Thioalbamide inhibits FoF1-ATPase in breast cancer cells and reduces tumor proliferation and invasiveness in breast cancer in vivo models.

OBJECTIVE: Thioalbamide is a ribosomally synthesized and post-translationally modified peptide (RiPP) belonging to the family of thioamitides, a rare class of microbial specialized metabolites with unusual post-translational modifications and promising biological activities. Recent studies have demonstrated the ability of thioalbamide to exert highly selective cytotoxic effects on tumor cells by affecting their energy metabolism, thus causing abnormal ROS production and triggering apoptosis. This study is aimed to investigate the molecular mechanisms underlying the antitumor activity of thioalbamide in order to identify its exact molecular target. METHODS: Wild type MCF-7 and MDA-MB-231 breast cancer cell lines as well as cancer cells deprived of mitochondrial DNA (ρ0 cells) were employed in order to assess thioalbamide effects on tumor bioenergetics. In this regard, metabolic profile was evaluated by a Seahorse XFe96 analyzer, and the activity of the enzyme complexes involved in oxidative phosphorylation was quantified by spectrophotometric assays. Thioalbamide effects on tumor invasiveness were assessed by gelatin zymography experiments and invasion assays. In vivo experiments were carried out on breast cancer xenograft and "experimental metastasis" mouse models. RESULTS: Experiments carried out on ρ0 breast cancer cells, together with Seahorse analysis and the application of spectrophotometric enzymatic assays, highlighted the ability of thioalbamide to affect the mitochondrial respiration process, and allowed to propose the FoF1-ATPase complex as its main molecular target in breast cancer cells. Additionally, thioalbamide-mediated OXPHOS inhibition was shown, for the first time, to reduce tumor invasiveness by inhibiting metalloproteinase-9 secretion. Furthermore, this study has confirmed the antitumor potential of thioalbamide in two different in vivo models. In particular, experiments on MCF-7 and MDA-MB-231 xenograft mouse models have confirmed in vivo its high anti-proliferative and pro-apoptotic activity, while experiments on MDA-MB-231 ″experimental metastasis" mouse models have highlighted its ability to inhibit breast cancer cell invasiveness. CONCLUSIONS: Overall, our results shed more light on the molecular mechanisms underlying the pharmacological potential of thioamidated peptides, thus reducing the gap that separates this rare class of microbial metabolites from clinical studies, which could validate them as effective tools for cancer treatment.

[Refeeding syndrome]. / Syndrome de renutrition inappropriée.

Refeeding syndrome (RS) is a rare but severe condition that is poorly understood, often under-diagnosed and can lead to death. It occurs within 5 days after refeeding in patients after prolonged fasting or in a context of undernutrition. As a consequence of the abrupt transition from catabolism to anabolism, RS is defined as a decrease in plasma levels of phosphorus, potassium and/or magnesium, whether or not associated with organ dysfunction resulting from a decrease in one of the electrolytes or a thiamine deficiency, after refeeding. The clinical symptoms are varied and non-specific and are related to hydro electrolyte disorders, sodium-hydroxide retention or failure of one or more organs. Patient management should be appropriate with regular clinical examination and careful biological monitoring, including hydro electrolyte monitoring. The correction of hydroelectrolytic disorders and systematic thiamine supplementation are essential during refeeding, that must be done carefully and very progressively, whatever its form (oral, enteral or parenteral). The severity of the refeeding syndrome indicates that its prevention and screening are the corners of its management in at-risk patients.

European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD) and European Association for the Study of Obesity (EASO) clinical practice recommendations for the management of non-alcoholic fatty liver disease: evaluation of their application in people with Type 2 diabetes.

