Publications by authors named "Milena Nasi"

103 Publications

Modulation of Tregs and iNKT by Fingolimod in Multiple Sclerosis Patients.

Cells 2021 11 26;10(12). Epub 2021 Nov 26.

Neurology Unit, Azienda Ospedaliero-Universitaria of Modena, 41126 Modena, Italy.

The altered numbers and functions of cells belonging to immunoregulatory cell networks such as T regulatory (Tregs) and invariant Natural Killer T (iNKT) cells have been reported in Multiple Sclerosis (MS), an immune-mediated disease. We aimed to assess the frequencies of Tregs and iNKT cells in MS patients throughout a one-year treatment with fingolimod (FTY) and to correlate immunological data with efficacy and safety data. The percentage of Tregs (defined as Live Dead-CD3 + CD4 + FoxP3 + CD25++/CD127- cells) increased steadily throughout the year, while there was no significant difference in the absolute number or percentage of iNKT cells (defined as CD3 + CD14-CD19- Vα24-Jα18 TCR+ cells). However, out of all the iNKT cells, the CD8+ iNKT and CD4-CD8- double-negative (DN) cell percentages steadily increased, while the CD4+ iNKT cell percentages decreased significantly. The mean percentage of CD8+ T cells at all time-points was lower in patients with infections throughout the study. The numbers and percentages of DN iNKT cells were more elevated, considering all time-points, in patients who presented a clinical relapse. FTY may, therefore, exert its beneficial effect in MS patients through various mechanisms, including the increase in Tregs and in iNKT subsets with immunomodulatory potential such as CD8+ iNKT cells. The occurrence of infections was associated with lower mean CD8+ cell counts during treatment with FTY.
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http://dx.doi.org/10.3390/cells10123324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8699557PMC
November 2021

Molecular Mechanisms of mtDNA-Mediated Inflammation.

Cells 2021 10 26;10(11). Epub 2021 Oct 26.

Department of Life Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy.

Besides their role in cell metabolism, mitochondria display many other functions. Mitochondrial DNA (mtDNA), the own genome of the organelle, plays an important role in modulating the inflammatory immune response. When released from the mitochondrion to the cytosol, mtDNA is recognized by cGAS, a cGAMP which activates a pathway leading to enhanced expression of type I interferons, and by NLRP3 inflammasome, which promotes the activation of pro-inflammatory cytokines Interleukin-1beta and Interleukin-18. Furthermore, mtDNA can be bound by Toll-like receptor 9 in the endosome and activate a pathway that ultimately leads to the expression of pro-inflammatory cytokines. mtDNA is released in the extracellular space in different forms (free DNA, protein-bound DNA fragments) either as free circulating molecules or encapsulated in extracellular vesicles. In this review, we discussed the latest findings concerning the molecular mechanisms that regulate the release of mtDNA from mitochondria, and the mechanisms that connect mtDNA misplacement to the activation of inflammation in different pathophysiological conditions.
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http://dx.doi.org/10.3390/cells10112898DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8616383PMC
October 2021

Mitochondrial DNA and Exercise: Implications for Health and Injuries in Sports.

Cells 2021 09 28;10(10). Epub 2021 Sep 28.

Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy.

Recently, several studies have highlighted the tight connection between mitochondria and physical activity. Mitochondrial functions are important in high-demanding metabolic activities, such as endurance sports. Moreover, regular training positively affects metabolic health by increasing mitochondrial oxidative capacity and regulating glucose metabolism. Exercise could have multiple effects, also on the mitochondrial DNA (mtDNA) and vice versa; some studies have investigated how mtDNA polymorphisms can affect the performance of general athletes and mtDNA haplogroups seem to be related to the performance of elite endurance athletes. Along with several stimuli, including pathogens, stress, trauma, and reactive oxygen species, acute and intense exercise also seem to be responsible for mtDNA release into the cytoplasm and extracellular space, leading to the activation of the innate immune response. In addition, several sports are characterized by a higher frequency of injuries, including cranial trauma, associated with neurological consequences. However, with regular exercise, circulating cell-free mtDNA levels are kept low, perhaps promoting cf-mtDNA removal, acting as a protective factor against inflammation.
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http://dx.doi.org/10.3390/cells10102575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8533813PMC
September 2021

Anti-GD2 CAR MSCs against metastatic Ewing's sarcoma.

Transl Oncol 2022 Jan 12;15(1):101240. Epub 2021 Oct 12.

Division of Oncology, Department of Medical and Surgical Sciences for Children & Adults, University-Hospital of Modena and Reggio Emilia, Modena, Italy; Rigenerand Srl, Medolla, Modena, Italy. Electronic address:

Background: Ewing's sarcoma (ES) is an aggressive cancer affecting children and young adults. We pre-clinically demonstrated that mesenchymal stromal/stem cells (MSCs) can deliver tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) against primary ES after local injection. However, ES is often metastatic calling for approaches able to support MSC targeting to the ES multiple remote sites. Considering that the disialoganglioside GD2 is expressed by ES and to optimise MSC tumour affinity, bi-functional (BF) MSCs expressing both TRAIL and a truncated anti-GD2 chimeric antigen receptor (GD2 tCAR) were generated and challenged against ES.

