Upregulation of HLA-II related to LAG-3+CD4+ T cell infiltration is associated with patient outcome in human glioblastoma.

Glioblastoma (GBM) is the most common malignant diffuse glioma of the brain. Although immunotherapy with immune checkpoint inhibitors (ICIs), such as programmed cell death protein (PD)-1/PD ligand-1 inhibitors, has revolutionized the treatment of several cancers, the clinical benefit in GBM patients has been limited. Lymphocyte-activation gene 3 (LAG-3) binding to human leukocyte antigen-II (HLA-II) plays an essential role in triggering CD4+ T cell exhaustion and could interfere with the efficiency of anti-PD-1 treatment; however, the value of LAG-3-HLA-II interactions in ICI immunotherapy for GBM patients has not yet been analyzed. Therefore, we aimed to investigate the expression and regulation of HLA-II in human GBM samples and the correlation with LAG-3+CD4+ T cell infiltration. Human leukocyte antigen-II was highly expressed in GBM and correlated with increased LAG-3+CD4+ T cell infiltration in the stroma. Additionally, HLA-IIHighLAG-3High was associated with worse patient survival. Increased interleukin-10 (IL-10) expression was observed in GBM, which was correlated with high levels of HLA-II and LAG-3+ T cell infiltration in stroma. HLA-IIHighIL-10High GBM associated with LAG-3+ T cells infiltration synergistically showed shorter overall survival in patients. Combined anti-LAG-3 and anti-IL-10 treatment inhibited tumor growth in a mouse brain GL261 tumor model. In vitro, CD68+ macrophages upregulated HLA-II expression in GBM cells through tumor necrosis factor-α (TNF-α). Blocking TNF-α-dependent inflammation inhibited tumor growth in a mouse GBM model. In summary, T cell-tumor cell interactions, such as LAG-3-HLA-II, could confer an immunosuppressive environment in human GBM, leading to poor prognosis in patients. Therefore, targeting the LAG-3-HLA-II interaction could be beneficial in ICI immunotherapy to improve the clinical outcome of GBM patients.

Conversion of Photoluminescence Blinking Types in Single Colloidal Quantum Dots.

Almost all colloidal quantum dots (QDs) exhibit undesired photoluminescence (PL) blinking, which poses a significant obstacle to their use in numerous luminescence applications. An in-depth study of the blinking behavior, along with the associated mechanisms, can provide critical opportunities for fabricating high-quality QDs for diverse applications. Here the blinking of a large series of colloidal QDs is investigated with different surface ligands, particle sizes, shell thicknesses, and compositions. It is found that the blinking behavior of single alloyed CdSe/ZnS QDs with a shell thickness of up to 2 nm undergoes an irreversible conversion from Auger-blinking to band-edge carrier blinking (BC-blinking). Contrastingly, single perovskite QDs with particle sizes smaller than their Bohr diameters exhibit reversible conversion between BC-blinking and more pronounced Auger-blinking. Changes in the effective trapping sites under different excitation conditions are found to be responsible for the blinking type conversions. Additionally, changes in shell thickness and particle size of QDs have a significant effect on the blinking type conversions due to altered wavefunction overlap between excitons and effective trapping sites. This study elucidates the discrepancies in the blinking behavior of various QD samples observed in previous reports and provides deeper understanding of the mechanisms underlying diverse types of blinking.

Discovery of a highly selective fluorescent probe for hydrogen peroxide and its biocompatibility evaluation and bioimaging applications in cells and zebrafish.

As one of the most widely distributed reactive oxygen species in vivo, hydrogen peroxide plays divergent and important roles in cell growth, differentiation and aging. When the level of hydrogen peroxide in the body is abnormal, it will lead to genome mutation and induce irreversible oxidative modification of proteins, lipids and polysaccharides, resulting in cell death or even disease. Therefore, it is significant to develop a sensitive and specific probe for real-time detection of hydrogen peroxide in vivo. In this study, the response mechanism between hydrogen peroxide and probe QH was investigated by means of HRMS and the probe showed good optical properties and high selectivity to hydrogen peroxide. Note that the evaluating of probe biocompatibility resulted from cytotoxicity test, behavioral test, hepatotoxicity test, cardiotoxicity test, blood vessel toxicity test, immunotoxicity test and neurotoxicity test using cell and transgenic zebrafish models with more than 20 toxic indices. Furthermore, the detection performance of the probe for hydrogen peroxide was evaluated by multiple biological models and the probe was proved to be much essential for the monitoring of hydrogen peroxide in vivo.