AIMS: To evaluate the application of the recently proposed recommendations by the European Association for the Study of the Liver, European Association for the Study of Diabetes and European Association for the Study of Obesity for the diagnosis, treatment and follow-up of non-alcoholic fatty liver disease in people with Type 2 diabetes. METHODS: A total of 179 people with Type 2 diabetes were included in this study. Liver fat content (assessed using proton magnetic resonance spectroscopy), fatty liver index score, non-alcoholic fatty liver disease fibrosis score, and SteatoTest and FibroTest scores were determined. RESULTS: According to proton magnetic resonance spectroscopy, 68.7% of participants had steatosis (liver fat content >5.5%). The application of the guidelines using several combinations (fatty liver index + non-alcoholic fatty liver disease fibrosis scores, Steatotest + FibroTest scores, proton magnetic resonance spectroscopy + non-alcoholic fatty liver disease fibrosis score, proton magnetic resonance spectroscopy + FibroTest) resulted in a referral to a liver clinic for 33.5-84.9% people with Type 2 diabetes. CONCLUSIONS: The application of these new algorithms for the diagnosis, and follow-up of non-alcoholic fatty liver disease would lead to an excessive number of people with Type 2 diabetes being referred to a liver clinic. We suggest that new clinical and/or biological biomarkers of steatosis and fibrosis be specifically validated in people with Type 2 diabetes.

Polypharmacology of dopamine receptor ligands.

Most neurological diseases have a multifactorial nature and the number of molecular mechanisms discovered as underpinning these diseases is continuously evolving. The old concept of developing selective agents for a single target does not fit with the medical need of most neurological diseases. The development of designed multiple ligands holds great promises and appears as the next step in drug development for the treatment of these multifactorial diseases. Dopamine and its five receptor subtypes are intimately involved in numerous neurological disorders. Dopamine receptor ligands display a high degree of cross interactions with many other targets including G-protein coupled receptors, transporters, enzymes and ion channels. For brain disorders like Parkinsons disease, schizophrenia and depression the dopaminergic system, being intertwined with many other signaling systems, plays a key role in pathogenesis and therapy. The concept of designed multiple ligands and polypharmacology, which perfectly meets the therapeutic needs for these brain disorders, is herein discussed as a general ligand-based concept while focusing on dopaminergic agents and receptor subtypes in particular.

Potential influence of Type A personality on plasma C-reactive protein levels in people with diabetes.

AIM: Type A personality, although classically known as a factor linked to increased vascular risk, has recently been associated with increased survival in patients with diabetes. As low-grade inflammation predicts a poor outcome, the present study explored the potential associations between Type A and plasma levels of C-reactive protein (CRP) in diabetes. METHODS: Type A personality was assessed by the Bortner questionnaire in people with diabetes. The association between Type A and plasma CRP levels was examined by multivariable linear regression, and structural equation modelling (SEM) was performed to determine the impact of the major clinical, biological and psychological confounders. RESULTS: The study included 626 participants with type 1 and type 2 diabetes from the Diabetes and Psychological Profile study. Multivariable analyses showed an independent inverse association between Type A score and CRP levels. The structural model adjusted for age, gender, diabetes type and duration, body mass index (BMI), smoking status, alcohol abuse, oral antidiabetic and statin treatments, HbA1c levels, lipids, perceived stress, anxiety and depression revealed significant associations between CRP and Type A (ß=-0.135, 95% CI: -0.242, -0.028; P=0.014), BMI (ß=0.194, 95% CI: 0.038, 0.350; P=0.015) and HDL cholesterol (ß=-0.132, 95% CI: -0.245, -0.020; P=0.014). CONCLUSION: Our present study data indicate that Type A personality is independently associated with lower CRP levels. This lower level of inflammation might explain the better clinical outcomes associated with Type A personality in patients with diabetes.

[Alteration in quality of life in anorexia nervosa and improvement under treatment: validation of a new questionnaire, the QUAVIAM]. / Altération de la qualité de vie dans l'anorexie mentale et amélioration sous traitement : validation d'un nouveau questionnaire, le QUAVIAM.

