The autoinflammatory diseases are characterized by seemingly unprovoked episodes of inflammation, without high-titer autoantibodies or antigen-specific T cells The concept was proposed ten years ago with the identification of the genes underlying hereditary periodic fever syndromes This nosology has taken root because of the dramatic advances in our knowledge of the genetic basis of both mendelian and complex autoinflammatory diseases, and with the recognition that these illnesses derive from genetic variants of the innate immune system Herein we propose an updated classification scheme based on the molecular insights garnered over the past decade, supplanting a clinical classification that has served well but is opaque to the genetic, immunologic, and therapeutic interrelationships now before us We define six categories of autoinflammatory disease: IL-1β activation disorders (inflammasomopathies), NF-κB activation syndromes, protein misfolding disorders, complement regulatory diseases, disturbances in cytokine signaling, and macrophage activation syndromes A system based on molecular pathophysiology will bring greater clarity to our discourse while catalyzing new hypotheses both at the bench and at the bedside

/pdf/horror-autoinflammaticus-the-molecular-pathophysiology-of-16vahq02rm.pdf

Horror Autoinflammaticus: The Molecular Pathophysiology of Autoinflammatory Disease

Most anti-cancer drugs are derived from natural resources such as marine, microbial and botanical sources. Cutaneous malignant melanoma is the most aggressive form of skin cancer, with a high mortality rate. Various treatments for malignant melanoma are available, but due to the development of multi-drug resistance, current or emerging chemotherapies have a relatively low success rates. This emphasizes the importance of discovering new compounds that are both safe and effective against melanoma. In vitro testing of melanoma cell lines and murine melanoma models offers the opportunity for identifying mechanisms of action of plant derived compounds and extracts. Common anti-melanoma effects of natural compounds include potentiating apoptosis, inhibiting cell proliferation and inhibiting metastasis. There are different mechanisms and pathways responsible for anti-melanoma actions of medicinal compounds such as promotion of caspase activity, inhibition of angiogenesis and inhibition of the effects of tumor promoting proteins such as PI3-K, Bcl-2, STAT3 and MMPs. This review thus aims at providing an overview of anti-cancer compounds, derived from natural sources, that are currently used in cancer chemotherapies, or that have been reported to show anti-melanoma, or anti-skin cancer activities. Phytochemicals that are discussed in this review include flavonoids, carotenoids, terpenoids, vitamins, sulforaphane, some polyphenols and crude plant extracts.

Review of Natural Compounds for Potential Skin Cancer Treatment

Sensitization to contact allergens requires activation of the innate immune system by endogenous danger signals. However, the mechanisms through which contact allergens activate innate signaling pathways are incompletely understood. In this study, we demonstrate that mice lacking the adenosine triphosphate (ATP) receptor P2X(7) are resistant to contact hypersensitivity (CHS). P2X(7)-deficient dendritic cells fail to induce sensitization to contact allergens and do not release IL-1β in response to lipopolysaccharide (LPS) and ATP. These defects are restored by pretreatment with LPS and alum in an NLRP3- and ASC-dependent manner. Whereas pretreatment of wild-type mice with P2X(7) antagonists, the ATP-degrading enzyme apyrase or IL-1 receptor antagonist, prevents CHS, IL-1β injection restores CHS in P2X(7)-deficient mice. Thus, P2X(7) is a crucial receptor for extracellular ATP released in skin in response to contact allergens. The lack of P2X(7) triggering prevents IL-1β release, which is an essential step in the sensitization process. Interference with P2X(7) signaling may be a promising strategy for the prevention of allergic contact dermatitis.

/pdf/lack-of-the-purinergic-receptor-p2x7-results-in-resistance-3t4kykm8b2.pdf

Lack of the purinergic receptor P2X7 results in resistance to contact hypersensitivity

An important method of drug discovery is examination of diverse life forms, including medicinal plants and natural products or bioactive compounds isolated from these sources. In cancer research, lead structures of compounds from natural sources can be used to design novel chemotherapies with enhanced biological properties. Betulinic acid (3β-hydroxy-lup-20(29)-en-28-oic acid or BetA) is a naturally occurring pentacyclic triterpene with a wide variety of biological activities, including potent antitumor properties. Non-malignant cells and normal tissues are not affected by BetA. Because BetA exerts its effects directly on the mitochondrion and triggers death of cancerous cells, it is an important alternative when certain chemotherapy drugs fail. Mitochondrion-targeted agents such as BetA hold great promise to circumvent drug resistance in human cancers. BetA is being developed by a large network of clinical trial groups with the support of the U.S. National Cancer Institute. This article discusses recent advances in research into anticancer activity of BetA, relevant modes of delivery, and the agent's therapeutic efficacy, mechanism of action, and future perspective as a pipeline anticancer drug. BetA is a potentially important agent in cancer therapeutics.

