Bogdan Manolescu

Hepcidin – central regulator of iron metabolism

The knowledge about mammalian iron metabolism has advanced dramatically over the past decades. Studies of genetics, biochemistry and molecular biology allowed us the identification and characterization of many of the molecules involved in regulation of iron homeostasis. Important progresses were made after the discovery in 2000 of a small peptide – hepcidin – that has been proved to play a central role in orchestration on iron metabolism also providing a link between iron metabolism and inflammation and innate immunity. Hepcidin directly interacts with ferroportin (FPN), the only known mammalian iron exporter, which is expressed by enterocytes, macrophages and hepatocytes. The direct hepcidin–FPN interaction allows an adaptative response from the body in situations that alter normal iron homeostasis (hypoxia, anemia, iron deficiency, iron overload, and inflammation).

Natural compounds and the hypoxia-inducible factor (HIF) signalling pathway

A decline in the tissue oxygen level below normal leads to cellular hypoxia. This situation is very frequently encountered in solid tumors as existing blood vessels cannot satisfy the requirements in oxygen of the rapidly growing tumor. Like hyperoxia, hypoxia is a stress factor for cells and tissues. Adapting to this stressful situation leads to activation of the dimeric transcription factor hypoxia-inducible factor-1 (HIF-1) that induces gene expression in promoting tumor cell survival. In addition, hypoxia acts as a selection factor for radio- and chemotherapy resistant tumor cells with a high potential of malignancy. Consequently, over expression of the HIF-1alpha subunit is associated with an advanced disease stage and poor prognosis of cancer patients. During the last few years intense effort has been made in investigating natural compounds that can be used as HIF-1 inhibitors. These compounds aim to suppress tumor hypoxia and to increase the susceptibility of tumor cells to radio- and chemo-therapy. In this review we summarize recent findings concerning HIF-1 regulation and present a survey of HIF-1 inhibiting natural compounds that have been discovered in the last few years.

Review article: The role of adipose tissue in uraemia‐related insulin resistance

SUMMARY:  Adipose tissue is no longer considered to be an inert tissue of which function is to store fat. It actively secretes a number of biologic active compounds that are involved in the regulation of many processes like food intake, energy expenditure, metabolism homeostasis, immunity and blood pressure homeostasis. General metabolism alteration in patients with chronic kidney disease has a profound impact on biology of adipocytes. Chronic renal failure is a pathological condition, of which two major hallmarks are chronic inflammation and insulin resistance. In uraemic patients, adipose tissue became an important source of molecules that are responsible, at least in part, for the metabolic disturbances seen in these patients. Some of these molecules act as pro‐inflammatory agents contributing to the maintenance and enhancement of the chronic inflammatory response. These pro‐inflammatory molecules, along with other molecules secreted by the adipose tissue, have a central position in the aetiology of uraemia‐associated insulin resistance. In this review, we intend to summarize some aspects of the biology of adipokines in uraemia, with emphasis on the link between these molecules and insulin resistance.

Breaking down barriers to identify hemorrhagic transformation in ischemic stroke

Hemorrhagic transformation (HT) is a major complication in ischemic stroke, associated with increased morbidity and mortality. Identifying ischemic stroke patients at risk of HT could have substantial clinical implications, especially in the setting of thrombolytic therapy. Acute stroke patients at very high risk for HT could foreseeably have alternative treatment, such as a modified dose of thrombolytic agent or coadministration of a second agent able to reduce HT risk. In this issue of Neurology ®, Kazmierski et al.1 sought to predict clinical deterioration due to HT in ischemic stroke by measurements of proteins in blood. A total of 458 stroke patients were enrolled in their study, 85 of whom experienced clinical deterioration, and 33 of whom had HT. Stroke patients who developed HT had increased fasting glucose and decreased platelet count compared to those …

Dynamics of Inflammatory Markers in Post-Acute Stroke Patients Undergoing Rehabilitation

Stroke is a pathological condition associated with an enhanced inflammatory response that has a multifactorial etiology. We evaluated the dynamic of plasma concentrations of IL-1α, IL-6, IL-8, TNF-α, soluble form of intercellular adhesion molecule 1, and lipoprotein (a) [Lp(a)] during the rehabilitation of post-acute stroke patients (n = 20), in parallel with control subjects (n = 24). Stroke patients had significantly increased concentrations of IL-6, TNF-α, and Lp(a) when compared to healthy controls. It was found that the changes in the IL-6, IL-8, and TNF-α concentrations associated with the pathological condition were statistically significant (χ2 = 4.81, p = 0.028, χ2 = 10.40, p = 0.005 and χ2 = 6.73, p = 0.034, respectively). The decrease of Lp(a) during the rehabilitation had statistical significance (p = 0.043), while the decrease of IL-1α had marginal significance (p = 0.071). IL-1α, TNF-α, and Lp(a) concentrations were significantly negatively correlated with the Barthel index values, suggesting that the decrease of these inflammatory markers was beneficial for patients’ recovery.

