Serena Cabaro

Background/Objective: Cystic Fibrosis (CF) is a common, life-threatening genetic disorder that leads to progressive lung function decline, respiratory failure, and premature death. Musculoskeletal complications, affecting both peripheral and respiratory muscles, are major concerns in CF patients. Inflammatory cytokines seem to be responsible for the activation of the molecular pathways involved in the imbalance between protein synthesis and catabolism, with consequent loss of muscle mass and function. This study aims to assess the effects of amino acid supplements on functional status, muscle mass and strength, inflammation, and quality of life in adult CF patients. Methods: We conducted a randomized, double-blind, placebo-controlled pilot trial with 60 adult CF patients, aged 18 or older. Participants were randomly assigned to receive either amino acid supplementation or a placebo for 4 weeks. Physical function tests and self-assessment questionnaires on quality of life, global health, and sleep status, as well as blood samples to measure pro-inflammatory cytokines, were performed at baseline and after the treatment period. Results: The amino acid supplementation group showed a significant improvement in self-perceived physical performance and health status. Interleukin-6 serum levels were significantly reduced in this group compared to those who received the placebo (p = 0.042). Conclusions: Amino acid supplementation in adult CF patients improves self-perception of health status and may reduce systemic inflammation, significantly decreasing serum levels of Interleukin-6. This suggests potential benefits for the overall well-being of CF patients and a reduction in their inflammatory status.

Marine natural products constitute a great source of potential new antidiabetic drugs. The aim of this study was to evaluate the role of phosphoeleganin (PE), a polyketide purified from the Mediterranean ascidian Sidnyum elegans, and its derivatives PE/2 and PE/3 on insulin sensitivity in human hepatocellular carcinoma (HepG2) cells. In our experiments, insulin stimulates the phosphorylation of its receptor (INSR) and AKT by 1.5- and 3.5-fold, respectively, whereas in the presence of PE, PE/2, and PE/3, the insulin induced INSR phosphorylation is increased by 2.1-, 2-, and 1.5-fold and AKT phosphorylation by 7.1-, 6.0-, and 5.1-fold, respectively. Interestingly, PE and PE/2 have an additive effect on insulin-mediated reduction of phosphoenolpyruvate carboxykinase (PEPCK) expression. Finally, PE and PE/2, but not PE/3, decrease interleukin 6 (IL6) secretion and expression before and after palmitic acid incubation, while in the presence of high glucose (HG), only PE reduces IL6. Levels of other cytokines are not significantly affected by PE and its derivates. All these data suggest that PE and its synthetic-derived compound, PE/2, significantly decrease IL6 and improve hepatic insulin signaling. As IL6 impairs insulin action, it could be hypothesized that PE and PE/2, by inhibiting IL6, may improve the hepatic insulin pathway.

PREP1 is a homeodomain transcription factor that impairs metabolism and is involved in age-related aortic thickening. In this study, we evaluated the role of PREP1 on endothelial function. Mouse Aortic Endothelial Cells (MAECs) transiently transfected with a Prep1 cDNA showed a 1.5- and 1.6-fold increase in eNOS^Thr495 and PKCα phosphorylation, respectively. Proinflammatory cytokines Tnf-α and Il-6 increased by 3.5 and 2.3-fold, respectively, in the presence of Prep1, while the antioxidant genes Sod2 and Atf4 were significantly reduced. Bisindolylmaleimide reverted the effects induced by PREP1, suggesting PKCα to be a mediator of PREP1 action. Interestingly, resveratrol, a phenolic micronutrient compound, reduced the PREP1 levels, eNOS^Thr495, PKCα phosphorylation, and proinflammatory cytokines and increased Sod2 and Atf4 mRNA levels. The experiments performed on the aorta of 18-month-old Prep1 hypomorphic heterozygous mice (Prep1^i/+) expressing low levels of this protein showed a 54 and 60% decrease in PKCα and eNOS^Thr495 phosphorylation and a 45% reduction in Tnf-α levels, with no change in Il-6, compared to same-age WT mice. However, a significant decrease in Sod2 and Atf4 was observed in Prep1^i/+ old mice, indicating the lack of age-induced antioxidant response. These results suggest that Prep1 deficiency partially improved the endothelial function in aged mice and suggested PREP1 as a novel target of resveratrol.

In Alzheimer’s disease (AD), microglia, brain resident immune cells, become chronically inflammatory and neurotoxic. In recent years, neuroinflammation has attracted particular interest in the scientific community. The genetic variants of molecules associated with ‘‘microgliopathies’’, including the triggering receptor expressed in myeloid cells-2 (TREM2), result in increased risk of developing AD and cognitive decline. We performed a set of in vitro assays using human neuronal (SH-SY5Y) and microglial (BV2 and C13NJ) cell models. Cells were differentially treated with extra virgin olive oil (EVOO) polyphenols, oleuropein aglycone (OleA) and hydroxytyrosol (HT) before adding LPS. We evaluated the protective effects of these EVOO products by a set of biochemical and cell biology assays, including ELISA, MTT, ROS detection, Western blotting and immunofluorescence. Our results provide an integrated understanding of the neuroprotection exerted by polyphenols in terms of: (i) reduction of pro-inflammatory cytokines release (IL-6, IL-8, IP-10 and RANTES); (ii) activation of the TREM2-dependent anti-inflammatory pathway; (iii) enhancement of protective microglial activity favoring the M2 polarization phenotype. Such findings provide new and important insights into the mechanisms by which the dietary olive polyphenols exert beneficial properties against neuroinflammation and neuronal impairment.

