Nadia Gambuzza - Academia.edu (original) (raw)

Papers by Nadia Gambuzza

Annals of Agricultural and Environmental Medicine, Jun 12, 2017

Introduction. The increasing development of marine traffic has led to a rise in the incidence of ... more Introduction. The increasing development of marine traffic has led to a rise in the incidence of legionellosis among travellers. It occurs in similar environments, especially closed and crowded, and aboard ships Legionella survives and multiplies easily in water pipes, spreading into the environment through air conditioning systems and water distribution points. Although in recent years in the construction of cruise ships preventive measures aimed at curbing the proliferation of Legionella (design, materials, focus on the operation and maintenance of the water system), have been taken account, little or no attention has been paid to small ships which, in many cases, are old and not well maintained. Objective. The aim of the study was to evaluate the frequency and severity of Legionella contamination in ferries and cruise ships in order to adopt more specific control measures. Materials and method. A prevalence study was carried out on 10 ferries and 6 cruise ships docking or in transit across the port of Messina (Sicily, Italy). Water and air samples collected from many critical points were tested for qualitative and quantitative identification of Legionella. Results and conclusions. Legionella pneumophila sg 1 was isolated from the samples of shower and tap water in 7 (70%) of the 10 ferries examined, and in 3 (33%) of the 6 cruise ships examined, and L. pneumophila sg 2-14 in 8 (80%) and 1 (16.7%) of these ships, respectively. No Legionella contamination was found in whirlpool baths, air and ice samples. In conclusion, the data obtained confirm higher levels of Legionella contamination in local ferries and cruise ships, underlining the need to adopt corrective actions more specific for these smaller vessels.

Drugs & Aging, Mar 28, 2023

Older patients are at high risk of infections, which often present atypically and are associated ... more Older patients are at high risk of infections, which often present atypically and are associated with high morbidity and mortality. Antimicrobial treatment in older individuals with infectious diseases represents a clinical challenge, causing an increasing burden on worldwide healthcare systems; immunosenescence and the coexistence of multiple comorbidities determine complex polypharmacy regimens with an increase in drug-drug interactions and spread of multidrug-resistance infections. Aging-induced pharmacokinetic and pharmacodynamic changes can additionally increase the risk of inappropriate drug dosing, with underexposure that is associated with antimicrobial resistance and overexposure that may lead to adverse effects and poor adherence because of low tolerability. These issues need to be considered when starting antimicrobial prescriptions. National and international efforts have been made towards the implementation of antimicrobial stewardship (AMS) interventions to help clinicians improve the appropriateness and safety of antimicrobial prescriptions in both acute and long-term care settings. AMS programs were shown to decrease consumption of antimicrobials and to improve safety in hospitalized patients and older nursing home residents. With the abundance of antimicrobial prescriptions and the recent emergence of multidrug resistant pathogens, an in-depth review of antimicrobial prescriptions in geriatric clinical practice is needed. This review will discuss the special considerations for older individuals needing antimicrobials, including risk factors that shape risk profiles in geriatric populations as well as an evidence-based description of antimicrobial-induced adverse events in this patient population. It will highlight agents of concern for this age group and discuss interventions to mitigate the effects of inappropriate antimicrobial prescribing. Key Points Older patients are at high risk of infections and adverse events due to antimicrobial medications.

Springer briefs in molecular science, 2019

Gases intended for food-related applications are ‘volatile’ agents. Each food gas has to be produ... more Gases intended for food-related applications are ‘volatile’ agents. Each food gas has to be produced by authorised companies which should be registered as food business operator in the European Union. As a result, gases intended for food-related applications need to be specifically traceable, similarly to food components. Moreover, the safe use (and related health consequences) of gaseous products and mixtures have to be shared between the final user and all other interested ‘stakeholders’ of the food chain (also with reference to possible food fraud episodes). In addition, the possible mixing of different food gases does not constitute reason for diminishing regulatory and legal responsibilities. With concern to physical and chemical features, and according to the main regulatory document ruling food gases in the European Union, food gases may be subdivided as foaming agents, packaging gases, propellants, or raising substances, although another classification may consider their physical and chemical features when used. This chapter discusses chemical and physical features of commonly used food gases in the food and food packing industries.

