Journal of Pharmaceutical Analysis
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2025
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IF 8.9
Jia Guo,Yuqing Song,Mengru Sun,Jun Qian,Dihang See,Tian Tian,Yunqing Song,Wei Liu,Hongping Deng,Yao Sun,Guangbo Ge,Yongfang Zhao
Osteoporosis, a severe systemic skeletal disorder characterized by decreased bone mineral density, leads to increased risks of bone fragility and fracture. Although some herbal medicines are clinically used for treating osteoporosis, the crucial anti-osteoporotic constituents and their mechanisms have not been well-elucidated. Notum, a negative regulator of Wnt/β-catenin signaling, has been validated as a druggable target for enhancing cortical bone thickness and alleviating osteoporosis. Herein, we showcase an efficient strategy for uncovering the key anti-Notum constituents from herbal medicines via integrating biochemical, phytochemical, computational, and cellular assays. Following screening the anti-Notum potentials of herbal medicines, Polygonum multiflorum Thunb. (PM), a commonly used anti-osteoporosis herb , showed potent and competitive inhibition against Notum. Phytochemical profiling coupling with docking-based virtual screening suggested that three anthraquinones, including rhein, emodin, and chrysophanol, showed high binding-potency towards Notum. Biochemical assays validated that three anthraquinones were strong competitive inhibitors of Notum, while rhein was the most potent one (IC 50 = 9.98 nM). Cellular investigations demonstrated that rhein markedly promoted osteoblast differentiation in dexamethasone-challenged MC3T3-E1 osteoblasts, while RNA sequencing showed that rhein remarkably regulated Wnt signaling-related and osteogenic differentiation-related genes. In vivo tests showed that rhein displayed favorable safety profiles in healthy mice and this agent significantly elevated bone mineral density, augmented trabecula and cortical bone thickness in dexamethasone-induced osteoporotic mice. Collectively, this study showcases an efficient strategy for uncovering the key anti-Notum constituents from herbal medicines, while rhein was identified as a naturally occurring Notum inhibitor that shows favorable safety profiles and impressive anti-osteoporosis effects.
研究领域:
药理学
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生物化学
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计算生物学
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DOI
高影响因子
Food Frontiers
·
2021
·Vol. 2
·期 3
·305-315
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IF 0
Erdong Yuan,Liangyun Liu,Min Huang,Bo Chang,Chunli Qi,Na Gou,Jiaoyan Ren
Five complex extracts (CEs) of seven Chinese herbs ( Astragalus , Poria cocos , Alpinia officinarum Hance , Radix Puerariae , Ginseng , Licorice , Hericium erinaceus ) were prepared by hot water extraction and evaluated for their effect on gastric ulcer in rats. In rats with acetic acid-induced chronic gastric ulcer, gross and microscopic appearance showed that gastric mucosal injury index and lesion inhibition rate were improved after CEs gavage for 21 days. Pretreatment with CEs for 21 days in rats with acute gastric ulcer could also improve the gastric mucosal injury by ethanol. CE1, CE4, and CE5 showed more obvious effect in two models. The cell experiments results showed that CE1, CE4, and CE5 effectively inhibited Wnt signaling activity. Thus, they could protect gastric mucosa through inhibiting Wnt signaling pathway. These results indicated that CE1, CE4, and CE5 had significant protective effects on gastric mucosal injury by inhibiting Wnt signalling pathway and could be developed into safe functional products.
研究领域:
药理学
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胃肠病学
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中医
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DOI
Cells
·
2025
·Vol. 14
·期 6
·394
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IF 5.2
Min Jiang,Jiaqi Hou,Qianqian Chai,Shihao Yin,Qian Liu
Pulmonary fibrosis due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is the leading cause of death in patients with COVID-19. β-catenin, a key molecule in the Wnt/β-catenin signaling pathway, has been shown to be involved in the development of pulmonary fibrosis (e.g., idiopathic pulmonary fibrosis, silicosis). In this study, we developed a SARS-CoV-2-infected A549-hACE2 cell model to evaluate the efficacy of the A549-hACE2 monoclonal cell line against SARS-CoV-2 infection. The A549-hACE2 cells were then subjected to either knockdown or overexpression of the effector β-catenin, and the modified cells were subsequently infected with SARS-CoV-2. Additionally, we employed transcriptomics and raw letter analysis approaches to investigate other potential effects of β-catenin on SARS-CoV-2 infection. We successfully established a model of cellular fibrosis induced by SARS-CoV-2 infection in lung-derived cells. This model can be utilized to investigate the molecular biological mechanisms and cellular signaling pathways associated with virus-induced lung fibrosis. The results of our mechanistic studies indicate that β-catenin plays a significant role in lung fibrosis resulting from SARS-CoV-2 infection. Furthermore, the inhibition of β-catenin mitigated the accumulation of mesenchymal stroma in A549-hACE2 cells. Additionally, β-catenin knockdown was found to facilitate multi-pathway crosstalk following SARS-CoV-2 infection. The fact that β-catenin overexpression did not exacerbate cellular fibrosis may be attributed to the activation of PPP2R2B.
