Design and Synthesis of Fluoroacylshikonin as an Anticancer Agent

A series of shikonin derivatives, selectively acylated by various fluorinated carboxylic acids at the side chain of shikonin, were synthesized and their anticancer activity evaluated, in which eight compounds are reported for the first time. Among all the compounds tested, compound S7 showed the most potent anticancer activity against B16‐F10 (malignant melanoma cells), MG63 (human osteosarcoma cells), and A549 (lung cancer cells) with IC₅₀ 0.39 ± 0.01, 0.72 ± 0.04 and 0.58 ± 0.02 µmol/L. Docking simulation of compound S7 was carried out to position S7 into a tubulin active site to determine the probable binding conformation. All the results suggested that compound S7 may be a potential anticancer agent. Chirality 25:757–762, 2013. © 2013 Wiley Periodicals, Inc.     

Circular Dichroism Spectroscopy Study of Crystalline‐to‐Amorphous Transformation in Chiral Platinum(II) Complexes

Two couples of enantiomeric platinum(II) complexes: Pt(L_1a)Cl ( 1a ), Pt(L_1b)Cl ( 1b ) and Pt(L_1a)(C ≡ C ? Ph) ( 2a ), Pt(L_1b)(C ≡ C ? Ph) ( 2b ) (L_1a = (+)‐1,3‐di‐(2‐(4,5‐pinene)pyridyl)benzene, L_1b = (?)‐1,3‐di‐(2‐(4,5‐pinene)pyridyl)benzene) were synthesized and characterized. Their absolute configurations were determined by single crystal X‐ray diffraction and further verified by circular dichroism (CD) spectra (including electronic circular dichroism [ECD] and vibrational circular dichroism [VCD]). These complexes show interesting mechanoluminescence and/or vapoluminescence due to crystalline‐to‐amorphous transformation. The crystalline solids, grinding‐induced amorphous powders, and vapor‐induced amorphous powders of complexes 2a and 2b were comparatively investigated by solid‐state ECD and VCD spectra. The transformation from crystalline solids to amorphous powders was accompanied by significant variances of the spectral feature in both ECD and VCD spectra. Chirality 25:384–392, 2013. © 2013 Wiley Periodicals, Inc.     

Epigenetic Maternal Effects on Endogenous Rhythms in Precocial Birds

Development involves interactions between genetic and environmental influences. Vertebrate mothers are generally the first individuals to encounter and interact with young animals. Thus, their role is primordial during ontogeny. The present study evaluated non‐genomic effects of mothers on the development of rhythms of precocial Japanese quail (Coturnix c. japonica). First, we investigated the influence of mothering on the ontogeny of endogenous rhythms of young. We compared circadian and ultradian rhythms of feeding activity of quail reared with or without adoptive mothers. More brooded than non‐brooded quail presented a circadian and/or an ultradian rhythm. Thus, the presence of the mother during the normal brooding period favors, in the long term, expression of rhythms in the young. Second, we investigated the influence of rhythmic phenotype of the mother on the development of endogenous rhythms of young by comparing quail brooded by circadian‐rhythmic adoptive mothers (R) to quail brooded by circadian‐arrhythmic adoptive mothers (A). More R‐brooded than A‐brooded quail expressed circadian rhythmicity, and circadian rhythm clarities were greater in R‐brooded than A‐brooded quail. Ultradian rhythmicity did not differ between R‐ and A‐brooded quail, nor between R and A adoptive mothers. Thus, the rhythmic phenotypes of quail mothers influence the rhythmic phenotypes of their young. Our results demonstrate that mothers of precocial birds influence epigenetically the ontogeny of endogenous rhythms of the young they raise.     

The mechanism underlying the effects of the cell surface ATP synthase on the regulation of intracellular acidification during acidosis

