Dihydrodehydrodiisoeugenol enhances adipocyte differentiation and decreases lipolysis in murine and human cells.

Loss of subcutaneous fat is a hallmark of ageing usually starting in the face. Attempts to ameliorate cosmetically the appearance of subcutaneous fat loss have been of limited success as they fail to rebuild the missing subcutaneous tissue. Ageing-driven loss of subcutaneous fat results from (i) the reduced capacity of pre-adipocytes to differentiate into adipocytes and (ii) the fact that adipocytes of the elderly secrete increased amounts of TNFα, that in turn enhances lipolysis, inhibits pre-adipocyte differentiation and induces dedifferentiation of adipocytes. The neolignan dihydrodehydrodiisoeugenol (DDE) caused a 30% increase in lipid accumulation in murine 3T3-L1 cells. This effect was accompanied by an induction of the differentiation-associated transcription factors peroxisome proliferator-activated receptorγ (PPARγ2), CAAT/enhancer-binding protein α (C/EBPα), fatty acid binding protein 4 and adiponectin, and a loss of the pre-adipocyte marker Pref1. In addition, DDE diminished both basal and TNFα-induced lipolysis. Similar results were obtained in human subcutaneous (hsc) pre-adipocytes cultured in an age-adapted hormone mix with reduced levels of insulin and dexamethasone. In this system, DDE significantly increased lipid accumulation by 71% and 94% and was associated with an induction of PPARγ2 and adiponectin mRNA expression. DDE also reduced basal lipolysis in mature hsc adipocytes. DDE acted as a partial PPARγ agonist because (i) DDE displaced PPARγ ligand from the human PPAR ligand-binding site, (ii) DDE-induced lipid accumulation and (iii) DDE-induced adiponectin secretion could be overcome by the addition of PPARγ antagonists. Taken together, these studies identify DDE as a compound well suited to prevent and reverse loss of subcutaneous fat.

Inhibition of TRPV1 for the treatment of sensitive skin.

During the past years, the topic sensitive skin became one of the most important fields in dermatology. The tremendous interest is based on several studies showing that about 50% of the population declares to have sensitive skin. The human thermoreceptor hTRPV1 was previously identified to contribute to this skin condition while facilitating neurogenic inflammation leading to hyperalgesia. Furthermore, skin sensitivity towards capsaicin, a natural activator of TRPV1, was shown to correlate with sensitive skin. In a screening campaign based on recombinant HEK293-cells stably transfected with hTRPV1, the selective antagonist trans-4-tert-butylcyclohexanol was identified. This antagonist is able to inhibit capsaicin-induced hTRPV1 activation with an IC(50) value of 34 ± 5 µm tested in HEK293-cells as well as in electrophysiological recordings performed in oocytes expressing hTRPV1. Strikingly, in a clinical study with 30 women using topical treatment with o/w emulsions containing 31.6 ppm capsaicin, we were able to show that 0.4% of this inhibitor significantly reduces capsaicin-induced burning (P < 0.0001) in vivo. Thus trans-4-tert-butylcyclohexanol has the potential as a novel bioactive for the treatment of sensitive skin.

Sunscreens with an absorption maximum of > or =360 nm provide optimal protection against UVA1-induced expression of matrix metalloproteinase-1, interleukin-1, and interleukin-6 in human dermal fibroblasts.

UVA1-induced expression of matrix metalloproteinase-1 (MMP-1) is mediated by an autocrine mechanism involving the cytokines interleukin-1 and -6 (IL-1 and IL-6). The subsequent degradation of collagen fibers is thought to be the main cause of skin wrinkling. As it is currently not known which wavelengths within the UVA1 range are responsible for these effects, we have assessed 5 UVA1 filters (experimental filters HRH21328 and HRH22127, butyl methoxydibenzoylmethane (BMDM), diethylaminohydroxybenzylbenzoic acid hexyl ester (DHBB) and anisotriazine) with different absorption maxima for their capacity to protect against UVA1-induced MMP-1 expression. To test the efficacy of these hydrophobic filters in a cell culture system, UVA1 irradiation of primary human fibroblasts was performed through a quartz microplate filled with ethanolic solutions of the UVA filters placed on top of the cell microplate. Inhibition of UVA1-induced gene expression was detected by real time RT-PCR. The efficacy to protect against UVA1-induced MMP-1 expression was wavelength dependent: the protection by HRH22127 was best, followed by HRH21328, DHBB, BMDM, and anisotriazine. In addition, HRH22127 and HRH 21328 both significantly inhibited UVA1-induced expression of IL-1alpha and IL-6 with HRH21238 being superior to HRH22127. These studies indicate that UVA1 filters with a maximum absorption at > or =360 nm are most effective in preventing UVA1 radiation-induced MMP-1, IL-1alpha, and IL-6 expression pointing towards a critical role for effective filtering beyond > or =360 nm for protection against UVA1-induced photoaging.

PAF-mediated pulmonary edema: a new role for acid sphingomyelinase and ceramide.

Platelet-activating factor (PAF) induces pulmonary edema and has a key role in acute lung injury (ALI). Here we show that PAF induces pulmonary edema through two mechanisms: acid sphingomyelinase (ASM)-dependent production of ceramide, and activation of the cyclooxygenase pathway. Agents that interfere with PAF-induced ceramide synthesis, such as steroids or the xanthogenate D609, attenuate pulmonary edema formation induced by PAF, endotoxin or acid instillation. Our results identify acid sphingomyelinase and ceramide as possible therapeutic targets in acute lung injury.