EUROPEAN JOURNAL OF PHARMACOLOGY
·
2020
·
IF 3.263
Hui Zhang,Junfeng Hui,Jing Yang,Jianjun Deng,Daidi Fan
Eurocristatine (ECT) is an alkaloid isolated from Eurotium cristatum , and it has been used in multiple applications. However, its use as a treatment for type 2 diabetes mellitus (T2DM) has not yet been reported. In this study, we investigated the anti-T2DM effect of ECT and explored its potential molecular mechanism. In vivo , after treatment with ECT (20, 40 mg/kg) for 6 weeks, fasting blood glucose (FBG) was remarkably reduced in db/db mice. Moreover, glucose tolerance, insulin sensitivity and hyperinsulinemia were ameliorated treatment with ECT. The values of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) also showed that ECT could alleviate liver toxicity caused by diabetes in db/db mice. In vitro , ECT (15 and 30 μM) alleviated insulin resistance by increasing glucose consumption, glucose uptake and glycogen content in high glucose-induced HepG2 cells. The Western blotting (WB) results showed that ECT could upregulate the expression of phosphatidylinositol 3-kinase (PI3K), increase the phosphorylation of insulin receptor substrate 1 (IRS1) and protein kinase B (AKT) in vivo and in vitro . Besides, ECT improved the glycogen content by inhibiting the expression of glycogen synthase kinase3β (GSK3β) and promoting that of glycogen synthase (GS). Furthermore, administration of the PI3K/AKT signaling pathway inhibitor LY294002 abolished the beneficial effects of ECT. These findings are the first to verify that ECT has the potential to improve glucose metabolism and alleviate insulin resistance by activating the PI3K/AKT signaling pathway in db/db mice.
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CELLULAR SIGNALLING
·
2025
·
IF 3.7
Biao-Hu Quan,Xin-Yue Liu,Zhou-Yan Li,Sheng-Zhong Han,Qi-Chao Cui,Shuang-Yan Chang,Si-Tong Lv,Xi-Jun Yin,Shuang Liang
Pulmonary fibrosis is a chronic interstitial lung disease characterized by irreversible, progressive lung scarring and eventual respiratory failure. Fibroblast activation plays a crucial role in the progression of pulmonary fibrosis. Transforming growth factor-β (TGF-β) signaling contributes to pulmonary fibrosis by regulating lung fibroblast activation. Currently, most studies focus on TGF-β1 regulatory effects on fibroblasts, with limited reports on myostatin (MSTN), another member of the same family. This study used MSTN gene knockout (MSTN −/− ) boars as animal models to explore MSTN regulatory effects on pulmonary fibrosis by modulating lung fibroblast activation. Studies have demonstrated that MSTN is significantly upregulated in the lungs during pulmonary fibrosis, promoting the activation of downstream Smad and AKT signaling pathways. MSTN −/− inhibits alveolar collapse and interstitial thickening in pulmonary fibrosis pigs and suppresses downstream Smad and AKT signaling. In vitro experiments showed that MSTN −/− inhibits lung fibroblast activation by blocking Smad/AKT signaling. These findings suggest that the MSTN/Smad/AKT signaling axis suppresses pulmonary fibrosis by inhibiting lung fibroblast activation, indicating that MSTN could be a potential therapeutic target for pulmonary fibrosis.
