Babao Dan Alleviates Cancer Cachexia in Mice Via Inhibiting IL-6/STAT3 Signaling Pathway.

BACKGROUND: Cancer cachexia is a common but severe condition that causes muscle wasting, body weight loss, and progressive functional impairment, affecting over 50% of cancer patients. Currently, there are no effective treatments that can alleviate cachexia, and hence the discovery of new therapeutics that can effectively prevent or even reverse cancer cachexia is crucial. Babao Dan (BBD) is a Traditional Chinese Medicine (TCM) formula that has been used clinically in combating various cancers, however, its therapeutic potential in alleviating cancer cachexia remains unexplored. Our current study aims to determine the anti-cachectic effects of BBD treatment in alleviating cancer cachexia, as well as determining the underlying mechanisms involved. METHODS: Mouse models of cancer cachexia were induced via implantation of CT26 colon adenocarcinoma cells, and the anti-cachectic effects and mechanisms of BBD were determined via examinations of body weight and muscle mass, as well as serum and muscle markers of cachexia and muscle atrophy. RESULTS: CT26 tumor implantation reduced in the rapid occurrence of cancer cachexia characterized by marked reductions in body weight and muscle mass, functional decrease in muscle function and accelerated deaths. BBD administration not only demonstrated robust anti-cachectic ability via preventing decreases in body weight, muscle mass, and muscle atrophy, but also markedly prolonged survival. The effects of BBD in alleviating cancer cachexia and its associated adverse effects were due to its ability in preventing the activation of IL-6/STAT3 signaling post-CT26 tumor implantation. CONCLUSION: Our findings demonstrated the robust ability of BBD in preventing cancer cachexia and alleviating the main cachexia-induced symptoms as well as prolonging survival via inhibiting activation of IL-6/STAT3 signaling pathway. Therefore, our study demonstrating the strong anti-cachectic effects of BBD in mice may provide a theoretical basis for the use of BBD as a safe and effective drug in the treatment of cancer cachexia.

Identification and Analysis of p53-Regulated Enhancers in Hepatic Carcinoma.

Enhancers can act as cis-regulatory elements to control transcriptional regulation by recruiting transcription factors (TFs) in a distance and orientation-independent manner. However, it is still unclear how p53 participates in the enhancer network as TF in hepatic carcinoma under the condition of DNA damage. A total of 14,286 active enhancers were identified through the integration of stable and unstable enhancer RNAs (eRNAs) captured by CAGE and GRO-seq, respectively. Furthermore, 218 p53-bound enhancers (Enhp53) were identified by analyzing p53 ChIP-seq in HepG2 cells after DNA damage. The results showed that the enhancer expression and histone markers of enhancers (H3K4me1, H3K4me2, H3K4me3, H3K9ac, and H3K27ac) revealed significantly higher level on Enhp53 than Enhno-p53 which suggested that p53 participated in regulating enhancer activity and chromatin structure. By analyzing 124 TFs ChIP-seq from ENCODE, 93 TFs were found significantly enriched on Enhp53 such as GATA4, YY1, and CTCF, indicating p53 may co-regulate enhancers with TFs participation. Moreover, significantly differentially expressed 438 miRNAs and 1,264 mRNAs were identified by analyzing small RNA-seq and RNA-seq, and 26 Enhp53-miRNAs and 145 Enhp53-mRNA interactions were identified by the integration of 3D genome data and genomic distance. The functional enrichment analysis showed that these miRNA targets and mRNAs were significantly involved in tumor biological processes and signaling pathways such as DNA replication, p53 signaling pathway, hepatitis B, focal adhesion, etc. The above results indicated that p53 participated in regulating enhancer network in hepatic carcinoma and Enhp53 exhibited significantly different characteristics with Enhno-p53.

Genome-Wide Identification and Analysis of Enhancer-Regulated microRNAs Across 31 Human Cancers.

Enhancers are cis-regulatory DNA elements that positively regulate the transcription of target genes in a tissue-specific manner, and dysregulation of target genes could lead to various diseases, such as cancer. Recent studies have shown that enhancers can regulate microRNAs (miRNAs) and participate in their biological synthesis. However, the network of enhancer-regulated miRNAs across multiple cancers is still unclear. Here, a total of 2,418 proximal enhancer-miRNA interactions and 1,280 distal enhancer-miRNA interactions were identified through the integration of genomic distance, co-expression, and 3D genome data in 31 cancers. The results showed that both proximal and distal interactions exhibited a significant cancer type-specific feature trend at the tissue level rather than at the single-cell level, and there was a noteworthy positive correlation between the expression of the miRNA and the number of enhancers regulating the same miRNA in most cancers. Furthermore, we found that there was a high correlation between the formation of enhancer-miRNA pairs and the expression of enhancer RNAs (eRNAs) whether in distal or proximal regulation. The characteristics analysis showed that miRes (enhancers that regulated miRNAs) and non-miRes presented significant differences in sequence conservation, guanine-cytosine (GC) content, and histone modification signatures. Notably, GC content, H3K4me1, and H3K36me3 were present differently between distal and proximal regulation, suggesting that they might participate in chromosome looping of enhancer-miRNA interactions. Finally, we introduced a case study, enhancer: chr1:1186391-1186507 ∼ miR-200a was highly relevant to the survival of thyroid cancer patients and a cis-eQTL SNP on the enhancer affected the expression of the TNFRSF18 gene as a tumor suppressor.

