Use of Tregs as a cell‐based therapy via CD39 for benign prostate hyperplasia with inflammation

Benign prostatic hyperplasia (BPH) occurs most commonly among older men, often accompanied by chronic tissue inflammation. Although its aetiology remains unclear, autoimmune dysregulation may contribute to BPH. Regulatory T cells (Tregs) prevent autoimmune responses and maintain immune homeostasis. In this study, we aimed to investigate Tregs frequency, phenotype, and function in BPH patients and to evaluate adoptive transfer Tregs for immunotherapy in mice with BPH via CD39. Prostate specimens and peripheral blood from BPH patients were used to investigate Treg subsets, phenotype and Treg‐associated cytokine production. Sorted CD39^+/? Tregs from healthy mice were adoptively transferred into mice before or after testosterone propionate administration. The Tregs percentage in peripheral blood from BPH patients was attenuated, exhibiting low Foxp3 and CD39 expression with low levels of serum IL‐10, IL‐35 and TGF‐β. Immunohistochemistry revealed Foxp3+ cells were significantly diminished in BPH prostate with severe inflammatory. Although the Tregs subset was comprised of more effector/memory Tregs, CD39 was still down‐regulated on effector/memory Tregs in BPH patients. Before or after testosterone propionate administration, no alterations of BPH symptoms were observed due to CD39‐ Tregs in mice, however, CD39⁺Tregs existed more potency than Tregs to regulate prostatic hyperplasia and inhibit inflammation by decreasing IL‐1β and PSA secretion, and increasing IL‐10 and TGF‐β secretion. Furthermore, adoptive transfer with functional Tregs not only improved prostate hyperplasia but also regulated muscle cell proliferation in bladder. Adoptive transfer with Tregs may provide a novel method for the prevention and treatment of BPH clinically.     

Long noncoding RNA CPS1-IT1 suppresses melanoma cell metastasis through inhibiting Cyr61 via competitively binding to BRG1

Long noncoding RNA CPS1-IT1 is recently recognized as a tumor suppressor in several cancers. Here, we investigate the role of CPS1-IT1 in human melanoma. Presently, our study reveals the low expression of CPS1-IT1 in human melanoma tissues and cell lines, which is significantly associated with metastasis and tumor stage. Besides, the potential of CPS1-IT1 as a prognosis-predictor is strongly indicated. Functionally, CPS1-IT1 overexpression inhibits cell migration, invasion, epithelial–mesenchymal transition, and angiogenesis in melanoma cells. CYR61, an angiogenic factor that participates in tumor metastasis as well as a recognized oncogene in melanoma, is shown to be confined under CPS1-IT1 overexpression in melanoma cells. Furthermore, enforced expression of Cyr61 in CPS1-IT1-silenced melanoma cells dramatically normalized the protein level of Cyr61 and that of its downstream targets vascular endothelial growth factor and matrix metalloproteinase-9, as well as the repressive effect of CPS1-IT1 overexpression on melanoma cell metastasis. BRG1, a core component of SWI/SNF complex, is implied to interact with both CPS1-IT1 and Cyr61 in melanoma cells. Moreover, CPS1-IT1 negatively regulates Cyr61 expression by blocking the binding of BRG1 to Cyr61 promoter. Jointly, CPS1-IT1 controls melanoma metastasis through impairing Cyr61 expression via competitively binding with BRG1, uncovering a novel potential therapeutic and prognostic biomarker for patients with melanoma.     

Novel TNF-α converting enzyme (TACE) inhibitors as potential treatment for inflammatory diseases

Our research on hydantoin based TNF-α converting enzyme (TACE) inhibitors has led to an acetylene containing series that demonstrates sub-nanomolar potency (K(i)) as well as excellent activity in human whole blood. These studies led to the discovery of highly potent TACE inhibitors with good DMPK profiles.     

