Toxics
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2025
·Vol. 13
·期 4
·274
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IF 4.1
Jie Gu,Huilin Jin,Jun Hu,Jian Wang,Daqiang Yin
Endocrine-disrupting chemicals (EDCs) are exogenous substances discharged into the environment through human activities. 3-Isopropylphenol, a typical alkylphenol-based EDC, has been extensively studied due to its broad application and potential ecological impacts. However, the mechanism of its neurotoxicity remains unclear. In this study, the neurotoxic effects of 3-isopropylphenol were examined using the zebrafish model. We predicted its potential toxic mechanisms and action targets using network toxicology and molecular docking and verified them via RT-qPCR. Results showed that 3-isopropylphenol exposure inhibits the cAMP/PKA signaling pathway in zebrafish larvae, promoting apoptosis, impairing neural development, and suppressing locomotor behavior. These findings enhance our understanding of the toxic effects and mechanisms of 3-isopropylphenol on zebrafish larval neural development and aid in evaluating its potential ecological hazards.
研究领域:
毒理学
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环境科学
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分子生物学
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PubMed
高影响因子
Cell Death Discovery
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2026
·
IF 10.4
Chen Yu,Wen Yuetao,Xu Diru,Hao Lei,Liu Qinglin,Kuang Jia,Zhao Wang,Yang Zhao
Depression is associated with complex hippocampal pathology, including disrupted signaling and neuronal damage. In this study, we developed a novel targeted nanoplatform using nucleic acid aptamer-modified astrocyte-derived extracellular vesicles loaded with geniposide (Apt-EVs@GP) to investigate its therapeutic mechanism, with a focus on the GATA binding protein 1 (GATA1)/adrenergic receptor beta 2 (ADRB2) axis in a chronic unpredictable mild stress (CUMS) mouse model. Apt-EVs@GP exhibited excellent biocompatibility and targeted accumulation in the hippocampus. Apt-EVs@GP treatment significantly ameliorated depression-like behaviors, as evidenced by enhanced locomotor activity and reduced immobility in standard behavioral assays. Transcriptomic analysis combined with molecular validation identified a key regulatory mechanism: Apt-EVs@GP suppressed stress-induced upregulation of GATA1, thereby relieving its transcriptional repression of ADRB2. This regulatory interaction was confirmed by chromatin immunoprecipitation and dual-luciferase reporter assays. Restoration of ADRB2 expression led to robust activation of the downstream cAMP/PKA/CREB signaling pathway. Functionally, reprogramming of the GATA1/ADRB2/cAMP axis conferred comprehensive hippocampal protection, including attenuation of neuroinflammation, suppression of neuronal apoptosis, and restoration of synaptic integrity. Our findings demonstrate that Apt-EVs@GP alleviates depression by targeting a novel GATA1/ADRB2 mechanism, highlighting its potential as a promising therapeutic strategy against depression-related hippocampal pathology. The alternative text for this image may have been generated using AI.
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FOOD MICROBIOLOGY
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2026
·
IF 5.4
Yu Zhao,Xiaoyun Zhang,Solairaj Dhanasekaran,Esa Abiso Godana,Jun Li,Zhenpeng Zhang,Lina Zhao,Hongyin Zhang
Aspergillus carbonarius- induced sour rot is an important postharvest disease affecting grapes. Previous study demonstrated that cAMP induction boosts the biocontrol efficiency of Sporidiobolus pararoseus Y16 in combating postharvest sour rot of grapes. Oxidative stress experienced by the antagonistic yeast at fruit wound sites is a key factor limiting its biocontrol efficacy. This research investigated how inducing yeast cells with cAMP effects on tolerance to oxidative stress and explored underlying mechanisms. Results showed that cAMP treatment significantly increased yeast survival rate under exogenous oxidative stress. Physiological analysis revealed a synergistic enhancement on enzyme activities, such as SOD, POD, and CAT in cAMP-induced yeast, accompanied by reduced levels of reactive oxygen species (ROS) under H 2 O 2 stress in vitro and at grape wound sites. Furthermore, levels of protein carbonylation, malondialdehyde (MDA) and trehalose were decreased. Transcriptomic analysis identified upregulation of key genes involved in one-carbon metabolism, thiamine biosynthesis, and amino acid metabolism, such as MTHFR , THI5 , ALDH7A1 , CTH , and proB, which collectively promoted NADPH regeneration, glutathione (GSH) synthesis, aldehyde detoxification, and direct ROS scavenging. In conclusion, cAMP induction activates a multilayered antioxidant defense system in S. pararoseus Y16 through metabolic reprogramming, significantly enhancing its adaptability to the oxidative stress microenvironment of grapes. These findings provide a theoretical basis for optimizing the performance of biocontrol yeasts, demonstrating their significant application prospects.
