Search Results (57)

Cognitive problems are associated with impaired learning ability and memory dysfunction. Neuroinflammation has been identified as an important factor in the progression of anxiety and depressive disorders. Zingerone is a phenolic alkanone derived from ginger (Zingiber officinale Roscoe), which is known for its antioxidant and anti-inflammatory properties. A number of studies have investigated the effect of zingerone on neuroinflammation and cognitive impairment. However, this evidence has not been systematically reviewed. This study sought to systematically review the effect of zingerone on neuroinflammation and neurobehavioural changes associated with memory and learning impairment and anxiety-like and depressive-like behaviours. A systematic review was conducted using pre-defined search criteria on Google Scholar, Scopus and Web of Science. The records obtained were screened based on inclusion criteria, and data was extracted from the included studies. Out of the 482 studies that were identified, only 9 studies met the inclusion criteria. Neuroinflammatory markers such as interleukin 1β (IL-1β), interleukin 6 (IL-6), tumour necrosis factor-alpha (TNF-α) and ionized calcium binding adaptor molecule (IBA-1), as well as behavioural parameters including Morris water maze, Y-Maze, recognition test, passive avoidance test, elevated plus maze, sucrose preference test and forced swimming test were measured. Zingerone exhibited anti-neuroinflammatory effects by improving IL-1β, IL-6 and TNF-α levels. However, zingerone did not show any significant changes on activated microglia. The anti-neuroinflammatory mechanisms of zingerone were linked to the inhibition of nuclear factor kappa B (NF-kB) activation and the NOD-like receptor family, pyrin domain-containing 3 (NLRP3) inflammasome, as well as the reduction in neuronal nitric oxide synthase (nNOS). The anxiolytic and anti-depressive effects of zingerone were also associated with an improvement in cortical cholinergic transmission, the mitigation of oxidative stress and the upregulation of neurotransmitters such as serotonin and dopamine. This review provides scientific evidence on the cognitive enhancing and neuroprotective mechanisms of zingerone, which may be beneficial for future experimental investigations. Full article

Neuroblastoma (NB) is a malignant childhood tumour, which originates from neuroblasts with an incidence of approximately 15,000 new cases per year worldwide. Therapy-induced secondary tumorigenesis and the emergency of drug resistance in its high-risk (HR-NB) forms drive to a survival rate of <50%, despite aggressive treatments. Our recent research is focused on testing in vitro the effects of synthetized triphenyl phosphonium (TPP)-based bola amphiphilic nanovesicles (BPPBs) against both drug-sensitive and multi-drug-resistant (MDR) cancer cell lines. In the present study, BPPB demonstrated sub-micromolar IC₅₀ values (0.4–0.9 µM) towards drug-sensitive HTLA 230, while 1.20–1.35 µM IC₅₀ were determined on MDR HTLA ER. Noteworthily, we have demonstrated that BPPB triggers apoptosis of both NB cell populations. Additionally, since MDR NB cells (HTLA ER) are equipped with higher levels of antioxidants than sensitive ones (HTLA 230), the potential involvement of reactive oxygen species (ROS) in the cytotoxic action of BPPB was also investigated. Then, a novel analytical approach was applied to the results of cell viability and ROS monitoring for their better interpretation. Proper dispersion graphs and their best fitting nonlinear regression models were used to verify if the cytotoxic effects of BPPB could depend on BPPB concentrations, exposure times, and/or ROS generation, and if ROS increase could depend on BPPB concentrations and/or exposure times. A ROS-dependent mechanism was found in 24 h and 24/48 h treatments of HTLA ER and HTLA 230, respectively. Furthermore, the potential clinical development of BPPB as a new curative option for children affected by HR-NB was assessed by testing BPPB on astrocyte and neuron primary cell cultures, and analytical correlation studies were used to interpret the results. Notably, BPPB administration was sufficiently and well tolerated by neurons and astrocytes, respectively, allowing selectivity index values of up to 23.7. These in vitro results, associated with the low haemolytic activity of BPPB, pave the way for future in vivo investigations and, upon confirmation, for the possible development of BPPB as a novel therapeutic strategy to treat MDR HR-NB. Full article