Life cycle assessment of hepatotoxicity induced by cyhalofop-butyl in environmental concentrations on zebrafish in light of gut-liver axis.

Cyhalofop-butyl (CB) poses a significant threat to aquatic organisms, but there is a discrepancy in evidence about hepatotoxicity after prolonged exposure to environmental levels. The aim of this study was to investigate long-term hepatotoxicity and its effects on the gut-liver axis through the exposure of zebrafish to environmental concentrations of CB (0.1,1,10 µg/L) throughout their life cycle. Zebrafish experienced abnormal obesity symptoms and organ index after a prolonged exposure of 120 days. The gut-liver axis was found to be damaged both morphologically and functionally through an analysis of histology, electron microscopy subcellular structure, and liver function. The disruption of the gut-liver axis inflammatory process by CB is suggested by the rise in inflammatory factors and the alteration of inflammatory genes. Furthermore, there was a noticeable alteration in the blood and gut-liver axis biochemical parameters as well as gene expression linked to lipid metabolism, which may led to an imbalance in the gut flora. In conclusion, the connection between the gut-liver axis, intestinal microbiota, and liver leads to the metabolic dysfunction of zebrafish exposed to long-term ambient concentrations of CB, and damaged immune system and liver lipid metabolism. This study gives another knowledge into the hepatotoxicity component of long haul openness to ecological centralization of CB, and might be useful to assess the potential natural and wellbeing dangers of aryloxyphenoxypropionate herbicides.

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.

Tumor Necrosis Factor α-Dependent Lung Inflammation Promotes the Progression of Lung Adenocarcinoma Originating From Alveolar Type II Cells by Upregulating MIF-CD74.

Lung adenocarcinoma is the most common type of lung cancer. We recently reported that inflammation-driven lung adenocarcinoma (IDLA) originates from alveolar type (AT)-II cells, which depend on major histocompatibility complex (MHC) class II to promote the expansion of regulatory T cells. The MHC class II-associated invariant chain (CD74) binds to the macrophage migration inhibitory factor (MIF), which is associated with promoting tumor growth and invasion. However, the role of MIF-CD74 in the progression of lung adenocarcinoma and the underlying mechanisms remain unclear. We aimed to explore the role of MIF-CD74 in the progression of lung adenocarcinoma and elucidate the mechanisms by which tumor necrosis (TNF)-α-mediated inflammation regulates CD74 and MIF expression in IDLA. In human lung adenocarcinoma, CD74 was upregulated on the surface of tumor cells originating from AT-II cells, which correlated positively with lymph node metastasis, tumor origin/nodal involvement/metastasis stage, and TNF-α expression. MIF interaction with CD74 promoted the proliferation and migration of A549 and H1299 cells in vitro. Using a urethane-induced IDLA mouse model, we observed that CD74 was upregulated in tumor cells and macrophages. MIF expression was upregulated in macrophages in IDLA. Blocking TNF-α-dependent inflammation downregulated CD74 expression in tumor cells and CD74 and MIF expression in macrophages in IDLA. Conditioned medium from A549 cells or activated mouse AT-II cells upregulated MIF in macrophages by secreting TNF-α. TNF-α-dependent lung inflammation contributes to the progression of lung adenocarcinoma by upregulating CD74 and MIF expression, and AT-II cells upregulate MIF expression in macrophages by secreting TNF-α. This study provides novel insights into the function of CD74 in the progression of IDLA.

TNF-α-dependent lung inflammation upregulates PD-L1 in monocyte-derived macrophages to contribute to lung tumorigenesis.

