Minocycline alleviates depression-like symptoms by rescuing decrease in neurogenesis in dorsal hippocampus via blocking microglia activation/phagocytosis.

Clinical studies examining the potential of anti-inflammatory agents, specifically of minocycline, as a treatment for depression has shown promising results. However, mechanistic insights into the neuroprotective and anti-inflammatory actions of minocycline need to be provided. We evaluated the effect of minocycline on chronic mild stress (CMS) induced depressive-like behavior, and behavioral assays revealed minocycline ameliorate depressive behaviors. Multiple studies suggest a role of microglia in depression, revealing that microglia activation correlates with a decrease in neurogenesis and increased depressive-like behavior. The effect of minocycline on microglia activation in different areas of the dorsal or ventral hippocampus in stressed mice was examined by immunohistochemistry. We observed the increase in the number of activated microglia expressing CD68 after exposure to three weeks of chronic stress, whereas no changes in total microglia number were observed. These changes were observed throughout the DG, CA1 and CA2 regions in dorsal hippocampus but restricted to the DG of the ventral hippocampus. In vitro experiments including western blotting and phagocytosis assay were used to investigate the effect of minocycline on microglia activation. Activation of primary microglia by LPS in vitro causes and ERK1/2 activation, enhancement of iNOS expression and phagocytic activity, and alterations in cellular morphology that are reversed by minocycline exposure, suggesting that minocycline directly acts on microglia to reduce phagocytic potential. Our results suggest the most probable mechanism by which minocycline reverses the pathogenic phagocytic potential of neurotoxic M1 microglia, and reduces the negative phenotypes associated with reduced neurogenesis caused by exposure to chronic stress.

Oral Phyto-thymol ameliorates the stress induced IBS symptoms.

Physical stressors play a crucial role in the progression of irritable bowel syndrome (IBS). Here we report a heterogeneous physical stress induced IBS rat model which shows depression and subsequent modulation of IBS by oral treatment of thymol. Oral administration of Thymol reduces the stress induced IBS significantly altering the stress induced gastrointestinal hypermotility, prolonged the whole gut transit time, and increased abdominal withdrawal reflex suggesting gastrointestinal hypermotility and visceral discomfort caused the onset of depression. Immunohistochemical analysis in small intestine and colon of rats shows the decreased 5-HT3AR expression level while thymol treatment normalized the 5-HT3AR expression in the stressed rats. Molecular docking studies showed that thymol competes with endogenous serotonin and an antagonist, Tropisetron and all have similar binding energies to 5-HT3AR. Molecular dynamics simulations revealed that thymol and tropisetron might have similar effects on 5-HT3AR. Our study suggest that thymol improves IBS symptoms through 5-HT3AR, could be useful for the treatment of IBS.

Denatonium enhanced the tone of denuded rat aorta via bitter taste receptor and phosphodiesterase activation.

Bitter taste receptors (Tas2rs) initiate a bitter taste signaling involving the activation of taste-specific G protein gustducin and phosphodiesterases (PDEs); it leads to the decrease of cytosolic level of cyclic adenosine monophosphate (cAMP) in taste cells. Recent studies have identified the expression of Tas2rs in a variety of non-lingual tissues including vascular smooth muscle (VSM), pulmonary smooth muscle and airway smooth muscle. The current study aims to determine the expression of Tas2rs and gustducin in rat aortic smooth muscle tissue and to investigate the effect of Tas2rs agonist denatonium on the tone of isolated denuded aorta rings. Here we reported the expression of six subtypes of Tas2r mRNA and the taste receptor-associated G proteins in endothelium-denuded aorta. Immunostaining experiments showed that the protein of gustducin expressed in vascular smooth muscle cells (VSMCs). Furthermore, denatonium increased the tone of freshly isolated denuded aorta rings in a concentration-dependent manner, and the potentiation effect of denatonium was blocked by a Tas2rs antagonist adenosine 5'-monophosphate (5'-AMP), by the cAMP-hydrolyzing PDE inhibitors, and by a cAMP-synthesizing enzyme activator forskolin, respectively. The blockade of Gßγ signaling did not have a negative impact on the denatonium-induced tonic contractions. These findings suggested that the functional Tas2rs and gustducin are expressed in rat aortic smooth muscle and that denatonium might increase the smooth muscle tone through a Tas2rs signaling pathway involving the activation of PDEs.

Nanoparticle Assisted Remodeling of Proteotoxic SOD1 Mutants Alters the Biointerface of the Functional Interaction of Microtubules and Kinesin Motors.

Transport deficits with motor neuron degeneration have been implicated in amyotrophic lateral sclerosis (ALS). We report a biomimetic system composed of microtubules/kinesin motor that mimics the dysregulated motor dynamics of ALS. Pathogenic ALS mutants A4V SOD1 completely shut off motility. Treatment with 5 nm citrate coated gold nanoparticles recovers the impaired motor stepping by remodeling the A4V SOD1 rather than stabilizing microtubules or protein folding. Instead, gold nanoparticles alter the protein by a mechanism that reforms protein elements of A4V SOD1, in turn fixing the aberrant interaction of kinesin with microtubules. Reinstating kinesin motility holds potential for managing debilitating ALS.

Regulation of Integrin α6 Recycling by Calcium-independent Phospholipase A2 (iPLA2) to Promote Microglia Chemotaxis on Laminin.

Microglia are the immune effector cells that are activated in response to pathological changes in the central nervous system. Microglial activation is accompanied by the alteration of integrin expression on the microglia surface. However, changes of integrin expression upon chemoattractant (ADP) stimulation still remain unknown. In this study, we investigated whether ADP induces the alteration of integrin species on the cell surface, leading to changes in chemotactic ability on different extracellular matrix proteins. Flow cytometry scans and on-cell Western assays showed that ADP stimulation induced a significant increase of α6 integrin-GFP, but not α5, on the surface of microglia cells. Microglia also showed a greater motility increase on laminin than fibronectin after ADP stimulation. Time lapse microscopy and integrin endocytosis assay revealed the essential role of calcium-independent phospholipase A2 activity for the recycling of α6 integrin-GFP from the endosomal recycling complex to the plasma membrane. Lack of calcium-independent phospholipase A2 activity caused a reduced rate of focal adhesion formation on laminin at the leading edge. Our results suggest that the alteration of integrin-mediated adhesion may regulate the extent of microglial infiltration into the site of damage by controlling their chemotactic ability.