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Aging is a complex, multifaceted process affecting all organ systems, with vascular aging playing a central role in organismal health decline. Beyond its role in circulation, the vascular system acts as a dynamic interface between tissues, influencing countless physiological functions such as tissue regeneration and repair, immune responses, and metabolic balance. Importantly, age‐related vascular impairment—characterized by a peculiar set of endothelial aging hallmarks—exacerbates age‐related diseases (ARDs) such as cardiovascular disorders, neurodegeneration, chronic kidney disease, sarcopenia, and osteoporosis. This review combines basic concepts of angioscience and aging biology with translational interventions to devise clinical strategies promoting a functional rejuvenation of old and compromised blood vessels, fostering the prevention, delay or treatment of ARDs. Starting from the description of the cellular and molecular mechanisms driving vascular aging, a cutting‐edge perspective on the organ‐specific vascular impairment and its impact on tissue function is offered. Given the central role of the vasculature in aging, how targeting vascular aging through pharmacological, genetic, and lifestyle interventions holds promise for mitigating its systemic consequences and improving healthspan is discussed. Finally, how the combination of animal models (e.g., parabiosis) and novel microphysiological systems, coupled with multi‐omics and artificial intelligence‐driven analyses, is advancing the field toward the identification of strategies that promote vascular resilience and extend healthspan, addressing one of the most pressing biomedical challenges of a worldwide aging population is highlighted. This review spotlights the emerging field of vascular aging, providing a comprehensive and critical overview of the molecular processes and clinical manifestations of vascular dysfunction during aging. By combining basic angioscience concepts with a critical analysis of innovative pre‐clinical aging models and lifestyle interventions, it offers a cutting‐edge perspective fostering the translation of geroscience discoveries into geromedicine.

Non-healing ulcers are a serious complication of diabetes mellitus and a major unmet medical need. A major cause for the lack of healing is the impairment of spontaneous vascularization in the skin, despite mostly normal blood flow in deeper large vessels. Therefore, pro-angiogenic treatments are needed to increase therapeutic perfusion by recruiting new arterial connections (therapeutic arteriogenesis). Vascular endothelial growth factor (VEGF) is the master regulator of angiogenesis in physiology and disease, but exploitation of its therapeutic potential requires careful control of its dose distribution in tissue. Co-delivery of platelet derived growth factor-BB (PDGF-BB) has been shown to expand the therapeutic window of VEGF and also improve associated arteriogenesis. We used a highly controlled protein delivery system, based on a clinically applicable fibrin-based platform, to investigate the angiogenic and arteriogenic potential of engineered versions (TG-) of VEGF and PDGF-BB proteins in the skin of diabetic and obese db/db mice. Intradermal delivery of therapeutically relevant doses of TG-VEGF and TG-PDGF-BB induced robust growth of new microvascular networks with similar efficacy as in normal littermate control mice. Further, TG-PDGF-BB prevented the formation of aberrant vascular enlargements by high TG-VEGF levels. As fibrin was degraded after the first week, the induced angiogenesis mostly regressed by 4 weeks, but it promoted effective arteriogenesis in the dermal layer. Therefore, controlled co-delivery of TG-VEGF and TG-PDGF-BB recombinant proteins is effective to induce angiogenesis and arteriogenesis in diabetic mouse skin and should be further investigated to promote diabetic wound healing.

Chronic wounds in type-2 diabetic patients present areas of severe local skin ischemia despite mostly normal blood flow in deeper large arteries. Therefore, restoration of blood perfusion requires the opening of arterial connections from the deep vessels to the superficial skin layer, that is, arteriogenesis. Arteriogenesis is regulated differently from microvascular angiogenesis and is optimally stimulated by high doses of Vascular Endothelial Growth Factor-A (VEGF) together with Platelet-Derived Growth Factor-BB (PDGF-BB). Here we found that fibrin hydrogels decorated with engineered versions of VEGF and PDGF-BB proteins, to ensure protection from degradation and controlled delivery, efficiently accelerated wound closure in diabetic and obese db/db mice, promoting robust microvascular growth and a marked increase in feeding arterioles. Notably, targeting the arteriogenic factors to the intact arterio-venous networks in the dermis around the wound was more effective than the routine treatment of the inflamed wound bed. This approach is readily translatable to a clinical setting.

