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The brain-gut-microbiota interplay in depression: A key to design innovative therapeutic approaches.
Varesi, A, Campagnoli, LIM, Chirumbolo, S, Candiano, B, Carrara, A, Ricevuti, G, Esposito, C, Pascale, A
Pharmacological research. 2023;:106799
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Abstract
Depression is the most prevalent mental disorder in the world associated with huge socio-economic consequences. While depressive-related symptoms are well known, the molecular mechanisms underlying disease pathophysiology and progression remain largely unknown. The gut microbiota (GM) is emerging as a key regulator of the central nervous system homeostasis by exerting fundamental immune and metabolic functions. In turn, the brain influences the intestinal microbial composition through neuroendocrine signals, within the so-called gut microbiota-brain axis. The balance of this bidirectional crosstalk is important to ensure neurogenesis, preserve the integrity of the blood-brain barrier and avoid neuroinflammation. Conversely, dysbiosis and gut permeability negatively affect brain development, behavior, and cognition. Furthermore, although not fully defined yet, changes in the GM composition in depressed patients are reported to influence the pharmacokinetics of common antidepressants by affecting their absorption, metabolism, and activity. Similarly, neuropsychiatric drugs may shape in turn the GM with an impact on the efficacy and toxicity of the pharmacological intervention itself. Consequently, strategies aimed at re-establishing the correct homeostatic gut balance (i.e., prebiotics, probiotics, fecal microbiota transplantation, and dietary interventions) represent an innovative approach to improve the pharmacotherapy of depression. Among these, probiotics and the Mediterranean diet, alone or in combination with the standard of care, hold promise for clinical application. Therefore, the disclosure of the intricate network between GM and depression will give precious insights for innovative diagnostic and therapeutic approaches towards depression, with profound implications for drug development and clinical practice.
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Hypothermia: Beyond the Narrative Review-The Point of View of Emergency Physicians and Medico-Legal Considerations.
Savioli, G, Ceresa, IF, Bavestrello Piccini, G, Gri, N, Nardone, A, La Russa, R, Saviano, A, Piccioni, A, Ricevuti, G, Esposito, C
Journal of personalized medicine. 2023;(12)
Abstract
Hypothermia is a widespread condition all over the world, with a high risk of mortality in pre-hospital and in-hospital settings when it is not promptly and adequately treated. In this review, we aim to describe the main specificities of the diagnosis and treatment of hypothermia through consideration of the physiological changes that occur in hypothermic patients. Hypothermia can occur due to unfavorable environmental conditions as well as internal causes, such as pathological states that result in reduced heat production, increased heat loss or ineffectiveness of the thermal regulation system. The consequences of hypothermia affect several systems in the body-the cardiovascular system, the central and peripheral nervous systems, the respiratory system, the endocrine system and the gastrointestinal system-but also kidney function, electrolyte balance and coagulation. Once hypothermia is recognized, prompt treatment, focused on restoring body temperature and supporting vital functions, is fundamental in order to avert preventable death. It is important to also denote the fact that CPR has specificities related to the unique profile of hypothermic patients.
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Non-Enzymatic Antioxidants against Alzheimer's Disease: Prevention, Diagnosis and Therapy.
Varesi, A, Campagnoli, LIM, Carrara, A, Pola, I, Floris, E, Ricevuti, G, Chirumbolo, S, Pascale, A
Antioxidants (Basel, Switzerland). 2023;(1)
Abstract
Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive memory loss and cognitive decline. Although substantial research has been conducted to elucidate the complex pathophysiology of AD, the therapeutic approach still has limited efficacy in clinical practice. Oxidative stress (OS) has been established as an early driver of several age-related diseases, including neurodegeneration. In AD, increased levels of reactive oxygen species mediate neuronal lipid, protein, and nucleic acid peroxidation, mitochondrial dysfunction, synaptic damage, and inflammation. Thus, the identification of novel antioxidant molecules capable of detecting, preventing, and counteracting AD onset and progression is of the utmost importance. However, although several studies have been published, comprehensive and up-to-date overviews of the principal anti-AD agents harboring antioxidant properties remain scarce. In this narrative review, we summarize the role of vitamins, minerals, flavonoids, non-flavonoids, mitochondria-targeting molecules, organosulfur compounds, and carotenoids as non-enzymatic antioxidants with AD diagnostic, preventative, and therapeutic potential, thereby offering insights into the relationship between OS and neurodegeneration.
