Maria João Neuparth

Bladder cancer-induced skeletal muscle wasting: disclosing the role of mitochondria plasticity.

Loss of skeletal muscle is a serious consequence of cancer as it leads to weakness and increased risk of death. To better understand the interplay between urothelial carcinoma and skeletal muscle wasting, cancer-induced catabolic profile and its relationship with muscle mitochondria dynamics were evaluated using a rat model of chemically induced urothelial carcinogenesis by the administration of N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN). The histologic signs of non-muscle-invasive bladder tumors observed in BBN animals were related to 17% loss of body weight and high serum levels of IL-1β, TNF-α, TWEAK, C-reactive protein, myostatin and lactate and high urinary MMPs activities, suggesting a catabolic phenotype underlying urothelial carcinoma. The 12% loss of gastrocnemius mass was related to mitochondrial dysfunction, manifested by decreased activity of respiratory chain complexes due to, at least partially, the impairment of protein quality control (PQC) systems involving the mitochondrial proteases paraplegin and Lon. This was paralleled by the accumulation of oxidatively modified mitochondrial proteins. In overall, our data emphasize the relevance of studying the regulation of PQC systems in cancer cachexia aiming to identify therapeutic targets to counteract muscle wasting.

Adiponectin, Leptin, and Chemerin in Elderly Patients with Type 2 Diabetes Mellitus: A Close Linkage with Obesity and Length of the Disease

Obesity, insulin resistance, and aging are closely associated and adipokines seem to have a crucial role in their pathophysiology. We aim to study the relationship between aging and chemerin, adiponectin, and leptin levels in type 2 diabetes mellitus (T2DM). Age correlated positively with chemerin and leptin and inversely with adiponectin. Body mass index (BMI) correlated positively with leptin (in males) and chemerin and inversely with adiponectin. The patients with ≥65 years (n = 34) showed significantly higher leptin and chemerin and lower adiponectin levels than middle-aged (38–64 years) patients (n = 39) and controls (n = 20). After statistical adjustment for length of disease, there was a loss of significance, between T2DM groups, for adiponectin and, in female, for leptin. In the older group, BMI correlated with adiponectin and with leptin, but not with chemerin. Adiponectin and leptin levels in elderly T2DM patients seem to be closely linked to obesity and to length of the disease. In elderly T2DM patients, chemerin concentrations are increased and seem to be independent of length of disease and BMI, suggesting that adipocyte dysfunction is enhanced with aging. The understanding of the glucose homeostasis impairment in the elderly is mandatory in order to achieve ways to improve their quality of life and longevity.

OXPHOS susceptibility to oxidative modifications: the role of heart mitochondrial subcellular location.

In cardiac tissue two mitochondria subpopulations, the subsarcolemmal and the intermyofibrillar mitochondria, present different functional emphasis, although limited information exists about the underlying molecular mechanisms. Our study evidenced higher OXPHOS activity of intermyofibrillar compared to subsarcolemmal mitochondria, paralleled by distinct membrane proteins susceptibility to oxidative damage and not to quantitative differences of OXPHOS composition. Indeed, subsarcolemmal subunits of respiratory chain complexes were more prone to carbonylation while intermyofibrillar mitochondria were more susceptible to nitration. Among membrane protein targets to posttranslational modifications, ATP synthase subunits alpha and beta were notoriously more carbonylated in both subpopulations, although more intensely in subsarcolemmal mitochondria. Our data highlight a localization dependence of cardiac mitochondria OXPHOS activity and susceptibility to posttranslational modifications.

Vitamin E prevents hypobaric hypoxia-induced mitochondrial dysfunction in skeletal muscle

In the present study, the effect of vitamin E (alpha-tocopherol) on mice skeletal muscle mitochondrial dysfunction and oxidative damage induced by an in vivo acute and severe hypobaric hypoxic insult (48 h at a barometric pressure equivalent to 8500 m) has been investigated. Male mice (n=24) were randomly divided into the following four groups (n=6): control (C), hypoxia (H), vitamin E (VE; 60 mg/kg of body weight intraperitoneally, three times/week for 3 weeks) and hypoxia+VE (HVE). A significant increase in mitochondrial protein CGs (carbonyl groups) was found in the H group compared with the C group. Confirming previous observations from our group, hypoxia induced mitochondrial dysfunction, as identified by altered respiratory parameters. Hypoxia exposure increased Bax content and decreased the Bcl-2/Bax ratio, whereas Bcl-2 remained unchanged. Inner and outer mitochondrial membrane integrity were significantly affected by hypoxia exposure; however, vitamin E treatment attenuated the effect of hypoxia on mitochondrial oxidative phosphorylation and on the levels of CGs. Vitamin E supplementation also prevented the Bax and Bcl-2/Bax ratio impairments caused by hypoxia, as well as the decrease in inner and outer mitochondrial membrane integrity. In conclusion, the results suggest that vitamin E prevents the loss of mitochondrial integrity and function, as well as the increase in Bax content, which suggests that mitochondria are involved in increased cell death induced by severe hypobaric hypoxia in mice skeletal muscle.

