Publications by authors named "Giuseppe Valacchi"

229 Publications

Early elevation of BACE1 in dementia.

Aging (Albany NY) 2021 Nov 29;13(22):24480-24481. Epub 2021 Nov 29.

Department of Translational Medicine and for Romagna, University of Ferrara, Ferrara 44121, Italy.

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http://dx.doi.org/10.18632/aging.203727DOI Listing
November 2021

Oxidative metabolism in the cardiorespiratory system after an acute exposure to nickel-doped nanoparticles in mice.

Toxicology 2021 Dec 2;464:153020. Epub 2021 Nov 2.

Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Química Analítica y Fisicoquímica, Cátedra de Química General e Inorgánica, Argentina; Universidad de Buenos Aires, CONICET, Instituto de Bioquímica y Medicina Molecular (IBIMOL), Facultad de Farmacia y Bioquímica, Argentina. Electronic address:

There is an increasing concern over the harmful effects that metallic nanoparticles (NP) may produce on human health. Due to their redox properties, nickel (Ni) and Ni-containing NP are particularly relevant. Hence, the aim of this study was to establish the toxicological mechanisms in the cardiorespiratory oxidative metabolism initiated by an acute exposure to Ni-doped-NP. Mice were intranasally instilled with silica NP containing Ni (II) (Ni-NP) (1 mg Ni (II)/kg body weight) or empty NP as control, and 1 h after exposure lung, plasma, and heart samples were obtained to assess the redox metabolism. Results showed that, NP were mainly retained in the lungs triggering a significantly increased tissue O consumption rate, leading to Ni-NP-increased reactive oxygen species production by NOX activity, and mitochondrial HO production rate. In addition, an oxidant redox status due to an altered antioxidant system showed by lung GSH/GSSG ratio decreased, and SOD activity increased, resulting in an increased phospholipid oxidation. Activation of circulating polymorphonuclear leukocytes, along with GSH/GSSG ratio decreased, and phospholipid oxidation were found in the Ni-NP-group plasma samples. Consequently, in distant organs such as heart, Ni-NP inhalation alters the tissue redox status. Our results showed that the O metabolism analysis is a critical area of study following Ni-NP inhalation. Therefore, this work provides novel data linking the redox metabolisms alterations elicited by exposure to Ni (II) adsorbed to NP and cardiorespiratory toxicity.
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http://dx.doi.org/10.1016/j.tox.2021.153020DOI Listing
December 2021

"Plurethosome" as Vesicular System for Cutaneous Administration of Mangiferin: Formulative Study and 3D Skin Tissue Evaluation.

Pharmaceutics 2021 Jul 23;13(8). Epub 2021 Jul 23.

Department of Chemical and Pharmaceutical Sciences, University of Ferrara, I-44121 Ferrara, Italy.

Human skin is dramatically exposed to toxic pollutants such as ozone. To counteract the skin disorders induced by the air pollution, natural antioxidants such as mangiferin could be employed. A formulative study for the development of vesicular systems for mangiferin based on phosphatidylcholine and the block copolymer pluronic is described. Plurethosomes were designed for mangiferin transdermal administration and compared to ethosome and transethosome. Particularly, the effect of vesicle composition was investigated on size distribution, inner and outer morphology by photon correlation spectroscopy, small angle X-ray diffraction, and transmission electron microscopy. The potential of selected formulations as vehicles for mangiferin was studied, evaluating encapsulation efficiency and in vitro diffusion parameters by Franz cells. The mangiferin antioxidant capacity was verified by the 2,2-diphenyl-1-picrylhydrazyl assay. Vesicle size spanned between 200 and 550 nm, being influenced by phosphatidylcholine concentration and by the presence of polysorbate or pluronic. The vesicle supramolecular structure was multilamellar in the case of ethosome or plurethosome and unilamellar in the case of transethosome. A linear diffusion of mangiferin in the case of ethosome and transethosomes and a biphasic profile in the case of plurethosomes indicated the capability of multilamellar vesicles to retain the drug more efficaciously than the unilamellar ones. The antioxidant and anti-inflammatory potential effect of mangiferin against pollutants was evaluated on 3D human skin models exposed to O. The protective effect exerted by plurethosomes and transethosomes suggests their possible application to enhance the cutaneous antioxidant defense status.
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http://dx.doi.org/10.3390/pharmaceutics13081124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8398752PMC
July 2021

Mitochondrial involvement in the development and progression of diseases.

Arch Biochem Biophys 2021 10 13;711:109006. Epub 2021 Aug 13.

Department of Pathology and Biological Responses, Nagoya University Graduate School of Medicine, Nagoya, Japan; Center for Low-temperature Plasma Sciences, Nagoya University, Nagoya, Japan; Sydney Medical School, The University of Sydney, Sydney, NSW, Australia. Electronic address:

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http://dx.doi.org/10.1016/j.abb.2021.109006DOI Listing
October 2021

Gastrointestinal tissue as a "new" target of pollution exposure.

IUBMB Life 2021 Jul 21. Epub 2021 Jul 21.

Department of Animal Science, Plants for Human Health Institute, Kannapolis, North Carolina, USA.

