EUROPEAN JOURNAL OF PHARMACOLOGY
·
2020
·
IF 3.263
Guanyin Yuan,Yang Jing,Ting Wang,Vitor S. Fernandes,Wenkuan Xin
Bitter taste receptors (Tas2rs), the members of the G-protein-coupled receptors, mediate the bitter taste and express in extra-oral tissues. Previous studies have shown that Tas2r mRNAs are expressed in the whole heart and cultured cardiomyocytes of neonatal rats. This study aimed to determine the expression of Tas2rs and their function in the adult rat hearts by using RT-qPCR techniques, Langendorff-perfused isolated hearts, and isolated sinoatrial (SA) nodes. The data presented here revealed the mRNA expression of Tas2rs and their coupled G-protein subunits in the SA node and left ventricle of adult rat hearts. Tas2r agonists, quinine and chloroquine , decreased the heart rate and increased the RR interval and QRS duration in Langendorff-perfused isolated rat hearts; they reduced the spontaneous beating rate of isolated SA nodes with pEC 50 values of 4.907 ± 0.045 and 4.968 ± 0.030, respectively. The blockade of Tas2r108 with abscisic acid , the inhibition of phosphodiesterases (PDEs) with 3-isobutyl-1-methylxanthine (IBMX), or the selective inhibition of PDE3 and PDE4 with a cocktail of cilostamide and rolipram , attenuated the negative chronotropic effects of quinine and chloroquine on the SA node. Furthermore, quinine and chloroquine suppressed the tachycardia effect of isoprenaline on the SA node and shifted the concentration-response curve of isoprenaline rightward. In summary, we provided a few lines of evidence that Tas2r agonists, quinine and chloroquine, decreased the heart rate by prolonging ventricular depolarization, and by attenuating the SA node pace in a PDE-dependent manner; they can counteract with β -adrenergic receptor activation and eliminate isoprenaline-induced tachycardia.
研究领域:
心脏病学
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药理学
·
分子生物学
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DOI
PubMed
高影响因子
ACS Pharmacology & Translational Science
·
2019
·
IF 0
Jennifer Jin Ruan,Yan Yu,Wei Hou,Zhao Chen,Jinzhang Fang,Jingjing Zhang,Muowei Ni,Di Li,Shiying Lu,Jingjing Rui,Rui Wu,Wei Zhang,Benfang Helen Ruan
Tumor metabolism has been deeply investigated for cancer therapeutics. Here, we demonstrate that glutamine deficiency alone could not completely inhibit cancer cell growth and that many potent kidney-type glutaminase (KGA) inhibitors did not show satisfying in vivo efficacy. The potent KGA allosteric inhibitor, CB-839, resulted in up to 80% growth inhibition of all tested cell lines, whereas Hexylselen (CPD-3B), a KGA/glutamate dehydrogenase (GDH) inhibitor, showed essentially no toxicity to normal cells up to a 10 μM concentration and could completely inhibit the growth of many aggressive cell lines. Further analyses showed that CPD-3B targets not only KGA and GDH but also thioredoxin reductase (TrxR) and amidotransferase (GatCAB), which results in corresponding regulation of Akt/Erk/caspase-9 signaling pathways. In an aggressive liver cancer xenograft model, CPD-3B significantly reduced tumor size, caused massive tumor tissue damage, and prolonged survival rate. These provide important information for furthering the drug design of an effective anticancer KGA allosteric inhibitor.
研究领域:
肿瘤学
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分子生物学
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药理学
·
癌症代谢
✓ 已验证
DOI
PubMed
JOURNAL OF ELECTROANALYTICAL CHEMISTRY
·
2019
·
IF 3.218
Yang Luo,Yitao Zhang,Liqin Lu,Hongxia Luo
A graphene platform electrode (GPE) was fabricated by transferring chemical vapor deposition (CVD) graphene films from copper foils to flexible polyethylene terephthalate substrates supported by polymethyl-methacrylate. l -Aspartic acid ( l -Asp) was immobilized onto the surface of GPE by electrodeposition to form a poly- l -Asp/GPE, which was characterized by scanning electron microscopy, energy dispersive spectroscopy and Raman spectroscopy. Hence, a novel poly- l -Asp modified GPE was created for the simultaneous electrochemical determination of acetaminophen (AC), epinephrine (EP) and tyrosine (TY). Cyclic voltammetry was used for investigating the electrocatalytic activity of the poly- l -Asp/GPE sensor towards the detection of AC, EP and TY in comparison with that of GPE. The simultaneous determination of AC, EP and TY was realized by the differential pulse voltammetry technique at poly- l -Asp/GPE. The broad linear ranges to AC, EP and TY were obtained by chronoamperometry, which were from 0.05 to 108.25 μM for AC, 0.025 to 123.3 μM for EP and 0.1 to 93.9 μM for TY, with detection limits (S/N = 3) of 0.011 μM, 0.006 μM and 0.31 μM, respectively. Furthermore, the as-fabricated sensor showed extraordinary stability as well as high anti-interference ability, and was utilized successfully in detecting real samples.