The Positive Effect of Moderate Walking Exercise on Chemerin Levels in Portuguese Patients With Type 2 Diabetes Mellitus

Background Physical exercise intervention is known to be crucial in the management of type 2 diabetes mellitus (T2DM). We aimed to evaluate, in patients with T2DM, the effect of regular moderate walking exercise on markers of oxidative stress, lipid metabolism, and inflammation. Methods We studied 30 patients with T2DM who walked regularly during the last year and 53 patients with T2DM who did not perform any type of exercise. The patients were evaluated for chemerin, adiponectin, leptin, oxidized low-density lipoprotein, and C-reactive protein (CRP) levels. Results The active T2DM patients showed significantly lower body mass index, as compared with the inactive patients. The active T2DM patients showed significantly lower levels of chemerin and CRP than those of the inactive T2DM patients (CRP lost significance after adjustment for body mass index). The active patients, compared with the inactive, presented a trend toward higher levels of adiponectin and lower values of oxidized low-density lipoprotein. Leptin differed significantly between sexes, and the active women presented a trend toward lower levels as compared with the inactive women. Conclusions In the patients with T2DM, the practice of moderate walking in a regular basis was sufficient to reduce chemerin levels, which suggests that practice of regular physical exercise should be encouraged.

Adipokines, Oxidized Low-Density Lipoprotein, and C-Reactive Protein Levels in Lean, Overweight, and Obese Portuguese Patients with Type 2 Diabetes

Aim. Our aim was to study how different BMI scores may influence the levels of inflammation, oxidative stress, adipogenesis, glucose, and lipid metabolism, in lean, overweight, and obese Portuguese patients with type 2 diabetes mellitus (T2DM). Methods. We studied 28 lean, 38 overweight, and 17 obese patients with T2DM and 20 controls (gender and age matched). The circulating levels of oxLDL, CRP, and some adipokines—adiponectin, leptin, and chemerin—and the lipid profile were evaluated. Results. Obese patients presented significantly lower levels of adiponectin and higher leptin, oxLDL, and chemerin levels, as compared to the overweight, lean, and control groups. Overweight, compared to lean and control, subjects showed significantly lower adiponectin and higher leptin and chemerin levels; oxLDL values were significantly higher in overweight than in lean patients. Lean patients presented significantly higher chemerin values than the control. Obese patients presented significantly higher CRP values, as compared to lean patients and the control group. Obese and overweight patients presented significantly higher triglycerides values than lean patients. Except for CRP, all the observed significant changes between control and patients remained significant after statistical adjustment for the body mass index (BMI). Conclusion. The levels of leptin, adiponectin, oxLDL, CRP, and triglycerides in patients with T2DM seem to be more associated with obesity and less with diabetes. Chemerin levels were raised in lean, overweight, and obese patients, suggesting that, independently of BMI, an adipocyte dysfunction occurs. Moreover, chemerin may provide an important early biomarker of adipocyte dysfunction and a link between obesity and type 2 diabetes mellitus.

Remodeling of liver phospholipidomic profile in streptozotocin-induced diabetic rats.

Lipid homeostasis in liver is known to be altered with diabetes mellitus, ultimately leading to liver damage and related complications. The present work aimed to evaluate changes in the liver phospholipid profile after 4 months of uncontrolled hyperglycemia. Twenty Wistar rats were divided into two groups: control and streptozotocin-treated (T1DM). After 4 months, animals were sacrificed and morphological characterization of liver was performed and related with serum markers of hepatic damage. Lipid extracts were obtained from liver and phospholipid (PL) classes were quantified. Lipid molecular species were determined by LC-MS and LC-MS/MS, and fatty acids by GC-MS. Concomitantly with signs of hepatic damage we found variations in the relative amount of phospholipid classes in T1DM, characterized by a decrease in PLs with choline head group, and by an increase in the relative content of other PL classes. A remodeling in PL fatty acyl chains was observed in T1DM liver, with a similar pattern to all the PL classes, and consisting in the reduction of 16:0 and an increase of 18:0 and 18:2 acyl chains. The observed changes in T1DM lipid profile may contribute to the altered membrane properties underlying hepatic damage, worsening the metabolic alterations that characterize T1DM.

Long-term exercise training prevents mammary tumorigenesis-induced muscle wasting in rats through the regulation of TWEAK signalling.

