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Keywords = peripheral nervous system disease

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21 pages, 546 KiB  
Review
The Inflammatory Bridge Between Type 2 Diabetes and Neurodegeneration: A Molecular Perspective
by Housem Kacem, Michele d’Angelo, Elvira Qosja, Skender Topi, Vanessa Castelli and Annamaria Cimini
Int. J. Mol. Sci. 2025, 26(15), 7566; https://doi.org/10.3390/ijms26157566 - 5 Aug 2025
Abstract
Chronic low-grade inflammation is a hallmark of both metabolic and neurodegenerative diseases. In recent years, several studies have highlighted the pivotal role of systemic metabolic dysfunction, particularly insulin resistance, in shaping neuroinflammatory processes and contributing to impaired cognitive performance. Among metabolic disorders, type [...] Read more.
Chronic low-grade inflammation is a hallmark of both metabolic and neurodegenerative diseases. In recent years, several studies have highlighted the pivotal role of systemic metabolic dysfunction, particularly insulin resistance, in shaping neuroinflammatory processes and contributing to impaired cognitive performance. Among metabolic disorders, type 2 diabetes mellitus has emerged as a major risk factor for the development of age-related neurodegenerative conditions, suggesting a complex and bidirectional crosstalk between peripheral metabolic imbalance and central nervous system function. This review aims to explore the cellular and molecular mechanisms underlying the interaction between metabolic dysregulation and brain inflammation. By integrating current findings from endocrinology, immunology, and neuroscience, this work provides a comprehensive overview of how chronic metabolic inflammation may contribute to the onset and progression of neurodegenerative conditions. This interdisciplinary approach could offer novel insights into potential therapeutic strategies targeting both metabolic and neuroinflammatory pathways. Full article
(This article belongs to the Collection Latest Review Papers in Endocrinology and Metabolism)
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11 pages, 579 KiB  
Case Report
Thirty-Three Years Follow-Up of a Greek Family with Abetalipoproteinemia: Absence of Liver Damage on Long-Term Medium Chain Triglycerides Supplementation
by John K. Triantafillidis, Areti Manioti, Theodoros Pittaras, Theodoros Kozonis, Emmanouil Kritsotakis, Georgios Malgarinos, Konstantinos Pantos, Konstantinos Sfakianoudis, Manousos M. Konstadoulakis and Apostolos E. Papalois
J. Pers. Med. 2025, 15(8), 354; https://doi.org/10.3390/jpm15080354 - 4 Aug 2025
Abstract
Background: The long-term clinical and laboratory results of a 33-year follow-up of a Greek family with abetalipoproteinemia (ABL) are described. Case Report: The patients (two brothers and their sister, aged 57, 49, and 62 years, respectively) are still alive, being under close surveillance. [...] Read more.
Background: The long-term clinical and laboratory results of a 33-year follow-up of a Greek family with abetalipoproteinemia (ABL) are described. Case Report: The patients (two brothers and their sister, aged 57, 49, and 62 years, respectively) are still alive, being under close surveillance. In two of the three patients, diarrhea appeared in early infancy, while in the third, it appeared during adolescence. CNS symptomatology worsened after the second decade of life. At the same time, night blindness appeared in the advanced stages of the disease, resulting in almost complete loss of vision in one of the male patients and severe impairment in the other. The diagnosis was based on the clinical picture, ophthalmological findings, serum lipid estimations, and presence of peripheral acanthocytosis. All patients exhibited typical serum lipidemic profile, ophthalmological findings, and acanthocytes in the peripheral blood. During the follow-up period, strict dietary modifications were applied, including the substitution of fat with medium-chain triglycerides (MCT oil). After 33 years since the initial diagnosis, all patients are alive without any sign of liver dysfunction despite continuous use of MCT oil. However, symptoms from the central nervous system and vision impairment worsened. Conclusion: The course of these patients suggests that the application of a modified diet, including MCT oil, along with close surveillance, could prolong the survival of patients without significant side effects from the liver. Full article
(This article belongs to the Special Issue Clinical and Experimental Surgery in Personalized Molecular Medicine)
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13 pages, 994 KiB  
Article
Evaluation of the Metabolomics Profile in Charcot–Marie–Tooth (CMT) Patients: Novel Potential Biomarkers
by Federica Murgia, Martina Cadeddu, Jessica Frau, Giancarlo Coghe, Lorefice Lorena, Alessandro Vannelli, Maria Rita Murru, Martina Spada, Antonio Noto, Luigi Atzori and Eleonora Cocco
Metabolites 2025, 15(8), 520; https://doi.org/10.3390/metabo15080520 - 1 Aug 2025
Viewed by 182
Abstract
Background: Charcot–Marie–Tooth (CMT) is a group of inherited diseases impairing the peripheral nervous system. CMT originates from genetic variants that affect proteins fundamental for the myelination of peripheral nerves and survival. Moreover, environmental and humoral factors can impact disease development and evolution. Currently, [...] Read more.
