Extensive research into the therapeutics of asthma has yielded numerous effective interventions over the past few decades. However, adverse effects and ineffectiveness of most of these medications especially in the management of steroid resistant severe asthma necessitate the development of better medications. Numerous drug targets with inherent airway smooth muscle tone modulatory role have been identified for asthma therapy. This article reviews the latest understanding of underlying molecular aetiology of asthma towards design and development of better antiasthma drugs. New drug candidates with their putative targets that have shown promising results in the preclinical and/or clinical trials are summarised. Examples of these interventions include restoration of Th1/Th2 balance by the use of newly developed immunomodulators such as toll-like receptor-9 activators (CYT003-QbG10 and QAX-935). Clinical trials revealed the safety and effectiveness of chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2) antagonists such as OC0000459, BI-671800 and ARRY-502 in the restoration of Th1/Th2 balance. Regulation of cytokine activity by the use of newly developed biologics such as benralizumab, reslizumab, mepolizumab, lebrikizumab, tralokinumab, dupilumab and brodalumab are at the stage of clinical development. Transcription factors are potential targets for asthma therapy, for example SB010, a GATA-3 DNAzyme is at its early stage of clinical trial. Other candidates such as inhibitors of Rho kinases (Fasudil and Y-27632), phosphodiesterase inhibitors (GSK256066, CHF 6001, roflumilast, RPL 554) and proteinase of activated receptor-2 (ENMD-1068) are also discussed. Preclinical results of blockade of calcium sensing receptor by the use of calcilytics such as calcitriol abrogates cardinal signs of asthma. Nevertheless, successful translation of promising preclinical data into clinically viable interventions remains a major challenge to the development of novel anti-asthmatics.
The course of Trichinella (T.) spiralis infection includes intestinal and muscle phases. The aims of this work were to evaluate IL-23 and cyclooxygenase-2 (COX-2) by immunohistochemistry in the muscles of T. spiralis infected mice in a time-course study and to correlate their level with the serum levels of IL-23, IFN-γ, IL-4 and IL-10 cytokines. The mice were divided into an un-infected control group (UC) (10 mice) and 5 infected mouse groups (each 10 mice/group. Each mouse was infected with 200 T. spiralis larvae) and sacrificed on days 7, 14, 21, 28 and 35 post-infection (dpi). IL-23 showed weak expression (+1) on the 21st dpi, then it became moderately expressed (+2) on the 28th dpi and on day 35 pi, the immunoreactivity was strong (+3). COX-2 expressed weakly on 14 dpi, while the other mouse groups (21, 28 and 35) showed strong (+3) expression. IL-23 serum concentrations increased gradually in a significant pattern, in comparison to that of UC mice, from the 21st dpi to the end of the experiment. IFN-γ increased gradually and was significantly higher than those of UC mice from the 7th dpi, reached its maximum level on the 21st dpi, after which it decreased non-significantly. IL-4 up-regulated significantly in all infected groups in comparison to UC mice achieving its highest level on the 21st dpi and decreased after that. IL-10 increased significantly on the 7th dpi, but dropped at the 14th dpi, then reached its peak on the 21st dpi, and decreased again on the 28th and 35th dpi. In conclusion, T. spiralis infection caused increased expression of IL-23 and COX-2 in the muscle of infected mice, the effect being strongest on the 35th day. Also, the infection induced a mixed Th1/Th2 profile with a predominance of Th2 at the early muscle phase, after which the immune repose became mainly Th2.
Tamm-Horsfall glycoprotein (THP) and uromodulin are the most abundant glycoproteins in non-pregnant women's/men's and pregnant women's urine, respectively. However, the bioactivities of these glycoproteins are still unclear.