CHEMICAL RESEARCH IN CHINESE UNIVERSITIES
·
2013
·Vol. 29
·期 4
·730-734
·
IF 0.735
Zhang Lei,Zhang Shi-tao,Zhang Xiao-ping,Sun Jing,Wang Yong-sen,Liu Yue-long,Xue Miao-miao,Wang Zhi,Xing Shu,Ma Jun-feng,Li Wan-nan,Fu Xue-qi
The protein tyrosine phosphatases(PTPs) comprise a family of enzymes that specifically dephosphorylate tyrosyl residues. Among them, SHP-1 has been regarded as one of the best validated intracellular tyrosine phosphatases. Downregulation of SHP-1 has shown remarkable efficacy in improving insulin sensitivity in vivo in insulin signaling pathway. In this study, we found the role of Candesartan cilexetil targeting at SHP-1. The results indicate that Candesartan cilexetil was a competitive inhibitor to SHP-1(IC 50 =85.6 μmol/L and K
i =24 μmol/L). We also found that Candesartan cilexetil was more sensitive towards SHP-1 compared with other PTPs. Through the consequence of Western blotting, it showed that Candesartan cilexetil can strengthen the level of tyrosine phosphorylation of several key cellular proteins[such as insulin receptor(IR), insulin receptor substrate(IRS) and ERK]_in insulin signaling pathway in HepG 2 cells and improve the insulin sensitivity through inhibiting the protein phosphorylation of SHP-1. These findings showed that Candesartan cilexetil might be an important inhibitor of SHP-1 and had a great application potential in the treatment of diabetes through inhibiting the level of SHP-1 in insulin signaling pathway.
研究领域:
药理学
·
分子生物学
·
糖尿病研究
✓ 已验证
产品关联
DOI
高影响因子
Frontiers in Microbiology
·
2021
·
IF 5.64
Xu Lanlan,She Pengfei,Chen Lihua,Li Shijia,Zhou Linying,Hussain Zubair,Liu Yaqian,Wu Yong
Staphylococcus aureus is an important pathogen causing hospital-acquired infections. Methicillin-resistant S. aureus (MRSA), biofilms, and persisters are highly tolerant to traditional antibiotics and make it difficult to treat. Therefore, new antimicrobial agents are urgently needed to treat hard-to-eradicate diseases caused by this bacterium. In this study, candesartan cilexetil (CC), an angiotensin hypertension drug, had strong antimicrobial activity against S. aureus with minimal inhibitory concentrations (MICs) and minimal bactericidal concentrations (MBCs) of 8–16 μg/ml and 16–32 μg/ml. CC exhibited limited cytotoxicity and low potential to induce drug resistance. In addition, it showed a synergistic antibacterial effect when combined with gentamicin and tobramycin. The effective concentrations to inhibit MRSA biofilm formation were 16–64 μg/ml, and intractable persisters were killed at 4–8 × MIC. Through the analysis of its mechanism of action, it was evident that the membrane permeability was disrupted as well as the cell structure was damaged. Furthermore, we demonstrated that CC had antibacterial effects in vivo in MRSA-infected murine skin abscess models. In conclusion, these results imply that CC might be a potential antibacterial agent for the treatment of S. aureus-associated infections.
研究领域:
药理学
·
微生物学
·
传染病学
✓ 已验证
DOI
PubMed
高影响因子
ACS Omega
·
2024
·
IF 3.7
Chengchun Chen,Duoyun Li,Yongpeng Shang,Zhiwei Lin,Zewen Wen,Peiyu Li,Zhijian Yu,Zhong Chen,Xiaoju Liu
Enterococcus faecalis infections pose a significant clinical challenge due to their multidrug resistance and propensity for biofilm formation. Exploring alternative treatment options, such as repurposing existing drugs, is crucial in addressing this issue. This study investigates the antibacterial activity of candesartan cilexetil against E. faecalis and elucidates its mechanism of action. Candesartan cilexetil exhibited notable antibacterial activity against both E. faecalis and Enterococcus faecium, with minimum inhibitory concentration (MIC) of ≤25 μM. Time-kill curves demonstrated concentration-dependent bactericidal effects. Candesartan cilexetil could significantly inhibited biofilm formation at the concentration of 1/4× MIC and induced alterations in biofilm structure. Permeability assays revealed compromised bacterial membranes, accompanied by the dissipation of membrane potential in E. faecalis cells after treatment with candesartan cilexetil. Checkerboard analysis showed that bacterial membrane phospholipids phosphatidylglycerol and cardiolipin could neutralize the antibacterial activity of candesartan cilexetil in a dose-dependent manner. Biolayer interferometry (BLI) assay indicated specific interactions between candesartan cilexetil and phosphatidylglycerol or cardiolipin. This study demonstrates the promising antibacterial and antibiofilm activities of candesartan cilexetil against multidrug-resistant E. faecalis. The mechanism of action involves disruption of bacterial membranes, possibly by interacting with membrane phospholipids. These findings underscore the potential utility of candesartan cilexetil as an effective therapeutic agent for combating E. faecalis infections, offering a valuable strategy in the battle against antibiotic-resistant pathogens.