Anorexia nervosa (AN) is a chronic and often severe eating disorder, which could have a serious impact on various life domains. AN may lead to physical, mental, behavioural and socioprofessional impairment. Thus, one could expect a poor quality of life (QoL) in AN patients. QoL is certainly a key factor to provide quantitative measurement of treatment efficacy that will facilitate clinical decision-making and treatment planning. Despite that QoL was rarely prospectively analyzed in AN patients, one could conclude that AN patients showed reduced QoL, as compared to normal controls and other psychiatric-disordered patients. It seems that mental health components of QoL are more impaired than the physical ones in AN patients, who showed a modest impact in the physical domain. Thus, our aim was to analyse the QoL using a new, French, questionnaire, the QUAVIAM (qualité de vie dans l'anorexie mentale). After a bibliography research (including EDE, EDI, SF-36, QOL.ED), the choice of 12 themes, regrouped in six scores, was made by three eating disorder specialists and two recovered patients. For each score, 10 to 15 questions were written by the experts, and then corrections and validation were made by the five experts and 21 patients. After this, we prospectively determined the reproducibility (3 days interval), the specificity, and the sensitivity for short-term change in patients exhibiting an "active" AN (n=54, mean age: 31 ± 9 yrs, mean BMI: 14.1 ± 2.8 kg/m(2), AN duration: 2.6 ± 1.9 yrs), and again after cognitive behavioral therapy (CBT). We also analyzed the QUAVIAM score and subscores in 48 recovering patients and in 56 subjects without eating disorder. The QUAVIAM final version (61 questions) was collected in 76 patients and the 56 healthy controls matched for sex and age. Its reproducibility was 91% (intra-questionnaire) and 94% (inter-questionnaire), its specificity 98% (versus controls; P<0.0001) and its sensitivity 99%. The QUAVIAM global score of the AN patients was more impaired (389 ± 87) than that of the recovering patients (157 ± 82) and the normal controls (89 ± 49; P<0.0001). Each of the six subscores was higher (more altered) in active AN than in recovering AN patients and in normal subjects: the somatic, the psychological, the hedonic, the socioprofessional, the affective and the TCA-related ones (P<0.001 for each comparison). The QUAVIAM global score and its subscores were significantly improved (decreased) by the 3-month CBT: 385 ± 25 before and 189 ± 30 after CBT (P<0.0001). The changes were observed for all the subscales (P<0.0001). The somatic subscore did not decrease less than the other subscores. Thus, the present study permits proposing the QUAVIAM for analysis of physical, mental, behavioural and socioprofessional impairment or improvements in AN patients.

Deleterious effect of glycation on the ability of HDL to counteract the inhibitory effect of oxidized LDL on endothelium-dependent vasorelaxation.

BACKGROUND: Contrary to high-density lipoprotein (HDL) from normolipidaemic and normoglycaemic subjects, HDL from diabetic patients loses its ability to reverse the inhibition of vasorelaxation induced by oxidized low-density lipoprotein (LDL). The aim of this study was to analyze the role of glycation, a major abnormality observed in diabetes, on the impairment of the vasorelaxant effect of HDL. METHODS: HDL from healthy subjects was glycated in vitro by incubation in glucose 200 mmol/L for 3 days. Vasoreactivity was evaluated by the relaxation response to acetylcholine of rabbit aorta rings pre-contracted with noradrenaline, before and after 2 h incubation with or without different lipoprotein fractions (Krebs buffer, oxidized LDL, normal or glycated HDL alone and with oxidized LDL). RESULT: The fructosamine/apolipoprotein AI ratio was significantly increased in glycated HDL compared with native HDL (53.63 ± 7.91 vs 18.51 ± 4.10 µmol/g; p < 0.05). Oxidized LDL inhibited endothelium-dependent vasodilation compared with Krebs buffer [maximal relaxation (Emax) = 53.15 ± 6.50 vs 98.67 ± 2.07%, p < 0.001]. Native HDL was able to counteract the oxidized LDL-induced inhibition of vasorelaxation (Emax = 76.93 ± 5.41 vs 53.15 ± 6.50%, p < 0.001). On the other hand, glycated HDL had no effect on oxidized LDL-induced inhibition of endothelium vasorelaxation compared with incubation with oxidized LDL alone (Emax = 52.98 ± 2.07 vs 53.15 ± 6.50%, not significant). CONCLUSION: Glycation of HDL induces the loss of the ability of HDL to counteract the inhibitory effect of oxidized LDL on endothelium-dependent vasorelaxation, this is likely contributing to the impairment of antiatherogenic properties of HDL in diabetic patients.

