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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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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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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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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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Postprandial Glycemic and Insulinemic Response by a Brewer's Spent Grain Extract-Based Food Supplement in Subjects with Slightly Impaired Glucose Tolerance: A Monocentric, Randomized, Cross-Over, Double-Blind, Placebo-Controlled Clinical Trial.
Ullah, H, Esposito, C, Piccinocchi, R, De Lellis, LF, Santarcangelo, C, Minno, AD, Baldi, A, Buccato, DG, Khan, A, Piccinocchi, G, et al
Nutrients. 2022;(19)
Abstract
Dietary fiber exerts beneficial effects on human health reducing the risk factors of metabolic related diseases such as hyperglycemia, insulin resistance, and hypercholesterolemia. The aim of this study is to demonstrate the efficacy of a food supplement based on brewer's spent grain (BSG) extract in the reduction of postprandial glycemia and insulinemia in normoglycemic subjects. BSG was chemically characterized, revealing the presence of resistant starch (14.64 g/100 g), arabinoxylans (7.50 g/100 g), β-glucans (1.92 g/100 g) and other soluble fibers (6.43 g/100 g), and bioaccessible ferulic acid (91.3 mg/100 g). For the clinical study, 40 normoglycemic subjects were randomized into two groups, 1 and 2 (n = 20), for a cross-over clinical design and received either BSG extract-based food supplement or placebo. Postprandial blood glucose values were significantly lower than corresponding values in the placebo group after 90 and 120 min, while at the baseline and in the first 60 min, the two glycemic curves overlapped substantially. This improved clinical outcome was corroborated by significant reductions in postprandial insulinemia. None of the subjects reported adverse effects. This study showed that the tested BSG extract-based food supplement improves glucose metabolism and insulinemic response in normoglycemic subjects with at most a mild insulin resistance.
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Clinical correlates of serum 25-hydroxyvitamin D in Parkinson's disease.
Barichella, M, Cereda, E, Iorio, L, Pinelli, G, Ferri, V, Cassani, E, Bolliri, C, Caronni, S, Pusani, C, Schiaffino, MG, et al
Nutritional neuroscience. 2022;(6):1128-1136
Abstract
BACKGROUND Parkinson's disease (PD) patients have lower levels of serum 25-hydroxyvitamin D (25(OH)D) than the general population. Previous studies have suggested a negative association between 25(OH)D and clinical features of PD, but the data are inconsistent. MATERIALS AND METHODS We conducted a cross-sectional, observational study. Serum 25(OH)D, disease (Hoehn-Yahr stage [HY]) and clinical symptom (Unified Parkinson Disease Rating Scale [UPDRS]) severity and global cognitive functions (Mini-Mental State Examination [MMSE]) were studied in 500 consecutive PD patients not using vitamin D supplements. Information on sunlight exposure and dietary intakes (using a 66-item food frequency questionnaire) were also collected. A convenient sample of age and sex-matched community healthy controls (N = 100) was included as a control group. RESULTS PD patients had lower 25(OH)D serum levels than controls. Deficiency status (<20 ng/mL) was found in 65.6% of patients. 25(OH)D levels were independently correlated to sunlight exposure (P = .002) and vitamin D intake (P = .009). In multivariate models, using a Mendelian randomization approach, lower serum 25(OH)D was associated with more severe disease (HY, P = .035), worse clinical symptoms (UPDRS Part-III total score [P = .006] and dopaminergic [P = .033] and non-dopaminergic subscores [P = .001]) and greater global cognitive function impairment (P = .041). Neither cognitive functions nor clinical features were associated with reduced intake of vitamin D and sunlight exposure. CONCLUSION : Serum 25(OH)D was negatively correlated with disease and symptoms severity, as well as with global cognitive functions. Our study adds to the evidence that low 25(OH)D may affect the progression of PD negatively. Intervention studies in this area are required.
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Roxadustat for the treatment of anemia in chronic kidney disease patients not on dialysis: a Phase 3, randomized, double-blind, placebo-controlled study (ALPS).