Background: Charcot–Marie–Tooth (CMT) is a group of inherited diseases impairing the peripheral nervous system. CMT originates from genetic variants that affect proteins fundamental for the myelination of peripheral nerves and survival. Moreover, environmental and humoral factors can impact disease development and evolution. Currently, no therapy is available. Metabolomics is an emerging field of biomedical research that enables the development of novel biomarkers for neurodegenerative diseases by targeting metabolic pathways or metabolites. This study aimed to evaluate the metabolomics profile of CMT disease by comparing patients with healthy individuals. Methods: A total of 22 CMT patients (CMT) were included in this study and were demographically matched with 26 healthy individuals (C). Serum samples were analyzed through Nuclear Magnetic Resonance spectroscopy, and multivariate and univariate statistical analyses were subsequently applied. Results: A supervised model showed a clear separation (R2X = 0.3; R2Y = 0.7; Q2 = 0.4; p-value = 0.0004) between the two classes of subjects, and nine metabolites were found to be significantly different (2-hydroxybutyrate, 3-hydroxybutyrate, 3-methyl-2-oxovalerate, choline, citrate, glutamate, isoleucine, lysine, and methyl succinate). The combined ROC curve showed an AUC of 0.94 (CI: 0.9–1). Additional altered metabolic pathways were also identified within the disease context. Conclusion: This study represents a promising starting point, demonstrating the efficacy of metabolomics in evaluating CMT patients and identifying novel potential disease biomarkers. Full article
(This article belongs to the Section Endocrinology and Clinical Metabolic Research)
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8 pages, 212 KiB  
Communication
Retrospective Evaluation of L-Acetyl Carnitine and Palmitoylethanolamide as Add-On Therapy in Patients with Fibromyalgia and Small Fiber Neuropathy
by Crescenzio Bentivenga, Arrigo Francesco Giuseppe Cicero, Federica Fogacci, Natalia Evangelia Politi, Antonio Di Micoli, Eugenio Roberto Cosentino, Paolo Gionchetti and Claudio Borghi
Pharmaceutics 2025, 17(8), 1004; https://doi.org/10.3390/pharmaceutics17081004 - 31 Jul 2025
Viewed by 159
Abstract
Fibromyalgia is a complex disorder characterized by chronic widespread pain and a variety of related symptoms. Growing evidence suggests that the central and peripheral nervous systems are involved, with small fiber neuropathy playing a key role in its development. We retrospectively reviewed the [...] Read more.