Identification and functional analysis of pathogenic genes and key transcription factors in prostate adenocarcinoma / 中国肿瘤生物治疗杂志

@#[Abstract] Objective: To investigate the pathogenesis of prostate cancer by analyzing the associated hub gene modules of prostate cancer and identifying key transcription factors and genes that affect these modules. Methods: WGCNA (weighted gene co-expressed network analysis) was used to identify hub gene modules associated with important clinicopathological features of prostate cancer, such as pathological staging, Gleason grading etc. The OPOSSUM online tool was used to analyze the transcription factors enriching and regulating those genes. Pathway enrichment analysis and protein-protein interaction network analysis were used to identify key genes in prostate cancer. Finally, the effects of these genes on clinical features and disease-free survival (DFS) of prostate cancer patients were analyzed. Results: Three hub modules were identified, and they were highly associated with pathologic T stage, pathologic N stage and Gleason grading of prostate cancer, respectively. Further screening revealed 13 key dysregulated transcription factors that participated in the regulation of these three hub modules. The differentially expressed genes regulated by the 13 key transcription factors were significantly enriched in Calcium signaling pathway, cGMP-PKG signaling pathway and cAMP signaling pathway. 14 key genes (PRKG1, PRKG2, CYSLTR2, GRPR, CHRM3, ADCY5, ADRA1D, EDNRA, EDNRB, CYSLTR2, AGTR1, GRPR, GRIA1 and OXT) were at important nodes in the gene network. Among them, the high expression of ADRA1A, PRKG2, CHRM3, ADRA1D and EDN3 significantly extended the DFS of patients with prostate cancer (all P<0.01). Conclusion: ADRA1A, PRKG2, CHRM3, ADRA1D and EDN3 are regulated by key dysregulated transcription factors and highly associated with clinical features of prostate cancer. Their high expressions will significantly prolong the DFS of prostate cancer patients, which may shed light to the discovery of mechanism in prostate adenocarcinoma.

[Protective effect of HS-6101 on rhesus monkeys with severe hematopoietic acute radiation sickness].

This study was purposed to investigate the protective effects of lipoprotein HS-6101(6101) on rhesus monkey total body irradiated with 7.0 Gy 6°Coγ-ray. A total of 30 health adult rhesus monkeys were randomly divided into symptomatic therapy (ST), WR2721 and HS-6101 30, 90 and 270 mg/kg groups (n = 6), the rhesus monkeys of each groups were injected with physiological saline 0.3 ml/kg, WR-2721 30 mg/kg, or HS-6101 30, 90 and 270 µg/kg, respectively. All agents were once intramuscularly injected at 1 hr prior irradiation. General observation, peripheral blood cell counts, colony forming unite assay of bone marrow hemopoietic progenitor cells, and histopathological examination were performed. The results showed that animals in symptomatic therapy group begin to die on the 13(th) day and 4 animals died within 24 days, the average survival time was 18.2 ± 4.3 days; 2 animals in WR-2717 groups died on day 15.8 and day 18.5 post irradiation respectively. 1 animal in HS-6101 270 mg/kg group died on day 35.8, all other animals survived. Nadirs of peripheral blood white blood cells, neutrophils and platelets of animals in HS-6101 treatment groups were significantly higher than those in other 2 groups including ST and WR-2721 groups, and the hemopoietic recovery were also significantly speeding up(P < 0.05 and 0.01). In vitro results showed that HS-6101 obviously promoted 7.0 Gy 6°Coγ irradiated monkey's bone marrow mononuclear cells to form various hematopoietic progenitor cell colonies (P < 0.05 and 0.01) . Compared with symptomatic therapy and WR-2717 groups, bone marrow histopathological changes in HS-6101 treatment groups showed more active hemopoietic cell proliferation and higher density structure. It is concluded that HS-6101 90 µg/kg treatment can promote the bone marrow recovery of 7.0 Gy 6°Coγ irradiated monkey, alleviate their animal symptom, simplify the treatment measures and improve the animal survival rate. The HS-6101 shows remarkable radioprotective effects as compared with the currently internationally acknowledged radioprotectant of WR-2721.

Herpes B virus gD interaction with its human receptor--an in silico analysis approach.