研究领域:
分子生物学
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病毒学
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医学
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DOI
PubMed
高影响因子
AAPS PHARMSCITECH
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2025
·Vol. 26
·期 4
·1-17
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IF 4
Luo Zhilin,Sun Yao,Cai Shihao,Liu Hongting,Zhao Conglu,Xu Xiang,Xu Aiguo,Zhou Honggang,Yang Cheng,Gu Xiaoting,Ai Xiaoyu
Idiopathic Pulmonary Fibrosis (IPF) is a rare and serious chronic interstitial lung disease that may endanger the lives of patients. The median survival time of patients with idiopathic pulmonary fibrosis is short, and the mortality rate is higher than that of many types of cancer. At present, pirfenidone (PFD) and nintedanib (NDNB) have been approved by FDA for IPF, but they can only delay the process of pulmonary fibrosis and cannot cure the disease. Therefore, it is urgent to develop other drugs with the effect of improving pulmonary fibrosis. Ellagic acid (EA) can inhibit the Wnt-signaling pathway and has an effect in treating pulmonary fibrosis induced by bleomycin (BLM) in mice. However, its solubility is poor, resulting in its low bioavailability and limited therapeutic benefits, so its clinical application has been limited. Herein, based on the characteristics of nano-drug lung delivery system, chitosan (CS) was selected as the carrier, and ellagic acid-loaded chitosan nanoparticles (EA-CS-NPs) were prepared by ionic gelation method. The EE% and DL% of prepared EA-CS-NPs was 73.73 ± 4.52% and 6.23 ± 1.09%, the particle size was 119.6 ± 5.51 nm (PDI = 0.234 ± 0.017), the zeta potential was 29.833 ± 0.503 mV. The morphology of the nanoparticles was observed by TEM microscope, which was round, uniform dispersion, indicating that the preparation process is stable and feasible. The toxicity experiment showed that EA-CS-NPs maintained 80% cell viability, significantly higher than that of the NDNB group, indicating lower toxicity and better inhibitory effects on TGF-β1-stimulated MLg and NIH-3T3 cells. Wound healing assay results showed that the inhibitory effect of EA-CS-NPs on cell migration was more pronounced than that of EA in the same amount of EA-containing drugs. Drug uptake experiments revealed that EA-CS-NPs significantly enhanced drug uptake in MLg and NIH-3T3 cells. In vivo , Cy7-CS-NPs exhibited higher fluorescence intensity in rat lungs compared to Cy7 solution, indicating better lung retention. The in vivo efficacy test showed that compared with the EA group, EA-CS-NPs could better reduce the area of pulmonary fibrosis and collagen deposition, improve lung function, and have a longer retention time in the lung. In summary, our results revealed that EA-CS-NPs may be a good choice for the treatment of pulmonary fibrosis. Graphical
研究领域:
药剂学
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呼吸病学
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纳米医学
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DOI
PubMed
高影响因子
Cancer Management and Research
·
2023
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IF 3.3
Ping Huang,Shi-Xia Du
Objective The effect of PUE on enhancing the anti-cancerous efficacy of DDP on drug-resistant A549/DDP cancer and the underlying mechanisms were thoroughly investigated.Materials and Methods The cytotoxicity of PUE, DDP, and PUE + DDP to A549 cells and A549/DDP cells, respectively, is determined by cell apoptosis experiments. Anti-proliferation effect of PUE, DDP, and PUE + DDP on A549 cells and A549/DDP cells is evaluated by the cell cloning assay. Qualitative and quantitative analysis of the levels of PUE, DDP, and PUE + DDP of cell proliferation-related genes and proteins expressions in A549/DDP cells are determined by Western blot assay. The levels of VEGF in A549/DDP cells after different treatment strategies are determined by ELISA assay. Qualitative and quantitative determination of VEGF expression in tumor tissues are done by immunohistochemical staining.Results In vitro cellular experiments revealed that co-incubation of A549/DDP cells with PUE and DDP led to a dramatically decreased cell viability and cell survival rate compared with the cells only treated by DDP. Such a stimulating effect of PUE on DDP was further confirmed in vivo with results shown that the A549/DDP cancer-bearing mice treaded by combination therapy achieved the lowest tumor growth rate and longest survival time.Conclusion Taking these results together, we can draw the conclusion that the PUE enhances the anti-tumor effect of DDP on the drug-resistant A549 cancer in vivo and in vitro through activation of the Wnt signaling pathway.