Shutov, E, Sułowicz, W, Esposito, C, Tataradze, A, Andric, B, Reusch, M, Valluri, U, Dimkovic, N
Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2021;(9):1629-1639
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Abstract
BACKGROUND Roxadustat is an orally active hypoxia-inducible factor prolyl hydroxylase inhibitor for the treatment of chronic kidney disease (CKD) anemia. METHODS This Phase 3, multicenter, randomized, double-blind, placebo-controlled study examined patients with Stages 3-5 CKD, not on dialysis (NCT01887600). Patients were randomized (2:1) to oral roxadustat or placebo three times weekly for 52-104 weeks. This study examined two primary efficacy endpoints: European Union (European Medicines Agency)-hemoglobin (Hb) response, defined as Hb ≥11.0 g/dL that increased from baseline (BL) by ≥1.0 g/dL in patients with Hb >8.0 g/dL or ≥2.0 g/dL in patients with BL Hb ≤8.0 g/dL, without rescue therapy, during the first 24 weeks of treatment; US Food and Drug Administration-change in Hb from BL to the average Hb level during Weeks 28-52, regardless of rescue therapy. Secondary efficacy endpoints and safety were examined. RESULTS A total of 594 patients were analyzed (roxadustat: 391; placebo: 203). Superiority of roxadustat versus placebo was demonstrated for both primary efficacy endpoints: Hb response [odds ratio = 34.74, 95% confidence interval (CI) 20.48-58.93] and change in Hb from BL [roxadustat - placebo: +1.692 (95% CI 1.52-1.86); both P < 0.001]. Superiority of roxadustat was demonstrated for low-density lipoprotein cholesterol change from BL, and time to first use of rescue medication (both P < 0.001). The incidences of treatment-emergent adverse events were comparable between groups (roxadustat: 87.7%, placebo: 86.7%). CONCLUSIONS Roxadustat demonstrated superior efficacy versus placebo in terms of both Hb response rate and change in Hb from BL. The safety profiles of roxadustat and placebo were comparable.
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Safety and efficacy of alpha-lipoic acid oral supplementation in the reduction of pain with unknown etiology: A monocentric, randomized, double-blind, placebo-controlled clinical trial.
Esposito, C, Ugo Garzarella, E, Santarcangelo, C, Di Minno, A, Dacrema, M, Sacchi, R, Piccinocchi, G, Piccinocchi, R, Daglia, M
Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie. 2021;144:112308
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The management of pain with no apparent cause, or idiopathic pain, is a real challenge. In the absence of any underlying disease that is treatable, idiopathic pain is usually addressed by relieving symptomatic pain with medication. Whereby these medications can be fast and effective, they can have limited benefits and, in some cases, considerable side effects. Alpha-lipoic acid (ALA) is a food supplement and naturally occurring compound in humans, animals and plants. Previous research suggested that it is effective in managing diabetic nerve pain. As reactive oxygen species and antioxidants appear to play a role in pain regulation, the antioxidant and anti-inflammatory activities of ALA are of interest here. In addition, ALA has a strong safety record. This study sought to investigate the safety and effectiveness of ALA in non-diabetic individuals who were diagnosed with idiopathic pain. 210 male and female subjects, from age 18-75, who were non-diabetic and on no pain medication were randomly assigned to receive either a placebo or 400 mg/day or 800 mg/day of ALA over a course of two months. The pain was tracked with two pain scoring questionnaires, whilst blood samples were monitored for adverse effects, including blood sugar, kidney and liver markers. The ALA intervention group showed a significant reduction in both pain scores compared to placebo. Treated subjects showed a marginal decrease in blood sugars of no clinical significance and no other adverse effects were reported. The authors concluded that ALA as a food supplement has suitable potential for the management of idiopathic pain. And given its safety and efficacy compared to commonly used pain medication it could be of interest in clinical application.
Abstract
INTRODUCTION Extensive evidence suggests that alpha-lipoic acid (ALA) is effective in diabetic neuropathy pain management. However, little is known on its safety and efficacy in reducing idiopathic pain in normoglycemic subjects. The aim of this study was to evaluate ALA food supplement safety and efficacy in the reduction of different forms of idiopathic pain. METHODS Two-hundred and ten normoglycemic adults suffering from idiopathic pain (i.e. 57 subjects with primitive neuropathic pain, 141 subjects with arthralgia with unknown etiology, and 12 subjects with idiopathic myalgia) were randomized to receive placebo, 400 mg/day, or 800 mg/day of ALA. Participants underwent two visits (at baseline = t0, and after 2 months = t1) in which two validated questionaries for pain (numerical rating scale [NRS] and visual analogue scale [VAS]) were collected; fasting blood glucose assessment, adverse effects, and renal and hepatic toxicity were also monitored. RESULTS At t1, none of subjects treated with ALA reported a decreased glycemia or adverse effects. The treated subjects showed a significant reduction in NRS (p < 0.001) while the placebo group did not show any NRS reduction (p = 0.86). Similar results were also obtained for VAS. Statistical analysis aimed at detecting possible differences in NRS and VAS scores among treatment groups based on the source of pain did not reveal any significant effect. CONCLUSIONS Since the management of idiopathic pain is challenging for physicians, the use of ALA food supplements could be a feasible option, based on its safety and efficacy compared to commonly-used analgesic drugs.