研究领域:
电化学
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材料科学
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分析化学
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生物传感器
✓ 已验证
DOI
高影响因子
JOURNAL OF CONTROLLED RELEASE
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2021
·
IF 9.776
Xingyue Yang,Qian Qiu,Gengqi Liu,He Ren,Xiaojie Wang,Jonathan F. Lovell,Yumiao Zhang
Effective delivery of antimicrobial agents to intracellular pathogens represents a major bottleneck for a wide variety of infectious diseases. To address this, we developed SIR-micelles(+), as a new delivery vehicle comprising antibiotic-loaded micelles with rapid self-immolation within cells for targeted delivery to macrophages, where most intracellular bacterial reside. After phagocytosis, SIR-micelles(+) rapidly release the pristine antibiotic after the cleavage of the disulfide bonds by intracellular reducing agents such as glutathione (GSH). Colistin , a hydrophilic and potent “last-resort” antibiotic used for the treatment of drug-resistant bacterial infection, was encapsulated in SIR-micelles with 40% yield and good short-term storage stability. Hydrophobic moieties and mannose ligands in SIR-micelles(+) enhanced the delivery of colistin into macrophages. The traceless and thiol-responsive release of colistin effectively eliminated intracellular Escherichia coli within twenty minutes. In a murine pneumonia model, SIR-micelles(+) significantly reduced bacterial lung burden of multidrug-resistant Klebsiella pneumoniae . Furthermore, SIR-micelles(+) improved the survival rate and reduced the bacterial burden of organs infected by intracellular bacteria transferred from donor mice. Using this formulation approach, the nephrotoxicity and neurotoxicity induced by antibiotic were reduced by about 5– 15 fold. Thus, SIR-micelles(+) represent a new class of material that can be used for targeting treatment of intracellular and drug-resistant pathogens.
研究领域:
药学
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感染性疾病
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纳米技术
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药物递送系统
✓ 已验证
DOI
PubMed
高影响因子
Science Advances
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2019
·Vol. 5
·期 7
·
IF 12.804
Jingjing Duan,Jian Li,Gui-Lan Chen,Yan Ge,Jieyu Liu,Kechen Xie,Xiaogang Peng,Wei Zhou,Jianing Zhong,Yixing Zhang,Jie Xu,Changhu Xue,Bo Liang,Lan Zhu,Wei Liu,Cheng Zhang,Xiao-Li Tian,Jianbin Wang,David E. Clapham,Bo Zeng,Zongli Li,Jin Zhang
The transient receptor potential canonical subfamily member 5 (TRPC5), one of seven mammalian TRPC members, is a nonselective calcium-permeant cation channel. TRPC5 is of considerable interest as a drug target in the treatment of progressive kidney disease, depression, and anxiety. Here, we present the 2.8-Å resolution cryo–electron microscopy (cryo-EM) structure of the mouse TRPC5 (mTRPC5) homotetramer. Comparison of the TRPC5 structure to previously determined structures of other TRPC and TRP channels reveals differences in the extracellular pore domain and in the length of the S3 helix. The disulfide bond at the extracellular side of the pore and a preceding small loop are essential elements for its proper function. This high-resolution structure of mTRPC5, combined with electrophysiology and mutagenesis, provides insight into the lipid modulation and gating mechanisms of the TRPC family of ion channels.