研究领域:
肿瘤学
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药理学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
ENVIRONMENTAL POLLUTION
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2024
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IF 7.6
Yu-Jia Lin,Hong-Mei Li,Yan-Rong Gao,Ping-Fan Wu,Bin Cheng,Chen-Long Yu,Yu-Xin Sheng,Hai-Ming Xu
The aim of this study is to investigate the adverse effects of benzophenones (BPs) on the intestinal tract of mice and the potential mechanism. F1-generation ICR mice were exposed to BPs (benzophenone-1, benzophenone-2, and benzophenone-3) by breastfeeding from birth until weaning, and by drinking water after weaning until maturity. The offspring mice were executed on postnatal day 56, then their distal colons were sampled. AB-PAS staining, HE staining, immunofluorescence, Transmission Electron Microscope, immunohistochemistry, Western Blot and RT-qPCR were used to study the effects of BPs exposure on the colonic tissues of offspring mice. The results showed that colonic microvilli appeared significantly deficient in the high-dose group, and the expression of tight junction markers Zo-1 and Occludin was significantly down-regulated and the number of goblet cells and secretions were reduced in all dose groups, and the expression of secretory cell markers MUC2 and KI67 were decreased, as well as the expression of intestinal stem cell markers Lgr5 and Bmi1 , suggesting that BPs exposure caused disruption of intestinal barrier and imbalance in the composition of the intestinal stem cell pool. Besides, the expression of cellular inflammatory factors such as macrophage marker F4/80 and tumor necrosis factor TNF-α was elevated in the colonic tissues of all dose groups, and the inflammatory infiltration was observed, which means the exposure of BPs caused inflammatory effects in the intestinal tract of F1-generation mice. In addition, the contents of Notch/Wnt signaling pathway-related genes, such as Dll-4 , Notch1 , Hes1 , Ctnnb1 and Sfrp2 were significantly decreased in each high-dose group ( P < 0.05), suggesting that BPs may inhibit the regulation of Notch/Wnt signaling pathway. In conclusion, exposure to BPs was able to imbalance colonic homeostasis, disrupt the intestinal barrier, and trigger inflammation in the offspring mice, which might be realized through interfering with the Notch/Wnt signaling pathway.
研究领域:
毒理学
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分子生物学
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环境科学
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产品关联
DOI
PubMed
高影响因子
LIFE SCIENCES
·
2025
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IF 5.1
Wenwen Zha,Ziang Wang,Weitao Hu,Chenkai Ge,Wenbin Yuan,Qinyuan Shen,Weirong Li,Wanqing Chen,Jingrong Tang,Zhonghao Xiao,Yunlong Meng,Lirong Huang,Zilin Zhong,Tao-Sheng Li,Jianjun Chen,Zigang Cao
Bexarotene (Bex) is a selective retinoid X receptor (RXR) agonist and is commonly used as an anti-tumor drug in the clinic to treat patients with cutaneous T-cell lymphoma (CTCL). With the widespread use of this drug, people are increasingly concerned about its side effects and safety of use. At present, the effects of bexarotene drugs on the health of organisms remain uncertain, but retinoid drugs are generally biologically active and may pose potential risks to them. Therefore, in this study, we used a zebrafish model to evaluate the effects of Bex on embryonic development. Six hours after fertilization, we exposed zebrafish embryos to 3 μg/L, 6 μg/L, and 9 μg/L bexarotene. At 96 hpf, compared with the control group, zebrafish embryos exposed to bexarotene showed obvious heart and liver development defects, including reduced hatching rate, pericardial enlargement, heart rate disorder, yolk sac edema, small liver area and abnormal photo-optical motor responses. Transcriptome and qPCR results showed abnormal expression of genes related to heart and liver development was induced by Bexarotene. Mechanistically, bexarotene induced a significant upregulation of the transcriptional expression levels of genes related to the Wnt signaling pathway, and IWR-1 was able to effectively rescue the heart and liver developmental defects of zebrafish caused by bexarotene. Therefore, our study showed that bexarotene may cause zebrafish embryonic developmental defects by upregulating the Wnt signaling pathway, revealing the side effects and associated novel mechanisms of bexarotene, and providing a theoretical basis for its safe and effective use in the treatment of clinically related diseases.
