Antioxidant Functions of Vitamin D and CYP11A1-Derived Vitamin D, Tachysterol, and Lumisterol Metabolites: Mechanisms, Clinical Implications, and Future Directions.

Evidence is increasing that vitamin D and CYP11A1-derived vitamin D, tachysterol, and lumisterol metabolites play a significant antioxidant role beyond its classical functions in bone health and calcium metabolism. Several recent studies have linked these elements to reduced oxidative stress as well as improved immune, cardiovascular, and neurological functions as a result of chronic kidney disease and cancer. Additionally, supplementation with this vitamin has been shown to be one of the most cost-effective micronutrient interventions worldwide, highlighting its potential as a therapeutic approach. The underlying mechanisms and implications of this antioxidant function of vitamin D or CYP11A1-derived vitamin D, tachysterol, and lumisterol metabolites are not well understood. This comprehensive and narrative review is aimed at summarizing the current evidence regarding the molecular mechanisms implicated in this antioxidant function of vitamin D, as well as to provide a general overview and to identify key research areas for the future, offering an extensive perspective that can guide both researchers and clinicians in the management of diseases associated with oxidative stress and/or insufficient vitamin D status.

Dysregulated expression of hypoxia-inducible factors augments myofibroblasts differentiation in idiopathic pulmonary fibrosis.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is an age-related, progressive and lethal disease, whose pathogenesis is associated with fibroblasts/myofibroblasts foci that produce excessive extracellular matrix accumulation in lung parenchyma. Hypoxia has been described as a determinant factor in its development and progression. However, the role of distinct members of this pathway is not completely described. METHODS: By western blot, quantitative PCR, Immunohistochemistry and Immunocitochemistry were evaluated, the expression HIF alpha subunit isoforms 1, 2 & 3 as well, as their role in myofibroblast differentiation in lung tissue and fibroblast cell lines derived from IPF patients. RESULTS: Hypoxia signaling pathway was found very active in lungs and fibroblasts from IPF patients, as demonstrated by the abundance of alpha subunits 1 and 2, which further correlated with the increased expression of myofibroblast marker αSMA. In contrast, HIF-3α showed reduced expression associated with its promoter hypermethylation. CONCLUSIONS: This study lends further support to the involvement of hypoxia in the pathogenesis of IPF, and poses HIF-3α expression as a potential negative regulator of these phenomena.

Behavioral, neurochemical and molecular changes after acute deep brain stimulation of the infralimbic prefrontal cortex.

Deep brain stimulation (DBS) is a treatment that has shown some efficacy in treatment-resistant depression. In particular, DBS of the subcallosal cingulate gyrus (Brodmann's area 25, Cg25) has been successfully applied to treat refractory depression. In the rat, we have demonstrated that DBS applied to infralimbic (IL) cortex elevates the levels of glutamate and monoamines in the prefrontal cortex, and requires the stimulation of cortical α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors for its antidepressant-like effects. However, the molecular targets of IL DBS are not fully known. To gain insight into these pathways, we have investigated whether IL DBS is able to reverse the behavioral, biochemical and molecular changes exhibited by the olfactory bulbectomized (OBX) rat. Our results revealed that 1 h IL DBS diminished hyperlocomotion, hyperemotionality and anhedonia, and increased social interaction shown by the OBX rats. Further, IL DBS increased prefrontal efflux of glutamate and serotonin in both sham-operated and OBX rats. With regard to molecular targets, IL DBS increases the synthesis of brain-derived neurotrophic factor (BDNF) and the GluA1 AMPA receptor subunit, and stimulates the Akt/mammalian target of rapamycin (mTOR) as well as the AMPA receptor/c-AMP response element binding (CREB) pathways. Temsirolimus, a known in vivo mTOR blocker, suppressed the antidepressant-like effect of IL DBS in naïve rats in the forced swim test, thus demonstrating for the first time that mTOR signaling is required for the antidepressant-like effects of IL DBS, which is in line with the antidepressant response of other rapid-acting antidepressant drugs.

Activation of AMPA Receptors Mediates the Antidepressant Action of Deep Brain Stimulation of the Infralimbic Prefrontal Cortex.

Although deep brain stimulation (DBS) has been used with success in treatment-resistant depression, little is known about its mechanism of action. We examined the antidepressant-like activity of short (1 h) DBS applied to the infralimbic prefrontal cortex in the forced swim test (FST) and the novelty-suppressed feeding test (NSFT). We also used in vivo microdialysis to evaluate the release of glutamate, γ-aminobutyric acid, serotonin, dopamine, and noradrenaline in the prefrontal cortex and c-Fos immunohistochemistry to determine the brain regions activated by DBS. One hour of DBS of the infralimbic prefrontal cortex has antidepressant-like effects in FST and NSFT, and increases prefrontal efflux of glutamate, which would activate AMPA receptors (AMPARs). This effect is specific of the infralimbic area since it is not observed after DBS of the prelimbic subregion. The activation of prefrontal AMPARs would result in a stimulation of prefrontal output to the brainstem, thus increasing serotonin, dopamine, and noradrenaline in the prefrontal cortex. Further, the activation of prefrontal AMPARs is necessary and sufficient condition for the antidepressant response of 1 h DBS.

Importance of inter-hemispheric prefrontal connection in the effects of non-competitive NMDA receptor antagonists.

Previous studies have shown that systemic, but not unilateral intra-prefrontal cortex administration of non-competitive NMDA antagonists, increased prefrontal activity, the cortical efflux of serotonin, and induced stereotypies. In this work we used in-vivo microdialysis and immunohistochemistry to test the hypothesis as to whether MK-801 and ketamine need to act on both prefrontal cortices to reproduce these neurochemical and behavioural changes. Dialysis probes were implanted in the medial prefrontal cortex, and extracellular serotonin as well as behavioural stereotypies was measured after systemic administration of MK-801 and ketamine (1 mg/kg and 25 mg/kg, respectively), and unilateral and bilateral perfusion of both drugs (300 µm and 3 mm, respectively). Additionally, the prefrontal (glutamatergic) level of activity was measured using c-Fos immunohistochemistry. Systemic and bilateral (but not unilateral) prefrontal administration of MK-801 and ketamine increased serotonin efflux whereas only systemic administration of both drugs produced hyperlocomotion and stereotypies. The unilateral perfusion of 1 µm tetrodotoxin in the medial prefrontal cortex reduced increases of serotonin in both hemispheres, the expression of c-Fos in the contralateral side, and stereotypy scores after systemic NMDA antagonists. Our results support the hypothesis that a bilateral impairment of cortical inhibition in the medial prefrontal cortex is needed for non-competitive NMDA antagonists to induce the state of pyramidal cell hyperactivity and concurrent efflux of serotonin. Furthermore, hyperlocomotion and stereotypies produced by MK-801 and ketamine do not appear to result from changes in the activity of prefrontal cortex although this structure exerts some control over these behaviours.