Fibromyalgia is a complex disorder characterized by chronic widespread pain and a variety of related symptoms. Growing evidence suggests that the central and peripheral nervous systems are involved, with small fiber neuropathy playing a key role in its development. We retrospectively reviewed the medical records of 100 patients diagnosed with primary fibromyalgia. Those showing symptoms indicative of small fiber dysfunction who were treated with L-Acetyl Carnitine (LAC) and Palmitoylethanolamide (PEA) alongside standard care (SOC) were compared to matched controls who received only SOC. To ensure comparable groups, propensity score matching was used. Changes in Fibromyalgia Impact Questionnaire Revised (FIQR) scores over 12 weeks were analyzed using non-parametric tests due to the data’s non-normal distribution. After matching, 86 patients (43 in each group) were included. The group receiving LAC and PEA as add-on therapy experienced a significant median reduction in FIQR scores (−19.0 points, p < 0.001), while the SOC-only group showed no significant change. Comparisons between groups confirmed that the improvement was significantly greater in the LAC+PEA group (p < 0.001). These results suggest that adding LAC and PEA to standard care may provide meaningful symptom relief for fibromyalgia patients with suspected small fiber involvement. This supports the hypothesis that peripheral nervous system dysfunction contributes to the disease burden in this subgroup. However, further prospective controlled studies are needed to confirm these promising findings. Full article
(This article belongs to the Special Issue Emerging Drugs and Formulations for Pain Treatment)
9 pages, 340 KiB  
Communication
Sciatic Integrity Is Necessary for Fast and Efficient Scrapie Infection After Footpad Injection
by Franco Cardone, Flavia Porreca, Marco Sbriccoli, Anna Poleggi, Anna Ladogana, Mei Lu, Maurizio Pocchiari and Luigi Di Giamberardino
Int. J. Mol. Sci. 2025, 26(15), 7273; https://doi.org/10.3390/ijms26157273 - 28 Jul 2025
Viewed by 231
Abstract
The agents of prion diseases have the capacity to efficiently infect susceptible hosts by peripheral routes and to project to clinical target areas of the central nervous system (CNS) via peripheral nerves. Understanding the process of prion spread from the site of infection [...] Read more.
The agents of prion diseases have the capacity to efficiently infect susceptible hosts by peripheral routes and to project to clinical target areas of the central nervous system (CNS) via peripheral nerves. Understanding the process of prion spread from the site of infection to the CNS may allow us to identify novel therapeutic strategies. To investigate the mechanism involved in the intranerval transit of 263K scrapie prions in golden Syrian hamsters (GSHs), we transected the sciatic nerve at increasing times post-footpad injection and recorded the incubation periods as estimates of the efficiency of infection. We calculated that intranerval transit of this strain of scrapie is at least 10 times faster than previously reported and may reach 50 mm/day, similar to other neurotropic viruses. By in vivo exposure/injection of sciatic nerves to 263K infectivity, we have also shown that prion entry likely occurs via nerve terminals rather than by direct contact with the sciatic nerve. Application of this experimental approach in other forms of prion diseases could allow verification of the timing of neuroinvasion, a relevant parameter for the definition of therapeutic interventions. Full article
(This article belongs to the Section Molecular Neurobiology)
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30 pages, 352 KiB  
Review
New Perspectives in Modulating the Entero-Insular Axis in Pediatric Obesity
by Loredana-Maria Dira, Loredana-Maria Marin, Simona-Georgiana Popa, Cristina-Elena Singer, Carmen-Simona Cosoveanu, Ionut Donoiu and Andreea-Loredana Golli
Int. J. Mol. Sci. 2025, 26(13), 6143; https://doi.org/10.3390/ijms26136143 - 26 Jun 2025
Viewed by 533
Abstract
A growing global trend of adult obesity and the increasing prevalence of overweight/obesity in children indicate a higher risk in the future of adult diseases related to obesity. Current anti-obesity medications regulate appetite and metabolism by acting either in peripheral tissues or in [...] Read more.
A growing global trend of adult obesity and the increasing prevalence of overweight/obesity in children indicate a higher risk in the future of adult diseases related to obesity. Current anti-obesity medications regulate appetite and metabolism by acting either in peripheral tissues or in the central nervous system. On the other hand, subsequent weight regain is a typical response to weight loss methods, and there is little evidence that current anti-obesity medications can help maintain long-term weight loss without causing a range of undesirable side effects. The combination of anti-obesity drugs targets multiple molecular pathways and structures in the central nervous system that are involved in weight regulation. This systematic review involves trials performed in pediatric populations, published up to 2025 and systematically searched on the ClinicalTrials.gov database, using “Glucagon like peptide-1 analog, Glucagon like peptide-1 receptor agonists” as the criterion for the “Intervention/treatment” category. We evaluated the entero-insular axis in pediatric patients with obesity, along with the mechanisms of action and therapeutic potential of the Glucagon like peptide-1receptor agonists. We analyzed incretin hormones and summarized the drugs approved by the Food and Drug Administration. Our objective is to identify new treatment strategies as we improve our understanding of the pathophysiology of obesity and the incretin axis. Full article
(This article belongs to the Special Issue Advances in Metabolic Phenotypes of Pediatric Obesity)
29 pages, 1484 KiB  
Review
Adenylyl Cyclases as Therapeutic Targets in Neuroregeneration
by Julia Tomczak, Agnieszka Kapsa and Tomasz Boczek
Int. J. Mol. Sci. 2025, 26(13), 6081; https://doi.org/10.3390/ijms26136081 - 25 Jun 2025
Viewed by 844
Abstract
Adenylyl cyclases (ACs) are key regulators of cyclic adenosine monophosphate (cAMP) signaling—a pathway critical for neuroregeneration, synaptic plasticity, and neuronal survival. In both the central and peripheral nervous systems, injury-induced activation of ACs promotes axonal outgrowth and functional recovery through the stimulation of [...] Read more.
