A Combination of α-Lipoic Acid (ALA) and Palmitoylethanolamide (PEA) Blocks Endotoxin-Induced Oxidative Stress and Cytokine Storm: A Possible Intervention for COVID-19.

The global scientific community is striving to understand the pathophysiological mechanisms and develop effective therapeutic strategies for COVID-19. Despite overwhelming data, there is limited knowledge about the molecular mechanisms involved in the prominent cytokine storm syndrome and multiple organ failure and fatality in COVID-19 cases. The aim of this work is to investigate the possible role of of α-lipoic acid (ALA) and palmitoylethanolamide (PEA), in countering the mechanisms in overproduction of reactive oxygen species (ROS), and inflammatory cytokines. An in vitro model of lipopolysaccharide (LPS)-stimulated human epithelial lung cells that mimics the pathogen-associated molecular pattern and reproduces the cell signaling pathways in cytokine storm syndrome has been used. In this model of acute lung injury, the combination effects of ALAPEA, administered before and after LPS injury, were investigated. Our data demonstrated that a combination of 50 µM ALA + 5 µM PEA can reduce ROS and nitric oxide (NO) levels modulating the major cytokines involved on COVID-19 infection when administered either before or after LPS-induced damage. The best outcome was observed when administered after LPS, thus reinforcing the hypothesis that ALA combined with PEA to modulate the key point of cytokine storm syndrome. This work supports for the first time that the combination of ALA with PEA may represent a novel intervention strategy to counteract inflammatory damage related to COVID-19 by restoring the cascade activation of the immune response and acting as a powerful antioxidant.

Preventing c2c12 muscular cells damage combining magnesium and potassium with vitamin D3 and curcumin.

BACKGROUND AND AIM: Physical activity is defined as any bodily movement produced by skeletal muscles which causes energy consumption; moderate and constant physical activity is known to be beneficial and to slow the muscle loss process associated with aging. The aim of the present study was to test, in an in vitro exercise model, the biological effects of a new formulation composed of magnesium and potassium combined with vitamin D and curcumin created to support muscle activity and to prevent hypercontraction damage. EXPERIMENTAL PROCEDURE: C2C12 cells were treated with vitamin D, buffered magnesium bisglycinate, curcumin, and potassium citrate. Cell viability, morpho-functional changes, calcium and magnesium movements, and the main kinases involved in glucose uptake were analyzed. The glycogen level and lactate were also evaluated. RESULTS AND CONCLUSION: Important results about a positive effect on mitochondrial activity, ATP production, oxygen consumption and in the physiological differentiation of C2C12 cells were obtained. Further experiments were performed under conditions that mimic the biological aspects of strenuous exercise. The combination of magnesium, vitamin D3, curcumin, and potassium citrate revealed beneficial effects on skeletal muscle cells under physiological conditions as well as while mimicking intense activity. In particular, in an in vitro model, they were able to control the hypercontraction, restoring ion fluxes, reducing inflammation signaling and supporting the main mechanism involved on aerobic activity. Our results have indicated for the first time that this new combination could be considered as a new nutraceutical formulation to improve physical performance and muscle recovery.

Ovotransferrin Supplementation Improves the Iron Absorption: An In Vitro Gastro-Intestinal Model.

Transferrins constitute the most important iron regulation system in vertebrates and some invertebrates. Soluble transferrins, such as bovine lactoferrin and hen egg white ovotransferrin, are glycoproteins with a very similar structure with lobes that complex with iron. In this in vitro study, a comparison of bovine lactoferrin and ovotransferrin was undertaken to confirm the comparability of biological effects. An in vitro gastric barrier model using gastric epithelial cells GTL-16 and an in vitro intestinal barrier model using CaCo-2 cells was employed to evaluate iron absorption and barrier integrity. An analysis of the molecular pathways involving DMT-1 (divalent metal transporter 1), ferritin and ferroportin was also carried out. These in vitro data demonstrate the activity of both 15% saturated and 100% saturated ovotransferrin on the iron regulation system. Compared with the commercial bovine lactoferrin, both 15% saturated and 100% saturated ovotransferrin were found to act in a more physiological manner. Based on these data, it is possible to hypothesise that ovotransferrin may be an excellent candidate for iron supplementation in humans; in particular, 15% saturated ovotransferrin is the overall best performing product. In vivo studies should be performed to confirm this in vitro data.

Effects of a New Combination of Natural Extracts on Glaucoma-Related Retinal Degeneration.

