Effects of Trehalose and Polyphenols in Vasculopathic Patients
Condition: Oxidative Stress; Cardiovascular Diseases
MeSH terms: Cardiovascular Diseases
Study type: Interventional

Summary: 
      Peripheral arterial disease (PAD) is an important manifestation of systemic atherosclerosis
      and is characterized by obstruction of the arteries of the lower extremities. PAD is usually
      associated with vascular complications that occur not only in peripheral circulation but also
      in cerebral and coronary trees (PubMed ID: 9892517). Endothelial dysfunction, reduced glucose
      oxidation, accumulation of toxic metabolites, alteration in nitric oxide (NO) generation and
      oxidative stress seem to play a role among the factors that contribute to reducing blood flow
      in PAD patients (PubMed ID: 17298965).

      Hypertension is a risk factor for vascular disorders, including PAD. In fact, it has been
      shown that 55% of PAD patients are hypertensive. (PubMed ID: 15579058) PAD and hypertension
      patients have a risk of cardiovascular and cerebrovascular mortality increased two to three
      times compared to healthy subjects. The alteration of platelet function is implicated in the
      development and progression of atherosclerosis, as well as in the pathogenesis of acute
      cardiac ischemic events. Platelet activation is increased in patients with PAD and
      hypertension compared to healthy controls, suggesting a pro-thrombotic state.

      Polyphenols are a class of natural, synthetic and semisynthetic substances with beneficial
      effects on human health. In particular, the polyphenols exert their beneficial effect through
      1) the inhibition of NADPH oxidase (Nox2), which is crucial for the formation of reactive
      oxygen species (ROS); 2) an antiplatelet effects 3) the activation of autophagy. Trehalose is
      a natural disaccharide that performs multiple functions such as a protective action against
      oxidative stress, temperature changes, accumulation of protein aggregates and dehydration.
      Furthermore, recent evidence has shown that trehalose could prevent inflammatory responses
      induced by endotoxic shock both in vivo and in vitro.

      Therefore the purpose of this work will be to determine in PAD and hypertension patients the
      effect of the intake of trehalose and a polyphenol mix on oxidative stress biomarkers,
      autophagic activity and endothelial dysfunction.
    

Detailed description: 
      Peripheral arterial disease (PAD) is an important manifestation of systemic atherosclerosis
      and is characterized by obstruction of the arteries of the lower limbs. PAD is usually
      associated with vascular complications that occur not only in peripheral circulation but also
      in cerebral and coronary trees (PubMed ID: 9892517). Intermittent claudication, the typical
      clinical manifestation of the disease that affects about a third of PAD patients, is
      identified by an alteration in blood flow to the lower extremities during exercise, worsens
      in 25% of patients and about 5% suffers an amputation (PubMed ID: 2647761). Arteries,
      arterioles, and capillaries that serve the skeletal muscle tissue distal to the site of the
      stenosis play a key role in the onset of claudication. Endothelial dysfunction, reduced
      glucose oxidation, accumulation of toxic metabolites, alteration in nitric oxide (NO)
      generation and oxidative stress seem to play a role among the factors that contribute to
      reducing blood flow in PAD patients (PubMed ID: 17298965). Nitric oxide (NO) is synthesized
      by L-arginine, is constitutively released by endothelial cells and serves to regulate
      vascular tone and to inhibit platelet function. NO is a potent anti-atherosclerotic molecule,
      as shown by an experimental study that shows that the integration of L-arginine reduces the
      progression of atherosclerosis. The generation of NO is reduced in patients with PAD and
      among the different mechanisms involved in the reduced generation of NO, the increase in
      oxidative stress could play a key role leading to accelerated degradation of NO or inhibition
      of NO synthase.

      Increased serum levels of isoprostanes and autoantibodies against low-density oxidized
      lipoproteins confirm the increase in oxidative stress in these patients. Furthermore, the
      role of oxidative stress is confirmed by an intervention study in which PAD patients treated
      with propionyl-L-carnitine (6 g / day) for 7 days significantly increased the maximum
      distance traveled (MWD), an increase in bioavailability of NO and a reduction in oxidative
      stress.

