Roles of the peroxisome proliferator-activated receptors (PPARs) in the pathogenesis of hepatocellular carcinoma (HCC).

Hepatocellular carcinoma (HCC) holds a prominent position among global cancer types. Classically, HCC manifests in individuals with a genetic predisposition when they encounter risk elements, particularly in the context of liver cirrhosis. Peroxisome proliferator-activated receptors (PPARs), which are transcription factors activated by fatty acids, belong to the nuclear hormone receptor superfamily and play a pivotal role in the regulation of energy homeostasis. At present, three distinct subtypes of PPARs have been recognized: PPARα, PPARγ, and PPARß/δ. They regulate the transcription of genes responsible for cellular development, energy metabolism, inflammation, and differentiation. In recent years, with the rising incidence of HCC, there has been an increasing focus on the mechanisms and roles of PPARs in HCC. PPARα primarily mediates the occurrence and development of HCC by regulating glucose and lipid metabolism, inflammatory responses, and oxidative stress. PPARß/δ is closely related to the self-renewal ability of liver cancer stem cells (LCSCs) and the formation of the tumor microenvironment. PPARγ not only influences tumor growth by regulating the glucose and lipid metabolism of HCC, but its agonists also have significant clinical significance for the treatment of HCC. Therefore, this review offers an exhaustive examination of the role of the three PPAR subtypes in HCC progression, focusing on their mediation of critical cellular processes such as glucose and lipid metabolism, inflammation, oxidative stress, and other pivotal signaling pathways. At the end of the review, we discuss the merits and drawbacks of existing PPAR-targeted therapeutic strategies and suggest a few alternative combinatorial therapeutic approaches that diverge from conventional methods.

Hypermethylation of PPARG-encoding gene promoter mediates fine particulate matter-induced pulmonary fibrosis by regulating the HMGB1/NLRP3 axis.

The inflammatory response induced by fine particulate matter (PM2.5), a common class of air pollutants, is an important trigger for the development of pulmonary fibrosis. However, the specific mechanisms responsible for this phenomenon are yet to be fully understood. To investigate the mechanisms behind the onset and progression of lung fibrosis owing to PM2.5 exposure, both rats and human bronchial epithelial cells were subjected to varying concentrations of PM2.5. The involvement of the PPARG/HMGB1/NLRP3 signaling pathway in developing lung fibrosis caused by PM2.5 was validated through the utilization of a PPARG agonist (rosiglitazone), a PPARG inhibitor (GW9662), and an HMGB1 inhibitor (glycyrrhizin). These outcomes highlighted the downregulation of PPARG expression and activation of the HMGB1/NLRP3 signaling pathway triggered by PM2.5, thereby eliciting inflammatory responses and promoting pulmonary fibrosis. Additionally, PM2.5 exposure-induced DNA hypermethylation of PPARG-encoding gene promoter downregulated PPARG expression. Moreover, the DNA methyltransferase inhibitor 5-azacytidine mitigated the hypermethylation of the PPARG-encoding gene promoter triggered by PM2.5. In conclusion, the HMGB1/NLRP3 signaling pathway was activated in pulmonary fibrosis triggered by PM2.5 through the hypermethylation of the PPARG-encoding gene promoter.

Changes in microbial community during hydrolyzed sludge reduction.

In this study, the effects of different enzymes (lysozyme, α-amylase and neutral protease) on sludge hydrolysis efficiency and microbial community in sequencing batch reactor (SBR) were introduced. The results showed that the hydrolysis efficiencies of the three enzymes were 48.5, 22.5 and 31%, respectively, compared with the accumulated sludge discharge of the blank control group. However, it has varying degrees of impact on the effluent quality, and the denitrification and phosphorus removal effect of the system deteriorates. The lysozyme that achieves the optimal sludge hydrolysis effect of 48.5% has the greatest impact on the chemical oxygen demand (COD), total nitrogen (TN), and nitrate nitrogen (NO3--N) of the effluent. The sludge samples of the control group and the groups supplemented with different enzyme preparations were subjected to high-throughput sequencing. It was found that the number of OTUs (Operational Taxonomic Units) of the samples was lysozyme > α-amylase > blank control > neutral protease. Moreover, the abundance grade curve of the sludge samples supplemented with lysozyme and α-amylase was smoother, and the community richness and diversity were improved by lysozyme and α-amylase. The species diversity of the sludge supplemented with lysozyme and neutral protease was great, and the community succession was obvious. The introduction of enzymes did not change the main microbial communities of the sludge, which were mainly Proteobacteria, Actinobacteria and Bacteroidetes. The effects of three enzyme preparations on sludge reduction and microbial diversity during pilot operation were analyzed, the gap in microbial research was filled, which provided theoretical value for the practical operation of enzymatic sludge reduction.

