Repurposing of tibolone in alzheimer’s disease

Alzheimer’s disease (AD) is a debilitating neurodegenerative disease characterised by the accumulation of amyloid-beta and tau in the brain, leading to the progressive loss of memory and cognition. The causes of its pathogenesis are still not fully understood, but some risk factors, such as age, genetics, and hormones, may play a crucial role. Studies show that postmenopausal women have a higher risk of developing AD, possibly due to the decrease in hormone levels, especially oestrogen, which may be directly related to a reduction in the activity of oestrogen receptors, especially beta (ERβ), which favours a more hostile cellular environment, leading to mitochondrial dysfunction, mainly affecting key processes related to transport, metabolism, and oxidative phosphorylation. Given the influence of hormones on biological processes at the mitochondrial level, hormone therapies are of clinical interest to reduce the risk or delay the onset of symptoms associated with AD. One drug with such potential is tibolone, which is used in clinics to treat menopause-related symptoms. It can reduce amyloid burden and have benefits on mitochondrial integrity and dynamics. Many of its protective effects are mediated through steroid receptors and may also be related to neuroglobin, whose elevated levels have been shown to protect against neurological diseases. Its importance has increased exponentially due to its implication in the pathogenesis of AD. In this review, we discuss recent advances in tibolone, focusing on its mitochondrial-protective effects, and highlight how valuable this compound could be as a therapeutic alternative to mitigate the molecular pathways characteristic of AD.</p

Comparison of antioxidant capacity and network pharmacology of phloretin and phlorizin against neuroinflammation in traumatic brain injury

Neuroinflammation is a hallmark of traumatic brain injury (TBI)’s acute and chronic phases. Despite the medical and scientific advances in recent years, there is still no effective treatment that mitigates the oxidative and inflammatory damage that affects neurons and glial cells. Therefore, searching for compounds with a broader spectrum of action that can regulate various inflammatory signaling pathways is of clinical interest. In this study, we determined not only the in vitro antioxidant capacity of apple pomace phenolics, namely, phlorizin and its metabolite, phloretin, but we also hypothesize that the use of these bioactive molecules may have potential use in TBI. We explored the antioxidant effects of both compounds in vitro (DPPH, iron-reducing capacity (IRC), and Folin– Ciocalteu reducing capacity (FCRC)), and using network pharmacology, we investigated the proteins involved in their protective effects in TBI. Our results showed that the antioxidant properties of phloretin were superior to those of phlorizin in the DPPH (12.95 vs. 3.52 mg ascorbic acid equivalent (AAE)/L), FCRC (86.73 vs. 73.69 mg gallic acid equivalent (GAE)/L), and iron-reducing capacity (1.15 vs. 0.88 mg GAE/L) assays. Next, we examined the molecular signature of both compounds and found 11 proteins in common to be regulated by them and involved in TBI. Meta-analysis and GO functional enrichment demonstrated their implication in matrix metalloproteinases, p53 signaling, and cell secretion/transport. Using MCODE and Pearson’s correlation analysis, a subcluster was generated. We identified ESR1 (estrogen receptor alpha) as a critical cellular hub being regulated by both compounds and with potential therapeutic use in TBI. In conclusion, our study suggests that because of their vast antioxidant effects, probably acting on estrogen receptors, phloretin and phlorizin may be repurposed for TBI treatment due to their ease of obtaining and low cost. </p

Network pharmacology and topological analysis on tibolone metabolites and their molecular mechanisms in traumatic brain injury

Traumatic brain injury (TBI) is a pathology of great social impact, affecting millions of people worldwide.  Despite the scientific advances to improve the management of TBI in recent years, we still do not have a specific  treatment that controls the inflammatory process after mechanical trauma. The discovery and implementation of  new treatments is a long and expensive process, making the repurpose of approved drugs for other pathologies a  clinical interest. Tibolone is a drug in use for the treatment of symptoms associated with menopause and has been  shown to have a broad spectrum of actions by regulating estrogen, androgen and progesterone receptors, whose  activation exerts potent anti-inflammatory and antioxidant effects. In the present study, we aimed to investigate  the therapeutic potential of the tibolone metabolites 3α-Hydroxytibolone, 3β-Hydroxytibolone, and Δ4-Tibolone  as a possible therapy in TBI using network pharmacology and network topology analysis. Our results demonstrate that the estrogenic component mediated by the α and β metabolites can regulate synaptic transmission and  cell metabolism, while the Δ metabolite may be involved in modulating the post-TBI inflammatory process. We  identified several molecular targets, including KDR, ESR2, AR, NR3C1, PPARD, and PPARA, which are known to  play critical roles in the pathogenesis of TBI. Tibolone metabolites were predicted to regulate the expression of  key genes involved in oxidative stress, inflammation, and apoptosis. Overall, the repurposing of tibolone as a  neuroprotective treatment for TBI holds promise for future clinical trials. However, further studies are needed to  confirm its efficacy and safety in TBI patients. </p