Increased erythrocytes n-3 and n-6 polyunsaturated fatty acids is significantly associated with a lower prevalence of steatosis in patients with type 2 diabetes.

BACKGROUND & AIMS: Non-alcoholic fatty liver disease (NAFLD) is commonly associated with obesity, metabolic syndrome and type 2 diabetes. Although dietary fat contributes substantially to the accumulation of liver fat, the role of individual fatty acids in this accumulation is unclear. OBJECTIVE: In this study, we set out to determine whether liver fat content (LFC), was associated with red blood cell fatty acid (RBC-FA) composition in people with type 2 diabetes. DESIGN, SETTINGS, AND PARTICIPANTS: One hundred and sixty-two type 2 diabetic patients were included in this study. LFC was measured using (1)H-MR Spectroscopy. RBC-FA composition was measured by gas chromatography. RESULTS: One hundred and nine (67.2%) patients had steatosis. Patients with steatosis had a higher BMI (p = 0.0005), and higher plasma triglyceride levels (p = 0.009) than did patients without steatosis. We report a significant association between palmitic acid (16:0), palmitoleic acid (16:1n-7) concentrations and ratio of monounsaturated to saturated fatty acid (palmitoleic acid to palmitic acid) and higher liver fat content. Total polyunsaturated fatty acid (PUFA), homo-gamma-linolenic acid (20:3n-6), docosahexaenoic acid (22:6n-3), and arachidonic acid (20:4 n-6) were associated with lower LFC. CONCLUSIONS: Our data showed that an increased erythrocytes long-chain n-3 and n-6 fatty acids was associated with a lower prevalence of steatosis in patients with type 2 diabetes. These results suggest that n-3 and n-6 fatty acids supplementation could be a promising treatment for NAFLD in patients with type 2 diabetes.

Non-ultrasound-guided ethanol sclerotherapy for the treatment of thyroid cysts.

OBJECTIVE: Ethanol injection under ultrasound (US) guidance has been proposed as an alternative to surgery in the treatment of recurrent benign thyroid cysts following aspiration. We aimed to set up a new procedure of ethanol sclerotherapy without US guidance for the treatment of pure thyroid cysts in order to make this useful treatment, available to more patients, more particularly when access to centers specialized in thyroid ultrasonography is limited. PATIENTS AND METHODS: Nine patients with recurrent large thyroid cysts following aspiration, and showing symptoms of compression and/or cosmetic complaints were treated by ethanol injection without US guidance and followed for up to 11 years. RESULTS: After ethanol injection, mean cyst volume was significantly reduced (9.9 ± 13.6 vs. 31.3 ± 34.1 ml, P=0.007) and the mean percentage volume reduction was 72.7%. A size reduction of the thyroid lesion more than 50% was achieved in eight of the nine patients (89%). Compressive symptoms and cosmetic complaints totally disappeared after sclerotherapy in all patients. During a mean follow-up of 48 months (ranging from 12 to 135 months), no recurrences were observed. The treatment was well tolerated with no major side effects. CONCLUSION: Non-US-guided ethanol sclerotherapy is a safe and "easy-to-use" procedure to treat benign thyroid cysts effectively. Because this new treatment does not need US-guidance, it can be performed by endocrinologists during outpatient visits. This new procedure may be useful in some areas, such as developing countries, where access to US examination is limited.

Cardiovascular complications in type 1 diabetes mellitus.

Although the issue of cardiovascular complications in type 2 diabetic patients is widely discussed, and recommendations for such screening are available, it is less common to do so for type-1 diabetes. Yet, independent of age, the mortality rate due to ischaemic cardiac disease is higher among type 1 diabetic patients (both male and female) than in the general population. Type 1 diabetic patients have certain specific characteristics related not only to atherosclerotic plaque and cardiovascular risk factors, but also to their capacity for physical activity and to the prevention of cardiovascular complications induced by hypoglycaemia.

