Protective Effect of Silibinin on Learning and Memory Impairment in LPS-Treated Rats via ROS–BDNF–TrkB Pathway

Silibinin, a flavonoid derived from the herb milk thistle (Silybum marianum), has been used as a hepato-protectant in the clinical treatment of liver disease. In the present study, the effect of silibinin on lipopolysaccharide (LPS)-induced neuroinflammatory impairment in rats is investigated. Injection of LPS into lateral ventricle caused learning and memory impairment. Rats were treated with silibinin to see the effect in comparison with resveratrol as a positive control. Y-maze and Morris water maze tests showed that silibinin significantly attenuated memory damage caused by LPS treatment. At the molecular analysis, the levels of IL-1β and of IL-4 in the hippocampus were decreased and enhanced, respectively, by the treatment with silibinin. NF-κB expression was attenuated by silibinin treatment. Furthermore, generation of total reactive oxygen species (ROS) in the hippocampus was elevated in silibinin-treated groups, and so were the expressions of brain-derived neurotrophic factor (BDNF) and tyrosine receptor kinase B (TrkB). At the same time, LPS-induced reduction of neurons in hippocampus was reversed by silibinin. In conclusion, silibinin ameliorated the impairment of learning and memory of LPS-injection rats, possibly due to the activation of ROS–BDNF–TrkB pathway in the hippocampus as well as the suppression of inflammatory response. This study gives an insight on the beneficial consequences of ROS in central nervous system. Silibinin might be a potential candidate drug for neurodegenerative diseases.     

The TIR-NBS protein TN13 associates with the CC-NBS-LRR resistance protein RPS5 and contributes to RPS5-triggered immunity in Arabidopsis

Nucleotide-binding site (NBS)–leucine-rich repeat (LRR) domain receptor (NLR) proteins play important roles in plant innate immunity by recognizing pathogen effectors. The Toll/interleukin-1 receptor (TIR)-NBS (TN) proteins belong to a subtype of the atypical NLRs, but their function in plant immunity is poorly understood. The well-characterized Arabidopsis thaliana typical coiled-coil (CC)-NBS-LRR (CNL) protein Resistance to Pseudomonas syringae 5 (RPS5) is activated after recognizing the Pseudomonas syringae type III effector AvrPphB. To explore whether the truncated TN proteins function in CNL-mediated immune signaling, we examined the interactions between the Arabidopsis TN proteins and RPS5, and found that TN13 and TN21 interacted with RPS5. However, only TN13, but not TN21, was involved in the resistance to P. syringae pv. tomato (Pto) strain DC3000 carrying avrPphB, encoding the cognate effector recognized by RPS5. Moreover, the regulation of Pto DC3000 avrPphB resistance by TN13 appeared to be specific, as loss of function of TN13 did not compromise resistance to Pto DC3000 hrcC⁻ or Pto DC3000 avrRpt2. In addition, we demonstrated that the CC and NBS domains of RPS5 play essential roles in the interaction between TN13 and RPS5. Taken together, our results uncover a direct functional link between TN13 and RPS5, suggesting that TN13 acts as a partner in modulating RPS5-activated immune signaling, which constitutes a previously unknown mechanism for TN-mediated regulation of plant immunity.     

Profile of microRNA in Giant Panda Blood: A Resource for Immune-Related and Novel microRNAs