Gracilaria species, a widely distributed genus of red macroalgae, have gathered significant attention for their diverse medical applications attributable to their bioactive sulphated polysaccharides (SPs). This review examines the global narrative of various Gracilaria SP applications in terms of their therapeutic potential and mechanistic insights into the use of these SPs against a range of medical conditions, including cancer, inflammation, neurodegenerative disorders, diabetes, and immune dysfunctions. SPs extracted from G. lemaneiformis and G. fisheri have demonstrated potent anti-tumour activities by inducing apoptosis through various mechanisms, including the upregulation of CD8⁺ T cells and IL-2, inhibition of EGFR/MAPK/ERK signalling pathways, and activation of the Fas/FasL pathway. Selenium nanoparticles (SeNPs) conjugated with SPs further enhanced the targeted delivery and efficacy of these SPs against glioblastoma by the downregulation of ROS followed by the activation of p53, MAPK, and AKT pathways. The anti-inflammatory properties of SPs are evidenced by key suppressive inflammatory markers like NO, TNF-α, IL-1β, and IL-6 in mutant rodent models. SPs from G. cornea and G. birdiae effectively reduce neutrophil migration and vascular permeability, offering potential treatments for acute inflammation and conditions such as colitis by modulating pathways involving COX-2 and NF-κB. Neuroprotective effects by SPs (from G. cornea and G. gracili) studied in 6-OHDA-induced rats, which mitigate oxidative stress and enhance neuronal cell viability, facilitate the management of neurodegenerative diseases like Parkinson’s and Alzheimer’s. Regarding the hypoglycaemic effect, SPs from G. lemaneiformis exhibit a glucose-modulating response by improving insulin regulation, inhibiting α-amylase activity, repairing pancreatic β-cells, and modulating lipid metabolism. Moreover, immunomodulatory activities of Gracilaria-derived SPs include the stimulation of macrophages, T-cell proliferation, and cytokine production, underscoring their potential as functional food and immunotherapeutic agents. Recently, Gracilaria-derived SPs have been found to modulate gut microbiota, promote SCFA production, and enhance gut microbials, suggesting their potential as prebiotic agents (G. rubra and G. lemaneiformis). This review highlights the multifaceted medical applications of Gracilaria sulphated polysaccharides, providing detailed mechanistic insights and suggesting avenues for future clinical translation and therapeutic innovations. Full article

Background and Clinical Significance: Neuroendocrine expressing goblet cell adenocarcinomas (GCAs) are uncommon clinically aggressive tumours of the digestive system, originating almost exclusively in the ileocecal appendix. GCA’s singularity comes from its amphicrine nature, expressing both neuroendocrine and exocrine characteristics. The case report’s objective is to raise awareness of this neoplasia’s possible extra-appendiceal localisation by showcasing a GCA involving the cecum with no detectable appendiceal tumour. Case Presentation: The authors present a case of GCA with neuroendocrine expression in an 82-year-old male patient with severe anaemia and comorbidities who underwent a right colectomy and had no histopathological evidence of appendiceal tumour involvement. Immunohistochemical testing was performed using synaptophysin, chromogranin A, neuronal specific enolase, CD56, CDX-2, CK20, CEA, MUC2 and Ki67, thus establishing the final diagnosis of high-grade extra-appendiceal goblet-cell adenocarcinoma of the cecum, G3. The patient died on postoperative day 26 due to pneumonia and acute renal failure in a chronic renal disease context. Conclusions: Extremely few cases of extra-appendiceal GCA have been reported. Appendiceal evaluation with the exclusion of this possible origin should be mandatory in such cases for a correct classification. These tumours do not benefit from any official management protocols concerning clinical evaluation, and their treatment is commonly based on the tumour’s stage, as in classical adenocarcinoma. Full article

