Oxidative Medicine and Cellular Longevity
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2022
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IF 7.31
Bingjie Xue,Bo Ma,Yaoyao Yao,Aimei Zhao,Ying Gao,Jianxun Liu
Cerebral microinfarcts (CMIs) are characterized by sporadic obstruction of small vessels leading to neurons death. They are associated with increased risk of cognitive impairments and may have different risk factors compared with macroinfarcts. CMIs have a high incidence and result in heavy social burden; thus, it is essential to provide reasonable treatment in clinical practice. However, there are relatively few researches on the mechanism and treatment of CMIs, and the literature is composed almost exclusively of community—or hospital based on autopsy or imageological studies focusing on elderly patients. The Bu Yang Huan Wu (BYHW) decoction, a traditional Chinese herbal formula, has long been used to treat stroke and stroke-related diseases, including cognitive impairments. We applied microsphere-induced CMI model in rats to investigate the behavioral and molecular consequences of CMIs and to determine how they were ameliorated by BYHW decoction treatment. We then used the Morris water maze, quantitative proteomics, immunohistochemistry, and other molecular assays and found that activation of the PKA/CREB pathway by BYHW decoction treatment may reverse mitochondrial dysfunction, inhibit apoptosis of hippocampal neurons, and ameliorate CMI-induced cognitive impairments in rats. Collectively, these findings confirmed the therapeutic potential of the BYHW decoction in treating cognitive impairments induced by CMIs and demonstrated a viable mechanism for its action.
研究领域:
神经科学
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药理学
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中医药学
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分子生物学
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行为科学
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JOURNAL OF PHARMACY AND PHARMACOLOGY
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2026
·Vol. 78
·期 2
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IF 3.7
Wang Baoying,Liu Hui,Zhang Changjing,Yan Xiangli,Xu Erping,Bai Ming,Li Yucheng
ObjectivesFormononetin (FMN) is known for its significant neuroprotective effects, this study aims to investigate the antidepressant potential and underlying mechanisms of FMN.MethodsAntidepressant efficacy was evaluated in corticosterone (CORT)-induced depression models. In vivo, CORT-exposed mice received FMN to assess behavioral and hippocampal changes (dendritic spine density, synaptic markers: MAP-2/GAP-43). In silico, network pharmacology and molecular docking predicted FMN’s binding affinity and enriched pathways. In vitro, HT22 cells pretreated with FMN (10 μM, 6 h) were subjected to CORT injury, with mechanistic validation via ERα antagonist (MPP) and ERK inhibitor (PD98059).Key findingsFMN alleviated depressive-like behaviors and preserved hippocampal integrity in mice. Bioinformatics analysis revealed FMN’s strong binding to ER subtypes and enrichment in estrogen/MAPK pathways. In vitro, FMN pretreatment activated the ERK-CREB-BDNF axis in CORT-injured HT22 cells, enhancing neuronal survival and synaptic function. The activation was ERα/ERK-dependent, as evidenced by the abolition of protective effects following pharmacological inhibition with MPP (ERα antagonist) or PD98059 (ERK inhibitor). Concomitantly, in vivo FMN treatment restored hippocampal p-ERK/ERK ratios in mice, directly corroborating the ERK-CREB-BDNF pathway activation and highlighting its efficacy in reversing CORT-induced signaling deficits.ConclusionFMN exerts antidepressant effects via ERα-mediated neurotrophic signaling (ERK-CREB-BDNF), offering a mechanistic foundation for natural antidepressant development.
