Telomeres: the role of shortening and senescence in major depressive disorder and its therapeutic implications.

Major depressive disorder (MDD) is one of the most prevalent and debilitating psychiatric disorders, with a large number of patients not showing an effective therapeutic response to available treatments. Several biopsychosocial factors, such as stress in childhood and throughout life, and factors related to biological aging, may increase the susceptibility to MDD development. Included in critical biological processes related to aging and underlying biological mechanisms associated with MDD is the shortening of telomeres and changes in telomerase activity. This comprehensive review discusses studies that assessed the length of telomeres or telomerase activity and function in peripheral blood cells and brain tissues of MDD individuals. Also, results from in vitro protocols and animal models of stress and depressive-like behaviors were included. We also expand our discussion to include the role of telomere biology as it relates to other relevant biological mechanisms, such as the hypothalamic-pituitary-adrenal (HPA) axis, oxidative stress, inflammation, genetics, and epigenetic changes. In the text and the discussion, conflicting results in the literature were observed, especially considering the size of telomeres in the central nervous system, on which there are different protocols with divergent results in the literature. Finally, the context of this review is considering cell signaling, transcription factors, and neurotransmission, which are involved in MDD and can be underlying to senescence, telomere shortening, and telomerase functions.

Anti-inflammatory Therapy by Cholinergic and Purinergic Modulation in Multiple Sclerosis Associated with SARS-CoV-2 Infection.

The virus "acute respiratory syndrome coronavirus 2" (SARS-CoV-2) is the etiologic agent of coronavirus disease 2019 (COVID-19), initially responsible for an outbreak of pneumonia in Wuhan, China, which, due to the high level of contagion and dissemination, has become a pandemic. The clinical picture varies from mild to critical cases; however, all of these signs already show neurological problems, from sensory loss to neurological diseases. Thus, patients with multiple sclerosis (MS) infected with the new coronavirus are more likely to develop severe conditions; in addition to worsening the disease, this is due to the high level of pro-inflammatory cytokines, which is closely associated with increased mortality both in COVID-19 and MS. This increase is uncontrolled and exaggerated, characterizing the cytokine storm, so a possible therapy for this neuronal inflammation is the modulation of the cholinergic anti-inflammatory pathway, since acetylcholine (ACh) acts to reduce pro-inflammatory cytokines and acts directly on the brain for being released by cholinergic neurons, as well as acting on other cells such as immune and blood cells. In addition, due to tissue damage, there is an exacerbated release of adenosine triphosphate (ATP), potentiating the inflammatory process and activating purinergic receptors which act directly on neuroinflammation and positively modulate the inflammatory cycle. Associated with this, in neurological pathologies, there is greater expression of P2X7 in the cells of the microglia, which positively activates the immune inflammatory response. Thus, the administration of blockers of this receptor can act in conjunction with the action of ACh in the anticholinergic inflammatory pathway. Finally, there will be a reduction in the cytokine storm and triggered hyperinflammation, as well as the level of mortality in patients with multiple sclerosis infected with SARS-CoV-2 and the development of possible neurological damage.

Targeting the purinergic pathway in breast cancer and its therapeutic applications.

Breast cancer (BC) is the most frequent cause of death among women, representing a global public health problem. Here, we aimed to discuss the correlation between the purinergic system and BC, recognizing therapeutic targets. For this, we analyzed the interaction of extracellular nucleotides and nucleosides with the purinergic receptors P1 and P2, as well as the influence of ectonucleotidase enzymes (CD39 and CD73) on tumor progression. A comprehensive bibliographic search was carried out. The relevant articles for this review were found in the PubMed, Scielo, Lilacs, and ScienceDirect databases. It was observed that among the P1 receptors, the A1, A2A, and A2B receptors are involved in the proliferation and invasion of BC, while the A3 receptor is related to the inhibition of tumor growth. Among the P2 receptors, the P2X7 has a dual function. When activated for a short time, it promotes metastasis, but when activated for long periods, it is related to BC cell death. P2Y2 and P2Y6 receptors are related to BC proliferation and invasiveness. Also, the high expression of CD39 and CD73 in BC is strongly related to a worse prognosis. The receptors and ectonucleotidases involved with BC become possible therapeutic targets. Several purinergic pathways have been found to be involved in BC cell survival and progression. In this review, in addition to analyzing the pathways involved, we reviewed the therapeutic interventions already studied for BC related to the purinergic system, as well as to other possible therapeutic targets.