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BASIC & CLINICAL PHARMACOLOGY & TOXICOLOGY
·
2025
·Vol. 136
·期 6
·e70045
·
IF 3.3
Dong Yan,Yuanwei Fu,Jie Mei,Junhong Wang,Ayijiang Jiamaliding,Ying Liu,Zanmei Zhao,Qingbian Ma
Phosgene, used in large‐scale industrial production, is highly toxic and irritant. Accidental exposure can lead to varying degrees of injuries, with severe cases potentially resulting in acute lung injury or acute respiratory distress syndrome, resulting in a mortality rate of 40%–50%. The indirect damages of phosgene (inflammation and oxidative stress) are considered important factors in phosgene‐induced acute lung injury (P‐ALI). The expression of Liver X Receptor α (LXRα) significantly reduces during periods of inflammation. LXRs were initially discovered to be highly expressed in the liver, whereas LXRs are expressed in immune cells and vascular endothelial cells, playing a significant role in anti‐inflammatory and antioxidant responses. LXRα may have pulmonary protection in P‐ALI. However, evidence to verify this association is still lacking. In this study, rats were divided into six groups to explore the potential role of LXRα in P‐ALI. This study found that GW3965 effectively activated LXRα, upregulated its expression and downregulated the levels of proinflammatory cytokines, inhibited malondialdehyde activity while enhancing superoxide dismutase activity, suppressed apoptosis and ameliorated the pathological processes of P‐ALI, ultimately exerting pulmonary protection in P‐ALI. Further validation revealed that the pulmonary protective effect of LXRα may be associated with the PI3K/Akt and NF‐kB signalling pathways.
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Journal of Materials Chemistry B
·
2021
·Vol. 9
·期 16
·3489-3501
·
IF 6.331
Xinran Zhang,Jinjie Cui,Liming Cheng,Kaili Lin
Osteoporosis (OP) is a major systemic bone disease leading to an imbalance in bone homeostasis which remains a challenge in the current treatment of bone defects. Our previous studies on strontium (Sr) doping apparently stimulated osteogenesis of bioceramics, which suggested a promising strategy for the treatment of bone defects. However, the potential effects and the underlying mechanisms of Sr-doping on osteoporotic bone defects still remain unclear. Autophagy is a conventional self-degradation process of cells involved in bone homeostasis and regeneration under physiological and pathological conditions. Therefore, it is essential to design appropriate biomaterials and investigate the associated osteogenic mechanisms via autophagy. Based on this hypothesis, Sr-doped 45S5 bioglass (Sr/45S5) was fabricated, and ovariectomy bone marrow-derived mesenchymal stem cells (OVX-BMSCs) were applied as the in vitro cell culture model. First, the optimal Sr-doping concentration of 10 mol% was screened by cell proliferation, ALP staining, alizarin red S staining and the real-time PCR assay. Then, the results of western blot (WB) analysis showed that Sr-induced osteogenic differentiation of OVX-BMSCs was associated with time-dependent modulation of autophagy and related to the AKT/mTOR signaling pathway. Meanwhile, the autophagy in Sr-induced osteogenic differentiation of OVX-BMSCs was detected by WB, immunofluorescence staining and transmission electron microscopy. Furthermore, the effect of osteogenic differentiation of OVX-BMSCs has been significantly inhibited by the administration of autophagy inhibitors and the AKT/mTOR pathway inhibitors, respectively, in the early and late periods of osteogenic differentiation. Finally, the results of the model of femoral condyle defects in OVX-rats indicated that Sr10/45S5 granules remarkably enhanced bone regeneration which provided the evidences in vivo. Our research indicates that Sr-doping provides a promising strategy to promote osteogenic differentiation of OVX-BMSCs and bone regeneration in osteoporotic bone defects via early improvement of autophagy and late activation of the Akt/mTOR signaling pathway.
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JOURNAL OF ANIMAL SCIENCE
·
2024
·
IF 2.7
Ma Zifeng,Li Qiao,Xu Hongmei,Li Yueyue,Wang Shujin,Xiong Yan,Lan Daoliang,Li Jian,Xiong Xianrong,Fu Wei
Zearalenone (ZEN), a mycotoxin from Fusarium fungi, impairs fertility and milk production in female animals, however, the mechanisms remain poorly understood. Using the bovine mammary epithelial cells (MAC-T) as the model, this study investigated the impacts of ZEN on programmed cell death (PCD) and milk fat synthesis, and explored the underlying mechanism. We found that 10 ng/mL prolactin (PRL) notably enhanced the differentiation of MAC-T cells, promoting the expression of genes related to the synthesis of milk fat, protein, and lactose. Next, the toxic effects of different doses of ZEN on the differentiated MAC-T with PRL treatment were determined. 10 μM and 20 μM ZEN significantly reduced cell viability, induced oxidative stress, and triggered PCD (e.g. apoptosis and necrosis). Notably, ZEN exposure downregulated the mRNA/protein levels of critical factors involving in milk fat synthesis by disrupting the AKT-mTOR-PPARγ-ACSL4 pathway. Interestingly, melatonin (MT), known for its antioxidant properties, protected against the above ZEN-induced effects by enhancing the binding of PPARγ to the promoter regions of ACSL4, which led to the upregulated expression of ACSL4 gene. These results underscored the potential of MT to mitigate the adverse effects of ZEN on mammary cells, highlighting a way for potential therapeutic intervention.
