JOURNAL OF MATERIALS SCIENCE & TECHNOLOGY
·
2023
·
IF 10.9
Jianmao Zheng,Jiyuan Zuo,Cairong Xiao,Qining Guo,Xiaobin Fu,Chengyun Ning,Peng Yu
The induction of dental pulp stem cells (DPSCs) into odontogenic differentiation is a cutting-edge method of dental pulp regeneration treatment. However, it remains a challenge to develop biomaterials and therapies that can induce odontogenic differentiation. Here, we propose a wireless electrical stimulation strategy to induce DPSCs odontogenic differentiation via K 0.5 Na 0.5 NbO 3 piezoelectric nanoparticles (KNN) and polarized KNN (PKNN), which can be endocytosed by DPSCs. In vitro, several odontogenic differentiation indexes were also increased in DPSCs treated with KNN and PKNN, and the increase was more obvious in the PKNN group. Intracellular wireless electrical field promoted mitochondrial calcium concentration via mitochondrial calcium unidirectional transporter (MCU), increased the production of adenosine triphosphate (ATP), and induced odontogenic differentiation through the activation of the cAMP-PKA signaling pathway. In vivo, dental pulp-like tissue was induced by electrical stimulation wirelessly with KNN and PKNN, which was more clinically friendly compared with the wired device, and the induction was more obvious in the PKNN group consistent with in vitro experiments. In conclusion, this work demonstrates the potential of PKNN as an effective stimulus that can induce odontogenic differentiation of DPSCs and be applied to dental pulp regeneration treatment.
研究领域:
牙科学
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生物材料
·
干细胞生物学
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纳米技术
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再生医学
✓ 已验证
产品关联
DOI
高影响因子
EMBO Molecular Medicine
·
2025
·
IF 8.3
FengShengyong,MaEnhao,NaXiaona,WangZongmei,TaiWanbo,BaoXinhui,WangMao,ChangHan,WuBaolei,LiuMiaoxi,LiJuzhen,ShiHuicheng,YangCeli,XiMenglu,YangHaibing,LiYuhan,ZhuYibin,WangPenghua,ZhaoLing,ZhaoAi,ChengGong
Vaccination offers the most effective protection against contagious infectious diseases primarily by inducing humoral immunity. Vaccination efficacy is influenced by various factors. We report that dietary administration of arachidonic acid (ARA) significantly boosts rabies vaccine-induced production of neutralizing antibodies and protection against lethal rabies virus (RABV) infection in mice. In human volunteers, oral supplementation of ARA accelerates the expression of neutralizing antibodies to the levels sufficient for protection against RABV as early as one week after primary immunization. Mechanistically, ARA is enriched in lymph nodes and metabolized into immune modulators there. One of the ARA metabolites, prostaglandin I2 (PGI2), via the cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) axis, upregulates the expression of costimulatory molecule CD86, and activates activation-induced cytidine deaminase (AID) in B cells. These results suggest that ARA can be a potent dietary adjuvant to foster germinal center (GC) B cell response and humoral immunity.
研究领域:
免疫学
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营养科学
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病毒学
·
疫苗研究
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产品关联
DOI
PubMed
高影响因子
CELLULAR SIGNALLING
·
2016
·
IF 4.191
Wenjun Zhao,Aiyun Li,Xin Feng,Ting Hou,Kang Liu,Baolin Liu,Ning Zhang
This study aims to investigate the effects of metformin and resveratrol on muscle insulin resistance with emphasis on the regulation of lipolysis in hypoxic adipose tissue. ICR mice were fed with high fat diet (HFD) for 10 days with administration of metformin, resveratrol, or intraperitoneal injection of digoxin . Adipose hypoxia, inflammation and cAMP/PKA-dependent lipolysis were investigated. Moreover, lipid deposition and insulin resistance were examined in the muscle. Metformin and resveratrol attenuated adipose hypoxia, inhibited HIF-1α expression and inflammation in the adipose tissue of HFD-fed mice. Metformin and resveratrol inhibited lipolysis through prevention of PKA/HSL activation by decreasing the accumulation of cAMP via preserving PDE3B . Metformin and resveratrol reduced FFAs influx and DAG accumulation, and thus improved insulin signaling in the muscle by inhibiting PKCθ translocation. This study presents a new view of regulating lipid metabolism to ameliorate insulin resistance and provides the clinical guiding significance for obesity and type 2 diabetes with metformin and resveratrol treatment.
