Cell Death & Disease
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2026
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IF 12.2
Xian Chunmei,Huang An,Bao Zheng,Wang Long,Zhang Jinyue,Kong Xi,Wu Yuanyuan,Luo Sen,Yi Simeng,Huang Min,Peng Jianhua,Yin Shigang,Jiang Yong,Xie Bingqing,Xie Huangfan
Definitive endoderm (DE) specification is essential for gastrointestinal and respiratory organogenesis, yet upstream regulators that integrate signaling pathways with metabolic and epigenetic cues remain poorly understood. Here, we identified cyclin-dependent kinase 8 (CDK8) as an important regulator of human DE commitment. CDK8 deficiency significantly impaired DE formation and subsequent hepatic differentiation via EPAC-dependent cAMP hyperactivation and lysosomal acidification impairment. Multi-omics analyses revealed that CDK8 repressed neuroectoderm and cAMP pathway genes while activating endodermal and lysosomal programs, with associated changes in promoter-proximal H3K27me3 deposition. We further found that CDK8 and OTX2 coordinately regulated a FOSL2 / HNF4A / FOXH1 network in which FOXH1 serves as a downstream effector node, maintaining EPAC-dependent cAMP homeostasis and lysosomal acidification, thereby suppressing neuroectodermal gene expression while promoting endodermal commitment. Moreover, OTX2 could compensate for CDK8 loss in regulating this process. In summary, our study identified CDK8 as an upstream regulator that coordinates signaling, metabolic, and epigenetic cues to promote endodermal specification while restraining neuroectodermal mis-specification, providing new mechanistic insights into human endoderm development.
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JOURNAL OF CHEMICAL RESEARCH
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2024
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IF 1
Haodong Zhou,Yulan Zhu,Xianfeng Huang
PDE4 is a potential target for treating mental diseases including depression, Alzheimer’s disease and schizophrenia involving in the hydrolysis of cAMP. Curcumin is well-known for its potential as a neuroprotective compound against depression. It was able to inhibit PDE4 with IC50 value in the range of 10 to 20 μM with low selectivity. However, curcumin itself cannot be used clinically because of its poor drug-like properties. Herein, a series of new curcumin derivatives were designed and synthesized. Their PDE4 inhibitory activities and antidepressant effects in vivo were also evaluated. Consequently, most of these curcumin derivatives demonstrated good inhibitory activities against PDE4. Furthermore, compound 4e exhibited the most potent activity at nanomolar level (IC50 value: 23 nM). It also could improve depression-like behaviors induced by chronic stress including sugar forced swimming and water consumption tests in vivo.
研究领域:
药理学
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神经科学
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FOOD CHEMISTRY
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2025
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IF 9.8
Yongzhao Bi,Xingming Sun,Yan Huang,Baoguo Sun,Li Liang,Yuyu Zhang
The molecular basis of bitterness in soy sauce was investigated through an integrated approach combining peptidomics, sensory evaluation, cell biology, and molecular docking. Ethanol-extracted bitter peptides (BPs) were identified via liquid chromatography-tandem mass spectrometry. Seventeen BP candidates were shortlisted based on toxicity, allergenicity, bitterness predictions and hydrophobicity calculation. Sensory evaluation showed that 13 peptides exhibited bitterness, with 8 significantly enhancing bitterness of 6 key free amino acids in soy sauce. Using a HEK-293T cell-based cAMP assay, FYL and VLY were identified as hTAS2R4 ligands (EC₅₀ = 62.11 and 199.51 μM, respectively). Molecular docking revealed that both peptides bind primarily via hydrophobic interactions to residues such as VAL85, PHE88, and PHE62. These findings provide a theoretical basis for bitterness mechanism and flavor improvement of soy sauce.
研究领域:
食品科学
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分子生物学
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感官科学
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细胞生物学
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代谢组学
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Acta Pharmaceutica Sinica B
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2025
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IF 14.6
Chao Chen,Hongxia Zhang,Lingling Qi,Haoqi Lei,Xuefei Feng,Yingjie Chen,Yuanyuan Cheng,Defeng Pang,Jufeng Wan,Haiying Xu,Shifeng Cao,Baofeng Yang,Yan Zhang,Xin Zhao
Obesity is a significant risk factor for cancer and is associated with breast cancer metastasis. Nevertheless, the mechanism by which alterations in systemic metabolism affect tumor microenvironment (TME) and consequently influence tumor metastasis remains inadequately understood. Herein, we found that perturbations in circulating metabolites induced by obesity promote metastasis-like phenotypes in breast cancer. Oleoylcarnitine (OLCarn) concentrations were elevated in the serum of obese mice and humans. Administration of exogenous OLCarn induces metastasis-like characteristics in breast cancer cells. Mechanistically, OLCarn directly interacts with the Arg176 site of adenylate cyclase 10 (ADCY10), leading to the activation of ADCY10 and enhancement of cAMP production. Mutations at Arg176 prevent OLCarn from binding to ADCY10, disrupting the ADCY10-mediated activation of cyclic adenosine monophosphate (cAMP) signaling pathway. This activation promotes transcription factor 4 (TCF4)-dependent kinesin family member C1 (KIFC1) transcription, thereby driving breast cancer metastasis. Conversely, the neutralization of both ADCY10 and KIFC1 through knockdown or pharmacological inhibition abrogates the oncogenic effects mediated by OLCarn. Hence, obesity-induced systemic environmental changes lead to the aberrant accumulation of OLCarn within the TME, making it a potential therapeutic target and biomarker for breast cancer.
