Thyroid hormone inhibition in L6 myoblasts of IGF-I-mediated glucose uptake and proliferation: New roles for integrin αvβ3

Thyroid hormones L-thyroxine (T4) and 3,3′,5-triiodo-L-thyronine (Se

Role of thyroid hormones in insulin resistance and diabetes

Abstract: Several recent studies suggest that thyroid hormones role is not completely understood in insulin resistance as well as in the development of type 2 diabetes mellitus. Through the perturbation of gene expression linked to glucose metabolism both hyper- and hypothyroidism may cause impaired glucose utilization in skeletal muscle or overproduction of hepatic glucose, thus contributing to the induction of insulin resistance. The complex crosstalk between immune cells and skeletal muscle cells and adipose tissue, the ability of macrophages to release thyroid hormones, the ability of T3 to induce M2 macrophage polarization, the proinflammatory role of thyroid hormones and the antinflammatory effects of insulin all represent important events where thyroid hormone interference may lead to insulin resistance. The crosstalk between thyroid hormones and insulin in the modulation of oxidative status, and also to some extent in the antagonistic effects on several aspects of mitochondrial activities, could represent novel downstream targets for future therapeutic strategies in the treatment of insulin resistance and type 2 diabetes

Baicalein reverts L-valine-induced persistent sodium current up-modulation in primary cortical neurons.

L-valine is a branched-chain amino acid (BCAA) largely used as dietary integrator by athletes and involved in some inherited rare diseases such as maple syrup urine disease. This pathology is caused by an altered BCAA metabolism with the accumulation of toxic keto acids in tissues and body fluids with consequent severe neurological symptoms. In animal models of BCAA accumulation, increased oxidative stress levels and lipid peroxidation have been reported. The aim of this study was to analyze both whether high BCAA concentrations in neurons induce reactive oxygen species (ROS) production and whether, by performing electrophysiological recordings, the neuronal functional properties are modified. Our results demonstrate that in primary cortical cultures, a high dose of valine increases ROS production and provokes neuronal hyperexcitability because the action potential frequencies and the persistent sodium current amplitudes increase significantly compared to non-treated neurons. Since Baicalein, a flavone obtained from the Scutellaria root, has been shown to act as a strong antioxidant with neuroprotective effects, we evaluated its possible antioxidant activity in primary cortical neurons chronically exposed to L-valine. The preincubation of cortical neurons with Baicalein prevents the ROS production and is able to revert both the neuronal hyperexcitability and the increase of the persistent sodium current, indicating a direct correlation between the ROS production and the altered physiological parameters. In conclusion, our data show that the electrophysiological alterations of cortical neurons elicited by high valine concentration are due to the increase in ROS production, suggesting much caution in the intake of BCAA dietary integrators

Lung abscess in a child secondary to Mycoplasma pneumoniae infection

Lung abscess is a very rare infectious condition in children and is most commonly encountered as a complication of bacterial pneumonia. We present a case of a lung abscess in a child 6-year-old admitted with a history of right hemithorax pain lasting for 15 days and the onset of mild fever in the last two days. Etiological research showed positivity of IgM antibodies to Mycoplasma pneumoniae after seven days of admission. The child has been successfully treated with antibiotic therapy, without the use of macrolides, for a duration of 4 weeks. Our study suggests that the Mycoplasma pneumoniae infection may predispose to severe infections, such as lung abscess, caused by typical respiratory pathogens. The reported case of lung abscess is one of the few reported in the literature in the modern antibiotic era and is the first preceded by Mycoplasma pneumoniae infection

Thyroid hormones crosstalk with growth factors: Old facts and new hypotheses.

