Pharmacological PPARγ modulation regulates sebogenesis and inflammation in SZ95 human sebocytes.

The nuclear receptor peroxisome proliferator-activated receptor gamma (PPARγ) controls the expression of genes involved in the regulation of lipid and glucose metabolism, cell proliferation/differentiation as well as inflammatory pathways. Pivotal studies in human sebocytes and isolated sebaceous glands have raised the interesting possibility that compounds acting on PPARγ can modulate sebaceous lipids and inflammation and, as such, may be useful in the treatment of acne. To investigate the role of this receptor in the regulation of lipid synthesis, proliferation and inflammation, we used the SZ95 sebaceous gland cell line stimulated with insulin. In sebocytes, insulin signaling activated the phosphatidylinositide 3-kinase-Akt (PI3K/Akt) and mammalian target of rapamycin (mTOR) pathways, which, in turn, induced high protein/lipid synthesis, increased cell growth and proliferation as well as inflammation. As regards lipogenesis, insulin initially stimulated the formation of unsaturated lipids and then the neosynthesis of lipids. The results showed, that the modulation of PPARγ, counteracted the insulin-induced altered lipogenesis, evident through a decrease in gene expression of key enzymes responsible for the synthesis of fatty acids, and through a reduction of lipid species synthesis analyzed by Oil/Nile Red staining and GC-MS. PPARγ modulation also regulated the insulin-induced proliferation, inhibiting the cell cycle progression and p21WAF1/CIP1 (p21) protein reduction. Moreover, the expression of inflammatory cytokines, induced by insulin or lipopolysaccharide (LPS), was down-modulated. In PPARγ-deficient cells or in the presence of GW9662 antagonist, all these observed effects were abolished, indicating that PPARγ activation plays a role in regulating alteration of lipogenesis, cell proliferation and inflammatory signaling. We demonstrated that selective modulation of PPARγ activity is likely to represent a therapeutic strategy for the treatment of acne.

Modulation of sebum oxidation and interleukin-1α levels associates with clinical improvement of mild comedonal acne.

BACKGROUND: Sebum plays a key role in the initiation of the acne lesions. Oxidized sebum lipids cause keratynocytes hyperproliferation and inflammatory cytokines release. Association between sebum oxidation and comedogenesis has been little investigated in comedonal acne. OBJECTIVES: Evaluation of sebum oxidation parameters and levels of inflammatory cytokines (IL-1α) in patients with mild comedonal acne (MCA) before and after the treatment with a mixed RetinSphere® - vitamin E formulation. METHODS: Sebum excretion rate (SER), squalene concentration, and oxidation degree of sebum were measured in 18 MCA patients and 10 controls. IL-1α levels in the stratum corneum were measured in both lesional and non-lesional facial areas of MCA patients. Sebum parameters and IL-1α were measured at week 4 of topical treatment. Reflectance confocal microscopy (RCM) was performed in a subset of four patients at the baseline and at week 4 and all patients were assessed clinically before and following the 8 week-treatment. RESULTS: Sebum excretion rate and squalene concentration were comparable between MCA patients and healthy controls. Lipid peroxidation (LPO) and the percentage of oxidized squalene (SQOX) were significantly elevated in the sebum of MCA patients. The concentration of the proinflammatory cytokine IL-1α in stratum corneum was significantly higher in the lesional area compared with non-lesional area of the MCA patients at the baseline. At week 4, while SER and squalene concentration did not vary significantly, the LPO levels and the SQOX percentage resulted decreased at a significant extent. Following the treatment, IL-1α concentration in the lesional area reached values comparable to those of unaffected areas. Consistent with the biochemical data, RCM showed the reduction of hyperkeratinization and of inflammatory cells infiltration of the adnexal structures epithelium, significant clinical improvement was recorded at week 8. CONCLUSION: The data further support the involvement of lipid oxidation and particularly by-products of squalene oxidation in comedogenesis.

Subjective and metabolic effects of clodronate in patients with advanced breast cancer and symptomatic bone metastases.

Twenty postmenopausal women (aged between 46 and 67 years old) with skeletal metastases from breast carcinoma were treated with clodronate 450 mg i.v. daily for 5 days and thereafter with 100 mg i.m. daily for 10 days. All patients received standard hormonal therapy (tamoxifen). Symptomatic pain (evaluated according to a linear analog scale), performance status (according to Karnofsky), serum alkaline phosphatase, serum creatinine and osteocalcin were measured before and after treatment on days 5, 15, 30 and 45. Scanning by radiology were performed pre- and post-therapy. Bone pain was significantly reduced in 15 out of 20 patients. After clodronate treatment the base line value of circulating osteocalcin (3.2 +/- 1.6 ng/ml) showed a significant increase on days 30 and 45 (p less than 0.001). Radiological assessment of bone lesions showed stable disease in 18 patients and progression in two patients. No adverse side effects were observed. These data show that clodronate provided pain relief in 75% of treated patients and the increase in circulating osteocalcin levels can be considered a marker of the stabilization of skeletal metastatic lesions.

Stimulation of drug-metabolizing enzymes by nitrous oxide in the rat.

Wistar male rats were subchronically (150 h continuously) or chronically (5 h daily for 15 days) exposed to a 50% nitrous oxide/oxygen mixture. As an index of enzyme induction liver N-demethylase and benzo(a)pyrene-hydroxylase activities, serum gamma-glutamyltranspeptidase activity, urinary d-glucaric acid and pentobarbital sleeping time were evaluated in comparison with a control group. No effect was observed after subchronic exposure to the anaesthetic gas. Chronic exposure, on the contrary, decreased pentobarbital sleeping time, increased urinary d-glucaric acid, liver N-demethylase and serum gamma-glutamyltranspeptidase activities. No increase of liver benzo(a)pyrene-hydroxylase was observed. Chronic nitrous oxide exposure under appropriate conditions can modify some enzymes, metabolizing drugs and xenobiotic compounds.

Impairment of antipyrine metabolism in urinary tract cancer.

The metabolism of antipyrine was studied in 13 patients with cancer and bladder papillomas and in 11 control subjects, matched for interfering factors like smoking, diet, age and sex. The mean antipyrine half-life was significantly longer in patients with urinary tract cancer (14.7 +/- 1.32 h SE) than in control subjects (11 +/- 0.55 h SE) (P less than 0.025); other clinical parameters did not vary.