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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INTERNATIONAL IMMUNOPHARMACOLOGY
·
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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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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Cell Death Discovery
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2026
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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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BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
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2024
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IF 2.5
Le Wang,Zhaobin Lei,Guanjie Zhang,Yang Cheng,Mingwei Zhong,Guangyong Zhang,Sanyuan Hu
The escalating incidence of metabolic pathologies such as obesity and diabetes mellitus underscores the imperative for innovative therapeutics targeting lipid metabolism modulation. Within this context, augmenting thermogenic processes in adipose cells emerges as a viable therapeutic approach. Given the limitations of previous β3-adrenergic receptor (β3-AR) agonist treatments in human diseases, there is an increasing focus on therapies targeting the β2-adrenergic receptor (β2-AR). Olodaterol (OLO) is a potent β2-AR agonist that is a potential novel pharmacological candidate in this area. Our study explores the role and underlying mechanisms of OLO in enhancing brown adipose thermogenesis, providing robust evidence from in vitro and in vivo studies. OLO demonstrated a dose-dependent enhancement of lipolysis, notably increasing the expression of Uncoupling Protein 1 (UCP1) and raising the rate of oxygen consumption in primary brown adipocytes. This suggests a significant increase in thermogenic potential and energy expenditure. The administration of OLO to murine models noticeably enhanced cold-induced nonshivering thermogenesis. OLO elevated UCP1 expression in the brown adipose tissue of mice. Furthermore, it promoted brown adipocyte thermogenesis by activating the β2-AR/cAMP/PKA signaling cascades according to RNA sequencing, western blotting, and molecular docking analysis. This investigation underscores the therapeutic potential of OLO for metabolic ailments and sheds light on the intricate molecular dynamics of adipocyte thermogenesis, laying the groundwork for future targeted therapeutic interventions in human metabolic disorders.
研究领域:
药理学
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代谢学
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内分泌学
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细胞生物学
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Frontiers in Immunology
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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
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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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Scientific Reports
·
2025
·Vol. 15
·期 1
·1-19
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IF 3.9
Liu Yunxiao,Wang Shuanghu,Younas Ayesha,Lv Jiaojian,Al Mamun Abdullah,Shao Chuxiao
Nonalcoholic Fatty Liver Disease (NAFLD) is characterized by excessive lipid accumulation in hepatocytes and is closely associated with metabolic disturbances such as obesity, dyslipidemia, and insulin resistance. Despite its increasing prevalence and potential progression to severe liver conditions, there is currently no approved pharmaceutical intervention for NAFLD. Traditional Chinese Medicine (TCM) formulations, such as Xiaoyao San (XYS), have shown therapeutic efficacy in treating NAFLD, but the underlying mechanisms remain unclear. This study employed a multi-omics approach to elucidate the therapeutic mechanisms of XYS in NAFLD. A rat model of NAFLD was established using a high-fat diet (HFD). The chemical constituents of XYS were analyzed using UPLC-MS/MS. Transcriptomics and proteomics analyses were performed to identify potential biological targets and signaling pathways involved in the therapeutic effects of XYS. The results were validated using ELISA and Western blotting. UPLC-MS/MS identified 225 prototype chemical components of XYS in the blood. XYS significantly reduced body weight, liver index, and Lee’s index in NAFLD model rats. It ameliorated HFD-induced hepatic steatosis, down-regulated serum levels of ALT, AST, GGT, TG, TC, LDL-C, FBG, IL-1β, IL-6, TNF-α, and ROS, and up-regulated HDL-C levels. Transcriptomics and proteomics analyses revealed that XYS modulated key signaling pathways, including cAMP, TGF-β, NF-κB, and necroptosis. Specifically, XYS down-regulated the expressions of NF-κB, p-NF-κB, FOXO1, TGF-β1, RIP3, and p-MLKL, while up-regulating cAMP, PKA, p-PKA, and PPARα. XYS improves NAFLD by regulating the cAMP/PKA-mediated PPARα, FOXO1, and NF-κB signaling pathways. This study provides a comprehensive understanding of the molecular mechanisms underlying the therapeutic effects of XYS in NAFLD and supports its potential as a novel therapeutic intervention for this condition.
