Classic biphasic pulmonary blastoma: A case report and review of the literature.

Pulmonary blastomas represent about 0.5% of primary pulmonary malignancies. The prognosis is poor. Standard treatment consists of surgical excision. There are no published series on which to judge the efficacy of chemotherapy or radiation therapy. We describe an unusual case of classic biphasic pulmonary blastoma (CBPC), with long-term survival despite numerous and varied cancer-related events and review the literature. Our 71-year-old Caucasian woman presented with history of blood in sputum in 2009. Right lower lobectomy yielded a diagnosis of sarcomatoid carcinoma (pneumoblastoma). Unusually, our patient is still alive 7 years after initial surgery, despite metastatic first relapse after 2 years. Metastatic progression was confirmed histologically on three separate occasions during the disease course. The patient received a combination of cisplatin (or carboplatin) and etoposide on three separate occasions. Molecular biology studies of CBPC are needed to identify effective treatments, and a patient registry should be created.

[Management and clinical outcome in patients over 80 years with rectal cancer treated between 2006 and 2008 in Southern France (PACA region)]. / Prise en charge et devenir des patients de plus de 80ans atteints d'un cancer du rectum, en région Provence-Alpes-Côte-d'Azur de 2006 à 2008.

PURPOSE: Rectal cancer is increasingly prevalent in elderly patients. Their clinical history and outcome after treatment are poorly described. This retrospective study was undertaken to provide more data and to compare therapeutic strategies to the standard of care for younger patients. PATIENTS AND METHODS: Patients concerned were aged 80 years or older, with a rectal cancer diagnosed between 2006 and 2008 and treated in Provence-Alpes-Côte-d'Azur (PACA), irrespective of stage and treatment of the disease. Overall survival and relapse-free-survival were correlated with patients' characteristics and treatment. The adopted therapeutic strategy was then compared to the standard-of-care for younger patients. RESULTS: With a median follow-up of 36 months, among the 160 patients included, the 3-year overall survival and relapse-free survival were 59.2% and 76.6%, respectively for the 117 patients who received a treatment with curative intent. In the multivariate analysis, node status and surgery independently influenced overall survival, while relapse-free survival was influenced by age, N status, and gender. For T0-T2 tumours, patients were treated similarly to younger patients with an overall survival of 83.6% and a relapse-free survival of 95.2%. For T3-T4 tumours, the 3-year relapse-free survival was 65%, even with a less aggressive strategy. CONCLUSION: Surgical resection after evaluation using the Comprehensive Geriatric Assessment (CGA) test should be the standard treatment for localized rectal cancer (T0-T2) in elderly patients, as it is in younger patients. For locally advanced lesions (T3-T4), results obtained after a conservative approach suggest that a non-surgical strategy can be used in elderly patients.

A phase III adjuvant randomised trial of 6 cycles of 5-fluorouracil-epirubicine-cyclophosphamide (FEC100) versus 4 FEC 100 followed by 4 Taxol (FEC-T) in node positive breast cancer patients (Trial B2000).

BACKGROUND: Standard adjuvant chemotherapy regimens for patients with node positive (N+) breast cancer consisted of anthracycline followed by taxane. The European Association for Research in Oncology embarked in 2000 on a phase III trial comparing 6 cycles of FEC100 versus 4 FEC100 followed by 4 Taxol. Primary end-point was disease free survival. Secondary end-points were overall survival, local recurrence free interval, metastases free interval and safety. PATIENTS AND METHODS: Between March 2000 and December 2002, 837 patients were randomised between 6FEC100 for 6 cycles (417patients) or FEC100 for 4 cycles then Taxol 175mg/m(2)/3 weeks for 4 cycles (4FEC100-4T) (420 patients). One thousand patients had been planned initially but the trial was closed earlier due to slow accrual. RESULTS: Hazard ratios (HRs) were 0.99 for disease-free survival (DFS) (95%CI: 0.77-1.26; p=0.91), and 0.85 for overall survival (OS) (95%CI: 0.62-1.15; p=0.29). Nine-year DFS were 62.9% versus 62.5% for 6FEC100 and 4FEC100-4T, respectively. Nine-year OS were 73.9% versus 77% for 6FEC100 and 4FEC100-4T, respectively. Toxicity analyses based on 803 evaluable patients showed that overall grade 3-4 toxicities were similar in both arms (63% versus 58% for 6FEC100 arm and 4FEC100-4T arm, respectively; p=0.16). CONCLUSION: In this trial replacing the last 2 FEC100 cycles of 6FEC100 regimen by 4 Taxol does not lead to a discernable DFS or OS advantage. The lack of a significant difference between the randomised treatment arms may however be due to a lack of power of this trial to detect small, yet clinically worthwhile, treatment benefits.

