JOURNAL OF CELLULAR AND MOLECULAR MEDICINE
·
2018
·Vol. 23
·期 2
·1224-1234
·
IF 4.302
Min Jiang,Yufei Yan,Kai Yang,Zhuochao Liu,Jin Qi,Hanbing Zhou,Niandong Qian,Qi Zhou,Tianqi Wang,Xing Xu,Xiangshu Xiao,Lianfu Deng
Bone is the most common metastatic site for breast cancer. The excessive osteoclast activity in the metastatic bone lesions often produces osteolysis. The cyclic-AMP (cAMP)-response element binding protein (CREB) serves a variety of biological functions including the transformation and immortalization of breast cancer cells. In addition, evidence has shown that CREB plays a key role in osteoclastgenesis and bone resorption. Small organic molecules with good pharmacokinetic properties and specificity, targeting CREB-CBP (CREB-binding protein) interaction to inhibit CREB-mediated gene transcription have attracted more considerations as cancer therapeutics. We recently identified naphthol AS-E (nAS-E) as a cell-permeable inhibitor of CREB-mediated gene transcription through inhibiting CREB-CBP interaction. In this study, we tested the effect of nAS-E on breast cancer cell proliferation, survival, migration as well as osteoclast formation and bone resorption in vitro for the first time. Our results demonstrated that nAS-E inhibited breast cancer cell proliferation, migration, survival and suppressed osteoclast differentiation as well as bone resorption through inhibiting CREB-CBP interaction. In addition, the in vivo effect of nAS-E in protecting against breast cancer-induced osteolysis was evaluated. Our results indicated that nAS-E could reverse bone loss induced by MDA-MB-231 tumour. These results suggest that small molecules targeting CREB-CBP interaction to inhibit CREB-mediated gene transcription might be a potential approach for the treatment of breast cancer bone metastasis.
研究领域:
肿瘤学
·
分子生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Acta Biomaterialia
·
2022
·
IF 10.633
Jingjing Zhou,Zhaopeng Wang,Changyan Yang,Hanru Zhang,Muhammad Subaan Fareed,Yuhang He,Jie Su,Panpan Wang,Zhiqiang Shen,Wenjin Yan,Kairong Wang
Bacterial infection and local growth factor deficiency are two of the major causes of the nonunion of diabetic wounds. Antimicrobial peptides (AMPs) are believed to be alternatives to antibiotics against drug-resistant bacterial infections. 8-Bromoadenosine-3’, 5’-cyclic monophosphate (8Br-cAMP) can promote cells to secrete growth factors and accelerate cell proliferation . In the present study, we constructed a hydrogel with antimicrobial peptide Jelleine-1 (J-1) and 8Br-cAMP without any other gelators or chemical crosslinking agents. The hydrogel was proved to promote the secretion of transforming growth factor-β (TGF-β) and vascular endothelial growth factor-A (VEGFA) in vitro and in vivo . Notably, it exhibited potent potential for wound healing in methicillin-resistant Staphylococcus aureus ( MRSA ) infected diabetic wounds. This would be attributed to the retention of AMPs and 8Br-cAMP on the wound site by the hydrogel system. In addition, the hydrogel also showed good biodegradability , proper stability, and good biocompatibility. This study would shed light on the development of carrier-free and multifunctional hydrogel for wound healing. Statement of significance Bacterial infection and local growth factor deficiency are two of the major causes for the nonunion of refractory wounds. In the present study, an injectable carrier-free hydrogel was constructed of a natural antimicrobial peptide J-1 and 8Br-cAMP by eco-friendly physical crosslinking without any other gelators or chemical crosslinking agents. The hydrogel exhibited excellent antimicrobial activity and was proved to promote the secretion of TGF-β and VEGFA in vitro and in vivo . Correspondingly, the hydrogel showed exceptionally wound healing effects in the wound model of MRSA infected diabetic rats. This study would provide an alternative strategy or a potential hydrogel dressing for the treatment of chronic or refractory wounds.
