Synthesis and Evaluation of Trehalose‐Based Compounds as Novel Inhibitors of Cancer Cell Migration and Invasion

As a continuous research for the discovery of trehalose‐based anti‐invasive agents, we developed a convenient synthetic approach for the preparation of 6,6′‐dideoxy‐6,6′‐bis(acylamino)‐α,α‐D‐trehaloses. A series of trehalose‐based amides were prepared through the trityl protection of the two primary hydroxyls of α,α‐D‐trehalose, benzoylation, the removal of the trityl protective group, mesylation, azidation, catalytic hydrogenation in the presence of hydrochloride, coupling reaction with a variety of acids, and subsequent debenzoylation and deacetylation in some cases. Compound 8b , 6,6′‐dideoxy‐6,6′‐bis(2‐hydroxybenzamide)‐ α , α ‐D‐trehalose, was just as potent as the natural brartemicin against the invasion of murine colon 26‐L5 cells. It exhibited no cytotoxicity on human breast adenocarcinoma MDA‐MB‐231 and murine colon 26‐L5 cells. It can significantly inhibit the migration and invasion of the MDA‐MB‐231 cells. The anti‐invasive effect of 8b was possibly related to its inhibitory activity on MMP‐9, its suppression on the expression of MMP‐9 and VEGF, and its deactivation of Akt.     

Matrix metalloproteinase abundance in human myocardial fibroblasts: effects of sustained pharmacologic matrix metalloproteinase inhibition

BACKGROUND: A cause-effect relationship has been established between matrix metalloproteinases (MMPs) and left ventricular (LV) myocardial remodeling through the use of pharmacologic MMP inhibitors. However, the direct effects of MMP inhibition on MMPs and endogenous tissue inhibitors of metalloproteinases (TIMPs) in LV human myocardial fibroblasts (LVHMFs) remain unknown. This study measured MMP-2, MMP-9, MMP-13, MT1-MMP, and TIMP-1 release in LVHMFs. METHODS AND RESULTS: LVHMF cultures were established from six individual patients (passages 2-5) and incubated with and without the broad-spectrum MMP inhibitor PD166793 (100 microM) for 12-36 h. While PD166793 did not influence MMP-2 release, MMP-9 levels based on substrate zymography increased at 36 h by over 30% (P < 0.05). TIMP-1 levels increased in a time-dependent manner with no effect from PD166793 incubation. However, the MMP-9/TIMP-1 ratio was increased by over 20% from time-matched values following 12-36 h of exposure to PD166793 (P < 0.05). Similar results obtained after incubation of LVHMF cultures with the broad-spectrum MMP inhibitor Batimastat (BB-94) suggest that these observations are due to a general class effect of broad-spectrum MMP inhibitors. CONCLUSIONS: This study is the first to demonstrate that a selective induction and release of an MMP species occurs with sustained exposure to pharmacologic MMP inhibition in LVHMFs. These observations may have particular importance with respect to controlling this proteolytic system in the context of LV myocardial remodeling.     

Structural and functional remodeling of the left atrium: clinical and therapeutic implications for atrial fibrillation

Left atrial (LA) structural and functional remodeling reflects a spectrum of pathophysiological changes that have occurred in response to specific stressors. These changes include alterations at the levels of ionic channels, cellular energy balance, neurohormonal expression, inflammatory response, and physiologic adaptations. There is convincing evidence demonstrating an important pathophysiological association between LA remodeling and atrial fibrillation (AF). Measures that will prevent, attenuate, or halt these processes of LA remodeling may have a major public health impact with respect to the epidemic of AF. In this review, we describe the mechanisms involved in LA remodeling and highlight the existing and potential therapeutic options for its reversal, and implications for AF development.     

细胞因子在初治肺结核患者血液中表达的研究

目的研究初治肺结核患者IL-2、IL-4、IL-18、IFN-γ及MMP-9的表达情况,并了解其在肺结核病治疗过程中的变化。方法应用ELLSA法检测100例初治肺结核患者治疗前后及90例健康志愿者血清IL-2、IL-4、IL-18、IFN-γ及MMP-9的表达。结果 100例结核涂阳患者,治疗2个月后79例转阴,痰菌转阴率79%;研究组与对照组比较,研究组治疗前各种细胞因子水平明显高于对照组,差异有统计学意义(P0.01);研究组治疗后IL-4、IL-18水平高于对照组,差异有统计学意义(P0.05),IL-2、IFN-γ及MMP-9与对照组比较,差异无统计学意义(P0.05);研究组治疗后各种细胞因子水平明显低于治疗前(P0.05),差异有统计学意义(P0.05);转阴患者五种细胞因子与未转阴患者间比较,差异有统计学意义(P0.05)。结论在进行抗肺结核物治疗时动态观察细胞因子水平,有利于监测肺结核病情的转归,利用细胞因子的变化趋势,可以预知治疗方案的有效性。     