Springer briefs in molecular science, 2019

Food gases are supplied to the food industry as additives, support or in contact with food ingred... more Food gases are supplied to the food industry as additives, support or in contact with food ingredients. Consequently, these gases must respect very strict standards in order to come into contact with foodstuffs and therefore in order to ensure food security. In particular, they must comply with precise rules on labelling, purity and hygiene criteria. The relevant legislation was inspired by the White Paper on Food Safety, published in 2000 by the European Commission which has defined the environmental, public health, animal health and consumer protection as joint objectives, freedom of competition. The Regulation (EC) No 178/2002 defines a food as any substance produced, processed or distributed to be ingested, or reasonably expected to be ingested. Food gases are used in the food industry in different applications. This chapter considers the role of food gases in Europe on the regulatory ground with several observations concerning basic features, food safety approaches, classifications and conditions for use.

Springer briefs in molecular science, 2019

The European legislator has defined the matter of food gases by means of three regulatory documen... more The European legislator has defined the matter of food gases by means of three regulatory documents at least: Regulation (EC) No 178/2002 (general principles and requirements of food law), Reg. (EC) No 852/2004 (hygiene of foodstuffs), and Reg. (EC) No 1935/2004 (materials and articles intended to come into contact with food). Actually, there are different national regulations on these arguments (food and non-food applications in the European Union). The comprehension of the intended use of food gases, according to recent European regulations concerning the safe use of chemicals, is critical. Other points of interest are the identification of the food business operator and the definition of food gas as ‘ingredient’, ‘technological aid’, or ‘food additive’. This chapter discusses the regulatory classification of food (and non-food) gases in the European Union, with possible exclusions.

Springer briefs in molecular science, 2019

Food gases are used in the food industry as ‘ingredients’, ‘technological aids’, or ‘food additiv... more Food gases are used in the food industry as ‘ingredients’, ‘technological aids’, or ‘food additives’. Anyway, these substances are in contact with foods and beverages. As a result, food security has to be assured with reference to food gases. On these bases, and because of the evident identification of gases used for food applications as ‘food’, each food gas producer is certainly a food business operator, similar to all players in the food supply chain. The hygienic approach imposes to consider food gases as a single component for food and/or beverage productions. The hazard analysis and critical control points strategy is needed and mandatory in this situation. However, food technologists, biologists, chemists, hygiene experts, and other experienced professionals can have their own opinion in the ambit of safety evaluation and assessment. Consequently, this chapter would give readers some idea in relation to risk assessment of food gases in connection with their European classification as foaming agents, packaging gases, propellants, or raising substances.

Springer briefs in molecular science, 2019

Reviews in The Neurosciences, Jan 7, 2014

Multiple sclerosis (MS) is a chronic disease of the central nervous system (CNS) characterized by... more Multiple sclerosis (MS) is a chronic disease of the central nervous system (CNS) characterized by inflammation, demyelination, and axonal pathology. The exact causes of MS are unknown, but environmental factors including pathogens are believed to contribute to the development of disease. Toll-like receptors (TLRs) are a family of receptors important in pathogen recognition and host defense. TLRs are expressed by a variety of peripheral immune cells as well as resident cells of the CNS. Studies indicate that TLRs play a significant role in modulating MS, as well as experimental autoimmune encephalomyelitis (EAE), an animal model of MS. This review will discuss the current understanding of the role of TLRs in modulating EAE and MS.

Cns & Neurological Disorders-drug Targets, Mar 13, 2018

BACKGROUND & OBJECTIVE The innate immune response is a common occurrence in many neuroinflamm... more BACKGROUND & OBJECTIVE The innate immune response is a common occurrence in many neuroinflammatory diseases. Central Nervous System (CNS) resident immune cells are able to detect and react to infections and sterile trauma. Peripheral immune cell migration into CNS is regulated by the blood-brain barrier, although peripheral immune cells can invade CNS through meninges, choroid plexus, perivascular spaces, and cerebrospinal fluid. Consequently, in the brain, immune reactions can be mediated by both resident and peripheral immune cells. Both in the periphery and within the CNS, innate immune response is regulated by a wide array of pattern recognition receptors, including Tolllike, scavenger, Retinoic Acid-inducible Gene-1 like, and nucleotide-binding oligomerization domainslike responsible for inflammasome formation. Inflammasome pathway activation induces pyroptosis, a highly inflammatory cell death pattern that occurs to remove intracellular pathogens. Legionella pneumophila is an intracellular microorganism responsible for Legionnaires' disease, a lung infection always associated to neurological dysfunctions. Recent studies have been shown that Toll-like receptors, nucleotide-binding oligomerization domains-like receptors, and RIG-1 like, are activated by L. pneumophila. This flagellated bacterium is able to replicate in phagocytic cells, including macrophages and microglia, responding by activating inflammasome pathways that may be the cause of CNS dysfunction detected in several infected patients. CONCLUSION The aim of this review is to bring together the latest findings concerning L. pneumophila infection and innate immune host cell responses. A deeper knowledge of these processes could allow the use of immunomodulatory compounds able to counteract CNS involvement following L. pneumophila infection.

