EXPERIMENTAL AND MOLECULAR PATHOLOGY
·
2025
·
IF 3.7
Jinpeng Lv,Kun Zou,Chuanwei Yin,Wenhui Xu,Duo Meng,Huansha Zhang,Wenhao Yu,Peiwen Jiang,Changjun Yun,Hui Xue,Nan Hu,Rongyin Gao
Daidzin, a prominent isoflavone found in soybeans, Pueraria lobata , and various legumes, has been extensively investigated for its diverse pharmacological activities, which include anticancer, antioxidant, anti-inflammatory, antiepileptic, and alcohol detoxification properties. Previous studies have shown that the dichloromethane fraction of Pueraria lobata stem (DCM-PLS) exhibits significant anti-melanogenic activity, with daidzin identified as the principal active compound. However, the precise role of daidzin in pigmentation remains incompletely understood. This study aimed to investigate the effects of daidzin on pigmentation and to elucidate the underlying mechanisms. Our findings revealed that daidzin not only inhibited basal melanin production but also reduced melanin synthesis induced by α-MSH, ACTH, and UV exposure. The effects of daidzin were primarily mediated through the activation of the extracellular signal-regulated protein kinase (ERK) and protein kinase B (AKT) pathways. Upon activation, these pathways facilitated the ubiquitination and degradation of Melanocytes Inducing Transcription Factor (MITF), resulting in decreased expression of tyrosinase, TRP-1, and TRP-2, ultimately inhibiting melanogenesis. Importantly, our research further demonstrated that daidzin reduced pigmentation in both zebrafish and human skin explants, highlighting its potential application as a therapeutic approach for disorders related to skin pigmentation.
研究领域:
药理学
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皮肤科学
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生物化学
·
分子生物学
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植物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2024
·
IF 10
Zongpu Han,Yixiong Lin,Xinyu Guo,Jieyun Xu,Xiaomeng Gao,Ruihan Yang,Yuan Zhao,Mixiao Gui,Linjun Zhang,Yuanlong Guo,Zetao Chen
The strategy of re-organogenesis provides an optimal framework for restoring complex organ structures and functions in adult damage. While the focus has often been on restoring organogenesis stem cells, there is limited investigations of reverting the environmental niche to support this approach. The guiding principle of “Nature selects the fittest to survive” drives the intricate dynamic changes in cellular events within the niche environment, especially through immune surveillance. The extracellular matrix (ECM) serves as the “self-associated molecular patterns” of the niche, containing extensive data on cell-niche reaction data and acting as the active tuner of immune surveillance. In this study, hyaluronic acid (HA) is identified as a unique component of the ECM in cranial osteo-organogenesis. Mechanistically, HA activates the Cluster of Differentiation 44 (CD44)-Mitogen-Activated Protein Kinase (MAPK)/Extracellular Signal-Regulated Kinase (ERK)-Ets Variant 1/5 (ETV1/5)- Mannose Receptor C-Type 1 (MRC1) axis in macrophages, establishing a distinct immune surveillance during osteo-organogenesis. Furthermore, HA is utilized as a novel engineered material for an “Osteo-organogenesis niche”, restoring immune surveillance and synergistically regulating stem cells to achieve re-osteo-organogenesis in cranial defects of rats. Taken together, the study unveils a previously unknown strategy for leveraging re-organogenesis by utilizing “organogenesis niche” ECM engineered materials to manipulate immune surveillance, thereby comprehensively regulating stem cells and other tissue cells effectively for re-organogenesis.
