Translational research : the journal of laboratory and clinical medicine
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The central nervous system (CNS) largely comprises nonregenerating cells, including neurons and myelin-producing oligodendrocytes, which are particularly vulnerable to immune cell-mediated damage. To protect the CNS, mechanisms exist that normally restrict the transit of peripheral immune cells into the brain and spinal cord, conferring an "immune-specialized" status. Thus, there has been a long-standing debate as to how these restrictions are overcome in several inflammatory diseases of the CNS, including multiple sclerosis (MS). ⋯ The resulting robust meningeal inflammation elicits loss of localized blood-brain barrier (BBB) integrity and facilitates a large-scale influx of immune cells into the CNS parenchyma. We propose that targeting the cells and molecules mediating these inflammatory responses within the meninges offers promising therapies for MS that are free from the constraints imposed by the BBB. Importantly, such therapies may avoid the systemic immunosuppression often associated with the existing treatments.
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Tumor necrosis factor (TNF) production is amplified in several autoimmune disorders. In the 1990s, it became a validated therapeutic target used for the treatment of conditions such as rheumatoid arthritis and inflammatory bowel disease. Biologic drugs targeting TNF include engineered monoclonal antibodies and fusion proteins. ⋯ Pharmacokinetics of the TNF inhibitors is affected by routes of administration, clearance mechanisms of immunoglobulins, and immunogenicity. Finally, strategies for management of treatment efficacy and increasing evidence for monitoring of serum concentration of TNF inhibitors are discussed, assessing for the presence of the antidrug antibodies and the different analytical methods available for laboratory testing. As clinical applications of the TNF inhibitors expand, and other classes join the revolution in the treatment of chronic inflammatory disorders, therapeutic drug monitoring of biologics will become increasingly important, with the potential to dramatically improve patient care and management.
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We investigated whether melatonin ameliorates fibrosis and limits the expression of fibrogenic genes in mice treated with carbon tetrachloride (CCl4). Mice in treatment groups received CCl4 5 μL/g body weight intraperitoneally twice a week for 4 or 6 weeks. Melatonin was given at 5 or 10 mg/kg/d intraperitoneally, beginning 2 weeks after the start of CCl4 administration. ⋯ Furthermore, melatonin treatment resulted in significant inhibition of the expression of collagens I and III, TGF-β, PDGF, CTGF, amphiregulin, and phospho-Smad3. The MMP-9 activity decreased and the expression of nuclear factor erythroid-2-related factor 2 (Nrf2) increased in mice receiving melatonin. Data obtained suggest that attenuation of multiple profibrogenic gene pathways contributes to the beneficial effects of melatonin in mice with CCl4-induced liver fibrosis.