The effects of soil intake on the growth performance, rumen microbial community and tissue mineral deposition of German Mutton Merino sheep.

Soil ingestion by livestock is common in grazing ecosystems, but few studies have been conducted to assess its effect on the animal organism. The topic is worthy of attention because these potential effects are likely to be enriched in the food chain and interfere with animal and human health. In this study, we present an indoor feeding trial conducted based on a completely randomized design to comprehensively evaluate the effects of simulated soil ingestion during grazing on nutrient digestibility, rumen fermentation, and microflora, and mineral deposition in the organs and tissues of sheep. Eighteen Mutton Merino crossbred sheep (42.7 ± 2.34 kg) were randomly allotted to three treatments and fed diets containing 0% (Control), 5% (SOIL5), and 10% (SOIL10) for 62 d, including a 7-d metabolism trial. It was found that soil intake altered the rumen fermentation in sheep, as evidenced by a decrease in total volatile fatty acids (VFA) and acetate concentrations in rumen fluid of 50.6% and 51.3%, respectively (p < 0.01), with soil proportion in the diet increased from 0% to 10%. Soil ingestion also reduced the species richness of rumen bacteria, with the relative abundance of Bacteroidetes decreasing significantly (p < 0.01), while that of Firmicutes and Proteobacteria increased considerably (p < 0.05). In terms of mineral elements deposition, higher levels of iron (Fe) were detected in the spleen and liver, and a higher concentration of copper (Cu) and zinc (Zn) in the liver were found in sheep fed a diet containing 5% soil compared to the other two groups (p < 0.05). Moreover, the concentrations of lead (Pb) in the liver and kidney, and arsenic (As) in the heart were also clearly increased after ingestion of soil (p < 0.05). Our findings indicate that although soil intake had no significant effect on the growth performance of sheep, it altered ruminal fermentation and increased the risk of excessive Fe, Pb, and As in their organism. This study supplies a theoretical basis for risk assessment of soil ingestion in grazing livestock.

Research on lightweight laminate for car body with excellent cushioning and energy absorption characteristics.

With the development of the economy, car ownership is increasing day by day. In the context of energy shortage and environmental pollution, it is very important to study lightweight and ensure car safety. In this paper, a lightweight fiber metal laminate (FML) with excellent cushioning and energy absorption characteristics for car body is proposed by studying the deformation and energy absorption mechanism of ordinary groove plate under flat pressure. The FML is made up of an M-shaped aluminum alloy sandwich plate and two carbon fiber reinforced composite outer panels. By means of experiment and finite element simulation, it is proved that this structure had good cushioning energy absorption effect. Under the same conditions, the peak force of the M-shaped corrugated core FML with 2.5 mm groove depth is 46.3% of that of the traditional trapezoidal corrugated-core FMLs. Besides, the energy absorption capacity of the M-shaped corrugated core FML with 2 mm groove depth is 1.62 times of that of the traditional trapezoidal corrugated-core FMLs, before the top plate of sandwich unit touches the bottom plate. And cushioning energy absorption mechanism of M-shaped corrugated core FML is further explained by simulation.

Recombinant MUC1-MBP fusion protein combined with CpG2006 vaccine induces antigen-specific CTL responses through cDC1-mediated cross-priming mainly regulated by type I IFN signaling in mice.

In this study, we explored the initiation and regulation mechanism of antigen-specific CTL responses induced by a novel cancer vaccine containing recombinant human mucin1-maltose-binding protein fusion protein (MUC1-MBP) and CpG2006. First, DC subsets were analyzed by flow cytometry in vivo and in vitro. After vaccination, the proportion and maturation of cDC1s in mouse dLNs were upregulated, and the proportion of cDC2s and pDCs was also increased. In vitro studies on vaccine components showed similar changs, which may mainly depend on the activity of CpG2006. Subsequently, the regulatory effect of type Ⅰ IFN signaling on CTL triggering was confirmed through co-culture of sorted DC subsets and T cells and subsequent CTL activity experiments. CTL killing activity exhibited a 61.9% decrease once type I IFN signaling was blocked. Further analysis showed that blocking IFNAR1 on cDC1s but not on CTLs resulted in significant defects in CTL killing activity. Collectively, M-M combined with CpG2006 vaccine promotes MUC1-specific CTL responses by increasing the cDC1 activity in mice, and this is mainly regulated by type Ⅰ IFN signaling in cDC1s.

