Fabrication of taxifolin loaded zein-caseinate nanoparticles and its bioavailability in rats

Taxifolin loaded zein-caseinate nanoparticles(TZP)were fabricated by the anti-solvent method and were used as an oral delivery vehicle to improve their bioavailability in the rat.The formulations of TZP were optimized.With mass ratio of 1:1:2 between taxifolin,zein and sodium caseinate,the particle size andζpotential of TZP were(168.74±0.35)nm and−(57.67±0.25)mV,while the encapsulation and loading efficiency of taxifolin were(85.83±0.89)%and(17.11±0.88)%,respectively.After freeze-drying,TZP exhibited excellent redispersibility in water without aggregation.Physicochemical characterization showed that taxifolin existed in amorphous form in TZP and its interaction with the protein was observed.After encapsulating in TZP,the excellent dispersion of taxifolin in water signifi cantly improve its diffusion velocity through a semipermeable membrane.After oral administration,taxifolin and its 5 metabolites were identifi ed in rat plasma by ultra high performance liquid chromatography(UPLC)with quadrupole time-of-flight mass spectrometry(UPLC-QTOF-MS).The dynamic variation of taxifolin and its metabolites in plasma were then quantifi ed by UPLC with a triple-quadrupole typemass spectroscopy(UPLC-QqQ-MS/MS).A pharmacokinetic study showed that the bioavailability of taxifolin increased from 0.35%to 0.52%through TZP fabrication.The plasma concentration of taxifolin glucuronide and methylated taxifolin glucuronide was much higher than taxifolin.Glucuronidation was the dominating metabolism pathway of taxifolin in vivo.

沉默MPZL1调控β-catenin对A549/Tax细胞干性及耐药性的影响

目的探讨髓磷脂蛋白零样蛋白1(MPZL1)沉默后是否通过调控β-catenin表达对A549/Tax耐药性和细胞干性产生影响。方法采用不同浓度阿霉素和紫杉醇处理A549和A549紫杉醇耐药性(A549/Tax)细胞,观察两种细胞的耐药性差异。实时荧光定量聚合酶链式反应(qRT-PCR)和Western blot检测A549和A549/Tax细胞中MPZL1的表达量差异。对A549/Tax细胞沉默或者过表达MPZL1,进一步将细胞分为对照(control)组、短发卡RNA阴性对照(sh-NC)组、MPZL1沉默(sh-MPZL1)组、过表达阴性对照(OE-NC)组、MPZL1过表达(OE-MPZL1)组,运用细胞计数试剂盒8(CCK-8)和平板克隆实验分别检测MPZL1的表达变化对A549/Tax细胞增殖和克隆形成能力的影响。Western blot检测Wnt/β-catenin抑制剂XAV939和激活剂CHIR-99201处理细胞后,不同蛋白的表达变化。结果A549/Tax细胞对阿霉素和紫杉醇的半数抑制浓度(IC 50)较A549细胞明显增加(P<0.01)。MPZL1在A549/Tax中呈更高的表达趋势。MPZL1敲除后A549/Tax对阿霉素和紫杉醇的IC 50分别为2.731 mg/ml和4.939μg/ml,较阴性对照组的4.541 mg/ml和13.55μg/ml降低(P<0.01)。CCK-8和克隆形成实验结果显示,MPZL1敲除抑制肺癌A549/Tax细胞的增殖活力和克隆形成能力(P<0.05);Western blot结果显示,与阴性对照组相比,MPZL1、肿瘤干性相关蛋白(CD44和CD133)、多药耐药蛋白1(MDR1)、肺耐药相关蛋白(LRP)和β-catenin在sh-MPZL1中的表达水平明显减少(P<0.01)。此外,XAV939可抑制MPZL1、CD44、CD133、MDR1、LRP和β-catenin的表达。CHIR-99201处理细胞后部分逆转敲除MPZL1对上述蛋白的抑制作用。结论MPZL1在肺癌A549/Tax细胞中高表达。敲除MPZL1可抑制肿瘤干性和细胞增殖,增强肺癌A549/Tax细胞对阿霉素和紫杉醇的敏感性。