研究领域:
再生医学
·
免疫学
·
组织工程学
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产品关联
DOI
PubMed
高影响因子
FASEB JOURNAL
·
2020
·Vol. 34
·期 6
·8402-8415
·
IF 4.966
Xingquan Xu,Rongliang Wang,Rui Wu,Wenjin Yan,Tianshu Shi,Qing Jiang,Dongquan Shi
Bone loss is a severe complication of primary biliary cirrhosis (PBC). Trehalose was intermittently administered in bile duct-ligated (BDL) male rats, a PBC-related osteoporosis model, for 4 weeks to reduce osteoporosis. Femoral bones were assessed ex vivo by micro computed tomography (CT) and histomorphometry. The potential mechanisms related to the reduction of osteoporosis were explored by evaluating the effect of trehalose on osteoblast autophagy, osteogenesis, osteoclastogenesis, and ERK phosphorylation. The results demonstrated that trehalose reduced osteoporosis of BDL rats and decreased osteoblast-mediated osteoclast differentiation by enhancing osteoblast autophagy to regulate osteoprotegerin (OPG) secretion. Hydroxychloroquine (HCQ) increased the expression of OPG and OPG /receptor activator genes for nuclear factor-κB ligand (RANKL) ratio, and reduced osteoblast-mediated osteoclastogenesis by inhibiting autophagy flux and inducing autophagosome formation. Furthermore, trehalose increased the phosphorylation of ERK1/2 in MC3T3-E1 cells, and the ERK inhibitor PD98059 reversed the upregulation of OPG gene and reduction of trehalose-induced osteoclastogeneis. The treatment with HCQ markedly increased the ERK phosphorylation. The correlation between autophagosome formation and ERK phosphorylation was confirmed in autophagy proteins (ATG) 4B or ATG5-deficient cells. Thus, trehalose could decrease osteoblast-mediated osteoclastogenesis and reduce PBC-related bone loss by regulating ERK phosphorylation via autophagosome formation.
研究领域:
药理学
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病理学
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分子生物学
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骨科
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产品关联
DOI
PubMed
高影响因子
CLINICAL SCIENCE
·
2022
·Vol. 136
·期 4
·291-307
·
IF 6.876
Liang Liping,Liu Le,Zhou Wanyan,Yang Chenghai,Mai Genghui,Li Haolin,Chen Ye
Ulcerative colitis (UC) is majorly associated with dysregulation of the dynamic cross-talk among microbial metabolites, intestinal epithelial cells, and macrophages. Several studies have reported the significant role of butyrate in host–microbiota communication. However, whether butyrate provides anti-inflammatory profiles in macrophages, thus contributing to UC intestinal mucus barrier protection, has currently remained elusive. In the current study, we found that butyrate increased mucin production and the proportion of mucin-secreting goblet cells in the colon crypt in a macrophage-dependent manner by using clodronate liposomes. Furthermore, in vivo and in vitro studies were conducted, validating that butyrate facilitates M2 macrophage polarization with the elevated expressions of CD206 and arginase-1 (Arg1). In macrophages/goblet-like LS174T cells co-culture systems, butyrate-primed M2 macrophages significantly enhanced the expression of mucin-2 (MUC2) and SPDEF (goblet cell marker genes) than butyrate alone, while blockade of WNTs secretion or ERK1/2 activation significantly decreased the beneficial effect of butyrate-primed macrophages on goblet cell function. Additionally, the adoptive transfer of butyrate-induced M2 macrophages facilitated the generation of goblet cells and mucus restoration following dextran sulfate sodium (DSS) insult. Taken together, our results revealed a novel mediator of macrophage–goblet cell cross-talk associated with the regulation of epithelial barrier integrity, implying that the microbial metabolite butyrate may serve as a candidate therapeutic target for UC.
研究领域:
免疫学
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胃肠病学
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微生物学
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细胞生物学
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产品关联
DOI
PubMed
高影响因子
ANTICANCER RESEARCH
·
2024
·Vol. 44
·期 7
·2861-2870
·
IF 1.6
YINA ZHANG,XIAOCEN NIU,YUANHE WANG,SHUTING BAO,PEIYUE JIANG,XIAORUI DONG
Background/Aim: Glutamine metabolism is crucial in cell proliferation, aging, and apoptosis across various cancer types. Existing research indicates that Sirtuin 4 (SIRT4), primarily located in mitochondria, modulates this process. This study aimed to clarify the regulatory relationship between SIRT4 and glutamine metabolism in cervical cancer. Materials and Methods: SIRT4 mRNA levels and their clinical correlation to cervical cancer were analyzed using the UALCAN database. Immunohistochemistry (IHC) was performed to assess SIRT4 protein expression in tissue samples from cervical cancer patients. Transient transfection was employed to create Hela and Siha cell lines with overexpressed SIRT4, mitogen-activated extracellular signal-regulated kinase (MEK), and glutaminase 1 (GLS1). The impact on cellular functions was studied using MTT, soft agar, transwell, and western blotting assays. Glutamate and ATP levels were also measured to evaluate metabolic changes. Results: Low levels of SIRT4 mRNA in cervical cancer tissues correlated with tumor metastasis and poor survival rates. Overexpression of SIRT4 led to suppressed cell proliferation, colony growth, and motility, along with significant down-regulation of GLS expression, a key contributor to glutamine metabolism. Additionally, SIRT4 overexpression resulted in the inactivation of the MEK/ERK/c-myc signaling pathway, while overexpression of MEK reversed these effects. Notably, the inhibitory effects of SIRT4 on cell proliferation, colony formation, migration, and invasion in Hela and Siha cells were significantly attenuated following GLS1 overexpression. Conclusion: SIRT4 acts as an anti-cancer agent in cervical cancer by inhibiting glutamine metabolism through the MEK/ERK/c-myc signaling pathway, providing a novel sight for cervical cancer therapy.