Paraneoplastic cerebellar degeneration (PCD) is a rapidly progressive, immune-mediated syndrome characterized by the degeneration of Purkinje cells, often associated with the presence of antibodies targeting intracellular antigens within these cells. These autoantibodies are implicated in the induction of cytotoxicity, leading to Purkinje cell death, as demonstrated in in vitro models. However, the precise roles of antibodies and T lymphocytes in mediating neuronal injury remain a subject of ongoing research, with T cells appearing to be the main effectors of cerebellar injury. Notably, at least 50% of PCD cases involve anti-Yo autoantibodies, also referred to as anti-PCA1 (Purkinje cell antigen 1) antibodies, which specifically target cerebellar degeneration-related protein 2 (CDR2) and its paralogue, CDR2-like (CDR2L). Another recognized antigen is CDR 34, a 34 kDa Purkinje cell antigen characterized by tandem repeats and a B-cell epitope; its detection in non-cerebellar tissues necessitates further in situ hybridization studies. Onconeural antigens are expressed in both Purkinje cells and tumour cells, where they localize in the cytoplasm and associate with membrane-bound and free ribosomes, playing critical roles in regulating transcription and calcium homeostasis. Recent studies suggest that the breakdown of immune tolerance is linked to genetic alterations in tumour cell antigens, leading to the formation of neoantigens that can elicit autoreactive T cells, which may underscore the function of Yo antibodies. In vitro studies indicate that anti-Yo antibodies can induce cell death independent of T lymphocytes. The disease progresses by initial lymphocytic infiltration, followed by a rapid loss of Purkinje cells without significant inflammation. However, in vivo models showcase that anti-Yo PCD is primarily T-cell mediated, with antibodies serving as biomarkers rather than direct effectors of neuronal death. This review examines the mechanisms underlying PCD, focusing on the roles of CDR2 and CDR2L in tumour development and their potential role in the degeneration of cerebellar Purkinje neurons. A comprehensive understanding of these processes is essential for advancing diagnostic, prognostic, and therapeutic strategies for PCD and associated malignancies. Full article

Neuroendocrine prostate cancer (NEPC), an aggressive and lethal subtype of prostate cancer (PCa), often arises as a resistance mechanism in patients undergoing hormone therapy for prostate adenocarcinoma. NEPC is associated with a significantly poor prognosis and shorter overall survival compared to conventional prostate adenocarcinoma due to its aggressive nature and limited response to standard of care therapies. This transdifferentiation, or lineage reprogramming, to NEPC is characterised by the loss of androgen receptor (AR) and prostate-specific antigen (PSA) expression, and the upregulation of neuroendocrine (NE) biomarkers such as neuron-specific enolase (NSE), chromogranin-A (CHGA), synaptophysin (SYP), and neural cell adhesion molecule 1 (NCAM1/CD56), which are critical for NEPC diagnosis. The loss of AR expression culminates in resistance to standard of care PCa therapies, such as androgen-deprivation therapy (ADT) which target the AR signalling axis. This review explores the drivers of NE transdifferentiation. Key genetic alterations, including those in the tumour suppressor genes RB1, TP53, and PTEN, and changes in epigenetic regulators, particularly involving EZH2 and cell-fate-determining transcription factors (TFs) such as SOX2, play significant roles in promoting NE transdifferentiation and facilitate the lineage switch from prostate adenocarcinoma to NEPC. The recent identification of several other key novel drivers of NE transdifferentiation, including MYCN, ASCL1, BRN2, ONECUT2, and FOXA2, further elucidates the complex regulatory networks and pathways involved in this process. We suggest that, given the multifactorial nature of NEPC, novel therapeutic strategies that combine multiple modalities are essential to overcome therapeutic resistance and improve patient outcomes. Full article