Chronic inflammation, which is dominated by macrophage-involved inflammatory responses, is an instigator of cancer initiation. Macrophages are the most abundant immune cells in healthy lungs, and associated with lung tumor development and promotion. PD-L1 is a negative molecule in macrophages and correlated with an immunosuppressive function in tumor environment. Macrophages expressing PD-L1, rather than tumor cells, exhibits a critical role in tumor growth and progression. However, whether and how PD-L1 in macrophages contributes to inflammation-induced lung tumorigenesis requires further elucidation. Here, we found that higher expression of PD-L1 in CD11b+ CD206+ macrophages was positively correlated with tumor progression and PD-1+ CD8+ T cells population in human adenocarcinoma patients. In the urethane-induced inflammation-driven lung adenocarcinoma (IDLA) mouse model, the infiltration of circulating CD11bhigh F4/80+ monocyte-derived macrophages (MoMs) was increased in pro-tumor inflamed lung tissues and lung adenocarcinoma. PD-L1 was mainly upregulated in MoMs associated with enhanced T cells exhaustion in lung tissues. Anti-PD-L1 treatment can reduce T cells exhaustion at pro-tumor inflammatory stage, and then inhibit tumorigenesis in IDLA. The pro-tumor lung inflammation depended on TNF-α to upregulate PD-L1 and CSN6 expression in MoMs, and induced cytokines production by alveolar type-II cells (AT-II). Furthermore, inflammatory AT-II cells could secret TNF-α to upregulate PD-L1 expression in bone-marrow driven macrophages (BM-M0). Inhibition of CSN6 decreased PD-L1 expression in TNF-α-activated macrophage in vitro, suggesting a critical role of CSN6 in PD-L1 upregulation. Thus, pro-tumor inflammation can depend on TNF-α to upregulate PD-L1 in recruited MoMs, which may be essential for lung tumorigenesis.

Identification and characterization of a strong constitutive promoter stnYp for activating biosynthetic genes and producing natural products in streptomyces.

BACKGROUND: Streptomyces are well known for their potential to produce various pharmaceutically active compounds, the commercial development of which is often limited by the low productivity and purity of the desired compounds expressed by natural producers. Well-characterized promoters are crucial for driving the expression of target genes and improving the production of metabolites of interest. RESULTS: A strong constitutive promoter, stnYp, was identified in Streptomyces flocculus CGMCC4.1223 and was characterized by its effective activation of silent biosynthetic genes and high efficiency of heterologous gene expression. The promoter stnYp showed the highest activity in model strains of four Streptomyces species compared with the three frequently used constitutive promoters ermEp*, kasOp*, and SP44. The promoter stnYp could efficiently activate the indigoidine biosynthetic gene cluster in S. albus J1074, which is thought to be silent under routine laboratory conditions. Moreover, stnYp was found suitable for heterologous gene expression in different Streptomyces hosts. Compared with the promoters ermEp*, kasOp*, and SP44, stnYp conferred the highest production level of diverse metabolites in various heterologous hosts, including the agricultural-bactericide aureonuclemycin and the antitumor compound YM-216391, with an approximately 1.4 - 11.6-fold enhancement of the yields. Furthermore, the purity of tylosin A was greatly improved by overexpressing rate-limiting genes through stnYp in the industrial strain. Further, the yield of tylosin A was significantly elevated to 10.30 ± 0.12 g/L, approximately 1.7-fold higher than that of the original strain. CONCLUSIONS: The promoter stnYp is a reliable, well-defined promoter with strong activity and broad suitability. The findings of this study can expand promoter diversity, facilitate genetic manipulation, and promote metabolic engineering in multiple Streptomyces species.

Blinking Mechanisms and Intrinsic Quantum-Confined Stark Effect in Single Methylammonium Lead Bromide Perovskite Quantum Dots.

Lead halide perovskite quantum dots (QDs) are promising materials for next-generation photoelectric devices because of their low preparation costs and excellent optoelectronic properties. In this study, the blinking mechanisms and the intrinsic quantum-confined Stark effect (IQCSE) in single organic-inorganic hybrid CH3 NH3 PbBr3 perovskite QDs using single-dot photoluminescence (PL) spectroscopy is investigated. The PL quantum yield-recombination rates distribution map allows the identification of different PL blinking mechanisms and their respective contributions to the PL emission behavior. A strong correlation between the excitation power and the blinking mechanisms is reported. Most single QDs exhibit band-edge carrier blinking under a low excitation photon fluence. While under a high excitation photon fluence, different proportions of Auger-blinking emerge in their PL intensity trajectories. In particular, significant IQCSEs in the QDs that exhibit more pronounced Auger-blinking are observed. Based on these findings, an Auger-induced IQCSE model to explain the observed IQCSE phenomena is observed.

TNF-α-dependent lung inflammation upregulates superoxide dismutase-2 to promote tumor cell proliferation in lung adenocarcinoma.