研究领域:
药理学
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代谢疾病
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系统生物学
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高影响因子
PHYTOMEDICINE
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2026
·
IF 11.3
Wen-Biao Zu,Zhao-Jie Wang,Dong-Mei Tang,Qin-Yu Lu,Yan-Yan Zhu,Zhong-Shun Zhou,Mei-Zhen Wei,Xiao-Dong Luo
Background Fungal diseases affect over one billion individuals worldwide and represent a significant public health concern. Oral candidiasis (OC) is a common fungal infection primarily caused by Candida albicans. Eriocapitella rivularis is a traditional medicinal herb for the treatment of oral fungal infections. Purpose This study aimed to identify potent antifungal compounds from E. rivularis and elucidate their underlying mechanisms of action. Methods Bio-guided isolation combined with network pharmacology was used to identify anti- C. albicans compounds from E. rivularis , followed by metabolomics analysis to explore potential regulatory pathways. Antifungal activity and synergistic efficacy were evaluated using broth microdilution, checkerboard, and time-kill assays. Biofilm inhibition was assessed through quantitative and biochemical analyses. Reverse transcription quantitative polymerase chain reaction was performed to elucidate molecular mechanisms. An in vivo murine OC model was employed to verify efficacy. Results Prosapogenin CP4 disrupted the fungal cell wall, targeted ergosterol to induce plasma membrane permeabilization, inactivated mitochondrial function, and inhibited hyphal growth, potentially through interference with ABC transporters, modulation of cAMP export, and induction of metabolic disorders. Prosapogenin CP4 and ursolic acid exhibited a synergistic inhibitory effect against fluconazole-resistant C. albicans (FICI = 0.375) with low resistance. This combination regulated genes in the Ras/cAMP/PKA signalling pathway, significantly inhibited biofilm formation and reduced fungal burden, inflammatory responses, and fungal colonisation in murine oral tissues, with efficacy comparable or superior to that of nystatin. Conclusion The finding presents a synergistic phytomedicine strategy using two triterpenoids from E. rivularis as a promising therapeutic approach for OC, particularly biofilm-associated infections.
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ONCOGENE
·
2018
·Vol. 37
·期 22
·2953-2966
·
IF 6.854
Cheng Yan,Gao Xing-Hua,Li Xian-Jing,Cao Qiu-Hua,Zhao Dan-Dan,Zhou Jin-Rong,Wu Hong-Xi,Wang Yun,You Lin-Jun,Yang Hong-Bao,He Yun-Long,Li Yong-Ren,Bian Jin-Song,Zhu Qing-Yi,Birnbaumer Lutz,Yang Yong
Depression drives cancer progression and induces poor clinical outcome. However, the mechanisms underlying depression and cancer outcomes are unclear. In this work, we investigated 98 prostate cancer patients and found that patients with high score of psychological depression were correlated with tumor invasion and metastasis. We found focal adhesion kinase (FAK) was increased in cancer patients with metastatic features and high score of depression. FAK knockdown completely blocked depression-promoted tumor invasion in orthotopic transplantation tumors. In Hi-myc mice and a murine model of depression, sympathetic activation was detected in the prostate tissue. Further we showed that FAK activation was dependent on a cAMP-PKA signaling pathway. Our results demonstrated that the activation of a sympathetic-FAK signaling pathway in prostate cancer patients with high degrees of depression facilitates tumor invasion. We suggest that blocking β2AR with propranolol or inhibiting FAK activation with PF562 271 may be novel strategies for depressed patients with invasive prostate cancer.
研究领域:
肿瘤学
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精神病学
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分子生物学
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PHYTOTHERAPY RESEARCH
·
2025
·
IF 6.3
Xian Zheng,Yuanyue Jiang,Wenbo Wang,Kekang Sun,Libin Zhou,Yanru Zhang,Jie Cui,Haiyan Yu,Wenbin Dong,Baofei Yan
Ulcerative colitis (UC) is a chronic inflammatory disease of the colon, characterized by recurrent flare-ups and limited effectiveness of available drug therapies. Asiatic acid (AA), a triterpenoid compound extracted from Centella asiatica , has shown promising pharmacological activities and therapeutic potential in several inflammation-related diseases. However, AA's efficacy in treating UC and its precise mechanisms of action remain to be fully explored. This study aimed to provide a comprehensive assessment of AA's therapeutic effects on UC and to investigate its underlying mechanisms, with a focus on gut microbiota interactions. In our study, a dextran sulfate sodium-induced UC mouse model was used to evaluate AA's therapeutic potential and explore its impact on gut microbiota composition and function. We further used an antibiotic cocktail and fecal microbiota transplantation assays to substantiate the role of gut microbiota in AA's mechanisms of action. A metabolomic analysis was also conducted to identify key metabolic pathways and gut microbiota-derived metabolites involved in AA's effects. Our findings demonstrated that AA significantly alleviates symptoms of UC, including reducing weight loss, slowing disease progression, mitigating colonic inflammation, and restoring immune balance. Mechanistically, the beneficial effects of AA were strongly linked to alterations in the gut microbiota and its metabolites, particularly γ-glutamyltyrosine. This metabolite was found to regulate the cyclic adenosine monophosphate/protein kinase A/nuclear factor kappa-B signaling pathway, which plays a crucial role in inflammatory responses. Overall, these findings strongly suggest that AA holds promise as a therapeutic agent for UC by modulating the gut microbiota and influencing critical inflammatory pathways.
研究领域:
药理学
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胃肠病学
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微生物组研究
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炎症性疾病
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代谢组学
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PubMed
高影响因子
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