High-content analysis for mitophagy response to nanoparticles: A potential sensitive biomarker for nanosafety assessment

Mitophagy, a selective autophagy of mitochondria, clears up damaged mitochondria to maintain cell homeostasis. We performed high-content analysis (HCA) to detect the increase of PINK1, an essential protein controlling mitophagy, in hepatic cells treated with several nanoparticles (NPs). PINK1 immunofluorescence-based HCA was more sensitive than assays and detections for cell viability and mitochondrial functions. Of which, superparamagnetic iron oxide (SPIO)-NPs or graphene oxide-quantum dots (GO-QDs) was selected as representatives for positive or negative inducer of mitophagy. SPIO-NPs, but not GO-QDs, activated PINK1-dependent mitophagy as demonstrated by recruitment of PARKIN to mitochondria and degradation of injured mitochondria. SPIO-NPs caused the loss of mitochondrial membrane potential, decrease in ATP, and increase in mitochondrial reactive oxide species and Ca²⁺. Blocking mitophagy with PARKIN siRNA aggravated the cytotoxicity of SPIO-NPs. Taken together, PINK1 immunofluorescence-based HCA is considered to be an early, sensitive, and reliable approach to evaluate the bioimpacts of NPs.     

Geraniin inhibits oral cancer cell migration by suppressing matrix metalloproteinase‐2 activation through the FAK/Src and ERK pathways

Geraniin has been reported to have numerous biological activities, including antiviral, antihypertensive, antihyperglycaemic, liver protective, antidiabetic, and apoptotic activities. However, the anti‐migration effects of geraniin on oral cancer remain elusive. In this study, we revealed the potential antitumor mechanisms of geraniin through the inhibition of the migration and invasion of human oral cancer cell lines SCC‐9 and SCC‐14. The results of gelatin zymography and Western blot assays revealed that geraniin significantly reduced the activity and expression of matrix metalloproteinase‐2 (MMP‐2) of oral cancer cells in a concentration‐dependent manner. Furthermore, geraniin potently suppressed the phosphorylation of focal adhesion kinase (FAK), Src, and extracellular signal‐regulated kinase (ERK)1/2 but did not affect the phosphorylation of p38 mitogen‐activated protein kinase (MAPK) and c‐Jun N‐terminal kinase 1/2. Moreover, blocking the MAPK/ERK1/2 pathway significantly enhanced the anti‐migration ability of geraniin in oral cancer cells. In conclusion, we demonstrated that geraniin inhibits the motility of SCC‐9 and SCC‐14 cells in vitro through a molecular mechanism that involves the attenuation of MMP‐2 expression and activity mediated by decreased FAK/Src and ERK1/2 pathways.     

A protective polymorphism in MMP16, improved blood gas levels,and chronic obstructive pulmonary diseases: Family and two population‐based studies

The aberrant expression of matrix metalloproteinases (MMPs) is known to contribute to the pathogenesis of airway remodeling and alveolar disruption in chronic obstructive pulmonary disease (COPD). In the discovery stage, 11 COPD from five families were subjected to whole‐genome sequencing, and 21 common polymorphisms in MMPs and TIMPs were identified. These polymorphisms were genotyped in two subsequent verification studies. Of these polymorphisms, c.2392G>A (rs2664370T>C) and c.4158C>A (rs2664369T>G) in MMP16 remained significantly different. Functionally, we found that MMP16 expression was significantly increased in peripheral blood monocytes (PBMCs) from COPD and in cigarette smoke extract‐treated 16HBE cells compared with controls. This was also shown by bioinformatics analysis. COPD carrying rs2664370CC showed decreased levels of MMP16 in the plasma and in PBMCs compared with those carrying CT and TT. Treatment with hsa‐miR‐576‐5p mimics led to a greater reduction in luciferase reporter activity in cells transfected with rs2664370CC. Moreover, blood levels of base excess, PCO₂, and PO₂ in COPD with rs2664370CC were significantly lower than those with rs2664370CT+TT. Taken together, these results demonstrate that the rs2664370T>C polymorphism in MMP16 protects against the risk of COPD, likely by favoring interaction with hsa‐miR‐576‐5p, leading to reduced MMP16 expression and improved blood gas levels.