研究领域:
结构生物学
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药理学
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神经科学
✓ 已验证
DOI
PubMed
高影响因子
JOURNAL OF CHEMICAL THERMODYNAMICS
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2019
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IF 2.29
Yameng Wan,Rui Zhao,Pengshuai Zhang,Haixia He,Jiao Sha,Tao Li,Baozeng Ren
Solubility of ( R )-(-)-phenylephrine hydrochloride ( R -PEHC) in ten pure solvents including methanol (MtOH), ethanol (EtOH), n -propanol (NPrOH), iso-propanol (IPrOH), 2-methoxyethanol, 2-ethoxyethanol, 2-propoxyethanol, 2-butoxyethanol, N-methyl pyrrolidone (NMP) and N,N-dimethylformamide (DMF) was determined by using a laser monitoring technique in the range of 278.15 K to 323.15 K under 0.1 MPa. Solubility of R -PEHC increases with the increment of temperature. The solvent effect on R -PEHC solubility was investigated by the linear solvation energy relationships concept (Kamlet-Taft parameters). The interaction energy ( E inter ) between R -PEHC and selected solvents was calculated by molecular simulation to explain the solubility behavior. Experimental solubility was correlated by five activity coefficient models including the Two-Suffix Margules model, Wilson model, NRTL model, NRTL-SAC model and uniquac model. Five models can fit experimental solubility values well. Furthermore, thermodynamic properties of solutions of R -PEHC in selected solvents were investigated by the van’t Hoff equation.
研究领域:
物理化学
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热力学
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药学
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分子模拟
✓ 已验证
DOI
高影响因子
Discover Oncology
·
2024
·Vol. 15
·期 1
·1-18
·
IF 2.8
Feng Rui,Li Haolin,Meng Tong,Fei Mingtian,Yang Cheng
Purpose This study aimed to construct an m6A and cuproptosis-related long non-coding RNAs (lncRNAs) signature to accurately predict the prognosis of kidney clear cell carcinoma (KIRC) patients using the information acquired from The Cancer Genome Atlas (TCGA) database. Methods First, the co-expression analysis was performed to identify lncRNAs linked with N6-methyladenosine (m6A) and cuproptosis in ccRCC. Then, a model encompassing four candidate lncRNAs was constructed via univariate, least absolute shrinkage together with selection operator (LASSO), and multivariate regression analyses. Furthermore, Kaplan–Meier, principal component, functional enrichment annotation, and nomogram analyses were performed to develop a risk model that could effectively assess medical outcomes for ccRCC cases. Moreover, the cellular function of NFE4 in Caki-1/OS-RC-2 cultures was elucidated through CCK-8/EdU assessments and Transwell experiments. Dataset outcomes indicated that NFE4 can have possible implications in m6A and cuproptosis, and may promote ccRCC progression. Results We constructed a panel of m6A and cuproptosis-related lncRNAs to construct a prognostic prediction model. The Kaplan–Meier and ROC curves showed that the feature had acceptable predictive validity in the TCGA training, test, and complete groups. Furthermore, the m6A and cuproptosis-related lncRNA model indicated higher diagnostic efficiency than other clinical features. Moreover, the NFE4 function analysis indicated a gene associated with m6A and cuproptosis-related lncRNAs in ccRCC. It was also revealed that the proliferation and migration of Caki-1 /OS-RC-2 cells were inhibited in the NFE4 knockdown group. Conclusion Overall, this study indicated that NFE4 and our constructed risk signature could predict outcomes and have potential clinical value.
研究领域:
生物信息学
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癌症生物学
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分子生物学
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基因组学
✓ 已验证
DOI
PubMed
高影响因子
BIOMEDICINE & PHARMACOTHERAPY
·
2024
·
IF 6.9
Lei Wang,Yufeng Tao,Xuesong Wang,Yuhan Gan,Yuting Zeng,Shasha Li,Qing Zhu
Phellinus igniarius is an important medicinal and edible fungus with diverse biological activities. This study aimed to investigate the effects of aqueous extract from P. igniarius (API) on the treatment of hyperuricemia (HUA) and related kidney damage. The chemical constituents of API were determined. The therapeutic effects of API on HUA and renal injury were assessed in adenine/potassium oxonate (PO)-treated mice. The constituent analysis of API revealed a predominance of polysaccharides (33.4 %), followed by total flavonoids (9.1 %), and total triterpenoids (3.5 %). Compared to control, the adenine/PO treatment greatly elevated serum uric acid (UA) levels but this elevation was attenuated by API. In the liver, the expression and activity of xanthine oxidase (XOD) were increased by HUA which were diminished by API. Furthermore, API was found to enhance the expression of UA transporter ABCG2 in the kidney and intestine of HUA mice, suggesting elevating UA excretion. Additionally, API ameliorated HUA-induced renal injury, as indicated by reduced serum BUN/creatinine levels, decreased glomerular and tubular damage, and lowered fibrotic levels. Network pharmacology analysis predicted that P. igniarius may regulate mitochondrial function to improve HUA-related renal injury. This prediction was then substantialized by the API-induced upregulation of NAD+/NADH ratio, ATP level, SOD2 activity, and expression of SOD2/PCG-1α/PPARγ in the kidney of HUA mice. Our results demonstrate that API may effectively ameliorate HUA by reducing UA production in the liver and enhancing UA excretion in the kidney and intestine, and it might be a potential therapy to HUA-related renal injury.
