INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY
·
2019
·
IF 3.144
Jinpeng Lv,Ying Fu,Rongyin Gao,Jiawen Li,Maofan Kang,Guoqiang Song,Changjun Yun
Diazepam is a medicament of the benzodiazepine family and it typically produces a sedative effect. Researchers have revealed that diazepam can induce melanogenesis and produce dendrite-like structures in B16 melanoma cells. However, the associated mechanisms of melanogenesis and phenotypic alterations have mostly remained unknown. In this study, we determined the effects of diazepam on melanogenesis, cellular phenotypic alterations, the location of melanosomes and the expression of relevant proteins in melanocytes using Masson–Fontana ammoniacal silver staining , scanning electron microscopy, immunocytochemistry and western blot analysis . Our results collectively indicated that diazepam had a pivotal role in melanocytes by enhancing melanin synthesis, melanocyte dendricity, melanosome trafficking, and capture at the dendrite tips. These functions might be attributed to the fact that diazepam activated the peripheral benzodiazepine receptor (PBR). This increased intracellular levels of cAMP, which stimulated the phosphorylation of cAMP response element-binding (CREB). As a result, this increased the tyrosinase , microphthalmia-associated transcription factor (MITF), Rab27a, Myosin Va, Rab17 and Cdc42 expression. This caused melanogenesis and melanosome transport. Therefore, our findings may provide a potential strategy for treating anti-hypopigmentation disorders.
研究领域:
药理学
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细胞生物学
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分子生物学
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皮肤科
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BIOCHEMICAL PHARMACOLOGY
·
2026
·
IF 6.5
Jiajia Chen,Xiaoxiao Liu,Ruoyu Wang,Jinjin Li,Zhifei Xu,Bo Yang,Qiaojun He,Xiaochun Yang,Hao Yan,Peihua Luo
Sotorasib, a first-in-class KRAS G12C inhibitor, has demonstrated substantial clinical efficacy in KRAS G12C–mutant malignancies but is frequently associated with gastrointestinal adverse events, the mechanisms of which remain poorly understood. In this study, we investigated the molecular basis of sotorasib-induced intestinal toxicity using complementary in vitro and an HP-β-CD-optimized in vivo model. Sotorasib treatment disrupted intestinal epithelial homeostasis by promoting apoptosis and suppressing proliferative capacity, resulting in impaired epithelial barrier integrity. Mechanistically, sotorasib markedly suppressed intracellular cAMP signaling in intestinal epithelial cells, as evidenced by reduced protein kinase A (PKA) activity and decreased phosphorylation of the transcription factor CREB. These effects were consistently observed in IEC-6 cells and murine colonic tissues lacking the KRAS G12C mutation, indicating a KRAS-independent mechanism. Pharmacological elevation of intracellular cAMP with forskolin partially restored CREB phosphorylation, attenuated epithelial apoptosis, enhanced proliferative activity, and improved expression of barrier-associated markers. In contrast, in NCI-H358 cells, forskolin increased CREB phosphorylation but failed to rescue sotorasib-induced growth inhibition, highlighting a pronounced cell type-dependent response to sotorasib. Collectively, our findings identify suppression of the cAMP/PKA/CREB signaling axis as a key mechanism underlying sotorasib-induced intestinal epithelial injury and provide mechanistic insight into the tissue-selective gastrointestinal toxicity of KRAS G12C-targeted therapy
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Toxics
·
2025
·Vol. 13
·期 4
·274
·
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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ANALYTICAL SCIENCES
·
2020
·Vol. 37
·期 7
·1039-1043
·
IF 2.049
Liu Shanshan,Zheng Sitian,Chu Jing
In this work, a novel colorimetric assay based on polythiophene derivative (PMNT) was designed for the detection of protein kinase A (PKA). PKA can catalyze the phosphorylation of peptide, leading to the conformation change of PMNT from random-coil to planar, with the disappearance of absorption peaks above 500 nm and a color change from pink to yellow. The fabricated assay exhibits a wide linear range of 0.05 – 20 U/mL with a detection limit of 0.02 U/mL for PKA activity detection. The proposed protocol has promising prospects for use in clinical diagnosis related to PKA activity.
