Design, Synthesis, and Biological Activity of Novel Triketone-Containing Phenoxy Nicotinyl Inhibitors of HPPD.

4-Hydroxyphenylpyruvate dioxygenase (HPPD) is a crucial target enzyme in albino herbicides. The inhibition of HPPD activity interferes with the synthesis of carotenoids, blocking photosynthesis and resulting in bleaching and necrosis. To develop herbicides with excellent activity, a series of 3-hydroxy-2-(6-substituted phenoxynicotinoyl)-2-cyclohexen-1-one derivatives were designed via active substructure combination. The title compounds were characterized via infrared spectroscopy, 1H and 13C nuclear magnetic resonance spectroscopies, and high-resolution mass spectrometry. The structure of compound III-17 was confirmed via single-crystal X-ray diffraction. Preliminary tests demonstrated that some compounds had good herbicidal activity. Crop safety tests revealed that compound III-29 was safer than the commercial herbicide mesotrione in wheat and peanuts. Moreover, the compound exhibited the highest inhibitory activity against Arabidopsis thaliana HPPD (AtHPPD), with a half-maximal inhibitory concentration of 0.19 µM, demonstrating superior activity compared with mesotrione (0.28 µM) in vitro. A three-dimensional quantitative structure-activity relationship study revealed that the introduction of smaller groups to the 5-position of cyclohexanedione and negative charges to the 3-position of the benzene ring enhanced the herbicidal activity. A molecular structure comparison demonstrated that compound III-29 was beneficial to plant absorption and conduction. Molecular docking and molecular dynamics simulations further verified the stability of the complex formed by compound III-29 and AtHPPD. Thus, this study may provide insights into the development of green and efficient herbicides.

Individual ambient ozone exposure during pregnancy and adverse birth outcomes: Exploration of the potentially vulnerable windows.

BACKGROUND: Ambient ozone (O3) exposure during pregnancy might be associated with preterm birth (PTB) and low birth weight (LBW); however, existing evidence remains inconclusive. It is necessary to explore the relationships and potential susceptible periods further. METHODS: To explore the relationship between O3 exposure and adverse birth outcomes, a study using records of 34,122 singleton live births in Beijing between 2016 and 2019 was conducted. The O3 exposure in each gestational week of pregnant women was estimated, and Cox proportional hazard models were used to estimate the hazard ratios (HRs) and corresponding 95% confidence intervals (CIs). Distributed lag nonlinear model (DLNM) incorporated in Cox proportional hazard models were used to explore potential critical windows. RESULTS: An increase of 10 µg/m3 in O3 exposure was associated with a 3.9% (95%CI: 0.6-7.3%) higher risk of PTB. Additionally, this increase in O3 exposure was positively linked to PTB during the 2nd - 7th, 22nd - 29th, and 37th gestational weeks, and LBW during the 2nd - 7th, 24th - 29th, and 37th gestational weeks. CONCLUSIONS: This study demonstrates a positive correlation between O3 exposure and PTB, and identified specific sensitive periods during pregnancy when the risk was higher.

Thermoresponsive Ozone-Enriched Spray Gel for Postsurgical Treatment of Hepatocellular Carcinoma.

Surgical resection of hepatocellular carcinoma suffers from a high recurrence rate. Ozone directly kills tumor cells by generating reactive oxygen species in vitro, but its high reactivity and short half-life severely limit its tumor accumulation and penetration for the treatment of tumors in vivo. Herein, a thermoresponsive ozone-enriched spray gel is developed to suppress the tumor recurrence of hepatocellular carcinoma (Huh-7 tumors). Briefly, a perfluorocarbon nanoemulsion (PFTBA@LIP) consisting of a perfluorotributylamine core and a lipid monolayer is fabricated, which is encapsulated in the thermoresponsive hydrogel. Ozone is then dissolved in the nanoemulsion owing to its high affinity to PFTBA (O3/PFTBA@LIP@Gel), which effectively improves its stability. Of note is that O3/PFTBA@LIP@Gel induces both ferroptosis and apoptosis by regulating the expression of relevant genes (GPX4, ACSL4, CDKN1A, etc.) and inducing considerable lipid peroxidation, which significantly reduces the tumor recurrence of the Huh-7 tumor by spraying the gel in the surgical cavity and prolongs the survival of tumor-bearing mice.

A FRET-Based Ratiometric H2S Sensor for Sensitive Optical Molecular Imaging in Second Near-Infrared Window.