Management and clinical outcome of rectal cancer in patients ≥ 80 years treated in southern France (PACA region) between 2006 and 2008.

BACKGROUND: Rectal cancer is increasingly prevalent in the elderly patients. Their clinical history and outcome after treatment are poorly described. This retrospective study was undertaken to provide more data and to compare therapeutic strategies to the standard of care for younger patients. PATIENTS AND METHODS: Data were retrospectively provided by gastroenterologists, oncologists, and gerontologists of Provence-Alpes-Côte-d'Azur (PACA). Patients concerned were aged 80 years or older, with a rectal cancer diagnosed between 2006 and 2008, irrespective of stage and (the) treatment of the disease. Overall survival (OS) and relapse-free-survival (RFS) were correlated with patient characteristics and treatment. The adopted therapeutic strategy was then compared to the standard-of-care for younger patients. RESULTS: Median follow-up was 36 months. The 3-year OS was 47.4% for the 160 patients analyzed, and 59.2% for the 117 patients treated with curative intent. The 3-year RFS was 76.6% in the "curative" population. In the multivariate analysis, node status and surgery independently influenced OS, while RFS was influenced by age, N status, and gender. For T0-T2 tumors, patients were treated similar to younger patients with an OS of 83.6% and a RFS of 95.2%, respectively. For T3-T4 tumors, 3-year RFS was 65%, even with a less aggressive strategy. CONCLUSION: Surgical resection after evaluation using Comprehensive Geriatric Assessment (CGA) should be the standard treatment for localized rectal cancer (T0-T2) in elderly patients, as it is in younger patients. For locally advanced lesions (T3-T4), results obtained after a conservative approach suggest that a non-surgical strategy can be used in elderly patients.

[Adenoid cystic carcinoma of the head and neck: a retrospective series of 169 cases]. / Carcinomes adénoïdes kystiques ORL : étude rétrospective multicentrique de 169 cas.

