ROS-mediated NRF2/p-ERK1/2 signaling-involved mitophagy contributes to macrophages activation induced by CdTe quantum dots.

Cadmium telluride (CdTe) quantum dots (QDs) have garnered significant attention for tumor imaging due to their exceptional properties. However, there remains a need for further investigation into their potential toxicity mechanisms and corresponding enhancements. Herein, CdTe QDs were observed to accumulate in mouse liver, leading to a remarkable overproduction of IL-1ß and IL-6. Additionally, there was evidence of macrophage infiltration and activation following exposure to 12.5 µmol/kg body weight of QDs. To elucidate the underlying mechanism of macrophage activation, CdTe QDs functionalized with 3-mercaptopropionic acid (MPA) were utilized. In vitro experiments revealed that 1.0 µM MPA-CdTe QDs activated PINK1-dependent mitophagy in RAW264.7 macrophages. Critically, the autophagic flux remained unimpeded, as demonstrated by the absence of p62 accumulation, LC3 turnover assay results, and successful fusion of autophagosomes with lysosomes. Mechanically, QDs increased reactive oxygen species (ROS) and mitoROS by damaging both mitochondria and lysosomes. ROS, in turn, inhibited NRF2, resulting in the phosphorylation of ERK1/2 and subsequent activation of mitophagy. Notably, 1.0 µM QDs disrupted lysosomes but autophagic flux was not impaired. Eventually, the involvement of the ROS-NRF2-ERK1/2 pathway-mediated mitophagy in the increase of IL-1ß and IL-6 in macrophages was confirmed using Trolox, MitoTEMPO, ML385, specific siRNAs, and lentivirus-based interventions. This study innovatively revealed the pro-inflammatory rather than anti-inflammatory role of mitophagy in nanotoxicology, shedding new light on the mechanisms of mitochondrial disorders induced by QDs and identifying several molecular targets to comprehend the toxicological mechanisms of CdTe QDs.

Low-dose cadmium telluride quantum dots trigger M1 polarization in macrophages through mTOR-mediated transcription factor EB activation.

The increasing application of quantum dots (QDs) increases interactions with organisms. The inflammatory imbalance is a significant manifestation of immunotoxicity. Macrophages maintain inflammatory homeostasis. Using macrophages differentiated by phorbol 12-myristate 13-acetate-induced THP-1 cells as models, the study found that low-dose (5 µM) cadmium telluride QDs (CdTe-QDs) hindered monocyte-macrophage differentiation. CD11b is a surface marker of macrophage, and the addition of CdTe-QDs during induction resulted in a decrease in CD11b expression. Moreover, exposure of differentiated THP-1 macrophage (dTHP-1) to 5 µM CdTe-QDs led to the initiation of M1 polarization. This was indicated by the increased surface marker CD86 expression, along with elevated level of NF-κB and IL-1ß proteins. The potential mechanisms are being explored. The transcription factor EB (TFEB) plays a significant role in immune regulation and serves as a crucial regulator of the autophagic lysosomal pathway. After exposed to CdTe-QDs, TFEB activation-mediated autophagy and M1 polarization were observed to occur simultaneously in dTHP-1. The mTOR signaling pathway contributed to TFEB activation induced by CdTe-QDs. However, mTOR-independent activation of TFEB failed to promote M1 polarization. These results suggest that mTOR-TFEB is an advantageous target to enhance the biocompatibility of CdTe-QDs.

Protein corona exacerbated inflammatory response in macrophages elicited by CdTe quantum dots.