Infection and Immunity, Feb 1, 2004

The production of proinflammatory cytokines is likely to play a major pathophysiological role in ... more The production of proinflammatory cytokines is likely to play a major pathophysiological role in meningitis and other infections caused by Haemophilus influenzae type b (Hib). Previous studies have shown that Hib porin contributes to signaling of the inflammatory cascade. We examined here the role of Toll-like receptors (TLRs) and the TLR-associated adaptor protein MyD88 in Hib porin-induced production of tumor necrosis factor alpha (TNF-␣) and interleukin-6 (IL-6). Hib porin-induced TNF-␣ and IL-6 production was virtually eliminated in macrophages from TLR2-or MyD88-deficient mice. In contrast, macrophages from lipopolysaccharide (LPS)-hyporesponsive C3H/HeJ mice, which are defective in TLR4 function, responded normally to Hib porin. Moreover anti-TLR2 antibodies but not anti-TLR4 antibodies significantly reduced Hib porin-stimulated TNF-␣ and IL-6 release from the human monocytic cell line THP-1. These data indicate that the TLR2/MyD88 pathway plays an essential role in Hib porin-mediated cytokine production. These findings may be useful in the development of alternative therapies aimed at reducing excessive inflammatory responses during Hib infections.

Journal of Clinical Trials, 2016

Recent studies have shown that many pathological conditions, including neurodegenerative disorder... more Recent studies have shown that many pathological conditions, including neurodegenerative disorders, are always the result of innate immune dysregulations. In multiple sclerosis (MS), innate immunity has shown induce proinflammatory responses, mainly mediated by specific innate immune receptors, as well as Toll-like receptors (TLRs). Interestingly, whereas activation of TLR-MyD88 dependent signaling pathway induces inflammation and MS progression, TLR3 activation MyD88 independent seems to play a beneficial effect, probably due to its ability to enhance endogenous IFN-β production, that in turn down regulates proinflammatory responses. Consequently, new therapeutic approaches based on TLR up and/or down regulation could offer promising results. In addition to several classes of TLR antagonists represented by different types of antibodies, nanobodies, mimetic molecules and RNAselective interference compounds, TLR3 agonists appear particularly interesting due to their capability of inducing IFN-β production. Among these, Ampligen® shows early promise, since it has shown positive results in several phase III trials for the treatment of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME), an illness that shows remarkable levels of similarity with MS.

Journal of Clinical & Cellular Immunology, 2015

Perturbations in immune processes play an important role in multiple sclerosis (MS), an autoimmun... more Perturbations in immune processes play an important role in multiple sclerosis (MS), an autoimmune disorder where specific innate immune pattern-recognition receptors (PRRs), such as Toll-like receptors (TLRs) have recently been shown to play a major role in the initiation disease, the triggering of relapses, and regulation of CNS damage. The abnormal immune response in MS has been shown to be dependent on genetic background, despite environmental factors, including pathogens capable of overstimulating innate immune response through TLRs, appear to contribute to the development of autoreactive T cells that in turn cause myelin damage. However, whereas the upregulation of most TLRs plays a detrimental role in MS pathogenesis, recent studies suggest an ameliorative role of TLR3 in the onset and progression of MS and experimental autoimmune encephalomyelitis (EAE), a murine model of MS. TLR3 activation appears to protect from the disease, mainly through induction of interferon (IFN)β. Therefore, TLR3 stimulation with synthetic immunomodulators could represent a potential alternative approach in MS therapy. Among the investigational compounds TLR3-targeting, the mismatched double-stranded RNA molecule Ampligen ® , can offer promise in the treatment of relapsing MS patients. Ampligen ® is currently in phase III clinical trial in the treatment of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME), an illness that shows remarkable levels of similarity with MS. The aim of this paper is to provide a brief overview about Ampligen® historical development, clinical pharmacology, clinical trials, and safety data, and to discuss about its potential role in MS treatment in the context of existing therapeutic options.

