Synthesis and Biological Profiling of Seven Heparin and Heparan Sulphate Analogue Trisaccharides.

Researchers are paying increasing attention to the strongly negatively charged heteropolysaccharides in cells, in the extracellular matrix or in the cell wall. Examples of such molecules are glycosaminoglycans (e.g.

TRPA1 up-regulation mediates oxidative stress in a pulpitis model in vitro.

Background And Purpose: Pulpitis is associated with tooth hypersensitivity and results in pulpal damage. Thermosensitive transient receptor potential (TRP) ion channels expressed in the dental pulp may be key transducers of inflammation and nociception. We aimed at investigating the expression and role of thermo-TRPs in primary human dental pulp cells (hDPCs) in normal and inflammatory conditions.

Anti-Nociceptive Effects of Sphingomyelinase and Methyl-Beta-Cyclodextrin in the Icilin-Induced Mouse Pain Model.

The thermo- and pain-sensitive Transient Receptor Potential Melastatin 3 and 8 (TRPM3 and TRPM8) ion channels are functionally associated in the lipid rafts of the plasma membrane. We have already described that cholesterol and sphingomyelin depletion, or inhibition of sphingolipid biosynthesis decreased the TRPM8 but not the TRPM3 channel opening on cultured sensory neurons. We aimed to test the effects of lipid raft disruptors on channel activation on TRPM3- and TRPM8-expressing HEK293T cells in vitro, as well as their potential analgesic actions in TRPM3 and TRPM8 channel activation involving acute pain models in mice.

The dual role of cannabidiol on monocyte-derived dendritic cell differentiation and maturation.

Introduction: Extracts and compounds isolated from hemp (Cannabis sativa) are increasingly gaining popularity in the treatment of a number of diseases, with topical formulations for dermatological conditions leading the way. Phytocannabinoids such as ( )-cannabidiol, ( )-cannabinol and ( )-Δ9-tetrahydrocannabivarin (CBD, CBN, and THCV, respectively), are present in variable amounts in the plant, and have been shown to have mostly anti-inflammatory effects both in vitro and in vivo, albeit dominantly in murine models. The role of phytocannabinoids in regulating responses of dendritic cells (DCs) remains unclear.

Pruritogenic molecules in the skin of patients with dermatomyositis.

Introduction: Pruritus is a common excruciating symptom in systemic autoimmune diseases such as dermatomyositis (DM) but the pathogenesis is not fully understood. We intended to investigate the targeted expression analysis of candidate molecules involved in the development of pruritus in lesional vs. non-lesional skin samples of patients affected with active DM.

TRPV4 Activation Increases the Expression of CD207 (Langerin) of Monocyte-Derived Langerhans Cells without Affecting their Maturation.

Langerhans cells (LCs) are the sole professional antigen-presenting cell normally found in the human epidermal compartment. Research into their physiological role is hindered by the fact that they are invariably activated during isolation from the skin. To overcome this challenge, we turned to a monocyte-derived LC (moLC) model, which we characterized with RNA sequencing, and compared the transcriptome of moLCs with that of donor-matched immature dendritic cells.

Synthesis of a Heparinoid Pentasaccharide Containing l-Guluronic Acid Instead of l-Iduronic Acid with Preserved Anticoagulant Activity.

l-Iduronic acid is a key constituent of heparin and heparan sulfate polysaccharides due to its unique conformational plasticity, which facilitates the binding of polysaccharides to proteins. At the same time, this is the synthetically most challenging unit of heparinoid oligosaccharides; therefore, there is a high demand for its replacement with a more easily accessible sugar unit. In the case of idraparinux, an excellent anticoagulant heparinoid pentasaccharide, we demonstrated that l-iduronic acid can be replaced by an easier-to-produce l-sugar while maintaining its essential biological activity.

Opioidergic Signaling-A Neglected, Yet Potentially Important Player in Atopic Dermatitis.

