Zanthoxylum bungeanum seed oil inhibits tumorigenesis of human melanoma A375 by regulating CDC25A/CyclinB1/CDK1 signaling pathways in vitro and in vivo

Background:Zanthoxylum bungeanum seed oil (ZBSO) is extracted from the seeds of the traditional Chinese medicine Z. bungeanum Maxim, which has been shown to have anti-melanoma effects. However, the specific mechanisms are not illustrated adequately.Aims: To further investigate the mechanism by which ZBSO inhibits melanoma and to provide scientific evidence to support ZBSO as a potential melanoma therapeutic candidate.Methods: CCK-8 assays were used to detect the function of ZBSO on A375 cells. Based on transcriptomics analyses, Western blot analysis was applied to determine whether an association existed in ZBSO with the CDC25A/CyclinB1/CDK1 signaling pathway. In addition, RT-qPCR and immunohistochemistry analysis validated that ZBSO has the anti-melanoma effect in a nude mouse xenograft model of human melanoma. Then, 16S rRNA sequencing was used to detect the regulation of gut microbes.Results: Cellular assays revealed that ZBSO could inhibit A375 cell viability by regulating the cell cycle pathway. Further studies presented that ZBSO could constrain CDC25A/CyclinB1/CDK1 signaling pathway in vitro and in vivo models of melanoma. ZBSO did not produce toxicity in mice, and significantly reduced tumor volume in xenotransplants of A375 cells. Genome analysis indicated that ZBSO successfully altered specific gut microbes.Conclusion: ZBSO inhibited the growth of A375 cells by regulating CDC25A/cyclinB1/CDK1 signaling pathway both in vitro and in vivo, suggesting that ZBSO may be a novel potential therapeutic agent

Association analyses of East Asian individuals and trans-ancestry analyses with European individuals reveal new loci associated with cholesterol and triglyceride levels

Large-scale meta-analyses of genome-wide association studies (GWAS) have identified >175 loci associated with fasting cholesterol levels, including total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG). With differences in linkage disequilibrium (LD) structure and allele frequencies between ancestry groups, studies in additional large samples may detect new associations. We conducted staged GWAS meta-analyses in up to 69,414 East Asian individuals from 24 studies with participants from Japan, the Philippines, Korea, China, Singapore, and Taiwan. These meta-analyses identified (P < 5 × 10-8) three novel loci associated with HDL-C near CD163-APOBEC1 (P = 7.4 × 10-9), NCOA2 (P = 1.6 × 10-8), and NID2-PTGDR (P = 4.2 × 10-8), and one novel locus associated with TG near WDR11-FGFR2 (P = 2.7 × 10-10). Conditional analyses identified a second signal near CD163-APOBEC1. We then combined results from the East Asian meta-analysis with association results from up to 187,365 European individuals from the Global Lipids Genetics Consortium in a trans-ancestry meta-analysis. This analysis identified (log10Bayes Factor ≥6.1) eight additional novel lipid loci. Among the twelve total loci identified, the index variants at eight loci have demonstrated at least nominal significance with other metabolic traits in prior studies, and two loci exhibited coincident eQTLs (P < 1 × 10-5) in subcutaneous adipose tissue for BPTF and PDGFC. Taken together, these analyses identified multiple novel lipid loci, providing new potential therapeutic targets

Can Carbon Offset Policies Be Effectively Implemented in All Regions of China? An Evolutionary Game Analysis of Decision-Making Dynamics of Local Governments

Carbon offset policies are an effective means of coordinating regional ecological conservation, promoting environmentally friendly economic development, and achieving carbon neutrality; they are being gradually implemented in all regions of China. This study analyzed the decision-making behavior of local governments before and after the introduction of incentive and restraint mechanisms. To this end, it constructed a dynamic evolutionary game model for local governments with a carbon surplus and those with a carbon deficit. The results indicate that it is difficult to implement carbon offset policies between regions without the intervention of the central government. They also show that the effects of different incentive and restraint mechanisms vary significantly. Specifically, a mechanism that targets both carbon surplus and carbon deficit local governments and a unilateral mechanism that targets only carbon deficit local governments are shown to be effective. Finally, the results indicate that the implementation costs of incentive and restraint mechanisms differ, and their implementation intensity affects the time required for carbon offset policies to be rolled out in all regions. Based on these findings, we propose policy recommendations for promoting the implementation of carbon offset policies in all regions of China and alleviating carbon emission pressure

