The exact etiology of Parkinson’s disease (PD) remains obscure, lacking effective diagnostic and prognostic biomarkers. In search of novel molecular factors that may contribute to PD pathogenesis, ...emerging evidence highlights the multifunctional role of the calcium-binding protein S100B that is widely expressed in the brain and predominantly in astrocytes. Preclinical evidence points towards the possible time-specific contributing role of S100B in the pathogenesis of neurodegenerative disorders including PD, mainly by regulating neuroinflammation and dopamine metabolism. Although existing clinical evidence presents some contradictions, estimation of S100B in the serum and cerebrospinal fluid seems to hold a great promise as a potential PD biomarker, particularly regarding the severity of motor and non-motor PD symptoms. Furthermore, given the recent development of S100B inhibitors that are able to cross the blood brain barrier, novel opportunities are arising in the research field of PD therapeutics. In this review, we provide an update on recent advances in the implication of S100B protein in the pathogenesis of PD and discuss relevant studies investigating the biomarker potential of S100B in PD, aiming to shed more light on clinical targeting approaches related to this incurable disorder.
Despite extensive research, gliomas are associated with high morbidity and mortality, mainly attributed to the rapid growth rate, excessive invasiveness, and molecular heterogeneity, as well as ...regenerative potential of cancer stem cells. Therefore, elucidation of the underlying molecular mechanisms and the identification of potential molecular diagnostic and prognostic biomarkers are of paramount importance. HOX transcript antisense intergenic RNA (
HOTAIR
) is a well-studied long noncoding RNA, playing an emerging role in tumorigenesis of several human cancers. A growing amount of preclinical and clinical evidence highlights the pro-oncogenic role of
HOTAIR
in gliomas, mainly attributed to the enhancement of proliferation and migration, as well as inhibition of apoptosis. In vitro and in vivo studies demonstrate that
HOTAIR
modulates the activity of specific transcription factors, such as MXI1, E2F1, ATF5, and ASCL1, and regulates the expression of cell cycle–associated genes along with related signaling pathways, like the Wnt/β-catenin axis. Moreover, it can interact with specific miRNAs, including miR-326, miR-141, miR-148b-3p, miR-15b, and miR-126-5p. Of importance,
HOTAIR
has been demonstrated to enhance angiogenesis and affect the permeability of the blood–tumor barrier, thus modulating the efficacy of chemotherapeutic agents. Herein, we provide evidence on the functional role of
HOTAIR
in gliomas and discuss the benefits of its targeting as a novel approach toward glioma treatment.
Parkinsonism is an umbrella term that refers to multisystemic neurodegenerative disorders characterized by a broad spectrum of motor and non-motor symptoms (NMSs) ....
Parkinson's disease (PD) presents the second most common neurodegenerative disorder with largely unknown pathogenesis and inefficient therapeutic management. Accumulating data indicate that ...neuroinflammation, autophagy impairment, α‐synuclein aggregation, and mitochondrial dysfunction may contribute to PD onset; however, the molecular mechanisms underlying these pathophysiological processes are still under elucidation. Interestingly, recent evidence has indicated that High‐mobility group box 1 (HMGB1), a DNA‐binding protein that can be actively secreted by inflammatory cells and passively released by necrotic cells may play a key role in PD pathogenesis. HMGB1 has been shown to participate in neuroinflammation, modulate autophagy and apoptosis as well as regulate gene transcription. Furthermore, therapeutic targeting of HMGB1 with either anti‐HMGB1 antibodies or selective inhibitors, such as glycyrrhizin, has been shown to inhibit neurodegeneration in animal models. This review provides an update of recent data on the emerging role of HMGB1 in PD pathogenesis and discusses potential therapeutic approaches.
Recent evidence implicates High‐mobility group box 1 (HMGB1) protein in Parkinson's disease pathogenesis with potential for therapeutic targeting. HMGB1 is implicated in neuroinflammation via macrophage antigen complex 1 (Mac1)‐HMGB1 interaction that activates nuclear factor‐κΒ (NF‐κB) and nicotinamide adenine dinucleotide phosphate (NADPH), inducing tumor necrosis factor‐α (TNF‐α), interleukin‐1 β (IL‐1β), and nitric oxide (NO) production. It is also involved in neurodegeneration processes via Mac1‐HMGB1 interaction and blood–brain barrier (BBB) disruption. HMGB1 regulates autophagy, mitochondrial function, α‐synuclein (SNCA) gene transcription, and tyrosine hydroxylase (TH) expression via Receptor for Advanced Glycated End products (RAGE)‐HMGB1 interaction and c‐Jun N‐terminal kinase (JNK) activation.