Non-linear relations between life expectancy, socio-economic, and air pollution factors: a global assessment with spatial disparities.

Influential factors of socio-economic and air pollution on life expectancy (LE) show complexity. The investigations of non-linear functions of LE, socio-economic, and air pollution factors have not been largely conducted, and spatial and temporal differences of the linear or non-linear relations between LE and the influential factors have been obscured across countries in the world. In this study, the non-linear relations between LE and factors of per capita gross national income (GNIpc), urban population rate (UPR), and fine-particulate (PM2.5) were estimated from 2000 to 2015 by using a generalized additive model (GAM). The collected data included the 219 countries and regions with sufficient data and covers the period 2000-2015. The results demonstrate that at the global level, the GNIpc plays a stable and significant non-linear role in LE, while the non-linear relationships between UPR, PM2.5, and LE are not significant. The temporal variation was further investigated that the non-linear effect of PM2.5 on LE is gradually strengthened, and the non-linear effect of UPR on LE shows a weakened trend. However, GNIpc always plays a significantly non-linear role in the LE level. Furthermore, the spatial difference in the non-linear relations among different continents is detected. In sum, it cannot be ignored the non-linear effects of socio-economic and air pollution factors on LE at a global scale and across different continents.

TRAF6-overexpressing dendritic cells loaded with MUC1 peptide enhance anti-tumor activity in B16-MUC1 melanoma-bearing mice.

Tumor necrosis factor receptor (TNFR)-associated factor 6 (TRAF6) signaling is a critical positive mechanism for the development, homeostasis and activation of immune cells. We investigated the effect of TRAF6 overexpression on dendritic cells (DCs) maturation. TRAF6-overexpressing DCs had increased expression of costimulatory molecules, major histocompatibility complex (MHC) molecules and IL-12 expression. This indicated that TRAF6 promoted the maturation of DCs and indirectly promoted Th1 activation. The antitumor activities between TRAF6-overexpressing DCs and control DCs were compared by administering DCs pulsed with mucin 1 (MUC1) Ag peptide in a therapeutic human MUC1-overexpressing mouse B16 melanoma cells (B16-MUC1) model. Administration of TRAF6-overexpressing DCs significantly inhibited the growth of B16-MUC1 tumors, accompanied by an increase in MUC1-specific Th1 responses and Tc1 responses, as well as a decrease in Tregs levels. TRAF6 signaling has been found to be involved in DCs maturation and Th1 activation in vitro, as well as therapeutic tumor models in vivo, indicating that TRAF6-overexpressing DCs may be a promising approach for cancer immunotherapy.

Dual roles of myeloid-derived suppressor cells induced by Toll-like receptor signaling in cancer.

Myeloid-derived suppressor cells (MDSCs) are one of the major components of the tumor microenvironment (TME), and are the main mediators of tumor-induced immunosuppression. Recent studies have reported that the survival, differentiation and immunosuppressive activity of MDSCs are affected by the Toll-like receptor (TLR) signaling pathway. However, the regulatory effect of TLR signaling on MDSCs remains controversial. TLR-induced MDSC can acquire different immunosuppressive activities to influence the immune response that can be either beneficial or detrimental to cancer immunotherapy. The present review summarizes the effects of TLR signals on the number, phenotype and inhibitory activity of MDSCs, and their role in cancer immunotherapy, which cannot be ignored if effective cancer immunotherapies are to be developed for the immunosuppression of the TME.

Mechanism by which TRAF6 Participates in the Immune Regulation of Autoimmune Diseases and Cancer.

Tumor necrosis factor (TNF) receptor-associated factor 6 (TRAF6), an E3 ubiquitin ligase, is a signal transduction molecule shared by the interleukin-1 receptor (IL-1R)/Toll-like receptor (TLR) family and the TNFR superfamily. TRAF6 has a unique TRAF domain and RING finger domain that mediate intracellular signaling events. In the immune system, TRAF6-mediated signaling has been shown to be critical for the development, homeostasis, and activation of a variety of immune cells, including B cells, T cells, dendritic cells, and macrophages. Although the pathogenesis and etiology of autoimmune diseases and cancer are not fully understood, it is worth noting that existing studies have shown that TRAF6 is involved in the pathogenesis and development of a variety of these diseases. Herein, we reviewed the role of TRAF6 in certain immune cells, as well as the function and potential effect of TRAF6 in autoimmune diseases and cancer. Our review indicates that TRAF6 may be a novel target for autoimmune diseases and cancer.