研究领域:
微生物学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
AAPS PHARMSCITECH
·
2026
·Vol. 27
·期 1
·76
·
IF 4
Zheng Kai,Wang Tianyi,Chen Hao,Zhao Yuyang,Jia Fucong,Yang Xinggang
Candesartan cilexetil (CC) suffers from poor solubility, first-pass effect, and low bioavailability. In order to solve these problems, a solid supersaturated self-nanoemulsifying drug delivery system containing phospholipids (solid PC-S-SNEDDS) was constructed in this study. The system was based on the traditional self-nanoemulsifying drug delivery system (SNEDDS) with the addition of precipitation inhibitors, phospholipids and solid carriers to inhibit crystallisation, increase lymphatic transport, and facilitate transport and storage. SNEDDS, supersaturated self-nanoemulsifying drug delivery system (S-SNEDDS), supersaturated self-nanoemulsifying drug delivery system containing phospholipids (PC-S-SNEDDS), and solid PC-S-SNEDDS were prepared by central composite design and single factor investigation. The spectra of PXRD and FT-IR showed that the drugs in the solid PC-S-SNEDDS existed in an amorphous or molecular form and did not form new chemical bonds with the excipients. The results of dissolution experiments showed that compared with CC and marketed capsules, the four self-nanoemulsions could significantly increase the dissolution rate and cumulative dissolution of CC. The stability results demonstrate that the stability of the PC-S-SNEDDS was improved after curing. The results of pharmacokinetics in rats showed that the bioavailability of solid PC-S-SNEDDS was 568.17% and 415.00% of CC suspension and marketed capsules. In the lymphatic transport experiment, compared with CC suspension, solid PC-S-SNEDDS increased the proportion of lymphatic transport from 18.69% to 62.14%. The results showed that solid PC-S-SNEDDS improved the solubility, reduced the first-pass effect, and greatly improved the bioavailability of CC, which was a promising drug delivery system to solve the problem of CC. Graphical
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Pharmaceutics
·
2021
·Vol. 13
·期 4
·497
·
IF 6.321
Surendra Poudel,Dong Wuk Kim
Candesartan cilexetil (CC), a prodrug and highly effective antihypertensive agent, is a poorly soluble (BCS Class II) drug with limited bioavailability. Here, we attempted to improve CC’s bioavailability by formulating several CC-loaded amorphous solid dispersions with a hydrophilic carrier (PVPK30) and pH modifier (sodium carbonate) using the spray drying technique. Solubility, in vitro dissolution, and moisture content tests were used for screening the optimized formulation. We identified an optimized formulation of CC/PVPK30/SC, which at the ratio of 1:0.5:1 (w/w/w) exhibited a 30,000-fold increase in solubility and a more than 9-fold enhancement in dissolution compared to pure CC. Solid-state characterization revealed that in pH-modulated CC amorphous solid dispersion (CCSDpM), CC’s crystallinity was altered to an amorphous state with the absence of undesirable interactions. Stability studies also showed that the optimized formulation was stable with good drug content and drug release under accelerated conditions of up to 4 weeks and real-time stability conditions of up to 12 weeks. Furthermore, pharmacokinetic parameters, such asAUCandCmaxof candesartan, had a 4.45-fold and 7.42-fold improvement, respectively, in CCSDpM-treated rats compared to those in the CC-treated rats. Thus, these results suggest that CCSDpMis highly effective for increasing oral absorption. The application of these techniques can be a viable strategy to improve a drug’s bioavailability.
研究领域:
药剂学
·
药物化学
✓ 已验证
DOI
高影响因子
危险品化学品经营许可证（带存储）