Adenylyl cyclases (ACs) are key regulators of cyclic adenosine monophosphate (cAMP) signaling—a pathway critical for neuroregeneration, synaptic plasticity, and neuronal survival. In both the central and peripheral nervous systems, injury-induced activation of ACs promotes axonal outgrowth and functional recovery through the stimulation of protein kinase A (PKA), exchange proteins directly activated by cAMP (Epac), and cAMP-response element-binding protein (CREB). Among the various AC isoforms, calcium-sensitive AC1, AC8, and AC5, as well as bicarbonate-responsive soluble AC (sAC), have emerged as crucial mediators of neuroplasticity and axon regeneration. These isoforms coordinate diverse cellular responses—including gene transcription, cytoskeletal remodeling, and neurotransmitter release—to metabolic, synaptic, and injury-related signals. Dysregulation of AC activity has been implicated in the pathophysiology of neurodegenerative diseases such as Parkinson’s disease, Alzheimer’s disease, and amyotrophic lateral sclerosis, as well as in chronic pain syndromes. Pharmacological modulation of cAMP levels through AC activation, phosphodiesterase (PDE) inhibition, or pituitary adenylyl cyclase-activating polypeptide (PACAP) receptor signaling has shown therapeutic promise in preclinical models by enhancing neurogenesis, remyelination, and synaptic repair. Conversely, targeted inhibition of specific AC isoforms, particularly AC1, has demonstrated efficacy in reducing maladaptive plasticity and neuropathic pain. This review highlights the diverse roles of ACs in neuronal function and injury response and discusses emerging strategies for their therapeutic targeting. Full article
(This article belongs to the Special Issue Latest Review Papers in Molecular Neurobiology 2025)
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18 pages, 923 KiB  
Review
Pathogenic Crosstalk Between the Peripheral and Central Nervous System in Rheumatic Diseases: Emerging Evidence and Clinical Implications
by Marino Paroli and Maria Isabella Sirinian
Int. J. Mol. Sci. 2025, 26(13), 6036; https://doi.org/10.3390/ijms26136036 - 24 Jun 2025
Viewed by 633
Abstract
Systemic autoimmune rheumatic diseases (SARDs), such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and Sjögren’s syndrome (SS), are traditionally characterized by chronic inflammation and immune-mediated damage to joints and other tissues. However, many patients also experience symptoms such as widespread pain, persistent [...] Read more.
Systemic autoimmune rheumatic diseases (SARDs), such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and Sjögren’s syndrome (SS), are traditionally characterized by chronic inflammation and immune-mediated damage to joints and other tissues. However, many patients also experience symptoms such as widespread pain, persistent fatigue, cognitive dysfunction, and autonomic disturbances that cannot be attributed directly or entirely to peripheral inflammation or structural pathology. These conditions suggest the involvement of interactions between the nervous and immune systems, which probably include both peripheral and central components. This review summarizes the current knowledge of neurological and neuroimmune mechanisms that may contribute to these symptoms in SARDs. Glial cell activation and neuroinflammation within the central nervous system (CNS), small-fiber neuropathy (SFN) affecting peripheral nociceptive pathways, central pain sensitization, and autonomic nervous system dysfunction will be discussed. In addition, the role of molecular mediators, including cytokines, neuropeptides, and microRNAs, that could potentially modulate neuroimmune signaling will be highlighted. Integrating findings from pathology, immunology, and neuroscience, this review seeks to provide a useful framework for understanding neuroimmune dysregulation in SARDs. It also highlights the clinical relevance of these mechanisms and summarizes new directions for diagnosis and treatment. Full article
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27 pages, 1432 KiB  
Review
Neurosteroids Progesterone and Dehydroepiandrosterone: Molecular Mechanisms of Action in Neuroprotection and Neuroinflammation
by Tatiana A. Fedotcheva and Nikolay L. Shimanovsky
Pharmaceuticals 2025, 18(7), 945; https://doi.org/10.3390/ph18070945 - 23 Jun 2025
Viewed by 901
Abstract
Neurosteroids pregnenolone, progesterone, allopregnanolone, and dehydroepiandrosterone have been actively studied in the last years as candidates for the treatment of neurodegenerative diseases and postinjury rehabilitation. The neuroprotective mechanisms of these neurosteroids have been shown in clinical studies of depression, epilepsy, status epilepticus, traumatic [...] Read more.