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Materials Today Bio
·
2025
·
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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高影响因子
Drug and Alcohol Dependence Reports
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2026
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IF 3.5
Tianqi Wang,Shu Tian,Mengru He,Siyu Tang,Xinyu Ji,Qixin Deng,Wenjuan Zhang,Ge Jin,Jian Mao,Haifeng Zhang
Nicotine withdrawal-induced anxiety is a key contributor to cigarette smoking relapse. Cordycepin, an adenosine analogue, is hypothesized to counteract the withdrawal-induced decline in hippocampal AMP/ATP ratios and consequent AMP-activated protein kinase (AMPK) dephosphorylation, as its monophosphate derivative structurally mimics AMP and directly activates AMPK. In this study, a mouse model of chronic nicotine exposure followed by withdrawal was used to investigate whether cordycepin mitigates nicotine withdrawal-induced anxiety and its underlying mechanisms. Our results revealed that chronic nicotine exposure significantly elevated hippocampal AMPK phosphorylation, whereas nicotine withdrawal led to a sharp decline in p-AMPK levels (p-AMPK/t-AMPK: F = 23.11, P < 0.001), concomitant with pronounced anxiety-like behaviors in the elevated plus maze (open-arm time: F = 16.18, P < 0.01) and open field tests (center time: F = 6.63, P < 0.01). Pretreatment with cordycepin (10 mg/kg) effectively alleviated nicotine withdrawal-induced anxiety-like behaviors (open-arm time: F = 11.74, P < 0.01; center time: F = 5.79, P < 0.01), an effect that was counteracted by the AMPK inhibitor Compound C. Further mechanistic studies via Western blot and immunohistochemical analyses further demonstrated that cordycepin activated the hippocampal AMPK/CREB/BDNF signaling pathway, restoring withdrawal-induced reductions in p-AMPK, p-CREB, and BDNF expression. This effect was further validated in PC12 cell experiments. In conclusion, cordycepin alleviates nicotine withdrawal-induced anxiety by activating the AMPK/CREB/BDNF pathway, offering preliminary experimental evidence for its potential as an adjunctive therapy for smoking cessation.
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EXPERT OPINION ON THERAPEUTIC TARGETS
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2015
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IF 5.139
Xue Wang,Yu Ren,Haihui Zhuang,Xiangyu Meng,Shuaishuai Huang,Yanyuan Li,Michael Hehir,Ping Wang
Objective: Cyclic-AMP-responsive element-binding protein (CREB) is a proto-oncogenic transcription factor. The authors’ previous reports showed that blocking the CREB binding site at Ser 133 inhibited the expression of target genes, which related to the progression of some tumors. In this study, the authors investigated the role of phosphorylated CREB (pCREB) at Ser133 in renal cell carcinoma (RCC) growth and metastases.Methods: Immunohistochemistry, xenograft model in nude mice, cell proliferation assay, cell invasion/migration assay, fluorescent immunocytochemistry and Western analysis were performed in an immortalized proximal tubule epithelial cell line and clear-cell RCC.Results: The authors’ results showed that knockdown of pCREB inhibited kidney cancer cells growth in vivo. Furthermore, suppression of the pCREB level blunted the capabilities of cell migration and invasion in vitro and was accompanied with significantly decreased expression of MMP-2 and MMP-9, the filopodia formation and epithelial-mesenchymal transition-related proteins. Surprisingly, no changes of expression or location of vimentin were revealed in the experiment. Bioinformatic software explained the possible reason for this is that the promoter of vimentin does not contain the CRE sequence.Conclusions: These data suggest that decreasing the level of pCREB inhibits the growth and metastasis of RCC by targeting the Ser 133 site.
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COMBINATORIAL CHEMISTRY & HIGH THROUGHPUT SCREENING
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2024
·Vol. 28
·期 6
·1011-1025
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IF 1.6
Xiaotian Yang,Yajie Qin,Huifang Zhou
BackgroundPrimary dysmenorrhea (PDM) is a prevalent menstrual disorder among women, often underreported and undertreated. Wen-Jing-Zhi-Tong Decoction (WJZTD), a patented Traditional Chinese Medicine (TCM) herbal decoction, has shown efficacy in treating PDM. However, the underlying therapeutic mechanism of WJZTD in PDM treatment remains to be elucidated.ObjectiveThis study aimed to employ integrative pharmacology and experimental validation to investigate the potential therapeutic mechanisms of WJZTD in treating PDM.MethodsThe bioactive compounds of WJZTD were identified by UPLC-Q-Exactive-Orbitrap MS/MS and GC-MS. Putative targets of WJZTD were obtained from Swiss Target Prediction, STITCH, and BATMAN-TCM databases. Known targets of PDM were retrieved from Gene Cards and Drug Bank databases. Protein-to-protein interactions were constructed to screen key targets using the STRING database. Subsequently, GO and KEGG pathway enrichment analyses were performed based on Metascape. Finally, a PDM rat model was established to validate the potential therapeutic mechanisms of WJZTD using Western Blot, PCR, and ELISA.Results390 bioactive compounds in WJZTD were identified through UPLC-Q-Exactive-Orbitrap MS/MS and GC-MS. Network pharmacology revealed 7 key compounds with 20 targets and pathways that are crucial for WJZTD in treating PDM. Behavioral tests confirmed that WJZTD can effectively ameliorate menstrual pain in PDM. WJZTD also inhibited prostaglandin production, thereby relieving uterine smooth muscle contraction. The downregulation of the BDNF/TrkB/ERK/CREB signaling pathway, identified as the key target and pathway through network pharmacology, may be crucial to the anti-nociceptive and anti-inflammatory effects of WJZTD in treating PDM.ConclusionThis study provides the first comprehensive analysis of the key compounds, targets, and pathways of WJZTD, laying a solid foundation for future pharmacological studies on PDM. The anti-nociceptive and anti-inflammatory effect may be attributed to the downregulation of the BDNF/TrkB/ERK/CREB signaling pathway.