研究领域:
肿瘤学
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分子生物学
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细胞生物学
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癌症代谢
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DOI
PubMed
高影响因子
MOLECULES
·
2022
·Vol. 27
·期 15
·4996
·
IF 4.927
Guang-Xi Yu,Ying Hu,Wei-Xin Zhang,Xin-Yi Tian,Sai-Yang Zhang,Yan Zhang,Shuo Yuan,Jian Song
[1,2,4]Triazolo[1,5-a]pyrimidine and indole skeletons are widely used to design anticancer agents. Therefore, in this work, a series of [1,2,4]triazolo[1,5-a]pyrimidine indole derivatives were designed and synthesized by the molecular hybridization strategy. The antiproliferative activities of the target compoundsH1–H18against three human cancer cell lines, MGC-803, HCT-116 and MCF-7, were tested. Among them, compoundH12exhibited the most active antiproliferative activities against MGC-803, HCT-116 and MCF-7 cells, with IC50values of 9.47, 9.58 and 13.1 μM, respectively, which were more potent than that of the positive drug5-Fu. In addition, compoundH12could dose-dependently inhibit the growth and colony formation of MGC-803 cells. CompoundH12exhibited significant inhibitory effects on the ERK signaling pathway, resulting in the decreased phosphorylation levels of ERK1/2, c-Raf, MEK1/2 and AKT. Furthermore, compound12induced cell apoptosis and G2/M phase arrest, and regulated cell cycle-related and apoptosis-related proteins in MGC-803 cells. Taken together, we report here that [1,2,4]triazolo[1,5-a]pyrimidine indole derivatives, used as anticancer agents via the suppression of ERK signaling pathway and the most active compound,H12, might be a valuable hit compound for the development of anticancer agents.Keywords:[1,2,4]triazolo[1,5-a]pyrimidine;indole;antiproliferative activities;ERK signaling pathway
研究领域:
药物化学
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肿瘤学
·
药理学
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DOI
PubMed
高影响因子
NEUROSCIENCE
·
2023
·
IF 3.3
Lu-Lu Lin,Gui-Jun Song,Hui Zhang,Yan Yin,Shi-Meng Xin,Li Ding,Yu Li
Alzheimer's disease (AD) is a serious neurodegenerative disease characterized by amyloid-β (Aβ) aggregation and neuroinflammation. G-protein-coupled receptor 34 (Gpr34) was found highly expressed in the hippocampus of APP/PS1 mice. However, its role in AD remains unclear. Herein, the role of Gpr34 as well as its molecular mechanism was explored. Data in GSE85162 were analyzed and the differently expressed genes in the hippocampus tissues of APP/PS1 mouse model of AD were subjected to GO, KEGG and GSEA enrichment analyses. APP/PS1 mice were used as an animal model of AD and the cognitive impairment was evaluated by a water maze test. The level of Gpr34 in hippocampus and BV-2 cells as well as the activation of ERK/NF-κB signal was determined by quantitative real-time PCR, western blot or immunofluorescence. Our results showed that, in BV-2 cells exposed to Aβ 1-42 , Gpr34 knockdown decreased the levels of TNF-α, IL-1β, IL-6 and iNOS and suppressed the activation of ERK/NF-κB signal. Moreover, the Gpr34-overexpression-induced activation of ERK/NF-κB signal and up-regulated levels of TNF-α, IL-1β, IL-6 and iNOS were abolished by FR180204, an ERK inhibitor. On the other hand, the in vivo study showed that Gpr34 knockdown ameliorated the cognitive impairment in APP/PS1 mice, decreased the levels of TNF-α, IL-1β and IL-6, the activation of microglia and ERK/NF-κB signal. In conclusion, Gpr34 knockdown relieved cognitive deficits in APP/PS1 mice and suppressed neuroinflammation and microglial activation, maybe via the ERK/NF-κB signal. It is indicated that the high level of Grp34 in hippocampus may contribute to the pathogenesis of AD.