Neurosteroids pregnenolone, progesterone, allopregnanolone, and dehydroepiandrosterone have been actively studied in the last years as candidates for the treatment of neurodegenerative diseases and postinjury rehabilitation. The neuroprotective mechanisms of these neurosteroids have been shown in clinical studies of depression, epilepsy, status epilepticus, traumatic brain injury, fragile X syndrome, and chemical neurotoxicity. However, only the allopregnanolone analogs brexanolone and zuranolone have been recently approved by the FDA for the treatment of depression. The aim of this review was to evaluate whether the endogenous neurosteroids can be used in clinical practice as neuroprotectors. Neurosteroids are multitarget compounds with strong anti-inflammatory, immunomodulatory, and cytoprotective action; they stimulate the synthesis and release of BDNF and increase remyelination and regeneration. In addition to nuclear and membrane steroid hormone receptors, such as PR, mPR, PGRMC1,2, ER, AR, CAR, and PXR, they can bind to GABAA receptors, NMDA receptors, Sigma-1 and -2 receptors (σ1-R/σ2-R). Among these, mPRs, PGRMC1,2, sigma receptors, and mitochondrial proteins attract comprehensive attention because of strong binding with the P4 and DHEA, but subsequent signaling is poorly studied. Other plasma membrane and mitochondrial proteins are involved in the rapid nongenomic neuroprotective action of neurosteroids. P-glycoprotein, BCL-2 proteins, and the components of the mitochondrial permeability transition pore (mPTP) play a significant role in the defense against the injuries of the brain and the peripheral nervous system. The role of these proteins in the molecular mechanisms of action in neuroprotection and neuroinflammation has not yet been clearly established. The aspects of their participation in these pathological processes are discussed. New formulations, such as lipophilic emulsions, nanogels, and microneedle array patches, are attractive strategies to overcome the low bioavailability of these neurosteroids for the amelioration and treatment of various nervous disorders. Full article
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19 pages, 1132 KiB  
Review
The Interplay Between Exosomes and Gut Microbiota in Neuroinflammation: A New Frontier in Alzheimer’s Disease
by Sara Uceda, Manuel Reiriz, Víctor Echeverry-Alzate and Ana Isabel Beltrán-Velasco
Int. J. Mol. Sci. 2025, 26(12), 5828; https://doi.org/10.3390/ijms26125828 - 18 Jun 2025
Cited by 1 | Viewed by 876
Abstract
Alzheimer’s disease (AD) is a complex neurodegenerative condition that is characterized by the accumulation of amyloid-β, the hyperphosphorylation of tau, and persistent neuroinflammation. However, these hallmarks alone do not fully capture the intricacies of AD pathology, thus necessitating the investigation of emerging mechanisms [...] Read more.