Methods: The anti-GD2 BF MSCs delivering a soluble variant of TRAIL (sTRAIL) were tested in several in vitro ES models. Tumour targeting and killing by BF MSCs was further investigated by a novel immunodeficient ES metastatic model characterized by different metastatic sites, including lungs, liver and bone, mimicking the deadly clinical scenario.

Findings: In vitro data revealed both tumour affinity and killing of BF MSCs. In vivo, GD2 tCAR molecule ameliorated the tumour targeting and persistence of BF MSCs counteracting ES in lungs but not in liver.

Interpretation: We here generated data on the potential effects of BF MSCs within a complex ES metastatic in vivo model, exploring also the biodistribution of MSCs. Our BF MSC-based strategy promises to pave the way for potential improvements in the therapeutic delivery of TRAIL for the treatment of metastatic ES and other deadly GD2-positive malignancies.
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http://dx.doi.org/10.1016/j.tranon.2021.101240DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8517927PMC
January 2022

Depression pandemic and cardiovascular risk in the COVID-19 era and long COVID syndrome: Gender makes a difference.

Trends Cardiovasc Med 2022 01 5;32(1):12-17. Epub 2021 Oct 5.

Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia, Modena, Italy; National Institute for Cardiovascular Research - INRC, Bologna, Italy.

The ongoing COVID-19 pandemic highlighted a significant interplay between cardiovascular disease (CVD), COVID-19 related inflammatory status, and depression. Cardiovascular (CV) injury is responsible for a substantial percentage of COVID-19 deaths while COVID-19 social restrictions emerged as a non-negligible risk factor for CVD as well as a variety of mental health issues, and in particular, depression. Inflammation seems to be a shared condition between these two disorders. Gender represents a potential modifying factor both in CVD and depression, as well as in COVID-19 short- and long-term outcomes, particularly in cases involving long-term COVID complications. Results from emerging studies indicate that COVID-19 pandemic affected male and female populations in different ways. Women seem to experience less severe short-term complications but suffer worse long-term COVID complications, including depression, reduced physical activity, and deteriorating lifestyle habits, all of which may impact CV risk. Here, we summarize the current state of knowledge about the interplay between COVID-19, depression, and CV risk in women.
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http://dx.doi.org/10.1016/j.tcm.2021.09.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8490128PMC
January 2022

Letter: Does Obesity Affect the Severity of Exercise-Induced Muscle Injury? (J Obes Metab Syndr 2021;30:132-40).

J Obes Metab Syndr 2021 Sep;30(3):312-314

Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.

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http://dx.doi.org/10.7570/jomes21050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8526289PMC
September 2021

Mitophagy and Oxidative Stress: The Role of Aging.

Antioxidants (Basel) 2021 May 17;10(5). Epub 2021 May 17.

Department of Life Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy.

Mitochondrial dysfunction is a hallmark of aging. Dysfunctional mitochondria are recognized and degraded by a selective type of macroautophagy, named mitophagy. One of the main factors contributing to aging is oxidative stress, and one of the early responses to excessive reactive oxygen species (ROS) production is the induction of mitophagy to remove damaged mitochondria. However, mitochondrial damage caused at least in part by chronic oxidative stress can accumulate, and autophagic and mitophagic pathways can become overwhelmed. The imbalance of the delicate equilibrium among mitophagy, ROS production and mitochondrial damage can start, drive, or accelerate the aging process, either in physiological aging, or in pathological age-related conditions, such as Alzheimer's and Parkinson's diseases. It remains to be determined which is the prime mover of this imbalance, i.e., whether it is the mitochondrial damage caused by ROS that initiates the dysregulation of mitophagy, thus activating a vicious circle that leads to the reduced ability to remove damaged mitochondria, or an alteration in the regulation of mitophagy leading to the excessive production of ROS by damaged mitochondria.
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http://dx.doi.org/10.3390/antiox10050794DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8156559PMC
May 2021

Microglia activation: a role for mitochondrial DNA?

Neural Regen Res 2021 Dec;16(12):2393-2394

Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia, via Campi, Modena, Italy.

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http://dx.doi.org/10.4103/1673-5374.313034DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8374575PMC
December 2021

Sex Difference in Access to Sports: A 1-Year Retrospective Study.

Am J Lifestyle Med 2021 Jan-Feb;15(1):108-112. Epub 2020 Dec 29.

Department of Surgery, Medicine, Dentistry and Morphological Sciences, University of Modena and Reggio Emilia, Modena, Italy (MN, AVM).