Second near-infrared (NIR-II) window optical molecular imaging kicks off a new revolution in high-quality imaging in vivo, but always suffers from the hurdles of inevitable tissue autofluorescence background and NIR-II probe development. Here, we prepare a Förster resonance energy transfer-based ratiometric NIR-II window hydrogen sulfide (H2S) sensor through the combination of an H2S-responsive NIR-II cyanine dye (acceptor, LET-1055) and an H2S-inert rhodamine hybrid polymethine dye (donor, Rh930). This sensor not only exhibits high sensitivity and selectivity, but also shows rapid reaction kinetics (~20 min) and relatively low limit of detection (~96 nM) toward H2S, allowing in vivo ratiometric NIR-II fluorescence imaging of orthotopic liver and colon tumors and visualization of the drug-induced hepatic H2S fluctuations. Our findings provide the potential for advancing the feasibility of NIR-II activity-based sensing for in vivo clinical diagnosis.

Cyr61 decreases Cytarabine chemosensitivity in acute lymphoblastic leukemia cells via NF-κB pathway activation.

Elevated Cyr61 levels have been reported in various malignancies. Elevation of Cyr61 protein levels contributes to the proliferation, metastasis, and chemotherapy resistance of malignant cells. Previously, it was discovered that Cyr61 is elevated in both the plasma and the bone marrow supernatants of patients with acute lymphoblastic leukemia (ALL), promoting ALL cell survival. However, the role of Cyr61 in the chemotherapeutic resistance of ALL cells remains unknown. The aim of the current study was to investigate the role of Cyr61 in regulating ALL cell chemosensitivity to Ara­C. It was found that Cyr61 is overexpressed in bone marrow mononuclear cells from patients with ALL. Increased Cyr61 effectively decreased Ara­C­induced apoptosis of ALL cells, and its function was blocked by the use of the anti­Cyr61 monoclonal antibody 093G9. Furthermore, Cyr61 increased the level of Bcl­2 in Ara­C­treated ALL cells. Mechanistically, it was shown that Cyr61 affected ALL cell resistance to Ara­C partially via the NF­κB pathway. Taken together, the present study is the first, to the best of our knowledge, to reveal that Cyr61 is involved in ALL cell resistance through the NF­κB pathway. The findings support a functional role for Cyr61 in promoting chemotherapy resistance, suggesting that targeting Cyr61 directly or its relevant effector pathways may improve the clinical responses of patients with ALL.

Marine microalgae bioengineered Schizochytrium sp. meal hydrolysates inhibits acute inflammation.

Bioengineered marine microalgae Schizochytrium sp. is currently used to produce docosahexaenoic acid (DHA). However, following DHA extraction, the remaining protein-rich materials are not well utilized. In this study, we report that marine microalgae bioengineered Schizochytrium sp. hydrolysate (MESH), which exhibits a unique peptide profile as identified by Ultra Performance Liquid Chromatography coupled with Q-TOF mass spectrometry(UPLC/Q-TOF-MS), ameliorated bowel inflammation in mice. In a mouse model of experimentalcolitis induced by dextran sulfate sodium, compared with the control mice, the mice treated with MESH were highly resistant to colitis, as demonstrated by marked reductions in body weight loss, clinical colitis scores, colonic histological damage, and colonic inflammation. Mechanistically, MESH attenuated the induction of pro-inflammatory cytokines and increased the induction of anti-inflammatory cytokines. MESH also promoted the proliferation of colonic crypt stem cells and progenitor cells required for crypt repair. Collectively, these results reveal a previously unrecognized role of MESH as a potential anti-inflammatory treatment for colitis.

[Biological Characteristics and Therapeutic Efficacy of 103 Patients with Acute Erythroleukemia].