研究领域:
药理学
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内分泌学
·
代谢学
✓ 已验证
DOI
PubMed
高影响因子
AQUACULTURE
·
2024
·
IF 3.9
Kunyin Jiang,Hong Yu,Lingfeng Kong,Shikai Liu,Shaojun Du,Qi Li
The visually appealing shell colours and intricate patterns of shellfish not only attract consumers but also enhance their economic value. Understanding the inheritance pattern of shell colour and the molecular mechanism of pigmentation is highly important for enhancing breeding efficiency. This study involved the identification of a tyrosine hydroxylase gene ( CgTH ) and the investigation of its function in the metabolism of tyrosine and pigmentation in Pacific oysters. CgTH contains a conserved Biopterin_H domain that consists of a binding site for iron atoms and a binding site for tetrahydrobiopterin (BH4). Quantitative PCR (qPCR) and immunofluorescence analysis revealed that the expression of CgTH was higher in the mantle of black shell oysters in comparison to the white strain. The in vitro and in vivo experiments confirmed that Cg TH is involved in tyrosine metabolism through the catalysis of the conversion of L-tyrosine to L-DOPA. In order to examine its functions in melanin synthesis in oysters, 3-Iodo-L-tyrosine (3-IT) treatment, RNA interference (RNAi), and L-DOPA treatment assays were conducted. The results of our study showed that 3-IT effectively inhibited Cg TH activity, leading to a suppression of tyrosine metabolism. Knockdown of Cg TH hindered the cAMP-CREM-MITF axis and decreased pigmentation. On the other hand, L-DOPA stimulated melanin production through cAMP signaling and counteracted the inhibitory effects of 3-IT on the metabolism of tyrosine. These data indicated that there may be a feedback loop involving Cg TH and the cAMP-CREM-MITF axis that regulates tyrosine metabolism and melanogenesis in Pacific oysters. This study enhances our understanding of the molecular mechanism that governs oyster pigmentation and offers a possible molecular indicator for the targeted breeding of particular strains of Pacific oysters ( Crassostrea gigas ).
研究领域:
海洋生物学
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分子生物学
·
遗传学
·
水产养殖
✓ 已验证
DOI
高影响因子
ACTA BIOCHIMICA ET BIOPHYSICA SINICA
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2022
·
IF 3.511
Wentao Sun,Yang Zhou,Hongmei Xue,Haitao Hou,Guowei He,Qin Yang
Although the association of elevated homocysteine level with cardiac hypertrophy has been reported, the molecular mechanisms by which homocysteine induces cardiac hypertrophy remain inadequately understood. In this study we aim to uncover the roles of cyclic nucleotide phosphodiesterase 1 (PDE1) and endoplasmic reticulum (ER) stress and their relationship to advance the mechanistic understanding of homocysteine-induced cardiac cell hypertrophy. H9c2 cells and primary neonatal rat cardiomyocytes are exposed to homocysteine with or without ER stress inhibitor TUDCA or PDE1-specific inhibitor Lu AF58027, or transfected with siRNAs targeting PDE1 isoforms prior to homocysteine-exposure. Cell surface area is measured and ultrastructure is examined by transmission electron microscopy. Hypertrophic markers, PDE1 isoforms, and ER stress molecules are detected by q-PCR and western blot analysis. Intracellular cGMP and cAMP are measured by ELISA. The results show that homocysteine causes the enlargement of H9c2 cells, increases the expressions of hypertrophic markers β-MHC and ANP, upregulates PDE1A and PDE1C, promotes the expressions of ER stress molecules, and causes ER dilatation and degranulation. TUDCA and Lu AF58027 downregulate β-MHC and ANP, and alleviate cell enlargement. TUDCA decreases PDE1A and PDE1C levels. Silencing of PDE1C inhibits homocysteine-induced hypertrophy, whereas PDE1A knockdown has minor effect. Both cAMP and cGMP are decreased after homocysteine-exposure, while only cAMP is restored by Lu AF58027 and TUDCA. TUDCA and Lu AF58027 also inhibit cell enlargement, downregulate ANP, β-MHC and PDE1C, and enhance cAMP level in homocysteine-exposed primary cardiomyocytes. ER stress mediates homocysteine-induced hypertrophy of cardiac cells via upregulating PDE1C expression Cyclic nucleotide, especially cAMP, is the downstream mediator of the ER stress-PDE1C signaling axis in homocysteine-induced cell hypertrophy.
