The mechanisms of progression from fatty liver to steatohepatitis and cirrhosis are not well elucidated. Mitochondrial dysfunction represents a key factor in the progression of non-alcoholic ...steatohepatitis (NASH) as mitochondria are the main cellular site of fatty acid oxidation, ATP synthesis and reactive oxygen species (ROS) production.
(1) To evaluate the role of the uncoupling protein 2 in controlling mitochondrial proton leak and ROS production in NASH rats and humans; and (2) to assess the acute liver damage induced by ischaemia-reperfusion in rats with NASH.
Mitochondria were extracted from the livers of NASH humans and rats fed a methionine and choline deficient diet. Proton leak, H(2)O(2) synthesis, reduced glutathione/oxidised glutathione, 4-hydroxy-2-nonenal (HNE)-protein adducts, uncoupling protein-2 (UCP2) expression and ATP homeostasis were evaluated before and after ischaemia-reperfusion injury.
NASH mitochondria exhibited an increased rate of proton leak due to upregulation of UCP2. These results correlated with increased production of mitochondrial hydrogen peroxide and HNE-protein adducts, and decreased hepatic ATP content that was not dependent on mitochondrial ATPase dysfunction. The application of an ischaemia-reperfusion protocol to these livers strongly depleted hepatic ATP stores, significantly increased mitochondrial ROS production and impaired ATPase activity. Livers from patients with NASH exhibited UCP2 over-expression and mitochondrial oxidative stress.
Upregulation of UCP2 in human and rat NASH liver induces mitochondrial uncoupling, lowers the redox pressure on the mitochondrial respiratory chain and acts as a protective mechanism against damage progression but compromises the liver capacity to respond to additional acute energy demands, such as ischaemia-reperfusion. These findings suggest that UCP2-dependent mitochondria uncoupling is an important factor underlying events leading to NASH and cirrhosis.
Mitochondrial dysfunction acts as a common pathogenetic mechanism in several acute and chronic liver diseases, such as Alcoholic and Non-Alcoholic Fatty Liver Disease (NAFLD), drug-induced ...steatohepatitis, viral hepatitis, biliary cirrhosis, hepatocellular carcinoma, ischemia/reperfusion injury and transplant rejection. In particular mitochondrial uncoupling,has been recently identified to play a determinant role in the pathogenesis of liver diseases by causing decrease of mitochondrial proton motive force and ATP depletion. Damaged mitochondria present defects in lipid homeostasis, bioenergetics impairment and overproduction of Reactive Oxygen Species (ROS), leading to lipid accumulation and oxidative stress. Dysfunctional and/or uncoupled mitochondria enhance the susceptibility of hepatocytes to cell death by necrosis, via ATP depletion, or by apoptosis, via membrane permeabilization. Thus, prevention of mitochondrial alterations promises to be an effective strategy for treatment of liver diseases. However, no therapy has proven to be absolutely effective, whereas those that are beneficial present several side effects. The present review summarizes the recent approaches in mitochondrial drug deliver systems and focuses on mitochondria-targeted molecules application in liver disease. New selective molecules and nanocarriers technology are also considered as potentially effective in the targeting of mitochondrial dysfunction in liver pathology.
Nutritional alterations are highly prevalent in older rather than adult hospitalized patients. In these subjects, a loss of physical performance is dependent on the impairment of muscle architecture. ...This study aimed to investigate the association between the nutritional status and muscle architecture in elderly patients hospitalized in internal medicine wards. 68 aged patients admitted in internal medicine wards were consecutively enrolled and stratified in three groups based on the Mini Nutritional Assessment (MNA) score: well-fed (WF), at risk of malnutrition (RM), and malnourished (M). Biochemical indices and anthropometric parameters were sampled at hospital admission. Furthermore, all patients were assessed at admission and after 7 days of hospitalization for muscle strength (hand-grip test), mass (bioimpedentiometry), and architecture (ultrasonography of vastus lateralis). At hospital admission, M patients showed lower percentage of fat free mass and muscle mass with respect to WF and RM. Furthermore, M group presented with lower muscle thickness and pennation angle, as compared to WF and RM. At admission, the MNA score was positively related to the pennation angle and muscle strength. Multivariate linear regression analysis showed that the nutritional status at admission was the only significant factor influencing pennation angle. Finally, during the first 7 days of hospitalization, a decrease of pennation angle occurred in all the groups studied. We conclude that malnutrition at admission is associated with impaired muscle architecture in elderly patients hospitalized in internal medicine wards. Moreover, muscle architecture is impacted by early hospitalization, irrespective of nutritional status.