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JOURNAL OF ETHNOPHARMACOLOGY
·
2025
·
IF 5.4
Yuewei Lin,Qi He,Baihao Chen,Zuang Li,Chuyi Chen,Wei Deng,Haishan Li,Jiamin Yang,Bin Mai,Zhen Zhang,Dongping Wang,Huizhi Guo,Yongchao Tang,Kai Yuan,Guoye Mo,Liangliang Xu,Yongxian Li,Haibin Wang,Shuncong Zhang
Ethnopharmacological relevance Zuogui Pill (ZGP) is a classic herbal formula in Traditional Chinese Medicine, primarily used to tonify the kidney and replenish essence, and is widely applied in treating various kidney deficiency-related conditions. Over time, ZGP has demonstrated significant efficacy in addressing symptoms such as fatigue, weakness, and soreness of the lower back and knees, which are often caused by kidney deficiency. According to Traditional Chinese Medicine theory, the kidneys govern the bones, meaning that sufficient kidney essence is closely related to bone strength. By nourishing the kidneys and replenishing essence, ZGP helps to increase bone density and improve bone microstructure, making it an important therapeutic option for osteoporosis. Aim of the study To investigate the protective effects of ZGP in iron overload-induced osteoporosis and elucidate its molecular mechanisms through the activation of the Phosphoinositide 3-Kinase (PI3K)/Protein Kinase B (AKT) and Nuclear Factor Erythroid 2-Related Factor 2 (Nrf2)/Heme Oxygenase-1 (HO-1) pathways, which reduce oxidative stress, inhibit osteoblast apoptosis, and promote osteoblast differentiation and mineralization. Materials and methods An in vivo mouse model of iron overload-induced osteoporosis and an in vitro MC3T3-E1 osteoblast model were used. In vitro experiments involved the use of ZGP containing-serum, along with transcriptomic analysis, Western blot, flow cytometry, TUNEL staining, and immunofluorescence, to assess the effects on oxidative stress, mitochondrial function, and apoptosis. In vivo experiments evaluated the effects of ZGP on bone mass, oxidative stress, and apoptosis using Micro-computed tomography (micro-CT), Hematoxylin and eosin staining (H&E), TUNEL staining, and immunohistochemistry. Results The study found that ZGP containing-serum significantly enhanced the viability of osteoblasts induced by iron overload and reduced apoptosis through the reactive oxygen species (ROS)-mediated Phosphoinositide 3-Kinase (PI3K) / Protein Kinase B (AKT) pathway while mitigating mitochondrial damage. In vivo , micro-computed tomography results showed that ZGP improved bone mass, and decreased ROS and apoptosis, consistent with the in vitro findings. Conclusion ZGP demonstrates significant antioxidant and anti-apoptotic effects in iron overload-induced osteoporosis, primarily through the ROS-mediated PI3K/AKT pathway and by reducing mitochondrial damage. These findings suggest that ZGP may be a promising therapeutic agent for treating osteoporosis associated with iron overload.
