Investigation of the Novel Aspects of Human Sebaceous Gland Biology: Focus on the Non-Psychotropic Phytocannabinoids and the Nicotinic Acid

A akne egy gyakori bőrbetegség, amelyet a megnövekedett faggyútermelés és a faggyúmirigyek gyulladása jellemez. Korábban bebizonyítottuk, hogy egy nem pszichotróp fitokannabinoid ((-) - kannabidiol [CBD]) komplex pattanásgátló hatást fejtett ki azáltal, hogy normalizálta a pattanást utánzó anyagok által kiváltott túlzott faggyú-termelést, csökkentve a proliferációt és enyhítve a gyulladást az emberi SZ95-szocitákban. Kísérleteink első felében azt tűztük ki célul, hogy megvizsgáljuk egyes nem-pszichotróp pCB-ok biológiai hatásait humán SZ95 szebocitákon. Kimutattuk, hogy a pCB-ok 10 μM-os koncentrációig a sejtek életképességének csökkentése nélkül eltérő módon befolyásolják a szebociták legjellemzőbb biológiai funkcióját, azaz a bazális faggyúlipid-szintézist. A CBG és a CBGV az eCB-okra jellemző módon növelte a lipogenezist, a CBDV-nek nem volt szignifikáns hatása, míg a CBC és a THCV csökkentette a bazális faggyúlipid-szintézist. Mivel valamennyi pCB hatékonyan csökkentette a szebociták LPS-sel indukált gyulladásos válaszát, ezek az eredmények azt sugallják, hogy a CBG és a CBGV kedvező hatással lehet a bőrszárazsággal járó, gyulladással kísért kórképekben. Kísérleteink folytatásában azt találtuk, hogy a CBC, a CBDV és a THCV képes szignifikánsan csökkenteni az AA-indukálta lipogenezist. A fentiek közül leghatékonyabbnak bizonyult THCV-t tovább vizsgálva megállapítottuk, hogy „univerzális” liposztatikumként viselkedik (azaz képes az AA-tól eltérő jelátviteli útvonalakon ható lipogének hatásának kivédésére is), anti-proliferatív hatású, és (amint arról már szó esett) szinte teljesen normalizálja a gyulladásos citokinek LPS-sel indukált expresszióját a felszabadulását. Kísérleteink második felében megállapítottuk, hogy a NA az életképesség és a homeosztatikus faggyúlipid-termelés befolyásolása nélkül hatékonyan csökkenti a szebociták proliferációját, valamint a különféle lipogén ágensekkel kiváltott, aknét modellező, kórosan fokozott faggyúlipid-szintézist. Kimutattuk azt is, hogy a NA hatásait a HCA2 receptor aktivációja és a következményes Ca2+-beáramlás közvetíti. Eredményeinket összefoglalva elmondható tehát, hogy a NA és a pCB-ok is komplex módon befolyásolják a humán szebociták biológiai folyamatait, és ígéretes, új eszközök lehetnek a különféle FM-diszfunkcióval jellemezhető kórképek (bőrszárazság, akne, szeborrea stb.) kezelésében.Acne is a common skin disease characterized by elevated sebum production and inflammation of the sebaceous glands. We have previously shown that a non-psychotropic phytocannabinoid ((–)-cannabidiol [CBD]) exerted complex anti-acne effects by normalizing ‘pro-acne agents’-induced excessive sebaceous lipid production, reducing proliferation and alleviating inflammation in human SZ95 sebocytes. In the first half of our experiments, we aimed to investigate the biological effects of certain non-psychotropic pCBs on human SZ95 sebocytes. We have shown that pCBs up to 10 μM have different effects on the most typical biological function of sebocytes, i.e. basal sebaceous lipid synthesis, without reducing cell viability. CBG and CBGV increased lipogenesis similarly to eCBs, CBDV had no significant effect, whereas CBC and THCV decreased basal sebaceous lipid synthesis. Because all pCBs were effective in reducing the LPS-induced inflammatory response of sebocytes, these results suggest that CBG and CBGV may have a beneficial effect on dermatitis-associated inflammatory disease. Continuing our experiments, we found that CBC, CBDV and THCV were able to significantly reduce AA-induced lipogenesis. Further examination of THCV, which was found to be the most effective of the above, found that it behaves as a “universal” lipostatic agent (i.e., it is also capable of blocking the action of lipogens acting on signaling pathways other than AA), is anti-proliferative, and almost completely normalizes LPS-induced expression of inflammatory cytokines. In the second half of our experiments, NA was found to effectively reduce sebocyte proliferation without affecting viability and homeostatic sebaceous lipid production, as well as pathologically enhanced sebaceous lipid synthesis induced by various lipogenic agents. It has also been shown that the effects of NA are mediated by HCA2 receptor activation and consequent Ca2+ influx. Taken together, our results suggest that both NA and pCB have complex effects on the biological processes of human sebocytes, and may be promising new tools for treating various FM dysfunctions (dry skin, acne, seborrhea, etc.