Manganese superoxide dismutase (SOD-2), an important primary antioxidant enzyme located in mitochondria, plays a critical role in tumor progression. Reportedly, the proinflammatory cytokine, tumor necrosis factor (TNF)-α, can increase SOD-2 expression in a human lung adenocarcinoma cell line in vitro, indicating that TNF-α-mediated inflammation may regulate SOD-2 expression, which may be related to cancer promotion. Using a urethane-induced inflammation-driven lung adenocarcinoma (IDLA) mice model, we investigated whether and how TNF-α-mediated inflammation upregulated SOD-2 expression in lung adenocarcinoma. Our results showed that SOD-2 was mostly expressed on surfactant protein-C+ AT-II cells (alveolar type II cell) and tumor cells in IDLA mice, which were surrounded by CD68+ macrophages. Blocking TNF-α-dependent inflammation downregulated SOD-2 expression in inflamed lung tissues at the protumor stage and also inhibited SOD-2 expression in tumor cells in the IDLA model. In human lung adenocarcinoma, both the number of infiltrating CD68+ macrophages and TNF-α expression correlated positively with SOD-2 expression, which is related to lymph node metastasis and TNM stage. We collected the conditioned medium from lipopolysaccharide-activated phorbol myristate acetate-induced THP1 (M1) cells to stimulate A549 and H1299 cells and observed that THP1-M1 upregulated SOD-2 by secreting TNF-α. Blocking SOD-2 expression significantly inhibited TNF-α-induced cell proliferation in A549 and H1299 cells in vitro. Thus, TNF-α-mediated lung inflammation can upregulate SOD-2 expression in lung adenocarcinoma, and macrophages contribute to SOD-2 upregulation by secreting TNF-α.

EGFR-ERK pathway regulates CSN6 to contribute to PD-L1 expression in glioblastoma.

Glioblastoma (GBM) is the most common and malignant brain tumor in adults. Recently, programmed death-1/programmed death-ligand 1 (PD-1/PD-L1) checkpoint blockades have been applied for GBM treatment. However, the mechanism of PD-L1 upregulation in GBM is still unclear. COP9 signalosome 6 (CSN6) is crucial for maintaining the protein stabilization in cancer cells. In this study, we applied human GBM specimens and cell lines to investigate whether the EGFR-ERK pathway regulates CSN6 for PD-L1 upregulation. Data from The Cancer Genome Atlas dataset showed that high expression of EGFR, CSN6, and PD-L1 in patients with glioma was associated with poor prognosis. In 47 human GBM specimens, high expression of PD-L1 was associated with low amount of CD8+ T cell infiltration as well as the poor prognosis of patients. CSN6 was positively correlated with EGFR and PD-L1 expression in human GBM specimens. We treated two GBM cell lines (U87 and U251) with epidermal growth factor (EGF) in vitro, and found EGF-upregulated p-EGFR, p-ERK, CSN6, and PD-L1 expression in GBM cells. PD98059, the ERK blocker, inhibited upregulations of CSN6 and PD-L1 in EGF-treated cells. Inhibition of CSN6 by small interfering RNA decreased PD-L1 expression but also increased CHIP expression in GBM cells. When the cells were treated with EGF and cycloheximide (CHX), a protein synthesis inhibitor, EGF-reduced CHX-induced CSN6 and PD-L1 turnover in GBM cells. Furthermore, CSN6-mediated downregulation of PD-L1 was inhibited by MG132, a proteasome inhibitor in U87 cells. Thus, these results suggest that the EGFR-ERK pathway may upregulate CSN6, which may inhibit PD-L1 degradation and subsequently maintain PD-L1 stability in GBM.

Effects of nursing methods for emergency pci and non-emergency PCI on the treatment of patients with acute myocardial infarction.

OBJECTIVE: To study the effect of emergency nursing methods on the treatment of acute myocardial infarction (AMI). METHODS: A total of 100 patients with AMI were divided into emergency percutaneous coronary intervention (PCI) group (group A, 50 cases) and non-emergency PCI control group (group B, 50 cases). The clinical outcome, average left ventricular ejection fraction (LVEF), angina pectoris, heart failure, and reperfusion arrhythmia after myocardial infarction were compared between the two groups. RESULTS: The average hospitalization days of emergency PCI group were less than those of the control group, and the incidence of angina pectoris and heart failure after myocardial infarction was lower than that of the control group. The average LVEF of emergency PCI group was higher than that of the control group. CONCLUSIONS: This shows that emergency nursing of AMI can quickly and efficiently dredge the infarcted artery, reduce the occurrence of cardiovascular events after AMI and the average hospitalization days of patients, improve the left ventricular function and prevent heart failure. This method is a very effective treatment for improving the prognosis in patients with AMI.