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Chinese Medicine
·
2024
·Vol. 19
·期 1
·1-24
·
IF 5.3
Cao Ting,Wang Xue-lian,Rao Jiang-yan,Zhu Hui-feng,Qi Hong-yi,Tian Zhen
Background Parkinson’s disease (PD) is a chronic neurodegenerative disorder that currently has no curable strategies. More and more evidence suggests that endoplasmic reticulum (ER) stress plays an essential role in PD pathogenesis. Periplaneta americana L. ( P. americana ) is a traditional Chinese medicine with diverse therapeutic properties. This study aims to investigate the neuroprotective effect and underlying mechanism of P. americana in in vitro and in vivo PD models. Methods The exposure of SH-SY5Y cells to 1-methyl-4-phenyl-pyridinium (MPP + ) was used as the in vitro PD model. MTT assay, Hoechst staining, Calcein AM-PI staining and flow cytometry were performed to measure the cell viability and apoptosis. DCFH-DA and JC-1 assay were used to measure the intracellular ROS and mitochondrial membrane potential (Δψm), respectively. Western-blot and immunostaining were conducted to detect the expression of key molecules related with ER stress. For the in vivo PD model induced by 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydro-pyridine (MPTP), the motor function of mice was assessed by behavioral tests, the level of TH was examined by western-blot and immunostaining, the expression of key molecules related with ER stress was measured by western-blot. Results Periplaneta americana ethanol extract (PAE) concentration-dependently inhibited MPP + -induced cell loss and increased cell viability. PAE also remarkably attenuated ROS accumulation, the decline of Δψm as well as the excessive ER stress. The neuroprotective effects of PAE could be blocked by ROS inducer trimethylamine N-Oxide or ER stress activator tunicaymycin, while the antioxidant N-Acetyl-L-cysteine or ER stress inhibitor sodium 4-phenylbutyrate mimicked the effects of PAE. Furthermore, we found that PAE could activate AKT/GSK3β/β-catenin pathway. The effect of PAE on ROS production, Δψm and ER stress was blocked by AKT inhibitor MK-2206. In in vivo model, PAE significantly improved motor function, prevented dopaminergic neuronal loss and attenuated ER stress in substantia nigra and striatum of MPTP-treated mice. Similarly, the effects of PAE on MPTP-treated mice were also abolished by MK-2206. Conclusions Our results suggest that P. americana exerts neuroprotective effects through inhibiting ER stress via AKT-dependent pathway. Periplaneta americana may represent a promising therapeutic agent for PD treatment and is worthy of further being exploited.
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CURRENT MEDICINAL CHEMISTRY
·
2024
·Vol. 32
·期 33
·7357-7376
·
IF 3.5
Jinna Di,Wei Bo,Chun Wang,Chunying Liu
IntroductionThe effectiveness of therapy is strongly impacted by the resistance of lung cancer cells to cisplatin. The objective of this research is to characterize the impact of ailanthone on cisplatin resistance in non-small cell lung cancer (NSCLC) and examine any potential in vivo and in vitro molecular pathways.MethodsFollowing treatment of A549/DDP cells with ailanthone and cisplatin, cell survival and apoptosis were measured using flow cytometry and Cell Counting Kit-8 (CCK8) assays, respectively. mRFP-GFP-LC3 adenovirus transfection was used to track autophagy, and protein expression levels were analyzed by western blotting. Hematoxylin and eosin (H&E) staining was used after the organs of the mice were removed for in vivo investigations. In A549/DDP cells, ailanthone and cisplatin together induced autophagy and apoptosis in a dose and time-dependent manner (p< 0.05). After receiving combined treatment with ailanthone and cisplatin, the expression levels of cleaved caspase-3, Bcl-2, cleaved PARP, Beclin 1, LC3B-II were considerably elevated by inhibiting the PI3K/AKT/mTOR signaling pathway.ResultsOur findings show that ailanthone, without causing adverse effects in vivo, greatly suppressed the growth of A549/DDP-grafted tumors and improved the anti-tumor efficaciousness of cisplatin.ConclusionAccording to this study, ailanthone may increase sensitivity to cisplatin and promote autophagy and death in NSCLC A549/DDP cells through the signaling pathway of PI3K/AKT/mTOR.