Nicotinic acid suppresses sebaceous lipogenesis of human sebocytes via activating hydroxycarboxylic acid receptor 2 (HCA )

Nicotinic acid (NA) activates hydroxycarboxylic acid receptor 2 (HCA2), and it is widely used in treating dyslipidemias. Since its side effects include skin dryness, whereas its deficiency can be accompanied by dyssebacia, characterized by sebaceous gland enlargement, we asked if HCA2 is expressed on human sebocytes, and if NA influences sebocyte functions. By using human immortalized SZ95 sebocytes, we found that non-cytotoxic (≤100 μM; MTT-assay) concentrations of NA had no effect on the homeostatic sebaceous lipogenesis (SLG; Nile Red), but normalized excessive, acne-mimicking SLG induced by several lipogenic agents (arachidonic acid, anandamide, linoleic acid+testosterone; Nile Red; 48-hr treatments). Moreover, it exerted significant anti-proliferative actions (CyQUANT-assay), and increased [Ca2+]IC (Fluo-4 AM-based Ca2+-measurement). Although NA did not prevent the lipopolysaccharide-induced pro-inflammatory response (up-regulation [Q-PCR] and release [ELISA] of several pro-inflammatory cytokines) of the sebocytes, collectively, these data support the concept that NA may be effective in suppressing sebum production in vivo. While exploring the mechanism of the sebostatic actions, we found that sebocytes express HCA2 (Q-PCR, immunofluorescent labeling), siRNA-mediated silencing of which prevented the NA-induced Ca2+-signal and the lipostatic action. Collectively, our data introduce NA, and HCA2 activators in general, as novel, potent, and most likely safe sebostatic agents, with possible anti-acne potential.K

Differential effectiveness of selected non-psychotropic phytocannabinoids on human sebocyte functions implicates their introduction in dry/seborrhoeic skin and acne treatment

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Anthocyanin-Rich Sour Cherry Extract Attenuates the Lipopolysaccharide-Induced Endothelial Inflammatory Response

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GPR119 Is a Potent Regulator of Human Sebocyte Biology

We have previously shown that endocannabinoids promote sebaceous lipogenesis, and sebocytes are involved in the metabolism of the “endocannabinoid-like” substance oleoylethanolamide (OEA). OEA is an endogenous activator of GPR119, a recently de-orphanized receptor, which is currently being investigated as a promising anti-diabetic drug target. Thus, in the current study, we investigated the effects of OEA as well as the expression and role of GPR119 in human sebocytes. We found that OEA promoted differentiation of human SZ95 sebocytes (elevated lipogenesis, enhanced granulation, and the induction of early apoptotic events), and it switched the cells to a pro-inflammatory phenotype (increased expression and release of several pro-inflammatory cytokines). Moreover, we could also demonstrate that GPR119 was expressed in human sebocytes, and its siRNA-mediated gene silencing suppressed OEA-induced sebaceous lipogenesis, which was mediated via JNK, ERK1/2, Akt/PKB, and CREB activation. Finally, our pilot data demonstrated that GPR119 was down-regulated in sebaceous glands of acne patients, arguing that GPR119 signaling may indeed be disturbed in acne. Collectively, our findings introduce the OEAGPR119 signaling as a new positive regulator of sebocyte differentiation, and highlight the possibility that dysregulation of this pathway may contribute to the development of seborrhea and acne

Endocannabinoid Tone Regulates Human Sebocyte Biology

We have previously shown that endocannabinoids (eCBs)(e.g., anandamide) are involved in the maintenance of homeostatic sebaceous lipid production inhuman sebaceous glands and thateCB treatment dramatically increases sebaceous lipid production. Here, we aimed to investigate the expression of the major eCB synthesizing and degrading enzymes and to study the effects of eCB uptake inhibitors on human SZ95 sebocytes, thus exploring the role of the putative eCB membrane transporter, which has been hypothesized to facilitate the cellular uptake and subsequent degradation of eCBs. We found that the major eCB synthesizing (N-acyl phosphatidylethanolaminespecific phospholipase D, and diacylglycerol lipase-a and -b) and degrading (fatty acid amide hydrolase, monoacylglycerol lipase) enzymes are expressed in SZ95 sebocytes and also in sebaceous glands (except for diacylglycerol lipase-a, the staining of whichwas dubious in histological preparations). eCB uptake-inhibitionwith VDM11 induced amoderate increase insebaceous lipid production and also elevated the levels of variouseCBs and related acylethanolamides. Finally, we found that VDM11 was able to interfere with the proinflammatory action of the TLR4 activator lipopolysaccharide. Collectively, our data suggest that inhibition of eCB uptake exerts anti-inflammatory actions and elevates both sebaceous lipid production and eCB levels; thus, these inhibitors might be beneficial in cutaneous inflammatory conditions accompanied by dry skin

Cryptococcus neoformans Wee1 génjének interspecifikus komplementációs vizsgálata

Cryptococcus neoformans Wee1 génjének interspecifikus komplementációs vizsgálataBscbiológiag