Melatonin suppresses milk fat synthesis by inhibiting the mTOR signaling pathway via the MT1 receptor in bovine mammary epithelial cells.

Milk fat content is an important criterion for assessing milk quality and is one of the main target traits of dairy cattle breeding. Recent studies have shown the importance of melatonin in regulating lipid metabolism, but the potential effects of melatonin on milk fat synthesis in bovine mammary epithelial cells (BMECs) remain unclear. Here, we showed that melatonin supplementation at 10 µmol/L significantly downregulated the mRNA expression of lipid metabolism-related genes and resulted in lower lipid droplet formation and triglyceride accumulation. Moreover, melatonin significantly upregulated melatonin receptor subtype melatonin receptor 1a (MT1) gene expression, and the negative effects of melatonin on milk fat synthesis were reversed by treatment with the nonselective MT1/melatonin receptor subtype melatonin receptor 1b (MT2) antagonist. However, a selective MT2 antagonist did not modify the negative effects of melatonin on milk fat synthesis. In addition, KEGG analysis revealed that melatonin inhibition of milk fat synthesis may occur via the mTOR signaling pathway. Further analysis revealed that melatonin significantly suppressed the activation of the mTOR pathway by restricting the phosphorylation of mTOR, 4E-BP1, and p70S6K, and the inhibition of melatonin on milk fat synthesis was reversed by mTOR activator MHY1485 in BMECs. Furthermore, in vivo experiments in Holstein dairy cows showed that exogenous melatonin significantly decreased milk fat concentration. Our data from in vitro and in vivo studies revealed that melatonin suppresses milk fat synthesis by inhibiting the mTOR signaling pathway via the MT1 receptor in BMECs. These findings lay a foundation to identify a new potential means for melatonin to modulate the fat content of raw milk in Holstein dairy cows.

Carbon Nanotubes Disrupt Iron Homeostasis and Induce Anemia of Inflammation through Inflammatory Pathway as a Secondary Effect Distant to Their Portal-of-Entry.

Although numerous toxicological studies have been performed on carbon nanotubes (CNTs), a few studies have investigated their secondary and indirect effects beyond the primary target tissues/organs. Here, a cascade of events are investigated: the initiating event and the subsequent key events necessary for the development of phenotypes, namely CNT-induced pro-inflammatory effects on iron homeostasis and red blood cell formation, which are linked to anemia of inflammation (AI). A panel of CNTs are prepared including pristine multiwall CNTs (P-MWCNTs), aminated MWCNTs (MWCNTs-NH2 ), polyethylene glycol MWCNTs (MWCNTs-PEG), polyethyleneimine MWCNTs (MWCNTs-PEI), and carboxylated MWCNTs (MWCNTs-COOH). It has been demonstrated that all CNT materials provoke inflammatory cytokine interleukin-6 (IL-6) production and stimulate hepcidin induction, associated with disordered iron homeostasis, irrespective of exposure routes including intratracheal, intravenous, and intraperitoneal administration. Meanwhile, PEG and COOH modifications can ameliorate the activation of IL-6-hepcidin signaling. Long-term exposure of MWCNTs results in AI and extramedullary erythropoiesis. Thus, an adverse outcome pathway is identified: MWCNT exposure leads to inflammation, hepatic hepcidin induction, and disordered iron metabolism. Together, the combined data depict the hazardous secondary toxicity of CNTs in incurring anemia through inflammatory pathway. This study will also open a new avenue for future investigations on CNT-induced indirect and secondary adverse effects.

Polychlorinated biphenyls (PCBs) inhibit hepcidin expression through an estrogen-like effect associated with disordered systemic iron homeostasis.

