Environmental cadmium exposure perturbs systemic iron homeostasis via hemolysis and inflammation, leading to hepatic ferroptosis in common carp (Cyprinus carpio L.).

Cadmium (Cd) pollution is considered a pressing challenge to eco-environment and public health worldwide. Although it has been well-documented that Cd exhibits various adverse effects on aquatic animals, it is still largely unknown whether and how Cd at environmentally relevant concentrations affects iron metabolism. Here, we studied the effects of environmental Cd exposure (5 and 50 µg/L) on iron homeostasis and possible mechanisms in common carp. The data revealed that Cd elevated serum iron, transferrin saturation and iron deposition in livers and spleens, leading to the disruption of systemic iron homeostasis. Mechanistic investigations substantiated that Cd drove hemolysis by compromising the osmotic fragility and inducing defective morphology of erythrocytes. Cd concurrently exacerbated hepatic inflammatory responses, resulting in the activation of IL6-Stat3 signaling and subsequent hepcidin transcription. Notably, Cd elicited ferroptosis through increased iron burden and oxidative stress in livers. Taken together, our findings provide evidence and mechanistic insight that environmental Cd exposure could undermine iron homeostasis via erythrotoxicity and hepatotoxicity. Further investigation and ecological risk assessment of Cd and other pollutants on metabolism-related effects is warranted, especially under the realistic exposure scenarios.

Understanding immune microenvironment alterations in the brain to improve the diagnosis and treatment of diverse brain diseases.

Abnormal inflammatory states in the brain are associated with a variety of brain diseases. The dynamic changes in the number and function of immune cells in cerebrospinal fluid (CSF) are advantageous for the early prediction and diagnosis of immune diseases affecting the brain. The aggregated factors and cells in inflamed CSF may represent candidate targets for therapy. The physiological barriers in the brain, such as the blood‒brain barrier (BBB), establish a stable environment for the distribution of resident immune cells. However, the underlying mechanism by which peripheral immune cells migrate into the brain and their role in maintaining immune homeostasis in CSF are still unclear. To advance our understanding of the causal link between brain diseases and immune cell status, we investigated the characteristics of immune cell changes in CSF and the molecular mechanisms involved in common brain diseases. Furthermore, we summarized the diagnostic and treatment methods for brain diseases in which immune cells and related cytokines in CSF are used as targets. Further investigations of the new immune cell subtypes and their contributions to the development of brain diseases are needed to improve diagnostic specificity and therapy.

Intestinal Toxicity of Metal Nanoparticles: Silver Nanoparticles Disorder the Intestinal Immune Microenvironment.

Albeit numerous studies have been conducted on the toxicity evaluation of engineered metal nanoparticles (NPs), significant knowledge gaps remain regarding the influence of oral exposure to metal NPs on the intestine system, especially the effects on the intestinal immune microenvironment. Herein, we examined the long-term effects of representative engineered metal NPs on the intestine through oral exposure and identified silver NPs (Ag NPs) that resulted in severe damage. Oral Ag NP exposure damaged the epithelial structure, reduced the thickness of the mucosal layer, and altered the intestinal microbiota. Particularly, the reduced thickness of the mucosal layer increased the phagocytosis of Ag NPs by dendritic cells (DCs). Comprehensive animal and in vitro experiments unraveled that Ag NPs directly interacted with DCs, resulting in the abnormal activation of DCs by generating reactive oxygen species and inducing uncontrolled apoptosis. Furthermore, our data unveiled that the interactions between Ag NPs and DCs reduced the proportion of CD103+CD11b+ DCs and induced Th17 cell activation with inhibition of regulatory T-cell differentiation, resulting in the disordered immune microenvironment in the intestine. Collectively, these results represent a new point of view on the cytotoxicity of Ag NPs on the intestine system. This study provides additional insights into the health risks of engineered metal NPs, especially Ag NPs.

Airborne fine particles drive H1N1 viruses deep into the lower respiratory tract and distant organs.