研究领域:
药剂学
·
材料科学
·
生物医学工程
·
伤口愈合
·
抗菌治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Immunity Inflammation and Disease
·
2024
·Vol. 12
·期 7
·e1149
·
IF 3.1
Guoliang Li,Xin Xu,Lixin Chai,Qunhao Guo,Wei Wu
Background Bile acids (BAs) concentration can affect metabolic improvement caused by bariatric surgery and BA concentrations increase in patients after sleeve gastrectomy (SG). Here, how BAs after SG affect metabolism in nonalcoholic fatty liver disease (NAFLD) was studied. Methods Mice were given high-fat diet (HFD) to induce NAFLD and received SG surgery. Hepatic and fecal BA concentrations in mice were detected by liquid chromatography-tandem mass spectrometry method. BA-related genes were detected by quantitative real-time polymerase chain reaction. G protein BA receptor 1 (GPBAR1) expression was identified using western blot analysis. NAFLD mice after SG received GPBAR1 inhibitor Triamterene. The weight of mice and mice liver was detected. Mouse liver tissue was observed by hematoxylin–eosin and Oil Red O staining. Triglyceride (TG), nonesterified fatty acid (NEFA), and cyclic adenosine monophosphate (cAMP) levels in mouse liver tissue were analyzed by metabolic assay and enzyme-linked immune sorbent assay. Results SG boosted increase in hepatic total/conjugated BAs and related genes and GPBAR1 expression, and attenuated increase in fecal total BAs/muricholic acid in HFD-induced mice and increased fecal taurine-BAs in HFD-induced mice. Triamterene (72 mg/kg) reversed the inhibitory role of SG in HFD-induced increase of body weight, lipid accumulation, inflammatory cell infiltration, and increase of hepatic weight and TG/NEFA content, and counteracted the positive role of SG in HFD-induced increase of hepatic cAMP concentration in mice. Conclusions BAs improve metabolism via activating GPBAR1 to increase cAMP in NAFLD mice after SG.
研究领域:
代谢学
·
肝病学
·
内分泌学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
ANALYTICA CHIMICA ACTA
·
2024
·
IF 5.7
Hui Zhang,Jiangyu Yao,Guyu Xiao,Jianhui Xie,Shuying Mao,Chenghong Sun,Jingchun Yao,Jizhong Yan,Pengfei Tu
Target discovery of natural products is a key step in the development of new drugs, and it is also a difficult speed-limiting step. In this study, a traditional Chinese medicine microspheres (TCM-MPs) target fishing strategy was developed to discover the key drug targets from complex system. The microspheres are composed of Fe 3 O 4 magnetic nanolayer, oleic acid modified layer, the photoaffinity group (4- [3-(Trifluoromethyl)-3H-diazirin-3-yl] benzoic acid, TAD) layer and active small molecule layer from inside to outside. TAD produces highly reactive carbene under ultraviolet light, which can realize the self-assembly and fixation of drug active small molecules with non-selective properties. Here, taking Shenqi Jiangtang Granules (SJG) as an example, the constructed TCM-MPs was used to fish the related proteins of human glomerular mesangial cells (HMCs) lysate. 28 differential proteins were screened. According to the target analysis based on bioinformatics, GNAS was selected as the key target, which participated in insulin secretion and cAMP signaling pathway. To further verify the interaction effect of GNAS and small molecules, a reverse fishing technique was established based on bio-layer interferometry (BLI) coupled with UHPLC-Q/TOF-MS/MS. The results displayed that 26 small molecules may potentially interact with GNAS, and 7 of them were found to have strong binding activity. In vitro experiments for HMCs have shown that 7 active compounds can significantly activate the cAMP pathway by binding to GNAS. The developed TCM-MPs target fishing strategy combined with BLI reverse fishing technology to screen out key proteins that directly interact with active ingredients from complex target protein systems is significant for the discovery of drug targets for complex systems of TCM.
研究领域:
药学
·
生物技术
·
分子生物学
·
中医药
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Food Bioscience
·
2026
·
IF 6.2
Fenyi Min,Jiaqing Wang,Liping Qin,Yuxin Wang,Yizhou Li,Xuebo Liu,Lijun Sun
Plant-derived bioactive peptides have been suggested as a class of compounds with neuroprotective properties. This study focused on the cognitive-enhancing effects of Cyperus esculentus peptide (CEP) based on ‘in silico-drosophila-mice’ stepwise cognitive impairment models, followed by systematical elucidation in multi-target mechanism of its function. Specifically, network pharmacology prediction indicated that CEP exerted the modifying effects through essential nodes including cAMP signaling pathways and neuroinflammation regulation. Behavioral experiments confirmed that CEP effectively enhanced learning and memory capability of stress-modeled fruit flies and scopolamine-induced cognitive impairment mice. Then, mechanism investigation indicated that CEP could activate the cAMP-PKA-CREB-BDNF signaling axis within the central nervous system, enhancing synaptic plasticity (upregulated PSD-95 expression) while concurrently alleviating oxidative stress, cholinergic imbalance, and neuroinflammation. Additionally, CEP remodeled gut microbiota ecology, increasing beneficial bacteria abundance such as Akkermansia and Bifidobacterium and substantially enhancing short-chain fatty acid (SCFA) production. This further activated FFAR2/3 receptor signaling, restored intestinal barrier integrity and suppressed peripheral inflammation, indicating a neuroprotective pathway via the microbiota-gut-brain axis. Conclusively, this study confirmed CEP as a highly promising cognitive enhancer in a synergistic mode of coordinated regulation of central nervous and peripheral pathways, which provided theoretical underpinnings for intervention strategies of bioactive peptides in Cyperus esculentus targeting neurodegenerative diseases via the gut-brain axis.