Atopic dermatitis (AD) is one of the most common skin diseases, the prevalence of which is especially high among children. Although our understanding about its pathogenesis has substantially grown in recent years, and hence, several novel therapeutic targets have been successfully exploited in the management of the disease, we still lack curative treatments for it. Thus, there is an unmet societal demand to identify further details of its pathogenesis to thereby pave the way for novel therapeutic approaches with favorable side effect profiles.

Pruritus: A Sensory Symptom Generated in Cutaneous Immuno-Neuronal Crosstalk.

Pruritus or itch generated in the skin is one of the most widespread symptoms associated with various dermatological and systemic (immunological) conditions. Although many details about the molecular mechanisms of the development of both acute and chronic itch were uncovered in the last 2 decades, our understanding is still incomplete and the clinical management of pruritic conditions is one of the biggest challenges in daily dermatological practice. Recent research revealed molecular interactions between pruriceptive sensory neurons and surrounding cutaneous cell types including keratinocytes, as well as resident and transient cells of innate and adaptive immunity.

Anandamide Concentration-Dependently Modulates Toll-Like Receptor 3 Agonism or UVB-Induced Inflammatory Response of Human Corneal Epithelial Cells.

Photodamage-induced and viral keratitis could benefit from treatment with novel nonsteroid anti-inflammatory agents. Therefore, we determined whether human corneal epithelial cells (HCECs) express members of the endocannabinoid system (ECS), and examined how the endocannabinoid anandamide (AEA, N-arachidonoyl ethanolamine) influences the Toll-like receptor 3 (TLR3) agonism- or UVB irradiation-induced inflammatory response of these cells. Other than confirming the presence of cannabinoid receptors, we show that endocannabinoid synthesizing and catabolizing enzymes are also expressed in HCECs in vitro, as well as in the epithelial layer of the human cornea in situ, proving that they are one possible source of endocannabinoids.

TRPM3 in Brain (Patho)Physiology.

Already for centuries, humankind is driven to understand the physiological and pathological mechanisms that occur in our brains. Today, we know that ion channels play an essential role in the regulation of neural processes and control many functions of the central nervous system. Ion channels present a diverse group of membrane-spanning proteins that allow ions to penetrate the insulating cell membrane upon opening of their channel pores.

Synthesis and Cell Growth Inhibitory Activity of Six Non-glycosaminoglycan-Type Heparin-Analogue Trisaccharides.

The design and synthesis of heparin mimetics with high anticancer activity but no anticoagulant activity is an important task in medicinal chemistry. Herein, we present the efficient synthesis of five Glc-GlcA-Glc-sequenced and one Glc-IdoA-Glc-sequenced non-glycosaminoglycan, heparin-related trisaccharides with various sulfation/sulfonylation and methylation patterns. The cell growth inhibitory effects of the compounds were tested against four cancerous human cell lines and two non-cancerous cell lines.

The TRPM3 ion channel mediates nociception but not itch evoked by endogenous pruritogenic mediators.

During the molecular transduction of itch, the stimulation of pruriceptors on sensory fibers leads to the activation or sensitization of ion channels, which results in a consequent depolarization of the neurons. These ion channels mostly belong to the transient receptor potential (TRP) channels, which are involved in nociception and thermosensation. In particular, TRPV1 and TRPA1 were described in the transduction of both thermal nociception as well as histaminergic and non-histaminergic itch.

Synthesis and HPLC-ECD Study of Cytostatic Condensed -Heterocycles Obtained from 3-Aminoflavanones.

Racemic chiral -heterocycles containing 2-arylchroman or 2-aryl-2-chromene subunit condensed with morpholine, thiazole, or pyrrole moieties at the C-3-C-4 bond were synthesized with various substitution patterns of the aryl group by the cyclization of - or -3-aminoflavanone analogues. The 3-aminoflavanone precursors were obtained in a Neber rearrangement of oxime tosylates of flavanones, which provided the diastereomer as the major product and enabled the isolation of both the - and -diastereomers. The - and -aminoflavanones were utilized to prepare three diastereomers of 5-aryl-chromeno[4,3-b][1,]oxazines.