Examination of the 1,4-disubstituted azetidinone ring system as a template for combretastatin A-4 conformationally restricted analogue design

A series of novel 1,4-diaryl-2-azetidinones was prepared by stereospecific Staudinger reaction as conformationally restricted analogues of combretastatin A-4 because molecular modeling studies suggested close geometric similarities. They were evaluated for cytotoxicity against a number of human tumor and normal cell lines. Strong potencies were observed, with the best compounds exhibiting IC(50)'s of 25-74 nM against human neuroblastoma IMR 32 cell growth and a variety of other cell lines. Compounds inhibited tubulin polymerization with potencies commensurate with their cytotoxic activity and a more soluble anilino-containing analogue was very effective in inhibiting the growth of AR42J rat pancreatic tumors transplanted into in nude mice. Further studies on this interesting group of compounds as anti-cancer agents appear warranted.     

Hypermethylation of growth Arrest DNA-damage-inducible gene 45 in non-small cell lung cancer and its relationship with clinicopathologic features

The growth arrest DNA-damage-inducible protein 45 (GADD45) can serve as a key coordinator of the stress response by regulating cell cycle progression, genomic stability, DNA repair, and other stress-related responses. Although deregulation of GADD45 expression has been reported in several types of human tumors, its role in lung cancer is still unknown. DNA hypermethylation of promoter CpG islands is known to be a major mechanism for epigenetic inactivation of tumor suppressor genes. We investigated the methylation status of GADD45 family genes (GADD45A, B, and G) in 139 patients with non-small cell lung cancer (NSCLC) using methylation-specific PCR (MSP) and correlated the results with clinicopathologic features of the patients. Methylation frequencies in tumors were 1.4% for GADD45A, 7.2% for GADD45B, and 31.6% for GADD45G. RT-PCR and MSP analysis showed that promoter methylation of the GADD45G gene resulted in downregulation of its mRNA expression. GADD45G methylation was significantly more frequent in female patients than male patients (P = 0.035). This finding suggests that methylation-associated down-regulation of the GADD45G gene may be involved in lung tumorigenesis.     

Mechanical response and conformational amplification in α-helical coiled coils

α-Helical coiled coils (CCs) are ubiquitous tertiary structural domains that are often found in mechanoproteins. CCs have mechanical rigidity and are often involved in force transmission between protein domains. Although crystal structures of CCs are available, information about their conformational flexibility is limited. The role of hydrophobic interactions in determining the CC conformation is not clear. In this work we examined the mechanical responses of typical CCs and constructed a coarse-grained mechanical model to describe the conformation of the protein. The model treats α-helices as elastic rods. Hydrophobic bonds arranged in a repeated pattern determine the CC structure. The model is compared with molecular-dynamics simulations of CCs under force. We also estimate the effective bending and twisting persistence length of the CC. The model allows us to examine unconventional responses of the CC, including significant conformational amplification upon binding of a small molecule. We find that the CC does not behave as a simple elastic rod and shows complex nonlinear responses. These results are significant for understanding the role of CC structures in chemoreceptors, motor proteins, and mechanotransduction in general.     

PLK1 Down-Regulates Parainfluenza Virus 5 Gene Expression

The paramyxoviruses are a family of negative-sense RNA viruses that includes many important human and animal pathogens. Paramyxovirus RNA synthesis requires the viral phosphoprotein (P) and the large (L) protein. Phosphorylation of P is thought to regulate viral gene expression, though direct proof remains elusive. Recently, we reported that phosphorylation of a specific residue (Ser157) of the P protein of parainfluenza virus 5 (PIV5), a prototypical paramyxovirus, correlates with decreased viral gene expression and cytokine expression in infected cells. Here, we show that: Polo-like kinase 1 (PLK1), a serine/theronine kinase that plays a critical role in regulating the cell cycle, interacts with PIV5 P through the S157 residue; PLK1 inhibition increases viral gene expression; PLK1 over-expression inhibits viral gene expression; and PLK1 directly phosphorylates P in vitro, indicating that PLK1 down-regulates viral gene expression by phosphorylating P. Furthermore, we have determined the PLK1 phosphorylation site on P and found that mutant recombinant PIV5 whose P proteins cannot either bind to or be phosphorylated by PLK1 have similar phenotypes. Increased viral gene expression in PIV5 with mutations in the PLK1 binding/phosphorylation sites correlates with increased induction of cell death and cytokine expression, suggesting that PIV5 limits its viral gene expression to avoid these host effects. It is possible that targeting PLK1 will enhance host innate immune responses, leading to a novel strategy of clearing paramyxovirus infections quickly.     