Airborne pollution has become a leading cause of global death in industrialized cities and the exposure to environmental pollutants has been demonstrated to have adverse effects on human health. Among the pollutants, particulate matter (PM) is one of the most toxic and although its exposure has been more commonly correlated with respiratory diseases, gastrointestinal (GI) complications have also been reported as a consequence to PM exposure. Due to its composition, PM is able to exert on intestinal mucosa both direct damaging effects, (by reaching it either via direct ingestion of contaminated food and water or indirect inhalation and consequent macrophagic mucociliary clearance) and indirect ones via generation of systemic inflammation. The relationship between respiratory and GI conditions is well described by the lung-gut axis and more recently, has become even clearer during coronavirus disease 2019 (COVID-19) pandemic, when respiratory symptoms were associated with gastrointestinal conditions. This review aims at pointing out the mechanisms and the models used to evaluate PM induced GI tract damage.
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http://dx.doi.org/10.1002/iub.2530DOI Listing
July 2021

Novel Spray Dried Algae-Rosemary Particles Attenuate Pollution-Induced Skin Damage.

Molecules 2021 Jun 22;26(13). Epub 2021 Jun 22.

North Carolina Research Campus, Plants for Human Health Institute, Food, Bioprocessing & Nutrition Sciences, North Carolina State University, Kannapolis, NC 28081, USA.

The present study investigated the effect of spray-dried algae-rosemary particles against pollution-induced damage using ex-vivo human biopsies exposed to diesel engine exhaust (DEE). For this, the complexation of hydroalcoholic rosemary extract with Chlorella (RCH) and Spirulina (RSP) protein powders was conducted. The process efficiency and concentration of rosmarinic acid (RA), carnosic acid (CA), and carnosol (CR) phenolic compounds of both products were compared. The RSP spray-dried production was more efficient, and RSP particles presented higher CR and CA and similar RA concentrations. Therefore, spray-dried RSP particles were prioritized for the preparation of a gel formulation that was investigated for its ability to mitigate pollution-induced skin oxinflammatory responses. Taken altogether, our ex-vivo data clearly demonstrated the ability of RSP gel to prevent an oxinflammatory phenomenon in cutaneous tissue by decreasing the levels of 4-hydroxynonenal protein adducts (4HNE-PA) and active matrix metalloproteinase-9 (MMP-9) as well as by limiting the loss of filaggrin induced by DEE exposure. Our results suggest that the topical application of spirulina-rosemary gel is a good approach to prevent pollution-induced skin aging/damage.
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http://dx.doi.org/10.3390/molecules26133781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8270324PMC
June 2021

Altered Bone Status in Rett Syndrome.

Life (Basel) 2021 Jun 3;11(6). Epub 2021 Jun 3.

Animal Science Department, Plants for Human Health Institute, North Carolina State University, Kannapolis, NC 28081, USA.

Rett syndrome (RTT) is a monogenic neurodevelopmental disorder primarily caused by mutations in X-linked gene, encoding for methyl-CpG binding protein 2 (MeCP2), a multifaceted modulator of gene expression and chromatin organization. Based on the type of mutation, RTT patients exhibit a broad spectrum of clinical phenotypes with various degrees of severity. In addition, as a complex multisystem disease, RTT shows several clinical manifestations ranging from neurological to non-neurological symptoms. The most common non-neurological comorbidities include, among others, orthopedic complications, mainly scoliosis but also early osteopenia/osteoporosis and a high frequency of fractures. A characteristic low bone mineral density dependent on a slow rate of bone formation due to dysfunctional osteoblast activity rather than an increase in bone resorption is at the root of these complications. Evidence from human and animal studies supports the idea that mutation could be associated with altered epigenetic regulation of bone-related factors and signaling pathways, including SFRP4/WNT/β-catenin axis and RANKL/RANK/OPG system. More research is needed to better understand the role of MeCP2 in bone homeostasis. Indeed, uncovering the molecular mechanisms underlying RTT bone problems could reveal new potential pharmacological targets for the treatment of these complications that adversely affect the quality of life of RTT patients for whom the only therapeutic approaches currently available include bisphosphonates, dietary supplements, and physical activity.
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http://dx.doi.org/10.3390/life11060521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8230033PMC
June 2021

Cultivating a Three-dimensional Reconstructed Human Epidermis at a Large Scale.

J Vis Exp 2021 05 28(171). Epub 2021 May 28.

Dow Silicones Belgium SRL;

A three-dimensional human epidermis model reconstructed from neonatal primary keratinocytes is presented. Herein, a protocol for the cultivation process and the characterization of the model is described. Neonatal primary keratinocytes are grown submerged on permeable polycarbonate inserts and lifted to the air-liquid interface three days after seeding. After fourteen days of stimulation with defined growth factors and ascorbic acid in high calcium culture medium, the model is fully differentiated. Histological analysis revealed a completely stratified epidermis, mimicking the morphology of native human skin. To characterize the model and its barrier functions, protein levels and localization specific for early-stage keratinocyte differentiation (i.e., keratin 10), late-stage differentiation (i.e., involucrin, loricrin, and filaggrin) and tissue adhesion (i.e., desmoglein 1), were assessed by immunofluorescence. The tissue barrier integrity was further evaluated by measuring transepithelial electrical resistance. Reconstructed human epidermis was responsive to proinflammatory stimuli (i.e., lipopolysaccharide and tumor necrosis factor alpha), leading to increased cytokine release (i.e., interleukin 1 alpha and interleukin 8). This protocol represents a straightforward and reproducible in vitro method to cultivate reconstructed human epidermis as a tool to assess environmental effects and a broad range of skin-related studies.
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http://dx.doi.org/10.3791/61802DOI Listing
May 2021

Formulative Study and Intracellular Fate Evaluation of Ethosomes and Transethosomes for Vitamin D3 Delivery.