Nano-bio interface is significant concern in nanomedicine. When nanoparticles (NPs) come into contact with cells, they form complexes with proteins known as protein corona (PC). Cadmium telluride quantum dots (CdTe QDs) have been applied as bioimaging probes and for macrophage theragnostic. However, the impact of protein corona on the behavior of CdTe QDs is not well understood. Macrophages play a crucial role in defending against NPs. In this study, RAW264.7 cells were used to investigated the inflammatory response in macrophages when exposed to CdTe QDs before and after PC formation in fetal bovine serum. The results indicated that protein corona polarized more macrophages towards M1 phenotype. Transcriptomics analysis revealed that PC-CdTe QDs altered a greater number of differentially expressed genes (DEGs) compared to CdTe QDs (177 and 398) at 1.0 µM in macrophages. The DEGs affected by PC-CdTe QDs contained several personalized inflammatory cytokines. The enriched pathways after PC formation included Cytokine-cytokine receptor interaction, NOD-like receptor signaling pathway, and TNF signaling pathway, etc. Furthermore, PC specifically exacerbated the overexpression of CCL2 and IL-1ß proteins. Importantly, PC altered the mechanism of CdTe QD-induced pyroptosis, shifting it from activating NLRC4 to both NLRP1 and NLRP3 inflammasomes, and from cleaving GSDMD and GSDMB to GSDMB alone. Overall, protein corona exacerbated the inflammatory response induced by CdTe QDs in macrophages. This study provides valuable insight into the pro-inflammatory effect of protein corona on CdTe QDs, with implications for their use in bioimaging or macrophage theragnostic by either exploiting or eliminating this biological interface effect.

Influence of silver doping on pro-inflammatory and pro-fibrogenic effects of nano-titanium dioxide in murine lung.

Silver is usually loaded on nano-titanium dioxide (TiO2 ) through photodeposition method to enhance visible-light catalytic functions for environment purification. However, little is known about how the toxicity changes after silver doping and how the physicochemical properties of loaded components affect nanocomposite toxicity. In this study, Ag-TiO2 with different sizes and contents of silver particles were obtained by controlling photodeposition time (PDT) and silver addition amount. Pro-inflammatory and pro-fibrogenic responses of these photocatalysts were evaluated in male C57BL/6J murine lung. As a result, silver was well assembled on TiO2 , promoting visible-light catalytic activity. Notably, the size of silver particles increased with PDT. Meanwhile, toxicity results showed that pure TiO2 (P25) mainly caused neutrophil infiltration, while 2 wt/wt% silver-loaded TiO2 recruited more types of inflammatory cells in the lung. Both of them caused the increase of proinflammatory cytokines while decreasing the anti-inflammatory cytokine in bronchoalveolar lavage fluid. However, 2 wt/wt% silver doping also accelerated the lung pro-fibrogenic response of photocatalysts in the subacute phase from evidence of collagen deposition and hydroxyproline concentrations. Mechanistically, the overactivation of TGFBR2 receptors in TGF-ß/smads pathways by silver-loaded TiO2 rather than pure TiO2 may be the reason why silver-loaded TiO2 can promote pro-fibrogenic effect response. Intriguingly, the increased toxicity caused by silver doping can be rescued by increasing the size of the loaded silver or decreasing the silver amount. These results may be important for the new understanding of the toxicity of TiO2 -based photocatalysts.

Ag/TiO2 nanohybrids induce fibrosis-related epithelial-mesenchymal transition in lung epithelial cells and the influences of silver content and silver particle size.

The controlled synthesis of silver nanoparticles (AgNPs) decorated TiO2 nanohybrids (Ag/TiO2) for photocatalysis has received considerable attention. These photocatalysts are widely used in environment and energy, resulting in human exposure through inhalation. Pure TiO2 is generally considered a low-toxic nanomaterial. However, little is known about the toxicity after AgNPs loading. In this study, silver-decorated TiO2 nanohybrids were controllably synthesized by the photodeposition method, and their toxic effects on murine lung and human lung epithelial cells were explored. As a result, silver loading significantly enhanced the effect of TiO2 photocatalyst on EMT in lung epithelial cells, potentially acting as a pro-fibrogenic effect in murine lung. Meanwhile, the increase in autophagy vacuoles, LC3-II marker, stub-RFP-sens-GFP-LC3 fluorescence assay, and LC3 turnover assay showed that silver loading also significantly increased autophagy flux. Furthermore, analysis of autophagy inhibition by 3-Methyladenine indicated that the promotion of EMT by silver loading was related to the increased autophagy flux. Intriguingly, the autophagy and EMT biological effects could be alleviated when the silver loading amount was reduced or silver particle size was increased, and the enhanced pro-fibrogenic effect was mitigated at the same time. This study supplemented safety information of Ag-decorated TiO2 nanohybrids and provided methods of controlled synthesis for reducing toxicity.