PURPOSE: Adenoid cystic carcinoma represents 1% of head and neck cancers. Adenoid cystic carcinomas are slow growing tumours with high potential for local recurrence. Treatment usually associates radiotherapy and surgery, but the role of radiotherapy remains unclear. We report a retrospective multicentric study of the management and prognostic factors of 169 adenoid cystic carcinomas of head and neck. PATIENTS AND METHODS: Between 1982 and 2010, 169 patients with adenoid cystic carcinoma of the head and neck were referred to the Cercle des oncologues radiothérapeutes du Sud departments of radiotherapy either for primary untreated tumour (n=135) or for a recurrence of previously treated tumour (n=34). The site of adenoid cystic carcinoma was: parotid gland (n=48, 28.4%), minor salivary gland (n=35, 20.7%), submandibular gland (n=22, 13%), sinus cavities (n=22, 13%), other (n=42, 24.9%). Tumour stages were: T1 (12.4%); T2 (14.2%); T3 (12.4%); T4 (41.4%) and Tx (19.5%). Lymph node involvement was 13% and distant metastasis 8.9%. For adenoid cystic carcinomas of the parotid gland, major nerve involvement was evaluated. Preferential site of metastasis was the lung (87.5%). Treatments were: surgery alone (n=27), surgery and adjuvant radiotherapy (n=89), surgery and adjuvant chemoradiotherapy (n=12), exclusive chemoradiotherapy (n=13), exclusive radiotherapy (n=14), other associations (n=5) and no treatment (n=7). Radiotherapy was delivered through photons (n=119), neutrons (n=6), both (n=4). Two patients had a brachytherapy boost. Median prescribed doses to T and N were respectively 65 Gy and 50 Gy for the 119 photons treated patients. RESULTS: Mean follow-up was 58 months (range 1-250 months). As of December 1, 2010, 83 patients were alive with no evolutive disease (49%), 35 alive and had recurred, 18 had uncontrolled evolutive disease, 28 had died of adenoid cystic carcinoma and 5 of intercurrent disease. Overall survival and disease free survival were respectively 72% and 72% at 5 years, 53% and 32% at 10 years; 5 and 10-year freedom from local recurrence were 81% and 52% respectively. Nerve involvement was found in 17/48 parotid gland adenoid cystic carcinomas. The Cox model including all patients, showed that surgery (P<0.001), surgical margins (P=0.015), nerve involvement (P=0.0079), length of radiotherapy (P=0.018), and tumour location (P=0.041) were associated with disease free survival. CONCLUSION: In this large series of adenoid cystic carcinoma of head and neck with a majority of T3-T4 tumours, 10-year survivals were achieved for 50% of patients. Radiotherapy did not impact survival.

[Evaluation of immediate breast reconstruction and radiotherapy: factors associated with complications]. / Reconstruction mammaire immédiate après mastectomie suivie de radiothérapie: facteurs de risque de complications.

OBJECTIVES: To determine prospectively the factors associated with reconstruction failure (i.e. requiring expander removal) and capsular contracture in patients undergoing mastectomy and immediate two-stage breast reconstruction with a tissue expander and implant, and radiotherapy for breast cancer. This is a multi-institutional prospective nonrandomized trial. PATIENTS AND METHODS: Between 2/1998 and 9/2006, we prospectively evaluated 141 consecutive patients who received 141 implants after mastectomy and underwent chest wall radiotherapy (46 to 50 Gy in 23 to 25 fractions). Patients were evaluated after 24 to 36 months by two senior physicians (radiation oncologist and surgeon). RESULTS: Medical follow-up was 37 months. Baker 1 and 2 capsular contracture was observed in 67.5% of patients, Baker 3 and 4 in 32.5%. There were 32 reconstruction failures. In a univariate analysis, the following factors were associated with Baker 3 and 4 capsular contracture: surgeon, use of hormonotherapy and smoking, of which only one remained in the multivariate analysis: surgeon. In a univariate analysis, the following factors were associated with reconstruction failure: tumor size T3 or T4, smoking, pN+ axilla. Three factors remained associated with reconstruction failure in a multiple logistic regression: large tumors T3/T4, smoking and pN+ axilla. CONCLUSIONS: Mastectomy, radiotherapy and immediate breast reconstruction with a tissue expander and implant should be considered when breast conserving surgery has been denied. Adequate patients can be easily selected by using three factors of favourable outcome.

Immediate post-mastectomy breast reconstruction followed by radiotherapy: risk factors for complications.