Betulinic Acid: Recent Advances in Chemical Modifications, Effective Delivery, and Molecular Mechanisms of a Promising Anticancer Therapy

Purpose of reviewTo summarize recent findings that highlight the importance of the innate inflammatory immune responses in contact dermatitis and their role for the adaptive T-cell response to contact allergens. Implications for anti-inflammatory therapy based on recent reports are discussed.Recent

From innate to adaptive immune responses in contact hypersensitivity.

The European mistletoe Viscum album L. is a plant used for remedies in cancer treatment. The benefit of commonly used aqueous extracts is controversial but the plant contains water insoluble triterpene acids providing interesting anticancer properties. Triterpene extracts (TE) from plants and single triterpenoids such as oleanolic acid (OA) or betulinic acid (BA) are known for their cytotoxic effects on cancer cell lines in vitro. We report here cytotoxic effects of a novel OA-rich triterpene extract from mistletoe (V. album L., Santalaceae) solubilized by 2-hydroxypropyl-β-cyclodextrin (2-HP-β-CD) on B16.F10 mouse melanoma cells. The 2-HP-β-CD solubilized triterpene extract (STE) was highly cytotoxic by causing DNA fragmentation, followed by loss of membrane integrity and intracellular adenosine-5'-triphosphate (ATP). Blocking the caspase machinery by inhibitors aborted DNA fragmentation and delayed the cytotoxic effects but did not prevent cell death. The solubilization by 2-HP-β-CD allows a solvent-free application of triterpene extracts in the in vitro setting. These findings suggest the use of STE from mistletoe as a solvent-free anticancer drug for preclinical animal experiments and clinical trials.

A novel triterpene extract from mistletoe induces rapid apoptosis in murine B16.F10 melanoma cells.

Purpose
Mistletoe extracts are often used in complementary cancer therapy although the efficacy of that therapy is controversially discussed. Approved mistletoe extracts contain mainly water soluble compounds of the mistletoe plant, i.e. mistletoe lectins. However, mistletoe also contains water-insoluble triterpenoids (mainly oleanolic acid) that have anti-tumorigenic effects. To overcome their loss in watery extracts we have solubilized mistletoe triterpenoids with cyclodextrins, thus making them available for in vivo cancer experiments.

/pdf/triterpenoids-amplify-anti-tumoral-effects-of-mistletoe-2ajyg6bmjt.pdf

Triterpenoids Amplify Anti-Tumoral Effects of Mistletoe Extracts on Murine B16.F10 Melanoma In Vivo

Allergic contact dermatitis is induced by chemicals or metal ions. A hallmark of this T cell mediated skin disease is the activation of the innate immune system by contact allergens. This immune response results in inflammation and is a prerequisite for the activation of the adaptive immune system with tissue-specific migration of effector and regulatory T cells. Recent studies have begun to address in detail the innate immune cells as well as the innate receptors on these cells and the associated signaling pathways which lead to skin inflammation. We review here recent findings regarding innate and adaptive immune responses and immune regulation of contact dermatitis and other skin diseases as well as recent developments towards an in vitro assessment of the allergenic potential of chemicals. The elucidation of the innate inflammatory pathways, cellular components and mediators will help to identify new drug targets for more efficient treatment of allergic contact dermatitis and hopefully also for its prevention.

Christian M. Struh

Papers

A novel triterpene extract from mistletoe induces rapid apoptosis in murine B16.F10 melanoma cells.

Triterpenoids Amplify Anti-Tumoral Effects of Mistletoe Extracts on Murine B16.F10 Melanoma In Vivo

Innate and adaptive immune responses in allergic contact dermatitis and autoimmune skin diseases.