The therapeutic effect of wasp venom (Vespa magnifica, Smith) and its effective part on rheumatoid arthritis fibroblast-like synoviocytes through modulating inflammation, redox homeostasis and ferroptosis.

ETHNOPHARMACOLOGICAL RELEVANCE: Rheumatoid arthritis (RA) is a chronic inflammatory disease that is related to the aberrant proliferation of fibroblast-like synoviocytes (FLS). Wasp venom (WV, Vespa magnifica, Smith), an insect secretion, has been used to treat RA in Chinese Jingpo national minority's ancient prescription. However, the potential mechanisms haven't been clarified. AIM OF THE STUDY: The purposes of this paper were two-fold. First, to investigate which was the best anti-RA effective part of WV-I (molecular weight less than 3 kDa), WV-II (molecular weight 3-10 kDa) and WV-III (molecular weight more than 10 kDa) that were separated from WV. Second, to explore the underlying molecular mechanism of WV and WV-II that was best effective part in RA. MATERIALS AND METHODS: The wasps were electrically stimulated and the secretions were collected. WV-I, WV-II and WV-III were acquired by ultracentrifuge method according to molecular weight. Next, WV, WV-I, WV-II and WV-III were identified by HPLC. Functional annotation and pathway analysis of WV used to bioinformatics analysis. RNA-seq analyses were constructed to identify differentially expressed genes (DEGs). GO and KEGG pathway analyses were performed by Metascape database. STRING was used to analyze the PPI network from DEGs. Next, PPI network was visualized using Cytoscape that based on MCODE. The pivotal genes of PPI network and MCODE analysis were verified by qRT-PCR. Subsequently, MH7A cells were performed by MTT assay to evaluate the ability of inhibiting cell proliferation. Luciferase activity assay was conducted in HepG2/STAT1 or HepG2/STAT3 cells to assess STAT1/3 sensitivity of WV, WV-I, WV-II and WV-III. Additionally, interleukin (IL)-1ß and IL-6 expression levels were detected by ELISA kits. Intracellular thioredoxin reductase (TrxR) enzyme was evaluated by TrxR activity assay kit. ROS levels, lipid ROS levels and Mitochondrial membrane potential (MMP) were assessed by fluorescence probe. Cell apoptosis and MMP were measured by using flow cytometry. Furthermore, the key proteins of JAK/STAT signaling pathway, protein levels of TrxR and glutathione peroxidase 4 axis (GPX4) were examined by Western blotting assay. RESULTS: RNA-sequencing analysis of WV displayed be related to oxidation-reduction, inflammation and apoptosis. The data displayed that WV, WV-II and WV-III inhibited significantly cells proliferation in human MH7A cell line compared to WV-I treatment group, but WV-III had no significant suppressive effect on luciferase activity of STAT3 compared with IL-6-induced group. Combined with earlier reports that WV-III contained major allergens, we selected WV and WV-II further to study the mechanism of anti-RA. In addition, WV and WV-II decreased the level of IL-1ß and IL-6 in TNF-α-induced MH7A cells via inactivating of JAK/STAT signaling pathway. On the other hand, WV and WV-II down-regulated the TrxR activity to produce ROS and induce cell apoptosis. Furthermore, WV and WV-II could accumulate lipid ROS to induce GPX4-mediated ferroptosis. CONCLUSIONS: Taken together, the experimental results revealed that WV and WV-II were potential therapeutic agents for RA through modulating JAK/STAT signaling pathways, redox homeostasis and ferroptosis in MH7A cells. Of note, WV-II was an effective part and the predominant active monomer in WV-II will be further explored in the future.

Design of a mutation-integrated trimeric RBD with broad protection against SARS-CoV-2.