不同林龄长白落叶松人工林碳储量

基于7—41 a长白落叶松人工林样地生物量调查,探讨了不同发育阶段长白落叶松人工林碳储量的时空变化规律。结果表明:随林龄的增大,长白落叶松人工林林木和各器官生物量增加,树干所占比例增加,生物量转换因子(BEF)、根茎比(R)等参数分布正常。林下植被层、倒落木质物层生物量随林龄增大呈增加趋势。群落总碳储量的空间分布序列是:乔木层倒落木质物层林下植被层。未成林期、幼龄林、中龄林、近熟林和成熟林群落的碳储分别为6.585、66.934、90.019、125.103、162.683t.hm-2,乔木层碳储量分别为3.254、58.521、78.086、108.02、138.096 t.hm-2,倒落木质物层和林下植被层碳储量平均值分别为10.859、1.988 t.hm-2。乔木层、倒落木质物层和林下植被层碳储量占总量的平均比率分别为85.99%、2.17%和11.85%。在不同发育阶段群落和乔木层碳储量的年生产力呈先降后升的变化趋势,中龄林的碳储量累积速率高于幼龄林及成熟林,碳素年固定量分别为0.940、3.889、3.615、3.628、3.968 t.hm-2,乔木层年生产力分别为0.465、3.39、3.137、3.133、3.368 t.hm-2。林下植被层年生产力呈"U"形变化,平均值为0.079 t.hm-2。倒落木质物层的年生产力呈线性增长,平均值为0.423 t.hm-2。研究认为长白落叶松人工林群落碳储量随林龄增加的变化规律明显,碳汇潜力巨大。     

Diversity and distribution of parasitic angiosperms in China

Parasitic plants are an important component of vegetation worldwide, but their diversity and distribution in China have not been systematically reported. This study aimed to (1) explore floral characteristics of China's parasitic plants, (2) map spatial distribution of diversity of these species, and (3) explore factors influencing the distribution pattern. We compiled a nationwide species list of parasitic plants in China, and for each species, we recorded its phylogeny, endemism, and life form (e.g., herb vs. shrub; hemiparasite vs. holoparasite). Species richness and area‐corrected species richness were calculated for 28 provinces, covering 98.89% of China's terrestrial area. Regression analyses were performed to determine relationships between provincial area‐corrected species richness of parasitic plants and provincial total species richness (including nonparasitic plants) and physical settings (altitude, midlongitude, and midlatitude). A total of 678 species of parasitic angiosperms are recorded in China, 63.13% of which are endemic. Of the total, 59.73% (405 species) are perennials, followed by shrubs/subshrubs (14.75%) and vines (1.47%). About 76.11% (516 species) are of root hemiparasites, higher than that of stem parasites (100, 14.75%), root holoparasites (9.00%), and endophytic parasites (0.15%). A significant positive relationship is found between the area‐corrected species richness and the total species richness, which has been previously demonstrated to increase with decreasing longitude and latitude. Moreover, more parasitic species are found in the southwest high‐altitude areas than low areas. Consistently, the area‐corrected species richness increases with increasing altitude, decreasing latitude, and decreasing longitude, as indicated by regression analyses. China is rich in parasitic flora with a high proportion of endemic species. Perennials and root hemiparasites are the dominant types. The spatial distribution of parasitic plants is largely heterogeneous, with more species living in southwest China, similar to the distribution pattern of Chinese angiosperms. The positive relationship between parasitic and nonparasitic plant species richness should be addressed in the future.