研究领域:
药理学
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医学
·
生物化学
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分子生物学
✓ 已验证
DOI
PubMed
高影响因子
Science China-Life Sciences
·
2024
·
IF 8
Zhang Zhen,Huang Weijun,Zhang Xiaoran,Wang Zhecun,Xie Manting,Xie Bingbing,Wang Yiling,Chen Xiaoyong,Xiang Andy Peng,Xiang Qiuling
Despite substantial advancements in modern medicine, the management of hypertension remains a major challenge. Stem cell-based therapies have recently demonstrated remarkable efficacy in treating cardiovascular diseases, including hypertension. However, the antihypertensive mechanism of mesenchymal stem cells (MSCs) has not been extensively explored. This study aimed to investigate the role of injected MSCs in regulating blood pressure homeostasis. Our previous study demonstrated that human induced pluripotent stem cell-derived mesenchymal stem cells (hiPSC-MSCs) are functional and homogeneous sources for MSC-based therapy. After the injection of hiPSC-MSCs, a significant reduction in blood pressure and end target organ inflammation were observed in spontaneously hypertensive rats (SHRs). Cell tracking assays demonstrated that the injected hiPSC-MSCs accumulated in the spleens of the SHRs. The injected hiPSC-MSCs accumulated adjacent to the splenic nerve, potentially contributing to the antihypertensive effects. Furthermore, the hiPSC-MSCs released abundant glutamate, which acts as a neuromodulator to activate the splenic sympathetic nerve. After inhibition of glutamate synthesis by siRNA, the ability of hiPSC-MSCs to activate sympathetic nerves was significantly diminished. In addition, the antihypertensive effects of hiPSC-MSCs were eliminated after splenic nerve denervation (SND), underscoring the critical role of the splenic nerve. Moreover, activation of the splenic nerve resulted in increased release of norepinephrine (NE), which increased the number of choline acetyltransferase-positive (ChAT + ) cells in the spleen and peripheral blood. Consequently, the acetylcholine (ACh) produced by elevated ChAT + cells could act as a vasodilator, lowering blood pressure and mitigating inflammation in end target organs. In summary, our findings indicate that hiPSC-MSCs effectively lower blood pressure in hypertension by influencing the splenic nerves and regulating ChAT + cells. The connection between blood pressure regulation and the splenic nerve may offer new insights into the treatment of hypertension.
研究领域:
干细胞治疗
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心血管疾病
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高血压
·
神经科学
·
药理学
✓ 已验证
DOI
PubMed
高影响因子
ACS Omega
·
2018
·
IF 0
Changfen Bi,Yulu Liang,Lijin Shen,Shanshan Tian,Kai Zhang,Yiliang Li,Xiwen He,Langxing Chen,Yukui Zhang
Efficient enrichment glycoproteins/glycopeptides from complex biological solutions are very important in the biomedical sciences, in particular biomarker research. In this work, the high hydrophilic polyethylenimine conjugated polymaltose polymer brushes functionalized magnetic Fe3O4 nanoparticles (NPs) denoted as Fe3O4–PEI–pMaltose were designed and synthesized via a simple two-step modification. The obtained superhydrophilic Fe3O4–PEI–pMaltose NPs displayed outstanding advantages in the enrichment of N-linked glycopeptides, including high selectivity (1:100, mass ratios of HRP and bovine serum albumin (BSA) digest), low detection limit (10 fmol), large binding capacity (200 mg/g), and high enrichment recovery (above 85%). The above-mentioned excellent performance of novel Fe3O4–PEI–pMaltose NPs was attributed to graft of maltose polymer brushes and efficient assembly strategy. Moreover, Fe3O4–PEI–pMaltose NPs were further utilized to selectively enrich glycopeptides from human renal mesangial cell (HRMC, 200 μg) tryptic digest, and 449 N-linked glycopeptides, representing 323 different glycoproteins and 476 glycosylation sites, were identified. It was expected that the as-synthesized Fe3O4–PEI–pMaltose NPs, possessing excellent performance (high binding capacity, good selectivity, low detection limit, high enrichment recovery, and easy magnetic separation) coupled to a facile preparation procedure, have a huge potential in N-glycosylation proteome analysis of complex biological samples.