BACKGROUND: The glycoprotein D (gD) is essential for Herpes B virus (BV) entry into mammalian cells. Nectin-1, an HSV-1 gD receptor, is found to be the receptor which mediated BV induced cell-cell fusion, while HVEM does not mediate fusion by BV glycoprotein. However, the specific sequence and structural requirements of the BV gD for the recognition of and binding to Nectin-1 are unknown. Moreover, the 3D structures of BV gD and the BV gD-receptor complex have not been determined. In this study, we propose a reliable model of the interaction of the BV gD with receptor using bioinformatics tools. RESULTS: The three-dimensional structures of two BV gD-receptor complexes were constructed using homology modelling and docking strategy. Based on the models of these complexes, the BV gD receptor interaction patterns were calculated. The results showed that the interface between the BV gD and nectin-1 molecule is not geometrically complementary. The computed molecular interactions indicated that two terminal extensions were the main region of BV gD that binds to nectin-1 and that hydrophobic contacts between the two molecules play key roles in their recognition and binding. The constructed BV gD-HVEM complex model showed that this complex had a lower shape complementarity value and a smaller interface area compared with the HSV-1 gD-HVEM complex, and the number of intermolecular interactions between BV gD-HVEM were fewer than that of HSV-1 gD-HVEM complex. These results could explain why HVEM does not function as a receptor for BV gD. CONCLUSION: In this study, we present structural model for the BV gD in a complex with its receptor. Some features predicted by this model can explain previously reported experimental data. This complex model may lead to a better understanding of the function of BV gD and its interaction with receptor and will improve our understanding of the activation of the BV fusion and entry process.

Genetic diversity of Bartonella quintana in macaques suggests zoonotic origin of trench fever.

Bartonella quintana is a bacterium that causes a broad spectrum of diseases in humans including trench fever. Humans were previously considered to be the primary, if not the only, reservoir hosts for B. quintana. To identify the animal reservoir and extend our understanding of the ecological and evolutionary history of B. quintana, we examined blood samples from macaques and performed multilocus sequence typing (MLST) analysis. We demonstrated the prevalence of B. quintana infection was common in macaques from main primate centres in mainland China. Overall, 18.0% (59/328) of rhesus macaques and 12.7% (39/308) of cynomolgus macaques were found to be infected with B. quintana by blood culture and/or polymerase chain reaction. The infection was more frequently identified in juvenile and young monkeys compared with adult animals. In contrast with the relatively low level of sequence divergence of B. quintana reported in humans, our investigation revealed much higher genetic diversity in nonhuman primates. We identified 44 new nucleotide variable sites and 14 novel sequence types (STs) among the B. quintana isolates by MLST analysis. Some STs were found only in cynomolgus macaques, while some others were detected only in rhesus macaques, suggesting evidence of host-cospeciation, which were further confirmed by phylogenetic analysis and Splits decomposition analysis. Our findings suggest that trench fever may primarily be a zoonotic disease with macaques as the natural hosts.

Toll-like receptor 9 interaction with CpG ODN--an in silico analysis approach.

BACKGROUND: Toll-like receptor 9 (TLR9) recognises unmethylated CpG DNA and activates a signalling cascade, leading to the production of inflammatory cytokines such as TNF-α, IL-1, IL-6 and IL-12 via the adaptor protein MyD88. However, the specific sequence and structural requirements of the CpG DNA for the recognition of and binding to TLR9 are unknown. Moreover, the 3D structures of TLR9 and the TLR9-ODN complex have not been determined. In this study, we propose a reliable model of the interaction of the TLR9 ECD with CpG ODN using bioinformatics tools. RESULTS: The three-dimensional structures of two TLR9 ECD-CpG ODN complexes were constructed using a homology modelling and docking strategy. Based on the models of these complexes, the TLR9 ECD-CpG ODN interaction patterns were calculated. The results showed that the interface between the human TLR9 and the CpG ODN molecule is geometrically complementary. The computed molecular interactions indicated that LRR11 is the main region of TLR9 that binds to CpG ODN and that five positively charged residues within LRR11 are involved in the binding of the TLR9 ECD to the CpG ODN. Observations in the close-up view of these interactions indicated that these five positively charged residues contribute differently to the binding region within the TLR9 ECD-CpG ODN complex. 337Arg and 338Lys reside in the binding sites of ODN, forming hydrogen bonds and direct contacts with the CpG ODN, whereas 347Lys, 348Arg, and 353His do not directly contact the CpG ODN. These results are in agreement with previously reported experimental data. CONCLUSION: In this study, we present two structural models for the human and mouse TLR9 ECD in a complex with CpG ODN. Some features predicted by this model are consistent with previously reported experimental data. This complex model may lead to a better understanding of the function of TLR9 and its interaction with CpG ODN and will improve our understanding of TLR9-ligand interaction in general.