Complement C3a Enhances the Phagocytic Activity of B Cells Through C3aR in a Fish.

The complement system is an important part of the immune system of teleost fish. Besides, teleost B cells possess both phagocytic activity and adaptive humoral immune function, unlike mammalian B1 cells with phagocytic activity and B2 cells specific to adaptive humoral immunity. However, the cross talk between complement system and phagocytic B cells in teleost fish still requires elucidation. Here, we show that, unlike tetrapods with a single C3 gene, nine C3 genes were identified from the grass carp (Ctenopharyngodon idella) genome, named C3.1-C3.9. Expression analysis revealed that C3.1 is the dominant C3 molecule in grass carp, for its expression was significantly higher than that of the other C3 molecules both at the mRNA and protein levels. The C3a fragment of C3.1 (C3a.1) was determined after the conserved C3 convertase cleavage site. Structural analysis revealed that C3a.1 consists of four α-helixes, with the C-terminal region forming a long α-helix, which is the potential functional region. Interestingly, we found that the recombinant GST-C3a.1 protein and the C-terminal α-helix peptide of C3a.1 both could significantly enhance the phagocytic activity of IgM+ B cells. Further study revealed that the C3a receptor (C3aR) was highly expressed in grass carp IgM+ B cells, and the phagocytosis-stimulating activity of C3a.1 could be dramatically inhibited by the anti-C3aR antibodies, indicating that C3a.1 performed the stimulating function through C3aR on IgM+ B cells. Taken together, our study not only uncovered the novel phagocytosis-stimulating activity of C3a, but also increased our knowledge of the cross talk between complement system and phagocytic B cells in teleost fish.

Novel kojic acid derivatives with anti-inflammatory effects from Aspergillus versicolor.

Two novel kojic acid derivatives, kojicones A and B (1 and 2), along with the precursors kojic acid (3) and (2R,4R)-4-hydroxy-5-methoxy-2,4-dimethyl-2- [(2R)-2-methylbutyryloxy]-5-cyclohexen-1,3-dione (4), were isolated from a fungal strain Aspergillus versicolor. Their structures and absolute configurations were accurately confirmed by HRESIMS data, NMR analysis, and electronic circular dichroism (ECD) calculations. Kojicones A and B were the first examples of kojic acid adducts with cyclohexen-1,3-dione possessing unprecedented tricycle skeletons. Compounds 1-3 were found to have inhibition on the NO production of murine RAW 264.7 cells. They can also reduce the mRNA expression of four cytokines (IL-6, IL-1ß, TNF-α, and iNOS) and promote the expression of IL-4 at 20 µM. Moreover, kojic acid (3) could treat the DSS (dextran sulfate sodium)-induced colitis on mice with the effectiveness similar to that of the positive control. The results suggested that kojic acid and its derivatives could be a promising anti-inflammatory source for the medicinal and cosmetic industry.

[Characteristics of temporal-spatial differentiation in landscape pattern vulnerability in Nansihu Lake wetland, China.] / å—å››æ¹–æ¹¿åœ°æ™¯è§‚æ ¼å±€è„†å¼±åº¦çš„æ—¶ç©ºåˆ†å¼‚ç‰¹å¾.

With remote sensing images from 1985, 2000 Lantsat 5 TM and 2015 Lantsat 8 OLI as data sources, we tried to select the suitable research scale and examine the temporal-spatial diffe-rentiation with such scale in the Nansihu Lake wetland by using landscape pattern vulnerability index constructed by sensitivity index and adaptability index, and combined with space statistics such as semivariogram and spatial autocorrelation. The results showed that 1 km × 1 km equidistant grid was the suitable research scale, which could eliminate the influence of spatial heterogeneity induced by random factors. From 1985 to 2015, the landscape pattern vulnerability in the Nansihu Lake wetland deteriorated gradually. The high-risk area of landscape pattern vulnerability dramatically expanded with time. The spatial heterogeneity of landscape pattern vulnerability increased, and the influence of non-structural factors on landscape pattern vulnerability strengthened. Spatial variability affected by spatial autocorrelation slightly weakened. Landscape pattern vulnerability had strong general spatial positive correlation, with the significant form of spatial agglomeration. The positive spatial autocorrelation continued to increase and the phenomenon of spatial concentration was more and more obvious over time. The local autocorrelation mainly based on high-high accumulation zone and low-low accumulation zone had stronger spatial autocorrelation among neighboring space units. The high-high accumulation areas showed the strongest level of significance, and the significant level of low-low accumulation zone increased with time. Natural factors, such as temperature and precipitation, affected water-level and landscape distribution, and thus changed the landscape patterns vulnerability of Nansihu Lake wetland. The dominant driver for the deterioration of landscape patterns vulnerability was human activities, including social economy activity and policy system.