New alternatives for erythropoietin therapy in chronic renal failure

Erythropoietin (EPO) is one of the main cytokines involved in the regulation of erythropoiesis. The main site of EPO production are the kidneys. An altered EPO production leads to pathological conditions such as anemia and polycythaemia. Due to the progressive loss of renal peritubular cells, patients with chronic kidney disease (CKD) have low EPO plasma levels. This decreases erythron stimulation with the direct consequence of developing anemia. Before the introduction in the clinical practice of rHuEpo, in the late 1980s, the only solution for treating this type of anemia were blood transfusions and anabolic steroids. Even rHuEpo has proven to be safe and effective for treatment of anemias, there are some concerns about its cost, the need for frequent parenteral administration, and development of anti-EPO antibodies. These inconveniences prompted the search for novel erythropoiesis stimulating agents. Different strategies lead to isolation or chemical synthesis of such agents as darbepoetin alfa and EPO mimetics. In this review, we present some general aspects of EPO biology, with emphasis on chronic renal failure, and expose some of the alternatives to EPO used for anemia correction.

Effect of the nutritional supplement ALAnerv® on the serum PON1 activity in post-acute stroke patients.

BACKGROUND Paraoxonase-1 (PON1) is one of the HDL-associated proteins which contributes to the antioxidant properties of these lipoproteins. The aim of this pilot study was to evaluate the effect of the nutritional supplement ALAnerv® on serum PON1 activity in post-acute stroke patients undergoing rehabilitation. METHODS We enrolled 28 post-acute stroke patients and randomly divided them into (-) ALA or (+) ALA study groups. All the patients underwent the same rehabilitation program and received comparable standard medications. Moreover, (+) ALA patients received ALAnerv® for two weeks (2 pills/day). The serum PON1 activity was assessed on blood samples taken at the admission and at the discharge moments, respectively. We used paraoxon (paraoxonase activity, PONA), phenyl acetate (arylesterase activity, ARYLA) and dihydrocoumarin (lactonase activity, LACTA) as substrates, the latter activity being regarded as physiologically relevant. A control group of 14 apparently healthy subjects was also created. RESULTS In the (+) ALA group, LACTA significantly increased during the study period (17.6 ± 3.2 vs. 27.6 ± 3.5, p = 0.002). Moreover, the percentage of LACTA variation between (-) ALA and (+) ALA groups during the study was also statistically different (-11.7 ± 6.9% vs. +95.1 ± 29.7%, p < 0.0001). CONCLUSIONS These preliminary results suggest that ALA nerv® could contribute to the improvement of the physiologically relevant LACTA of PON1 in post-acute stroke patients, enabling this enzyme to contribute to the redox correction. Also, this study raises the question about the effect of a longer treatment period over the other enzymatic activities of serum PON1.

The effect of the ALAnerv nutritional supplement on some oxidative stress markers in postacute stroke patients undergoing rehabilitation.

Stroke is a pathologic condition associated with redox imbalance. This pilot study was designed to evaluate the effect of the consumption of the nutritional supplement ALAnerv on some oxidative stress markers in postacute stroke patients undergoing rehabilitation. To achieve this goal, we assigned 28 patients to 2 study groups: (-)ALA and (+)ALA. Patients in both groups participated in the same rehabilitation program and received comparable standard medications; however, patients in the (+)ALA group received ALAnerv for 2 weeks (2 pills per day). We assessed total and nonproteic thiols, protein carbonyls, ceruloplasmin, oxidized low-density lipoprotein (LDL) particles, lipid hydroperoxide concentrations, gamma-glutamyl transpeptidase activity, and total antioxidant capacity. Regression analysis indicated that supplementation with ALAnerv was responsible for the significant decrease in glucose (p = 0.002) and oxidized LDL particles (p < 0.001) during the study period. For both parameters, the variation in the percent of concentration between the 2 groups during the study period reached statistical significance (p = 0.012 and p < 0.001, respectively). Moreover, Barthel Index values at discharge were significantly influenced by ALAnerv treatment. These preliminary results indicate that ALAnerv might be helpful because it rapidly corrects plasma fasting glucose and corrects serum oxidized LDL particle concentrations, suggesting the need for longer treatment with 2 pills or more per day.