✓ 已验证
DOI
高影响因子
JOURNAL OF NANOBIOTECHNOLOGY
·
2025
·Vol. 23
·期 1
·1-19
·
IF 12.6
Wang Lirui,Xiong Manyi,Zhang Jian,Li Sisi,Ma Sheng,Jiang Shengyao,Jiang Yanping,Li Xinhong
Introduction Preservation of porcine semen is essential for artificial insemination and genetic improvement in pig breeding programs. However, the overproduction of reactive oxygen species (ROS) and lower levels of protein phosphorylation emerge as two challenges during semen preservation. Inspired by the innate ligand-receptor binding biofunction of dopamine, herein, a dual-task nano-protectant that combines ROS-scavenging and protein phosphorylation-regulating properties via incorporating the natural antioxidant epigallocatechin gallate (EGCG) into polydopamine nanoparticles (EGCG@PDA NPs) was proposed to enhance the quality of pig semen during storage at 4 ℃. The results suggested that EGCG@PDA NPs significantly maintained sperm motility, acrosome integrity and mitochondrial membrane potential, extending semen storage time from 3 days to 10 days. Furthermore, EGCG@PDA NPs effectively scavenged excess ROS and inhibited ROS-mediated sperm apoptosis through the extracellular regulated protein kinases (ERK) signaling pathway. Intriguingly, EGCG@PDA NPs could degrade into ultrasmall particles (< 10 nm) in the semen or H 2 O 2 systems. These particles could target and activate the dopamine D2 receptor (D2DR) on membrane surface of sperm midpiece, thereby enhancing protein phosphorylation via the downstream cyclic adenosine monophosphate/protein kinase A (cAMP/PKA) signaling pathway, ultimately improving sperm motility parameters. This study presents a novel nano-strategy to boost the quality of pig semen, offering significant implications for the pig industry. Graphical
研究领域:
动物繁殖学
·
生物化学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
MOLECULAR PLANT PATHOLOGY
·
2024
·Vol. 25
·期 9
·e70003
·
IF 4.8
Kai Yin,Zhijian Hu,Meiting Yuan,Weidong Chen,Xinping Bi,Guobing Cui,Zhibin Liang,Yi Zhen Deng
Sugarcane smut fungus Sporisorium scitamineum produces polyamines putrescine (PUT), spermidine (SPD), and spermine (SPM) to regulate sexual mating/filamentous growth critical for pathogenicity. Besides de novo biosynthesis, intracellular levels of polyamines could also be modulated by oxidation. In this study, we identified two annotated polyamine oxidation enzymes (SsPAO and SsCuAO1) in S. scitamineum . Compared to the wild type ( MAT-1 ), the ss1pao Δ and ss1cuao1 Δ mutants were defective in sporidia growth, sexual mating/filamentation, and pathogenicity. The addition of a low concentration of cAMP (0.1 mM) could partially or fully restore filamentation of ss1pao Δ × ss2pao Δ or ss1cuao1 Δ × ss2cuao1 Δ. cAMP biosynthesis and hydrolysis genes were differentially expressed in the ss1pao Δ × ss2pao Δ or ss1cuao1 Δ × ss2cuao1 Δ cultures, further supporting that SsPAO- or SsCuAO1-based polyamine homeostasis regulates S. scitamineum filamentation by affecting the cAMP/PKA signalling pathway. During early infection, PUT promotes, while SPD inhibits, the accumulation of reactive oxygen species (ROS) in sugarcane, therefore modulating redox homeostasis at the smut fungus–sugarcane interface. Autophagy induction was found to be enhanced in the ss1pao Δ mutant and reduced in the ss1cuao1 Δ mutant. Exogenous addition of cAMP, PUT, SPD, or SPM at low concentration promoted autophagy activity under a non-inductive condition (rich medium), suggesting a cross-talk between polyamines and cAMP signalling in regulating autophagy in S. scitamineum . Overall, our work proves that SsPAO- and SsCuAO1-mediated intracellular polyamines affect intracellular redox balance and thus play a role in growth, sexual mating/filamentation, and pathogenicity of S. scitamineum .