Int J Mol Sci 2021 May 19;22(10). Epub 2021 May 19.

Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, I-37134 Verona, Italy.

In this pilot study, ethosomes and transethosomes were investigated as potential delivery systems for cholecalciferol (vitamin D3), whose deficiency has been correlated to many disorders such as dermatological diseases, systemic infections, cancer and sarcopenia. A formulative study on the influence of pharmaceutically acceptable ionic and non-ionic surfactants allowed the preparation of different transethosomes. In vitro cytotoxicity was evaluated in different cell types representative of epithelial, connective and muscle tissue. Then, the selected nanocarriers were further investigated at light and transmission electron microscopy to evaluate their uptake and intracellular fate. Both ethosomes and transethosomes proven to have physicochemical properties optimal for transdermal penetration and efficient vitamin D3 loading; moreover, nanocarriers were easily internalized by all cell types, although they followed distinct intracellular fates: ethosomes persisted for long times inside the cytoplasm, without inducing subcellular alteration, while transethosomes underwent rapid degradation giving rise to an intracellular accumulation of lipids. These basic results provide a solid scientific background to in vivo investigations aimed at exploring the efficacy of vitamin D3 transdermal administration in different experimental and pathological conditions.
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http://dx.doi.org/10.3390/ijms22105341DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8161393PMC
May 2021

Ethosomes and Transethosomes for Mangiferin Transdermal Delivery.

Antioxidants (Basel) 2021 May 12;10(5). Epub 2021 May 12.

Department of Chemical, Pharmaceutical and Agricultural Sciences, University of Ferrara, I-44121 Ferrara, Italy.

Mangiferin is a natural glucosyl xanthone with antioxidant and anti-inflammatory activity, making it suitable for protection against cutaneous diseases. In this study ethosomes and transethosomes were designed as topical delivery systems for mangiferin. A preformulation study was conducted using different surfactants in association with phosphatidylcholine. Vesicle dimensional distribution was monitored by photon correlation spectroscopy, while antioxidant capacity and cytotoxicity were respectively assessed by free radical scavenging analysis and MTT on HaCaT keratinocytes. Selected nanosystems were further investigated by cryogenic transmission electron microscopy, while mangiferin entrapment capacity was evaluated by ultracentrifugation and HPLC. The diffusion kinetics of mangiferin from ethosomes and transethosomes evaluated by Franz cell was faster in the case of transethosomes. The suitability of mangiferin-containing nanovesicles in the treatment of skin disorders related to pollutants was investigated, evaluating, in vitro, the antioxidant and anti-inflammatory effect of ethosomes and transethosomes on human keratinocytes exposed to cigarette smoke as an oxidative and inflammatory challenger. The ability to induce an antioxidant response (HO-1) and anti-inflammatory status (IL-6 and NF-kB) was determined by RT-PCR and immunofluorescence. The data demonstrated the effectiveness of mangiferin loaded in nanosystems to protect cells from damage. Finally, to gain insight into the keratinocytes' uptake of ethosome and transethosome, transmission electron microscopy analyses were conducted, showing that both nanosystems were able to pass intact within the cells.
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http://dx.doi.org/10.3390/antiox10050768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8150765PMC
May 2021

BACE1: from biomarker to Alzheimer's disease therapeutical target.

Aging (Albany NY) 2021 05 11;13(9):12299-12300. Epub 2021 May 11.

Department of Translational Medicine and for Romagna, University of Ferrara, Ferrara, 44121, Italy.

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http://dx.doi.org/10.18632/aging.203064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8148506PMC
May 2021

BACE1 role in Alzheimer's disease and other dementias: from the theory to the practice.

Neural Regen Res 2021 Dec;16(12):2407-2408

Department of Translational Medicine and for Romagna, University of Ferrara, Ferrara, Italy.

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http://dx.doi.org/10.4103/1673-5374.313041DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8374572PMC
December 2021

Selective Fatty Acid Amide Hydrolase Inhibitors as Potential Novel Antiepileptic Agents.

ACS Chem Neurosci 2021 05 23;12(9):1716-1736. Epub 2021 Apr 23.

Laboratory of Neurophysiology, Department of Physiology and Biochemistry, Faculty of Medicine and Surgery, University of Malta, MSD2080 Msida, Malta.

Temporal lobe epilepsy is the most common form of epilepsy, and current antiepileptic drugs are ineffective in many patients. The endocannabinoid system has been associated with an on-demand protective response to seizures. Blocking endocannabinoid catabolism would elicit antiepileptic effects, devoid of psychotropic effects. We herein report the discovery of selective anandamide catabolic enzyme fatty acid amide hydrolase (FAAH) inhibitors with promising antiepileptic efficacy, starting from a further investigation of our prototypical inhibitor . When tested in two rodent models of epilepsy, reduced the severity of the pilocarpine-induced status epilepticus and the elongation of the hippocampal maximal dentate activation. Notably, did not affect hippocampal dentate gyrus long-term synaptic plasticity. These data prompted our further endeavor aiming at discovering new antiepileptic agents, developing a new set of FAAH inhibitors (-). Biological studies highlighted and as the best performing analogues to be further investigated. In cell-based studies, using a neuroblastoma cell line, and could reduce the oxinflammation state by decreasing DNA-binding activity of NF-kB p65, devoid of cytotoxic effect. Unwanted cardiac effects were excluded for (Langendorff perfused rat heart). Finally, the new analogue reduced the severity of the pilocarpine-induced status epilepticus as observed for .
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http://dx.doi.org/10.1021/acschemneuro.1c00192DOI Listing
May 2021

Cutaneous antimicrobial peptides: New "actors" in pollution related inflammatory conditions.

