The heat shock response has been extensively studied by a number of investigators to understand the molecular mechanism underlying the cellular response to severe heat stress (higher than 42°C). But, ...body or tissue temperature increases by only a few degrees Celsius during physiological events. Therefore, the physiological cellular response to mild heat stress rather than severe heat stress is likely to be more important. Repeated exposure to hyperthermia for consecutive 5 days induces heat acclimation which is an adaptive physiological process in humans and animals. However, thus far, the effect of continuous exposure to heat stress on cells has not been fully evaluated. In this study, we investigated an adaptive physiological process that is induced in culture cells by continuous exposure to mild heat stress for 5 days. Exposure to heat activated p38-mitogen-activated protein kinase; inhibited cell growth without apoptosis; and increased the levels of HSPs and HSF-1 in mouse fibroblast cells. Interestingly, exposure to heat regulated the expression of aquaporins and induced morphological change. In a physiological sense, these results suggested that continuous exposure to mild heat stress for 5 days, in which heat acclimation is attained in humans and animals, might induce molecular adaptation to heat in cells.
A series of boronic acid containing cis‐stilbenes as potent inhibitors of tubulin polymerization was synthesized by the introduction of boronic acid as an acceptor‐type functional group into the ...aromatic ring B of the combretastatin framework. High cell‐growth inhibition was observed with boron compounds 13 c and 13 d, in which a hydroxy group on the aromatic ring B of combretastatin A‐4 was replaced with boronic acid; IC50 values toward B‐16 and 1‐87 cell lines are 0.48–2.1 μM. Compounds 13 c and 13 d exhibited significant inhibitory activity toward tubulin polymerization (IC50=21–22 μM). The carboxylic acid derivative 17, which can be considered as a mimic of boronic acid 13 c, did not show significant inhibition of cell growth or tubulin polymerization. According to the FACScan analysis using Jurkat cells, apoptosis was induced after incubation for 8 h with 13 c at a concentration of >10−8 M. Growth inhibitory experiments against a panel of 39 human cancer cell lines revealed 13 c to inhibit growth differently than combretastatin A‐4; the correlation coefficient (r) between the two compounds was 0.553 in the COMPARE analysis.
Is boronic acid an alternative functional group for drug design? A series of boronic acid containing cis‐stilbenes as potent inhibitors of tubulin polymerization was synthesized by the introduction of boronic acid as an acceptor‐type functional group into the aromatic ring B of the combretastatin framework.
Ras-p44/42 mitogen-activated protein kinase (MAPK) and Akt signaling are the key pathways involved in the promotion of glioblastoma formation. Notably, phosphodiesterase 4 (PDE4) is widely expressed ...in brain tumors and promotes their growth. PDE4 inhibitors have been reported to suppress glioblastoma growth in vitro and in vivo. The mechanisms underlying these actions, however, have yet to be elucidated. The aim of this study was to investigate whether intracellular cyclic adenosine monophosphate (cAMP) was able to suppress the Ras-p44/42 MAPK signaling pathway via protein kinase A (PKA) and exchange protein directly activated by cAMP (Epac) in U87MG human malignant glioma cells. Forskolin, an activator of adenylate cyclase, inhibited cell growth and the phosphorylation of p44/42 MAPK in U87MG cells, whereas the non-hydrolyzable cAMP analog 8-bromoadenosine 3′,5′-cAMP (8-Br-cAMP) considerably suppressed cell growth and phosphorylation of p44/42 MAPK. The inhibitory effects of forskolin were partially prevented by the PKA inhibitor H89. The Epac-selective agonist 8-(4-chlorophenylthio)-2′-O-methyladenosine cAMP (8-CPT-cAMP) inhibited phosphorylation of p44/42 MAPK. These findings suggest that PKA and Epac are involved in the effect of intracellular cAMP on the Ras-p44/42 MAPK signaling pathway.
Rapid (0.5 to 10 s), mild, inexpensive, and less wasteful lactamization was achieved using highly electrophilic triphosgene in a micro‐flow reactor. This work reports two methods using NMM and NMI, ...respectively. The slight difference in basicity is critical in the lactamization depending on the type of lactam. A plausible reaction mechanism was discussed. Various lactams as well as a cyclic peptide containing acid‐ and/or heat‐labile functional groups were synthesized in good to high yields without tedious purifications. More information can be found in the Full Paper by S. Fuse et al. (DOI: 10.1002/chem.202100059).
No highly effective pharmacologic interventions to prevent delirium have been identified. We examined whether suvorexant, a potent and selective orexin receptor antagonist, is effective for the ...prevention of delirium.
We conducted a multicenter, rater-blinded, randomized, placebo-controlled clinical trial in intensive care units and regular acute wards between April 2015 and March 2016. Eligible patients were 65 to 89 years old, newly admitted due to emergency, and able to take medicine orally and had an expected stay or life expectancy of 48 hours or more. Seventy-two patients were randomly assigned using the sealed envelope method to receive suvorexant (15 mg/d; 36 patients) or placebo (36 patients) every night for 3 days. The primary outcome measure was incidence of delirium as determined by the DSM-5. Trained psychiatrists assessed for delirium.
We found that delirium developed significantly less often among patients taking suvorexant than among those taking placebo (0% n/N = 0/36 vs 17% 6/36, respectively, P = .025). Comparison by log-rank test also showed that delirium developed significantly less often among patients taking suvorexant than among those taking placebo (χ² = 6.46, P = .011). Analysis of variance revealed a tendency for main effect of treatment (F = 3.79, P = .053) on the sleep-wake cycle disturbance score (item 1) of the Japanese version of the Delirium Rating Scale-Revised-98 (DRS-R-98-J). There were no significant differences in adverse events.
Suvorexant administered nightly to elderly patients admitted for acute care may provide protection against delirium. Larger studies are needed to show the potential of suvorexant to improve the circadian core domain of delirium.
UMIN Clinical Trials Registry identifier: UMIN000015681.
It currently remains unclear whether parabens, which are preservatives added to cosmetics, shampoos, and personal care products that exhibit biocidal activities, exert allergic effects in adults. The ...aim of the present study was to examine the relationship between the use of parabens and the prevalence of allergic diseases in Japanese adults. This population-based cross-sectional study comprised 2005 participants aged 40 years or older living in Shika Town in Japan who answered a self-administered questionnaire on allergic diseases and the daily use of household goods. The information obtained was then analyzed to assess the exposure to parabens (response rate: 77.9%). The prevalence of nasal allergies, atopic conjunctivitis, and total allergies was significantly higher in women who used parabens. These differences remained significant after adjustments for confounding factors including age, body mass index, smoking, alcohol, exercise, sleep, income, education, and marital status. No relationship between the prevalence of atopic dermatitis and the use of parabens was observed in men or women. However, the present results demonstrated that the prevalence of nasal allergies and atopic conjunctivitis was associated with use of parabens in women, suggesting that parabens may induce allergic responses.
Propargylic diisopropylamines containing heterocycles, which were prepared readily from heterocyclic bromides and propargyldiisopropylamine by the Sonogashira coupling reaction, underwent the allene ...transformation reaction in the presence of Pd2(dba)3·CHCl3 catalyst (2.5 mol %) and 1,2-bisbis(pentafluorophenyl)phosphinoethane (10 mol %) at 100 °C in CHCl3, giving the corresponding heterocyclic allenes in good to high yields via the palladium-catalyzed hydride-transfer reaction.
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