TALANTA
·
2024
·
IF 5.6
Haojie Xie,Lin Wang,Xiaomeng Yu,Tianci Zhou,Minghui Wang,Jie Yang,Tao Gao,Genxi Li
The construction of hybrid materials is significant for the exploration of functionalities in colorimetric biosensing due to its structural designability and synergy effects. In this work, a COF-on-MOF hybrid nanomaterial has been newly synthesized for colorimetric biosensing. Experimental results reveal that on-surface synthesis of COF on MOF brings nanoscale proximity between COF and MOF, which exhibits more than two folds of peroxidase-like activity as compared to single Fe-MOF. Therefore, by using the MCA@Fe-MOF nanomaterial with the assist of a specific acetyl-peptide, MCA@Fe-MOF can serve as an efficient signal reporter for colorimetric assay of histone deacetylase (HDAC), and the limit of detection (LOD) can be as low as 0.261 nM. Looking forward, the demand for diverse and promising COF-on-MOF nanomaterials with varied functionalities is anticipated, propelling further exploration of their role in colorimetric biosensing.
研究领域:
材料科学
·
纳米技术
·
生物传感
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Acta Pharmaceutica Sinica B
·
2019
·
IF 5.808
Cai-Ping Chen,Kun Chen,Zhiqi Feng,Xiaoan Wen,Hongbin Sun
Artemisinin and its derivatives (ARTs) were reported to display heme-dependent antitumor activity. On the other hand, histone deacetylase inhibitors (HDACi) were known to be able to promote heme synthesis in erythroid cells. Nevertheless, the effect of HDACi on heme homeostasis in non-erythrocytes remains unknown. We envisioned that the combination of HDACi and artesunate (ARS) might have synergistic antitumor activity through modulating heme synthesis. In vitro studies revealed that combination of ARS and HDACi exerted synergistic tumor inhibition by inducing cell death. Moreover, this combination exhibited more effective antitumor activity than either ARS or HDACi monotherapy in xenograft models without apparent toxicity. Importantly, mechanistic studies revealed that HDACi coordinated with ARS to increase 5-aminolevulinate synthase (ALAS1) expression, and subsequent heme production, leading to enhanced cytotoxicity of ARS. Notably, knocking down ALAS1 significantly blunted the synergistic effect of ARS and HDACi on tumor inhibition, indicating a critical role of ALAS1 upregulation in mediating ARS cytotoxicity. Collectively, our study revealed the mechanism of synergistic antitumor action of ARS and HDACi. This finding indicates that modulation of heme synthesis pathway by the combination based on ARTs and other heme synthesis modulators represents a promising therapeutic approach to solid tumors.
研究领域:
肿瘤学
·
药理学
·
分子生物学
✓ 已验证
DOI
PubMed
高影响因子
DRUG DEVELOPMENT RESEARCH
·
2022
·Vol. 83
·期 8
·1758-1765
·
IF 5.004
Longxue Cai,Renqing Zeng,Qi Huang,Xianfa Liu,Zuohong Cao,Qicai Guo
Neuropathic pain affects millions of people in the worldwide, but the major therapeutics perform limited effectiveness. Paeonol (PAE) is widely distributed in Paeonis albiflora , and has manifested anti-inflammatory and antioxidative effects in multiple diseases. The present study aims to elucidate the effect of Paeonol (PAE) on neuropathic pain (NP) and the potential targets. Chronic constriction injury model was established to mimic NP in vivo in rats. The expression of GFAP, HDAC2, AHDAC3, Ac-H3K9, Histone-H3, Ac-H4K12, Histone-H4, TNF-α, IL-1β, and IL-6 was assessed by real-time polymerase chain reaction, western blot, and/or enzyme-linked immunosorbent assay kits. Ultimately, results indicated that intervention of PAE significantly blocked neuroinflammation and astrocytic activation via blocking HDAC/miR-15a signaling in CCI rats. These data revealed PAE is a novel therapeutic target for the treatment of neuropathic pain.
