Tetrahydrocurcumin induces G2/M cell cycle arrest and apoptosis involving p38 MAPK activation in human breast cancer cells

Curcumin (CUR) is a major naturally-occurring polyphenol of Curcuma species, which is commonly used as a yellow coloring and flavoring agent in foods. In recent years, it has been reported that CUR exhibits significant anti-tumor activity in vivo. However, the pharmacokinetic features of CUR have indicated poor oral bioavailability, which may be related to its extensive metabolism. The CUR metabolites might be responsible for the antitumor pharmacological effects in vivo. Tetrahydrocurcumin (THC) is one of the major metabolites of CUR. In the present study, we examined the efficacy and associated mechanism of action of THC in human breast cancer MCF-7 cells for the first time. Here, THC exhibited significant cell growth inhibition by inducing MCF-7 cells to undergo mitochondrial apoptosis and G2/M arrest. Moreover, co-treatment of MCF-7 cells with THC and p38 MAPK inhibitor, SB203580, effectively reversed the dissipation in mitochondrial membrane potential (Δψm), and blocked THC-mediated Bax up-regulation, Bcl-2 down-regulation, caspase-3 activation as well as p21 up-regulation, suggesting p38 MAPK might mediate THC-induced apoptosis and G2/M arrest. Taken together, these results indicate THC might be an active antitumor form of CUR in vivo, and it might be selected as a potentially effective agent for treatment of human breast cancer.     

Concepts and hypothesis: integrin cytoplasmic domain-associated protein-1 (ICAP-1) as a potential player in cerebral cavernous malformation

Cerebral cavernous malformation (CCM) is a common vascular disease in central nervous system that frequently predisposes to stroke, seizure, and cerebral hemorrhage. CCM lesions are characterized by dilated and leaky intracranial capillaries composed of a thin layer of vascular endothelial cells with abnormal subendothelial extracellular matrix. Despite the understanding that genetic mutation of three CCM genes (CCM1, CCM2, and CCM3) results in hereditary CCM, the molecular mechanism underlying vascular defects in CCM lesions remains poorly understood. Recent studies have shown that integrin cytoplasmic domain-associated protein-1 (ICAP-1, also known as integrin β1 binding protein1, ITGB1BP), a cytoplasmic protein interacting with both β1 integrin subunit and CCM1 protein (also known as Krit1), is implicated in vascular development. Analysis of data on the biochemistry and cellular biology of ICAP-1 highlights that bidirectional interaction of ICAP-1 with CCM1 and integrin might regulate diverse pathological processes of CCM disorder. Specifically, emerging evidence supports the hypothesized involvement of ICAP-1 in CCM pathogenesis through its significant effect in attenuating excessive vascular growth, its indispensable function in activating CCM1 protein, and its essential role in regulating integrin functions.     

Diabetes mellitus and risk of all-cause mortality among patients with tuberculosis in the state of Georgia, 2009–2012

PurposeTo estimate the association between diabetes mellitus (DM) and all-cause mortality during tuberculosis (TB) treatment.MethodsFrom 2009 to 2012, a retrospective cohort study among reported TB cases in Georgia was conducted. Patients aged 16 years or older were classified by DM and human immunodeficiency virus (HIV) status at the time of TB diagnosis and followed during TB treatment to assess mortality. Hazard ratios were used to estimate the association between DM and death.ResultsAmong 1325 patients with TB disease, 151 (11.4%) had DM, 147 (11.1%) were HIV-infected, and seven (0.5%) had both DM and HIV. Patients with TB-DM were more likely to have cavitary lung disease compared with those with TB alone (51.0% vs. 34.7%) and those with TB-HIV were more likely to have military/disseminated disease (12.9% vs. 3.4%) and resistance to rifampin or isoniazid (21.8% vs. 9.0%) compared with those without HIV infection (P < .05). In multivariable analysis, DM was not associated with death during TB treatment (hazard ratio, 1.22; 95% confidence interval, 0.70–2.12) or any death (adjusted odds ratio, 1.05; 95% confidence interval, 0.60–1.84).ConclusionsAmong TB patients in Georgia, the prevalence of comorbid DM and coinfection with HIV was nearly identical. In adjusted models, TB patients with DM did not have increased risk of all-cause mortality.     

Pre-surgical cortical activation to food pictures is associated with weight loss following bariatric surgery

BackgroundRecent research suggests that preintervention functional magnetic resonance imaging (fMRI) data may predict weight loss outcomes among patients who participate in a behavioral weight loss plan. No study has examined whether presurgical brain activation can predict outcomes following bariatric surgery.MethodThe aim of the present study was to determine if brain activations during a presurgical fMRI food-motivation paradigm are associated with weight loss 3 and 6 months following laparoscopic adjustable gastric banding (LAGB). Nineteen participants viewed food and nonfood pictures from a well-established food motivation paradigm during an fMRI scanning session before LAGB surgery. Weight was assessed presurgery and 3 and 6 months postsurgery; data for all participants was available at each time point. fMRI data were analyzed using the BrainVoyager QX statistical package. Whole brain voxelwise correlations of presurgery (food–nonfood) brain activation and weight, corrected for multiple comparisons, were performed to analyze the relationship between presurgical brain activation and subsequent weight loss. The settings were a medical university brain imaging center and 2 surgical weight loss centers in a major metropolitan area.ResultsIncreased activity in frontal regions associated with cognitive control (medial, middle, superior frontal gyrus) and posterior cingulate cortex was associated with weight loss following LAGB.ConclusionWe found that neural activity in previously established regions associated with cognitive and behavioral self-regulation predicts weight loss following bariatric surgery. These preliminary findings highlight the role of neural circuitry in the success and maintenance of weight loss and suggest a possible future use of fMRI in screening LAGB surgery candidates.     

