BACKGROUND: Cerebral circulation delivers the blood flow to the brain through a dedicated network of sanguine vessels. A healthy human brain can regulate cerebral blood flow (CBF) according to any physiological or pathological challenges. The brain is protected by its self-regulatory mechanisms, which are dependent on neuronal and support cellular populations, including endothelial ones, as well as metabolic, and even myogenic factors. OBJECTIVES: Accumulating data suggest that “non-pharmacological” approaches might provide new opportunities for stroke therapy, such as electro-/acupuncture, hyperbaric oxygen therapy, hypothermia/cooling, photobiomodulation, therapeutic gases, transcranial direct current stimulations, or transcranial magnetic stimulations. We reviewed the recent data on the mechanisms and clinical implications of these non-pharmaceutical treatments. METHODS: To present the state-of-the-art for currently available non-invasive, non-pharmacological-related interventions in acute ischemic stroke, we accomplished this synthetic and systematic literature review based on the Preferred Reporting Items for Systematic Principles Reviews and Meta-Analyses (PRISMA). RESULTS: The initial number of obtained articles was 313. After fulfilling the five steps in the filtering/selection methodology, 54 fully eligible papers were selected for synthetic review. We enhanced our documentation with other bibliographic resources connected to our subject, identified in the literature within a non-standardized search, to fill the knowledge gaps. Fifteen clinical trials were also identified. DISCUSSION: Non-invasive, non-pharmacological therapeutic/rehabilitative interventions for acute ischemic stroke are mainly holistic therapies. Therefore, most of them are not yet routinely used in clinical practice, despite some possible beneficial effects, which have yet to be supplementarily proven in more related studies. Moreover, few of the identified clinical trials are already completed and most do not have final results. CONCLUSIONS: This review synthesizes the current findings on acute ischemic stroke therapeutic/rehabilitative interventions, described as non-invasive and non-pharmacological.

Recent studies underscore the role of gut and oral microbiota in influencing neuroinflammation through the microbiota–gut–brain axis, including in Alzheimer’s disease (AD). This review aims to provide a comprehensive synthesis of recent findings on the involvement of gut and oral microbiota in the neuroinflammatory processes associated with AD, emphasizing novel insights and therapeutic implications. This review reveals that dysbiosis in AD patients’ gut and oral microbiota is linked to heightened peripheral and central inflammatory responses. Specific bacterial taxa, such as Bacteroides and Firmicutes in the gut, as well as Porphyromonas gingivalis in the oral cavity, are notably altered in AD, leading to significant changes in microglial activation and cytokine production. Gut microbiota alterations are associated with increased intestinal permeability, facilitating the translocation of endotoxins like lipopolysaccharides (LPS) into the bloodstream and exacerbating neuroinflammation by activating the brain’s toll-like receptor 4 (TLR4) pathways. Furthermore, microbiota-derived metabolites, including short-chain fatty acids (SCFAs) and amyloid peptides, can cross the blood-brain barrier and modulate neuroinflammatory responses. While microbial amyloids may contribute to amyloid-beta aggregation in the brain, certain SCFAs like butyrate exhibit anti-inflammatory properties, suggesting a potential therapeutic avenue to mitigate neuroinflammation. This review not only highlights the critical role of microbiota in AD pathology but also offers a ray of hope by suggesting that modulating gut and oral microbiota could represent a novel therapeutic strategy for reducing neuroinflammation and slowing disease progression.

Background: Stroke is a significant public health problem and a leading cause of death and long-term disability worldwide. Several treatments for ischemic stroke have been developed, but these treatments have limited effectiveness. One potential treatment for this condition is Actovegin^®/AODEJIN, a calf blood deproteinized hemodialysate/ultrafiltrate that has been shown to have pleiotropic/multifactorial and possibly multimodal effects. The actual actions of this medicine are thought to be mediated by its ability to reduce oxidative stress, inflammation, and apoptosis and to enhance neuronal survival and plasticity. Methods: To obtain the most up-to-date information on the effects of Actovegin^®/AODEJIN in ischemic stroke, we systematically reviewed the literature published in the last two years. This review builds upon our previous systematic literature review published in 2020, which used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) method to search for and select related articles over almost two decades, between 1 January 2001 and 31 December 2019. Additionally, we compared the results of our PRISMA search (human intelligence-based) with those obtained from an interrogation of a GPT-based chatbot (ChatGPT) in order to ensure comprehensive coverage of potentially relevant studies. Results: Our updated review found limited new evidence on the use of Actovegin^®/AODEJIN in ischemic stroke, although the number of articles on this subject consistently increased compared to that from our initial systematic literature review. Specifically, we found five articles up to 2020 and eight more until December 2022. While these studies suggest that Actovegin^®/AODEJIN may have neuroprotective effects in ischemic stroke, further clinical trials are needed to confirm these findings. Consequently, we performed a funnel analysis to evaluate the potential for publication bias. Discussion: Our funnel analysis showed no evidence of publication bias, suggesting that the limited number of studies identified was not due to publication bias but rather due to a lack of research in this area. However, there are limitations when using ChatGPT, particularly in distinguishing between truth and falsehood and determining the appropriateness of interpolation. Nevertheless, AI can provide valuable support in conducting PRISMA-type systematic literature reviews, including meta-analyses. Conclusions: The limited number of studies identified in our review highlights the need for additional research in this area, especially as no available therapeutic agents are capable of curing central nervous system lesions. Any contribution, including that of Actovegin (with consideration of a positive balance between benefits and risks), is worthy of further study and periodic reappraisal. The evolving advancements in AI may play a role in the near future.