Platelet products are commonly used in regenerative medicine due to their effects on the acceleration and promotion of wound healing, reduction of bleeding, synthesis of new connective tissue, and revascularization. Furthermore, a novel approach for the treatment of damaged tissues, following trauma or other pathological damages, is represented by the use of mesenchymal stem cells (MSCs). In dogs, both platelet-rich plasma (PRP) and MSCs have been suggested to be promising options for subacute skin wounds. However, the collection of canine PRP is not always feasible. In this study, we investigated the effect of human PRP (hPRP) on canine MSCs (cMSCs). We isolated cMSCs and observed that hPRP did not modify the expression levels of the primary class of major histocompatibility complex genes. However, hPRP was able to increase cMSC viability and migration by at least 1.5-fold. hPRP treatment enhanced both Aquaporin (AQP) 1 and AQP5 protein levels, and their inhibition by tetraethylammonium chloride led to a reduction of PRP-induced migration of cMSCs. In conclusion, we have provided evidence that hPRP supports cMSC survival and may promote cell migration, at least through AQP activation. Thus, hPRP may be useful in canine tissue regeneration and repair, placing as a promising tool for veterinary therapeutic approaches.

In March 2020, the World Health Organization Department declared the coronavirus (COVID-19) outbreak a global pandemic, as a consequence of its rapid spread on all continents. The COVID-19 pandemic has been not only a health emergency but also a serious general problem as fear of contagion and severe restrictions put economic and social activity on hold in many countries. Considering the close link between human and animal health, COVID-19 might infect wild and companion animals, and spawn dangerous viral mutants that could jump back and pose an ulterior threat to us. The purpose of this review is to provide an overview of the pandemic, with a particular focus on the clinical manifestations in humans and animals, the different diagnosis methods, the potential transmission risks, and their potential direct impact on the human–animal relationship.

Introduction: Hidradenitis suppurativa (HS) is a severe chronic inflammatory skin disease. Although the pathogenesis remains unclear, at the basis of HS there is an enhancement of the immune and inflammatory response together with a susceptibility to environmental factors. Cytokines dysregulation is crucial in HS severity and progression. Objectives: the aim of this study was to analyze serum levels of different cytokines focusing on adiponectin concentration and its oligomeric distribution in serum from HS patients compared to both obese and healthy subjects. Methods: The concentrations of adiponectin and cytokines were measured using ELISA assay; the oligomeric distribution of adiponectin was evaluated through Western Blotting analysis. Results: Total Adiponectin is statistically higher in HS patients compared to matched controls (28.54 ±4.49μg/mL vs 24.67±3.35 μg/mL, p=0.00). Interestingly, Adiponectin oligomerization state is altered in HS, with an increase of HMW oligomers. Serum levels of PDGF-BB, IL-1b, IL-5, Il-6, IL12, IL13, IL15, IL-17, GMCSF, INFg, VEGF and MCP-1 are statistically higher while IL-1ra and RANTES levels are statistically lower in HS patients compared to healthy controls. Interestingly, adiponectin positively correlates with PDGF-BB, and IL-13. Conclusions: HS patients have a dysregulated immune homeostasis correlated with altered metabolism. Indeed, our data suggest that Adiponectin and its HMW oligomers are involved in HS representing a potential biomarker of disease. In particular, the specific correlation of adiponectin with PDGF-BB, and IL-13 extends its role in modulation of immune responses suggesting that this adipokine might act regulating the innate immune system rather that the adaptive one.

Tight control of glycemia is a major treatment goal for type 2 diabetes mellitus (T2DM). Clinical studies indicated that factors other than poor glycemic control may be important in fostering T2DM progression. Increased levels of methylglyoxal (MGO) associate with complications development, but its role in the early steps of T2DM pathogenesis has not been defined. Here, we show that MGO accumulation induces an age‐dependent impairment of glucose tolerance and glucose‐stimulated insulin secretion in mice knockdown for glyoxalase 1 (Glo1KD). This metabolic alteration associates with the presence of insular inflammatory infiltration (F4/80‐positive staining), the islet expression of senescence markers, and higher levels of cytokines (MCP‐1 and TNF‐α), part of the senescence‐activated secretory profile, in the pancreas from 10‐month‐old Glo1KD mice, compared with their WT littermates. In vitro exposure of INS832/13 β‐cells to MGO confirms its casual role on β‐cell dysfunction, which can be reverted by senolytic treatment. These data indicate that MGO is capable to induce early phenotypes typical of T2D progression, paving the way for novel prevention approaches to T2DM.

The identification of novel strategies to control Helicobacter pylori (Hp)-associated chronic inflammation is, at present, a considerable challenge. Here, we attempt to combat this issue by modulating the innate immune response, targeting formyl peptide receptors (FPRs), G-protein coupled receptors that play key roles in both the regulation and the resolution of the innate inflammatory response. Specifically, we investigated, in vitro, whether Caulerpin—a bis-indole alkaloid isolated from algae of the genus Caulerpa—could act as a molecular antagonist scaffold of FPRs. We showed that Caulerpin significantly reduces the immune response against Hp culture filtrate, by reverting the FPR2-related signaling cascade and thus counteracting the inflammatory reaction triggered by Hp peptide Hp(2–20). Our study suggests Caulerpin to be a promising therapeutic or adjuvant agent for the attenuation of inflammation triggered by Hp infection, as well as its related adverse clinical outcomes.