Mechanical stress induced EndoMT in endothelial cells through PPARγ downregulation.

Portal hypertension is a group of clinical syndromes induced by increased portal system pressure due to various etiologies including cirrhosis. When portal hypertension develops, the portal vein dilates and endothelial cells (ECs) in the portal vein are subjected to mechanical stretch. In this study, elastic silicone chambers were used to simulate the effects of mechanical stretch on ECs under portal hypertension. We found that mechanical stretch decreased PPARγ expression in ECs by blocking the PI3K/AKT/CREB signaling pathway or increasing NEDD4-mediated ubiquitination and degradation of PPARγ. Moreover, PPARγ downregulation triggered Endothelial-to-mesenchymal transition (EndoMT) in ECs under stretch by promoting Smad3 phosphorylation. The PPARγ agonist rosiglitazone mitigated stretch-induced EndoMT in vitro and alleviated EndoMT of the portal vein endothelium in cirrhotic rats.

Global Burden of Digestive Diseases: A Systematic Analysis of the Global Burden of Diseases Study, 1990 to 2019.

BACKGROUND & AIMS: This study assessed the worldwide burden of digestive diseases between 1990 and 2019. METHODS: We analyzed data from the Global Burden of Diseases study, covering 18 digestive diseases across 204 countries and territories. Key disease burden indicators, including incidence, prevalence, mortality, and disability-adjusted life years (DALYs), were studied. Linear regression analysis was applied to the natural logarithm of age-standardized outcomes to determine the annual percent change. RESULTS: In 2019, there were 7.32 billion incidents and 2.86 billion prevalent cases of digestive diseases, resulting in 8 million deaths and 277 million DALYs lost. Little to no decrease in global age-standardized incidence and prevalence of digestive diseases was observed between 1990 and 2019, with 95,582 and 35,106 cases per 100,000 individuals in 2019, respectively. The age-standardized death rate was 102 per 100,000 individuals. Digestive diseases accounted for a significant portion of the overall disease burden, with more than one-third of prevalent cases having a digestive etiology. Enteric infections were the primary contributor to incidence, death, and DALYs lost, whereas cirrhosis and other chronic liver diseases had the highest prevalence rate. The burden of digestive diseases was inversely related to the sociodemographic index, with enteric infections being the predominant cause of death in low and low-middle quintiles and colorectal cancer in the high quintile. CONCLUSIONS: Despite significant reductions in deaths and DALYs due to digestive diseases from 1990 to 2019, they remain prevalent. A significant disparity in the burden of digestive diseases exists among countries with different development levels.

Global increase of colorectal cancer in young adults over the last 30 years: an analysis of the Global Burden of Disease Study 2019.

OBJECTIVES: The US Preventive Services Task Force lowered the recommended starting age for colorectal cancer (CRC) screening in average-risk adults from 50 to 45 years. We aimed to estimate the global burden and trends of colorectal cancer in adults aged 20-49 years (early-onset CRC). METHODS: This is an analysis of the Global Burden of Diseases, Injuries, and Risk Factors Study 2019 (GBD 2019). The GBD 2019 estimation methods were used to describe the incidence, mortality, and disability-adjusted life years (DALYs) of early CRC from 1990 to 2019. Data from 204 countries and geographic areas were available. RESULTS: The global incidence rate of early-onset CRC increased from 4.2/100 000 to 6.7/100 000 from 1990 to 2019. Mortality and DALYs of early-onset CRC also increased. The CRC incidence rate increased faster in younger adults (1.6%) than in adults aged 50-74 years (0.6%) as measured by the annual percentage change. The increase in early-onset CRC incidence was consistently observed in all five socio-demographic index (SDI) regions and 190 out of 204 countries and territories. Middle and high-middle SDI regions had faster annual increases in early-onset CRC, which warrants further attention. CONCLUSIONS: The global incidence, mortality, and DALYs of early-onset CRC increased from 1990 to 2019. The increase in early-onset CRC incidence was prevalent worldwide. Several countries were found to have higher incidence rates than the United States or fast increase in early-onset CRC, which warrants further attention.