Production-Use Water Pricing and Corporate Water Use in China: An Evolutionary Game Theory Model

Decisions related to pricing production-use water are a critical issue that local governments in China are facing. Its significance has increased in recent years, as a serious corporate water-supply shortage has surfaced with rapid economic development and urbanization. Different from developed countries, the pricing of production-use water is a complex issue in China that involves the distribution of benefits among local governments, water-supply companies, and water-consuming companies, where the overall balance is affected by every slight adjustment. Based on the evolutionary game theory, this study constructs an evolutionary game model involving water-supply companies and water-consuming companies with a systematic analysis of the interaction process between the policy formulation related to water pricing by water-supply companies and the decision making related to water consumption by water-consuming companies. The research finds that the difficulty of balancing corporate financial benefits and public water conservation benefits has led to the complexity of water pricing. Moreover, raising water prices will not necessarily cause companies to save water, but it will increase the production cost of the entire economy. This is the direct cause of low water prices, implemented by water-supply companies, in many regions of China

Detection of a new emerging strain of rabbit haemorrhagic disease virus 2 (GI.2) in China

In May 2020, an outbreak of rabbit haemorrhagic disease 2 (RHD2) caused by the rabbit haemorrhagic disease virus 2 (RHDV2, GI.2) occurred in Sichuan, China. The acute onset and short disease course resulted in rabbit mortality as high as 42.86%. Currently, basic research on the aetiology and genetic characteristics of GI.2 is lacking in China

<i>PEP4</i>-Allele Modification Provides an Industrial Brewing Yeast with Malate Stress Tolerance

Acid stress is a challenging condition that yeast cells must overcome during fermentation. Enhancing the inherent tolerance of industrial Saccharomyces cerevisiae to organic acid stresses is crucial for increasing fermentation efficiency and reducing economic costs. In a previous study, we constructed a Saccharomyces cerevisiae strain SWY85S with improved tolerance to citric acid stress by modifying the second PEP4-allele. Malic acid is a dominant organic acid in grapefruit, which forms the acidic constituents of wine fermentation mash and finished products. We investigated the malic acid stress tolerance of the strain SWY85S in comparison with that of a strain with one PEP4-allele disrupted and the wild-type strain in this study. Our results revealed that the strain SWY85S demonstrated greater tolerance of malic acid stress, regardless of whether it was cultured with adequate nutrient supplies or under amino acid starvation. Moreover, the strain SWY85S performed remarkably in converting glucose to ethanol during fermentation under malic acid stress. This study provides insights into the role of a vacuolar PEP4-allele coding product in response to environmental stress and the physiological mechanism of yeast to withstand organic acid stress

Generation and characterization of a highly effective protein substrate for analysis of FLT3 activity

<p>Abstract</p> <p>Background</p> <p>Gain-of-function mutations of tyrosine kinase FLT3 are frequently found in acute myeloid leukemia (AML). This has made FLT3 an important marker for disease diagnosis and a highly attractive target for therapeutic drug development. This study is intended to generate a sensitive substrate for assays of the FLT3 enzymatic activity.</p> <p>Methods</p> <p>We expressed in <it>Escherichia coli</it> cells a glutathione S-transferase (GST) fusion protein designated GST-FLT3S, which contains a peptide sequence derived from an autophosphorylation site of FLT3. The protein was used to analyze tyrosine kinase activity of baculovirus-expressed FLT3 and crude cell extracts of bone marrow cells from AML patients. It was also employed to perform FLT3 kinase assays for FLT3 inhibitor screening.</p> <p>Results</p> <p>GST-FLT3S in solution or on beads was strongly phosphorylated by recombinant proteins carrying the catalytic domain of wild type FLT3 and FLT3D835 mutants, with the latter exhibiting much higher activity and efficiency. GST-FLT3S was also able to detect elevated tyrosine kinase activity in bone marrow cell extracts from AML patients. A small-scale inhibitor screening led to identification of several potent inhibitors of wild type and mutant forms of FLT3.</p> <p>Conclusions</p> <p>GST-FLT3S is a sensitive protein substrate for FLT3 assays. It may find applications in diagnosis of diseases related to abnormal FLT3 activity and in inhibitor screening for drug development.</p