The objective is to prospectively determine the factors responsible for reconstruction failure and capsular contracture in mastectomized breast cancer patients who underwent immediate two-stage breast reconstruction with a tissue expander and implant, followed by radiotherapy. This is a multicenter, prospective, non-randomized study. Between February 1998 and September 2006, we prospectively examined 141 consecutive patients, each of which received an implant after mastectomy, followed by chest wall radiotherapy at 46-50 Gy in 23-25 fractions. Radiotherapy was delivered during immediate post-mastectomy reconstruction. Patients were evaluated by both a radiation oncologist and a surgeon 24-36 months after treatment. The median follow-up duration was 37 months. According to Baker's classification, capsular contracture was grade 0, 1, or 2 in 67.5% of cases; it was grade 3 or 4 in 32.5% of cases. In total, 32 breast reconstruction failures required surgery. In univariate analysis, the following factors were associated with Baker grade 3 and 4 capsular contraction: adjuvant hormone therapy (P = 0.02), the surgeon (P = 0.04), and smoking (P = 0.05). Only one factor was significant in multivariate analysis: the surgeon (P = 0.009). Three factors were associated with immediate post-mastectomy breast reconstruction failure in multiple logistic regression analysis: T3 or T4 tumors (P = 0.0005), smoking (P = 0.001), and pN+ axillary status (P = 0.004). Patients with none, 1, 2, or all 3 factors have a probability of failure equal to 7, 15.7, 48.3, and 100%, respectively (P = 3.6 x 10(-6)). The model accurately predicts 80% of failures. Mastectomy, immediate reconstruction (expander followed by implant), and radiotherapy should be considered when conservative surgery is contraindicated. Three factors may be used to select patients likely to benefit from this technique with a low failure rate.

Dose-dense adjuvant chemotherapy in node-positive breast cancer: docetaxel followed by epirubicin/cyclophosphamide (T/EC), or the reverse sequence (EC/T), every 2 weeks, versus docetaxel, epirubicin and cyclophosphamide (TEC) every 3 weeks. AERO B03 randomized phase II study.

BACKGROUND: Adding a taxane to anthracycline-based adjuvant chemotherapy prolongs survival in node-positive patients but optimal dose and schedule remain undetermined. This study aimed to select a dose-dense regimen for further assessment in phase III studies. PATIENTS AND METHODS: Ninety-nine patients with node-positive invasive breast adenocarcinoma were randomly assigned to docetaxel (Taxotere) (T) 75 mg/m2, epirubicin (E) 75 mg/m2 and cyclophosphamide (C) 500 mg/m2 (TEC)x6, every 3 weeks; E 100 mg/m2, C 600 mg/m2 x 4, then T 100 mg/m2 x 4 (EC-->T) or the reverse sequence (T-->EC), every 2 weeks, with pegfilgrastim support. The primary end point was the incidence of grade 4 toxicity. RESULTS: Dose intensity was almost doubled with dose-dense regimens, compared with TEC. Twenty-seven patients experienced grade 4 toxicity: 26%, 40% and 18% with TEC, EC-->T and T-->EC, respectively, mainly neutropenia, but febrile neutropenia occurred only in 11%, 10% and 3%. Grade 3-4 nail disorders, hand-foot syndrome and peripheral neuropathy occurred in 46%, 73% and 68% of patients with TEC, EC-->T and T-->EC, respectively. CONCLUSIONS: Dose-dense regimens yield more frequent and severe nonhematological toxic effects than standard dose TEC regimen. Though grade 4 toxicity rates appear acceptable with the T-->EC regimen, the incidence of grade 3-4 events makes it difficult to recommend either dose-dense regimen for further investigation.

The transcriptional regulating protein of 132 kDa (TReP-132) differentially influences steroidogenic pathways in human adrenal NCI-H295 cells.