The continuous emergence of SARS-CoV-2 variants highlights the need of developing vaccines with broad protection. Here, according to the immune-escape capability and evolutionary convergence, the representative SARS-CoV-2 strains carrying the hotspot mutations were selected. Then, guided by structural and computational analyses, we present a mutation-integrated trimeric form of spike receptor-binding domain (mutI-tri-RBD) as a broadly protective vaccine candidate, which combined heterologous RBDs from different representative strains into a hybrid immunogen and integrated immune-escape hotspots into a single antigen. When compared with a homo-tri-RBD vaccine candidate in the stage of phase II trial, of which all three RBDs are derived from the SARS-CoV-2 prototype strain, mutI-tri-RBD induced significantly higher neutralizing antibody titers against the Delta and Beta variants, and maintained a similar immune response against the prototype strain. Pseudo-virus neutralization assay demonstrated that mutI-tri-RBD also induced broadly strong neutralizing activities against all tested 23 SARS-CoV-2 variants. The in vivo protective capability of mutI-tri-RBD was further validated in hACE2-transgenic mice challenged by the live virus, and the results showed that mutI-tri-RBD provided potent protection not only against the SARS-CoV-2 prototype strain but also against the Delta and Beta variants.

FOXM1-Dependent Transcriptional Regulation of EZH2 Induces Proliferation and Progression in Prostate Cancer.

BACKGROUND: Prostate cancer is one of the most commonly diagnosed cancers and one of the most common causes of cancer-related deaths among men worldwide. Patients who are diagnosed with localized prostate cancer and treated with radical prostatectomy often respond well to therapy. The current standard therapy for prostate cancer involves maximal surgical resection, followed by radiotherapy and chemotherapy. Clarifying the molecular mechanism of tumor proliferation and recurrence becomes more and more important for clinical therapies of prostate cancer. METHODS: Quantitative Real-Time PCR and Western-blot were used in the detection of mRNA and protein expression. Lentivirus infection was used to overexpress or knockdown the target gene. Flow cytometry analysis was performed to test protein expression and apoptosis level. Immunohistochemistry was used to identify protein expression in tissue. Statistical differences between the two groups are evaluated by two-tailed t-tests. The comparison among multiple groups is performed by one-way Analysis of Variance (ANOVA) followed by Dunnett's posttest. The statistical significance of the Kaplan-Meier survival plot is determined by log-rank analysis. RESULTS: In this study, we identified that FOXM1 expression was significantly enriched in prostate cancer compared with normal tissue. Additionally, FOXM1 was functionally required for tumor proliferation and its expression was associated with poor prognosis in prostate cancer patients. Mechanically, FOXM1-dependent regulation of EZH2 is essential for proliferation and progression in prostate cancer. CONCLUSION: Taken together, our data suggest that oncogenic transcription factor FoxM1 is up-regulated in prostate cancer, suggesting that the growth of cancer cells may depend on FOXM1 activity. FOXM1 may serve as a clinical prognostic factor and a therapeutic target for prostate cancer.

BUB1B Promotes Proliferation of Prostate Cancer via Transcriptional Regulation of MELK.

BACKGROUND: Prostate cancer remains one of the most common and deadliest forms of cancer, generally respond well to radical prostatectomy and associated interventions, up to 30% of individuals will suffer disease relapse. Although BUB1B was found to be essential for cell growth and proliferation, even in several kinds of tumor cells, the specific importance and mechanistic role of BUB1B in prostate cancer remain unclear. METHODS: Quantitative Real-Time PCR and Western-blot were used in the detection of mRNA and protein expression. Lentivirus infection was used to overexpression or knock down the target gene. Flow cytometry analysis was performed to test protein expression and apoptosis level. Immunohistochemistry was used to identify protein expression in tissue. Statistical differences between the two groups are evaluated by two-tailed t-tests. The comparison among multiple groups is performed by one-way Analysis of Variance (ANOVA) followed by Dunnett's posttest. The statistical significance of the Kaplan-Meier survival plot is determined by log-rank analysis. RESULTS: In the present report, we found BUB1B expression to be highly increased in prostate cancer tissues relative to normal controls. We further found BUB1B to be essential for efficient tumor cell proliferation, and to correlate with poorer prostate cancer patient outcomes. From a mechanistic perspective, the ability of BUB1B to regulate MELK was found to be essential for its ability to promote prostate cancer cell proliferation. CONCLUSION: Altogether, our data suggest that BUB1B is up-regulated in prostate cancer, suggesting that the growth of cancer cells may depend on BUB1B-dependent regulation of MELK transcription. BUB1B may serve as a clinical prognostic factor and a druggable target for prostate cancer.

Coronary CT Angiography Using Low Iodine Delivery Rate and Tube Voltage Determined by Body Mass Index: Superiority in Clinical Practice.