Efficacy of fresh frozen plasma transfusion in decompensated cirrhosis patients with coagulopathy admitted to ICU: a retrospective cohort study from MIMIC-IV database

Abstract We aimed to explore the association between FFP transfusion and outcomes of DC patients with significant coagulopathy. A total of 693 DC patients with significant coagulopathy were analyzed with 233 patients per group after propensity score matching (PSM). Patients who received FFP transfusion were matched with those receiving conventional therapy via PSM. Regression analysis showed FFP transfusion had no benefit in 30-day (HR: 1.08, 95% CI 0.83–1.4), 90-day (HR: 1.03, 95% CI 0.80–1.31) and in-hospital(HR: 1.30, 95% CI 0.90–1.89) mortality, associated with increased risk of liver failure (OR: 3.00, 95% CI 1.78–5.07), kidney failure (OR: 1.90, 95% CI 1.13–3.18), coagulation failure (OR: 2.55, 95% CI 1.52–4.27), respiratory failure (OR: 1.76, 95% CI 1.15–2.69), and circulatory failure (OR: 2.15, 95% CI 1.27–3.64), and even associated with prolonged the LOS ICU (β: 2.61, 95% CI 1.59–3.62) and LOS hospital (β: 6.59, 95% CI 2.62–10.57). In sensitivity analysis, multivariate analysis (HR: 1.09, 95%CI 0.86, 1.38), IPTW (HR: 1.11, 95%CI 0.95–1.29) and CAPS (HR: 1.09, 95% CI 0.86–1.38) showed FFP transfusion had no beneficial effect on the 30-day mortality. Smooth curve fitting demonstrated the risk of liver failure, kidney failure and circulatory failure increased by 3%, 2% and 2% respectively, for each 1 ml/kg increase in FFP transfusion. We found there was no significant difference of CLIF-SOFA and MELD score between the two group on day 0, 3, 7, 14. Compared with the conventional group, INR, APTT, and TBIL in the FFP transfusion group significantly increased, while PaO2/FiO2 significantly decreased within 14 days. In conclusion, FFP transfusion had no beneficial effect on the 30-day, 90-day, in-hospital mortality, was associated with prolonged the LOS ICU and LOS hospital, and the increased risk of liver failure, kidney failure, coagulation failure, respiratory failure and circulatory failure events. However, large, multi-center, randomized controlled trials, prospective cohort studies and external validation are still needed to verify the efficacy of FFP transfusion in the future

Tyrosine kinase inhibitors targeting FLT3 in the treatment of acute myeloid leukemia

Acute myeloid leukemia (AML) is a cancer of the myeloid lineage of blood cells. Although significant progress has been made in treating many types of cancers during recent years, AML remains a deadly disease with survival rate lagging behind other blood cancers. A combination of toxic chemotherapies has been the standard AML treatment for more than 40 years. With intensive efforts to define the pathogenesis of AML, novel therapeutic drugs targeting key molecular defects in AML are being developed. Mutated in nearly 30% of AML, FMS-like tyrosine kinase 3 (FLT3) represents one of the most attractive targets. FLT3 mutants resulted from either internal tandem duplication (ITD) or point mutations possess enhanced kinase activity and cause constitutive activation of signaling. To date, several small molecule inhibitors of FLT3 have been developed but their clinical efficacy is limited due to a lack of potency and the generation of drug resistance. Therefore, next-generation FLT3 inhibitors overcoming these limitations are urgently in need. This review focuses on the pathological role of mutant FLT3 in the development of AML, the current status of FLT3 inhibitor development, and mechanisms underlining the development of resistance to existing FLT3 inhibitors