BACKGROUND: Glaucoma is currently the leading cause of irreversible blindness; it is a neuropathy characterized by structural alterations of the optic nerve, leading to visual impairments. The aim of this work is to develop a new oral formulation able to counteract the early changes connected to glaucomatous degeneration. The composition is based on gastrodin and vitamin D3 combined with vitamin C, blackcurrant, and lycopene. METHODS: Cells and tissues of the retina were used to study biological mechanisms involved in glaucoma, to slow down the progression of the disease. Experiments mimicking the conditions of glaucoma were carried out to examine the etiology of retinal degeneration. RESULTS: Our results show a significant ability to restore glaucoma-induced damage, by counteracting ROS production and promoting cell survival by inhibiting apoptosis. These effects were confirmed by the intracellular mechanism that was activated following administration of the compound, either before or after the glaucoma induction. In particular, the main results were obtained as a preventive action of glaucoma, showing a beneficial action on all selected markers, both on cells and on eyecup preparations. It is therefore possible to hypothesize both the preventive and therapeutic use of this formulation, in the presence of risk factors, and due to its ability to inhibit the apoptotic cycle and to stimulate cell survival mechanisms, respectively. CONCLUSION: This formulation has exhibited an active role in the prevention or restoration of glaucoma damage for the first time.

Can Brain Health Be Supported by Vitamin D-Based Supplements? A Critical Review.

This review presents recent knowledge on the neuroprotective effects of vitamin D and their usefulness as oral supplementation when combined with other molecules, such as curcumin. A critical look at the effectiveness of vitamin D in this field is also provided. Vitamin D plays a crucial role in neuroprotection and in the cognitive decline associated with aging, where vitamin D's levels are related to the levels of several neurotrophic factors. An important role of vitamin D has also been observed in the mechanism of neuroinflammation, which is the basis of several aging conditions, including cognitive decline and neurodegeration; furthermore, the neuroprotective effect of vitamin D in the cognitive decline of aging has recently been reported. For this reason, many food supplements created for humans contain vitamin D alone or combined with other molecules with antioxidant properties. However, recent studies also explored negative consequences of the use at a high dosage of vitamin D. Vitamin D in tissues or brain cells can also modulate calbindin-D28K, parvalbumin, and calretinin, and is involved in immune function, thanks also to the combination with curcumin. Curcumin acts as a free radical scavenger and antioxidant, inhibiting lipid peroxidation and oxidative DNA damage. In particular, curcumin is a potent immune-regulatory agent and its administration has been reported to attenuate cognitive impairments. These effects could be exploited in the future to control the mechanisms that lead to the brain decay typical of neurodegenerative diseases.

The Role of BDNF on Aging-Modulation Markers.

An important link between brain aging and a class of growth/survival factors called neurotrophins has recently been demonstrated. In particular, brain-derived neurotrophic factor (BDNF) plays a fundamental role during age-related synaptic loss, preventing cerebral atrophy and cognitive decline. The aim of the present study was to investigate whether the use of low dose BDNF sequentially kinetic activated (SKA) was able to counteract some mechanisms underlying the degeneration and aging of nervous tissue by increasing endogenous protection mechanisms. Both in vitro and in vivo experiments were performed to assess the ability of BDNF SKA to protect and regenerate survival-related molecular pathways, studying intestinal absorption in vitro and brain function in vivo. Our pioneering results show that BDNF SKA is able to induce the endogenous production of BDNF, using its receptor TrkB and influencing the apolipoprotein E expression. Moreover, BDNF SKA exerted effects on ß-Amyloid and Sirtuin 1 proteins, confirming the hypothesis of a fine endogenous regulatory effect exerted by BDNF SKA in maintaining the health of both neurons and astrocytes. For this reason, a change in BDNF turnover is considered as a positive factor against brain aging.

Study of Magnesium Formulations on Intestinal Cells to Influence Myometrium Cell Relaxation.

Background: Magnesium is involved in a wide variety of physiological processes including direct relaxation of smooth muscle. A magnesium imbalance can be considered the primary cause or consequence of many pathophysiological conditions. The smooth muscle tissue of the uterus, i.e., the myometrium, undergoes numerous physiological changes during life, fundamental for uterine activities, and it receives proven benefits from magnesium supplementation. However, magnesium supplements have poor absorption and bioavailability. Furthermore, no data are available on the direct interaction between intestinal absorption of magnesium and relaxation of the myometrium. Methods: Permeability in human intestinal cells (Caco-2 cells) and direct effects on myometrial cells (PHM1-41 cells) of two different forms of magnesium, i.e., sucrosomial and bisglycinate, were studied in order to verify the magnesium capacity of modulate contractility. Cell viability, reactive oxygen species (ROS) and nitric oxide (NO) production, magnesium concentration, contractility, and pathways involved were analyzed. Results: Data showed a better influence of buffered chelate bisglycinate on intestinal permeability and myometrial relaxation over time with a maximum effect at 3 h and greater availability compared to the sucrosomial form. Conclusions: Magnesium-buffered bisglycinate chelate showed better intestinal absorption and myometrial contraction, indicating a better chance of effectiveness in human applications.