Effect of taxifolin on cold-shock damages in spermatozoa in rabbits

Objective:To investigate the effect of taxifolin added to rabbit semen on freezing-induced cold-shock damages in spermatozoa.Methods:Semen was collected from six adult New Zealand rabbits once a week by artificial vagina.The collected semen was pooled at 38℃ and divided into four equal volumes.They were diluted with 0,50,100 and 200μM taxifolin-containing Tris+egg yolk extender at 38℃ and their temperatures were lowered to 4℃.Following equilibration,semen drawn into 0.25 mL straws were frozen in an automatic semen freezing device and stored in liquid nitrogen container at-196℃.Samples were thawed in 38℃ water for 25 s and the analyses of motility,kinematic parameters,morphological deformities,changes in membrane integrity,mitochondrial membrane potential,dead-live ratio,acrosomal damages and as well as oxidative stress analyses were performed in semen.Results:Addition of 50μM taxifolin significantly improved motility(total,progressive,rapid and static),high mitochondrial membrane potential and the ratios of spermatozoa with acrosomal damage compared to the control group.Compared to the control group,malondialdehyde(MDA)levels in the 50 and 100μM taxifolin groups were significantly lower,while the MDA level was high and viable spermatozoa ratio was low in the 200μM taxifolin group.There were no significant differences between the groups in terms of kinematic parameters,morphological deformities,membrane integrity and antioxidant levels.Conclusions:The low dose of taxifolin(50μM)has a positive effect and the high dose(200μM)has a negative effect.Therefore,it is concluded that the addition of low-dose(50μM)taxifolin to the extenders would be a useful additive in reducing cold-shock damage that occurs during freezing of rabbit semen.

TAX1BP1 and FIP200 orchestrate non-canonical autophagy of p62 aggregates for mouse neural stem cell maintenance

Autophagy plays a pivotal role in diverse biological processes,including the maintenance and differentiation of neural stem cells(NSCs).Interestingly,while complete deletion of Fip200 severely impairs NSC maintenance and differentiation,inhibiting canonical autophagy via deletion of core genes,such as Atg5,Atg16l1,and Atg7,or blockade of canonical interactions between FIP200 and ATG13(designated as FIP200-4A mutant or FIP200 KI)does not produce comparable detrimental effects.This highlights the likely critical involvement of the non-canonical functions of FIP200,the mechanisms of which have remained elusive.Here,utilizing genetic mouse models,we demonstrated that FIP200 mediates non-canonical autophagic degradation of p62/sequestome1,primarily via TAX1BP1 in NSCs.Conditional deletion of Tax1bp1 in fip200hGFAP conditional knock-in(cKI)mice led to NSC deficiency,resembling the fip200hGFAP conditional knockout(cKO)mouse phenotype.Notably,reintroducing wild-type TAX1BP1 not only restored the maintenance of NSCs derived from tax1bp1-knockout fip200hGFAP cKI mice but also led to a marked reduction in p62 aggregate accumulation.Conversely,a TAX1BP1 mutant incapable of binding to FIP200 or NBR1/p62 failed to achieve this restoration.Furthermore,conditional deletion of Tax1bp1 in fip200hGFAP cKO mice exacerbated NSC deficiency and p62 aggregate accumulation compared to fip200hGFAP cKO mice.Collectively,these findings illustrate the essential role of the FIP200-TAX1BP1 axis in mediating the non-canonical autophagic degradation of p62 aggregates towards NSC maintenance and function,presenting novel therapeutic targets for neurodegenerative diseases.

Effect of Property Tax on Optimization and Upgrading of Industrial Structure

China's economic growth and economic development has entered a new stage,and the optimization and upgrading of industrial structure is the core driving force for China to achieve high-quality economic development during the"14 th Five-Year Plan"period.Property tax has a conductive effect on the upgrading of industrial structure.Therefore,from the perspective of property tax and industrial structure adjustment and the relationship between them,this study summarizes the relevant research of domestic and foreign scholars.On the basis of the research,the paper puts forward some relevant policy suggestions on improving China's property tax and promoting the optimization and upgrading of China's industrial structure.