Regular physical activity is a cornerstone in the prevention and treatment of cardiovascular disease thanks to its anti-inflammatory effects. Thus, favoring the access to sports is of importance for promoting well-being. The aim of the present study was to investigate how the practice of different sports is distributed among different age groups and between men and women, by taking a picture of the medical certificate request in 2017 for sports in the population of the province of Modena, Italy. We analyzed the difference in distribution of requested medical certificate from 18 874 males and 7625 females stratified for age (<18 years, 18-40 years, and >40 years) and for different sporting disciplines (athletics, football, bike, swimming, basketball, volleyball, tennis, other team sports, other individual sports, and disabled sports). Men requested medical certificates more than women (more than 2.5 times). The distribution of requested certificates differs significantly (chi-square test < .0001) at different ages and between males and females of same age. Certificate for men aged less than 18 years were 7550 and for women were 4131 and the difference increase with age. . In order to decrease the imbalance between men and women access to sports, it is mandatory to promote a healthy lifestyle and reduce, as consequence, cardiovascular risks, mostly in women after 40 years.
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http://dx.doi.org/10.1177/1559827620911610DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781057PMC
December 2020

NLRP3 and IL-1β Gene Expression Is Elevated in Monocytes From HIV-Treated Patients With Neurocognitive Disorders.

J Acquir Immune Defic Syndr 2021 04;86(4):496-499

Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia, Modena, Italy.

Background: Systemic immune activation and inflammation in chronic HIV infection are driving factors of non-AIDS-related events, including neurocognitive impairment. The role of inflammasome in monocytes from patients with HIV infection has been extensively studied, but its association with the extent of neurocognitive dysfunction has been poorly investigated.

Methods: We enrolled 79 HIV-positive patients; 44 with varying levels of HIV-associated neurocognitive disorder (HAND) and 35 without and 8 healthy donors. HAND subtypes included asymptomatic neurocognitive impairment (asymptomatic neurocognitive impairment; n = 19), mild neurocognitive disorder (MND; n = 17), and HIV-associated dementia (n = 8). We quantified plasmatic concentrations of proinflammatory cytokines (TNF-α, IL-6, IL-17A, IL-1β, and IFN-γ) for all HIV patients, and the mRNA expression of genes involved in the inflammasome activity (NLRP3, PYCARD, NAIP, AIM2, IL-1β, and IL-18) in monocytes of a subgroup of 28 HIV patients and 8 healthy donors.

Results: HIV patients' plasma concentrations of IFN-γ, IL-1β, and IL-17A were undetectable. Levels of TNF-α and IL-6 were similar among the HIV patient groups. A trend toward an increased expression of inflammasome genes according to neurocognitive disorder severity was observed. Of note, the NLRP3 mRNA relative expression was higher in MND compared with other groups, and IL-1β was lower in MND than HIV-associated dementia patients.

Conclusions: Changes in inflammasome components in circulating monocytes according to different HAND severity suggest that NLRP3 may be a possible biomarker or target to better understand and treat the link between systemic inflammation and neurocognitive impairment in HIV infection.
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http://dx.doi.org/10.1097/QAI.0000000000002588DOI Listing
April 2021

Effects of whole-body cryotherapy on the innate and adaptive immune response in cyclists and runners.

Immunol Res 2020 12 7;68(6):422-435. Epub 2020 Nov 7.

Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia, Modena, Italy.

The study aimed to identify the effects of whole-body cryotherapy (WBC) on immunological, hormonal, and metabolic responses of non-professional male athletes. Ten cyclists and ten middle-distance runners received 3 once-a-day sessions of WBC. Before initiating and after the final WBC session, a full set of hematologic parameters, serum chemistry profile, hormones, circulating mitochondrial (mt) DNA levels, cytokines, and chemokines concentration were evaluated. The phenotype of monocyte, T cells, and B cells was analyzed. mRNA expression of 6 genes involved in inflammasome activation (NAIP, AIM2, NLRP3, PYCARD, IL-1β, and IL-18) was quantified. WBC reduced glucose and C and S protein and increased HDL, urea, insulin-like growth factor (IGF)-1, follicle-stimulating hormone, IL-18, IL-1RA, CCL2, and CXCL8. Intermediate and non-classical monocyte percentages decreased, and the CD14, CCR5, CCR2, and CXCR4 expressions changed in different subsets. Only IL-1β mRNA increased in monocytes. Finally, a redistribution of B and T cell subsets was observed, suggesting the migration of mature cells to tissue. WBC seems to induce changes in both innate and adaptive branches of the immune system, hormones, and metabolic status in non-professional male athletes, suggesting a beneficial involvement of WBC in tissue repair.
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http://dx.doi.org/10.1007/s12026-020-09165-1DOI Listing
December 2020

The Immune Response of the Invasive Golden Apple Snail to a Nematode-Based Molluscicide Involves Different Organs.

Biology (Basel) 2020 Oct 30;9(11). Epub 2020 Oct 30.

Department of Life Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy.