研究领域:
真菌学
·
植物病理学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
FISH & SHELLFISH IMMUNOLOGY
·
2023
·
IF 4.7
Yihan Yu,Dandan Tian,Sanghyok Ri,Tongchol Kim,Kwangjin Ju,Jiongming Zhang,Shuangshuang Teng,Weixia Zhang,Wei Shi,Guangxu Liu
Although accumulating data demonstrated that gamma-aminobutyric acid (GABA), an inhibitory neurotransmitter , plays an important regulatory role in immunity of vertebrates, its immunomodulatory function and mechanisms of action remain poorly understood in invertebrates such as bivalve mollusks . In this study, the effect of GABA on phagocytic activity of hemocytes was evaluated in a commercial bivalve species, Tegillarca granosa . Furthermore, the potential regulatory mechanism underpinning was investigated by assessing potential downstream targets. Data obtained demonstrated that in vitro GABA incubation significantly constrained the phagocytic activity of hemocytes. In addition, the GABA-induced suppression of phagocytosis was markedly relieved by blocking of GABA A and GABA B receptors using corresponding antagonists. Hemocytes incubated with lipopolysaccharides (LPS) and GABA had significant higher K + -Cl - cotransporter 2 (KCC2) content compared to the control. In addition, GABA treatment led to an elevation in intracellular Cl − , which was shown to be leveled down to normal by blocking the ionotropic GABA A receptor. Treatment with GABA A receptor antagonist also rescued the suppression of GABA A receptor-associated protein ( GABARAP ), KCC , TNF receptor associated factor 6 ( TRAF6 ), inhibitor of nuclear factor kappa-B kinase subunit alpha ( IKKα ), and nuclear factor kappa B subunit 1 ( NFκB ) caused by GABA incubation. Furthermore, incubation of hemocytes with GABA resulted in a decrease in cAMP content, an increase in intracellular Ca 2+ , and downregulation of cAMP-dependent protein kinase ( PKA ), calmodulin kinase II ( CAMK2 ), calmodulin ( CaM ), calcineurin ( CaN ), TRAF6 , IKKα , and NFκB . All these above-mentioned changes were found to be evidently relieved by blocking the metabotropic G-protein-coupled GABA B receptor. Our results suggest GABA may play an inhibitory role on phagocytosis through binding to both GABA A and GABA B receptors, and subsequently regulating corresponding downstream pathways in bivalve invertebrates.
研究领域:
免疫学
·
分子生物学
·
海洋生物学
·
无脊椎动物生理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF CHEMICAL RESEARCH
·
2023
·
IF 1.4
Yingcong Yu,Yan Zhao,Yajing Wang,Xianfeng Huang
PDE4 inhibitors exhibit anti-stress and antidepressant-like abilities by catalyzing the hydrolysis of cAMP, a primary regulator for intracellular communication in the brain. Herein, novel diarylpyrazole derivatives are synthesized and investigated for their ability to inhibit PDE4. In vitro studies indicate that most of the synthesized compounds show significant potency for the inhibition of PDE4. Specifically, N-(4-(3-(3,5-dimethoxyphenyl)-1H-pyrazol-5-yl)benzyl)-2-morpholinoethan-1-amine exhibits the most potent PDE4 inhibition, with an IC50 value of ca. 0.09 μM. It also produces antidepressant-like activities in sugar water consumption and in forced swimming tests in vivo.