Mounting data suggest that environmental pollution due to airborne fine particles (AFPs) increases the occurrence and severity of respiratory virus infection in humans. However, it is unclear whether and how interactions with AFPs alter viral infection and distribution. We report synergetic effects between various AFPs and the H1N1 virus, regulated by physicochemical properties of the AFPs. Unlike infection caused by virus alone, AFPs facilitated the internalization of virus through a receptor-independent pathway. Moreover, AFPs promoted the budding and dispersal of progeny virions, likely mediated by lipid rafts in the host plasma membrane. Infected animal models demonstrated that AFPs favored penetration of the H1N1 virus into the distal lung, and its translocation into extrapulmonary organs including the liver, spleen, and kidney, thus causing severe local and systemic disorders. Our findings revealed a key role of AFPs in driving viral infection throughout the respiratory tract and beyond. These insights entail stronger air quality management and air pollution reduction policies.

Computer-Aided Discovery of Potent Broad-Spectrum Vaccine Adjuvants.

Adjuvants stimulate the immune system to vigorously respond to a vaccine. While current adjuvants such as aluminum salts and oil-in-water emulsions have been used for decades, they do not generate broad and long-lasting responses in many vaccines. Consequently, more potent adjuvants are needed. Here, using computer-aided molecule design and machine learning, we discovered 2 new, broad-spectrum adjuvants that can boost vaccine responses. Our library containing 46 toll-like receptor (TLR)-targeting agonist ligands were assembled on Au nanoparticles. Comprehensive in vitro, ex vivo and in vivo studies showed both leads promoted dendritic cell activation via multiple TLRs and enhanced antigen presentation to T cells. When used together with tumor-specific antigens to immunize mice against B16-OVA melanoma and 4T1-PD1 breast cancer, both adjuvants unleashed strong immune responses that suppressed tumor growth and lung metastases. Our results show computer-aided design and screening can rapidly uncover potent adjuvants for tackling waning immunity in current vaccines.

Newly identified lncRNA-45 promotes breast cancer metastasis through activating the mTOR signaling pathway.

BACKGROUND: Metastasis, a complex multi-stage process, is the primary cause of breast cancer-related death. Unfortunately, the molecular mechanisms underlying tumor metastasis have not been fully elucidated thus far. Long noncoding RNAs (lncRNAs) dictate the behaviours of tumor cells via multiple signaling pathways, resulting in tumor cell migration and invasion, as well as all stages of cancer progression. LncRNAs function as regulators in shaping cellular activities directly through influencing key genes involved in biological processes of the tumor, and representing promising novel targets in cancer diagnosis and therapy. We therefore sought to define the correlations between lncRNA expression and breast cancer metastasis, especially to investigate the functional pathway underlying lncRNA-mediated tumor invasion and metastasis process. RESULTS: In this study, we compared the lncRNA transcriptome profiles between primary breast cancer 4T1 cells and high metastatic 4T1-LG12 cells. We found that many differently expressed lncRNAs greatly correlated to the metastatic propensity of 4T1-LG12 cells, particularly lncRNA-45, a new lncRNA without functional annotations, which was found to be the most upregulated lncRNA transcribed by an internal region within the regulatory associated with protein of mechanistic target of rapamycin kinase (mTOR) complex 1 (Rptor) gene. LncRNA-45 was uncovered to be involved in the epithelial-to-mesenchymal transition process of breast cancer cells, as evidenced by the observation that lncRNA-45 knockdown significantly suppressed the invasive capability of parental 4T1-LG12 cells. Molecular mechanistic investigation showed that reduced activity of mTORC1-associated pathway led to a decrease of total ribosomal protein S6 kinase, polypeptide 1 (S6K1) content and enhancement of autophagy, consequently compromising the metastatic propensity in lncRNA-45 knockdown cells. CONCLUSIONS: Overall, our experiments uncovered that the newly identified lncRNA-45 played a regulatory role in breast cancer cell metastasis.

Distinct responses from triglyceride and cholesterol metabolism in common carp (Cyprinus carpio) upon environmental cadmium exposure.