研究领域:
心脏病学
·
分子生物学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2022
·
IF 5.195
Jinfeng Shang,Qiannan Li,Tingyue Jiang,Lei Bi,Yinghui Lu,Jiakang Jiao,Qi Song,Mingxue Yan,Lizha Shabuerjiang,Jingyi Wang,Xin Liu
Ethnopharmacological relevance Huanglian Jiedu Decoction (HLJDD) has the effect of clearing heat and detoxifying, and has been considered as an effective prescription for cerebral ischemia (CI) for thousands of years in traditional Chinese medicine (TCM). It can improve the quality of life of patients with ischemic stroke, but its pharmacological mechanism remains unclear. Aim of the study The study aimed to explore the pharmacological action and potential mechanism of HLJDD against CI by systems pharmacology, proteomics and in vivo experiments. Materials and methods In this study, databases such as TCMIP V2.0 and Genecards were used to predict compounds, targets and CI related targets, and network topology criteria of protein-protein interaction (PPI) network was used to screen core targets. The Database for Annotation, Visualization and Integrated Discovery database (DAVID) was used to discover biological processes and pathways. In addition, molecular docking was performed between the screened core biological active compounds and targets to verify the binding activity. Finally, proteomics and Western blot were performed on cerebral cortex tissues of middle cerebral artery occlusion (MCAO) model rats with HLJDD intervention to further verify the predicted results. Results 77 compounds and 308 targets of HLJDD were identified, 54 of which were predicted to be associated with cerebral ischemia. PPI network and enrichment results showed that 8 targets, including AKT1, PTGS2 and TLR4 , were core targets of HLJDD in CI. And 19 signaling pathways, including Rap1 signaling pathway, cAMP signaling pathway and arachidonic acid metabolism, were identified as key pathways to the therapeutic activity of HLJDD in CI. Combined with proteomics studies, we identified that Rap1 signaling pathway and upstream and downstream targets were the key mechanisms. Molecular biology experiments showed that RAP1A and AKT expression levels were significantly up-regulated in middle cerebral artery occlusion (MCAO) rats treated with HLJDD ( P < 0.0001), GRIN1 expression level was significantly down-regulated ( P < 0.0001). However, ACTB expression level was slightly down-regulated ( P > 0.05), which may be related to the biological function. Conclusion This study confirms the pharmacological effect of HLJDD on cerebral ischemia. These results indicate that HLJDD mediates various pathways such as inhibition of apoptosis , regulation of oxygen balance, inhibition of excitatory toxicity and maintenance of basic cell functions to improve CI by regulating Rap1 signaling pathway.