The spreading of alien and invasive species poses new challenges for the ecosystem services, the sustainable production of food, and human well-being. Unveiling and targeting the immune system of invasive species can prove helpful for basic and applied research. Here, we present evidence that a nematode ()-based molluscicide exerts dose-dependent lethal effects on the golden apple snail, . When used at 1.7 g/L, this biopesticide kills about 30% of snails within one week and promotes a change in the expression of , an orthologue of mammalian bactericidal/permeability increasing protein (BPI). Changes in expression, as monitored by quantitative PCR (qPCR), occurred in two immune-related organs, namely the anterior kidney and the gills, after exposure at 18 and 25 °C, respectively. Histological analyses revealed the presence of the nematode in the snail anterior kidney and the gills at both 18 and 25 °C. The mantle and the central nervous system had a stable expression and seemed not affected by the nematodes. Fluorescence in situ hybridization (FISH) experiments demonstrated the expression of in circulating hemocytes, nurturing the possibility that increased expression in the anterior kidney and gills may be due to the hemocytes patrolling the organs. While suggesting that -based biopesticides enable the sustainable control of spread, our experiments also unveiled an organ-specific and temperature-dependent response in the snails exposed to the nematodes. Overall, our data indicate that, after exposure to a pathogen, the snail can mount a complex, multi-organ innate immune response.
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http://dx.doi.org/10.3390/biology9110371DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7692235PMC
October 2020

The importance of advanced cytometry in defining new immune cell types and functions relevant for the immunopathogenesis of HIV infection.

AIDS 2020 12;34(15):2169-2185

University of Modena and Reggio Emilia School of Medicine, Modena.

: In the last years, novel, exciting immunological findings of interest for HIV research and treatment were identified thanks to different cytometric approaches. The analysis of the phenotypes and functionality of cells belonging to the immune system could clarify their role in the immunopathogenesis of HIV infection, and to elaborate key concepts, relevant in the treatment of this disease. Important discoveries have been made concerning cells that are important for protective immunity like lymphocytes that display polyfunctionality, resident memory T cells, innate lymphoid cells, to mention a few. The complex phenotype of myeloid-derived suppressor cells has been investigated, and relevant changes have been reported during chronic and primary HIV infection, in correlation with changes in CD4 T-cell number, T-cell activation, and with advanced disease stage. The search for markers of HIV persistence present in latently infected cells, namely those molecules that are important for a functional or sterilizing cure, evidenced the role of follicular helper T cells, and opened a discussion on the meaning and use of different surface molecules not only in identifying such cells, but also in designing new strategies. Finally, advanced technologies based upon the simultaneous detection of HIV-RNA and proteins at the single cell level, as well as those based upon spectral cytometry or mass cytometry are now finding new actors and depicting a new scenario in the immunopathogenesis of the infection, that will allow to better design innovative therapies based upon novel drugs and vaccines.
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http://dx.doi.org/10.1097/QAD.0000000000002675DOI Listing
December 2020

Obesity risk during collective quarantine for the COVID-19 epidemic.

Obes Med 2020 Dec 9;20:100263. Epub 2020 Jun 9.

Surgical, Medical and Dental Department of Morphological Sciences Related to Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, Via Del Pozzo, 71 41124, Modena, Italy.

In March 2020, when COVID-19 epidemics involved several countries, the WHO defined the infection as a pandemic. Government adopted measures to prevent the diffusion of infection; i.e. quarantine and isolation. One of the consequences of quarantine-induced stress is a change in lifestyle and eating habits leading to obesity. The present commentary briefly analyzes the effects of quarantine on obesity.
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http://dx.doi.org/10.1016/j.obmed.2020.100263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7282788PMC
December 2020

Mitochondrial damage-associated molecular patterns stimulate reactive oxygen species production in human microglia.

Mol Cell Neurosci 2020 10 20;108:103538. Epub 2020 Aug 20.

Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia, via Campi, 287, 41125 Modena, Italy; National Institute of Cardiovascular Research, via Irnerio, 48, 40126 Bologna, Italy.

Microglia are the resident innate immune cells of the central nervous system and exert functions of host defense and maintenance of normal tissue homeostasis, along with support of neuronal processes in the healthy brain. Chronic and dysregulated microglial cell activation has increasingly been linked to the status of neuroinflammation underlying many neurodegenerative diseases, including multiple sclerosis (MS). However, the stimulus (or stimuli) and mechanisms by which microglial activation is initiated and maintained MS are still debated. The purpose of our research was to investigate whether the endogenous mitochondrial (mt)-derived damage-associated molecular patterns (MTDs) mtDNA, N-formyl peptides and cardiolipin (CL) contribute to these phenomena. We characterized the effects of the abovementioned MTDs on microglia activation in vitro (i.e. using HMC3 cells) by evaluating the expression of gene coding for proteins involved in their binding and coupled to downstream signaling pathways, the up-regulation of markers of activation on the cell surface and the production of pro-inflammatory cytokines and reactive oxygen species. At the transcriptional level, significant variations in the mRNA relative expression of five of eleven selected genes were observed in response to stimulation. No changes in activation of antigenic profile or functional properties of HMC3 cells were observed; there was no up-regulation of HLA-DR expression or increased secretion of tumor necrosis factor-α and interleukin-6. However, after stimulation with mtDNA and CL, an increase in cellular oxidative stress, but not in the mt ROS O, compared to control cells, were observed. There were no effects on cell viability. Overall, our data suggest that MTDs could cause a failure in microglial activation toward a pro-inflammatory phenotype, possibly triggering an endogenous regulatory mechanism for the resolution of neuroinflammation. This could open a door for the development of drugs selectively targeting microglia and modulating its functionality to treat MS and/or other neurodegenerative conditions in which MTDs have a pathogenic relevance.
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http://dx.doi.org/10.1016/j.mcn.2020.103538DOI Listing
October 2020

Short Communication: Circulating Mitochondrial DNA and Lipopolysaccharide-Binding Protein but Not Bacterial DNA Are Increased in Acute Human Immunodeficiency Virus Infection.