Redox Biol 2021 05 31;41:101952. Epub 2021 Mar 31.

Plants for Human Health Institute Animal Science Dept, NC Research Campus Kannapolis, NC, 28081, USA; Department of Neuroscience and Rehabilitation, University of Ferrara, Ferrara, Italy; JP Therrien Consulting, LLC, USA; Kyung Hee University, Department of Food and Nutrition, South Korea. Electronic address:

Ozone (O) exposure has been reported to contribute to various cutaneous inflammatory conditions, such as eczema, psoriasis, rush etc. via a redox-inflammatory pathway. O is too reactive to penetrate cutaneous tissue; it interacts with lipids present in the outermost layer of skin, resulting in formation of oxidized molecules and hydrogen peroxide (HO). Interestingly, several inflammatory skin pathologies demonstrate altered levels of antimicrobial peptides (AMPs). These small, cationic peptides are found in various cells, including keratinocytes, eccrine gland cells, and seboctyes. Classically, AMPs function as antimicrobial agents. Recent studies indicate that AMPs also play roles in inflammation, angiogenesis, and wound healing. Since altered levels of AMPs have been detected in pollution-associated skin pathologies, we hypothesized that exposure to O could affect the levels of AMPs in the skin. We examined levels of AMPs using qRT-PCR, Western blotting, and immunofluorescence in vitro (human keratinocytes), ex vivo (human skin explants), and in vivo (human volunteer subjects exposed to O) and observed increased levels of all the measured AMPs upon O exposure. In addition, in vitro studies have confirmed the redox regulation of AMPs in keratinocytes. This novel finding suggests that targeting AMPs could be a possible defensive strategy to combat pollution-associated skin conditions.
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http://dx.doi.org/10.1016/j.redox.2021.101952DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059092PMC
May 2021

Alterations in oxygen metabolism are associated to lung toxicity triggered by silver nanoparticles exposure.

Free Radic Biol Med 2021 04 14;166:324-336. Epub 2021 Feb 14.

Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Química Analítica y Fisicoquímica, Cátedra de Química General e Inorgánica, Argentina; Universidad de Buenos Aires, CONICET, Instituto de Bioquímica y Medicina Molecular (IBIMOL), Facultad de Farmacia y Bioquímica, Argentina. Electronic address:

Along with the AgNP applications development, the concern about their possible toxicity has increasingly gained attention. As the respiratory system is one of the main exposure routes, the aim of this study was to evaluate the harmful effects developed in the lung after an acute AgNP exposure. In vivo studies using Balb/c mice intranasally instilled with 0.1 mg AgNP/kg b.w, were performed. Tc-AgNP showed the lung as the main organ of deposition, where, in turn, AgNP may exert barrier injury observed by increased protein content and total cell count in BAL samples. In vivo acute exposure showed altered lung tissue O consumption due to increased mitochondrial active respiration and NOX activity. Both O consumption processes release ROS triggering the antioxidant system as observed by the increased SOD, catalase and GPx activities and a decreased GSH/GSSG ratio. In addition, increased protein oxidation was observed after AgNP exposure. In A549 cells, exposure to 2.5 μg/mL AgNP during 1 h resulted in augment NOX activity, decreased mitochondrial ATP associated respiration and higher HO production rate. Lung 3D tissue model showed AgNP-initiated barrier alterations as TEER values decreased and morphological alterations. Taken together, these results show that AgNP exposure alters O metabolism leading to alterations in oxygen metabolism lung toxicity. AgNP-triggered oxidative damage may be responsible for the impaired lung function observed due to alveolar epithelial injury.
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http://dx.doi.org/10.1016/j.freeradbiomed.2021.02.008DOI Listing
April 2021

Impaired mitochondrial quality control in Rett Syndrome.

Arch Biochem Biophys 2021 03 4;700:108790. Epub 2021 Feb 4.

Department of Biomedical and Specialist Surgical Sciences, University of Ferrara, Ferrara, Italy; Plants for Human Health Institute, Animal Science Dept., North Carolina State University, Kannapolis, NC, USA; Kyung Hee University, Department of Food and Nutrition, Seoul, South Korea. Electronic address:

Rett Syndrome (RTT) is a rare neurodevelopmental disorder caused in the 95% of cases by mutations in the X-linked MECP2 gene, affecting almost exclusively females. While the genetic basis of RTT is known, the exact pathogenic mechanisms that lead to the broad spectrum of symptoms still remain enigmatic. Alterations in the redox homeostasis have been proposed among the contributing factors to the development and progression of the syndrome. Mitochondria appears to play a central role in RTT oxidative damage and a plethora of mitochondrial defects has already been recognized. However, mitochondrial dynamics and mitophagy, which represent critical pathways in regulating mitochondrial quality control (QC), have not yet been investigated in RTT. The present work showed that RTT fibroblasts have networks of hyperfused mitochondria with morphological abnormalities and increased mitochondrial volume. Moreover, analysis of mitophagic flux revealed an impaired PINK1/Parkin-mediated mitochondrial removal associated with an increase of mitochondrial fusion proteins Mitofusins 1 and 2 (MFN1 and 2) and a decrease of fission mediators including Dynamin related protein 1 (DRP1) and Mitochondrial fission 1 protein (FIS1). Finally, challenging RTT fibroblasts with FCCP and 2,4-DNP did not trigger a proper apoptotic cell death due to a defective caspase 3/7 activation. Altogether, our findings shed light on new aspects of mitochondrial dysfunction in RTT that are represented by defective mitochondrial QC pathways, also providing new potential targets for a therapeutic intervention aimed at slowing down clinical course and manifestations in the affected patients.
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http://dx.doi.org/10.1016/j.abb.2021.108790DOI Listing
March 2021

Connection between the Altered HDL Antioxidant and Anti-Inflammatory Properties and the Risk to Develop Alzheimer's Disease: A Narrative Review.

