Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glucocorticoids play an essential role in the response to environmental stressors, serving initially to mobilize bodily responses to challenge and ultimately serving to restrain neuroendocrine and immune reactions. A number of diseases including autoimmune, infectious and inflammatory disorders as well as certain neuropsychiatric disorders such as major depression have been associated with decreased responsiveness to glucocorticoids (glucocorticoid resistance), which is believed to be related in part to impaired functioning of the glucocorticoid receptor (GR). Glucocorticoid resistance, in turn, may contribute to excessive inflammation as well as hyperactivity of corticotropin releasing hormone and sympathetic nervous system pathways, which are known to contribute to a variety of diseases as well as behavioral alterations. Recent data indicate that glucocorticoid resistance may be a result of impaired GR function secondary to chronic exposure to inflammatory cytokines as may occur during chronic medical illness or chronic stress. Indeed, inflammatory cytokines and their signaling pathways including mitogen-activated protein kinases, nuclear factor-kappaB, signal transducers and activators of transcription, and cyclooxygenase have been found to inhibit GR function. Mechanisms include disruption of GR translocation and/or GR-DNA binding through protein-protein interactions of inflammatory mediators with the GR itself or relevant steroid receptor cofactors as well as alterations in GR phosphorylation status. Interestingly, cAMP signal transduction pathways can enhance GR function and inhibit cytokine signaling. Certain antidepressants have similar effects. Thus, further understanding the effects of cytokines on GR signaling and the mechanisms involved may reveal novel therapeutic targets for reversal of glucocorticoid resistance and restoration of glucocorticoid-mediated inhibition of relevant bodily/immune responses during stress and immune challenge.
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PMID:Cytokine-effects on glucocorticoid receptor function: relevance to glucocorticoid resistance and the pathophysiology and treatment of major depression. 1707 Jun 67

Dexanabinol (HU-211) is an artificially synthesized cannabinoid derivative that exerts neuroprotective effects through anti-inflammatory and antioxidant effects. Curcumin exhibits antidepressant effects in the treatment of major depressive disorder. To investigate the antidepressant effects of solid lipid nanoparticles loaded with both curcumin and dexanabinol, and the underlying mechanisms associated with this combination, we established wild-type (CBR1+/+) and cannabinoid receptor 1 (CBR1) knockout (CBR1-/-) mouse models of major depressive disorder, through the intraperitoneal injection of corticosterone, for 3 successive days, followed by treatment with intraperitoneal injections of solid lipid nanoparticles loading with curcumin (20 mg/kg) and dexanabinol (0.85 mg/kg), for 2 successive days. Our results revealed that solid lipid nanoparticle loading with curcumin and dexanabinol increased the mRNA and protein expression levels of the mature neuronal markers neuronal nuclei, mitogen-activated protein 2, and neuron-specific beta-tubulin III, promoted the release of dopamine and norepinephrine, and increased the mRNA expression of CBR1 and the downstream genes Rasgef1c and Egr1, and simultaneously improved rat locomotor function. However, solid lipid nanoparticles loaded with curcumin and dexanabinol had no antidepressant effects on the CBR1-/- mouse models of major depressive disorder. This study was approved by the Institutional Ethics Committee of Tongji Hospital of Tongji University, China (approval No. 2017-DW-020) on May 24, 2017.
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PMID:Solid lipid nanoparticles loading with curcumin and dexanabinol to treat major depressive disorder. 3298 84