Neurodegenerative diseases constitute a broad range of central nervous system disorders, characterized by neuronal degeneration. Alzheimer's disease, Parkinson's disease, amyolotrophic lateral ...sclerosis (ALS), and progressive forms of multiple sclerosis (MS) are some of the most frequent neurodegenerative diseases. Despite their diversity, these diseases share some common pathophysiological mechanisms: the abnormal aggregation of disease-related misfolded proteins, autophagosome-lysosome pathway dysregulation, impaired ubiquitin-proteasome system, oxidative damage, mitochondrial dysfunction and excessive neuroinflammation. There is still no effective drug that could halt the progression of neurodegenerative diseases, and the current treatments are mainly symptomatic. In this regard, the development of novel multi-target pharmaceutical approaches presents an attractive therapeutic strategy. Ibudilast, an anti-inflammatory drug firstly developed as an asthma treatment, is a cyclic nucleotide phosphodiesterases (PDEs) inhibitor, which mainly acts by increasing the amount of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP), while downregulating the pro-inflammatory factors, such as tumor necrosis factor-α (TNF-α), macrophage migration inhibitory factor (MIF) and Toll-like receptor 4 (TLR-4). The preclinical evidence shows that ibudilast may act neuroprotectively in neurodegenerative diseases, by suppressing neuroinflammation, inhibiting apoptosis, regulating the mitochondrial function and by affecting the ubiquitin-proteasome and autophagosome-lysosome pathways, as well as by attenuating oxidative stress. The clinical trials in ALS and progressive MS also show some promising results. Herein, we aim to provide an update on the emerging preclinical and clinical evidence on the therapeutic potential of ibudilast in these disorders, discuss the potential challenges and suggest the future directions.
Huntington’s disease (HD) is an autosomal-dominant neurodegenerative disorder caused by an increased and unstable CAG DNA expansion in the
Huntingtin
(
HTT
) gene, resulting in an elongated ...polyglutamine tract in huntingtin protein. Despite its monogenic cause, HD pathogenesis remains elusive and without any approved disease-modifying therapy as yet. A growing body of evidence highlights the emerging role of high-mobility group box 1 (HMGB1) protein in HD pathology. HMGB1, being a nuclear protein, is primarily implicated in DNA repair, but it can also translocate to the cytoplasm and participate into numerous cellular functions. Cytoplasmic HMGB1 was shown to directly interact with huntingtin under oxidative stress conditions and induce its nuclear translocation, a key process in the HD pathogenic cascade. Nuclear HMGB1 acting as a co-factor of ataxia telangiectasia mutated and base excision repair (BER) complexes can exert dual roles in CAG repeat instability and affect the final DNA repair outcome. HMGB1 can inhibit mutant huntingtin aggregation, protecting against polyglutamine-induced neurotoxicity and acting as a chaperon-like molecule, possibly via autophagy regulation. In addition, HMGB1 being a RAGE and TLR-2, TLR-3, and TLR-4 ligand may further contribute to HD pathogenesis by triggering neuroinflammation and apoptosis. Furthermore, HMGB1 participates at the unfolded protein response (UPR) system and can induce protein degradation and apoptosis associated with HD. In this review, we discuss the multiple role of HMGB1 in HD pathology, providing mechanistic insights that could direct future studies towards the development of targeted therapeutic approaches.