研究领域:
药理学
·
神经科学
·
疼痛管理
✓ 已验证
DOI
PubMed
高影响因子
MOLECULES
·
2019
·Vol. 24
·期 14
·2569
·
IF 3.06
Feifei Yang,Na Zhao,Jiali Song,Kongkai Zhu,Cheng-shi Jiang,Peipei Shan,Hua Zhang
A series of novel coumarin-based hydroxamate derivatives were designed and synthesized as histone deacetylase inhibitors (HDACis). Selective compounds showed a potent HDAC inhibition with nM IC50values, with the best compound (10e) being nearly 90 times more active than vorinostat (SAHA) against HDAC1. Compounds10eand11dalso increased the levels of acetylated histone H3 and H4, which is consistent with their strong HDAC inhibition. In addition,10eand11ddisplayed a higher potency toward human A549 and Hela cancer cell lines compared with SAHA. Moreover,10eand11dsignificantly arrested A549 cells at the G2/M phase and enhanced apoptosis. Molecular docking studies revealed the possible mode of interaction of compounds10eand12awith HDAC1. Our findings suggest that these novel coumarin-based HDAC inhibitors provide a promising scaffold for the development of new potential cancer chemotherapies.Keywords:coumarin;hydroxamate;HDAC inhibitors;antitumor growth;structure–activity relationship
研究领域:
药理学
·
肿瘤学
·
药物化学
✓ 已验证
DOI
PubMed
高影响因子
AMERICAN MINERALOGIST
·
2020
·Vol. 105
·期 11
·1686-1694
·
IF 2.924
Huan Chen,Hao Cui,Richen Zhong,Yuling Xie,Chang Yu,Zimeng Li,Yifan Ling
Sulfate is traditionally considered to have retrograde solubility in aqueous solutions. However, our recent hydrothermal diamond-anvil cell (HDAC) experiments have shown that the solubility of Na 2 SO 4 changes from retrograde to prograde in the presence of silica, leading to the formation of sulfate-rich solutions at high temperatures, in line with observations on natural geofluids. In this study, we use synthetic inclusions of fused silica capillary capsules containing saturated Na 2 SO 4 solutions and Na 2 SO 4 crystals to quantitatively investigate the solubility of Na 2 SO 4 at different temperatures in the Na 2 SO 4 -SiO 2 -H 2 O system. Sulfate concentrations were measured using Raman spectroscopy and calibrated using Cs 2 SO 4 solutions with known concentrations. The solubility of crystalline Na 2 SO 4 dropped slightly when heated from 50 to 225 °C and dramatically from 225 to 313 °C. At 313 °C, the Na 2 SO 4 crystals began to melt, forming immiscible sulfate melt coexisting with the aqueous solution, with or without solid Na 2 SO 4 . With the formation of sulfate melt, the solubility of Na 2 SO 4 was reversed to prograde (i.e., solubility increased considerably with increasing temperatures). The solubility of Na 2 SO 4 in the measured solution was significantly higher than that predicted in the absence of SiO 2 over the entire temperature range (except for temperatures around 313 °C). This indicates that the presence of SiO 2 greatly changes the dissolution behavior of Na 2 SO 4 , which may be caused by the formation of a sulfate–silicate intermediates such as Si ( OH ) 4 SO 4 2 − . Considering that most crustal fluids are silica-saturated, the solubility curve of Na 2 SO 4 obtained in this study can better reflect the characteristics of geofluids when compared to that of Na 2 SO 4 -H 2 O binary system. At temperatures of 313–425 °C, the solubility of Na 2 SO 4 increases with temperature following the function C sulfate = –3173.7/ T + 5.9301, where C sulfate and T represent the solubility of Na 2 SO 4 in mol/kg H 2 O and temperature in Kelvin, respectively. As an application, this temperature-solubility relationship can be used to evaluate the sulfate contents in fluid inclusions that contain sulfate daughter minerals, based on the temperature of sulfate disappearance obtained from microthermometric analysis. The sulfate concentrations of the ore-forming fluids of the giant Maoniuping carbonatite-related rare earth element (REE) deposit (southwest China) were calculated to be 4.67–4.81 m (mol/kg H 2 O). These sulfate concentrations were then used as internal standards to calibrate the previously reported semi-quantitative results of laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) analysis of REE-forming stage fluid inclusions at this deposit. The calculated Ce concentrations in the REE-mineralizing fluid range from 0.42 to 0.49 wt%. The high fluid REE contents suggest that the sulfate-rich fluids are ideal solvents for REE transport. A mass-balance calculation was carried out to evaluate the minimal volume of carbonatite melt that was required for the formation of the giant Maoniuping REE deposit. The result indicates that the carbonatite dikes in the mining area are enough to provide the required fluids and metals, and thus a deep-seated magma chamber is not necessary for ore formation.