Exploring Corporate Tax Compliance in the Era of Digital Tax Collection and Administration:Insights from the“Golden Tax Phase Four”Project

This article primarily examines the current state of tax collection and management,alongside other associated issues.It integrates insights from China’s“14th Five-Year Plan”and anticipates the imminent implementation of the“Golden Tax Phase Four.”With this backdrop,the article offers recommendations for advancing the reform of the tax collection and management system,fostering the development of intelligent taxation,and accelerating the modernization of tax collection and management in China.

Cumulative Effect of Debt and Tax on Firm Value:Optimal Capital Structure Theories in the Light of EMM

We have shown that cornerstone articles considering effects of corporate debt on the firm value and constituting the basis of the trade-off theory of capital structure are wrong.Their main mistake is in ignoring the business securing expenses(BSEs).In the framework of the extended Merton model(EMM),we consider the cumulative effect of debt and corporate taxes on the firm value and its survival,in other words,we revisit Modigliani-Miller Proposition 3(MMP3).We show that(1)debt affects the firm value and its survival,(2)this effect is negative,diminishing the firm value and its chances to survive,(3)the pressure increases as the debt grows provoking the firm’s default,(4)the main factors depressing the levered firm are its debt payments added to the BSEs of the identical unlevered firm and the length of debt maturity,(5)corporate taxes cause development of positive skewness in the asset distribution,but do not affect the location of this distribution in the asset axis.The presented model helps estimate the consequences of choosing this or that level of debt in the presence of corporate taxes and can make a useful instrument for practicing financial managers.

Research on Tax Risk Regulation and Strategic Management in the Context of Big Data

With the rapid development of big data,big data has been more and more applied in all walks of life.Under the big data environment,massive big data provides convenience for regional tax risk control and strategic decision-making but also increases the difficulty of data supervision and management.By analyzing the status quo of big data and tax risk management,this paper finds many problems and puts forward effective countermeasures for tax risk supervision and strategic management by using big data.

Taxation Models and Improvement Proposals for Personal Income Tax in the Sharing Economy

As an innovative economic model,the sharing economy has seen rapid growth globally in recent years.It has not only brought a profound impact on traditional economies but also injected new vitality and momentum into the sustainable development of the social economy.However,for the sharing economy,the process of collecting personal income tax is facing several issues,such as the ambiguity of tax policies regarding personal income,challenges in identifying taxpayers,and difficulties in defining income.To achieve the fairness and efficiency of personal income tax collection in the sharing economy,this study proposes optimized regulatory mechanisms and conducts in-depth discussions on the adjustment of personal income tax policies,innovation in tax management technology,and improvement in the quality of personal income tax services.

Analysis and Innovative Strategies of Tax Preferential Policies to Promote the Sustainable Development of Small-Scale Individual Businesses

This study conducted an in-depth analysis of the current tax preferential policies for small-scale individual businesses and compared them with similar policies both domestically and internationally,aiming to reveal the advantages and disadvantages of the current system.After examining the impact of these tax preferential policies on the economic status of individual business owners and the broader social economy,this article proposes a set of innovative tax preferential strategies based on theoretical foundations.By developing these innovative strategies and clarifying their implementation paths,the aim is to promote the sustainable and healthy development of small-scale individual businesses,thereby fostering comprehensive socio-economic progress.The conclusion of this study not only summarizes policy recommendations with practical significance but also provides theoretical support for the optimization and innovation of future related systems.

Consideration of the Application and Risk Prevention of VAT Tax Rebate Policy for Construction Enterprises at the End of the Period

The“Announcement on Deepening the Value-Added Tax Reform”clearly outlines the preferential policy regarding incremental retention tax rebates.With the advancement of value-added tax(VAT)reform and the improvement of VAT legislation in China,VAT tax planning for construction enterprises,particularly related to retained tax credits,has become routine.This paper,focusing on the characteristics of construction enterprises,analyzes VAT retained tax credits at the end of the period,the status of tax refunds,practical issues,and related processes,and offers suggestions for policy application and risk prevention.