研究领域:
肿瘤学
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代谢学
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分子生物学
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癌症生物学
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INTERNATIONAL JOURNAL OF BIOCHEMISTRY & CELL BIOLOGY
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2019
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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
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2026
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IF 6.5
Jiamin Xie,Xiaojuan Pan,Yan Xia
Hepatocellular carcinoma (HCC) is a lethal malignancy with limited therapeutic options. Cellular senescence exerts a critical role in tumor progression, but the regulatory mechanisms remain unclear. This study investigates the role of pyruvate dehydrogenase phosphatase 1 (PDP1) in modulating senescence-associated malignant progression in HCC. Our study suggests that PDP1 is upregulated in patients with HCC and is significantly associated with poor prognosis. Functionally, PDP1 induces cellular senescence, activates cyclic adenosine monophosphate (cAMP)/Ca 2+ signaling, and promotes senescence-associated secretory phenotype (SASP)-driven epithelial-mesenchymal transition (EMT), stemness, and malignant progression. Xenograft models further demonstrate that PDP1 enhances tumor growth in vivo , accompanied by activation of senescence-associated pathways, including p16, p21, cAMP, and Ca 2+ . Adenylyl cyclase 5 (ADCY5), a membrane-associated enzyme responsible for catalyzing ATP into cAMP, is identified as a critical downstream mediator of these effects and serves as a major source of intracellular cAMP production. Mechanistically, PDP1 suppression enhances glycolysis and histone H3 lysine 18 lactylation (H3K18la), a recently identified lactate-derived epigenetic modification, leading to activation of DNA methyltransferase 1 (DNMT1), the primary enzyme maintaining DNA methylation patterns, and subsequent ADCY5 promoter hypermethylation and transcriptional silencing. Importantly, glycolysis inhibition restores senescence and reverses PDP1-driven malignant phenotypes. Collectively, these findings identify that PDP1 drives senescence-associated malignant progression in HCC by linking glycolytic regulation, histone lactylation, and DNA methylation to the control of ADCY5 expression and subsequent cAMP/Ca 2+ signaling, underscoring its potential as a therapeutic target.
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BIOCHEMICAL PHARMACOLOGY
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2026
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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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COLLOIDS AND SURFACES B-BIOINTERFACES
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2018
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IF 3.997
Qianqian Zhu,Wei Zhuang,Huanqing Niu,Lei Ge,Byron Villacorta Hernandez,Jinglan Wu,Kai Wang,Dong Liu,Yong Chen,Chenjie Zhu,Hanjie Ying
The development of an orientation immobilization technique via affinity between polyhistidine tags and metal ions aims at maintaining biocatalytic activity of the enzymes. In this work, to tackle the issue of the immobilization of adenylate cyclase (AC), a simple and effective approach of synthesizing iminodiacetic acid (IDA)-Ni 2+ particles was applied for simultaneously purifying and immobilizing his-tagged AC. We chose agarose particles as carriers, and then decorated them with IDA, leading to the formation of a coordination combination of Ni 2+ . The porous carriers with a large pore size of 50 nm and a specific surface area of 45.8 m 2 /g exhibited favorable enzymatic activity and loading capacity. The optimal pH of the immobilized enzyme increased from 8.0 to 9.0 and the optimal temperature increased from 30 °C to 35 °C, compared to the free AC. Moreover, the immobilized AC retained a residual activity of approximately 80% after storing it at 25 °C for 48 h, whereas only 40% of the activity was left in the free AC at the same conditions. Maximum yield of cyclic adenosine-3′, 5′- monophosphate (cAMP) reached up to the summit of the reaction. The immobilized AC by affinity adsorption will provide a promising route for the industrial production of cAMP.