Are elderly patients with diabetes being overtreated in French long-term-care homes?

AIM: In France, diabetes prevalence and ageing of the population are both on the increase, yet little information on diabetes in elderly patients living in geriatric institutions is available. Moreover, institutionalized diabetic patients are not included in the French recommendations for the management of diabetes in the elderly. For this reason, the aim of the present study was to evaluate diabetes management in older, institutionalized patients. METHODS: The medical records of 100 diabetic patients, aged 65 years and over, and living in seven geriatric institutions in the Côte d'Or region of France, were studied from May 2008 to January 2009. RESULTS: Prevalence of diabetes in these seven geriatric institutions was 15.46±4.9%, higher than in the general population. The diabetic patients had a mean age of 81.85±11.93 years, and 32% had glycated haemoglobin (HbA(1c)) less or equal to 6.5%, indicating a high risk of severe hypoglycaemia. A diet for diabetes was prescribed in 54% of the patients, but HbA(1c) levels did not differ between patients following and not following the diet (7.26±1.36% vs 7.11±1.10%, respectively; P=0.27). Creatinine was assessed in 87% of the patients, and 16% were ophthalmologically followed-up. Daily capillary blood glucose monitoring was performed in 100% of the patients taking insulin and in 17% of those taking oral antidiabetic treatment (P<0.0001). CONCLUSION: Our data show that, among older institutionalized patients, the prevalence of diabetes is high and the control of diabetes too tight, with a potential risk of hypoglycaemia. Antidiabetic treatment should be reduced when the HbA(1c) value is less than 7.5% in this frail and functionally dependent population. Furthermore, a diabetic diet, prescribed for more than half this population, is useless for glycaemic control and may even impinge on quality of life.

Postprandial hyperglycaemia: to treat or not to treat?

Accumulating evidence suggests that the postprandial or the post-75 g glucose load rise in plasma glucose are a contributing factor to the development of atherosclerosis. Many epidemiological studies have shown that post-load hyperglycaemia is a strong and independent risk factor for cardiovascular disease. The few interventional studies available also support a role for postprandial or post-load hyperglycaemia on cardiovascular disease or mortality or on validated surrogates of atherosclerosis. The mechanism through which acute hyperglycaemia could exert its deleterious effects on the vessel wall is very likely multifactorial, but the overproduction of free radicals is probably involved. There is growing evidence that treating postprandial hyperglycaemia should probably be part of the strategies for the prevention and management of cardiovascular diseases in pre-diabetes as well as in diabetes.

The prevention of type 2 diabetes: what is the evidence?