Journal of Neurology

Parkinson’s disease (PD) is a chronic progressive neurodegenerative disorder characterized by mot... more Parkinson’s disease (PD) is a chronic progressive neurodegenerative disorder characterized by motor and non-motor disturbances as a result of a complex and not fully understood pathogenesis, probably including neuroinflammation, oxidative stress, and formation of alpha-synuclein (α-syn) aggregates. As age is the main risk factor for several neurodegenerative disorders including PD, progressive aging of the immune system leading to inflammaging and immunosenescence may contribute to neuroinflammation leading to PD onset and progression; abnormal α-syn aggregation in the context of immune dysfunction may favor activation of nucleotide-binding oligomerization domain-like receptor (NOD) family pyrin domain containing 3 (NLRP3) inflammasome within microglial cells through interaction with toll-like receptors (TLRs). This process would further lead to activation of Caspase (Cas)-1, and increased production of pro-inflammatory cytokines (PC), with subsequent impairment of mitochondria and ...

Journal of AOAC INTERNATIONAL, 2020

The interest in polyphenols from vegetable sources has been progressively increased because of th... more The interest in polyphenols from vegetable sources has been progressively increased because of the demonstrated correlation between their abundance in certain foods or food preparations of traditional importance and heritage, and the answer of anti-inflammatory strategies in hospitalized patients in the presence of polypehnol-rich foods (as a complementary therapy). Consequently, research involving the accessory role of polyphenols as anti-tumoral aids have been carried out with the aim of finding new additional strategies. The purpose of this paper to evaluate the role of phenolic compounds in foods with reference to health effects for human beings. The importance of these molecules has been evaluated by the health and safety perspectives in terms of: fight to cardiovascular diseases; prevention of chronic-degenerative disorders; general antioxidant properties; and anticarcinogenic features. Moreover, the role of polyphenols-rich foods as anticancer agents has been discussed with r...

The Journal of Immunology, 2007

STAT1 Regulates IFN-αβ-and IFN-γ-Dependent Control of Infection with Chlamydia pneumoniae by Nonh... more STAT1 Regulates IFN-αβ-and IFN-γ-Dependent Control of Infection with Chlamydia pneumoniae by Nonhemopoietic Cells

Infection and immunity, 1997

Cytokines are suspected to play an important role in systemic infections by group B streptococci ... more Cytokines are suspected to play an important role in systemic infections by group B streptococci (GBS), an important cause of neonatal sepsis. This work was undertaken to determine if interleukin 12 (IL-12) is produced in mouse pups infected with GBS and has a role in this sepsis model. IL-12 elevations were measured by both an enzyme-linked immunosorbent assay and a bioassay in plasma samples obtained from 12 to 72 h after GBS challenge. Pretreatment with neutralizing anti-IL-12 antibodies significantly increased lethality and blood CFU (P < 0.05). Conversely, either prophylactically or therapeutically administered recombinant IL-12 (rIL-12) significantly improved survival time and decreased blood CFU. Since these beneficial effects were associated with increased spleen gamma interferon (IFN-gamma) production, we examined whether the latter cytokine mediated the observed rIL-12 effects. Pretreatment with neutralizing anti-IFN-gamma monoclonal antibodies significantly counteracte...

CNS & Neurological Disorders - Drug Targets, 2014

Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp... more Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease (AD) is a neurodegenerative disorder mainly characterized by amyloid-β (Aβ) plaques, neurofibrillary tangles, loss of synapses and neurons and chronic neuroinflammation. Emerging data highlight the involvement of innate immunity, that has been shown to play opposing roles during the AD progression. Activated microglia and reactive astrocytes exert neuroprotection mediated through Aβ phagocytosis in the early stage, whereas, as the disease progresses, they fail in Aβ clearance and exert detrimental effects, including neuroinflammation and neurodegeneration. Specific toll-like receptors (TLRs) and coreceptors can directly or indirectly be activated to induce Aβ uptake or inflammatory responses, depending on the disease stage. Fibrillar Aβ can directly interact with TLR2, TLR4, and CD14 to induce microglial Aβ phagocytosis in the beginning stages, and neuroinflammatory responses in the late stages. Early TLR3-mediated signal enhances neuronal Aβ autophagy, although it increases neuronal apoptosis in the late AD stage. Similarly, TLR7, TLR8 and TLR9 can enhance microglial Aβ uptake in the early stage, but over time they contribute to neuroinflammation. Therefore, TLRs, and in particular TLR2 and TLR4, represent a suitable target for therapeutic intervention within the disease progression and targeting them carefully could increase Aβ autophagy and phagocytosis or reduce inflammatory responses. Several modulators with selective TLR agonist or antagonist activity have been developed, and many of them could have a therapeutic benefit in AD patients. This paper outlines the role of specific TLRs in AD, also focusing on TLR-targeted compounds yet indicated for the treatment of other inflammatory diseases, that could be used to treat the different stages of the disease.