Oxid Med Cell Longev 2021 8;2021:6695796. Epub 2021 Jan 8.

Department of Morphology, Surgery and Experimental Medicine, University of Ferrara, 44121 Ferrara, Italy.

The protein composition of high-density lipoprotein (HDL) is extremely fluid. The quantity and quality of protein constituents drive the multiple biological functions of these lipoproteins, which include the ability to contrast atherogenesis, sustained inflammation, and toxic effects of reactive species. Several diseases where inflammation and oxidative stress participate in the pathogenetic process are characterized by perturbation in the HDL proteome. This change inevitably affects the functionality of the lipoprotein. An enlightening example in this frame comes from the literature on Alzheimer's disease (AD). Growing lines of epidemiological evidence suggest that loss of HDL-associated proteins, such as lipoprotein phospholipase A2 (Lp-PLA2), glutathione peroxidase-3 (GPx-3), and paraoxonase-1 and paraoxonase-3 (PON1, PON3), may be a feature of AD, even at the early stage. Moreover, the decrease in these enzymes with antioxidant/defensive action appears to be accompanied by a parallel increase of prooxidant and proinflammatory mediators, in particular myeloperoxidase (MPO) and serum amyloid A (SAA). This type of derangement of balance between two opposite forces makes HDL dysfunctional, i.e., unable to exert its "natural" vasculoprotective property. In this review, we summarized and critically analyzed the most significant findings linking HDL accessory proteins and AD. We also discuss the most convincing hypothesis explaining the mechanism by which an observed systemic occurrence may have repercussions in the brain.
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http://dx.doi.org/10.1155/2021/6695796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7811424PMC
September 2021

Inflammasome Activation in Pollution-Induced Skin Conditions.

Plast Reconstr Surg 2021 01;147(1S-2):15S-24S

From the Plants for Human Health Institute, North Carolina State University, Department of Animal Science Department of Biomedical and Specialist Surgical Sciences, University of Ferrara; and Department of Food and Nutrition, Kyung Hee University, Seoul.

Summary: Exposure to air pollutants has been now associated with detrimental effects on a variety of organs, including the heart, lungs, GI tract, and brain. However, recently it has become clear that pollutant exposure can also promote the development/exacerbation of a variety of skin conditions, including premature aging, psoriasis, acne, and atopic dermatitis. Although the molecular mechanisms by which pollutant exposure results in these cutaneous pathological manifestations, it has been noticed that an inflammatory status is a common denominator of all those skin conditions. For this reason, recently, the activation of a cytosolic multiprotein complex involved in inflammatory responses (the inflammasome) that could promote the maturation of proinflammatory cytokines interleukin-1β and interleukin-18 has been hypothesized to play a key role in pollution-induced skin damage. In this review, we summarize and propose the cutaneous inflammasome as a novel target of pollutant exposure and the eventual usage of inflammasome inhibitor as new technologies to counteract pollution-induced skin damage. Possibly, the ability to inhibit the inflammasome activation could prevent cutaneous inflammaging and ameliorate the health and appearance of the skin.
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http://dx.doi.org/10.1097/PRS.0000000000007617DOI Listing
January 2021

Evaluating the effect of ozone in UV induced skin damage.

Toxicol Lett 2021 Mar 3;338:40-50. Epub 2020 Dec 3.

Plants for Human Health Institute Animal Science Dept., NC Research Campus Kannapolis, NC, 28081, United States; Department of Life Sciences and Biotechnology, University of Ferrara, Ferrara, Italy; Kyung Hee University, Department of Food and Nutrition, South Korea. Electronic address:

Air pollution represents one of the main risks for both environment and human health. The rapid urbanization has been leading to a continuous release of harmful manmade substances into the atmosphere which are associated to the exacerbation of several pathologies. The skin is the main barrier of our body against the external environment and it is the main target for the outdoor stressors. Among the pollutants, Ozone (O) is one of the most toxic, able to initiate oxidative reactions and activate inflammatory response, leading to the onset of several skin conditions. Moreover, skin is daily subjected to the activity of Ultraviolet Radiation which are well known to induce harmful cutaneous effects including skin aging and sunburn. Even though both UV and O are able to affect the skin homeostasis, very few studies have investigated their possible additive effect. Therefore, in this study we evaluated the effect of the combined exposure of O and UV in inducing skin damage, by exposing human skin explants to UV alone or in combination with O for 4-days. Markers related to inflammation, redox homeostasis and tissue structure were analyzed. Our results demonstrated that O is able to amplify the UV induced skin oxinflammation markers.
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http://dx.doi.org/10.1016/j.toxlet.2020.11.023DOI Listing
March 2021

A proteomics approach to further highlight the altered inflammatory condition in Rett syndrome.

Arch Biochem Biophys 2020 12 5;696:108660. Epub 2020 Nov 5.