The prevalence of diabetes is increasing in epidemic proportion worldwide. Because of the morbidity and mortality associated with the disease, it is becoming a major burden for the health care system. With a better understanding of the pathogenesis of type 2 diabetes, the concept of primary prevention has emerged. A number of studies demonstrated that both lifestyle modification program and pharmacological interventions in subjects with impaired glucose tolerance (IGT) can prevent or delay the progression to diabetes. The Diabetes Prevention Study (DPS) and the Diabetes Prevention Program (DPP) convincingly showed that an intensive lifestyle modification program is highly effective in decreasing the risk of diabetes in a high risk population (risk reduction of 58%). Four other smaller studies have made similar observations. The DPP study showed that metformin can reduced the risk of diabetes by 31% in subjects with IGT. The STOP-NIDDM trial confirmed the efficacy of acarbose in decreasing the risk of diabetes by 36% in similar high risk population. The TRIPOD study showed that troglitazone can reduce the incidence of diabetes by 55% in Hispanic women with a history of gestational diabetes. And more recently, the XENDOS study showed that in very obese population on intensive lifestyle modification program, xenical treatment was associated with a 37% reduced incidence of diabetes compared to placebo. Three studies suggested that bariatric surgery in morbidly obese subjects with or without IGT can reduce the incidence of diabetes to near zero. Eight of 10 studies showed that treatment with inhibitors of the renin-angiotensin aldosterone system in high risk population for cardiovascular disease (CVD) were associated with a significant reduction in the subsequent development of diabetes as a secondary outcome. The WOSCOPS study and the HERS study examined the effect of pravastatin and estrogen/progestin respectively on cardiovascular events and observed that these pharmacological interventions were associated with a 30% and 35% reduction in the incidence of diabetes as secondary outcome. There are 3 major trials currently in progress examining the effect of rosiglitazone/ramipril (the DREAM study), nateglinide/valsartan (the NAVIGATOR study) and pioglitazone (the ACT NOW study) on the development of diabetes in IGT subjects as a primary outcome. We also have 3 studies studying the prevention of diabetes as secondary outcomes: the ONTARGET-TRANSCEND study examining telmisartan with or without ramipril, and the ORIGIN study testing glargine insulin/omega 3. The evidence is overwelming-diabetes can be prevented or delayed in high risk population through lifestyle modification or pharmacological interventions. This new information now has to be translated in the real world into well defined strategies for screening and treating high risk population. Prevention of the disease is our only chance to alleviate the ever growing burden of diabetes mellitus in the world.

Serum adiponectin and metabolic parameters in HIV-1-infected patients after substitution of nevirapine for protease inhibitors.

BACKGROUND: In the context of HIV infection and antiretroviral therapy, adiponectin concentrations have been shown to be related to lipodystrophy, metabolic alterations and HIV-protease inhibitor (PI) use. The replacement of PI by nevirapine has improved the lipid profile of patients under antiretroviral therapy. The aim of the present study was to examine whether adiponectin concentration or insulin sensitivity level correlate with the modifications of lipid parameters after the switch of PI by nevirapine. MATERIAL AND METHODS: The evolution of metabolic parameters before and after 6 months of substitution of nevirapine for protease inhibitors was evaluated in a cohort of 55 HIV-1 infected patients. Adiponectin concentration, insulin sensitivity, lipid profile, cholesterol ester transfer protein (CETP) mass concentration and triglyceride enrichment of HDL were determined before and after the replacement of PI by nevirapine. Insulin sensitivity was evaluated by the HOMA model assessment. RESULTS: Twenty-four weeks of treatment with nevirapine improved significantly the lipid profile with a significant reduction of apoB (from 0.98 to 0.92 g L(-1); P = 0.005) and triglyceride (from 2.02 to 1.66 mmol L(-1); P = 0.02). HDL cholesterol and apoA1 increased significantly (from 0.99 to 1.19 mmol L(-1); P = 0.001 and from 1.40 to 1.57 g L(-1); P < 0.001, respectively). The triglyceride enrichment of HDL significantly decreased after the replacement of PI by nevirapine (from 0.248 +/- 0.092 to 0.213 +/- 0.093; P = 0.003). At baseline, and after 24 weeks of nevirapine treatment, we observed significant correlations between adiponectin level and lipid parameters [(HDL-cholesterol (r = 0.66, P = 0.001 and r = 0.69, P = 0.001); triglycerides (r = -0.42, P = 0.002 and r = -0.57, P = 0.001), and triglyceride enrichment of HDL (r = -0.43, P = 0.005 and r = -0.53, P = 0.005)]. Twenty-four weeks of treatment with nevirapine did not significantly change adiponectin concentrations (from 984 to 1086 micro g L(-1), P = 0.22), CETP mass and insulin sensitivity. CONCLUSION: This study shows that even though a strong correlation was found between adiponectin and some metabolic parameters at baseline and after 24 weeks of treatment by nevirapine, the improvement of lipid profile observed after the replacement of PI by nevirapine was not in relation to the change of plasma adiponectin concentration. The significant decrease of triglyceride enrichment of HDL after the replacement of PI by nevirapine probably leads to a decreased catabolism of HDL lipoprotein, and consequently explains the increase of plasma HDL concentration observed in this study.