The Journal of Immunology, 2008

Annals of Agricultural and Environmental Medicine, Jun 12, 2017

Introduction. The increasing development of marine traffic has led to a rise in the incidence of ... more Introduction. The increasing development of marine traffic has led to a rise in the incidence of legionellosis among travellers. It occurs in similar environments, especially closed and crowded, and aboard ships Legionella survives and multiplies easily in water pipes, spreading into the environment through air conditioning systems and water distribution points. Although in recent years in the construction of cruise ships preventive measures aimed at curbing the proliferation of Legionella (design, materials, focus on the operation and maintenance of the water system), have been taken account, little or no attention has been paid to small ships which, in many cases, are old and not well maintained. Objective. The aim of the study was to evaluate the frequency and severity of Legionella contamination in ferries and cruise ships in order to adopt more specific control measures. Materials and method. A prevalence study was carried out on 10 ferries and 6 cruise ships docking or in transit across the port of Messina (Sicily, Italy). Water and air samples collected from many critical points were tested for qualitative and quantitative identification of Legionella. Results and conclusions. Legionella pneumophila sg 1 was isolated from the samples of shower and tap water in 7 (70%) of the 10 ferries examined, and in 3 (33%) of the 6 cruise ships examined, and L. pneumophila sg 2-14 in 8 (80%) and 1 (16.7%) of these ships, respectively. No Legionella contamination was found in whirlpool baths, air and ice samples. In conclusion, the data obtained confirm higher levels of Legionella contamination in local ferries and cruise ships, underlining the need to adopt corrective actions more specific for these smaller vessels.

Drugs & Aging, Mar 28, 2023

Older patients are at high risk of infections, which often present atypically and are associated ... more Older patients are at high risk of infections, which often present atypically and are associated with high morbidity and mortality. Antimicrobial treatment in older individuals with infectious diseases represents a clinical challenge, causing an increasing burden on worldwide healthcare systems; immunosenescence and the coexistence of multiple comorbidities determine complex polypharmacy regimens with an increase in drug-drug interactions and spread of multidrug-resistance infections. Aging-induced pharmacokinetic and pharmacodynamic changes can additionally increase the risk of inappropriate drug dosing, with underexposure that is associated with antimicrobial resistance and overexposure that may lead to adverse effects and poor adherence because of low tolerability. These issues need to be considered when starting antimicrobial prescriptions. National and international efforts have been made towards the implementation of antimicrobial stewardship (AMS) interventions to help clinicians improve the appropriateness and safety of antimicrobial prescriptions in both acute and long-term care settings. AMS programs were shown to decrease consumption of antimicrobials and to improve safety in hospitalized patients and older nursing home residents. With the abundance of antimicrobial prescriptions and the recent emergence of multidrug resistant pathogens, an in-depth review of antimicrobial prescriptions in geriatric clinical practice is needed. This review will discuss the special considerations for older individuals needing antimicrobials, including risk factors that shape risk profiles in geriatric populations as well as an evidence-based description of antimicrobial-induced adverse events in this patient population. It will highlight agents of concern for this age group and discuss interventions to mitigate the effects of inappropriate antimicrobial prescribing. Key Points Older patients are at high risk of infections and adverse events due to antimicrobial medications.

Springer briefs in molecular science, 2019

Gases intended for food-related applications are ‘volatile’ agents. Each food gas has to be produ... more Gases intended for food-related applications are ‘volatile’ agents. Each food gas has to be produced by authorised companies which should be registered as food business operator in the European Union. As a result, gases intended for food-related applications need to be specifically traceable, similarly to food components. Moreover, the safe use (and related health consequences) of gaseous products and mixtures have to be shared between the final user and all other interested ‘stakeholders’ of the food chain (also with reference to possible food fraud episodes). In addition, the possible mixing of different food gases does not constitute reason for diminishing regulatory and legal responsibilities. With concern to physical and chemical features, and according to the main regulatory document ruling food gases in the European Union, food gases may be subdivided as foaming agents, packaging gases, propellants, or raising substances, although another classification may consider their physical and chemical features when used. This chapter discusses chemical and physical features of commonly used food gases in the food and food packing industries.