研究领域:
药理学
·
神经科学
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中医
·
分子生物学
·
生物信息学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2024
·
IF 4.8
Linlin Liu,Mozhu Jin,Xueying Han,Deqiang Dou
Ethnopharmacological relevance The nature of Chinese medicine is a unique index to measure its efficacy. Generally, treating the hot syndrome with cold nature medicine and vice versa. Ginseng medicines, a renowned Chinese medicine known for its qi tonifying action, encompasses various herbal materials such as ginseng, red ginseng, and black ginseng (GS, RG, and BG, respectively), ginseng leaves (GL), and American ginseng (AG), which exhibited different natures, thought contained similar ginsenosides. This traditional effect of GS and RG “reinvigorate the pulse for relieving qi depletion”. It is closely linked to anti-heart failure (HF), HF is a clinical manifestation of deficiency of “heart- qi ”. However, the elucidation of the mechanism underlying the anti-HF effects of ginseng medicines with different natures remains a significant challenge. Aim of the study To elucidate pharmacological mechanisms underlying the effect of ginseng medicines on HF, and to identify biomarkers associated with their various natures. Furthermore, it provides the basis for the different applications of ginseng medicines with various natures. Materials and methods This study established a rat model of HF induced by isoproterenol (ISO) combined with a specific diet. Four representative hot / cold herbs were selected as compared references for the medicine natures. The divergent effects of these herbs on the HF model were investigated by analyzing RNA-seq data to identify genes expressed differentially. Additionally, pathways associated with medicine natures were obtained using KEGG. Furthermore, UPLC-QqQ-MS/MS, as well as ELISA, were used to measure indexes associated with the nervous system, energy metabolisms, and endocrinology systems, such as BNP, CK, IL-1, T3, T4, cAMP, cGMP, AD, adrenal hormones (DOC, CORT, and COR), progestogens (pregnenolone, P, 17-OH-PR, and 17-OH-P), androgens (DHEA, A4, and T), and estrogens hormones (E2). Results All ginseng medicines demonstrated varying levels of efficacy in alleviating HF and GS exhibited a significant protective effect on HF. The ginseng medicines with qi tonifying primarily achieve their effect by enhancing the levels of adrenal hormones (DOC, CORT, and COR), T4, elevation of cAMP/cGMP, and activation of AchE. Warm nature qi tonifying ginseng medicines increased the levels of 17-OH-PR and P while decreasing 17-OH-P and the ratio of E2/T. On the other hand, cold nature qi tonifying ginseng medicines decreased the levels of A4 and T while increasing the ratio of E2/T. Conclusion Overall, the effects of warm nature ginseng medicines are stronger on HF compared to cold nature ginseng medicines. Our research firstly reported that the E2/T ratio, progestogens (17-OH-PR, 17-OH-P, and P), and androgens (A4 and T) have been identified as significant biomarkers for discerning the mechanism differences of ginseng medicines with differences natures in treatment of HF.
研究领域:
民族药理学
·
药理学
·
分子生物学
·
内分泌学
·
心脏病学
✓ 已验证
DOI
PubMed
高影响因子
CELL
·
2025
·
IF 42.5
Zhao Yang,Yu-Qi Ping,Ming-Wei Wang,Chao Zhang,Shu-Hua Zhou,Yue-Tong Xi,Kong-Kai Zhu,Wei Ding,Qi-Yue Zhang,Zhi-Chen Song,Ru-Jia Zhao,Zi-Lu He,Meng-Xin Wang,Lei Qi,Christian Ullmann,Albert Ricken,Torsten Schöneberg,Zhen-Ji Gan,Xiao Yu,Peng Xiao,Fan Yi,Ines Liebscher,Jin-Peng Sun
Androgens, such as 5α-dihydrotestosterone (5α-DHT), regulate numerous functions by binding to nuclear androgen receptors (ARs) and potential unknown membrane receptors. Here, we report that the androgen 5α-DHT activates membrane receptor GPR133 in muscle cells, thereby increasing intracellular cyclic AMP (cAMP) levels and enhancing muscle strength. Further cryoelectron microscopy (cryo-EM) structural analysis of GPR133-Gs in complex with 5α-DHT or its derivative methenolone (MET) reveals the structural basis for androgen recognition. Notably, the presence of the “Φ(F/L) 2.64 -F 3.40 -W 6.53 ” and the “F 7.42 ××N/D 7.46 ” motifs, which recognize the hydrophobic steroid core and polar groups, respectively, are common in adhesion GPCRs (aGPCRs), suggesting that many aGPCRs may recognize different steroid hormones. Finally, we exploited in silico screening methods to identify a small molecule, AP503, which activates GPR133 and separates the beneficial muscle-strengthening effects from side effects mediated by AR. Thus, GPR133 represents an androgen membrane receptor that contributes to normal androgen physiology and has important therapeutic potentials.