研究领域:
中药学
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药理学
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分子生物学
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Materials Today Bio
·
2026
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IF 11
Minghao Jiang,Wenjie Lu,Junyu Zhuang,Jiahui Song,Yanfang Zhao,Cheng Zhou,Yangbo Zhou,Weizhi Shu,Zhongwei Zhu,Lelin Jiang,Ping Wu,Aimin Wu,Sunren Sheng,Sipin Zhu,Zhouguang Wang
Spinal cord injury (SCI) induces severe neurological impairment, exacerbated by secondary inflammation and disrupted neural circuitry. Inspired by the spinal cord's electromechanical microenvironment, we developed a biomimetic conductive nerve scaffold via directional freeze-casting of gelatin methacryloyl (GelMA) hydrogel incorporated with N-acetylcysteine-modified silver nanowires (NAC-AgNWs). The scaffold exhibits axially aligned microchannels, tunable mechanical strength, and conductivity akin to native spinal tissue. In a rat model of complete spinal cord transection (2 mm), the scaffold exhibited dual therapeutic effects: (1) early-stage anti-inflammatory modulation (mediated by the synergistic interplay between AgNWs and NAC), and (2) sustained neural reconstruction, evidenced by robust axonal bridging across the lesion, synapse reformation, and significant functional recovery. Integrated transcriptomic analyses revealed the FGF13/Ca 2+ /CaMK2A/CREB axis as the activated pathway driving neurite outgrowth and neural circuit reconstruction. This biomaterial design establishes a novel therapeutic paradigm for SCI repair, integrating structural guidance, immunomodulation, and activation of pro-regenerative signaling.
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Frontiers in Pharmacology
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2026
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IF 5.4
Kanglu Yang,Lanyibo Liu,Caifeng Li,Shiwen Deng,Junxian Cao,Junqi Chen,Shaoping Wang,Qiangpu Chen,Peng Chen
Introduction Cellular senescence drives aging and age-related diseases, posing a critical barrier to stem cell-based regeneration. While selective elimination of senescent cells (senolysis) remains a theoretically promising strategy, safe natural senotherapeutic agents are limited. Human exfoliated deciduous tooth stem cells (SHED) possess high regenerative potential yet are vulnerable to senescence, compromising their therapeutic utility. Methods We performed a phenotypic screen of 800 natural compounds in replicatively senescent SHED. The hit compound, the phytochemical melissic acid, was then validated in two independent senescence models—replicative exhaustion and doxorubicin-induced stress. Melissic acid (5–20 μM) was assessed for cytotoxicity and anti-senescence efficacy via SA-β-Gal staining and senescence marker expression. Transcriptomic profiling and mechanistic assays were performed to dissect the underlying molecular pathways. Results Melissic acid exhibited minimal cytotoxicity but significantly reduced SA-β-Gal positivity and senescence markers in both models. Transcriptomic profiling revealed marked upregulation of ADCY5 and coordinated changes in cAMP signaling, autophagy, and lipid metabolism genes. Mechanistically, melissic acid increased CREB Ser133 phosphorylation, enhanced Beclin-1 expression, and reduced p62/SQSTM1, indicating activation of cAMP/CREB-dependent autophagy. It also decreased lipid peroxidation, restored mitochondrial membrane potential, and relieved G0/G1 arrest via upregulation of Cyclin D1 and Rb Ser780 phosphorylation. Discussion Collectively, melissic acid alleviates SHED senescence through the ADCY5/cAMP/CREB-autophagy axis, promoting autophagic clearance, mitochondrial recovery, and cell-cycle re-entry—thereby ameliorating senescence-associated phenotypes in senescent stem cells. This study identifies melissic acid as a natural senomorphic candidate for stem cell function restoration and provides a mechanistic link between cAMP-dependent autophagy and amelioration of stem cell aging, offering a potential strategy to overcome stem cell exhaustion and regenerative limits imposed by cellular senescence.