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Blood-Based Biomarkers for Alzheimer's Disease Diagnosis and Progression: An Overview.
Varesi, A, Carrara, A, Pires, VG, Floris, V, Pierella, E, Savioli, G, Prasad, S, Esposito, C, Ricevuti, G, Chirumbolo, S, et al
Cells. 2022;(8)
Abstract
Alzheimer's Disease (AD) is a progressive neurodegenerative disease characterized by amyloid-β (Aβ) plaque deposition and neurofibrillary tangle accumulation in the brain. Although several studies have been conducted to unravel the complex and interconnected pathophysiology of AD, clinical trial failure rates have been high, and no disease-modifying therapies are presently available. Fluid biomarker discovery for AD is a rapidly expanding field of research aimed at anticipating disease diagnosis and following disease progression over time. Currently, Aβ1-42, phosphorylated tau, and total tau levels in the cerebrospinal fluid are the best-studied fluid biomarkers for AD, but the need for novel, cheap, less-invasive, easily detectable, and more-accessible markers has recently led to the search for new blood-based molecules. However, despite considerable research activity, a comprehensive and up-to-date overview of the main blood-based biomarker candidates is still lacking. In this narrative review, we discuss the role of proteins, lipids, metabolites, oxidative-stress-related molecules, and cytokines as possible disease biomarkers. Furthermore, we highlight the potential of the emerging miRNAs and long non-coding RNAs (lncRNAs) as diagnostic tools, and we briefly present the role of vitamins and gut-microbiome-related molecules as novel candidates for AD detection and monitoring, thus offering new insights into the diagnosis and progression of this devastating disease.
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Home pharmacological therapy in early COVID-19 to prevent hospitalization and reduce mortality: Time for a suitable proposal.
Pandolfi, S, Chirumbolo, S, Ricevuti, G, Valdenassi, L, Bjørklund, G, Lysiuk, R, Doşa, MD, Lenchyk, L, Fazio, S
Basic & clinical pharmacology & toxicology. 2022;(2):225-239
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Abstract
The COVID-19 pandemic is a highly dramatic concern for mankind. In Italy, the pandemic exerted its major impact throughout the period of February to June 2020. To date, the awkward amount of more than 134,000 deaths has been reported. Yet, post-mortem autopsy was performed on a very modest number of patients who died from COVID-19 infection, leading to a first confirmation of an immune-thrombosis of the lungs as the major COVID-19 pathogenesis, likewise for SARS. Since then (June-August 2020), no targeted early therapy considering this pathogenetic issue was approached. The patients treated with early anti-inflammatory, anti-platelet, anticoagulant and antibiotic therapy confirmed that COVID-19 was an endothelial inflammation with immuno-thrombosis. Patients not treated or scarcely treated with the most proper and appropriate therapy and in the earliest, increased the hospitalization rate in the intensive care units and also mortality, due to immune-thrombosis from the pulmonary capillary district and alveoli. The disease causes widespread endothelial inflammation, which can induce damage to various organs and systems. Therapy must be targeted in this consideration, and in this review, we demonstrate how early anti-inflammatory therapy may treat endothelia inflammation and immune-thrombosis caused by COVID-19, by using drugs we are going to recommend in this paper.
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The Interplay between Gut Microbiota and Parkinson's Disease: Implications on Diagnosis and Treatment.
