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

Druggable cavities and allosteric modulators of the cell division cycle 7 (CDC7) kinase

Cell division cycle 7 kinase (CDC7) has been found overexpressed in many cancer cell lines being also one of the kinases involved in the nuclear protein TDP-43 phosphorylation in vivo. Thus, inhibitors of CDC7 are emerging drug candidates for the treatment of oncological and neurodegenerative unmet diseases. All the known CDC7 inhibitors are ATP-competitives, lacking of selectivity enough for success in clinical trials. As allosteric sites are less conserved among kinase proteins, discovery of allosteric modulators of CDC7 is a great challenge and opportunity in this field. Using different computational approaches, we have here identified new druggable cavities on the human CDC7 structure and subsequently selective CDC7 inhibitors with allosteric modulation mainly targeting the pockets where the interaction between this kinase and its activator DBF4 takes place.</p

Tibolone pre-treatment ameliorates the dysregulation of protein translation and transport generated by palmitic acid-induced lipotoxicity in human astrocytes: A label-free MS-based proteomics and network analysis

Excessive accumulation and release of fatty acids (FAs) in adipose and non-adipose tissue are characteristic of obesity and are associated with the leading causes of death worldwide. Chronic exposure to high concentrations of FAs such as palmitic acid (pal) is a risk factor for developing different neurodegenerative diseases (NDs) through several mechanisms. In the brain, astrocytic dysregulation plays an essential role in detrimental processes like metabolic inflammatory state, oxidative stress, endoplasmic reticulum stress, and autophagy impairment. Evidence shows that tibolone, a synthetic steroid, induces neuroprotective effects, but its molecular mechanisms upon exposure to pal remain largely unknown. Due to the capacity of identifying changes in the whole data-set of proteins and their interaction allowing a deeper understanding, we used a proteomic approach on normal human astrocytes under supraphysiological levels of pal as a model to induce cytotoxicity, finding changes of expression in proteins related to translation, transport, autophagy, and apoptosis. Additionally, tibolone pre-treatment showed protective effects by restoring those same pal-altered processes and increasing the expression of proteins from cell survival processes. Interestingly, ARF3 and IPO7 were identified as relevant proteins, presenting a high weight in the protein-protein interaction network and significant differences in expression levels. These proteins are related to transport and translation processes, and their expression was restored by tibolone. This work suggests that the damage caused by pal in astrocytes simultaneously involves different mechanisms that the tibolone can partially revert, making tibolone interesting for further research to understand how to modulate these damages. </p