Blocking OLFM4/HIF-1α axis alleviates hypoxia-induced invasion,epithelial–mesenchymal transition,and chemotherapy resistance in non-small-cell lung cancer

Hypoxia is a common biological hallmark of solid cancers, which has been proposed to be associated with oncogenesis and chemotherapy resistance. The purpose of the present study was to investigate the role and underlying mechanisms of olfactomedin 4 (OLFM4) in the hypoxia-induced invasion, epithelial–mesenchymal transition (EMT), and chemotherapy resistance of non-small-cell lung cancer (NSCLC). We observed dramatically upregulated expression of OLFM4 in several NSCLC cell lines, and this effect was more pronounced in A549 and H1299 cells. In addition, our data revealed that OLFM4 expression was remarkably increased in both A549 and H1299 cells under hypoxic microenvironment, accompanied by enhanced levels of hypoxia-inducible factor (HIF)-1α protein. The HIF-1α level was elevated in response to hypoxia, resulting in the regulation of OLFM4. Interestingly, OLFM4 was a positive regulator of hypoxia-driven HIF-1α production. Moreover, depletion of OLFM4 modulated multiple EMT-associated proteins, as evidenced by the enhanced E-cadherin levels along with the diminished expression of N-cadherin and vimentin in response to hypoxia, and thus blocked invasion ability of A549 and H1299 cells following exposure to hypoxia. Furthermore, ablation of OLFM4 accelerated the sensitivity of A549 cells to cisplatin under hypoxic conditions, implying that OLFM4 serves as a key regulator in chemotherapeutic resistance under hypoxia. In conclusion, OLFM4/HIF-1α axis might be a potential therapeutic strategy for NSCLC.     

Heterotrophic carbon metabolism and energy acquisition in Candidatus Thioglobus singularis strain PS1, a member of the SUP05 clade of marine Gammaproteobacteria

A hallmark of the SUP05 clade of marine Gammaproteobacteria is the ability to use energy obtained from reduced inorganic sulfur to fuel autotrophic fixation of carbon using RuBisCo. However, some SUP05 also have the genetic potential for heterotrophic growth, raising questions about the roles of SUP05 in the marine carbon cycle. We used genomic reconstructions, physiological growth experiments and proteomics to characterize central carbon and energy metabolism in Candidatus Thioglobus singularis strain PS1, a representative from the SUP05 clade that has the genetic potential for autotrophy and heterotrophy. Here, we show that the addition of individual organic compounds and 0.2 μm filtered diatom lysate significantly enhanced the growth of this bacterium. This positive growth response to organic substrates, combined with expression of a complete TCA cycle, heterotrophic pathways for carbon assimilation, and methylotrophic pathways for energy conversion demonstrate strain PS1's capacity for heterotrophic growth. Further, our inability to verify the expression of RuBisCO suggests that carbon fixation was not critical for growth. These results highlight the metabolic diversity of the SUP05 clade that harbours both primary producers and consumers of organic carbon in the oceans and expand our understanding of specific pathways of organic matter oxidation by the heterotrophic SUP05.     

Chemically Sulfated Polysaccharides from Agaricus blazei Murill: Synthesis,Characterization and Anti-HIV Activity

AIDS, caused by HIV-1, is one of the most dangerous infectious diseases in the world. Therefore, it is necessary to develop new drugs with more potent bioactivities, less toxicity and higher tolerability for controlling the viral load, particularly by using the raw materials that are widely available. Agaricus blazei Murill (AbM), known in China as jisongrong, is of great importance as a food source and as a health-promoting supplement for immunomodulation. The polysaccharides of AbM exhibit various biological activities, such as regulating cellular immunity and providing anti-oxidative, anti-infective, and anti-inflammatory effects. At present, to our knowledge, no report has explored the chemically sulfated and anti-HIV-1 activity of AbM polysaccharides. Herein, the sulfated AbM polysaccharides with different sulfur contents were prepared by the chlorosulfonic acid-pyridine method. The characteristics of sulfated derivatives were established by the determination of the sulfur content, the relative molecular weight, and the Fourier-transform infrared spectroscopy. The anti-HIV activities of the sulfated AbM polysaccharides were evaluated by CCK-8 and the single-cycle pseudovirus infection (TZM-bl) assay. The sulfated AbM polysaccharides had strong antiviral properties, and the half-maximal inhibitory concentrations approached that of the positive control, azidothymidine. Sulfated modification of AbM polysaccharides can increase their anti-HIV pharmacological activity, which makes them promising alternative candidates as bioactive macromolecules for biomedical applications in HIV/AIDS.     