Due to high persistence and bioavailability, Cadmium (Cd) is one of the most prevalent environmental contaminants, posing an elevating threat to the ecosystems. It has been evidenced that high-dose Cd elicits deleterious effects on aquatic organisms, but the potential toxicities of Cd at environmentally relevant concentrations remains underappreciated. In this study, we used common carp to investigate how environmental Cd exposure affects triglyceride (TG) and cholesterol metabolism and underlying mechanisms. The data indicated that Cd resulted in the shift of TG from the liver to blood and the movement of cholesterol in the opposite direction, ultimately giving rise to the storage of crude lipid in liver and muscle, especially hepatic cholesterol retention. Cholesterol, instead of TG, became the principal cause during the progression of hepatic lipid accumulation. Mechanistic investigations at transcriptional and translational levels further substantiated that Cd blocked hepatic biosynthesis of TG and enhanced TG efflux out of the liver and fatty acid ß-oxidation, which collectively led to the compromised TG metabolism in the liver and accelerated TG export to the serum. Additionally, strengthened synthesis, retarded export and oxidation of cholesterol detailed the hepatic prominent cholesterol retention. Taken together, our results demonstrated that environmental exposure to Cd perturbed lipid metabolism through triggering distinct responses from hepatic TG and cholesterol homeostasis. These indicated that environmental factors (such as waterborne Cd) could be a potential contributor to the prevalence of non-alcoholic fatty-liver disease in aquaculture and more efforts should be devoted to the ecological risk assessment of pollutants under environmental scenarios.

Folic acid targets splenic extramedullary hemopoiesis to attenuate carbon black-induced coagulation-thrombosis potential.

Due to its wide applications in tire and rubber products, carbon black (CB) implicates concerns on its safety during production, collection, and handling. Here we report that exposure CB, increases coagulation-thrombosis potential in a splenic extramedullary hemopoiesis (EMH)-dependent manner. Adult C57BL/6 mice are kept in whole-body inhalation chambers, and exposed to filtered room air (FRA) or CB for 28 consecutive days. CB exposure resulted in splenic EMH characterized with platelet precursor cells, megakaryocytes (MKs), hyperplasia and enhanced in vivo blood coagulation ability. Metabolomics analysis suggests significant enhance in PGE2 production but reduction in folic acid (FA) levels in murine serum following CB exposure. Mechanistically, activation of COX-dependent PGE2 production promotes IL-6 expression in splenic macrophages, which subsequently results in splenic EMH and increased platelet counts in circulation. Administration of FA protects the mice against CB-induced splenic EMH through inhibiting prostaglandin-endoperoxide synthase 2 (Ptgs2 or Cox2) and prostaglandin E synthase (Ptges) expression in splenic macrophages, eventually recover the coagulation capacity to normal level. The results strongly suggest the involvement of splenic EMH in response to CB exposure and subsequently increased coagulation-thrombosis potential. Supplementation with FA may be a candidate to prevent thrombosis potential attributable to CB exposure.

Binding of Benzo[a]pyrene Alters the Bioreactivity of Fine Biochar Particles toward Macrophages Leading to Deregulated Macrophagic Defense and Autophagy.

Contaminant-bearing fine biochar particles (FBPs) may exert significantly different toxicity profiles from their contaminant-free counterparts. While the role of FBPs in promoting contaminant uptake has been recognized, it is unclear whether the binding of contaminants can modify the biochemical reactivity and toxicological profiles of FBPs. Here, we show that binding of benzo[a]pyrene (B(a)P, a model polycyclic aromatic hydrocarbon) at environmentally relevant exposure concentrations markedly alters the cytotoxicity of FBPs to macrophages, an important line of innate immune defense against airborne particulate matters (PMs). Specifically, B(a)P-bearing FBPs elicit more severe disruption of the phospholipid membrane, endocytosis, oxidative stress, autophagy, and compromised innate immune defense, as evidenced by blunted proinflammatory effects, compared with B(a)P-free FBPs. Notably, the altered cytotoxicity cannot be attributed to the dissolution of B(a)P from the B(a)P-bearing FBPs, but appears to be related to B(a)P adsorption-induced changes of FBPs bioreactivity toward macrophages. Our findings highlight the significance of environmental chemical transformation in altering the bioreactivity and toxicity of PMs and call for further studies on other types of carbonaceous nanoparticles and additional exposure scenarios.

A Designed α-GalCer Analog Promotes Considerable Th1 Cytokine Response by Activating the CD1d-iNKT Axis and CD11b-Positive Monocytes/Macrophages.

