The recent advance of Interleukin-1 receptor associated kinase 4 inhibitors for the treatment of inflammation and related diseases.

The interleukin-1 receptor associated kinase 4 (IRAK-4) is a member of serine-threonine kinase family, which plays an important role in the regulation of interleukin-1 receptors (IL-1R) and Toll-like receptors (TLRs) related signaling pathways. At present, the IRAK-4 mediated inflammation and related signaling pathways contribute to inflammation, which are also responsible for other autoimmune diseases and drug resistance in cancers. Therefore, targeting IRAK-4 to develop single-target, multi-target inhibitors and proteolysis-targeting chimera (PROTAC) degraders is an important direction for the treatment of inflammation and related diseases. Moreover, insight into the mechanism of action and structural optimization of the reported IRAK-4 inhibitors will provide the new direction to enrich the clinical therapies for inflammation and related diseases. In this comprehensive review, we introduced the recent advance of IRAK-4 inhibitors and degraders with regards to structural optimization, mechanism of action and clinical application that would be helpful for the development of more potent chemical entities against IRAK-4.

Synergistic effect of siRNA-mediated silencing of TGF-ß R1 and TGF-ß R2 genes on the proliferation and apoptosis of penile urethral epithelial cells in hypospadiac male rats.

The study elucidated the effects associated with silencing growth factor-ß R1 (TGF-ß R1) and TGF-ß R2 genes on the proliferation and apoptosis of penile urethral epithelial cells (UECs) in hypospadiac male rats. Seventy-five male rats were distributed into the normal, model, TGF-ß R1/2-siRNA, TGF-ß R1-siRNA and TGF-ß R2-siRNA groups. The UECs of the rats included in the study were cultured in vitro and subsequently divided into the control, blank, TGF-ß R1/2-siRNA, TGF-ß R1-siRNA and TGF-ß R2-siRNA groups. The mRNA and protein expressions of TGF-ß R1/R2 were measured by quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting. Cell proliferation and apoptosis were evaluated by cell counting kit-8 (CCK-8) assay as well as by flow cytometry. Compared with the normal group, the apoptotic rate of the UECs in the model, TGF-ß R1/2-siRNA, TGF-ß R1-siRNA and TGF-ß R2-siRNA groups displayed remarkable increases; compared with the model group, the apoptotic rate of the UECs in the TGF-ß R1/2-siRNA, TGF-ß R1-siRNA and TGF-ß R2-siRNA groups displayed significant decreases, similar observations were made regarding mRNA and protein expressions of TGF-ß R1 and TGF-ß R2. Compared with the TGF-ß R1/2-siRNA group, the apoptotic rates of the UECs in the TGF-ß R1-siRNA and TGF-ß R2-siRNA groups were up regulated, while cell proliferation in the TGF-ß R1-siRNA and TGF-ß R2-siRNA groups decreased accompanied by an increased rate of apoptosis. This study ultimately demonstrated that the silencing of TGF-ß R1 and TGF-ß R2 genes could promote cell proliferation and inhibit apoptosis of penile UECs in hypospadiac male rats.

Expression of nestin in embryonic tissues and its effects on clinicopathological characteristics of patients with placenta previa.

In this study, we examined expression of nestin in the spinal cord, lung, kidney, stomach, colon, and intestine tissues at different stages of embryos in patients with placenta previa. Fetuses of 75 patients with placenta previa were assigned to case group and 80 fetuses from healthy pregnant women with normal placenta who voluntarily terminated pregnancy to control group. Clinical data of pregnant women were collected at the time of admission. Blood from elbow vein was collected to determine expression of serum nestin. Tissues from spinal cord, lung, kidney, stomach, colon, and intestine in 3-7 months fetuses of the two groups were extracted. Expression of nestin in tissues was detected by immunohistochemistry, Western blotting and RT-qPCR. The mRNA expression of nestin in the case group was increased. Nestin expression was correlated with the gestational age, age of foetus, and type of placenta previa in patients with placenta previa. Positive nestin expression was detected in the spinal cord, lung, kidney, stomach, intestine, and colon tissues in normal and placenta previa embryo at Stage I. The positive cell density and nestin expression decreased at Stage II, and further decreased at Stage III. The case group had higher nestin mRNA and protein levels throughout human fetal development. Findings of this study suggested that, nestin, as a specific marker of neural precursor cells, was expressed in various tissues of the embryo in patients with placenta previa and nestin expression was lower with increased maturation of the embryo.