Springer briefs in molecular science, 2019

Food gases are supplied to the food industry as additives, support or in contact with food ingred... more Food gases are supplied to the food industry as additives, support or in contact with food ingredients. Consequently, these gases must respect very strict standards in order to come into contact with foodstuffs and therefore in order to ensure food security. In particular, they must comply with precise rules on labelling, purity and hygiene criteria. The relevant legislation was inspired by the White Paper on Food Safety, published in 2000 by the European Commission which has defined the environmental, public health, animal health and consumer protection as joint objectives, freedom of competition. The Regulation (EC) No 178/2002 defines a food as any substance produced, processed or distributed to be ingested, or reasonably expected to be ingested. Food gases are used in the food industry in different applications. This chapter considers the role of food gases in Europe on the regulatory ground with several observations concerning basic features, food safety approaches, classifications and conditions for use.

Springer briefs in molecular science, 2019

The European legislator has defined the matter of food gases by means of three regulatory documen... more The European legislator has defined the matter of food gases by means of three regulatory documents at least: Regulation (EC) No 178/2002 (general principles and requirements of food law), Reg. (EC) No 852/2004 (hygiene of foodstuffs), and Reg. (EC) No 1935/2004 (materials and articles intended to come into contact with food). Actually, there are different national regulations on these arguments (food and non-food applications in the European Union). The comprehension of the intended use of food gases, according to recent European regulations concerning the safe use of chemicals, is critical. Other points of interest are the identification of the food business operator and the definition of food gas as ‘ingredient’, ‘technological aid’, or ‘food additive’. This chapter discusses the regulatory classification of food (and non-food) gases in the European Union, with possible exclusions.

Springer briefs in molecular science, 2019

Food gases are used in the food industry as ‘ingredients’, ‘technological aids’, or ‘food additiv... more Food gases are used in the food industry as ‘ingredients’, ‘technological aids’, or ‘food additives’. Anyway, these substances are in contact with foods and beverages. As a result, food security has to be assured with reference to food gases. On these bases, and because of the evident identification of gases used for food applications as ‘food’, each food gas producer is certainly a food business operator, similar to all players in the food supply chain. The hygienic approach imposes to consider food gases as a single component for food and/or beverage productions. The hazard analysis and critical control points strategy is needed and mandatory in this situation. However, food technologists, biologists, chemists, hygiene experts, and other experienced professionals can have their own opinion in the ambit of safety evaluation and assessment. Consequently, this chapter would give readers some idea in relation to risk assessment of food gases in connection with their European classification as foaming agents, packaging gases, propellants, or raising substances.

Springer briefs in molecular science, 2019

Reviews in The Neurosciences, Jan 7, 2014

Multiple sclerosis (MS) is a chronic disease of the central nervous system (CNS) characterized by... more Multiple sclerosis (MS) is a chronic disease of the central nervous system (CNS) characterized by inflammation, demyelination, and axonal pathology. The exact causes of MS are unknown, but environmental factors including pathogens are believed to contribute to the development of disease. Toll-like receptors (TLRs) are a family of receptors important in pathogen recognition and host defense. TLRs are expressed by a variety of peripheral immune cells as well as resident cells of the CNS. Studies indicate that TLRs play a significant role in modulating MS, as well as experimental autoimmune encephalomyelitis (EAE), an animal model of MS. This review will discuss the current understanding of the role of TLRs in modulating EAE and MS.

Cns & Neurological Disorders-drug Targets, Mar 13, 2018

BACKGROUND & OBJECTIVE The innate immune response is a common occurrence in many neuroinflamm... more BACKGROUND & OBJECTIVE The innate immune response is a common occurrence in many neuroinflammatory diseases. Central Nervous System (CNS) resident immune cells are able to detect and react to infections and sterile trauma. Peripheral immune cell migration into CNS is regulated by the blood-brain barrier, although peripheral immune cells can invade CNS through meninges, choroid plexus, perivascular spaces, and cerebrospinal fluid. Consequently, in the brain, immune reactions can be mediated by both resident and peripheral immune cells. Both in the periphery and within the CNS, innate immune response is regulated by a wide array of pattern recognition receptors, including Tolllike, scavenger, Retinoic Acid-inducible Gene-1 like, and nucleotide-binding oligomerization domainslike responsible for inflammasome formation. Inflammasome pathway activation induces pyroptosis, a highly inflammatory cell death pattern that occurs to remove intracellular pathogens. Legionella pneumophila is an intracellular microorganism responsible for Legionnaires' disease, a lung infection always associated to neurological dysfunctions. Recent studies have been shown that Toll-like receptors, nucleotide-binding oligomerization domains-like receptors, and RIG-1 like, are activated by L. pneumophila. This flagellated bacterium is able to replicate in phagocytic cells, including macrophages and microglia, responding by activating inflammasome pathways that may be the cause of CNS dysfunction detected in several infected patients. CONCLUSION The aim of this review is to bring together the latest findings concerning L. pneumophila infection and innate immune host cell responses. A deeper knowledge of these processes could allow the use of immunomodulatory compounds able to counteract CNS involvement following L. pneumophila infection.

