tris(2-pyridylmethyl)amine and Disease-Models--Animal

Carcinogen-induced skin tumorigenesis depends heavily on proinflammatory tumor-promoting processes. Here, we show that leukocytic Runx3 expression is central to the two-stage DMBA/TPA-induced skin tumorigenesis. Runx3-null mice were highly resistant to this process and concomitant ablation of Runx3 in dendritic and T cells fully recapitulated this resistance. Mechanistically, this resistance was associated with a shift in the skin cytokine milieu toward a tumor nonpermissive microenvironment. Specifically, leukocytic Runx3 loss substantially increased the antitumorigenic cytokine thymic stromal lymphopoietin (TSLP) and profoundly decreased two protumorigenic cytokines, interleukin-17a and osteopontin. Therefore, inflammation-mediated tumor promotion requires leukocytic Runx3 expression, as its loss creates a unique cytokine composition that polarizes the tumor microenvironment to a potent antitumorigenic state.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Carcinogens; Core Binding Factor Alpha 3 Subunit; Cytokines; Disease Models, Animal; Flow Cytometry; Immunoblotting; Immunohistochemistry; Leukocytes; Mice; Mice, Knockout; Polymerase Chain Reaction; Pyridines; Skin Neoplasms

Cyrtocarpa procera Kunth (Anacardiaceae) is a Mexican endemic tree; its bark has been traditionally employed in Mexico since prehispanic times to relieve digestive disorders.. To perform an acute evaluation of the toxicity, gastroprotective, and anti-inflammatory properties, as well as the anti-Helicobacter pylori action of C. procera bark extracts, in order to determine polypharmalcological activities.. Five different polarity extracts (hexanic, CH(2)Cl(2), CH(2)Cl(2)-MeOH, methanolic, and aqueous) were prepared. Each of them was evaluated in the following acute mice models: toxicity Lorke test, ethanol-induced gastric ulcer, TPA-induced ear edema; and the in vitro anti-H. pylori activity with a broth dilution method.. None of the extracts were toxic under acute administration. The methanolic, hexanic, and aqueous extracts possess remarkable gastroprotective activity. All the extracts inhibit H. pylori growth, being the hexanic the most active, and only this one showed significant anti-inflammatory effect.. This work demonstrates that C. procera bark has polypharmacological activities; which makes it a promising asset to the development of an integral treatment for gastritis or peptic ulcer related or not to H. pylori. Our findings contribute to the ethnopharmacological knowledge about this species.

Topics: Animals; Anti-Inflammatory Agents; Anti-Ulcer Agents; Disease Models, Animal; Ear; Edema; Ethanol; Ethnopharmacology; Helicobacter pylori; Magnoliopsida; Male; Medicine, Traditional; Mexico; Mice; Mice, Inbred Strains; Phytotherapy; Plant Extracts; Pyridines; Stomach Ulcer

Mitogen- and stress-activated protein kinase (MSK)1/2 are two kinases involved in inflammation as well as in cell transformation.. To examine the role of MSK1/2 in skin tumor development.. MSK1/2 knockout mice developed significantly fewer skin tumors compared with wild-type mice. The myeloperoxidase activity in TPA-treated skin from MSK1/2 knockout mice was significantly elevated compared with wild-type mice. Furthermore, the mRNA and protein levels of IL-1β as well as the mRNA expression of TNF-α were significantly increased in MSK1/2 knockout mice.. These data provide in vivo evidence that MSK1/2 signaling represents a novel tumor-promoting axis in skin carcinogenesis.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Carcinogens; Cell Transformation, Neoplastic; Cytokines; Disease Models, Animal; Enzyme-Linked Immunosorbent Assay; Mice; Mice, Inbred C57BL; Mice, Knockout; Pyridines; Reverse Transcriptase Polymerase Chain Reaction; Ribosomal Protein S6 Kinases, 90-kDa; Signal Transduction; Skin Neoplasms

The human body has its own innate electrical system that regulates the body's functions via communications among organs through the well-known neural system. While the effect of low-level electrical stimulation on wound repair has been reported, few studies have examined the effect of electric potential on non-wounded, intact skin. A galvanic couple comprised of elemental zinc and copper was used to determine the effects of low-level electrical stimulation on intact skin physiology using a Dermacorder device. Zn-Cu induced the electrical potential recorded on intact skin, enhanced H(2)O(2) production and activated p38 MAPK and Hsp27 in primary keratinocytes. Treatment with Zn-Cu was also found to reduce pro-inflammatory cytokines, such as IL-1α, IL-2, NO and TNF-α in multiple cell types after stimulation with PHA or Propionibacterium acnes bacteria. The Zn-Cu complex led to a dose-dependent inhibition of TNF-α-induced NF-κB levels in keratinocytes as measured by a dual-luciferase promoter assay, and prevented p65 translocation to the nucleus observed via immunofluorescence. Suppression of NF-κB activity via crosstalk with p38 MAPK might be one of the potential pathways by which Zn-Cu exerted its inflammatory effects. Topical application of Zn-Cu successfully mitigated TPA-induced dermatitis and oxazolone-induced hypersensitivity in mice models of ear edema. Anti-inflammatory activity induced by the Zn-Cu galvanic couple appears to be mediated, at least in part, by production of low level of hydrogen peroxide since this activity is reversed by the addition of Catalase enzyme. Collectively, these results show that a galvanic couple containing Zn-Cu strongly reduces the inflammatory and immune responses in intact skin, providing evidence for the role of electric stimulation in non-wounded skin.

Topics: Adult; Animals; Cells, Cultured; Copper; Dermatitis; Dinoprostone; Disease Models, Animal; Edema; Electric Stimulation Therapy; Female; Galvanic Skin Response; Humans; Hydrogen Peroxide; Inflammation; Keratinocytes; Male; Metal Nanoparticles; Mice; Middle Aged; NF-kappa B; p38 Mitogen-Activated Protein Kinases; Pyridines; Reactive Oxygen Species; Skin Physiological Phenomena; Zinc