Background: Alzheimer’s disease (AD) is a neurodegenerative disorder traditionally characterised by the presence of amyloid beta (Aβ) plaques and neurofibrillary tau tangles in the brain. However, emerging research has highlighted additional metabolic hallmarks of AD pathology. These include the metabolic reprogramming of microglia in favour of glycolysis over oxidative phosphorylation. This shift is attributed to an ‘M1′-like pro-inflammatory phenotype, which exacerbates neuroinflammation and contributes to neuronal damage. The urea cycle also presents as an altered metabolic pathway in AD, due to elevated urea levels and altered expression of urea cycle enzymes, metabolites, and transporters in the brain. However, to date, these changes remain largely unexplored. Methods: This study focuses on understanding the effects of extracellular urea and urea transporter-B (UT-B) inhibition on inflammatory changes in lipoteichoic acid (LTA)-stimulated BV2 microglia and on the viability of SH-SY5Y neuronal cells under oxidative stress and neurotoxic conditions. Results: In BV2 microglia, UT-B inhibition demonstrated a notable anti-inflammatory effect by reducing the formation of nitric oxide (NO) and the expression of tumour necrosis factor α (TNFα) and CCL2 in response to stimulation with the toll-like receptor (TLR)2 agonist, lipoteichoic acid (LTA). This was accompanied by a reduction in extracellular urea and upregulation of UT-B expression. The application of exogenous urea was also shown to mediate the inflammatory profile of BV2 cells in a similar manner but had only a modest impact on UT-B expression. While exposure to LTA alone did not alter the microglial metabolic profile, inhibition of UT-B upregulated the expression of genes associated with both glycolysis and fatty acid oxidation. Conversely, neither increased extracellular urea nor UT-B inhibition had a significant impact on cell viability or cytotoxicity in SH-SY5Y neurones exposed to oxidative stressors tert-butyl hydroperoxide (t-BHP) and 6-hydroxydopamine (6-OHDA). Conclusions: This study further highlights the involvement of urea transport in regulating the neuroinflammation associated with AD. Moreover, we reveal a novel role for UT-B in maintaining microglial metabolic homeostasis. Taken together, these findings contribute supporting evidence to the regulation of UT-B as a therapeutic target for intervention into neuroinflammatory and neurodegenerative disease. Full article

Currently, the biomimetic approach of drawing inspiration from nature has frequently been employed in designing drug nanocarriers (NCs) of actively target various diseases, ranging from cancer to neuronal and inflammation pathologies. The cell-membrane coating can confer upon the inner nanomaterials a biological identity and the functions exhibited by the cells from which the membrane is derived. Monocyte- and macrophage-membrane-coated nanomaterials have emerged as an ideal delivery system to target inflamed vasculature. Herein, we developed two biomimetic NCs using a human-derived leukaemia monocytic cell line (THP-1), either undifferentiated or differentiated by phorbol 12-myristate 13-acetate (PMA) into adherent macrophage-like cells as membrane sources for NC coating. We employed a secondary oil-in-water nano-emulsion (SNE) as the inner core, which served as an optimal NC for high payloads of lipophilic compounds. Two different biomimetic systems were produced, combining the biomimetic features of biological membranes with the physicochemical and nano-sized characteristics of SNEs. These systems were named Monocyte NEsoSome (M-NEsoSome) and Macrophage NEsoSome (M0-NEsoSome). Their uptake ability was investigated in tumour necrosis factor alfa (TNFα)-treated human umbilical vein endothelial cells (HUVECs), selected as a model of inflamed endothelial cells. The M0 membrane coating demonstrated accelerated internalisation compared with the monocyte coating and notably surpassed the uptake rate of bare NCs. In conclusion, M0-NEsoSome NCs could be a therapeutic system for targeting inflamed endothelial cells and potentially delivering anti-inflammatory drugs in vascular inflammation. Full article

