LSKL, a Peptide Antagonist of Thrombospondin-1, Attenuates Renal Interstitial Fibrosis in Rats with Unilateral Ureteral Obstruction

Xi-sheng Xie,Fei-yan Li,Heng-chuan Liu,Yao Deng,Zi Li,Jun-ming Fan 대한약학회 2010 Archives of Pharmacal Research Vol.33 No.2

The effects of LSKL, the peptide antagonist of thrombospondin-1 (TSP-1), on renal interstitial fibrosis in rats subjected to unilateral ureteral obstruction (UUO) were investigated. Rats were divided randomly into three groups (n = 20 each): UUO group, sham-operation group and UUO plus LSKL treatment group. Collagen deposition was studied using histopathology and reverse transcription polymerase chain reaction analysis (RT-PCR). TSP-1, transforming growth factor beta 1 (TGF-β1), phosphorylated Smad2 (pSsmad2) and α-smooth muscle actin (α-SMA) in the kidney were measured using immunocytochemistry, western blotting analysis, RT-PCR and enzyme-linked immunosorbent assay. Biochemical analyses in the serum and urine were made. Histopathology showed severe tubular dilatation and atrophy, interstitial inflammation and collagen accumulation after surgery and LSKL significantly inhibited interstitial fibrosis including tubular injury as well as collagen deposition. The protein and mRNA levels of TSP-1 increased notably at different time point and significantly decreased in the presence of LSKL. The expression of TGF-β1 and pSmad2 were upregulated in the obstructed kidney and substantially suppressed by LSKL treatment. Myofibroblast accumulation could be alleviated after administration of LSKL. Biochemical parameters did not show differences among the three groups. As TSP-1 is the major activator of TGF-β1, we demonstrate that LSKL can attenuate renal interstitial fibrosis in vivo by preventing TSP-1-mediated TGF-β1 activation.

The complete mitochondrial genome of a threatened loach (Sinibotia reevesae) and its phylogeny

Yuan‑Chao Zou,Bi‑Wen Xie,Chuan‑Jie Qin,Yong‑Ming Wang,Deng‑Yue Yuan,Rui Li,Zheng‑Yong Wen 한국유전학회 2017 Genes & Genomics Vol.39 No.7

In present study, the complete mitochondrial genome of Sinibotia reevesae was first sequenced using the next-generation sequencing technology and annotated using bioinformatic tools. The circular mitochondrial genome was 16,572 bp in length, and contained 13 proteincoding genes, 2 ribosomal RNA genes, 22 transfer RNA genes, and 1 displacement loop locus. It presents a typical gene organization and order for completely sequenced cypriniformes mitogenomes. The control region could be divided into three parts included the extended termination associated sequence domain, the central conserved domain and the conserved sequence block. Interestingly, two stemloop domains were found in control region and OL region, respectively. Furthermore, phylogenetic analyses using concatenated amino acid and nucleotide sequences of the 13 protein-coding genes with two different methods (Maximum likelihood and Bayesian analysis) both highly supported the close relationship of S. reevesae and Sinibotia superciliaris, which was in line with the previous classifications based on morphological and molecular studies. These data provide useful information for a better understanding of the mitogenomic diversities and evolution in fish as well as novel genetic markers for studying population genetics and species identification.

Fibulin2: a negative regulator of BMSC osteogenic differentiation in infected bone fracture healing

Li Shi-Dan,Xing Wei,Wang Shao-Chuan,Li You-Bin,Jiang Hao,Zheng Han-Xuan,Li Xiao-Ming,Yang Jing,Guo De-Bin,Xie Xiao-Yu,Jiang Ren-Qing,Fan Chao,Li Lei,Xu Xiang,Fei Jun 생화학분자생물학회 2023 Experimental and molecular medicine Vol.55 No.-

Bone fracture remains a common occurrence, with a population-weighted incidence of approximately 3.21 per 1000. In addition, approximately 2% to 50% of patients with skeletal fractures will develop an infection, one of the causes of disordered bone healing. Dysfunction of bone marrow mesenchymal stem cells (BMSCs) plays a key role in disordered bone repair. However, the specific mechanisms underlying BMSC dysfunction caused by bone infection are largely unknown. In this study, we discovered that Fibulin2 expression was upregulated in infected bone tissues and that BMSCs were the source of infection-induced Fibulin2. Importantly, Fibulin2 knockout accelerated mineralized bone formation during skeletal development and inhibited inflammatory bone resorption. We demonstrated that Fibulin2 suppressed BMSC osteogenic differentiation by binding to Notch2 and inactivating the Notch2 signaling pathway. Moreover, Fibulin2 knockdown restored Notch2 pathway activation and promoted BMSC osteogenesis; these outcomes were abolished by DAPT, a Notch inhibitor. Furthermore, transplanted Fibulin2 knockdown BMSCs displayed better bone repair potential in vivo. Altogether, Fibulin2 is a negative regulator of BMSC osteogenic differentiation that inhibits osteogenesis by inactivating the Notch2 signaling pathway in infected bone.