Identification of HMGCR, PPGARG and prohibitin as potential druggable targets of dihydrotestosterone for treatment against traumatic brain injury using system pharmacology

Background: Traumatic Brain Injury (TBI) has long-term devastating effects for which there is no accurate and  effective treatment for inflammation and chronic oxidative stress. As a disease that affects multiple signalling  pathways, the search for a drug with a broader spectrum of pharmacological action is of clinical interest. The fact  that endocrine disruption (e.g hypogonadism) has been observed in TBI patients suggests that endogenous  therapy with testosterone, or its more androgenic derivative, dihydrotestosterone (DHT), may attenuate, at least  in part, the TBI-induced inflammation, but the underlying molecular mechanisms by which this occurs are still  not completely clear.  Aims and methods: In this study, the main aim was to investigate proteins that may be related to the pathophysiological mechanism of TBI and also be pharmacological targets of DHT in order to explore a possible  therapy with this androgen using network pharmacology.  Results and conclusions: We identified 2.700 proteins related to TBI and 1.567 that are potentially molecular  targets of DHT. Functional enrichment analysis showed that steroid (p-value: 2.1–22), lipid metabolism (p-value:  2.8–21) and apoptotic processes (p-value: 5.2–21) are mainly altered in TBI. Furthermore, being mitochondrion  an organelle involved on these molecular processes we next identified that out of 32 mitochondrial-related  proteins 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMGCR), peroxisome proliferator activated receptor gamma (PPGARG) and prohibitin are those found highly regulated in the network and potential targets of  DHT in TBI. In conclusion, the identification of these cellular nodes may prove to be essential as targets of DHT  for therapy against post-TBI inflammation.  </p

Identification of difluorinated curcumin molecular targets linked to traumatic brain injury pathophysiology

Traumatic brain injury (TBI) affects approximately 50% of the world population at some point in their lifetime.  To date, there are no effective treatments as most of the damage occurs due to secondary effects through a variety  of pathophysiological pathways. The phytoceutical curcumin has been traditionally used as a natural remedy for  numerous conditions including diabetes, inflammatory diseases, and neurological and neurodegenerative dis?orders. We have carried out a system pharmacology study to identify potential targets of a difluorinated cur?cumin analogue (CDF) that overlap with those involved in the pathophysiological mechanisms of TBI. This  resulted in identification of 312 targets which are mostly involved in G protein-coupled receptor activity and  cellular signalling. These include adrenergic, serotonergic, opioid and cannabinoid receptor families, which have  been implicated in regulation of pain, inflammation, mood, learning and cognition pathways. We conclude that  further studies should be performed to validate curcumin as a potential novel treatment to ameliorate the effects  of TBI. </p

Editorial: Noncoding RNA-based spatiotemporal modulation and therapeutics in neuroinflammation

Neuroinflammation is a multifactorial process occurring in the central nervous system (CNS) that is intimately linked to temporal and spatial regulation of gene expression mediated by noncoding RNAs (ncRNAs). ncRNAs are present at high concentrations in the CNS and show specific multidimensional expression, exerting immunomodulatory effects via direct or indirect interactions with various effector proteins or other molecules to form complex networks that regulate downstream immune response pathways (1, 2). Next-generation sequencing has identified various ncRNAs dysregulated in CNS disorders, including long ncRNAs (lncRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs) (3–5). Genome-wide association studies (GWAS) have also revealed numerous single nucleotide polymorphisms within lncRNAs and miRNAs (6), providing promising candidates for therapeutic targets or biomarkers for CNS disorders. This Research Topic focuses on the latest discoveries, insights, and advances in ncRNA-based signaling pathways related to novel drug targets and biomarkers in neuroinflammation.</p

