CURRENT ISSUES IN MOLECULAR BIOLOGY
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2026
·Vol. 48
·期 5
·510
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IF 4.1
Guliziremu Ainiwaer,Xiaoxuan Zhang,Mukatansi Tayier,Xin Luo
Background: The development of Slow Transit Constipation (STC) is associated with intestinal barrier damage.Coreopsis tinctoriaNutt. (CT) is effective in treating STC, but the mechanisms are unclear.Methods: We investigated three CT extracts—traditional aqueous extract, and an aqueous extract from supercritical fluid extraction, with or without lipophilic components—on intestinal transit in a loperamide-induced STC rat model. The potential therapeutic targets of CT for STC were initially predicted using an integrated approach of network pharmacology and molecular docking. The therapeutic effect of CT was evaluated in a STC rat model by assessing defecation parameters (fecal count, water content, intestinal transit), colon histology (H&E and AB-PAS staining), inflammatory markers (ELISA), and target protein expression (Western blotting and immunohistochemistry). In parallel, an LPS-induced IEC-6 cell injury model was used to investigate intestinal barrier protection, analyzing cell viability (CCK-8), apoptosis (flow cytometry and Western blotting), migration (scratch assay), and protein expression (Western blotting).Results: Docking and enrichment analysis highlighted hub targets (TNF, AKT1, Caspase3, STAT3, and BCL-2) and the PI3K/AKT pathway. In vivo, CT treatment improved defecation function, reduced colonic damage, and decreased markers of inflammation and apoptosis in STC rats. It also up-regulated ZO-1 and Occludin, lowered serum markers of intestinal permeability D-lactate (D-LA) and Diamine oxidase (DAO), and restored intestinal barrier function. Furthermore, CT reduced Caspase3 expression and increased the expression of proteins such as BCL-2, PI3K, and P-AKT/AKT. These findings were further supported by in vitro experiments.Conclusions: CT improves STC and its associated intestinal barrier damage by activating the PI3K/AKT pathway and suppressing inflammation and apoptosis, among which the aqueous extract from supercritical fluid extraction combined with the lipophilic fraction exhibits the best efficacy.
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Frontiers in Pharmacology
·
2026
·
IF 5.4
ZeYue Xu,ZhuangYin Qu,Xia Wu
Hyperglycemia can lead to excessive production of reactive oxygen species (ROS), contributing to diabetes and its complications, such as diabetic cardiomyopathy (DCM). This study aims to elucidate the protective mechanisms of Curcumin (CUR) against hyperglycemia-induced cardiomyocyte injury. We constructed a high-glucose (HG) model using primary cardiomyocytes and determined the optimal concentration of CUR by assessing cell viability with the CCK-8 assay. Enzyme-linked assays were used to measure the activities of HO-1, T-SOD, and GSH-Px, investigating the antioxidant effects of the Nrf2 signaling pathway. Flow cytometry was employed to measure apoptosis and mitochondrial membrane potential (ΔΨm). Mitochondria were isolated from cardiomyocytes to examine cytosolic and mitochondrial cytochrome c (cytc) expression. Western blotting was used to analyze the expression levels of Nrf2, PI3K, AKT, Keap1, HO-1, Bcl-2, and Bax proteins. Our findings suggest that CUR enhanced the viability and antioxidant enzyme activity of primary cardiomyocytes under HG conditions, stabilized ΔΨm, reduced ROS production, and decreased apoptosis. Moreover, CUR alleviated HG-induced cardiomyocyte damage by upregulating Nrf2, PI3K, AKT, HO-1, and Bcl-2 expression, while downregulating Bax. These findings demonstrate that the protective effect of CUR against diabetic cardiac injury may be mediated through activation of the Nrf2 and PI3K/AKT signaling pathways and upregulation of antioxidant enzyme expression, aiming to provide a theoretical foundation for further research into the therapeutic application of CUR in DCM.