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JOURNAL OF ETHNOPHARMACOLOGY
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2023
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IF 5.4
Jiangyan Rao,Hongpu Li,Haonan Zhang,Xiaoxia Xiang,Xinyu Ding,Li Li,Funeng Geng,Hongyi Qi
Ethnopharmacological relevance Periplaneta americana (L.) (PA) has been used in traditional Chinese medicine for thousands of years for the effect of invigorating blood circulation and removing blood stasis . Modern pharmacological research shown that PA extract exhibits promising effects in promoting wound healing and regeneration, as well as in brain diseases such as Parkinson's disease (PD). However, whether it is effective for neuroregeneration and neurological function recovery after stroke still unknown. Aim of the study This study aims to investigate the potential effect of PA extract to promote brain remodeling through the activation of endogenous neurogenesis and angiogenesis, in addition, preliminary exploration of its regulatory mechanism. Methods Firstly, BrdU proliferation assay and immunofluorescence (IF) staining were used to evaluate the effect of PA extract on the neurogenesis and angiogenesis in vitro and in vivo . Subsequently, the effects of PA extract on brain injury in stroke rats were assessed by TTC and HE. While mNSS score, adhesive removal test, rota-rod test, and morris water maze test were used to assess the impact of PA extract on neurological function in post-stroke rats. Finally, the molecular mechanisms of PA extract regulation were explored by RNA-Seq and western blotting . Results The number of BrdU + cells in C17.2 cells, NSCs and BMECs dramatically increased, as well as the expression of astrocyte marker protein GFAP and neuronal marker protein Tuj-1 in C17.2 and NSCs. Moreover, PA extract also increased the number of BrdU + DCX + , BrdU + GFAP + , BrdU + CD31 + cells in the SGZ area of transient middle cerebral artery occlusion model (tMCAO) rats. TTC and HE staining revealed that PA extract significantly reduced the infarction volume and ameliorated the pathological damage. Behavioral tests demonstrated that treatment with PA extract reduced the mNSS score and the time required to remove adhesive tape, while increasing the time spent on the rotarod. Additionally, in the morris water maze test, the frequency of crossing platform and the time spent in the platform quadrant increased. Finally, RNA-Seq and Western blot revealed that PA extract increased the expression of p-ERK, p-CREB and BDNF . Importantly, PA extract mediated proliferation and differentiation of C17.2 and NSCs reversed by the ERK inhibitor SCH772984 and the BDNF inhibitor ANA-12, respectively. Conclusion Our study demonstrated that PA extract promoted neurogenesis and angiogenesis by activating the CREB/ERK signaling pathway and upregulating BDNF expression, thereby recovering neurological dysfunction in post-stroke.
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TOXICOLOGY
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2024
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IF 4.8
Linjing Xu,Huan Liu,Yifeng Rang,Lizi Zhou,Xukai wang,Yinhuan Li,Chunhong Liu
Nonylphenol (NP) and octylphenol (OP) are environmental contaminants with potential endocrine disrupting effects. However, there is limited research on the mechanisms and intervention of combined NP and OP exposure-induced neurotoxicity. This study aims to explore the cytotoxicity of combined NP and OP exposure and evaluate the potential of Lycium barbarum polysaccharides (LBP) in mitigating the aforementioned toxicity. In present study, LBP (62.5, 125 and 250 µg/mL) were applied to intervene rat adrenal pheochromocytoma (PC-12) cells treated with combined NP and OP (NP: OP = 4:1, w/w; 1, 2, 4 and 8 µg/mL). The results showed that NP and OP induced oxidative stress, disrupted the 5-hydroxytryptamine (5-HT) and cholinergic systems in PC-12 cells. Additionally, they activated the p38 protein kinase (p38) and suppressed the expression of silent information regulation type 1 (SIRT1), monoamine oxidase A (MAOA), phosphorylated cyclic-AMP response binding protein (p-CREB), brain-derived neurotrophic factor (BDNF) and phosphorylated tropomyosin-related kinase receptor type B (p-TrkB). However, N-acetyl-L-cysteine (NAC) treatment counteracted the changes of signalling molecule p38, SIRT1/MAOA and CREB/BDNF/TrkB pathways-related proteins induced by NP and OP. LBP pretreatment ameliorated combined NP and OP exposure-induced oxidative stress and neurotransmitter imbalances. Furthermore, the application of LBP and administration of a p38 inhibitor both reversed the alterations in the signaling molecule p38, as well as the proteins associated to the SIRT1/MAOA and CREB/BDNF/TrkB pathways. These results implied that LBP may have neuroprotective effects via p38-mediated SIRT1/MAOA and CREB/BDNF/TrkB pathways.