Facile route to versatile nanoplatforms for drug delivery by one-pot self-assembly

There is still unmet demand for developing powerful approaches to produce polymeric nanoplatforms with versatile functions and broad applications, which are essential for the successful bench-to-bedside translation of polymeric nanotherapeutics developed in the laboratory. We have discovered a facile, convenient, cost-effective and easily scalable one-pot strategy to assemble various lipophilic therapeutics bearing carboxyl groups into nanomedicines, through which highly effective cargo loading and nanoparticle formation can be achieved simultaneously. Besides dramatically improving water solubility, the assembled nanopharmaceuticals showed significantly higher bioavailability and much better therapeutic activity. These one-pot assemblies may also serve as nanocontainers to effectively accommodate other highly hydrophobic drugs such as paclitaxel (PTX). PTX nanomedicines thus formulated display strikingly enhanced in vitro antitumor activity and can reverse the multidrug resistance of tumor cells to PTX therapy. The special surface chemistry offers these assembled entities the additional capability of efficiently packaging and efficaciously transfecting plasmid DNA, with a transfection efficiency markedly higher than that of commonly used positive controls. Consequently, this one-pot assembly approach provides a facile route to multifunctional nanoplatforms for simultaneous delivery of multiple therapeutics with improved therapeutic significance.     

低浓度甲醛吸入对不同年龄Wistar大鼠海马脑片长时程增强的影响

目的探讨低浓度甲醛吸入后大鼠离体海马脑片长时程增强(LTP)的变化及此变化是否具有年龄差异性。方法选取健康Wistar大鼠32只。其中成年鼠和幼年鼠各12只,新生鼠8只。每个年龄段的大鼠随机分为对照组和甲醛染毒组。甲醛染毒组大鼠暴露于质量浓度为0.5 mg.m-3甲醛,染毒时间为每天2 h,连续30 d。染毒结束后制作离体海马脑片,利用膜片钳技术记录高频刺激(HFS)后海马脑片LTP,并分析兴奋性突触后场电位(fEPSP)的斜率和幅度变化。结果各年龄段甲醛染毒组在HFS后的第30分钟fEPSP的斜率和幅度均较同龄对照组降低。新生鼠中甲醛染毒组与对照组海马脑片HFS后30 min fEPSP的斜率分别为(118.1±9.7)%和(281.8±40.2)%,差异有统计学意义(P<0.01);在幼年鼠,甲醛染毒组与对照组海马脑片HFS后30 min fEPSP的斜率分别为(107.7±5.2)%和(289.5±64.7)%,差异有统计学意义(P<0.05);在成年鼠,甲醛染毒组与对照组海马脑片HFS后30 min fEPSP的斜率分别为(120.7±6.5)%和(197.9±38.1)%,无统计学差异(P>0.05)。新生鼠甲醛染毒组与其对照组海马脑片HFS后30 min fEPSP的幅度分别为(111.1±4.9)%和(293.4±46.8)%,差异有统计学意义(P<0.01);幼年鼠甲醛染毒组与其对照组海马脑片HFS后30 min fEPSP的幅度分别为(101.9±4.2)%和(266.9±51.0)%,差异有统计学意义(P<0.05);成年鼠甲醛染毒组与其对照组海马脑片HFS后30 min fEPSP的幅度分别为(122.9±4.2)%和(191.2±33.6)%,无统计学差异(P>0.05)。结论甲醛吸入染毒可抑制Wistar大鼠海马LTP的形成,且这种抑制作用具有年龄差异性,年龄越小,甲醛所造成的损伤越大。     

乳腺CEUS预测模型诊断乳腺恶性病灶的观察者间一致性:多中心研究

目的 探讨拉伸指数模型DWI鉴别诊断乳腺良恶性病变的价值。方法 收集58例乳腺病变患者,共63个病灶（良性33个,恶性30个）,行多b值DWI及动态增强MRI （DCE-MRI）扫描。计算ADC、扩散分布指数（DDC）和扩散异质性指数（α）值,并生成时间-信号强度曲线（TIC）。比较良恶性病变间各参数差异,采用ROC曲线评价各参数诊断效能。结果 恶性病变ADC、DDC和α分别为（1.01±0.19）×10^-3 mm²/s、（0.89±0.23）×10^-3 mm²/s和0.75±0.09,良性病变分别为（1.41±0.27）×10^-3 mm²/s、（1.49±0.29）×10^-3 mm²/s和0.87±0.07,恶性病变均低于良性病变（P均<0.01）。各参数中DDC曲线下面积（AUC）最大（AUC=0.958）,最佳诊断界值1.22×10^-3 mm²/s,敏感度和特异度分别为96.67%、81.82%,DDC与TIC联合所得AUC为0.976,对应敏感度和特异度分别为93.33%、93.94%。结论 拉伸指数模型DWI参数DDC、α能够鉴别诊断乳腺良恶性病变,DDC与TIC联合的诊断效能高于ADC和DCE。