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JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY
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2026
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IF 3.3
Haiya Feng,Qianqian Li,Yangjun Lu,Hui Wang
Objective This study aimed to investigate the anti-tumor effects of the natural flavonoid Isorhamnetin (ISO) on BC and elucidate its underlying molecular mechanisms. Methods We integrated network pharmacology and bioinformatic analysis to predict the core targets and pathways between BC and ISO. In vitro functional assays were performed using the human BC cell line 5637. Cell viability, proliferation, apoptosis, migration, invasion, and adhesion were assessed via CCK-8, colony formation, flow cytometry, Transwell, and adhesion assays. Glycolytic function was evaluated by measuring extracellular acidification rate (ECAR), oxygen consumption rate (OCR), glucose uptake, and lactate production. Molecular docking and cellular thermal shift assays (CETSA) were used to validate ISO-SRC binding. Western blot and RT-qPCR analyses were conducted to examine protein and mRNA expression of key signaling and glycolytic components. For the rescue experiments, SRC was overexpressed along with treatment using the PI3K inhibitor LY294002. Results ISO significantly inhibited BC cell proliferation, migration, invasion, adhesion, and glycolysis while inducing G0/G1 phase arrest and apoptosis. Network pharmacology and molecular docking identified SRC as a direct target of ISO, with CETSA confirming their binding. ISO treatment downregulated phosphorylation of SRC and its downstream effectors (PI3K, Akt, mTOR), reduced the expression of glycolytic enzymes (HK2, GLUT1, PFKFB3), and decreased ECAR, OCR, glucose uptake, and lactate production. SRC overexpression reversed the anti-tumor and anti-glycolytic effects of ISO. Furthermore, administration of LY294002 on this basis counteracted the effects induced by SRC overexpression, confirming the critical role of the SRC/PI3K/Akt axis. Conclusion ISO inhibits the malignant progression of BC by directly targeting SRC to suppress glycolysis mediated by the PI3K/Akt signaling pathway. These findings provide a mechanistic basis for considering ISO as a potential metabolic-targeting agent for BC, warranting further preclinical evaluation.
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Journal of Functional Foods
·
2026
·
IF 3.9
Lu Wang,Kejian Wei,Jiahua Yan,Kun Wang,Siqi Liu,Fei Fang,Yu Jiang
As a major citrus flavonoid, hesperidin (HP) shows bone-protective potential, yet its role in calcium–phosphorus homeostasis and antioxidant mechanisms remains unclear. This study investigated the anti-osteoporotic effects of HP in retinoic acid (RA)-induced osteoporotic mice and primary bone marrow mesenchymal stem cells (BMSCs). HP promoted BMSC proliferation, migration, and osteogenic differentiation, with increased alkaline phosphatase (ALP) activity and mineralization. Network pharmacology identified antioxidant PI3K/AKT/FOXO1 pathways as key targets, with fibroblast growth factor 23 (FGF23) as a pivotal effector. In osteoporotic mice, HP normalized serum calcium, phosphorus, and 25-hydroxyvitamin D, increased bone formation and decreased resorption markers, alleviating bone loss and preserving trabecular microarchitecture and enhancing biomechanical properties. Mechanistically, PI3K/AKT/FOXO1-mediated FGF23 suppression was essential for osteoprotection, as confirmed using a PI3K inhibitor. Collectively, these findings suggest that HP ameliorates RA-induced osteoporosis by restoring calcium–phosphorus homeostasis via PI3K/AKT/FOXO1-dependent FGF23 inhibition, underscoring its potential as a functional food ingredient.
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PHYTOTHERAPY RESEARCH
·
2025
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IF 6.3
Yanhong Bu,Hong Wu,Ran Deng,Yan Wang,Peirong Gan,Xintong Dong,Jiangtao Ke
Angiogenesis driven by aerobic glycolysis in endothelial cells sustains rheumatoid arthritis (RA) progression. Geniposide (GE), an iridoid ether extracted from the Rubiaceae plant Gardenia jasminoides J. Ellis, has shown anti-angiogenic potential in experimental arthritis. However, its role in metabolic regulation of angiogenesis remains unclear. The purpose was to explore the roles of GE on metabolism in angiogenesis and potential mechanisms. Adjuvant arthritis (AA) rat models and human umbilical vein endothelial cells (HUVECs) were established. Network pharmacology predicted potential targets of GE, while metabolomics analysis was conducted on RA patient serum and AA rat synovial tissue. The role of PFKFB3, a key glycolytic enzyme, was validated by gene silencing and pharmacological interventions. The signaling axis was further explored using inhibitors, agonists, and protein interaction assays. The role of the key glycolytic enzyme PFKFB3 and the upstream–downstream relationship of the signaling axis were validated through gene silencing and pharmacological intervention. GE improved angiogenesis in vivo and in vitro models, and PFKFB3 may be a potential target. Metabolomics has shown that GE significantly inhibited the elevated levels of glycolysis metabolism in arthritis rats, which may be related to the inhibition of PFKFB3 expression. PFKFB3-siRNA down-regulated angiogenesis in HUVECs, demonstrating that PFKFB3-mediated glycolysis was involved in angiogenesis. SphK1-siRNA indicated that PFKFB3 was regulated and activated by the SphK1-PI3K-AKt signal and induced a high level of glycolytic metabolism phenotype. GE intervention significantly downregulated the levels of glycolysis metabolism in arthritis models by inhibiting the SphK1-PI3K-AKt-PFKFB3 signal. The SphK1-PI3K-Akt-PFKB3 signal is the metabolic mechanism of the natural product active ingredient GE in anti-angiogenesis, revealing the important role of glycolytic metabolism in RA angiogenesis. This provides new insights into metabolic regulation in RA treatment and potential therapeutic strategies for metabolic targeted interventions.