研究领域:
地球化学
·
矿物学
·
矿床地质
·
热水系统
✓ 已验证
DOI
高影响因子
Theranostics
·
2024
·
IF 12.4
Zhiyong Shi,Miaomiao Liu,Xiaowen Zhang,Jingyang Wang,Junwei Zhang,Zeyan Peng,Li Meng,Ruijing Wang,Lihong Guo,Qiang Zhang,Jing Li,Liang Yang,Jie Liu,Yang Xu,Jie Yan,Jianlin Cui,Shan Ren,Yang Gao,Yanming Wang,Zhi Qi
Cancer therapy has moved from single agents to more mechanism-based targeted approaches. In recent years, the combination of HDAC inhibitors and other anticancer chemicals has produced exciting progress in cancer treatment. Herein, we developed a novel prodrug via the ligation of dichloroacetate to selenium-containing potent HDAC inhibitors. The effect and mechanism of this compound in the treatment of prostate cancer were also studied. Methods: The concerned prodrug SeSA-DCA was designed and synthesized under mild conditions. This compound's preclinical studies, including the pharmacokinetics, cell toxicity, and anti-tumor effect on prostate cancer cell lines, were thoroughly investigated, and its possible synergistic mechanism was also explored and discussed. Results: SeSA-DCA showed good stability in physiological conditions and could be rapidly decomposed into DCA and selenium analog of SAHA (SeSAHA) in the tumor microenvironment. CCK-8 experiments identified that SeSA-DCA could effectively inhibit the proliferation of a variety of tumor cell lines, especially in prostate cancer. In further studies, we found that SeSA-DCA could also inhibit the metastasis of prostate cancer cell lines and promote cell apoptosis. At the animal level, oral administration of SeSA-DCA led to significant tumor regression without obvious toxicity. Moreover, as a bimolecular coupling compound, SeSA-DCA exhibited vastly superior efficacy than the mixture with equimolar SeSAHA and DCA both in vitro and in vivo . Our findings provide an important theoretical basis for clinical prostate cancer treatment. Conclusions: Our in vivo and in vitro results showed that SeSA-DCA is a highly effective anti-tumor compound for PCa. It can effectively induce cell cycle arrest and growth suppression and inhibit the migration and metastasis of PCa cell lines compared with monotherapy. SeSA-DCA's ability to decrease the growth of xenografts is a little better than that of docetaxel without any apparent signs of toxicity. Our findings provide an important theoretical basis for clinical prostate cancer treatment.