Plants for Human Health Institute, Animal Science Dept., NC Research Campus, NC State University, 600 Laureate Way, Kannapolis, NC, 28081, USA; Department of Biomedical and Specialist Surgical Sciences, University of Ferrara, Ferrara, Italy; Kyung Hee University, Department of Food and Nutrition, Seoul, South Korea. Electronic address:

Rett syndrome (RTT) is a progressive neurodevelopmental disorder caused by mutations in the X-linked MECP2 gene. RTT patients show multisystem disturbances associated with perturbed redox homeostasis and inflammation, which appear as possible key factors in RTT pathogenesis. In this study, using primary dermal fibroblasts from control and RTT subjects, we performed a proteomic analysis that, together with data mining approaches, allowed us to carry out a comprehensive characterization of RTT cellular proteome. Functional and pathway enrichment analyses showed that differentially expressed proteins in RTT were mainly enriched in biological processes related to immune/inflammatory responses. Overall, by using proteomic data mining as supportive approach, our results provide a detailed insight into the molecular pathways involved in RTT immune dysfunction that, causing tissue and organ damage, can increase the vulnerability of affected patients to unknown endogenous factors or infections.
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http://dx.doi.org/10.1016/j.abb.2020.108660DOI Listing
December 2020

Bench approaches to study the detrimental cutaneous impact of tropospheric ozone.

J Expo Sci Environ Epidemiol 2021 02 30;31(1):137-148. Epub 2020 Oct 30.

Dow Silicones Belgium SRL, Seneffe, Belgium.

Being exposed to ground-level ozone (O), as it is often the case in polluted cities, is known to have a detrimental impact on skin. O induces antioxidant depletion and lipid peroxidation in the upper skin layers and this effect has repercussions on deeper cellular layers, triggering a cascade of cellular stress and inflammatory responses. Repetitive exposure to high levels of O may lead to chronic damages of the cutaneous tissue, cause premature skin aging and aggravate skin diseases such as contact dermatitis and urticaria. This review paper debates about the most relevant experimental approaches that must be considered to gather deeper insights about the complex biological processes that are activated when the skin is exposed to O. Having a better understanding of O effects on skin barrier properties and stress responses could help the whole dermato-cosmetic industry to design innovative protective solutions and develop specific cosmetic regime to protect the skin of every citizen, especially those living in areas where exposure to high levels of O is of concern to human health.
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http://dx.doi.org/10.1038/s41370-020-00275-4DOI Listing
February 2021

SARS-CoV-2 infection, COVID-19 pathogenesis, and exposure to air pollution: What is the connection?

Ann N Y Acad Sci 2021 02 6;1486(1):15-38. Epub 2020 Oct 6.

Animal Science Department, Plants for Human Health Institute, N.C. Research Campus, North Carolina State University, Kannapolis, North Carolina.

Exposure to air pollutants has been previously associated with respiratory viral infections, including influenza, measles, mumps, rhinovirus, and respiratory syncytial virus. Epidemiological studies have also suggested that air pollution exposure is associated with increased cases of SARS-CoV-2 infection and COVID-19-associated mortality, although the molecular mechanisms by which pollutant exposure affects viral infection and pathogenesis of COVID-19 remain unknown. In this review, we suggest potential molecular mechanisms that could account for this association. We have focused on the potential effect of exposure to nitrogen dioxide (NO ), ozone (O ), and particulate matter (PM) since there are studies investigating how exposure to these pollutants affects the life cycle of other viruses. We have concluded that pollutant exposure may affect different stages of the viral life cycle, including inhibition of mucociliary clearance, alteration of viral receptors and proteases required for entry, changes to antiviral interferon production and viral replication, changes in viral assembly mediated by autophagy, prevention of uptake by macrophages, and promotion of viral spread by increasing epithelial permeability. We believe that exposure to pollutants skews adaptive immune responses toward bacterial/allergic immune responses, as opposed to antiviral responses. Exposure to air pollutants could also predispose exposed populations toward developing COIVD-19-associated immunopathology, enhancing virus-induced tissue inflammation and damage.
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http://dx.doi.org/10.1111/nyas.14512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7675684PMC
February 2021

Postexercise Inflammasome Activation and IL-1β Production Mitigated by Flavonoid Supplementation in Cyclists.

Int J Sport Nutr Exerc Metab 2020 Sep 15:1-9. Epub 2020 Sep 15.

NC State University.

Inflammasomes are multiprotein signaling platforms of the innate immune system that detect markers of physiological stress and promote the maturation of caspase-1 and interleukin 1 beta (IL-1β), IL-18, and gasdermin D. This randomized, cross-over trial investigated the influence of 2-week mixed flavonoid (FLAV) versus placebo (PL) supplementation on inflammasome activation and IL-1β and IL-18 production after 75-km cycling in 22 cyclists (42 ± 1.7 years). Blood samples were collected before and after the 2-week supplementation, and then 0 hr, 1.5 hr, and 21 hr postexercise (176 ± 5.4 min, 73.4 ± 2.0 %VO2max). The supplement (678 mg FLAVs) included quercetin, green tea catechins, and bilberry anthocyanins. The pattern of change in the plasma levels of the inflammasome adaptor oligomer ASC (apoptosis-associated speck-like protein containing caspase recruitment domain) was different between the FLAV and PL trials, with the FLAV ASC levels 52% lower (Cohen's d = 1.06) than PL immediately following 75-km cycling (interaction effect, p = .012). The plasma IL-1β levels in FLAV were significantly lower than PL (23-42%; Cohen's d = 0.293-0.644) throughout 21 hr of recovery (interaction effect, p = .004). The change in plasma gasdermin D levels were lower immediately postexercise in FLAV versus PL (15% contrast, p = .023; Cohen's d = 0.450). The patterns of change in plasma IL-18 and IL-37 did not differ between the FLAV and PL trials (interaction effects, p = .388, .716, respectively). These data indicate that 2-week FLAV ingestion mitigated inflammasome activation, with a corresponding decrease in IL-1β release in cyclists after a 75-km cycling time trial. The data from this study support the strategy of ingesting high amounts of FLAV to mitigate postexercise inflammation.
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http://dx.doi.org/10.1123/ijsnem.2020-0084DOI Listing
September 2020

Increased blood BACE1 activity as a potential common pathogenic factor of vascular dementia and late onset Alzheimer's disease.