Varesi, A, Campagnoli, LIM, Fahmideh, F, Pierella, E, Romeo, M, Ricevuti, G, Nicoletta, M, Chirumbolo, S, Pascale, A
International journal of molecular sciences. 2022;(20)
Abstract
The bidirectional interaction between the gut microbiota (GM) and the Central Nervous System, the so-called gut microbiota brain axis (GMBA), deeply affects brain function and has an important impact on the development of neurodegenerative diseases. In Parkinson's disease (PD), gastrointestinal symptoms often precede the onset of motor and non-motor manifestations, and alterations in the GM composition accompany disease pathogenesis. Several studies have been conducted to unravel the role of dysbiosis and intestinal permeability in PD onset and progression, but the therapeutic and diagnostic applications of GM modifying approaches remain to be fully elucidated. After a brief introduction on the involvement of GMBA in the disease, we present evidence for GM alterations and leaky gut in PD patients. According to these data, we then review the potential of GM-based signatures to serve as disease biomarkers and we highlight the emerging role of probiotics, prebiotics, antibiotics, dietary interventions, and fecal microbiota transplantation as supportive therapeutic approaches in PD. Finally, we analyze the mutual influence between commonly prescribed PD medications and gut-microbiota, and we offer insights on the involvement also of nasal and oral microbiota in PD pathology, thus providing a comprehensive and up-to-date overview on the role of microbial features in disease diagnosis and treatment.
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The Potential Role of Gut Microbiota in Alzheimer's Disease: From Diagnosis to Treatment.
Varesi, A, Pierella, E, Romeo, M, Piccini, GB, Alfano, C, Bjørklund, G, Oppong, A, Ricevuti, G, Esposito, C, Chirumbolo, S, et al
Nutrients. 2022;14(3)
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Plain language summary
Alzheimer’s Disease (AD) affects 50,000,000 people world-wide. The disease is characterized by the deposition of beta amyloid (Aβ) plaques and tangles of hyperphosphorylated tau neurofibrils, leading to neuroinflammation and progressive cognitive decline. It is not completely clear what causes AD or how it evolves. Different therapeutic options have been proposed but many have not produced significant benefits. Recent studies have liked changes in the gut microbiome to neurodegeneration via the gut microbiota brain axis (GMBA). This review summarises the role of the gut microbiota in brain health and disease and it shows evidence for its dysregulation in AD patients. The review discusses how certain markers of dysbiosis might be used as a diagnostic tool for AD. Therapeutic interventions such as prebiotics, specific probiotics, fecal microbiota transplantation and diets are discussed. Although promising results have been published, more research is needed before considering a clinical application.
Abstract
Gut microbiota is emerging as a key regulator of many disease conditions and its dysregulation is implicated in the pathogenesis of several gastrointestinal and extraintestinal disorders. More recently, gut microbiome alterations have been linked to neurodegeneration through the increasingly defined gut microbiota brain axis, opening the possibility for new microbiota-based therapeutic options. Although several studies have been conducted to unravel the possible relationship between Alzheimer's Disease (AD) pathogenesis and progression, the diagnostic and therapeutic potential of approaches aiming at restoring gut microbiota eubiosis remain to be fully addressed. In this narrative review, we briefly summarize the role of gut microbiota homeostasis in brain health and disease, and we present evidence for its dysregulation in AD patients. Based on these observations, we then discuss how dysbiosis might be exploited as a new diagnostic tool in early and advanced disease stages, and we examine the potential of prebiotics, probiotics, fecal microbiota transplantation, and diets as complementary therapeutic interventions on disease pathogenesis and progression, thus offering new insights into the diagnosis and treatment of this devastating and progressive disease.
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The Role of Antioxidants in the Interplay between Oxidative Stress and Senescence.
Varesi, A, Chirumbolo, S, Campagnoli, LIM, Pierella, E, Piccini, GB, Carrara, A, Ricevuti, G, Scassellati, C, Bonvicini, C, Pascale, A
Antioxidants (Basel, Switzerland). 2022;(7)
Abstract
Cellular senescence is an irreversible state of cell cycle arrest occurring in response to stressful stimuli, such as telomere attrition, DNA damage, reactive oxygen species, and oncogenic proteins. Although beneficial and protective in several physiological processes, an excessive senescent cell burden has been involved in various pathological conditions including aging, tissue dysfunction and chronic diseases. Oxidative stress (OS) can drive senescence due to a loss of balance between pro-oxidant stimuli and antioxidant defences. Therefore, the identification and characterization of antioxidant compounds capable of preventing or counteracting the senescent phenotype is of major interest. However, despite the considerable number of studies, a comprehensive overview of the main antioxidant molecules capable of counteracting OS-induced senescence is still lacking. Here, besides a brief description of the molecular mechanisms implicated in OS-mediated aging, we review and discuss the role of enzymes, mitochondria-targeting compounds, vitamins, carotenoids, organosulfur compounds, nitrogen non-protein molecules, minerals, flavonoids, and non-flavonoids as antioxidant compounds with an anti-aging potential, therefore offering insights into innovative lifespan-extending approaches.