Selective helper T cell 1 (Th1) priming agonists are a promising area of investigation for immunotherapeutic treatment of various diseases. α-galactosylceramide (α-GalCer, KRN7000), a well-studied Th1-polarizer, simultaneously induces helper T cell 2 (Th2)-type responses, which is a major drawback for its clinical applications. Based on surflex-docking computation, α-GalCer-diol, with added hydroxyl groups in the acyl chain, is designed and synthesized. Structural analyses reveal stronger affinity between α-GalCer-diol and cluster of differentiation 1d (CD1d), leading to enhanced antigen presentation by dendritic cells (DCs) and self-activation, as reflected by tight binding of the T-cell receptor (TCR)/KRN7000/CD1d ternary complex and elevated production of interleukin 12 (IL-12) and interferon-γ (IFN-γ). Consequently, invariant natural killer T cells (iNKTs) are activated and exhibit an improved Th1-type cytokine profile ex vivo and in vivo. Different from KRN7000, α-GalCer-diol markedly boosts the expansion of the CD11b+ subpopulation and enhances IFN-γ content in CD11b+ cells. These reinforced Th1-type responses collectively endow α-GalCer-diol more robust antitumor activity in a xenograft animal model using B16-F10 melanoma cells. Together, the data demonstrate a new mechanism through which α-GalCer-diol induces stronger Th1-type responses by stimulating CD11b+ leukocyte expansion and DC-conducted CD1d-restricted and TCR-mediated iNKT activation. Hence, this study may facilitate the development of novel Th1 priming agonists.

Black Phosphorus-Based Multimodal Nanoagent: Showing Targeted Combinatory Therapeutics against Cancer Metastasis.

In breast cancer chemophotothermal therapy, it is a great challenge for the development of multifunctional nanoagents for precision targeting and the effective treatment of tumors, especially for metastasis. Herein, we successfully design and synthesize a multifunctional black phosphorus (BP)-based nanoagent, BP/DTX@PLGA, to address this challenge. In this composite nanoagent, BP quantum dots (BPQDs) are loaded into poly(lactic-co-glycolic acid) (PLGA) with additional conjugation of a chemotherapeutic agent, docetaxel (DTX). The in vivo distribution results demonstrate that BP/DTX@PLGA shows striking tropism for targeting both primary tumors and lung metastatic tumors. Moreover, BP/DTX@PLGA exhibits outstanding controllable chemophotothermal combinatory therapeutics, which dramatically improves the efficacy of photothermal tumor ablation when combined with near-light irradiation. Mechanistically, accelerated DTX release from the nanocomplex upon heating and thermal treatment per se synergistically incurs apoptosis-dependent cell death, resulting in the elimination of lung metastasis. Meanwhile, in vitro and in vivo results further confirm that BP/DTX@PLGA possesses good biocompatibility. This study provides a promising BP-based multimodal nanoagent to constrain cancer metastasis.

Carbon black-induced detrimental effect on osteoblasts at low concentrations: Remarkably compromised differentiation without significant cytotoxicity.

Due to similar aerodynamic and micro-nano sized properties between airborne particles and synthetic nanoparticles, a large number of studies have been conducted using carbon-based particles, such as carbon black (CB), carbon nanotubes and graphite, in order to achieve deeper understandings of their adverse effects on human health. It has been reported that particulate matters can aggravate morbidity of patients suffering from bone and joint diseases, e.g. arthritis. However, the molecular mechanism is still elusive thus far. Under this context, we employed two cell lines of osteoblasts, MC3T3-E1 and MG-63, upon exposure to 4 different CB samples with differential physicochemical properties in research of mechanistic insights. Our results indicated that the carbon/oxygen ratio differed in these 4 CB materials showing the order: SB4A < Printex U < C1864 < C824455. In stark contrast, their cytotoxicity and capacity to trigger reactive oxygen species (ROS) in MC3T3-E1 and MG-63 cells closely correlated to oxygen content, revealing the reverse order: SB4A < Printex U < C1864 < C824455. It would be reasonable to speculate that ROS production was a predominant cause of CB cytotoxicity, which strongly relied on the oxygen content of CB. Our study further manifested that all CB samples even at low concentrations significantly inhibited osteoblast differentiation, as reflected by remarkably reduced activity of alkaline phosphatase (ALP) and compromised expression of the differentiation-related genes. And the inhibition on osteoblast differentiation also closely correlated to oxygen content of CB samples. Taken together, our combined data recognized oxygen-associated toxicity towards osteoblasts for CBs. More importantly, we uncovered a new adverse effect of CB exposure: suppression on osteoblast differentiation, which has been overlooked in the past.