Profiling Gene Expression During Gland Morphogenesis of a Glanded and a Glandless Upland Cotton

Ying-Fan Cai,Min Chen,Quan Sun,Yong-Fang Xie,Sheng-Wei Li,Jian-Chuan Mo,Ming-Feng Jiang,You-Lu Yuan,Yu-Zhen Shi,Huai-Zhong Jiang,Zheng Pan,Yun-Ling Gao,Peng-Sheng Ye,Hua-Lan Zeng 한국식물학회 2009 Journal of Plant Biology Vol.52 No.6

The pigment gland is an important character of the Gossypium plant. With the aim of identifying genes involved in pigment gland morphogenesis in cotton, gene expression during pigment gland morphogenesis in Chuan 2802, which is glanded both in seed and plant, and a glandless line N5 was profiled using Affymetrix Cotton microarray. The results showed that there were 564 differentially expressed genes greater than twofold during gland morphogenesis. About 60.2% of these genes shares similarity with known genes on GenBank and about 39.8% with no functional description in the database. These described genes may play roles in defense response, response to oxidative stress, peroxidase activity, and the other metabolic pathways. The KEGG Orthology-Based Annotation System indicated that these above twofold expressed genes involved seven biochemical pathways on KEGG. These findings suggest that a complicated regulation is associated with pigment gland morphogenesis and the associated defense response including gossypol biosynthesis in cotton.

Elevated FBXL6 expression in hepatocytes activates VRK2-transketolase-ROS-mTOR-mediated immune evasion and liver cancer metastasis in mice

Zhang Jie,Lin Xiao-Tong,Yu Hong-Qiang,Fang Lei,Wu Di,Luo Yuan-Deng,Zhang Yu-Jun,Xie Chuan-Ming 생화학분자생물학회 2023 Experimental and molecular medicine Vol.55 No.-

Metastatic hepatocellular carcinoma (HCC) is the most lethal malignancy and lacks effective treatment. FBXL6 is overexpressed in human hepatocellular carcinoma (HCC), but whether this change drives liver tumorigenesis and lung metastasis in vivo remains unknown. In this study, we aimed to identify FBXL6 (F-Box and Leucine Rich Repeat Protein 6) as a key driver of HCC metastasis and to provide a new paradigm for HCC therapy. We found that elevated FBXL6 expression in hepatocytes drove HCC lung metastasis and was a much stronger driver than Kras mutation (KrasG12D/+;Alb-Cre), p53 haploinsufficiency (p53+/-) or Tsc1 loss (Tsc1fl/fl;Alb-Cre). Mechanistically, VRK2 promoted Thr287 phosphorylation of TKT and then recruited FBXL6 to promote TKT ubiquitination and activation. Activated TKT further increased PD-L1 and VRK2 expression via the ROS-mTOR axis, leading to immune evasion and HCC metastasis. Targeting or knockdown of TKT significantly blocked FBXL6-driven immune evasion and HCC metastasis in vitro and in vivo. Notably, the level of active TKT (p-Thr287 TKT) was increased and was positively correlated with the FBXL6 and VRK2 expression levels in HCC patients. Our work provides novel mechanistic insights into FBXL6-driven HCC metastasis and suggests that targeting the TKT-ROS-mTOR-PD-L1/VRK2 axis is a new paradigm for treating patients with metastatic HCC with high FBXL6 expression.

Elevated expression of WSB2 degrades p53 and activates the IGFBP3-AKT-mTOR-dependent pathway to drive hepatocellular carcinoma

Li Xun,Zhang Cheng-Cheng,Lin Xiao-Tong,Zhang Jie,Zhang Yu-Jun,Yu Hong-Qiang,Liu Ze-Yu,Gong Yi,Zhang Lei-Da,Xie Chuan-Ming 생화학분자생물학회 2024 Experimental and molecular medicine Vol.56 No.-

Dysregulation of wild-type p53 turnover is a key cause of hepatocellular carcinoma (HCC), yet its mechanism remains poorly understood. Here, we report that WD repeat and SOCS box containing protein 2 (WSB2), an E3 ubiquitin ligase, is an independent adverse prognostic factor in HCC patients. WSB2 drives HCC tumorigenesis and lung metastasis in vitro and in vivo. Mechanistically, WSB2 is a new p53 destabilizer that promotes K48-linked p53 polyubiquitination at the Lys291 and Lys292 sites in HCC cells, leading to p53 proteasomal degradation. Degradation of p53 causes IGFBP3-dependent AKT/mTOR signaling activation. Furthermore, WSB2 was found to bind to the p53 tetramerization domain via its SOCS box domain. Targeting mTOR with everolimus, an oral drug, significantly blocked WSB2-triggered HCC tumorigenesis and metastasis in vivo. In clinical samples, high expression of WSB2 was associated with low wild-type p53 expression and high p-mTOR expression. These findings demonstrate that WSB2 is overexpressed and degrades wild-type p53 and then activates the IGFBP3-AKT/mTOR axis, leading to HCC tumorigenesis and lung metastasis, which indicates that targeting mTOR could be a new therapeutic strategy for HCC patients with high WSB2 expression and wild-type p53.