研究领域:
生物医学科学
·
蛋白质组学
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纳米技术
·
分析化学
✓ 已验证
DOI
PubMed
RSC Advances
·
2016
·Vol. 6
·期 103
·100765-100771
·
IF 3.289
Chang Shu,Eboka Majolene B. Sabi-mouka,Wen Yang,Zhongyang Li,Li Ding
In this work, we designed a self-assembly peptide hydrogel encapsulated paclitaxel (PTX) and suberoylanilide hydroxamic acid (SAHA) for cancer co-delivery (Nap–PTX–SAHA). The hydrogels exhibited uniform nanofibers that entangle to form stable networks and pore microstructures (about 140–180 nm) resulting in absorption and storage of hydrophobic drugs. The circular dichroism (CD) spectra of hydrogels exhibit β-turn-like features. Nap–PTX–SAHA hydrogels achieved control over different types of drugs loading and released by diffusion and relaxation processes. Hydrogels exhibited better therapeutic effect and greater synergetic effect compared to the free drugs in vitro and in vivo. Injection of the hydrogels appears to achieve long-term drug release with higher efficacy and better biocompatibility than free drugs. As for the drug biodistribution studies in tumor-bearing mice, the PTX and SAHA from Nap–PTX–SAHA gels uptake in liver, lung and tumor were more than that of free PTX and SAHA. In comparison with free PTX or SAHA, the Nap–PTX–SAHA gels lower the uptake of released drug significantly in the heart, spleen, and kidney to reduce the cardiotoxicity and renaltoxicity. In conclusion, the Nap–PTX–SAHA gels certainly reduce the side effects of PTX and SAHA, enhance synergistic anticancer effects and suppress the drug resistance of PTX. This strategy can be a basis for designing appropriate clinical trials and will hold promise in nanomedicine for different drug combinations.
研究领域:
药学
·
癌症研究
·
纳米技术
·
药物递送系统
·
生物医学工程
✓ 已验证
DOI
高影响因子
International Journal of Biological Sciences
·
2022
·
IF 10.75
Wuping Yang,Kenan Zhang,Zedan Zhang,Jingcheng Zhou,Lei Li,Yawei Xu,Jianhui Qiu,Lin Cai,Yanqing Gong,Kan Gong
Our previous study has proved that down-regulation of CLDN10 (Claudin-10) in ccRCC (clear cell renal cell carcinoma) was closely related to tumor metastasis and predicted an unfavorable prognosis by analyzing TCGA-KIRC data. However, the effects of CLDN10 on the progression of ccRCC and its mechanisms of action remain elusive. During the study, a large number of clinical samples were utilized to verify the reduced expression of CLDN10 in ccRCC and its association with tumor metastasis and poor prognosis, and our results confirmed that lower CLDN10 expression was an independent predictor of shorter OS (HR: 4.0860, 95%CI: 2.4737-6.7490, P<0.0001) and DFS (HR: 4.3680, 95%CI: 2.2800-8.3700, P<0.0001) in metastatic ccRCC patients. CLDN10 overexpression accelerated cell apoptosis and restrained cell proliferation, migration and invasion in vitro . Besides, CLDN10 overexpression suppressed ccRCC growth and lung metastasis and promoted apoptosis in orthotopic models. Mechanistically, we found that CLDN10 overexpression up-regulated the acetylation and expression levels of ATP5O (ATP synthase subunit O, mitochondrial), leading to the dysfunction of mitochondrial, thereby suppressing the growth and metastasis of ccRCC through increasing the levels of NDUFS2, ROS, Cleaved-Caspase 3, E-cadherin and SDHB and decreasing the levels of N-cadherin and mitochondrial membrane potential. Moreover, knockdown of ATP5O expression based on the overexpression of CLDN10 could reverse the increase in NDUFS2, ROS, Cleaved-Caspase 3, E-cadherin and SDHB levels, the decrease in N-cadherin and mitochondrial membrane potential levels and the inhibition of ccRCC phenotypes caused by CLDN10 overexpression. Taken together, these findings for the first time illuminate the mechanism by which CLDN10 overexpression suppresses the growth and metastasis of ccRCC.
研究领域:
肿瘤学
·
分子生物学
·
细胞生物学
·
癌症研究
✓ 已验证
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）