Structure-activity relationships study of neolamellarin A and its analogues as hypoxia inducible factor-1 (HIF-1) inhibitors

The novel marine pyrrole alkaloid neolamellarin A derived from sponge has been shown to inhibit hypoxia-induced HIF-1 activity. In this work, we designed and synthesized neolamellarin A and its series of derivatives by a convergent synthetic strategy. The HIF-1 inhibitory activity and cytotoxicity of these compounds were evaluated in Hela cells by dual-luciferase reporter gene assay and MTT assay, respectively. The results showed that neolamellarin A 1 (IC₅₀ = 10.8 ± 1.0 μM) and derivative 2b (IC₅₀ = 11.9 ± 3.6 μM) had the best HIF-1 inhibitory activity and low cytotoxicity. Our SAR research focused on the effects of key regions aliphatic carbon chain length, aromatic ring substituents and C-7 substituent on biological activity, providing a basis for the subsequent research on the development of novel pyrrole alkaloids as HIF-1 inhibitors and design of small molecule probes for target protein identification.     

Distribution of alkaline phosphatase genes in cyanobacteria and the role of alkaline phosphatase on the acquisition of phosphorus from dissolved organic phosphorus for cyanobacterial growth

Phosphorus is a vital nutrient for cyanobacterial growth. Aside from dissolved inorganic phosphorus, dissolved organic phosphorus (DOP) is used by cyanobacterial species via the activity of alkaline phosphatase (APase), which likely plays an important role in acquiring phosphorus for algal growth in the same manner as it does in other bacteria. In this work, APase genes phoA, phoD, and phoX were found distributed in the cyanobacterial strains included in the algal genome collection of the NCBI database. PhoX has a wider distribution than the classical phoA and phoD. Furthermore, multiple types of APase genes were simultaneously identified in a single strain or genome. Anabaena flos-aquae FACHB-245 was selected as a typical strain to study the performance of cyanobacteria growing on DOP. In algal growth involving AMP or lecithin, APase regulates the release of phosphorus from DOP as confirmed by the relative quantification of phoD and phoX expression levels. Our results confirmed that the distribution of APase is prevalent in cyanobacteria and thus provides a new insight into the potential role of cyanobacterial APase on phosphorus acquisition in natural environment.     

Reconciling the biogeography of an invader through recent and historic genetic patterns: the case of topmouth gudgeon <Emphasis Type="Italic">Pseudorasbora parva</Emphasis>

The genetic variability and population structure of introduced species in their native range are potentially important determinants of their invasion success, yet data on native populations are often poorly represented in relevant studies. Consequently, to determine the contribution of genetic structuring in the native range of topmouth gudgeon Pseudorasbora parva to their high invasion success in Europe, we used a dataset comprising of 19 native and 11 non-native populations. A total of 666 samples were analysed at 9 polymorphic microsatellite loci and sequenced for 597 bp of mitochondrial DNA. The analysis revealed three distinct lineages in the native range, of which two haplogroups were prevalent in China (100%), with a general split around the Qinling Mountains. Dating of both haplogroups closely matched past geological events. More recently, its distribution has been influenced by fish movements in aquaculture, resulting in gene flow between previously separated populations in Northern and Southern China. Their phylogeography in Europe indicate as few as two introductions events and two dispersal routes. Microsatellite data revealed native populations had higher genetic diversity than those in the invasive range, a contrast to previous studies on P. parva. This study confirms the importance of extensive sampling in both the native and non-native range of invasive species in evaluating the influence of genetic variability on invasion success.     

Bactrocera dorsalis (Hendel) (Diptera: Tephritidae) is not invasive through Asia: It's been there all along

Oriental fruit fly, Bactrocera dorsalis (Hendel), is a highly polyphagous fruit fly which, in the last 15 years, has invaded (with or without establishment) Africa, Europe and North America. As a direct result of these invasions, there is increasing research interest in the invasion history and spread patterns of this fly. A statement being repeatedly used in the B. dorsalis invasion literature is that the species was first identified from Taiwan in 1912 and that it subsequently spread through South‐East and South Asia during the 20th century. This assumption is incorrect and stems from: (a) an incomplete knowledge of B. dorsalis taxonomic history; and (b) a confounding of first taxonomic record with first invasion record. Rather than being first detected in Taiwan in 1912, the first record of oriental fruit fly was from “East India” (India orientali) under the synonymous name of Musca ferruginea by Fabricius in 1794, and in the 1910s, it was known not only from Taiwan, but widely across tropical Asia with records from India, Burma, Bengal, Sri Lanka (as Ceylon), Singapore and Indonesia (multiple islands). The taxonomic literature is very clear that oriental fruit fly has not invaded the rest of Asia from Taiwan since 1912, and this error should not continue to be repeated in the literature.