The Effect of Different Immunization Cycles of a Recombinant Mucin1-Maltose-Binding Protein Vaccine on T Cell Responses to B16-MUC1 Melanoma in Mice.

We explored the effect of a recombinant mucin1-maltose-binding protein vaccine, including immunization cycles of recombinant mucin1-maltose-binding protein (MUC1-MBP) and CpG 2006 on T cell responses to human MUC1-overexpressing mouse melanoma B16 cells (B16-MUC1) melanoma in mice. We found that the vaccine had a significant antitumor effect, with the most obvious tumor-suppressive effect being observed in mice immunized five times. After more than five immunizations, the tumor inhibition rate decreased from 81.67% (five immunizations) to 43.67% (eight immunizations). To study the possible mechanism, Mucin-1(MUC1)-specific antibodies, IFN-γ secretion by lymphocytes, and cytotoxic T lymphocyte (CTL) cytotoxicity were measured by enzyme-linked immunosorbent assay (ELISA) and a real-time cell analyzer (RTCA). T cell subsets and immunosuppressive cells in the mouse spleen and tumor microenvironment were analyzed by FACS. These results showed that five immunizations activated MUC1-specific Th1 and CTL and reduced the ratio of myeloid-derived suppressor cells (MDSCs) and Th17 in mice more significantly than eight immunizations, indicating that excessive frequency of the immune cycle leads to the increased numbers of immunosuppressive cells and decreased numbers of immunostimulatory cells, thereby inhibiting antitumor immune activity. This data provide an experimental foundation for the clinical application of a recombinant MUC1-MBP vaccine.

Effects of over-load iron on nutrient digestibility, haemato-biochemistry, rumen fermentation and bacterial communities in sheep.

There is a risk of iron overload in grazing livestock. However, the effects on nutrient absorption and rumen function induced by excessive iron have not been well understood. Therefore, the purpose of present study was to investigate the impact of over-load iron on growth performance, nutrient digestibility, blood biochemistry, rumen fermentation and bacterial communities in sheep. Twenty-four German Mutton Merino cross-bred sheep with weight (42.66 ± 2.34 kg BW) were randomly divided into 4 groups, each with 6 replicates and 1 sheep per replicate. The basal diet consisted of 60% Leymus chinensis hay and 40% concentrate. The sheep in 4 groups were fed the basal diets supplemented with 50 (Control), 500 (T1), 1,000 (T2) and 1,500 (T3) mg Fe/kg as ferrous sulphate monohydrate (FeSO4 ·H2 O) respectively. And the actual contents of iron in the diet were determined to be 457.68 (control), 816.42 (T1), 1,256.78 (T2) and 1,725.63 (T3) mg/kg respectively. The experiment lasted 62 days including a 7-day metabolism trial. During the whole experiment, the digestibility of dry matter, organic matter, neutral detergent fibre and acid detergent fibre showed a quadratic increase with increasing over-load iron levels (p < .05), and maximum responses were found with 500 mg/kg supplementation. However, the response of total VFA concentration showed a quadratic decrease, as did the concentrations of propionate, butyrate and valerate (p < .05). Serum total iron-binding capacity on day 30 showed a quadratic decrease with the increase in high-dose iron, while the serum iron content increased linearly at day 60 (p < .05). Excessive iron resulted in the change in bacterial communities. An increase in over-load iron linearly decreased the abundance of bacteria in the phylum Bacteroidetes (p < .05), but linearly increased the Firmicutes (p = .037) and Proteobacteria (p = .018). In addition, there was a quadratic effect (p = .003) on the Fibrobacteres, which was higher in the 500 and 1,000 mg/kg Fe-supplemented groups. At the genus level, there were quadratic effects on the abundances of Selenomonas_1 (p = .023) and Ruminococcaceae_UCG-014 (p = .016). Furthermore, feeding of iron linearly increased the relative abundances of Succiniclasticum and Succinivibrionaceae_UCG-002 (p < .05). These results indicate that increasing ferrous sulphate monohydrate in diets had no negative impact on the growth performance, but it changed nutrient digestibility, blood iron parameters, rumen fermentation and bacterial communities in sheep.