Taxifolin和EGCG对IFN-γ诱导的HaCaT细胞iNOS表达的影响

紫杉叶素和L-(-)-表没食子儿茶素没食子酸酯(EGCG)均属于类黄酮物质,具有抗炎活性.本文采用激光共聚焦显微镜和流式细胞仪检测SMT(iNOS抑制子)对800U/mL IFN-γ诱导的iNOS表达的影响,结果发现人表皮角质细胞HaCaT中800U/mL IFN-γ诱导iNOS蛋白的表达显著提高,同时SMT可以抑制IFN-γ诱导iNOS蛋白的表达.分别用40μg/mL紫杉叶素和40μg/mL EGCG预处理HaCaT细胞,然后用800U/mL IFN-γ诱导HaCaT细胞,结果发现紫杉叶素和EGCG均可以抑制iNOS蛋白的表达,并且EGCG的效果更好.因此,单体类黄酮紫杉叶素和EGCG可用于皮肤炎症的治疗,并在相同浓度下EGCG效果更强.

EWS Knockdown and Taxifolin Treatment Induced Differentiation and Removed DNA Methylation from p53 Promoter to Promote Expression of Puma and Noxa for Apoptosis in Ewing’s Sarcoma

Ewing’s sarcoma is a pediatric tumor that mainly occurs in soft tissues and bones. Malignant characteristics of Ewing’s sarcoma are correlated with expression of EWS oncogene. We achieved knockdown of EWS expression using a plasmid vector encoding EWS short hairpin RNA (shRNA) to increase anti-tumor mechanisms of taxifolin (TFL), a new flavonoid, in human Ewing’s sarcoma cells in culture and animal models. Immunofluorescence microscopy and flow cytometric analysis showed high expression of EWS in human Ewing’s sarcoma SK-N-MC and RD-ES cell lines. EWS shRNA plus TFL inhibited 80% cell viability and caused the highest decreases in EWS expression at mRNA and protein levels in both cell lines. Knockdown of EWS expression induced morphological features of differentiation. EWS shRNA plus TFL caused more alterations in molecular markers of differentiation than either agent alone. EWS shRNA plus TFL caused the highest decreases in cell migration with inhibition of survival, angiogenic and invasive factors. Knockdown of EWS expression was associated with removal of DNA methylation from p53 promoter, promoting expression of p53, Puma, and Noxa. EWS shRNA plus TFL induced the highest amounts of apoptosis with activation of extrinsic and intrinsic pathways in both cell lines in culture. EWS shRNA plus TFL also inhibited growth of Ewing’s sarcoma tumors in animal models due to inhibition of differentiation inhibitors and angiogenic and invasive factors and also induction of activation of caspase-3 for apoptosis. Collectively, knockdown of EWS expression increased various anti-tumor mechanisms of TFL in human Ewing’s sarcoma in cell culture and animal models.

Taxifolin attenuates ischemia-reperfusion induced oxidative ovarian damage in rats

Objective:To investigate preventive effects of taxifolin on ischemia-reperfusion induced oxidative ovarian damage in rats.Methods:A total of 18 female Wistar albino rats were randomly and equally divided into three groups:the sham group,the ovarian ischemia reperfusion group,and the 50 mg/kg taxifolin+ovarian ischemia reperfusion group.The ovarian ischemia reperfusion and taxifolin+ovarian ischemia reperfusion groups were exposed to ischemia for 2 h and then followed by two-hour reperfusion protocol.Biochemical and histopathologic examinations were performed on the extracted ovaries.Results:Levels of malondialdehyde and cyclooxygenase-2 were increased,while reduced-glutathione and cyclooxygenase-1 were decreased in the ovarian ischemia reperfusion group.However,these values were reversed in the taxifolin+ovarian ischemia reperfusion group.Similarly,the number of primordial and developing follicules decreased in the ovarian ischemia reperfusion group,while they were within normal range in the taxifolin+ovarian ischemia reperfusion group.Conclusions:Ischemia followed by reperfusion leads to oxidative stress-related ovarian injury,and taxifolin may be useful for protecting ovarian tissue from such injury.