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BRITISH JOURNAL OF CANCER
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2025
·
IF 6.8
Chen Xiao,Cao Lixia,Feng Mengdan,Shuai Qiuying,Guo Min,Li Zhaoxian,Qi Chunchun,Shi Jie,Liu Yuxin,Zuo Siyu,Yu Tianwen,Hu Huayu,Wang Yanjing,Xue Yao,Sun Peiqing,Shi Yi,Wang Hang,Liu Lei,Yang Shuang
Background Breast cancer cells that break through the basement membrane interact directly with neighboring adipocytes. Therefore, adipocytes adjacent to the invasive front of tumour undergo lipolysis and transform into cancer-associated adipocytes (CAAs), which is vital for the malignant progression of breast cancer. However, tumor-derived factors that trigger this process are still to be determined. Methods Transcriptome sequencing was used to identify the downstream transcription factor of adrenomedullin (AM). Tet-On system was used to construct the 3T3-L1 cell line with inducible overexpression of Zeb1. Adipocyte-specific knock-in Zeb1 transgenic mice ( Zeb1 adiTG ) were used to construct an allograft tumor model. Results Breast cancer cell-derived AM downregulated the transcriptional expression of Zeb1 by triggering the cAMP/PKA/Creb1 pathway, thereby exerting lipolytic effects in CAAs. On the contrary, adipose tissue-specific upregulation of Zeb1 significantly attenuated AM-induced lipolytic phenotypes. Of note, we used the Zeb1 adiTG mice to construct allograft tumor models. The results confirmed that breast cancer cell-derived AM conferred tumorigenicity in vivo, which effect was predominantly dependent on the aberrant expression of adipocyte-specific Zeb1. Conclusions These findings collectively suggested that breast cancer cell-derived AM promotes lipid metabolic reprogramming through a Zeb1-dependent manner in CAAs, which displays significant clinical implications and may provide promising therapeutic approaches for targeting the breast cancer-associated adipose microenvironment.
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CHEMISTRY & BIODIVERSITY
·
2024
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IF 2.3
Xin Chen,Kexin Ye,Qing Li,Zhijie Luo,Qianchen Lu,Xue Rui,Yan Li,Jie Jin,Chenchen Jing,Meiling Hong,Mingcheng Qian,Shuai Zhao,Yanan Hou
We designed and synthesized 27 new amide and dipeptide derivatives containing a substituted phenylalanine as negative allosteric modulators (NAMs) for the beta-2 adrenergic receptor (β2AR). These analogs aimed to improve the activity of our lead compound, Cmpd-15, by introducing variations in three key regions: the meta-bromobenzyl methylbenzamide (S1), para-formamidophenylalanine (S2), and 1-cyclohexyl-1-phenylacetyl (S3) groups. The synthesis involved the Pd-catalyzed β-C(sp3)-H arylation of N-acetylglycine with 1-iodo-4-substituent-benzenes as the key step. GloSensor cAMP accumulation assay revealed that six analogs (A1, C5, C6, C13, C15 and C17) surpass Cmpd-15 in β2AR allosteric function. This highlights the crucial role of the S1 region (meta-bromobenzyl methylbenzamide) in β2AR allostery while suggesting potential replaceability of the S2 region (para-formamidophenylalanine). These findings serve as a valuable springboard for further optimizing Cmpd-15, potentially leading to smaller, more active, and more stable β2AR-targeting NAMs.