研究领域:
药理学
·
药物化学
·
神经科学
✓ 已验证
DOI
高影响因子
STEM CELLS AND DEVELOPMENT
·
2023
·
IF 4
Mr. Genghua Xu,Ms. Nuoya Liu,Ms. Yaqing Qiu,Ms. Jiayu Qi,Prof. Danyan Zhu
The histamine H3 receptor, prominently expressed in neurons with a minor presence in glial cells, acts as both an autoreceptor and an alloreceptor, controlling the release of histamine and other neurotransmitters. The receptor impacts various essential physiological processes. Our team's initial investigations had demonstrated that the histamine H3 receptor antagonists could facilitate the nerve regeneration via promoting the histamine H1 receptors on primary neural stem cells in the traumatic brain injury mouse, which suggested the potential of histamine H3 receptor as a promising target for treating neurological disorders and promoting nerve regeneration. Pitolisant (PITO) is the only histamine H3 receptor antagonist approved by the FDA for treating narcolepsy. However, there are no reports on Pitolisant in neural development or regeneration, and it is urgent to be further studied in strong biological activity models in vitro. The embryonic stem (ES) cells were differentiated into neural cells in vitro, which replicated the neurodevelopmental processes that occur in vivo. It also provided an alternative model for studying neurodevelopmental processes and testing drugs for neurological conditions. Therefore, we aimed to elucidate the regulatory role of Pitolisant in the early differentiation of ES cells into neural cells. Our results demonstrated that Pitolisant could promote the differentiation of ES cells towards neural stem cells (NSCs) and stimulated the formation of growth cones. Furthermore, Pitolisant was capable of inducing the polarization of NSCs through the cAMP-LKB1-SAD/MARK2 pathway, but had no significant effect on later neuronal maturation. Pitolisant altered mitochondrial morphology and up-regulated the levels of mitochondrial-related proteins TOM20, Drp1, and p-Drp1, and reversed the inhibitory effect of Mdivi-1 on mitochondrial fission during the early neural differentiation of ES cells. Additionally, Pitolisant induced the increase in cytosolic Ca2+. Our study provided an experimental foundation for the potential application of histamine H3 receptor-targeted modulators in the field of neuroregeneration.
研究领域:
神经科学
·
干细胞生物学
·
药理学
·
细胞生物学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF MEDICINAL CHEMISTRY
·
2024
·
IF 6.8
Zheng-Jiong Zhao,Mei-Yan Jiang,Meng-Xing Huang,Yi-Yi Yang,Ling-Ling Feng,Chen Zhang,Yi-You Huang,Hai-Bin Luo,Yinuo Wu
Liver fibrosis is a common pathological feature of most chronic liver diseases with no effective drugs available. Phosphodiesterase 1 (PDE1), a subfamily of the PDE super enzyme, might work as a potent target for liver fibrosis by regulating the concentration of cAMP and cGMP. However, there are few PDE1 selective inhibitors, and none has been investigated for liver fibrosis treatment yet. Herein, compound AG-205/1186117 with the dihydropyrimidine scaffold was selected as the hit by virtual screening. A hit-to-lead structural modification led to a series of dihydropyrimidine derivatives. Lead 13h exhibited the IC50 of 10 nM against PDE1, high selectivity over other PDEs, as well as good safety properties. Administration of 13h exerted significant anti-liver fibrotic effects in bile duct ligation-induced fibrosis rats, which also prevented TGF-β-induced myofibroblast differentiation in vitro, confirming that PDE1 could work as a potential target for liver fibrosis.
研究领域:
药理学
·
药物化学
·
肝病学
✓ 已验证
DOI
PubMed
高影响因子
BIOORGANIC CHEMISTRY
·
2025
·
IF 4.7
Xinyan Shen,Xuemei Shao,Bowei Dong,Yuting Gu,Jingjing Sun,Yujie Zhang,Yan Li,Shuai Zhao,Yanan Hou,Xin Chen,Mingcheng Qian
In this study, we designed and synthesized 12 novel non-steroidal cholic acid (CA) analogues as potential Takeda G protein coupled receptor 5 (TGR5) allosteric agonists based on scaffold hopping strategy. Biological results showed that all final compounds were able to activate the receptor both in human TGR5 (hTGR5) and mouse TGR5 (mTGR5) by Glosensor cAMP accumulation assay. Remarkably, lactone A1 and lactam A10 displayed 48- and 24-fold higher potencies than that of CA in hTGR5 cAMP accumulation, respectively. Furthermore, target compounds exhibited higher selectivity for cAMP formation compared to β-arrestin2 recruitment. Interestingly, target compounds A1–10 positively modulated the functional activity and potency of lithocholic acid (LCA) in TGR5, indicating that A1–10 are TGR5 allosteric agonists. Molecular docking study displayed that both lactone in A5 and lactam in A10 formed H-bonds with the key amino acid residue Thr131, which are critical for TGR5 allosteric effect. Unexpectedly, none of target compounds A1–10 could activate farnesoid X receptor (FXR), indicating that final compounds are potent and selective TGR5 allosteric agonists. More importantly, both A1 and A10 exhibited significant glucose-lowering effects in the oral glucose tolerance test (OGTT) in mice. Taken together, we discovered two potent and selective TGR5 allosteric agonists A1 and A10 , which could be employed as lead compounds to further study TGR5 allostery with potential antidiabetic effects.
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）