Computed tomography imaging features to evaluate the severity of portal hypertension and predict the rebleeding risk after endoscopic treatment in cirrhotic patients with variceal hemorrhage.

PURPOSE: To investigate the association of computed tomography (CT) imaging features and severity of portal hypertension (PH) and develop a nomogram to predict high-risk PH in cirrhotic patients with gastroesophageal variceal hemorrhage (GVH). METHODS: The study retrospectively enrolled 158 cirrhotic patients with a history of endoscopic treatment for GVH. Hepatic vein pressure gradient (HVPG) was measured and the patients were classified into high-risk (HVPG > 16 mmHg) or low-risk (HVPG ≤ 16 mmHg) PH group. Pre-treatment CT features, including cavernous transformation of portal vein (CTPV), hilar periportal space (a distance between right portal vein and posterior edge of segment IV of the liver), and depth of right posterior hepatic notch sign (a sharp indentation in the right medial posterior liver surface), were evaluated. Risk factors associated with high-risk PH were analyzed, and a nomogram based on the imaging features was developed. RESULTS: High-risk PH group showed a higher rebleeding rate after treatment than that of the low-risk (P = 0.029). Multivariate analysis indicated that larger hilar periportal space (P < 0.001), less frequencies of CTPV (P = 0.044) and deeper right posterior hepatic notch (P < 0.001) were independent risk factors associated with high-risk PH. A nomogram based on the three CT imaging features was established to predict high-risk PH with an excellent discrimination (c-statistic 0.854). CONCLUSION: The nomogram based on CT features of hilar periportal space, depth of right posterior hepatic notch and CTPV can help to distinguish cirrhotic patients with high-risk PH, who are more vulnerable of variceal rebleeding after endoscopic treatment.

Increased Factor VIII Activity Is Predictive of the Occurrence of Portal Vein Thrombosis in Cirrhosis.

BACKGROUND: The aim of this study was to identify the role of factor VIII (FVIII) in portal vein thrombosis (PVT) occurrence in cirrhotic patients with gastroesophageal variceal bleeding. METHODS: A total of 453 cirrhotic patients with gastroesophageal varices were enrolled. Computed tomography was performed at baseline and patients were divided into PVT and non-PVT groups (n = 131 vs. 322). Individuals without PVT at baseline were followed up for the development of PVT. Time-dependent receiver operating characteristic analysis of FVIII for PVT development was performed. The Kaplan-Meier methodology was used to analyze the predictive ability of FVIII for PVT incidence at 1 year. RESULTS: FVIII activity (177.00 vs. 153.70, p = 0.001) was significantly increased in the PVT group compared with the non-PVT group in cirrhotic patients with gastroesophageal varices. FVIII activity was positively correlated with the severity of PVT (161.50 vs. 171.07 vs. 187.05%, p = 0.001). Furthermore, FVIII activity (hazard ratio [HR]: 3.48, 95% confidence interval [CI]: 1.14-10.68, p = 0.029 in model 1; HR: 3.29, 95% CI: 1.03-10.51, p = 0.045 in model 2) was an independent risk factor of 1-year PVT development in patients without PVT at baseline, which was confirmed by two separate Cox regression analysis and competing risk models. Patients with elevated FVIII activity exhibit a higher incidence of PVT in the non-PVT group at 1 year (15.17 vs. 3.16%, p < 0.001). The predictive value of FVIII remains significant in individuals who have never received splenectomy (14.76 vs. 3.04%, p = 0.002). CONCLUSION: Elevated FVIII activity was potentially associated with the occurrence and the severity of PVT. It might be helpful to identify cirrhotic patients at risk of PVT.

