No abstract

No abstract

We had previously shown that both locally produced endocannabinoids and exocannabinoids, via cannabinoid receptor-1 (CB1), are powerful inhibitors of human hair growth. To further investigate the role of the cannabinoid system in pilosebaceous unit biology, we have explored in the current study whether and how endocannabinoids have an impact on human sebaceous gland biology, using human SZ95 sebocytes as cell culture model. Here, we provide the first evidence that SZ95 sebocytes express CB2 but not CB1. Also, prototypic endocannabinoids (arachidonoyl ethanolamide/anandamide, 2-arachidonoyl glycerol) are present in SZ95 sebocytes and dose-dependently induce lipid production and (chiefly apoptosis-driven) cell death. Endocannabinoids also up-regulate the expression of key genes involved in lipid synthesis (e.g., PPAR transcription factors and some of their target genes). These actions are selectively mediated by CB2-coupled signaling involving the MAPK pathway, as revealed by specific agonists/antagonists and by RNA interference. Because cells with "silenced" CB2 exhibited significantly suppressed basal lipid production, our results collectively suggest that human sebocytes utilize a paracrine-autocrine, endogenously active, CB2-mediated endocannabinoid signaling system for positively regulating lipid production and cell death. CB2 antagonists or agonists therefore deserve to be explored in the management of skin disorders characterized by sebaceous gland dysfunctions (e.g., acne vulgaris, seborrhea, dry skin).

The newly discovered endocannabinoid system (ECS; comprising the endogenous lipid mediators endocannabinoids present in virtually all tissues, their G-protein-coupled cannabinoid receptors, biosynthetic pathways and metabolizing enzymes) has been implicated in multiple regulatory functions both in health and disease. Recent studies have intriguingly suggested the existence of a functional ECS in the skin and implicated it in various biological processes (e.g. proliferation, growth, differentiation, apoptosis and cytokine, mediator or hormone production of various cell types of the skin and appendages, such as the hair follicle and sebaceous gland). It seems that the main physiological function of the cutaneous ECS is to constitutively control the proper and well-balanced proliferation, differentiation and survival, as well as immune competence and/or tolerance, of skin cells. The disruption of this delicate balance might facilitate the development of multiple pathological conditions and diseases of the skin (e.g. acne, seborrhea, allergic dermatitis, itch and pain, psoriasis, hair growth disorders, systemic sclerosis and cancer).

In eukaryotic cells, variations in the levels of cytosolic free calcium regulate processes as important and disparate as chemotaxis, chromosome segregation, fertilization, ion transport, muscle contraction, passage through cell cycle transition points, proteolysis, secretion, and substrate uptake (7). Cytosolic free calcium concentration is tightly controlled by the action of specific pumps and channels in the plasma membrane and subcellular organelles (8,83). Response to increased cytosolic free calcium concentration is mediated by either direct binding to calcium-sensitive enzymes, such as protein kinase C (49) and calpain (72), or activation of a protein transducer, such as calmodulin (15).In prokaryotic cells, an equivalent important role for calcium has been harder to demonstrate but is now becoming evident (53,59,69). Research on a variety of bacterial processes has passed from the phase of demonstrating a likely involvement of calcium to clarifying the nature of this involvement. In this minireview, recent evidence on the existence of bacterial components (both proteinaceous and nonproteinaceous) concerned with calcium regulation is evaluated, since investigation of these components is one of the surest routes to confirming the involvement of calcium in a process. These components include voltage-gated calcium channels responsible for influx that can be formed from poly-3-hydroxybutyratepolyphosphate complexes, primary and secondary transporters responsible for efflux, and calmodulin-like proteins responsible for mediating responses to calcium. Such calcium-dependent regulation may be exerted directly by changes in nucleoid structure or indirectly by phosphorylation or proteolysis of target proteins. Despite the problems sometimes associated with studies of calcium, this ion is increasingly implicated in a number of bacterial functions, including heat shock, pathogenicity, chemotaxis, differentiation, and the cell cycle. INTRACELLULAR CALCIUM LEVELSEstimates of the intracellular free calcium concentration of 0.1 and 1 M in the model organism Escherichia coli have been obtained with Fura-2 {1-[2-(5-carboxyoxazol-2-yl)-6-aminobenzofuran -5 -oxy] -2-(2Ј -amino -5Ј -methylphenoxy)ethane-N,N,NЈ,NЈ-tetraacetic acid} (24, 77) and aequorin (85), respectively. Such levels are similar to those in eukaryotic cells and are a 1,000 times less than those typically found outside the cell. Three factors are considered responsible for this low level: the low permeability of the envelope with tightly controlled influx mechanisms, a high buffering capacity, and effective export systems. CALCIUM INFLUXIn eukaryotic cells, a number of mechanisms for gated entry of calcium have been characterized. Families of calcium channels have been identified, which can be classified broadly by the stimulus for channel opening into voltage-operated, receptoroperated, mechanically operated or tonically active calcium channels (83). In particular, eukaryotic L-type, voltage-operated calcium channels (VOCCs) are activated by membrane depolari...

No abstract

The results suggest that marked apico-basal electrical inhomogeneity exists in the canine-and probably in the human-ventricular myocardium, which may result in increased dispersion, and therefore, cannot be ignored when interpreting ECG recordings, pathological alterations, or drug effects.

Recent studies strongly suggest that the cannabinoid system is a key player in cell growth control. Since the organ-culture of human hair follicles (HF) offers an excellent, clinically relevant model for complex tissue interaction systems, we have asked whether the cannabinoid system plays a role in hair growth control. Here, we show that human scalp HF, intriguingly, are both targets and sources of endocannabinoids. Namely, the endocannabinoid N-arachidonoylethanolamide (anandamide, AEA) as well as the exocannabinnoid delta (9) -tetrahydrocannabinol dose-dependently inhibited hair shaft elongation and the proliferation of hair matrix keratinocytes, and induced intraepithelial apoptosis and premature HF regression (catagen). These effects were inhibited by a selective antagonist of cannabinoid receptor-1 (CB1). In contrast to CB2, CB1 was expressed in a hair cycle-dependent manner in the human HF epithelium. Since we successfully identified the presence of endocannabinoids in human HF, our data strongly suggest that human HF exploit a CB1-mediated endocannabinoid signaling system for negatively regulating their own growth. Clinically, CB1 agonists may therefore help to manage unwanted hair growth, while CB1 antagonists might counteract hair loss. Finally, human HF organ culture offers an instructive, physiologically relevant new research tool for dissecting "nonclassical" effects of endocannabinoids and their receptor-mediated signaling in general.