Management of diabetes in older adults Sesti, G.; Antonelli Incalzi, R.; Bonora, E. ...
NMCD. Nutrition Metabolism and Cardiovascular Diseases,
March 2018, 2018-03-00, 20180301, Letnik:
28, Številka:
3
Journal Article
Recenzirano
Odprti dostop
Type 2 diabetes prevalence is high in older adults and is expected to rise in the next decades. Diabetes in the population of frail older adults is accompanied by functional disability, several ...comorbidities, and premature mortality. A comprehensive geriatric assessment, including functional, cognitive, mental and social status, is advisable for identifying the glycemic targets and glucose-lowering therapies, focused on patient preferences, needs, and risks. The therapeutic options for older adults with diabetes are like those for the adult population. However, the pharmacological treatments must be carefully prescribed and monitored, taking into consideration the patient cognitive capacities, the potentially life-threatening drug–drug interactions, the cardiovascular risk, and with the main goal of avoiding hypoglycemia. Also, a careful nutritional evaluation with appropriate tools, as well as a balanced and periodically monitored physical activity, contribute to an effective tailored care plan, as needed by older adults with diabetes. This review evaluates the currently available hypoglycemic drugs and the current indications to the Italian diabetology community, specifically with regard to the treatment of adults aged 75 years or older with diabetes, including the unmet needs by the guidelines.
Abstract This review summarizes available evidence on the beneficial effects of inorganic nitrates and the monounsaturated fatty acid (MUFA) oleic acid, largely contained in Mediterranean diet, on ...blood pressure and coagulation activity. Inorganic nitrate . Normal vascular function requires NO production from the 1 -arginine–NO synthase (NOS) pathway. This process is defective in conditions of local hypoxia, and here nitrite can substitute for 1 -arginine–NOS derived NO. In this context, NO generation from the nitrate–nitrite–NO pathway mostly derived from green leafy vegetables appears to be an alternative source for NOS-dependent NO production, ensuring NO bioavailability also in situations when the endogenous 1 -arginine/NO synthase pathway is dysfunctional or physiologically reduced in local hypoxic conditions. Olive oil and oleic acid . In addition to effects on lipoprotein metabolism and oxidation, the beneficial effects of oleic acid occur also on coagulation activity, namely on coagulation factor VII (FVII). Normally, a substantial increase of FVII coagulant activity (FVIIc) occurs within 2–3 h after a fatty meal and persists for several hours thereafter. When a background diet high in MUFA is consumed, a lower post-prandial increase of FVIIc takes place.