The IgLON family of cell adhesion molecules consists of five members (LSAMP, OPCML, neurotrimin, NEGR1, and IgLON5) discovered as supporters of neuronal development, axon growth and guidance, and synapse formation and maintenance. Tumour suppression properties have recently been emerging based on antiproliferative effects through the modulation of oncogenic pathways. Available evidence endorses a role for non-coding RNAs or microRNAs as relevant controllers of IgLON molecule expression that can impact their critical physiological and pathological roles. Current findings support a function for long non-coding RNAs and microRNAs in the modulation of LSAMP expression in cell senescence, cancer biogenesis, addiction, and pulmonary hypertension. For OPCML, data point to a role for several microRNAs in the control of tumorigenesis. MicroRNAs were detected in neurotrimin-mediated functions in cancer biogenesis and in Schwann cell responses to peripheral nerve injury. For NEGR1, studies have mainly investigated microRNA involvement in neuronal responses to ischaemic injury, although data also exist about tumorigenesis and endothelial cell dysfunction. For IgLON5, information is only available about microRNA involved in myocardial infarction. In conclusion, despite much information being still missing and further research needed, the emerging picture favours a model in which non-coding RNAs exert a crucial role in modulating IgLON expression, ultimately affecting their important physiological functions. Full article

Radiotherapy (RT) plays a key role in brain tumours but can negatively impact functional outcomes and quality of life. The aim of this study was to analyse anti-neural and onconeural autoantibodies and markers of blood–brain barrier (BBB) disruption in patients with primary brain cancer undergoing RT. Materials and methods. A prospective study was conducted on 45 patients with a brain tumour scheduled for intensity-modulated radiotherapy. Assessments were performed at baseline, post-RT, and at three months. We measured serum levels of BBB disruption biomarkers and anti-neural, onconeural, and organ-specific antibodies. Results. Antibodies against nucleosome antigens and neuronal surface antigens were detected in 85% and 3% of cases, respectively; anti-neural and onconeural antibodies were observed in 47% and 5.8%. In 44% patients, ≥2 antibody types were detected. No significant changes in BBB biomarkers were observed. Conclusion. The findings of this study show that a humoral immune response is common in patients undergoing RT for brain cancer. This response appears to be non-organ specific but rather directed against nucleosome antigens, but onconeural antibodies were uncommon, suggesting a low risk of a neurological paraneoplastic syndrome. Our data suggested that radiotherapy may not affect BBB integrity, but larger studies are needed to better characterise the pathophysiological effects of RT. Full article

Approximately 30% of glioma patients are able to survive beyond one year postdiagnosis. And this short time is often overshadowed by glioma-associated epilepsy. This condition severely impairs the patient’s quality of life and causes great suffering. The genetic, molecular and cellular mechanisms underlying tumour development and epileptogenesis remain incompletely understood, leading to numerous unanswered questions. The various types of gliomas, namely glioblastoma, astrocytoma and oligodendroglioma, demonstrate distinct seizure susceptibility and disease progression patterns. Patterns have been identified in the presence of IDH mutations and epilepsy, with tumour location in cortical regions, particularly the frontal lobe, showing a more frequent association with seizures. Altered expression of TP53, MGMT and VIM is frequently detected in tumour cells from individuals with epilepsy associated with glioma. However, understanding the pathogenesis of these modifications poses a challenge. Moreover, hypoxic effects induced by glioma and associated with the HIF-1a factor may have a significant impact on epileptogenesis, potentially resulting in epileptiform activity within neuronal networks. We additionally hypothesise about how the tumour may affect the functioning of neuronal ion channels and contribute to disruptions in the blood–brain barrier resulting in spontaneous depolarisations. Full article

Targeting tumour metabolism through glucose transporters is an attractive approach. However, the role these transporters play through interaction with other signalling proteins is not yet defined. The glucose transporter SLC2A3 (GLUT3) is a member of the solute carrier transporter proteins. GLUT3 has a high affinity for D-glucose and regulates glucose uptake in the neurons, as well as other tissues. Herein, we show that GLUT3 is involved in the uptake of arsenite, and its level is regulated by peroxiredoxin 1 (PRDX1). In the absence of PRDX1, GLUT3 mRNA and protein expression levels are low, but they are increased upon arsenite treatment, correlating with an increased uptake of glucose. The downregulation of GLUT3 by siRNA or deletion of the gene by CRISPR cas-9 confers resistance to arsenite. Additionally, the overexpression of GLUT3 sensitises the cells to arsenite. We further show that GLUT3 interacts with PRDX1, and it forms nuclear foci, which are redistributed upon arsenite exposure, as revealed by immunofluorescence analysis. We propose that GLUT3 plays a role in mediating the uptake of arsenite into cells, and its homeostatic and redox states are tightly regulated by PRDX1. As such, GLUT3 and PRDX1 are likely to be novel targets for arsenite-based cancer therapy. Full article