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CURRENT CANCER DRUG TARGETS
·
2023
·Vol. 23
·期 6
·471-481
·
IF 3
Peng Chen,Zhang Chunming,Yu Wenjie,Li Le,Zhang Zhen,Liu Ting,Zhang Yan,Fan Gaiping,Huangfu Hui
Background: Thyroid carcinoma (TC) is a common malignant tumor in human and its incidence has been increasing in recent years. Studies have shown that receptor type protein tyrosine phosphatase epsilon (PTPRE) is a key regulator of tumorigenesis in cancer progression, but its role in
TC has not been revealed. Objective: Here, in this work, we explored the essential role of PTPRE in TC progression. Methods: The expression of PTPRE in TC clinical samples and cell lines was detected by RT-qPCR and Western blot. Cell proliferation was measured by MTT and cell cycle
analysis. Cell migration, invasion and epithelial-mesenchymal transition (EMT) were analyzed by wound healing, transwell, and immunofluorescent staining assays. AKT and ERK1/2 signaling pathway related protein level was analyzed by Western blot. Results: PTPRE was highly expressed in
TC clinical samples and cell lines, especially anaplastic thyroid carcinoma (ATC). High level of PTPRE was associated with tumor size and TNM stage. Upregulated PTPRE promoted cell proliferation, and enhanced the migration, invasion and EMT of TC cells, whereas the knockdown of PTPRE suppressed
these behaviors. Importantly, we confirmed that the AKT and ERK1/2 signaling pathways were activated by PTPRE, reflected by the enhanced protein level of phosphorylated AKT and ERK1/2. Conclusion: Accordingly, we indicated that PTPRE plays an oncogenic role in TC progression via activating
the AKT and ERK1/2 signaling pathway. These findings indicated that modulation of PTPRE expression may as a potential strategy to interfere with the progression of TC.
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PHARMACOLOGICAL RESEARCH
·
2026
·
IF 12.2
Muqiu Liu,Huaizhi Du,Junhui Zheng,Min Liu,Zhihao Jiang,Jieying Huang,Sihe Jiang,Lang Yi,Lingyu Zhang,Yanwu Li,Qun Du,Liang Liu,Haojie Ni,Xiaojun Zhang,Hua Zhou,Yan Dong
Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is a severe extra-articular manifestation with limited treatment options. Identifying anti-arthritic agents that concurrently protect against ILD is clinically significant. Sinomenine (SIN), a natural alkaloid used clinically to treat RA, shows potential anti-fibrotic activity, but its efficacy and mechanism in RA-ILD remain unclear. Here, integrative bioinformatic analyses identified ILD-associated signature characterized by upregulated CHRNA7 (encoding α7nAChR) and downregulated GLUL , specifically in pulmonary fibroblasts and myofibroblasts, and GLUL was a crucial mediator between RA and ILD. In the adjuvant-induced arthritis (AIA) model with pulmonary inflammatory and fibrotic remodeling, the phenotype that recapitulates early-stage RA-ILD, pulmonary ACh and α7nAChR expression were observed upregulated. SIN ameliorated arthritis and pulmonary lesions, suppressed pulmonary α7nAChR signaling, inhibited AKT/FOXO3 activation, restored GLUL expression and improved autophagy-related changes in this model. Microscale thermophoresis (MST), molecular docking and molecular dynamics simulation supported a direct binding between SIN and α7nAChR. In vitro , α7nAChR activation with PNU-282987 promoted fibroblast-to-myofibroblast transition (FMT), whereas its genetic knockdown inhibited FMT, suppressed AKT/FOXO3 activation, and restored GLUL expression in TGF-β-stimulated MRC-5 cells. We confirmed direct FOXO3 binding to the GLUL promoter by ChIP-qPCR. SIN inhibited FMT and regulated the AKT/FOXO3/GLUL axis in an α7nAChR-dependent manner. Pharmacological inhibition and siRNA-mediated knockdown of GLUL abolished SIN-mediated regulation of mTOR-autophagy signaling and FMT. Our findings identify the α7nAChR/AKT/FOXO3/GLUL axis as a novel fibrotic driver and highlight SIN as a potential therapeutic candidate to inhibit RA-ILD by targeting this axis.