Steroid hormones synthesized from cholesterol in the adrenal gland are important regulators of many physiological processes. It is now well documented that the expression of many genes required for steroid biosynthesis is dependent on the coordinated expression of the nuclear receptor steroidogenic factor-1 (SF-1). However, transcriptional mechanisms underlying the species-specific, developmentally programmed and hormone-dependent modulation of the adrenal steroid pathways remain to be elucidated. Recently, we demonstrated that the transcriptional regulating protein of 132 kDa (TReP-132) acts as a coactivator of SF-1 to regulate human P450scc gene transcription in human adrenal NCI-H295 cells. The present study shows that overexpression of TReP-132 increases the level of active steroids produced in NCI-H295 cells. The conversion of pregnenolone to downstream steroids following TReP-132 expression showed increased levels of glucocorticoids, C(19) steroids and estrogens. Correlating with these data, TReP-132 increases P450c17 activities via the induction of transcript levels and promoter activity of the P450c17 gene, an effect that is enhanced in the presence of cAMP or SF-1. In addition, P450aro activity and mRNA levels are highly induced by TReP-132, whereas 3beta-hydroxysteroid dehydrogenase type II and P450c11aldo transcript levels are only slightly modulated. Taken together, these results demonstrate that TReP-132 is a trans-acting factor of genes involved in adrenal glucocorticoid, C(19) steroid and estrogen production.

Hawthorn extracts inhibit LDL oxidation.

Polyphenol-rich diet decreases cardiovascular risk. LDL oxidation is the primary event in atherosclerosis plaque formation and antioxidants such as polyphenols were shown to inhibit LDL oxidation and atherosclerosis development. Hawthorn (Crataegus) and derived pharmaceuticals are rich in polyphenols and already prescribed to treat moderate heart failure, nervousness and sleep disorders. Extracts either from fresh plant parts (flower buds, flowers, young leaves or green fruits) or from dried pharmaceutical parts (flowers and flowering tops) were previously shown to be effective inhibitors of lipoperoxidation and scavengers of oxygen species. In this study, the capacity of total and ethyl-acetate extracts from dried pharmaceutical flowers, tops and fruits to inhibit Cu(2+)-induced LDL oxidation was tested. This capacity was positively linked to their content in total polyphenols, proanthocyanidins (global and oligomeric forms), as well as to their content in two individual phenolics: a flavanol, the dimeric procyanidin B2 and a flavonol glycoside, hyperoside. Flavanol-type phenolics showed to be higher active than the majority of the flavonoids tested in inhibiting Cu(2+)-induced LDL peroxidation. This study suggests that hawthorn could be a source of polyphenols able to inhibit LDL oxidation.

Peroxisome proliferator-activated receptor (PPAR) agonists decrease lipoprotein lipase secretion and glycated LDL uptake by human macrophages.

Lipoprotein lipase (LPL) acts independently of its function as triglyceride hydrolase by stimulating macrophage binding and uptake of native, oxidized and glycated LDL. Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors expressed in monocyte/macrophages, where they control cholesterol homeostasis. Here we study the role of PPARs in the regulation of LPL expression and activity in human monocytes and macrophages. Incubation of human monocytes or macrophages with PPARalpha or PPARgamma ligands increases LPL mRNA and intracellular protein levels. By contrast, PPAR activators decrease secreted LPL mass and enzyme activity in differentiated macrophages. These actions of PPAR activators are associated with a reduced uptake of glycated LDL and could influence atherosclerosis development associated with diabetes.

Breast cancer occurred after treatment for Hodgkin's disease: analysis of 133 cases.