AIDS Res Hum Retroviruses 2020 10 17;36(10):817-820. Epub 2020 Aug 17.

Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia, Modena, Italy.

Microbial translocation has been suggested as a major driver of chronic immune activation HIV infection. Thus, we compared the extent of microbial translocation in patients with acute HIV infection and patients followed after CD4-guided structured treatment interruption (STI) by measuring different circulating markers: (1) lipopolysaccharide (LPS)-binding protein (LBP), (2) bacterial DNA, (3) soluble CD14 (sCD14), and (4) mitochondrial DNA (mtDNA). Bacterial DNA and sCD14 levels were similar in all groups. Patients in acute phase showed higher levels of LBP and mtDNA. In STI, we found a positive correlation between the percentage of CD8+ T cells and bacterial DNA levels. Considering all patients, LBP was positively correlated with the percentage and the absolute count of CD8+ T cells, and with mtDNA stressing the importance of mitochondrial products in sustaining chronic immune activation.
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http://dx.doi.org/10.1089/AID.2020.0098DOI Listing
October 2020

Efficient T-Cell Compartment in HIV-Positive Patients Receiving Orthotopic Liver Transplant and Immunosuppressive Therapy.

J Infect Dis 2021 02;223(3):482-493

Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia, Modena, Italy.

Background: In patients undergoing orthotopic liver transplant (OLT), immunosuppressive treatment is mandatory and infections are leading causes of morbidity/mortality. Thus, it is essential to understand the functionality of cell-mediated immunity after OLT. The aim of the study was to identify changes in T-cell phenotype and polyfunctionality in human immunodeficiency virus-positive (HIV+) and -negative (HIV-) patients undergoing immunosuppressive treatment after OLT.

Methods: We studied peripheral blood mononuclear cells from 108 subjects divided into 4 groups of 27: HIV+ transplanted patients, HIV- transplanted patients, HIV+ nontransplanted patients, and healthy subjects. T-cell activation, differentiation, and cytokine production were analyzed by flow cytometry.

Results: Median age was 55 years (interquartile range, 52-59 years); the median CD4 count in HIV+ patients was 567 cells/mL, and all had undetectable viral load. CD4+ and CD8+ T-cell subpopulations showed different distributions between HIV+ and HIV- OLT patients. A cluster representing effector cells expressing PD1 was abundant in HIV- transplanted patients and they were characterized by higher levels of CD4+ T cells able to produce interferon-γ and tumor necrosis factor-α.

Conclusions: HIV- transplanted patients have more exhausted or inflammatory T cells compared to HIV+ transplanted patients, suggesting that patients who have already experienced a form of immunosuppression due to HIV infection respond differently to anti-rejection therapy.
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http://dx.doi.org/10.1093/infdis/jiaa395DOI Listing
February 2021

Impaired Mitochondrial Morphology and Functionality in Mice.

J Clin Med 2020 Jun 8;9(6). Epub 2020 Jun 8.

Department of Life Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy.

LONP1 is a nuclear-encoded mitochondrial protease crucial for organelle homeostasis; mutations of have been associated with Cerebral, Ocular, Dental, Auricular, and Skeletal anomalies (CODAS) syndrome. To clarify the role of LONP1 in vivo, we generated a mouse model in which was ablated. The homozygous mouse was not vital, while the heterozygous showed similar growth rate, weight, length, life-span and histologic features as wild type. Conversely, ultrastructural analysis of heterozygous enterocytes evidenced profound morphological alterations of mitochondria, which appeared increased in number, swollen and larger, with a lower complexity. Embryonic fibroblasts (MEFs) from mice showed a reduced expression of and , whose expression is regulated by LONP1. Mitochondrial DNA was also reduced, and mitochondria were swollen and larger, albeit at a lesser extent than enterocytes, with a perinuclear distribution. From the functional point of view, mitochondria from heterozygous MEF showed a lower oxygen consumption rate in basal conditions, either in the presence of glucose or galactose, and a reduced expression of mitochondrial complexes than wild type. In conclusion, the presence of one functional copy of the gene leads to impairment of mitochondrial ultrastructure and functions in vivo.
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http://dx.doi.org/10.3390/jcm9061783DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7355737PMC
June 2020

Increased Plasma Levels of Mitochondrial DNA and Normal Inflammasome Gene Expression in Monocytes Characterize Patients With Septic Shock Due to Multidrug Resistant Bacteria.

Front Immunol 2020 5;11:768. Epub 2020 May 5.

Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia, Modena, Italy.