Polychlorinated biphenyls (PCBs), with 209 congeners, are a large family of persistent organic pollutants. PCBs elicit a wide range of toxicities, such as neurotoxicity, hepatoxicity, oncogenicity, and endocrine-disrupting effects. However, an understanding of the potential disruption of systematic iron metabolism by PCBs is still limited. To maintain iron homeostasis, the hepcidin-ferroportin (FPN) axis is critically important, and hepcidin is the central governor in guiding dietary iron absorption and iron egress from macrophages. Hepcidin is secreted by hepatocytes and binds to FPN to promote its degradation. Dysregulation of hepcidin gives rise to disordered iron homeostasis, associated with diverse diseases including anemia and ß-thalassemia. Our previous study demonstrated that there is an estrogen response element (ERE) within the promoter of hepcidin gene and that its expression is regulated by estrogen. In the current study, we demonstrated that both PCB153 and PCB126 greatly suppress hepcidin expression in HepG2 cells, with a greater repression occurring in cells upon PCB126 treatment. Further studies uncovered that both PCB153 and PCB126 harbor estrogenic activity and that the estrogenic activity of PCB126 was stronger than that of PCB153 in HepG2 cells. Mechanistic investigation revealed that PCBs suppress hepcidin transcription through a functional ERE within the hepcidin promoter, analogous to the action of 17ß-estradiol. Moreover, hepatic hepcidin was downregulated in wild-type mice upon PCB126 administration, coupled with elevated serum iron content as well as reduced hepatic and splenic iron mass. These changes were not replicated in hepcidin-deficient mice upon PCB administration. Additionally, hepatocytes were observed with severe accumulation of lipid droplets in the livers of mice challenged with PCB126, irrespective of the presence of hepcidin. To summarize, our results have deciphered a suppressive role of PCBs in restraining the expression of hepcidin through mimicking estrogenic activity and revealed a novel property of PCBs in disrupting systemic iron metabolism. This study also unearthed a PCB-mediated connection linking estrogen-like activity, iron effects, and lipid homeostasis.

An important role of the hepcidin-ferroportin signaling in affecting tumor growth and metastasis.

Epidemiological and experimental studies have suggested that deregulated hepcidin-ferroportin (FPN) signaling is associated with the increased risk of cancers. However, the effects of deregulated hepcidin-FPN signaling on tumor behaviors such as metastasis and epithelial to mesenchymal transition (EMT) have not been closely investigated. In this study, LL/2 cancer cells were found to exhibit an impaired propensity to home into lungs, and a reduced ability to develop tumors was also demonstrated in lungs of Hamp1(-/-) mice. Moreover, hepatic hepcidin deficiency was found to considerably favor tumor-free survival in Hamp1(-/-) mice, compared with wild-type mice. These data thus underscored a contributive role of hepatic hepcidin in promoting lung cancer cell homing and fostering tumor progression. To explore the role of FPN in regulating tumor progression, we genetically engineered 4T1 cells with FPN over-expression upon induction by doxycycline. With this cell line, it was discovered that increased FPN expression reduced cell division and colony formation in vitro, without eliciting significant cell death. Analogously, FPN over-expression impeded tumor growth and metastasis to lung and liver in mice. At the molecular level, FPN over-expression was identified to undermine DNA synthesis and cell cycle progression. Importantly, FPN over-expression inhibited EMT, as reflected by the significant decrease of representative EMT markers, such as Snail1, Twist1, ZEB2, and vimentin. Additionally, there was also a reduction of lactate production in cells upon induction of FPN over-expression. Together, our results highlighted a crucial role of the hepcidin-FPN signaling in modulating tumor growth and metastasis, providing new evidence to understand the contribution of this signaling in cancers.

Disruption of iron homeostasis and resultant health effects upon exposure to various environmental pollutants: A critical review.

Environmental pollution has become one of the greatest problems in the world, and the concerns about environmental pollutants released by human activities from agriculture and industrial production have been continuously increasing. Although intense efforts have been made to understand the health effects of environmental pollutants, most studies have only focused on direct toxic effects and failed to simultaneously evaluate the long-term adaptive, compensatory and secondary impacts on health. Burgeoning evidence suggests that environmental pollutants may directly or indirectly give rise to disordered element homeostasis, such as for iron. It is crucially important to maintain concerted cellular and systemic iron metabolism. Otherwise, disordered iron metabolism would lead to cytotoxicity and increased risk for various diseases, including cancers. Thus, study on the effects of environmental pollutants upon iron homeostasis is urgently needed. In this review, we recapitulate the available findings on the direct or indirect impacts of environmental pollutants, including persistent organic pollutants (POPs), heavy metals and pesticides, on iron homeostasis and associated adverse health problems. In view of the unanswered questions, more efforts are warranted to investigate the disruptive effects of environmental pollutants on iron homeostasis and consequent toxicities.