研究领域:
毒理学
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神经科学
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药理学
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环境科学
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高影响因子
Scientific Reports
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2025
·Vol. 15
·期 1
·1-13
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IF 3.9
Chen Juanli,Wei Chuanfei,Zhang Yingchao,Chen Qingfa,Li Xuemei,Zhang Wei,Zhang Xiaoping,Han Fabin
Alzheimer’s disease (AD) is characterized by the accumulation of amyloid beta (Aβ) plaques, leading to neuronal death. Notably, there are no therapeutically efficacious treatments for this disorder. This study investigates the neuroprotective mechanisms of curcumin. In vitro experiments demonstrated that curcumin significantly promoted the proliferation of neural stem cells (NSCs) derived from E16 mouse embryos. Additionally, in the APP/PS1 transgenic mouse model, curcumin improved cognitive function, as evidenced by a shorter escape latency and increased platform crossing frequency in the Morris water maze test and enhanced novel object recognition. Histological analysis showed that curcumin reduced Aβ accumulation in the hippocampal and cortical regions. Molecular studies revealed that curcumin upregulated the expression of BDNF and enhanced phosphorylation of CREB. Collectively, these findings indicate that curcumin exerts neuroprotective effects through multiple mechanisms, including promoting NSC proliferation, reducing Aβ accumulation, and the potential modulation of the BDNF-CREB signaling pathway.
研究领域:
神经科学
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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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神经退行性疾病
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高影响因子
NEUROCHEMICAL RESEARCH
·
2021
·Vol. 47
·期 3
·713-722
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IF 3.996
Zhang Haiju,Yu Shiqian,Xia Liping,Peng Xia,Wang Shun,Yao Baozhen
Epilepsy (SE) is a common and serious neurological disease. NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome participates in the pathogenesis of SE, while its underlying mechanism is still unclear. Here, we attempted to explore the mechanism of action of NLRP3 inflammasome in SE. SE mouse model was constructed by administration of kainic acid (KA). Astrocytes were treated with KA to mimic SE cell model. MCC950 (NLRP3 inhibitor) and Z-YVAD-FMK (Caspase-1 inhibitor) were used to treat astrocytes to inhibit the activity of NLRP3 and Caspase-1. Nissl staining was performed to examine the morphology of neuron. Western blot, enzyme-linked immunosorbent assay and immunofluorescence staining were performed to assess protein expression. SE mouse model exhibited an increase of neuronal loss, and an up-regulation of Cleaved-Caspase-1, IL-1β and IL-18 in hippocampus. The levels of GFAP + ADK + cells were significantly increased in SE mice. MCC950 or Z-YVAD-FMK abolished these impacts conferred by KA in SE mice. Moreover, KA treatment enhanced the expression of NLRP3, Cleaved-Caspase-1, IL-1β and IL-18 in astrocytes, which was rescued by knockdown of NLRP3 or Caspase-1. Additionally, CREB, p-CREB, REST were up-regulated, and SP1 was down-regulated in the KA-treated SE mice and KA-treated astrocytes. Inhibition of NLRP3 or Caspase-1 rescued these proteins expression in KA-treated astrocytes. CREB or REST silencing reduced adenosine kinase (ADK) expression, while SP1 knockdown enhanced ADK expression in KA-treated astrocytes. In conclusion, NLRP3 inflammasome activation enhances ADK expression to accelerate SE in mice through regulating CREB/REST/SP1 signaling pathway. Thus, inhibition of NLRP3 inflammasome may be a treatment for SE.
研究领域:
神经科学
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免疫学
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药理学
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细胞生物学
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高影响因子
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