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Neurodegenerative diseases, such as Alzheimer's disease (AD) and Parkinson's disease (PD), are severe age-related disorders with complex and multifactorial causes. Recent research suggests a critical link between neurodegeneration and the gut microbiome, via the gut-brain communication pathway. This review examines the role of trimethylamine N-oxide (TMAO), a gut microbiota-derived metabolite, in the development of AD and PD, and investigates its interaction with microRNAs (miRNAs) along this bidirectional pathway. TMAO, which is produced from dietary metabolites like choline and carnitine, has been linked to increased neuroinflammation, protein misfolding, and cognitive decline. In AD, elevated TMAO levels are associated with amyloid-beta and tau pathologies, blood-brain barrier disruption, and neuronal death. TMAO can cross the blood-brain barrier and promote the aggregation of amyloid and tau proteins. Similarly, TMAO affects alpha-synuclein conformation and aggregation, a hallmark of PD. TMAO also activates pro-inflammatory pathways such as NF-kB signaling, exacerbating neuroinflammation further. Moreover, TMAO modulates the expression of various miRNAs that are involved in neurodegenerative processes. Thus, the gut microbiome-miRNA-brain axis represents a newly discovered mechanistic link between gut dysbiosis and neurodegeneration. MiRNAs regulate the key pathways involved in neuroinflammation, oxidative stress, and neuronal death, contributing to disease progression. As a direct consequence, specific miRNA signatures may serve as potential biomarkers for the early detection and monitoring of AD and PD progression. This review aims to elucidate the complex interrelationships between the gut microbiota, trimethylamine-N-oxide (TMAO), microRNAs (miRNAs), and the central nervous system, and the implications of these connections in neurodegenerative diseases. In this context, an overview of the current neuroradiology techniques available for studying neuroinflammation and of the animal models used to investigate these intricate pathologies will also be provided. In summary, a bulk of evidence supports the concept that modulating the gut-brain communication pathway through dietary changes, the manipulation of the microbiome, and/or miRNA-based therapies may offer novel approaches for implementing the treatment of debilitating neurological disorders.

Trimethyl- N -oxide (TMAO) has been linked to peripheral artery disease (PAD). Taurisolo Ⓡ is a natural, balanced phytocomplex containing resveratrol, quercetin, catechins, procianidins, gallic acid, and caffeic acid. Numerous studies have shown that Taurisolo Ⓡ reduces the damage of TMAO and exerts a protective effect on endothelial cells (ECs). The aim of this randomized, double-blind, single-center study was to evaluate the effects of Taurisolo Ⓡ on claudication in patients with PAD (Rutheford grade I, category II, Fontaine Classification: Stage IIA, American Medical Association Whole Person Impairment Classification: Class 0-WPI 0%) in two parallel groups of 31 patients. The primary outcomes were an increase in the pain-free walking distance and the ankle/brachial pressure index at the beginning and at the end of the treatment with Taurisolo. The secondary endpoint was the serum TMAO changes. The claudication distance improved by 14.1% in the Taurisolo group and by 2.0% in the placebo group, while the maximal distance increased by 15.8% and 0.6% only, respectively (both p < 0.05). The TMAO plasma levels decreased from 3.97 ± 2.13 micromole/L to 0.87 ± 0.48 ( p < 0.0001) in the treated group. All these changes were highly significant both in univariate mixed models as well as in the adjusted model. Ultimately, Taurisolo Ⓡ might be an effective intervention to ameliorate intermittent claudication.

N-acetylcysteine (NAC), a mucolytic agent and an antidote to acetaminophen intoxication, has been studied in experimental conditions and trials exploring its analgesic activity based on its antioxidant and anti-inflammatory properties. The purpose of this study is to investigate additional mechanisms, namely, the inhibition of nerve growth factor (NGF) and the activation of the Tropomyosin receptor kinase A (TrkA) receptor, which is responsible for nociception. In silico studies were conducted to evaluate dithiothreitol and NAC's interaction with TrkA. We also measured the autophosphorylation of TrkA in SH-SY5Y cells via ELISA to assess NAC's in vitro activity against NGF-induced TrkA activation. The in silico and in vitro tests show that NAC interferes with NGF-induced TrkA activation. In particular, NAC breaks the disulfide-bound Cys 300-345 of TrkA, perturbing the NGF-TrkA interaction and producing a rearrangement of the binding site, inducing a consequent loss of their molecular recognition and spatial reorganization, which are necessary for the induction of the autophosphorylation process. The latter was inhibited by 40% using 20 mM NAC. These findings suggest that NAC could have a role as a TrkA antagonist, an action that may contribute to the activity and use of NAC in various pain states (acute, chronic, nociplastic) sustained by NGF hyperactivity and/or accompanied by spinal cord sensitization.