PURPOSE: To assess the clinical and histological characteristics of breast cancer (BC) occurring after Hodgkin's disease (HD) and give possible therapies and prevention methods. MATERIALS AND METHODS: In a retrospective multicentric analysis, 117 women and two men treated for HD subsequently developed 133 BCs. The median age at diagnosis of HD was 24 years. The HD stages were stage I in 25 cases (21%), stage II in 70 cases (59%), stage III in 13 cases (11%), stage IV in six cases (5%) and not specified in five cases (4%). Radiotherapy (RT) was used alone in 74 patients (63%) and combined modalities with chemotherapy (CT) was used in 43 patients (37%). RESULTS: BC occurred after a median interval of 16 years. TNM classification (UICC, 1978) showed 15 T0 (11.3%), 44 T1 (33.1%), 36 T2 (27.1%), nine T3 (6.7%), 15 T4 (11.3%) and 14 Tx (10.5%). Ductal infiltrating carcinoma and ductal carcinoma in situ (DCIS) represented 81.2 and 11.3% of the cases, respectively. Among the infiltrating carcinoma, the axillary involvement rate was 50%. Seventy-four tumours were treated by mastectomy without (67) or with (ten) RT. Forty-four tumours had lumpectomy without (12) or with (32) RT. Another four received RT alone, and one CT alone. Sixteen patients (12%) developed isolated local recurrence. Thirty-nine patients (31.7%) developed metastases and 34 died; 38 are in complete remission whereas five died of intercurrent disease. The 5-year disease-specific survival rate was 65.1%. The 5-year disease-specific survival rates for the pN0, pN1-3 and pN>3 groups were 91, 66 and 15%, respectively (P<0.0001), and 100, 88, and 64% for the TIS, T1 and T2. For the T3 and T4, the survival rates decreased sharply to 32 and 23%, respectively. These secondary BC are of two types: a large number of aggressive tumours with a very unfavourable prognosis (especially in the case of pN>3 and/or T3T4), and many tumours with a 'slow spreading' such as DCIS and microinvasive lesions. These lesions developed especially in patients treated exclusively by RT. CONCLUSIONS: The young women and girls treated for HD should be carefully monitored in the long-term by clinical examination, mammography and ultrasonography. We suggest that a baseline mammography is performed 5-8 years after supradiaphragmatic irradiation (complete mantle or involved field) in patients who were treated before 30 years of age. Subsequent mammographies should be performed every 2 years or each year, depending on the characteristics of the breast tissue (e.g. density) and especially in the case of an association with other BC risk factors. This screening seems of importance due to excellent prognosis in our T(1S)T(1) groups, and the possibility of offering these young women a conservative treatment.

Role of the parasite-derived prostaglandin D2 in the inhibition of epidermal Langerhans cell migration during schistosomiasis infection.

Epidermal Langerhans cells (LCs) play a key role in immune defense mechanisms and in numerous immunological disorders. In this report, we show that percutaneous infection of C57BL/6 mice with the helminth parasite Schistosoma mansoni leads to the activation of LCs but, surprisingly, to their retention in the epidermis. Moreover, using an experimental model of LC migration induced by tumor necrosis factor (TNF)-alpha, we show that parasites transiently impair the departure of LCs from the epidermis and their subsequent accumulation as dendritic cells in the draining lymph nodes. The inhibitory effect is mediated by soluble lipophilic factors released by the parasites and not by host-derived antiinflammatory cytokines, such as interleukin-10. We find that prostaglandin (PG)D2, but not the other major eicosanoids produced by the parasites, specifically impedes the TNF-alpha-triggered migration of LCs through the adenylate cyclase-coupled PGD2 receptor (DP receptor). Moreover, the potent DP receptor antagonist BW A868C restores LC migration in infected mice. Finally, in a model of contact allergen-induced LC migration, we show that activation of the DP receptor not only inhibits LC emigration but also dramatically reduces the contact hypersensitivity responses after challenge. Taken together, we propose that the inhibition of LC migration could represent an additional stratagem for the schistosomes to escape the host immune system and that PGD2 may play a key role in the control of cutaneous immune responses.

PPAR-alpha and PPAR-gamma activators induce cholesterol removal from human macrophage foam cells through stimulation of the ABCA1 pathway.