Exercise training has been suggested as a non‐pharmacological approach to prevent skeletal muscle wasting and improve muscle function in cancer cachexia. However, little is known about the molecular mechanisms underlying such beneficial effect. In this study, we aimed to, firstly, examine the contribution of TWEAK signalling to cancer‐induced skeletal muscle wasting and, secondly, evaluate whether long‐term exercise alters TWEAK signalling and prevents muscle wasting.

Systemic inflammation and proinflammatory interleukin-17 signalling persist at the end of therapy in patients with metabolic syndrome and psoriasis, reducing the length of remission

DEAR EDITOR, Psoriasis, a recurrent inflammatory skin condition, has been associated with metabolic syndrome (MS) and obesity. In psoriasis, obesity is closely related to hypoadiponectinaemia and hyperleptinaemia. High body mass index (BMI) adversely influences psoriasis therapy. C-reactive protein (CRP), a marker of psoriasis severity, and Psoriasis Area and Severity Index (PASI) are determinants of the length of psoriasis remission. CRP and pentraxin (PTX) 3, independent inflammatory markers of cardiovascular disease (CVD) risk, remain high after successful treatment. T helper (Th)17 and interleukin (IL)-17 signalling play crucial roles in psoriasis pathogenesis. Increased IL-17and Th17-related cytokines in psoriasis have led to the proposal of therapeutic agents targeting IL-17. Considering the overlap of inflammatory features in obesity and psoriasis, and the association of both conditions with CVD, we wondered about the impact of MS risk factors in psoriasis. We evaluated the levels of IL-17, inflammatory markers and adipokines before and after psoriasis treatment, in order to evaluate whether MS influences the response to treatment and the length of psoriasis remission. We studied 26 patients with psoriasis vulgaris in the active phase of psoriasis (T0) and 12 weeks after starting treatment (T12). Patients with MS (n = 10), according to the World Health Organization classification, presented insulin resistance and/or impaired glucose regulation – median glucose 175 mg dL 1 [interquartile range (IQR) 149–188] – with low levels of high-density lipoprotein (HDL) cholesterol (mean 37 3 mg dL ) and BMI ≥ 30 0 kg m 2 [median 30 8 kg m 2 (IQR 30 1–31 3)]. Patients without MS (n = 16) presented glucose 80 mg dL 1 (IQR 69–91), HDL cholesterol 52 9 mg dL 1 and BMI 24 4 kg m 2 (IQR 20 1–26 6). In the MS group, 30% of patients were treated with narrowband ultraviolet B (NB-UVB), 50% with psoralen plus UVA (PUVA) and 20% with topical therapy (calcipotriol and/ or betamethasone dipropionate). In the group without MS, 38% were treated with PUVA, 38% with NB-UVB and 25% with topical therapy. The treatment protocols have been described previously. After treatment, patients reached complete, or > 90%, clearance of lesions. When patients presented exacerbation of psoriasis lesions, needing another interventional therapy, the time since clearance of lesions was registered as the length of remission.

Inflammatory markers of cardiovascular disease risk in Portuguese psoriatic patients: relation with narrow-band ultraviolet B and psoralen plus ultraviolet A

Psoriasis is known to associate with cardiovascular disease (CVD) events, and patients with psoriasis present a high prevalence of CVD risk factors. Patients with high levels of C-reactive protein (CRP), a short-chain pentraxin produced in the liver, have an increased risk for adverse cardiovascular outcome. Increased CRP has been recognized as a direct contributor to atherosclerosis, and it is one of the strongest predictors of coronary artery disease and mortality risk. Pentraxin 3 (PTX3) is a long-chain pentraxin produced by macrophages, dendritic cells, and endothelial cells, in response to inflammatory signals. High PTX3 levels have been associated with cardiovascular events. The association of PTX3 with CVD and with all causes of death is independent of CRP and other CVD risk factors; indeed, PTX3 seems to reflect aspects of the inflammatory process that are different for CRP. Increased levels of both inflammatory markers, PTX3 and CRP, have been reported in patients with psoriasis. Indeed, Bevelacqua et al. and Ctirad et al. reported that CRP and PTX3 are increased at psoriasis exacerbation stage. However, their data concerning correlation of Psoriasis Area and Severity Index (PASI) with PTX3 was not consensual; the first group found a positive significant correlation between PTX3 levels and PASI, but the second did not observe any correlation between them. Ctirad et al. found that Goeckermans therapy, the combination of coal tar with ultraviolet B (UVB), decreased PTX3 and CRP levels significantly. We aimed to clarify these findings by studying the effect of narrow-band UVB (NB-UVB) and psoralen plus UVA (PUVA) therapies on PTX3 and CRP levels. Thirty patients (18 women/12 men; 48.3 ± 14.7 years old), presenting moderate to severe psoriasis vulgaris