Maternal exposure to sunlight-irradiated graphene oxide induces neurodegeneration-like symptoms in zebrafish offspring through intergenerational translocation and genomic DNA methylation alterations.

The physiochemical properties of graphene oxide may be affected by sunlight irradiation. However, the underlying mechanisms that alter the properties and subsequent intergenerational effects are not sufficiently investigate. Epigenetics is an early sensitive marker for the intergenerational effects of nanomaterial exposure due to the epigenetic memory. In this study, we investigate changes in the physicochemical properties and the intergenerational effects of maternal exposure to simulated sunlight-irradiated polyethyleneimine-functionalized graphene oxide (SL-PEI-GO). Results show that the physicochemical properties of polyethyleneimine-functionalized graphene oxide (PEI-GO) can be altered significantly by the oxidation of carbon atoms with unpaired electrons present in the defects and on the edges of PEI-GO by sunlight. First, the positive charges, sharp edges, defects and disordered structures of SL-PEI-GO make it translocate from maternal zebrafish to offspring, thus catalyzing the production of reactive oxygen species and damaging mitochondria directly. In addition, changes in DNA methylation reduce the expression of protocadherin1a, protocadherin19 and cadherin4, thus destroying cell membrane integrity, cell adhesion and Ca2+ binding. The alteration of DNA methylation induced by maternal exposure activates the Ca2+-CaMKK-brsk2a pathway, which catalyzes the phosphorylation of Tau and eventually results in the appearance of neurodegeneration-like symptoms, including the loss of neurons and neurobehavioral disorders. This study demonstrates that maternal exposure to SL-PEI-GO induces clear neurodegeneration-like symptoms in offspring through both the intergenerational translocation of nanomaterials and differential DNA methylation. These findings may provide new insights into the health risks of nanomaterials altered by nature conditions.

The perspectives of NETosis on the progression of obesity and obesity-related diseases: mechanisms and applications.

Obesity is a disease commonly associated with urbanization and can also be characterized as a systemic, chronic metabolic condition resulting from an imbalance between energy intake and expenditure. The World Health Organization (WHO) has identified obesity as the most serious chronic disease that is increasingly prevalent in the world population. If left untreated, it can lead to dangerous health issues such as hypertension, hyperglycemia, hyperlipidemia, hyperuricemia, nonalcoholic steatohepatitis, atherosclerosis, and vulnerability to cardiovascular and cerebrovascular events. The specific mechanisms by which obesity affects the development of these diseases can be refined to the effect on immune cells. Existing studies have shown that the development of obesity and its associated diseases is closely related to the balance or lack thereof in the number and function of various immune cells, of which neutrophils are the most abundant immune cells in humans, infiltrating and accumulating in the adipose tissues of obese individuals, whereas NETosis, as a newly discovered type of neutrophil-related cell death, its role in the development of obesity and related diseases is increasingly emphasized. The article reviews the significant role that NETosis plays in the development of obesity and related diseases, such as diabetes and its complications. It discusses the epidemiology and negative impacts of obesity, explains the mechanisms of NETosis, and examines its potential as a targeted drug to treat obesity and associated ailments.

NAT10 accelerates pulmonary fibrosis through N4-acetylated TGFB1-initiated epithelial-to-mesenchymal transition upon ambient fine particulate matter exposure.

Exposure to ambient fine particulate matter (PM2.5) has been linked to a higher pulmonary fibrosis risk. Dysregulation of the epitranscriptome results in abnormal expression of mRNAs during fibrosis development. N4-acetylcytidine (ac4C) is one of the most frequent RNA epigenetic alterations, however, its function in PM2.5-triggered fibrosis is yet unknown. In this study, lung epithelial and murine models were established and exposed to PM2.5 to analyze the function of ac4C alteration in pulmonary fibrosis and underlying mechanisms. Meanwhile, the expression levels of only known ac4C "writer" protein, N-acetyltransferase 10 (NAT10), were significantly induced in pulmonary epithelia, relative to the control. Subsequently, NAT10 enhanced the stability of transforming growth factor beta 1 (TGFB1) mRNA as well as protein levels. As an up-stream driver, TGFB1 accelerated EMT and fibrosis process. Inhibition of NAT10 significantly protected against pulmonary EMT and fibrosis driven by PM2.5 exposure, whereas TGFB1 overexpression reversed the protective effects of NAT10 inhibition. Thus, NAT10 accelerated PM2.5-triggered pulmonary fibrosis via increasing TGFB1 mRNA stability in an ac4C-dependent manner. Our results reveal a pivotal role of NAT10-regulated mRNA ac4C acetylation in PM2.5-triggered pulmonary fibrosis and uncover the potential epitranscriptional mechanism.

