Summary Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative therapy for hematological malignancies, due to graft-versus-leukemia (GVL) activity mediated by alloreactive donor T cells. However, graft-versus-host disease (GVHD) is also mediated by these cells. Here, we assessed the effect of attenuating TCR-mediated SLP76:ITK interaction in GVL vs. GVHD effects after allo-HSCT. CD8 + and CD4 + donor T cells from mice expressing a Y145F mutation in SLP-76 did not cause GVHD but preserved GVL effects against B-ALL cells. SLP76Y145FKI CD8 + and CD4 + donor T cells also showed less inflammatory cytokine production and migration to GVHD target organs. We developed a novel peptide to specifically inhibit SLP76:ITK interactions, resulting in decreased phosphorylation of PLCγ1 and ERK, decreased cytokine production in human T cells, and separation of GVHD from GVL effects. Altogether, our data suggest that inhibiting SLP76:ITK interaction could be a therapeutic strategy to separate GVHD from GVL effects after allo-HSCT treatment.

Background/Aim: Glycyrrhizin (GL) is an important derivative of certain herbal medicines used in Asian countries. Currently, GL is used to treat hepatitis and allergic disease worldwide because of its anti-viral and anti-allergy effects. In addition to these prominent functions, GL likely regulates cellular functions such as tumor cell growth and cellular immunity. However, how GL affects the keratinocyte inflammation response remains poorly understood. The current paper investigates the effect of GL on psoriasis and explores the mechanisms involved. Methods: We used an in vitro cell model of tumor necrosis factor (TNF)-a-induced keratinocyte inflammation and the topical application of imiquimod (IMQ) using an animal model (mouse skin) of IMQ-induced psoriasis-like inflammation (IPI) to investigate the effect of GL on skin inflammation. Cell viability was analyzed using the Cell Counting Kit-8 (CCK8). Carboxyfluorescein succinimidyl ester (CFSE) labeling was used to trace monocyte adherence to keratinocytes. A Western blot analysis was used to detect the expression of intercellular adhesion molecule 1 (ICAM-1) and the activation of the nuclear factor (NF)-κB/mitogen-activated protein kinase (MAPK) signaling pathway. A modified version of the Psoriasis Area Severity Index (PASI) was used to monitor disease severity. Hematoxylin and eosin (H&E) staining was used to observe pathological changes. An immunohistochemistry (IHC) analysis was used to detect ICAM-1 expression in mouse skin. Results: GL treatment significantly reduced the levels of ICAM-1 in TNF-a-stimulated HaCaT cells, inhibited subsequent monocyte adhesion to keratinocytes, and suppressed the nuclear translation and phosphorylation of p65 following the degradation of inhibitor κB (IκB). GL treatment blocked the phosphorylation of extracellular signal-regulated kinase (ERK)/p38 MAPK. GL effectively delayed the onset of IPI in mice and ameliorated ongoing IPI, thereby reducing ICAM-1 expression in epidermal tissues. Conclusions: These results demonstrate that GL treatment ameliorates skin inflammation by inhibiting ICAM-1 expression via interference with the ERK/p38 MAPK and NF-κB signaling pathways in keratinocytes. Therefore, GL can be used as an anti-psoriasis drug.

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BackgroundTemperature is an essential condition in red ginseng processing. The pharmacological activities of red ginseng under different steam temperatures are significantly different.MethodsIn this study, an ultrahigh-performance liquid chromatography quadrupole time-of-flight tandem mass spectrometry was developed to distinguish the red ginseng products that were steamed at high and low temperatures. Multivariate statistical analyses such as principal component analysis and supervised orthogonal partial least squared discrimination analysis were used to determine the influential components of the different samples.ResultsThe results showed that different steamed red ginseng samples can be identified, and the characteristic components were 20-gluco-ginsenoside Rf, ginsenoside Re, ginsenoside Rg1, and malonyl-ginsenoside Rb1 in red ginseng steamed at low temperature. Meanwhile, the characteristic components in red ginseng steamed at high temperature were 20R-ginsenoside Rs3 and ginsenoside Rs4. Polar ginsenosides were abundant in red ginseng steamed at low temperature, whereas higher levels of less polar ginsenosides were detected in red ginseng steamed at high temperature.ConclusionThis study makes the first time that differences between red ginseng steamed under different temperatures and their ginsenosides transformation have been observed systematically at the chemistry level. The results suggested that the identified chemical markers can be used to illustrate the transformation of ginsenosides in red ginseng processing.

Introduction: Ulcerative colitis (UC) is an inflammatory bowel disease with a high incidence rate and a difficult treatment regimen. Recently, significant advances in the treatment of intestinal diseases, particularly UC, have been made with the use of the drugs baicalin and baicalein, separately or in combination. However, the therapeutic efficacy and mechanism of action of baicalin, baicalein, and their combination therapy, in the treatment of UC has not been fully elucidated.Materials and Methods: we constructed a UC rat model that encompassed a variety of complex factors, including a high-sugar and high-fat diet, a high temperature and humidity environment (HTHE), excess drinking, and infection of Escherichia coli. Model rats were then treated with baicalin, baicalein, or a combination of the two. Results:The results showed significant differences in the therapeutic effects of baicalin, baicalein, and the combination therapy, in the treatment of UC, as well as differences in the inhibition of inflammation via the nuclear factor-κB and MAPK pathways. The rat model of UC was established as described above. Then, the rats were treated for 7 days with baicalin (100 mg kg -1 ), baicalein (100 mg kg -1 ), or both (100 mg kg -1 , baicalin: baicalein = 4:1/1:1). Clinical symptoms and signs, body temperature, organ indices, histopathology, blood biochemistry, and metabolites were examined to compare treatment effects and indicators of UC. Baicalin, YSR (Young Scutellaria baicalensis ratio of baicalin and baicalein), baicalein, and WSR (Withered Scutellaria baicalensis ratio of baicalin and baicalein) had significantly different effects in terms of clinical symptoms and signs, body temperature, organ indices, serum inflammatory cytokine levels, blood biochemistry, and histopathology changes in the main organs; YSR exhibited the best treatment effects. LC-MS/MS was used to detect the conversion of baicalin, baicalein, or both, into the six types of metabolites: baicalin, wogonoside, oroxin A, baicalein, wogonin, and oroxylin A. The levels of the six metabolites under the different treatment Frontiers in Pharmacology | www.frontiersin.org Baicalin, Baicalein and Their Combinations on UC Liang et al.conditions were significantly different in the large intestine, small intestine, and lungs, but not in the blood. The levels of the six metabolites were significantly different in the large intestine, small intestine, and lung, but not in the serum.Conclusion: All these results indicate that baicalin and baicalein should be used more accurately in specific diseases, especially baicalin or high content of baicalin in Scutellaria baicalensis (Tiaoqin) should be preferred in treatment of UC.