研究领域:
药理学
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化学生物学
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INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
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2022
·Vol. 24
·期 1
·320
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IF 6.208
Xiaoyu Zhang,Yuan Gao,Zhuangzhuang Liu,Wenjing Li,Yuan Kang,Ximeng Li,Zhenlu Xu,Cheng Peng,Yun Qi
As a worldwide health issue, obesity is associated with the infiltration of monocytes/macrophages into the adipose tissue causing unresolved inflammation. Monocyte chemoattractant protein-1 (MCP-1) exerts a crucial effect on obesity-related monocytes/macrophages infiltration. Clinically, aspirin and salsalate are beneficial for the treatment of metabolic diseases in which adipose tissue inflammation plays an essential role. Herein, we investigated the effect and precise mechanism of their active metabolite salicylate on TNF-α-elevated MCP-1 in adipocytes. The results indicated that salicylate sodium (SAS) could lower the level of MCP-1 in TNF-α-stimulated adipocytes, which resulted from a previously unrecognized target phosphodiesterase (PDE), 3B (PDE3B), rather than its known targets IKKβ and AMPK. The SAS directly bound to the PDE3B to inactivate it, thus elevating the intracellular cAMP level and activating PKA. Subsequently, the expression of MKP-1 was increased, which led to the decrease in p-EKR and p-p38. Both PDE3B silencing and the pharmacological inhibition of cAMP/PKA compromised the suppressive effect of SAS on MCP-1. In addition to PDE3B, the PDE3A and PDE4B activity was also inhibited by SAS. Our findings identify a previously unrecognized pathway through which SAS is capable of attenuating the inflammation of adipocytes.Keywords:cAMP;MKP-1;p-ERK;p-p38;metaflammation
研究领域:
药理学
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免疫学
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代谢
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JOURNAL OF PINEAL RESEARCH
·
2026
·Vol. 78
·期 2
·e70139
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IF 7.5
Yi Zheng,Qing-qing Chen,Hai-xiang Guo,Yu-xin Zhang,Ling-ling Qiu,Bing-bing Wang,Song Yu,Jia-rui Gao,Zhe Zhang,Jia-bao Zhang,Guo-shi Liu,Bao Yuan
Melatonin, a signaling molecule secreted by the pineal gland, is closely associated with physiological activities, such as animal growth, development, and reproduction. Multiple studies have indicated that melatonin acts on the adenohypophysis to promote the synthesis and secretion of growth hormone (GH), but the specific mechanism of melatonin remains unclear. We have previously reported that melatonin levels in bovine serum are closely correlated with GH levels. In the present study, transcriptome sequencing was performed on primary bovine adenohypophyseal cells treated with melatonin, which identified FOXO1 as a key transcription factor that is responsive to melatonin and regulates GH synthesis and secretion. Cellular experiments revealed that melatonin binds to the MTNR1A in bovine adenohypophyseal cells, activates the cAMP/PKA signaling pathway, and promotes the expression of FOXO1 protein. Dual-luciferase reporter assays verified the binding of FOXO1 to the GH1 promoter. Treatment with Luzindole, 4P-PDOT, 2′,5′-Dideoxyadenosine or H-89 elucidated the molecular mechanism through which melatonin promotes GH synthesis and secretion in adenohypophyseal cells through the cAMP/PKA/CREB/FOXO1 pathway. The present study provides critical evidence for the direct action of melatonin on adenohypophyseal cells and its targeted regulatory sites, and it offers new insights into the conserved and species-specific modes of action of melatonin across different species, providing data and theoretical support for the application of melatonin in promoting animal growth and development.
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Frontiers in Immunology
·
2025
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IF 5.9
Jikai He,Jiaqi Jia,Wenhao Qu,Shuyu Zhang,Keyu Fan,Runze Lin,Wei Zhao,Yan Niu,Yanqiang Huang,Lizhou Jia
Objective To analyze differences in gut microbiota composition, metabolites, and metabolic pathways between healthy individuals and colorectal cancer (CRC) patients, and to investigate the inhibitory effects of N-methylserotonin (NMS) produced by Bacteroides ovatus (B.o) from orange fiber on CRC progression and its underlying mechanisms. Methods (1) Fecal samples from CRC patients (n=26) and healthy controls (n=20) were collected for metagenomic sequencing and untargeted metabolomics analysis; (2) The ability of B.o to produce NMS from orange fiber was validated in vitro ; (3) A CRC mouse model was established using azoxymethane (AOM)/dextran sulfate sodium (DSS) induction, followed by evaluation of body weight, rectal bleeding, colorectal length, tumor number, and intestinal barrier function; (4) Network pharmacology, molecular docking, and western blot analysis were combined to verify the mechanism of action; (5) 16S rRNA sequencing was performed to analyze gut microbiota changes. Results (1) CRC patients showed significantly increased metabolic pathways including glycolysis, methane metabolism, beneficial amino acid degradation, and linoleic acid degradation, along with significantly decreased B.o abundance and NMS levels, which were positively correlated; (2) NMS significantly inhibited CRC cell proliferation, migration, and invasion, while promoting apoptosis; (3) Combined treatment with B.o and orange fiber or NMS alone reduced tumorigenesis and improved intestinal barrier function; (4) Mechanistic studies revealed that these effects could be mediated through downregulation of 5-hydroxytryptamine receptor 1D (HTR1D) expression and inhibition of the cAMP/PKA/IκBα/NF-κB pathway; (5) The treatments optimized gut microbiota structure and metabolite composition. Conclusion B.o and its metabolite NMS possibly inhibit CRC progression by modulating the HTR1D-mediated cAMP/PKA/NF-κB signaling pathway, while improving gut microbiota structure, providing a novel therapeutic target for CRC prevention and treatment.