Fluoxetine, a commonly prescribed medication for depression, has been studied in Alzheimer’s disease (AD) patients for its effectiveness on cognitive symptoms. The aim of this systematic review is to ...investigate the therapeutic potential of fluoxetine in cognitive decline in AD, focusing on its anti-degenerative mechanisms of action and clinical implications. According to PRISMA, we searched MEDLINE, up to 1 April 2024, for animal and human studies examining the efficacy of fluoxetine with regard to the recovery of cognitive function in AD. Methodological quality was evaluated using the ARRIVE tool for animal AD studies and the Cochrane tool for clinical trials. In total, 22 studies were analyzed (19 animal AD studies and 3 clinical studies). Fluoxetine promoted neurogenesis and enhanced synaptic plasticity in preclinical models of AD, through a decrease in Aβ pathology and increase in BDNF, by activating diverse pathways (such as the DAF-16-mediated, TGF-beta1, ILK-AKT-GSK3beta, and CREB/p-CREB/BDNF). In addition, fluoxetine has anti-inflammatory properties/antioxidant effects via targeting antioxidant Nrf2/HO-1 and hindering TLR4/NLRP3 inflammasome. Only three clinical studies showed that fluoxetine ameliorated the cognitive performance of people with AD; however, several methodological issues limited the generalizability of these results. Overall, the high-quality preclinical evidence suggests that fluoxetine may have neuroprotective, antioxidant, and anti-inflammatory effects in AD animal models. While more high-quality clinical research is needed to fully understand the mechanisms underlying these effects, fluoxetine is a promising potential treatment for AD patients. If future clinical trials confirm its anti-degenerative and neuroprotective effects, fluoxetine could offer a new therapeutic approach for slowing down the progression of AD.
Alzheimer's disease (AD) is a devastating neurodegenerative disorder and a leading cause of dementia, with accumulation of amyloid-beta (Aβ) and neurofibrillary tangles (NFTs) as defining ...pathological features. AD presents a serious global health concern with no cure to date, reflecting the complexity of its pathogenesis. Recent evidence indicates that neuroinflammation serves as the link between amyloid deposition, Tau pathology, and neurodegeneration. The high mobility group box 1 (HMGB1) protein, an initiator and activator of neuroinflammatory responses, has been involved in the pathogenesis of neurodegenerative diseases, including AD. HMGB1 is a typical damage-associated molecular pattern (DAMP) protein that exerts its biological activity mainly through binding to the receptor for advanced glycation end products (RAGE) and toll-like receptor 4 (TLR4). RAGE and TLR4 are key components of the innate immune system that both bind to HMGB1. Targeting of HMGB1, RAGE, and TLR4 in experimental AD models has demonstrated beneficial effects in halting AD progression by suppressing neuroinflammation, reducing Aβ load and production, improving spatial learning, and inhibiting microglial stimulation. Herein, we discuss the contribution of HMGB1 and its receptor signaling in neuroinflammation and AD pathogenesis, providing evidence of its beneficial effects upon therapeutic targeting.
Brain injuries are devastating conditions, representing a global cause of mortality and morbidity, with no effective treatment to date. Increased evidence supports the role of neuroinflammation in ...driving several forms of brain injuries. High mobility group box 1 (HMGB1) protein is a pro-inflammatory-like cytokine with an initiator role in neuroinflammation that has been implicated in Traumatic brain injury (TBI) as well as in early brain injury (EBI) after subarachnoid hemorrhage (SAH). Herein, we discuss the implication of HMGB1-induced neuroinflammatory responses in these brain injuries, mediated through binding to the receptor for advanced glycation end products (RAGE), toll-like receptor4 (TLR4) and other inflammatory mediators. Moreover, we provide evidence on the biomarker potential of HMGB1 and the significance of its nucleocytoplasmic translocation during brain injuries along with the promising neuroprotective effects observed upon HMGB1 inhibition/neutralization in TBI and EBI induced by SAH. Overall, this review addresses the current advances on neuroinflammation driven by HMGB1 in brain injuries indicating a future treatment opportunity that may overcome current therapeutic gaps.
Stress has deleterious effects on brain health and yet, the prognostic value of psychosocial stress regarding the most common types of dementias, including Alzheimer disease, is still unclear. The ...primary aim of this systematic review was to explore the association between psychosocial stress and late onset dementia. We classified 24articles from Medline, PsycINFO, CINAHL, and Web of Science, as pertaining toxic categories of psychosocial and trauma-related stress (low socio-economic status SES related inequalities, marital status, posttraumatic stress disorder, work stress, “vital exhaustion” VE, and, combined stressors). Using the Quality of Prognosis Studies in Systematic Reviews tool, we judged the quality of evidence to be low. This systematic review provided some non-robust, yet suggestive evidence that the above psychosocial types of stress are associated with increased risk of dementia in later life. Future robust, longitudinal studies with repeated validated measures of psychosocial stress and dementiaare required to strengthen or refute these findings.
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