The F1F0 ATP synthase has recently become the focus of anti‐cancer research. It was once thought that ATP synthases were located strictly on the inner mitochondrial membrane; however, in 1994, it was found that some ATP synthases localized to the cell surface. The cell surface ATP synthases are involved in angiogenesis, lipoprotein metabolism, innate immunity, hypertension, the regulation of food intake, and other processes. Inhibitors of this synthase have been reported to be cytotoxic and to induce intracellular acidification. However, the mechanisms by which these effects are mediated and the molecular pathways that are involved remain unclear. In this study, we aimed to determine whether the inhibition of cell proliferation and the induction of cell apoptosis that are induced by inhibitors of the cell surface ATP synthase are associated with intracellular acidification and to investigate the mechanism that underlines the effects of this inhibition, particularly in an acidic tumor environment. We demonstrated that intracellular acidification contributes to the cell proliferation inhibition that is mediated by cell surface ATP synthase inhibitors, but not to the induction of apoptosis. Intracellular acidification is only one of the mechanisms of ecto‐ATP synthase‐targeted antitumor drugs. We propose that intracellular acidification in combination with the inhibition of cell surface ATP generation induce cell apoptosis after cell surface ATP synthase blocked by its inhibitors. A better understanding of the mechanisms activated by ecto‐ATP synthase‐targeted cancer therapies may facilitate the development of potent anti‐tumor therapies, which target this enzyme and do not exhibit clinical limitations. J. Cell. Biochem. 114: 1695–1703, 2013. © 2013 Wiley Periodicals, Inc.     

Src kinases mediate VEGFR2 transactivation by the osteostatin domain of PTHrP to modulate osteoblastic function

Parathyroid hormone‐related protein (PTHrP) stimulates osteoblastic function through its N‐ and C‐terminal domains. Since the osteogenic action of the latter domain appears to depend at least in part on its interaction with the vascular endothelial growth factor (VEGF) system, we aimed to explore the putative mechanism underlying this interaction in osteoblasts. Using native conditions for protein extraction and immunoblotting, we found that both PTHrP (107–139) and the shorter PTHrP (107–111) peptide (known as osteostatin), at 100 nM, promoted the appearance of a VEGF receptor (VEGFR) 2 protein band of apparent Mr. wt. 230 kDa, which likely represents its activation by dimer formation, in mouse osteoblastic MC3T3‐E1 cells. Moreover, osteostatin (100 nM) maximally increased VEGFR2 phosphorylation at Tyr‐1059 within 5–10 min in both MC3T3‐E1 and rat osteoblastic osteosarcoma UMR‐106 cells. This phosphorylation elicited by osteostatin appears to be VEGF‐independent, but prevented by the VEGFR2 activation inhibitor SU1498 and also by the Src kinase inhibitors SU6656 and PP1. Furthermore, osteostatin induced phosphorylation of Src, extracellular signal‐regulated kinase (ERK) and Akt with a similar time course to that observed for VEGFR2 activation in these osteoblastic cells. This osteostatin‐dependent induction of ERK and Akt activation was abrogated by SU6656. Up‐regulation of VEGF and osteoprotegerin gene expression as well as the pro‐survival effect induced by osteostatin treatment were all prevented by both SU1498 and SU6656 in these osteoblastic cells. Collectively, these findings demonstrate that the osteostatin domain of C‐terminal PTHrP phosphorylates VEGFR2 through Src activation, which represents a mechanism for modulating osteoblastic function. J. Cell. Biochem. 114: 1404–1413, 2013. © 2012 Wiley Periodicals, Inc.     

Thermoregulatory effects of melatonin in relation to sleepiness

Thermoregulatory processes have long been implicated in the initiation of human sleep. In this paper, we review our own studies conducted over the last decade showing a crucial role for melatonin as a mediator between the thermoregulatory and arousal system in humans. Distal heat loss, via increased skin temperature, seems to be intimately coupled with increased sleepiness and sleep induction. Exogenous melatonin administration during the day when melatonin is essentially absent mimics the endogenous thermophysiological processes occurring in the evening and induces sleepiness. Using a cold thermic challenge test, it was shown that melatonin‐induced sleepiness occurs in parallel with reduction in the thermoregulatory set‐point (threshold); thus, melatonin may act as a circadian modulator of the thermoregulatory set‐point. In addition, an orthostatic challenge can partially block the melatonin‐induced effects, suggesting an important role of the sympathetic nervous system as a link between the thermoregulatory and arousal systems. A topographical analysis of finger skin temperature with infrared thermometry revealed that the most distal parts of the fingers, i.e., fingertips, represent the important skin regions for heat loss regulation, most probably via opening the arteriovenous anastomoses, and this is clearly potentiated by melatonin. Taken together, melatonin is involved in the fine‐tuning of vascular tone in selective vascular beds, as circulating melatonin levels rise and fall throughout the night. Besides the role of melatonin as “nature's soporific”, it can also serve as nature's nocturnal vascular modulator.