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Frontiers in Nutrition
·
2025
·
IF 5.1
Jia Li,Lijia Li,Tahui Lin,Houtan Huang,Jie Ren,Jengyuan Yao
Background: Food-derived flavonoids are emerging as nutraceutical agents for glycemic control. Dihydromyricetin (DMY), the signature flavanonol of vine tea (Ampelopsis grossedentata), has long been consumed in South China, yet its antidiabetic potential remains underexplored.Methods: We administered DMY (50 and 100 mg/kg/day, 12 days) to streptozotocin-induced type 1 diabetic mice. Fasting glycemia, lipid panels, and HOMA-β were evaluated 4 weeks after DMY administration. Untargeted UPLC-QTOF metabolomics combined with network pharmacology pinpointed pathway hubs, while experiments in INS-1 β-cells using the PI3K inhibitor LY294002 verified the pathway’s involvement.Results: DMY reduced hyperglycemia, corrected dyslipidemia, and preserved islet architecture. Metabolomics indicated a shift toward a normal plasma profile, with the arachidonic acid, linoleic acid, and steroid hormone pathways being the most responsive. Six hub targets (PTGS2, IL6, AKT1, IL1B, BCL2, CASP3) mapped to eicosanoid signaling, apoptosis, and PI3K/AKT axis. Docking and cell assays confirmed direct binding and PI3K/AKT-dependent cytoprotection, evidenced by restored p-AKT, lowered ROS, and reduced caspase-3 cleavage.Conclusion: DMY, a readily accessible food-derived bioactive compound, reprograms lipid-inflammatory metabolism and activates PI3K/AKT to safeguard β-cell viability, highlighting its nutraceutical promise for dietary management of autoimmune diabetes.
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BIOORGANIC CHEMISTRY
·
2026
·
IF 5.1
Man Li,Yuxin Jiang,Yongkang Xue,Yuanqi Duan,Yanan Liu,Xianghao Xin,Xiaoyu Wei,Zhengyu Hu,Pengcheng Yang,Shengbao Diao,Wei Zhou,Jinfeng Sun,Gao Li
Ischemic stroke (IS) is the leading cause of prevalence and mortality in China and a major global public health problem. Eupalinolide B (EB) stands as the main biologically active constituent extracted from Eupatorium lindleyanum , exhibits diverse pharmacological activities, with particular emphasis on its neuroprotective potential in neurodegenerative disorders. Nevertheless, the precise therapeutic outcomes and the specific molecular pathways mediating the protective effects of EB against cerebral ischemia-reperfusion injury (CIRI) are still not fully elucidated. This study systematically explores the potential therapeutic targets and regulatory networks of EB in CIRI treatment through an integrative approach combining network pharmacology analysis with in vitro oxygen-glucose deprivation/reoxygenation (OGD/R) modeling in PC12 cells and in vivo middle cerebral artery occlusion/reperfusion (MCAO/R) modeling in mice. Our findings demonstrate that EB modulates a network composed of 54 core therapeutic targets, including apoptosis regulators (Bcl-2) and components of the PI3K/Akt signaling cascade. In vitro experiments indicate that EB significantly improves the viability of PC12 cells induced by OGD/R, while attenuating intracellular reactive oxygen species (ROS) accumulation and restoring mitochondrial membrane potential. Complementary in vivo studies reveal that the administration of EB activates the PI3K/Akt/GSK3β(Ser9) signaling pathway in MCAO/R mice, leading to reduced neurological deficits, decreased cerebral infarction area, and a mitigation of neuronal pathological changes. Collectively, these findings indicate that EB inhibits neuronal apoptosis by activating the PI3K/Akt/GSK3β(Ser9) signaling pathway, thereby exerting a preventive effect against CIRI. This provides robust experimental evidence for the potential of EB as a new anti-IS therapy.