      The main risk factors involved in the onset of PAD include age, smoking, obesity,
      hyperlipemia and hypertension. Because hypertension is associated with the development of
      atherosclerosis, particularly in the coronary and cerebral circulation, it is also associated
      with an increased risk of developing PAD. In fact, of hypertensives at presentation, about
      2-5% have intermittent claudication, with increasing prevalence with age. Otherwise, 35-55%
      of patients with PAD at presentation also show hypertension. Therefore, treatment of
      hypertension could lead to a reduction in the incidence of PAD. (PubMed ID:15579058) PAD
      patients have a risk of cardiovascular and cerebrovascular mortality increased two to three
      times compared to healthy subjects. The alteration of platelet function is implicated in the
      development and progression of atherosclerosis, as well as in the pathogenesis of acute
      cardiac ischemic events. Platelet activation is increased in patients with lower limb
      ischemia compared to healthy controls since it suggests a pro-thrombotic state.

      Polyphenols are a class of natural, synthetic and semisynthetic molecules characterized by
      the presence of phenolic units. In recent decades, prospective and epidemiological studies
      that show potentially beneficial effects of these molecules on human health (for example on
      the cardiovascular and nervous systems). In particular, the polyphenols exert their
      beneficial effect through the inhibition of NADPH oxidase (Nox2), which is crucial for the
      formation of reactive oxygen species (ROS). There are several flavonoids that can exert
      antiplatelet effects for example by attenuating the process of platelet activation. Moreover,
      polyphenols can also exert beneficial effects through the activation of autophagy.

      Autophagy is an intracellular cytoprotective process that mediates protein degradation,
      organelle turnover, and recycling of cytoplasmic components in conditions of nutrient
      deprivation and cellular stress (PubMed ID: 15068787). Furthermore, autophagy plays an
      important role in the removal of excess cellular ROS by maintaining a redox balance (PubMed
      ID: 27200146). The degraded materials in the autophagosome are then used for anabolic
      reactions, to sustain energy levels and provide simple molecules deriving from the
      degradation process that can be reused by cells for other functions. Autophagy, therefore,
      helps cells adapt to energy and stress changes by supporting cellular metabolism,
      homeostasis, and survival (PubMed ID: 18006683). The insufficient autophagic activity can
      contribute to cell death. Several studies have shown that inhibition of autophagic flow can
      contribute to the pathogenesis of cardiovascular diseases, diabetes, inflammatory disorders,
      cancer and physical stress (PubMed ID: 18191218).

      Trehalose is a natural disaccharide composed of two glucose molecules linked by an
      α1-1-glycosidic bond, which is synthesized by lower organisms such as yeasts, insect
      bacteria, and plants but not by mammals. Trehalose performs multiple functions that
      distinguish it from other common disaccharides, including a protective action against various
      stressors, such as oxidative stress, temperature changes, accumulation of protein aggregates
      and dehydration (PubMed ID: 12626396). Furthermore, recent evidence has shown that trehalose
      could prevent inflammatory responses induced by endotoxic shock both in vivo and in vitro
      (PubMed ID: 17172986 and PubMed ID: 18555988). The oral administration of this disaccharide
      is able to drastically reduce the development and progression of neurodegenerative disorders,
      hepatic steatosis, renal damage, insulin resistance, atherosclerosis, post-ischemic cardiac
      remodelling and pancreatitis (PubMed ID: 22689910, PubMed ID: 21147367 and PubMed ID:
      29724354) mainly through the stimulation of autophagy. Indeed, it has been shown that
      trehalose is a strong inducer of autophagy (PubMed ID: 17182613 ). Furthermore, our
      preliminary in vitro data showed that trehalose in combination with a mix of polyphenols
      (catechin and epicatechin) can reduce platelet activation, and oxidative stress and improves
      autophagic flow. Finally, we observed in the endothelial cells that the mix could increase
      the production of NO, angiogenetic property and cell viability.
    

Intervention name(s): Supplementation with mix of threalose plus polyphenols; No Supplementation with mix of threalose plus polyphenols
Intervention type(s): Other; Other
Intervention description(s): The patients will be treated with a mix of trehalose plus polyphenols for 60 days; The patients will not be treated with a mix trehalose plus polyphenols for 60 days
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Single (Investigator)
Primary purpose: Treatment