The giant panda (Ailuropoda melanoleuca) is one of the world’s most beloved endangered mammals. Although the draft genome of this species had been assembled, little was known about the composition of its microRNAs (miRNAs) or their functional profiles. Recent studies demonstrated that changes in the expression of miRNAs are associated with immunity. In this study, miRNAs were extracted from the blood of four healthy giant pandas and sequenced by Illumina next generation sequencing technology. As determined by miRNA screening, a total of 276 conserved miRNAs and 51 novel putative miRNAs candidates were detected. After differential expression analysis, we noticed that the expressions of 7 miRNAs were significantly up-regulated in young giant pandas compared with that of adults. Moreover, 2 miRNAs were up-regulated in female giant pandas and 1 in the male individuals. Target gene prediction suggested that the miRNAs of giant panda might be relevant to the expressions of 4,602 downstream genes. Subseuqently, the predicted target genes were conducted to KEGG (Kyoto Encyclopedia of Genes and Genomes) pathway analysis and we found that these genes were mainly involved in host immunity, including the Ras signaling pathway, the PI3K-Akt signaling pathway, and the MAPK signaling pathway. In conclusion, our results provide the first miRNA profiles of giant panda blood, and the predicted functional analyses may open an avenue for further study of giant panda immunity.     

Assessment of Thiosemicarbazone-Containing Compounds as Potential Antileukemia Agents against P-gp Overexpressing Drug Resistant K562/A02 Cells

P-Glycoprotein (P-gp) overexpression is considered to be the leading cause of multidrug resistance (MDR) and failure of chemotherapy for leukemia. In this study, seventeen thiosemicarbazone-containing compounds were prepared and evaluated as potential antileukemia agents against drug resistant K562/A02 cell overexpressing P-gp. Among them, N-hydroxy-6-({(2E)-2-[(3-nitrophenyl)methylidene]hydrazinecarbothioyl}amino)hexanamide could significantly inhibit K562/A02 cells proliferation with an IC₅₀ value of 0.96 μM. Interestingly, N-hydroxy-6-({(2E)-2-[(3-nitrophenyl)methylidene]hydrazinecarbothioyl}amino)hexanamide could dose-dependently increase ROS levels of drug resistant K562/A02 cells, thus displaying a potential collateral sensitivity (CS)-inducing effect and selectively killing K562/A02 cells. Furthermore, N-hydroxy-6-({(2E)-2-[(3-nitrophenyl)methylidene]hydrazinecarbothioyl}amino)hexanamide possessed potent inhibitory effect on HDAC1 and HDAC6, and could promote K562/A02 cells apoptosis via dose-dependently increasing Bax expression, reducing Bcl-2 protein level, and inducing the cleavage of PARP and caspase3. These present findings suggest that N-hydroxy-6-({(2E)-2-[(3-nitrophenyl)methylidene]hydrazinecarbothioyl}amino)hexanamide might be a promising lead to discover novel antileukemia agents against P-gp overexpressing leukemic cells.     

SLC7A2 deficiency promotes hepatocellular carcinoma progression by enhancing recruitment of myeloid-derived suppressors cells

The main reason for poor prognosis in hepatocellular carcinoma (HCC) patients is high metastasis and recurrence. Cancer progression depends on a tumor-supportive microenvironment. Therefore, illustrating the mechanisms of tumor immunity in underlying HCC metastasis is essential. Here, we report a novel role of solute carrier family 7 member 2 (SLC7A2), a member of the solute carrier family, in HCC metastasis. The reduction of SLC7A2 was an independent and significant risk factor for the survival of HCC patients. Upregulation of SLC7A2 decreased HCC invasion and metastasis, whereas downregulation of SLC7A2 promoted HCC invasion and metastasis. We further found that deficient SLC7A2 medicated the upregulation of CXCL1 through PI3K/Akt/NF-kκB pathway to recruit myeloid-derived suppressor cells (MDSCs), exerting tumor immunosuppressive effect. Moreover, we found that G9a-mediated di-methylation of H3K9 (H3K9me2) silenced the expression of SLC7A2 to suppress HCC metastasis and immune escape. In conclusion, G9a-mediated silencing of SLC7A2 exerts unexpected functions in cancer metastasis by fostering a tumor-supportive microenvironment through CXCL1 secretion and MDSCs recruitment. Thus, SLC7A2 may provide new mechanistic insight into the cancer-promoting property of MDSCs.Subject terms: Cancer microenvironment, Cancer immunotherapy, Metastasis