The activity and regulation of inflammasome is receiving increasing attention in septic shock. Moreover, there is a growing body of evidence suggesting that mitochondrial DNA (mtDNA) can play a role as biomarker of disease severity and even mortality both in adults and children in critically ill setting. However, no data are available on the amount of circulating mtDNA and inflammasome gene expression in multi-drug resistant (MDR) bacteria septic shock. For this reason, the aim of this study was to determine whether plasma mtDNA levels and inflammasome gene expression in monocytes could be related to severity in patients admitted to intensive care unit (ICU) with septic shock due to MDR pathogens. Peripheral blood mononuclear cells (PBMC) and plasma were isolated from up to 20 ml of venous blood by density gradient centrifugation in patients admitted to ICU with the diagnosis of septic shock due to MDR-bacteria. Then, CD14+ monocytes were sorted, and RNA and DNA were extracted. NLRP3, PYCARD, AIM2 and NAIP expression level was analyzed by RT-PCR. Plasma circulating mtDNA levels were quantified by digital droplet PCR. Basal and outcome characteristics of the patients were collected. Age-matched healthy subjects were chosen as controls. Nineteen patients with septic shock and 20 healthy subjects were enrolled in the study. A small trend toward an increased expression of inflammasome genes was observed in septic shock patients, who also displayed a marked tendency to an increased expression of IL-18 and IL-1β genes. Circulating mtDNA levels were significantly higher in septic shock patients if compared to healthy subjects, and patients who died in ICU were characterized by higher level of mtDNA if compared to those who were dismissed after 7 days. No correlations were found between mtDNA and inflammasome level and other clinical variables. Despite many limitations, our data suggest that in patients with septic shock caused by MDR pathogens the expression of main inflammasome genes was comparable to that of healthy patients without infection. Furthermore, our data evidence a possible role of mtDNA as a prognostic marker of severity in septic shock from MDR.
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http://dx.doi.org/10.3389/fimmu.2020.00768DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214691PMC
March 2021

COVID-19 pandemic: the effects of quarantine on cardiovascular risk.

Eur J Clin Nutr 2020 Jun 5;74(6):852-855. Epub 2020 May 5.

Surgical, Medical and Dental Department of Morphological Sciences related to Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy.

COVID-19 is causing a global pandemic with a high number of deaths and infected people. To contain the diffusion of COVID-19 virus, Governments have enforced restrictions on outdoor activities or even collective quarantine on the population. One important consequence of quarantine is a change in lifestyle: reduced physical activity and unhealthy diet. 2019 guidelines for primary prevention of cardiovascular disease indicate that "Adults should engage in at least 150 minute per week of accumulated moderate-intensity or 75 minute per week of vigorous-intensity aerobic physical activity (or an equivalent combination of moderate and vigorous activity) to reduce ASCVD risk." During quarantine, strategies to further increase home-based physical activity and to follow a healthy diet should be implemented. Quarantine carries some long-term effects on cardiovascular disease, mainly related to unhealthy lifestyle and anxiety. Following quarantine a global action supporting healthy diet and physical activity is mandatory to encourage people to return to good lifestyle.
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http://dx.doi.org/10.1038/s41430-020-0646-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7199203PMC
June 2020

COVID-19 outbreak: impact of the quarantine-induced stress on cardiovascular disease risk burden.

Future Cardiol 2020 11 30;16(6):539-542. Epub 2020 Apr 30.

Surgical, Medical & Dental Department of Morphological Sciences related to Transplant, Oncology & Regenerative Medicine, University of Modena & Reggio Emilia, Italy.

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http://dx.doi.org/10.2217/fca-2020-0055DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7202322PMC
November 2020

Relationship between socioeconomic status and asymptomatic peripheral arterial disease: a retrospective study.

J Cardiovasc Med (Hagerstown) 2020 09;21(9):720-721

Surgical, Medical and Dental Department of Morphological Sciences Related to Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia.

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http://dx.doi.org/10.2459/JCM.0000000000000960DOI Listing
September 2020

Synthesis and Anticancer Activity of CDDO and CDDO-Me, Two Derivatives of Natural Triterpenoids.

Molecules 2019 Nov 13;24(22). Epub 2019 Nov 13.

Department of Life Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy.

Triterpenoids are natural compounds synthesized by plants through cyclization of squalene, known for their weak anti-inflammatory activity. 2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oic acid (CDDO), and its C28 modified derivative, methyl-ester (CDDO-Me, also known as bardoxolone methyl), are two synthetic derivatives of oleanolic acid, synthesized more than 20 years ago, in an attempt to enhance the anti-inflammatory behavior of the natural compound. These molecules have been extensively investigated for their strong ability to exert antiproliferative, antiangiogenic, and antimetastatic activities, and to induce apoptosis and differentiation in cancer cells. Here, we discuss the chemical properties of natural triterpenoids, the pathways of synthesis and the biological effects of CDDO and its derivative CDDO-Me. At nanomolar doses, CDDO and CDDO-Me have been shown to protect cells and tissues from oxidative stress by increasing the transcriptional activity of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2). At doses higher than 100 nM, CDDO and CDDO-Me are able to modulate the differentiation of a variety of cell types, both tumor cell lines or primary culture cell, while at micromolar doses these compounds exert an anticancer effect in multiple manners; by inducing extrinsic or intrinsic apoptotic pathways, or autophagic cell death, by inhibiting telomerase activity, by disrupting mitochondrial functions through Lon protease inhibition, and by blocking the deubiquitylating enzyme USP7. CDDO-Me demonstrated its efficacy as anticancer drugs in different mouse models, and versus several types of cancer. Several clinical trials have been started in humans for evaluating CDDO-Me efficacy as anticancer and anti-inflammatory drug; despite promising results, significant increase in heart failure events represented an obstacle for the clinical use of CDDO-Me.
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http://dx.doi.org/10.3390/molecules24224097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6891335PMC
November 2019

Increased plasma levels of mitochondrial DNA and pro-inflammatory cytokines in patients with progressive multiple sclerosis.