Diabetes mellitus (DM) is a frequent medical problem, affecting more than 4% of the population in most countries. In the context of diabetes, the vascular endothelium can play a crucial pathophysiological role. If a healthy endothelium—which is a dynamic endocrine organ with autocrine and paracrine activity—regulates vascular tone and permeability and assures a proper balance between coagulation and fibrinolysis, and vasodilation and vasoconstriction, then, in contrast, a dysfunctional endothelium has received increasing attention as a potential contributor to the pathogenesis of vascular disease in diabetes. Hyperglycemia is indicated to be the major causative factor in the development of endothelial dysfunction. Furthermore, many shreds of evidence suggest that the progression of insulin resistance in type 2 diabetes is parallel to the advancement of endothelial dysfunction in atherosclerosis. To present the state-of-the-art data regarding endothelial dysfunction in diabetic micro- and macroangiopathy, we constructed this literature review based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). We interrogated five medical databases: Elsevier, PubMed, PMC, PEDro, and ISI Web of Science.

Accumulating data suggest that chronic neuroinflammation-mediated neurodegeneration is a significant contributing factor for progressive neuronal and glial cell death in age-related neurodegenerative pathology. Furthermore, it could be encountered as long-term consequences in some viral infections, including post-COVID-19 Parkinsonism-related chronic sequelae. The current systematic review is focused on a recent question aroused during the pandemic’s successive waves: are there post-SARS-CoV-2 immune-mediated reactions responsible for promoting neurodegeneration? Does the host’s dysregulated immune counter-offensive contribute to the pathogenesis of neurodegenerative diseases, emerging as Parkinson’s disease, in a complex interrelation between genetic and epigenetic risk factors? A synthetic and systematic literature review was accomplished based on the ”Preferred Reporting Items for Systematic Principles Reviews and Meta-Analyses” (PRISMA) methodology, including registration on the specific online platform: International prospective register of systematic reviews—PROSPERO, no. 312183. Initially, 1894 articles were detected. After fulfilling the five steps of the selection methodology, 104 papers were selected for this synthetic review. Documentation was enhanced with a supplementary 47 bibliographic resources identified in the literature within a non-standardized search connected to the subject. As a final step of the PRISMA method, we have fulfilled a Population-Intervention-Comparison-Outcome-Time (PICOT)/Population-Intervention-Comparison-Outcome-Study type (PICOS)—based metanalysis of clinical trials identified as connected to our search, targeting the outcomes of rehabilitative kinesitherapeutic interventions compared to clinical approaches lacking such kind of treatment. Accordingly, we identified 10 clinical trials related to our article. The multi/interdisciplinary conventional therapy of Parkinson’s disease and non-conventional multitarget approach to an integrative treatment was briefly analyzed. This article synthesizes the current findings on the pathogenic interference between the dysregulated complex mechanisms involved in aging, neuroinflammation, and neurodegeneration, focusing on Parkinson’s disease and the acute and chronic repercussions of COVID-19. Time will tell whether COVID-19 neuroinflammatory events could trigger long-term neurodegenerative effects and contribute to the worsening and/or explosion of new cases of PD. The extent of the interrelated neuropathogenic phenomenon remains obscure, so further clinical observations and prospective longitudinal cohort studies are needed.

One of the most complex and challenging developments at the beginning of the third millennium is the alarming increase in demographic aging, mainly—but not exclusively—affecting developed countries. This reality results in one of the harsh medical, social, and economic consequences: the continuously increasing number of people with dementia, including Alzheimer’s disease (AD), which accounts for up to 80% of all such types of pathology. Its large and progressive disabling potential, which eventually leads to death, therefore represents an important public health matter, especially because there is no known cure for this disease. Consequently, periodic reappraisals of different therapeutic possibilities are necessary. For this purpose, we conducted this systematic literature review investigating nonpharmacological interventions for AD, including their currently known cellular and molecular action bases. This endeavor was based on the PRISMA method, by which we selected 116 eligible articles published during the last year. Because of the unfortunate lack of effective treatments for AD, it is necessary to enhance efforts toward identifying and improving various therapeutic and rehabilitative approaches, as well as related prophylactic measures.