Asthma and chronic obstructive pulmonary disease (COPD) exacerbations are commonly associated with respiratory syncytial virus (RSV), rhinovirus (RV) and influenza A virus (IAV) infection. The ensuing airway inflammation is resistant to the anti-inflammatory actions of glucocorticoids (GCs). Viral infection elicits transforming growth factor-β (TGF-β) activity, a growth factor we have previously shown to impair GC action in human airway epithelial cells through the activation of activin-like kinase 5 (ALK5), the type 1 receptor of TGF-β. In the current study, we examine the contribution of TGF-β activity to the GC-resistance caused by viral infection. We demonstrate that viral infection of human bronchial epithelial cells with RSV, RV or IAV impairs GC anti-inflammatory action. Poly(I:C), a synthetic analog of double-stranded RNA, also impairs GC activity. Both viral infection and poly(I:C) increase TGF-β expression and activity. Importantly, the GC impairment was attenuated by the selective ALK5 (TGFβRI) inhibitor, SB431542 and prevented by the therapeutic agent, tranilast, which reduced TGF-β activity associated with viral infection. This study shows for the first time that viral-induced glucocorticoid-insensitivity is partially mediated by activation of endogenous TGF-β. In this study, we investigate how respiratory viral infection interferes with the anti-inflammatory actions of glucocorticoid (GC) drugs, which are a highly effective group of anti-inflammatory agents widely used in the treatment of chronic inflammatory airway diseases, including asthma and chronic obstructive pulmonary disease (COPD). Exacerbations of both asthma (“asthma attacks”) and COPD are often caused by viral infection, which does not respond well to GC therapy. Patients are often hospitalized placing a large burden on healthcare systems around the world, with the young, elderly, and those with a poor immune system particularly at risk. We show that viral infection of airway epithelial cells causes increased expression and activity of transforming growth factor-beta (TGF-β), which interferes with GC drug action. Importantly, we have shown for the first time that inhibiting TGF-β activity in the airways could serve as a new strategy to prevent and/or treat viral exacerbations of chronic airway diseases.

Major depressive disorder (MDD) is a common, complex disease with poorly understood pathogenesis. Disruption of glucose metabolism is implicated in the pathogenesis of depression. AMP-activated protein kinase (AMPK) has been shown to regulate the activity of several kinases, including pAKT, p38MAPK, and mTOR, which are important signaling pathways in the treatment of depression. This study tested the hypothesis that rosiglitazone (RGZ) has an antidepressant impact on dexamethasone (DEXA)-induced depression by analyzing the function of the pAKT/p38MAPK/mTOR pathway and NGF through regulation of AMPK. MDD-like pathology was induced by subcutaneous administration of DEXA (20 mg/kg) for 21 days in all groups except in the normal control group, which received saline. To investigate the possible mechanism of RGZ, the protein expression of pAMPK, pAKT, p38MAPK, and 4EBP1 as well as the levels of hexokinase, pyruvate kinase, and NGF were assessed in prefrontal cortex and hippocampal samples. The activities of pAMPK and NGF increased after treatment with RGZ. The administration of RGZ also decreased the activity of mTOR as well as downregulating the downstream signaling pathways pAKT, p38MAPK, and 4EBP1. Here, we show that RGZ exerts a potent inhibitory effect on the pAKT/p38MAPK/mTOR/4EBP1 pathway and causes activation of NGF in brain cells. This study has provided sufficient evidence of the potential for RGZ to ameliorate DEXA-induced depression. A new insight has been introduced into the critical role of NGF activation in brain cells in depression. These results suggest that RGZ is a promising antidepressant for the treatment of MDD.

Background/Objectives: Cadmium (Cd) is a harmful metal commonly used in industry. Numerous clinical diseases, including osteomalacia, testicular damage, renal and hepatic failure, and pulmonary edema, are associated with Cd exposure. The current study evaluated the protective effect of Sinapic acid (SA) against Cd-induced hepatotoxicity by investigating different mechanistic pathways interfering with Cd-related liver injury. Methods: Forty rats were randomly assigned to four groups as follows; group 1 served as negative control and received saline, group 2 received saline for 14 days and CdCl₂ (3.5 mg/kg IP) as a single dose on day 14, groups 3 and 4 were treated with SA (20, 40 mg/kg PO), respectively, for 14 days and injected with CdCl₂ (3.5 mg/kg IP) on day 14. Serum was collected to evaluate liver function. Liver samples were collected for histopathological examination and the assessment of markers related to oxidative stress, inflammation, and apoptosis. Results: Acute Cd administration elevated liver enzymes and induced pathological changes in liver specimens, with the concurrent release of inflammatory markers and reduced antioxidant capabilities. Pretreatment with SA improved liver function and Cd-induced histopathological changes and elevated the activities of antioxidant enzymes. SA ameliorated inflammation, as evidenced by decreased expression of NF-κB, TNF-α, TLR-4, and COX-2, iNOS, and IL-1β levels along with suppression of mTOR, JNK, ERK, BAX, and Bcl-2. Conclusions: The present data suggest that SA represents a promising protective agent against Cd-induced hepatic injury by attenuating oxidative stress, inflammation, and apoptosis.