Synthesis and antiproliferative activity of 6-naphthylpterocarpans.

The Heck-oxyarylation of racemic 2-(1-naphthyl)- and 2-(2-naphthyl)-2H-chromene derivatives were carried out resulting diastereoselectively in (6S*,6aR*,11aR*)-6-(1-naphthyl)- and 6-(2-naphthyl)-pterocarpans as major products and bridged (6R*,12R*)-6,12-methanodibenzo[d,g][1,3]dioxocine derivatives as minor products. Antiproliferative activity of two 6-naphthylpterocarpans was identified by MTT assay against A2780 and WM35 human cancer cell lines with low micromolar IC50 values. The measured 0.

Volatile anaesthetics inhibit the thermosensitive nociceptor ion channel transient receptor potential melastatin 3 (TRPM3).

Background: Volatile anaesthetics (VAs) are the most widely used compounds to induce reversible loss of consciousness and maintain general anaesthesia during surgical interventions. Although the mechanism of their action is not yet fully understood, it is generally believed, that VAs depress central nervous system functions mainly through modulation of ion channels in the neuronal membrane, including 2-pore-domain K+ channels, GABA and NMDA receptors. Recent research also reported their action on nociceptive and thermosensitive TRP channels expressed in the peripheral nervous system, including TRPV1, TRPA1, and TRPM8.

Endogenous Factors That Can Influence Skin pH.

Regulation of pH is one of the most complex mechanisms in human physiology. Indeed, the H+ ion concentration not only contributes to the establishment and maintenance of the body's homeostasis (by defining isohydria) but it also acts as an ionic, electric or osmotic driving force; provides optimum conditions for the proper functions of a plethora of molecules; behaves as an extra- and intracellular signaling system; exerts protective functions, and so on. The versatile role of pH requires delicate, well-orchestrated regulatory machineries that are controlled by a multitude of endogenous mechanisms - this is especially true for the skin whose pH is quite unique within the body.

TRPA1 Acts in a Protective Manner in Imiquimod-Induced Psoriasiform Dermatitis in Mice.

This study revealed the modulatory role of transient receptor potential ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1) cation channels in the Aldara-induced (5% imiquimod) murine psoriasis model using selective antagonists and genetically altered animals. We have also developed a refined localized model to enable internal controls and reduce systemic effects. Skin pathology was quantified by measuring skin thickness, scaling, blood flow, and analyzing dermal cellular infiltrate, whereas nocifensive behaviors were also observed.

Recent advances in the endocrinology of the sebaceous gland.

The sebaceous gland, long considered an evolutionary relic with little-to-no physiological relevance in humans, has emerged in recent decades as a key orchestrator and contributor to many cutaneous functions. In addition to the classical physico-chemical barrier function of the skin against constant environmental challenges, a more novel, neuro-immune modulatory role has also emerged. As part of the complex intercellular communication network of the integumentary system, the sebaceous gland acts as a "relay station" in the skin for many endocrine factors.

Definition of two agonist types at the mammalian cold-activated channel TRPM8.

Various TRP channels act as polymodal sensors of thermal and chemical stimuli, but the mechanisms whereby chemical ligands impact on TRP channel gating are poorly understood. Here we show that AITC (allyl isothiocyanate; mustard oil) and menthol represent two distinct types of ligands at the mammalian cold sensor TRPM8. Kinetic analysis of channel gating revealed that AITC acts by destabilizing the closed channel, whereas menthol stabilizes the open channel, relative to the transition state.

Opening of an alternative ion permeation pathway in a nociceptor TRP channel.

Sensory neurons detect chemical stimuli through projections in the skin and mucosa, where several transient receptor potential (TRP) channels act as primary chemosensors. TRP channels are tetramers, and it is generally accepted that binding of ligands causes the opening of a single central cation-conducting pore. Contrary to this view, we here provide evidence for a second permeation pathway in the TRP channel TRPM3, which can be gated by combined application of endogenous neurosteroids and exogenous chemicals such as clotrimazole or several structurally related drugs.