研究领域:
肿瘤学
·
药理学
·
分子生物学
·
癌症治疗
✓ 已验证
产品关联
DOI
PubMed
高影响因子
LIFE SCIENCES
·
2022
·
IF 6.78
Wenjie Zhang,Qin Zhang,Yanrong Zhu,Yajing Zhang,Yufeng Xia,Zhifeng Wei,Yue Dai
Butyrate, given by oral administration or in drinking water, has been shown to improve experimental pulmonary fibrosis (PF) in mice despite of very low bioavailability. The pharmacokinetic-pharmacodynamics disconnection attracts us to explore its anti-PF mechanism in view of the intestinal expression of anti-PF factors. In bleomycin-induced PF in mice, rectal administration of butyrate (500 mg/kg) exhibited a significant anti-PF effect, with a maximum plasma concentration largely lower than the minimum effective concentration (1 mM) at which butyrate inhibited the expression of pro-inflammatory factors by lung epithelial cells and the production of extracellular matrix by lung fibroblasts. The rectal administration of butyrate significantly upregulated the mRNA expression of hepatocyte growth factor (HGF) in the colons of PF mice, but showed no significant effect on the mRNA expression of HGF in the small intestines, lungs and livers. In colon epithelial cells, the monocarboxylate transporter inhibitor α-cyano-4-hydroxycinnamic acid (CHC) abrogated butyrate-induced expression of HGF, indicating that butyrate functions through entering into cells. Butyrate showed no significant effect on the histone acetylation in the promoter region of HGF, suggesting that it promotes HGF expression not by directly affecting the histone deacetylation of HGF but by other pathways. GW9662, the inhibitor of PPARγ, significantly attenuated the effect of butyrate to promote the mRNA expression of HGF. Butyrate was able to enhance the acetylation of PPARγ, and a targeted mutation of lysine at the position 240 (K240) of PPARγ markedly diminished the induction of butyrate on HGF expression, suggesting that butyrate promoted HGF expression in colon epithelial cells by upregulating PPARγ K240 acetylation. In summary, rectal administration of butyrate promotes the expression of HGF in colonic epithelial cells through upregulating PPARγ acetylation via inhibition of HDAC activity. The findings of the present study provide a reasonable explanation for the anti-PF action mode of butyrate based on the ‘lung-gut axis’, and found that intestine-derived butyrate and HGF may be involved in the modulation of the occurrence and progression of PF.
研究领域:
药理学
·
肺科学
·
胃肠病学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF ETHNOPHARMACOLOGY
·
2022
·
IF 5.195
Zheng Liu,Wen-ting Dong,Wen-feng Wei,Jin-hai Huo,Wei-ming Wang
Ethnopharmacological relevance Traditional Chinese medicine categorizes Mycoplasma pneumoniae pneumonia as “lung heat”, and treatment with heat clear and detoxify. Traditional Chinese medicine believes that the lungs and intestines come from the same source, and the intestine is related to pneumonia. This is the same as the gut-lung axis theory. Qinbaiqingfei concentrate pills (QBs) were modified based on Cough San in the ancient medical book Medical Awareness . It clears lung heat, moisturizes the lungs and dredges collaterals, and has a good ability to treat Mycoplasma pneumoniae . Aim of the study A rat model of Mycoplasma pneumoniae was established. From the aspect of intestinal flora and mucosal immunity, the potential mechanism of the QBs was researched. Materials and methods First, the content of Mycoplasma pneumoniae in lung tissue and the levels of the inflammatory factors IL-4, IL-10, TNF-α and INF-γ were detected. To determine the expression of NF-kB related proteins in lung tissue, which can understand the ability in treating disease. Next, metagenomic sequencing was performed to detect changes in short-chain fatty acids, proving the ability of the drug to regulate intestinal microecology. Finally, HDAC , LPS , SIgA, etc. were detected to facilitate the correlation of the overall experimental indicators. Results QBs reduces the levels of IL-4, IL-10, TNF-α and INF-γ in the serum by inhibiting the expression of MyD88 , IKKα, IκBα, and NF-κB p65 in lung tissue. In addition, QBs restores the ratio of gram-negative bacteria to gram-positive bacteria in the intestine, restores the secretion of acetic acid, propionic acid , butyric acid , isobutyric acid and isovaleric acid , and promotes the secretion of NF-κB p65 and SIgA by HDAC1/3. The result is that the lung tissue is repaired and the proliferation of Mycoplasma pneumoniae is inhibited. Conclusions From the “gut-lung axis”, a new research perspective was discovered. QBs intervened in the intestines and lungs to treat Mycoplasma pneumoniae .
