Role of Endocrine-Disrupting Chemicals in the Pathogenesis of Non-Alcoholic Fatty Liver Disease: A Comprehensive Review

Non-alcoholic fatty liver disease (NAFLD) is considered the most common liver disorder, affecting around 25% of the population worldwide. It is a complex disease spectrum, closely linked with other conditions such as obesity, insulin resistance, type 2 diabetes mellitus, and metabolic syndrome, which may increase liver-related mortality. In light of this, numerous efforts have been carried out in recent years in order to clarify its pathogenesis and create new prevention strategies. Currently, the essential role of environmental pollutants in NAFLD development is recognized. Particularly, endocrine-disrupting chemicals (EDCs) have a notable influence. EDCs can be classified as natural (phytoestrogens, genistein, and coumestrol) or synthetic, and the latter ones can be further subdivided into industrial (dioxins, polychlorinated biphenyls, and alkylphenols), agricultural (pesticides, insecticides, herbicides, and fungicides), residential (phthalates, polybrominated biphenyls, and bisphenol A), and pharmaceutical (parabens). Several experimental models have proposed a mechanism involving this group of substances with the disruption of hepatic metabolism, which promotes NAFLD. These include an imbalance between lipid influx/efflux in the liver, mitochondrial dysfunction, liver inflammation, and epigenetic reprogramming. It can be concluded that exposure to EDCs might play a crucial role in NAFLD initiation and evolution. However, further investigations supporting these effects in humans are required.     

The Age-Sensitive Efficacy of Calorie Restriction on Mitochondrial Biogenesis and mtDNA Damage in Rat Liver

Calorie restriction (CR) is the most efficacious treatment to delay the onset of age-related changes such as mitochondrial dysfunction. However, the sensitivity of mitochondrial markers to CR and the age-related boundaries of CR efficacy are not fully elucidated. We used liver samples from ad libitum-fed (AL) rats divided in: 18-month-old (AL-18), 28-month-old (AL-28), and 32-month-old (AL-32) groups, and from CR-treated (CR) 28-month-old (CR-28) and 32-month-old (CR-32) counterparts to assay the effect of CR on several mitochondrial markers. The age-related decreases in citrate synthase activity, in TFAM, MFN2, and DRP1 protein amounts and in the mtDNA content in the AL-28 group were prevented in CR-28 counterparts. Accordingly, CR reduced oxidative mtDNA damage assessed through the incidence of oxidized purines at specific mtDNA regions in CR-28 animals. These findings support the anti-aging effect of CR up to 28 months. Conversely, the protein amounts of LonP1, Cyt c, OGG1, and APE1 and the 4.8 Kb mtDNA deletion content were not affected in CR-28 rats. The absence of significant differences between the AL-32 values and the CR-32 counterparts suggests an age-related boundary of CR efficacy at this age. However, this only partially curtails the CR benefits in counteracting the generalized aging decline and the related mitochondrial involvement.     

氮含量及固溶温度对21-6-9奥氏体不锈钢组织和硬度的影响

为了探讨氮含量及固溶温度对21-6-9不锈钢组织和硬度的影响,分别在950、1000、1050和1100 ℃对3种不同氮含量的热轧态21-6-9不锈钢进行1 h固溶处理,通过光学显微镜观察其组织结构,结合Thermo-Calc热力学计算对试验钢的微观组织进行分析,并对其进行硬度测试。结果表明,0.20%~0.28%N的21-6-9不锈钢热轧后沿轧制方向析出铁素体,且钢中铁素体经950~1100 ℃固溶处理可消除,当N含量达到0.34%时,试验钢中不再出现铁素体。随着固溶处理温度的升高,21-6-9不锈钢的晶粒组织长大,硬度降低。N含量的增加可显著提高固溶态21-6-9不锈钢的硬度,其增加程度随固溶处理温度的升高而减弱。     

