Despite all of the progress in understanding its molecular biology and pathogenesis, glioblastoma (GBM) is one of the most aggressive types of cancers, and without an efficient treatment modality at the moment, it remains largely incurable. Nowadays, one of the most frequently studied molecules with important implications in the pathogenesis of the classical subtype of GBM is the epidermal growth factor receptor (EGFR). Although many clinical trials aiming to study EGFR targeted therapies have been performed, none of them have reported promising clinical results when used in glioma patients. The resistance of GBM to these therapies was proven to be both acquired and innate, and it seems to be influenced by a cumulus of factors such as ineffective blood–brain barrier penetration, mutations, heterogeneity and compensatory signaling pathways. Recently, it was shown that EGFR possesses kinase-independent (KID) pro-survival functions in cancer cells. It seems imperative to understand how the EGFR signaling pathways function and how they interconnect with other pathways. Furthermore, it is important to identify the mechanisms of drug resistance and to develop better tailored therapeutic agents.

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.

Background (1): Men’s football is a physically demanding contact sport that involves intermittent bouts of sprinting, jogging, walking, jumping and changes of direction. The physical demands of the game vary by level of play (amateur club, sub-elite and open club or international), but injury rates at all levels of the men’s football game remain the highest of all sports. Objective: The aim of this study is to conduct a systematic review of data from the epidemiological literature regarding the profile, severity and mechanisms of injuries and the frequency of recurrent injuries in professional and amateur football players. Methods (2): A systematic review, according to PRISMA guidelines, was performed up to June 2023 in the databases of PubMed, Web of Science, Google academic, Google scholar and the Diva portal. Twenty-seven studies that reported data on the type, severity, recurrence and mechanisms of injury in professional and amateur men’s football were selected and analyzed. Two reviewers independently audited data and assessed the study quality using the additional and adapted version of the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement and the Newcastle Ottawa Scale (NOS) to assess risk of bias for the quality of external validity. Results (3): In professional male football players, the mean prevalence of muscle/tendon injuries was 39.78%, followed by joint and ligament injuries—21.13%, contusions—17.86%, and fractures—3.27%, and for amateur football players, the prevalence’s were 44.56% (muscle/tendon injuries), 27.62% (joint and ligament injuries), 15.0% (contusions) and 3.05% (fracture), respectively. The frequency of traumatic injuries was higher in amateur football players (76.88%) compared to professional football players (64.16%), the situation being reversed in the case of overuse injuries: 27.62% in professional football players and 21.13% in amateur football players. Most contact injuries were found in professional footballers (50.70%), with non-contact injuries predominating in amateur footballers (54.04%). The analysis of the severity of injuries showed that moderate injuries dominated in the two categories of footballers; the severe injuries in amateur footballers exceeded the severe injuries recorded in professional footballers by 9.60%. Recurrence proportions showed an inverse relationship with the level of play, being higher in amateur footballers (16.66%) compared to professional footballers (15.25%). Conclusions (4): Football-related injuries have a significant impact on professional and amateur football players and their short- and long-term health status. Knowing the frequency of severe diagnoses, such as strains, tears and cramps of the thigh muscles, ankle ligament sprains and hip/groin muscle strain requires the establishment of adequate programs to prevent them, especially in amateur football players, who are more prone to serious injuries.

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.

This systematic review investigates the potential health and wellness benefits of natural calcium-rich mineral waters. It emphasizes the importance of dietary calcium sourced from natural mineral waters in promoting bone health, maintaining cardiovascular function, aiding in weight management, and enhancing overall well-being. The review process involved the comprehensive analysis of peer-reviewed articles, clinical trials, and experimental studies published within the last decade. Findings reveal that consuming calcium-rich mineral water can contribute significantly to daily calcium intake, particularly for those with lactose intolerance or individuals adhering to plant-based diets. The unique bioavailability of calcium from such waters also appears to enhance absorption, thus potentially offering an advantage over other calcium sources. The potential benefits extend to the cardiovascular system, with some studies indicating a reduction in blood pressure and the prevalence of cardiovascular diseases. Emerging evidence suggests that calcium-rich mineral water might have a role in body weight management, though further research is needed. The review identifies several areas requiring additional research, such as the potential interaction between calcium-rich mineral water and other dietary components, the effects on populations with specific health conditions, and the long-term effects of consumption. In conclusion, natural calcium-rich mineral waters show promise as a readily accessible and bioavailable sources of dietary calcium, potentially beneficial for a broad range of individuals. However, further investigation is required to fully understand its range of health impacts and define optimal intake levels.

Hydrogen sulfide (H₂S), a gas traditionally considered toxic, is now recognized as a vital endogenous signaling molecule with a complex physiology. This comprehensive study encompasses a systematic literature review that explores the intricate mechanisms underlying H₂S-induced vasodilation. The vasodilatory effects of H₂S are primarily mediated by activating ATP-sensitive potassium (K_ATP) channels, leading to membrane hyperpolarization and subsequent relaxation of vascular smooth muscle cells (VSMCs). Additionally, H₂S inhibits L-type calcium channels, reducing calcium influx and diminishing VSMC contraction. Beyond ion channel modulation, H₂S profoundly impacts cyclic nucleotide signaling pathways. It stimulates soluble guanylyl cyclase (sGC), increasing the production of cyclic guanosine monophosphate (cGMP). Elevated cGMP levels activate protein kinase G (PKG), which phosphorylates downstream targets like vasodilator-stimulated phosphoprotein (VASP) and promotes smooth muscle relaxation. The synergy between H₂S and nitric oxide (NO) signaling further amplifies vasodilation. H₂S enhances NO bioavailability by inhibiting its degradation and stimulating endothelial nitric oxide synthase (eNOS) activity, increasing cGMP levels and potent vasodilatory responses. Protein sulfhydration, a post-translational modification, plays a crucial role in cell signaling. H₂S S-sulfurates oxidized cysteine residues, while polysulfides (H₂Sn) are responsible for S-sulfurating reduced cysteine residues. Sulfhydration of key proteins like K_ATP channels and sGC enhances their activity, contributing to the overall vasodilatory effect. Furthermore, H₂S interaction with endothelium-derived hyperpolarizing factor (EDHF) pathways adds another layer to its vasodilatory mechanism. By enhancing EDHF activity, H₂S facilitates the hyperpolarization and relaxation of VSMCs through gap junctions between endothelial cells and VSMCs. Recent findings suggest that H₂S can also modulate transient receptor potential (TRP) channels, particularly TRPV4 channels, in endothelial cells. Activating these channels by H₂S promotes calcium entry, stimulating the production of vasodilatory agents like NO and prostacyclin, thereby regulating vascular tone. The comprehensive understanding of H₂S-induced vasodilation mechanisms highlights its therapeutic potential. The multifaceted approach of H₂S in modulating vascular tone presents a promising strategy for developing novel treatments for hypertension, ischemic conditions, and other vascular disorders. The interaction of H₂S with ion channels, cyclic nucleotide signaling, NO pathways, ROS (Reactive Oxygen Species) scavenging, protein sulfhydration, and EDHF underscores its complexity and therapeutic relevance. In conclusion, the intricate signaling paradigms of H₂S-induced vasodilation offer valuable insights into its physiological role and therapeutic potential, promising innovative approaches for managing various vascular diseases through the modulation of vascular tone.