Alzheimer’s disease (AD) is a complex neurodegenerative condition that is characterized by the accumulation of amyloid-β, the hyperphosphorylation of tau, and persistent neuroinflammation. However, these hallmarks alone do not fully capture the intricacies of AD pathology, thus necessitating the investigation of emerging mechanisms and innovative tools. Exosomes (nanoscale vesicles involved in cell communication and immune modulation) have emerged as pivotal cellular vehicles due to their dual role—both in the propagation of pathological proteins and the regulation of inflammatory responses. Furthermore, these vesicles have been demonstrated to play a crucial role in the mediation of the effects of microbiota-derived metabolites and the reflection of systemic influences such as dysbiosis, thereby establishing a link between the gut–brain axis and the progression of AD. A comprehensive narrative literature review was conducted using the following databases: ScienceDirect, Scopus, Wiley, Web of Science, Medline, and PubMed, covering studies published between 2015 and 2025. Inclusion and exclusion criteria were established to select research addressing exosomal biogenesis, their functional and diagnosis role, their therapeutic potential, and the emerging evidence on microbiota–exosome interplay in Alzheimer’s disease. Exosomes have been identified as integral mediators of intercellular communication, reflecting the molecular state of the central nervous system. These particles have been shown to promote the propagation of pathological proteins, modulate neuroinflammatory responses, and serve as non-invasive biomarkers due to their detectability in peripheral fluids. Advances in exosomal engineering and microbiome-based interventions underscore the potential for targeting systemic and CNS-specific mechanisms to develop integrative therapies for AD. Exosomes present a promising approach for the early diagnosis and personalized treatment of Alzheimer’s disease. However, methodological challenges and ongoing controversies, including those related to the influence of systemic factors such as dysbiosis, necessitate multidisciplinary research to optimize and standardize these strategies. Full article
(This article belongs to the Section Molecular Microbiology)
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33 pages, 5009 KiB  
Article
Quercetin as a Therapeutic Option in a Rat Model of Aluminum Chloride- and D-Galactose-Induced Neurodegeneration
by Marina Kukolj, Nada Oršolić, Lea Langer Horvat, Barbara Nikolić, Tatjana Ocrt, Karmen Branović Čakanić, Romana Gračan, Ivana Zrinščak, Maja Jazvinšćak Jembrek and Goran Šimić
Int. J. Mol. Sci. 2025, 26(12), 5743; https://doi.org/10.3390/ijms26125743 - 15 Jun 2025
Cited by 1 | Viewed by 864
Abstract
Aluminum (Al) is one of the most abundant metals on Earth and is well known as an environmental neurotoxic agent in the pathogenesis of Alzheimer’s disease. Aluminum toxicity is associated with oxidative stress, reduction of antioxidant enzymes, and disruption of the balance of [...] Read more.
Aluminum (Al) is one of the most abundant metals on Earth and is well known as an environmental neurotoxic agent in the pathogenesis of Alzheimer’s disease. Aluminum toxicity is associated with oxidative stress, reduction of antioxidant enzymes, and disruption of the balance of cellular metals, such as iron (Fe), calcium (Ca), and copper (Cu), which causes structural and functional changes in the nervous tissue of the brain or peripheral nervous system. The intake of functional foods, rich in antioxidants, such as quercetin, may be beneficial in combating oxidative stress and neurodegenerative changes in the brain. The aim of this study was to provide deeper insight into the cellular and molecular neuroprotective effects of quercetin in regulating amyloid-beta (Aβ) accumulation, tau pathology, and neuroinflammation in the Al/D-galactose-induced rat model (Al/D-gal) of AD. The results showed that quercetin successfully modulated the impaired homeostatic and neuropathological consequences of aluminum chloride and D-galactose administration over 28 days: it directly protected neurons by regulating the level of oxidative stress and antioxidants, reduced Aβ aggregation by inhibiting the activity of acetylcholinesterase (AChE), increased the survival, growth, and differentiation of nerve cells by maintaining the level of brain-derived neurotrophic factor (BDNF), and regulated microglial immunoreactivity and neuroinflammation by reducing the level of proinflammatory cytokines. The multiple effects confirm that quercetin can be applied as an alternative non-pharmaceutical approach in reducing Al-induced neurotoxicity and maintaining adaptive homeostasis, which consequently affects the functioning of the central nervous system and the whole organism. Full article
(This article belongs to the Special Issue Targeting Oxidative Stress for Disease: 2nd Edition)
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23 pages, 1309 KiB  
Review
Barriers in the Nervous System: Challenges and Opportunities for Novel Biomarkers in Amyotrophic Lateral Sclerosis
by Lorena Pisoni, Luisa Donini, Paola Gagni, Maria Pennuto, Antonia Ratti, Federico Verde, Nicola Ticozzi, Jessica Mandrioli, Andrea Calvo and Manuela Basso
Cells 2025, 14(11), 848; https://doi.org/10.3390/cells14110848 - 5 Jun 2025
Viewed by 1196
Abstract
Amyotrophic Lateral Sclerosis (ALS) is a complex neurodegenerative disorder characterized by wide phenotypic heterogeneity. Despite efforts to carefully define and stratify ALS patients according to their clinical and genetic features, prognosis prediction still remains unreliable. Biomarkers that reflect changes in the central nervous [...] Read more.