OBJECTIVE: To investigate the biological characteristics and therapeutic efficacyt of acute erythroleukemia (AEL,AML-M6). METHODS: Blood cell count, liver function, lactate dehydrogenase level, coagulation, morphology, immunology, cell genetics and molecular biology were retrospectively analyzed in 103 cases of acute erythroleukemia patients admitted in our department from May 2016 to June 2009. The therapeutic efficacy was observed by means of remission rate, relapse rate, relapse-free survival and overall survival. RESULTS: The medians of white blood cells, granulocyte, hemoglobin and platelet were 3.04×109/L, 0.67×109/L, 66 g/L, and 45×109/L,respectively. Nucleated red blood cells were found in the peripheral blood smears from 71.1% of AEL patients. None of the patients showed abnormal coagulation function. Flow cytometry analysis indicated that CD13 (93.5%),CD117(89.1%), HLA-DR(87.0%), and CD34 (80.0%) were highly expressed in AEL, and lymphoid antigens of CD4 (42.9%) and CD7(28.9%) were expressed in partial patients. Karyotype analysis in 82 patients showed 52.4% (43/82) normal karyotype, 41.5% (34/82) abnormal karyotype, and 6.1% (5/82) failed tests. In the 34 cases with abnormal karyotype, there were 14(41.2%) cases with simple chromosomal abnomality and 20(58.8%) cases with complex karyotype. The positive rate of fusion gene accounted for 16.7% in 60 patients, and the gene mutations accounted for 77.8% in 27 patients. Among 103 cases of AEL, 81 cases were treated with chemotherapy, but 66 cases can be used for therapeutic analysis, as a results the total complete remission rate derived from 2 courses of treatment was 45.5% (30/66). The relapse rate was 36.7% (11/30), and the median relapse time was 15.5 months (6.2-50 months). The median survival time of 66 patients for therapeutic analysis was 29 months. The median survival time of CR patients was very significantly longer than that of the non-CR patients(P=0.001). The 5 year survival rate of CR patients was 65%, the median time of relapse-free survival (RFS) was 46.2 months and 3-years RFS was 58%. CONCLUSION: AEL is characterized by the highly expressed CD34 antigen, and complex karyotype. Although AEL has lower CR rate and poor prognosis, CR patients can achieve long-term survival and have good quality of life.

Cyr61 participates in the pathogenesis of acute lymphoblastic leukemia by enhancing cellular survival via the AKT/NF-κB signaling pathway.

Cyr61 (CCN1) is the product of a growth factor-inducible immediate early gene and is involved in cell adhesion, survival, proliferation, and differentiation. Cyr61 is overexpressed in human tumors and is involved in the development of tumors. However, the role that Cyr61 plays in acute lymphoblastic leukemia (ALL) cells remains undetermined. The aim of this study was to identify the role of Cyr61 in regulating ALL cell survival. Here, we found that the level of Cyr61 was increased in the plasma and bone marrow (BM) from ALL patients compared with samples from normal control patients. Furthermore, we observed that Cyr61 could effectively stimulate Jurkat (T ALL cell lines), Nalm-6 (B ALL cell lines), and primary ALL cell survival. Mechanistically, we showed that Cyr61 stimulated ALL cell survival via the AKT/NF-κB signaling pathways and the consequent up-regulation of Bcl-2. Taken together, our study is the first to reveal that Cyr61 is elevated in ALL and promotes cell survival through the AKT/NF-κB pathway by up-regulating Bcl-2. Our findings suggest that Cyr61 plays an important role in the pathogenesis of ALL.

Lentivirus-mediated RNA interference of DC-STAMP expression inhibits the fusion and resorptive activity of human osteoclasts.

Cell-cell fusion is a critical step in osteoclast development, because only after osteoclasts become multinucleated can they efficiently resorb bone. Although recent studies suggest that dendritic cell-specific transmembrane protein (DC-STAMP) may play a key role in the process of fusion of mouse osteoclasts, little information has been available on the role of DC-STAMP in human osteoclasts. In this study, we screened and identified an in vitro-transcribed short-hairpin RNA targeting human DC-STAMP from four candidates and generated a lentivirus vector. Subsequent experiments indicated that this lentiviral transgenic system could effectively transfer into target human osteoclasts, at more than 80 % gene transfer efficiency at multiplicity of infection of 15, and significantly and specifically inhibited DC-STAMP expression at both mRNA and protein levels. We also found that DC-STAMP inhibition by RNAi consequently suppressed fusion and bone resorption of human osteoclasts. In conclusion, these data indicated the lentivirus-mediated RNAi was capable of efficiently suppressing DC-STAMP expression in primary human osteoclasts and inhibiting osteoclastogenesis, demonstrating an essential role of DC-STAMP in the differentiation of human osteoclasts.

[Effect of bcl-2 siRNA on apoptosis of Burkitt's lymphoma cell line CA46].

The aim of this study was to investigate the effect of bcl-2 siRNA on bcl-2 gene expression and apoptosis of lymphoma cell line CA46. A siRNA was designed and synthesized. Then siRNA was transfected into CA46 cells by cationic liposome. At 48 hours after transfection, apoptosis and mitochondria transmembrane potential of CA46 cells were detected by flow cytometry, the expression of bcl-2 mRNA and BCL-2 protein in CA46 cells were detected by RT-PCR and flow cytometry respectively. The results showed that at 48 hours after transfection, apoptosis of CA46 cells occurred, mitochondria transmembrane potential changed. The expression of bcl-2 mRNA and BCL-2 protein in CA46 cells decreased significantly. In conclusion, bcl-2 siRNA depresses the expression of bcl-2 gene in CA46 cells specifically, then changes the mitochondria transmembrane potential, resulting in apoptosis of CA46 cells.