Risk factors associated with failure of endoscopic combined treatment to prevent varices rebleeding in patients with liver cirrhosis.

BACKGROUND: The aim of this study is to investigate risk factors associated with gastroesophageal variceal rebleeding after endoscopic combined treatment. RESEARCH DESIGN AND METHODS: Patients who had liver cirrhosis and underwent endoscopic treatment to prevent variceal rebleeding were retrospectively recruited. Hepatic venous pressure gradient (HVPG) measurement and CT examination of portal vein system were performed before endoscopic treatment. Endoscopic obturation for gastric varices and ligation for esophageal varices were performed simultaneously at the first treatment. RESULTS: One hundred and sixty-five patients were enrolled, and after the first endoscopic treatment, recurrent hemorrhage occurred in 39 patients (23.6%) during 1-year follow-up. Compared to the non-rebleeding group, HVPG was significantly higher (18 mmHg vs.14 mmHg, P = 0.024) and more patients had HVPG exceeding 18 mmHg (51.3% vs.31.0%, P = 0.021) in the rebleeding group. No significant difference was found in other clinical and laboratory data between two groups (P > 0.05 for all). By a logistic regression analysis, high HVPG was the only risk factor associated with failure of endoscopic combined therapy (OR = 1.071, 95%CI, 1.005-1.141, P = 0.035). CONCLUSIONS: The poor efficacy of endoscopic treatment to prevent variceal rebleeding was associated with high HVPG. Therefore, other therapeutic options should be considered for the rebleeding patients with high HVPG.

Incidence and outcomes of thromboembolic and bleeding events in patients with liver cirrhosis in the USA.

BACKGROUND & AIMS: Understanding the epidemiology of bleeding and thromboembolism (clotting) in liver cirrhosis provides important data for future studies and policymaking; however, head-to-head comparisons of bleeding and clotting remain limited. METHODS: This is a populational retrospective cohort study using the US National Readmission Database of 2018 to compare the incidence and outcomes of bleeding and clotting events in patients with liver cirrhosis. The primary outcomes were the 11-month incidence proportion of bleeding and clotting events. RESULTS: Of 1 304 815 participants, 26 569 had liver cirrhosis (45.0% women, mean age 57.2 [SD, 12.7] years). During the 11-month follow-up, in patients with cirrhosis, for bleeding and clotting events, the incidence proportions was 15.3% and 6.6%; the risk-standardized all-cause mortality rates were 2.4% and 1.0%; the rates of intensive care intervention were 4.1% and 1.9%; the rates of rehabilitation transfer were .2% and .2%; the cumulative length of stays were 45 100 and 23 566 days; total hospital costs were 147 and 84 million US dollars; total hospital charges were 620 and 365 million US dollars. Compared to non-cirrhosis, liver cirrhosis was associated with higher rates of bleeding (adjusted hazard ratio, 3.02 [95% CI, 2.85-3.20]) and portal vein thrombosis (PVT) (18.46 [14.86-22.92]), and slightly lower risks of other non-PVT venous thromboembolic events (.82 [.75-.89]). CONCLUSIONS: Bleeding is more common than thromboembolism in patients with liver cirrhosis, causes higher morbidity, mortality and resource utilization. Liver cirrhosis is an independent risk factor for bleeding and PVT, but not non-PVT thromboembolism including venous thromboembolism, acute myocardial infarction and ischemic stroke.

Platelet-derived TGF-ß1 is related to portal vein thrombosis in cirrhosis by promoting hypercoagulability and endothelial dysfunction.

