The Inhibition of Mitogen-Activated Protein Kinases (MAPKs) and NF-κB Underlies the Neuroprotective Capacity of a Cinnamon/Curcumin/Turmeric Spice Blend in Aß-Exposed THP-1 Cells.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by an increased level of ß-amyloid (Aß) protein deposition in the brain, yet the exact etiology remains elusive. Nowadays, treatments only target symptoms, thus the search for novel strategies is constantly stimulated, and looking to natural substances from the plant kingdom. The aim of this study was to investigate the neuroprotective effects of a spice blend composed of cinnamon bark and two different turmeric root extracts (CCSB) in Aß-exposed THP-1 cells as a model of neuroinflammation. In abiotic assays, CCSB demonstrated an antioxidant capacity up to three times stronger than Trolox in the ORAC assay, and it reduced reactive oxygen species (ROS) induced by the amyloid fragment in THP-1 cells by up to 39.7%. Moreover, CCSB lowered the Aß stimulated secretion of the pro-inflammatory cytokines IL-1ß and IL-6 by up to 24.9% and 43.4%, respectively, along with their gene expression by up to 25.2% and 43.1%, respectively. The mechanism involved the mitogen-activated protein kinases ERK, JNK and p38, whose phosphorylation was reduced by up to 51.5%, 73.7%, and 58.2%, respectively. In addition, phosphorylation of p65, one of the five components forming NF-κB, was reduced by up to 86.1%. Our results suggest that CCSB can counteract the neuroinflammatory stimulus induced by Aß-exposure in THP-1 cells, and therefore can be considered a potential candidate for AD management.

Anti-Aggregative and Protective Effects of Vicenin-2 on Heat and Oxidative Stress-Induced Damage on Protein Structures.

Vicenin-2, a flavonoid categorized as a flavones subclass, exhibits a distinctive and uncommon C-glycosidic linkage. Emerging evidence challenges the notion that deglycosylation is not a prerequisite for the absorption of C-glycosyl flavonoid in the small intestine. Capitalizing on this experimental insight and considering its biological attributes, we conducted different assays to test the anti-aggregative and antioxidant capabilities of vicenin-2 on human serum albumin under stressful conditions. Within the concentration range of 0.1-25.0 µM, vicenin-2 effectively thwarted the heat-induced HSA fibrillation and aggregation of HSA. Furthermore, in this study, we have observed that vicenin-2 demonstrated protective effects against superoxide anion and hydroxyl radicals, but it did not provide defense against active chlorine. To elucidate the underlying mechanisms, behind this biological activity, various spectroscopy techniques were employed. UV-visible spectroscopy revealed an interaction between HSA and vicenin-2. This interaction involves the cinnamoyl system found in vicenin-2, with a peak of absorbance observed at around 338 nm. Further evidence of the interaction comes from circular dichroism spectrum, which shows that the formation of bimolecular complex causes a reduction in α-helix structures. Fluorescence and displacement investigations indicated modifications near Trp214, identifying Sudlow's site I, similarly to the primary binding site. Molecular modeling revealed that vicenin-2, in nonplanar conformation, generated hydrophobic interactions, Pi-pi stacking, and hydrogen bonds inside Sudlow's site I. These findings expand our understanding of how flavonoids bind to HSA, demonstrating the potential of the complex to counteract fibrillation and oxidative stress.

Ferroptosis: Emerging Role in Diseases and Potential Implication of Bioactive Compounds.

Ferroptosis is a form of cell death that is distinguished from other types of death for its peculiar characteristics of death regulated by iron accumulation, increase in ROS, and lipid peroxidation. In the past few years, experimental evidence has correlated ferroptosis with various pathological processes including neurodegenerative and cardiovascular diseases. Ferroptosis also is involved in several types of cancer because it has been shown to induce tumor cell death. In particular, the pharmacological induction of ferroptosis, contributing to the inhibition of the proliferative process, provides new ideas for the pharmacological treatment of cancer. Emerging evidence suggests that certain mechanisms including the Xc- system, GPx4, and iron chelators play a key role in the regulation of ferroptosis and can be used to block the progression of many diseases. This review summarizes current knowledge on the mechanism of ferroptosis and the latest advances in its multiple regulatory pathways, underlining ferroptosis' involvement in the diseases. Finally, we focused on several types of ferroptosis inducers and inhibitors, evaluating their impact on the cell death principal targets to provide new perspectives in the treatment of the diseases and a potential pharmacological development of new clinical therapies.

AAPH-induced oxidative damage reduced anion exchanger 1 (SLC4A1/AE1) activity in human red blood cells: protective effect of an anthocyanin-rich extract.