研究领域:
生物化学
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分析化学
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分子生物学
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ACS Omega
·
2026
·
IF 5.2
Xintong Zhai,Mengjiao Wang,Wenfei Li,Xinyi Yin,Huiran Qi,Yuejiu Pang,Shupeng Su
Stabilizing Pickering emulsions with highly hydrophilic biopolymers such as chitosan remains challenging due to their strong hydrophilicity. By adjusting the pH to impart minimal or zero charge, these highly hydrophilic particles can form stable Pickering emulsions. However, no consensus has been reached regarding the optimal pH to fabricate stable Pickering emulsions. Hence, this study focused on the narrow pH window near the pKa of chitosan (pH 6.1–6.9) to clarify the optimal pH and the related formation and stability mechanisms. At pKa (pH 6.5), chitosan formed self-aggregated particles with optimal amphiphilicity and moderate surface charge, facilitating robust adsorption at the oil–water interface. The resulting emulsions exhibit remarkably small droplet sizes, good fluidities, high encapsulation capacities, and exceptional stability against creaming, coalescence, flocculation, and centrifugation. In contrast, emulsions prepared at pH below 6.5 suffered from excessive hydrophilicity and poor coalescence stability, while those at pH above 6.5 experienced particle overaggregation and gelation, leading to compromised fluidity and interfacial integrity. This superior performance of Pickering emulsions at the optimal pH was attributed to the optimal hydrophilic–hydrophobic balance and moderate surface charge of the chitosan particles, facilitating smaller droplet formation and uniform particle coverage. This finding is pivotal for future applications of chitosan Pickering emulsions and offers insights for developing food-grade Pickering emulsions with other hydrophilic charged particles.
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INTERNATIONAL IMMUNOPHARMACOLOGY
·
2026
·
IF 5.6
Qiao Li,Tiantian Li,Yunduan Wang,Yueyue Li,Shujin Wang,Daoliang Lan,Jian Li,Wei Fu
The present study aimed to investigate the toxic effects of zearalenone (ZEN) on the mammal ovaries and its impact on estradiol (E 2 ) synthesis, as well as to explore the detoxifying role of melatonin (MT) on ZEN. Firstly, we reanalyzed the transcriptome data between ZEN-exposed piglet ovaries and corresponding control group. We identified 3124 differentially expressed genes (DEGs), implying that ZEN significantly altered ovarian gene expression patterns. These DEGs were then subjected to GO and KEGG analyses, parts of which were specifically enriched in the production of ovarian hormones. By using an in vitro mouse granulosa cells (mGCs) model, we found that ZEN significantly reduced cell viability, increased intracellular ROS levels, and decreased mitochondrial membrane potential, with a significant downregulation of mRNA expression levels of E 2 synthesis genes ( Cyp19a1 , Cyp11a1 , Star and Hsd3b ) ( P < 0.05). Specially, MT was able to reverse the abovementioned indicators by increasing intracellular cAMP content, thus activating the cAMP-PKA pathway. In mice model, ZEN caused the swelling of mouse vulva, and significantly reduced sex hormone level in serum including E 2 , progesterone (PROG), follicle stimulating hormone (FSH), luteinizing hormone (LH), and the expression of E 2 synthesis genes ( P < 0.05), excepting for gonadotropin releasing hormone (GnRH) levels, which were significant increased. Of note, MT significantly recovered serum levels of E 2 , PROG, GnRH, and the expression of E 2 synthesis genes to the normal level by activating the cAMP-PKA pathway. In summary, ZEN altered piglet ovarian gene expression patterns, and disrupted gene expression involving in E 2 synthesis; ZEN caused oxidative stress and E 2 synthesis disorders in mGCs, and disturbed the secretion of reproductive hormones in mice, leading to endocrine disruption with reproductive toxicity; Whereas, MT could partially alleviate the disturbances in E 2 synthesis induced by ZEN through the cAMP-PKA pathway, suggesting MT as a potential remedy to alleviate the reproductive toxicity of ZEN.
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Food Science and Human Wellness
·
2022
·
IF 8.022
Chunxing Pan,Xiaoying Liu,Yating Zheng,Zejun Zhang,Yongliang Li,Biao Che,Guangrong Liu,Lanyue Zhang,Changzhi Dong,Haji Akber Aisa,Zhiyun Du,Zhengqiang Yuan
Glabridin is the main ingredient of hydrophobic fraction in licorice extract and has been shown to have anti-melanogenesis activity in skins. However, the underlying mechanism(s) remain not completely understood. The aim of this study is thus to elucidate the possible mechanisms related to the melanogenesis suppression by glabridin in cultured B16 murine melanoma cells and in UVA radiation induced hyperpigmentation model of BALB/c mice as well. Molecular docking simulations revealed that between catalytic core residues and the compound. The treatment by glabridin significantly downregulated both transcriptional and/or protein expression of melanogenesis-related factors including melanocyte stimulating hormone receptor (MC1R), microphthalmia-associated transcription factor (MITF), tyrosinase (TYR), TYR-related protein-1 (TRP-1) and TRP-2 in B16 cells. Both PKA/MITF and MAPK/MITF signaling pathways were found to be involved in the suppression of melanogenesis by glabridin in B16 cells. Also in vivo glabridin therapy significantly reduced hyperpigmentation, epidermal thickening, roughness and inflammation induced by frequent UVA exposure in mice skins, thus beneficial for skin healthcare. These data further look insights into the molecular mechanisms of melanogenesis suppression by glabridin, rationalizing the application of the natural compound for skin healthcare.
