CKBA suppresses mast cell activation via ERK signaling pathway in murine atopic dermatitis.

Atopic dermatitis (AD) is a common inflammatory skin disorder. Mast cells play an important role in AD because they regulate allergic reactions and inflammatory responses. However, whether and how the modulation of mast cell activity affects AD has not been determined. In this study, we aimed to determine the effects and mechanisms of 3-O-cyclohexanecarbonyl-11-keto-ß-boswellic acid (CKBA). This natural compound derivative alleviates skin inflammation by inhibiting mast cell activation and maintaining skin barrier homeostasis in AD. CKBA markedly reduced serum IgE levels and alleviated skin inflammation in calcipotriol (MC903)-induced AD mouse model. CKBA also restrained mast cell degranulation both in vitro and in vivo. RNA-seq analysis revealed that CKBA downregulated the extracellular signal-regulated kinase (ERK) signaling in BM-derived mast cells activated by anti-2,4-dinitrophenol/2,4-dinitrophenol-human serum albumin. We proved that CKBA suppressed mast cell activation via ERK signaling using the ERK activator (t-butyl hydroquinone) and inhibitor (selumetinib; AZD6244) in AD. Thus, CKBA suppressed mast cell activation in AD via the ERK signaling pathway and could be a therapeutic candidate drug for AD.

2,4-Dinitrophenol as an Uncoupler Augments the Anthracyclines Toxicity against Prostate Cancer Cells.

One of the strategies for the treatment of advanced cancer diseases is targeting the energy metabolism of the cancer cells. The compound 2,4-DNP (2,4-dinitrophenol) disrupts the cell energy metabolism through the ability to decouple oxidative phosphorylation. The aim of the study was to determine the ability of 2,4-DNP to sensitize prostate cancer cells with different metabolic phenotypes to the action of known anthracyclines (doxorubicin and epirubicin). The synergistic effect of the anthracyclines and 2,4-DNP was determined using an MTT assay, apoptosis detection and a cell cycle analysis. The present of oxidative stress in cancer cells was assessed by CellROX, the level of cellular thiols and DNA oxidative damage. The study revealed that the incubation of LNCaP prostate cancer cells (oxidative phenotype) with epirubicin and doxorubicin simultaneously with 2,4-DNP showed the presence of a synergistic effect for both the cytostatics. Moreover, it contributes to the increased induction of oxidative stress, which results in a reduced level of cellular thiols and an increased number of AP sites in the DNA. The synergistic activity may consist of an inhibition of ATP synthesis and the simultaneous production of toxic amounts of ROS, destroying the mitochondria. Additionally, the sensitivity of the LNCaP cell line to the anthracyclines is relatively higher compared to the other two (PC-3, DU-145).

[Tc1-mediated contact sensitivity reaction, its mechanism and regulation]. / Reakcja nadwrazliwosci kontaktowej Tc1 zalezna, jej mechanizm i regulacja.

The contact hypersensitivity reaction (CHS) to haptens is a classic example of cell-mediated immune response. In the effector phase, two stages can be distinguished: an early component, that appears only 2 hours after subsequent contact with the hapten, and the late component that develops approximately 24 hours later which is mediated by TCRαß+ cells. The effector lymphocytes may be CD4+ T helper 1 (Th1) cells or CD8+ T cytotoxic 1 (Tc1) cells, which depends on the employed hapten and/or mice strain. NKT lymphocytes play the crucial role in the CHS initiation, by supporting B1 cells in the antigen-specific IgM antibodies production. The development of an early component is essential for the recruitment of T effector (Teff) cells to the side of hapten deposition and for the complete expansion of inflammatory reaction. The CHS reaction is under T regulatory (Treg) cells control, both in the induction phase as well as in the effector phase. A new view of a negative regulation of the Tc1 mediated CHS response is based on the suppression induced by epicutaneous (EC) application of protein antigen. The DNP-BSA skin application, on a gauze patch, leads to a state of immunosuppression. This maneuver results in rising the population of Treg cells with TCRαß+CD4+CD25+Foxp3+ phenotype. The mechanism of suppression requires direct contact between Treg cells and Teff cells and the participation of CTLA-4 molecule is also necessary. The described method of evoking immune tolerance via EC immunization may contribute to elaborate a new method of allergic contact dermatitis therapy. This is because of its effectiveness, ease of induction and non-invasive protein antigen application.

Uncouple my heart: the benefits of inefficiency.

Myocardial ischemia/reperfusion (IR) injury leads to structural changes in the heart muscle later followed by functional decline due to progressive fibrous replacement. Hence approaches to minimize IR injury are devised, including ischemic pre-and postconditioning. Mild uncoupling of oxidative phosphorylation is one of the mechanisms suggested to be cardioprotective as chemical uncoupling mimics ischemic preconditioning. Uncoupling protein 2 is proposed to be the physiological counterpart of chemical uncouplers and is thought to be a part of the protective machinery of cardiomyocytes. Morphological changes in the mitochondrial network likely accompany the uncoupling with mitochondrial fission dampening the signals leading to cardiomyocyte death. Here we review recent data on the role of uncoupling in cardioprotection and propose that low concentrations of dietary polyphenols may elicit the same cardioprotective effect as dinitrophenol and FCCP, perhaps accounting for the famed "French paradox".