Interleukin-1ß polarization in M1 macrophage mediates myocardial fibrosis in diabetes.

BACKGROUND: Diabetes is a global health problem whose common complication is diabetic cardiomyopathy, characterized by chronic inflammation of the heart muscle. Macrophages are the main white blood cells found in the resting heart. Therefore, we investigated the underling mechanism of macrophage on myocardial fibrosis in diabetes. METHODS: Here, echocardiography was utilized to evaluate cardiac function, and the degree of myocardial fibrosis was assessed using Masson's trichrome staining, followed by single-cell RNA sequencing (scRNA-seq) to analyze the phenotype, function, developmental trajectory, and interactions between immune cells, endothelial cells (ECs), and fibroblasts (FBs) in the hearts of db/db mice at different stages of diabetes. Macrophages and cardiac fibroblasts were also co-cultured in order to study the signaling between macrophages and fibroblasts. RESULTS: We found that with the development of diabetes mellitus, myocardial hypertrophy and fibrosis occurred that was accompanied by cardiac dysfunction. A significant proportion of immune cells, endothelial cells, and fibroblasts were identified by RNA sequencing. The most significant changes observed were in macrophages, which undergo M1 polarization and are critical for oxidative stress and extracellular matrix (ECM) formation. We further found that M1 macrophages secreted interleukin-1ß (IL-1ß), which interacted with the receptor on the surface of fibroblasts, to cause myocardial fibrosis. In addition, crosstalk between M1 macrophages and endothelial cells also plays a key role in fibrosis and immune response regulation through IL-1ß and corresponding receptors. CONCLUSIONS: M1 macrophages mediate diabetic myocardial fibrosis through interleukin-1ß interaction with fibroblasts.

M2 macrophages independently promote beige adipogenesis via blocking adipocyte Ets1.

Adipose tissue macrophages can promote beige adipose thermogenesis by altering local sympathetic activity. Here, we perform sympathectomy in mice and further eradicate subcutaneous adipose macrophages and discover that these macrophages have a direct beige-promoting function that is independent of sympathetic system. We further identify adipocyte Ets1 as a vital mediator in this process. The anti-inflammatory M2 macrophages suppress Ets1 expression in adipocytes, transcriptionally activate mitochondrial biogenesis, as well as suppress mitochondrial clearance, thereby increasing the mitochondrial numbers and promoting the beiging process. Male adipocyte Ets1 knock-in mice are completely cold intolerant, whereas male mice lacking Ets1 in adipocytes show enhanced energy expenditure and are resistant to metabolic disorders caused by high-fat-diet. Our findings elucidate a direct communication between M2 macrophages and adipocytes, and uncover a function for Ets1 in responding to macrophages and negatively governing mitochondrial content and beige adipocyte formation.

Correlation of MTAP immunohistochemical deficiency with CDKN2A homozygous deletion and clinicopathological features in pleomorphic xanthoastrocytoma.

Pleomorphic xanthoastrocytoma (PXA) is a rare tumor ranging from World Health Organization (WHO) grades 2-3 and can potentially recur and metastasize throughout the central nervous system (CNS). Cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) deletion is a frequent genomic alteration of PXA. Methylthioadenosine phosphorylase (MTAP) immunohistochemistry is a promising surrogate marker for CDKN2A homozygous deletion in different cancers but has not been examined in PXA. Therefore, we performed CDKN2A fluorescence in situ hybridization and MTAP immunohistochemistry on specimens from 23 patients with CNS WHO grades 2 (n = 10) and 3 (n = 13) PXAs, including specimens from primary and recurrent tumors, and determined whether MTAP immunohistochemistry correlated with CDKN2A homozygous deletion and clinicopathological features. CDKN2A homozygous deletion was detected in 30% (3/10) and 76.9% (10/13) of CNS WHO grades 2 and 3 PXAs, respectively. In addition, MTAP loss was inconsistent with CDKN2A homozygous deletion (sensitivity = 86.7%, specificity = 100%). Furthermore, CDKN2A homozygous deletion was correlated with WHO grade (p = 0.026) and the Ki-67 labeling index (p = 0.037). Therefore, MTAP immunostaining can be a suitable surrogate marker for CDKN2A homozygous deletions in PXAs, and CDKN2A homozygous deletions may be an important prognostic factor for PXAs.