Amyotrophic Lateral Sclerosis (ALS) is a complex neurodegenerative disorder characterized by wide phenotypic heterogeneity. Despite efforts to carefully define and stratify ALS patients according to their clinical and genetic features, prognosis prediction still remains unreliable. Biomarkers that reflect changes in the central nervous system would be useful, but the physical impossibility of direct sampling and analysis of the nervous system makes them challenging to validate. A highly explored option is the identification of neuronal-specific markers that could be analyzed in peripheral biofluids. This review focuses on the description of the physical and biological barriers to the central nervous system and of the composition of biofluids in which ALS disease biomarkers are actively searched. Finally, we comment on already validated biomarkers, such as the neurofilament light chain, and show the potential of extracellular vesicles (EVs) and cell-free DNA as additional biomarkers for disease prediction. Full article
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37 pages, 1622 KiB  
Review
The Role of APOA-I in Alzheimer’s Disease: Bridging Peripheral Tissues and the Central Nervous System
by Guanfeng Xie, Gege Jiang, Liqin Huang, Shangqi Sun, Yuwei Wan, Fang Li, Bingjie Wu, Ying Zhang, Xiaoyi Li, Bingwan Xiong and Jing Xiong
Pharmaceuticals 2025, 18(6), 790; https://doi.org/10.3390/ph18060790 - 25 May 2025
Viewed by 960
Abstract
Lipid metabolism disorders represent a significant risk factor for the pathogenesis of Alzheimer’s disease (AD). Apolipoprotein E (APOE) has been regarded as a pivotal regulator of lipid homeostasis in the central nervous system (CNS), with polymorphic alleles identified as genetic risk factors for [...] Read more.
Lipid metabolism disorders represent a significant risk factor for the pathogenesis of Alzheimer’s disease (AD). Apolipoprotein E (APOE) has been regarded as a pivotal regulator of lipid homeostasis in the central nervous system (CNS), with polymorphic alleles identified as genetic risk factors for late-onset AD. Despite advances in APOE research and the development of numerous pharmaceutical approaches targeting distinct APOE isoforms, there remain limited treatment approaches for AD that focus on lipid metabolic homeostasis. Consequently, it is necessary to reevaluate the lipid metabolic process in the CNS. Apolipoprotein A1 (APOA-I), a major component of high-density lipoprotein (HDL), plays a crucial role in reverse cholesterol transport from tissues to the liver to maintain lipid homeostasis. Over the past few decades, numerous studies have suggested a connection between reduced APOA-I levels and a higher risk of AD. APOA-I is synthesized exclusively in the liver and intestines, and there is a lack of conclusive evidence supporting its functional significance within the central nervous system, in contrast to APOE, which is produced locally by glial cells and neurons within the CNS. Moreover, APOA-I’s ability to penetrate the blood-brain barrier (BBB) is still poorly understood, which causes its significance in central lipid metabolism and AD pathophysiology to be mainly disregarded. Recent advancements in tracing methodologies have underscored the essential role of APOA-I in regulating lipid metabolism in the CNS. This review aims to elucidate the physiological functions and metabolic pathways of APOA-I, integrating its associations with AD-related pathologies, risk factors, and potential therapeutic targets. Through this discourse, we aim to provide novel insights into the intricate relationship between AD and APOA-I, paving the way for future research in this field. Full article
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12 pages, 549 KiB  
Article
Lipoperoxides as Prognostic Markers in Pediatric B-Acute Lymphocytic Leukemia Patients Undergoing Induction Chemotherapy
by Bruna Yukie Koizumi, Marina Rayciki Sotomayor, Carolina Coradi, Ana Luiza Goulart Starck, Anna Will Ribeiro, Maikely Bruna Leite, Maria Eduarda Pardal Simonato, Rafael Gomes Paz, Vinicius de Melo Tizzo, Stefania Tagliari Longo, Geise Ellen Broto, Fausto Celso Trigo and Carolina Panis
Lymphatics 2025, 3(2), 11; https://doi.org/10.3390/lymphatics3020011 - 19 May 2025
Viewed by 766
Abstract
B-type acute lymphoblastic leukemia (B-ALL) is the most common childhood cancer. Despite significant advancements in treatment, chemotherapy resistance and relapse remain major challenges to be overcome. Oxidative stress markers, including lipoperoxides, have emerged as potential biomarkers in B-ALL patients under treatment. This study [...] Read more.