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Roxadustat for the Maintenance Treatment of Anemia in Patients with End-Stage Kidney Disease on Stable Dialysis: A European Phase 3, Randomized, Open-Label, Active-Controlled Study (PYRENEES).
Csiky, B, Schömig, M, Esposito, C, Barratt, J, Reusch, M, Valluri, U, Sulowicz, W
Advances in therapy. 2021;(10):5361-5380
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Abstract
INTRODUCTION Roxadustat is an orally administered hypoxia-inducible factor prolyl hydroxylase inhibitor being developed for the treatment of anemia of chronic kidney disease (CKD). This European, phase 3, randomized, open-label, active-controlled study investigated efficacy and safety of roxadustat in patients with end-stage kidney disease on dialysis for at least 4 months. METHODS Patients were randomized to switch from an erythropoiesis-stimulating agent (ESA) (epoetin alfa or darbepoetin alfa) to roxadustat three times/week or to continue their previous ESA. Roxadustat and ESA doses were adjusted to maintain hemoglobin within 10.0-12.0 g/dL during the treatment period (day 1 up to 52-104 weeks). Primary endpoints were hemoglobin change from baseline (CFB) to the average of weeks 28-36 without rescue therapy and hemoglobin CFB to the average of weeks 28-52 regardless of rescue therapy. Treatment-emergent adverse events (TEAEs) were assessed descriptively. RESULTS Of 1081 screened patients, 836 were randomized and received treatment (roxadustat, n = 415; ESA, n = 421). The least squares means (95% CI) of the treatment difference (roxadustat - ESA) for hemoglobin CFB to weeks 28-36 (without rescue therapy) and CFB to weeks 28-52 (regardless of rescue therapy) were 0.235 (0.132, 0.339) g/dL and 0.171 (0.082, 0.261) g/dL, respectively, demonstrating non-inferiority of roxadustat to ESA (non-inferiority margin of - 0.75 g/dL). The proportions of patients who achieved target hemoglobin without rescue therapy during weeks 28-36 were 84.2% (roxadustat) and 82.4% (ESA). Roxadustat was superior to ESA in decreasing LDL cholesterol from baseline to the average of weeks 12-28. Serious TEAEs occurred in 50.7% (roxadustat) and 45.0% (ESA) of patients. Common TEAEs in both treatment groups included hypertension, arteriovenous fistula thrombosis, headache, and diarrhea. CONCLUSION Roxadustat was non-inferior to ESAs in maintaining hemoglobin levels in this cohort of patients with anemia of CKD on dialysis for at least 4 months who were previously treated with ESAs. Observed TEAEs were consistent with previous studies.
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Toward an individualized determination of dialysis adequacy: a narrative review with special emphasis on incremental hemodialysis.
Torreggiani, M, Fois, A, Njandjo, L, Longhitano, E, Chatrenet, A, Esposito, C, Fessi, H, Piccoli, GB
Expert review of molecular diagnostics. 2021;(11):1119-1137
Abstract
INTRODUCTION The search for the 'perfect' renal replacement therapy has been paralleled by the search for the perfect biomarkers for assessing dialysis adequacy. Three main families of markers have been assessed: small molecules (prototype: urea); middle molecules (prototype β2-microglobulin); comprehensive and nutritional markers (prototype of the simplified assessment, albumin levels; composite indexes as malnutrition-inflammation score). After an era of standardization of dialysis treatment, personalized dialysis schedules are increasingly proposed, challenging the dogma of thrice-weekly hemodialysis. AREAS COVERED In this review, we describe the advantages and limitations of the approaches mentioned above, focusing on the open questions regarding personalized schedules and incremental hemodialysis. EXPERT OPINION In the era of personalized dialysis, the assessment of dialysis adequacy should be likewise personalized, due to the limits of 'one size fits all' approaches. We have tried to summarize some of the relevant issues regarding the determination of dialysis adequacy, attempting to adapt them to an elderly, highly comorbidity population, which would probably benefit from tailor-made dialysis prescriptions. While no single biomarker allows precisely tailoring the dialysis dose, we suggest using a combination of clinical and biological markers to prescribe dialysis according to comorbidity, life expectancy, residual kidney function, and small and medium-size molecule depuration.