Respirasome Proteins Are Regulated by Sex-Hormone Interactions in the Brain

The existence of sex differences in disease incidence is attributed, in part, to sex differences in metabolism. Uncovering the precise mechanism driving these differences is an extraordinarily complex process influenced by genetics, endogenous hormones, sex-specific lifetime events, individual differences and external environmental/social factors. In fact, such differences may be subtle, but across a life span, increase susceptibility to a pathology. Whilst research persists in the hope of discovering an elegant biological mechanism to underpin sex differences in disease, here, we show, for the first time, that such a mechanism may be subtle in nature but influenced by multiple sex-specific factors. A proteomic dataset was generated from a gonadectomized mouse model treated with Tibolone, a menopausal hormone therapy. Following functional enrichment analysis, we identified that Alzheimer’s disease and the electron transport chain-associated pathways were regulated by sex-hormone interactions. Specifically, we identified that the expression of three respirasome proteins, NDUFA2, NDUFA7 and UQCR10, is significantly altered by compounding factors that contribute to sex differences. These proteins function in bioenergetics and produce reactive oxygen species, which are each dysregulated in many diseases with sex differences in incidence. We show sex-specific reprogrammed responses to Tibolone following gonadectomy, which primarily influence the expression of proteins contributing to metabolic pathways. This further infers that metabolic differences may underpin the observed sex differences in disease, but also that hormone therapy research now has potential in exploring sex-specific interventions to produce an effective method of prevention or treatment. </p

Editorial: Novel therapeutic target and drug discovery for neurological diseases

The Research Topic “Novel Therapeutic Target and Drug Discovery for Neurological Diseases” consists of 20 articles, including 12 original research papers, seven reviews, and one systematic review, with contributions from more than 140 authors. This work aims to compile a collection of articles focused on recent advances in promising therapeutic targets and biomarkers, new pathological mechanisms, and novel therapeutic agents in order to provide valuable clues for developing new therapeutic strategies for neurological diseases </p

The impact of curcumin on migraine: A comprehensive review

Migraine, a neurovascular condition, is a chronic and lifelong disease that affects about 15% of the population  worldwide. Although the exact pathophysiology and etiology of migraine are still unclear, oxidative stress,  inflammation, and neuroendocrine imbalances are identified as the critical risk factors for migraine attacks.  Curcumin is an active component and a polyphenolic diketone compound extracted from turmeric. Curcumin is a  promising candidate for preventing and controlling migraine due to its anti‑inflammatory, antioxidative, anti-protein aggregate, and analgesic effects. In the present review, we have evaluated experimental and clinical  studies investigating the impact of liposomal curcumin and nano-curcumin on the frequency and severity of  migraine attacks in patients. Although the results are promising, more studies should be conducted in this area to  show the exact efficacies of curcumin on clinical symptoms of migraine and investigate its potential mechanisms.  </p

Palmitic acid upregulates type I interferon–mediated antiviral response and cholesterol biosynthesis in human astrocytes

Chronic intake of a high-fat diet increases saturated fatty acids in the brain causing the progression of neurodegenerative diseases. Palmitic acid is a free fatty acid abundant in the diet that at high concentrations may penetrate the blood–brain barrier and stimulate the production of pro-infammatory cytokines, leading to infammation in astrocytes. The use of the synthetic neurosteroid tibolone in protection against fatty acid toxicity is emerging, but its transcriptional efects on palmitic acid–induced lipotoxicity remain unclear. Herein, we performed a transcriptome profling of normal human astrocytes to investigate the molecular mechanisms by which palmitic acid causes cellular damage to astrocytes, and whether tibolone could reverse its detrimental efects. Astrocytes undergo a profound transcriptional change at 2 mM palmitic acid, afecting the expression of 739 genes, 366 upregulated and 373 downregulated. However, tibolone at 10 nM does not entirely reverse palmitic acid efects. Additionally, the protein–protein interaction reveals two novel gene clustering modules. The frst module involves astrocyte defense responses by upregulation of pathways associated with antiviral innate immunity, and the second is linked to lipid metabolism. Our data suggest that activation of viral response signaling pathways might be so far, the initial molecular mechanism of astrocytes in response to a lipotoxic insult by palmitic acid, triggered particularly upon increased expression levels of IFIT2, IRF1, and XAF1. Therefore, this novel approach using a global gene expression analysis may shed light on the pleiotropic efects of palmitic acid on astrocytes, and provide a basis for future studies addressed to elucidate these responses in neurodegenerative conditions, which is highly valuable for the design of therapeutic strategies.</p