研究领域:
生物化学
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酶工程
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Drug Design Development and Therapy
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2023
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IF 4.8
Junhui He,Dongbo Han,Chunlian Jia,Jiaxiu Xie,Fucui Zhu,Jie Wei,Dongmei Li,Dongmei Wei,Yi Li,Li Tang,Guining Wei,Jing Yan,Yuanming Tong,Lifang Yang,Xuecai Tan
Purpose To investigate the mechanisms of antidepressant action of active fraction of Polyrhachis vicina Rogers (AFPR) through network pharmacology, molecular docking and experimental validation.Methods GC-MS was used to predict chemical compounds, corresponding databases were used to predict chemical compound targets and depression targets, Cytoscape software was used to construct and analyze the protein interaction network map, DAVID database was used to analyze gene ontology (GO) and KEGG signaling pathway, and AGFR software was used to perform molecular docking. Subsequently, the underlying action mechanisms of AFPR on depression predicted by network pharmacology analyses were experimentally validated in a CORT-induced depression model in vitro and in vivo.Results A total of 52 potential targets of AFPR on antidepressant were obtained. GO is mainly related to chemical synaptic transmission, signal transduction and others. KEGG signaling pathways are mainly related to cAMP signaling pathway and C-type lectin receptor signaling pathway. The experiment results showed that AFPR significantly increased the expression of PRKACA, CREB and BDNF in mouse brain tissue and PC12 cells. Furthermore, after interfered of cAMP in PC12 cells, the decreased expression of PRKACA, CREB and BDNF was reversed by AFPR.Conclusion AFPR may exert antidepressant effects through multiple components, targets and pathways. Furthermore, it could improve neuroplasticity via the cAMP signaling pathway to improve depression-like symptoms.
研究领域:
药理学
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神经科学
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JOURNAL OF NANOBIOTECHNOLOGY
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2026
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IF 15
Shaoyong Weike,Jiang Shouchuan,Wang Yingqian,Li Wei,Wang Zilong,Yang Yixiao,Du Juan,Liu Zhongjie
Chronic exposure of the liver to diverse insults can lead to metabolic dysfunction-associated steatohepatitis (MASH), a complex metabolic disorder characterized by hepatic steatosis and inflammation, often accompanied by progressive fibrosis, intestinal barrier dysfunction, and intestinal endocrine imbalance. No approved pharmacotherapies effectively treat MASH largely because of the difficulty in reversing fibrosis and restoring extracellular matrix homeostasis. Managing intestinal barrier dysfunction and GLP1 secretion has emerged as a promising therapeutic strategy against the progression of metabolic-associated fatty liver (MAFL) to MASH. This study presents MSN@HTL, fabricated using trehalose and temsirolimus on mesoporous silica nanoparticles (MSNs) and encapsulated with sodium alginate using an electrostatic spraying system. After oral administration, MSN@HTL protects against intestinal barrier injury and GLP1 secretion, consequently inhibiting the progression of MAFL. MSN@HTL stimulated intestinal stem cell self-renewal, proliferation, and GLP1 secretion. Mechanistically, MSN@HTL induces lysosomal autophagy to recycle disrupted mitochondria, increasing mitochondrial fusion and energy metabolism, elevating cAMP concentration, and inducing PKA phosphorylation-mediated intestinal barrier revision and GLP1 secretion, thereby impairing MAFL-to-MASH progression. Given its availability and functionality, our study demonstrates the potential of MSN@HTL as a pharmaceutical agent for managing MAFL-to-MASH progression via the mitochondria/cAMP/PKA signaling pathway in humans. Graphical
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JOURNAL OF MOLECULAR ENDOCRINOLOGY
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2026
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IF 3.1
Xin Ning,Doudou Guo,Qing Huang,Cencen Wang,Yating Li,Yanfen Zhou,Xin Li
In mammals, chemerin and its receptor CMKLR1 might be downstream effectors in response to long photoperiod in the ependymal cells lining the third ventricle in rats. Iodothyronine deiodinase 2 (DIO2) is a main product of the involvement of TSH in photoperiodic signaling. Thus, the potential interplay of TSH and Chemerin/CMKLR1 signaling might exist during photoperiodic changes. Our study aimed to investigate whether Chemerin/CMKLR1 signaling could stimulate DIO2 production and how TSH could affect Chemerin/CMKLR1 signaling in primary rat ependymal cells. Colocalization of Chemerin with its receptor, CMKLR1, was observed using immunohistochemistry assay. The expression of chemerin and CMKLR1 was identified using real-time PCR and western blot analysis respectively. DIO2 expression, which involves a dual signaling pathway (an increase in cAMP levels and phosphorylation of ERK1/2, was detected by western blot assay and enzyme-linked immunosorbent assay (ELISA). Our study showed the potential interaction between Chemerin and CMKLR1 in primary rat ependymal cells. TSH could upregulate the expression of chemerin and CMKLR1 in Chemerin-pretreated primary ependymal cells. In vitro treatment of primary ependymal cells with Chemerin (10 ng/mL) or TSH (60 mIU/mL) could induce an increase in cAMP levels, ERK1/2 phosphorylation and DIO2 expression. Furthermore, we found that TSH could promote the effect of Chemerin/CMKLR1 signaling on DIO2 production through an increase in cAMP level and the phosphorylation of ERK1/2. We concluded that Chemerin/CMKLR1 signaling could enhance DIO2 activity in primary rat ependymal cells in vitro, and this effect could be promoted by TSH through cAMP and phosphorylation of ERK1/2.
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INTERNATIONAL IMMUNOPHARMACOLOGY
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2026
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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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