Impact of taxes on the 2030 Agenda for Sustainable Development:Evidence from Organization for Economic Cooperation and Development(OECD)countries

Multiple ecological and socioeconomic problems have occurred worldwide,raising the awareness of sustainability.This study aims to examine the impact of taxes on Sustainable Development Goals(SDGs)in the context of Organization for Economic Co-operation and Development(OECD)countries.This research used effective average tax(EAT),tax on personal income(TPI),tax on corporate profits(TCP),and tax on goods and services(TGS)as the variables of taxes,and employed secondary data from 38 OECD countries covering 2000–2021.The study also used Breusch-Pagan Lagrange Multiplier(LM),Pesaran Scaled LM,Bias-Corrected Scaled LM,and Pesaran Cross-sectional dependence(CSD)tests to analyze the existence of crosssectional dependency.Then,we established the stationarity of variables through second-generation panel unit root tests(Cross-sectional Augmented Dickey-Fuller(CADF)and Cross-sectional Im,Pesaran,and Shin(CIPS)),and confirmed the long-run cointegration of the variables by using secondgeneration panel cointegration test(Westerlund cointegration test).The results showed that EAT,TPI,TCP,and TGS are positively associated with SDGs.However,the change in TPI has a smaller effect on SDGs than the change in EAT or TCP or TGS.The result of panel causality indicated that EAT,TPI,and TGS have a unidirectional causal relationship with SDGs.The study also found that TCP has a bi-directional causal relationship with SDGs.Moreover,the finding indicated that the OECD countries need to focus on tax policies to achieve the 2030 Agenda for Sustainable Development.This study is based on the theory of optimal taxation(TOT),which suggests that tax systems should be designed to maximize social welfare.Finally,we suggests the importance of taking a comprehensive approach for the managers and policy-makers when analyzing the impact of taxes on SDGs.

Dynamic decision and its complex dynamics analysis of low-carbon supply chain considering risk-aversion under carbon tax policy

This study establishes a low-carbon supply chain game model under the centralized decision situation and the decentralized decision situation considering the manufacturer risk-aversion behavior, and discusses the influence of the manufacturer risk-aversion behavior on the optimal decision, profit, coordination, and complex dynamics of the supply chain. We find that comparing with the risk-neutral decentralized decision, the increase of manufacturer's risk tolerance attitude can narrow the gap between the supply chain profit and the centralized decision, but it will further reduce the carbon emission reduction level. The increase of risk tolerance of the manufacturer and carbon tax will narrow the stable region of the system. Under this situation, the manufacturer should carefully adjust parameters to prevent the system from losing stability,especially the adjustment parameters for carbon emission reduction level. When the system is in a chaotic state, the increase of carbon tax rate makes the system show more complex dynamic characteristics. Under the chaotic state, it is difficult for the manufacturer to make correct price decision and carbon emission reduction strategy for the next period, which damages its profit, but increases the profit of the retailer and the supply chain. Finally, the carbon emission reduction cost-sharing contract is proposed to improve the carbon emission reduction level and the supply chain efficiency, achieving Pareto improvement. The stability region of the system is larger than that in the centralized decision situation, but the increase of the cost sharing coefficient will reduce the stability of the system in the decentralized decision-making situation.

A Multi-Module Machine Learning Approach to Detect Tax Fraud

Tax fraud is one of the substantial issues affecting governments around the world.It is defined as the intentional alteration of information provided on a tax return to reduce someone’s tax liability.This is done by either reducing sales or increasing purchases.According to recent studies,governments lose over$500 billion annually due to tax fraud.A loss of this magnitude motivates tax authorities worldwide to implement efficient fraud detection strategies.Most of the work done in tax fraud using machine learning is centered on supervised models.A significant drawback of this approach is that it requires tax returns that have been previously audited,which constitutes a small percentage of the data.Other strategies focus on using unsupervised models that utilize the whole data when they search for patterns,though ignore whether the tax returns are fraudulent or not.Therefore,unsupervised models are limited in their usefulness if they are used independently to detect tax fraud.The work done in this paper focuses on addressing such limitations by proposing a fraud detection framework that utilizes supervised and unsupervised models to exploit the entire set of tax returns.The framework consists of four modules:A supervised module,which utilizes a tree-based model to extract knowledge from the data;an unsupervised module,which calculates anomaly scores;a behavioral module,which assigns a compliance score for each taxpayer;and a prediction module,which utilizes the output of the previous modules to output a probability of fraud for each tax return.We demonstrate the effectiveness of our framework by testing it on existent tax returns provided by the Saudi tax authority.