J Neuroimmunol 2020 01 7;338:577107. Epub 2019 Nov 7.

Department of Medical and Surgical Sciences for Children and Adults, University of Modena and Reggio Emilia, via Campi, 287, 41125 Modena, Italy; National Institute of Cardiovascular Research, via Irnerio, 48, 40126 Bologna, Italy.

The role of damage-associated molecular patterns in multiple sclerosis (MS) is under investigation. Here, we studied the contribution of circulating high mobility group box protein 1 (HMGB1) and mitochondrial DNA (mtDNA) to neuroinflammation in progressive MS. We measured plasmatic mtDNA, HMGB1 and pro-inflammatory cytokines in 38 secondary progressive (SP) patients, 35 primary progressive (PP) patients and 42 controls. Free mtDNA was higher in SP than PP. Pro-inflammatory cytokines were increased in progressive patients. In PP, tumor necrosis factor-α correlated with MS Severity Score. Thus, in progressive patients, plasmatic mtDNA and pro-inflammatory cytokines likely contribute to the systemic inflammatory status.
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http://dx.doi.org/10.1016/j.jneuroim.2019.577107DOI Listing
January 2020

Guidelines for the use of flow cytometry and cell sorting in immunological studies (second edition).

Eur J Immunol 2019 Oct;49(10):1457-1973

Flow Cytometry Laboratory, Institute of Molecular Toxicology and Pharmacology, Helmholtz Zentrum München, German Research Center for Environmental Health, München, Germany.

These guidelines are a consensus work of a considerable number of members of the immunology and flow cytometry community. They provide the theory and key practical aspects of flow cytometry enabling immunologists to avoid the common errors that often undermine immunological data. Notably, there are comprehensive sections of all major immune cell types with helpful Tables detailing phenotypes in murine and human cells. The latest flow cytometry techniques and applications are also described, featuring examples of the data that can be generated and, importantly, how the data can be analysed. Furthermore, there are sections detailing tips, tricks and pitfalls to avoid, all written and peer-reviewed by leading experts in the field, making this an essential research companion.
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http://dx.doi.org/10.1002/eji.201970107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7350392PMC
October 2019

The role of physical activity in individuals with cardiovascular risk factors: an opinion paper from Italian Society of Cardiology-Emilia Romagna-Marche and SIC-Sport.

J Cardiovasc Med (Hagerstown) 2019 Oct;20(10):631-639

Department of Surgical, Medical and Dental Department of Morphological Sciences Related to Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, Modena.

: Regular physical activity is a cornerstone in the prevention and treatment of atherosclerotic cardiovascular disease (CVD) due to its positive effects in reducing several cardiovascular risk factors. Current guidelines on CVD suggest for healthy adults to perform at least 150 min/week of moderate intensity or 75 min/week of vigorous intensity aerobic physical activity. The current review explores the effects of physical activity on some risk factors, specifically: diabetes, dyslipidemia, hypertension and hyperuricemia. Physical activity induces an improvement in insulin sensitivity and in glucose control independently of weight loss, which may further contribute to ameliorate both diabetes-associated defects. The benefits of adherence to physical activity have recently proven to extend beyond surrogate markers of metabolic syndrome and diabetes by reducing hard endpoints such as mortality. In recent years, obesity has greatly increased in all countries. Weight losses in these patients have been associated with improvements in many cardiometabolic risk factors. Strategies against obesity included caloric restriction, however greater results have been obtained with association of diet and physical activity. Similarly, the beneficial effect of training on blood pressure via its action on sympathetic activity and on other factors such as improvement of endothelial function and reduction of oxidative stress can have played a role in preventing hypertension development in active subjects. The main international guidelines on prevention of CVD suggest to encourage and to increase physical activity to improve lipid pattern, hypertension and others cardiovascular risk factor. An active action is required to the National Society of Cardiology together with the Italian Society of Sports Cardiology to improve the prescription of organized physical activity in patients with CVD and/or cardiovascular risk factors.
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http://dx.doi.org/10.2459/JCM.0000000000000855DOI Listing
October 2019

Mitochondrial functionality and metabolism in T cells from progressive multiple sclerosis patients.

Eur J Immunol 2019 12 16;49(12):2204-2221. Epub 2019 Aug 16.

Department of Life Sciences, University of Modena and Reggio Emilia, Modena, Italy.