Dinitrophenol and obesity: an early twentieth-century regulatory dilemma.

In the early 1930s, the industrial chemical dinitrophenol found widespread favor as a weight-loss drug, due principally to the work of Maurice Tainter, a clinical pharmacologist from Stanford University. Unfortunately the compound's therapeutic index was razor thin and it was not until thousands of people suffered irreversible harm that mainstream physicians realized that dinitrophenol's risks outweighed its benefits and abandoned its use. Yet, it took passage of the Food, Drug, and Cosmetic Act in 1938 before federal regulators had the ability to stop patent medicine men from selling dinitrophenol to Americans lured by the promise of a drug that would safely melt one's fat away.

A targeting model of boron neutron-capture therapy to hepatoma cells in vivo with a boronated anti-(alpha-fetoprotein) monoclonal antibody.

We described previously that 10B atoms delivered by monoclonal antibody (mAb) exerted a cytotoxic effect on AH66 cells in a dose-dependent manner upon thermal neutron irradiation in vitro. In the present study, the delivering capacity of boronated anti-(alpha-fetoprotein) (AFP) mAb to carry 10B atoms to AFP-producing tumor xenografts in nude mice was determined. Boronated mAb was prepared by conjugating 50 mM 10B compound to an anti-AFP mAb (2 mg/ml) using N-succinimidyl-3-) (2-pyridyldithio) propionate. The number of 10B atoms conjugated directly to the mAb was estimated to be 459/antibody by prompt gamma-ray spectrometry. Boron concentrations in tumor tissue obtained 12, 24, 72, and 120 h after injection of 3.0 mg 10B-conjugated anti-AFP mAb were 11.10 +/- 3.12 (SD, n = 6). 29.30 +/- 5.11, 33.02 +/- 11.8, and 12.91 +/- 5.62 ppm respectively. For control 10B-conjugated anti-dinitrophenol (DNP) mAb, the values were 9.59 +/- 0.99, 10.37 +/- 2.86, 10.00 +/- 2.95, and 8.83 +/- 4.71 ppm respectively. The concentrations in blood were less than 0.40 +/- 0.10 ppm with anti-AFP mAb and less than 0.51 +/- 0.15 ppm with anti-DNP mAb at each sampling time (12, 24, 72, and 120 h). The number of 10B atoms delivered to the tumor cells was calculated to be 0.62 x 10(9), 1.63 x 10(9), 1.84 x 10(9) and 0.72 x 10(9) at each sampling time after injection of 10B-anti-AFP mAb. The amount of 10B atoms necessary for effective boron neutron-capture therapy was estimated to be 10(9)/tumor cell. We were able to carry 1.84 x 10(9) 10B atoms to AH66 tumor cells by using 10B-anti-AFP mAb. The accumulation reached its peak 72 h after injection. These data indicated that the 10B-conjugated antitumor mAb could deliver a sufficient amount of 10B atoms to the tumor cells to induce cytotoxic effects 72 h after injection upon thermal neutron irradiation.

[Inhibitor interaction in the suppression of ribosomal RNA synthesis in Ehrlich ascites carcinoma cells]. / Vzaimodeistvie ingibitorov pri podavlenii sinteza ribosomnoi RNK v kletkakh astsitnoi kartsinomy Erlikha.

Kinetic analysis of inhibitory action of papaverine, 2,4-dinitrophenol (DNP) and actinomycin D on RNA synthesis in the intact Ehrlich ascites carcinoma cells has shown that the action of these agents is mediated by their effect on the same step of rRNA synthesis.

Pharmacological approaches to treating the obese patient.

It should be obvious from the foregoing discussion that, at the present time, there is not an acceptably safe and effective pharmacological treatment for obesity. This patent inadequacy of present drug regimens has spawned the investigation into the diverse pharmacological approaches reviewed in this paper as well as investigation into the intestinal bypass operation (see Chapter 10). We feel that the eventual, safe and effective therapy for obesity will come from the pharmacological realm. Glucose-blocking drugs, growth hormone analogues, and hydroxycitrate are but three of the potentially safe and effective approaches to the problem for the future. It will be truly fascinating to watch the development in the treatment of obesity and, specifically, the pharmacological treatment for this problem over the next five to ten years.

Developments in delayed-type hypersensitivities: 1950-1975.

Significant developments during the last 25 years are discussed and interpreted. The following areas of delayed hypersensitivity are included: the mode of active sensitization to simple allergenic chemicals; evidence for anamnestic responses; cell types and cell-cell interactions via lymphokines; function of skin and lymphatics, and the role of the carrier in initial sensitization to allergenic chemicals; acquired tolerance; transfer factor. Some prognostications for the future are attempted.