研究领域:
药理学
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分子生物学
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皮肤科
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细胞生物学
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Nature Communications
·
2025
·Vol. 16
·期 1
·1-19
·
IF 15.7
Peng Han,Xu Qikui,Zhang Ting,Zhu Jiakai,Pan Jinheng,Guan Xiaoyu,Feng Shan,Wu Jianping,Hu Qi
Lipid droplets (LDs) are the main cellular storage sites for triacylglycerols (TAGs), playing an important role in energy homeostasis and cell signaling. Hydrolysis of the stored TAGs begins with conversion of TAGs into diacylglycerols (DAGs) by adipose triglyceride lipase (ATGL), followed by hydrolysis of DAGs by hormone-sensitive lipase (HSL). Despite the central role of HSL in lipolysis, the molecular determinants for its LD association have remained elusive. Here, we report the cryo-EM structure of human HSL at 3.4 Å. Combining this with hydrogen-deuterium exchange mass spectrometry, biochemical and cellular assays, we identify residues 489-538, referred to as the “H-motif”, and the N-terminal 4-helix bundle of HSL as LD-binding motifs mediating direct interaction of HSL with LDs. LD binding mediated by the LD-binding motifs is independent of HSL phosphorylation catalyzed by the cAMP-dependent kinase PKA. Our findings provide insight into the LD binding mechanism of HSL, advancing our understanding of the regulation of lipolysis.
研究领域:
分子生物学
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细胞生物学
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结构生物学
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CELL DEATH AND DIFFERENTIATION
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2024
·
IF 13.7
Wang Shuai,He Ting,Luo Ya,Ren Kexin,Shen Huanming,Hou Lingfeng,Wei Yixin,Fu Tong,Xie Wenlong,Wang Peng,Hu Jie,Zhu Yu,Huang Zhengrong,Li Qiyuan,Li Weihua,Guo Huiling,Li Boan
Brown adipose tissue (BAT) is critical for non-shivering thermogenesis making it a promising therapeutic strategy to combat obesity and metabolic disease. However, the regulatory mechanisms underlying brown fat formation remain incompletely understood. Here, we found SOX4 is required for BAT development and thermogenic program. Depletion of SOX4 in BAT progenitors ( Sox4-MKO ) or brown adipocytes ( Sox4-BKO ) resulted in whitened BAT and hypothermia upon acute cold exposure. The reduced thermogenic capacity of Sox4-MKO mice increases their susceptibility to diet-induced obesity. Conversely, overexpression of SOX4 in BAT enhances thermogenesis counteracting diet-induced obesity. Mechanistically, SOX4 activates the transcription of EBF2, which determines brown fat fate. Moreover, phosphorylation of SOX4 at S235 by PKA facilitates its nuclear translocation and EBF2 transcription. Further, SOX4 cooperates with EBF2 to activate transcriptional programs governing thermogenic gene expression. These results demonstrate that SOX4 serves as an upstream regulator of EBF2, providing valuable insights into BAT development and thermogenic function maintenance.
研究领域:
分子生物学
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细胞生物学
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代谢
·
肥胖研究
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JOURNAL OF ENZYME INHIBITION AND MEDICINAL CHEMISTRY
·
2023
·
IF 5.6
Hao Zhou,Mengjiao Li,Hui Liu,Zheng Liu,Xuekun Wang,Shiben Wang
In this study, four series of piperazine derivatives were designed, synthesised and subjected to biological test, and compound 6a with potential antidepressant activity was obtained. An affinity assay of compound 6a with 5-hydroxytryptamine (serotonin, 5-HT)1A receptor (5-HT1AR) was undertaken, and the effects on the 5-HT level in the brains of mice were also tested. The results showed that compound 6a had the best affinity with 5-HT1AR (Ki = 1.28 nM) and significantly increased the 5-HT level. The expression levels of 5-HT1AR, BDNF, and PKA in the hippocampus were analysed by western blot and immunohistochemistry analyses. The results showed that the expression of 5-HT1AR, BDNF, and PKA in the model group was reduced compared to that of the control group, and compound 6a could reverse this phenomenon. Molecular docking was performed to investigate the interactions of the studied compound 6a with 5-HT1AR on the molecular level.
研究领域:
药理学
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神经科学
·
药物化学
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Cell Death Discovery
·
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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INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
·
2022
·Vol. 24
·期 1
·320
·
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
·
代谢
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