Melatonin is present in virtually all organisms from bacteria to mammals, and it exhibits a broad spectrum of biological functions, including synchronization of circadian rhythms and oncostatic activity. Several functions of melatonin are mediated by its membrane receptors, but others are receptor-independent. For the latter, melatonin is required to penetrate membrane and enters intracellular compartments. However, the mechanism by which melatonin enters cells remains debatable. In this study, it was identified that melatonin and its sulfation metabolites were the substrates of oligopeptide transporter (PEPT) 1/2 and organic anion transporter (OAT) 3, respectively. The docking analysis showed that the binding of melatonin to PEPT1/2 was attributed to their low binding energy and suitable binding conformation in which melatonin was embedded in the active site of PEPT1/2 and fitted well with the cavity in three-dimensional space. PEPT1/2 transporters play a pivotal role in melatonin uptake in cells. Melatonin's membrane transportation via PEPT1/2 renders its oncostatic effect in malignant cells. For the first time, PEPT1/2 were identified to localize in the mitochondrial membrane of human cancer cell lines of PC3 and U118. PEPT1/2 facilitated the transportation of melatonin into mitochondria. Melatonin accumulation in mitochondria induced apoptosis of PC3 and U118 cells. Thus, PEPT1/2 can potentially be used as a cancer cell-targeted melatonin delivery system to improve the therapeutic effects of melatonin in cancer treatment.

In recent years, the development and research of flexible sensors have gradually deepened, and the performance of wearable, flexible devices for monitoring body temperature has also improved. For the human body, body temperature changes reflect much information about human health, and abnormal body temperature changes usually indicate poor health. Although body temperature is independent of the environment, the body surface temperature is easily affected by the surrounding environment, bringing challenges to body temperature monitoring equipment. To achieve real-time and sensitive detection of various parts temperature of the human body, researchers have developed many different types of high-sensitivity flexible temperature sensors, perfecting the function of electronic skin, and also proposed many practical applications. This article reviews the current research status of highly sensitive patterned flexible temperature sensors used to monitor body temperature changes. First, commonly used substrates and active materials for flexible temperature sensors have been summarized. Second, patterned fabricating methods and processes of flexible temperature sensors are introduced. Then, flexible temperature sensing performance are comprehensively discussed, including temperature measurement range, sensitivity, response time, temperature resolution. Finally, the application of flexible temperature sensors based on highly delicate patterning are demonstrated, and the future challenges of flexible temperature sensors have prospected.

BackgroundAndrographolide (Andro), a diterpenoid lactone, has been used for treatment of various cancers with less adverse effects. However, the underlying mechanisms regarding its anti-tumor mechanism still remain unclear.MethodsCell viability and proliferation were measured by CCK8 and CFSE dilution assay. The localization of p50/p65 or cytochrome c was determined using confocal immunofluorescence. Streptavidin-agarose pulldown or ChIP assays were used to detect the binding of multiple transactivators to COX-2 promoter. The promoter activity was examined by a dual-Luciferase reporter assay. The functions of Andro on COX-2-mediated angiogenesis were also investigated using human HUVEC cells through tube formation and spheroids sprouting assay. The in vivo anti-tumor efficacy of Andro was analyzed in xenografts nude mice.ResultsThe results indicated that Andro could significantly inhibit the proliferation of human breast cancers, and suppress COX-2 expression at both protein and mRNA levels. Furthermore, Andro could dose-dependently inhibit COX-2-mediated angiogenesis in human endothelial cells. We have also found that Andro significantly promoted the activation of cytochrome c and activated caspase-dependent apoptotic signaling pathway. Our further explorations demonstrated that Andro inhibited the binding of the transactivators CREB2, C-Fos and NF-κB and blocked the recruitment of coactivator p300 to COX-2 promoter. Moreover, Andro could effectively inhibit the activity of p300 histone acetyltransferase (HAT), thereby attenuating the p300-mediated acetylation of NF-κB. Besides, Andro could also dramatically inhibit the migration, invasion and tubulogenesis of HUVECs in vitro. In addition, Andro also exhibited effective anti-tumor efficacy as well as angiogenesis inhibition in vivo.ConclusionIn current study, we explore the potential effects of Andro in suppressing breast cancer growth and tumor angiogenesis, as well as the precise mechanisms. This work demonstrated the potential anti-cancer effects of Andro, indicating that Andro could inhibit COX-2 expression through attenuating p300 HAT activity and suppress angiogenesis via VEGF pathway, and thereby could be developed as an antitumor agent for the treatment of breast cancer.