Introduction: During their lifespan in the bloodstream, red blood cells (RBCs) are exposed to multiple stressors, including increased oxidative stress, which can affect their morphology and function, thereby contributing to disease. Aim: This investigation aimed to explore the cellular and molecular mechanisms related to oxidative stress underlying anion exchanger 1 activity (band 3, SLC4A1/AE1) in human RBCs. To achieve this aim, the relationship between RBC morphology and functional and metabolic activity has been explored. Moreover, the potential protective effect of an anthocyanin-enriched fraction extracted from Callistemon citrinus flowers was studied. Methods: Cellular morphology, parameters of oxidative stress, as well as the anion exchange capability of band 3 have been analyzed in RBCs treated for 1 h with 50 mM of the pro-oxidant 2,2'-azobis (2-methylpropionamide)-dihydrochloride (AAPH). Before or after the oxidative insult, subsets of cells were exposed to 0.01 µg/mL of an anthocyanin-enriched fraction for 1 h. Results: Exposure to AAPH caused oxidative stress, exhaustion of reduced glutathione, and over-activation of the endogenous antioxidant machinery, resulting in morphological alterations of RBCs, specifically the formation of acanthocytes, increased lipid peroxidation and oxidation of proteins, as well as abnormal distribution and hyper-phosphorylation of band 3. Expected, oxidative stress was also associated with a decreased band 3 ion transport activity and an increase of oxidized haemoglobin, which led to abnormal clustering of band 3. Exposure of cells to the anthocyanin-enriched fraction prior to, but not after, oxidative stress efficiently counteracted oxidative stress-related alterations. Importantly, protection of band3 function from oxidative stress could only be achieved in intact cells and not in RBC ghosts. Conclusion: These findings contribute a) to clarify oxidative stress-related physiological and biochemical alterations in human RBCs, b) propose anthocyanins as natural antioxidants to neutralize oxidative stress-related modifications, and 3) suggest that cell integrity, and therefore a cytosolic component, is required to reverse oxidative stress-related pathophysiological derangements in human mature RBCs.

Functionalization of Polyhydroxyalkanoates (PHA)-Based Bioplastic with Phloretin for Active Food Packaging: Characterization of Its Mechanical, Antioxidant, and Antimicrobial Activities.

The formulation of eco-friendly biodegradable packaging has received great attention during the last decades as an alternative to traditional widespread petroleum-based food packaging. With this aim, we designed and tested the properties of polyhydroxyalkanoates (PHA)-based bioplastics functionalized with phloretin as far as antioxidant, antimicrobial, and morpho-mechanic features are concerned. Mechanical and hydrophilicity features investigations revealed a mild influence of phloretin on the novel materials as a function of the concentration utilized (5, 7.5, 10, and 20 mg) with variation in FTIR e RAMAN spectra as well as in mechanical properties. Functionalization of PHA-based polymers resulted in the acquisition of the antioxidant activity (in a dose-dependent manner) tested by DPPH, TEAC, FRAR, and chelating assays, and in a decrease in the growth of food-borne pathogens (Listeria monocytogenes ATCC 13932). Finally, apple samples were packed in the functionalized PHA films for 24, 48, and 72 h, observing remarkable effects on the stabilization of apple samples. The results open the possibility to utilize phloretin as a functionalizing agent for bioplastic formulation, especially in relation to food packaging.

Catechins and Proanthocyanidins Involvement in Metabolic Syndrome.

Recent studies on natural antioxidant compounds have highlighted their potentiality against various pathological conditions. The present review aims to selectively evaluate the benefits of catechins and their polymeric structure on metabolic syndrome, a common disorder characterized by a cluster of three main risk factors: obesity, hypertension, and hyperglycemia. Patients with metabolic syndrome suffer chronic low inflammation state and oxidative stress both conditions effectively countered by flavanols and their polymers. The mechanism behind the activity of these molecules has been highlighted and correlated with the characteristic features present on their basic flavonoidic skelethon, as well as the efficient doses needed to perform their activity in both in vitro and in vivo studies. The amount of evidence provided in this review offers a starting point for flavanol dietary supplementation as a potential strategy to counteract several metabolic targets associated with metabolic syndrome and suggests a key role of albumin as flavanol-delivery system to the different target of action inside the organism.

Targets Involved in the Anti-Cancer Activity of Quercetin in Breast, Colorectal and Liver Neoplasms.

Phytochemicals have long been effective partners in the fight against several diseases, including cancer. Among these, flavonoids are valuable allies for both cancer prevention and therapy since they are known to influence a large panel of tumor-related processes. Particularly, it was revealed that quercetin, one of the most common flavonoids, controls apoptosis and inhibits migration and proliferation, events essential for the development of cancer. In this review, we collected the evidence on the anti-cancer activity of quercetin exploring the network of interactions between this flavonol and the proteins responsible for cancer onset and progression focusing on breast, colorectal and liver cancers, owing to their high worldwide incidence. Moreover, quercetin proved to be also a potentiating agent able to push further the anti-cancer activity of common employed anti-neoplastic agents, thus allowing to lower their dosages and, above all, to sensitize again resistant cancer cells. Finally, novel approaches to delivery systems can enhance quercetin's pharmacokinetics, thus boosting its great potentiality even further. Overall, quercetin has a lot of promise, given its multi-target potentiality; thus, more research is strongly encouraged to properly define its pharmaco-toxicological profile and evaluate its potential for usage in adjuvant and chemoprevention therapy.

The Neuroprotective Potentiality of Flavonoids on Alzheimer's Disease.

Alzheimer's disease (AD), due to its spread, has become a global health priority, and is characterized by senile dementia and progressive disability. The main cause of AD and other neurodegenerations (Huntington, Parkinson, Amyotrophic Lateral Sclerosis) are aggregated protein accumulation and oxidative damage. Recent research on secondary metabolites of plants such as polyphenols demonstrated that they may slow the progression of AD. The flavonoids' mechanism of action in AD involved the inhibition of acetylcholinesterase, butyrylcholinesterase, Tau protein aggregation, ß-secretase, oxidative stress, inflammation, and apoptosis through modulation of signaling pathways which are implicated in cognitive and neuroprotective functions, such as ERK, PI3-kinase/Akt, NFKB, MAPKs, and endogenous antioxidant enzymatic systems. This review focuses on flavonoids and their role in AD, in terms of therapeutic potentiality for human health, antioxidant potential, and specific AD molecular targets.