Infection and Immunity, Feb 1, 2004

The production of proinflammatory cytokines is likely to play a major pathophysiological role in ... more The production of proinflammatory cytokines is likely to play a major pathophysiological role in meningitis and other infections caused by Haemophilus influenzae type b (Hib). Previous studies have shown that Hib porin contributes to signaling of the inflammatory cascade. We examined here the role of Toll-like receptors (TLRs) and the TLR-associated adaptor protein MyD88 in Hib porin-induced production of tumor necrosis factor alpha (TNF-␣) and interleukin-6 (IL-6). Hib porin-induced TNF-␣ and IL-6 production was virtually eliminated in macrophages from TLR2-or MyD88-deficient mice. In contrast, macrophages from lipopolysaccharide (LPS)-hyporesponsive C3H/HeJ mice, which are defective in TLR4 function, responded normally to Hib porin. Moreover anti-TLR2 antibodies but not anti-TLR4 antibodies significantly reduced Hib porin-stimulated TNF-␣ and IL-6 release from the human monocytic cell line THP-1. These data indicate that the TLR2/MyD88 pathway plays an essential role in Hib porin-mediated cytokine production. These findings may be useful in the development of alternative therapies aimed at reducing excessive inflammatory responses during Hib infections.

Journal of Clinical Trials, 2016

Recent studies have shown that many pathological conditions, including neurodegenerative disorder... more Recent studies have shown that many pathological conditions, including neurodegenerative disorders, are always the result of innate immune dysregulations. In multiple sclerosis (MS), innate immunity has shown induce proinflammatory responses, mainly mediated by specific innate immune receptors, as well as Toll-like receptors (TLRs). Interestingly, whereas activation of TLR-MyD88 dependent signaling pathway induces inflammation and MS progression, TLR3 activation MyD88 independent seems to play a beneficial effect, probably due to its ability to enhance endogenous IFN-β production, that in turn down regulates proinflammatory responses. Consequently, new therapeutic approaches based on TLR up and/or down regulation could offer promising results. In addition to several classes of TLR antagonists represented by different types of antibodies, nanobodies, mimetic molecules and RNAselective interference compounds, TLR3 agonists appear particularly interesting due to their capability of inducing IFN-β production. Among these, Ampligen® shows early promise, since it has shown positive results in several phase III trials for the treatment of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME), an illness that shows remarkable levels of similarity with MS.

Journal of Clinical & Cellular Immunology, 2015

Perturbations in immune processes play an important role in multiple sclerosis (MS), an autoimmun... more Perturbations in immune processes play an important role in multiple sclerosis (MS), an autoimmune disorder where specific innate immune pattern-recognition receptors (PRRs), such as Toll-like receptors (TLRs) have recently been shown to play a major role in the initiation disease, the triggering of relapses, and regulation of CNS damage. The abnormal immune response in MS has been shown to be dependent on genetic background, despite environmental factors, including pathogens capable of overstimulating innate immune response through TLRs, appear to contribute to the development of autoreactive T cells that in turn cause myelin damage. However, whereas the upregulation of most TLRs plays a detrimental role in MS pathogenesis, recent studies suggest an ameliorative role of TLR3 in the onset and progression of MS and experimental autoimmune encephalomyelitis (EAE), a murine model of MS. TLR3 activation appears to protect from the disease, mainly through induction of interferon (IFN)β. Therefore, TLR3 stimulation with synthetic immunomodulators could represent a potential alternative approach in MS therapy. Among the investigational compounds TLR3-targeting, the mismatched double-stranded RNA molecule Ampligen ® , can offer promise in the treatment of relapsing MS patients. Ampligen ® is currently in phase III clinical trial in the treatment of chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME), an illness that shows remarkable levels of similarity with MS. The aim of this paper is to provide a brief overview about Ampligen® historical development, clinical pharmacology, clinical trials, and safety data, and to discuss about its potential role in MS treatment in the context of existing therapeutic options.