Sci Rep 2020 09 11;10(1):14980. Epub 2020 Sep 11.

Department of Morphology, Surgery, and Medical Sciences, University of Ferrara, Via Luigi Borsari 46, 44121, Ferrara, Italy.

Late onset Alzheimer disease (LOAD) is traditionally considered as a separate disease from vascular dementia (VAD). However, growing evidence suggests that β-amyloid (Aβ) accumulation, that initiates LOAD-related neurodegeneration, is preceded by vascular events. Previous in vitro studies showed that β-secretase 1 (BACE1), the key-enzyme of amyloidogenesis, is upregulated by cerebrovascular insult; moreover, its activity is increased both in brain and serum of LOAD patients. We aimed to investigate whether BACE1 serum activity is altered also in dementias related, or not, to cerebrovascular disease. Thus, we evaluated serum BACE1 activity in a sample of individuals, including patients with LOAD (n. 175), VAD (n. 40), MIXED (LOAD/VAD) dementia (n. 123), other types of dementia (n. 56), and healthy Controls (n. 204). We found that BACE1 was significantly higher not only in LOAD (+ 30%), but also in VAD (+ 35%) and MIXED dementia (+ 22%) (p < 0.001 for all), but not in the other types of dementia (+ 10%). Diagnostic accuracy was 77% for LOAD, 83% for VAD, and 77% for MIXED dementia. In conclusion, we showed for the first time that the increase in peripheral BACE1 activity is a common feature of LOAD and VAD, thus underlying a further pathogenic link between these two forms of dementia.
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http://dx.doi.org/10.1038/s41598-020-72168-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486910PMC
September 2020

Blueberry Extracts as a Novel Approach to Prevent Ozone-Induced Cutaneous Inflammasome Activation.

Oxid Med Cell Longev 2020 13;2020:9571490. Epub 2020 Aug 13.

Plants for Human Health Institute, Animal Sciences Dept., NC Research Campus Kannapolis, NC State University, 28081, NC, USA.

The World Health Organization estimates that 7 million people die every year due to pollution exposure. Among the different pollutants to which living organism are exposed, ozone (O) represents one of the most toxic, because its location which is the skin is one of the direct tissues exposed to the outdoor environment. Chronic exposure to outdoor stressors can alter cutaneous redox state resulting in the activation of inflammatory pathways. Recently, a new player in the inflammation mechanism was discovered: the multiprotein complex NLRP1 inflammasome, which has been shown to be also expressed in the skin. The topical application of natural compounds has been studied for the last 40 years as a possible approach to prevent and eventually cure skin conditions. Recently, the possibility to use blueberry (BB) extract to prevent pollution-induced skin toxicity has been of great interest in the cosmeceutical industry. In the present study, we analyzed the cutaneous protective effect of BB extract in several skin models (2D, 3D, and human skin explants). Specifically, we observed that in the different skin models used, BB extracts were able to enhance keratinocyte wound closure and normalize proliferation and migration responses previously altered by O. In addition, pretreatment with BB extracts was able to prevent ozone-induced ROS production and inflammasome activation measured as NRLP1-ASC scaffold formation and also prevent the transcripts of key inflammasome players such as CASP1 and IL-18, suggesting that this approach as a possible new technology to prevent cutaneous pollution damage. Our data support the hypothesis that BB extracts can effectively reduce skin inflammation and be a possible new technology against cutaneous pollution-induced damage.
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http://dx.doi.org/10.1155/2020/9571490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443250PMC
May 2021

NADPH oxidase and mitochondria are relevant sources of superoxide anion in the oxinflammatory response of macrophages exposed to airborne particulate matter.

Ecotoxicol Environ Saf 2020 Dec 24;205:111186. Epub 2020 Aug 24.

Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Departamento de Química Analítica y Fisicoquímica, Cátedra de Química General e Inorgánica, Argentina; CONICET - Universidad de Buenos Aires, Instituto de Bioquímica y Medicina Molecular (IBIMOL), Facultad de Farmacia y Bioquímica, Argentina. Electronic address:

Exposure to ambient air particulate matter (PM) is associated with increased cardiorespiratory morbidity and mortality. In this context, alveolar macrophages exhibit proinflammatory and oxidative responses as a result of the clearance of particles, thus contributing to lung injury. However, the mechanisms linking these pathways are not completely clarified. Therefore, the oxinflammation phenomenon was studied in RAW 264.7 macrophages exposed to Residual Oil Fly Ash (ROFA), a PM surrogate rich in transition metals. While cell viability was not compromised under the experimental conditions, a proinflammatory phenotype was observed in cells incubated with ROFA 100 μg/mL, characterized by increased levels of TNF-α and NO production, together with PM uptake. This inflammatory response seems to precede alterations in redox metabolism, characterized by augmented levels of HO, diminished GSH/GSSG ratio, and increased SOD activity. This scenario resulted in increased oxidative damage to phospholipids. Moreover, alterations in mitochondrial respiration were observed following ROFA incubation, such as diminished coupling efficiency and spare respiratory capacity, together with augmented proton leak. These findings were accompanied by a decrease in mitochondrial membrane potential. Finally, NADPH oxidase (NOX) and mitochondria were identified as the main sources of superoxide anion () in our model. These results indicate that PM exposure induces direct activation of macrophages, leading to inflammation and increased reactive oxygen species production through NOX and mitochondria, which impairs antioxidant defense and may cause mitochondrial dysfunction.
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http://dx.doi.org/10.1016/j.ecoenv.2020.111186DOI Listing
December 2020

KRIT1 as a possible new player in melanoma aggressiveness.