An Australian case series study demonstrated the effectiveness of the REsilience and Activities for every DaY for people with multiple sclerosis (READY for MS), a resilience group training program based on Acceptance and Commitment Therapy, in improving quality of life in people with MS. This study aimed to evaluate the feasibility and acceptability of the Italian READY for MS program, and to preliminary assess its efficacy when compared to an active control intervention (group relaxation). Single-blind phase II randomized controlled trial (RCT) and nested qualitative study (ISRCTN registration number: 38971970). Health-related quality of life (primary study outcome), mood, resilience, psychological flexibility and its protective factors were measured at baseline, after seven, 12 and 24 weeks. READY participants completed the purpose-built satisfaction questionnaire after 12 weeks. After trial completion, the control group also received READY. One-to-one participant interviews were conducted within three months of finishing the READY groups. Four intervention groups were conducted with 39 participants (20 READY, 19 relaxation). Two patients (READY) withdrew before beginning the intervention due to unexpected work commitments. Feasibility and acceptability of READY were good, with high participant engagement and satisfaction. No statistical effects of READY were detected vs relaxation. Thirty participants were interviewed (18 READY; 12 relaxation + READY). Content data analysis revealed seven overarching themes: \"Attitudes towards participation\"; \"Perceptions of program composition\"; \"Program impacts on life domains\"; \"Program active elements\"; \"Program improvement trajectories\"; \"Program differences and similarities\"; \"Suggested READY improvements\". READY was well accepted by MS patients with varied socio-demographic and clinical characteristics. Qualitative (but not quantitative) data provided evidence in favour of READY. Our findings will inform methodological and intervention refinements for the multi-centre RCT that will follow.

Purpose The common marmoset is a small nonhuman primate that has emerged as a valuable animal model in neuroscience research. Accurate analysis of brain tissue is crucial to understand marmoset neurophysiology and to model neurodegenerative diseases. Many studies to date have complemented magnetic resonance imaging (MRI) with histochemical staining rather than immunofluorescent labeling, which can generate more informative and higher resolution images. There is a need for high‐throughput immunolabeling and imaging methodologies to generate resources for the burgeoning marmoset field, particularly brain histology atlases to display the organization of different cell types and other structures. Methods and Findings Here, we have characterized a set of marmoset‐compatible fluorescent dyes and antibodies that label myelin, axons, dendrites, and the iron‐storage protein ferritin, and developed a batch‐style multiplex immunohistochemistry protocol to uniformly process large numbers of tissue slides for multiple cell‐type specific markers. Conclusion We provide a practical guide for researchers interested in harnessing the potential of marmoset models to advance understanding of brain structure, function, and pathophysiology. To support high‐throughput immunolabeling and imaging methodologies for the burgeoning marmoset field, we characterize a set of marmoset‐compatible fluorescent dyes and antibodies and provide a practical batch‐style multiplex immunohistochemistry protocol for researchers interested in harnessing the potential of marmoset models to advance understanding of brain connectomics, function, and pathophysiology.

BackgroundAssessing the coverage by public or private resources in meeting health-related and social-related needs may be useful for service planning and guide optimization of care, important especially in view of an increase in the prevalence of multiple sclerosis (MS).MethodsAn ad hoc questionnaire assessed satisfaction of health-related and social care–related needs in a cross-sectional study of 1014 people with MS identified through MS outpatient clinics and local branches and social media channels of the Italian MS Society.Results87.1% and 79.8% of the responders had experienced at least one health-related or social-related need, respectively. The study demonstrated significant gaps between perceived needs and service provision. Rehabilitation, residential care, and psychological support were most frequently unsatisfied health-related needs, while the more commonly unmet social-related needs were financial support, elimination of architectural barriers, workplace adaptations, and career guidance. The multivariate analysis highlighted that the satisfaction of health-related needs was primarily associated with geographic area of residence. Social-related needs correlated with both clinical and sociodemographic aspects.ConclusionThe results provide insight into the range of interventions, care, and support people with MS report to be important to them at different points in their disease trajectory. More emphasis should be put on the inequitable distribution of NHS services in different geographic areas of Italy as well as on particularly fragile subgroups of the MS population (older individuals, and those with higher levels of disability) because the care of these individuals continues to be assumed by the family.

Whether T H 1 or T H -17 cells initiate experimental autoimmune encephalomyelitis is unclear. Sallusto and colleagues now show that CCR6 + T H -17 lymphocytes initiate it by entering the brain through the choroid plexus. Interleukin 17–producing T helper cells (T H -17 cells) are important in experimental autoimmune encephalomyelitis, but their route of entry into the central nervous system (CNS) and their contribution relative to that of other effector T cells remain to be determined. Here we found that mice lacking CCR6, a chemokine receptor characteristic of T H -17 cells, developed T H -17 responses but were highly resistant to the induction of experimental autoimmune encephalomyelitis. Disease susceptibility was reconstituted by transfer of wild-type T cells that entered into the CNS before disease onset and triggered massive CCR6-independent recruitment of effector T cells across activated parenchymal vessels. The CCR6 ligand CCL20 was constitutively expressed in epithelial cells of choroid plexus in mice and humans. Our results identify distinct molecular requirements and ports of lymphocyte entry into uninflamed versus inflamed CNS and suggest that the CCR6-CCL20 axis in the choroid plexus controls immune surveillance of the CNS.

