay, measurement of reactive oxygen species (ROS) levels flow cytometry, and Western blot analysis. We found that eight of the compounds were more potent than PPT. Of these, compound V-31 was the most active (IC 50 = 0.079 ± 0.0049 µM). Further research indicated that compound V-31 inhibited its proliferation and migration, increased the level of ROS in cells, and induced apoptosis by downregulating p-PI3K, p-Akt, and Bcl-2, and upregulating cleaved caspase-3 and Bax. Our research provides the first insight into the application of PPT derivatives in HemECs, may provide an effective medicine for IH treatment.
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EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
·
2018
·
IF 4.816
Long Ma,Yuanyuan Meng,Chunhao Tu,Xiuqi Cao,Haiyue Wang,Yuyin Li,Shuli Man,Jin Zhou,Miao Li,Zhenxing Liu,Yanfang Su
Experiments have been undertaken and for the first time, we have identified that a new cardiac glycoside (CG) isolated from Helleborus thibetanus Franch. a plant endemic to China, bears potent anti-cancer activity. We have named it as HTF-1. By using in vitro cell models, we have found that HTF-1 induces apoptosis against several types of cancer cells in a concentration- and time-dependent manner. It is able to inhibit cancer cell in proliferation, migration and invasion. HTF-1 causes S cell cycle arrest . Further-on, we have identified that HTF-1 triggers caspase-9 dependent apoptosis pathway and double strand DNA breaks (DSBs). Additionally, HTF-1 activates JNK , but suppresses ERK and PI3K-Akt-mTOR pathways. Collectively, the above-mentioned mechanisms contribute to the anti-cancer activity of HTF-1. It is rare to discover novel anti-cancer CG during the past couple of decades. We believe that our work will enrich the understanding of CGs; also, pave the way for natural product-based anti-cancer drug development.
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