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BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
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2023
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IF 5.1
Ziyuan Tong,Yuan Shen,Quan Yuan,Honghao Yu
Despite recent advances in understanding the biological behavior of osteosarcoma (OS), OS is still the most common primary bone sarcoma that endangers the health of children and adolescents. High-temperature requirement A (HTRA) protease family plays an important regulatory role in numerous malignancies and acts as a prognostic biomarker. However, the function and underlying mechanisms of the HTRA family in OS development remain unknown. Through analyzing the GSE126209 dataset obtained from different Gene Expression Omnibus (GEO) databases, we found that HTRA3 as a member of the HTRA family was downregulated in OS tissues compared with that in normal tissues. Functional experiments indicated that HTRA3 overexpression suppressed malignant behaviors of OS cells in vitro and tumor growth in vivo . Mechanistically, we found that HTRA3 co-localized with the X-linked inhibitor of apoptosis protein (XIAP) and decreased XIAP stability. Further investigation showed that XIAP knockdown inhibited the degradation of phosphatase and tensin homolog (PTEN) and that HTRA3 caused the blockage of PTEN/phosphoinositide 3-kinase (PI3K)/AKT pathway, characterized as the reverse of cell function caused by HTRA3 overexpression after PTEN inhibitor BpV (HOpic) treatment. Detailed investigations showed that forkhead box protein 1 (FOXP1), an oncogene in OS progression, downregulated HTRA3 expression and inhibited the transcriptional activity of HTRA3 , suggesting that HTRA3 was regulated negatively by FOXP1. In conclusion, our study demonstrates that HTRA3 is a repressor involved in OS development via the PTEN/PI3K/AKT pathway under the modulation of transcription factor FOXP1, and it may provide a therapeutic direction for OS patients.
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BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
·
2023
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IF 3.1
Yong-xin Chen,Hong Yang,Da-song Wang,Yu-ting Yao,Ting-ting Chen,Ling Tao,Yan Chen,Xiang-chun Shen
Vascular dementia (VaD), the second most common type of dementia, is attributed to lower cerebral blood flow. To date, there is still no available clinical treatment for VaD. The phenolic glucoside gastrodin (GAS) is known for its neuroprotective effects, but the role and mechanisms of action on VD remains unclear. In this study, we aim to investigate the neuroprotective role and underlying mechanisms of GAS on chronic cerebral hypoperfusion (CCH)-mediated VaD rats and hypoxia-induced injury of HT22 cells. The study showed that GAS relieved learning and memory deficits, ameliorated hippocampus histological lesions in VaD rats. Additionally, GAS down-regulated LC3II/I, Beclin-1 levels and up-regulated P62 level in VaD rats and hypoxia-injured HT22 cells. Notably, GAS rescued the phosphorylation of PI3K/AKT pathway-related proteins expression , which regulates autophagy. Mechanistic studies verify that YP-740, a PI3K agonist, significantly resulted in inhibition of excessive autophagy and apoptosis with no significant differences were observed in the YP-740 and GAS co-treatment. Meantime, we found that LY294002 , a PI3K inhibitor, substantially abolished GAS-mediated neuroprotection. These results revealed that the effects of GAS on VaD are related to stimulating PI3K/AKT pathway-mediated autophagy, suggesting a potentially beneficial therapeutic strategy for VaD.
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PLoS One
·
2023
·Vol. 18
·期 2
·e0282427
·
IF 3.7
Tingting Fang,Ruofei Xu,Shaopeng Sun,Yineng He,Yi Yan,Hongyang Fu,Hongbin Luo,Yi Cao,Maocan Tao
Purpose
Caizhixuan hair tonic (CZX) is a topical traditional Chinese medicine (TCM) preparation for the treatment of androgenetic alopecia (AGA). However, its active compounds and underlying mechanism for treating AGA are still unclear. The purpose of this study was to observe the effects of CZX on hair growth promotion in AGA mice and to explore the active components and mechanism.
Methods
Testosterone propionate was administered subcutaneously to mice to establish an AGA mouse model. The therapeutic effects of CZX on AGA were evaluated by observing skin colour changes, hair growth time, and average hair length; calculating the hair growth score; and performing skin histopathological analysis. Following that, CZX chemical components were analysed by ultra-high-performance liquid chromatography-quadrupole-time-of-flight mass spectrometry (UPLC–Q–TOF/MS). Network pharmacology was used to predict the major effects and possible mechanisms of CZX for the treatment of AGA. Furthermore, RT-qPCR and Western blotting were performed to assess the expression of key genes and proteins involved in PI3K/Akt and apoptosis pathways in order to validate CZX’s predicted mechanism in AGA.