The autosomal recessive disorder Ataxia-Telangiectasia is caused by a dysfunction of the stress response protein, ATM. In the nucleus of proliferating cells, ATM senses DNA double-strand breaks and coordinates their repair. This role explains T-cell dysfunction and tumour risk. However, it remains unclear whether this function is relevant for postmitotic neurons and underlies cerebellar atrophy, since ATM is cytoplasmic in postmitotic neurons. Here, we used ATM-null mice that survived early immune deficits via bone-marrow transplantation, and that reached initial neurodegeneration stages at 12 months of age. Global cerebellar transcriptomics demonstrated that ATM depletion triggered upregulations in most neurotransmission and neuropeptide systems. Downregulated transcripts were found for the ATM interactome component Usp2, many non-coding RNAs, ataxia genes Itpr1, Grid2, immediate early genes and immunity factors. Allelic splice changes affected prominently the neuropeptide machinery, e.g., Oprm1. Validation experiments with stressors were performed in human neuroblastoma cells, where ATM was localised only to cytoplasm, similar to the brain. Effect confirmation in SH-SY5Y cells occurred after ATM depletion and osmotic stress better than nutrient/oxidative stress, but not after ATM kinase inhibition or DNA stressor bleomycin. Overall, we provide pioneer observations from a faithful A-T mouse model, which suggest general changes in synaptic and dense-core vesicle stress adaptation. Full article

The key challenges to treating glioblastoma multiforme (GBM) are the heterogeneous and complex nature of the GBM tumour microenvironment (TME) and difficulty of drug delivery across the blood–brain barrier (BBB). The TME is composed of various neuronal and immune cells, as well as non-cellular components, including metabolic products, cellular interactions, and chemical compositions, all of which play a critical role in GBM development and therapeutic resistance. In this review, we aim to unravel the complexity of the GBM TME, evaluate current therapeutics targeting this microenvironment, and lastly identify potential targets and therapeutic delivery vehicles for the treatment of GBM. Specifically, we explore the potential of aptamer-targeted delivery as a successful approach to treating brain cancers. Aptamers have emerged as promising therapeutic drug delivery vehicles with the potential to cross the BBB and deliver payloads to GBM and brain metastases. By targeting specific ligands within the TME, aptamers could potentially improve treatment outcomes and overcome the challenges associated with larger therapies such as antibodies. Full article

Melanoma is one of the deadliest forms of cancer. Most melanoma deaths are caused by distant metastases in several organs, especially the brain, the so-called melanoma brain metastases (MBMs). However, the precise mechanisms that sustain the growth of MBMs remain elusive. Recently, the excitatory neurotransmitter glutamate has been proposed as a brain-specific, pro-tumorigenic signal for various types of cancers, but how neuronal glutamate shuttling onto metastases is regulated remains unknown. Here, we show that the cannabinoid CB₁ receptor (CB₁R), a master regulator of glutamate output from nerve terminals, controls MBM proliferation. First, in silico transcriptomic analysis of cancer-genome atlases indicated an aberrant expression of glutamate receptors in human metastatic melanoma samples. Second, in vitro experiments conducted on three different melanoma cell lines showed that the selective blockade of glutamatergic NMDA receptors, but not AMPA or metabotropic receptors, reduces cell proliferation. Third, in vivo grafting of melanoma cells in the brain of mice selectively devoid of CB₁Rs in glutamatergic neurons increased tumour cell proliferation in concert with NMDA receptor activation, whereas melanoma cell growth in other tissue locations was not affected. Taken together, our findings demonstrate an unprecedented regulatory role of neuronal CB₁Rs in the MBM tumour microenvironment. Full article