研究领域:
肿瘤学
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微生物组研究
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分子生物学
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代谢组学
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胃肠病学
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药理学
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Materials Today Bio
·
2025
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IF 10.2
Yimurang Hamiti,Kai Liu,Xin Yang,Sulong Wang,Xiriaili Kadier,Aihemaitijiang Yusufu
Large bone defects present significant clinical challenges, with distraction osteogenesis (DO) requiring prolonged treatment periods and yielding suboptimal outcomes. Calcitonin gene-related peptide (CGRP) demonstrates potent bone-forming activity but suffers from rapid degradation and a short half-life, limiting its therapeutic applications. This study engineered sustained-release CGRP microspheres using poly(D,L-lactide-co-glycolide)/nano-hydroxyapatite/graphene oxide (PLGA/nHA/GO) composite matrices via W/O/W double emulsion-solvent evaporation method to address these limitations. The fabricated microspheres exhibited uniform spherical morphology (51.15 ± 0.40 μm), high encapsulation efficiency (86.14 ± 2.5 %), and sustained CGRP release over 42 days. In vitro studies compared four groups: control (untreated), blank microspheres, free CGRP solution, and CGRP-loaded microspheres. CGRP microspheres significantly enhanced rat bone marrow mesenchymal stem cell proliferation, migration capacity, and osteogenic differentiation compared to all other treatment groups. Mechanistic investigations confirmed activation of the cAMP/PKA/CREB signaling pathway with upregulation of osteogenic transcription factors (Runx2, Osterix) and bone matrix proteins (osteopontin, osteocalcin). In a rat femoral distraction osteogenesis model, CGRP microspheres demonstrated superior bone regeneration compared to control, blank microspheres, and free CGRP groups: substantially increased bone mineral density, significantly improved biomechanical properties, and accelerated bone formation. Histological analysis confirmed enhanced bone maturation and integration This engineered sustained-release system represents a promising therapeutic platform for enhancing bone regeneration through targeted molecular pathway activation, offering significant potential for clinical translation in orthopedic applications.
研究领域:
生物医学工程
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骨科
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组织工程
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药物递送系统
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分子生物学
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PubMed
高影响因子
PHARMACOLOGICAL RESEARCH
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2022
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IF 10.334
Jingjing Liu,Wanghui Jing,Tianyu Wang,Zhe Hu,Haitao Lu
Pancreatic cancer (PC) is one of the most malignant cancers, owing to extremely high aggressiveness and mortality. Yet, this condition currently incurs widely drug resistance and therapeutic deficiency. In this study, we proposed a novel functional metabolomics strategy as Spatial Temporal Operative Real Metabolomics (STORM) to identify the determinant functional metabolites in a dynamic and visualized pattern whose level changes are mechanistically associated with therapeutic efficiency of gemcitabine against PC. Integrating quantitative analysis and spatial-visualization characterization of functional metabolites in vivo, we identified that the AMP-cAMP axis was a novel therapeutic target of PC to intermediate therapeutic efficiency of gemcitabine. Gemcitabine could induce the dual accumulation of cyclic AMP (cAMP) and AMP in tumor tissues. Quantitative analysis of associated biosynthetic enzymes and genes revealed that two independent intracellular ATP derived biosynthetic pathways to promote the dual activation of AMP-cAMP axis in a lower-level energetic environment. Then, gemcitabine induced the dual accumulation of AMP and cAMP can separately activate signaling pathways of AMPK and PKA, leading to the inhibition of tumor growth by the upregulation of the downstream tumor suppressor GADD45A. Collectively, our new STORM strategy was the first time to identify novel target of PC from a metabolic perspective as the dual activation of AMP-cAMP axis induced by gemcitabine can efficiently suppress PC tumor growth. In addition, such discovery has the capability to lower drug resistance of gemcitabine by specifically interacting with novel target, contributing to the improvement of therapeutic efficiency.