Pathological, genetic, biochemical and pharmacological studies support the hypothesis that brain accumulation of oligomeric species of beta-amyloid (Abeta) peptides may cause Alzheimer's disease ...(AD). Drugs currently used for the treatment of AD produce limited clinical benefits and do not treat the underlying causes of the disease. In the last 10 years, new therapeutic approaches targeting Abeta have been discovered and developed with the hope of modifying the natural history of the disease. Several active and passive immunotherapy approaches are under investigation in clinical trials with the aim of accelerating Abeta clearance from the brain of the AD patients. The most advanced of these immunological approaches is bapineuzumab, composed of humanized anti-Abeta monoclonal antibodies, that is being tested in two large late-stage trials. Compounds that interfere with proteases regulating Abeta formation from amyloid precursor protein (APP) are also actively pursued. Unfortunately, the most biologically attractive of these proteases, beta-secretase, that regulates the first step of the amyloidogenic APP metabolism, was found to be particularly problematic to block and only one compound (CTS21166) has reached clinical testing so far. Conversely, several inhibitors of gamma-secretase, the protease that regulates the last metabolic step generating Abeta, have been identified, the most advanced being LY-450139 (semagacestat), presently in Phase III clinical development. Compounds that stimulate alpha-secretase, the enzyme responsible for the non-amyloidogenic metabolism of APP, are also being developed one of them, EHT-0202, has recently started a Phase II study. Furthermore, brain penetrant inhibitors of Abeta aggregation have been identified and one of such compounds, PBT-2, has produced encouraging neuropsychological results in a recently completed Phase II study. With all these anti-Abeta approaches in clinical testing, we will know in few years if the Abeta hypothesis of AD is correct.
Abstract
Oxysterols are oxidized species of cholesterol coming from exogenous (e.g. dietary) and endogenous (in vivo) sources. They play critical roles in normal physiologic functions such as ...regulation of cellular cholesterol homeostasis. Most of biological effects are mediated by interaction with nuclear receptor LXRα, highly expressed in the liver as well as in many other tissues. Such interaction participates in the regulation of whole-body cholesterol metabolism, by acting as "lipid sensors". Moreover, it seems that oxysterols are also suspected to play key roles in several pathologies, including cardiovascular and inflammatory disease, cancer, and neurodegeneration. Growing evidence suggests that oxysterols may contribute to liver injury in non-alcoholic fatty liver disease. The present review focuses on the current status of knowledge on oxysterols' biological role, with an emphasis on LXR signaling and oxysterols' physiopathological relevance in NAFLD, suggesting new pharmacological development that needs to be addressed in the near future.
Due to early metastasis and delayed diagnosis, lung cancer is the leading cause of cancer-related deaths. Although the most common metastasis sites are brain, bone, lung, adrenal glands, liver, and ...extra-thoracic lymph node, soft tissues, such as skeletal muscles, skin, and subcutaneous tissues, can also be undermined. This article aims to report the first case of an asymptomatic radial extensor muscle metastasis generating from a lung adenocarcinoma that was diagnosed by ultrasound-guided fine-needle aspiration biopsy (FNAB).
ABSTRACT
Background Mitochondrial dysfunction is considered a key player in non‐alcoholic steatohepatitis (NASH) but no data are available on the mitochondrial function and ATP homeostasis in the ...liver during NASH progression. In the present paper we evaluated the hepatic mitochondrial respiratory chain activity and ATP synthesis in a rodent model of NASH development.
Materials and methods Male Wistar rats fed a High Fat/Methionine‐Choline Deficient (MCD) diet to induce NASH or a control diet (SHAM), and sacrificed after 3, 7 and 11 weeks. The oxidative phosphorylation, the F0F1ATPase (ATP synthase) and the ATP content were assessed in liver mitochondria.
Results NASH mitochondria exhibited an increased rate of substrate oxidation at 3 weeks, which returned to below the normal level at 7 and 11 weeks, concomitantly with the coupling between the phosphorylation activity and the mitochondrial respiration (ADP/O). Uncoupling of NASH liver mitochondria did not allow the recovery of the maximal respiration rate at 7 and 11 weeks. The ATPase (ATP synthase) activity was similar in NASH and SHAM rats, but the mitochondrial ATP content was significantly lower in NASH livers.
Conclusions The loss of hepatic ATP stores is not dependent on the F0F1‐ATPase but resides in the respiratory chain. Dysfunction of both Complex I and II of the mitochondrial respiratory chain during NASH development implies a mitochondrial adaptive mechanism occurring in the early stages of NASH.
PDF