Increased IL-17-producing CD4(+) T cells in patients with esophageal cancer.

Increased interleukin-17 (IL-17)-producing Th (Th17) cells have been described in a variety of human carcinoma cases, however, the mechanism of Th17 cells' accumulation in a tumor microenvironment remains elusive. This study was designed to investigate whether Th17 cells were involved in the development of esophageal cancer. We found that the proportion of Th17 cells increased within the peripheral blood and tumor tissues of esophageal cancer patients. Furthermore, the proportion of circulating Th17 cells was higher in advanced esophageal cancer patients than that in early esophageal cancer patients. In addition, the Th17 cells differentiation-related cytokines (IL-23, IL-1ß, and IL-6) and accumulation-related chemokines (CCL22 and CCL20) were present in a tumor microenvironment. Therefore, the findings may partly explain the cause for the increased proportion of Th17 cells and indicate a potential prognostic marker of Th17 cells in esophageal cancer.

Protothecosis: report of a case with 20-year follow-up, and review of previously published cases.

We present a Prototheca wickerhamii wound infection case that failed treatment with ketoconazole but was cured with amphotericin-B plus tetracycline. The patient was immunocompetent but had had local steroid injections. We reviewed another 159 cases from the literature. Prototheca has infected many areas of the human body, but most often skin, olecranon bursa, or wounds. Prior treatment with steroids and immune deficiencies are contributing factors. Itraconazole and fluconazole are reasonable initial treatments for patients with mild infections. For serious infections, or for infections that have failed azole treatment, amphotericin-B is the treatment of choice.

Epichloë endophytes improved Leymus chinensis tolerance to both neutral and alkali salt stresses.

Symbiotic relationships with microbes may influence how plants respond to environmental change. In the present study, we tested the hypothesis that symbiosis with the endophytes promoted salt tolerance of the native grass. In the field pot experiment we compared the performance of endophyte-infected (E+) and endophyte-uninfected (E-) Leymus chinensis, a dominant species native to the Inner Mongolia steppe, under altered neutral and alkaline salt stresses. The results showed that under both neutral and alkaline salt stresses, endophyte infection significantly increased plant height, leaf length and fibrous root biomass. Under neutral salt stress, endophyte infection decreased Na+ content and Na+/K+ ratio (p=0.066) in the leaf sheath while increased Ca2+ and Mg2+ content in the rhizome. Under alkali salt stress, endophyte infection tended to increase K+ content in the fibrous root, enhance Mg2+ content in the fibrous root while reduce Na+/K+ ratio in the leaf blade in the 100 mmol/L alkali salt treatment. Although endophyte-infected L. chinensis cannot accumulate Na+ high enough to be halophytes, the observed growth promotion and stress tolerance give endophyte/plant associations the potential to be a model for endophyte-assisted phytoremediation of saline-alkaline soils.

Ecotoxicological responses of the earthworm Eisenia fetida to EDTA addition under turfgrass growing conditions.

As a commonly used chelator, ethylenediaminetetraacetic acid (EDTA) enters soil environment inevitably and has the potential to cause negative effects on soil organisms. The objective of the current study was to investigate the effects of EDTA on earthworm growth, survival and activities of antioxidant enzymes. The assessment for EDTA toxicity toward earthworms (Eisenia fetida) was conducted on day 14 and 35 after exposure to four concentrations (0, 5, 10, 15 mmol kg-1) of EDTA under turfgrass growing conditions. Exposure to EDTA resulted in a significant decrease of earthworm growth and survival. The toxicity of EDTA increased with the increase in concentration and exposure duration. The activities of antioxidant enzymes increased at low concentration and decreased at high concentration, which indicates that oxidative stress was induced by EDTA addition. These results suggest EDTA is highly toxic and ecologically dangerous to earthworms.

Cystatin m: a novel candidate tumor suppressor gene for breast cancer.

The contribution of pericellular proteolysis to tumor progression is well documented. To better understand protease biology and facilitate clinical translation, specific proteolytic systems need to be better defined. In particular, the precise role of endogenous protease inhibitors still needs to be deciphered. We reported previously that cystatin M, a potent endogenous inhibitor of lysosomal cysteine proteases, significantly suppressed in vitro cell proliferation, migration, and Matrigel invasion. Here, we show that scid mice orthotopically implanted with breast cancer cells expressing cystatin M show significantly delayed primary tumor growth and lower metastatic burden in the lungs and liver when compared with mice implanted with mock controls. The incidence of metastasis, however, appeared to be unaltered between the cystatin M group and the control group. Experimental metastasis assays suggest that cystatin M suppressed tumor cell proliferation at the secondary site. By using laser capture microdissection and quantitative reverse transcription-polymerase chain reaction, we found consistent expression of cystatin M in normal human breast epithelial cells, whereas expression was decreased by 86% in invasive ductal carcinoma (IDC) cells of stage I to IV patients. Complete loss of expression of cystatin M was observed in two of three IDCs from stage IV patients. Immunohistochemical studies confirmed that expression of cystatin M in IDCs was partially or completely lost. We propose cystatin M as a novel candidate tumor suppressor gene for breast cancer.