Background Experimental autoimmune encephalomyelitis (EAE) is the most common animal model of multiple sclerosis (MS), a neuroinflammatory and demyelinating disease characterized by multifocal perivascular infiltrates of immune cells. Although EAE is predominantly considered a T helper 1-driven autoimmune disease, mounting evidence suggests that activated dendritic cells (DC), which are the bridge between innate and adaptive immunity, also contribute to its pathogenesis. Sirtuin 6 (SIRT6), a NAD + -dependent deacetylase involved in genome maintenance and in metabolic homeostasis, regulates DC activation, and its pharmacological inhibition could, therefore, play a role in EAE development. Methods EAE was induced in female C57bl/6 mice by MOG35-55 injection. The effect of treatment with a small compound SIRT6 inhibitor, administered according to therapeutic and preventive protocols, was assessed by evaluating the clinical EAE score. SIRT6 inhibition was confirmed by Western blot analysis by assessing the acetylation of histone 3 lysine 9, a known SIRT6 substrate. The expression of DC activation and migration markers was evaluated by FACS in mouse lymph nodes. In addition, the expression of inflammatory and anti-inflammatory cytokines in the spinal cord were assessed by qPCR. T cell infiltration in spinal cords was evaluated by immunofluorescence imaging. The effect of Sirt6 inhibition on the migration of resting and activated bone marrow-derived dendritic cells was investigated in in vitro chemotaxis assays. Results Preventive pharmacological Sirt6 inhibition effectively delayed EAE disease onset through a novel regulatory mechanism, i.e., by reducing the representation of CXCR4-positive and of CXCR4/CCR7-double-positive DC in lymph nodes. The delay in EAE onset correlated with the early downregulation in the expression of CD40 on activated lymph node DC, with increased level of the anti-inflammatory cytokine IL-10, and with a reduced encephalitogenic T cell infiltration in the central nervous system. Consistent with the in vivo data, in vitro pharmacological Sirt6 inhibition in LPS-stimulated, bone marrow-derived DC reduced CCL19/CCL21- and SDF-1-induced DC migration. Conclusions Our findings indicate the ability of Sirt6 inhibition to impair DC migration, to downregulate pathogenic T cell inflammatory responses and to delay EAE onset. Therefore, Sirt6 might represent a valuable target for developing novel therapeutic agents for the treatment of early stages of MS, or of other autoimmune disorders.

A potential overlap in symptoms between post-acute COVID-19 syndrome and post-COVID-19 vaccination syndrome has been noted. We report a paired description of patients presenting with similar manifestations involving the central (CNS) or peripheral nervous system (PNS) following SARS-CoV-2 infection or vaccination, suggesting that both may have triggered similar immune-mediated neurological disorders in the presence of anti-idiotype antibodies directed against the ACE2 protein. Four patients exhibited overlapping neurological manifestations following SARS-CoV-2 infection or vaccination: radiculitis, Guillain-Barré syndrome, and MRI-negative myelitis, respectively, sharing positivity for anti-ACE2 antibodies. Autoantibodies against AQP-4, MOG, GlyR, GAD, and amphiphysin, onconeural antibodies for CNS syndromes, and anti-ganglioside antibodies for PNS syndromes tested negative in all patients. Anti-idiotype antibodies against ACE2 have been detected in patients who recovered from COVID-19 infection, and it has been hypothesized that such antibodies may mediate adverse events following SARS-CoV-2 infection or vaccination, resulting in the activation of the immune system against cells expressing ACE2, such as neurons. Our data reveal clinically overlapping syndromes triggered by SARS-CoV-2 infection or vaccination, sharing positivity for anti-ACE2 antibodies. Their presence, in the absence of other classic autoimmune markers of CNS or PNS involvement, suggests that they might play an active role in the context of an aberrant immune response. Anti-idiotype antibodies directed against ACE2 may be triggered by both SARS-CoV-2 infection and vaccination, possibly contributing to neurological autoimmune manifestations. Their pathogenic role, however, remains to be demonstrated in large-scale, more structured studies.

The reliable and efficient production of radioisotopes for diagnosis and therapy is becoming an increasingly important capability, due to their demonstrated utility in Nuclear Medicine applications. Starting from the first processes involving the separation of 99mTc from irradiated materials, several methods and concepts have been developed to selectively extract the radioisotopes of interest. Even though the initial methods were based on liquid-liquid extraction (LLE) approaches, the perceived difficulty in automating such processes has slowly moved the focus towards resin separation methods, whose basic chemical principles are often similar to the LLE ones in terms of chelators and phases. However, the emerging field of flow chemistry allows LLE to be easily automated and operated in a continuous manner, resulting in an even improved efficiency and reliability. In this contribution, we will outline the fundamentals of LLE processes and their translation into flow-based apparatuses; in addition, we will provide examples of radioisotope separations that have been achieved using LLE methods. This article is intended to offer insights about the future potential of LLE to purify medically relevant radioisotopes.