Impact of gut-peripheral nervous system axis on the development of diabetic neuropathy.

Diabetes is a chronic metabolic disease caused by a reduction in the production and/or action of insulin, with consequent development of hyperglycemia. Diabetic patients, especially those who develop neuropathy, presented dysbiosis, with an increase in the proportion of pathogenic bacteria and a decrease in the butyrate-producing bacteria. Due to this dysbiosis, diabetic patients presented a weakness of the intestinal permeability barrier and high bacterial product translocation to the bloodstream, in parallel to a high circulating levels of pro-inflammatory cytokines such as TNF-α. In this context, we propose here that dysbiosis-induced increased systemic levels of bacterial products, like lipopolysaccharide (LPS), leads to an increase in the production of pro-inflammatory cytokines, including TNF-α, by Schwann cells and spinal cord of diabetics, being crucial for the development of neuropathy.

Ouabain-Na+/K+-ATPase Signaling Regulates Retinal Neuroinflammation and ROS Production Preventing Neuronal Death by an Autophagy-Dependent Mechanism Following Optic Nerve Axotomy In Vitro.

Ouabain is a classic Na+K+ATPase ligand and it has been described to have neuroprotective effects on neurons and glial cells at nanomolar concentrations. In the present work, the neuroprotective and immunomodulatory potential of ouabain was evaluated in neonatal rat retinal cells using an optic nerve axotomy model in vitro. After axotomy, cultured retinal cells were treated with ouabain (3 nM) at different periods. The levels of important inflammatory receptors in the retina such as TNFR1/2, TLR4, and CD14 were analyzed. We observed that TNFR1, TLR4, and CD14 were decreased in all tested periods (15 min, 45 min, 24 h, and 48 h). On the other hand, TNFR2 was increased after 24 h, suggesting an anti-inflammatory potential for ouabain. Moreover, we showed that ouabain also decreased Iba-1 (microglial marker) density. Subsequently, analyses of retrograde labeling of retinal ganglion cells (RGC) were performed after 48 h and showed that ouabain-induced RGC survival depends on autophagy. Using an autophagy inhibitor (3-methyladenine), we observed a complete blockage of the ouabain effect. Western blot analyses showed that ouabain increases the levels of autophagy proteins (LC3 and Beclin-1) coupled to p-CREB transcription factor and leads to autophagosome formation. Additionally, we found that the ratio of cleaved/pro-caspase-3 did not change after ouabain treatment; however, p-JNK density was enhanced. Also, ouabain decreased reactive oxygen species production immediately after axotomy. Taken together, our results suggest that ouabain controls neuroinflammation in the retina following optic nerve axotomy and promotes RGC neuroprotection through activation of the autophagy pathway.

The trophic effect of ouabain on retinal ganglion cells is mediated by IL-1ß and TNF-α.

Ouabain is a steroid hormone that binds to the enzyme Na(+), K(+) - ATPase and stimulates different intracellular pathways controlling growth, proliferation and cell survival. IL-1ß and TNF-α are pleiotropic molecules, conventionally regarded as pro-inflammatory cytokines with well-known effects in the immune system. In addition, IL-1ß and TNF-α also play important roles in the nervous system including neuroprotective effects. Previous data from our group showed that ouabain treatment is able to induce an increase in retinal ganglion cell survival kept in mixed retinal cell cultures. The aim of this work was to investigate if IL-1ß and TNF-α could be mediating the trophic effect of ouabain on retinal ganglion cells. Our results show that the trophic effect of ouabain on retinal ganglion cell was inhibited by either anti-IL-1ß or anti-TNF-α antibodies. In agreement, IL-1ß or TNF-α increased the retinal ganglion cells survival in a dose-dependent manner. Accordingly, ouabain treatment induces a temporal release of TNF-α and IL-1ß from retinal cell cultures. Interestingly, TNF-α and IL-1ß regulate each other intracellular levels. Our results suggest that ouabain treatment triggers the activation of TNF-α and IL-1ß signaling pathways leading to an increase in retinal ganglion cell survival.

The Role of the Adrenal-Gut-Brain Axis on Comorbid Depressive Disorder Development in Diabetes.

Diabetic patients are more affected by depression than non-diabetics, and this is related to greater treatment resistance and associated with poorer outcomes. This increase in the prevalence of depression in diabetics is also related to hyperglycemia and hypercortisolism. In diabetics, the hyperactivity of the HPA axis occurs in parallel to gut dysbiosis, weakness of the intestinal permeability barrier, and high bacterial-product translocation into the bloodstream. Diabetes also induces an increase in the permeability of the blood-brain barrier (BBB) and Toll-like receptor 4 (TLR4) expression in the hippocampus. Furthermore, lipopolysaccharide (LPS)-induced depression behaviors and neuroinflammation are exacerbated in diabetic mice. In this context, we propose here that hypercortisolism, in association with gut dysbiosis, leads to an exacerbation of hippocampal neuroinflammation, glutamatergic transmission, and neuronal apoptosis, leading to the development and aggravation of depression and to resistance to treatment of this mood disorder in diabetic patients.

COVID-19 pandemic impact on children and adolescents' mental health: Biological, environmental, and social factors.

Since the Coronavirus disease 2019 (COVID-19) pandemic, caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) was announced, we had an unprecedented change in the way we organize ourselves socially and in our daily routine. Children and adolescents were also greatly impacted by the abrupt withdrawal from school, social life and outdoor activities. Some of them also experienced domestic violence growing. The stress they are subjected to directly impacts their mental health on account of increased anxiety, changes in their diets and in school dynamics, fear or even failing to scale the problem. Our aim is to bring up a discussion under different aspects and to alert public health and government agents about the need for surveillance and care of these individuals. We hope that the damage to their mental health as a result of the side effect of this pandemic can be mitigated by adequate and timely intervention.

Impact of gut-peripheral nervous system axis on the development of diabetic neuropathy

Diabetes is a chronic metabolic disease caused by a reduction in the production and/or action of insulin, with consequent development of hyperglycemia. Diabetic patients, especially those who develop neuropathy, presented dysbiosis, with an increase in the proportion of pathogenic bacteria and a decrease in the butyrate-producing bacteria. Due to this dysbiosis, diabetic patients presented a weakness of the intestinal permeability barrier and high bacterial product translocation to the bloodstream, in parallel to a high circulating levels of pro-inflammatory cytokines such as TNF-α. In this context, we propose here that dysbiosis-induced increased systemic levels of bacterial products, like lipopolysaccharide (LPS), leads to an increase in the production of pro-inflammatory cytokines, including TNF-α, by Schwann cells and spinal cord of diabetics, being crucial for the development of neuropathy.