Adverse Effects of Fine-Particle Exposure on Joints and Their Surrounding Cells and Microenvironment.

Current understanding of the health risks and adverse effects upon exposure to fine particles is premised on the direct association of particles with target organs, particularly the lung; however, fine-particle exposure has also been found to have detrimental effects on sealed cavities distant to the portal-of-entry, such as joints. Moreover, the fundamental toxicological issues have been ascribed to the direct toxic mechanisms, in particular, oxidative stress and proinflammatory responses, without exploring the indirect mechanisms, such as compensated, adaptive, and secondary effects. In this Review, we recapitulate the current findings regarding the detrimental effects of fine-particle exposure on joints, the surrounding cells, and microenvironment, as well as their deteriorating impact on the progression of arthritis. We also elaborate the likely molecular mechanisms underlying the particle-induced detrimental influence on joints, not limited to direct toxicity, but also considering the other indirect mechanisms. Because of the similarities between fine air particles and engineered nanomaterials, we compare the toxicities of engineered nanomaterials to those of fine air particles. Arthritis and joint injuries are prevalent, particularly in the elderly population. Considering the severity of global exposure to fine particles and limited studies assessing the detrimental effects of fine-particle exposure on joints and arthritis, this Review aims to appeal to a broad interest and to promote more research efforts in this field.

Iron homeostasis in pregnancy and spontaneous abortion.

During pregnancy, iron requirements are increased to support maternal erythropoietic expansion and fetal growth and development. To meet these requirements, dietary iron absorption increases, and available iron stores are mobilized. These adjustments are thought to be in large part mediated by the iron-regulatory hormone hepcidin, which controls the concentrations of ferroportin, the sole exporter of iron into the extracellular fluid and blood plasma. Hepcidin regulation of iron availability during healthy and abnormal pregnancies is not well understood. In our cross-sectional study, we compared hepcidin, iron and hematological parameters between nonpregnant control women, healthy pregnant women in the first and second trimester, and women with spontaneous abortion in the first trimester. We found that in healthy pregnancy, hepcidin increased in the first trimester compared with nonpregnant women, but then decreased during the second trimester. The second trimester hepcidin levels decreased despite stable serum iron concentrations, suggesting active suppression of hepcidin, presumably to enhance iron availability as iron demand increases. In women with spontaneous abortion during the first trimester, hepcidin, serum iron, and ferritin concentrations were all increased compared with the first trimester healthy pregnancy. Although the specific mechanisms remain to be determined, our findings demonstrate that maternal hepcidin is regulated by signals related to the progression of pregnancy, and that pregnancy loss is associated with profound changes in maternal iron metabolism. These observations highlight the existence of fetoplacental signals that modulate maternal iron homeostasis.

Radial extracorporeal shock wave promotes the enhanced permeability and retention effect to reinforce cancer nanothermotherapeutics.

Since most cancer nanomedicine relies on the enhanced permeability and retention (EPR) effect to eradicate tumors, strategies that are able to promote nanoparticle (NP) delivery and extravasation are presupposed to elevate the EPR effect for more effective cancer therapeutics. However, nanothermotherapeutics still suffers from limited drug delivery into tumor sites, for even though numerous efforts have been made to enhance the selective tumor targeting of NPs. In this study, we uncovered that radial extracorporeal shock wave therapy (rESWT), an important approach in physical therapy that has been overlooked in cancer treatment in the past, can largely improve the EPR-dependent tumor uptake of NPs. We here defined the optimal low dosage and desirable combinatory manner for rESWT in driving NP accumulation towards tumors. Two underlying biophysical mechanisms responsible for the rESWT-enhanced EPR effect were proposed. On one hand, rESWT-conducted compressive and tensile forces could relieve high intra-tumoral pressure; on the other hand, rESWT-induced cavitation bubbles could directly distend and disrupt tumor blood vessels. All these together synergistically promoted vessel vasodilation, tumor perfusion and NP extravasation. Further experiments revealed that the combinatory therapeutics between rESWT and nanothermotherapeutics greatly improved the tumor-killing efficacy. Thus, our findings open a new path to improve EPR-mediated drug delivery with the assistance of rESWT.