研究领域:
神经科学
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分子生物学
·
神经退行性疾病
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产品关联
DOI
PubMed
高影响因子
Scientific Reports
·
2016
·Vol. 6
·期 1
·1-10
·
IF 5.228
Peng Mei,Huang Yanjun,Tao Ting,Peng Cai-Yun,Su Qiongli,Xu Wanjun,Darko Kwame Oteng,Tao Xiaojun,Yang Xiaoping
EGFR is a potential therapeutic target for treating bladder cancer, but has not been approved for clinical use yet. Metformin is a widely used antidiabetic drug and has demonstrated interesting anticancer effects on various cancer models, alone or in combination with chemotherapeutic drugs. The efficacy of gefitinib, a well-known EGFR tyrosine kinase inhibitor, combined with metformin was assessed on bladder cancer and underlying mechanisms were explored. This drug combination induced a strong anti-proliferative and anti-colony forming effect and apoptosis in bladder cancer cell lines. Gefitinib suppressed EGFR signaling and inhibited phosphorylation of ERK and Akt. Metformin amplified this inhibitory effect and enhanced gefitinib-induced activation of AMPK signaling pathway. In vivo intravesical treatment of metformin and gefitinib on syngeneic orthotopic mice confirmed the significant inhibitory effect on bladder tumor growth. These two drugs may be an excellent combination for the treatment of bladder cancer through intravesical instillation.
研究领域:
肿瘤学
·
药理学
·
分子生物学
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产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2023
·
IF 5.6
Sisi Ruan,Jiqing Xie,Linhai Wang,Lulu Guo,Yan Li,Wu Fan,Rongzhan Ji,Zhenlin Gong,Yan Xu,Jian Mao,Jianping Xie
Introduction: Nicotine (Nic) has previously been proven to reduce neurodegeneration in the models of Parkinson’s disease (PD). The present study is intended to investigate the detailed mechanisms related to the potential neuroprotective effects of Nic in vivo . Methods: We established a PD model using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced C57BL6 mice (25 mg/kg/d, 5 d, i.p.) to investigate the neuropharmacological modulation of Nic pretreatment (2.5 mg/kg/d, 5 d, i.p., 30 min before MPTP injection) from the perspectives of neurobehavioral assessment, the pathological alterations, microglial cell inflammation and MAPK signaling pathways in specific brain regions. Results: The open field test, elevated plus maze, rotarod and traction test suggested that Nic pretreatment could significantly improve MPTP-induced motor impairment and had an anxiolytic effect. Nic was found to improve neuroapoptosis, enhance tyrosine hydroxylase activity, and reduce the accumulation of the phosphorylated α-synuclein in the substantia nigra and striatal regions of PD mice by TUNEL and immunohistochemical assays. Immuno-fluorescent method for labeling Iba1 and CD68 indicated that Nic remarkably alleviates the activation of microglia which represents the M1 polarization state in the mice brain under MPTP stimulation. No significant difference in the expression of p38/MAPK pathway was found in the nigrostriatal regions, while Nic could significantly inhibit the elevated p-JNK/JNK ratio and increase the declined p-ERK/ERK ratio in the substantia nigra of MPTP-exposed brains, which was further confirmed by the pretreatment of CYP2A5 inhibitor to decline the metabolic activity of Nic. Discussion: The molecular signaling mechanism by which Nic exerts its neuroprotective effects against PD may be achieved by regulating the JNK and ERK signaling pathways in the nigra-striatum related brain regions.