Background: Portal vein thrombosis (PVT) is a serious complication of cirrhosis accompanied by unclear pathogenesis. Transforming growth factor-beta (TGF-ß) has been implicated in atherosclerosis and venous thrombosis whereas study regarding its part in PVT is lacking. The aim of this study was to explore the role of cytokine TGF-ß1 in PVT and the potential mechanism. Materials and methods: We included patients with cirrhotic gastroesophageal varices and divided them into two groups according to the presence of PVT. Serum levels of TGF-ß1 were detected using Cytometric Bead Array kit and compared between two groups. Coagulation status was assessed using thromboelastography (TEG). Primary liver sinusoidal endothelial cells were treated with TGF-ß1 and evaluated for endothelial dysfunction by RT-PCR. Results: Our results uncovered that TGF-ß1 (6,866.55 vs. 3,840.60 pg/ml, P = 0.015) significantly increased in the PVT group. Splenectomy might promote PVT by increasing platelet-derived TGF-ß1 levels. Other cytokines showed no difference between PVT and non-PVT groups. Besides, TGF-ß1 was correlated with platelet, fibrinogen, TEG-CI, TEG-MA, and TEG-α (coef = 0.733, 0.494, 0.604, 0.608, and 0.511; P < 0.001, 0.027, 0.004, 0.004, and 0.021, respectively), which indicated a hypercoagulable state in PVT patients. RT-PCR of liver sinusoidal endothelial cells showed a markable increment of von Willebrand Factor (vWF), thrombomodulin(TM), intercellular adhesion moleclar-1(ICAM-1), and vascular endothelial growth factor(VEGF) after TGF-ß1 treatment, suggesting the involvement of endothelial dysfunction. Conclusion: Elevated platelet-derived TGF-ß1 exhibited association with hypercoagulability and promoting effect on endothelial dysfunction, closely related with PVT in cirrhotic patients.

Characteristics of myeloproliferative neoplasm-associated portal hypertension and endoscopic management of variceal bleeding.

Background: Myeloproliferative neoplasms (MPNs) are a rare yet important clinical cause of portal hypertension, which may cause recurrent gastroesophageal variceal bleeding (GVB). MPN-associated variceal bleeding lacks specific guidelines and clinical consensus and desiderates cohort studies. We performed a multicenter retrospective study to investigate the efficacy of endoscopic management of bleeding in MPNs. Methods: We included consecutive MPN patients with gastroesophageal varices in eight tertiary university hospitals between January 2007 and March 2020. The clinical characteristics of participants were summarized. MPN patients with a history of GVB were followed up for the rebleeding and death, compared with controls suffering from schistosomiasis-associated portal hypertension who received endoscopic treatment for variceal bleeding at the same period. Results: A total of 62 MPN patients with gastroesophageal varices were identified, and 37 had a history of GVB. Of these, 24 patients received endoscopic variceal ligation and endoscopic injection of cyanoacrylate for the prophylaxis of variceal rebleeding. Endoscopic treatment significantly reduced the rebleeding rate in MPN patients with a history of GVB (28.2% versus 68.3%, p = 0.0269). Multivariable Cox regression indicated that endoscopic treatment (HR = 0.10, 95% CI: 0.02-0.54, p = 0.008) was the independent protective factor for decreasing the 3-year rebleeding rate, while the use of non-selective beta-blockers (NSBB) (HR = 13.41, 95% CI: 2.15-83.42, p = 0.005) was the risk factor for increasing the 3-year rebleeding rate. As for the efficacy of endoscopic management, 3-year rebleeding rate was significantly lower in MPN patients in contrast to 46 controls with schistosomiasis-associated variceal bleeding (32.9% versus 59.0%, p = 0.0346). Conclusion: Endoscopic treatment might be a feasible and potent approach in the management of gastroesophageal variceal rebleeding in MPNs, while NSBB might be ineffective.

CdTe quantum dots trigger oxidative stress and endoplasmic reticulum stress-induced apoptosis and autophagy in rat Schwann cell line RSC96.