Patients with primary progressive (PP) and secondary progressive (SP) forms of multiple sclerosis (MS) exhibit a sustained increase in the number of Th1, T cytotoxic type-1 and Th17 cells in peripheral blood, suggesting that the progressive phase is characterized by a permanent peripheral immune activation. As T cell functionality and activation are strictly connected to their metabolic profile, we investigated the mitochondrial functionality and metabolic changes of T cell subpopulations in a cohort of progressive MS patients. T cells from progressive patients were characterized by low proliferation and increase of terminally differentiated/exhausted cells. T cells from PP patients showed lower Oxygen Consumption Rate and Extracellular Acidification Rate, lower mitochondrial mass, membrane potential and respiration than those of SP patients, a downregulation of transcription factors supporting respiration and higher tendency to shift towards glycolysis upon stimulation. Furthermore, PP effector memory T cells were characterized by higher Glucose transporter -1 levels and a higher expression of glycolytic-supporting genes if compared to SP patients. Overall, our data suggest that profound differences exist in the phenotypic and metabolic features of T cells from PP and SP patients, even though the two clinical phenotypes are considered part of the same disease spectrum.
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http://dx.doi.org/10.1002/eji.201948223DOI Listing
December 2019

Plasma neurofilaments correlate with disability in progressive multiple sclerosis patients.

Acta Neurol Scand 2020 Jan 26;141(1):16-21. Epub 2019 Aug 26.

Department of Neurosciences, Ospedale Civile, Azienda Ospedaliero-Universitaria, Modena, Italy.

Objectives: Cerebrospinal fluid (CSF) and blood neurofilaments (NFLs) are markers of axonal damage and are being investigated, mostly in relapsing-remitting (RR) MS, as a marker of disease activity and of response to treatment, while there are less data in progressive MS patients. Primary aim was to measure NFL in plasma samples of untreated patients with primary (PP) and secondary (SP) progressive MS and to correlate them with disability, disease severity, and prior/subsequent disability progression.

Materials And Methods: Neurofilament concentrations were measured using SIMOA (Single Molecule Array, Simoa HD-1 Analyzer; Quanterix).

Results: Neurofilament concentrations were measured on plasma samples of 70 progressive (27 PP and 43 SP), 21 RRMS patients, and 10 HCs. Longitudinal plasma NFL (pNFL) concentrations (median interval between sampling: 25 months) were available for nine PP/SP patients. PNFL concentrations were significantly higher in PP/SP compared to RRMS patients. They correlated with EDSS and MS Severity Score values. There was no difference in pNFL levels between PP/SP patients with EDSS progression in the preceding year (14% of patients) or during a median follow-up of 27 months (41%). In the longitudinal sub-study, pNFL levels increased in all patients between sampling by a mean value of 23% while EDSS mostly remained stable (77% of cases).

Conclusion: In PP/SP progressive MS patients, pNFL levels correlate with disability and increase over time, but are not associated with prior/subsequent disability progression, as measured by EDSS, which may not be a sufficiently sensitive tool in this context.
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http://dx.doi.org/10.1111/ane.13152DOI Listing
January 2020

Effects of Caffeine on Colon: A Potential Clinical Use of Coffee in Surgical Patients.

Dig Surg 2020 28;37(3):265-266. Epub 2019 Mar 28.

Department of Surgical, Medical and Dental Department of Morphological Sciences Related to Transplant, Oncology and Regenerative Medicine (University of Modena and Reggio Emilia), Modena, Italy.

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http://dx.doi.org/10.1159/000499198DOI Listing
February 2021

Titanium Surface Properties Influence the Biological Activity and FasL Expression of Craniofacial Stromal Cells.

Stem Cells Int 2019 13;2019:4670560. Epub 2019 Jan 13.

Department of Surgery, Medicine, Dentistry and Morphological Sciences with Interest in Transplant, Oncology and Regenerative Medicine, University of Modena and Reggio Emilia, Modena, Italy.

Mesenchymal stromal cells (MSCs) can be easily isolated form craniofacial bones during routine dentistry procedures. Due to their embryological origin from neural crest, they represent a suitable cell population to study cell-biomaterial interaction in the craniofacial field, including osteoinductive/osteointegrative processes. The biological and immunomodulatory properties of MSCs may be influenced by chemistry and topography of implant surfaces. We investigated if and how three different titanium surfaces, machined (MCH), sandblasted with resorbable blasting medium (RBM), and Ca-nanostructured (NCA), may affect biological activity, osseointegration, and immunomodulatory properties of craniofacial MSCs. Cell proliferation, morphology, osteogenic markers, and FasL were evaluated on MSCs isolated from the mandibular bone after seeding on these three different surfaces. No statistically significant differences in cell proliferation were observed whereas different morphologies and growth patterns were detected for each type of surface. No difference in the expression of osteogenic markers was revealed. Interestingly, FasL expression, involved in the immunomodulatory activity of stem cells, was influenced by surface properties. Particularly, immunofluorescence analysis indicated that FasL expression increased on MCH surface compared to the others confirming the suggested role of FasL in promoting osteogenic differentiation. Titanium surface treatments and topography might reflect different biological behaviours of craniofacial MSCs and influence their osseointegration/immunomodulation properties.
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http://dx.doi.org/10.1155/2019/4670560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6348805PMC
January 2019
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