Results
CZX promoted hair growth and improved the pathological morphology of hair follicles in the skin. In UPLC–Q–TOF/MS analysis, 69 components from CZX were isolated. Based on network pharmacology, CZX alleviated AGA by regulating PI3K/Akt and apoptosis pathways. According to RT-qPCR and Western blotting, CZX upregulated the expressions of PI3K, Akt, and Bcl-2, while downregulating that of Bax and caspase-3.
Conclusions
CZX promotes hair growth to treat AGA by regulating the PI3K/Akt and apoptosis pathways.
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BIOORGANIC CHEMISTRY
·
2023
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IF 5.1
Shuai Wang,Jian-Tao Shi,Xing-Rong Wang,Hong-Xia Mu,Xue-Ting Wang,Kai-Yan Xu,Qing-Shan Wang,Shi-Wu Chen
The PI3K/AKT/mTOR signaling pathway is one of the most common abnormal activation pathways in tumor cells, and has associated with multiple functions such as tumor cell growth, proliferation, migration, invasion, and tumor angiogenesis. Here, a series of 3-amino-1 H -indazole derivatives were synthesized, and their antiproliferative activities against HT-29, MCF-7, A-549, HepG2 and HGC-27 cells were evaluated. Among them, W24 exhibited the broad-spectrum antiproliferative activity against four cancer cells with IC 50 values of 0.43–3.88 μM. Mechanism studies revealed that W24 inhibited proliferation by affecting the DNA synthesis, induced G 2 /M cell cycle arrest and apoptosis by regulating Cyclin B1, BAD and Bcl-xL, meanwhile induced the change of intracellular ROS and mitochondrial membrane potential in HGC-27 cells. Moreover, W24 inhibited the migration and invasion of HGC-27 cells by decreasing EMT pathway related proteins and reducing the mRNA expression levels of Snail, Slug and HIF-1α. Furthermore, W24 displayed low tissue toxicity profile and good pharmacokinetic properties in vivo . Therefore, 3-amino-1 H -indazole derivatives might serve as a new scaffold for the development of PI3K/AKT/mTOR inhibitor and anti-gastric cancer reagent.
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Frontiers in Pharmacology
·
2022
·
IF 5.988
Yue Wang,Ying Li,Liang Wang,Buze Chen,Miaolin Zhu,Chunyi Ma,Chunyan Mu,Aibin Tao,Shibao Li,Lan Luo,Ping Ma,Shuai Ji,Ting Lan
Ovarian cancer is one of the most common gynecological malignancies in women worldwide with a poor survival rate. Cinnamaldehyde (CA), a bioactive substance isolated from cinnamon bark, is a natural drug and has shown that it can inhibit the progression of other tumors. However, the role of CA in ovarian cancer and its mechanism is poorly understood. In this study, wound healing assays, plate cloning, CCK-8, and transwell assays were used to determine cell proliferation and invasion. Western blot and flow cytometry were used to detect apoptosis levels. Western blot and immunofluorescence were used to detect changes in cellular EMT levels. The Western blot was used to detect levels of the PI3K/AKT signaling pathway. In vivo , we established a subcutaneous transplantation tumor model in nude mice to verify the role of CA in the progression and metastasis of ovarian cancer. Our data showed that in vitro CA was able to inhibit the cell viability of ovarian cancer. The results of scratch assay and transwell assay also showed that CA inhibited the proliferation and invasion ability of A2780 and SKOV3 cells. In addition, CA promoted apoptosis by increasing the expression of cleaved-PARP and cleaved-caspase 3 in ovarian cancer cells. Mechanistically, we found that CA inhibited the EGF-induced PI3K/AKT signaling pathway and reduced the phosphorylation levels of mTOR, PI3K, and AKT. The EGF-induced EMT process was also abolished by CA. The EMT process induced by AKT-specific activator SC79 was also suppressed by CA. Furthermore, in in vivo , CA significantly repressed the progression of ovarian cancer as well as liver metastasis. In all, our results suggest that CA inhibits ovarian cancer progression and metastasis in vivo and in vitro and inhibits EGF-induced EMT processes through the PI3K/AKT signaling pathway.
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