Preinduced molecular chaperones in the endoplasmic reticulum protect cardiomyocytes from lethal injury.

Although molecular chaperones in the endoplasmic reticulum (ER) are known to be involved in folding and assembly of glycosylated proteins, it is unclear whether preinduced ER chaperones can protect cardiomyocytes from lethal injury. In this study we used tunicamycin, an inhibitor of N-linked glycosylation in the ER, to preinduce ER chaperones in H9c2 cardiomyocytes and we tested the cytoprotective role of preinduced ER chaperones in the cardiomyocytes. Expression of GRP78 at both protein and mRNA levels was markedly increased in cardiomyocytes pretreated with tunicamycin, when compared to non-treatment controls. Following prolonged ATP depletion or oxidative stress, which was used to simulate cardiac ischemia and reperfusion injury, respectively, the release of lactate dehydrogenase (LDH) from tunicamycin-pretreated cardiomyocytes was significantly lower than from non-pretreated cardiomycocytes. Tunicamycin-pretreated cardiomyocytes showed significantly higher Ca2+ release into cytoplasm than controls when treated with both caffeine and thapsigargin, indicating higher storage of Ca2+ in the ER. After oxidative stress, cytosolic Ca2+ levels were maintained relatively stable in tunicamycin-pretreated cardiomyocytes, when compared to control cardiomyocytes. These observations suggest that preinduced ER chaperones protect cardiomyocytes from lethal injury, at least in part, by preventing an increase in cytosolic Ca2+.

Endophyte-mediated effects on the growth and physiology of Achnatherum sibiricum are conditional on both N and P availability.

The interaction of endophyte-grass associations are conditional on nitrogen (N) availability, but the reported responses of these associations to N are inconsistent. We hypothesized that this inconsistency is caused, at least in part, by phosphorus (P) availability. In this experiment, we compared the performance of endophyte-infected (EI) and endophyte-free (EF) Achnatherum sibiricum subjected to four treatments comprising a factorial combination of two levels of N (N+ vs. N-, i.e. N supply vs. N deficiency) and two levels of P (P+ vs. P-, i.e. P supply vs. P deficiency) availability. The results showed that A. sibiricum-Neotyphodium associations were conditional on both N and P availability, but more conditional on N than P. Under N+P- conditions, endophyte infection significantly improved acid phosphatase activity of EI plants, such that the biomass of EI plants was not affected by P deficiency (i.e. similar growth to N+P+ conditions), and resulted in more biomass in EI than EF plants. Under N-P+ conditions, biomass of both EI and EF decreased compared with N+P+; however, EI biomass decreased slowly by decreasing leaf N concentration more rapidly but allocating higher fractions of N to photosynthetic machinery compared with EF plants. This change of N allocation not only improved photosynthetic ability of EI plants but also significantly increased their biomass. Under N-P- conditions, EI plants allocated higher fractions of N to photosynthesis and had greater P concentrations in roots, but there was no significant difference in biomass between EI and EF plants. Our results support the hypothesis that endophyte-grass interactions are dependent on both N and P availability. However, we did not find a clear cost of endophyte infection in A. sibiricum.

The candidate tumor suppressor CST6 alters the gene expression profile of human breast carcinoma cells: down-regulation of the potent mitogenic, motogenic, and angiogenic factor autotaxin.

We recently coined CST6 as a novel candidate tumor suppressor gene for breast cancer. CST6 indeed is expressed in the normal human breast epithelium, but little or not at all in breast carcinomas and breast cancer cell lines. Moreover, ectopic expression of CST6 in human breast cancer cells suppressed cell proliferation, migration, invasion, and orthotopic tumor growth. To obtain insights into the molecular mechanism by which CST6 exhibits its pleiotropic effects on tumor cells, we compared global gene expression profiles in mock- and CST6-transfected human MDA-MB-435S cells. Out of 12,625 transcript species, 61 showed altered expression. These included genes for extracellular matrix components, cytokines, kinases, and phosphatases, as well as several key transcription factors. TaqMan PCR assays were used to confirm the microarray data for 7 out of 11 genes. One down-regulated gene product, secreted autotaxin/lyso-phospholipase D, was of particular interest because its down-regulation by CST6 could explain most of CST6's effect on the breast cancer cells. This study thus provides the first evidence that CST6 plays a role in the modulation of genes, particularly, genes that are highly relevant to breast cancer progression.