Recent advances of HIF-2α in pulmonary hypertension / 药学学报

Pulmonary hypertension (PH) is a kind of disease characterized by progressive increase of pulmonary vascular resistance and occlusive vascular remodeling. Hypoxic inductive factor-2α (HIF-2α) plays an important role in the abnormal proliferation of pulmonary vascular cells and pulmonary vascular remodeling. This review focuses on the role of HIF-2α in pulmonary hypertension at the cellular and the global level, and candidates targeting HIF-2α for the treatment of pulmonary hypertension, in order to better understand the pathogenesis of PH and find effective treatments.

Treatment of pulmonary hypertension based on inhibition of pulmonary vascular cell proliferation / 药学学报

Pulmonary hypertension is a rapidly progressing disease of the lung vasculature with poor prognosis, ultimately leading to right heart failure and death. The remodeling of small pulmonary arteries represents an important pathological characteristic of pulmonary hypertension. Pulmonary arterial smooth muscle cells (PASMCs) located in the middle layer of pulmonary artery exhibit hyperproliferation and resistance to apoptosis, which is the main initiator of pulmonary vascular remodeling and similar to that seen in tumor cells. In this review we focus on the signaling pathways that play a key role in PASMCs proliferation and the latest research progress on inhibitors targeting cell proliferation pathways to provide a new perspective for the treatment of PH．

Hypoxia inducing factor related genetic adaptation in high-altitude and pharmacological modulation / 药学学报

Adaptation to hypoxia of the plateau environment has been a focus of scientific research in decades. The geographical distributions of such living environment include the Qinghai-Tibet Plateau, Andean Plateau in South America and Ethiopian Plateau. Over the past century, the unique features of physiological adaptation to high-altitude chronic hypoxia have been documented scientifically. The genetic studies of hypoxic adaptation in the past decade have revealed genetic bases of human high-altitude adaptation, with a close relationship to the hypoxia inducible factor (HIF) pathway and hypoxia response elements (HREs). Interestingly, the genetic pattern of adaptation to hypoxia is not the same among the three plateau populations. Tibetan has developed the best high-altitude adaptation, with modification of the HIF pathway as the key genetic element. Due to the wide range of HIF pathways, HIFs could regulate hundreds of downstream genes and are closely related to various diseases such as cancer, inflammation, ischemia, acute organ damage and infection, etc. The treatment researches of these diseases through HIFs-related regulations have led to the development of stabilizers and inhibitors of HIF pathway. We review here the adaptive responses of the three plateau populations to the hypoxic environment, and the genetic mechanism of HIF and HREs in the different ethnic high-altitude populations. Classes of HIF inhibitors, such as PI3K and/or mammalian target of rapamycin (mTOR) inhibitors, DNA-binding inhibitors, histone deacetylase inhibitors, heat-shock protein 90 inhibitors, cardiac glycosides, transcription inhibitors, topoisomerase inhibitors, and HIF activators including 2-OG mimics, Fe2+ chelators, prolyl hydroxylase (PHD) active-site blockers and CUL2 deneddylators have been presented with the drug examples. In addition, the top 3 chemical-disease and chemical-gene (protein) co-occurrences have been presented from the Pubmed literature search. The review could serve as references for research of hypoxia adaptation and HIF-related diseases.

Legionella pneumophila lvgA and Hsp60 gene splicing and the fusion gene expression in E.coli / 南方医科大学学报

<p><b>OBJECTIVE</b>To fuse Legionella virulence gene (lvgA) with heat shock protein 60 gene (Hsp60) by PCR and detect the fusion gene expression in E.coli.</p><p><b>METHODS</b>The fragments of lvgA and Hsp60 genes having matching sequences at their ends to be fused were amplified from the genomic DNA of Legionella pneumophila by PCR, and the PCR products were mixed, denatured, reannealed, so that the strands with matching sequences at their 3' ends overlapped to serve as primers for each other. Extension of this overlap by DNA polymerase produced recombinant products. After amplification with outer primers, sufficient product of the fusion gene was harvested, which was inserted into the prokaryotic expression vector pGEX-4T-1 to construct the prokaryotic expression recombinant plasmid. After identification with restriction enzyme analysis, polymerase chain reaction and nucleotide sequence analysis, the E.coli BL21 containing the recombinant plasmid pGlvgA/Hsp60 was induced with IPTG and the expression of lvgA/Hsp60 was detected by SDS-PAGE and Western blot analysis.</p><p><b>RESULTS</b>The lvgA/Hsp60 fusion gene of 2,292 bp was amplified and the recombinant plasmid pGlvgA/Hsp60 was constructed successfully. A 117-kD GST-lvgA-Hsp60 fusion protein was detected in the E.coli containing the recombinant plasmid.</p><p><b>CONCLUSION</b>The recombinant plasmid for Legionella pneumophila lvgA/Hsp60 fusion gene is constructed successfully and this fusion protein can be expressed in prokaryotic cells efficiently, which make possible the immunological characterization of this fusion gene.</p>