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors that regulate lipid and glucose metabolism and cellular differentiation. PPAR-alpha and PPAR-gamma are both expressed in human macrophages where they exert anti-inflammatory effects. The activation of PPAR-alpha may promote foam-cell formation by inducing expression of the macrophage scavenger receptor CD36. This prompted us to investigate the influence of different PPAR-activators on cholesterol metabolism and foam-cell formation of human primary and THP-1 macrophages. Here we show that PPAR-alpha and PPAR-gamma activators do not influence acetylated low density lipoprotein-induced foam-cell formation of human macrophages. In contrast, PPAR-alpha and PPAR-gamma activators induce the expression of the gene encoding ABCA1, a transporter that controls apoAI-mediated cholesterol efflux from macrophages. These effects are likely due to enhanced expression of liver-x-receptor alpha, an oxysterol-activated nuclear receptor which induces ABCA1-promoter transcription. Moreover, PPAR-alpha and PPAR-gamma activators increase apoAI-induced cholesterol efflux from normal macrophages. In contrast, PPAR-alpha or PPAR-gamma activation does not influence cholesterol efflux from macrophages isolated from patients with Tangier disease, which is due to a genetic defect in ABCA1. Here we identify a regulatory role for PPAR-alpha and PPAR-gamma in the first steps of the reverse-cholesterol-transport pathway through the activation of ABCA1-mediated cholesterol efflux in human macrophages.

Di-tert-butylhydroxylated flavonoids protect endothelial cells against oxidized LDL-induced cytotoxicity.

The protective effect of di-tert-butylhydroxylated flavonoids (chalcones and arylidenes) against minimally oxidized LDL (mO-LDL)-induced cytotoxicity was studied in cultured bovine aortic endothelial cells. Most of the tested compounds decreased aldehydes formation in medium containing mO-LDL, but their capacity to inhibit LDL oxidation in the cellular medium was not sufficient to totally reduce the cellular toxicity of mO-LDL. Most of the tested flavonoids improved the integrity of cells exposed to mO-LDL, whereas butylated hydroxytoluene was ineffective and quercetin worsened the toxicity of mO-LDL. Moreover these flavonoids induced an increase in GSH cellular levels and their protective effects might be because of their inability to reduce metal ion. Arylidene 6 substituted at position 7 by a hydroxyl group was the most potent compound.

Antioxidant properties of di-tert-butylhydroxylated flavonoids.

Epidemiological evidence suggests an inverse relationship between dietary intake of flavonoids and cardiovascular risk. The biological activities of flavonoids are related to their antioxidative effects, but they also can be mutagenic, due to the prooxidant activity of the catechol pattern. To prevent these problems, we synthesized new flavonoids where one or two di-tert-butylhydroxyphenyl (DBHP) groups replaced catechol moiety at position 2 of the benzopyrane heterocycle. Two DBHP moieties can also be arranged in an arylidene structure or one DBHP fixed on a chalcone structure. Position 7 on the flavone and arylidene or position 4 on the chalcone was substituted by H, OCH(3), or OH. New structures were compared with quercetin and BHT in an LDL oxidation system induced by Cu(II) ions. Arylidenes and chalcones had the best activities (ED(50) = 0.86 and 0.21) compared with vitamin E, BHT, and quercetin (ED(50) = 10.0, 7. 4, and 2.3 microM). Activity towards stable free radical 1, 1-diphenyl-2-picryl-hydrazyl (DPPH) was measured by log Z and ECR(50) parameters. Synthesized flavones proved to be poor DPPH radical scavengers, the activity increasing with the number of DBHP units. In contrast, arylidenes and chalcones were stronger DPPH radical scavengers (log Z > 3, 0.3 < ECR(50) < 2.12) than BHT (log Z = 0.75, ECR(50) = 12.56) or quercetin (log Z = 2.76, ECR(50) = 0.43). Unlike quercetin, synthesized compounds neither chelated nor reduced copper, proving that these new flavonoids had no prooxidant activity in vitro.

Paraoxonase activity is dramatically decreased in patients positive for anticardiolipin antibodies.

It has been reported that paraoxonase 1 (PON1) activity inhibits low-density lipoprotein (LDL) oxidation and modulates the risk of coronary heart disease. This study shows that autoantibodies (IgG) directed against modified LDL were increased in 71 patients positive for anticardiolipin antibodies. In a representative subgroup of these patients (n = 36) PON1 activity was dramatically decreased and the prevalence of the RR genotype of this enzyme tended to be increased in patients who had developed arterial thrombosis. This study suggests that PON1 abnormalities play a role in the antiphospholipid syndrome.