Tax avoidance and earnings management:a neural network approach for the largest European economies

In this study,we investigate the relationship between tax avoidance and earnings management in the largest five European Union economies by using artificial neural network regressions.This methodology allows us to deal with nonlinearities detected in the data,which is the principal contribution to the previous literature.We ana-lyzed Compustat data for Germany,the United Kingdom,France,Italy,and Spain for the 2006–2015 period,focusing on discretionary accruals.We considered three tax avoidance measures,two based on the effective tax rate(ETR)and one on book-tax differences(BTD).Our results indicate the presence of nonlinear patterns and a posi-tive,statistically significant relationship between discretionary accruals and both ETR indicators implying that when companies resort to earnings management,a larger tax-able income—and thus higher ETR and lesser tax avoidance–would ensue.Hence,as also highlighted by the fact that discretionary accruals do not appear to affect BTD,our evidence does not suggest that companies are exploiting tax manipulation to reduce their tax payments;thus,the gap between accounting and taxation seems largely unaf-fected by earnings management.

Fairness in Climate Change Mitigation: The Case of Carbon Taxation

Environmental economists have advocated carbon taxation for its efficiency and effectiveness in reducing Greenhouse Gas (GHG) emissions. Yet, whether the policy would be fair in any given context needs to be better realized. While the distributive effects of carbon taxation have been widely discussed, a more comprehensive understanding of tax fairness is lacking. This paper reviews the academic literature through the lens of three justice concepts -recognition, procedure, and distribution—to understand the implications of previous studies for fair carbon tax policy-making. Upon examining the relevant literature, the findings highlight the limited evidence concerning recognition and procedural justice in carbon taxation, particularly in developing country context. This calls for more assessments through these perspectives. It also emphasizes the importance of recognition for vulnerable groups, such as women, with an intersectionality approach;a fair policy process through information provision, inclusive representation, fair level playing field;and proportionate burden sharing through context-specific design elements such as targeted revenue use.

Does higher tax rate affect tobacco usage?Unravelling the nexus between tobacco regulatory control and public health concern

Objectives:Bangladesh stands as a prominent global consumer of tobacco,with alarming consequences on public health.The Global Adult Tobacco Survey reported that tobacco consumption claimed over 126000 lives in 2018,contributing to 13.5%of all deaths in the country.This study aims to explore the effectiveness of higher tax rates and tobacco use regulation as control mechanisms in mitigating tobacco consumption and health care cost burden,with a particular emphasis on its implications for public health.Methods:This study is based on the annual time series data over the period 2000-2020.The study employs the ordinary least square method to analyze the quantitative confirming the stationarity of data at level.This research uses different models to investigate individual effects and combined effects on both tobacco consumption and tobacco health care cost burden.Results:The study finds a negative relationship between tobacco tax rate and tobacco consumption.More specifically,the higher tax rate of tobacco(low(β=-0.3495),medium(β=-0.2319),high(β=-0.9033),premium(β=-0.7322),filtered(β=-0.2114),and non-filtered(β=-0.3452)categories)is significant to reduce tobacco use at 1%level of significance.The study finds similar results when it applied tobacco retail price instead of tobacco tax rate as the independent variable.Finally,the study investigates the impact on health care cost through tobacco consumption,tobacco control law,growth rate,export-import,and tobacco production.The results indicate that tobacco consumption,export-import,and tobacco production increases health care cost burden while tobacco use regulatory decreases it.By reducing tobacco consumption,higher taxes and tobacco use regulation contribute to alleviating the burden on the healthcare system,promoting healthier lifestyles,and aligning with global health objectives.Conclusions:Higher tax rate on tobacco products is necessary to increase the retail price so that tobacco users cannot consume tobacco.Specific tax and uniform tax base are needed so that tobacco users cannot switch to lower priced brands.Tobacco control laws need to revised and proper implementation should be ensured as well,to achieve the goal of tobacco free Bangladesh by 2040.Tobacco-related diseases,responsible for a significant proportion of deaths in the country,could witness a considerable decline with the successful implementation of higher tax rates and tobacco use regulation.This study provides insights that not only contribute to the economic discourse but also accentuate the broader public health benefits arising from effective tobacco taxation policies.