In the current study, the cytotoxicity and mechanisms of cadmium telluride quantum dots (CdTe QDs) on RSC96 cells were evaluated by exposing different doses of CdTe QDs for 24 h. Two types of cell death, including apoptosis and autophagy, as well as two important organelles, mitochondria and endoplasmic reticulum, were focused after CdTe QDs exposure. The results showed that CdTe QDs induced apoptosis in RSC96 cells in a concentration-dependent manner; promoted the accumulation of intracellular reactive oxygen species; decreased the mitochondrial membrane potential; caused the release of cytochrome c; and also increased the expression of Bcl-2 associated X protein, caspase-3, and cytochrome c proteins and decreased the expression of Bcl-2 protein. Further results also confirmed that CdTe QDs could be internalized by RSC96 cells, and the exposure and internalization of CdTe QDs could induce excessive endoplasmic reticulum stress in the cells, and the expression levels of binding immunoglobulin protein, C/EBP homologous protein, and caspase12 proteins were increased in a concentration-dependent manner. Moreover, autophagy-related proteins LC3II, Beclin1, and P62 all increased after CdTe QDs exposure, suggesting that CdTe QDs exposure both promoted autophagosome formation and inhibited autophagosome degradation, and that CdTe QDs affected the autophagic flow in RSC96 cells. In conclusion, CdTe QDs are able to cause apoptosis and autophagy in RSC96 cells through mitochondrial and endoplasmic reticulum stress pathways, and the possible neurotoxicity of CdTe QDs should be further investigated.

Protein corona mitigated the cytotoxicity of CdTe QDs to macrophages by targeting mitochondria.

Despite the potential of cadmium telluride quantum dots (CdTe QDs) in bioimaging and drug delivery, their toxic effects have been documented. It is known that the immunotoxicity of CdTe QDs targeting macrophages is one of their adverse effects, and the protein corona (PC) will affect the biological effects of QDs. In order to prove whether the PC-CdTe QDs complexes could alleviate the toxicity of CdTe QDs without weakening their luminescence, we investigated the impact of protein corona formed in fetal bovine serum (FBS) on the cytotoxicity of CdTe QDs to mitochondria. RAW264.7 cells were used as the model to compare the effects of CdTe QDs and PC-CdTe QDs complexes on the structure, function, quantity, morphology, and mitochondrial quality control of mitochondria. As result, the protein corona form in FBS alleviated the inhibition of CdTe QDs on mitochondrial activity, the damage to mitochondrial membrane, the increase of ROS, and the reduction of ATP content. Also, CdTe QDs increased the number of mitochondria in macrophages, while the complexes did not. In line with this, the morphology of mitochondrial network in macrophages which were exposed to CdTe QDs and PC-CdTe QDs complexes was different. CdTe QDs transformed the network into fragments, punctuations, and short rods, while PC-CdTe QDs complexes made the mitochondrial network highly branched, which was related to the imbalance of mitochondrial fission and fusion. Mechanically, CdTe QDs facilitated mitochondrial fission and inhibited mitochondrial fusion, while protein corona reversed the phenomenon caused by QDs. Besides mitochondrial dynamics, mitochondrial biogenesis and mitophagy were also affected. CdTe QDs increased the expression of mitochondrial biogenesis signaling molecules including PGC-1α, NRF-1 and TFAM, while PC-CdTe QDs complexes played the opposite role. With regard to mitophagy, they both showed promoting effect. In conclusion, the formation of protein corona alleviated the toxic effects of CdTe QDs on the mitochondria in macrophages and affected mitochondrial quality control. Under the premise of ensuring the fluorescence properties of CdTe QDs, these findings provided useful insight into reducing the toxicity of CdTe QDs from two perspectives: protein corona and mitochondria, and shared valuable information for the safe use of QDs.

Effects of dietary nucleotides on growth performance, immune response, intestinal morphology and disease resistance of juvenile largemouth bass, Micropterus salmoides.