巨型水轮发电机剪断销研发与质量控制

为获得设计需要的巨型水轮发电机剪断销的剪切力,得到剪切力波动受控的批量剪断销,通过拉伸试验、冲击试验、硬度试验和剪断销剪切试验等讨论了全尺寸剪断销剪切试验的可行性,分析了剪切试验时正常剪断和非正常剪断的剪断销材料性能差异,探究了剪断销的剪切力质量稳定性控制方法。结果表明:控制剪断销料坯的布氏硬度波动,可实现间接控制剪断销剪切强度的波动;通过试验总结的六步法可达到控制批量剪断销质量和剪切力波动的目的。     

Neoagarooligosaccharide Protects against Hepatic Fibrosis via Inhibition of TGF-β/Smad Signaling Pathway

Hepatic fibrosis occurs when liver tissue becomes scarred from repetitive liver injury and inflammatory responses; it can progress to cirrhosis and eventually to hepatocellular carcinoma. Previously, we reported that neoagarooligosaccharides (NAOs), produced by the hydrolysis of agar by β-agarases, have hepatoprotective effects against acetaminophen overdose-induced acute liver injury. However, the effect of NAOs on chronic liver injury, including hepatic fibrosis, has not yet been elucidated. Therefore, we examined whether NAOs protect against fibrogenesis in vitro and in vivo. NAOs ameliorated PAI-1, α-SMA, CTGF and fibronectin protein expression and decreased mRNA levels of fibrogenic genes in TGF-β-treated LX-2 cells. Furthermore, downstream of TGF-β, the Smad signaling pathway was inhibited by NAOs in LX-2 cells. Treatment with NAOs diminished the severity of hepatic injury, as evidenced by reduction in serum alanine aminotransferase and aspartate aminotransferase levels, in carbon tetrachloride (CCl₄)-induced liver fibrosis mouse models. Moreover, NAOs markedly blocked histopathological changes and collagen accumulation, as shown by H&E and Sirius red staining, respectively. Finally, NAOs antagonized the CCl₄-induced upregulation of the protein and mRNA levels of fibrogenic genes in the liver. In conclusion, our findings suggest that NAOs may be a promising candidate for the prevention and treatment of chronic liver injury via inhibition of the TGF-β/Smad signaling pathway.     

Dense and core-rim structured B4C-TiB2 ceramics with Mo-Co-WC additive

B₄C-TiB₂ ceramics (TiB₂ ranging 5~70 vol%) with Mo-Co-WC as the sintering additive were prepared by spark plasma sintering. In comparison with B₄C-TiB₂ without additive, the enhanced densification was evident in the sintered specimen with Mo-Co-WC additive. Core-rim structured grain was observed around TiB₂ grains. The interface of the rim between TiB₂ and B₄C phases demonstrated different feature: the inner borderline of the rim exhibited a smooth feature, whereas a sharp curved grain boundary was observed between the rim and the B₄C grain. The formation mechanism is discussed: the epitaxial growth of (Ti,Mo,W)B₂ rim around the TiB₂ core may occur as a result of the solid solution and dissolution-precipitation between TiB₂ phase and the sintering additive. It was revealed that the fracture toughness increased as the content of TiB₂ content increased, alongside the decreased hardness. B₄C-30 vol% TiB₂ specimen demonstrated the optimal combination of mechanical properties, reaching Vickers hardness of 24.3 GPa and fracture toughness of 3.33 MPa·m^1/2.     

The Role of CTLA4 and Its Polymorphisms in Solid Organ and Haematopoietic Stem Cell Transplantation

HLA matching, transplantation technique, or underlying disease greatly influences the probability of long-term transplantation success. It has been hypothesised that genetic variation affecting antigen presentation also contributes to the outcomes of both solid organ transplantation and allogeneic haematopoietic stem cell transplantation (AHSCT). Those genes, along with those responsible for innate and adaptive immunity, have become targets of investigation. In this review, we focus on the role of CTLA4 in the process of acute graft rejection and summarise the progress in our understanding of its role in predicting the outcome. We present the results of the latest studies investigating the link between CTLA4 gene variability and AHSCT, as well as organ transplantation outcomes. While some studies found a link between +49 A/G and −318 C/T and transplantation outcomes, comprehensive meta-analyses have failed to present any association. The most recent field reviews suggest that the −1772 T/C (rs733618) CC genotype is weakly associated with a lower risk of acute graft rejection, while +49 A/G might be clinically meaningful when investigated in the context of combinations with other polymorphisms. Studies verifying associations between 12 CTLA4 gene SNPs and AHSCT outcomes present inexplicit results. Some of the most commonly studied polymorphisms in this context include +49 A/G (rs231775) and CT60 A/G (rs3087243). The results signify that, in order to understand the role of CTLA4 and its gene polymorphisms in transplantology, further studies must be conducted.     