4-Mercaptoimidazoles derived from the naturally occurring antioxidant ovothiols 1. Antioxidant properties.

4-Mercaptoimidazoles derived from the naturally occurring family of antioxidants, the ovothiols, were assayed for their antioxidant properties. These compounds are powerful HOCl scavengers, more potent than the aliphatic thiol N-acetylcysteine. They react slowly with hydrogen peroxide with second order rate constants of 0.13-0.89 M(-1)s(-1). Scavenging of hydroxyl radical occurs at a diffusion-controlled rate (k=2.0-5.0 x 10(10)M(-1)s(-1)) for the most active compounds, which are also able to inhibit copper-induced LDL peroxidation. The combination of radical scavenging and copper chelating properties may explain the inhibitory effects on LDL peroxidation. Two molecules of mercaptoimidazole can chelate a copper ion and form a square planar complex detected by EPR. Compounds bearing an electron-withdrawing group on position 2 of the imidazole ring are the most potent antioxidant molecules in this series.

Oxidized phospholipids activate PPARalpha in a phospholipase A2-dependent manner.

The peroxisome proliferator-activated receptor alpha (PPARalpha) is a transcription factor belonging to the PPAR subfamily of nuclear receptors. Fatty acids and eicosanoids are natural PPARalpha ligands. Here, we show using transient transfection assays that oxidized (oxLDL) but not native low-density lipoproteins (LDL) dose-dependently activate PPARalpha in endothelial cells without affecting PPARalpha protein expression. Fractioning of oxLDL lipids followed by transactivation experiments demonstrated that the oxidized phospholipid component in oxLDL is responsible for PPARalpha activation. Using specific inhibitors, it is shown that oxLDL-mediated PPARalpha activation requires phospholipase A2 activity and that the oxidized fatty acids 9- and 13-HODE activate PPARalpha directly. Finally, we found that, similar to the synthetic PPARalpha ligand Wy-14643, oxLDL induced expression of the fatty acid transport protein-1 in human primary endothelial cells. Our findings define a novel group of PPARalpha activators and provide a molecular basis for certain effects of these biologically active phospholipids on gene transcription.

Phenylpropanoids from Ballota nigra L. inhibit in vitro LDL peroxidation.

From the European plant Ballota nigra L. various polyphenols including phenylpropanoid derivatives were isolated. There is increasing evidence that oxidized low-density lipoproteins (Ox-LDL) might be involved in the pathogenesis of atherosclerosis and it has been reported that polyphenols inhibit LDL peroxidation and atherogenesis. The goal of this study was to test whether the major polyphenolic compounds extracted from Ballota nigra, four phenylpropanoid glycosides, verbascoside, forsythoside B, arenarioside, and ballotetroside and one non-glycosidic phenylpropanoid, caffeoyl-L-malic acid, inhibit Cu(2+)-induced LDL peroxidation. The effectiveness of these compounds was compared to the activity of quercetin, a well-known polyphenol inhibitor of Cu(2+)-induced LDL oxidation. Antioxidant efficacious doses (ED 50) of arenarioside and ballotetroside were 1.8 microM and 7.5 microM respectively, while in the same conditions, the ED 50 of forsythoside B and verbascoside were similar (1 microM) and those of quercetin and of caffeoyl-L-malic acid were 2.3 microM and 9.5 microM respectively. Spectrophotometric studies show that quercetin is a Cu(2+) chelator while phenylpropanoid glycosides and caffeoyl-L-malic acid are not Cu(2+) chelators. Therefore, phenylpropanoid glycosides are strong inhibitors of Cu(2+)-induced LDL oxidation, independent of any capacity to act as Cu(2+) chelators.