An 8 week feeding trial was carried out to investigate the effects of dietary nucleotides on growth performance, intestinal morphology, immune response and disease resistance of juvenile largemouth bass, Micropterus salmoides. Five grades of dietary nucleotide levels were designed as 0, 0.2, 0.4, 0.8 and 1.2 g kg-1 , respectively. Each group had 3 replicates, with 40 fish in each replicate. After the feeding experiment, 15 fish from each tank were infected with Aeromonas hydrophila for 14 days. The results indicated that fish fed the diets containing 0.4, 0.8 and 1.2 g kg-1 nucleotides had higher growth performance and feed utilization than those fed the control diet. Nonetheless, there were no significant differences in survival between all the groups, although fish fed the diets with all-level nucleotides obtained higher survival than those fed the control diet. Dietary nucleotides significantly affected the superoxide dismutase, acid phosphatase and catalase activities in serum but not the malondialdehyde content. Fish fed the 0.4 g kg-1 nucleotide diets had the highest fold height, enterocyte height and muscular layer thickness significantly. The average mortality of largemouth bass infected with A. hydrophila was significantly influenced by dietary nucleotides. The mortality was significantly higher in the control group (91.11%) and 0.02% nucleotide group (73.11%) followed by the other groups and lowest in the 0.8 g kg-1 nucleotide group. In summary, dietary 0.4-0.8 g kg-1 nucleotides promoted growth performance, enhanced immunity and improved intestinal morphology and disease resistance of largemouth bass.

Increased PD-L1 Restricts Liver Injury in Nonalcoholic Fatty Liver Disease.

PD-L1 is a critical checkpoint that protects tissues from autoimmune injury. Nevertheless, the role of PD-L1 in nonalcoholic fatty liver disease- (NAFLD-) induced liver damage is still unclear. In this study, we examined the role and mechanism of PD-L1 expression on NAFLD-induced liver damage in vitro and in vivo. PD-L1 expression in the livers from patients with NAFLD, and LO2 cells treated by FFA, was significantly increased. FFA triggers a large amount of ROS (generated from NOX4 and damaged mitochondria), promoting the ZNF24 expression and suppressing ZN24 sumoylation, both of which enhance the PD-L1 transcription and expression. The knockdown of PD-L1 increases CD8 + T cells' damage to FFA-treated LO2 cells, while its upregulation limits the liver injury in NAFLD models. Collectively, we demonstrate that FFA promotes PD-L1 expression through the ROS/ZNF24 pathway and suppresses UBE2I-mediated ZNF24 sumoylation to enhance its transcriptional activity of PD-L1. PD-L1 upregulation limits FFA-induced injury of hepatocytes in vitro and in vivo.

The role of ferroptosis mediated by NRF2/ERK-regulated ferritinophagy in CdTe QDs-induced inflammation in macrophage.

Cadmium telluride quantum dots (CdTe QDs) exist in the environment due to the abandonment of products. There is a potential risk to organisms and toxic mechanism is worth exploring. In this study, 12.5 µmol/Kg body weight CdTe QDs triggered systemic and local inflammatory response in mice and activated macrophages, then the mechanism of activating macrophages to overexpress IL-1ß and IL-6 was explored. RAW264.7 macrophages were used, and after macrophages exposing to 1 µM CdTe QDs for 24 h, oxidative stress occurred. Further investigation found that CdTe QDs triggered ferroptosis in RAW264.7 cells. And deferoxamine mesylate alleviated the excessive lipid hydroperoxide caused by QDs. Mechanistically, CdTe QDs-provoked decrease of nuclear factor erythroid 2-related factor 2 (NRF2) elicited phosphorylation of extracellular regulated protein kinases1/2 (ERK1/2) and then activated ferritinophagy, which made ferritin heavy chain 1 (FTH1) degraded in lysosome and proteasome to release free iron ions to initiate ferroptosis in macrophages. This paper updates the mechanism of macrophage activation by CdTe QDs with regard to ferritinophagy, and more importantly, identifies the key role of NRF2 and ERK1/2. Our research extends the role of ferroptosis in inflammatory responses triggered by nanoparticles (NPs) in macrophages and provides insightful reference for toxicity assessment of NPs.