BACKGROUNDAlzheimer's disease (AD) is an aging-associated form of dementia characterized by the pathological deposition of toxic misfolded proteins in the central nervous system (CNS), which is closely related to the clearance impairment of meningeal lymphatic vessels (mLVs). Thus, enhancement dural meningeal lymphatic drainage to remove amyloid-β (Aβ) is usually considered as a potential therapeutic target for AD.PURPOSEThis study aimed to investigate the mechanisms of Jiawei Xionggui Decoction (JWXG) to attenuate cognitive dificits in APP/PS1 mice with impaired meningeal lymphatic drainage.METHODSLigation of deep cervical lymph nodes (dcLNs) was performed to establish the mice model of the impaired meningeal lymphatic drainage in APP/PS1 mice. Cognitve behaviors and pathological morphology of mice were assessed. Cerebral blood flow (CBF) of mice was determined using Laser speckle contrast imaging analysis. Serum non-targeted metabolomics analysis was applied to decipher the mechanisms of JWXG in rescuing the impairment of mLVs, and C8-D1A cells were employed to validate in vitro.RESULTSDisruption of mLVs in APP/PS1 mice deteriorated cognitive dysfunction, accelerated Aβ burden and glia activation, accompanied by more severe neuropathological damage, CBF reduction and neuroinflammation exacerbation. Serum non-targeted metabolomics analysis indicates the increase of arachidonic acid (AA) metabolic pathway was the key contributor to the neuropathological exacerbation of dcLNs ligation APP/PS1 mice. Interestingly, clinically equivalent dose of JWXG was sufficient to restore mLVs drainage and rescue cognitive performance by inhibiting neuroinflammation depended by AA metabolic pathway in dcLNs ligation APP/PS1 mice.CONCLUSIONOur findings establish a novel mechanism that rescue mLVs by inhibiting AA metabolic pathway to clear brain Aβ, and support JWXG as a feasible treatment strategy for AD by suppressing AA metabolic pathway to improve mLVs drainage efficiency.

2018-09-04·Molecular Pharmaceutics2区 · 医学

An Indole–Chalcone Inhibits Multidrug-Resistant Cancer Cell Growth by Targeting Microtubules

2区 · 医学

Article

作者: Bian, Tengfei ; Cong, Hui ; Zhao, Xinghua ; Zhuang, Chunlin ; Odde, David J. ; Pomeroy, Emily J. ; Sham, Yuk Yin ; Eckfeldt, Craig E. ; Lee, John ; Xing, Chengguo ; Wang, Yi ; Zhang, Wannian ; Castle, Brian T. ; Miao, Zhenyuan ; Zhou, Bo

Multidrug resistance and toxic side effects are the major challenges in cancer treatment with microtubule-targeting agents (MTAs), and thus, there is an urgent clinical need for new therapies. Chalcone, a common simple scaffold found in many natural products, is widely used as a privileged structure in medicinal chemistry. We have previously validated tubulin as the anticancer target for chalcone derivatives. In this study, an α-methyl-substituted indole-chalcone (FC77) was synthesized and found to exhibit an excellent cytotoxicity against the NCI-60 cell lines (average concentration causing 50% growth inhibition = 6 nM). More importantly, several multidrug-resistant cancer cell lines showed no resistance to FC77, and the compound demonstrated good selective toxicity against cancer cells versus normal CD34⁺ blood progenitor cells. A further mechanistic study demonstrated that FC77 could arrest cells that relate to the binding to tubulin and inhibit the microtubule dynamics. The National Cancer Institute COMPARE analysis and molecular modeling indicated that FC77 had a mechanism of action similar to that of colchicine. Overall, our data demonstrate that this indole-chalcone represents a novel MTA template for further development of potential drug candidates for the treatment of multidrug-resistant cancers.

2013-12-05·Chinese Medical Journal3区 · 医学

Effect of partial liquid ventilation on lung function in oleic acidinduced lung injury model of piglets

3区 · 医学

ArticleOA

作者: Zhang, Yan-bo ; Li, Ling-ke ; Li, Gang ; Zhu, Yao-bin ; Xu, Yu-lin ; Zhang, Ji-zhuo

BackgroundPediatric patients are susceptible to lung injury that does not respond to traditional therapies. Partial liquid ventilation (PLV) has been developed as an alternative ventilatory strategy for treating severe lung injury. The aim of this study is to investigate the effect of PLV on lung function in immature piglets.MethodsAcute lung injury was induced in 12 Chinese immature piglets by oleic acid (OA). The animals were randomly assigned to two groups (n=6 each group): (1) conventional mechanical ventilation (MV) group and (2) PLV with FC-77 (10 ml/kg) group. Mean arterial blood pressure (MAP), mean pulmonary arterial pressure (MPAP), central venous pressure (CVP), left atrial pressure (LAP), systemic vascular resistance (SVR), pulmonary vascular resistance (PVR), cardiac output (CO), mean pressure of airway (Paw), dynamic lung compliance (Cydn), and arterial blood gases were measured during the observation period.ResultsNo piglet died in either group with severe lung injury. After four hours of ventilation, pH in the MV group gradually decreased to lower than 7.20, while in the PLV group, pH also gradually decreased but remained higher than 7.20 (P<0.05). Partial pressure of oxygen in artery (PaO2) decreased in both groups, but with a significant difference between the PLV group and MV group (P<0.05). Partial pressure of carbon dioxide in artery (PaCO2) increased in both groups, but with a significant difference between the PLV group and MV group (P<0.05). Paw increased in both groups, but was not significantly different (P>0.05). Cydn decreased in both groups, but without a significant difference (P>0.05). At four hours, heart rate (HR) and MAP in both groups decreased. MPAP in both groups increased, and there was a significant difference between the two groups (P<0.05). CVP was stable in both groups. At four hours, PVR and LAP were increased in both groups. CO was decreased in both groups (P<0.05). SVR was stable during the observation time.ConclusionPLV did not improve outcome in changes of lung function.

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