Arch Biochem Biophys 2020 09 28;691:108483. Epub 2020 Jul 28.

Department of Biotechnology, Chemistry and Pharmacy, University of Siena, Italy. Electronic address:

Krev interaction trapped protein 1 (KRIT1) is a scaffold protein known to form functional complexes with distinct proteins, including Malcavernin, PDCD10, Rap1 and others. It appears involved in several cellular signaling pathways and exerts a protective role against inflammation and oxidative stress. KRIT1 has been studied as a regulator of endothelial cell functions and represents a determinant in the pathogenesis of Cerebral Cavernous Malformation (CCM), a cerebrovascular disease characterized by the formation of clusters of abnormally dilated and leaky blood capillaries, which predispose to seizures, neurological deficits and intracerebral hemorrhage. Although KRIT1 is ubiquitously expressed, few studies have described its involvement in pathologies other than CCM including cancer. Cutaneous melanoma represents the most fatal skin cancer due to its high metastatic propensity. Despite the numerous efforts made to define the signaling pathways activated during melanoma progression, the molecular mechanisms at the basis of melanoma growth, phenotype plasticity and resistance to therapies are still under investigation.
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http://dx.doi.org/10.1016/j.abb.2020.108483DOI Listing
September 2020

Impact of airborne particulate matter on skin: a systematic review from epidemiology to in vitro studies.

Part Fibre Toxicol 2020 07 25;17(1):35. Epub 2020 Jul 25.

Adolphe Merkle Institute, University of Fribourg, Chemin des Verdiers 4, CH-1700, Fribourg, Switzerland.

Background: Air pollution is killing close to 5 million people a year, and harming billions more. Air pollution levels remain extremely high in many parts of the world, and air pollution-associated premature deaths have been reported for urbanized areas, particularly linked to the presence of airborne nano-sized and ultrafine particles.

Main Text: To date, most of the research studies did focus on the adverse effects of air pollution on the human cardiovascular and respiratory systems. Although the skin is in direct contact with air pollutants, their damaging effects on the skin are still under investigation. Epidemiological data suggested a correlation between exposure to air pollutants and aggravation of symptoms of chronic immunological skin diseases. In this study, a systematic literature review was conducted to understand the current knowledge on the effects of airborne particulate matter on human skin. It aims at providing a deeper understanding of the interactions between air pollutants and skin to further assess their potential risks for human health.

Conclusion: Particulate matter was shown to induce a skin barrier dysfunction and provoke the formation of reactive oxygen species through direct and indirect mechanisms, leading to oxidative stress and induced activation of the inflammatory cascade in human skin. Moreover, a positive correlation was reported between extrinsic aging and atopic eczema relative risk with increasing particulate matter exposure.
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http://dx.doi.org/10.1186/s12989-020-00366-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7382801PMC
July 2020

Evaluation of oxidative damage and Nrf2 activation by combined pollution exposure in lung epithelial cells.

Environ Sci Pollut Res Int 2020 Sep 5;27(25):31841-31853. Epub 2020 Jun 5.

Department of Biomedical and Specialist Surgical Sciences, University of Ferrara, Ferrara, Italy.

The lungs are one the main organs exposed to environmental pollutants, such as tropospheric ozone (O) and particulate matter (PM), which induce lung pathologies through similar mechanisms, resulting in altered redox homeostasis and inflammation. Although numerous studies have investigated the effects of these pollutants in the respiratory tract, there are only a few evidences that have evaluated the combined effects of outdoor stressors, despite the fact that humans are consistently exposed to more pollutants simultaneously. In this study, we wanted to investigate whether exposure to PM and O could have an additive, noxious effect in lung epithelial cells by measuring oxidative damage and the activity of redox-sensitive nuclear factor erythroid 2-related factor 2 (Nrf2) which is a master regulator of cellular antioxidant defenses. First, we measured the cytotoxic effects of O and PM individually and in combination. We observed that both pollutants alone increased LDH release 24 h post-exposure. Interestingly, we did observe via TEM that combined exposure to O and PM resulted in increased cellular penetration of PM particles. Furthermore, we found that levels of 4-hydroxy-nonenal (4HNE), a marker of oxidative damage, significantly increased 24 h post-exposure, in response to the combined pollutants. In addition, we observed increased levels of Nrf2, in response to the combined pollutants vs. either pollutant, although this effect was not followed by the increase in Nrf2-responsive genes expression HO1, SOD1, GPX, or GR nor enzymatic activity. Despite these observations, our study suggests that O exposure facilitate the cellular penetration of the particles leading to an increased oxidative damage, and additive defensive response.
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http://dx.doi.org/10.1007/s11356-020-09412-wDOI Listing
September 2020
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