Background: Bone marrow (BM)-derived stem cells were implanted to induce angiogenesis in patients with no-option critical limb-threatening ischemia. Considering the potential for this therapy, conflicting results related to BM harvesting methods have been reported that could affect stem cell concentrations and quality., Methods: A total of 75 patients with no-option critical limb-threatening ischemia were treated with BM implantation. For 58 patients, BM was harvested using a BM aspirate concentrate system (Harvest Technologies; group HT) with a standard aspiration needle, followed by an automated centrifugation process, to produce BM aspirate concentrate. For 17 patients, BM was harvested using the Marrow Cellution system (Aspire Medical Innovation; group MC). CD34 + cells/mL, CD117 + cells/mL, CD133 + cells/mL, CD309 + cells/mL, hematocrit, and BM purity were compared between the two BM preparations., Results: The retrospective analysis of a subset group after adjustment for age shows that the quality of BM obtained using the Marrow Cellution system is better, in terms of purity, than the classic harvesting method before centrifugation. Harvested BM before centrifugation is characterized by a higher percentage of CD133 + cells compared with BM after centrifugation. In contrast, the MC aspirate had a larger amount of very small embryonic-like cells, as indicated by the higher percentage of CD133 + , CD34 + , and CD45 - cells. These differences translated into an increased occurrence of leg amputations in group HT than in group MC and an increase in transcutaneous oxygen pressure in patients treated with BM aspirated using MC., Conclusions: BM manipulation, such as centrifugation, affects the quality and number of stem cells, with detrimental consequences on clinical outcomes, as reflected by the different amputation rates between the two groups., Competing Interests: None., (© 2023 by the Society for Vascular Surgery. Published by Elsevier Inc.)

The kidney has a prominent role in maintaining glucose homeostasis by using glucose as a metabolic substrate. This occurs by generating glucose through gluconeogenesis, and by reuptaking filtered glucose through the sodium-glucose cotransporters SGLT1 and SGLT2 located in the proximal tubule. In recent studies, the administration of sodium-glucose cotransporters inhibitors demonstrated that inhibition of renal glucose reabsorption significantly reduces adverse renal events and heart failure exacerbations, in type 2 diabetic patients with and without cardiovascular damage as well as in advanced chronic kidney disease and heart failure patients with reduced ejection fraction with and without diabetes. The benefit was consistent throughout the different investigated clinical conditions, ameliorating overall patient outcome. The efficacy of sodium glucose cotransporters inhibitors was prominently linked to the limitation of renal damage as highlighted by the significant reduction on global mortality achieved in the studies investigating diabetic and not diabetic populations with advanced chronic kidney disease. Both studies were halted at the interim analysis because of unquestionable evidence of treatment benefit. In current review, we examine the role of SGLT2 and SGLT1 in the regulation of renal glucose reabsorption in health and disease and the effect of SGLT2 inhibition on clinical outcomes of populations with different cardiovascular conditions investigated with large-scale outcome trials., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

In the essential homeostatic role of kidney, two intrarenal mechanisms are prominent: the glomerulotubular balance driving the process of Na + and water reabsorption in the proximal tubule, and the tubuloglomerular feedback which senses the Na + concentration in the filtrate by the juxtaglomerular apparatus to provide negative feedback on the glomerular filtration rate. In essence, the two mechanisms regulate renal oxygen consumption. The renal hyperfiltration driven by increased glomerular filtration pressure and by glucose diuresis can affect renal O 2 consumption that unleashes detrimental sympathetic activation. The sodium-glucose co-transporters inhibitors (SGLTi) can rebalance the reabsorption of Na + coupled with glucose and can restore renal O 2 demand, diminishing neuroendocrine activation. Large randomized controlled studies performed in diabetic subjects, in heart failure, and in populations with chronic kidney disease with and without diabetes, concordantly address effective action on heart failure exacerbations and renal adverse outcomes.

Advancing age of the global population is one of the main reasons for the uprising trend in atrial fibrillation (AF) prevalence worldwide leading to a proper "AF epidemic". Strictly related to the increasing prevalence of AF in the elderly is the relevant burden of cardiac end extra-cardiac comorbidities that these patients show. Patients with AF are frequently asymptomatic (i.e., asymptomatic or silent AF) and thus the arrhythmia is generally underdiagnosed. Detainment of proper treatment in elderly and comorbid patients may potentially result in significant morbidity and mortality. Therefore, in recent years, several screening strategies (systematic vs opportunistic screening) for asymptomatic AF have been developed and early diagnosis of AF is an important treatment goal that can improve prognosis. This review will focus on the prevalence of asymptomatic AF in the elderly, frequently associated comorbidities, screening strategies, and implications for a correct AF diagnosis.