Structure,mechanical and thermal properties of Y-doped CrAlN coatings

CrAlYN coatings with different Y contents (0, 5 and 12 at.%) were deposited by cathodic arc evaporation to investigate the influence of Y-addition on the structure, mechanical and thermal properties of CrAlN coatings by using X-ray diffraction, scanning electron microscopy, differential scanning calorimetry, thermal gravimetric analysis and nanoindentation. The structural transformation of single phase cubic Cr_0.42Al_0.58N and Cr_0.39Al_0.56Y_0.05N coatings to cubic–wurtzite mixed Cr_0.32Al_0.56Y_0.12N coating leads to a drop in hardness from (30.2±0.7) GPa of Cr_0.42Al_0.58N and (32.0±1.0) GPa of Cr_0.39Al_0.56Y_0.05N to (25.2±0.7) GPa of Cr_0.32Al_0.56Y_0.12N. The incorporation of 5 at.% Y retards the thermal decomposition of CrAlN, verified by the postponed precipitation of w-AlN and N-loss upon annealing. Correspondingly, Cr_0.39Al_0.56Y_0.05N coating consistently exhibits the highest hardness value during thermal annealing. Nevertheless, alloying with Y exerts an adverse effect on the oxidation resistance of CrAlN.     

Repeated low-velocity impact responses of SiC particle reinforced Al metal-matrix composites

This study aimed to investigate experimentally the repeated low-velocity impact behaviors of SiC reinforced aluminum 6061 metal-matrix composites for different volume fractions and energy levels. In addition, the hardness variations were measured by the Vickers hardness tests from the impacted and impact-free cross-sections of the particle reinforced metal-matrix composites. Low-velocity impact tests were applied to composite samples manufactured by powder metallurgy (in 10, 20, and 30% volume fractions) at two total energy levels (15 and 60 J as single) and in repetitions equal to the sum of these energy levels (5 + 5 + 5 and 20 + 20 + 20 J as repeated). As a result, in increasing the impact number for all volume fractions, the total contact time was shortened and the peak contact force increased, whereas both the permanent central deflection and the absorbed energies reduced. Hence, these variations obtained under repeated impacts (5 + 5 + 5 and 20 + 20 + 20 J) revealed that metal-matrix composites showed a tougher behavior with an increase in the impact numbers from 1st to 3rd, particularly because of the strain hardening effect. Furthermore, an increase in volume fraction from 10 to 30% resulted in an increase in the impact strength under all repeated and single impacts despite changing deformation and damage mechanisms due to increasing the strain hardening effect and particle fractures. The hardness was affected by the volume fraction and increased as the volume fraction increased in both the impacted and impact-free zones. The repeated impact increased the impacted zone hardness more than the single impact for all volume fractions. Additionally, the hardness of the impacted zone under 20 + 20 + 20 J repeated impact was measured as the highest value in the 30% volume fraction. Therefore, metal-matrix composites can behave harder with the strain hardening effect under repeated impacts.     

胆汁淤积性肝病治疗药物的临床研究进展

胆汁淤积性肝病是指由各种原因导致胆汁形成、分泌、排泄异常,从而引起肝脏发生病变。目前,治疗胆汁淤积性肝病的药物主要为熊去氧胆酸(UDCA),但近一半的患者对UDCA应答不充分或不耐受。这部分患者仅有奥贝胆酸(OCA)可用。随着近几年胆汁淤积性肝病的发病率明显上升,急需新型有效的治疗药物。临床研究表明,FXR激动剂、PPAR-α/γ激动剂和ASBT抑制剂能够有效改善胆汁淤积,有望成为新型胆汁淤积性肝病的临床治疗药物。针对以上靶点,对近几年较有前景的胆汁淤积性肝病治疗药物临床研究进展进行了综述,为此类药物的研究提供参考。