研究领域:
药理学
·
分子生物学
·
结构生物学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Pharmacology
·
2026
·
IF 5.4
Jie Weng,Songlian Liu,Yajun Tong,Kewei Tang,Leilan Yin,Site Bai,Ludi Ou,Qinghua Yin,Qiang Zhou
Introduction Cervical cancer ranks as the fourth most common malignancy among women worldwide. It is closely associated with the dysregulation of numerous genes and signaling pathways. Conventional treatments for cervical cancer often lead to adverse side effects and the development of drug resistance. Methods In this study, network pharmacology was employed to identify the active components and potential targets of Crocus sativus L. Molecular docking and surface plasmon resonance analyses were used to validate the interaction between lauric acid and a key target. Lauric acid‐modified gold nanoparticles (Au@LA) were synthesized and characterized. Results Twenty‐three active components and 819 potential targets of Crocus sativus L. were identified, with PTGS2 being the main target. Au@LA selectively inhibited HeLa cell proliferation, induced apoptosis, downregulated SLC7A11 and GPX4, and modulated oxidative stress markers. In macrophages, Au@LA shifted M2 polarization to the pro‐inflammatory M1 phenotype and modulated the PGE2/EP2/cAMP‐PKA signaling axis. Conclusion Our findings indicate that Au@LA has dual anti‐cervical cancer properties through inducing ferroptosis in HeLa cells and reprogramming macrophage polarization. It shows promise as a candidate for natural product‐based nanomedicine in cervical cancer therapy, potentially opening new avenues for more effective and targeted treatments in the future.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Redox Biology
·
2025
·
IF 11.9
Jing Fu,Congping Su,Yin Ge,Zhou Ao,Li Xia,Yingxiang Chen,Yizheng Yang,Shiwei Chen,Rui Xu,Xiaoyan Yang,Kai Huang,Qin Fu
Cyclic adenosine monophosphate (cAMP) plays a major role in normal and pathologic signaling in the heart. Phosphodiesterase 4 (PDE4) is a major PDE degrading cAMP in the heart. There are inconsistencies concerning the roles of the PDE4 isoforms 4B and 4D in regulation of cardiac function. Cardiac PDE4B overexpression is beneficial in remodeling and heart failure (HF), however, the effect of PDE4D and PDE4 inhibitor in HF remains unclear. We generated global and conditional cardiac-specific heterozygous PDE4D knockout mice and adeno-associated virus serotype 9-PDE4D overexpression to determine the role of PDE4D in cardiac hypertrophy and HF. PDE4D upregulation was observed in failing hearts from human and isoproterenol injection and TAC mice. In vitro , isoproterenol stimulation increased PDE4D expression via PKA but had no effect on PDE4B expression in cardiomyocytes. PDE4D overexpression per se induced oxidative stress, mitochondrial damage and cardiomyocyte hypertrophy by decreasing PINK1/Parkin-mediated mitophagy through inhibiting cAMP-PKA-CREB-Sirtuin1 (SIRT1) signaling pathway, while PDE4B overexpression did not affect CREB-SIRT1 pathway and mitophagy but exhibited a protective effect on isoproterenol-induced oxidative stress and hypertrophy in cardiomyocytes. PDE4D silencing or inhibition with PDE4 inhibitor roflumilast ameliorated isoproterenol-induced mitochondrial injury and cardiomyocyte hypertrophy. In vivo , ISO injection or TAC inhibited cardiac mitophagy and caused cardiac hypertrophy and HF, which were ameliorated by roflumilast or cardiac-specific PDE4D haploinsufficiency. Conversely, cardiac PDE4D overexpression suppressed cardiac mitophagy and abolished the protective effects of global PDE4D haploinsufficiency on TAC-induced cardiac hypertrophy and HF. In conclusion, these studies elucidate a novel mechanism by which sustained adrenergic stimulation contributes to cardiac hypertrophy and HF by increasing PDE4D via cAMP-PKA signaling, which in turn reduces cAMP-PKA activity, resulting in cardiomyocyte hypertrophy and mitochondrial injury via inhibition of CREB-SIRT1 signaling-mediated mitophagy . PDE4D inhibition may represent a novel therapeutic strategy for HF.