Recent development of transition metal complexes with in vivo antitumor activity.

The often severe side effects displayed by currently used platinum and ruthenium complexes have motivated researchers to design and develop transition metal-based anti-tumor agents with reduced toxicity. Distinct from organic anti-tumor drugs, transition metal complexes possess several properties that render them as promising scaffolds for anti-cancer drug discovery. While a vast number of metal complexes have been synthesized and reported to be promising and potent in vitro anticancer active compounds, fewer have shown efficacy in in vivo models. The demonstration of in vivo potency is an essential step for lead candidates for clinical trials. In this review, we highlight examples of transition metal-based complexes that have shown in vivo anti-tumor activities that have been described in recent years.

A Rhodium(III)-Based Inhibitor of Lysine-Specific Histone Demethylase 1 as an Epigenetic Modulator in Prostate Cancer Cells.

We report herein a novel rhodium(III) complex 1 as a new LSD1 targeting agent and epigenetic modulator. Complex 1 disrupted the interaction of LSD1-H3K4me2 in human prostate carcinoma cells and enhanced the amplification of p21, FOXA2, and BMP2 gene promoters. Complex 1 was selective for LSD1 over other histone demethylases, such as KDM2b, KDM7, and MAO activities, and also showed antiproliferative activity toward human cancer cells. To date, complex 1 is the first metal-based inhibitor of LSD1 activity.

A rhodium(III)-based inhibitor of autotaxin with antiproliferative activity.

BACKGROUND: Cancer of the skin is by far the most common of all cancers. Melanoma accounts for only about 1% of skin cancers but causes a large majority of skin cancer deaths. Autotaxin (ATX), also known as ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2), regulates physiological and pathological functions of lysophosphatidic acid (LPA), and is thus an important therapeutic target. METHODS: We synthesized ten metal-based complexes and a novel cyclometalated rhodium(III) complex 1 was identified as an ATX enzymatic inhibitor using multiple methods, including ATX enzymatic assay, thermal shift assay, western immunoblotting and so on. RESULTS: Protein thermal shift assays showed that 1 increased the melting temperature (Tm) of ATX by 3.5°C. 1 also reduced ATX-LPA mediated downstream survival signal pathway proteins such as ERK and AKT, and inhibited the activation of the transcription factor nuclear factor κB (NF-κB) and signal transducer and activator of transcription 3 (STAT3). 1 also exhibited strong anti-proliferative activity against A2058 melanoma cells (IC50=0.58µM). Structure-activity relationship indicated that both the rhodium(III) center and the auxiliary ligands of complex 1 are important for bioactivity. CONCLUSIONS: 1 represents a promising scaffold for the development of small-molecule ATX inhibitors for anti-tumor applications. To our knowledge, complex 1 is the first metal-based ATX inhibitor reported to date. GENERAL SIGNIFICANCE: Rhodium complexes will have the increased attention in therapeutic and bioanalytical applications.

Antagonizing STAT5B dimerization with an osmium complex.

Targeting STAT5 is an appealing therapeutic strategy for the treatment of hematologic malignancies and inflammation. Here, we present the novel osmium(II) complex 1 as the first metal-based inhibitor of STAT5B dimerization. Complex 1 exhibited superior inhibitory activity against STAT5B DNA binding compared to STAT5A DNA binding. Moreover, 1 repressed STAT5B transcription and blocked STAT5B dimerization via binding to the STAT5B protein, thereby inhibiting STAT5B translocation to the nucleus. Furthermore, 1 was able to selectively inhibit STAT5B phosphorylation without affecting the expression level of STAT5B.