研究领域:
发育生物学
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毒理学
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分子生物学
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DOI
PubMed
高影响因子
ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY
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2021
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IF 6.291
Meifeng Li,Tingting Yu,Jingli Lai,Xue Han,Jihuan Hu,Zeyuan Deng,Dongming Li,Zuocheng Ye,Shanghong Wang,Chengyu Hu,Xiaowen Xu
Ethoprophos is an effective and widely pesticide that used in controlling nemathelminth and soil insect. However, ethoprophos has been frequently detected in environment and freshwater. The potential toxicity to aquatic organisms is still not be explored. In this study, zebrafish embryo model was used to evaluated the toxicity of ethoprophos during cardiovascular developmental process of zebrafish. Zebrafish embryos were separately exposed to 10 mg/L, 20 mg/L, 30 mg/L, 40 mg/L and 50 mg/L of ethoprophos exposure at 96 h post-fertilization (hpf), which induced cardiac defects, such as low heart rate, pericardium edema and long SV-BA distance, but had no influence to vascular development. Mechanistically, the expression of cardiac-related genes were abnormal. Moreover, ethoprophos exposure significantly increased oxidative stress in zebrafish embryos by inhibiting the production of antioxidant enzyme (SOD) and activating reactive oxygen species. Expectedly, some apoptosis genes were induced and the apoptotic cardiomyocytes were detected by acridine orange staining. In addition, ethoprophos exposure also inhibited the expression of genes in wnt signaling pathway, such as β-catenin, Axin2, GSK3β and Sox9b. BML284, an activator of wnt signaling pathway, can rescue the cardiotoxic effect of embryos. These results indicated that oxidative stress and blocking wnt signaling pathway were molecular basis of ethoprophos-induced injure in zebrafish. Generally, our study showed that ethoprophos exposure led to severe cardiotoxicity to zebrafish embryo.
研究领域:
毒理学
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发育生物学
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环境科学
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产品关联
DOI
PubMed
高影响因子
Cell Regeneration
·
2023
·Vol. 12
·期 1
·1-18
·
IF 0
Liu WenYe,Lin ShuHui,Li LingYa,Tai ZhiPeng,Liu Jing-Xia
EAF1 and EAF2, the eleven-nineteen lysine-rich leukemia (ELL)-associated factors which can assemble to the super elongation complex (AFF1/4, AF9/ENL, ELL, and P-TEFb), are reported to participate in RNA polymerase II to actively regulate a variety of biological processes, including leukemia and embryogenesis, but whether and how EAF1/2 function in hematopoietic system related hypoxia tolerance during embryogenesis remains unclear. Here, we unveiled that deletion of EAF1/2 (eaf1−/− and eaf2−/−) caused reduction in hypoxia tolerance in zebrafish, leading to reduced erythropoiesis during hematopoietic processes. Meanwhile, eaf1−/− and eaf2−/− mutants showed significant reduction in the expression of key transcriptional regulators scl, lmo2, and gata1a in erythropoiesis at both 24 h post fertilization (hpf) and 72 hpf, with gata1a downregulated while scl and lmo2 upregulated at 14 hpf. Mechanistically, eaf1−/− and eaf2−/− mutants exhibited significant changes in the expression of epigenetic modified histones, with a significant increase in the binding enrichment of modified histone H3K27me3 in gata1a promoter rather than scl and lmo2 promoters. Additionally, eaf1−/− and eaf2−/− mutants exhibited a dynamic expression of canonical WNT/β-catenin signaling during erythropoiesis, with significant reduction in p-β-Catenin level and in the binding enrichment of both scl and lmo2 promoters with the WNT transcriptional factor TCF4 at 24 hpf. These findings demonstrate an important role of Eaf1/2 in erythropoiesis in zebrafish and may have shed some light on regeneration medicine for anemia and related diseases and on molecular basis for fish economic or productive traits, such as growth, disease resistance, hypoxia tolerance, and so on.