研究领域:
心血管研究
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药理学
·
分子生物学
·
细胞生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
CELL DEATH AND DIFFERENTIATION
·
2024
·
IF 13.7
Shi Dingfang,Bai Yunhao,Long Ruiling,Xia Jing,Xu Wenxuan,Qin Dongshen,Yang Xuejun,Ding Ming,Hou Xiao-Yu
Lysosomes regulate cellular metabolism to maintain cell survival, but the mechanisms whereby they determine neuronal cell fate after acute metabolic stress are unknown. Neuron-enriched lysosomal membrane protein LAMP2A is involved in selective chaperone-mediated autophagy and exosome loading. This study demonstrates that abnormalities in the neuronal LAMP2A-lysosomal pathway cause neurological deficits following ischemic stroke and that this is an early inducer of the PANoptosis-like molecular pathway and neuroinflammation, simultaneously inducing upregulation of FADD, RIPK3, and MLKL after ischemia. Quantitative proteomic and pharmacological analysis showed that after acute metabolic stress, the neuronal LAMP2A pathway induced acute synaptic degeneration and PANoptosis-like responses involving downregulation of protein kinase A (PKA) signaling. LAMP2A directed post-stroke lysosomal degradation of adenylyl cyclases (ADCY), including ADCY1 and ADCY3 in cortical neurons. Post-stroke treatment with cAMP mimetic or ADCY activator salvaged cortical neurons from PANoptosis-like responses and neuroinflammation, suggesting that the neuronal ADCY–cAMP–PKA axis is an upstream arrester of the pathophysiological process following an ischemic stroke. This study demonstrates that the neuronal LAMP2A-lysosmal pathway drives intricate acute neurodegenerative and neuroinflammatory responses after brain metabolic stress by downregulating the ADCY–PKA signaling cascade, and highlights the therapeutic potential of PKA signal inducers for improving stroke outcomes.
研究领域:
神经科学
·
细胞生物学
·
分子生物学
·
药理学
·
神经病学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Cell Metabolism
·
2022
·
IF 31.373
Jie Cheng,Zhao Yang,Xiao-Yan Ge,Ming-Xin Gao,Ran Meng,Xin Xu,Yu-Qi Zhang,Rui-Zhe Li,Jing-Yu Lin,Zhao-Mei Tian,Jin Wang,Shang-Lei Ning,Yun-Fei Xu,Fan Yang,Jing-Kai Gu,Jin-Peng Sun,Xiao Yu
Summary Along with functionally intact insulin, diabetes-associated insulin peptides are secreted by β cells. By screening the expression and functional characterization of olfactory receptors (ORs) in pancreatic islets, we identified Olfr109 as the receptor that detects insulin peptides. The engagement of one insulin peptide, insB:9-23, with Olfr109 diminished insulin secretion through Gi-cAMP signaling and promoted islet-resident macrophage proliferation through a β cell-macrophage circuit and a β-arrestin-1-mediated CCL2 pathway, as evidenced by β-arrestin-1 −/− mouse models. Systemic Olfr109 deficiency or deficiency induced by Pdx1-Cre +/− Olfr109 fl/fl specifically alleviated intra-islet inflammatory responses and improved glucose homeostasis in Akita - and high-fat diet (HFD)-fed mice. We further determined the binding mode between insB:9-23 and Olfr109. A pepducin-based Olfr109 antagonist improved glucose homeostasis in diabetic and obese mouse models. Collectively, we found that pancreatic β cells use Olfr109 to autonomously detect self-secreted insulin peptides, and this detection arrests insulin secretion and crosstalks with macrophages to increase intra-islet inflammation.
研究领域:
内分泌学
·
免疫学
·
分子生物学
·
糖尿病研究
✓ 已验证
DOI
PubMed
高影响因子
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