研究领域:
肿瘤学
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代谢组学
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药理学
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分子生物学
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COMPARATIVE BIOCHEMISTRY AND PHYSIOLOGY A-MOLECULAR & INTEGRATIVE PHYSIOLOGY
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2019
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IF 2.142
Rong Xiong,Wei Zhao,Xi Chen,Tian Li,Haiyin Li,Yan Li,Wangshang Shen,Ping Chen
Serotonin is involved in the regulation of many physiological and behavioral processes in vertebrates and invertebrates. The effects of serotonin are mediated through interactions of several 5-HT receptor types. The expression and pharmacological properties of 5-HT1 have received more attention than other serotonin receptors, but its functions at the individual level are little studied in arthropods. Silkworm , a Lepidoptera model, almost has no reports about serotonin receptors. To analyze the function of Bm5-HT1A receptor in vitro , the ORF of Bm5-HT1A was cloned into the pcDNA3.1 vector and expressed in HEK 293 cells . Serotonin activation of Bm5-HT1A -expressing cells decreased forskolin-stimulated cAMP synthesis and had the most potent effect compared to other biogenic amines. Serotonin reduced cAMP synthesis in a dose-dependent manner, and half-maximal activation (EC50) occurred at a concentration of 1.17 × 10 −7 M (117 nM). The pharmacological analysis demonstrated that the rank potency of agonists was pimozide >8-OH-DPAT >5-MeOT ~ αm-5-HT, and antagonists was WAY-100635 > prazosin > SB-269970 > methiothepin at the Bm5-HT1A receptor. Injecting the antagonist of Bm5-HT1A receptor into larvae caused slow or weak motility, and adults lowered courtship vitality or moving speed. Injecting dsRNA of Bm5-HT1A into adults also dropped locomotivity in courtship. These results show that the Bm5-HT1A receptor is related to locomotor activity. This study provides the first information of serotonin receptor on pharmacological in silkworm and on individual functions in arthropods.
研究领域:
神经生物学
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药理学
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昆虫生理学
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分子生物学
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Journal of Herbal Medicine
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2023
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IF 2.3
Ying Liu,Xia Zhang,Huaiyu Cheng,Yifang Li,Guangxiong Zhou
ABSTRACT Introduction It has a long history to employ Macleaya cordata (Willd.) R. Br. (Papaveraceae) for the treatment of a variety of diseases in China. Chelerythrine, one of the major of M. cordata with detoxifying and anti-inflammatory effect, is reported to combat bacteria and fungus. This work aims to explore the effect of chelerythrine against fluconazole-resistant C. albicans and also illustrate its potential mechanism. Methods The microdilution method, following CLSI-M27-A3 was used to evaluate the effect of chelerythrine against fluconazole-resistant C. albicans. Meanwhile, biofilm viability was assessed by XTT assay and cell morphology was observed by inverted microscope. RT-qPCR and confocal laser scanning microscope were employed to detect the mRNA expression and DCFH-DA staining, respectively. Fluorescence intensity was quantified by flow cytometry. Results The total alkaloids extract of M. cordata significantly inhibited the viability of C. albicans, concentration of which in 64 μg/mL presented to 40% inhibitory effect . In addition, the MIC 80 for chelerythrine was 8 μM, whereas chelerythrine in 4 μM inhibited biofilm formation by 47.7%. Further studies revealed that chelerythrine reduced the hydrophobicity of cellular surface, inhibited hyphal growth, downregulated the expression of genes related to cAMP pathway, increased cellular permeability and promoted the production of reactive oxygen species (ROS). Conclusion Chelerythrine inhibited biofilm formation by decreasing CSH and inhibiting the cAMP pathway. Chelerythrine increased cellular permeability and promoted the production of reactive oxygen species, which leads to the cell death of fluconazole-resistant C. albicans .
研究领域:
药理学
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微生物学
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植物化学
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抗真菌研究
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高影响因子
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