In this Communication, the confocal microscopy images given in Figure 5B-ii and 5Bviii were found to be incorrect. The correct microscopy images for Figure 5B are given below.These errors do not affect the statistical results or conclusions of this Communication. The authors apologize for these mistakes. Figure 5. Fluorescenceimages of CYP3A4 in living zebrafish. […] B) Fish incubated with NEN in the present of clinical drugs (10 mm)T KZ (i);indinavir,I DV (ii);nilotinib, NT (iii);a cetaminophen, APAP (iv);omeprazole, OME (v);m ontelukast, MK (vi);sulfaphenazole, SZ (vii); clomethiazole, CZ (viii). Excitation wavelength = 800 nm, emission window = 520-560 nm. Scale bar = 50 mm. The pixel intensity from image (Ctrl) is defined as 1.0. Angewandte Chemie

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Normal high-density lipoprotein (nHDL) in normal, healthy subjects is able to promote angiogenesis, but the mechanism remains incompletely understood. HDL from patients with coronary artery disease may undergo a variety of oxidative modifications, rendering it dysfunctional; whether the angiogenic effect is mitigated by such dysfunctional HDL (dHDL) is unknown. We hypothesized that dHDL compromises angiogenesis. The angiogenic effects of nHDL and dHDL were assessed using endothelial cell culture, endothelial sprouts from cardiac tissue from C57BL/6 mice, zebrafish model for vascular growth and a model of impaired vascular growth in hypercholesterolemic low-density lipoprotein receptor null(LDLr -/- )mice. MiRNA microarray and proteomic analyses were used to determine the mechanisms. Lipid hydroperoxides were greater in dHDL than in nHDL. While nHDL stimulated angiogenesis, dHDL attenuated these responses. Protein and miRNA profiles in endothelial cells differed between nHDL and dHDL treatments. Moreover, nHDL suppressed miR-24-3p expression to increase vinculin expression resulting in nitric oxide (NO) production, whereas dHDL delivered miR-24-3p to inhibit vinculin expression leading to superoxide anion (O 2 •- ) generation via scavenger receptor class B type 1. Vinculin was required for endothelial nitric oxide synthase (eNOS) expression and activation and modulated the PI3K/AKT/eNOS and ERK1/2 signaling pathways to regulate nHDL- and VEGF-induced angiogenesis. Vinculin overexpression or miR-24-3p inhibition reversed dHDL-impaired angiogenesis. The expressions of vinculin and eNOS and angiogenesis were decreased, but the expression of miR-24-3p and lipid hydroperoxides in HDL were increased in the ischemic lower limbs of hypercholesterolemic LDLr -/- mice. Overexpression of vinculin or miR-24-3p antagomir restored the impaired-angiogenesis in ischemic hypercholesterolemic LDLr -/- mice. Collectively, nHDL stimulated vinculin and eNOS expression to increase NO production by suppressing miR-24-3p to induce angiogenesis, whereas dHDL inhibited vinculin and eNOS expression to enhance O 2 •- generation by delivering miR-24-3p to impair angiogenesis, and that vinculin and miR-24-3p may be therapeutic targets for dHDL-impaired angiogenesis.

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Curcumin, a natural polyphenolic compound, has commonly been used as a food additive or in many traditional medicine remedies for over 2,000 years in many Asian countries. Melatonin is a hormone secreted from pineal glands of mammals and possesses diverse physiological functions. Both curcumin and melatonin have the effective potential to inhibit proliferation of various types of cancers, but there is no report on their combination for bladder cancer treatment, and the underlying mechanism remains poorly understood. In the present study, we investigated whether the combination of curcumin and melatonin leads to an enhanced inhibition of cell proliferation in bladder cancer cells. Our results showed that the combinational treatment enhanced the repression of nuclear translocation of NF-κB and their binding on COX-2 promoter via inhibiting IKKβ activity, resulting in inhibition of COX-2 expression. In addition, combined treatment with curcumin and melatonin induced cell apoptosis in bladder cancer through enhancing the release of cytochrome c from the mitochondrial intermembrane space into the cytosol. These results, therefore, indicated that melatonin synergized the inhibitory effect of curcumin against the growth of bladder cancer by enhancing the anti-proliferation, anti-migration, and pro-apoptotic activities, and provide strong evidence that combined treatment with curcumin and melatonin might exhibit an effective therapeutic option in bladder cancer therapy.