研究领域:
发育生物学
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血液学
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分子生物学
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DOI
INTERNATIONAL JOURNAL OF BIOLOGICAL MACROMOLECULES
·
2025
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IF 8.5
Taojing Yu,Qiteng Ding,Ning Wang,Shuai Zhang,Zhiqiang Cheng,Chunli Zhao,Qingjie Li,Chuanbo Ding,Wencong Liu
This study aimed to enhance the treatment of bone defects and increase peptide bioavailability. To achieve this, antioxidant-active peptides (DBPs) were extracted from deer antler blood and incorporated into an oxidised sodium alginate/amino gelatine injectable hydrogel (OSA/N-Gel). This bioscaffold was created through the Schiff base reaction, resulting in the development of an injectable hydrogel comprising OSA, amino gelatine, and deer antler blood peptides (OSA/N-Gel/DBP). OSA/N-Gel/DBP is characterised by a loose and porous structure that enhances nutrient flow and confers good degradability, enabling the gradual release of DBP to meet the long-lasting treatment requirements for bone repair. In vitro , 5-Ethynyl-2′-deoxyuridine (EDU), alkaline phosphatase (ALP), and Alizarin Red S (ARS) staining showed the pro-proliferative and pro-mineralising abilities of OSA/N-Gel and OSA/N-Gel/DBP on osteoblasts (MC3T3). OSA/N-Gel/DBP effectively promoted the expression of osteogenesis-related genes, such as ALP and vascular endothelial growth factor (CD31), and deposition of collagen (COL-1), and activated the wingless-related integration site (Wnt) signalling pathway, thereby promoting bone regeneration. The effect of OSA/N-Gel/DBP was significantly superior to that of the OSA/N-Gel group, indicating that DBP has good osteogenic properties. We successfully repaired bone defects and broadened the application of antler blood, thereby providing a novel approach to treating bone defects.
研究领域:
生物材料学
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骨再生医学
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分子生物学
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产品关联
DOI
PubMed
高影响因子
Journal of Pharmaceutical Analysis
·
2025
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IF 8.9
Na Liu,Yuzhen Tu,Hanyu Wang,Xiaoqiang Zheng,Fanpu Ji,Mingsha Geng,Xin Wei,Jingman Xin,Wangxiao He,Qian Zhao,Tianya Liu
The Wnt/β-catenin signaling pathway is renowned for its contribution to the immunosuppressive microenvironment in non-small cell lung cancer (NSCLC). Consequently, inhibiting this pathway has emerged as a promising strategy to enhance immune activation and reinstate T cell responses in cancer treatment. In this study, we initially investigate the metabolic characteristics of Wnt-hyperactivated NSCLC using mass spectroscopic detection in a mouse in-situ model and unveil its significant feature of acid accumulation at tumor sites. Building upon this discovery, we design an acid-sensitive peptide-carnosic acid (CA) supramolecular droplet, Pep1@CA, which leverages the acidic microenvironment characteristic of NSCLC for controlled release. By doing so, we aim to enhance targeting efficiency while minimizing off-target effects. As anticipated, Pep1@CA demonstrates potent tumor-specific inhibition of the Wnt signaling pathway and effectively reactivates T cell immunity in Wnt-hyperactivated NSCLC. Importantly, comprehensive in vivo evaluations reveal significant antitumor efficacy alongside excellent biosafety profiles. Collectively, this study provides a therapeutic strategy with promising clinical translational potential for targeting the Wnt signaling pathway and offers theoretical support for its application in immunotherapy. This innovative approach underscores that targeting pathways beyond traditional immunotherapy can also activate tumor immunity, thereby expanding the potential of cancer immunotherapy.
研究领域:
肿瘤学
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免疫学
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药理学
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产品关联
DOI
PubMed
高影响因子
Aging-US
·
2019
·
IF 5.515
Jun Ma,Changgui Shi,Zhongyang Liu,Bin Han,Lei Guo,Lei Zhu,Tianwen Ye
Glucocorticoids contribute to the increased incidence of secondary osteoporosis. Hydrogen sulfide (H 2 S) is a gasotransmitter and plays an essential role in bone metabolism. In this study, we investigated the therapeutic effects of H 2 S on glucocorticoid-induced osteoporosis (GIO). We found that dexamethasone (Dex) decreased serum H 2 S and two key H 2 S-generating enzymes in the bone marrow in vivo , cystathione b-synthase and cystathione g-lyase. Treatment of H 2 S-donor GYY4137 in rat significantly relieved the inhibitory effect of Dex on bone formation. Dex inhibited osteoblasts proliferation and osteogenic differentiation and decreased the expressions of the two H 2 S-generating enzymes. Further investigation showed that H 2 S was involved in Dex-mediated osteoblasts proliferation, differentiation, and apoptosis. Mechanistically, GYY4137 promoted osteoblastogenesis by activating Wnt signaling through increased production of the Wnt ligands. In comparison, the blockage of Wnt/β-catenin signaling pathway significantly alleviated the effect of H 2 S on osteoblasts. In conclusion, the restoration of H 2 S levels is a potential novel therapeutic approach for GIO.
研究领域:
药理学
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内分泌学
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骨代谢
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分子生物学
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产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）