Nongenomic effects of thyroid hormones typically start at the cell surface and do not primarily involve the classical nuclear receptors, but rather a plasma membrane receptor site identified about ten years ago on the integrin αvβ3. Transduction of the thyroid hormone signal from this integrin receptor involves activation of the MAPK pathway and may lead to events such as angiogenesis or tumor cell proliferation. This review focuses on the interaction of thyroid hormones with growth factors, in fact the integrin αvβ3 has been reported to a be a co-receptor for several growth factors such as EGF, IGF-1 and the FGF family, but also for small molecules like resveratrol. Binding of the ligand to integrin αvβ3 is inhibited by tetrac, a metabolite of L-thyroxine, and by its nanoparticulate formulation nanotetrac. Recent microarray studies on tumor cells have shown that tetrac has antiinflammatory effects that are mediated by integrin αvβ3, and tetrac can downregulate the expression of several interleukin genes. Crosstalk between thyroid hormones and vascular growth factors is important for cell migration, vascular calcification and the angiogenic process. Thyroid hormones also show pleiotropic effects on osteoblast function and differentiation, as well as in early pregnancy. The importance of thyroid hormone interaction with neurotrophins and interleukins has also been examined. With integrin αvβ3 firmly established as the plasma membrane receptor future studies will focus on the crosstalk between thyroid hormones and growth factors in order to verify the efficiency of new pharmacological tools, such as nanotetrac

Extranuclear effects of thyroid hormones and analogs during development: An old mechanism with emerging roles

Thyroid hormones, T-3 (triiodothyronine) and T-4 (thyroxine), induce a variety of long-term effects on important physiological functions, ranging from development and growth to metabolism regulation, by interacting with specific nuclear or cytosolic receptors. Extranuclear or nongenomic effects of thyroid hormones are mediated by plasma membrane or cytoplasmic receptors, mainly by alpha v beta 3 integrin, and are independent of protein synthesis. A wide variety of nongenomic effects have now been recognized to be elicited through the binding of thyroid hormones to this receptor, which is mainly involved in angiogenesis, as well as in cell cancer proliferation. Several signal transduction pathways are modulated by thyroid hormone binding to alpha v beta 3 integrin: protein kinase C, protein kinase A, Src, or mitogen-activated kinases. Thyroid hormone-activated nongenomic effects are also involved in the regulation of Na+-dependent transport systems, such as glucose uptake, Na+/K+-ATPase, Na+/H+ exchanger, and amino acid transport System A. Of note, the modulation of these transport systems is cell-type and developmental stage-dependent. In particular, dysregulation of Na+/K+-ATPase activity is involved in several pathological situations, from viral infection to cancer. Therefore, this transport system represents a promising pharmacological tool in these pathologies

Thyroid hormones inhibit cell migration and proliferation activated by IGF-1 and MCP-1 in THP-1 monocytes through integrin αvβ3 by different mechanisms.

Interaction between thyroid hormones (THs) and the immune system is reported in the literature. Thyroid hormone (THs), thyroxine, T4, but also T3 act nongenomically through mechanisms that involve a plasma membrane receptor αvβ3 integrin, a co-receptor for Insulin-like growth factor-1 (IGF-1). Previous data from our laboratory show a cross-talk between THs and IGF-1 because THs inihibit the IGF-1-stimulated glucose uptake and cell proliferation in L-6 myoblasts and the effects are mediated by integrin αvβ3. IGF-1 also behaves as a chemokine, being an important factor for tissue regeneration after damage. In the present study, using THP-1 human leukemic monocytes, expressing αvβ3 integrin in their cell membrane, we focused on the cross-talk between THs and either IGF-1 or monocyte chemoattractant protein-1 (MCP-1) studying cell migration and proliferation stimulated by the two chemokines, and the role of αvβ3 integrin, using inhibitors of αvβ3 integrin and downstream pathways. Our results show that IGF-1 is a potent chemoattractant in THP-1 monocytes stimulating cell migration and thyroid hormone inhibits the effect through αvβ3 integrin. Thyroid hormone also inhibits IGF-1-stimulated cell proliferation through αvβ3 integrin, an example of a cross-talk between genomic and nongenomic effects. We also studied the effects of Thyroid hormone on cell migration and proliferation induced by MCP-1, together with the pathways involved, by a pharmacological approach and docking simulation. Our findings show a different downstream signalling for IGF-1 and MCP-1 in THP-1 monocytes mediated by the plasma membrane receptor of THs, integrin αvβ3