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PHYTOMEDICINE
·
2026
·
IF 11.3
Jing-Yu Feng,Jing-Ling Yang,Rui Zhang,Kiran Thakur,Jian-Guo Zhang,Jianbo Xiao,Zhao-Jun Wei
DT-13 potently inhibits CRC metastasis with a favorable biosafety profile. • Plectin (PLEC) is identified as the direct intracellular binding target of DT-13. • DT-13 occupies the PLEC CH domain to physically disrupt the PLEC-TPM4 interactome. • Target engagement down-regulate TPM4 and suppresses Akt/ERK-driven EMT programs. Background Metastasis is the leading cause of colorectal cancer (CRC) mortality. Standard 5-fluorouracil (5-FU) has limited anti-metastatic efficacy and dose-dependent toxicities, underscoring the need for therapeutic alternatives with improved safety profiles. Methods This study investigated the anti‑metastatic mechanism of Liriope muscari baily saponins C (DT‑13) in CRC. Cell viability, migration, and invasion were assessed in HCT116 cells. An orthotopic CRC model was established in BALB/c nude mice to compare the therapeutic efficacy and hematological safety of DT-13 against 5-FU. Direct targets of DT-13 were identified using chemical proteomics (small‑molecule pull‑down, cellular thermal shift assay, drug affinity responsive target stability assay) and molecular dynamics simulations. Results DT-13 inhibited HCT116 proliferation (IC 50 ∼19 μM) and reduced migration and invasion by 78% and 90% in vitro. In vivo , DT-13 achieved a comparable reduction in tumor volume to 5-FU (21% of control volume), while exhibiting a favorable safety profile. Chemical proteomics identified plectin (PLEC) as a primary direct target of DT-13. Molecular docking revealed a binding affinity of –7.654 kcal/mol. Mechanistically, DT-13 occupied the calponin homology domain of PLEC, disrupting its interaction with tropomyosin-4 (TPM4). This led to TPM4 downregulation and subsequently inhibition of Akt and ERK signaling pathways, thereby suppressing the epithelial-mesenchymal transition process. Conclusion DT‑13 exerts anti-metastatic effects in CRC by disrupting the PLEC/TPM4 cytoskeletal scaffold. DT-13 achieved potent anti-metastatic efficacy with a significantly improved systemic safety profile compared to 5-FU. These findings highlight the clinical potential of DT-13 as a safer therapeutic alternative for patients with metastatic CRC. Download: Download high-res image (126KB) Download: Download full-size image
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KAOHSIUNG JOURNAL OF MEDICAL SCIENCES
·
2025
·
IF 3.1
Yan-Jun Yang,Jiu-Sheng Li
Sacubitril/valsartan (Sac/Val) has emerged as an effective compound with myocardium-protective functions in experimental and clinical trials for heart failure. This study investigated the function of Sac/Val in hypertensive heart disease (HHD) and explored the underlying mechanism. Spontaneous hypertensive rats (SHRs) were used as an animal model of HHD. Sac/Val administration ameliorated pathological injury, fibrosis, cell apoptosis, inflammatory cytokine production, and oxidative stress in the myocardial tissues of HHD rats. Similar findings were observed in vitro, where Sac/Val treatment reduced inflammation, oxidative stress, and fibrosis-related markers in Ang II-challenged H9C2 cells. Calcium/calmodulin-dependent protein kinase kinase 2 (CAMKK2) was identified as a target of Sac/Val which was downregulated in HHD models, and CAMKK2 protein levels were restored by Sac/Val treatment. Lentiviral vector-induced CAMKK2 knockdown reduced the phosphorylation levels of AMPKα, AKT, and GSK-3β, thereby negating the treatment effects of Sac/Val. Further treatment with AICAR, an AMPK agonist, significantly reactivated the AMPK/AKT/GSK-3β cascade and alleviated inflammatory injury in both models. Collectively, this study suggests that Sac/Val ameliorates inflammation and oxidative stress in HHD by restoring the CAMKK2 protein and activating the AMPK/AKT/GSK-3β cascade.
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危险品化学品经营许可证（带存储）