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Rates of Intracranial Hemorrhage in Mild Head Trauma Patients Presenting to Emergency Department and Their Management: A Comparison of Direct Oral Anticoagulant Drugs with Vitamin K Antagonists.
Savioli, G, Ceresa, IF, Luzzi, S, Gragnaniello, C, Giotta Lucifero, A, Del Maestro, M, Marasco, S, Manzoni, F, Ciceri, L, Gelfi, E, et al
Medicina (Kaunas, Lithuania). 2020;(6)
Abstract
Background and objectives: Anticoagulants are thought to increase the risks of traumatic intracranial injury and poor clinical outcomes after blunt head trauma. The safety of using direct oral anticoagulants (DOACs) compared to vitamin K antagonists (VKAs) after intracranial hemorrhage (ICH) is unclear. This study aims to compare the incidence of post-traumatic ICH following mild head injury (MHI) and to assess the need for surgery, mortality rates, emergency department (ED) revisit rates, and the volume of ICH. Materials and Methods: This is a retrospective, single-center observational study on all patients admitted to our emergency department for mild head trauma from 1 January 2016, to 31 December 2018. We enrolled 234 anticoagulated patients, of which 156 were on VKAs and 78 on DOACs. Patients underwent computed tomography (CT) scans on arrival (T0) and after 24 h (T24). The control group consisted of patients not taking anticoagulants, had no clotting disorders, and who reported an MHI in the same period. About 54% in the control group had CTs performed. Results: The anticoagulated groups were comparable in baseline parameters. Patients on VKA developed ICH more frequently than patients on DOACs and the control group at 17%, 5.13%, and 7.5%, respectively. No significant difference between the two groups was noted in terms of surgery, intrahospital mortality rates, ED revisit rates, and the volume of ICH. Conclusions: Patients with mild head trauma on DOAC therapy had a similar prevalence of ICH to that of the control group. Meanwhile, patients on VKA therapy had about twice the ICH prevalence than that on the control group or patients on DOAC, which remained after correcting for age. No significant difference in the need for surgery was determined; however, this result must take into account the very small number of patients needing surgery.
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Neuroinflammation, immune system and Alzheimer disease: searching for the missing link.
Guerriero, F, Sgarlata, C, Francis, M, Maurizi, N, Faragli, A, Perna, S, Rondanelli, M, Rollone, M, Ricevuti, G
Aging clinical and experimental research. 2017;(5):821-831
Abstract
Due to an increasingly aging population, Alzheimer disease (AD) represents a crucial issue for the healthcare system because of its widespread prevalence and the burden of its care needs. Several hypotheses on AD pathogenesis have been proposed and current therapeutical strategies have shown limited effectiveness. In the last decade, more evidence has supported a role for neuroinflammation and immune system dysregulation in AD. It remains unclear whether astrocytes, microglia and immune cells influence disease onset, progression or both. Amyloid-β peptides that aggregate extracellularly in the typical neuritic plaques generate a constant inflammatory environment. This causes a prolonged activation of microglial and astroglial cells that potentiate neuronal damage and provoke the alteration of the blood brain barrier (BBB), damaging the permeability of blood vessels. Recent data support the role of the BBB as a link between neuroinflammation, the immune system and AD. Hence, a thorough investigation of the neuroinflammatory and immune system pathways that impact neurodegeneration and novel exciting findings such as microglia-derived microvesicles, inflammasomes and signalosomes will ultimately enhance our understanding of the pathological process. Eventually, we should proceed with caution in defining a causal or consequential role of neuroinflammation in AD, but rather focus on identifying its exact pathological contribution.