To explore the feasibility and superiority of iodine delivery rate (IDR) and tube voltage determined by patients' body mass index (BMI) in coronary CT angiography (CCTA), a total of 1567 patients undertaking CCTA during Feb. and Dec. 2016 were enrolled and divided into two groups. In the control group, the IDR and tube voltage were fixed, while in the experimental group, the IDR and tube voltage were determined by patients' BMI. The volume of iodinated contrast media (ICM), extravasation rate, extravasation volume, extravasation recovery interval, incidence rate of adverse reactions, effective dose (ED) and image quality of the two groups were compared. The experiments demonstrated that the ICM volume, extravasation rate, extravasation volume, extravasation recovery interval, incidence of adverse reactions and ED were lower or shorter in the experimental group than in the control group, and the differences were statistically significant (all P<0.05). However, there were no significant differences in the mean CT value, image noise, signal to noise ratio and contrast to noise ratio between the two groups (all P<0.05), which were consistent with the diagnosticians' subjective evaluation outcomes. Our findings suggested that in CCTA, it is feasible to determine the IDR and tube voltage based on patients' BMI; low tube voltage and IDR are superior to the fixed tube voltage and IDR and are worthy of clinical promotion.

Deterministic distribution of four-photon Dicke state over an arbitrary collective-noise channel with cross-Kerr nonlinearity.

We present two deterministic quantum entanglement distribution protocols for a four-photon Dicke polarization entangled state resorting to the frequency and spatial degrees of freedom, which are immune to an arbitrary collective-noise channel. Both of the protocols adopt the X homodyne measurement based on the cross-Kerr nonlinearity to complete the task of the single-photon detection with nearly unit probability in principle. After the four receivers share the photons, they add some local unitary operations to obtain a standard four-photon Dicke polarization entangled state.

[Responses of soybean cultivar Dongsheng-1 to different O3 concentrations in northeast China].

Soybean cultivar Dongsheng No. 1 [Glycine max (L.) Mer.] was exposed to charcoal-filtered air (CFA), non-filtered air (NFA) and non-filtered air with ozone addition (NFA + O3) in nine open-top chambers. Individual yield and yield components at maturity, C, N concentration in leaf and seed, gas exchange, chlorophyll a fluorescence and pigments content at the full bloom stage were measured with an AOT40 value of 10.6 microL x L(-1) x h during the growing season. Compared to CFA, NFA reduced individual yield and 100-seed weight by 4.5% and 4% respectivley, while NFA + O3 treatment significantly reduced each of them by 34% and 18%. However, plant height, node numbers of main stem, pods per plant and number of seeds per pod remained unchanged by O3 addition. Leaf C, N concentrations at the seed filling stage under NFA + O3 also significantly increased by 3% and 26%, respectively, while the CN ratio significantly decreased by 18%. Moreover, compared to CFA and NFA, NFA + O3 caused significant reductions in the photosynthetic parameters at the full bloom stage, e.g. significant declines in net photosynthetic rates, stomatal conductance, water use efficiency, fluorescence parameters of F'(v)/F'(m) and phi(PS II). It is proposed that lower photosynthetic rates, reduced photochemical efficiency in PS II and the decline in 100-seed weight might be the main reasons contributing to the lower individual yield of soybean plant by elevated O3.

Effects of elevated atmospheric CO2 and O3 on Hill activity and Ca2+/Mg2+-ATPase activity of Pinus tabulaeformis Carr.

The main photo-physiological characteristics of Pinus tabulaeformis Carr. were analyzed in open-top chambers under elevated carbon dioxide and ozone concentrations. The results indicated that the leaves net photosynthetic rates (p < 0.05), Hill activity, Ca2+/Mg2+-ATPase activity, soluble sugar and starch contents all increased under elevated carbon dioxide concentration in whole growing season. While under elevated ozone concentration, the leaves net photosynthetic rates, Hill activity, Ca2+/Mg2+-ATPase activity, soluble sugar and starch contents all decreased. Under elevated carbon dioxide and ozone concentration, the leaves net photosynthetic rates, Hill activity, soluble sugar and starch contents all increased, but Ca2+-ATPase activity increased during the earlier growing season, decreased in later growing season, while Mg2+-ATPase activity responded contrarily.