研究领域:
神经科学
·
药理学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2021
·
IF 5.811
Lv Jinpeng,Yang Ying,Jia Bingyi,Li Siqi,Zhang Ximei,Gao Rongyin
The therapeutic use of curcumin and chemically modified curcumin (CMC) for suppressing melanogenesis and tyrosinase activity have been recognized. J147 is a modified version of curcumin with superior bioavailability and stability. However, there is no report about the effects of J147 on pigmentation in vitro and in vivo. In our studies, we investigated the hypopigmentary effects of J147 treatment on melanocytes and explored the underlying mechanism. The present studies suggested that J147 suppressed both basal and α-MSH-induced melanogenesis, as well as decreased melanocyte dendricity extension and melanosome transport. J147 played these roles mainly by activating the extracellular signal-regulated protein kinase (ERK) pathway. Once activated, it resulted in MITF degradation and further down-regulated the expression of tyrosinase, TRP-1, TRP-2, Myosin Va, Rab27a and Cdc42, ultimately inhibited melanin synthesis and melanosome transport. Furthermore, the hypopigmentary effects of J147 were demonstrated in vivo in a zebrafish model and UVB-induced hyperpigmentation model in brown guinea pigs. Our findings also suggested that J147 exhibited no cytotoxicity in vitro and in vivo. Taken together, these data confirmed that J147 may prove quite useful as a safer natural skin-whitening agent.
研究领域:
药理学
·
皮肤病学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cell Death & Disease
·
2018
·Vol. 9
·期 9
·1-11
·
IF 5.638
Wang Yunchuan,Zheng Jianping,Han Yue,Zhang Yijie,Su Linlin,Hu Dahai,Fu Xiaobing
Junctional adhesion molecule-A (JAM-A) belongs to the immunoglobulin superfamily, it predominantly exists at the tight junctions of epithelial and endothelial cells. JAM-A is known to regulate leukocyte trans-endothelial migration, however, how it affects the proliferation and migration of keratinocytes, the two essential steps during wound healing, has less been explored. In this study, we showed that JAM-A was significantly expressed in normal skin epidermis. RNAi-mediated JAM-A knockdown remarkably promoted the proliferation and migration of keratinocytes. We also found that loss of JAM-A increased the protein levels of p -FAK, p -Erk1/2, and p -JNK; however, FAK inhibitor PF-562271 restrained the expression of p -FAK and p -Erk1/2 elevated by JAM-A RNAi, but not p -JNK, and also slowed down keratinocyte proliferation and migration. Finally, in a rat wound model we showed that absence of JAM-A significantly promoted the wound healing process, while the use of PF-562271 or Erk1/2 inhibitor PD98059 repressed those effects. These data collectively demonstrate that suppressing JAM-A expression could promote the proliferation and migration of keratinocytes and accelerate the healing process of rat skin wounds, potentially via FAK/Erk pathway, indicating that JAM-A might serve as a potential therapeutic target for the treatment of chronic refractory wounds.
研究领域:
分子生物学
·
细胞生物学
·
伤口愈合研究
·
信号通路
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DOI
PubMed
高影响因子
Advanced Healthcare Materials
·
2021
·Vol. 10
·期 12
·2100196
·
IF 9.933
Chunxia Ren,Xinqing Hao,Lu Wang,Yue Hu,Lin Meng,Shize Zheng,Feilong Ren,Wenhuan Bu,Huan Wang,Daowei Li,Kai Zhang,Hongchen Sun
The osteogenic potential of mesenchymal stem cells (MSCs) is severely impaired under persistent inflammation of periodontitis. A highly efficient way to promote or rescue osteogenic potential of MSCs under inflammation remains an unmet goal. Herein, metformin carbon dots (MCDs) with excellent biocompatibility are prepared from metformin hydrochloride and citric acid via a hydrothermal method. The MCDs can more effectively enhance the alkaline phosphatase (ALP) activity, calcium deposition nodules formation, expression of osteogenic genes and proteins in rat bone marrow mesenchymal stem cells (rBMSCs) than metformin under both inflammatory and normal conditions. Moreover, a novel pathway of extracellular signal-regulated kinases (ERK)/AMP-activated protein kinase (AMPK) signaling is involved in the MCDs-induced osteogenesis. In periodontitis rats, MCDs can effectively regenerate the lost alveolar bone, but not the metformin. Taken together, MCDs can be the promising candidate nanomaterial for periodontitis treatment. This work may provide a new pharmacological target of ERK/AMPK pathway for treating bone loss and also give additional insights into developing nanodrugs from the numerous medications.
研究领域:
药理学
·
牙科科学
·
纳米技术
·
干细胞生物学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）