Journal of Neurology

Parkinson’s disease (PD) is a chronic progressive neurodegenerative disorder characterized by mot... more Parkinson’s disease (PD) is a chronic progressive neurodegenerative disorder characterized by motor and non-motor disturbances as a result of a complex and not fully understood pathogenesis, probably including neuroinflammation, oxidative stress, and formation of alpha-synuclein (α-syn) aggregates. As age is the main risk factor for several neurodegenerative disorders including PD, progressive aging of the immune system leading to inflammaging and immunosenescence may contribute to neuroinflammation leading to PD onset and progression; abnormal α-syn aggregation in the context of immune dysfunction may favor activation of nucleotide-binding oligomerization domain-like receptor (NOD) family pyrin domain containing 3 (NLRP3) inflammasome within microglial cells through interaction with toll-like receptors (TLRs). This process would further lead to activation of Caspase (Cas)-1, and increased production of pro-inflammatory cytokines (PC), with subsequent impairment of mitochondria and ...

Journal of AOAC INTERNATIONAL, 2020

The interest in polyphenols from vegetable sources has been progressively increased because of th... more The interest in polyphenols from vegetable sources has been progressively increased because of the demonstrated correlation between their abundance in certain foods or food preparations of traditional importance and heritage, and the answer of anti-inflammatory strategies in hospitalized patients in the presence of polypehnol-rich foods (as a complementary therapy). Consequently, research involving the accessory role of polyphenols as anti-tumoral aids have been carried out with the aim of finding new additional strategies. The purpose of this paper to evaluate the role of phenolic compounds in foods with reference to health effects for human beings. The importance of these molecules has been evaluated by the health and safety perspectives in terms of: fight to cardiovascular diseases; prevention of chronic-degenerative disorders; general antioxidant properties; and anticarcinogenic features. Moreover, the role of polyphenols-rich foods as anticancer agents has been discussed with r...

The Journal of Immunology, 2007

STAT1 Regulates IFN-αβ-and IFN-γ-Dependent Control of Infection with Chlamydia pneumoniae by Nonh... more STAT1 Regulates IFN-αβ-and IFN-γ-Dependent Control of Infection with Chlamydia pneumoniae by Nonhemopoietic Cells

Infection and immunity, 1997

Cytokines are suspected to play an important role in systemic infections by group B streptococci ... more Cytokines are suspected to play an important role in systemic infections by group B streptococci (GBS), an important cause of neonatal sepsis. This work was undertaken to determine if interleukin 12 (IL-12) is produced in mouse pups infected with GBS and has a role in this sepsis model. IL-12 elevations were measured by both an enzyme-linked immunosorbent assay and a bioassay in plasma samples obtained from 12 to 72 h after GBS challenge. Pretreatment with neutralizing anti-IL-12 antibodies significantly increased lethality and blood CFU (P < 0.05). Conversely, either prophylactically or therapeutically administered recombinant IL-12 (rIL-12) significantly improved survival time and decreased blood CFU. Since these beneficial effects were associated with increased spleen gamma interferon (IFN-gamma) production, we examined whether the latter cytokine mediated the observed rIL-12 effects. Pretreatment with neutralizing anti-IFN-gamma monoclonal antibodies significantly counteracte...

CNS & Neurological Disorders - Drug Targets, 2014

Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp... more Alzheimer&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s disease (AD) is a neurodegenerative disorder mainly characterized by amyloid-β (Aβ) plaques, neurofibrillary tangles, loss of synapses and neurons and chronic neuroinflammation. Emerging data highlight the involvement of innate immunity, that has been shown to play opposing roles during the AD progression. Activated microglia and reactive astrocytes exert neuroprotection mediated through Aβ phagocytosis in the early stage, whereas, as the disease progresses, they fail in Aβ clearance and exert detrimental effects, including neuroinflammation and neurodegeneration. Specific toll-like receptors (TLRs) and coreceptors can directly or indirectly be activated to induce Aβ uptake or inflammatory responses, depending on the disease stage. Fibrillar Aβ can directly interact with TLR2, TLR4, and CD14 to induce microglial Aβ phagocytosis in the beginning stages, and neuroinflammatory responses in the late stages. Early TLR3-mediated signal enhances neuronal Aβ autophagy, although it increases neuronal apoptosis in the late AD stage. Similarly, TLR7, TLR8 and TLR9 can enhance microglial Aβ uptake in the early stage, but over time they contribute to neuroinflammation. Therefore, TLRs, and in particular TLR2 and TLR4, represent a suitable target for therapeutic intervention within the disease progression and targeting them carefully could increase Aβ autophagy and phagocytosis or reduce inflammatory responses. Several modulators with selective TLR agonist or antagonist activity have been developed, and many of them could have a therapeutic benefit in AD patients. This paper outlines the role of specific TLRs in AD, also focusing on TLR-targeted compounds yet indicated for the treatment of other inflammatory diseases, that could be used to treat the different stages of the disease.

The Journal of Immunology, 2008