Ruxolitinib, a JAK1/JAK2 selective inhibitor, ameliorates acute and chronic steroid-refractory GvHD mouse models

Aim: Graft-versus-host disease (GvHD) is a major complication arising in patients undergoing allogenic hematopoietic stem cell transplantation. Material & methods: We tested ruxolitinib (a selective JAK1/2 inhibitor) efficacy in three different preclinical models of GvHD. Results: Ruxolitinib, at doses that mimic clinically achievable human JAK/signal transducers and activators of transcription target inhibition, significantly reduced alloreactive T-cell activation and infiltration in the lung and skin, leading to improved outcomes in two experimental models of steroid-refractory acute and chronic GvHD. Additionally, we describe a novel humanized GvHD model in which immunodeficient NOG animals are engineered to produce human IL-15 to facilitate enhanced T- and NK cell engraftment, leading to severe GvHD. Conclusion: Ruxolitinib treatment ameliorated disease symptoms resulting from targeted immune modulation via JAK/signal transducers and activators of transcription signaling inhibition.

Cinnamic Acid Reduces Inflammation and Apoptosis in Necrotizing Enterocolitis

Necrotizing enterocolitis is characterized by an inflammatory condition in the intestine that could result in intestinal necrosis and cell death. Cinnamic acid, an unsaturated carboxylic acid, possesses anti-inflammatory capacity. However, the regulatory role of cinnamic acid on necrotizing enterocolitis has not been investigated yet. To this end, human fetal colon cells were incubated with increasing concentrations of lipopolysaccharides to establish a necrotizing enterocolitis cell model. Data from 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide analysis showed that lipopolysaccharides, in a dosage-dependent manner, reduced cell viability of fetal human colon cells. Also, cinnamic acid prevented the cytotoxic effect of lipopolysaccharides on fetal human colon cells and increased the cell viability. Furthermore, cinnamic acid attenuated lipopolysaccharides-induced decrease in interleukin-10 and increase in interleukin-6 and tumor necrosis factor-α caused by lipopolysaccharides. The lipopolysaccharides-induced increase in cell apoptosis in fetal human colon cells was accompanied with upregulated B-cell lymphoma 2 protein-associated X protein and downregulated B-cell lymphoma 2 protein. These changes were reversed by cinnamic acid treatment. Lastly, expression of protein for suppressor of cytokine signaling 3 was reduced, while phosphorylation of Janus kinase 2 and signal transducers and activators of transcription 3 were enhanced in lipopolysaccharides-induced fetal human colon cells. Once again, cinnamic acid reversed the expression of suppressor of cytokine signaling 3, phospho- Janus kinase 2, and phospho-signal transducers and activators of transcription 3 in lipopolysaccharides-induced fetal human colon cells. In conclusion, cinnamic acid exerted antiapoptotic and anti-inflammatory effects and protected enterocytes against necrotizing enterocolitis through regulation of signal transducers and activators of transcription-mediated Janus kinase 2/signal transducers and activators of transcription 3 pathway.

Ginkgetin Inhibits Growth and Invasion of Endometrial Carcinoma by Disruption of Janus Kinase 1/Signal Transducers and Activators of Transcription 3 and Phosphoinositide-3-Kinase/ Protein Kinase B Pathways

Ginkgetin, a bioflavonoid derived from Ginkgo biloba leaves has been shown to promote tumor cell apoptosis and suppress cell growth in a variety of tumors. This study has examined the role and mechanism of ginkgetin on the tumorigenesis of endometrial carcinoma. Results of the studies show that ginkgetin treatment led to a dose-dependent decrease in cell viability, enhanced expression of cleaved caspase-3 protein, and reduced expression of Bcl-2 protein. In addition, cell migration and invasion of HEC1B and Ishikawa cells were repressed by ginkgetin treatment. Levels of phosphoprotein kinase B, Janus kinase 1, and signal transducers and activators of transcription 3 were decreased in HEC1B and Ishikawa cells by ginkgetin treatment. In conclusion, ginkgetin presents with potential for further investigations into its possible role in management of endometrial carcinoma.