研究领域:
民族药理学
·
微生物学
·
免疫学
·
中医药
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
JOURNAL OF MOLECULAR STRUCTURE
·
2021
·
IF 3.196
Haiping Zhou,Junhao Jiang,Jinyu Lu,Dongzhi Ran,Zongjie Gan
Dual or multiple-targeting inhibition of oncogenic targets in a single molecule could be an alternative approach to drug combinations. Previous studies have revealed that histone deacetylases (HDAC) inhibitor in combination with janus kinase (JAK) inhibitor could exhibit synergistically anti-proliferative effects in cancer treatment. Herein, we presented a novel series of 2,4-dianilinopyrimidine derivatives, which could simultaneously inhibit JAK2 and HDAC1. Among which, 7l was found to be the most potent compound and displayed balanced inhibitory activity against HDAC1 (IC 50 = 1.9 nM) and JAK2 (IC 50 = 0.5 nM), respectively. 7l also demonstrated good antiproliferative activity against tested cancer cell lines (A549, HepG-2, MDA-MB-231 and Jurkat). Moreover, flow cytometric analysis showed that 7l induced apoptosis and cell cycle arrest in a dose-dependent manner, and the insight into mechanisms of 7l indicated that it could decrease the phosphorylation of STAT-3 and promote histone acetylation. In conclusion, these results together suggested that 7l would be a promising lead candidate and deserved further research and development.
研究领域:
药理学
·
肿瘤学
·
药物化学
✓ 已验证
DOI
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2024
·
IF 6.9
Dan Wang,Ziran Yu,Ranqi Yao,Jingnan Zhang,Wenqi Cui,Jiaohua Dai,Jian Li,Heng Qian,Xiujuan Zhao
Perimenopausal depression is a subtype of depression and is prevalent among perimenopausal women, which has brought a heavy burden to family and society. The pathogenesis of perimenopausal depression is still unclear, which affects the prevention and treatment of perimenopausal depression to a certain extent. Quercetin is a flavonoid compound, and has estrogenic activity and pharmacological effects such as antioxidant, anti-inflammatory, and neuroprotective effects. This study investigated whether quercetin improved perimenopausal depression-like behaviors and potential mechanism. The results demonstrated that quercetin could alleviate the depression-like behaviors in perimenopausal depression rat model, inhibit astrocyte activation, improve ferroptosis-associated mitochondrial damage (such as mitochondrial pyknosis and mitochondrial cristae reduction) in hypothalamus, increase the expressions of histone 3 lysine 9 acetylation (acetyl-H3K9), ferroptosis-associated protein including glutathione peroxidase 4 (GPX4) and Xc- antiporter (SLC7A11), and reduce the expressions of endoplasmic reticulum stress-related proteins including inositol-requiring enzyme 1 (IRE1α), phosphorylated IRE1α (p-IRE1α), X-box binding protein 1 (XBP1) and glucose-regulated protein 78 (GRP78) in hypothalamus of perimenopausal depression rat model. Furtherly, in vitro study indicated that quercetin could restore histone acetylase (HAT)/histone deacetylase (HDAC) homeostasis through binding to estrogen receptors and increase the expression of acetyl-H3K9, inhibiting ferroptosis through IRE1α/XBP1 pathway in astrocytes of hypothalamus. Our findings demonstrated that acetyl-H3K9 is a crucial target in development of perimenopausal depression, and quercetin exhibited antidepressant effects through modulating acetyl-H3K9 mediated ferroptosis in perimenopausal depression. Quercetin might be the prevention and adjuvant treatment strategy of perimenopausal depression.
研究领域:
神经科学
·
药理学
·
分子生物学
·
内分泌学
✓ 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）