B-type acute lymphoblastic leukemia (B-ALL) is the most common childhood cancer. Despite significant advancements in treatment, chemotherapy resistance and relapse remain major challenges to be overcome. Oxidative stress markers, including lipoperoxides, have emerged as potential biomarkers in B-ALL patients under treatment. This study evaluated lipoperoxide levels in the peripheral blood of pediatric B-ALL patients during the induction phase of chemotherapy using high-sensitivity chemiluminescence and analyzed their association with clinical prognostic factors and patient outcomes, including definitive hospital discharge, disease relapse, and patient death. Lower lipoperoxide levels were observed in patients over 10 years old, those who achieved remission and were discharged from the hospital, and those with central nervous system (CNS) involvement. In contrast, significantly higher lipoperoxide levels were found in patients who relapsed, died, or had platelet counts exceeding 50,000/mm3. Receiver operating characteristic (ROC) curve analysis suggests that lipoperoxides may serve as potential biomarkers during the induction phase of chemotherapy, distinguishing B-ALL patients undergoing treatment from those not in treatment (sensitivity: 92.31%; specificity: 71.43%). These findings highlight the potential utility of lipoperoxides as prognostic biomarkers in B-ALL patients. Full article
(This article belongs to the Collection Acute Lymphoblastic Leukemia (ALL))
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15 pages, 4318 KiB  
Brief Report
Guinea Pigs Are Not a Suitable Model to Study Neurological Impacts of Ancestral SARS-CoV-2 Intranasal Infection
by Jonathan D. Joyce, Greyson A. Moore, Christopher K. Thompson and Andrea S. Bertke
Viruses 2025, 17(5), 706; https://doi.org/10.3390/v17050706 - 15 May 2025
Viewed by 685
Abstract
Neurological symptoms involving the central nervous system (CNS) and peripheral nervous system (PNS) are common complications of acute COVID-19 as well as post-COVID conditions. Most research into these neurological sequalae focuses on the CNS, disregarding the PNS. Guinea pigs were previously shown to [...] Read more.
Neurological symptoms involving the central nervous system (CNS) and peripheral nervous system (PNS) are common complications of acute COVID-19 as well as post-COVID conditions. Most research into these neurological sequalae focuses on the CNS, disregarding the PNS. Guinea pigs were previously shown to be useful models of disease during the SARS-CoV-1 epidemic. However, their suitability for studying SARS-CoV-2 has not been experimentally demonstrated. To assess the suitability of guinea pigs as models for SARS-CoV-2 infection and the impact of SARS-CoV-2 infection on the PNS, and to determine routes of CNS invasion through the PNS, we intranasally infected wild-type Dunkin-Hartley guinea pigs with ancestral SARS-CoV-2 USA-WA1/2020. We assessed PNS sensory neurons (trigeminal ganglia, dorsal root ganglia), autonomic neurons (superior cervical ganglia), brain regions (olfactory bulb, brainstem, cerebellum, cortex, hippocampus), lungs, and blood for viral RNA (RT-qPCR), protein (immunostaining), and infectious virus (plaque assay) at three- and six-days post infection. We show that guinea pigs, which have previously been used as a model of SARS-CoV-1 pulmonary disease, are not susceptible to intranasal infection with ancestral SARS-CoV-2, and are not useful models in assessing neurological impacts of infection with SARS-CoV-2 isolates from the early pandemic. Full article
(This article belongs to the Section Coronaviruses)
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